Ocular Pathology [8th Edition] 9780323547574, 9780323547567

Table of contents :
Cover......Page 1
Ocular Pathology......Page 3
Copyright Page......Page 4
Foreword......Page 5
Forewords to the First Edition......Page 6
Preface......Page 8
Acknowledgments......Page 10
Dedication......Page 11
Phases of Inflammation......Page 12
Background......Page 29
Humoral Immunoglobulin (Antibody)......Page 34
Immunohistochemistry......Page 35
Immunodeficiency Diseases......Page 36
Neoplasia......Page 40
Necrosis (Table 1.11)......Page 41
Apoptosis......Page 42
Pigmentation......Page 43
Epigenetics and Ocular Disease......Page 44
Modern Molecular Pathology Diagnostic Techniques......Page 45
Concluding Comments......Page 48
Immunobiology......Page 49
Modern Molecular Pathology Diagnostic Techniques......Page 50
Meningocutaneous Angiomatosis (Encephalotrigeminal Angiomatosis; Sturge–Weber Syndrome [SWS])......Page 52
Neurofibromatosis (Figs. 2.3–2.5)......Page 54
Tuberous Sclerosis (Bourneville’s Disease; Pringle’s Disease)......Page 57
Other Phakomatoses......Page 59
Chromosomal Aberrations......Page 60
Trisomy 13 (47,13+; Patau’s Syndrome)......Page 61
Triploidy......Page 62
Chromosome 47 Deletion Defect......Page 63
Mosaicism......Page 64
Congenital Rubella Syndrome (Gregg’s Syndrome)......Page 65
Lysergic Acid Diethylamide (LSD) (Fig. 2.16)......Page 67
Cyclopia and Synophthalmos......Page 68
Anophthalmos (Fig. 2.18)......Page 70
Oculocerebrorenal Syndrome of Miller......Page 71
Subacute Necrotizing Encephalomyelopathy (Leigh’s Disease)......Page 72
Menkes’ Kinky-Hair Disease......Page 73
Ectrodactyly–Ectodermal Dysplasia (EEC)......Page 74
Other Syndromes......Page 75
Neurofibromatosis......Page 76
Chromosomal Trisomy Defects......Page 77
Drug Embryopathy......Page 78
Other Congenital Anomalies......Page 79
Classification......Page 81
Examples......Page 83
Classification......Page 85
Examples......Page 86
Iris......Page 91
Retina......Page 93
End Stage of Diffuse Ocular Diseases......Page 94
Nonsuppurative, Chronic Nongranulomatous Uveitis and Endophthalmitis......Page 96
Sequelae of Uveitis, Endophthalmitis, and Panophthalmitis......Page 97
Sympathetic Uveitis (Sympathetic Ophthalmia [SO], Sympathetic Ophthalmitis)......Page 98
Phacoanaphylactic (Phacoimmune, Phacoantigenic, or Phacogenic) Endophthalmitis......Page 99
Viral......Page 101
Bacterial......Page 104
Fungal......Page 109
Parasitic......Page 112
Sarcoidosis (Figs. 4.22–4.27)......Page 118
Granulomatous Scleritis......Page 120
Vogt–Koyanagi–Harada Syndrome (Uveomeningoencephalitic Syndrome)......Page 121
Familial Chronic Granulomatous Disease of Childhood......Page 122
Viral......Page 123
Bacterial......Page 124
Fungal......Page 125
Parasitic......Page 126
Sarcoidosis......Page 127
Vogt–Koyanagi–Harada Syndrome......Page 128
Familial Chronic Granulomatous Disease of Childhood......Page 129
Immediate......Page 130
Postoperative......Page 134
Delayed......Page 142
Intravitreal Injections......Page 151
Immediate......Page 152
Postoperative......Page 153
Delayed......Page 156
Introduction......Page 157
Penetrating Keratoplasty (Graft)......Page 158
Other Refractive Keratoplasties......Page 160
Complications of Glaucoma Surgery......Page 162
Introduction......Page 163
Contusion......Page 165
Penetrating and Perforating Injuries......Page 178
Intraocular Foreign Bodies......Page 179
Chemical Injuries......Page 182
Burns......Page 184
Ocular Effects of Injuries to Other Parts of the Body......Page 185
Radiation Injuries (Electromagnetic)......Page 187
Complications of Retinal Detachment and Vitreous Surgery Including Intraocular Injections......Page 191
Complications of Corneal Surgery......Page 193
Complications of Nonsurgical Trauma......Page 194
Bulla......Page 197
Polarity......Page 200
Phakomatous Choristoma......Page 201
Cryptophthalmos (Ablepharon)......Page 202
Epicanthus......Page 203
Eyelash Anomalies......Page 204
Ichthyosis Congenita......Page 206
Xeroderma Pigmentosum......Page 207
Dermatochalasis and Blepharochalasis......Page 208
Herniation of Orbital Fat......Page 209
Terminology......Page 210
Viral Diseases......Page 213
Fungal and Parasitic Diseases......Page 215
Cutis Laxa......Page 216
Pseudoxanthoma Elasticum......Page 217
Erythema Multiforme......Page 218
Epidermolysis Bullosa......Page 220
Contact Dermatitis......Page 221
Collagen Diseases......Page 222
Granulomatous Vasculitis......Page 228
Vasculitis-Like Disorders and Leukemia/Lymphoma......Page 229
Xanthelasma......Page 231
Necrobiotic Xanthogranuloma......Page 232
Juvenile Xanthogranuloma (JXG)......Page 233
Calcinosis Cutis......Page 234
Lipoid Proteinosis (Urbach–Wiethe Disease, Hyalinosis Cutis et Mucosae)......Page 235
Idiopathic Hemochromatosis......Page 236
Benign Cystic Lesions......Page 237
Benign Tumors of the Surface Epithelium......Page 241
Precancerous Tumors of the Surface Epithelium......Page 246
Cancerous Tumors of the Surface Epithelium......Page 247
Tumors of the Epidermal Appendages (Adnexal Skin Structures)......Page 251
Merkel Cell Carcinoma (Neuroendocrine Carcinoma, Trabecular Carcinoma) (Fig. 6.45)......Page 262
Normal Anatomy (Fig. 6.46)......Page 263
Blockage of Tear Flow Into the Nose......Page 264
Epithelial......Page 266
Miscellaneous......Page 267
Congenital Abnormalities......Page 268
Inflammation......Page 270
Lid Manifestations of Systemic Dermatoses or Disease......Page 271
Cysts, Pseudoneoplasms, and Neoplasms......Page 274
Tumors......Page 277
Normal Anatomy......Page 278
Hereditary Hemorrhagic Telangiectasia (Rendu–Osler–Weber Disease)......Page 279
Laryngo-Onycho-Cutaneous (LOC or Shabbir) Syndrome......Page 280
Sickle-Cell Anemia......Page 281
Hemangioma and Lymphangioma......Page 282
Basic Histologic Changes......Page 283
Infectious......Page 287
Noninfectious......Page 289
Deposition of Metabolic Products......Page 291
Skin Diseases......Page 292
Pinguecula......Page 293
Amyloidosis......Page 294
Conjunctivochalasis......Page 297
Cysts......Page 298
Pseudocancerous Lesions......Page 299
Cancerous Epithelial Lesions......Page 307
Stromal Neoplasms......Page 313
Inflammation......Page 316
Cysts, Pseudoneoplasms, and Neoplasms......Page 317
Normal Anatomy......Page 321
Abnormalities of Size......Page 324
Congenital Corneal Opacities......Page 325
Clinicopathologic Types—Specific......Page 326
Epithelial Erosions and Keratitis......Page 334
Stromal (Interstitial) Keratitis......Page 335
Peripheral......Page 337
Central......Page 338
Inflammations—Corneal Sequelae......Page 341
Epithelial......Page 342
Stromal......Page 344
Classification of Dystrophies......Page 354
Primary in the Corneal......Page 356
Melanin......Page 392
Kayser–Fleischer Ring......Page 393
Drug-Induced......Page 394
Crystals......Page 396
Neoplasm......Page 397
Ochronosis (Alkaptonuria)......Page 398
Episcleritis......Page 400
Introduction......Page 401
Episcleral Osseous Choristoma and Episcleral Osseocartilaginous Choristoma......Page 404
Ectopic Lacrimal Gland......Page 405
Congenital Defects......Page 406
Degenerations: Stromal......Page 407
Dystrophies: Stromal......Page 408
Dystrophies: Descemet’s Membrane and Endothelial......Page 409
Heredofamilial......Page 410
Crystals......Page 411
Inflammations......Page 412
Persistent Tunica Vasculosa Lentis......Page 413
Aniridia (Hypoplasia) of the Iris......Page 415
Coloboma......Page 417
Cysts of the Iris and Anterior Ciliary Body (Pars Plicata)......Page 419
Diabetes Mellitus......Page 420
Juvenile Xanthogranuloma (Nevoxanthoendothelioma)......Page 421
Iris Neovascularization (Rubeosis Iridis)......Page 423
Choroidal Folds......Page 424
Choroidal Dystrophies......Page 425
Epithelial......Page 427
Muscular......Page 429
Vascular......Page 430
Leukemic and Lymphomatous (See Chapter 14)......Page 431
Other Tumors......Page 433
Secondary Neoplasms......Page 434
Types......Page 435
Congenital and Developmental Defects......Page 436
Dystrophies......Page 437
Tumors......Page 438
Uveal Edema......Page 440
Fleck Cataract......Page 441
Anterior Polar Cataract......Page 442
Posterior Polar Cataract......Page 443
Posterior Lenticonus (Lentiglobus)......Page 444
General Reactions......Page 445
Exfoliation of the Lens Capsule......Page 447
Pseudoexfoliation Syndrome (Pseudoexfoliation of Lens Capsule, Exfoliation Syndrome, Basement Membrane Exfoliation Syndrome, Fibrillopathia Epitheliocapsularis) (Figs. 10.8–10.11)......Page 448
Anterior Subcapsular Cataract (ASC) (Figs. 10.12–10.15)......Page 452
Posterior Subcapsular Cataract (PSC) (Figs. 10.16 and 10.17; see Fig. 10.15)......Page 453
Cortex (“Soft Cataract”)......Page 454
Age-Related (Senile) Cataracts......Page 459
Glaucoma......Page 461
Congenital......Page 463
Congenital Anomalies......Page 468
Capsule......Page 469
Secondary Cataracts......Page 470
Ectopic Lens......Page 471
Albinism (Fig. 11.4)......Page 472
Coloboma......Page 474
Lange’s Fold......Page 475
Myelinated (Medullated) Nerve Fibers......Page 476
Foveomacular Abnormalities......Page 477
Causes......Page 478
Complications of Retinal Ischemia......Page 480
Histology of Retinal Ischemia......Page 481
Causes and Risk Factors of Hemorrhagic Infarction......Page 482
Types of Hemorrhagic Infarction......Page 483
Histology of Retinal Hemorrhagic Infarction (see Fig. 11.12)......Page 485
Hypertensive and Arteriolosclerotic Retinopathy......Page 487
Sickle-Cell Disease......Page 489
Eales’ Disease (Primary Perivasculitis of the Retina)......Page 491
Disseminated Intravascular Coagulation......Page 492
Specific Retinal Inflammations (see Chapters 2–4)......Page 493
Microcystoid Degeneration......Page 495
Degenerative Retinoschisis......Page 496
Paving Stone (Cobblestone) Degeneration (Peripheral Chorioretinal Atrophy; Equatorial Choroiditis)......Page 499
Idiopathic Serous Detachment of the RPE (Fig. 11.25)......Page 500
Idiopathic Central Serous Choroidopathy (Central Serous Retinopathy; Central Angiospastic Retinopathy) (see Fig. 11.25)......Page 501
Drusen......Page 502
Dry Age-Related Macular Degeneration (Dry, Atrophic, or Senile Atrophic Macular Degeneration)......Page 505
Age-Related Exudative Macular Degeneration (Exudative, Wet, or Senile Disciform Macular Degeneration; Kuhnt–Junius Macular Degeneration)......Page 507
Exudative Macular Degeneration Secondary to Focal Choroiditis (Juvenile Disciform Degeneration of the Macula)......Page 510
Toxic Retinal Degenerations......Page 511
Cancer-Associated Retinopathy (Paraneoplastic Syndrome; Paraneoplastic Retinopathy; Paraneoplastic Photoreceptor Retinopathy; Melanoma-Associated Retinopathy)......Page 513
Traumatic Retinopathy......Page 514
X-Linked Retinoschisis (Juvenile Retinoschisis, Vitreous Veils; Congenital Vascular Veils; Cystic Disease of the Retina; Congenital Retinal Detachment)......Page 515
Stargardt’s Disease (Fundus Flavimaculatus)......Page 517
Best Vitelliform Disease (Vitelliform Foveal Dystrophy; Vitelliform Macular Degeneration; Vitelliruptive Macular Degeneration; Exudative Central Detachment of the Retina—Macular Pseudocysts; Cystic Macular Degeneration; Exudative Foveal Dystrophy)......Page 519
Dominant Cystoid Macular Dystrophy (DCMD)......Page 520
Cone–Rod Dystrophy......Page 521
Retinitis Pigmentosa (Retinopathia Pigmentosa; Pigmentary Degeneration of the Retina)......Page 522
Pigment Epithelial Dystrophy......Page 524
Patterned Dystrophies of the Retinal Pigment Epithelium (Reticular Dystrophy or Sjögren Dystrophia Reticularis Laminae Pigmentosae Retinae; Butterfly-Shaped Pigment Dystrophy of the Fovea; Macroreticular or Spider Dystrophy)......Page 525
Bietti’s Crystalline Dystrophy (Bietti’s Tapetoretinal Degeneration With Marginal Corneal Dystrophy, Crystalline Retinopathy)......Page 526
Angioid Streaks......Page 527
Mucolipidoses......Page 528
Sphingolipidoses......Page 529
Other Lipidoses......Page 530
Disorders of Carbohydrate Metabolism......Page 531
Collagen Diseases......Page 532
Glia......Page 533
Definitions......Page 538
Classification of Neural Retinal Detachment......Page 539
Predisposing Factors to Neural Retinal Detachment......Page 541
Pathologic Changes After Neural Retinal Detachment......Page 543
Pathologic Complications After Neural Retinal Detachment Surgery......Page 545
Vascular Disease......Page 546
Inflammation......Page 547
Degenerations......Page 548
Hereditary Primary Retinal Dystrophies......Page 552
Hereditary Secondary Retinal Dystrophies......Page 555
Retinal Detachment......Page 556
Post Nonsurgical and Surgical Trauma......Page 558
Iridescent Particles......Page 561
Vitreous Detachment......Page 563
Proteinaceous Deposits......Page 564
Amyloid......Page 565
Autosomal-Dominant Vitreoretinochoroidopathy (ADVIRC; Peripheral Annular Pigmentary Dystrophy of the Retina)......Page 567
Complications......Page 568
Vitreous Opacities......Page 571
Vitreous Hemorrhage......Page 572
Hypoplasia......Page 573
Congenital (Familial) Optic Atrophies......Page 576
Coloboma (Table 13.1)......Page 577
Causes......Page 580
Histology of Optic Disc Edema......Page 581
Causes......Page 582
Causes......Page 588
Primary......Page 589
Secondary......Page 597
Congenital Defects and Anatomic Variations......Page 598
Optic Neuritis......Page 599
Tumors......Page 601
Microphthalmos With Cyst......Page 603
Congenital Alacrima......Page 605
Chronic......Page 606
Penetrating Wounds......Page 608
Graves’ Disease (Fig. 14.10)......Page 609
Mitochondrial Myopathies......Page 611
Dermatomyositis......Page 612
Primary Orbital Tumors......Page 613
Secondary Orbital Tumors......Page 665
Orbital Inflammation......Page 667
Ocular Muscle Involvement in Systemic Disease......Page 668
Tumors: Mesenchymal–Vascular......Page 669
Tumors: Mesenchymal–Muscle......Page 670
Tumors: Neural......Page 671
Tumors: Epithelial of Lacrimal Gland......Page 672
Tumors: Malignant Lymphoma......Page 673
Tumors Leukemia......Page 675
Secondary Tumors......Page 676
Natural History......Page 677
Ocular Surface Disease......Page 679
Lens......Page 683
Iris......Page 685
Ciliary Body and Choroid......Page 686
Neural Retina......Page 690
Vitreous......Page 707
Optic Nerve......Page 709
Ocular Surface Disease......Page 711
Lens......Page 713
Retina......Page 714
Vitreous......Page 715
Optic Nerve......Page 716
Normal Anatomy (Figs. 16.1–16.3)......Page 717
Introduction......Page 720
Congenital Glaucoma (Table 16.3)......Page 724
Primary Glaucoma (Closed- and Open-Angle)......Page 728
Causes......Page 735
Secondary Open-Angle Glaucoma......Page 742
Cornea (Figs. 16.26–16.28; See Also Fig. 8.49A,B)......Page 751
Iris......Page 752
Ciliary Body......Page 753
Neural Retina (Fig. 16.31)......Page 754
Optic Nerve......Page 755
Impaired Outflow: Congenital Glaucoma......Page 758
Impaired Outflow-Secondary Open-Angle......Page 759
Tissue Changes Caused by Elevated Intraocular Pressure......Page 760
Lentigo......Page 761
Nevus......Page 763
Malignant Melanoma......Page 767
Lentigo......Page 769
Nevus......Page 770
Primary Acquired Melanosis (PAM; Figs. 17.15 and 17.16; see also Table 17.2)......Page 774
Primary Malignant Melanoma of Conjunctiva (Fig. 17.17; see also Fig. 17.16)......Page 777
Reactive Tumors......Page 781
Nonreactive Tumors......Page 786
Acquired Neoplasms......Page 789
Iris......Page 791
Ciliary Body and Choroid......Page 797
Melanocytoma (Magnocellular Nevus of the Nerve Head)......Page 824
Malignant Melanoma......Page 825
Melanotic Tumors of the Orbit......Page 826
Melanocytic Tumors of the Uvea: Ciliary Body and Choroid......Page 829
Melanocytic Tumors of the Orbit......Page 831
General Information......Page 832
Heredity......Page 835
Clinical Features......Page 837
Histology......Page 840
Overview......Page 848
General Information......Page 850
Leukokoria (Box 18.1)......Page 851
Discrete Retinal or Chorioretinal Lesions......Page 865
Retinoblastoma—Heredity......Page 866
Retinoblastoma—Prognosis......Page 867
Lesions Simulating Retinoblastoma (Pseudoglioma)—Leukokoria: Persistent Fetal Vasculature......Page 868
Lesions Simulating Retinoblastoma (Pseudoglioma)—Leukokoria: Coats’ Disease......Page 869
Lesions Simulating Retinoblastoma (Pseudoglioma)—Leukokoria: Other Causes......Page 870
A......Page 871
B......Page 872
C......Page 873
D......Page 876
E......Page 877
F......Page 878
G......Page 879
H......Page 880
I......Page 881
L......Page 882
M......Page 884
N......Page 885
O......Page 886
P......Page 887
R......Page 889
S......Page 890
T......Page 892
V......Page 893
Z......Page 894

Citation preview

OCULAR PATHOLOGY

OCULAR PATHOLOGY EIGHTH EDITION MYRON YANOFF MD Chair Emeritus, Ophthalmology Professor of Ophthalmology & Pathology Departments of Ophthalmology & Pathology College of Medicine Drexel University Philadelphia, PA, USA

JOSEPH W. SASSANI MD MHA Professor of Ophthalmology and Pathology Pennsylvania State University The Milton S. Hershey Medical Center Hershey, PA, USA For additional online content visit ExpertConsult.com

Edinburgh London New York Oxford Philadelphia St Louis Sydney 2020

© 2020, Elsevier Inc. All rights reserved. First edition 1975 Second edition 1982 Third edition 1989 Fourth edition 1996 Fifth edition 2002 Sixth edition 2009 Seventh edition 2015 No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: 978-0-323-54755-0 E-ISBN: 978-0-323-54756-7

Content Strategists: Russell Gabbedy/Kayla Wolfe Content Development Specialist: Sharon Nash Project Manager: Joanna Souch Design: Brian Salisbury Marketing Manager: Claire McKenzie Printed in China Last digit is the print number: 9 8 7 6 5 4 3 2 1

F O R E WO R D Myron Yanoff did his residency at the Scheie Eye Institute of the University of Pennsylvania in Ophthalmology followed by a residency in the Department of Pathology. He then did a fellowship at the Armed Forces Institute of Pathology (AFIP) in Washington, DC, under the directorship of Lorenz Zimmerman. Yanoff ’s colleague, Ben Fine, was also Zimmerman’s student. Ben Fine was an excellent electron microscopist, and he and Yanoff authored the book, Ocular Histology: A Text and Atlas. Dr. Yanoff developed a series of lectures presented at the Annual Postgraduate Course in Ophthalmology at the Scheie Eye Institute and the Lancaster Course in Colby College, Maine, as well as the Biannual Course in Ophthalmic Pathology at the AFIP. These lectures led to the first edition of Ocular Pathology: A Text and Atlas by Drs. Yanoff and Fine, which was published in 1975. The text was presented in outline form, similar to the lecture series, with ample illustrations in black and white and a few color plates. This book became the standard ocular pathology text for residents in ophthalmology and, indeed, I used this textbook when I was an ophthalmology resident. Dr. Yanoff went on to be Chair of the Department of Ophthalmology at the University of Pennsylvania, then Chair at Hahnemann University and, subsequently, Drexel University, where he maintained a comprehensive ophthalmology practice. He and Dr. Fine updated their textbook every several years, with the second edition in 1982, third edition in 1989, fourth edition in 1996, and fifth edition in 2002. By that time, Yanoff’s resident, Joe Sassani, was ready to replace Ben Fine as the coauthor of this textbook. Dr. Sassani completed his ophthalmology residency and fellowship in Ophthalmic Pathology at the University of Pennsylvania, and developed a practice focused on glaucoma. Dr. Sassani is currently on the faculty at Penn State University in Hershey, Pennsylvania. Drs. Yanoff and Sassani completed the sixth edition of Ocular Pathology in 2009 and the seventh edition in 2015. The textbook retained its outline format; however, virtually all of the illustrations are now in color, and the book is replete with references. The textbook has kept up with the times, as it has added new information including immunohistochemistry, molecular biology, and confocal microscopy over the years. The story of ocular pathology is one of successive waves of confluences of technology, clinicopathologic correlations and, most importantly, people. An important confluence of technologies occurred in the mid-1800s when Hermann von Helmholtz in Heidelberg developed the ophthalmoscope and Rudolf Virchow in Berlin established cellular pathology as the basis of disease.

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This enabled correlation of findings in the eye as seen with the ophthalmoscope with cellular pathology viewed under the microscope. This led to important clinicopathologic correlations in ocular pathology, including tumors such as retinoblastoma and melanoma. As time progressed, more and more disease entities were defined by clinicopathologic correlations. Zimmerman and his students, Yanoff being one of them, described the pathology of most ocular diseases during the so-called “golden age of eye pathology” from the late 1950s through the 1980s. Subsequently, many of Zimmerman’s students, and in turn, their students, Sassani being one of them, applied newer technologies to the descriptions of these ocular diseases. This enabled updates of their book, Ocular Pathology. Ocular pathology has advanced with the confluence of technologies now being molecular biology and digital technology, including imaging technology such as confocal microscopy. The most important element in advancing knowledge and teaching of ocular pathology are individuals, in this case Drs. Yanoff and Sassani. Remarkably, they have updated their textbook, now in its eighth edition, keeping up with new discoveries in ocular pathology and clinicopathologic correlations, including using modern methods of investigation, such as ocular coherence tomography. Some examples of the updates in the eighth edition include the ocular manifestations of Zika virus infection, descriptions of the pathology of intravitreal injections, ocular injuries associated with terrorism, stem cells in the conjunctiva, the latest genetic information regarding corneal dystrophies, the genetics of retinal dystrophies, the TNM classification in the latest edition of the AJCC Cancer Staging Manual, and others. Indeed, Drs. Yanoff and Sassani have kept up with the times in a remarkable fashion. The definition of a classic textbook is that it endures the test of time and builds upon itself to a point where it becomes a standard text that remains current. In this case, the text began as an outgrowth from the long-standing and storied history of the venerable AFIP, including Yanoff, a disciple of Zimmerman, and Sassani, a student of Yanoff. Ocular Pathology has stood the test of time, remains current, and remains a standard textbook for the study of ocular pathology, the basis of ocular disease. I congratulate Drs. Yanoff and Sassani for their continued efforts in the production of this beautiful textbook, which is now the classic textbook for ophthalmology residents and fellows and pathology residents and fellows. Hans E. Grossniklaus MD Professor of Ophthalmology and Pathology Emory University School of Medicine

F O R E WO R D S T O T H E F I R S T E D I T I O N During the year of the observance of the 100th anniversary (1874–1974) of the University of Pennsylvania’s Department of Ophthalmology, it is exciting to have the publication of a volume whose coauthors have contributed significantly to the strides in ocular pathology taken by the Department in the past several years. Myron Yanoff, a highly regarded member of our staff, began a residency in ophthalmology in 1962, upon graduating from the University’s School of Medicine. The residency continued for the next five years, during the first two of which he also held a residency in the Department of Pathology. His keen interest and ability in ocular pathology were readily apparent, and I encouraged him to apply for a fellowship at the Armed Forces Institute of Pathology (AFIP), Washington, DC. From July 1964 through June 1965, he carried out exceptional research at the AFIP in both ophthalmology and pathology. He returned to our Department in July 1965, where the caliber both of his clinical and research work was of the highest. When he completed his residency in June 1967, I invited him to join the staff, and he has recently attained the rank of full professor. During the ensuing years, he has contributed substantially to the literature, particularly in the fields of ophthalmic and experimental pathology. He is Board certified in ophthalmology and in pathology. Ben Fine, noted for his work in electron microscopy at AFIP and at George Washington University, has shared his expertise in the field through lectures presented as part of the curriculum of the annual 16-week Basic Science Course in the Department’s graduate program. It can be said that 100 years ago ophthalmology was a specialty that had been gradually evolving during the preceding 100 years, dating from the time of the invention of bifocals by Benjamin Franklin in 1785. Few American physicians of that era, however, knew how to treat diseases of the eye, but as medical education became more specialized it was inevitable that ophthalmology would also become a specialty. With the invention of the ophthalmoscope in 1851, great advances were made in the teaching and practice of ophthalmology. This contributed greatly, of course, to setting the scene for the establishment of the University’s Department of Ophthalmology. It was on February 3, 1874, that Dr. William F. Norris was elected First Clinical Professor of Diseases of the Eye. Similar chairs had been established earlier in only three other institutions. The chair at the University of Pennsylvania later became known as the William F. Norris and George E. de Schweinitz Chair of Ophthalmology. Both Dr. Norris and Dr. de Schweinitz actively engaged in the study of ocular pathology. Dr. Norris stressed the importance of the examination of the eye by microscopy and of the correlation of findings from pathology specimens with the clinical signs. Dr. de Schweinitz was instrumental in having a member of his staff accepted as ophthalmic pathologist with the Department of Pathology.

In the years that followed under succeeding chairmen of the Department, other aspects of ophthalmology were stressed. Then, in 1947, during the chairmanship of Dr. Francis Heed Adler, Dr. Larry L. Calkins was appointed to a residency. Dr. Calkins, like Dr. Yanoff, displayed a keen interest in ocular pathology. Accordingly, he was instrumental in its study being revitalized during the three years of his residency. Another resident, Dr. William C. Frayer, who came to the Department in 1949, joined Dr. Calkins in his interest in ocular pathology. Dr. Frayer received additional training in the Department of Pathology and then became the ophthalmic pathologist of the Department. The importance of ocular pathology was increasingly evident, but facilities for carrying out the work in the Department of Ophthalmology were unfortunately limited. Until 1964, the pathology laboratory had been confined to a small room in the outpatient area of the Department. Then we were able to acquire larger quarters in the Pathology Building of the Philadelphia General Hospital located next door to the Hospital of the University of Pennsylvania. Although the building was earmarked for eventual demolition, the space was fairly adequate for research and also for conducting weekly ophthalmic pathology teaching conferences. Despite the physical aspects, we saw to it that Dr. Yanoff and his team of workers had a well-equipped laboratory. During the next several years as I saw that my dream for an eye institute with facilities for patient care, teaching, and research under one roof was to become a reality, I was delighted to be able to include prime space on the research floor for the ever enlarging scope of ocular pathology. In addition to all that Dr. Yanoff has had to build upon from the past tradition of our Department of Ophthalmology, I would like to think that the new facilities at the Institute have in some measure contributed to the contents of this excellent volume. With grateful appreciation, therefore, I look upon this book as the authors’ birthday present to the Department. From these same facilities, as Dr. Yanoff and Dr. Fine continue to collaborate, I can hope will come insights and answers for which all of us are ever searching in the battle against eye disease. Harold G. Scheie, MD Chairman, Department of Ophthalmology University of Pennsylvania Director, Scheie Eye Institute From their earliest days in ophthalmology, Myron Yanoff and Ben Fine impressed me as exceptional students. As they have matured and progressed up the academic ladder, they have become equally dedicated and effective teachers. Their anatomical studies of normal and diseased tissues have always been oriented toward providing meaningful answers to practical as well as esoteric clinical questions. Their ability to draw upon their large personal experience in clinical ophthalmology, ocular pathology, and laboratory investigation for their lectures at the Armed Forces Institute of Pathology and at the University of Pennsylvania has contributed immeasurably to the success of those courses. Now vii

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Forewords to the First Edition

they have used the same time-tested approach in assembling their material for this book. Beginning with their basic lecture outlines, then expanding these with just enough text to substitute for what would have been said verbally in lecture, adding a remarkable amount of illustrative material for the amount of space consumed, and then providing pertinent references to get the more ambitious student started in the pursuit of a subject, Drs. Yanoff and Fine have provided us with a sorely needed teaching aid for both the student and the teacher of ocular pathology. It should prove to be especially popular among medical students and residents in both ophthalmology and ocular pathology. With it one gets good orientation from the well-conceived outlines and fine clinicopathologic correlations from the selection of appropriate illustrations. It is with considerable pride and admiration that I’ve watched the evolution of the authors’ work and its fruition in the form

of this latest book. I am proud that both authors launched their respective careers with periods of intensive study at the Armed Forces Institute of Pathology and that ever since, they have remained loyal, dedicated, and highly ethical colleagues. I admire their youthful energy, their patient, careful attitude, their friendly cooperative nature, and their ability to get important things accomplished. I’m appreciative of this opportunity to express my gratitude for the work they have been doing. If it is true that “by his pupils, a teacher will be judged,” I could only wish to have had several dozen more like Drs. Yanoff and Fine. Lorenz E. Zimmerman, MD Chief, Ophthalmic Pathology Division Armed Forces Institute of Pathology Washington, DC

P R E FA C E This edition of Ocular Pathology has been revised extensively to reflect the many developments in the field since the publication of the 7th edition. While maintaining a focus on histopathologic and immunohistopathologic features upon which most diagnoses are made, we have expanded coverage of supplemental and correlative techniques such as clinical confocal microscopy and optical coherence tomography. Moreover, we have placed additional emphasis on the pathobiology underlying established and new diagnoses. This emphasis is reflected particularly in expanded coverage of genetics as it relates to disease entities. For a more in-depth analysis of the latest developments in genetics please see: Wiggs JL: Part 1 Genetics, in Yanoff M, Duker JS: Ophthalmology (5th Ed). London: Elsevier 2018. There are many online resources to catalog these conditions, including Online Mendelian Inheritance in Man (OMIM, http://www.ncbi.nlm.nih.gov/omim), RetNet (https://sph.uth.edu/Retnet/), and Retina International (http://www.retina-international.org/). Virtually every chapter has seen extensive revision including the addition of salient new material. Chapter 1, on the Basic Principles of Pathology, incorporates an expanded discussion of the role of the complement system in ocular homeostasis and disease. The section on immunobiology includes the concept of the inflammasome as a component of innate immunity. A section on autoimmunity and autoinflammation has been added. The discussion of HIV infection has been expanded including newer developments relative to its complications. There are entirely new sections on epigenetics and on modern molecular pathology diagnostic techniques. All of these changes are found in only the first chapter! Chapter 2, Congenital Anomalies, revises multiple topics including the phakomatoses, chromosomal anomalies, and syndromes such as Noonan syndrome and Walker–Warburg syndrome. Relevant genetic alterations are cited throughout the chapter. Chapter 3, Nongranulomatous Inflammation: Uveitis, Endophthalmitis, Panophthalmitis, and Sequelae, includes new attention on the ocular manifestations of Zika virus infection. Chapter 4, Granulomatous Inflammation, updates the discussion of sympathetic uveitis (ophthalmia, ophthalmitis) and nontraumatic infectious causes, such as tuberculosis. Chapter 5, Surgical and Nonsurgical Trauma, includes an expanded discussion of ophthalmic operative and postoperative surgical complications. A section on intravitreal injections has been added. A discussion of ocular injuries associated with modern warfare and terrorism has been added to the section on nonsurgical trauma. Numerous sections have been expanded in scope including the information on radiation injuries. Chapter 6, Skin and Lacrimal Drainage System, has an expanded discussion of congenital lesions and anomalies. The new classification system for ichthyosis has been added, as has information regarding its genetic correlates. The section on aging has been expanded significantly, as has the discussion of numerous individual entities, such as pseudoxanthoma elasticum,

epidermolysis bullosa, and erythema multiforme. There is an extensive revision of the sections on degenerative diseases, collagen diseases, and other inflammatory skin conditions, such as the vasculitides. Particular attention has been given to the section on adnexal tumors. Chapter 7, Conjunctiva, contains an enhanced discussion of stem cells. The congenital anomalies section is expanded significantly, with new entities added. The degenerations section has been revised to include the new classification of amyloidosis. The information regarding multiple types of cystic and neoplastic lesions has been expanded significantly, with a particular emphasis on cancerous epithelial lesions. Chapter 8, Cornea and Sclera, contains an extensive revision of the section on congenital lesions. The ever-changing classification of corneal dystrophies is reflected in further revisions to that section that also include the latest genetic information impacting our understanding of these disorders. The section on nonheredofamilial disorders also has been revised extensively. Significant new information is found in the section on sclera. Chapter 9, Uvea, includes updates on aniridia, coloboma, and choroidal dystrophies such as those involving choriocapillaris atrophy. Chapter 10, Lens, reflects particular attention on congenital cataracts and those associated with syndromes. The section on pseudoexfoliation has been revised, as have other sections including lens-related complications and ectopic lens. Chapter 11, Neural (Sensory) Retina, reflects updates in congenital and hereditary retinal disorders, vascular diseases, and inflammatory disorders. Particular attention has been directed to retinal degenerations. Multiple modifications have been made to the section on retinal dystrophies with a particular emphasis on the genetics of these disorders. Chapter 12, Vitreous, has seen a revision on the amyloid section and on familial exudative vitreoretinopathy and other familial disorders. Chapter 13, Optic Nerve, reflects updates in the section on congenital and familial disorders including relevant syndromes. The section on ischemic optic neuropathies has been revised, as has been the section on optic nerve tumors. Chapter 14, Orbit, has an extensively revised discussion of thyroid orbitopathy and muscular disorders. The section on the reticuloendothelial system and related disorders, including relative genetic anomalies, has been revised extensively, and the section on Lymphomas and related disorders has been significantly expanded. Chapter 15, Diabetes Mellitus, includes a new section on ocular surface disease secondary to diabetes. Additional new information and pertinent diagnostic techniques are discussed relative to diabetic complications for each anatomic region of the eye. The information on the pathobiology of ocular diabetic complications is expanded greatly. Chapter 16, Glaucoma, contains a comprehensively revised discussion of the anatomic basis for aqueous outflow and the ix

x

Preface

histopathologic correlates in glaucoma. The information on the genetics of glaucoma is revised extensively as is the discussion of pathobiology for each of the glaucomas where appropriate. Particular attention has been paid to the discussion of pseudoexfoliation. Much information has been added regarding the pathobiology of optic nerve damage in glaucoma. Chapter 17, Ocular Melanocytic Lesions, reflects the TMN classification as found in the 8th edition of the AJCC Cancer Staging Manual. Additionally, particular emphasis has been placed on genetic and chromosomal correlates to prognosis in ocular melanoma. The pathobiology underlying the correlations also is discussed. Chapter 18, Retinoblastoma and Simulating Lesions, is revised extensively, including the chapter title itself, which drops reference to “pseudoglioma.” The latest classifications for retinoblastoma are presented including the principles on which they are based. Genetic mutations and chromosomal abnormalities relative to retinoblastoma have been revised. Prognostic factors for

retinoblastoma and the latest information on overall survival are included. The section on simulating lesions includes new entities and the latest terminology. Particular attention has been paid to the latest developments in retinopathy of prematurity. Adjunctive diagnostic techniques are discussed. The 8th edition of Ocular Pathology is replete with new information reflecting the rapidly evolving world of ophthalmic pathology. Nevertheless, as we state in the very first line of our textbook, “The most important tool that the pathologist has at his/her disposal is meaningful communication with the patient’s clinician regarding the suspected diagnosis so that the pathologist can choose the appropriate strategy for processing whatever tissue or other samples are received.” No matter how sophisticated our techniques become, accurate communication remains the bedrock for accurate pathologic diagnoses in support of the best care for our patients. MY, JS

AC K N OW L E D G M E N T S This book could not have been completed without the understanding and patience of our wives Karin L. Yanoff, PhD, and Gloria Sassani, MA. We also wish to acknowledge the help of our assistants, Kelly McAnally and Sherri Maslasics. Finally, the members of the Elsevier production and editorial team lead by Russell Gabbedy, Kayla Wolfe and Sharon Nash, and including project manager Joanna Souch, designer Brian Salisbury and illustration managers Paula Catalano and Teresa McBryan all have provided invaluable help and guidance in the production of this 8th edition of Ocular Pathology.

xi

We dedicate this book to our wives, Karin and Gloria, and to our children.

1  Basic Principles of Pathology

The most important tool that the pathologist has at his/her disposal is meaningful communication with the patient’s clinician regarding the suspected diagnosis so that the pathologist can choose the appropriate strategy for processing whatever tissue or other samples are received. As will be seen in the discussion under Modern Molecular Pathology Diagnostic Techniques, there is a dizzying array of techniques at the pathologist’s disposal; however, it is only through communication with the clinician that the pathologist can determine which of these techniques to utilize to best serve the patient.

INFLAMMATION Definition I. Inflammation is the response of a tissue or tissues to a noxious stimulus. A. The tissue may be predominantly cellular (e.g., retina), composed mainly of extracellular materials (e.g., cornea), or a mixture of both (e.g., uvea). B. The response may be localized or generalized, and the noxious stimulus may be infectious or noninfectious. II. In a general way, inflammation is a response to a foreign stimulus that may involve specific (immunologic) or nonspecific reactions. Immune reactions arise in response to specific antigens, but they may involve other components (e.g., antibodies, T cells) or nonspecific components (e.g., natural killer [NK] cells, lymphokines). III. There is an interplay between components of the inflammatory process and blood clotting factors that shapes the inflammatory process.

Causes I. Noninfectious causes A. Exogenous causes: originate outside the eye and body, and include local ocular physical injury (e.g., perforating trauma), chemical injuries (e.g., alkali), or allergic reactions to external antigens (e.g., conjunctivitis secondary to pollen). B. Endogenous causes: sources originating in the eye and body, such as inflammation secondary to cellular immunity (phacoanaphylactic endophthalmitis [phacoantigenic uveitis]); spread from continuous structures (e.g., the sinuses); hematogenous spread (e.g., foreign particles); and conditions of unknown cause (e.g., sarcoidosis).

II. Infectious causes include viral, rickettsial, bacterial, fungal, and parasitic agents.

Phases of Inflammation (Table 1.1 lists the actions of the principal mediators of inflammation.) I. Acute (immediate or shock) phase (Fig. 1.1) A. Five cardinal signs: (1) redness (rubor) and (2) heat (calor)—both caused by increased rate and volume of blood flow; (3) mass (tumor)—caused by exudation of fluid (edema) and cells; (4) pain (dolor) and (5) loss of function (functio laesa)—both caused by outpouring of fluid and irritating chemicals. Table 1.2 lists the roles of various mediators in the different inflammatory reactions. B. The acute phase is related to histamine release from mast cells and factors released from plasma (kinin, complement, and clotting systems). 1. Histamine is found in the granules of mast cells, where it is bound to a heparin–protein complex. Serotonin (5-hydroxytryptamine), found in platelets and some neuroendocrine cells, has a similar effect to histamine. 2. The kinins are peptides formed by the enzymatic action of kallikrein on the α2-globulin kininogen. Kallikrein is activated by factor XIIa, which is the active form of the coagulation factor XII (Hageman factor). Factor XIIa converts plasma prekallikrein into kallikrein. Plasmin also can activate Hageman factor. 3. Plasmin, the proteolytic enzyme responsible for fibrinolysis, has the capacity to liberate kinins from their precursors and to activate kallikrein, which brings about the formation of plasmin from plasminogen. Plasmin cleaves C3 complement protein, resulting in the formation of C3 fragments. It also breaks down fibrin to form fibrin split products. 4. The complement system (see Table 1.3, which lists the complement molecules found in the normal eye, and Table 1.4, which lists the complement molecules found in diseased eyes) consists of almost 60 proteins present in blood plasma, on the cell surfaces, or within the cell. Its vital nature is evidenced by the fact that it has been preserved by evolution for more than a billion years. 1

2

CHAPTER 1  Basic Principles of Pathology

TABLE 1.1  The Actions of the Principal Mediators of Inflammation Mediator

Principal Sources

Actions

Cell-Derived Histamine Serotonin Prostaglandins Leukotrienes

Mast cells, basophils, platelets Platelets Mast cells, leukocytes Mast cells, leukocytes

Platelet-activating factor

Leukocytes, mast cells

Reactive oxygen species Nitric oxide Cytokines (TNF, IL-1) Chemokines

Leukocytes Endothelium, macrophages Macrophages, endothelial cells, mast cells Leukocytes, activated macrophages

Vasodilation, increased vascular permeability, endothelial activation Vasodilation, increased vascular permeability Vasodilation, pain, fever Increased vascular permeability, chemotaxis, leukocyte adhesion and activation Vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst Killing of microbes, tissue damage Vascular smooth muscle relaxation, killing of microbes Local endothelial activation (expression of adhesion molecules), fever/ pain/anorexia/hypotension, decreased vascular resistance (shock) Chemotaxis, leukocyte activation

Plasma Protein-Derived Complement products (C5a, C3a, C4a)

Plasma (produced in liver)

Kinins

Plasma (produced in liver)

Proteases activated during coagulation

Plasma (produced in liver)

Leukocyte chemotaxis and activation, vasodilation (mast cell stimulation) Increased vascular permeability, smooth muscle contraction, vasodilation, pain Endothelial activation, leukocyte recruitment

IL-1, interleukin-1; MAC, membrane attack complex; TNF, tumor necrosis factor. (Reproduced from Table 2.4, Kumar R, Abbas A, DeLancey A et al.: Robbins and Cotran Pathologic Basis of Disease, 8th edn. Philadelphia, Saunders. © 2010 by Saunders, an imprint of Elsevier Inc.)

A

B

C

D

Fig. 1.1  Acute inflammation. A, Corneal ulcer with hypopyon (purulent exudate). Conjunctiva hyperemic. B, Polymorphonuclear leukocytes (PMNs) adhere to corneal endothelium and are present in the anterior chamber as a hypopyon (purulent exudate). C, Leukocytes adhere to limbal, dilated, blood-vessel wall (margination) and have emigrated through endothelial cell junctions into edematous surrounding tissue. D, PMNs in corneal stroma do not show characteristic morphology but are recognized by “bits and pieces” of nuclei lining up in a row. (C and D are thin sections from rabbit corneas six hours post-corneal abrasion.)

Inflammation

TABLE 1.2  Role of Mediators in Different

TABLE 1.3  Complement Molecules Found

Role in Inflammation

Mediators

Vasodilation

Prostaglandins Nitric oxide Histamine Histamine and serotonin C3a and C5a (by liberating vasoactive amines from mast cells, other cells) Bradykinin Leukotrienes C4, D4, E4 PAF Substance P TNF, IL-1 Chemokines C3a, C5a Leukotriene B4 (Bacterial products; e.g., N-formyl methyl peptides) IL-1, TNF Prostaglandins Prostaglandins Bradykinin Lysosomal enzymes of leukocytes Reactive oxygen species Nitric oxide

Complement Molecules Expressed in the Healthy Eye

Reactions of Inflammation

Increased vascular permeability

Chemotaxis, leukocyte recruitment and activation

Fever Pain Tissue damage

in the Normal Eye







a. Initially named because it was seen to “complement” antibody and cell-mediated immune defenses against microbes. b. Classic functions: Fig. 1.2 highlights some of the myriad functions performed by complement. 1) Removal of immune (antigen–antibody) complexes. 2) Labeling (opsonization) of foreign antigens for enhanced removal by phagocytes. 3) Recruitment and activation of nearby leukocytes. 4) Direct cytolysis of invading microorganisms. c. Performs multiple functions in addition to those “classically” ascribed to it. d. Complement achieves its effect through a cascade of the separate components working in coordination and in specific sequences leading through activation of C3. (Fig. 1.3 is a schematic representation of the three primary routes or pathways of complement cascade activation through C3.) 1) The three pathways leading to activation of C3 are: a) Classical pathway. b) Lectin pathway. c) Alternative pathway.

Eye-Associated Remarks

Complement System Activators Amyloid precursor proteins (APP) Retina C-reactive protein (CRP) Retina Complement Proteins C1q, C2, C3

C4 C5–8 C9 C5b–9 Factor B Complement Regulators Factor H

Factor H-like protein 1 (FHL-1) C1 inhibitor (C1-INH) CD46 (MCP)

IL-1, interleukin-1; PAF, platelet-activating factor; TNF, tumor necrosis factor. (Reproduced from Table 2.7, Kumar R, Abbas A, DeLancey A et al.: Robbins and Cotran Pathologic Basis of Disease, 8th edn. Philadelphia, Saunders. © 2010 by Saunders, an imprint of Elsevier Inc.)



3

CD55 (DAF)

CD59 (protectin)

Vitronectin Clusterin Complement Receptors Complement receptor-1 (CR1) C3aR C5aR

Cornea, choroid, inner retina, sclera, optic nerve, retinal pigmented epithelium (RPE) cell Sclera Cornea, scleral tissue Soft drusen from non-AMD eyes, retina, optic nerve Bruch’s membrane, increase with age in non-AMD eyes Cornea, sclera Cornea, sclera, iris, ciliary body, retina, choroidal tissue outside Bruch’s membrane, optic nerve Bruch’s membrane Cornea Cornea and corneal limbus, vitreous humor, RPE basolateral surface, photoreceptors Cornea and corneal limbus, conjunctiva, iris, ciliary body, vitreous humor, retinal nerve fiber layer (NFL) and photoreceptors Cornea and corneal limbus, conjunctiva, iris, ciliary body, choroid, vitreous humor, vessels in the inner retina Soft drusen from non-AMD eyes Soft drusen from non-AMD eyes RPE apical surface Retinal ganglion cells, NFL Inner plexiform layer (IPL), Müller cells, NFL

AMD, age-related macular degeneration; RPE, retinal pigment epithelium. (From Mohlin et al.: The link between morphology and complement in ocular disease. Mol Immunol 89:84–99, 2017. Table 1. Elsevier.)



2) Cleavage of C3 produces the active fragments C3a and C3b. a) C3a is anaphylatoxin leading to chemotactic and proinflammatory responses. b) C5a also is an anaphylatoxin. c) C3b results in opsonization of foreign surfaces. 3) Thus, C3 has a major role in complement activation and generation of immune responses.

4

CHAPTER 1  Basic Principles of Pathology

TABLE 1.4  Complement Molecules Found in the Human Diseased Eye, i.e., in Age-Related

Macular Degeneration (AMD), Glaucoma, Neuromyolitis Optica (NMO) and in Uveitis Complement Molecules Expressed in the Diseased Eye

Eye Disease–Associated Remarks

Complement System Activators Amyloid precursor proteins (APP) C-reactive protein (CRP) Immunoglobulin Lipoprotein

Age-Related Macular Degeneration (AMD) Drusen Drusen, choroid Drusen Drusen

Complement Proteins/Activation Products C1q Drusen Mannose binding protein (MBL) Drusen C2a C3a, C3c, C3d, C3dg, C3b, iC3b, Bb Choroid, drusen, retinal pigmented epithelial (RPE) cell C5b–9 (MAC) and sC5b−9a Drusen, RPE, choroid, macula Factor Ba Drusen, choroid Factor Da Drusen, retina Complement Regulators Factor Ia Factor Ha FHL-1 Complement receptor 1 (CR1, CD35) CD46 (MCP) Vitronectin Clusterin Complement Anaphylatoxins C3a C5a

Drusen, inner retina Drusen, retinal pigmented epithelial (RPE) cell, choroid, macula Drusen, choroid Drusen, RPE Drusen, choroidal vessels, basolateral RPE Drusen, RPE Drusen

Complement Molecules Expressed in the Diseased Eye

Eye Disease–Associated Remarks

Complement System Activators Immunoglobulin Retina, optic nerve Complement Proteins/Activation Products C1q Retina, ganglion cells (GCL) and nerve fiber layer (NFL) C3, C3b Retina, GCL and NFL C5b-9 (MAC) Retina, GCL Complement Regulators Factor H

GCL Uveitis

Complement System Activators Immunoglobulin Ocular proteins Complement Proteins/Activation Products C3c, C3d Aqueous humor C4a Aqueous humor Factor B and Bb Aqueous humor Complement Anaphylatoxins C3a, C5a

Aqueous humor Neuromyelitis optica (NMO)

Complement System Activators Immunoglobulin Optic nerve

Aqueous humor, drusen Drusen Glaucoma

a

Complement-associated genes connected with AMD: (Adamus et al., 2017; Edwards et al., 2005; Hageman et al., 2005; Haines et al., 2005; Heckner et al., 2010; Klein et al., 2005; Gold et al., 2006; Maller et al., 2007; Park et al., 2009) and uveitis: (Thompson et al., 2013; Yang et al., 2011, 2013; Xu et al., 2015). (From Mohlin et al., The link between morphology and complement in ocular disease. Mol Immunol 89:84–99, 2017. Table 2. Elsevier.)





e. C1 has been called the “defining component” of the classical complement pathway. 1) Functions as a molecular scaffold for binding of other complement components. 2) Activates and cleaves complement components to continue the complement cascade. 3) Helps to trigger Wnt receptor signaling. 4) Participates in the process of apoptosis. 5) Cleaves MHC class I molecule and other proteins. 6) Can adapt to multiple molecular and cellular processes besides the complement system. f. Complement plays major roles in immune defense against microorganisms and in clearing damaged host components. 1) It responds to recognition of pathogenassociated molecular patterns (PAMPs) when they bind to host pattern-recognition receptors



(PRRs) and/or internally produced dangerassociated molecular patterns (DAMPs). g. Activation of complement pathways results in a proinflammatory response that includes the generation of membrane attack complexes (MACs), which mediate cell lysis, the release of chemokines to attract inflammatory cells to the site of damage, and the enhancement of capillary permeability. (See Fig. 1.3 for the steps leading to activation of MAC.) 1) Composed of five terminal complement proteins: C5b, C6, C7, C8, and C9. Multiple C9 molecules may be involved. 2) There are numerous levels regulating the activity of MAC and protecting heathy cells from attack. In fact, control of the system is the responsibility of almost half of its components.

Inflammation



Increased vascular permeability

Lysis of foreign cells

8 Lysis of bacteria

7

1

Neutrophil activation and chemotaxis

5



2

Complement 6

Smooth muscle contraction

4

3

Mast cell degranulation



Localization of complexes in germinal Opsonization centers and phagocytosis of bacteria

Fig. 1.2  Summary of the actions of complement and its role in the acute inflammatory reaction. Note how the elements of the reaction are induced. Increased vascular permeability (1) due to the action of C3a and C5a on smooth muscle (2) and mast cells (3) allows exudation of plasma protein. C3 facilitates both the localization of complexes in germinal centers (4) and the opsonization and phagocytosis of bacteria (5). Neutrophils, which are attracted to the area of inflammation by chemotaxis (6), phagocytose the opsonized microorganisms. The membrane attack complex, C5–C9, is responsible for the lysis of bacteria (7) and other cells recognized as foreign (8). (Adapted with permission from Roitt IM, Brostoff J, Male DK: Immunology, 2nd edn. London, Gower Medical. © Elsevier 1989.)







h.

i.

j.



k.



l.

a) Disorders resulting from impaired regulation of complement are termed complementopathies. Complement proteins opsonize or lyse cells. Therefore, they may injure healthy tissue, particularly when there is a defect in complement regulation. Complement is important in such diseases as macular degeneration, rheumatoid arthritis, multiple sclerosis, Alzheimer’s disease, schizophrenia, and angioedema. T cells and other cell types contain multi­ ple complement components, which have been called the “complosome” in analogy to the inflammasome, which will be discussed later in this chapter. (Fig. 1.4 provides an overview of the multiple ways in which the cell complosome and other complement components may impact key cell processes when faced with various challenges.) Other immune system cells that may produce or be involved in complement function are polymorphonuclear leukocytes, mast cells, monocytes, macrophages, dendritic cells, natural killer (NK) cells, and B cells. Plays a role in adaptive immune response involving T and B cells, and functions as a bridge between innate and adaptive immunity.









5

m. Helps maintain tissue homeostasis and cellular integrity, and functions in tissue regeneration. Also functions in early sperm–egg interactions in fertilization, regulation of epiboly and organogenesis, and in refinement of cerebral synapses. n. The complement system is implicated in multiple ocular diseases including age-related macular degeneration, glaucoma, and neuromyelitis optica (Table 1.4 lists elements of the complement system and how they may be involved in these disorders). o. Complement system, components and their genetic deficiency. 1) Deficiency of early components of the classical pathway (C1q, C1r/s, C2, C4, and C3) is associated with autoimmune diseases resulting from failure of clearance of immune complexes and apoptotic materials and impairment of humoral response. 2) Deficiencies of mannan-binding lectin and the early components of the alternative (factor D and properdin) and terminal pathways (from C3 onward components C5, C6, C7, C8, and C9) increase susceptibility to infections and to their recurrence. 3) See also the discussion of monogenic autoinflammatory syndromes later in this chapter. p. Activation of complement in the tumor microenvironment enhances tumor growth and increases metastasis. 5. Prostaglandins (prostanoids), which have both inflammatory and anti-inflammatory effects, are 20-carbon, cyclical, unsaturated fatty acids with a 5-carbon ring and two aliphatic side chains. a. They are produced by mast cells, macrophages, endothelial cells, and others. b. With leukotrienes, they are designated eicosanoids. Leukotrienes are metabolized through the lipoxygenase pathway and prostaglandins through the cyclooxygenase pathway. c. Active in vascular and systemic reactions of inflammation, oxidative stress, and physiologic functions. d. Cyclooxygenase helps catalyze the biosynthesis of prostaglandins from arachidonic acid. e. Prostaglandins, cytokines, and leukotrienes function to dilate lymphatics at a site of injury. f. Prostaglandins play an important role in nociception and pain. 6. Major histocompatibility complex (MHC), called the human leukocyte antigen (HLA) complex in humans, is critical to the immune response. a. HLAs are present on all nucleated cells of the body and platelets.

The HLA region is on autosomal chromosome 6. In practice, the blood lymphocytes are the cells tested for HLA.

6

CHAPTER 1  Basic Principles of Pathology

Fig. 1.3  Schematic of the complement cascade. The three primary routes for activation of complement are: (1) the lectin pathway (LP), (2) the classical pathway (CP), and (3) the alternative pathway (AP). The LP and CP are activated when specific triggers are recognized by host pattern-recognition receptors (PRRs). The AP is constitutively active. Initial activation through the LP or CP generates a shared C3 convertase (C4b•C2a). In the AP, C3b pairs with factor B (FB) to form the AP proconvertase (C3b•B), which is processed by factor D (FD) to form the AP C3 convertase (C3b•Bb). Both types of C3 convertases cleave C3 to generate C3a and C3b. C3a is an anaphylatoxin, a substance that promotes an inflammatory response. C3b that lands on the surface of a healthy host cell is quickly inactivated; C3b that attaches to the surface of a pathogen or altered host cell triggers a rapid amplification loop to generate more C3b, resulting in opsonization. C3b also complexes with the C3 convertases to form the C5 convertases (C4b•C2a•C3b and C3b•Bb•C3b). In the terminal complement cascade, C5 convertases cleave C5 into C5a (an anaphylatoxin) and C5b. C5b combines with C6–9 to form the membrane attack complex (MAC), also referred to as the terminal complement complex (TCC). Regulatory factors act at various stages of the cascade to control complement activation via their decay accelerating activity and/or cofactor activity. Additional abbreviations: MASPs, mannose-binding lectin-associated serine proteases; MBL, mannose-binding lectin; PAMPs, pathogen-associated molecular patterns. (From Baines AC, Brodsky RA: Complementopathies. Blood Rev 31:213–223, 2017. Figure 1. Elsevier.)





b. The three genetic loci belonging to HLA class I are designated by the letters HLA-A, HLA-B, and HLA-C. Class II MHC molecules are encoded at the locus HLA-D with three subregions HLA-DP, HLA-DQ, and HLA-DR. 1) Class I MHC molecules display proteins derived from foreign antigens, which are recognized by CD8+ T lymphocytes. 2) Class II MHC molecules present antigens that are contained in intracellular vesicles and derived from foreign organisms and soluble proteins. c. A tentatively identified specificity carries the additional letter “W” (workshop) and is inserted between the locus letter and the allele number— for example, HLA-BW 15.



d. The HLA system is the main human leukocyte isoantigen system and the major human histocompatibility system. 1) HLA-B 27 is positive in a high percentage of young women who have acute anterior uveitis and in young men who have ankylosing spondylitis or Reiter’s disease. 2) HLA-B 51 is strongly associated with Behçet’s disease. 7. Nonspecific soluble mediators of the immune system include cytokines, such as interleukins, which are mediators that act between leukocytes, interferons (IFNs), colony-stimulating factors (CSFs), tumor necrosis factor (TNF), transforming growth factor-β, and lymphokines (produced by lymphocytes).

Inflammation

sĞƐŝĐƵůĂƌ ^ƚŽŵĂƚŝƚŝƐ ǀŝƌƵƐ

7

ƵƌŬŚŽůĚĞƌŝĂ ŬůĞďƐŝĞůůĂ

Fig. 1.4  Suggestions on the potential impact of complosome-derived and/or pathogen-shunted intracellular complement on key cell processes during the host/pathogen interaction. Pathogens trigger an array of responses when interacting with complement during cell infection processes – some of which are beneficial for the microbe and some of which support host protection. For example, infection of human papillomavirus (HPV) triggers globular C1q receptor signaling (gC1qR), which leads to mitochondrial dysfunction and apoptosis (1). Opsonized bacteria trigger mitochondrial antiviral signaling, which increases the expression of AP-1- and NF-κB-controlled genes and proinflammatory cytokine responses. C3-opsonized viruses, on the other hand, are targeted for degradation via the proteosome (2). Opsonized Listeria is also targeted in an intracellular complement-dependent fashion for degradation after cell entry through v-set immunoglobulin domain containing 4 (VSIG4)-driven autophagosome formation (3). Supporting viral and bacterial propagation, gC1R signaling on mitochondria was also shown to block retinoic acid-inducible gene I (RIG-I) activation in a process that promoted the replication of vesicular stomatitis virus (4), while opsonized Klebsiella and other species use vitronectin to gain entry in nonphagocytic cells (5). Although in most of these processes, complement fragments were “dragged” into the cell by microbes, we propose that there will also be (subsequent) interactions of invading intracellular pathogens with components of the complosome, for example C3 and C5 activation fragments (6). In line with the “scheme” observed for the role of serum-derived complement, we further predict that in some cases the complosome will mediate clearance of the pathogen while in other cases, it will be utilized by the pathogen to promote its survival. (From Arbore G et al.: Intracellular complement – the complosome – in immune regulation. Mol Immunol 89:2–9, 2017. Figure 2. Elsevier.)







a. The TNF ligand family encompasses a large group of secreted and cell surface proteins (e.g., TNF and lymphotoxin-α and -β) that may affect the regulation of inflammatory and immune responses. b. The actions of the TNF ligand family are somewhat of a mixed blessing in that they can protect against infection, but they can also induce shock and inflammatory disease. C. Immediately after an injury, the arterioles briefly contract (for approximately five minutes) and then gradually relax and dilate because of the chemical mediators discussed previously and from antidromic axon reflexes.

After the transient arteriolar constriction terminates, blood flow increases above the normal rate for a variable time (up to a few hours) but then diminishes to below normal (or ceases) even though the vessels are still dilated. Part of the decrease in flow is caused by increased viscosity from fluid loss through the capillary and venular wall. The release of heparin by mast cells during this period probably helps to prevent widespread coagulation in the hyperviscous intravascular blood.



D. During the early period after injury, the leukocytes (predominantly the PMNs) stick to the vessel walls, at first

8

CHAPTER 1  Basic Principles of Pathology

momentarily, but then for a more prolonged time; this is an active process called margination (see Fig. 1.1C). 1. Ameboid activity then moves the PMNs through the vessel wall (intercellular passage) and through the endothelial cell junctions (usually taking 2–12 minutes); this is an active process called emigration. 2. PMNs, small lymphocytes, macrophages, and immature erythrocytes may also pass actively across endothelium through an intracellular passage in a process called emperipolesis. 3. Mature erythrocytes escape into the surrounding tissue, pushed out of the blood vessels through openings between the endothelial cells in a passive process called diapedesis. E. Chemotaxis, a positive unidirectional response to a chemical gradient by inflammatory cells, may be initiated by lysosomal enzymes released by the complement system, thrombin, or the kinins. F. PMNs (neutrophils; Fig. 1.5) are the main inflammatory cells in the acute phase of inflammation. All blood cells originate from a small, common pool of multipotential hematopoietic stem cells. Regulation of the hematopoiesis requires locally specialized bone marrow stromal cells and a coordinated activity of a group of regulatory molecules—growth factors consisting of four distinct regulators known collectively as CSFs.

1. PMNs are born in the bone marrow and are considered “the first line of cellular defense.” 2. CSFs (glycoproteins that have a variable content of carbohydrate and a molecular mass of 18–90 kDa) control the production, maturation, and function of

A

PMNs, macrophages, and eosinophils mainly, but also of megakaryocytes and dendritic cells. 3. PMNs are the most numerous of the circulating leukocytes, making up 50–70% of the total. 4. PMNs function at an alkaline pH and are drawn to a particular area by chemotaxis (e.g., by neutrophilic chemotactic factor produced by human endothelial cells). 5. The PMNs remove noxious material and bacteria by phagocytosis and lysosomal digestion. PMNs produce highly reactive metabolites, including hydrogen peroxide, which is metabolized to hypochlorous acid and then to chlorine, chloramines, and hydroxyl radicals—all important in killing microbes. Lysosomes are saclike cytoplasmic structures containing digestive enzymes and other polypeptides. Lysosomal dysfunction or lack of function has been associated with numerous heritable storage diseases: Pompe’s disease (glycogen storage disease type 2) has been traced to a lack of the enzymes α-1,4-glucosidase in liver lysosomes (see Chapter 11); Gaucher’s disease is caused by a deficiency of the lysosomal enzyme β-glucosidase (see Chapter 11). Metachromatic leukodystrophy is caused by a deficiency of the lysosomal enzyme arylsulfatase-A (see Chapter 11). Most of the common acid mucopolysaccharide, lipid, or polysaccharide storage diseases are caused by a deficiency of a lysosomal enzyme specific for the disease (see under appropriate diseases in Chapters 8 and 11). Chédiak–Higashi syndrome may be considered a general disorder of organelle formation (see section on congenital anomalies in Chapter 11) with abnormally large and fragile leukocyte lysosomes.

B

Fig. 1.5  Polymorphonuclear leukocyte (PMN). A, Macroscopic appearance of abscess—that is, a localized collection of pus (purulent exudate)—in vitreous body. B, PMNs are recognized in abscesses by their segmented (usually three parts or trilobed) nucleus. C, Electron micrograph shows segmented nucleus of typical PMN, and its cytoplasmic spherical and oval granules (storage granules or primary lysosomes).

C

Inflammation

A

9

B

Fig. 1.6  A, Eosinophils are commonly seen in allergic conditions such as this case of vernal catarrh. B, Eosinophils are characterized by bilobed nucleus and granular, pink cytoplasm. C, Electron micrograph shows segmentation of nucleus and dense cytoplasmic crystalloids in many cytoplasmic storage granules. Some granules appear degraded.

C



6. PMNs are end cells; they die after a few days and liberate proteolytic enzymes, which produce tissue necrosis. G. Eosinophils and mast cells (basophils) may be involved in the acute phase of inflammation. 1. Eosinophils (Fig. 1.6) originate in bone marrow, constitute 1% or 2% of circulating leukocytes, increase in number in parasitic infestations and allergic reactions, and decrease in number after steroid administration or stress. They elaborate toxic lysosomal components (e.g., eosinophil peroxidase) and generate reactive oxygen metabolites. 2. Mast cells (basophils; Fig. 1.7) elaborate heparin, serotonin, and histamine, and they are imperative for the initiation of the acute inflammatory reaction.

Except for location, mast cells appear identical to basophils; mast cells are fixed-tissue cells, whereas basophils constitute approximately 1% of circulating leukocytes. Basophils are usually recognized by the presence of a segmented nucleus, whereas the nucleus of a mast cells is large and nonsegmented.



H. The acute phase is an exudative phase (i.e., an outpouring of cells and fluid from the circulation) in which the nature of the exudate often determines and characterizes an acute inflammatory reaction. 1. Serous exudate is primarily composed of protein (e.g., seen clinically in the aqueous “flare” in the anterior chamber or under the neural retina in a rhegmatogenous neural retinal detachment). 2. Fibrinous exudate (Fig. 1.8) has high fibrin content (e.g., as seen clinically in a “plastic” aqueous). 3. Purulent exudate (see Figs. 1.1 and 1.5) is composed primarily of PMNs and necrotic products (e.g., as seen in a hypopyon). The term “pus” as commonly used is synonymous with a purulent exudate.

4. Sanguineous exudate is composed primarily of erythrocytes (e.g., as in a hyphema). II. Subacute (intermediate or reactive countershock and adaptive) phase. A. The subacute phase varies greatly and is concerned with healing and restoration of normal homeostasis

10

CHAPTER 1  Basic Principles of Pathology

A

B

C

D Fig. 1.7  A, Mast cell seen in center as round cell that contains slightly basophilic cytoplasm and round to oval nucleus. B, Mast cells show metachromasia (purple) with toluidine blue (upper right and left and lower right) and C, positive (blue) staining for acid mucopolysaccharides with Alcian blue. D, Electron microscopy of granules in cytoplasm of mast cell often shows typical scroll appearance.





(formation of granulation tissue and healing) or with the exhaustion of local defenses, resulting in necrosis, recurrence, or chronicity. B. PMNs at the site of injury release lysosomal enzymes into the area. 1. The enzymes directly increase capillary permeability and cause tissue destruction. 2. Indirectly, they increase inflammation by stimulating mast cells to release histamine, by activating the kiningenerating system, and by inducing the chemotaxis of mononuclear (MN) phagocytes. C. Mononuclear (MN) cells (Fig. 1.9) include lymphocytes and circulating monocytes. 1. Monocytes constitute 3%–7% of circulating leukocytes, are bone marrow-derived, and are the progenitor of a family of cells (monocyte–histiocyte–macrophage family) that have the same fundamental characteristics, including cell surface receptors for complement and the Fc portion of immunoglobulin, intracellular lysosomes, and specific enzymes; production of monokines; and phagocytic capacity. 2. Circulating monocytes may subsequently become tissue residents and change into tissue histiocytes, macrophages, epithelioid histiocytes, and inflammatory giant cells.





3. CSFs (glycoproteins that have a variable content of carbohydrate and a molecular mass of 18–90 kDa) control the production, maturation, and function of MN cells. 4. These cells are the “second line of cellular defense,” arrive after the PMN, and depend on release of chemotactic factors by the PMN for their arrival. a. Once present, MN cells can live for weeks, and in some cases even months. b. MN cells cause much less tissue damage than do PMNs, and they are more efficient phagocytes. 5. Monocytes have an enormous phagocytic capacity and are usually named for the phagocytosed material (e.g., blood-filled macrophages [erythrophagocytosis] and lipid-laden macrophages; Fig. 1.10). 6. Monocytes replace neutrophils as the predominate cell 24–48 hours after the onset of inflammation. D. Lysosomal enzymes, including collagenase, are released by PMNs, MN cells, and other cells (e.g., epithelial cells and keratocytes in corneal ulcers) and result in considerable tissue destruction. In chronic inflammation, the major degradation of collagen may be caused by collagenase produced by lymphokine-activated macrophages.

Inflammation



11

E. If the area of injury is tiny, PMNs and MN cells alone can handle and “clean up” the area with resultant healing. F. In larger injuries, granulation tissue is produced. 1. Granulation tissue (Fig. 1.11) is composed of leukocytes, proliferating blood vessels, and fibroblasts. 2. MN cells arrive after PMNs, followed by an ingrowth of capillaries that proliferate from the endothelium of pre-existing blood vessels. The new blood vessels tend to leak fluid and leukocytes, especially PMNs.

A

3. Fibroblasts (see Fig. 1.11), which arise from fibrocytes and possibly from other cells (monocytes), proliferate, lay down collagen (Table 1.5), and elaborate ground substance. 4. With time, the blood vessels involute and disappear, the leukocytes disappear, and the fibroblasts return to their resting state (fibrocytes). This involutionary process results in shrinkage of the collagenous scar and a reorientation of the remaining cells into a parallel arrangement along the long axis of the scar. 5. If the noxious agent persists, the condition may not heal as described previously, but instead may become chronic. 6. If the noxious agent that caused the inflammation is immunogenic, a similar agent introduced at a future date can start the cycle anew (recurrence).

C

B

Fig. 1.8  A, Cobweb appearances of fibrinous exudate, stained with periodic acid–Schiff. Cells use fibrin as scaffold to move and to lay down reparative materials. B, Electron micrograph shows periodicity of fibrin cut in longitudinal section. C, Fibrin cut in cross-section.

Histiocyte/macrophage

?

Activated macrophage

?

?

Multinucleated inflammatory giant cell

Langhans

Foreign body

Activated macrophages

?

Touton Epithelioid cells

A

B Fig. 1.9  A, Monocytes have lobulated, large, vesicular nuclei and moderate amounts of cytoplasm, and they are larger than the segmented polymorphonuclear leukocytes and the lymphocytes, which have round nuclei and scant cytoplasm. B, Possible origins of multinucleated inflammatory giant cells and of epithelioid cells.

12

CHAPTER 1  Basic Principles of Pathology

A

B Fig. 1.10  A, Foamy and clear lipid-laden macrophages in subneural retinal space. B, Cytoplasm of macrophages stains positively for fat with oil red-O technique.

A

B Fig. 1.11  Granulation tissue. A, Pyogenic granuloma, here in region of healing chalazion, is composed of granulation tissue. B, Three components of granulation tissue are capillaries, fibroblasts, and leukocytes.

III. Chronic phase A. The chronic phase results from a breakdown in the preceding two phases, or it may start initially as a chronic inflammation (e.g., when the resistance of the body and the inroads of an infecting agent, such as the organisms of tuberculosis or syphilis, nearly balance; or in conditions of unknown cause such as sarcoidosis). B. Chronic nongranulomatous inflammation is a proliferative inflammation characterized by a cellular infiltrate of lymphocytes and plasma cells (and sometimes PMNs or eosinophils). 1. The lymphocyte (Fig. 1.12) constitutes 15%–30% of circulating leukocytes and represents the competent immunocyte. a. All lymphocytes probably have a common stem cell origin (perhaps in the bone marrow) from which they populate the lymphoid organs: the thymus, spleen, and lymph nodes. b. Two principal types of lymphocytes are recognized: (1) The bone marrow-dependent (or bursal equivalent) B-lymphocyte is active in humoral immunity, is the source of immunoglobulin production

(Fig. 1.13), and is identified by the presence of immunoglobulin on its surface; (2) the thymusdependent T lymphocyte participates in cellular immunity, produces a variety of lymphokines, and is identified by various surface antigens. 1) Helper-inducer T lymphocytes (CD4-positive) initiate the immune response in conjunction with macrophages and interact with (helper) B lymphocytes. CD4+ T cells are activated after interaction with antigen–MHC complex and differentiate into Helper subsets. These functionally distinct T-helper subsets participate in host defense and immunoregulation. Classically, T-helper 1 (Th1) and T-helper 2 (Th2) cells secrete a distinctive suite of cytokines: Th1 express T-bet and produce interferon-γ and are involved predominantly in cellmediated immunity (e.g., cytotoxic T-cell response); Th2 express Gata3 and produce interleukins-4, -5, and -13. Regulatory T (Treg) cells also are CD4+-derived cells,

Inflammation

13

TABLE 1.5  Heterogeneity of Collagens in the Cornea* Type

Polypeptides

I

[α1(I)]2α2(I)

II

[α1(II)]3

III

[α1(III)]3

IV

[α1(IV)]2α2(IV)

V

[α1(V)]2α2(V)

VI

[α1(VI)]2α2(VI)α3(VI)

VII

[α1(VII)]3?

VIII

[α1(VIII)]2α2(VIII)?

IX

[α1(IX)]2α2(IX)α3(IX)

XII

[α1(XII)]3

Monomer

Polymer

*At least 10 genetically distinct collagens have been described in the corneas of different animal species, ages, and pathologies. Types I, II, III, and V collagens are present as fibrils in tissues. Types IV, VI, VII, and VIII form filamentous structures. Types IX and XII are fibril-associated collagens. The sizes of the structures are not completely known. Type II collagen is found only in embryonic chick collagen associated with the primary stroma. Type III collagen is found in Descemet’s membrane and in scar tissue. Types I and V form the heterotypic fibrils of lamellar stroma. Type VII has been identified with the anchoring fibrils, and type VIII is present only in Descemet’s membrane. Type IX collagen, associated with type II fibrils in the primary stroma, and type XII collagen, associated with type I/V fibrils, are part of a family of fibril-associated collagens with interrupted triple helices. Both type IX and type XII are covalently associated with a chondroitin sulfate chain. (Reproduced from Cintron C: The molecular structure of the corneal stroma in health and disease. In Podos SM, Yanoff M, eds: Textbook of Ophthalmology, vol. 8. London, Mosby. © Elsevier 1994.)

serve an immunosuppressive function, and express the master transcription factor FoxP3. There are thymic-derived natural, nTreg cells and peripherally induced iTreg cells that relate to autoimmunity. T-helper 17 (Th17) cells participate in protective tumor immunity; however, Th17-associated cytokines may be associated with tumor initiation and growth and also with autoimmune diseases. Finally, there are follicular T-helper (Tfh) cells that are in proximity to B cells in the germinal centers of lymphoid tissue. They promote class switching of B cells and express the master regulator Bc16 and the effector cytokine IL-21 as well as other surface molecules. Fig. 1.14 illustrates the complexity, flexibility and plasticity of the relationships between T-helper cells.

2) Suppressor-cytotoxic T lymphocytes (CD8positive) suppress the immune response and are capable of killing target cells (e.g., cancer cells) through cell-mediated cytotoxicity. 3) MHC molecules present antigenic peptides to CD8+ T cells, thereby providing the foundation for immune recognition. 2. The plasma cell (Fig. 1.15) is produced by the bone marrow–derived B lymphocyte, elaborates immunoglobulins (antibodies), and occurs in certain modified forms in tissue sections. After germinal center B cells undergo somatic mutation and antigen selection, they become either memory B cells or plasma cells. CD40 ligand directs the differentiation of germinal center B cells toward memory B cells rather than toward plasma cells.

14

CHAPTER 1  Basic Principles of Pathology

rbc

m

A

B

C Fig. 1.12  Lymphocyte. A, Low magnification shows cluster of many lymphocytes appearing as a deep blue infiltrate. Cluster appears blue because cytoplasm is scant and mostly nuclei are seen. B, Electron micrograph shows lymphocyte nucleus surrounded by small cytoplasmic ring containing several mitochondria, diffusely arrayed ribonucleoprotein particles, and many surface protrusions or microvilli (rbc, red blood cell). C, Lymphocytes seen as small, dark nuclei with relatively little cytoplasm. Compare with polymorphonuclear leukocytes (segmented nuclei) and with larger plasma cells (eccentric nucleus surrounded by halo and basophilic cytoplasm).

N

VL

N CL VH

C CH1

Antigenbinding sites

C CH2

CH3 C

C

N N

Heavy chain

Light chain

Fig. 1.13  The basic immunoglobulin structure. The unit consists of two identical light polypeptide chains linked together by disulfide bonds (gray). The amino-terminal end (N) of each chain is characterized by sequence variability (VL, VH), whereas the remainder of the molecule has a relatively constant structure (CL, CH1–CH3). The antigen-binding sites are located at the N-terminal end. (Adapted with permission from Roitt IM, Brostoff J, Male DK: Immunology, 2nd edn. London, Gower Medical. © Elsevier 1989.)

a. Plasmacytoid cell (Fig. 1.16A and B): This has a single eccentric nucleus and slightly eosinophilic granular cytoplasm (instead of the normal basophilic cytoplasm of the plasma cell). b. Russell body (Fig. 1.16C and D): This is an inclusion in a plasma cell whose cytoplasm is filled and enlarged with eosinophilic grapelike clusters (morular form), with single eosinophilic globular structures, or with eosinophilic crystalline structures; usually the nucleus appears as an eccentric rim or has disappeared. The eosinophilic material in plasmacytoid cells and in Russell bodies appears to be immunoglobulin that has become inspissated, as if the plasmacytoid cells can no longer release the material because of defective transport by the cells (“constipated” plasmacytoid cells).

Inflammation

C. Chronic granulomatous inflammation is a proliferative inflammation characterized by a cellular infiltrate of lymphocytes and plasma cells (and sometimes PMNs or eosinophils). 1. Epithelioid cells (Fig. 1.17) are bone marrow–derived cells in the monocyte–histiocyte–macrophage family (Fig. 1.18). a. In particular, epithelioid cells are tissue monocytes that have abundant eosinophilic cytoplasm, somewhat resembling epithelial cells. Tfh Bcl6

Plasticity Th1 Bcl6 T-bet

T-bet

T-bet RORyt

Bcl6 FoxP3 Flexibility

RORyt FoxP3 RORyt Th17

Th2 Bcl6 Gata3

Gata3



b. They are often found oriented around necrosis as large polygonal cells that contain pale nuclei and abundant eosinophilic cytoplasm whose borders blend imperceptibly with those of their neighbors in a pseudosyncytium (“palisading” histiocytes in a granuloma). c. All cells of this family interact with T lymphocytes, are capable of phagocytosis, and are identified by the presence of surface receptors for complement and the Fc portion of immunoglobulin. 2. Inflammatory giant cells, probably formed by fusion of macrophages rather than by amitotic division, predominate in three forms: a. Langhans’ giant cell (Fig. 1.19; see Fig. 1.17): This is typically found in tuberculosis, but it is also seen in many other granulomatous processes. When sectioned through its center, it shows a perfectly homogeneous, eosinophilic, central cytoplasm with a peripheral rim of nuclei.

Gata3 FoxP3

If the central portion is not homogeneous, foreign material such as fungi may be present: the cell is then not a Langhans’ giant cell but a foreign-body giant cell. When a Langhans’ giant cell is sectioned through its periphery, it simulates a foreign-body giant cell.

T-bet FoxP3 FoxP3 Tregs

Fig. 1.14  Flexibility and plasticity of helper T cells. Recent studies continue to reveal surprising flexibility in expression of “master regulator” transcription factors. In addition, there are now many examples in which helper T cell phenotypes can change their pattern of expression of signature cytokines and gene expression. Striking examples exist in which apparently fully committed “lineages” readily switch their phenotype, and there are now many circumstances in which helper T cells have been shown to express more than one master regulator. This may be advantageous in terms of host defense, but it needs to be borne in mind in thinking about effective therapies for immune-mediated disease and vaccine development. (From Nakayamada S, Takahashi H, Kanno Y et al.: Helper T cell diversity and plasticity. Curr Opin Immunol 24:297, 2012.)

A

15

b. Foreign-body giant cell (Fig. 1.20): This has its nuclei randomly distributed in its eosinophilic cytoplasm and contains foreign material. c. Touton giant cell (Fig. 1.21), frequently associated with lipid disorders such as juvenile xanthogranuloma, appears much like a Langhans’ giant cell with the addition of a rim of foamy (fat-positive) cytoplasm peripheral to the rim of nuclei. 3. Three patterns of inflammatory reaction may be found in granulomatous inflammations: a. Diffuse type (Fig. 1.22A): This typically occurs in sympathetic uveitis, disseminated histoplasmosis

B Fig. 1.15  Plasma cell. A, Plasma cells are identified by eccentrically located nucleus containing clumped chromatin and perinuclear halo in basophilic cytoplasm that attenuates opposite to nucleus. Plasma cells are larger than small lymphocytes, which contain deep blue nuclei and scant cytoplasm. B, Electron microscopy shows exceedingly prominent granular endoplasmic reticulum that accounts for cytoplasmic basophilia and surrounds nucleus. Mitochondria are also present in cytoplasm.

16

CHAPTER 1  Basic Principles of Pathology

A

B

C

D Fig. 1.16  Altered plasma cells. A, Electron micrograph shows that left plasmacytoid cell contains many small pockets of inspissated material (γ-globulin) in segments of rough endoplasmic reticulum; right cell contains large globules (γ-globulin), which would appear eosinophilic in light microscopy. B, Plasmacytoid cell in center has eosinophilic (instead of basophilic) cytoplasm that contains tiny pink globules (γ-globulin). C, Russell body appears as large anuclear sphere or D, multiple anuclear spheres.

Activated macrophage

Lymphokine

Langerhans’ cell

? Monocyte/ macrophage

Giant cell

?

Fig. 1.17  Epithelioid cells in conjunctival, sarcoidal granuloma, here forming three nodules, which are identified by eosinophilic color resembling epithelium. Giant cells, simulating Langhans’ giant cells, are seen in nodules.

?

Foreign body

? Epithelioid cell

Touton

Fig. 1.18  Proposed scheme for the terminal differentiation of cells of the monocyte/macrophage system. The pathologic changes result from the inability of the macrophage to deal effectively with the pathogen. Lymphokines from active T cells induce monocytes and macrophages to become activated macrophages. Where prolonged antigenic stimulation exists, activated macrophages may differentiate into epithelioid cells and then into giant cells in vivo, in granulomatous tissue. The multinucleated giant cell may be derived from the fusion of several epithelioid cells. (Adapted with permission from Roitt IM, Brostoff J, Male DK: Immunology, 2nd edn. London, Gower Medical. © Elsevier 1989.)

Inflammation

and other fungal infections, lepromatous leprosy, juvenile xanthogranuloma, Vogt–Koyanagi–Harada syndrome, cytomegalic inclusion disease, and toxoplasmosis. The epithelioid cells (sometimes with macrophages or inflammatory giant cells or both)

Fig. 1.19  Langhans’ giant cells have homogeneous central cytoplasm surrounded by rim of nuclei.

A

are distributed randomly against a background of lymphocytes and plasma cells. b. Discrete type (sarcoidal or tuberculocidal; see Fig. 1.22B): This typically occurs in sarcoidosis, tuberculoid leprosy, and miliary tuberculosis. An accumulation of epithelioid cells (sometimes with inflammatory giant cells) forms nodules (tubercles) surrounded by a narrow rim of lymphocytes (and perhaps plasma cells). c. Zonal type (see Fig. 1.22C): This occurs in caseation tuberculosis, some fungal infections, rheumatoid scleritis, chalazion, phacoanaphylactic (phacoantigenic) endophthalmitis, toxocara endophthalmitis, and cysticercosis. 1) A central nidus (e.g., necrosis, lens, and foreign body) is surrounded by palisaded epithelioid cells (sometimes with PMNs, inflammatory giant cells, and macrophages) that in turn are surrounded by lymphocytes and plasma cells. 2) Granulation tissue often envelops the entire inflammatory reaction.

B Fig. 1.20  A, Foreign-body giant cell (FBGC) simulating Langhans’ giant cells, except that homogeneous cytoplasm is interrupted by large, circular foreign material. B, Anterior-chamber FBGCs, here surrounding clear clefts where cholesterol had been, have nuclei randomly distributed in cytoplasm.

A

17

B Fig. 1.21  A, Touton giant cells in juvenile xanthogranuloma closely resemble Langhans’ giant cells except for the addition of peripheral rim of foamy (fat-positive) cytoplasm in the former. B, Increased magnification showing fat positivity of peripheral cytoplasm with oil red-O technique. (Case presented by Dr. M Yanoff to the Eastern Ophthalmic Pathology Society, 1993, and reported in Arch Ophthalmol 113:915, 1995.)

18

CHAPTER 1  Basic Principles of Pathology

A

B

Fig. 1.22  Patterns of granulomatous inflammation. A, Diffuse type in sympathetic uveitis. B, Discrete (sarcoidal or tuberculocidal) type in sarcoidosis. C, Zonal type in phacoanaphylactic endophthalmitis.

C

Staining Patterns of Inflammation I. Patterns of inflammation are best observed microscopically under the lowest (scanning) power. II. With the hematoxylin and eosin (H&E) stain, an infiltrate of deep blue tint (basophilia) usually represents a chronic nongranulomatous inflammation. The basophilia is produced by lymphocytes that have blue nuclei (when stained with hematoxylin) and practically no cytoplasm (if it were present, it would stain pink with eosin) and by plasma cells that have blue nuclei and blue cytoplasm. III. A deep blue infiltrate with scattered gray (pale pink) areas (“pepper and salt”) usually represents a chronic granulomatous inflammation, with the blue areas lymphocytes and plasma cells, and the gray areas islands of epithelioid cells. IV. A “dirty” gray infiltrate usually represents a purulent reaction with PMNs and necrotic material. A. If the infiltrate is diffuse (Fig. 1.23; e.g., filling the vitreous [vitreous abscess]), the cause is probably bacterial. B. If the infiltrate is localized into two or more small areas (Fig. 1.24; i.e., multiple abscesses or microabscesses), the cause is probably fungal.









IMMUNOBIOLOGY Background I. There are three levels of human defense against invading organisms:



A. Anatomical and physiological barriers 1. Examples are the skin, enzymes in secretions, mucoid surface secretions, surfactant, and gastric pH. B. Innate immunity (See also discussion of complement earlier in this chapter.) 1. This system has few receptors for antigens, but ones that are widespread among potential invaders. 2. Inflammasome (Fig. 1.25) illustrates how activation of one of the upstream sensors precipitates inflammasome formation leading to cell membrane breach and cell death through pyroptosis. a. It is a multiprotein complex composed of a sensor protein, the adapter protein ASC (apoptosisassociated speck-like protein containing caspase recruitment domain), and the inflammatory protease caspase-1. b. Downstream substrates are gasdermin D, IL-1β, and IL-18 and are responsible for an inflammatory form of cell death called pyroptosis with gasdermin D functioning as the actual instrument of cell death by forming pores in the cell membrane. 1) Following its activation, caspase-1 induces activation of IL-1β, and IL-18 thereby resulting in inflammation. c. Upstream sensors include NLRP (nucleotidebinding domain and leucine-rich repeat containing) 1, NLRP3, NLRC4, AIM2, and pyrin.

Immunobiology

A

B

19

C

Fig. 1.23  Staining patterns of inflammation. A, Macroscopic appearance of diffuse vitreous abscess. B, Diffuse abscess, here filling vitreous, characteristic of bacterial infection. C, Special stain shows Gram positivity of bacterial colonies in this vitreous abscess.

A

B

C

Fig. 1.24  Staining patterns of inflammation. A, Macroscopic appearance of multiple vitreous microabscesses, characteristic of fungal infection. B, One vitreous microabscess contiguous with detached retina. C, Septate fungal mycelia (presumably Aspergillus) from same case stained with Gomori’s methenamine silver.







1) Activated by stimuli such as infection and changes in cell homeostasis. d. Involved in monogenic autoinflammatory disorders in which there is apparently spontaneous inflammation in the absence of inciting auto-antibodies or antigen-specific T cells. (See section on autoinflammation later in this chapter). 1) Abnormal response to endogenous or exogenous factors that results in exaggerated activation of inflammation and usually mediated by the inflammasome. 2) May involve the eye in idiopathic granulomatous disorders, familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and cryopyrin-associated periodic syndrome. e. Involved in the pathogenesis of glaucoma, agerelated macular degeneration, diabetic retinopathy, dry eye, and ocular infections. f. Activity by certain inflammasomes is associate with susceptibility to infections, autoimmunity, and tumorigenesis.







g. When the cell is in a steady state, inflammasome components are present in the cytosol, but their assembly is prevented by auto-inhibitory mechanisms mediated by chaperone protein. h. Autophagy inducers reduce symptoms of inflammasome-related diseases, while deficiencies in autophagy-related proteins may induce aberrant activation of inflammasome-mediated tissue damage. C. Adaptive immunity 1. The main components of this system are B and T lymphocytes. Their strength is in their ability to generate a response to a diverse population of potential pathogens. The immune system provides the body with a mechanism to distinguish “self” from “nonself.” The distinction, made after a complex, elaborate process, ultimately relies on receptors on the only immunologically specific cells of the immune system, the B and T lymphocytes.

20

CHAPTER 1  Basic Principles of Pathology

Fig. 1.25  Inflammasome. (From Place DE, Kanneganti TD: Recent advances in inflammasome biology. Curr Opin Immunol 50:32–38, 2018. Figure 1. Elsevier.)

II. Table 1.6 lists the major effector elements in our immunologic defense system. III. All lymphocytes in mammalian lymph nodes and spleen have a remote origin in the bone marrow. Those that have undergone an intermediate cycle of proliferation in the thymus (thymus-dependent, or T lymphocytes) mediate cellular immunity, whereas those that seed directly into lymphoid tissue (thymus-independent, or B lymphocytes) provide the precursors of cells that produce circulating antibodies. A. Thus, mediators of immune responses can be either specifically reactive lymphocytes (cell-mediated immunity) or freely diffusible antibody molecules (humoral immunity). B. Antibody-producing B cells or killer T-type cells are only activated when turned on by a specific antigen.

When an antigen (immunogen) penetrates the body, it binds to an antibody-like receptor on the surface of its corresponding lymphocyte that proliferates and generates a clone of differentiated cells. Some of the cells (large B lymphocytes and plasma cells)

secrete antibodies; T cells secrete lymphokines; and other lymphocytes circulate through blood, lymph, and tissues as an expanded reservoir of antigensensitive (memory) cells. When the immunogen encounters the memory cells months or years later, it evokes a more rapid and copious secondary anamnestic response. Other immune cells (e.g., NK) are less specific and eliminate a variety of infected or cancerous cells.

IV. T lymphocytes derive from lymphoid stem cells in the bone marrow and mature under the influence of the thymus. A. T lymphocytes are identified by surface antigens (T3, T4, T8, and T11). 1. T lymphocytes are divided into two major subsets that express either CD4 or CD8 protein on their surface. CD4+ and CD8+ T cells depend on different signaling pathways to support their development and survival. B. T lymphocytes are the predominant lymphocytes in the peripheral blood and reside in well-defined interfollicular areas in lymph nodes and spleen.

21

Immunobiology

TABLE 1.6  Host Effector Mechanisms Name Soluble Effectors Complement system Coagulation system Kinin system Antibodies

Properties

Effector Mechanisms

Proteolytic cascade, activated by antibody, directly by microbial components, or via PRRs Proteolytic cascade, activated by tissue and vascular damage Proteolytic cascade triggered by tissue damage

Direct destruction of pathogens via pore formation; recruit inflammatory cells; enhance phagocytosis and killing Prevents blood loss; bars access to bloodstream; proinflammatory Proinflammatory; causes pain response; increases vascular permeability to allow increased access to plasma proteins Directly neutralize pathogens; activate complement; opsonize pathogens to enhance phagocytosis and killing

Antigen-specific proteins produced by B cells; recognize a broad range of antigens

Cellular Effectors Monocyte/macrophage dendritic cell Neutrophil Eosinophil Basophil/mast cell NK cell

B lymphocyte T lymphocyte

Have PRRs to recognize pathogens; activated by specific T cells and chemokines Have PRRs to recognize pathogens, activated antibody and complement Recognize antibody-coated parasites Associated with IgE-mediated responses

Phagocytosis and microbial killing via multiple mechanisms; antigen presentation Phagocytosis and microbial killing via multiple mechanisms Killing of multicellular pathogens Release of granules containing histamine and other mediators of anaphylaxis Induce death of infected cells via membrane pores and induced apoptosis

Lymphocyte lacking antigen-specific reactivity; recognize PAMPs of intracellular pathogens, activated by chemokines and by membrane proteins of infected cells Recognize antigens presented by APCs; regulated by T cells and chemokines Recognize antigens presented by APCs; regulate major portions of both adaptive and innate immunity

Produce antibody Directly kill infected cells via membrane pores and induced apoptosis; activate macrophages; many other functions

APCs, antigen-presenting cells; PAMPs, pathogen-associated molecular patterns; PRRs, pattern-recognition receptors. (Reproduced from Table 3.1, Coleman WB, Tsongalis GJ, eds: Molecular Pathology. Burlington, MA, Academic Press. © 2009, Elsevier Inc. All rights reserved.)









C. The T-lymphocyte system is responsible for the recognition of antigens on cell surfaces and, thus, monitors self from nonself on live cells (Fig. 1.26). D. The MHC (HLA) system allows T cells to recognize foreign antigen in cells and then, aided by macrophages, mobilizes helper T cells to make killer T cells to destroy the antigen-containing cells. E. T lymphocytes, therefore, initiate cellular immunity (delayed hypersensitivity), are responsible for graftversus-host reactions, and initiate the reactions of the body against foreign grafts such as skin and kidneys (host-versus-graft reactions). F. When activated (by an antigen), they liberate lymphokines such as macrophage inhibition factor (MIF), macrophage activation factor (MAF), interferon (IFN), and interleukins IL-2 (previously called T-cell growth factor), IL-3, and IL-15 (Fig. 1.27). The proliferation and differentiation of T lymphocytes are regulated by cytokines that act in combination with signals induced by the engagement of the T-cell antigen receptor. A principal cytokine is IL-2, itself a product of activated T cells. IL-2 also stimulates B cells, monocytes, lymphokine-activated killer cells, and glioma cells. Another growth factor that stimulates

Thymus-derived precommitted lymphocyte

Aggregated antigen A

B

E

Macrophage

C

Lymphoblast

D

Sensitized lymphocyte

Fig. 1.26  Cellular immunity. A, The participants in the cellular immune response include the thymus-derived precommitted lymphocyte (T cell), bone marrow-derived monocyte (macrophage), and the aggregated antigens. B, Aggregated antigen is seen attaching to the surface of the macrophage. C, The T cell is shown as it attaches to the aggregated antigen. D, The substance originating in the macrophage passes into the T cell, which is attached to the antigen. E, The combined T cell, antigen, and macrophagic material causes the T cell to enlarge into a lymphoblast. Sensitized or committed T lymphocytes arise from lymphoblasts. (From Yanoff M, Fine BS: Ocular Pathology: A Color Atlas, 2nd edn. New York, Gower Medical. © Elsevier 1992.)

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CHAPTER 1  Basic Principles of Pathology

Sensitized T lymphocyte Uncommitted lymphocyte Polymorphonuclear lymphocyte

Aggregated antigen

Thymus-derived lymphocyte

Macrophage

Bone marrowderived lymphocyte

A Monocyte

Capillary

Immunoglobulin (antibody)

Antigen Tuberculosis organisms within macrophage A

Plasma cell

B B

C

D

Fig. 1.27  Cellular immunity. A, Sensitized T lymphocytes (SL) are seen in a capillary. Along with the SL are other leukocytes, including monocytes, at an antigenic site. A macrophage, which contains tubercle bacilli and antigen, may be seen in the surrounding tissue. B, Monocytes become sensitized when cytophilic antibody from SL is transferred to them. They migrate toward the antigenic stimulus. C, Biologically active molecules, which cause the monocytes and leukocytes to travel to the area, are released by SL when they have encountered a specific antigen. D, Monocytes arriving at the site are immobilized by migration inhibitory factor (MIF), which is released by SL, which also release cytotoxin and mitogenic factor. Cytotoxin causes tissue necrosis (caseation), and mitogenic factor causes proliferation of cells. Some of these cells undergo transformation, becoming epithelioid cells, causing the formation of a tuberculoma. (From Yanoff M, Fine BS: Ocular Pathology: A Color Atlas, 2nd edn. New York, Gower Medical. © Elsevier 1992).

the proliferation of T lymphocytes, the cytokine IL-15, competes for binding with IL-2 and uses components of the IL-2 receptor. T lymphocytes will not go “into action” against an “enemy” unless they are triggered by several signals at once. When one of the signals needed is lacking, the T cell becomes “paralyzed” (anergy).



G. T lymphocytes also regulate B-cell responses to antigens by direct contact and by the release of diffusible factors that act as short-range stimulators of nearby B cells. H. Many reactions in cellular immunity are mediated by lymphocyte-derived soluble factors known collectively as lymphokines, which exert profound effects on inflammatory cells such as monocytes, neutrophils, and lymphocytes. Such action falls into three main categories: (1) effects on cell motility (migration inhibition, chemotaxis, and chemokinesis); (2) effects on cell proliferation or cellular viability; and (3) effects on cellular activation for specific specialized functions. V. The B lymphocyte also arises from lymphoid stem cells in the bone marrow, but it is not influenced by the thymus. A. It resides in follicular areas in lymphoid organs distinct from the sites of the T lymphocyte.

B. The B-lymphocyte system is characterized by an enormous variety of immunoglobulins having virtually all conceivable antigenic specificities that are capable of being recognized by at least a few B-lymphocyte clones.

After germinal center B cells undergo somatic mutation and antigen selection, they become either memory B cells or plasma cells. CD40 ligand directs the differentiation of germinal center B cells toward memory B cells rather than toward plasma cells.





C

Fig. 1.28  Humoral immunity. A and B, Four prerequisites for immunoglobulin formation are demonstrated, including thymus-derived lymphocyte (T cell), thymus-independent bone marrow-derived lymphocyte (B cell), bone marrow-derived monocyte (macrophage), and aggregated antigen. In A, aggregated antigens are seen attached to macrophages. In B, T and B cells are seen attached to different determinants on the aggregated antigen. C, Cooperative interaction that occurs between T and B cells causes the B cells to differentiate into plasma cells. (From Yanoff M, Fine BS: Ocular Pathology: A Color Atlas, 2nd edn. New York, Gower Medical. © Elsevier 1992.)

C. The system is well designed to deal with unpredictable and unforeseen microbial and toxic agents. D. The B lymphocyte can be stimulated by antigen to enlarge, divide, and differentiate to form antibody-secreting plasma cells (Fig. 1.28). In most circumstances, T lymphocytes collaborate with B lymphocytes during the induction of antibodyforming cells by the latter (see the section on humoral immunoglobulin, later).

VI. Null lymphocytes, which constitute approximately 5% of lymphocytes in peripheral blood, lack the surface markers used to identify T and B lymphocytes. A. Most null cells carry a surface receptor for the Fc portion of the immunoglobulins, can function as killer cells in antibody-dependent cell-mediated cytotoxicity, and are called NK cells.

Immunobiology



B. When stimulated, NK cells release perforin, which forms pores in the cell membrane. C. They also release substances through the pores that can precipitate apoptosis in the target cell. VII. Initially, the sheep red blood cell resetting test (especially with fixed, embedded tissue) and the immunofluorescence or immunoperoxidase techniques that demonstrate surface immunoglobulins were the principal techniques for identification of T or B lymphocytes, respectively. A. Now, monoclonal antibodies (especially with fresh tissue) are used for the localization of lymphocyte subsets in tissue sections, and their use has revolutionized research in immunology, cell biology, molecular genetics, diagnosis of infectious diseases, tumor diagnosis, drug and hormone assays, and tumor therapy. B. A myriad of different types of monoclonal antibodies now exist, and new ones are continuously being created. C. Monoclonal antibodies can be obtained against B and T lymphocytes, monocytes, Langerhans’ cells, keratins, type IV collagen, retinal proteins (e.g., human S-100), and tumor antigens (e.g., factor VIII and intermediate filaments—cytokeratins, vimentin, desmin, neurofilaments, and glial filaments—neuron-specific enolase, and glial fibrillary acidic protein; all may be found in tumors).

Cellular Immunity (Delayed Hypersensitivity) I. Two distinct cell types participate in cellular immunity: the T lymphocyte and the macrophage (histiocyte). A. Phagocytic cells of the monocytic line (monocytes, reticuloendothelial cells, macrophages, Langerhans’ dendritic cells, epithelioid cells, and inflammatory giant cells—all are different forms of the same cell) are devoid of antibody and immunologic specificity. 1. Macrophages, however, have the ability to process proteins (antigens) and activate the helper T cells. 2. Macrophages also secrete proteases, complement proteins, growth-regulating factors (e.g., IL-1), and arachidonate derivatives. B. All lymphocytes seem to be pre-committed to make only one type of antibody, which is cell-bound.

23

II. The delayed hypersensitivity reaction begins with perivenous accumulation of sensitized lymphocytes and other MN cells (i.e., monocytes, which constitute 80%–90% of the cells mobilized to the lesion). The infiltrative lesions enlarge and multiply (e.g., in tuberculosis, where the lesions take a granulomatous form), and cellular invasion and destruction of tissue occur. III. Delayed hypersensitivity is involved in transplantation immunity; in the pathogenesis of various autoimmune diseases (e.g., sympathetic uveitis); and in defense against most viral, fungal, protozoal, and some bacterial diseases (e.g., tuberculosis and leprosy). Perhaps the most important role is to act as a natural defense against cancer—that is, the immunologic rejection of vascularized tumors and immunologic surveillance of neoplastic cells.

Humoral Immunoglobulin (Antibody) I. Four distinct cell types participate in humoral immunoglobulin (antibody) formation: the T lymphocyte, the B lymphocyte, the monocyte (macrophage), and the plasma cell. A. Macrophages process antigen in the early stage of the formation of cellular immunity and secrete IL-1. B. Specifically, pre-committed cells of both T and B lymphocytes attach to different determinants of the antigen; T cells then secrete a B-cell growth factor (BCGF). C. BCGF and IL-1 evoke division of triggered B cells, which then differentiate and proliferate into plasma cells that elaborate specific immunoglobulins. All humoral immunoglobulins (antibodies) are made up of multiple polypeptide chains and are the predominant mediators of immunity in certain types of infection, such as acute bacterial infection (caused by streptococci and pneumococci) and viral diseases (hepatitis). II. The B lymphocyte, once a specific antigen causes it to become committed (sensitized) to produce an immunoglobulin, makes that immunoglobulin and none other, as does its progeny. It, or its progeny, may produce immunoglobulin or become a resting memory cell to be reactivated at an accelerated rate (anamnestic response) if confronted again by the same antigen. Table 1.7 enumerates the immunoglobulin classes and functions produced by B cells.

TABLE 1.7  Antibody Classes and Functions Class

Location*

Structure

Function

IgD IgM

Surface of B cells only Plasma

IgG

Widely distributed in extracellular fluid Mucosal tissues, surfaces, and secretions Bound to mast cells and basophils

2 κ or λ light chains, 2 δ heavy chains 2 κ or λ light chains, 2 µ heavy chains, arranged in pentamers with 1 J chain 2 κ or λ light chains, 2 γ heavy chains

Unknown; expressed early in differentiation along with IgM Activated complement; first functional immunoglobulin formed in immune response Complement activation, transfer to neonate via placenta, opsonization, neutralization of viruses and other pathogens Important in mucosal immunity; has opsonizing activity

IgA IgE

2 κ or λ light chains, 2 α heavy chains, arranged in dimers with 1 J chain 2 κ or λ light chains, 2 ε heavy chains

Binds to and activates mast cells and basophils; important in defense versus parasites

*All immunoglobin classes are found on B cells as antigen receptors. (Reproduced from Table 3.2, Coleman WB, Tsongalis GJ, eds: Molecular Pathology. Burlington, MA, Academic Press. © 2009, Elsevier Inc. All rights reserved.)

24

CHAPTER 1  Basic Principles of Pathology

Autoimmunity and Autoinflammation I. Autoimmune diseases are caused by abnormalities in adaptive immunity regulation, while autoinflammatory disorders are attributed to defects in innate immunity proteins and are characterized by the absence of pathogenic autoantibodies or autoreactive T cells. In both situations, the patient’s own immunological systems becomes a source of tissue damage rather than its protector. II. Monogenic autoinflammatory syndromes have been defined as inherited conditions caused by mutations in one or both copies of a single gene that result in over-activation of the innate immune system causing inappropriate inflammation. A. Appear to be unprovoked attacks of inflammation most commonly directed at the eye, skin, joints, and gut. B. Mechanisms by which genetic defects cause autoinflammatory disease: 1. Affect intracellular sensor function. 2. Lead to accumulation of intracellular triggers that cause cell stress and activate intracellular sensors. 3. Cause loss of a negative regulator of inflammation. 4. Affect signaling molecules that upregulate innate immune cell function. C. Mediated by IL-1 secretion stimulated by monocytes and macrophages. D. Induction of inflammation in many of these disorders is triggered by the inflammasome pathway (see discussion above regarding inflammasomes, pyroptosis, and associated monogenic ocular disorders). E. IL-1 secretion in response to Toll-like receptor stimulation, and ultimately, the triggering of NLRP3 inflammasome may occur not only in response to exogenous microbial stimulation, but also to “endogenous stress molecules” by setting off an autoinflammatory process. F. Other monogenic autoinflammatory disorders arise from perturbations in signaling by the transcription factor NF-κB, ubiquitination, cytokine signaling, protein folding, and type I interferon production, and complement activation. G. Some immunologic diseases have combined features of autoinflammation, autoimmunity, and/or immunodeficiency.

A



H. Monogenic autoinflammatory syndromes include idiopathic granulomatous diseases, familial Mediterranean fever (FMF), TNF receptor–associated periodic syndrome (TRAPS), deficiency of mevalonate kinase (MKD), cryopyrin-associated periodic fever syndrome (CAPS, consisting of familial cold autoinflammatory syndrome or FCAS, Muckle–Wells syndrome or MWS, and chronic infantile neurologic cutaneous articular syndrome or CINCA syndrome). III. The eye is considered an immunologically privileged site due to 1) absence of blood and lymphatic vessels in the anterior chamber, 2) anterior chamber–associated immune deviation (ACAID) that controls the proinflammatory milieu, and 3) retinal protection identified in phagocytosis of damaged receptors and retinal pigment epithelium, which also helps construct part of the blood–retinal barrier through its tight intercellular junctions. Another important component of the blood–retinal barrier resides in the tight junctions between retinal vascular endothelial cells. Nevertheless, autoimmune disorders do occur and may have devastating consequences. A. A particularly devastating but, fortunately, rare autoimmune disorder is sympathetic ophthalmia in which the ocular immune barriers are breached, and autoimmunity develops to uveal protein resulting in a delayed hypersensitivity reaction characterized by diffuse granulomatous inflammation involving the entire uveal tract in both the inciting and sympathizing eyes.

Immunohistochemistry I. As stated previously, monoclonal antibodies can be obtained against B and T lymphocytes, monocytes, Langerhans’ cells, keratins, type IV collagen, retinal proteins, and so forth (Figs. 1.29 and 1.30). Table 1.8 lists antibody tests that are helpful in differentiating various tumors when they lack sufficient differentiation for accurate microscopic diagnosis. II. Commonly used antibodies include the following: A. Cytokeratins (AE1/AE3, CAM 5.2, CK7, and CK20) and epithelial membrane antigen are markers for epithelia. B. Factor VIII and Ulex europaeus-1 are markers for vascular endothelia.

B Fig. 1.29  Immunocytochemistry. A, Cathepsin-D, which here stains cytoplasm of conjunctival submucosal glands (shown under increased magnification in B), is an excellent stain for lipofuscin.

Immunobiology

A

B

C

D

25

Fig. 1.30  Immunocytochemistry. A, Monoclonal antibody against desmin, one of the cytoskeletal filaments, reacts with both smooth and striated muscles, and it helps to identify tumors of muscular origin. B, Monoclonal antibody against λ chains in plasma cells. C and D, Polyclonal antibody against S-100 protein in melanocytes and Langerhans’ cells in epidermis (C) and in malignant melanoma cells (D). (From Schaumberg-Lever G, Lever WF: Color Atlas of Pathology of the Skin. Philadelphia, Lippincott, 1988, with permission.)

C. Intermediate filaments: Vimentin is a marker for mesenchymal cells, including smooth muscle, Schwann cells, histiocytes, and fibrocytes; desmin is a marker for smooth and striated muscles; cytokeratin is a marker for epithelia; neurofilament is a marker for neurons; and glial fibrillary acidic protein is a marker for astrocytes and Schwann cells. D. Neuron-specific enolase is a marker for Schwann cells, neurons, smooth muscle, and neuroendocrine cells. E. S-100 is a marker for neural crest-derived tissues including melanocytes, but only melanocytic tumors should be positive for HMB45 and Mel-A. F. Smooth muscle actin (SMA) is a marker for smooth muscles and myoepithelial cells. G. Many antibodies are available for immunophenotyping of lymphomas and leukemias, both on fresh and on paraffin-embedded tissue. Table 1.9 lists the immunohistochemical paradigm for differentiating hematolymphoid neoplasms. H. Many other markers are available, and new markers seem to appear almost weekly. 1. Useful websites for further information regarding immunohistochemical stains and techniques include the following: a. http://www.immunoquery.com

2. Throughout this textbook, appropriate key immunohistochemical markers are cited where appropriate for each histopathologic diagnosis. 3. Similarly, although genetics is not the focus of this textbook, critical genetic abnormalities are highlighted as appropriate.

Immunodeficiency Diseases I. The following are disorders associated with immunodeficiency discussed elsewhere in this textbook: A. Wiskott–Aldrich syndrome (see Chapter 6) B. Ataxia–telangiectasia (see Chapter 2) C. Chédiak–Higashi syndrome (see Chapter 11) II. Severe combined immunodeficiencies (SCIDs)—heterogeneous group of inherited disorders characterized by 1) absence or very low number of T cells (T, p.(Arg574Cys) c.3227C>T, p.(Arg1093Cys) Unknown COL1A1, COL1A2 ADAMTS2 PLOD1 FKBP14 ZNF469 PRDM5 β4GALT7 β3GALT6 SLC39A13 CHST14 DSE COL12A1 C1R C1S

Tenascin XB Type I collagen Type III collagen Type I collagen

Unknown Type I collagen ADAMTS-2 LH1 FKBP22 ZNF469 PRDM5 β4GalT7 β3GalT6 ZIP13 D4ST1 DSE Type XII collagen C1r C1s

AD, autosomal dominant; AR, autosomal recessive; IP, inheritance pattern; NMD, nonsense-mediated mRNA decay. (From Malfait et al.: The 2017 International Classification of the Ehlers–Danlos Syndromes. Am J Med Genet Part C (Seminars in Medical Genetics) 175C:8–26, 2017. Wiley.)

Pseudoxanthoma Elasticum I. Pseudoxanthoma elasticum (PXE) is inherited in an autosomal-recessive manner. A. The classic triad is involvement of the skin, the eyes, and the cardiovascular system. The gastrointestinal tract also may be involved. B. Linkage analysis and mutation detection techniques have shown mutations in the ATP-binding cassette (ABC) transporter gene ABCC6 on chromosome 16. 1. ABCC6 gene mutations account for 90%–95% of affected individuals. 2. A PXE-like disease has been identified that has coagulation factor deficiencies. a. It is caused by mutations in the gamma-glutamyl carboxylase (GGCX) gene. b. This mutation also points up the importance of vitamin-dependent inhibitors of mineralization, such as matrix Gla protein (MGP). 3. ABCC6 and GGCX genes may interact with GGCX acting as modifiers of ABCC6. 4. Mutations in the ENPP1 gene, which codes for the enzyme ectonucleotide pyrophosphatase phosphodiesterase 1, also may interact with ABCC6. ENPP1 mutations may cause a rare form of PXE.







5. There probably are other genetic or environmental modifiers to induce phenotypic variability in PXE. C. The prevalence is between 1 : 25,000 and 1 : 100,000. D. The skin of the face, neck, axillary folds, cubital areas, inguinal folds, and periumbilical area (often with an umbilical hernia) becomes thickened and grooved, with the areas between the grooves diamond-shaped, rectangular, polygonal, elevated, yellowish (resembling chicken skin) papules. 1. The lateral side is affected first, often followed by the axillae. 2. The skin in the involved areas becomes lax, redundant, and relatively inelastic. 3. The skin changes may not be noted until the second decade of life or later. E. The ocular fundus shows angioid streaks (see Fig. 11.40), sometimes with subretinal neovascularization (see discussion in Chapter 11). 1. In one study, angioid streaks were found in 93.75% of patients. 2. Neovascularization occurred at a mean age of 44.28 years. It is frequent and is associated with poor vision. a. Examination of the fundus also may show a background pattern, called peau d’orange, in the

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CHAPTER 6  Skin and Lacrimal Drainage System

A

B

C

D Fig. 6.16  Cutis laxa. A, Pulling easily extends loose skin of face. B, Corneal opacities occur in all layers of stroma. C, Skin appears relatively normal at low magnification. D, Verhoeff’s elastica stain shows fragmentation and granular degeneration of dermal elastic tissue. (A and B, Courtesy of Dr. JA Katowitz.)

posterior aspect of the eyes, caused by multiple breaks in Bruch’s membrane. b. The optic nerve may contain drusen, which were found in 16.9% of patients in one study. Drusen of the optic nerve occur 20 to 50 times more often in pseudoxanthoma elasticum than in the general, healthy population. F. There is increased risk of atherosclerosis. Cardiovascular system manifestations include increased risk of stroke, hypertension, weak or absent peripheral pulses, intermittent claudication, angina pectoris, and internal hemorrhages. II. There is progressive calcification of connective tissue rich in elastic fibers. The basic defect seems to be related to progressive calcification. III. Histologically, the amount of elastin is elevated. A. The skin shows elastin abnormalities only in the midepidermis, with elastin band swelling, granular degeneration, and fragmentation. B. The elastin fibers may become calcified. C. Normal elastin and collagen is present above and below the affected zone. D. Clumping and calcification of elastin are only present in homozygous individuals and only in clinically affected skin.

E. Angioid streaks consist of breaks in Bruch’s membrane. IV. Transmission electron microscopic (TEM) evaluation demonstrates aberrant elastic fibers with an irregular outline and heterogenic inner structures. A. Collagen fibers have normal structure with irregular distribution. B. Scanning electron microscopy shows disorganization of collagen fibers and small “stone-like” deposits that measure 5 µm associated with bigger structures ranging from 10–15 µm. C. The smaller structures have a polyhedral shape or are squared. D. These structures have been interpreted as representing altered elastic fibers seen on TEM.

Erythema Multiforme I. Erythema multiforme (EM), an acute, self-limited dermatosis, is a common-pathway, cutaneous reaction to drugs, viral or bacterial infections, or unknown causes. More than 90% of EM is caused by infections, especially herpesvirus infection; however, Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are related to drugs in more than 95% of cases (see below). II. Erythema multiforme shows multiform lesions of macules, papules (most common lesion), vesicles, and bullae.

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185

TABLE 6.3  Differential Diagnosis of SJS/TEN Disease

Mucositis

Morphology

Onset

Drug-induced pemphigoid Staphylococcal scalded skin syndrome Drug-induced pemphigus Drug-triggered pemphigus Paraneoplastic pemphigus Acute graft versus host disease Acute generalized exanthematous pustulosis Drug-induced linear IgA bullous dermatosis

Rare Absent Usually absent Present Present (usually severe) Present Rare Rare

Tense bullae, sometimes hemorrhagic Erythema, skin tenderness, perioral crusting Erosions, crusts, patchy erythema Mucosal erosions, flaccid bullae Polymorphous skin lesions, flaccid bullae Morbilliform rash, bullae, and erosions Superficial pustules (resembles pustular psoriasis) Tense, subepidermal bullae (resembles pemphigoid)

Acute Acute Gradual Gradual Gradual Acute Acute Acute

(From Kohanim et al.: Stevens Johnson syndrome/toxic epidermal necrolysis-A comprehensive review and guide to therapy. I. Systemic Disease. The Ocular Surface 14(1):2–19, 2016. Table 3. Elsevier.)

Characteristic “target” lesions are noted as round to oval erythematous plaques that contain central darkening and marginal erythema.

III. Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are often viewed as ends of a continuum and are discussed concurrently (Table 6.3). A. Mortality rates may be as high as 35%. B. They are characterized in the acute phase by a febrile cold-like illness followed by skin and mucous membrane necrosis and detachment. C. The associated keratinocyte death and epidermal necrosis result in splitting of the subepidermal layers with resulting loss at skin and mucosal surfaces. D. These changes are described as rapid and irreversible, and may lead to severe morbidity and even death. E. Classification 1. If less than 10% of the body surface area (BSA) is involved the disease is termed SJS. 2. If greater than 30% of the BSA is involved it is TEN. 3. Those patients with BSA involvement between 10% and 30% are categorized as having SJS-TEN overlap. F. The worldwide incidence of SJS and TEN is estimated to be 1.9 per million individuals. G. They are delayed hypersensitivity reactions. 1. There are genetic predispositions to these disorders, which commonly are precipitated by medications, particularly cold medications such as dipyrone, NSAIDs and cold medication ingredients such as acetaminophen. 2. Viral infections also may be involved, and have been postulated to predispose patients to medication reactions by altering the inflammatory and immunologic homeostasis. 3. The genetic risk factors are drug-specific, and vary among populations and/or ethnic groups. 4. Younger patient age, and patient exposure to NSAIDS or cold remedies may be predictive of acute ocular severity. 5. SJS/TEN also may be triggered by malignancies. H. The keratinocyte apoptosis seen in SJS/TEN is thought to occur through T-cell mediated Fas-Fas ligand, perforin/

granzyme B, tumor necrosis factor-alpha, and nitric oxide. I. The incidence of ocular involvement in the acute phase has been reported to be 60%–100%. 1. The spectrum of ocular involvement may range between conjunctiva hyperemia and massive sloughing of the ocular surface epithelium. 2. A final blinding result of SJS/TEN may be from end-stage corneal changes associated with symblepharon formation, ocular xerosis, limbal stem cell deficiency, etc. J. Although the focus of discussion tends to be on ocular and cutaneous complications of SJS/TEN, other systems that may be significantly affected are the respiratory, gastrointestinal/hepatic, oral, otorhinolaryngologic, gynecologic/genitourinary, and renal systems. K. Even after they recover from skin involvement, some SJS/TEN patients continue to suffer with severe ocular complications. 1. Increased levels of inflammatory oxylipins are found on plasma lipid profiling in these patients with severe ocular complications. 2. Oxidized phosphatidylcholines and ether-type diacylglycerols also are found in patients with chronic severe ocular complications, while phosphoglycerolipids decrease. 3. Moreover, decreased levels of ether-type phosphatidylcholines containing arachidonic acid are found in these patients, and are the most specific plasma lipid alterations for them. L. Serum IL-17 levels may have prognostic and diagnostic value in these patients. M. Neutrophilic infiltrate is present in mildly inflamed or clinically quiescent conjunctival mucosa in patients with SJS-TEN where neutrophil numbers inversely correlate with disease duration. N. The following are discussions of SJS and TEN viewed as entities at the extremes of a spectrum. IV. Stevens–Johnson syndrome (SJS) is a severe form of erythema multiforme, starting suddenly with high fever and prostration and showing predominantly a bullous eruption of the skin and mucous membranes, including conjunctiva. The systemic syndrome may lead to death.

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CHAPTER 6  Skin and Lacrimal Drainage System

A. Conjunctival microbial flora is increased in SJS so that bacterial cultures are positive in 59% of affected eyes compared to healthy controls. The most common organisms isolated are coagulase-negative staphylococci followed by Corynebacteria species and Staphylococcus aureus. B. Histologic findings 1. In the skin of Stevens–Johnson syndrome, a dense lymphohistiocytic inflammation obscures the dermoepidermal junction and is associated with progressive necrosis of keratinocytes from the basilar to the uppermost portions of the epidermis. 2. In the conjunctiva, epithelial goblet cells and openings of the accessory lacrimal glands may be destroyed, leading to marked drying of the conjunctiva and epidermidalization. 3. Both intraepidermal and subepidermal vesiculation may lead to severe scarring, including symblepharon and entropion. 4. The cellular infiltrate consists largely of lymphocytes, mainly T4 (helper) cells in the dermis and T8 (cytotoxic) cells in the epidermis. 5. Conjunctival scarring may result in the sequestration of conjunctival epithelium that may lead to diverticulum formation and subsequent chronic relapsing conjunctivitis. V. Toxic epidermal necrolysis A. Toxic epidermal necrolysis (TEN) (Lyell’s disease; epidermolysis necroticans combustiformis; acute epidermal necrolysis; scalded-skin syndrome) really consists of two different diseases, Lyell’s disease (subepidermal type or true toxic epidermal necrolysis—probably a variant of severe erythema multiforme), and Ritter’s disease (subcorneal type or staphylococcal scalded-skin syndrome— not related to toxic epidermal necrolysis). B. TEN (Lyell’s disease) is probably a variant of severe erythema multiforme, frequently occurs as a drug allergy, often overlaps with Stevens–Johnson syndrome, and histologically resembles the epidermal type of erythema multiforme. C. Staphylococcal scalded-skin syndrome (Ritter’s disease) is not related to erythema multiforme, occurs largely in the newborn and in children younger than 5 years, and occurs as an acute disease. 1. Its onset begins abruptly with diffuse erythema accompanied by severe malaise and high fever. 2. Large areas of epidermis form clear fluid-filled, flaccid bullae, which exfoliate almost immediately, so that the denuded areas resemble scalded skin. Phage group II staphylococci are absent from the bullae but are present at a distant site (e.g., purulent conjunctivitis, rhinitis, or pharyngitis). The bullae are caused by a staphylococcal toxin called exfoliatin.

3. The mortality may be as high as 25%–50%.



D. Histologically, most cases of TEN show a severe degeneration and necrosis of epidermal cells resulting in detachment of the entire epidermis (flaccid bullae). In the acute stage, it is considered a T-cell mediated, type IV hypersensitivity disorder.

Epidermolysis Bullosa I. Epidermolysis bullosa hereditaria (mechanobullous diseases) (EB) includes a group of rare, inherited, noninflammatory, nonimmunologic diseases characterized by the susceptibility of the skin to blister after even mild trauma. The prevalence of EB varies from 8.22 to 60 per 1 million with an incidence of 19.6 to 50 per 1 million live births. A. More than 100 mutations in more than 15 structural genes encoding several structural proteins have been associated with various subtypes of EB. B. Each of the subtypes of inherited EB is defined by its mode of transmission, and a combination of phenotypic, ultrastructural, immunohistochemical and molecular findings. C. Inherited EB is divided into EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler syndrome. Fig. 6.17 illustrates the histological level of tissue splitting, for each type of inherited EB and the associated protein. In general, the use of eponyms has decreased for these disorders. 1. EBS (previously referred to as epidermolytic EB) represents all subtypes of EB having mechanical fragility and blistering confined to the epidermis. It is further subdivided into suprabasal and basal subgroups based on the histopathologic suite of cleavage. 2. JEB refers to all subtypes of EB in which blisters develop within the mid portion or junction (lamina lucida) of the skin basement membrane zone (BMZ). a. Underlying the plasma membrane of the basal epithelial cells is a comparatively electron-lucent zone, the lamina lucida, which separates the trilaminar plasma membrane (approximately 8 nm wide) from the medium-dense basement membrane (lamina densa). 3. DEB (previously referred to as dermolytic EB) encompasses all EB subtypes in which blistering occurs within the uppermost dermis, which is beneath the lamina densa of the skin BMZ. It is divided into dominant and recessive subtypes. 4. Kindler syndrome is characterized by the presence of clinical phenotype features of photosensitivity and blistering that arises in multiple levels within and/ or beneath the BMZ, rather than within a discrete plane. Associated skin changes later in life are termed poikiloderma. D. The inheritance for EBS is thought be autosomal dominant and JEB is autosomal recessive. Dystrophic EB can have either an autosomal dominant or autosomal recessive inheritance pattern, and Kindler syndrome has autosomal recessive inheritance.

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Fig. 6.17  A schematic representation of the epidermis, the skin basement membrane zone, the location of specific proteins pertinent to the pathogenesis of epidermolysis bullosa (EB), and the level in which blisters develop in different EB types. The scheme depicts the cell layers of the epidermis, the basal keratinocytes, and above them the suprabasal keratinocyte layers (spinous and granular layers), which are covered by the horny layer (pink). The epidermis is attached to the dermis by the bilayered basement membrane consisting of lamina lucida and lamina densa (red bar). On the left, the level of blister formation is indicated. In EB simplex (EBS) suprabasal, the blisters form within the middle/upper epidermal layers, depending on which protein is mutated. In EBS basal, the cleavage plain is within the basal keratinocytes. In junctional EB (JEB), the separation takes place within the lamina lucida, and in dystrophic EB (DEB), within the sublamina densa region within the uppermost dermis. In Kindler syndrome (KS), cleavage can occur within the basal keratinocytes, at the level of the lamina lucida or below the lamina densa. On the right, the localizations of the relevant mutated proteins are indicated. Transglutaminase 5 is present in the uppermost cell layers of the epidermis. Plakoglobin and desmoplakin are desmosomal proteins that are panepidermal, compared with plakophilin 1, which is expressed mainly in the suprabasal epidermis. Keratins 5 and 14, plectin, BP230, exophilin 5 and kindlin-1 are found mainly within the basal keratinocytes. Integrin α6β4, integrin α3, and collagen XVII are transmembrane proteins with extracellular domains emanating from the plasma membrane of the basal keratinocytes into the lamina lucida. Laminin 332 is a lamina lucida protein and collagen VII, the major component of the anchoring fibrils, is found in the sublamina densa region. (From Fine et al.: Inherited epidermolysis bullosa: Updated recommendations on diagnosis and classification. J Am Acad Dermatol 70(6):1103–1126, 2014. Figure 1. Elsevier.)

II. Ocular complications (especially in recessive epidermolysis bullosa) include loss of eyelashes, obstruction of the lacrimal ducts, and epiphora. A. The incidence of ocular complications varies among EB subtypes. B. They are most severe in the dystrophic recessive and junctional subtypes; however, they also may be significant in Kindler syndrome. C. Late complications include cicatricial ectropion, exposure keratitis, recurrent corneal erosions and ulcers, and even corneal perforation. D. Most children with EB exhibit signs of meibomian gland dysfunction. III. Histologically, according to the different types, blisters can form at various levels in the epidermis. A. The use of immunofluorescence antigen mapping (IFM) and/or targeted next-generation sequencing multi-gene panel in combination can be very helpful, particularly for resolving unusual phenotypes.

1. IFM helps determine the precise level of skin cleavage using monoclonal antibodies to EB-specific basement membrane zone protein.

Contact Dermatitis I. The most common cause of periorbital dermatitis is contact allergy (54%), followed by atopic dermatitis (25%), periorbital rosacea (5%), periorbital psoriasis vulgaris (2%), and allergic conjunctivitis (2%). A. Female gender, atopic skin diathesis, and age over 40 years are risk factors for periorbital dermatitis. II. Contact dermatitis includes a spectrum of reactions including irritant contact dermatitis, allergic contact dermatitis, contact urticaria, phototoxic contact dermatitis, and photoallergic contact dermatitis. A. Irritant contact dermatitis is the most common around the face, and is reflected in erythematous, burning, pruritic skin that may develop microvesiculation and later desquamation.

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1. There is stratum corneum damage without immunologic manifestations. 2. Once damaged, the stratum corneum loses its protective function so that anything subsequently applied may heighten the response and appear, falsely, to generate an allergy to that second product. B. Allergic contact dermatitis is the second most common type of contact dermatitis (Box 6.1). 1. It may manifest in a manner similar to irritant contact dermatitis, although when it is acute it may produce more vesiculation. 2. It is immunologically based and depends upon antigen-processing cells independent of the condition of the protective stratum corneum. C. Contact urticaria may be an immunologic or nonimmunologic reaction that is characterized by the development of a wheal-and-flare response to topically applied products (Table 6.4). 1. Some products may elicit this response by the direct stimulation of histamine without an immunologic response per se. Other products may require prior sensitization.







Anterior subcapsular cataracts (usual form) and posterior subcapsular cataracts (rare form) seem to occur with increased frequency in patients who have a history of atopia.

BOX 6.1  Sources of Allergic Contact

Dermatitis in Skin Care Products and Cosmetics Fragrances Preservatives P-phenylenediamine (permanent hair dyes) Lanolin (moisturizers) Glyceryl thioglycolate (permanent wave solutions) Propylene glycol (moisturizers) Toluenesulfonamide/formaldehyde resin (nail polishes) Sunscreens

(From Draelos ZD: Facial skin care products and cosmetics. Clin Dermatol 32:809–812, 2014. Table 2. Elsevier.)

TABLE 6.4  Contact Urticaria Inducing Skin

Care and Cosmetic Ingredients Nonimmunologic

Immunologic

Acetic acid Alcohols Balsam of Peru Benzoic acid Cinnamic acid Cinnamic aldehyde Formaldehyde Sodium benzoate Sorbic acid

Acrylic monomer Alcohols Ammonia Benzoic acid Benzophenone Diethyltoluamide Formaldehyde Henna Menthol Parabens Polyethylene glycol Polysorbate 60 Salicylic acid Sodium sulfide

(From Draelos ZD: Facial skin care products and cosmetics. Clin Dermatol 32:809–812, 2014. Table 3. Elsevier.)

D. Phototoxic and photoallergic dermatitis are found in light exposed areas. 1. Phototoxic reactions are nonimmunologically based, and result from products that more readily absorb ultraviolet A radiation. 2. Photoallergic dermatitis is less common, and is immunologically based. Therefore, it usually requires repeat exposure. a. Clinically appears as erythema, edema, and vesiculation. E. Eyedrops, particularly atropine and brimonidine, and associated preservatives, may produce contact dermatitis. Additionally, any medication placed on the eye gains access to the systemic circulation following drainage through the lacrimal system, and in this manner, may produce systemic side effects. F. Metals contained in cosmetics are increasingly being recognized as sources for dermatitis and even systemic side effects.

III. Histology A. In the acute stage, epidermal (intraepidermal vesicles) and dermal edema predominate along with a lymphocytic infiltrate. Spongiosis or intercellular edema between squamous cells contributes to the formation of vesicles (unilocular bullae). Intracellular edema, however, results in reticular degeneration and the formation of multilocular bullae.



B. In the chronic stage, there is acanthosis, orthokeratosis, and some parakeratosis together with elongation of rete pegs. 1. Mild spongiosis is present, but vesicle formation does not occur. 2. In the dermis, perivascular lymphocytes, eosinophils, histiocytes, and fibroblasts are found. Histologically, a distinction cannot be made between a primary allergic contact dermatitis and an irritant-induced or toxic dermatitis, except possibly in the early stage. Atopic dermatitis, which is a chronic, severely pruritic dermatitis associated with a personal or family history of atopy, does not show vesicles, although it does show lichenified and scaling erythematous areas, which when active may show oozing and crusting.

Collagen Diseases I. Dermatomyositis (see Chapter 14). II. Periarteritis (polyarteritis) nodosa (see Fig. 6.18 and Box 6.2, containing the vessel size impacted by the major

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Fig. 6.18  Distribution of vessel involvement by large vessel vasculitis, medium vessel vasculitis, and small vessel vasculitis. Note that there is substantial overlap with respect to arterial involvement, and an important concept is that all 3 major categories of vasculitis can affect any size artery. Large vessel vasculitis affects large arteries more often than other vasculitides. Medium vessel vasculitis predominantly affects medium arteries. Small vessel vasculitis predominantly affects small vessels, but medium arteries and veins may be affected, although immune complex small vessel vasculitis rarely affects arteries. Not shown is variable vessel vasculitis, which can affect any type of vessel, from aorta to veins. The diagram depicts (from left to right) aorta, large artery, medium artery, small artery/arteriole, capillary, venule, and vein. Anti-GBM, antiglomerular basement membrane; ANCA, antineutrophil cytoplasmic antibody. (From Jennette et al.: Revised international Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 65(1):1–11, 2013. Figure 2. Wiley.)

BOX 6.2  Names for Vasculitides Adopted by the 2012 International Chapel Hill Consensus

Conference on the Nomenclature of Vasculitides Large Vessel Vasculitis (LVV) Takayasu arteritis (TAK) Giant cell arteritis (GCA) Medium Vessel Vasculitis (MVV) Polyarteritis nodosa (PAN) Kawasaki disease (KD) Small Vessel Vasculitis (SVV) Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) Microscopic polyangiitis (MPA) Granulomatosis with polyangiitis (Wegener’s) (GPA) Eosinophilic granulomatosis with polyangiitis (Churg–Strauss) (EGPA) Immune complex SVV Anti-glomerular basement membrane (anti-GBM) disease Cryoglobulinemic vasculitis (CV) IgA vasculitis (Henoch–Schönlein) (IgAV) Hypocomplementemic urticarial vasculitis (HUV) (anti-C1q vasculitis) Variable Vessel Vasculitis (VVV) Behçet’s disease (BD) Cogan’s syndrome (CS)

Single-Organ Vasculitis (SOV) Cutaneous leukocytoclastic angiitis Cutaneous arteritis Primary central nervous system vasculitis Isolated aortitis Others Vasculitis Associated With Systemic Disease Lupus vasculitis Rheumatoid vasculitis Sarcoid vasculitis Others Vasculitis Associated With Probable Etiology Hepatitis C virus-associated cryoglobulinemic vasculitis Hepatitis B virus-associated vasculitis Syphilis-associated aortitis Drug-associated immune complex vasculitis Drug-associated ANCA-associated vasculitis Cancer-associated vasculitis Others

(From Jennette et al., Revised international Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 65(1):1–11, 2013. Table 2. Wiley.)

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vasculitides and the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides for them, respectively.) A. Periarteritis nodosa is characterized by a necrotizing panarteritis of small- and medium-sized, muscular-type arteries. 1. It most commonly affects men in their fourth to sixth decades. 2. It is not associated with antineutrophil cytoplasmic antibodies (ANCAs). 3. Patients present with systemic symptoms and signs of multisystem involvement, which may include skin lesions, hypertension, renal insufficiency, neurologic dysfunction, and abdominal pain. 4. It can be associated with familial Mediterranean fever. a. Mononeuropathy multiplex occurs in up to 80% of patients. b. Cerebral vasculitis occurs in 5%–10% of patients, and may result in cerebral infarcts. c. Ocular involvement may include retinal vasculitis, ischemic optic neuropathy, scleritis, and orbital inflammation. d. Rheumatoid arthritis, systemic lupus erythematosus, relapsing polychondritis, Wegener’s granulomatosis (granulomatosis with polyangiitis), polyarteritis nodosa, and Churg–Strauss syndrome are the most common systemic diseases associated with corneoscleral disease.





C. The Systemic Lupus International Collaboratory Clinics Classification Criteria for Systemic Lupus Erythematosus lists 17 clinical and immunological criteria useful for making the diagnosis. D. Vasculitis has been reported in up to one-third of patients with SLE. E. SLE affects the eyes in approximately one-third of patients. Table 6.5 lists the ocular manifestations of SLE. 1. There may be immune complex deposition in the basement membrane of endothelial cells of small blood vessels. Involvement usually takes the form of inflammation or thrombosis, such as keratoconjunctivitis sicca, retinopathy, episcleritis, and scleritis. TABLE 6.5  Ocular Involvement in

Systemic Lupus Erythematosus Structure

Clinical Findings

Orbital and external eye disease

Discoid lupus-type rash over the eyelids Panniculitis Orbital masses Periorbital edema Orbital myositis Orbital vasculitis, acute orbital ischemia and infarction Conjunctivitis Dry eye syndrome Recurrent corneal erosions Peripheral corneal infiltrates Peripheral ulcerative keratitis Interstitial keratitis Endotheliitis Keratoconus Scleritis Episcleritis Anterior uveitis Lupus retinopathy (cotton wool spots, intraretinal hemorrhages, and vascular tortuosity) Retinal hard exudates Retinal vasculitis Retinal artery and/or vein occlusion Arteriolar narrowing and arteriovenous crossing changes Macular pigmentary mottling Retinal scarring Macular infarction Central serous chorioretinopathy Optic nerve involvement Optic neuritis Ischemic optic neuropathy Papilledema Central nervous system vasculitis Internuclear ophthalmoplegia Nystagmus Cranial nerve palsies Homonymous hemianopia

Conjunctival involvement Corneal involvement

Rarely it may present as bilateral optic neuropathy. Sclera and episclera



B. Histologically, four stages may be seen 1. The degenerative or necrotic stage: foci of necrosis (fibrinoid necrosis) involve the coats of the artery and may result in localized dehiscences or aneurysms. 2. The inflammatory stage: transmural infiltrate characterized by predominantly neutrophils, but also eosinophils and lymphocytes, infiltrates the necrotic areas, which frequently represent fibrinoid necrosis. Small caliber vessels such as glomerular and pulmonary capillaries are not affected. 3. The granulation stage: healing occurs with the formation of granulation tissue, which may occlude the vascular lumens. 4. The fibrotic stage: healing ends with scar formation. III. Systemic lupus erythematosus (SLE) can have protean manifestations, and the diagnosis is based on a combination of clinical and laboratory findings, serology, and histology of affected organs. A. It affects more than 300,000 individuals in the United States, and millions of people worldwide. B. Over 100 genetic loci have been associated with SLE. Additionally, epigenetic biomarkers hold promise for diagnosing and monitoring lupus diseases and the risk of organ damage.

Uveal involvement Retinal involvement

Choroidal involvement Neuro-ophthalmic findings

(From Shoughy & Tabbara, Ocular findings in systemic lupus erythematosus. Saudi J Ophthalmol 30:117–121, 2016. Table 1. Elsevier.)

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2. Other findings may include conjunctivitis, peripheral ulcerative keratitis, anterior uveitis, choroidopathy, orbital inflammation and optic neuropathy. 3. Drusen-like deposits have been reported in young adults with SLE. 4. Antiphospholipid syndrome may accompany SLE. It has resulted in bilateral retinal arterial and venous occlusions with vasculitis. 5. Bilateral concurrent superior ophthalmic vein occlusions have been reported in SLE. F. SLE includes cutaneous lesions in 72%–85% of patients, and they can develop at any stage of the disease irrespective of disease activity. 1. They represent the first sign of the disease in 23%–28% of patients. 2. Cutaneous lupus erythematosus (CLE) manifestations are divided into lupus-nonspecific and specific lesions. a. Among the nonspecific lesions are periungual telangiectasia, livedo racemosa, thrombophlebitis, Raynaud’s phenomenon, acral occlusive vasculopathy, leukocytoclastic vasculitis (palpebral purpura or urticarial vasculitis), papular mucinosis, calcinosis cutis, nonscarring alopecia, and erythema multiforme. b. SLE-specific lesions constitute the subtypes of cutaneous SLE. c. They are divided into three categories based upon clinical features of the various lesions, histopathological findings in skin biopsy specimens, and laboratory findings. 1) The categories of cutaneous lupus erythematosus are acute (ACLE), subacute (SCLE), and chronic (CCLE). 2) Discoid lupus erythematosus, subacute cutaneous lupus erythematosus, lupus erythematosus panniculitis, and lupus erythematosus tumidus all fall within the subtype of CLE. 3) Only discoid lupus erythematosus will be discussed more specifically in this chapter. a) Discoid lupus erythematosus may be limited to the skin or there may be systemic involvement. b) Discoid lupus erythematosus (DLE) is the most common subtype of cutaneous lupus. c) It is classified as a chronic (CCLE) form of cutaneous involvement. d) It represents 80% of all cutaneous lupus cases. e) It may present as eyelid edema an erythema. f) There is an increased risk of squamous cell carcinoma in longstanding DLE lesions, and these tumors have a higher rate of recurrence, metastasis, and death. g) Transition from the chronic discoid type to the systemic type occurs infrequently. h) Histology is similar in the various CLE subtypes, and overall is not useful in

191

differentiating among them. Nevertheless, features that have been cited as favoring a diagnosis of chronic discoid lupus erythematosus (CDLE), which is DLE without systemic disease, over other CLE subtypes are the presence of hyperkeratosis, basement membrane thickening, follicular damage, leukocytic infiltration and involvement in CDLE; however, they have been questioned as to their validity for this purpose. 4) In general, dermatologic changes in CLE are: (1) orthokeratosis with keratotic plugging found mainly in the follicular openings but also found elsewhere; (2) atrophy of the squamous layer of epidermis and of rete pegs; (3) liquefaction degeneration of basal cells (i.e., vacuolation and dissolution of basal cells— most significant finding); (4) focal lymphocytic dermal infiltrates mainly around dermal appendages; and (5) edema, vasodilatation, and extravasation of erythrocytes in the upper dermis. 5) IgG antibodies are critical for the development of CLE associated with SLE. a) Tissue specific antibodies such as anti-RPLP0 and anti-Galactin-3 antibodies, rather than conventional lupus-related autoantibodies, are responsible for lupus skin damage. b) The cutaneous inflammatory infiltrate in CDLE are dominated by the T-helper (Th1), but not Th17 cells in contrast to the findings in SLE. c) Keratinocytes undergo apoptosis and may produce proinflammatory cytokines in both SLE and in CDLE. d) Location of lesions, characteristic features of damage, and absence of Ro/SSA antibody may be most effective in differentiating CDLE from other cutaneous lupus erythematosus subtypes. IV. Scleroderma (Fig. 6.19) has been described as a clinically heterogeneous connective tissue disorder characterized by fibroblast dysfunction, small-vessel vasculopathy, and autoantibody production. A. It exists in three forms: (1) a more benign circumscribed form, limited cutaneous systemic sclerosis (lcSSc), also known as morphea and characterized by CREST syndrome, which is characterized by Calcinosis, Raynaud’s phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasis. It is predominantly restricted to the skin and subcutaneous tissue, and almost never progresses or transforms to the systemic form; (2) a systemic form, diffuse cutaneous systemic sclerosis (dcSSc) or (progressive systemic sclerosis or scleroderma), which may prove fatal; and (3) SSC without skin involvement.

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A

B

Fig. 6.19  Scleroderma. A, Typical changes in face and hands of patient who has scleroderma. B, Cotton-wool spots seen in fundus of person with advanced scleroderma. C, Dermis thickened and subcutaneous tissue mostly replaced by collagen. Atrophic sweat glands appear trapped in midst of collagen bundles.

C









B. Morphea occurs equally in adults and children, and is more common in women. It presents with systemic symptoms of fatigue, myalgia, arthralgia and skin induration that worsens over time. Eventually, there is loss of adnexal structures. 1. Some have referred to this as limited cutaneous systemic sclerosis because there also may be pulmonary hypertension as a late finding and primary biliary cirrhosis. 2. Antinuclear antibodies, recognized as chromosomal centromere proteins, are present in 50% of patients. C. Systemic involvement in dcSSc may include skin, gastrointestinal tract, lungs, kidneys, skeletal muscle and pericardium. D. The characteristic lesion is a sclerotic plaque with an ivory-colored center and appearing bound-down when palpated. E. Ocular findings include pseudoptosis secondary to swollen lids, ectropion, madarosis, hyposecretion of tears with trophic changes in the cornea and conjunctiva (Sjögren’s syndrome), ocular muscle palsies, temporal arteritis, unilateral glaucoma, exophthalmos, thinner corneas, posterior subcapsular cataract, anterior uveitis, neural retinal cotton-wool patches, signs of hypertensive retinopathy, choroidal impairment, macular thinning, defects of the retinal pigment epithelium near the macula, central serous choroidopathy, retinal artery occlusion, and fluorescein leaks of thickened retinal capillaries.





F. Histologically, the morphea and the systemic forms are similar, if not identical. 1. Early stage: dermal collagen bundles appear swollen and homogeneous and are separated by edema. Round inflammatory cells, mainly lymphocytes, are found around edematous blood vessel walls and between collagen bundles (panniculitis). 2. Intermediate stage: subcutaneous tissue is infiltrated by round inflammatory cells, dermal collagen becomes further thickened, and dermal adnexa are involved in the process. Blood vessel walls show edema with intimal proliferation and narrowing of their lumina. 3. Late stage: dermis is thickened by the addition of new collagen at the expense of subcutaneous tissue. Inflammation is minor or absent. a. The subcutaneous fat is replaced by collagen, and blood vessels are fibrotic. b. The thickened dermis contains hyalinized, hypertrophic, closely packed collagen bundles, atrophic sweat glands trapped in the midst of collagen bundles, decreased fibrocytes, and few or no sebaceous glands or hair structures. 4. The overlying epidermal structure, including rete ridges, is rather well preserved except in the late stages of the systemic form, when atrophy occurs. 5. The underlying muscle, especially in the systemic form, may be involved and shows early degeneration, swelling, and inflammation, followed by late fibrosis.

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G. Increased levels of inflammatory proteins are found in the serum of patients with SSC who have not yet shown evidence of fibrotic disease. H. Genomic and genetic studies of patients with SSC and family members provide evidence that chromosomal breakage is a main feature in these families. 1. HLA studies find that HLA-DRB1, HLA-DQA1, HLA-DQB1 and HLA-DPB1 are identified most frequently. 2. The most frequent gene associations are with STAT4, CD247, and IRF5. 3. CXCL4 and adiponectin are two serologic biomarkers that have demonstrated prognostic utility in systemic sclerosis. 4. Antibody profiling is becoming important in systemic sclerosis. A relationship has been established between RNAP and cancer diagnosis in a subset of patients. I. Parry–Romberg syndrome (PRS) (progressive hemifacial atrophy, idiopathic hemifacial atrophy, or hemiatrophia faciei [progressive]), and linear scleroderma en coup de sabre (LSCS). (For an excellent review of PRS, the reader is referred to the article by Bucher et al. in the bibliography for this chapter). 1. Both are considered forms of linear morphea, which is a type of localized scleroderma, characterized by thickening and hardening of the skin from increased collagen production. 2. Both have a similar clinicopathologic appearance. a. Up to 28% of patients with LSCS have features of PRS such as progressive hemifacial atrophy or histopathologic similarities on skin biopsy. It has been noted that conversion from LACS to PRS may occur. b. Deeper tissues of the head and neck usually are not involved in LSCS. 3. PRS is an acquired disorder accompanied by slowly progressive atrophy of facial subcutaneous tissues, muscles, osteocartilaginous structures, and possibly with cerebral involvement. Table 6.6 lists the periocular findings in PRS. a. It usually is unilateral. b. Ocular manifestations occur in 10%–35% of patients and may involve the contralateral eye. Table 6.7 lists the ocular manifestations of PRS. c. Neuro-ophthalmic findings may include abnormalities of the pupil, including anisocoria; optic nerves, including papillitis and neuroretinitis; and extraocular muscles. d. Systemic manifestations are protean and may include neurologic, dermatologic, cardiac, endocrine, infectious, orthodontic, and maxillofacial abnormalities. 4. LSCS usually involves the frontoparietal scalp and/ or the paramedian forehead. The disorder gets its name from the fact that is resembles a scar secondary to a wound from a sword.

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TABLE 6.6  Periocular Findings in

Parry–Romberg Syndrome Periocular Structure

Periocular Manifestations

Skin Eyebrows/lashes

Hyperpigmentation/depigmentation Alopecia Asymmetry Retraction Lagophthalmos Atrophy Pseudoptosis Pseudocoloboma Enophthalmos due to retroorbital fat atrophy Enophthalmos due to bone atrophy Alterations of orbital wall and retroocular structures Orbital tumors Deviation toward the affected side of hemifacial atrophy

Eyelid

Orbit

Mouth and nose

(From Bucher et al.: Ophthalmological manifestations of ParryRomberg syndrome. Surv Ophthalmol 61:693–701, 2016. Table 1. Elsevier.)

TABLE 6.7  Ocular Manifestations in

Parry–Romberg Syndrome Ocular Structure

Ocular Manifestations

Conjunctiva Cornea

Palpebral pigmentation Band keratopathy Exposure keratopathy Decreased corneal nerves Reduced corneal sensation Flourlike stromal deposits Primary corneal endothelial failure Discrete, irregularly round, glassy precipitates Refractive changes Photophobia Spontaneous scleral melting Anterior uveitis Iris atrophy Iris crystalline deposits Fuchs heterochromic iridocyclitis Panuveitis Inflammation Hypotony/phthisis (Bilateral) vitritis Retinal vasculitis Retinal telangiectasia Retinal pigment epithelial changes Retinal edema Retinitis pigmentosa Retinal detachment Coats disease Sectional chorioretinal atrophy Central retinal artery occlusion Choroidal/retinal folding and hyperopia due to phthisis

Sclera Iris/Uvea

Ciliary body Vitreous Retina

(From Bucher et al.: Ophthalmological manifestations of ParryRomberg syndrome. Surv Ophthalmol 61:693–701, 2016. Table 2. Elsevier.)

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a. LSCS is the most common form of scleroderma in childhood. b. Ninety percent of affected children present between 2 and 14 years of age. c. The eye and adnexa may be involved. It frequently is associated with other internal organ involvement, particularly of the central nervous system. 1) In one multicenter study in children, the eyelids, eyelashes or lacrimal glands are the most frequently involved ocular or periocular structures (41.7%). 2) Anterior segment inflammation was present in 29.2%. 3) Other ocular findings included pupillary mydriasis associated with CNS abnormalities, enophthalmos, partial iris atrophy, stellate neuroretinitis, retinal telangiectasia, strabismus, pseudopapilledema, and refractive errors. 4) Systemic manifestations included epilepsy, peripheral neuropathy, pseudotumor cerebri, arthritis, aortic insufficiency, abnormal pulmonary function tests, and Raynaud’s phenomenon. 5) Patients with ocular involvement had a higher incidence of internal organ involvement, particularly of the CNS, than those lacking ocular findings (45.8% vs 21.6%). 6) ANA was positive in 50% of patients with LSCS. 7) Other studies have found episcleral vascular anomaly, retinal telangiectasia, and exudative retinal detachment with a Coats-like response in association with LSCS.

Granulomatous Vasculitis







Table 6.8 lists the revised classification of vasculitis based on histopathologic feature of granuloma formation. I. Granulomatosis with polyangiitis (GPA) (Wegener’s granulomatosis) A. Grouped with eosinophilic granulomatosis with polyangiitis (EGPA) (formerly Churg–Strauss syndrome) as an ANCA-associated granulomatous vasculitis involving small vessels.



1. Another ANCA-positive vasculitis, microscopic polyangiitis (MPA) is characterized by nongranulomatous inflammation. 2. They are termed the “ANCA-associated vasculitides.” 3. Other forms of non-ANCA-associated vasculitis, typically, are characterized by the presence of immune complex deposition (lupus vasculitis, Henoch– Schönlein purpura, and Goodpasture’s disease). B. Classic form: characterized by generalized small-vessel vasculitis, necrotizing granulomas, focal necrotizing glomerulonephritis, and vasculitis of the upper and lower respiratory tract. 1. Otorhinologic manifestations are found in 90% of patients, and it is the most commonly involved organ system. 2. Pulmonary involvement is present in 85% of patients, but may be asymptomatic. 3. Rapidly progressive glomerulonephritis is a presenting finding in 20% of patients; however, up to 80% of patients ultimately develop it. 4. It may have the unique finding of strawberry gingival enlargement. 5. Typical presentation is a persistent inflammatory nasal and sinus disease associated with systemic symptoms of fever, malaise, and migratory arthritis. 6. Serum antineutrophil cytoplasmic antibodies (ANCAs) are a sensitive and rather specific marker for GPA. 7. The ANCAs are divided into perinuclear or p-ANCA, or cytoplasmic or c-ANCA. a. C-ANCA pattern with leukocyte proteinase 3 (PR3) positivity is found in 90% of GPA patients with active disease. b. Most MPA patients have p-ANCA with positive myeloperoxidase (MPO). 8. In both the classic and limited forms, most of the ocular findings can occur. 9. Ocular involvement, most commonly orbital, occurs in up to 50%, and neurologic involvement in up to 54% of cases. C. Ocular findings include dry eyes, nasolacrimal obstruction, blepharitis, conjunctivitis, scleritis or episcleritis,

TABLE 6.8  Classification of Vasculitis Based on Histopathologic Feature of Granuloma

Formation

Large-Vessel Vasculitis Granulomatous inflammation Nongranulomatous inflammation

Medium-Vessel Vasculitis

Small-Vessel Vasculitis

Classic polyarteritis nodosa Kawasaki disease

Granulomatosis with polyangiitis* Eosinophilic granulomatosis with polyangiitis† Microscopic polyangiitis IgA vasculitis‡ Essential cryoglobulinemic vasculitis Cutaneous leucocytoclastic vasculitis

Temporal arteritis Takayasu arteritis

*Previously known as Wegener’s granulomatosis. † Previously known as Churg–Strauss syndrome. ‡ Previously known as Henoch–Schönlein purpura. (From Sharma et al.: Granulomatous vasculitis. Dermatol Clin 33:475–487, 2015. Table 1. Elsevier.)

Lid Manifestations of Systemic Dermatoses or Disease

corneoscleral ulceration, uveitis, retinal vein occlusion, retinal pigmentary changes, acute retinal necrosis, choroidal folds, optic neuritis, and exophthalmos secondary to orbital involvement. It has presented as cicatricial conjunctival inflammation with trichiasis. D. Histologically, the classic triad of necrotizing vasculitis (granulomatous and disseminated small-vessel), tissue necrosis, and granulomatous inflammation are characteristic. 1. The vasculitis can be seen in three forms: a. Microvasculitis or capillaritis—infiltration and destruction of capillaries, venules, and arterioles by neutrophils. b. Granulomatous vasculitis (most characteristic)— granulomatous vasculitis involving small or medium-sized arteries and veins. c. Necrotizing vasculitis involving small or mediumsized arteries and veins but not associated with granulomatous inflammation. 2. Extravascular granulomatosis is a major factor differentiating MPA from GPS. In EGPA, the extravascular lesions usually are not associated with necrotizing granulomatous inflammation. E. It is associated with HLA-DRB1*04, DPB1*0401, PRTN3 (A546G poly), and AAT polymorphisms (SERPINA1). F. Among the precipitating factors are believed to be environmental, drugs, and infectious triggers. II. Eosinophilic granulomatosis with polyangiitis (EGPA) (formerly allergic granulomatosis, allergic vasculitis, or Churg– Strauss syndrome) involves the same-size arteries as periarteritis, but differs in having more prominent respiratory symptoms including asthma, pulmonary infiltrates, systemic and local eosinophilia, intravascular and extravascular granulomatous lesions, and often cutaneous and subcutaneous nodules and petechial lesions. It has been suggested that the associated asthma resembles a nonallergic eosinophilic asthma phenotype. A. The three disease phases are prodromal, eosinophilic, and vasculitic. 1. The main features of the prodromal stage are asthma and allergic rhinitis with or without polyposis. Upper airway involvement is milder than in GPA. 2. The second stage is marked by peripheral and tissue eosinophilia. 3. The vasculitic phase includes multiple system involvement including nerves, heart, lungs, gastrointestinal tract, and kidneys. Peripheral nerves and skin are most frequently involved. B. The most common skin lesions are purpura and nodules most commonly on the limbs and scalp. C. It is considered a Th2-mediated disease. B cells and humoral response also may contribute to its pathobiology. D. ANCA-positivity is present only in about 40% of patients. E. Histopathologic evaluation in the early phase demonstrates extravascular tissue infiltration in any organ.

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1. The vasculitic phase is characterized by inflammation involving small to medium-sized vessel walls. 2. The vasculitis involves fibrinoid necrosis and infiltration of the vessel walls by eosinophils. F. There may a limited form of the disease that is confined to single organs. III. Temporal arteritis (see Chapter 13)

Vasculitis-Like Disorders and Leukemia/Lymphoma I. Natural killer (NK) T-cell lymphoma (polymorphic reticulosis or angiocentric T-cell lymphoma) (also see discussion in Chapter 14) A. NK cells are a distinct non-T, non-B lineage of lymphocytes that mediate major histocompatibility complexunrestricted cytotoxicity. B. NK/T-cell malignancies are uncommon and were previously known as polymorphic reticulosis or angiocentric T-cell lymphomas. The World Health Organization further divides these lesions into NK/T-cell lymphoma (nasal and extranasal) type and aggressive NK-cell leukemia. 1. Its lymphoma cells are CD2+ and CD3ε+. C. Relatively common in Asia, Mexico, and South America, but extremely rare in most western countries. D. Lethal midline granuloma form of NK/T-cell lymphoma is a rare entity, usually arises in the nasal cavity, has a male preponderance and a wide age range, is extremely aggressive, and has approximately a 20% 5-year survival. E. Apoptosis, necrosis, and angioinvasion are typical features of the lymphoma. F. Invasion and blockage of blood vessels by lymphoma cells result in marked ischemic necrosis of normal and neoplastic tissues. G. The leukemic form tends to affect younger patients, who often present with advanced disease and multiple organ involvement. 1. Survival is particularly brief. H. Gamma-delta T-cell receptor clonality is the most common T-cell receptor rearrangement in several T-cell lymphomas, including NK/T-cell lymphoma. I. Characteristic patterns of genomic alteration typify aggressive NK-cell leukemia and extranodal NK/T-cell lymphoma, nasal type. J. Epstein–Barr virus (EBV) can encode multiple genes that drive cell proliferation and confer resistance to cell death, including two viral proteins that mimic the effects of activated cellular signaling proteins. 1. Infection with the virus is associated with a variety of lymphomas and lymphoproliferative disorders, including Burkitt’s lymphoma, NK/T-cell lymphoma, lymphoma and lymphoproliferative diseases in immunocompromised individuals, and Hodgkin’s lymphoma. 2. The presence of EBV-infected cells in the aqueous humor originating from nasal NK/T-cell lymphoma has been reported.

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K. The majority of ocular adnexal lymphomas are marginal zone B-cell (mucosal-associated lymphoid tissue: MALT) lymphomas. L. NK/T-cell lymphoma has occasionally involved the eye. II. CD30+ lymphoid proliferations (Table 6.9) A. Includes lymphoid papulosis, primary cutaneous anaplastic large cell lymphoma, and systemic anaplastic large cell lymphoma. B. 30% of all cutaneous T-cell lymphomas. C. Spectrum of clinical aggressiveness. D. Proper diagnosis requires clinical and pathologic correlation. E. Pseudocarcinomatous hyperplasia has been reported in association with lymphomatous papulosis. F. A benign atypical intravascular CD30+ T-cell proliferation has been reported in association with inflammation or trauma, and must be distinguished from intravascular T-cell lymphoma.



G. Lymphoid papulosis can be malignant histologically, but clinically benign and characterized by rhythmic paradoxical eruptions of erythematous papules. 1. There is a 10%–20% risk for developing lymphoma or a nonlymphoid tumor. 2. It has been divided into 4 histological types with type A resembling Hodgkin’s disease, type B resembling mycosis fungoides, type C resembling anaplastic large-cell lymphoma, and type D simulating aggressive epidermotropic CD8+ T-cell lymphoma. 3. A recent variant, type E, is an angiocentric and angiodestructive infiltrate of small- to medium-sized atypical lymphocytes that are CD30+ and frequently express CD8. 4. Type C has been reported to involve the eyelid in a teenage girl in whom the dermis contained a heavy superficial and deep infiltrate that included numerous large atypical lymphoid cells.

TABLE 6.9  Clinical and Pathologic Findings in CD30+ Lymphoid Proliferations Demographics Symptoms/clinical findings

Histology

Contrasts in immunohistochemistry

Treatment

Prognosis

LyP

cALCL

Systemic ALCL

Median age: 45 years • Recurrent papular/nodular lesions on trunk/extremities ± ulceration with spontaneous regression after 4–6 weeks • Hyper- or hypopigmented scar may remain A: Resembles Hodgkin’s disease with large cells resembling Reed– Sternberg cells B: Resembles mycosis fungoides with cerebriform cells C: Resembles ALCL with clusters and sheets of large cells

Median age: 60 years • ≥1 lesion that is >2 cm in diameter ± erythema and ulceration • No extracutaneous involvement

Males cALCL > LyP CD56: Expressed in ALCL > cALCL > LyP; poor prognosis in ALCL Fascin: Expressed in ALCL > cALCL > LyP TRAF-I: Expressed in LyP ≫ cALCL > ALCL • Usually none • Resection ± irradiation • Low-dose MTX for skin-restricted • PUV A or low- dose MTX has been used for aggressive disease disease • Chemotherapy for extracutaneous disease • Benign • Less aggressive than systemic ALCL • Increased risk for progressing to • Better survival rate than for systemic mycosis fungoides, Hodgkin’s ALCL; 5-year survival rate of 90% lymphoma, or ALCL • Spontaneous regression occurs in ≥40%

• Local radiation with combination chemotherapy

• ALK translocation-positive ALCL with better prognosis (5-year survival rate 70–80%) than ALK translocationnegative ALCL (5-year survival rate 30–40%)

ALCL, systemic anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; cALCL, primary cutaneous anaplastic large cell lymphoma; CLA, cutaneous lymphocyte antigen; EMA, epithelial membrane antigen; LyP, lymphomatoid papulosis; MTX, methotrexate; PUVA, psoralen plus ultraviolet A; TRAF-I, tumor necrosis factor receptor-associated factor-1. (From Sanka RK, Eagle RC, Jr., Wojno TH et al.: Spectrum of CD30+ lymphoid proliferations in the eyelid: lymphomatoid papulosis, cutaneous anaplastic large cell lymphoma, and anaplastic large cell lymphoma. Ophthalmology 117:343–351, 2010.)

Lid Manifestations of Systemic Dermatoses or Disease



a. The nuclei were pleomorphic and bizarre with multinucleated forms. b. The infiltrate was both perivascular and interstitial, and included moderated numbers of small- to medium-sized mildly atypical lymphoid cells. c. The large pleomorphic cells were positive for CD30 and CD45, and were ALK negative. T-cell receptor analysis suggested T-cell receptor gene rearrangement. III. Mycosis fungoides (also see discussion in Chapter 14) A. Most common type of cutaneous T-cell lymphoma but rarely involves eyelids. B. Recalcitrant clinical course. C. Three classic phases: macular or patch, infiltrative or plaque, and tumor stage. D. Among the eyelid presentations are ulceration, plaques, facial swelling, and eyelid ectropion. IV. Other T-cell lymphomas involving the eyelids have been reported.



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A. The lesions appear as bilateral, soft, yellowish plaques most commonly at the inner aspects of the upper and lower lids. B. Although usually localized, extensive lesions have been reported. C. There is a 4.4% prevalence. D. Xanthelasma is the most common cutaneous form of xanthoma (i.e., a tumor containing fat mainly within cells [intracellular]), whereas a lipogranuloma (e.g., a chalazion) is a tumor containing fat mainly outside cells (extracellular). E. Other xanthomatous lesions that may occur in the periorbital area are Langerhans’ cell histiocytosis, diffuse normolipemic xanthoma, and non-Langerhans’ cell histiocytoses (papular xanthoma, juvenile xanthogranuloma, xanthoma disseminatum, adult-onset xanthogranuloma, adult-onset asthma and periocular xanthogranuloma, necrobiotic xanthogranuloma, Erdheim–Chester disease, Rosai–Dorfman disease, and reticulohistiocytosis). 1. Malignant melanoma involving the eyelid has masqueraded as a xanthogranuloma and included histopathologic findings of an inflammatory infiltrate of lymphocytes, histiocytes, and giant cells with Touton giant cell features. The associated malignancy was consistent with melanoma.





Xanthelasma I. Xanthelasma (Fig. 6.20) most commonly occurs in middleaged or elderly women; however, female predominance has not been found universally.

A

B

C

D Fig. 6.20  Xanthelasma. A, Characteristic clinical appearance of xanthelasmas that involve inner aspect of each upper lid. B, Lipid-laden foam cells are present in dermis and tend to cluster around blood vessels. C, High magnification of foam cells clustered around blood vessels. D, Oil red-O stain for fat demonstrates dermal lipid positivity (red globules).

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F. It may occur in primary hypercholesterolemia or with nonfamilial serum cholesterol elevation. It frequently is associated with abnormal serum lipid levels. 1. It is a risk factor for myocardial infarction, ischemic heart disease, severe atherosclerosis, and death independent of other cardiovascular risk factors, such as plasma cholesterol and triglyceride concentrations. 2. The presence of a tendency for increased cardio-ankle vascular index in asymptomatic patients with xanthelasma has been seen to indicate increased arterial stiffness in these individuals, which is a noninvasive marker for atherosclerosis. 3. Compounding risk factors for cardiovascular disease frequently have been noted in patients with xanthelasma. The risk factors in one study included nicotine addiction (39.3%), dyslipidemia (60%), hypertension (37.7%), prehypertension (8.77%), diabetes mellitus (18.03%), and prediabetes (26.3%). 4. It has been proposed that alterations in serum levels of apolipoprotein A1 (decrease) and B (increase) may predispose to the deposition of lipids in the skin as is found in xanthelasma, and may contribute to the systemic deposition of lipids thereby facilitating the development of atherosclerosis. Compared to control individuals, patients with xanthelasmas had an accompanying increase in carotid intima media thickness compatible with atherosclerosis. Evidence suggests that xanthelasma may be associated with qualitative and quantitative abnormalities of lipid metabolism (increased levels of serum cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B; and decreased levels of high-density lipoprotein subfraction 2 cholesterol) that may favor lipid deposition in the skin and arterial wall, that xanthelasma is a marker of dyslipidemia, and that patients who have xanthelasma should undergo a full lipid profile to identify those who are at an increased risk for cardiovascular disease.

II. After initial surgical excision, the recurrence rate is slightly less than half. III. Recurrence is more likely if all four lids are involved, if an underlying hyperlipemia syndrome is present, or if there have been previous recurrences. Lid lesions resembling xanthelasma occur in Erdheim– Chester disease, which is an idiopathic, widespread, multifocal, granulomatous disorder characterized by cholesterol-containing foam cells infiltrating viscera and bones, including the orbit, and sometimes bilateral xanthelasmas. It is one of the Langerhans’ cell histiocytoses and can be viewed as an inflammatory myeloid clonal disorder based on the presence of activating mutations along the mitogen activated protein kinase–extracellular signal regulated kinase (MAPK-ERK) pathway with the

most notable variant being a valine to a glutamic acid substitution at amino acid 600 in the B-rapidly accelerated fibrosarcoma protein (BRAFV600E). When the orbit is involved, there tends to be bilateral involvement. Histologically, the lesions show broad sheets of lipid-filled xanthoma cells and scattered foci of chronic inflammatory cells, mainly lymphocytes and plasma cells, along with significant fibrosis. Touton giant cells may be found.

IV. Histologically, lipid-containing foam cells are found in the superficial dermis. The cells cluster around blood vessels and may even involve their walls. A. In one study of 1541 excised lesions on which histopathology had been performed, it represented 7.6% of lesions. B. A comparative histopathologic and immunohistochemical study between blepharoplasty specimens and excised xanthelasmas demonstrated more intense chronic lymphocytic infiltrate, more intense CD3+ T-cell and CD163+ histiocytic infiltrate, and increased cyclooxygenase and inducible nitric oxide synthetase expressing cells in the xanthelasma specimens compared to the blepharoplasty tissue. The authors concluded that these findings resembled the inflammatory milieu similar to that found in the early stages of atherosclerosis. V. Periorbital hyperpigmentation has been noted in 82.4% of patients with xanthelasma. This finding occurred predominantly in women (86.2%) compared to men (13.8%). Unfortunately there was no control population to exclude an ethnic or other basis for these findings. VI. Injected foreign material, such as poly-L-lactic acid, used as tissue fillers may cause a reaction that clinically resembles a xanthelasma, but histopathologically is a paraffinoma.

Necrobiotic Xanthogranuloma I. Necrobiotic xanthogranuloma is rare, with only approximately 100 cases having been reported, and over 80% were in the periorbital region. A. Cutaneous involvement is universal, with the periorbital region a site of predilection. B. The typical lesion is an indurated papule, nodule, or plaque that is violaceous to red-orange, often with a central ulceration or atrophy. II. The most characteristic abnormal laboratory finding is a paraproteinemia. A. It is associated with monoclonal gammopathy. 1. IgG-kappa type is most common (65%), followed by IgG lambda (35%). 2. Other associations have been reported. 3. Multiple myeloma has been diagnosed in a patient with a 20 year history of indolent bilateral xanthogranulomas of the eyelids. III. Systemic findings include hepatomegaly, splenomegaly, lymphadenopathy, arthralgia or arthritis, pulmonary disease, and hypertension.

Lid Manifestations of Systemic Dermatoses or Disease

IV. It tends to involve the periocular skin or anterior orbit, and may produce secondary exophthalmos, ptosis or motility disturbance. A. Other ocular findings include conjunctivitis, episcleritis, keratitis, and anterior uveitis. B. Orbital involvement can include the lacrimal gland, extraocular muscles, or other orbital tissue. V. Histologically, it is a type of non-Langerhans’ cell histiocytosis, which exhibits granulomatous masses separated by broad bands of hyaline necrobiosis. Giant cells are of the foreign-body type and often the Touton type. The lesions most closely resemble necrobiosis lipoidica diabeticorum, but they may also be confused with juvenile xanthogranuloma, granuloma annulare, erythema induratum, atypical sarcoidosis, Erdheim–Chester disease, Rothman–Makai panniculitis, foreign-body granulomas, various xanthomas, nodular tenosynovitis, and the extraarticular lesions of proliferative synovitis.

Juvenile Xanthogranuloma (JXG) I. JXG constitutes a family of non-Langerhans’ cell histiocytoses that include papular xanthoma, benign cephalic histiocytosis, xanthoma disseminatum, progressive nodular histiocytosis, spindle cell xanthogranuloma, and generalized eruptive histiocytosis. See Box 6.3 for a list of these lesions. II. JXG is the most common non-Langerhans’ cell histiocytosis. A. Nevertheless, JXG involving the eyelid is uncommon. It is found in only 10% of cases of ocular JXG.

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B. The ocular manifestations can be quite variable, but spontaneous hyphema is a common presenting sign of iris involvement. III. Almost 50% of JXG occurs in the first year of life. An unusual presentation of JXG has been as a papillary eyelid lesion in an adult.

IV. It is believed to result from disordered macrophage response to a nonspecific injury. V. Histologically it is characterized by the presence of benign mononuclear cells, Touton giant cells, and an inflammatory infiltrate of T lymphocytes and eosinophils. A. The mononuclear cells usually are CD68 positive with CD14 membrane staining. They are said to express CD163 at the cell surface and stain strongly for Factor XIIIa and Fascin. B. S100 usually is negative but can be weak. CD1a and CD207 (Langerin), however, are negative. C. Giant cells usually are CD68 positive in a zonal pattern and S100 is negative, but they are strongly positive for Fascin and variable for XIIIa. D. There is a “mitotically active” form of JXG, but it lacks nuclear atypia or atypical mitoses. E. Touton giant cells are not necessary for the diagnosis of JXG, and they tend to be reduced in number or absent in extracutaneous lesions compared to subcutaneous JXG. They also are found rarely in early lesions. Table 6.10 lists the types of multinucleated giant cell types in nonepithelial skin tumors.

BOX 6.3  Non-Langerhans’ Cell

Histiocytosis

Cutaneous Non-LCH Juvenile xanthogranuloma (JXG) family: Benign cephalic histiocytosis Juvenile xanthogranuloma Generalized eruptive histiocytoma Adult xanthogranuloma Progressive nodular histiocytosis Non-JXG cutaneous histiocytosis: Solitary reticulohistiocytoma Non-LCH dendritic cell histiocytosis Indeterminate histiocytosis Cutaneous With a Major Systemic Component JXG family: Xanthoma disseminatum Non-JXG family: Multicentric reticulohistiocytoma Systemic Non-LCH JXG family: Erdheim–Chester disease Non-JXG family: Sinus histiocytosis with massive lymphadenopathy (From Ranganathan S: Histiocytic proliferations. Semin Diagn Pathol 33:396–409, 2016. Table 4. Elsevier.)

TABLE 6.10  Multinucleated Giant Cell

Types in Nonepithelial Skin Tumors Cell Type

Cutaneous Nonepithelial Tumors

Touton

Juvenile xanthogranuloma Necrobiotic xanthogranuloma Xanthomas Dermatofibroma Reticulohistiocytoma Multicentric reticulohistiocytosis Xanthogranuloma (adult) Soft-tissue giant cell tumor Plexiform fibrohistiocytic tumor Atypical fibroxanthoma Dermatofibroma Giant cell fibroblastoma Pleomorphic lipoma Multinucleate cell angiohistiocytoma Giant cell collagenoma Juvenile xanthogranuloma Necrobiotic xanthogranuloma Dermatofibroma Reticulohistiocytoma

Glassy

Osteoclast-like

Floret-like

Foreign body

(From Gomez-Mateo & Monteagudo: Nonepithelial skin tumors with multinucleated giant cells. Semin Diagn Pathol 30:58–72, 2013. Table 1. Elsevier.)

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VI. The presence of neurofibromatosis type 1 and JXG in the same patient indicates the need for monitoring for the possible development of juvenile myelomonocytic leukemia. VII. Cutaneous JXG accompanies ocular involvement in only 10% of cases. See also Chapter 9.

Amyloidosis Rarely, nodular cutaneous amyloid tumors of the eyelid may occur in the absence of systemic amyloidosis. See also Chapter 7.

Atrophic Papulosis (Köhlmeier–Degos Disease) (Benign and Malignant) I. The syndrome is a rare syndrome of unknown cause characterized by the diffuse eruption of asymptomatic skin lesions with porcelain-white atrophy centers. A. The lesions have a telangiectatic rim. B. They are most commonly found on the trunk and proximal extremities, but can involve the face, scalp and genitals. C. Their occurrence marks the onset of the disease. D. The skin lesions are characteristic of the disorder; however, similar lesions also may occur in primary antiphospholipid syndrome caused by lupus, and can coexist with dermatomyositis. E. They also have occurred in association with lupus without antiphospholipid syndrome. F. Moreover, skin pathology in lupus can be similar to it. II. Systemic involvement involves infarcts of the gastrointestinal system, central nervous system and other organs and in one study of 39 patients occurred in 29% of individuals. A. Family history for the disorder was positive in 9% of patients. B. Mortality was 73% in patients with systemic involvement (5-year survival, 54.5%), and 73% of the individuals who died developed intestinal perforation. C. None of the patients lacking systemic disease died. D. Thus, the cutaneous form of the disease is benign; however, the mortality in the malignant form, which has systemic manifestations, is high. III. Involves small blood vessels. A. There is endothelial dysfunction and immune dysregulation in the pathogenesis of the disorder. 1. It also has been suggested that complement activation and enhanced endothelial cell apoptosis contribute to the pathobiology of the malignant form of the disease, although large vessel proliferative intimal changes were not thought to be secondary to complement activation. IV. Ocular lesions include porcelain-white lid lesions; a characteristic white, avascular thickened plaque of the conjunctiva; telangiectasis of conjunctival blood vessels and microaneurysms; strabismus; posterior subcapsular cataract, choroidal lesions such as peripheral choroiditis, small plaques of atrophic choroiditis, gray avascular areas, and discrete loss of choroidal pigment and peripheral retinal pigment epithelium; visual field changes; and intermittent diplopia

and papilledema, associated with progressive central nervous system involvement. V. Histologically, there is a wedge-shaped area of degenerate dermal connective tissue with an arteriole at the base that displays a hyalinized wall and/or luminal thrombosis. A. Capillaries are occluded by endothelial proliferation and swelling; the end-arterioles show endothelial proliferation, swelling, and fibrinoid necrosis involving only the intima; arterial involvement is greater than venous; thrombosis may occur secondary to endothelial changes; and no significant inflammatory cellular response is noted. B. It has been proposed that these changes can resolve with time.

Calcinosis Cutis I. Calcinosis cutis has five forms: A. Metastatic calcinosis cutis, or calcium deposition secondary to either hypercalcemia (e.g., with parathyroid neoplasm, hypervitaminosis D, and extensive destruction of bone by metastatic carcinoma) or hyperphosphatemia (e.g., with chronic renal disease and secondary hyperparathyroidism). 1. Deposition occurs after the calcium phosphate product exceeds 70. 2. Most commonly seen in chronic renal failure. 3. Also seen in hypervitaminosis D, hyperparathyroidism, sarcoidosis, milk-alkali syndrome and malignancies. B. Dystrophic calcinosis cutis (i.e., deposition in previously damaged tissue) 1. Most common variety. 2. Normal laboratory values for calcium and phosphorus. 3. Secondary to an underlying disease, such as systemic sclerosis, dermatomyositis, mixed connective tissue disease or lupus that produces the site that will be the focus for the calcification. a. Found in 25%–40% of patients with limited systemic sclerosis (CREST) after 10 years. b. Develops in 30% of adults, and 70% of children and adolescents with dermatomyositis. 1) Most often involves pressure areas such as elbows, knees, buttocks, and fingers. 2) May be related to intensity of inflammation and the local production of TNFα. c. Related to release of phosphate-binding protein by dying cells. d. Also related to chronic inflammation. e. Anti-nuclear matrix protein 2 (Anti-NXP2) autoantibodies are associated with calcinosis in pediatric dermatomyositis. C. Idiopathic is not associated with previous tissue injury or abnormal laboratory studies (Fig. 6.21). 1. Includes tumoral calcinosis, subepidermal calcified nodules, and scrotal calcinosis.

Lid Manifestations of Systemic Dermatoses or Disease

A

201

B

Fig. 6.21  Subepidermal calcified nodule. A, Clinical photo of subcutaneous nodule resembling a cystic lesion at the medial canthus. B, Photomicrograph demonstrating acanthotic papillomatous epidermis overlying calcific deposits. (Courtesy of Dr. Tatyana Milman.)

2. Tumoral calcinosis also is seen in familial tumoral calcinosis, which is an autosomal recessive disorder characterized by extraosseous deposition of calciumphosphate crystals in soft tissues and peri-articular spaces. a. All mutations are related to the stability or signaling efficacy of fibroblast growth factor 23 (FGF23), which is a protein involved in phosphate homeostasis. 3. Acral milia-like idiopathic calcinosis cutis usually occurs in children with Down syndrome. a. It usually is found on the hands and feet, and the lesions usually resolve by adulthood. b. They are described as multiple, round, firm white papules resembling milia, and may have an associated erythematous halo. c. The lesions may spontaneously perforate and discharge their calcium contents. d. There may be associated palpebral and perilesional syringomas. D. Iatrogenic is caused by exogenous administration of a calcium- or phosphate-containing substance that then results in the precipitation of calcium salts. E. Calciphylaxis is a rare disease characterized by calcification of small- and medium-sized blood vessels in the dermis and subcutis with intimal fibrosis, and associated, in particular, with renal failure and dialysis. It has a high mortality rate. 1. It occurs in 4% of patients on chronic hemodialysis. 2. Calciphylaxis also may be seen in POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome, which is associated with plasma cell dyscrasias and upregulation of vascular endothelial growth factor (VEGF). a. Skin changes include hyperpigmentation, acrocyanosis, hemangioma, telangiectasia, hypertrichosis, and skin thickening. II. Histologically, forms A and B show large deposits of calcium (appears as granules that are black with von Kossa’s stain)

in the subcutaneous tissue and small, granular deposits in the dermis, whereas form C shows deposits of irregular granules and globules in the upper dermis and can show a foreign-body reaction.

Lipoid Proteinosis (Urbach–Wiethe Disease, Hyalinosis Cutis et Mucosae) I. Lipoid proteinosis (Fig. 6.22) is a rare condition of the lids and mucous membranes that has an autosomal-recessive inheritance pattern. A. The disorder maps to 1q21, and is caused by mutations in the extracellular matrix protein 1 (ECM1) gene. B. The main function of the ECM1 protein appears to be that of a biological glue that maintains dermal homeostasis, and regulates basement membrane and interstitial collagen fibril micro assembly. II. Presents in early childhood. Earliest sign may be hoarseness or a weak cry in infancy. III. Two stages that may overlap: A. First stage lasts until late teens, and lesions are pustules, bullae, and hemorrhagic crusts of the skin mouth and throat. Skin lesions resolve with “ice-pick” acneiform scar. B. Second stage marked by increased deposits in the dermis, and the skin becomes thickened, yellowed, and waxy. 1. Papules and plaques develop progressively over several years on the face, scalp, neck, and extremities. The scalp may show alopecia areata. 2. “Woody” changes develop in the tongue with changes affecting other mucosal surfaces. 3. Characteristic changes are the development of beaded papules on the eyelid margins (moniliform blepharosis), which are a diagnostic finding. a. They are multiple, waxy, pearly nodules, 2 to 3 mm in diameter, cover the lid margins linearly along the roots of the cilia. b. They appear after the age of 4 years.

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A

B

C

D Fig. 6.22  Lipoid proteinosis. A, Multiple, waxy, pearly nodules cover the lid margins. B, Histologic section shows papillomatosis with collections of amorphous material in dermis. Material is positive for lipid (C, Sudan IV stain) and is also periodic acid–Schiff-positive (D). (Case presented by Dr. J Duke at the Eastern Ophthalmic Pathology Society meeting, 1966.)

IV. Other ocular findings A. Prominent corneal nerves are present independent of age, and are more apparent in patients with more severe genetic mutations. 1. Confocal microscopy of the cornea can be helpful in corneal nerve examination; however, it failed to demonstrate abnormalities other than prominent corneal nerves in one study. 2. Corneal sensation is normal. B. There may be focal degeneration of the macula, and drusen formation in Bruch’s membrane in 30%–50% of patients. C. Other ocular abnormalities reported in association with lipoid proteinosis have involved glaucoma, cataract, cornea, uveitis, iris, conjunctiva, ocular surface, lacrimal gland, and nasolacrimal duct obstruction. D. Keratoconus has been reported. V. Whitish plaques are found on mucous membranes. VI. Characteristic calcifications are seen on radiologic examination. These include oval symmetrical intracranial calcification of the hippocampal gyri in 50% of cases. Neurologic and psychiatric manifestations can include memory impairment, paranoia, rage attacks, mental retardation, and temporal lobe epilepsy.

VII. Histologically, there is papillomatosis of the epidermis with hyperkeratosis and acanthosis. There is dermal thickening and deposition of extracellular, homogeneous, hyaline material in the upper dermis. A. The material is PAS-positive without inflammation. B. There is deposition of pale, eosinophilic, hyaline material in the walls of small blood vessels. C. Electron microscopy shows large masses of an extracellular, finely granular, amorphous material without a fibrillar structure. D. It has been suggested that there is overproduction of basement membrane collagens (type IV and V) by blood vessel endothelial cells, and underproduction of fibrous collagens (type I and II).

Idiopathic Hemochromatosis I. Brown pigmentation of the lid margin, conjunctiva, cornea, and around the disc margin (see Chapter 1). II. Histologically, the pigmentation is caused by an increased melanin content of the epidermis, especially the basal layer. A. The peripapillary pigmentation may result from small amounts of iron in the peripapillary retinal pigment epithelium.

Cysts, Pseudoneoplasms, and Neoplasms



B. Intraocular deposition of iron is most prominent in the nonpigmented ciliary epithelium, but may also be found in the sclera, corneal epithelium, and peripapillary retinal pigment epithelium.

Relapsing Febrile Nodular Nonsuppurative Panniculitis (Weber–Christian Disease) I. The condition, which is of unknown cause, occurs most often in middle-aged and elderly women. It is characterized by malaise and fever and by the appearance of crops of tender nodules and papules in the subcutaneous fat, usually on the trunk and extremities. II. Ocular findings include necrotic eyelid and subconjunctival nodules and, rarely, ocular proptosis, anterior uveitis, and macular hemorrhage. Uveitis, which may be granulomatous, and retinitis have been reported. III. Histologically, three stages can be seen. A. An early, rapid phase shows fat necrosis and an acute inflammatory infiltrate of neutrophils, lymphocytes, and histiocytes. B. A second stage shows a granulomatous inflammation with lipid-filled macrophages, epithelioid cells, and foreign-body giant cells. C. A third stage of fibrosis may result clinically in depression of the overlying skin.

Pigmentation

keratinocytes in these patients have abundant mature melanosomes compared to controls. III. Periocular orange pigmentation may be a manifestation of carotenoderma, which represents the deposition of carotene mainly in the stratum corneum of the skin, and may reflect food consumption rich in oranges and carrots.

CYSTS, PSEUDONEOPLASMS, AND NEOPLASMS In a study of 5504 eyelid skin tumors, the 5 most frequent subtypes were squamous cell papilloma (26%), seborrheic keratosis (21%), melanocytic nevus (20%), hidrocystoma (8%), and xanthoma/xanthelasma (6%). Basal cell carcinoma was the most frequent malignant tumor (86%), followed by squamous cell carcinoma (7%) and sebaceous carcinoma (3%).

Benign Cystic Lesions I. Epidermoid (Fig. 6.23) and dermoid (see Figs. 14.12 and 14.13) cysts are congenital lesions that tend to occur at the outer upper portion of the upper lid. II. Epidermal inclusion cysts (see Fig. 6.23) appear identical histologically to congenital epidermoid cysts; the former are not congenital, but are caused by traumatic dermal implantation of epidermis or are follicular cysts of the hair follicle infundibulum that result from occlusion of its orifice, sometimes the result of trauma.

I. Argyrosis A. Periocular and eyelid skin can be involved in argyrosis, resulting in the typical grayish discoloration.

Milia are identical histologically to epidermal inclusion cysts; they differ only in size, milia being the smaller. They may represent retention cysts, caused by the occlusion of a pilosebaceous follicle or of sweat pores, may represent benign keratinizing tumors, or they may have a dual origin. Multiple epidermal inclusion cysts, especially of the face and scalp, may occur in Gardner’s syndrome.

Chronic use of eyelash tint has been an unusual cause for the disorder.

II. Prostaglandin treatment for glaucoma or for eyelash enhancement may result in increased melanin pigmentation of the periocular skin without melanocyte proliferation. The

A

203

B Fig. 6.23  Epidermoid cyst. A, Large epidermoid cyst present on outer third of left upper lid. Note xanthelasma in corner of left upper lid. B, The cyst has no dermal appendages in its wall and is lined by stratified squamous epithelium that desquamates keratin into its lumen. Histologically, an epidermoid cyst is identical to an epithelial inclusion cyst, but it differs from a dermoid cyst in that the latter has epidermal appendages in its wall.

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CHAPTER 6  Skin and Lacrimal Drainage System

Histologically, the cyst is lined by epithelial cells simulating surface epithelium. The cavity contains loose, laminated keratin. III. Sebaceous (pilar, trichilemmal) cysts are caused by obstruction of the glands of Zeis, of the meibomian glands, or of the isthmus portion of the hair follicle, from which keratinization analogous to the outer root sheath of the hair or trichilemma arises. Histologically, the cyst is lined by epithelial cells that possess no clearly visible intercellular bridges. A. The peripheral layer of cells shows a palisade arrangement, and the cells closest to the cavity are swollen without distinct cell borders. B. The cyst cavity contains an amorphous eosinophilic material. The epithelial cells lining the sebaceous cyst are different from the typical cells lining an epidermal inclusion cyst, in which the cells are stratified squamous epithelium. The cystic contents of the sebaceous cyst are different from the horny (keratinous) material filling the epidermal inclusion cyst. “Old” sebaceous cysts, however, may show stratified squamous epithelial metaplasia of the lining, resulting in keratinous material filling the cyst and producing a picture identical to an epidermal inclusion cyst, unless a microscopic section accidentally passes through the occluded pore of the sebaceous cyst.

IV. Comedo (blackhead, primary lesion of acne vulgaris) presents clinically as follicular papules and pustules. A. The comedo occludes the sebaceous glands of the pilosebaceous follicle, which may undergo atrophy. B. Histologically, the comedo results from intrafollicular orthokeratosis that leads to a cystic collection of sebum and keratin. C. With rupture of the cyst wall, sebum and keratin are released, causing a foreign-body giant cell granulomatous reaction. Bacteria, especially Propionibacterium acnes, may be found. D. Eventually, epithelium grows downward and encapsulates the inflammatory infiltrate. E. The lesion heals by fibrosis. V. Steatocystoma A. Steatocystoma may occur as a solitary cyst (simplex) or as multiple cysts (multiplex), the latter often inherited as an autosomal-dominant trait. B. The small, firm cysts, which exude an oily or creamy fluid when punctured, are derived from cystic dilatation of the sebaceous duct that empties into the hair follicle. 1. A ruptured canthal steatocystoma simplex has presented as a lacrimal sac mass. C. Histologically, a thick, eosinophilic cuticle covers the several layers of epithelial cells lining the cyst wall. Sebaceous lobules are present either within or close to the cyst wall.

VI. Calcifying epithelioma of Malherbe (pilomatrixoma; Fig. 6.24) A. Calcifying epithelioma of Malherbe is a cyst derived from the hair matrix that forms the hair. B. It can occur at any age, but most appear in the first two decades of life; it presents as a solitary tumor, firm, deepseated, and covered by normal skin. Nevertheless, it is frequently misdiagnosed when occurring in young adults. If superficial, it produces a blue-red discoloration. 1. It is reported to be the most common adnexal skin tumor in young patients. a. A review of 16 cases found that 75% of patients were younger than 13 years. A similarly young demographic for the lesion has been reported by others. 2. It has been reported to have a rapid onset following blunt trauma to the eyebrow. 3. The lesion has simulated a chalazion. Conversely, an inflammatory tumor of the eyelid that probably was secondary to IgG4-related sclerosing disease has mimicked pilomatrixoma. 4. Presentation as a rapidly enlarging recurrent mass in an elderly, 97-year-old patient has been reported. A rapidly enlarging lesion in a 5-year-old child clinically raised the suspicion of rhabdomyosarcoma. Periorbital pilomatrixoma has occurred in a 3-yearold girl with a history of bilateral retinoblastoma. C. Histologically, the tumor is sharply demarcated and composed of basophilic and shadow cells. 1. Basophilic cells closely resemble the basaloid cells of a basal cell carcinoma (dark basophilic nucleus surrounded by scant basophilic cytoplasm). 2. Shadow cells stain faintly eosinophilic, have distinct cell borders, and instead of nuclei show central, unstained regions where the nuclei should be. In older tumors, basophilic cells may have disappeared completely so that only shadow cells remain. 3. The stroma may show areas of keratinization, fibrosis, calcification, foreign-body granuloma, and ossification. 4. In one study, only 18.75% of lesions were diagnosed correctly clinically. Follicular hybrid cyst of the tarsus, which had features of pilomatricoma and steatocystoma, has been reported to perforate the palpebral surface of the conjunctiva.

D. Pilomatrix carcinoma may develop from malignant transformation of a benign pilomatricoma or may arise de novo. VII. Hidrocystoma (Figs. 6.25 and 6.26) A. Cysts resulting from occlusion of the eccrine or apocrine duct are referred to as hidrocystomas. 1. When multiple, these can be associated with Goltz– Gorlin syndrome (GGS) or Schopf–Schulz–Passarge syndrome (SSPS).

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205

B A

Fig. 6.24  Calcifying epithelioma of Malherbe (pilomatricoma). A, Clinical photo of lesion involving the lateral aspect of the right lower eyelid. B, Low-magnification photomicrograph demonstrating position of lesion relative to the skin surface and light areas of necrosis containing shadow cells and dark basophilic cells. C, High magnification of pale shadow cells on left and dark basophilic cells on right. (A and B, Courtesy of Dr. Morton Smith; C, courtesy of Armed Forces Institute of Pathology, Washington, DC, accession number 984935.)

C







a. GGS usually is sporadic; however, it also may be X-linked dominant. It is characterized by mesoectodermal defects that may involve the skin, eyes, or teeth. 1) The skin may display linear or reticulated atrophic hypo- or hyperpigmented lesions, papillomas and periocular multiple hidrocystomas. 2) There may be microcephaly; midfacial hypoplasia; malformed ears; microphthalmia; papillomas of the lip, tongue, anus, and axilla; skeletal abnormalities; and mental retardation. b. SSPS is an autosomal form of ectodermal dysplasia. It is characterized by hypodontia, hypoplastic nails, hypotrichosis, palmoplantar keratosis, cysts of the eyelid margins, and multiple periocular apocrine hidrocystomas. c. Multiple eccrine hidrocystomas also are found in association with Graves’ disease. 2. Apocrine hidrocystomas usually occur in adults as solitary (sometimes multiple) lesions, often with a blue tint, and are usually located in the skin near the eyes. 3. A congenital massive orbital lesion has resulted in “extrusion” of the globe. Other large lesions have caused eyelid ptosis.





4. The extrusion of lipofuscin pigment into an apocrinerich cyst can result in a pigmented hidrocystoma containing brown-black contents. B. Eccrine hidrocystomas may be solitary or multiple, and clinically are indistinguishable from apocrine hidrocystomas. 1. They can become very large and may even cause eyelid ptosis. Large orbital lesions can impact eyelid function. 2. The lesion may arise on the tarsal plate. 3. Based on immunohistochemical studies, apocrine hidrocystomas probably predominate over eccrine hidrocystomas in the eyelids. C. Histology 1. The apocrine hidrocystoma, which is derived from the apocrine sweat glands of Moll, is an irregularly shaped cyst, and has an outer myoepithelium layer and an inner (luminal) layer of columnar epithelium, showing apical decapitation secretion. 2. The eccrine hidrocystoma, which is derived from the eccrine sweat glands, is more rounded and shows a flattened wall that contains one or two layers of cuboidal epithelium and sometimes contains papillary projections into the lumen of the cysts (mean age at diagnosis is 59 years; 71% of lesions are single;

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A

B

Fig. 6.25  Ductal cyst, probably apocrine, caused by clogged sweat duct, may take many forms. A, Ductal cyst noted near the outer margin of the right lower lid. B, Multiloculated large ductal cyst appears empty. C, The cyst is lined by a double layer of epithelium.

C

A

B

Fig. 6.26  Eccrine hidrocystoma. A, Clinical appearance of lesion. B, Histologic section shows a flattened wall lined by one or two layers of cuboidal epithelium and containing papillary projections into the lumen of the cysts. C, Increased magnification of papillary projections.

C

Cysts, Pseudoneoplasms, and Neoplasms

and 87% are located near but not on the eyelid margin).

epidermis showing a normal polarity but some degree of acanthosis and hyperkeratosis, along with variable parakeratosis and elongation of rete pegs.

Benign Tumors of the Surface Epithelium I. Papilloma (Figs. 6.27 and 6.28) A. Papilloma is an upward proliferation of skin resulting in an elevated irregular lesion with an undulating surface. B. Six conditions show this type of proliferation as a predominant feature: (1) nonspecific papilloma (most common); (2) nevus verrucosus (epidermal cell nevus; Jadassohn); (3) acanthosis nigricans; (4) verruca vulgaris (see earlier under subsection Viral Diseases); (5) seborrheic keratosis; and (6) actinic keratosis (see later under section Precancerous Tumors of the Surface Epithelium). C. Histologically, a papilloma is characterized by finger-like projections or fronds of papillary dermis covered by

The dermal component may have a prominent vascular element. Usually, histologic examination of a papillomatous lesion indicates which of the different papillomatous conditions is involved.



A

B

C

D

D. Nonspecific papilloma (see Fig. 6.28) 1. Nonspecific papilloma, a polyp of the skin, is usually further subdivided into a broad-based and a narrowbased type. The broad-based type is called a sessile papilloma and the narrow-based type is called a pedunculated papilloma, a fibroepithelial papilloma, acrochordon, or simply a skin tag.

Fig. 6.27  Differences between benign and malignant skin lesions. A, An elevated skin lesion sitting as a “button” on the skin surface. This is characteristic of benign papillomatous lesions. When such lesions appear red histologically under low magnification, they show acanthosis, as in actinic keratosis. B, Lesions structurally similar to A but that appear blue under low magnification are caused by proliferation of basal cells, as in seborrheic keratosis. C, An elevated lesion that invades the underlying skin is characteristic of a malignancy. Invasive lesions that appear red under low magnification are caused by proliferation of the squamous layer (acanthosis), as in squamous cell carcinoma. D, A lesion structurally similar to C but that appears blue under low magnification represents proliferation of basal cells, as seen in basal cell carcinoma.

A

207

B Fig. 6.28  Fibroepithelial papilloma. A, Clinical appearance of two skin tags (fibroepithelial papillomas) of left upper lid. B, Fibroepithelial papilloma consists of a narrow-based (to the right) papilloma whose fibrovascular core and finger-like projections are covered by acanthotic, orthokeratotic (hyperkeratotic) epithelium.

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2. Histologically, finger-like projections of papillary dermis are covered by normal-thickness epithelium showing elongation of rete ridges and orthokeratosis. E. Nevus verrucosus (epidermal cell nevus; Jadassohn) 1. Nevus verrucosus consists of a single lesion present at birth or appearing early in life. 2. Histologically, the lesion consists of closely set, papillomatous, orthokeratotic papules, marked acanthosis, and elongation of rete pegs. F. Acanthosis nigricans Acanthosis nigricans exists in five types, all showing papillomatous and verrucous brownish patches predominantly in the axillae, on the dorsum of fingers, on the neck, or in the genital and submammary regions.







1. Hereditary (benign) type: not associated with an internal adenocarcinoma, other syndromes, or endocrinopathy; benign type: associated with insulin resistance, endocrine disorders, and other disorders such as Crouzon’s disease; pseudoacanthosis nigricans: a reversible condition related to obesity; drug-induced type; and adult (malignant) type: associated with an internal adenocarcinoma, most commonly of the stomach. 2. The benign form associated with obesity, insulin resistance, diabetes mellitus, and drug use is relatively common and comprises 80% of cases of the disorder. a. In particular, facial involvement may be a morphologic marker for metabolic syndrome. b. It is the most frequent manifestation of pediatric obesity, and occurs in 66% of overweight adolescents and in 56% to 92% of children and adolescents with type 2 diabetes mellitus. c. There is a particularly high incidence in Native American children associated with obesity and diabetes. 3. When associated with malignancy, it is observed in 58% of patients before the tumor is diagnosed. The malignant form is associated with tumor products, tumor necrosis factors, and insulin-like activity. 4. Histologically, the first four are identical and show marked orthokeratosis and papillomatosis and mild acanthosis and hyperpigmentation. a. The fifth has additional malignant cytologic changes. b. The dark color is said to be more related to hyperkeratosis than to the presence of melanin. G. Seborrheic keratosis results from an intraepidermal proliferation of benign basal cells (basal cell acanthoma; see Fig. 6.27; Fig. 6.29). 1. Seborrheic keratosis increases in size and number with increasing age and is most common in the elderly. 2. The lesions tend to be sharply defined, brownish, softly lobulated papules or plaques with a rough, almost warty surface.

sk s

A

B Fig. 6.29  Seborrheic keratosis. A, The “greasy” elevated lesion is present in the middle nasal portion of the left lower lid. Biopsy showed this to be a seborrheic keratosis (sk). The smaller lesion just inferior and nasal to the seborrheic keratosis proved to be a syringoma (s; see Fig. 6.42). Another seborrheic keratosis is present on the side of the nose. B, Histologic section shows a papillomatous lesion that lies above the skin surface and is blue. The lesion contains proliferated basaloid cells and keratin-filled cysts.

3. Rarely, squamous cell carcinoma may arise in seborrheic keratosis. 4. Seborrheic keratosis may be pigmented either secondary to environmental debris deposited on the lesion’s heavily keratinized surface, or from actual melanin produced by melanocytes, which can contribute to the lesion being mistaken for a malignant melanoma. 5. In one report, the lesion comprised 12.6% of 4521 specimens received for histopathologic examination. Of course, this number represents only those lesions about which the patient or surgeon were concerned, and in no way represents the actual prevalence of the lesion in the population. 6. Histologically, the lesion has a papillomatous configuration and an upward acanthosis so that it sits as a “button” on the surface of the skin and contains a proliferation of cells closely resembling normal basal cells, called basaloid cells. The histologic appearance of a seborrheic keratosis is variable. The lesion frequently contains cystic accumulations of horny (keratinous) material. Six

Cysts, Pseudoneoplasms, and Neoplasms subtypes are recognized: acanthotic, hyperkeratotic, reticulated (adenoid), clonal, irritated (IFK; see later), and melanoacanthoma. All show acanthosis, orthokeratosis, and papillomatosis. Some may show an epithelial thickening (acanthotic) or a peculiar adenoid pattern in which the epithelium proliferates in the dermis in narrow, interconnecting cords or tracts (reticulated). It may be deeply pigmented (melanoacanthoma) and even confused clinically with a malignant melanoma.



7. Inverted follicular keratosis (IFK) (irritated seborrheic keratosis, basosquamous cell epidermal tumor, basosquamous cell acanthoma; Fig. 6.30) resembles a seborrheic keratosis but has an additional squamous element. a. IFK is a benign epithelial skin lesion found most frequently on the face in middle-aged or older people, typically presenting as an asymptomatic, pink to flesh-colored, small papule, rarely pigmented. Rarely, IFK may recur rapidly after excision. Re-excision cures the lesion.





c. Most IFKs are identical to irritated seborrheic keratoses, whereas others may be forms of verruca vulgaris or a reactive phenomenon related to pseudoepitheliomatous hyperplasia (see later). d. Histologically, IFK is similar to a seborrheic keratosis or verruca vulgaris, but with the addition of basaloid cells around whorls of squamous epithelium forming squamous eddies. II. Pseudoepitheliomatous hyperplasia (invasive acanthosis, invasive acanthoma, carcinomatoid hyperplasia; Fig. 6.31) consists of a benign proliferation of the epidermis simulating an epithelial neoplasm. A. It is seen frequently at the edge of burns or ulcers, near neoplasms such as basal cell carcinoma, malignant melanoma, or granular cell tumor, around areas of chronic inflammation such as blastomycosis, scrofuloderma, and gumma, or in lesions such as keratoacanthoma and perhaps IFK. B. Histologically, the usual type of pseudoepitheliomatous hyperplasia, no matter what the associated lesion, if any, consists of irregular invasion of the dermis by squamous cells that may show mitotic figures, but do not show dyskeratosis or atypia, and frequent infiltration of the squamous proliferations by leukocytes, mainly neutrophils.

b. It usually shows a papillomatous configuration, exists as a solitary lesion, and may exhibit rapid growth.

A

Although an inflammatory infiltrate is frequently seen under or around a squamous cell carcinoma, the

B

Fig. 6.30  Inverted follicular keratosis. A, Clinical appearance of lesion in the middle of the right lower lid. B, Histologic section shows a papillomatous lesion above the skin surface composed mainly of acanthotic epithelium. C, Increased magnification shows separation or acantholysis of individual squamous cells that surround the characteristic squamous eddies.

C

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A

B

Fig. 6.31  Pseudoepitheliomatous hyperplasia. A, Clinical appearance. B, Histologic section shows marked acanthosis, mild orthokeratosis, and inflammation characteristically present in dermis and epidermis. C, High magnification shows polymorphonuclear leukocytes in dermis and epidermis.

C

A

B Fig. 6.32  Keratoacanthoma. A, This patient had a six-week history of a rapidly enlarging lesion. Note the umbilicated central area. B, Histologic section shows that the lesion is above the surface epithelium and has a cup-shaped configuration and a central keratin core. The base of the acanthotic epithelium is blunted (rather than invasive) at the junction of the dermis.

inflammatory cells almost never infiltrate the neoplastic cells directly. If inflammatory cells admixed with squamous cells are seen, especially if the inflammatory cells are neutrophils, a reactive lesion such as pseudoepitheliomatous hyperplasia should be considered.

III. Keratoacanthoma (Fig. 6.32) A. Keratoacanthoma (KA) may be a type of pseudoepitheliomatous hyperplasia, although most dermatopathologists believe it is a type of low-grade squamous cell





carcinoma of hair follicle origin, and use the classification, squamous cell carcinoma, keratoacanthoma type, to reflect this conclusion. B. Classically, it is described as consisting of a solitary lesion (occasionally grouped lesions) that develops on exposed (usually hairy) areas of skin in middle-aged or elderly people, grows rapidly for 2 to 6 weeks, shows a raised, smooth edge and an umbilicated, crusted center, and then involutes in a few months to a year, leaving a depressed scar. C. It has been reported in infants in association with xeroderma pigmentosa.

Cysts, Pseudoneoplasms, and Neoplasms



a keratoacanthoma from squamous cell carcinoma, and indeed, some keratoacanthomas show areas of undisputed squamous cell carcinoma differentiation. The superficially invasive variant of keratoacanthoma, called invasive keratoacanthoma, may not involute spontaneously and probably represents a more aggressive form of squamous cell carcinoma.

D. Multiple KAs are rare, and may be sporadic or familial. 1. Generalized eruptive keratoacanthomas of Grzybowski occur on sun-exposed areas, and may cause a characteristic masked face from periocular involvement (sign of Zorro, which is named for a Johnston McCulley fictional character). Ectropion may be a consequence. a. Sudden onset of hundreds to thousands of lesions. b. Lesions are intensely pruritic. c. May be associated with visceral neoplasms.



IV. Warty dyskeratoma A. It presents primarily on the scalp, face, or neck as an umbilicated, keratotic papule, resembling a keratoacanthoma. B. Histologically, a cup-shaped invagination is filled with keratin and acantholytic, dyskeratotic cells. Villi of dermal papillae lined by a single layer of basal cells project into the base of the crater. The histopathology is identical to Darier’s disease. C. May be related to a localized error in epithelial maturation and cohesiveness similar to Darier’s disease, which is an ATP2A2 mutation (Fig. 6.33).

Rarely, keratoacanthoma can occur on the conjunctiva.



E. Histologically, keratoacanthoma is characterized by its dome- or cup-shaped configuration with elevated wall and central keratin mass seen under low magnification, and by acanthosis with normal polarity seen under high magnification. The deep edges of the tumor appear wide and blunt, rather than infiltrative.

Corps ronds (i.e., dyskeratotic cells containing pyknotic nuclei, surrounded by a clear halo, present in the granular layer at the entrance to the invagination) are reminiscent of Darier’s disease.

In the past, the tumor has been confused with “aggressive” squamous cell carcinoma. The typical noninvasive, elevated cup shape with a large central keratin core, as seen under low-power light microscopy, along with the benign cytology and wide and blunt deep edges seen under high-power light microscopy, should lead to the proper diagnosis of keratoacanthoma. If, however, only a small piece of tissue (e.g., a partial biopsy) is available for examination, it may be difficult or impossible to differentiate

A

211

V. Large cell acanthoma A. Large cell acanthoma appears as a slightly keratotic, solitary lesion, usually smaller than 1 cm, and has a predilection for the face and neck, followed by the upper

B Fig. 6.33  Warty dyskeratoma (WD) of the right lower eyelid in a 60-year-old woman presenting as a slowly growing papule. A, Benign and malignant epithelial neoplasms were considered in the clinical differential. B, Histologically, the lesion was an endo-exophytic epithelial neoplasm composed of uniform keratinocytes with zones of acantholysis and dyskeratosis with corps ronds and corps grains. The cause of WD is unknown. The presence of acantholysis and dyskeratosis suggests a localized error in epithelial maturation and cohesiveness akin to that seen in Darier’s disease (ATP2A2 mutation). Attempts to define human papillomavirus as pathogenic have been uniformly unsuccessful. (From Phelps et al.: Warty dyskeratoma of the eyelid. Ophthalmology 122(7):1282, 2015. Elsevier.)

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extremities. It has not been documented to progress to squamous carcinoma. B. Histologically, it is a benign hyperpigmented epidermal lesion showing a moderately acanthotic epidermis that contains sharply circumscribed, uniformly hyperplastic keratinocytes, a wavy, orthokeratotic, and parakeratotic granular cell layer, and sometimes a papillomatosis. Polyploidy may be present. C. Some have considered it a variant of solar lentigo with cellular hypertrophy. 1. It also has been viewed as a subtype of seborrheic keratosis or a human papillomavirus-induced acanthoma. 2. Other conclusions also have been reported.





II. Xeroderma pigmentosum—see section Congenital Abnormalities earlier in this chapter. III. Radiation dermatosis A. The chronic effects include atrophy of epidermis, dermal appendages, and noncapillary blood vessels; dilatation or telangiectasis of capillaries; and frequently hyperpigmentation. B. Squamous cell carcinoma (most common), basal cell carcinoma, or mesenchymal sarcomas such as fibrosarcoma may develop years after skin irradiations (e.g., after radiation for retinoblastoma). IV. Actinic keratosis (senile keratosis; solar keratosis) occurs as multiple lesions on areas of skin exposed to sun (Fig. 6.34; see Fig. 6.27). A. Fair-skinned people are prone to development of multiple neoplasms, including solar keratosis and basal and squamous cell carcinomas. B. The lesions tend to be minimally elevated, slightly scaly, and flesh-colored to pink, but present as a papilloma or as a projecting cutaneous horn.

Dysplastic enlarged keratinocytes and an increased number of Civatte bodies (necrotic keratinocytes) may be found.

VI. Benign keratosis consists of a benign proliferation of epidermal cells, usually acanthotic in form, which does not fit into any known classification.

A cutaneous horn (cornu cutaneum) is a descriptive clinical term. The lesion has many causes, e.g. actinic keratosis, verruca vulgaris, seborrheic keratosis, IFK, squamous cell carcinoma (uncommonly), and even sebaceous gland carcinoma (rarely). Approximately 77% are associated with benign lesions at the base, 15% are premalignant, and 8% are associated with

Precancerous Tumors of the Surface Epithelium I. Leukoplakia—this is a clinical term that describes a white plaque but gives no information about the underlying cause or prognosis; the term should not be used in histopathology.

A

B Fig. 6.34  Actinic keratosis. A, The clinical appearance of a lesion involving the left upper lid. B, Histologic section shows a papillomatous lesion that is above the skin surface, appears red, and has marked hyperkeratosis and acanthosis. C, Although the squamous layer of the skin is increased in thickness (acanthosis) and the basal layer shows atypical cells, the normal polarity of the epidermis is preserved.

C

Cysts, Pseudoneoplasms, and Neoplasms malignant lesions. In another study of 13 cases involving the eyelid, the incidence of malignancy was 23%. Therefore, an underlying malignancy must be considered in evaluating all lesions that present as a cutaneous horn. The most common histopathologic benign diagnosis is seborrheic keratosis; premalignant, actinic keratosis; and malignant, squamous cell carcinoma.



C. Histologically, actinic keratosis is characterized by focal to confluent parakeratosis overlying an epidermis of variable thickness. Both cellular atypia and mitotic figures appear in the deeper epidermal layers, which may form buds extending into the superficial dermis. The underlying dermis usually shows actinic elastosis and an inflammatory reaction mainly of lymphocytes and some plasma cells.

and tends to be only locally invasive, almost never metastasizing. The overproduction of Sonic Hedgehog, the ligand for PTC (tumor suppressor gene PATCHED) mimics loss of PTC function and induces basal cell carcinomas in mice; it may play a role in human tumorigenesis. Ptch-1 mutations have been suggested to contribute to the development of BCC.





Actinic keratosis may become quite pigmented and then mimic, both clinically and histopathologically, a primary melanocytic tumor. Actinic keratosis also may resemble squamous cell carcinoma or Bowen’s disease. It differs from the former in not being invasive and from the latter in not showing total replacement (loss of polarity) of the epidermis by atypical cells. Squamous cell carcinoma infrequently and basal cell carcinoma rarely may arise from actinic keratosis.



Cancerous Tumors of the Surface Epithelium Handheld in vivo reflectance confocal microscopy holds promise for supplementing traditional clinical methods in the evaluation of lesions of the eyelids and conjunctiva. In general, the strongest evidence from published reports regarding the treatment of malignant eyelid tumors supports complete surgical removal using histologic controls for verifying tumor-free surgical margins.

I. Basal cell carcinoma (BCC) (Figs. 6.35 and 6.36; see Fig. 6.27) A. Over 500,000 new cases of skin cancer occur each year in the United States; at least 75% are basal cell carcinoma. Approximately 16% are located on the eyelids, most commonly on the lower eyelids. B. BCC is, by far, the most common malignant tumor of the eyelids and accounts for 85%–90% of all malignant epithelial eyelid tumors in non-Asian countries. 1. It occurs most frequently on the lower eyelid, followed by the inner canthus, the upper eyelid, and then the lateral canthus. 2. It occurs most commonly in fair-skinned people on skin areas exposed to ultraviolet radiation (i.e., sunexposed areas). C. The neoplasm has no sex predilection, is found most often in whites, mainly in the seventh decade of life,

213





D. The clinical appearance varies greatly, but most present as a painless, shiny, waxy, indurated, firm, pearly nodule with a rolled border and fine telangiectases. 1. Ulceration and pigmentation may occur. 2. Approximately 5% of BCCs are pigmented. a. The pigment usually varies in density and distribution rather than being uniform. b. Histopathologic examination reveals melanophages within the stroma accompanied by basaloid cell melanization. 3. Rarely, metastases may occur. E. Histologically and clinically, the tumor has considerable variation, but it can be grouped into four major types: nodular, superficial, micronodular, and infiltrative. 1. In the periocular areas, the relative frequency of these subtypes is nodular (65.7%), infiltrative (17.5%), superficial (12.6%), and micronodular (4.2%). 2. Infiltrative and micronodular tumors have a significantly increased risk of recurrence and morbidity. 3. An additional and aggressive variety of BCC of particular significance on the face is morpheaform BCC, which also will be discussed. 4. It is particularly important to report evidence of perineural invasion, lymphovascular invasion, and level of invasion on histopathologic examination for high rick BCC. 5. Infiltrative and superficial subtypes of BCC occur more frequently in the periocular region, and at lower latitudes compared with on the head and neck, and at higher latitudes. 6. Moreover, although individual subtypes of BCC are delineated here, a mixed histology may occur in up to 38.5% of tumors with nodular mixed with infiltrative, or nodular with superficial being particularly common in the periocular region. F. Most common varieties of BCC 1. Nodular (garden-variety) type occurs most commonly. a. Small, moderate-sized, or large groups or nests of cells resembling basal cells show peripheral palisading. 1) Cells in the nests contain large, oval, or elongated nuclei and little cytoplasm, may be pleomorphic and atypical but tend to be fairly uniform, and may contain mitotic figures. 2) The abnormal cells show continuity with the basal layer of surface epithelium.

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b ds d

A

B

pp

ds C

D Fig. 6.35  Basal cell carcinoma. A, This firm, indurated painless lesion had been present and growing for approximately eight months. B, Excisional biopsy shows epithelial proliferation arising from the basal layer of the epidermis (b, basal cell carcinoma). The proliferated cells appear blue and are present in nests of different sizes. Note the sharp demarcation of the pale-pink area of stroma supporting the neoplastic cells from the underlying (normal) dark-pink dermis (d, relatively normal dermis). This stromal change, called desmoplasia (ds, desmoplastic stroma), is characteristic of neoplastic lesions. Compare with the benign lesions in Figs. 6.27–6.30, where the dermis does not show such a change. C, The nests are composed of atypical basal cells and show peripheral palisading (pp). Mitotic figures are present. Again, note the pseudosarcomatous change (desmoplasia) (ds, desmoplastic stroma) of the surrounding supporting stroma, which is light-pink and contains proliferating fibroblasts. D, Higher magnification illustrates characteristic features of basal cell carcinoma, including atypical cells and separation artifact between nests of cells and desmoplastic surrounding connective tissue. (A, Courtesy of Dr. HC Scheie; D, courtesy of Dr. Morton Smith.)



b. The neoplasm may show surface ulceration, large areas of necrosis resulting in a cystic structure, areas of glandular formation, and squamous or sebaceous differentiation (nodular basal cell carcinoma variants include keratotic, adenoidal, and pigmented).

(i.e., the fibroblasts become large, numerous, and often bizarre, and the mesenchymal tissue becomes mucinous, loose, and “juicy” in appearance). The stromal desmoplastic reaction is typical of the basal cell neoplasm and helps differentiate the tumor from the similarly appearing adenoid cystic carcinoma (see Fig. 14.37), which frequently has an amorphous, relatively acellular surrounding stroma.

Some basal cell carcinomas may be heavily pigmented from melanin deposition and clinically simulate malignant melanomas.



c. The surrounding and intervening invaded dermis undergoes a characteristic pseudosarcomatous (resembling a sarcoma) change called desmoplasia



d. Ductal and glandular differentiation may occur in basal cell carcinoma. Such tumors are more common on the eyelid, face, and scalp, and display

Cysts, Pseudoneoplasms, and Neoplasms

A

215

B Fig. 6.36  Basal cell carcinoma. A, The inner aspect of the eyelids is ulcerated by the infiltrating tumor. B, Histologic section shows the morphea-like or fibrosing type, where the basal cells grow in thin strands or cords, often only one cell layer thick, closely resembling metastatic scirrhous carcinoma of the breast (“Indian file” pattern). This uncommon type of basal cell carcinoma has a much worse prognosis than the more common types (i.e., nodular [Fig. 6.35], ulcerative, and multicentric).













the presence of ducts of varying size and glandular structures occasionally suggesting apocrine secretion. e. Cystic BCC usually presents as small and multiple cysts; however, it may appear as a larger lesion that may even be translucent. It lacks apocrine gland differentiation that would be present in a BCC having ductal or glandular differentiation. f. There is a significantly increased prevalence and density of demodicosis in patients with eyelid basal cell carcinoma compared to control individuals, and may act as a triggering factor for carcinogenesis in individuals predisposed by trauma, irritation, or chronic inflammation. g. Eyelid location is a predictive factor for extensive subclinical spread of basal cell carcinoma. 2. Superficial basal cell carcinoma shows irregular buds of basaloid cells arising from a unicentric focus or multicentric foci of the epidermal undersurface. a. The cells resemble primordial germ cells. b. Tends to occur at a younger age particularly in females. 3. Micronodular type has a plaque-like shape. a. It resembles nodular BCC; however, it is smaller and forms micronodules that are approximately the size of hair bulbs. b. Minimal palisading is seen. c. The surrounding stroma is myxoid. 4. Infiltrative a. Considered a continuum between the nodular and morpheaform types. b. Different size nodules. c. Mucinous stroma. d. Invasive behavior. 5. Morpheaform (fibrosing) type a. Thin islands and strands of tumor cells that have an aggressive behavior. b. Lines of tumor cells may only be one layer thick.





c. No peripheral palisading. d. Closely resembling metastatic scirrhous carcinoma of the breast (“Indian file” pattern). e. The stroma, rather than being juicy and loose (desmoplastic), shows considerable proliferation of connective tissue into a dense fibrous stroma, reminiscent of scleroderma or morphea. The tumor strands tend to shrink in processing, leaving surrounding retraction spaces. f. In the morpheaform variant, it is difficult clinically to determine the limits of the lesion. The tumor tends to be much more aggressive, to invade much deeper into underlying tissue, and to recur more often than the nodular or superficial type. The basal cell nevus syndrome (Gorlin’s syndrome), inherited in an autosomal-dominant fashion, consists of multiple basal cell carcinomas of the skin associated with defects in other tissues such as odontogenic cysts of the jaw, bifid rib, abnormalities of the vertebrae, and keratinizing pits on the palms and soles. Histologically, the skin tumors are indistinguishable from the noninherited form of basal cell carcinoma. The defective gene is in the tumor suppressor gene PATCHED, a gene on chromosome 9q.



G. Frozen section-controlled excision is particularly important in preventing re-recurrence in recurrent BCC. H. “Horrifying basal cell carcinoma” was first used in 1973 to describe 33 cases of BCC that met the criteria of tumor size greater than 3 cm, and exhibited behavior characterized by local destruction, recurrence, and metastasis. 1. The initial report noted that these tumors were histologically indistinguishable from ordinary basal cell carcinomas.

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2. The term, “problematic aggressive” has been used to designate these tumors and BCCs that are frequently recurrent, often after histologically confirmed excision. 3. They have been associated with more aggressive pattern such as morpheaform, multifocal, and infiltrative growth. 4. Others have concluded that horrifying tumors do not have intrinsically different growth patterns or proliferation characteristics. They cite reports of denial on the part of the patient, and delay in seeking care, or inadequate early management, particularly of infiltrative tumors as key factors contributing to horrifying BCCs. I. It has been suggested that impression cytology may be useful in the diagnosis of eyelid tumors. II. Squamous cell skin carcinoma (Fig. 6.37; see Fig. 6.27) A. Squamous cell carcinoma rarely involves the eyelid, and is seen at least 40 times less frequently than eyelid basal cell carcinoma. The most frequent sites of periocular involvement are the lower eyelid (49%), medial canthus (36%), and the upper eyelid (23%). The opposite situation exists in the conjunctiva (see Chapter 7), where squamous cell carcinoma is the most common epithelial malignancy and basal cell carcinoma is the rarest.

A









B. From the 1960s to the 1980s, the incidence of squamous cell skin carcinoma increased 2.6 times in men and 3.1 times in women, attributed to presumed voluntary exposure to sunlight (ultraviolet radiation). C. Intraepidermal squamous cell carcinoma (squamous cell carcinoma in situ) 1. When epidermal atypia becomes full-thickness, intraepidermal squamous cell carcinoma (carcinoma in situ) is present. It may arise de novo or from precancerous keratoses (e.g., actinic keratosis). 2. Clinically, the area is indurated and plaquelike. 3. Histologically, the lesion resembles the precancerous keratoses except for more advanced changes. a. Carcinoma in situ is characterized by replacement of the epidermis by an atypical proliferation of keratinocytes showing loss of polarity, nuclear hyperchromatism and pleomorphism, cellular atypia, and mitotic figures. Better differentiation may be accompanied by the presence of “squamous pearls or dyskeratotic pearls” formed by clusters of abnormal gradually keratinizing atypical squamous cells. These structures must be differentiated from “horn cysts” that are common in benign squamous lesions and consist of keratinfilled cysts that do not display the gradual keratinization commonly found in dyskeratotic pearls, or with the “squamous eddy” typical of IFK. b. The overlying stratum corneum is parakeratotic.

B

Fig. 6.37  Squamous cell carcinoma. A, The patient had an ulcerated lesion of the lateral aspect of the eyelids that increased in size over many months. B, Histologic section of the excisional biopsy shows epithelial cells with an overall pink color that infiltrate the dermis deeply. The overlying region is ulcerated. C, Increased magnification shows the invasive squamous neoplastic cells making keratin (pearls) in an abnormal location (dyskeratosis). Numerous mitotic figures are present. Note the pseudosarcomatous (dysplastic) change in the surrounding stroma.

C

Cysts, Pseudoneoplasms, and Neoplasms





D. Invasive squamous cell carcinoma 1. Carcinoma in situ may remain fairly stationary or enlarge slowly and invade the dermis (i.e., invasive squamous cell carcinoma). 2. Histologically, if the intraepidermal squamous cell carcinoma penetrates through the epidermal basement membrane and invades the dermis, the lesion is classified as invasive squamous cell carcinoma. The supporting dermal stroma then undergoes a proliferative, desmoplastic, pseudosarcomatous reaction. 3. Squamous cell skin carcinomas less than 2 mm thick (approximately 50% of total) almost never metastasize (“no-risk carcinomas”); of those between 2 and 6 mm thick (moderate differentiation and invasion not extending beyond the subcutis), approximately 4.5% metastasize (“low-risk carcinomas”); and of those over 6 mm thick, especially with infiltration of the musculature, perichondrium, or periosteum, approximately 15% metastasize (“high-risk carcinomas”). 4. The rate of regional lymph node metastasis in patients with eyelid or periocular squamous cell carcinoma may be as high as 24%. Sentinel lymph node biopsy may be helpful in the evaluation of conjunctival and eyelid malignancies. a. Preoperative lymphoscintigraphy facilitates identifying sentinel lymph nodes. b. Overexpression of cluster of differentiation 44 variant 6 is correlated with the progress and metastasis of ocular squamous cell carcinoma and is associated with proliferating cell nuclear antigen labeling index. 5. Perineural invasion is an adverse prognostic finding. Cutaneous squamous cell carcinoma may show perineural spread of the neoplasm through the orbit. The tumor may also metastasize to regional lymph nodes in about 24% of patients. 6. Squamous cell carcinoma needs to be differentiated from pseudocarcinomatous (pseudoepitheliomatous) hyperplasia, which shows minimal or absent individual cell keratinization and lacks nuclear atypia (see Fig. 6.31). 7. Increased expression of αv integrin protein in squamous cell carcinoma is associated with less differentiated and more invasive lesions. Conversely, well-differentiated squamous cells and carcinoma in situ express low levels of αv integrin protein. 8. Immunoexpression of VEGF and epidermal growth factor receptor is higher in moderate/poorly differentiated eyelid squamous cell carcinomas compared to well-differentiated tumors. These markers are associated with the acquisition of aggressive and angiogenic phenotype. 9. Methylation and associated low expression of CDH1, which encodes E-cadherin, a glycoprotein that is important in cell–cell interaction, are significantly



217

associated with advanced and aggressive phenotypes of eyelid squamous cell carcinoma. In this regard, CDH1 methylation and CDH1 expression are both prognostic factors for eyelid squamous cell carcinoma. 10. Strong p16 expression was observed in all ocular surface and periorbital squamous tumors in one study. E. Bowen’s disease (intraepidermal squamous cell carcinoma, Bowen type) 1. Bowen’s disease is a clinicopathologic entity that consists of an indolent, solitary (or multiple), erythematous, sharply demarcated, scaly patch. It grows slowly in a superficial, centrifugal manner, forming irregular, serpiginous borders. The lesions may remain relatively stationary for up to 30 years. 2. Bowen’s disease is associated with other skin tumors, both malignant and premalignant, in up to 50% of patients. The suggested association with internal malignancies has not been definitely established. Arsenic concentration in Bowen’s disease lesions is high and may even cause them.

3. Rarely, Bowen’s disease may invade the underlying dermis, and then it behaves like an invasive squamous cell carcinoma. 4. Histologically, the lesion is characterized by a loss of polarity of the epidermis so that the normal epidermal cells are replaced by atypical, sometimes vacuolated or multinucleated, haphazardly arranged cells not infrequently showing dyskeratosis and mitotic figures that are often bizarre. The basal cell layer is intact, and the underlying dermis is not invaded. Histologically, the clinicopathologic entity of Bowen’s disease and intraepidermal squamous cell carcinoma unrelated to Bowen’s disease (see earlier) cannot be distinguished. Bowen’s disease is not a histopathologic diagnosis, but rather a clinicopathologic one.



F. Adenoacanthoma, a rare tumor, may represent a pseudoglandular (tubular and alveolar formations in the tumor) form of squamous cell carcinoma, or it may be an independent neoplasm. The prognosis is somewhat more favorable than for the usual squamous cell carcinoma. Clear cell acanthoma (Degos’ acanthoma) is a benign, solitary, well-circumscribed, noninvasive neoplasm. Histologically, there is a proliferation of glycogen-rich, clear, large epidermal cells.

Tumors of the Epidermal Appendages (Adnexal Skin Structures) Benign adnexal tumors include apocrine or eccrine hydrocystoma (80%), pilomatrixoma (5%), syringoma (5%), trichilemmoma

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(5%), syringocystadenoma papilliferum (2%), trichoepithelioma (1%), and trichofolliculoma (1%). I. Tumors of, or resembling, sebaceous glands A. Congenital sebaceous gland hyperplasia (organoid nevus syndrome, nevus sebaceus of Jadassohn, congenital sebaceous gland hamartoma) 1. Congenital sebaceous gland hyperplasia consists of a single, hairless patch, usually on the face or scalp that usually reaches its full size at puberty. 2. The tumor seems to be a developmental error, resulting in a localized hyperplasia of sebaceous glands frequently associated with numerous imperfectly developed hair follicles and occasionally apocrine glands. The tumor can be considered hamartomatous. Epibulbar choristoma and conjunctival choristomas, choroidal colobomas, macro optic discs, and focal yellow discoloration in the fundus may occur in the nevus sebaceus of Jadassohn. Linear nevus sebaceus syndrome consists of nevus sebaceus of Jadassohn, seizures, and mental retardation.

A

B Fig. 6.38  Adenoma sebaceum of Pringle in tuberous sclerosis. A, Clinical appearance. B, Dermal capillary dilatation and fibrosis are typical components of the lesion (i.e., angiofibroma).

3. Histologically, a group or groups of mature sebaceous gland lobules, with or without hair follicles, and frequently with underlying apocrine glands, are present just under the epidermis, along with overlying papillomatosis. Basal cell carcinoma may develop in up to 20% of the lesions, and more rarely other tumors may develop (e.g., syringocystadenoma papilliferum and sebaceous carcinoma). Moreover, syringocystadenoma papilliferum may mimic basal cell carcinoma clinically.



B. Acquired sebaceous gland hyperplasia (senile sebaceous gland hyperplasia, senile sebaceous nevi, adenomatoid sebaceous gland hyperplasia) 1. Acquired sebaceous gland hyperplasia consists of one or more small, elevated, soft, yellowish, slightly umbilicated nodules occurring on the face (especially the forehead) in the elderly. 2. Histologically, a greatly enlarged sebaceous gland is composed of numerous lobules grouped around a central large sebaceous duct. Sebaceous gland hyperplasia may follow chronic dermatitis, especially acne rosacea and rhinophyma.



C. Adenoma sebaceum of Pringle (angiofibromas of face; Fig. 6.38) 1. The small, reddish, smooth papules seen on the nasolabial folds, on the cheeks, and on the chin in people with tuberous sclerosis (Chapter 2) have been



called adenoma sebaceum (Pringle) but are truly angiofibromas. 2. Histologically, the sebaceous glands are usually atrophic. Dilated capillaries and fibrosis are seen in the smaller lesions, whereas capillary dilatation is minimal or absent in the larger lesions, where markedly sclerotic collagen is arranged in thick concentric layers around atrophic hair follicles. D. Sebaceous adenoma 1. Although rare, it has a predilection for the eyebrow and eyelid and appears as a single, firm, yellowish nodule. The presence of a solitary sebaceous gland lesion (mainly adenoma) may be associated with a visceral malignancy, primarily of the gastrointestinal tract (Muir–Torre syndrome), which is a rare autosomal dominantly inherited subtype of Lynch syndrome II and caused by DNA mismatch repair proteins. Immunohistochemical staining of eyelid sebaceous adenomas for the mismatch repair proteins mutL homologue 1 (MLH1) and mutS homologue 2 (MSH2) is useful for evaluating for Muir–Torre syndrome. Nevertheless, neither loss of mismatch repair genes, nor microsatellite instability are commonly associated with sporadic sebaceous carcinoma of the ocular adnexa. Both benign sebaceous and transitional squamosebaceous neoplasms should be considered as possible manifestations of the syndrome. Multiple sebaceous adenomas and extraocular sebaceous carcinoma have been reported in a patient with multiple sclerosis.

Cysts, Pseudoneoplasms, and Neoplasms







2. Histologically, the irregularly shaped lobules are composed of three types of cells. a. The presence of generative or undifferentiated cells, identical in appearance to the cells present at the periphery of normal sebaceous glands, allows the diagnosis to be made. b. Mature sebaceous cells. c. Transitional cells between the preceding two types. 3. Rapid growth in a sebaceous adenoma due to hyperplasia has simulated malignancy. Malignancy was excluded secondary to lack of infiltrative border, low Ki-67 index, and low proliferative ability. E. Sebaceous gland carcinoma (Fig. 6.39; see Fig. 6.4B) 1. Sebaceous gland carcinoma (SGC) is more common in middle-aged women, has a predilection for the

eyelids, and arises mainly from the meibomian glands, but also from the glands of Zeis, and sebaceous glands. a. It is the most common eyelid malignancy after basal cell carcinoma affecting in descending order the upper lid (two to three times more often than the lower), the lower lid, the caruncle, and then the brow. It accounts for only 1%–5.5% of eyelid malignancies in Caucasians; however, it represents 39% and 37.5% of eyelid malignancies in Chinese and Japanese people, respectively. 2. Clinically, a SGC is often mistaken for a chalazion. The lesion, however, may mimic many conditions, and is called the great masquerader.



A

B

C

D

Fig. 6.39  Sebaceous gland carcinoma. A, Upper-lid lesion resembles a chalazion. Note loss of cilia in area of lesion. B, Excisional biopsy shows large tumor nodules in the dermis, most of which exhibit central necrosis. C, Increased magnification shows numerous cells resembling sebaceous cells. A number of mitotic figures are present. D, Oil red-O fat stain shows marked positivity in the cytoplasm of abnormal cells. Any recurrent or suspect chalazion should be sampled for biopsy. E, In another case, large tumor cells are scattered throughout the surface epidermis, simulating Paget’s disease (i.e., pagetoid change). The cancerous invasion of the epithelium can cause a chronic blepharoconjunctivitis (masquerade syndrome). E

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a. Any recurrent chalazion should be considered for histologic study, and any chronic, recalcitrant, atypical blepharitis or atypical unilateral papillary conjunctivitis should be considered for biopsy, especially when accompanied by loss of lashes (madarosis). b. Clinical dermoscopic examination of the lesion can demonstrate polymorphous vessels with a yellowish background to assist in the diagnosis. c. SGC can be found in association with Muir–Torre syndrome (also see above). The syndrome has been reported in a patient with bilateral eyelid cancers, including SGC, and breast cancer. Mutational inactivation of p53 may be involved in the progression of sebaceous carcinoma.

3. The mortality rate is approximately 22%. Treatment by Mohs micrographic surgery may significantly reduce the mortality. Metastatic breast cancer to the eyelid margin has masqueraded as SGC.





4. Histologically, irregular lobular masses of cells resemble sebaceous adenoma but tend to be more bizarre and to show distinct invasiveness. a. Focally, cells show abundant cytoplasm signifying sebaceous differentiation. b. Fat stains of frozen sections of fixed tissue show that many of the cells are lipid-positive. c. The malignant epithelial cells may invade the epidermis, producing an overlying change resembling Paget’s disease called pagetoid change. d. In one study, immunohistochemical staining for androgen receptor and for adipophilin was found to be helpful in distinguishing among SGC, squamous carcinoma, melanoma and basal cell carcinoma. 1) SGC is positively for both stains. 2) Conversely, squamous carcinoma and melanoma stain for neither. 3) Basal cell carcinoma very rarely shows staining. 4) Androgen receptor is more helpful for detecting pagetoid spread of SGC than is adipophilin. 5) Others have supported a role for androgen receptor (NR3C4) as a significant prognostic indicator in SGC. 6) In another report, positive adipophilin staining was found in 100% of SGCs, 100% of cutaneous squamous cell carcinomas, 95% of basal cell carcinomas, 73% of conjunctival squamous cell carcinomas, and 60% of mucoepidermoid carcinomas.

7) Nevertheless, the authors concluded that the pattern and intensity of adipophilin staining were helpful in distinguishing SGC from other neoplasms with overlapping histology. 8) Additionally, factor XIIIa (AC-1A1) has proven helpful as a sensitive and specific nuclear marker for sebaceous differentiation and in complementing adipophilin in differentiating SGC from squamous cell carcinoma and basal cell carcinoma. 9) SGC immunohistochemical staining for perforin is useful for highlighting intraepithelial tumor spread, and appears better than EMA in this regard. Intraepithelial SGC (pagetoid change) can spread to the conjunctiva and cornea. Resultant diffuse loss of lashes may simulate a blepharitis. Rarely, intraepithelial sebaceous carcinoma may be the only evidence of the lesion with no underlying invasion present. The intraepithelial invasion may involve the lids and conjunctiva together, or only the conjunctiva and cornea. 10) Factors predictive of regional lymph node metastasis include duration of symptoms >6 months and orbital tumor extension. Factors predictive of systemic metastasis are orbital tumor extension and perivascular invasion. Orbital tumor invasion also predicts death due to systemic metastasis. 11) Overexpression of X-linked inhibitor of apoptosis (XIAP) has been found in 62% of eyelid SGCs, and is associated with advanced age, large tumor size, and reduced disease-free survival. 12) Low levels of MicroRNA (miRNA)-200c and miRNA-141 facilitate sebaceous tumor progression by promoting epithelialmesenchymal transition (EMT) and are predictive of shorter disease-free survival in SGC. 13) ZEB2/SIP1 also is important in regulating EMT, and down-regulates E-cadherin expression. Cytoplasmic overexpression of ZEB2 and membranous loss of E-cadherin have been seen in 68% and 66% of cases of eyelid SGC, respectively. Moreover, overexpression of ZEB2 significantly correlates with lymph node metastasis, orbital invasion, large tumor size, and advanced tumor stages. As might be anticipated, patients overexpressing ZEB2 also have poor survival. 14) Expression of ALDH1 by SGC is a predictor of a poor outcome. 15) Activation of the Shh and Wnt signaling pathway is associated with aggressive behavior in SGC.

Cysts, Pseudoneoplasms, and Neoplasms

16) Retinoic acid signaling also appears to play a role in the pathogenesis of SGC. 17) Human papilloma virus infection does not appear to be related to the development of SGC. II. Tumors of or resembling hair follicles A. Trichoepithelioma (epithelioma adenoides cysticum, benign cystic epithelioma) Trichoepithelioma is probably a special variety of trichoblastoma, characterized by its almost universal facial location, its dermal rather than subcutaneous location, its mainly cribriform pattern, and its compartmentalized clefts between fibroepithelial units. Trichoblastoma, a benign tumor of hair germ cells (follicular germinative cells), includes the entities panfolliculoma, trichoblastoma with advanced follicular differentiation, immature trichoepithelioma, and trichoepithelioma. Trichoepithelioma comprised 1.3% of 228 benign adnexal tumors in one study.





1. The tumor may occur as a small, single, rosy yellow or glistening flesh-colored nodule (Fig. 6.40), as a few isolated nodules, or as multiple symmetric nodules with onset at puberty. It occurs predominantly on the face and is inherited as an autosomal-dominant trait (Brooke’s tumor). The nodule tends to grow to several millimeters or even to 1 cm. 2. Histologically, multiple squamous cell cysts (i.e., horn cysts, consisting of a keratinized center surrounded by basaloid cells) are the characteristic finding and represent immature hair structures. a. Basaloid cells, indistinguishable from the cells that constitute basal cell carcinoma, are present around the horn cysts and in the surrounding tissue as a lacework or as solid islands. 1) They may display peripheral palisading and a follicular stroma characterized by concentric collagen. 2) Spindled fibroblasts are arranged in parallel to the periphery of the tumor nodules. b. Occasionally the cysts have openings to the skin surface and resemble abortive hair follicles. The

A

221

cysts may rupture, inducing granulomatous inflammation, or they may become calcified. The horn cyst shows complete and abrupt keratinization, thereby distinguishing it from the horn pearl of squamous cell carcinoma, which shows incomplete and gradual keratinization.

3. Can be found in Brooke–Spiegler syndrome, which is associated with germline mutations in the tumor suppressor gene CYLD. B. Trichofolliculoma 1. Trichofolliculoma is found in adults and consists of a small, solitary lesion often with a central pore. a. The vast majority are on the face or ears. b. They usually are reported in adolescents or young adults; however, congenital cases do occur.





Trichoadenoma, a rare benign cutaneous tumor, resembles trichofolliculoma, but the cells appear less mature; conversely, the cells appear more mature than the cells in trichoepithelioma.

2. Histologically, a large dermal cystic space lined by squamous epithelium and containing keratin and hair shaft fragments is surrounded by smaller, welldifferentiated, secondary hair follicles. a. The stroma was composed of spindle cells, with peripheral inflammation in most cases in one report of 90 cases. b. Immunochemistry of 10 specimens from that study demonstrated intense CK17 expression in the inner and outer root sheath. c. PHLDA1 positivity was found particularly in the immature follicles. d. BerEP4 was strongly positive, especially in the peripheral immature component, forming bulbar images. e. Outer and inner root sheaths were negative. Sebaceous glands also may be seen.









B Fig. 6.40  Trichoepithelioma. A, Clinical appearance of a lesion in the middle of the right upper lid near the margin. B, Histologic section shows the tumor diffusely present throughout the dermis. The tumor is composed of multiple squamous cell horn cysts that represent immature hair structures.

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B

Fig. 6.41  Trichilemmoma. A, Histologic section shows lobular acanthosis of clear cells (shown with increased magnification in B) oriented around hair follicles. C, The clear cells are strongly periodic acid–Schiff-positive.

C



C. Trichilemmoma (Fig. 6.41) 1. It tends to be a solitary, asymptomatic lesion located on the face and mainly found in middle-aged people. The lesion has no sex predilection. 2. Characteristically, trichilemmoma often shows a central pore that contains a tuft of wool-like hair.

of central desmoplasia, outer root sheath differentiation of the tumor cells, and CD34 positivity. These features help differentiate it from basal cell carcinoma.



Patients who have multiple (not solitary) facial trichilemmomas may have Cowden’s disease (multiple hamartoma syndrome), an autosomaldominant disease characterized by multiple trichilemmomas, acral keratoses, occasional Merkel cell carcinoma, oral papillomas, goiter, hypothyroidism, ovarian cysts, uterine leiomyomas, oral and gastrointestinal polyps, and breast disease.



3. Histologically, a central cystic space represents an enlarged hair follicle. a. A lobular acanthosis of glycogen-rich cells is oriented about hair follicles. b. The edge of the lesion usually shows a palisade of columnar cells that resemble the outer root sheath of a hair follicle and rest on a well-formed basement membrane. Desmoplastic trichilemmoma may simulate a verruca, follicular keratosis, or a basal cell carcinoma. It is characterized by the presence





D. Hybrid cysts 1. Have apocrine, trichilemmal and infundibular differentiation. 2. Cystic structure lined by combination of apocrine, infundibular (epidermoid) and trichilemmal epithelium. 3. Lumen contains keratin debris, and serous material. 4. Often contiguous with a hair follicle. 5. Immunohistochemistry positive for high-molecularweight cytokeratin, and cystic structures positive for carcinoembryonic antigen. 6. Origin from the junction of keratinizing squamous and glandular epithelium of the hair follicle has been suggested. E. Trichilemmal carcinoma 1. Trichilemmal carcinoma is a rare tumor that arises from the hair sheath, mainly on the face or ears of the elderly. a. It rarely involves the eyelid. b. It is locally invasive. c. Actinic damage, long-term low-dose irradiation, and transformation from benign trichilemmoma

Cysts, Pseudoneoplasms, and Neoplasms

have been postulated as possible pathogenetic mechanisms. 2. Histologically, it is composed of follicular-oriented, lobular sheets of atypical, clear, glycogen-containing cells resembling the outer root sheath of a hair follicle. a. There are prominent nucleoli, nuclear atypia, and a high mitotic rate. b. An attempt is made to form immature pilosebaceous units. c. The mitotic rate is increased. d. Immunohistochemical staining is negative for Ber-EP4. e. Histologically, it may be confused with basal cell carcinoma or trichoepithelioma. 3. Malignant proliferating trichilemmal tumor is characterized by proliferation of outer hair sheath epithelium with multiple central areas of trichilemmal keratinization. E. Calcifying epithelioma of Malherbe (pilomatricoma; see earlier section Benign Cystic Lesions). F. Adnexal carcinoma—the term adnexal carcinoma should be restricted to those tumors that are histologically identical to basal cell carcinoma, but in which the site of origin (e.g., epidermis, hair follicle, sweat gland, sebaceous gland) cannot be determined. III. Tumors of or resembling sweat glands: apocrine sweat glands are represented in the eyelids by Moll’s glands; eccrine sweat

glands are present in the lids both at the lid margin and in the dermis over the surface of the eyelid. A. Syringoma (Fig. 6.42) 1. Syringoma is a common, benign, adenomatous tumor of the eccrine sweat structure occurring mainly in young women and consisting of small, soft papules, usually only 1 or 2 mm in size, found predominantly on the lower eyelids. a. It probably arises from intraepidermal eccrine ducts. b. In a review of 244 cases, multiple lesions were noted in 76% of cases. c. The face was a preferred location in 56.7%, with eyelid involvement in 36.3%. 2. Histologically, dermal epithelial strands of small basophilic cells are characteristic, as are cystic ducts lined by a double layer of flattened epithelial cells and containing a colloidal material. The ducts often have comma-like tails that give them the appearance of tadpoles. a. A variant of syringoma is the chondroid syringoma (mixed tumor of the skin—see later) 1) The lesions are classified into an apocrine type having tubular cystic branching lumens lined by two layers of epithelial cells, and the eccrine type having small tubular lumens lined by a single layer of epithelial cells.







e

t

t

A

cs cs

C

t

B

cs

cs

223

Fig. 6.42  Syringoma. A, Clinical appearance of lesions just below and nasal to seborrheic keratosis of left lower lid (same patient as in Fig. 6.29). B, Histologic section shows that the dermis contains proliferated eccrine sweat gland structures that form epithelial strands and cystic spaces (e, surface epithelium; t, tumor “ducts” and epithelial strands). C, Increased magnification demonstrates epithelial strands and cystic spaces lined by a double-layered epithelium (cs).

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2) Each of these types may have benign, atypical, and malignant variants. There is also a myxoid, adipocytic, chondroid, and/or fibrous stroma. 3) Complete excision and regular follow-up of even cytologically benign lesions are recommended because they may recur with malignant transformation. 4) Apocrine chondroid syringoma also has been reported to involve the eyelid. 5) Another syringoma variant reported to involve the eyelid is the plaque-type syringoma. B. Syringomatous carcinoma Many names have been given to the entity of syringomatous carcinoma: syringoid eccrine carcinoma, eccrine epithelioma, basal cell epithelioma with eccrine differentiation, eccrine carcinoma with syringomatous features, sclerosing sweat duct carcinoma, many examples of microcystic adnexal carcinoma, malignant syringoma, sclerosing sweat duct syringomatous carcinoma, sweat gland carcinoma with syringomatous features, basal cell carcinoma with eccrine differentiation, and eccrine basaloma. About 80% of cases of microcystic adnexal carcinoma that have histopathology checked are misdiagnosed initially.







1. The tumor usually occurs as a single nodule and can be classified as well, moderately, or poorly differentiated syringomatous carcinoma. a. Well-differentiated syringomatous carcinoma is characterized by many discrete tubules, lack of nuclear atypia, some mitotic figures, often aggregations of cells showing a solid basaloid or cribriform, adenoid cyst-like pattern, and usually desmoplastic or sclerotic stroma. b. Moderately differentiated syringomatous carcinoma consists of easily recognized, well-formed tubules, nuclear atypia, few or no mitotic figures, and usually desmoplastic or sclerotic stroma.

A



c. Poorly differentiated syringomatous carcinoma consists of focal subtle tubular differentiation, striking nuclear atypia, numerous mitotic figures, strands of neoplastic cells between collagen bundles, and usually desmoplastic or sclerotic stroma. 2. Infiltration of the underlying subcutaneous tissue, perineural spaces, and muscle, often with focal inflammation, is common. 3. In addition to PAS positivity in some lumina and lining cells, immunohistochemical staining is positive for S-100 protein, high-molecular-weight cytokeratins (AE1/AE3), and epithelial membrane antigen (negative for K-10 and the low-molecular-weight cytokeratin CAM 5.2). C. Syringocystadenoma papilliferum (papillary syringadenoma) (Fig. 6.43) 1. Syringocystadenoma papilliferum is usually classified an adenoma of apocrine sweat structures that differentiates toward apocrine ducts, although some have claimed an eccrine origin for the lesion. 2. The lesion is usually solitary and occurs in the scalp as a hairless, smooth plaque until puberty, after which it becomes raised, nodular, and verrucous. In one study of 14 patients, 64% of the lesions were associated with other apocrine, eccrine, or sebaceous tumors or malformations; none of which were malignant. In 75% of cases, the lesion arises in a pre-existent nevus sebaceus (see elsewhere in this chapter); the other 25% occur as an isolated finding. Malignant tumors, particularly basal cell carcinoma, may arise in association with syringocystadenoma papilliferum developing with nevus sebaceus.



3. Histologically, the epidermis is papillomatous. a. One or more cystic invaginations (frequently forming villus-like projections), lined by a double layer of cells composed of luminal high columnar

B

Fig. 6.43  Syringocystadenoma papilliferum of the eyelid. A, Lower power demonstrates papillary configuration. B, Higher magnification demonstrates papillary structure is lined by bilayered apocrine epithelium. (Courtesy of Dr. Tatyana Millman.)

Cysts, Pseudoneoplasms, and Neoplasms







cell hidradenoma shows two cell types: a polyhedral to fusiform cell with slightly basophilic or eosinophilic cytoplasm, and a clear (glycogen-containing) cell. The epithelial cells stain positively for cytokeratins AE1 and AE3 (high-molecular-weight cytokeratins), epithelial membrane and carcinoembryonic antigens, and muscle-specific actin. Although the clear cell hidradenoma is thought to be of eccrine origin, it may be of apocrine gland origin. A further variant of the clear cell hydradenoma is the apocrine mixed tumor. The histologic appearance is the same as that of the lacrimal gland mixed tumor. A more probable variant of eccrine spiradenoma is the eccrine hidrocystoma (see earlier subsection Benign Cystic Lesions). Hidradenoma papilliferum usually is found in the anogenital, periumbilical, and axillary areas as an adenoma with apocrine differentiation. As an ectopic lesion, it may appear on the head and neck, but only very rarely on the eyelid where it may be solid or cystic. Histochemical features include periodic acid–Schiff positive, diastase resistant granules in luminal cells. These cells also are positive for nonspecific esterase and acid phosphatase. The differential diagnosis includes: syringocystadenoma, which would be suggested by the presence of a plasma cell infiltrate; tubular apocrine adenoma, which would be suggested by the presence of a lobular pattern, and tubular apocrine structures with an epidermal connection; and clear-cell adenoma, which is suggested by cytoplasmic clearing.

cells and outer myoepithelial cells, extend into the dermis. b. The cystic spaces open from the surface epithelium rather than representing closed spaces entirely within the dermis. 4. Squamous carcinoma has developed in syringocystadenoma papilliferum of the eyelid. a. In a report of 10 cases of carcinoma, one was found to arise in a previously existing syringocystadenoma papilliferum. b. Apocrine differentiation with decapitation was present in 4 cases. c. Regional lymph node metastasis occurred in 4 patients. d. Histologically, papillations were lined by two layers of epithelium, an outer basal layer of small cuboidal cells and an inner luminal layer of columnar cells. 1) The inner layer of cells displayed loss of polarity. 2) The neoplastic cells displayed significant nuclear and cellular atypia with some cells exhibiting large nuclei and prominent nucleoli. 3) Abnormal mitotic figures were seen. 4) Invasion was seen in 9 cases. In most cases, a heavy plasma cell inflammatory infiltrate is present. Congenital abnormalities of sebaceous glands and hair follicles are often also present.







D. Eccrine spiradenoma (nodular hidradenoma, clear cell hidradenoma, clear cell carcinoma, clear cell myoepithelioma, myoepithelioma) 1. Eccrine spiradenomas usually occur in adults as deep, solitary, characteristically painful dermal nodules that arise from eccrine structures. 2. Histologically, the tumor is composed of one or more basophilic dermal islands arranged in intertwining bands, as well as tubules containing two types of cells and surrounded by a connective tissue capsule. a. Small, dark cells with dark nuclei and scant cytoplasm are present toward the periphery of the bands and tubules. b. Cells with large, pale nuclei and scant cytoplasm are present in the center of the bands and tubules, and line the few small lumina usually present. A possible variant of the eccrine spiradenoma is a tumor composed primarily of cells containing clear cytoplasm called a clear cell hidradenoma (eccrine acrospiroma, clear cell myoepithelioma, solid cystic hidradenoma, clear cell papillary carcinoma, porosyringoma, nodular hidradenoma). An intradermal nodule that may ulcerate or enlarge rapidly secondary to internal hemorrhage, the clear

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E. Eccrine mixed tumor (chondroid syringoma; see earlier) 1. Eccrine mixed tumor is rarer than the apocrine mixed tumor, but is histologically similar. 2. Histologically, it has tubular lumina lined by a single layer of flat epithelial cells. Conversely, the epithelial lining of apocrine mixed tumors is larger, more irregularly shaped, and consists of at least a double layer of epithelial cells.







a. The epithelial lining stains positively for cytokeratin, carcinoembryonic antigen, and epithelial membrane antigen. b. The outer cell layers stain positive for vimentin, S-100 protein, neuron-specific enolase, and sometimes glial acidic protein. The stroma stains immunohistochemically like the outer cell layers. F. Cylindroma (turban tumor) 1. Cylindroma is probably of apocrine origin, is benign, often has an autosomal-dominant inheritance pattern, has a predilection for the scalp, and appears in early adulthood.

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CHAPTER 6  Skin and Lacrimal Drainage System

a. Cylindromas and trichoepitheliomas are frequently associated and may occur in such numbers as to cover the whole scalp like a turban, hence the name turban tumor as seen in Brooke–Spiegler syndrome. 1) This syndrome is autosomal dominant in inheritance. 2) It is associated with adenoma and carcinoma of the parotids, sebaceous nevus, basocellular carcinomas, milium, xeroderma pigmentosa, hypo- and hyperchromia, polycystosis of the lungs, kidneys, breast, and multiple fibromas. 3) Malignant transformation of the associated cylindromas may occur with possible metastasis. 4) The tumors also may infiltrate the skull. 5) The development of multiple adnexal tumors such as cylindromas, trichoepitheliomas, and spiradenomas may occur. 6) This syndrome is caused by a mutation in the CYLD gene on chromosome 16. 2. Histologically, islands of cells fit together like pieces of a jigsaw puzzle and consist of two types of cells, irregular in size and shape, separated from each other by an amorphous, hyaline-like stroma: cells with small, dark nuclei and scant cytoplasm are found in the periphery of the islands; and cells with large, pale nuclei and scant cytoplasm are present in the center of the islands. Tubular lumina are usually present and are lined by cells demonstrating decapitation secretion, like cells seen in apocrine glands. G. Eccrine poroma 1. Eccrine poroma is a common, benign, slowly growing tumor that seldom involves the eyelid. 2. It usually occurs on the soles of the feet as firm, dome-shaped, slightly pedunculated, pinkish-red tumors, but it may occur elsewhere. 3. It arises from the eccrine duct as it courses through the epidermis. 4. Histologically, it consists of intraepidermal masses of cells connected by cellular bridges and resemble squamous cells, but are more cuboidal and smaller, and have a basophilic nucleus that thicken the epidermis and extend down into the dermal area. Small ductal lumina are usually present and are lined by a PAS-positive, diastase-resistant cuticle.

Eccrine porocarcinoma is a rare form of eccrine adenocarcinoma. Most commonly it arises on the lower extremity and has a variable prognosis. Rarely it has been reported to occur on the eyelid.



H. Oncocytoma 1. Oncocytoma may occur in the caruncle (see Fig. 7.22), lacrimal gland, lacrimal sac, and much more rarely on the lids. It arises from apocrine glands.



2. Histologically, the tumor usually shows cystic and papillary components. Electron microscopy shows malformed mitochondria in the tumor cells. I. Sweat gland carcinomas are rare. 1. Eccrine sweat gland carcinomas Two groups occur: one arises from benign eccrine tumors (or de novo) as a malignant counterpart. These include eccrine porocarcinoma, malignant eccrine spiradenoma, malignant hidradenoma, and malignant chondroid syringoma. The second group comprises primary eccrine carcinomas and includes classic eccrine adenocarcinoma (ductal eccrine carcinoma), syringomatous carcinoma (see earlier), microcystic adnexal carcinoma (see later), mucinous (adenocystic) carcinoma, and aggressive digital papillary adenocarcinoma. Mucinous eccrine adenocarcinoma is a rare ocular adnexal tumor that can involve the eyelid and periocular skin, can be locally invasive, and has a high risk of local recurrence even after Mohs surgery. Nevertheless, the prognosis following excision with confirmed tumor-free margins is good.







a. They have a tubular, or rarely, an adenomatous (adenocarcinoma) structure, or even more rarely a histiocytoid variant. b. Histologically, it is difficult to differentiate eccrine carcinoma from metastatic carcinoma; the diagnosis of metastatic carcinoma, therefore, should always be considered before making a final diagnosis of eccrine carcinoma. c. Microcystic adnexal carcinoma 1) Usually solitary and occurs as a nodule or indurated, deep-seated plaque. Many tumors previously diagnosed as microcystic adnexal carcinomas are really syringomatous carcinoma. Also, signet-ring cell carcinoma of the eccrine sweat glands of the eyelid should not be confused with syringomatous carcinoma.

2) In the superficial part of the tumor, small keratocytes are often seen, whereas deeper in the tumor, microtubules and thin trabeculae predominate. 3) Infiltration of the underlying subcutaneous tissue, perineural spaces, and muscle, often with focal inflammation, is common. 4) The histogenesis is unknown—theories include eccrine and pilar origin. 2. Apocrine sweat gland carcinomas (from Moll’s glands in the eyelid) are adenocarcinomas and occur in two varieties: a ductopapillary tumor located exclusively in the dermis, and an intraepidermal proliferation (i.e., extramammary Paget’s disease) that rarely invades the dermis. Apocrine carcinoma of the eyelids

Cysts, Pseudoneoplasms, and Neoplasms

may demonstrate an aggressive behavior, including distant metastasis. a. Primary signet-ring/histiocytoid tumors of the eyelid are extremely rare, but most commonly present on the eyelid and can resemble chronic inflammation or a chalazion. b. They are slow growing and locally aggressive, but the tumor can metastasize. 1) Infiltration to involve the upper and lower eyelids may produce a monocle-like appearance, which has resulted in the appellation, “monocle tumor.” c. Most commonly affect elderly men. d. Histopathology characterized by infiltration of the dermis by single cells, or cords of single rows of cells between collagen bundles. 1) In eyelid lesions, the epidermis is not involved. 2) Cells have a bland character with histiocytoid morphology.







227

3) Cytoplasmic inclusions producing the signetring appearance are PAS and colloidal iron positive. e. Both apocrine and eccrine origins have been proposed, but more recent reports suggest an apocrine origin, possible from glands of Moll based on MUC6 and GCDFP15 immunopositivity. 1) GCDFP15, ER and PgR expression are useful in distinguishing the primary eyelid tumor from those with a gastrointestinal origin. 2) Must be differentiated from metastasizing histiocytoid mammary carcinoma. f. Excision with wide margins has been recommended for this lesion. 3. Primary mucinous carcinoma (adenocystic, colloid, mucinous eccrine carcinoma) (Fig. 6.44) a. Rare, low-grade, carcinoma. b. It is believed to arise from the deepest portion of the eccrine sweat duct.







A

B

C

D Fig. 6.44  Primary mucinous carcinoma. A, Clinical photograph of upper eyelid lesion. B, Cystic lesion with pools of mucin. C, Higher magnification shows islands of neoplastic cells floating in mucin pools with intervening fibrous septa. The tumor cells have a solid to cribriform arrangement. D, Island of basaloid tumor cells with a round to cuboidal shape, moderate amount of cytoplasm, and relatively few mitoses. (From Papalas JA, Proia AD: Primary mucinous carcinoma of the eyelid: A clinicopathologic and immunohistochemical study of 4 cases and an update on recurrence rates. Arch Ophthalmol 128:1160, 2010.)

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CHAPTER 6  Skin and Lacrimal Drainage System

c. 38% occur on the eyelid. d. Histopathology demonstrates an unencapsulated, dermis-based tumor containing islands of basaloid cells with solid to cribriform pattern. 1) The tumor cells are found in basophilic, PASpositive, Alcian blue-positive, mucicarminepositive, and hyaluronidase-resistant mucin pools, which may have fibrous septae. 2) The tumor cells are round to cuboidal with moderate cytoplasm and a low mitotic rate. 3) May be positive for cytokeratins (CK7, CAM5.2), carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), estrogen receptor (ER), progesterone receptor (PR), p63, mucous-associated peptides of the trefoil factor family (TFF1 and 3), and tumor-associated glycoprotein (TAG-72). 4) It must be differentiated from metastatic tumors. e. Recurrence rate may be reduced utilizing Mohs surgery or excision with frozen section control. f. Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a low-grade sweat gland carcinoma with a predilection for the eyelid. 1) Presents as a slowly growing cyst or swelling. 2) Tend to be well-circumscribed and multinodular. 3) Have papillary areas and may have focal cribriform arrangement. 4) Composed of small- to medium-sized oval to polygonal cells with lightly eosinophilic to bluish cytoplasm. 5) Bland nuclei and mitotic activity present, but not brisk. 6) Intracytoplasmic and extracellular mucin is present. 7) Characteristically display neuroendocrine markers. 8) Associated with cystic areas lined by benign epithelium resembling that from eccrine ducts. 9) Myoepithelial cells may be present in areas of in situ carcinoma. 10) Postulated to represent a progression from noninvasive sweat gland neuroendocrine carcinoma to endocrine mucin-producing carcinoma. 11) Wilms tumor 1 (WT1) protein is expressed in the neoplastic cells of EMPSGC, areas of atypical intraductal proliferations, and mucinous carcinoma; however, there is absence of WT1 expression in areas of benign eccrine cyst and cutaneous sweat glands. These findings have suggested to some that upregulation of WT1 plays a role in tumor cell proliferation and progression of EMPSGC to primary cutaneous mucinous carcinoma.

Merkel Cell Carcinoma (Neuroendocrine Carcinoma, Trabecular Carcinoma) (Fig. 6.45) I. The Merkel cell, first described by Friedrich Merkel in 1875, is a distinctive, nondendritic, nonkeratinocytic epithelial clear cell believed to migrate from the neural crest to the epidermis and dermis.

Merkel cells, specialized epithelial cells that probably act as touch receptors, are sporadically present at the undersurface of the epidermis. Other specialized cells present in the epidermis include the three types of dendritic cell (i.e., Langerhans’ cells, melanocytes, and the intermediate dendritic cells).



A. Tumors arising from Merkel cells occur on the head and neck area, the trunk, arms, and legs, mainly (75%) in patients 65 years of age or older. Merkel cell carcinoma, like other neuroectodermal tumors (e.g., neuroblastoma, malignant melanoma, and pheochromocytoma), may show a distal deletion involving chromosome 1p35–36. Also, Merkel cell carcinoma may occur in Cowden’s disease (see earlier discussion of trichilemmoma).



B. Clinically, the most common appearance is that of a nonulcerated, violaceous nodule. C. The tumor is aggressive, has variable clinical manifestations, tends to spread early to regional lymph nodes, and should probably be treated with radical surgical therapy. There is a high rate of local recurrence (14%), regional lymph node invasion (20%), and metastasis (5%). D. Increasing in incidence at a rate of 8% annually. II. Histologically, they resemble a primary cutaneous lymphoma or cutaneous metastasis of lymphoma or carcinoma. A. The tumor is composed of solid arrangements of neoplastic cells, simulating large-cell malignant lymphoma cells, separated from the epidermis by a clear space. There is a high mitotic rate. B. Immunohistochemical staining is strongly positive for neuron-specific enolase, chromogranin, and cytokeratins 8, 18, and 19 (low-molecular-weight type); it is weakly positive for synaptophysin, but negative for leukocytic markers. C. Electron microscopy shows characteristic membranebound, dense-core neurosecretory granules; paranuclear aggregates of intermediate filaments; and cytoplasmic actin filaments. III. DNA for Merkel polyomavirus is present in 80% of the tumors, and may play a role in its pathogenesis. IV. There is an increased incidence in older immunosuppressed patients.

Normal Anatomy

A

B

C

D

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Fig. 6.45  Merkel cell tumor. A, Patient has lesions on the middle portion of upper lid. B, Excisional biopsy shows nests of dark, poorly differentiated cells in the dermis. C, Increased magnification demonstrates round cells that resemble large lymphoma cells. Numerous mitotic figures are seen. D, Electron micrograph shows the nucleus in the upper right corner. Many cytoplasmic, small, dense-core, neurosecretory granules are seen. (Case presented by Dr. DA Morris at the meeting of the Eastern Ophthalmic Pathology Section, 1985; D, courtesy of Dr. A di Sant’Agnese and Ms. KWJ de Mesy Jensen.)

Malacoplakia

Metastatic Tumors

I. Malacoplakia is a rare disorder in which tumors occur subjacent to an epithelial surface. A. Malacoplakia often arises in immunodeficient or immunosuppressed patients. B. It is characterized by persistent bacterial infection. In 90% of cases it is a coliform organism most often Escherichia coli. C. It probably is related to deficient cytoplasmic levels of cyclic guanine monophosphate in histiocytes within the lesion. II. Histologically, aggregates of histiocytes (von Hansemann histiocytes) contain characteristic inclusions (Michaelis– Gutmann bodies, which represent partially degraded organisms).

I. Metastasis to the eyelids is uncommon and usually a late manifestation of the disease. A. The most frequent primary tumor is breast carcinoma, followed by lung carcinoma and cutaneous melanoma. B. Rarer primary tumors include stomach, colon, thyroid, parotid, and trachea carcinomas. C. Although metastatic cancer is usually unilateral, the presence of lesions involving eyelids of both eyes does not exclude the possibility of metastatic disease. II. The histologic appearance depends on the nature of the primary tumor.

Pigmented Tumors See Chapter 17.

Mesenchymal Tumors The same mesenchymal tumors that may occur in the orbit may also occur in the eyelid and are histopathologically identical (see subsection Mesenchymal Tumors in Chapter 14).

LACRIMAL DRAINAGE SYSTEM NORMAL ANATOMY (Fig. 6.46) The excretory portion of the lacrimal system consists of the canaliculi (upper and lower), common canaliculus, lacrimal sac, and nasolacrimal duct. The nasolacrimal apparatus develops during the sixth week of prenatal life as a line of epithelium formed by the overlapping of lateral nasal processes by the

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CHAPTER 6  Skin and Lacrimal Drainage System

3–5 mm

2 mm

8 mm

10 mm

12 mm 5 mm Fig. 6.46  Schematic functional anatomy of the lacrimal excretory system. (From de Toledo AR, Chandler JW, Buffman FV: Lacrimal system: Dry-eye states and other conditions. In Podos SM, Yanoff M, eds: Textbook of Ophthalmology, vol. 8. © Elsevier 1994.)

maxillary processes. The height of the bony nasolacrimal duct increases 1.8-fold, the average diameter increases 1.4-fold, and the volume increases 4.6-fold between two weeks and 34 months of age. Most of the increase occurs during the first 6 months of life. I. Tears pool toward the medial canthus at the lacus lacrimalis and then enter the lacrimal puncta that lie near the nasal end of each eyelid. A. The lower punctum lies slightly lateral to the upper. B. Normally, both are turned inward to receive tears, and therefore are not visible to direct inspection. C. The puncta vary from 0.5 to 1.5 mm in diameter. II. The canaliculi are lined by stratified, nonkeratinized squamous epithelium. III. The lacrimal sac is also lined with nonkeratinized squamous epithelium but, unlike the canaliculi, it contains many goblet cells and foci of columnar ciliated (respiratory-type) epithelium. The vascular plexus (cavernous body) that surrounds the lacrimal sac and nasolacrimal duct is subject to autonomic control and plays an important role in regulating the rate of tear outflow. IV. The nasolacrimal duct occupies roughly 75% of the 3- to 4-mm-wide bony nasolacrimal canal. Many so-called valves have been described in the duct, but these represent folds of the mucosa rather than true valves, although presumably they may retard flow in some individuals. V. Tear duct-associated lymphoid tissue is commonly found in individuals with symptomatically normal nasolacrimal ducts, and appears to be most associated with the scarring of symptomatic dacryostenosis.

CONGENITAL ABNORMALITIES Atresia of the Nasolacrimal Duct I. The nasolacrimal duct usually becomes completely canalized and opens into the nose by the eighth month of fetal life. II. The duct may fail to canalize (usually at its lower end) or epithelial debris may clog it.

III. Most ducts not open at birth open spontaneously during the first 6 months postpartum. IV. Congenital dacryocystocele is a rare anomaly accompanied by swelling of the lacrimal sac that is present at birth and resulting from obstruction of the lacrimal system either above or below the lacrimal sac.

Atresia of the Punctum I. Atresia of the punctum may occur alone or be associated with atresia of the nasolacrimal duct. II. An acquired form may result secondary to scarring from any cause. Lacrimal outflow dysgenesis may involve multiple components of the system, including absent or hypoplastic punctum, canaliculus, lacrimal sac, and/or nasolacrimal duct. The dysgenesis is proximal in 89%, distal in 33%, and both in 22%. Systemic syndrome or dysmorphism is present in 40% of cases and positive family history is noted in 36%.

III. Punctal stenosis may be an acquired condition having a variety of causes, including chronic blepharitis (45%), unknown etiology (27%), ectropion (23%), and drug-related (5%). Punctal stenosis may be accompanied by obstruction of the lacrimal drainage system at other levels.

Congenital Fistula of Lacrimal Sac (Minimal Facial Fissure) I. An opening of the lacrimal sac directly into the nose (internal fistula) or out on to the cheek (external fistula—the more common of the two) is a not uncommon finding. II. The opening, which may be unilateral or bilateral, is quite narrow and may be overlooked. There are many other anomalies of the lacrimal puncta, canaliculus, sac, and nasolacrimal duct, but these are beyond the scope of this book.

INFLAMMATION—DACRYOCYSTITIS (Fig. 6.47) Blockage of Tear Flow Into the Nose I. Most inflammations and infections of the lacrimal sac are secondary to a blockage of tear flow at the level of the sac opening into the nasolacrimal duct or distal to that point. II. A cast of the lacrimal sac (see Fig. 4.12) may be formed by Streptothrix (Actinomyces), which also can cause a secondary conjunctivitis. III. Treatment for dry-eye syndromes utilizing punctal plugs or of canalicular injury with stents may occasionally result in pyogenic granuloma formation. Such lesions may eventuate in extrusion of the punctal plug in 4.2% of such plugs. Other complications have been reported. IV. Lacrimal sac biopsies represent approximately 1.8% of the specimens sent to a busy ophthalmic pathology laboratory.

Inflammation—Dacryocystitis

A

231

B

Fig. 6.47  Dacryocystitis. A and B, The patient had a history of tearing and a lump in the region of the lacrimal sac. Pressure over the lacrimal sac shows increasing amounts of pus coming through the punctum. C, Another patient had an acute canaliculitis. A smear of the lacrimal cast obtained at biopsy shows large colonies of delicate, branching, intertwined filaments characteristics of Streptothrix (Actinomyces).

C

The most common diagnoses are: nongranulomatous inflammation (85.1%), granulomatous inflammation consistent with sarcoidosis (2.1%), lymphoma (1.9%), papilloma (1.11%), lymphoplasmacytic infiltrate (1.1%), transitional cell carcinoma (0.5%), and single cases of adenocarcinoma, undifferentiated carcinoma, granular cell tumor, plasmacytoma, and leukemic infiltrate. Another study of the histopathology of the lacrimal drainage system found the following diagnoses: dacryocystitis (79%), dacryolithiasis (7.9%), tumor (4.5%), trauma (3.0%), congenital malformation (1.4%), canaliculitis (1.2%), and granulomatous inflammation (1.2%). B-cell lymphoma was the most common malignant tumor detected. There is some disagreement regarding the relative involvement of the lacrimal drainage system by leukemia/lymphoma, and leukemia may be the more common lesion. Nevertheless, even NK/T-cell lymphoma has occurred in the lacrimal sac.



A. Unsuspected malignant tumor is found in lacrimal sac biopsy in 0.6% to 2.1% of cases with a clinical diagnosis of dacryocystitis/lithiasis. Routine submission of lacrimal sac biopsy tissue taken during dacryocystorhinostomy surgery for histopathological examination has been recommended. 1. Granulomatosis with polyangiitis (Wegener’s granulomatosis) may rarely involve the wall of the lacrimal sac and present as a mass lesion.

2. Canaliculitis and dacryolith formation are uncommon in children but may occur as a cause of chronic or recurrent nasolacrimal obstruction in them. a. Plasmacytoma of the canaliculus has presented as canaliculitis. 3. Hematoma of the lacrimal sac may mimic a tumor. 4. Adenocarcinoma of the lacrimal sac may arise from pleomorphic adenoma. Another rare tumor that has arisen in this region is mucoepidermoid carcinoma. V. Treatment with docetaxel may result in lacrimal drainage obstruction by inducing stromal fibrosis in the mucosal lining of the lacrimal drainage apparatus. VI. Rarely, nasolacrimal duct obstruction may result from ethmoiditis producing symptoms suggestive of acute dacryocystitis. VII. Ascending inflammation from the nose or descending inflammation from the eye may precipitate and maintain a cascade of changes that contribute to acquired malfunction of the lacrimal drainage system. VIII. Several terms are used to designate specific types of lacrimal sac cystic dilation. A. Dacryocystocele: generic term referring to any cystic dilation of the lacrimal sac resulting from proximal and distal obstruction to the drainage system. They most commonly are found in newborn infants. B. Dacryocystomucocele: contains mucus.

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C. Dacryocystomucopyocele: implies purulent material admixed with mucus and the presence of infection (dacryocystitis). 1. Giant dacryocystomucopyocele resulting in globe displacement and enlargement of the nasolacrimal duct has been reported.

majority are epithelial in origin (73%), and of these, 75% are malignant. C. Histology 1. The papillomas may be squamous (see Chapter 7), transitional, or adenomatous.



Rarely, a lacrimal sac papilloma may undergo oncocytic metaplasia (i.e., an eosinophilic cystadenoma or oncocytoma).

TUMORS Epithelial Malignant tumors constitute 70% of lacrimal sac neoplasms and squamous cell carcinoma accounts for most of these lesions. I. From lacrimal sac lining epithelium A. The epithelial lining of the lacrimal sac is the same as the rest of the upper respiratory tract (i.e., pseudostratified columnar epithelium).

2. Squamous cell carcinomas (Fig. 6.48) are identical to those found elsewhere (see Chapter 7) and are the most common. 3. Transitional cell carcinomas are composed of transitional cell epithelium showing greater or lesser degrees of differentiation. 4. Inverted papilloma is an uncommon neoplasm that has a tendency to recur, is associated with malignancy, and may invade adjacent structures. It has been reported to invade the orbit through the nasolacrimal duct. 5. Primary lymphoma of the lacrimal drainage system is extremely rare, and is usually a B-cell lesion when it does occur. Female sex may be an unfavorable prognostic factor for these lesions. Primary nonHodgkin’s lymphoma has rarely been reported to involve the lacrimal sac in children.

Tumors, therefore, are similar to those found elsewhere in the upper respiratory system, namely, papillomas, squamous cell carcinomas, transitional cell carcinomas, and adenocarcinomas.



HPV appear to be involved in the genesis of both benign (HPV 11) and malignant (HPV 18) neoplasms of the epithelium of the lacrimal sac. B. Tumors of the lacrimal sac, however, are relatively rare. They usually cause early symptoms of epiphora. The

A

B

Fig. 6.48  Squamous cell carcinoma of the lacrimal sac. A, Clinical appearance of tumor in region of right lacrimal sac. B, Strands and cords of cells are infiltrating the tissues surrounding the lacrimal sac. C, Increased magnification shows the cells to be undifferentiated malignant squamous cells. (Case presented by Dr. AC Spalding to the meeting of the Verhoeff Society, 1982.)

C

Tumors

6. Cytokeratin-negative undifferentiated (lymphoepithelial) carcinoma has been reported to involve the lacrimal sac. a. The lesion is associated with Epstein–Barr virus infection. b. Usually the tumor expresses cytokeratin. c. 5-year survival rate is from 58% to 75%. II. From lacrimal sac glandular elements A. Benign 1. Oncocytoma (eosinophilic cystadenoma) 2. Benign mixed tumor (pleomorphic adenoma) 3. Adenoacanthoma B. Malignant 1. Oncocytic adenocarcinoma 2. Adenoid cystic carcinoma 3. Adenocarcinoma

Melanotic Melanotic tumors arising from the lacrimal sac (i.e., malignant melanomas) are quite rare and are similar histologically to those found in the lid (see section Melanotic Tumors of Eyelids in Chapter 17).

Mesenchymal The same mesenchymal tumors that may involve the lids and orbit may involve the lacrimal sac (see subsection Mesenchymal Tumors in Chapter 14).

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Miscellaneous I. Localized amyloidosis may rarely involve the lacrimal sac and nasolacrimal duct, resulting in tearing. II. Concretions actually are not calcified so terms “dacryolith and “mucolith” not appropriate. A. Mucopeptide 1. Found only in the lacrimal sac. 2. Lack cellular components. 3. Composed of amorphous, eosinophilic material that is acellular. 4. Stains positively with periodic acid–Schiff stain. B. Bacterial 1. Found mostly in the canaliculus. 2. Consist of matted filamentous organisms consistent with Actinomyces. a. May be associated with cocci organisms. C. Mixed 1. Combination of the previous two types. 2. Infrequently encountered.   References available online at expertconsult.com.

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Al-Rohil RN, Meyer D, Slodkowska EA, et al: Pigmented eyelid cysts revisited: apocrine retention cyst chromhidrosis, Am J Dermatopathol 36:318–326, 2014. Anzalone CL, Cohen PR: Generalized eruptive keratoacanthomas of Grzybowski, Int J Dermatol 53:131–136, 2014. Atamney M, Gutman D, Fenig E, et al: Merkel cell carcinoma of the eyelid, Isr Med Assoc J 18:126–128, 2016. Aurora AL: Solitary trichoepithelioma of the eyelid, Indian J Ophthalmol 22:32–33, 1974. Babu NA, Rajesh E, Krupaa J, et al: Genodermatoses, J Pharm Bioallied Sci 7:S203–S206, 2015. Balasoiu AT, Ciurea RN, Manescu MR, et al: Assessment of VEGF and EGFR in the study of angiogenesis of eyelid carcinomas, Rom J Morphol Embryol 57:1229–1234, 2016. Barbarino S, McCormick SA, Lauer SA, et al: Syringocystadenoma papilliferum of the eyelid, Ophthal Plast Reconstr Surg 25:185–188, 2009. Baselga Torres E, Torres-Pradilla M: Cutaneous manifestations in children with diabetes mellitus and obesity, Actas Dermosifiliogr 105:546–557, 2014. Bhardwaj M, Sen S, Chosdol K, et al: MiRNA-200c and miRNA-141 as potential prognostic biomarkers and regulators of epithelial-mesenchymal transition in eyelid sebaceous gland carcinoma, Br J Ophthalmol 101:536–542, 2017. Bhardwaj M, Sen S, Sharma A, et al: ZEB2/SIP1 as novel prognostic indicator in eyelid sebaceous gland carcinoma, Hum Pathol 46:1437–1442, 2015. Braverman IM: Skin manifestations of internal malignancy, Clin Geriatr Med 18:1–19, v, 2002. Brent AJ, Mota PM, Nebojsa A, et al: Squamous cell carcinoma arising from syringocystadenoma papilliferum of the eyelid, Can J Ophthalmol 52:e235–e237, 2017. Celebi AR, Kiratli H, Soylemezoglu F: Evaluation of the ‘hedgehog’ signaling pathways in squamous and basal cell carcinomas of the eyelids and conjunctiva, Oncol Lett 12:467–472, 2016. Chai MK, Tenzel P, Iacob C, et al: Eyelid trichilemmal carcinoma, Saudi J Ophthalmol 31:183–185, 2017. Charles NC, Proia AD, Lo C: Endocrine mucin-producing sweat gland carcinoma of the eyelid associated with mucinous adenocarcinoma, Ophthal Plast Reconstr Surg 34:e37–e38, 2018. Chen M, Liu H, Fu X, et al: Brooke-Spiegler syndrome associated with cylindroma, trichoepithelioma and eccrine spiradenoma, Int J Dermatol 52:1602–1604, 2013. Choi YJ, Lee MJ, Kim N, et al: Inflammatory pseudotumor of eyelid: a probable IgG4-related sclerosing disease clinically mimicking eyelid pilomatrixoma, BMC Ophthalmol 15:23, 2015. Ciarloni L, Frouin E, Bodin F, et al: Syringoma: A clinicopathological study of 244 cases, Ann Dermatol Venereol 143:521–528, 2016. Cinotti E, Singer A, Labeille B, et al: Handheld in vivo reflectance confocal microscopy for the diagnosis of eyelid margin and conjunctival tumors, JAMA Ophthalmol 135:845–851, 2017. Davies EC, Jakobiec FA, Stagner AM, et al: A rapidly enlarging recurrent eyebrow pilomatrixoma in a nonagenarian, Ophthal Plast Reconstr Surg 32:e157–e160, 2016. Eshraghi B, Abtahi MA, Sonbolastan SA, et al: Presentation of massive orbital hidrocystoma at birth: case report and review of the literature, Eye Vis (Lond) 4:5, 2017. Falzon K, Kalantzis G, Chang B, et al: Rapidly enlarging eyelid mass, J Pediatr 164:937–938, 2014. Fattah A, Pollock J, Maheshwar A, et al: Big bad BCCs: craniofacial resection and reconstruction for atypical basal cell carcinomata, J Plast Reconstr Aesthet Surg 63:e433–e441, 2010.

Ferraz LB, Burroughs JR, Satto LH, et al: Three adult cases of orbital hidrocystoma presenting with blepharoptosis, J Clin Med 4:150–158, 2015. Fraga GR, Amin SM: Large cell acanthoma: a variant of solar lentigo with cellular hypertrophy, J Cutan Pathol 41:733–739, 2014. Gauthier AS, Campolmi N, Tumahai P, et al: Sebaceous carcinoma of the eyelid and Muir-Torre syndrome, JAMA Ophthalmol 132:1025–1028, 2014. Gorovoy IR, Layer N, Kim HJ, et al: Pilomatrixoma in a patient with bilateral retinoblastoma, J AAPOS 17:103–104, 2013. Gossman WG, Bhimji SS: Acanthosis nigricans: StatPearls, Treasure Island, FL, 2017, StatPearls Publishing LLC. Gowda KK, Agarwal P, Bal A: Mucinous eccrine carcinoma of the eyelid: re-emphasizing the need for awareness of rare lesions, Dermatol Reports 6:5498, 2014. Hada M, Meel R, Kashyap S, et al: Eyelid pilomatrixoma masquerading as chalazion, Can J Ophthalmol 52:e62–e64, 2017. Han X, Jing H, Liu C, et al: Clinicopathological characteristics of xeroderma pigmentosum associated with keratoacanthoma in an infant, J Cancer Res Ther 11:665, 2015. Hirata A: Eccrine hidrocystoma arising at the tarsal plate during childhood, Case Rep Ophthalmol 4:61–63, 2013. Hoguet A, Warrow D, Milite J, et al: Mucin-producing sweat gland carcinoma of the eyelid: diagnostic and prognostic considerations, Am J Ophthalmol 155:585–592, 2013. Horlock N, Wilson GD, Daley FM, et al: Cellular proliferation characteristics do not account for the behaviour of horrifying basal cell carcinoma. A comparison of the growth fraction of horrifying and non horrifying tumours, Br J Plast Surg 51:59–66, 1998. Huang YY, Liang WY, Tsai CC, et al: Comparison of the clinical characteristics and outcome of benign and malignant eyelid tumors: an analysis of 4521 eyelid tumors in a tertiary medical center, Biomed Res Int 2015:453091, 2015. Huang YY, Tsai CC: Rapid onset of eyebrow pilomatrixoma after blunt trauma, Orbit 34:234–235, 2015. Hudson LE, Craven CM, Wojno TH, et al: Giant chondroid syringoma of the lower eyelid, Ophthal Plast Reconstr Surg 33:e43–e44, 2017. Iwaya M, Uehara T, Yoshizawa A, et al: A case of primary signet-ring cell/histiocytoid carcinoma of the eyelid: immunohistochemical comparison with the normal sweat gland and review of the literature, Am J Dermatopathol 34:e139–e145, 2012. Jackson R, Adams RH: Horrifying basal cell carcinoma: a study of 33 cases and a comparison with 435 non-horror cases and a report on four metastatic cases, J Surg Oncol 5:431–463, 1973. Jagan L, Zoroquiain P, Bravo-Filho V, et al: Sebaceous adenomas of the eyelid and Muir-Torre syndrome, Br J Ophthalmol 99:909–913, 2015. Jakobiec FA, Mendoza PR, Colby KA: Clinicopathologic and immunohistochemical studies of conjunctival large cell acanthoma, epidermoid dysplasia, and squamous papilloma, Am J Ophthalmol 156:830–846, 2013. Jakobiec FA, Werdich X: Androgen receptor identification in the diagnosis of eyelid sebaceous carcinomas, Am J Ophthalmol 157:687–696, e681–e682, 2014. Jayaraj P, Sen S, Dhanaraj PS, et al: Immunohistochemical expression of x-linked inhibitor of apoptosis in eyelid sebaceous gland carcinoma predicts a worse prognosis, Indian J Ophthalmol 65:1109–1113, 2017.

Bibliography Jordao C, de Magalhaes TC, Cuzzi T, et al: Cylindroma: an update, Int J Dermatol 54:275–278, 2015. Kaliki S, Gupta A, Ali MH, et al: Prognosis of eyelid sebaceous gland carcinoma based on the tumor (T) category of the American Joint Committee on Cancer (AJCC) classification, Int Ophthalmol 36:681–690, 2016. Kamisasanuki T, Uchino E, Fukushima J, et al: A case of Muir-Torre syndrome with multiple cancers of bilateral eyelids and breast, Korean J Ophthalmol 27:204–207, 2013. Kim N, Choung HK, Lee MJ, et al: Cancer stem cell markers in eyelid sebaceous gland carcinoma: high expression of ALDH1, CD133, and ABCG2 correlates with poor prognosis, Invest Ophthalmol Vis Sci 56:1813–1819, 2015. Kim N, Kim JE, Choung HK, et al: Expression of Shh and Wnt signaling pathway proteins in eyelid sebaceous gland carcinoma: clinicopathologic study, Invest Ophthalmol Vis Sci 54:370–377, 2013. Kinoshita Y, Takasu K, Yoshizawa K, et al: Horrifying basal cell carcinoma: cytological, immunohistochemical, and ultrastructural findings, Case Rep Oncol 7:459–464, 2014. Kobalka PJ, Abboud JP, Liao X, et al: P16INK4a expression is frequently increased in periorbital and ocular squamous lesions, Diagn Pathol 10:175, 2015. Korekawa A, Nakajima K, Nakano H, et al: Translucent basal cell carcinoma with a single cyst of the upper eyelid, J Dermatol 44:e154–e155, 2017. Kryatova MS, Okoye GA: Dermatology in the North American Indian/Alaska native population, Int J Dermatol 55:125–134, 2016. Kumar DA, Agarwal A: Giant eyelid eccrine hidrocystoma-induced progressive ptosis in childhood, Indian J Ophthalmol 65:884–886, 2017. Kumar MA, Srikanth K, Vathsalya R: Chondroid syringoma: a rare lid tumor, Indian J Ophthalmol 61:43–44, 2013. Kusumesh R, Ambastha A, Bhadrapriya Singh S: Well-differentiated squamous cell carcinoma presenting as branched eyelid cutaneous horn: a case report with review of literature, Indian Dermatol Online J 8:261–263, 2017. Kwiek B, Schwartz RA: Keratoacanthoma (KA): an update and review, J Am Acad Dermatol 74:1220–1233, 2016. Lee V, Lucarelli MJ, Ramey NA, et al: Multiple pigmented basal cell carcinomas of the eyelids, JAMA Ophthalmol 131:1412, 2013. Levy J, Ilsar M, Deckel Y, et al: Eyelid pilomatrixoma: a description of 16 cases and a review of the literature, Surv Ophthalmol 53:526–535, 2008. Liau JY, Liao SL, Hsiao CH, et al: Hypermethylation of the CDKN2a gene promoter is a frequent epigenetic change in periocular sebaceous carcinoma and is associated with younger patient age, Hum Pathol 45:533–539, 2014. Martin J, Fung MA, Lin LK: Breast cancer metastasis masquerading as the great masquerader: sebaceous cell carcinoma, Case Rep Oncol 10:485–488, 2017. McKenzie CA, Chen AC, Choy B, et al: Classification of high risk basal cell carcinoma subtypes: experience of the ONTRAC study with proposed definitions and guidelines for pathological reporting, Pathology 48:395–397, 2016. Milman T, Schear MJ, Eagle RC Jr: Diagnostic utility of adipophilin immunostain in periocular carcinomas, Ophthalmology 121:964–971, 2014. Mir A, Wu T, Orlow SJ: Cutaneous features of Crouzon syndrome with acanthosis nigricans, JAMA Dermatol 149:737–741, 2013. Mittal R, Araujo I, Czanner G, et al: Perforin expression in eyelid sebaceous carcinomas: a useful and specific immunomarker for

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Raven ML, Selid PD, Lucarelli MJ: Merkel cell carcinoma of the eyelid, Ophthalmology 123:2126, 2016. Romero-Perez D, Garcia-Bustinduy M, Cribier B: Clinicopathologic study of 90 cases of trichofolliculoma, J Eur Acad Dermatol Venereol 31:e141–e142, 2017. Rungananchai C, Triwongwaranat D: Plaque-type syringoma: a case report, Case Rep Dermatol 9:190–193, 2017. Sahan B, Ciftci F, Ozkan F, et al: The importance of frozen section-controlled excision in recurrent basal cell carcinoma of the eyelids, Turk J Ophthalmol 46:277–281, 2016. Sarabi K, Khachemoune A: Hidrocystomas–a brief review, Medgenmed 8:57, 2006. Satomura H, Ogata D, Arai E, et al: Dermoscopic features of ocular and extraocular sebaceous carcinomas, J Dermatol 44:1313–1316, 2017. Sen S, Lyngdoh AD, Pushker N, et al: Impression cytology diagnosis of ulcerative eyelid malignancy, Cytopathology 26:26–30, 2015. Shon W, Salomao DR: WT1 expression in endocrine mucin-producing sweat gland carcinoma: a study of 13 cases, Int J Dermatol 53:1228–1234, 2014. Silva JA, Mesquita Kde C, Igreja AC, et al: Paraneoplastic cutaneous manifestations: concepts and updates, An Bras Dermatol 88:9–22, 2013. Stagner AM, Jakobiec FA, Iwamoto MA: Invasive squamous cell carcinoma with clear cell change of the eyelid arising in a seborrheic keratosis, JAMA Ophthalmol 133:1476–1477, 2015. Stagner AM, Jakobiec FA, Yoon MK: Ruptured canthal steatocystoma simplex presenting as a lacrimal sac mass, Clin Exp Ophthalmol 43:385–387, 2015. Stanoszek LM, Wang GY, Harms PW: Histologic mimics of basal cell carcinoma, Arch Pathol Lab Med 141:1490–1502, 2017. Sun MT, Wu A, Huilgol SC, et al: Periocular basal cell carcinoma pathological reporting, Br J Ophthalmol 97:1612–1613, 2013. Takayama K, Usui Y, Ito M, et al: A case of sebaceous adenoma of the eyelid showing excessively rapid growth, Clin Ophthalmol 7:667–670, 2013. Taniguchi S, Hamada T: Trichofolliculoma of the eyelid, Eye (Lond) 10(Pt 6):751–752, 1996. Tetzlaff MT: Immunohistochemical markers informing the diagnosis of sebaceous carcinoma and its distinction from its mimics: adipophilin and factor XIIIa to the rescue? J Cutan Pathol 45:29–32, 2018. Tjarks BJ, Pownell BR, Evans C, et al: Evaluation and comparison of staining patterns of factor XIIIa (AC-1A1), adipophilin and GATA3 in sebaceous neoplasia, J Cutan Pathol 45:1–7, 2018. Tsai YJ, Wu SY, Huang HY, et al: Expression of retinoic acid-binding proteins and retinoic acid receptors in sebaceous cell carcinoma of the eyelids, BMC Ophthalmol 15:142, 2015.

Vani D, T R D, H B S, et al: Multiple apocrine hidrocystomas: a case report, J Clin Diagn Res 7:171–172, 2013. Vu PP, Whitehead KJ, Sullivan TJ: Eccrine poroma of the eyelid, Clin Exp Ophthalmol 29:253–255, 2001. Wang YQ, Yuan Y, Jiang S, et al: Promoter methylation and expression of CDH1 and susceptibility and prognosis of eyelid squamous cell carcinoma, Tumour Biol 37:9521–9526, 2016. Wu A, Sun MT, Huilgol SC, et al: Histological subtypes of periocular basal cell carcinoma, Clin Exp Ophthalmol 42:603–607, 2014. Zembowicz A, Garcia CF, Tannous ZS, et al: Endocrine mucin-producing sweat gland carcinoma: twelve new cases suggest that it is a precursor of some invasive mucinous carcinomas, Am J Surg Pathol 29:1330–1339, 2005. Zhang Y, Kong YY, Cai X, et al: Syringocystadenocarcinoma papilliferum: clinicopathologic analysis of 10 cases, J Cutan Pathol 44:538–543, 2017. Zheng JF, Mo HY, Wang ZZ: Clinicopathological characteristics of xeroderma pigmentosum associated with keratoacanthoma: a case report and literature review, Int J Clin Exp Med 7:3410–3414, 2014. Zloto O, Fabian ID, Dai VV, et al: Periocular pilomatrixoma: a retrospective analysis of 16 cases, Ophthal Plast Reconstr Surg 31:19–22, 2015.

Lacrimal Drainage System Darusman KR: Congenital supernumary lacrimal duct, J Pediatr Ophthalmol Strabismus 50:256, 2013. Moscato EE, Kelly JP, Weiss A: Developmental anatomy of the nasolacrimal duct: implications for congenital obstruction, Ophthalmology 117:2430–2434, 2010.

Tumors Dave TV, Mishra D, Mittal R, et al: Accidentally diagnosed transitional cell papilloma of the lacrimal sac, Saudi J Ophthalmol 31:177–179, 2017. Keelawat S, Tirakunwichcha S, Saonanon P, et al: Cytokeratin-negative undifferentiated (lymphoepithelial) carcinoma of the lacrimal sac, Ophthal Plast Reconstr Surg 33:e16–e18, 2017. Koturovic Z, Knezevic M, Rasic DM: Clinical significance of routine lacrimal sac biopsy during dacryocystorhinostomy: a comprehensive review of literature, Bosn J Basic Med Sci 17:1–8, 2017. Krishna Y, Coupland SE: Lacrimal sac Tumors–a review, Asia Pac J Ophthalmol (Phila) 6:173–178, 2017. Tsao WS, Huang TL, Hsu YH, et al: Primary diffuse large B cell lymphoma of the lacrimal sac, Taiwan J Ophthalmol 6:42–44, 2016.

7  Conjunctiva NORMAL ANATOMY I. The conjunctiva (Fig. 7.1) is a mucous membrane, similar to mucous membranes elsewhere in the body, whose surface is composed of nonkeratinizing squamous epithelium, intermixed with goblet (mucus) cells, Langerhans’ cells (dendritic-appearing cells expressing class II antigen), and occasional dendritic melanocytes. A. Stem cells 1. Stem cells for the epithelium are located near the limbus and their loss can result in exhaustion of the conjunctival epithelial population. Such stem cell loss, which may be exhibited as a late complication, may have many causes, including the use of antimetabolites in glaucoma filtration surgery. 2. K12 immunohistochemical positivity is highly specific for corneal epithelium while K7/K13/MUC5AC positivity reflects conjunctival differentiation. These characteristics are helpful in the diagnosis of limbal stem cell deficiency in which conjunctival cells migrate onto the central corneal surface. 3. In cases of stem cell deficiency without an identifiable origin, such as aniridia, neurotrophic keratopathy, pterygium and loss or absence of meibomian glands, it may be that the force of the eyelids during blinking results in repeated microtrauma to the superior limbus either directly or in association with contact lens wear leading to superior limbal stem cell failure. 4. Limbal stem cells also are characterized by “slow cycling”, which helps insure that they are protected from DNA damage. 5. Idiopathic stem cell deficiency is rare, most commonly found in women, and may be familial in some cases. Patients exhibit severe photophobia and, on clinical examination, have corneal vascularization accompanied by loss of the limbal palisades of Vogt, hazy peripheral corneal epithelium, and the presence of conjunctival goblet cells by impression cytology. Rarely, it has been reported in children. B. The homeostasis of the conjunctiva is dependent, in part, on the maintenance of a normal tear film, which is comprised of lipid, aqueous, and mucoid layers (the mucoid layer is most closely apposed to the corneal epithelium and the lipid layer is at the tear film:air interface). Multiple disorders are associated with abnormal tear composition, quantity and/or quality, and secondary ocular surface changes. 234

1. Tear film abnormalities have been documented in association with cigarette smoking, pseudoexfoliation syndrome, and pseudoexfoliation glaucoma, and are reflected in abnormal conjunctival impression cytology and altered goblet-cell morphology. Cigarette smoking has a deteriorating effect on the tear film in general, and on its lipid layer in particular. It results in decreased quantity and quality of the tear film, decreased corneal sensitivity and squamous metaplasia, and this deterioration is related to the amount of smoking.

2. The pattern of human leukocyte antigen (HLA)-DR expression in mild and moderate dry eyes appears to reflect disease progression, and suggests that inflammation may be a primary cause of ocular surface damage. 3. Squamous metaplasia of the ocular surface epithelium and ocular tear function abnormalities have been associated with interferon and ribavirin treatment for hepatitis C. Similarly, conjunctiva in betathalassemia exhibits goblet-cell loss and conjunctival squamous metaplasia. 4. Inflammation plays a significant role in the pathogenesis of dry eye. 5. Complete androgen-insensitivity syndrome may promote meibomian gland dysfunction and increase the signs and symptoms of dry eye. In patients with dry eyes, the degree of conjunctival metaplasia, characterized by increased stratification, epithelial cellular size, and a general loss of goblet cells, correlates with the clinical severity of their disorder. 6. Mucin gene expression levels, particularly MUC1, are decreased in dry eye, and are biomarkers, which can be evaluated using impression cytology specimens. 7. Marx’s line represents a narrow line of epithelial cells posterior to the tarsal gland orifices along the lid marginal zone, averaging 0.10 mm in width, and is stained with lissamine green dye. It is believed to be the natural site of frictional contact between the eyelid margin and the surfaces of the bulbar conjunctiva and cornea, rather than the edge of the tear meniscus or location of the edge of the lacrimal river. II. The conjunctival epithelium rests on a connective tissue, the substantia propria.

Congenital Anomalies

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t

b

A

B

C

D Fig. 7.1  Conjunctiva. A, The normal conjunctiva, a mucous membrane composed of nonkeratinizing squamous epithelium intermixed with goblet cells, sits on a connective tissue substantia propria. It is divided into three zones: tarsal, fornical–orbital, and bulbar. B, Increased magnification shows the tight adherence of the substantia propria of the tarsal (palpebral) conjunctival epithelium (t) to the underlying tarsal connective tissue and the loose adherence of the substantia propria of the bulbar conjunctival epithelium (b) to the underlying tissue. C, The goblet cells of the bulbar conjunctiva are seen easily with this periodic acid–Schiff stain. D, The tarsal conjunctiva becomes keratinized as it becomes continuous with the keratinized squamous epithelium of the skin on the intermarginal surface of the lid near its posterior border.

III. The conjunctiva is divided into three zones: tarsal, fornical– orbital, and bulbar. A. The substantia propria of the tarsal conjunctiva adheres tightly to the underlying tarsal connective tissue, whereas the substantia propria of the bulbar conjunctiva (and even more so the fornical–orbital conjunctival substantia propria) adheres loosely to the underlying tissue (the fornical–orbital conjunctiva being thrown into folds). The bulbar conjunctiva inserts anterior to Tenon’s capsule toward the limbus. Small ectopic lacrimal glands of Krause are found in both the upper and lower fornices, with very few on the nasal side; glands of Wolfring are found around the upper border of the tarsus in the nasal half of the upper lid, and in lesser numbers, in the lower lid near the lower tarsal border; and glands of Popoff reside in the plica semilunaris and caruncle.



B. The periodic acid–Schiff (PAS) stain-positive goblet cells are most numerous in the fornices, the semilunar fold, and the caruncle. The latter is composed of modified conjunctiva containing hairs, sebaceous glands, acini of lacrimal glandlike cells, globules of fat, on occasion smooth-muscle fibers, and rarely cartilage.



C. The tarsal conjunctiva meets the keratinized squamous epithelium of the skin on the intermarginal surface of the lid near its posterior border.

CONGENITAL ANOMALIES Cryptophthalmos (Ablepharon) See Chapter 6.

Epitarsus I. Epitarsus consists of a fold of conjunctiva attached to the palpebral surface of the lid or lids of one or both eyes. The fold has a free edge, and both surfaces (front and back) are covered by conjunctival epithelium. II. Histologically, the folded conjunctival tissue looks like normal conjunctiva except for the occasional presence of islands of cartilage.

Hereditary Hemorrhagic Telangiectasia (Rendu–Osler–Weber Disease) I. It is a generalized vascular dysplasia characterized by multiple telangiectases in the skin, mucous membranes, and viscera, with recurrent bleeding and an autosomal-dominant inheritance pattern.

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A. Caused by gene coding mutations, and 3 genes account for 85% of cases. They are: (1) HHT type 1 mutation of ENG coding for endoglin, (2) HHT type 2 mutation of ACVRL1 coding for activin receptor-like kinase (ALK), and (3) the combined disorder of juvenile polyposis/ HHT mutation in MADH4 that codes for transcription factor SMAD4. B. The genetic mutations result in impaired blood vessel development. C. Recurrent epistaxis is the most common symptom and often leads to iron deficiency anemia. D. A definite diagnosis is based on the presence of three of the following disease characteristics: (1) spontaneous or recurrent epistaxis, (2) positive family history, (3) cutaneo-mucous telangiectasis, and (4) visceral lesions. II. Dilated conjunctival blood vessels, frequently in a star or sunflower shape, may appear at birth, but are not usually fully developed until late adolescence or early adult life. III. Histologically, abnormal, dilated blood vessels are seen in the conjunctival substantia propria.

Ataxia–Telangiectasia (Louis–Bar Syndrome) See Chapter 2.

Congenital Conjunctival Lymphedema (Milroy’s Disease, Nonne–Milroy–Meige Disease) I. This condition of hypoplastic lymphatics is characterized by massive edema, mainly of the lower extremities and rarely of the conjunctiva. A. Mutations in FLT4 that encodes the vascular endothelial growth factor receptor-3 (VEGFR3) gene on chromosome 5q35 cause Milroy disease. These mutations are found in 70% of patients with congenital onset primary lymphedema of the lower extremities. 1. Inherited as autosomal dominant with 85% penetrance. B. Late-onset hereditary lymphedema may be associated with distichiasis (lymphedema–distichiasis syndrome) and has an autosomal-dominant inheritance pattern, mapped to 16q24.3 and to mutations in the FOXC2 gene. 1. Congenital heart disease and cleft palate are present in approximately 7% and 4% of affected individuals, respectively. Congenital ptosis is present in 31% of these individuals. II. The disease is thought to be due to a congenital dysplasia of the lymphatics, resulting in chronic lymphedema. III. Histologically, dilated lymphatic channels and edematous tissue are seen.

Miscellaneous I. Phosphatase and tensin homologue (PTEN) hamartoma syndrome. A. Results from germline mutation of PTEN gene. 1. Manifests as Cowden syndrome, Bannayan–Riley– Ruvalcaba syndrome, PTEN-related Proteus syndrome, and Proteus-like syndrome.





B. Has been associated with conjunctival hamartoma with eosinophilia. 1. Contains sclerotic stroma with layered collagen fibers, spindle cells, capillaries and chronic inflammatory cells (lymphocytes and plasma cells) with numerous eosinophils centered around capillaries. 2. Spindle cells have oval vesicular nuclei and tapering eosinophilic cytoplasm. a. Positive for factor XIIIa and CD68, and focally positive for smooth muscle actin. b. Negative for CD1a, EMA, CD117, desmin, CD34, S100, Melan A, Alk-1, calretinin and cytokeratins. 3. Plasma cells are negative for IgG4.

Dermoids, Epidermoids, and Dermolipomas See also elsewhere in this chapter and in Chapter 14. I. An unsuspected dermoid cyst of conjunctival origin has been diagnosed at the time of cataract surgery when the administration of the retrobulbar block perforated the cyst and resulted in leaking of the cyst fluid onto the surgical field. II. Rarely a dermoid cyst may have trichilemmal differentiation of the cyst lining, which will stain positively with calretinin, an immunostain for trichilemmal differentiation. III. Lipodermoid has been reported in Emanuel syndrome (supernumerary der(22)t(11; 22) syndrome), which is associated with a supernumerary chromosome, the derivative 22 (der(22)) chromosome, which consists of redundant genetic material from chromosomes 11 and 22 in addition to 2 normal copies of chromosomes 11 and 22. A. There appears to be a phenotypic overlap between Emanuel and Goldenhar syndromes. B. Emanuel syndrome also is associated with multiple congenital anomalies, craniofacial dysmorphism, and significant developmental delay. 1. Other findings are ear pits, micrognathia, heart malformations, cleft palate, preauricular tags, and microtia. 2. Ocular abnormalities are myopia, strabismus, astigmatism and ptosis; however, it is not usually associated with congenital ocular anomalies or lipodermoids. IV. Subconjunctival epidermoid cysts are found in association with Gorlin–Goltz syndrome.

Choristomas I. Limbal epibulbar choristomas, like all choristomas, are comprised of normal tissue in an abnormal location. A recently reported lesion was composed of stratified squamous and columnar epithelium, adipose tissue lobules, cartilage, and lacrimal gland tissue.

Laryngo-Onycho-Cutaneous (LOC or Shabbir) Syndrome I. LOC is an autosomal-recessive epithelial disorder characterized by cutaneous erosions, nail dystrophy, and exuberant vascular granulation in certain epithelia, especially the conjunctiva and larynx.

Vascular Disorders

II. The diagnosis is in the first months of infancy and progresses to multiple cutaneous manifestations. III. Patients develop facial erosions from brief blistering, conjunctival papules, and notched teeth deformities. IV. Classified as a subtype of junctional epidermolysis bullosa. A. The initially reported cases were confined to the Punjabi Muslim population, and caused by an unusual N-terminal deletion of the laminin alpha3a isoform, thereby demonstrating that the laminin α3a N-terminal domain is a key regulator of the granulation tissue response. The protein product is secreted by basal keratinocytes of stratified epithelia, and it has been postulated that LOC results from an altered extracellular matrix homeostasis when the basal keratinocytes secrete the abbreviated α3 chain.

VASCULAR DISORDERS See Table 7.1 for a comparison of non-neoplastic periocular vascular lesions.

237

Sickle-Cell Anemia See Chapter 11. I. In homozygous sickle-cell disease, conjunctival capillaries may show widespread sludging of blood. The venules may show saccular dilatations. II. The characteristic findings (marked in SS disease and mild in SC disease), however, are multiple, short, comma-shaped or curlicued conjunctival capillary segments, mostly near the limbus, often seemingly isolated from the vascular network (Paton’s sign). Similar conjunctival capillary abnormalities may occasionally be seen in patients without sickle cell disease. Inferior conjunctival abnormalities, however, are found almost exclusively in patients with sickle-cell disease. The vascular abnormalities seem positively related to the presence of sickled erythrocytes. The comma-shaped capillaries are most easily seen after local application of phenylephrine.

TABLE 7.1  Brief Comparative Descriptions of Nine Non-Neoplastic Periocular Vascular

Lesions Entity

Characteristics

Varix

Fusiform saccular dilation of thin wall segments of a pre-existent vein lacking an elastica; may be acquired or congenital if part of a venous malformation Morphologically resembles a venous angioma but behaves more like a venous malformation; large lumens with variably prominent walls composed of myofibroblastic cells; congenital or acquired, usually declaring itself in early middle age Anarchic collection of maldeveloped venous channels, some with large lumens conducive to phlebolith formation; superficial masses can have grape-like (racemose) collections of lobules or soft nodules; congenital; must be distinguished from venous angioma, a proliferation of venous channels with prominent muscular walls lacking an elastic lamina and an acquired lesion Tumefactive superficial dermal skin (acral) lesions (not true tumors) and deeper soft-tissue lesions recognized; redundant, proliferating cirsoid (variceal or aneurysmal) arteries with an elastic lamina and veins without an elastic lamina; superficial lesions acquired, deeper lesions congenital; typically encountered as periocular and retinal lesions in Wyburn–Mason syndrome Both arteries and veins conspicuously enlarged with loop-like intercommunication; absence of proliferation thereby failing to generate thickness or tumefaction; congenital and acquired variants Lymphatic malformation of tumoral proportions with variably sized lumens most often arising as a choristoma in orbit where there are normally no lymphatics; irregular thin walled channels that are D2-40-positive; chocolate cysts result from hemorrhage into delicate cavernous lymphatic spaces; scattered lymphoid aggregates; conjunctival lesions rarely isolated but typically coexist with deeper orbital disease; congenital Maldeveloped vessels with muscular walls and CD31-positive vascular endothelial cells; juxtaposed areas of lymphangioma with lymph-filled thin walled spaces and D2-40-positive lymphatic endothelium; scattered lymphoid aggregates sometimes with germinal centers; congenital Nontumefactive dilated epibulbar lymphatic spaces sometimes abnormal in character; strictly localized to conjunctiva; endothelium D2-40-positive; not a tumor because of absence of proliferation; no lymphoid aggregates; Leber’s hemorrhagic, nonhemorrhagic, unilateral and bilateral forms recognized; congenital; distinguished from simple lymphatic dilation due to intraluminal lymphstasis and from interstitial lymphedema Nontumefactive dilated abnormal capillaries and post-capillary venules with weakened walls that typically do not hemorrhage; associated in conjunctiva with ataxia telangiectasia and Sturge–Weber syndrome with diffuse choroidal hemangioma and eyelid nevus flammeus; different from dilation due to retrograde blood flow from deeper orbital or cavernous sinus shunts or arteriovenous malformations; congenital but can become more pronounced with aging; distinguished from simple passive vascular dilation or engorgement from inflammation

Orbital cavernous hemangioma Venous malformation (racemose)

Arteriovenous malformation (cirsoid)

Arteriovenous shunts Lymphangioma

Lymphaticovenous malformation

Lymphangiectasia

Telangiectasia

(From Jakobiec et al.: An analysis of conjunctival and periocular venous malformations: clinicopathologic and immunohistochemical features with a comparison of recemose and cirsoid lesions. Surv Ophthalmol 59:236–244, 2014. Table 1. Elsevier.)

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CHAPTER 7  Conjunctiva

III. Histologically, the capillary lumen is irregular and filled with sickled erythrocytes.

Conjunctival Hemorrhage (Subconjunctival Hemorrhage) I. Intraconjunctival hemorrhage (see Fig. 5.31) into the substantia propria, or hemorrhage between conjunctiva and episclera, most often occurs as an isolated finding without any obvious cause. II. The condition may occasionally result from trauma; severe conjunctival infection (e.g., leptospirosis and typhus); local vascular anomalies; sudden increase in venous pressure (e.g., after a paroxysm of coughing or sneezing); local manifestations of such systemic diseases as arteriolosclerosis, nephritis, diabetes mellitus, and chronic hepatic disease; blood dyscrasias, especially when anemia and thrombocytopenia coexist; acute febrile systemic infection (e.g., subacute bacterial endocarditis); spontaneously during menstruation; and trichinosis. III. Histologically, blood is seen in the substantia propria of the conjunctiva.

Lymphangiectasia I. Abnormal diffuse enlargement of lymphatics appears clinically as chemosis. Localized, dilated lymphatics appear clinically as a cyst or a series of cysts, the latter commonly in the area of the interpalpebral fissure. II. When involvement is diffuse, the cause is not usually known.

An old scar, a pinguecula, or some other conjunctival lesion usually obstructs localized, dilated lymphatics secondarily.

III. Histologically, the lymphatic vessels are abnormally dilated.

A

Lymphangiectasia Hemorrhagica Conjunctivae I. The condition is characterized by a connection between a blood vessel and a lymphatic so that the latter is permanently or intermittently filled with blood. II. In classic descriptions, the condition involves sudden, rapid filling of the conjunctival lymphatics with blood by retrograde filling from the conjunctival vessels followed by rapid clearing of the blood usually within 3–4 days. In distinction to the common conjunctival hemorrhage, the blood in this disorder remains within distended lymphatics without extravasation into the tissues. This fact accounts for the usually rapid clearing of the blood.

III. It usually involves one quadrant of the globe, although circumferential cases have been reported. IV. The cause is not known.

Ataxia–Telangiectasia See Chapter 2.

Diabetes Mellitus See section Ocular Surface Disease in Chapter 15.

Hemangioma and Lymphangioma See also Chapter 14. I. Acquired sessile hemangioma of the conjunctiva (Fig. 7.2) A. Mean age at diagnosis, 58 years (31–83 years); 8 women, 3 men; usually a coincidental finding. B. Flat collection of intertwining, mildly dilated blood vessels usually on the bulbar conjunctiva. C. Feeding artery and draining vein seen with leakage of fluorescein dye from deeper, but not more superficial, vessels.

B Fig. 7.2  Acquired sessile hemangioma. A, Clinical appearance of an acquired sessile hemangioma. B, Histopathologic examination demonstrates two layers of enlarged, congested blood vessels immediately beneath the conjunctival epithelium (hematoxylin and eosin, ×20). (Reproduced by permission from Shields JA, Kligman BE, Mashayekhi A et al.: Acquired sessile hemangioma of the conjunctiva: A report of 10 cases. Am J Ophthalmol 152:55, 2011. © Elsevier, Inc.)

Inflammation

A

239

B Fig. 7.3  Acute conjunctivitis. A, Clinical appearance of a mucopurulent conjunctivitis of the left eye. The pupil reacted normally. The conjunctival infection was least at the limbus and increased peripherally. B, The major inflammatory cell of acute bacterial conjunctivitis is the polymorphonuclear leukocyte, which here infiltrates the swollen edematous epithelium and the substantia propria.



D. Lesion is nonprogressive without systemic disease associations. E. Histopathologic examination shows two to three layers of dilated, congested blood vessels that otherwise appear to be normal.

True membrane Epithelium

INFLAMMATION Basic Histologic Changes I. Acute conjunctivitis (Fig. 7.3) A. Edema (chemosis), hyperemia, and cellular exudates are characteristic of acute conjunctivitis. B. Inflammatory membranes (Fig. 7.4) 1. A true membrane consists of an exudate of fibrin– cellular debris firmly attached to the underlying epithelium by fibrin that characteristically, on attempted removal, the epithelium is stripped off and leaves a raw, bleeding surface. a. The condition may be seen in epidemic keratoconjunctivitis, Stevens–Johnson syndrome, and infections caused by Pneumococcus, Staphylococcus aureus, Streptococcus pyogenes and Corynebacterium diphtheriae. 2. A pseudomembrane consists of a loose fibrin–cellular debris exudate not adherent to the underlying epithelium, from which it is easily stripped, usually without bleeding. 3. Ligneous conjunctivitis (Fig. 7.5) is an unusual bilateral, chronic, recurrent, membranous or pseudomembranous conjunctivitis of childhood, most commonly in girls. a. Characterized by deficiency in type 1 plasminogen. The lack of plasmin activity results in the formation of fibrin-rich pseudomembranes. Present as a symptom in 80% of cases of plasminogen deficiency. b. Persists for months to years and may become massive. c. Rarely, this disorder occurs in adults. d. Some cases may have an autosomal recessive inheritance.

Bleeding Substantia propria A Pseudomembrane Epithelium

B Fig. 7.4  Inflammatory membranes. A, In a true membrane, when the membrane is stripped off, the epithelium is also removed and a bleeding surface remains. B, In a pseudomembrane, when the membrane is stripped off, it separates from the epithelium, leaving it intact and causing no surface bleeding.

Ligneous conjunctivitis has been reported coexisting with IgG4-related disease.





e. The conjunctivitis is characterized by wood-like induration of the palpebral conjunctiva, chronicity, and rapid recurrence after medical or surgical treatment. Severe corneal complications may occur. f. Most often involves the upper palpebral conjunctiva. g. Similar lesions may also occur in the larynx, vocal cords, trachea, nose, vagina, cervix, and gingiva.

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B

A

Fig. 7.5  Ligneous conjunctivitis. A, A thick membrane covers the upper palpebral conjunctiva. Ligneous conjunctivitis is a chronic, bilateral, recurrent, membranous or pseudomembranous conjunctivitis of childhood characterized by deficiency in Type 1 plasminogen. B, Biopsy shows a thick, amorphous material contiguous with an inflammatory membrane composed mostly of mononuclear inflammatory cells, mainly plasma cells, and some lymphocytes. (Case presented by Dr. JS McGavic at the meeting of the Verhoeff Society, 1986).

A

B

Fig. 7.6  Chronic conjunctivitis. A, The conjunctiva is thickened and contains tiny yellow cysts. B, Histologic section of the conjunctiva demonstrates the cyst lined by an epithelium that resembles ductal epithelium and that contains a pink granular material. A chronic nongranulomatous inflammation of lymphocytes and plasma cells surrounds the cyst, along with a proliferation of the epithelium of the palpebral conjunctiva, forming structures that resemble glands and are called pseudoglands (Henle).

Rarely, the middle ear may exhibit a similar histopathologic process. h. Histologically, the conjunctival epithelium is thickened and may be dyskeratotic. The subepithelial tissue consists of an enormously thick membrane composed primarily of fibrin, albumin, immunoglobulin G (IgG), and an amorphous eosinophilic PAS-positive material with an adjacent infiltrate containing acute and chronic inflammatory cells comprising neutrophils, T cells, macrophages, B cells, and mast cells. C. Ulceration, or loss of epithelium with or without loss of subepithelial tissue associated with an inflammatory cellular infiltrate, may occur with acute conjunctivitis. D. A phlyctenule usually starts as a localized, acute inflammatory reaction, followed by central necrosis and infiltration by lymphocytes and plasma cells. II. Chronic conjunctivitis (Fig. 7.6) A. The epithelium and its goblet cells increase in number (i.e., become hyperplastic).

Infoldings of the proliferated epithelium and goblet cells may resemble glandular structures in tissue section and are called pseudoglands (Henle). Commonly, the surface openings of the pseudoglands, especially in the inferior palpebral conjunctiva, may become clogged by debris. They form clear or yellow cysts called pseudoretention cysts, containing mucinous secretions admixed with degenerative products of the epithelial cells.



B. The conjunctiva may undergo papillary hypertrophy (Fig. 7.7), which is caused by the conjunctiva being thrown into folds. Papillary hypertrophy is primarily a vascular response. 1. The folds or projections are covered by hyperplastic epithelium and contain a core of vessels surrounded by edematous subepithelial tissue infiltrated with chronic inflammatory cells (lymphocytes and plasma cells predominate).

Inflammation

A

241

B Fig. 7.7  Papillary conjunctivitis. A, The surfaces of the papillae are red because of numerous tiny vessels, whereas their bases are pale. The yellow staining is caused by fluorescein. B, Histologic section of the conjunctiva demonstrates an inflammatory infiltrate in the substantia propria and numerous small vessels coursing through the papillae. The inflammatory cells are lymphocytes and plasma cells.

A

B Fig. 7.8  Follicular conjunctivitis. A, The surfaces of the follicles are pale, whereas their bases are red. B, Histologic section of the conjunctiva shows a lymphoid follicle in the substantia propria.

reaction. Lymphoid hyperplasia develops in such diverse conditions as drug toxicities (e.g., atropine, pilocarpine, eserine), allergic conditions, and infections (e.g., trachoma). It has been reported, presumably, as secondary to extremely thin sclera in high myopia. Clinically, lymphoid follicles are smaller and paler than papillae and lack the central vascular tuft.

2. The lymphocyte (even lymphoid follicles) and plasma cell infiltrations are secondary. Clinically, the small (0.1 to 0.2 mm), hyperemic projections are fairly regular, are most marked in the upper palpebral conjunctiva, and contain a central tuft of vessels. The valleys between the projections are pale and relatively vessel-free. Papillae characterize the subacute stage of many inflammations (e.g., vernal catarrh and the floppyeyelid syndrome; decreased tarsal elastin may contribute to the laxity of the tarsus in the floppyeyelid syndrome).



C. The conjunctiva may undergo follicle formation. Follicular hypertrophy (Fig. 7.8) consists of lymphoid hyperplasia and secondary visualization. Lymphoid tissue is not present in the conjunctiva at birth but normally develops within the first few months. In inclusion blennorrhea of the newborn, therefore, a papillary reaction develops, whereas the same infection in adults may cause a follicular









D. Vitamin A deficiency or drying of the conjunctiva (e.g., chronic exposure with lid ectropion) may cause keratinization. E. Chronic inflammation during healing may cause an overexuberant amount of granulation tissue to be formed (i.e., granuloma pyogenicum; see Fig. 6.11). F. The conjunctiva may be the site of granulomatous inflammation (e.g., sarcoid; see Chapter 4). G. Conjunctival epithelium of patients on chronic topical medical treatment, such as individuals with glaucoma, demonstrates increased expression of immunoinflammatory markers such as HLA-DR, and interleukins IL-6, IL-8, and IL-10 in impression cytology specimens. H. Clinical and/or histopathologic demonstration of tarsal conjunctival disease may be evidenced by: (1)

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CHAPTER 7  Conjunctiva

conjunctival hyperemia and granuloma formation, areas of necrosis, or active fibrovascular changes in the tarsus or conjunctiva; or (2) an inactive fibrovascular scar associated with subglottic stenosis and nasolacrimal duct obstruction in patients with Wegener’s granulomatosis (granulomatosis with polyangiitis). III. Ligneous conjunctivitis (see earlier, this chapter). IV. Scarring of conjunctiva A. Ocular cicatricial pemphigoid (benign mucous membrane pemphigoid, pemphigus conjunctivae, chronic cicatrizing conjunctivitis, essential shrinkage of conjunctiva) 1. This is a rare, T-cell immune-mediated, bilateral (one eye may be involved first), blistering, chronic conjunctival disease. It may involve the conjunctiva alone or, more commonly, other mucous membranes and skin in elderly people. The conjunctiva is the only site of involvement in most cases. Drugs such as echothiophate iodide, pilocarpine, idoxuridine, and epinephrine may induce a pseudopemphigoid conjunctival reaction.

2. The disease results in shrinkage of the conjunctiva (secondary to scarring), trichiasis, xerosis, and finally, reduced vision from secondary corneal scarring. An acute or subacute papillary conjunctivitis and diffuse hyperemia are common at its onset. One or two small conjunctival ulcers covered by a gray membrane are often noted. Keratinization of the caruncular region (i.e., medial canthal keratinization) is a reliable early sign of ocular cicatricial pemphigoid, especially if entities such as Stevens– Johnson are excluded. The ulcers heal by cicatrization, as new ulcers form. The condition occurs more frequently in women.



3. Squamous neoplasia has been reported to accompany ocular cicatricial pemphigoid. 4. Symptomatic dry eye is a characteristic finding in both pemphigoid and pemphigus. About 22% of patients who have systemic, nonocular, mucous membrane pemphigoid develop ocular disease. 5. Histology a. Subepithelial conjunctival bullae rupture and are replaced by fibrovascular tissue containing lymphocytes (especially T cells), dendritic (Langerhans’) cells, and plasma cells. 1) The epithelium has an immunoreactive deposition (immunoglobulin or complement) along its basement membrane zone. The presence of circulating antibodies to the epithelial basement membrane zone can also be helpful in making the diagnosis. Such immunohistochemical confirmation is important because the clinical characteristics of ocular mucous

membrane pemphigoid and pseudopemphigoid are similar, which may lead to a clinical misdiagnosis. Increased expression of connective tissue growth factor has been demonstrated in the conjunctiva of patients with ocular cicatricial pemphigoid, and it is probably one of the factors involved in the pathogenesis of the typical conjunctival fibrosis in the disorder. Macrophage colony-stimulating factor has increased expression in conjunctiva in ocular cicatricial pemphigoid, and there is a positive correlation between its expression and the accumulation of macrophages in conjunctival biopsies in patients with pemphigoid.

2) The vascular and inflammatory components lessen with chronicity, resulting in contracture of the fibrous tissue with subsequent shrinkage, scarring, symblepharon, ankyloblepharon, and so forth. The use of the immunoperoxidase technique in biopsy material may increase the diagnostic yield in clinically suspected cases. Ocular cicatricial pemphigoid, bullous pemphigoid, and benign mucous membrane pemphigoid, all immune-mediated blistering diseases, resemble each other clinically, histopathologically, and immunologically. Ocular cicatricial pemphigoid, however, appears to be a unique entity separated from the others by antigenic specificity of autoantibodies. Another systemic blistering condition, epidermolysis bullosa acquisita, can cause symblepharon and small, subepithelial corneal vesicles.

3) Expression of macrophage migration inhibitory factor is increased in cicatricial pemphigoid and may help regulate the inflammatory events in this disorder. 4) Elevated numbers of conjunctival mast cells are present in ocular cicatricial pemphigoid, as well as in atopic keratoconjunctivitis and Stevens–Johnson syndrome. Pemphigus, a group of diseases that have circulating antibodies against intercellular substances or keratinocyte surface antigens, unlike pemphigoid, is characterized histologically by acantholysis, resulting in intraepidermal vesicles and bullae rather than subepithelial vesicles and bullae. The bullae of pemphigus, unlike those of pemphigoid, tend to heal without scarring. It

Inflammation is caused by autoantibodies against desmosomal adhesion molecules. These antibodies have been shown to cause blister formation and p38MAPK activation in the conjunctiva similar to their activity in the epidermis. In pemphigus, the conjunctiva is rarely involved, and even then, scarring is not a prominent feature. Unilateral refractory (erosive) conjunctivitis has been reported in 16.5% of patients with pemphigus vulgaris.









5) The histopathologic alterations in the ocular surface from abnormal tear film vary considerably depending upon the nature of the precipitating ocular condition. a) Dryness secondary to facial nerve palsy is an aqueous-deficient process resulting in a relatively pure squamous metaplasia response. b) Ocular cicatricial pemphigoid is primarily a mucous-deficient syndrome and results in hypertrophy and hyperplasia of the ocular surface epithelium. c) Patients with primary Sjögren syndrome, which involves deficiency of both the aqueous and mucin tear components, start with a squamous metaplasia process, but display hypertrophy and hyperplasia at later stages of the disease. B. Secondary scarring occurs in many conditions.

vision loss. The keratopathy can be an early and severe complication. Other ocular complications include lens opacities (18%), hypotrichosis (12%), anisometropic amblyopia (5.9%), and myopia (5.9%). 1. The responsible gene is AIRE (for autoimmune regulator) and is mapped to chromosome 21q22.3. More than 75 mutations have been described.

Specific Inflammations Infectious I. Virus—see subsection Chronic Nongranulomatous Inflammation in Chapter 1. A. As an alternative to viral culture, the most sensitive and specific methods of confirming adenovirus conjunctival infection are PCR (100%), IgM detection (92.9%), and direct antigen detection by fluorescent stain (85.8%). II. Bacteria—see sections Phases of Inflammation in Chapter 1 and Suppurative Endophthalmitis and Panophthalmitis in Chapter 3. Also see Chlamydiae below. III. Chlamydiae cause trachoma, lymphogranuloma venereum, and ornithosis (psittacosis). A. They are gram-negative, basophilic, coccoid or spheroid bacteria. B. The chlamydiae are identified taxonomically into order Chlamydiales, family Chlamydiaceae, genus Chlamydia, and species trachomatis and psittaci. The agents that cause both trachoma and inclusion conjunctivitis, Chlamydia trachomatis, are almost indistinguishable from each other, and the term TRIC agent encompasses both. Reproduction of chlamydiae starts with the attachment and penetration of the elementary body, an infectious small particle 200 to 350 nm in diameter with an electron-dense nucleoid, into the host-cell cytoplasm. The phagocytosed agent, surrounded by the invaginated host-cell membrane, forms a cytoplasmic inclusion body. The elementary body then enlarges to approximately 700 to 1000 nm in diameter to form a nonmotile obligate intracellular (cytoplasmic) parasite known as an initial body that does not contain electron-dense material. Initial bodies then divide by binary fission into numerous, small, highly infectious elementary bodies. The host cell ruptures, the elementary bodies are released, and a new infectious cycle begins.

Examples include chemical burns, erythema multiforme (Stevens–Johnson syndrome), old membranous conjunctivitis (diphtheria, β-hemolytic Streptococcus, adenovirus, primary herpes simplex), trachoma, trauma (surgical or nonsurgical), paraneoplastic pemphigus, and pemphigus vulgaris, and deliberate chronic use of high-dose topical hydrogen peroxide. Cicatricial conjunctivitis may be a manifestation of porphyria cutanea tarda.





C. Conjunctival involvement in toxic epidermal necrolysis has been reported in association with autoimmune polyglandular syndrome type I, which is defined as the presence of two of the following diseases: Addison’s disease, hypoparathyroidism, and chronic mucocutaneous candidiasis. D. Autoimmune polyendocrinopathy syndrome type 1 (polyendocrinopathy–candidiasis–ectodermal dystrophy) is a rare autosomal recessive disorder. It usually presents with chronic mucocutaneous candidiasis and autoimmune targeted endocrinopathy resulting in hypoparathyroidism and adrenal insufficiency. The ocular complications are characterized by reduced tear production (63%) that can result in corneal scarring and

243



C. Trachoma (Fig. 7.9) 1. Trachoma, caused by C. trachomatis, is an obligate intracellular bacteria. It is one of the world’s leading causes of blindness and primarily affects the conjunctival and corneal epithelium. It remains a significant cause of blindness in spite of World Health Organization efforts to eradicate it. Inflammation progresses in adults even without the presence of detectable organisms. Healing is marked by scarring or cicatrization that can produce trichiasis and secondary corneal damage.

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e

i A

B

e

Fig. 7.9  Trachoma. A, The patient has a trachomatous pannus growing over the superior conjunctiva. With healing, the follicles disappear from the peripheral cornea, leaving areas filled with a thickened transparent epithelium called Herbert’s pits. The palpebral conjunctiva scars by the formation of a linear, white, horizontal line or scar near the upper border of the tarsus, called von Arlt’s line. B, A conjunctival smear from another case of trachoma shows a large cytoplasmic basophilic initial body (i). Small cytoplasmic elementary bodies (e) are seen in some of the other cells. C, Small cytoplasmic elementary bodies (e) are seen in numerous cells. (A, Courtesy of Dr. AP Ferry.)

e C





2. In vivo confocal microscopy can be used clinically to quantify inflammatory and scarring changes in the conjunctiva in trachoma in which dendritic cells are closely associated with the scarring process. 3. Histology of MacCallan’s classic four stages: a. Stage I: early formation of conjunctival follicles, subepithelial conjunctival infiltrates, diffuse punctate keratitis, and early pannus. 1) The conjunctival epithelium undergoes a marked hyperplasia, and its cytoplasm contains clearly defined, glycogen-containing intracellular microcolonies of minute elementary bodies and large basophilic initial bodies (epithelial cytoplasmic inclusion bodies of Halberstaedter and Prowazek). The subepithelial tissue is edematous and infiltrated by round inflammatory cells. 2) Fibrovascular tissue from the substantia propria proliferates and starts to grow into the cornea under the epithelium, destroying Bowman’s membrane; the tissue is then called an inflammatory pannus. b. Stage II: florid inflammation, mainly of the upper tarsal conjunctiva with the early formation of follicles appearing like sago grains, and then like papillae. The follicles cannot be differentiated histologically from lymphoid follicles secondary to other causes (e.g., allergic).

The corneal pannus increases and large macrophages with phagocytosed debris (Leber cells) appear in the conjunctival substantia propria.



c. Stage III: scarring (cicatrization): in the peripheral cornea, follicles disappear and the area is filled with thickened, transparent epithelium (Herbert’s pits); as the palpebral conjunctiva heals, a white linear horizontal line or scar forms near the upper border of the tarsus (von Arlt’s line). Cicatricial entropion and trichiasis may result. Ocular rosacea can produce chronic cicatrizing conjunctivitis of the upper eyelids, which was previously thought to be unique to trachoma. Conjunctival impression cytology in ocular rosacea demonstrates significant ocular surface epithelial degeneration involving both the upper bulbar and inferonasal interpalpebral bulbar epithelium compared to normal individuals. The inflammatory infiltrate of the tarsal conjunctiva is predominantly composed of T cells (CD4+ and CD8+), and suggests that T cells may be involved in the genesis of both tarsal thickening and conjunctival scarring in the late stages of trachoma.



d. Stage IV: arrest of the disease

Inflammation



D. Inclusion conjunctivitis (inclusion blennorrhea) 1. Inclusion conjunctivitis is caused by the bacterial agent C. trachomatis (oculogenitale). 2. It is an acute contagious disease of newborns quite similar clinically and histologically to trachoma, except the latter has a predilection for the upper rather than the lower palpebral conjunctiva and fornix.

acute disorders (seasonal allergic conjunctivitis and perennial allergic conjunctivitis), and chronic diseases (vernal conjunctivitis, atopic keratoconjunctivitis, giant papillary conjunctivitis). Mast cells play a central role in the pathogenesis of ocular allergy. Their numbers are increased in all forms of allergic conjunctivitis, and may participate in the process through their activation, resulting in the release of preformed and newly formed mediators. Chronic conjunctivitis may be accompanied by remodeling of the ocular surface tissues.

Inclusion conjunctivitis can also occur in adults, commonly showing corneal involvement (mainly superficial epithelial keratitis, but also subepithelial nummular keratitis, marginal keratitis, and superior limbal swelling and pannus formation).





3. Histologically, a follicular reaction is present with epithelial cytoplasmic inclusion bodies indistinguishable from those of trachoma. E. Lymphogranuloma venereum (inguinale) 1. Lymphogranuloma venereum, caused by C. trachomatis, is characterized by a follicular conjunctivitis or a nonulcerating conjunctival granuloma, usually near the limbus and associated with a nonsuppurative regional lymphadenopathy. The clinical picture is that of Parinaud’s oculoglandular syndrome (see later). Keratitis may occur, usually with infiltrates in the upper corneal periphery, associated with stromal vascularization and thickened corneal nerves. An associated anterior uveitis may also occur.

2. Histologically, a granulomatous conjunctivitis and lymphadenitis occur, the latter containing stellate abscesses. Elementary bodies and inclusion bodies cannot be identified in histologic sections. IV. Fungal—see the subsection Fungal, section Nontraumatic Infections in Chapter 4. V. Parasitic—see the subsection Parasitic, section Nontraumatic Infections in Chapter 4 and Chapter 8. VI. Rickettsial—Organisms range in size from 250 nanometers to more than 1 micrometer, have no cell wall but are surrounded by a cell membrane, and are intracellular parasites. VII. Parinaud’s oculoglandular syndrome (granulomatous conjunctivitis and ipsilateral enlargement of the preauricular lymph nodes) consists of a granulomatous inflammation and may be caused most commonly by cat-scratch disease, but also by Epstein–Barr virus infection, tuberculosis, sarcoidosis, syphilis, tularemia, Leptothrix infection, soft chancre (chancroid—Haemophilus ducreyi), glanders, lymphogranuloma venereum, Crohn’s disease, and fungi.

Noninfectious I. Physical—see subsections Burns and Radiation Injuries (Electromagnetic) in Chapter 5. II. Chemical—see subsection Chemical Injuries in Chapter 5. III. Allergic A. Allergic conjunctivitis is usually associated with a type 1 hypersensitivity reaction and can be subdivided into

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B. Vernal keratoconjunctivitis (vernal catarrh, spring catarrh; Fig. 7.10) 1. Vernal keratoconjunctivitis is a bilateral, recurrent, self-limited conjunctival disease occurring mainly in warm weather and affecting young people (mainly boys). a. It is of unknown cause, but is presumed to be an immediate hypersensitivity reaction to exogenous antigens. b. The disease is associated with increased serum levels of total IgE, eosinophil-derived products, and nerve growth factor. c. The cells infiltrating the conjunctiva in vernal conjunctivitis include lymphocytes, eosinophils, mast cells, and natural killer (NK) cells. A condition called giant papillary conjunctivitis resembles vernal conjunctivitis. It occurs in contact lens wearers as a syndrome consisting of excess mucus and itching, diminished or destroyed contact lens tolerance, and giant papillae in the upper tarsal conjunctiva.





2. Vernal conjunctivitis may be associated with, or accompanied by, keratoconus (or, more rarely, pellucid marginal corneal degeneration, keratoglobus, or superior corneal thinning). 3. Involvement may be limited to the tarsal conjunctiva (palpebral form), the bulbar conjunctiva (limbal form), or the cornea (vernal superficial punctate keratitis form), or combinations of all three. It is mediated, at least in part, by IgE antibodies produced in the conjunctiva. 4. Histology a. The tarsal conjunctiva may undergo hyperplasia of its epithelium and proliferation of fibrovascular connective tissue along with an infiltration of round inflammatory cells, especially eosinophils and basophils. Papillae that form as a result can become quite large, clinically resembling cobblestones. b. The epithelium and subepithelial fibrovascular connective tissue of the limbal conjunctival region may undergo hyperplasia and round-cell

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CHAPTER 7  Conjunctiva

A

B

Fig. 7.10  Vernal catarrh. A, Clinical appearance of the papillary reaction of the palpebral conjunctiva. B, Clinical appearance of the less commonly seen limbal reaction. C, Histologic examination of a conjunctival smear shows the presence of many eosinophils. (B and C, Courtesy of Dr. IM Raber.)

C





inflammatory infiltration, with production of limbal nodules. c. In the larger yellow or gray vascularized nodules, concretions, containing eosinophils, appear clinically as white spots (Horner–Trantas spots). d. Degeneration and death of corneal epithelium result in punctate epithelial erosions that are especially prone to occur in the upper part of the cornea. Eosinophilic granule major basic protein (the core of the eosinophilic granule) may play a role in the development of corneal ulcers associated with vernal keratoconjunctivitis.





C. Inflammatory cells (eosinophils and neutrophils) in brush cytology specimens from the tarsus correlate with corneal damage in atopic keratoconjunctivitis. In atopic blepharoconjunctivitis, the tear content of group IIA phospholipase A2 is decreased without any dependence on the quantity of different conjunctival cells. 1. Other characteristic ocular surface pathologic changes in atopic keratoconjunctivitis include inflammation, decreased corneal sensitivity, tear film instability, and changes in conjunctival epithelial mucins 1, 2 and 4 mRNA expression. D. Hayfever conjunctivitis E. Contact blepharoconjunctivitis F. Phlyctenular keratoconjunctivitis

IV. Immunologic A. Graft-versus-host disease (GVHD) conjunctivitis 1. GVHD has been reported in 10%–90% of patients undergoing hematopoietic stem cell transplantation and the eye is affected in 40%–60% of these patients. 2. There are two forms, acute and chronic. a. Typical ocular complications in acute GVHD are pseudomembranous conjunctivitis, and acute hemorrhagic conjunctivitis, which occur in 12%–17% of patients. b. Ocular complications are more common in chronic GVHD. 3. There appears to be a subclinical cell-mediated immune reaction, involving activated T cells, cytokines such as tumor necrosis factor-α, and other immune cells. Other specific contributors include type 1 T-helper cells, interleukin-2, interferon-γ, and interleukin-1. These processes appear to be directed particularly at conjunctival and lacrimal gland tissues. 4. Dry eye disease is a hallmark sign of GVHD. It is reflected in abnormalities in tear osmolarity, corneal staining score, and Ocular Surface Disease Index. GVHD accounted for 9% of patients with an inflammatory disorder evaluated for dry eye in one tertiary care facility. a. Gene expression profiles are modified in patients with dry eye secondary to GVHD. 5. Subepithelial fibrosis of the conjunctiva also may be a significant sign of GVHD. Other changes include

Conjunctival Manifestations of Systemic Disease

inflammatory destruction of conjunctiva and lacrimal glands with decreased goblet cells and secondary decreased tear production. Meibomian glands also are involved. 6. A clinical picture resembling superior limbal keratoconjunctivitis accompanied by superior limbal stem cell dysfunction may be seen in GVHD. Tear cytokine and chemokine levels are informative biomarkers in ocular GVHD. Epidermal growth factor and interferon inducible protein-10/CXCL10 levels are significantly decreased in ocular chronic GVHD, positively correlate with tear production and stability, and negatively correlate with symptoms, hyperemia and vital staining. Conversely, interleukin (IL)-1 Ra, IL-8/CXCL8, and IL-10 are significantly increased in ocular chronic GVHD with the first two correlating positively with symptoms, hyperemia, and ocular surface integrity, but negatively correlating with tear production and stability. CD8-positive lymphocytes, as detected by impression cytology, are increased in GVHD, but are not necessarily predictive of ocular involvement, although frequently present.



B. Wegener’s granulomatosis (granulomatosis with polyangiitis, WG) 1. It should be considered when conjunctival inflammation is recurrent and not typical of other conjunctival inflammatory conditions. Based on assessment of the presence of major basic protein and eosinophil cationic protein, it has been suggested that activated eosinophils in the sclera or conjunctiva of patients with ocular limited WG may predict the progression to complete WG. 2. Uncommon presentations of WG include as cicatricial conjunctival inflammation with trichiasis, and as a painless conjunctival ulcer and central retinal artery occlusion. 3. Tarsal-conjunctival disease is characterized by inflammation of the palpebral conjunctiva and tarsus followed by fibrovascular proliferation and scar formation. It has been associated with subglottic stenosis. C. Inflammatory pseudotumor, characterized by the presence of aggregates of chronic inflammatory cells (lymphocytes, plasma cells, neutrophils, and fibroblasts) without noncaseating epithelioid granuloma formation, has been reported to occur simultaneously in the conjunctiva and lung. D. Rarely, conjunctival ulceration may be a manifestation of Behçet’s disease, and is characterized on histopathologic examination by disrupted epithelium, infiltration by both acute and chronic inflammatory cells, and high endothelial venules. Immunohistologic studies of the inflammatory infiltrate reveal primarily T-cell populations admixed with several B cells and CD68-positive histiocytes. V. Neoplastic processes (e.g., sebaceous gland carcinoma) can cause a chronic nongranulomatous blepharoconjunctivitis





247

with cancerous invasion of the epithelium and subepithelial tissues. A. Sebaceous carcinoma may involve the conjunctival epithelium in 47% of cases, of which the superior tarsal and forniceal conjunctiva are involved in 100%, inferior tarsal conjunctiva in 68%, inferior forniceal conjunctiva in 64%, superior bulbar conjunctiva in 68%, and inferior bulbar conjunctiva in 57%. The caruncle is involved in 54% and the cornea in 39%. Metastasis occur in 11%. B. Impression cytology may be useful in the detection of conjunctival intraepithelial invasion by sebaceous gland carcinoma; however, full-thickness biopsies are necessary to confirm the diagnosis.

INJURIES See Chapter 5.

CONJUNCTIVAL MANIFESTATIONS OF SYSTEMIC DISEASE Deposition of Metabolic Products I. Cystinosis (Lignac’s disease)—see Chapter 8. II. Ochronosis—see Chapter 8. III. Hypercalcemia—see Chapter 8. IV. Addison’s disease: melanin is deposited in the basal layer of the epithelium. V. Mucopolysaccharidoses—see Chapter 8. VI. Lipidosis—see Chapter 11. VII. Dysproteinemias VIII. Porphyria IX. Jaundice A. Bilirubin salts are deposited diffusely in the conjunctiva and episclera, but not usually in the sclera unless the jaundice is chronic and excessive; even in the latter case, the bulk of the bilirubin is in the conjunctiva (scleral icterus, therefore, is a misnomer). B. Rarely, the icterus can extend into the cornea. X. Malignant atrophic papulosis (Degos’ syndrome)—see Chapter 6. XI. Fabry disease. The characteristic anterior-segment finding is corneal verticillata, which is secondary to glycosphingolipid deposition in the cornea. In vivo confocal microscopy of the conjunctiva demonstrates abnormalities throughout the ocular surface, including bright roundish intracellular inclusions, which are more pronounced in tarsal than in bulbar conjunctiva. XII. Marfan syndrome with ectopia lentis. Consistent, qualitative abnormalities in conjunctival fibrillin-1 staining pattern can be seen in the conjunctiva. XIII. Chronic renal failure requiring hemodialysis. Squamous metaplasia of the conjunctival epithelium and corneoconjunctival calcification may be seen. Abnormal tear function is associated with squamous metaplasia, but not with corneoconjunctival calcification. Similarly, although impression cytology demonstrates

248

CHAPTER 7  Conjunctiva more frequent and extensive deposits of calcium in the conjunctiva of chronic renal failure patients on regular hemodialysis compared to control patients, the severity of conjunctival squamous metaplasia associated with chronic renal failure appears not to be related to calcium deposition, but rather, to acute conjunctival inflammation.

Deposition of Drug Derivatives I. Argyrosis (Fig. 7.11) A. Long-term use of silver-containing medications may result in a slate-gray discoloration of the mucous membranes, including the conjunctiva, and of the skin, including the lids. The discoloration may also involve the nasolacrimal apparatus. B. Histologically, silver is deposited in reticulin (i.e., loose collagenous) fibrils of subepithelial tissue and in basement membranes of epithelium, endothelium (e.g., Descemet’s membrane), and blood vessels. II. Chlorpromazine—see Chapter 8. III. Atabrine IV. Epinephrine— historically, epinephrine was used to treat glaucoma. With long-term treatment, conjunctival or corneal deposition has been reported. Epinephrine may deposit under

an epithelial bleb, where it becomes oxidized to a compound similar to melanin; in fact, occasionally, the black corneal deposit (black cornea) has been mistaken for malignant melanoma of the cornea. Histologically, an amorphous pink material that bleaches and reduces silver salts is found between corneal epithelium and Bowman’s membrane or in conjunctival cysts.

V. Mercury VI. Arsenicals VII. Minocycline hydrochloride, which is a semisynthetic derivative of tetracycline, may cause pigmentation of the sclera and conjunctiva, and other tissues, including skin, thyroid, nails, teeth, oral cavity, and bone.

Vitamin A Deficiency: Bitot’s Spot See Chapter 8.

Sjögren’s Syndrome See Chapter 8 and Chapter 14.

Skin Diseases I. Erythema multiforme (Stevens–Johnson syndrome)—see Chapter 6. II. Atopic dermatitis III. Rosacea—see Chapter 6.

A

B

C

D Fig. 7.11  Argyrosis. A, Patient had taken silver-containing drops for many years. Note the slate-gray appearance of conjunctiva. B, The cornea shows a diffuse granular appearance. C, The granular corneal appearance is caused by silver deposition in Descemet’s membrane. D, Histologic section of another case shows silver deposited in the epithelium and in the mucosal basement membrane of the lacrimal sac. (D, Adapted from Yanoff M, Scheie HG: Argyrosis of the conjunctiva and lacrimal sac. Arch Ophthalmol 72:57, 1964. © American Medical Association. All rights reserved.)

Degenerations

IV. Xeroderma pigmentosum—see Chapter 6. V. Ichthyosis congenita—see Chapter 6. VI. Molluscum contagiosum—see Chapter 6. VII. Dermatitis herpetiformis, epidermolysis bullosa, ery thema nodosum, and many others may show conjunctival manifestations.

249

deficiency, proptosis with exposure, familial dysautonomia, chemical burns, and erythema multiforme (Stevens–Johnson syndrome). II. Histologically, the epithelium undergoes epidermidalization with keratin formation, and the underlying subepithelial tissue frequently shows cicatrization.

Pterygium

DEGENERATIONS

See Chapter 8.

Xerosis

Pinguecula

I. Xerosis (dry eyes; Fig. 7.12) owing to conjunctival disease may result from keratoconjunctivitis sicca (Sjögren’s syndrome), ocular pemphigoid, trachoma, measles, vitamin A

I. Pinguecula (Fig. 7.13) is a localized, elevated, yellowish-white area near the limbus, usually found nasally and bilaterally, and seen predominantly in middle and late life.

A

B Fig. 7.12  Xerosis. A, After rubeola infection, the cornea and conjunctiva have become dry and appear skinlike. B, The corneal and limbal conjunctival epithelium show marked epidermidalization. The corneal stroma is thickened and scarred. (A, Courtesy of Dr. RE Shannon.)

A

B Fig. 7.13  Pinguecula. A, A pinguecula characteristically involves the limbal conjunctiva, most frequently nasally, and appears as a yellowish-white mound of tissue. B, Histologic section shows basophilic (actinic) degeneration of the conjunctival substantia propria. C, Another case shows even more marked basophilic degeneration that stains heavily black when the Verhoeff elastica stain is used.

C

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CHAPTER 7  Conjunctiva

Pigmented, triangular, brown pingueculae may appear during the second decade of Gaucher’s disease. Lesions sampled for biopsy contain Gaucher cells. Patients with Gaucher’s disease may also show congenital oculomotor apraxia (50%) and white retinal infiltrates (38%). Corneal opacities in the posterior two-thirds of the stroma may also occur in Gaucher’s disease. The genetic defect in Gaucher’s disease resides on chromosome 1q21.

II. Histologically, it appears identical to a pterygium except for lack of vascularization and corneal involvement. A. The subepithelial tissue shows senile elastosis (basophilic degeneration) and irregular, dense subepithelial concretions. The elastotic material stains positively for elastin but is not sensitive to elastase (elastotic degeneration). B. The elastotic material is positive for elastin, microfibrillar protein, and amyloid P, components that never normally co-localize. The control of elastogenesis is seriously defective so that the elastic fibers are not immature, but are abnormal in their biochemical organization. A marked reduction of elastic microfibrils, rather than an overproduction, appears to prevent normal assembly of elastic fibers. p53 mutations in limbal epithelial cells, probably caused by ultraviolet irradiation, may be an early event in the development of pingueculae, pterygia, and some limbal tumors. The subepithelial dense concretions stain positively for lysozyme.

Lipid Deposits I. Biomicroscopic examination of peripheral bulbar conjunctiva and episcleral tissue, especially in the region of the palpebral fissure, often reveals lipid globules. A. The globules, which increase with age, vary from 30 to 80 nm in diameter, but tend to be fairly uniform in size in each patient. B. The deposits assume two basic patterns: most often, multiple globules lying adjacent to blood vessels; and sometimes globules occurring in isolated foci unrelated to blood vessels. C. Subconjunctival and episcleral lipid deposits are asymptomatic (except for rare granulomatous response to the lipids) and occur in approximately 30% of patients. II. Histologically, lipid material may be present free within extracellular spaces in the subepithelial conjunctival and episcleral loose connective tissue or, rarely, within a granulomatous inflammatory process.

of amyloid deposits are charged glycosaminoglycans and the acute phase protein serum amyloid P. B. Conjunctival amyloidosis should be considered in any patient with recurrent hyposphagma (conjunctival hemorrhage) of unknown cause. C. Amyloid deposition is found around and in walls of ocular blood vessels, especially retinal and uveal. Skin and conjunctiva may be involved, but this is not as important as involvement of other ocular structures. D. Conjunctival amyloid deposition is uncommon. In a study of 2455 conjunctival lesions, amyloid was diagnosed in only 5 cases (0.2%). Nevertheless, it is the most common location for periocular amyloid. In a recent review of ocular adnexal and orbital amyloidosis, 64% of cases involved primarily the eyelids and/or conjunctiva with most of these cases, 81%, localized to the conjunctiva. E. A high index of suspicion is required to make the diagnosis of conjunctival amyloidosis. Lesions may present as inflammation, papillomatous proliferations, tumor of unknown origin, lymphoma, or hemorrhage. Similarly, there is no single color in which lesions commonly present. Thus, the clinical presentations have been very variable. II. Classification (Table 7.3) A. Divided into organ-specific localized disease, such as that characteristic of the brain in Alzheimer disease, and systemic amyloidosis. 1. Localized amyloidosis (e.g. localized nodular amyloidosis; see also Chapter 8) a. Thought to be due to an isolated production of fragmented monoclonal light chains with predominately N-terminal fragments by a site-specific plasma cell clone. b. Small and large, brownish-red nodules may be found in the conjunctiva and lids. c. The intraocular structures are not involved. d. Based on autopsy analysis, the most frequently involved ocular tissues are: conjunctiva (89%), iris (44%), trabecular meshwork (11%), and vitreous body (11%). Lattice corneal dystrophy, one of the inherited corneal dystrophies, is considered by some to be a primary, localized form of amyloidosis of the cornea (see Chapter 8). Rarely, a localized amyloidosis of the cornea unrelated to lattice corneal dystrophy may occur idiopathically (e.g., in climatic droplet keratopathy). Conversely, lattice corneal dystrophy occurs rarely in primary systemic amyloidosis.

Amyloidosis See also Chapter 12. I. Introduction A. Amyloidosis comprises 30 protein-folding diseases characterized by the extracellular deposition of a specific soluble precursor protein that aggregates to form insoluble fibrils (Table 7.2). Also contributing to the formation



e. Secondary localized amyloidosis (Fig. 7.14) may result from such chronic local inflammations of the conjunctiva and lids as trachoma, and chronic nongranulomatous, idiopathic conjunctivitis, and blepharitis.

Degenerations

251

TABLE 7.2  Amyloid Fibril Proteins and Their Precursors in Humans Systemic or Localized

Acquired or Hereditary

Immunoglobulin light chain Immunoglobulin heavy chain β2-microglobulin, wild type β2-microglobulin, variant Transthyretin, wild type Transthyretin, variants (Apo) serum amyloid A Apolipoprotein A I, variants

S, L S, L S S S, L S S S

A A A H A H A H

Apolipoprotein A II, variants Apolipoprotein A IV, wild type Gelsolin, variants Lysozyme, variants Leukocyte chemotactic factor-2 Fibrinogen α, variants Cystatin C, variants ABriPP, variants ADanPP, variants Aβ protein precursor, wild type Aβ protein precursor, variant Prion protein, wild type Prion protein, variants (Pro)calcitonin Islet amyloid polypeptide† Atrial natriuretic factor Prolactin Insulin Lung surfactant protein Galectin 7 Corneodesmin Lactadherin Kerato-epithelin Lactoferrin Odontogenic ameloblast-associated protein Semenogelin 1

S S S S S S S S L L L L L L L L L L L L L L L L L L

H A H H A H H H H A H A H A A A A A A A A A A A A A

Fibril Protein

Precursor Protein

AL AH Aβ2M ATTR AA AApoAI AApoAII AApoAIV AGel ALys ALect2 AFib ACys ABri ADan* Aβ APrP ACal AIAPP AANF APro AIns ASPC AGal7 ACor AMed AKer ALac AOaap ASem1

Target Organs All organs except CNS All organs except CNS Musculoskeletal system ANS Heart mainly in men, tenosynovium PNS, ANS, heart, eye, leptomeninges All organs except CNS Heart, liver, kidney, PNS, testis, larynx (C-terminal variants), skin (C-terminal variants) Kidney Kidney medulla and systemic PNS, cornea Kidney Kidney, primarily Kidney, primarily PNS, skin CNS CNS CNS CNS CJD, fatal insomnia CJD, GSS syndrome, fatal insomnia C-cell thyroid tumors Islets of Langerhans, insulinomas Cardiac atria Pituitary prolactinomas, aging pituitary Iatrogenic, local injection Lung Skin Cornified epithelia, hair follicles Senile aortic, media Cornea, hereditary Cornea Odontogenic tumors Vesicula seminalis

ANS, autonomic nervous system; CJD, Creutzfeldt–Jakob disease; CNS, central nervous system; GSS, Gerstmann–Straussler–Scheinker syndrome; PNS, peripheral nervous system. *ADan is the product of the same gene as Abri. †Also called amylin. (Data from Sipe JD, Benson MD, Buxbaum JN, et al.: Amyloid fibril protein nomenclature: 2012 recommendations from the Nomenclature Committee of the International Society of Amyloidosis. Amyloid 19:167–70, 2010. From Hazenberg: Amyloidosis: a clinical overview. Rheum Dis Clin North Am. 39(2):323–345, 2013. Table 1. Elsevier.)







f. Rarely, periocular amyloid may present as a pseudopemphigoid process with severe and progressive symblepharon formation. g. May result from chronic inflammation in which an altered antigenic response stimulates amyloidogenic plasma cells. h. Unlike systemic amyloidosis, localized amyloid light chain amyloidosis often is associated with a significant number of foreign body giant cells. 2. The four most common forms of systemic amyloidosis are AL, AA, ATTR, and Aβ2M (Fig. 7.15; see Table 7.2)



a. AL: most common type. 1) Caused by plasma cell dyscrasia, such as multiple myeloma. 2) Associated with production of lambda or kappa immunoglobin free light chain. 3) Portions of immunoglobulin light chains, most often fragments of the variable region of the N-terminal end of the lambda light chain, are the major constituents of the amyloid filamentous substance (i.e., the deposited amyloid filaments found in tissues are portions of immunoglobulin light chains). Lambda light chains contain six variable-region subgroups.

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TABLE 7.3  Amyloidosis Nomenclature According to Amyloid Precursor Name of Amyloid Protein

Fibrillar Protein Precursor

Amyloid Distribution

Type

Amyloidosis Form, Syndrome

AL AA

Immunoglobulin light chain Serum amyloid A

Systemic or localized Systemic

Acquired Acquired

Ab-2 M ATTR ATTR

Beta-2 microglobulin Transthyretin Transthyretin

Systemic Systemic Systemic

Acquired Hereditary Acquired

Primary amyloidosis, B-cell dyscrasia, commonly multiple myeloma Secondary amyloidosis, outcome of chronic inflammation or infection (Reiter syndrome, ankylosing spondylitis, familial Mediterranean fever, Sjögren syndrome, rheumatoid arthritis, etc.) Chronic renal failure or hemodialysis Prototypical familial amyloid polyneuropathy (FAP) Senile heart, vessels

Some of the common amyloidosis subtypes according to the protein precursor prone to aggregation. Such amyloid precursors interact with glycosaminoglycans (GAGs) and serum amyloid P precipitating the amyloid complex. The protein component determines the name and characteristics of the disease and is specific for each subtype of amyloidosis. Primary and secondary amyloidoses account for most cases. Primary amyloidosis is abbreviated AL owing to the accumulation of fibril-forming monoclonal immunoglobulin (Ig) light chains (LC). Secondary amyloidosis is abbreviated AA owing to serum amyloid A, an acute phase protein that accumulates in the setting of chronic inflammatory states. (From Siakallis L et al.: Amyloidosis: review and imaging findings. Semin Ultrasound CT MRI 35(3):225–239, 2014. Table. Elsevier.)

A

B Fig. 7.14  Localized amyloidosis. A, The patient has a smooth “fish-flesh” redundant mass in the inferior conjunctiva of both eyes, present for many years. The underlying cause was unknown, and the patient had no systemic involvement. Clinically, this could be lymphoid hyperplasia, lymphoma, leukemia, or amyloidosis. The lesion was biopsied. B, Histologic section shows an amorphous pale hyaline deposit in the substantia propria of the conjunctiva that stains positively with Congo red stain. The scant inflammatory cellular infiltrate consists mainly of lymphocytes, and plasma and mast cells. (B, Congo red; reported in Glass R, Scheie HG, Yanoff M: Conjunctival amyloidosis arising from a plasmacytoma. Ann Ophthalmol 3:823, 1971. Reproduced with kind permission of Springer Science and Business Media.)







b. AA: second most common type. 1) Associated with chronic inflammation. 2) Precursor is HDL3-associated apolipoprotein serum A protein, which is an acute phase reactant. c. ATTR: third most common type. 1) Usually familial and caused by many autosomal dominantly inherited point mutations of the precursor protein transthyretin, which is the transport protein for thyroid hormone and retinol-binding protein. There also is a type associated with old age that does not involve mutated TTR, but rather, the normal (wild type). a) There are more than 100 TTR mutations. The most common mutation is TTR-Met30. b) Familial amyloidotic polyneuropathy (see Chapter 12). The most common ocular findings are dry eye, scalloped iris,

glaucoma, vitreous amyloid and amyloidotic retinal angiopathy.



d. Aβ2M 1) Caused by end-stage renal disease with chronically high serum levels of β2-microglobulin, which is not removed by dialysis. Much less common now due to the introduction of highperformance dialysis techniques and novel dialysis membranes. 2) Hereditary form also exists. e. Vitreous opacities are the most important ocular finding in systemic amyloidosis, but ecchymosis of lids, proptosis, ocular palsies, internal ophthalmoplegia, neuroparalytic keratitis, and glaucoma may result from amyloid deposition in tissues (see Chapter 12). 3. Amyloid light chain amyloidosis has been confirmed by mass spectrometry after presenting in the

Degenerations

A

B

C

D

253

Fig. 7.15  Secondary systemic amyloidosis. A, Patient had bruises involving eyelids for 10 months and spontaneous bleeding for four months. B, Hematoxylin and eosin-stained section of lid biopsy shows increased superficial dermal vascularization and ribbons of an amorphic pink material, best seen in the middle dermis on the right. The material is Congo red-positive (C) and metachromatic with crystal violet (D). Approximately one year later, multiple myeloma was diagnosed.

conjunctiva in the absence of an underlying systemic plasma cell disorder. III. Histology A. Amyloid appears as amorphous, eosinophilic, pale hyaline deposits free in the connective tissue, or around or in blood vessel walls. A nongranulomatous inflammatory reaction or, rarely, a foreign-body giant-cell reaction or no inflammatory reaction may be present. 1. The presence of glycosaminoglycans in amyloid (starch-like) deposits gives the disease its name because they stain blue with iodine in a manner consistent with starch. Amyloid may have a natural green positive birefringence both in unstained sections and in hematoxylin and eosin-stained sections. The green birefringence is enhanced by Congo red staining.



B. The material demonstrates metachromasia (polycationic dyes such as crystal violet change color from blue to purple), positive staining with Congo red, dichroism (change in color that varies with the plane of polarized light, usually from green to orange with rotation of polarizer), birefringence (double refraction with polarized light) of Congo red-stained material, and fluorescence with thioflavine-T.

Birefringence is the change in refractive indices with respect to light polarized in different directions through a substance. Dichroism is the property of a substance absorbing light polarized in a certain direction. When light is polarized at right angles to this direction, it is transmitted to a greater extent. In contrast to birefringence, dichroism can be specific for a particular substance. Dichroism can be observed in a microscope with the use of either a polarizer or an analyzer, but not both, because the dichroic substance itself (e.g., amyloid) serves as polarizer or analyzer, depending on the optical arrangement. Amyloid is only dichroic to green light.



C. Electron microscopically, amyloid is composed of ordered or disordered, or both, filaments that have a diameter of approximately 7.5 nm.

Conjunctivochalasis I. Conjunctivochalasis is usually found in older individuals and consists of an elevation of the bulbar conjunctiva along the lateral or central lower-lid margin. It may also involve the upper bulbar conjunctiva. A. It is a cause for tearing, pain, redness, blurred vision, and tired eye feeling. There is an altered tear meniscus. Symptoms worsen on downgaze.

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CHAPTER 7  Conjunctiva

A

B Fig. 7.16  Dermolipoma. A, The patient shows the typical clinical appearance of bilateral temporal dermolipomas. B, The histologic specimen shows that the dermolipoma is almost entirely composed of fatty tissue. Rarely, dermolipomas may also show structures such as epidermal appendages and fibrous tissue.



B. A possible mechanism for its development is as a result of mechanical forces between the lower eyelid and conjunctiva interfering with lymphatic flow which, when chronic, may result in lymphatic dilatation and, eventually, conjunctivochalasis. C. Inflammation plays an important role in severe conjunctivochalasis. D. There is an increased prevalence of conjunctivochalasis in patients with autoimmune thyroid disease compared to individuals without thyroid disease (88% and 52%, respectively). E. The severity of conjunctivochalasis involving the nasal and temporal conjunctiva is significantly correlated with the grade of pinguecula located in these areas. II. The most common histopathologic findings are elastosis or chronic nongranulomatous inflammation. Additionally, microscopic lymphangiectasia is typically present. Nevertheless, on light microscopic examination, some investigators have failed to find noticeable differences between involved conjunctiva and that of age-matched controls relative to elastosis, fibrosis, lymphangiectasia, or infiltration of inflammatory cells. They have postulated that the primary abnormality may not be within the conjunctiva, itself, but be related to loose attachment of the conjunctiva to the underlying tissue thereby resulting in the folds in the bulbar conjunctiva.

CYSTS, PSEUDONEOPLASMS, AND NEOPLASMS Choristomas I. Epidermoid cyst—see Chapter 14. II. Dermoid cyst—see Chapter 14.

III. Dermolipoma (Fig. 7.16) A. Dermolipoma usually presents as bilateral, large, yellowish-white soft tumors near the temporal canthus and extending backward and upward. B. Dermolipomas comprised 4.2% of 192 excised conjunctival lesions in one clinicopathologic review. C. It is a form of solid dermoid composed primarily of fatty tissue. Serial sections of the tumor must be made to find nonfatty elements such as stratified squamous epithelium and dermal appendages. Nevus lipomatosus (pedunculated nevus) has been reported on the eyelid of an 11-year-old boy having an eyelid papule that had been present since birth and was gradually enlarging. Histologically, the lesion was polypoid in shape and consisted of mature adipocytes within the dermis and subconjunctival mucosa consistent with nevus lipomatosus.

IV. Epibulbar (episcleral) osseous choristoma (bone-containing choristoma of the conjunctiva) is usually located in the supratemporal quadrant and may contain other choristomatous tissue as frequently as 10% of the time. The lesion may be attached to the underlying muscle or sclera. A. Unusual presentations include as a pedunculated mass in a newborn infant, and as a lesion involving the lateral rectus muscle.

Hamartomas I. Lymphangioma—see Chapter 14. II. Hemangioma—see Chapter 14. III. Phakomatoses—see Chapter 2.

Cysts Most limbal dermoids are solid and contain epidermal, dermal, and fatty tissue. Rarely, they may be cystic and may contain bone, cartilage, lacrimal gland, teeth, smooth muscle, brain, or respiratory epithelium.

I. Cysts of the conjunctiva (Fig. 7.17) may be congenital or acquired, with the latter predominating. II. Acquired conjunctival cysts are mainly implantation cysts of surface epithelium, resulting in an epithelial inclusion

Cysts, Pseudoneoplasms, and Neoplasms

A

255

B Fig. 7.17  Conjunctival cyst. A, A clear cyst is present just nasal to the limbus. B, Histologic section of another clear conjunctival cyst shows that it is lined by a double layer of epithelium, suggesting a ductal origin.

cyst. Other cysts may be ductal (e.g., from accessory lacrimal glands) or inflammatory. III. Histologically, the structure depends on the type of cyst. A. Epidermoid and dermoid cyst—see Chapter 14. B. Epithelial inclusion cysts, lined by conjunctival epithelium, contain a clear fluid. C. Intratarsal keratinous cyst of the meibomian gland (intratarsal epidermal inclusion cyst, tarsal keratinous cyst, intratarsal inclusion cyst) (Fig. 7.18). 1. Although not frequently discussed, it is the third most common primary intratarsal lesion after chalazia and sebaceous cell tumors. 2. Tends to occur primarily in an older population (middle age and older). 3. There may be a history of preceding surgical trauma to the eyelid. 4. Varying color including white, pale yellow, or bluish. 5. Thick wall or capsule fused to the tarsus, but the overlying skin is free. 6. If opened, contains a milky to viscid fluid that does not resemble the typical cheesy contents of a chalazion. 7. Most often confused with a chalazion, but recurs if tarsal excision is not performed. 8. Rarely, may be multiple in the same eyelid. 9. Transconjunctival leakage of cyst material from this lesion has been reported. 10. Histopathology a. Cyst filled with compact keratin. b. Cyst lined by multilaminar squamous epithelium lacking keratohyalin granules. c. Minimal to no inflammatory infiltrate. d. Innermost cells have undulations and the innermost layer lining the cyst has an eosinophilic color. e. May be adjacent atrophic meibomian glands, which are not usually present in the cyst wall, nor are goblet cells. f. Negative on Alcian blue and periodic acid–Schiff staining.









g. Immunohistochemistry: positive for CK17, CEA, and EMA, which is similar to ducts including meibomian ducts. By contrast, epidermal cysts are negative for CK17, CEA, and EMA. The positive CEA staining may be the lesion’s most specific marker. May be CK14 positive, which can be seen in some sebaceous carcinomas. May be some variability in staining for CK5/6, CK7, and AE1/ AE3 suggesting that keratin expression in these lesions may vary. 11. Must be distinguished from steatocystoma simplex or multiplex, which usually is present in much younger individuals and those cysts contain yellow sebum and scattered hair shafts in comparison to the fluid keratin present in intratarsal keratinous cysts of the meibomian gland. Sebaceocytes in the cyst wall would suggest a diagnosis of steatocystoma. a. Rarely, steatocystoma simplex may involve the caruncle. The cyst is lined by squamous epithelium and the wall contains sebaceous glands and invaginations resembling hair follicles. 12. Sebaceous gland carcinoma has been diagnosed as intratarsal keratinous cysts of the meibomian gland. D. Ductal cysts (e.g., Wolfring dacryops) are lined by a double layer of epithelium and contain a PAS-positive material. E. Inflammatory cysts contain polymorphonuclear leukocytes and cellular debris.

Pseudocancerous Lesions I. Hereditary benign intraepithelial dyskeratosis (HBID; Fig. 7.19; also see Fig. 6.4A) A. HBID is a bilateral dyskeratosis of the conjunctival epithelium associated with comparable lesions of the oral mucosa, which are similar to those of white sponge nevus and inherited as an autosomal-dominant trait. 1. It is one of the genodermatoses, which are inherited cutaneous disorders characterized by multisystem involvement.

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A

B

C

D

E

F Fig. 7.18  For legend, see opposite page.

Cysts, Pseudoneoplasms, and Neoplasms Fig. 7.18  Photomicrographs showing meibomian gland keratinous cysts. A, Full-thickness eyelid resection containing two adjacent intratarsal keratinous cysts. On the bottom left, note the uninflamed scarred tarsus devoid of meibomian ducts and acini. The surviving meibomian acini near the eyelid margin and next to the smaller cyst fail to exhibit squamous metaplasia (hematoxylin and eosin, ×40 magnification). B, The larger cyst displays trichilemmal keratinization without keratohyalin granular or cuticular layers. Hematoxylinophilic granular material is prominent within the intracavitary compactions of anuclear keratin. The outer inset demonstrates collections of bacteria; the inner inset reveals the presence of calcium. Prussian blue staining failed to reveal iron. A meibomian secretory acinus with an inconspicuous outer basal germinal cell layer is present on the bottom right and shows preservation of centrally located, well-differentiated sebocytes without any evidence of squamous metaplasia (hematoxylin and eosin, ×100 magnification). C, Two levels through a single cyst. The component on the upper left includes a segment of the tarsus with embedded meibomian glands displaying central lipidization (hematoxylin and eosin, ×30 magnification). D, The wall of the cyst is composed of poorly vascularized, tightly woven bundles of tarsal collagen without inflammation. The epithelial lining is undulating and the keratin in the cyst is string-like and loose. The inset highlights a delaminating inner cuticular layer surmounting the crenulated squamous epithelium that lacks a keratohyalin granular layer. Intracavitary string-like keratin has accumulated (hematoxylin and eosin, ×100 magnification; inset, ×400 magnification). E, Collapsed serpiginous cyst with a prominent epithelial lining and a thick, uninflamed fibrous wall (hematoxylin and eosin, ×40 magnification). F, The epithelial lining is composed of 4 to 5 layers of corrugated squamous epithelium. Note the string-like, deeply eosinophilic keratin strands in the lumen. The fibrous wall is constituted by tarsal collagen. The inset discloses the thick keratin strands that have shed from the cuticle of the epithelial lining (hematoxylin and eosin, ×100 magnification; inset, ×400 magnification). (From Jakobiec et al.: Intratarsal keratinous cysts of the meibomian gland: distinctive clinicopathologic and immunohistochemical features in 6 cases. Am J Ophthalmol 149:82–94, 2010. Figure 2. Elsevier.)

A

B

C

D Fig. 7.19  Hereditary benign intraepithelial dyskeratosis (HBID). The patient has limbal, nasal, vascularized pearly lesions in her right (A) and left (B) eyes. The patient also has bilateral temporal lesions, but they are difficult to see because of light reflection. The patient’s mother had similar bilimbal, bilateral lesions. C, Histologic section shows an acanthotic epithelium that contains dyskeratotic cells, shown with increased magnification in D. HBID is indigenous to family members of a large triracial (Native American, black, and white) isolate from Halifax County, North Carolina. (Modified from Yanoff M: Hereditary benign intraepithelial dyskeratosis. Arch Ophthalmol 79:291, 1968, with permission. © American Medical Association. All rights reserved.)

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The disease is indigenous to family members of a large triracial (Native American, black, and white) isolate in Halifax County, North Carolina. Members of the family now live in other parts of the United States, so the lesion may be encountered outside North Carolina. Other pedigrees without Native American ancestry have been described. It also has been reported in an individual lacking the classic mixed racial heritage who had a de novo 4q35 duplication that overlapped the duplication previously reported in association with HBID. The phenotype has been described in a Caucasian French family involving 17p13.2 in the gene NLRP1.





B. Clinically, irregularly raised, horseshoe-shaped, granularappearing, richly vascularized, gray plaques are present at the nasal and temporal limbus in each eye. A whitish placoid lesion of the mucous membrane of the mouth (tongue or buccal mucosa) is also present. C. There is duplication in chromosome 4 (4q35), which results in triple alleles for 2 linked markers suggesting that gene duplication is responsible for the disorder developing during childhood. Corneal abnormalities may be found, especially stromal vascularization and dyskeratotic plaques of the corneal epithelium. The corneal plaques, like the conjunctival limbal plaques, invariably recur if excised.



D. Histologically, considerable acanthosis of the epithelium is present along with a chronic nongranulomatous

A

inflammatory reaction and increased vascularization of the subepithelial tissue. A characteristic dyskeratosis, especially prominent in the superficial layers, is seen. 1. Papanicolaou stained cytologic preparations can be helpful in the diagnosis by demonstrating rounded squamous epithelial cells with dense homogeneous orange cytoplasm and hyperchromatic pyknotic or crenated nuclei. II. Pseudoepitheliomatous hyperplasia (PEH; see Chapter 6) A. PEH may mimic a neoplasm clinically and microscopically. B. Epithelial hyperplasia and a chronic nongranulomatous inflammatory reaction of the subepithelial tissue, along with neutrophilic infiltration of the hyperplastic epithelium, are characteristic of PEH. PEH may occur within a pinguecula or pterygium and cause sudden growth that simulates a neoplasm. C. Keratoacanthoma (see Chapter 6) may be a specific variant of PEH, perhaps caused by a virus, or more likely a low-grade type of squamous cell carcinoma. 1. Conjunctival keratoacanthoma with ocular invasion has been reported. No-touch technique may be indicated during the surgical excision of these lesions. 2. A familial disorder characterized by self-healing palmoplantar carcinoma, a predisposition to skin cancer, and conjunctival keratoacanthomas has been reported. The latter are found in 80% of affected individuals. III. Papilloma (squamous papilloma; Fig. 7.20) A. Conjunctival papillomas tend to be pedunculated when they arise at the lid margin or caruncle, but sessile with

B

Fig. 7.20  Papilloma. A, A large sessile papilloma of the limbal conjunctiva is present. B, Histologic section shows a papillary lesion composed of acanthotic epithelium with many blood vessels going into the individual fronds, seen as red dots in the clinical picture in A. The base of the lesion is quite broad. C, Increased magnification shows the blood vessels and the acanthotic epithelium. Although the epithelium is thickened, the polarity from basal cell to surface cell is normal and shows an appropriate maturation. (A, Courtesy of Dr. DM Kozart.)

C

Cysts, Pseudoneoplasms, and Neoplasms

259

7.21, Box 7.1). The lesion displays squamous cells pushing into the conjunctival substantia propria around fibrovascular cores, but without significant cytologic atypia. Immunohistochemical evaluation of one conjunctival inverted squamous papilloma was diffusely positive for CK7 and positive for CK14 in the basilar and suprabasilar cells, as in normal conjunctiva. The proliferation index with Ki67 was low as was the p53 nuclear staining. The lesion was negative for HPV.

a broad base at the limbus. They comprise 14.5% of excised conjunctival lesions. 1. Papillomas are rare in locations other than the lid margin, interpalpebral conjunctiva, or caruncle. 2. Approximately one-fourth of all the lesions of the caruncle are papillomas. Although inverted papillomas (Schneiderian or mucoepidermoid papillomas if there is a prominent subpopulation of goblet cells) typically involve mucous membranes of the nose, paranasal sinuses, and lacrimal sac, where they are aggressive and may undergo malignant transformation. They only occasionally involve the conjunctiva where they typically have a benign course (Fig.

3. There are over 180 types of human papillomavirus (HPV) and they are divided into five genera with the α-PV genus, which contains HPV-6 and HPV-11, being the most important in relation to conjunctival

A

B

C

D Fig. 7.21  Conjunctival inverted squamous papilloma. A, An inferonasal epibulbar lesion in a 63-year-old man has a sessile and papillary character. The tumor approximates the corneoscleral limbus. B, The lesion displays an inverted (endophytic) growth pattern wherein it has pushed down into the substantia propria with a rounded, noninfiltrative pushing margin (arrow). The deep margin is represented by a straight line, an artifactual nonsurgical edge, resulting from malorientation of the tissue in the paraffin block. C, The tumor cells blend with a nondysplastic surface epithelium (crossed arrow). The arrows indicate widely spaced small papillary vascular cores. D, The eosinophilic squamous cells have small, regular nuclei without significant pleomorphism. The arrows point to small papillary cores. (B, C, D, hematoxylin and eosin, ×12.5, ×40, ×200). (From Stagner et al.: Conjunctival inverted squamous papilloma: A case report with immunohistochemical analysis and review of the literature. Surv Ophthalmol 60:263–268, 2015. Figure 1. Elsevier.)

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CHAPTER 7  Conjunctiva HPV-18 characterize precancerous and squamous cell lesions of the conjunctiva. Co-infections are frequently observed. Higher signal intensity is observed in dysplasia grades 1 and 2, and in better-differentiated areas of the invasive component of conjunctival carcinoma compared to less-differentiated areas. Focal epithelial hyperplasia is rare and caused by HPV-13 or -32. Although thought to infect the oral mucosa exclusively, HPV-13 has been reported to cause multiple conjunctival papillomas in an otherwise healthy patient. p53 mutations in limbal epithelial cells, probably caused by ultraviolet irradiation, may be an early event in the development of some limbal tumors, including those associated with HPV.

BOX 7.1  Features Distinguishing

Conjunctival Inverted Squamous Papillomas From Squamous Carcinomas • Blending of subsurface proliferation with surface epithelium, which lacks cytologic signs of dysplasia or carcinoma in situ • No sharp demarcation between proliferating epithelium and normal surface epithelium • Absence of obvious nuclear pleomorphism, hyperchromasia and conspicuous mitotic figures • Well-defined and circumscribed margins in substantia propria rather than infiltrating borders • Absence of prominent perilesional inflammatory infiltrate • Often multiple cysts with goblet cells • Eosinophilic globoid cytoplasmic inclusions representing inspissated mucus • Spectrum of human papillomaviruses more often negative than positive • CK7 positive squamous cells, as in normal conjunctiva • CK17 negative squamous cells, unlike CK17 positivity that is usually present in conjunctival squamous dysplasias and carcinomas • Low p53 nuclear positivity (10%–20%), contrasting with >50% in dysplasias/ carcinomas • Low Ki67 proliferation index (25% for dysplasias and carcinomas (From Stagner et al.: Conjunctival inverted squamous papilloma: A case report with immunohistochemical analysis and review of the literature. Surv Ophthalmol 60:263–268, 2015. Table 2. Elsevier.)





squamous papillomas. Human papillomavirus (HPV) types 6, 11, 16, 18, and 33 have been identified in 44%–92% of conjunctival papillomas when tested by polymerase chain reaction. The most common types in conjunctival papillomas are HPV-6 and HPV-11, which are in the low-risk group for malignant transformation. Types 6 and 11 are more common in children, and types 16 and 18 in adults. 4. Clinical and histological features of papillomas associated with HPV infection are extra-limbal location, nonkeratinizing squamous epithelium, presence of goblet cells, and absence of elastosis, while lesions not related to HIV infection are associated with epithelial keratinization and elastosis. a. HPV-16 is associated with malignant dysplasia of the cervix and oropharynx, and has been reported in association with conjunctival squamous cell carcinoma arising in an anophthalmic socket and extending into the eyelids and the lacrimal gland fossa with metastasis to a parotid lymph node requiring orbital exenteration, parotidectomy, neck dissection, and postoperative radiation to the involved orbit. b. Conversely, some authors have concluded that HPV infection is not a cause, but a cofactor in disease development. 5. See also section on Cancerous Epithelial Lesions, below. In subtropical Tanzania, where dysplastic lesions and neoplasms of the conjunctiva account for 2% of all malignant lesions, HPV-6/11, HPV-16, and



B. Histologically, the fronds or finger-like projections are covered by acanthotic epithelium, tending toward slight or moderate keratinization. The fronds have a core of fibrovascular tissue. Koilocytes, which are vacuolated cells with clear cytoplasm or perinuclear halos and nuclear pyknosis may occasionally be seen as may varying degrees of dysplasia. Goblet cells are common in the papillomas, except those arising at the limbus. Ocular rhinosporidiosis has mimicked conjunctival papilloma.

IV. Oncocytoma (eosinophilic cystadenoma, oxyphilic cell adenoma, apocrine cystadenoma; Fig. 7.22) A. Oncocytoma is a rare tumor of the caruncle. They represent less than 1% of all ocular adnexal lesions coming to biopsy or excision. Only 15 oncocytic neoplasms were found among the patients seen at the Ocular Oncology Service of the Wills Eye Hospital over a 25-year period. Rarely, they may occur in the bulbar conjunctiva or plica. 1. Most commonly, the tumor presents as a small, yellowish-tan or reddish mass arising not from surface epithelium but from accessory lacrimal glands in the caruncle, especially in elderly women. It can also arise from the conjunctival accessory lacrimal glands, lacrimal sac, or eyelid. 2. High-frequency ultrasound of the lesion reveals low internal reflectivity and a cystic component. Multiple hypoechogenic tumor stroma components correlate with multiple cystic glandular structures on histopathologic examination. 3. Rarely, the tumor may undergo carcinomatous transformation, but this is extremely rare for lesions involving the caruncle. B. Histologically, one or more cystic cavities are lined by proliferating epithelium, resembling apocrine epithelium (hence, apocrine cystadenoma). 1. Based on histopathologic architecture, the tumors are classified into various subtypes that differ between

Cysts, Pseudoneoplasms, and Neoplasms

261

e cs

t

A

B

Fig. 7.22  Oncocytoma (eosinophilic cystadenoma, oxyphilic cell adenoma). A, A fleshy, vascularized lesion is present at the caruncle. B, Histologic section shows proliferating epithelium around a cystic cavity (e, surface epithelium; cs, cystic spaces; t, tumor). C, Increased magnification shows large eosinophilic cells that resemble apocrine cells and are forming glandlike spaces (l, lumina surrounded by epithelial cells). (A, Courtesy of Dr. HG Scheie.)

l

l

l C



l

authors. In general, tumors with a solid pattern behave in a more aggressive manner in noncaruncular areas, in contrast to cystic micropapillary lesions, which consistently have a benign behavior. 2. Characteristic cell is the oncocyte (also termed Hürthle, Askanazy, or oxyphil cell) a. Epithelial cell swollen by abundant eosinophilic cytoplasm. b. Contains a large amount of “burned out” mitochondria. c. Oncocytic degenerative process, itself, can be seen in other cell types, including melanocytes. d. Oncocytes are characterized by the abundance of oxidative enzymes and adenosine triphosphate (ATP). 3. Electron microscopy reveals that the distinction between the light and dark cells seen on light microscopy in these lesions is based on the concentration of mitochondria within the cells. The mitochondria are abnormal by TEM examination, showing great variation in size and shape and containing densely packed longitudinal oriented cristae. 4. The immunohistochemical characteristics of oncocytic lesions: MU213-UC produces a distinct and intense immunostaining of all oncocytic lesions. Basal-type oncocytic cells react with CK5/6, CK7, CK8, CK13,







CK14, CK17, CK18, and CK19. Suprabasal cells are positive for CK4, CK7, CK8, CK18, and CK19. No reaction to CK1+10 and CK 20. a. Immunoreactivity similar to the lacrimal and accessory lacrimal gland duct elements thereby supporting the theory that these lesions originate in the lacrimal and accessory lacrimal glands. b. p63 and CK5/6 positive cells in an abluminal location probably represent basal-type epithelial cells in various stages of maturation toward oncocytic secretory cells. 5. Ectopic lacrimal or accessory gland or the glands of Moll are cited as possible sites of origin for periocular oncocytomas. 6. Very rarely, oncocytomas may involve the forniceal conjunctiva, or the peripunctal region. In the latter case they have been suggested to arise from the epithelium of the lacrimal canaliculus. 7. Oncocytomas of the caruncle tend to have a very benign course following excision. a. Lesions located in other areas such as the lacrimal sac or gland, eyelid, or the noncaruncular conjunctiva may display one or more of the following worrisome features: (1) infiltrative growth pattern, (2) more than a rare mitotic figure, (3) nuclear atypia, (4) architectural disorganization.

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b. The lacrimal sac or the lacrimal gland is the location for 89% of periocular oncocytic adenocarcinomas. Such lesions may be aggressive. V. Myxoma A. Myxomas are rare benign tumors that resemble primitive mesenchyme, and are often mistaken for cysts. The incidence is 0.001% to 0.002% among excised conjunctival lesions. 1. They have a well-circumscribed, smooth, fleshy, yellow-to-pink, translucent-to-solid, gelatinous appearance and are slow-growing. Ninety percent of ocular lesions involve the bulbar conjunctiva, and most are temporal. 2. Carney complex is an autosomal-dominantly inherited lentiginosis syndrome. It is characterized by: (1) spotty mucocutaneous pigmentation including lentigines (see Chapter 17), freckling, café-au-lait spots, and blue nevi; (2) bilateral adrenal hyperplasia leading to Cushing syndrome; (3) growth hormone-secreting pituitary adenoma or pituitary somatotropic hyperplasia leading to acromegaly; and (4) thyroid and gonadal tumors including predisposition to thyroid cancer. Other tumors associated with Carney complex include: (1) myxomas of the heart, breast, and other locations; (2) psammomatous melanotic schwannomas, which can become malignant; and (3) a predisposition to a variety of cancers. a. The most common ophthalmic manifestations of Carney complex are facial and palpebral lentigines, pigmented lesions of the caruncle or conjunctival semilunar fold, and eyelid myxomas. b. Carney complex is caused by inactivating mutations or large deletions of the PRKAR1A gene located at 17q22–24 coding for the regulatory subunit type I alpha of the cyclic AMP-dependent protein kinase A gene. B. Histologically, myxomas are hypocellular and composed of stellate and spindle-shaped cells, some of which have small intracytoplasmic and intranuclear vacuoles. 1. The stroma contains abundant hyaluronic acid, mucopolysaccharide material, sparse reticulin, and delicate collagen fibers. 2. The spindle and stellate cells are vimentin and α-smooth muscle actin positive. 3. Tumor cells are desmin, myoglobin, and S100 protein negative. VI. Dacryoadenoma A. Dacryoadenoma is a rare benign conjunctival tumor arising from metaplasia of the surface epithelium. B. Histologically, an area of metaplastic surface epithelium with cuboidal to columnar cells invaginates into the underlying connective tissue, forming tubular and glandlike structures. Electron microscopy shows cells containing zymogen-type lacrimal secretory granules. VII. Neurothekeoma A. Rare tumor that is even more rarely reported to involve the conjunctiva.

TABLE 7.4  A Comparison of Nerve Sheath

Myxoma and Neurothekeoma (Cellular Neurothekeoma) Feature Common sites

Gender Age Morphology Capsule Septa Syncytial epithelioid cells Immunophenotype S100 GFAP Epithelial membrane antigen Neuron-specific enolase Recurrence

Nerve Sheath Myxoma

Neurothekeoma

Hands Knees Ankles M=F 4th decade

Face Upper extremities Shoulder girdle F>M 2nd decade

Present Present Present

Absent Absent or ill-defined Absent

+ + +

− − −

+ >40%

− C (p. L132P) in exon 1 of the KRT12 gene. 2. Myriad, tiny, punctate vacuoles are present in the corneal epithelium that only rarely cause vision problems, and then not until later in life. a. Confocal microscopy can be informative relative to the nature of and the development of these characteristic findings.



The tiny intraepithelial cysts (vacuoles) appear relatively transparent on retroillumination by slit-lamp examination. Only the cysts that reach the surface and rupture take up fluorescein and stain.

3. The involved corneas are prone to recurrent irritations. 4. Histologically, a characteristic “peculiar substance” is seen in corneal epithelial cells and a vacuolated, dense, homogeneous substance is most commonly found in corneal intraepithelial cysts and less commonly in corneal epithelial cells. The primary disturbance probably involves the cytoplasmic ground substance of the corneal epithelium and, ultimately, results in complete homogenization of cells and formation of intraepithelial cysts. Thickening of the corneal epithelial basement membrane varies, and is a nonspecific response by the epithelial basal cells.

B Fig. 8.39  Meesmann’s dystrophy. A and B show tiny, fine, punctate, clear vacuoles in the corneal epithelium. C, Histologic section shows an intraepithelial cyst that contains debris (called peculiar substance in electron microscopy). The epithelial basement membrane is thickened here. (C, Periodic acid–Schiff stain; case reported in Fine BS, Yanoff M, Pitts E et al.: Meesmann’s epithelial dystrophy of the cornea: Report of two families with discussion of the pathogenesis of the characteristic lesion. Am J Ophthalmol 83:633. © Elsevier 1977.)

C

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A B Fig. 8.40  Meesmann’s dystrophy. A, In this thin, plasticembedded section, numerous tiny cysts of uniform size and one surface pit are present in the epithelium. One cyst to the right of center resembles a cell. B, Characteristic intracytoplasmic degeneration—”peculiar substance”— involves cytoplasmic filaments (i.e., “cytoskeleton”). C, Cyst contains vacuolated, homogeneous, dense material (i.e., filament-free). (Modified from Fine BS, Yanoff M, Pitts E et al.: Meesmann’s epithelial dystrophy of the cornea: Report of two families with discussion of the pathogenesis of the characteristic lesion. Am J Ophthalmol 83:633. © Elsevier 1977.)

C







E. Lisch epithelial corneal dystrophy (LECD) C2 (bandshaped and whorled microcystic dystrophy of the corneal epithelium) (Fig. 8.41). 1. Characterized clinically by gray, band-shaped and whorled microcystic changes in the corneal epithelium having a “feathery” margin. Intraepithelial, densely crowded, clear microcysts on retroillumination. a. Confocal microscopy: highly hyperreflective epithelial cytoplasm with hyporeflective nuclei. Fullthickness epithelial involvement. 2. LECD is distinct from epithelial basement membrane dystrophy and Meesmann dystrophy and maps to Xp22.3. It may be confused with epithelial dysplasia. 3. Histopathology: mostly empty microscopic vacuoles in epithelial cytoplasm containing scant nonspecific osmophilic material. The cytoplasmic vacuoles also contain glycogen and stain positive with PAS stain. 4. High-resolution corneal OCT demonstrates hyperreflectivity of the involved cornea without stromal involvement. A sharp demarcation is seen with the uninvolved cornea. F. Gelatinous drop-like corneal dystrophy (GDLD): subepithelial amyloidosis, primary familial amyloidosis (Grayson), C1G.





1. Caused by loss-of-function mutation of the tumorassociated calcium transducer 2 (TACSTD2) gene located on the short arm of chromosome 1 and inherited as an autosomal recessive disease. a. More than 90% of the GDLD patients have a Q118X mutation of TACSTD2. b. These mutations result in destabilized tight junction proteins including claudins, ZO-1, and occludin, which may explain loss of corneal epithelial barrier function in these patients. 2. It usually presents between 8 and 18 years with Salzmann-like corneal lesions. a. Vascularization may develop. b. There are four clinical phenotypes: band keratopathy, stromal opacities, kumquat-like, and the typical mulberry appearance. 3. Symptoms include photophobia, lacrimation, foreign body sensation, blepharospasm, and progressively deteriorating vision. 4. It is said to share no clinical characteristics with Reis–Bücklers’ dystrophy. 5. Light microscopy: Destructive changes in the epithelial basement membrane and Bowman’s layer are seen along with Alcian-blue positivity.

Dystrophies and Simulating Disorders

A

B

C

D

315

Fig. 8.41  Lisch corneal dystrophy (band-shaped and whorled corneal epithelial dystrophy). A, Gray superficial lesion with sharply defined finger-like borders. B, Corneal epithelium shows bubbly intracytoplasmic vacuoles (H&E, ×204). C, Electron micrograph shows nearly empty intracytoplasmic vacuoles (original magnification ×4640). D, Electron micrograph displays vacuoles, which contain scant, weakly osmophilic material (arrowheads) (original magnification ×11 520). (Courtesy of Norman C. Charles, MD; from Charles NC, Young JA, Kumar A et al.: Band-shaped and whorled microcystic dystrophy of the corneal epithelium. Ophthalmology 107:1761, 2000.)









a. Damage to these structures may be by anterior displacement from accumulating deeper deposits. b. Patchy Congo red-positive amyloid within the epithelium and Bowman’s layer, and in the anterior stroma with KE2 positivity. c. Bowman’s membrane may be absent in the area of the deposit. d. Masson trichrome is negative in the deposits. e. Deposits have staining characteristics of Congo red positivity and apple green birefringence typical for amyloid. f. Immunohistochemistry is positive for lactoferrin, although the specific mutation involved in the disorder is not directly associated with the lactoferrin gene. 6. Electron microscopy: Amyloid deposits are mainly located in the anterior stroma and in Bowman’s layer, and in the basal area of some epithelial cells. 7. All affected but no unaffected family members have heterozygous missense mutation in exon 14 of the TGFB1 gene (G→A transition at nucleotide 1915)

replacing glycine by aspartic acid amino acid (Gly623Asp) at position 623 of the KE protein. 8. Deposits are well localized by optical coherence tomography. (See subsection on Lattice Corneal Dystrophy, below) II. Epithelial–stromal TGFB1 corneal dystrophies Transforming growth factor beta-induced gene (TGFBI, BIGH3, βigh3) encodes transforming growth factor betainduced protein (TGFBIp), which mediates cell adhesion, migration, proliferation, and differentiation. Mutations related to TGFBI are the most common heritable forms of corneal dystrophy worldwide. Depending upon the nature of the mutant TGFBI protein, the phenotype will present as either lattice or granular in appearance. Moreover, mutation-specific differences in the processing of mutant TGFBIp species may contribute to the variable phenotypes present in TGFBI-related dystrophies. The expression of extracellular matrix proteins gives some indication of commonalities particularly between lattice and granular corneal dystrophies. For example, fibrillin-2 and tenascin-C are expressed in granular type I corneal dystrophy and in lattice

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type I dystrophy, while fibrillin-2, tenascin-C, matrillin-2 and matrillin-4 may be seen in the development of either granular or lattice type I corneal dystrophies. In general, there is a strong correlation between genotype and phenotype for the majority of TGFBI mutations except for the p.G623D mutation, which causes a greater proportion of TGFBI-related disease than expected, and is associated with variable phenotypes including EBMD.





A. Reis–Bücklers corneal dystrophy (RBCD): corneal dystrophy of Bowman’s layer, type I (CDB I), geographic corneal dystrophy (Weidle), superficial granular corneal dystrophy, atypical granular dystrophy, granular corneal dystrophy (GCD), type 3, anterior limiting membrane dystrophy, type I (ALMD I) C1; Fig. 8.42). It is autosomal dominant and primarily affects Bowman’s membrane. 1. Erosions are more frequent than in Thiel–Behnke corneal dystrophy (TBCD). 2. Develop confluent opacities at the level of Bowman’s membrane and superficial stroma that may extend horizontally and deeper. 3. Histopathology a. Light microscopy: Connective tissue sheet develops to replace Bowman’s membrane. b. TEM: Subepithelial rod-shaped, electron-dense bodies similar to those in granular corneal dystrophy type I are present. These are different from the deposits found in TBCD, which are “curly fibers.”

A



c. Immunohistochemistry: The characteristic rodshaped bodies are positive for transforming growth factor B-induced protein (keratoepithelin). 4. Confocal microscopy: Deposits in the epithelial basal layer show extremely high reflectivity from small granular material without any shadows. Bowman’s membrane replaced by pathological material having much higher reflectivity than that in TBCD. B. Thiel–Behnke corneal dystrophy (TBCD): Cl; potential variant C2: corneal dystrophy of Bowman layer type II (CDB2), honeycomb-shaped corneal dystrophy, anterior limiting membrane dystrophy type II, curly fibers corneal dystrophy, Waardenburg–Jonkers corneal dystrophy 1. Clinically, it is characterized by autosomal-dominant inheritance, early manifestation, slow progression, painful erosions during childhood, subepithelial corneal opacities with a clear limbal zone, honeycombshaped opacity pattern, and recurrence in the graft following keratoplasty. 2. Histopathology: subepithelial fibrous tissue in wavelike pattern is present. TEM reveals curly filaments, which are said to be the distinguishing and characteristic feature of TBCD. 3. Confocal microscopy: a. Deposits in the epithelial basal layer show homogeneous reflectivity with round edges accompanying dark shadows. b. Bowman’s membrane replaced by pathological material having lower reflectivity than that in RBCD.







Fig. 8.42  Reis–Bücklers dystrophy. A, The characteristic honeycomb corneal pattern is seen. B, Slit-lamp view shows very superficial location of opacity. C, Histologic section in another case shows central degeneration of Bowman’s membrane and irregularity of overlying epithelium. D, Trichrome stain demonstrates disruption (d) of Bowman’s membrane by fibrous tissue, along with a fibrous plaque between Bowman’s membrane (b) and epithelium (e). (A and B, Courtesy of Dr. IM Raber.)

B

e

d

b C

D

b

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4. Immunohistochemistry: Curly fibers are immunopositive for transforming growth factor beta-induced keratoepithelin in 5q31. 5. Multiple specific mutations have been reported especially in individuals of Chinese descent. C. Grayson–Wilbrandt corneal dystrophy 1. This has been eliminated in the latest IC3D edition 2 classification system. (See Table 8.7 for a comparison of the staining characteristics of lattice, granular and macular corneal dystrophies.)



D. Lattice corneal dystrophy (Figs. 8.43–8.44) 1. Lattice corneal dystrophy, TGFBI type (LCD): classic lattice corneal dystrophy (LCD1) Cl, variants (III, IIIA, I/IIIA, and IV) are Cl: see Figs. 8.43 and 8.44, Table 8.3, and Chapter 7). a. Six forms exist: (1) LCD type I; (2) LCD type III; (3) LCD type IIIA; (4) gelatinous droplike corneal dystrophy; (5) LCD type II (OMIM 204870); and (6) polymorphic corneal amyloidosis. 1) The R124C mutation frequently accompanies LCD.



TABLE 8.7  Histopathologic Differentiation of Granular, Macular, and Lattice Dystrophies Dystrophy Granular Macular Lattice

Trichrome

AMP*

Periodic Acid–Schiff

Amyloid†

Birefringence‡

Heredity

+ − +

− + −

− + +

− or + − +

− − +

Dominant Recessive Dominant

§

*Stains for acid mucopolysaccharides (e.g., Alcian blue and colloidal iron). † Stains for amyloid (e.g., Congo red and crystal violet). ‡ To polarized light. § Periphery of granular lesion (and occasionally within the lesion) stains positively for amyloid.

A

B

C

D Fig. 8.43  Lattice dystrophy. A, Translucent branching lines of typical lattice dystrophy (lattice corneal dystrophy [LCD type I]) seen best by retroillumination. B, Another patient shows an accentuated form of lattice, perhaps LCD type III. C and D, Corneal deposits appear as granules, similar to granular corneal dystrophy. Histology of cornea, however, is consistent with lattice dystrophy (see Fig. 8.44A). This is the Avellino-type corneal dystrophy. (A, Courtesy of Dr. JH Krachmer; C and D, case reported in Yanoff M, Fine BS, Colosi NJ et al.: Lattice corneal dystrophy: Report of an unusual case. Arch Ophthalmol 95:651, 1977. © American Medical Association. All rights reserved.)

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CHAPTER 8  Cornea and Sclera

A

B

C

D

Fig. 8.44  Lattice dystrophy (Avellino type). A, Histologic section shows focal areas of “hyalin” irregularities. B, Top and bottom taken with both polarizers in place in Congo red-stained section. Birefringence is demonstrated by a change in color when the bottom polarizer is turned 90° (when only one polarizer is in place, the corneal amyloid deposit—stained with Congo red—acts as second polarizer and dichroism is demonstrated by a change in color when the one polarizer is turned 90°). Electron microscopy shows that lesions are composed of myriad individual filaments either in disarray and therefore nonbirefringent (C) or (D) highly aligned and therefore birefringent.



2) Typically, the deposits in LCD are in the midstroma, with a mean distance of 79 nm from the epithelium. 3) In contrast, deposits in GCD are mostly superficial, having a mean distance from the epithelium of 28 nm. b. Atypical midperipheral lattice corneal dystrophy presenting with adult onset and negative family history should arouse suspicion for an association with paraproteinemia or amyloidosis. Amyloidosis may be classified into two basic groups: systemic (primary and secondary) and localized (primary and secondary). Secondary systemic amyloidosis, the most frequently encountered type, rarely involves the eyes and is not an important ophthalmologic entity. Lattice dystrophy of the cornea is now considered by many to be a hereditary form of primary localized amyloidosis. The epithelial basement membrane abnormalities are responsible for secondary epithelial erosions and are partially responsible for the vision impairment.









2. LCD type I (classic primary LCD) shows corneal lines forming a lattice configuration present centrally in the anterior stroma, leaving the peripheral cornea clear. a. The central lattice lines are difficult to visualize with direct illumination. 1) Some authors believe that the lattice lines may represent nerves or nerve degeneration. 2) Proof for this hypothesis is lacking. b. LCD type I can progress to involve deeper stromal layers. c. Also seen are epithelial abnormalities (e.g., recurrent erosion, band keratopathy, and loss of surface luster), which may be caused by epithelial basement membrane abnormalities. d. This autosomal-dominant condition begins in the first decade or early second decade and may progress fairly rapidly; many affected people have marked vision impairment by 40 years of age. e. LCD rarely is unilateral; however, it may be extremely asymmetrical at the time of presentation. f. The associated mutation is p.arg124Cys in classic LCDI; however almost all of the other variants of LCD arise from domain 4 of TGFBI.

Dystrophies and Simulating Disorders

















g. Amyloid deposition may recur in a corneal transplant graft. h. Immunochemical and electron microscopic findings consistent with structural alterations in cell–matrix adhesion molecules and basement membrane components possibly partially explain delayed epithelial healing in LCD. 3. LCD type III primary corneal lattice dystrophy has an autosomal-recessive inheritance pattern, has thicker lines extending from limbus to limbus, and has a later onset than type I. 4. LCD type II (Meretoja) lattice corneal dystrophy, gelsolin type, Meretoja’s disease, AGel amyloidosis (LCD2), C1. The disorder is also called type IV familial neuropathic syndrome, familial amyloid polyneuropathy type IV, or amyloidotic polyneuropathy. (This is not a true corneal dystrophy but usually is discussed in relationship to the other similar dystrophies.) a. Dominantly inherited, familial form of systemic paramyloidosis or secondary corneal amyloidosis. b. Mainly in people of Finnish origin, G654A or G654T mutation. LCD type II is caused by mutations in the gelsolin gene on chromosome 9 (9q32–34). c. Consists of lattice corneal changes (more peripheral than in LCD type I). d. It can result in corneal lattice changes, early aging, facial paralysis, cranial neuropathies, brow ptosis, blepharochalasis, oral disturbances, and drooping of facial tissues. It may produce sicca syndrome and mimic Sjögren’s disease. e. Major symptoms appear in the fifth decade of life. f. Mutation in gelsolin gene leading to production and aberrant processing of variant gelsolin and deposition of its fragments in various tissues in the form of amyloid fibrils. Nevertheless, accumulation of gelsolin may be seen in various forms of amyloidosis and may not be confined to Meretoja’s disease. g. Clinical confocal microscopy (CFM) confirms that symptom levels and slit-lamp findings correlate positively with corneal haze intensity, and correlate inversely with visibility of epithelial and stromal nerves. In severe cases, stromal and epithelial nerves are not visible, suggesting progressive neural degeneration. h. The lattice lines have been attributed to amyloid deposits and not to corneal nerves based on CFM. i. Nerve damage is the probable cause of decreased corneal mechanical and, to a lesser degree, thermal sensitivity. j. Vitreous opacities do not occur. 5. Polymorphic corneal amyloidosis has been associated with A546D mutation in the TGFBI gene; however, this has been questioned as a universal association.























319

a. Multiple polymorphic, polygonal, refractile, chipped ice-appearing gray and white opacities are seen at multiple depths of the cornea. b. Occasional deep, filamentous lines that do not form a distinct lattice pattern are noted. c. A phenotypic variant of LCD characterized by bilateral, symmetric, radially arranged branching refractile lines within and surrounding an area of central anterior stromal haze accompanied by polymorphic refractile deposits in the mid and posterior stroma may be seen. d. Light and electron microscopy demonstrates amyloid and excludes material characteristic of GCD. e. Ala546Asp and Pro551Gln missense changes in exon 12 of the TGFBI gene may be seen. f. Corneal amyloidosis can be associated with lactoferrin, and a Glu561Asp mutation with or without accompanying Aal11Thr and Glu561Asp mutations. 6. Histology of lattice deposits a. An eosinophilic, metachromatic, PAS-positive and Congo red-positive, birefringent, and dichroic deposit is present in the stroma, mainly superficially. b. The epithelium is abnormal and shows areas of hypertrophy and atrophy along with excessive basement membrane production. It seems that not only keratocytes but, on occasion, corneal epithelial cells have the ability to elaborate the abnormal material considered to be amyloid. LCD may recur in the donor button after corneal graft. c. In addition, unesterified cholesterol is found in areas corresponding to the Congo red positivity. d. Electron microscopy shows masses of delicate filaments, many in disarray, whereas others are highly aligned. Filaments also infiltrate between collagen fibrils of normal diameter, and alignment is at the edges of lesions. e. LCD type III shows larger amyloid deposits than types I and II, and contains a ribbon of amyloid between Bowman’s membrane and the stroma. E. Granular corneal dystrophy C1 (Fig. 8.45). 1. Granular corneal dystrophy, type 1 (classic) (GCD1) C1: corneal dystrophy Groenouw type I. a. Sharply defined, variably sized, white opaque “breadcrumb” granules are seen in the axial region of the superficial corneal stroma; the intervening stroma is clear. b. The deposits are irregular and highly reflective being 50 µm in diameter on confocal microscopy. c. At least two clinical phenotypes exist. 1) Family members with the R555W mutation (C1710T) in exon 12 may present with an unusual vortex pattern of corneal deposits. Another atypical phenotype of GCD demonstrates white dotlike opacities scattered in the

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CHAPTER 8  Cornea and Sclera

A

B

C

D Fig. 8.45  Granular dystrophy. A, Clear cornea is present between the small, sharply outlined, white stromal granules. B, Histologic section shows that the granules stain deeply with hematoxylin and eosin and (C) stain red with the trichrome stain. The periodic acid–Schiff stain and stain for both glycosaminoglycans and amyloids are negative. The condition is inherited as an autosomal-dominant trait. D, The granules seen by light microscopy also appear as granules by electron microscopy. Many granules are “apertured.”

anterior and mid-stroma of the central cornea. The mutation results in a nucleotide transversion at codon 123 (GAC→CAC), causing Asp → His substitution (D123H); however, there is low penetrance for GCD. 2) An early-onset, superficial variant begins in childhood and is characterized by confluent subepithelial and superficial stromal opacities, frequent attacks of recurrent erosion, and early visual loss. The peripheral stroma is clear. The variant may be confused histologically with Reis–Bücklers dystrophy. Electron microscopic examination clarifies the diagnosis by demonstrating rod-shaped granules in a plane localized to, or near, Bowman’s membrane. The granules may be enveloped by amyloid (9- to 11-nm filaments). 3) A milder, late-onset variety is characterized by multiple, crumb-like stromal opacities, slow progression, fewer attacks of recurrent



erosion, less visual disturbance, and less need for corneal grafting. The peripheral stroma is clear. d. Inheritance is autosomal dominant with complete penetrance. Chromosome linkage analysis shows Reis– Bücklers, Thiel–Behnke, granular, superficial granular, Avellino, and lattice type I dystrophies are linked to a single locus on chromosome 5q31. These dystrophies may represent different clinical forms of the same entity. The severe phenotype of granular dystrophy is caused by homozygous mutations in the keratoepithelin gene TGFBI (formally, BIGH3). In classic granular dystrophy, the specific mutation in the TGFBI gene is a R555W mutation.

2. Granular corneal dystrophy, type 2 (granular-lattice) (GCD2) C1: combined granular-lattice corneal

Dystrophies and Simulating Disorders

dystrophy, Avellino corneal dystrophy (see Figs. 8.43C and D, and 8.44) a. Many patients who have granular and lattice dystrophy changes in the same eye can trace their origins to the region surrounding Avellino, Italy. b. Chromosome linkage analysis shows Reis–Bücklers, Thiel–Behnke, granular, superficial granular, Avellino, and lattice types I and IIIA dystrophies are linked to a single locus on chromosome 5q31 (associated with the R124H mutation of the TGFBI gene). These five dystrophies may represent different clinical forms of the same entity. c. Clinically, well-circumscribed granular lesions are seen along with corneal lesions that are larger than lattice type I opacities and appear snowflake-like. d. Three signs characterize Avellino corneal dystrophy: anterior stromal discrete, grayish-white deposits; lattice-like lesions located in the mid to posterior stroma; and anterior stromal haze. e. The granular lesions occur early in life, whereas the lattice component appears gradually, maturing later in life. f. Histologically, both eosinophilic, trichrome-positive granular deposits and Congo red-positive fusiform













deposits are found. Electron microscopy shows discrete, homogeneous, electron-dense deposits and apertured deposits enclosing lacunae of filaments in the superficial stroma. Loosely arranged fibrils, many of which are oriented randomly, are seen at the periphery of the superficial deposits, as contrasted to the parallel packing of amyloid fibrils seen in the fusiform deposits of deeper stroma. 3. Granular corneal dystrophy, type 3 (RBCD) = Reis– Bucklers C1; see above. III. Stromal dystrophies A. Macular corneal dystrophy (MCDI) C1: Groenouw corneal dystrophy type II, Fehr spotted dystrophy, Bücklers type II, primary corneal acid mucopolysaccharidosis; (Fig. 8.46; see Table 8.8). 1. Localized corneal mucopolysaccharidosis caused by a disorder of keratin sulfate metabolism. Unsulfated keratin sulfate is deposited both within keratocytes and corneal endothelial cells and in the extracellular corneal stroma. A wide range of keratocyte-specific proteoglycan and glycosaminoglycan remodeling processes are activated during degeneration of the stromal matrix in MCD.

ep

A bl

B

321

C

nug

Fig. 8.46  Macular dystrophy. A, The corneal stroma between the opacities is cloudy. B, Histologic section shows that keratocytes and vacuolated cells beneath the epithelium (stained yellow) are filled with glycosaminoglycan (stained blue). In this condition, the trichrome stain and stains for amyloid are negative, but the periodic acid–Schiff stain is positive. The condition is inherited as an autosomal-recessive trait. The cornea and serum of most patients who have type I macular dystrophy lack detectable antigenic keratan sulfate, whereas it is present in the cornea and serum in type II. C, Keratocyte beneath Bowman’s layer (bl) filled with vesicles containing acid mucopolysaccharide (AMP)-positive substance (ep, epithelium; nug, nucleus of keratocyte). (A, Courtesy of Dr. JH Krachmer; B, AMP stain.)

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CHAPTER 8  Cornea and Sclera

TABLE 8.8  Mucopolysaccharidoses and Mucolipidoses: Clinical Features and Diagnostic Tests Disease MPS MPS I (Hurler, Scheie, Hurler/ Scheie) MPS II (Hunter)

MPS III (Sanfilippo)   IIIA  

IIIB

 

IIIC

 

IIID

Enzyme Deficiency

Storage Chromosome Gene Material Location Mutations

Screening Diagnostic Test Test

Prenatal Diagnosis

Main Clinical Features

Iduronidase

DS, HS

4p16.3

Urine GAGs

WBC enzyme assay

CVB*

HSM, CNS, SD, DYS, OPH, CAR

Iduronate-2sulfatase

DS, HS

Xq27–28

W402X, Q70X plus many others No common mutations

Urine GAGs

Plasma enzyme CVB† assay

HSM, CNS, SD, DYS, OPH, CAR, SK

Heparan-Nsulfatase N-acetylglucosaminidase Acetyl CoA glucosamine N-acetyl transferase N-acetylglucosamine-6sulfatase

HS

17q25.3

Urine GAGs

HS

17q21.1

HS

8p11.1

R245H,R74C and many others No common mutations No common mutations

WBC enzyme CVB assay Plasma enzyme CVB assay WBC enzyme CVB assay

CNS, SD (+/−), DYS (+/−) CNS, SD (+/−), DYS (+/−) CNS, SD (+/−), DYS (+/−)

HS

12q14

Very few patients Urine GAGs studied

WBC enzyme assay

CVB

CNS, SD(+/−), DYS (+/−)

KS

16q24 3p21-pter

WBC enzyme assay WBC enzyme assay WBC enzyme assay

CVB

KS

I113F (UK and Ireland) No common mutations No common mutations

SD, CAR, OPH (+/−) SD, CAR

CVB‡

HSM, SD, DYS, OPH, CAR HF, HSM, CNS, SD, DYS, OPH, CAR ARTH

MPS IV (Morquio) IVA Galactose-6sulfatase   IVB β-Galactosidase  

Urine GAGs Urine GAGs

Urine GAGs Urine GAGs

MPS VI (Maroteaux– Lamy) MPS VII (Sly)

Galactosamine-4sulfatase

DS

5q13–q14

β-Glucuronidase

HS, DS

7q21.1–q22

Very few patients Urine GAGs studied

WBC enzyme assay

CVB

MPS IX

Hyaluronidase

HA

3p21.3

Very few patients None studied

Cultured cells

Unknown

SA

10pter-q23

Cultured cells

Cultured cells

Transferase§ α and β subunits

Many

12q23.3

No common Urine sialic mutations acid Very few patients Urine oligos studied

As ML II

Many

12q23.3

Transferase-δsubunit Unknown

Many

16p13.3

Unknown

19p13.2–13.3

ML ML I (Sialidosis I) Neuraminidase ML II (I Cell, GNPTAB α/β) ML III (pseudoHurler)   III (GNPTAB, α/β)  

III (GNTPG γ)

ML IV

Urine GAGs

CVB

CNS, CRS, SD (+/−) Plasma enzyme Cultured cells HSM, CNS, SD, assays or AF or DNA DYS, OPH, CAR

Very few patients Urine oligos studied

Plasma enzyme Cultured cells HSM (+/−), CNS assays or AF or DNA (+/−), SD, DYS(+/−), CAR Very few patients Urine oligos Plasma enzyme Cultured cells As ML III A studied assays or AF or DNA R750W (20%) Blood gastrin Histology Histology of CNS, OPH CVB or DNA

AF, amniotic fluid; ARTH, arthropathy; CAR, cardiac disease; CNS, regression; CRS, cherry-red spot; CVB, chorion villus biopsy; DS, dermatan sulfate; DYS, dysmorphic appearance; GAGs, glycosaminoglycans; HA, hyaluronic acid; HF, hydrops fetalis; HS, heparan sulfate; HSM, hepatosplenomegaly; KS, keratan sulfate; ML, mucolipidoses; MPS, mucopolysaccharidoses; Oligos, oligosaccharides; OPH, eye signs, corneal clouding; SA, sialic acid; SD, dysostosis multiplex; SK, dermatological signs; SKA, angiokeratoma; WBC, white blood cell; (+/−), sign not always present or mild. *Low activity in CVB – caution re contamination with maternal decidua. † Always do fetal sexing as some unaffected female fetuses will have very low enzyme results. ‡ Difficult because of cross-reactivity from other sulfatases. § UDP-N-acetylglucosamine: lysosomal hydrolase N-acetylglucosamine-1-phosphotransferase (GlcNAc-PT). (From Wraith JE: Mucopolysaccharidoses and mucolipidoses. In: Dulac et al.: Handbook of Clinical Neurology, Volume 113, Chapter 177, 2013, pp. 1723–1729. Table 177.1. Elsevier.)

Dystrophies and Simulating Disorders

















2. Diffuse cloudiness of superficial stroma and aggregates of gray-white opacities in the axial region are seen; the intervening stroma is also diffusely cloudy. 3. Decrease in N-acetylglucosamine 6-O-sulfotransferase (GlcNAc6ST) activity in the cornea may result in the occurrence of low-sulfate or nonsulfated keratan sulfate and thereby cause the corneal opacity. 4. Cloudiness usually develops rapidly so that vision in most patients is seriously impaired by 30 years of age, necessitating corneal grafting. 5. Macular dystrophy may recur in the donor button after corneal graft. 6. Type I, the most prevalent type, shows a lack of detectable antigenic keratan sulfate in the cornea and serum. a. Type IA has been described in which a lack of detectable antigenic keratan sulfate occurs in the corneal stroma and serum, but in which corneal fibroblasts do react with keratan sulfate monoclonal antibody. A further subdivision of this type can be achieved on the basis of reactivity to monoclonal antibody 3D12/H7. b. Type II shows detectable antigenic keratan sulfate in the cornea and serum. 7. Inheritance is autosomal recessive. a. The carbohydrate sulfotransferase 6 (CHST6) gene for this dystrophy is located on chromosome 16 (16q22). b. Although gene mutation heterogeneity exists among patients, it may not be reflected in phenotype heterogeneity as assessed by confocal microscopy. c. Multiple mutations have been identified as causative in this disorder and new ones are being discovered. d. In contrast to European-derived populations, macular corneal dystrophy represented the diagnosis in 93% of corneal transplant specimens in one study from Saudi Arabia. 8. Macular dystrophy is thought to result from an inability to catabolize corneal keratan sulfate (keratan sulfate I). Keratan sulfate may be absent from the serum of patients who have macular corneal dystrophy. 9. Histologically, basophilic deposits, which stain positively for acid mucopolysaccharides (glycosaminoglycams), are present in keratocytes, in endothelial cells, and in small pools lying extracellularly in or between stromal lamellae. a. In addition, unesterified cholesterol is found throughout the stroma. Amyloid is sometimes present in the deposits. b. Some cases show excrescences of Descemet’s membrane. c. 3D image analysis reveals that the proteoglycan areas are significantly larger in corneas with macular corneal dystrophy. Moreover, ultrastructural 3D imaging also shows that the



323

production of unsulfated keratin sulfate may lead to degeneration of micro-collagen fibrils within the collagen fibrils. 10. Concomitant keratoconus and macular corneal dystrophy have been reported in two siblings. B. Schnyder corneal dystrophy (SCD) C1: Schnyder crystalline corneal dystrophy (SCCD), Schnyder crystalline dystrophy sine crystals, hereditary crystalline stromal dystrophy of Schnyder, crystalline stromal dystrophy, central stromal crystalline corneal dystrophy, corneal crystalline dystrophy of Schnyder, Schnyder corneal crystalline dystrophy. Central discoid corneal dystrophy may be a variant of Schnyder corneal dystrophy.

1. Clinically, five morphologic phenotypes have been described: (1) disc-shaped central opacity lacking crystals; (2) central crystalline disc-shaped opacity with an ill-defined edge; (3) crystalline discoid opacity with a garland-like margin of sinuous contour (central full-thickness disciform lesion having a mosaic pattern instead of the more typical collection of crystals or diffuse haze may also occur); (4) ring opacity with local crystal agglomerations with a clear center; and (5) crystalline ring opacity with a clear center. a. Bilateral, symmetric, relatively nonprogressive condition (although it may progress significantly over time) is probably not related to blood lipoprotein abnormalities, but occasionally may coexist with a hyperlipoproteinemia. b. Rarely, the crystals can regress (e.g., after corneal epithelial erosion). c. Crystals are present in only 54% of patients. 2. Inheritance is autosomal dominant. Associated with mutation in UBIAD1 gene, which alters mitochondrial prenyltransferase thereby downregulating protein function. a. UBIAD1 synthesizes menaquinone-4 (MK-4, vitamin K2), which may play a role in maintaining corneal clarity. 3. Histologically, lipids (predominantly phospholipid, unesterified cholesterol, and cholesterol ester) are seen in Bowman’s membrane (layer) and corneal stroma. a. The deposits stain positively with oil red-O and filipin (a fluorescent probe specific for unesterified cholesterol). b. The dystrophy appears to be related to a primary disorder of corneal lipid metabolism. 1) The corneas have a 10-fold increase in cholesterol levels and 5-fold increase in phospholipid levels. C. Congenital stromal corneal dystrophy (CSCD) (Table 8.9 compares congenital hereditary endothelial dystrophy and congenital hereditary stromal dystrophy) (congenital hereditary stromal dystrophy, congenital stromal dystrophy of the cornea).

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CHAPTER 8  Cornea and Sclera

TABLE 8.9  Comparison of Features of Congenital Hereditary Endothelial Dystrophy (CHED)

and Congenital Hereditary Stromal Dystrophy (CHSD) Clinical Characteristics

Histologic Findings

CHED

CHSD

Bilateral Inherited Present at birth, progressive disease with epithelial changes Thickened cornea Thickened cornea (edema) Secondary changes in epithelium and Bowman’s membrane Stroma: Collagen fibrils of normal or large diameter separated by irregular lakes of fluid

Bilateral Inherited Present at birth, usually stationary Normal thickness cornea Normal thickness cornea Epithelium and Bowman’s membrane normal Stroma: Uniform distribution of loose and compact lamellae composed of collagen filaments of small diameter; the loose lamellae always related to keratocytes Essentially normal Descemet’s membrane

Secondary changes in Descemet’s membrane (thickening); homogeneous or fibrous basement membrane

(Modified from Witschel H, Fine BS, Grützner P et al.: Congenital hereditary stromal dystrophy of the cornea. Arch Ophthalmol 96:1043. © 1978 American Medical Association.)











1. Congenital, nonprogressive corneal opacification with diffuse and homogeneous small opacities. 2. Inheritance is autosomal dominant. a. Associated with truncating mutations in the decorin gene leading to accumulation of decorin in interlamellar amorphous deposits. 3. It must be differentiated from other causes of congenital corneal clouding including birth trauma, sclerocornea, Peters’ anomaly, infection, inflammation, congenital glaucoma, mucopolysaccharidosis, corneal dystrophy such as congenital hereditary endothelial dystrophy (CHED), congenital hereditary stromal dystrophy (CHSD) and posterior polymorphous dystrophy, and dermoids. 4. Histologically, the characteristic changes consist of a rather widespread, uniform clefting of the stromal lamellae, composed of collagen filaments of small diameter. a. Stroma is thickened caused by cleaving of the lamellae by alternating layers of smalldiameter collagen fibrils arranged in random fashion. b. Remaining corneal layers (epithelial, Bowman’s, endothelial, and Descemet’s membrane) are normal. c. Electron microscopy reveals prominent keratocyte rough endoplasmic reticulum and increased intracytoplasmic vesicles. d. Electron tomography also demonstrates regions of abnormal stroma where collagen fibrils come together to form thicker fibrillar structures thereby showing that decorin plays a role in the maintenance of order in the normal corneal extracellular matrix. It has been postulated that the truncated decorin found in this disorder has a different spatial geometry from the normal one with the truncation removing a major part of the site that interacts with collagen, compromising its ability to bind effectively.









D. Fleck corneal dystrophy (FCD) C1: hérédodystrophie mouchetée) 1. Clinically, the condition is characterized by small punctate, ringlike, or wreathlike opacities that contain clear centers and distinct margins, and are present throughout all layers of the corneal stroma. The opacities vary in size, shape, and depth. a. The opacities correspond to dilated keratocytes containing intracytoplasmic vesicles filled with complex lipids and glycosaminoglycans. 2. Hereditary fleck dystrophy is congenital, bilateral, and nonprogressive with little or no interference with vision. 3. Inheritance is autosomal dominant. a. The gene locus is on chromosome 2q35. b. Various mutations have been reported. c. Abnormal endosomal phosphoinositide related mutations have been implicated in the pathogenesis of this disorder. 4. Rarely, affected members of families also may have posterior crocodile shagreen, keratoconus, lens opacities, pseudoxanthoma elasticum, or atopic disease. 5. Histologically, the keratocytes are abnormal, and appear swollen and vacuolated. They contain membrane-limited intracytoplasmic vacuoles of a granular to fibrogranular material that stains positively for acid mucopolysaccharides and complex lipids. E. Posterior amorphous corneal dystrophy (PACD) C3: Posterior amorphous stromal dystrophy (Fig. 8.47). 1. Characterized by broad, sheetlike opacification, with intervening clear areas, of the posterior stroma associated with corneal flattening and thinning. 2. Inheritance is autosomal dominant. It has been mapped to chromosome 12q21.33. The abnormal genes may encode for small leucine-rich proteoglycans, which play an important role in collagen fibrillogenesis and matrix assembly. 3. Associated findings may include other abnormalities of the anterior ocular segment such as scleralization

Dystrophies and Simulating Disorders



A



B





C Fig. 8.47  Posterior amorphous corneal dystrophy (PACD). A, Clinical slit-lamp photo of PACD. B, Histopathologic section of a cornea from a patient with PACD demonstrating colloidal iron-positive stroma deposits. C, Higher magnification of A. (Courtesy of Dr. Anthony J Aldave, Ricardo F Fausto, and George OD Rosenwasser.)



325

of the peripheral cornea, iris coloboma, corectopia, iris atrophy, and iridocorneal adhesions. 4. Histologically, by both light and electron microscopy, an irregularity of the stroma is seen just anterior to Descemet’s membrane, whereas the endothelium is normal. Stromal deposits stain with colloidal iron. F. Central cloudy dystrophy of Francois (CCDF) C4 (posterior crocodile shagreen) 1. Characterized by large, polygonal gray lesions that are separated by relatively clear lines, seen in the axial two-thirds of the cornea, and most dense in the deep stroma. 2. Inheritance is autosomal dominant. 3. In vivo CFM has demonstrated multiple dark striae and abnormal stromal deposits in the disorder. 4. Histologically, an extracellular deposit of mucopolysaccharide and lipid-like material is seen. 5. Electron microscopy shows an irregular, sawtoothlike configuration of the collagen lamellae interspersed with areas of 100-nm spaced collagen, along with extracellular vacuoles, some of which contained fibrillogranular material. G. Pre-Descemet corneal dystrophy (PDCD) C4 1. It may be isolated, in which case no associated genetic locus exists. When it is associated with X-linked ichthyosis, the genetic locus is Xp22.31. In the latter instance, deletion of the steroid sulfatase gene occurs. 2. May be associated with other entities including: a. Posterior polymorphous dystrophy b. Anterior membrane dystrophy c. Keratoconus d. Ichthyosis 1) Light and electron microscopic examination of corneal tissue in X-linked ichthyosis with pre-Descemet deposits revealed thick amorphous subepithelial proteinaceous material, disorganized collagen fibers, and electrondense granular material. a) Numerous round and elongated empty spaces, some containing polymorphic and lamellated electron-dense material, are present along the anterior aspect of Descemet’s membrane and throughout the stroma. b) These changes are said to resemble those seen in lecithin cholesterol acetyltransferase disease and were postulated to represent accumulation of cholesterol sulfate. 2) Confocal microscopy reveals regular distributed hyperreflective particles inside the enlarged and activated keratocytes in the posterior stroma. Hyperreflective particles also may be seen outside the keratocytes in the posterior stroma. 3) Examination by anterior segment OCT and Scheimpflug tomography demonstrate

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pathology involving the entire corneal stroma and endothelium, and not just the posterior stroma. 3. Confocal microscopy may be helpful in characterizing these deposits. 4. Confusing term that may describe multiple entities or subtypes that were classified by Grayson and Wilbrandt based on the location, size, shape, and visibility with direct or indirect illumination including: a. Punctiform and polychromatic pre-Descemet’s dominant corneal dystrophy 1) Opacities are punctiform, polychromatic, uniform in size, and evenly distributed over the whole cornea. 2) No visual impairment. 3) Autosomal dominant with high penetrance. 4) Colored opacities may help differentiate it from similar entities. b. Cornea farinata 1) Grayish, punctiform, thin elements and wavy lines resembling a coma. 2) Not visible on direct illumination. 3) Does not involve corneal periphery. c. Deep filiform dystrophy 1) Composed of filaments in curls or punctiform. 2) White on direct illumination. 3) Blue-gray on indirect illumination. 4) Central to paracentral location. 5) Pre-Descemet immunoglobin deposits have been documented on immunohistochemical and ultrastructural examination in one case in which no systemic dysproteinemia was detected. d. Deep punctiform dystrophy 1) Small groups of filaments some of which are dendritic and others are “cane or coma shaped.” 2) Bluish white color. 3) Visible on direct or indirect illumination. 4) Ring or axial distribution. 5. Light and electron microscopic examination of a case of pre-Descemet corneal dystrophy found enlarged vacuolated posterior keratocytes containing dense, intracytoplasmic inclusions that the authors conclude were secondary lysosomes containing lipofuscin-like material. IV. Descemet’s membrane and endothelial dystrophies A. Fuchs endothelial corneal dystrophy (FECD) C1, C2, or C3: endoepithelial corneal dystrophy, (Fuchs combined dystrophy; Figs. 8.48 and 8.49). 1. In 1910, Ernst Fuchs described the epithelial component, which is really a degeneration, secondary to the primary endothelial dystrophy (cornea guttata). Koeppe, in 1916, noted the endothelial changes. Vogt coined the term guttae in 1921. 2. It is the most common endothelial corneal dystrophy and is responsible for up to 50% of all corneal transplants performed in developed countries.















3. It occurs predominantly in elderly women and is bilateral. 4. Seven varieties are recognized (FECD1–7). 5. Most cases probably are sporadic but may be familial or have a dominant inheritance pattern. a. Early-onset FECD1 is associated with genetic locus 1p34.3–p32. Mutations in the SLC4A11 transport protein gene have been associated with late-onset FECD and may be associated with apoptosis. b. Late-onset FECD types have the following gene locus associations:13pter-q12.13 (FECD2), 18q21.2– q21.3 (FECD3), 20p13–p12 (FECD4), 5q33.1– q35.2 (FECD5), 10p11.2 (FECD6), 9p24.1–p22.1 (FECD7), and 15q25 (FECD8). 6. The association of cornea guttata and anterior polar cataract, dominantly inherited in people of Scandinavian origin, has also been reported. 7. Four stages are seen clinically and histologically. a. Asymptomatic stage: excrescences resembling Hassall–Henle warts are present centrally. Electron microscopic studies of cornea guttata demonstrate foci of hyperproduction of Descemet’s membrane in an abnormal format. b. Stage of painless decrease in vision and symptoms of glare: early changes occur as a mild stromal and intraepithelial edema (mainly the basal layer—corneal bedewing) followed by a subepithelial ingrowth of a layer of cells from the superficial stroma through Bowman’s membrane, leading to production of a subepithelial fibrous membrane of varying thickness (degenerative pannus). c. Stage of periodic episodes of pain: a later change is moderate to marked stromal edema and interepithelial edema leading to epithelial bullae (bullous keratopathy) that periodically rupture, causing pain. The corneal epithelium shows areas of atrophy, hypertrophy, and increased basement membrane formation. d. Stage of severely decreased vision but no pain: the degenerative pannus thickens so that the resultant scarring decreases vision. The advanced pannus tends to lessen bullae formation. 8. Other late complications include glaucoma and ruptured bullae that may lead to corneal infection, ulceration, and even perforation. 9. Oxytalan (oxytalan, elaunin, and elastic fibers are all part of the normal elastic system of fibers), not normally present in the cornea, is found in cornea guttata in the corneal subepithelial tissues and most abundantly deep to the endothelium and surrounding, but not in, the guttate bodies. 10. Secondary lipid keratopathy is a frequent later finding. a. Reticulin fibers are prominent in both the guttate bodies and posterior Descemet’s membrane.

Dystrophies and Simulating Disorders

A

B

C

D

327

Fig. 8.48  Cornea guttata. A, The central cornea shows thickening, haze, and distortion of the light reflex. B, The typical beaten-metal appearance of the cornea is seen in the fundus reflex. C, Periodic acid–Schiff stain demonstrates the characteristic wartlike bumps present in Descemet’s membrane, shown better in D by scanning electron microscopy. (D, Courtesy of Dr. RC Eagle, Jr.)









b. Disturbance in the regulation of endothelial apoptosis may contribute to the guttata process. 11. Trinucleotide repeat of CTG18.1 in the transcription factor 4 gene is found in most patients in Caucasian cohorts of this disorder. It has been suggested that this results in RNA toxicity that contributes to the pathogenesis of FECD. a. The clinical severity of FECD is strongly associated with the expansion of the CTG repeat in the transcription factor 4 (TCF4) gene. 12. Oxidative stress also has been postulated to contribute to the pathobiology of FECD, particularly related to mutations in the SLC4A11 gene. a. This mechanism may be facilitated by decreased efficiency of DNA repair following such injury. 13. There is significant variability in staining for the COL8A2 α2-chain of collagen type VIII in corneas in FECD. a. Type VIII collagen comprises a large part of the abnormally secreted posterior collagenous layer in FECD and may have importance relative to the pathological response of the endothelium to aging and to trauma. 14. Significant downregulation of ion transporters occurs that may result in compromised corneal endothelial pump function in FECD dystrophy.



15. Increasing clinical severity of FECD is associated with attenuation of density and mild diminution in function of the subbasal corneal nerve plexus as evaluated by confocal microscopy and esthesiometry. 16. Similarities in pathobiologic alterations between FECD and some neurologic diseases have suggested to some that FECD may be a neurodegenerative disorder. In this regard, it is interesting that FECD has been reported in association with myotonic dystrophy. 17. Environmental and genetic factors may impact the development of FECD. For example, smoking is associated with advanced FECD. B. Posterior polymorphous corneal dystrophy (PPCD) C1 or C2: posterior polymorphous dystrophy (PPMD), hereditary deep dystrophy of Schlichting (Fig. 8.50; see Table 16.4). 1. Irregular, polymorphous opacities and vesicles with central pigmentation and surrounding opacification are seen in the central cornea at the level of endothelium and Descemet’s membrane. 2. CFM has demonstrated craters, streaks, and cracks over the corneal endothelial surface accompanied by endothelial pleomorphism and polymegathism. Wide variation in endothelial cell counts and other abnormalities of Descemet’s membrane have also been noted.

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CHAPTER 8  Cornea and Sclera

A

B

C

D Fig. 8.49  Cornea guttata. A, Early cornea guttata causes intracellular edema of the basal layer of epithelium (seen clinically as corneal bedewing). B, The edema then spreads intercellularly and, with increased corneal fluid, collects under the epithelium, leading to bullous keratopathy. C, Trichrome stain shows a central subepithelial ingrowth of cells from superficial corneal stroma through Bowman’s membrane leading to production of a subepithelial fibrous membrane between epithelium and Bowman’s membrane, called a degenerative pannus, shown with increased magnification in D.

A

B

Fig. 8.50  Posterior polymorphous dystrophy. A and B, Clinical appearance of cornea. C, Scanning electron micrograph of posterior surface of cornea shows epithelial-like appearance of endothelium, caused by numerous surface microvilli. (A and B, Courtesy of Dr. JH Krachmer; C, courtesy of Dr. RC Eagle, Jr.)

C

Dystrophies and Simulating Disorders











3. The corneal abnormalities may vary greatly, even within the same family. Some individuals show only a few isolated vesicles; others manifest severe secondary stromal and epithelial edema; still others show any stage in between. Posterior corneal vesicles may also occur as an isolated finding unrelated to PPCD. 4. Ruptures in Descemet’s membrane and glaucoma (either open-angle or associated with iridocorneal adhesions) may be found. 5. The differential diagnosis between the bandlike structures in PPCD and Haab’s striae (see Fig. 16.6) depends on the clinical appearance. The edges of Haab’s striae are thickened and curled and contain a secondary hyperproduction of Descemet’s membrane; the area between the edges is thin and smooth. PPCD bands are just the opposite. 6. Inherited as autosomal-dominant. There are 2 loci: chromosome 20 (known as the PPCD1 locus) and chromosome 10 (known as the PPCD3 locus). a. PPCD1 is associated with promotor region mutations in the ovo-like 2 (OVOL2) gene. 1) PPCD1 and congenital hereditary endothelial dystrophy (CHED1) are allelic conditions with CHED1 as the extreme of the disease spectrum. b. PPCD3 is associated with mutations in the zinc finger E-box binding homeobox 1 (ZEB1) gene. 1) PPCD3 has been associated with some cases of agenesis and hypoplasia of the corpus callosum. c. 37% of all patients with PPCD and 86% of those with PPCD3 have abnormally steep corneas, which has led to the suggestion that PPCD be considered both a corneal dystrophy and an ectatic disorder. 7. It should not be confused with the rare, autosomaldominant disorder posterior amorphous corneal dysgenesis (dystrophy), which is characterized by gray, sheetlike opacities in the posterior stroma. 8. An association of Alport’s syndrome and PPCD has been reported. A mutation in COL8A2 may cause PPCD in some families. 9. Histologically, the most posterior layers of stroma demonstrate fracturing, the endothelial cells are attenuated, and Descemet’s membrane may be focally or diffusely thickened, or occasionally thinned. a. The total number of endothelial cells is decreased. b. Electron microscopically, the posterior stromal lamellae are disorganized and Descemet’s membrane is interrupted by bands of collagen resembling stroma. c. The posterior surface of the cornea is covered in a geographic pattern by endothelial- and epithelial-like cells with numerous desmosomes, apical villi, and prominent bundles of intracytoplasmic filaments, sometimes creating vesicles and sometimes creating partially detached sheets of cells.













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d. The microvilli-covered cells are present at the onset of the process, and are not a secondary change of long-standing disease. e. A layer of cells may be present beneath the corneal epithelium, but epithelial edema is not common. f. Although some of the changes may superficially resemble those seen in the iridocorneal endothelial syndrome (see Table 16.4) and in cornea guttata, they are usually easily distinguishable because they result from interstitial keratitis and keratoconus. 10. Elevated levels of transforming growth factor-β2 have been found in the aqueous humor of these patients. 11. Giant macular hole and maculopathy may be seen in PPCD. The concomitant occurrence of PPMD and large colloid drusen have been reported, and are presumed to be related to dysfunction of the collagen architecture in the basement membrane layer and further suggest the possibility of a common pathogenic pathway. 12. The entity “posterior corneal vesicles” has been proposed to be distinct from PPMD. a. Lesions are unilateral and involve the endothelium and Descemet’s membrane. They are distributed in a broad band-shape in most cases, but there may be multiple vesicle lesions. b. The lesions are distinct from forceps injury. c. The lesions have been described as arborizing, scalloped lesions, groups of discrete vesicles, linear track-like lesions, C-shaped linear track lesions and band-shaped lesions. 1) The common feature is the presence of small vesicular lesions with a coalescence of these lesions resulting in the band-shaped lesion. d. Confocal microscopy demonstrates the border of the lesions to be low reflective irregular lines with some highly reflective dots, which is said to indicate that the border between the normal corneal endothelium and the vesicular lesions is irregular. 1) Endothelial cells within the area of the vesicular lesions have iso-reflective and low reflective cell membranes, which is said to be typical of normal corneal endothelial cells. 2) Nevertheless, severe polymegathism and pleomorphism are present. 3) Cell density is decreased. e. The endothelial cells do not give evidence of epithelial transformation. C. Congenital hereditary endothelial dystrophy 1 (CHED1) C2 and congenital hereditary endothelial dystrophy (CHED2, Maumenee corneal dystrophy, autosomal recessive congenital hereditary endothelial dystrophy) C1 (Fig. 8.51; see also Table 8.9) The International Classification of Corneal Dystrophies (IC3D): Edition 2 has dropped CHED1 as a distinct

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CHAPTER 8  Cornea and Sclera

A

B

C

D

entity because they state that there is no convincing published evidence to support the existence of autosomal-dominant CHED separate from PPCD. Thus, some literature references to CHED when used without distinction, probably refer to the previously designated CHED2. Nevertheless, authors will be cited in this chapter who refer to it, particularly as related to PPCD. Therefore, CHED2 as used in this chapter is the same as the current IC3D designated CHED.

1. CHED2, the recessive form of congenital hereditary corneal dystrophy, is the most common form of the disorder. 2. Clinically, a diffuse blue-white opacity (ground-glass appearance) involves the cornea.

Fig. 8.51  Congenital hereditary endothelial dystrophy (CHED). A, Clinical appearance right eye (left) and left eye (right) of a patient with CHED, previously reported as Hurler’s disease (patient No. 5 in Scheie HG, Hambrick GW Jr, Barness LA: A newly recognized forme fruste of Hurler’s disease (gargoylism). Am J Ophthalmol 53:753, 1962). B, Left side shows banded (arrow) Descemet’s membrane near stroma and thickened posterior layer interspersed with fibrous basement membrane and patches of banded-type basement membrane. Right side shows high magnification of multilaminar patches (asterisk) of homogeneous basement membrane interspersed with multilaminar sheets of fibrous basement membrane. C, Collagen fibrils in normal corneal stroma measure approximately 24 nm in diameter. D, Stromal collagen fibrils in CHED often measure approximately 48 nm, with some reaching diameters of up to 72 nm. (B–D, From Kenyon KR, Maumenee AE: The histological and ultrastructural pathology of congenital hereditary corneal dystrophy: A case report. Invest Ophthalmol 7:475. © Elsevier 1968.)

3. It tends to be bilateral and progressive, and may be associated with nystagmus and glaucoma, or with agenesis of the corpus callosum. 4. The differential diagnosis of CHED includes congenital hereditary stromal dystrophy, congenital glaucoma, cornea guttata, congenital leukoma, hereditary corneal edema, mucopolysaccharidoses, Peters’ anomaly, sclerocornea, and stromal dystrophies (e.g., macular corneal dystrophy). 5. Two modes of inheritance have been reported: an autosomal-recessive, CHED type 2 (CHED2), and a rarer autosomal-dominant type CHED type 1 (CHED1). CHED2 has been reported in a patient having a heterozygous family member with late onset Fuchs’ endothelial corneal dystrophy.

Dystrophies and Simulating Disorders



a. In the more common autosomal-recessive type, corneal clouding is present at birth or within the neonatal period. b. It is caused by mutations in the sodium bicarbonate transporter-like solute carrier family 4 member 11 (SLC4A11) gene also called the borate cotransporter on chromosome 20p13. Many distinct mutations have been reported associated with CHED2. The target for the disorder is a membranebound sodium-borate cotransporter, and the mutation causes loss of function of the protein either by blocking its membrane targeting or nonsense-mediated decay. c. Harboyan syndrome, which includes congenital CHED2 and perceptive deafness, also is caused by SLC4A11 mutations. 1) It appears that individuals with CHED2 eventually experience some degree of sensorineural hearing loss, and it has been postulated that variable age of onset of these symptoms may be related to some unknown differences in the expression of genetic modifiers or exposure to environmental factors. d. In the autosomal-dominant type (20q12–q13.1), the cornea is usually clear early in life. Corneal opacification develops slowly and is progressive. e. CHED1 and PPCD1 are allelic disorders caused by noncoding mutations in the promoter of OVOL2. f. De novo mutations may result in CHED and it has been reported in a patient lacking a family history of this disorder. EDICT (endothelial dystrophy, iris hypoplasia, congenital cataract, and stromal tinning) syndrome is caused by a single-base substitution in the seed region of mir-184. It maps to chromosome 15q22.1–q25.3.







6. Histologically, increased diameter of the stromal collagen fibrils may produce a thick cornea. Spheroidal degeneration may also be present. a. Descemet’s membrane shows fibrous thickening (similar, if not identical to, cornea guttata), implying an endothelial abnormality. b. Secondary corneal amyloidosis may occur, particularly in association with a subepithelial fibrous pannus. 7. Immunohistochemical staining of corneal endothelium in PPMD and CHED are similar relative to cytokeratins expressed, including CK7, which is not present in normal endothelium or surface epithelium. D. X-linked endothelial corneal dystrophy (XECD) C2 (see Fig. 8.52 for histopathologic and electron microscopic findings in this new corneal endothelial dystrophy). 1. Male predominance (X inheritance). 2. No iridocorneal adhesions.

331

3. No systemic disease association. 4. Clinical findings include corneal opacification that may be congenital and varies from severe opacification to ground glass or milky. Late subepithelial band keratopathy may be present and there may be endothelial changes resembling “moon craters.” a. Endothelial changes best seen in carriers after dilating pupil and examination in direct and indirect illumination. b. Endothelial changes have been described as moon crater-like. 5. Light and electron microscopy: Focal discontinuation and degeneration of the endothelial cell layer with marked thickening of Descemet’s membrane. a. Endothelium may be multi-layered but no epithelial-like changes. 6. Mapped to Xq25. V. Heredofamilial—secondary to systemic disease: Fabry’s disease (angiokeratoma corporis diffusum; see Box 11.2). Table 8.10 lists lysosomal storage diseases. They include the sphingolipidoses, such as Fabry’s disease and Gaucher’s disease, and the mucopolysaccharidoses, which will be discussed in this section. A. Sphingolipidosis (see Chapter 11) 1. Fabry’s disease a. The typical maculopapular skin eruptions (angiokeratoma corporis diffusum) are seen in a girdle distribution and start in early adulthood. The lesions are dark red to blue-black in color and do not blanch. Other findings may be dry mouth and hypohydrosis. Systemic complications include left ventricular hypertrophy, arrhythmias, chronic kidney disease, ischemic stroke, and cerebral small vessel disease. Survival is usually to 40 or 50 years. 1) Two-thirds of women with the disease do not have angiokeratoma. 2) Elevated systemic levels of VEGF-A are significantly associated with angiokeratomas, sweating abnormalities, and Fabry (pseudoacromegalic) facies. TABLE 8.10  The Lysosomal Storage

Disease

1. Stored substrate sphingolipids (×12), e.g.:   Tay–Sachs disease   Fabry’s disease   Gaucher’s disease – infantile, childhood, & adult   Niemann–Pick disease types A&B 2. Mucopolysaccharidosis (×6), e.g.:   Niemann–Pick disease type C 3. Oligosaccharides/glycopeptides 4. Multiple enzyme deficiencies 5. Stored substrate monosaccharides/amino acids/monomers 6. S-Acetylated proteins (From Stern G: Niemann–Pick’s and Gaucher’s diseases. Parkinsonism & Related Disorders 20(Suppl 1):S143-S146, 2014. Table 1. Elsevier.)

A

Di

Dii

Diii

Div

Dv

Dvi

B

C Fig. 8.52  A, Clinical photograph of male child with X-linked corneal dystrophy (XECD) showing bilateral, milky, ground-glass corneal clouding. B, Slit-lamp corneal photo from mother of male child with XECD. The photo illustrates endothelial changes resembling moon craters. C, Histologic section of cornea from male child with XECD demonstrates atypical endothelial cells that are often arranged in multilayers (arrow). Note the bare area of Descemet’s membrane with loss of endothelial cells at other sites (arrowhead). Magnification bar = 15 µm. D, Transmission electron micrographs of a corneal button from male patient with XECD showing alterations of the posterior and anterior subepithelial corneal layers. (Top left) Overview of corneal endothelium and thickened Descemet’s membrane (DM) (AZ, abnormal anterior banded zone; PZ, abnormal posterior banded zone). (Top right) Composition of the abnormal posterior banded zone of Descemet’s membrane of long-spacing collagen (1), microfibrillar bundles (2), amorphous material (3), type VIII-like collagen (4), and type I-like collagen fibers (5). (Middle left) Corneal endothelial cells of varying electron density forming multiple layers (MV, microvilli; N, nucleus). (Middle right) Degenerative endothelial cell adjacent to denuded area (arrow) of Descemet’s membrane (DM) (N = nucleus). (Bottom left) Detail of intact endothelial cell forming apical microvilli (MV), but normal intercellular junctions (arrows) overgrowing a degenerated endothelial cell (DC). (Bottom right) Detail of Bowman’s lamella (BL) containing plaques of amorphous material (asterisks); the epithelial basement membrane is completely lacking (CE, corneal epithelium). (Magnification bars = 1 µm in top right, bottom left, and bottom right, and 5 µm in top left, middle left, and middle right). (From Schmid et al.: A new, X-linked endothelial corneal dystrophy. Am J Ophthalmol 141:478–487, 2006. Figures 2, 3, 6 & 7. Elsevier.)

Dystrophies and Simulating Disorders



b. Whorl-like (vortex-like) epithelial corneal opacities are seen. 1) The presence of ocular signs correlates with disease severity. Verticillata, in particular, correlate with disease severity in pediatric patients. 2) Early diagnosis followed by recombinant enzyme replacement therapy can have a significant impact on the disease prognosis. Cornea verticillata (Fleischer–Gruber), the corneal manifestation of Fabry’s disease, is the term found in the older literature. Quite similar corneal appearances are found in other entities (Table 8.11). Among other possible entities in the differential diagnosis of cornea verticillata, one must consider Fabry’s disease in someone having compatible heart disease who also is taking amiodarone.







c. The fundus shows tortuous retinal vessels containing visible mural deposits. The deposits may be so pronounced as partially to occlude the lumen, resulting in sausage-shaped vessels; the blood in the arterioles becomes much darker than normal from stasis. d. Fabry’s disease is caused by a generalized inborn error of glycolipid metabolism wherein αgalactosidase deficiency results in intracellular storage of ceramide trihexoside. e. Inheritance is X-linked recessive. TABLE 8.11  Causes of Cornea Verticillata In addition to Fabry disease, cornea verticillata can be caused by: Long-term therapy with any of the following drugs: Amiodarone Aminoquinolones (chloroquine, hydroxychloroquine, amodiaquine) Atovaquone Clofazimine Gentamicin (subconjunctival) Gold Ibuprofen Indomethacin Mepacrine Monobenzone (topical skin ointment) Naproxen Perhexiline maleate Phenothiazines Suramin Tamoxifen Tilorone hydrochloride Environmental exposure to silica dust Multiple myeloma

(From Samiy N: Ocular features of Fabry disease: Diagnosis of a treatable life-threatening disorder. Surv Ophthalmol 53(4):416, 2008. © Elsevier Inc. All rights reserved.)

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Amniotic fluid can be analyzed during early gestation for levels of α-galactosidase, thereby detecting the condition during early pregnancy.















f. Histologically, lipid-containing, finely laminated inclusions are present in corneal epithelium, lens epithelium, endothelial cells in all organs, liver cells, fibrocytes of skin, lymphocytes, smoothmuscle cells of arterioles, and capillary pericytes. 1) The cornea shows material between the epithelium and Bowman’s membrane. Oil red-O positive material is present in the subepithelial layer. 2) Duplication of basal lamina is detected on electron microscopic examination. 2. Gaucher’s disease a. Most common lysosomal storage disease, but still is rare. 1) 1/40,000 to 1/60,000 births, but 1/800 in Ashkenazi Jews. b. Caused by mutation in the glucocerebrosidase gene located on chromosome 1q21. The substrate, glucosylceramide, accumulates in macrophages. c. Divided into 3 types based on the absence (type 1) or presence (types 2 and 3) of central nervous system involvement. 1) Type 1 disease is found in 90% of patients in the USA and Europe. a) It is associated with visceral disease such as splenomegaly, hepatomegaly, liver or spleen lesions, bleeding disorder, and bone lesions. Skin pigmentation may be found. b) Carriers of the GBA1 mutation are predisposed to Parkinson’s disease. c) Possible predisposition to neoplasia. 2) Type 2 has acute neuropathic disease presenting at birth and is associated with a very short life expectancy 3) Type 3 is intermediate between types 1 and 2 and has a later onset in childhood than type 1, but may have visceral and neurologic involvement. d. It was the first lipid storage disease treated with enzyme replacement therapy. e. Patients with the a distinct calcific cardiovalvular subtype and the homozygous D409H mutation may have fine linear corneal opacities with intervening clear spaces located in the posterior twothirds of the stroma. In contrast, patients with mucopolysaccharidoses have full-thickness corneal opacification and lack clear areas. A rare case of Gaucher’s disease with a F216Y/ L444P non-neurogenic variant of the disease having corneal opacities has been reported in an index patient and two siblings. Slit-lamp

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CHAPTER 8  Cornea and Sclera examination revealed opacities at all corneal levels with scattered zones of subepithelial haze and the stroma demonstrated focal zones of thickening and haze mainly in the posterior one-third. Horizontal folds were noted in Descemet’s membrane. Corneal thickness was increased, and endothelial cell count was reduced. Confocal microscopy demonstrated multiple tiny white dots in the corneal stroma, and the anterior corneal architecture was distorted. Tiny white dots were interspersed between the keratocytes. The posterior stroma also was abnormal.



B. Mucopolysaccharidoses (Fig. 8.53; see Table 8.8). Corneal opacification is found as an early feature in MPS I Hurler and Hurler–Scheie, MPS IV A Morquio, MPS VI Maroteaux–Lamy and MPS VII Sly. 1. These changes may impact the accuracy of IOP measurements. Accurate IOP measurement is important for these patients who must be followed for the development of glaucoma. 2. They all have mucopolysacchariduria. 3. They all are characterized by defects of specific lysosomal enzymes involved in degradation of glycosaminoglycans (GAGs), which have traditionally been called mucopolysaccharides. GAGs are degradation products of proteoglycans. 4. Inheritance is autosomal recessive except MPS II (Hunter), which is X-linked recessive. 5. Optical coherence tomography of the anterior segment may be helpful in demonstrating anterior segment

A

crowding and increased corneal thickness, particularly in patients with MPS I H and MPS VI. 6. Histologically, vacuolated cells (histiocytes, corneal epithelium and endothelium, keratocytes, and iris and ciliary body epithelia) contain acid mucopolysaccharides in the vacuoles. The different classes show varying pathologic findings, fairly consistent within each class. a. Expression of α-smooth muscle actin and disorganized expression of collagen I and IV were noted in the corneal transplant button from a 14-year-old patient with MPS I H who had undergone bone marrow transplantation at age 2. There was a 30-fold expression of collagen I, a 12-fold increase in collagen IV, and a 2.4-fold increase in collagen VI expression compared to a normal control cornea. These findings suggested myofibroblast conversion within the cornea. Such changes may contribute to corneal clouding in these patients. b. A patient with MPS I HS demonstrated diffuse hyperreflectivity throughout the uniformly thickened cornea. The basal epithelium had clearer cells with cytoplasm filled with hyperreflective granules and white cells with hyperreflective cytoplasm. The stroma also was hyperreflective. Endothelium was disorganized. Corneal histopathologic examination showed the stroma to be irregularly arranged and to contain many small holes. The keratocytes stained positively with PAS stain. The epithelial basal cells were on different planes and





B Fig. 8.53  Mucopolysaccharidoses. A, The cornea is diffusely clouded in a case of Hurler–Scheie syndrome. B, Histologic section of a case of Maroteaux–Lamy syndrome shows acid mucopolysaccharides (AMP; stained blue) deposited in epithelial cells and in stromal keratocytes, and in C in endothelial cells. (A, Courtesy of Dr. HG Scheie; B and C, AMP stain, courtesy of Dr. GOS Naumann.)

C

Dystrophies and Simulating Disorders

appeared to have a perinuclear halo and granular cytoplasm. Endothelium and Descemet’s membrane appeared normal. On electron microscopic evaluation the epithelial cell apical surfaces were formed by branched microfolds. Many desmosomes were present between the epithelial cells, which contained vesicles. Striking findings were present in the keratocytes, which contained foamy cytoplasm and were separated by clefts filled with foamy material. In Maroteaux–Lamy syndrome, donor corneal grafts reaccumulate mucopolysaccharides as early as 1 year postgrafting, but some patients may remain clear up to 5 years. Partial clearing of the host cornea may occur after transplantation. Proteoglycans may be present in the corneal epithelium, intercellular spaces, and in swollen desmosomes. Keratocytes may be abnormal. Beta ig-h3 labeling is around electron-lucent spaces in the stroma. CFM has detected abnormal keratocytes, particularly in the middle and posterior stroma in this condition in which macular retinal folds are also described.



2. It is caused by a mutation in the cystinosin (CTNS) gene located at 17p13 that codes for cystinosin, which is a transmembrane protein that transports the cystine amino acid out of the lysosome. 3. Three types of cystinosis are recognized: a. Childhood type (nephropathic)—characterized by renal rickets, growth retardation, progressive renal failure, and death usually before puberty; autosomal-recessive inheritance.



By biomicroscopy, narrowing of the angle and a ciliary body configuration similar to plateau iris may be seen. Also, by gonioscopy, crystals may be seen in the trabecular meshwork.

1) The activity of the cystine transport system in patients’ leukocytes is deficient. b. Adolescent type—onset in the first or second decade, mild nephropathy, diminished life expectancy; probably autosomal-recessive inheritance. c. Adult (benign) type—onset from late second to sixth decade, typical corneal crystals but no renal disease, normal life expectancy; no known hereditary pattern. 4. Patients who have childhood cystinosis may show a retinopathy that does not seem to cause any abnormality of retinal function. The retinopathy consists of a very fine pigmentation accompanied by tiny, multiple refractile crystals, probably at the level of retinal pigment epithelium and choroid. 5. Histologically, cystine crystals are deposited in many ocular tissues, including the conjunctiva and cornea.





C. Mucolipidosis (see Chapter 11 and Table 8.8) D. Ochronosis (see section in this chapter) E. Cystinosis (Lignac’s disease; Figs. 8.54 and 8.55) 1. The disease, a rare congenital disorder of amino acid metabolism, is characterized by dwarfism and progressive renal dysfunction resulting in acidosis, hypophosphatemia, renal glycosuria, and rickets.

A

B

Fig. 8.54  Cystinosis. A, Myriad tiny opacities give the cornea a cloudy appearance. B, Tiny opacities predominantly in corneal epithelium. C, Polarization of an unstained histologic section of cornea shows birefringent cystine crystals (c) (e, epithelium). (A and B, Courtesy of Dr. DB Schaffer.)

e

c C

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CHAPTER 8  Cornea and Sclera

A

B

Fig. 8.55  Cystinosis. A, Myriad tiny crystals seen in retinal fundus. B, Unstained histologic section of sclera, choroid, and retina shows abundant gray crystalline bodies throughout the choroid. C, The choroidal bodies are birefringent to polarized light. (B and C, Case presented by Dr. FC Winter to the meeting of the Verhoeff Society, 1975.)

C

6. Corneal involvement with cystine deposits is associated with photophobia, blepharospasm, superficial punctate keratopathy, and recurrent erosions. Filamentary keratopathy, band keratopathy and peripheral corneal neovascularization may occur in older patients. 7. Confocal microscopy has demonstrated that the intensity of photophobia in these patients correlates with the density of the corneal crystals. Cystine can be seen clinically with a slit lamp as tiny, multicolored crystals. Although cystine crystals are stored in the liver, spleen, lymph nodes, bone marrow, eyes (conjunctiva, cornea, retina, and choroid), and kidneys (and probably other organs), they seem to be relatively innocuous. Progressive renal failure starts in the first decade of life with proximal tubular involvement (De Toni–Debré–Fanconi syndrome), but it does not seem to be directly related to renal cystine storage. The underlying enzyme defect is not yet known, but the accumulating cystine is often found in the lysosomal components of the cell.





F. Hypergammaglobulinemia (Table 8.12) 1. Corneal crystalline deposits (see subsection Crystals, later in this chapter) are a rare manifestation of hypergammaglobulinemic states such as may be found in multiple myeloma, benign monoclonal gammopathy, Hodgkin’s disease, and other dysproteinemias. a. These disorders may be misdiagnosed as corneal dystrophies such as lattice-corneal dystrophy, granular corneal dystrophy, Reis–Bücklers corneal dystrophy, stromal corneal dystrophies, and preDescemet corneal dystrophy

TABLE 8.12  Classification of Plasma-Cell

Proliferative Disorders

I. Monoclonal gammopathies of undetermined significance (MGUS) A. Benign (IgG, IgA, IgD, IgM, and, rarely, free light chains) B. Associated neoplasms or other diseases not known to produce monoclonal proteins C. Biclonal and triclonal gammopathies D. Idiopathic Bence Jones proteinuria II. Malignant monoclonal gammopathies A. Multiple myeloma (IgG, IgA, IgD, IgE, and free light chains) 1. Symptomatic multiple myeloma 2. Smoldering multiple myeloma 3. Plasma-cell leukemia 4. Nonsecretory myeloma 5. IgD myeloma 6. POEMS syndrome: polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (osteosclerotic myeloma) 7. Solitary plasmacytoma of bone 8. Extramedullary plasmacytoma B. Malignant lymphoproliferative disorders 1. Waldenström’s macroglobulinemia 2. Malignant lymphoma 3. Chronic lymphocytic leukemia III. Heavy-chain diseases (HCDs) A. γHCD B. αHCD C. μHCD IV. Cryoglobulinemia V. Primary amyloidosis (AL) (From Kyle & Rajkumar: Epidemiology of the plasma-cell disorders. Best Practice & Research Clinical Haematology 20(4):637–664, 2007. Table 1. Elsevier.)

Dystrophies and Simulating Disorders

Fig. 8.56  Left cornea showing brown-green discoloration at the level of Descemet’s membrane and sparing of the outer 1–2 mm. The discoloration is stippled and most noticeable pericentrally. The anterior lens capsule is discolored, but poorly visible. This photograph shows light reflection off the anterior lens capsule. (From Shah et al.: Ocular manifestations of monoclonal copper-binding immunoglobulin. Surv Ophthalmol 59:115–123, 2014. Figure 1. Elsevier.)









b. It has been recommended that serum protein electrophoresis be performed in all cases of bilateral corneal opacification of uncertain origin with or without corneal neovascularization to include or exclude paraproteinemic keratopathy. 2. Histologically, positive deposits of immunoglobulin may be seen in corneal stroma (at all levels), conjunctiva, ciliary processes, pars plana, and choroid. 3. The term “immunotactoid keratopathy” has been used to describe corneal immunoglobulin G kappa deposits that appear as tubular, electron-dense, crystalloid deposits having a central lucent core on electron microscopy associated with paraproteinemia. 4. Dense accumulation of copper in Descemet’s membrane and lens capsule is characteristic of circulating monoclonal antibody with strong affinity to copper (Figs. 8.56–8.59). G. Familial high-density lipoprotein deficiency syndromes (Table 8.13) 1. High-density lipoprotein (HDL) deficiency syndromes involve defects in the genes for apolipoprotein A-I (apoA-I), adenosine triphosphate-binding cassette transporter A1 (ABCA1), or lecithin:cholesterol acetyltransferase (LCAT). a. These proteins are involved in determining the concentration, composition, shape, and size of HDL by influencing its biogenesis, remodeling, and catabolism. b. Abnormalities related to them cause: (1) apoA1deficiency, (2) apoA-1 variants, (3) Tangier disease, (4) familial lecithin:cholesteryl ester acetyltransferase (LCAT) deficiency (FLD), and (5) fish eye disease (FED).

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Fig. 8.57  Left cornea 6 years after photograph in Fig. 8.56 was taken. The corneal discoloration is now confluent brown. The anterior lens capsule is more pigmented but now difficult to visualize. (From Shah et al.: Ocular manifestations of monoclonal copper-binding immunoglobulin. Surv Ophthalmol 59:115–123, 2014. Figure 2. Elsevier.)

A

B Fig. 8.58  A, Descemet membrane appears to have mild posterior undulations. Just anterior to endothelium are two distinct pigmented lines. Endothelial cells display no pathologic alterations (hematoxylin and eosin; bar = 10 µm). B, Left anterior lens capsule showing pigment deposits adjacent to lens epithelium. Lens epithelial cells are normal (hematoxylin and eosin; bar = 10 µm). (From Shah et al.: Ocular manifestations of monoclonal copper-binding immunoglobulin. Surv Ophthalmol 59:115–123, 2014. Figure 3. Elsevier.)

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CHAPTER 8  Cornea and Sclera

c. Abnormalities in HDL levels are associated with cardiovascular disease and other disorders. 2. Apolipoprotein A-I (apoA-I) deficiency a. ApoA-I is the major protein component of HDL in the plasma, and is important in HDL metabolism. b. Clinically, corneal clouding is present. Retinopathy and neuropathy also may be associated findings. c. Histopathology: Vesicles are present in the extracellular matrix throughout the corneal stroma. They are not within keratocytes. Vesicles are 200 nm to 2 µm in size and are round to oval in shape. They are believed to be lipid droplets. 3. Lecithin cholesterol acyltransferase (LCAT) deficiency a. LCAT deficiency results from an inborn error of metabolism and consists of a normochromic anemia, proteinuria, renal failure, arteriosclerosis, a high serum level of free cholesterol and lecithin, and greatly reduced esterified cholesterol and lysolecithin. b. LCAT enzyme is absent. c. The gene location is chromosome 16q22. d. The cornea has a cloudy appearance because of the myriad tiny, grayish stromal dots, evenly













Fig. 8.59  Rhodanine stain showing strong positive reaction in lens capsule (bar = 12 µm). (From Shah et al.: Ocular manifestations of monoclonal copper-binding immunoglobulin. Surv Ophthalmol 59:115–123, 2014. Figure 4. Elsevier.)

distributed except for being more concentrated near the limbus, where they mimic an arcus. e. Vision is not severely affected until late in life. f. In addition, retinal hemorrhages, optic disc protrusions, and ruptures in Bruch’s membrane may be the result of lipid deposits. g. Light microscopy shows a vague, mild, diffuse, tiny vacuolation of the corneal stroma. h. Electron microscopy strikingly demonstrates myriad tiny vacuoles, many containing membranes and particles, in Bowman’s membrane and stroma (larger vacuoles in stroma). 1) The corneal epithelial basement membrane is thickened. 2) Amyloid deposition may be found in addition to the other corneal changes. 4. Fish eye disease a. Classical LCAT deficiency is caused by a broad spectrum of missense and nonsense mutation mutations involving the synthesis, secretion, or catalytic activity of LCAT. Fish-eye disease is caused by a limited number of nonsynonymous point mutations that alter the surface polarity and interfere with the binding of the enzyme apoA-I containing lipoproteins. b. It is autosomal recessive. c. The disorder gets its name because the progressive corneal opacification can lead to the appearance of boiled fish eyes. d. Corneal deposits begin in childhood or adolescence as numerous minute greyish dots in the entire corneal stroma. e. Marfanoid features may be present. f. Histopathologic examination of the corneas has demonstrated normal epithelium with microvascularization of a normal thickness Bowman’s membrane. 1) Some areas of the stroma contained marked infiltration by oval and round confluent vacuoles between the collagen bundles. 2) Other areas were relatively clear. 3) The vacuoles tended to become confluent peripherally.

TABLE 8.13  Clinical Differentiation of Familial High-Density Lipoprotein (HDL) Deficiency

Syndromes

Affected gene Tonsil anomalies Hepato-splenomegaly Neuropathy Corneal opacities Xanthomas Nephropathy

Tangier Disease

Apo A-I Deficiency

Familial LCAT Deficiency

Fish-Eye Disease

ABCA1 Occasionally Occasionally Occasionally + No No

APOA1 No No No +/+++ Occasionally No

LCAT No No No +++ Occasionally Yes

LCAT No No No +++ No No

(From von Eckardstein A: Differential diagnosis of familial high density lipoprotein deficiency syndromes. Atherosclerosis 186:231–239, 2006. Table 5.)

Dystrophies and Simulating Disorders

4) Vacuoles stained positive with Sudan III for lipid. 5) Keratocytes were diminished in number and were engorged with vacuoles. 6) Descemet’s membrane and endothelium appeared normal. g. Transmission electron microscopy demonstrated fine vacuoles in the epithelium. 1) Most vacuoles were empty, but some contained myelinated figures. 2) A significant number of mitochondria appeared to be distended by inclusion membranes. 3) Bowman’s membrane and stroma were diffusely infiltrated by vacuoles with massive amounts in the stroma. 4) The vacuoles tended to coalesce in the periphery significantly distorting the tissue. 5) Some keratocytes appeared normal, but others contained myelinated intracytoplasmic material. 6) Descemet’s membrane appeared normal, but the endothelium had increased mitochondrial activity and the presence of fine vacuoles.



Classic familial LCAT deficiency and fisheye disease have been reported in the same family.

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5. Tangier disease a. It is named after the Tangier Island in the Chesapeake Bay, which was home of the family in whom the disease was first detected. b. It is autosomal recessive in inheritance. c. The cause is due to mutations in both alleles of the ABCA1 gene. d. Peripheral neuropathy occurs in over 50% of patients. e. The corneas have been described as having a slightly cloudy appearance with random soft densities involving the entire stromal thickness. In another case, the decreased corneal transparency was most marked centrally and more prominent in the posterior stroma. f. Corneal tissue disruption is noted on light microscopy, but little staining for excess lipid occurs. g. Transmission electron microscopy demonstrates numerous membranous myelin-like lamellar bodies in the corneal stroma with periodicity 6.06 nM, apparent gap 3 nM. These findings have been diagnosed as consistent with lipid involvement and phospholipid excess. VI. Nonheredofamilial A. Keratoconus (Figs. 8.60–8.62) 1. Ectasia of the central cornea usually becomes manifest in youth or adolescence, progresses for 5 to 6

A

B

C

D Fig. 8.60  Keratoconus. A, When patient looks down, the cone in each eye causes the lower lids to bulge (Munson’s sign). B, Slit-lamp beam passes through apex of cone, which is slightly nasal and inferior to center. Note scarring at apex of cone. C, Histologic section through the center of the cone shows corneal thinning, stromal scarring, and breaks in Bowman’s membrane. D, The thinner peripheral part of the cone is to the left and the more normal-thickness cornea is to the right.

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A

B Fig. 8.61  Keratoconus—Fleischer ring. A, A brown line (i.e., Fleischer ring) is seen in the slit-lamp beam above the apex of the cone. B, A cobalt-blue filter shows the Fleischer ring as a black circular line. C, Perl’s stain for iron demonstrates the epithelial positivity (blue) in the region of the Fleischer ring.

C

A

B Fig. 8.62  Acute hydrops. A, Corneal edema developed rapidly in this eye with keratoconus. Penetrating keratoplasty was performed. B, Histologic section shows a markedly thickened and edematous cornea. A break has occurred in Descemet’s membrane, shown with increased magnification in C. (Case courtesy of Dr. RA Levine.)

C



years, and then tends to arrest. Approximately 90% of cases are bilateral. 2. The prevalence is 1 in 2000 individuals in the general populations. 3. The condition progresses most rapidly during the second and third decades of life. a. A high irregular astigmatism is common. b. An increased incidence of keratoconus occurs in Down’s syndrome (see Chapter 2), and human leukocyte antigen (HLA)-327 may be found.



c. Unilateral keratoconus is rare, and most patients with so-called unilateral keratoconus, if followed long enough, eventually acquire keratoconus in the other eye. 4. Earlier onset is associated with a more severe phenotype. 5. There is no gender preference. 6. Most cases are sporadic, but 6%–24% of patients have a positive family history. It also is associated with many syndromes and diseases.

Dystrophies and Simulating Disorders









7. The 5q chromosomal region is associated with the disorder; however, multiple specific loci and mutations have been identified, and are the subject of in-depth reviews. 8. The ocular surface disease in keratoconus is characterized by abnormal tear quality, squamous metaplasia, and goblet cell loss, all of which appear to relate to the extent of keratoconus progression. 9. Multiple over- and underexpressed genes have been related to this disorder. a. The upregulation of keratocan expression may be specific for keratoconus. b. Keratocan is said to be one of three keratan sulfate proteoglycans important for structure of the stromal matrix and maintenance of corneal transparency. c. Similarly, decreased alcohol dehydrogenase in keratoconus corneal fibroblasts is a strong marker and possible mediator of keratoconus. 10. The primary symptoms are reduced visual acuity, photophobia, monocular diplopia, and glare. 11. The apex of the cone is usually slightly inferior and nasal to the anterior pole of the cornea and tends to show stromal scarring. 12. Munson’s sign occurs when the lower lid bulges on downward gaze. 13. Vogt’s vertical lines are seen in the stroma. CFM suggests that Vogt’s striae, which are seen to radiate from the center of the cone, represent stressed collagen lamellae. 14. Fleischer ring (see Fig. 8.61) is caused by iron deposition in the epithelium circumferentially around the base of the cone. a. It is best seen with the light of the slit-lamp through a cobalt-blue filter. b. The iron is mainly deposited in the basal layer of epithelium, but is also found in epithelial wing cells. 15. Ruptures in Bowman’s membrane (early, giving rise to anterior clear spaces), and in Descemet’s membrane (late), and increased visibility of corneal nerves are common. (See histopathology, below.) 16. Keratoconus has been associated with many ocular abnormalities and systemic disorders (Box 8.1). 17. Clinical and histopathologic features compatible with keratoconus have been demonstrated in transplant grafts as long as 40 years after the initial corneal transplant for keratoconus. Population of the graft stroma by host keratocytes or aging of the graft has been postulated to cause this phenomenon. 18. Histology: although multiple corneal anatomic layers are affected by keratoconus, the primary pathologic process probably involves the anterior cornea and stroma with secondary changes in other corneal layers. a. In typical keratoconus, the epithelium is attenuated, the central cornea is thinned, the central

















341

portion of Bowman’s membrane is destroyed, “curly” breaks in Bowman’s membrane are present elsewhere, the central stroma is scarred, and the central portion of Descemet’s membrane often shows ruptures. b. In atypical keratoconus, less thinning of the central epithelium occurs, and there are no breaks in Bowman’s membrane. c. The typical histopathologic pattern is found in 80% of corneas. d. In the periphery of keratoconic corneas, fine cellular processes of keratocytes can be seen to penetrate Bowman’s membrane. These cells may have elevated levels of cathepsins B and G. e. Increased visibility of corneal nerves is characteristic and may be due, in part, to stromal thinning. 1) The subbasal nerve plexus is attenuated. a) Reduced corneal sensitivity is may be present. f. Stromal lamellae are decreased, and there is decreased keratocyte density. 1) There is splitting of the collagen bundles in the stromal lamellae. 2) The stromal lamellae have a significant change in their organization. 3) The collagen fibrillar mass has been demonstrated to be unevenly distributed, particularly at the apex of the cone, indicating inter- and intralamellar slippage and displacement leading to the clinical morphologic changes characteristic of keratoconus. g. Ruptures in Descemet’s membrane may occur. 1) Acute rupture of Descemet’s membrane results in sudden cornea edema, termed “hydrops,” and extreme discomfort and photophobia. a) There may be increased risk of hydrops in Down’s syndrome. 2) Guttata may occur. 3) Endothelial cells may exhibit pleomorphism and polymegathism. h. CFM has demonstrated a significant reduction in the density of keratocytes in the stroma. Reduced anterior keratocyte density is particularly associated with a history of atopy, eye rubbing, and the presence of corneal staining. CFM has also shown corneal epithelial abnormalities in this disorder, that have been confirmed by light microscopy. 1) Patients with atopic syndrome appear to have a younger onset of keratoconus. 2) Vernal conjunctivitis may be complicated by keratoconus. 19. Multiple factors probably contribute to the development of keratoconus. a. Proteomic and gene expression studies in keratoconus have found deregulation of various

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CHAPTER 8  Cornea and Sclera

BOX 8.1  Diseases Reported in Association With Keratoconus Multisystem Disorders Alagille’s syndrome Albers–Schonberg disease Angleman syndrome Apert’s syndrome Autographism Anetoderma Bardet–Biedl syndrome Crouzon’s syndrome Down’s syndrome Ehlers–Danlos syndrome Goltz–Gorlin syndrome Hyperornithemia Ichthyosis Kurz syndrome Laurence–Moon–Bardet–Biedl syndrome Marfan’s syndrome Mulvihill–Smith syndrome Nail–patella syndrome Neurocutaneous angiomatosis Neurofibromatosis Noonan’s syndrome Osteogenesis imperfecta Oculodentodigital syndrome Pseudoxanthoma elasticum Rieger’s syndrome Rothmund’s syndrome Tourette’s disease Turner’s syndrome Xeroderma pigmentosa Other Systemic Disorders Congenital hip dysplasia False chordae tendinae of left ventricle Joint hypermobility Mitral valve prolapse Measles retinopathy Ocular hypertension Thalesselis syndrome

Ocular Disorders (Noncorneal) Aniridia Anetoderma and bilateral subcapsular cataracts Ankyloblepharon Bilateral macular coloboma Blue sclerae Congenital cataracts Ectodermal and mesodermal anomalies Floppy-eyelid syndrome Gyrate atrophy Iridoschisis Leber’s congenital amaurosis Persistent pupillary membrane Posterior lenticonus Retinitis pigmentosa Retinal disinsertion syndrome Retrolental fibroplasia Vernal conjunctivitis Corneal Disorders Atopic keratoconjunctivitis Axenfeld’s anomaly Avellino’s dystrophy Chandler’s syndrome Corneal amyloidosis Deep filiform corneal dystrophy Essential iris atrophy Fleck corneal dystrophy Fuchs’ corneal dystrophy Iridocorneal dysgenesis Lattice dystrophy Microcornea Pellucid marginal degeneration Posterior polymorphous dystrophy Terrien’s marginal degeneration

(From Rabinowitz YS: Keratoconus. Surv Ophthalmol 42:297, 1998. © Elsevier Science Inc. All rights reserved.)





structural proteins, signaling molecules, cytokines, proteases, and enzymes. b. The following are a few of those that have been described: 1) It had been thought that keratoconus is a noninflammatory disorder based on the lack of neovascularization and inflammatory cell infiltration. Recent evidence, however, suggests that inflammation may play a role, particularly in the presence of eye rubbing, which may induce proinflammatory cytokines and proteinases in the tear film resulting in epithelial thinning and set up consequences for other corneal layers. a) Tear proteomics may help further elucidate this potential contributing mechanism in the pathobiology of the disease.





2) Reactive oxygen species and oxidative stress probably play a role in the pathogenesis of keratoconus. 3) Proteoglycan changes resulting in reduced adhesion between corneal stromal lamellae may contribute to regional corneal weakness. 4) Epigenetic factors have been postulated in the pathogenesis of keratoconus. B. Keratoglobus 1. Keratoglobus is a rare, bilateral, globular configuration of the cornea. The cornea shows generalized thinning from limbus to limbus, but most marked in the periphery. As the name implies, there is globular protrusion of the cornea. a. Congenital and acquired forms have been described. It is distinct from megalocornea.

Pigmentations



















b. Males are more common than females, being 2 : 1 in one study. 2. The cornea is transparent, and an iron ring is absent. 3. The condition tends to be stationary, but hydrops can develop. 4. Keratoglobus is probably a variant of keratoconus and may occur in different members of the same family. 5. Associated conditions are dysthyroid ophthalmopathy, idiopathic orbital inflammation, vernal keratoconjunctivitis, and chronic marginal blepharitis. a. Like keratoconus, eye rubbing may be associated. b. It can be associated with connective tissue disorders such as Ehlers–Danlos syndrome type VI, Marfan’s syndrome, and Rubenstein–Taybi syndrome. c. It also has been reported in association with pellucid marginal degeneration, choroidal osteoma, retinitis pigmentosa, and pigment epithelial detachment. 6. Histopathologic examination demonstrates diffuse stromal thinning with focal disruptions in Bowman’s membrane. a. Disruptions in or thickening of Descemet’s membrane may occur. b. Stromal neovascularization also may be found. 7. Immunohistochemical findings are similar to keratoconus. a. There can be decreased expression of proteinase inhibitor alpha-1-PI and increased expression of the transcription factor Sp11 in the corneal epithelial cells. b. These alterations may contribute to tissue degradation. c. Similarly, there may be increased expression of matrix metalloproteinases 1, 2, and 3 within the epithelial cells, which also could contribute to tissue degradation. C. Brittle cornea syndrome 1. The characteristic feature from which the disorder gets its name is corneal fragility with a tendency for the cornea to rupture either spontaneously or after minor trauma. 2. Rare autosomal recessive connective tissue disorder. a. Underlying mutations involve PRDM5, which encodes PR domain-containing 5, and ZNF469, which encodes zinc finger protein 469. 1) These transcription factors may act on a common pathway regulating extracellular matrix genes, particularly fibrillar collagens. 3. Associated systemic findings may include joint hypermobility, skin hyperelasticity, kyphoscoliosis, osteopenia, hearing defects, dental abnormalities, hernias, and, rarely, mental retardation. a. Brittle cornea has been reported unaccompanied by systemic manifestations of a connective tissue disorder.









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4. Keratoconus and keratoglobus as well as high myopia may be found in these patients. 5. Marked corneal thinning, fragility, and blue sclera occur. a. Abnormalities in Bruch’s membrane, reflected in reduced expression of major collagenous components, may lead to choroidal neovascularization. 6. One must wonder how many patients previously described as simply having keratoglobus, actually harbored this syndrome. D. Pellucid marginal degeneration 1. Pellucid marginal degeneration is a progressive, bilateral, usually inferior, peripheral thinning of the cornea in a crescentic fashion; rarely, it can occur superiorly or even temporally. 2. The area of involved cornea is clear with no scarring, infiltration, or vascularization. 3. Protrusion of the cornea occurs above a band of thinning located 1 to 2 mm from the limbus and measuring 1 to 2 mm in width, usually from 4 to 8 o’clock. Acute hydrops may occur. 4. The condition becomes apparent between 20 and 40 years of age; it occurs in both men and women, and results in high irregular astigmatism. a. Males predominate. b. It was unilateral in 25% of patients in one large study. 1) In apparently unilateral cases, keratoconus may be present in the fellow eye. c. There may be a history of allergy. 5. Scleroderma has been reported in association with a case of pellucid marginal degeneration. 6. Pellucid marginal degeneration may be an atypical form of keratoconus. 7. Spontaneous hydrops and even perforation may occur rarely.

PIGMENTATIONS (Table 8.14) Melanin I. Pigmentation of the basal layer of epithelium, especially in the peripheral cornea, is normally found in dark races (Fig. 8.63A). II. A posterior corneal membrane may be caused by a proliferation of uveal melanocytes or pigment epithelial cells on to the posterior cornea after an injury. Lipofuscin pigments, sometimes confused with melanin, may rarely become deposited in the cornea, a condition called corneal lipofuscinosis.

III. Krukenberg’s spindle represents melanin pigment forming a vertical line on the posterior central cornea in contrast to other melanin pigment depositions that tend to be more circular or diffuse in distribution (see Fig. 16.21).

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TABLE 8.14  Differential Diagnosis of Metal Exposure and Pathologic Ocular Pigments Exposure or Condition

Source/Etiology

Ocular Effect

Copper

Foreign body Chalcosis (tissue toxicity); Usually attributed to copper content >60% Treatment of trachoma

Purulent panophthalmitis; discoloration of the cornea, iris, lens, and vitreous

Copper sulfate Argyrosis

Long-term use of silver-containing medications or industrial exposure to organic silver salts

Chrysiasis

Systemic administration of gold compounds

Siderosis

Retained iron foreign body

Hemosiderosis Chlorpromazine

Persistent anterior chamber hemorrhage Systemic treatment for psychosis, nausea/ vomiting, sedation, tetanus, porphyria

Greenish yellow deposits in the deep corneal stroma peripherally; lens deposits occasionally Gray-blue-green or golden sheen of Descemet’s membrane or deep stroma; slate-gray bulbar conjunctival pigmentation; anterior subcapsular lens discoloration Fine, dust-like, gold-to-purple granules in the conjunctiva and deep corneal stroma Stroma and keratocytes show rust-brown color; Descemet’s membrane may have dirty gray appearance Iron found in corneal endothelium and keratocytes Yellow-brown or white dots along deep layers of stroma and endothelium; beneath anterior lens capsule; epithelial streaks; conjunctival granules

(From Shah et al.: Ocular manifestations of monoclonal copper-binding immunoglobulin. Surv Ophthalmol 59:115–123, 2014. Table 1. Elsevier.)

III. The cornea clears first peripherally, and may take several years to clear completely. Corneal blood staining may be permanently visionthreatening in a small child because dense amblyopia may occur during the period of a year or more that may be required for spontaneous corneal clearing. A

B

Fig. 8.63  A, Melanin pigment may extend into epithelium of cornea, as depicted in the diagram. B, Fleischer ring of keratoconus drawn as it would appear in the left eye (i.e., slightly nasal and inferior to center of cornea). (A, From Gass JE: The iron lines of the superficial cornea. Arch Ophthalmol 71:348, 1964, with permission. © American Medical Association. All rights reserved.)

When a Krukenberg’s spindle is present unilaterally, ocular trauma is the usual cause; however, other causes for pigment dispersion such as a degenerating uveal melanoma must be considered. Similarly unilateral pigmentation of the anterior chamber angle may reflect the presence of a “ring” melanoma.

Blood I. Blood staining of the cornea occurs in the presence of a hyphema when intraocular pressure has been increased for at least 48 hours (see Fig. 5.32). Its rate of formation is more rapid in the presence of injured endothelium. Staining may occur earlier or even without glaucoma if the endothelium is diseased.

II. Staining of the cornea is due to hemoglobin and other breakdown products of erythrocytes. The small amount of hemosiderin present is usually contained within keratocytes.

IV. Histologically, amorphous extracellular hemoglobin globules, and tiny round spheres and rods (all orange in hematoxylin and eosin-stained sections) are mainly seen between corneal lamellae, but also in keratocytes and in Bowman’s membrane. The extracellular hemoglobin does not stain positive for iron, as does the intracellular oxidized hemoglobin (i.e., hemosiderin) in keratocytes.

Iron Lines I. Fleischer ring (see Fig. 8.61B; see also Fig. 8.63; see section Dystrophies, subsection Stromal dystrophies, earlier) II. Hudson–Stähli line (Figs. 8.64 and 8.65)—deposition of iron in the corneal epithelium in a horizontal line just inferior to the center of the interpalpebral fissure. III. Stocker line (see Fig. 8.64)—deposition of iron in the epithelium at the advancing edge of a pterygium. IV. Ferry line (see Fig. 8.64)—deposition of iron in the corneal epithelium at the corneal margin of a filtering bleb. V. Iron lines may occur in many conditions, such as the annular lines in the donor epithelium of corneal grafts, around old corneal scars, centrally after refractive keratoplasty, and in association with overnight orthokeratology.

Kayser–Fleischer Ring I. The Kayser–Fleischer ring (Fig. 8.66) is associated with hepatolenticular degeneration (Wilson’s disease): A. Increased absorption of copper from gut. B. Decrease in serum ceruloplasmin.

Pigmentations

C. Usually, an autosomal-recessive inheritance pattern (defect on chromosome 12q14–21), but may have a dominant type. II. The Kayser–Fleischer ring (i.e., copper in Descemet’s membrane) is usually apparent by late childhood or early adolescence and may be accompanied by a “sunflower” cataract. A. The ring is found in about 63% of children with Wilson’s disease, and in all patients with neurologic manifestations of the disease, but in only 58% of patients with only hepatic presentation.

Descemet’s membrane, iris surface, and lens capsule of both eyes has been reported as the presenting sign of multiple myeloma.



The Kayser–Fleischer ring can be simulated exactly as a result of a retained intraocular copper foreign body. In this event, however, the ring is only present in the eye containing the foreign body. Rarely, a Kayser–Fleischer ring may be the presenting sign of Wilson’s disease. Conversely, it may be present in other forms of liver diseases, such as alcoholic liver disease. Ocular deposition of copper involving central

345

III. Histologically, the copper, bound to sulfur, is deposited in the posterior half of the peripheral portion of Descemet’s membrane and in the deeper layers of the central anterior and posterior lens capsule.

Tattoo I. Corneal tattooing (Fig. 8.67) is usually done to disguise unsightly leukomas. II. It is performed by chemical reduction of metallic salts (e.g., gold chloride or platinum black). III. Histologically, the foreign material is seen in the corneal stroma.

Drug-Induced I. Oxidized epinephrine II. Chloroquine (see Fig. 11.33) A. Long-term chloroquine used systemically causes a decreased corneal sensitivity. B. The corneal epithelial deposits vary from diffuse, fine, punctate opacities to focal aggregations arranged in radial, whorling lines that diverge from just below the center of the cornea. Similar corneal appearances are seen in Fabry’s disease, and in amiodarone (Fig. 8.68), suramin, clofazimine and indomethacin keratopathies. These are drug-induced lipidoses (see Table 8.11).

Fig. 8.64  Iron lines. Ferry line depicted at top in front of (i.e., below) filtering bleb; Stocker line depicted on left in front of (to right of) advancing edge of pterygium; Hudson–Stähli line (see also Fig. 8.65) across (horizontal) cornea just below center. All three lines caused by iron in epithelial cells. (Modified with permission from Gass JE: The iron lines of the superficial cornea. Arch Ophthalmol 71:348, 1964. © American Medical Association. All rights reserved.)

A

The deposits may disappear after stoppage of chloroquine. C. Confocal microscopy (CFM) demonstrates that the impact of amiodarone on the cornea may extend deeper than the epithelium as, in eyes with advanced keratopathy, microdots can be seen in the anterior and posterior stroma, and on the endothelial cell layer. Moreover, keratocyte density is decreased.



B Fig. 8.65  Hudson–Stähli line. A, A curved horizontal brown line is seen just below the central cornea (lower pupillary space) in the epithelium. B, Histologic section shows that the line is caused by iron deposition in the epithelium. The other iron lines (Fleischer, Stocker, and Ferry) have a similar histologic appearance. (B, Perl’s stain.)

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A

B

C

D Fig. 8.66  Kayser–Fleischer ring. A, The deposition of copper in the periphery of Descemet’s membrane, seen as a brown color, partially obstructs the view of the underlying iris, especially superiorly. A “sunflower” (disciform) cataract is present in the lens of this patient with Wilson’s disease. B, An unstained section shows copper deposition in the inner portion of peripheral Descemet’s membrane. C, The sunflower cataract is better seen with the pupil dilated. A line of copper is also present deep within the central anterior (D) (and posterior) lens capsule and accounts for the clinically observed cataract. (Modified from Tso MOM, Fine BS, Thorpe HE: Kayser–Fleischer ring and associated cataract in Wilson’s disease. Am J Ophthalmol 79:479. © Elsevier 1975.)

A

B

Fig. 8.67  Corneal tattoo. Corneal scar before (A) and after (B) tattooing. C, Tattoo in another case is noted histologically as dark black deposits of platinum in the corneal stroma. (A and B, Courtesy of Dr. JA Katowitz.)

C

Infections

347

A

B

C Fig. 8.68  Amiodarone. A and B, A brown epithelial deposit is seen as radial, whorling, branching lines that diverge from just below the center of the cornea. C, Electron microscopy shows electron-dense inclusions in the basal corneal epithelial cell. (C, Case presented by Dr. AH Friedman at the meeting of the Verhoeff Society, 1990.)

III. Chlorpromazine A. The pigmentation (melanin-like) is present immediately under the anterior capsule of the lens in the central (axial) area and in the conjunctival substantia propria in the interpalpebral fissure area. B. In the area of the interpalpebral fissure, the corneal pigmentation appears as epithelial curvilinear and linear opacifications. 1. In the corneal stroma, it appears as diffuse, granular yellow pigmentations. 2. In the corneal endothelium, it appears as fine deposits. IV. Other drugs A. Other drugs, such as indomethacin, suramin, amiodarone (see Fig. 8.68), and Argyrol (argyrosis; see Chapter 7), can cause a corneal keratopathy. Antimetabolites, such as cytarabine, can result in degeneration of basal cells and secondary epithelial microcyst formation.







INFECTIONS Keratitis secondary to dematiaceous fungal infection may result in the formation of a pigmented corneal plaque. The fungi are septate and contain brown to black pigment in the cell walls in most cases.



Crystals I. Infectious crystalline keratopathy (ICK; Fig. 8.69) A. ICK is a distinctive microbial corneal infection, characterized by fernlike intrastromal opacities.



B. The first description of this entity was in 1983 and related to a corneal transplant wherein progressive branching, needle-like stromal opacities were seen within the transplant. 1. Gram-positive cocci were the cause of this infection. 2. Term “infectious crystalline keratopathy” was used first by Meisler and associates in their description of three patients, two of whom had infections caused by cocci. 3. Since then, the causative organisms most frequently are cocci, particularly Streprococcus; however, other organisms including amoebas, and even fungi have been reported. 4. ICK most often occurs following surgery or another pre-existing ocular surface disorder. 5. Frequently there is a history of topical steroid use. C. There usually is minimal anterior segment or corneal inflammation. Organisms are found in the interlamellar spaces. D. Although the infection usually is located in the anterior stroma, epithelial and posterior corneal foci have been reported. E. Contact lens use and topical anesthetic abuse also have been associated with ICK. F. It has been postulated that the presence of biofilm on the colonies of organisms may contribute to the failure of recruitment of polymorphonuclear leukocytes in these lesions. II. Noninfectious crystalline keratopathy A. Many causes of noninfectious crystalline keratopathy exist, including Schnyder’s corneal dystrophy; lipid

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CHAPTER 8  Cornea and Sclera

A

B

Fig. 8.69  Infectious crystalline keratopathy. A, Patient had “relaxing incisions” to correct postpenetrating keratoplasty astigmatism. Rounded crystalline-like infiltrates developed on both sides of one of the two incisions. B, Histologic section shows the posterior aspect of the healing cornea incision. C, Brown–Brenn stain shows multiple gram-positive cocci in the region of the incision. (Case presented by Dr. MC Kincaid at the Eastern Ophthalmic Pathology Society, 1990, and reported in Kincaid MC, Fouraker BD, Schanzlin DJ: Infectious crystalline keratopathy after relaxing incisions. Am J Ophthalmol 111:374. © Elsevier 1991.)

C





keratopathy; Bietti’s crystalline retinal and corneal dystrophy; infantile, adolescent, and adult forms of cystinosis; gout; chronic renal failure; hypercalcemia; some familial lipoprotein disorders; dysproteinemias associated with multiple myeloma, malignant lymphoma, and other lymphoproliferative disorders (gammopathies); Dieffenbachia keratitis; and long-term drug therapy with colloidal gold (chrysiasis), chlorpromazine, chloroquine, 5-fluorouracil subconjunctival injection, clofazimine, and immunoglobulin therapy for pyoderma gangrenosum. 1. Gatifloxacin, a fourth-generation fluoroquinolone, may deposit as crystals in the stroma as a result of compromised corneal epithelium. A similar process has been described for ciprofloxacin. 2. Immunotactoid keratopathy is a distinct type of paraprotein crystalline keratopathy associated with a monoclonal immunoglobulin G kappa light chain (IgGk) protein. a. EM: Immunotactoid microtubular deposits measuring >30 nm in diameter with a central lucent core. B. Increasing longevity of patients with nephropathic cystinosis has led to varied anterior-segment manifestations in more mature patients. In addition to classic crystalline deposits, these findings include superficial punctate keratopathy, filamentary keratopathy, severe peripheral corneal neovascularization, band



keratopathy, and posterior synechiae with iris thickening and transillumination. C. The histologic appearance depends on the cause.

NEOPLASM I. The cornea is rarely the primary site for neoplasms, but it is frequently involved secondarily in conjunctival tumors such as squamous cell carcinoma and malignant melanoma. A. Corneal involvement was found in 38% of 287 cases of conjunctival squamous cell neoplasia (CIN). 1. Confocal microscopic features of corneal involvement with CIN correlate well with histopathologic examination findings. 2. In the rare instance when squamous cell carcinoma is primary in the cornea, the adjacent conjunctiva may be spared. B. Occasionally, conjunctival melanoma may present as a corneal mass. Such lesions have been termed “corneally displaced malignant conjunctival melanoma.” II. Myxoma A. Myxoma is rarely reported as a corneal tumor in an individual lacking a history of prior corneal disease. B. The tumor is composed of spindle-shaped cells in a myxomatous ground substance. 1. Ultrastructurally, the cellular elements have features characteristic of keratocytes with no basement

Congenital Anomalies

membrane, much rough endoplasmic reticulum, and vacuoles containing mucoid-like material. 2. Immunohistopathologic characteristics of the tumor cells are positive for vimentin, muscle-specific actin, and smooth-muscle antigen. C. Primary corneal myxoma and myxomatous corneal degeneration (see discussion earlier in this chapter) have very similar histopathologic features. The term “primary corneal myxoma” probably should be reserved for cases in which there is no history of corneal trauma. III. Primary nevi are most uncommon on the cornea. IV. Juvenile xanthogranuloma has been reported to involve the corneoscleral limbus in a child, and an adult. V. Primary diffuse neurofibroma may involve the cornea in von Recklinghausen disease.







SCLERA CONGENITAL ANOMALIES Blue Sclera I. Blue sclera may occur alone or with brittle bones and deafness. A. Blue sclera may be seen in association with brittle cornea with spontaneous perforation (see the discussion earlier in this chapter) B. Blue sclera has also been reported in association with Alport’s syndrome and cutis laxa. C. Similarly, the Sanjad–Sakati syndrome/Kenny–Caffey syndrome type 1 has been associated with blue sclera, intrauterine growth retardation, short stature, small hands and feet, deep-set eyes, microcephaly, persistent hypocalcemia, and hypothyroidism. D. Blue sclera also may be associated with the Loeys–Deitz syndrome (triad of arterial tortuosity and aneurysms, hypertelorism and bifid uvula) involving Western populations but not in Korean individuals. It is secondary to heterozygous mutations of transforming growth factor beta receptors 1 and 2. II. Osteogenesis imperfecta (OI)—usually apparent at birth (Table 8.15) A. OI is a rare hereditary disease involving type I collagen amount, structure or processing. B. It has an incidence of 1 in 15,000 to 20,000 births depending on the study. C. The hallmark of the disorder is an increased susceptibility to bony fractures; however, tremendous variability exists in disease severity among the many recognized disease varieties. Most patients present with the milder forms of the disease. D. Associated nonskeletal findings are blue sclera, dentinogenesis imperfecta, vascular fragility, joint hyperextensibility, abnormal callus formation (type V), CNS complications, and hearing loss. E. As many as 15 classified and unclassified varieties have been identified and, no doubt, the classification system



349

will continue to evolve based on newer genetic and biochemical developments in the field. F. Approximately 90% of cases are caused by autosomaldominant mutations in the COLA1 or COL1A2 genes. 1. These genes encode the α1 (I) and α2 (I) chains of type I collagen. 2. The mutations either reduce the amount of type I collagen (quantitative defects) or affect its structure (qualitative defects). G. Proteins have been discovered recently that interact directly or indirectly with collagen biosynthesis and result in rare forms of mostly autosomal recessive OI. 1. Resemble typical OI, but lack the primary defects in type I collagen. H. The following are the 5 most common varieties of OI. See Table 8.15 for more data regarding them. 1. Type I is autosomal dominantly inherited, is the mildest form and is characterized by skeletal osteopenia, fractures, dentinogenesis imperfecta (in some patients), and blue sclera throughout life. 2. Type II usually results in death in the perinatal period. 3. Type III is a rare autosomal-recessive disorder, which is milder than type II, but severe, progressive skeletal deformities occur. The sclera may be blue at birth but becomes normal by adolescence or adulthood. 4. Type IV is autosomal dominantly inherited and is characterized by skeletal osteopenia and blue sclera at birth, which become normal by adulthood. 5. Type V is characterized by a hypertrophic bony callus following trauma and surgery that can be confused with chondrosarcoma. Other orthopedic problems may be present. I. The sclera retains its normal fetal translucency so that the deep-brown uvea shows through as blue. J. Central corneal thickness is reduced in osteogenesis imperfecta, and negatively correlates with the blueness of the sclera in this disorder. The Russell–Silver syndrome may phenotypically overlap OI including the presence of blue sclera.



K. Histologically, the sclera is usually thinner than normal, but may be thicker and more cellular than normal. Its collagen fibers are abnormal, being reduced in thickness by approximately 25% in the cornea and more than 50% in the sclera.

Ochronosis (Alkaptonuria) I. Because the enzyme homogentisic acid oxidase (homogentisate 1,2-dioxygenase) is lacking, homogentisic acid deposits in tissues (especially cartilage, elastic, and collagen, e.g., sclera) and forms a melanin-like substance. II. Characterized by: A. Homogentistic acid in the urine, which oxidizes on standing to produce a dark, melanin-like product. B. Ochronosis, which is a blue-black pigmentation of connective tissue.

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CHAPTER 8  Cornea and Sclera

TABLE 8.15  Classification of Osteogenesis Imperfecta (OI) Name

Type

Pattern of Inheritance

Non-deforming form

Type 1

AD

Perinatal lethal form

Type 2

AD, AR

Progressively deforming form

Type 3

AD, AR

Locus or Gene

Protein

COL1A1 COL1A2 COL1A1 COL1A2 CRTAP LEPRE1 PPIB COL1A1 COL1A2 CRTAP LEPRE1 PPIB SERPINH1

α1 chain of type 1 collagen α2 chain of type 1 collagen α1 chain of type 1 collagen α2 chain of type 1 collagen Cartilage-associated protein Prolyl 3-hydroxylase 1 Cyclophilin B α1 chain of type 1 collagen α2 chain of type 1 collagen Cartilage-associated protein Prolyl 3-hydroxylase 1 Cyclophilin B Heat-shock protein 47

BMP1

Bone morphogenetic protein 1

FKBP10 PLOD2 SERPINF1 SP7 WNT1 TMEM38B

Peptidyl prolyl isomerase FKBP65 Lysyl hydroxylase 2 Pigment epithelium-derived factor Osterix Wingless family member 1 Trimeric intracellular cation channel subtype B cAMP response element-binding protein 3-like 1 Protein-component of the COPII complex α1 chain of type 1 collagen α2 chain of type 1 collagen Cartilage-associated protein Cyclophilin B Peptidyl prolyl isomerase FKBP65 Pigment epithelium-derived factor Wingless family member 1 Osterix Bone-restricted IFITM-like protein

CREB3L1 SEC24D Moderate form

With calcification of the interosseous membranes and/or hypertrophic callus

Type 4

Type 5

AD, AR

AD

COL1A1 COL1A2 CRTAP PPIB FKBP10 SERPINF1 WNT1 SP7 IFITM5

Protein Function

Hydroxylation of proline in the α1 and α2 chains

Hydroxylation of proline in the α1 and α2 chains

Assembly and stability of the triple helix of collagen Cleavage of the collagen C-terminal domain of procollagen Crosslinking of collagen chains Bone mineralization Osteoblast differentiation Osteoblast differentiation and function Intracellular calcium release Regulation of the expression of COL1A1 Regulation of the secretion of matrix proteins Export of procollagen from the endoplasmic reticulum

Hydroxylation of proline in the α1 and α2 chains Crosslinking of collagen chains Bone mineralization Osteoblast differentiation and function Osteoblast differentiation Bone mineralization

AD, autosomal dominant; AR, autosomal recessive. (From Tournis & Dede: Osteogenesis imperfecta – A clinical update. Metabolism 80:27–37, 2018. Table 1. Elsevier.)



C. Arthritis, which can mimic ankylosing spondylitis in its large-joint distribution. D. Other findings are renal stone formation and cardiac valvulopathy. III. Ocular findings A. Ocular signs on average begin around age 41. B. The most common sign is symmetric brown scleral pigment, which is present in approximately 83% of cases. C. Brown pigment spots resembling oil droplets are said to be pathognomonic and are found in 75% of patients. D. Conjunctival vermiform pigment deposits or increased conjunctival vessel diameter are seen frequently.



E. Hyperpigmentation of the anterior chamber angle may be accompanied by increased intraocular pressure. F. Rapidly progressive astigmatism secondary to corneoscleral pigment accumulation may occur. IV. The condition is inherited as an autosomal-recessive trait and is caused by mutations in the homogentisate 1,2-dioxygenase gene located to a 16-cM region of the 3q21–q23 chromosome. The enzyme converts homogentisic acid to maleylacetoacetic acid in the tyrosine degradation pathway. V. Histology: A. Amorphous strands and curlicues are seen in the sclera and overlying the substantia propria of the conjunctiva.

Inflammations



B. The central cornea is clear, although there may be pigment phagocytosis by corneal endothelial cells. C. The limbal “oil droplets” consist of globular accretions adjoining Bowman’s membrane or infiltrating the anterior stroma. D. All parts of the sclera may contain pigment granules, but the heaviest deposits extend from the rectus muscle insertions to the pars plana. 1. Pigment may be extracellular or intracellular in macrophages or fibrocytes. 2. Collagen fiber degeneration is most prominent in the areas of heaviest pigmentation. VI. Confocal microscopy has demonstrated hyper-reflective crystalline deposits at the level of Descemet’s membrane forming an acellular band. A. Scattered microdeposits were seen as arborizing lines between epithelium and the anterior stroma. B. The other corneal layers did not appear to be involved. VII. “Exogenous ochronosis” refers to pigmentation similar to ochronosis, but is believed to be secondary to prolonged use of topical agents such as hydroquinone, resorcinol, phenol, mercury, and/or picric acid. A. Histopathologic examination reveals stout, sharply defined ochre-colored fibers in the papillary and superficial reticular dermis, which have a distinct shape for which they have been termed “banana bodies.” 1. Basophilia is present in the collagen fibers of the upper dermis. 2. There is homogenization and swelling of the collagen bundles. 3. Altered texture and arrangement of the elastic fibers in the dermis resembles solar elastosis.

data are derived from a referral practice or from a more general patient base.

Episcleritis I. Episcleritis (Fig. 8.70) involves one eye two-thirds of the time, and is characterized by redness of the eye and discomfort, rarely described as pain. A. Hyperemia, edema, and infiltration are entirely within the episcleral tissue; the sclera is spared. B. The episcleral vascular network is congested maximally, with some congestion of the conjunctival vessels and minimal congestion of the scleral vessels. C. Episcleritis usually is a benign recurring condition. Episcleritis usually resolves without treatment in 2 to 21 days. Episcleritis does not progress to scleritis except in herpes zoster, which sometimes starts as an episcleritis and shows the vesicular stage of the eruption. It reappears approximately 3 months later as a scleritis in the same site.



D. No clear conclusions can be drawn as to the cause of episcleritis. E. It is more common in women. F. Episcleritis may be associated with glaucoma, although this association has been questioned. G. In patients with systemic necrotizing vasculitis, episcleritis was present in 3%. It has accompanied Sweet syndrome.



Although usually idiopathic, approximately one-third of the cases of episcleritis may be associated with systemic entities such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, relapsing polychondritis, and systemic vasculitic diseases (e.g., Wegener’s granulomatosis and Cogan’s syndrome); or with local eye diseases such as ocular rosacea, keratoconjunctivitis sicca, and atopic keratoconjunctivitis. It has been reported as part of a poststreptococcal syndrome.

INFLAMMATIONS Imaging techniques such as anterior segment OCT may be helpful in the diagnosis and monitoring of episcleritis and scleritis. The incidence of ocular complications from episcleritis and scleritis appear to differ greatly depending upon whether the

A

351

B Fig. 8.70  Episcleritis. A, Clinical appearance. B, Biopsy of conjunctiva shows infiltration with lymphocytes and plasma cells.

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CHAPTER 8  Cornea and Sclera

II. Classification Classically, episcleritis has been divided into simple and nodular. A. Simple episcleritis 1. Redness caused by engorged episcleral vessels that retain their normal radial position and architecture. In episcleritis, after local instillation of 2.5% phenylephrine, the redness usually mostly disappears, whereas in scleritis, the redness persists.

2. Diffuse edema. 3. Sometimes small gray deposits. B. Nodular episcleritis 1. Localized redness and edema. 2. An intraepiscleral nodule that is mobile on the underlying sclera. III. Histologically, chronic nongranulomatous inflammation of lymphocytes, plasma cells, and edema is found in the episcleral tissue. Rarely, a chronic granulomatous inflammatory infiltrate may be seen.

Scleritis (Fig. 8.71) Introduction Classically scleritis is divided into anterior scleritis, either diffuse, nodular, or necrotizing, and posterior scleritis, either diffuse

A

or nodular. More recently, this classification has been modified and scleritis has been further divided into diffuse scleritis; non-necrotizing and necrotizing forms of nodular scleritis; and vaso-occlusive, surgically induced necrotizing scleritis (SINS), granulomatous, and scleromalacia varieties of necrotizing scleritis. It has been postulated that necrotizing scleritis and diffuse and nodular scleritis not only have different clinical courses, but also have different pathogenesis. In the latter regard non-necrotizing scleritis is considered to be the result of an autoimmune response while necrotizing scleritis is the complication of a preexisting systemic immune-mediated systemic disease and associated vasculitis. The pain secondary to scleritis typically is described as insidious in onset, boring in nature, and retrobulbar in location, although it may radiate to the forehead and temporal region. It usually is worse at night. I. Anterior scleritis A. Diffuse (most benign and most common form) 1. Diffuse anterior scleritis in women is most common in the fourth to seventh decades, with no predilection for any of those decades, whereas in men it is most prevalent in the third to sixth decades and peaks during the fourth. 2. Conjunctival sensation may be decreased in areas of previous scleritis, and more diffusely in herpetic scleritis even in areas that did not have previous active inflammation.

B

r

s

gr

C

D

sc

Fig. 8.71  Scleritis. Scleritis can go on to (A) thickening (brawny scleritis) and (B) necrosis. C, Healing of the necrotic area leads to scleromalacia perforans. D, Histologic section shows a zonal granulomatous reaction (gr) around necrotic scleral collagen (sc) (r, retina; s, sclera). (D, Presented by Dr. IW McLean to the meeting of the Armed Forces Institute of Pathology alumni, 1973.)

Inflammations

Rarely, mucosal-associated lymphoid tissue (MALT) lymphoma can present as a scleritis.







3. Approximately half of the patients have bilateral involvement. 4. Up to 42% of patients who have scleritis have an associated uveitis. 5. Diffuse anterior scleritis is one of the very few severely painful eye conditions. 6. As in all forms of scleritis, scleral edema and inflammation are present. a. The diagnostic features differentiating it from episcleritis are the outward displacement of the deep vascular network of the episclera and the typical blue-red color. b. A small area or the whole anterior segment may be involved. 7. There may be stromal keratitis. B. Nodular 1. Nodular anterior scleritis is most prevalent in both women and men from the fourth to sixth decades, but in women a noticeable peak occurs in the sixth decade. Nodular scleritis can be considered of intermediate severity between diffuse and necrotizing disease.

2. Approximately half of the patients have bilateral involvement. 3. The pain is as described in diffuse anterior scleritis. 4. The nodule, unlike the one in nodular episcleritis, is deep red, totally immobile, and quite separate from the overlying congested episcleral tissues. Rarely, biopsy of such nodule may be diagnostic of sarcoidosis. Latent syphilis also has presented as anterior nodular scleritis.





C. Necrotizing—with inflammation (most severe form of scleritis) 1. Necrotizing anterior scleritis with inflammation mostly occurs in women. 2. Approximately half of the patients have bilateral involvement. 3. The pain is as described for the diffuse form except that it is the most severe type of ocular pain. 4. It is the most destructive form of scleritis, with over 60% of eyes experiencing complications other than scleral thinning and 40% losing visual acuity. a. The patients may present with severe edema and acute congestion (brawny scleritis) or a patch of avascular episcleral tissue overlying or adjacent to an area of scleral edema.



353

b. In some cases, the inflammation remains localized to one small area and may result in almost total loss of scleral tissue from that area. c. Most often, the inflammation starts in one area and then spreads circumferentially around the globe until the whole of the anterior segment is involved. 5. Often severe corneal involvement. 6. Necrotizing scleritis is associated with systemic disease, particularly vasculitis or autoimmune diseases associated with vasculitis. D. Necrotizing—without inflammation (scleromalacia perforans) 1. Necrotizing anterior scleritis without inflammation mostly afflicts women. 2. Approximately half of the patients have bilateral involvement. 3. Patients rarely complain of pain in scleromalacia perforans and present without subjective symptoms. 4. A grayish or yellowish patch on the sclera, without inflammation, may progress to complete dissolution of sclera and episclera, covered by a thin layer of conjunctiva. 5. It is an obliterative endarteritis of the scleral arterioles. a. Vasculitic process associated with rheumatoid arthritis. II. Posterior scleritis A. Posterior scleritis and anterior scleritis are usually associated, and occur most frequently in women in their sixth decade. B. Over 70% are women, and 16% have bilateral disease. C. Most cases are idiopathic (62%); however, rheumatoid polyarteritis, systemic lupus erythematosus and pANCA(+) systemic vasculitis are the most frequently associated systemic diseases and occur at a higher rate in individuals over 50 years of age. 60% have a systemic disorder accompanied by vasculitis. D. There is a recurrence rate of 37%. E. Most patients have unilateral involvement. F. The pain is as described for diffuse anterior scleritis. G. Proptosis, exudative detachment, and other fundus changes such as optic disc edema may be seen in addition to anterior scleritis. Optic nerve swelling is a common fundus finding (45%) followed by serous retinal detachment (39%), macular edema (27%), subretinal mass (17%), ring choroidal detachment (14%), intraretinal deposits (13%), choroidal folds (11%), pigment epithelial detachment (8%), and subretinal discoloration (6%) (percentages are rounded to nearest whole number). H. Posterior scleritis in a nodular configuration may simulate choroidal neoplasm. I. Histopathology 1. Chronic inflammation comprised of lymphocytes and plasma cells, macrophages, and occasionally giant cells. 2. Active scleral vasculitis frequently is seen.

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CHAPTER 8  Cornea and Sclera

3. “Onion skin” vascular thickening as evidence of previous vasculitis may be seen. 4. Smudging and loss of polarization of collagen also may be seen. 5. Choroidal vasculitis is common. 6. Subretinal exudate may accompany scleral vasculitis. 7. Retinal vasculitis is lacking. 8. There may be focal loss of retinal pigment epithelium with inflammation in areas in continuity with underlying choroiditis can scleritis. J. Newer imaging techniques have led to an increasing diagnosis of posterior scleritis. Imaging techniques can help differentiate diffuse from nodular presentations. Bilateral posterior scleritis has accompanied cytomegalic virus infection.

III. Complications (see comment at the beginning of this section on the variability of the rates of apparent complications depending on the nature of the practice from which the data are derived) A. A decrease in visual acuity (14%) may result from keratitis, cataract, anterior uveitis, or posterior uveitis. B. Keratitis (29%) 1. Diffuse anterior scleritis a. Localized stromal keratitis b. Localized sclerosing keratitis 2. Nodular anterior scleritis a. Acute stromal keratitis b. Sclerosing keratitis c. Corneal gutter 3. Necrotizing scleritis a. Sclerosing keratitis b. Keratolysis C. Corneal vascularization (9%) D. Cataract (7%)



E. Uveitis (30%) F. Glaucoma (12%) G. Scleral thinning and scleral defects (perforation of the globe is rare except after subconjunctival steroid injection) 1. Spontaneous rupture of a posterior staphyloma has been reported. IV. Associated systemic diseases Table 8.16 presents the most common systemic disease associations with scleritis. A. Almost half of the patients with scleritis have a known associated systemic disease, approximately 15% of which represent connective tissue diseases. Almost 80% of the associated systemic diseases are known prior to the onset of the initial scleritis. Scleromalacia perforans is associated with longstanding rheumatoid arthritis in approximately 46% of patients. The connective tissue diseases are most prevalent in necrotizing anterior scleritis with inflammation. Twenty-one percent of patients with necrotizing anterior scleritis with inflammation, which is probably the malignant phase of systemic connective tissue disease, die within 8 years of diagnosis.





B. Other associated systemic diseases include hypersensitivity disorders (e.g., erythema nodosum, asthma, erythema multiforme, contact dermatitis, Wegener’s granulomatosis [granulomatosis with polyangiitis]; Fig. 8.72, and see Chapter 6), polychondritis, Goodpasture’s syndrome, granulomatous conditions (e.g., tuberculosis, syphilis), viral and bacterial infection (e.g., herpes zoster, HSV, Pseudomonas), porphyria, and metabolic disorders (e.g., gout). C. Systemic diseases, such as leukemia, may mimic scleritis.

TABLE 8.16  The Most Common Systemic Disease Associations of Scleritis Disease

Key Points

Rheumatoid arthritis (RA)

Features: Symmetrical arthritis including hands, skin nodules, anemia, pericarditis, fibrosing alveolitis, peripheral neuropathy Frequency: 17%–33% of all patients with scleritis have RA; 0.2%–6.3% of patients with RA have scleritis Helpful investigations: Rheumatoid factor positive in 60%–80% of RA patients; joint X-rays with osteopenia and erosions Features: Epistaxis, sinusitis, hemoptysis; ocular involvement in 50%; may involve orbit but necrotizing scleritis in 79% with peripheral ulcerative keratitis (50%) Helpful investigations: Serum c-ANCA is highly specific; tissue biopsy shows vasculitis and necrotizing granuloma Features: Pain or swelling of ear pinnae, tracheal inflammation (in 25% with hoarse voice, cough, stridor, expiratory wheeze), collapsed nasal bridge, hearing loss, cardiac valve dysfunction, polyarthritis Helpful investigations: Raised ESR, 30% of patients have co-existing autoimmune disease, biopsy of auricular cartilage Features: Malar rash, skin photosensitivity, peripheral arthritis, pleuritis, pericarditis, seizures Helpful investigations: ANA positive or extractable nuclear antigen (Ro) positive; high anti-ds DNA title (present in 30%–50%), proteinuria or casts, anemia, leukopenia or thrombocytopenia Features: Scleritis, ulcerative keratitis, uveitis, retinal vasculitis, pseudotumor, myalgia, weight loss, fever, arthralgia, purpura, livedo reticularis, neuropathy, hypertension, nephropathy Helpful investigations: Multiple aneurysms of either the mesenteric, hepatic, or renal systems on angiography; muscle or sural nerve biopsy may be definitive

Wegener’s granulomatosis

Relapsing polychondritis

Systemic lupus erythematosus

Polyarteritis nodosa

(From Okhravi N, Odufuwa B, McCluskey P et al.: Scleritis. Surv Ophthalmol 50(4):351, 2005.)

Tumors

A

B

C

D

355

Fig. 8.72  Limited Wegener’s granulomatosis (granulomatosis with polyangiitis). A, Recurrent swelling and edema of the upper lids present for approximately two months. B, Magnetic resonance imaging scan shows bilateral lacrimal gland masses. Antineutrophilic cytoplasmic antibody test was positive. Biopsy was performed. C, Histologic section shows a necrotizing granulomatous reaction with epithelioid cells and inflammatory giant cells along with eosinophils and necrotic foci containing neutrophils. D, Increased magnification of epithelioid cells and inflammatory giant cells. (Case presented by Dr. ME Smith at the meeting of the Verhoeff Society, 1994.)

V. Histology—the basic lesion is a granulomatous inflammation surrounding abnormal scleral collagen. A. Vasculitis with fibrinoid necrosis and neutrophil invasion of the vessel wall are present in 75% of scleral and 52% of conjunctival specimens. Vascular immunodeposits are present in 93% of scleral and 79% of conjunctival specimens. B. In the conjunctiva, there are increased T cells of all types, macrophages, and B cells. C. In the sclera, increased T cells of all types and macrophages are seen. D. Increased HLA-DR expression is markedly increased in both conjunctiva and sclera.

TUMORS

Nodular Fasciitis See discussion of mesenchymal tumors in subsection Primary Orbital Tumors, Chapter 14.

Hemangiomas See discussion of mesenchymal tumors in subsection Primary Orbital Tumors, Chapter 14.

Neurofibromas See discussion of mesenchymal tumors in subsection Primary Orbital Tumors, Chapter 14.

Contiguous Tumors Conjunctival Tumors I. Uveal malignant melanoma

Fibromas

Episcleral Osseous Choristoma and Episcleral Osseocartilaginous Choristoma

See discussion of mesenchymal tumors in subsection Primary Orbital Tumors, Chapter 14.

I. The tumor (Fig. 8.73) is typically present between the lateral and upper recti.

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CHAPTER 8  Cornea and Sclera

B

A

Fig. 8.73  Episcleral osseous choristoma. A, Clinical appearance of surgically exposed tumor in typical superotemporal location. B, Histologic section shows that the tumor is composed of compact bone. C, Polarized light demonstrates subunits consisting of concentric osteon lamellae surrounding a central canal (haversian canal). (Modified from Ortiz JM, Yanoff M: Epipalpebral conjunctival osseous choristoma. Br J Ophthalmol 63:173, 1979, with permission.)

C

II. It is symptomless, is present at birth, and characteristically contains bone. III. Histologically, normal-appearing bone is seen in the abnormal episcleral location. IV. The differential diagnosis includes classical limbal dermoids, epithelial inclusion cysts, prolapsed orbital fat, papillomas, dermolipomas, and complex choristomas. Bone formation occurs through the condensation of mesenchyme in two ways: (1) membranous bone forms from mesenchymal condensation directly without first forming

cartilage (e.g., many skull bones and intraocular ossification); and (2) bone forms from mesenchymal formation of cartilaginous template (e.g., ribs)—both types of bone formation occur in episcleral osseous choristoma and episcleral osseocartilaginous choristoma.

Ectopic Lacrimal Gland See Chapter 14.   References available online at expertconsult.com.

Bibliography

BIBLIOGRAPHY Normal Anatomy Dua HS, Faraj LA, Branch MJ, et al: The collagen matrix of the human trabecular meshwork is an extension of the novel pre-Descemet’s layer (dua’s layer), Br J Ophthalmol 98:691–697, 2014. Dua HS, Faraj LA, Said DG, et al: Human corneal anatomy redefined: a novel pre-Descemet’s layer (dua’s layer), Ophthalmology 120:1778–1785, 2013. McKee HD, Irion LC, Carley FM, et al: Human corneal anatomy redefined: a novel pre-Descemet layer (dua’s layer), Ophthalmology 121:e24–e25, 2014.

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Inflammations: Nonulcerative Detorakis ET: Epidemic adenoviral keratoconjunctivitis complicated by massive bilateral lower eyelid cysts, Ophthal Plast Reconstr Surg 30:82, 2014. Gautam, Jhanji V, Satpathy G, et al: Microsporidial keratitis after collagen cross-linking, Ocul Immunol Inflamm 21:495–497, 2013. Murthy SI, Sangit VA, Rathi VM, et al: Microsporidial spores can cross the intact Descemet membrane in deep stromal infection, Middle East Afr J Ophthalmol 20:80–82, 2013. Pradhan S, Mascarenhas J, Srinivasan M: Microsporidial stromal keratitis masquerading as acute graft rejection, Cornea 34:353–354, 2015. Sun YC, Liou HM, Shen EP, et al: Stem cell factor and thymic stromal lymphopoietin overexpression with correlation to mast cells in superior limbic keratoconjunctivitis, Cornea 34:1487–1492, 2015. Thanathanee O, Athikulwongse R, Anutarapongpan O, et al: Clinical features, risk factors, and treatments of microsporidial epithelial keratitis, Semin Ophthalmol 31:266–270, 2016.

Inflammations: Ulcerative Hamrah P, Cruzat A, Dastjerdi MH, et al: Unilateral herpes zoster ophthalmicus results in bilateral corneal nerve alteration: an in vivo confocal microscopy study, Ophthalmology 120:40–47, 2013. Hamrah P, Sahin A, Dastjerdi MH, et al: Cellular changes of the corneal epithelium and stroma in herpes simplex keratitis: an in vivo confocal microscopy study, Ophthalmology 119:1791–1797, 2012. Kaye S: Herpes simplex keratitis: bilateral effects, Invest Ophthalmol Vis Sci 56:4907, 2015. Liu Z, Zhang P, Liu C, et al: Split of Descemet’s membrane and pre-Descemet’s layer in fungal keratitis: new definition of corneal anatomy incorporating new knowledge of fungal infection, Histopathology 66:1046–1049, 2015. Muller RT, Pourmirzaie R, Pavan-Langston D, et al: In vivo confocal microscopy demonstrates bilateral loss of endothelial cells in unilateral herpes simplex keratitis, Invest Ophthalmol Vis Sci 56:4899–4906, 2015.

Degenerations: Epithelial Achtsidis V, Eleftheriadou I, Kozanidou E, et al: Dry eye syndrome in subjects with diabetes and association with neuropathy, Diabetes Care 37:e210–e211, 2014. DeMill DL, Hussain M, Pop-Busui R: Shtein RM: ocular surface disease in patients with diabetic peripheral neuropathy, Br J Ophthalmol 100:924–928, 2016. Diez-Feijoo E, Duran JA: Optical coherence tomography findings in recurrent corneal erosion syndrome, Cornea 34:290–295, 2015. Labbe A, Liang Q, Wang Z, et al: Corneal nerve structure and function in patients with non-Sjogren dry eye: clinical correlations, Invest Ophthalmol Vis Sci 54:5144–5150, 2013. Manaviat MR, Rashidi M, Afkhami-Ardekani M, et al: Prevalence of dry eye syndrome and diabetic retinopathy in type 2 diabetic patients, BMC Ophthalmol 8:10, 2008. Villani E, Magnani F, Viola F, et al: In vivo confocal evaluation of the ocular surface morpho-functional unit in dry eye, Optom Vis Sci 90:576–586, 2013.

Degenerations: Stromal Belliveau MJ, Liao WN, Brownstein S, et al: Myxomatous corneal degeneration: a clinicopathological study of six cases and a review of the literature, Surv Ophthalmol 57:264–271, 2012. Das P, Gokani A, Bagchi K, et al: Limbal epithelial stem-microenvironmental alteration leads to pterygium development, Mol Cell Biochem 402:123–139, 2015. Fox T, Gotlinger KH, Dunn MW, et al: Dysregulated heme oxygenase-ferritin system in pterygium pathogenesis, Cornea 32:1276–1282, 2013. Julio G, Lluch S, Pujol P, et al: Tear osmolarity and ocular changes in pterygium, Cornea 31:1417–1421, 2012. Maharana PK, Sharma N, Das S, et al: Salzmann’s nodular degeneration, Ocul Surf 14:20–30, 2016. Molho-Pessach V, Mechoulam H, Siam R, et al: Ophthalmologic findings in H syndrome: a unique diagnostic clue, Ophthalmic Genet 36:365–368, 2015. Notara M, Refaian N, Braun G, et al: Short-term UVB-irradiation leads to putative limbal stem cell damage and niche cell-mediated upregulation of macrophage recruiting cytokines, Stem Cell Res 15:643–654, 2015. Rousseau A, Cauquil C, Dupas B, et al: Potential role of in vivo confocal microscopy for imaging corneal nerves in transthyretin

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Dystrophies: Introduction and Classification Abreu EB, Novaes GA, Fernandes BF, et al: Corneal stromal dystrophies: a clinical pathologic study, Arq Bras Oftalmol 75:390–393, 2012. Alzuhairy S, Alkatan HM, Al-Rajhi AA: Prevalence and histopathological characteristics of corneal stromal dystrophies in Saudi Arabia, Middle East Afr J Ophthalmol 22:179–185, 2015. Szalai E, Felszeghy S, Hegyi Z, et al: Fibrillin-2, tenascin-c, matrilin-2, and matrilin-4 are strongly expressed in the epithelium of human granular and lattice type I corneal dystrophies, Mol Vis 18:1927–1936, 2012. Weiss JS, Moller HU, Aldave AJ, et al: IC3d classification of corneal dystrophies–edition 2, Cornea 34:117–159, 2015.

Dystrophies: Epithelial-Stromal Including TGFB1 Corneal Dystrophies Cabral-Macias J, Zenteno JC, Ramirez-Miranda A, et al: Familial gelatinous drop-like corneal dystrophy caused by a novel nonsense TACSTD2 mutation, Cornea 35:987–990, 2016. Cao W, Yan M, Hao Q, et al: Autosomal-dominant meesmann epithelial corneal dystrophy without an exon mutation in the keratin-3 or keratin-12 gene in a Chinese family, J Int Med Res 41:511–518, 2013. Chen JL, Lin BR, Gee KM, et al: Identification of presumed pathogenic KRT3 and KRT12 gene mutations associated with meesmann corneal dystrophy, Mol Vis 21:1378–1386, 2015. Courtney DG, Poulsen ET, Kennedy S, et al: Protein composition of TGFBI-r124c- and TGFBI-r555w-associated aggregates suggests multiple mechanisms leading to lattice and granular corneal dystrophy, Invest Ophthalmol Vis Sci 56:4653–4661, 2015. El Sanharawi M, Sandali O, Basli E, et al: Fourier-domain optical coherence tomography imaging in corneal epithelial basement membrane dystrophy: a structural analysis, Am J Ophthalmol 159:755–763, 2015.

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exclusion of coding region mutations in KERA, LUM, DCN, and EPYC, Invest Ophthalmol Vis Sci 51:4006–4012, 2010. Arnold-Worner N, Goldblum D, Miserez AR, et al: Clinical and pathological features of a non-crystalline form of Schnyder corneal dystrophy, Graefes Arch Clin Exp Ophthalmol 250:1241–1243, 2012. Carstens N, Williams S, Goolam S, et al: Novel mutation in the CHST6 gene causes macular corneal dystrophy in a black South African family, BMC Med Genet 17:47, 2016. Gee JA, Frausto RF, Chung DW, et al: Identification of novel PIKFYVE gene mutations associated with fleck corneal dystrophy, Mol Vis 21:1093–1100, 2015. Hung C, Ayabe RI, Wang C, et al: Pre-Descemet corneal dystrophy and x-linked ichthyosis associated with deletion of xp22.31 containing the STS gene, Cornea 32:1283–1287, 2013. Jing Y, Kumar PR, Zhu L, et al: Novel decorin mutation in a Chinese family with congenital stromal corneal dystrophy, Cornea 33:288–293, 2014. Kamma-Lorger CS, Pinali C, Martinez JC, et al: Role of decorin core protein in collagen organisation in congenital stromal corneal dystrophy (CSCD), PLoS ONE 11:e0147948, 2016. Kawasaki S, Yamasaki K, Nakagawa H, et al: A novel mutation (p.Glu1389AspfsX16) of the phosphoinositide kinase, FYVE finger containing gene found in a Japanese patient with fleck corneal dystrophy, Mol Vis 18:2954–2960, 2012. Kim EK, Lee H, Choi SI: Molecular pathogenesis of corneal dystrophies: Schnyder dystrophy and granular corneal dystrophy type 2, Prog Mol Biol Transl Sci 134:99–115, 2015. Kim MJ, Frausto RF, Rosenwasser GO, et al: Posterior amorphous corneal dystrophy is associated with a deletion of small leucine-rich proteoglycans on chromosome 12, PLoS ONE 9:e95037, 2014. Malhotra C, Jain AK, Dwivedi S, et al: Characteristics of Pre-Descemet membrane corneal dystrophy by three different imaging modalities-in vivo confocal microscopy, anterior segment optical coherence tomography, and Scheimpflug corneal densitometry analysis, Cornea 34:829–832, 2015. Nickerson ML, Bosley AD, Weiss JS, et al: The UBIAD1 prenyltransferase links menaquinone-4 [corrected] synthesis to cholesterol metabolic enzymes, Hum Mutat 34:317–329, 2013. Nowinska AK, Wylegala E, Teper S, et al: Phenotype and genotype analysis in patients with macular corneal dystrophy, Br J Ophthalmol 98:1514–1521, 2014. Park SH, Ahn YJ, Chae H, et al: Molecular analysis of the CHST6 gene in Korean patients with macular corneal dystrophy: identification of three novel mutations, Mol Vis 21:1201–1209, 2015. Purcell JJ Jr, Krachmer JH, Weingeist TA: Fleck corneal dystrophy, Arch Ophthalmol 95:440–444, 1977. Schumacher MM, Elsabrouty R, Seemann J, et al: The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase, Elife 4:2015. Shi H, Qi XF, Liu TT, et al: In vivo confocal microscopy of pre-Descemet corneal dystrophy associated with x-linked ichthyosis: a case report, BMC Ophthalmol 17:29, 2017. Weiss JS: Schnyder corneal dystrophy, Curr Opin Ophthalmol 20:292–298, 2009. Weiss JS: Visual morbidity in thirty-four families with Schnyder crystalline corneal dystrophy (an American Ophthalmological Society thesis), Trans Am Ophthalmol Soc 105:616–648, 2007.

Dystrophies: Descemet’s Membrane and Endothelial Aldave AJ, Ann LB, Frausto RF, et al: Classification of posterior polymorphous corneal dystrophy as a corneal ectatic disorder following confirmation of associated significant corneal steepening, JAMA Ophthalmol 131:1583–1590, 2013. Aldave AJ, Han J, Frausto RF: Genetics of the corneal endothelial dystrophies: an evidence-based review, Clin Genet 84:109–119, 2013. Bucher F, Adler W, Lehmann HC, et al: Corneal nerve alterations in different stages of Fuchs’ endothelial corneal dystrophy: an in vivo confocal microscopy study, Graefes Arch Clin Exp Ophthalmol 252:1119–1126, 2014. Chung DW, Frausto RF, Chiu S, et al: Investigating the molecular basis of PPCD3: characterization of ZEB1 regulation of COL4a3 expression, Invest Ophthalmol Vis Sci 57:4136–4143, 2016. Cunnusamy K, Bowman CB, Beebe W, et al: Congenital corneal endothelial dystrophies resulting from novel de novo mutations, Cornea 35:281–285, 2016. Czarny P, Kasprzak E, Wielgorski M, et al: DNA damage and repair in Fuchs endothelial corneal dystrophy, Mol Biol Rep 40:2977–2983, 2013. Davidson AE, Liskova P, Evans CJ, et al: Autosomal-dominant corneal endothelial dystrophies CHED1 and PPCD1 are allelic disorders caused by non-coding mutations in the promoter of OVOL2, Am J Hum Genet 98:75–89, 2016. Del Turco C, Pierro L, Querques G, et al: Posterior polymorphous corneal dystrophy concomitant to large colloid drusen, Eur J Ophthalmol 25:177–179, 2015. Du J, Aleff RA, Soragni E, et al: RNA toxicity and missplicing in the common eye disease Fuchs endothelial corneal dystrophy, J Biol Chem 290:5979–5990, 2015. Frausto RF, Wang C, Aldave AJ: Transcriptome analysis of the human corneal endothelium, Invest Ophthalmol Vis Sci 55:7821–7830, 2014. Gattey D, Zhu AY, Stagner A, et al: Fuchs endothelial corneal dystrophy in patients with myotonic dystrophy: a case series, Cornea 33:96–98, 2014. Gendron SP, Theriault M, Proulx S, et al: Restoration of mitochondrial integrity, telomere length, and sensitivity to oxidation by in vitro culture of Fuchs’ endothelial corneal dystrophy cells, Invest Ophthalmol Vis Sci 57:5926–5934, 2016. Hamill CE, Schmedt T, Jurkunas U: Fuchs endothelial cornea dystrophy: a review of the genetics behind disease development, Semin Ophthalmol 28:281–286, 2013. Jalimarada SS, Ogando DG, Bonanno JA: Loss of ion transporters and increased unfolded protein response in Fuchs’ dystrophy, Mol Vis 20:1668–1679, 2014. Jang MS, Roldan AN, Frausto RF, et al: Posterior polymorphous corneal dystrophy 3 is associated with agenesis and hypoplasia of the corpus callosum, Vision Res 100:88–92, 2014. Kao L, Azimov R, Shao XM, et al: Multifunctional ion transport properties of human slc4a11: comparison of the SLC4A11-b and SLC4A11-c variants, Am J Physiol Cell Physiol 311:C820–c830, 2016. Kim JH, Ko JM, Tchah H: Fuchs endothelial corneal dystrophy in a heterozygous carrier of congenital hereditary endothelial dystrophy type 2 with a novel mutation in SLC4a11, Ophthalmic Genet 36:284–286, 2015. Lagrou L, Midgley J, Romanchuk KG: Punctiform and polychromatophilic dominant Pre-Descemet corneal dystrophy, Cornea 35:572–575, 2016.

Bibliography Loganathan SK, Schneider HP, Morgan PE, et al: Functional assessment of SLC4a11, an integral membrane protein mutated in corneal dystrophies, Am J Physiol Cell Physiol 311:C735–c748, 2016. Mootha VV, Hussain I, Cunnusamy K, et al: TCF4 triplet repeat expansion and nuclear RNA foci in Fuchs’ endothelial corneal dystrophy, Invest Ophthalmol Vis Sci 56:2003–2011, 2015. Nielsen E, Nielsen K, Ivarsen A, et al: Fuchs endothelial corneal dystrophy: a systematic immunofluorescence study of collagen type VIII suggests heterogeneous pathophysiology, Cornea 35:872–877, 2016. Nita M, Grzybowski A: The role of the reactive oxygen species and oxidative stress in the pathomechanism of the age-related ocular diseases and other pathologies of the anterior and posterior eye segments in adults, Oxid Med Cell Longev 2016:3164734, 2016. Patel SP, Parker MD: SLC4a11 and the pathophysiology of congenital hereditary endothelial dystrophy, Biomed Res Int 2015:475392, 2015. Roy S, Praneetha DC: Vendra VP: mutations in the corneal endothelial dystrophy-associated gene SLC4a11 render the cells more vulnerable to oxidative insults, Cornea 34:668–674, 2015. Sacchetti M, Macchi I, Tiezzi A, et al: Pathophysiology of corneal dystrophies: from cellular genetic alteration to clinical findings, J Cell Physiol 231:261–269, 2016. Savige J, Sheth S, Leys A, et al: Ocular features in Alport syndrome: pathogenesis and clinical significance, Clin J Am Soc Nephrol 10:703–709, 2015. Schrems-Hoesl LM, Schrems WA, Cruzat A, et al: Cellular and subbasal nerve alterations in early stage Fuchs’ endothelial corneal dystrophy: an in vivo confocal microscopy study, Eye (Lond) 27:42–49, 2013. Shiraishi A, Zheng X, Sakane Y, et al: In vivo confocal microscopic observations of eyes diagnosed with posterior corneal vesicles, Jpn J Ophthalmol 60:425–432, 2016. Siddiqui S, Zenteno JC, Rice A, et al: Congenital hereditary endothelial dystrophy caused by SLC4a11 mutations progresses to Harboyan syndrome, Cornea 33:247–251, 2014. Soliman AZ, Xing C, Radwan SH, et al: Correlation of severity of Fuchs endothelial corneal dystrophy with triplet repeat expansion in TCF4, JAMA Ophthalmol 133:1386–1391, 2015. Stadnikova A, Dudakova L, Skalicka P, et al: Active transforming growth factor-beta2 in the aqueous humor of posterior polymorphous corneal dystrophy patients, PLoS ONE 12:e0175509, 2017. Sundin OH: Genetics of Fuchs corneal dystrophy comes of age: sweet repeats, JAMA Ophthalmol 133:1392, 2015. Vasanth S, Eghrari AO, Gapsis BC, et al: Expansion of CTG18.1 trinucleotide repeat in TCF4 is a potent driver of Fuchs’ corneal dystrophy, Invest Ophthalmol Vis Sci 56:4531–4536, 2015. Wieben ED, Aleff RA, Tang X, et al: Trinucleotide repeat expansion in the transcription factor 4 (TCF4) gene leads to widespread mRNA splicing changes in Fuchs’ endothelial corneal dystrophy, Invest Ophthalmol Vis Sci 58:343–352, 2017. Xia D, Zhang S, Nielsen E, et al: The ultrastructures and mechanical properties of the Descement’s membrane in Fuchs endothelial corneal dystrophy, Sci Rep 6:23096, 2016. Zhang X, Igo RP Jr, Fondran J, et al: Association of smoking and other risk factors with Fuchs’ endothelial corneal dystrophy severity and corneal thickness, Invest Ophthalmol Vis Sci 54:5829–5835, 2013.

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Zhu AY, Eberhart CG, Jun AS: Fuchs endothelial corneal dystrophy: a neurodegenerative disorder? JAMA Ophthalmol 132:377–378, 2014.

Heredofamilial Abrahamov A, Elstein D, Gross-Tsur V, et al: Gaucher’s disease variant characterised by progressive calcification of heart valves and unique genotype, Lancet 346:1000–1003, 1995. Ahmed TY, Turnbull AM, Attridge NF, et al: Anterior segment OCT imaging in mucopolysaccharidoses type I, II, and VI, Eye (Lond) 28:327–336, 2014. Alp A, Akdam H: Vortex keratopathy: fabry related or amiodarone induced? Am J Cardiol 116:826, 2015. Aragona P, Wylegala E, Wroblewska-Czajka E, et al: Clinical, confocal, and morphological investigations on the cornea in human mucopolysaccharidosis IH-s, Cornea 33:35–42, 2014. Ashworth J, Flaherty M, Pitz S, et al: Assessment and diagnosis of suspected glaucoma in patients with mucopolysaccharidosis, Acta Ophthalmol 93:e111–e117, 2015. Cindik N, Ozcay F, Suren D, et al: Gaucher disease with communicating hydrocephalus and cardiac involvement, Clin Cardiol 33:E26–E30, 2010. Ganesh A, Bruwer Z, Al-Thihli K: An update on ocular involvement in mucopolysaccharidoses, Curr Opin Ophthalmol 24:379–388, 2013. Geens S, Kestelyn P, Claerhout I: Corneal manifestations and in vivo confocal microscopy of Gaucher disease, Cornea 32:e169–e172, 2013. Guemes A, Kosmorsky GS, Moodie DS, et al: Corneal opacities in Gaucher disease, Am J Ophthalmol 126:833–835, 1998. Hoffman HN, Fredrickson DS: Tangier disease (familial high density lipoprotein deficiency). Clinical and genetic features in two adults, Am J Med 39:582–593, 1965. Hogarth V, Hughes D, Orteu CH: Pseudoacromegalic facial features in Fabry disease, Clin Exp Dermatol 38:137–139, 2013. Horner ME, Abramson AK, Warren RB, et al: The spectrum of oculocutaneous disease: part I. Infectious, inflammatory, and genetic causes of oculocutaneous disease, J Am Acad Dermatol 70:795, e1–25, 2014. Javed A, Aslam T, Jones SA, et al: Objective quantification of changes in corneal clouding over time in patients with mucopolysaccharidosis, Invest Ophthalmol Vis Sci 58:954–958, 2017. Kalkum G, Pitz S, Karabul N, et al: Paediatric Fabry disease: prognostic significance of ocular changes for disease severity, BMC Ophthalmol 16:202, 2016. Koster H, Savoldelli M, Dumon MF, et al: A fish-eye disease-like familial condition with massive corneal clouding and dyslipoproteinemia. Report of clinical, histologic, electron microscopic, and biochemical features, Cornea 11:452–464, 1992. Liang H, Baudouin C, Tahiri Joutei Hassani R, et al: Photophobia and corneal crystal density in nephropathic cystinosis: an in vivo confocal microscopy and anterior-segment optical coherence tomography study, Invest Ophthalmol Vis Sci 56:3218–3225, 2015. Lisch W, Wasielica-Poslednik J, Kivela T, et al: The hematologic definition of monoclonal gammopathy of undetermined significance in relation to paraproteinemic keratopathy (an American Ophthalmological Society thesis), Trans Am Ophthalmol Soc 114:T7, 2016. Mahapatra HS, Ramanarayanan S, Gupta A, et al: Co-existence of classic familial lecithin-cholesterol acyl transferase deficiency and

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fish eye disease in the same family, Indian J Nephrol 25:362–365, 2015. Pitz S, Kalkum G, Arash L, et al: Ocular signs correlate well with disease severity and genotype in Fabry disease, PLoS ONE 10:e0120814, 2015. Rader DJ: deGoma EM: approach to the patient with extremely low HDL-cholesterol, J Clin Endocrinol Metab 97:3399–3407, 2012. Saraclar M, Atalay S, Kocak N, et al: Gaucher’s disease with mitral and aortic involvement: echocardiographic findings, Pediatr Cardiol 13:56–58, 1992. Schaefer EJ, Anthanont P, Diffenderfer MR, et al: Diagnosis and treatment of high density lipoprotein deficiency, Prog Cardiovasc Dis 59:97–106, 2016. Shah S, Espana EM, Margo CE: Ocular manifestations of monoclonal copper-binding immunoglobulin, Surv Ophthalmol 59:115–123, 2014. Sivley MD: Fabry disease: a review of ophthalmic and systemic manifestations, Optom Vis Sci 90:e63–e78, 2013. Uyama E, Takahashi K, Owada M, et al: Hydrocephalus, corneal opacities, deafness, valvular heart disease, deformed toes and leptomeningeal fibrous thickening in adult siblings: a new syndrome associated with beta-glucocerebrosidase deficiency and a mosaic population of storage cells, Acta Neurol Scand 86:407–420, 1992. von Eckardstein A: Differential diagnosis of familial high density lipoprotein deficiency syndromes, Atherosclerosis 186:231–239, 2006. Wasielica-Poslednik J, Butsch C, Lampe C, et al: Comparison of rebound tonometry, Perkins applanation tonometry and ocular response analyser in mucopolysaccharidosis patients, PLoS ONE 10:e0133586, 2015. Winder AF, Alexander R, Garner A, et al: The pathology of cornea in tangier disease (familial high density lipoprotein deficiency), J Clin Pathol 49:407–410, 1996. Yuan C, Bothun ED, Hardten DR, et al: A novel explanation of corneal clouding in a bone marrow transplant-treated patient with Hurler syndrome, Exp Eye Res 148:83–89, 2016. Zampetti A, Gnarra M, Borsini W, et al: Vascular endothelial growth factor (VEGF-a) in fabry disease: association with cutaneous and systemic manifestations with vascular involvement, Cytokine 61:933–939, 2013.

Nonheredofamial Dystrophy-Like Syndromes Chen S, Mienaltowski MJ, Birk DE: Regulation of corneal stroma extracellular matrix assembly, Exp Eye Res 133:69–80, 2015. Galvis V, Sherwin T, Tello A, et al: Keratoconus: an inflammatory disorder? Eye (Lond) 29:843–859, 2015. Ghosh A, Zhou L, Ghosh A, et al: Proteomic and gene expression patterns of keratoconus, Indian J Ophthalmol 61:389–391, 2013. Gordon-Shaag A, Millodot M, Shneor E, et al: The genetic and environmental factors for keratoconus, Biomed Res Int 795738:2015, 2015. Ionescu C, Corbu CG, Tanase C, et al: Inflammatory biomarkers profile as microenvironmental expression in keratoconus, Dis Markers 1243819:2016, 2016. Jeyabalan N, Shetty R, Ghosh A, et al: Genetic and genomic perspective to understand the molecular pathogenesis of keratoconus, Indian J Ophthalmol 61:384–388, 2013. Joshi SA, Uppapalli S, More P, et al: Unusual case of globe perforation: the brittle cornea without systemic manifestations, BMJ Case Rep 2016:2016.

Karolak JA, Gajecka M: genomic strategies to understand causes of keratoconus, Mol Genet Genomics 292:251–269, 2017. Khaled ML, Helwa I, Drewry M, et al: Molecular and histopathological changes associated with keratoconus, Biomed Res Int 7803029:2017, 2017. McMonnies CW: Epigenetic mechanisms might help explain environmental contributions to the pathogenesis of keratoconus, Eye Contact Lens 40:371–375, 2014. Meghpara B, Nakamura H, Vemuganti GK, et al: Histopathologic and immunohistochemical studies of keratoglobus, Arch Ophthalmol 127:1029–1035, 2009. Micheal S, Khan MI, Islam F, et al: Identification of mutations in the PRDM5 gene in brittle cornea syndrome, Cornea 35:853–859, 2016. Porter LF, Gallego-Pinazo R, Keeling CL, et al: Bruch’s membrane abnormalities in PRDM5-related brittle cornea syndrome, Orphanet J Rare Dis 10:145, 2015. Puy P, Stoica BT, Alejandre N, et al: Temporal pellucid marginal degeneration displaying high “with-the-rule” astigmatism, Can J Ophthalmol 48:e142–e144, 2013. Rabinowitz YS: Keratoconus. [review] [164 refs], Surv Ophthalmol 42:297–319, 1998. Rathi VM, Murthy SI, Bagga B, et al: Keratoglobus: an experience at a tertiary eye care center in India, Indian J Ophthalmol 63:233–238, 2015. Rohrbach M, Spencer HL, Porter LF, et al: ZNF469 frequently mutated in the brittle cornea syndrome (BCS) is a single exon gene possibly regulating the expression of several extracellular matrix components, Mol Genet Metab 109:289–295, 2013. Shajari M, Eberhardt E, Muller M, et al: Effects of atopic syndrome on keratoconus, Cornea 35:1416–1420, 2016. Shimazaki J, Maeda N, Hieda O, et al: National survey of pellucid marginal corneal degeneration in Japan, Jpn J Ophthalmol 60:341–348, 2016. Solomon A: Corneal complications of vernal keratoconjunctivitis, Curr Opin Allergy Clin Immunol 15:489–494, 2015. Spadea L, Salvatore S, Vingolo EM: Corneal sensitivity in keratoconus: a review of the literature, ScientificWorldJournal 2013:683090, 2013. Wallang BS, Das S: Keratoglobus, Eye (Lond) 27:1004–1012, 2013. Wisse RP, Kuiper JJ, Gans R, et al: Cytokine expression in keratoconus and its corneal microenvironment: a systematic review, Ocul Surf 13:272–283, 2015. Wojcik KA, Kaminska A, Blasiak J, et al: Oxidative stress in the pathogenesis of keratoconus and Fuchs endothelial corneal dystrophy, Int J Mol Sci 14:19294–19308, 2013.

Crystals Christakopoulos CE, Prause JU, Heegaard S: Infectious crystalline keratopathy histopathological characteristics, Acta Ophthalmol Scand 81:659–661, 2003. Garcia-Delpech S, Diaz-Llopis M, Udaondo P, et al: Fusarium keratitis 3 weeks after healed corneal cross-linking, J Refract Surg 26:994–995, 2010. Georgiou T, Qureshi SH, Chakrabarty A, et al: Biofilm formation and coccal organisms in infectious crystalline keratopathy, Eye (Lond) 16:89–92, 2002. Gorovoy MS, Stern GA, Hood CI, et al: Intrastromal noninflammatory bacterial colonization of a corneal graft, Arch Ophthalmol 101:1749–1752, 1983.

Bibliography Huerva V, Espinet R, Ascaso FJ: Enterococcal infectious crystalline keratopathy in a wearer bandage contact lens, Eye Contact Lens 38:72, 2012. Kintner JC, Grossniklaus HE, Lass JH, et al: Infectious crystalline keratopathy associated with topical anesthetic abuse, Cornea 9:77–80, 1990. Meisler DM, Langston RH, Naab TJ, et al: Infectious crystalline keratopathy, Am J Ophthalmol 97:337–343, 1984. Mesiwala NK, Chu CT, Raju LV: Infectious crystalline keratopathy predominantly affecting the posterior cornea, Int J Clin Exp Pathol 7:5250–5253, 2014. Sharma N, Vajpayee RB, Pushker N, et al: Infectious crystalline keratopathy, CLAO J 26:40–43, 2000. Shtein RM, Newton DW, Elner VM: Actinomyces infectious crystalline keratopathy, Arch Ophthalmol 129:515–517, 2011. Sridhar MS, Sharma S, Garg P, et al: Epithelial infectious crystalline keratopathy, Am J Ophthalmol 131:255–257, 2001. Tu EY, Joslin CE, Nijm LM, et al: Polymicrobial keratitis: acanthamoeba and infectious crystalline keratopathy, Am J Ophthalmol 148:13–19, e12, 2009.

Congenital Anomalies Azami A, Maleki N: Tavosi z: alkaptonuric ochronosis: a clinical study from Ardabil, Iran, Int J Rheum Dis 17:327–332, 2014. Chowdary S, Mahalingam M, Vashi NA: Reading between the layers: early histopathological findings in exogenous ochronosis, Am J Dermatopathol 36:989–991, 2014. Fratzl-Zelman N, Misof BM, Roschger P, et al: Classification of osteogenesis imperfecta, Wien Med Wochenschr 165:264–270, 2015. Kang H, Aryal ACS, Marini JC: Osteogenesis imperfecta: new genes reveal novel mechanisms in bone dysplasia, Transl Res 181:27–48, 2017. Kocabeyoglu S, Sevim D, Mocan MC, et al: Clinical and in vivo confocal microscopic findings of a patient with ocular ochronosis, Can J Ophthalmol 49:e38–e40, 2014. Lindner M, Bertelmann T: On the ocular findings in ochronosis: a systematic review of literature, BMC Ophthalmol 14:12, 2014. Thomas IH, DiMeglio LA: Advances in the classification and treatment of osteogenesis imperfecta, Curr Osteoporos Rep 14:1–9, 2016. Tournis S, Dede AD: Osteogenesis imperfecta—a clinical update, Metabolism 80:27–37, 2017. Valadares ER, Carneiro TB, Santos PM, et al: What is new in genetics and osteogenesis imperfecta classification? J Pediatr (Rio J) 90:536–541, 2014.

Inflammations Accorinti M, Abbouda A, Gilardi M, et al: Cytomegalovirus-related scleritis, Ocul Immunol Inflamm 21:413–415, 2013.

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Axmann S, Ebneter A, Zinkernagel MS: Imaging of the sclera in patients with scleritis and episcleritis using anterior segment optical coherence tomography, Ocul Immunol Inflamm 24:29–34, 2016. Calthorpe CM, Watson PG, McCartney AC: Posterior scleritis: a clinical and histological survey, Eye (Lond) 2(Pt 3):267–277, 1988. Cunningham ET Jr, McCluskey P, Pavesio C, et al: Scleritis, Ocul Immunol Inflamm 24:2–5, 2016. Doshi RR, Harocopos GJ, Schwab IR, et al: The spectrum of postoperative scleral necrosis, Surv Ophthalmol 58:620–633, 2013. Escott SM, Pyatetsky D: Unilateral nodular scleritis secondary to latent syphilis, Clin Med Res 13:94–95, 2015. Homayounfar G, Borkar DS, Tham VM, et al: Clinical characteristics of scleritis and episcleritis: results from the Pacific Ocular Inflammation study, Ocul Immunol Inflamm 22:403–404, 2014. Honik G, Wong IG, Gritz DC: Incidence and prevalence of episcleritis and scleritis in northern California, Cornea 32:1562–1566, 2013. Karmiris K, Avgerinos A, Tavernaraki A, et al: Prevalence and characteristics of extra-intestinal manifestations in a large cohort of Greek patients with inflammatory bowel disease, J Crohns Colitis 10:429–436, 2016. Katz MS, Chuck RS, Gritz DC: Scleritis and episcleritis, Ophthalmology 119:1715, e1, 2012. Kwok T, Mahmood MN, Salopek TG: Sweet syndrome with panniculitis, arthralgia, episcleritis, and neurologic involvement precipitated by antibiotics, Dermatol Online J 20:2014. Lavric A, Gonzalez-Lopez JJ, Majumder PD, et al: Posterior scleritis: analysis of epidemiology, clinical factors, and risk of recurrence in a cohort of 114 patients, Ocul Immunol Inflamm 24:6–15, 2016. Pikkel J, Chassid O, Srour W, et al: Is episcleritis associated to glaucoma? J Glaucoma 24:669–671, 2015. Sainz de la Maza M, Molina N, Gonzalez-Gonzalez LA, et al: Clinical characteristics of a large cohort of patients with scleritis and episcleritis, Ophthalmology 119:43–50, 2012. Shoughy SS, Jaroudi MO, Kozak I, et al: Optical coherence tomography in the diagnosis of scleritis and episcleritis, Am J Ophthalmol 159:1045–1049, e1041, 2015. Somkijrungroj T, Pimolrat W, Gonzales JA, et al: Conjunctival sensation in scleritis, Ocul Immunol Inflamm 24:24–28, 2016. Wakefield D, Di Girolamo N, Thurau S, et al: Scleritis: immunopathogenesis and molecular basis for therapy, Prog Retin Eye Res 35:44–62, 2013. Watson P, Romano A: The impact of new methods of investigation and treatment on the understanding of the pathology of scleral inflammation, Eye (Lond) 28:915–930, 2014. Watson PG, Hayreh SS, Awdry PN: Episcleritis and scleritis. I, Br J Ophthalmol 52:278–279 contd, 1968. Young N: Poststreptococcal episcleritis, N Z Med J 130:66–67, 2017.

9  Uvea NORMAL ANATOMY I. The uvea is composed of three parts: iris, ciliary body, and choroid (Figs. 9.1 and 9.2). A. The iris is a circular, extremely thin diaphragm separating the anterior or aqueous compartment of the eye into anterior and posterior chambers. 1. The iris can be subdivided from pupil to ciliary body into three zones—pupillary, mid, and root—and from anterior to posterior into four zones—anterior border layer, stroma (the bulk of the iris), partially pigmented anterior pigment epithelium (which contains the dilator muscle in its anterior cytoplasm and pigment in its posterior cytoplasm), and completely pigmented posterior pigment epithelium. 2. The sphincter muscle, neuroectodermally derived like the dilator muscle and pigment epithelium, lies as a ring in the pupillary stroma. B. The ciliary body, contiguous with the iris anteriorly and the choroid posteriorly, is divisible into an anterior ring, the pars plicata (approximately 1.5 mm wide in meridional sections), containing 70–75 meridional folds or processes, and a posterior ring, the pars plana (approximately 3.5–4 mm wide in meridional sections). 1. The ciliary body is wider on the temporal side (approximately 6 mm) than on the nasal side (approximately 5 mm). 2. From the scleral side inward, the ciliary body can be divided into the suprachoroidal (potential) space, the ciliary muscles (an external longitudinal, meridional, or Brücke’s; a middle radial or oblique; and an internal circular or Müller’s), a layer of vessels, the external basement membrane, the outer pigmented and inner nonpigmented ciliary epithelium, and the internal basement membrane. C. The largest part of the uvea, the choroid, extends from the ora serrata to the optic nerve. 1. The choroid nourishes the outer half of the retina through its choriocapillaris and acts as a conduit for major arteries, veins, and nerves. 2. From the scleral side inward, the choroid is divided into the suprachoroidal (potential) space and lamina fusca; the choroidal stroma, which contains uveal melanocytes, fibrocytes, occasional ganglion cells, collagen, blood vessels (outer or Haller’s large vessels and inner or Sattler’s small vessels), and nerves; the

choriocapillaris (the largest-caliber capillaries in the body); and the outer aspect of Bruch’s membrane. 3. The choriocapillaris in the posterior region of the eye has a lobular structure, with each lobule fed by a central arteriole and drained by peripheral venules.

CONGENITAL AND DEVELOPMENTAL DEFECTS Persistent Pupillary Membrane (PPM) I. PPM (Fig. 9.3), a common clinical finding, is caused by incomplete atrophy (resorption) of the anterior lenticular fetal vascular arcades and associated mesodermal tissue derived from the primitive annular vessel. Incomplete persistence is the rule. Because the remnants represent fetal mesodermal tissue, they are nonpigmented except when attached to the anterior surface of the lens. The remnants may be attached to the iris alone (invariably to the collarette) or may run from the collarette of the iris to attach onto the posterior surface of the cornea, where occasionally there is an associated corneal opacity. Isolated nonpigmented or pigmented remnants may be found on the anterior lens capsule (“stars”) or drifting freely in the anterior chamber. Total persistence of the fetal pupillary membrane is extremely rare and usually associated with other ocular anomalies, especially microphthalmos.

II. Rarely, PPM is bilateral. III. Histologically, fine strands of mesodermal tissue are seen, rarely with blood vessels.

Persistent Tunica Vasculosa Lentis I. Persistence of the tunica vasculosa lentis is caused by incomplete atrophy (resorption) of the fetal tunica vasculosa lentis derived posteriorly from the primitive hyaloid vasculature and anteriorly from the primitive annular vessel posterior to the fetal pupillary membrane. Persistence of the posterior part of the tunica vasculosa lentis is usually associated with persistence of a hyperplastic primary vitreous, the composite whole being known as persistent fetal vasculature (formerly called persistent hyperplastic primary vitreous; see Fig. 18.18), and may or may not be associated with persistence of the anterior part of the tunica vasculosa lentis. The entire tunica vasculosa lentis may persist without an

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A

B

Fig. 9.1  Iris and ciliary body. A and B, The iris is lined posteriorly by its pigment epithelium and anteriorly by the avascular anterior border layer. The bulk of the iris is made up of vascular stroma. Considerable pigment is present in the anterior border layer and stroma in the brown iris (A), as contrasted to little pigment in the blue eye (B and C). The iris pigment epithelium is maximally pigmented in A–C; the color of the iris, therefore, is only determined by the amount of pigment in the anterior border layer and stroma. A–C: The ciliary body is wedge-shaped and has a flat anterior end, continuous with the very thin iris root, and a pointed posterior end, continuous with the choroid. (Courtesy of Dr. RC Eagle, Jr.) C

A

C

B

Fig. 9.2  Choroid. A, The choroid lies between the sclera (blue in this trichrome stain) and the retinal pigment epithelium. Uveal tissue spills out into most scleral canals, as into this scleral canal of the long posterior ciliary artery. B, The choroid is composed, from outside to inside, of the suprachoroidal (potential) space and lamina fusca, the choroidal stroma (which contains uveal melanocytes, fibrocytes, collagen, blood vessels, and nerves), the fenestrated choriocapillaris, and the outer aspect of Bruch’s membrane. C, Whereas the normal capillary in the body is large enough for only one erythrocyte to pass through, the capillaries of the choriocapillaris—the largest capillaries in the body—permit simultaneous passage of numerous erythrocytes. The choriocapillaris basement membrane and associated connective tissue compose the outer half of Bruch’s membrane, whereas the inner half is composed of the basement membrane and associated connective tissue of the retinal pigment epithelium. Note that the pigment granules are larger in the retinal pigment epithelial cells than in the uveal melanocytes (see also Fig. 17.1C).

Congenital and Developmental Defects of the Pigment Epithelium

A

359

B Fig. 9.3  Persistent pupillary membrane (PPM). A, Massive PPM, extending from collarette to collarette over anterior lens surface. B, Photomicrograph shows vascular membrane extending across pupil in three-day-old premature infant.

A

B Fig. 9.4  Hematopoiesis. A, Infant weighing 1070 g died on the first day of life. Photomicrograph shows choroid thickened by hematopoietic tissue. B, Increased magnification demonstrates blood cell precursors.

associated primary vitreous. The condition is extremely rare, however, and is usually associated with other ocular anomalies (e.g., with the ocular anomalies of trisomy 13).

II. Histologically, fine strands of mesodermal tissue, usually with patent blood vessels, are seen closely surrounding the lens capsule. Persistence and hyperplasia of the primary vitreous may or may not be present.

Heterochromia Iridis and Iridum Heterochromia iridum (see Chapter 17) is a difference in pigmentation between the two irises, as contrasted to heterochromia iridis, which is an alteration within a single iris.

Hematopoiesis I. Hematopoiesis in the choroid is a normal finding in premature infants and even in full-term infants for the first 3–6 months of life (Fig. 9.4).

is the rule after 20 years of age. However, hematopoiesis may occur in some cases at any age, especially after trauma.

II. Histologically, hematopoietic tissue containing blood cell precursors is seen in the uvea.

Ectopic Intraocular Lacrimal Gland Tissue I. Tissue appearing histologically similar to lacrimal gland tissue has been found in the iris, ciliary body, choroid, anterior chamber angle, sclera, and limbus (Fig. 9.5). II. Histologically, the tissue resembles normal lacrimal gland tissue.

CONGENITAL AND DEVELOPMENTAL DEFECTS OF THE PIGMENT EPITHELIUM See Chapter 17.

Hematopoietic tissue may occur abnormally in association with intraocular osseous metaplasia (the bonecontaining marrow spaces), usually in chronically inflamed eyes in people younger than age 20 years. A fatty marrow

Aniridia (Hypoplasia) of the Iris I. Complete absence of the iris, called aniridia, is exceedingly rare. In almost all cases, gonioscopy reveals a rudimentary

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A

B

C

D Fig. 9.5  Ectopic intraocular lacrimal gland. A, Clinical appearance of ciliary body tumor that has caused a sector zonular dialysis. B, Grossly, a cystic ciliary body tumor is present. C, Histologic section shows an intrascleral and ciliary body glandular tumor. D, Increased magnification demonstrates the resemblance to lacrimal gland tissue. (Case presented by Dr. S Brownstein to the meeting of the Eastern Ophthalmic Pathology Society, 1983, and reported by Conway VH et al.: adapted and published courtesy of Ophthalmology 92:449. © Elsevier 1985.)

s c

l

A

i

cb

B Fig. 9.6  Hypoplasia of iris. A, Clinical appearance of inferior and slightly nasal, partial stromal coloboma. B, Histologic section of another case shows marked hypoplasia of the iris (c, cornea; cb, ciliary body; i, hypoplastic iris; l, lens; s, sclera).

iris in continuity with the ciliary body (i.e., iris hypoplasia; Fig. 9.6; see also Figs. 2.20 and 16.5).

Aniridia is caused by point mutations or deletions affecting the PAX6 gene, located on chromosome 11p13. Abnormal tear film stability and meibomian gland

dysfunction are associated with aniridia, and they correlate with the severity of the disease. Impression cytology has confirmed varying degrees of limbal stem cell deficiency in these patients.

II. Photophobia, nystagmus, and poor vision may be present. III. Glaucoma is often associated with hypoplasia of the iris.

Congenital and Developmental Defects of the Pigment Epithelium

IV. Human aniridia limbal epithelial cells lack expression of keratins K3 and K12. V. Other ocular anomalies may be present—for example, corneal opacity (congenital or developmental), central corneal thickness, dry eyes, cataract, absent fovea, small optic disc, peripheral corneal vascularization, and persistent pupillary membrane. VI. Aniridia may be associated with Wilms’ tumor (see section Other Congenital Anomalies in Chapter 2). VI. The condition may be autosomal dominant or, less commonly, autosomal recessive. VII. Histologically, only a rim of rudimentary iris tissue is seen.

Ectropion Uveae (Hyperplasia of Iris Pigment Border or Seam) I. Two forms are found: congenital and acquired. A. Congenital ectropion uveae (Fig. 9.7) results from a proliferation of iris pigment epithelium onto the anterior surface of the iris from the pigment border (seam or ruff), where the two layers of pigment epithelium are continuous. 1. Glaucoma is often present. 2. The condition may be an isolated finding or may be associated with neurofibromatosis, facial hemihypertrophy, peripheral corneal dysgenesis, or the Prader– Willi syndrome (approximately 1% of patients with Prader–Willi syndrome, a chromosome 15q deletion syndrome, have oculocutaneous albinism).

A

Histologically, flattened iris pigment epithelium lines the anterior surface of the involved iris, which may show increased neovascularization. B. The more common form, acquired ectropion, often after trauma, is acquired and progressive, usually a result of iris neovascularization.



Peripheral Dysgenesis of the Cornea and Iris See Chapter 8.

Coloboma I. A coloboma (i.e., localized absence or defect) of the iris may occur alone or in association with a coloboma of the ciliary body and choroid (Fig. 9.8; see also Fig. 2.10). A. Typical colobomas occur in the region of the embryonic cleft, inferonasally, and may be complete, incomplete (e.g., iris stromal hypoplasia; see Fig. 9.6A), or cystic in the area of the choroid. Choroidal coloboma and posterior staphyloma are two clinically distinct entities and need to be differentiated.



B. Atypical colobomas occur in regions other than the inferonasal area. C. Typical colobomas are caused by interference with the normal closure of the embryonic cleft, producing defective ectoderm.



B Fig. 9.7  Congenital ectropion uveae. A, At six months of age, infant was noted to have abnormal left eye. Here, at eight years of age, child has normal right eye but lighter left eye with ectropion uveae (B) and glaucoma. Filtering procedure was performed. C, Histologic section of iridectomy specimen shows a pigmented anterior iris surface. Case was previously mistakenly reported as iridocorneal endothelial syndrome. (Case 7 in Scheie HG, Yanoff M: Iris nevus (Cogan–Reese) syndrome: A cause of unilateral glaucoma. Arch Ophthalmol 93:963, 1975. © American Medical Association. All rights reserved.)

C

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A

v r

s B

C

Fig. 9.8  Coloboma of iris and choroid. A, External and fundus pictures from right eye of same patient show microcornea and iris coloboma (left) and choroidal coloboma (right) with involvement of optic disc. B, Photomicrograph of another case shows an absent retinal pigment epithelium (RPE) and choroid. The atrophic neural retina (r) lies directly on the sclera (s) (v, vitreous). Coloboma (absence) of RPE is the primary cause of coloboma (absence) of choroid. C, Leukokoria (cat’s eye reflex) when patient looks down. (A, Courtesy of Dr. RC Lanciano, Jr.)

The anterior pigment epithelium seems primarily to be defective. Iridodiastasis is a coloboma of the iris periphery that resembles an iridodialysis. In the ciliary body, mesodermal and vascular tissues that fill the region of the coloboma often underlie the pigment epithelial defect. The ciliary processes on either side of the defect, however, are hyperplastic. The mesodermal tissue may contain cartilage in trisomy 13 (see Fig. 2.10). Zonules may be absent so that the lens becomes notched, producing the appearance of a coloboma of the lens. The retinal pigment epithelium (RPE) is absent in the area of a choroidal coloboma but is usually hyperplastic at the edges. The neural retina is atrophic and gliotic and may contain rosettes. The choroid is partially or completely absent. The sclera may be thin or ectatic, sometimes appearing as a large cyst (see subsection Microphthalmos with Cyst in Chapter 14).



C. It may consist of a linear area of pigmentation or RPE and choroidal thinning in any part of the fetal fissure. III. Colobomas may occur alone or in association with other ocular anomalies. Approximately 8% of eyes with congenital chorioretinal coloboma contain a retinal or choroidal detachment.

IV. The condition may be inherited as an irregular autosomaldominant trait. V. Histology A. The iris coloboma shows a complete absence of all tissue in the involved area. Iris coloboma is often associated with heterochromia iridum.

II. The extent of a coloboma of the choroid varies. A. It may be complete from the optic nerve to the ora serrata inferonasally. B. It may be incomplete and consist of an inferior crescent at the inferonasal portion of the optic nerve.



B. The ciliary body coloboma shows a defect filled with mesodermal and vascular tissues (also cartilage in trisomy 13) with hyperplastic ciliary processes at the edges. C. The choroidal coloboma shows an absence or atrophy of choroid and an absence of RPE with atrophic and gliotic retina, sometimes containing rosettes.

Congenital and Developmental Defects of the Pigment Epithelium

1. The RPE tends to be hyperplastic at the edge of the defect. 2. The sclera in the region is usually thinned and may be cystic; the cystic space is often filled with proliferated glial tissue, which may become so extensive (i.e., massive gliosis) as to be confused with a glial neoplasm.

Rarely, an occult, intrauterine limbal perforation of the anterior chamber with a needle may occur during amniocentesis. Circumferential ciliary body cysts can mimic acute pigment dispersion and ocular hypertension.



C. Histologically, the cysts are lined by a multilayered epithelium resembling corneal or conjunctival epithelium that may have goblet cells. The cysts usually contain a clear fluid surrounded by a layer of epithelium. II. Iris or ciliary body epithelial cysts are associated with the nonpigmented epithelium of the ciliary body or the pigmented neuroepithelium on the posterior surface of the iris or at the pupillary margin. A. With the possible exception of the development of a secondary closed-angle glaucoma or pupillary obstruction, the clinical course of the pigment epithelial cysts is usually benign.

Cysts of the Iris and Anterior Ciliary Body (Pars Plicata) I. Iris stromal cysts (Figs. 9.9 and 9.10) resemble implantation iris cysts after nonsurgical or surgical trauma. A. The cysts can become quite large and cause vision problems by impinging on the pupil; they may also occlude the angle and cause secondary closed-angle glaucoma. Ultrasonographic biomicroscopy has shown that approximately 54% of “normal” patients may have asymptomatic ciliary body cysts.



363

Multiple iris and ciliary body pigment epithelial cysts may be found in congenital syphilis. Secondary closedangle glaucoma frequently develops in these eyes. Rarely, plateau iris can be caused by multiple ciliary body cysts.

B. The origin of the cysts is poorly understood, although evidence suggests a two-part derivation: a component from cells of the iris stroma and an epithelial component from nonpigmented neuroepithelial cells.

Fig. 9.9  Cyst of the iris. A, A bulge is present in the iris from the 9 to 10 o’clock position. The stroma in this area is slightly atrophic. B, Gonioscopic examination of the region clearly delineates a bulge caused by an underlying cyst of the pigment epithelium of the peripheral iris. C, Electron microscopy of iris epithelial cyst shows thin basement membrane (bm), apical adherens junction (arrow), and apical villi, which indicate polarization of cells in layer, like that of normal iris pigment epithelium, and the presence of glycogen (g), similar to normal iris pigment epithelium.

A

B

C

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A

B Fig. 9.10  A, Gross specimen shows clear cyst of pars plicata of ciliary body. B, Scanning electron micrograph of nonpigmented ciliary epithelial cyst present at anterior margin of pars plicata. C, Proliferating nonpigmented epithelial cells in cyst wall. Note thin basement membrane on one side (arrow) and poorly formed multilaminar basement membrane on the other. (A and B, Courtesy of Dr. RC Eagle, Jr.)

C





B. The cysts form as the posterior layer of iris pigment epithelium or the inner layer of ciliary epithelium proliferates. C. Cysts of the iris pigment epithelium most often affect the peripheral region (iridociliary) and rarely require intervention. Occasionally, a cyst may break off and float in the anterior chamber. The cyst may then implant in the anterior chamber angle, where it has occasionally been mistaken for a malignant melanoma. The cyst may also float freely, enlarge, and so obstruct the pupil that surgical removal of the cyst is necessary.

III. Histologically, the pigmented cysts are filled with a clear fluid and are lined by epithelial cells having all the characteristics of mature pigment epithelium.

Cysts of the Posterior Ciliary Body (Pars Plana) I. Most cysts of the pars plana (Fig. 9.11) are acquired. II. Pars plana cysts lie between the epithelial layers and are analogous to detachments (separations) of the neural retina. Clinically, the typical pars plana cysts and those of multiple myeloma appear almost identical. With fixation, however, the multiple myeloma cysts turn from clear

to white or milky (see Fig. 9.11E and F), whereas other cysts remain clear. The multiple myeloma cysts contain γ-globulin (immunoglobulin). Cysts similar to the myeloma cysts but extending over the pars plicata have been seen in nonmyelomatous hypergammaglobulinemic conditions.

III. Histologically, large intraepithelial cysts are present in the pars plana nonpigmented ciliary epithelium. The nonmyelomatous cysts appear empty in routinely stained sections but are shown to contain a hyaluronidase-sensitive material when special stains are used to demonstrate acid mucopolysaccharides.

INFLAMMATIONS See Chapters 3 and 4.

INJURIES See Chapter 5.

SYSTEMIC DISEASES Diabetes Mellitus See sections Iris and Ciliary Body and Choroid in Chapter 15.

Systemic Diseases

A

B

C

D

E

F

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Fig. 9.11  Cyst of the pars plana. A, Histologic section shows a large cyst of the pars plana of the ciliary body. A special stain, which stains acid mucopolysaccharides blue, shows that the material in the cyst stains positively. B, If the section is first digested with hyaluronidase and then stained as in A, the cyst material is absent, demonstrating that the material is hyaluronic acid. C, Apical surface of nonpigmented epithelial layer (npe) of pars plana cyst. Note the presence of apical microvilli (v), dense apical attachments (arrows; zonula adherens prominent), and desmosomes (d) between adjacent cells. D, Apical surface of pigment epithelial layer (pe) of pars plana cyst. Note apical villi and apical attachments (arrow; d, desmosome). Nonpigmented ciliary epithelial cysts are common in the region of pars plicata. E, Gross, fixed specimen shows milky appearance of multiple myeloma cysts of the pars plicata and pars plana, shown with increased magnification in F. (E and F, Courtesy of Dr. RC Eagle, Jr.)

Vascular Diseases See section Vascular Diseases in Chapter 11.

Cystinosis See Chapter 8.

Homocystinuria

Juvenile Xanthogranuloma (Nevoxanthoendothelioma) I. Juvenile xanthogranuloma (JXG), a non-Langerhans’ cell histiocytoses (Fig. 9.12; see also Fig. 1.21), is a benign cutaneous disorder of infants and young children. A. The typical raised orange-skin lesions occur singly or in crops and regress spontaneously.

See Chapter 10.

Amyloidosis See Chapters 7 and 12.

Solitary spindle-cell xanthogranuloma (SCXG), another of the non-Langerhans’ cell histiocytoses, may involve the eyelids and contains Touton giant cells, but it

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A

B

C

D Fig. 9.12  Juvenile xanthogranuloma (JXG). A, Patient has multiple orange-skin lesions (biopsy-proved JXG) and involvement of both irises. Hyphema in right eye resulted in glaucoma and buphthalmos. B, Another patient shows a superior limbal epibulbar orange mass of the right eye that was sampled for biopsy. C, Histologic section shows diffuse involvement of the conjunctival substantia propria by histiocytes and Touton giant cells (see also Fig. 1.21). D, Oil red-O shows positive lipid staining of peripheral cytoplasm of Touton giant cell. (A, Courtesy of Dr. HG Scheie; Case in B–D presented by Dr. M Yanoff to the meeting of the Eastern Ophthalmic Pathology Society, 1993, and reported in Yanoff M, Perry HD: Juvenile xanthogranuloma of the corneoscleral limbus. Arch Ophthalmol 113:915, 1995. © American Medical Association. All rights reserved.)

differs from JXG in containing more than 90% spindle cells. SCXG may be an early form of JXG.



B. The skin lesions may predate or postdate the ocular lesions, occur simultaneously, or be absent. II. Ocular findings include mainly diffuse or discrete iris involvement and occasionally ciliary body and anterior choroidal lesions, epibulbar involvement, corneal lesions, nodules on the lids, and orbital granulomas. A. Most ocular lesions occur unilaterally in the very young, most younger than six months of age. Rarely, a limbal nodule can occur in an adult. B. The iris lesions are quite vascular and bleed easily. When confronted with an infant who has a spontaneous hyphema, the clinician must consider JXG along with retinoblastoma, medulloepithelioma, and trauma (the parents may think that the hemorrhage was spontaneous, but unknown trauma could have caused it).

III. JXG is separate from the group of nonlipid reticuloendothelioses called Langerhans’ granulomatoses or histiocytosis X (eosinophilic granuloma, Letterer–Siwe disease, and Hand–Schüller–Christian disease; see discussion of reticuloendothelial system in subsection Primary Orbital Tumors in Chapter 14). IV. Histologically, a diffuse, often vascular, granulomatous inflammatory reaction with many histiocytes and often with Touton giant cells is seen. (Touton giant cells may also be found in necrobiotic xanthogranuloma and liposarcoma.)

JXG may be confused histologically with necrobiosis lipoidica diabeticorum, granuloma annulare, erythema induratum, atypical sarcoidosis, Erdheim–Chester disease, Rothmann–Makai panniculitis, foreign-body granulomas, various xanthomas, nodular tenosynovitis, and the extraarticular lesions of proliferative synovitis.

Atrophies and Degenerations

Langerhans’ Granulomatoses (Histiocytosis X) See discussion of reticuloendothelial system in subsection Primary Orbital Tumors in Chapter 14.

Collagen Diseases See subsection Collagen Diseases in Chapter 6.

Mucopolysaccharidoses See Chapter 8.

ATROPHIES AND DEGENERATIONS See subsections Atrophy and Degeneration and Dystrophy in Chapter 1.

Iris Neovascularization (Rubeosis Iridis) See Figs. 9.13 and 9.14; see also Fig. 15.4. The term rubeosis iridis means “red iris” and should be restricted to clinical usage; iris neovascularization is the proper histopathologic term. I. Causes include vascular hypoxia (central retinal vein occlusion, central retinal artery occlusion, temporal arteritis, aortic arch syndrome, carotid artery disease, retinal vascular disease, and ocular ischemic syndrome), neoplastic (uveal malignant melanoma, retinoblastoma, metastatic uveal tumors, and embryonal medulloepithelioma), inflammatory (chronic uveitis, post retinal detachment surgery, post

A

radiation therapy, fungal endophthalmitis, and posttraumatic), and neural diseases (diabetic retinopathy, chronic neural retinal detachment, Coats’ disease, chronic glaucoma, sickle-cell retinopathy, Eales’ disease, persistent fetal vasculature, Leber’s miliary microaneurysms, and Norrie’s disease). II. Iris neovascularization may be induced by hypoxia, by products of tissue breakdown, or by a specific angiogenic factor. Neovascularization of the iris is always secondary to any of a host of ocular and systemic disorders. III. Neovascularization often starts in the pupillary margin and the iris root concurrently, but it can start in either place first; the mid stromal portion is rarely involved early. Early iris neovascularization in the angle does not cause synechiae and a closed angle but, rather, a secondary open-angle glaucoma, owing to obstruction of outflow by the fibrovascular membrane. Synechiae are rapidly induced, and chronic secondary closed-angle glaucoma ensues. Rarely, however, the rubeosis iridis involves the angle structures and anterior iris surface without causing synechiae, as may occur in Fuchs’ heterochromic iridocyclitis.

IV. A secondary closed-angle glaucoma (called neovascular glaucoma) and hyphema are the main complications of iris neovascularization.

B

Fig. 9.13  Iris neovascularization (IN). A, Early stage of IN in partially open angle. B, Histologic section of another case that had a central retinal vein occlusion, IN, and secondary glaucoma. Gonioscopy showed angle partially closed. Eye was enucleated. Histologic section shows apparent open angle. Closer examination reveals material in angle and other evidence that the posterior trabecular meshwork had been closed before enucleation, but fixation caused an artifactitious opening of the angle. C, The same region shown with a thin plasticembedded section clearly demonstrates IN and closure of the posterior trabecular meshwork. (A, Courtesy of Dr. HG Scheie.) C

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A

B

C

D Fig. 9.14  Iris neovascularization (IN). A, Significant IN extends to the pupillary margin (and had closed the angle). B, Gonioscopy of another case shows vessels climbing angle wall and a red line of vessels on posterior trabecular meshwork. The angle is closed to the left. C, Histologic section shows IN completely occluding angle. D, Thin section shows early IN partially occluding angle.

Iris neovascularization is best differentiated from normal radial iris vessels by the random distribution found in iris neovascularization. Fluorescein angiography can be helpful in differentiating normal from abnormal iris vessels by demonstrating leakage from the abnormal vessels.

V. Histologically, fibrovascular tissue is found almost exclusively on the anterior surface of the iris and in the anterior chamber angle. A. The blood vessels are derived initially from the ciliary body near the iris root or from iris stromal blood vessels. B. The new vascular growth seems to leave the iris stroma rapidly (most commonly toward the pupil) to grow on and over the anterior surface of the iris. With contracture of the myoblastic component of the fibrovascular tissue, the pupillary border of the iris is turned anteriorly (ectropion uveae). Synechiae are characteristically only present in the area of the anterior chamber angle peripheral to the end of Descemet’s membrane. Therefore, they can be differentiated from such broadbased synechiae as may be caused by a persistent flat chamber, chronic closed-angle glaucoma, or iris bombé.

Choroidal Folds I. The condition consists of lines, grooves, or striae, often arranged parallel and horizontally. Occasionally, the folds may be vertical, oblique, or so irregular as to resemble a jigsaw puzzle. II. The folds appear as a series of light and dark lines, often temporal and confined to the posterior pole, rarely extending beyond the equator. Fluorescein angiography shows a series of alternating hyperfluorescent (peaks of folds) and hypofluorescent (valleys of folds) streaks that start early in the arteriovenous (AV) phase, persist through the late venous phase, and do not leak. The hyperfluorescent areas may be the result of RPE thinning or atrophy. The hypofluorescent areas may be caused by an inclination of the RPE in the valleys, which results in increased RPE thickness blocking the choroidal fluorescence, or may be caused by a partial collapse of the choriocapillaris in the valleys. Choroidal folds are differentiated from neural retinal folds by the latter’s finer appearance and normal fluorescein pattern.

III. Causes of choroidal folds include hypermetropia, macular degeneration, neural retinal detachment, hypotony, trauma,

Dystrophies

orbital tumors, thyroid disease, scleritis, uveitis, and others, including no known cause. IV. Histologically, the choroid and Bruch’s membrane are corrugated or folded. RPE involvement seems to be a secondary phenomenon.

Heterochromia See subsection Heterochromia Iridis and Iridum, this chapter, and Chapter 17.

Macular Degeneration See Chapter 11.

DYSTROPHIES

Choroidal Dystrophies I. Regional choroidal dystrophies A. Choriocapillaris atrophy involving the posterior eyegrounds 1. Involvement of the macula alone (central areolar choroidal sclerosis [Fig. 9.15], central progressive areolar choroidal dystrophy, central choroidal angiosclerosis) a. The condition probably has an autosomal (recessive or dominant) inheritance pattern and is characterized by the onset of an exudative and edematous maculopathy in the third to the fifth decade.

Iris Nevus Syndrome

Autosomal-dominant central areolar sclerosis is caused by an Arg-142-Trp mutation in the peripherin/RDS gene. Other mutations that code to the peripherin/RDS gene include retinitis pigmentosa, macular dystrophy, pattern dystrophy, and fundus flavimaculatus. Mutations in the GUCY2D gene has been reported to cause the disorder. This mutation also is associated with dominant cone-rod dystrophy and recessive forms of Leber’s congenital amaurosis.

See Chapter 16.

Chandler’s Syndrome See Chapter 16.

Essential Iris Atrophy See Chapter 16.

Iridoschisis See Chapter 16.

A

B

r rpe

er

ee C

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Fig. 9.15  Central areolar choroidal sclerosis. A, Clinical appearance (left eye) of fundus in patient who had bilateral symmetric macular lesions. B, Histologic section of another case shows that the retinal pigment epithelium (RPE) and neural retina, which are relatively normal on the far left, show an abrupt transition to a chorioretinal abnormality that involves the outer neural retinal layers, RPE, and choroid. C, Increased magnification of the transition zone shows an intact Bruch’s membrane but loss of photoreceptors and RPE and obliteration of the choriocapillaris; no blood-containing vessels are seen in the remainder of choroid (ee, end of retinal pigment epithelium; er, end of retinal receptors; r, neural retina; rpe, retinal pigment epithelium). (A, Courtesy of Dr. WE Benson.)

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b. Typical slow progression leads to a sharply demarcated, atrophic appearance involving only the posterior pole area, causing a central scotoma without night blindness.



Rarely, the initial lesion, or the only lesion, may be in the macula. Tuberculous choroiditis may mimic serpiginous choroiditis. Additionally, Mycobacterium tuberculosis genome has been found in the vitreous fluid of eyes with multifocal serpiginous choroiditis.

Clinically, the condition may be indistinguishable from geographic RPE atrophy of agerelated macular degeneration.



c. Histologically, the area of involvement shows an incomplete or complete loss of the choriocapillaris, the RPE, and the outer retinal layers. 2. Involvement of the peripapillary area—peripapillary choroidal sclerosis a. The area of involvement, mainly the posterior one-third of the globe surrounding the optic nerve, shows a sharply demarcated atrophic area and easily seen, large choroidal vessels. b. Histologically, the area of involvement shows absence of choriocapillaris, RPE, and photoreceptors and a decrease in choroidal arteries and veins. Bruch’s membrane is intact except for some breaks in the immediate peripapillary region. Angioid streaks may also be found. 3. Involvement of the paramacular area—also called serpiginous choroiditis or circinate choroidal sclerosis (Fig. 9.16) a. The dystrophy, usually bilateral, is characterized by well-defined gray lesions seen initially at the level of the pigment epithelium, usually contiguous with or very close to the optic nerve. 1) Each new lesion remains stationary. 2) With healing, degeneration of the pigment epithelium, geographic atrophy of the choroid, or even subretinal neovascularization and subretinal scar formation (disciform macular degeneration) may occur. b. The disease progress is away from the optic disc, with new attacks occurring in areas previously uninvolved.









A

c. Visual acuity is only affected if the central fovea is involved in an attack.



d. Histologically, the choriocapillaris, the RPE, and the outer neural retinal layers are degenerated and sharply demarcated from adjacent normal chorioretinal areas. Diffuse and focal areas of round cell inflammation (mainly lymphocytes) may be found. 4. Involvement with nasal and temporal foci—also called progressive bifocal chorioretinal atrophy (PBCRA) The gene for PBCRA has been linked to chromosome 6q near the genomic assignment for North Carolina macular dystrophy. The phenotype of PBCRA, although similar to North Carolina macular dystrophy, is quite distinct.

5. Involvement of the disc—also called choroiditis areata, circumpapillary dysgenesis of the pigment epithelium, and chorioretinitis striata 6. Malignant myopia (see Chapter 11) II. Diffuse choroidal dystrophies A. Diffuse choriocapillaris atrophy—also called generalized choroidal angiosclerosis, diffuse choroidal sclerosis, and generalized choroidal sclerosis Histologically, the choriocapillaris, the RPE, and the outer neural retinal layers are degenerated.



B. Diffuse total choroidal vascular atrophy 1. Autosomal-recessive inheritance (carried on chromosome 10q26)—also called gyrate atrophy of the choroid

B TEMPORAL Fig. 9.16  A, Photograph shows macular serpiginous choroiditis, with old inactive lesion (red arrows) and active lesion at the margin (white arrow). B, OCT scanning shows choroidal hyper-reflectivity (white arrow), outer retinal thickening and disruption of the ellipsoid IS–OS layer (black arrow). (From Duker J: Handbook of Retinal OCT. Elsevier 2014. Figure 17.3.1a & Figure 17.3.2.)

Tumors





a. In gyrate atrophy, chorioretinal patches develop in the periphery (often with glistening crystals scattered at the equator), progressing more centrally than peripherally, and partially fusing. b. Other ocular findings include posterior subcapsular cataracts and myopia, cystoid macular edema (well seen with OCT imaging), choroidal neovascularization, and, rarely, retinitis pigmentosa. A peripapillary atrophy may develop simultaneously. In the final stage, all of the fundi except the macula may be involved so that the condition may resemble choroideremia.













c. Patients have hyperornithinemia (10- to 20-fold increased ornithine concentration in plasma and other body fluids), caused by a deficiency of the mitochondrial matrix enzyme ornithineδ-aminotransferase (OAT). They may also show subjective sensory symptoms of peripheral neuropathy. 1) OAT catalyzes the major catabolic pathway of ornithine, which involves the interconversion of ornithine, glutamate, and proline through the intermediate pyrroline-5-carboxylate and requires pyridoxal phosphate (vitamin B6) as coenzyme. 2) The OAT gene maps to chromosome 10q26, and OAT-related sequences have also been mapped to chromosome Xp11.3–p11.23 and Xp11.22–p11.21. d. The condition becomes manifest in the second or third decade of life, slowly progresses, causing a concentric reduction of the visual field, leading to tunnel vision and ultimately to blindness in the fourth to seventh decade of life. Decreasing vision and night blindness are prominent symptoms, along with electrophysiologic dysfunction. e. An arginine-restricted diet slows the progress of the condition, whereas creatine supplementation appears to have no effect. f. Histologically, the iris, corneal endothelium, nonpigmented ciliary epithelium, and, to a lesser extent, photoreceptors show abnormal mitochondria. An abrupt transition occurs between the normal and the involved chorioretinal area; the latter shows near-total atrophy of the neural retina, RPE, and choroid. 2. X-linked inheritance—also called choroideremia, progressive tapetochoroidal dystrophy, and progressive chorioretinal degeneration (Fig. 9.17) a. This condition is characterized by almost complete degeneration of the retina and choroid (except in the macula) in affected men. b. It becomes manifest in childhood and progresses slowly until complete at approximately 50 years of age.



371

c. Choroideremia is caused by mutations in a single gene (Rab escort protein-1) on chromosome Xq21.2. The fundus picture in carrier women resembles that seen in the early stages in affected men, namely degeneration of the peripheral RPE giving a salt-and-pepper appearance. Mutations can cause severe visual loss in female carriers. Fundus autofluorescence is helpful in making the diagnosis.





d. Abnormalities of photoreceptor outer segments interdigitation zone and rod dysfunction are the earliest central abnormalities observed. e. Histologically, the choroid and RPEs are absent or markedly atrophic, and the overlying outer neural retinal layers are atrophic. Uveal vascular endothelial cell and RPE abnormalities may be found where uveal vessels still persist. Abnormalities of the photoreceptor outer segments and rod dysfunction are the earliest central abnormalities.

III. All of the aforementioned choroidal entities, although usually called atrophies, should more properly be called dystrophies with secondary retinal changes; it is likely that the primary dystrophic abnormality resides in the choroidal vasculature or the RPE.

TUMORS Epithelial I. Hyperplasias (see Chapter 1 and section Melanotic Tumors of Pigment Epithelium of Iris, Ciliary Body, and Retina in Chapter 17) Occasionally, pseudoadenomatous hyperplasias may become extreme and produce masses that are noted clinically, either localized to the posterior chamber or, rarely, proliferated into the anterior chamber.

II. Benign adenoma of Fuchs (Fuchs’ reactive hyperplasia, coronal adenoma, Fuchs’ epithelioma, benign ciliary epithelioma; Fig. 9.18) A. The small, age-related tumor is present in more than 25% of older people, is located in the pars plicata of the ciliary body, is benign, and is usually found incidentally when an enucleated globe is being examined microscopically. B. It may rarely cause localized occlusion of the anterior chamber angle. C. The tumor is proliferative rather than neoplastic—that is, a hyperplasia and not an adenoma.

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CHAPTER 9  Uvea

A

B

v

r

c C

s

D

Fig. 9.17  Choroideremia. A, Appearance of right eye in male patient who had bilateral choroideremia. B, Peripheral fundus of female carrier shows peripheral pigmentation. C, Histologic section of another case shows the absence of RPE and atrophy of both the overlying neural retina and the underlying choroid (c, atrophic choroid; r, atrophic retina; s, sclera; v, vitreous). D, Electron micrograph shows choroidal vessel deep to choriocapillaris. Both endothelial (e) and pericyte (p) basement membranes are absent centrally. A small amount of fragmented basement membrane (arrow) persists on the left. (A, Courtesy of Dr. WE Benson; B, courtesy of Dr. G Lang; C, presented by Dr. WS Hunter at the AOA-AFIP meeting, 1969; D, modified from Cameron JD, Fine BS, Shapiro I: Histopathologic observations in choroideremia with emphasis on vascular changes of the uveal tract. Ophthalmology 94:187. © Elsevier 1987.)

i s

ce

A

cb

B Fig. 9.18  Fuchs’ adenoma. A, The lesion is seen grossly as a white tumor in the pars plicata of the ciliary body. B, Histologic section shows a proliferation of nonpigmented ciliary epithelium that is elaborating considerable basement membrane material (cb, ciliary body; ce, proliferating ciliary epithelium; i, iris; s, Schlemm’s canal).

Tumors



D. Histologically, it is a benign proliferation of cords of the nonpigmented ciliary epithelium interspersed with abundant, amorphous, eosinophilic, acellular basement membrane material, acid mucopolysaccharides, and glycoproteins. III. Medulloepithelioma (see Chapter 17)

Muscular I. Leiomyomas—benign smooth-muscle tumors—may rarely occur in the iris, ciliary body, or choroid. A. Leiomyomas have a predilection for women. B. The tumors tend to affect the ciliary body and anterior choroid.



Many cases previously diagnosed as leiomyoma are probably melanocytic, rather than smooth muscle, lesions. It is difficult to differentiate a leiomyoma from an amelanotic spindle cell nevus and low-grade melanoma without the use of electron microscopy and immunohistochemical studies.



plasmalemmal vesicles, plasmalemma-associated densities, and myriad longitudinally aligned, intracytoplasmic filaments with scattered associated densities— characteristics that allow for identification of the cells in less than optimally fixed tissue. In addition, immunohistochemical stains for muscle-specific actin, smooth muscle actin, desmin, and vimentin are positive; trichrome stain highlights the spindle-shaped cells. D. Mesectodermal leiomyoma (see Chapter 14) 1. This rare variant of leiomyoma, which microscopically resembles a neurogenic tumor, presumably originates from the neural crest. 2. Histologically (Fig. 9.19), widely spaced tumor cell nuclei are set in a fibrillar cytoplasmic matrix and may show immunoexpression of neural markers. The cells are positive for smooth muscle actin, desmin, h-caldesmon, CD56, and neuron-specific enolase stainings. The tumors resemble ganglionic, astrocytic, and peripheral nerve tumors. The presence of a reticulum differentiates mesectodermal leiomyoma from astrocytic tumors, where the fiber is absent.

C. Electron microscopic criteria for smooth muscle cells include an investing thin basement membrane,

A

C

373

B

D Fig. 9.19  Mesectodermal leiomyoma. A, A 47-year-old woman suspected of having a ciliary body melanoma. B, Histologic section shows large ciliary body tumor composed of widely spaced tumor cell nuclei in a fibrillar cytoplasmic matrix (shown under increased magnification in C). D, Electron microscopy shows a dense osmophilic structure called skeinoid fibers. (Case presented by Dr. J Campbell at the combined meeting of the Verhoeff and European Ophthalmic Pathology Societies, 1996; Case reported in Campbell RJ, Min K-W, Zolling JP: Skenoid fibers in mesectodermal leiomyoma of the ciliary body. Ultrastruct Pathol 21:559, 1997.)

374

CHAPTER 9  Uvea Immunohistochemistry and electron microscopy are needed to differentiate the tumor from peripheral nerve tumors. The diagnosis is made when immunohistochemical and ultrastructural features of smooth muscle cells are found.



E. Leiomyosarcoma has been reported as a rare iris neoplasm. II. A rhabdomyosarcoma is an extremely rare tumor of the iris and is probably atavistic.

II. Hemangioma of the choroid (Fig. 9.20) A. Hemangioma of the choroid occurs in two types: circumscribed and diffuse. 1. Circumscribed is usually solitary and not associated with any systemic process. 2. Diffuse may rarely occur as an isolated finding but mostly is part of the Sturge–Weber syndrome (see Fig. 2.2). OCTA is helpful in differentiating hemangioma from other vascular tumors.

Vascular I. True hemangiomas of the iris and ciliary body are extremely rare. A. Presumed iris hemangioma has been reported in association with multiple central nervous system (CNS) cavernous hemangiomas and may represent a distinct form of phakomatosis. Iris racemose hemangioma, detected by optical coherence tomography angiography (OCTA), has been reported.



B. Over long intervals of observation, choroidal hemangiomas may show slight enlargement. C. Clinically, it presents as a circumscribed, orangered mass that shows early fluorescence with fluorescein and indocyanine green. Subretinal fluid is quite common. D. Histologically, the choroidal tumor shows large, dilated, blood-filled spaces lined by endothelium and sharply demarcated from the normal, surrounding choroid.





d

h

A

C

B

D Fig. 9.20  Hemangioma of choroid. A, An elevated lesion, which shows a characteristic orange color, is seen in the inferior nasal macular region. B, A histologic section of another case shows a total retinal detachment (d) and an extensive hemangioma (h) of the choroid in the macular area. C, Increased magnification of the temporal edge of the hemangioma shows that it is blunted and well demarcated from the adjacent normal choroid to the left. D, Similarly, the nasal edge of the hemangioma is blunted and easily demarcated from the adjacent choroid. This hemangioma was not associated with any systemic findings; in Sturge–Weber syndrome, the choroidal hemangioma is diffuse and not clearly demarcated from the adjacent choroid.

Tumors

III. Hemangiopericytoma A. Hemangiopericytomas are much more common in the orbit (see Chapter 14) than intraocularly. B. Histologically, well-vascularized spindle cell proliferation is present in the uvea in a sinusoidal pattern. 1. The cells stain positive for vimentin, factor XIIIa, and HLA-DR. IV. Arteriovenular (AV) malformation of the iris A. AV iris malformation, also called racemose hemangioma, is rare. B. It consists of a unilateral continuity between an artery and a vein without an intervening capillary bed. C. The lesion is benign and stationary.

Osseous I. Choroidal osteoma (osseous choristoma of the choroid; Fig. 9.21) A. This benign, ossifying lesion is found mainly in women in their second or third decade of life and is bilateral in approximately 25% of patients. 1. Growth may be seen in approximately 51% of cases with long-term follow-up. 2. An associated subretinal fluid, neovascularization, or hemorrhage may be present. Over 10 years, approximately 56% of all patients will have decreased vision to 20/200 or worse. Choroidal osteomas may follow ocular inflammation, be associated with systemic illness, or be familial. Rarely, they may undergo growth or spontaneous involution. Bilateral osseous choristoma of the choroid has been reported in an 8-month-old girl. Also, they may present as a yellowish dome-shaped choroidal tumor, mimicking melanoma.



2. Diffuse, mottled depigmentation of the overlying pigment epithelium and multiple small vascular networks on the tumor surface. C. The tumor is dense ultrasonically; tissues behind the tumor are silent.



Calcified tumors show a distinctive latticework pattern of reflectivity, similar to spongy bone, by Fourierdomain optical coherence tomography. Decalcification occurs over time in almost 50% of patients.



D. Histologically, mature bone with interconnecting marrow spaces is seen sharply demarcated from the surrounding choroid.

Melanomatous See Chapter 17.

Leukemic and Lymphomatous (See Chapter 14) I. Acute granulocytic (myelogenous; Fig. 9.22) and lymphocytic leukemias not infrequently have uveal, usually posterior choroidal, infiltrates as part of the generalized disease. Specific esterase activity, as determined by using naphthol ASD-chloroacetate, is present exclusively in granulocytic cells, thus differentiating acute granulocytic from acute lymphocytic leukemia. Demonstrating specific esterase activity histologically is especially helpful in diagnosing leukemic infiltrates (called myeloid [granulocytic] sarcoma), particularly in the orbit, where granulocytic leukemic infiltrates may appear greenish clinically because of the presence of the pigment myeloperoxidase, and then are called chloromas.



A. Approximately 30% of autopsy eyes from fatal leukemic cases show ocular involvement, mainly leukemic infiltrates in the choroid. Also, 42% of newly diagnosed cases of acute leukemia show ocular findings, especially intraretinal hemorrhages, white-centered hemorrhages, and cotton-wool spots.

B. The characteristic clinical findings include: 1. A slightly irregularly elevated, yellow-white, juxtapapillary choroidal tumor with well-defined geographic borders.

A

375

B Fig. 9.21  Choroidal osteoma. A, The patient has an irregular, slightly elevated, yellow-white juxtapapillary lesion. Ultrasonography showed the characteristic features of bone in the choroid. B, A histologic section of another case shows that the choroid is replaced by mature bone that contains marrow spaces. (A, Courtesy of Dr. WE Benson; B, presented by Dr. RL Font at the meeting of the Eastern Ophthalmic Pathology Society, 1976.)

376

CHAPTER 9  Uvea

A

B

C

D Fig. 9.22  Acute leukemia. A, A patient presented with a large infiltrate of leukemic cells positioned nasally in the conjunctiva of the right eye, giving this characteristic clinical picture. These lesions look similar to those caused by benign lymphoid hyperplasia, lymphoma, or amyloidosis. B, A biopsy of the lesion shows primitive blastic leukocytes. C, In another case, the iris is infiltrated by leukemic cells. A special stain (Lader stain) shows that some of the cells stain red, better seen when viewed under increased magnification in D. This red positivity is characteristic of myelogenous leukemic cells.

primarily, it can simulate a chronic uveitis, often with a vitreitis. Concentrations of interleukin-10 from vitreous aspirates may be helpful in making the diagnosis.

Rarely, the first sign of granulocytic leukemia relapse is ocular adnexal involvement.



B. Retinal hemorrhages are most likely to occur in patients who have both anemia and thrombocytopenia combined; when the two are severe (hemoglobin 90% immunoblastic tumor cells • Anaplastic: polymorphic often bizarre tumor cells • T-cell rich: only 10% tumor cells with 90% T-cell infiltrate and macrophages

• CD79a , CD20a • BCL-6+ (~70% of cases) • CD10+ (~25%–50%) • IgM > IgG > IgA in 50%–75% of cases • CD30+ in lymphoma with anaplastic morphology • Rarely CD5+ or CD23+ • No FDC-MW • Ki-67 nearly always >40%

FL

• Usually follicular growth pattern with occasional diffuse areas; rarely purely diffuse • Mixture of centrocytes and centroblasts with dominance of former • Monomorphic GCs with loss of zonation • Minimal or no apoptosis in GC • Usually no macrophages with tingible bodies • Thin or even absence of the follicle mantle • Rarely pure diffuse growth pattern

Classical BL

• Diffuse monotonous infiltration pattern • Medium-sized tumor cells, round nuclei, clumped chromatin, basophilic cytoplasm • Extremely high proliferation rate with numerous mitoses and apoptotic bodies • Starry sky pattern due to admixed histiocytes

• CD20+, CD10+, BCL-2+ (90%), BCL-6+, IgM+ (50%), IgG (50%) • CD43− (95%), CD23−, CD5− • Dense follicular FDC-MW • Obvious reduction in growth fraction in neoplastic GCs versus reactive GCs, particularly in BCL-2+ cases • Often CD10+ and BCL-6+ B cells in the interfollicular region • Dense well-defined FDC meshworks in neoplastic germinal centers (demonstrated with CD 21) • CD79a+, CD20+, CD10+, BCL-6+, IgM+ • CD21+ (endemic form) • CD5−, CD23−, TdT−, BCL-2− • Ki-67 = 100%

Molecular Biological Changes

Cell of Origin

• Clonal IgH and IgL rearrangements† • Numerous mutations in V region of IgH gene • Bcl-6 gene rearrangements in up to 40% of cases • Bcl-2 gene rearrangements in 20%–30% of cases • C-myc gene rearrangements extremely rare • REL gene amplification in 20% mainly extranodal lymphoma • p53 gene mutations only in secondary lymphoma arising from a FL • Clonal IgH and IgL rearrangements† • Numerous mutations in V region of IgH gene with “ongoing” mutations (intraclonal diversity) • t(14;18) in 90%, resulting in the expression of BCL-2 in neoplastic germinal centers • Mutations of p53 gene and c-myc rearrangement in high-grade transformed cases

• Mature germinal center B cell or postgerminal center B cell (memory B cell)

• 40% extranodal (gastrointestinal tract > skin > soft tissue > central nervous system) • 60% nodal • Average age: 60–70 years • Rapidly growing solitary nodal or extranodal tumor • Aggressive clinical course

• Germinal center B cell

• 40% of all NHL in the United States; 20%–30% in Europe • Fifth and sixth decades of life (mean age, 59 years); unusual before 20 years of age • Male:female = 1 : 1 • Lymph nodes mainly infiltrated, but also spleen, bone marrow, and skin • Often advanced disease (stage III/IV) at the time of diagnosis • 5-year survival rate: 75% • Transformation to DLBCL in 30% of cases

• Clonal IgH rearrangements • Germinal with somatic mutations center B • Translocation of MYC: t(8;14), cell t(2;8), or t(8;22) • Inactivation of TP53 due to mutations (30%) • EBV genomes can be demonstrated in tumor cells in nearly all endemic cases, 25%–40% in immunodeficient cases, and adults (ages 4–7 years), male:female = 2 : 1, mandible maxilla and orbital bones • Sporadic form: children > adults, 1%–2% of all NHL in United States, male:female = 2 or 3 : 1, distal ileum, cecum and mesenteric lymph nodes • Immunodeficiency associated BL: adults > children, HIV infection, predominantly lymph nodes • Often bulky tumor disease due to rapid proliferation rate of tumors • Prognosis dependent on stage, particularly bone marrow involvement

Clinical Characteristics

Continued

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CHAPTER 14  Orbit

TABLE 14.4  Morphological, Immunophenotypic, Molecular–Biological, and Clinical

Characteristics of the Five Lymphoma Subtypes Presented—cont’d Lymphoma Subtype Morphology Classical HL

Tumor Cell Immune Profile

• Tumor cells: typical HRS cells • Architecture: mainly diffuse or an interfollicular infiltrate composed of eosinophils, neutrophils, lymphocytes, plasma cells, and macrophages

+

+

• CD30 , CD15 • EBV+ (40-50%) • EMA 5%+ • CD20−/+, CD79−/+ • CD45−, J-chain−

Molecular Biological Changes

Cell of Origin

• Clonal IgH rearrangements with numerous somatic mutations without “ongoing” mutations

• Germinal center B cell

Clinical Characteristics • Mainly 30–40 years • Male:female = 3 : 1 • Lymph node enlargement, particularly cervical, axillary, and inguinal • Extranodal involvement mainly in mediastinum, spleen, less often lung, liver, and bone marrow • B symptoms in 35% of cases • Prognosis dependent on stage of disease at diagnosis • 5-year survival: 85%–90%

BL, Burkitt’s lymphoma; DLBCL, diffuse large cell B-cell lymphoma; EBV, Epstein–Barr virus; EMZL, extranodal marginal zone B-cell lymphoma; FDC-MW, follicular dendritic cell meshworks; FL, follicular lymphoma; HL, Hodgkin’s lymphoma; IgH, immunoglobin heavy chain; IgL, immunoglobulin light chain; NHL, non-Hodgkin’s lymphoma. † Rearrangements demonstrable in only 50%–70% of cases due to the presence of somatic mutations. (From Coupland SE, Hummel M, Stein H: Ocular adnexal lymphomas: five case presentations and a review of the literature. Surv Ophthalmol 47:470, 2002, with permission from Elsevier.)

TABLE 14.5  Immunophenotype Analysis of Ocular Adnexal Lymphoproliferative Lesions Type EMZL Follicular Mantle cell Lymphoplasmacytic Diffuse large B-cell lymphoma

CD3

CD5

− − − − −

− − + + − (+)

CD10 − + − − + (25%–50%)

CD20

CD23

CD43

CD79

Bcl-2

Bcl-6

Cyclin D1

+ + + + +

− +/−

+ −

+

− + −

− +

− − +

+

+

(From Bardenstein DS: Ocular adnexal lymphoma: Classification, clinical disease, and molecular biology. Ophthalmol Clin North Am 18:187, 2005.)

TABLE 14.6  Genetic Alterations in Types of Non-Hodgkin’s Lymphoma Presenting as Ocular

Adnexal Lymphoproliferative Lesions Type

Genetic Change

Mechanism

Frequency (%)

Proto-Oncogene

EMZL

t(11;18)(q21;q21)

Follicular Mantle cell Lymphoplasmacytic Diffuse large B-cell lymphoma

t(14;18)(q32;q21) t(11;14) T(9;14)(p13;q32) Der(3)(q27)

Fusion Transcript deregulation Transcript deregulation Transcript deregulation Transcript deregulation Transcript deregulation

50 Rare 80–90 70 50

AP12/MLT Bcl-10 Bcl-2 Bcl-1 (encodes cyclin D1) PAX-5 Bcl-6

(From Bardenstein DS: Ocular adnexal lymphoma: Classification, clinical disease, and molecular biology. Ophthalmol Clin North Am 18:187, 2005.)

Neoplasms and Other Tumors

571

TABLE 14.7  B-Cell Lymphomas and Associated Genetic Aberrations Most Common

Others

Utility in Diagnosis

DLBCL

BCL6 (translocation or mutation)

BCL2 (translocation), MYC (translocation)

FL

t(14;18)(q32;q21) IGH@-BCL2

BCL6 translocation

SLL/CLL

del(13q14)

del (11q22–23), +12, del(17p13), del(6q21)

MCL

t(11;14)(q13;q32) CCNDI-IGH@

Rare translocations involving cyclin D2 or D3

MZL

t(11;18)(q12;q21), BIRC3-MALTI

t(14;18)(q32;q21), IGH@-MALTI t(3;14)(p14.1;q32), FOXPI-IGH@ t(1;14)(p22;q32), IGH@-BCLI0

BL

t(8;14)(q24;q32), MYC-IGH@

t(2;8)(p12;q24), IGK@MYC t(8;22)(q24;q11), MYC- IGL@

None required for diagnosis; MYC testing helpful in predicting aggressive disease The presence of a t(14;18)(q32;q21), IGH@-BCL2 can help facilitate the diagnosis del(13q14)—favorable prognosis, del(11q22–23), del(17p13)—unfavorable prognosis The presence of a t(11;14)(q13;q32), CCNDI-IGH@ can help facilitate the diagnosis t(11;18)(q12;q21), BIRC3-MALTI in gastric MALT lymphoma associated with resistance to antibiotic therapy The presence of a t(8;14)(q24;q32), MYC-IGH@ can help facilitate the diagnosis

(From Ochs RC, Bagg A: Molecular genetic characterization of lymphoma: Application to cytology diagnosis. Diagn Cytopathol 40:542, Table I, 2012.)

TABLE 14.8  T-Cell Lymphomas and Associated Genetic Aberrations Most Common

Others

Utility in Diagnosis

ALCL

t(2;5)(p23;q35) NPMI-ALK

Numerous variant ALK translocations

ALK translocations favorable

Peripheral T-cell lymphoma T-cell prolymphocytic leukemia

Gains: 7q, 8q, 17q, 22q Losses: 4q, 5q, 6q, 9q, 10q, 12q, 13q Inv14q(q11;q32)

Hepatosplenic T-cell lymphoma

i(7)(q10)

Enteropathy-associated T-cell lymphoma Extranodal NK/T-cell lymphoma, nasal type

9q31.3 complex amplifications del(6)(q21q25), i(6)(p10)

Not established t(8;8)(p11–12;q12), trisomy 8q, idic(8p11)

del16q12.1

The presence of inv(14q)(q11;q32) helps to facilitate the diagnosis The presence of i(7)(q10) helps to facilitate the diagnosis The presence of the 9q amplification helps to facilitate the diagnosis Not established

(From Ochs RC, Bagg A: Molecular genetic characterization of lymphoma: Application to cytology diagnosis. Diagn Cytopathol 40:542, Table III, 2012.)



A. The term “ocular adnexal lymphoproliferative disease” encompasses all lymphoid diseases around the eye whether there are or are not malignant features, which can be assessed best using histomorphic, immunophenotypic, and molecular genetic techniques. 1. If one considers the ocular adnexa as a region including the orbit, conjunctiva, eyelid and caruncle, the relative frequency of such lesions is orbit 46%, conjunctiva 29%, eyelid 21% and caruncle 4%. 2. In one series, approximately 12% of these ocular adnexal cases were lymphoma including extranodal marginal-zone B-cell lymphoma 64%, follicle center lymphoma 10%, diffuse large cell B-cell lymphoma 9%, plasmacytoma 6%, and lymphoplasmacytic lymphoma 5%. In a series of 5002 conjunctival tumors, lymphoma comprised 7% of tumors and benign reactive lymphoid hyperplasia represented only 2% of lesions. 3. Ocular adnexal lymphomas account for 5%–10% of all extranodal lymphomas. Lymphomas are the

most common malignancy of the orbit and lacrimal gland, and third most common behind squamous cell carcinoma and melanoma among conjunctival malignancies. 4. The eyelid more commonly is involved secondarily due to spread from the conjunctiva or orbit. 5. Among 263 conjunctival lymphomas in an international multicenter review, the most frequent subtype was extranodal marginal zone lymphoma (68%), followed by follicular lymphoma (16%), mantle cell lymphoma (7%) and diffuse large B-cell lymphoma (5%). 6. In a recent international multicenter retrospective study of lymphoma of the eyelid, the relative frequencies of forms of lymphoma were: extranodal marginal zone lymphoma 37%, follicular lymphoma 23%, diffuse large B cell lymphoma 10%, mantle cell lymphoma 8%, and mycosis fungoides 9%. Diffuse large B-cell lymphoma and mycosis fungoides frequently were secondary lymphomas 56% and 88%, respectively.

572





CHAPTER 14  Orbit

7. In 2016 the World Health Organization revised its 2008 classification of lymphoid and myeloid neoplasms and acute leukemia. a. Recent reviews summarize the significant features of these revisions. b. Only a few of the key aspects of the revisions can be included in this chapter; however, the reader is referred to the preceding references for specific details. c. The TMN classification is the accepted scheme for staging primary ocular adnexal lymphoma.

3. In the past, atypical lesions doubtless included many low-grade non-Hodgkin’s lymphomas. 4. Fortunately, modern technologies, including molecular genetics, allow this latter group more frequently to be divided into reactive lymphoid hyperplasia or lymphoma. 5. IgG4-related disease also must be excluded in these cases. 6. Fig. 14.45 presents the diagnostic flow scheme for differentiating reactive lymphoid hyperplasia from atypical lesions.

Non-Hodgkin’s lymphoma is more common among Asians and Pacific Islanders than among Western populations.



8. Among extraconal orbital tumors, 22% are reactive lymphoid hyperplasia and 20% are malignant lymphoma. a. In one study, 20% of orbital lymphoid lesions were idiopathic chronic inflammation, 40% were lymphoid hyperplasias, and 40% were lymphomas. The relative percentage of B cells in the various lesions was inflammation 35%, hyperplasia 65.9%, and lymphoma 87.3%.











Probably represents approximately 8% to 27% of the cases of lymphoproliferative lesions of the ocular adnexa.

b. If one considers ophthalmic and intraocular nonHodgkin’s lymphoma, 42% are intraorbital and 35% are conjunctival. c. There may be a high incidence of orbital malignant lymphoma among Japanese patients. About 3% of patients who have chronic lymphocytic leukemia develop non-Hodgkin’s syndrome (usually large B-cell lymphoma); this sequence of malignancies is called Richter’s syndrome. In general, ocular involvement with chronic lymphocytic leukemia is rare. d. Although Hodgkin’s lymphoma represents almost 30% of all lymphoma, orbital involvement with Hodgkin’s lymphoma is rare although even bilateral orbital involvement has been reported. e. Orbital lymphomatoid lesions usually present as a palpable mass with proptosis, diplopia, and conjunctival (“salmon-pink”) swelling. Uncommon presentations include ptosis. B. Reactive lymphoid or plasma cell hyperplasia (RLH) (see Fig. 14.43) 1. Historically, this term referred to lymphoid lesions that were benign to light microscopic examination and the term “atypical” was used for lesions that were not unequivocally benign but which, on the other hand, were not frankly malignant. 2. More recently, the term has been used for lesions that are entirely benign both from a morphologic perspective and on an immunophenotypic basis.









7. “True” reactive lymphoid hyperplasia usually consists of a virtually pure lymphoproliferative lesion of small lymphocytes that, by immunophenotyping and immunogenotyping, shows a polyclonal T- and B-cell infiltrate and an absence of Dutcher bodies; mitoses, if present, are restricted to germinal centers where macrophages contain scattered debris (tingible bodies). a. Reactive lymphoid follicles reminiscent of normal lymphoid architecture are usually seen within the infiltrate. 1) The B and T cells demonstrate appropriate compartmentalization with B cells being located in the follicular zone and T cells in the interfollicular zone. 2) Germinal center cells are positive for CD10, CD20, BCL6 and retinoblastoma protein and follicular dendritic cells are positive for CD21 and CD23. CD3 and CD5 are located within the interfollicular zones. 3) Follicles of RLH are negative for BCL2 compared to follicular lymphoma where they are positive. b. Polyclonal expression of the immunoglobulin heavy and light chains and no IgH gene rearrangement on PCR are usually found. c. No polymorphism or ancillary evidence of inflammation occurs. d. The tumors lack anaplasia. e. Various infectious organisms have been investigated as possible causes for RLH. Although no specific infectious cause has been identified relative to the ocular adnexa, H. pylori infection is associated with lymphoid hyperplasia at other anatomic sites. f. Among 24 patients with childhood conjunctiva RLH, the mean age was 11 years and 23 were male. Fifty percent of the cases were unilateral, and the lesion was nasally located in 96% of cases. All patients had a benign clinical course without systemic dissemination or malignant transformation.

Neoplasms and Other Tumors

Nevertheless, PCR demonstrated monoclonality suggestive of lymphoma in two cases. C. Lymphoma (see Figs. 14.46–14.50) 1. Immunophenotyping and genetic profiling are helpful in characterizing non-Hodgkin’s lymphomas (see Table 14.4 and 14.5). 2. Non-Hodgkin’s lymphoma—B-cell 3. The following diagnostic criteria point to malignant extranodal B-cell lymphoma: a. The absence of the following histologic tetrad: 1) Cellular polymorphism (i.e., different types of inflammatory cells, including lymphocytes, non-Dutcher body-containing plasma cells, histiocytes, and eosinophils). a) Dutcher bodies are intranuclear pseudoinclusions. 2) Lymphoid follicles with germinal centers. Mitotic figures are normally found in the germinal centers of lymphoid follicles. Although lymphoid follicles are highly suggestive of inflammatory pseudotumors, they may occur in small B-cell lymphomas (e.g., ENMZL/MALT lymphomas).

this scheme, mature naïve B-cells would produce mantle cell lymphoma. Germinal centers would give rise to follicular lymphoma and diffuse large B-cell lymphoma. Finally, memory B cells would be the source for extranodal marginal zone lymphoma and lymphoplasmacytic lymphoma. The term “low grade lymphoma” frequently is used to describe ocular adnexal extranodal marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma and chronic leukemia/small lymphocytic lymphoma. Nevertheless, the diagnosis can be difficult in some cases particularly in the case of extra nodal marginal zone lymphoma.



3) Absence of atypia. Absence of atypia, however, can also occur in small B-cell lymphomas.







4) Ancillary evidence of inflammation (e.g., plasmacytoid cells, Russell bodies, and proliferation of capillaries with swollen, enlarged endothelial cells) b. The following findings are consistent with a diagnosis of lymphoma: 1) Formation of a mass, tissue architectural effacement, cellular monomorphism, cytologic atypia, presence of proliferative centers, and plasma cells containing Dutcher bodies are all features of low-grade B-cell lymphomas. 2) Immunoglobulin light-chain restriction or an aberrant B-cell phenotype are immunologic features that, if demonstrated, help to support a malignant diagnosis. a) A ratio of κ/λ immunoglobulin lightchain-expressing B lymphocytes in excess of 5 : 1 or less than 0.5 : 1 indicates a monoclonal κ or λ B-cell population. b) Immunoglobulin light-chain restriction is accepted as a marker of clonality in identifying B-cell lymphomas. 4. It has been postulated that the stage of maturation of B-cells at the time of malignant transformation correlates with the type of lymphoma produced. In

573







5. Extranodal marginal zone lymphoma of mucosaassociated lymphoid tissue (ENMZL/MALT lymphoma). a. In the World Health Organization classification system, MALT lymphomas are classified as extranodal marginal-zone lymphomas; however, some note that many marginal zone lymphomas of orbital soft tissue lack features associated with MALT-type marginal zone lymphomas, and suggest that the diagnosis of MALT lymphoma be avoided in these cases. Additionally, orbital marginal zone lymphomas infrequently demonstrate reactive follicles, rarely show epithelial tissue, and do not show lymphoepithelial lesions. Conversely, the lacrimal gland, conjunctiva, and lacrimal sac are considered MALT. Therefore, the inclusive designation, ENMZL/MALT lymphoma, will be used in this discussion so as to respect the most current terminology and to reference the traditional designation that has been more indiscriminately applied to all adnexal areas. b. It is the most frequent ocular adnexal lymphoma. It is found in 42% of all lymphoid lesions and comprises 62% of all primary ocular adnexal lymphoma. c. A high percentage of orbital lymphomas have clinical, pathologic, and biologic ENMZL/MALT characteristics. 1) Clinically, ENMZL/MALT tumors arise in extranodal sites from post-germinal center memory B cells, mainly mucosal. 2) Some suggest that the incidence of ENMZL/ MALT lymphoma is increasing. d. Classically, the histopathology of ENMZL/MALT lesions recapitulates Peyer’s patches (i.e., reactive follicles), marginal zone or monocytoid B cells, plasma cells, occasional Dutcher bodies, scattered transformed blasts (entoblasts and immunoblasts), and sometimes epithelial lesions in the form of lymphoepithelium. The cells are small to medium-sized with round or indented nuclei, clumped chromatin, inconspicuous nucleoli,

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and inconspicuous to moderately abundant cytoplasm. e. ENMZL/MALT tumors are positive for CD20, BCL2, paired boc5 (PAX5) and CD79A, but usually do not express CD5, CD10, or CD23. Fewer than 5% are positive for CD5. f. Trisomy of chromosomes 3, 12, and 18 are frequently present; however, gain of chromosome 6, including trisomy, is more specific for ocular adnexal ENMZL/MALT tumors. g. Gene translocations target MALT1, BCL10, or FOXP1 genes. The three translocations seen in MALT lymphoma, namely t(14;18)(q32;q21)/ IGH-MALT1, t(1;14)(p22;q32)/BCL10-IGH, and t(11;18)(q21;q21)/BIRO (API2)-MALT1, are capable of activating both canonical and noncanonical NF-κB pathways. Nevertheless, the frequency of translocations involving the MALT1- and IGH-gene loci is low in the ocular region. h. Biologically, the tumor cells are B cells, proliferate in mucosal and other extranodal sites, and usually show reactive germinal centers, often interacting with epithelium. 1) Chronic antigenic stimulation, particularly in the setting of chronic infection, has been postulated to contribute to the development of these lesions. a) Chlamydia (C. psittaci and C. pneumoniae) and hepatitis C may play a role in the development of ENMZL/MALT lymphoma. b) Treatment of such infections may lead to lymphoma response in as high as 75% to 80% of cases after H. pylori eradication. c) Moreover, there may be a geographic heterogeneity in the distribution of lymphomas that may be attributed to infectious causes. d) Nevertheless, there is a subset of these lymphomas that are C. psittaci-negative and for which the molecular mechanisms underlying their pathogenesis remain to be elucidated. 2) NF-κB dysregulation may play a role in the oncogenesis of these tumors. Rarely, ENMZL/MALT present as a scleritis.





tumors

can

i. Many genetic alterations have been uncovered for non-Hodgkin’s lymphomas (see Tables 14.6–14.8) 6. Follicular lymphoma. a. It is the second most common ocular adnexal lymphoma and comprises 17% of such lesions. It may occur more frequently in elderly women.





















b. In one study in the ocular adnexa, it occurred most frequently in the orbit and conjunctiva. In another report, the distribution was lacrimal gland 38%, and orbit 33%. c. Among 98 patients with ocular adnexal follicular lymphoma, 70% had primary disease, 19% had concurrent systemic disease, and 10% presented with an ocular adnexal relapse. d. Histologically composed of uniform densely packed atypical follicles. 1) There are small centrocytes with cleaved, indented, angulated nuclei, and large blastic centrocytes, which may be cleaved or noncleaved. 2) Variable large cells, which are centroblasts or immunoblasts with vesicular nuclei containing nucleoli often adjacent to the nuclear membrane, may be present. e. Usually positive for CD20, CD10, BCL2, and BCL6. Usually negative for CD5, CD43 and MUM1. f. The translocation t(14;18)(q32.3;q21.3) is a hallmark of follicular lymphoma and is present in 85% of cases. 1) It is associated with recurrence following therapy. 2) This translocation leads to the upregulation of BCL2 and the prevention of apoptosis. 3) In one study, the overall 10-year survival in all patients was 59%. 7. Diffuse large B-cell lymphoma (DLBCL) a. Most common non-Hodgkin’s lymphoma encompassing 25% to 30% of cases, although it is not the lymphoma most frequently involving the ocular adnexa where it represents only 10% of such lesions. b. It most commonly presents unilaterally in the orbit in elderly patients. c. There is diffuse involvement by large lymphoid cells that stain positive for the B-cell markers CD19, CD20, CD79a and PAX5, and variably express BCL2. d. MYC oncogene rearrangement is associated with a worse outcome and may be accompanied by other translations involving BCL2 and/or BCL6. e. Ki-67 proliferation index is moderate to high. f. Survival is associated with anatomic location. 1) The 5-year survival for vitreoretinal disease is 41.4% compared to that involving the ocular adnexal or uveal disease (59.1%). 2) Disease in both of these regions has a better survival than that located outside the CNS and ophthalmic regions. Others have suggested a much worse prognosis. g. Primary DLBCL comprises 57% of these lesions in the ocular adnexa. Most patients with ocular

Neoplasms and Other Tumors











adnexal DLBCL are diagnosed with TMN T2 disease and have a median survival of 3.5 years. h. High-grade B-cell lymphomas have MYC and BCL2 and/or BCL6 gene rearrangements, so called “double hit” lymphomas. They are aggressive tumors that have a separate provisional designation in the World Health Organization Classification of Lymphoid Tumors. 1) These tumors may have morphologic features of DLBCL, Burkitt’s lymphoma (BL), or intermediate between DLBCL and BL. 2) Immunohistochemical and cytogenetic analysis are required to make this characterization. 3) It appears that there are fundamental differences in the miRNA expression between ocular adnexal ENMZL and DLBCL, primarily due to differences in MYC and NF-κB regulatory pathways. i. A subset of these DLBCL are Epstein–Barr virus (EBV)-positive, and four types of EBV-positive DLBCL have been described: monomorphic (DLBCL-like, monotonous sheets of large cells), polymorphic in the inflammatory background, T-cell/histiocyte-rich large cell lymphoma, and plasmacytoid differentiation. 1) The tumor cells express pan B-cell markers (CD20, PAX55, CD79a, OCT-2 and BOB-1). 2) They are mostly CD30-positive but lack CD15 expression. 3) Other EBV-associated B-cell lymphoproliferative diseases are: infectious mononucleosis, chronic active EBV of B-cell type, ENV mucocutaneous ulcer, diffuse large B-cell lymphoma associated with chronic inflammation and lymphomatoid granulomatosis. j. DLBCL of the orbit has been reported in association with idiopathic CD4+ lymphocytopenia (HIV-negative AIDS). 8. Burkitt’s lymphoma (BL) (see Fig. 14.48) a. It can be subdivided into African (endemic), nonendemic/sporadic American), and human immunodeficiency-associated subtypes. b. Endemic BL (a diffuse, poorly differentiated, large B-cell lymphoma) is the most common malignant tumor among children in tropical Africa (it is the most common orbital tumor in Uganda, regardless of age); its distribution, however, is worldwide. 1) It is one of the fastest-growing malignancies in the pediatric population in the United States. 2) Its incidence in Africa is up to 50 times higher than in the Western world. 3) Peak incidence of endemic is in years 4 to 7 while sporadic variety more common in children and young adults.

575

4) Immunodeficiency-associated BL is 1000 times more common in HIV-infected individuals compared to those negative for HIV. Burkitt’s lymphoma and diffuse large B-cell lymphoma constitute the majority of nonlymphoblastic lymphomas in the pediatric population.









5) The tumor has a predilection for the face and jaws, and may be induced by an insectvectored agent in the endemic variety. Nonendemic Burkitt’s lymphoma seldom presents involving the orbit, paranasal sinuses and facial bones. c. The incidence of Burkitt’s lymphoma is markedly increased when associated with infection with the malarial organism Plasmodium falciparum (PF). 1) Nevertheless, EBV is not spread by mosquitoes. 2) It appears that PF induces the DNA-mutating and double-strand-breaking enzyme activation-induced cytidine deaminase (AID). 3) Moreover, animal studies have demonstrated that AID induced by malaria is a risk factor for DNA damage and lymphoma. 4) It is postulated, therefore that PF malaria is a risk factor for BL because it drives high throughput virus-infected cells through the lymph node germinal center where it also deregulates AID leading to DNA damage, c-myc translocations and lymphoma. d. In 70%–100% of cases, BL involves the MYC oncogene on chromosome 8 usually at 8q24.21 so that one of the immunoglobulin genes is brought in proximity to MYC and disrupts its normal regulation. (MYC protein also is present in 30%–40% of diffuse large B-cell lymphoma, 60% of high-grade B-cell lymphomas, and 5% of normal germinal center B cells.) 1) In about 70% of cases of BL there also are mutations in TCF3, or its negative regulator ID3, which encodes a protein that blocks TCF3 action. 2) Another associated mutation involves CCND3 in 38% of sporadic cases. e. It is aggressive and has an extremely high proliferation fraction and a high fraction of apoptosis, which is responsible for the classic “starry sky” histopathologic appearance of this lesion. f. Epstein–Barr virus (EBV) infection is causative for Burkitt’s lymphoma in the endemic areas and is virtually always detected in lesions in the endemic areas. 1) It is present in 25%–40% of cases of sporadic immunodeficiency-associated BL.

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2) EBV can contribute to genomic instability and may function as an oncogenic role. g. The prognosis for life is poor. h. Histologically, the tumor shows tightly packed, undifferentiated, large B-type lymphoid cells with basophilic cytoplasm with small vacuoles and round nuclei with small nucleoli. There also are scattered large histiocytes that contain abundant, almost clear cytoplasm and phagocytosed cellular debris. i. It is derived from germinal center B cells, which are positive for CD10, BCL6, CD20, CD 79a, and CD45. 1) They are negative for terminal deoxynucleotidyl transferase (TdT), CD5, and BCL2. Ki67 staining approaches 100%. 2) There is a high expression of c-MYC target genes, and low expression of MHC class 1 molecules and NF-κB target genes. 3) The ki67 proliferation index is close to 100%. 9. Mantle cell lymphoma (MCL) a. MCL represent about 6%–7% of all nonHodgkin’s lymphomas. b. It is said to combine the worst characteristics of both the low- and high-grade lymphomas including the incurability of the low-grade lymphomas and the aggressive nature of high-grade lymphomas. c. The cell of origin normally is the mantle zone cell of the lymph node, which is a post-germinal center B cell. d. It is a disease mainly of the elderly and has a male preponderance. e. A chromosomal translocation t(11 : 14)(q13;q32) is the molecular hallmark of MCL and is present in 95% of cases. It results in the overexpression of cyclin D1. 1) Cyclin D1 is detected by immunohistochemistry in 98% of cases. 2) The absence of SOX-11 or a low Ki-67 may correlate with a more indolent form of MCL. f. Immunohistochemical staining is generally positive for CD20 and cyclin-D1; CD5 is positive in about 70% of cases, and p53 is negative in most cases. g. MCL presenting in the ocular adnexal region is associated with advanced-stage disease and short progression-free survival, but an overall survival similar to MCL at other sites. h. Cutaneous precursor B-cell lymphoblastic lymphoma is rare but has presented with orbital bone involvement. 1) Immunohistochemical staining was positive for CD79a and CD43 in all six cases in one report. 2) Cell marker studies by flow cytometry are positive for CD10 and CD19.















3) In another study involving 21 tumors, all were positive for CD20, CD79α, BCL2, and cyclin D-1 and negative for CD3, CD10, CD23, and BCL6. All but 5 showed CD5 coexpression. 10. The majority of extranodal non-Hodgkin’s lymphomas, including those that involve the orbit, are of the B-cell variety (conversely, most that involve the skin are T-cell). 11. A morphologic progression of low-grade, small B-cell lymphoma to diffuse, large-cell lymphoma is well recognized. D. IgG4-related systemic sclerosing disease (see Fig. 14.49) 1. Initial descriptions of this entity were in the pancreas; however, involvement with multiple organs and anatomic locations including the orbit and adnexa, particularly the lacrimal gland, have been cited. a. Typically, there is mass formation with fibrosclerosis and obliterative phlebitis of medium and small veins occurs. b. Most frequently, patients are middle-aged or older men. c. There is an elevation of serum IgG4, which is the least common (3%–6%) of the four subclasses of IgG. 2. It may be difficult to differentiate MALT lymphoma from IgG4-related disease. 3. IgG4-related sclerosing disease may be more common than previously recognized in association with orbital lymphoma. In one study, IgG4-related disease criteria were met in approximately 50% of patients with immunohistochemical diagnosis of orbital MALT lymphoma. 4. It is characterized by the presence of lymphoplasmacytic infiltrate, and fibrosis, which often is storiform. Additionally, there are increased numbers of IgG4-positive plasma cells or an IgG4 to IgG ratio >40%. a. When the ratio of IgG4-expressing plasma cells is high, particularly if they comprise more than 50% of the plasma cells (although others might use 30% or higher as a criteria), IgG4 disease should be suspected. Some would include IgG4 positive plasma cells >100 per high-power field. b. Plasma cells are not atypical. c. Although not usually present, 10%–15% of ocular adnexal patients display B-cell monoclonality, and MALT lymphoma arising in IgG4 patients has been reported. IgG4-related disease may be a precursor to MALT lymphoma in some patients. d. Other features include architectural effacement, prominent lymphoplasmacytic infiltrate, and lack of findings associated with infectious or other lymphoid lesions such as lymphoepithelial lesions. e. It may mimic reactive lymphoid hyperplasia clinically and histologically, so IgG4 and IgG

Neoplasms and Other Tumors

immunostaining should be performed to rule out IgG4-related disease. 5. Eosinophilic angiocentric fibrosis may fall within the spectrum of this disorder. 6. Orbital necrobiotic xanthogranuloma has been found in association with IgG4 disease. 7. It may be associated with the development of lymphoma in the ocular adnexa. 8. Other orbital sclerosing inflammations (Wegener’s disease, sarcoidosis, and Sjögren’s syndrome) and neoplasms (lymphoma and metastatic breast cancer) should be excluded before making the diagnosis of IgG4-related disease. Idiopathic CD4+ lymphopenia (human immunodeficiency virus-negative acquired immunodeficiency syndrome) may be complicated by orbital large B-cell lymphoma. Primary T-cell/histiocyte-rich large B-cell lymphoma also has presented in the orbit. Intravascular lymphoma is a rare, large B-cell non-Hodgkin’s lymphoma that is characterized by the growth of neoplastic cells within the blood vessel lumen. Although usually a cutaneous or central nervous system lesion, it has presented as an orbital mass.





E. Non-Hodgkin’s lymphoma—T cell 1. Represents 10% of non-Hodgkin lymphoma. 2. T-cell lymphoma of the anaplastic large-cell type is defined by mutually exclusive rearrangements of ALK, DUSP22/IRF4, and TP63. 3. Non-Hodgkin’s T-cell lymphomas can be divided into three groups: a. Those derived from prethymic and thymic T cells (lymphoblastic lymphoma/leukemia)









Lymphoblastic lymphoma/leukemia (T-cell leukemia/lymphoma) has an association with a retrovirus, the human T-lymphotropic virus type I (HTLV-I). It has presented with bilateral orbital tumors. It also has presented as a red, painless firm swelling in Tenon’s capsule.



b. Those derived from postthymic or peripheral T cells (called peripheral T-cell lymphomas) and composed of a morphologically and immunologically heterogeneous group of lymphoproliferative disorders (T-cell chronic lymphocytic leukemia, T-prolymphocytic leukemia, monomorphous T-cell lymphoma, immunoblastic T-cell lymphoma) 1) Immunohistochemistry has shown that the following appear to be abnormal or neoplastic T-cell lymphoproliferative disorders: benign lymphocytic vasculitis, lymphomatoid granulomatosis, midline malignant reticulosis, angiocentric lymphoma, and many cases of angioimmunoblastic lymphadenopathy.



577

2) Natural killer (NK) cells are the third cell lymphoid cell line in addition to T and B cells. NK cells and T cells share a common lymphoid precursor. a) NK cells are cytolytic and express cytotoxic molecules including granzyme B and perforin. b) NK cells express CD2, cytoplasmic CD3 epsilon, but not surface CD3, CD16, CD56, CD94, and killer-cell immunoglobulinlike receptors (KIRs). 3) The most recent 2016 World Health Organization classification recognizes that some tumors previously thought to be NK tumors display T-cell markers. Therefore, these lymphomas are classified as NK/T-cell lymphomas to reflect their potential cellular origins. a) NK/T-cell malignancies are uncommon and were previously known as polymorphic reticulosis or angiocentric T-cell lymphomas. The World Health Organization further divides these lesions into NK/T-cell lymphoma (nasal and extranasal types) and aggressive NK-cell leukemia. Approximately 80% of NK/T-cell lymphoma is of the nasal variety. b) The nasal form of NK/T-cell lymphoma, which has a poor prognosis, can arise in the orbit or extend into the orbit and CNS. 4) It has been known by multiple designations including lethal midline granuloma, malignant midline reticulosis, idiopathic midline destructive disease, and nonhealing midline granuloma. 5) It often causes extensive midface destruction related to its propensity for necrosis. 6) The neoplastic cells often display angiocentricity and angiodestruction that can lead to the characteristic tissue necrosis. 7) The cells are large, granular lymphocytes that express CD2, cytoplasmic CD3ε, CD56, and cytotoxic molecules (perforin, granzyme B, T-cell intracellular antigen 1, TIA1). They are surface CD3 negative. 8) It is derived from natural killer cells or cytotoxic T-lymphocytes. 9) There is positivity for Epstein–Barr virus (EBV) encoded RNA or EBV latent membrane protein. a) Plasma EBV DNA is an accurate surrogate biomarker for lymphoma load. 10) The nasal type is endemic to East Asia and parts of Central and South America. 11) The ocular and periocular involvement by NK/T-cell lymphoma usually either is as a uveitis/vitreitis or as an orbital infiltration.

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12) Periorbital involvement is characterized by painless eyelid swelling and a history of sinonasal disease. 13) Extranodal NK/T-cell lymphoma, nasal type can mimic recurrent orbital cellulitis. It also has caused contralateral dacryoadenitis. 14) Conjunctival involvement without nasal or paranasal sinus involvement has been reported. 15) NK/T-cell lymphoma also may exhibit disseminated disease that may originate in a nasal primary. c. Mycosis fungoides (MF) and Sézary’s syndrome (SS) are special forms of cutaneous T-cell lymphomas that have relatively protracted courses (see Fig. 14.50). They are the most common forms of cutaneous T-cell lymphoma and are incurable for the majority of patients. 1) MF constitutes 9%–13% of eyelid lymphomas. a) Sézary’s syndrome is a leukemic variant of mycosis fungoides. i) Characterized by erythroderma, generalized lymphadenopathy, and circulating atypical T cells with cerebriform nuclei (Sézary cells). ii) Palmoplantar hyperkeratosis, generalized alopecia, and severe pruritus are additional symptoms that are associated with Sézary’s syndrome iii) The circulating cells are most frequently CD4-positive; however, CD8-positive variants have been reported. iv) The circulating cells express CCR7 and L-selectin, as well as the differentiation marker CD27, which is consistent with memory T-cells. v) The Sézary cells, which have so-called “cerebriform nuclei,” display skin homing epidermotropism and the formation of Pautrier’s microabscesses, which are intraepidermal collections of malignant cells. 2) MF and its subset, SS, are characterized by monoclonal proliferation of CD4 and CD45RO positive memory T cells that express adhesion molecules such as CCR4 and CLA. Nevertheless, in contrast to the circulating T cells in SS, the T cells isolated from skin in MF lacked CCR7/L-selectin and CD27 but strongly express CCR4 and CLA, which is a phenotype suggestive of effector memory T cells. 3) The most common ocular presentation of MF is eyelid ectropion caused either indirectly by tumor infiltration of the facial skin or directly by tumor involvement of the eyelid skin.

4) Although mycosis fungoides rarely involves the orbit, it does so more commonly than the other T-cell lymphomas. 5) Very rarely, mycosis fungoides can involve the vitreous, or choroid. It also may result in an apparent anterior uveitis. 6) Altered forms of the retrovirus HTLV-I have been incriminated in the causation of some cases of mycosis fungoides and Sézary’s syndrome. F. Hodgkin’s lymphoma (HL)‡ 1. It is the most common lymphoma affecting younger individuals. It has a bimodal distribution with peaks at ages 15 to 34 and after age 60 years. a. It represents 10% of lymphomas. b. Classic HL is aggressive in 95% of cases. c. Nevertheless 90% of early-stage patients are cured with conventional treatment. 2. Classic HL is divided into four variants on a morphologic basis. They are in decreasing order of frequency: nodular sclerosing, mixed cellularity, lymphocyte rich, and lymphocyte depleted. a. Nonclassical HL is the nodular lymphocyte predominant variety, which is much less aggressive than classic HL. b. Nodular sclerosing HL represents 80% of cases in Western countries. 3. The classic Reed–Sternberg (RS) cell is very uncommonly distributed in the tissue, but is characteristic of Hodgkin’s lymphoma. a. It is a large cell derived from germinal center B lymphocytes, and is resistant to apoptosis. b. It has a large rim of cytoplasm and two or more large nuclei with central, inclusion-like nucleoli, often acidophilic on H & E staining. c. Hodgkin (H) cells have only one nucleus. d. RS and H cells express CD30, MUM1, variably express CD15, and typically weakly express PAX5. H and RS cells usually have downregulated B-cell markers. e. Tumor cells of the nodular lymphocytepredominant HL resemble germinal center B cells in their immunophenotype. 4. Hodgkin’s lymphoma very rarely presents initially with orbital involvement, and orbital involvement is rare in any stage of the disease. 5. Epstein–Barr virus is found in 30%–40% of cases of classic HL in Europe and North America. In contrast, it is found in 80% of cases in Central and South America. XI. Leukemia† (Fig. 14.51; see Chapter 9) A. Orbital leukemic infiltrates most commonly occur late in the disease. B. Myeloid sarcoma (MS), also known as chloroma or extramedullary granulocytic sarcoma, is rare and usually is associated with systemic disease given that 65%–85% of patients with myeloid sarcoma have preexisting acute

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Neoplasms and Other Tumors

l

l

s

A

s

B

b b

r

C

r

D

Fig. 14.51  Leukemia. A, A 9-year-old boy who presented with a left, painless exophthalmos died approximately two years after diagnosis. Initially, the work-up, including a complete blood count, showed normal results. Orbital biopsy was performed. B, Histologic section shows a diffuse cellular infiltrate of primitive granulocytic leukemic cells (l, large blast cells; s, small blast cells). C, Bone marrow smear shows blast cells (b, blast cells; r, red blood cells). Acute granulocytic leukemia diagnosed. D, A touch preparation of another case of granulocyte sarcoma shows Auer rods. (Case in A–C reported by Brooks HW, Evans AE, Glass RM et al.: Chloromas of the head and neck in childhood: The initial manifestation of myeloid leukemia in three patients. Arch Otolaryngol 100(4):306, 1974; D, courtesy of Dr. RC Eagle, Jr., who presented case to the meeting of the Verhoeff Society, 1994.)





myeloid leukemia or concurrent acute myeloid leukemia. Moreover, patients without preexisting disease will exhibit it within a mean of 7 months after presentation. 1. Orbital involvement may be the presenting manifestation of MS. a. Such involvement may be reflected in exposure keratopathy. b. Cases presenting as fulminant orbitopathy and orbital pseudotumor in the setting of acute myeloid leukemia also have been reported. 2. The term, “chloroma” derives from green tint of these lesions due to the presence of myeloperoxidase. 3. Myeloid sarcoma may be a reflection of underlying acute myeloid leukemia or a myeloproliferative disorder such as chronic myelogenous leukemia, multiple myeloma, myelodysplastic syndrome or myelofibrosis. 4. It occurs most frequently in young children, although it is rare even in this group. a. Overall, leukemias and lymphomas account for 10% of orbital tumors in children.







b. The orbit is the second most common location for MS in children. c. The most common presentation is unilateral exophthalmos in children. MS should be considered, particularly, in the presence of bilateral disease. d. In children, the differential diagnosis should include rhabdomyosarcoma, neuroblastoma metastases, and Burkitt’s lymphoma. Neuroblastoma and Ewing’s sarcoma are associated with more bone destruction. 5. Immunostaining of 31 orbital biopsy-proven cases was positive for MPO, CD34, CD43, and CD117 in all cases. CD45 was positive in 71%. In all cases, tumor cells were negative for CD20, CD3, EMA, panCK, NSE, CD30, synaptophysin, and HMB45. Ki67 activity ranged from 56%–89%. 6. MS has presented as an eyelid mass, and with proptosis and facial palsy. C. Other recently reported leukemic causes of exophthalmos are chronic (CLL) and acute (ALL) lymphocytic leukemia.

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1. CLL has been documented to develop Richter syndrome in the orbit as the sole extranodal site. 2. Orbital apex tumor has been caused by CLL. XII. Monoclonal and polyclonal gammopathies‡ A. Monoclonal (single species of antibody) and polyclonal (multiple species of antibodies) macroglobulinemia may be seen in a variety of lymphoproliferative disorders such as nodular lymphoid hyperplasia, immunoblastic lymphadenopathy, nodular malignant lymphoma, and the plasma cell dyscrasias multiple myeloma, Waldenström’s macroglobulinemia, and rare entities such as light-chain deposition disease and heavy-chain disease. 1. Monoclonal gammopathies are immunoglobulin products of single clones of plasma cells and B lymphocytes; polyclonal gammopathies are produced by more than one clone. 2. Most monoclonal gammopathies do not evolve into a malignant condition (all polyclonal gammopathies do not so evolve) and are termed monoclonal gammopathies of undetermined significance. B. Multiple myeloma‡ (MM) (Fig. 14.52) 1. MM shows evidence of bone marrow plasmacytosis, monoclonal gammopathy in serum or urine (Bence Jones protein), and lytic bone lesions.

2. Direct orbital infiltration by myeloma cells, mimicking a primary orbital tumor, is uncommon. a. The orbital involvement, however, may be the initial manifestation of the systemic disease. 3. Extramedullary plasmacytoma (EMP) a. Represents 3% of malignant plasma cell tumors, and 80% of these lesions are located in the head and neck. b. EMP is more common in males between the 6th and 7th decades. c. In a review of 30 orbital plasmacytomas, 60% of patients were diagnosed with MM before and 37% were diagnosed with MM after orbital plasmacytoma. Four distinct anatomical patterns were identified for these lesions: (1) bony plasmacytoma affecting the superotemporal orbit, epidural space and temporal fossa (50% of patients); (2) discrete orbital plasmacytoma (23%); (3) infiltrative plasmacytoma either originating from a sinus (13%); or (4) originating from the floor and infiltrating facial soft tissue (13%). d. Isolated plasmacytoma of the lateral rectus muscle and medial rectus muscle without evidence of MM have been the subjects of separate reports.









A

B

C

D Fig. 14.52  Multiple myeloma. A, Left exophthalmos present. B, Computed tomography scan shows mass (+) in orbital region. C, Immunoperoxidase-stained sections show many plasma cells with negative staining for λ light chains on left panel and positive staining for κ light chains on right. D, Electron microscopy shows abnormal plasma cells. (Case presented by Dr. MW Scroggs to the meeting of the Eastern Ophthalmic Pathology Society, 1989.)

Neoplasms and Other Tumors



Another presentation of the tumor was with diplopia and variable ptosis. e. Primary orbital plasmacytoma has mimicked a lacrimal gland tumor. 4. Bilateral orbital ecchymoses may indicate the presence of immunoglobulin light chain amyloidosis related to multiple myeloma. Some cases show necrobiotic xanthogranuloma of the eyelid. The eyelids may also show characteristic hemorrhagic lesions.



C. Waldenström’s macroglobulinemia‡ 1. Waldenström’s macroglobulinemia is a small B-cell lymphocytic lymphoma that produces monoclonal IgM, a pentameric immunoglobulin of high molecular weight. 2. Clinical symptoms are mainly related to anemia, bleeding, or symptoms of hyperviscosity. A progressive macroglobulinemia-associated retinopathy may develop with associated antibodies against the connecting cilia of the photoreceptors.

A

D. In vitro immunologic and immunohistochemical techniques can aid in the diagnosis of plasma cell infiltrates. E. Corneal, and even iris, crystals can be found in some patients who have monoclonal gammopathy. F. Intranuclear and intracytoplasmic inclusions may be found in plasma cells and lymphocytes. 1. Intranuclear pseudo-inclusions (Dutcher bodies; see Fig. 14.43D) are invaginated PAS-positive collections of monoclonal macroglobulins. In some cases, the inclusions show no PAS positivity. 2. Intracytoplasmic inclusions (Russell bodies; see Fig. 1.16, and Chapter 1) are PAS-positive collections of monoclonal or polyclonal macroglobulins.

Secondary Orbital Tumors I. Direct extension† A. Intraocular neoplasms, especially malignant melanoma and retinoblastoma B. Eyelid neoplasms, especially basal cell carcinoma, squamous cell carcinoma, malignant melanoma, and sebaceous gland carcinoma C. Conjunctival neoplasms, especially squamous cell carcinoma and malignant melanoma D. Paranasal sinus cysts (mucoceles; Fig. 14.53) and neoplasms, especially squamous cell carcinoma, adenoid

B Fig. 14.53  Orbital mucocele. A, A 66-year-old man had left exophthalmos for six months and a 40-year history of sinusitis and a number of facial injuries. B, Histologic section of the surgically removed mucocele shows that the lumen is lined by respiratorytype, pseudostratified, ciliated columnar epithelium (shown with increased magnification in C) and contains scattered round inflammatory cells in its wall. (Courtesy of Dr. WR Green.)

C

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A

B

C

D Fig. 14.54  Metastatic neuroblastoma. A, A 12-year-old child who had had abdominal neuroblastoma at age four years presented with sudden-onset ecchymosis of right lower lid. B, Computed tomography scan shows mass in right temporal fossa and erosion into sphenoid sinus and orbit. Histologic appearance similar to retinoblastoma in bone marrow (C) and orbit (D). (Case presented by Dr. E Torczynski at the meeting of the Eastern Ophthalmic Society, 1994.)

cystic carcinoma (malignant cylindroma), and mucoepidermoid carcinoma E. Intracranial, especially meningioma II. Metastatic† A. Metastases from other cancers constitute 1% to 13% of orbital tumors. B. Neuroblastoma in children usually occurs as a late manifestation of the disease. Frequently, the orbital metastases are heralded by the onset of lower-lid ecchymosis (Fig. 14.54). C. Breast cancer accounts for 48% to 53% of orbital metastases followed by metastatic prostate carcinoma, melanoma and lung cancer.

In the past, breast carcinoma was much more common in women than lung carcinoma. With increased smoking by women, however, lung carcinoma has become much more common. Lung carcinoma tends to metastasize early, whereas breast metastases tend to be a late manifestation.



D. All other sites of primary neoplasms are rare.   References available online at expertconsult.com.

Bibliography

BIBLIOGRAPHY Normal Anatomy Bernardo A, Evins AI, Mattogno PP, et al: The orbit as seen through different surgical windows: extensive anatomosurgical study, World Neurosurg 106:1030–1046, 2017. Buffam FV: Lacrimal disease. In Podos SM, Yanoff M, editors: Textbook of ophthalmology (vol 4), New York, 1993, Gower Medical, pp 7.1–7.6. D’Août C, Nisolle JF, Navez M, et al: Computed tomography and magnetic resonance anatomy of the normal orbit and eye of the horse, Anat Histol Embryol 44:370–377, 2015. Dutton JJ: Clinical anatomy of the orbit. In Yanoff M, Duker JS, editors: Ophthalmology, ed 2, St. Louis, 2004, Mosby, pp 641–648. Levine MR, Larson DW: Orbital tumors. In Podos SM, Yanoff M, editors: Textbook of ophthalmology (vol 4), New York, 1993, Gower Medical, pp 10.4–10.13. Matsuo T, Takeda Y, Ohtsuka A: Stereoscopic three-dimensional images of an anatomical dissection of the eyeball and orbit for educational purposes, Acta Med Okayama 67:87, 2013. Obata H, Yamamoto S, Horiuchi H, et al: Histopathologic study of human lacrimal gland: statistical analysis with special reference to aging, Ophthalmology 102:678, 1995. Wojno TH: Orbital trauma and fractures. In Podos SM, Yanoff M, editors: Textbook of ophthalmology (vol 4), New York, 1993, Gower Medical, pp 9.1–9.4.

Exophthalmos Fang ZJ, Zhang JY, He WM: CT features of exophthalmos in Chinese subjects with thyroid-associated ophthalmopathy, Int J Ophthalmol 18:146, 2013. Guo J, Qian J, Yuan Y: Computed tomography measurements as a standard of exophthalmos? Two-dimensional versus threedimensional techniques, Curr Eye Res 29:1–7, 2018. Kodsi SR, Shetlar DJ, Campbell RJ, et al: A review of 340 orbital tumors in children during a 60-year period, Am J Ophthalmol 117:177, 1994. Shields JA, Bakewell B, Augsburger JJ, et al: Classification and incidence of space-occupying lesions of the orbit: A survey of 645 biopsies, Arch Ophthalmol 102:1984, 1606. Zimmerman RA, Bilaniuk LT, Yanoff M, et al: Orbital magnetic resonance imaging, Am J Ophthalmol 100:312, 1985.

Developmental Abnormalities Bögershausen N, Altunoglu U, Beleggia F, et al: An unusual presentation of kabuki syndrome with orbital cysts, microphthalmia, and cholestasis with bile duct paucity, Am J Med Genet A 170:3282–3288, 2016. Hoepner J, Yanoff M: Craniosynostosis and syndactylism (Apert’s syndrome) associated with a trisomy 21 mosaic, J Pediatr Ophthalmol 8:107, 1971. Kivelä T, Tarkkanen A: Orbital germ cell tumors revisited: A clinicopathological approach to classification, Surv Ophthalmol 38:541, 1994. Li W, Gong C, Qi Z, et al: Identification of AAAS gene mutation in allgrove syndrome: a report of three cases, Exp Ther Med 10:1277–1282, 2015. Pasquale LR, Romayananda N, Kubacki J, et al: Congenital cystic eye with multiple ocular and intracranial anomalies, Arch Ophthalmol 109:985, 1991. Pokorny KS, Hyman BM, Jakobiec FA, et al: Epibulbar choristomas containing lacrimal tissue: clinical distinction from dermoids and

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histologic evidence of an origin from the palpebral lobe, Ophthalmology 94:1249, 1987. Shields JA, Shields CL: Orbital cysts of childhood—classification, clinical features, and management, Surv Ophthalmol 49:281, 2004. Tovetjärn R, Tarnow P, Maltese G, et al: Children with Apert syndrome as adults: A follow-up study of 28 Scandinavian patients, Plast Reconstr Surg 130:573, 2012. Wilkins RB, Hoffmann RJ, Byrd WA, et al: Heterotopic brain tissue in the orbit, Arch Ophthalmol 105:390, 1987. Yanoff M, Rorke LB, Niederer BS: Ocular and cerebral abnormalities in 18 chromosome deletion defect, Am J Ophthalmol 70:391, 1970.

Orbital Inflammation Badiee P, Jafarpour Z, Alborzi A, et al: Orbital mucormycosis in an immunocompetent individual, Iran J Microbiol 4:210, 2012. Duda S, Witte T, Stangel M, et al: Autoantibodies binding to stathmin-4: new marker for polyneuropathy in primary Sjögren’s syndrome, Immunol Res 65:1099–1102, 2017. Font RL, Yanoff M, Zimmerman LE: Benign lymphoepithelial lesion of the lacrimal gland and its relationship to Sjögren’s syndrome, Am J Clin Pathol 48:365, 1967. Gravanis MB, Giansanti DMD: Malignant histopathologic counterpart of the benign lymphoepithelial lesion, Cancer 26:1332, 1970. Haneji N, Nakamura T, Takio K, et al: Identification of α-fodrin as a candidate antigen in primary Sjögren’s syndrome, Science 276:604, 1997. Hanioka Y, Yamagami K, Yoshioka K, et al: Churg–Strauss syndrome concomitant with chronic symmetrical dacryoadenitis suggesting Mikulicz’s disease, Intern Med 51:2457, 2012. Jones DT, Monroy D, Ji Z, et al: Sjögren’s syndrome: cytokine and Epstein–Barr viral gene expression within the conjunctival epithelium, Invest Ophthalmol Vis Sci 35:3493, 1994. Kattah JC, Zimmerman LE, Kolsky MP, et al: Bilateral orbital involvement in fatal giant cell polymyositis, Ophthalmology 978:520, 1990. Klapper SR, Patrinely JR, Kaplan SL, et al: Atypical mycobacterial infection of the orbit, Ophthalmology 102:1995, 1536. Klein A, Eliakim R, Karban A, et al: Early histological findings quantified by histomorphometry allow prediction of clinical phenotypes in Crohn’s colitis patients, Anal Quant Cytol Histol 35:95, 2013. Kraus P, Horácek J: Problems of the so-called benign lymphoepithelial lesion of the salivary glands (Godwin) [in German], Monatsschr Ohrenheilkd Laryngorhinol 104:251, 1970. Maehara T, Moriyama M, Nakashima H, et al: Interleukin-21 contributes to germinal centre formation and immunoglobulin G4 production in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz’s disease, Ann Rheum Dis 71:2012, 2011. McNab AA, Wright JE: Orbitofrontal cholesterol granuloma, Ophthalmology 97:28, 1990. Metwaly H, Cheng J, Ida-Yonemochi H, et al: Vascular endothelial cell participation in formation of lymphoepithelial lesions (epi-myoepithelial islands) in lymphoepithelial sialadenitis (benign lymphoepithelial lesion), Virchows Arch 443:17, 2003. Meyer D, Yanoff M, Hanno H: Differential diagnosis in Mikulicz’s syndrome, Mikulicz’s disease and similar disease entities, Am J Ophthalmol 71:516, 1971. Okawa S, Sugawara M, Takahashi S, et al: Tolosa–hunt syndrome associated with cytomegalovirus infection, Intern Med 52:1121, 2013.

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Paović J, Paović P, Bojković I: Tolosa–Hunt syndrome: diagnostic problem of painful ophthalmoplegia, Vojnosanit Pregl 69:627, 2012. Parken B, Chew JB, White VA, et al: Lymphocytic infiltration and enlargement of the lacrimal glands: a new subtype of primary Sjögren’s syndrome? Ophthalmology 112:2040, 2005. Shirlaw PJ, Khan A: Oral dryness and Sjögren’s: an update, Br Dent J 223:649–654, 2017. Streeten BW, Rabuzzi DD, Jones DB: Sporotrichosis of the orbital margin, Am J Ophthalmol 77:750, 1974. Szabo K, Papp G, Barath S, et al: Follicular helper T cells may play an important role in the severity of primary Sjögren’s syndrome, Clin Immunol 147:95, 2013. Tsubota K, Fujita H, Tsuzaka K, et al: Mikulicz’s disease and Sjögren’s syndrome, Invest Ophthalmol Vis Sci 41:2000, 1666. Wali U, Balkhair A, Al-Mujaini A: Cerebro-rhino orbital mucormycosis: an update, J Infect Public Health 5:116, 2012.

Injuries See Chapter 5 for bibliography.

Vascular Disease See bibliography under appropriate sections. Foroozan R, Shields CL, Shields JA, et al: Congenital orbital varices causing extreme neonatal proptosis, Am J Ophthalmol 129:693, 2000. Lacey B, Rootman J, Vangveeravong S, et al: Distensible venous malformations of the orbit, Ophthalmology 106:1197, 1999. Menon SV, Shome D, Mahesh L, et al: Thrombosed orbital varix: A correlation between imaging studies and histopathology, Orbit 23:13, 2004. Putthirangsiwong B, Selva D, Chokthaweesak W, et al: Orbital lymphatic-venous malformation with concomitant spontaneous orbital arteriovenous fistula: case report, J Neurosurg Pediatr 21:141–144, 2018. Wright JF, Sullivan TJ, Garner A, et al: Orbital venous abnormalities, Ophthalmology 104:905, 1997.

Ocular Muscle Involvement in Systemic Disease Ahmad SS, Ghani SA: Kearns–Sayre syndrome: an unusual ophthalmic presentation, Oman J Ophthalmol 5:115, 2012. Almasi M, Motamed MR, Mehrpour M, et al: A mitochondrial disorder in a middle age Iranian patient: report of a rare case, Basic Clin Neurosci 8:337–341, 2017. Bartley GB, Fatourechi V, Kadrmas EF, et al: Clinical features of Graves’ ophthalmopathy in an incidence cohort, Am J Ophthalmol 121:284, 1996. Bartley GB, Gorman CA: Diagnostic criteria for Graves’ disease, Am J Ophthalmol 119:792, 1995. Carta A, D’Adda T, Carrara F, et al: Ultrastructural analysis of external muscle in chronic progressive external ophthalmoplegia, Arch Ophthalmol 118:1441, 2000. Castillo F, Garrity JA, Kravitz DJ: Intractable graves ophthalmopathy? JAMA Ophthalmol 131:269, 2013. Castro D, Derisavifard S, Anderson M, et al: Juvenile myasthenia gravis: a twenty-year experience, J Clin Neuromuscul Dis 14:95, 2013. Chang TS, Johns DR, Walker D, et al: Ocular clinicopathologic study of the mitochondrial encephalomyopathy overlap syndromes, Arch Ophthalmol 111:1254, 1993.

Crisp M, Starkey KJ, Lane C, et al: Adipogenesis in thyroid eye disease, Invest Ophthalmol Vis Sci 41:3249, 2000. Cruz AA, Ribeiro SF, Garcia DM, et al: Graves upper eyelid retraction, Surv Ophthalmol 58:63, 2013. Echenne B, Bassez G: Congenital and infantile myotonic dystrophy, Handb Clin Neurol 113:1387, 2013. Eliana F, Suwondo P, Asmarinah A, et al: The role of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) gene, thyroid stimulating hormone receptor (TSHR) gene and regulatory T-cells as risk factors for relapse in patients with Graves disease, Acta Med Indones 49:195–204, 2017. Eshaghian J, March WF, Goossens W, et al: Ultrastructure of cataract in myotonic dystrophy, Invest Ophthalmol Vis Sci 17:289, 1978. Ferradini V, Cassone M, Nuovo S, et al: Targeted next generation sequencing in patients with myotonia congenita, Clin Chim Acta 470:1–7, 2017. Finsterer J, Zarrouk-Mahjoub S: Diagnosing Kearns-Sayer syndrome requires genetic confirmation, Chin Med J 129:2267–2268, 2016. Folberg R, Rummelt V, Ionasescu V: MELAS syndrome. Presented at the meeting of the Verhoeff Society, 1993. Henry C, Patel N, Shaffer SW, et al: Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes-MELAS syndrome, Ochsner J 17:296–301, 2017. Herzberg NH, van Schooneveld MJ, Bleeker-Wagemakers EM, et al: Kearns–Sayre syndrome with a phenocopy of choroideremia instead of pigmentary retinopathy, Neurology 43:218, 1993. Isak VJ, Jorizzo JL: Recent developments on treatment strategies and the prognosis of dermatomyositis: a review, Dermatolog Treat 22:1–10, 2017. Jakubíková M, Piťha J, Latta J, et al: Myasthenia gravis, Castleman disease, pemphigus, and anti-phospholipid syndrome, Muscle Nerve 47:447, 2013. Jayawant S, Parr J, Vincent A: Autoimmune myasthenia gravis, Handb Clin Neurol 113:1465, 2013. Lax NZ, Campbell GR, Reeve AK, et al: Loss of myelin-associated glycoprotein in Kearns–Sayre syndrome, Arch Neurol 69:490, 2012. Li H, Wang T: The autoimmunity in Graves’s disease, Front Biosci 18:782, 2013. Liu Y-H, Chen Y-J, Wu H-H, et al: Single nucleotide polymorphisms at the PRR3, ABCF1, and GNL1 genes in the HLA class 1 region are associated with Graves’ ophthalmopathy in a gender-dependent manner, Ophthalmology 121:2033–2039, 2014. Mainetti C, Terziroli Beretta-Piccoli B, Selmi C: Cutaneous manifestations of dermatomyositis: a comprehensive review, Clin Rev Allergy Immunol 53:337–356, 2017. Murakami H, Ono K: MELAS: mitochondrial encephalomyopathy, Lactic acidosis and Stroke-like episodes, Brain Nerve 69:111–117, 2017. Nagia L, Lemos J, Abusamra K, et al: Prognosis of ocular myasthenia gravis. Retrospective multicenter analysis, Ophthalmology 122:1517–1521, 2015. Nikolic A, Rakocevic Stojanovic V, Romac S, et al: The coexistence of myasthenia gravis and myotonic dystrophy type 2 in a single patient, J Clin Neurol 9:130, 2013. Ohtsuka K, Hashimoto M: 1H-magnetic resonance spectroscopy of retrobulbar tissue in graves ophthalmopathy, Am J Ophthalmol 128:715, 1999. Papadopoulos C, Kekou K, Xirou S, et al: Early onset posterior subscapular cataract in a series of myotonic dystrophy type 2 patients, Eye (Lond) 32:622–625, 2018.

Bibliography Regensburg NI, Wiersinga WM, Berendschot TTJM, et al: Do subtypes of Graves’ orbitopathy exist? Ophthalmology 118:191, 2011. Ruggiro L, Fiorillo C, Nesti C, et al: Sporadic chronic progressive external ophthalmoplegia with single large mitochondrial DNA deletion and neurogenic findings, J Neurol 264:597–599, 2017. Rummelt V, Folberg R, Ionasescu V, et al: Ocular pathology of MELAS syndrome with mitochondrial DNA nucleotide 3243 point mutation, Ophthalmology 100:1993, 1757. Shiro N, Mukherjee B, Krishnakumar S, et al: Cholesterol granuloma: a case series & review of the literature, Graefes Arch Clin Exp Ophthalmol 254:185–188, 2016. Stein JD, Childers D, Gupta S, et al: Risk factors for developing thyroid-associated ophthalmopathy among individuals with Graves disease, JAMA Ophthalmol 133:290–296, 2015. Wong LL, Lee NG, Amarnani D, et al: Orbital angiogenesis and lymphangiogenesis in thyroid eye disease. An analysis of vascular growth factors with clinical correlation, Ophthalmology 123:2028–2036, 2016. Yen MY, Murdock J, Thyparampil PJ: Unilateral ptosis and homolateral weakness in chronic progressive external ophthalmoplegia, Neuroophthalmology 41:167, 2017. Yanoff M: Pretibial myxedema: a case report, Med Ann DC 34:319, 1965.

Tumors: Choristoma Bonavolontà G, Strianese D, Grassi P, et al: An analysis of 2480 space-occupying lesions of the orbit from 1976 to 2011, Ophthal Plast Reconstr Surg 29:79, 2013. Boynton JR, Searl SS, Ferry AP, et al: Primary nonkeratinized epithelial (“conjunctival”) orbital cysts, Arch Ophthalmol 110:1238, 1992. Cavazza S, Laffi GL, Lodi L, et al: Orbital dermoid cyst of childhood: clinical pathologic findings, classification and management, Int Ophthalmol 31:93, 2011. Chawla B, Chauhan K, Kashyap S, et al: Mature orbital teratoma with an ectopic tooth and primary anophthalmos, Orbit 32:67, 2013. Eijpe AA, Koornneef L, Verbeeten B, et al: Intradiploic epidermoid cysts of the bony orbit, Ophthalmology 98:1991, 1737. Goldstein MH, Soparkar CNS, Kersten RC, et al: Conjunctival cysts of the orbit, Ophthalmology 105:2056, 1998. Lenzi R, Casani AP, Sellari-Franceschini S: Ectopic intraorbital lacrimal ductal cyst: a case report, Orbit 31:350, 2012. Meyer DR, Lessner AM, Yeatts P, et al: Primary temporal fossa dermoid cyst: characterization and surgical management, Ophthalmology 106:342, 1999. Pellerano F, Guillermo E, Garrido G, et al: Congenital orbital teratome, Ocul Oncol Pathol 3:11–16, 2017. Pokorny KS, Hyman BM, Jakobiec FA, et al: Epibulbar choristomas containing lacrimal tissue: clinical distinction from dermoids and histologic evidence of an origin from the palpebral lobe, Ophthalmology 94:1249, 1987. Polito E, Pichierri P, Trivella F, et al: Orbital teratoma masquerading as lymphangioma, J AAPOS 15:381, 2011. Shields JA, Shields CL: Orbital cysts of childhood: classification, clinical features, and management, Surv Ophthalmol 49:281, 2004. Veselinović D, Krasić D, Stefanović I, et al: Orbital dermoid and epidermoid cysts: case study, Srp Arh Celok Lek 138:755, 2010.

Tumors: Hamartomas Arora V, Prat MC, Kazim M: Acute presentation of cavernous hemangioma of the orbit, Orbit 30:195, 2011.

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Atchison EA, Garrity JA, Castillo F, et al: Expression of vascular endothelial growth factor receptors in benign vascular lesions of the orbit. A case series, Ophthalmology 123:209–213, 2016. Chang EL, Rubin PAD: Bilateral multifocal hemangilas of the orbit in the blue rubber bleb nevus syndrome, Ophthalmology 109:258, 2002. Harris GJ, Sakol PJ, Bonavolonta G, et al: An analysis of thirty cases of orbital lymphangioma, Ophthalmology 97:1990, 1583. HeImayama S, Murakamai Y, Hashimoto H, et al: Spindle cell hemangioendothelioma exhibits the ultrastructural features of reactive vascular proliferation rather than of angiosarcoma, Am J Clin Pathol 97:279, 1992. Jakobiec FA, Zakka FR, Papakostas TD, et al: Angiomyofibroma of the orbit: a hybrid of vascular leiomyoma and cavernous hemangioma, Ophthal Plast Reconstr Surg 28:438, 2012. Katz SE, Rootman J, Vangveeravong S, et al: Combined venous lymphatic malformations of the orbit (so-called lymphangiomas): association with noncontiguous intracranial vascular anomalies, Arch Ophthalmol 105:176, 1998. Kazim M, Kennerdell JS, Rothfus W, et al: Orbital lymphangioma, Ophthalmology 99:1993, 1588. Lee V, Azari AA, Nehls S, et al: Leiomyoma of the lower eyelid, JAMA Ophthalmol 131:1083, 2013. Mishra A, Abuhajar R, Alsawidi K, et al: Congenital orbital lymphangioma in a 20-year-old girl: a case report and review of literature, Libyan J Med 4:162, 2009. Neufeld M, Pe’er J, Rosenman E, et al: Intraorbital glomus cell tumor, Am J Ophthalmol 117:539, 1994. Reddy AR, Chang BY, Bradbury JA: Is this really a capillary haemangioma? Orbit 26:327, 2007. Reeves SW, Miele DL, Woodward JA, et al: Retinal folds as initial manifestation of orbital lymphangioma, Arch Ophthalmol 123:2005, 1756. Saha K, Leatherbarrow B: Orbital lymphangiomas: a review of management strategies, Curr Opin Ophthalmol 23:433, 2012. Sugiyama K, Hiraoka T, Okamoto Y, et al: Acute severe exophthalmos in an infant with orbital capillary hemangioma, Jpn J Ophthalmol 55:67, 2011. Tunç M, Sadri E, Char DH: Orbital lymphangioma: an analysis of 26 patients, Br J Ophthalmol 83:76, 1999.

Tumors: Mesenchymal–Vascular Azari AA, Kanavi MR, Lucarelli M, et al: Angiolymphoid hyperplasia with eosinophilia of the orbit and ocular adnexa, JAMA Ophthalmol 132:633–636, 2014. Cheuk W, Wong KOY, Wong CSC, et al: Immunostaining for human herpesvirus 8 latent nuclear antigen-1 helps distinguish Kaposi sarcoma from its mimickers, Am J Clin Pathol 121:335, 2004. Collaço L, Gonçalves M, Gomes L, et al: Orbital Kaposi’s sarcoma in acquired immunodeficiency syndrome, Eur J Ophthalmol 10:88, 2000. Furusato E, Valenzuela IA, Fanburg-Smith JC, et al: Orbital solitary fibrous tumor: encompassing terminology for hemangiopericytoma, giant cell angiofibroma, and fibrous histiocytoma of the orbit: reappraisal of 41 cases, Hum Pathol 42:120, 2011. Gao Y, Chen Y, Yu GY: Clinicopathologic study of parotid involvement in 21 cases of eosinophilic hyperplastic lymphogranuloma (Kimura’s disease), Oral Surg Oral Med Oral Pathol Oral Radiol Endod 102:651, 2006.

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Karcioglu ZA, Nasr A, Haik BG: Orbital hemangiopericytoma: clinical and morphologic features, Am J Ophthalmol 124:661, 1997. Kurumety UR, Lustbader JM: Kaposi’s sarcoma of the bulbar conjunctiva as an initial clinical manifestation of acquired immunodeficiency syndrome, Arch Ophthalmol 113:978, 1995. Lee JT, Pettit TH, Glascow BJ: Epibulbar hemangiopericytoma, Am J Ophthalmol 124:546, 1997. McEachren TM, Brownstein S, Jordan DR, et al: Epithelioid hemangioma of the orbit, Ophthalmology 107:806, 2000. Pribila JT, Cornblath WT, Ramocki JM, et al: Glomus cell tumor of orbit, Arch Ophthalmol 128:144, 2010. Radu O, Pantanowitz L: Kaposi sarcoma, Arch Pathol Lab Med 137:289, 2013. Sánchez-Acosta A, Moreno-Arredondo D, Rubio-Solornio RI, et al: Angiolymphoid hyperplasia with eosinophilia of the lacrimal gland: a case report, Orbit 27:195, 2008. Yanai T, Tanaka T, Ogawa T: Immunohistochemical demonstration of cyclooxygenase-2 in glomus tumors, J Bone Joint Surg Am 95:725, 2013.

Tumors: Mesenchymal–Fatty Ali SE, Farber M, Meyer DR: Fbrolipoma of the orbit, Ophthol Plast Reconstr Surg 29:e79–e81, 2012. Chi MJ, Roh JH, Lee JH, et al: A case of orbital lipoma with exophthalmos and visual disturbance, Jpn J Ophthalmol 53(4):442, 2009. Daniel CS, Beaconsfield M, Rose GF, et al: Pleomorphic lipoma of the orbit: a case series and review of the literature, Ophthalmology 110:101, 2003. Doyle M, Odashiro AN, Pereira PR, et al: Primary pleomorphic liposarcoma of the orbit: a case report, Orbit 31:168, 2012. Feinfield RE, Hesse RJ, Scharfenberg JC: Orbital angiolipoma, Arch Ophthalmol 106:1093, 1988. Madge SN, Tumuluri K, Strianese D, et al: Primary orbital lipoma, Ophthalmology 117:628, 2010. Small ML, Green WR, Johnson LC: Lipoma of the frontal bone, Arch Ophthalmol 97:129, 1979. Ulivieri S, Olivieri G, Motolese PA: Spindle cell lipoma of the orbit: A case report of an unusual orbital pathology, Neurol Neurochir Pol 44:419, 2010. Yoganathan P, Meyer DR, Farber MG: Bilateral lacrimal gland involvement with Kimura disease in an African American male, Arch Ophthalmol 122:917, 2004.

Tumors: Mesenchymal–Fibrous–Histiocytic Bernardini FP, de Concilius C, Schneider S, et al: Solitary fibrous tumor of the orbit: is it rare? Report of a case series and review of the literature, Ophthalmology 110:1442, 2003. Boynton JR, Markowitch W, Searl SS: Atypical fibroxanthoma of the eyelid, Ophthalmology 96:1480, 1989. Conway RM, Holbach LM, Naumann GOH, et al: Benign fibrous histiocytoma of the corneoscleral limbus: unique clinicopathologic features, Arch Ophthalmol 121:2003, 1776. Dickey GE, Sotelo-Avila C: Fibrous hamartoma of infancy: current review, Pediatr Dev Pathol 2:236, 1999. Feurman JM, Flint A, Elner VM: Cystic solitary fibrous tumor of the orbit, Arch Ophthalmol 128:385, 2010. Font RL, Hidayat AA: Fibrous histiocytoma of the orbit: A clinicopathologic study of 150 cases, Hum Pathol 13:199, 1982. Furusato E, Valenzuela IA, Fanburg-Smith JC, et al: Orbital solitary fibrous tumor: encompassing terminology for

hemangiopericytoma, giant cell angiofibroma, and fibrous histiocytoma of the orbit: reappraisal of 41 cases, Hum Pathol 42:120, 2011. Gold JS, Antonescu CR, Hajdu C, et al: Clinicopathologic correlates of solitary fibrous tumors, Cancer 94:1057, 2002. Hartstein ME, Grove AS Jr, Woog JJ, et al: The multidisciplinary management of psammomatoid ossifying fibroma of the orbit, Ophthalmology 105:591, 1998. Hayashi N, Borodic G, Karesh JW, et al: Giant cell angiofibroma of the orbit and eyelid, Ophthalmology 106:1223, 1999. Jakobiec FA: Solitary fibrous tumor. Presented at the meeting of the Verhoeff Society, 1994. Jakobiec FA, Klapper D, Maher E, et al: Infantile subconjunctival and anterior orbital fibrous histiocytoma: ultrastructural and immunohistochemical studies, Ophthalmology 95:516, 1988. John T, Yanoff M, Scheie HG: Eyelid fibrous histiocytoma, Ophthalmology 88:1193, 1981. Jones WD III, Yanoff M, Katowitz JA: Recurrent facial fibrous histiocytoma, Br J Plast Surg 32:46, 1979. Kau HC, Yang CF, Liu IT, et al: Benign fibrous histiocytoma associated with a frontoethmoidal mucopyocele and orbital abscess, Ophthal Plast Reconstr Surg 23:236, 2007. Krishnakumar S, Subramanian N, Mohan ER, et al: Solitary fibrous tumor of the orbit: A clinicopathologic study of six cases with review of the literature, Surv Ophthalmol 48:544, 2003. Lakshminarayanan R, Konia T, Welborn J: Fibrous hamartoma of infancy, Arch Pathol Lab Med 129:520, 2005. Linhares P, Pires E, Carvalho B, et al: Juvenile psammomatoid ossifying fibroma of the orbit and paranasal sinuses: A case report, Acta Neurochir (Wien) 153:2011, 1983. Ma CK, Zarbo RJ, Gown AM: Immunohistochemical characterization of atypical fibroxanthoma and dermatofibrosarcoma protuberans, Am J Clin Pathol 97:478, 1992. Park SW, Kim HJ, Lee JH, et al: Malignant fibrous histiocytoma of the head and neck: CT and MR imaging findings, AJNR Am J Neuroradiol 30:71, 2009. Song A, Syed N, Kirby PA, et al: Giant cell angiofibroma of the ocular adnexae, Arch Ophthalmol 123:1438, 2005. Westfall AC, Mansoor A, Sullivan SS, et al: Orbital and periorbital myofibromas in childhood: two case reports, Ophthalmology 110:2003, 2000. Yanoff M, Scheie HG: Fibrosarcoma of the orbit: report of two cases, Cancer 19:1966, 1711. Zlota O, Aviel-Rosner M: An unusual location of fibrous hamartoma of infancy in the eyelid, Ocul Oncol Pathol 3:8–10, 2017.

Tumors: Mesenchymal–Muscle Akyüz C, Sari N, Yalçin B, et al: Long-term survival results of pediatric rhabdomyosarcoma patients: A single-center experience from Turkey, Pediatr Hematol Oncol 29:38, 2012. Frayer WC, Enterline HT: Embryonal rhabdomyosarcoma of the orbit in children and young adults, Arch Ophthalmol 62:203, 1959. Gündüz K, Shields JA, Eagle RC Jr, et al: Malignant rhabdoid tumor of the orbit, Arch Ophthalmol 116:243, 1998. Hill DA, O’Sullivan MJ, Zhu X, et al: Practical application of molecular genetic testing as an aid to the surgical pathologic diagnosis of sarcomas: a prospective study, Am J Surg Pathol 26:965, 2002. Hou LC, Murphy MA, Tung GA: Primary orbital leiomyosarcoma: a case report with MRI findings, Am J Ophthalmol 135:408, 2003.

Bibliography Karcioglu ZA, Hadjistilianou D, Rozans M, et al: Orbital rhabdomyosarcoma, Cancer Control 11:328, 2004. Mendez Mdel C, Muiños Y, Blanco G, et al: Embryonal rhabdomyosarcoma of the caruncle in a 4-year-old boy: case report, Arq Bras Oftalmol 75:207, 2012. Porterfield JF, Zimmerman LE: Orbital rhabdomyosarcoma: A clinicopathologic study of 55 cases, Virchows Arch Pathol Anat 335:329, 1962. Rasool N, Lefebvre DR, Latina MA, et al: Orbital leiomyosarcoma metastasis presenting prior to diagnosis of the primary tumor, Digit J Ophthalmol 23:22–26, 2017. Shields CL, Shields JA: Rhabdomyosarcoma: review for the ophthalmologist, Surv Ophthalmol 48:39, 2003. Taylor SF, Yen KG, Patel BCK: Primary conjunctival rhabdomyosarcoma, Arch Ophthalmol 120:668, 2002. Turner JH, Richmon JD: Head and neck rhabdomyosarcoma: a critical analysis of population-based incidence and survival data, Otolaryngol Head Neck Surg 145:967, 2011. Van den Broek PP, de Faber J-THN, Kliffen M, et al: Anterior orbital leiomyoma: possible pulley smooth muscle tissue tumor, Arch Ophthalmol 123:2005, 1614. Xia SJ, Pressey JG, Barr FG: Molecular pathogenesis of rhabdomyosarcoma, Cancer Biol Ther 1(2):97, 2002. Yeniad B, Tuncer S, Peksayar G, et al: Primary orbital leiomyosarcoma, Ophthal Plast Reconstr Surg 25:154, 2009.

Tumors: Mesenchymal–Cartilage Alam MS, Subramanian N, Desai AS, et al: Mesenchymal chondrosarcoma of the orbit: a case report with 5 years of follow-up, Orbit 37:73–75, 2018. Harrison A, Loftus S, Pambuccian S: Orbital chondroma, Ophthal Plast Reconstr Surg 22:484, 2006. Pasternak S, O’Connell JX, Verchere C, et al: Enchondroma of the orbit, Am J Ophthalmol 122:444, 1996. Patel R, Mukherjee B: Mesenchymal chondrosarcoma of the orbit, Orbit 31:126, 2012. Tuncer S, Kebudi R, Peksayar G, et al: Congenital mesenchymal chondrosarcoma of the orbit: case report and review of the literature, Ophthalmology 111:1016, 2004.

Tumors: Mesenchymal–Bone Afghani T, Mansoor H: Types of orbital osteoma–a descriptive analysis, Orbit 37:3–8, 2018. Bahrami E, Alireza T, Ebrahim H, et al: Maxillary and orbital brown tumor of primary hyperparathyroidism, Am J Case Rep 13:183, 2012. Caltabiano R, Serra A, Bonfiglio M, et al: A rare location of benign osteoblastoma: case study and a review of the literature, Eur Rev Med Pharmacol Sci 16:2012, 1891. Fan JC, Lamont DL, Greenbaum AR, et al: Primary orbital extraskeletal osteosarcoma, Orbit 30:297, 2011. Gonzalez-Martínez E, Santamarta-Gómez D, Varela-Rois P, et al: Brown tumor of the orbital roof as an initial and isolated manifestation of secondary hyperparathyroidism, Orbit 29:278, 2010. Katz BJ, Nerad JA: Ophthalmic manifestations of fibrous dysplasia: a disease of children and adults, Ophthalmology 105:2207, 1998. Kayaci S, Kanat A, Gucer H, et al: Primary osteoma of the orbit with atypical facial pain: case report and literature review, Turk Neurosurg 22:389, 2012. Mercado GV, Shields CL, Gunduz K, et al: Giant cell reparative granuloma of the orbit, Am J Ophthalmol 127:485, 1999.

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Mooy CM, Naus NC, de Klein A, et al: Orbital chondrosarcoma developing in a patient with Paget’s disease, Am J Ophthalmol 127:619, 1999. Parmar DN, Luthert PH, Cree IA, et al: Two unusual osteogenic orbital tumors: presumed parosteal osteosarcoma, Ophthalmology 108:1452, 2001. Sadeghi SM, Hosseini SN: Spontaneous conversion of fibrous dysplasia into osteosarcoma, J Craniofac Surg 22:959, 2011. Sires BS, Benda PM, Stanley RB Jr, et al: Orbital osteoid osteoma, Arch Ophthalmol 117:414, 1999. Weiss JS, Bressler SB, Jacobs EF, et al: Maxillary ameloblastoma with orbital invasion: A clinicopathologic study, Ophthalmology 92:710, 1985. Yazici Z, Yazici B, Yalcinkaya U, et al: Sino-orbital osteoma with osteoblastoma-like features: case reports, Neuroradiology 54:765, 2012. Yu JW, Kim KU, Kim SJ, et al: Aneurysmal bone cyst of the orbit: a case report with literature review, J Korean Neurosurg Soc 51:113, 2012.

Tumors: Neural Allman MI, Frayer WC, Hedges TR Jr: Orbital neurilemoma, Ann Ophthalmol 9:1409, 1977. Arora R, Sarkar C, Betharia SM: Primary orbital primitive neuroectodermal tumor with immunohistochemical and electron microscopic confirmation, Orbit 12:7, 1993. Brannan PA, Schneider S, Grosniklaus HE, et al: Malignant mesenchymoma of the orbit: case report and review of the literature, Ophthalmology 110:314, 2003. Briscoe D, Mahmood S, O’Donovan DG, et al: Malignant peripheral nerve sheath tumor in the orbit of a child with acute proptosis, Arch Ophthalmol 120:653, 2002. Cheng SF, Chen YI, Chang CY, et al: Malignant peripheral nerve sheath tumor of the orbit: malignant transformation from neurofibroma without neurofibromatosis, Ophthal Plast Reconstr Surg 24:413, 2008. Chokthaweesak W, Annunziata CC, Alsheikh O, et al: Primitive neuroectodermal tumor of the orbit in adults: a case series, Ophthal Plast Reconstr Surg 27:173, 2011. Han JC, Kim YD, Suh YL, et al: Fibroblastic low-grade malignant peripheral nerve sheath tumor in the orbit, Ophthal Plast Reconstr Surg 28:97, 2012. Hill DA, Pfeifer JD, Marley EF, et al: WT1 staining reliably differentiates desmoplastic small round cell tumor from Ewing sarcoma/primitive neuroectodermal tumor: an immunohistochemical and molecular diagnostic study, Am J Clin Pathol 114:345, 2000. Irace C: Isolated intraorbital schwannomas: the genesis, J Craniofac Surg 23:1228, 2012. Kano T, Sasaki A, Tomizawa S: Primary Ewing’s sarcoma of the orbit: case report, Brain Tumor Pathol 26:95, 2009. Kashyap S, Pushker N, Meel R, et al: Orbital schwannoma with cystic degeneration, Clin Experiment Ophthalmol 37:293, 2009. Li T, Goldberg RA, Becker B, et al: Primary orbital extraskeletal Ewing sarcoma, Arch Ophthalmol 121:1049, 2003. Lucas DR, Bentley G, Dan ME, et al: Ewing sarcoma vs. lymphoblastic lymphoma: A comparative immunohistochemical study, Am J Clin Pathol 115:11, 2001. Majumdar K, Saran R, Tyagi I, et al: Cytodiagnosis of alveolar soft part sarcoma: report of two cases with special emphasis on the first orbital lesion diagnosed by aspiration cytology, J Cytol 30:58, 2013.

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Messmer EP, Camara J, Boniuk M, et al: Amputation neuroma of the orbit: report of two cases and review of the literature, Ophthalmology 91:1420, 1984. Pecorella I, Toth J, Lukats O: Ancient schwannoma of the orbit, Pathologica 104:182, 2012. Rawlings NG, Brownstein S, Robinson JW: Orbital schwannoma: histopathologic correlation with magnetic resonance imaging, Can J Ophthalmol 42:326, 2007. Ribeiro SFT, Queirós T, Amorim JM, et al: An unusual differential diagnosis of orbital cavernous hemangioma: ancient schwannoma, Case Rep Ophthalmol 8:294–300, 2017. Shields JA, Font RL, Eagle RC, et al: Melanotic schwannoma of the choroid, Ophthalmology 101:843, 1994.

Tumors: Miscellaneous Candy EJ, Miller NR, Carson BS: Myxoma of bone involving the orbit, Arch Ophthalmol 109:919, 1991. Fernandes BF, Belfort Neto R, Odashiro AN, et al: Clinical and histopathological features of orbital granular cell tumor: case report, Arq Bras Oftalmol 75:137, 2012. Guerriero S, Giancipoli G, Sborgia A, et al: Orbital granular cell tumor in a patient with Churg–Strauss syndrome: the importance of biopsy, Orbit 30:30, 2011. Kiratli H, Erkan Balci K, Güler G: Primary orbital endodermal sinus tumor (yolk sac tumor), J AAPOS 12:623, 2008. Majumdar K, Saran R, Tyagi I, et al: Cytodiagnosis of alveolar soft part sarcoma: report of two cases with special emphasis on the first orbital lesion diagnosed by aspiration cytology, J Cytol 30:58, 2013. Makhdoomi R, Nayil K, Santosh V, et al: Orbital paraganglioma: A case report and review of the literature, Clin Neuropathol 29:100, 2010. Margo CE, Folberg R, Zimmerman LE, et al: Endodermal sinus tumor (yolk sac tumor) of the orbit, Ophthalmology 90:1426, 1983. Vogel MH: Granular cell myoblastoma of the ciliary body. Presented at the combined Meeting of the Verhoeff Society and the European Ophthalmic Pathology Society, Houston, 1996. Yang D, McLaren S, Van Vliet C, et al: Progressive orbital granular cell tumour associated with medial rectus, Orbit 36:356–358, 2017.

Tumors: Epithelial of Lacrimal Gland Alyahya GA, Stenman G, Persson F, et al: Pleomorphic adenoma arising in an accessory lacrimal gland of wolfring, Ophthalmology 113:879, 2006. Argyris PP, Pambuccian SE, Cayci Z, et al: Lacrimal gland adenoid cystic carcinoma with high-grade transformation to myoepithelial carcinoma: report of a case and review of literature, Head Neck Pathol 7:85, 2013. Bernardini FP, Croxatto O, Bandelloni R: Primary undifferentiated large cell carcinoma of the lacrimal gland, Ophthalmology 118:1189, 2011. Bianchi FA, Tosco P, Campisi P, et al: Mucoepidermoid carcinoma of the lacrimal sac masquerading as dacryocystitis, J Craniofac Surg 21:797, 2010. Bonavolontà G, Tranfa F, Staibano S, et al: Warthin tumor of the lacrimal sac, Am J Ophthalmol 124:857, 1997. Brar ST, Meyer D: Diagnosis and management of mucoepidermoid carcinoma of the lacrimal duct, Orbit 30:34, 2011. Conlon MR, Chapman WB, Burt WL, et al: Primary localized amyloidosis of the lacrimal glands, Ophthalmology 98:1991, 1556.

Devoto MH, Croxatto O: Primary cystadenocarcinoma of the lacrimal gland, Ophthalmology 110:2003, 2006. Font RL, Smith SL, Bryan RG: Malignant epithelial tumors of the lacrimal gland: A clinicopathologic study of 21 cases, Arch Ophthalmol 116:589, 1998. Grossniklaus HE, Abbuhl MF, McLean IW: Immunohistologic properties of benign and malignant mixed tumor of the lacrimal gland, Am J Ophthalmol 110:540, 1990. von Holstein SL, Fehr A, Persson M, et al: Adenoid cystic carcinoma of the lacrimal gland: MYB gene activation, genomic imbalances, and clinical characteristics, Ophthalmology 120:2130–2138, 2013. von Holstein SL, Fehr A, Persson M, et al: Lacrimal gland pleomorphic adenoma and carcinpma ex pleomorphic adenoma. Genomic profiles, gene fusions, and clinical characteristics, Ophthalmology 121:1125–1133, 2014. Jakobiec FA, Stacy RC, Mehta M, et al: IgG4-positive dacryoadenitis and Küttner submandibular sclerosing inflammatory tumor, Arch Ophthalmol 128:915, 2010. Jakobiec FA, Zakka FR, Perry L: The cytologic composition of dacryops: an investigation of 15 lesions compared to normal lacrimal gland, Am J Ophthalmol 155:380, 2013. Kaliki SK, Mishra DK: Orbital chordoma: an extremely rare tumor, Ophthalmology 123:116, 2016. Kay L, Brownstein S, Jordan DR, et al: Dacryops. A series of 5 cases and a proposed pathogenesis, JAMA Ophthalmol 131:929–932, 2013. Khalil M, Arthurs B: Basal cell adenocarcinoma of the lacrimal gland, Ophthalmology 107:164, 2000. Lin YC, Chen KC, Lin CH, et al: Clinicopathological features of salivary and non-salivary adenoid cystic carcinomas, Int J Oral Maxillofac Surg 41:354, 2012. McNab AA, Satchi K: Recurrent lacrimal gland pleomorphic adenoma: clinical and computed tomography features, Ophthalmology 118:2088, 2011. Milman T, Shields JA, Husson M, et al: Primary ductal adenocarcinoma of the lacrimal gland, Ophthalmology 112:2052S, 2005. Mudhar SM, Currie ZI, Salvi SM: Lacrimal gland intra-lobular duct cysts associated with focal vasculitis, Ocul Oncol Pathol 1:225–230, 2015. Mulay K, Puthyapurayil FM, Mohammad JA: Adenoid cystic carcinoma of the lacrimal gland: role of nuclear survivin (BIRC5) as a prognostic marker, Histopathology 62:840, 2013. Pasquale S, Strianese D, Mansueto G, et al: Epithelioid myoepithelioma of lacrimal gland, Virchows Arch 446:97, 2005. Proia A: Mixed tumor of the choroid, Arch Ophthalmol 128:381, 2010. Rao NA, Kaiser E, Quiros PA, et al: Lymphoepithelial carcinoma of the lacrimal gland, Arch Ophthalmol 120:1745S, 2002. Selva D, Davis GJ, Dodd T, et al: Polymorphous low-grade adenocarcinoma of the lacrimal gland, Arch Ophthalmol 122:915, 2004. Shields CL, Shields JA, Eagle RC, et al: Adenoid cystic carcinoma of the lacrimal gland simulating a dermoid cyst in a 9-year-old boy, Arch Ophthalmol 116:1998, 1673. Singh G, Sharma MC, Agarwal S, et al: Epithelial–myoepithelial carcinoma of the lacrimal gland: a rare case, Ann Diagn Pathol 16:292, 2012. Teo L, Seah LL, Choo CT, et al: A survey of the histopathology of lacrimal gland lesions in a tertiary referral centre, Orbit 32:1, 2013.

Bibliography Vagefi MR, Hong JE, Zwick OM, et al: Atypical presentations of pleomorphic adenoma of the lacrimal gland, Ophthal Plast Reconstr Surg 23:272, 2007. Von Holstein SL, Fehr A, Heegaard S, et al: CRTC1–MAML2 gene fusion in mucoepidermoid carcinoma of the lacrimal gland, Oncol Rep 27:1413, 2012. Walsh RD, Vagefi MR, McClelland CM, et al: Primary adenoid cystic carcinoma of the orbital apex, Ophthal Plast Reconstr Surg 29:33, 2013. Zimmerman LE, Stangl R, Riddle PJ: Primary carcinoid tumor of the orbit: A clinicopathologic study with histochemical and electron microscopic observations, Arch Ophthalmol 101:1395, 1983.

Tumors: Reticuloendothelial System Alayed K, Medeiros LJ, Patel KP, et al: BRAF and MAP2k1 mutations in Langerhans cell histiocytosis: a study of 50 cases, Hum Pathol 52:61–67, 2016. Berres ML, Merad M, Allen CE: Progress in understanding the pathogenesis of Langerhans cell histiocytosis: back to histiocytosis x? Br J Haematol 169:3–13, 2015. Chang Y, Li B, Zhang X, et al: Ocular trauma as the first presentation of Langerhans cell histiocytosis, Eye Sci 28:204–207, 2013. Colby TV: Current histological diagnosis of lymphomatoid granulomatosis, Mod Pathol 25(Suppl 1):S39–S42, 2012. Collin M, Bigley V, McClain KL, et al: Cell(s) of origin of Langerhans cell histiocytosis, Hematol Oncol Clin North Am 29:825–838, 2015. El Demellawy D, Young JL, de Nanassy J, et al: Langerhans cell histiocytosis: a comprehensive review, Pathology 47:294–301, 2015. Garabedian L, Struyf S, Opdenakker G, et al: Langerhans cell histiocytosis: a cytokine/chemokine-mediated disorder? Eur Cytokine Netw 22:148–153, 2011. Geissmann F, Manz MG, Jung S, et al: Development of monocytes, macrophages, and dendritic cells, Science 327:656–661, 2010. Low LK, Song JY: B-cell lymphoproliferative disorders associated with primary and acquired immunodeficiency, Surg Pathol Clin 9:55–77, 2016. Picarsic J, Jaffe R: Nosology and pathology of Langerhans cell histiocytosis, Hematol Oncol Clin North Am 29:799–823, 2015. Pineles SL, Liu GT, Acebes X, et al: Presence of Erdheim–Chester disease and Langerhans cell histiocytosis in the same patient: a report of 2 cases, J Neuroophthalmol 31:217–223, 2011. Ranganathan S: Histiocytic proliferations, Semin Diagn Pathol 33:396–409, 2016. Sivak-Callcott JA, Rootman J, Rasmussen SL, et al: Adult xanthogranulomatous disease of the orbit and ocular adnexa: new immunohistochemical findings and clinical review, Br J Ophthalmol 90:602–608, 2006. Usmani GN, Woda BA, Newburger PE: Advances in understanding the pathogenesis of HLH, Br J Haematol 161:609–622, 2013. Weissman HM, Hayek BR, Grossniklaus HE: Reticulohistiocytoma of the orbit, Ophthal Plast Reconstr Surg 31:e13–e16, 2015. Yin J, Zhang F, Zhang H, et al: Hand-Schuller-Christian disease and Erdheim-Chester disease: coexistence and discrepancy, Oncologist 18:19–24, 2013.

Tumors: Inflammatory Pseudotumor Amin S, Ramsay A: Orbital and lacrimal gland progressive transformation of germinal centres–an underdiagnosed entity? Br J Ophthalmol 96:1242–1245, 2012.

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Azari AA, Kanavi MR, Lucarelli M, et al: Angiolymphoid hyperplasia with eosinophilia of the orbit and ocular adnexa: report of 5 cases, JAMA Ophthalmol 132:633–636, 2014. Esmaili DD, Chang EL, O’Hearn TM, et al: Simultaneous presentation of Kimura disease and angiolymphoid hyperplasia with eosinophilia, Ophthal Plast Reconstr Surg 24:310–311, 2008. Ferry JA, Zukerberg LR, Harris NL: Florid progressive transformation of germinal centers. A syndrome affecting young men, without early progression to nodular lymphocyte predominance Hodgkin’s disease, Am J Surg Pathol 16:252–258, 1992. Good DJ, Gascoyne RD: Atypical lymphoid hyperplasia mimicking lymphoma, Hematol Oncol Clin North Am 23:729–745, 2009. Ho ST, Lakey M, Crawford B, et al: I feel it in my bones: a rare presentation of idiopathic sclerosing orbital inflammation with hyperostosis, Clin Exp Ophthalmol 41:304–305, 2013. Rosenbaum JT, Choi D, Wilson DJ, et al: Fibrosis, gene expression and orbital inflammatory disease, Br J Ophthalmol 99:1424–1429, 2015. Rosenbaum JT, Choi D, Wilson DJ, et al: Molecular diagnosis of orbital inflammatory disease, Exp Mol Pathol 98:225–229, 2015. Rosenbaum JT, Choi D, Wilson DJ, et al: Orbital pseudotumor can be a localized form of granulomatosis with polyangiitis as revealed by gene expression profiling, Exp Mol Pathol 99:271–278, 2015. Seregard S: Angiolymphoid hyperplasia with eosinophilia should not be confused with Kimura’s disease, Acta Ophthalmol Scand 79:91–93, 2001.

Tumors: Malignant Lymphoma Ahmed AH, Foster CS, Shields CL: Association of disease location and treatment with survival in diffuse large b-cell lymphoma of the eye and ocular adnexal region, JAMA Ophthalmol 135:1062–1068, 2017. Akoz AG, Dagdas S, Soysal H, et al: Bilateral proptosis as the initial presentation of systemic nodular lymphocyte predominant Hodgkin lymphoma, Leuk Lymphoma 48:1434–1436, 2007. AlAkeely AG, Alkatan HM, Alsuhaibani AH, et al: Benign reactive lymphoid hyperplasia of the conjunctiva in childhood, Br J Ophthalmol 101:933–939, 2017. Amin S, Ramsay A, Marafioti T: Diagnostic pitfalls in “low-grade lymphoma” of the orbit and lacrimal gland, Orbit 34:206–211, 2015. Andrew N, Kearney D, Selva D: IgG4-related orbital disease: a meta-analysis and review, Acta Ophthalmol 91:694–700, 2013. Andrew NH, Coupland SE, Pirbhai A, et al: Lymphoid hyperplasia of the orbit and ocular adnexa: A clinical pathologic review, Surv Ophthalmol 61:778–790, 2016. Arber DA, Orazi A, Hasserjian R, et al: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia, Blood 127:2391–2405, 2016. Aronow ME, Portell CA, Rybicki LA, et al: Ocular adnexal lymphoma: assessment of a tumor-node-metastasis staging system, Ophthalmology 120:1915–1919, 2013. Asadi-Amoli F, Nozarian Z, Bonaki HN, et al: Clinicopathologic assessment of ocular adnexal lymphoproliferative lesions at a tertiary eye hospital in Iran, Asian Pac J Cancer Prev 17:3727–3731, 2016. Bonavolonta G, Strianese D, Grassi P, et al: An analysis of 2,480 space-occupying lesions of the orbit from 1976 to 2011, Ophthal Plast Reconstr Surg 29:79–86, 2013.

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Cai Q, Medeiros LJ, Xu X, et al: MYC-driven aggressive B-cell lymphomas: biology, entity, differential diagnosis and clinical management, Oncotarget 6:38591–38616, 2015. Campbell JJ, Clark RA, Watanabe R, et al: Sezary syndrome and mycosis fungoides arise from distinct T-cell subsets: a biologic rationale for their distinct clinical behaviors, Blood 116:767–771, 2010. Cheuk W, Chan JK: IgG4-related sclerosing disease: a critical appraisal of an evolving clinicopathologic entity, Adv Anat Pathol 17:303–332, 2010. Cheuk W, Chan JK: Lymphadenopathy of IgG4-related disease: an underdiagnosed and overdiagnosed entity, Semin Diagn Pathol 29:226–234, 2012. Cheuk W, Yuen HK, Chan AC, et al: Ocular adnexal lymphoma associated with igg4+ chronic sclerosing dacryoadenitis: a previously undescribed complication of IgG4-related sclerosing disease, Am J Surg Pathol 32:1159–1167, 2008. Coupland SE, Krause L, Delecluse HJ, et al: Lymphoproliferative lesions of the ocular adnexa. Analysis of 112 cases, Ophthalmology 105:1430–1441, 1998. Cruz AA, Valera FC, Carenzi L, et al: Orbital and central nervous system extension of nasal natural killer/T-cell lymphoma, Ophthal Plast Reconstr Surg 30:20–23, 2014. Diefenbach CS, Connors JM, Friedberg JW, et al: Hodgkin lymphoma: current status and clinical trial recommendations, J Natl Cancer Inst 109:2017. Du MQ: MALT lymphoma: A paradigm of NF-kappab dysregulation, Semin Cancer Biol 39:49–60, 2016. Du MQ: MALT lymphoma: genetic abnormalities, immunological stimulation and molecular mechanism, Best Pract Res Clin Haematol 30:13–23, 2017. Dunleavy K, Little RF, Wilson WH: Update on Burkitt lymphoma, Hematol Oncol Clin North Am 30:1333–1343, 2016. Eftekhari K, Say EA, Shields CL, et al: Orbital lymphoma in the setting of idiopathic CD4+ lymphocytopenia (HIV-negative AIDS), Ophthal Plast Reconstr Surg 27:e134–e136, 2011. Elenitoba-Johnson KS, Wilcox R: A new molecular paradigm in mycosis fungoides and Sezary syndrome, Semin Diagn Pathol 34:15–21, 2017. Ferry JA, Klepeis V, Sohani AR, et al: IgG4-related orbital disease and its mimics in a western population, Am J Surg Pathol 39:1688–1700, 2015. Foss FM, Girardi M: Mycosis fungoides and Sezary syndrome, Hematol Oncol Clin North Am 31:297–315, 2017. Grasso D, Borreggine C, Ladogana S, et al: Sporadic Burkitt’s lymphoma/acute B-cell leukaemia presenting with progressive proptosis and orbital mass in a child, Neuroradiol J 29:231–235, 2016. Guffey Johnson J, Terpak LA, Margo CE, et al: Extranodal marginal zone B-cell lymphoma of the ocular adnexa, Cancer Control 23:140–149, 2016. Ho C, Kluk MJ: Molecular pathology: predictive, prognostic, and diagnostic markers in lymphoid neoplasms, Surg Pathol Clin 9:489–521, 2016. Hon C, Kwok AK, Shek TW, et al: Vision-threatening complications of nasal t/NK lymphoma, Am J Ophthalmol 134:406–410, 2002. Hother C, Rasmussen PK, Joshi T, et al: MicroRNA profiling in ocular adnexal lymphoma: a role for MYC and NFKB1 mediated dysregulation of microRNA expression in aggressive disease, Invest Ophthalmol Vis Sci 54:5169–5175, 2013. Hsi ED: 2016 WHO classification update—what’s new in lymphoid neoplasms, Int J Lab Hematol 39(Suppl 1):14–22, 2017.

Jusufbegovic D, Char DH: Clinical variability of ocular involvement in mycosis fungoides, JAMA Ophthalmol 133:341–343, 2015. Kim HJ, Ko YH, Kim JE, et al: Epstein-Barr virus-associated lymphoproliferative disorders: review and update on 2016 WHO classification, J Pathol Transl Med 51:352–358, 2017. Kim JW, An JH: Extranodal natural killer/t-cell lymphoma, nasal type, of the orbit mimicking recurrent orbital cellulitis, J Craniofac Surg 25:509–511, 2014. Kiratli H, Uzun S, Yesilirmak A, et al: Conjunctival extranodal natural killer/T-cell lymphoma, nasal type, Cornea 34:710–712, 2015. Kirkegaard MM, Rasmussen PK, Coupland SE, et al: Conjunctival lymphoma–an international multicenter retrospective study, JAMA Ophthalmol 134:406–414, 2016. Leonard JP, Martin P, Roboz GJ: Practical implications of the 2016 revision of the World Health Organization classification of lymphoid and myeloid neoplasms and acute leukemia, J Clin Oncol 35:2708–2715, 2017. Lokdarshi G, Pushker N, Bajaj MS: Sclerosing lesions of the orbit: a review, Middle East Afr J Ophthalmol 22:447–451, 2015. Luemsamran P, Pornpanich K, Uiprasertkul M, et al: NK/t-cell lymphoma of the nasal cavity causing contralateral dacryoadenitis, Orbit 32:250–252, 2013. Mathas S, Hartmann S, Kuppers R: Hodgkin lymphoma: pathology and biology, Semin Hematol 53:139–147, 2016. McKelvie P, McNab AA, Hardy T, et al: Comparative study of clinical, pathological, radiological, and genetic features of patients with adult ocular adnexal xanthogranulomatous disease, Erdheim-Chester disease, and IgG4-related disease of the orbit/ocular adnexa, Ophthal Plast Reconstr Surg 33:112–119, 2017. Mettu P, Griffith M, Yohe S, et al: Nodular lymphocyte predominant Hodgkin lymphoma presenting with unilateral orbital involvement, Ophthal Plast Reconstr Surg 33:e29–e31, 2017. Molyneux E, Scanlan T, Chagaluka G, et al: Haematological cancers in African children: progress and challenges, Br J Haematol 177:971–978, 2017. Moslehi R, Coles FB, Schymura MJ: Descriptive epidemiology of ophthalmic and ocular adnexal non-Hodgkin’s lymphoma, Expert Rev Ophthalmol 6:175–180, 2011. Moslehi R, Schymura MJ, Nayak S, et al: Ocular adnexal non-Hodgkin’s lymphoma: a review of epidemiology and risk factors, Expert Rev Ophthalmol 6:181–193, 2011. Mugnaini EN, Ghosh N: Lymphoma, Prim Care 43:661–675, 2016. Munch-Petersen HD, Rasmussen PK, Coupland SE, et al: Ocular adnexal diffuse large B-cell lymphoma: a multicenter international study, JAMA Ophthalmol 133:165–173, 2015. Ogwang MD, Zhao W, Ayers LW, et al: Accuracy of Burkitt lymphoma diagnosis in constrained pathology settings: importance to epidemiology, Arch Pathol Lab Med 135:445–450, 2011. Oles K, Skladzien J, Szczepanski W, et al: Immunoglobulin G4-related disease (IgG4-RD) in the orbit: mucosa-associated lymphoid tissue (MALT)-type lymphomas, Med Sci Monit 21:1043–1050, 2015. Ott G: Aggressive b-cell lymphomas in the update of the 4th edition of the World Health Organization classification of haematopoietic and lymphatic tissues: refinements of the classification, new entities and genetic findings, Br J Haematol 178:871–887, 2017. Parham P: MHC class I molecules and KIRs in human history, health and survival, Nat Rev Immunol 5:201–214, 2005.

Bibliography Pon JR, Marra MA: Clinical impact of molecular features in diffuse large B-cell lymphoma and follicular lymphoma, Blood 127:181–186, 2016. Raderer M, Kiesewetter B, Ferreri AJ: Clinicopathologic characteristics and treatment of marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), CA Cancer J Clin 66:153–171, 2016. Raess PW, Moore SR, Cascio MJ, et al: MYC immunohistochemical and cytogenetic analysis are required for identification of clinically relevant aggressive B cell lymphoma subtypes, Leuk Lymphoma 1–8:2017. Rasmussen P, Sjo LD, Prause JU, et al: Mantle cell lymphoma in the orbital and adnexal region, Br J Ophthalmol 93:1047–1051, 2009. Rasmussen PK, Coupland SE, Finger PT, et al: Ocular adnexal follicular lymphoma: a multicenter international study, JAMA Ophthalmol 132:851–858, 2014. Rasmussen PK, Ralfkiaer E, Prause JU, et al: Diffuse large B-cell lymphoma of the ocular adnexal region: a nation-based study, Acta Ophthalmol 91:163–169, 2013. Rasmussen PK, Ralfkiaer E, Prause JU, et al: Follicular lymphoma of the ocular adnexal region: a nation-based study, Acta Ophthalmol 93:184–191, 2015. Rath S, Connors JM, Dolman PJ, et al: Comparison of American Joint Committee on Cancer TNM-based staging system (7th edition) and Ann Arbor classification for predicting outcome in ocular adnexal lymphoma, Orbit 33:23–28, 2014. Reddy R, Kim SJ: Intraocular t-cell lymphoma due to mycosis fungoides and response to intravitreal methotrexate, Ocul Immunol Inflamm 19:234–236, 2011. Rothschild PR, Pagnoux C, Seror R, et al: Ophthalmologic manifestations of systemic necrotizing vasculitides at diagnosis: a retrospective study of 1286 patients and review of the literature, Semin Arthritis Rheum 42:507–514, 2013. Sesques P, Johnson NA: Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements, Blood 129:280–288, 2017. Shet T, Suryawanshi P, Epari S, et al: Extranodal natural killer/T cell lymphomas with extranasal disease in non-endemic regions are disseminated or have nasal primary: a study of 84 cases from India, Leuk Lymphoma 55:2748–2753, 2014. Shields CL, Alset AE, Boal NS, et al: Conjunctival tumors in 5002 cases. Comparative analysis of benign versus malignant counterparts. The 2016 James D. Allen lecture, Am J Ophthalmol 173:106–133, 2017. Sjo LD, Heegaard S, Prause JU, et al: Extranodal marginal zone lymphoma in the ocular region: clinical, immunophenotypical, and cytogenetical characteristics, Invest Ophthalmol Vis Sci 50:516–522, 2009. Sjo LD, Ralfkiaer E, Prause JU, et al: Increasing incidence of ophthalmic lymphoma in Denmark from 1980 to 2005, Invest Ophthalmol Vis Sci 49:3283–3288, 2008. Sjo LD: Ophthalmic lymphoma: epidemiology and pathogenesis, Acta Ophthalmol 87:1–20, 2009. Thesis 1. Stacy RC, Jakobiec FA, Schoenfield L, et al: Unifocal and multifocal reactive lymphoid hyperplasia vs follicular lymphoma of the ocular adnexa, Am J Ophthalmol 150:412–426, 2010. Svendsen FH, Heegaard S: Lymphoma of the eyelid, Surv Ophthalmol 62:312–331, 2017. Svendsen FH, Rasmussen PK, Coupland SE, et al: Lymphoma of the eyelid—an international multicenter retrospective study, Am J Ophthalmol 177:58–68, 2017.

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Tumors Leukemia Aggarwal E, Mulay K, Honavar SG: Orbital extra-medullary granulocytic sarcoma: clinicopathologic correlation with immunohistochemical features, Surv Ophthalmol 59:232–235, 2014. Bhadauria M, Ranjan P, Mishra D: Primary orbital plasmacytoma mimicking lacrimal gland tumor, Orbit 33:305–307, 2014. Chaudhry SR, Kreis AJ, Underhill HC, et al: Orbital mass secondary to acute lymphoblastic leukaemia in a child: a rare presentation, Orbit 33:421–423, 2014. Garala K, Jayaramachandran P, Knopp M, et al: Orbital apex tumour caused by chronic lymphocytic leukaemia: an unlikely suspect, BMJ Case Rep 2013:2013. Kiratli H, Tarlan B, Uzun S, et al: Orbital Richter syndrome, Orbit 32:381–383, 2013. Mangla D, Dewan M, Meyer DR: Adult orbital myeloid sarcoma (granulocytic sarcoma): two cases and review of the literature, Orbit 31:438–440, 2012. O’Neill JP, Harrison AR, Cameron JD, et al: Granulocytic sarcoma of the orbit presenting as a fulminant orbitopathy in an adult with acute myeloid leukemia, Ophthal Plast Reconstr Surg 33:S118–S120, 2017. Payne C, Olivero WC, Wang B, et al: Myeloid sarcoma: a rare case of an orbital mass mimicking orbital pseudotumor requiring neurosurgical intervention, Case Rep Neurol Med 395196:2014, 2014.

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Phelps PO, Marcet MM, Hong AR, et al: Eyelid myeloid sarcoma: ominous presentation of acute myelogenous leukemia, Orbit 34:30–32, 2015. Qian X, Gigantelli JW, Abromowitch M, et al: Myeloid sarcoma in the orbit, J Pediatr Ophthalmol Strabismus 53:e64–e68, 2016. Rath S, Agarwal S, Charan Das P, et al: Orbital myeloid sarcoma in adults presenting with exposure keratopathy and hearing loss, Can J Ophthalmol 50:e78–e81, 2015. Samborska M, Derwich K, Skalska-Sadowska J, et al: Myeloid sarcoma in children—diagnostic and therapeutic difficulties, Contemp Oncol (Pozn) 20:444–448, 2016. Shields JA, Stopyra GA, Marr BP, et al: Bilateral orbital myeloid sarcoma as initial sign of acute myeloid leukemia: case report and review of the literature, Arch Ophthalmol 121:138–142, 2003. Shields JA, Bakewell B, Augsburger JJ, et al: Space-occupying orbital masses in children. A review of 250 consecutive biopsies, Ophthalmology 93:379–384, 1986. Takhenchangbam DS, Laishram RS, Thoudem TS, et al: Proptosis and facial palsy as an unusual clinical presentation of acute myeloid leukemia, Iran J Cancer Prev 6:52–54, 2013. Thakur B, Varma K, Misra V, et al: Granulocytic sarcoma presenting as an orbital mass: report of two cases, J Clin Diagn Res 7:1704–1706, 2013. Wilson ME, Thornton S, Murchison AP, et al: Clinical challenge: an orbital Hickam’s dictum, Surv Ophthalmol 61:799–805, 2016.

Zimmerman LE, Font RL: Ophthalmologic manifestations of granulocytic sarcoma (myeloid sarcoma or chloroma). The third Pan American Association of Ophthalmology and American Journal of Ophthalmology lecture, Am J Ophthalmol 80:975–990, 1975.

Tumors: Monoclonal and Polyclonal Gammopathies Colucci G, Alberio L, Demarmels Biasiutti F, et al: Bilateral periorbital ecchymoses. An often missed sign of amyloid purpura, Hamostaseologie 34:249–252, 2014. Galea M, McMillan N, Weir C: Diplopia and variable ptosis as the sole initial findings in a case of orbital plasmacytoma and multiple myeloma, Semin Ophthalmol 30:235–237, 2015. Painter SL, Dickens E, Elston JS: Isolated extraocular muscle infiltration with plasmacytoma treated with localized injection of dexamethasone, J Neuroophthalmol 35:168–170, 2015. Tenzel PA, Mishra K, Andron A, et al: Extramedullary plasmacytoma of the lateral rectus muscle, Orbit 36:78–80, 2017. Thuro BA, Sagiv O, Shinder R, et al: Clinical presentation and anatomical location of orbital plasmacytomas, Ophthal Plast Reconstr Surg 34:258–261, 2018.

Secondary Tumors Tailor TD, Gupta D, Dalley RW, et al: Orbital neoplasms in adults: clinical, radiologic, and pathologic review, Radiographics 33:1739–1758, 2013.

15  Diabetes Mellitus NATURAL HISTORY I. Diabetes mellitus (DM) is a heterogeneous group of disorders characterized by elevated blood glucose and other metabolic abnormalities. The HbA1c (glycated hemoglobin) level is important in making the diagnosis of diabetes and is used as a measure of the quality of diabetic care. It also is predictive of mortality and associated with significant variations in single nucleotide polymorphisms (SNPs) based on racial and ethnic differences in populations. The presence of pre-diabetes varies considerably on a racial basis.



A. The disorder may result from decreased circulating insulin or from ineffective insulin action in target cells. B. DM, which affects approximately 5% of the United States population and 29% of the population 65 years or older, is classified as either type 1 (previously called insulindependent) or type 2 (previously called noninsulindependent) DM. Traditionally, type 2 diabetes has been a disease of adults. As the prevalence of obesity among adolescents has risen, there has been an emergence of type 2 diabetes in that segment of the population.





C. Type 1 diabetes, which is an autoimmune disorder, probably related to infections, early childhood diet, and insulin resistance, represents a worldwide epidemic. D. Worldwide, there are approximately 93 million people with diabetic retinopathy, 17 million with proliferative diabetic retinopathy, 21 million with diabetic macular edema, and 28 million with vision-threatening diabetic retinopathy. Longer diabetes duration, and poorer glycemic and blood pressure control are strongly associated with diabetic retinopathy (DR). Diabetes constitutes a worldwide epidemic. In 2010, worldwide there were twice as many deaths attributed to diabetes as in 1990. By 2025, 380 million people worldwide are expected to have diabetes.



E. Intensive lifestyle interventions can prevent the onset of diabetes in high-risk individuals. Control of blood











sugar levels, blood pressure, and blood lipids can prevent or delay the onset of diabetes-related complications. Type 2 DM accounts for approximately 90% of diabetic patients. Target-cell resistance occurs in both types, but is a central feature in type 2. Genetic defects in the cellular insulin receptor may account for the insulin resistance. II. DR is a leading cause of blindness in the United States. A. Over three-fourths of the blind are women. B. There is a significantly higher prevalence of DR in individuals of black or Hispanic descent compared to whites or Chinese. C. The most important factor in the occurrence of DR is how long the patient has been diabetic. 1. Although approximately 60% of patients develop retinopathy after 15 years of diabetes, and almost 100% after 30 years, the risk of legal blindness in a given diabetic person is only 7% to 9% even after 20 to 30 years of DM. a. When the onset of type 1 DM is before 30 years of age and no DR is present at onset, approximately 59% of patients have developed DR 4 years later, and almost 100% 20 years later. In this group, the incidence of proliferative diabetic retinopathy (PDR) stabilizes after 13 to 14 years of diabetes at between 14% and 17%. b. When the onset of type 1 DM is after 30 years of age and no DR is present at onset, approximately 47% of patients have developed DR 4 years later. Among patients older than 30 years of age who develop type 2 DM, 34% develop DR 4 years later. In this group of patients with type 1 DM, 7% who were free of PDR at onset of DM developed PDR 4 years later; 2% of the patients with type 2 DM developed PDR 4 years later. c. The prevalence of diabetic retinopathy and visionthreatening diabetic retinopathy is particularly high among non-Hispanic black individuals. 2. Overall, there has been a decline in the cumulative incidence of severe DR in patients with type 1 diabetes. Similarly, the rate of nonproliferative DR is declining in the United States. 3. Over a 25-year period of follow-up, the mortality in diabetic blind individuals is 61% compared to 41% for those who are not blind. Moreover, there is significant racial difference in the quality-adjusted life-years for individuals with diabetes and visual impairment, with 583

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whites having a higher quality-adjusted life expectancy compared to black individuals. a. Factors associated with mortality are glycemic regulation, dyslipidemia, and creatinine level. 4. Baseline factors associated with progression to blindness include the presence of maculopathy and glycemic control (HbA1c level). 5. Ocular symptoms occur in approximately 20% to 40% of diabetic patients at the clinical onset of the disease, but these symptoms are mainly caused by refractive changes, rather than by DR. 6. The low frequency of retinopathy in secondary diabetes (e.g., chronic pancreatitis, pancreatectomy, hemochromatosis, Cushing’s syndrome, and acromegaly) may be due to the decreased survival among patients with secondary diabetes. A positive correlation exists between the presence of DR and nephropathy (Kimmelstiel–Wilson disease).

7. It appears that the risk for developing DR in type 1 DM is reduced if glycemic control is achieved from the time of diagnosis; conversely, if DR is already present, early intensive insulin treatment can initially worsen the DR in about 10% of those individuals. The worsening may be related to increased VEGF production. Control of accompanying hypertension can facilitate the regression of diabetic retinopathy. 8. Among diabetic individuals, plasma lipid levels are associated with the presence of hard retinal exudates. Carotid artery intima–media wall thickness is associated with retinopathy; however, other manifestations of atherosclerosis and most of its risk factors are not associated with the severity of DR. 9. Diabetic retinopathy is independently associated with coronary artery calcification suggesting that common pathophysiologic processes may underlie both microand macrovascular disease. III. In type 1 DM, PDR is uncommon in patients younger than 20 years of age, and almost unheard of in patients younger than 16 years of age. A. Background DR (BDR; especially microaneurysms), however, can be demonstrated on fluorescein angiography in type 1 diabetic patients as young as 3 years of age, and is present in most patients older than 10 years of age. The autoimmune process leading to type 1 diabetes, involves a T-cell response with the pancreatic beta cell as the target. Enteroviruses, especially Coxsackievirus B4 virus, have been suggested as potential inducers or aggravating factors of type 1 diabetes in genetically predisposed individuals. Others question the virus’s causative role. It also must be noted that

viruses not only may contribute to the pathogenesis of type 1 diabetes by accelerating the progression of the disease, they also may provide protection from autoimmunity. Additionally, viruses can infect pancreatic beta cells with results ranging from functional damage to cell death. Other viruses have been suggested as possibly causative for type 1 diabetes; however, Coxsackie virus is the most frequently cited. See Table 15.1 for a list of the viruses most commonly suggested as possible causative agents for type 1 diabetes.

IV. Most diabetic patients never acquire PDR, and in those who do, it develops only after at least 15 years of DM. Rarely, a patient presents with BDR, or even with PDR before any systemic evidence of DM (such as hyperglycemia) is discovered. V. Other associations A. Primary open- and closed-angle glaucoma may occur more often in diabetic patients than in nondiabetic individuals. There may be ethnic differences in these associations. 1. The presence of type 2 diabetes and longer duration of type 2 diabetes are associated with an increased risk of open-angle glaucoma in individuals of Hispanic descent. 2. Diabetic patients also may be at greater risk for failure of glaucoma surgery. B. Diagonal ear lobe crease (DELC) (Frank’s sign) has been cited as a marker for coronary artery disease. It may be particularly helpful in patients with other risk factors for coronary artery disease. Moreover, it has been suggested that it may be associated with an increased risk of diabetic retinal angiopathy. This latter contention has been called into question. C. A positive association exists between DR and the presence of elevated blood pressure (especially increased diastolic blood pressure), glycosylated hemoglobin, and smoking. D. Other risk factors for the development of DR include hypertension and abdominal obesity. E. Genetic variants associated with diabetic retinopathy are VEGF, AKR1B1, and EPO. F. Epigenetic modifications of genes encoding mitochondrial superoxide dismutase and matrix metalloproteinase-9 are found in association with diabetic retinopathy. These changes are accompanied by increased activates of epigenetic modification enzymes, histone lysine demethylase 1, and DNA methyltransferase, and the microRNAs responsible for regulating nuclear transcriptional factor and VEGF are upregulated. At least in animal models of diabetes, reversal of these epigenetic modifications are extremely difficult to halt even after a relatively brief period of hyperglycemia. VI. Diabetic peripheral neuropathy affects about 50% of diabetic patients.

Ocular Surface Disease

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TABLE 15.1  Key Viral Suspects and Main Findings on the Association of Viral Infection With

Type 1 Diabetes Key Suspects

Main Findings

Enteroviruses

Coxsackieviruses (CBV4, CBV1)

Herpesviruses

EBV

CMV

HHV-6 Parechoviruses

Rotaviruses

• A strain of CBV4 was isolated from the pancreas of a recent-onset type 1 diabetic patient and was later shown to induce diabetes in mice. • CVB1 was found to be associated with an increased risk of β-cell autoimmunity in the DIPP study. • Presence of enteroviral capsid protein 1 (VP1) in 6/6 patients and EV genome in 4/6 patients along with hyperexpression of MHC-I in the DiViD study. • Sequence homology of HLA-DQ8 with BERF4-encoded EBNA3C protein of EBV and association with T1D. • The antibody levels against the EBV capsid were significantly lower in diabetic children than in controls, interpreted as possible abnormalities in the EBV-specific immune response. • Significantly higher antibody responses to EBV in T1D patients compared to control cases. • CMV has sequence homology with GAD65 and might play a role in the pathogenesis of the disease. • Case report from a Canadian group showed a strong correlation between CMV genome and islet autoantibodies suggesting a potential role for persistent CMV infections in the pathogenesis of some T1D cases. • GAD65-specific T cells recognized an HHV6-derived peptide. • Parechovirus positivity was more common in autoantibody-positive males than in control males in the 6 months preceding seroconversion. • Antibodies to Ljungan virus correlated with insulin autoantibodies (IAA) and HLA-DQ8 in young children, suggesting a possible role in T1D induction. • Presence of rotavirus antibodies and antibodies to insulin, tyrosine phosphatase-like insulinoma antigen 2 (IA-2) or GAD65. • Similar peptides between the capsid protein VP7 and T-cell epitopes in GAD65 and IA-2. • Rotavirus infection triggers apoptosis in the pancreas and is associated with the involution of the organ, which compromises insulin secretion and expression, inducing hyperglycemia in mice.

(From Rodriguez-Calvo et al.: The viral paradigm in type 1 diabetes: Who are the main suspects? Autoimmunity Reviews 15:964–969, 2016. Table 1. Elsevier.)

OCULAR SURFACE DISEASE



Ocular surface disease represents the confluence of multiple factors such as tear film quantity and quality, corneal epithelial health, and corneal sensitivity. They converge in causing ocular discomfort and keratopathy including punctate epithelial erosions, and even nonhealing corneal epithelial defects and ulcers.



An endogenous opioid mediated growth regulatory system may play a role in the pathobiology of dry eye, decreased corneal sensitivity and delayed corneal wound healing in diabetes. In this system, opioid growth factor (OGF), [Met5]enkephalin, acts by binding with its specific receptor, OGFr, to downregulate cell division and other cellular activities. Blockade of binding of OGF to OGFr using the strong opioid antagonist, naltrexone, can reverse dry eye, decreased corneal sensitivity, and poor corneal epithelial wound healing secondary to diabetes. Similarly, topical insulin can ameliorate corneal epithelial wound healing dysfunction in diabetes; however, it is not additive to the effect of topical naltrexone.

I. Tear film A. Diabetic patients have abnormal tear functions compared to nondiabetic individuals. 1. 57% of type 1 diabetics and 70% of type 2 diabetics have dry eye disease. 2. One component of this disorder is meibomian gland dysfunction marked by quantitative and qualitative abnormalities in the tear film lipid layer.







a. Insulin stimulates, but high glucose is toxic for meibomian gland epithelial cells. B. Diabetes is one of the leading systemic risk factors for dry eye syndrome. 1. There is increased tear osmolarity and decreased tear production in diabetic patients. 2. Tear osmolarity also correlates with duration of diabetes. a. Tear osmolarity increases with severity of diabetic peripheral neuropathy as do other measures of tear film abnormality. 3. Similarly, increased tear osmolarity and reduced tear production also are found in children with diabetes. C. Diabetic patients with dry eye have a significantly shorter tear break up time compared to diabetics without dry eye. 1. Nevertheless, even commonly used tear film diagnostic tests may underestimate the presence of dry eye disease in diabetic individuals in comparison to fluorescein staining of the cornea or lissamine green staining of the conjunctiva. D. Individuals with diabetes have a higher percentage of dry eye symptoms compared to normal individuals or to diabetic patients without dry eye. 1. These symptoms may be masked secondary to corneal neuropathy and so detection of ocular surface disease may be dependent on direct ocular surface and tear film examination.

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E. Patients with proliferative diabetic retinopathy and/or clinically significant macular edema are particularly predisposed to impaired tear function. F. Tear protein profile changes with disease duration in diabetes. There is increased expression of apoptosisrelated proteins, such as annexin A1, and immunity- and inflammation-related proteins, including neutrophil elastase 2 and clusterin, and glycometabolism-related proteins, like apolipoprotein A-II. G. Both dry eye and retinopathy correlate with HbA1c levels and with each other. H. These changes in tear production and characteristics are reflected in abnormal conjunctival brush cytology and impression cytology. 1. Conjunctival cytology also is abnormal in diabetic children. 2. Conjunctival levels of interleukin-1β and tumor necrosis factor-α are increased in biopsy specimens in diabetic patients with dry eye. I. Lacrimal gland damage may be seen secondary to diabetes. 1. Lacrimal gland acinar cells in diabetic animals have significantly smaller and more homogeneous secretory granules, compared to control animals. The lacrimal glands of these animals also contain significantly less peroxidase, and secrete a significantly decreased quantity of enzyme in response to stimulation. These findings have been interpreted to indicate that diabetes is associated with lacrimal gland insufficiency as a result of acinar morphology and reduced peroxidase content and secretion. 2. It has been postulated that histological alterations in the lacrimal glands of diabetic rodents, which can be prevented with insulin treatment, are secondary to hyperglycemia-induced oxidative stress, which may contribute to diabetic dry eye. a. This conclusion is supported by the fact that aspirin treatment can prevent such experimentallyinduced changes. J. Cataract surgery may exacerbate dry eye in diabetic patients who also may recover more slowly than nondiabetic patients. K. Inflammation also may play a significant role in the pathogenesis of diabetic dry eye. L. Ocular surface disease problems can be particularly vexing in the setting of topical treatment for glaucoma. II. Conjunctiva A. Conjunctival microaneurysms may be found in diabetic individuals, but they are of questionable diagnostic significance because they also occur in nondiabetic subjects. B. Transmural lipid imbibition may occur in conjunctival capillaries in diabetic lipemia retinalis (Fig. 15.1). Histologically, lipid-laden cells, either endothelial cells or



subintimal macrophages, are present projecting into and encroaching on conjunctival capillary lumens. C. The conjunctiva may show decreased vascularity in the capillary bed, increased capillary resistance, and decreased area occupied by the microvessels. There is contraction of larger conjunctival vessels. The development of diabetic retinopathy is associated with dilation of smaller conjunctival vessels. Microvascular abnormalities have even been detected in the conjunctiva of pediatric diabetic patients. The severity of these findings correlates with HbA1c levels, but not with the duration of the disease. Such conjunctival microvascular changes correlate significantly with disease severity in type 2 diabetes, but not with disease duration since diagnosis.





D. The prevalence and grade of pinguecula are more significant in diabetics than in nondiabetic individuals. E. Conjunctival vasculopathy in type 2 diabetes may precede retinal changes, thereby possibly providing a window of opportunity for earlier intervention in these individuals. F. Inflammatory markers such as ICAM-1 (intercellular adhesion molecule) and VCAM-1 (vascular cell adhesion molecule) are upregulated in the conjunctiva of type 2 diabetic individuals with and without retinopathy. ICAM-1, VEGF and p53 are strongly expressed in the conjunctiva of patients with proliferative DR compared to nondiabetic controls, and are expressed to some degree even in diabetic individuals lacking proliferative DR. The presence of upregulation for these mediators in the conjunctiva, often before the presence of clinical retinopathy, suggests a possible role for these mediators in the pathogenesis of diabetic microangiopathy.



G. Positive bacterial conjunctival cultures are found in a higher percentage of diabetic patients compared to normal controls and may be related to increased diabetesrelated ocular infections. There is a higher percentage of bilaterally positive cultures in patients with proliferative diabetic retinopathy. III. Cornea The following discussion treats anatomic components of the cornea separately; however, one must be mindful of their interdependent functions. For example, corneal epithelial cells and subbasal nerve fibers are reduced in diabetes, and these abnormalities have been demonstrated to be interrelated and correlated with modifiable risk factors, such as duration of diabetes and diastolic blood pressure. Similarly, corneal confocal microscopy demonstrates that young adult diabetic patients have widespread corneal changes including lower epithelial and endothelial cell densities,

Ocular Surface Disease

A

B

C

D

587

Fig. 15.1  Lipemia retinalis. Right eye (A and C) and left eye (B and D) of same patient taken one month apart. Lipemia retinalis is more marked in C and D than in A and B. Transmural lipid imbibition may also occur in conjunctival capillaries in diabetic lipemia retinalis.



higher keratocyte cell density, and decreased nerve branch density and nerve fiber length compared to healthy controls. These changes are increased in severity when retinopathy is present. Corneal nerves and corneal epithelium probably actively engage and influence each other, including during the process of epithelial wound healing, and diabetes negatively impacts these interactions. Finally, even the biomechanical properties of the cornea are changed in diabetes so that there is increased corneal resistance factor in diabetic corneas. A. Epithelium (Table 15.2 lists manifestations of corneal diabetes some of which will be highlighted in this chapter) 1. Corneal abnormalities related to diabetes include increased epithelial defects, epithelial fragility, recurrent erosions, corneal ulcers, superficial punctate keratitis, and delayed and incomplete wound repair. 2. Corneal epithelial closure rates are decreased in experimental wounds in diabetic animals, and the healing epithelium displays connection abnormalities, edema, and microvillus reduction when examined by scanning electron microscopy.

Decreased penetration of “anchoring” fibrils from the corneal epithelial basement membrane into the corneal stroma may be responsible for the loose adhesion between the corneal epithelium and the stroma. The corneal epithelium in diabetic patients is much easier to wipe off, often in a single sheet (e.g., during vitrectomy procedures), than is the epithelium of nondiabetic patients. Approximately 50% of diabetic patients undergoing vitrectomy surgery have corneal complications following the procedure, with 44.6% having an epithelial disturbance, and 23.8% exhibiting corneal edema. These complications are significantly correlated with the degree of surgical invasion during the procedure.

3. It has been postulated that an imbalance between marked expression of interleukin-1β and suppression of the secreted form of IL-receptor antagonist results in a reduced early innate/inflammatory response in diabetic corneal epithelial wound healing leading to delayed wound healing in these corneas.

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CHAPTER 15  Diabetes Mellitus individuals, but 8.5% in nondiabetics, and is associated with tear film abnormalities, particularly nonuniformity of the tear lipid layer, in diabetic patients.

TABLE 15.2  Manifestations of Corneal

Diabetes

Abnormality

Manifestation

Neuropathy (nerves)

Decreased sensitivity Decreased subbasal nerve fiber and branch density Delayed nerve regeneration after injury Increased stromal nerve thickness and tortuosity Delayed wound healing Compromised barrier function Persistent epithelial defects Recurrent erosions Epithelial fragility Edema Ulceration Low cell density Stem cell dysfunction Increased autofluorescence Dendritic cell accumulation Abnormal collagen bundles Stromal edema Decreased cell density Cell pleomorphism Low tear secretion Increased tear osmolarity Increased corneal response factor

Keratopathy (epithelium)

Immune cell alterations Stromal changes Endothelial changes Tear film changes Biomechanics problems



(From Ljubimov AV: Diabetic complications in the cornea. Vision Research 139:138–152, 2017. Table 1. Elsevier.)

4. MicroRNAs are short noncoding oligonucleotides that regulate gene expression by repressing translation. The microRNA, miR-146a, has been suggested to be active in limbal stem cell maintenance at the corneal periphery and is downregulated during epithelial migration centrally, particularly during epithelial wound healing. Upregulation of miR-146a could contribute to delayed corneal epithelial wound healing in diabetes. 5. TGFβ signaling is altered in diabetes with TGF-β1 and β3 being upregulated in response to epithelial wounding in normal epithelial cells, but TGF-β1 is suppressed by hyperglycemia in animal models of type 1 and type 2 diabetes. Exogenously added TGFβ1 restores and accelerates epithelial healing in these animal models of diabetes. 6. Advanced glycation end products delay epithelial wound healing through reactive species generation. Keratoepitheliopathy, conjunctival squamous metaplasia, and abnormal corneal sensitivity, tear breakup time, Schirmer test, and tear secretion level are all related to the status of metabolic control, diabetic neuropathy, and stage of DR. The prevalence of keratoepitheliopathy is 22.8% in diabetic



B. Endothelium 1. Specular microscopic studies show corneal endothelial structural abnormalities reflected in an increased coefficient of variation of cell area, a decreased percentage of hexagonal cells, an increased corneal autofluorescence, polymegathism and pleomorphism, and an increased intraocular pressure. The changes in corneal endothelium resemble those that occur with aging. 2. In the Ocular Hypertension Treatment Trial, increased central corneal thickness was associated with younger age, female gender, and diabetes. 3. Contact lens studies in patients who have type 2 DM have demonstrated that the diabetic corneal endothelium shows significantly lower function than the nondiabetic corneal endothelium, even though the morphometry of corneal endothelial cells and central corneal thickness in diabetic patients who wear soft contact lenses are not appreciably different from the values found in contact lens-wearing control individuals. 4. Corneal endothelial cell density is reduced and polymegathism as reflected in the coefficient of variation of cell area is increased in subjects with type 2 diabetes. Endothelial cell density is inversely correlated with HbA1c levels, which are correlated with mean endothelial cell area. These corneas also are thicker than those of healthy control subjects. a. Diabetic children have thicker corneas, lower endothelial cell density, increased polymegathism, and decreased pleomorphism compared to normal children. All of these changes are correlated only with duration of diabetes. 5. Mitochondrial function is impaired in diabetic corneal endothelium and is reflected in reduced spare respiratory capacity and corresponding changes in mitochondrial morphology. Corneal endothelial cells of diabetic individuals are more susceptible to damage during cataract surgery than nondiabetics. Such patients may exhibit a delay in recovering from postoperative corneal edema. Diabetes is also a significant risk factor for unsuccessful initial corneal transplant grafts because of endothelial failure.



C. Corneal nerves 1. The cornea is the most densely innervated mammalian tissue. 2. Decreased corneal sensitivity is a component of diabetic keratopathy.

Intraocular Changes

















3. The subbasal corneal nerve plexus is located between the basal epithelium and Bowman’s layer. 4. Experimentally, nerve fiber damage is evident in the subbasal nerve plexus before terminal epithelial nerve loss. 5. The evaluation of corneal nerve morphology with confocal microscopy and histopathology demonstrates significant changes in the diabetic corneal nerve paralleling other forms of diabetic polyneuropathy. Corneal confocal microscopy evaluation of intra-epidermal nerve fiber density can be useful in the diagnosis of diabetic peripheral neuropathy. a. Subbasal nerve abnormalities correlate with reduced corneal epithelial basal cell density. These abnormalities are more pronounced in patients with proliferative disease. Moreover, they have been documented to progress over time. They are stable, however, in healthy nondiabetic individuals. b. Corneal nerve tortuosity may relate to the severity of the neuropathy in diabetic patients. c. Corneal confocal microscopy demonstrates that corneal nerve fiber density and branch density are reduced in diabetic patients compared to control individuals, and these measures tend to be worse in individuals with more severe neuropathy. Moreover, the grade of diabetic foot syndrome correlates with corneal nerve changes and corneal sensation. d. It has been claimed that the whorl-like pattern of the subbasal corneal nerves in the inferocentral cornea may more accurately define the extent of diabetic corneal nerve damage. Nevertheless, this claim has been questioned. e. Corneal nerve morphology as evaluated by confocal microscopy improves with improvement in risk factors for diabetic neuropathy. f. Morphologic changes in corneal nerve fibers can be detected earlier in diabetes than abnormalities in corneal sensation testing and vibration assessment. These changes also are present in the absence of retinopathy or microalbuminuria. They may even be present at the early stage of impaired glucose tolerance. g. Abnormalities in corneal nerve fiber morphology on in vivo confocal microscopic examination are significant even in patients without neuropathy. Moreover, they may be predictive of future polyneuropathy. h. Corneal nerve changes also occur in parallel to cardiac autonomic neuropathy and peripheral neuropathy. i. Substance P levels are significantly decreased in diabetic patients compared with healthy controls. Substance P levels correlate with corneal nerve density. It may act through a neurokinin-1 receptor.



589

6. Corneal Langerhans’ cell density is increased in diabetic patients, particularly in the earlier phases of corneal nerve damage suggesting a possible immunemediated mechanism for corneal nerve damage. 7. In experimentally induced diabetes, corneal dendritic cells are reduced, and there is retarded corneal nerve regeneration following corneal wounding. Dendritic cells are a major source of ciliary neurotrophic factor (CNTF). Addition of exogenous CNTF to wounded diabetic corneas accelerates nerve regeneration. Conversely, blockade of the CNTF receptor induces sensory nerve degeneration and retarded regeneration even in normal corneas. Thus, CNTF reduction contributes significantly to reduced corneal nerve regeneration in wounded diabetic corneas. a. Similarly, neuropeptide FF signaling through its receptor contributes to recovery from injury to corneal nerves in diabetes. 8. Tear levels of insulin-like growth factor binding protein 3 more tightly correlate with changes in nerve fiber length and branch density in diabetes than does HbA1c.

Calcification of corneal nerves has been demonstrated by slit-lamp biomicroscopy and confocal microscopy in a diabetic patient.

INTRAOCULAR CHANGES Lens I. “Snowflake” cataract of type 1 diabetic patient A. The cataract consists of subcapsular opacities with vacuoles and chalky-white flake deposits. B. The whole lens may become a milky-white cataract (occasionally the process is reversible), and even may be bilateral. C. The histopathology has not been defined. II. Adult-onset diabetic cataract (Fig. 15.2) A. The cataract (cortical and nuclear) is indistinguishable clinically and histopathologically from the “usual” agerelated cataracts. Diabetic patients, however, are at an increased risk for cataracts compared with nondiabetic subjects. Nevertheless, diabetes is not universally accepted as a risk factor for nuclear cataracts. 1. Diabetes is a strong risk factor for the development of posterior subcapsular cataract.

Decreased antioxidant protection may contribute to diabetic cataracts. In particular, lens damage is believed to be caused by peroxynitrite and methylglyoxal (MGO), which are diabetes-related compounds. That damage can be prevented by ascorbic acid and glutathione, which are the main

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CHAPTER 15  Diabetes Mellitus

7. Animal models of type 1 and type 2 diabetes suggest that osmotic damage, reduced glutathione, and decreased adenosine triphosphate production may be important pathological mechanisms for cataract formation in type 1 diabetes, while crystallin modification and cross-linking/aggregation as well as intermediate filament degradation are more important in type 2 diabetes cataract formation. 8. Expression of 78 kDa glucose-regulated protein and activating transcription factor 6, which are two factors in the unfolded protein response, are both elevated in senile cataracts, and 30% higher and 35% higher, respectively, in diabetic cataracts than in senile cataracts. These findings indicate that the unfolded protein response may be significant in the pathogenesis of these cataracts. 9. Multiple other metabolic pathway abnormalities also occur in the diabetic lens, but are not within the scope of our discussion.

Fig. 15.2  Cataract. Histologic section shows marked cortical and nuclear cataractous changes in diabetic patient. The changes are nonspecific and, therefore, indistinguishable from those in nondiabetic patients.

components of the lens antioxidant defense mechanism. Moreover, MGO may alter active and passive DNA demethylation pathway enzymes in human lens epithelial cells ultimately resulting in unfolded protein response activation. Other factors that may contribute to diabetic cataracts are zinc deficiency, socioeconomic issues in various cultures, and abnormalities related to the advanced glycation process. Improved diabetic control and smoking prevention may reduce the risk of developing cataracts in diabetes.

Decreased proliferation of lens epithelial cells and increased expression of ICAM-1 may play a role in the progression of cataract in type 2 diabetes. Similarly, the density of lens epithelial cells is decreased in type 2 diabetes and correlates with the level of erythrocyte aldose reductase and the level of HbA1c or diabetic retinopathy. Thus, the polyol pathway mediated by aldose reductase may be associated with the reduction in lens epithelial cells in diabetes.

2. Apoptosis plays an important role in the development of cataracts in DR compared to senile cataract. There is a reduced lens diameter in diabetic individuals compared to age-matched controls.

3. Nuclear fiber compaction analysis demonstrates no difference in compaction between diabetic and nondiabetic cataracts, although diabetes does appear to accelerate the formation of cataracts that are similar to age-related nuclear cataracts. 4. Improved diabetic control and smoking prevention may reduce the risk of developing cataracts in diabetes. 5. Decreased proliferation of lens epithelial cells and increased expression of ICAM-1 may play a role in the progression of cataract in type 2 diabetes. Similarly, the density of lens epithelial cells is decreased in type 2 diabetes and correlates with the level of erythrocyte aldose reductase and the level of HbA1c or diabetic retinopathy. Thus, the polyol pathway mediated by aldose reductase may be associated with the reduction in lens epithelial cells in diabetes. 6. Lens epithelial cell apoptosis is increased in diabetes with or without retinopathy.



B. Patients with diabetes may have transient lens opacities and induced myopia during hyperglycemia.

Aldose reductase probably plays an important role in initiating the formation of lens opacities in diabetic patients, as it does in galactosemia. Calpains may be responsible for the unregulated proteolysis of lens crystallins, thereby contributing to diabetic cataract development.



C. Cataract surgery and progression of DR 1. As compared to individuals without diabetes, cataract surgery takes place approximately 20 years earlier in type 1 diabetic patients. Moreover, age and maculopathy at baseline are both predictive of cataract surgery. 2. The visual prognosis for patients who have pre-existing DR, both nonproliferative and proliferative, and who undergo cataract extraction and posterior-chamber lens implantation is less favorable than for patients who have no retinopathy.

Intraocular Changes



3. The poorer prognosis results from increased frequency of cystoid macular edema (CME) and progression of DR, both background and proliferative, after cataract extraction, which may result, in part, from changes in concentrations of angiogenic, antiangiogenic, and anti-inflammatory factors after cataract surgery. 4. Posterior capsule opacification is greater in diabetic individuals following cataract surgery than in nondiabetic control patients; however, among diabetic individuals, neither the stage of DR nor the systemic status of the diabetes correlates with the degree of posterior capsule opacification. a. It has been postulated that increased production of advanced glycation end products in the human lens capsule in diabetes may promote TGFβ2mediated epithelial-to-mesenchymal transition of lens epithelial cells, and thereby contribute to an increased rate of posterior capsule opacification in these individuals.

591

5. There are significant internal structural changes in the type 1 diabetic lens compared to type 2 diabetics or normal controls. Specifically, there is an increase in thickness of the lens nucleus and different cortical layers in type 1 diabetes. 6. Higher postoperative levels of cytokine activities and accompanying lens epithelial cell morphologic changes may indicate increased proliferative activity and contribute to strong anterior lens capsule contraction. D. Children with type 1 diabetes have decreased lens clarity and increased lens thickness even in cases of wellcontrolled diabetes without diabetic retinopathy.



Iris I. Vacuolation of iris pigment epithelium (Fig. 15.3) A. Vacuolation of the iris pigment epithelium is present in 40% of enucleated diabetic eyes. The vacuoles contain glycogen.

A

B

C

D Fig. 15.3  Lacy vacuolation of iris pigment epithelium. A, Transpupillary retroillumination shows myriad pinholes of transillumination of the iris just to the right of pupil (light coming from left). Fine points of light tend to follow pattern of circumferential ridges of posterior pigment epithelial layer. Transmission caused by swelling of epithelial cells and displacement of pigment, not by loss of pigment from cells. B, Vacuolation involves both layers of iris pigment epithelium and ceases abruptly at the iris root. Vacuoles appear empty in sections stained with hematoxylin and eosin. C, Vacuoles stain positively with periodic acid–Schiff stain. Circumferential ridges (cut here meridionally) are greatly accentuated. D, Glycogen particles (very dark, tiny dots) present throughout pigment epithelial vacuoles, along with large melanin granules. Plasma membranes separate adjacent cells. (A, Modified from Fine BS, Berkow JW, Helfgott JA: Diabetic lacy vacuolation of iris pigment epithelium. Am J Ophthalmol 69:197. © Elsevier 1970. B and C, modified from Yanoff M: Ocular pathology of diabetes mellitus. Am J Ophthalmol 67:21. © Elsevier 1969.)

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CHAPTER 15  Diabetes Mellitus

Rupture of the vacuoles when the intraocular pressure is suddenly reduced, as in entering the anterior chamber during cataract surgery, results in release of pigment into the posterior chamber. The pigment is visible clinically as a cloud moving through the pupil into the anterior chamber. Lacy vacuolation and “damage” to the overlying dilator muscle may be the cause of delayed dilatation of the iris after instillation of mydriatics.



B. Pinpoint “holes” may be seen clinically with the slit lamp when transpupillary retroillumination is used. The holes may be seen in at least 25% of known diabetic patients who have blue irises. In autopsy eyes from diabetic patients, vacuolation of the iris pigment epithelium may be related to increased blood glucose levels before death. The vacuolation is also seen histologically in neonates and in patients who have systemic mucopolysaccharidoses (the vacuoles contain acid mucopolysaccharides), Menkes’ syndrome, and multiple myeloma.

II. Neovascularization of iris (rubeosis iridis; Fig. 15.4; see also Figs. 9.13 and 9.14) A. Rubeosis iridis is the clinical descriptive term for iris neovascularization. 1. It is present in fewer than 5% of diabetic patients without PDR, but in approximately 50% of patients who have PDR. 2. The new iris vessels arise from venules. Ischemic retina resulting in proliferative DR increases the intraocular level of VEGF, resulting in the proliferation of new, abnormal blood vessels on the iris surface. Access of VEGF to the anterior chamber inducing the development of iris neovascularization is facilitated by lensectomy and vitrectomy, both of which remove these barriers leading to the development of iris neovascularization in approximately 50% of cases.





B. Neovascularization of the iris may arise from the anteriorchamber angle, the pupillary border, midway between, or all three. C. Early, anterior chamber angle neovascularization causes a secondary, open-angle glaucoma that progresses rapidly to a closed-angle glaucoma, caused by peripheral anterior synechiae. As the fibrovascular tissue on the anterior iris surface contracts, ectropion uveae may develop. The term, ectropion uveae, refers to traction by a contracting membrane resulting in drawing the pigment epithelium from the region of the posterior pupillary border onto the anterior iris surface. This result can be caused

by other membranes on the iris surface, such as an endothelial membrane, and is not specific for a neovascular membrane. The new blood vessels often give a reddish hue to the iris surface. This finding commonly is called rubeosis irides. These newly formed blood vessels tend to bleed easily, hence the misused and poor term hemorrhagic glaucoma; neovascular glaucoma is the preferred term so as not to confuse the entity with glaucoma secondary to traumatic hemorrhage. Even without the development of iris neovascularization, an increased incidence of both primary open- and closed-angle glaucoma exists in diabetes.

Ciliary Body and Choroid I. Ciliary body Basement membrane of ciliary pigment epithelium (external basement membrane of ciliary epithelium; Fig. 15.5) A. The multilaminar basement membrane of the pigment epithelium is diffusely thickened in the region of the pars plicata. B. The diffuse thickening of the external basement membrane of ciliary pigment epithelium in diabetic patients is different from the “spotty” or “patchy” thickening that may be seen in nondiabetic subjects. C. The multilaminar basement membrane of ciliary nonpigmented epithelium (internal basement membrane of ciliary epithelium) is not affected. D. Fibrovascular core of ciliary processes (see Fig. 15.5) E. Fibrosis results in obliteration of capillaries in the “core” of the ciliary processes. F. The capillary basement membrane is often significantly thickened. II. Choroid A. Various forms of optical coherence tomography have provided almost an histopathologist’s view of the pathobiology of diabetic changes in the choroid. Various authors, however, have disagreed on specific findings. Overall, there is good repeatability and reproducibility of choroidal vessel layer measurements, at least when using enhanced depth optical coherence tomography (ED-OCT). In time, these differences probably will resolve as we are better able to coordinate choroidal changes with other staging factors in the spectrum of the pathobiology of diabetes. 1. Optical coherence tomography (OCT) demonstrates that, compared to individuals without diabetes, diabetic patients have significantly thinner mean choroidal thickness, smaller choroidal volume, and less choroidal vascular area within the foveal and macular regions. Moreover, among diabetic patients, those with diabetic retinopathy have significantly thicker mean choroidal thickness, greater choroidal volume, and greater choroidal vascular area at the foveal and macular regions compared to those without diabetic retinopathy.

Intraocular Changes

593

A B

D C Fig. 15.4  Neovascularization of iris. A, Clinical appearance of rubeosis iridis. Histologic section (B) and scanning electron microscopy (C) of another case show peripheral anterior synechia, secondary angle closure, and tissue anterior to the anterior border layer of the iris; the last, which constitutes iris neovascularization, is shown with increased magnification in D and E. (C and E, Courtesy of Drs. RC Eagle, Jr and JW Sassani.)

E

2. Choriocapillaris nonperfusion on optical coherence tomography angiography (OCTA) is correlated significantly with disease severity in eyes with diabetic retinopathy. 3. Macular choroidal thickness is significantly reduced in the ischemic stage of diabetic maculopathy compared with the nonischemic stage. Others have reported increasing subfoveal choroidal thickness with severity of diabetic retinopathy. 4. Swept source optical coherence tomography (SS-OCT) of the choroid in diabetes reveals unvisualized vessels

in Sattler’s layer in 30% of scans, and focal narrowing of vessels in Haller’s layer in 50.9%. Additionally, choroidal vessels end in the superficial or middle portion of Haller’s layer as vascular stumps in 18.2%. These vascular stumps are significantly related to diabetic retinopathy severity, logMAR VA, and central retinal and choroidal thickness. 5. Indocyanine green angiography and ED-OCT have demonstrated late choroidal nonperfusion regions, inverted inflow phenomena, higher subfoveal choroidal thickness, and larger choroidal area as

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CHAPTER 15  Diabetes Mellitus

pep

m-bm

A

ce

B

C

c

c

bm

D

el

E

Fig. 15.5  Ciliary body. A, Periodic acid–Schiff stain shows diffuse thickening of the pigmented ciliary epithelial basement membrane of the pars plicata. B, Increased magnification shows the thickened basement membrane characteristic of diabetes. Note marked decrease in number of core capillaries. C, Multilaminar external basement membrane (m-bm) of ciliary epithelium in region of pars plicata thickened markedly. Distal edge demarcated by plane of attenuated nonpigmented uveal cells (ce). Numerous small granules (arrows), presumably calcific, present in distal parts of basement membrane (c, collagen; pep, bases of pigment epithelial cells). D, Normally thick homogeneous external basement membrane (bm) of ciliary epithelium in region of pars plana not altered; sample from same patient as in C (c, collagen; el, elastic lamina). E, Capillary in pars plicata shows diffuse and asymmetric homogeneous thickening of basement membrane (arrows).

Intraocular Changes





manifestations of diabetic choroidopathy. Late choroidal nonperfusion has been cited as a risk factor for diabetic retinopathy. 6. SS-OCT has shown reduced subfoveal choroidal thickness (SFCT) in patients with diabetic macular edema compared to healthy controls. While some reports support this conclusion, others find no difference in SFCT related to diabetic retinopathy or macular edema. One study actually found a slightly, but statistically significant, thicker subfoveal choroid in diabetic patients, and there were no SFCT changes on OCT associated with the presence or stage of diabetic retinopathy. SFCT has not been found to be related to duration of diabetes. Finally, evaluation by spectral domain optical coherence tomography (SD-OCT) has found thinning of the central choroid in eyes with diabetic retinopathy, but not in association with macular edema or proliferative changes. a. A thinner choroid has been found in diabetic patients with microalbuminuria, especially in the subfoveal region and temporal to the fovea. b. ED-OCT has found SFCT to be similar between diabetic children and healthy controls.

595

A

r

Obstructive sleep apnea (OSA) and type 2 diabetes share a pathophysiologic pathway, specifically, insulin resistance. In fact, OSA is associated with an increased risk of diabetic retinopathy in both type 1 and type 2 diabetes. Similarly, common pathobiologic mechanisms have been suggested for choroidal alterations in OSA and diabetes. Patients with OSA also have greater variability in their glycemic control. Exacerbation of OSA has been associated with a unique retinal neurodegeneration characterized by a decrease in the nasal retinal nerve fiber layer thickness. The combination of OSA and diabetes is a strong risk marker and independent predictor for a major adverse cardiac and cerebrovascular event following percutaneous cardiac intervention.



B. Choriocapillaris, Bruch’s membrane, and retinal pigment epithelium (Figs. 15.6 and 15.7) 1. Periodic acid–Schiff-positive material thickens and may partially obliterate the lumen of the choriocapillaris in the macula. 2. The cuticular portion of Bruch’s membrane (basement membrane of the retinal pigment epithelium; basal laminar-like deposits) may become thickened, and the lumen of the choriocapillaris narrowed by endothelial cell proliferation and basement membrane elaboration and is approximately fourfold greater in diabetic patients than in nondiabetic subjects. 3. Drusen are common.

B Fig. 15.6  Choroidopathy. A, Histologic section of the foveomacular region shows diffuse thickening of choroidal vessels, especially involving the choriocapillaris, which are partially occluded by periodic acid–Schiff-positive material. B, Electron micrograph shows choroidal arteriole apposed to characteristic basement membrane material of outer layer of Bruch’s membrane. Note red blood cell (r) in small lumen of vessel. Endothelial cells swollen and junctional attachments (arrows) present. Smooth muscle cells in arteriole wall also present.



4. Scanning electron microscopy of choroidal vascular casts shows increased tortuosity, dilatation and narrowing, hypercellularity, vascular loop and microaneurysm formation, “dropout” of choriocapillaris, and formation of sinus-like structures between choroidal lobules. 5. Arteries and arterioles of choroid (see Figs. 15.6 and 15.7) a. Arteriosclerosis occurs at a younger age in diabetic patients than in the general population. 1) The incidence increases sharply beyond the 15th year of the disease. 2) The change is reflected in atherosclerosis and arteriolosclerosis of the choroidal vessels.

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CHAPTER 15  Diabetes Mellitus

B A pep bm ch

ch

D

db

m C

bm

h Fig. 15.7  Choroidopathy. A, Histologic section of foveal region shows choroidal artery partially occluded by eosinophilic material. Choriocapillaris occluded in this area. B, Periodic acid–Schiff (PAS) stain of same region shows PAS-positive material in walls of arterioles and choriocapillaris. C, Inner choroid, foveomacula. Segment of choriocapillaris (ch) is small. Thickening of the basement membrane is most apparent along the outer capillary wall. Masses of disordered banded (trilaminar) basement membrane form the intercapillary columns. Masses of multilaminar (m), homogeneous (h), and disordered banded (db) basement membrane lie along the inner wall of a deeper choroidal vessel. A moderately thickened basement membrane lies along the vessel outer wall (bm, normally thin basement membrane of pigment epithelium). D, Region of choriocapillaris (ch), foveomacula. Thin basement membrane (arrows) of pigment epithelium (pep) is unaltered. Focal hyperproduction of choriocapillaris homogeneous basement membrane has occurred along the inner capillary wall (“drusen” of choriocapillaris). Segments of ordered banded basement membrane are present in the choriocapillaris drusen. Adjacent, to the left, are myriad fragments of disordered banded (trilaminar) basement membrane. The outer capillary basement membrane (bm) is also focally thickened. (A and B, Modified from Yanoff M: Ocular pathology of diabetes mellitus. Am J Ophthalmol 67:21. © Elsevier 1969.)

Retinal Vasculature in Normal Subjects and Diabetic Patients Fig. 15.8 shows examples of retinal vasculature in normal subjects and diabetic patients (see also section Neural Retina, below).

Neural Retina Diabetic retinopathy is the primary cause of visual impairment in the working-age population of the Western world. Although this section highlights specific factors that contribute to the pathobiology of diabetic retinopathy, one must not lose sight

of the interplay of these actors, such as loss of neurovascular coupling of metabolic demand and supply, gradual neurodegeneration, gliosis, and neuroinflammation, that occur even before there is observable vascular pathology, and are the basis for the clinically detectable retinopathy that follows. Moreover, a mutual contribution between inflammation and angiogenesis has been suggested as contributing to diabetic retinopathy. I. The four most commonly cited mechanisms underlying the pathogenesis of hyperglycemia-induced tissue damage are: (1) increased flux of the polyol pathway; (2) protein kinase C activation; (3) increased cellular production of

Intraocular Changes



o faz

A

Healthy Retinal capillary

Basement membrane “envelope” where pericyte nucleus had been

Endothelial cell nucleus Pericyte nucleus

B



Diabetic

e sr

sr

p C

D

Fig. 15.8  Retinal vasculature (normal and diabetic). A, Periodic acid– Schiff- and hematoxylin-stained trypsin digest of normal neural retina shows the optic nerve (o) and major blood vessels. The arterioles, darker and slightly smaller than the venules (ratio of vein to artery, 5 : 4), are surrounded by a narrow, characteristic, capillary-free zone. The foveal avascular zone (faz) is clearly seen. B, Diagram of healthy retinal capillary shows normal 1 : 1 ratio of pericyte to endothelial cell nuclei. The ratio is decreased in the diabetic patient because of a loss of pericyte nuclei, perhaps by apoptosis. C, Trypsin digest of normal neural retina shows retinal capillary with its normal 1 : 1 ratio of pericyte (p) to endothelial (e) cell nuclei. D, Trypsin digest of diabetic neural retina shows capillary with a decreased pericyte-to-endothelial cell nuclei ratio. Endothelial cell nuclei are present but appear pyknotic. Pericyte nuclei are absent from their basement membrane shells (sr).

advanced glycation end products (AGEs); and (4) overactivation of the hexosamine pathway. These mechanisms have in common mitochondrial overproduction of reactive oxygen species (ROS). In the latter regard, one should not overlook that photoreceptors are the most abundant cell type in the retina and contain 75% of the total retinal mitochondria. Diabetes induces abnormalities in mitochondrial structure, function and DNA in the retina and its vasculature, and the mitochondrial DNA repair machinery and biogenesis are compromised. These facts have led some to implicate photoreceptors in the pathogenesis of diabetic retinopathy. A more complete listing of the proposed causes of DR is contained in Table 15.3, which provides a listing of pathogenic mechanisms leading to DR, and Fig. 15.9, which provides an overview of mechanisms leading to sightthreatening endpoints in DR (see also discussion of PDR later in this section).

597

A. Although DR is usually discussed relative to the characteristic and clinically apparent vascular changes, recent evidence suggests that DR involves alterations in all of the retinal cellular elements, including: vascular endothelial cells and pericytes, glial cells including macroglia (Müller cells and astrocytes) and microglia, and neurons, including photoreceptors, bipolar cells, amacrine cells, and ganglion cells (Table 15.4). Each of these elements makes unique contributions to visual function, and participates in multiple homeostatic relationships to the other cellular elements. B. Damage to multiple retinal neuronal elements through apoptosis, and accompanying glial cell reactivity and microglial activation, suggest that DR might be classified as a neurodegenerative disorder, and not simply as a vasculopathy. In this regard, there is cell death involving neurons in the inner retina including retinal ganglion cells, and both dopaminergic and cholinergic amacrine cells identified in both animal models and in human samples of diabetic retinas. Electrophysiologic testing confirms appropriate functional loss reflecting such cellular death. Neurodegeneration has been widely postulated to precede visible vasculopathy in diabetic retinopathy, although this has been questioned by some authors, particularly in the presence of moderate glycemic control. Some contend that diabetic retinal neurodegeneration actually causes the microvascular changes in diabetic retinopathy. Certainly, neural retinal defects are among the earliest detectable changes in diabetes. 1. SD-OCT provides support for the concept that neural retinal changes precede diabetic vasculopathy. Using this technique, reduction in thickness in the retinal ganglion cell layer and nerve fiber layer have been identified in diabetic patients without diabetic retinopathy. 2. Further support for the concept of a neurodegenerative processes in diabetes is found in the fact that neurovisual tests are abnormal in type 1 diabetic individuals prior to the onset of clinically apparent retinopathy. Viewed from this perspective, it is doubtful that the entity that we call “diabetic retinopathy” is the manifestation of a single pathophysiologic disturbance or of the malfunction of one cell type. Rather, as can be seen in Table 15.4, multiple pathophysiologic mechanisms come into play in DR, including structural alterations, cell death, inflammation, cellular proliferation, and atrophy. These apparent alterations must require the participation of numerous biologically active mediators. For example, advanced glycation end products (AGEs) and/or lipoxidation end products form on the amino groups of proteins, lipids, and DNA, and may impact the retina by modifying the structure and function of proteins and/or cause intramolecular and intermolecular cross-link formation. AGEs not only alter structure and function of molecules, they also increase oxidative stress. AGEs with polyol pathway

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CHAPTER 15  Diabetes Mellitus

TABLE 15.3  Proposed Pathogenic Mechanisms for Diabetic Retinopathy Proposed Mechanism*

Putative Mode of Action

Proposed Therapy

Aldose reductase

Increases production of sorbitol (sugar alcohol produced by reduction of glucose) and may cause osmotic or other cellular damage Increases adherence of leukocytes to capillary endothelium, which may decrease flow and increase hypoxia; may also increase breakdown of blood–retinal barrier and enhance macular edema

Aldose reductase inhibitors (clinical trials in retinopathy and neuropathy thus far have been unsuccessful) Aspirin (ineffective in the Early Treatment Diabetic Retinopathy Study but did not increase vitreous hemorrhage; therefore not contraindicated in patients with diabetes who require it for other reasons); corticosteroids (intravitreal injection or slow-release implants for macular edema now being tested) Clinical trials of a protein kinase Cβ isoform inhibitor in retinopathy have thus far been unsuccessful

Inflammation

Protein kinase C

Reactive oxygen species Nonenzymatic glycation of proteins; advanced glycation end products Inducible form of nitric oxide synthase Altered expression of critical gene or genes Apoptotic death of retinal capillary pericytes, endothelial cells VEGF

PEDF

Growth hormone and IGF-1

Protein kinase C upregulates VEGF and is also active in “downstream” actions of VEGF following binding of the cytokine to its cellular receptor; protein kinase C activity is increased by diacylglycerol, which is accelerated by hyperglycemia Oxidative damage to enzymes and to other key cellular components Inactivation of critical enzymes; alteration of key structural proteins Enhances free radical production; may upregulate VEGF May be caused by hyperglycemia in several poorly understood ways; may cause long-lived alteration of one or more critical cellular pathways Reduces blood flow to retina, which reduces function and increases hypoxia Increased by retinal hypoxia and possibly other mechanisms; induces breakdown of blood–retinal barrier, leading to macular edema; induces proliferation of retinal capillary cells and neovascularization Protein normally released in retina inhibits neovascularization; reduction in diabetes may eliminate this infection. Permissive role allows pathologic actions of VEGF; reduction in growth hormone or IGF-1 prevents neovascularization.

Antioxidants (limited evaluation in clinical trials) Aminoguanidine (clinical trial for nephropathy halted by sponsor) Aminoguanidine None at present

None at present Reduction of VEGF by extensive (panretinal) laser photocoagulation; several experimental medical therapies being tested (specific VEGF inhibitors are used to treat neovascularization and macular edema) PEDF gene in nonreplicating adenovirus introduced into eye to induce PEDF formation in retina (phase I clinical trial ongoing) Hypophysectomy (now abandoned); pegvisomant (growth hormone receptor blocker; brief clinical trial failed); octreotide (somatostatin analogue, clinical trial now in progress)

IGF-1, insulin-like growth factor-1; PEDF, pigment epithelium-derived factor; VEGF, vascular endothelial growth factor. *For all the proposed mechanisms, hyperglycemia accelerates the progression to diabetic retinopathy. (Modified from Frank RN: Diabetic retinopathy. N Engl J Med 350:48, 2004.)

TABLE 15.4  Diabetic Alterations in Retinal

Cellular Elements Cell Type

Changes

Vascular

Altered tight junctions Endothelial cell and pericyte death Altered contacts with vessels Release inflammatory mediators Impaired glutamate metabolism Increased numbers Release inflammatory mediators Death of ganglion cells, inner nuclear layer Axonal atrophy

Glial

Microglial Neuronal

(Modified from Gardner TW, Antonetti DA, Barber AJ et al.: Diabetic retinopathy: More than meets the eye. Surv Ophthalmol 47(Suppl 2):S253. © Elsevier, 2002.)

activation may mediate the direct impairment of retinal endothelial cell barrier function caused by high glucose levels. N-epsilon-carboxymethyl lysine also has been cited as a key modulator for the development of nonproliferative retinopathy. 3. Optical coherence tomography changes of ocular neurodegeneration are more evident when diabetic neuropathy or polyneuropathy is present. 4. Diabetic conditions promote increased glial cell activation. 5. Progressive retinal nerve fiber thinning on SD-OCT, particularly in the superior quadrant, is found in association with diabetic peripheral neuropathy. 6. Retinal nerve fiber layer defects in diabetes, as demonstrated by OCT, differ from those typical of glaucoma in that those associated with the former are

Intraocular Changes

599

Fig. 15.9  Schematic overview of pathogenic mechanisms leading to the sight-threatening end points of DR. DR arises through a complex interplay between neuroglial and vascular damage that results from hyperglycemia-induced metabolic stress. From the microvascular perspective, hypoperfusion early in the disease due to loss of the cells making up the endothelium ultimately leads to compensatory growth of new fragile and leaky blood vessels. Compromise of the blood retinal barrier (BRB) integrity leads to the extravasation of fluid and inflammatory mediators, creating sight-threatening edema and exacerbating inflammatory conditions. Concurrent or preceding neuroglial dysfunction perpetuates damage. (From Lechner et al.: The pathology associated with diabetic retinopathy. Vision Research 139:7–14, 2017. Figure 4. Elsevier.)



located predominantly in the superior hemisphere and tend to be narrower, shallower, and farther from the fovea compared to those in glaucoma. 7. There is a reduction in the ganglion cell–inner plexiform region and in the retinal nerve fiber thickness values in the early stages of diabetic retinopathy compared to healthy control patients. These changes are present in both type 1 and type 2 diabetes. a. Low serum vitamin D may exacerbate these early retinal nerve fiber layer thickness changes. 8. The macular ganglion cell complex, as measured by SD-OCT, is reduced much earlier than the peripapillary retinal nerve fiber layer thinning in diabetic



patients without retinopathy. Similarly, there is a concomitant reduction in pattern electrogram response. 9. In animal studies, the proportion of activated microglia increases in diabetes in the retinal nerve fiber layer and ganglion cell layer, but decreases in the inner plexiform layer. The retinal mRNA level of Iba-1, a microglial-specific marker, also is increased. 10. Longer ocular axial length is associated with a decreased risk an severity of diabetic retinopathy. C. Apoptosis contributes to retinal ganglion cell death in DR. Glial cells may modify the expression of such

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CHAPTER 15  Diabetes Mellitus

apoptosis. It has been proposed that caspase-dependent apoptosis is associated with early stages of retinal changes in diabetes. Alterations in connexin gene expression in a high glucose retinal environment would interfere with gap junction intercellular communication and may contribute to apoptosis and other pathological changes. D. Inflammation appears to play a significant role in the pathogenesis of diabetic retinopathy. It is said to have the characteristics of a chronic neuroinflammation and a vasculopathy. 1. Vascular cellular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP) are inflammatory mediators that are upregulated in diabetes with the development and progression of diabetic microvascular complications. 2. Müller cells exhibit a proinflammatory response in diabetes that may be regulated, in part, by the receptor for advanced glycation and end products (RAGE) and its ligands.



Capillary pericytes probably contribute to the mechanical stability of the capillary wall.

Upregulation of anti-inflammatory mediators and their receptors, such as the retinal pigment epithelial receptor GPR109A and its ligand beta-HB, appears to be an attempt by ocular tissue to suppress this inflammatory response. Activated microglia and microglial vasculitis has been implicated in the pathogenesis of diabetic vasculopathy, neuropathy and retinopathy. Declining retinal microvascular blood flow correlates with the progression of insulin resistance in diabetes.

II. The diagnosis of DR—the best way to diagnose DR is by means of a thorough fundus examination through a dilated pupil. Nevertheless, newer imaging techniques can be very helpful in complementing the clinical examination, and in some instances actually surpass the ability of clinical examination to detect the earliest diabetic retinal changes (see below). Ancillary studies, such as spectral-domain OCT, can be very helpful in demonstrating the scope of retinal involvement. For example, retinal thickness has been found to be abnormal diffusely (but not uniformly) in the retina and not just in the areas exhibiting clinically apparent retinopathy. Microaneurysms, acellular capillaries, and pericyte ghosts are more numerous in the temporal retina than in the nasal retina; however, retinal capillary basement membrane thickness does not exhibit such regional variation.







III. Specific constellation of vascular findings—clinical BDR microvascular changes in the macular region can be detected significantly earlier by OCT and OCT angiography evaluation than by clinical examination. Using such techniques,

retinal capillary perfusion decreases with progression of diabetic retinopathy. A. Loss of capillary pericytes (see Fig. 15.8)



1. In the normal retinal capillary, the pericyte-to-endothelial cell ratio is 1 : 1. 2. In the diabetic retinal capillary, the pericyte-toendothelial cell ratio is less than 1 : 1 because of a selective loss of pericytes. 3. Pericyte death is accompanied by morphologic nuclear changes and lack of inflammation characteristic of apoptosis (see Chapter 1). Activation of nuclear factor-κB, induced by high glucose in diabetes, may regulate a proapoptotic program in retinal pericytes. 4. Multiple anatomic and anatomic/functional abnormalities contribute to retinal vascular changes and loss of the blood–retinal barrier in diabetes and include changes in tight junctions, pericyte loss, endothelial cell loss, retinal vessel leukostasis, upregulation of vesicular transport, increased permeability of the surface membranes of retinal vascular endothelium and retinal pigment epithelial cells, activation of advanced glycation end product receptors, downregulation of glial cell derived neurotropic factors, retinal vessel dilation, and vitreoretinal traction. B. Capillary microaneurysms (Figs. 15.10 and 15.11) 1. Many more retinal capillary microaneurysms (RCMs) are detected microscopically and by fluorescein angiography than are seen clinically with the ophthalmoscope. 2. An increase in the number of RCMs can be directly correlated with the loss of pericytes. 3. RCMs are formed in response to a hypoxic environment in which abortive attempts at neovascularization or regressed changes, or both, have been made in a previously proliferating vessel. a. RCMs, which are randomly distributed across the arteriolar and venular sides of the capillary network, start as thin outpouchings (saccular) from the wall of a capillary. b. The retinal capillary endothelial cells proliferate and lay down increased amounts of basement membrane (Figs. 15.11 and 15.12). c. Ultimately, all of the endothelial cells may disappear; ghost retinal capillaries result. d. The lumen of the RCM may remain patent or may become occluded by the accumulated basement membrane material. C. Thickening of retinal capillary basement membrane (see Figs. 15.1, 15.11, and 15.12)

Intraocular Changes

A

B

m

n

m

C

n

D Fig. 15.10  Background diabetic retinopathy. A, Background diabetic retinopathy consists of retinal capillary microaneurysms (RCMs), hemorrhages, edema, and exudates (here in a circinate pattern). B, The RCMs are seen more easily with fluorescein. The areas of circinate retinopathy show leakage (see also Figs. 15.13 and 15.14). C, Trypsin digest preparation shows that an RCM consists of a proliferation of endothelial cells (m, microaneurysm; n, nonviable capillaries). D, A histologic section shows a large blood-filled space lined by endothelium (m, microaneurysm). The caliber is approximately that of a venule. Venules, however, do not occur in this location (in the inner nuclear layer) but, rather, are mainly found in the nerve fiber layer. By a process of elimination, the “vessel” is therefore identified as a cross-section of an RCM. (A and B, Courtesy of Dr. GE Lang.)

A

B Fig. 15.11  Retinal capillary microaneurysm (RCM). A, RCMs randomly distributed between arterioles and venules. “Young” RCMs appear as saccular capillary outpouchings that contain a few proliferated endothelial cells. “Older” RCMs appear as larger sacs that contain numerous endothelial cells and increased periodic acid–Schiff (PAS) positivity (increased basement membrane deposition). “Oldest” RCMs appear as solid black balls with their lumina obliterated by PAS-positive material. B, Foveomacular area shows “broken” foveal capillary ring and scattered microaneurysms.

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CHAPTER 15  Diabetes Mellitus

l

A

l

B Fig. 15.12  Diabetic retinal vessels. A, Diabetic retinal capillary in nerve fiber layer of macula. Lumen (l) is exceedingly narrow and contains small amount of fibrinous, proteinaceous material. Endothelial cell junctional attachments (adherentes) are present (arrows). Basement membrane of capillary wall is thickened. B, Small retinal vessel from foveomacular ganglion cell layer of diabetic patient. Lower endothelial cell (E1) hypertrophic, whereas upper endothelial cell (E2) necrotic (liquefaction). Vessel lumen (l) greatly narrowed. Adherentes of cell junctions present (arrows). Secondarily (age-related) vacuolated basement membrane of vessel wall probably normal thickness for age.



D. Arteriolovenular connections (“shunts”: actually, collaterals; Fig. 15.13) 1. Arteriolovenular connections (collaterals) are secondary phenomena (i.e., secondary to the surrounding environmental hypoxic stimulus). 2. The arteriolovenular connections have a decreased rate of blood flow, unlike true shunts.



E. Other findings 1. Often, an irregular, large foveal avascular zone is present (its irregularity and greater size with BDR are even more pronounced with PDR). 2. Diabetic patients show an abnormal macular capillary blood flow velocity, and decreased entoptically perceived leukocytes, over age-matched nondiabetic

Intraocular Changes

A

603

B

v

av

av a

C

D Fig. 15.13  Background and preproliferative diabetic retinopathy. A, Cotton-wool spot of recent onset is present just inferior to the superior arcade. Note also retinal “hard” exudates, capillary microaneurysms, and hemorrhages. B, Trypsin digest preparation shows sausage-shaped dilated venules. C, Arteriolovenular collateral vessel (av) is present (a, arteriole; v, venule). D, Intraretinal microvascular abnormalities are present in the form of dilated capillaries, capillary buds and loops, and areas of capillary closure.

subjects. Conversely, choroidal blood flow is significantly decreased in the foveal region, particularly in diabetic macular edema (DME). Pulsatile ocular blood flow is unaffected in early DR, increases significantly in eyes with moderate to severe nonproliferative DR, and decreases following laser treatment of PDR.

3. Partitions of the larger retinal venules by a double layer of endothelial cells anchored to a thin basement membrane are associated with the formation of venous loops and reduplications that are caused by gradual venous occlusion. 4. In general, wider venular caliber and narrower retinal arteriolar caliber are associated with diabetes. Patients with retinal arteriolar narrowing are significantly more likely to have nephropathy and macrovascular disease. 5. Leukostasis, which is the adherence of white blood cells to vascular endothelial cells, has been demonstrated in the retinal vasculature in diabetic animal models. The role that it may play in the pathogenesis of diabetic retinopathy remains to be determined.

6. Changes in membrane lipid–protein interactions and increased internal viscosity due to glycosylation lead to decreased deformability in red blood cells in diabetes, which may contribute to reducing blood flow. 7. Marked increases in coagulation and fibrinolytic factors, including plasma kallikrein, thrombin, and urokinase have been detected in ocular samples from patients with advanced diabetic retinopathy. These factors not only contribute to thrombosis and hemostasis, they also promote retinal inflammation, vascular dysfunction, and proteolytic disruption of the extracellular matrix and intercellular junctional complexes. IV. Exudative retinopathy (Figs. 15. 14 and 15.15) A. “Hard” or “waxy” exudates (Fig. 15.14; see also Figs. 15.10 and 15.13) 1. Hard or waxy discrete exudates are collections of serum and glial–neuronal breakdown products located predominantly in the outer plexiform (Henle) layer. One of the earliest changes in the neural retina in diabetic patients, often before BDR is evident clinically, is a breakdown of the blood–neural retinal barrier in the retinal capillaries. Fluorescein

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CHAPTER 15  Diabetes Mellitus

A

B

C

D

E

F Fig. 15.14  Exudates. A, Diagram shows exudates predominantly in outer plexiform (Henle fiber) layer of macula. Exudates on right contain fat-filled (lipidic) histiocytes (gitter cells). B, Diagram shows exudates in outer plexiform layer (Henle fiber layer) of fovea. In foveal area, fibers run obliquely, resulting in clinically seen star figure. C, Fundus appearance of exudates, small hemorrhages, microaneurysms, and early neovascularization of temporal disc. Note star figure in fovea, an unusual finding in diabetic patients. D, Histologic section shows exudates present in outer plexiform layer. E, Oil red-O stain shows lipid-positivity of exudates. F, Electron microscopy shows exudates filled with foamy (lipidic) histiocytes. (A and B, Modified from drawings by Dr. RC Eagle, Jr.)

Intraocular Changes

605

A

B Fig. 15.15  A, Optical coherence tomography (OCT) image of diabetic retinopathy with vitreous traction on the internal limiting membrane and disruption of the retinal architecture by hemorrhages and exudates. Compare with the regular well-organized features in B. (Courtesy of retinal angiographers Mr. Timothy Bennett and Mr. James Strong.)

angiography and vitreous fluorophotometry can show “leakage” of fluorescein from retinal capillaries in diabetic patients who do not show signs of DR when examined by conventional clinical methods. In patients who have BDR, elevated serum lipids are associated with an increased risk of retinal hard exudates.

2. The discrete exudates are removed by macrophages in 4 to 6 months; it may take a year or more if the exudates are confluent. 3. When they are distributed around the fovea, hard exudates may form a macular “star.”





Although macular edema is common in diabetic patients, macular star formation is uncommon, unlike in grades III and IV hypertensive retinopathy, where a macular star is quite common.





B. Macular edema 1. Clinically significant macular edema (CSME) is the greatest single cause of vision impairment in diabetic patients and affects approximately 75,000 new patients in the United States annually. a. The overall incidence of CSME is approximately 3%–8% in the diabetic population after 4 years’ follow-up from the baseline examination; 32% after 20 years of younger-age onset, insulin-dependent diabetes; 18% after 20 years of





non-insulin dependent, older-age onset diabetes; and 32% after the same period of older-age onset, insulin-dependent diabetes. b. The greater incidence is associated with younger age or more severe DR at the baseline examination, increased levels of glycosylated hemoglobin, increased duration of the diabetes, and an absence of posterior vitreous detachment. c. Systemic factors that can contribute to CSME in diabetes include poor metabolic control of the diabetes, elevated blood pressure, intravascular fluid overload, anemia, and hyperlipidemia. Fluid overload is relative, and may reflect decreased serum oncotic pressure, such as from decreased serum albumin. 2. Fig. 15.16 summarizes factors implicated in the pathogenesis of diabetic macular edema. Morphologic evidence suggests that macular edema may be caused by functional damage to the retinal vascular endothelium (e.g., hypertrophy or liquefaction necrosis of endothelial cells of the retinal capillaries or venules; see Fig. 15.12); pericyte degeneration probably also plays a role. a. Fluid leaks out of the retinal vessels, enters Müller cells, and causes intracellular swelling. b. Mild to moderate amounts of intracellular fluid collections in Müller cells may result in macular edema (see Figs. 15.16 and 15.17), a reversible process. c. Excessive swelling (ballooning) and rupture or death of Müller cells produces pockets of fluid

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CHAPTER 15  Diabetes Mellitus

Sustained hyperglycemia

DAG ↑

Histamine ↑ H-receptors on the retinal blood vessels

AGE ↑

PKC ↑

ET ↑

Vasoconstriction

ET-receptors on pericytes

Hypoxia

IL-6 ↑

RAS activation

LPO ↑ NADH/NAD+ ↑ NO ↑ Antioxidant enzymes

Oxidative damage

VEGF ↑

All ↑ Accumulation of cytokeratin and glial fibrillary acidic protein

Phosphorylation of tight junction proteins. Disorganization of BRB

Destabilization of vitreous. Abnormalities in collagen crosslinking ↑ activity of MMP PPVP

Vitreo-macular traction

Macular edema

Fig. 15.16  Pathogenesis of diabetic macular edema. AGE, advanced glycation end products; AII, angiotensin II; DAG, diacylglycerol; ET, endothelin; LPO, lypoxygenase; NO, nitric oxide; PKC, protein kinase C; RAS, renin–angiotensin system; VEGF, vascular endothelial growth factor. (From Bhagat N, Grigorian RA, Tutela A et al.: Diabetic macular edema: Pathogenesis and treatment. Surv Ophthalmol 54:1, 2009.)

A

B Fig. 15.17  Exudates. Microcystoid or macrocystoid (retinoschisis) macular degeneration may occur as a result of exudation. A, Small exudates can coalesce into larger ones. B, Eventually, coalescence of exudates can result in a macrocyst (macular retinoschisis), as occurred here. Note hole (smooth edge shows it is not an artifact) in inner wall of macrocyst.



and cell debris (i.e., cystoid macular edema), a process that may be irreversible. d. Adjacent neurons undergo similar changes secondarily. e. Foveal ischemia in diabetic macular edema causes photoreceptor outer segment shortening and inner segment–outer segment disruption resulting in atrophic changes and secondary visual loss.

Laser retinal photocoagulation has been the standard of care for diabetic macular edema, and reduces the risk of moderate visual loss by approximately 50%. Nevertheless, new strategies in the treatment of DME, specifically directed at VEGF, have largely replaced laser treatment for this purpose. These drugs are delivered by intravitreal injection and have

Intraocular Changes proven to be not only effective, but safe. Intravitreal steroid injections also have been employed.









3. Newer imaging modalities have been particularly helpful in evaluating the presence, progression and pathobiology of diabetic macular edema. a. Lack of disruption of the retinal external limiting membrane as demonstrated by OCT closely relates to better measured visual acuity in patients with diabetic macular edema. b. Increased serum globulin, which is a positive phase reactant of inflammation, has been found to be a significant independent risk factor for OCTdetected serous diabetic macular edema. 4. The presence of a cilioretinal artery may worsen DME. C. Microcystoid degeneration of the neural retinal macula (see Figs. 15.16, 15.17 and 15.18) 1. Exudates or edema fluid, or both, may cause pressure atrophy of the neural retina or enlargement of the intercellular spaces, and result in microcystoid degeneration, especially in the macular area. 2. Microcystoid neural retinal degeneration may progress to macular retinoschisis (cyst), and even partial (inner layer of schisis) or complete macular hole formation. D. “Soft” exudates or “cotton-wool” spots (see Figs. 11.9, 11.11, 11.14, and 15.13) 1. The cotton-wool spots observed clinically are a result of microinfarcts (coagulative necrosis) of the nerve







607

fiber layer of the retina and are not true exudates. They usually disappear from view in weeks to months. 2. They are present most commonly in the preproliferative or early part of the proliferative stage of DR, especially during a phase of rapid progression. 3. Cotton-wool spots are formed at the edges of microinfarcts of the nerve fiber layer of the neural retina (see Chapter 11) and represent back-up of axoplasmic flow. 4. Cytoid bodies are the characteristic histologic counterpart of the cotton-wool spot, and are caused by the swollen ends of ruptured axons in the nerve fiber layer in the infarcted area. They resemble a cell with its nucleus when cut in cross-section thereby leading to the appellation, “cytoid.” V. Hemorrhagic retinopathy (Fig. 15.19). The clinical appearance of a retinal hemorrhage is determined by the microanatomy of the retinal layer in which the hemorrhage is located. A. Dot-and-blot hemorrhages 1. Dot-and-blot hemorrhages are relatively small hemorrhages located in the inner nuclear layer that spread to the outer plexiform layer of the neural retina. 2. In three-dimensional view, they appear serpiginous. B. Splinter (flame-shaped) hemorrhages are small hemorrhages located in the nerve fiber layer. C. Globular hemorrhages are caused by the spread of dotand-blot hemorrhages in the middle neural retinal layers. D. Confluent hemorrhages are large and involve all of the neural retinal layers.

A

B Fig. 15.18  A, Optical coherence tomography (OCT) image of diabetic retinopathy involving the macula and resulting in cystoid macular edema. Compare with the regular well-organized features in B. (Courtesy of retinal angiographers Mr. Timothy Bennett and Mr. James Strong.)

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CHAPTER 15  Diabetes Mellitus

Larger hemorrhages (globular and confluent) may herald the onset of the proliferative (malignant) phase of the disease.



A

B

C Fig. 15.19  Hemorrhagic retinopathy. A, Dot, blot, flame-shaped, and globular hemorrhages are present in the neural retina. B, Flame-shaped or splinter hemorrhages consist of small collections of blood in the nerve fiber layer. Dot-and-blot hemorrhages are caused by small hemorrhagic collections in the inner nuclear and outer plexiform layers. C, Diagram shows dot-and-blot and globular hemorrhages in middle layers, and splinter hemorrhage in nerve fiber layer of neural retina. Large hemorrhage under internal limiting membrane (submembranous intraneural retinal hemorrhage) has broken through neural retina into the vitreous compartment. (C, Modified from a drawing by Dr. RC Eagle, Jr.)

E. Massive hemorrhages may break through the internal limiting membrane to extend beneath or into the vitreous body or, rarely, into the subneural retinal space. VI. Preproliferative DR (Fig. 15.20; see also Fig. 15.13) consists of: A. Increased neural retinal hemorrhages B. Cotton-wool spots C. Venous dilatation D. Venous beading E. Intraretinal microangiopathy (IRMA) 1. OCT demonstrates that, in neovascularization, the abnormal vessels break through the posterior hyaloid and they do not do so in IRMA. VII. PDR (“malignant” stage; Figs. 15.21–15.24) A. Classically, PDR has been characterized as a vascular response to a hypoxic neural retinal environment. Numerous other factors contribute to its pathobiology. 1. Some of these factors include hyperglycemia, retinal arteriolar and capillary closure; hemodynamic alterations in retrobulbar circulation and microcirculation; retinal capillary basement membrane alterations; immunogenic mechanisms related to insulin; pregnancy; absence of female hormones; altered plasma proteins that cause platelet and red cell aggregation; increased blood viscosity; altered ability of the blood to transport oxygen; virus induction of DM; and abnormal metabolic pathways in the retinal capillaries. Additionally, retinal blood flow decreases in the early stages of diabetes and is accompanied by decreased oxygen consumption. Development of anemia in a diabetic patient may cause background retinopathy to progress rapidly to PDR. An adequate number of functioning photoreceptors appears to be required for the development of PDR because neonatal mice with hereditary retinal degeneration fail to develop reactive retinal neovascularization in a model of oxygen-induced PDR.

2. Table 15.5 lists some of the myriad vitreous and serum factors that are altered in PDR. They may be produced, in part, by retinal cellular elements, and in turn, probably help modify the behavior of these cellular retinal constituents. 3. Other putative factors implicated in PDR are advanced glycation end products and macrophages. 4. Among the mediators acting during the development of PDR, vascular endothelial growth factor (VEGF) and its receptor, flt-1, play a key role.

Intraocular Changes

A

B

Fig. 15.20  Preproliferative retinopathy. Fundus (A) and fluorescein (B) appearance. Note numerous areas of nonperfusion. C, Trypsin digest of neural retina shows mainly nonviable capillaries. Some capillaries on left demonstrate endothelial cell proliferation and increased basement membrane deposition, representing intraretinal microvascular angiopathy. (A and B, Courtesy of Dr. GE Lang.)

C

A

B

C

D Fig. 15.21  Proliferative retinopathy. Neovascularization of optic disc. A and B, Same patient, same eye, pictures taken one year apart. Severe neovascularization of optic disc has developed. C, Moderate to severe neovascularization of optic disc. D, Histologic section of another case shows shrinkage and contracture of a preretinal fibroglial vascular membrane that had arisen from the optic disc and caused a total neural retinal detachment with fixed folds of the internal limiting membrane (see also Fig. 15.24D). Intraretinal cystic spaces are often present in long-standing detachments.

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CHAPTER 15  Diabetes Mellitus

A

B

C

D

Fig. 15.22  Proliferative retinopathy. Neovascularization of neural retina. A–C, Fundus and fluorescein pictures of same eye. Nonperfusion of neural retina most marked on left side. Areas of neovascularization elsewhere (NVE) present, mainly temporal retina. D, Trypsin digest of neural retina shows nonviable capillaries (presumably corresponding to areas of nonperfusion), mainly toward the lower left corner. Surrounding capillaries show marked endothelial cell proliferation and increased basement membrane deposition, representing early intraretinal neovascularization. E, Histologic section shows usual site of origin of NVE (i.e., from a venule). (A–C, Courtesy of Dr. GE Lang.)

E

VEGF is strongly expressed in the endothelial cells of the new blood vessels in fibrovascular membranes removed at vitrectomy for PDR. Conversely, pigment epithelium-derived factor (PEDF), which inhibits angiogenesis, is only weakly expressed in such membranes. VEGF levels are increased in the aqueous humor of diabetic patients, but PEDF levels are decreased in such individuals, particularly those with PDR. Moreover, lowered PEDF levels in aqueous humor of diabetic patients strongly predicts those who will have progressive retinopathy. In a similar manner, levels of VEGF and endostatin, which is an inhibitor of angiogenesis, in aqueous humor

and vitreous vary appropriately to reflect the severity of DR.

5. It is important that the constituents of PDR membranes be compared to those resulting from other forms of intraocular proliferation in order to determine the characteristics of PDR. For example, proteolytic activation appears to be involved in extracellular matrix production in PDR and in nondiabetic membranes, and neovascular membranes in retinopathy of prematurity are associated with the glucose transporter GLUT1, which is lacking in proliferative retinopathy.

Intraocular Changes

A

B Fig. 15.23  Proliferative retinopathy. Neovascularization of neural retina. A, The superior venule is dilated and beaded. Neovascular tufts arise from the venules. B, A histologic section of another case shows new blood vessel arising from a retinal venule, perforating the internal limiting membrane, and spreading out on the internal surface of the retina between the internal limiting membrane and the vitreous body. In this location, the fragile new abnormal blood vessels may be subject to trauma (e.g., vitreous detachment), resulting in a subvitreal hemorrhage between the retinal internal limiting membrane and the posterior hyaloid of the separated vitreous body.

A

B

l

o n s C

D Fig. 15.24  Proliferative retinopathy. Neovascularization of optic disc and retina. A, Tuft of neovascularization arising from the optic nerve head is attached to the posterior surface of an otherwise detached vitreous body. B, Scanning electron micrograph shows blood vessels arising from the internal surface of the neural retina and attaching to the posterior surface of the partially detached vitreous. C, Periodic acid–Schiff-stained histologic section shows blood vessels originating from a retinal venule and attaching to the posterior surface of the vitreous. D, The gross specimen shows the end stage of diabetic retinopathy. Extensive neovascularization of the retina and the detached vitreous have resulted in a traction neural retinal detachment. The subneural retinal space is filled with a gelatinous material (l, lens; n, neural retina; o, organized vitreous; s, subneural retinal exudate). The absence of similar material underlying a retinal detachment in any fixed specimen should raise the suspicion that the detachment is an artifact of sectioning and was not present in vivo. (B, Courtesy of Dr. RC Eagle, Jr.)

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TABLE 15.5  Vitreous and Serum Factors

Altered in Human Proliferative Diabetic Retinopathy Increased in vitreous and/or retina

Increased in vitreous and/or retina Decreased in vitreous and/or retina No change in vitreous and/or retina Increased in serum Decreased in serum

Proangiogenic Peptide growth factors: VEGF, HGF, FGF-5, leptin, IGF-1, IGF-2, PDGF-AB, SDF-1, angiogenin Extracellular matrix adhesion molecules, ICAM-1, oncofetal fibronectin Inflammatory cytokines: IL-6, IL-8, endothelin-1, TNF-α, TGF-β1, AGEs Complement: complement C(4) fragment Polyamines: spermine, spermidine Vasoactive peptides: endothelin-1, angiopoietin-2, angiotensin-2, adrenomedullin, ACE, nitrate Inflammatory cells: CD4 and CD8 (T lymphocytes), CD22 (B lymphocytes), macrophages, HLA-DR Antiangiogenic Endostatin, angiostatin, PEDF, TGF-β1 Undefined retinal function: α1-antitrypsin, α2-HS glycoprotein Angiopoietin-2, putrescine, kallistatin, chymase, TGF-β2 activation, CD55, CD59 ACE, C1q and C4



NO, sIL-2R, IL-8, TNF-α, VEGF, angiotensin-2, renin, endothelin Soluble angiopoietin receptor Tie2, IL-1β, IL-6

ACE, angiotensin-converting enzyme; AGE, advanced glycation end products; FGF, fibroblast growth factor; HGF, hepatocyte growth factor (scatter factor); HLA, human leukocyte antigen; ICAM, intercellular adhesion molecule; IGF, insulin-like growth factor; IL, interleukin; NO, nitric oxide; PDGF, platelet-derived growth factor; PEDF, pigment epithelium-derived factor; SDF-1, stromal-derived factor 1; sIL-2R, soluble interleukin-2 receptor; TGF-α1, transforming growth factor α1; TNF-β, tumor necrosis factor-β; VEGF, vascular endothelial growth factor. (From Gariano RF, Gardner TW: Retinal angiogenesis in development and disease. Nature 438:960, 2005.)

6. Decreased serum insulin and high glucose levels have been postulated to contribute to decreased fibroblast growth factor-2 production in the RPE and increased glial cell activation in the diabetic retina. 7. PEDF may help protect against pericyte apoptosis. It is suppressed by angiotensin II, which may contribute to exacerbation of DR in hypertensive patients. Conversely, blockade of the renin–angiotensin system can confer retinal protection in experimental models of DR. 8. Elevated expression of matrix metalloproteinases in the diabetic retina may contribute to increased vascular permeability by a mechanism involving proteolytic degradation of the tight junction protein occludin and subsequent disruption of the tight junction complex. 9. The NH2-terminal connective tissue growth factor fragment is increased in the vitreous in PDR and is

found within myofibroblasts in active PDR membranes, suggesting a local paracrine mechanism for the induction of fibrosis and neovascularization. 10. Circulating systemic factors cannot be ignored. For example, growth hormone-sufficient diabetic patients have an increased prevalence of DR over growth hormone-deficient diabetic patients. Somatostatin analogs that block the local and systemic production of insulin-like growth factor and growth hormone may prevent DR progression to the proliferative stage. Pregnant women are at particular risk for the development and progression of DR. 11. Neovascularization in PDR tends to arise from retinal venules, usually at the edge of an area of capillary nonperfusion. Rarely, they may arise from retinal arterioles. The new retinal vessels contain both endothelial cells and pericytes. 12. Angiopoietin-2 is induced by hypoxia and plays a role in the initiation of retinal neovascularization. It is involved in pericyte recruitment and modulates intraretinal and preretinal vessel formation. B. Neovascularization initially is intraretinal, but usually breaks through the internal limiting membrane to lie between it and the vitreous. Endothelial cell-associated proteinases can locally disrupt basement membrane (internal limiting membrane) and facilitate angiogenesis. 1. Neovascular membranes that lie flat on the internal surface of the neural retina are called epiretinal neovascular membranes. 2. Elevated neovascular membranes are called preretinal neovascular membranes. Vitreous shrinkage (i.e., detachment) may tear the new vessels, leading to a hemorrhage. If a subvitreal hemorrhage results (the common type of diabetic “vitreous” hemorrhage between the posterior surface of the vitreous body and the internal limiting membrane of the neural retina), it clears rapidly in weeks to a few months. If a hemorrhage extending into the formed vitreous (vitreous framework) results, it may take from many months to years to clear. In such patients, vitrectomy may be indicated.



3. Doppler OCT can be helpful for detecting and evaluating the 3-dimensional vascular structure of neovascularization in proliferative retinopathy. C. Pure neovascularization is eventually accompanied by a fibrous and glial (Müller cells and fibrous astrocytes) component; it is then called retinitis proliferans. 1. The membranes are composed of blood vessels, fibrous and glial matrix tissue, fibroblasts, glial cells, scattered B and T lymphocytes, and monocytes, along with immunoglobulin, complement deposits, and class II major histocompatibility complex antigens. 2. Shrinkage of the fibroglial component often leads to a neural retinal detachment, which is usually

Intraocular Changes



nonrhegmatogenous (i.e., without a neural retinal tear or hole). 3. Ultimately, the whole process of PDR tends to “burn out” and become quiescent. 4. Connective tissue growth factor contributes to proliferation of the fibrous component of these membranes. D. Once blindness develops, the average life expectancy is less than 6 years. E. Cataract surgery and progression of DR (see earlier in this chapter under section Lens). F. Optical coherence tomography can be helpful in evaluating vascular changes associated with diabetic retinopathy.

Vitreous I. Vitreous detachment (Fig. 15.24; see also Fig. 15.15 and Figs. 12.8 and 12.9) A. Vitreous detachment (“contracture”) is more common in diabetic patients than in nondiabetic subjects and seems to occur at an earlier age. 1. Nevertheless, the vitreous attachment to the macula is stronger and longer lasting throughout life in diabetic individuals. In eyes with diffuse DME associated with vitreomacular traction and a thickened premacular cortical vitreous, ultrastructural examination demonstrates native vitreous collagen with single cells interspersed within the collagenous layer or a cellular monolayer. Eyes with tangential vitreomacular traction exhibit multilayered membranes on a layer of native vitreous collagen. The predominant cell types are fibroblasts and fibrous astrocytes, with some myofibroblasts and macrophages. Thus, the vitreomacular interface is characterized by a layer of native vitreous collagen and a varying cellular component in eyes with diffuse DME.



2. Peripapillary vitreoretinal traction can cause optic nerve head elevation resembling edema. OCT can be helpful in confirming the diagnosis. 3. Extrafoveal vitreous traction may be associated with diffuse macular edema. B. The proliferating fibroglial vascular tissue from the optic nerve head or neural retina usually grows between the vitreous and the neural retina (i.e., along the inner surface of the internal limiting membrane of the neural retina), along the external surface of a detached vitreous, or into Cloquet’s canal. The proliferating tissue does not grow directly into a formed vitreous. A preoptic disc canal-like structure, probably Cloquet’s canal and the area of Martegiani, is associated with PDR. 1. High levels of VEGF are present in the vitreous in PDR and proliferative vitreoretinopathy (PVR). 2. Elevated levels of other growth factors and inflammatory mediators have been found in diabetic vitreous (see Table 15.5).





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3. Proteomics presents an even more complicated picture of the vitreous constituents in proliferative diabetic retinopathy and nondiabetic patients. In one study, 531 proteins were identified with 415 and 346 proteins identified in PDR and nondiabetic vitreous humor samples, respectively. 4. The microRNA, Mir-21, is a fibrotic mRNA and is increased in vitreous associated with proliferative vitreoretinal disease and proliferative diabetic retinopathy. RPE cells are capable of epithelial– mesenchymal transition. The expression of Mir-21 can be induced from retinal pigment epithelial (RPE) cells by transforming growth factor-β, which is a key growth factor involved in fibrogenesis. Moreover, this effect is enhanced by high glucose culture conditions. a. Analysis of epiretinal membranes from patients with PDR using immunohistochemical staining has suggested that endothelial cells undergo a similar transition to mesenchymal cells and can assume a myofibroblast character. Circulating fibrocytes also may be a source for these myofibroblasts that contribute to PDR. 5. Levels of protease-activated receptor-1 (PAR-1), which is expressed in vascular endothelial cells, CD45-expressing leukocytes and myofibroblasts, are elevated in epiretinal membranes in proliferative diabetic retinopathy (PDR). Similarly, there is increased expression of thrombin, matrix metalloproteinase-1 (MMP-1), and VEGF in vitreous samples from patients with PDR compared to nondiabetic controls. It has been proposed that interactions among PAR-1, thrombin, MMP-1, and VEGF might facilitate angiogenesis in PDR. a. Other authors have suggested that MMP-1 and MMP-9 may contribute to the angiogenic switch in PDR. 6. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has been found in vitreous fluid from PDR patients and has been cited as contributing to the promotion of proliferation or fibrosis of retinal cells. 7. There is a marked decrease in the vitreous and serum levels of Omentin-1, an adipokine that inhibits inflammation, in patients with PDR compared to diabetic patients without retinopathy or only nonproliferative retinopathy. 8. Elevated levels of interleukin-6, interleukin-8, monocyte chemoattractant protein-1, and VEGF are present in the vitreous of patients with PDR and in those with Eales’ disease. 9. Some have suggested that diabetes may be protective against optic nerve head changes in glaucoma, although this contention has been challenged. 10. Increased clotting factors in the vitreous of diabetic patients not only facilitate thrombotic complications per se, but also stimulate inflammation. The increased

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A

B

C

D Fig. 15.25  Vitreous hemorrhage. A, New blood vessels (lower left) lie between internal limiting membrane of neural retina and vitreous body. Partial detachment of vitreous (upper right) has caused traction on neural retina. B, If no further detachment of the vitreous occurs, vessels may grow onto the posterior surface of the detached vitreous. C, With further vitreous detachment, the fragile new vessels can break, resulting in hemorrhage into the vitreous compartment (D).

accumulation of proinflammatory factors, such as plasma kallikrein, thrombin, and urokinase, in the vitreous of diabetic patients has been postulated to contribute to vascular dysfunction in these patients. The overall results of these changes contribute to retinal ischemia and edema. II. Hemorrhage into vitreous compartment (Figs. 15.25 and 15.26) A. A hemorrhage into the subvitreal space is more common than into the vitreous body.

Vitreous hemorrhage does not seem to be related to activity. In fact, approximately 60% of vitreous hemorrhages follow sleep or resting. This fact may be related to an increased neural retinal blood flow that normally occurs in the dark (at night).



B. Organization of the hemorrhage with fibroglial overgrowth may occur, usually along the external surface of the detached vitreous. III. Asteroid hyalosis—some studies show a correlation between asteroid hyalosis and diabetes; others do not. A review of 10,801 autopsy eyes examined over the period 1965–2000

found no correlation between the presence of asteroid hyalosis and diabetes. IV. Vitreous imaging A. SD-OCT may demonstrate hyperreflective foci in the vitreous. The average number of these foci correlates with the severity of diabetic retinopathy. V. Vitreous composition A. Vitreous levels of both glutamate and lactate are elevated in diabetic patients with and without retinopathy compared to nondiabetic controls. B. Postmortem vitreous sampling for glucose and for the ketone body, beta-hydroxybutyrate, can be helpful as an indicator of premortem diabetic ketoacidosis. C. Vitreous levels of plasma prekallikrein and kallikrein are elevated significantly in patients with diabetic macular edema. D. The neurotrophin-3 and neurotrophin-4/tropomyosin receptor kinase axis is upregulated in the ocular microenvironment in patients with proliferative diabetic retinopathy as reflected in vitreous samples and epiretinal membrane specimens from such patients. E. Vitreous levels of heparin sulfate (HS) increase with age. The lower levels of HS and increased localization of VEGF at the retinal surface in younger patients have been offered as explanations why there is a higher

Intraocular Changes

615

Fig. 15.26  Vitreous hemorrhage. A, Clinical appearance of vitreous hemorrhage. B, Hemosiderin-laden macrophages and red blood cells present in vitreous compartment. C, Macrophages stain positive for hemosiderin (blue) with iron stain, but red blood cells do not.

A

B

C

susceptibility of younger patients with diabetes to develop proliferative retinopathy.

Optic Nerve I. Neovascularization (see Fig. 15.21)—the optic disc is a site of predilection for neovascularization, which often grows into Cloquet’s canal. A. Disc neovascularization may respond to intravitreal injection of anti-VEGF therapy. B. OCT angiography is helpful in differentiating optic disc neovascularization from venous collateral vessels. II. Ischemic (nonarteritic) optic neuropathy A. Retrobulbar neuritis, papillitis, optic disc edema, and optic atrophy, all occurring infrequently, may be ischemic manifestations of diabetic microangiopathy in the optic nerve head when collateral circulation is inadequate. B. Diabetic papillopathy (transient bilateral optic disc edema and minimal impairment of function) may develop in patients with type 1 or type 2 diabetes. Although the vision decrease tends to be quite mild, serious visual loss has been reported. 1. Diabetic papillopathy is rare. Fewer than 130 cases had been reported by 2012. 2. Transient visual obscurations have been reported; however pain or other ocular or neurologic symptoms are absent. 3. The condition usually resolves without treatment over 2 to 12 months, although local steroid injection or anti-VEGF treatment may be helpful. a. Little or no optic atrophy usually can be found following resolution of disc edema.



4. It should not be confused with neovascularization of the disc or central nervous system-induced papilledema. 5. It is characterized by optic disc swelling caused by vascular leakage and axonal edema around the optic nerve head. It may be accompanied by intraretinal hemorrhages and hard exudates. 6. It may be associated with small cup/disc ratio and rapid reduction in blood sugar. Bilateral papillopathy has been reported in a patient having both of these risk factors. 7. Diabetic papillopathy has been reported to progress to nonarteritic anterior ischemic optic neuropathy in a patient with cystic fibrosis. a. Some have postulated that it simply is a form of nonarteritic anterior ischemic optic neuropathy. b. Sight-threatening diabetic retinopathy is much more common in diabetic patients with nonarteritic ischemic anterior optic neuropathy (30.1%), compared to diabetic patients without sightthreatening retinopathy (13.1%). 8. It is important that other causes of disc edema be excluded before a diagnosis of diabetic papillopathy is made. Diabetic papillopathy may rarely be associated with a rapidly progressive optic disc neovascularization, particularly during pregnancy. Transient optic disc edema secondary to vitreous traction in a quiescent eye with PDR may mimic diabetic papillopathy. The development of bilateral nonarteritic

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CHAPTER 15  Diabetes Mellitus anterior ischemic optic neuropathy from diabetic papillopathy has been reported.

III. Central retinal vein occlusion (see Chapter 11) Based on animal studies, diabetes is a risk factor for glaucomatous optic neuropathy. Diabetes is also among the risk factors for optic disc hemorrhages in glaucoma. Nerve fiber layer is decreased, particularly in the superior segment of the retina, in diabetic patients even before the development of clinical retinopathy. Nerve fiber layer

thickness further decreases with the development of DR and with impairment of metabolic regulation. This finding may impact the evaluation of nerve fiber layer in glaucomatous diabetic patients. IV. Comparison of OCT the analysis of the optic nerves of patients with diabetes and those of stable patients with normal pressure glaucoma reveal significant differences in their respective parameters suggesting a fundamental pathogenic difference between the two diseases.   References available online at expertconsult.com.

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CHAPTER 15  Diabetes Mellitus

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Abu El-Asrar AM, Mohammad G, De Hertogh G, et al: Neurotrophins and neurotrophin receptors in proliferative diabetic retinopathy, PLoS ONE 8:e65472, 2013. Abu El-Asrar AM, Mohammad G, Nawaz MI, et al: Relationship between vitreous levels of matrix metalloproteinases and vascular endothelial growth factor in proliferative diabetic retinopathy, PLoS ONE 8:e85857, 2013. Akkaya S, Can E, Ozturk F: Comparison of optic nerve head topographic parameters in patients with primary open-angle glaucoma with and without diabetes mellitus, J Glaucoma 25:49–53, 2016. Chen DY, Su GF: Tumor necrosis factor-like weak inducer of apoptosis association with proliferative diabetic retinopathy and promotes proliferation and collagen synthesis in retinal ARPE-19 cells, Genet Mol Res 15:2016. Kita T, Clermont AC, Murugesan N, et al: Plasma kallikrein-kinin system as a VEGF-independent mediator of diabetic macular edema, Diabetes 64:3588–3599, 2015. Mizukami T, Hotta Y, Katai N: Higher numbers of hyperreflective foci seen in the vitreous on spectral-domain optical coherence tomographic images in eyes with more severe diabetic retinopathy, Ophthalmologica 238:74–80, 2017. Murugeswari P, Shukla D, Kim R, et al: Angiogenic potential of vitreous from proliferative diabetic retinopathy and Eales’ disease patients, PLoS ONE 9:e107551, 2014. Nesmith BL, Palacio AC, Schaal Y, et al: Diabetes alters the magnitude of vitreomacular adhesion, Retina 37:749–752, 2017. Nishiguchi KM, Ushida H, Tomida D, et al: Age-dependent alteration of intraocular soluble heparan sulfate levels and its implications for proliferative diabetic retinopathy, Mol Vis 19:1125–1131, 2013. Palmiere C, Bardy D, Mangin P, et al: Postmortem diagnosis of unsuspected diabetes mellitus, Forensic Sci Int 226:160–167, 2013. Palmiere C: Postmortem diagnosis of diabetes mellitus and its complications, Croat Med J 56:181–193, 2015. Simsek IB, Artunay O: Evaluation of biochemical composition of vitreous of eyes of diabetic patients using proton magnetic resonance spectroscopy, Curr Eye Res 42:754–758, 2017. Usui-Ouchi A, Ouchi Y, Kiyokawa M, et al: Upregulation of Mir-21 levels in the vitreous humor is associated with development of proliferative vitreoretinal disease, PLoS ONE 11:e0158043, 2016. Wan W, Li Q, Zhang F, et al: Serum and vitreous concentrations of omentin-1 in diabetic retinopathy, Dis Markers 2015:754312, 2015.

Optic Nerve Arnold AC, Costa RM, Dumitrascu OM: The spectrum of optic disc ischemia in patients younger than 50 years (an American Ophthalmological Society thesis), Trans Am Ophthalmol Soc 111:93–118, 2013.

Bargiota A, Kotoula M, Tsironi E, et al: Diabetic papillopathy in pregnancy: a marker for progression to proliferative retinopathy, Obstet Gynecol 118:457–460, 2011. Chin EK, Almeida DR, Sohn EH: Sustained and expedited resolution of diabetic papillopathy with combined PRP and bevacizumab, Can J Ophthalmol 50:e88–e91, 2015. Feng J, Qu JF, Jiang YR: Resolution of diabetic papillopathy with a single intravitreal injection of bevacizumab combined with triamcinolone acetonide, Graefes Arch Clin Exp Ophthalmol 251:2651–2652, 2013. Giuliari GP, Sadaka A, Chang PY, et al: Diabetic papillopathy: current and new treatment options, Curr Diabetes Rev 7:171–175, 2011. Hayreh SS, Zimmerman MB: Nonarteritic anterior ischemic optic neuropathy: clinical characteristics in diabetic patients versus nondiabetic patients, Ophthalmology 115:1818–1825, 2008. Iosfina I, Chuo JY, Godinho DV, et al: Optic disc swelling and vision loss in a patient with cystic fibrosis and diabetes, Case Rep Endocrinol 2013:843795, 2013. Kim M, Lee JH, Lee SJ: Diabetic papillopathy with macular edema treated with intravitreal ranibizumab, Clin Ophthalmol 7:2257–2260, 2013. Ornek K, Ogurel T: Intravitreal bevacizumab for diabetic papillopathy, J Ocul Pharmacol Ther 26:217–218, 2010. Ostri C, Lund-Andersen H, Sander B, et al: Bilateral diabetic papillopathy and metabolic control, Ophthalmology 117:2214–2217, 2010. Ostri C: Intraocular surgery in a large diabetes patient population: risk factors and surgical results, Acta Ophthalmol 92 Thesis 1:1–13, 2014. Reddy D, Rani PK, Jalali S, et al: A study of prevalence and risk factors of diabetic retinopathy in patients with non-arteritic anterior ischemic optic neuropathy (NA-AION), Semin Ophthalmol 30:101–104, 2015. Sayin N, Kara N, Pekel G: Ocular complications of diabetes mellitus, World J Diabetes 6:92–108, 2015. Singh A, Agarwal A, Mahajan S, et al: Morphological differences between optic disc collaterals and neovascularization on optical coherence tomography angiography, Graefes Arch Clin Exp Ophthalmol 255:753–759, 2017. Suh MH, Kim SH, Park KH, et al: Optic disc rim area to retinal nerve fiber layer thickness correlation: comparison of diabetic and normal tension glaucoma eyes, Jpn J Ophthalmol 57:156–165, 2013. Wallace IR, Mulholland DA, Lindsay JR: Diabetic papillopathy: an uncommon cause of bilateral optic disc swelling, QJM 105:583–584, 2012. Yildirim M, Kilic D, Dursun ME, et al: Diabetic papillopathy treated with intravitreal ranibizumab, Int Med Case Rep J 10:99–103, 2017.

16  Glaucoma NORMAL ANATOMY (Figs. 16.1–16.3) I. The aqueous outflow is divided into conventional and unconventional pathways. The conventional pathway includes the trabecular meshwork, canal of Schlemm, collector channels, aqueous veins of Ascher, and episcleral vessels. The unconventional (uveoscleral) pathway includes the uvea, ciliary body and muscle, supraciliary and suprachoroidal spaces. In humans, the conventional pathway drains most aqueous; however, the unconventional pathway may be responsible for 3%–82% of aqueous outflow in different species, and 4%–14% in humans. Another potential unconventional aqueous outflow pathway involves lymphatic vessels within the ciliary body. As yet, this uveolymphatic pathway, is not widely accepted. II. Conventional outflow pathway anatomy—the outermost or corneoscleral layer of the eye can be separated into corneal and scleral portions by two circumferential grooves, a shallow outer one, the outer scleral sulcus, and a deeper inner one, the inner scleral sulcus (Fig. 16.1). A. The posterior boundary of the inner scleral sulcus is a ridge, mainly composed of circumferentially oriented bundles of collagen fibrils, the scleral roll or Schwalbe’s posterior-border ring. B. A short distance posteriorly, the ridge or roll tapers and finally blends with the more predominant, obliquely arranged collagenous lamellae of the sclera. C. Deep within this inner sulcus and applied closely to the collagenous tissue of the corneosclera lies the large vessel called the canal of Schlemm. 1. This circumferentially arranged branching vessel is formed by a continuous layer of nonfenestrated endothelial cells with a rather patchy or diffuse basement membrane. It is called an aqueous vessel because in vivo it contains aqueous fluid alone (the structure of the canal of Schlemm closely resembles the structure of a lymphatic). Nevertheless, blood may reflux into it if the episcleral venous pressure is elevated. 2. The outer wall of the canal also rests on a basement membrane that is separated from the dense collagenous lamellae of cornea and sclera by a few loose cells. 3. The inner wall rests on a thinner or patchy basement membrane that is associated with a zone of delicate connective tissue, the juxtacanalicular connective tissue.













a. The juxtacanalicular connective tissue is a special zone of the corneoscleral trabecular meshwork and consists of cells surrounded by a variety of fibrous and mucinous extracellular materials. The juxtacanalicular connective tissue is irregular in thickness from front to back in any single meridional section; it is more delicate in the younger eye and more prominent in the adult eye. b. Examination of trabeculectomy specimens containing the external portion of the trabecular meshwork reveals severely decreased cellularity in glaucoma. 4. Pores are present in the wall of Schlemm’s canal. a. It has been postulated that the pore size and density in the inner wall of Schlemm’s canal are adequate to account for the outflow of aqueous, but when combined with the outflow rate of aqueous are sufficiently small to prevent the retrograde diffusion of large molecular weight solutes and serum proteins into the canal and back into the human eye, thereby supporting the blood–aqueous barrier. b. Pore density is lower in glaucoma patients. c. Pore formation is altered in Schlemm’s canal cells in glaucoma. d. The distribution of pores may result in “segmental flow” in which not all segments of the trabecular meshwork participate equally in aqueous outflow. 5. Aqueous outflow resistance is thought to be comprised primarily of extracellular matrix at the level of the deepest portions of the juxtacanalicular connective tissue and the Schlemm’s canal inner wall basement membrane. a. The major pathways for egress of aqueous within the conventional outflow pathway are: 1) Transcellular through the vacuoles in the inner wall endothelial cells of Schlemm’s canal. 2) Paracellular by passing between Schlemm’s canal inner wall endothelial cells. 3) Through extracellular matrix turnover. b. Through the process of “funneling”, the extracellular matrix directs aqueous flow to the pores in Schlemm’s canal endothelium. Extracellular matrix represents the medium through which aqueous must pass to exit through either the transcellular or paracellular pathways. 617

618

CHAPTER 16  Glaucoma

1

jct

s

1

cs

2

u 2 3

Fig. 16.1  Normal adult angle. Schematic representation of meridional section of corneoscleral coat. Circumferential shallow outer sulcus (1) and deeper, inner sulcus (2) are present in region of union of sclera with cornea. Posterior boundary of inner sulcus is thickened by scleral roll (posterior border ring of Schwalbe).







c. Increased turnover of extracellular matrix material, such as by the increased expression of matrix metalloproteinases is one method by which intraocular pressure (IOP) may be regulated by adjusting outflow resistance. d. Matricellular proteins, are nonstructural secreted glycoproteins that aide in cellular communication with and control over surrounding extracellular matrix, thereby contributing to the regulation of aqueous outflow. 1) They allow cells to modulate their attachments with and alter the characteristics of their surrounding extracellular matrix. 2) Specific matricellular proteins that may prove important in the pathogenesis of glaucoma are SPARC (secreted protein, acidic and rich in cysteine), myocilin, CTGF (connective tissue growth factor), TSP-1 (thrombospondin-1), TSP-2, and galectins. 6. Ultrastructural analysis of ocular basement membrane components fails to demonstrate significant differences between the characteristics of these structures in normal and glaucomatous eyes. 7. Schlemm’s canal cells are extremely contractile and change shape and stiffness in response to stretching. D. Large endothelium-lined channels (collector channels) connect the canal of Schlemm either anterior or, more commonly, posterior to the intrascleral venous plexus that drains both the canal of Schlemm and the longitudinal ciliary muscle. If the collector channels reach the surface of the sclera unconnected, they can be observed in vivo as the clear aqueous veins of Ascher.

Fig. 16.2  Normal adult angle. The trabecular meshwork is a loose collagenous meshwork that fills the inner scleral sulcus and extends as an open fan to the root of the iris. The meshwork may be separated into two parts by an imaginary line extending from the end of Descemet’s membrane (1) to the scleral roll (2). The meshwork lying external to the line and extending from cornea to sclera is known as the corneoscleral (cs) meshwork. The meshwork lying internal to the line and in continuity with the uveal tract posteriorly (3) is known as the uveal (u) meshwork. A third part, which rests on the inner wall of the canal of Schlemm (s), is a thin or patchy basement membrane associated with a zone of delicate connective tissue called the juxtacanalicular connective tissue (jct).







E. The trabecular meshwork 1. In meridional sections of a young eye, a loose collagenous meshwork can be seen filling the inner scleral sulcus and extending as an open fan to the root of the iris. The “handle” of this fan is located just anterior to the end of Descemet’s membrane—Schwalbe’s anterior-border ring—where a few layers of meshwork enter into and blend with the deep peripheral corneal stroma. 2. The meshwork may be easily and usefully separated into two parts by an imaginary line extending from the scleral roll to the end of Descemet’s membrane (see Fig. 16.2). a. The meshwork lying external to the line and extending from cornea to sclera is known as the corneoscleral meshwork. b. The meshwork lying internal to the line and in continuity with the uveal tract posteriorly is known as the uveal meshwork. 3. A single trabecula of uveal meshwork consists of a collagenous core surrounded by a single layer of polarized cells (“endothelium”—in reality a mesothelium). A basement membrane separates the polarized endothelial cells from the underlying collagenous core and, not infrequently, patches of this basement membrane present a periodic structure (banded basement membrane) measuring 100 nm (1000 → A).

Normal Anatomy

c

c cc

619

pc

sc

sc

s tm

tm

a i ix

sr

i cb

A

ip

B

C

D Fig. 16.3  Normal adult angle. A, Scanning electron microscopy shows the main aqueous drainage area (i.e., the angle [a] of the anterior chamber). Aqueous drains through the trabecular meshwork (tm) into Schlemm’s canal (sc), the collector channels (cc), and the aqueous veins, as well as into the uveal tract and out through the anterior ciliary and vortex veins. Some aqueous also drains into the iris and out through the iris vessels (c, cornea; i, iris; ip, iris pigment epithelium; ix, iris in cross-section; pc, posterior surface of cornea; sr, scleral roll/spur). B, In an adult, the scleral roll becomes thickened by compacting of the uveal meshwork to form the scleral spur (s), a bipartite structure. Between the scleral portion and the cornea lies the corneoscleral trabecular meshwork (tm). Just posterior lies the uveal trabecular meshwork, and just anterior, adjacent to Schlemm’s canal (sc), lies the juxtacanalicular connective tissue (c, cornea; cb, ciliary body; i, iris). C, We usually view the transtrabecular and intertrabecular trabecular meshwork spaces meridionally. A section perpendicular to this plane, through the dotted lines, results in an anterior view of the trabecular meshwork. Just posterior lies the trabecular drainage spaces or canals, as seen in D (see Figs. 16.9A and 16.9C). (A, Courtesy of Dr. RC Eagle, Jr.)



4. Lying within the tightly packed collagenous cores of the trabeculae are many aggregates of filamentous and homogenous elastic tissue whose density increases with age (the aggregates also take stains for elastic tissue). 5. The endothelial cells covering the connective tissue core have apical surfaces, line intertrabecular spaces, and therefore are bathed by aqueous. They have similarities to cells of the lamina cribrosa, particularly related to cell contractility and interaction with extracellular matrix. a. Characteristic features of trabecular endothelial cells are: 1) Growth in a monolayer with a nonthrombogenic cell surface. 2) The production of plasminogen activator. 3) Avid phagocytosis.







4) The ability to synthesize glycosaminoglycans, collagen, fibrinogen, and other connective tissue elements. 5) Expression of crosslinking enzymes. a) Crosslinking is the formation of chemical bridges between proteins or other molecules. b) Crosslinking can prevent proteolytic breakdown and, therefore, can lead to decreased extracellular matrix breakdown. c) These enzymes include tissue transglutaminase, lysyl oxidase, and lysyl oxidaselike 1. 6) Increased expression of myocilin following treatment with dexamethasone. 7) Variation in expression profile when cells are exposed to stretching.

620

CHAPTER 16  Glaucoma

a) Autophagy is a process through which cellular components, including organelles, are degraded by lysosomes. This process appears to be triggered in trabecular cells by elevating IOP. It also can be demonstrated in cells lining the inner wall of Schlemm’s canal in response to shear stress. Abnormalities in this vital function would impair the ability of trabecular cells to repair damage induced by mechanical, oxidative or phagocytic stress. 8) Ability to migrate. 6. The trabeculae of the meshwork are roughly arranged into circumferential sheets lying superimposed one on the other. They can be fairly easily separated from one another mechanically, especially in the uveal meshwork. The spaces between adjacent sheets are called intertrabecular spaces. Large oval apertures traverse each trabecular sheet and may be called transtrabecular spaces. The transtrabecular apertures are not superimposed, and decrease in size in the direction of the corneoscleral meshwork. The corneoscleral sheets differ only slightly from the uveal in having somewhat flatter trabeculae as observed in cross-section and in lacking the staining characteristics for elastic fibers. The transtrabecular apertures here are more circular and smaller than those of the uveal meshwork. All intertrabecular and transtrabecular spaces thus may be considered extensions of the anterior chamber.

7. Spaces between individual sheets are well seen in proper meridional section, and here are termed the intertrabecular spaces. In the uveal meshwork, the intertrabecular spaces pass the scleral roll to continue with the tissue spaces lying between the smooth-muscle cells of the ciliary muscles—especially those of the meridional (longitudinal) ciliary muscle. If serially sectioned in a frontal or coronal plane, the spaces can be seen as large-apertured, relatively straight, short tubes. Such a grouping of tubes with apertured walls might be termed a system of compound aqueous tubes. In the corneoscleral meshwork, which blends posteriorly with the region of the scleral roll, the intertrabecular spaces (tubes) abut the canalicular extensions of the canal of Schlemm. Such extensions are frequent in this region.

8. The blind inpouchings of the canal of Schlemm (canals of Sondermann), here termed canaliculi, are endothelium-lined, and do not appear to be in

continuity with the intertrabecular spaces. Their function, presumably, is to drain off aqueous passing laterally along the corneoscleral trabecular meshwork (i.e., along the intertrabecular spaces). 9. The ciliary muscle tendons appear to connect to the trabecular lamellae through an elastin network within the trabecular lamellae. 10. Contraction of myofibroblast-like cells in the trabecular meshwork and the adjacent scleral spur, or the contraction of the ciliary muscle decreases aqueous outflow resistance. These myofibroblast-like cells are positive for α-smooth muscle actin. III. Unconventional outflow pathway A. This pathway involves passage of aqueous humor through the posterior aspect of the uveal portion of the trabecular meshwork, through the ciliary muscle, and into the supraciliary and suprachoroidal spaces to reach the capillaries of the ciliary body or the orbital lymphatics. B. It is estimated to represent 4%–14% of human aqueous outflow. C. It also has been postulated that the presence of lymphatic channels within the uvea contribute to the unconventional outflow of aqueous. D. Outflow resistance in the ciliary body probably is regulated by extracellular matrix turnover in the stroma and by cellular tone in the ciliary body muscle.

INTRODUCTION The cell and molecular biology, and gene rearrangement aspects of the glaucomas are fascinating, but an in-depth analysis of these matters is beyond the scope of our discussion. For example, genome-wide expression profiling of patients with primary openangle glaucoma (POAG) identified 542 genes that were significantly dysregulated in the glaucomas compared with normal controls. These genes impact numerous functions including nucleoside, nucleotide, and nucleic acid metabolism, the mitogenactivated protein kinase kinase kinase (MAPKKK) cascade, apoptosis, protein synthesis, cell cycle, intracellular signaling cascade, and nervous system development and function. Therefore, we will only highlight a few salient facts regarding these areas. Presently, the chromosome loci designated GLC1A to GLC3A are associated with POAG (Table 16.1 lists the glaucoma-associated loci from linkage analysis). Candidate genes include myocilin (GLC1A), interleukin 20 receptor subunit beta (IL20RB), ankyrin repeat and SOCS box containing 10 (ASB10), WD repeat domain 36 (WDR36) (GLC1G), optineurin (GLC1E), EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1), TANKbinding kinase 1 (TBK1) and neurotrophin-4 (NTF4) (optineurin is discussed with normal pressure glaucoma later in this chapter). Other candidates have been suggested. Nevertheless, it has been estimated that mutations in known glaucoma genes account for less than 15% of cases. There are 353 genes potentially important in the development of POAG from all study types (Table 16.2). CYP1B1 mutations have been observed in a majority of primary congenital glaucoma patients from all over the globe. Only some single nucleotide polymorphisms (SNPs) involving

Introduction

621

TABLE 16.1  Genetic Loci for Primary Open-Angle Glaucoma Gene

Location

Phenotype MIM Number

Clinical Characteristics

Inheritance Pattern

GLC1A (MYOC/TIGR) GLC1B GLC1C GLC1D GLC1E (OPTN) GLC1F (ASB10) GLC1G (WDR36) GLC1H GLC1I GLC1J GLC1K GLC1L GLC1M GLC1N GLC1O (NTF4) GLC1P (TBK1/NAK) GLC1Q Glaucoma 3A (CYP1B1) − − − − − − − − − − −

1q24.3–q25.2 2cen–q13 3q21–q24 8q23 10p14 7q35–q36 5q22.2 2p16–p15 15q11–q13 9q22 20p12 3p22–p21 5q22 15q22–q24 19q13.3 12q14 4q35.1–q35.2 2p22.2 19q12 17q25.1–17q25.3 14q11.1–14q11.2 14q21.1–q21.3 17p13 10p12.33–p12.1 2q33.1–q33.3 2p14 2p15–16 1p32 10q22

137750 606689 601682 602429 137760 603383 609887 611276 609745 608695 608696 137750 610535 611274 613100 615141 − 231,300 − − − − − − − − − − −

Juvenile onset, high IOP Adult onset (over 50), 1/3 NTG Adult onset (over 50) Adult onset Mainly NTG Adult onset (over 50) 2/3 POAG, 1/3 NTG Adult onset (over 50), middle to high IOP Adult onset (over 50) Juvenile-onset Juvenile-onset Adult onset (over 60) Juvenile-onset Juvenile-onset Adult onset, NTG Adult onset, NTG Adult onset Congenital/juvenile/adult onset − − − − − − − − − − −

AD AD AD AD AD AD AD; complex AD Complex AD AD AD AD AD Complex Complex AD AR − − − − − − − − − − −

AD, autosomal dominant; AR, autosomal recessive; ASB10, ankyrin repeat and SOCS box containing 10; CYP1B1, cytochrome P450 family 1 subfamily B polypeptide 1; GLC, glaucoma; MIM, Mendelian inheritance in man; MYOC, myocilin; NAK, NF-kappa-B-activating kinase; NTF4, neurotrophin 4; OPTN, optineurin (optic neuropathy inducing protein); TBK1, TANK-binding kinase 1; TIGR, trabecular meshwork-induced glucocorticoid response protein; WDR36, WD repeat domain 36. (From Kumar et al.: Candidate genes involved in the susceptibility of primary open angle glaucoma. Gene 577:119–131, 2016. Table 1. Elsevier.)

the cytochrome p450 1B1 (CYP1B1) gene appear to be associated with the development of glaucoma, particularly congenital glaucoma. SNPs involving a region near the CAV1 and CAV2 loci on chromosome 7q31 that code for two members of the caveolin family of proteins, are associated with POAG in some populations. These proteins impact modulation of endothelial cell membranes, which could alter the process of ocular aqueous fluid drainage. In general, however, SNPs will not be discussed in any detail, but have been described elsewhere (see references). Gene copy number variations also may play a role in the development of POAG. For example, homozygous deletions that reduce galactosylceramidase activity may increase the risk of POAG. I. Glaucoma is characterized by an IOP sufficient to produce ocular tissue damage, either transient or permanent. A. Glaucoma is a “family” of diseases having in common a type of optic atrophy called optic nerve head cupping or excavation that is accompanied by death of retinal ganglion cells and loss of the associated nerve fibers. 1. Various systemic abnormalities have been associated with glaucoma, including elevation of the 20S proteasome alpha-subunit of leukocytes. Certain class I HLA

haplotypes (A9–B12, A2–B40, A1-B8) are associated with progression of optic nerve head changes in glaucoma. 2. The appearance of the optic disc is an important diagnostic finding in glaucoma. The ratio of the diameter of the optic cup to the disc is moderately heritable. A more appropriate name may be glaucomatous optic neuropathy because the primary defect, especially in chronic open-angle glaucoma, appears to be within the optic nerve head.



B. Although most individuals associate glaucoma with an elevated IOP, the pressure may, in fact, be within the statistically “normal” range and still cause ocular tissue damage in normal-tension (improperly called low-tension) glaucoma. 1. IOP is a risk factor for glaucoma, and the higher the pressure, the greater the probability of the development of the disorder.

622

CHAPTER 16  Glaucoma

TABLE 16.2  Results of CPDB’s Pathway Analysis and IPA’s Core Analysis of the 353 Genes

Potentially Important in Development of POAG from All Study Types Primary Open-Angle Glaucoma CPDB Pathways (All Genes Included) Pathway (Rank) Pathway Source Pathway-Input Gene Overlap Extracellular matrix organization

Reactome

Cytokine–cytokine receptor interaction – Homo sapiens (human)

KEGG

Senescence and autophagy in cancer

Wikipathways

Spinal cord injury

Wikipathways

p-value

COL15A1, MMP1, FBLN5, ITGA4, DCN, TIMP1, DAG1, FBLN1, SDC1, BMP2, FBLN2, COL1A2, BMP1, P3H2, EFEMP1, THBS1, COL1A1, COL11A1, BMP4, HAPLN1, COL4A1, LOXL1, LTBP2, COL3A1, JAM2, FN1, P4HB, MMP9, TGFB1, COL13A1, CD47, FGF2, SPP1, MFAP4, PDGFA, ITGA6, MMP2, TGFB2, SPARC, PLOD2, CDH1, DMD, VCAN, BMP7, SDC2, PCOLCE2, COL8A2, COL18A1, A2M, CD44, ITGA2B, COL5A2, AGRN, LOX, ITGA2, SDC4, LAMC1, ITGB1, COL5A1 IL13RA1, TNFRSF9, PDGFA, EPO, IL20RB, IL18RAP, TNFRSF11B, BMP2, BMP7, LEPR, IL1R2, NGFR, CCL3, CCR1, CCL4, CCL5, CCR4, CXCL11, CCR5, INHBA, CNTF, VEGFA, VEGFC, LTBR, TGFB2, TNFRSF1A, TGFBR2, FAS, FLT1, OSM, CSF1, CSF1R, CSF2RB, EGFR, IL6, IL2RG, TNFRSF13B, TNF, OSMR, IL1A, IL1B, TGFB1, IL3RA IGF1, IL1B, IL1A, THBS1, MAP1LC3A, IL6, MAP2K1, PLAT, SPARC, TP53, BMP2, JUN, CDKN1B, CDKN1A, CD44, CDKN2A, SMAD3, CCL3, BECN1, INHBA, COL1A1, COL3A1, FN1, TGFB1 PTGS2, IL1B, IL1A, C1QB, EGFR, TNF, APEX1, IL6, NGFR, ANXA1, BDNF, TP53, TLR4, CDKN1B, CD47, COL4A1, GJA1, FOS, VCAN, NOS2, MMP9, PPP3CA, MBP, TGFB1

3.17e-37

3.16e-21

9.05e-16

1.00e-14

Top Upstream Regulators of Primary Open-Angle Glaucoma (IPA Core Analysis of All Genes) Regulator Target Genes From Input List

p-value

TNF

3.52e-42

TGFB1

SP1

NFκB (complex)

ERBB2

ACTA2, ADM, ALDH2, APOE, BMP2, CCL3, CCL4, CCL5, CCR4, CD44, CD47, CDH1, CDH11, CDH2, CDKN1A, CFD, COL1A2, CSF1, CXCL11, EDN1, EGFR, EPO, FAS, FLT1, FN1, FOS, FST, IL1A, IL1B, IL6, INHBA, ITGA4, JUN, LCN2, LTBP2, MMP1, MMP2, MMP9, MYLK, NFKB1, NGF, NOS2, OSMR, PLOD2, PTGS2, RFTN1, RXRA, SAA1, SDC4, SELE, SOD2, STAT1, TAP1, TDRD7, TGFB1, TGFBR2, TIMP1, TIMP3, TJP1, TLR2, TLR4, TM4SF1, TNF, TNFRSF11B, TP53, VEGFA, VEGFC, XIAP ACTA2, AKR1C1/AKR1C2, BMP1, BMP7, CCL5, CD44, CDH1, CDH11, CDH2, CDKN1A, CDKN1B, CDKN2B, COL18A1, COL1A1, COL1A2, COL3A1, COL5A1, CSF1R, CTGF, CTNNB1, EDN1, ESR2, FAS, FGF2, FLT1, FN1, FOS, IGF1, IL6, ITGA2, ITGA4, ITGA6, ITGB1, JUN, JUNB, LTBP2, MMP1, MMP2, MMP9, PDGFA, PLOD2, PTGS2, SDC1, SMAD3, SPARC, SPOCK1, TGFB1, TGFBI, TGFBR2, TGM2, THBS1, TIMP1, TNF, TP53, VEGFA ATF3, BMP4, CAV1, CDH1, CDH2, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CEBPD, COL1A1, CR2, EGFR, ESR1, FGF2, FLT1, FN1, GJA1, HK2, HSD17B1, HSPA5, ITGA2, JUN, MMP2, NF1, NFKB1, NGFR, NOS3, NTF4, NTRK1, OGG1, PTGS2, PTN, SMAD3, SNCG, SOD2, SPP1, STAT1, TFPI2, TGFB1, TGFB2, TGFBR2, TLR2, TNF, TP53, VEGFA BAD, BECN1, BMP2, CCL3, CCL4, CCL5, CD44, CDKN1A, CLU, CTNNB1, CXCL11, CYP3A4, EDN1, EDNRB, FAS, FTH1, IL1B, IL6, ITGB1, JUNB, LCN2, MMP1, MMP2, MMP9, NFKB1, NOS2, PTGS2, RFTN1, SDC4, SENP1, SMAD3, SOD2, TAP1, TFPI2, TGFB1, TGM2, TNF, TNFRSF1A, TP53, VEGFC, XIAP BMP1, BMP7, CDH11, CDH2, CDKN1A, CDKN1B, CDKN2B, COL18A1, COL1A1, COL5A1, CSF1R, CTGF, EDN1, EGFR, FN1, FOS, IL1A, IL6, ITGA2, ITGB1, JUN, JUNB, LCN2, LTBP2, MMP1, PTGS2, SDC1, SMAD3, SPOCK1, THBS1, TNF, TP53, VEGFA, VEGFC

6.07e-38

1.4e-32

1.3e-28

3.45e-25

Pathway analysis and functional annotation were performed using ConsensusPathDB (CPDB) and Ingenuity® Pathway Analysis (IPA®, QIAGEN Redwood City, http://www.qiagen.com/ingenuity). (From Danford et al.: Characterizing the “POAGome”: A bioinformatics-driven approach to primary open-angle glaucoma. Progress in Retinal and Eye Research 58:89–114, 2017. Table 5. Elsevier.)



Similarly, CCT is thinner in patients with vascular risk factors for glaucoma. Patients with congenital aniridia have CCT that is significantly thicker than normal. This abnormality is not secondary to corneal edema resulting from endothelial dysfunction.

a. The accurate measurement of IOP is vital to the proper diagnosis and treatment of glaucoma. b. Central corneal thickness (CCT) impacts the validity of IOP measurements, particularly in the diagnosis of ocular hypertension. Thicker corneas produce an artificially high IOP measurement compared to manometrically measured “true” IOP. Conversely, thinner corneas produce an inappropriately low pressure on Goldmann applanation tonometry. Decreased CCT is present in normal-tension glaucoma and the CCT is thinner than in POAG.



c. CCT is increased in children with ocular hypertension. There is considerable racial variation in CCT. Osteogenesis imperfecta may be associated with an abnormally thin CCT. Alterations in

Introduction corneal thickness related to forkhead gene dosage can result in errors in IOP measurement. Increased CCT is associated with segmental gene duplication.









d. Glaucoma, therefore, is not an IOP reading, it is a syndrome. In fact, the cause of the glaucoma may be due to factors (mostly poorly understood) other than IOP. IOP is simply one risk factor. 2. Normal-tension glaucoma (NTG) probably accounts for approximately one-third of all cases of POAG. a. Optineurin (OPTN) 1) The optineurin gene is associated with several disorders including NTG, amyotrophic lateral sclerosis, other neurodegenerative disorders, and Paget’s disease of bone. 2) The E50K optineurin mutation has been the mutation most clearly shown to be associated with glaucoma, which has an earlier onset and increased severity. 3) A glaucoma-causing gene has been identified at GLC1E, and sequence variations in this optineurin (OPTN) gene on GLC1E have been found to be associated with the development of normal-tension glaucoma. The gene is located on chromosome 10. 4) The glaucoma associated with optineurin is not characterized by marked IOP elevation. 5) There may be racial differences in glaucomaassociated optineurin genotypes. Its primary effect may be to increase susceptibility of retinal ganglion cells to premature cell death. 6) TBK1 is located on the GLC1P POAG linkage locus on chromosome 12q14, and its interaction with OPTN may be enhanced by overexpression of E50K. 7) TBK1 plays a role in the regulation of inflammatory responses to foreign agents. Optineurin may serve an optic nerve protective effect that is lost through mutation. 8) Optineurin gene alterations do not appear to have a significant role in typical POAG. 9) Among the functions in which optineurin is involved are membrane vesicle trafficking, host defense against pathogens, and autophagy. 10) Autophagy is a cellular mechanism that removes damaged proteins and organelles through lysosomal degradation. a) In the latter regard, it interacts with autophagosomal protein, LC3, and ubiquitin. b) The optineurin mutation, E50K, impairs autophagy as well as vesicle trafficking, which leads to death of retinal cells by apoptosis.

623

Disc hemorrhage is a significantly negative prognostic factor in normal-tension glaucoma.















3. Optic atrophy type 1 (OPA1) on chromosome 3 is the gene responsible for dominant optic atrophy (DOA). It is mutated in 65%–90% of cases of DOA. a. It encodes for an inner mitochondrial membrane protein that is crucial for normal mitochondrial function. b. There is increased mitochondrial fragmentation and instability of mitochondrial respiratory chain complexes. c. Mutations in this gene, which is located on chromosome 3q28–q29, are of importance in glaucoma by targeting retinal ganglion cells. d. OPA1 is down-regulated in POAG, but is most associated with damage from normal pressure glaucoma. e. Some cases of normal-tension glaucoma are associated with polymorphisms of the OPA1 gene. f. This association raises the possibility that normaltension glaucoma may result from mitochondrial dysfunction. Gene polymorphisms vary with ethnicity. g. It can modulate retinal ganglion cell survival. Alterations in this gene may facilitate ganglion cell death through glutamate excitotoxicity and oxidative stress, and mitochondrial dysfunction. h. Apoptosis ensues and bilateral visual loss begins early in life. i. Characteristic histopathologic finding is primary degeneration of retinal ganglion cells preferentially in the papillomacular bundle, which results in temporal optic disc pallor and cecocentral scotoma. 4. Over 6% of patients with normal-tension glaucoma may have relevant intracranial compressive lesions. Such lesions are usually lacking in POAG. 5. Predictive factors for progression of normal-tension glaucoma differ from those of POAG, possibly suggesting different pathobiologic mechanisms for these disorders. 6. Elevated levels of plasma levels of endothelin-1 have been found in patients with NTG, which suggests the possibility of vascular dysfunction in these individuals. Elevated levels also have been found in patients with POAG. Papillorenal syndrome is associated with optic disc and visual field anomalies that may lead to an erroneous diagnosis of normal-tension glaucoma.

II. Glaucoma suspect A. Increased IOP without detectable ocular tissue damage or visual functional impairment is called ocular

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CHAPTER 16  Glaucoma

hypertension. An individual who has some features of glaucoma, but in whom a definitive diagnosis has not yet been confirmed, is termed a glaucoma suspect. B. Ocular hypertension may be tolerated by the person or eventually it may lead to ocular tissue damage and hence to glaucoma. The prevalence of glaucoma suspect in the general adult population is approximately 8% depending on age and race. The incidence of or progression to glaucoma among glaucoma suspects is approximately 1% per year.

III. Glaucoma is the leading cause of blindness among the 500,000 legally blind people in the United States— approximately 14% (1 in 7) of blind people. The second leading cause of blindness is retinal disease (exclusive of diabetic retinopathy), mainly age-related macular degeneration, followed by cataract. Optic nerve disease is fourth; diabetic retinopathy, fifth; uveitis, sixth; and corneal and scleral disease, seventh. Leading causes of new cases of blindness, in order of importance, are macular degeneration, glaucoma, diabetic retinopathy, and cataract.



A. Glaucoma of all types affects approximately 0.5% to 1% of the general population, 2% of people age 35 years or older, and 3% of people age 65 years or older. B. POAG accounts for approximately two-thirds of all glaucoma seen in white patients. 1. The prevalence of POAG in white patients ranges from approximately 0.9% in people 40 to 49 years of age to approximately 2.2% in those 80 years of age or older. 2. The prevalence of POAG in black patients ranges from approximately 1.2% in people 40 to 49 years of age to approximately 11.3% in those 80 years of age or older. 3. In 2015, 57.5 million people were affected by POAG globally, and the number is expected to increase to 65.5 million by 2020. IV. Primary closed-angle glaucoma has a prevalence of less than 0.5%, and is much less common in black patients than in white patients. A high percentage of black patients who develop angle-closure, however, have chronic closed-angle glaucoma instead of the acute type. The prevalence of primary closed-angle glaucoma is highest amongst Inuits (approximately 2% to 3%), followed by Asians (approximately 1%).

V. There is considerable racial and genetic variation in the incidence and prevalence of the various forms of glaucoma.

NORMAL OUTFLOW Hypersecretion I. Hypersecretion glaucoma is rare and has no antecedent cause. II. Outflow facility is normal. The elevated IOP is presumed to be caused by an increased production of aqueous humor. III. The glaucoma mainly affects middle-aged women, especially when they have neurogenic systemic hypertension. IV. Histologically, the angle of the anterior chamber shows no abnormalities.

IMPAIRED OUTFLOW Congenital Glaucoma (Table 16.3) I. General information A. The rate of congenital glaucoma is from 1 : 5000 to 1 : 10,000 live births. B. Accounts for approximately 22% of all pediatric glaucoma cases and 18% of childhood blindness. C. It is usually inherited as an autosomal-recessive trait, but can have an infectious cause (e.g., congenital rubella and Zika virus infections). D. Approximately 60% to 70% of affected children are boys. E. The disease is bilateral in 64% to 88% of cases. F. Age of onset: (1) present at birth: 40%; (2) between birth and 6 months: 34%; (3) between 6 months and 1 year: 12%; (4) between 1 year and 6 years: 11%; (5) over 6 years: 2%; and (6) no information: 1%. II. Pathogenesis (many theories) A. Barkan’s membrane (mesodermal surface membrane or imperforate innermost uveal sheet) mechanically prevents the aqueous from leaving the anterior chamber (histologic proof for this theory is scarce). B. Congenital absence of Schlemm’s canal (congenital absence of Schlemm’s canal is very rare, if it exists at all. Most often, the canal is compressed or collapsed as a secondary change resulting from chronically elevated IOP. The canal, therefore, may be difficult to find histologically). C. An “embryonic” anterior-chamber angle that results from faulty cleavage of tissue during embryonic development of the eye prevents the aqueous from leaving the anterior chamber. 1. Histologically, the angle shows an anterior “insertion” of the iris root, anteriorly displaced ciliary processes, insertion of the ciliary meridional muscles into the trabecular meshwork instead of into (or over) the scleral roll, and mesenchymal tissue in the anteriorchamber angle (Fig. 16.4). 2. Many nonglaucomatous infant eyes of similar age show a similar anterior-chamber angle structure. 3. To interpret angle histology accurately, it is necessary to study truly meridional sections through the anterior-chamber angle. a. Tangential sectioning makes interpretation difficult (see Fig. 16.4C and D).

Impaired Outflow

625

TABLE 16.3  Conditions/Syndromes Associated With Infantile Glaucoma CLINICAL FEATURES Disorder

Gene(s)

MOI

Eye Findings

Other

Aniridia

PAX6 WT1*

AD

May occur either as an isolated ocular abnormality w/out systemic involvement or as part of WAGR syndrome*

Anterior segment dysgenesis syndromes (e.g., Peters Plus syndrome) Axenfeld–Rieger anomaly (anterior segment disorder)

See footnote**

Microcornea

Unknown†

Congenital hereditary endothelial dystrophy (CHED; OMIM 217700)

SLC4A11

AR

Lowe syndrome

OCRL

XL

Neurofibromatosis type 1

NF1

AD

• Complete or partial iris hypoplasia w/associated foveal hypoplasia, resulting in reduced visual acuity & nystagmus • Presents in early infancy • Frequently associated w/other ocular abnormalities, often of later onset, incl cataract, glaucoma, & corneal opacification & vascularization Phenotypically & genotypically distinct from PCG in general, but severe or advanced PCG can be difficult to distinguish clinically from some of the anterior segment dysgenesis syndromes (e.g., Peters’ anomaly) • Presents w/posterior embryotoxon & (variably) iris strands adherent to Schwalbe’s line, iris hypoplasia, focal iris atrophy, & ectropion uveae • Glaucoma develops in ~50% of affected individuals but is more common in those w/central iris changes & marked anterior iris insertion • Always bilateral, but may be distinctly asymmetric • Corneal diameter 20/100 • Almost all affected males have some ID • Iris Lisch nodules • CG rarely observed

Nance–Horan syndrome (OMIM 302350) Sturge-Weber syndrome (OMIM 185300)

NHS

XL

Cataract and microcornea

Congenital hypotonia, delayed development, proximal renal tubular dysfunction (renal Fanconi type), progressive chronic renal failure and ESRD after age 10–20 yrs Multiple café-au-lait spots, axillary & inguinal freckling, cutaneous neurofibromas, learning disabilities in ≥50% of individuals Skeletal features

GNAQ

See footnote §

CG w/associated angle anomalies in ≤60% of affected individuals

Nevus flammeus of the face, angioma of the meninges

FOXC1 PITX2

AD

Peters Plus syndrome: developmental delay, mild to severe ID, cleft lip, cleft palate May occur in the setting of Axenfeld–Rieger syndrome (OMIM 180500): dysmorphic features, dental anomalies, sensorineural hearing loss, cardiac malformations, endocrine & orthopedic abnormalities May be a feature of systemic syndromes

Sensorineural hearing loss

AD, autosomal dominant; AR, autosomal recessive; CG, congenital glaucoma; ESRD, end-stage renal disease; ID, intellectual disability; MOI, mode of inheritance; WAGR, Wilms’ tumor–aniridia–genital anomalies–retardation; XL, X-linked. *Pathogenic variants or deletions in PAX6 or its control elements are associated with isolated aniridia. Contiguous gene deletions including PAX6 and WT1 are associated with aniridia and the risk of one or more additional manifestations of WAGR. **Anterior segment dysgenesis syndromes are a heterogeneous group of disorders that are usually inherited in an autosomal dominant manner with reduced penetrance. † Huang X, Xiao X, Jia X et al.: Mutation analysis of the genes associated with anterior segment dysgenesis, microcornea and microphthalmia in 257 patients with glaucoma. Int J Mol Med 36:1111–1117, 2015. ‡ Ramamurthy B, Sachdeva V, Mandal AK et al.: Coexistent congenital hereditary endothelial dystrophy and congenital glaucoma. Cornea 26:647–649, 2007. § Somatic mosaic pathogenic variants in GNAQ have been reported in individuals with Sturge–Weber syndrome. (From Abu-Amero KK, Edward DP: Primary congenital glaucoma. GeneReviews®. Table 2. © University of Washington, Seattle, 1993–2018. GeneReviews is a registered trademark of the University of Washington, Seattle. The content is used with permission. All rights reserved.)

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CHAPTER 16  Glaucoma

A

B

C

D Fig. 16.4  Congenital glaucoma. A and B from premature infants (A, 700 g—died soon after birth; B, 1050 g— lived one day); neither had clinical or histologic evidence of glaucoma. Note each has anterior “insertion” of iris root, anteriorly displaced ciliary processes, continuity of ciliary meridional muscles with uveal trabecular meshwork, and mesenchymal tissue in anterior-chamber angle. C, Eye obtained from 2-year-old child at time of accidental drowning but sectioned tangentially. Bilateral congenital glaucoma well documented; goniotomy and goniopuncture had been performed in another area of eye; pressure well controlled after surgery. Note similarity to nonglaucomatous premature eyes shown in A and B. D, However, when eye shown in C is sectioned properly (meridionally), the angle appears completely normal compared with that of other 2-year-olds.









b. Unfortunately, in the usual serial sectioning of a whole eye, because of the continuously curved surface, only a few sections from the center of the embedded tissue are truly meridional. D. Primary congenital glaucoma (PCG) has a strong genetic basis. 1. Polymorphism in the cytochrome P4501B1 (CYP1B1) gene located on chromosome 2p22.2, is the predominant cause of primary congenital glaucoma and accounts for 10%–20% of cases of PCG. a. The distribution of mutations in the CYP1B1 gene suggests that ethnic and geographic differences in primary congenital glaucoma may be associated with different CYP1B1 mutation patterns. b. The mechanism through which it causes glaucoma is not known; however, it is important in the in utero development of ocular structures.

2. Other genes that have been implicated in PCG include myocilin, Forkhead-related transcription factor C1 (FOXC1), and latent transforming growth factor betabinding protein 2 (LTBP2). Mitochondrial mutations also may be of significance in the pathogenesis of PCG, particularly regarding trabecular meshwork dysgenesis. III. Associated diseases and conditions (Table 16.3 lists conditions and syndromes associated with infantile glaucoma). A. Iris anomalies (see Chapter 9) 1. Hypoplasia of the iris (“aniridia”) and iris coloboma may be associated with congenital glaucoma. a. The PAX6 point mutation defect (1630A > T) on band p13 of chromosome 11 has been associated with some cases of aniridia. PAX6 mutations result in alterations in corneal cytokeratin expression, cell adhesion, and glycoconjugate expression.

Impaired Outflow

There also is corneal stem-cell deficiency, which contributes to associated keratopathy. 1) There always is some residual iris. Therefore, glaucoma may result from congenital abnormalities in the differentiation of the angle structures or from progressive angle-closure caused by the residual stump of iris. b. Aniridia may be found in Brachmann–de Lange syndrome, which may also include conjunctivitis, blepharitis, microcornea, and corectopia. 2. Associated findings are nystagmus, foveal hypoplasia, and cataract. 3. Aniridia is inherited as either autosomal dominant or sporadically. B. Axenfeld’s anomaly and Rieger’s syndrome (see Chapter 8) 1. Anterior segment dysgenesis phenotypes are associated with mutations in genes expressed during neural crest development. Forkhead box C1 (FOXC1) and paired-like homeodomain 2 (PITX2) variants increase the risk of anterior segment dysgenesis phenotypes in humans. 2. Autosomal-dominant inheritance with variable expressivity but high penetrance. 3. Associated with increased IOP and glaucoma in 50% of patients. 4. Associated systemic findings are cardiovascular outflow malformations, craniofacial and dental defects, umbilical abnormalities, and pituitary abnormalities with endocrine sequelae. C. Peters’ anomaly (see Chapter 8, and Chapter 2). Peters’ anomaly and primary congenital glaucoma may share a common molecular pathophysiology. Both of these disorders can be associated with mutation in the cytochrome P4501B1 (CYP1B1) gene (see above). D. Phakomatoses 1. Sturge–Weber syndrome (see Chapter 2) a. Phakomatosis pigmentovascularis (PPV) types IIA and IIB are associated with melanosis bulbi and glaucoma. Ectodermal and mesodermal migration disorders have been postulated to be involved in the pathogenesis of this disorder. PPV IIB is also associated with iris mamillations, Sturge–Weber syndrome, hemifacial, and hemicorporal, or limb hypertrophy without venous insufficiency. 2. Neurofibromatosis (see Chapter 2) a. Ectropion uvea in neurofibromatosis-1 is secondary to endothelialization of the anterior-chamber angle and is associated with severe pediatric glaucoma. E. Lowe’s syndrome (see Chapter 10) F. Pierre Robin syndrome—hypoplasia of the mandible, glossoptosis, cleft palate, and ocular anomalies such as glaucoma, high myopia, cataract, neural retinal detachment, and microphthalmos. G. Rubella (see Chapter 2) H. Marfan’s syndrome (see Chapter 10)

627



I. Homocystinuria (see Chapter 10) J. Microcornea (see Chapter 8) K. Spherophakia (see Chapter 10) 1. Homozygous mutation in the LTBP2 gene is associated with some cases of microspherophakia. Young children with the findings of megalocornea, spherophakia and/or lens dislocation may develop Marfanoid features as they age and may develop elevated IOP. This syndrome is marked by homozygous truncating mutations of LTBP2 gene. L. Chromosomal abnormalities (e.g., trisomy 13; see Chapter 2) M. Persistent fetal vasculature (formerly known as persistent hyperplastic primary vitreous; see Chapter 18) N. Retinopathy of prematurity (see Chapter 18) O. Retinoblastoma (see Chapter 18) P. Juvenile xanthogranuloma (see Chapter 9) Q. Hennekam syndrome, which includes lymphedema, lymphangiectasis, and developmental delay. Other associated findings are dental anomalies, hearing loss, and renal anomalies. R. Nail–patella syndrome is characterized by dysplasia of the nails, patellar aplasia or hypoplasia, iliac horns, dysplasia of the elbows, and frequently glaucoma and progressive nephropathy. The underlying gene involved is LMX1B, which is a LIM-homeodomain transcription factor. The gene is located at 9q34. S. Subtelomeric deletion of chromosome 6p results in a syndrome characterized by ptosis, posterior embryotoxin, optic nerve abnormalities, mild glaucoma, Dandy– Walker malformation, hydrocephalus, atrial septal defect, patent ductus arteriosus, and mild mental retardation. Other associated findings may be hearing loss, hypertelorism, midface hypoplasia, small nose, and high arched palate. This syndrome phenotypically overlaps Ritscher– Schinzel (or craniocerebellocardiac [3C] syndrome). T. Neurofibromatosis type 1 should be excluded in newborns with unilateral congenital glaucoma. U. Subepithelial amyloid deposits, in a recessive form of congenital hereditary endothelial dystrophy, can be associated with congenital glaucoma. IV. Secondary histologic ocular effects in young eyes ( men Third and fourth decades Fairly rapid formation of synechiae and severe glaucoma

Ectropion uveae Glaucoma Hereditary Transmission Laterality Sex Distribution Onset of Symptoms Progression

Histopathology Cornea

Chamber angle

Occasional 13% Present (autosomal-dominant) Bilateral Equal Any age, including congenital Corneal changes often progress to edema and degeneration; iridocorneal adhesions may progress very slowly Thickened, multilayered Descemet’s membrane; endothelial cells resemble epithelial cells (microvilli, desmosomes, cytoplasmic tonofilaments) Corneal endothelium and Descemet’s membrane over trabecular meshwork and iris

Thickened, multilayered Descemet’s membrane; endothelial cells attenuated, reduced in number, and missing in areas

Corneal endothelium and Descemet’s membrane over trabecular meshwork and iris

(Modified from Rodrigues MM, Phelps CD, Krachmer JH et al.: Glaucoma due to endothelialization of the anterior chamber angle: A comparison of posterior polymorphous dystrophy of the cornea and Chandler’s syndrome. Arch Ophthalmol 98:688, 1980. © American Medical Association. All rights reserved.)

angle, and glaucoma. Differences between the entities include the structure of the corneal endothelium (epithelial-like in PPMD), hereditary transmission (positive in PPMD), laterality (bilateral in PPMD), and progression (relatively stable in PPMD).





B. Iris nevus syndrome (Figs. 16.11 and 16.12). 1. The iris nevus syndrome mainly occurs in young women, and is characterized by several of the following signs: peripheral anterior synechiae, often associated with atrophic defects in adjacent iris stroma; matted appearance of iris stroma; a velvety, whorl-like iris surface; loss of iris crypts; fine iris nodules; pupillary eversion (ectropion uveae); heterochromia; secondary glaucoma; and corneal edema at only slightly elevated, or even normal, IOP. 2. Histologically, the two main features are: (1) a diffuse or nodular, or both, nevus of the anterior surface of the iris; and (2) corneal endothelialization of the anterior-chamber angle and anterior surface of the iris. C. Chandler’s syndrome (Fig. 16.13) 1. The condition, probably the most common variant of the ICE syndrome, is unilateral and occurs mainly in young women. The glaucoma is usually mild.

2. Endothelial dystrophy causes corneal edema to d