2011-2012 Basic and Clinical Science Course, Section 4: Ophthalmic Pathology and Intraocular Tumors (Basic & Clinical Science Course)

Basic and

Ophthalmic Pathology and Intraocular Tumors Section 4

2011-2012

t::1D. AMERICAN ACADEMY \V OF OPHTHALMOLOGY The Eye .\-f .D. Association

l "

ElON G

E D U CATION ""''''''

O'tl THAlMOlOGI S r"

The Basic and Clinical Science Course (BCSC) is one component of the Lifelong Education for the Ophthalmologist (LEO) framework, which assists members in planning their continuing medical education. LEO includes an array of clinical education products that members may select to form individualized, self-directed learning plans for updating their clinical knowledge. Active members or fellows who use LEO components may accumulate sufficient CME credits to earn the LEO Award. Contact the Academy's Clinical Education Division for further information on LEO. The American Academy of Ophthalmology is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The American Academy of Ophthalmology designates this enduring material for a maximum of 10 AMA PRA Category 1 Credits TM. Physicians should claim only credit commensurate with the extent of their participation in the activity.

The BCSC is designed to increase the physician's ophthal m ic knowledge through study and review. Users of this activity are encouraged to read the text and then answer the study questions provided at the back of the book. To claim AMA PRA Category 1 Credits™ upon completion of this activity, learners must demonstrate appropriate knowledge and participation in the activity by taking the posttest for Section 4 and ach ieving a score of 80% or higher. For further details, please see the instructions for requesting CME credit at the back of the book. The Academy provides this material for educational purposes only. 11 is not intended to represent the only or best method or procedure in every case, nor to replace a physi cian's own judgment or give specific advice for case management. Including all indications, contraindications, side effects, and alternative agents for each drug or treatment is beyond the scope of this material. All information and recommendations should be verified, prior to use, with current information included in the manufacturers' package inserts or other independent sources, an d considered in light of the patient's condition and history. Reference to certain drugs, instruments, and other products in this course is made for illustrative purposes only and is not intended to constitute an endorsem*nt of such. Some material may include information on applications that are not considered community standard, that reflect indications not included in approved FDA labeling, or that are approved for use only in restricted research setti ngs. The FDA has stated that it is the responsibility of the physician to determine the FDA status of each drug or device he or she wishes to use, and to use th em with appropriate, informed patient consent in compliance with applicable law. The Academy specifically disclaims any and all liability for injury or other damages of any kind, from negligence or otherwise, for any and all claims that may arise from the use of any recommendations or other information contained herein . Cover image courtesy of Robert H. Rosa, Jr, MD.

Basic and Clinical Science Course Gregory L. Skuta, MD, Oklahoma City, Oklaho ma, Senior Secretary for Clinical Education Louis B. Cantor, MD, Indianapolis, Indiana, Secretary for Ophthalmic Knowledge jayne S. Weiss, MD, Detroit, Michigan, BCSC Course Chair

Section 4 Facu lty Responsible for This Edition Robert H. Rosa, jr, MD, Chair, Temple, Texas Ronald Buggage, MD, New York, New York George j. Ha rocopos, MD, St Louis, Missouri Theresa Retue Kramer, MD, Tucson, Arizona

Tatyana Milman, MD, New York, New York Nasreen Syed, MD, Iowa City, Iowa Matthew W Wilson, MD, Memphis, Tennessee jacob Pe'er, MD, Consultant, jerusalem, Israel Robert G. Fante, MD, Denver, Colorado Practicing Ophthalmologists Advisory Committee for Education Ron W. Pelton, MD, PhD, Colorado Springs, Colorado Practicing Ophthalmologists Advisory Committee for Education The Academy wis hes to acknowledge the American Association of Ophthalmic Pathology for recommendi ng faculty members to the BCSC Section 4 committee.

Fina ncial Disclosures The following Academy staff members state that they have no Significant financial interest or other relationship with the manufacturer of any commercial product discussed in this course or with the manufacturer of any competing commercial produc t: Christine Arturo,

Steve Huebner, Stephanie Tanaka, and Brian Veen. The authors state the followi ng financial relationships: Dr Buggage: Nova rtis Pharmaceuticals, employee, equity ownership/stock options Dr Rosa: Genentech, grant reci pient; Nation al Eye Institute, grant recipient

The other authors state that they have no significant financial interest or other relationship with the manufacturer of any commercial product discussed in the chapters that they contributed to this course or with the manufacturer of any competing com mercial product.

Recent Past Faculty Patricia Chevez- Barrios, MD Sander Dubovy, MD Debra j. Shetlar, MD

In addition, the Academy gratefully ack nowledges the contribu tions of nu m erous past fac ulty and advisory committee members who have played an important role in th e development of previous editions of the Basic and Clinical Science Course.

American Academy of Ophthalmology Staff Ri chard A. Zorab, Vice President, Ophth almic Knowledge Hal Straus, Director, Pu blications Department Christine Artu ro,

Acquisitions Manager

Stephanie Tanaka, Publica tions Manager D. jean Ray, Produ ction Manager Brian Veen , Medical Editor Steven Huebner, Administrative Coordinator

t:lD. AMERICAN ACADEMY

~ OF OPHTHALMOLOGY Tlte Eye M.D. A$$ociatioJl

655 Beach Street Box 7424 San Francisco, CA 94120- 7424

Contents General Introduction

xiii

Objectives

PART I

Ophthalmic Pathology

1 Introduction to Part I .

Organization. To pography Disease Process. General Diagnosis. Differential Diagnosis

.5 .6 .6

2 Wound Repair . General Aspects of Wo und Repai r. Healing in Specific Ocular Tissues Cornea Sclera . Limbus Uvea Lens . Reti n a. Vitreous. Eyelid, O rbit, and Lacrimal Tissues Histolog ic Sequelae of Ocular Trauma .

3 Specimen Handling .

11 11

13 13 !3

13 16 16 16 17 17 17 17 18

Communication Orientati on Transillumination . Gross Dissection . Processing and Staini ng. Fixati ves. Tissue Processing . Tissue Staining

25 26 26 27 28 28 29 30

4 Special Procedures

Immunohistochemistry Flow Cytometry, Molecular Pathology, and Diagnostic Electron Microscopy Flow Cytometry.

33 36 36

• Contents

Molecular Pathology. Diagnosti c Electron Microscopy. Special Techniques Fine- ' eedle Aspiratio n Biopsy Frozen Section

Conjunctiva Topography Congenital Anomalies. Choristomas Hamartomas. Inflammations Papillary Versus Follicular Conjunctivitis. Granu lomatous Conjunctivitis Infectious Conj unctivitis. Noninfectious Conjunctivitis. Pyoge nic Granuloma Degenerations Pinguecula and Pterygium AmylOid Deposits. Epithelial Inclusion Cyst. Neoplasia . Squamous Lesions. Melanocytic Lesio ns. Lymphocytic Lesions Glandular Lesions. Other Neoplas ms

6 Cornea Topograph y Introduction to Corneal Pathology Congenital Anomalies. Congenital Hereditary Endothelial Dystrophy. Posterior Polymorphous Dystrophy Dermoid. Peters Anomaly . Inflammations . Infectious Keratitis Noninfectious Keratitis Degenerations and Dystrophies. Degenerations Dys trophies Neoplasia

37 43 43 43 44

47 47 47 47 50 50 50 52 53 54 56 56 56 58 59 61 61 65 71

75 75

77 77

78 79 79 80 80 81 82 82 87 87 87 94

100

Anterior Chamber and Trabecular Meshwork .

101

Topography . Congenital Anomalies. Primary Congenital Glaucoma Anterior Segment Dysgenesis .

101 . 102 . 102 102

Contents. vii

Degenerations . Iridocorneal Endothelial Syndrome Secondary Glaucoma With Material in the Trabecular Meshwork

8 Sclera . Topography Episclera. Stroma. Lamina Fusca . Congenital Anomalies. Choristoma Nanophthalmos. Inflammations. Episcleritis . Scleritis Degenerations . Senile Calcific Plaque Scleral Staphyloma Neoplasia Fibrous Histiocytoma Nodular Fasciitis

Lens . Topography Capsule Epithelium. Cortex and Nucleus. Zonular Fibers Congenital Anomalies. Congenital Aphakia. Lens Coloboma. Anterior Lenticonus (Lentiglobus). Posterior Lenticonus (Lentiglobus) In flammations. Phacoantigenic Uveitis. Phacolytic Glaucoma Propionibacterium acnes Endophthalmitis Degenerations Cataract and Other Abnor malities. Neoplasia and Associations With SystemiC Disorders Pathology of Intraocular Lenses.

10 Vitreous Topography Congenital Anomalies . Persistent Fetal Vasculature . Bergmeister Papilla Mittendorf Dot.

· 104 · 104 · 106

111 III III

112 ll2 ll2 ll2 112 113 113 ll4 llS 115 ll6 116 11 7 llS

119 ll9 119 119 120 120 121 121 121 121 121 122 122 123 123 124 124 129 129

131 131 132 132 133 133

viii . Co ntents

Prepapillary Vascu lar Loops Vitreous Cysts Inflam_mations. . . . . Degenerations . . Syneresis and Aging. Posterior Vitreous D etach ment Rhegmatogenous Retinal Detachment and Proliferative Vit reoretinopath y . Macular Holes . . Hemorrhage Asteroid Hyalosis . Vit reous Amyloidosis Neoplasia . . . . . . Int raoc ular Lymphoma

133 133 133 134 134 134

11 Retina and Retinal Pigment Epithelium

145

Topography . . ..... . Neurosensory Retina Retinal Pigme nt Epithelium Congenital Anomalies. Albinism. Myelinated Ne rve Fibers. Vascular Ano malies. . . Congen ital Hypertrophy of the RPE . Inflammations . . Infectious . . Noninfect ious Degenerations . . Typical and Reticular Peripheral Cystoid Degeneration and Retinosch isis. . . Lattice D egeneration. . . . Paving-Stone Degeneration. Ischem ia . . . . .... Specific Ischemic Retinal Disorders Diabetic Retinopathy . . . Ret inopathy of Prematurity. Age- Related Macular Degeneration Polypoidal Choroidal Vasc ulopath y ..... Macular Dystrophies Diffuse Photoreceptor Dystrophies Neoplasia . Retinoblastoma. Retinoc ytoma. . Medulloepithelioma . Fuchs Ade noma . . . Combined Ham arto ma of the Retina and RPE Ade nomas and Adenocarcinomas of the RPE .

135 136 137 138 139 140 140

145 145 148

148 148

148 149

149 l SI · 151

153 154 154 ISS

156 156 162 165 167 167 17 1

· 172

· 175 · 178

178 181 183 184 184 184

Contents. ix

12 Uveal Tract.

185

Topography Iris

Ci li ary Body Choro id Congenital Anomalies. Ani ridia .

Colo boma. In flammations. Infectious Noninfectious Degenerations . Rubeosis Iridis

· ·

Hyalinization of the Ciliary Body Choroidal Neovascularization.

Neoplasia Iris

Choroid and Ciliary Body Metastatic Tumors

Other Uveal Tumors. Trauma

13 Eyelids Topography Congenital Anomalies. Distichiasis.

Phakomato us Choristoma Dermoid Cyst Inflammations. Infectious Noninfectious Degenerations . Xanthelasma

Amyloid. Cysts . Epidermoid and Dermoid Cysts. Ductal Cysts . Neoplasia Epidermal Neoplasms Dermal Neoplasms Appendage Neoplasms. Melanocytic Neoplasms

14 Orbit Topography Bony Orbit and Soft Tissues Congenital AnomaHes.

Dermoid and Other Epithelial Cysts .

· · ·

185 185 186 186 188 188 188 188 188 189 192 192 192 193 193 193 195 200 200 203

205 · 205 · 207 · 207 · 207 .207 .208 .208 · 210 · 211 .211 · 211 · 213 · 213 · 213 · 214 .214 · 219 · 221 · 224

229 .229 · 229 · 229 .229

x • Contents

Inflammations Noninfectious Infectious Degenerations Amyloid. Neoplasia . . Lacrimal Sac Neoplasia Lacrimal Gland Neoplasia Lymphoproliferative Lesio ns Soft-Tissue Tumors Vascular Tumors . Tumors With Fibrous Differentiatio n Tumors \Nith Muscle D ifferentiation . Nerve Sheath Tumo rs Adipose Tumors Bony Lesions of the Orbit Metastatic Tumors.

15 Optic Nerve Topography . Congenital Anomalies. Colobomas . Inflammations . Infectious Noninfectious Degenerations Optic Atrophy Drusen Neoplasia Melanocytoma Glioma . Ivleningioma .

PART II

Intraocular Tumors: Clinical Aspects.

16 Introduction to Part II

.230 .230 .234 .235 · 235 .235 .235 · 235 · 238 · 240 · 240 .240 .242 .244 · 245 · 245 · 247

249 .249 · 249 · 249 · 25 1 · 25 1 .252 · 253 .253 · 255 · 256 · 256 · 257 .258

261 263

Melanocytic Tumors

265

Introduction. . . . . . Iris Nevus Nevus of the Ciliary Body or Choroid. Melanocytoma of the Iris, Ciliary Body, or Choroid Iris Melanoma Melanoma of the Cilia ry Body or Choroid Diagnostic Evaluation Differential Diagnosis . . . . . . .

· 265 · 265 · 266 .268 .268 .273 · 274 .277

Co ntents . xi

Classifi cation. . . . Me tastatic Evaluation Treatment . . Prognosis and Prognostic Factors Pigmented Epithelial Tumo rs of the Uvea and Retina Adenoma and Adenocarcinoma. Acquired Hyperplasia . Combined Hamartoma

· 28 1 · 28 1 · 282 · 286 · 288 · 288 .288 . 289

18 Angiomatous Tumors .

291

Hemangiomas . Choroidal He mangiomas . Retinal Angiomas. Arteriovenous Malfo rmation.

. 291 .29 1 .294 . 296

Retinoblastoma .

299

Genet ic Counseling. . Diagnostic Evaluation. Clin ical Examination Differential Diagnosis Classification . Associated Conditions. Retinocyto ma. Trilateral Retino blastoma. Treatment. Enucleation Chemotherapy Photocoagulatio n and Hyperthermia ..... . Cryotherapy . External- Beam Radiation Therapy . . Plaque Radiotherapy (Brac hytherapy) Targeted Therapy . Spontaneous Regression. PrognOSiS .

· 299 · 301 · 301 . 304 · 307 · 309 · 309 · 309 · 310 · 3 10 · 3 10 · 3 11 · 312 · 3 12 · 3 12 · 3 13 · 3 13 · 313

Ocular Involvement in Systemic Malignancies

315

Secondary Tumors of the Eye . Me tastatic Carcinoma. . . D irect Intraocular Extension Lymphomatous Turno rs . Primary Int raocular Lympho ma. Uveal LymphOid Infiltration Ocular Manifestat ions of Leukemia .

· · . · · · ·

Appe nd ix: Ame rican loint Committee on Cancer (AICC) Staging Forms, 20 10 Basic Texts .

· 329 . 353

31 5 3 15 322 323 323 325 326

xii. Contents

Related Academy Materials . . Requesting Continuing Medical Education Credit. CME Credit Request Form. . Study Questions . Answer Sheet for Section 4 Study Questions Ans\vers. Index

· 355 · 356 . 357 .359 · 369 · 371 .377

General Introduction The Basic and Clinical Science Course (BCSC) is designed to meet the needs of residents and practitioners for a comprehensive yet concise curriculum of the field of ophthalmology. The BCSC has developed from its original brief outline format, which relied heavily on outside readings, to a more convenient and educationally useful self-contained text.

The Academy updates and re vises the course annually, with the goals of integrating the basic science and clinical practice of ophthalmology and of keeping ophthalmologists current wi th new developments in the various subspecialties.

The SCSC incorporates the effort and expertise of mo re than 80 ophthalmologists, organized into 13 Section faculties, worki ng with Academy editorial staff. In addition, the course continues to benefit from many lasting contributions made by the faculties of previous editions. Mem bers of the Academy's Practicing Ophthalmologists Advisory Committee for Education serve on each facu lty and , as a group, review every volume before and after m ajor revisions .

Organization of the Course The Basic and Clinical Science Course comprises 13 volumes, in corporating fundamental

ophthalmic knowledge, subspecialty areas, and speCial top ics: 1 2 3 4 5 6 7

Update on General Medicine Fundamentals and Principles of Ophthalmology Clinical Optics Ophthalmic Pathology and Intraocular Tumors Neuro-Ophthalmology Pediatric Ophthalmology and Strabismus Orbit, Eyelids, and Lacrimal System

8 External Disease and Cornea 9 Intraocular Inflammation and Uve itis

10 Glaucoma 11 Lens and Cataract 12 Retina and Vitreous

13 Refracti ve Surger y In addition, a comprehensive 1vlaster Index allows the reader to easily locate subjects throughout the entire series.

References Readers wh o wish to explore specific top ics in greater detail may consult the references

cited within each chapter and listed in the Basic Texts section at the back of the book.

xiii

xiv. Generallntroduction

These references are intended to be selective rather than exhaustive, chosen by the BCSC facul ty as being important, current, and readily available to residents and practitioners. Related Academy ed ucational materials are also listed in th e appropriate sections. They include books, online and audiovisual materials, self-assessment programs, clinical modules, and interactive programs.

Study Questions and CME Credit Each volume of the BCSC is designed as an independent study activity fo r ophthalmology residents and practit ioners. The learning objectives for this vo lume are given on page I. The text, illustrations, and references provide the information necessary to achieve the objectives; the study questions allow readers to test their understanding of the material and their mastery of the objectives. Physicians who wish to claim CME credit for th is educational activity may do so by folloWing the instructions given at the end of the book.

Conclusion The Basic and Cli nical Science Course has expanded greatly over the years, with the addition of much new text and numerous illustrations. Recent ed itions have sought to place a greater emphasis on clinical applicability while maintaining a solid foundation in basic science. As with any educational program, it reflects the experience of its authors. As its faculties change and as medicine progresses, new viewpoints are always emerging on controve rsial subjects and techniques. Not all alternate approaches can be included in this series; as with any educational endeavor, the learn er should seek additional sources, including such carefully balanced opinions as the Acade my's Preferred Practice Patterns. The BCSC faculty and staff are continuously striving to improve the educational usefu ln ess of the coursej you, the reader, can co ntribute to this ongoing process. If you have any suggestions or questions about the series, please do not hesitate to contact the faculty or the editors. The authors, edi to rs, and reviewers hope that your study of the BCSC will be of lasting value and that each Section will serve as a practical resource fo r quality patient care.

Objectives Upon completion of BCSC Section 4, Ophthalmic Pathology and Intraocular Tumors, the reader sho ul d be able to descr ibe a structured approach to und erstandin g major ocular conditions based on a hierarch ical framework of topography, disease process, general diagnosis, and differential diag nosis summarize the steps in handling ocular specimens for pathologic study, including obtaining, dissecting, processing, and sta in in g ti ssues

explain the basic principles of special procedures used in o phthalmic pathology, includi ng im munoh istochem istr y, flow cytometr y, molecular pathology, and diagnostic electron microscopy

communicate effectively with the pathologist regarding types of specimens, processing, an d techniques appropriate to the clin ical situation summarize the histopathology of common ocular cond itions

correlate clinical and pathological findings list the steps in wou nd healing in ocular tissues summarize current information about the most common primary tumors of the eye

• identify those ophthalmic lesions that ind icate system ic disease and are potentially life threatening provide useful genetic infor mation to families affected by retinoblastoma summarize current treatment modalities for ocular tumo rs in terms of patient prognosis and ocular function

CHAPTER

Introduction to Part I

The purpose of BCSC Section 4, Ophthalmic Pathology and Intraocular Tumors, is to provide a general overview of the fields of ophthalmic pathology and ocular oncology. Although there is some overlap between the 2 fields, it is useful to approach specific disease processes from the standpoint of 2 separate discipli nes. This book contains numerous illustrations of entities commonly encountered in an ophthalmic pathology laboratory and in the practice of ocular o ncology. In ad dit io n, important but less common entities are

included for teaching purposes. For more comprehensive reviews of ophthalmic pathology and ocular oncology, the reader is referred to the excellent textbooks listed in Basic Texts at the end of this volume. Part I of this text provides a framework for the study of ophthalmic pathology, with the following hierarchical organizational parad igm (explained in detail in the next section): topography, disease process, general diagnosis, differential diagnosis. Chapter 2 briefly covers basic principles and speCific aspects of wound repair as it applies to ophthalmic tissues, wh ich exhibit distinct responses to trauma, including end-stage processes such as

phthisis bulbi. Chapter 3 discusses specimen handling, including orientation and dissection, and emphasizes the critical commu nication between the ophthalmologist and the pathologist. Although most ophthalmic pathology specimens are routinely processed and slides are stained with hematoxylin and eosin (H&E), speCial procedures are used in selected cases. Chapter 4 details several of these procedures, including immunohistochemical staining, flow cytometry, polymerase chai n reaction (PCR), and electron microscopy. Also discussed are indications in some instances for special techniques in obtaining the

specimen, such as fine- needle aspi ration biopsy, and speCial ways of preparing slides for examination, such as frozen sections. Chapters 5 through 15 apply the organizational paradigm to speCific anatomical locations.

Organization Chapters 5 through 15 are each devoted to a particular ocular structure. Within the chapter, the text is organized from ge neral to speCific, according to the following hierarchical framework:

topography disease process

general diagnosis differential diagnosis 5

6 • Ophthalmic Pathology and Int raoc ula r Tum ors

Topography The microscopic evaluation of a specimen, whether on a glass slide or depicted in a photograph, should begin with a description of any normal tissue. For instance, the topography of the cornea is characterized by non keratini zed stratified squamous epithelium, the Bowman layer, stroma, the Descemet membrane, and endothelium. By recognizing a particular structure, such as the Bowman layer or the Descemet membrane, in a biopsy specimen, an examiner might be able to identify the topography in question as cornea. It may not be possible, however, to identify the specific tissue source from the topography present on a glass slide or in a photograph. For example, a specimen showing the topographic features of keratinized stratified squamous epithelium overlying dermis with dermal appendages may be classified as skin; however, unless specific eyelid structures such as a tarsal plate are identified, that skin is not necessarily from the eyelid. See BCSC Section 2, Fundamentals and Principles of Ophthalmology, fo r a review of ophthalmic anatomy. Disease Process

After identifying a tissue source, the pathologist should attempt to categorize the general disease process. These processes include congenital anomaly inflammation degeneration and dystrophy neoplasia Congenital anomaly

Congenital anomalies usually involve abnormalities in size, location, organization, or amount of tissue. An example of congen itally enlarged tissue is congenital hypertrophy of the retinal pigment epithelium (C HRPE) (see Chapter 11 , Fig 11 -5; and Chapter 17, Fig 17-10). Many congenital abnormalities may be classified as choristomas or hamartomas. A choristoma consists of normal, mature tissue at an abnormal location. It occu rs when 1 or 2 embryonic germ layers form mature tissue that is abnormal for a given topographic location. An example of a choristoma is a dermoid: skin that is otherwise normal and mature present at the abnormal location of the limbus. A tumor made up of tissue derived from all 3 embryonic germ layers is called a teratoma (Fig 1-1). In contrast, the term hamartoma descri bes an exaggerated hypertrophy and hyperplasia (abnormal amount) of mature tissue at a normal location. An example of a hamartoma is a caven10US hemangioma, an encapsulated mass of mature venous channels in the orbit. Inflammation

The next disease process in the schema, inflammation, is classified in several ways. It may be acute or chronic in onset and focal or diffuse in location. Chronic inflammation is subdivided further as either granulomatous or nongranulomatous. For example, a bacterial corneal ulcer is generally an acute, focal, nongranulomatous inflammation, whereas sympathetic ophthalmia is a chronic, diffuse, gra nulomatous inflammation. Polymorphonuclear leukocytes (PMNs), eosinophils, and basophils all circulate in the blood and may be present in tissue in early phases of the inflammatory process (Figs 1-2,

CHAPTER 1: Introduction to Part I • 7

Figure 1·1 Orbital teratoma with tissu e from 3 germ layers . Note gastrointestinal mucosa (asterisk) and carti lage (arrows) in the tumor. (Courtesy of Hans E. Grossniklaus, MD.)

1-3, 1-4). The types of leukocytes present at the site of inflammation vary according to the inflammator y response. PMNs, also known as neutrophils. typify acute inflanunator y cells and can be recognized by a multiseg mented nucleus and intracytoplasmic granules. They may be present in a variety of ac ute in fla mmatory processes; for example, they are assoc iated with bacterial infection and found in the walls of blood vessels in some forms of vasculitis. Eosinophils have bilobed nuclei and prominent intracytoplasmic eosinophilic granules. They are commonly found in allergic reactions, although they may also be present in chronic inflammatory processes such as sympathetic ophthalmia. Basophils contain basophilic intracytoplasmic granules. Mast cells are the tissue-bound equivalent of the blood borne basophils. Inflammatory cells that are relatively characteristic of chronic inflammatory processes include monocytes (Fig 1-5) and lymphocytes (Fig 1-6). Monocytes may migrate from the intravascular space into tissue, in which case they are classified as histiocytes, or macrophages. Histiocytes have eccentric nuclei and abundant eosinophilic cytoplasm. In some instances, histiocytes may take on the appearance of epithelial cells, with abundant eosinophilic cytoplasm and sharp cell borders, becoming known in th e process as epithelioid histiocytes. EpitheliOid histiocytes may fo rm a ball-like aggregate known as a gra nuloma, the sine qua non for gran ulomatous inflammation. These granulomas may contain only histologicall y intact cells Chard" tubercles, Fig 1-7), or they may exhibit necrotic centers ("caseating" granulomas, Fig 1-8). Epithelioid histiocytes may merge to form a syncytium with multiple nuclei known as a multinucleated giant cell. Giant cells formed from histiocytes come in several variet ies, including Langhans cells, characterized by a horseshoe arrangement of the nuclei (Fig 1-9) Touton giant cells, which have an annulus of nuclei surrounded by a lipid-filled clear zone (Fig 1-10) foreign body giant cells, with haphaza rd ly arranged nuclei (Fig I - I I)

Ly mphocy tes are small cells with ro und, hyperchromatic nuclei and scant cytoplasm. Circulating lymphocytes infiltrate tissue in all types of chronic inflammatory processes.

8 • Oph thalmic Pa thology and Intraocula r Tu mors

•

Figure 1-2 Polymorph onuclear leukocyte with multilobulated nucleus. (Courtesy of Hans E. Gross-

Figure 1-3

Eosinophil w ith bilobed nucleus and intracytoplasmic eosinophilic granules.

niklaus, MD.)

(Courtesy of Hans E. Grossniklaus, MD.)

Figure 1-4 Basophil with in tra cytop lasmic basophilic granu les. (Courtesy of Hans E. Gross-

Figure 1-5

Monocyte with indented nucleus.

(Courtesy of Hans E. Grossniklaus, MD.)

niklaus, MD.)

Figure 1-6 Lymphocy1e with small, hyperchromatic nucleus and scant cytoplasm. (Co urtesy of Hans E. Grossniklaus, MD.)

1-7 Noncaseating granulomas, or "hard" tube rcies, are formed by aggregates of epithel ioid histiocytes . (Courtesy of Hans E. Figure

Grossniklaus, MD.)

CHAPTER 1:

...,.-, ,-_7. . ,7

Introduct io n to Part I • 9

.,.

- .. •

-. ~ -.\

•

• Figure 1·8 Granu lomas with necrotic centers are classified as ca seating granulomas. (Cour·

Figure 1·9 Langhans giant ce ll.

tesy of Hans E. Grossmklaus, MDJ

$.."

.' ~

•6'

Figure 1·10 Touton giant cell.

Figure 1-11

Forei gn body giant cell.

These cells terminally differentiate in the thym us (T cells) or bursa equ ivalent (B cells), although it is not possible to distinguish between Band T lymphocytes with routine histologic stai ns. B cells may produce immu noglobulin and differentiate into plasma cells, with eccentric "cartwheel:' or "clockface," nuclei and a perinuclear halo corresponding to the Goigi apparatus. These cells may become completely distended with imm unoglobulin and form Russell bodies, which may be extracellular. BeSe Section 9, Intraocular Infla m mation and Uve itis, discusses the cells involved in the inflammatory process in depth in Part I, Immunology.

Degeneration and dystrophy The term degel1eratiol1 refers to a wide variety of deleterious tissue changes that occur over time. Degenerative processes are not usually associated with a proliferation of cells; rather. there is often an accumulation of acellular material or a loss of tissue mass. Extracellular deposits may resu lt from cellular overproduction of normal material or me tabolically abnormal material. These processes, which have a va riety of pathologic appearances, may occu r in response to an inj ury or an inflammatory process. As used in this book, "degeneration" is an artificial category used to encompass a wide variety of disease processes. Various

10 • Ophthalmic Pathology and Intraocu lar Tumors categories of diseases, such as those due to vascular causes, normal aging or invo lutional

causes, and trauma, could be considered separately. However, in order to efficiently convey the hierarchical scheme used in th is book, these causes are lumped under the rubric of "degeneration:' Dystrophies are defined as bilateral, symmetric, inherited conditions that appear to have little or no relationship to environmental or systemic factors. Degeneration of tissue may be seell in conjunction with other general disease processes. Examples include calcification of the lens (degeneration) in association with a congen ital cataract (congenital anomaly) ; corneal amyloid (degeneration) in associatio n with trachoma (inflammation); and orbital amyloid (degeneration) in association with a lymphoma (neoplasm). The ophthalmic manifestations of diabetes mellitus can be classified as degenerative changes associated with a metabolic disease. Neoplasia A neoplasm is a stereotypic , monotonous new growth of a particular tissue phenotype.

Neoplasms can

OCCllr

in either benign or malignant forms. Examples found in particu lar

tissu es include

adenoma (benign) versus adenocarci noma (maligna nt) in glandu lar epithelium topography + oma (be nign ) versus topography + sarcoma (malignant) in soft tissue hyperplasia!infiltrate (benign) versus leukemia/lymphoma (malignant) in hematopoietic tissue

Some neoplastic proliferations are called borderline, in that they are difficult to clasSify histologically as benign or malignant. Althou gh most of the neoplasms illustrated and discussed in this text are classified as benign or malignant, the reader should be aware that tissue evaluation in a particular disease can give only a static portrait of a dynam iC process. Thus, it may be impossible to determine whether the process will ultimately be benign or malignant, and in some instan ces "ind eterminate" or "borderline" is a legit imate interpretation. Table I-I summarizes the origin, general classification of benign ve rsus m alignant, and grO\¥th pattern of neoplasms originating in various tissues. The growth patterns described in Table I-I are shown in Figure 1-12. General histo-

logiC signs of malignancy include nuclear and cellular pleomorphism, necrosis, hemorrh age, and mitotic activity.

Table

1-1

Classification of Neoplasia

- - Malignant -

Tissue Origin

Ben ig n

Epithelium

Hyperplasia/ adenom a

Soft tissue Hematopoietic tissue

Topography + oma Hyperplasia/ infiltrate

Carcinoma Aden ocarcinoma Topography + sarcoma Leukemia Lymph oma

Gro wth Pattern Cords Tubules Coherent sheets

Loosely arranged

CHAPTER 1: Introductio n to Part I • 11

Carci noma : cords, tubules

(!TiEl- l ew

••• ~

~ Sarcoma: coherent sheets

Leu kemia, Lymph oma : loosely arranged

. Figure 1-12

® @

®@ ®

Genera l clas sificat ion and growth patterns of malignant tumors. (llIustrarion by

Chris tine Grafapp.)

General Diagnosis After considering the topography and disease process, the examiner formulates the gen eral diagnosis. Recognizing a tissue index feature is a critical step in arriving at the gen-

eral diagnosis. Index feat ures are morphologic identifiers that help to define the disease process more speCifically. Examples include the presence of pigment in a pigmented neoplasm, necrosis in a necrotizing gran ulomatous inflammation , and accum ulation of

smudgy extracellular mate rial in a smudgy eosinophilic corneal degeneration. The index feature should differentiate the particular specimen fro m others demonstrating the same general disease process. For instance, reti noblastoma and melanoma are both intraocular

maligna nt neoplasms; the for mer is a retinal malignancy, and the latter is a uveal tract malignancy. Other index features for distinguishing between these lesions could be "small, rou nd, blue cell tumor" for the retinob lastoma and "melanocytic proliferation" for the melanoma. Althoug h the most basic index features can be recognized without great difficul ty, it takes experience and practice to identify subtle index features.

Differential Diagnosis After the examiner has distingUished a key index feature and formulated a general diagnosis, developing a differential diagnos is is the next step. The differential diagnosis is a limited list of speCific conditions resulting from pathologiC processes that were identified in the general diagnosis. For instance, the differential diagnosis based on the features of noncaseating gran ulomatous inflammation of the conjunctiva includes sarcoidosis} foreign

12 • Ophtha lmic Pathology and Int raoc ular Tumors body, fung us, and mycobacterium. The differential diagnosis of melanocytic proliferation of the conjunctiva includes nevus, primary acquired melanosis, and melanoma. Readers are encouraged to practice working through the hierarchical framework by verbalizing each step in sequence while examining a pathologic specimen. Chapters 5 through 15 of this book provide tissue-specific examples of the diffe rential diagnoses for each of the 4 disease process categories. The expanded organizational paradigm is shown in Table 1-2.

Table 1-2 Organizational Paradigm for Ophthalmic Pathology Topography Conjunctiva Cornea Anterior chamber/t rabecular meshwork Sclera Lens Vitreous Retina

Uveal tract Eyelids Orbit Optic ne rve Disease process Congenital anomaly Choristoma versus hamartoma

Inflammation Acute vers us chronic Focal versus diffuse Granulomatous versus nongranulomatous Degeneration (inc ludes dystrophy) Neoplasia Benign versus malignant Epithelial versus soft tissue versus hematopo ietic General diagnosis

Index feature Differential diagnosis Limited list

CHAPTER

Wound Repair

General Aspects of Wound Repair Wound healing, though a common physiologic process, requires a complicated sequence of ti ssue even ts . The purpose of woun d healing is to restore the anatomical and fu nctional

integrity of an organ or tissue as quickly and perfectly as possible. Repair may take a year, and the result of wound healing is a scar with variable consequences (Fig 2-1). A series of react ions fo llO\~s a wound, including an ac ute infla m matory phase, regenerati on / repair, and co ntract ion:

The acute inflammatory phase may last from minutes to hours. Blood clots quickly in adjacent vessels in response to tissue activators. Neutrophils and fl uid enter the

extracellular space. Macrophages remove deb ris from the damaged tissues, new vessels for m, and fibroblasts begin to produce coll age n. Regenera tion is the replacement aflost cell s; this process occurs only in tissues composed of labile cells (eg, epithelium), which undergo mitosis throughout life. Repair is the rest ructuri ng of tissues by granu lation tissu e that matures into a fibrous scar. Finally, contraction causes the reparative tissues to shrink so that the scar is smaller than the surrounding uninjured tissues.

Healing in Specific Ocular Tissues The processes summarized in the following sections are also discussed in oth er volumes of the BCSC; consult the Master Index. Also see the appropriate chapters in this volume

for a specific topography.

Cornea A corneal abrasion, a pai nful but rapidly heali ng defect, is limited to the surface corneal epithelium, altho ugh the Bowman layer and superfici al stroma may also be involved. Withi n an hour of injury the parabasilar epithelial cells begin to slide and migrate across the denuded area until they touch other migrating cells; then contact inhibition stops further migration. Simultaneously, the surrou nding basal cells undergo mitosis to supply additional cells to cover the defect. Although a large corneal abrasion is usually covered by migrating epithelial cells within 24-48 hours, complete healing, which includes restoration of the full thickness of epithelium (4-6 layers) and re-formation of the anchoring

14 • Ophtha lmic Pathology and Intraocula r Tumors

1 hour

2 hours

1 week

Figure 2-1

6 weeks

Sequence of general wound healing with an epithe lia l surface. 1, The wound is

created. Blood clots in the vessels; neutrophils migrate to the wound; the wounded edges begin to disintegrate. 2, The woun d edges are reapposed with the various tissue planes in good alignment. The epithelium is lost over the wound but starts to migrate. The subcutane-

ous fibroblasts enlarge and become activated. Fibronectin is deposited at the wound edges.

The blood vessels begin to produce buds. 3, The epithelium seals the surface. Fibroblasts and blood vessels enter the wound and lay down new collagen. Much of the debris is removed

by macrophages. 4, As the scar matures, the fibroblasts subside. New ly formed blood vessels recanalize. New col lagen strengthens the wound, which contracts. Note that the striated muscle cells {permanent cellsl at bottom are replaced by scar (arrow)

fibrils, takes 4- 6 weeks. The epithelial cells are labile; that is, some are continuously active mitotically and thus are able to completel y replace the lost cells. If a thi n layer of anterior cornea is lost with the abrasion, the shallow crater will be filled by epithelium, forming a face t.

Corneal stromal healing is avascular. Unlike with other tissues, heali ng in the corneal stroma occurs by means of fibrosis rather than by fibrovascular proliferation. This avascular aspect of corneal wound healing is critical to the success of pe net rating keratoplasty as well as photo refractive keratectomy (PRK), laser in situ keratom ileusis (LASIK), laser epithelial keratomileusis (LASEK), and other corneal refractive su rgical procedures.

CHAPTER 2:

Wound Repair.

Following a central corneal wou nd, neutrophils are carried to the site by th e tears (Fig 2- 2), and th e ed ges of the wound swell. Healing factors derived from vessels are not present. The matri x glycosa m inoglycan s, which in the corn ea are keratan sulfate and

chondro itin sulfate, diSintegrate at the edge of th e wound. The fibrob lasts of the stroma become activated, eve ntuall y migrating across the wound, laying down collagen and fibronectin. The directio n of the fibrobl asts and collagen is not parallel to stromal lamellae. Hence, cells are d irected anteriorly and posteriorly across a wou nd that is always visible m ic roscopically as an irregularity in the st ro ma and clinically as an opacity. If the wou nd edges are separated, th e gap is not completely filled by proliferating fib roblasts, and a parti all y filled crater results. Both the epithelium and the endothelium are critical to good central wou nd healing. Ifth e epithelium do es not cover th e wound within days, th e subjacent stroma l healing is limited and the wound is weak. Growth factors fro m the epitheliu m stim ulate and su stain

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Figure 2-2 Clear corneal wound. 1, The tea r film ca rri es neutrophils with Iysozymes to the wound within an hour. 2, With closure of the incision, the woun d edge shows early disintegra-

tion and edema. The glycosa minoglycans at the edg e are de graded . The nearby fib roblasts are activated. 3, At 1 w ee k, migratin g epith elium and end othel ium partia lly sea l th e wound;

fibroblasts beg in to migra te and supply collagen. 4, Fi broblast act ivity and collagen and matri x depOSi tion co ntinue. The endothelium, sealing the inn er w ound, lays down new De scemet

membra ne. 5, Epi thelial regen eration is complete. Fibroblasts fill the wound wi th type I collagen and repair slows. 6, The final wound contracts. Th e collagen fibers are not parallel with the surrounding lamellae. The number of fibroblasts decreases .

16 • Ophthalmic Pathology and Intraoc ular Tumors

healing. The endothelial cells adjacent to the wound slide across the posterior cornea; a few cells are replaced through mitoti c activity. Endothelium lays down a new th in layer of the Descemet membrane. If the in terna l margin of the wound is not covered by Descemet membrane, stromal fibroblasts may continue to proliferate into the anterior chamber as fibrous ingrowth, or th e posterior wound may remain permanently open. The initial fib ril lar collagen is replaced by stronger collage n in the late months of healing. The Bowman layer does not regenerate when incised or destroyed. In an ulcer. the surface is covered by epithelium, but little of the lost stroma is replaced by fibrous tissue. Modification of the healing process by use of topical anti metabolites, such as 5-tluorouracil and mitomycin C, may be desirable in certain clin ical situations (see BCSC Section 10, Glaucoma, Chapter 8).

Sclera The sclera differs frol11 the cornea in that the collagen fibers are randomly distributed rather than laid dO\~n in orderly lamellae, an d the glycosaminoglycan is dermat .., sulfate. Sclera is relatively avascular and hypocellu lar. When stimulated by wounding, the episclera migrates down the scleral wound, suppl ying vessels, fibroblasts, an d activated macrophages. The final wou nd contracts, creating a pinched-in appearance. If the adjacent uvea is damaged, uveal fibrovascula r tissue may enter the scleral wound, resulting in a scar with a dense adhesion between uvea and sclera. Indolent episcleral fibrosis produces a dense coat around an extrascleral fo reign body such as an encircling scleral buckling element or a glaucoma drainage device.

Limbus The limbus is a complex region of corneal, scleral, and episcleral tissues. Wounds of the limbus cause swelling in the cornea and shr inking of the sclera. Healing involves episcleral ingrowth and clear corneal fib roblast ic migration. Coll ector channels in the sclera do not contribute to the healing. Alterations in surgical technique between clear corneal and lim bal incisions may prod uce differe nt healing responses. Differences include the potential for vascular ingrowt h from episcleral vessels into a limbal wound and the absence of vascularity of a clear corneal wound surface remodeling of epitheliu m over a clear corneal wound that does not occur over a limbal wound

Uvea Under ordinary circ*mstances, wounds of the iris do not stimulate a healing response in either the stroma or the epithelium. Though ri chly endowed with blood vessels an d fibrobl asts, the iridic stroma does not produce granu lation tissue to close a defect. T he pigmented epithelium may be stimu lated to migrate in some circ*mstances, such as excessive inflammation, but its migration is usually limited to the subjacent surface of the lens capsule, where subsequent adhesion of epithelial cells occurS. When fibrovascular tissue forms, it usually does so on the anterior surface of the iris as an exuberant and aber-

CHAPTER 2:

Wound Repair.

rant membrane (eg, rubeosis iridis) that may cross iridectomy or pupillary openings. The fibrovascular tissue may arise from the iris, the chamber angle, or the cornea. Stroma and melanocytes of the ciliar y body and choroid do not regenerate after injury. Debris is removed, and a thin fibrous scar develops that appears white and atrophic clinically. Dunn SP. Iris repair: putting the pieces back together. Focal Poir/ts: Clinical Modules for Oph-

thalmologists. San Francisco: American Academy of Ophthalmology; 2002 , module 1 I.

Lens Small rents in the lens capsule are sealed by nearby lenticular epithelial cells. When posterior synechiae make the lenticular epithelium anoxic or hypoxic, a metaplastic response occurs, producing fibrous plaques interm ixed with basem*nt membrane.

Retina The retina is made of terminally differe ntiated cells that typically do not regenerate when injured. Glial cells (Miiller cells and fib rous ast rocytes) proliferate in response to retinal trauma. Surgical techniques to close openings in the peripheral retina are successful when the neurosensory retina and retinal pigment epithelium (RPE) are destroyed (eg, cryotherapy, photocoagulation) and the surrounding tissues form an adhesive, atrophic scar. Retinal scars are produced by glia rather than fibroblasts. After inflammatory cells have cleared away the debris, the tissues most damaged by the therapeutic modality remain as a thin, atrophic area in the center of the scar. Increasing numbers of residual viable cells encircle the zone of greatest destruction. Adhesion between the residual neurosensory retina and Bruch membrane develops according to the size of the original wound and the type of injury. The internal limiting membrane and the Bruch membrane provide the architectural planes for glial scarring. Adhesions from the internal limiting membrane to the Bruch membrane may incorporate a rare residual glial cell, and variable numbers of retinal cells and RPE may be present between the mem branes. If the wound has damaged the Bruch membrane, choroidal fibroblasts and vessels may participate in the formation of the final scar. The end result is a metaplastic collagenous plaque in the sub-neurosensory retina and sub-RPE areas. The RPE usually proliferates rather exuberantly in such scars, giving rise to the dense black clumps seen clinically in scars of the fundus.

Vitreous The vitreous has few cells and no blood vessels. Nonetheless, in conditions that cause vitreal inflammation, mediators stimulate the formation of membranes composed of new vessels and the proliferation of glial and fibro us tissue. With contraction of these membranes, the retina becomes distorted and detached.

Eyelid, Orbit, and Lacrimal Tissues The rich blood supply of the skin of the eyelids supports rapid healing. On about the third day after injur y to the skin, myofibroblasts derived from vascular pericytes migrate

18 • Ophtha lmic Pa t hology an d Intraocular Tum ors around the wound and actively contract, res ultin g in a volumetric decrease in the size of the wound. The eyelid and orbit are compartmentalized by intertwi ni ng fascial membranes enclosing muscular, tendinous, fa tty, lacrimal, and ocular tissues that a re disto rted b'Y'scarring. Exube rant cont racting d istorts m uscle ac tion, produci ng dysfunctional scars. The str~ated muscles of the orbic ularis oculi and ext raocular muscles a re made of te rmi nally d iffere nt iated cells th at do no t rege ne rate, but the via ble cells may hyp er troph y.

Histologic Sequelae of Ocular Trauma n upture of the Descemet membrane may occur after minor trau ma (eg, in keratoconus; Fig 2-3) or major trauma (eg, after forceps injury; Fig 2-4). T he anterio r chamber angle structu res, especiall y the trabecu lar beams, are vul nerable to distortion of the anterior globe. Cyclodialysis results from dis insertion of the lon gitudina l muscle of the ci liary bo dy fro m the scleral spur (Fig 2-5). T his condit ion ca n lead to hypoton y because the ,aqueous of the anterior chamber now has free access to the sup rac horoidal space; and beca use the blood supply to the cil ia ry body is d imi n ished , the p roduction of aqueous is decreased. Traumatic recession of the anterior chamber angle is due to a tear in th e Ciliary body between the longitudinal and circular muscles with posterior displacement of the iris root (Fig 2-6) . Concu rre nt da mage to the tra becula r meshwo rk may lead to gla ucoma. The uveal tract is attached to the sclera at 3 poi nts: the scleral spur, the internal ostia of th e vortex veins, and the peripapillary tissue. Th is anatomical a rran ge men t is th e bas is of th e evisceration techn iq ue and explains th e vulnerability of the eye to expu lsive choroi-

2-3 A break in th e Descemet membran e in keratoconus shows anteri or curling of Descemet membrane towa rd th e corn eal stroma (arrow). (Courtesy of Hans E. Grossniklaus. M D.)

Figure

Figure 2-4 A break in the Descem et membrane as a result of forceps injury shows anterior curling of the original membrane (arrow) and production of a secondary thickened membra ne. (Courtesy of Hans E. Grossniklaus, MD.)

CHAPTER 2: Wou nd Repa ir . 19

,, Figure 2-5

Cyclod ialysis (arrow) shows disin-

sertion of ci liary body muscle (asterisk) from the scleral spur (arrowhead).

(Counesy of Hans E

Grossniklaus, MD.)

Figure 2-6 Angle recession shows a rupture in the ciliary body in the plane between the ext ernal longitudinal muscle fibers and the internal circu lar and oblique fibers (arrow); the iris root is displaced posteriorly (arrowhead). Note the scleral spur (astenskJ,

dal hemorrhage. The borders of the dome-shaped choroidal hemorrhage are defined by the position of the vo rtex veins and the scleral spur (Fig 2- 7) . An iridodialysis is a rupture of the iris at the th in nest portion of the diaphragm , the iris base, where it inserts into the supporti ve tissue of the ciliary body (Fig 2-8) . Only a small amount of supporti ng tissue surrounds the iris sphincter. If the sphincter m uscle is ru ptured, contracti on of th e remaining muscle wil l create a notch at the pupillary border.

Figure 2-7 A, Th is eye developed an expulsive hemorrhage after a corneal perforation. B, The

intraocular choroidal hemorrhage is dome shaped (arrowheads), delineated anteriorly by the insertion of the choroid at the scleral spur (arrow). (Courtesy of Hans E. Grossmklaus. MD.)

20 • Ophthalmic Path ology and Intraocular Tum ors

\ A

Figure 2-8

A, Clinical photograph showing iridodia lys is with a tea r in the base of the iris. B, Gross photograph showing posterior view of iri dodia lys is (arrows). (Part A courtesy of Hans E. Grossniklaus, MO.)

The iris diaphragm may be lost completely through a relatively sman limbal rupture as~ sociated with 360" iridodialysis. A Vossius ring appears when compression and rupture of iris pigment epithelial cells agai nst the anterior surface of the lens occur, depositing a ring of melanin pigment concentric to the pupiL A cataract may form immediately if the lens capsule is ruptured . The lens capsule is thinnest at the posterior pole, a point farthest away from the lens epithelial cens. The epithelium of the lens may be stimulated by trauma to form an anterior lenticular fibrous plaque. The lens zonular fibers are points of relative weakness; if the y are ruptured, dis~ placement of the lens can be partial (s ubluxation) or complete (luxation). Focal areas of zonular rupture may allow formed vitreous to enter the anterior chamber. Commotio retinae (Berlin edema) often complicates blunt trauma to the eye. Most prominent in the macula, commotio retinae can affect any portion of the retina. Originally, the retinal opacification seen clinically was thought to result from retinal edema (extracellular accumu lation of fluid), but experimental evidence shows that a disruption in the architecture of the photoreceptor elements causes the loss of retinal transparency. Retinal dialysis is most likely to develop in the inferotemporal or superonasal quad~ rant. The retina is anchored anteriorly to the nonpigmented epithelium of the pars plana. This union is reinforced by the attachment of the vitreous base, which straddles the ora serrata. Deformation of the eye can result in a circumferential retinal tear at the point of attachment of the ora or immediately posterior to the point of attachment of the vitreous base. Vitreoretinal traction may cause tears in a retina weakened by necrosis. Intraocular fibrocellular proliferation may occur after a penetrating injury. Such proliferation may lead to vit reous/subretinallchoroidal hemorrhage; traction retinal detach ment; proliferative vitreoretino pathy (PVR) , induding anterior PVR (Fig 2~9); hypotony; and ultimately phthisis bulbi. Formation of proliferative intraocular membranes may affect the timing of vitreoretinal surgery. The timing of the drainage of a ciliochoroidal hemorrhage is based on lysis of the blood dot (10-14 days). Hemosiderin forms at ap~ proximately 72 hours after hemorrhage. Sequelae of intraocular hemorrhage indude sid~ erosis bulbi, cholesterosis, and hemoglobin spherulosis.

CHAPTER 2: Wound Repa ir . 21

Figure 2-9

Anterior proliferative vitreoretinopathy (PVRl. A, Traction of the vitreous base on

the peripheral retina (arrow) and ciliary body epithelium (asterisks). B, Incorporation of peripheral retinal (arrow) and ciliary body tissue (arrowheads) into the vitreous base. C, Condensed vitreous base (asterisk), adherent retina (arrow), and RPE hyperplasia (arrowhead). (Counesyof Hans E. Grossniklaus, MO.}

22 • Ophthalmic Pathology and Intraocular Tumors

Figure 2-10 Focal posttra umatic choroida l granu lomatous inflammation. A, Enucleated eye with a projectile caus ing a perforating limbal inju ry that extends to the posterior cho roid. 8, Microscopic examination shows a f ocus of choroidal granulomatous inflammat ion (between arrowheads). (Courtesy of Hans E. Grossniklaus. MD.)

Rupture of the Bruch membrane or choroidal rupture may occur after direct or indirect injury to the globe. Choroidal neovascularization, granulation tissue proliferation, and scar formation may occur in an area of choroidal rupture. A subset of direct choroidal ruptures, those usually occurring after a projectile injury, may result in focal posttraumatic choroidal granulomatous inflammation (Fig 2-10). This may be related to foreign material introduced into the choroid. A chorioretinal rupture and necrosis is known as sclopetaria. Phthisis bulbi is defined as atrophy, shrinkage, and disorganization of the eye and intraocular contents. Not all eyes rendered sightless by trauma become phthisical. If the nutritional status of the eye and near-normal intraocular pressure (lOP) are maintained during the repair process, the globe will remain clinically stable. However, blind eyes are at high risk of repeated traU111a with cumulative destructive effects. Slow, progressive functional decompensation may also prevail. Many blind eyes pass through several stages of atrophy and disorganization into the end stage of phthisis bulbi:

Atrophia bulbi without shrinkage. Initially, the size and shape of the eye are maintained. The atrophic eye often has elevated lOP. The following structures are most sensitive to loss of nutrition: the lens, which becomes cataractous; the retina, which atrophies and becomes separated from the RPE by serous fluid accumulation; and the aqueous outflow tract, where anterior and posterior synechiae develop. Atrophia bulbi with shrinkage. The eye becomes soft because of ciliary body dysfunction and progressive diminution of lOP. The globe becomes smaller and assumes a squared-off configuration as a result of the influence of the 4 rectus muscles. The anterior chamber collapses. Associated corneal endothelial cell damage results initially in corneal edema followed by opacification from degenerative pannus, stromal scarring, and vascularization. Most of the remaining internal structures of the eye will be atrophic but recognizable histologically. Phthisis bulbi (Fig 2-11). The size of the globe shrinks from a normal average diameter of24-26 mm to an average diameter of 16- 19 mm. Most of the ocular contents become disorganized. In areas of preserved uvea, the RPE proliferates and drusen may be seen. Extensive calcification of the Bowman layer, lens, retina, and drusen usually occurs. Osseous metaplasia of the RPE with bone formation may be a prominent feature. The sclera becomes massively thickened, particularly posteriorly.

CHAPTER 2:

Wound Repair. 23

B Figure 2·11 Phthisis bulbi. A, Gross photograph showing globe with irregular contour, cataractous lens with calcif ication (asterisk), cycl*tic membrane with adherent retina (arrowheads), orga nized ci liochoroi dal effusion (open arrows), and bone formatio n (between green arrows). B, Photomicrograph demonstrating histopathologic correlation with gross photograph in A. (Courtesy of Robert H. Rosa, Jr, MD.)

CHAPTER

Specimen Handling

Communication Communication with the pathologist before, duri ng, and after surgical procedures is an essential aspect of quality patient care. Standards for the technical handling of specimens and reporting of results have been developed and are available on the website of the College of American Pathologists (www.cap.org). The fi nal histologic diagnos is reflects successful collaborative work between clin ician and pathologist. The ophthalmologist should provide a relevant and reasonably detailed cl inical history when the specimen is submitted to the laboratory. This history facilitates clinicopathologic correlation and enables the pathologist to provide the most accurate interpretation of the specimen. Where there is an ongoing relationship between a pathologist and an ophthalmologist, communication usually can be accomplished through the pathology request form and the pathology report. However, if a malignancy is suspected or if the biopsy will be used to establish a critical diagnosis, direct and personal com munication between the ophthalmic surgeon and the pathologist can be essential. This preoperative consultation allows the surgeon and pathologist to discuss the best way to submit a specimen. For example, the pathologist may wish to have fres h tissue for immunohistochemical stains and molecular diagnostic studies, gluta raldehyde-fixed tissue for electron microscopy, and formalin-fixed tissue for routine paraffi n embedding. If the tissue is simply submit ted in formalin, the opportunity for a defin itive diagnOS iS may be lost. Communication between clinician and pathologist is espeCially important in ophthalmic pathology, where specimens are often very small and require ve ry careful handling. In some cases, carefu l

selection of the surgical faCi li ty is necessary to ensure proper specimen handling. Biopsies may be incisionaI. in which only a portion of the tumor is sampled, or excisional, in which the entire lesion is removed. See BCSC Section 7, Orbit, Eyelids, and Lacrimal System, Chapter 10, for further discussion. Any time a previous biopsy has been performed at the site of the present pathology, the sections of the previous biopsy should be requested and reviewed with the pathologist who will interpret the second biopsy. The su rgical plan may be altered substantially if the initial biopsy was thought to represent, for example, a basal cell carcinoma when in fact the disease was a sebaceous carcinoma. In addition, the pathologist will be able to in terpret intraoperative frozen sections more accurately when the case has been reviewed

in advance.

26 • Ophthalmic Pathology and Intraocular Tumors If substantial disagreement arises between the clinical diagnosis and the histologic diagnosis, the ophthal mologist should contact the pathologist d irectly and promptly to resolve the discrepancy. Mislabeling of pathology specimens or reports through a si mple typing error, for example, can have serious consequences. Merely correcting the patient age on the pathology request form may change the interpretation of melanotic lesions of the conjunctiva. Benign melanotic lesions in children may have a histologic appearance similar to that of malignant melano tic lesions in adults. Whether the patient is age 4 or age 44 makes a tremendous difference in interpretation.

Orientation Globes may be oriented according to the location of the extraocular muscles and of the long posterior Ciliary arteries and nerves, which are located in the horizontal meridian. The medial, inferior, lateral, and superior rectus muscles insert progressively farther fro m the limbus. Locating the insertion of the inferior oblique muscle is very helpful in distin gUishing between a right an d a left eye (Fig 3- 1). The inferior oblique inserts tempo rally over the macula, with its fibers runn ing inferiorly. Once the laterality of the eye is determined, the globe may be transilluminated and dissected.

Transillumination Eyes are transilluminated with bright light prior to gross dissection. This helps to identify intraocular lesions such as a tumor that blocks the transilluminated light and casts

Superior rectus

Superior oblique

Vortex veins

Medial rectus

Lateral rectus

Inferior oblique

Inferior rectus

Figure 3-1 Posterior view of right globe. N = nasal, T illustra tion by Thomas A. Weingeist, PhD, MD.)

tempora l. (Modified by CH. Woolev from an

CHAPTER 3:

Specimen Handling.

D L!:=-_ _ _.....J Figure 3-2 Preparation of an intraocular tumor specimen. A, Transillumination shows blockage to light secondary to an intraocular tumor. 8, The area of blockage to ligh t is marked with a marking pen ci l. C, The opened eye shows the intraocular tumor that was demonstrated by

transillum ination. D, The pa ra ff in-embedded eye shows the in traocular tumor E, The H&Estained se ction shows th at the maximu m exten t of th e tumor demonstrated by trans illumination is in th e ce nter of the section, which includes the pu pil and optic nerve. (Courtesy of Hans E. Grossniklaus, MD.J

a shadow (Fig 3-2A). The shadow can be outl ined with a marking pencil on the sclera (Fig 3-2B). This outline can then be used to guide the gross dissection of the globe so that the center of th e section will incl ude the maximum extent of th e area of interest (Figs 3-2C to 3-2£).

Gross Dissection A globe is opened so as to display as much of the pathologic change as possible on a Single slide. The majority of eyes are cut so that the pupil and optic nerve are present in the same section, the PO section . The meridian, or clock-hour, of the section is determ ined by the unique features of the case, such as the presence of an intraocular tumor or a histor y of previous surgery or trauma. In routine cases, with no prior surgery or intraocular neo plasm, most eyes are opened in the horizontal meridian, which includes the macu la in th e same section as the pupil and optic nerve (Fig 3-3). Globes with a surgical or nonsurgical

28 • Ophthalmic Pathology and Intraocu la r Tumors

{)

B ~ ;?

Figure 3-3 A, The goal of section ing is to ob tain a pupil-optic nerve (PO) section that contains the maximum area of interest. 8 Two caps, or calottes, are removed to obtai n a PO section. e, The first cut is generally performed from posterior to an terior. D, The second cut will yield the PO section. (Illustration by Christine Graiapp.) f

wound should be opened so the wound will be perpendicular to, and included in, the PO section, which often means opening the globe vertically. Globes with intraocular tumors are opened in a way (hori zo nta\' vertical, or oblique) that places the center of the tumor as outlined by transillumi nation in the PO section. The globe can also be opened coronally with separatio n of the anterior and posterior compartments. The tumor can be visualized directly with this technique, an d a section

includi ng ~_~um extent of the tumor may then be obtained.

Processin!l and Stainin!l Fixatives The most commonly used fixative is 10% neutral bu ffered formal in. Formalin is a 40% solution of formaldehyde in water that stabilizes protein, lipid, and carbohydrates and prevents postmortem enzymatic destruction of th e tissue (autol ys is), In specific instan ces,

CHAPTER 3:

Specimen Handling . 2 9

other fIxatives may be preferred, such as glutaraldehyde for electron microscopy, ethyl alcohol for cytologic preparations, and Michel medium fo r immunofluorescence studies. Table 3-1 lists examples of some commonly used fIxatives. Formalin diffuses rather quickly thro ugh tissue. Because most of the func tional tissue of the eye is within 2-3 mm of the surface, it is not necessary or desirable to open the eye. Opening the eye before fIxation may damage or distort sites of pathology, makin g histologiC interpretation difficult or impossible. The adu lt eye measures approXimately 24 mm in diameter, and formalin diffuses at a rate of approximately 1 mm/hr; therefore, globes should be fIxed at least 12 hours prior to processing. It is generall y desirable to suspend an eye in formalin in a volume of approXimately 10: 1 for at least 24 hours prior to processing to ensure adequate fixat ion. Different institutions may use different protocols, and preoperative consultation is critical.

Tissue Processing The infiltration and embedding process removes most of the water from the tissue and re places the water with paraffin. OrganiC solvents used in this process will dissolve lipid and may dissolve some synthetic materials. Routine processing usually dissolves intraocular lenses made of polymethylmethacrylate (PMMA) , polypro pylene, and silicone, altho ugh the PMMA may fall out during sectioni ng. Silk, nylon, and other synthetiCsutures do not dissolve during routine processing. Specimens are routinely processed through increasing concentrations of alcohol followed by xylene or another clearing agent prior to infiltration with paraffi n. Alcohol dehydrates water, and xylene replaces alcohol prior to paraffin infiltration. The paraffll1 mechanically stabilizes the tissue, making possible the cutting of sections. The processing of even a "routine" specimen usually takes a day. Thus, it is unreasonable for a surgeon to expect an interpretation of a specimen sent fo r permanent sections to be available on the same day as the biopsy. Tech niques for the rapid processing of special surgical pathology material are generall y reserved for biopsy specimens that require emergent handling. Because the quality of histologic preparation after rapid processing is usually inferior to that of standard processed tissue, it should not be requested routinely. Surgeons should commun icate directl y with their pathologists about the availability and shortcomings of these techniques.

Table 3·' Common Fixatives Used in Ophthalmic Pathology

------

Fixati ve

Color

Exampl es of Use

Forma li n Bou in solution

Clear Yellow Clear Clear Clear Light pink Orange

Routine fixation of all tissues Small bi opsie s Lymphoproliferative tissue (eg, lymph node) Electron microscopy Crystals (eg, urate crystals of gout) Immunofluorescence Muscle differentiation

65 Glutaraldehyde Ethanol/meth ano l Michel fixative Zenker acetic fixative

-------

30 • Ophthalmic Pathology and Int ra ocu la r Tumors

Tissue Staining Tissue sections are usually cut at 4- 6 ~ m. A tissue adhesive is sometimes used to secure the thi n paraffi n section to a glass slide. The cut section is colorless except for areas of indigenous pigmentation, and various tissue dyes- principally hematoxylin and eosin (H&E) and periodic acid- Schiff (PAS)-are used to color the tissue for identificatio n (Fig 3-4). Other histochemical stai ns used in ophthalmic pathology are alcian blue or col loidal iron for acid mucopolysaccharides, Congo red for amyloid, Gram stain for bacteria, Masson trichrome for collagen, Gomor i methenamine silver stain for fungi, and oil red 0 for lipid. A small amount of resi n is placed over the stained section and covered with a thin glass coverslip to protect and preserve it. Tabl e 3-2 lists some common stains and gives examples of their use in ophthalmic pathology.

LF. Montgomery lab, Emor), Univer it)'

Figure 3-4

LF. Montgomery L.I". _ ,lOfY (Jl1ivc

!tv

l.F. Montgomory lab.

Univer~lty

•

The section of a melanoma at the far left is colorless except for mild indigenous

pigmentation in the tissu e. Moving to th e right, note th e sl ides stained w ith hematoxylin only, eosin only, and both hematoxylin and eosin. (Courtesy of Hans E. Grossniklaus, MD.)

CHAPTER 3:

Specimen Han dli ng .

Table 3-2 Common Stains Used in Ophthalmic Pathology Stain

Material Stained: Color

Example

Hematoxylin and eos in (H& E)

Nucleus: blu e Cytoplasm: red Glycogen and proteog lycans: magenta Acid mucopolysaccharide: bl ue Calcium: red Acid muco polysaccharide: blue Amylo id: orange, red-green dichroism Ac id-fast orga ni sms: red Fungal elements: black

Gene ral tissue stain (Fig 3-2EI Descemet membrane (Fig 6-17EI Cave rn ous optic atrophy (Fig 15-1 0BI Band ke ratopathy Macular dystrophy (Fig 6-21CI Lattice dy strophy (Fig 6-23C, DI Atypica l m ycobacterium Fusarium (Fig 6-7B)

Amyloid: pu rp le, violet Bacteria positive: blue Bacteria neg ative: red

Lattice d ystrop hy Bacteria l infection

Collagen: blue

Granul ar dystrophy (F ig 6-22CI Red depos its Hemosi d erosis bulbi Lattice dystrophy Temporal artery elastic laye r Band ke rat opathy (Fig 6-1 2CI

Periodic acid-Schiff (PAS) Alcian blue Alizarin red Colloidal iron Congo red Ziehl-Neelsen Gomori methenamine silver (GMSI Crystal violet Gram stain (tissue Brown & Brenn IB&BI or Brown & Hopps IB&Hl stain ) Masson trichrome

Perls Prussian blue Thioflavin T (ThT) Verhoeff-van Gieson von Kassa

Musc le: red Iron : blue Amyloid: flu orescent yellow Elastic fibers: black Calcium p hosp hate salts: bl ack

CHAPTER

Special Procedures

New technologies have contributed to improvements in the diagnosis of infectious agents

and tumors as well as to the classification of tumors, especially the non-Hodgkin lymphomas (NHLs), childhood tumors, and sarcomas. Use of a more extensive test menu of paraffin-active monoclonal antibodies for immunohistochemistry; molecular cytogenetic stud ies , including standard cytogenetics; multicolor flu orescence in situ hybridiza-

tion (FISH); polymerase chain reaction (PCR) and its many variations; and locus-specific FISH; as well as developments in high-resolution techniques, including microarray gene expression profiling, proteomics, and array comparative genomic hybridization (CGH), allow a m ore accurate diagnosis and more precise defi nition of biomarkers of value in risk stratification and prognosis. The ophthalmic surgeon is responsible for appropriately ob taining and submitting tissue for evaluation and consulting with the ophthalmic pathologist. See Table 4-1 for a checklist of important considerations when submitting tissue for pathologic consultation .

Immunohistochemistry Pathologists making a diagnosis take ad vantage of the property that a give n cell can express speCific antigens. The immunohistochemical sta ins commonly used in ophthalmic

pathology work because a primary antibody binds to a specific antigen in or on a cell, and because th at antibody is linked to a chromogen, usually through a secondary antibody (Fig 4- I). The color product of the ch romogens gene rally used in ophthalmic pathology is brown or red in tissue sections, depending on the chromogen selected for use (Fig 4-2). Red chromogen is especially helpful in working with ocular pigmented tissues and melanomas, because it differs from the brown melanin pigment (see Fig 4-7) . The precise cell or cells that display the speCific antigen can be identified using these methods. Many antibodies are used routinely for diagnosis, treatment, and prognosis:

cytokeratins for lesions composed of epithelial cells (adenoma, carcinoma) desmin , myoglobin, or actin for lesions with smooth muscle or skeletal muscle fea -

tures (leiomyoma, rhabdomyosarcoma) 5-100 protein for lesions of neuroectodermal origin (schwannoma, neurofibroma, melanoma)

HMB-45 and Melan A for melanocytic lesions (nevus, melanoma)

34 • Ophthalmi c Pathology and Intraocul ar Tumors

Table 4-' Checklist for Requesting an Ophthalmic Patholog ic Consultation Routin e Specime ns (cornea, con juncti va, eye li d lesions) 1. Fill out requisition form a. Sex and age of patient b. Location of lesion (late rality and exact location) c. Previous biopsies of the site and diagnosis d. Pertinent clinical history e. Clinical differential diagnosis f. Ophthalmologist phone and fax numbers 2. Specimen submitted in adequately sealed container with a. Ample amount of 10% formalin (at least 5 times th e size of the biopsy) b. Label with patient's name and location of biopsy 3. Drawing/map of site of biopsy for or ientation of margin s (eyelid lesions for margins, en bloc resections of conjunctiva, sclera, and cil iary body/ iri s tum ors) Frozen Secti ons 1. If possible , previous communication with ophthalmic pathologist 2. Fi l l out specific frozen section requisition form, specifying the reason for submitting tissue, such as a. Margins b. Diagnosis c. Adequacy of sampling d. Obtaining tissue for molecular diagnosis (reti nob la stoma, rhabdomyosarcoma, metastatic neuroblastoma, etc) or flow cyto metry 3. Map/diagram of lesion indicati ng margins and orientation 4. Labeling of tissue (in k, sutures) to orient acco rding to the diagram (for margins) Fi ne-Needl e Asp irati on Bio psy and Cyto logy 1. Previous communication wi th ophthalmic pathologist to discuss a. Logistics of the biopsy i. Possible adequacy check during the biopsy (intraocular tumors) ii. Fixative to be used iii. Fresh tissue for possible mo lecula r diagnosi s b. Specific cytology form to be filled out Flow Cytometry 1. Previous communication with ophthalmic pathologist to discuss a. Fresh tissue is critical. b. Adequate samp le is essenti al. c. Geographic proximity to the laboratory Molecu lar Techniqu es and Elect ron M icroscopy 1. Previous communication w ith ophthalmic pathologist to discuss a. Differential diagnosis b. Fixative (fresh vs alcohol vs glutaraldehyde vs oth er) c. Logistics of the biopsy i. Time and date (availabi lity of specia lized personnel) ii. Geographic proxim ity to laboratory

chromogranin and synapto phys in fo r neuroendocrine lesions (metastatic carcinoid [see Fig 4-2], small cell carcinoma) leukocyte common antigen for lesions of hematopoi etic origin (leukemia, lymphoma) CD ant igens for subtypi ng white blood cells Her2 eu and c-Kit for prognosis and treatment (metastatic breast ca rci noma, mastocytosis)

CHA PTER 4:

Special Procedures.

•• ~

antigen

secondary antibody

primary antibody v_ _-"--_ _ __ _--' _

chromogen

Figure 4·' Schematic representation of the general immunohistochemistry method. 1, The cellular antigen is recognized by the specific primary antibody, 2. A secondary antibody, 3, directed against the primary antibody, reacts with the enzymatic complex to create t he chromogen, 4. The f inal product allows t he vi sualization of th e ce ll contain ing the antigen. (Courtesy of Patricia CMvez-Barrios. MO.)

Figure 4-2 A metastatic carcinoid to the orbit seen by H&E (A) shows bland epithel ial cha racteristics. 8, Ch romogranin antibody highlights the neuroendocrine nature of the cells. (Courtesy of Patricia CMvez-Barrios. MO.)

36 • Ophtha lmic Patho logy and Int raocul a r Tumors These antibodies vary in their specificity and sens itivity. Specificities and sensitivities of new an tibodies are continually being evaluated (for examples, see the online immunohistology query system at W\vvv.imffiunoquery.com) . Automated equi pment and antigen retrieval techniques are currently used to increase sensitivity and dec rease tu rnaround time.

Flow Cytometry, Molecular Patho logy, and Diagnostic Electron Microscopy Flow Cytometry Flow cytometry is used to analyze the physical and chemical properties of particles or cells moving in Si ngle fil e in a fluid stream (Fig 4-3, a) . An example of flow cytometry is immunophenotyping of leukocytes. The cells need to be fresh (unfixed). Fluorochrome-labeled specific antibodies bind to the surface of lymphoid cells, and a suspension of labeled cells is sequentially illuminated by a light source (usually argon laser) for approximately 10- 6 second (Fig 4-3, b). As the excited fluoroc hro me retu rns to its resting energy level, a specific wavelength of light is emitted (Fig 4-3, c) , which is sorted by wavelength stream (Fig 4-3, d) and received by a photodetector (Fig 4-3, e) . This Signal is then converted to

............ ... 0

_:. . . . ·1

0 . ~

- -- - -

--:

~'\

E T E

c T

Fi gure 4-3 Flow cytometry ana lyzes particles or cells moving in single file in a fluid st ream (a). Fluorochrome-labeled specifi c antibod ies bind to t he surface of cells, and a suspension of lab eled ce ll s is sequen tially illuminated by a laser (b). As th e exc ited fl uorochrome retu rn s to its resti ng en ergy level, a spe cif ic wave length of ligh t is emitted (c), w hich is sorted by w aveleng th (d) and rece ived by a photodetector (e). This signal is the n converted to electron ic

impulses, wh ich are in turn analyzed by computer softwa re.

(Courtesv of Patricia Chevez-Barrios, MD.)

CHAPTER 4:

Special Procedures.

electronic impulses, which are in turn analyzed by computer software. The results may be imaged by a multicolored dot-plot histogram (Fig 4-4). The most common use of flow cytometry in clinical practice is for immunophenotyping hematopoietic proliferations. Th is procedure may be performed on vitreous, aqueous, or ocular adnexal tissue. In addition, m ultiple antibodies and cell ular size can be analyzed, and the relative percentages of cells may be displayed. For example, CD4 (helper T cells), CDS (suppresso r T cells), both CD4+ and CDS+' or either CD4+ or CDS+ may be displayed for a given lymphocytic infiltrate. The advantage of this method is that it actuall y shows the percentages of particular cells in a specimen. Disadvantages are the fail ure to show the location and distribution of these cells in tissue and the possibility of sampling erro rs. Depending on th e number of cells in the sample and on clinical information, the flow cytometrist chooses the panel of antibodies to be tested. Flow cytometric data shou ld therefore be used as an adjunct to morphologic H&E and sometimes immunohistochemistry interpretation. Flow cytometric analysis is particularly useful for the evaluation of lymphoid proliferations.

Molecular Pathology Molecular biology techniques are used increasingly in diagnostic ophthalmiC pathology and extensively in experimental pathology (Table 4-2). More recentl y, their use has expanded to include prognostication of disease and determination of treatment. Molecular path olog y is used to identify tumor-promoting or tumor-inhibiting genes (CGH, PCR, array CGH ), such as the retinoblastoma gene; and viral DNA or RNA strands, such as those seen in herpesviruses and Epstein-Barr virus (PCR, in situ hybridization [ISH ]) . The evolution of molecular pathology techniques has made it possible not only to recogni ze the presence or absence of a strand of nucleic acid but also to localize specific DNA

t;. W 0-

« o

c:J

::;;

« --'

10'

CD5APC -> Fi gure 4-4 Flow cytometry scatter graphs showing a clonal populat ion of C01 9+ kappa restricted lymphocytes . Note that most of the CD19+ (red in left graph) cells fa il to express lambda light chains; however. the cells do exhibit strong kappa expression (red in right graph!. (Courtesy of Patricia Cha vez·Barrios. MD.)

38 • Ophthalmic Pathology and Intraocu lar Tu mors Table 4·2 Summa ry of Molecular Techniques Used in Diagnostic Pathology Tech niqu e

Method

Adva ntages

Disadvantages

SNP oligonucleotide microarray analysis (SOMA)

Type of DNA microarray

1. SN Ps are highly

Unable to detect mosaicism, balanced chromosomal translocations, inversions, and whole-genome ploidy changes

Multiplex ligationdependent probe amplification

(MLPA)

Fluorescence in situ hybridization (FISH)

Polymerase chain reaction (peR )

used to detect single nucleotide polymorph isms (SNPs), the most frequent type of variation in t he genome, w ith in a population. Uses array that conta ins immobilized nucleic acid sequences and 1 or more labeled allele-spec ific oligonucleotide (ASO) probes Amplification of multiple targets using only a single primer pair within a single peR mixture to produce amplicons of varying sizes t hat are specific to different DNA sequences Chromosome regionspecific, flu oresce ntly labeled DNA probes (cloned pi eces of genomic DNA) able to detect their complementary DNA sequences Amplification of a single strand o f DNA (nucle ic aci d) based on the rmal cycles of repeated heating and cooling of the reaction fo r DNA melting and enzymatic replicat ion of the DNA. Clinica l ly used for early detection of cancer, heredita ry diseases, and infectious diseases

conserved between species and within a population and serve as a genotypic marker for research. 2. Able to detect copy numbe r neutral loss of heterozygosity to uniparental disomy 3. Has huge potential in cancer diagnostics

Addi tional information may be gained from a single test run.

Targets must be different enough to form distinct bands when visualized by gel electrophoresis.

M icrofluidic chip allows automation and clinical use.

Known type and location of expected aberrations

Quality snap-frozen tissue (optimal) and archival paraffin embedded tissue

1. Variable success rate of DNA extraction 2. Contamination with other nucleic acid material

CHAPTER 4: Special Procedure s . 39

Table 4·2 (continued) Technique

Method

Advantages

Disadvantages

Reverse tra nscriptasepolym erase cha in react ion (RT-PCR )

Amplifi es DNA from RNA. Clinicall y used to determine the ex pressio n of a gene

Quality snap-frozen tissue (opt ima l) and arch ival para ffinembedded t iss ue

Rea l-ti me quantitative PCR IRT·PCR)

M easu rement of PCR-product acc umulation during the ex ponential pha se of t he PCR reaction using a d ual -labeled fluo rogenic pro be

Com parative ge nomi c hybridi zation (CGH)

Molecula r cytogenet ic method for analys is of co py numbe r chan ges (ga ins/ losses) in the DN A co ntent of an individ ual, often in t um or cells. Uses epifluoresce nce and quantitative, reg ional diffe ren ces in th e fl uorescence ratio of ga ins/ losses v s contro l DNA to identify abn orm al region s in the ge nome at a resol ution of 20-80 base pai rs Differe nti all y labe led test and reference DNAs, hybridized to cloned fragments, genomic DNA o r cDNA, w hich are spotted on a g lass sl ide (t he array). Th e DNA copy nu m ber aberrat ions me asured by detect ing intensi ty d iffe rence s in the hybridi za tion pattern s

Direct detectio n of PC R-product formation by meas uring t he increase in fl uorescent emi ssion contin uou sly durin g the PCR reacti on 1. Detects and maps alteratio ns in co py number of DNA seq uences 2. A nalyzes all chromosom es in a si ng le experiment and no d ividi ng ce lls req uired

1. Va ri abl e success rate of RNA ext ractio n 2. Co ntamination w ith ot her nuclei c aci d m aterial Var iab le succe ss rate of RNA ext racti on

Mi croa rray-based CGH (a rray CGH )

Hi gh reso lu ti on

In abil ity to detect mosa icism , ba lanced chromosoma l translocations , inve rsions, and w hole-geno m e ploi dy changes

1. Inability to detect aberrat ions not res ul t ing in copy number chang es 2. Limited in its ab il ity to detect mosaicis m

40 • Ophthalmic Path ol og y and Int raocular Tumors

sequences within specific cells (FISH , ISH ). Two m ajor techniques have markedJy ad · vanced o ur knowledge of developmental biology and tu morigenesis: PCR (and its vari a· tio ns) and microarray (and its subtypes).

Polymerase chain reaction A com mo n molecular biology tech niq ue is the polymerase chain reaction (p eR), which amplifies a single st rand of nucle ic acid across several o rders of magnitu de, generatin g thousands to millions of copies of a particular DNA sequence (Fig 4·5). The PCR method

Heat to 95°C. DNA strands separate.

A __~~~~~~~~~~~~~~~~~~~-'

I Cool to 55'C.

Primers bind to template DNA strands.

72' C Taq polymerase synthesizes new DNA strands between primer sequences. T

Two new DNA molecules produced.

Figure 4-5

.............. ....."""""'"

"Cycles repeated. /

_ ,"""''"' """""''''''''

A, A polymerase chai n reaction (peR) starts with a denaturing step where DNA sampl es are heated to 95°C to separate the target DNA into sing le strands. B, Next, the temperature is lowered to 55°C to allow the primers to anneal to their complementary sequences. The primers are designed to bracket the DN A region to be amplified. C, The temperature is raised to 72°C to allow Taq polymeras e to attach at each priming site and extend or synthesize a new DNA strand between primer sequences producing 2 new DNA molecules . D, Step C is repeated multiple times to generate thousands of copies. (Courtesy of Theresa Kramer. MD.)

CHAPTER 4:

Special Proced ures. 41

relies on thermal cycles of repeated heating and cooling of the DNA sample for D A melting and enzymatic replica tion. Primers, which are short DNA fragments containing sequences complementary to the ta rget region, DNA polymerase, and nucleotides are the components required in order for selective and repeated amplification to occur. The selectivity of PCR is due to the use of primers that are complementar y to the DNA region targeted fo r ampli fication. The techniques of PCR have advanced considerably in recent yea rs, and there are now approximately 20 variat ions on peR, including real- time and quantitative real-t ime PCR. The va riations center arou nd quantification; increased definition of the sequence amplified (allele, single nucleotide, generation of long sequences with overlap technology, intersequences, flan king sequences and genomic inserts, methylation-specific sequences, conserved sequences, simultaneous multiple gene amplificati on); isothermal amplification methods fo r use in living cells (PAN -AC); and increased resolution of the sequence (multiplex ligation -dependent probe amplification, MLPA). MLPA permits multiple targets to be amplifi ed simultaneously with only a single primer pair and is becoming important in prognostication of tumors. The clinical relevance of detecting a PC R product depends on numerous variables, including the primers selected, the laboratory controls, and the demographic considerations. Thus, for the clinician making a clinicopathologic diagnosis, PCR should be used mainly to derive supplementary information. See also Part III, Ge netics, in BCSC Section 2, Fundamentals and Principles of Ophthalmology.

Microarray Microarrays are used to survey the expression of thousands of genes in a single assay, the output of which is called a gene expression profile. Using microarray technology, scientists and clinicians can atte mpt to understand fundamental aspects of growth and development, as well as to explore the molecular mechanisms underlying normal and dysfun ctional biological processes and elucidate the ge netic causes of ma ny human diseases. DNA microarray, microRNA mi croarray (MMChips), protein microa rray, tissue microarray (Fig 4-6), cellular (or transfection) microarray, antibody m icroarray, and carbohydrate (glycoarray) m icroa rray are some of the different types of microarrays available. Although there are a variety of DNA microarray platforms, the basic process underlying all of them is straightforward: A glass slide or chip is spotted or "arrayed" with oligonucleotides or DNA frag ments that represent speCific gene coding regions (called probes) . Fluorescently or chemiluminescently labeled purified eDNA or cRNA (called target) is hybridized to the "arrayed" slide/chip. After the chip is washed, the raw data are obtained by laser scanning, entered into a database (some public, others mined), and analyzed by statistical methods. An example of one of these microarray platforms is the DualChip low-denSity microarray. These DNA microarrays we re developed as a flexi ble tool capable of reliably quantifying the expression of a limited nu mber of genes of clinical relevance, but DualChip technology has also been applied to tumor diag nosis and tumo r-acqui red drug resistance. Validation of the results of microa rray expe riments is a critical step in the analysis of gene expression . Quantitative real- time PCR is the method of choice for validation of ge ne expression profili ng.

42 • Ophthalmic Pathology and Intraocu lar Tumors

)

Figure 4·6

Tissue microarrays are constructed w ith small core biopsi es of differe nt t umors/

tissues. A core is obtained fro m the donor paraffin block of the tumor (a). A recipient paraffin

block is prepared, creating empty cores (b). The cores are inco rporated into the slots (c) until all are occupied (d)' Glass s lides are prepared an d stained with a selected antibody (e). Microscopic exa m ination reveals th e diff eren t sta inin g patterns of each core (f) . (Courtes y of Patricia CMvez-8amos, MOJ

Clinical use of PCR and microarray Routine clinical use of PCR and microarray is li m ited to the diagnosis of leukemias, lymphomas, soft-tissue tumors, and tum ors with nondiagnostic histopathology results. Commercial microarray and PCR platforms now exist that can be used for assigning biopsy-sized tumor samples to 1 of2 di stinct molecular classes, based on gene expression analysis that distinguishes low-grade tumors from high -grade tumors. The selecti on of commercially available microarray and PCR kits is growing rapidly. Leukemias, lymphomas, and soft-tissue tumors represent a heteroge neous group of lesions whose classification continues to evolve as a result of advances in cytogenetic and molecular techniques. In the 1990s, tradi tional diagnostic approaches were supplemented by the successful application of these newer techniques (see Table 4-2) to fo rm alin-fixed, paraffin -embedded tissue, making it possible to subject a broader range of clinical material to molecular analysis. T hus, molecular genetics has already become an integral part of the workup of tumors, such as pediatric orbital tumors (rhabdomyosarcomas,

CHAPTER 4:

Special Procedures . 43

neuroblastomas. peripheral neuroectodermal tu mors [PNETJ). that demonstrate characteristic translocations. Based on the results. treatment can be directed and prognostic features associated with certain mutations and translocations. Hicks J, Mierau GW The spec trum of pediatric tumors in infancy, childhood, and adoles· cence: a comprehensive review with emphasis on special techniques in diagnosis. Ultrastruct

Pa'''o!' 2005;29(3 -4),175-202. Oostlander AE, Meijer GA, Ylstra B. Microarray-based compa rative genomiC hybridization and its applications in human genetics. Clill Genet . 2004;66(6):488-495.

Diagnostic Electron Microscopy Diagnostic electron microscopy (OEM) is used primarily to indicate the cell of origin of a tumor of questionable diffe rentiation rather than to distinguish between benign and malignant processes. Although immunopathologic studi es are less expensive and performed more rapidl y than OEM. in some cases, OEM complements immunopathologic studies. The surgeon should consult with the pat hologist before surgery to determine whether OEM might playa role in the study of a parti cular tissue specimen.

Special Techniques Fine-Needle Aspiration Biopsy Fine-needle aspi rat ion biopsy (FNA B) has been used instead of excisional biopsy by nonophthalmic surgeons and pathologists. It is especially useful if the physician performing the biopsy can grasp the lesion (usually between the thu mb and forefinger) and make several passes with the needle to obtain representative areas. The use of F AB (with the results interpreted by a well-trained cytologist or ophthalmic pathologist) is becoming more common in ophthalmology. Intrao cu lar FNAB may be useful in distinguishi ng between primary uveal tum ors and metastases. and biopsy specimens can undergo genetic analys is using a microsatellite assay in order to identi fy monosomy 3 in uveal melanoma. which would indicate a poo r prognosis. Intraocular FNAB has also been ut ilized in the diagnosis of primary intraocular lymphoma, and the biopsy specimens can undergo flow cytometric analysis. immunocytologic analysis. cytokine analysis. or molecular biological analysis (using peR on both fixed and non fixed material). Special fixatives are used for cytology specimens. The procedure is performed under direct visualization through a dilated pupil. Iris tumors may be accessible for FNAB duri ng slit-lamp biomicroscopy. However. FNAB alone cannot reliably predict the prognosis of a uveal melanoma because the sample with intraocular FNAB is limited. Intraocular FNA B may also enable tumor cells to escape the eye; this possibility is an area of some controversy. In general. prope rly performed. FNAB does not pose a significant risk for seeding a tumOf. but retinoblastoma is a notable exception. FNAB of a possible retinob lastoma lesion. if indicated. should be performed by an ophthalmiC oncologist with ample experience in making the diagnosis and performing the procedure.

44 • Ophtha lmic Pathology and Intraocular Tum ors T he cells obtained through FNAB can be processed through cytospin of fluid or preparation of a cell block (Fig 4-7). Cell block allows the patholo gist to employ special stains, immunohistochem istry, in situ hybridization, m icroarray, and gene expression profiling, if needed. Som e orbital surgeons have used FNAB in the diagnosis of orbital lesions, especially presumed m etastases to the orbit and optic nerve tumors. However, because it is difficult to make several passes at different angles through an int raorbital tumor, FNAB of orbital masses may not adequately sample representative areas of the tumor. Specific indications for when and when not to perform intraocular or intraorbital FNAB are beyo nd the scope of this discuss ion, but some of these in d ications are discussed in Part II of this book, Intraocular Tumors: Clinical Aspects. Ophthalm ic FNAB should be perform ed only when an ophthalm ic pathologist or cytologist experienced in the preparation and interpretation of these specimens is available. Cohen VM, Dinakaran S, Parsons MA, Rennie IG. Transvitreal fme needle aspiration biopsy: the influence of intraocular lesion size on diagnostic biopsy result. Eye. 2001;15(Pt 2): 143- 147.

Frozen Section Permanent sections (tissue that is processed after fixation through alcohols and xylenes, embedded in paraffin, and sectioned) are always preferred in ophthalm ic pathology because of the in herent small size of samples. If the lesion is too small, it co uld be lost during frozen sectioning. A frozen section (tissue that is snap-frozen and immedi ately sectioned in a cryostat) is indicated when the results of the study will affect management of the patient in the operating room. For example, the most frequent ind icati on for a frozen

• A Figure 4-7 Fine-needle aspirati on bi opsy (FNAB) of choroidal tumor. A, Cytolog ic liquid-based prepa ration displays promi nent nucleoli (arrow) and some brown pigment (arrowh ead) sug-

gestive of me lanoma. B, Cell block of the aspirated cells, sta ined with HMB-45 usi ng a red chromogen, is posit ive, confirming the diagnosis of melanoma. Noti ce the difference betw een th e red chromogen (arro w s) and the brown melani n (arrowh eads). (Courtesy of Patricia ChevezBarrios, MD.}

CHAPTER 4:

Special Procedures. 45

section is to determine whether the resection margins are free of tumor, especially in eyelid carcinomas. Appropriate orientation of the specimen, correlated with documentation (through drawings of the excision site, labeled margins, or margins of the excised tissue that are tagged with sutures or other markers), is crucial when tissue is submitted for margin evaluation. Two techniques are used for accessing the margins in eyelid carcinomas (basal cell carcinoma, squamous cell carcinoma, and sebaceous carcinoma): routine frozen sections and Mohs micrographic surgery. Mohs surgery preserves tissue while obtaining free margins. Eyelid lesions, especially those located in the canthal areas, require tissue conservation to maintain adequate cosmetic and functional results. Other frequent indications for frozen sections are to determine whether the surgeon has obtained, through biopsy, representative material for diagnosis (especially metastasis) and to submit fresh tissue for flow cytometry and molecular genetics (eg, cancers). Frozen sections are a time-intensive and costly process and should be used with discretion. It is considered inappropriate to order frozen sections and then to proceed with a case before receiving the results from the pathologist. To ensure adequate understanding ofthe case and facilitate the best possible results for the patient, the surgeon should communicate with the pathologist ahead of time if a frozen section is anticipated. Chevez-Barrios P. Frozen sec lion diagnosis and indications in ophthalmic pathology. Arch Pathol Lab Med. 2005;129(12),1626 - 1634.

CHAPTER

Conjunctiva

Topography The conjunctiva is a mucous membrane lining the posterior surface of the eyelids and the ante rior surface of th e globe as far as the limbus. It can be subd ivided in to palpebral, forniceal, bulbar, and caruncular sections. The conjunctiva consists of epithelium and un~ derlying·stroma. The epithelium is nonkerati ni zing stratified squam ous, with goblet cells. The conjunctival epitheli um is continuous with the corneal epithelium, but the latter has no goblet cells. In th e fo rn iceal and bulbar areas, the conjunctival epithelium is fl at and regular, while in the palpebral area, it exhibits ridges (Fig 5-1A, B) . T he go blet cells of the epithelium are most numerous in the fornices and plica semilunaris (Fig 5-1C, D). Beneath the epithelium is the conjunctival stroma, or substantia propria, which is thickest in the fornices and thin nest covering the tarsus. Constituents of this stromal layer include loosely arranged collagen fibers; vessels; lymphatics; nerves; occasional accessory lacrim al glands; and resident lymphocytes, plasma cells, macrophages, and mast cells. In places, th e lymphocytes are organized into lymphoid follicles, and this conjunctiva -associated lymphoid tissue (CALT) is an example of mucosa-associated lymphoid tissue (MALT) (see the section Lymphocytic Lesions). The bulbar portion of the substantia propria fuses with the underlying Tenon capsule. In the medial canthal area, the conjunct iva forms a vertical fold, the plica semilunaris, and medial to this is the caruncle. The stroma of th e caruncle is the only part of the conjunctiva that (like ski n) also contains sebaceous glands and hair follicles (Fig 5-1E) . See BCSC Section 2, Fundamentals and Principles of Ophthalmology, and Section 8, External Disease and Cornea, for further discussion .

Congenital Anomalies Choristomas A choristoma is a benign, congenital proliferation of histologically mature tissue elements not normally present at the site of occurrence. This heterotopic congenital lesion results from normal tissue migrating to or remaining in an abnormal location during embryogenesis (hence the deri vatio n from the Greek word for "separated mass"). Examples include

Iimbal dermoid Iipodermoid (or dermolipoma) ectopic lacrim al gland

48 • Ophthalmic Pathology and Intraocular Tumors

E Figure 5-1 A, Epibulbar conjunctiva with regular, nonkeratinizing stratified squamous epi thelium . B, Palpebral conjunctiva with epithelial ridges. St roma contains vessels and inflammatory cells (arrow). C, Conjunctiva at the fornix may contain pseudoglands of Henle, infoldings of conJu nctiva with abundant goblet cells (arrows). D, Periodic acid-Sch iff (PASI stain highlights the mucin in goblet cel ls (arrow). E, Caruncul ar conj unctiva, containing sebaceous glands (5) and hair follicles (H). (Parts A-D courtesy of Patricia Chevez-8arrios, MD; part E courtesy of George J. Harocopos, MD.)

episcleral osseous choristoma and osseocartilaginous choristoma complex choristoma Dermoids are finn, dome-shaped, white-yellow papules typically at or straddling the limbus, most commonly in the inferotemporal quadrant (Fig 5-2A, B). They may also in volve the central cornea. Size varies from a few millimeters to more than 1 cm. Dermoids may occur in isolation or. particularly when bilateral, as a manifestation of a congenital complex such as Goldenhar syndro me (oculoauriculovertebral dysgenesis, characterized by epibulbar dermoid, upper eyelid coloboma, preauricular skin tags, and vertebral anomalies) or linear nevus sebaceous syndro me (an oculoneurocutaneous disorder), A dermoid often contai ns dermal adnexal structures. The surface epithelium mayor may not be keratinized (F ig 5-2C) .

CHAPTER 5:

Conjuncti va .

E Figure 5·2 Ocular surface choristomas. A, Limbal dermoid, clinical appea rance. 8, Higher magnification shows hairs emanating from the dermoid. C, Histology shows ke ratinized epithel ium, dense stroma, and sebaceous glands with hair foll icles (arrows). 0, A lipodermoid differs from a dermoid in that significant amounts of mature adipose tissue (A) are present. This lipodermoid also contains dermal adnexal structures, including sebaceous glands (5) and hair follicles (H). E, An osseous choristoma con ta ins bone, and complex choristomas combine features of mu[tiple types of choristomas, in thi s case osseous (0) plus [ipodermoid (L). (Parts A and B courtesy of Morton E. Smith, MO; parts C-£ courtesy of George J. Harocopos, MD.)

50 • Ophthalmic Patho logy a nd Int raocula r Tumo rs Lipodermoids (or dermolipo mas) occur mo re frequently in the superotemporal quad ~ rant toward the fornix and may extend posteriorly into the orbit. As a result of its adipose tissue component, a lipodermoid is softer and yellower than a dermoid (Fig 5~2D). De r ~ mal adnexal struc tures mayor may not be present. Lipodermoids, like dermoids, may be associated with Goldenhar syndrom e or lin ear nevus sebaceous syndrome. Osseous choristomas contain bone. Complex choristomas comb ine features of multi -

ple types of choristomas, fo r example, dermoid or li podermoid plus osseous cho ristoma (Fig 5~2E). Clin ically, they are often indistingu ishable fro m derm oids or lipodermoids. See BCSC Section 6, Pediatric Ophthalmology and Strabismus, and Section 8, External Disease and Cornea.

Hamartomas Hamartomas, like choristomas, are benign, congenital proliferations; but in contrast to choristomas, they are abnormal overgrowths of mature tissue normall y present at that site (hence the derivation from the Greek word for "mistake mass"). In the conjunctiva, the most common variety of hamartoma is a capillary hemangioma, although this hamartoma most often involves the eyelid and may involve the orbit (see Chapter 13). Some consider hemangiomas to be true (acq uired) neoplas ms.

Inflammations Because the conjunctiva is an exposed surface, a variety of organisms, allergens, and toxic agents can initiate an in flam matory response kn own as conjunctivitis. The response can be subdivided according to the time frame of symptoms and signs (ac ute or chron ic); accordi ng to the appearance of the conjun ctiva (papillary, follic ular, or less commo nly, granulomatous); or accordi ng to etiology (infectious, non in fect ious). See BCSC Section 6, Pediatric Ophthalmology and Strabismus, and Section 8, External Disease and Cornea, for additional discussion.

Papillary Versus Follicular Conjunctivitis Most cases of conjunctivitis may be categorized as either papillary or foll icular, accord~ ing to the macroscopic and m icroscopic appearance of the conj unctiva (Fig 5 ~3) . Ne i ~ ther type is pathognomonic for a particula r disease entity. Papillary conjunctivitis shows a cobblestone arrangement of flattened nodules with central vascula r cores (Fig 5 ~4). It is most com 1110nly associated with an all ergic im mune response, as in vernal and atopic keratoconjunctivitis, or it is a response to a fore ign body such as a co ntact lens o r ocular

prosthesis. Papillae coat the ta rsal surface of the upper eyelid and may reach large size (giant papillary conjunctivitis). Li mbal papillae may occur in vernal keratoconj un ctivitis (Horner~ Trantas dots). The histologiC appea rance of papillar y conjunctivi tis is identi cal, regardless of the cause: closely packed, flat~ topped projections, with numerous eos i no ~ phils, lymphocytes, plas ma cells, and mast cells in the stroma surrounding a central vas~ cular channel.

CHAPTER 5:

Conjunctiva. 51

B Figure 5-3

Schematic representation of papil lary and follicular conjunctivit is. A, In papillary conjunctivitis, the conjunctival epithe lium (checkered blue) covers fibrovascular core s w ith blood vessels (red), and the stroma contains eosinophils (pink circles) and lymphocytes and plasma cells (blue circles). B, In follicular conjunctivitis, the conjunctival epithelium covers lymphoid follicles, which have a paler germinal center surrounded by a darker corona (central pale blue surrounded by dark blue!, and the surrounding stroma contains lymphocytes and plasma ce lls (small blue circles). (Courtesy of Patricia CMvez-Barrios, MD.)

A Figure 5-4

Papillary conjunctivitis. A, Clinical appearance. Papillae efface the normal palpebral conj unctival surface and form a conf luent cobble stone pattern. B, Low-power photom icrogra ph exhibits the closely packed, flat-topped papi llae with centra l fibrovascu lar cores (arrows). The normal meibomian glands (M) of the tarsus are also shown. (Part A courtesy of Harry H. Brown. MD; part B courtesy of George J. Harocopos, MO.)

Follicular conjunctivitis (Fig 5-5) is seen in a variety of conditions, including inflam mation caused by pathogens such as viruses; atypical bacteria; and toxins, including topical m edications (glaucoma medications, especially brimonidine, or over-the-counter ophthalmic deco ngestants), In contrast to papillae, follicl es are small, dom e-shaped nodules without a prominent central vessel. Accordi ngly, whereas a papilla clinically appears more red on its surface and more pale at its base, a follicle appea rs more pale on its surface and more red at its base. Histologically, a lymphOid follicle is situated in the subepitheli al region and consists of a germinal center, containing imnlature, proliferat ing lymphocytes; and surroundin g corona, containing mature lymphocytes and plasma cells. The follicles in follicul ar conjunctivitis are typically most prominent in the inferior palpebral and forniceal conjunctiva.

52 • Ophthal mic Path ology and Int raocu lar Tum ors

, A

Figure 5· 5 Follicular conjunctivitis . A, Clinical photograp h s howing foll icles. B, High·power photomicrograph shows lymphoid follicl e with bounda ry between germinal center and corona (arrowheads). Note the paler, re latively larger, immature lymphocytes in the germ inal center, as compared to the darker, small, mature lymphocytes and plasma cells in the corona. (Parr A courtesy of Anthony J. Lubniewski, MD; part B courtes y of George J. Harocopos, MO.)

Granulomatous Conjunctivitis Though less common than papillary or fo llicular conjunctivitis, granulomatous conjunc· tivitis does occur. Clinically. the nodular elevations observed in granu lomatous conjunc-

tivitis may be difficult to distinguish from follicles, but clinical history and other systemic symptoms may point to th e diagnosis. Granulomatous co njunctiviti s in associatio n with preauricular lymphadenopathy is known as Parinaud oculoglandular syndrome. Bacteria such as Bartonella henselae (cat-scratch disease) and Francisella tularensis (tularemia),

mycobacteria (eg, tuberculosis), and trepo nemes (eg, syphiliS) are possible causes. The diagnOSiS can be made by serology, culture, polymerase chain reaction (PCR), or a combi· nation of these. If conjunctival biopsy is performed, the granulomas in in fectious granulomatous conj unctivitis will typically demonstrate central necrosis (caseation). The bacteria may be demo nstrated with Gram, acid· fast, or Warth in-Starry stains, depending on the organism. There are also noninfectious causes of granulomatous conjunctivitis. Sarcoidosis may

involve all ocular tissues, including the conjunctiva. It manifests as small, tan nodules, primarily within the forniceal conjunctiva (Fig 5-6). The nodules are often present even in the absence of an obvious conjunctivitis, that is. in noninjected) asymptomatic eyes. Conjunctival biopsy can be a simple, expedient way of proViding diagnostic confirmation of this systemic disease. Histologically, noncaseating gra nulomatous "tubercles" (round to oval aggregates of epithelioid histiocytes) are present within the conjunctival stroma with a variable, but usually minimal, cuff of lymphocytes and plasma cells. Multinucleated giant cells may or may not be present within the granulomas. Central necrosis is not characteristic and, if present, should suggest infectious causes of granulomatous inflammation. The diagnosis of sarcoidosis is tenable only when supported by clinical findin gs and after other causes of granulomatous inflammation have been excluded by histochemical stains andlor by culture. See also Chapter 12 in this volume and BCSC Section 9, Intra ocular Inflam mation and Uveitis.

CHAPTER 5:

Conjunctiva . 53

A Fi gure 5·6 Sarcoidosis. A, Clinical appearance of sarcoid granulomas of the conjunctiva. 8, Histology shows noncaseatlng granulomatous tubercle, with pale-staining histioctyes, Including giant cell (arrowhead). Note the minimal surrounding cuff of lymphocytes and plasma cells. (Courtesy of George J. Harocopos. MD.J

As an exposed surface , the conj unctiva is vu lnerable to contac t w ith foreign bodies. Some may be transient and /or inert, whe reas othe rs may become embedded and incite a foreign-body reaction , identifiable histologically as a granuloma surrounding the foreign object. Multi nucl eated giant cells are com mon. Viewing the tissue section under polarized light may be helpful in identifying the offending foreign material (Fig 5-7) .

Infectious Conjunctivitis A wide variety of pathogens may infect th e conju nct iva, including viruses, bacteria, atypi cal bacteria (eg, chlamydiae), fungi, and pa rasites. The most com mon offending agents in children are bacterial (Haemophilus inj7uenzae, Streptococcus pneumoniae) and , in adults, vi ral; the usual culprits are adenovirus and the herpesviruses (simplex and zoster). Viral infec tions , in add iti on to inciting a follicular conjunctivitis, often affect the cornea,

Figure 5-7 Conjunctival foreign-body granuloma. A, Clinical appearance on the bulbar conjunctiva. Bi Histologi C analysis of the specimen from a different patient under polarized light shows multiple foreign fibers of various colors, with surrounding foreign-body granulomatous reaction, Including multiple giant ce lls (arrowheads). (Parr A counesyof AnthonyJ Lubmewski. MO; parr B courtesy of George J Harocopos. MDJ

54 • Ophthalmic Pathology and Int raocular Tum ors

result ing in ulcers in herpetic disease (see Chapte r 6) and subepithelial infiltrates in adenoviral disease. Specific diagnosis of infectious conjunctivitis may be made based on clinical history and examination (typically sufficient for viral disease), or it may require Gram stain/cuiture, PCR, or serology, depend ing on the organism. In cases of diagnostic uncertainty or cases unresponsive to initial treatm ent, exfoliative (ie, im pression) cytology of ocular surface epithelium or tissue biopsy may be helpful in establishing a defin itive diagnosis. Chlamydiae are obligate intracell ular pathogens that may cause follicular conjunctivitis. Chlamydia trachomatis is a majo r cause of ocular infection (trachoma), particularly in the Middle East. Serotypes A, B, and C are associated wi th trachoma; serotypes D through K cause neonatal and adult inclusion conjunctivitis. Exfoliative cytology of ocular surface epithelium (Giemsa stain) or tissue biopsy may demonstrate these intracellular organisms (Fig 5-8). When the conjunctiva alone is in fected, fungi are ra rely the inciting pathogen. Fungal ocular surface in fections typically involve the cornea (see Chapter 6). Microsporida, a group of obligate intracellular parasites, may cause conjunctivitis, keratitis, or keratoconjunctivitis, part icularl y in patients with acquired immunodefi ciency syndrome (AIDS). Rhinosporidium seeberi, which may cause an isolated conjunctivitis (typically affects the palpebral/fo rniceal conj unctiva), is seen most often in areas such as India and Southeast Asia but has also been reported in the southeastern United States. Infection is typically associated with exposure to stagnan t water. This organism was initially classified as a fung us but has been reclassified as a protozoon. The protozoon Acanthamoeba occaSionally causes an isolated conjunctivitis but typically also infects the cornea (see Chapter 6). This diagnosis should be considered in chronic unilateral conjunctivitis unresponsive to standard therapy; exfoliative cytology may be helpful in establishing the diagnosis.

Noninfectious Conjunctivitis As discussed previously, most pap illary co njuncti vitis, some forms of granulomatous conjunctivitis, and toxic follicular conjunctivitis are associated with noninfectious etiologies. See the sections Papillary Versus Follicular Conjunctivitis and Granulomatous Conjunctivitis for specific examples. Ocular cicatricial pemphigoid (OCP) is a form of cicatrizing conjunctivitis that is of autoimmune etiology. It typically also involves other mucous membranes and sometimes involves the skin. When this diagnosis is suspected clinically, conjunctival biopsy is performed to establish the diagnosis. Half of the specimen should be submitted in fo rmalin for routine histology, and half submitted in Michel medium or saline for im munofl uorescence analysis. Histology shows bullae of the epithelium and a subepithelial band of chronic inflammatory cells, predominantly plas ma cells (Fig 5-9). Immunofluorescence demonstrates IgG, IgM, and/or IgA imm unoglobuli ns, and/or complement (C3) positivity in the epithelial basem*nt membrane zo ne. The clinician must bear in mind that the sensitivity of immunofluorescence may be as low as 50% (particularly in lo ng-standing cases with severe cicatrization) . Thus, a negati ve result does not rule out the possibility of ocr. See also BCSC Section 8, External Disease and Cornea.

CHAPTER 5: Con junct iva. 55

________________

__________

Exfoliative conju nctiva l cytology. A, Lymphocytes (arrows) predom ina te in viral co njunctivitis. S, A mixture of neu t rophi ls (arrow) and eosinophils (arrowhead) is typica l of verna l conjunctivitis. C, Gram stain reveals t he polymorphonuclear leukocyte res ponse to gonococca l conjunct ivitis. Note the intrace llu lar gram·negative diplococci (arrow). 0, A case of Moraxelfa lacunata angular conjunctivit is demonstrating the bacilli, which ofte n are found in pairs (arrow). E, Chlamvdia, conjunctival scraping, Giemsa stain. The cytoplasmic inclusion body (asterisk), composed of multiple chlamydial organisms, can be seen capping the nucleus (N). A distinct space separates the inclusion body from the nuclear chromatin. Figure 5·8

56 • Ophtha lm ic Pathology and Intraocula r Tumors

Figure

5-9

Ocular

cicatricial

pemphigoid

(OCP). A, Clinical appearance. B, Histology shows epithelial bullae (arrows) and dense plasma cell in filtrate in the substa ntia propria (arrowheads). C, Immunofluorescent staining of th e epithelial ba sem*nt membra ne (arro wheads) in OCP. (Part A courtesy of Andrew J. W. Huang. MD; part B courtesy of George J. Harocopos, MO.)

c Pyogenic Granuloma A pyogenic granuloma appears as a reddish nodular elevation on the ocular surface, typi cally occurring in association with a chalazion (on the palpebral conjunctiva), or at a site of prior accidental or surgical trauma. Classic examples of the latter include a site of strabismus surgery (at the muscle insertion), retinal surgery, or enucleation. The name of this condition is somewhat of a misnomer because the lesion is not necrotic, nor is it a true granuloma. Rather, it consists of granulation tissue, that is, a pedunculated mass composed of a mixture of acute and chronic inflammatory cells, with proliferating capillaries that claSSically form a "spoke-wheel" pattern (Fig 5-10).

Degenerations Pinguecula and Pterygium A pinguecula is a small, yellowish nodule, often bilateral, situated at the nasal andlor temporal limbus (Fig 5-11 A). It is a manifestation of actin ic damage (exposure to sunlight) and is therefore more common with advancing years. Pingueculae are typicall y asymptomatic

and may generally be observed. On histology, the stromal collagen shows fragmentation and basophilic degeneration called elastotic degeneration because the degenerated collagen stai ns positivel y with histochemical stains for elastic fibers such as the Verhoeff-van Gieson (VVG) stain (Fig 5-11 B, C). See Chapter 6 for a discussion of actinic keratopathy, which may be regarded as the corneal analogue of pinguecula.

CHAPTER 5:

Conjuncti va. 57

A '--_ _ _"'"

Figure 5-10 Pyog en ic granuloma. A, Clinical appea rance, at a site of prior strabismus surgery. 8, Histology at low magnificat ion shows a pedunculated mass of granulation tissue, with a "spoke-wh eel" vascular pattern . C, High magnification shows a mixture of acute and chronic

inflammatory cells: note neutrophils

(N),

both within the lumen of blood vessels and also Infil-

trating the tissue; chronic inflammatory cells are also present, predominantly lymphocytes (LJ in this field. (Part A courtesy of Gregg T. Lueder. MD; parts Band C courtesy of George J. Harocopos, MD.)

A pterygium has similar etiology and location, but it differs from a pinguecula in that it exhibits prominent vasc ularity and also encroaches onto the cornea in a winglike fashion (Fig 5- 12A). Pterygia are excised when they threaten the visual axis, thereby becoming vis ually significant. or when they cause chronic irritation. Histology typically shows elastotic degeneration. as in a pinguecula. but also shows prominent blood vessels. correlating with the vasc ularity seen clinically (Fig 5- 12B. C). and variable degrees of chronic inflammation. So-called recurrent pterygia may com pletely lack the histologic feature of elastotic degeneration and are more accurately classified as an exuberant fibroconnective ti ssue response. In pingueculae and pterygia. the overlying epithelium may exhibit mild squamous metaplasia. for example. loss of goblet cells and surface keratini zation. Some studies have demonstrated that there is abnormal expression of Ki-67 (a proliferation marker) and of tumor suppressor genes such as p53 and p63. as well as loss of heterozygosity and microsatellite instability. Thus. as with actinic da mage to the skin. there is always the potential

58 • Ophtha lm ic Patho logy and Intraocular Tum o rs

-. A

Figure 5-11

Pinguecu la. A, Clinica l appearance adjacent to the nasal and temporal

limbus. B, On histology, note the acellular, slightly basophilic material in the substantia propria (asterisk) and thick curly fibers (arrows) indicative of ela stotic degeneration.

C, With VVG stain for e lastin, th e materia l stains black. (Parts A and C courtes y of George J. Harocapos, MD; part B courtesy of Hans E. Grossniklaus, MD.)

c for future maligna nt transformati on, although this occurs on ly rarely in association with pingueculae and pterygia. W hen conju nctival squamous neoplasia does arise, however, it often occurs overlying an area of preexisting elastotic degenerat ion. If fea tures such as epithelial hyperplasia, nuclear hyperch romasia and pleomorphism , and excessive m itotic figu res are ide ntified in an excised pi nguecula or pterygium, th en a d iag nosis of ocular surface squa mous neoplas ia should be aSS igned (see the secti on "Ocular surface squamous neoplasia" under Squamous Lesions) . See also sese Section 8, External Disease and Corn ea. Dong N, Li W, Lin H, et al. Abnormal epithelial d iffe rentiation and tear film alteration in pin guecula. blvest Ophtha/mol Vis Sci. 2009;50(6):2710-2715.

Amyloid Deposits Amyloid depos iti on in the conjunctiva is most common ly an id iopathic, pri mary loca li zed process seen in healthy you ng and mid dl e-aged adul ts. Less often, it occurs secondary to preexisting, long-standing inflammatio n, such as with trachoma (ie, secondary localized amyloidoSiS). Occasionally, conjunctival amyloidosis may occur secondary to a systemic

CHAPTER 5: Conj unctiva. 59

c Figure 5-12 Pterygium . A, Clinical appearance. B, Histologically, a focus of elastotic degeneration is present (arro w), as we ll as prominent blood vessels (arrowheads), with surgica lly induced hemorrhage. C, In this case, the conjunctival and corneal portions of the pterygium are evident. Note the promin ent blood vesse ls in the conjunctival port ion (arrow), and the destruction of the Bowman layer by ingrowth of fibroconnective ti ssue in the corneal portion (arrowheads). (Part A courtesy of Hans F Grossniklaus, MO,- parts Band C courtesy of George J. Harocopos, MD.)

disease such as multiple myeloma. Localized or systemic amyloidosis may also involve the orbit. Cli nically, conjunctival amyloidosis typically presents as a salmon-colored nodular elevation (Fig 5-13). The color m ay resemble the "salmon patch" appea rance of a lymphoid lesion (discussed later). Histologically, amylo id appears as eosinophilic, extracellular deposits within the stroma, sometimes demonstrating a perivascular distribution. On Congo red stain, under standa rd light, amyloid dep osits appear orange; but when viewed with polarized light and a rotating polarization filter, they exhibit birefringence with dichro ism . That is, they change from orange to apple green as the filter is rotated. Other useful staining methods include crystal violet and the fluorescen t stain thioflavin T. Electron microscopy shows characteristic fibrils (see Chapter 10, Fig 10-1 1). in localized amyloidosis, local clonal proliferations of plasma cells have been demonstrated, and it is thought that locally secreted monoclonal immunoglobulins are the prec ursors of biochemically identified immunoglobulin-derived amylOid proteins. See Chapter 6 of this volume for examples of primary and secondary localized amyloidosis of the cornea and BCSC Section 8, External Disease and Cornea. Kaplan B, Martin BM, Cohen HI , et al. Primary local orbital amyloidosis: biochemical identi fication of the immunoglobuli n light chain KIIf subtype in a small formalin fixed, paraffin wax embedded tissue sample. J Clin Pathol, 2005 ;58(5):539-542.

Epithelial Inclusion Cyst A conjunctival epithelial inclusion cyst may form at a site of prior accidental or surgical trauma (eg, after strabismus surgery, retinal surgery, or enucleation), Clinically, the lesion

60 • Ophthalmic Pathology and Intraocular Tumo rs

Figure 5·13 Conjunctival amyloidosis. A, Clinical appearance at the limbus and adjacent bulbar conjunctiva . B, On histology, note the diffuse ext racellu lar amorphous eosinophilic material

throughout the substantia propria. C, Congo red stain, under standard light, high lights the amyloid orange. 0, On Congo red stain under polarization , amyloid exhibits birefri ngence with dichroism (orang e and apple-green colors). (Parts A, C, and 0 courtesy of George J. Harocopos, MO; part B courtesy of Shu-Hong Chang, MD.}

appears as a transparent, cystic elevation on the ocular surface. There may be associated injection (Fig 5- 14). Histology shows a cystic space lined by conjunctival epithelium, located in the substantia propria. The lumen may be empty or may contain inspissated proteinaceous material and cellular debris.

A Figure 5-14 Epithelial inclusion cyst. A, Clinical appearance. 8 , The cyst is lined by nonkeratini zing, stratified squamous epithelium, characteristic of conjunctiva .

CHAPTER 5:

Conjunctiva. 61

Neoplasia Squamous lesions

Squamous papillomas The most common ocular surface neoplasms are those of the squamous family. Squamous papillomas may be divided clinically into pedunculated and sessile subtypes. Pedunculated papillomas are exophytic, pink-red, strawberry-like papillary growths (Fig 5-15A) that occur more commonly in children, in whom multiple lesions often exist. They are associated with human papillomavirus (HPV) subtypes 6 and 11. The histologic examination of a pedunculated papilloma demonstrates papillary fibrovascular fro nds covered by hyperplastic squamous epithelium (Fig 5-15B). Goblet cells may be present as in normal conjunctival epithelium. If there is overlying tear-film disruption resulting in exposure, the number of goblet cells may be reduced and the surface keratinized. Neutrophils may be seen within the epithelium, and a chronic inflammatory infiltrate may occupy the stroma, to varying degrees, which may be indicative of eye rubbing. Pedunculated papillomas exhibit benign behavior. They may spontaneously involute over months or years, and a small, nonirritating papilloma may be observed. Excisional biopsy may be performed for an irritating or cosmetically objectionable papilloma or if the diagnosis is in doubt. Sessile papillomas occur more commonly in adults, arising on the bulbar conjunctiva, especially adjacent to the limbus. They may be difficult to distinguish clinically from ocular surface squamous neoplasia (see the following discussion). In sessile papillomas, the distinction between truly "benign" and "premalignant" is often not clear-cut. Sessile papillomas are associated with HPV subtypes 16 and 18, the same subtypes associated

Squamous papi lloma. A, Clinica l appearance at th e caruncle. B, The epit helium is hyperpla stic, draped over f ibrovas cula r co re s. (Part A courtesy of Vahid Feiz, M O.)

Figure 5-15

62 • Ophthalm ic Pathology and Intraocular Tum ors

with squamous neoplasia. Worrisome clinical features suggestive of transformation into

neoplasia would include leukoplakia (white surface) and inflammation. Sessile papillomas may be observed closely if there are no suspicious features, but biopsy is often required for

histologic diagnosis. Histologically, a sessile papilloma exhibits a broad base (as opposed to the more narrow base seen in a pedunculated papilloma) and lacks the fingerlike projections seen in a pedunculated papilloma. The epithelium exhibits hyperplasia, but the individual cells should appear normal. If there are features such as nuclear hyperchromasia and pleomorphism, altered cell polarity, and abundant mitotic figures, then a diagnOSiS of ocular surface squamous neoplasia should be made.

Ocular surface squamous neoplasia Ocular surface squamous neoplasia (OSSN) typically arises adjacent to the limbus, over a preexisting pinguecula, that is, over an area of solar elastosis, similar to actinic kerato-

ses of the skin. Ultraviolet light (UV) exposure, especially in individ uals with light skin pigmentation, is a known risk facto r fo r OSSN, and the prevalence of OSSN is higher in equatorial regions of the world. UV-associ ated mutations in tumor suppressor genes such as p53 have been demonstrated in OSSN, and hereditary deficiency of DNA repair such as in xeroderma pigmentosum increases the risk of OSSN formation. OSSN is also associ-

ated with HPV infection, subtypes 16 and 18, as well as with human immunodeficiency virus (HIV) infection. HIV-associated OSSN is especially common in sub-Saharan Africa, and HIV should be suspected in any patient with OSSN youngerthan 50 years. Non-HI Vrelated immunosuppression is also a risk factor fo r OSSN. Other risk factors include older age and smoking. The clinical appearance of OSSN is characterized by epithelial thickening, and the lesion may extend onto the peripheral cornea. There may be a prominent "corkscrew" vascular pattern, or the surface may appear gelatinous or leukoplakic, indicative of surface

keratinization (Fig 5-16). Surface keratinization is not pathognomonic for OSSN and may be seen over any elevated lesion not covered adequately by the tear film; however, it is very commonly seen in OSSN and must the refore arouse suspicion. The adjacent conjunctiva

may appear injected, with prominent "feeder" vessels leading to the lesion. Histologically, the epithelium exhibits hyperplasia, loss of goblet cells, loss of normal cell polarity, nuclear hyperchromasia and pleomorphism, and mitotic figures . There is often surface keratinization, correlating with the leukoplakia observed clinically. Dyskeratosis (non-surface cells producing keratin) may also be seen. A chronic inflammatory response is often present in the substantia propria.

The most important assessme nt to be made histologically in OSSN is whether the neoplasia is contained by the basem*nt membrane (ie, intraepithelial or in situ) or whether neoplastiC cells have traversed the epithelial basem*nt membrane and invaded the stroma. For lesions contained by the basem*nt membrane, the term conjunctival in traepithelial neoplasia (eIN) may be used. The neoplaSia may be graded as mild, moder-

ate, or severe, according to the degree of cellular atypia (although this grading does not necessarily have clinical utility in terms of prognosis). In cases with the most severe atypia, full -thickness involvement of the epithelium is seen, often with squamous eddies or keratin whorls/pearls. For these more advanced lesions, the term squamous carcinoma in situ

CHAPTER 5:

Conjuncti va.

E Figur. 5-16 Ocular surface squamous neoplasia (aSSN). A, Clinical appearance: note the "corkscrew" vascular pattern of the conjunctival portion and leukoplakia of the corneal portion. Also note feeder vessels. B, Note the sharp demarcation (arrow) between normal and abnormal epithelium in aSSN. The epithelium is hyperplastic, with surface keratinization (K) With the basem*nt membrane intact, a diagnosis of conjunctival intraepithelial neoplasia (CIN) is made. There is a chronic inflammatory response in the substantia propria (CI). Also note areas of elastotic degeneration in the substantia propria (arrowheads), indicati ng t hat the lesion arose over a pinguecula . C, Hig h magnification (different patient) shows transiti on zone where neoplasia begins (arrow). To t he right of the arrow, the epithelium exhibits mild ke ratinization, hyperplasia, nuclear hyperchromasia, loss of goblet celis, altered ce llular polarity, significant pleomorphism, full-thickness involvement, and mitotic figures (M). The basem*nt membrane is intact (arrowheads), with an underlying chronic inflammatory response. 0, In invasive squamous carcinoma, tongues of epithelium violate the basem*nt membrane and invade the stroma (arrows), with squamous eddies (arrowheads). E, Gross photograph of squamous carcinoma invading the limbus and anterior chamber angle through a previous surgical incision (arrow). (Part A courtesy of Vahid Feiz, M D; parts 8-E courtesy of George J Harocopos, MD.)

64 • Ophthal mic Pathology and Intraocula r Tumors may be used. If, however, the neoplastic cells have invaded the stroma, th en the diagnosis is invasive squamous cell carcinoma (Fig 5-17; see Fig 5-16). Clinically, the term eIN has fallen out of favor in preference to the more general term aSSN, because it is not possible to determine on cl inical examination wheth er stromal invasion has occurred. eIN should be regarded as a histologic term, reserved for noninvasive lesions. Invasion through the sclera or cornea and intraocular spread are uncomm on complications of invasive squamOllS carcinoma. When there is intraocular spread, it often occurs at the site of a previous surgical procedure, such as cataract surgery. However, intraocular invasion may also occur through previously nonviolated sclera, especially in immunosuppression -related cases and cases occurring in ozone-depleted areas, as these cases tend to be more aggres-

sive. Although regional lymph node metastasis is not as common as it is with squamous carcinomas of th e skin or other sites, dissemination and death can occu r. Mucoepidermoid carcinoma and spindle cell carcinoma are fare variants of squamous cell carcinoma. Both entities are more aggressive neoplasms with higher rates of recurrence and intraocular spread. Treatment options for suspected squamous neoplasms of the ocular surface include

excisional biopsy with 3-4 mm margins and cryotherapy to the edges of excision; or topical chemotherapy with interferon (IFN) alfa -2b, 5-f1uorouracil (5 -FU), or mitomycin e (MMC). For specimen submission, the lesion should be placed flat on filter paper and allowed to dry for 30- 60 seconds (so that its flat orientation is retained on the paper and the lesion is not folded over onto itself), and then the paper with specimen is gently placed in a formalin jar. It is ideal for the surgeon to mark 2 adjacent margins with different-colored sutures and to include a diagram depicting this orientation on the pathology requisition form. The status of the lateral and deep margins is important for prognosis. See the appendix for the American loint Committee on Cancer (A ICC) definitions and staging of squamous carcinoma of the conjunctiva. See also BCSC Section 8, External

Disease al1d Cornea. Sudesh 5, Rapuano CJ, Cohen EJ, Eagle RC Jr, Laibson PRo Surgical management of ocular sur ~ face squamous neoplasms: the experience from a cornea center. Cornea. 2000; 19(3):278-283.

Invasive carcinoma

Figure 5-17 Schematic representation of the progression of OSSN. The fi rst panel represents normal epithelium with basem*nt membrane (pink line). In conjunctival in traepithelial neopla-

sia (CIN), a portion of the epithelium is replaced with dysp lastic cells. Carcinoma in situ is the complete repl acement of epithelium by dysplastic celis, with the basem ent membrane still intact. In invasive squamous cell carcinoma, note the invasion through the basem*nt membrane into the strom a. (Courresy of Parricia Chevez-Barrios. MD.)

CHAPTER 5:

Table 5-1

Conjuncti va .

Clinical Comparison of Ocular Surfa ce Melanocytic Lesions

l esion

Onset

Size/Panern

Location

Ma lignant Potential

Conjunctiva l nevus

Youth

Sma ll, usually unilateral

Conjun ctiva

Ocular and oculode rma l melanocytosis Ben ign acquired melanosis

Congenital

Patchy or diffuse; us ually unilateral Patch y or diffuse; bilateral

Un der conjunctiva (episclera/sclera)

Yes, but low (conjunctival melanoma ) Yes (uveal me lanoma )

Conj unctiva

None to minimal

Diffuse; usual ly unilatera l

Co njunctiva; m ain ly bulbar

Yes (conjunctival melanoma )

(BA M) Primary acquired melanosis (PAM)

Young adulthood Middle age

Melanocytic lesions Table 5-1 summarizes key clinical features of ocular surface melanocytic lesions.

Melanocytic nevi As with hemangiomas) melanocytic nevi are classified by some authors as hamartomas and by others as neoplasms, with this distinction resting upon whether the lesion is congenital or acquired. Conjunctival melanocytic nevi usually appear on the bulbar conjunctiva in ch ildhood. Analogous to cutaneous melanocytic nevi, conjunctival nevi undergo evolutionary changes. In the initial junctional phase, nevus cells are arranged in nests (theques) at the interface (junction) between the epithelium and the substantia propria. As the nevus evolves, the nests descend into the substantia propria and may lose connection with the epithelium. Nevi residing exclusively at the epithelial-stromal junction are called junctional nevi, whereas nevi exclusively in the substantia propria are termed subepithelial or stromal nevi; nevi with both junctional and subepithelial components are deSignated compound nevi. Epithelial inclusion cysts are often encountered within compound nevi. The presence of these cysts, in conjunction with melanocytes exhibiting a nested pattern , is a histologiC feature of a benign lesion (Fig 5-18). Nevi also occur fairly commonly in the caruncle. Nevi in the caruncle and on the bulbar conjunctiva may be nonpigmented (amelano tic), in which case they have a pinkish appearance and the diagnosis may be more challenging clinically. The pigmentation of a nevus may increase duri ng puberty, at which point the lesion may be first noticed by the patient or parents. Nevi occur only rarely in the palpebral conjunctiva; pigmented lesions in this area are more likely to represent intraepithelial melanosis or melanoma. Nevi can be further categorized, for example, into Spitz nevus, halo nevus, and blue nevus. A blue nevus is a dark blue-gray to blue-black nevus in which the melanocytes are located in the deep stroma and have spindly morphology, similar to that of nevus cells seen in the uveal tract. Ocular, dermal, and oculodermal melanocytosis are forms of blue nevi typically seen unilaterally in darkly pigmented (eg, African, Hispanic, Asian) individuals. In ocular me/anocytosis, the nevus is located in the deep episclera and sclera, resulting in a slate-gray appearance to the ocular surface (Fig 5-19), and also in the uveal tract, often resu lting in iris heterochromia; the conjunctiva (epithelium and substantia propria)

66 • Ophthalm ic Pathology and Intraocular Tum o rs

B Figure 5-18 Conjunctival melanocytic nevus . A, Cl inica l appearance, wit h characteristic cyst ic area s (arrows). 8, On histology, th e melanocytes are rou nd, oval, or pear-shap ed celi s, mostly arrang ed in nests (arrowheads). M elanocyt es are prese nt at t he epit helial-stromal junct ion (arrow); hence, thi s is a compound nevus. Note the epithelial inclusion cysts (as terisks) withi n th e lesi on, correlating w ith th e clinica l appea rance. (Part B courtesy of George J. Harocopos, MD.}

A Figure 5-19

B Ocu lar melanocytosis. A, Clinical appea rance . B. Histology shows an abnormally

increased population of me lanocytes In the deep episclera

(E),

sclera

(5 ),

and uveal tra ct

(U).

(Part A courtesy of Gabriela M Espinoza, MD, parr 8 courtes y of George J. Harocopos, MD.)

is uninvolved. In dermal melanocytosis, the nevus is located in the periocular skin. Dermal melanocytosis may also occur in conjunction with orbital melanocytosis, that is, dermal orbital melanocy tosis. Oculodermal melanocy tos is, also known as nevus of Ota, combines the features of ocular and dermal melanocytosis. Although these conditions are rare in lightly pigmented individuals, it is these individuals who are at risk for malignant transfo rmation. When transformation into melanoma occurs, it is generally seen in the uvea] tract; cutaneous, conjunctival, orbital, and meningeal melanomas are rare. Recent studies have shown that nevi of Ota ma nifest the same mutation in the G protein a -subunit gene (GNAQ) as primary ciliochoroidal and central nervous system melanomas. Patients with ocular and oculodermal melanocytosis (regardl ess of race) are also at increased risk fo r secondary glaucoma.

CHAPTER 5:

Conju nctiva.

Intra epithelial melanosis lntraepithel ial melanosis of the conjunctiva may be divided into 2 categories: benign acquired melanosis (BAM) and primary acquired melanosis (PAM). BAM appears as bilateral, flat patches of brown pigmentation with irregular margins, in individuals with dark skin pigmentation (Fig 5-20). BAM typically involves the bulbar conjunctiva and limbus. Streaks and whorls of melanotic pigmentation may extend onto the peripheral cornea, called striate melanokeratosis. The caruncle and palpebral conjunctiva may also be involved. The term BAM is appropriate for these lesions because they are almost always benign, with an exceedi ngly low rate of malignant transformation . Histologically, BAM consists of a lentiginous proliferation of benign-appearing melanocytes along the basal epithelial layer. In contrast, PAM is most often unilateral, generally occurring in individuals with lighter skin. The clinical appearance is otherwise simila r to that of BAM (Fig 5-21). PAM most commonly presents in middle-aged adults. It may occasionally be amelanotic. The lesion l11ay remain stable or grow slowly over a period of 10 or more years. It may be difficult to predict clinically in any given patient whether PAM is likely to progress to melanoma, and thus the recommendations regarding when to observe ve rsus perform biopsy are controversial. Retrospective data suggest that the number of clock-hours of conjunctiva involved may help predict the risk of malignant transformation: lesions less than 1 clock-hour in extent have a low chance of progressing to malignancy, whereas lesions involving 3 clock-hours or more have a greater tha n 20% chance of malignant transformation. Lesions less than 1 clock-hour may therefo re be observed, and biopsy should be considered for lesions at least 3 clock-hours in size. In addition, involvement of the caruncle, fo rn ix, or palpebral conj unctiva may prompt biopsy, because malig nant transformation in these regions of the conjunctiva would be associated with a worse prognosis (discussed later). The technique for excisional biopsy and specimen submission of PAM is similar to that described earlier for squamous lesions. MMC may also be considered as primary therapy in extensive cases; howeve r, the efficacy of th is treatment remains to be proven in a large clinical series.

A Figure 5-20

Benign acquired me lanosis. A , Clinical appearance . S, Histol ogy shows a proliferation of melanocytes confi ned to t he basal layer of th e epithe lium (arrows). The melanocytes are smal l, with no ce llular atypia. (Courtes y of GeorgeJ. Harocopos. MO)

68 • Ophthalmic Pathology and Int ra ocula r Tu mors

"'""'_-=- _ --",""'"'--__....

Figure 5-21 Primary acquired melanosis (PAM). A, Clinical appearance of mild PAM , involving only about 1 clock-hour of conjunctiva adjacent to the limbus. Th is lesion is unlikely to harbor atypia and may be observed. S, Histology of PAM without atypia. The melanocytic proliferation is confined to the basal layer of the epithelium (arrows), and there is no cellular atypia. C, Clinical appearance of extensive PAM, involving much of the ocular surface, including the caruncle, as well as palpebral conjunctiva and eyelid margin nasally. This lesion likely harbors atypia and w arran ts biopsy. D, Histology of PAM with mild to moderate atypia. Most of the melanocytic proliferation is located in the basa l epithelial layer (arrowheads), and the melanocytes are small, w ithout prominent nucleoli. However, some melanocytes are seen in the more superfici al epithelium (arrows); also note the white spaces around many of the melanocytes, indicating discohesiveness. The patient is at low to moderate risk for transformation to melanoma. E, Histology of PAM with severe atypia. The melanocytic proliferation (arrows) involves most of the epithelial thickness. (In this case, the lesion is minimally pigmented.) F, Higher magnification of PAM with severe atypia (different patient!. showing epithelioid melanocytes (arrows) wit hin the epithelium. These latter two patients are at significant risk for progression to melanoma. (Parts A, D, and E courtesy of George J. Harocopos, MD; parr Ccourtesy of Vahid Feiz. MD.)

CHAPTER 5:

Conjunctiva. 69

Histologic criteri a have been developed to identify patients at high risk for malignancy. PA lvl lVithout atypia, essentially histologically identical to BAM , denotes a len tiginous prol iferation of melanocytes without at)'Pical features, confined to the basal epithelial layer. PAM without atypia does not progress to melanoma. In PAM lVith atypia, mela nocytes mig rate into the more superficial epitheliu m (pagetoid spread) and exhi bit discohesiveness; a portion of th e cells often exhi bit epithelio id mo rph ology, with large hyperchromatic nuclei and prominent nucleoli. Mito ti c figu res may be present. A chronic

inflammator y response may be present in the substantia propria. As with squamous lesions, the atypia may be graded as n1ild, moderate, or severe, and full -thickness replacement of th e epithelium may be termed melanoma in situ. In PAM with mild atypia, only a few melan ocytes will be seen extending into the more superficial epithelium; there is mi nimal. if any. risk of malignant transformati on. With moderate or greater atypia. the risk of mal ignant tra nsformation correlates "I/ith the degree of atypia. PAM with atypia is similar histol ogicall y to lentigo maligna of the ski n. The current dermatologic literature, however, has largely discarded the term le1ltigo 1nalig1la in favor of the term melanoma ;11 situ, whe reas for conjunctiva, many ophthalmic path ologists prefer to reserve the term melanoma in situ fo r only the most severe lesions with full-thickness epithelial involvement. ote that lent igo maligna of the eyelid skin is somet imes seen in continuity with PAM of th e pal peb ral conju nctiva.

Melanoma App rox imately 50%-70% of cases of conjunctival me/anol'lla arise fro m PAM with atypia (Fig 5-22); th e remainder develop either from a nevus (a few percent ) or de novo. Mela-

nomas are usually nodular growths with vascu larity that may in volve any portion of the conjun cti va. The nodule may be pigmented but may be amelanotic. even if arising from pigmented PAM. Histo logically, the cellula r mo rphology in mela nomas may range from spind le to epitheliOid. similar to that in melanomas of the lIveal tract. In more aggressive lesions. mitotic figures may be identified. Im munohistochemical stains for melanocytes such as Melan-A red, MART- I , and H MB-45 may help to identify problematic cases as melanocytic. Conjunctival melanomas are more akin to cutaneous melanomas than to uveal melanomas in behavior; that is, metastasis generally occurs by lymphatic spread rather tha n hematoge no usly. Typically, metastases first develop in preauricular, subman dibular. or cervical lymph nodes. and the tumor may metastasize to the lungs. liver. brai n, bone, and skin . Unfavo rable clinical and histo logic prognostic factors in conjunctival melanoma include nonepibulbar location, that is, caruncular, fo rnicea l, or palpebral or in volvement of the eyelid skin or orbit greater tumor thickness scleral invasion positive lateral margin of excision The treat ment of conjunctival melano ma is surgical (see BeSe Section 8, External Disease ami Cornea, Chapter 8) . The overall mortality rate from conjuncti val melanoma ranges from approximately 15% to 30% in published studies (somewhat lower than the overall mortality rate from cutaneous melanoma).

70 • Ophthalmic Pathology and Intraocular Tum ors

PAM

-_ B

...._,

c Figure 5·22

Melanoma arisin g f ro m PAM . A, Clinica l appearan ce. Note the elevated melanoma nodule adjacent to th e lim bus ari sing from a background of PAM (diff use, flat, brown pigmentat ion). Also note promin ent vascu larity. B, On histology, melanom a (M ) is seen arisi ng from PAM , w ith arrowhead indicati ng the t rack of invas ion. C, M el an-A red immunostain highlights melanocytes, confirm ing the diagnosis of melan oma arisi ng from PAM . (Part A courtesy of Morton E. Smith, MO; parts B and C courtesy of George J. Harocopos, M O.)

Occasionally, melanoma of the uveal tract that has eroded through the anterior sclera will present initially as an episcleral/conjunctival mass. This possibility should be consid ered espeCially for a pigmented or amelanotic episcleral nodule overlying the Ciliary body (ie, intercalary location), with no surrounding PAM (Fig 5-23 ). A complete dilated funduscopic examination should always be performed in any patient with a conjunctival mass. In rare instances, conjunctival mela noma may represent a metastasis from cutaneous melanoma or from another site. In these cases, there is generally a kn own history of prior primary melanoma elsewhere, and it can be seen histologically that the melanoma is not arising from PAM . See the appendix for the A)CC definitions and staging of conjunctival melanoma. See also BCSC Section 8, External Disease and Cornea. Shields JA, Shields CL, Mashayekhi A, et al. Primary acquired melanosis of the conjunctiva: risks for progression to melanoma in 311 eyes. The 2006 Lorenz E. Zimmerman lecture. Ophthalmology. 2008; 11 5( 3);511 - 519.

CHAPTER 5:

Conjunctiva .

Figure 5·23 Melanoma of the cil iary body with extra scleral extension , presenting as an ocular surface mass. Note that there is no PAM surrounding the nodu le, a clue that the lesion might have an intraocular origin. Also note that the lesion does not obscure the overlying conjunctival vessels. This indicates that the lesion is deep to the conjunctiva. (Courtesy of J. William Harbour, M D.)

Lymphocytic Lesions The normal conjunctiva is an example of m ucosa-associated lymphoid tissue (MALT), and a few small foll icles are often visible clinically in the normal inferior fo rn ix. As described previously, the normal lymphoid foll icle consists of a germi nal center and surrounding corona (see Fig 5-5). The corona is further subdivided into marginal and mantle zones, although these are not well delineated histologically without the use of special stains. Occasionally in asymptomatic patients (generally children or adolescents), nUinerous, prom inent follicles may be incidentally found in the inferior fornix bilaterally, a condition called benign lymphoid folliculos is. Ly mphoid follicles of the palpebral/forniceal conjunctiva may also become more prominent and increase in number when associated with conjunctival inflammation, that is, foll icu lar conjunctivitis (discussed earlier). Lymphoid tissue may proliferate in the conjunctiva abnormally, often in the absence of inflammation, and this lymphoid hyperplasia may be benign or malignant. Clinically, both benign and malignant lymphoprolifera tive lesions of the conju nctiva have a salmonpink appearance with a smooth surface an d are usually soft (Fig 5-24A, B). Both ben ign and malignant lesions may be unilateral or bil ateral. Lymphocytic lesions are often seen in the inferior fornix but may also be seen on th e bulbar, tarsal, or caru ncular conjunctiva. A lymphocytic lesion involving the for niceal conjunctiva or caruncle may also have an orbital component. As benign and malignant lymphocytic lesions of the conjunctiva may appear similar clinically, incisional biopsy is generally required to make a precise diagnosis. For biopsy of suspected lymphoid les io ns of the conjunctiva, 4-5 mm of tissue is generally sufficient, and the biopsy m ay usuall y be performed in the office with topical or subconjunctival anesthetic. The specimen should be submitted in formalin for rout ine H&E sections and immunohistochemistr y. If possible, an additional 4-5 mm of tissue may be harvested and subm itted in saline or special flow cytometry medium, on ice.

72 • Ophtha lmic Path ology and Intraoc ular Tumors

Figure 5-24 Lymphocytic lesion s of the conjunctiva. A, Clinical appearance ("salmon patch ") in the inferior forn ix. B, Clinical appea rance on the bulbar co njunctiva. C, Histology of benign lym phoid hyperplasia, showin g normal follicu lar architect ure, w it h we ll-defined germinal cen-

ter (G) and corona (0 D, Histology of lymp homa, s howing a s heet of lymp hocytes infi ltrat ing the substantia propria, w ithout w ell-define d follicles .

(Part A courtesy of Anthony J Lubniewski, MD; part B courtesy of Anjali K. Pathak, MD; parts C and 0 courtesy of George J. Harocopos, MD.)

Histologic features favoring a di ag nosis of benign lymphoid hyperplasia on routine H&E sectio ns include the presence of normal-appeari ng lymphoid follicles with distin ct germinal centers an d with small, mature coronal lymphocytes (Fig 5-24C) . In contrast, ly mphom a often demo nstrates a solid sheet of lymphocytes in the substantia propri a, without well-defi ned follicles (Fig 5-24D). However, mos t conju nctival lymphomas are low grade, and these low-grade malignant lesions are sometimes difficult to differentiate frmn benign lesio ns o n H&E sections. Im mu nohistochemistry, flow cytometry, and other techniques are useful diagnostically, as discussed later. Also, it shou ld be noted th at so me patients with "benign" lymphOid hyperp lasia eventuall y develop lymphoma.

Lymphoma T he most common fo rm of lymphoma of the conjunctiva (and also of the orbit), seen in over half of cases, is extra nodal marginal zone ly mphoma (for merl y known as MALToma ), so named because the pathogenesis involves expansion of the follicle's marginal zone. EXt/'anodal refers to the site of the tumor being somewhere o ther than a lymph node. Co njunctival marginal zo ne lymphoma may be unilateral or bilateral and often presents in the fo rn iceal conjunctiva but may present on the bulbar conjunctiva. This is a fo rm oflow-grade B-cell lymphoma, and histology shows small lym phocytes (Fig 5-25).

CHAPTER 5:

Conjunctiva.

c Figure 5·25 Histology of m arginal zo ne lymp homa A, High er magnification of the sam e ca se shown in Fig 5-24D, showing smali lymphocytes . B, CD2 0 Immunostain (brown) for B celi s, staining po sitive in th e vast majority of the lymphocytes. C, In sit u hybridi zation (I SH) for)c li ght chain, exhibiting promin ent positivity (blue cells), confi rming A c10nality and establishin g th e diagn osis of marginal zone lymph oma . (Courtesy of George J. Harocopos. MO l

Immunohistochemistry for B-cell and T-cell markers demonstrates a preponderance of B cells, although a variable proportion of normal T cells will be present. Tissue in situ hybridization (ISH) for immunoglobulin light chains often demonstrates B-cell monoclonality by revealing either K or A light-chain predominance. However, ISH is not as sensitive as flow cytometry for detecting K or ), clonality, and thus flow cytometry is especially useful in cases that fail to show clonality by ISH. Another technique to detect clonality, which can be performed on fresh or formalin -fixed tissue, is IgH (immunoglobulin heavy chain) gene rearrangement testing by peR In addition, fluorescence in situ hybridization (FISH) may be performed on fresh or formalin-fixed tissue to test for specific genetic translocations. The t(3;14) translocatio n, involving the FOXPI gene, and other translocahons have been described in marginal zo ne lymphoma; and various translocations have been found in other forms of conjunctival lymphoma. Interestingly, the same translocation may be associated with more than one type oflymphoma. Other forms of conjunctival lymphoma include follicular lymphoma (arising from the germinal center) and, less commonly, mantle cell lymphoma (which arises from the mantle zone). Also less common in the conjunctiva are diffuse large B-celllymphoma, Burkitt lymphoma, Hodgkin lymphoma, and plasmacytoma. T-cell lymphomas are rare. High-grade lymphomas such as diffuse large B-cell lymphoma are readily recognized as

74 • Op ht ha lmi c Path o logy a nd In t raoc ul ar Tumors malignant by virtue of t heir nuclear featu res ("coarse clu mp ing" chromatin pattern, th at is, multi ple nu cleoli) an d high m itotic rate. Large B-ceil lympho ma is relatively rare in the conjunctiva and is more commonly seen in the central nervous system and vit reous (see C hapters 10 and 20 of this vo lu me) . App rox imately two-thi rd s of conjun cti va l lymph omas are locali zed to the co njunctiva and not associated with systemic disease. In contrast, nearl y two-th irds of lympho mas arising in the preseptal skin eventually show evidence of systemic involvement. However. the li kelihood of systemic involvement vari es accord ing to the type of lymph oma; that is, margina l zo ne lymph oma presenting on the conjunct iva has been estimated in some stud ies to be locali zed in up to 90% of cases, whereas mantle cell lymphoma often has system ic involvement. The vast majority of cases of conjunctival marginal zone lymphoma present initially to the ophthalmologist, with no known systemic d isease; th e frequency of known p reexisting syste mic disease is greater with higher-grade lymphomas. Any patient prese nting with conj u nctival lymp homa must be referred to an oncologist for a systemic wo rkup. Th e treatment of conj u nctival lymp homa dep en ds on the prese nce or absence of systelnic involvement. When disease is localized to the conjunctiva, the mainstay of treatment is orbital rad iat ion; in cases with systemic involvement, the treatment is chemotherapy. See Chapter 8 in BCSC Secti on 8, External Disease and Cornea, and Section 7, Orbit, Eyelids, ari d Lacrimal System, fo r additional discussion. Inte rest ingly, some case series have provided evidence of an infectious trigge r (Chlamydia psittaci) fo r conj un ctival lym phoma, fo r example, by demonstrating chl amyd ial DNA in a high proportion of cases of marginal zone lymphoma. Less common m icrobial associations with conjunctivallorbital lym phoma include Chlamydia pneumoniae, Chlamydia trachomatis, an d Helicobacter pylori, th e latter being more co mm only associate d with gast ri c lymphoma. Acco rdingly, cases of regression have been reported with o ral doxycycline treatment. Viruses such as hepatitis C an d Epstein-Barr have also been implicated in Iymphoproli fe rat ive disorde rs. T he overall prognosis in conjun ctiva l lymphoma is good, give n that most cases are low-g rade neoplasm s. Howeve r, t he prognosis in any given case depends on th e subtype of lymph oma, because this has bearing o n th e li kelihood of systemic di sease. In the abse nce of system ic involvement, the rem ission rate at 10 years is 75%- 100% for patien ts treated with radiat ion therapy; with systemic involve ment, disease-free survival at 5 years is only 20%. Lymphoma- related death is sig ni fica ntly associated with advanced clinical stage and age older tha n 60 years. The extent of p53 positivi ty (tu mor supp ressor gene) and M 18- 1 positivity (cell proli feration marker) has also been show n to affect prog nosis, although these stains are not routin ely obtained in all cases. The average tim e frame for relapse of margi nal zone lymphoma is more than 5 years after in it ial remissio n. Thus, these pat ients requ ire long-term (over 5 years) follow-up. See the ap pendix fo r th e AjCC staging. Shields CL, Shields JA, Carvalho C. Rundle p, Sm ith AF. Conjunctival lymphoid tumors: cli nical analysis of 117 cases and relalio nship to systemic lymphoma. Ophthalmology. 2001; 108(5}:979-984.

Swerdlow SH, Campo E. Harris NL, et al. WHO Classifica tion of Tumours of Haematopoietic alld Lymphoid Tissues. 4th ed. Lyon, Fran ce: IARC; 2008.

CHAPTER 5:

Conjunctiva. 75

Glandular lesions Oncocytoma is a benign proliferation of apocrine or accessory lacrimal gland epithelium, that is, an adenoma. It typically ar ises in the caruncle, although it may occasionally be seen elsewhere on the conjunctiva. Oncocytoma most commonly occurs in elderly women. Clinically, it appears as a tan to reddish, vascularized nodule (Fig 5-26). When this lesion is seen clinically, the differential diagnosis typically includes squamous, melanocytic, and lymphocytic lesions, as well as amyloid. Histologically, the lesion is composed of proliferating epithelial cells, similar in appearance to apocrine (gland of Moll) epithelium, around glandlike spaces. Because of the cystic appearance of these spaces, the term apocrine cystadenoma is also used to describe th is lesion. The epithelial cells exhibit distinctive eosinophilic cytoplasm; hence, this lesion is also referred to as oxyphilic (eosinophilic) cystadenoma. Malignant apocrine neoplas ms may also occur but are very rare.

Othe r Neop lasms Virtually any neoplasm that can occur in the orbit may occaSionally arise in the conjunctiva, including neural, muscular, vascular, and fib rous tumors. Metastatic lesions to the conjunctiva are rare but may occur. See Chapter 14 of this volume. See also BCSC Section 8, External Disease and Cornea, and Section 7, Orbit, Eyelids, and Lacrimal System.

B Fi gure 5·26 Oncocyt oma, A , Clinica l appea rance at the caruncle. B, Histol ogy shows p ro~ Illeration 01 glandular epithelial ce lis, with deeply eOSinophilic cytop lasm . Som e 01 the cel ls surround protein-filled lumina (arrows). (Part A courtesy of Mark J Mannis, MD,· parT B courtesy of George J Ha rocopos, MD.)

CHAPTER

Cornea

Topography The normal cornea is composed of Slayers: epitheli um, Bowman layer, stroma, Descemet

membrane, and endothelium (Fig 6-1). See BeSe Section 2, Fundamentals and Prin ciples of Ophthalmology, and Section 8, External Disease and Cornea, for a discussion of the embryoogy, structure, and physiology of the corn ea. The corneal epithelium is nonkerati nized, stratified squam ous, ranging between 5 and 7 cell layers in thickness. The epitheli al basem*n t membrane is th in and is best seen with periodic acid-Schiff (PAS) stain . The base ment membrane is more easily visualized when it becomes pathologically thickened, such as in anterior basem*nt dystrophy (ie, map-dotfingerprint dystrophy) or secondary to endothelial decompensation. The Bo wman layer is located immediately beneath the epithelial basem*nt membrane. It is also known as the Bowman "membrane;' but this term may be misleading because this layer is not a true basem*nt mem brane; that is, it is not elaborated by the epithelial cells. Rather, it is more properly regarded as the most anterior layer of the stroma. The Bowman layer is acellular and is composed of irregularly arranged collagen fibrils. It is not restored after injury but is replaced by fibroconnective scar ti ssue. The corneal stroma makes up 90% of the total corneal thickness. It consists of collagenproducing keratocytes, collagenous lamellae, and proteoglycan ground substance. The elongated collagenous lamellae are regula rl y arranged in a precise orientation to yield transparency, allowing for the orderly passage of light through the cornea. The next layer, the Descemet membrane, is the basem*nt membrane elaborated by the corneal endothelium. The production of Descemet membrane begins during fetal development and continues throughout adulthood. The thickness of this membrane may increase further in endothelial disease states. The Descemet membrane (like the epithelial basem*nt membrane) is a true basem*nt me mbrane, composed primarily of type IV col-

lagen, and is strongly PAS-positive. The corneal endothelium is composed of a single layer of cells. The cells appear mostly hexagonal en face, such as on confoca l microscopy. In a histologic cross-section of the cornea, the endothelial cells have a cuboidal appearance. The primary function of the endothelium is to maintain corneal clar ity by pumping water from the corneal stroma.

The number of endothelial cells graduall y dec reases with age, and endothelial cell loss is accelerated in endothelial disease states. Human endothelial cells cannot regenerate; so as

78 • Ophthalmic Pathology and Intraocular Tumors

c Figure 6-1 Normal cornea. A, The cornea is composed of epi the liu m (Ep), t he Bowman layer (BJ, stroma (SJ, the Descemet membrane (OJ, and endothelium (En). B, On higher magnification, PAS stain hig hlights the epithe lial basem*nt membrane (EBM), disting uish ing it from the Bowman layer (B). Because of dehydration of the ti ssue during processing for pa ra ffin embedding, mu lti ple areas of separation (clefts) of the stroma l lame llae are evident (arrows). If the stroma l clefts are absen t, cornea l edema or fi brosis is suspected (the former if the cornea is thick, and the latter if thin). Th is is an example of a mean ingf ul artifact. C, Higher magn ifica ti on (H& E sta in) also delineates Descemet membrane (O) and endothe lium (En). Th e ke ratocyte nucle i (arrow) are apparent. (Note that PAS stain also highlig hts Descemet membrane .) (Courtesy of George J. Harocopos, MO.)

the endothelial cell number declines, the remaining cells flatten and elongate to provide coverage of the posterior corneal surface.

Introduction to Corneal Pathology Corn eal speci mens are among the most common specimens seen by the ophthalmic pathologist. In the pathology laboratory, specimens submitted from penetrating keratoplasty are referred to as corneal "buttons:' The most common indications for keratoplasty are listed in Table 6-1 and are discussed later in this chapter. In recent years, alternatives to penetrating surgery have become more widely utilized for certain corneal conditions in which only some of the corneal layers are diseased. For example, if the anterior cornea is diseased but the endothelium is healthy, then deep anterior lamellar keratoplasty (DALK) may be an option. On the other hand, if only the endothelium is diseased, then

CHAPTER 6:

Corn ea .

Table 6-' Most Common Indications for Ke ratoplasty Fuchs endothelia l dystrophy Pseudophakic/aphakic bul lous keratopath y Keratoconus Visually significant corneal opac ity (eg, fol lowi ng infect io us kerat itis, especially herpetic) Failure of an existing corneal gra ft

endokeratoplasty may be an option (eg, Descemet stripp ing endothelial keratoplasty [DSEK], in which only Descemet membrane and endothelium are removed) . Exam ples of specimens from these procedures are shown in their correspondi ng sections.

Congen ital Anomalies Congenital Hereditary Endothelial Dystrophy There are 2 forms of congenital hereditary endothelial dystrophy (CHED), with both forms causing bilate ral corneal edema. The autosomal recessive form, the more common of these, is apparent at birth , accompanied by nystagmus, but non progressive. The autosomal dom inant form is apparent within the fi rst few years of life, not accompanied by nystagmus, but progressive (Fig 6-2A) . The genetic loci fo r the autosomal dominant and recessive forms ofCHED have been mapped to 20 p I1.2-q l1.2 and 20p13, respectively. Despite their clinical differences, the 2 forms of CH ED appear similar histologically. The corneal stroma is diffus ely edematous, accounti ng fo r the marked increase in thickness observed clinically. The Descemet memb rane appears thickened, wi thout guttae (Fig 6-2B). En dothel ial cell loss may be diffuse or focal. T he histologic findi ngs overall are very similar

Figure 6-2 Congenital hereditary e ndothe lial dystrophy. A, Clinical appearance with bilateral corneal Clouding. S, Note diffuse edema, with bullous keratopathy (arrow). The Descemet membrane is diff usely thicken ed, without guttae, and endothelial cells are absent. Hans E. Grossniklaus, MD.)

(Courresyof

80 • Ophthalmic Pathology and Intraocu la r Tu mors to those seen in pseudophakic/aphakic bullous keratopathy. T he primary abnormality in CHED is thought to be a degeneration of endothelial cells during or after the fifth month of ges tation. No systemic abnormalities are consistently associated with CHED. See also SCSC Section 8, Extern al Disease and Cornea. Klintworth GK. The molecular genetics of the corneal dystrophies-current status. Front Biosci. 2003;8:d687-7 13.

Posterior Polymorphous Dystrophy Posterior polymorphous dys trophy (Fig 6-3) is another endothelial dystrophy that may be inherited in autosomal dominant or recessive fashion, with the mutation mapped to 20q ll. In this condition, the endothelium has epithelial-like charac teristics. These include multilayering, which may be seen histologically on routine light microscopy, and microvilli, which are best demo nstrated on electron microscopy. T he total number of endothelial cells may be decreased. Variable thickeni ng of the Descemet membrane and guttae may be observed. There may also be secondary glaucoma, either open-angle or associated with iridocorneal adhesions. The resultant corneal clouding is typi call y central, but the degree of opacification varies greatly, with some patients never requi ring corneal transplantation and others requiring keratoplasty in childhood or even infancy. See also SCSC Section 8, External Disease and Cornea .

Dermoid Dermoid, a type of choristoma that may involve the cornea, is discussed in Chapter 5 (see Fig 5-2). Dermoids are typically located at the limbus but may involve the central corn ea. See also sesc Section 6, Pediatric Ophthalmology and Strabismus.

Figure 6-3 Posterior polymorphou s dystrophy. A, Clinica l appearance, sh owing nummular opaciti es (arrows) on the endothelial surface . B, Note multilayerin g of endothelial ce ll s (arrow). (Parr A courtesy of Andrew J. W. Huang, MD; parr 8 courtesy of George J. Harocopos. MD.)

CHAPTER 6:

Cornea.

Peters Anomaly Peters anomaly represents the more severe end of the spectrum of anterior segment dys ~ genesis syndromes, in wh ich neural crest migration, with respect to angle development and cleavage of the lens from the corneal endothelium, does not occur properly. This anomaly is typically bilateral and sporadic, although autosomal dominant and recessive modes of inheritance have also been reported. In this anomaly, there is a localized defect in the central or paracentral portion of the Descemet membrane, known as internal ulcer of von Hippel, at the edges of which, typically, are iris strands adherent to the posterior corneal surface. In the most severe form of Peters anomaly, the lens is also adherent to the posterior corneal surface. These defects result in variable degrees of corneal clouding, often requiring corneal transplantation (Fig 6-4). A related entity in the spectrum of anterior segment dysgenesis syndromes is sclerocornea. Whereas the corneal clouding in Peters anomaly is central, the clouding in

Figure 6-4

Peters anomaly. A, Clinical appearance . Note th e centra l corneal opacities, diffuse cornea l clouding, and vascu lariza tion. 6, PAS stain demonstrates internal ulcer of von Hippe!. The Descemet membrane t rails off at the edge of the internal ulcer (arrow). Iris tissue (to the right of the arrow) adheres to the posterior corneal surface at the edge of the internal ulcer. Also note endothelial cell loss. C, Severe case showing lens t issue adh erent to posterior corneal surface. The arrow marks the edge of the inte rnal ulce r. Note lens capsule (arrowheads), swol len lens epithelial cells (E), lens f ibers (F), and iris ti ssue with melanin pigment (/). (Part A courtesy of Andrew J W Huang, MO; parts Band C courtesy of George J Harocopos, MD.)

82 • Opht hal m ic Pathology and Intraocu lar Tu mors sclerocornea is typically peripheral, although it may involve the entire co rnea. The limbus is usually poorly defined, and vessels that are extensions of scleral, episcleral, and conjunctival vessels extend across the cornea. T he most common ocular asso ciati on is cornea plana, found in 80% of cases. Histologically, stromal vascularization and d isorderly stromallamellae of va riable thickness may be present, correlating with the peripheral clouding seen clinically. Histologic findings sim ilar to those of Peters anomaly are typica ll y present. See also BCSC Section 8, External Disease and Cornea, and Section 6, Pediatric Ophthalmology and Strabismus.

Inflammations Infecti ous Keratitis The cornea may be affected by infectious p rocesses caused by a number of different microbial agents. Severe inflammation can lead to corneal necrosis, ulce ratio n, and perforation . See also BCSC Section 8, External Disease and Cornea.

Bacterial infections Co rneal infecti ons caused by bacterial age nts often follow a disruption in the corneal epithelial integrity resulting from contact lens wear, trauma, alteration in imm unologic defenses (eg, use of topical or systemic im mu nosuppressives). antecedent corneal disease (eg, dry eye, exposure keratopathy), ocular medication toxicity, or contamination of ocu lar med ications. Bacterial organisms commonly involved in co rn eal in fections include Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumoniae, and Enterobacteriaceae. Scrapings obtained fro m infected co rn eas show collections of neutrophils admixed with necrotic debris. The presence of orga nisms may be demonstrated on Gram stain. Cult ure is h elpful for accurate identification of specific organisms and for assessment of antibio tic sensitivities. Follo\ving sterilization of the ulcer with antibiotic therapy, penetrating keratoplasty may be required in cases of visually Significant corneal scarring. Keratoplasty is sometim es required urge ntly in the acute phase of infection, for example, for perforation or im pending perforation (F ig 6-5).

Herpes simp/ex virus keratitis Us ually a self-li mited corneal epithelial disease, herpes simplex virus keratitis is character ized by a linea r arborizing pattern of shallow ulceration a nd swelli ng of epithelial cells called a dendrite (Fig 6-6A) . The diag nosis may generally be made clinically. Corneal scrapings obtained from a dendrite and prepared using the Gie msa stain reveal the presence of intran uclear viral inclusions. Vi ral culture, antigen detec tion, or polymerase chai n reaction (PCR) techniques may be helpful in atypical cases. A de nd ri te is associated with subepithelial infilt ration by chronic in fl a mmatory cells and loss of th e Bowman layer. Stromal keratitis (Fig 6-6B) may accompa ny or follow epithelial infection, lead ing to st romal scarring and possibl y vasc ularization. Histologically, chronic in flamm atory cells and blood vessels may be see n tracking between stromal lamellae, that is, interstitial keratitis

CHAPTER 6:

Cornea. 83

Bacterial ulcer. A, Clinical appearance of pseudomonal ulcer. 8, In th is patient, penetrating ke ratoplasty was performed during the acut e phase of infection. On H& E sta in, the cornea l button shows ulcera tive kerati tis, wit h stroma l necros is and neut rophilic infi ltrati on (arrow). C, Ke ratoplasty specimen (diffe rent pa tie nt) showing scar from hea led keratitis. Note loss of the Bowman layer (between arrowheads) and stromal thinn ing/fi brosis (arrow), with compensatory epithelial thicke ning . (Part A courtesy of Andrew J. W. Huang, MD; parts Band C courtesy of

Figure 6-5

George J. Harocopos, MD )

(Fig 6-6C) (discussed later). Endothel iitis may also occur, with a granulomatous reactio n at the level ofthe Descemet membrane (Fig 6-6D), which corresponds to disciform keratitis clinically. Visually significant corneal scarri ng from herpetic keratitis is the single most common infection-related indication for penetrating keratoplasty. Postherpetic neurotrophic keratopathy may result from corneal hypoesthesia or anesthesia and is characterized histologically by a featureless corneal stroma with a paucity ofkeratocytes (Fig 6-6E).

Fungal keratitis Mycotic keratitis is often a complication of trauma, especially involving plant or vegetable matter, or microtrauma related to contact lens wear. Corticosteroid use, especially topical, is another major risk factor. Un like most bacteria, fungi are able to penetrate the cornea and extend through the Descemet me mbrane into the ante rior chamber. The most common organisms are the septated, filamentous fungi Aspergillus and Fusarium and the yeast Candida; Mucor (nonseptated, filamentous) is less common. Culture, particularly on Sabouraud aga r, is helpful for accurate identification of specific organisms and for assessment of antifungal sensitivities. When cultu re is negative and organism identity remains

84 • Ophthalmic Path olo gy and Intraocular Tumors

Figure 6-6

Herpes simplex viru s keratitis. Clinical photo-

graphs depicting dendr itic (A) and stromal (B) keratitis. C, Histology of corneal button shows stromal keratitis with loss of the Bowman layer (asterisk), stromal scarring and vascularization (arrowhead), and scattered chronic inflam-

matory cel ls (arrows). D, Highe r·power photomicrograph

shows granulomatous reaction (between arrows) in the region of Descemet membrane (arrowhead). Note the fibrous retrocorneal membrane (asterisk), scattered chronic inflam-

matory cells, and blood vessel (open arrow). E, Post herpetic neurotrophic keratopathy. Photomicrograph shows featureless corneal stroma (asterisks) with only rare keratocytes (arrow).

(Parts A and B courtesy of Anthony J. Lubniewski, MD,

parts C and

o courtesy of Tatyana Milman, M D; part E courtesy of Robert H. Rosa, Jr, MD.) E

elusive, corneal biopsy may be considered, for both histologic evaluation and peR. Many fun gi can be seen in tissue sections with the use of special stains such as Grocott-Gomori methena mi ne-silver nitrate (GMS ) or PAS (Fig 6·7). Fungi (eg, Mucor) are sometimes apparent on routine H&E sections. Acanthamoeba

keratitis

Acanthamoeba protozoa most common ly cause infection in soft contact lens wearers who do not take appropriate precautions in cleaning and sterilizing thei r lenses or whose

CHAPTER 6:

Cornea .

Fusarium ke ratit is. A, Clinica l photograph show s gray-white, dry-appea ring stromal infiltrate w it h fea thery ma rgins . B, Grocott-Gomori met henami ne- silver nitrate (GMS) stain of cornea l bu tton demonst rat es f unga l hyp hae (black). Note t hat fungi have penetrated throug h the Descemet membrane (arrow). (Parr A courtesy of Andrew J W Huang. MD; part B courtesy of George J Figure 6·7

Harocopos, MD.)

lenses come into contact with contaminated stagnant water (eg, as found in hot tubs and ponds). The most freq uentl y involved species are Acanthamoeba castellani and Acantha moeba polyphagia. Patients presenting with Acanthamoeba keratitis usually have severe eye pain . Clinically, radi al keratoneuritis and, in late stages, a rin g infiltrate may be present (Fig 6-SA). Special culture techniques and media, including nonnutrient blood agar layered with Escherichia coli, are required to grow Acanthamoeba. In later stages of disease, the organism s penetrate into deeper layers of the stroma and may be di fficult to isolate from superficial scraping. Confocal m icroscopy may be useful for demonstrating the organisms. Scrapings, biopsy specimens, or corn eal buttons may show cysts and trophozoites (Fig 6-8B). The organisms may generally be visualized with routine H&E sections but m ay be n10re easily seen with PAS stain. Calcofluor white or acridine orange sta in may also be us ed. Infectious crystalline keratopathy Infectious crystalline keratopathy (ICK) typically occurs in patients on long-term topical corticosteroid the rapy, as, fo r example, follo wing penetrating keratoplasty. The infect ion typi cally arises along a suture track. The most common etiologic microo rganism is viridans group (a-hemolytic) Streptococci, although a host of other organisms have been reported, including bacteria and fungi. It is thought that chronic ilnmunosuppression, combined with properties of the organism's glycocalyx that sequester the organism from the in11llune system , promote growth of the orga nism in this condition. No true crystals are involved; rather, this condition derives its name from the crystalloid appeara nce of th e opacity seen clinically (Fig 6-9A). The overlying epitheliu m is often intact, making diagnosis challengin g in the early stages of the disease and also ma king the organism difficult to cultu re. In many cases, the diagnosis is missed clinically and is made histologically after failure of a corneal graft. On histology, colonies of bacteria are present withi n the interlamellar spaces of the st rom a. The inflammatory cell infiltrate is typically insignificant,

86 • Ophthalmic Pathology and Intraocula r Tumo rs

Figure 6-8 Acanthamoeba kera titis. A, Clinical photog rap h depicting ring inf iltrate and smal l hypopyon. B, Note the cyst (C) and trophozoite iT! forms. The cyst has a double wall, that is, endocyst and exocyst (arrows). (Part A courtesy of Sander Dubovy,. MO.)

al though in some cases rCK is associated with an adjacent corneal ulcer. The organisms may sometimes be appare nt on H&E stain but may be more easil y seen on Gram stain or, fo r some speci es, on GMS or PAS stain (F ig 6-9B).

Interstitial keratitis Interstitial keratitis OK) refers to nonsuppurative inflam mator y cell infiltrat ion in the in -

terlamellar spaces of the corneal stro ma, often with vascularization, and typically with an

Figure 6-9 Infectious crystallin e keratopathy. A, Clinical photograph depicting crystalloidappearing (or "fernlike") stromal infiltrate (arrow), with intact overlying epithelium. The infection arose along a suture track following repai r of a corneal laceration. 8, Gram stain demonstrates colon ies of gra m-posit ive cocci interposed between stromal col lagen lame llae (arrows). (Part A courtesy of Anthony J Lubniewski, MO; part 8 courtesy of Morton E. Smith, MD.)

CHAPTER 6:

A ....._ _ __

Cornea.

B Figure 6·1 0 Interstit ial keratiti s of congenita l syph ilis. A, Clinical photograph depict ing stromal opacity, wi th intact overlyi ng epitheliu m. B, Histology show s vasculariza ti on (arrowheads) in th e midstroma and deep stroma, with surrounding chronic in flammatory cel ls tracki ng along the in te rl amellar spaces. Note th e in tact epithel ium . Corn eal thic kness measured less than 400 ~m, indicative of visually signif icant stroma l fibrosis. (Part A courtesy of An thony J. Lubniewski, MD; parr B courtesy of George J. Harocopos, MD.)

intact overlying epithelium. Transplacental infection of the fetus by Treponema pallidum (congenital syphilis) may cause IK (Fig 6-10). These changes are thought to result from an immunologic response to infectious microorganisms or their antigens. Chronicirecurrent IK may lead to stromal scarring. Although congenital syphilis represents the "classic" cause of IK, the single most common etiologic agent of IK is herpes (see Fig 6-6) . Other causative organisms of IK include Mycobacterium tuberculosis, Mycobacterium leprae, Borrelia burgdorferi, and Epstein-Barr virus. Noninfectious Keratitis

Corneal inflammation can also be caused by noninfectious agents. For example, autoimmune diseases, especially rheumatoid arthritis and graft-vs-host disease, may be associ ated with sterile corneal ulceration. Topical medication toxicity (eg, overuse of topical anesthetics, nonsteroidal anti-inflammatory drugs [NSAlDs], or antivirals) may also result in corneal melting. On histology, such cases often appear similar to infectious ulcerations on H&E sections, but no organisms are demonstrated on special stains. See also BCSC Section 8, External Disease and Cornea.

Degenerations and Dystrophies Degenerations

Corneal degenerations are secondary changes that occur in previously normal tissue. They are often associated with aging, are not inherited, and are not necessarily bilateral. See also BCSC Section 8, External Disease and Cornea.

88 • Ophthalmic Pathology and Intraocula r Tumors

Salzmann nodular degeneration Salzmann nodular degeneration is a noninflam matory corneal degeneration that may occur secondary to long-sta nding keratitis or may be idiopathic. It may be bilateral and is more commonly seen in middle-aged and older women. often in association with blepharitis. Gray-white or bluish flat or raised lesions are present where the eyelid margin contacts the cornea in primary gaze andlor in the central and paracentral cornea (Fig 6- II A). Histologic examination discloses irregular epithelial thickness and replacement of the Bowman layer with disorganized collagenous tissue (Fig 6-IIB). Thickening of the epithelial basem*nt membran e may also be seen.

Calcific band keratopathy Seen clinically as a band-shaped calcific plaque in the interpalpebral zone and typically sparing the most peripheral clear cornea. band keratopathy is characterized by the deposition of calcium at the level of the Bowman layer and the anterior stroma. T he calcium deposits appear as basophilic granules in H&E sections; the presence of calcium can be further confirmed by the use of special stains such as alizari n red or von Kassa stain

(Fig 6-12). Band keratopathy may develop afte r any chroni c local corneal disease. following prolonged chronic inflammation (es pecially in eyes with a history of chronic juvenile idiopathic arthritis-associated uveitis and in blind. painful eyes). and. less commonly. in association with system ic hypercalcem ic states.

Actinic keratopathy Also known as spheroidal degeneration or Labrador keratopathy. actinic keratopathy in volves elastotic degeneration of corneal collagen similar to that seen in pingueculae. pterygia. and solar elastosis of the skin. This condi tion may be caused by prolonged exposure to solar (actinic) irradiation. It may also be caused by corneal infl am mation, sometimes in association with calcific band keratopathy. The actinic damage usually occurs withi n the interpalpebral fissure. Clinical examinat io n discloses translucent. golden-brown spheroidal deposits in the superficial cornea (Fig 6-13A). H&E-stained sections show basophilic globules beneath the epithelium in the region of the Bowman layer and the anterior

B Figure 6-11 Sa lzmann nodular degeneration. A, Clinical appearance. Note the gray-white corneal opacities. B, Histology of superficial keratectomy specimen (PAS stain) shows irregular

epithelial thickness and diffuse loss of the Bowman layer, with this layer replaced by disorganized collagenous tissue (as terisk) . (Courtesy of George J. Harocopos, MO)

CHAPTER 6:

Cornea.

Calcific band keratopathy. A, Clinical appearance. B, Calcific keratopathy may be treated with epithelial scraping and chelation with ethylenediaminetetraacetic acid (EDTA "scrub"). The calcium is deposited at the level of the Bowman layer (arrows), appearing deeply basophilic (purple) on H&E stain . C, Calcium deposits appear black on von Kassa stain. Figur. 6-12

(Pari A courtes y of Anthony J. Lubniewski. MD; parr B courtesy of George J. Harocopos, MD; part C courtesy of Hans E Grossniklaus, MD.)

stroma (Fig 6-1 3B). The deposits stain black with special stains for elastin, such as the Verhoeff- van Gieson (VVG) stain. Pannus

Pan nus refers to th e growth of fibrovascula r or fibrous tissue between the epithelium and the Bowman layer (Fig 6-14). T he Bowman layer may be dis rupted. Pannus is frequentl y seen in cases of chronic corneal edema or following prolonged corneal inflammation .

Bullous keratopathy Intraocular surgery, most commonly cataract surgery. invariably results in some loss of corneal endothelial cells. In cases of extensive endothelial cell loss, the cornea may decompensate postoperatively, either early in the postoperative period or yea rs later, after more endothelial cells are lost with age. When the endothelium begins to decompensate, Descemet folds and stromal edema occur, followed by intracellular epithelial edema and, ultimately, separation of the epithelium fro m the Bowman laye r. Small separations are referred to as "microcysts"; these may coalesce to form large separations. known as bullae. In more advanced cases of bullous keratopath y, as in Fuchs endot helial dystrophy (discussed later), secondary epithelial basem*nt membrane changes and fibro us pannus may be seen. The Descemet membrane may be thickened, but it typi cally does not show guttae (Fig 6-15). Although bullous keratopathy is more commonly seen after cataract surgery,

90 • Ophtha lmic Path o logy and Intraocular Tum o rs

A Actinic ke ratopat hy (spheroidal degeneration ). A , Gross appearanc e of cornea l butto n. The ai r bubbles are art ifacts. B, Histology shows lightly stainin g basoph ilic globules (arrows) in th e epi thelium and superficial stroma. (Courtesy ofHansE Grossniklaus, MD.) Figure 6-13

Figure 6-14 Fibrovascular pannus. A, Clinical appearance on the supe rior corn ea. 8 , Fibrovascu lar pann us (between arrows) is interposed between the epitheliu m and t he Bowma n layer. (Pan A courtes y of George J. Harocopos, MD.)

Figure 6-15 Pseudopha kic bullous keratopathy. A, Clinica l appea rance of seve re bullous ke ratopat hy associated w it h an ante ri or chamber lens implant. 8, Corn ea l butto n fro m penet rating keratop lasty. Note t he subepithe lial bu llae (arrow s) Also note diffu se endothelial ce ll loss, wit hout guttae of Descemet membrane . (Parr A courtes y of Andrew JW Huang, M O; part B courtesy af George J Harocapos, M O.)

CHAPT ER 6:

Cornea.

in which case it is termed pseudophakic or aphakic bullous keratopathy, it may also be seen after other forms of intraocular surgery, for example, multiple glaucoma procedures or retinal detachment repair with silicone oil ("silicone oil keratopathy"). Corneal graft failure Failure of an existing corneal graft is one of the most common indications for penetrating keratoplasty. The final common pathway of graft failure is endothelial cell loss. The endothelial cells of a graft may gradually decrease ove r time until failure occurs, or there may be an acute event resulting in endothelial cell loss, such as a rejection ep isode or ulcerative keratitis. When endothelial failure occurs, there is often associated bullous keratopathy. In about half of cases, a fibrous retrocorneal membrane is visualized (Fig 6-16). If the membrane is thick and contiguous with the corneal stroma in the region of an incision, then the membrane may be termed fibrous downgrowth or ingrowth. Less commonly, a graft may fail because of growth of surface epithelium through a poorly apposed wound and onto the retrocorneal surface, that is, epithelial downgro wth or ingrowth. The main risk factor for fib ro us or epithelial down growth is multiple prior penetrating keratoplasties. Both types of down growth are very poor prognostic signs for graft survival and for general ocular healt h, as they are typically associated with secondary angle-closure glaucoma. Keratoconus Keratoconus is a bilateral noninflammatory condition characterized by central or inferocentral ectasia of the cornea, typically diagnosed during adolescence or young adulthood (Fig 6-17 A). It is often sporadic, but family history is positive in some cases, thereby blurring the distinction between degeneration and dystrophy in this condition. Keratoco nus can occur as an isolated finding, or it may be associated with other oc ular disorders or with systemic conditions, including atopy, Down syndrome, and Ma rfan syndrome. The alteration in the normal corneal contour produces myopia and irregular astigmatism. In advanced disease, visually significant apical scarring develops, often requiring therapeutic keratoplasty. A small percentage of keratoconus patients develop a spontaneous break in Descemet membrane, resulting in acute corneal edema known as corneal hydrops. Histologic findings in keratoconus include central stromal thinning and focal discontinuities in th e Bowman layer. Apical anterior stromal fibrosis is often present (Fig 6- 17B, C). Iron deposition in the basal epithelial layers at the base of the cone (Fleischer ring) can sometimes be demonstrated with Prussian blue stain (Fig 6-17D). In patients with a history of hydrops, a break in Descemet membrane may be observed (Fig 6-17E). Occasionally, amylOid material may accumulate in the anterior cornea in advanced kera toconus (an example of secondary localized amyloidosis). Pellucid marginal degeneration is ano ther ectatic disorder and is likely part of the same disease spectrum as keratoconus . The stromal thinning of pellucid marginal degeneration is typically more inferior than that of keratoconus. Pigment deposits

Krukenberg spindle is seen in pigment dispersion syndrome, a form of secondary openangle glaucoma typically occurring in young to middle-aged adults with myopia, associated

92 • Ophthalmic Pathology and Intraocu lar Tumors

E Figure 6· 16

Corneal graft failure. A, PAS stain of corne al button, showing diffuse endothelial

cell loss and fibrous retrocorneal membrane (F). There is secondary bullous keratopathy (arrowhead) and e pithelial base ment memb ran e t hickening/redundancy (arrow). B, Clinical appearance of fibrous downgrowth (arrows). C, PAS stain of corneal button (different patient) showing fibrous downgrowth (FO). The continuity between the fibrous downgrowth and the corneal stroma may be seen through th e break in Descemet membrane (arrow) at the grafthost interface. Also note peripheral anterior synechiae, with iris tissue (I) adherent to the

fibrous membrane. 0 , Clinical appearance of epithelial downgrowth (arrowheads). E, Histology of failed graft (different patient) with epit he lia l downgrowth (arrowhead) and diffuse endothelial cell loss. Also note secondary bullous keratopathy, with ruptured bulla (arrows). (Parts A. C. and E coulTesy of George J. Harocopos, MD; parts Band 0 courtesy of Anthony J Lubniewski, MD.)

with posterior bowing of the midper ipheral iris. The m elanin pigment is located within the corneal endothelial cells and may also be found extracellularly on the posterior corneal surface (Fig 6-18). [n pigment dispersion syndrome, melanin pigment is also seen in and arou nd th e endothelial cells lining the trabecular meshwork, correlati ng with the abnormally dark color of the meshwork observed gon ioscopically (see Chapter 7, Fig 7-13). See also BCSC Section 10, Glaucoma. Blood staining of the cornea may complicate hyphema when th e intraocular pressure (lOP) is very high for a long duration; however, if the endothelium is compromised, blood

CHAPTER 6:

Cornea.

~_.,_,:,~~: ~ {:;",. ~~€,:;:r,;._"

D Keratoconus. A, Clinical appearance. B, Low-magnification view shows apical stromal thinning (arrow). C, Masson trichrome stain demonstrates focal disruption of the Bowman layer (arrow). 0 , Prussian blue stain demonstrates intraepithelial iron deposition (Fleischer Figure 6·17

ring). E. In a patient with prior hydrops. PAS stain highlights rupture of Descemet membrane. with rolled-up edges On either side (arrows).

(Part A courtesy of Sander Dubow, MD; part Hans E. Grossniklaus, MD; part E courtesy of George J Harocopos. MD.)

C courtesy of

staining can occur even at normal or low lOP (Fig 6- 19). Histologically, red blood cells and their brea kdown products (mostly hemoglobin and also small amounts of hemosiderin) are seen in the corneal stroma. The hemosiderin is located in the cytoplasm ofkeratocytes and may be demonstrated with iron stains sllch as Prussian blue. Iron deposition in the corneal epithelium in keratoconus (Fleischer ring) was previously discussed (see Fig 6-17D ). See BeSe Section 8, External Disease and Cornea, for additio nal discussion of blood staining of the cornea as well as other forms of ocu lar surface iron li nes.

94 • Ophthalmic Patho logy and Intraoc ular Tumors

A Figure 6-18

______

________

Krukenberg s pind le. A, Cl inical appea rance of Krukenbe rg spindle (arrow) . B, Mel-

anin pigment is found within the cytopla sm of endothelia l cell s (arrows). (Part A courtesy of L.J. Katz, MO; part B courtesy of Debra J. Shetlar, MD.)

A_ _

-...

.....;

--- - - -------.·~f,·~:~ c · -- ! - -

.-:. ~-

: ~,. ~ -

...

---..-

..-

:. _ ~ ,",'_ ~

~._

~ . ~~:~i. .:..:.~ :~..

o!:..~ <' '-

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B" :: ~ ~" "': ' '''''':~~-''' '''' _:l

Figure 6-19

Corneal blood staining. A, Clinical appeara nce. S, Masson trichrom e stain . The red particles represent erythrocytic debris and hemoglobin in the corneal strom a. C, An iron stain demonstrates hemosiderin (arrows), confined to the stromal keratocytes. (PartAcounesyo( Anthony J Lubniewski, MD: parts 8 and C courtesy of Hans E. Grossniklaus. MD.)

Dystrophies Dystrophies of th e cornea are primary, gene rall y in herited, bilateral diso rders, categorized by the layer of the cornea most involved (ie, epithel ial, stroma l, end oth elial). Kerato conus (previously discussed) may be considered a dystrophy, except that it is often sporadic an d likely multifactorial in etiology_ O nly th e most common corneal dystroph ies are discussed in the following sections. See also BCSC Section 8, External Disease and Cornea.

CHAPTER 6:

Cornea • 95

Epithelial dystrophy Also called map-dot-fi ngerprint dystrophy, Cogan microcystic dystrophy, anterio r basem*nt membrane dystrophy (ABM D), and epithelial basem*nt membrane dystrophy (EBMD), epithelial dystrop hy may be the most common of th e corneal dys trophies seen by the comprehensive ophthalmologist (Fig 6-20). It is often sporadic but may be inherited in an autosomal dom inant fashion. In this condition , the basem*nt me mbra ne is thickened and may extend into the epithelium (fo rmi ng "map" and "fi nge rprint" lines). The intraepithelial basem*nt membrane red unda ncies may encircle foci of epithel ial cells, which may then degenerate, resulting in epithelial deb ris wit hi n cystoid spaces ("dots") (see Fig 6-20C). Patients with epithelial dystro phy often present with symptoms of recu rrent erosion syndrome.

A ~

Fi g ur.6-20 Epithel ial basem*nt membrane dystrophy (EBMD. map-dot-fingerprlnt dystrophy) . A, Clinical appearance depicting fi ne, lacy opaci ties (arrows). B, Retro illumination demonstrating wavy lines (arrow) and dotli ke lesions (arrowhead). C, The changes in primary map-dotfingerprint dystrophy are essentially identical to those seen in cases of chronic corneal edema secondary to endothelial decompensation. Note the intraepithelial basem*nt membrane (8M) and the degenerating epithelial cells trapped within cystoid spaces (e). D, When surgical treatment is required for EBMD, removal of abnormal epithelium (superficial keratectomy) may be performed, as in this case. PAS stain highlights numerous folds (arrowheads) in the epithelial basem*nt membrane. (Part A courtesy of Andrew J. W Huang. MD; part 0 courtesy of George J. Harocopos. MD.)

96 • Ophthalmic Pathology and Intraocular Tu mors

Stromal dystrophies The corneal stromal d ystrophies presented in the following subsections (macular, granular, lattice, Avellino) are all inherited disorders and may present with symptoms of decreased vision and recurrent erosion syndrome. All of the stromal dystrophies may recur

in corneal grafts. The genetics of the stromal dystrophies have become elucidated in recent years, en hancing

OUf

understanding of these disorde rs. At the same time, the genetic discoveries

raise questions rega rding the proper class ification of the corneal dystrophies: the same dystrophy may be associated with multiple different mutations, wh ile the same mutation may result in multiple different clin ical phenotypes. The In ternational Committee for Classification of Corneal Dystrophies (IC3D) was created for the purpose of devising a current, accurate. and uniform nom encl atu re. The information given in the fo llOWing subsections reflects the current IC3D no menclature. The IC3D classification is available o n th e website of The Cornea Society (ww-w.co m easociety.orglic3d). Weiss JS, M011er HU. Lisch W, et al. The lC30 classification of the corneal dystrophies. Cornea.

2008;27(SuppI2 ):SI -S80. Macular dystrophy Macula r dystrophy, an autosomal recessive stromal dystrophy, involves the entire cornea (ie, limbus to limbus) and may invol ve the full thickness of the cornea, including the endothelium. Clinicall y, it is characterized by poorly defined stromal lesions (focal opacities) wi th hazy in te rveni ng stroma. Mucopolysaccharide material is deposited both intracellularly and extracell ularly in the corneal stroma (Fig 6-21). The material stains bl ue with alcian blue and colloidal iron stains, with the majority of mucopolysaccharide depOSits seen in the interl amell ar spaces and in keratocytes . Cornea l thinning may occur as well . The number of endothelial cells may be decreased, and guttae may be seen in the Descemet membrane. Macular dystroph y is caused by mutations in the carbohydrate sulfotransferase 6 gene (CHST6) on chromosome 16 (l6q22), which is responsible for the sulfation ofkeratan sulfa te. Numerous different mutations in this gene have been described in macular dystrophy, with certain mutations having greater prevalence in speCific regions of the world. Granular dystrophy Granular dystro phy (type I) is an autosomal domi nant stromal dystrophy that involves the central cornea and has sharp ly defined lesions with clear intervening stroma (Fig 6-22). Histologically, irregu larly shaped, well-circ*mscribed deposits of hyaline material are visible in the stroma. This material stains bright red with the Masson trichrome stain. The mutation causing granula r dystrophy occurs in the TGFfJ! (Pig-h3 = BIGH3 = keratoepi thelin) gene on chromosome 5 (Sq31 ). Several different mutations in this gene have been described in association with granular dystrophy. Lattice dystrophy Lattice dystrophy (type 1) is an autosomal dominant stromal dystrophy th at involves the central corn ea and is cha ra cterized by refract il e lines with hazy intervening stroma (Fig 6-23). This disorder is a fo rm of primary localized amyloidOSiS, in which amyloid deposits may arise from epithelial cells and keratocytes. Histologically, the amyloid deposits are concen trated most heavi ly in the anterior st roma, but they may also occur in th e subepithelial area and deeper stroma. The amylOid material stains posi tive (orange) with the Congo red stain on standard light microscopy, and under polarized

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Figure 6·21 Macular dystrophy. A, Clinica l appearance depicting diffusely hazy cornea with foca l opacities. S, H&E stain. Note the clear spaces surrounding the keratocytes and in the stroma. C, Colloidal iron stains mucopolysaccharides in the keratocytes and stroma. (Parr A courtesy of Sander Dubovy. MD.)

light, it exhibits birefrin gence with d ich ro ism (orange and apple green) . Amyloid demonstrates metachromasia \vith crystal violet stain. The fl uorescent stain th iofla vin T may also be used to demonstrate amyloid. As in gra nul ar dystrophy, several di fferent mutations in the BIGH3 gene o n Sq31 have been reported to ca use lattice dystrophy. Avell ino dystrophy Features of both granu lar and lattice dystrop hy appear in Avellino dystrophy, first descri bed in patients tracing thei r ancest ry to Avellino, Italy. Histologically, both hyaline deposits (typical of granular dyst roph y) and amyloid deposits (characteristic of lattice dystrophy) are present within the corneal stroma (Fig 6-24)_ This autosomal dominant dystrophy, like granular and lattice dyst rophy, has been attributed to mutations in th e BIGH3 ge ne on Sq31. See Table 6-2 fo r a histologic com parison of macular, granular, lattice, and Avell ino dystrophies.

Ta b le 6-2 Histologic Differentiation of Macular, Granular, lattice,

a nd Avellino Dystrophies Dystro phy Ma cu lar Granular Lattice Avellino

Tri chrome

Al da n Blue

Congo Red

Birefringen ce

+ +

+ + +

98 • Ophtha lmic Path ology a nd Int raocula r Tumo rs

B Figure 6-22 Granular dystrophy. A , Clinical appearance; note the clear intervening stroma . B. H&E stain. Note the eosinophilic deposits (arrows) at al l levels of the corn eal stroma . C, Masson trichrome stain. Th e stromal background sta ins blue, and the granul ar deposits

stain brill iant red.

Endothelial dystrophy Fuchs dystrophy is in herited in an autosomal dom inant fashio n or may be sporadic. It is one of the leading causes of bullous keratopathy (discussed earlier). Its defi ning characteristic is the presence of anvil-shaped excrescences of Descemet membrane, called guttae, which protrude il1to the anterior chamber or may be buried within a thickened Descemet membrane (Fig 6-25). Guttae may be recog nized cl inically in you ng ad ulthood, long before the cornea decompensates. Ove r time, progressive endothelial cell loss occurs , ultimately resulting in visually significant corneal edema and bullous keratopathy, typicall y in m iddle-aged to older individuals. As in bullous keratopathy fro m other causes, there are varying degrees of secondary epithelial basem*nt membrane changes and subepithelial fi brosis, similar to changes seen in map-dot-finge rprint dystrophy. In cases of endothelial decompensation without extensive subepithelial fibrosi s, endokeratoplasty rather than penetrating keratoplasty m ay be an alternative surgical optio n. O ther endotheli al

CHAPTER 6:

______L -______

B L-_

Cornea. 99

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Figure 6-23

Lattice dystrophy. A, Clinical appearance with lattice lines (arrows). B, H&E stain shows scattered fusiform, eosinophilic material deposited at all levels of the stroma. C, Congo red stain (orange) demonstrates that the fusiform deposits are amyloid. D, With Congo red stain, under polarized light, amyloid deposits exhibit birefringence and dichroism. (Parts 8-0 courtes y of Hans E. Grossniklaus, MD.)

A L-__.......

Figure 6-24 Avellino dystrophy. A, Clinical appearance, showing both lattice lines (i) and granular deposits (2). B. Trichrom e stain of deep anterior lamellar keratoplasty (DALK) button highlights hyaline deposits at the level of the Bowman layer and anterior stroma (arrowheads). Other deposits at various levels of the stroma stain a darker blue than the stromal background (triple arrow); these deposits were found on Congo red stain to be amyloid. (Part A modified with permission from Krachmer JH, Palay DA Cornea Atlas. 2nd ed. Philadelphia: Mosby-Elsevier; 2006: 163. Part 8 courtes y of George J. Harocopos, MD.)

100 • Ophtha lmic Pathology an d Int raocu lar Tum o rs

..., ' ..

c Figure 6·25

Fuchs dystrophy. A, Slit-beam illumination of cornea shows " beaten bronze" appearance of Descemet membrane. B, Corneal button from penetrating keratoplasty shows endothelial cell loss, with few su rviving endothelial cells tEl. Numerous guttae are seen in Descemet membrane, either protruding into the anterior chambe r (arrows) or buri ed w ithin thickened Descemet membrane (arrow head). The resu lt of endothe lial decompensat ion is diffuse stromal edema Inote loss of Interl am el lar cleftsl and bu llous ke ratopath y (asterisk). C, Speci-

men from Descemet stri pping endothe lial keratop lasty IDSEKI shows few endothel ial ce lls and numerou s guttae (arrows) .

(E)

(Part A reproduced from External Disease and Cornea: A Multimedia Collection .

San Francisco: American Academy of Ophthalmology; 2000. Parts Band

C courtesy of George J. Harocopos, MD.)

d ystroph ies (ie, co ngenital hered itary endothelial d ystrop hy an d posterior polym orphous d ystrophy) were d iscussed previo usly un der Conge ni ta l Anomali es.

Neoplasia Primary conjuncti val intraepithelial neoplas ia may exte nd from the li mbus and invol ve th e co rn eal epitheliu m. This condition is descr ibed furth er in C hapter 5. In rare cases, intrae pithelial squa mous neoplasia may arise in the co rn ea .

CHAPTER

Anterior Chamber and Trabecular Meshwork

Topography The anterior chamber is bounded anteriorly by the corneal endothelium, posteriorly by the anterior surface of the iris- ciliary body and pupillary portion of the lens, and peripherally by the trabecula r meshwork (Fig 7-1). The depth of the anterio r ch amber is approximately 3.5 mm. T he trabecular meshwork is derived predominantly from th e neural crest, while the Schlem m canal is derived from mesoderm. Histologic features of the anterior chamber angle correlate with gonioscopic landmarks (Fig 7-2) . The termination of Descemet membrane is manifes ted gonioscopically as the Schwalbe line. The scleral spur, a triangular extension of the sclera that appears as a white band gonios copically, can be identifi ed histologically by tracing th e outermost longitudinal ciliary body muscle to its insertion. The trabecular meshwork and the Schlemm

Schwalbe li ne - - --

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Figure 7-1 The normal anterior chamber angle, th e site of drainage f or the major portion of t he aqueous hu mor flow, is defined by the anterior border of the iris, the face of the ci liary body, the in terna l surface of the trabecul ar meshwork, and the posterior surface of the cornea. (Courtes y of Nasreen A. Syed, MD)

101

102 • Ophthalmic Pathology and Intraoc ul a r Tumors

'1..____ Schwalbe

Figure 7-2 Normal anterior chamber angle. Gonioscopic landma rks of t he anterior chamber angle with histolog ic correlation. TM = trabecular meshwork. (Courtesv of Tatyana Milman, MD.)

canal are nested in the groove formed by th e scleral spu r and corneoscleral tissue (internal scleral sulcus). See also Figures 2- 1B and 2-2 in BeSe Section 10, Glaucoma.

Congenital Anomalies Bese Section 10, Glaucoma, also discusses th e conditio ns described in the following section s.

Primary Congenital Glaucoma Prima ry congen ital glaucoma, also referred to as congen ital or infantile glaucoma, becomes evident at birth or within the first few years of li fe. T he pathogenesis of primary congenital glauco ma may be related to the arrested development of th e anter ior chamber angle stru ctures. Histo logically, the anterior chamber angle retains an "embryonic" or "fetal" con formation, characterized by anterior in sertion of the iris root. a poorly developed scleral

spur with insertion of the Ciliary body muscle directl y into the trabecular meshwork, and mesenchymal tissue in the anterior chamber angle (Fig 7-3). See BeSe Section 6, Pediatric Ophthalmology and Strabismus, fo r detailed d iscussio n.

Anterior Segment Dysgenesis Anterior segment dysgenesis is the term used for a spec trum of developmental anomalies res ulting from abnorma lities of neural crest migratio n an d differentiation during embryo-

logic development (Axe nfeld- Rieger synd rome, Peters anomaly, posterior keratoconus, and iridoschisis). Maldevelopm ent of th e anterior chall1ber angle is most promin ent in Axenfeld-Rieger syndrome, an au tosomal domin an t disorder, which itself encompasses a

spectrum of ano malies, ranging from isolated bilate ral ocular defects to a fully manifested systemic disord er. The Single most important clinical feature ofAxenfeld-Rieger syndrome phenotypes is that they confer at least a 50% risk of developi ng glaucoma. Ocular manifestat ions ofAxenfeld-Rieger syndrome include posteriorembryotoxon (a

thickened and anteriorly displaced Schwalbe li ne [term inat io n of Descemet membrane)) ,

CHAPTER 7:

Anterior Cham ber and Trabecu lar Meshwork.

103

Figure 7·3 Congenital glaucoma. Fetal anterior chamber angle demonstrates anterior insertion of the iris root (red arrow), anteriorly displaced ci liary processes, and a poorly developed scleral spur (black arrow) and trabecu lar meshwork (arrowhead). (Courtesy of Taryana Milman, MD.)

iris strands ad herent to the Schwalbe line, iris hypoplasia, corectopia and polycoria, and a maldeveloped or "fetal" anterior chamber angle (discussed earl ier) (Figs 7~4, 7~5) . See also BCSC Section 8, External Disease and Cornea. Espinoza HM, Cox C], Semina EV, Amendt EA. A molecular basis for differe ntial developmental anomalies in Axenfel d-Rieger syndrome. HI/m Mol Genet. 2002;11(7):743-753.

Fi gure 7·4 Posterior embryotoxon . Light micrograph shows a nodular prominence at the termination of the Descemet membrane (arrow). TM = trabecular meshwork. (Courtes y of Hans E. Grossniklaus, MD.)

104 • Ophthalmic Pat hology a nd Intra ocula r Tumors

B Figure 7-5 A, Clinical photograph of t he anterior segm en t in a pa tient with Axenfeld-R ieger syndrome. Iris atrophy, poiycoria, and iris st rands in th e periphery are present. Posterior embryotoxon can be seen laterally (arrows). B. Gross photograph shows a prom inent Schwalbe line and the anterior insertion of iris strands (Axenfeld anomaly). C, Light micrograph shows iris strands that insert anteriorly on the Schwalbe line (arrow). (Part A courtesy of Wallace L.M. Alward,

MD. Copyright University of Iowa. Parr B courtesy of Robert Y. Foos, MD; part C modified with permission from Yanoff M Fine BS. Ocu lar Pathology: A Color Atlas. New York : Gower; 1988.)

Degenerations Iridocorneal Endothelial Syndrome

Iridocorneal endothelial (ICE) syndrome refers to a spectrum of acqu ired un ilateral abnormali ties of the corneal endothelium, anteri or chamber angle, and iris typically affecting youn g to middle-aged adu lts. T hree cli nical variants are recognized (the firs t letter of each type, when combined, forms the mnemonic ICE) : • iris nevus (Cogan-Reese) syndrome • Chandler syndrome essential iris at rophy Epithelial-li ke metapl as ia and abnormal proliferatio n of the corneal endothelium are constant featu res of all forms of the ICE synd rome. Ab normal endoth el ial cells migrate over

CHAPTER 7:

Anterior Chamber and Trabecular Mesh work.

105

the ante rior chamber angle, leading to peripheral anterior synechiae (PAS) formation and subsequent secondary angle-closure glaucoma in approximately half of the patients with this condition (Fig 7-6). See BCSC Section 8, External Disease and Cornea, and Section 10, Glaucoma, for further discussion. Levy SG, McCartney AC, Baghai MH, Barrett MC, Moss ]. Pathology of the iridocornealendothel ial syndrome. The ICE-cell. Invest Ophthalmol Vis Sci. 1995;36( 13):2592- 2601.

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Figure 7-6 ICE syndrome . A, Iris nevu s syndrome. The normal anter ior iris architect ure is effaced by a membrane growin g on th e anterior iris surface (as terisk). The membrane pinch es off islan ds of norma l iris stroma, res ulti ng in a nodular, nevu slike appearance (arrowheads). B, Essent ial iris atrophy. At ro phic holes in t he iris and a narrow anterior chambe r, co nsistent with PAS formation. C, A membrane composed of spindle ce ll s lines the posterior surface of th e cornea and th e anterior surface of the atroph ic iri s (arrows). These meta plastic endothel ial cell s deposit on t he iris su rface a thi n basem*nt mem brane that has a posit ive peri odic acidSchiff reaction and is ana logou s to th e Descemet membrane. 0, Descemet membrane lines t he anteri or surface of t he iris (arrows). The iris is apposed to th e co rn ea (peripheral anteri or synechiae, asterisk). (Pa rt A courtesy of Paul A. Sidoti, MD; parts Band C courtes y of Tatya na Milman, MD .J

106 • Ophtha lmic Pathology and Intraocular Tumors

Secondary Glaucoma With Material in the Trabecular Meshwork Exfoliation syndrome Also known as pseudoexfoliation, exfoliation syndrome is a systemi c co ndition that is usu-

aUy identified in individuals older than 50 years and is characte ri zed by the production an d progressive accumulation of a fibrill ar material in tissues throughout th e anterior

segment and in the connective tissue of various visceral organs (Fig 7-7). These deposits distinguish exfoliation syndrome fro m true exfoliation , which is the splitting of the lens capsule induced by in frared radiation. Recent data support the pathogenic concept of exfoliation syndrome as a type of stress- induced elastosis associ ated with the excessive producti on and abnormal aggrega-

tion of elastic fib er components. Mutatio ns in the lysyl oxidase-li ke 1 gene, LOX Ll , on chromosome 15 ( 15q24) were found to be a major genetic risk facto r for exfoliation syndrome. Lysyl oxidase is a pivotal enzyme in extracellular matrix formation, catalyzing covalent crosslinking of collagen and elastin. Exfoliative material is most apparent on the surface of the anterio r segment stru ctures, where it exhibits a positive periodic acid - Schiff reaction and presents as delicate,

feathery or brushlike fibrils arranged perpendicular to the surfaces of the intraocular structures (Fig 7-SA, B). Exfoliative mate ria l also accumulates in the trabecular meshwork and the wall of the Schlemm canal. Associated degenerative changes in the iris pigment epithelium are manifested histologically by a "saw-toothed" configuration (Fig 7-SC). See also BCSC Section 10, Glaucoma, and Section II , Lens and Cataract. Sch lotzer-Schrehard t U. Molecular pathology of pseudo exfoliation synd rome/glaucoma- new insights fro m LOXLl gene associations. Exp bye Res. 2009;88(4 ):776-785.

Phacolytic glaucoma The condition know n as phacoly tic glaucoma occurs w hen denatured len s protein leaks fro m a hyperma ture cataract through an intact but permeable lens capsule. The trabec ular

Figure 7-7 Gross photograph shows fibrillar deposits on the lens zonular fibers (arrows) in exfoliati on syndrome (pseudoexfoliation). (Courtesy of Hans E. Grossniklaus, MDJ

CHAPTER 7:

Anterior Chamber and Trabecular Meshwork. 107

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Figure 7·8 Exfoliation syndrome (pseudoexfoliation). A, Abnormal material appears on the anterior lens capsule like iron filings on

the edge of a magnet (arrows). B, Note the pigmentation and small clumps of eosinophilic pseudoexfoliative material (arrow) in the anterior chamber angle. C, The iris pigment epithelium demonstrates a "saw-toothed" configuration, cons istent with pseudoexfoliation. (Pan Ccourresy of Taryana M ilman, MD.)

c meshwork becomes occluded by both the lens protein and the macrop hages engorged with phagocytosed proteinaceous, eosinophilic lens material (Fig 7 -9). Trauma Followi ng an intraocular hemorrhage, blood breakdown products may acc umulate in the trabecular mes hwork. The spherical shape and rigidi ty of hemolyzed erythrocytes make

Figure 7·9 Phacolytic glaucoma. A, Low magnification of macrophages filled with degenerated lens cort ical material in the angle. B, Higher magnification.

108 • Ophthalm ic Pathology and Intraoc ul ar Tumors

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Aqueous aspirate demonstrating numerous ghost red blood cells. The degenerating hemoglobin is present as small globules known as Hein z bodies (arrows). (Counesy of NasFigure 7·10

reen A. Syed, MD.)

it difficult for them to escape through the trabecular meshwork, leading to ghost cell glaucoma (Fig 7- 10). In hemolytic glaucoma, macrophages in th e anter ior chamber have been noted to phagocytose erythrocytes and their breakdown products. These hemoglobin-laden and hemosiderin-laden macrophages block the trabecular outflow channels (Fig 7-11 ). It is possible that macrophages are a sign of trabecul ar obstruction rather tha n the actual cause of an obstruction. In other cases of secondary open-angle glaucoma associated with chronic intraocular hemorrhage, histologic examination has revealed hemosiderin within the trabecular endothelium and within many ocular epithelial stru ctures (see Fig 7- 11 ). The presence of hemosiderin may be a sign of damage that occurred during oxidation of hemoglobin. The iron stored in the cells may be an enzyme toxin that damages trabecular function

Fig ure 7- "

HemolytiC glaucoma. The ante-

rior chamber angle is filled with degenerated red blood cel ls and macrophages containing rust-colored intracytoplasm ic material, hemosiderin (arrows). Hemosiderin is also observed within the trabecu lar meshwork endothelium (arrowheads). (Courtesy of Tatyana Milman, MD)

CHAPTER 7:

Anter ior Ch amber and Trabecular Meshwork. 109

in hemosiderosis oculi. Iron deposition in hemosiderosis oculi can be demonstrated by means of the Prussian blue reaction. Blunt injury to the globe may be associated with angle recession, cyclodialysis, and iridodialysis. Progressive degenerative changes in the trabecular meshwork can contribute to the pathogenesis of glaucoma after injury. See the section Histologic Sequelae of Ocular Trauma in Chapter 2.

Pigment dispersion associations Pigment dispersion may be associated with a variety of other conditions in which pigment epithelium or uveal melanocytes are injured, such as uveitis or uveal melanoma. These conditions are characterized by pigment within the trabecular meshwork and in macrophages littering the angle (Fig 7-12). Secondary open-angle glaucoma can occur as a result of the pigment dispersion sy ndrome (Fig 7-13). This type of glaucoma is characterized by radia lly oriented defects in the midperiphe ral iris and pigment in the trabecular meshwork, the corneal endothelium (Krukenberg spindle; see Chapter 6, Fig 6-18), and other anterior segment structures, such as the lens capsule. The dispersed pigment is presumed to be from iris pigment epithelium mechanically rubbed off by contact with le ns zo nula r fibers. See also BCSC Section 10, Glaucoma . Neoplasia Melanocytic nevi and melanomas that arise in the iris or extend to the iris from the ciliary body may obstruct the trabecular meshwork (Fig 7-14). See also Chapte r 17. In addition, pigment elaborated from melanomas and melanocytomas may be shed into the trabecular meshwork and produce secondary glaucoma (melanomalytic glaucoma ) (see Fig 7- 12). Occasionally, epibulbar tumors such as conjunctival carcinoma can invade the eye through the limbus, leading to trabecula r outflow obstruction and glaucoma. See the section Neoplasia in Chapter 5.

Figure 7·12 Secon dary open-angle glaucoma. The tra becular meshwork is obstructed by macrophages th at have ingested pigm ent from a necrotic intraoc ular melanoma (m elanomalvtic glaucoma).

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Pigment dispersion syndrome. A, Gross photograph demonstrating radially oriented transillumination defects in the iris. 8, Scheie stripe. Melanin is present on the anterior surface of the lens. C, Note the foca l loss of iris pigment epithelium (arrow). Chafing of the zonules against the epithelium may release the pigment that is dispersed in this condition. 0, Note the accumulation of pigment in the trabecular meshwork.

Figu re 7·13

Photom icrograph shows melanoma ce lls f illing th e anterior cham ber angle and obstruct ing th e trabecular meshwork. Note the iris pigment epithel ium in the lowe r right eo(ner of the photomicrograph. (Courtesy of Hans E. Grossniklaus. MD.)

Figure 7- 14

CHAPTER

Sclera

Topography The sclera is the white, nearl y opaque portion of the outer wall of the eye, covering fro m four-fi fths to five-sixths of the eye's surface area. It is continuo lls anteriorly at the li mbus with the corneal stroma. Posteriorly, the outer two-thirds of the sclera merges with the dura of the optic nerve sheath; the in ner one- third continu es as the la mina cribrosa,

thro ugh which pass axonal fi bers of the optic nerve (see Chapter 15, Fig 15-1). The diameter of the scleral shell ave rages 22 mm, and its thickness varies from I mm posteriorly to 0.3 111m just posterior to the insertions of the 4 rectus muscles. Histo logically, the sclera is divided into 3 layers (fro m outermost inwa rd): episclera, stroma, and lam ina fusca (Fig 8-1). The sclera is derived predom inantly fro m the neural crest.

Episclera The episclera is a thi n, loose fi brovas cular ti ssue that covers th e outer surface of the scleral

stroma.

Episclera

Figure 8-' Normal sclera demon strating emissary structures , including ci liary arte ri es (black arrowheads) and nerves (red arrowheads) entering and traversing the sclera. (Courtes y of Nasrsen A. Syed, MD.J

111

112 • Ophthalmic Pathology and Intra ocular Tumors

Figure 8-2 An emissary channel throu gh the sclera for the Axenfe ld nerve loop is present overlyi ng the pars plana (trichrome sta in). (Courtes y of Harry H. Brown, MD. )

Stroma

The bulk of the sclera is made up of sparsely vascularized, dense type I collagen fibe rs whose diameters range from 28 nm to more than 300 nm. In comparison to corneal stroma, scleral collagen fibers are th icker and more variable in thickness and orientation. Transmural emissary channels provide outlets withi n the stroma as follows (Fig 8-2; see also Fig 8-1 ): in the posterior region, for posterio r ciliary arteries and ner ves in the equatorial regio n, for vortex veins in the ante rior regions, for anterior ciliary arteries and veins and long posterior ci li ~ ary nerves (Axenfeld nerve loops) lamina Fusca

The lamina fusca is a delicate, pigmented fibrovascular tissue that loosely binds the uvea to the sclera. Sclerouveal attachments are strongest along the major emissary channels, the anterior base of the ciliary body, and the juxtapapillary region.

Congenital Anomalies Choristoma

Epibulbar dermoids and episcleral osseous choristoma are discussed in Chapters 5 and 6. Nanophthalmos

Nanophthalmos is a rare developmental disorder characterized by an eye with short axial length (15 - 20 mm), a normal or slightly enlarged lens, thickened sclera, and a predisposition to uveal effusion and glaucoma. The condition is usually bilateral.

CHAPTER 8:

Sclera •

113

In studies, the thick an d nonelastic sclera in nanophthalmos was found to demon strate frayi ng and splitting of the collagen fibril s and abnormalities in the glycosaminoglycan matrix. These scleral changes may predispose the nanophthalmic eye to uveal effusion due to reduced protein permeability and impaired venous outflow through the vo rtex ve ins. Glaucoma in nanophthalmic eyes may be caused by a va riety of mechanisms, including angle closure, pupillary block, and open angle with elevated episcleral venous pressure. Stewart DH Ill, Streeten Bv¥, Brockhurst R], Anderson DR, Hirose T, Gass DM. Abnormal scleral collagen in nanophthalmos. An ultrastructural study. Arch Ophtha/Illol. 1991;109 (7): 1017- 1025.

Inflammations See BeSe Section 8, External Disease and Cornea, for additional disc ussion of episcleritis and scleritis.

Episcleritis Simple episc/eritis is a self-limited, frequently recurrent condition that most commonly presents in the thi rd to fifth decades as a slightly tender, movable, sectorial red area involving the an terior episclera. It affects males and females equally. T here is usually no association with antecedent injury or systemic illness. Histologic examination shows vascu lar congestion; stromal edema; and a chronic non granulomatous perivascular inflam matory infiltrate, composed primarily oflymphocytes (Fig 8-3). In contrast to simple episcleritis, nodular episc/eritis more often affects females and those with system ic illness, such as rheumatoid arthritis. It is characterized by tender, elevated, pink-red nodules on the anterior episclera. Histologicall y, the nodules are composed of necrobiotic granulomatous inflammatory infiltrate, a palisading arrangement of epithelioid histiocytes around a central core of necrotic collagen. This light microscopic pattern is the same as that seen in rheumatoid nodules in subcutaneous tissue .

.. Fi g ure 8-3 Simple episcleritis. Episcleral biopsy specimen from a patient with simple episcleritis demonstrates chron ic nongranulomatous inflammatory infiltrate. (Counesy of George J. Harocopos. MD.)

114 • Ophthalmic Pathology and Intraocu lar Tumors

Scleritis Scleritis is a painful, often progressive ocular disease with potentially serious sequelae. There is a high association with systemic autoimmune vasculitic connective tissue diseases. Histologic examination of scleritis reveals 2 main categories: necrotizing and non necrotizing inflammation. Either type may occur anteriorly or posteriorly. Necrotizing scleritis may be nodular or diffuse, so-called brawny scleritis (Figs 8-4, 8-5). Both patterns demonstrate a palisading arrangement of epithelioid histiocytes and multinucleated giant cells surrounding sequestered areas of necrotic collagen (necrobiotic granuloma) (Fig 8-6). Peripheral to the histiocytes is a rim of lymphocytes and plasma cells. Multiple foci may show different stages of evolution. In the course of healing, the necrotic stroma is resorbed, leaving in its wake a thinned scleral remnant prone to staphyloma for mation (Fig 8-7). Severe ectasia of the scleral shell predisposes to herniation of uveal tissue through the defect, a condition known as scleromalacia perforans. Nonnecrotizing scleritis is characterized by a perivascular lymphocytic and plasmacytic infiltrate without a granulomatous inflammatory component. Vasculitis may be present in the fo rm of fibrinoid necrosis of vessel walls. Dubord PJ , Chambers A. Scleritis and episcleritis: diagnosis and management. Focal Points: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalmology; 1995, module 9.

8-4 This patient has a sectora l nodular anterior scleritis that causes severe ocular pain and photophobia. (Courtesy of Harry H

Figure

Brown, MD.)

8-5 Diffuse posterior scleritis (brawny scle ritis) demonstrates marked thickening of the posterior sclera . (Courtesy of Harry H. Brown, MO.) Figure

CHAPTER 8:

Sclera. 11 5

A Figure 8·6

Necrotizing granulomatous scleritis. A, An area of necrosis (asterisk) is seques-

tered by a zonal inflammatory reaction of histiocytes, lymphocytes, and plasma cells. B, Highmagnification photomicrograph of scleral (5) biopsy illustrates palisading arrangement of histiocytes and multinucleated giant cells (arrows) around necrobiotic scleral collagen (asteri s k ). (Part A courresy of Harry H. Brown, MD; part B courtesy of Roberr H. Rosa, Jr, MO)

A posterior staphyloma (between arrowheads) is present in th is eye as a sequela of scleritis. rCou rres y of Hans E. Grossniklaus, MD.J Figure 8-7

Degenerations Senile Calcific Plaque Senile calcific plaques occur com monly in elderly individuals as fiat, fi rm, sharply circ*mscribed, gray rectangu lar to ovoid patches. Illeasurin g 1 el11 in greatest dimension. The plaq ues appear bilaterally and are typically located anterior to th e medial and lateral rectus muscle inse rtions (Fig 8-8A). The eti ology is unknown; dehyd ratio n, actinic damage, and stress on scleral collagen exerted by rectus muscle inse rtions have been proposed but not proven. On histologic sections, the calcium is present within th e mid portion of the scleral strom a. It initially occ urs as a finely granular deposition but may progress to a confluent plaque invo lving both superficial and deep sclera (Fig 8-8B). Senile plaq ues may be highlighted by speci al stains for calcium, such as vo n Kossa and ali zarin red.

116 • Oph t ha lmic Pathology and Int raocular Tum o rs

B Figur.8-8 A calcific plaque of the sclera. A, Calcific plaques (arrow! are typically located lust anterior to the insertion of the medial and lateral rectus muscles. B, Basophilic calci fic deposits are noted in the sclera (arrowheads) anterior to the rectus muscle insertion (arrow). (Pan A courlesyof Vinay A. Shah, MB BS; parr B courtes y of Ta ryana Milman, MD.)

Scleral Staphyloma Scle ra l staphylomas are scleral ectas ias that a re lined internall y by uveal tiss ue an d th at may occur at poi nts of weakness in th e scleral shell, eit her in in he rently thin areas (such as posterior to the rectus muscle insertions; Fig 8-9) or in areas weake ned by tissue destruction (as in scleri tis; see Fig 8-7). In children , staphylom as m ay occ ur as a result of lo ng-standing increased int raocula r pressu re or axial myopia, owing to the relative disten sibility of th e sclera in the young. Locati on and age at onset, the refo re, vary accordi ng to th e und erlying etiology. Histologic exami nat ion invariably reveals thi nn ed sclera, with o r without fibrosis and scarri ng, again depend ing on the cause.

Neoplasia Neoplasms of the sclera a re exceed ing ly rare. Tu m ors ori ginate predo min antly in th e episcle ra or Tenon cap sul e rather than in the sclera pro per.

Scleral staphylomas. Several regions of scl era l thinning (arrows), wh ich appear bl ue because of th e unde rlYing uveal tissue, are present posterior to the rectus muscle insertions (arrowheads) and in the equatorial sclera. (Courresyof Nasreen A Syed, MDJ

Figure 8-9

CHAPTER 8: Sclera • 117

Fibrous Histiocytoma Fibrous histiocytoma, also known as fibroxanthoma or fibrohistiocy tic tumor, is a benign soft-tissue tumor with fibrous differentiation, formed by a proliferation offibrocytes and histiocytes, characteristically in a whorled (storiform) pattern (see Chapter 14, Fig 14-11 ). Though more common in the orbit, it may occasionally involve the sclera, particularly the corneosclerallimbus (Fig 8-10). Malignant fibrous histiocy tom a (atypical fibroxanthoma ) of the corneosclerallimbus demonstrates increased mitotic activity, nuclear pleomorphism,

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Fibrous histi ocytoma of t he corneoscleral limbus A, A gelati nous, gray, vascularized, dom e-shaped nodule ext ends into the cornea l stroma. B, M icroscopic evalua ti on reveals a prol iferation of spind le fib roblasts, rou nded histi ocytes, and occasion al multinuc leate d giant cells (arrow); scattered lymp hocytes are also seen (arro wheads). (Part A courtesy of Ira J Udell; part B Figure 8·10

courtes y of Ta ryana Milman, MO .)

118 • Ophthalm ic Path ology and Intraocula r Tumors necrosis, and an invasive growt h pattern. Although malignant fibrous histiocytoma of th e corneosclerallimbus can be locally aggress ive, the tumor generally does not metastasi ze.

Nodul ar Fa sc iitis Nodular fasciitis is a reactive process that may. in rare in stances. cause a tumefaction in the episclera. The disease usually affects yo un g adu lts as a rapidly growi ng, round to oval, firm white-gray nodule that measures 0.5- l. 5 cm and appears at the limbus or anterior to a rectus muscle insertion. Antecedent trauma has been implicated as an etiolog ic factor for the developm ent of nodular fasciitis in other body sites) but such an association is

infrequent in the sclera . Though self-limited. nodular fasciiti s is usually excised because of its rapid growth. Histologic examinatio n reveals a ci rc*mscribed spindle cell proliferation in which the appearance of individual cells resembles that of fibroblasts growing in tissue culture. These spindle cells aggregate in short fascicles, admixed with a chronic inflammatory in filtrate, in a vascula r, myxoid stroma (Fig 8-1 1). Older lesions may show foci of de nse collagen deposition. Although mitotic figures may be present, unbalanced (eg, tripolar) mitoses are absent. Because of the cellular nature of these proli ferations and the presence of m itotic figures, nodular fasciitis may be misinterp reted histologically as sarcoma (softtissue malignancy), a pitfall to avoid.

Figure 8·11 Nodular fasciitis. Activated spindled fi broblasts are loosely arranged in short fascicles (between arrowheads). A prominent capillary network (arrows) and chronic inflammatory infiltrate are also observed . (Courtesy of Tatyana Milman, MD.}

CHAPTER

Lens

Topography The crystalline lens is a soft, elastic, avascular, biconvex structure that in the adult measures approximately 9- 10 mm in diameter and 5 111m anteroposteriorly (Fig 9-1). The lens is derived from surface ectoderm. See BCSC Section 11, Lens and Cataract, for discussion of the structure, embryology, and pathology of the lens.

Capsule The lens capsule surrounds the entire lens (Fig 9-2). It is a thick basem*nt membrane elaborated by the lens epithelial cells and composed, in part, of type IV collagen fibers. The lens capsule is thickest anteriorly (12-2 1 ~m ) and peripherally near the equator and thinnest posteriorly (2-9 ~m ). The capsule provides insertions for the zonular fibers and plays an important part in molding the lens shape in accommodation.

Epithelium The lens epithelium is derived from the cells of th e original lens vesicle that did not differentiate into primary lens fibers . The anterior or axial lens epithelium forms a Single layer

Figure 9-1

Posterior aspect of the crysta lline lens, depicting its relati onsh ip to the peripheral

iris and ciliary body.

(Courtesy of Hans E. Grossniklaus, MD.)

119

120. Ophthalmic Pathology and Intraocul ar Tumors

Nucleus

___ Zonular fibers

Termination of ep itheli um Figure 9-2

Microscopic appearance of the adu lt lens .

(Courtesy of Tatyan a Milman, MD.)

of cuboidal cells with their basilar surface toward the anterior lens capsule, whereas the equatorial, mitotically active cells appear more elongated as they differentiate into lens fibers. Epithelial cells are not normally observed posterior to the lens equator (see Fig 9-2).

Cortex and Nucleus The center of the lens contains the oldest lens fibers, the embryonic and fetal lens nucleus, while the outer cortical fibers are derived from postnatally differentiated lens epithelial cells. New lens fibers are continuously laid down from the outside as the lens epithelial cells differentiate. Differentiation oflens epithelial cells into cortical lens fibers occurs at the equator. In this region, termed the equatorial lens bow, the lens epithelial cells move centrally, elongate, acquire crystallins, lose organelles, and transform into cortical lens fibers. As is the case clinically, the histologic demarcation between the nucleus and cortex is not well defined (see Fig 9-2).

Zonular Fibers The lens is supported by the zonular fibers that attach to the anterior and posterior lens capsule in the midperiphery (see Fig 9-2 and Chapter 7, Fig 7-7) . These fibers hold the lens in place through their attachme nts to the Ciliary body processes.

CHAPTER 9: Lens. 121

Congenital Anomalies See BCSC Section 6, Pediatric Ophthalmology and Strabismus, and Section 11, Lens and Cataract, fo r discllssion of ectopia lentis and congenital cataract, as well as additional discussion of the following topics.

Congenital Aphakia Congenital apha kia is a rare anomaly that can be subdivided into 2 fo rms: primary and secondary. Histologically, the lens is abse nt in primary congenital aphaki a. The histologiC find ings of secondary congen ital aphakia depend on the underlying etiology. Primary congenital ap hak ia results from failed inducti on of the surface ectoderm during embryogenesis and has been associated with mutations in the PAX6 gene and severe ocular and systemic developmental anomalies. In seconda ry congenital aphakia, the lens has developed but has been resorbed or extruded befo re or duri ng birth. This fo rm of aphakia is often associated with congenital infections, such as congenital rubella.

Lens Coloboma A lens coloboma is characterized by a notch in the lens, typically in an inferonasallocation. This congen ital anomaly is characteristically associated with Ciliary body coloboma and likely occurs secondary to the focal absence or abnormal development of zonular fibers.

Anterior Lenticonus (Lentiglobus) The anterior surface of the lens can assume an abnormal shape) either conical (lenticonus) or spherical (lentiglobus). Clinically, an "oil d roplet" red reflex is present. Anteri or lenticonus may be unilatera l or bilateral. Bilateral anterior lenticonus is usually associated \vith Alport syndrome, whi ch is typically an autosomal dominant disease and is characterized by hemorrhagic nephritis, deafness, anterior polar cataract, retinal flecks, and retinal and iris neovascularization, in addition to anterior lent iconus. Mutations in type IV collagen genes have been described in some forms of Alport syndrome. Histology reveals th inning of and deh iscences in the anterior lens capsule, a decrease in the number of anterior lens epithelial cells, and bulging of the ante rior cortex. Ultrastructural alterat ions of lens capsule collagen and immunohistochemical abnormalities in type 1V collage n have been observed.

Posterior Lenticonus (Lentiglobus) Posterior lenticonus is characterized by a spherical deformity of the posterior surface of the lens (Fig 9-3) . Cli nically, an "oil droplet" red re fl ex is seen. Posterior lenticonus usually occurs as a spo radic, unilateral anomaly and is associated with congenital cataract. Other, rare ocular associations include microphthalmos, microcornea, persistent anterior hyaloid vasc ulature, and uveal colobomas. Posterior lenticonus may also occur as a part of Alport syndro me and the oculocerebro renal syndrome of Lowe. The oculocerebrorenal syndrome of Lowe is an X-linked cond iti on characterized by systemic acidosis, renal rickets, hypoton ia, and congenital cataracts, which histologically d isplay focal, internally directed excrescences of the lens capsule.

122 • Ophthalmic Pathology and Intraocular Tumors

Figure 9-3

Posterior lenticonus,

(Courtesy of

Hans E. Grossniklaus, MD.)

Inflammations Phacoantigen ic Uveitis Also known as phacoanaphylactic endophthalmitis or lens-induced granulomatous en dophthalmitis, this type of lens-induced intraocular inflammation is mediated by IgG immunoglo bulins directed against lens protein. The inflammation may follow accidental or surgical trauma to the lens. Histologically, lens-induced gran ulomatous endophthalmitis consists of a central nidus of degenerating lens material surroun ded by concentric layers of inflammatory cells (zonal granuloma). Multinucleated giant cel ls and neutrophils are present within the inner layer adjacent to degenerating lens material. Lymphocytes and plasma cells make up the intermediate mantle of cells. These cells may be surrounded by fibrovascular connective tissue, depend ing on the duration of the inflammatory response (Figs 9-4, 9-5). See also BCSC Section 9, Intraocular Inflammation an d Uveitis.

Phacoa ntigen ic endopht halmitis, in wh ich inflammatory reacti on surrounds the lens (lower le ft) . The torn caps ule can be observe d in the pupillary region (arrow) . Also note corn eal scar (arrowhead), representing the site of ocular penetration. Figure 9-4

CHAPTER 9:

Lens. 123

. . .. Figure 9-5 Phacoantigenic endophtha lm iti s. Acute and gra nulomatous inflammation, including giant cells (arrow), surrounds inciting lens fibers (aste risk).

Phacolytic Glaucoma See Chapter 7 for a discussion of this topic.

Propionibacterium acnes Endophthalmitis Chronic postoperative endophthalmitis secondary to P acnes may develop following cataract surgery, usually 2 months to 2 years later. O nset of the inflammation may follow Nd:YAG laser capsulotomy that allows release of the sequestered organisms. Propionibacterium acnes endophthalmitis can present with granulomatous keratic precipitates, a small hypopyon, vitritis, and a white plaque containing bacte ria and residual lens material sequestered within the capsular bag (Figs 9-6, 9-7) .

Figure 9-6 Clinical photograph of eye with P aenes endophthalmitis. Note injection of the conjunctiva and small hypopyon. (Courtesy of William C. Lloyd III, MD, and Ralph

Eag/e.

Jr, MD.)

124 • Ophthal mic Pathology and Intraocular Tu mors

Figure 9-7 Histology of a lens capsule from a case of P aenes endophtha lmitis. A, Colonies of bacteria are sequestered within the PAS-positive capsular bag (asterisks). 8, Gram-positive coccobacilli (P aenes) within the capsular bag (a sterisk). (Part A courtesy of William C. Lloyd III, MD, and Ralph C. Eagle, Jr, MD; part 8 courtesy of Taryana Milman, MDJ

Degenerations Cataract and Other Abnormalities

Capsule Mild thicke ning of the lens capsule can be associated with pathologic proliferation of lens epithelium or with chronic inflammation of the anterior segment. Elements with an affinity for basem*nt membranes, such as cop per (chalcosis) and silver (a rgyrosis), can form pigmented deposits in the anterior lens capsule.

Epithelium A severe elevation of intraocular pressure causes injur y to the lens epithelial cells, leading to degeneration of the cells. Clinically, patches of white flecks (glaukomflecken) are seen beneath the lens capsule. Histology shows focal areas of necrotic lens epithelial cells beneath the anterior lens capsule. Associate d degenerated subepithelial cortical material is also present. See also BCSe Section 10, Glaucoma. Injury to the lens epithelium can also be caused by inflammation, ischemia, or trauma and can stimulate epithelial hyperplasia and formatio n of anterior subcapsular fibrous plaques (Fig 9-8A). In this situation, the epithelial cells have undergone metaplast ic transformation into fibroblast-like cells, which are capable of producing collagen. These functionally transform ed epithelial cells arise in response to a variety of stimuli, including inflammation, ischemia, and trauma. Following resolution of the inciting stimulus. the lens epithelium may produce another capsule, thereby completely surrounding the fibrous plaque and prodUCin g a duplication cataract (Fig 9-8B) . Retention of iron-containing metallic foreign bodies in the lens may lead to lens epithelial degeneration and necrosis, secondary to siderosis. The presence of iron within the epithelial cells can be demonstrated by Pe rls Prussian blue stain. Posterior subcapsular cataract may be the most common abnormality involving the lens epithelium. There are a number of risk factors for this condition, including chronic

CHAPTER 9:

Lens. 125

Figure 9-8 Anter ior and posterior subcaps ular cataracts. A, Gross photog raph shows white an terior (arrow) and posterior (arrowh ead) subcapsu lar plaques located centrally. B, Fibrous plaqu e (asterisk) is present posterior to t he origina l lens capsu le (arrowhead). (Part A courtesy of Tatyana Milman, MD; part B courtesy of Hans E. Grossniklaus, MD.)

intraocular inflammation, diabetes m ellitus, ionizing radiation exposure, smoking, and prolonged corticosteroid use (Fig 9-9A; see Fig 9-8A). Posterior subcapsular cataract is frequently associated with cortical degeneration and nuclear sclerosis. Histologically, development of this type of cataract begins with epithelial disarray at the equator, followed by posterior migration of the lens epithelium. As the cells m igrate posteriorly, they enlarge and swell to 5-6 times their normal size. These swollen cells, referred to as bladder cells of Wedl, can cause significant visual impairment if they involve the axial portion of the lens (Fig 9-9B). Disruption of the lens capsule often results in proliferation of lens epithelial cells. FollOWing extracapsular cataract extraction, for exalllple, remaining epithelial cells can proliferate and cover the inner surface of the posterior lens capsule, producing clinically appreciable posterior capsule opacification. These collections of proliferating epithelial cells may form partially transparent globular masses, called Elschnig pearls, which are

A Posterior subcapsu lar cataract. A, Viewed at the slit lamp. B, Wed I ce lls. Note t he large, ro und, nucleated bladder or Wedl cells (arrows) and th e sma ller lens epith elial cells lin ing the posterior lens capsu le (arrowhead). (Part A courtesy of ClBA Pharmaceutical Co, division of CIBA-GEIGY

Figure 9-9

Corp _Reproduced with permission from Clinical Sympos ia. Part B courtesy of Robert H. Rosa, Jr, MD.)

126 • Ophthalmic Patholo gy and Intraocular Tumors

Eischnig pearls. Ai Clinica l appearance using retroillumination to demonstrate posterior capsule opacit ies . B, Histology depict ing proli ferat ing lens epit helium (arrows) on posterior capsule. (Part A courtesy of Sander Dubovy, MD: part B courtesy of Debra J Shetlar, MD.) Figure 9·10

histologically identical to bladder cells of Wedl (Fig 9-10). Sequestration of proliferating lens fibers in the equatorial region, often as a result of incomplete cortical removal during cataract surgery, may create a doughnut-shaped configuration referred to as a Soemmering ring cataract (Fig 9-11). Cortex

Opacities of the cortical lens fibers are most often associated with nuclear sclerosis, posterior subcapsular cataracts, and ultraviolet light exposure. Clinically. cortical degenerative changes fall into 2 broad categories: generalized discolorations with loss of transparency and focal opacifications. Generalized loss of transpare nc y cannot be diagnosed histologically with reliability, as histologic stains that are used to colori ze th e lens after it is processed prevent the assessment of lens clarity. The earliest sign offoeal cortical degeneration is hydropic swelling of the lens fibers with decreased intensity of the eosinophilic staining. Focal cortical

Figure 9·"

Soemmering ring cataract. A, Doughnut-shaped white cataractous material is present in the equatoria l reg ion of the lens capsule and surrounds one lens haptic (arrows). The lens optic and a second haptic are positioned in front of the lens capsular bag, in the sulcus. B, Ring cata ract, photomicrogra ph (arrows). (Parr A courtesy of Taryana Mitman, MD.J

CHAPTER 9:

Lens.

127

opacities become more appare nt when fiber degeneration is advanced enough to cause liquefactive change. Light microscopy shows the accumulation of eosinophilic globules (morgagn ian globules) in slitlike spaces between the lens fibers, which is a reliable histologic sign of cortical degeneration (Fig 9-12; see Fig 9- 13C). As focal cortical lesions progress, the slitlike spaces become confluent, formin g globular collections of lens protein. Ultimately, the entire cortex can become liquefied, allowing the nudeus to sink downward and the capsule to wrinkle (morgagnian cataract) (Fig 9-13). Denatured lens protein can escape through an intact lens capsule and provoke an anterior chamber macrophagic inflammato ry reaction, a condition known as phacolytic glaucoma (discussed in Chapter 7) .

Nucleus The continued production of lens fibers subjects the nucleus in the ad ult lens to the lifelong stress of mechanical compression. This compression causes hardening of the lens nucleus. Aging is also associated with alterations in the chemical composition of the nuclear fibers. The pathogenesis of nuclear discoloration is poorly understood and probably involves more than 1 mechanism, including accum ulation of urochrome pigment. Clinically, the lens nucleus may appear yellow, brunescent, or deep brown (Fig 9- 14). Nuclear cataracts are difficult to assess histologically because they take on a subtle hom*ogeneous eOSinophilic appearance. The loss of cellular lam inations (artifactitious clefts) probably correlates better with fir mness of the nucleus than it does with optical opacification clinically (see Fig 9- 13C). OccaSionally, crystalline deposits, identified as calcium oxalate, may be observed within a nuclear cataract (Fig 9-15). These deposits are birefringent under polarized light.

B Figure 9-12 Cataract. A, Extensive corti ca l changes are present (asterisk). B, Cortica l degeneration. Lens ce ll fibers (asterisk) have sw ollen and fragmented to form morgagni an globules (arrowheads). The lenticul ar frag ments are opaqu e and will increase osmotic pressure wit hin the capsule. (Courtesy of Hans E. Grossniklaus, MD.)

128 • Ophtha lm ic Pathology and Intraocular Tumo rs

B ~

________

____

Figure 9-13 Morgagnian cataract A, The brunescent nucleus has sunken inferiorly with in the liquefied cortex. 8 , The lens cortex is liquefied, leaving the lens nucleus lasterisk) floating free within the capsular bag . C, Note the artifactitious, sharply angul ated clefts (arrows) in this nuclear sclerotic cataract. A zone of morgagnian globules 1M) is identified. (Part A courtesy of Bradford Tannen, MD; part B courtesy of Debra J. Sherfar; MD.)

Figure 9-14 Surgically extracted lens nucl ei showing varying degrees of brunescence and opacification . (Courtesy of Hans E. Grossniklaus, MD.)

CHAPTER 9: Lens.

129

Figure 9-15 Crysta lline deposi t s of calcium oxalate are noted withi n t he len s (arrows). A cortical cl eft wit h morgagn ian globules (arrowheads) is also seen. (Courtesy of Tatyana Milman, MD.)

Neoplasia and Associations With Systemic Disorders There are no reported examples of neoplasms arising in the human lens. Premature opacification of the lens has been noted in many systemic disorders. See BCSC Section II , Lens

and Cataract.

Pathology of Intraocular Lenses Placement of an intraocular lens following the removal of a cataract has become standard in most cases of cataract su rgery. See BCSC Section 11, Lens and Cataract, for discussion of th is topic.

CHAPTER

Vitreous

Topography The vitreous humo r makes up most of the volume of the globe and is important in many diseases that affect the eye. BeSe Section 12, Retina and Vitreous, discusses the vitreous in detail. The average volume of the adult vitreo us is 4 mL. The vitreous is composed of 99% water and severa l mac ro molecules, including

types II and IX collagen glycosaminoglycans soluble proteins glycoproteins The outer portion of the vit reous has a greater number of collagen fibr ils and is termed the

vitreous cortex. The outer surface of the co rtex is kn own as the hyaLOid face. The vitreous is bordered ante riorly by the lens, where its attachme nt to the lens capsule is called the hyaloideocapsular ligamen t. This attach ment is fir m in young patients and becomes increaSingly tenuous with age. The vit reous is attached to the internal limiting membrane (ILM) of the retina by the insertion of the cortical collagen into the basem*nt membrane structure that comprises th e basal lam ina of the ciliary epitheli um and the ILM. The vitreous attaches most fir mly to the vitreous base, a 360' band that straddles the ora serrata and va ries in width from 2 to 6

111m.

The vitreous base ex tends more posteri-

orly with advancing age. Other relatively fi rm attachments of the vit reous are at the margins of the optic nerve head along the course of major retinal vessels in a circu lar area around the fovea at the edges of areas of vitreoretina l degeneration such as lattice degeneration

The strength of the vitreoreti nal attachment is important in the pathogenesis of ret inal tears and detachment, macular hole fo rmation, and vitreous hemorrhage from neovascularization.

The embryologic development of the vitreous is generally divided into 3 stages: 1. primary vitreous 2. secondary vitreous 3. tertiary vitreous 131

132 • Ophthalmic Path ology and Intraocular Tumors The primary vitreous consists of fib rillar material; mesenchymal cells; and vascular components: the hyalOid artery, vasa hyaloidea propria, and tunica vasculosa lentis (see Fig 4-3 in BCSC Section I I , Lens and Cataract). The secondary vitreous begins to form at approximately the ninth week of gestation and is destined to becom e the main portion of the vitreolls in th e postnatal and adult eye. The primary vit reou s atrophies w ith formati on of the secondary vit reous, leaving on ly a clear ce ntral zo ne through the vitreous (called

the hyalOid canal, or the Cloquet canal) and, occasionally, the Bergmeister papilla and Mittendorf dot as vestigial remnants (discussed later). The secondary vitreous is relatively acellular and completely avasc ul ar. The cells present in the secondary vitreous are called hyalocytes. The lens zonular fibers represe nt the tertiary vitreous.

Congenital Anomalies Persistent Fetal Vasculature Persistent fetal vasculature (PFV; previously known as persistent hyp erpla stic primary vitreous, or PHPV ) is characterized by the persistence of variable components of the primary vitreous and is most often un ilateral. In most cases of clinically sign ificant PFV, a fibro vascular plaque in the retrolental space extends laterally to involve the ciliary processes, which may be pulled cent ripetally by tractio n from the fibrovascular tissue. The clinical and gross appearance of elongated ciliary processes results. The ante rior fi brovascular plaque is generally contiguous posteriorly with a remnant of the hyaloid artery that may attach to the optic nerve head (Fig 10-l) . Involvement of the posterior structures may be more extensive, with tractional detachment of the peripapillary retina resulting from traction from preretinal membranes. The lens is often cataractous. and nonoc ular tissues such

Persisten t fetal va scula ture . Note th e prominent ante rior fibrovascular plaqu e (arrowhead). The posterior remnant of the persiste nt hyaloid artery is evident at the optic nerve head (arrow) . (Courtesy of Hans E. Grossniklaus, MD.)

Figure 10-'

CHAPTER 10:

Vitreous.

133

as adipose tissue and cartilage may be present in the retrolental mass. Eyes affected by PFV are often microphthalmic. See also Chapter 19 in this volume and BeSe Section 6, Pediatric Ophthalmology and Strabismus.

Bergmeister Papilla Persistence of a small part of the posterior portion of the hyaloid artery is referred to as a Bergmeister papilla. This anomaly generally takes the form of a veil-like structure or a fingerli ke projection extending anteriorly from the surface of the optic nerve head.

Mittendorf Dot The hyalOid artery attaches to the tunica vasculosa lentis just inferior and nasal to the center of the lens. With regression of these vascular structures, it is not uncommon to see a focal lens opacity at this site, which is referred to as a Mittendorf dot (see Fig 2-41 in BeSe Section 2, Fundamentals and Principles of Ophthalmology) .

Prepapillary Vascular Loops Retinal vessels may grow into a Bergmeister papilla and then return to the optic nerve head, creating the appearance of a vascular loop. These loops should not be mistaken for neovascularization of the optic nerve head. See Fig 12-3 in BeSe Section 12, Retina and Vitreous .

Vitreous Cysts Vitreous cysts generally occur in eyes with no other pathologic findings, but they have been seen in eyes with retinitis pigmentosa, those with uveitis, and eyes with remnants of the hyaloid system. Histologic studies have suggested the presence of hyalOid rem nants in the vitreous cysts. The exact origin of the cysts is not known.

Inflammations As a relat ively acellular and completely avascular structure, the vit reous is not an active participant in inflammatory disorders. It does become involved secondarily in in flammatory conditions of adjacent tissues, however. The term vitritis is used to denote the presence of benign or malignant white blood cells in the vit reous. Vitreous inflammat ion associated with infectious agents, particularly bacteria and fungi, is clinically referred to as infectious endophthalmitis. Bacterial endo phthalmitis is characterized by neutrophilic infiltration of the vitreous (Fig 10-2). This infiltration leads to liquefaction of the vitreous, with subsequent posterior vitreous detachment. Severe inflammation may be accompanied by formation of fibrocellular membranes, which typically form in the retrolental space and may exert tract ion on the peripheral retina. The vitreous infiltrate in noninfectious uveitis is typically composed of chronic inflammatory cells, including T and B lym phocytes, macrophages, and histiocytes. See also BeSe Section 9, Intraocular Inflammation and Uveitis.

134 • Ophthalmic Pathol ogy and Intraocular Tumors

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A, Gross photograph of opacif ica ti on and inf iltration of th e vitre ous as a result of bacte rial endophthalmitis. B, Secti on shows ce ll ular infiltrati on of vit reou s in endopht halmit is (retinal detachm ent is artifactiti ous). (Courtesy of Hans E. Grossniklaus, MO .)

Degenerations Syneresis and Aging Syneresis of the vitreous is defined as liquefaction of the gel. Syneresis of the central vit reous is an almost universal consequence of aging. It also occurs as a consequence of vi treous inflammation and hemorrhage and in the setting of pathologic myopia. The prom inent lamellae and strands that develop in aging and folloWing inflammation or hemorrhage are the result of abnormally aggregated collagenous vitreous fibe rs arou nd syneretic areas (Fig 10-3 ). Syneresis is one of the contributing factors leading to vitreous detachment.

Posterior Vitreous Detachment

Posterior vitreous detachment (PVD) occurs whe n a dehiscence in the vitreous cortex allows fluid from a syneretic cavity to gain access to the potential sub hyaloid space, causing

Figure 10·3

Gross photograph of vit reous co ndensations ou tlining syn eret ic caviti es.

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CHAPTER 10:

Figure 10-4 Gross photograph of posterior vitreous detachmen t.

Vitreous.

135

(Courresyof Hans E. Grossniklaus, MD,)

the remaining cortex to be stripped from the ILM (Fig 10-4). As fluid drains out of the syneretic cavities under the newly formed posterior hyaloid, the vitreous body colJapses anteriorly, remaining attached only at its base. Vitreous detachment generally occurs rapidly over the course of a few hours to days. A weakening of the adherence of the cortical vitreous to the ILM with age also plays a role in PVDs. The reported incidence of PVD is up to 65% at age 65 and is increased by intraocular inflammation, aphakia or pseudophakia, trauma, and vitreoretinal disease. PVD is important in the pathogenesis of many conditions, including retinal tears and detachment, vitreous hemorrhage, and macular hole formation. See BeSe Section 12, Retina and Vitreous, for additional discuss ion. Rhegmatogenous Retinal Detachment and Proliferative Vitreoretinopathy

Retinal tears form from vitreous traction on the retina during or after PVD or secondary to ocular trauma. Tears are most likely to occur at sites of greatest vitreoretin al adhesion, such as the vitreous base (Fig 10-5) or the margin of lattice degeneration. The

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Figure 10-5 A, Gross photograph of retina l tea rs at vitreous base. 8, Photom1crograph shows condensed vitreous (arrow) attached to anterior flap of ret inal tea r. (Courresyof W Richard Green, MD.)

136 • Ophthalmic Pathology and Intraocula r Tumors

histopathology of retinal tears reveals that the vitreous is adherent to the retina along the flap of the tear. In the area of reti na separated fro m the underlying retinal pigment epitheliUIn (RPE), there is loss of photo receptors. Retinal detachment occurs when vitreous traction and fluid currents resulting from eye movements combine to overcome the forces maintaining retinal adhesion to the RPE. The principal histopathologic findings in retinal detachment consist of the following: degeneration of the outer segments of the photoreceptors eventual loss of photoreceptor cells migration of Mi.iller cells proliferation and migration of RPE cells Small cystic spaces develop in the detached retina, and in chronic detachment, these cysts may coalesce into large macro cysts (Fig 10-6). With rhegmatogenous retinal detachment, cellular membranes may fo rm on either surface (anterior or posterior) of the retina (Fig 10-7). Cli nically, this process is referred to as proliferative vitreoretinopathy (PVR). PVR membranes form as a result of proliferation of RPE cells and other cellular elements, including glial cells (Miiller cells, fibro us astrocytes), macrophages, fibroblasts, myofibroblasts, and possibly hyalocytes. The cell biology of PVR is complex and involves the interaction of various grmvth factors, integrins, and cellular proliferation. Studies have shown a significant association between clinical grades of PVR and the expression levels of specific cytokines and/or grovvth factors in the vitreous fluid . Harada C, Mitamura Y, Harada T. The role of cytokines and trophic factors in epiretinal mem branes: involvement of Signal transduction in gli al cells. Prog Retin Eye Res. 2006;2s{2): 149 164 . Epub 2005 Dec 27 .

Macular Holes Idiopathic macular holes most likely form as the result of degenerative changes in the vitreous. Optical coherence tomography (OCT) has greatly advanced our understanding

Figure 10-6 Long-standing tota l retinal detachment with macrocystic degenerati on of the retina.

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of the anatomical features of full -thickness macular holes and early macular hole formation. These studies are most consistent with a focal anteroposterior traction mechanism, but some inconsistencies in clinical cases suggest a role for degeneration of the inner retinal layers. Localized perifoveal vitreous detachme nt (an early stage of age-related PVD ) appears to be the primary pathogenetic event in idiopathic macular hole formation (Fig 10-S) . Detach ment of the posterior hyaloid from the pericentral retina exerts anterior traction on the foveola and localizes the dynamic vitreous traction associated ·with ocular rotations into the peri foveolar region . OCT has clarified the pathoanatomy of early macular hole stages, beginning with a foveal pseudocyst (stage la), typically followed by disruption ofthe outer retina (stage Ib), before progressing to a full-thickness dehiscence (stage 2). Histologically, full -thickness macular holes are similar to holes in other locations. A full-thickness retinal defect with rounded tissue margins (stage 3) is accompanied by loss of the photoreceptor outer segments in adjacent ret ina that is separated from the RPE by subretinal fluid (see Fig 10-SC). An epiretinal membrane composed ofMiiller cells, fibrous astrocytes, and fibroblasts with myoblastic differentiation is often present on the surface of the retina adjacent to the macular hole. Cystoid macular edema in the parafoveal ret ina adjacent to the full-t hickness macular hole is relatively common . Following surgical repair of macular holes, closer apposition of the remaining photoreceptors and variable glial scarring close the macular defect. See BCSC Section 12, Retina and Vitreous, for further discussion . Gass JD. Reappraisal of biomicroscopic classification of stages of development of a macular hole. Am J Ophthalmol. 1995;119(6);752- 759 . Smiddy WE, Flynn HW Jr. Pathogenesis of macular holes and therapeuti c implications. Am J Ophthalmol. 2004;137(3);525- 537.

Hemorrhage A constellation of pathologic features may develop in the vitreous following vitreous hem 0rrhage. After 3-10 days, red blood cell clots undergo fibrinolysis and red blood cells may

138 • Ophthalmic Pathology and Intraocular Tu mors

Optic nerve

Macular holes. A, Spectral doma in OCT showing stage 3 macular hole wit h ful l~ thickn ess retinal defect, round ed margins, cysto id macular edema (as terisks), an d opercu lum (arrowh ead). Note the posterior hyaloid face (arrow) teth ered to th e peripapill ary retina near

Figure 10-8

the optiC diSC . B, Gross photog rap h of full-thickness macu lar hole (arrow). C, Histology of fullthickne ss macular hole showing rounded gliotic margi n (arrow) with positive staining for glial fi bri llary acidic protei n (GFAP), highl ig ht ing the M uller ce ll s and fi brou s astrocytes . (Parts A and B courtesy of Robert H. Rosa, Jr. MD, and Terry Hanke, CRA; part C courtes y of Patricia Chevez-Barrios, MD.)

diffuse throughout the vitreous cavity. At th is time. breakdown of the red blood cells also occurs. Loss of hemoglobin from the red blood cells produces ghost cells (see Chapter 7. Fig 7-10) and hemoglobin spherules (Fig 10-9). Obstruction of the trabecular meshwork by these cells may lead to ghost cell glaucoma. See also BCSC Section 10, Glaucoma . The process of red blood cell dissolution attracts macrophages, which phagocytose the effete red blood cells. The hemoglobin is broken down to hemosiderin and then removed from the eye. In massive hemorrhages, cholesterol crystals caused by the breakdown of red blood cell membranes may be present, often surrounded by a foreign body giant cell reaction. Cholesterol appears clinically as refractile intravitreal crystals (synchesis scintillans). Syneresis of the vitreo us and PVD are common after vit reous hemorrhage. Asteroid Hyalosis

Asteroid hyalosis is a condition with a spectacular clinical appearance (see Fig 12-7 in BCSC Section 12, Retina and Vitreous) but little clinical significance. Histologically, asteroid bodies are rounded structures measuring 10- 100 nm that stain positively with alcian

CHAPTER 10:

Vit reous. 139

A Figure 10-9 A, Clinical photograph of retrolental hemoglobin spherules. B, Cytologic preparation of hemog lobin spherules removed from the vitreous cavity, (Reproduced with permission from SprauJ Cw, Grossniklaus HE. Vitreous hemorrhage . Surv Ophtha lmol, 1997;42(1):3-39.)

blue and positively with stains for neutral fats, phospholipids, and calcium (Fig 10-10). The bodies stain metachromatically and exh ibit birefringence. Occasionally, asteroid bodies will be surro unded by a foreign body giant cell, but the condition is not generally associated with vitreous inflammation. The exact mechanism of formation of asteroid bodies is not known; however, element

mapping by electron spectroscopic imaging has revealed a hom*ogeneous distribution of calcium, phosphorus, and oxygen. The electron energy loss spectra of these elements show details sim ilar to those found for hydroxyapatite. Im munofluorescence microscopy has revealed the presence of chondroitin-6-sulfate at the periphery of asteroid bodies; and carbohydrates speCific for hyaluronic acid were observed by lectin -gold labeling to be part of the inner mat rix of asteroid bodies. Thus, asteroid bodies exhibit structural and elemental Similarity to hydroxyapatite, and proteoglycans and their glycosam inoglycan side chains appear to playa ro le in regu lat ing the biomineralizatio n process. Wi nkJe r J. Lu nsdorf H. Ultrastructure and composition of asteroid bodies. Invest Ophthalmol

Vis Sci. 200 1;4 2(5) :902-907.

Vitreous Amyloidosis The term amylOidosis refers to a group of diseases that lead to extracellular deposition of amylOid. AmylOid is composed of various proteins that have a characteristic ultrastructural

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Fi gure 10-10 Asteroid bodies (arrows) and eryth rocyt ic debris within the vitreous. (Courtesy of Taryana Milman, MD.)

140 • Ophthalmic Path ology and Int raocula r Tumors

Figure 10-11 Electron photomicrograph shows characteristic amyloid fibrils. (Courtesy of David J. Wilson, MO)

Figure 10-12 Polarized light photomicrograph of the Congo red- stained vitreous from a

patient with familial amyloid polyneuropathy. (Courtesv of David J. Wilson, MD.)

appearance of nonbranching fibrils with variable length and a diameter of 75-100 A (Fig 10-11). The proteins forming amyloid also have in common the ability to form a tertiary structure characterized as a ~-p leated sheet, which then enables the proteins to bind Congo red stain and show birefringence in polarized light (Fig 10-12). Amyloid may be derived from various types of protein, and the protein of origin is characteristic for different forms of amyloidosis. Amyloid deposits occur in the vitreous when the protein forming the amyloid is tral1sthyretil1, previously known as prealbumil1. Multiple genetic mutations have been described that result in various am ino acid substitutions in the transthyretin protei n. The most common mutations were originally described in familial amyloid polyneuropathy (FAP) types I and II. Systemic manifestations in patients with FAP include vitreous opacities and perivascular infiltrates (Fig 10-13), peripheral neuropathy, cardiomyopathy, and carpal tunnel syndrome. The mechanism by which the vit reous becomes involved is not known with certai nty. Because amyloid deposits are found withi n the walls of retinal vessels and in the RPE, amyloid may gain access to the vitreous through these tissues. In addition, because transthyretin is a blood protein, it may gain access to the vitreous by crossing the blood- aqueous or blood-retina barrier.

Neoplasia Intraocular lymphoma Primary neoplastic invo lvement of the vit reous is uncommon because of the relatively acellular nature of the vitreous. However, the vitreous can be the site of primary involvement

CHAPTER 10:

Figure 10-13

Vit reous. 141

Perivascular sheath ing (arrow) associated with vit reou s amyloidosis.

(Courtesy of

Hans E. Grossniklaus, MO.)

in cases of B-cell lymphoma. This type of lymphoma has been refer red to as primary intraocular!central nervous system lymphoma, large cell lymphoma, and vitreoretinal/ retinal lymphoma. lmmunohistochemical and molecular genetic studies have confirmed that this entity is typically a B-ceillymp homa; however, T-cell lymphomas may occur in rare instances. Clinically, primary intraocular lymphoma (PIOL) presents most commonly as a vitritis. Some patients have sub-RPE infiltrates (Fig 10-14) with a very characteristic speckled pigmentation overlying tumor detachments of the RPE. The sub-RPE infiltrates are present in a mino rity of patients with intraocular lymphoma. Recent evidence suggests that the lymphoma cells may be attracted to the RPE by B-cell chemokines and subsequently migrate from the sub- RPE space into the vit reous. More than half of patients presenting with ocular findings have or will develop involvement of the central nervous system.

Figure 10-14 Sub-RPE infiltrate s in a pat ient w ith primary intraocular lymphoma. Note the characteristic speckled pigmentation over th e tumor detachments of the RPE. (Courtesy of Roben H. Rosa, Jr, MD.)

142 • Ophthalmic Pathology and Intraocular Tumors

The diagnosis of intraocular lymphoma is made by cytologic analysis of vitrectomy specimens. Immunohistochemical study of cell markers, flow cytometry, or gene amplification studies can be performed on vitreous specimens, although the standard method of diagnosis is cytology. Cytologically, the vitreous infiltrate in intraocular lymphoma is heterogeneous. The atypical cells are large lymphoid cells, frequentl y with a convoluted nuclear memb rane and multiple, conspicuous nucleoli. An acco mpanyi ng infiltrate of small lymphocytes almost always appears, and the normal cells may obscure the neoplastic cell population. These small round lym phocytes are mostly reactive T cells. Numerous cell ghosts are usually present, and this feature is very suggestive of a diagnosis of intraocular lymphoma (Fig 10-15). Immunohistochemically, the viable tumor cells can be labeled as a monoclonal population ofB cells. Flow cytometry is helpful in demonstrating a monoclonal population. Other laboratory tests that may be useful in the diagnosis and follow-up of patients with intraocular lymphoma are determination of the interleukin-IO to interleukin-6 ratio and the use of microdissection and polymerase chain reaction (PCR) for the detection of immunoglobulin gene rearrangement and translocation. The subretinal/sub- RPE infiltrates are composed of neoplastic lymphoid cells (Fig 10-1 6). With or without treatment, the subretinal infiltrates may resolve, leaving a focal area of RPE atrophy. Optic nerve and retinal infiltration may also be present. Infiltrates in these locations tend to be perivascular and may lead to ischemic retinal or optic nerve damage. The choroid is most ofte n free of lymphoma cells; however, secondary ch ronic inflammation may be present in the choroid . In the setting of systemic lymphoma with ocular involvement, the choroid (rather than the vitreous, retina, or subretinal space) is the primary site of involvement. Coupland SE, Hummel M, Muller HH, Stein H. Molecular analysis of immunoglobulin genes in primary intraocular lymphoma. Invest Ophthalmol Vis Sci. 2005;46(10):3507-3514. Levy-Clarke GA, Chan CC, Nussenblatt RB. Diagnosis and management of primary intraocular lymphoma. Hematol Oneal Clin North Am. 2005;19(4):739-749 . Read R\"~ Zamir E, Rao NA. Neoplastic masquerade syndromes. Surv aphtha/mol. 2002;47(2): 81 -124.

Figure 10-15

Cytologic preparation of vit re-

ous lymphoma. Note the atypical ce lls (arrowheads) with large nuclei and multiple nucleoli. Cell ghosts (arrows) are also present. (Courtesv of David J. Wilson, MD.)

CHA PTER 10:

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Vitreous. 143

Figure 10-1 6 Primary intraocular lymphoma. Note the detachment of the RPE by tumor (arrow) overlying retinal gliosis (asterisk), and intact Bruch membrane (arrowhead). Secondary chronic inflammation is present in the choroid . (Courtesy of Robert H. Rosa, Jr, MDJ

CHAPTER

Retina and Retinal Pigment Epithelium

Topography The retina and the retinal pigment epithelium (RPE) make up 2 distinct layers that together line the inner two-thi rds of the globe: 1. The RPE is a pigmented layer derived from the outer layer of the optic cup. 2. The neurosensory retina is a delicate, tran sparent layer derived from the inn er

layer of the optic cup. Ante riorly. the RPE becomes continuous with the pigmented epithelium of the ciliary body. and the retina becomes continuous with the nonpigmented ciliary body epithelium. Posteriorl y, the RPE terminates at the optic nerve. just prior to the term ination of the Bruch mem brane. The nuclear. photoreceptor. and synaptic layers of the retina gradually taper at the optic nerve head. and only the nerve fiber layer (NFL) continues on to fo rm the optic nerve. See BeSe Section 12. Retina and Vitreous. for additional discussion.

Neurosensory Retina The topographic va ri ation in the structures of th e retina is strikin g, wi th regjonal variati on in the neural stru ctures as well as the retinal vasc ulature. The neurosensory retina

has 9 layers (Fig 11 -1). Begin ning on the vitreous side and progressing to the choroidal side. they are 1. internal lim iting membrane (ILM; a true basem*nt membrane syntheSized by Muller cells) 2. nerve fiber layer 3. ganglion cell layer 4. inner plexiform layer 5. inner nuclear layer 6. outer plexiform layer 7. outer nuclear layer (n uclei of the photoreceptors) 8. external lim iting membrane (ELM; not a true membrane but rather an apparent membrane for med by a series of desmosomes between Muller cells and photo receptors) 9. photo receptors (inner and outer segments) of the rods and cones 145

146 • Oph t ha lmic Pathology and Intraocu lar Tumors

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Norma l retinal layers. From vitreo us to choro id: ILM = internal limiting membrane, NFL = nerve fibe r layer, GeL = ganglion ce ll layer, IPL = inner plexiform layer, INL = inner nuclear layer, OPL = outer plexiform layer, ONL = outer nuclear layer, P = photoreceptors (inner/ outer segments) of rods and cones. RPE = ret inal pigment epithelium. Bruch membra ne, arrowhead; choroid, asterisk. The external lim iting membrane (ELM) is not shown in t his figure. (Courtesy of Robert H. Rosa, Jr, MD. ) Figure 11-1

The arrangement of the retina (in tissue sections oriented perpendicular to the retinal surface) is vertical from outer to inner layers, except for the NF L, where the axons run horizontally toward the optic nerve head. Consequently, deposits and hemorrhages in the deep retinal layers have a round appearance clinically when viewed on edge, whereas those in the NF L have a feathery appearance. The blood supply of the retina comes from 2 sources, with a watershed zone inside the inner nuclea r layer. The retinal blood vessels supply the NFL, ganglion cell layer, inner plexiform layer, and inner two-thirds of the inner nuclear layer. The choroidal vasculature supplies the outer one-third of the inner nuclear layer, outer pleXiform layer, outer nuclear layer, photo recep tors, and RPE. Because of th is division of the blood supply to the retina, ischemic choroidal vascular lesions and ischemic lesions attributed to the retinal vasculature produce different histologic pictures. Ischemic retinal injury produces inner ischemic atrophy of the retina (see Fig 11-13), and choroidal ischemia produces outer ischemic retinal atrophy (see Fig 11 -12). Histologicall y, the term macula refers to that area of the retina where the ganglion cell layer is th icker than a Single cell (Fig 11 -2) . Clinically, this area corresponds approximately with the area of the retina bound by the inferior and superior vascular arcades. The macula is subdivided into the foveola, the fovea, the parafovea, and the perifovea. Only

CHAPTER 11:

A ......_ . I I I

Retina and Retinal Pigment Epitheli um . 147

Fi g ur. " -2 A, The normal mac ula is identified histolog ica lly by a mu lticellular, thick ganglion ce ll layer and an area of focal thinnin g, the foveola. Note the nerve fiber layer (arrowhead) in

the nasal macular region and the oblique orienta tion of the nerve fiber layer of Henle (outer plexiform layer, asterisk). Clinically, the macula lies between the inferior and superior vascular

arcades. S, Spectral domain optical coherence tomography ISO-OCT) of the macula showing in vivo histologic assessment with tremendous details of the lamellar architecture of the ret ina. Note the nerve fiber layer (arrowhead) in the nasal macular region, the nerve fiber layer of Henle louter plexiform layer, asteriskl. and the external limiting membrane (arrow). C, In the region of the foveola , the inner cellular layers are absent, with an increased density of pigment in the RPE Note the external limiting membrane (ELM) . The inc iden t light falls directly on the photoreceptor outer segments, reducing the poten tial for distortion of light by overlying tissue elements. (Parr B counesyof Roberr H. Rosa, Jr, MO.)

photoreceptor cells appear in the ce ntral foveola; the ganglion cells, other nucleated cells (including Muller cells), an d blood vessels are not present. The concen tration of cones is greater in the macula than in the peripheral retina, and only cones are present in the fovea. Nerve fibers in the outer plexiform laye r (nerve fi ber layer of Henle) of the macula run obliquely (see Fig [[ -2A). This morphologic feature results in the flowe r-petal appearance of cystoid macul ar edema (eME) observed on fluorescein angiography and the star-shaped configuration of hard exudates observed ophthalmoscopically in conditions that cause macular edema. Xanthophyll pigment gives the macula its yellow appearance clinically and grossly (macula luteal, but the xanthophyll dissolves during tissue processing an d is not present in histologic sections.

148 • Ophthalmic Pathology and Intraocular Tumo rs

Retinal Pigment Epithelium The RPE consists of a monolayer of hexago nal cells with ap ical microvilli and a basem*nt membrane at the base of the cells. This monolayer has the following specialized functio ns: vitam in A metabolism maintenance of the outer blood- retina barr ier phagocytosis of the photorecepto r outer segments absorption of light heat exchange for mation of the basal lamina of the inner portion of the Bruch membrane production of the mucopolysacchar ide matrix that surrounds the photoreceptor outer segments active transport of materials into and out of the subretinal space

Compared with that of the retina, the topograph ic variation of the RPE is subtle. In the macula, the RPE is taller, narrower, and more heavily pigmented, and it forms a regular hexagonal array. In the equatorial and mid peripheral area, the RPE cells are larger in d iameter and thinner. Variability in the diameter of the RPE cells increases in the peripheral ret ina. The amount of cytoplasm ic pigment, primarily lipofuscin, increases with age, particularly within the RPE in the mac ular region.

Congenital Anomalies Albinism Albinism is a general term that refers to a congenital di lution of the pigment of the skin, the eyes and the skin, or just the eyes. The cond ition results from genetic mutations that cause abnormalities in the biosynthesis of melanin pigment. True albinism has been subdivided into oculocutaneo"s and ocular albinism. This distinction is somewhat helpfu l clinically, but in reality all cases of ocular albinism have some degree of mild cutaneOllS involvement. There is a pathophysiologic diffe rence betwee n the 2 types of albinism. In oculocutaneous albinism, transmission is commonly autosomal recessive, and the amou nt of melanin in each melanosome is reduced, whereas in ocular albinism, transmission is com monly X-linked recessive, and the nu mber of melanosomes is reduced (Fig 11 -3). See BCSC Section 6, Pediatric Ophthalmology and Strabismus, and Section 12, Retina and Vitreous, for further discussion.

Myelinated Nerve Fibers Generally, myeli nation of the nerve fibers in the optic pathways terminates at the lamina cribrosa. However, myelination produced by oligodendroglial cells in the NFL can occur (see Fig 24-3 in BCSC Section 6, Pediatric Ophthalmology and Strabismus). Though usually contiguous with the optic nerve head, myeli nat ion may also occur in isolation away from the optic nerve head and, iflarge, can produce a cl inically significant scotoma. Myelinated nerve fibers have been associated wi th myopia, amblyopia, strabismus, and nystagmus.

CHAPTER 11:

Retina and Retinal Pigment Epithelium.

149

Figure 11-3 Albinisim. A, Iris transillumination. 8, Fundus hypopigmentation . C, Photomicrograph illustrates decreased pigmentation in the iris pigment epithelium (smaller melanosomes) allowing visualization of the nuclei (arrow). No appreciable pigmentation is present in the iris stroma (asterisk). D, Photomicrograph shows RPE and choroid in an albino eye. Note the apical distribution of melanin granules and overa ll decreased pigmentation in the RPE (arrow), rare giant melanosomes (arrowh ead) in the RPE, and lack of appreciable pigmentation in the choroidal stroma (asterisk). (Parts A and 8 courtesy of Robert H. Rosa, Jr, MD; parts C and 0 courtesy of Taryana Milman, MD, and Ralph C. Eagle, Jr, MD.)

Vascular Anomalies There are numerous congenital anomalies of the retinal vasculature. including capillary hemangioma and cavernous hemangioma, parafoveal telangiectasia. and Coats disease. Many of these anomalies and their clinical features are covered in BCSC Section 12, Retina and Vitreous. In Coats disease. exudative retinal detachment occurs as a result of leakage from abnormalities in the peripheral ret ina, including telangiectatic vessels, microaneurysms, and saccular dilations of retinal vessels (Fig 11-4). Histologically, retinal detachments secondary to Coats disease are characterized by the presence of "foamy" macrophages and cholesterol crystals in the subretinal space.

Congenital Hypertrophy of the RPE Congenital hypertrophy of the RPE (CHRPE), a relatively common congenital lesion, is characterized clinicall y by a flat, dark black lesion varying in size from a few to 10 mm in diameter (see Chapter 17, Fig 17 -10). Frequently, central lacunae and a peripheral zone of less dense pigmentation appear within the lesion. This lesion is histologically characterized

150 • Ophthalmic Pathology and Intraocular Tumors

C L-_ _ _.....i A, Leukocoria as a resu lt of Coa ts disease. B, Tota l exudative retinal detachment in Coats disease. Note the dense subretinal prote inaceous fluid (asterisk). C, Telangiectatic vessels (asterisks) and "foamy" macrophages (arrowhead) typical of Coats disease . D, High magnification of subretinal exudate showin g lipld- and pigment-laden macrophages (arrows) and cholestero l clefts (arrowheads). (Parts A-C courtesy of Hans E. Grossniklaus, MD; part 0 courtesy of Figure 11-4

George J. Harocopos, MD. )

by enlarged RPE cells with densely packed and larger-than-normal, spherical melani n granules (Fig 11-5). This benign conge nital condition can generally be distinguished from choroidal nevi and melanoma on the basis of ophthalmoscopic features. Adenoma and adenocarcinoma of the RPE may develop, in rare instances, in an area of CHRPE. RPE lesions mimicking CHRPE may be present in Gardner syndrome, or familial adenomatous polyposis. Histologic study of the RPE changes in Gardner syndrome reveals that they are more consistent with hyperplasia of the RPE than with hypertrophy. The RPE changes in

In CHRPE, the RPE cel ls are larger than normal and contain more dense ly packed melanin granules (arrows). For cl inIca l images of CHRPE, see Chapter 17, Figure 17-10. (Courtesy of Hans E. Grossniklaus. MD)

Figure "·5

CHAPTER 11:

Retina and Retina l Pigment Epithe lium . 151

Gardner syndrome are probably more appropriately termed hamartomas, consistent with the loss of regulato ry control of cell growth that gives rise to the other soft-tissue changes in this syndrome. Traboulsi E1. Ocular manifestations of fami lial adenomatous polyposis (Gardner syndrome). Ophthalmol Cli" North Am. 2005;18 (1),163- 166.

Inflammations Infectious Viral Multiple viruses may cause retinal infections. including rubella. measles. human immunodefiCiency virus (HI V), herpes simplex virus (HSV), varicella-zoster vi rus (VZV, or herpes zoster), and cytomegalovirus (CMV). Two of the most frequent clinical presentations of retinal viral infection, acute retinal necrosis (ARN) and CMV retinitis, are discussed here. Acute retinal necrosis is a rapidly progressive, necrotizing retinitis caused by infection wi th HSV types 1 and 2, VZV, and, in ra re instances, CMV. ARN can occur in healthy or immu nocomprom ised persons. The histologic findings include infl ammation in the vitreous and ante rior chamber, with a prom in ent obliterative retinal vasc ulitis and retinal necrosis (Fig 11 -6A). Electron microscopy has demonstrated viral incl usions in retinal cells (Fig 11-6B). Polymerase chain reaction (PCR) analysis of aqueous or vitreous biopsy specimens can be used to rapidly demonstrate the viral cause of ARN, reducing the need for oth er diagnostic techniques such as viral culture, intraocular antibody analys is, or immunohistochemistry. CMV retinitis is an opportunistic infection that may occur in imm unosuppressed patients, especiall y AIDS patients (Fig 11 -7). This infection is histologicall y characterized by retinal necrosis, which leads to a thin fibroglial scar with heali ng. Acute lesions show large neurons (20-30 ~m ) that contain large eosinophilic intranuclea r or intracytoplasmic inclusion bodies. At the cellular level, CMV may infect vascular endothelial cells, retinal neurons, and macrophages.

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Figure 11-6 A, Acute retinal necrosis (ARN) is characterized by full-thickness necrosis of the retina (between arrows). B, Electron microscopy demonstrates viral particles (arrows) with in retinal cell s. (Courtesy of Hans E. Grossniklaus, MD.)

152 • Ophthalmic Pathology and Int raocula r Tumors

B Figure 11-7

AI CMV retinitis/papillitis. Intra retinal hemorrhages and areas of opaque retina are

present nasal to the optic disc. Note the marked optic disc and peripapillary retinal swelling and cotton-wool spots temporal to the optic disc. B, Histologically, full-thickness retinal necrosis, cytomegalo cells, and intranuclear (arrowheads) and/or intracytoplasmic inclusions are present. (Pan A courtesy of R Doug Davis, MD, part 8 courtesy of Robert H. Rosa, Jr, MO.)

Bacterial See the discussion of endophthalmitis in Chapter 10 and in BCSC Section 9, Intraocular

Illflammation and Uveitis.

Fungal Fungal infections of the retina are uncommon, occurring almost exclusively in im munosuppressed patients as a result of fungemia. These infections usually begin as sin gle or multiple foci of choroidal and retina l infection (Fig 11-8). The most common causat ive fungi are Candida species. Less comm o n agents include Aspetgillus species and Cryptococ-

cus neoformans. Histologically, fungal infections are typified by necrotizing granulomatous inflammation. A central zone of necrosis is typicall y surrounded by granulomatous inflammation, and a surroundi ng infiltrate of lymphocytes is common. W ith treatment, the lesions

CHAPTER 11:

Retina and Retinal Pigment Epitheliu m. 153

__________________

Figure "·8 A, Vitreous, reti nal, and choroi da l infi ltrate in a patient with fun ga l chorioretiniti s. B, Granulomatous in filt ration surroundin g centra l area of necrosis (as terisk). C, Gomori methenamine- silve r nitrate stain of secti on para llel to B shows numerous fungal hyphae {black staining). (CourtesyofDavidJ. Wilson, MD.}

heal with a fibrous scar The causative agent can usually be identified by culture or by the specific features of the fungal hyphae in histopathologic material. Toxoplasmosis

Ocular toxoplasmosis, the most common infectious retinitis, may occur because of reactivation of congen itally acquired disease or as the result of an acquired Toxoplasma infection in healthy or immunocompromised persons. In patients with reactivated disease, ocular toxoplasmosis typically presents as a posterior uveitis or pan uveitis ,vith marked vitritis and focal retinochoroiditis adjacent to a pigmented chorioretinal scar. The absence of prior chorioretinal scarring suggests newly acquired disease. Microscopic examination of active toxoplasmic retinitis reveals necrosis of the retina, a prominent infiltrate of neu trophils and lymphocytes, and Toxoplasma organisms in the form of cysts and tachyzoites (Fig 11-9), There is generally a prominent lymphocytic infiltrate of the vitreous and the anterior segment and, not uncommonly, granulomatous inflammation in the inner choroH Healing brings resolution of the inflammatory cell infiltrate with encystment of the organisms in the retina adjacent to the chorioretinal scar.

Noninfectious Noninfectious (autoi mmune) inflammatory conditions involving the retina are discussed in BCSC Section 9, Intraocular Infla m mation and Uveitis, and Section 12, Retina and Vitreous.

154 • Op hthalmic Pat hology and Intraocular Tumors

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A, Chorioretinal scars wi th pigmentation (double arrow) typical of prior infect ion w ith toxopl asmosis. Active retiniti s (arrowhead) and perivascular shea thing (arrow) are present . B, Cysts (arrow) and rel eased organisms (tachyzoi tes, arrowhead) in active toxoplasmosis. (Courtesv of Hans E. Grossniklaus. MOl

Figure 11·9

Degenerations Typ ical and Reticular Peripheral Cystoid Degeneration and Retinoschisis Typical peripheral cy stoid degeneration (TPCD) is a universal finding in the eyes of persons ol der than 20 years. In TPCD, cystic spaces develop in the outer plexiform layer of the retina. Reticular peripheral cystoid degeneration (RPCD) is less common. In RPCD, the cystic spaces are present in the NF L. When present, RPCD occurs posterior to areas of TPCD (Fig 11 -10). Coalescence of the cystic spaces of TPCD fo rms typical degenerative retinoschisis, which is usually inferotemporal in location. In reticular degenerative retinoschisis, the splitting of retinal layers occurs in the NFL.

Figure 1'-10 Retina l degeneration. Typica l peripheral cystoid deg en erat ion cons ists of cystoi d spaces in th e outer plexifor m laye r (asterisk) on t he low er left (anter ior retina). In t he upper ri ght (po sterior retinal, reticular peripheral cystoid degeneration (arrow) is present .

CHAPTER 11: Retina and Retinal Pigme nt Epith elium. 155

Lattice Degeneration Lattice dege neration may be a fam ilial cond ition (Fig 11-11 ). It is found in up to 10% of the general populatio n, but only a small number of affected persons develop retinal detachment. In contrast, lattice degeneration is seen in up to 40% of all rhegmatogenous detachments. The most important histopathologic features of lattice degeneration include discontinuity of the ILM of the retina an overlying pocket of liquefied vit reous sclerosis of the retinal vessels, which remai n phYSiologicall y patent condensation and adherence of vit reous at the margins of the lesion va riable degrees of atrophy of the inner layers of the retina Although atrophic holes often de velop in the center of the lattice lesion, they are rarely the cause of retinal detachment because the vitreous is liquefied over the surface of th e lattice, and thus no vit reous traction occurs. Retinal detachment associated with lattice degeneration is generally the result of vitreous adhesion at the margin of lattice dege neration, leading to retinal tears in th is location with vitreous detachment. Radial perivascular

A ~~~~

______________

Figure 11-11 Ret inal lattice degeneration. A, Lattice degeneration may present as prominent sclerotic vessels (arrows) in a wicker or lattice pattern. The clinical presentatio n has many variat ions. B, The vitreous directly ove r lattice degeneration is liquefied (asterisk), but formed vitreous remains adherent at the margins (arrowheads) of the degenerated area. The internal limiting membrane is discontinuous, and the inn er reti nal layers are atroph ic.

156 • Ophthalmic Pathology and In traocu lar Tumors lattice degeneration has the same histopathologic features as typical lattice degeneration but occurs more posteriorly along the course of retinal vessels. Paving-Stone Degeneration In contrast to retinal vascular occlusion, which leads to inner retinal ischemia, occlusion of the choriocapillaris can lead to loss of the outer retinal layers and RPE. This type of atrophy, called cobblestone or paving-stone degenemtion, is very common in the retinal periphe ry. The well-demarcated, fla t, pale lesions seen clinically correspond to circum scribed areas of outer retinal and RPE atrophy with adh erence of the inner nuclear layer to the Bruch membrane (Fig 11-12). Ischemia There are many causes of retinal ischemia, including di abetes mellitus, retinal artery and ve in occlusion, radiation retin opathy, retinopathy of prematurity, sickle cell retinopathy,

vasculitis, and carotid occlusive disease. The specific aspects of some of these diseases are disc ussed later in the chapter. However, certain histopathologic findings are common to all the disorders that result in retinal ischemia. The retinal changes that occur with ischemia can be grouped into cellular responses an d vascular responses.

Cellular responses The neurons in the retina are highly active metabolically, requiring, on a per gram oft issue basis, large amollnts of oxygen fo r production of ade nosine triphosphate (ATP) (see also BeSe Section 2, Fundamentals and Principles of Ophthalmology, Part IV, Biochemistry and Metabolism). This makes them highl y sensitive to interruption of the ir blood supply. With prolonged oxygen deprivation (greater than 90 minutes in experimenta l studies), the

Figure 11-12 A, Paving-stone degeneration appears as areas of depigmentation (arrows) in the periphery of the retina near the ora serrata. B, Histologically, paving-stone degeneration consists of atrophy of the outer retinal elements and chorioretinal adhesion to the remaining inner retinal elements. A sharp boundary (arrowheads) exists between normal and atrophic retina, corresponding to the clinical appearance of paving-stone degeneration.

CH A PTER 11 :

Retin a and Retinal Pi gment Epithelium. 157

neuronal cells become pyknotic; they are subsequently phagocytosed, and they disappear. The extent and the location of the area of atroph ic retina resu lting from ischemia depend on the size of the occluded vessel and on whether it is a retinal or a choroidal blood vessel. As described earlier, the retinal circulation supplies the inner retina, and the choroidal circul ation supplies the outer retina and RPE. Infarction s of the retinal circulation lead to inner ischemic retinal atrophy (Fig 11 -13), and infarctions of the choroidal circulation lead to outer ischemic retinal atrophy (Fig 11 - 14). The neu rona l cells of th e retina have no capacity for regenerati on after ischemic dam-

age. Following ischemic damage to the nerve fibers of the ga nglion cells, cytoid bodies (swollen axo ns) become apparent histologicall y (Fig II - IS). These are localized accumulat ions ofaxo pl asmic m aterial that are present in ischemic infarcts of the N FL. Cotton -wool spots are the cl inical correlate of ischemic infarcts of the N FL that resolve ove r 4-12 weeks, leaving an area of in ner ischemic atrophy.

Glial cells, like axo ns, degenerate in areas of infa rction. Prol iferation of the glial cells m ay occur adj acent to local areas of infarction or i n areas of ischem ia wi thout i nfarctio n, resulting in a glial scar.

Figure 11-13 Inner retinal ischemia. The photoreceptor nuclei (outer nuclear layer, GNU and the outer portion of the inner nuclear layer (lNL) are identifiable. The inner portion of the inner nuclear layer is absent. There are no ganglion celis, and the NFL is absent. This pattern of ischemia corresponds to the supply of the retinal arteriolar circulation and may be observed in arterial and venular occlusions.

Figure 11·14 Begin at t he right edge of the photograph and trace the gang lion cell and the inner nuclear layer toward t he left. In this case, the re is loss of the nuclei of t he photoreceptor layer (outer nuclear layer, arrovv), t he photoreceptor inne r and outer segments, and the RPE (arrowhead). ThiS is the pattern of outer retinal atrophy, secondary to interruption in the choroidal vascular blood supply. Compare with Figure 11-13.

158 • Opht halm ic Pathology and Intra ocular Tumo rs

Figur. 11-15 Cytoid bodies (arrows) within the NFL. Cystoid spaces (asterisks) are filled with proteinaceous fluid. (Counesy of W. Richard Green, MD.)

Microglial cells are actually tissue macro phages rather than true glial cells. These cells are involved in the phagocytosis of necrotic cells as well as of extracellular material, such as li pid and blood, that accumulates in areas of ischemia. Microglial cells are fairly resistant to ischemia.

Vascular responses Many of the vascula r changes in retinal ischemia are medi ated by vasc ular endothelial growth factor (VEGF). This growth factor is a potent mediator of vasc ular permeabi lity and angiogenesis. It has been shown to playa role in numerous ocular conditions associated with vascularization.

In add ition to those changes secondary to ischemia itself, vascular changes may be caused by the specific disease process responsible for the ischemia. Edema and hemorrhages are common vvith acute retinal ischemia. Retinal capillary closure, microaneurysms, lipid exudates, and neovascularization may develop with chronic retinal ischemia. Edema, one of the earliest manifestations of retin al ischemia, is a result of transu -

dation across the inner blood- retina barrier (Fig 11 -16). Fluid and serum com ponents accum ulate in the extracellula r space, and the fl uid pockets are delimited by the surrou nding neurons and glial cells. Exudate accu mulating in the outer plexifo rm laye r of the macula (Henle layer) produces a star figure because of the orientation of the nerve fibe rs in this layer (Fig 11- 17). In cases of chro nic edema, the extracellular deposits will become richer in protei n and lipids, as th e water component of the exudate is more efficiently removed, resul ting in so-called hard exudates. Histologicall y, reti nal exudates appear as eosinophilic, sharply circ*mscribed spaces wi thin the retina (Fig I I - I 8). Chronic edema may result in intraret in al lipid deposits that are contained with in the

microglial cells. Intravitreally administered triamcinolone acetonide (IVTA) and recently developed biologiC agents inhibiting VEG F (pegaptanib, ran ibizumab, and bevacizumab) are now being employed in the treatment of various retinal diseases associated with macular

CHAPTER 11:

Retina and Retinal Pigme nt Epithelium. 159

.. Fi gure " -' 6 Cystoid spaces in inner nuclear and outer plexiform layers (asterisks).

(Courtesy of

W Richard Green, MD.)

Fi gure " -' 7 Intraretinal lipid deposits, or hard exudates. (Courtesy of David J. Wilson, MD.)

Figure " ·' 8 Intra retinal exudates (asterisks) surrounding intraretinal microvascu lar abnormalities (arrow). (Courtesy of W. Richard Green, MD.)

edema and choroidal neovascularization. Gain in visual acuity, which is mostly secondary to a decrease in macular edema, has been demonstrated in stud ies in which these treatments were used for such conditions as diabetic macular edema, cent ral and branch retinal vein occlusions, uveitic macular edema, and retinal and choroidal neovascularization (Fig 11 -19). Hypotheses regarding the mechanism of action of IVTA include an antiinflammatory effect, in hibition ofVEGF, improvement in diffusio n, and reestablishment

160 • Ophthalmic.Patho logy and Intraoc ul ar Tumors

B A , SO-OCT sh ows cystoid macular edema (arrowhead), subretinal f luid (asterisks), and irregular elevation and detachment of t he RPE (white arrow) secondary to exudative age-related macu lar degeneration. Note the outer aspect of Bruch m embrane (red arrow s). B, SO-OCT after anti-vascu lar endoth elial growth factor t herapy show s resolution of the cystoid mac ular ede ma and detac hment of the RPE. Focal areas of geog rap hic atrophy of the RPE wit h attenuation of the photoreceptor ce ll layer are more apparent (between arrowheads). Note the hyperrefl ectivity (be tween dashed lines) in th e choroid correspond ing to the areas of geographic atrophy. (Courtes y of Robert H. Rosa, J r, MD .)

Figure 11-19

of the blood- retina barrier through a reduction in permeability. VEGF inhibition in the eye arrests angiogenesis and reduces vascular permeability. Pegaptanib is an RNA aptamer (an oligonucleotide ligand) that binds specifically to the VEGF , 65 isoform, the reby pre venting receptor binding of the VEGF isoform. Ranibizumab is a recombinant humanized monoclonal antibody fragment, whereas bevacizumab is a full-length monoclonal antibody. Both ranibizumab and bevacizumab inhibit recep to r binding of all isoforms of VEGF-A, which may explain the enhanced anatomical and visual effects that have been observed clinically with use of these agents. Retinal hemorrhages also develop as a result of ischemic damage to the inner bloodreti na barrier. As with edema and exudates, the shape of the hemorrhage confo rms to the surrounding reti nal tissue. Consequently, hemorrhages in the nerve fiber are flame shaped, whereas those in the nuclear or inner plexiform layer are circular, or "dot and blot" (Fig 11-20). Subhyaloid and sub- ILM hemorrhages have a boat-shaped configuration. White-centered hemorrhages (Roth spots) may be present in a number of cond itions. The white centers of the hemorrhages can have a number of causes, including aggregates of white blood cells, platelets, and fibrin; or they may be due to retinal light reflexes. Hem0rrhages clear over a period of time ranging from days to months. Chronic retinal ischemia leads to architectural changes in the retinal vessels. The capillary bed becomes acellular in an area of vascular occlusion . Adjacent to acellular areas, dilated irregular vascular channels known as intra retinal microvascular abnormalities (IRMA) and micro aneurysms often appear (Figs 11-21, 11 -22). Microaneurysms are

CHAPTER 11 :

Retina and Retinal Pigm ent Epithe lium . 161

B Figure 11-20 Intraretinal hemorrhage. A, Fundus photograph showing dot-and-blot (arrowhead), flame-shaped (arrow), and boat-shaped (asterisk) hemorrhages in diabetic retinopathy.

B, Histologically, the dot-and-blot hemorrhage corresponds to blood in the middle layers linner nuclear and outer plexiform layers) of t he retina (arrowhead). The flame-shaped hemorrhage corresponds to blood in the NFL (arrow), and the boat-shaped hemorrhage corre sponds to subhyaloid blood. (Courtesy of Robert H. Rosa, Jr. MD.J

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Figure 11-21 Tryps in digest preparat ion, illustrating ace llula r capillaries (arrowheads) adjacent to intraretinal microvascular abnormalities (IRMA, arrow). (Courtesy of W Richard Green, MDJ

162. Ophthal mic Pathology and Int ra oc ular Tumo rs

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fusiform or saccular outpouchings of the retinal capillaries best seen clinically with fluorescein angiography and histologically with PAS-stained tr ypsin digest preparations (see Fig 11-22), The density of the endothelial cells lining th e microaneurysms and IRMA is frequentl y variable, Microaneurys ms evolve from thin-walled hyperceUular microaneurys ms to hyalini zed, hypocellular microa neurysms, In some cases of retinal ischemia, neovascular ization of the retina and the vitreous may occur, most commonly in diabetes and central retinal vein occlusion. Retinal neovascularization generally consists of the growth of new vessels on the vitreous side of th e ILM (Fig 11 -23); only rarely does neovascularization occur within th e retina itself. Hemorrhage m ay develop from reti nal neovascularizatio n as the associated vitreous exerts traction on th e fragile new vessels, Reti nal neovascularization should be distingUished from retinal collaterals and arteriovenous shunts, which represent dil ati on and increased flow in existing retin al vessels.

Specific Ischemic Retinal Disorders

Central and branch retinal artery and vein occlusions Central retinal artery occlusions (CRAO) result from localized arteriosclerotic changes, an embolic event. and, in rare instances, vasculi tis (as in temporal arteri tiS) . As the retina becomes ischemic, it swells and loses its transparency, This swelling is best appreciated clinically and histologically in th e posterior pole. where th e NFL and the ganglion cell

CHAPTER 11:

Retina and Retinal Pig ment Epithelium . 163

Acute central retinal artery occlusion. Histologically. necrosis occurs in the inner reti na (asterisk) corresponding to th e retinal w hitening observed by ophthalmoscopic examination . Note the pyknotic nuclei (arrow) in the inner aspect of the inner nuclear layer. (Counesyof

Figure 11·24

Robert H. Rosa, Jr, MD. )

layer are the thickest (Fig 11-24). Because the ganglion cell layer and the NFL are thickest in the macula but absent in the fovea, the norm al color of the choroid shows through in the fovea and produces a cherry-red spot, ophthalmoscopically suggesting CRA~. The retinal swell ing eventually clears an d leaves th e classic histologic picture of inner ischem ic atrophy (see Fig 11 -13 ). Scarring and neovascularization followi ng CRAO are rare. Branch retinal artery occlusion (BRAO) is usually the result of emboli that lodge at the bifurcation of a ret inal arteriole. Hollellhorst plaques, which are cholesterol emboli within ret inal arterioles, seldom occlude the vessel. Emboli may be the first or most importa nt clue to a significant systemic disord er such as carotid vascular disease (Hollenhorst plaques), cardiac valvular disease (calci fic em boli), or thro mboem bolism (platelet-fibrin emboli). The histology of the acute phase of BRAO is characterized by swelling of the inner retinal layers with the death of all nuclei. As the edema resolves, a classic picture emerges of inner ischemic atrophy in the distributi on of the reti na supplied by the occluded arteriole. The NFL, the ganglion cell layer, the in ner plexiform layer, and the inner nuclear layer are affected (see Fig 11- 13). Arteriolar occlusions result in infarcts with complete post necrotic atrophy of the affected laye rs. Central retinal vein occlusion (CR VO) occurs at th e level of the lamina cribrosa. T he pathophYSiology of CRVO is the same as that of hem iretinal vei n occlusion but different from that of branch retinal vein occlusion (see the following discussion). CRVOs develop as a result of structural changes in the central retinal artery and the lamina cribrosa that lead to compress ion of the central retinal vein . This compression creates turbulent flow in

164 • Ophthalmic Pathology and Intraocul ar Tumo rs the ve in and predisposes to thrombosis. These stru ctural cha nges occur in arteriosclerosis . hypertension, diabetes, an d glaucoma. Pnpillophlebitis refers to a condition in which

the clinical features ofCRVO are present, but there is no history of vascular disease. In this variant of CRVO, which typically occurs in yo un ger patients «50 years), inflammation of the retinal vessels at the optic disc has been shown to be a causative factor in retinal ve in occlusion.

CRVO is recognized clinically by the presence of retinal hemorrhages in all 4 quadrants. Usually, prominent edema of the optic nerve head occurs, along \'vith dilation of th e retinal veins, variable numbers of cotton-wool spots, and macular edema. CRVO occurs in 2 forms: a milder, perfused type and a more severe, nonperfused type.

NOl1pelfused CRVO was defined in the Central Vein Occlusion Study (CVOS) as a CRVO in which greater than 10 disc areas showed nonperfusion on fluorescein angi-

ography. Nonperfused CRVOs typically have extensive retinal edema and hemorrhage. Marked venular diJation and a variable number of cotton-woo] spots are found.

Acute ischemic CRVO is characterized histologically by marked retinal edema; focal retinal necrosis; and subretinal, intraretin al, and preretinal hemorrhage. With long-

standing CRVO, glial cells respond to the insult by replication and intracellular deposition of filaments (gliosis). The hemorrhage, hemosiderosis, disorganization of the retinal architecture, and gliosis seen in vein occlusions distingu ish the fi nal histologic picture from

that seen in CRAO (Fig 11-25). Numero us microaneurysms are present in the ret inal capillaries following CRVO, and acellular capillary beds are present to a variable degree. With time, dilated coilateral vessels develop at the optic nerve head. Neovascularization of the iris is common following ischem ic CRVO. Branch retinal vein occlusion (BRVO) is a disorder in which occlusion of a tributary retinal vein occurs at the site of an arter iovenous crossing. At the crossing of a branch reti nal artery and vein, the 2 vessels share a common adventitial sheath. \"'ith arteriosclerotic changes in the arteriole, the retinal venule may become compressed. leading to turbulent flow, which predisposes to thrombosis. This condition is more common in patients with arteriosclerosis and hypertension.

BRVO leads to retinal hemorrhages and cotton -wool spots. Because BRVO does not always result in total inner retinal ischem ia and death of all tissue, neovascularization is

unlikely unless the ischemia is extensive (>5 disc diameters) . Findings in eyes with permanent vision loss from BRVO include CME, retinal nonperfusion, pigmentary macular disturbance, macular edema with hard lipid exudates, subretinal fibrosis, and epiretinal membrane formation.

The histologic picture of BRVO resembles that seen in CRVO but is localized to the area of the retina in the distribution of the occluded vein. Inner ischemic retinal atrophy is a characteristic late histologic find in g in both retinal arterial and venous occlusions

(see Fig 11-13). Numerous microaneurysms and dilated collateral vessels may be present. Acellular retinal capillaries are present to a variable degree, correlating with retinal capil-

lary nonperfusion on fl uorescein angiography. Baseline and early natural history report. The Central Vein Occlusion Study. Arch Ophthalmol. 1993; III (8) , 1087- 1095.

CHAPTER 11:

Retina and Retina l Pi gment Epithelium. 165

B Figure 11-25 A, Diffuse retinal hemorrhage following CRVO. The damaged retina will be replaced by gliosis. B, Histology of long-standing CRVO shows loss of the normal lamellar architecture of the retina, marked edema w ith cystic spaces (asterisk) containing blood and proteinaceous exudate, vitreous hemorrhage, and nodular hyperplasia of the RP E (arrow). (Part B courtesy of Roben H. Rosa, Jr, MD.J

Diabetic Retinopathy Diabetic retinopathy is 1 of the 4 most frequent causes of new blindness in the United States and the leading cause among 20- to 60-year-olds. Early in the course of diabetic retinopathy, certain ph ysiologic ab normalities occur: im paired autoregulation of the retinal vasculature

alterations in retinal blood flow breakdown of the blood-retina barrier

166 • Ophthalmic Pathology and Intraocular Tumors Histologically, the primary changes occur in the retin al microcirculatio n. These changes include thickening of the reti nal capillary basem*nt membrane selective loss of pericytes compared with retin al capillary e ndothelial cells • microaneurysm fo rmation (see Fig 11-22) retinal capillary closure (see Fig II -21) (histologically recognized as acellular capillary beds) Dilated intraretinal telangiectatic vessels, or intraretinal microvascular abnorm al ities (i RMA), may develop, as shown in Figure II -21, and n eovascularization may follow (see Fig 11 -23). Intraretinal ede ma, hemorrhages, exudates, and microinfarcts of the inner retina m ay develop seconda ry to the primary retinal vascular changes. Acutely, mi crainfarcts of the inner retina (see Fig 11 - 15) are characte rized clinically as cotton-wool spots. Subsequently, focal inner ischem ic atrophy appears (see Fig II - 13).

Other histologic changes in diabetes In diab etes, the corneal epi thelial basem*nt membrane is thickened . Th is change is as sociated with in adequate adh erence of the epith elium to the underlying Bowman layer, pred isposing diabetic patients to corneal abrasions and poor corneal epithelial healing. Lacy vac uolation of the iris pigment epitheliunl (Fig 11 -26) occurs in association with hyperglycemia; histologically, the in traepithelial vac uoles contain glycogen (PAS-posi tive and diasta se-sensitive). Histopathologically, thicken ing of the pigmented ciliary epithelial basem*nt membrane (see Fig 11-26) is almost unive rsally present in diabetic eyes. The incide nce of cataract formatio n is increased.

Figure 11-26

Photomicrograph showing iris neovascularization (black arrowhead), lacy vacu-

olation of the iris pigment epithe lium (red arrowheads), and thickening of the basem*nt membrane of the pigmented ciliary epithelium (red arrow). These histologic findings a re tYPically found in the eyes of patients with diabetes.

(Counesv of Tatyana Milman, MD.)

CHAPTE R 11: Retina and Reti na l Pigment Epithelium. 167

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Laser photocoagulation scar characterized by absence of the RPE centrally (asterisk) with peripheral RPE hyperplasia (arrows) and loss of the photo receptors, the outer nuclear layer, and a portion of the inner nuclear layer. (Courtesy of DavidJ Wilson, MD.)

Figure 11·27

Argon laser photocoagulation, used for the treatment of diabetic retinopathy, resu lts in var iable destruction of the outer retina, destruction of the RPE, and occlusion of the choriocapillaris (Fig J J -27) . These lesions heal by proliferation of the adjacent RPE and

glial scarring.

Retinopathy of Prematurity Retinal ischemi a also plays a role in retinopathy of prematurity (ROP ). This ischemia develops not because of the occlusion of existing vessels but rather because of the absence of retinal vessels in the incompletely developed ret inal peripher y. A decrease in reti nal blood flow from oxygen- induced vasoconstriction may also be a contributing factor.

The clinical and histologic features of ROP are so mewhat di fferent from those present in other retinal ischemic states. Retin al edema and exudates do not develop. Ret inal hemorrhages and retinal vasc ular di lation develop only in the most severe cases (plus or rush disease). Neovasculari zation of th e ret ina and vitreous may develop as a result of

proli feration of new vessels at the border between the vasculari zed and avascular periph eral retina. Fib rovascular proliferation in to the vit reous at this site may lead to tractional retinal detachment, macular heterotopia, and high myopia. See BCSC Section 6, Pediatric Ophthalmology and Strabismus, and Section J 2, lletina and Vitreous, fo r a more detailed d iscussion.

Age-Related Macular Degeneration Age-related macular degeneration (AM D) is the leading cause of new blindness in the Un ited States. Although the etiology of AM 0 remains unknown, evidence suggests that both genes and environmental factors play a role in the disease pathogenesis. Recently, single nucleotide polymorph isms within the complement factor H gene (CFH) have been found to be associated with the development of AMD in 60% of cases. Increasing age,

168 • Ophthalmic Pathology and Intraocular Tumors cigarette smoking, posit ive family history, and cardiovascular disease increase the risk of

developing AMD. In addition, randomized clinical trials showing the benefit of antioxidant supplementation in AMD provide support for the role of oxidative stress in progression of the disease. See BeSe Section 12, Retina and Vitreous, for additional discussion. Several characteristic changes in the retina, RPE, Bruch membrane, and choroid occur in AMD. Perh aps the first detectable pathologic change is the appearance of deposits between the basem*nt membrane of the RPE and the elastic portion of the Bruch membrane (basal li near deposits) and sim ilar deposits between the plasma membrane of the RPE and the basem*nt membrane of the RPE (basal laminar deposits). These deposits are not clinicall y vis ibl e and may require electron microscopy to be distinguished. In advanced cases, these deposits may become confluent and can be seen at the light microscopic level

(Fig 11 -28). This appearance has been described as diffuse drusen. The first clinically detectable feature of AMD is the appearance of drusen. The clinical ter m drusen has been correlated pathologically to large PAS-positive deposits between the RPE and Bruch membrane. Many eyes with clinically apparent dr usen (especially soft drusen) are fo und to have basal la minar and/or basal linear deposits and diffuse d rusen on histologic analysis. Drusen, which may be transient, have been classified clinically as fo llows: hard (hyaline) drusen: the typical discrete, yellowish lesions that are PAS-positive nodu les composed of hyaline material between the RPE and Bruch membrane (Fig 11-29)

Figure 1'·28

Diffuse drusen. There is diffuse deposition of eosinophilic material (arrowheads)

beneath the RPE. Choroidal neovascularization (asterisk) is present between the diffuse drusen and the elastic portion of the Bruch membrane (arrows).

Figure' '·29

Hard drusen (arrow). Note the

period ic acid-Schiff stai ning of the domeshaped, nod ular, hard druse. (Reproduced

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1997, American Medical

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CHAPTER 11:

Retina an d Retinal Pigment Epithelium. 169

soft drusen : drusen with amorphous, poorly demarcated boundaries, usually >63 flm in size; histologically, they represent cleavage of the RPE and basal laminar or linear deposits from the Bruch membrane (Fig 11-30) basal laminar or cuticular drusen : diffuse, small, regular, and nodular depos its of drusenlike material in the macula calcific drusen: sharply dema rcated, glisten ing, refractile lesions usually associated with RPE atrophy

Photoreceptor atrophy occurs to a va riable degree in macular degeneration. It is not clear whether this atrophy is a primary abnormality of the photoreceptors or is secondary to the underlying changes in the RPE and Bruch membrane. In addition to photoreceptor atrophy, large zones ofRPE atrophy may appear (Fig 11 -31) . When this occurs centrally, it is termed geographic atrophy (formerly, central areolar atrophy of the RPE). Drusen, photoreceptor atrophy, and RPE atrop hy may all be present to varying degrees in dry, or nonexudative, AMD. Eyes with choroidal neovascularization (neovascular, wet, or exudative AMD) have fib rovascular tissue present between the inner and outer layers of the Bruch membrane, beneath the RPE, or in the subretinal space (Fig 11 -32). The new blood vessels leak fluid and may rupture easily. producing the exudative consequences of neovascular AMD, including macular edema, serous ret inal detachment, and sub retinal and intraretinal hemorrhages. VEGF inhibition achieved with intravi treally administered anti- VEGF agents (pegaptanib, ranibizumab, or bevacizumab) has been shown to reduce the macular edema, slow the progression of the choroidal neovascularization, and improve the visual outcomes of patients with neovascular AMD (also see the section "Vascular responses"). Sub retinal choroidal neovascular membranes have been classified as type 1 or type 2, based on their pathologic and clinical feat ures. Type 1 neovascularization (Fig 11-32A) is typically associated with the presence of basal laminar deposits and diffuse drusen and characterized by neovascularization within the Bruch membrane in the sub-RPE space. In this type of neovascularization, the RPE is often abnormally oriented or absent across a broad expanse of the inner portion of Bruch membrane. Type 2 neovascularization (Fig 11-32B) occurs in the sub retinal space and generally features only a small defect in

A Figure 11-30 A , Clin ica l photog raph of mu ltip le conf luent drusen. 8, Thick eosinophilic deposits (asterisk) between th e RPE and the elastic portion (arrows) of Bruch membrane. (Reproduced with permission from Sprau/ Cw, Grossniklaus HE. Characteristics of druse n and Bruch's membrane in postmortem eyes with age-related macular degeneration . Arch Ophthaimol . 1997,115(2):267- 273. © 1997, American Medical Association.)

170 • Ophthalmic Pathology and Intraocula r Tumors

.' B Figure 11-31 Geographic a1rophy of the RPE . A. Fundus photograph shows foca l geographic atrophy of the RPE (arrowhead) and drusen in nonexudatlve AMD. B. Histologically. there IS loss of the photoreceptor cell layer, RPE. and choriocapillaris Ileft of arrow) with an abrupt transition zone (arrow) to a more normal-appearing retlna/RPE (right of arrow). Note the thickened ganglion eel! layer identifying the macular region. (Counesyof Roben H. Rosa, Jr, MD)

which the RPE is abnorma ll y oriented or absent. Type 1 neovasculari zat ion is more characteristic of AMD. whereas type 2 is more characteristic of ocular histoplasmosis. Type 2 membranes are more amenable to su rgical removal than are type 1 membranes because native RPE wo uld be excised with a type I mem brane, leavi ng an atro phic lesion (without RPE) in the area of membrane excision. Surgically excised choroidal neovascular membranes (see Fig I 1-3 2) are co mposed of vasc ular chann els, RPE, and va rious oth er components of th e RP E- Bruch membrane complex, incl uding photoreceptor outer segments, basal laminar and linear deposits, hyperplastic RPE, and inflammatory cells. Grossniklaus HE, Gass JD. Clinicopathologic correlations of surgicall y excised type 1 and type 2 submacula r choroidal neovasclliar membranes. Am JOphtha/mol. 1998;126( 1):59-69. Grossniklaus HE. Miskala PH, Green WR, et al. Histopathologic and ultrastructural features of su rgically excised subfoveal choroidal neovasclIlar lesions: sllb macular surgery trials report 110.7. Arclr Oplr'halmol. 2005;123(7);91 4- 921.

CHAPTER 11:

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Retina and Retinal Pi gment Epithelium. 171

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A, Choroidal neovascularization (CNV) located between the inner (arrow) and

outer (arrowhead) layers of Bruch me mbrane (sub-RPE, type 1 CNVI. Note loss of the overlying photoreceptor inner and outer segm ents, RPE hyperplasia, and the PAS-positive basal laminar deposit (arrow). B, Surgically excised CNV (subretina l, type 2 CNVI composed of fibrovasc ular tissue (asterisk) lined externa lly by RPE (arrow) wit h adherent photoreceptor outer segme nts (arrowhead), (Courtesy of Robert H. Rosa, Jr, MD.) Montezuma SR, Sobrin L, Seddon JM. Review of genetics in age-related macular degenerati on. Semin Ophthalmol. 2007;22(4):229-240.

Polypoidal Choroidal Vasculopathy Polypoidal choroidal vas culopathy (peV), previo usly desc rib ed as posterior uveal bleeding syndrome and multiple recurrent serosanguineous RPE detachments, is a disorder in which dilated, thin-walled vascul ar channels (F igs 11- 33, 11 -34), apparent ly a ri sing from th e

short posterior cil iary arteries, penetrate into the Bruch membrane. Associated choroi dal neovascularization is often present in these lesions, as observed in several histologic specimens. Rosa RH ]r, Davi s JL, Eifrig CW. Clinicopathologic reports, case reports, and smal! case series: clinicopathologic co rrelation of idiopathic polypoidal choroidal vasculopathy. Arch Gplt tlwlmol. 2002;120 (4) :502-508 .

172 • Ophthalmic Pathology and Int raoc ula r Tumors

c Figure "-33 Polypoidal choroidal vasculopathy (peV). A, Peripapillary dilated vascular channels (arrow) between the RPE and outer aspect of Bruch membrane (arrowheads). Note the dense subretinal hemorrhage (as terisk). ON = optic nerve. B, Higher-power view of thin-walled vascular channels (asterisks) interposed between the RPE and Bruch membrane (arrowhead). C, Hemorrhagic RPE detachments (arrows) and serosanguineous subretinal fluid (asterisk). (Courtesy of Robert H. Rosa, Jr, MD.)

Macular Dystrophies See BCSC Section 12, Retina and Vitreous, for ad d itional discussion of the following topics.

Fundus f1avimaculatus and Stargardt disease Fundus flavimaculatus and Stargardt disease are thou ght to represent 2 ends of the spectru m of a disease process characterized by yellowish flecks at the level of the RPE, a gen eralized verm ilion (reddish) color to th e fundu s on clinical exami nat ion, a dark choroid on fluorescein angiography (Fig 11 -35A, B; see also Figs 9-7 and 9-8 in BCSC Section 12, Retina and Vitreous), and gradually dec reasing visual acuity_ The inheritance pattern is generally autosomal recessive, but autosomal do minant form s have been reported as well. Several genetic mutations have been observed in patients with a Stargardt-like phenotype, includ ing the A BCA4, STGD4, ELO V4, and RDS/peripherin genes. Mutati ons in ABCA4 are responsible fo r most cases of Stargardt disease. The A BCA4 ge ne encodes a protein called RIM protein, which is a m ember of th e adenosine triphosphate (ATP)-binding cassette transporter fami ly. It is expressed in th e ri ms of rod and cone photoreceptor disc membranes and is involved in the transport of vitamin A derivatives to the RPE. The most st riking feature of Stargardt d isease on light and electron microscopy is the marked engorgement of RPE cells (Fig 11 -35C, D; see also Fig 9-9 in BeSe Section 12, Retina and Vitreous) with lipofuscin -like, PAS-positi ve materi al, with apical d isplacement of the no rmal RPE melanin granules.

Figure 11-34 Polypoidal choroidal vasculopathy (PCVI. A, Elevated, red-orange nodular and tubular lesions in the peripapillary and macular regions. B. Late fluorescein angiogram {860 secondsl shows hyperfluorescent polypoidal lesions (arrows) without apparent leakage. C, Dense subretinal hemorrhage in same patient as in A and B. Note the persistent red-orange lesions nasal and superior to the optic disc. (CourresyofRobenH. Rosa, Jr, M D.)

174 • Ophtha lmic Pathology and Int raocular Tum ors

______________

figure 11·35 Stargardt disease. A, Fundus photograph shows characteristic retinal flecks and pigment mottling in the macular region. B, Fluorescein angiogram (midphase) shows late hyperfluorescence in a "bull's-eye" pattern in the central macula. Note the dark choroid (eg,

absence of normal background choroidal blush), which is characteristic of Stargardt disease.

C, Histology with periodic acid- Schiff (PAS) stain discloses hypertrophic RPE cells with numerous PAS-positive cytoplasmic granules containing lipofuscin. This histopathologic finding corresponds to the retinal flecks seen clinically. D, In advanced stages of Stargardt disease,

geographic RPE atrophy with loss of the photoreceptor cell layer (asterisks) may be observed. (Courresy of Sander Dubovy. MO.)

Best disease Best disease, or Best vitelliform macular dystrophy, is a dom ina ntly inherited, early-onset macular degenerative disease that exhibits some histopathologic similarities to AMD. The diagnosis of Best disease is based on the presence of a vitelli form (resembling th e yolk of an egg) lesion (see Fig 9-10 in BeSe Section 12, Retil," and Vitreous ) or pigmentary changes in the central macula and a reduced ratio of the light peak to dark trough in the electro-oculogram . Mutations in the VMD2 gene on chromosome 11 (llqI3) encoding

CHAPTER 11 :

Retina and Retinal Pigment Epitheliu m . 175

the bestrophin protein have been identified in Best disease. The gene prod uct, bestrophin, localizes to the basolateral plasma membrane of the RPE and represents a family of chloride ion channels. Investigators have reported that bestrophins are volume·sensitive and may playa role in cell volume regulation in the RPE cells. Fischmeister R, Hartzell He. Volume sensitivity of the bestrophin family of chloride channels. J Physioi. 2005;562(Pt 2):477-491. Marmorstein AD, Marmorstein LY, Rayborn M, Wang X. Hollyfield JG, Petrukhin K. Bestro · phin, the product of the Best vitelliform macul ar dystrophy gene (VMD2), loca lizes to the basolatera l plasma membrane of the ret inal pigment epithelium. Proc Natl Acnd Sci USA. 2000;97(23): 12758- 12763.

Pattern dystrophies The term pattern dystrophies refers to a heterogeneous group of inherited macu lar disorders characterized by varying patterns of pigment deposition in the macula at the level of the RP E. Recogni zed pattern dystroph ies include butterfly-shaped pattern dystroph y (BPD), adult-onset foveom acular vitelliform dyst rophy (AFMVD ), re ticula r dystrophy, and fundus pulve rulentus. BPD is characterized by a butterfly-shaped, ir regular, depigmen ted lesion at th e level of the RPE. AFMV D is characte rized by the presence of slightly elevated, symmetric, round to oval, yellow lesions at the level of the RPE, which are typically smaller tha n the vitelliform lesion characteristic of Best disease (Fig 11 -36). Optical coherence to mography (O CT) has demonstrated elevation of the photoreceptor laye r, with localizatio n of the dystrophic mate rial between the photoreceptors and RP E. The most common gene tic mutation associated with th e pattern dystroph ies is in the RDS/ peripheril1 gene. Histologic studies revea l centr al loss of the RPE and photoreceptor cell layer, with a moderate number of pigment·containing macrophages in the subretinal space and outer ne urosensory retina (see Fig 11 -36). To either side, the RP E is distended with lipofuscin. Basal lam inar and linear deposits are present throughout the macular region. The pathologic finding of pigment-contain ing cells with lipofuscin in the subretinal space correlates cl inicall y with the vi tell ifo rm appearance. See BeSe Secti o n 12, Retina and Vitreous, for furthe r discussion. Dubovy SR, Hairston RJ, Schatz. H, et al. Adult· onset foveomacular pigment epit helial dystrophy: clinicopathologic correlation of three cases. Retina. 2000 ;20(6):638 - 649.

Diffuse Photoreceptor Dystrophies Inherited dystrophies affecting the rods an d cones are discussed in greater detail elsewhere in the BeSe (see BeSe Sectio n 12, Retina al1d Vitreous). Only the most common diffuse photoreceptor dystrophy, retinitis pigm entosa, is discussed here. Retinitis pigmentosa (RP) is a group of inherited retinal diseases characterized by photoreceptor and RPE dysfunction resu lting in progressive visual field loss. The genetics of RP are complex. It can be sporad ic, autosomal dominant, autosomal recessive, or X-linked. Mutations in the rhodopsin gene (RHO) are the most com mon cause of autosomal dominant RP. Ophthalmoscopic fi ndin gs include pigment arranged in a bone spicule- like configuration around the ret inal arterioles, arteriolar narrow ing, and optic

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c Figur. 11·36 Adult-onset foveomacular vitelli form dystrophy. A. Yellowish, egg yolk-like lesion in the central macula. B, Histologic findings include pigment-containing cells in the subretinal space (arrowheads) and outer neurosensory retina (arrow). C, Electron microscopy shows pigment-containing cells filled wi th lipofuscin (arrowheads). (Courresyof Sander Dubovv, MD.)

CHAPTER 11 :

Retina and Retina l Pigment Epithelium. 177

disc atrophy (Fig 11 -37A). The disease is characterized primarily by the loss of rod photoreceptor cells by apoptosis. Cones are seldom directl y affected by the identified mutations; however, they degenerate secondarily to rods. The term retinitis pigmentosa is a misnomer, because clear evidence of inflammation is lacking. Microscopically, photoreceptor cell loss occurs, as well as RPE hyperplasia with migration into the retina around retinal vessels (Fig 11-37B). The arterioles, though narrowed clinically, show no histologic abnormality initially. Later, thickening and hyalin ization of the vessel walls appear. The optic nerve may show diffuse or sectoral atrophy, with gliosis as a late change. Ben-Arie -Weintrob Y, Berson EL, Dr yja TP. Histopathologic-genotypic correlations in retin itis pigmentosa and allied diseases. Ophthalmic Genet. 2005;26 (2):91-1 00 .

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Figure 11-37 Retinitis pigm entosa . AI Fundus photograph shows mild optic disc atroph y, marked ret ina l arteriolar narrowing, and bone-spicule pigmentat ion in the fundu s. B, Histol ogica lly, note th e marked photoreceptor ce ll loss and RPE pig ment migration into t he ret ina in a perivascular distribution, corresponding to the bone spicu le-like pattern seen clinical ly. The reti na is artifactitiou sl y detach ed. (Part A cou rtesy of Robert H. Rosa, Jr. MD .J

178 • Ophthalmic Pathology and Intraocu lar Tu mors

Neoplasia Retinoblastoma Retinoblastoma is the most common primary intraocular malignancy in childhood, occurring in 1 in 14,000-20,000 live births; the incidence varies slightly from country to country. Chapter 19 in this volume discusses ret inoblastoma at length, from a more clinical point of view. Several other volu mes of the BCSC cover various aspects of this topic as well; consult the Master Index. For American Joint Committee on Cancer (AJCC) definitions and staging of retinoblastoma, see the appendix at the back of this text. Pathogenesis

Although retinoblastoma was once considered to be of glial origin (lesions clinically simulating retinoblastoma were for merly called pseudogliomas), the neuroblastic origin of this tumor from the nucleated layers of the retina has been well established. Immunohistochemical studies have demonstrated that tumor cells stain positive for neuron-specific

enolase, rod-outer segment photoreceptor-specifi c S antigen, and rhodopsin . Tumor cells also secrete an extracellular substance known as interphotoreceptor retinoid-binding protein, a product of normal photoreceptors. Retinoblastoma tumor cells grown in culture have been shown to express a red and a green photopigment gene. as well as cone cell alpha subunits of transducin. These fi ndings further support the concept that retinoblastoma may be a neoplasm of cone ceLl li neage. However, immunohistochemical and molecular studies cast some doubt on the hypothesis that a Single cell type is the progen itor of retinoblastoma. The presence of small amou nts of glial tissue within retinoblastoma suggests that tumor cells may possess the ab il ity to differentiate into astroglia or that the resident glial cells proliferate in response to primary neoplastic cells. The so-called retinoblastoma gene, localized to the long arm of chromosome 13, is deceptively named, as it does not actively cause retinoblastoma. The normal gene suppresses the development of retinoblastoma (and possibly other tumors, such as osteosarcoma). Retinoblastoma develops when both hom*ologous loci of the suppressor gene become nonfunctional either by a deletion error or by mutation . Al though 1 normal gene is sufficient to suppress the development of retinoblastoma, the presence of 1 normal gene and 1 abnormal gene is apparently an unstable situation that may lead to mutation in the normal gene and the loss of tumo r suppression, thus allowing retinoblastoma to develop. Dq1a TP, Cavenee W, White R, et al. hom*ozygosity of chromosome 13 in retinoblastoma. N EnglI Med. 1984;310(9),550- 553.

Histologic features

Histologically, reti noblastoma consists of cells with round, oval, or spindle-shaped nuclei that are approximately twice the size of a lymphocyte (Fig 11-38). Nuclei are hype rchromatic and surrounded by an almost imperceptible amount of cytoplasm. Mitotic activity is usually high, although pyknotic nuclei may make this difficult to assess. As tumors expand into the vitreous or subretinal space, they frequently outgrow their blood supply, creating a characteristic pattern of necrosis with the formation of pseudo rosettes (viable

CHAPTER 11:

Figure 11-38

Retina and Retinal Pigment Epithel ium.

179

Ret inoblastoma. Note the viable tumor cells (asterisk) surrounding a blood ves-

sel (arrow) and the alternating zones of necrosis

(N).

This histo logic arrangement is referred

to as a pseudorosette.

tumor cells surrounding a blood vessel); calcification is a common findi ng in areas of necrosis (Fig 11 -39). Cuffs of viable cells course along blood vessels with regions of ischemic necrosis beginning 90-120 ~m from nutrient vessels. DNA released from nec rotic cells may be detected within tumor vessels and with in blood vessels in tissues remote from the tumo r, such as the iris. Neovascularizat ion of the iris can complicate retinoblastoma (Fig 11 -40). Cells shed frorn retinoblastoma tumors remain viable in the vitreous and subretinal space, and they may eventually give rise to implants thro ughout the eye. It may be difficult

Figure 11-39 Retinoblastoma. Zones of viable tumor (usually surrounding blood vessels) alternate with zones of tumor necrosis (asterisk). Calcium (arrow) is present in the necrotic area. The basophilic material surrounding the blood vessels is DNA, presumably liberated from the necrotic tumor.

180 • Ophtha lmic Pat hology and Intraocular Tumors

Figu re 11·40 Retinoblastoma. Note the thick iris neovascu lar membrane (arrow) and the free-floating tumor cells (arrowhead) in the anterior chamber.

to determine histologically whether multiple int raocular foci of the tumor represent m ultiple primary tumors, imp lyi ng a systemic d istribution of the abnormal gene, or tumor seeds (see Chapter 19, Fig 19-7). The formation of highly organized Ffexner- Wintersteiner rosettes is a charac teristic feature of retinoblastoma that does not occur in other neuroblastic tumors, with th e rare exception of some pinealoblastomas and ec topi c intracranial retinoblastomas. FlexnerWi ntersteiner rosettes are expressions of retinal differentiation. The cells of these rosettes surround a central lumen li ned by a refractil e structure. The refractile lining corresponds to the external limiting membrane of th e retina th at represents sites of attachments be· tween photo receptors and Muller cells. The rosette is characterized by a Single row of columnar cells with eosinophilic cytoplas m and peripherally situated nuclei (Fig 11 -4 1A) . The chro mati n of cell nuclei in rosettes is usually looser th an that of nuclei from undi fferentiated cells in adjacent tumor. A less commonly encountered rosette, without features of retinal differentiat ion, known as the Homer Wright rosette, can be found in other neuroblastic tumors, such as neuroblastoma and medulloblastoma of the cerebellum, as well as in retinoblastoma. T he lumen of a Homer Wright rosette is filled with a tangle of eosinophilic cytoplasmic pro- . cesses (Fig 11 -41 B). Evidence of photoreceptor differentiati on has also been documented fo r another fl owerlike str ucture knmvn as aJleurette. Fleurettes are curvili near clusters of cells com · posed of rod and cone inne r segments that are often attached to abo rtive outer segments (Fig 11-41C). The fleurette expresses a greater degree of retinal differentiation than does the Flexner-Wintersteiner rosette. In a typ ica l retinoblastoma, the undifferentiated tumor cells greatly outnumber the fleurettes and Flexner- Winte rsteiner rosettes, and differentiation is not an im portant prognostic indicator.

Progression The most common route for retinoblastoma tumor to escape from the eye is by way of the optic nerve. Direct inflltration of the optic nerve can lead to extension into the brain. Cells that spread into the leptomeninges can gain access to the subarachnoid space, with the potential for seeding throughout the central ne rvo us system (Fig 11 -42). Invasion of the optic nerve is a poor prognostiC sign (Fig 11 -43). See Chapter 19 for a d iscussion of prog nosis. Massive uveal invasion, in contrast, th eore ti cally increases the risk of hematogenous dissem ination. Spread to reg ional lymph nodes may be seen \vhen a tumor involvi ng the

CHAPTER 11:

Retina and Retinal Pigment Epithelium.

1 81

Figur e 11·41 Retinoblastoma rosettes . A, Flexner-Wintersteiner rosettes: note the ce ntral lumen (L). a, Homer Wright rosettes: note t he neurofibrillary tangle (arrow) in the center of the se structures. C, The fleurette (arrow) demonstrates bulbous cellular extension of retinobl astoma ce lls that repre sent different iation along t he lines of photoreceptor inner segments.

anterior segment grows into the conjunctival substantia propria, especially when the trabecular mes hwo rk is involved.

Retinocytoma Retinocytoma is characterized histologically by numero us fleurettes admixed with individual cells that demonstrate varying degrees of photoreceptor differentiation (Fig 11 -44) . Retinocytoma should be distinguished from the spontaneous regression of retinoblastoma that is the end result of coagulative necrosis. See the discussion in Chapter 19. Also referred to as retinoma) retinocytoma differs from ret inoblastoma in the following ways: Retinocytoma cells have more cytoplasm and more evenly dispersed nuclear chromatin than do retinoblastoma cells. Mitoses are not observed in retinocytoma. Altho ugh calcification may be identified in retinocytoma, necrosis is usually abse nt.

182 • Ophthalmic Pathology and Intraocu lar Tum ors

B Figure 11 -42 Retinoblastoma . A, Massive invasion of the globe posteriorly by retinoblastoma with bulbous enlargement of the optiC nerve (arrow) caused by direct extension. B. A cross section of the optic nerve taken at the surg ical margin of transection. Tumor (arrows) is present in the nerve at this point, and th e prognosis is poor.

Figure 1 1-43 Retinoblastoma has invaded the optic nerve and extended to the margin of resection posterior to the lamma cnbrosa (asterisk). This is an extremely poor prognostic sign.

CHAPTER 11:

Retina and Retinal Pigment Epitheliu m . 183

Figure 11 -44 Retinocytom a. Note the exquisite degree of photoreceptor differentiation with apparent stubby inner segm ents (arrow).

Medulloepithelioma Also known as diktyoma, medulloepithelioma is a congenital neuroepithelial tumor arising from primitive medullary epitheliu m. This tumor usually occurs in the ciliary body but has also been documented in the retina and optic nerve. Clinically, med ulloepithelioma may appea r as a lightly pigmented or amelanotic, cystic mass in the Ciliary body, with erosion into the anterior chamber and iris root (see Part II , Intraocular Tumors, Chapter 19, Fig 19-12). Although the tumor develops before the medullar y epithelium shows substantial sign s of differen tiation , cells are organized into ribbonlike structures that have a distinct cellular polarity (Fig 11-45). These ribbonlike structures are composed of undifferentiated ro un d to oval cells possessing little cytoplasm. Cell nuclei are stratified in 3 to 5 layers, and th e entire stru cture is lined on one side by a thin basem*nt memb.rane. One surface secretes a mucinous substance, rich in hyaluronic acid, that resembles primitive vitreous. StratiAed sheets of cells are capable of form ing mucinous cysts that are clinically characteristic. Homer Wright and Flexner-\<\'intersteiner rosettes can also be seen. Medulloepitheliomas that contain solid masses of ne uroblastic cells indistinguishable from retinoblastoma are more dimcult to classify. Medulloepitheliomas that have substan tial numbers of undifferent iated cells with high mitotic rates and that demonst rate tissue invasion are considered malignant, although patients treated with enucleation have high

Figure 11-45 Medulloepithelioma. Histology shows a ciliary process (between arrows)

surrounded by ribbons, cords, and small sheets of blue tumor cells with pockets of vitreous (asterisks) and occasional FlexnerWintersteiner rosettes (arrowhead). (Counesy of George J. Harocopos. MD.)

184 • Ophthal mic Pathology and Intraocu lar Tumors survival rates, and "malignant" medulloepithelioma typically follows a relatively benign course if the tumor remains confined to the eye. Heteroplastic tissue, such as cartilage or smooth muscle, may be fo und in medulloepi-

theliomas. Tumors composed of cells from 2 different embryonic germ layers are referred to as teratoid medulloepitheliomas. Malignant teratoid medulloepitheliomas demonstrate either solid areas of undifferentiated neuroblastic cells or sarcomatous transformation of

heteroplastic elements.

Fuchs Adenoma Fuchs adenoma, an acquired tumor of the nonpigmented epithelium of the ciliary body, may be associated with sectoral catarac t and may simulate other iris or ciliary body neo -

plasms. Fuchs adenomas consist of hyperplastic, nonpigmented ciliary epithelium arranged in sheets and tubules with alternatin g areas of PAS-positive basem*nt membrane

material.

Combined Hamartoma of the Retina and RPE A combined hamartoma of the retina and RPE is characterized clinicall y by the presence of a slightly elevated, variably pigmented mass involVing the RPE, peripapillary retina, optic nerve, and overlying vitreous (see Chapter 17, Fig 17-15). Frequentl y, a preretinal membrane is present that distorts the tumor's inner retinal surface. The lesion is often di-

agnosed in childhood, supporting a probable hamartomatous origin, but it is possible that the vascular changes are primary, with secondary changes in the adjacent RPE. The tumo r is characterized by th ickeni ng of the optic nerve head and peripapillary retina, with an increased number of vessels. The RPE is hyperplastic and frequently migrates into a perivascular location. Vitreous condensation and fibroglial proliferation may be present on the surface of the tumor.

Adenomas and Adenocarcinomas of the RPE Neoplasia of the RP E is uncommon and is distinguished from hyperplasia of the RPE principally by the absence of a history of, or pathologic features suggesti ng, pri or trauma or eye disease. Adenomas of the RPE typically retain characteristics of RPE cells, including basem*nt membranes, cell junctions, and microvilli. Adenocarcinomas are distinguished from adenomas by greater anaplasia, mitotic act ivity, and invasion of the choroid or retina. No metastases have ever been documented to occur in patients with RPE aden ocarcinomas. Spencer \'VH, ed. Ophthalmic Pathology : An Atlas and Textbook. 4th ed. Philadelphia: Saunders; 1997,1291 - l313.

CHAPTER

Uveal Tract

Topography The iris, ciliary body, and choroid constitute the uveal tract (Fig 12- 1). The uveal tract is embryologically derived frolll mesoderm and neural crest. Firm attachments between th e

uveal tract and the sclera exist at only 3 sites:

• scleral spur • exit points of th e vo rtex vein s optic nerve

Iris The iris is located in front of the crystalline lens. It separates the anterior segment of th e eye into 2 compartments, the anterior chamber and th e posteri or chamber, and forms a circular apertu re (pupil) that controls the amou nt of light transmitted into the eye. The iris is composed of 5 layers: anterior border layer stroma • muscular layer anteri or pigment epithe lium posterior pigment epithelium The anterio r border layer represents a condensation of iri s stroma and melanocytes and

is coarsely ri bbed with numerous crypts (Fig 12-2). The stroma contains blood vessels, nerves, melanocytes, fibrocytes, and clump cells. The clump cells are both macrophages

Fi gur. 12-1 Uvea l topog raphy. The uveal tract con sists of th e iris (red). th e ciliary body (green), and th e choroid (blue). (CourresyofNasreen A. Syed, MD.)

185

186 • Ophthalmic Pathology a nd Intraocu la r Tumors

Figure 12·2

Histologic appearance of the iris: the anterior border layer is thrown in to numer-

ous crypts and folds . The sphincter muscle (red arrows)

present at the pupillary border.

whereas the dilator muscle (black arrows) lies just anterior to the posterior pigment epithelium. Normal iris vessels demonstrate a thick collagen cuff (arrowhead). (Courresyof NasreenA. Syed, MD.)

containing phagocytosed pigment (type I, or clump cells of Koga nei) and variants of smooth -muscle cells (type II clump cells) . The vessels within the stroma have a thick collar of collagen. The muscular layer is made up of the dilato r muscle and the sphincter muscle. Both are smooth muscle under autonomic control; however, the dil ator muscle is un ique in that it is derived from the anteri o r laye r of pigm ent epitheliu m. The posterior iris is

lined by a double layer of cub oidal epithelium arranged in an apex-to-apex configu ration. The cytoplas m of these cells is packed with mela nin granules. Iris color is determined by th e number and size of the melan in pigment granules in the anterior stromal melanocytes.

Ciliary Body T he ciliary body, which is approximately 6.0- 6.5 mm wide, extends from the base of the iris and becomes con tin uo us with the choroid at the ora serrata. The ci liary body is com posed of 2 areas: • the pars plicata, which contains the ci li ary processes • the pars plana The inner portion of the ciliary body is li ned by a double layer of epithelial cells, the in ner nonpigm ented laye r and the outer pigmented layer (Fig 12-3). T he zonular fibers of the lens attach to the ciliary processes. The ciliary smooth muscle has 3 types of fibers: longitudinal (Briicke muscle), radial, and the innermost circular (Miiller muscle). These muscle groups functi on as a unit during accommodation.

Choroid T he choroid is the pigmented vasc ular tissue that forms the middle coat of the posteri or part of the eye. It extends fro m the ora serrata ante riorly to the optic nerve posteriorly and consists of 3 principal laye rs:

• lamina fusca (suprachoroid layer)

CHAPT ER 12:

Uve al Tract. 187

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Fi g ur.1 2·3 Normal ciliary body. The inner face of the ciliary body is lined with a double layer of epithelium. The inner layer is non pigmented (red arrow) and the outer layer is pigmented (black arrow). (Courtesy of Nasreen A. Syed, MD.)

stroma chori ocapillaris

The cho ri ocapillaris is the blood supply for the reti nal pig men t epithelium (RPE) and the outer retinal layers (Fig 12-4).

Choroid

-'--

.".

~ Scle ra

Figure 12-4 The choroid is a vascular, pigmented structure present between the retinal pigment epithelium and the sclera. The layer closest to th e pigment epithelium is composed of capillari es and is known as the choriocapillaris (arrowheads). (Courtesy of NasreenA. Syed, MD.)

188 • Ophthalmic Pathology and Intraoc ul ar Tumors

Cong enital Anoma lies Aniridia True aniridia, or complete absence of the iris, is rare. Most cases of anirid ia are incon1plete, with a narrovv rim of rudimentary iris tissue present. Aniridia is usually bilateral,

though sometimes asymmetric. Histologically, the rudimentary iris consists of underdeveloped ectodermal-mesodermal neural crest elements. The angle is often incompletely developed, and peripheral anterior synechiae with an overgrowth of corneal endothelium are often present, most likely accounting for the high incidence of glaucoma associated with aniridia. Other ocular findings in aniridia include cataract, corneal pannus, and fo-

veal hypoplasia. Both autosomal dominant and recessive inheritance patterns for an iridia have been described. An association between sporadic aniridia and Wilms tumor has been linked to IIpl3 deletions and to mutations in the PAX6 gene, located in the same region. Micro-

cephaly, mental retardation, and genitourinary abnormalities have also been described in association with aniridia.

See also BeSe Section 2, Fundamentals and Principles of Ophthalmology, and Section 6, Pediatric Ophthalmology and Strabismus. Hanson 1M , Seawright A, Hardman K, et aL PAX6 mutations in aniridia . Hum Mol Genet.

1993;2(7), 915 - 920.

Coloboma A coloboma-the absence of part or all of an ocular tissue-may affect the iris, ciliary body, choroid, or all 3 structures. Histologically, colobomas appear as an area nearly or entirely devoid of tissue. See sese Section 2, Fundam entals and Principles of Ophthalmology, and Section 6, Pediatric Ophthalmology and Strabismus, for further discussion of uveal colobomas.

Inflammations Bese Section 9, Intraocular Inflammation and Uveitis, discusses the conditions described in the following sections and also explains in depth the immunologic processes involved.

Infectious The uveal tract may be involved in infectio us processes that appear restricted to a single intraocular structure or that may be part of a generalized inflammation affecting several or

all coats of the eye. If the eye is the primary source of the infection, as with posttraumatic bacterial infection, the infection is termed exogenous. If, however, the infection originates

elsewhere in the body, such as with a ruptured diverticulum, and subsequently spreads hematogenously to involve the uveal tract, the infection is referred to as endogenous . A wide variety of organisms can cause infections of the uveal tract, including bacteria, fungi, viruses, and protozoa.

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189

Histopathology often shows a mixed acute and chronic inflammatory infiltrate within the choroid, ciliary body, or iris stroma. In cases of viral, fungal, or protozoal (eg, toxoplasmosis) agents, the presence of epithelioid histiocytes is typical (granulomatous inflammation). Special stains (see Table 3~2) for microorganisms (tissue Gram, Gomori methenamine silver, PAS [periodic acid-Schiff], Ziehl-Neelsen) may be helpful if infection is suspected.

Noninfectious Sympathetic ophthalmia Sympathetic ophthalmia is a rare bilateral granulomatous panuveitis that occurs after accidental or surgical injury to 1 eye (the exciting, or inciting, eye) foLlowed by a latent period and development of uveitis in the uninjured globe (the sympathizing eye). The inflammation in the sympathizing eye may occur as early as 9 days or as late as 50 years following the suspected triggering incident. Enucleation of the inciting eye, if blind, is thought to help control inflammation or reduce the risk of inflammation in the other eye. Histologically, a diffuse granulomatous inflammatory reaction is present within the uveal tract and is composed of lymphocytes and epithelioid histiocytes containing phagocytosed melanin pigment (Figs 12-5, 12-6). Plasma cells are usually scant, suggesting a cell-mediated response. Typically, the choriocapillaris is spared. Varying degrees of in flammation may be present in the anterior chamber, such as collections ofhistiocytes deposited on the corneal endothelium (mutton -fat keratic precipitates). Dalen-Fuchs nodules, which are collections of epithelioid histiocytes and lymphocytes between the RPE and the Bruch membrane, may be seen in some cases (Fig 12-7). However, Dalen-Fuchs nodules may be present in other diseases, such as Vogt-Koyanagi-Harada syndrome, and thus are not pathognomonic of sympathetic ophthalmia. Vogt-Koyanagi-Harada syndrome

Vogt-Koyanagi -Harada (VKH) syndrome is a rare cause of posterior or diffuse uveitis and may have both ocular and systemic manifestations. The syndrome occurs more

Sympathetic ophthal mia . Diffuse in fi lt ration of th e uveal tract by chronic inflammatory cells (arrow s). (Courtesv o f Hans E. Grossniklaus, MD.)

Figure 12-5

190 • Ophthalmic Pathology and Intraocular Tumors

B Figure 12-6

Sympathetic ophthalmia. A, Diffuse granulomatous inf lammation wit hin the choro id. 8 , Higher magnification shows the presence of multinucleated giant cells (arrowheads) . (Courresy of Hans E. Grossniklaus, MD.)

A Figure 12-7

Dalen-Fuchs nodules in sympathetic ophthal mia. A, Focal collections of inf lammatory cells are located between the RPE and Bruch membrane (arrows). B, Higher magnificat ion demonstrates th e presence of epithel ioid hist iocytes containing cytoplasmic pigment (a rrows ) wit hin th e nodules . (Courtesy of Hans E. Grossnik/aus. MD.)

commonly in patients with Asian or Native American ancestry and usuall y affects individuals between 30 and 50 years of age. A chronic, diffuse granulomatous uveitis resembles that seen in sympathetic ophthalmia. However, in VKH, the entire choroid, including the choriocapillaris, tends to be involved by the inflammatory reactio n. The granulomatous inflammation may extend to involve the retina. Because the disease is one of exacerbation and remission, chorioretinal scarring and RPE hyperplasia and/or atrophy may also be observed.

Sarcoidosis Sarcoidosis is a multisystem granulomatous disease characterized by inflammatory nod ules, which can occur in various organs and tissues. The uveal tract is the most common site of ocular involvement by sarcoidosis. Anteriorly, inflammatory nodules of the iris may be seen, either at the pupillary margin (Koeppe nodules) or elsewhere on the iris (Busacca nodules). In the posterior segment, chori oreti nitis, periphlebitis, and chorioretinal nodules may be seen. Periphlebitis may appear clinically as inflammatory lesions described as candlewax drippings. The optic nerve may be edematous because of inflammatory infiltration.

CHAPTER 12:

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Histologically, the classic sarcoid nod ul e is composed of noncaseating granulom as. These are collections of epithelioid histiocytes, sometimes accompanied by multinucleated giant cells, that have a sur rounding cuff of lymphocytes (Fig 12-8). Not/caseating refers to the lack of necrosis in the center of the nodule. In the uvea, the inflam matory infiltrate may show a more d iffuse distribution of lymphocytes and epithelioid hist iocytes (granulomatous inflam mat ion). The multinucleated giant cells may demonstrate asteroid bodies (star-shaped, acidophilic bodies) and Schaumann bodies (spherical, basophilic, calcified bodies). Neither asteroid nor Schauman n bod ies are pathognomonic for sarcoidosis.

Juvenile xanthogranuloma Ju ve nile xanthogranuloma is an uncommon inflammatory condition that occurs in chUd ren. T he skiJ1 and uvea are commonl y affected areas and, in the uveal tract, lesions may present as a solid mass, mim icki ng a tumor. HistologicalJy, the lesions have a characteristic appearance with the presence of lipid-laden histiocytes, TOUlon giant cells, lymphocytes, and occasional eosi nophils (Fig 12-9). The lesions are often vascularized, and these blood vessels tend to be fragile. This results in intralesional hemorrhage and, in the iris, may resul t in spontaneous hyphema.

Figure 12-8 Sarcoidosis . A, Gross appearance of mult iple discrete nodules on the skin of the uppe r extrem ity. B, Histology of sarcoid nodule sh owing epith el ioid histiocytes (between arrowh eads) and multinucleated giant cells (arrow). (Part A courtesy of Curtis E. Margo, MD; part B courtesy of Hans E. Grossniklaus, M D.)

Figure 12-9 Juvenile xanth ogranuloma. Touton giant ce lls (arrow), foamy histiocytes (arrowhead), and lym phocytes are adm ixed . (Courtes y of Nasreen A. Syed, MD.)

192 • Ophth alm ic Pathology and Int raoc ular Tum ors

De!lenerations Rubeosis Iridis Rubeosis iri dis, o r neovascu larization of the iris, is a cOlll mo n find ing in surgicall y enucle-

ated blind eyes. It may be associated with a wide variety of conditio ns (Table 12- 1). Histologically, the new vessels tend to lack su pporting tissue and do not possess the encircl ing thick fibrous cuff seen in no rm al iris vessels. The vessels grow on th e anterior surface o f the iri s and may extend to involve the angle. The neovascula r m em bra ne has a fibrous

component consisting of myofi broblasts, which contract and eventually lead to angle closure due to fo rmation of peripheral anterior synechiae. Neovascu larization of the angle often results in neovascular glaucoma, a secondary type of glaucoma. Cont raction of the memb ranes may also lead to ectropion uveae, an ante rior displacement or draggin g o f th e

posterior iris pigment epithelium at the pupillary bord er. The an terior surface of the iris often becomes flattened. In advanced cases, atrophy of the dilator m uscle, attenuation of the pigment epithelium, and stromal fibrosis occur (Fig 12- 10).

Hyalinization of the Ciliary Body Over ti me, the Ciliary body processes become hyali nized and fibro sed, with loss of stromal cellularity. The thin, delicate processes become blunted and attenuated, and th e stroma becomes more eosinophilic. This process is a normal aging change of the ciliary body and is not considered pathologic, although it does contribute functionally to the development of presbyo pia.

Table 12-1 Conditions Associated With Rubeosis Iridis Vascular disorders Ce ntral retinal ve in occlus ion Central retinal artery occ lusion Bra nch retinal vei n occlusion Carotid occlusive disease Ocular diseases Intraoc ular inflam mation Infectious (e9, seve re cornea l ulcer) Non infecti o us (eg, uveit is) Ret ina l detachment Coats disease Secondary glaucoma Surgery and radiation therapy Ret inal detachment su rgery

Rad iati on Systemic diseases Diabetes mellitus Sickle cell disease Neoplastic diseases Retinoblastoma M el an oma of the choroid/ir is Metastatic carcino ma

Trauma

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193

p Figure 12·10 Iris neovascularization (rubeosis), Small blood vessels sprout from existing iris vasculature, typica lly on the surface of the iris (black arrows). Note the flat anterior surface of the iris (A = anterior, P = poste ri or). The contractile com ponent of the neovascular membrane may result in dragging of the iris pigment epitheliu m (red arrow) and sphincter muscle (arrowheads) ante riorly at the pupillary margin, in turn res ulting in ectropion uveae. (Courtes y of Nasreen A. Syed, MD.)

Choroidal Neovascularization Choroidal neovascularization is discussed at length in Chapter 11 and in BCSC Section 12, Retina and Vi treous.

Neoplasia Uveal neoplasms are also discussed in detail in Chapters 17, 18, and 20. The discussion o f uveal neoplasms in this chapter foc uses pri maril y on histopathology.

Iris

Nevus An iris nevus represents a localized proliferation of melanocytic cells that generally appears as a darkly pigmented lesion of the iris stroma with minimal d istortion of the iris architecture (see Chapter 17, Fig 17-1). An iris nevus appears histologically as a collection of branching dendr itic cells or spindle cells, usually with melani n granules in the cytoplasm. The nuclei of these cells are typically oblong or ovoid with a bland appearance and indistinct nucleoli. Less commonly, epithelioid nevus cells may be present. A variety of growth patterns and cytologiC appearances is possible, but cell ular atypia and significant mitotic activity are not present. The nevus ce lls are present as an aggregate within th e stroma and occasionall y are also present in a plaq uelike distribution on the surface of the iris. Occasionally, the cells may extend into the adjacent angle structures.

Melanoma Melanomas ar ising in the iris tend to follO\v a nonaggressive clinical course compared to posterior (ciliochoroidal) melanomas. The majority of iris melanomas occur in the

194 • Ophtha lmic Pathology and Intraocular Tumors inferior sectors of the iris (see Chapter 17, Fig 17-3). The lesions can be quite vascularized and ll1ay occasionally cause spontaneous hyphema. Iris melanomas are composed of spindle melanoma cells, epithelioid melanoma cells, or a combination of these. Histologically, spindle cells possess plump, spindle-shaped nuclei that have a coarse, granular appearance and prominent nucleoli. These cells are the equivalent of spindle-B cells in posterior melanoma (see the "Melanoma" section under Choroid and Ciliary Body). Epithel ioid cells are polyhedral in shape, with large, round nuclei that have a clumped chromatin pattern and prominent eosinophilic nucleoli. Both types of cells tend to have a high nuclear-to-cytoplasmic ratio. The cytoplasm of melano ma cells can range from lightly to heavily pigmented. Typically, they grow as a solid mass in the stroma, sometimes with a surface plaque. Occasionally, iris melanomas may demonstrate satellite lesions or a diffuse growth pattern that replaces normal stroma (Fig 12-11). The modified Callender classification for posterior melanomas (see the discussion later in the chapter) is not applicable to iris melanomas in terms of prognostic significance. Although iris melanomas may grow in a locally aggressive fas hion, they rarely metastasize. One exception occurs when melanomas grow to diffusely involve the entire iris stroma. In such cases, the melanoma may extend posteriorly into the chamber angle and involve the ciliary body.

A , Clinical appearance of iris melanoma. The pigmented tumor is seen between 10:30 and 1 :00. B, Gross appearance of pigmented iris mass (between arrows). C, Low magnification shows the iris melanoma complete ly rep lacing t he normal iris stroma, extending into the anterior chamber, touching the posterior cornea, and occluding the angle. 0 , Histology of iris melanoma shows numerous plump epithelioid melanoma cells containing prominent nucleoli (arrowheads). (Courresv of Hans E. Grossniklaus, MO.) Figure 12-11

CHAPTER 12:

Uveal Tract. 195

Choroid and Ciliary Body Nevus

Most nevi of the uveal tract occur in the choroid (see Chapter 17, Fig 17-2). One review of 100 nevi showed that fewer than 6% involved the ciliary body; the remainder were present in the choroid. Four types of nevus cells have been described. They are • plump polyhedral: abundant cytoplasm filled with pigment and a small, round to oval nucleus with bland appearance • slender spindle (Fig 12-12): cytoplasm contains scant pigment and a small, dark, elongated nucleus • plump fusiform dendritic: morphology is intermediate between plump polyhedral and slender spindle • balloon cells: abundant, foamy cytoplasm that lacks pigment and has a bland nucleus

Depending on the size and location of the nevus, it may exert nonspecific effects on adjacent ocular tissues. The associated choriocapillaris may become compressed or obliterated, and drusen may be seen overlying the nevus. Less commonly, localized serous detachments of the overlying RPE or neurosensory retina develop. Most choroidal nevi remain stationary over long periods of observation. However, the presence of nevus cells associated with some melanomas supplies evidence that melanomas may arise from choroidal nevi.

Melanocytoma The melanocytoma is a specific type of uveal tract nevus (magnocellular nevus) that warrants separate consideration. These jet-black lesions may occur anywhere in the uveal tract, but they most commonly appear in the peripapillary region (see Chapter 17, Fig 17-12). Histologically, a melanocytoma is composed of plump polyhedral cells with small nuclei and abundant cytoplasm. Because the nevus cells are so heavily pigmented, it is usually necessary to obtain bleached sections to accurately study the cytologic features. Areas of cystic degeneration or necrosis may be obser ved.

Melanoma Melanoma arising from the ciliary body and choroid is the most common primary intraocular malignancy in adults. When this tumor achieves significant size, it may extend

Spindle cell choroid al nevus (between arrows) is co mpose d of slender, spindle-shaped cells with thin, hom*og eneou s nuclei. (Courtesy of Nasreen A. Syed, MD.! Figure 12-12

196 • Ophtha lm ic Pathology and Intraocul ar Tu mors

beyond its site of origin (ie, from the choroid to the ciliary body and vice versa). Unlike iris melanomas, ciliary body and choroidal melanomas exhibit similar features and are usually considered to be the same type of tumo r, with similar histologic features and prognostic implications. Histologicall y, ciliary body and choroidal melanomas are composed of spindle cells and/or epithelioid cells (Figs 12-13, 12-14, 12-15). Less commonly, balloon cells similar to those seen in nevi may be present. Spindle cell melanomas consist pri maril y of spindle-B melanoma cells. They may also contain spindle-A cells; however, a tumor consisting en tirely of spindle-A cells is considered a nevus. Melanoma cells can vary considerably with regard to cytoplasmic melanin content. The mitotic rate in melanomas tends to be low, and

Spindle-A cell s have slender, elongated nuclei with small nucleoli. A centra l stripe may be present dow n the long axis of th e nucleus (arrowheads). Tum ors composed exclusively of spindle-A cells are considered to be nevi. (Courtes y of Nasreen A. Syed, MD.)

Figure 12-13

Figure 12-14 Compared with spindle-A cel ls, spindle-B cells demonstrate a higher nuclearto-cytop lasmic rat io; more coarse ly granu lar chrom atin; and plumper, large nucle i. Nucleoli are prominent and mitoses are present. t hough not in large numbers. Tumors composed of a mix of spindle-A and spind le-B cell s are designated spindle cell melanomas. (Courtesy of Nasreen A. Syed, MD.)

12-15 Epithelioid melanoma ce lls. Cell s resemble epithelium because of abundant eosinophilic cytoplasm and en larged ova l to polygona l nuclei. Epit helioid me lanoma cel ls often lack cohesiveness and demon strate marked pleomorphi sm, including t he for mation of multinucleated tumor giant cell s. Nuclei have a conspicuou s nuclea r membrane, very coarse chromatin, and large nucleo li. (Courtesy of Nasreen A. Syed, MD.)

Figure

CHAPTER 12:

Uveal Tract. 197

these tumo rs may exhibit various amounts of necrosis. Pigment -laden macrophages or a lymphocytic inflammatory infiltrate (tumor-infiltrating lymphocytes) may be present. Melanomas typically start as dome-shaped lesions and, as they grow and break through the Bruch membrane, they acquire a mushroom or collar-button shape (Fig 12-16). Less commonly, choroidal lesions may grow in a diffuse pattern, replacing normal choroid without achieving significant height. In the ciliary body, the equivalent of the diffuse pattern is the ring melanoma, in which the tumor extends for the entire circumference of the ciliary body (Figs 12-17, 12 -18) .

Figure 12-16 Choroida l me lanoma with rupture through the Bruch membrane. A, Gross appearance. B, Microscop ic appearance. Note t he subretinal fluid (SRF) adjacent to the tumor.

Some melanomas grow in a diffuse placoid fashion, replacing normal choro id, without achieving signif icant height (arrows). Note the eosinoph ilic protei naceous material (asterisks) interposed between th e retina and t he tumor, corresponding to exudative retinal detachment overlying the tumor.

Figure 12-17

By definition, a ring melanoma (asterisks) follows the major arterial circle of the iris circumferentially around the eye.

Figure 12-18

198 • Ophth almic Pathology and Intraocular Tumors Choroidal melanomas may also cause serous detachments of the overlying and adjacent retina, with subsequent degenerative changes in the outer segments of the photoreceptors (Fig 12-19). Melanomas may extend through scleral emissary channels to gain access to the episcleral surface and the orbit (Fig 12-20). Less commonly, aggressive melanomas may directly invade the underl ying sclera or overlying retina (see Fig 12-19). Direct invasion of the anterior chamber may lead to secondary glaucoma. In addition. tumor necrosis may lead to the liberation of melanin pigment, which can then gain access to the anterior chamber and angle, causing a type of secondary glaucoma called me/anomaly tic glaucoma. Several factors that can be identified on pathologic examination have been significa ntly correlated with survival in patients with choroidal and ciliary body melanomas. The 2 most important va riables associated with survival are

the size of the largest tumor dimension in contact with the sclera • the cell type making up the tumor

Fi gure 12·19

Invasion of neurosensory retina

by melanoma (arrows). Note the atrophy of

overlying outer retina . cystoid edema, and intraretinal hemorrhage. (Courtesy of Nasreen A. Syed, MDJ

B 1IZ:Iao_'"

Figur e 12-20 A, Note the melanoma ce lls tracking along scleral emissary canals (arrows). B, Melanoma is found within the

vortex vein (arrows). C, Some melanomas (ar-

rows) track along the outer sheaths of posterior ciliary vessels (asterisks) and nerves.

CHAPTER 12:

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The modified Callender classification is used for the cytologic classification of uveal melanomas: spindle cell melanoma epithelioid melanoma mixed-cell type (mixture of spindle and epithel ioid cells) OccaSionally, a melanoma undergoes extensive necrosis, which precludes classification. Spindle cell melanoma has the best prognosis, an d epithelioid melanoma the worst. Melanomas of mixed-cell type have an intermedi ate prognosis. Some authors have suggested that survival following en ucleation decreases with Lncreasing proportions of epithelioid cells in mixed-cell melanomas. Totally necrotic melanomas assume the same prognosis as mixed-cell melanomas. The modified Callender classification has some disadvantages. First, there is continuing controversy about the minimum number of epithelioid cells needed for a melanoma to be classified as mixed-cell type. Second, the scheme is difficult to reproduce, even among experienced ophthalmic pathologists. This difficulty arises because the cytologic features of the melanoma cells reflect a continuous spectrum. Cytomorphometric measurements of melanoma cells have been studied. One such measureme nt is the mean of the 10 largest melanoma cell nuclei (MLN) . T his parameter has been shown to correlate well with mortality after enucleation. The correlation with morphom etry is enhanced further when combined with the largest dimensio n of scleral contact by tumor. Intrinsic tumor microvascu lar patterns have also been studied and shown to have prognostic Significance. Tumors containing more complex microvascular patterns such as vascular closed loops or vascular networks (3 vascular loops located back-to-back) are associated with an increased incidence of subsequent metastases (Fig 12-21). CytogenetiC studies of uveal melanoma have shown that approximately half of uveal melanomas demonstrate monosomy of chromosome 3. A smaller proportion demonstrates

A Figure 12·21 Intrinsic microvascular pa ttern s in uvea l melanoma. A, Microvascu lar closed loop (L) . B, M icrovascular network: 3 or more back-to-back loops . (Counesyof NasreenA. Syed. MD. )

200 • Ophthalmic Pathology and Intraocu lar Tumors

changes in chromosome 8, with either gain or loss of a chromosome. Monosomy 3 and trisomy 8 are associated with increased mortality from the tumor. Mutations in the gene coding for the G protein a-subunit (GNAQ) have been described in up to half of uveal melanomas. This discovery may lead to new, more targeted therapies for uveal melanoma in the future. Other factors associated with an increased mortality rate include extrascleral extension, anterior or juxtapapillary location of the tumor, and the presence of tumorinfiltrating lymphocytes. Invasion through the Bruch membrane does not affect survival. Lymphatic spread of ciliary body and choroidal melanomas is rare. Metastases almost invariably result from the hematogenous spread of melanoma to the liver. The reason for the propensity of melanomas to spread to the liver is unknown, although more than 95% of tumor-related deaths have liver involvement. In as many as one-third of tumor-related deaths, the liver is the sole site of metastasis. Some types of uveal melanomas show biologic behavior that cannot be predicted according to the criteria just discussed. Survival rates of patients with d iffuse ciliary body melanomas (ring melanoma) are particularly poor. These relatively flat tumors are almost always of mixed-cell type, and they may grow circumferentially without becoming significantly elevated. Diffuse choroidal melanomas similarly have a poo r prognosis. See Chapter 17. Also see the appen dix for the American Joint Committee on Cancer (AJCc) staging form for uveal melanoma.

Metastatic Tumors Metastatic lesions are the most common intraocular tumors in adults. These lesions most often involve the choroid, but any ocular structure can be affected. Un1.ike primary uveal melanoma, metastatic lesions are often multiple and may be bilateral. Although these lesions typically assume a flattened growth pattern , rare cases of collar-button or mushroomshaped lesions have been reported. The most common primary tumors metastasizing to the eye are breast carcinoma in women and lung carcinoma in men (Fig 12-22), although tumors from many different primary sites have been reported. Histologically, metastatic tumors may recapitulate the appearance of the primary lesion, or they may appear less differentiated. Special histochemical and immunohistochemical stains can be helpful in diagnosing the metastatic les ion and determining its origin. The importance of a careful clinical history cannot be overemphasized. See Chapter 20 for further discussion.

Other Uveal Tumors Hemangioma Hemangiomas of the choroid occur in 2 specific forms. The localized choroidal hemangioma typically occurs in patients without systemic disorders. The diffuse choroidal hem angioma is generally seen in patien ts with Sturge-Weber syndrome (encephalofacial angiomatosis). Histologically, both the diffuse and localized hemangiomas show collections of variably sized vessels within the choroid (Fig 12 -23). The lesions may appear as predominantly

CHAPTER 12: Uveal Tract. 201

__________

Figure 12-22 A, Clinical appearance of a metastatic lesion from a primary lung tumor. B, Gross appea rance of lesion (between arrowheads). C, Choroidal metastasis from lung adenocarci noma; histology shows adenocarcinoma (between arrows) w ith mucin production (asterisk) . Note overlying retina l detachment. D, Higher magnification depicts a wel l ~diffe ren t i ated adenocarcinoma with distinct gla ndu lar appearance. (Courtesy of Hans E. Grossniklau s, MO.)

A Figure 12-23 Choroidal hema ng ioma w ith a la rge number of thin -walled, variab ly sized vessels within t he choro id . A, Low-ma gnification view illustrating exudative retinal detachment overlying the lesion (asterisk). Arrows designate t he Bruch membrane. 8, Higher magnif ication; arrows designate Bruch membrane. (Courtesy of NasreenA. Syed, MO.)

202 • Ophthalmic Pathology and Intraocular Tum ors capillary hemangiomas or cavernous hemangiomas or a mixed pattern. The adjacent and overlying choroid may show compressed melanocytes, hyperplastic RPE, and fibro us tissue proliferation. See also Chapter 18 and Figures 18- 1 and 18-2 in this volume and BCSC Section 12, Retina and Vitreous.

Choroidal osteoma Choroidal osteomas are benign bony tumors that typically arise from the juxtapapillary choroid and are seen in adolescent to young adult patients. more commonly in femal es.

The characteristic lesion appears yellow to orange and has well -defined margins (see Chapter 17, Fig 17 -13) . Histologically, the tumor is composed of compact bone located in the peripapillary choro id. The intratrabecular spaces are filled with a loose connective tissue containing large and small blood vessels, vacuolated mesenchymal cells, and scattered mast cells. The bony trabeculae contain osteocytes, cement lines, and occasional osteoclasts. See Chapter 17 fo r fur ther discussion.

Lymphoid proliferation The choroid may be the site of lymphOid proliferation, either as a primary ocular process or in association with syste m ic lymphoproliferative disease.

Uveal lymphoid infiltration (formerly reactive lymphoid hyperplasia ) of the uveal tract is sim ilar to the spectrum oflow-grade lymphOid lesions that occur in the orbit (see Chapter 14) and conjunctiva. There may be diffuse involvement of the uveal tract by a mixture of lymphocytes and plasma cells, and lymphoid follicles may be present. In addition, there may be a similar infiltrate located along the posterior episclera. Lymphocyte typing reveals a polymorphic population without clonal restriction; this finding distinguishes inflammatory pseudotumor from lymphoma. Lymphoma of th e uveal tract occurs almost exclUSively in association with system ic lymphoma (Fig 12 -24) as an extranodal site. The classification of lymphomas is discussed in Chapter 14. Gross niklaus HE, Martin DF, Avery R, et al. Uveal lymphoid infiltration: report of four cases and cl inicopathologic review. Ophthalmology. 1998; 105(7):1265-1273.

Figure 12· 24

Diffuse expansion of choroid by lymphoma . R = RP E, 5 = sclera.

magnification depicts atypical lym phocytes. (Court9syof Hans E. Grossnlklaus, MDJ

Higher

CHAPTER 12:

Uveal Tract . 203

Neural sheath tumors Neurilemomas (schwa nnomas) and neurofibromas are rare tumors of the uveal tract. Multi ple neurofibromas may occur in the ciliary body, iris, and choroid in patients with neurofibromatos is. The histopathologic features of these tumors are discussed in Chapter 14.

Leiomyoma Neoplasms arising from the smooth muscle of the ciliary body have been reported only rarely. When th ey occur, they may be confused with amelanotic melanoma or neurofibroma clinically. Histologically, they consist of a proliferation of tightly packed slender spindle cells lacking pigment. Immunohistochemical stains may be useful in making the diagnosis, as leiomyomas express smooth muscle- related antigens. By light and transmission electron microscopy, these tumors sometimes exhibit both myogenic and neurogenic features . In such cases, the term mesectodermal leiomyoma is employed.

Trauma The uveal tract is frequently involved in cases of ocular trauma. Prolapse of uveal tissue through a perforating ocular injury is a common association. Rupture of the choroid may occur as the result of a blunt or penetrating injury. The pattern of the rupture most frequently appears as semici rcular lines circ*mscribing the optic nerve head in the peripapillary region. If the macula is involved, the prognosis for vision recovery is guarded. Sub retinal neovascularization can occur as a late complication. More severe injury may cause rupture of both the choroid and the retina, a condition termed chorioretinitis

sclopetaria. Choroidal detachm ent, either localized or diffuse, may occur after traumatic globe rupture or surgery. Serous or hemorrhagic fluid accumulates in the suprachoroidal space between the choroid and the sclera. Depending on the etiology, the flu id may spontaneously resorb, allowing for reattachment of the choroid. In other cases, surgical drain age of the fluid may be required.

CHAPTER

Eyelids

Topography The eyelids extend from the eyebrow superiorly to the cheek in feri orly and can be subdi vided into orbital and tarsal components. At the level of the tarsus, the eyelid consists of 4 mai n histologic layers. from anterior to posterior:

skin • orbicularis oculi muscle

• tars LIS • palpebra l conjunctiva A surgical plane of dissection through an incision along the gray li ne of the eyelid margin is possible between the orbicularis and the tarsus, functionally dividing the eyelid into ante rior and posterior lamellae (Fig 13- i). See also BCSC Section 7, Orbit, Eyelids,

and Lacrimal System. Th e skin of the eyelids is thinner than that of most other body sites. It consists of an epid erm is of keratinizi ng strati fied squamous epitheliu m, whi ch also contains melano cytes and antigen-presenting Langerhans cells; and a dermis of loose collagenous connective tissue, which contains the following: cilia and associated sebaceous glands (of Zeis) apocrine sweat glands (of Moll) eccrine sweat glands • pilosebaceous units

Eyelid elevation is effected by the levator palpebrae superioris, of which only the aponeurotic portion is present in the eyelid, and Muller muscie (s mooth muscle connecting the upper border of the tarsus with the levator). Eyelid closure is accomplished by the orbicularis oculi (striated skeletal muscle). The tarsal plate, a thick plaque of dense, fibrous connect ive tissue, contai ns the sebaceous meibom ian glands. Also present near the upper

border of the superior tarsal plate (and less so along the lower border of the inferior tarsal plate) are the accessory lacrimal glands of Wolfring; the accesso ry lacrimal glands of Krause are located in the conjunctival fo rni ces. The palpebral conjunctiva is tightly adh erent to the posterior surface of the tarsus. Eyelid glands secrete their products in various ways. Apoc rine sweat gla nds secrete sweat by decapitation of the apical portion of the cell. Eccri ne sweat glands and lacrimal gla nds secrete without losing any part of the cell. Sebaceous glands are holocrine glands,

205

206 • Ophthalmic path ology and Int raocu lar Tumors Epidermis

Dermis

Orbicularis

Tarsal plate

Meibomian glands

Conjunctiva

Figure 13·1 Cross section of a normal eyelid. Proceeding from top (anterior) to bottom (posterior), note the e piderm is; the dermis, resting on the orbicularis; th e tarsus , surrounding th e

meibomian glands; and the palpebralltarsal) conjunctiva.

meani ng that they shed the entire cell as they secrete. Table 13 -1 lists the norm al functions of the eyelid glands and some of the pathologic conditions related to them. FollOWing are several terms used commonly in dermatopathology:

acanthosis: increased thickn ess (hyperplasia ) of the stratum malpighii (co nsisting of the strata basale, spinosum, and granul osum ) of the epidermiS hyperkeratOSiS: increased thickness of the stratum corn eum of the epiderm iS • parakeratosis: retention of nuclei within the stratum corneum with corresponding absence of the stratum granulosum papillomatosis: form ati on of finge rlike upward projections of epidermis lining fi brovascular cores dyskeratosis: premature individual cell keratinization within the stratum malpighii acantholysis: loss of cohesion (dissolution of intercellular bridges) between adj ace nt epithelial cells spongiosis: widening of intercellular spaces between cells in the stratum malpighii due to edema

CHAPTER

n Eyelids.

207

Table 13-1 Secretory Elements of the Eyel id: Function and Pathology Secretory Element

Normal Function

Pathology

Conjunctival goblet cells

Mucin secretion to enhance

Numbers diminished in some dry-eye states Mucoepidermoid carcinoma Sjogren syndrome

corneal wetting Accessory lacrimal glands of Krause and Wolfring

Basal tear secret ion of the aqueous layer

Meibomian (sebaceous) glands Sebaceous glands of Zeis

Secretion of li pid layer of tears to retard evaporation Lubrication of the cilia

Apocrine glands of Moll

Lubrication of the ci li a

Graft-vs-host disease Rare tumors (benign mixed tumor) Chalazion Sebaceous carcinoma External hordeolum Sebaceous carcinoma Ductal cyst (sudoriferous cyst, apocrine h idrocystoma) Apocrine carcinoma

Eccrine g lands

Secretions for temperature control, electrolyte balance

Ductal cyst (sudoriferous cyst, eccri ne hidrocystoma) Syringoma Sweat gland carc in oma

Congenital Anomalies See also BCSC Section 7, Orbit, Eyelids, and Lacrimal System. Distichiasis

Distichiasis is the aberrant formation within the tarsus of cilia that exit the eyelid margin through the orifices of the meibomian glands. The pathogenesis of distichiasis is thought to be an ano malous formation within the tarsus of a complete pilosebaceous unit rather than the normal sebaceous (meibomian) gland. Histologically, hair follicles can be seen within the tarsal plate_ The tarsus may be rudimentary, and the glands of Moll are often hypertrophic. See BCSC Section 6, Pediatric Ophthalmology and Strabismus, and Section 8, External Disease and Cornea, for additional discussion. Phakomatous Choristoma

A rare congenital tumor, phakomatous choristoma (Zimmerman tumor) is formed from the aberrant location of lens epithelium within the inferonasal portion of the lower eyelid. These cells may undergo cytoplasmic en largement, identical to the "bladder" cell in a cataractous lens. PAS-positive basem*nt memb rane material is produced, recapitulating the lens capsule (Fig 13-2). The nodule formed is usually present at birth and enlarges slowly. Complete excision is the usual treatment. Dermoid Cyst

Dermoid cysts may occur in the eyelid, but they are more common in the orbit and are discussed in Chapter 14.

208 • Ophthalmic Path olo gy and Intraocular Tumors

Figure 13-2 Phakomatous chori stoma of the eyelid. The dermis displays a disorganized proliferation of lens epithelium and occasional "bladder" cel ls (arrows). Note the large amount of eosinoph ilic material that represent s lens nuclear/cortical prot eins. (Courres y of Nasreen A. Syed, MD.J

Inflammations Infectious De pending on the causative agent, infecti ons of the eyelids may produce disease th at is localized (eg, hordeolum), multicentric (eg, papillomas), or diffuse (cellulitis). Routes of infection may be pri mary inoculation th rough a bite or wound, direct spread from a con tiguous site such as a paranasal sin us infection, or hematogenous disse mi nation from a remote site. Infectious agents may be bacterial, such as Staphylococcus aureus in hordeolum and infectio us blepharitis viral, such as mollusc um contagiosu m due to a poxvirus fungal, such as blastomycosis, coccidioidomycosis, or aspergillosis

Hordeolum Also known as a stye, hordeolum is a primary, acute, self-limited inflammatory process typically invol ving the glands of Zeis and, less often, the meibomian glan ds of the eyelids. A small abscess, or focal collectio n of neutrophils and necrotic debris (p us), forms at the site of infection . Lesions may drain spontaneously or require surg ical drainage.

Cellulitis The diffuse spread of acute inflammatory cells through tissue planes is known as cellulitis. Preseptal cellulitis involves the tissues of the eyelid anterior to the orbital septum, the fibro us membrane co nnecting the borders of the tarsal plates to the bony orbital rim . The condition is m ost often secondary to bacterial in fec tion of the paranasal sinuses. Histologically, th ere is neutrophilic infiltration of the soft tissues, accompanied by interstitial ede ma and, occasionally, necros is (Fig 13-3) .

CHAPTER 13,

Eyelids. 209

Figure 13-3 Neutrophils (arrows) dissect between the skeletal muscle fibers of the orbic-

ularis in this biopsy of a preseptal cellulitis of the eyelid.

Viral infections Human papillomavirus may in fect the skin of the eyel ids and typically manifests as verruca vulgaris, commonly kn own as a wart. Cli nically, it is usually an elevated papillary lesion. Histologically, the lesions demonst rate hype rkeratos is an d acanthosis and exh ibit a papillary growt h pattern. Infected cells may demonstrate cytoplasm ic clearing (koilocytosis). A mixed inflammatory infiltrate is typically present in the superfi cial derm is (Fig 13 -4).

A , Verruca vu lgaris is a form of infection of the eyelid with human papillomavirus (HPV). The lesion has a papillary growth pattern with finger like projections. B, Occasional koilocytes w ith nuclear con traction and cytopl asmic clearin g are present (arrow). (Courtesy of

Figure 13-4

Nasreen A. Syed, MD.J

21 0 • Opht halmic Pathology an d Intraocul ar Tumors

Molluscum contagiosum is caused by a member of the poxvi rus family. Dome-shaped, waxy epidermal nodules with central umbilication form and, if present on the eyelid margin, may cause a secondary follicular conj unctivitis (Fig 13-5). Histologically, the lesions are distinctive, with a nodular proliferation of infected epithelium producing a central focus of necrotic cells that are extruded to the skin surface. As the replicating virus fills the cytoplasm , the nucleus is displaced peripherally by large viral inclusions (molluscum bodies) and fin ally disappears as the cells are shed (Fig 13-6).

Noninfectious Chalazion A chalazion is a chronic, often painless nodule of the eyelid that occurs when the lipid secretions of the meibomian glands or, less often, the glands of Zeis are discharged into the

Figure 13·5 Molluscum con tagiosum in volving the eyelid marg in (arrow). Note the associated follicular conjunctivitis.

A Figure 13-6

""-'--'~

____ • ..IQ"._ _ __ ~

Molluscum contagiosum. A. Note the cup-shaped, thickened epidermis with a

central crater. B, Note the eosinophilic inclusion bodies (arrows) becoming basophilic as they migrate to the surface. (Courtesy of Nasreen A. Syed, MD.)

CHAPTER 13:

Eyelids. 211

Figure 13-7 Chalaz ion. Granul omato us infl ammation (epitheli oid histi ocytes and mu ltinucleated giant ce lls) surroun ds clea r spaces

formerly occupied by li pid (li pog ranuloma).

surrounding tissues, inciting a lipogranulomatous reaction (Fig 13-7). Because the lipid is dissolved by solvents during routine tissue processing, histologic sections show histiocytes and multinucleated giant cells enveloping optically clear ("lipid dropout") spaces. Lymphocytes, plasma cells, and neutrophils are also often present.

Degenerations Xanthelasma Xanthelasmas are Single or multiple soft yellow plaques occurring in th e medial canthal region of the eyelids. Associated hyperlipoproteinemic states, particularly hype rlipoproteinemia types 1I and III, are present in 30%-40% of patients with xanthelasma. These eyelid xanthom as consist of collections of histio cytes with foamy lipid-laden cytoplasm distributed diffusely, often around blood vessels, withi n the dermis (Fig 13-8). Associated inflammation is minimal to nonexistent.

Amyloid The term amyloid refers to a heterogeneous group of extracellular proteins that exhibit birefringence and dichroism under polarized light when stained with Congo red (see

Figure 13-8

A, Patient with prominent xa nthelasma. Note the ye ll ow papul es on th e med ial

aspect of the up pe r and lower eyelids . B, Note the foa m cells {filled with lipid) s urround ing a venul e (aste risk). (Part A from

Exte rn al Disease and Cornea: A Multimed ia Collection San Francisco: American

Academv of OphthalmologV; 1994:slide 10J

212 • Ophthalmic Pathology and Intraocular Tumors

Chapter 5 and Fig 5-13). These features result from the 3-dimensional configuration of the proteins into a ~ -pleated sheet. Examples of proteins that may form amyloid deposits include immunoglobulin light chain fragments (AL amyloid) in plasma cell dyscrasias transthyretin mutations in familial amyloid polyneuropathy (FAP) types I and 11 (see Chapter 10) gelsolin mutations in FAP type IV (Meretoja syndrome [lattice corneal dystrophy type II]) Amyloid within the skin of the eyelid is highly indicative of a systemic disease process, either primary or secondary, whereas deposits elsewhere in the ocular adnexa but not in the eyelid are more likely a localized disease process. Amyloid deposits in the skin are usually multiple, bilateral, symmetric, waxy yellowwhite nodules. The deposition of amyloid with in blood vessel walls in the skin causes increased vascular fragility and often results in intradermal hemorrhages, account ing for the purpura seen clinically (Fig 13 -9). On routine histologic sections, amyloid appears as an amorphous, eosinophilic extracellular deposit, usually within vessel walls but also in soft tissue and around peripheral nerves and sweat glands. Stains useful in demonstrating amyloid deposits include Congo red, crystal violet, and thioflavin T. Electron microscopy reveals the deposits to be composed of randomly oriented extracellular fibrils measuring 7- 10 nm in diameter (see Fig 10- 1i). Other systemic diseases with eyelid manifestations are listed in Table 13-2.

Figure 13-9 Cuta neous am ylo id in a patien t with mu ltiple myeloma . Note the waxy elevation and the associated purpura of th e low er eye li d. (Courtesy of John B. Holds, MD.)

CHAPTER 13,

Eyelids. 213

Table 13-2 Eyelid Manifestations of Systemic Diseases Systemic Condition

EVelid Manifestation

Erdheim-Chester disease Hyperlipoproteinemia Amyloidosis Sarcoidosis Wegener granulomatosis Scleroderma Polyarteritis nodosa Systemic lupus eryth ematosus Dermato myositi s Relapsing polychondritis Carney complex Fraser syndrome Treacher Collins syndrome

Xanthelasma, xanthogranuloma Xanthelasma Waxy papu les, ptosis , purpura Papules Edema, ptosis, low er eye li d retraction Reduced mobility, taut skin Focal infarct Telangiectasias, edema Edema, erythema

Papules Myxoma Cryptophthalmos Lower eyelid col oboma

Modified from Wiggs JL, Jakobi ec FA. Eyelid manifestations of systemic disease. In: Albert DM , Jakobiec FA, eds. Principles and Practice of Ophthalmology. Philadelphia: Saunders ; 1994:1859.

Cysts Epidermoid and Dermoid Cysts Epidermoid cysts, also known as epidermal inc/usion cysts, are common in the eyelids. They may arise spontaneously or as a result of the entrapment of epidermis beneath the skin surface fo llowing traumatic laceration or surgical incision. Epidermoid cysts are lined with strati fied squamous keratinizing epithelium and contain keratin (Fig 13-10). Dermoid cysts (disc ussed earlier in this chapte r) are similar to epidermoid cysts histologicall y, but they have skin adn exal structures such as hair follicl es and sebaceous glands in th e wall. T he lumen contains hair and sebum in addition to keratin.

Ductal Cysts Within the eyelid are the ducts of numerous structu res, including the apocrine and eccrine sweat glands and the lacrimal gland. Any of th ese ducts may give rise to 1 or more

.t'

.-' Figure 13-10 An epidermoid, or epid ermal inclu sion cyst, is present in the derm is. The cyst lining res embles epidermis, and the lumen contains ke ra ti n. (Courresyof NasreenA. Syed. MD.)

214 • Ophthalmic Patholo gy and Intraocular Tumors

Figure 13-11

An apocrine hidrocystoma is

typically lined with a double layer of cuboidal epithelium. Epithelial cells may demonstrate decapitation secretion. (Courtesy of Nasreen A Syed, MOJ

cysts. Ducts are typically lined with a double layer of cuboidal epithelium, as are du ctal cysts. The lumen of the cyst typicall y appears empty histologically. Cysts ar ising from sweat ducts are referred to as either apocrine or eccrine hidrocystomas (Fig 13- 11). A cyst arisi ng from the duct of the lacrimal gland is called a dacryops.

Neoplasia Epidermal Neoplasms

Seborrheic keratosis Seborrheic keratosis, a common benign epithelial proliferat ion, occurs in m iddle age. Clinically, it is a well-circ*mscribed, oval, dom e-s haped to ver ru coid "stuck-on" papule, varying fro m pink to brown in color. Histologically, several architectural patterns are possible, although all demonstrate hyperkeratosis, acanthosis, and some degree of papillomatosis. The acanthosis is a result of the proliferation of either polygonal or basaloid sq uamous cells without dysplasia. A characteristic finding in most types of seborrheic keratoses is the forma tion of pseudohorn cysts, which are concentrically laminated collections of surface keratin within the acanthotic epitheli um (Fig 13-12). Irritated seborrheic keratosis, also termed

A Figure 13-12 Seborrheic keratosis. A, The epidermis is acanthotic with a papillary configuration. Note the keratin-filled cysts (asterisks). B, Wh en serial histologic sections are studied, pseudoh orn cysts (asterisk) w ithin t he epidermis are seen to represent crev ices or infoldings of epi dermis (arrow). (Courtesv of Hans E. Grossniklaus, MD.J

CHAPTER 13: Eyelids. 215

Irritated seborrhe ic keratos is, also known as inverted follicular keratosis. Clinical ly, thi s lesion appeared as a cutaneous horn.

Figure 13-13

inverted follicular keratosis, shows nonkeratinizing squamous epithelial whorling, or squamous "eddies;' instead of pseudo horn cysts (Fig 13 -13). Heavy melanin phagocytosis by keratinocytes may impart a dark brown color to an otherwise typical seborrheic keratosis, which may then be confused clinically with melanoma. Sudden onset of multiple seborrheic keratoses is known as the Leser-Trelat sign and is associated with a malignancy, usually a gastrointestinal adenocarcinoma; these keratoses may in fact represent evolving acanthosis nigricans. Table 13-3 lists other systemic malignancies with cutaneous manifestations.

Table 13-3 Eyelid Neoplasms in Association With Systemic Malignancies Syndrome

-----

Mui r-Torre syndrome (visceral carcinoma, usually colon ) Cowden disease (breast carcinoma; fibrous hamartomas of breast, thyroid , GI tract ) Basa l cell nevus syndrome (medulloblastoma, fibrosarcom a)

Eyelid Manifestation

Keratoacanthoma, seba ceous neoplasm (adenoma, carcinoma) Multiple trichilemmomas Multiple basal cell carcinomas

Modified from Wiggs Jl, Jakobiec FA. Eyel id ma nifestations of systemic disease. In: Albert OM , Jakobiec FA, eds. Principles and Practice of Ophthalmology. Phi ladelphia: Saunders; 1994: 1859.

216 • Op hth alm ic Pathology and Intraocular Tumors

Keratoacanthoma Keratoa ca nth o ma is a rapidly growing epithelial prolifera tion with a potential for spon taneous in vo lu tion. T here is strong evidence supporting th e idea that keratoacantho mas are a va ri ant of a wel l-djfferentiated squamo us cell ca rcinoma. These studi es are based on expressio n of proli fe rat io n markers (cyclins and cyclin -dependent kinases) and oncoproteins (mutated p53) th at are expressed similarly by both entities. Dome-shaped nodules with a keratin -fi lled ce ntral crater may attain a co nsiderable size, up to 2.5 cm in diameter, with in a matter of weeks to months (Fig 13- 14). Th e natural history is typically spo nta neous invo lu tion over several months, resulting in a slightl y depressed scar. Histologically, keratoacanthomas show a clip-sh aped invagin*tion of well-differentiated squamous cel ls forming irregularly configured nests and strands and inciting a chronic inflammatory host response. The prolife ratin g epithelial cells und ermine the adjacent normal epi dermis. At the deep aspect of the proliferating nodul es, mitotic activity and nuclear atyp ia may o ccu r, making the distinction bet\veen kera toacanthoma and invasive squamOlls cell carcino ma problematic. If un eq ui voca l invasio n is prese nt, the lesion sho uJd be conside red a well-differe ntiated squa mous cell carcino ma. Many dermatopath ologists an d ophthalmi c pathologists have ceased to use th e te rm keratoacal1thoma altogether and prefer to call this lesion well-differentiated keratinizing squamous cell carcinoma because of the possibi lity of perineural invas ion and metastasis. W hen th e clinical differentia l di agnosis is keratoacanthoma vers us squamous cell ca rci no ma, the lesion should be completely excised to permit optimal histologic examination of the late ral and deep ma rg ins of the tumor- host inte rface.

Actinic keratosis Ac tini c keratoses are precancerous squamo us lesio ns that appear, cHnically, as erythematOllS, scaly macules or papules in middle age on su n -exposed skin , particularly on th e face

B Figure 13·14 A, Patien t with keratoacanthoma. Note the cuplike configu ration. In this case, the central crate r was originally f illed with keratin. 8, Low-power histologic sect ion illustrating the centra l keratin crater and th e downward (invasive) growth pa ttern. (Parr 8 courtesy of Nasreen A. Syed, MD.)

CHAPTER 13,

Eyelids . 217

and the dorsal surfaces of the hands. Actinic keratoses range fro m a few millimeters up to 1 em in greatest dim ension. Hyperkeratotic types may form a c utaneous horn, and hyper-

pigmented types may clinically simulate lentigo maligna. Squamous cell carcinoma may develop from preexisting actin ic keratosis; thus, biopsy of suspicious lesions and longterm follow-up are necessary in patients with this condition. However, when squamous cell carcinoma ari ses in acti nic keratosis, the risk of subsequent metastatic disseminat ion

is very low (0.5%-3.0%) . Histologically, there are 5 subtypes, ra nging fro m hypert rophic to atrophic; all types demonstrate changes in the epidermis wi th hyperkeratosis and parakeratosis. Cellular atypia such as nuclear hyperchromas ia and en largement, nuclear membrane irreg ulariti es, and increased nuclear-ta-cytop lasmic ratio is present and ranges from mild

(involving only the basal epithelial laye rs) to fran k carcinoma in situ, or full-thickn ess involvement of the epidermis. D yskerato sis (p rematu re individ ual cell keratinization ) and

mitotic fi gures above the basal epithelial layer are often present (Fig 13-15). The underlying dermis shows solar elastosis (elastotic degeneration of collagen) (Fig 13-16), which manifests as fragmentation, clumping, and loss of eosinophilia of dermal collagen. A chronic inflammatory cell infiltrate is usually present in the superficial derm is. The base of the lesion must be examined histologica lly to determi ne whethe r invasive squamous

cell carcinoma is present; fo r this reason, shave biopsy not including the base of the lesion is contraindicated.

Carcinoma Basal cell carcinoma (BCC) is the most common malignant neoplasm of the eyelids, accounting for more than 90% of all eyelid mal ignancies. Exposu re to sunlight is the main

risk factor, although genetic factors can playa role in familial syndromes. The lower eyelid is more commonly involved than the upper eyelid, with the medial canthus being the second most common site of involvement. Tumors in the medial canthal area are more

Figure 13- 15 Actinic keratosis. A, Note the epidermal thicken ing (acan thosis [If), disorganization within the epidermis (dysplasia), pa rakeratosis (asterisk), and inflammation within the dermis. B, Note the epidermal disorganization and mitotic figure s (arrows).

218 • Op hthalmic Pathology and Intraocular Tumors

Figure 13-16

Solar elas tosis. The collagen of the derm is ap-

pears bluish (a sterisks) in this H&E sta in, instead of pink. Th is is a histopathologic sign of ultraviolet light-induced damage.

likely to be deeply invasive and to involve the orbit. Clinically, BCC is a slowly enlarging, slightly elevated lesion with ulceration and pearly, raised, rolled edges (Fig 13-17). The morpheaform, or sclerosing, variant of BCC is a flat or slightly depressed pale yellow indurated plaque; this type is often infiltrative, and its extent is difficult to determine clinically. Other growth patterns include nodu lar (most common; Fig 13-17 A) and multicentric. A small percentage of BCCs are pigmented. As the name implies, Bees originate from the stratum basale, or stratum germinativum, of the epidermis and the outer roo t sheath of the hair follicle and occur only in hair-bearing tissue. Tumor cells are characterized by relatively bland, monomorphous nuclei and a high nuclear-ta -cyto plasmic ratio. Bee forms cohesive islands with nuclear palisading of the peripheral cell layer. Frequently, a clear space surrounds the islands of tumor cells, presumably an artifact of tissue processing (Fig 13-17B). BCCs may exh ibit a variety of histologic patterns, including keratotic (hair follicle), squamous (metatypical),

. . ..

, ,

__ _

__ r

;

••

"..

: ...".

-,~.# ,.

••

-' ... ~-:

Figure 13-17 Basal cell carcin oma. A, Clinical appeara nce of the nodular type. B, Histologic appea rance. Note th e characteristic pa lisading of the ce ll s around th e outer edge of the tumor (arrow) and the artifactitious separation between the nest of tumo r ce ll s and the dermis (retraction artifact, arrowhead).

CHAPTE R 13:

Eyelids.

219

Figure 13-18 Basa l cell carcinoma, morpheaform (sclerosing) type. Thin strands and cords of tumor cel ls are see n in a fibrotic (desmoplastic) dermis .

sebaceous, adenoid, and eccrine (syringoid) differentiation . The morphea (sclerosing) variant shows thin cords and strands of tumor cells set in a fibrotic stroma (Fig 13-18). Complete excision is the treatment of cho ice, and surgical margin control is required. Typically, margin control is achieved with frozen sections or Mohs micrographic excision. Morbidity in Bees" is almost always the result of local spread; metastasis is extremely unusuaL Although squamous cell carcinoma (SCC) may occur in the eyelids, it is at least 10 and perhaps up to 40 times less common than BCC. Because most SCCs arise in solardamaged skin, the lower eyelid is more frequently involved than the upper. However, the proportion of sees occurring in the upper eyelid is larger than the proportion of Bees occurring in the upper eyelid. The clinical appearance of see is diverse, ranging from ulcers to plaques to fungating or nodular growths. Accordingly, the clinical differential diagnosis is a long list, and pathologic examination of excised tissue is necessary for ac curate diagnosis. Histologic examination shows atypical squamous cells forming nests and strands, extending beyond the epidermal basem*nt membrane, infiltrating the dermis, and inciting a fibrotic tissue reaction (Fig 13-19). Tumor cells may be well differentiated (forming keratin and easily recognizable as squamous) , moderately differentiated, or poorly differentiated (requiring ancillary studies to confirm the nature of the neoplasm). The presence of intercellular bridges between tumor cells should be sought when the diagnos is is in question. Perineural and lymphatic invasion may be present and should be reported when identified microscopically. The use of frozen section (conventional or Mohs microsurgery) or permanent section margin control is ind icated to treat this tumor adequately. Regional lymph node metastasis is reported to occur in up to 20% of patients with see of the eyelid. Chevez- Barrios P. Frozen section diagnosis and indications in ophthalmic pathology. Arch Pathol Lab Med. 2005; 129(12n626- 1634.

Dermal Neoplasms Capillary hem angiomas are common in the eyelids of children. They usually appear at or shortly after birth as a bright red lesion, grow over weeks to months, and involute by school age. Intervention is reserved for those les ions that affect vision because of ptosis or astigmatism, promoting amblyopia.

220 • Ophthalmic Pathology and Intraocu lar Tumors

A '--_

Figure 13-19 Squamous cel l ca rcinoma. A, Clinical appearance. Note th e focal loss of lashes and scaly appearance of the lower eyel id. S, Note the tumor ce lls (T) invading the dermis. C, Kerat in (asterisk) is produced in t his well-differentiated squamous cel l carc inoma. (Part A courtesy of Keith D. Carter, MD.)

The histopathologic appearance depends on the stage of evolutio n of the hemangioma. Ea rly lesions may be very cellular, with solid nests of plump endothelial cells and correspondingly little vascular lu mi nal formation. Established lesions typically show welldeveloped, flattened, endothelium-lined capillary channels in a lobular configuration (Fig 13-20). Involuting lesions demonstrate increased fibrosis and hyalinization of capillary walls with luminal occlusion.

A ""-_ _ _ _-=-_

--'

Figure 13-20 Capillary hemang ioma . A, Infant wi th mult iple capil lary hemangiomas . B, Note the smal l cap illary-sized vessels and th e proliferation of benign endoth elial cel ls. (Part A courtesy of Sander Dubovy, MO.)

CHAPTER

n Eyelids'

221

Appendage Neoplasms

Syringoma Syringoma is a common benign lesion of the lower eyelid and typically manifests as multiple tiny papules. Syringomas res ult fro m a malformation of the eccrine sweat gland ducts. Histologically, syringo mas consist of m ultiple, comma-shaped or round ductules li ned with a dou ble laye r of epithelium and containing a cent ral lumen, often with secretory material (Fig 13-2 1).

Sebaceous hyperplasia Sebaceo us hyperplasia is an uncommon benign lesion of the eyel id and face. Clinically, it appea rs as a small, yellow papule. Histologically, it is typically a Single enlarged sebaceous gland with numerous glandular lobules attached to a Single central duct (Fig 13 -22) .

Sebaceous adenoma Sebaceous adenoma is a rare benign lesion of the eyelid that typically manifests as a yellow, circ*mscri bed nodule. Histologically, it is composed of multiple sebaceous lobules that are irregula rly shaped and incompletely differentiated (Fig 13-23). Muir-Torre syndrome should be considered when sebaceous ade noma is diagnosed (see Table 13-3).

Sebaceous carcinoma A sebaceous carcinoma most com mo nly involves the upper eyelid of elderly persons. It may originate in the meibomian glands of the tarsus, the glands of Zeis in the ski n of

Figure 13·2 1

Histologically, syringoma is com-

posed of small, epithelial-lined ductules that are round or com ma-shaped (arrows). (Courresy of Nasreen A. Syed, MD. )

Figure 13·22

Sebaceous hyperplasia. Numer-

ou s sebaceous lobu les (arrowheads) surro und a hair follicle (arrow). (Courtes yofNasreenA Syed, MD.J

222 • Ophthalmic Pathology and Intraocu lar Tumors

Figure 13-23 Sebaceous adenoma. Sebaceous lobules demonstrate focal proliferations of basophilic (blue) sebocytes. This lesion is most commonly associated with Muir-Torre syn-

drome.

(Courresy of Nasreen A Syed, MO)

the eyelid. or the sebaceous glands of the caruncle. Clinical diagnosis is often missed or delayed because of this lesion's propensity to m im ic a chalazion or chronic blepharocon-

ju nctivitis (Fig 13-24). Histologically. well-differentiated sebaceous carcinomas are readily identified by the microvesicular foamy nature of the tumor cell cytoplasm (Fig 13-25A). Moderately differentiated tumors may exhibit some degree of sebaceous differentiation. Poorly differentiated tumors, however, may be difficult to distingu ish from the other, more common

epithelial malignancies. The demonstration of li pid with in the cytoplasm of tumor cells by special stains. such as oil red 0 or Sudan black. is diagnostic. but it must be performed on tissue prior to processing and paraffin embedding.

When sebaceous carcinoma is suspected clinically. the pathologist should be alerted so that frozen section slides can be generated for lipid stains. Another feature. characteristic of but not pathognomonic for sebaceous cell carcinoma, is the dissemination of individual tumor cells and clusters of tum or cells within the epidermis or co njunctival

epithelium. known as pagetoid spread (Fig 13-25B). Another pattern in the conjunctiva is that of complete replacement of conjunctival epithelium by tu mor cells, or sebaceous carcinoma in situ (F ig 13-2SC). A rare va riant of sebaceolls carcinoma involves only the epidermis and conjunctiva without demonstrable invasive tumor.

B Figure 13·24 Sebaceous carcinoma. A, Note the eyelid erythema suggesting blepharitis. Note also the loss of eyelashes and the irregular eyelid thickening. B. This lesion mimics a chalazion of the lower eyelid. Focal lash loss is present. (Parr B courtesy of Roberta E. Gausas. MD.)

CHAPTER 13,

Eyelids . 223

--- ...-- -. -"

Figure 13-25 Sebaceous carcinoma, histology. A , Tumor cells often have hyperchromatic, atypical nuclei. The cytoplasm frequently has a foamy or vacuolated appearance. Note mitotic figure (arrow). B. Pagetoid invasion of epidermis by individual tumor cells and small clusters of tumor cells (arrows). C, Sebaceous carcinoma in situ with complete replacement of normal conjunctival epithelium by tumor cells (between arrows). (Counesy of Nasreen A Syed, MD.)

224 • Ophthalmic Pathology and Int raocu lar Tumors Treatment recommendations include wi de local excision of nodular les ions. Large or deeply invasive tumors may require exenterat io n. Frozen section control of surgical

margins and Mohs micrographic surgery may provide suboptimal results because of di ffi culty in ident ifyin g intraepithelial spread. Permanent margi ns are often more reliable.

Preoperative mapping by rout ine processing of multiple biopsies may afford a more accurate assessment of the extent of spread of th e carcinoma. Survival rates for sebaceous

carcinoma are worse than those for squamous cell carcinoma, but they have improved in recent years as a result of increased awareness, earHe r detection, more accurate diagnOSiS, and approp riate treatment. Metastases first involve regional lymph nodes. For American Joint Committee on Cancer defin itions and stagin g of malignant neo-

plas ms of the eyelid, see the appendix.

Melanocytic Neoplasms The term nevus may refer to a variety of hamartomato ll s lesions of the skin or m ay refer

to benign neoplastic proliferations of melanocytic cells. This d iscussion refers to the latter, mela nocytic nevi. Melanocytic nevi commonly occ ur on the eyelids and may be visible at birth (conge nital nevi) or become apparent in adolescence or adu lthood. Congenital nevi te nd to be larger than those appearing in later years, sometimes reaching substantial size. Nevi greater th an 20 em in diameter are referred to as giant congenital melanocytic nevi.

The risk for development of melanoma in congenital nevi is proportional to the size of the nevus; close follow-up and/or excision of conge ni tal nevi is warranted. Congenital nevi of

the eyelid may develop in utero before the separation of the upper and lowe r eyelids and result in a "kissing" nevus (Fig 13-26). Nevi in adu lts ofte n appear as dome-shaped lesions on the eyelid ma rgin. Histologically, most nevi are composed of nevus cells, specialized melanocytes that have a round rather than dendritic shape and tend to cluster together in nests. The cytoplasm of the nevus cell contains a variable amount of melanin pigment. Other character-

istics of these cells include growth within and aro und ad nexal structures, vessel walls, and the pe rineuriu m; and extension into the deep reticu lar derm is or subcutaneous tissue.

Nevi evolve with age and typically begin as macu lar (flat) lesions. Histologically, these lesions show nests of melanocytes along the epide rma l-dermal junction and are conse-

quently termed junctionaL nevi (Fig 13-27). Clin ically, a junctional nevus is indistinguishable frol11 an ephelis, or freckle; but in the latter, the basal layer of epidermal cells contains

Figure 13-26

Congenital split, or "kissing,"

nevus of the eyelid.

CHAPTER 13,

Eyelids. 225

Figure 13-27 Junctional nevus. Nests of nevus cel ls are seen at the junction be tween epidermis and derm is.

the pigment. Typically in adolescence, the ju nctional nests of nevus cells begin to migrate into the superficial dermis, and the nevus becomes increasingly elevated clinically. At this stage, the nevus may increase in pigmentation as well. When both junctional and intra dermal components are present, the histopathologic classification becomes compound nevus (Fig 13-28) . Finally, sometime in adulthood, the junctional component disappears, leaving only nevus cells within the dermis, and the classification accordingly becomes intradermal nevus (Fig 13 -29). An evolution in the cytomorphology of the nevus cells also takes place: those in the superficial portion of the nevus are polygonal, or epithelioid, in shape (type A nevus cells). Within the midportion of the nevus, the cells become smaller, have less cytoplasm, and resemble lymphocytes (type B nevus cells). At the deepest levels, the nevus cells become spindled and appear similar to Schwann cells of peripheral nerves (type C nevus cells) . Recognition of this "maturation" is useful in classifying melanocytic neoplasms as benign. Multinucleated giant melanocytes and interspersed adipose ti ssue are common in older nevi.

Figure 13-28 Compound nevus . Nests of nevu s ce lls are present in the derm is (arrows) as we ll as at the junction of epidermis and dermis (arrowheads). (Courtes y of Nasreen A. Syed, MD.)

226 • Ophthalmic Pat hology and Intraocular Tum ors

Fi gure 13-29

Intradermal nevus. The nests of nevus cells are

confined to the dermis.

Nevi that show some clinical or pathologic atypicality include the Spitz nevus and the dysplastic nevus. Spitz nevi develop in late child hood or in adolescence and are uncom mon after the second decade. In contrast to the clinical picture of the usual nevus, they may be larger (up to 1.0 cm) and have a tan-pink color. Histologically, they are usually compound and exh ibit nuclear and cytoplasmic en largement and pleomorphism, features

suggesting malignancy. Other features suggesting malignancy, however, such as atypical mitotic figures, intraepidermal migration, and lack of maturation, are generally lacking.

Clinical features suggesting a dysplastic nevus may incl ude size greater than 0.5 cm, irregular margins, and irregular pigmentat ion. Cytologic atypia is characterized by nuclear enlargement and hyperchromasia and prom inent nucleoli. Clinically suspicious lesions sho uld be completely excised. Persons with multiple dys plastic nevi are at increased risk for development of melanoma and may represent a genetic susceptibility, suggesting that family members should also be examined and observed closely. Cutaneous melanoma is a rare occurrence on the eyelids. It may be associated with a

preexisting nevus, or it may develop de novo. Cli nical featu res suggesting malignancy are the same as those just mentioned for dysplastic nevij in addition, invasive melanoma is heralded by a vertical (pe rpendicular to the skin surface) growth phase that results in an elevated or indurated mass. There are 4 main h istologic subtypes of melanoma: superficial spreading lentigo maligna nodu lar acral-lentiginous

Superficial spreading is the most common typ e of cutaneous melanoma and demonstrates

a radial (intraepidermal) growth pattern extending beyond the invasive component. Lentigo maligna melanoma occurs on the face of elderly individuals, with a long preinvasive phase. and is the most common type occurring on the eyelids. Acral-Ientiginous melanoma. as the name implies, involves the extremities and is not seen on tpe eyel ids

(Fig 13-30).

CHAPTER 13,

- -- - Epidermis --

Eyelids . 227

---;--

ju nction

A ......_ _- £.ILo......_

.......

.. .......... -:

,- '.-

- - Epiderm is - - - -

--Derm is- --=::D

______________

junction

C ________________--JT Figure 13-30

Schematic illustration of cu taneo us melan oma types. A, Lentigo maligna me la-

noma, Atypical melanocytes (brown cellsl proliferate predominantly in the basal laye rs of the epidermis in a linear or nested pattern, similar to primary acquired melanosis with atypia of the conjunct iva. Note the tendency of the melanocytes to involve the outer sheaths of the hair shafts. The invasive component is seen as brown cells (spindle and epithelioid) in the supe rficial dermis. B, Acral-Ientiginou s melanoma is similar to lentigo maligna melanoma, but atypi ca l melanocytes are also presen t in the more sup erf icial layers of the epid ermis . C, In superficial spreading melanoma, tum or cell nests are present in all levels of the epidermis, often in a pagetoid fashion , with cells or clusters of cells scattered among epithelial cells. Lentigo maligna, acral-Ientiginous, and superficial spreading melanomas spread horizontally

(radial growthl through the skin, staying close to the epidermal- dermal junction, D, Nodu· lar melanoma has a narrow intraepiderma l component and more prominent vertical growth w ithi n the dermis; it is therefore more deeply invasive co mpared with the other types. (Modified with permission from Spencer WH, ed. Ophthalm ic Pathology: An Atlas and Textbook. Vol 4. Philadelphia: WB Saunders; 1996:2270. Illustration by ChriSilne Gralapp.)

Histologic features characteristic of melanoma include pagetOid intraepidermal spread of atypical melanocytic nests an d Single cell s, nuclear abn ormalities as listed earlier, lack of maturation in th e deeper portions of the mass, an d atypi cal mitotic figu res, A bandlike lym phocytiC host response alo ng the base of the mass is more common in melanoma tha n in benign proliferations. Prognosis is correlated with depth of invasion (Breslow depth) in stage I (localized) disease, Metastases, when they occur, typically involve regionall yrnph nodes first

CHAPTER

Orbit

Topography Bony Orbit and Soft Tissues Seven bones form the boundaries of the orbit (see Figures \ -\ through \-3 in BCSC Section 7, Orbit, Eyelids, and Lacrimal System). These 7 bones are the frontal, zygomatic, palatine, lacrimal, sphenoid, ethmoid, and maxillary. The orbital cavity is pear-shaped and has a volume of 30 cc. Structures and tissues occupying the cavity are the globe, lacrimal gland, muscles, tendons, fat, fascia, vessels, nerves, sympathetic ganglia, and cartilaginous trochlea. Inflammatory and neoplastic processes that increase the volume of the orbital contents lead to proptosis (protrusion) of the globe and/or displacement (deviation) fro m the horizontal or vertical position. The degree and direction of ocular displacement help to localize the position of the mass. The lacrimal gland is situated anteriorly in the superotemporal quadrant of the orbit. The gland is divided into orbital and palpebral lobes by the aponeurosis of the levator palpebrae superioris muscle. The acini of the glands are composed of low cuboidal epithelium. The ducts, which lie within the fibrovascular stroma, are lined by low cuboidal epithelium with a second outer layer of low, flat myoepithelial cells. See BCSC Section 2, Fundamentals and PrinCiples of Ophthalmology, and Section 7, Orbit, Eyelids, and Lacrimal System, for additional discussion.

Congenital Anomalies Dermoid and Other Epithelial Cysts The major categories of orbital cysts of childhood include cysts of the surface epithelium, teratomatous cysts, neural cysts, secondary cysts (mucocele), inflammatory cysts (parasitic), and noncystic lesions with a cystic component. Congenital cysts of the surface epithelium are subdivided into dermoid cysts and Simple epithelial (epidermoid) cysts. Dermoid cysts are the most common and are believed to arise as embryoniC epithelial nests that became entrapped during embryogenesis. They may protrude through the frontozygomatic and frontomaxillary sutures to take a dumbbell shape. Most manifest in childhood as a mass in the superotemporal quadrant of the orbit. Rupture of cyst contents may produce a marked granulomatous reaction. Histologically, a dermoid cyst is encapsulated

229

230 • Ophthalmic Patho logy and Intraocular Tum ors

Figure 14-1 A, Clinical appearance of derm oid cyst of the right orbit. Note the typical superotempora l location. 8, Low-power photomicrograph discloses a cyst lined by keratinize d stratified squamous epithe li um . C, Th e w all of the cyst contains sebaceous glands (arrows) and adnexa l structures. (Part A courresy of Sander Dubovy. M D; parts B and C courtes y of Hans E. Grossniklaus. MDJ

and li ned by keratinized stratified squamous epithelium . The cyst contains keratin an d hair, and its walls are lined with dermal appendages and adnexal structures, including sebaceous glands, hair follicles, and sweat glands (Fig 14- 1). !fthe cyst wall does not have adnexal structures, the term Simple epithelial (epidermOid) cyst is applied. Simple epithelial cysts may also be lined by respiratory, conj uncti val, or apocrine epithelium.

Inflammations The term orbital inflammatory disease (OlD) broadly describes a variety of pathologic processes and clinical presentations related to inflammation of orbital tissue. Ol D may be idiopathic or secondary to a systemic inflammatory disease (such as Graves), reta ined foreign body, or infectious disease. OlD includes the spectrum of bacterial or fungal in fection s, diffuse inflammation of mul tiple tissues (eg, sclerosing orbititis, diffuse anterior OlD), and preferential involvement of specific orbital structures (eg, orbital myositis, optic perineuritis). Conditions masquerading as OlD incl ude congenital orbital mass lesions and orbital neoplastiCdisease such as lymphoma or rhabdomyosarcoma. These need to be ruled out before the diagnosis of OlD is considered.

Noninfectious Nonspecific orbital inflammation Nonspecific orbital inflammation (NSO I, also referred to as idiopathic orbital inflammation [IOIj and orbital inflammato ry sy ndrome [sclerosing orbi/itisj) refers to a space-occupying

CHAPTER 14:

Orbit . 23 1

inflam matory disorder that simulates a neo plasm (thus, it is sometim es kn own as orbital pseudotumor) but has no recogni zable cause. This d iso rd er acco unts fo r approximately 5% of o rbita l lesions. Clin icall y, patie nts have an abr upt course and usually com plain of pain . T he conditio n may affect ch ildren as well as adults. T he in Aammatory response may be diffuse or compartmentalized. When lo cali zed to an extraoc ular muscle, the condition is called orbital myositis (Fig 14-2); when localized to the lacri ma l gland, it is freq uentl y called dacryoadenitis. In the ea rly stages, in Aam malion predominates, with a polymorphous inAam matory response (eosinophils, neutrophils, plasma cells, lymphocytes, and macrophages) that is often perivascular and that frequently infiltrates muscle and fat, producing fat necrosis. In later stages, fibrosis is the predominant feature, often with interspersed lymphoid follicles bearing germinal centers. The fi brosis may inexorably replace orbital fat and encase extraocula r muscles and th e opti c nerve (Fig 14-3). Imm unophenotypic and molecul ar genetic analyses

Figure 14-2 Nonspecific orbital inflammation (NSOI; orbital inflammatory syndrome). Note the skeletal muscle fibers (arrows) surround ed by a dense infiltrate of ch ron ic inflam matory cells.

Unlike thyroid eye disease, in which the tendons of the muscles typically are spared, this condition can affect any orbital structure, including th e muscle tendons.

Figure 14-3 Nonspecific orbital inflammation. A, Note the mixture of inflammatory cells and

the bundle of collagen (asterisk) running through the orbital fat B, Diffuse fibrosis dominates the histologic picture of this fi brosing orbititis, considered by some authoriti es to represe nt a later stage of the condition illustrated in part A.

232 • Ophthalm ic Pathology and Int raocular Tumo rs

can differentiate NSOI from lymphoid tumors based on whether the proliferation of lymphocytes is polyclonal (NSOI) or monoclonal (lymphoma). CD20 and CD25 receptors have been demonstrated and may provide the basis for future treatments. Immunoglobulin G4 (IgG4)-positive plasmacytic infiltrates have recently become a marker for a sclerosing varian t of fi broinflammatory diseases. The nature of the pathologic findings dictates the recommended treatment. See also BCSC Section 7, Orbit, Eyelids, and Lacrimal System. Thyroid eye disease Thyroid eye disease (TED), also known as Graves disease, thyroid ophthalmopathy, and thyroid-associated orbitopathy, is related to thyroid dysfunction and is the most common cause of un ilateral or bilateral proptosis (exophthalmos) in adults. Signs and sym ptoms of TED are related to inflammation of the orbital connective tissue, inflammation and fibrosis of the extraocular muscles, and adipogenesis. The muscles appear fi rm and white, and the tendons are usually not involved. A cellular infiltrate of mononuclear cells, lymphocytes, plas ma cells, mast cells, and fibroblasts involves the interstitial tissues of the extraocular muscles, most commonly the inferio r and medial rectus muscles (Fig 14-4). In patients with and without TED, orbital fib roblasts are phenotypically distinct in that they express CD40 receptors generally found on B cells, and other surface receptors that typically play a role in modulating the inflam matory response. When the B-cell receptor is attached by T-cell- bound CD154, fibroblast inflammatory genes are up- regulated, including interleukin-6 (IL-6), ILS, and prostaglandin E, (PGE,) . In turn, synthesis of hyaluronan and glycosaminoglycans (GAG) is increased. This up-regulation of orbital fibroblasts is IOO-fold greater than that seen in nonorbital fibroblasts in response to the same stimulus. As a result of the increased bulk, the optic nerve may be compromised at the orbital apex, and optic nerve head swelling may result. Late stages of TED are associated with progressive fibros is that results in restriction of ocular movement and severe eyelid retraction with resultant exposure keratitis. In addi tion, orb ital fibroblasts expressing thyrotropin recepto r (TSH-R) are found in TED. The number ofTSH-R immunostained cells is high in early disease, decreases with disease duration , and is positively correlated with serum TSH -R antibody levels at the onset of TED. Stimulation of TSH-R res ults in up-regulation of TSH-R mRNA. Because orbital fibroblasts are derived from the neural crest and are pluripotent, the enhanced signaling promotes adipocyte differe ntiation and adipogenesis. Finally, studies have identified ci rculating IgG in patients with TED. IgG recognizes and activates the insulin-like growth factor 1 (I GF-I) recep tor expressed on the surface of numerous cell types, including fibro blasts. The stimulation of this factor by the circulating IgG may contribute to the development of TED by stimulating orbital fibroblasts to secrete glycosamin oglycans, cytokines, and chemoattractants. See also BCSC Section I, Update on General Medicine, and Section 7, Orbit, Eyelids, and Lacrimal System . Bahn RS. Understanding the immunology of Graves' ophthalmopathy. Is it an autoimmune disease? Endocrinol Metab Clin North Am. 2000;29(2):287- 296. Gerding MN , van der Meer JWC, Broenink M, Bakker 0, Wiersinga WM, Prum mel ME Asso ciation of thyrotropin recepto r antibodies with the clinical features of Graves' ophthalmopathy. elin Endocrinol. 2000;52(3);267- 271.

CHAPTER 14:

Orbit. 233

A ....._

c Thyroid eye disease. A, Clinical appearance demonstrating asymmetric proptosis and eyelid retraction, most prominent on the right side. B, CT scan (axial view) showing fusiform enlargement of the extraocular muscles (asterisks). C, The muscle bundles of the extraocular muscle are separated by f luid, accompanied by an infiltrate of mononuclear inflammatory cells. (Parts A and B courtesy of Sander Oubovy, MD.) Figure 14-4

Kazim M, Goldberg RA, Smith TJ. Insights into the pathogenesis of thyroid-associated orbitopathy: evolving rationale for therapy. Arc11 Op1lthalmol. 2002; 120(3):380-386. ',\' iers inga WM, Prummel MF. Pathogenesis of Graves' oph thalmopathy-current understand ing leditorialJ. f C/i" E"docr;"ol Me/ab. 2001;86(2);501-503.

234 • Ophthalmic Pathology and Intra ocu lar Tum o rs

Infectious Bacterial infections The causes of bacterial infections of the o rbit include bacte rem ia , trauma, retained surgical hardware, and spread from an adjacent sin us infect ion. Infection may involve a

variety of organisms, including Ha emophi/us irifluel1zae, Streptococcus, Staphylococcus aureus, Clostridium, Bacteroides, Klebsiella, and Proteus. Histologically, acute inflammation, necro sis, and abscess formation may be present. Tuberculosis, which rarely involves the orbit, produces a necrotizing granulomatous reaction.

Fungal and parasitic infections Rhino cerebral or rhino-orbitocerebral zygomycosis (mucormycosis) usually occurs in patients with poorly controlled diabetes mellitus (especially those with ketoacidosis), solid malignancies, or extensive burns; in patients undergo in g treatment with corticosteroid

agents; or in patients with neutropenia related to hema tologic malignancies. Fungal in fec tion of the orbit is caused by adjacent sinus infection. Histologically, inflammation (acute and chronic) is present in a background of necrosis and is often granulomatous. His-

tiocytes are common. Broad, nonseptated hyphae may be identified with H&E, periodic acid- Schi ff (PAS), and Gomori methenamine silver (GM S) stains. Diagnosis is achieved by biopsy of necrotic-appearing tissues in the nasopharynx. These fungi can invade blood vessel walls and produce a thrombosing vasculitis. Si no-orbital aspergillosis is caused by Aspergillus infection of the orbit from the ad jacent sinuses and may occur in imm unocompromised or otherwise healthy ind ivid ual s. With slowly progressive and insidious symptoms, s ino -orbital aspergillosis is often unrec-

ognized, producing a scleroSing granu lomatous d isease. Aspergillus has often been difficult to cu lture but may be observed in tissue as se ptated hyphae with 45° angle branching (Fig 14-5). Despite aggressive surgical therapy and adjunctive therapy with antifungal age nts, orbital infections with Aspergillus may be fatal if extension into the brain occurs. All ergic fungal sinusitis is a form of noninvasive fungal disease resulting from an IgE med iated hype rsensitivity reaction in atop ic indi vid uals and is caused by several species of fungi. The disease may extend into the o rbit and in tracraniall y in some instances.

Figure 14·5 Aspergillus infections of the orbit gene ra lly prod uce seve re , insidious orbital inflammation. A. Clinical appearance . B, Microscopic section demonstrates the branching fungal hyphae on silver stains. (Courtesy of Hans E Grossniklaus, MD.)

CHAPTER 14:

Orbit.

235

Parasitic infections of the orbit are rare and may be produced by Echinococcus (orbital hydatid cyst), Taenia solium (cysticercosis), and Loa loa ocular filariasis (loiasis). These infections are mostly seen in patients who come from, or have traveled to, areas where the in fections are endemic. Enzyme-linked immunosorbent assay for serum antibodies may be helpful in the di agnosis. See BCSC Section 7, Orbit, Eyelids, and Lacrimal System.

Degenerations Amyloid Amyloid depos ition in the orbit occurs in primary systemic amyloidoSiS. When it involves the extraocular muscles and nerves, it can produce ophthalmoplegia and ptosis. See Chapters 5, 6, 10, and 13 in this volume and BCSC Section 8, External Disease and Cornea .

Neoplasia Neoplasms of the orbit may be primary, they may be extensions of locall y invasive tumors from adjacent structures, or they may represent metastatic disease. Approximately 60% are benign and 40% maligna nt, with malignant lesions being more com mon in adults. The incidence of primary neoplasms is low, with lymphoma being the most common (10%) and hemangioma the next most common (5%) . Secondary tu mors, eith er metastatic or extending from adjacent structures, are slightly more common than pri mary tumors. In children, approximatel y 90% of orbital tumors are benign. Benign cystic lesions (epidermOid or simple epithelial cysts) are the most common cystic lesions and represent 50% of orbital lesions in childhood. Rhabdomyosarcoma is the most common orbital malignancy in childhood and represents 3% of all orbital masses. The orbit may be involved secondarily by ret inoblastoma, neuroblastoma, or leukemiallym phoma. See BCSC Section 7, Orbit, Eyelids, and Lacrimal System, for additional discussion.

Lacrimal Sac Neoplasia Lacrimal sac neoplasms are rare, and with endoscopic procedures, a representative biopsy sample may be diffi cu lt to achieve. In a study examining 377 nasolacrimal duct specimens obtained during dacryocystorhinostomy (DCR), neoplasms resulting in chronic nasolacrimal duct obstruction occurred in 5% of cases and were unsuspected prior to surgery in 2% of patients. Anderson NG, Wojno TH, Grossniklaus HE. Cli nicopathologic findings from lacrimal sac biopsy specimens obtained during dacryocystorhinostomy. Ophthal Plast Reconstr Surg. 2003;19(3);173- 176.

Lacrimal Gland Neoplasia Epithelial lacrimal gland tumors are classified according to the World Health Organization (WHO) epithelial salivary gland classification because the lacrimal gland is a

236 • Ophthalmic Pathology and Intraocular Tumors

modified salivary gland. The most common types of epithelial lacrimal gland tumors are the pleomorphic adenoma, adenocarcinoma (carcinoma ex pleomorphic adenoma), and adenoid cystic carcinoma. vVeis E, Rootman J, loly TJ, et al. Epithelial lacrimal gland tumors: pathologic classification and current understanding. Arch Ophtha/mol. 2009;127(8):1016- 1028.

Pleomorphic adenoma Pleomorphic adenoma (benign mixed tumor) is the most common epitheli al tumor of the

lacrimal gland. The tumor is pseudo encapsulated and grows slowly by expansion. This progressive expansive growth may indent the bone of the lacrimal fossa, producing excavation of the area. Tumor growth stimulates the periosteum to deposit a thin layer of new

bone (cortication). The adjacent orbital bone is not eroded. Typically, the patient experiences no pain. This tumor is more common in men than in women, and the median age at presentation is 35 years.

Histologically, pleomorphic adenoma has a fibrous pseudo capsule with microprojections extending from the capsule surface to the tumor (boss elation) and is composed of a mixture of ductal derived epithelial and stromal elements. The epithelial component may form nests or tubules lined by 2 layers of cells, the outermost laye r blending imperceptibly with the stroma (Fig 14-6). The stroma may appear myxoid and may contain heterologous elements, including cartilage and bone. Immunohistochemistry reflects the epithelial and myoepithelial components, both of which are derived from epithelium. It is typically positive for keratin and epithelial membrane antigen in the ductal portions and positive for keratin, actin, myosin, fibronectin, and S-l 00 in the myoepithelial areas. Chromosomal translocations are recognized in salivary gland tumors and pleomorphic adenomas. Specifically, translocations involving the PLGA1 (chromosome 8q12) or HMGA2 gene have been identified. These genes are involved in growth factor signaling

and cell cycle regulation. Transformation into a malignant mixed tumor may take place in a long- standing

pleomorphic adenoma with relatively rapid growth after a period of relative quiescence. Carcinomas, inclu ding adenocarcinoma (carcinoma ex pleomorphic adenoma) and ad enoid cystic carcinoma, may also arise in recurrent pleomorphic adenomas.

Adenoid cystic carcinoma As mentioned in the previous section, adenoid cystic carcinoma (ACe) can arise in a

pleomorphic adenoma or de novo in the lacrimal gland. The tumor is slightly more common in women tha n in men, an d the median age of presentation is about 40. Unlike pleomorphic adenoma, adenoid cystic carcinoma is not encapsulated; it tends to erode the adjacent bone and invade orbital nerves, accounting for the pain that is a frequent present-

ing complaint. Grossly, the appearance is grayish white, fi rm, and nodular. Histologically, a variety of patterns may appear, including the cribriform (Swiss cheese) pattern, which is the 1110st common (Fig 14-7) . Other histologic patterns include basaloid (solid), comedo, sclerosing, and tubular. Presence of a basaloid pattern has been associated with a worse

prognosis (S -yea r survival of 20%) compared to tu mors without a basaloid component (S-year survival of 70%). Immunohistochemistry is typically positive for S- 100, keratin, and actin with areas of epithelial and myoepithelial differentiation. There is a positive correlation between prognosis and protein expression of bcl-2 and bax. Expression of pS3 is

CHAPTER 14: Orbit • 237

6'" -. * ,I ..,'' ."-< ' " ~ ~ ,

. ; .-

..:

...

'!u5;I, :' :, \ ;'

C ,--_-,

Figure 14-6 Pleomorphic adenoma (benign mixed tumor) of the lacrimal gland. A, Clinical appearance. A superotemporal orbital mass is present, causing proptosis and downward displacement of the left globe. B, CT scan (coronal view) demonstrating left orbit tumor. C, Low power shows the circ*mscribed nature of this pleomorphic adenoma. D, Note bot h t he epithelial (arrows) and the mesenchymal (asterisk) elements. E, Well-differentiated glandular structu res (epith elial component) with lumina (aste risks) . (Parts A and 8 courtesy of Sander Dubovv. MD; parts C-E courtesy of Hans E. Grossniklaus, MDJ

Figure 14-7 Adenoid cystic carcinoma of the lacrimal gland. Note the cha racteristic cribriform (Swiss cheese) pattern of tumor cells. (Courtesy of Ben J. Glasgow, MDJ

238 • Ophthalmic Pathology and Intraocula r Tum ors

associated wi th a poor prognosis. Genetic microarray analysis has demonstrated loss of 1p36 as an initial event in the pathogenesis of adenoid cystic carcinoma. Because of the diffuse infiltration of this tumor, exenteration may be recon1mended, often with removal of adjacent bone. Despite aggressive surgical intervention, the longterm prognosis is poor. Ahmad SM, Esmaeli B, \,\'illiams M, et a1. American Joint Committee on Cancer class ification predicts outcome of patients with lacrimal gland adenoid cystic carcinoma. Ophthalmology. 2009;116(6); 1210- 1215. Font RL, Smith SL, Bryan RG. Malignant epithelial tumors of the lacrimal gland: a clinico pathologic study of21 cases. Arch Ophtha/mol. 1998;116(S}:613-616.

lymphoproliferative lesions Most classifications oflymphoid lesions have been based on lymph node architecture, and such nodal classifications have been difficult to apply to so-called extranodal lymphoid lesions. Because there are no lymph nodes in the orbit, it is problematic to classify these lesions according to the criteria used for lymph nodes. The development of classification schemes for lymphomas is, thus, an ongoing and controversial process. In general, lymphoproliferative lesions are divided into reactive lymphOid hyperplasia (RLH), atypical lymphOid hyperplasia (ALH), and ocular adnexal lymphoma (OAL). OAL is then subtyped according to the WHO Classification of Tumours ofHaematopoietic and LymphOid Tissues. The more recent American Joint Committee on Cancer-International Union Against Cancer TNM-based staging system for OAL defines disease extent and identifies clinical and histomorphologic features of prognostic Significance. Data revealing OAL patients' prognosis using these classifications are beginning to emerge. Many lymphOid masses in the orbit that were previously classified as reactive or atypical hyperplaSia would now be considered neoplastic under the TNM-based staging system. Unlike patients with nonspecific orbital inflammation, those with orbital Iymphoproliferative lesions present with a grad ual, painless progression of proptosis . Every patient with an orbitallymphoproliferative lesion must be investigated for evidence of systemic lymphoma, including examination for lymphadenopathy, a complete blood count (CBC) and differential, and imaging of the thoracic and abdominal viscera. In general, biopsy of an accessible lymph node is preferred over an orbital biopsy because nodal architectu re is helpful in diagnosis and the procedure may be safer. A bone marrow biopsy is preferred to an aspirate because it includes bone spicules; the presence of a paratrabecular lymphoid infiltrate may indicate systemic lymphoma. In contrast to most cases of nonspecific orbital inflammation, \\Thich are treated with corticosteroids, lymphoproliferative lesions confined to the orbit are treated with radiation . The ophthalmologist taking a biopsy of an orbital or conjunctivallymphoproliferative lesion should consult with the pathologist to determine the optimal method for handling the tissue. Fresh (unfIxed) tissue is preferred for touch preparations, immunohistochemistry, flow cytometr)" and gene rearrange ment studies. The type of fixative used for permanent sections varies from one laboratory to another. For biopsy of suspected lymphoma, the surgeon should alert the pathologist in advance and may need to perform the procedure near a pathology laboratory. Exposure of the biopsy specimen to air for long periods

CHA PTER 14,

Orbit •

239

sho uld be avoided. Tiss ue samples may be wrapped in saline-moistened gauze and transported on ice. It is very important that the tissue be handled gently; cru sh artifact can preve nt the pathologist from rendering a diagnosis. See also Chapter 4, Table 4- \. Dem irci H , Shield s CL, Karatza EC, Shields JA. Orbitallymphoproliferative tumors: analysis of cl in ical featu res and system ic involvement in 160 cases. Ophthalmology. 2008; 11 5(9):1626 1631. 1631.el-3. Swe rdlow SH , Cam po E, Harr is N L. et aL WHO Classification of Twnou rs of Haematopoietic mid Lymphoid Tissues. Lyon, France: lARC; 2008.

Reactive lymphoid hyperplasia Reactive lymphoid hype rplasia is composed of well-differentiated, so mewhat pleomorphic lymphocytes, with occasional plasma cells, mac rophages, eosinoph ils, and follicles with germinal centers. Usuall y, the follicles contain tingible body macrophages (contain ing apoptotic debris), and the re is mitotic activity; they also often have vessels with endo th elial hyperplasia. Atypical lymphoid hyperplasia

Atyp ical lymphOid hyperp las ia is diffus e lymphoid p roliferation, generall y without reactive genninal centers. It is composed of an admixture of small, matu re -appea rin g lymphocytes and larger lymphOid cells of questionab le maturity. Lymphoma

Lymphomas of the orbit may be a presenting manifestatio n of systemic lymphomas, or t hey may arise primarily fro m the orbit. The incidence of orbital involvement in systemic lymphomas is apprOXimately 1%-2%. Hodgkin disease is exceedingly rare in the orbit, and the majority of primary malignant orbital lymphomas are non -Hodgkin lymphomas. Multinucleated Reed -Sternberg cells are the characteristic histologic findi ng in Hodgkin d isease. Im munohistochem istry is typically positi ve for CD45. CD15, and CD30. NonHodgkin lymphomas constitute one-half of malignancies arising in th e orbit an d the ocular adnexa (Fig 14-8). They have diffuse archi tecture and mark im mu nophenotypica ll y as

/ A ~

__________________~

Figure 14-8

Low-grade B-cell lymphoma of the orbit. A. Low-power photomicrograph shows

a dense lymphoid infiltrate with a vague follicular arrangement. Note poorly defined follicles or germinal centers (arrows). B, Higher magnification shows small lymphocytes with mild nuclear membrane abnormalities, plasma celis, and atYPical lymphocytes with cytoplasmic clearing (monocytoid B celis, arrow). (Courtesy of Ben J . Glasgow. MO)

240 • Ophthalmic Pathology and Intraocu lar Tum ors B cells with immunopositivity for CD19 and CD20. [n rare instances, T-cell lymphomas of the orbit are found and demonstrate immunopositivity for CD3, CD4, and CD8. See Chapter 5.

Soft-Tissue Tumors Soft-tissue tumors make up a small subset of human benign and malignant tumors, but they can be life threatening and may pose significant diagnostic and therapeutic chal lenges. Recognizing the main histologic patterns of soft-tissue tumors, which include round cell, spindle cell, myxoid, epithelioid, pericytomatous, and pleomorphic, is the most important aspect in the diagnosis of these tumors. Immunohistochemistry is also helpful; the characteristic pathologic features and immunohistochemistry staining patterns of soft-tissue tumors can be found on websites such as Patholog yOutlines.com (http: // www.pathologyoutlines.com/eye.html) . Typically.apanelincludingS-1 00.CD99.CD34. vim entin, actin, desmin, and CD68 is used for initial differentiation, and the results direct further studies. Malignant soft-tissue tumors, or sarcomas, can be divided into 2 major genetic groups: (1 ) sarcomas with specific genetic alterations and usually simple karyotypes, such as reciprocal chromosomal translocations (eg, FUS -DDIT3 in myxoid liposarcoma) and specific oncogenic mutations (eg, KIT mutati on in gastrointestinal stromal tumors); and (2 ) sarcomas with nonspecific genetic alterations and complex unbalanced karyotypes. Some of these genetic abnormalities, including chromosomal numerical changes, translocations, gene amplifications, and large deletions, can be apparent at the cytogenetic level (karyotyping, fluorescence in situ hybridization), while others, such as small deletions, insertions, and point mutations, require molecular genetic techniques (polymerase chain reaction and sequence analysis) .

Vascular Tumors Lymphangiomas occur in children and are characterized by fluctuation in proptosis.

Lymphangiomas of the orbit are unencapsulated, diffusely infiltrating tumors that feature lymphatic vascular spaces and lymphoid aggregates in a fibrotic interstitium (Fig 14-9). Hemangioma in the adult is encapsulated and cons ists of cavernous spaces (cavernous hemangioma) with variably thick, fib rosed walls (Fig 14-10). Vessels may show thrombosis and calcification. Hemangioma in the child is unencapsulated, more cellular, and composed of capillary-sized vessels (capillary hemangioma).

Tumors With Fibrous Differentiation Fibrous histiocytoma (jibroxanthoma) is one of the most common mesenchymal tumors of the orbit in adults. The median age at presentation is 43 years (with a range of 6 months to 85 years), and the upper nasal orbit is the most common site. Most fibrous histiocytomas are benign. The tumor is composed of an admixture ofhistiocytes and fibroblasts, some of which fo rm a storiform (matlike or whorly) pattern (Fig 14-11 ). Immunohistochemistry is typically positive for CD45 and CD68. Although most are benign, intermediate and malignant varieties do exist. Malignant tumors are identified by a high rate of mitotic activity

CHAPTER 14:

Orbit. 241

Figure 14-9 Lymphangioma. A, Clinical appearance. A youn g boy with an inferior orbital lesion extending anteriorly and nasally below the left lower eyelid. B, CT scan (axial view) showing a multilobulated mass (white circles) w ithin the left orbit. C, Photomicrograph shows numerous vascular channels and lymphoid follicles (arrow) with a fibrotic stroma. 0 , Higher magnification demonstrates t he lymphocytes and plasma cells within the fibrous walls. (Parts A and B courtes y of Sander Dubavy, MD: parts C and 0 courtesy of Ben J. Glasgow, MD.)

Figure 14-10 Cavernous hemangioma. A, CT scan (a xial view) showing a well-c irc*mscribed retrobulba r mass (asterisk). B, Large spa ces of blood are separated by th ick septa. (Part A courtesy af Sander Dubavy, MD: part B courtesy of Hans E. Grossniklaus, MD.)

242 • Ophtha lmic Path ology and Intraocu lar Tum o rs

Figure 14-11 Fibrous histiocytoma. This photom icrograph illustra tes the storiform (ma t-

like or w ho rly) pattern.

(m ore than I mitotic figure per high -power fi eld ), nuclear pleomorphism, and necrosis. Othe r primary tumors of fibrous connective tissue include nodular fasciitis, fibroma, and fi brosarcoma. Hemangiopericytoma occurs mainly in adults (median age is 42 yea rs) and manifests with proptosis, pain, dipl opia, and decreased visual acuity. Histologicall y, a "staghorn" vascular pattern is displ ayed with densely packed spindle-shaped cell s (Fig 14-12). The reticulin stain is useful in demonstrating tum or cells that are individ ua ll y wrapp ed in a netwo rk of collagenous materiaL Hemangioperic ytomas include a spectrum of benign, intermediate, and malignant lesions. Features of malignancy include an infiltrating border, anaplasia, mitotic figures, an d necrosis. Immunohistochemistr y is typically positive for CD34. However, these features may be absent in tumors that eventually metastas ize. A solitary fibro us tumor is part of th e hemangi opericytoma spectrum.

Tumors With Muscle Differentiation Rhabdomyosarcoma

Rhabdomyosarcoma is th e most co mmon primar y malign ant orbital tumor of childhood (ave rage age of onset is 7-8 years). Proptosis is often sudden and rap id ly progreSSive; it requires emergency treatment. Reddish discolo rati on of th e eyelids is 110t accompanied by local heat or systemic fever, as it is in cellulitis. Orbital rhabdomyosarco mas have a better prognosis (overall 5-year survival of abo ut 90%) than do their extraorbital counterparts.

A Figure 14-12 Hemangiopericytoma . A. Photomicrograp h demon strates a dense, cel lular tumor w ith a characteristic branch ing vascular pattern . B. Higher magn ification demon strate s closely packed ce lls w ith ova l to spindle-shaped, vesic ula r nuclei. (Courtes y of Ben J. Glasgow, M D.)

CHAPTER 14,

Orbit •

243

Rh abdomyosarcomas arise from primitive mesenchymal cells that differentiate toward skeletal muscle. Three histologic types of orbital rhabdomyosarcoma are recogni zed (Fig 14-13):

1. embryonal (the most common) 2. alveolar 3. pleomorphic Embryo nal rhabdomyosarcoma may develop in the conjunctiva and may present as grapelike submucosal clusters (botryoid voriol/t). Histologically, spindle cells are arranged in a loose syncyt ium with occasional cells bearing cross-str iati ons, which are found in

apprOximately 60% of embr yo nal rh abdomyosarcomas. Well-differentiated rhabdomyosarcomas featu re numerous cells with strik in g cross-striations. Immunohistochem ica l reactivity is typica lly pos itive for desmin, muscle-specific ac tin , vim entin, and, less

Fi gure 14-13 Rhabdomyosarcoma. A, Chil d with a large right orbital mass. B, CT scan laxial view) showing a large, poorly circ*mscribed orbital tumor (asterisk) and proptosi s. C. In this embryonal example, cross-striations (arrow) representing Z-bands of actin-myosin complexes within the cytoplasm of a tumor cell can be identified . D, Poorly cohesive rhabdomyoblasts separated by fibrous septa (arrows) into "alveoli" are low-magnification histologic features of the alveolar varian t of rhabdomyosarcoma. This variant may have a less favorable natural history than the more common embryonal type. (Parts A and B courres¥ of Sander Oubovy. MD.)

244 • Ophtha lmic .pathology an d Intraocular Tumors

commonly, myogenin. Electron microscopy is helpful for demonstrating the typical sarcomeric banding pattern, especially in the less-well-differentiated cases of embryonal rhabdomyosarcoma. Leiomyomas and leiomyosarcomas

Tumors with smooth-muscle differentiation are rare. Leiomyomas are benign tumors that typically manifest with slowly progressive proptosis in patients in the fourth and fifth decades of life. Histologically, these spindle cell tumors show blunt-ended, cigar-shaped nuclei and trichrome-positive filamentous cytoplasm . Im munohistochemistry displays smooth-muscle differentiation . Leiomyosarcomas are malignant lesions that typically occur in patients in their seventh decade. Histologically, more cellularity, necrosis, nuclear pleomorphism, and mitotic figu res appear in leiomyosarcomas than in leiomyomas.

Nerve Sheath Tumors Neurofibromas are the most common nerve sheath tumo r. This slow-growing tumor in cludes an admixture of endoneural fib roblasts, Schwann cells, and axons. Neurofibromas may be circ*mscribed but are not encapsulated. The consistency is firm and rubbery. Microscopically, the spindle-shaped cells are arranged in ribbons and cords in a matrix of myxoid tissue and collagen that contains axons. Cytogenetic studies indicate that the most frequent structural rearrangements involve chromosome arm 9p. Isolated neurofibromas do not necessaril y indicate systemic involvement, but the plexiform type of neurofibroma is associated with neurofibromatosis type 1 (NF 1) (Fig 14-14). Studies indicate that a limited num ber of pathways are potentially involved in tumorigenesis of the plexiform neurofibroma. The CCNl gene may be a useful diagnostic or prognostic marker and fo rm the basis for novel therapeutic strategies. The CCNs (cysteine-rich proteins) have been shown to have key roles as matricellular proteins, serving as adaptor molecules that connect the cell surface and the extracellular matrix (ECM) . The neurilemoma (also called schwannoma ) arises from Schwann cells. Slow growing and encapsulated, this yellowish tumor may show cysts and areas of hemorrhagic necrosis. It may be solitary or associated with neurofibromatosis. Two histologic patterns appear microscopically: Anto ni A spindle cells are arranged in interlacing cords, whorls,

A Figure 14-14 Plexiform neurofi broma. A, Clinica l photograph depicting a typical S-shaped defor mity of t he upper eyelid. B, Note the th ickened, tortuous nerves (arrows) with proliferation of endon eural fibrobla sts an d Sch w ann ce lls. (Part A courtesy of Sander Dubovy, MD.)

CHAPTER 14:

Orbit • 245

or palisades that may form Verocay bodies (collections of fibrils resembling sensor y corpuscles) . The Antoni B pattern is made up of stellate cells with a mucoid stroma. Vessels are usually prominent and thick-walled, and no axons are present (Fig 14-15).lm munohistochemistry is typicall y positive for S-100, vimentin, and CD68. Liu K, DeAngelo P, Mah met K, Phytides P. Osborne L, Pletcher BA. Cytogenetics of neurofi bro mas: two case reports and literature review. Cancer Genet Cytogenet. 20 I0; 196( 1):93- 95. Pas mant E, Ortonne N . Ritt ie L, et a1. Differential exp ression of CCN lICYR61, CCN 3/NOV,

CCN4/W ISPl, and CCN5 /WISP2 in neurofibromatosis type 1 tumorigenesis. JNeuropathol Exp Neural. 20 lO;69( 1);60- 69.

Adipose Tumors Lipomas are rare in the o rbit. Pathologic characteristics include encapsulation and a distinctive lobular appearance. Because lipomas are histologically difficult to distinguish from nor mal or prolapsed fat, thei r incidence might have been previously overestimated. Liposarcomas are maligna nt tumors that are extremely rare in the orbit. Histologic criteria depend on the type of liposarcoma, but the unifying diagnostic feature is the presence oflipoblasts. These tumors tend to recur before they metastasize.

Bony lesions of the Orbit Fibrous dysplasia of bone may be monostotic or polyostotic. When the orbi t is affected, the condition is usually monostotic, and the patient often presents during the first 3 decades of life. The tumor may cross suture lines to involve multiple orbital bones. Narrowing of

Figure 14-15

Neuri le mom a (schwannom a).

A, The Antoni A pattern. Spindle cel ls are packed together. B. Palisading of nuclei ma y form a Verocay body (asterisk). C. The Antoni B pattern co nsists of a loosely arranged, mucoid stroma and represe nts degeneration withi n the tu mor.

246 • Ophth a lmic Pathology and Intraocula r Tumors the optic canal and lacrimal drainage system can occur. Plain radiographic studies show a ground-glass appearance with lytic foci. Cysts containing flu id also appear. As a result of arrest in the maturation of bone, trabeculae are composed of woven bone with a fibrous

stroma that is highly vascularized rather than lamellar bone. The bony trabeculae often have a C-shaped appearance (Fig 14-16). Fibro -osseus dysplasia (juvenile ossifying fibroma), a variant of fibrous dysplasia, is characterized histologically by spicules of bone rimmed by osteoblasts (Fig 14-17). At low magnification, ossifying fibroma may be confused with a psam momatous meningioma. Osseous and cartilaginous tumors are rare; of these, osteoma is the most common. It is slow growing, well circ*mscribed, an d comp osed of mature bone. Most commonly, an osteoma arises from the frontal sinus. Other primary tum ors in this gro up include

osteoblastoma giant cell tumor chondroma Ewing sarcoma osteogen ic sarcoma chondrosarcoma

See the appendix for AjCC definitions and staging of orbital sarcomas.

Figure 14-16

Fibrou s dysplasia. Bony tra-

beculae are C-shaped {arrow}, composed of immature woven bone, and sur ro unded by a

fibrou s stroma.

(Cou rtes y of Tatyana M ilman, MD.)

Figure 14-17 Fibro-osseus dysplasia (ossifying fi broma). Spicu les of lamellar bone are set in a cellular fib rous stroma. Note the osteoblasts (arrows) lining the bony spicules. (Courresy of Taryana Milman, MD.J

CHAPTER 14,

Orbit.

247

Metastatic Tumo rs Secondary orbital tumors are those that invade the orbit by di rect extension from adjacent structures, slich as sinus, bone, or eye. Metastatic tumors are those that spread from a primar y site. The most common pri mary tumor sites with orb ital metastasis are th e breast in women an d the prostate in men. In childre n, neuroblasto ma is the most common primary tumor metastatic to the orbit.

CHAPTER

Optic Nerve

Topography The optic nerve, embryologically derived from the optic stalk, is a continuation of the optic tract; thus, the pathology of the optic nerve reflects that of the central nervous system (CNS). The optic nerve extends from the eye to the optic chiasm and is 35-55 mm in length (intraocular portion, 0.7- /.0 m m; intraorbital portion, 25-30 mm; intracanalicular portion, 4-10 mm; intracran ial portion averages 10 mm ). Optic nerve axons originate from the retinal ganglion cell layer and have a myeli n coat posteri or to the lamina cribrosa. Oligodendrocytes, astrocytes, and microglial cells are glial cells (gUa = glue). Oligodendrocytes produce and maintain the myeli n sheath of the optic nerve. Astrocytes are involved with support and nutrition. Microglial cells (CNS histiocytes) have a phagocytic function. The meningeal coat that covers the optic ne rve includes the dura mater (wh ich merges wi th the sclera), the ceUular arachnoid layer, and the vascular pia mater. The pial vessels extend into the optic nerve and subdivide the nerve fibers into fascicles. The subarachnoid space, which contains cerebrospinal fl uid (CSF), ends blindl y at the termination of the meninges (Figs 15-1, 15-2). See BCSC Section 2, Fundamentals and Principles ofOphthalmology, and Section 5, Neuro- Ophthalmology, for additional discussion.

Congenital Anomalies Numerous congenital defects can involve the optic nerve, including optic nerve hypoplasia, optic nerve head pit, morning glory disc anomaly, Bergmeister papUla, and optic nerve coloboma. These are discussed in BCSC Section 5, Neuro-Ophthalmology, and Section 6, Pediatric Ophthalmology and Strabismus.

Colobomas Typical colobomas of the optic nerve head resu lt from defective closure of the embryonic fi ssure. They are observed inferonasally in the optic nerve head and are associated with colobomatous defects of the retina/choroid, Ciliary body, and iris, which may occur at any point along the course of the embryon ic fissure (Fig 15-3A) .

249

250 • Ophthalmic Pathology and Int raocular Tumo rs

Longitudinal section of norma l opt ic nerve Axons of the retinal ganglion ce lls (R) become axonal fibers of the optic nerve . Optic nerve axons pass t hrough the fenestrat ions in the lamina cribrosa (arrowh eads), which is cont inuous with the anterior sclera (5), The posterior sclera is continuous wit h the dura (0). C = choroid, A = arachnoid, P = pia, CRA = cent ral retina l artery, CRV = central retinal ve in. (Courtesy of Tatyana Milman, MD.) Figure 15-1

Figure 15-2 Transverse or cross section of th e normal optic nerve. The axons of the optic nerve are segregated into fa scicles by the delicate fibrovascular pi al septa. The nucle i of oligodendrocytes, astrocytes. and microgl ia are present between t he eosinophilic axons. The subdural space (asterisk) is re latively narrow in a normal optic nerve. (Courtesy of Tatyana Milman, MD.)

Histologically, an optic nerve coloboma consists of a large defect in the optic nerve, involving the retina, retinal pigment epithelium, and choroid. An atrophic and gliotic retina lines the defect. The sclera is ectatic and bowed posteriorly. The wall of the defect may . contain adipose tissue and even smooth muscle (Fig lS-3B).

CHAPTER 15:

Optic Nerve. 251

Figure 15-3 Optic nerve co loboma. A, Fundus photograph of the right eye shows a co lobomatou s defect in t he inferonasal optic nerve (arrow). B, The gli otic, disorganized ret ina (asterisk) prolapses into the defe ct, wh ich is lined by excavated sclera . Th e norma l retina, retinal pigment epithelium, and choroid termin ate at the edge of th e colobomatous defect (arrows). (Courresy of Tatyana Milman, MD.J

Inflammations Infectious Infections of the optic nerve may be secondary to bacterial or fungal infections of adjacent anatomical structures, such as the eye, brain, or sinuses, or they may occur as part of a systemic infection , particularly in an im munosupp ressed patient. Fungal infections include mucormycosis, cryptococcosis, and coccidiomycosis. Mucormycosis generally re~ sults from contiguous sinus infection. Cryptococcosis results from direct extension of the infection from the e N S and often produces multiple fo ci of necrosis with little infla mmatory reaction (Fig 15-4) . Coccidiomycosis produces necrotizing granulomas.

, Figure 15-4 Cryptococcosis of t he optic nerve in an immunocompromised pat ient. The dura is infilt rated by cryptococca l organ isms (ar~ rows). This yeast has a mu·copolysaccha ride capsu le, highlighted with mucicarm ine stain. No inflammatory infiltrate is observed. (Courtesy of Tatyana M ilman, MD.)

.... ' o

252 • Ophthalmic Pathology and Intraocular Tumors

Vi ral infections of the optic nerve are usually associated with other e NS lesions. Multiple sclerosis and acute disseminated encephalomyelitis afe immune-mediated demyelinating diseases with multifactorial etiologies, including infectious causes. The damaged myelin is rem oved by macrophages (Fig 15-5). Astrocytic proliferation ultimately produces a glial scar, known as a plaque.

Non infecti ous Noninfectious inflammatory disorders of the optic nerve include giant cell arteritis and sarcoidosis. Giant cell arteritis can produce granulomatous inflam mation in the blood vessel wall and occlusion of the posterior ciliary vessels with liquefactive necrosis of the optic nerve. Superficial temporal artery biopsy is the gold standard for histologic diagnosis of giant cell arteritis (Fig 15-6). The involvement of the vessel wall in giant cell arteritis can be patchy (skip lesions). Obtaining a biopsy specimen of adequate length (approximately 2 em) and performing a careful histologic examination of the specimen can increase the diagnostic yield.

Figure 15·5 Multiple sclerosis, optic nerve. A, Luxo l fast blu e sta in, count erstain ed with H& E. Th e blu e-sta ining area indicates normal myelin. Note the ab sence of myelin in the lower left corner of th e optic nerve (asterisk), correspondi ng to a focal lesion . 8 Higher magnif ication. Th e blue material (myeiin) is engulfed by macrophages. f

Figure 15·6 Giant cell arteritis, superficial tempora l artery. A, Vascular lumen (arrow) is narrow ed by concentric intimal hyperpl asia. Promi nent tra nsmural inflammatory infiltrate with numerou s multinucleated giant ce lls (arrowheads) is observed. 8 Elastic stain highlig hts t he diffuse loss of th e internal ela stic lamina. A short segment of remaining internal elastic la mina is marked with an arrow. Giant ce lls (arrowheads) are noted at t he level of th e internal elast ic la mina . I = intima, M = m edia, A = adventitia . (Courtesy of Tatyana Milman, MD.) f

CHAPTER 15:

Optic Nerve . 253

A Figure 15-7 Sarcoidosis. A, Low-magnifica tion photomicrograph of the optic nerve with discrete noncaseating granulomas (arrows). a, Higher magnification shows multinucleated giant cells (arrow) in the granulomas. (Courresyof Hans E. Grossniklaus, MD.)

Sarcoidosis of the optic nerve is often associated with retinal, vitreal, and uveitic lesio ns (Fig 15-7; see also Chapter 12, Fig 12-8). Unlike the characteristic noncaseating granulomas in the eye, optic nerve lesions may featu re necrosis.

Degene rations Optic Atrophy Injury to the retinal ganglion cells and to the axons of the peripheral optic nerve (that portion of the nerve near the retina) res ults in axo nal swelling. This swelling manifests clin ically as optic disc edema (Fig 15-8). Axonal swelling and loss of retinal ganglion cells are followed by retrograde degeneration ofaxons (ascending atrophy, Wallerian degeneration) toward the lateral geniculate body. Pathologic processes within the cranial cavity or

Figure 15-8 Optic disc edema. Swollen prelaminar axons demonstrate vacuolar alteration (red arrows) and displace the retina laterally (red arrowhead) from its normal termination just above the end of the Bruch membrane (black arrowhead) . Juxtapapiliary serous intra retinal fluid/ hard exudates (black arrows) and serous subretinal fluid (asterisk) are also observed . (Courtesy of Tatyana Milman, MO.)

254 • Op htha lmic Patho logy and Intraocular Tumo rs orbit result in descending atrophy toward the retinal ganglion cells (see BeSe Section 5, Neuro-Ophthalmology). Axonal degen eration is accompanied by loss of myelin and oligodendrocytes. Th e optic nerve shrinks despite the proliferation of astrocytes and of fib roconllective tissue in the pial septa (Fig 15-9). Cavernous optic atrophy of Sch nabel is characterized microscopically by large cysti c spaces th at are posterior to the lam ina cfi brosa and contain mu copolysaccharide material, which stains with aleian blue stain (Fig 15-10). Although the changes associated with cavernous optic atroph y were initially obse rved in glaucomatous eyes after acute intraocular pressure elevation, th e condition has been increasingly identified in nonglaucomatous elderly patients with generalized arteriosclerotic disease. The mucopolysaccharide was originally tho ught to be vitreous, forced by increased int raocular pressure into the ischemic necrosis- induced cavernous spaces, but it is more likely produ ced in situ. within th e atrophic spaces of the optic nerve.

eRA Fi gure 15-9 At rophi c opt ic nerve. A, Gross appearance of atrophic optic nerve . B, Lowmagnification photom ic rograph . Note the wide ned s ubd ura l space (asterisks). C, High magnification. Transverse or cross section of atro phic nerve shows loss of axons (arrowheads}, accompanied by glial proliferation and wi denin g of fibrovascular pial septa (arrows). D, Glaucomatous optic atrophy. Masson trichrome stains the collagen of the sclera, lamin a cribrosa, and meninges dark blue and the axonal fascicles pink. The optic nerve demonstrates advanced cupping (red arrow), accompanied by posterior bowing of the lamina crib rosa (arrowheads). Axonal atrophy an d thickening of pial septa are present. The intermeningeal space is widened due to severe optic nerve atrophy (double-ended arrow). eRA = central retinal artery, P = pia, A = arachnoid, 0 = dura. (Part A courtesy of Debra J. Sherlar. MD; parts Cand 0 courtesy of Ta ryana M ilman, MD.)

CHAPTER 15: Optic Nerve. 255

B L-__________L -_ _ _ _ _ _

Figure 15-10 Cave rnous optic atrophy of Schnabel. A, Photomicrograph shows cystic atrophy (asterisk) within the optic nerve . 8, The cystic space is fi lled wi th aleian blue-staining material. (Courtesy of Hans E. Grossniklau5, MD.)

Giarelli L, Falconieri G, Cameron JD, Pheley AM. Schnabel cavernous degeneration: a vasc ular change of the aging eye. Arch Pathol Lab Med. 2003; 127( 10): 1314- 13 19.

Drusen

Drusen of the optic disc are calcific, usually bilateral deposits embedded within the parenchyma of small, crowded optic discs with abnormal vasculature. When superficial, optic disc dr usen appear as refractile, rounded, pale yellow or whi te depos its. Deeper drusen may be mistaken for papilledema (pseudopapilledema). Optic disc drusen can be associated with angioid streaks, papillitis, optic at rophy, chronic glaucoma, and vascular occlusions, but they are more commonly observed in otherwise normal eyes and are occasionally dominantly inherited . Evidence suggests that abnormal axonal metabolism leads to mitochondrial calcification and drusen formation. Histologically, optic disc drusen appear as basophilic, calcified acellular deposits that contain mucopolysaccharides, amino acids, DNA, RNA, and iron. Most disc drusen are located anterior to the lamina cribrosa and posterior to Bruch membrane (lamina choroidalis portion of the intraocular optic nerve ) (Fig 15 -11 ). See also BeSe Section 5, Neuro -Ophthalmology, and Section 6, Pedia tric Oph tha lmology and Strabismus. Lam BL, Morais CG Jr, Pasol ]. Drusen of the opt ic disc. ClIrr Neurol Neurosci Rep. 2008;8(5): 404- 408.

Figure 15-11 Histolog ically, drusen of the optic nerve head appear as discrete ba sophilic zones of calcification (arrows) just anterior to the lamina cribrosa (as terisk). The cystic spac es in t he optic nerve head are histologic sectioning artifacts.

256 • Ophtha lm ic Pathology and Int raocula r Tumors

Neoplasia Tu mors may affect the optic nerve head (eg, melanocytoma, peripapillary choroidal melanoma, retinal pigment epithelial proliferation, and hemangioma) or the retrobulbar portion of the optic nerve (eg, glioma and meni ngioma).

Melanocytoma A melanocytoma is a benign, deeply pigmented melanocytic tumor situated eccentricall y on the optic disc. It may be slightly elevated and typically extends into the adjacent retina as well as posteriorly into the optic nerve, Slow growth can matian is rare.

OCC llr,

but malignant transfor~

Histologically, melanocytoma is a magnocellular nevus, composed of closely packed, maXimally pigmented, plump, polyhedral melanocytes. The de nse pigment obscures nuclear detail, so that bleached preparations are necessary to demonstrate bland cytologic features: abundant cytoplasm, small nuclei with fi nely dispersed chro matin, and small and regular nucleoli. Necrosis and melanophagic infiltration within melanocytoma can

be observed but are not indicative of aggressive behavior (Fig 15-12) . See also Chapter 17.

B Figure 15-12 M elanocytoma of the optic nerve. A, Low-power photomicrograph of melanacytoma shows a dome-shaped, jet-black mass involving the prelaminar optic nerve. The jux-

tapapillary choroid and ret ina are also involved by this tumor. B, Higher magnification shows

darkly pigmented polyhedral mela nocytes with dense intracytoplasmic pigment, obscuring the nuclear detail. C, Bleached preparation displays the bland nuclear morphology of melanocytom a cells. An area of necrosis within the tumor is also observed (arrow). (Courtesy of Taryana Milman, MD.)

CHAPTER 15:

Optic Nerve.

257

Glioma A glioma (astrocytoma) may arise in any part of the visual pathway, including the optic disc and optic nerve. Optic nerve gliomas are frequently associated with neurofibromatosis (NFl ). The tumors most commonly present in the first decade oflife and are low-grade ju venile pilocytic astrocytomas. Histology of juvenile pilocytic astrocytomas shows proliferation of spindle-shaped astrocytes wi th del icate, hairlike (pilocytic) cytoplasm ic processes that expand the optic nerve parenchyma. Enlarged, deeply eosinophilic filaments, representing degenerating cell processes known as Rosenthal fibers, may be found in these low-grade tumors (Fig 15 -13). Foci of microcystic degeneration and calcification may occur, and the pial septae are thickened. The meninges show a reactive hyperplasia and infiltration by astrocytes. The dura mater remains intact, so the nerve demonstrates fusiform or sausageshaped enlargement. High-grade tumors (grade 4 astrocy tomas, glioblastoma m ultiforme, malignant gliomas) rarel y involve the optic nerve. When this does occur, the optic nerve is usually involved secondarily from a brain tumor. Primary malignant gliomas of the anterior vi sual pathways occur primarily in adults and are characterized histologically by nuclear pleomorphism, high mitotic activity, necrosis, and hemorrhage. See also BCSC Section 5, Neuro-Ophthalmology, and Section 7, Orbit, Eyelids, a/ld Lacrimal System .

,.'

. .'

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c ;. Fi g u r. 15-13 Astrocytoma of the optic nerve. A, The right side of this photograph demonstrates normal optic nerve (asterisk), and the left side shows a pilocytic astrocy1Oma . B, The neoplastic glial cells are elongated to resemble hairs (hence the term pi/acytie). C, Degenerat, ing eosinophilic filaments. known as Rosenthal fibers (arrows), are not unique to astrocytoma of the optic nerve.

258 • Ophthalmic Patho logy and Intraocular Tu mors

Meningioma Primary optic nerve sheath meningiomas arise from the arachnoid sheath of the optic nerve. They are less frequent than seconda ry orbital meningiomas, which extend into the orbit from an intracranial primary site. Although meningioma may, in rare instances, be associated with neurofibromatosis in the younger age group, it is a less frequent hallmark of NFl than is optic nerve glioma. Primary optic nerve meningiomas may invade the nerve and the eye and may extend through the dura mater to invade muscle (Figs 15-14, 15-15). Histologically, the tumor (p rimary or secondary) is usually of the meningothelial type, composed of plump cells with indistinct cytoplasmic margins (syncytial growth pattern) arranged in who rls (see Fig 15- 14C). Psammoma bodies, extracellular rounded calcifications surrounded by a cluster of meningioma cells, tend to be sparse. See BCSC Section 5, Neuro -Ophthalmology, and Section 7, Orbit, Eyelids, and Lacrimal System . Miller NR . Primary rumours of the optic nerve and its sheath. Eye. 2004; 18(11): 1026-\ 037.

A ......_ _ _

_ _ _---'"

c Figure 15·14 Optic nerve meningioma A, Th is mening ioma (asterisks) has grown circumferentially around the opt ic nerve (outlined bV dashed line) and has compressed th e nerve (arrowhead = dura m ater). B, Meningioma (between arrows) of the optic nerve (ON) originates f rom the arachnoid . 0 = dura mater. C, Note the whorls of tumor ce ll s, character istic of the men ingothelial type of meningioma, the most common histologic va riant arising from t he optic nerve.

CHAPTER 15: Optic Nerve. 259

Figu re 15· 15 Optic nerve meningioma. The shaggy border of this gross specimen emphasizes the tendency of the peri optic meningioma to invade surrounding orbital tissues. Note the size of the optic nerve (arrow) in relation to the tumor.

CHAPTER

Introduction to Part II

Intraocular tumors constitute a broad spectrum of benign and malignant lesions that can

lead to loss of vision and loss of life. Effective management of these lesions depends on accurate diagnosis. In 1110St cases, experienced ophthalmologists diagnose intraocular neoplasms by clinical examination and ancillary diagnostic tests. In the past 2 decades, significant advances have been made in the management of intraocular tumors and in understanding their biology. Important information concerning the most common primary intraocular malig -

nant tumor in adults, choroidal melanoma, was gathered in the Collaborative Ocular Melanoma Study (COMS). The COMS incorporated both randomized clinical trials for patients with medium and large choroidal melanomas and an observational study for pa-

tients with small choroidal melanomas. The COMS reported outcomes for enucleation versus brachytherapy for the treatment of medium tumors and for enucleation alone versus pre-enucleation external -beam radiotherapy for large melanomas. Survival data from

the large, medium, and small treatment arms of the COMS are available. In addition to the study's primary objectives, the COMS has provided data regarding local tumor failure rates after iodine 125 brachytherapy as well as visual acuity outcomes following this globeconserving treatment. These findings have shifted the primary treatment of choroidal melanoma from enucleation toward globe-conserving brachytherapy (see Chapter 17). I n recent years, there have been several oth er advances in the management of choroi -

dal melanoma. Researchers have identified key cytogenetic aberrations, specifically mono somy 3 and isochromosome Sp, in choroidal melanoma that lead to metastatic disease. Fine-needle aspiration biopsy (FNAB, discussed in greater detail in Chapter 4) at the time of treatment can now confirm the diagnosis and yield important prognostic information

for the patient. FNAB can also be used to confirm the presence of a choroidal metastasis. Retinoblastoma is the most common prim ary intraocular malignan t tumor in chil -

dren. The predisposing gene for retinoblastoma has been isolated, cloned, and sequenced. As with the treatment of choroidal melanoma, treatment of retinoblastoma is undergoing a transition toward globe -conserving therapy, with a renewed interest in combined-

modality therapy focused particularly on systemic chemotherapy coupled with focal therapy. The trend away from primary external-beam radiotherapy and toward chemotherapy has been fueled by our growing understanding of the former's potential risk for increasing the incidence of secondary malignancies in children who have a germline mu tation of the retinoblastoma gene. Advances in our understanding of the molecular genetics of retinoblastoma continue to enhance our ability to screen for and treat this pediatric

ocular malignancy (see Chapter 19). 263

CHAPTER

Melanocytic Tumors

Introduction Intraocular melanocytic tumors arise from the uveal melanocytes in the iris, ciliary bo dy,

and choroid. In contrast to melanocytic tumors of the skin and mucosal membranes, which develop in ectodermal tissue and usually spread through the lymphatics, uveal melanocytic tumors arise in mesodermal ti ssue and typically dissem inate hematogenously, if th ere is m etastatic spread.

There are 2 groups of melanocytic tu mors of the uvea: the benig n nevi and the melanomas. Pigmented intraocular tumors that originate in the pigmented epithelium of the iris, ciliary body, and retina co nstitute an other group of melanocytic tumors. These rare

tumors are d iscussed separately at the end of this chapter. See also Chapter 12.

Iris Nevus An iris nevu s generally appears as a darkly pigmented lesion of the iris stroma with minimal distortion of the iris architecture (Fig 17-1). The true prevalence of iris nevi remains

Figure 17-1 Iris nevus, clinical appearan ce . The lesion is on ly slightly raised fro m the iris surface, and lesion color is hom*ogeneous brown.

265

266 • Ophthalmic Pathology and Intraoc ula r Tumors uncertain because many of these lesions produce no symptoms and are recognized inci dentally during routine ophthalm ic exam inat ion. Ir is nevi may present in 2 forms:

circ*mscribed iris nevus: typically nodular, involving a discrete portion of the iris

diffuse iris nevus: may involve an en tire sector or, rarely, the entire iris In some cases, the lesion causes slight ectropion iridis and sectoral cata ract. The incidence

of iris nevi may be higher in the eyes of patients with neurofibromatosis. Iris nevi are best evaluated by slit- lamp biomicroscopy coupled with gonioscopic evaluation of the angle structures. Specific attention should be given to lesions involv-

ing the angle structures to rule out a prev iously unrecognized ciliary body tumor. The most important possibility in the differential diagnosis of iris nevi is iris melanoma. v\Then

iris melanoma is included within the di ffe rential diagnosis, close observation with scheduled serial follow-up examinations is indicated. Cli nical evaluation of suspicious iri s nevi

should include slit-lamp photography and hi gh-frequency ultrasound biomicroscopy. Iris nevi usually require no treatment once they are d iagnosed, but, when suspected, they should be followed closely and photographed to evaluate for gro\\~h.

Nevus of the Ciliary Body or Choroid Nevi of the ciliary body are occasionally incidental findings in histopathologic examination of globes that are enucleated for other reasons. Choroidal nevi may occur in u p to 10% of the population. In most cases, they have no clinical symptoms and are recognized on routine ophthalmic examinatio n. The typ ical choroidal nevus appears ophthalmoscopically as a flat or minimally elevated, pigmented (gray-brown) choroidal lesion with indistinct margins (Fig 17-2). Some nevi are amelanotic and may be less apparent. Choroidal nevi may be associated with overlying RPE disturbance, drusen, serous detachment, cho-

roidal neovascular membranes, and orange pigment; and they may produce visual field defects. On fluorescein angiography, choroidal nevi may either hypofluoresce or hyperfluoresce, depending on the assoc iated findings. Ocular and oculodermal melanocytosis may predispose to uveal malignancy, with an est imated lifetime risk of 1 in 400 in the

white population. Choroidal nevi are d isti nguished from choroidal melanomas by clinical evaluation and anCiLlary testing. No single cl inical factor is pathognomonic for benign versus malignant choroidal melanocytic lesions. The differential diagnOSiS for pigmented lesions in the ocular fundus most com mo nly incl udes the following: choroidal nevus choroidal melanoma

atypical disciform scar associated with age-related macular degeneration (AMD) suprachoroidal hemorrhage RPE hyperplasia congenital hypertrophy of the ret ina l pigment epithelium (CHRPE) choroidal hemangioma with RPE hyperpigmentation melanocytoma metastatic carcinoma with RPE hyperp igmentation choroidal osteoma

CHAPTER 17:

Melanocytic Tumors. 267

B Figure 17-2 Choroidal nevi, cli nical appearance. A, Choroidal nevus with overlying drusen, under the lower te mporal ret inovascu lar arcade. B, Medium-sized choroidal nevu s with overlyin g drusen, superior to the optic nerve head . (CouftesyofJacobPe'er. MD.)

Virtually all choroidal melanocytic tumors thicker than 3 mm are melanomas, and virtually all choroidal melanocytic lesions thinn er than I mm are nevi. Many lesions 1-2 mm in thickness (apical height) may be benign, although the risk of malig nancy in creases with height. It is difficult to classify with certainty tumors that are 1- 2 mm in thickness, Flat lesions with a basal diameter of 10 mm or less are almost always benign. The risk of malignancy increases for lesions that are larger than 10 111m in basal diameter. Clinical risk fac tors for enlargement of choroidal melanocytic lesions have been well characteri zed and include • subjective clin ical symptoms such as metamorphopsia, photopsia, visual field loss • presence of orange pigmentation

268 • Ophthalmic Pathology and Intraoc ula r Tu mors associated sub reti nal fluid larger size at presentation juxtapapillary location absence of drusen or RPE changes hot spots on fluorescein photography hom*ogeneity on ultrasonography If definite enlargement is documented, malignant change should be suspected . The recommended management of choroidal nevi is photographic documentation for lesions less than 1 mm in thickness and photographic and ultrasonographic documentat ion for lesions greater than 1 IDm in thickness, coupled with regular, periodic reassessment for signs of growth.

Melanocytoma of the Iris, Ciliary Body, or Choroid Melanocytomas are rare tumors composed of characteristic large, polyhedral-shaped cells with small nuclei and cytoplasm filled with melanin granules (see Chapter 15, Fig 15-12). Cells from iris melanocytomas may seed to the anterior chamber angle, causing glaucoma. Melanocytomas of the ciliary body are usually not seen clinically because of their peripherallocation. In some cases, extrascleral extension of the tumor along an emissary canal appears as a darkly pigmented, fixe d subconjunctival mass. Melanocytomas of the choroid appear as elevated, pigmented tumors, simulating a nevus or melanoma. Melanocytomas have been reported to undergo malignant change in some instances. When a melanocytoma is suspected, photographic and echographic studies are appropriate. If growth is documented, the lesion should be treated as a malignancy. Shields CL, Furuta M, Berman EL, et al. Choroidal nevus transformation into melanoma: analysis of2514 consecutive cases. Arch Ophthalmol. 2009;127(8):981 - 987. Shields JA, Shields CL, Eagle RC Jr. Melanocytoma (hyperpigmented magnocellular nevus) of the uveal tract: the 34th G. Victor Simpson lecture. Retina. 2007;27(6):730- 739.

Iris Melanoma Iris melanomas account for 3%-10% of all uveal melanomas. Small melanomas of the iris may be impossible to differentiate cli nically from benign iris nevi and other simulating lesions. The following conditions may be included in a differential diagnosis of iris melanoma: iris nevus primary iris cyst (pigment epithelial and stromal) iridocorneal endothelial syndrome iris foreign body peripheral anterior synechiae metastatic carcinoma to the iris

CHAPTER 17:

Melanocytic Tumors.

269

aphakic iris cyst iris atrophy, miscellaneous pigment epithelial hyperplasia or migration juvenile xanthogranuloma retained lens material simulating iris nodule Signs suggesting malignancy include extensive ectropion iridis, prominent vascularity, sectoral cataract, secondary glaucoma, seeding of the peripheral angle structures, extrascleral extension, lesion size, and documented progressive growth. Iris melanomas range in appearance from amelanotic to dark brown lesions, and three-quarters of them involve the inferior iris (Fig 17-3). In rare instances, they assume a diffuse growth pattern, producing a syndrome of unilateral acquired hyperchromic heterochromia and secondary glaucoma. Clinical evaluation is identical to that for iris nevi. The differential diagnOSiS of iris nodules is listed in Table 17-1; Figure 17-4 illustrates the various iris nodules. See also Figure 12-11 in Chapter 12. Advances in high-frequency ultrasonography allow for excellent characterization of tumor size and anatomical relationship to normal ocular structures (Fig 17 -5). Fluorescein

Figu re 17-3 Iris me lanoma, clinical appe arance. A, Mi ld ly pigmented iris melanoma on the nasal side, involving also the anterior chamber angle. A senti nel vessel (arrow) is present. B, Melanoma in the lower part of the iris. C, Melanoma in th e lower temporal area, spreading to other parts of the iris. (Courtesy of Jacob Pe'er. M O.)

270 • Ophtha lm ic Pathology and Intraocular Tumors Table 17-1 Differential Diagnostic Features of Iris Nodules (alphabetical list) lesio n

Features

Brushfield spots (Down syndrome) (Fig 17-4Al

Elevated white to light yellow spots in periphery of iris, 10-20 per eye. Prevalence in Down syndrome is 85%; otherwise, ~25% . Histologically, the spots are areas of relative ly normal iris stroma surrounded by a ring of mild iris hypoplasia. Anterior border layer slightly increased in density. Each follows surgery or injury. Appears as serous or so lid cysts in continuity with the wound or as imp lantation cysts or membranes on the anterior iris surface. Usually becomes secondarily pigmented and may be associated with chronic i ridocycl*tis and peripheral anterior synechiae. Irregular yellow-white mass on iris. May be accompa nied by hypopyon or on ly mild inflammatory signs. The iris nodules of classic granulomatous anterior uveitis occur either superficially or deeply within the iris. Koeppe nodules occur at the pupillary border, and Busacca nodules li e on the anterior iris surface. Microscopically, they are composed of large and small mononuclear cells. Stationary, lightl y to darkly pigmented f lat areas on anterior iris surface composed of anterior border layer melanocytes containing increased pigmentation without increased number of melanocytes. Discrete mass(es) or nodule(s) on anterior iris surface and in the iris stroma. Variable pigmentat ion . Composed of benign nevus cells. Increased incidence of iris nevi in patients with neurofibromatosis. Acquired diffuse nevus of iris associated with unilateral glaucoma, heterochromia, peripheral anterior synechiae , and extension of endothelium and Descemet membrane over trabecular meshwork. Obliteration of normal iris architecture. (See ICE syndrome, Chapter 7.) Cysts encompassing both layers of neuroepithelium. Produce a localized elevation of stroma and may be pigmented. May transilluminate. May be better seen after dilation. B-scan ultrasonography of value in diagnosis. Congenital or acquired (trau ma or surgery) plaques of pigment epithelium displaying a blac k, velvety appearance . Yellowish to gray, poorly demarcated iris lesions associated with raised orange skin lesion{s) (single or mu ltiple) appearing in the first year of life. May be associated with spontaneous hyphema and secondary g laucoma. Histologically, there is a diffuse granulomatous infiltrate with lipid-conta ining histiocytes and Touton giant cells . The lesions regress spontaneously. May also be found in ci liary body, anterior choroid , episclera, cornea, eyelids, and orbit. May be well localized and even peduncu lated, often diffuse and flat, and usua l ly lightly pigmented. Electron microscopy may be helpfu l in differentiating leiomyoma from amelanotic spindle cell melanoma.

Epithelial invasion, serous cyst, so lid or pearl cyst, implantation membrane Foreign body, retained

Fungal endopht halm itis Iri docycl*tis

Iris freckle (Fig 17-48)

Iri s nevus (see Fig 17-1 )

Iri s nevus syndrome (Cogan-Reese)

Iris pigment ep ithelial cysts

IFig 17-4CI

Iris pigment epithelial proliferation Juvenile xanthogranuloma

Leiomyoma

CHAPTER 17:

Melanocytic Tumors . 271

Tab le 17·1 (contin ued) Lesion

Features

Leukemia (Fi g 17·40)

Very rare nodular or diffuse milky lesions with intense hyperemia. Often, the iris loses its architectu re, becomes thickened, and develops heterochromia . Pseudohypopyon is common. One of the diagnosti c criteria for neurofibromatosis. Multiple lesions varying from tan to dark brown and about the size of a pinhead. May be flat or project from the surface. Histo log ically, they are composed of collections of nevus cells. Generally unila teral with diffuse uveal nevus causing heterochromia iridis associated with blue or slate gray patches of sclera and episclera. In ocu lodermal melanocytosis, eyelid and brow are also invo lved. Malignant potentia l exists. Occurs as nodular or flat growths, usually in the periphery, especially inferior ly or inferotemporally. Variably pigmented, often with satellite pigmentation and pigmentatio n in the anterior chamber ang le and nutrient vessels. Pupil may dilate irregularly, and elevated lOP may be present. Gelatinous to w hite vascularized nodules on the iris surface and in the ante rior chamber angle. May be associated with anterior uve iti s, hyphema, rubeosis, and glaucoma. White foci on the anterior iris surface or in the ante rior chamber angle, or a pseudohypo pyon. Tapioca-like nodu les lying over a portion or all of the iris. May be translucent to lightly pigmented. Often associated w ith unilatera l glaucom a.

Lisch nodules (neurofibromatosis) (Fi g 17-4 E)

Melanocytosis, congeni tal ocular and oculod ermal

Melanoma (see Fig 17-3)

Metastatic carcinoma

Retinoblastoma Tapioca melanoma

angiography may document intrinsic vascula rity, although this finding is of limited value in establishing a differential diagnosis. In rare instances, biopsy may be considered when the management of the lesion is in question. In most cases, when growth or severe glau coma occurs, diagnostic and therapeutic excisional treatment is indicated. Brachytherapy using custom-desi gned plaques may be used in selected cases. Specificall y designed proton-beam radiotherapy has also been repor ted for iris melanoma. The prognosis for most patients with iris melanoma is excellent, with a lower mortality rate (l %-4%) than that for ciliary body and choroidal melanomas, possibly because the biological behavior of most of these iris tumors appears distinctly different from that of ciliary body or choroidal melanoma. Henderson E, Margo CEo Iri s melanoma. Arch Pathol Lab Med. 2008; 132(2):268-272 . Jakobiec FA, Silbert G. Are most iris "melanomas" really nevi? A clinicopathologic study of 189 lesions. Arc" Ophthalmol. 1981 ;99(12);211 7- 2 132.

272 • Ophtha lmic Patho logy and Intraocular Tumors

F Iris nodules. A, Brushfield spots in Down syndrome. S, Iris freckles . C, Pigment epithelial cyst. Before dilation (feft), the iris stroma is bowed forward (arrow) in the area of the cyst, which is invisible posteriorly. After dilation (right), the cyst of the posterior iris epithelium can be seen (arrow) w ith eye adducti on. D, Leukemic infiltration of the iris. Note co lor variation, prominent vascularity, and stroma l thickening. E, Multiple Lisch nodules in neurofibromatosis. F, Koeppe nodules at pupil margin (arrows) in sarcoidosis. G, Busacca nodu les in m id-iris (arrows) in sarcoidosis. (Part A courtesy of WR. Green, MD; parrs Band E courtesy of Timothy G. Murray, MD;

Figure 17-4

parts F and G courtesy of R. Christopher Walton, MD.)

CHAPTER 17:

_ __

Fi gure 17·5

Melanocytic Tum ors . 273

A , Iris melan om a, clinica l appearance. B, This high-freq uency ultrasonogram

shows a melanoma mass (asterisk) occupyin g the iris stroma and anterior ch amber ang le and abutting the posterior corneal surface (a rrow). (Parr A courtesy of Marrhew W. Wilson, MD; part B courtesy of Jacob Pe'er, MD.J

Melanoma of the Ciliary Body or Choroid Ciliary body and choroidal melanomas are the most common primary int raocular malignancies in adults. The incidence in the United States is approximately 6-7 cases per million. The tumor, extremely rare in children, primarily affects patients in their 50s and early 60s; it has a predilection for lightly pigmented individuals. Risk factors have not been conclusively identified but may include light-colored complexion (white skin , blue eyes, blond hai r) ocular me lanocytic conditions such as ocular and oculodermal melanocytosis

genetic predisposition (dysplastic nevus syndrome) cigarette smoking Cilia ry body melanomas can be asymptomatic in the earl y stages. Because of their location behind the iris, Ciliary body melanomas may be rather large by the time they are detected. Patients who have symptoms most commonl y note vision loss, photopsias, or visual field alterations. Ciliary body melanomas are not usually visible unless the pupil is widely dilated (Fig 17-6A). Some erode through the iris root into the anterior chamber and eventually become visible on external examination or with gonioscopy. In rare cases, tumors extend directly through the sclera in the Ciliary region, producing a dark epibulbar mass. The initial sign of a ciliary body melanoma may be dilated episcleral sentinel vessels in the quadrant of the tumor (Fig 17-6B). The tumor may eventually become quite large, producing a sectoral or diffuse cataract, subluxated lens (Fig 17-6e) , secondary glaucoma, retinal detachment, and even iris neovascular izati on. In rare in stances, a ciliary body mel-

anoma assumes a diffuse growth pattern that extends 180' -360' around the ciliary body. This type of melanoma is called a ring melanoma (see Chapter 12, Fig 12, 18). The typical choroidal melanoma is a pigmented, elevated, dome-shaped subretinal mass (Fig 17-7A, B). The degree of pigmentation ranges from totally am elan otic to dark brown. vVith ti me, many tumors erupt through th e Bruch membrane to assume a

mushroom-like shape (Fig 17-7C, D). Prominent clumps of orange pigment at the RPE level may appear over the surface of the tumor, and serous detachment of the neurosen sor y retina is common. If an extensive retinal detachment develops, anterior displacement

274 • Ophthalmic Pathology and Int raocu la r Tumors

Figure 17-6 A, Ciliary body melanoma, clinical appearance. Such tumors may not be evident unless the pupil is widely

dilated. B, Sentinel vessels. C, Ciliary body melanoma, gross pathology. Note mostly amelanotic appearance of this tumor, which is subluxing the lens (asterisk) and causing secondary angle closure. (Pan 8 courtesy of Timothy G. Murray, MD.)

c of the lens-iris diaphragm and secondary angle-closure glaucoma occasionally occur. Neovascularization of the iris may also appear in such eyes, and there may be spontaneous hemorrhage into the subretinal space. Vitreous hemorrhage is usually seen only in cases

when the melanoma has erupted through the Bruch membrane.

Diagnostic Evaluation Clinical evaluation of all suspected posterior uveal melanomas of the Ciliary body and the choroid should include a history, ophthalmoscopic evaluation, and ancillary testing to definitively establish the diagnosis. When used appropriately, the tests described here enab le accurate diagnosis of melanocytic tu mors in almost all cases. Atypical lesions may be characterized by several other testing modalities, such as fine-needle aspiration biopsy; or, when appropriate, lesions may be obser ved for characteristic changes in clinical behavior

that will establish a correct diagnosis. Indirect ophthalmoscopic viewing of the tumor remains the gold standard. It is the single most important diagnostic techni que for eva luating patients with intraocular tumors, as

it provides stereopsis and a wide field of view and facilitates visualization of the peripheral fundus, particularly when performed with scleral depression. Indirect ophthalmoscopy allows for clinical assessment of tumor basal d imension and apical height. However, it is not useful in eyes with opaque media, which require other diagnostic methods, such as ultrasonography, computed tomography (CT), andlor magnetic resonance imaging (MRl).

CHAPTER 17: Melanocyti c Tum ors. 275

Figure 17-7 Choroida l melanoma . A, Small choroida l melanoma touching t he nasa l border of the optic nerve head. S, Medium-sized choroidal m el anoma temporal to the macula. C, A large choroidal me lanoma surro unding the optic nerve head and extending upw ard to t he ora serrata . Note the ret inal detachment in the lower half of the retina (asterisk). D, Gross pathology. Note the mushroom-s haped cross section of thi s darkly pigmented tumor and the ass ociated retinal detachment. (Parts A- C courtesy of Jacob Pe'er, MO.)

Slit-lamp biom icroscopy used in combination with gonioscopy offers the best method for establishing the presence and extent of anterior involvement of ciliary body tumors. The use of high-frequency ultrasonography (biomicroscopy) enables excellent visualization of anterior ocular structures and is a significant adjunct to slit-lamp photograph y for the evaluation and do cumentation of anterior segment pathology. In addition, the presence of sectoral cataract, secondary angle involvement, or sentinel vessel forma tion may be a clue to the diagnosis of ciliary body tumo r. Hruby, Goldmann , and other wide-fi eld fundus lenses can be used with the slit lamp to evaluate lesions

276 • Ophthalm ic Pathology and Intraocul a r Tumors of the posterior fundus under high magnification. High-mag njfication fundus evaluation can delineate neurosensory retinal detachment, orange pigmentation, rupture of Bruch membrane, intraretinai tumor invasion, and vitreous involvement. Fundus biomicroscopy with the 3- mirror contact lens is useful in assessing lesions of the peripheral fundus. Ultrasonography is the most important anCillary tool for evaluating ciliary body and choroidal melanomas (Fig 17-8). It also re mains the anCillary test of choice for detection of orbital extension associated with intraocular malignancy. Standardized A-scan ultrasonography provides an accurate assessment of th e internal reflectivity and vascularity of a lesion, as we ll as a measurement of its thickn ess. Serial examination with A-scan ultrasonography can be used to document gro wth or regression of an intraocular tumor. A-scan ultrasonography usually demonstrates a solid tumor patte rn with highamplitude initial echoes and low-amplitude internal reflections (low internal reflectivity). Spontaneous vascular pulsations can also be demonstrated in most cases. B-scan exam ination proVides information about the relative size (height and basal diameters), general shape, and position of intraocular tum o rs. Occasio nally, cross-sectional tumor shape and associated retinal detachment can be detected more easily by ultrasonography than by ophthalmoscopy. B-scan ultrasonography usuall y shows a dome- or mushroom-shaped choroidal mass with a highly reflective anterior border, acoustic hollowness, choroidal excavation, and occasional orbital shadOWing. B-scan ultrasonography can be used to detect intraocular tumors in eyes with either clear or opaque media. Ultrasonography for ciliary body melanomas is more difficult to interpret because the peripheral location of these tumo rs makes the test technically more demanding to perform. High-frequency ultraso nography is not limited by the technical diffi culties associated with standard B-scan testing and en ables excellent imag ing of the anterior segment and Ciliary body.

Figu r. 17-8 A. Peripapillary choroidal melanoma. S, The peripapillary tumor (arrow) IS seen nasal to the optic nerve (asterisk). B-scan ultrasonography is used primarily to

show the tumor location and its topography. C, The A-scan ultrasonogram shows characteristic low Internal reflectivity (arrow).

CHAPTER 17:

Melanocytic Tum ors. 277

Although ultrasonography is generally considered highly reliable in the differential diagnosis of posterior uveal melanoma, it may be difficult or impossible to differentiate a necrotic melanoma from a small subret inal hematoma or a metastatic carcinoma. Advances in 3-dimensional ultrasound imaging may allow for better evaluation of tumor volume, and advances in high-resolution imaging may be able to determine tumor micro~

vasculature patterns predictive of tumor biology (see Chapter 12). Transillumination may be helpful in evaluating suspected ciliary body or anterior choroidal melanomas. It is valuable in assessing the degree of pigmentation within a lesion and in determining basal diameters of anterior tumors. The shadow of a tumor is visible

with a transilluminating light source, preferably a high-intensity fiber-optic device, placed either on the surface of the topically anestheti zed eye in a quadrant opposite the lesion or directly on the cornea with a smooth, dark, specially designed corneal cap (Fig 17-9). Fiber-optic trans illumination is used during surgery for radioactive applicator insertion

to locate the uveal melanoma and delineate its borders. Fundus photography is valuable for documenting the ophthalmoscopic appearance of choroidal melanoma and for identifying interval changes in the basal size of a lesion in follow-up examinations. Wide-angle fundus photographs (600~1800) of intraocular tumors can reveal the full extent of most lesions and can document the relationsh ip between lesions and other intraocular structures. The relative positions of retinal blood vessels can

be helpful markers of changes in the size of a lesion. Wide-angle fundus cameras enable accurate measurement of the basal diameter of a choroidal melanoma as well as changes in its size, using intrinsic scales. No patterns of fluorescein angiography are pathognomonic for choroidal melanoma. Although CTand MRI are not widely used in the assessment of uncomplicated intraocular melanocytic tumors, these modalities are useful in identifying tumors in eyes with opaque media and in determining extrascleral extension and involvement of other organs.

MRI may be helpful in differentiating atypical vascular lesions from melanocytic tumors.

Differentia l Di agnosis The most common lesions that should be considered in the differential diag nosis of posterior uveal melanoma include suspicious choroidal nevi, disciform macular and extramac-

ular lesions, congenital hypertrophy of the RPE (CHRPE), choroidal hemangioma (see Chapter 18), melanocytoma, hemorrhagic detachment of the choroid or RPE, metastatic

Figure 17·9 Trans illuminat ion (T I) of th e eye shows the shadow of a choroidal melanoma (decreased TI throu gh t he ·tumor). ThiS technique may be used to mark the tumor base to ensure accurate placemen t of the radioact ive plaque.

278 • Ophthalmic Pathology and Intraocular Tumors Table

17-2

Differential Diagnosis of Amelanotic Choroida l Mass Amelanotic melanoma Choroidal metastas is Choroidal hemangioma Choroidal osteoma Sclerochoroida l calc ificat ion Age-related macular or extramacular degeneration Choroidal detachment Posterior scleritis Chorioretinal granuloma Neurilemoma Leiomyoma

Modified from Shields JA, Shields CL. Differentia l diagnosis of posterior uveal melanoma. In: Shields JA, Sh ields Cl. Intraocular Tumors: A Text and At/as. Phi ladelphia: Saunders; 1992:137-153.

carcinoma (see Chapter 20), and choroidal osteoma. Table 17-2 offers a more complete list to be considered in cases with ameLanotic choroidal masses. Choroidal nevus has been discussed previously, but it should be reemphasized that no single clinical characteristic is pathognomon ic of choroidal melanoma. Diagnostic accuracy is associated with clinical experience and outstanding ancillary testing facilities. Evaluation and management of these complex cases within regional ocular oncology referral centers appears to enhance patient outcome. Age-related macular degeneration (AMDJ may present with extramacular or macular subretinal neovascularization and fibrosis accompanied by varying degrees and patterns of pigmentation. Hemorrhage, a common finding associated with disciform lesions, is not commonly seen with melanomas unless the tumor extends through the Bruch membrane. Clinical evaluation of the fellow eye is important in documenting the presence of degen erative changes in AMD. Fluorescein angiography results are virtually pathognomonic, revealing early hypofluorescence secondary to blockage from the hemorrhage, often fol lowed by late hyperfluorescence in the distribut ion of the choroidal neovascular membrane. Ultrasonographic testing may reveal increased heterogeneity and a lack of intrinsic vascularity on standardized A-scan. Serial observat ion wi.ll document involutional alterations of the evolving disciform lesion. CHRPE is a well-defined, flat, darkly pigmented lesion ranging in size from 1 mm to greater than 10 mm in diameter. Patients are asymptomatic. and the lesion is noted during ophthalmic exam ination, typically in patients in their teens or twenties. In you nger patients, CHRPE often appears hom*oge neo usly black; in older indi viduals, foci of depigmentation (lacunae) often develo p (Fig 17-10). The histology is identical to a condition known as grouped pigmentation of the retina, or bear tracks (Fig 17 -I I ). The presence of multiple patches of congenital hypertrophy in family members of patients who have Gardner syndrom e, a fam ilial polyposis, appears to be a marker fo r the development of colon carcinoma. Fundus findings enable the ophthalmologist to help the gastroenterologist determine the recommended frequency of colon carcinoma screening in family members (see Chapter 1I). Melanocytoma (magnocellular nevus) of the optic disc typically appears as a dark brown to black epipapillary lesion, often with fibrillar margins as a result of extension into

CHAPTER 17:

Melanocytic Tum ors. 279

Figure 17-10 Congenital hypertrophy of the RPE (CHRP E). Examples of varying clinical appearances. A, CHRPE. Note the hom*ogeneous black color and well-defined margins of the nummular lesion. B, Two lesions of CHRPE in the nasal periphery of the fundus. C, D, Color fundus photograph and corresponding fluorescein angiogram of a large CHRPE. Note foca l

loss of RPE archit ecture and pigmentation (lacunae) in part C and visible choroi dal vasculature

in pa rt D.

(Part B courtesy of Jacob Pe'er. MD; parts C and 0 courtesy of Timothy G. Murray, MO.)

Bear tracks . Grouped pigmentation of the retina/RPE represents a forme fruste

Figure 17·11

of CHRPE. Note the distinct bear track configuration (circfe) and increased pig mentati on.

th e nerve fibe r layer (Fig l 7- 12; see also Chapter l S, Fig 15-12). It is usuaUy located eccentricaUy over the optic di sc and may be elevated. It is important to differentiate this lesion from melanoma, beca use a melanocytoma has mi nimal malignant potential. Studies have shown that about one-thi rd of optic disc melanocytomas have a peripapillary nevus component and that 10% of cases will show min imal but definite growth over a S-year period. In addition, these lesions can produce an afferent pupillary defect and a va ri ety of visual field abnormalities, ranging from an enlarged blind spot to extensive nerve fibe r layer defects. Suprachoroidal detachments present in 2 form s: hemorrhagic and serous. These lesions are often associated with hypotony and may present in the im mediate period after

280 • Ophtha lmic Pat ho logy a nd Int raoc ul a r Tumors

A Figure 17-12

Melanocytoma of the optic disc. Note varying clinical appearance in these 2 ex-

amples based on degree of choroidal pigmentation: lesion in IAI darkly pigmented fundus and (BJ lightly pigmented fund us. (Part B courresyof Timothy G. Murray, MO.)

ophthalmic surgery. Cli nically, hemorrhagic detachments are often dome -shaped, they involve m ultiple quadrants, and th ey are associated with breakth rough vitreous bleeding. A- and B-scan ultrasonography readings may closely resemble those of melanoma bu t show an absence of intrinsic vascu larity and an evolution of the hemorrhage over time. Observational managernent is indicated in most cases. MRI with gadolin ium enhancement may be of benefit in selected cases to document characteristic alteratio ns. Choroidal osteomas are ben ign bon y tumors that typi call y arise from th e juxtapapillary choroid in adolescent to young adult patients (more com monly in women tha n men ) and are bilateral in 20%-25% of cases. T he characte ristic lesion appea rs yellow to orange, and it has well -defined margins (Fig 17-13). Ultraso nography reveals a high-amplitude echo correspondi ng to t he plate of bone and loss of the nor mal orbital echoes behi nd the lesion . T hese tu mors can also be seen on CT; their hallma rk is calcifica tion. Choroidal osteo mas typica ll y enlarge slowly ove r many years. If th ese lesions involve the macula, vision is generally impaired. Suhretinal neovascularization is a common complicat ion of mac ul ar choroidal osteomas. The etiology of th ese lesions is unkn own, but ch ronic lowgrade choroidal inflammation has been suspected in some cases (see Chapter 12).

Figure 17-1 3

Cho roidal osteom a, cl inical ap-

pearance. Note the yellow-ora nge color, welldefined pseudopod-like margins (arrows), and characteristic spotted pigmentation on the surface of this circumpapillary tumor.

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Melanocytic Tumo rs.

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Classification Mel anomas of the ciliary body and choroid have been categori zed by size in a number of di ffe rent ways. Although a size classification based on tumor volu me is logical, no simple an d reliable method for assessing tumor volume is cu rren tly available. The comm on practice of estimating tumor volume by multiplying maximal basal diameter, minimal basal diameter, and thickness yields only a crude assessment of actual tumor size. The Collaborative Ocular Melanoma Study (COMS) classifi ed posterior uveal melanomas as small, medi um, or large based on maxim al thickn ess and basal di am eter. Recently revised guideli nes developed by the American loint Comm ittee on Cancer (AICC) merge clinical and pathologic features of ciliary body and choroidal melanomas for staging. See the staging fo rm in the appendix for the AICC defin itions and staging.

Metastatic Evaluation In a study by Kujala and colleagues, the incidence of metastatic uveal melanoma was observed to be as high as 50% at 25 years after treatment for choroidal melanoma. The COMS reported an incidence of metastat ic disease of 25% at 5 years after in itial treatment and 34% at 10 years. Nevertheless, clinica ll y evident metastatic disease at the time of ini tial presentation can be detected in less than 2% of patients. Currently, it is hypothesized that many patients have undetectable micrometastatic disease at the time of their pri ma ry treatment. Despite the great acc uracy that has been achieved in diagnosing uveal melanoma, mortality owing to this tumor has not changed Significantly for many years. In general, survival with metastatic uvea l melano ma is poor, with a median survival of less than 6 months, although early detectio n and prompt treatment of liver metastases can in crease survival time significantly. The liver is the predominant organ involved in metastatic uveal melanoma. Liver involvement also tends to be the first manifestati on of metastatic disease. In the presence of liver involvement, lung, bone, and skin are other sites that may be affected. An assessment of metastatic disease patterns in the CO MS revealed liver involvement in at least 90% of patients, lung involvement in 25%, bo ne involve ment in nearly 20%, and skin and subcutaneous tissue involvement in approximately 10%. In cases that were autops ied, liver involvement was found in 100% and lung involvement in 50% of the patients with metastatic disease. All patients require metastatic evaluat io n prior to definit ive treatment of the intraocular melanoma (Table 17-3). The purpose of th is evaluation is twofold: l. To determ ine whether the patient has any other medical conditions that contrain-

dicate surgical treatmen t or need to be amel iorated before surgery. For example, in one small series, 15% of the patients had a second malignancy at the time of presentation or during the course of a IO-year follow-up; the COMS found preexisting independent primary cancers in approximately 10% of patients. If there is any question whether the lesion in th e eye is a metastatic tumor, this possibility must be ruled out with a thorough medi cal evaluati on directed at determining the site of primary malignancy. 2. To rule out the possibility of detectable metastati c melanoma from the eye. Only rarely is metastatic disease from uveal melanoma detectable at the tim e of initia l

282 • Ophthalmic Pathology and Intraoc ula r Tumors Table 17-3 Clinical Evaluation of Metastatic Uveal Melanoma liver imaging-ultrasonography in routine evaluation

• liver function tests • Chest x-ray

If any of the above are abnormal: Triphasic liver CT CT-PET of the abdomenlchest MRI of the abdomen/c hest

prese ntation. If metastatic disease is clinically present during the pretreatment evaluation of the eye tumor, enucleation is inappropriate unless th e eye is painful. To detect metastatic disease of uveal melanoma at an early stage, metastatic evaluation should be performed on all patients o n a yearly follow-up basis, and some centers ,,,,ill do so every 6 month s. Metastatic evaluation should include a comprehensive physical examination. Liver imaging studies are probably the most impo rtant com ponent of the metastatic evaluation. Ultrasonography of the abdomen is usually sufficient, but when a suspicion of metastatic disease is raised , triphasic CT, MRI, or PET-CT is usu ally recommended in order to evaluate the extent of the disease. Liver fu nction tests are usually perfor med; however, in recent yea rs, they have become less reliable in the evaluation of live r metastases, because of the com mon use of cholesterol-loweri ng statins, which may alter liver enzyme levels. Chest x-ray is also usually performed, although its yield was found to be low. Recently, research has been performed in several centers investigating possible blood markers for ea rl y detection of metastatic uveal melanoma. A live r or other organ site biopsy may be confirmatory of metastati c d isease and is appropriate befo re the institution of any treatment for metastatic di sease. The interval between the diagnosis of pri mary uveal melanoma an d its metastasis depends on var io us clinical, histopathologic, cytogenetic, and molecular genetic factors. It varies from 1- 2 years to over 15- 20 years. When metastatic di sease is diagnosed early enough, before developing miliary spread, th e options for treatment of the metastasis, mainly liver metastasis, include surgical resection; chemotherapy, includin g intra-arterial hepatic chemot herapy and chemoembolization; and immunotherapy. Kaiserman I, AlTIer R, Pe'er J. Liver function tests in metastatic uveal melanoma. Am JOphthalmol. 2004;137(2);236-243.

Treatment Ma nage ment of posterior uveal melanomas has long been the subject of considerabl e controversy. Two factors lie at the heart of th is co ntroversy; 1. the li m ited amount of data on the natural histo ry of untreated pati ents with posterior uveal melanoma

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2. thelack of groups of patients matched for known and for unknown risk facto rs and managed by di fferent therapeutic techniques to assess the comparative effectiveness of those treatments In 1882, Fuchs wrote that all intraocular melanomas we re treated by enucleation and the only untreated cases were in the "older literature:' Currently, both surgical and radiotherapeutic managernent are used for intraoc ular melanoma. The COMS has reported randomized, prospectively adm inistered treatment outcomes for patients wit h medium and large choro idal melanomas. The methods of patient management in use at th is tim e depend on several fac tors: size, location, and extent of the tumor visual status of the affected eye and of the fellow eye age and general health of the patient

Observation In certain instances, serial observation witho ut treatment of an int raocular tu mor is in di cated. Most types of benign retinal an d choroidal tumors, such as choroidal nevi, choroidal osteoma, an d hyper plasia of the RPE, can be managed with observation. Growth of small melanocytic lesions of the posterior uvea that are 1 mm or less in thickness can be documented periodicall y by fundus photogra phy and ultrasonograph y. Significant controversy persists regard ing the management of small choroidal mela nomas. Lesions greater than I mm in thickness, with documented growth , should be considered for definitive treatment. Observation of active larger tumors may be appropriate in el derly and systemica ll y ill patients who are not candidates for any sort of therapeutic intervention.

Enucleation Historically, enucleat ion has been the gold standard in the treatment of rnalignant intraocular tumors. Although some aut hors in the past hypotheSized that surgical manipulatio n of eyes containing melanoma leads to tumo r dissemination and increased mortali ty, this hypotheSiS is no longer accepted, and enucleatio n remains appropria te fo r some mediumsized, many large, and all extra-large choroidal melanomas. The COMS compared the applicatio n of pre-enucleation external-beam rad iation therapy followed by enucleation with enucleation alone for patients with la rge choroidal melanomas and fo und no statistically significant survival difference in 5-year mortality rates. Enucleation remains one of th e most common primary treatments for choroidal melanoma .

Brachytherapy (radioactive plaque) The application of a radioactive plaque to the sclera overlying an intraocular tumor is probably the most com mon method of treating uveal melanoma. It allqws th e delivery of a high dose of radiat ion to the tumor and a relatively low dose to the surro unding normal structures of the eye. The technique has been available since the 1950s. Al th ough various isotopes have been used (eg, strontiu m 90, iridiu m 192, and palladiu m 103), the most

284 • Ophthalmic Pathology and Intraocular Tumors common today are iodine 125 and ruthenium 106. Cobalt 60 plaques, which were the main source for brachytherapy in the past, are rarely used today. In the United States, 1251 is the isotope most frequently used in the treatment of ciliary body and choroidal melanomas. Advances in intraoperative localization, especially the use of ultrasound, have increased local tumor control rates to as high as 95%. In most patients, the tumor decreases in size (Fig 17-14); in others, the result is total flattening of the tumor with scar formation or no change in tumor size, although clinical and ultrasound changes can be seen. Regro,,1h is diagnosed in only about 10% of the treated tumors. Late radiation complications, especially optic neuropathy and retinopathy, are visually limiting in as many as 50% of patients undergoing treatment. Radiation complications appear dose -dependent, and they increase for tumors involVing, or adjace nt to, the macula or optic nerve.

Charged-particle radiation High-linear-energy transfer radiation with charged particles (protons and helium ions) has been used effectively in managing ciliary body and choroidal melanomas. The tech nique requires surgical attachment of tantalum clips to the sclera to mark the basal margins of the tumor prior to the first radiation fraction. The charged-particle beams deliver a more hom*ogeneous dose of radiation energy to a tumor than does a radioactive plaque, and the lateral spread of radiation energy from such beams is less extensive (Bragg peak effect) . Local tumor control rates of up to 98% have been reported. The response is similar to that seen after brachytherapy. Unfortunately, charged-particle radiation often delivers a higher dose to anterior segment st ructu res. Radiation complications, most commonly anterior, lead to uncontrolled neovascular glaucoma in 10% of treated eyes and vision loss in approximately 50%.

A Choroid al melanoma treat ed by rad ioact ive brachyth erapy. A, M ildly elevated remnants of me lanoma surrounded by at rophic cho r ioretin al scarring, na sal t o th e opti c nerve head. B, Flat rem nant s of me lanoma pig mentation surround ed by chorioretin al scarring loca t ed t empora l to the macu la. (Courtesy of Jacob Pe'e r, MD)

Figure 17·14

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External-beam radiation Conventional external- beam radiation therapy is ineffective as a single-modality treatment for melanoma. Pre· enucleation external-beam radiotherapy combined with enucleation appears to limit orbital recurrence in large melanomas and showed a non-statistically significa nt reduction in 5-year mortality in the COMS large-tumor trial. In recent years, several centers have used fractionated stereotactic radiotherapy and gamma knife radiosurger y, reporting good results. Cataract may develop following all types of radiotherapy. Surgical removal of radiation -i nduced cataract is indicated if the intraocular tumor is nonviable and the patient appears to have visual limitations attributab le to th e cataract. No increase in mortality after cataract extraction has been documented.

Alternative treatments Photoablation and hyperthermia Laser photocoagulation has played a limited role in the treatment of melanocytic tumors. Reports of focal/grid laser treatment to eradicate active su bretinal fluid in choroidal melanoma have documented a propensity for accelerated tumor growth with rupture of the Bruch membrane. Advances in the delivery ofhyperthermia (heat) using transpupillary thermotherapy (TTT) have been reported. Direct diode laser treatment usi ng long duration, large spot size, and relatively low-energy laser has been associated with a reduction in tumor volume. Some reports have suggested that TTT is associated with an increased rate of local tumor recurrence compared w-ith brachytherapy. Cryotherapy Although cryotherapy using a triple freeze-thaw tech nique has been tried in the treatment of small choroidal melanomas, it is not considered standard therapy and is not currently undergoing further evaluation for efficacy. Transscleral diathermy Diathermy is contraindicated in th e treatment of malignant intraocular tumors because the induced scleral damage may provide a route for extrascleral extension of tumor cells. Surgical excision of tumor Surgical excision has been performed successfully in many eyes with malignant and benign intraocular tumors. Concerns regarding surgical excision include the inability to evaluate tumor margins fo r residual disease and the high incidence of pathologically recognized scleral, retinal, and vitreous involvement in medium and large choroidal melanomas. When this treatment is used, the surgical techniques are generally quite difficult, requiring an experienced surgeon. In some centers, local excision of uveal melanoma has been coupled with globe-conserving radiotherapy, such as brachyth erapy. Chemotherapy Currently, chemotherapy is not effective in the treatment of primary or metastatic uveal melanoma. Vario us reg imens have been used, however, for palliative treatment of patients with metastatic disease. Immunotherapy Immunotherapy uses systemic cytokines, immunomodulato ry agents, or local vacci ne therapy to try to activate a tumor-d irected T-cell immu ne response. This treatment may be appropriate for uveal melanoma, because pri mary tumors arise in an

286 • Ophthalmic Pathology and Intraocular Tumors

immune-privileged organ and may express antigens to which the host is not sensitized. Currently, however, immunotherapy for primary uvea l melanoma is not available, and immunotherapy for metastatic disease is still under investigation. Exenteration Exenteration, traditionally advocated for patients with extrascleral exten-

sion of a posterior uveal melanoma, is rarely employed today. The current trend is toward more conservative treatment for these patients, with enucleation plus a limited tenonectomy. The addition of local radiotherapy appears to achieve survival outcomes sim il ar to those of exenteration. Bergman L, Nilsson B, Lundell G, Lundell M, Seregard S. Ruthenium brachytherapy for uveal melanoma, 1979-2003: survival and funct ional outcomes in the Swedish population. Oph thalmology 2005; 112(5);834- 840. Damato B, Jones AG. Uveal melanoma: resection techniques. Ophthalmol Clin North Am. 2005;18(1),1 19- 128. Diener-West M, Earle JD, Fine SL, et a1. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, Ill: initial mortality findings. COMS report no. 18. Arch Ophthalmol. 2001;119(7);969-982. Hawkins BS; Collaborative Ocular Melanoma Study Group. The Collaborative Ocular Mela noma Study (COMS) randomized trial of pre-enucleation radiation oflarge choroidal melanoma: IV. Ten-year mortality findings and prognostic factors. COMS report no. 24: Am J Ophthalmol. 2004; 138(6);936- 951.

Prognosis and Prognostic Factors

A meta-analysis from the published literature of tumor mortality after treatment documented a S-year mortality rate of 50% for large choroidal melanoma and 30% for mediumsized choroidal melanoma; 5-year melanoma-related mortality in treated patients with small choroidal melanoma has been reported to be as high as about 10%. Retrospective analysis of patients with melanoma suggests that clin ical risk factors for mortality are la rge r tumor size at time of treatment tumor growth anterior tumor location (eg, ciliary body) extraocular extension older age tumor regrowth after globe-conserving therapy • rapid decrease in tumor size after globe-conserving therapy juxtapapillary tumors HistologiC and molecular features associated with a higher rate of metastases include epithelioid cells high mitotic index and high cell proliferation indices extracellular matrix patterns (loops, networks of loops, and parallel with crosslinking) /~--mean of 10 largest nuclei

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tu mor-in fi lt ratin g lymphocytes monosomy 3 trisomy 8 gen e expression profiling (class I and ciass II ) A more in-depth discussion is p rovi ded in Chapter 12. Harbour JW. Mol ecul ar prognosti C testing and individua lized patient care in uveal melanoma . Alii J Ophtlwllllol. 2009; 148(6);823- 829. Sh ields el, Furuta M, Thangappan A, et al. Metastasis of lIvea l melanoma millimeter-bymillim eter in 8033 consecutive eyes. Arch Ophtha/mol. 2009;127(8):989-998 . Sisley K, Renni e IG, Parsons MA, et al. Abnormal iti es of chromosomes 3 and 8 in posterior lIvea l melanoma correlate with prognosis. Gerles Chromosomes Ca ncer. 1997;19(1):22 -28.

Collaborative Ocular Melanoma Study (COMS)

Survival data from the COMS have been reported for th e ran do mi zed clinical trials of la rge and med ium choroidal melanoma a nd for th e observa tional study of small choroi dal melano ma. These resu lts provide the framewo rk fo r patie nt di scussions concerni ng treatme nt- related long-term survival, rates of globe co nse rva tion with 125 1 brachytherapy, and pred ictors of small-tumor growth. COMS La rge Cho ro idal Melanoma Trial evaluated 1003 patients with choroidal melanomas greate r than 16 m m in basal diam eter andlo r greater than 10 mm in apical height compared enucleation alone with enucleation preceded by exte rnal-beam radi ot herapy reported no statistically Significant d iffe rence in 5-yea r survival rate between co horts (approXimately 60%) concl ud ed that adj uncti ve radiotherapy did not im prove overall survival established the appropriateness of primary enucl ea tion alone in managing large cho ro idal mela nomas that are not a me nab le to globe-conserving th erapy COMS Med ium C horoidal Melanoma Tri al evaluated 1317 patients with choroidal melanomas ranging in size fro m 6 mm to 16 m m in basal d iameter andlor 2.5 m m to 10 m m in apical height co rn pa red stan dardi zed enucleation and 125 1 brachyth erapy aU -cause mo rtality at 5 years: no Significant diffe ren ce between cohorts (approxi mately 20%) histologicall y confirmed metastases at 5 years found in app roxi mately 10% of pati ents in both co horts secondary finding in enucleated eyes: -on ly 2/660 en ucl eated eyes misdiagnosed as hav ing a choroida l melanoma seco ndary findings in patients undergo ing brachyth erapy: - 10% local tum or recurrence at 5 years - 13% risk of enucieation after brachytherapy at 5 years

288 • Ophthalmic Pathology and Intraocular Tu mors -local tumor recurrence weakly associated with a reduced survival - decline in visual acuity to 20/2 00 in approximately 40% of patients at 3 years - quadrupling of the visual angle (6 lines of visual loss) in approximately 50% of patients at 3 years COMS Small Choroidal Tumor Trial observational study of 204 patients with tumors measuring 4.0- 8.0 mm in basal diameter and/or 1.0- 2.4 mm in apical height melanoma -specific mortality 1% at 5 years

clinical growth factors included - greater initial thickness an d basal diameter - presence of orange pigmentation

- absence of drusen and/or retinal pigment epithelial changes - presence of tumor pinpoint hypertluorescence on angiography Detailed findings of the COMS can be found at www.jhu.edu/wctb/coms.

Pigmented Epithelial Tumors of the Uvea and Retina Adenoma and Adenocarcinoma Benign adenomas of the nonpigmented and pigmented ciliary epithelium may appear indistinguishable clinically from melanomas arising in the ciliary body. Benign adenomas of the RPE afe very rare. These lesions occur as oval, deeply melanotic tumors arising

abruptly from the RPE. Adenomas rarely enlarge and seldom undergo malignant change. Adenocarcinomas of the RPE are also ve ry [afe; only a few cases have been reported in the

literature. Although these lesions have malignant features histologically, their metastatic potential appears to be minimal.

Fuchs adenoma (pseudoadenomatous hyperplasia) is usually an incidental finding at autopsy and rarely becomes apparent clinically. It appears as a glistening, white, irregular tumor arising from a ciliary crest. H istologically, it consists of benign proliferation of the nonpigmented ciliary epithelium w ith accumulation of basem*nt membrane-like material.

Acquired Hyperplasia Hyperplasia of the pigmented Ciliary epithelium or the RPE usually occurs in response to trauma, inflammation, or other ocular insults. Ciliary body lesions, because of their location, often do not become evident clin ically. Occasionally, however, they may reach a large size and simulate a ciliary body melanoma. Posteriorly located lesions may be more commonly recognized and can lead to diagnostic uncertainty. In the early management of

these atypical lesions, observation is often appropriate to document stability of the lesion. Adenomatous hyperplasia, which has been reported only rarely, may clinically mimic a choroidal melanoma.

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Combined Hamartoma Combined hamartoma of the RPE and retina is a rare disorder that occurs most frequently at th e disc margin. Typ ically, it appe ars as a darkly pigmented, minimally elevated lesion with retinal traction and tortuous retinal vessels (Fig 17-15). Glial cells within this lesion may contract, producing the traction lines seen cl in ically in the retina. Exudative complications associated with the vascular com po nent of the lesion may be observed. This lesion has been mistaken for melanoma because of its dark pigmentation and slight elevation. In rare cases, a combined hamartoma may be situated in the peripheral fundus. Shields CL, Thangappan A, Hartzell K, Valente P, Pirondini C, Shields jA. Combined hamartoma of the retina and retinal pigment epithelium in 77 consecutive patients' visual outcome based on macular versus ext ra macular tumor location. Ophthalmology. 2008; 115(1 2):2246-2252.

c Figu re 17-15

Peripapillary combined hamartoma of the retina and RPE. A. Fundus photograph

showing obscuration of the retinal vessels in superi?r aspect of the optic disc, pigmentation, retinal striae (arrow). and hard exudates. B. Fluorescein angiogram (19.7 sec) showing the vascular component of this lesion composed of small capillary-like telangiectatic vessels. Note

the relative hypofluorescence superior to the optic disc due to the RPE component of th is lesion. C, Late fluorescein angiogram (1 Tmln) showing diffuse late fluorescein leakage in the distribution of the lesion. (Courtesy of Robert H. Rosa, Jr. MD)

CHAPTER

Angiomatous Tumors

Hemangiomas Choroidal Hemangiomas Hemangiomas of the choroid occur in 2 specific forms: circ*mscribed and diffuse. The circ*mscribed choroidal hem angioma is a benign vascular tumor that typically occurs in patients with no syste mic disorders. It generally appears as a red or orange tumor lo cated

in the postequatorial zo ne of the fundus, ofte n in the macular area (Fig 18- 1). Such tumors com mo nly produce a secondar y retin al detachment that extends into the foveal region. resul tin g in blurred vis ion, metamorphopsia, and micropsia. These tumors characteristi -

call y affect the overlying ret inal pigment epitheliu m (RPE) and cause cysto id degeneration of the outer retinal laye rs.

Figure 18-1 A, Circ*mscribed choroidal hemangioma (arrows). B, A-scan ultrasound study shows characteristic high internal reflectivity (arrow). C, B-scan ultrasound study shows a highly reflective tumor (asterisk).

291

292 • Ophthalmic Patho logy and Intraocular Tumors

The principal entities in the differential diagnosis of circ*mscribed choroidal hemang ioma include amelanotic choroidal melanoma choroidal osteoma • metastatic carcinoma to the choroid granuloma of the choroid

The diffuse choroidal hemangioma is generally seen in patients with Sturge-Weber syndrome (encephalofacial angiomatosis). This choroidal tumor produces diffuse reddish orange thickening of the entire fun dus, resulting in an ophthalmoscopic pattern com monly referred to as tomato ketchup fundus (Fig 18-2). Retinal detachment and glaucoma often occur in eyes with this lesion. See also Chapter 12 in this volume, BCSC Section 12, Retina and Vitreous, and BCSC Section 6, Pediatric Ophthalmology and Strabismus. Ancillary diagnostic studies may be of considerable help in evaluating choroidal hemangiomas. Fluo rescein angiography reveals the large choroidal vessels in the prearterial or arterial phases with late staining of the tumor and the overlying cystoid retina. Ultrasonography is helpful in differentiating choroidal hemangiomas fro m amelanotic melanomas and other simulating lesions. A-scan ultrasonography generally shows a highamplitude initial echo and high-amplitude broad internal echoes (high inte rnal reflectivity; see Fig IS-IB). B-scan ultrasonography demonstrates localized or diffuse· cho roidal thickening with prominent internal reflections (acoustic heterogeneity) without choroidal excavation or orbital shadowing (see Fig IS-IC). Radiographic studies, particularly CT scanning, can be helpful in differentiating a choroidal hemangioma from a choroidal osteoma. Asymptomatic choroidal hemangiomas require no treatment. The most common complication of both circ*mscribed and diffuse choroidal hemangiomas is serous detachment of the retina involving the fovea, with resultant vision loss. Traditionally, circ*mscribed choroid al hemangiomas have been managed by laser photocoagulation. The surface of the tumor is treated lightly with laser photocoagulation to create chorioret inal adhesions that prevent further accumulation of subretinal fluid. If the retinal detachment is extensive, photocoagulation is often unsuccessful. Recurrent detachments are common, and the long -term visual prognosis in patients with macular detachment or edema is guarded. Laser photocoagulation has recently been replaced by photodynamic therapy (PDT) as the primary treatment for symptomatic circ*mscribed choroidal hemangioma. PDT involves an intravenous infusion of verteporfin (6 mg/m2), which is followed by an application of diode laser (6S9 nm) IS minutes later at a light dose of 50-100 )/cm 2 for a duration of SO-1 70 seconds. Some authors have reported resolution of the subretinal fluid, improvement in visual acuity, and regression of the lesion with this treatment. Radiation, in the fo rms of brachytherapy, charged-particle, and external beam, has been used to treat choroidal hemangiomas. Brachytherapy and charged-particle therapy have been used to treat patients with ci rc*mscribed choroidal hemangioma, and externalbeam radiotherapy (low dose, fract ionated) has been used to treat patients with diffuse choroidal hemangioma. Each modality has been repo rted to cause involution of the

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B Figure 18-2 Choroi dal hemangioma , diffuse type, clinica l appea rance. The saturated red color of t he affected fundus IAI cont rasts marked ly with th e co lor of the unaffected fundus IBI of the sa m e pat ient.

hemangiomas, with subsequent resolution of the associated serous retinal detachment. Complications from the radiation and the serous retinal detachment may limit vision in patients who are irradiated. To date, little data have been published to support the use of vascular endothelial growth factor (VEGF) inhibitors in the treatment of choroidal hemangiomas. Boixadera A, Garda-Arumi J, Martinez-Castillo V, et al. Prospective clinical trial evaluating the efficacy of photodynamic therapy for symptomatic circ*mscribed choroidal hemangi oma. Ophthalmology. 2009;116(1 ): 100-105.

294 • Ophthalmic Pathology and Intraocular Tum ors

Retinal Angiomas

Capillary hemangioblastoma Retinal capillary hemangioblastoma (an gio matosis retinae, previously knovm as retinal capillary hemangioma) is a rare autosomal dominant condition with a reported incidence of 1 in 40,000. Typically, patients are diagnosed in the second to third decades of life, although retinal lesions may be present at birth. The retinal capillary hemangioblastoma appears as a red to orange tumor ad sing within the retina with large-caliber, tortuous afferent and efferent retinal blood vessels (Fig 18-3). Associated yellow-white retinal and subretinal exudates that have a predilection for foveal involvement may appear. Exudative detachments often occur in eyes with hemangioblastomas. Atypical variations include hemangiomas arising from the optic disc, which may appear as encapsulated lesions with or without pseudopapilledema, and in the retinal periphery, where vitreous traction may elevate the tumor from the surfa ce of the retina, giving the appearance of a free-floating vitreous mass. Fluorescein angiograph y of retinal capillary hemangioblastomas demonstrates a rapid arteriovenous transit, with immediate filling of the feeding arteriole, subsequent filling of the numerous fine blood vessels that constitute the tumor, and drainage by the dilated venule. Massive leakage of dye into the tumor and vitreous can occur. When a capillary hemangioblastoma of the retina occurs as a solitary finding, the condition is generally known as von Hippel disease. This condition is familial in about 20% of cases and bilateral in about 50%. The lesions may be multiple in I or both eyes. If retinal capillary hemangiomatosis is associated with a cerebellar hemangioblastoma, the term von Hippe/- Lindau syndrome is applied. The gene for von Hippel-Lindau syndrome has been isolated on chromosome 3. A number of other tumors and cysts may occur in patients with von Hippel- Lindau syndrome. The most important of these lesions are cerebellar hemangioblastomas, renal cell carcinomas, and pheochromocytomas. Genetic screening now allows for subtyping of patients w'ith von Hi ppel-Lindau to determine the

Figure 18-3 Retinal capillary hemangioblastoma . A, Note the dilated, tortuous retin al ve ssels (fee der artery and draining vein) emanati ng from t he optic disc. B, These tumors may be located anywhere in th e fundus and may exhibit red , orange, or yellow colorat ion. (Courtesy of Robert H. Rosa, Jr, MD. )

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Ang iomatous Tum ors.

295

risk for systemic manifestation s of the disease. W hen this diagnosis is suspected, appropriate genetic consultation and screening are critical for long -term follO\v-up of ocular manifestations and the associated systemic complications. Screening fo r systemic vascu lar anomalies (eg, cerebellar hemangioblastomas) and malignancies (eg, renal cell carcinoma ) may reduce mortality, while aggressive screening for and early treatment of retinal hemangioblastomas may reduce late complications of exudative detachment and improve long -term vis ual outcomes. The treatmen t of reti nal capillary he mangioblastomas includes photocoagulation for smaller lesions, cryotherapy for larger and more peripheral lesions, and scleral buckling with cryotherapy or penetrating diathermy fo r extremely large lesions with extensive retinal detachment. Exte rnal-beam and charged-particle radiotherapy have also been used. More recently, PDT has been used successfully to treat retinal capillary hemangioblastomas. Standard verteporfin dosing coupled with both standard and modified photodynamic protocols resulted in fibrosis of the hemangiomas with secondary retinal traction and improved visual acuity in recent studies. Recent case reports have suggested the utility of targeted antiangiogenic therapy in the management of retinal capillary hemangioblasto mas. The efficacy of antiangiogenic agents in the treatment of these vascular lesions is of compelling interest to von Hippel Lindau patients, who have a lifelong risk of developing retinal angiomas. Both systemic and intravitreal VEGF inhibitors have been used. Reports to date suggest that the principal efficacy of VEGF inhibitors is in reducing macular edema. T he impact on the actual size of the hemangiomas has been variable. Thus, the visual prognosis remains guarded for patients with la rge retinal lesions. Cavernous hemangioma Cavernous hemangioma of the retina is an uncommon lesion that resembles a cluster of grapes (Fig 18-4) . Lesions may also occur on the optic disc. Cavernous hemangiomas may be associated with similar skin and central nervous system lesions. Patients with intracranial lesions may have seizures. In contrast to Coats disease and retinal capillary hemangioblastomas, cavernous hemangiomas are generally not associated with exudation, and treatment is therefore rarel y required. However, small hemorrhages as well as areas of gliosis and fibrosis may appear on the surface of the lesion . Within the vascular spaces of the cavernous hemangioma, plasma- erythrocyte separation may appear that can best be demonstrated on fluorescein angiography. Fluorescein angiography is virtually diagnostic of cavernous hemangiomas of the retina. In contrast to a retinal capillary hemangioblastoma , a retinal cavernous hemangioma fills very slowly, and the fluorescein often pools in th e upper part of the vascular space, while the cellular elements (erythrocytes) pool in the lower part. The fluorescein remains in the vascular spaces for an extended period. Cavernous hemangiomas generally show no leakage of fluorescein into the vitreous. Histologically, a cavernous retinal hemangioma consists of dilated" th in -walled vascular channels. The dilated vessels may protrud e upward beneath the internal limiting membrane, and associated gliosis and hemorrhage may be seen.

296 • Ophthalmic Pathology and Intraocu lar Tumors

Reti nal cavernous hemangioma. A, Note multiple tiny vascular saccules and associated wh ite fi brovascular tissue. B, Note clumped vascular saccules (grape cluster configuration ). C, When lesions are small, findings may be subtle. (Part B courtesy of Timothy G. Murray, MD.)

Figure 18-4

Arteriovenous Malformation Congen ital retinal arteriovenous malformation (racemose hemangioma) is an anomalous artery-ta-vein anastomosis rangin g fro m a small , localized vascular com munication near

the optic disc or in the periphery to a prom inent tangle of large, tortuous blood vessels thro ughout most of the fu ndus (Fig 18-5). Racemose refers to the clustered or bunched natUfe of th e vessels. When associated with an arteriovenous malformation of the midbrain

region, this condition is generally referred to as Wyburn -Mason syndrome (see BeSe Section 5, Neuro-Ophthalmology, and Section 6, Pediatric Ophthalmology and Strabismus). Associated similar arteriovenous malformations may appear in the orbit and mand ible.

CHAPTER 18:

Angiomatous Tumo rs .

297

B Figure 18-5

Retinal arteriovenous malformation. A , Clinical appearance. B, Fluorescein angiogram showing absence of a capillary bed between the afferent and efferent arms of this retinal arteriovenous commun ication. Note the absence of fluorescein leakage, which is characteristic of this lesion. (Courres y of Robert H. Rosa, Jr, MD.)

CHAPTER

Retinoblastoma

Retinoblastoma is th e most common primary intraocular malignant tu mor of childhood, second only to uvea l melanoma as the most common primary intraocular malignant

tumor in all age gro ups (Table 19-1). The frequency of retinoblastoma ranges from 1 in 14,000 to I in 20,000 live births, dependi ng on the country. It is estimated that 250- 300 new cases occur in the United States each yea r. There is no sexual predilection, and the tumor occurs bilaterally in 30%-40% of cases. Approximately 90% of cases are diagnosed in patients you nger than 3 years. The mean age at diagnosis depends on family history and the laterality of the disease: patients with a known family history of retinoblastoma-4 months patients with bilateral disease- 12 mon ths patients with un ilateral disease- 24 months Geographic variat ion in the incidence of the d isease has been noted. In Mexico, 6.8 cases

per mil lion population have been reported compared to 4 cases per million in the United States. In Central America, there has been an increased incidence in recent years. The

highest incidence of the disease has been noted in Africa and India.

Genetic Counseling Retinoblastoma is caused by a mutation in the RBI tumor suppressor gene located on the long arm of chromosome 13 at locus 14 ( 13qI4). Both copies of the RBI gene must be mutated in order for a tumor to form. If a patient has bilateral retinoblastoma, there is approximately a 98% chance that it represents a germline mutation. Only about 5% of

Table 19-1 Epidemiology of Retinoblastoma Most co m mon primary intraocular cance r of childhood Third most common intraocular cancer overa ll after melanoma an d metastas is Incidence is 1/14,000-1/20,000 live births 90% of cases present before 3 yea rs of age Occurs equally in males and females Occurs equally in right and left eyes No racia l predilection 60%-70% un ilateral (mean age at diagnosis, 24 months ) 30%-40% bilateral (mean age at diagnosis, 12 months)

299

300 • Opht halm ic Pathology and Int raocula r Tumors retinoblastoma patients have a family history of retinoblastoma. The children of a retinoblastoma survivor who has the hereditary for m of retinoblastoma have a 45% chance of being affected (50% chance of inheriting and 90% chance of penetrance) . In these cases. the child inherits an abnormal gene from the affected parent. This abno rmal gene coupled with somatic mutations in the remaining normal RBi allele leads to the developmen t of multiple tumors in I or both eyes. Sporadic cases constitute approximately 95% of all retinoblastomas. Of these. 60% of patients have unilateral disease w ith no germline mutati ons. The remaini ng patients have new ger mline mutations and will develop multiple tumors. It should be noted that approx-

imately 15% of the sporadic unilateral patients are carriers of a germ li ne RBi mutatio n. Unless there are multiple tu mors in the affected eye. these patients cannot be distinguished from children without a germli ne mutation. Children with unilateral ret inoblastoma and a germline m utation, much like their coun terparts with bilateral retinoblastoma , are more

likely to present at an earlier age. Com mercial laboratories are available to test the blood of all reti noblastoma patients for germline mutations. Methods of genetic testing used in retinob lastoma screening include gene sequencing via quantitative polymerase chain reaction (PCR). karyotyping. fluorescent in situ hybridization (FISH). multiplex Iigationdepe ndent probe amplification (MLPA). and RNA analysis. There is approximately a 95% chance of finding a new mutation if one exists.

Genetic counseling for retinoblastoma can be very complex (Fig 19-1). A bilateral retinoblastoma sur vivo r has a 45% chance of having an affected ch ild , whereas a unilat-

eral survivor has a 7% chance of having an affected child. Normal parents of a ch ild with bilateral involvement have less than a 5% risk of haVing another child with retinoblastoma.

If parent:

Chance of offspring having retinoblastoma

Laterality

has bilateral retinoblastoma

has unilatera l retinoblastoma

55% unaffected

45% affected

7%-15% affected

is unaffected

85%-93% unaffected

Chance of next sibli ng having retinoblastoma

99% unaffected

/\ 1/\ 1/\ 1 A 1A

85% bilateral

15% unilateral

15%

85% bilateral

7\ral

Focality

« 1% affected

100% 96% 4% multi- multi - unifocal focal foca l

1 1 1

45%

100% 96% 4"/" multi - multi- un ifocal focal focal

1 1 1

45%

33%

67% unilateral

Teral

100% 15% 85% multi- multi- unifocal focal focal

, 0%

I111I

7%15%

5% " < 1% * < 1%"

-II parent is a carrier, then 45%

Figure 19-1

Genetic co unse lin g for ret inobl asto ma. (Chart created by David H. Abramson, MD.)

CHAPTER 19: Re tinoblastoma • 301

If 2 or more siblings are affected, the chance that another child will be affected increases to 45%. See also Chapter 11 in this volume and BCSC Section 6, Pediatric Ophthalmology and Strabismus. Abramson DH, Mendelsohn ME, Servodidio CA, Tretter T, Gombos DS. Familial retinoblastoma: where and when? Acta Ophthalmol Scand. 1998;76(3):334-338. Gallie BL, Dunn JM, Chan HS, Hamel PA, Phillips RA. The genetics of retinoblastoma: relevance to the patient. Pediatr Clin North Am. 1991 ;38(2):299-315 . Murphree AL. Molecular genetics of retinoblastoma. Ophthalmol Clin North Am. 1995;8: 155-166.

Diagnostic Evaluation Retinoblastoma is a clinical diagnos is. Fine-needle aspiration biopsy (Fl AB) should be undertaken only with extreme caution and only by an experi enced ocular oncologist, because of the risk of systemic dissemination of tumor.

Clinical Examination The presenting signs and symptoms of retinoblastoma are determined by the extent and location of tumor at the time of diagnosis. In the United States, the most common presenti ng signs of retinoblastoma are leukocoria (white pupillary reflex), strabismus, and ocular inflammation (Table 19-2; Fig 19-2). Other present ing features, such as iris heterochromia, spontaneous hyphema, and orbital celluli tis or inflam mation are uncommon. In rare instances, a small lesion may be found on routi ne exa mination . Visual complaints are infrequent because most patients are preschool-aged children. The di agnos is of retinoblasto ma can generally be suspected on the basis of an office examination with documented visual acuity. An examination under anesthesia (EUA) is needed in all patients suspected of having retinoblastoma to permit a complete assess ment of the extent of ocular disease prior to treatment (Fig 19-3). The intraocular pressure and

Table 19-2

Presenting Signs of Retinoblastoma

Among Patients <5 Years of Age

Among Patients ;::5 Years of Age

Leukocoria (",,60%) Strabismus (",,20%) Ocular inflammation (",,5%) Hypopyon Hyphema Iris heterochromia Spontaneous globe perforation Proptosis Cataract Gla ucoma Nystagmus Tea ring Anisocoria

Leukocoria (35%) Decreased vision (35%) Strabismu s (15%) Floaters (5%) Pain (5%)

302 • Ophthalmic Pathology and Intraocular Tum ors

Figure 19·2 Retinoblastoma . A, Clinical appearance shows leukocoria and strabismus associ· ated with advanced intraocular tumor. B, High magnifica tion . Note large retro lental tumor and secondary total exudative retinal detachment . (Courtesy of Tim othy G. M urray. M D)

Figure 19-3 Retinob lastoma. Multiple tumor foci in an eye of a patient w ith a germline RB 1 mutation . (Counesy of Marrhew W Wilson, MD.)

corneal diameter of both eyes should be measured intraoperatively. The location of all tumors in each eye should be clearly docu mented. Retinoblastoma begins as a translucent, gray to white intraretinal tumor) fed and drained by dilated, to rtuous retinal vessels (Fig 19-4). As the tumor grows, foc i of calci fication develop, giving the characteristic chalky white appearance. Exophytic tumors grow beneath the retina and m ay have an associated serous retinal detachment (Fig 19-5). As the tumor grows, the retinal detachment may become extensive, obscuring visualization of the tumor (Fig 19-6). Endophytic tumors grow on the retinal su rface into the vitreous cavity. Blood vessels may be difficult

Figure 19·4 Retinoblastoma, clin ical appearance . Small, discrete white tumor supplied by dilated retinal blood vessel s. (Courtesy of Timothy G Murray, M D.)

CHAPTER 19:

Figure 19-5 Retinoblastoma. Note the dilated retinal blood vessels, foc i of calcification

Retinoblastoma. 303

(arrow), and cuff of subretinal fluid (asterisk).

Figure 19-6 Retinoblastoma. Complete exudative detachment obscures tumor visualization. Note normal-appearing retinal vessels

(Counesy of Matthew W Wilson, MD.)

as opposed to those found in Coats disease. (Courtesy of Matthew W Wilson, MD.)

to discern in endophytic tumors. Endophytic tumors are more apt to give rise to vitreous seeds (Fig \9- 7). Cells shed fro m retinoblastoma remain viable in the vitreous and subretinal space and may eventually give rise to tumor implants througho ut the eye. Vitreous seeds may also enter the anterior chamber. where th ey can aggregate o n the iris to for m nodules or settle inferiorly to for m a pseudohypopyon (Fig \9-8). Secondary glaucoma and rubeos is iridis occur in approximately 50% of such cases. A rare va riant of retinoblastoma is the diffuse infiltrating retinoblastoma, wh ich is detected at a later age (> 5 years) and is typically un ilateral. Diffuse infiltrating retinoblastoma presents a diagnost ic di lemma, as the retina may be difficult to see through the dense vitreous cells. This varian t is often mistaken for an intermediate uveitis of unknown etiology. Ultrasonography can be helpful in the diagnosis of retinoblastoma by demonst rating characteristic calcifications within the tumor. Although these calcifications can also be seen on CT scan, MRI has become the preferred diagnostic modality for evaluating

Figure 19-7 Retinoblastoma. Large endophytic tumor with extensive vitreous seeding (arrows). (Courtesy of Matthew W Wilson, MD.)

Figure 19-8 Ret inoblastoma, cl inical appearance. Pseudohypopyon resulting from migration of tumor cells into the ante rio r chamber (masquerade syndrome).

304 • Ophthalmic Pathology and Intraocular Tumors

the optic nerve, orbits, and brain. MRI not only offers better soft-tissue resolution, but also avoids potentially harmful radiation exposu re. Recent studies have suggested that systemic metastatic eva luat ion, typica ll y bone marrow and lumbar puncture, is not indi cated in ch ildren with out neurologic abnormalities or evidence of extraocular extension. If optic nerve extension is suspected, lu mbar puncture may be performed. Parents and

siblings should be examined for evidence of untreated retinoblastoma or retinocytoma, as this would provide evidence for a hereditary predispositio n to the disease. Ch ildren with retinoblastoma should have a complete history and physical exami nation by a pediatric oncologist. In the United States, patients rarely present with metastases or intracranial extension at the time of diagnosis. The most frequently identified sites of metastatic involvement in children with retinoblastoma include skull bones, distal bones, brain, spinal cord, lymph nodes, and abdominal viscera. Retinoblastoma cells may escape the eye by invad ing the optic nerve an d extending into th e subarachnoid space. In addition , tumor cells may mas -

sively invade the choroid before traversing emissary canals or eroding throug h the sclera to enter the orbit. Extraocular extension may result in proptosis as the tumor grows in the orbit (Fig 19-9). In the anterior chamber, tumor cells may invade the trabecular meshwo rk, gain ing access to the conjunctival lymphatics. The patient may subsequently develop palpable preauricular and cervical lymph nodes.

Differential Diagnosis A number of lesions simulate retinoblastoma (Table 19-3). Most of these conditions can be differentiated from retinoblastoma on the basis of a comprehensive history, clin ical examination, and appropriate ancillary diagnostic testing.

Persistent fetal vasculature Persistent fetal vasculatu re (PFV) , previously known as persistent hyperplastic primary vitreous (PHPV), is typically recogn ized within days or weeks of birth. The condition is unilateral in two-th irds of cases and is associated with microphthalmos, a shallow or flat anterior chamber, a hypoplastic iris with prom inent vessels, and a retrolenticular fibrovascular mass that draws the ciliary body processes inward. On indirect ophthalmoscopy, a vascular stalk may be seen arising from the optic nerve head and attaching to the posterior lens capsule. Ultrasonography confi rms the diagnosis by showing persistent hyalOid

Figure 19-9 Retinoblastoma, clinical appearance. Proptosis caused by retinoblastoma

with orbital invasion.

CHAPTER 19:

Table 19-3

Retinoblastoma.

305

Differential Diagnosis of Retinob lastoma

Clinical Di agnosis in Pseudo retinoblastoma Pers istent fetal vasculature Retinopathy of prematurity Posterior cataract Coloboma of choroid or optic disc Uveitis Larval granulomatosis (Toxocara) Congeni tal retinal fold Coats disease Organi zing vitreous hemorrhage Retina l dysplasia

265 Cases·

Percent

76 Casest

Percent

51 36 36 30 27 18 13 10 9 7

19 13 13

15 3 5 7 2 20

20 4 7 9 3 26

12 3

16 4

"10 6 5 4 3 2

*Modified from Howard GM, Ellsworth RM. Differential diagnosis of retinoblastoma. Am J Ophthalmol.

1965;60,610-618. tFrom Shields JA, Stephens RT, Sarin LK. The different ia l diagnosis of retinoblastoma. In: Harley RD, ed. Pediatric Ophthalmology. 2nd ed. Philadelphia: Saunders; 1983: 114.

remnants arising from the optic nerve head, usually in association with a closed funnel reti nal detachment. No retinal tumor is seen, and the axjallength of the eye is shortened. Calcification may be present. PFV may be managed with combined lensectomy and vitrectomy approaches in selected cases. See also Chapter to in this volume and BCSC Section 6, Pediatric Ophthalmology and Strabismus.

Coats disease Coats disease is clinically evident within the first decade of li fe and is more common in boys. The lesion is typically characterized by unilateral retinal telangiectasia associated with intraretinal yellow exudation without a distinct mass (Fig 19-10). The progressive leakage of flui d may lead to an extensive retinal detachment and neovascular glaucoma. Ultrasonography documents the absence of a retinal tumor and shows the convection of cholesterol in the subretinal fluid . Fluorescein angiography shows classic telangiectatic vessels. Laser photocoagulation or cryoablation of the vascular anomalies eliminates the exudative component of the disease and may restore visual function. Subretinal fluid may be drained to facilitate these procedures. Serial evaluation and follow-up is critical for these patients.

Ocular toxocariasis Ocular toxocariasis typically occurs in older children with a history of soil ingestion or exposure to puppies. Toxocariasis presents with posterior and peripheral granulomas, with an associated uveitis. Exudative retinal detachment, organi zed vitreoretinal traction, and cataracts may be present. Ultrasonography shows the vitritis, retinal detachment, gra nulomas, retinal traction, and the absence of calcium. See BCSC Section 9, Intraocula r Inflammation and Uveitis, for additional discussion.

Astrocytoma Retinal astrocytoma, or astrocytic hamartoma, generally appears as a small, smooth, white, glistening tu mor located in the nerve fiber layer of the retina (Fig 19-11). It may be

306 • Ophtha lmic Pat hology and Intraoc ul a r Tu mors

D Figure 19-10 Coat s disease , A, Cl inica l appearance of characteristic lightbu lb aneurysms (arrowheads) observed in Coats disease. Note the associated exudative retinal detachment with subretinal exudate (as terisk). 8 , Fluorescein angiogram showi ng classic tela ngiectatic vesse ls (arrowhead). C, B-sca n in Coa t s disease shows ret inal detachment (arrow s). Of In contrast, 8-scan in retinoblastoma show s tota l retinal detachment (arrowhead) and a large t umor mass (asterisk) , (Parts A and B courtesy of Matthew W Wilson, MD.)

Figure 19-11 Retinal astrocytic hamartomas, clini ca l appearance. Note the more subtle opalescent lesion (between arrow s) superonasal to the optic disc and the larger " mulberry" lesion inferonasal t o th e di sc.

single or multiple, unilateral or bilateraL In some cases, it may become larger and calcified, typically having a mulberry appearance. Astrocytomas occasionally arise from the optic disc; such tum ors are often refe rred to as giant drusen. Astrocytomas of the retina commonly occur in patients with tubero us sclerosis and may also be seen in patients \vith neurofibromatosis. Most retinal astrocytomas are not associated with a phakomatosis.

CHAPTER 19:

Retinoblastoma. 307

Figure 19-12 Medulloeplthelioma. A, Pigmented lesion arising in ciliary body, with am elanotic apex (as terisk). B, T1-we ighted MRI with gadolinium, showing diffuse enhancem ent and mult iple cyst ic spaces. (Courtesy of Matthew W Wilson, M D.)

Medulloepithelioma Medulloepithelioma, or diktyoma, is a tumor derived from the inner layer of the optic cup (medullary epithelium) that occurs in both benign and malignant forms (see Chapter 11, Fig 11 -45) . This type of tumor typically becomes clinically evident in children aged 4-12 years, but it may also occur in adults. It usually appears as a variably pigmented mass arising from the ciliary body (Fig 19-12A), but it has also been documented in the retina and optic nerve. Smaller lesions may present with unexplained neovascular glaucoma with iris heterochromia. The tumor may erode through the iris root or grow along the lens zonules to enter the anterior chamber. Large cysts may be seen on the surface of the tumor or within the lesion on diagnostic imaging (Fig 19-12B). Chapter 11 discusses the histologic features of medulloepithelioma. Manage ment usually consists of enucleation or observation. Surgical resection is specifically avoided for most of these tumors because of late complications and documented metastases associated with this treatment. Fortunately, metastasis is rare with appropriate management, even if the tumor appears frankly malignant on histologic examination. Small lesions have been successfully treated with iodine 125 plaque brachytherapy.

Classification The Reese-Ellsworth Classification for Int raocular Tumors is the best-known method of grouping intraocular retinoblastoma (Table 19-4); it does not stage extraocular retinoblastoma. The classification takes into accou nt the nu mber, size, and location of tumors and the presence or absence of vitreous seeding. According to this classification, eye tumors are grouped from very favorable (gro up I) to very unfavorable (group V) by probability of eye preservation when treated with external-beam radiation alone. The Reese-Ellsworth classification does not provide prognostic information about patient su rvival or vision. The use of external-beam radiotherapy has given way to the use of primary systemic chemotherapy for the treatment of bilateral retinoblastoma. As a result, the International

308 • Ophtha lmic Pathology and Intraocu lar Tu mors Table 19-4 Reese·Ellsworth Classification of Retinoblastoma for Eye Preservation Group

-----A

I (very favorable)

Solitary tumor 4 disc diamete rs (DO ) at or beh ind eq uator

II (favorable) III (doubtful)

Solitary tumo r 4-10 DO or behind equator Any lesion anterior to eq uator

IV (unfavorable)

Multiple tumors, some larger than

V (very unfavorable)

Massive tumor occupy ing ha lf or more of retina

B Multiple tumors 4 DO at or behind equator Multiple tumors 4-10 DO at or behind equator Solitary tumor> 10 DO posterior to equator Any lesion anterior to ora serrata

10 DO Vitreous seed ing

Classification System for Intraocular Retinoblastoma has been adopted, with the hope that it can better predict an eye's response to chemotherapy. Eyes are grouped based on the size of the tumor and the presence of subreti nal fl uid, as well as the extent of vitreous and sub· retinal seeding. Eyes with anterior chamber involvement, neovascular glaucoma, vitreous hemorrhage, andlor necrosis are grouped as being unsalvageable (Table 19-5). The Ameri· can Joint Committee on Cancer (AjCC) also has a staging system for retinoblastoma that relates to both intraocular and extraocular disease; see the staging form in the appendix. Gallie BL, Truong 1~ Heon E, et a1. Retinoblastoma ABC classification survey_ 11th International Retinoblastoma Symposium, Paris, France; 2003. Murphree AL. Intraocular retinoblastoma: the case for a new group classification. Ophtha/mol Ciil1 North Am. 2005:18(1):41-53 . Reese AB. Tumors afthe Eye. 3rd ed. Hagerstown, MD: Harper & Row; 1976:pp 90- 132. Shields CL, Mashayekhi A, Demirci H, Meadows AT, Shields JA. Practical approach to management of retinoblastoma. Arch Ophthalmol. 2004; 122(5):729-735 .

Table 19-5 International Classification System for Response to Chemotherapy Group A Group B

Group C

Group 0

Group E

Small tumors ($3 mm) con fined to th e retina; >3 mm from the fovea; > 1.5 mm from the optic disc Tumors (>3 mm) confined to t he retina in any location, with clear subretinal fluid $;6 mm from the tumor m argi n Localized vitreous and/or sub retinal seeding «6 mm in total from tumor margin). If there is mo re than 1 site of subretinal/vitreous seeding, then the total of these sites must be <6 mm . Diffuse vitreous and/or subretinal seeding (;?:6 mm in total from tumor margin). If there is mo re than 1 site of subret inallvitreous seeding, then the total of these sites must be;::"6 mm. Subretina l fluid >6 mm from tumor margin . No visual potentia l; or Presence of any 1 or more of th e fo ll owing: • tumor in the anter ior segment • tumor in or on the cilia ry body • neovascular glaucoma • vitreous hemorrhage obscuring the tumor or significant hyphema • phthisical or pre -phth isical eye • orbital ce llulitis-like p rese ntat ion

CHAPTER 19:

Retinoblastoma. 309

Associated Conditions Retinocytoma Retinocytoma is clinically indistinguishable from retinoblastoma. Chapter 11 describes the histologic characteristics that distinguish retinocytoma from retinoblastoma (see Fig 11-44). The developmental biology of retinocytoma is subject to controversy. Some authorities consider retinocytoma to be ret inoblastoma that has undergone differentiation, analogous to ganglioneuroma, the differentiated form of neuroblastoma. Many other authorities contend that retinocytoma is a benign counterpart of retinoblastoma. Though histologically benign, retinocytoma carries the same genetic implications as retinoblastoma. A child harboring a retinoblastoma in one eye and a retinocytoma in the other should be considered capable of transmitting an RBl mutation to offspring.

Trilateral Retinoblastoma The term trilateral retinoblastoma is reserved for cases of bilateral retinoblastoma associated with ectopic intracranial retinoblastoma. The ectopic focus is usually located in the pineal gland or the parasellar region and historically has been termed a pinealoblastoma. This tumor affects up to 5% of children with a germline RBl mutation. Rarely, a child may present with ectopic intracranial retinoblastoma prior to ocular involvement. More commonly, this independent malignancy presents months to years after treatment of the intraocular retinoblastoma. Several different observations support the concept of primary intracranial pinealoblastoma. CT helped to establish that intracranial tumors in some patients dying from retinoblastoma are anatomically separate from the primary tumors in the orbit. These intracranial tumors are not associated with metastatic disease elsewhere in the body, and, unlike metastatic retinoblastoma, they often demonstrate features of differentiation such as Flexner-Wintersteiner rosettes (see Chapter 11, Fig 11-41). EmbryologiC, immunologiC, and phylogenie evidence of photoreceptor differentiation in the pineal gland offers further support for the concept of trilateral retinob lastoma. All patients with retinoblastoma should undergo baseline neuroimaging studies to exclude intracranial involvement. Patients with germ line RBi gene mutations (ie, bilateral retinoblastoma, unilateral multi focal retinoblastoma, or unilateral retinoblastoma with a positive family history) should undergo serial imaging of the central nervous system (CNS) . Studies suggest that serial MRI with and without contrast is most sensitive for eNS involvement and does not expose the child to radiation. Median survival of patients with retinoblastoma with eNS involvement is approximately 8 months. Recent studies report a decrease in the incidence of trilateral retinoblastoma in patients treated with systemic chemotherapy, suggesting a possible prophylactic effect. Jubran RF, Erdreich -Epstein A, Butturini A, Murphree AL, Villablanca JG. Approaches to treatment for extraocul ar retinoblastoma: Children's Hospital Los Angeles experience. JPe-

diatr Hematol Oneol. 2004;26(1 )31 - 34 . Shields CL, Meadows AT, Shields JA, Carvalho C, Smith AF. Chemoreduction for retinoblastoma may prevent intracranial neuroblastic malignancy (trilateral retinoblastoma). Arch

Ophthalmol. 2001;119(9),1269-1 272.

310 • Ophthalmic Pathology and Intraoc ular Tumors

Treatment "Vhen retinoblastoma is being treated, it is first and fore most important to understand that it is a malignancy. v\Then the disease is contained with in the eye, survival rates exceed 95% in the Western wo rld. However, with extraocul ar spread, survival rates decrease to under 50%. Therefore, when a treatment strategy is being decided, the first goal must be preservation of life, then preservation of the eye, and, finally, preservation of vision. The modern management of intraocular retinoblastOlna currently incorporates a combination of different treatment modalities, including enucleation, chemotherapy, photocoagulatio n, cryotherapy, external-beam radiation therapy, and plaque brachytherapy. Metastatic disease is managed using intensive chemotherapy, radiation, and bone marrow transplantation. The treatment of children with retinoblastoma requires a team approach, including an ocular oncologist, pediatric ophthalmologist, pediatric oncologist, and radiation oncologist.

Enucleation Enucleation remains the definitive treatment for ret inoblastoma, providing, in most cases, a complete surgical resection of the disease. Typically, enucleation is considered an ap propriate intervention when

the tumor involves more than 50% of the globe orbital or optic nerve involvement is suspected anterior segment involvement is present neovascular glaucoma is present there is limited visual potential in the affected eye Enucleation techniques are aimed at minimizing the potential for inadvertent globe penetration while obtai ning the greatest length of resected optic nerve that is feasible, typically longer than 10 mm. Porous integrated implants, such as hydroxyapatite or poro us polyethylene, are currently used by most surgeons. Attempts at globe-conserving therapy should be undertaken only by ophthalmologists well versed in the management of th is rare childhood tumor and in conjunction with similarly experienced pediatric oncologists. Fai led attemp ts at eye salvage may place a child at risk of metastatic disease.

Chemotherapy A significant advance in the management of bilateral intraocular retinoblastoma in the past 2 decades has been the use of pri mary systemic chemotherapy. Systemic administration of chemotherapy reduces tumor vo lume, allowing for subsequent application of consoli dative focal therapy with laser, cryotherapy, or radiotherapy (Fig 19-13). These changes have come about as a result of improvements in the treatment of both brain tumors and metastatic retinoblastoma. Current regimens incorporate var ying combinations of carboplatin, vincristine, etoposide, and cyclosporine. Children rece ive drugs in trave nously every 3-4 weeks for 4- 9 cycles of chemotherapy. Meanwhile, serial EUAs are performed, during which tu mor response is observed and focal therapies are admin istered.

CHAPTER 19:

A Figure 19- 13

Retinoblastoma. 311

Retinoblastoma . A, Before chemoth erapy. 8 , Reduced tumor vo lume after 2

cycles of chemothe rapy alone . Drug regim ens, ro utes of ad ministration, and dose schedules should be determined by a pediatric oncologist experienced in the treatment of children with retinoblastoma.

Local chemotherapy Subconjunctival carboplatin, with and witho ut systemic chemotherapy, has been used in the treatment of retinoblastoma. Both vitreo us seeding an d retinal tumors have bee n found to be responsive to this treatment. Orbital myositis, periocular fi brosis, and optic neuropathy due to carboplatin toxicity have been reported. Advances in interventional radiology now allow for selective canalization of th e ophthalmic artery with local d elivery of chemotherapeuti c agents.

Photocoagulation and Hyperthermia Xenon arc and argon laser (532 nm) have trad itionally been used to treat retinoblasto mas smaller than 3 mm in apical height wit h basal dimensions less than 10 mm. Two to 3 rows of encircli ng retinal photocoagul atio n destroy th e tumor's blood supply, with ensuing regression. Newer lasers allow for direct confluent treatment of the tumor surface. The diode laser (8 10 nm ) is used to provide hyperthermia. Direct application to the surface

increases the tumor's temperature to the 45°_60° Celsius range and has a direct cytotoxic effect, which can be augmented by both chemot herapy an d rad iation (Fig 19 -14).

Figur e 19-14 Ret inoblastoma . A, Before trea tment. B, Same eye 6 months later, afte r treatment with chemoreduction and laser thera py. (Counesyof7imorhyG. M urra y. MD.)

312 • Ophthalmic· Pathology and Intraocula r Tumors

Cryotherapy Also effective for tumors in the size range of less than 10 mm in basal dimension and 3 mm in apical thickness, cryotherapy is applied under direct visualization with a triple freeze-thaw technique. Typically, laser photoablatio n is chosen for posteriorly located tumors and cryoablation for more anteriorly located tumors. Repetitive tumor treatments are often required for both techniques, along with close follow-up for tumor growth or treatment complications.

External-B eam Radiation Therapy Retinoblastoma tumors are responsive to radiation. Current techniques use focused megavolt age radiation treatments, often employing lens-sparing techniques, to deliver 4000-4500 cGy over a 4-6-week treatment intervaL Typically, those treated are children with bilateral disease not amenable to laser or cryotherapy. Globe salvage rates are excel lent, with up to 85% of eyes being retained. Visual function is often excellent and limited only by tumor location or secondary com plications. Two major concerns have limited the application of external-beam radiotherapy using standard techniques: 1. the association of germ line mutations of the RBl gene with a lifelong increase in

the risk of second, independent primary malignancies (eg, osteosarcoma) that is exacerbated by exposure to external-beam radiotherapy 2. the potential for radiation-related sequelae, which include mid face hypoplasia, radiation-induced catarac t, and radiation optic neuropathy and retinopathy Evidence suggests that combined-modality therapy that uses lower-dose externalbeam radiotherapy coupled with chemotherapy may allow for increased globe conservation with decreased radiation morbidity. In addition, the use of systemic chemotherapy may delay the need for external-beam radiotherapy, allowing fo r greater orbital development and significantly decreasing the risk of second malignancies once the child is older than 1 year.

Plaque Radiotherapy IBrachytherapy) Radioactive plaque therapy may be used both as salvage therapy for eyes in which globeconserving therapies have failed to destroy all viable tumor and as a primary treatment for some children with relatively small to medium-sized tumors. This technique is ge ne rally applicable for tumors less than 16 mm in basal diameter and 8 mm in apical thickness. The most commonly used isotopes are iodine 125 and ruthenium 106. Intraoperative localization with ultrasound enhances local tumor control for plaque brachytherapy A greater likelihood of radiation optic neuropathy or retinopathy may be associated with this radiotherapy modality compared with external-beam radiotherapy Limiting the radiation dose to periocular structures may lower the incidence of radiation -induced second malignancies.

CHAPTER 19:

Retinoblastoma. 313

Targeted Therapy New fro ntiers in the treatment of retinoblastoma include the use of gene therapy and small- molecule inhibition. Adenoviral-mediated transfection of tumor cells with thymidine kinase renders the tumor susceptible to systemicall y administered ganciclovir. Phase 1 clinical trials have been completed, documenting both safety and efficacy. Although this targeted therapy is currently reserved as salvage therapy for eyes failing all conventional modalities of treatment, there is hope that it may become a mainstream treatment. The use of small-molecule inhibitors in aberrant cellular pathways has shov.m promise in precli nical models.

Spontaneous Regression Retinoblastoma is one of the more common malignant tumors to undergo complete and spontaneous necrosis (although this is rarely recognized with active disease) . Spontaneous regression is recognized clinically after involutional changes such as phthisis have occurred. The incidence of spontaneous regression is unknown, as no child with act ive retinoblastoma is observed with the hope of spontaneous involution. Although the mech an ism by which spontaneous regression occurs is not understood, its histologiC appearance is diagnostic. The vitreous cavities of these phth isical eyes are filled with islands of calcified cells embedded in a mass of fibroco nnective tissue. Close inspection of the peripheral portion of these calcified islands revea ls the ghosted contours of fo ssilized tumor cells. The process is often accompanied by exuberant proliferation of retinal pigment and ciliary epithelia.

Prognosis Children with intraocular retinoblastoma who have access to modern medical care have a very good prognosis for survival, with overall su rvival rates of over 95% for children in developed countries. The most important risk factor associated with death is extraocular extension of tumo r, either directly through the sclera or, more commonly, by invasion of the optic nerve, especially to the surgically resected margin (see Chapter 11, Fig 11-43). The importance of choroidal invasion is unclear. Although a multivariate analysis of a large case series has shown that choroidal invasion is not predictive of metastases, the significance of this pathologiC finding remains the subject of debate. A current multicenter study is investigating this further. Some evidence suggests, however, that bilateral tumors may increase the risk of death because of their association ,·"ith primary intracranial tu mors (see the discussion of trilateral retinoblastoma earlier in this chap ter) . Children who survive bilateral retinoblastoma have an increased incidence of non ocular malignancies later in life. The mean latency for second tumor development is approXimately 9 yea rs from management of the primary retinoblastoma. The RBI mutation is associated with approximately a 25% incidence of second tumor development within 50 years in patients treated without exposure to radiation therapy. External-beam

31 4 • Ophthalmic Pathology and Intraocular Tu mors

Tab le 19-6

Nonretinoblastoma Malignancies in Retinoblastoma Survivors Tumors Arising in the Fie ld of Radiation ofthe Eye

Pathologic Type Osteosarcoma Fibrosarcoma Soft-tissue sarcoma Anaplastic and unclassifiable Sq uamous cell carcinoma Rhabdomyosarcoma Assorted other

Tumors Arising Outside the Field of Radiation of the Eye Percent

40 10 8 8 5 5

Patho log ic Type Osteosarcoma Melanoma Pinealoma Ewing sarcoma Papillary thyroid carcinoma Assorted other

Percent

36 12 9

6 6 30

Modified with permission from Abram son DH, Ellsworth RM, Kitch in FD, el al. Second no nocular tumors in retinoblastoma survivors . Are they radiation-i nduced? Ophthalmologv. 1984;91:1351-1355.

radiation therapy decreases the latency period, in turn increasing the incidence of second tumors in the first 30 years of life, as well as increasing the proportion of tumors in the head and neck. The most common type of second cancer in these patients is osteogenic sarcoma. Other relatively common second malignancies include pinealomas, brain tumors, cutaneous melanomas, soft -tissue sarcomas, and primitive unclassifiable tumors (Table 19-6). Estimates suggest that up to 20% of patients who have bilateral retinoblastoma will develop an apparently unrelated neoplasm within 20 yea rs and that up to 40% will develop a third maligna ncy within 30 years. The prognosis for survival in retinoblastoma patients who later develo p sarcomas is less than 50%.

CHAPTER

Ocular Involvement in Systemic Malignancies

Secondary Tumors of the Eye Metastatic Carcinoma Since the first description in 1872 of a metastatic tumor in the eye of a patient with careinoma, a large body of literature has indicated that the most common type of intraocular or orbital tumor in adults is metastatic. There are several co mprehensive studies of ocular

metastatic tumors: some have reported the incidence of tumor metastases in a consecutive series in autops ies, some have dealt with tu mor incid ence in patients with generalized

malignancy, and others have used a clinicopathologic approach. As long-term survival from system ic primary malignancy continu es to increase, the ophthalmologist will be confronted with a growing incidence of int raocu lar and orbital metastatic disease requir-

ing prompt recognition and appropriate diagnostic and therapeutiC management. Metastases to the eye are being diagnosed with increasing frequency for various reasons:

increasing incidence of certain tumor types that metastasi ze to the eye Ceg, breast, lung) prolonged survival of patients with certain cancer types Ceg, breast cancer) increasing awa reness among medical o ncologists and ophthalmologists of the pattern of metastatic disease

Primary tumor sites The vast majority of metastatic solid tumors to the eye are carcinomas from various or-

gans. Cutaneo us melanoma rarely metastasizes to the eye. Table 20-1 shows the most common pr imary tumors that metastasize to the cho roid.

Mechanisms of metastasis to the eye The mechanism of intraocular metastasis depends on hematogenous dissemination of

tumor cells. The anatomy of the arterial blood supply to the eye dictates the predilection of tumor cell deposits within the eye. The posterior choroid, with its rich vascular supply, is the most favo red site of intraocular metastases, and it is affected 10-20 times more frequently than is the iris or ciliary body. The retina and optic disc, supplied by the single

3 15

316 • Ophtha lmic Pathology and Int raoc ular Tum ors

Table 20-1 Primary Sites of Choroidal Metastasis Mal es IN= 137)

Females (N: 287 )

Lung (40%)

Breast (70%)

Unknown (30%) Gastrointestinal (10%) Kidn ey (5%)

Prostate (5%) Skin « 5%) Others « 5%) Breast (1%)

Lung (10%)

Unknown (10%) Others « 5%) Gastrointestinal « 5% ) Sk in (1%) Kidney « 1%)

Modified from Shields eL, Shields JA, Gross NE, et al. Survey of 520 eyes with uveal metastases. Ophthalmology. 1997; 104: 1265-1276.

central retinal artery, are rarely the sole site of involvement. Bilateral oc ular involvement has been repor ted in approximately 25% of cases, an d multifocal deposits are freq uently seen within the in volved eye. Many patients with ocular metastases also have concurrent central nervo us system (eNS) metastases. Clinical evaluation The clinical features of intraocular metastases depend on the site of involvement. Metastases to the iris and ciliary body usually appea r as white or gray-white gelatinous nodules (Figs 20-1, 20-2, 20-3). The clinical featu res of anterior uveal metastases may include iridocycl*tis secondary glaucoma rubeosis iridis

Figure 20-' Metastasis to the iris associated with hyphema.

Figure 20-2 Metastasis from breast carcinoma to the iris. (Courtesy of Timothy G. Murray, MD.)

·CHAPTER 20:

Ocular Invo lvement in Systemi c Malignancies.

317

• hyphen,. • irregular pupil Anterior segment tu mors are best evaluated with slit-lamp biomicroscopy coupled with gonioscopy. High-resolution ultrasound imaging may quan tify tu mor size an d anatomical relationsh ips. Patients with a tumor in the posterior pole commonly complai n of loss of vision. Pain and photopsia may be concurrent symptoms. Indirect binocular ophthal moscopy may reveal a nonrhegmatogenous (ie, exudati ve) retinal detachm ent associated with a plaeoid amelanotie tumor mass (Figs 20-4, 20-5, 20-6). Multiple or bilateral lesions may be present in apprOXimately 25% of cases, highlighting the importance of close evaluation of th e fellow eye. These lesions are usually relatively flat and ill defined, often gray-yellow or yellow-white, with secondary alterations at the level of the retinal pigment epithelium (RPE) presenting as clumps of brown pigment ("leopard spottin g"; Fig 20-7). The mushroom configuration frequently seen in primary choroidal melanoma from breakthrough of the Bruch membrane is rarely present in uveal metastases. The retina overlying the me tastasis may appear opaque and becom e detached. Rapid tum or growth

Figure 20-3

Metastatic cutaneous melanoma to the iris. Note both lesions at periphery.

Figure 20-4

Mu ltiple metastatic lesions to

the choroid. Note the pa le yellow color and relative flatness.

318 • Ophthalm ic Pathology and Intraocular Tumors

B Figure 20-5 A, Metastatic lesion to the choroid inferiorly, associated with bullous retinal detachment (asterisks). B, Subtle meta static lesion to the choroid (arrows), near the fovea, as-

sociated with serous effusion .

with necrosis and uveitis are occasionally observed. Dilated epibulbar vessels may be seen in the quadrant overl ying the metastasis. For a differe ntial diagnosis of choroidal metastasis, see Table 20-2.

Ancillary tests Although fluorescein angiography may be helpful in defining the margins of a m etastati c tumor, it is typically less useful in differentiating a metastasis from a primary intraocular neoplasm. The doub le circulation pattern and prominent early choro idal filling often seen in choroidal melano mas are rarely found in metastatic tu mors.

CHAPTER 20: Ocu lar Involvement in System ic Malignancies. 319

B Figure 20-6 A, M etastatic ca rcinoma to t he choroid. Vision w as red uced to finger counting beca use of macular involvement. Note irreg ular pigmen tation on surfac e. 8, Same eye, 1 mon th after rad iati on th erapy. Vi sual acuity has improved to 20/20 . Note increa sed pigm entation, cha racteri sti c of irradiation effects.

Ultrasonography is diagnostically valuable in patients with a metastatic tumor. B-scan shows an echogenic choroidal mass with an ill -defined, sometimes lobulated, outline. Overlying secondary retinal detachment is commonly detected in these cases. A-scan demonstrates moderate to high internal reflectivity. Fine-needle aspiration biopsy may be helpful in rare cases when the 'diagnosis cannot be established by noninvasive procedures. Although metastatic tumors may recapitulate the histology of the primary tumor, they are often less differentiated. Special histochemical and immunohistochemical stains assist in the diagnosis of metastatic tumors.

320 • Ophthalm ic Path ology and Int raocu lar Tumors

Figure 20·7 Breast metastases, clinical appearance , Note the ame[anotic in filtrative choroidal mass with secondary overlying retinal pigment epi thelial chan ges accounting fo r the characteristic "leopard spots." (CourtesyofMarrhewW Wilson. MD.)

Table 20-2

Differential Diagnosis of Choroidal Metastasis Ame la notic nevus Amelanoti c melanom a Choroidal hemangio ma Choroidal osteoma Choroidal detachme nt Posterior scleritis

---

Vogt-Koya na gi-Harada syndrome Central serous retinopathy Infectious lesions Organized subretinal hemorrhage Extensive neovascular membranes Rhegmatogenous retinal detachment

Metastases to the optic nerve may produce disc edema, decreased visual acuity, and

visual fiel d defects. Becanse the metastases may involve the parenchyma or the optic nerve sheath, MRI as well as ultrasonography may be valuable in detecting the presence and location of the lesion(s) . Metastases to the retina, which are ver y rare, appear as white, noncohesive lesions,

often distributed in a perivascular location suggestive of cotton- wool spots (Fig 20-8). Because of secondary vitreo us seeding of tumor celis, these metastases sometimes resemble retinitis more than they do a true tumor. Vitreous aspirates for cytologic studies may con ~

fir m the di agnosis. Other diagnostic factors

One of the most important diagnostic factors in the evaluation of suspected metastatic tumors is a history of systemic malignancy. More tha n 90% of patients with uveal metastasis from carcinoma of the breast, for example, have a history of treatment prior to the development of ocular involvement. In the remain ing 10% of patients, the primary tumor can usuall y be diagnosed by breast examinatio n at the time the suspicious ocular lesion is detected. For other patients, however, often there is no prior histor y of malignanc y. This is especiall y true of patients with ocular metastasis fro m the lung. A complete systemic

CHAPTER 20:

Ocula r Invo lvement in Systemic Malignancies . 32 1

c Figure 20-8 A, Metastatic lung carcinoma to the retina, involving the macula, Vision was reduced to fing e r counting. B, Same eye , showing characterist ic perivascular distribution of metastases. C, Vitreous aspirate from same eye, showing an aggregate of tumor cells, characteristic of ade nocarcinoma of the lun g ,

evaluation, a family history, and a history of smoking may alert the ophthalmologist to the suspected site of an occult primary tum or. Any patient with an amelanotic fundus mass

suspected of being a metastatic focus should have a thorough systemic evaluation, including imagi ng of the breast, chest, abdomen, and pelvis. PET-CT scanning may help direct a more targeted evaluation.

Prognosis The diagnosis of tumor metastatic to the uvea implies a poor prognosis. because wide-

spread dissemination of the primary tumor has us ually occurred. In one report, the survival time following the diagnosis of metastasis to the uvea ranged from 1 to 67 months, depending on the primary cancer type. Metastatic carcinoid is associated with long survival times. Patients with breast carcinoma metastatic to th e uvea sur vive an average of 9- 13 months after the metastasis is recogni zed. but cases with long -term survival have

322 • Ophth a lmic Patho log y a nd Int raocula r Tumors now been reported . Shorter su rvival ti me is typica ll y seen in pati ents with lung carcinoma and carcino mas ar ising from the gast ro intestina l or gen itourin ary tracts, in which metastases hera ld th e p resence of the prim ary tum or. T he goal in ophthal mic manage ment of ocular metastases is prese rvation or restorati on of vis ion and pall iation of pain. Rad ical su rgical procedu res and treatm ents with risks g reater than the desired benefits should be avoide d.

Treatment Indications for trea tm ent include d ecreased vision, pain , dipl opia, and severe ocular pro ptosis. The patient's age an d health status and the condition of th e fellow eye are also criti cal in the decision-making process. The treatment modality in pati ents with metastatic oc ular disease should be individuall y tailo red. W hen ocular metastases are concu rrent with widespread metastatic d isease, system ic chem otherapy alone or in combination with local therapy is reasonable. In patients man ifesti ng metastases in the eye alone, local the rapy mo dalities may be suffi cient, allowing conservation of vis ual fu ncti on with mi ni mal system ic morb id ity. C hemotherapy o r hormonal th erapy for se nsitive tum ors (eg, breast ca ncer) m ay ind uce a prompt respo nse. In such patie nts, no additional ocular treatment m ay be indi cated . Howeve r. when vis ion is endangered by choroidal metastases in spi te of chemotherapy, addit ional m odalities of local therapy such as external-bea m rad iation, brachytherapy, laser photocoagulat io n, or transp upillary thermot herapy may be necessary. Rad ioth erapy is frequen tl y associated with rapid im provement of the patient's sym ptom s, alo ng with rapid resolution of ex udat ive retinal detachment and, often, d irect reductio n in tum or size. Possible adve rse effects of the radi ati on incl ude cataract, radi ation ret inopath y, and radi ation optic neuropathy. Rarely, enucleation is pe rform ed because of severe, unrelenting pain. Al11er R, Peer J. Chowers I, Anteby 1. Treatment options in the manageme nt of choroidal metastases. OphtlJafmologica. 2004;218(6):372- 377 . Ferry AP, Font RL. Ca rci noma metastatic to the eye and orbit. L A clinicopathologic study of 227 cases. Arch Ophtlwlmol. 1974;92(4)B6-286. Shields eL, Sh ields JA, Gross NE, Schwartz G r , Lally SE. Survey of 520 eyes with uveal me tas tases. Ophthalmology. 1997;104(8); 1265-1 276. Shields JA, Sh ields Cl, Brotman H K, Carvalho C. Perez N, Eagle RC Jr. Cancer metastati c to the o rbit: the 2000 Robert M. Curts lecture. Ophthal Piast Recollstr Surg. 2001; 17(5):346-354.

Direct Intraocular Extension Direct extension of extraocular tumo rs into th e eye is ra re. Jn traocular extensio n occurs most commonly wit h co nj u nctival squ amous cell carcinoma and less frequently with co njunctival melanoma and basal cell carcinoma of th e eyelid. The sclera is usually an effective barrier against intraocula r invasion. O n ly a small minority of carcinomas of the co njunctiva eve r successfull y penet rate the globe. but those that do are often variants of squamo us cell carcinoma: mucoepidermoid carcinoma or spindle cell variant. T hese more aggressive neoplasms usually recur several times afte r local excision before they invade the eye.

CHAPTER 20:

Ocular Involvement in Systemic Malignancies. 323

Lymphomatous Tumors Intraocu lar lymphomas may arise in different parts of the eye, exp ressing various clin i~ cal manifestations. Primary intraocular lymphoma (also known as large cell lymphoma, vitreoretinally mphoma, or retinal lymphoma) , is th e most common and most aggressive type of lymphoma involving the eye and is usually associated with primary central nervous system lymphoma (PCNS L). In these cases, the vitreous and retina are involved. Less frequ ently, the eye can be involved in systemic/visceral/l1odallymphoma. In these cases, the uveal tract is more commonly involve d, usually in a pattern of metastatic disease. In advanced cases, the intraocular findings of the 2 types may overlap. In recent decades, the incidence ofPCNSL has increased Significa ntly in both immuno competent and immunocompromised persons.

Primary Intraocular lymphoma Clinical evaluation O cular signs and symptoms may occur before CNS findings. In such cases, the disease may masquerade as a nonspecific uveitis. The onset of bilateral posterior uveitis in patients older than 50 years is suggestive oflarge cell lymphoma, as is "chronic" uveitis in patients in their fifth to seventh decades. Although 30% of patients prese nt with unilateral involvement, delayed involvement of the second eye occurs in approximately 85% of patients. Diffuse vitreous cells may be associated with deep subretinal yellow~white infiltrates (Fig 20 ~ 9). Often, fine details of the retina are obsc ured by the de nsity of the vitritis ("headlight in the fog"). Retinal vascul itis and/o r vascular occlusion may be observed. The RPE may reveal characteristic clumpi ng overlying the subretina l!sub ~ RPE infiltrates (see Fig 1 0~14 and the discussion of histologic find ings in Chapte r 10). Anterior chamber reaction may be minimal. Photographic and fluorescein angiographic stud ies document baseline clinical findings but are rarely helpful in defining a d ifferential di agnosis. Ultrasonographic

Figure 20-9 Fundus picture of a patient with vitreoretina l lymphoma. Note the vitreous haze, optic disc involvement, and peripapillary subretinal infi ltrates. (Courtesy of Jacob Pe 'er, MD.)

324 • Ophthalmic.Pathology and Intraocu lar Tumors

examination may reveal discrete nodular or placoid infiltration of the subretinal space, associated retinal detachment, and vitreous syneresis with increased reflectivity. Clinical history and neurologic evaluation may reveal neurologic deficits in up to 10% of patients, and 60% of patients show concomitant CNS involvement at the time of presentation. If the diagnosis is suspected, neurologic consultation coupled with CT or MRI studies and lumbar puncture should be coord inated with diagnostic vitrectomy.

Pathologic studies Diagnostic confirmation of ocular involvement requires sampling of the vitreous and, when appropriate, the subretinal space. Coordinated planning with the ophthalmic pathologist prior to surgery regarding sample handling is important. The ophthalmic pathologist should be skilled in the handling of small-volume intraocular specimens and experienced in the evaluation of vitreous samples. The best approach to pathologic evaluation of the specimen remains controversial. Diagnostic pars plana vitrectomy is indicated to obtain an undiluted or diluted vitreous specimen. If a subretinal nodule is accessible in a region of the retina unlikely to compromise visual function, subretinal aspiration of the lesion can be performed. A singlevitrectomy biopsy may not be adequate, and a second biopsy may be required. Evaluation of the vitreous and subretinal specimen may be performed using cytopathology (see Chapter 10, Fig 10-15), including immunohistochemical studies for subclassification of the cells, flow cytometry, and polymerase chain reactionlfluorescence in situ hybridization (PCR/FISH) analysis for gene rearrangements and the ratio of interleukin - IO (IL-I O) to IL-6 (see Chapters 3, 4, and 10). Preferably, a pathologist familiar with the diagnosis of intraocular large cell lymphoma should evaluate the specimen. If an adequate specimen is obtained, multiple pathologiC approaches may be employed. CytologiC evaluation is essential in establishing the diagnosis, with flow cytometry, PCR, and cytokine levels (IL-IO/IL-6) serving as anCillary studies. Specimens that reveal malignant lymphocytiC cells establish the diagnosis (Fig 20-10), and evaluation of cell surface markers may allow for subclassification of the tumor.

Treatment Because the blood- ocular barriers may limit penetration of chemotherapeutic agents into the eye, irradiation of the affected eye using fractionated external-beam radiation has remained popular in some centers for treatment of intraocular lymphoma. However, although radiotherapy may induce an ocular remission, the tumor invariably recurs, and further irradiation places the patient at high risk for irreversible vision loss caused by radiation retinopathy. Radiotherapy to the eye is often given with systemic or intrathecal chemotherapy. Some centers use systemic chemotherapy alone, mainly high-dose methotrexate, for the treatment of vitreoretinal lymphoma. However, studies have shown that drug penetration into the retina and vitreous is limited with systemic admin istration, and recurrence is common . Because of concern about the disadvantages of ocular irradiation and systemic chemotherapy, several groups use intraocular chemotherapy, injecting methotrexate into the vitreous, with very good responses and low recurrence rates. Recently, intravitreal injections of rituximab have been used experimentally. Parallel to the treatment of the intraocular disease, the CNS and/or systemic lymphoma should be treated by a medical oncologist.

CHAPTER 20; Ocular Invol vement in Systemic Malignancies. 325

Figure 20-10 Large cell lymphoma, cytology. Note the unusual nuclei and promin e nt nucl eol i (arrows) of th ese neopla stic lymphoid cells obta ined by f in e-needle aspira tion biopsy.

Prognosis The prognosis for patients with large cell lymphoma is poor, although advances in early diagnosis have produced a cohort oflong-term survivors. Serial follow-up with consultative management by an experienced medical oncologist is critical in the management of this disease. Patients with PCNSL should be observed carefully by an ophthalmologist for possible ocular involvement, even after remission ofthe eNS disease. Chan CC, Wallace DJ. Intraocular lymphoma: update on diagnosis and management. Cancer

Control. 2004;11 (5);285-295. Coupland SE, Damato B. Understanding intraocular lymphomas. Clin Exp Ophthalmol. 2008;

36(6)564 - 578. Frenkel S, Hendler K, Siegal T, Shalom E, Pe'er

J. lntravitreal methotrexate for treating vitreo-

retinal lymphoma. Ten years of experience. Br J Ophthalmol. 2008;92 (3} :383-388.

Uveal lymphoid Infiltration Uveal lymphoid inftltration, formerly known as reactive lymph oid hyperplasia, typically presents in patients in the sixth decade of life; it can occur at any uveal site. Similar lymphoid proliferation can occur in the conjunctiva and orbit (see also Chapter 5 for conjunctival involvement, Chapter 12 fo r uveal involvement, and Chapter 14 for orbital involvement).

Clinical evaluation Patients typically notice painless, progressive vision loss. Ophthalmoscopically, a diffuse or, rarely, nodular amelanotic thickening of the choroid is noted. Exudative retinal detachment and secondary glaucoma may be present in up to 85% of eyes. Frequently, delay between the onset of symptoms and diagnostic intervention is significant. This rare disorder is characterized pathologically by localized or diffuse inftltration of the uveal tract by lymphoid cells. The etiology is unknown. Clinically, this condition

326 • Ophthalmic Pathology and Intraoc ul ar Tumors

can simulate posterior uveal melanoma, metastatic carcinoma to the uvea, sympathetic ophthalmia, Vogt-Koyanagi-Harada syndrome, and posterior scieritis. Proptosis of the affected eye occurs in up to 15% of patients who develop simultaneous orbital infiltration with benign lymphOid cells. Ultrasonographic testing reveals a diffuse, hom*ogeneous choroidal infiltrate with associated secondary retinal detachment. Extraocular extension or orbital involvement may be best demonstrated with ultrasonography.

Pathologic studies Biopsy confirmation should be targeted to the most accessible tissue. If extraocular involvement is present, biopsy of the involved conjunctiva or orbit may be considered. Fine-needle aspiration biopsy or pars plana vitrectomy with biopsy may be indicated for isolated uveal involvement. Coordination with the ophthalmic pathologist is crucial to achieve the greatest likelihood of appropriate confirmation and cell marker studies. Treatment Historically, ey.es with this type of lym phoid infiltration were generally managed by enucleation because of presumed malignancy. Current management emphasizes globeconserving therapy aimed at preservation of vision. High-dose oral steroids may induce tumor regression and decrease exudative retinal detachment. Early intervention with 10\1-,'dose ocular and orbital fractionated external-beam radiotherapy may definitively manage the disease. Prognosis The prognosis for survival is excellent for patients with uveal lymphOid infiltration, with the rare exception of patients with systemic lymphoma. Preservation of visual function appears related to primary tumor location and secondary sequelae, including exudative retinal detachment or glaucoma. Early intervention appears to enhance the likelihood of vision preservation.

Ocu lar Manifestations of leukemia Ocular involvement with leukemia is common, occurring in as many as 80 % of the eyes of patients examined at autopsy. Clinical studies have documented ophthalmic findings in as many as 40% of patients at diagnos is. Patients may be asymptomatic, or they may complain of blurred or decreased vision. Clinically, the retina is the most commonly affected intraocular structure. Leukem ic retinopathy is characterized by intraretinal and subhyaloidal hemorrhages, hard exudates, cotton-wool spots, and white -centered retinal hemo rrhages (pseudo- Roth spots)-all of which are usually the result of associated anemia, hyperviscosity, and/or thrombocytopenia (Fig 20-11). Leukemic infiltrates appear as yellow deposits in the retina and the sub retinal space. Perivascul?-r leukemic infiltrates produce gray-white streaks in the retina. Vitreous involvement by leukemia is rare and most often resu lts from direct extension via retinal hemorrhage. If necessary, a diagnostic vitrectomy can be performed to establish a diagnosis. Although, clinically, the retina is the most commonly affected ocular structure, histologiC studies have shown that the uvea is more commonly affected than the retina. The

CHAPTER 20:

Ocular In vo lvement in Systemic Malignancies . 327

Figure 20-1' Retinal Involvement in leukemia . A. Leukemic retinopathy. Clinical photograph shows scanered Intraretinal hemorrhages, some of which have white centers (arrows). 8 , Whi te-centered hemorrhages. (ParrA courresyof Robert H. Rosa, Jr. MD; part 8 courresyof Jacob Pe 'er. MDJ

uveal tract may serve as a "sanctuary site:' predisposi ng the eye to be the structure in which recurrent disease first manifests clinically. Choroidal infiltrates may be difficult to detect with indirect ophthalmoscopy; they may be better detected on ultrasonography as di ffuse thickening of the choroid. Serous retinal detachments may overlie these infiltrates. Leukemic involvement of the iris manifests as a diffuse thickening with loss of the iris crypts, and, in some cases, small nodules may be seen at the margin of the pupil (see Chapte r 17, Fig 17-4D). Leukemic cells may invade the anterior chamber, formi ng a pseu dohypopyon. Infiltration of the angle by these cells ca n give rise to secondary glaucoma. A patient with leukemic inftitration of the opt ic nerve (Fig 20- 12) may present with severe vision loss and optic nerve edema. One or both eyes may be affected. This is an ophthalmic emergency and requires immediate treatment to preserve as much vision as

Figure 20-12 Leukemic infiltration of optic nerve. (Courtesy of Robert H. Rosa, Jr. MD.)

328. Ophthalmic Pathology and IntraocularTumors

possible. Systemic and intrathecal combination chemotherapy is needed with or without radiation. Leukemic infiltrates may also involve the orbital soft tissue, with resultant proptosis. These tumors, which are more common with myelogenous leukemias, are referred to as

granulocytic sarcomas or chloromas. They have a predilection for the lateral and medial walls of the orbit. Treatment ofleukemic involvement of the eye generally consists oflow-dose radiation therapy to the eye and systemic chemotherapy. The prognosis for vision depends on the type ofleukemia and the extent of ocular involvement.

APPENDIX

American Joint Committee on Cancer (AJCC) Staging Forms, 2010

[The material in this appendix is used with permission fro m Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. Ophthalmic Sites. In: AlCC Staging Manual. 7th ed. New York, NY: Springer; 2010:part X, pp 521-589.1 Carcinoma of the Eyelid Staging Form ,

Clinical Extent of disease before

Patholog ic Extent of disease through completion of definitive surgery

Stage Category Definitions

any treatment

o y clinical-

stag in g

completed after neoadjuvant therapy but before subseque nt su rgery

Tumor Size:

latera Iity: D left o ri ght

o y pathologic-staging completed after o bilateral

neoadjuvanttherapv AND subsequent surgery

Primary Tumor (T) 0 0 0 0

TX TO Tis

T2a

T2b

TJa

T3b

Primary tumor cannot be assessed.

No evide nc e of primary tumor Ca rc inoma in situ. Tumor 5 mm or less in greatest dimens ion. Not invading the tarsa l plate or eyelid margin, Tumor mo re than 5 mm, but not more than 10 mm in greatest dime nsion. Or, any tumor that in vades the tarsal plate or eyelid margin. Tumo r more than 10 mm, but not more than 20 mm in greatest dimension. Or, involves fu ll th ickness eyelid . Tumor more than 20 mm in greatest dimens ion. Or, any tumor that invades adjacent ocular, or orbital structures. Any T with perineura l tum or invasion. Tumor co mpl ete resection requires enucleation, exenteration or bone resection Tumo r is not resectable due to extensive invasion of ocular, orbital, craniofacial structures or brain.

0 0 0 0

TX TO

T2a

T2b

T3a

T3b

Tis

(Continued)

329

330 • Ophthalmic Pathology an d Intraocular Tumors Carcinoma of the Eyelid Staging Form (continued)

Patho logic

Cl inica l

Extent of disease through completion of definitive

Stage Category Definitions

Extent of disease before

any treatment

surgery

Regional Lymph Nodes (N)

0 0

NX NO

Region al lymph nodes cannot be assessed. No region al lymph node metastasis, based upon clini cal evalu ation or imag in g. No reg iona l lymp h node metastasis, based upon lymph node biopsy. Region al lymph no de metastasis.

Distant Metastasis (M)

No dista nt meta stasis (no patholog ic MO; use

Distant metastasis.

cli nica l M to complete stage grou p).

Anatomic Stage· Prognostic Groups

Clinical

Patholog ic

Group

0 0 0 0 0 0 0 0 0 0

li s

NO NO NO NO NO NO NI Any N Any N

MO MO MO MO MO MO MO MO MI

0 0 0 0 0 0 0 0 0 0

li s T1

NO NO NO NO NO NO NI Any N Any N

MO MO MO MO MO MO MO MO MI

IA TI T2, IB T2b Ie T3, II IliA T3b AnyT IIIB Il le T4 IV AnyT Stage unknown

IA T2, IB Ie T2b T3, II lilA T3 b IIIB AnyT IIle T4 Any T IV Stage unknown

Prognostic Fa ctors (Site-Specific Factors) Required for Staging: None Clinica l ly Significant: Sentinel Lym ph Nod e Biopsy (SLNB ) resu lts Re gional nodes identified on clinical or radiogra phic examination Pe rineural invasion Tumor necrosis Pa getoid spread More than 3 Moh s mi crogra phic su rgical layers required Imm unosuppression-patient has HIV Immunosuppression-history of solid orga n tra nsplant or leuke mia Prior radiation to the tumor field Excluding skin cance r, patient has histo ry of two or more ca rcinomas _ _ _ Patient has Muir·Torre syndrome Pati ent has xeroderm a pigmentosa For Eye lid Cutaneous Squamou s Cell Carcinoma only: Requ ire d for Stagi ng: Tumor thickness (in mm) Clark's Level Presence/absence of perineu ral invas ion Pri mary site loc ati on on ear or non·glabrous li p Histologic grade Size of la rgest lymph nod e metastasis

Gen eral Notes: For identification of special cases of TN M or pTNM classifi· cations, the ~m~ suffix and "y," ~r, " and "a " prefixes are used. Although they do not affect the stage grouping, they indicate cases needing se parate analysis. m suffix indicates the presence of multiple primary tumors in a single site and is recorded in parentheses: pT(m)NM. y prefix indicates those cases in which classific ation is pe r· formed during or following ini· tial multimodality therapy. The cTNM or pTNM category is iden· tified by a ~ y" prefix. The ycTNM or ypTN M categorizes the extent of tumor actually prese nt at the time of that examination.

APPENDIX: Ame rican Join t Committee o n Cancer (AJCC) Staging Fo rm s, 201 0 • 33 1

Carcin oma of the Eyelid Staging Form (con tin ued) Genera l Notes (continued):

Histologic Grade (G) (also known as overall grade) Grading system 2 grade system 3 grade system 4 grade system No 2, 3, or 4 grade system is ava ilab le

0 0 0 0

Grade

0 0 0 0

Grade Grade Grade Grade

I or 1 II or 2 II I or 3 IV or 4

Additi onal Descriptors Lymphatic Vessel Invasion (L) and Venous Invasion (V) have been combined into Lymph-Vascular Invasion (LV I) for collection by cancer registrars. The College of American Pathologi sts' {CAP l Checklist should be used as the primary source. Other sources may be used in the absence of a Checklist. Priority is given to positive results.

::J lymph-Vascular Invasion Not Present (absentl!Not Identified

Lymph-Vascular Invasion Present/Identified

0 Not Applicable 0 Un known!1ndete rminate Residual Tumor (R) The absence or prese nce of residual tumor afte r treatment. In some cases treated with surgery and/o r with neoadjuvant therapy there will be residual tumor at the primary site after treatment because of incomplete resection or local and regional disease that extends beyond the limit of ability of resection.

RX ORO o Rl o Rl

Presence of residual tumor cannot be assessed No residual tumor Microscopic residua l tumor Macroscopic residual tumor

The "y" categorization is not an estima te of tumor prior to multimodality therapy. r prefix indicates a recurrent tumor when staged after a disease -free interval, and is identified by the "r" prefix: rTNM. a prefix designates the stage determined at autopsy: aTNM. surgical margins is data field recorded by registrars describing the surgical margins of the resected primary site spec imen as determined only by the pathology repo rt. neoadjuvant treatment is radiation therapy or systemic therapy (consisting of chemotherapy, hormone therapy, or immunotherapy) administered prior to a definitive surgical procedure. If the surgical procedure is not performed, the administered therapy no longer meets the definition of neoa djuva nt therapy.

Hi stolog ic Grade (G) Grade is reported in regislry systems by the grade value. A two-grade, three-grade, or four-grade system may be used. If a grad ing system is not specified, generaHy the following system is used: GX GI G2 G3 G4

Grade cannot be assessed Well differentiated Moderately differentiated Poorly differentiated Undifferentiated

Hi sto pathologic Type The primary eyelid carcinoma tumors include the follow ing group and list of histologies: Basal cell carcinoma Squamous cell carci noma Mucoepi dermoid carcinoma Sebaceous carcinoma Primary eccrine adenocarcinoma Primary apocrine adenocarcinoma Adenoid cystic carci noma Merkel cel) carcinoma

332 • Op hthalmic Pathol ogy and Intraocula r Tumors

Carcinoma of the Conjunctiva Staging Form Pathologic

Clinical Extent of disease before any

Extent of disease through completion of definitive surgery

Stage Category Definiti ons

treatment

o y pathologic- staging completed after

o y clinical- staging

completed aher

Tum or Size:

l atera IltV:

neoadjuvant therapy but before subsequent surgery

o left

o right

o bilateral

neoadjuvant therapy AND subsequent surgery

Primary Tumor (T)

0 0 0 0 0

TX TO Tis

T1 T2

Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Tumor 5 mm or less in greatest dimension Tu mor more than 5 mm in greatest dimension,

0 ;:]

TX TO

0 0 0

T4a

0 :l 0

T4b T4c T4d

::J 0 0

NX NO N1

Ti s

without invasion of adjacent structures 0

T4a

0 0 0

T4b T4c T4d

Tumor invades adjacent structures (excluding the orbit) Tumor invades the orbit with or without further extension Tumor invades orbital soh tissues, without bone invasion Tumor invades bone Tumor invades adjacent paranasal sin uses Tumor invades brain

0 0 0

NX NO N1

Regional lymph nodes cannot be assessed No regional lymph node metastasis Regional lymph node metastasis

Regio nal Lymph Nodes tN)

Distant Metastasi s (M)

No dista nt metastasis (no patholog ic MO; use clinical M to complete stage group) Distant metastasis Anatomic Stage . Progn ostic Groups

Clinical No stage grouping is presently recommended

Pathologic No stage grouping is presently recommended

Prognostic factors (Site- Spe cific fa cto rs) Required for Staging: None Clinica lly Significant: Ki-67 growth fraction Histol ogic Grade (G) (also known as overall grade) Grading system

0 0 O

2 grade 3 grade 4 grade No 2, 3,

system system system or 4 grade system is available

Grade

0 0 ;:]

Grade Grade Grade Grade

I or 1 II or 2 til or 3 IV or 4

Gene ra l Notes: For identification of special cases of TNM or pTNM classifications, the "m" suffix and "y," "r,N and ~ a H prefixes are used. Although they do not affect the stage grouping, they indicate cases needing separate ana lysis. suffix indicates the presence of multiple primary tumors in a single site and is recorded in parentheses: pT(m)NM.

III

APPENDIX, Ame rican Joint Committee on Cancer (AJCC) Staging Form s, 2010 • 333

Carcinoma of the Conjunctiva Staging Form (co ntinued) Additional Descriptors Lymphatic Vessel Invasion (L) and Venous Invasion (V) have been

combined into Lymph-Va scular Invasion (LVI) for collection by cancer registrars. The College of American Patho logists' (CAP ) Checklist should be used as the primary source. Other sources may be used in the absence of a Checklist. Priority is given to positive resu lts .

o o a

Lymph -Va scular Invasion Not Present (absent)/Not Identified Lymph-Vascular Invasion Present/Identified Not Applic able Unknown/Indeterminate

Residual Tumor (R)

The absence or presence of residual tumor after treatment. In some cases treated with surgery and/or with neoad juvant therapy there will be resid ual tumor at the prima ry site after treatment because of incomplete resection or local and regional disease that extends beyond the limit of ability of resection.

RX Presenc e of residual tumor cannot be assessed ORO No residual tumor Rl Microscopic residual tumor R2 Macroscopic residu al tumor

o o

General Noles (continu ed): y prefix indic ates those cases in which classification is performed during or following initial multimodality therapy. The cTNM or pTNM category is identified by a HyH

prefix. The ycTNM or ypTNM categorizes the extent of tumor actually present at the time of that examination. The 'y categorization is not an estimate of tumor prior to multi modality therapy. r prefix indicates a recurrent tumor when staged afte r a disease-free interval, and is identified by the "r" prefix: rTNM. a prefix designates the stage determined at

autopsy: aTNM. su rgical margins is data field re co rded by registrars describing the surgical margins of the resected primary site specimen as determined only by the pathology report.

neoadjuva nt treatment is radiation therapy or systemic therapy (con sisting of chemotherapy, hormone therapy, or immunotherapy) administered prior to a definitive surgical procedure. If the surgical procedure is not performed, the administered therapy no longer meets the definition of neoadjuvanttherapy.

Hi stopathologic Type The classification applies only to carcinoma of the conjunctiva. Conjunctival intraepithel ial neoplasia (CIN) includ ing in situ squamous cell carcinoma Squamous cell carcinoma Mucoe pidermoid carcinoma Sp indle cell carci noma Sebaceous gland carcinoma including pagetOid (conjunctival) spread Basal cell carcinoma Hi stologic Grade (G) Grade is reported in registry systems by the grade value. A two-grade, three-grade, or fou r-grade system may be used. If a grading system is not specified, generall y the following system is used: GX G1 G2 G3 G4

Grade cannot be assessed Well differentiated Moderately differentiated Poorly differenti ated Undifferentiated

334 • Ophthalmic Pathology and Intraocular Tum ors Malignant Melanoma of the Conjunctiva Staging Form Cl inical Extent of disease before any

Stage Category Definitions

treatment

completion of definitive surgery

o y pathologic-staging

o yclinical-staging completed after neoadjuvant therapy but

Pathol ogic Extent of disease through

Tumor Size :

l atera lity: o left 0 right 0 bilatera l

before subsequent surgery

completed after neoadjuvant thera py AND subsequent surgery

Primary Tum or (T) Quad rants are defined by clock hour, starting at the limbus (eg, 6, 9, 12,3) extending from the central cornea to and beyond the eyelid margins. This wi11 bisect the caruncle.

:l 0 :l

TX TO

Primary tumor cannot be assessed No evid en ce of primary tumor

Tis

Melanoma confined to the conjunctival

TX TO Tis

pTl a

pTlb

:::l

pTlc

pTZa

pT2b

pT2c

Tla pTla

Tlb pTlb

Tlc pT1c

:l :l

Tld T2

T2a pT2a

T2b pT2b

T2c pT2e

T2d

epithelium Malignant conjunctival melanoma of the bulbar conjunctiva Less than or equa l to 1 quadrant* Melanoma of the bulbar conjunctiva not more than 0.5 mm in thickness with invasion of the substanti a propria More than 1 but less than or equal 10 2 quadrants Melanoma of the bulbar conjunctiva more than 0.5 mm but not more th an 1.5 mm in thickness with invasion of the substantia propria More than 2 but less than or equal to 3 quad rants Melanoma of the bulbar conjunctiva greater than 1.5 mm in thickness with invasion of the substantia propria Greater than 3 quadrants Malignant conjunctival melanoma of the nonbulbar (pa lpebral, forniceal, caruncular) Non -caruncular, less than or equal to I quadrant Melanoma of the palpebral, forniceal or caruncula r conjunctiva not more than 0.5 mm in thicknes s with inva sion of the substantia propria Non-caruncular. greater than 1 quadrant Melanoma more than 0.5 but not greater than 1.5 mm in thickness with inva sion of the substantia propria Any caruncular, less than or equ al to 1 quadrant Melanoma of the pa lpebral, forni ceal or caruncular conjunctiva greater than 1.5 mm in thicknes s wi th invasion of the substantia propria Any caruncular, greate r than 1 quadrant

APPEND IX: American Joint Comm ittee on Cancer (AJCC) Stag ing Forms, 20 10 • 335

Malignant Melanoma of the Conjunctiva Staging Form (contin ued) Clini cal Extent of disease before any treatment

T3 pT3

0 0 0 0 0

T3. T3b T3c T3d T4 pT4

Pathologic Extent of disease through completion of definitive surgery

Stage Category Definition s

Any malignant conjunctiva l melanoma with loca l invasion Melanoma invades the eye, eyelid, nasolacrimal system, sinuses or orbit Globe Eyelid Orbit Sinus Tumor inva des the central nervous system Melanoma invades the central nervous system

pT3

pT4

0 0

NX NO

* pT(is ) Melanoma in situ (inclu des the term primary acqu ired melanosis) with atypia replac ing greater tha n 75% of the normal epithel ial th ickness, with cytologic featu res of epithelioid ce lls, includ ing ab undant cytoplasm, vesicular nuclei or prominent nucleoli, and/or presence of intraep itheli al nests of atypical ce lls.

0 0 0

NX NOa (biopsy)

NOb (n. biopsy)

Regional l ymph Nod es (N ) Clinical Regional lymph nodes cannot be assessed No regional lymph node meta stasis, bi opsy performed No reg ional lymph nod e metastasis, biopsy not performed Regional lymph node metastasis Distant Meta stasis (M) No distant metastasis (no pathologic MO; use clinical M to complete stage group ) Distant metastasis Anatomi c Stage· Prognostic Grouping

Clinical No stag e grou ping is presently recommended

Pathologi c No stage grouping is presently recommended

Prog nosti c Factors (Site-Spec ific Factors) Required for Stagi ng: None Clini ca ll y Signifi ca nt Measured thickness {d epth ) Histologic Gra de (G) (also known as overall grade) Grading system

0 0 O 0

2 grade system 3 grade system 4 grade system No 2, 3, or 4 grade system is ava ilable

Grade

0 0 0 0

Grade Grade Grade Grade

I or 1 II or 2 III or 3 IV or 4

Genera l Notes: For identifi cation of specia l cases of TNM or pTNM classifications, the "m" suffix and "y," "r," and "a" prefixes are used. Although they do not affect the stage grouping, they indicate cases needing separate ana lysis m suffi x indicates the presence of mu ltiple primary tumors in a single site and is recorded in parentheses: pT(m}NM. (Contmued)

336 • Ophthalmic Path ology and Intra ocula r Tu m ors Malignant Melanoma of the Conjunctiva Staging Form (continued) Additional Descriptors Lymphatic Vessel Invasion (L) and Venous Invasion {V} have been combined into l ymph-Vascular Invasion (LVI) for collection by cancer registrars. The CoUege of American Pathologists' (CAP) Chec klist sh ould be used as the primary source. Other sou rces may be used in the absence of a Checklist. Priority is given to positive results.

o a o o

ing initial multimoda lity therapy. The cTN M or pTNM category is identified by a "y" prefix. The ycTNM or ypTNM categorizes the extent of tumor actually present at the time of that examination. The ~y~ catego-

Unknown/In determinate

multi modality therapy.

will be resi dual tumor at the primary site after trea tment because of incomplete resection or loca l and regional disease that exte nds beyond the limit of ability of resection.

RX RO

Presence of residual tumor cannot be assessed No residual tumor

Microscopic residual tumor

Macroscopic res idua l tumor

y prefix indicates those cases in which classification is performe d during or follow·

l ymph-Vasc ular Invasion Not Present (absentl/Not Identified Lymph-Vascula r Invasion Present/Identified Not Applicable

Residual Tumor (R) The absence or presen ce of residu al tumor after treatment. In some cases treated with surgery and/or with neoadjuvant therapy there

General Notes (continued):

rization is not an estimate of tumor prior to

r p refix indicates a recurrenttumor when staged after a disease-free interval, and is identified by the HrW prefix: rTNM. a prefix designates the stage determined at autopsy: aTNM. surgica l margins is data field recorded by registrars describing the surgical margins of the resected primary site specimen as determined only by the pathology report. neoad juvant treatment is radiatio n the rapy or syste mic therapy {consisting of chemotherapy, hormone therapy, or immunotherapy) administered prior to a definitive surgical procedure. If the surgical procedure is not performed, the administered therapy no longer meets the definition of neoadjuvant therapy.

Histopathologic Type This categorization applies only to melanoma of the conjunctiva. Histologic Grade (G) Histologic grade represents the origin of the primary tumor. GX Or igi n cannot be assessed GO Primary acquired melanosis without cellular atypia Conjunctival nevus G1 G2 Primary acqui red melanosis with cellular atypi a (epithelial disease on ly) G3 Primary acqu ired melanosis with epithelial cell ular atypia and invasive melanoma G4 De novo malignant melanoma

APPENDIX:

American Joint Committee on Can ce r (AJ CC) Staging Forms, 2010 • 337

Malignant Melanoma of the Uvea Staging Form Clinic al Extent of disease before any treatment

Stage Category Definitions

o y cl inica l-stagi ng comp leted after neoadjuva nt therapy but before subsequent su rge ry

Patholog ic Extent of disease through completion of definitive surgery

o Tumor Size:

laterality: o left 0 right 0 bi latera l

y patholog ic- staging completed after neoadj uvant therapy AND sub seq uent surgery

Primary Tumor (T)

All Uveal Melanomas 0 0

TX TO

0 0

Tl Tl,

Tlb

Tlc

T2,

0 0

T4 T4,

T4b

Primary tumor cannot be assessed No evidence of primary tumor Iris" Tumor limited to the iris Tumor limited to the iris not more than 3 clock hours in size Tumor limited to the iris more than 3 clock hours in size Tumor limited to the iris with seconda ry glaucoma Tumor confluent with or extending into the ci liary body, choroid or both Tumor confluent with or extending into the cil iary body, choroid or both, with secondary glaucoma Tumor confl uent with or extending into the cil iary body, choroid or both, with scleral extension Tumor confluent with or extending into the cil iary body, choroid or both, with scleral extension and secondary glaucoma Tumor with extrascleral extension Tumor with extrascleral extension less than or equal to 5 mm in diameter Tumor with extrascleral extension more than 5 mm in diameter

o o

TX TO

o o

Tl Tla

Tlb

Tlc

T2a

T3a

o o

T4b

Tl T1a

T4a

*Iris me lanomas originate from, and are predom inantly located in, this region of the uvea. If less than ha lf of the tumor vol ume is located within the iris, the tumor may have originated in the ciliary body and consideration should be given to classifying it according ly. Ciliary Body and Choroid (see Figure below)

o o

Tl Tla

Primary cil iary body and choro idal melanomas are classified according to the four tumor size categories be low: Tumor size category 1 Tumor size category 1 without ciliary body involvement and extraocular extens ion

(Continued)

338 • Ophthalmic Pat hology and Intraocular Tumors

Ma li gnant M el ano m a of the Uvea Staging Form (continued) Clini cal Extent of disease before any

Patho logic Stage Category Defin ition s

treatment 0

Tl b

TIc

Extent of disease through completion of definitive surgery

Tumor size catego ry 1 with ciliary body involvement Tumor size catego ry 1 without ciliary body

Tlb

TIc

TId

0 0

T2 T2a

T2b

::J

T2c

T2d

0 0

T3 T3a

T3b

T3c

T3d

0 0

T4 T4a

T4b

T4c

T4d

T4e

involvement but with extraocu lar extensi on 0

TId

less than or equal to 5 mm in dia meter Tumor size catego ry 1 with ciliary body invo lvement and extraocu lar extension less

0 0

T2 T2a

T2b

T2c

T2d

0 0

T3 T3a

T3b

T3 c

T3d

0 0

T4 T4a

T4b

T4c

T4d

T4e

than or equal to 5 mm in dia meter Tumor size category 2 Tumor size category 2 without cili ary body involvement and extraocular extension

Tumor size category 2 with ci liary body invo lvement Tumor size category 2 without ciliary body invo lvement but with extraocu lar exte nsio n less than or equal to 5 mm in diameter Tumor size category 2 with ci liary body involvement and extraocular extension less tha n or equal to 5 mm in diamete r Tumor size category 3 Tumor size category 3 witho ut ciliary body invo lvement and extraocular exte nsion Tumor size catego ry 3 with ciliary body invo lvement Tumor size category 3 without cili ary body involvement but with extraoc ul ar extension less than or eq ual to 5 mm in diameter Tumor size catego ry 3 with ciliary body involvement and extraoc ular extension less than or equal to 5 mm in diameter Tumor size category 4 Tumor size category 4 without cili ary body invo lv ement and extraoc ular extens ion Tumor size categ ory 4 with cil iary body invo lveme nt Tumor size category 4 without cili ary body involvement but with extraoc ul ar extensio n less than or equal to 5 mm in diameter Tumo r size category 4 with ci li ary body involvement and extraocula r exte nsion less than or equa l to 5 mm in diameter Any size tumor category with extraoc ul ar extension more than 5 mm in diameter * Clin ical : In clinica l practice, the largesttu mor basa l diameter may be estimated in optic disc diameters (dd, average: 1 dd = 1.5 mm ). Tumor

APPEN DIX, A merica n Jo int Committee o n Cance r (AJCC) Stag ing Fo rm s, 2010 • 339

Malignant Melanoma of the Uvea Staging Form (co ntinued) Clinical Extent of disease before any

Pathologic Extent of disease through completion of definitive

Stage Category Definitions

treatment

surgery

thickness may be estimated in diopters (average: 2.5 dioplers =1 mm). However. techni que s such as ultrasonography and fund us photography are used to provid e more accurate measurements. Ciliary body involveme nt can be eva lu ated by the slit-lamp, ophthalmoscopy. gonioscopy and transillumination . However, high frequency ultrasonography (ultrasound biomicroscopy) is used for more accurate assessme nt. Extension through the sclera is evaluated vis ually before and during surgery, and with ultrasonography, computed tomography or magnetic resonance imaging. t Pathologic: When histopathologic measurements are reco rded after fixation, tumor diameter and thickness may be unde restimated becaus e of tissue shrinkage. Regional lymph Nodes (N)

0 0 0

NX NO Nt

Regi ona l lymph nodes cannot be assessed No reg ion al lymph node metastasis Regional lymph node metastasis

0 0

MI MIa

Mlb

Mlc

No distant metastasis (no pathologic MO; use clinical M to complete stage group) Distant metastasis La rgest diameter of the largest metastasis :s:3cm largest diameter of the larg est metastasis 3. 1- 8.0 cm Largest diam eter of the largest metastasis 8. 1 cm or more

0 0 0

NX NO NI

0 0

Mt Mta

Mtb

Mtc

Distant Metastasis (M)

Thickness (mm)

>1 5.0

12.1- 15.0 9.1-12.0

6.1 - 9.0

3. 1- 6.0

==:3.0

3.1-6.0

6.1-9.0

9. 1- 12.0

:s:3.0

3 2

I I

12.1-15.0

15.1- 18.0

>18.0

Largest basal diameter (mm) Classification fo r cili ary body and choroid uveal melanoma based on thickness and diameter. (Co ntinued)

340 • OphthalmicP ath o logy and Intraocula r Tumo rs

Malignant Melanoma of the Uvea Staging Form (continued) Anatom ic Stage. Prognostic Grouping

Clinical

Gro up 0 0

I IIA

liB

lilA

Pathologic

Group

T1, T1b-d T2, T2b T3,

NO NO NO NO NO NO NO NO NO NO NO Nt

MO MO MO MO MO MO MO MO MO MO MO MO

0 0

Any N

Mla- c

T2c- d T3b- c

T4, T3d T4b-c T4d- e AnyT

IIIB

0 0

IIIC IV

AnyT Stage unknown

0 0

0 0 0 0

T1, T1b- d T2, liB T2b T3, T2c-d lilA T3b-c T4, II IB T3d T4b- c T4d-e II IC IV AnyT AnyT Stage unknown I IIA

Prog nosti c Factors (Site-Specific Factors)

Required for Stag in g: Tumor heig ht and largest diameter

Clin ica lly Significa nt:

NO NO NO NO NO NO NO NO NO NO NO Nt

MO MO MO MO MO MO MO MO MO MO MO MO

Any N

Mla- c

General Notes: For identification of special cases of TNM or pTNM cla ssifications. the "rn"

Measured thickness (depth) Chromosoma l alterations Gene expression profile Positron emission tomography/computed tomogra phy

suffix and "y," "r," and "a" prefixes are

Confocal indocyanine green angiography Mitotic count per 40 high power fields (H PF) Mean diameter of the ten large st nucleoli (M LN) Presence of extravascular matrix patterns Microvascular density (MVD) In sulin- like growth factor 1 receptor (IGF1-R) Tumor-infiltrating lymphocytes Tumor-infiltrating macrophages HLA Class I expression

m suffix indicates the presence of multipie primary tumors in a single site and is recorded in parentheses: pT{m)NM.

used. Although they do not affect the stage grouping, they indicate cases needing sepa rate analysis.

Histologic Grade (G) (also known as averalf grade) Grading system

0 0 0 0

2 grade system 3 grade system 4 grade system No 2, 3, or 4 grade system is available

Grade

0 0 0 0

Grade I or 1 Grade II or 2 Grade II I or 3 Grad e IV or 4

Additiona l Descripto rs

Lymphatic Vessel Invasion (L) and Venous Invasion (V) have been combined into Lymph-Vascular Invasion (LVI) for collection by cancer registrars. The College of American Pathologi sts' (CAP) Checklist should be used as the primary source. Other sourc es may be used in the absence of a Checklist. Priority is given to posit ive resu lts.

0 0 0 0

Lymph -Vascular Invasion Not Present (absent)/Not Id entified Lymph-Vascular Invasion Present/Identified Not Applicable Unknown/In determinate

APPENDIX, American Joint Committee on Cance r (AJCC ) Staging Form s, 2010 • 341

Malignant Melanoma of the Uvea Staging Form (co ntinued) Residual Tumor (R) The absenc e or presence of residual tumor after treatment In some cases treated with surgery and/or with neoadjuvant the rapy th ere will be residual tumor at the primary site after treatment because of inc omplete resection or local and regi onal disease that extends beyond the limit of ability of resection.

o o o o

RX RO Rl R2

Presence of residual tumor cannot be assessed

No residua l tumor Microscopic residual tumor Macro scopic residu al tumor

General Notes (continued): neoadjuvant treatment is radiation therapy or systemic therapy (consisting of chemotherapy, horm one therapy, or

immunotherapy) administered prior to a definitive surgical procedure. If the surgical procedure is not periormed, the

administered therapy no longer meets the definition of neoa diuvant therapy.

Hi stopathologic Type The histopathologic types are as follows: Spindle cell melanoma (greater than 90% spindle cells) Mixed cell melanoma (> 10% epithelioid cells and <90% spi ndle cells) Epithelioid cell melanoma (greater than 90% epithelioid cells) Histologic Grade (G)* GX GI G2 G3

Grade cannot be assessed Spindle cell melanoma Mixed cell melanoma EpitheliOid cell melanoma

* Note: Because of general lack of agreement regard ing which proportion of epithelioid cells classifies a tumor as mixed and epithelioid in type, some opht halmic pathologists currently combine grades 2 and 3 (nonspindle, epithelioid cells detected) and contrast them with grade 1 (spindle, no epithelioid cells detected) .

342 • Op ht halm ic Pathology and Intraocular Tu mors

Retinoblastoma Staging Form Clinical Extent of disease before any

Pathologic Stage Category Definitions

treatment

surgery

o y pathologic-staging

::J y clinical-staging completed after neoadjuvant therapy but before subsequent surgery

Extent of disease through completion of definitive

Tumor Size:

laterality: o left 0 right 0 bilateral

completed after neoa djuvant therapy AND subsequent surgery

Primary Tumor (T)

o o

TX TO Tl

pTl o

T1a

Tlb

Tl c

pT2 0

T2,

pT2a

T2b

pT2b

TJ pT3 T3, pTJ.

Primary tumor cannot be assessed. No evidence of primary tumor. Tumors no more than 2f3 the volume of the eye with no vitreous or subretinal seeding. Tumor confined to eye with no optic nerve or choroidal invasion.

pTX pTO

pTl

pT2

pTZa

pT2b

pT3

pTJ,

No tumor in either eye is greater than 3 mm in la rgest dimension or located closer than 1.5 mm to the optic nerve or fovea, At least one tumor is greater than 3 mm in largest dimension or located closer than 1.5 mm to the optic nerve or fovea. No retinal detachment or subretinal fluid beyond 5 mm from the base of the tumor. At le ast one tumor is greater than 3 mm in largest dimension or located closer than 1.5 mm to the optic nerve or fovea. With retinal detachment or subretinal fluid beyond 5 mm from the base of the tumor. Tumors no more than 0/3 the volume of the eye with vitreous or subretinal seeding. Can have retinal detachment. Tumor with minimal optic nerve and/or choroidal invasion. Foca l vitreous and/or subretinal seeding of fine aggregates of tumor cells is present, but no large clumps or "snowballs" of tumor cells. Tumor superficially invades optic nerve head but does not extend past lamina cribrosa or tumor exhibits focal choroidal inva sion. Massive vitreous and/or subretinal seeding is present, defined as diffuse clumps or "snow balls ~ of tumor cells. Tumor superficially invades optic nerve head but does not extend past lamina cribrosa and exhibits focal choroidal invasion. Seve re intraocular disease. Tumor with significant optic nerve and/or choroidal invasion. Tumor fills more than ~ of the eye. Tumor inva des optic nerve past lamina crib rosa but not to surgica l resection line ortumor exhibits massive choroidal invasion.

APPENDIK Am eri can Joint Committee on Cancer (AJCC) Staging Form s, 2010 • 343

Retinoblastoma Staging Form (continued) Clinical Extent of disease before any

Pathologic Stage Category Definitions

treatment 0

T3b

pT3b

T4 pT4 T4. pT4a

0 :I

T4b pT4b T4c T4d

Extent of disease through completion of definitive surgery

One or more complications present, which may

inc lude tumor-associated neovascu lar or angle closure glaucoma, tumor extension into the anterior segment, hyphema, vitreous hemorrhage, or orbital ce llulitis. Tumor invades optic nerve past lamina cfibrosa but not to surgical resection line and exhibits massive choroidal invasion. Extraocular disease detected by imaging studies. Tumor invades optic nerve to resection line or exhibits extraocular extension elsewhere. Invasion of optic nerve. Tumor invades optic nerve to resection line but no extraocular extension identified. Invasion into the orbit Tumor invades optic nerve to resection line and extraocular extension identified. Intracranial extension not past chiasm. Intracranial extension past chiasm.

pT3b

pT4

pT4a

pT4b

0 0 0

NX NO Nt

0 0 0 0 0

Ml Mla Mlb Mlc Mld

Mt.

Reg iona l l ymph Nodes IN)

:I :I 0

NX NO Nl

Clinical Regional lymph nodes cannot be assessed. No regional lymph node involvement. Regional lymph node involvement (preauricular, cervical, submandibular). Distant lymph node involvement. Di stant Metastasis 1M)

0 0 0 0 0 0

Ml Mla Mlb Mlc Mld Ml.

Clinical No distant metastasis Ino pathologic MO; use clinical M to complete stage group). Systemic metastasis. Single lesion to sites other th an CNS. Multiple lesions to sites other than CNS. Prechiasmatic CNS lesionls). Postchiasmatic CNS lesionls). leptomeningeal and/or CSF involvement. Pathologic Metastasis to sites othe r than CNS. Single lesion. Multiple lesions. eNS metastasis. Discrete massies) without leptomeningeal and/or CSF involvement. leptomeningeal and/or CSF involvement. Anatomic Stage· Prognostic Groups

Clinical No stage grouping is presently recommended

Pathologic No stage grouping is presently recommended (Continued)

344 • Ophthalmic Pathology and Intraocular Tumors

Retinoblastoma Staging Form (continued) Prognostic Factors (Site-Specific Factors)

Required for Staging: None

Clinically Significant: Extension evaluated at enucleation R8 gene mutation Pos itive family history of retinoblastoma Primary globe-sparing treatment fai lure Greatest linear extent of choroid involved by choroidal tumor invasion

m suffix ind icates the presence of multipie primary tumors in a single site and is recorded in parentheses: pTlm)NM.

Histologic Grade (G) (also known as overall grade) Grading system

0 D 0 0

2 grade 3 grade 4 grade No 2, 3,

system system system or4 grade system is available

Grade

0 0 0 0

Grade Grade Grade Grade

I or 1 II or 2 III or 3 IV or 4

Additional Descriptors

Lymphatic Vessel In vasion (L) and Venous Invasion (V) have been combined into Lymph-Vasc ular Invasion (LVI) for collection by cancer registrars. The College of American Pathologists' (CAP) Checklist shou ld be used as the pri mary source. Other sources may be used in the absence of a Checklist. Priority is given to positive results.

0 Lymp h-Vascu lar Invasion Not Present (absent)/Not Identified 0 Lymph-Vascu lar Invasion Prese nVl dentified

o o

Not Applicable Unknown/Indeterminate

Residual Tumor (R) The absence or presence of res id ua l t umor after treatment. In some cases treated with surgery and/or with neoadjuvant therapy there will be resid ua I tumor at the prima ry site after treatment bec ause of in com plete resection or local and regional disease that extends beyond the lim it of abi lity of resection.

RX O RO o Rl o R2

Presence of residual tumor cannot be assessed No residual tumor Mic roscopic residual tumor Macroscopic residual tumor

y prefix indicates those cases in which classification is performed during or fol lowing initial multi modality therapy. The cTNM or pTNM category is identified by a y' prefix. The ycTNM or ypTNM categorizes the extent of tumor actual ly present at the time of that examination. The "y" categorization is not an estimate of tumor prior to mu ltimodality therapy. r prefix indicates a rec urre nt tumo r when staged after a disease -free interval. and is identified by the "r" prefix: rTNM. a prefix designates the stage determined at autopsy: aTNM. surgical margins is data field recorded by registrars describing the surg ical margi ns of the resected primary site specimen as determined only by the patho logy report. neoadiuvant treatment is radiation therapy or systemic therapy (consisting of chemotherapy, hormone therapy, or immu notherapy) administered prior to a definitive surgical procedure. If th e surgica l procedure is not performed, the administered therapy no longer meets the definition of neoadj uvant therapy.

Histologic Grade (G) Grade is reported in registry systems by the grade value. A two-grade, three-grade, or four-grade system may be used. If a grading system is not specified, generally the following system is used: GX Grade cannot be assessed Well differentiated G1 G2 Moderately differentiated Poorly differentiated G3 G4 Undifferentiated Histopathologic Type This classification applies only to retinoblastoma.

APPENDIK A merican J oint Comm ittee on Cancer (AJ CC) Stag in g Form s, 2010 • 345

Carcinoma of the Lacrimal Gland Staging Form Pathologic

Clinical Extent of disease before any

Extent of disease through completion of definitive surgery

Stage Category Definition s

treatment

a yclinical-staging completed after neoadjuvant therapy but before subsequent surgery

o ypathologicTumor Size:

laterality: Olen o right o bilateral

staging completed after

neoadjuvanttherapv AND subsequent surgery

Primary Tumor (T)

0 0 :J

TX TO T1

Primary tumo r cannot be assesse d No evid enc e of prima ry tu mo r Tumor 2 em or less in greatest dimension, with

0 0 0

TX TO T1

or without extraglandular extension into the 0

0 T3 W T4 W T4a 0 T4b 0

T4c

orbital soft tissue Tumor more than 2 em but not more than 4 em in greatest dimension* Tumor more than 4 em in greatest dimen sion* Tumor invades periosteum or orb ital bone or adjac ent structures Tumor invades periosteum Tumo r invades orbital bone Tumor invades adjacent structures (brain, sinus, pterygoid fossa, temporal fossa )

W T2 0 T3 W T4

W T4a W T4b

T4c

NX NO Nl

*As the maximum size of the lacrimal gland is 2 cm, T2 and greater tu mors will usually extend into the orbital soft tissue. Regional Lymph Nod es (N )

0 0

NX NO Nl

Regional lymph nodes cannot be assessed No regional lymph node metastasis Regional lymph node metastasis

No distant metastasis (no pathologic MO; use clinical M to com pl ete stage group) Distant metastasis

Distant Metastasis (M)

Anatomic Stage . Prognostic Groups Cli nica l No stage grouping is presently recommended

Path olog ic No stage grouping is presently recommended

Pro gn osti c Fa ctors (Site-Specific Factors) Required fo r Stagin g: None Clinica lly Significant: Ki-67 growth fraction Nuclear NM 23 staining

346 • Ophthalmic Pathology and Intraocular Tumors Carcinoma of the Lacrimal Gland Staging Form (continu ed) Genera l Notes (continued):

Hist%gic Grade (G) (also known as overaff grade)

Grading system

Grade

Q 2 grade system Grade I or 1 Q Q 3 grade system Grade (I or 2 Q Q 4 grade system Grade III or 3 Q No 2, 3, or 4 grade system is available ___Q Grade IV or 4 i-==--'-C'-='2-=-c..=:=-:..::.c:::.=-~:C::=:"::' =---=~:::":--==-_---j Q

Additiona l Descriptors

Lymphatic Vessel Invasion (L) and Venous Invasion (V) have been combined into Lymph-Vascular Invasion (LVI) for coll ection by cancer registrars. The Co llege of American Patho logists' (CAP ) Che cklist should be used as the primary source. Other sources may be used in the ab se nce of a Checklist. Priority is given to po sitive results.

o o o o

Lymph-Vascular Invasion Not Present (absent)!N ot Identifi ed Lymph -Vascu lar Invasion PresenVldentified Not Applicab le Unknown/Ind eterminate

Residual Tumor (R) The absence or prese nce of residual tumor afte r treatment. In some cases treated with surgery and/or with neoad juva nt therapy there will be residual tumor at the primary site after treatm ent bec aus e of incomp lete resection or local and reg ional disease that extends beyond the limit of ability of resection.

Q RO

Q Rl Q R2

Prese nce of residual tumor cannot be assessed No residual tumor Microscopic residual tumor Macroscopic residual tumor

m suffi x indicates the presenc e of multiple primary tumors in a sing le site and is recorded in parenthese s: pT(m)NM.

V prefix indicates those cases in which classification is performed during or fol lowing initial multimodality therapy. The cTNM or pTNM category is identified by a "y" prefix. The ycTNM orypTNM categorizes the extent of tumor actually present at the time of that examination. The "y" categorization is not an estimate of tumor prior to multi modality therapy. r prefix indicates a recurrent tumor when staged after a disease-free interval, and is identified by the "r" prefix: rTNM. a prefix designates the stage determined at autopsy: aTNM. surgical margins is data field recorded by registra rs de sc ribing the surgical margins of the re sected primary site specimen as determined only by the pathology report. neoadjuva nt treatment is rad iation therapy or systemic therapy (consisti ng of chemotherapy, hormone therapy, or immunotherapy) adm inistered prior to a definitive surgical proced ure. If the surgical procedure is not performed, the administered therapy no longer meets the definition of neoadjuva nt therapy.

Histologic Grade (G) In most cases, the histology defines the grade of malignancy in lacrimal gland carcinomas as in salivary gland carcinomas. GX G1 G2 G3 G4

Grade cannot be assessed Well differentiated Moderately differentiated: includes adenoid cystic carcinoma without basaloid (sol id) pattern Poorly differentiated: includes adenoid cystic carcinoma with basaloid (solid) pattern Undifferentiated

Histopathologic Type The major malignant primary epithelial tumors include the following: Low Grade Carcinoma ex pleomorphic adenoma [where the carcinoma is noninvasive or minimally invasive as defined by the W HO classification (extension < l.5 mm beyond the capsule-into surrounding tissue) I Polymorphous low-grade carcinoma Mucoepidermoid carcinoma, grades I and 2 Epithelial-myoepithelial carcinoma

APPENDIX, American Jo int Committee on Cancer (AJCC ) Staging Forms, 2010 • 347

Cystadenocarcinoma and papilJary cystadenocarci noma Acinic cell carcinoma Basal cell adenocarcinoma Mucinous adenocarcinoma

High Grade Carcinoma ex pleomorphic adenoma (m alignant m ixed tumor) that includes adenocarcinoma and adenoid cystic carcinoma arisi ng in a pleomo rphic adenoma [where the carcinoma is invasive as defined by the WHO classification (extension> 1.5 mm beyond the capsule-into surrounding tissue)] Adenoid cystic carcinoma, not otherwise speci fi ed Aden oca rcinoma, not otherwise speci fi ed Mucoepidermoid carcinoma, grade 3 Ductal adenocarcinoma Squamous cell carcinoma Sebaceous adenocarcinoma Myoepithelial carcinoma Lymphoepithelia l carcinoma Other Rare and Unclassifiable Carcinomas

348 • Ophthalmic Pathology and Intraocular Tumors Sarcoma of the Orbit Staging Form Clinical Extent of disease before any

Pathologic Extent of disease through completion of definitive surgery

Stage Category Definitions

treatment o y clinica l-stag ing completed after

Tumor Si ze:

l aterality: Olen o right o bilateral

neoadiuvant therapy but before subsequent surgery

y pathologic- staging completed after neoadjuvant therapy AND subsequent surgery

Prima ry Tumor (T)

TX TO

D D D D

D D D

NX NO Nl

Prima ry tu mor cannot be assessed No evidence of primary tumor Tumor 15 mm or less in greatest dimension Tumor more tha n 15 mm in greatest dimension

TX TO

D D D D

D D D

NX NO Nl

without invasion of globe or bony wa ll Tumor of any size with invasion of orbital tissues and/or bony walls Tumor invasion of globe or periorbital structure, suc h as eyelids, temporal fossa, nasal cavity and paranasal sinuses, and/or central nervous system Regional Lymph Nodes (N) Regional lymph nodes cannot be assessed No regional lym ph node metastasis Regional lymph node metastasis Distant Metastasis (M)

No distant metasta sis (no patholog ic MO; use clinical M to complete stage group) Distant metastasis Anatomic Stage . Prognostic Groups

Cl inical No stage grouping is presently recommended

Pathologic No stage grouping is presently recommended

Prognostic Factors (Site-Specific Factors) Required for Staging: None Clinically Significant: None

Histologic Grade (G) (also known as overall grade) Grading system

:J D D D

2 grade system 3 grade system 4 grade system No 2, 3, or 4 grade system is available

Grade

D D D 0

Grade Grade Grade Grade

I or 1 II or 2 111 or 3 IV or 4

Gen eral Notes: For identification of special cases of TNM or pTN M classifications. the "m" suffix and "y," "r," and "a" prefixes are used. Although they do not affect the stage grouping , they indicate cases need ing separate analysis. m suffix indicates the presence of multipie primary tumors in a single site and is recorded in parentheses: pT(m)NM.

APPENDIX, American J oint Comm ittee on Cancer (AJ CC ) Staging Forms, 2010 • 349

Sarcoma of the Orbit Staging Form (continued) Additional Descriptors Lymphatic Vessel Invasion (L) and Venous Invasion (V) have been combined into l ymph-Vascular Invasion (LVI) for collection by cancer registrars. The College of American Pathologists' (CAP) Checklist should be used as the primary source. Other sources may be used in the absence of a Checklist. Priority is given to positive results.

o o o o

Lymph-Vascular Invasion Not Present (absentl/Not Id entified Lymph -Vascular Invasion PresenVldentified Not Applicable Unknown/Indeterminate

Residual Tumor (R) Th e absence or presence of residual tumor after treatm ent. In some cases trealed with surgery and/ or with neoadjuvant thera py there will be residual tumor at the primary site after treatment bec ause of incomplete resection or local and regional disease that extends beyond the limit of ability of resection.

o o o

RX RO Rl R2

Presence of residual tumor cannot be assessed No residual tumor Microscopic residual tumor Macroscopic residual tumor

General Notes (continued): y prefix indicates those cases in which classification is performed during or following initial multi modality therapy. The cTNM or pTNM category is identified by a HyHprefix. The yc TNM or yp TNM categorizes the extent of tumor actually present at the time of that examination. The "yH categorization is not an estimate of tumor prior to multimodalitytherapy. r prefix indicates a recurrent tumor when staged after a disease -free interval, and is identified by the HrH prefix: rTNM. a prefix designates the stage determined at autopsy: aTNM. surgical margins is data field recorded by registrars describing the surgica l margins of the resected primary site specimen as determined only by the pathology report. neoadjuvant treatment is radiation therapy or systemic therapy (consisting of chemotherapy, hormone therapy, or immunotherapy) administe red prior to a definitive surgical procedure. If the surgical procedure is not performed, the administered therapy no longer meets the definition of neoadjuvant therapy.

Grade cannot be assessed Well differentiated Moderately differentiated Poorly differentiated Undifferentiated

Histopathologic Type Malignancies of the orbit primarily include a broad spectrum of malignant soft tissue tumors.

350 • Ophtha lmic Pat hology and Intraocular Tumors

Ocular Adnexal Lymphoma Staging Form Clinical Extent of disease before any

Stage Category Definitions

treatment o y clinica l- staging completed after

neoadjuvant thera py but

Pathologic Extent of disease through completion of definitive surgery

o ypathologicTumor Size:

lateral ity:

o left

0 right 0 bilateral

before subsequent surgery

staging completed after neoadjuva nt therapy AN D subsequent su rgery

Primary Tumor (T)

o o

TO T1

o o o o

Tla T1b T1c T2

12.

T2b

T2c

T2d

o o o

T4a T4b T4c

T4d

Lymph oma extent not specified No evidence of lymphoma Lymphoma involving the conjunctiva alone without orbital involveme nt Bu lbar conjunctiva only Palpebra l conjunctiva +/- forni x +/- caruncle Extensive conjunctival involvement lymphoma with orbital involvement +/- any conjunctival involvement Anterior orbital involvement (+/- conjunctival involvement) Anterior orbital involvement (+/- con junctiva l involvement + lacrimal involvement) Posteri or orbital involvement (+/- conjunctival involvement +/- anterior involvement and +/- any extraocular muscle involvement) Na solacrimal dra inage system involvement (+/- conjunctiva l invo lvement but not inclu ding nasopharynx) Lymphoma with pre-septal eyelid involvement (defined above) +/- orbital involvement +/- any con junctival involvement Orbital adnexal lymp homa extending beyond orbit to adjacent structures such as bon e and brain Involvement of nasopharynx Osseous involvement (inc luding periosteum) Involvement of maxillofac ial, ethmoidal andfor frontal sinuses Intracranial spread

o o

TO T1

o o o o

11a T1b T1c T2

T2a

T2b

T2c

T2d

T4.

T4b T4c

T4d

o o o o

NX NO Nl

Regional lymph Nodes tN)

o o o

NX NO Nl

Regional lymph nodes ca nnot be assessed No evidence of lymph node involvement Involvement of ipsilateral regional lymph nodes* Involvement of contra lateral or bilateral regional lymph nodes* Involvement of peripheral lymph nodes not dra ining ocular ad nexal region Involvement of central lymph nodes *The region al lymph nodes in cluded preauricular (paroti d), submandibular, and cervica l.

APPENDIK

American Joint Comm ittee on Cancer (AJCC) Staging Forms, 2010 • 35 1

Ocular Adnexal Lymphoma Staging Form (continued) Patho logic

Cl inical Extent of disease before any

Extent of disease through completion of definitive

Stage Category Definitions

treatment

surgery Distant Metastasis (M)

MIa

No evidence of involvement of other extra nodal sites (no pathologic MO; use clinical M to complete stage group) Noncontiguous involvement of tissues or organs

MIa

0 0

Mlb Mlc

extern al to the ocular adnexa leg, parotid

0 0

Mlb Ml c

gland s, submandibular gland, lung, liver, spleen, kidney, breast, etel Lymphomatous involvement of the bone marrow

Both Mla and Mlb involvement Anatomic Stage. Prognostic Groups

Clin ica l No stage grouping is presently recommended

Pathologic No stage group ing is presently recommended

Progn ostic Factors (Site-Specific Factors) Required for Staging: None Clini ca ll y Significant: Tumor cell growth fraction !Ki-67, MIB-l) Serum lactate dehydrogenase (LDH) at dia gnosis History of rheumatoid arthritis History of Sjogren's syndrome History of connective tissue disease History of recurrent dry eye syndrome (sicca syndrome) Any evidence of a viral infecti on leg Hepatitis C or HIV) Any evidence of a bacterial infection leg Helieobaeter pylori) _ __ Any evidence of an infection caused by other micro-organisms (eg Chlamydia psittaei)

Histologic Grade (G) (also known as overa" grade) Grading system 2 grade system 3 grade system 4 grade syste m No 2, 3, or 4 grade system is availabl e

0 0 0 0

Grade

0 0 0 0

Grade I or 1 Grade II or 2 Grade III or 3 Grade IV or 4

Add itiona l Descriptors Lymphatic Vessel Invasion tL) and Venous Invasion (V) have been combined into Lymph-Vascular Invasion (LVI) for collection by cancer registrars. The College of American Pathologists' (CAP) Checklist should be used as the primary source. Oth er sources may be used in th e absence of a Checklist. Priority is given to positive results.

0 0 0 0

Lymph-Vascular Invasion Not Present (absent)/Not Identified Lymph-Vascular Invasion PresenVldentifi ed Not Applicable Unknown!1 ndeterminate

General Notes: For identification of special cases of TNM or pTNM classifications, the Hm H suffix and Hy,H "r, Hand Ha" prefixes are used. Although they do not affect the stage grouping, they indicate cases needing separate analysis. m suffi x indicates the presence of multipie primary tumors in a single site and is recorded in parentheses: pT(m)NM. y prefix indicates those cases in which classification is performed during or following initial multimodality therapy. The cTNM or pTNM category is identified by a "y" prefix. The ycTNM or ypTNM categorizes the extent of tumor actually present at the time of that examination. The "y" categorization is not an estimate of tumor prior to multimodality therapy. r prefi x indicates a recurrent tumor when staged after a disease·free interval, and is identified by the "rn prefix: rTNM. a prefix designates the stage determined at autopsy: aTNM. surgica l margins is data field recorded by registrars describing the surg ical margins of the resected primary site specimen as determined only by the pathology report. (Con tinued)

352 • Ophthalmic Pathology and Intraocu lar Tumors

Ocular Adnexal Lymphoma Staging Form (continued) Residual Tumor (R) The absence or presence of residual tumo r after treatment. In some cases treated with surgery and/or with neoadjuvant therapy there will be residual tumor at the primary site after treatment because of incomplete resection or local and regional disease that extends beyond the limit of ability of resection.

RX Presence of residual tumor cannot be assessed ORO No residual tumor o RI Microscopic residual tumor o R2 Macroscopic residual tumor

General Notes (continued): neoadjuvant treatment is radiation therapy or systemic therapy (consisting of chemotherapy, hormone therapy, or immunotherapy) administered prior to a definitive surgical procedure. If the

surgical procedure is not performed, the administered therapy no longer meets the definition of neoadjuvant therapy,

Histologic Grade (G) Grades are given only to Jollicular lymphomas as described by the 2002 WHO classification for malignant lymphomas as follows: GI G2 G3a G3b

1- 5 centrobJasts per 10 high power field Between 5 and 15 centroblasts per 10 high power fields More than 15 centroblasts per 10 high power fie lds but with admixed centrocytes More than 15 centroblasts per 10 high power fields but without ce ntrocytes

Histopathologic Type The lymphomas arising as primary tumors in the ocular adnexa are subtyped according to the WHO Lymphoma classification. The main ocular ad nexal lymphoma subtypes include the following: Extranodal marginal zone B-celllymphoma (MA LT lymphoma) Diffuse large B-celllymphoma Follicular lymphoma Mantle cell lymphoma Lymphoplasmacytic lymphoma Plasmacytoma Burkitt lymphoma Peripheral T-cell lymphoma, unspeCified Mycosis fungoides Extranodal NK/T-celllymphoma, nasal type Anaplastic large cell lymphoma Jaffe ES, Harris NL, Stein H, Vardiman ]W. World Health Orgallization Classification of Tu mours: Tumours oj Haematopoietic and Lymphoid Tissues. Pathology and Genetics. Lyo n, France: IARC; 2001.

Basic Texts Ophthalmic Pathology and Intraocular Tumors Albert OM, Jakobiec FA, eds. Atlas of Clinical Ophthalmology. Philadelphia: Saunders; 1996. Albert OM, Miller JW, eds. Albert & Jakobiec's Principles & Practice of Ophthalmology. 3rd ed. Philadelphia: Saunders; 2008. Apple OJ, Rabb ME Ocular Pathology: Clinical Applications and Self-Assessment. 5th ed. St Louis: Mosby; 1998. Bornfeld N, Gragoudas ES, Hopping W, et ai, eds. Tumors of the Eye. New York: Kugler; 1991. Char DH. Clinical Ocular Oncology. 2nd ed. Ph iladelphia: Lippincott Williams & Wilki ns; 1998. Cohen IK, Diegelmann RF, Lindblad WJ, eds. Wound Healing: Biochemical and Clinical Aspects. Philadelph ia: Saunders; 1992. Dutton Jj. Atlas of Clinical and Surgical Orbital Anatomy. Philadelphia: Saunders; 1994. Garner A, Kli ntworth GK, eds. Pathobiology of Ocular Disease: A Dynamic Approach. 2nd ed. New York: Informa Healthcare; 1994. Isenberg SJ, ed. The Eye in Infancy. 2nd ed. St Louis: Mosby; 1994. Margo CE, Grossniklaus HE. Ocular Histopathology: A Guide to Differential Diagnosis. Philadelphia: Saunders; 1991. McLean IW, Burnier MN, Zimmerman LE, Jakobiec FA. Tumors of the Eye and Ocular Adnexa. Washington: Armed Forces Institute of Pathology; 1994. Nauman GO H, Apple OJ. Pathology of the Eye. New York: Springer-Verlag; 1986. Sanborn GE, Gonder JR, Shields JA. Atlas of Intraocular Tumors. Philadelphia: Saunders; 1994. Sassani JW, ed. Ophthalmic Pathology With Clinical Correlations. Philadelphia: Lippincott Williams & Wilki ns; 1997. Shields JA, Shields CL. Atlas of Eyelid and Conjunctival Tumors. Philadelphia: Lippincott Williams & Wil kins; 1999. Shields JA, Shields CL. Atlas of Intraocular Tumors. Philadelphia: Lippi ncott Williams & Wilkins; 1999. Spencer WH, ed. Ophthalmic Pathology: An Atlas and Textbook. 4th ed. Philadelphia: Saunders; 1996. Yanoff M, Fine BS. Ocular Pathology. 5th ed. St Louis: Mosby; 2002.

353

Related Academy Materials Focal Points: Clinical Modules for Ophthalmologists de Imus GC, Arpey CJ. Periorbital skin cancers: the dermatologist's perspective (Module 1,2006). Helm Cj. Melanoma and other pigmented lesions ofthe ocular surface (Module 11,1996). Lane Stevens je. Retinoblastoma (Module 1, 1990). Margo CEo Nonpigmented lesions of the ocular surface (Module 9, 1996). Sainz de la Maza M, Vitale AT. Scleritis and episcleritis (Module 4, 2009) . Stefanyszyn MA. Orbital tumors in children (Module 9, 1990). Volpe Nj, Liu GT, Galetta SL. Idiopathic intracranial hypertension (IIH, pseudotumor cerebri) (Module 3, 2004).

Print Publications Wilson FM II, Blomquist PH, eds. Practical Ophthalmology: A Manual for Beginning Residents. 6th ed. (2009).

Preferred Practice Patterns Preferred Practice Patterns are available at http://one.aao.org/CE/PracticeGuidelines/PPP .aspx. Preferred Practice Patterns Committee, Cornea/External Disease Panel. Conjunctivitis (2008).

Online Materials Focal Points modules; http://one.aao.org/CE/EducationaIProducts/FocaIPoints.aspx Grippo TM, Finger PT, Milman T. Elderly Woman With Persistently High lOP. Academy Grand Rounds (March 2010); http://one.aao.org/CE/EducationaIContentiCases.aspx Hebson CE, Murchison AP, Grossniklaus HE. Toddler With Ecchymosis and Eyelid Edema. Academy Grand Rounds (March 2010); http: //one.aao.org/CE/EducationaIContent/ Cases.aspx

Ophthalmic Technology Assessments; http://o ne.aao.org/C E/PracticeGuidelines/ ophthalmic.aspx Practicing Ophthalmologists Learning System (2011); http://one.aao.org/CE/PO LS/ Default.aspx Preferred Practice Patterns; http: //one.aao.org/CE/PracticeGuidelines/I.'PP.aspx To order any of these materials, please order online at www.aao.org/store or call the Academy's Customer Service toll-free number, 866-561-8558, in the U.S. If outside the U.S., call 415-561-8540 between 8:00 AM and 5:00 PM PST.

355

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357

Study Questions Please note that these questions are not part of your CME reporting process. They are provided here for self-assessment and identification of personal professional practice gaps. The required CME postlest is available online or by request (see "Requesting CME Credit"). Following the questions are a blank answer sheet and answers with discussio ns. Although a concerted effort has been made to avoid ambiguity and redundancy in these questions, the authors recognize that differences of opinion may occur regarding the "best" answer. The discussions are provided to demonstrate the rationale used to derive the answer. They may also be helpful in confirming that your approach to the problem was correct Of, if necessary, in fixing the principle in your memory. The Section 4 faculty would like to thank the Self-Assessment Committee for working with them to provide these study questions and discussions. 1. What is a lesion composed of normal, mature tissue in an abnormal location? a. hamartoma b. choristoma c. hemangioma d. granuloma 2. Which of the following cells woul d most likely be observed on histologic examination of a specimen of a bacterial corneal ulcer? a. eosinophils b. basophil' c. epithelioid histiocytes d. neutrophils 3. Which of the following choices is a general h istologic sign of malignancy? a. nuclear/cellular pleomorphism b. dyskeratos is c. dysplasia

d. calcification 4. When glaucoma occurs in association with angle recession, it is most commonly because of which of the following? a. damage to the trabecular meshwork b. associated lens subluxation c. iridodialysis

d. a tear in the ciliary body muscle

359

360 • St udy Quest io ns 5. If a co njun ctival biopsy is being performed fo r suspicion of oc ular cicatricial pemphigoid, th en half of th e specimen should be submitted in fo rm alin fo r ro utine histology and the oth er half sho uld be submitted in what medium for immunofluorescence studies? a. M ichel mediu m b. gluta raldehyde

c. saUne d. abso lu te alcohol 6. W hat is the first step in preparing a specimen for electro n m icroscopy? a. glutaral dehyde fixati on b. thick sectio ns c. thin sectio ns

d. osm iflcat io n process 7. Frozen secti ons are appropriate for which o ne of the foll ow ing? a. to surgica ll y co ntrol the margins of a neoplas m b. to interpret a conjunctival lesion

c. to interpret a cutaneous lesion d. to ma ke a fo rmal d iagnosis 8. W hat is th e best way to d iagnose orbital hemangiopericyto ma?

a. mdiologic imag ing h. ultraso un d testin g c. fine -need le aspiratio n or open o rbital biopsy d. cl in ical symptoms and examinatio n 9. A 40-yea r-old man has a painiess, palpable mass in the right superolateral orbit that displaces th e glo be down an d inward. A CT sca n shows a heteroge neous mass in the region of the lac rimal gland with adjacent bo ne remodeling. Whi ch biopsy approach is correct? a. to tal primary excision through a lateral o rb ito to my b. incisio nal bio psy through a latera l o rbi to to my c. incisio nal biopsy through a medial orbitotom y d. total pri ma ry excision through a medial o rbitoto m y 10. What me thod can identify infectiolls agents, neop lastic cells, or degenerative con d it io ns and d istin guish lesions of neuroectodermal o rig in fro m neuro endocrin e les ions? a. G ram stain b. ch roma tography c. routine histo logic exam ination d. in1 n1ul1o histochemi stry

Study Questions. 361 II. Which of the following corneal stromal dystrophies is characterized by both hyaline and amyloid deposits?

a. granular b. lattice c. Avellino

d. macular 12. Which of the following forms of infectious keratitis displays double -walled cysts in the corneal stroma on histology? a. pseudomonal ulcer b. herpetic keratitis

c. A canthamoeba keratitis d. Fusarium keratitis

13. A 55-year-old diabetic black female has unilateral elevated intraocular pressure associated with long-standing intraocular hemorrhage. The pertinent slit-lamp finding consists of golden brown cells in the anterior chamber. What is the most likely etiology of her elevated intraocular pressure? a. aqueous fluid overproduction b. artifactual readings due to corneal edema

c. outflow obstruction due to red blood cell membrane rigidity d. traumatic pupillary block 14. What disease may be diagnosed by finding Heinz bodies on red blood cell membranes in an anterior chamber aspirate? a. lymphoma

b. siderosis c. pseudo exfoliation d. ghost cell glaucoma 15. A 35-year-old woman, recently diagnosed with rheumatoid arthritis, presents with a violaceous scleral nodule. The biopsy will most likely reveal which of the following? a. palisading arrangement ofhistiocytes/giant cells around necrotic/necrobiotic collagen fibers b. sparse inflammatory infiltrate composed of lymphocytes and plasma cells

c. colonies of gram-negative bacteria associated with acute necrotizing inflammation d. circ*mscribed proliferation of spindle cells in chronically inflamed, richly vascular, and myxoid stroma

362 • Study Questions 16. The pathophysiology of posterior subcapsular cataract may best be described by which of the following' a. posterior migration oflens epithelial cells b. disorganization of posterior lens fibers

c. infiltration of the posterior lens by inflammatory cells d. retention oflens fiber nuclei

17. What is the histopathologic appearance of the anterior chamber angle in a case of phacolytic glaucoma? a. infiltration by hemosiderin-laden macrophages b. lack of significant inflammatory cell infiltrate

c. infiltration by neutrophils d. infiltration by protein-laden macrophages 18. Of the following, which anatomic boundary is not a component of the vitreous?

a. hyaloid face b. .internal limiting membrane

c. hyaloideocapsular ligament d. vitreous base

19. Which of the following vitreous degenerations is not age related? a. vitreous syneresis

b. macular hole c. posterior vitreous detachment d. asteroid hyalosis 20. Pathologic examination of cystoid macular edema reveals cysts in which retinal layer? a. outer plexiform b. Bruch membrane c. internal limiting membrane d. retinal pigment epithelium

21. A 6-week-old child is brought by his parents because of a 1-cm reddish mass on the left upper eyelid, which prevents the eye from opening fully. It has grown rapidly since birth. MRJ shov.,s an enhancing vascu lar lesion. Wh ich entity is most likely? a. plexiform neurofibroma b. acute dacryocystitis c. capillary hemangioma d. benign mixed tumor of the lac rimal gland

St udy Questions. 363 22. Histopathologically, the uveitis seen in Vogt ~Koyanagi- Ha rada synd rome most closely re se mb les the uveitis seen in which o ne of the follmving diseases? a. juvenile idiopathic arthritis b. intraoc ular lymphoma

c. pars planitis d. sympathet ic ophthalmia 23. An asymptomatic, do me-shaped, orange mass is noted in th e mi dperipheral fundus of a 30-yea r-old woma n. An overlying exudative retin al detachm ent is prese nt. A-scan ultrasonography shows high internal reflectivity. Wh ich entity is most li kely' a. posterio r scleritis b. ce ntral serous retinopathy c. amelanot ic choro idal melanoma d. ci rc*mscribed choroidal hemangioma 24. Which patho logic fi nding would differentiate between a ru ptured der moid and ruptured epidermoid cyst? a. hair follicles b. lamellated kerat in

c. mixed in fl ammation d. sq uamous ep itheli um 25. W hat is the most co mmon type of intraocul ar tum or? a. mela noma b. ret inoblastoma c. lymphoma d . me tastatic neoplasm 26. A 25-year-old white male \vith a history of conjun ctivitis presents with a flesh -colored mass wi th a central umbilication o n th e upper eyelid. Examinati on of the pathologic specimen reveals invasive lobular acanthos is, a central umbil icati on, and eosinoph ilic and basoph ili c intracytoplasmic inclusions. What is the most li kely d iagnos is? a. sq uamous papill oma b. xanthelasma c. basal cell ca rcinoma d . Molluscum co ntagiosum

364 • Study Questions 27. A 22-year-old female presents with a pai nless, nontender, flesh-colored, hyperkeratotic eyelid mass. Path ologic examination shows acan thotic epitheliuI11 surrounding a fibrovascular core. What is th e most li kely etiology? a. bacterial

b. inflammation c. sun exposu re d. viral 28. Squamous cell ca rci no ma in situ is defined as a pathologiC anatomic limitation by which one of th e foll owing? a. superficial epithelium

b. strom al keratocytes c. basal epithe.lium d. basem*nt membrane 29. \"'ith which of the following is aniridi a most commonly associated? a. retinal pigment epithelial hyp erpl as ia b. optic nerve coloboma c. glaucoma d. opticall y empty vi treous 30. What phys iologic changes are associated with acquired optic atrophy?

a. increased myelin with thinning of the pial se pta b. shrinkage of the nerve diameter with widening of th e suba rachnoid space c. uniform changes across th e nerve witho ut variation

d. increased myeli n and sh rinking of the subarachnoid space 31. What is optic nerve glioma most frequentl y associated with ? a. Sturge- Weber syndrome b. neurofibromatosis type 1 c. Peters ano maly

d. neurofibro matosis type 2 32. Which of the following is not a clinical risk factor for met.astatic disease in patients with uveal melanoma? a. large tumor size b. ciliary body involve ment.

c. young age d. extraocula r extension

Study Questions. 365 33. Which of the following is the most important risk factor for the development of uveal melanoma? a. dysplastic nevus syndrome b. light -colored complexion c. ocular melanocytosis

d. ultraviolet light exposure 34. At the time a choroidal melanoma is diagnosed, which test is recommended to help rule out metastasis? a. serum glucose b. brain MRI c. bone marrow biopsy d. abdominal imaging

35. With which of the following organs must the ophthalmologist be most concerned about in a patient with retinal capillary hemangioblastoma? a. brain and kidney

b. liver and lung

c. bowel and skin d. organs of the immune system and central nervous system 36. What association distinguishes von Hippel-Lindau syndrome from von HippeJ disease? a. intracranial calcifications, ash-leaf spots, re tinal astrocytomas b. cafe-au -lait spots, Lisch nodules, optic pathway gliomas c. pheochromocytomas, cerebellar hemangioblastomas, renal cell carcinomas

d. limbal dermoids, upper eyelid colobomas, preauricular tags 37. W hich of the following is the most important histopathologic risk facto r fo r mortality in the enucleated globe from a patient with ret inoblastoma? a. the presence of anterior segment involvement b. the extent of retinal detachment c. the extent of optic nerve and choroidal invasion d. the size of the tumor 38. Which of the following clinical characteristics is typical of Coats disease? a. unilateral b. associated with HLA-B27 c. found in femal e patients

d. bilateral

366 • Study Questions

39. Intraocular calcification in the eye of a child is most diagnostic of what disease? a. retinoblastoma

b. toxocariasis c. persistent fetal vasculature d. Coats disease 40. What is the most common secondary tumor in retinoblastoma patients? a. fibrosarcoma b. melanoma c. pinealoblastoma d. osteosarcoma

41. When a parent has bilateral retinoblastoma, which risk factors apply to the affected parent's children? a. 85 % risk of developing retinoblasto ma b. risk of bilateral disease in all affected children

c. risk of developing retinoblastoma in males only d. 45% risk of developing retinoblastoma 42. What is the primary treatment fo r a 2-year-old child with unilateral retinoblastoma classified as International Classification Group E? a. systemic chemotherapy alone b. intra-arterial chemotherapy

c. enucleation d. radiation alone 43. What is the treatment of choice for metastatic carcinoma to the eye? a. chemotherapy b. external-beam radiation c. brachytherapy d. individually tailored in each case 44. What is the most common finding in ocular involvement in leukemia? a. retinal hemorrhages b. aqueous ceUs c. retinal perivascular sheathing d. vitreous cells

Study Questions . 367

45. What tumor frequentl y occurs in conjunction with central nervous system involvement? a. basal cell carcinoma of the eyelid b. primary intraocular lymphoma c. retinoblastoma

d. ciliary body melanoma 46. Leukemic retinopathy may cause hemorrhages in which level(s) of the retina? a. preretinal (subhyaloidal) and intraretinal b. subretinal c. choroidal

d. Leukemic retinopathy does not cause retinal hemorrhages.

Answer Sheet for Section 4 Study Questions Question

Answer

Question

Answer

abc d

369

Answers I. b. A choristoma is normal, mature tissue in an abnorma l location. A limbal dermoid is

an example of a choristoma-skin that is present at the abnormal location of the lim bus but otherw ise nor mal and mature. T he te rm hamartoma descr ibes an exaggerated hypertrophy and hyperplasia (abnor mal amount) of mature tissue at a no rmal locati o n. An example of a hamartoma is a caver nou s hem angioma, an encapsulated mass of ma ture venous channe ls in the orbit. A granuloma is an aggregate of epithelioid histiocytes within tissue in th e setting of chronic granu lo matous inflammation. 2. d. Neutrophils, or polymorphonuclear lettkocytes (PMNs), are identified by their m ulti seg mented nuclei and intracytoplasmic granules, and they predo minate in the acute inflammator y response in bacterial infec tio ns. Eosinophils have bilobed n uclei and prominent eosinophilic intracytoplasmic gra nules and are co mmo nly observed in allerg ic reactions. Basoph ils contain basophil ic intracytop lasm ic granu les, circ ulate in the bloodstream, and playa rol e in parasitic infectio ns and allergic responses. Epithelioid hi stio cytes have abundant eosinophiuc cytoplasm and sharp cell borders and are histologi c markers of granu lomatous inflam mation. 3. a . Malignant tumor cells are characterized histologically by cellular and nuclear pleomorphism (ie, cells and nu clei of different sizes and shapes) . Premature individual celJ kera tinization, or dys keratosis, may be see n in both benign and malig nant epithelial lesions. D ysplas ia (abnormal epithelia l maturatio n) is a premalignan t change. Calcification may be seen in benign an d malignant lesion s. 4. a. Traumatic recessio n of the anterior chamb er angle is due to a tear in the ciliary body, between the longitudinal and circular mu scl es, with posteri or di splacemen t of th e iri s root. Concurrent damage to the trabecular meshwork may lead to glaucoma. Lens subluxation and iridodialysis may be observed in addition to angle recession after blunt o cular trauma; however, th e glaucoma th at occurs in association with angle recession is most com monly caused by damage to the trabecular meshwork. 5. a. Michel (pro nounced mee-SHELL) transport medium is used to transport specimens for immunofluorescence studies. In ocular cicatricial pemphigo id, imm un ofluoresce nce studies demon strate IgG, IgM, andlor IgA immunoglobu lins, andlo r com plement (C3) positivity in the epithelial base ment membran e zone. M ichel med ium is not a fixative. It should be sto red refrigerated (not fr ozen) until use. Specimens may be kept in Michel medium for up to 5 days at room temperature. Glutaraldehyde is the preferred fixa tive fo r electron microscopy. No rmal saline solut ion (0.9% sodium chJ oride) and absolute ethyl alcoho l may be employed to transport tissue within 24 hours fo r RNA stud ies. 6. a. Gluta raldehyde (2.5 % sol ution in phosphate buffered saline) fixat ion is the first step in preparing a speci men for electron mi cro sco py. The tissue is th en washed in buffered so lutio n an d post fixed in osmium tetroxide (os mincation process). Representative pieces of tissue are processed in graded alcohol baths for dehydration and embedded in epoxy resi n. Thick sectio ns ( 1 ~lm in thickn ess) are cut to examine th e tiss'lle under light mi croscopy and ide ntify regio ns of greatest interest fo r ul trathin sectioni ng. The ultrathi n sections (50 11m in thickness) are cut with d iamond or glass kn ives attached to an ultra microtom e and th en 11l0unted 011 a 3-11l11l-ci.iameter copper grid. The mounted sections are then stained with uranyl acetate (or lea d citrate) to impart co ntrast to the tissue for elec tron microscopy. 37 1

372 • Answers

7. a. A frozen section is indicated when the results of the study will affect management of the patient in the operating room. Two com mon indications for frozen section are to determine whether resection margins are free of tumor and to determine whether the surgeon has obtained a representative biopsy specimen in the case of metastases. Interpretation or diagnosis of a lesion requires permanent sections. Permanent sections are always preferred and are the standard for formal diagnosis based on pathologic findings. 8. c. Hemangiopericytoma is a solid tumor, and radiologic imaging and ultrasonography would therefore provide only nonspecific features that are of poor diagnostic value. Hemangiopericytoma is a primary orbital tumor, and the clinical symptoms will be the same as the symptoms for any orbital tumor. One can expect proptosis, pain, and diplopia as presenting features. The diagnosis requires positive immunohistochemical staining for CD34. The staining can be done on fine-needle or open orbital biopsy specimen. 9. a. Pleomorphic adenoma (benign mixed tumor) is the most common epithelial tumor of the lacrimal gland. The tumor is pseudoencapsulated and grows by expansion . Progressive growth into the bone of the lacrimal fossa may cause excavation and stimulate new bone (cortication) formation in the area. Total primary excision through a lateral orbitotomy is the correct approach because when part of a tumor is left behind, tumor recurrence and, in rare instances, malignant transformation are possible. A lateral orbitotomy provides the best surgical exposure and allows for complete removal of the tumor. 10. d . Immunohistochemistry takes advantage of the property that a given cell can express specific antigens. In immunohistochem istry, a primary antibody binds to a specific antigen on the surface of or within a celL The antibody is linked to a chromogen, whose colored end-product is visualized under a microscope to determine the cell type. Hundreds of antibodies specific for cellular products or surface antigens are available, and immunohistochemistry is the only method capable of distinguishing lesions of neuroendocrine origin from those of neuroectodermal origin. Chromatography is the collective term for a set oflaboratory techniques used to separate colored chemical mixtures and is not routinely used in pathologic examination of tissues. A Gram stain can identify the morphology of an infectious bacterium and the bacterium's affinity for a specific histological stain, thus distinguishing betv'leen gram-positive and gram-negative bacteria. This information can be used in the selection of an antibiotic. Routine histologic examination cannot dis tinguish neuroendocrine fro m neuroectodermal lesions because their pathologic appearance is very similar. 11. c. Avellino dystrophy, or combined granular-lattice dystrophy, displays features of both granular dystrophy (type 1) and lattice dystrophy (type 1). Histologically, hyaline deposits (highlighted by the Masson trichrome stain) and amyloid deposits (highlighted by the Congo red stain) are present within the corneal stroma, which is characteristic of granular dystrophy and lattice dystrophy, respectively. Macular dystrophy exhibits mucopolysaccharide deposits (highlighted by the alcian blue and colloidal iron stains). 12. c. Acanthamoeba protozoa have a double-walled cyst morphology, and these cysts are difficult to eradicate from the corneal stroma. Less commonly, trophozoite forms may also be identified. Epithelial cells infected with herpes virus may display intranuclear inclusions, but these are rarely seen histologically because corneal grafting is not generally performed during the acute phase of infection. Pseudomonas is a gram-negative bacterium and is rod shaped (bacillus). 13. c. Long-standing intraocular hemorrhage leads to degenerative changes in erythrocytes, which lose intracellular hemoglobin and, clinically, appear golden brown or "khaki col-

Answe rs . 373 ored:' These rigid, spherical ghost cells may obstruct the trabecular meshwork, leading to ghost cell glaucoma. 14. d. Ghost cells are hemolyzed eryth rocytes that have lost most of their intracellular hemoglobin. Heinz bodies are the remaini ng denatured, precipitated hemoglobin particles within the ghost cells. 15. a. The clinical presentation is suggestive of nodu lar scleritis, related to rheumatoid arthritis. Choice a describes the histology of a rheumatoid nodule. 16. a. Under normal co nditions, the lens epitheli al cells terminate at the lens equator. When the equatorial lens epithelial cells migrate onto the posterior le ns capsule, they swell (referred to as bladder cells of Wedl), res ulting in posteri or subcapsular cataract formation. 17. d . In phacolytic glaucoma. denatured lens pro tein in a hypermature cataract leaks through microscopic openings in an intact lens capsule. T his lens protein is then phagocytosed by macrophages, which are present in the an teri or chamber angle. 18. b_ The internal limiting membrane is the innermost layer of the neurosensory retina and. though attached to the vi treous, is not considered a component of the vitreous. The h)'a loid face is the outer surface of the vitreo us cortex. The hyaloideocapsular ligament forms the anterior border of the vitreous, which is attached to the lens capsule. The vitreous base is a firm circumferential attachment of the vitreo us straddling the ora serrata. 19. d. The development of asteroid hyalos is is not known to be a consequence of age. Vitreous syneresis, macular hole, and posterior vitreous detachment can be considered age related, as the incidence of these co nditions increases with age. 20. a. Nerve fiber layers in the outer plexiform layer (nerve fiber layer of Henle) run obliquely, allowing for the accumulation of fluid in the macula, which appears as cysts when there is abnormal permeability of the blood-retina ba rri er. 21. c. Capillary hemangioma is the most common neoplasm of the eyelid in childhood and has a bright red appearance clinicall),. Plexifo rm neurofibromas typically affect the upper e),elid, are not particularly vascular, an d do not t),picall), cause discoloration of the e),elid. Acute dacryocystitis can occur in childre n, bu t it would affect the medial canthal region of the lower eyelid. Benign mixed tumor of the lacrimal gland is rare in children. It may cause a mass in the upper outer eyelid. typ ically without discoloration. If the eyelid is everted, the mass may be appreciated th rough the conjunctiva. 22. d. The inflammation seen in Vogt-Koya nagi- Harada (VKH) syndrome is very similar to that seen in sympathetic ophthalmia. Both demo nstrate the presence of lymphocytes and epithelioid histiocytes (g ranulomatous inflamma tion) in the posterior uveal tract. VKH involves the choriocapillaris more often than does sympathetic ophthalmia. Juvenile idiopathic arthritis typically involves the anterior uveal tract and does not demonstrate granulomatous inflammation. Pars planitis ilwolves th e peripheral retina, vitreous, and choroid. Typically, the inflammation is not granul omatous. 23. d. Circ*mscribed choroidal hem angioma typically has a red or orange appearance clinically, and it is characteristically highl y refl ec tive on ultrasonography. Posterior scleritis may be very difficult to appreciate on fun dus examination but may have an associated exudative retinal detachment. On B-scan echography, the sclera will appear th ickened, and a "T sign" may be seen arOlU1d the optic nerve. Central serous retinopathy wilJ have a localized exudative retinal detachment, typically wi thout Significant findings in the choroid. Amelanotic melanomas usually appear cream colored cl inically and have low to medium internal reflectiVity on A-scan echography.

374 • Answers

24. a. The correct answer is the presence of hair follicles. An epidermoid cyst is lined with keratinized stratified squamous epithelium similar to epidermis but does not have skin adnexal structures such as hair follicles or glands. A dermoid cyst is lined '",ith epidermal epithelium and has adnexal structures. Both types of cysts will generate a mixed inflammatory response if they rup ture. 25. d. The most common type of intraocular tumor overall is a metastatic neoplasm. The second most common type in adults is uveal melanoma. Retinoblastoma is uncommon overall, and lymphomas are rare. 26. d. Molluscum contagiosum is characterized by marked focal acanthosis of the epidermis with a central umbilication. Viral inclusions are present in most of the superficial epithelial cells. Squamous papilloma has an upward rather than downward growth pattern histologically. Xanthelasma consists of aggregates of foamy macrophages in the dermis. Basal cell carcinoma has an invasive (downward) growth pattern, with multiple islands of blue cells ,vith the characteristic peripheral palisading border of tumor cells. Basal cell carcinoma is more common on the lower eyelid. 27. d. The correct answer is viral. A papilloma, typical of infection of the skin with human papillomavirus, is defined as acanthotic epithelium with a fibrovascular core. Bacterial infections typically cause an abscess or cellulitis. Inflammatory lesions are typically erythematous. Sun exposure may cause hyperpigmentation, wrinkling, or actinic keratosis (ie, a flat, red, scaly lesion). 28. d. Squamous cell carcinoma in situ implies that the neoplasm is confined to the epithelium and does not break through the basem*nt membrane and extend into the underlying stroma. 29. c. Aniridia is most commonly associated with glaucoma. Foveal hypoplasia, cataract, and corneal pannus may also be present. 30. b. In acquired optic atrophy, there is loss of axonal fibers, which results in a decrease in the optic nerve diameter with corresponding widening of the intermeningeal (subarachnoid) space. Additional changes include gliosis and thickening of the fibrovascular pial septa. 31. b. Optic nerve glioma is most frequently associated w·ith neurofibromatosis type 1. 32. c. Old age was found to be a risk factor for metastatic uveal melanoma. The other choices are also well-established risk factors . 33. b. The risk of developing uveal melanoma is closely related to a person's complexion. Uveal melanoma appears mostly in whites, mainly in those of European origin, and is rare in other races. 34. d. The liver is by far the most frequen t site of metastasis from uveal melanoma, and metastasis to other organs, such as the lungs, skin, and bones, is rarely found without liver involvement. 35. a. The presence of a retinal capillary hemangioblastoma (previously knovm as retinal capillary hemangioma) suggests the possibility of von Hippel- Lindau (VHL) syndrome resulting from a mutation of the VHL gene on chromosome 3. ~atients with VHL syndrome are at risk for cerebellar hemangioblastomas, pheochromocytomas, and renal cell carcinomas. Genetic screening of such patients should be considered. 36. c. von Hippel disease is limited to a solitary finding, retinal capillary hemangioblastoma. VHL syndrome is associated with cerebellar hemangioblastomas. Patients with this syndrome are also at risk of develop ing pheochromocytomas and renal cell carcinomas.

Answers. 375

37. c. Invasion of the optic nerve increases the risk of central nervous system metastasis either by direct access in or along the nerve or by seeding of the subarachnoid space. Massive, deep invasion of the choroid increases the ri sk of hematogenous spread (metastases). 38. a. Coats disease is a unilateral retinal vascu lopathy occurring most commonly in boys younger than 10 years. Some studies have linked Coats disease to mutatio ns in the Norrie disease gene (NDP). There is no association with HLA-B27. 39. a. Intraocular calci fications are the hallmark of retinoblastoma and signify retin oblastoma until prove n othenvise. In rare instances, intraocular calcifications may be seen in toxocariasis, persistent fetal vasculature, and Coats disease. In these cases, calcifications are usua lly foca l and discrete, occurring within granulomas (toxoca riasis) or a retrolental membran e (persistent fetal vasculature) or at the level of the retinal pigment epithelium (Coats disease) . 40. d. Osteosarcomas represent 40% of tumors ar ising within the field of rad iation and 36% outside the field of radiation in patients previously treated for retinoblastoma. 4 1. d. A parent with retinoblastoma, in theory, has a somatic mutation of at least 1 allele of the reti noblastoma gene (RB!). Thus, there is a 50% chance that the parent will pass the mutated allele to each of his or her children . There is a 90% chance of penetrance if the abnormal allele is inherited. Therefore, the chil d's risk of developing ret inoblastoma is the sum of 0.50 x 0.90, which is 0.45, or 45%. 42. c. A 2-year-old child \vith unilateral retinoblastoma at diagnosis is unlikely to develop disease in the other eye. Any tumors that fo rm would most likely be peripheral to the macula and, with close surveillance, amenable to local treatment with laser or cryotherapy alone. Eyes classified as International Group E have the most advanced intraocular disease with limited visual potentia1. Tumors may invade the anterior chamber and ciliary body, and there may be associated neovascular glauco ma. Such eyes are unlikely to respond to conservative treatment measures. 43. d . Treatment of a patient with a metastasis to the eye should be individually tailored after consultation with the patient's oncologist. When the patient has other systemic metastases, systemic che motherapy-which may also affect the ocular metastasis-may be considered. \tVhen th ere are mu ltiple ocular metastases and chemotherapy is not planned, external-beam radi ation may be considered. When the ocular metastasis is solitary and no othe r system ic metastases are known, brachytherapy may be the treatment of choice. 44. a. Retinal hemorrhages, typically white-centered hemorrhages, are the most common ocular manifestation of leukemia. Patients with leukemia and retinal hemorrhages typically have anem ia and thrombocytopenia. The ot her findings are much less co mmon. 45. b. Primary intraocular lymphoma (also know n as large cell lymphoma, vitreoretinallymphoma, or retinal lymphoma), occurs in 15%-25% of patients with primary central nervous system lymp homa (PCNSL). On the other hand, more than half of patients with primary intraocular lymphoma have or will develop PCNSL. 46. a. Leukemic retinopathy is characterized by in tra retinal and preretinal (subhyaloidal) hemorrhages. The hemorrhages most often result from associated anemia or thrombocytopenia. Reti nal hemorrhages may have white centers, so-called pseudo-Roth spots. Additional fi ndings may include hard exudates, cotton-wool spots, and perivascular infiltrates.

Index (j '= figure; t == table) A-scan ultrasonography/echography in choroidal/ciliary body melanoma, 276, 276f in choroidal hemangioma, 29 If, 292 in metastatic eye disease, 319 ABCA4 gene, in Stargardt disease, 172 ABMD. See Anterior basem*nt membrane dystrophy Abrasions, corneal, 13 - 14 Acanthamoeba, keratitis/ocular infection caused by, 54, 84- 85,86/ Acantholysis, definition of, 206 Acanthosis, definition of, 206 ACe. See Adenoid cystic carcinoma Accessory lacrimal glands of Krause, 205, 207t of Wolfring, 205, 207t Acral-lentiginous melanoma, 226, 227/ Actin, in immunohistochemistry, 33 in adenoid cystic carcinoma, 236 Actinic (Labrador) keratopathy (spheroidal degeneration), 88-89,90f Actinic keratosis, 216-217, 217f, 218/ Acute disseminated encephalomyelitis, optic nerve involvement and, 252 Acute retinal necrosis, 151, 151f Adenocarcinoma, lOt of retinal pigment epithelium, 184, 288 Adenoid cystic carcinoma (cylindroma), oflacrimal glands, 236-238, 237/ Adenoma Fuchs (pseudoadenomatous hyperplasia), 184,288 pleomorphic (benign mixed tumor), of lacrimal gland, 236,237/ of retinal pigment epithelium, 184, 288 sebaceous, 21St, 221 , 222/ of uvea/ retina, 288 Adenomatous polyposis, familial (Gardner syndrome), retinal manifestations of, 150-151 Adenoviruses/adenoviral infection, follicular conjunctivitis, 53 Adipose tumors, of orbit, 245 Adult-onset foveomacular vitelliform dystrophy, 175,176/ AFMVD. See Adult-onset foveomacular vitelliform dystrophy Age/aging ciliary body hyalinization and, 192 posterior vitreous detachment and, 135 of sclera, 115, 116/ syneresis and, 134, 134/ Age-related cataracts, nuclear, 127, 128f, 129/ Age-related macular degeneration, 167- 170, 168f, 169f, 170J.171f drusen associated with, 168- 169, 168f, 169/ melanoma differentiated from, 278 neovascular (wet/exudative), 169- 170, 171f nonneovascular (dry/nonexudative), 169 AJCC (American loint Committee on Cancer), staging of ocular tumors by, 329- 352t Albinism, 148, 149/

Alcian blue stain, 30, 31 t Alcohol (ethanol) as tissue fIxative, 29, 29t for tissue proceSSing, 29 Alizarin red stain, 3lt Allergic fungal sinusitis, orbital involvement and, 234 Alport syndrome, 121 Alveolar rhabdomyosarcoma, 243, 243/ AMD. See Age-related macular degeneration Amelanotic choroidal masses, 266, 278, 278t Amelanotic conjunctival nevus, 65 Amelanotic melanoma, 69, 274f, 278, 278t American loint Committee on Cancer (AICc), staging of ocular tumors by, 329- 352t Amyloid AL, 212 Amyloidosis/ amyloid deposits, 139-1 40, 140f, 212 conjunctival, 58- 59, 60/ corneal in Avellino dystrophy, 97, 99/ in keratoconus, 91 in lattice dystrophy, 96-97, 99/ in eyelid, 211-212, 212f, 213t familial (amyloidosis IV/gelsolin -type lattice corneal dystrophy), 212 orbital,235 vitreous involvement in, 139- 140, 140j, 141/ Anesthesia, examination under, for retinoblastoma, 301 - 302,302/ Aneurysms (microaneurysms), 160- 162, 162f, 164 in diabetes, 166 Angiography, fluorescein. See Fluorescei n angiography Angiomas (angiomatosis) encephalofacial (Sturge-Weber syndrome), choroidal hemangioma in, 200, 292 retinal, 294- 295, 294f, 296/ Angiomatous tumors, 291 - 296, 297f See also specific type Angle closure/angle-closure glaucoma iridocorneal endothelial (ICE) synd rome and, 105 nanophthalmos and, 112, 113 trauma and, 18 Angle recession, traumatic, 18, 19f, 109 glaucoma and, 18. 109 Aniridia, 188 Anomalies, congenital. See specific type and Congenital anomalies Anterior basem*nt membrane dystrophy, 95, 95/ Anterior border/pigmented layer, of iris, 185, 186/ Anterior chamber congenital anomalies of, 102- 103, 103j, 104/ degenerations of, 104-109, 110/ depth of, 10 I disorders of, 101 - 109, 110j. See also specific type pigment dispersion affecting~ 109, 1091, 110/ topography of, 10 1-102, 10 If, 102/ Anterior chamber angle, 10 I- I 02, 102/ gonioscopy of, 10 1- 102, 102/ traumatic recession of, 18, 19f, 109 glaucoma and, 18, 109 Anterior lenticonus/lentiglobus, 121

377

378 • Index Anterior segment dysgenesis of, 81 - 82, 8 If, 102- 103, I03j, 104/ m etastatic disease of, 317 Anterior synechiae, in glaucoma, iridocorneal endothelial (ICE) syndrome and, 105, lOS! Anterior uveitis, iris nodules in, 270t Antiangiogenic agents, for reti nal capillary hemangioblastoma, 295 Antiox ida nts, age-related macular degeneration and, 168 Anti-V£GF agents for macular edema, 158- 160, 169 for retinal capillary hemangioblastoma, 295 Antoni A pattern/Antoni B pattern, in schwanno m as, 244- 245, 245f Aphakia, congenital, 121 Aphakic (pseudophakic) bullous ke ratopathy, after cataract surgery, 89-91, 90! Apocrine (eosinoph ilic/oxyphilic) cystadenoma (oncocytoma), 75 , 75[ Apocrine glands of eyelid, 205, 207t Apocrine hidrocystoma, 214, 214f Appendage neoplasms, 221 - 224, 22 1[, 222[, 223f Arachnoid mater, optic nerve, 249, 250/ Areolar atrophy of retinal pigment epithelium, central (geographic atrophy), 169, 170f Argon laser therapy for diabetic retinopathy/macular edema, 167 , 167f for retinoblastoma , 311 ARN. See Acute reti nal necrosis Array (m icroarray-based) comparative genomic hybridization (array CG H ), 391 Arterial occlusive disease, retinal branch retinal artery occlusion, 163 central retinal artery occlusion, 162-163, 163f Arteriovenous malformations, congenital retinal, 296.297/ Arteritis, giant cell (temporal), optic nerve affected in, 252,252f Ascending optic atrophy, 253- 254 Aspergillus (aspergillosis) keratitis caused by, 84 orbital infection caused by, 234, 234f Asteroid bodies, 138-139, 139f in sarcoidosis, 191 Asteroid hyalosis, 138- 139, 139/ Astrocytes, optic nerve, 249 Astrocytoma (astrocytic hamartoma) juvenile pilocytic, 257 optic nerve, 257, 257f retinoblastoma differentiated from, 305-306, 306f ATP binding cassette transporter mutations, in Stargardt disease, 172 Atroph ia bulbi with shrinkage, 22 without shrinkage, 22 Atrophic retinal boles, lattice degeneration and, 155 Atypia, cellular dysplastic nevi and, 226 primary acquired melanosis and, 68[, 69, 70/ Atypical fibroxanthoma (malignant fibrous histiocytom a), 117- 118,240-242 Atypical lymphoid hyperplasia, of orbit, 239 Avellino dystrophy, 97, 971, 99f Axenfeld anomaly/syndrome, 104/ Axenfeld nerve loop, 112, 112f Axenfeld-Rieger syndrome, 102-103, 103, 104/

B5 t issue fLXative, 29r B&B stain (Brown and Brenn stain), 311 B&H stain (Brown and Hopps stain), 31 t B-celilymphomas. See also Lymphomas conjunctival, 72 - 74, 73f intraocular (primary intraocular/central nervous systemllarge cell/vit reoret inal/ retinal/histiocytic/ non -Hodgkin ofCNS/reticulum cell sarcoma), 140-142,14 1/, 142f, 143f, 323 - 325, 323[, 325/ orbital, 239- 240, 2391 B cells (B lymphocytes), 9 8-scan ultrasonography/echography in choroidal/ciliary body melanoma, 276, 276/ in choroidal hemangioma, 291[, 292 in metastatic eye disease, 3 19 Bacteria conjunctivitis caused by, 53, 55/ corneal infections caused by, 82, 83/ endophthalm itis caused by, 133, 134/ keratitis caused by, 82, 831 optic nerve infection caused by, 251 orbital in fection caused by, 234 Balloon cells in choroidal/ciliary body melanoma, 196 in choroidal/ciliary body nevus, 195 BAM. See Benign acquired melanosis Band ke ratopathy, calcific, 88, 89/ Basal cell carci noma of eyelid, 2J 5t, 217- 219, 2 18[, 219/ intraocular extension of, 322 Basal cell nevus synd rome (Gorli n syndrome), eyelid m anifestations of, 2 15f Basal lamina, drusen of (cuticular drusen), 169 Basal laminar deposits, 168 Basal li near deposits, 168 Basem*nt membrane corneal endothelial. See Descemet membrane/layer corn eal epithelial, 77, 78/ Basem*nt membrane dystrophies, epithelial (map-dot fingerpri nt/Cogan m icrocystic/anterior basem*nt membrane), 95, 95/ Basophils, 7, 8/ bax expression, in adenoid cystic carcinoma, 33 bc1 -2 expression, in adenoid cystic carcinoma, 33 Bear tracks (grouped pigmentation of retina), 278, 279f Benign acquired melanosis, 65!, 67, 67/ Benign lymphoid foll iculosis, 7 1 Benign lymphoid hyperplasia, 72, 72f See also Lymphoid hyperplasia Ben ign mixed tumor (pleomorphic adenoma), oflacrimal gland, 236, 237/ Bergmeister papilla, 132, 133 Berlin edema (commotio retinae), 20 Best disease (vitelliform macular dystrophy), 174- 175 Bestrophin, m utations in, 175 fJig-T-l3 gene. See TGFfJT gene Bevacizumab, for macular edema, 160, 169 BIGH3 gene. See TGFril gene Biomicroscopy, slit- lamp in choroidal/ciliary body melanoma, 275 in iris nev us, 266 Birth defects. See specific type and Congenital anomalies Bladder (V-l ed!) celis, 125, 125/ Bli nd ness age-related macular d egeneration causing, 167 diabetic retinopathy causing, 165 Blood, cornea stained by, 92- 93, 94f

Index . 379 Blood-retina barrier, ischemic damage to, hemorrhages and, 160, 161f Blue nevus, 65 Blunt trauma commotio retinae and, 20 glaucoma and, 109 Bony orbit, 229. See also Orbit Bony tumors of orbit, 245-246, 246/ Borderline neoplastic proliferations, 10 Botryoid rhabdomyosarcoma, 243 Bouin solution, as tissue fixative, 291 Bowmanlayer/membrane, ii, 78/ healing/repair of, 16 BPD. See Butterfly pattern dystrophy Brachytherapy for choroidal hemangioma, 292-293 for melanoma, 283-284, 284/ of iris, 271 for metastatic eye disease, 322 for retinoblastoma, 312 Branch retinal artery occlusion, 163 Branch retinal vein occlusion, 164 BRAO. See Branch retinal artery occlusion Brawny scleritis, 114, 114f. 115/ Breast cancer, eye involvement and, 200, 21St, 316f, 3161, 318f, 320, 320f, 321, 322 Brown and Brenn (B&B) stain, 31t Brown and Hopps (B&H) stain, 31t Bruch membrane age·related macular degenerationlchoroidal neovascularization and, 168, 168f, 169, 169/ in retinal healing/repair, 17 rupture of, 22 Srucke muscle, 186 Brunescent cataract, 127, 128/ Brushfield spots, 270t, 272/ BRVO. See Branch retinal vein occlusion Bulbar conjunctiva, 47, 48/ Bulla. of cornea in keratopathy (bullous keratopathy), 89- 91, 90/ in ocular cicatricial pemphigoid, 54, 55/ Bullous keratopathy, 89-91, 90/ Busacca nodules in iridocycl*tis, 2701, 272/ in sarcoidosis, 190,272/ Butterfly pattern dystrophy, 175 c-Kit, in immunohistochemistry. 34 Calcific band keratopathy, 88, 89/ Calcific (calcified) drusen, 169 Calcific plaques, senile scleral, 115. 116/ Calcium oxalate crystals, in nuclear cataract, 127,129/ Callender claSSification, of uveal melanomas, 199 CALT. See Conjunctiva-associated lymphoid tissue Cancer. See also specific type or organ or structure affected and Carcinoma; Intraocular tumors; Tumors classification/growth patterns and, lOt, II/ Candida (candidiasis), keratitis caused by, 83 Candle\\'ax drippings, in sarcoidosis, 190 Capillary hemangioblastoma, of retina, 294-295, 294/ Capillary hemangiomas of conjunctiva, 50 of eyelid, 219- 220, 220/ of orbit, 240 of retina. See Capillary hemangioblastoma

Carbohydrate sulfotransferase 6 (CHST6) gene, in macular dystrophy, 96 Carboplatin, for retinoblastoma, 310, 311 Carcinoma, 101, II! See also Adenocarcinoma; Carcinoma in situ adenoid cystic (cylindroma), of lacrimal glands, 236-238,237/ basal cell, of eyelid, 215/, 217-219, 21Sj, 219/ intraocular extension of, 322 of conjunctiva intraocular extension and, 322 staging of, 332-3331 of eyelid, 217-219, 218f, 219f, 220/ intraocular extension of, 322 metastatic, 315- 322. See also Metastatic eye disease sebaceous, 2151, 221-224, 222f, 223/ squamous cell. See Squamous cell carcinoma thyrOid, retinoblastoma associated with, 314t Carcinoma in situ of conjunctiva, 63-64, 64/ of cornea, 100 sebaceous, 222, 223/ Carney complex, eyelid manifestations of, 213t Caruncle, 47, 48/ glandular lesions involving, 75 lymphocytic lesions involving, 71 nevi in, 65 Caseating granulomas, 7, 9/ Cataract, 124- 127, 125/, 127/. 128f, 129/ brunescent, 127, 12S/ cortical, 126-127, 127f, 12S/ duplication, 124, 125/ hypermature, phacolytic glaucoma and, 106- \07, 107/ rnorgagnian, 127, 128/ nuclear, 127, 128f, 129/ persistent fetal vasculature and, 132 phacolytic glaucoma and, 106-107, \07f, 127 subcapsular anterior (subcapsular fibrous plaques), 124, 125/ posterior, 124-125, 125/ retinoblastoma differentiated from, 30St traumatic, 20 Cataract surgery bullous keratopathy after, 89-91. 90/ endophthalmitis after, Propionibacterium awes causing, 123, 123f, 124 Cavernous hemangioma, 6 of orbit, 6, 240, 241/ of retina, 295, 296j Cavernous optiC atrophy of Schnabel, 254, 255/ CCNI gene, in neurofibromatosis, 244 CD antigens. See also specific I)'pe in immunohistochemistry, 34 CDI5, in lymphoma, 239 CD! 9, in lymphoma, 240 C020, in lymphoma, 240 CD20/CD25 receptors, in nonspecific orbital inflammation, 232 C030, in lymphoma, 239 CD34, in hemangiopericytoma, 242 C D40, o rbital fibroblast , th}'roid eye disease and, 232 CD45 in fibrous histiocytoma, 240 in lymphoma, 239 CD68, in fibrous histiocytoma, 240 CD154, orbital fibroblast, thyrOid eye disease and, 232

380 • Index Cellular atypia dysplastic nevi and, 226 primary acquired melanosis and, 68f, 69, 701 Cellulitis, 208, 209! Central areolar atrophy of retinal pigment epithelium (geographic atrophy), 169, 170! Central retinal artery, occlusion of, 162-163, 1631 Central retinal vein, occlusion of, 163- 164, 165/ Cerebellar hemangioblastoma, with retinal angiomatosis (von Hippel-Lindau disease), 294- 295 CFH (complement factor H) gene, in age-related macular degeneration , 167 CGH. See Comparative genomic hybridization Chalazion, 210-211, 211/ Chandler syndrome, 104 Charged-particle radiation for choroidal hemangioma, 292- 293 for melanoma, 284 for retinal capillary hemangioblastoma, 295 CHED. See Congenital hereditary endothelial dystrophy Chemotherapy (cancer) for lymphoma, 74, 324 for melanoma, 285 for metastatic eye disease, 322 for retinoblastoma, 310-311, 3Ilf Cherry-red spot, in central retinal artery occlusion, 163 Chlamydia conjunctival lymphoma and, 74 conjunctivitis caused by, 54, 55f plJeumOlliae, 74

psittaci, 74 trachoma tis, 54, 74 Chloroma (granulocytic sarcoma), 328 Cholesterol crystals, vitreous hemorrhage and, 138 Cholesterol emboli (Hollenhorst plaques), in branch retinal artery occlusion, 63 Choriocapillaris, 187, 187f Chorioretinitis fungal, 152, 153f sclopetaria, 203 Choristomas, 6, 4 7-50, 49f complex, 49f, 50 conjunctival, 47- 50, 49f osseous, 49f, 50 phakomatous (Zimmerman tumor), 20f, 207 Choroid amelanotic masses of, 266, 278, 2781 coloboma of, retinoblastoma differentiated from, 3051 detachment of, 203 focal posttraumatic granulomatous inflammation of, 22,22f healing/repair of, 17 hemangiomas of, 200- 202, 201f, 291-293, 291f, 293f in Sturge- Weber syndrome, 200, 292 in leukemia, 327 lymphoid proliferation in, 202, 202f melanocytoma of, 195, 268 melanoma of, 195-200, 196f, 197f, 198f, 199f, 263, 273 - 288. See also Choroidal/ciliary body melanoma clinical presentation of, 273-274, 27sf glaucoma caused by, 109, 109f, 198 nevus differentiated from, 266- 268, 278 staging of, 337-341t neovascularization of, 159, 168f in age-related macular degeneration, 169- 170, 171f

nevus of, 195, 195j, 266-268, 267/ melanoma differentiated from , 266- 268, 278 osteoma of, 202 melanoma differentiated from, 280, 280f rupture of, 22, 22f, 203 topography of, 186- 187, l87f tumors of, 195-200. See also Choroidal/ciliary body melanoma metastatic, 200, 20 If, 315, 316t, 317f, 318f, 31 9f, 320f vasculature of, retina supplied by, 146 Choroidal/ciliary body melanoma (posterior uveal melanoma), 195- 200, 196f, 197f, 198f, 199f, 263, 273-288 classification of, 199,281 diagnosis of, 274 - 277, 276f, 277f differential, 277-281, 2781, 279f, 280f, 28If epithelioid, 196, 199 glaucoma caused by, 109, 109f, 198 metastatic, 200 evaluation of, 281-282, 2821 nevus differentiated from, 266- 268, 278 ocular surface/conjunctival involvement and, 70, 71f prognosis/prognostic factors for, 198-200,286-288 spindle cell, 196, 196j, 199 spread of, 197- 198, 197f, 198f, 200 staging of, 337-34lt treatment of, 282 - 286, 284f Choroidal neovascularization, 159, 168f in age-related macular degeneration, 169-170, I71f Choroidal hemorrhage, expulsive, 18-19, 19f Choroidal vasculopathy, polypoidal (posterior uveal bleeding syndrome), 171, 172f, 173f Chromogens, in immunohistochemistry> 33, 35f C hromogranin, in immunohistochemistry, 34, 35f CHRPE. See Congenital hypertrophy of retinal pigment epithelium CHST6 gene, in macular dystrophy, 96 Cicatricial pemphigoid, 54, 56f Cilia (eyelashes), 205 Ciliary body healing/repair of, 17 hyalinization of, 192 melanocytoma of, 195> 268 melanoma of, 195- 200, 196f, 197f, 198f, 199f, 263, 273- 288. See also Choroidal/ciliary body melanoma clinical presentation of, 273, 2741 glaucoma caused by> 109, 109f, 198 staging of, 337- 341 t neoplastic disorders of, 195-200 metastatic, 316 nevus of, 195,266 tear in (angle recession), 18, 19f, 109 glaucoma and, 18, 109 topography of, J 86, l87f Ciliary epithelium nonpigmented, benign adenomas of, 288 pigmented acquired hyperplasia of, 288 benign adenomas of, 288 CIN. See Conjunctival intraepithelial neoplasia Circ*mscribed (localized) choroidal hemangioma, 200, 291,291f Circ*mscribed iris nevus, 266 Cloquet (hyaloid) canal, 132 Clump celis, in iris, 185-186

Index . 38 1 CMV See Cytomegaloviruses Coats disease, 149, 150J, 305, 306/ retinoblastoma differentiated from , 305, 305/, 306/ Cobblestone (paving-slOne) degeneration, 156, 156/ Coccidioides immitis (coccid ioidomycosis), optic nerve infection caused b}" 251 Cogan microcystic dystroph}', 95, 95/ Cogan-Reese (i ris nevus) syndrome, 104, lOS/, 270t Coherence tomography, optical. See Optical coherence tomography Collaborative Ocular Melanoma Study (CaMS), 263, 281, 287- 288 Collagen , in vitreous, 131 Colloidal iron stain, 30, 31t Colobomas lens, 121 optic nerve/optic disc, 249-250, 251/ retinoblastoma differentiated from, 305t uveal, 188 Combined hamartoma of retina and retinal pigment epithelium, 184,289,289/ Commotio retinae, 20 Communication, between d inician and pathologist, 25-26 Comparative genom ic hybridization (CGH), 391 microarra},-based (arra}' CGH), 39t Complement fac tor H (CFH) gene, in age-related macular degeneration. 167 Complex choristomas, 49/. 50 Compound nevi of conjunctiva, 65, 66/ of eyelid, 225, 22 5/ Compromised host, cytomegalovirus retinitis in, 151 Computed tomography (CT scan) in choroidal/ciliary body melanoma, 277 in retinoblastoma, 303 CaMS (Collaborative Ocular Melanoma Study), 263, 281, 287-288 Cone inner segments, 145, 146/ Cone outer segments, 145, 146/ Cones, 145. 146/. 147 retinoblastoma and, 178, 180 Congenital anomalies, 6, 7f See also specific type of anterior segmentlchamber, 102-103, 103/. 104/ of conjunctiva, 47-50, 49/ of cornea, 79-82, 79/. 80/' 81/ of eyelid, 207, 208/ glaucoma associated with, 102, 103/ of lens, 121, 122/ of optic disc and nerve, 249- 250, 251/ of orbit, 229-230, 230/ of retina and retinal pigment epithelium, 148-151, 149f, 150/ of sclera, 112- 113 of trabecular meshwork, 102- 103, 103/. 104/ of uveal tract, 188 of vitreous, 132-133, 132f Congenital aphakia, 121 Congenital glaucoma (primary congenital glaucoma), 102,103/ Congenital hereditary endothelial dystrophy, 79- 80, 79/ Congenital hypertrophy of retinal pigment epithelium (CHRPE), 149-151, 150/ melanoma differentiated from, 150. 278, 279/ Congenital retinal arteriovenous malformations, 296, 297[

Congenital rubella, aphakia and, 12 1 Congenital syphilis, corneal man ifesta tions of/interstitial keratitis, 87. 87/ Congo red stain, 30, 31t Conjunctiva, 47-75 amyloid deposits in, 58-59, 60/ biopsy of in cicatricial pemphigoid, 54 in granulomatous conjunctivitis, 52 in intraepithelial melanosis, 67 in lymphocytic lesions, 71 in squamous neoplasms, 64 bulbar, 47, 48/ card noma of intraocular extension and, 322 squamous cell in situ, 63-64, 64/ invasive, 63J, 64, 64/ staging of, 332-333t caru ncular. 47, 48/ lymphocytic lesions involving, 7 1 congenital anomalies of, 47-50, 49/ cysts of, 59-60, 60/ nevi and, 65 degenerations of, 56-60, 58/. 59f, 60/ disorders of, 47-75. See also specific type neoplastic, 61-75. See also Conjunctiva, tumors of epithelium of, 47, 48/ cysts of, 59-60. 60/ neviand,65 foreign body on, 53, 53/ fomiceal, 47, 48/ lymphocytic lesions involving, 71 goblet cells in, 47, 48/. 207t granuloma of foreign -bod}', 53, 53/ in Parinaud oculoglandular syndrome, 52 in sa rcoidosis. 52, 53/ infectionlin fl ammation of, 50-56, 51/. 52/. 53J, 55J, 56/. 57f See also Conjunctivitis intraepithelial neoplasia of (CIN), 62, 63/. 64/ See also Ocular surface squamous neoplasia l}'mphoid tissue associated with (CALT), 47 I}'mphoma of, 72, 72-74, 72/. 73/ melanoma of, 69-70. 70/' 71/ intraocular extension of, 322 pri mary acquired melanosis and, 67, 68J, 69, 70/ staging of, 334-336t nevus of, 65-66. 65t, 66/ palpebral, 47, 48/. 205, 206/ papillomas of, 61-62, 61/ stroma of, 47. 48/ topograph}' of, 47. 48/ tumors of, 61-75 glandular, 75, 75/ human papillomaviruses caus ing, 61 - 62, 61[ lymphocytic/lymphatic, 71-74, 72/. 73[ melanocytic, 65-70, 65t, 66/. 67/. 68/. 70/' il/ staging of, 332-336t • Conjunctiva -associated lymphoid tissue (CALT/ conjunctival MALT), 47 Conjunctival inclusion cysts, 59-60. 60/ neviand, 65 Conjunctival intraepilhelial neoplasia (ClN), 62, 63/. 64f See also Ocular surface squamous neoplasia

382 • Index Conjunctivitis, 50- 56 bacterial, 53, 55/ cicatricial, 54, 56! follicular, 51, 51[' 52/ giant papillary (contact lens-induced), 50 granulomatous, 52-53, 53/ Haemophilus causing, 53 infectious, 53-54, 55! noninfectious, 54, 56! papillary. 50, 51/ in Parinaud oculoglandular syndrome, 52 in sarcoidosis, 52, 53! viral, 53- 54, 55/ Contact inhibition, in corneal wound repair, i3 Contact lenses Acallthamocba keratitis associated with, 84- 85 conjunctivitis caused by, 50 Contraction, wound, 13, 14/ Cornea. See also under Corneal abrasions of, 13- 14 blood staining of, 92-93, 94/ Bowman layer/membrane of, 77, 78/ healing/repair of, 16 central, healing in, \5, IS! congenital/developmental anomalies of, 79- 82, 79f, SOf, 81f degenerations/dystrophies of, 87- 100. See also specific type and Corneal degenerations; Corneal dystrophies deposits in amyloid in Avellino dystrophy, 97, 99J in lattice dystrophy, 96- 97, 99f, 212 pigment, 91 - 93, 94/ disorders of, 77- 100. See also specific type and Keratitis; Keratopathy introduction to pathology of, 78- 79, 79t neoplastic, 100. See also specific tumor type endothelium of, 77- 78, 78f healing/repair of, 15- 16, 15/ epithelium of, 77, 78f healing/repair of, 13- 16, 15/ flat (cornea plana), sclerocornea and, 82 guttae, in Fuchs endothelial dystrophy, 99, 100f healing/repair of, \3- 16, IS! infection/inflammation of, 82- 87, 831, 841, 851, 86f, 87f See also Keratitis intraepithelial neoplasia of, 100 opacification of, in Peters anomaly, 81, 81f pigmentation/pigment deposits in, 91 -93, 94/ plana (Oat cornea), sclerocornea and, 82 stroma of, 77, 78/ healing/repair of, 14 thicknesslrigidity of, 77, 78/ topography of, 77- 78, 78/ transplantation of, rejection and, 91, 92/ tumors of, 100. See also specific type Corneal buttons, 78 Corneal degenerations, 87-93, 94f See also specific type alld Keratopathy Corneal dystrophies, 94- 100. See also specific Iype endothelial, 98-100,100/ epithelial, 95, 95/ stromal, 96- 97, 97f, 97t, 98f, 99/ Corneal grafts, rejection of, 91, 92/

Corneal hydrops, in keratoconus, 91, 93/ Corneal intraepithelial neoplasia, 100 Corneal nodules, Salzmann, 88, 88/ Corneal ulcers, in herpes Si mplex keratitis, 82, 83, 84/ Corona, lymphoid follicle, 51, 52f, 71 Cortex lens, 120, 120/ degenerations of, 126- 127, 127f, 128/ vitreous, 131 Cortical cataracts, 126-127, 127f, 128/ Corticosteroids (steroids), for uveal lymphoid inflitration, 326 Cotton-wool spots, 157 in branch retinal vein occlusion, 164 in central retinal vei.n occlusion, 164 in diabetic retinopathy, 166 in leukemia, 326 Cowden disease, eyelid manifestations of, 215t CRAO. See Central retinal artery, occlusion of CRVO. See Central retinal vein, occlusion of Cryotherapy for melanoma, 285 for retinal angiomas/hemangiomas, 295 for retinoblastoma, 312 Cryptococcus neoformans (cryptococcosis), optic nerve infection caused by, 251,251/ Crystal violet stain, 3lt Crystalline keratopathy, infectious, 85-86, 86f after penetrating keratoplasty, 85 Crystalline lens. See Lens Cutaneous horn, 21 7 Cuticular (basal laminar) drusen, 169 Cyclodialysis, 18, 19f, 109 Cystadenoma, apocrine/oxyphilic/eosinophilic (oncocytoma), 75, 75f Cysteine-rich proteins, in neurofibromatosis, 244 Cystic carcinoma, adenoid (cylindroma), of lacrimal glands, 236- 238, 237/ Cysticercus cellulosae (cysticercosis), orbital involvement and,235 Cystoid degeneration, peripheral, 154, 154/ Cytoid bodies, 157, 158/ Cytokeratins, in immunohistochemistry, 33 Cytomegaloviruses, retinitis caused by, 151, 152/ Dacryoadenitis, 231 Dacryops, 214 Dalen -Fuchs nodules, i.n sympathetic ophthalmia, 189, 190/ Deep anterior lamellar keratoplasty (DALK), 78 Degenerations, 9- 10,121 anterior chamber/trabecular meshwork, 104- 109, 1[0/ conjunctival, 56-60, 58I. 59f, 60f corneal, 87- 93, 94/ definition of, 9-10 elastotic (elastosis) in pinguecula/pterygium , 56, 58, 58f, 59/ solar, of eyelid, 217, 218/ eyelid, 211-212, 2llI. 212f, 2131 Jens, 124- 127, 125f, 126f, 127f, 128f, 129f See also Cataract optic nerve, 253-255, 253f, 254f, 255/ orbital,235 peripheral cystoid, 154, 154/ retinal, 154-177 scleral, 115- 116, 116/

Index. 383 uveal tract, 192-1 93, 1921, 193/ vitreous, 134- 140 Degenerative retinoschisis, typical and reticular, 154 OEM. See Diagnostic el ectro n microscopy Dend rites, 82, 84[ Dendritic cells, in choro idaVciliary body nevus, 195 Dendritic keratitis. herpes simplex, 82, 84f Dermal o rbital melanocytosis, 66 Dermatomyositis, eyel id manifestat ions of, 213f Dermis, eyelid, 205, 206f neoplasms of, 219-220, 220f Dcrmoids (dermo id cysts/tumors), 6, 48 conjunctival, 48, 49/ corneal. 81 of eyelid,207,213 Golde nhar syndrom e and. 48 limbal, 48, 49[ orbital. 229- 230, 230f Dermolipomas (lipodermoidsl. 49f, 50 Goldenhar syndrome and , 50 Dcscemet membrane/ layer, 77. 78f heali ng/repair of, 15f, 16 ruptu re of, 18, 18/ in keratoconus, 18, i8f, 9 1, 93/ Descemet stripping endotheli al keratoplasty (DSEK), 79 Descend ing optic atrophy, 254 Des min, in immunoh istochemistry, 33 Diabetic retinopathy, 165- 167, 166j. 167/ Diagnostic electron microscopy. 34t. 43 Dialyses, 20 Diathermy for retinal capillary hemangioblastoma, 295 Iransscleral, contraindicaliolls 10, 285 Diffuse cho ro idal hemangioma, 200, 292, 293/ Diffuse drusen, 168, 168/ Diffuse iris nevus, 266 Diklyoma (medulloepilheliom

Ductal cysts of eyelid, 213-214, 214/ Duplication , cataract, 124, 125/ Dura mater, optic nerve, 249, 250/ Dyske ratosis in actinic keratosis, 2 17, 217/ definition of, 206 Dysplasia of bony orbit, 245-246, 246f reti nal, retinoblastoma differentiated from, 305t Dysplastic nevus, 226 Dystrophies, 9-10,121 corneal, 94- 100. See (/lso specific type definit ion of, 10 macular, 96, 97J, 971 pattern, 175, 176/ photoreceptor, 175-177 stromal, 96-97, 97/, 97/, 98f, 99/ EI3MD. See Epithelial d ystrophies, basem*nt membrane Eccrine hidrocystoma , 214 Eccrine sweat glands of eyelid, 205, 2071 Echinococcus grmrulosu5 (echinococcosis), orbital infection caused by, 41 Ectropion, uveae, 192 Ede ma, retinallmacu lar, 158- 160, 159f, 160[ Elastotic degeneratio n/elastosis in ping uecula/pterygium. 56, 58, 58f 59/ solar, of eyelid, 217, 218/ Electro n m icroscopy, diagnostic, 34t, 43 Elevated intraocular pressure corneal blood staining and. 92-93 lens epit helium affected by, 124 II p13 syndrome (short arm II deletion syndrome), in an iridia, 188 F. LM. See External limit ing membrane ELOV4 gene, in Stargardt disease, 172 Elschnig pearls, 125-126, 126f Emboli, cholesterol (Ho llenhorst plaques), in branch retina l artery occlusio n, 163 Embryonal rhabdomyosarcoma, 243, 243J Embryonic lens nucleus, 120 Embryotoxon, posterior. 102- 103, 103j, 104/ Emissariafemi ssarial channels, I I If 112, 11 2/ melano ma spread via, 198, 198/ Encephalofacial angio matosis (Sturge- Weber syndro me), choroidal hemangio ma in, 200, 292 Encephalomyeliti s, acute d issem inated, optic nerve involvement and, 252 Endogenous infection, lIveal, 188 Endokeratoplasty,79 Endophthalmitis bacteria l, vitreous afTected in. 133, [34/ fu ngal, iris nodule in. 270t infectious, 133, 134/ phacoa naphylacticllens-ind uced granulomatous (phacoantigen k/lens-associated uveitis) , 122,

mf, 123/ Propionibacterium awes caUSing, 123, 123j, 124 Endothel ial d ystrophies, 98-1 00, 100f congenital hereditary, 79-80. 79/ Fuchs, 98- 100, 100/ posterior polymo rphous, 80, 80f genetics of, 80 Endothel ium, co rneal, 77-78. 78f healinglrepair of, 15-16, 15/

384 • Index Enucleation for melanoma, 283 for retinoblastoma, 310 rubcosis iridis and, 192, 193/ for sympathetic ophthalmia prevention, 189 for uveal lymphoid inftltration, 326 Eosinophilic (oxyphilic/apocrine) cystadenoma (onCOC)10ma), 75, 75/ Eosinophils, 7, 8f Ephelis, 224. See also Freckle Epidermis, eyelid, 205, 206/ neoplasms of, 214-219, 214f, 2ISf, 215t, 216f, 2171, 218f,219f,220j Epidermoid/epidermal cysts of eyelid, 213, 213/ of orbit, 229-230 Episclera, Ill, Ill! nodular fasciitis causing tumor of, 118, liS! Episcieritis, 113, 1131 Epithelial cysts, of orbit, 229- 230, 230/ Epithelial downgrowth (ingrowth), corneal graft failure and, 91, 92/ Epithelial dystrophies, basem*nt membrane (map-dotfingerprint/Cogan microcyst ie/anterior basem*nt membrane), 95, 95f Epithelial inclusion cysts, conjunctival, 59-60, 60f nevi and, 65 Epithelial invasion of iris, 2701 Epithelial tumors, lOt, I If pigmented, of uvea and retina, 288-289, 289f Epithelioid cells, in choroidal/ciliary body melanoma, 196,199 Epithelioid histiocytes, 7, 8f Epithelium ciliary nonpigmented, benign adenomas of, 288 pigmented acquired hyperplasia of, 288 benign adenomas of, 288 conjunctival, 47, 48f cysts of, 59- 60, 60f nevi and, 65 corneal, 77, 78f healing/repair of, 13- 16, 15j lens, 119- 120, 120j degenerations of, 124-126, 125f, 126/ See also Cataract Equator (lens), 120, 120j Equatorial lens bow, 120, 120j Erdheim-Chester disease (ECD), eyelid manifestations of,213t Essential iris atroph y, 104, 105j Ethanol as tissue fixative, 29, 291 for tissue processing, 29 Ewing sarcoma, retinoblastoma associated with, 3141 Examination under anesthesia, for retinoblastoma, 301-302,302f Exenteration, for melanoma, 286 Exfoliation, true, infrared radiation/heat causing, 106 Exfoliation syndrome (pseudoexfoliation), 106, !06f, 107j Exogenous infection, uveal, 188 Exophthalmos. See ProptOSis Expulsive choroidal hemorrhage, 18-19, 19j

External-beam radiation for choroidal hemangioma, 292-293 for lymphoma, 324 for melanoma, 285 for metastatic eye disease, 322 for retinal capillary hemangioblastoma, 295 for retinoblastoma, 312 secondary tumors and, 312, 313-314 , 314t for uveal lymphoid inflltration, 326 External limiting membrane, 145 Extranodal marginal zone lymphoma (MALToma), 72 - 73, 73f, 74 Extraocular muscles, in thyroid eye disease, 232, 233j Exudates, hard, 158, 159j in leukemia, 326

Eye congen ital anomalies of, 6, 7j phthisical (phthisis bulbi), 22, 23f in systemic malignancies, 315 - 328 tumors of. See Intraocular tumors Eyelashes (cilia), 205 Eyelids amyloid deposits in, 211 - 212, 212f, 213t basal cell carcinoma of, 2151, 217-219, 218f, 219f intraocular extension of, 322 congenital anomalies of, 207, 208j cysts of, 213- 214, 213f, 214j dermoid, 207, 213 ductal, 213 - 214, 214j epidermoid/epidermal, 213, 213j degenerations of, 211-212, 21 If, 212f, 213t disorders of, 205- 227. See aLso specific type neoplastic, 214- 227. See also Eyelids, tumors of in thyroid eye disease, 232, 233f glands of, 205 healing/repair of, 17- 18 infection/inflammation of, 208-211, 209f, 210f, 21 If keratosis of actinic, 216-217, 217/, 218j seborrheic, 214-215, 2 I"if, 215/ retraction of, in thyroid eye disease, 232, 233j skin of, 205, 206j melanoma arising in, 126- 227, 227f tumors of, 219- 220, 220j squamous cell carcinoma of, 219, 220j actinic keratosis and, 216-217, 217f, 2 18f well-differentiated keratinizing (keratoacanthoma), 215t, 216, 216j systemic diseases manifesting in, 211 - 212, 213t topography of, 205- 206, 206f, 207t tumors of, 214 - 227 appendage neoplasms, 221-224, 22 If, 222f, 223f basal cell carcinoma, 21St, 217- 219, 218f, 219j intraocular extension of, 322 dermal, 219 -220, 220/ epidermal, 214- 219, 214f, 21sf, 21St, 216f, 217f, 218f, 219f, 220f frozen section/Mohs surgery for, 45 melanocytic, 224- 227, 224J, 225f, 226j squamous cell carcinoma, 219, 220j actinic keratosis and, 216-217, 217f well-differentiated keratinizing (keratoacanthoma), 21St, 216, 216/ staging of, 329- 33lt systemic malignancies and, 215, 21St

Index . 385 Familial adenomatous polyposis (Gardner syndrome), retinal manifestations of, ISO-lSI Familial amyloidosis (amyloidosis IV /geJsolin-type latt ice corneal dystrophy), 2 12 Familial amyloidotic polyneuropathy types I and II, 140, 14 If, 212 type IV (gelsolin -type lattice corneal dystrophy), 212 vitreous involvement in, 140, 141/ FAP, See Familial amyloidotic polyneuropathy Fasciitis, nodular. 118, 118/ Fetal lens nucleus, 120 Fetal vasculature, persistent. See Persistent fetal vasculature Fiber layer of Henle, 147, 14 7/ See also Nerve fiber layer Fibroblasts, orbital, in thyroid eye disease, 232 Fibrocellular proliferation, intraocular, 20, 21/ Fibrohistiocytic tumor. See Fibrous histiocytoma Fibroma, ossifying, of orbit, 246, 246/ Fibro-osseous dysplasia (juvenile ossifying fibroma), of orbit. 246, 246/ Fibrosarcoma, retinoblastoma associated with, 314t Fibrous do\\'ngrowth (ingrowth), corneal graft failure and, 91,92f Fibrous dysplasia, of orbit, 245-246, 246/ Fibrous histiocytoma (fibrox

Foreign body giant ceUs, 7, 9/ Formalin, as tissue fixative, 28-29, 291 Fornices, 47, 48/ lymphocytic lesions involving, 71 Fovea, 146 Fovcola, 146, 147/ Foveomacular "itelliform dystrophy, adult-onset, 1i5,li6/ FOXPl gene. in extranodal margi nal zone lymphoma, i3

Fraser syndrome, eyelid manifestations of, 213t Freckle, 224 iris, 270t, 272/ Frozen section, for pathologic examination, 34(, 44- 45 Fuchs adenoma (pselldoadenomatous hyperplasia), 184,288 Fuchs endothelial dystrophy, 98-100, 100/ Fundus evaluation of, in choroidal/ciliary body melanoma, 275-276,277 flavimaculatus (Stargardt disease). 172, 174/ tomato ketchup, 292, 293/ Fundus photography, in choroidal/ciliary body melanoma, 277 Fu ngi allergic sinusitis caused by, orbital involvement and,234 chorioretinitis caused by, 152, 153/ endophthalmitis caused by, iris nodule in, 270t keratitis caused by, 83-84, 85/ optic nerve infection caused by, 251, 25if orbital infection caused by. 234, 234/ retinal infection caused by, 152- 153, 153/ Fusarium, keratitis caused by, 83, 85/ G protein (i-subunit, uveal melanoma and, 200 Ga nglion cells, retinal, 145, 146/ Gardner syndrome (familial adenomato us polyposis), retinal manifestations of, ISO-lS I Gastrointestinal cancer, metastatic eye disease and, 3161 Gelsolin gene mutation, amyloidosis/amyloid deposits and,212 Gcne expression profile, 41 Gene therapy, for retinoblastoma, 313 Genetic/hereditary factors in choroidal melanoma, 263 in retinoblastoma, 178,263,299-30 1,300/ Ge netic testing/counseling, in retinoblastoma, 299-301,300f Geographic atrophy, of retinal pigment epithelium, 169,170/ Germinal center, lymphoid follicle, 51, 52f, 71 Ghost cell glaucoma, 108, 108f, 138 Ghost celis, 108, 108f, 138 Giant cell arteritis, optic nerve affected in, 252, 252f Giant cells foreign body, 7, 9f Langhans, 7, 9/ multinucleated, 7, 9/ in sarcoidosis, 191, 191/ 'Ibulo n, 7, 9f in juvenile xanthogranuloma, 191, 19if Giant congenital melanocytic nevi, 224 Giant drusen, 306 Giant papillary (contact lens-induced) conjunctivitis, 50 Glands of Krause, 205, 207t

386 • Index Glands of Moil, 205, 207t Glands of Wolf ri ng, 205, 207t Glands of Zeis, 205 chalazion and, 210- 211, 211/ hordeolum and, 208 sebaceous adenocarcinoma arising in, 221 - 222 Glaucoma angle-recessio n, 18, 109 Axenfeld-Rieger syndrome and, 102 congen ital, 102, !O3! exfoliation syndrome/pseudoexfoliation and, 106, 106f 107/ ghost cell, 108, 108! hemolytic, 108, 108/ hemosiderin in, 108- 109, lOSf infantile, 102, !O3! iridocorneal endothelial (TCE) syndrome and, 105 melanocytoma and, 109,268 melanomalytic, 109, 109f, 198 nanop ht halmos and, 112, 113 neovascular, rubeosis iridis and, 192 phacolytic, 106- 107, i07f, 127 p igmentary/pigment dispersion syndrome and, 91 - 92, 94f 109, l09f 110/ primary, congenital, 102, 103! retinoblastoma and, 303 secondary leukemia an d , 327 with material in trabecular meshwork, 106- 109, ]] Of in uveal lymphoid infiltration, 325 trauma and, 107- 109, 108f tumors causing, ]09, II0f Glaukomflecken, 124 Glial cells optic ne rve, 249, 250f retinal in healing/repair, 17 in retinal ischemia, 157 Glioblastoma multifonne, optic nerve (malignant optic gliomas),257 Gliomas, optic nerve/pathway/ch iasm, 257, 257f Gliosis, retinal, 164, 165 Globe displacement of, 229 gross dissection of, for pathologic examination, 27- 28,2S/ orientation of, p athologic examination and, 26, 26f Glutaraldehyde, as tiss ue fixative, 29, 29t Glycoproteins, in vitreous, 131 Glycosaminoglycans in thyroid eye d isease, 232 in vitreous, 131 GMS. See Gomori methenamine silver stain GNAQ. See G protein a-subu nit GNAQ gene, in nevus of Ota, 66 Goblet celis, 47, 48f, 2071 Goldenhar syndrome, dermoids/dermolipomas/ lipodermoids and, 48, 50 Gomori methenamine silver stain, 30, 311 Gonioscopy chamber angle, 101-102, 102f in choroidallciliary body melanoma, 275 in iris nevus, 266 Grafts, corneal, rejection of, 91, 92f Gram stain, 30, 31 t Granular dystrophy (type 1), 96, 97t, 98f

Granulocytic sarcoma (chloroma), 328 Granulomas, 7, 8f, 9f conjunctival foreign -body, 53, 53f in Pari na ud oculoglandular syndrome, 52 pyogenic, 56, 57f in sarcoidosis, 52, 53f necrobiotic, in scleritis, 114, 115f in sarcoidosis, 52, 53f, 19 1, 191f zonal, 122 Granulomatosis larval (Toxocara), retinoblastoma d ifferentiated from , 305, 305t \Vegener, eyelid man ifestations of, 213t Granulomatous conjunctivitis, 52- 53, 53f Granulomatous inflammation, 6 conjunctivitis, 52- 53, 53f focal posttraumatic choroidal, 22, 22f Granulomatous inflammatory infiltrate, necrobiotic, in episcleritis, 113, I13f Graves disease. See Thyroid eye disease Gross dissection, for pathologic examination, 27- 28, 28f G rouped pigmentation of retina (bear tracks), 278, 279f H&E (hematoxylin and eosin) stain, 30, 301, 31 t Haemophilus injluenzae, conjunctivitis caused by, 53 Hamartomas, 6, 50 astrocytic (astrocytomas), 257, 257f juvenile pilocytic, 257 optic nerve, 257, 257f retinoblastoma differentiated from, 305-306, 306f combined, of retina and retinal pigment epithelium, 184,289, 289f of conjunctiva, 50 of retinal pigment epithelium combined, 184, 2S9, 289/ in Gardner syndrome, 151 Hard (hyaline) drusen, 168, 16Sf Hard exudates, ISS, 159f in leukemia, 326 "Hard" tubercles, 7, Sf See also Tubercles Healing, ophthalmic wound. See Wound healinglrepair Helicobacter pylori infection, conjunctival lymphoma and,74 Hemangioblastomas, retinal, 294-295, 294/ Hemangiomas, 291 - 295 of choroid, 200- 202, 2011, 29 1-293, 2911, 293f in Sturge-\Veber syndrome, 200, 292 of conjunctiva, 50 of eyelid, 219- 220, 220f of orbit, 240, 24lj capillary, 240 cavernous, 6, 240, 24 if racemose (Wyburn -Mason syndrome), 296, 297f of retina capillary. See Hemangioblastomas, retinal cavernous, 295, 296f Hemangiopericytoma, of orbit, 242, 242f Hematopoietic tissue, tumors arising in, lOt, Ilj Hematoxylin and eosin (H&E) stain, 30, 301, 31t Hemoglobin spherules, 138, 139f Hemolytic glaucoma, lOS, !08f Hemorrhages dot-and -blot, ischemia causing, 160, 161f expulsive choroidal, 18- 19, 19f fl ame, ischemia causing, 160, 161f

Index . 387 glaucoma and, 108- 109, 10Bf histologic sequelae of, 20 retinal ischemia causing, 160, 161f, 164, 165f in leukemia, 326, 327f vitreous, 137-138, 139f retinoblastoma differentiated from. 305t Hemorrhagic suprachoroidal detachment, melanoma differemiated from. 279-2BO Hemosiderin, in glaucoma, 10B-109. 108f Hemosiderosis oculi, 109 Henle fiber layer/ Henle layer, 147, 147f See also Nerve fibe r layer Her2Neu, in immunohistochemistry, 34 Hereditary d ystrophies endothelial, 79- 80, 79f photoreceptor (diffuse), 175-177 Herpes simplex virus acute retinal necrosis caused by, 151 conjunctivitis caused by, 53 keratitis caused by, 82-83, 84f Herpes zoster acute retinal necrosislretin itis caused by, 151 conjunctivitis and, 53 Hidrocystoma apocrine, 214, 214{ eccrine, 214 Histiocytes,7 epithelioid, 7, 8f Histioq10ma, fibrous (fibroxanthoma) malignant (atypical fibroxanthoma), 117-118, 240-242 orbital, 240-242, 242f scleral, 11 7-118, 117f Histogram, for flow cytometry results, 37, 37f HiV infection/ AIDS cytomegalovirus retinitis in, lSI microsporidiosis in, conjunctival involvement and, 54 ocular surface squamous neoplasia in, 62 HMB-45, in immunohistochemistry, 33 HMGA2 gene mutation, in pleomorphic adenoma, 236 Hodgkin disease, orbital, lymphoma and, 239 Holes macular, 136- 137,138f retinal, atrophic, lattice degeneration and, 155 Hollenhorst plaques (cholesterol emboli), in b ranch retinal artery occlusion, 163 Ho mer Wright rosettes, in retinoblastoma, 180, 181f Hordeolum (stye), 208 Ho rmonal therapy, for metastatic eye disease, 322 Ho rner-Trantas dots, 50 HPV. See Human papillomaviruses Human papillomaviruses conjunctival papillomas caused by, 61-62, 61f eyelid infections caused by, 209, 209f ocular surface squamous neoplasia and, 62 Hyaline deposits, in Avellino dystrophy, 97, 99f Hyaline (hard) drusen, 168, 16Bf Hyalocytes, 132 Hyaloid artery/system, persistencelremnants of, 132-133, 132/. 133 Hyaloid (Cloquet) canal, 132 Hyaloid face, of vitreous, 131 H yaloideocapsular ligament, 131 Hyalosis, asteroid, 138-139, 139/ Hyaluronan/hyaluronic acid, in thyrOid eye disease, 232

Hybridization comparative genomic (CGH), 391 microarray-based (arra y CGH), 39t fluorescence in situ (FISH ), 381 H ydatid cyst, orbital infection caused, 235 Hydrops, in keratoconus, 91, 93/ Hyperkeratosis in actin ic keratosis, 217 definition of, 206 Hyperlipoproteinemias, xanthelasma associated with, 211,

21 1f, 213t Hypermature cataract, phacolytic glaucoma and, 106- 107.107/ Hyperplasia, l Ot epithelial, ciliary pigmented, 288 lymphoid conjunctival, 71, 72f of uveal tract (uveal lymphoid infiltration), 202, 325- 326 pseudoade nomatous (Fuchs adenoma), 184, 288 sebaceous, 221 , 221/ Hyperthermia, therapeutic for melanoma, 285 fo r retinoblastoma, 311 Hyphema corneal blood staining and, 92-93, 94/ glaucoma/elevated intraocular pressure and, 108, 108/ IC3D classification of corneal dystrophies. 96 ICE. See Irid ocorneal endothelial (ICE) syndrome ICK. See Infectious crystalline keratopathy idiopathic orbital inflammation. See Nonspecific orbital inflammation IK. See Interstitial keratitis ILM. See Internal limiting membrane Immunocompromised host, cytomegalovirus retinitis in, 151 Immunoglobulin G (IgG), in th yroid eye disease, 232 Immunoglobulin G4-positive infiltrates, in nonspecific o rbital inflammation, 232 Immu nohistochemistry, 33-36, 35/ Im munothera py, for melanoma, 285-286 Implantation membrane, of iris, 270t I n situ hybridization, fluo rescence, 38t Inclusion cysts epide rmal, of eyelid, 213, 213f epithelial, conju nctival, 59-60, 60/ nevi and, 65 Index features, in diagnosis. II I nd irect ophthalmoscopy. in choroidaVciliary bo dy melanoma, 274 Infantile glaucoma, 102, 103/ Infection (ocular). See also under InfectiOUS eyelid, 208- 210, 209f, 210/ uveal tract, 188-189 Infectious conjunctivitis, 53-54, 55f. See also specific type

and causative agent Infectious crystalline keratopathy, 85-86, 86f after penetrating keratoplasty. 85 In fectious endophthalm itis, 133, 134/ infectious keratitis, 82-87. See also specific type and

causative agent In fl ammation (ocular), 6-9, 8f, 9f, 12t. See also specific

type or structure affected acute,6,13 choroidal, posttraumatic, 22, 22/

388 • Index chronic, 6 conjunctival, 50- 56, Slj, 52[' 53f, SSf, 56f, 57! corneal, 82- 87, 83f, 84f, SS/, 86f, 87/ eyelid, 208-211, l09j, 21Gj, 2llj granulomatous, 6 focal posttraumatic choroidal, 22, 22J lens-related, 122-123, 122f, 123f, 124f nongranulomatous. 6 optic nerve, 251 - 253, 25 1f, 252f, 253/ orbital, 230-235, 23 If, 233f, 234/ retinal, 151 -153, 151[' 152[, IS3/. 154/ in retinoblastoma, 30 I, 30lt scleral, 113-114, 113j, 114j, 115/ uveal tract, 188-191, l89/. 190f, 191/ vitreal, 133, 134/ Inflammatory inflltrate, necrobiotic granulomatous, in episcieritis, 113, I13! Inner ischemic retinal atrophy, 157, 157/ in retinal arterial and venous occlusions, 1571, 163, 164 Inner nuclear layer, 145, 146f Inner plexiform layer, 145, 146/ Insulin -like growth factor l, thyroid eye disease and, 232 Interleukin-6, thyroid eye disease and, 232 Interleukin -8, thyroid eye disease and, 232 Internal limiting membrane, 145, 146/ in retinal healing/repair, 17 vitreous detachment and, 135 Internal scleral sulcus, 102 Internal ulcer of von Hippel, 81, 81/ International Classification System for Intraocular Retinoblastoma, 307~308, 308t International Committee for the Classification of Corneal Dystrophies, 96 Interphotoreceptor retinoid-binding protein, 178 Interstitial keratitis, 86 ~87, 87f herpetic, 82- 83, 84f, 87 syphilitic, 87, 87/ Intracanalicular region of optic nerve, 249 Intracranial region of optic nerve, 249 Intradermal nevus, 225, 226/ Intraepithelial melanosis, 67~69, 67f, 68f Intraepithelial neoplasia conjunctival (CIN), 62, 63f, 64f. See also Ocular surface squamous neoplasia corneal, 100 Intraocular chemotherapy, for lymphoma, 324 Intraocular fine-needle aspiration biopsy (FNAB), 341, 43- 44,44/ Intraocular pressure, lens epithelium affected by, 124 Intraocular regio n of optic nerve, 249 Intraocular tumors. See also specific type o/tumor and structure affected

angiomatous, 291-296, 297f glaucoma caused by, 109, 110/ melanocytic, 265~289 retinoblastoma, 178- 181, 263, 299- 314 staging of, 329- 352t in systemic malignancies, 315-328. See also .Metastatic eye disease direct extension from extraocular tumors and, 322 leukemia and, 326-328, 327f lymphomatous, 140- 142, 141f, 142f, 143f, 323- 326, 323f, 325/ secondary, 315-322 transillumination in identification of, 26- 27, 27f

Intraorbital region of optic nerve, 249 Intraretinal microvascular abnormalities (IRMAs), 160, 161f in diabetic retinopathy, 166 Intravitreal triamcinolone acetonide (lVTA) . See Triamcinolone Inverted follicular keratosis, 215, 215/ Iodine, radioactive (iodine 125), for uveal melanoma, 284 IOl (idiopathic orbital inflammation). See Nonspecific orbital inflammation Iridocorneal endothelial (ICE) syndrome, 104- 105, 105f Iridocycl*tis, iris nodules in, 270t, 272/ Iridodialysis, 19-20, 20f, 109 IridoschisiS, 102 Iris absence of (aniridia), 188 anterior border/pigmented layer of, 185, 186f atrophy of, 104, 105/ cysts of, 270t, 272f epithelial invasion of, 2701 healing/ repairof,16- 17 in leukemia, 271t, 272f, 327 melanocytoma of, 268 melanoma of, 193- 194, 194f, 268- 271, 269f, 271t, 273f metastatic disease of, 2711, 316, 316f, 317/ neoplast ic disorders of, 193-194, 194f neovascularization of (rubeosis iridis), 192, 1921,193J

in diabetic patients, 166, 166f in retinoblastoma, 179, 180f, 303 stroma of, 185-186 topography of, 185- 186, 186f traumatic damage to, iridodialysis, 19-20, 20f, 109 Iris freckle, 2701, 272/ Iris nevus, 193, 265-266, 265f, 270t Iris nevus syndrome (Cogan · Reese syndrome), 104, lOSf, 2701 Iris nodules, 270- 27lt, 272f differential diagnosis of, 270- 271 t in leukemia, 27 11, 272f, 327 in metastatic disease, 27lt in retinoblastoma, 271 t, 303 in sarcoidosis, 190,272/ Iris pigment epithelium, 186, 186f cysts of, 270t, 272f in diabetic retinopathy, 166, 166J in healing/repair, 16 proliferation of, 270t IRMAs. See Intraretinal microvascular abnormalities Iron colloidal, for tissue staining, 30, 31t corneal deposits of, in keratoconus, 91, 93J foreign body of, siderosis caused by, 124 in hemosiderosis oculi, glaucoma and, \08-109, 108/ Ischemia, retinal, 156-164. See also Retinal ischemia IVTA (intravitreal triamcinolone acetonide). See Triamcinolone Junctional nevus of conjunctiva, 65 of eyelid, 224-225, 225/ Juvenile ossifying fibroma (fibro-osseous dys plasia), of orbit, 246, 246/ Juvenile pilocytic astrocytoma, 257

Index . 389 Juvenile xanthogranuloma ofi ris,191, 270t of uveallracl, 19 1, 191/ Keratan sulfate, macular dystrophy and, 96 Keratic precipitates, in sympathetic ophthalmia, 189 Keratin, in adenoid cystic carcinoma, 236 Keratinizing squamous cell carcinoma, well-differentiated (keratoacanthoma), eyel id, 21St, 21 6, 216/ Keratitis Acollt!mnloeba, 54, 84- 85, 86/ bacterial, 82, 83f contact lens wear and, 84-85 dendritic, 82, 84/ disciform, 83 fungal. 83-84, 85/ herpes simplex, 82-83, 84I. 87 infectious/microbial, 82-87. See also specific infectious

agent interstitial, 82- 83, 84f, 87, 87! noninfectious, 87 stromal, 83, 84/ syphi litic, 87, 87/ Keratoacanthoma, eyel id, 2 1St, 216, 216/ Keratoconus, 9 1, 93/ Descemet membrane rupture and, 18, lSI. 91, 93/ Keratoepithelin, gene for. See TGFpl gene Keratoneuritis, radiaJ, in Acanthamoeba keratitis, 85 Keratopathy actinic (Labrador keratopathy/spheroidal degeneration), 88-89, 90/ band, calcific, 88, 89/ bullous, 89-91, 90f infectio us crystalli ne, 85- 86, 86/ after penet rating keratoplasty, 85 neurotrophic, postherpetic, 83, 84/ Keratoplasty Descemet stripping endothelial (DSEK), 79 indications for, 78- 79, 79t lamellar, deep anterior (DALK), 78 penetrating (PK) for bacterial keratitis, 82, 83/ graft rejection and, 91 , 92/ pathology specimens from , 78, 83/ Keratosis actinic, 216- 2 17, 2 17I. 21 8/ inverted follicular, 2 15, 215/ seborrheic, 21 4-215, 214/, 215/ Ki-67, in pingueculae/pterygia, 57 "Kissing" nevi, 224, 224/ c-Kit. in immunohistochem istry, 34 Koeppe nodules in iridocycl*tis, 2701, 272/ in sarcoidosis, 190,272/ Koganei, clump cells of, 186 Krause, glands of, 205, 2071 Krukenberg spindles, 91-92, 94I. 109 Labrador (actinic) keratopathy, 88-89, 90/ Lacrimal glands. 229 accessory, 205, 207t tumors of, 235-238, 237/ staging of, 345-347t Lacrimal sac (tear sac), tumors of, 235 Lacrimal system, healing/repair of, 17-18

Lamina cribrosa, 111,249,250/ Lamina fusca, 112, 186 La nghans giant cells, 7, 9/ Large ceJllymphoma (pri mary intraocular lymphoma), 140- 142. 141f, 142f, 143f, 323- 325. 323f, 325/ Laser therapy (laser surgery). See also Photocoagulat ion for choroidal hemangioma, 292 for diabetic retinopathy, 167. 167/ for melanoma, 285 [or retinoblastoma, 311, 31 1/ Lattice degeneration, 155-156, 155/ radial perivascular, 155- 156 Latt ice dystrophy, 96- 97, 971, 99/ gelsolin-t)'pe, 212 Leiomyoma of ciliary body, 203 of iris, 270r of o rbit, 244 Leiomyosarcoma, of orbit, 244 Lens (crystalline) absence of, 121 capsule of See Lens capsule colobomas of, 121 congenital anomalies and abnormalities of, 121 , 122! cortex of, 120, 120/ degenerations of, 126-127, 127/. 128/ degenerations of, 124-127, 125/, 126f, 127/, 128I. 129/ See also Cataract d isorders of, 119- 129. See also specific type systemic disorders and, 129 epithelium of, 119-120, 120/ degenerations of, 124-126, 125I. 126f focal opacifications and, 126, 126- 127, 127/ generalized discoloration with loss of transparency and,126 glaucoma and, 106-107, 107/ healing/repair of, 17 infection/ inflammatio n of, 122- 123, 122I. 123I. 124/ nucleus of, 120, 120/ degenerations of, 127, 128f, 129/ topography of, 119-120, 11 9I. 120! uveitis and, 122, InI. 123/ zonular fibers of, 120, 120/ tertiary vitreous, 132 Lens-associated (phacoantigenic) uveitis (lens-induced gran ulomatous/phacoanaphylactic en do phthalmitis), 122, I22I. 123/ Lens capsule, 119, 120/ degenerations of, 124 healing/repair of, 17 rupture of, cataract formation and, 20 to pography of, 119, 120/ Lens fibers opacities of, 126-127, 127f, 128/ zonular, 120, 120/ tertiary vitreous, 132 Lens-induced granulomatous endophth almitis. See Lens-associated (phacoantigen ic) uveit is Lens proteins in phacoantigenic uveitis/endopht halm itis, 122 in phacolytic glaucoma, 107, 127 Lent ico nusllentiglobus anterior, 121 posterior, 121, 122/ Lentiglobus. See Lenticonus/lentiglobus

390 • Index Lentigo maligna melanoma, 69, 226, 2271 spotting,H317, 320/ Leser-Trelat sign, 215

~ Leopard

Leukemia, lOt, II! ocular involvement in, 326-328, 327/

choroid,317 iris, 271 t, 272f, 327 optic nerve. 327-328, 327/ orbit, 328 retina, 326, 327, 327/ uvea, 326-327 vitreous, 326 Leukemic retinopathy, 326, 327/ Leukaeoria in Coats disease, ISO! in retinoblastoma, 301, 301/, 302/ Leukocyte common antigen. in immunohistochemistry, 34 Leukocytes, in inflammat ion, 6-7, 8f Levator palpebrae superioris muscle, 205 Umbal dermoids, 48, 49/ Limbal papillae, 50 Limbus, healing/repair in, 16 Lim iting membrane external, 145 internal, 145, 146/ in retinal healing/repair. 17 \'i treo1l5 detachment and. 135 Lipodermoids (dermolipomas), 49f, 50 Goldenhar syndrome and, 50 Lipomas, of orbit, 245 Liposarcomas, of orbit, 245 Lisch nodules, 271t, 272/ Liver disease, metas tatic uveal melanoma causing. 281-282, 282t Loa loa (loiasis), o rbital involvement and, 235 Localized (circ*mscribed) choroidal hemangioma, 200, 291,291f Lowe syndrome (oculocerebrorenal syndrome), 121 LOXLl (lrsyl Oxidase-like) gene, in exfoliatio n! pseudoexfoliation, 106 Lung cancer, eye involvement and , 200, 20 1j, 3161,32If Lupus erythematosus, systemic, eyelid manifestations of,213r Lymphatic malformations (lymphangiomas), orbital. 240,241/ Lymphocytes, 7-9, 8/ Lymphocytic tumors, conjunctival, 71 - 74, 72f, 73/ LymphOid follicle. 51. 52f, 7 1 Lymphoid folliculosi s. benign, 7 1 Lymphoid hyperplasia {lpTlphoid infiltration} reactiw lymphoid hyperplasialbenign lymphoid pseudotumor/ pseudolym phoma) of conjunctiva, 71-72, 72/ of orbit, 239 atypical,239 of uveal tract (uveal lymp hoid infiltration), 202, 325-326 Lymphoid proliferation, uveal tract involvement and, 202, 202/ Lymphoid tissues. mucosa-associated (MALT), 47 of conjunctiva (conjunctiva-associated/CALT), 47 lymphoma of (extranodal marginal zone lymphoma). 72-73, 73f, 74

Lymphomas, lOt, 11/ conjunctival, 72, 72-74, nJ, 73/ extranodal marginal zone (mucosa-associated/MALT), 72 - 73, 73f, 74 intraocular (primary intraocular/central nervous systemllarge celUvitreoretinaVretinaVhistiocyticl non-Hodgkin of CNSlreticulum cell sarcoma). 140- 142, 14 1J, 142J, 143f, 323-325, 323j, 325/ ocular adnexa, staging of, 350-3521 orbital, 239-240, 239/ orbital inflammato ry syndrome diffe rent iated from, 232 of uveal trac t, 202, 202/ of vitreous, 140-142, 14 If, 142f, 143j, 323/ Lymphoproliferative lesionsllymphomatous tumors. See also specific type and Lymphoid hyperplasia; Lymphomas of orbit, 238-240. 239/ Lysyl oxidase-like (LOXLl ) gene, in exfoliation/ pseudoexfoliation, 106 Macrophages, i Macula/macula lutea, 146, 147/ re tinal pigment epithelium in, 148 Macular degeneratio n age- related. See Age· related macular degeneratio n \'itelliform adult·onset, 175, 176/ Best disease. 174-175 Macular dystrop hies. 96, 97f, 97t, 172- 175 Macular edema, 158-160, 159f, 160f Macular holes, 136-137. l38/ Magnetic resonance imaging (MRl) in choroidal/ciliary body melanoma, 277 in retinoblastoma, 303-304, 309 Magnocellular nevus, See MeJanocytoma Malignant fibrous histiocytoma (atypical fibroxanthoma), 11 7-118,240-242 Malignant lymphoma. See Lymphomas Malignant melanoma. See Melanoma MALT. See Mucosa-associated lymphoid tissue MALT lymphomafMALToma. See Mucosa-associated l)'ffiphoid tissue (MALT) lymphoma Mantle cell lymphoma, conjunctival, 73 Mantle zone, 7 1 Map-dot-fingerprint dys trophy (epithelial/a nterior basem*nt membrane dystrophy), 95, 95/ Marginal degeneration, pellucid, 91 Marginal zone, 71 extranodallymphoma (MALToma) involving, 72-73. 73f. 74 \'vlasson trich rome stain, 30, 31 f Mast cells, 7 Mean of the ten largest melanoma cell nuclei (MLN), 199 Medullary epithelium. medulloepithelioma (diktyoma) arising from, 183, 183J, 307 Medulloepithelioma (di ktyoma), 183-184, 183!,

307,307/ re tinoblastoma differentiated from, 307, 307/ teratoid, 184 Meibomian glands. 205, 206/ chaJazionlhordeolum caused by infection of, 208, 210-211,211/ sebaceous adenocarcinoma arising in, 221 Melan A, in immunohistochemistry, 33

In dex . 391 Melanin, in retinal pigment epithelium albinism and, 148, 149/ hypertrophy and, ISO, 150/ Melanocytic nevus of anterior chamber/trabecular meshwork, 109, 110/ congenital, 224, 224/ conjunctival, 65- 66, 65t, 66/ of e)'elid, 224-226, 224j. 225f, 226/ glaucoma and, 109 Melanocytic tumors, 265-289. See also specific type and Nevus of anterior chamber/t rabecular meshwork, 109, 110/ of conjunctiva, 65- 70, 65t, 66f, 67f, 68f, 70f, 71/ of eyelid, 224- 227, 224f, 225f, 226/ of ocular surface, 65-70, 65t, 66f, 67f, 68f, 70j, 7l/ Melanocytoma glaucoma and, 109,268 of iris/ciliary body/choroid. 195, 268 of optic disc/ optic nerve, 256, 256/ melanoma differentiated from , 278-279, 280/ Melanocytosis dermal orbital, 66 ocular, 65-66, 651, 66/ of iris, 2711 oculodermal (nevus o( Ota), 651, 66 of iris, 27 J t Melanokeratosis, striate, 67 Melanomalytic glaucoma, \09, 109/. 198 Melanomas acral-lentiginous, 226, 227/ amelanotic, 69, 274j, 278, 278t of anterior chamber/trabecular meshwork, 109, 110/ choroidaUciliary body (uveal), 195-200, 196j, 197j, 198/. 199f, 263, 273-288. See also Choroidallciliary body melanoma classification of, 199, 281 diagnosis of, 274- 277, 276f, 277/ differential, 277-28 1, 278t, 279f, 280f, 281/ epithelioid, 196, 199 glaucoma caused by, \09, 109f, 198 metastatic, 200 evaluation of, 28 1-282, 2821 nevus differentiated from, 266-268, 278 ocular surface/conjunctival involvement and, 70, 71f prognosis/prognostic factors for, 198-200,286-288 spindle cell, 196, 196f, 199 spread of, 197- 198, 197f, 198f, 200 staging of, 337-341 1 treatment of, 282-286, 284/ congenital hypertro phy ofRPE differentiated from, 150,278,279/ conjunctival, 69- 70, 70f, 71/ intraocular extension of, 322 primary acquired melanosis and, 67, 68j, 69, 70f staging of, 334- 336t of eyelid, 226-227, 227f in situ, 69 of iris, 193 - 194, 1941, 268-271, 269f, 271t, 273f lentigo maligna, 69, 226, 227/ nodular, 226, 227f retinoblastoma associated With, 314, 314t ring, 197, 197f, 200 superficial spreading, 226, 227/ tapioca,27lt uveal. See Melanomas, choroidallciliary body

Melanosis benign acquired, 65t, 67, 67/ intraepithclial, 67-69, 671, 68/ primary acquired, 65t, 67-69, 68/ melanoma and, 6;, 681, 69, 70/ Membranes implantation, of iris, 2701 retrocorneal fibrous, 91, 92/ Meni nges, optic nerve, 249, 250/ Meningiomas optic nerve sheath, 258, 258f, 259/ orbital, 258 Meningothelial optic meningioma, 258, 258f Meretoja syndrome {ge!solin-type lattice corneal dystrophy),212 Meseclodcrmalleiomyoma, 203 Mesodermal dysgenesis. See Axenfeld-Rieger syndrome Metastatic eye disease. See also specific type and structure

affected carcinoma, 315- 322 ancillary tests in evaluation of, 318-320 clinical features of, 316-318, 316f, 317j, 318f, 319/. 320j diagnostic factors in, 320-321, 32 If direct intraocular extension and, 322 mechanisms of intraocular metastasis and, 315-316 primary sites and, 315, 3161 prognosis for, 321-322 treatment of, 322 of choroid, 200, 2011, 315, 3161, 317f, 318/ ofiris, 27 It, 316, 316f, 317/ of optic disc/nerve, 315-316, 320 of orbit, 247 of retina, 315- 316, 320, 321/ retinoblastoma and, 304 of uvea, 200, 2011, 316-317, 316f, 317f Methanol, as tissue fixative, 29, 291 Methenamine silver stain, Gomori, 30, 3lt Methotrexate, for intraocular (primary central nervous system) lymphoma, 324 MI B-I marker, in conjunctival lymphoma, 74 Michel medium, as tissue fixative, 29, 291 Microaneurysms, retinal, 160-162, 162f, 164 in diabetes, 166 Microarray-based comparative genom ic hybridization (array CGH), 39t Microarrays, 41, 42/ clinical use of, 42-43 SNP oligonucleotide (SOMA), 381 tissue, 41, 42/ Microglial cells optic nerve, 249, 250/ retinal ischemia affecting, 158 Micrographic surgery, Mohs, for neoplastic disorders of eyelid,45 basal cell carcinoma, 45, 219 sebaceous adenocarcinoma, 224 squamous cell carcinoma, 45, 219 Microphthalmos, persistent fetal vasculature associated with, 133, 304 I"'icrosporida, conjunctivitis/ keratitis/keratoconjunctivitis caused by, 54 Microvascular abnormalities, intraretinal (lRMAs), 160,161j

392 • Index Mitomycin C for ocular surface squamous neoplasia/conjunctival intraepithelial neoplasia, 64 for primary acquired melanosis, 67

Mittendorfdot, 132 Mixed tumor, benign (pleomorphic adeno ma) , of lacrimal gland, 236, 237f MLN. See tvfean of the ten largest melanoma cell nuclei MLPA. See Multiplex ligation-dependent probe amplification Mohs micrographic surgery, for neoplastic disorders of

eyelid,45 basal cell carcinoma, 45, 219 sebaceous adenocarcinoma, 224 squamous cell carcinoma, 45, 219 Molecular pathology techniques, 341, 37- 43, 38- 39t,

40j, 42f Moil, glands of, 205, 207l Molluscum contagiosum, of eyelid, 210, 210! Monocytes, 7. 8f

Morgagnian cataract, 127, 128! Morgagnian globules, 127, 1271, 1281, 129f Morpheaform basal cell carcinoma, 21-8, 219, 2I9! Mucoepidermoid carcinoma, 64 lHllcor (mucormycosislzygomycosis) cornea involved in (keratitis), 83 optic nerve involved in, 251 orbit involved in, 234 Mucosa-associated lymphoid tissue (MALT), 47 of conjunctiva (conjunctiva-associated/CALT), 47 Mucosa-associated lymphoid tissue (MALT) lymphoma (MALToma/extranodal marginal zone lymphoma),

72- 73,731, 74 Muir-Torre syndrome, eyelid manifestations of, 2151,22 1 Muller cells, retinal , in healing/repair, 17 Muller muscle, 186, 205 Multicentric basal cell carcinoma, 218 Multinucleated giant cells, 7, 9/ in sarcoidosis, 191, 191f Multiple sclerosis, optic nerve involvement and, 252, 252f Multiplex ligation-dependent probe amplifICation (MLPA), 38t, 41 Mutton-fat keratic precipitates, in sympathetic ophthalmia, 189 Myco tic (fungal) keratitis, 83-84, 85f Myelinated retinal nerve fibers, 148 Myoglobin, in immunohistochemistry, 33 Myopathies, extraocular, in thyroid eye disease, 232 Myositis, orbital, 231, 231f Nanophthal mos, 112-113 Necrobiotic granuloma, in scleritis, 114, 115f Necrobiotic granulomatous inflammator y infil trate, in episcleritis, 113, ll3f Necrotizing retinitis, herpetic, 151, 151f Necrotizing scleritis, 114, 114f, 115/ Neoplasia, 10, 101 , I If, 121. See a/so specific Iype and Intraocular tumors; Tumo rs classification of, 101 definition of, iO Neovascular glaucoma, 192 Neovascular membrane, subretinal. See also Neovascularization in age-related macular degeneration, 169-170, 17lf

Neovascularization choroidal, 159, 168f in age- related macular degeneration, 169-170, 17 1f in diabetic patients, 166 in glaucoma, 192 of iris (rubeosis iridis), 192, L92t, L93f in diabetic patients, 166, 166/ in retinoblastoma, 179, 1801, 303 retinal in age-related macular degeneration, 169- 170, 17 1/ ischemia causing, 162, 162f, 163, 164 in retinopathy of prematurity, 167 Nerve fibe r layer, 145, 146f, 147 Nerve fibers, myelinated, 148 Nerve (neural) sheath tumors of orbit, 244- 245, 244{. 245/ of uveal tract, 203 Neurilemoma (schwannoma) of orbit, 244-245, 245f of uveal tract, 203 Neurofibromas of orbit, 244, 244/ of uveal tract, 203 Neurofibromatosis, von Recklinghause n (type I) Lisch nodules associated with, 27lt, 272/ optic nerve meningiomas and, 258 optic pathway/optic nerve gliomas and, 257 orbital involvement in, 244, 244f Neuroi maging, in retinoblastoma, 303-304, 309 Neurons, retinal, ischemia affecting, 156- 157, 157j, 158f Neurosensory retina, 145, 145- 147, 1461, 147f. See a/so Retina Neurotrophic keratopathy, postherpetic, 83, 84f Neutrophils, 7, 8f Nevus anterior chamber/trabecular meshwork affected by, 109 , 110f of choroid, 195, 1951, 266-268, 267f melanoma differentiated from, 266- 268, 278 of ciliary body, 195, 266 compound of conjunctiva, 65, 66/ of eyelid, 225, 225f congenital, 224, 224f conjunctival, 65- 66, 651, 66f dysplastic, 226 of eyelid, 224-226, 224j, 225j, 226f intradermal, 225, 226f iris, 193,265- 266, 265j, 2701 junctional of conjunctiva, 65 of eyelid, 224- 225, 225f "kissing:' 224, 224/ macular, 224- 225, 225f magnocellular. See Melanocytoma melanocytic of anterior chamber/trabecular meshwork,

109,IIOf congenital, 224, 2241 conjunctival, 65 - 66, 65t, 66f of eyelid, 224- 226, 224j, 225j, 226f glaucoma and, 109 of Ota (oculodermal melanocytosis), 651, 66 ofiris,271t Spitz, 226

Index. 393 stromal,65 subepithelial,65 Nevus celis, 224, 225, 225f, 226[ Nr:l. See Neurofibromatosis, von Recklinghausen (type I) NFL. See Nerve fiber layer Nodular basal cell carcinoma, 218, 2 18[ Nodular episcleritis, 113 Nodular fasc iitis, 118, 118[ Nodular melanoma, 226, 227[ Noncaseating granulomas, 8, 11-12 in granulomatous conjunctivitis, 52, 53/ in sarcoidosis, 52, 53[,191,191/ Nongranulomatous inflamm ation, 6 Non- Hodgkin lymphomas, orbital, 239 Noninfectious conjunctivitiS, 54, 56[ Noninfectious keratitis, 87 Noninfectious uveitis, 189- 191, See also specific cause vitreous infiltrate in, 133 Non necrotizing scleritis, 114 Nonperfused central retinal vein occlusion, 164 NonspeCific orbital inflammation (NSO I/orbital pseudotumor/ idiopathic orbital inflammation/orbital inflammatory syndrome), 230- 232, 231[ orbital lymphoma differentiated from, 232 NSOI. See Nonspecific orbital inflammation Nuclear cataracts, 12 7, 128f, 129[ Nuclear layer inner, 145, 146f outer, 145, 146f Nucleus, lens, 120, 120f degenerations of, 127, 128f, 129/ Occlusive retinal disease arterial branch retinal artery occlusion, 163 ce ntral retinal artery occlusion, 162- 163, 163[ venous branch retinal vein occlusion, 164 central retinal vein occlusion, 163-164, 165[ OCP. See Ocular cicatricial pemphigoid OCT. See Optical coherence tomography Ocular adnexa, staging of lymphoma of, 350-3521 Ocular albinism, 148 Ocular cicatricial pemphigoid, 54, 56! Ocular inflammation. See Infl ammation Ocular melanocytosis, 65-66, 65/, 66[ ofiris,27lt Ocular motility, disorders of, in thyroid eye disease, 232 Ocular surface squamous neoplasia (OSSN), 62- 64, 63f, 64f See also under Squamous Ocular surface tumors melanocytic, 65-70, 65/, 66f, 67f, 68[, 70[, 71/ squamous neoplasia, 62-64, 63f, 64/ Ocular (intraocular ) surgery for melanoma, 285 sympathetic ophthalmi a and, 189, 189f, 190! Ocular toxocariasis, retinoblastoma differentiated from , 305,3051 Ocular toxoplasmosis, 153, 154[ Oculoauriculovertebral dysplasia. See Goldenhar syndrome Oculocerebrorenal syndrome of Lowe, 121 Oculocutaneous albinism, 148 Oculodermal melanocytosis (nevus o(Ota), 651, 66 of iris, 27lt

Oculoglandular syndrome, Parinaud, 52 010. See Orbital inflammatory disease Oil red 0 stain, 30 Oligodendrocytes, 249 Oligonucleotide microarray ana lysis, SNP (SOMA), 381 Oncocytoma, 75, 75[ Oncologist, ophthalmic, 43 Opacities, vitreous, amyloidosis causing, 140 Open-angle glaucoma pigmentary/pigment dispersion syndrome and, 91-92, 94f, 109, I09f, IIO! primary congenital, 102, 103! trauma causing, 107- 109, 108! Ophthalmia, sympathetic, 189, 189f, 1901 Ophthalmic oncologist, 43 Ophthalmic pathology of anterior chamber/trabecular meshwork, 101-109,llOf checklist for requesting, 34t com mu nication among health care team members and, 25-26 congenital anomalies and, 6, 7f, 121 of conjunctiva, 47-75 of cornea, 77- 100 degeneration and dystrophy and, 9- 10, 12t diagnosis/differential diagnosis and, 11-12, 121 diagnostic electron microscopy in, 341, 43 of eyelids, 205- 227 fi ne-needle aspiration biopsy for, 341, 43- 44, 44f, 263 fl ow cytometry in, 341, 36-37, 36f, 37/ frozen section for, 341, 44-45 immunoh istochemistry in, 33-36, 35/ inflammation and, 6-9, 8f, 9f, 121 of lens, 119-129 molecular pathologic techniques in, 34 /, 37- 43, 38-39/, 40f, 42! neoplasia and, 10, l Ot, I If, 121 of optic nerve, 249- 259 of orbit, 229-247 organizational paradigm for, 5-12, 121 of retina, 145- 184 of sclera, 111- 118 special procedures in, 33-45, 341 specimen collection /handling for, 25- 30, 311 topography and, 6, 121 of uveal tract, 185- 203 of vitreous, 131 - 143 wound repair and, 13-23 Ophthalmk wound healing/repair, 13-23. See also Wound healing/repair Ophthalmopathy, thyroid (G raves). See Thyroid eye disease Ophthalmoscopy, indi rect, in choroidal/ciliary body melanoma, 274 Opportunistic infections, cytomegalovirus retinitis, 151,152! Optic atrophy, 253-254, 253f, 254f, 255[ ascending, 253-254 cavernous, of Schnabel, 254, 255[ descending, 254 OptiC disc (optic nerve head) coloboma of, 249-250, 251/ retinoblastoma differentiated from, 3051 drusen of, 255, 255[, 306 edema of, in optic atrophy, 253, 253[

394 • Index melanocytoma (magnocellular nevus) of, 256, 256f melanoma differentiated from, 278- 279, 280/ metastatic disease of, 315- 316, 320 tumors of, 256- 258, 256f, lS7f, 258f, 259/ Optic nerve (cranial nerve II) coloboma of, 249-2 50, 2sl! congenital abnormalities of, 249- 250, 2SI! degenerations of, 253- 255, 253f, 254f, 2551 disorders of, 249-259. See also specific type neoplastic, 256- 258, 256f, lS7f, 258j, 259f infectionlinflammation of, 251 - 253, lSI/. 252f, 253/ metastatic disease of, 315- 316, 320 retinoblastoma involving, 180, 182f in thyroid eye disease, 232 topography of, 249, 2501 tumors of, 256- 258, 256f, lS7/, 258f, 259f Optic nerve glioblastoma (malignant optic glioma), 257 Optic nerve (optic pathway/chiasm) glioma (pilocytic astrocytoma), 257, 257/ Optic nerve sheath meningioma, 258, 258f, 259/ Optical coherence tomography, in idiopathic macular hole, 136-1 37, 138/ Orbicularis oculi muscle, 205, 206/ Orbit amyloid deposits in, 235 biopsy of fine-needle aspi ration, 44 in lymphoproliferative lesions, 238- 239 bony, 229 congenital disorde rs of, 229- 230, 230/ cysts of, 229- 230, 230/ degenerations of, 235 disorders of, 229- 247. See also specific type neoplastic, 235- 247. See also Orbit, tumors of fibrous dysplasia of, 245-246, 246/ healing/repair of, 17-18 infection/inflammation of, 230- 235, 231f, 233f, 234/ idiopathic. See Nonspecific orbital inflammation lacrimal gland neoplasia and, 235- 238, 237/ lacrimal sac neoplasia and, 235 leukemic infiltration of, 328 lymphoproliferative lesion s of, 238- 240, 239/ m yositis affecting, 231, 231f retinoblastoma affecting, 304, 30'V soft tissues of, 229 tumors arising in, 240 in thyroid eye disease, 232, 233/ topography of, 229 tumors of, 235- 247 adipose, 245 bony, 245-246, 246/ with fibrous differentiation, 240- 242, 242/ lacrimal sac/gland , 235-238, 237/ lymphoproliferative, 238-240, 239/ metastatic, 247 with muscle differentiation, 242- 244, 243/ nerve sheath, 244- 245, 244f, 245/ secondary, 247 soft tissue, 240 staging of, 348- 349t vascular, 240, 241/ volume of, 229 Orbital fibroblasts, in thyroid eye disease, 232 Orbital inflammatory disease (OlD), 230- 235, 231f, 233f, 234f See also specific type or cause

Orbital inflammatory syndrome. See Nonspecific orbital inflammation Orbital pseudotumor. See Nonspecific orbital inflamma tion Orbititis, sclerosing. See Nonspecific orbital inflammation Orbitopathy, thyroid /thyroid-associated/Graves. See Thyroid eye disease Osseous choristoma, 49f, SO Ossifying fibroma, of orbit, 246, 246/ OSSN. See Ocular surface squamous neoplasia Osteoma choroidal, 202 melanoma differentiated from, 280, 280/ orbital,246 Osteosarcoma, re tinoblastoma associated with,

312,314t Ota, nevus of (oculodermal melanocytosis), 65t, 66 ofiris,271t Outer ischemic retinal atrophy, 157, 157/ Outer nuclear layer, 145, 146/ Outer plexiform layer, 145, 146/ Oxyphilic (eosinophilic/apocrine) cystadenoma (oncocytoma), 75, 75/ p53 gene

in adenoid cystic carcinoma, 236- 238 in conjunctival lymphoma, 74 in keratoacanthoma, 216 in ocular surface squamous neoplasia, 62 in pingueculae/pterygia, 57 p63 gene, in pingueculae/pterygia, 57 Pagetoid spread of melanoma, 227, 227/ in primary acquired melanosis, 69 of sebaceous carcinoma, 222, 223/ Pain, orbital, in nonspecific orbital inflammation, 231 Palpebral conjunctiva, 47, 48f, 205, 206/ PAM. See Primary acquired melanosis Pannus/micropannus, 89, 90[ Panuveitis, sympathetic ophthalmia and, 189, 189f, 190/ Papillae Bergmeister, 132 , 133 limbal, 50 Papillary conjunctivitis, 50, 51/ giant (contact lens-induced), SO Papillomas, conjunctival, 61 - 62, 61/ PapillomatosiS, definition of, 206 Papillomaviruses. See Human papillomaviruses Papiliophlebitis,164 Parafovea, 146 Parakeratosis in actinic keratosis, 217, 217/ definition of, 206 Parasites, orbital infection caused by, 235 Parinaud oculoglandular syndrome, 52 Pars plana, 186, 187/ Pars plana vitrectomy for intraocular lymphoma diagnosis, 142, 324 for uveal lymphoid infiltration diagnosis, 326 Pars plicata, 186, 187/ PAS. See Peripheral anterior synechiae PAS (periodic acid- Schiff) stai n, 30, 31 t Pathology, ophthalmic. See Ophthalmic pathology Pattern dystrophies, 175, 176[ Paving-stone (cobblestone) degeneration, 156, 156/

Index. 395 PA.X6 gene mutation in aniridia, 188 in congenital aphaki a, 121 PCNSL. See Prim ary intraocular/cent ral nervous system lymphomas PCR. See Polymerase chai n reaction PCV. See Polypoidal choroidal vasculopathy PDT. See Photodynamic therapy Pearl cyst, of iris, 270t Pedunculated papillo mas, conjunctival, 6 1, 61/ Pegaptanib, for macular edema, 160, 169 Pellucid marginal degeneration, 9 1 Pemphigoid, cicatricial, 54, 56/ Penetrating inj uries, fibrocellular proliferation and, 20 Penetrating keratoplasty. See Keratoplasty, penetrating Perifovea, 146 Periodic acid-Schiff (PAS) stain, 30, 311 Peripheral anterior synechiae (PAS), in glaucoma, iridocorneal endothelial (ICE) syndrome and, 10S,IOSf Peripheral cystoid degeneration, 154, 154/ Peripherin/RDS gene mutations in pattern dystrophies, 175 in Stargardt disease, 172 Periphlebitis, in sarcoidosis, 190 Perls Prussian blue stain, 3 11 Persistent fetal vasculature (persistent hyperplastic primary vitreo us), 132-133, 132/. 304-305, 3051 retinoblastoma differe ntiated from, 304-305, 305t Persistent hyaloid artery/system, 132-133, 132/. 133 Peters anomaly, 81 - 82, 8 I/. 102 PFV. See Persistent fet al vasculature Phacoanaphylactic endophthalm itis. See Phacoantigenic uveitis Phacoantigenic (lens-associated) uveitis (lens-induced granulomatous/phacoanaphylactic endophthalmitis), 122, 122/. 123/ Phacolytic glaucoma, 106-107, 107/. 127 Phakomatous choristoma (Zim merman tumor), 20j, 207 Photoablation, for melanoma, 285 Photocoagulation for choroidal hemangioma, 292 for diabetic retinopathy, 167, 167/ for melanoma, 285 for metastatic eye disease, 322 for retinal angiomas, 295 for retinoblastoma, 31 1 Photodynamic therapy for choroidal hemangiomil, 292 for retinal capillary hemangioblastoma, 295 Photoreceptor dystroph ies, 175-177 Photoreceptors, 145, 146/ atrophy of, in macular degeneration, 169 PHPV (persistent hyperplastic primary vitreous). See Persistent fetal vasculature Phthisis bulbi (phthisical eye), 22, 23/ Pia mater, optic nerve, 249, 250/ Pigment dispersion syndrome cornea affected in, 91-92, 94/ glaucoma and, 91 - 92, 94f, 109, 109j, 110/ Pigment epithelium. See Iris pigment epithelium; Retinal pigment epithelium Pigmentations/pigment deposits corneal, 9 1- 93, 94/ trabecular meshwork, 109, 109/. 110/

Pinealoblastoma/pinealoma, retinoblastoma and, 309, 314 ,314t Pinguecula, 56, 57- 58, 58/ PIOL. See Primary intraocular/central nervous system lymphomas Plaque radiotherapy. See Radioactive plaque therapy Plaques Hollenhorst (cholesterol emboli), ill branch retinal artery occlusion, 163 o pt ic nerve, 252 senile scleral, 11 5, 116/ Plasma ceUs, 9 Pleomorphic adenoma (benign mixed tumor), of lacrimal gland, 236, 23 7/ Pleomorphic rhabdomyosarcoma, 243 Plexiform layer inner, 145, 146/ outer, 145, 146/ Plexifo rm neurofibromas, of orbit, 244, 244/ PLGAI gene mutation, in pleomorph ic adenoma, 236 Plica semilu naris, 47 Plus disease, retinopathy of prematurity and, 167 PMNs. See Polymorphonuclear leukocytes PO (pupil- optic nerve) section, 27-28, 28/ Polyarteritis nodosa, eyelid manifestations of, 2 i3 t Polychondritis, relapsing, eyelid manifestations of,213r Polyhedral cells, in choroidaVciliary body nevus, 195 Polymerase chain reaction (pe R), 38t, 40-4 1,40/ cl inical use of, 42- 43 real-time quantitative, 391 reverse,39t Polymorphonuclear leukocytes, 7, 8/ Polymorphous dystrophy, posterior, 80, 80/ genetics of, 80 Polyneuropathy, familial amyloidotic types 1 an d II, 140, 141j, 2 12 type IV (gelsolin-type latt ice corneal dystrophy), 212 vitreous involvement in, 140, 14 1/ Polypoidal choroidal vasculopathy (posterior uveal bleed ing syndrome), 171, 172/. 173/ Polyposis, fa milial adenomato us (Gardner syndrome), retinal manifestations of, 150- 151 Posterior embryotoxon, 102-103, 103f, 104/ Posterior keratoconus, 102 Posterior lenticonus/!entiglobus, 12 1, 122/ Posterior polymorphous dystrophy, 80, 80/ genetics of, 80 Posterior segment, metastatic tumors of, 317-3 18, 317/. 31Sf, 319f, 320f Posterior subcapsular cataract, 124- 125, 125/ reti noblastoma differentiated from , 3051 Posterior U\'eal bleeding syndrome (polypoidal choroidal vasculopathy), 171, 1nj, 173/ Posterior uveal melanoma, 195-200, 196f, 197J, 198/. 199f, 263, 273- 288. See also Choroidal/ciliary body melanoma glaucoma caused by, 109, 109/. 198 nevus differentiated from , 266-268, 278 ocular sur face/conju nctival involvement and, 70, 71/ staging of, 337-341t Posterior vit reous detachment, 134-135, 135/ Postoperative endophthalmit is, after cataract surgery, Propionibacterium acnescausing, 123, 123f, 124 Prealbumin . See Transthyretin

396 • Index Prematurity, retinopathy of, 167 retinoblastoma differentiated from, 30St Prepapil1ary vascular loops, 133 Prescptal cellulitis, 208, 209! Primary acquired melanosis (PAM), 651, 67- 69, 68! melanoma arising fro m, 67, 68f, 69, 70j Primary aphakia, 121 Primary central nervous system lymphomas. See Primary intraocular/central nervous system lymphomas Primary intraocular/central nervous system lymphomas, 140- 142, 141f, 142f, 143f, 323-325, 323f, 325/ Primary vitreous, 132 persistent hyperplasia of. See Persistent fetal vasculature Primers, in polymerase chain reaction, 40f, 41 Probe amplification, multiplex ligation -dependent (MLPA), 38t, 41 Probes, DNA. See DNA probes Proliferative vitreoretinopathy, 20, 2 If, 136, 1371 Propionibacterium acnes, endophthalmitis caused by, 123,

123f, 124 Proptosis (exophthalmos), 229 in orbital lymphangioma, 240 in retinoblastoma, 304, 3041 in rhabdomyosarcoma, 242, 2431 in thyroid eye disease, 232, 2331 in uveal lymphoid infiltration, 326 Prostaglandin E2 , thyroid eye disease and, 232 Prostate cancer, metastatic eye disease and, 316t Proteins in rod outer segments ("rim" proteins), mutations of, 172 vitreous, 131 Prussian blue stain, Perls, 31 t Psammoma bodies, in optic nerve meningioma, 258 Pseudoadenomatous hyperplasia (Fuchs adenoma), 184,288 P~eudoexfoliation (exfoliation syndrome), 106, 106f, 107[ Pseudogliomas, 178 Pseudohorn cysts, 214, 2141 Pseudohypopyon in leukemia, 327 in retinoblastoma, 303, 3031 Pseudopapilledema, drusen and, 255 Pseudophakic/aphakic bullous keratopathy, after cataract surgery, 89- 91, 901 Pseudoretinoblastoma,3051 Pseudorosettes, in retinoblastoma, 178- 179, 179/ Pseudo-Roth spots, in leukemia, 326 Pseudotumor, orbital. See Nonspecific orbital inflammation Pterygiu m, 57, 57- 58, 591 Pupil-optic nerve (PO ) sect ion, 27-28, 281 PVD. See Posterior vitreous detachment PVR. See Vitreoretinopathies, proliferative Pyogenic granuloma, 56, 571 Race, Vogt-Koyanagi- Harada (VKH) syndrome and, 190 Racemose hemangioma (Wyburn-Mason syndrome), 296,297[ Radial keratoneuritis, in Acarlthamoeba keratitis, 85 il.adial perivascular lattice degeneration, 155-1 56 Radiation therapy for choroidal hemangioma, 292-293 for lymphoma, 74, 324 for melanoma, 283- 285, 2841 in iris, 271

for metastatic eye disease, 322 fo r retinal capillary hemangioblastoma, 295 for retinoblastoma, 312 secondary tumors and, 312, 3 13- 3 14, 314t for uveal lymphoid infiltrat ion, 326 Radioactive iodine, for uveal melanoma, 284 Radioactive plaque therapy (brachytherapy) for choroidal hemangioma , 292- 293 for melanoma, 283-284, 2841 of iris, 271 for metastatic eye disease, 322 for retinoblastoma, 312 Ranibizumab, for macular edema, 160, 169 RBI (retinoblastoma) gene, 178,263,299-300,309, 312,3\3 secondary malignancies and, 312, 313-314, 314t RDS/peripherin gene mutations in pattern dystrophies, 175 in Stargardt disease, 172 Reactive lymphoid hyperplasia. See also Lymphoid hyperplasia of orbit, 239 uveal. See Uveal lymphoid infiltration Real-time quantitative polymerase chain reaction (RT-PCR),39t Rectus muscles, in thyroid eye disease, 232 Recurrent pterygia , 57 Red reflex, in lenticonus/lentiglobus, 121 Reed -Sternberg cells, in Hodgkin disease, 239 Reese-Ellsworth Classification for Intraocular Tumors, 207,3081 Regeneration, 13. See also Wound healing/repair Rejection (graft), corneal allograft, 91, 92f Relapsing polychondritis, eyelid manifestations of, 2131 Renal cell carcinoma, metastatic eye disease and, 3161 Repair, 13. See also Wound healing/repair Reticular degenerative retinoschisis, 154 Reticular peripheral cystoid degeneration , 154, 154[ Retina, 145-148, 146f, 147f See also under Retinal astrocytic hamartoma of, retinoblastoma differentiated from, 305- 306, 3061 atrophy of, ischemia causing. See also Retinal ischemia in retinal arterial and venous occlusions, 157f, 163, 164 blood supply of. See Retinal blood vessels capillary hemangioblastoma of, 294 - 295, 2941 cavernous hemangioma of, 295, 296[ congenital disorders of, 148- 151, 149f, 150[ degenerations of. See Retinal degenerations detachment of. See Retinal detachment disorders of. See specific type and Retinal disease dysplasia of, retinoblastoma differentiated from, 3051 gliosis of, 164, 165 hamartomas of, 184,289, 289[ healing/repair of, 17 histologic sequelae of trauma to, 20 infection/inflammation of, 151 - 153, 151f, 152f, 153f, 154f See also specific disease and Retinitis in leukemia, 326, 327 , 327f melanoma invading, 198, 198[ necrosis of, acute, 151, lSI! neovascularization of in age-related macular degeneration, 169-170, 17lf disorders of in retinopathy of prematurity, 167 ischemia causing, 162, 1621

1 Ind ex . 397 neurosensory, 145, 145-147, 146/. 147/ topography of, 145-148, 146/. 147/ rumors of, 178-184. See also Retinoblastoma metastatic, 315- 316, 320, 321/ pigmented, 288-289, 289/ Retinal angiomatosis (angiomatosis retinae, von Hippel/ von Hippel- Lindau syndrome/disease), 294- 295, 294/ Retinal artery. microaneurysms of, 160-162, 162/. 164 in diabetes, 166 Retinal artery occlusion branch , 163 central, J62-163, 163/ Retinal blood vessels, 146 anomalies of, 149, 150/ ischemia and, 158- 162, I 59/. 160/' 161f, 162/ Retinal degenerations, 154- 177 ischemic, 156-164. See also Reti nal ischemia lanice, 155- 156, 155/ radial perivascular, 155-156 pavi ng-stone (cobblestone), 156, 156/ peripheral cystoid, 154, 154/ Retinal detachment, 136, 136/ choroidal/ciliary body melanoma and, 168 choroidal hemangioma and, 292 in Coats disease, 149, 150/.305,306/ lattice degeneration and, 155 in leukemia, 327 metastatic eye disease and. 317, 3 18/ proliferative vitreoretinopathy and, 136, 137/ in retinal capillary hemangioblastoma/von HippelLindau disease. 294 in retinoblastoma, 302, 303/ rhegmatogenous, 136, 136/ in uveal lymphoid infiltration, 325 Retinal dialyses, 20 Retinal disease, 145-184 congenital, 148- 151, 149/, 150/ degenerative, 154-177. See also Retinal degenerations inflammatory, 151 - 153, lS I/. IS2/. IS3/. 154f See also specific disorder and Retinitis neoplastic, 178- 184. See also Retinoblastoma metastatic, 315-316. 320, 321/ pigmented, 288-289. 289/ vascula r congenital, 149,150/ microaneurysms, 160- 162, 162/. 164 in diabetes, 166 Retinal dystrophies, photoreceptor, 175-177 Retinal edema, 158-160, 159/. 160/ Retinal folds, congenital, retinoblastoma differentiated from,30St Retinal hemorrhages ischemia caUSing, 160, 161/. 164, 165/ in leukemia, 326, 327/ Retinal holes, atrophic. lattice degeneration and, 155 Retinal ischemia, 156-164 cellul ar responses to, 156-158. IS7/. 158/ central and branch retinal artery and vein occlusions causing, 162- 164, 163/. 164/ inner ischemic retinal at rophy and, 157, 157/ in retinal arterial and venous occlusions, 157f, 163,164 outer ischemic retinal atrophy and, 157, 157/ retinopathy of prematurity and, 167 vascular responses to, 158-162, 159f, 160f, 161/. 162/

Retinal neovasculari zation in age-related macular degenerat ion, 169- 170, 171/ ischemia causing, 162, 162/ in retinopathy of prematurity, 167 Retinal nerve fibers. See also Nerve fiber layer myelinated,148 Retinal pigment epithelium (RPE), 14S, 146/ adenomas/adenocarcinomas of, 184, 288 congenital abnormalities of, 148-15 1, 149/. ISO/ hypertrophy. 149-15 1, t SO/ melanoma differentiated from, 150,278.279/ detachment of, multiple recurrent serosanguineous (polypoidal choroidal vasculopathy), 171, In/. 173/ disorders of, 145-184. See (lIsa specific type geographic atrophy of, 169, 170/ hamartoma of, 184.289.289/ in Gardner synd rome, 151 healing/repair of, 17 hypertrophy of. congenital, 149-151, 150/ melanoma differentiated from , 150.278,279/ topography of, 146/.148 tumors of, 288- 289. 289/ Retinal scars, 17 Retinal tears, 135-136, 135/ lattice degeneration and, 155 Retina l vein occlusion bran ch, 164 central, 163- 164, 165/ Retinitis cytomegalovirus, lSI, 152/ herpetic. necrotizing, l SI, 151/ Retin itis pigmentosa, 175- 177, 177/ Retinoblastoma, 178-181,263, 299-314 chemotherapy of, 310-311, 311/ classifica tion of, 307- 308, 308t clinical evaluation/diagnosis of, 301-307, 30lt, 302/. 303j. 304/

differential diagnosis and, 304-307, 305t. 306/. 307/ Coats disease differentiated from, 305. 305t, 306/ conditions associated with, 309 cryotherapy for, 312 diffuse infiltrating, 303 enucleation for, 310 epidemiology 0(, 299, 2991 Oeurettes in, 180, lSI/ genetics of, 178, 263,299-301,300/ counseling and, 299-301, 300/ histologic fea tures of, 178-180, 179/. 180/' 181/ intracranial,309 iris affected in, 2711. 303 leukocoria in, 301, 301 t, 302/ metastatic, 304 optic nerve affected in, 180, 182/ orbit affected in, 304, 304/ pathogenesis of, 178 persistent fetal vasculature differentiated from , 304-305,3051 photocoagulation/hyperthermia for, 311, 311/ presenting signs and symp tom~ of, 301-304, 30 1t, 302[' 303j. 304/

prognosis for, 313-3 14. 3141 progression of, 180- 181 radiation therapy of, 312 secondary tumors and, 312, 313-31 4, 314t rosettes in, 180, 181/

398 • Ind ex secondary malignancies and, 312, 313- 314, 314t spontaneous regression of, 313 staging of, 342- 344t targeted therapy of, 313 treatment of, 310-313, 311/ trilateral, 309 vitreous seeding and, 303, 303j Retinoblastoma (RBI ) gene, 178, 263, 299-300, 309, 312,313 secondary malignancies and, 312, 313- 314, 314t Retinocytoma (retinoma), 181, IS3f, 309 Retinoid-binding proteins, interphotoreceptor, 178 Retinoma (retinocytoma), 181, IS3/, 309 Retinopathy diabetic, 165- 167, 166f, 167f leukemic, 326, 327/ of prematurity, 167 retinoblastoma differentiated from, 3051 Retinoschisis, 154 reticular degenerative, 154 typical degenerative, 154 Retraction, eyelid, in thyroid eye disease, 232, 233/ Retrocorneal fibrous membrane, 91, 921 Reverse transcriptase-polymerase chain reaction (RT-PCR),39t Rhabdomyosarcoma of orbit, 242- 244, 243/ retinoblastoma associated with, 314t Rhegmatogenous retinal detachment. See Retinal detachment Rhinosporidium seeberi, conjunctivitis caused by, 54 RHO gene, in retinitis pigmentosa, 175 Rhodopsin, gene for, mutations in, in retinitis pigmentosa, 175 RIM proteins, mutations in, 172 Ring infiltrate, in Acanthamoeba keratitis, 85, 86/ Ring melanoma, 197, 197j, 200, 273 Rod inner segments, 145, 146/ Rod outer segments, 145, 146/ Rods, 145, 146/ ROP. See Retinopath y, of prematurity Rosenthal fibers, in optic nerve gliomas, 257, 257/ Rosettes, retinoblastoma, 180, 181/ Roth spots, 160 RP. See Retinitis pigmentosa RPCD. See Reticular peripheral cystoid degeneration RPE. See Retinal pigment epithelium RT-PCR. See Real -time quantitative polymerase chain reaction; Reverse transcriptase-polymerase chain reaction Rubella, congenital, aphakia and, 121 Rubeosis iridis (iris neovascularization), 192, 1921, 193/ in diabetic patients, 166, 166/ in retinoblastoma, 179, 180f, 303 Rush (plus) disease, retinopathy of prematurity and,167 Russell bodies, 9 Ruthenium 106, for uveal melanoma, 284 S- 100 protein, in immunohistochemistry, 33 in adenoid cystic carcinoma, 236 Salzmann nodular degeneration, 88, 88/ Sarcoidosis conjunctivitis and, 52, 53/ eyelid manifestations of, 213t

optic nerve involvement and, 253, 253/ uveal tract affected in, 190-191, 191f, 272] Sarcoma, lOt, 11/ Ewing, retinoblastoma associated with, 314t granulocytic (chloroma), 32S orbital, 240 staging of, 348-349t retinoblastoma associated with, 314, 314t Scars retinal, 17 wound repair and, 13, 14f Schaum ann bodies, in sarcoidosis, 191 Schlemrn canal, 101-102 Sch nabel, cavernous optic atrophy of, 254, 255/ Schwalbe linelring, 101, 102i prominent (posterior embryotoxon), 102- 103, 103f, 104/ Schwannoma (neurilemoma) of orbit, 244-245, 245/ of uveal tract, 203 Sclera. See also Episclera aging of, 115, 116/ congenital anomalies of, 112-113 degenerat ions of, 115- 116, 116f disorders of, Ill - liS. See also specific type neoplastic, 1I6-llS, 1I7f, liS/ healing/repair of, 16 infection/inflammation of, 113- 114, 1l3f, 114f, lIS! See also Episcleritis; Scleritis stroma of, 112, 112/ topography of, 111 - 112, III/ Scleral buckle, for retinal capillary hemangioblastoma, 295 Scleral plaques, senile, liS, 116/ Scleral spur, 10 I, 102] Scleral sulcus, internal, 102 Scleritis, 114, 114f, 115/ Sclerocornea, 81-S2 Scleroderma, eyelid manifestations of, 2131 Scleromalacia perforans, 114 Sclerosing (morpheaform) basal cell carcinoma, 218, 219,2l9/ Sclerosing orbititis. See Nonspecific orbital inflammation Sclopetaria, 22 chorioretinitis, 203 Sebaceous adenomas, 21St, 221, 222/ Sebaceous carcinoma/adenocarcinoma, 21St, 221~224, 222f, 223/ Sebaceous cysts (epidermal inclusion cysts), of eyelid, 213,2l3/ Sebaceous glands of eyelid, 205-206 tumors /lesions of, 221 - 224, 22 If, 222/, 223/ Sebaceous hyperplasia, 221 , 221/ Seborrheic keratosiS, 214~215, 2l4j, 215/ Secondary aphakia, 121 Secondary vitreous, 132 Senile scleral/calcific plaques, 115, 116/ Sentinel vessels, 269f, 273, 274f, 275 Serous suprachoroidal detachment, melanoma differentiated from, 279-2S0 Sessile papillomas, conjunctival, 61 ~62 SiderOSiS, 124 Simple (diffuse) episcleritis, 113, 113] Simple epithelial cysts. See also Epithelial cysts of orbit, 229, 230

Index . 399 Skin, eyelid, 205, 206/ tumo rs of, metastatic eye disease and, J 16t Skin cancer, metastatic eye disease and, 316t Skip lesions, 252 Slit·lamp biomicroscopy/examination in choroidaUciliary body melanoma, 275 in iris nevus, 266 Small-molecule inhibition, for retinoblastoma, 313 SNP oligonucleotide microarray analysis (SOl>

88-89,90/ Sphincter muscle, 186, 186/ Spindle cell carcinoma, 64 Spindle cells in choroidaVciliary body melanoma, 196, 196f, 199 in choroidal!ciliary body nevus, 195, 195/ in iris melanoma, 194 in iris nevus, 193 in nodular fasciitis, 118, 118/ in rhabdomyosarcoma, 243 Spitz nevus, 226 Spongiosis, definition of, 206 Squamous cell carcinoma of conjunctiva in situ, 63- 64, 64J invasive, 63f, 64, 64/ of eyelid, 219, 220/ actinic keratosis and, 216-217. 217[. 218/ well-differentiated keratinizing (keratoacanthoma), 21St, 216, 216/ retinoblastoma associated with, 3 14 t Squamous cell papilloma, o( conjunctiva, 61-62, 61/ Squamous neoplasia, ocular surface, 62-64, 63f, 64/ Stains/staining techniques, 30, 30f, 31 t immunohistochemical, 33-36, 35/ Staphylomas. scleral, 116, 116/ in scleritis, 114, 11Sj. 116 Stargardt disease (fundus flavimaculatus), 172, 174/ STGD4 gene, in Stargardt disease, 172 Stori(orm pattern, in fibrous histiocytoma, 117,240,242/ Strabismus, in retinoblastoma, 30 I, 301t, 302/ Streptococcus pneumoniC/e, conjunctivitis in children caused by, 53 Striate melanokeratosis, 67 Stroma choroidal, 187 conjunctival, 47, 48/ corneal, 77, 78/ wound healing/repair and, 14

iris, 185-186 wound healing/repair and, 16 scleral, 112, 112/ Stromal dystrophies, 96-97, 97j. 97t, 98f, 99/ Avellino, 97, 97t, 99/ genetics of, 96 granular (type 1). 96, 97t, 98/ lattice, 96-97. 97t, 99/ macular, 96, 97[. 971 nomenclature of, 96 Stromal keratitis, herpes simplex virus causing, 83, 84/ Stromal nevi, 65 Sturge-Weber syndrome (encephalofacial angiomatosis), choroidal hemangioma in, 200, 292 Stye (hordeolum), 208 Subarachnoid space. optic nerve in, 249, 250/ Subcapsular cataract anterior (subcapsular fibrous plaques), 124, 125/ posterior, 124-125, 125/ retinoblastoma differentiated (rom, 305t Subconjunctival carboplatin, for retinoblastoma, 311 Subcutaneous nodules, in sarcoidosis, 191, 191/ Subepithelial nevi, 65 Subretinal neovascular membranes. See also Neovascularization in age-related macular degeneration, 169- 170, 171/ Subretinal space, biopsy of in intraocular lymphoma, 324 Substantia propria, conjunctival (conjunctival stroma),

47,48/ Su nlight. See Ultraviolet light Suprachoroidal detachment, melanoma differentiated from, 279- 280 Surgery, for melanoma, 285 Sweat glands of eyelid, 205, 207t Sympathetic ophthalmia, 189, 189j. 190/ surgical procedures/injuries leading to, 189, 1891~ 190/ Synaptophysin, in immunohistochemistry, 34 Synchesis scintillans, 138 Synechiae. anterior, in glaucoma, iridocorneal endothelial (ICE) syndrome and, 105, 105/ Syneresis, 134, 134/ Syph ilis, interstitial keratitis caused by, 87, 87/ Syringomas, 221, 221/ Systemic lupus erythematosus, eyelid manifestations of,2131 Systemic/VisceralJnodallymphoma. See also Lymphomas eye involvement and, 140-142, 141/, 142f, 143f, 323-325, 323f, 325/ T-cell lymphomas, orbital, 24 T cells (T lymphocytes), 9 Taenia solium, orbital infection caused b)" 235 Tapioca melanoma, 271 t Target, in microarray, 41 Tarsal plates/tarsus, 205, 206! sebaceous adenocarcinoma arising in, 221 Tears (retinal). See Retinal tears TED. See Thyroid eye disease Tenon capsule, 47 Teratoid medulloepitheliomas, 184 Teratomas, 6, 7/ Tertiary vitreous, 132 TGFpI gene, corneal dystrophies associated with granular (type 1), 96 la11'ice,97

400 • Index Theques,65 Thermotherapy, transpupillary for melanoma, 285 for metastatic eye disease, 322 ThioOavin T (ThT) stain, 31 t Thyroid carcinoma, retinoblastoma associated with, 31 41 Thyroid eye disease (thyroid/thyroid-associated ophlhalmopathy/orbitopathy), 232, 233[ Thyrotropin (thyroid-stimulating hormonerrSH) receptor, thyroid eye d isease and, 232 Tissue microarrays, 41, 42/ Tissue preparation, for pathologic examination, 28-30, 29t,30f,31t fixa tives for, 28-29, 29 1 processing and, 29 special procedures and, 33-45, 34t st aining and, 30, 30/' 3 1t TMAs. See Tissue microarrays TNM staging system for conjunctival carci noma, 332-333t for conjunctival melanoma, 334-336t for eyelid carcinoma, 329-3311 for lacrimal gland carcinoma, 345-347/ for orbital sarcoma, 348-349/ for retinoblastoma, 342-3441 for uveal melanoma, 337-341/ Tomato ketchup fundus, 292, 293/ Tomography, optical coherence. See Optical coherence tomography Topography, 6 anterior chamber, 101- 102, 101f, 102/ chorOidal, 186- 187, 187/ ciliary body, 186, 187/ conjunctival, 47, 48J .----........ corneal, 77-78, 78f eyelid, 205-206, 206f, 207/ iris, 185- 186, 186J lens, 119- 120, 11 9f, 120f optic nerve, 249, 250f orbital, 229 retinal, 145- 148, 146f, 147/ reti nal pigment epithelium, 146f, 148 scleral, 111 - 112, IIIJ trabecular meshwork, 10 1- 102, lOll, 102f uveal tract, IS5- 187, 185f, 186f, 187f vitreous, 131 -132 Toulon giant cells, 7, 9f in juvenile xanthogranuloma, 191, 19 1f Toxocara (toxocariasis), retinoblastoma differentiated from, 305, 305r Toxoplasma (toxoplasmosis), retinal, 153, 154[ T PCD. See Typical peripheral cystoid degeneration Trabecular meshwork congenital anomalies of, 102- 103, 103f, 104[ degenerations of, 104- 109, 110/ disorders of, 101 - 109, 110! See a/so specific type material in, secondary glaucoma and, 106- 109, II0f pigment in, 109, 109f, IIOJ in pseudoexfoliation, 106, 106f, 107f secondary, 315-322 topography of, 101-102, WI/. 102j Trachoma, 54 Transillumination, 26-27, 27f in choroidal/ciliary body melanoma diagnosis, 277,277/ in pathologic examination, 26-27, 27f

Transplantation, corneal, rejection and, 91, 92J Transpupillary thermotherapy for melanoma, 2B5 fo r metastatic eye disease, 322 Transscleral diathermy, contraindications to, 285 Transthyreti n (prealbumin), amyloidosis/amyloid deposits and, 140, 212 Trauma. See also Wound healing/repair angle recession and, 18, 19f, 109 glaucoma and, IB, 109 glaucoma associated with, 107- 109, 108f angle recession and, 18, 109 histologic sequelae of, 1B-22 , 181, 19f, 20f, 21f, 22f, 23f lens damage/cataracts caused by, 20 phacoantigenic uveitis an d, 122 sympathetic ophthalmia and , 189, 189f, 190f uveal tract, 203 Traumatic recession of anterior chamber angle, 18, 19f, 109

glaucoma and, 18, 109 Treacher Collins syndrome, eyelid manifestations of. 2 13t Triamcinolone, intravitreal (l VTA), fo r macular edema, 158-160 Trich ile mmomas, 21St Trilateral retinoblastoma, 309 TTT. See Transpupillary thermotherapy Tuberdes "hard;' 7, Sf in sarcoidosis, 52, 53/ Tumors. See also specific type oj tllTIIOr and structure affected and Intraocular tumors of anterior chamber and trabecular meshwork, l 09, llOf of choroid and ciliary body, 195-200 conjunctival, 61 -75 corneal, 100 eyelid,2 14-227 iris, 193-194, 194f optic disc/nerve, 256-258, 256f, 257f, 25Sf, 259f of orbit, 235- 247 scleral, 116-118, 117/. 118j secondary, 315-322. See also Metastatic eye disease orbital,247 retinoblastoma and, 312, 313-3 14, 314t uveal tract, 193-203 of vitreous, 140- 142, 141f, 142/, 143/ Tunica vasculosa [entis, remnant of, Mittendorf dot, 133 Typical degenerative retinoschisis, 154 T}'picai peripheral cystoid degeneration, 154, 154f Ultrasonography/ultrasound (echography) in choroidal/ciliary body melanoma, 276-277, 276j in choroidal hemangioma, 29 If, 292 in iris melanoma, 269, 273/ in lymphoma, 323 -324 in metastatic eye disease, 319 in retinoblastoma, 303 in uveal lymphoid infiltration, 326 Ult raviolet light (ultraviolet radiation) basal cell carcinoma and, 217-219, 21Sf, 219/ eye d isorders/injury associated with actinic keratosis, 216-217, 2 17f, 218/ eyelid tumors, 218-219, 218f, 219/, 220j pinguecula, 56 spheroidal degeneration (Labrador/acti nic keratopathy), 88-89, 90f

Index . 401

ocular surface squamous neoplasia and, 62 squamous cell carcinoma and, 219, 220j Uvea (uveal tract). See also specific structure congenital anomalies of, 18S degenerations of, 192- 193, 1921, 193/ disorders of, 185- 203. See also specific type neoplastic, 193-203. See also Uvea (uveal tract), tumors of healing/repair of, 16-17 infection/inflammation of, 188-191, 189f, 190f, 191/ See also Uveitis lymphoid infiltration and, 202, 325-326 lymphoid proliferation and, 202, 202/ lymphoma of, 202, 202f, 323 melanoc)'toma of, 195, 268 melanoma of, 195-200, 196f, 197f, 198f, 199f, 263, 273-288. See also Choroidal/ciliary body melanoma; Iris, melanoma of nevus differentiated from , 266-268, 278 ocular surface/conjunctival involvement and, 70, 71/ staging of, 337- 34lt retinoblastoma involving, 180-181 sarcoidosis involving, 190-191, 19 If, 272/ topography of, 185-187, 185f, 186f, 187/ traumatic injury of, 203 tumors of, 193- 203. See also specific tumor metastatic, 200, 20 If, 316-317, 316f, 317f, 321-322 miscellaneous, 200-203, 20 If, 202/ pigmented, 288- 289, 289/ Uveal (posterior) bleeding syndrome (polypoidal choroidal vasculopathy), 171, 172f, 173/ Uveal lymphoid infiltration, 202, 325-326 Uveal prolapse, 203 Uveit is, 188-191 intraocular lymphoma and, 323 lens-associated/phacoantigenic, 122, 122f, 123/ noninfectious, vitreous infiltrate in, 133 retinoblastoma differentiated from, 305t sarcoidosis and, 190- 191, 191/ sympathetic ophthalm ia and, 189, 189f, 190/ Vogt-Koyanagi -Harada (V KH ) syndrome and, 189-190 Vascu lar endothelial growth factor (VEGF) agents inhibiting. See Anti-VEGF agents in retinal ischemia , 158 Vascular loops, prepapilJary, 133 Vascular system of retina, 146 anomalies of, 149, 150/ ischemia and, 158- 162, 159f, 160f, 161/, 162/ Vascular tumors, of orbit, 240, 241/ Vasculopathy, polypoidal choroidal (posterior uveal bleeding syndrome), 171 , Inf, 173/ VEGF. See Vascular endothelial growth factor Venous occlusive disease, retinal branch retinal vein occlusion, 164 central retinal vein occlusion, 163-164, 165/ Verhoeff-van Gieson stain, 31 I Verocay bodies, 245 Verrucae (warts), vulgaris, of eyelid, 209, 209/ Verteporfin, photod ynamic therapy with in choroidal hemangioma, 292 in retinal capillary hemangioblastoma, 295 Viruses conjunClivitis caused by, 53-54, 55/ eyelid infection caused by, 209-2 10, 209f, 210/

optic nerve infection caused by, 252 retinal infection caused by, lSI, 151f, 152/ Visualloss/impairment, in uveal lymphoid infiltration, 325 Vitelliformmacular dystrophy gene (VMD2), 174- 175 Vitrectomy for intraocular lymphoma diagnosis, 142,324 for uveal lymphoid inftltration diagnosis, 326 VitreoretinaVretinal (primary intraocular) lymphoma, 140- 142, 141f, 142f, 143f, 323-325, 323f, 325f Vitreoretinopathies, proliferative, 20, 21f, 136, 137/ Vitreous amyloidosis involving, 139-140, 140f, 141/ congen ital anomalies of, 132-133, 132/ cortex of, 131 cysts of, 133 degenerations of, 134-140 development of, 131-132 disorders of, 131-142, 143f See also specific type neoplastic, 140-142, 14 If, 142f, 143/ healing/repair of, 17 infection/inflammation of. 133, 13'if in Icukcmia, 326 opacification of, in amyloidosis, 140 primary, 132 persistent hyperplaSia of. See Persistent fetal vasculature proteins in, 131 secondary, 132 tert iary, 132 topography of, 131-132 zonula r fibers in, 132 Vitreous biopsy, in intraocular (primary central nervous system) lymphoma, 324 Vitreous detachment, posterior, 134- 135, 135/ Vitreous hemorrhage, 137-138, 139/ retinoblastoma differentiated from, 305t Vitreous seeds, in retinoblastoma, 303, 303/ Vitritis, 133 in intraocular (primary central nervous system) lymphoma, 141, 141f, 323, 323/ VK H. See Vogt-Koyanagi-Harada (VK H) syndrome VMD2 (vitelliform macular dystrophy) gene, 174- 175 Vogt-Koyanagi-Harada (VKH) syndrome, 189- 190 von Hippe], internal ulcer of, 81, 81/ von Hippe! disease/syndrome (ret inal angiomatosis), 294 with hemangioblastomas (von Hippel-Lindau disease/ syndrome), 294- 295 von Hippel-Lindau disease/syndrome, 294- 295 von Kossa stain, 31 I Vossius ri ng, 20 WaUerian degeneration, optic nerve, 253-254 Warts (verrucae), of eyelid, 209, 209/ Wedl (bladder) cells, 125, 125/ Wegener granulomatosis, eyelid manifestations of, 2131 Wilms tumor, aniridia and, 188 Wolfring, glands of, 205, 2071 Wound contraction, 13, 14/ Wound healing/repair, 13-23. See also specific lissue of cornea, 13-16, 15/ of eyelid/orbit/lacrimal tissues, 17-18 general aspects of, 13, 1'if histologic sequelae of trauma and, 18-22, lSI. 19f, 20f, 2 If, 22f, 23f of lens, 17

402 • Index oflimbus, 16 of retina, 17

Xanthoph)'l1s. in macula. 147 Xenon arc laser therapy, for retinoblastoma, 311

of sclera, 16 of m'ta, 16-1 7 of vitreous. 17 Wyburn-Mason syndrome (racemose hemangioma),

296,297/ Xanthelasma. See also Xanthomas of eyelid, 211. 21 If. 2131 Xanthogra nuloma. juvenile of iris, 19 1,2701 or uvea! iract, 191 , 191[

Xanthomas, fibrou s (fibrous histiocytoma) m3lignant (atypical fibroxanthoma), 11 7- 118,

240- 242 orbital, 240- 242. 242/

scleral.117- II B,117!

ais. glands of, 205 chalazion and, 210-211 , 211/ hordeolum and, 208 sebaceous adenocarcino ma arising in, 221-222

Zenker acetic tissue fixative, 291 Ziehl-Neelsen stain, 31t Zimmerman tumor (phakomatous choristoma), 20t. 207

Zonal gra nu loma. 122 Zonu lar fibers lens. 120, 120/ tcrti ary vitreous, 132 Zygomycosis (mucormycosis) cornea involved in (keratitis), 83 optic ncrve involved in, 251 o rbit involved in, 234

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2011-2012 Basic and Clinical Science Course, Section 4: Ophthalmic Pathology and Intraocular Tumors (Basic &amp; Clinical Science Course) - PDF Free Download (2024)

2011-2012 Basic and Clinical Science Course, Section 4: Ophthalmic Pathology and Intraocular Tumors (Basic & Clinical Science Course) - PDF Free Download (2024)