Ocular Pathology [8 ed.] 0323547559, 9780323547550

Table of contents :
Cover
Ocular Pathology
Copyright Page
Foreword
Forewords to the First Edition
Preface
Acknowledgments
Dedication
1 Basic Principles of Pathology
Inflammation
Definition
Causes
Phases of Inflammation
Staining Patterns of Inflammation
Immunobiology
Background
Cellular Immunity (Delayed Hypersensitivity)
Humoral Immunoglobulin (Antibody)
Autoimmunity and Autoinflammation
Immunohistochemistry
Immunodeficiency Diseases
Transplantation Terminology
Cellular and Tissue Reactions
Hypertrophy
Hyperplasia
Aplasia
Hypoplasia
Metaplasia
Atrophy
Dysplasia
Neoplasia
Degeneration and Dystrophy
Necrosis (Table 1.11)
Apoptosis
Calcification
Autolysis and Putrefaction
Pigmentation
Growth and Aging
Epigenetics and Ocular Disease
Modern Molecular Pathology Diagnostic Techniques
Concluding Comments
Bibliography
Inflammation
Immunobiology
Cellular and Tissue Reactions
Epigenetics and Ocular Disease
Modern Molecular Pathology Diagnostic Techniques
2 Congenital Anomalies
Phakomatoses (Disseminated Hereditary Hamartomas)
General Information
Angiomatosis Retinae (von Hippel’s Disease [VHL])
Meningocutaneous Angiomatosis (Encephalotrigeminal Angiomatosis; Sturge–Weber Syndrome [SWS])
Neurofibromatosis (Figs. 2.3–2.5)
Tuberous Sclerosis (Bourneville’s Disease; Pringle’s Disease)
Other Phakomatoses
Chromosomal Aberrations
Trisomy 8
Trisomy 13 (47,13+; Patau’s Syndrome)
Trisomy 18 (47,18+; Edwards’ Syndrome)
Trisomy 21 (47,21+; Down’s Syndrome)
Triploidy
Chromosome 4 Deletion Defect
Chromosome 5 Deletion Defect (46,5p−; Cri du Chat Syndrome)
Chromosome 11 Deletion Defect
Chromosome 13 Deletion Defect
Chromosome 17 Deletion (17p11.2; Smith–Magenis Syndrome)
Chromosome 18 Deletion Defect (46,18p−; 46,18q−; or 46,18r; Partial 18 Monosomy) (Fig. 2.11)
Chromosome 47 Deletion Defect
Mosaicism
Infectious Embryopathy
Congenital Rubella Syndrome (Gregg’s Syndrome)
Cytomegalic Inclusion Disease
Congenital Syphilis
Toxoplasmosis
Drug Embryopathy
Fetal Alcohol Syndrome (FAS) (Fig. 2.15)
Thalidomide
Lysergic Acid Diethylamide (LSD) (Fig. 2.16)
Other Congenital Anomalies
Cyclopia and Synophthalmos
Anencephaly
Anophthalmos (Fig. 2.18)
Microphthalmos
Noonan Syndrome (NS)
Walker–Warburg Syndrome
Oculocerebrorenal Syndrome of Miller
Subacute Necrotizing Encephalomyelopathy (Leigh’s Disease)
Meckel’s Syndrome (Dysencephalia Splanchnocystica; Gruber’s Syndrome)
Potter’s Syndrome
Menkes’ Kinky-Hair Disease
Aicardi’s Syndrome
Ectrodactyly–Ectodermal Dysplasia (EEC)
Trichothiodystrophy (TD)
Dwarfism
Other Syndromes
Bibliography
Angiomatosis Retinae
Meningocutaneous Angiomatosis
Neurofibromatosis
Tuberous Sclerosis
Other Phakomatoses
Chromosomal Trisomy Defects
Triploidy and Chromosomal Deletion Abnormalities
Mosaicism
Infectious Embryopathy
Drug Embryopathy
Other Congenital Anomalies
3 Nongranulomatous Inflammation
Definition
Classification
Terminology
Sources of Inflammation
Suppurative Endophthalmitis and Panophthalmitis
Clinical Features
Classification
Histology
Examples
Nonsuppurative, Chronic Nongranulomatous Uveitis and Endophthalmitis
Clinical Features
Classification
Examples
Sequelae of Uveitis, Endophthalmitis, and Panophthalmitis
Cornea
Anterior Chamber
Iris
Lens
Ciliary Body
Vitreous Compartment
Choroid
Retina
Glaucoma
End Stage of Diffuse Ocular Diseases
Bibliography
Suppurative Endophthalmitis and Panophthalmitis
Nonsuppurative, Chronic Nongranulomatous Uveitis and Endophthalmitis
Sequelae of Uveitis, Endophthalmitis, and Panophthalmitis
4 Granulomatous Inflammation
Introduction
Post-Traumatic
Sympathetic Uveitis (Sympathetic Ophthalmia [SO], Sympathetic Ophthalmitis)
Phacoanaphylactic (Phacoimmune, Phacoantigenic, or Phacogenic) Endophthalmitis
Foreign-Body Granulomas
Nontraumatic Infections
Viral
Bacterial
Fungal
Parasitic
Nontraumatic Noninfectious
Sarcoidosis (Figs. 4.22–4.27)
Granulomatous Scleritis
Chalazion
Xanthogranulomas (Juvenile Xanthogranuloma and Langerhans’ Granulomatoses; Histiocytosis X)
Granulomatous Reaction to Descemet’s Membrane
Chédiak–Higashi Syndrome
Allergic Granulomatosis and Midline Lethal Granuloma Syndrome
Weber–Christian Disease (Relapsing Febrile Nodular Nonsuppurative Panniculitis)
Vogt–Koyanagi–Harada Syndrome (Uveomeningoencephalitic Syndrome)
Familial Chronic Granulomatous Disease of Childhood
Bibliography
Sympathetic Uveitis
Phacoanaphylactic Endophthalmitis
Foreign-Body Granulomas
Viral
Bacterial
Fungal
Parasitic
Sarcoidosis
Granulomatous Scleritis
Granulomatous Reaction to Descemet’s Membrane
Vogt–Koyanagi–Harada Syndrome
Familial Chronic Granulomatous Disease of Childhood
5 Surgical and Nonsurgical Trauma
Causes of Enucleation
Complications of Intraocular Surgery
Adult Cataract Surgery
Immediate
Postoperative
Congenital Cataract Surgery
Delayed
Complications of Neural Retinal Detachment and Vitreous Surgery Including Intravitreal Injections
Intravitreal Injections
Incisional Vitreoretinal Surgery
Neural Retinal Detachment
Immediate
Postoperative
Delayed
Vitreous Surgery
Complications of Corneal Surgery
Endothelial Transplant Procedures
Introduction
Penetrating Keratoplasty (Graft)
Other Refractive Keratoplasties
Complications of Glaucoma Surgery
Complications of Nonsurgical Trauma
Introduction
Contusion
Penetrating and Perforating Injuries
Intraocular Foreign Bodies
Chemical Injuries
Burns
Ocular Effects of Injuries to Other Parts of the Body
Radiation Injuries (Electromagnetic)
Bibliography
Causes of Enucleation
Complications of Intraocular Surgery
Complications of Retinal Detachment and Vitreous Surgery Including Intraocular Injections
Complications of Corneal Surgery
Complications of Glaucoma Surgery
Complications of Nonsurgical Trauma
6 Skin and Lacrimal Drainage System
Skin
Normal Anatomy (Figs. 6.1 and 6.2)
Epidermis
Dermis
Subcutaneous Tissue
Terminology
Orthokeratosis and Parakeratosis
Acanthosis
Dyskeratosis
Acantholysis
Bulla
Atrophy
Atypical Cell
Leukoplakia
Polarity
Congenital Abnormalities
Dermoid and Epidermoid Cysts
Phakomatous Choristoma
Miscellaneous Choristomas and Hamartomas
Cryptophthalmos (Ablepharon)
Microblepharon
Coloboma
Epicanthus
Ectopic Caruncle
Lid Margin Anomalies
Eyelash Anomalies
Ptosis
Ichthyosis Congenita
Xeroderma Pigmentosum
Aging
Atrophy
Senile Ectropion and Entropion
Dermatochalasis and Blepharochalasis
Herniation of Orbital Fat
Floppy Eyelid Syndrome
Inflammation
Terminology
Viral Diseases
Bacterial Diseases
Fungal and Parasitic Diseases
Lid Manifestations of Systemic Dermatoses or Disease
Ichthyosis Congenita
Xeroderma Pigmentosum
Pemphigus
Ehlers–Danlos Syndrome (“India-Rubber Man”)
Cutis Laxa
Pseudoxanthoma Elasticum
Erythema Multiforme
Epidermolysis Bullosa
Contact Dermatitis
Collagen Diseases
Granulomatous Vasculitis
Vasculitis-Like Disorders and Leukemia/Lymphoma
Xanthelasma
Necrobiotic Xanthogranuloma
Juvenile Xanthogranuloma (JXG)
Amyloidosis
Atrophic Papulosis (Köhlmeier–Degos Disease) (Benign and Malignant)
Calcinosis Cutis
Lipoid Proteinosis (Urbach–Wiethe Disease, Hyalinosis Cutis et Mucosae)
Idiopathic Hemochromatosis
Relapsing Febrile Nodular Nonsuppurative Panniculitis (Weber–Christian Disease)
Pigmentation
Cysts, Pseudoneoplasms, and Neoplasms
Benign Cystic Lesions
Benign Tumors of the Surface Epithelium
Precancerous Tumors of the Surface Epithelium
Cancerous Tumors of the Surface Epithelium
Tumors of the Epidermal Appendages (Adnexal Skin Structures)
Merkel Cell Carcinoma (Neuroendocrine Carcinoma, Trabecular Carcinoma) (Fig. 6.45)
Malacoplakia
Pigmented Tumors
Mesenchymal Tumors
Metastatic Tumors
Lacrimal Drainage System
Normal Anatomy (Fig. 6.46)
Congenital Abnormalities
Atresia of the Nasolacrimal Duct
Atresia of the Punctum
Congenital Fistula of Lacrimal Sac (Minimal Facial Fissure)
Inflammation—Dacryocystitis (Fig. 6.47)
Blockage of Tear Flow Into the Nose
Tumors
Epithelial
Melanotic
Mesenchymal
Miscellaneous
Bibliography
Congenital Abnormalities
Aging
Inflammation
Lid Manifestations of Systemic Dermatoses or Disease
Cysts, Pseudoneoplasms, and Neoplasms
Lacrimal Drainage System
Tumors
7 Conjunctiva
Normal Anatomy
Congenital Anomalies
Cryptophthalmos (Ablepharon)
Epitarsus
Hereditary Hemorrhagic Telangiectasia (Rendu–Osler–Weber Disease)
Ataxia–Telangiectasia (Louis–Bar Syndrome)
Congenital Conjunctival Lymphedema (Milroy’s Disease, Nonne–Milroy–Meige Disease)
Miscellaneous
Dermoids, Epidermoids, and Dermolipomas
Choristomas
Laryngo-Onycho-Cutaneous (LOC or Shabbir) Syndrome
Vascular Disorders
Sickle-Cell Anemia
Conjunctival Hemorrhage (Subconjunctival Hemorrhage)
Lymphangiectasia
Lymphangiectasia Hemorrhagica Conjunctivae
Ataxia–Telangiectasia
Diabetes Mellitus
Hemangioma and Lymphangioma
Inflammation
Basic Histologic Changes
Specific Inflammations
Infectious
Noninfectious
Injuries
Conjunctival Manifestations of Systemic Disease
Deposition of Metabolic Products
Deposition of Drug Derivatives
Vitamin A Deficiency: Bitot’s Spot
Sjögren’s Syndrome
Skin Diseases
Degenerations
Xerosis
Pterygium
Pinguecula
Lipid Deposits
Amyloidosis
Conjunctivochalasis
Cysts, Pseudoneoplasms, and Neoplasms
Choristomas
Hamartomas
Cysts
Pseudocancerous Lesions
Potentially Precancerous Epithelial Lesions
Cancerous Epithelial Lesions
Pigmented Lesions of the Conjunctiva
Stromal Neoplasms
Bibliography
Normal Anatomy
Congenital Anomalies
Vascular Disorders
Inflammation
Conjunctival Manifestations of Systemic Diseases
Degenerations
Cysts, Pseudoneoplasms, and Neoplasms
8 Cornea and Sclera
Cornea
Normal Anatomy
Congenital Defects
Absence of Cornea
Abnormalities of Size
Aberrations of Curvature
Congenital Corneal Opacities
Clinicopathologic Types—General
Clinicopathologic Types—Specific
Inflammations—Nonulcerative
Epithelial Erosions and Keratitis
Subepithelial Keratitis
Superior Limbic Keratoconjunctivitis
Stromal (Interstitial) Keratitis
Endothelial
Inflammations—Ulcerative
Peripheral
Central
Inflammations—Corneal Sequelae
Injuries
Degenerations
Epithelial
Stromal
Endothelial
Dystrophies and Simulating Disorders
Introduction
Classification of Dystrophies
True Corneal Dystrophies (Table 8.5)
Primary in the Corneal
Pigmentations (Table 8.14)
Melanin
Blood
Iron Lines
Kayser–Fleischer Ring
Tattoo
Drug-Induced
Infections
Crystals
Neoplasm
Sclera
Congenital Anomalies
Blue Sclera
Ochronosis (Alkaptonuria)
Inflammations
Episcleritis
Scleritis (Fig. 8.71)
Introduction
Tumors
Fibromas
Nodular Fasciitis
Hemangiomas
Neurofibromas
Contiguous Tumors
Conjunctival Tumors
Episcleral Osseous Choristoma and Episcleral Osseocartilaginous Choristoma
Ectopic Lacrimal Gland
Bibliography
Normal Anatomy
Congenital Defects
Inflammations: Nonulcerative
Inflammations: Ulcerative
Degenerations: Epithelial
Degenerations: Stromal
Dystrophies: Introduction and Classification
Dystrophies: Epithelial-Stromal Including TGFB1 Corneal Dystrophies
Dystrophies: Stromal
Dystrophies: Descemet’s Membrane and Endothelial
Heredofamilial
Nonheredofamial Dystrophy-Like Syndromes
Crystals
Congenital Anomalies
Inflammations
9 Uvea
Normal Anatomy
Congenital and Developmental Defects
Persistent Pupillary Membrane (PPM)
Persistent Tunica Vasculosa Lentis
Heterochromia Iridis and Iridum
Hematopoiesis
Ectopic Intraocular Lacrimal
Gland Tissue
Congenital and Developmental Defects of the Pigment Epithelium
Aniridia (Hypoplasia) of the Iris
Ectropion Uveae (Hyperplasia of Iris Pigment Border or Seam)
Peripheral Dysgenesis of the Cornea and Iris
Coloboma
Cysts of the Iris and Anterior Ciliary Body (Pars Plicata)
Cysts of the Posterior Ciliary Body (Pars Plana)
Inflammations
Injuries
Systemic Diseases
Diabetes Mellitus
Vascular Diseases
Cystinosis
Homocystinuria
Amyloidosis
Juvenile Xanthogranuloma (Nevoxanthoendothelioma)
Langerhans’ Granulomatoses (Histiocytosis X)
Collagen Diseases
Mucopolysaccharidoses
Atrophies and Degenerations
Iris Neovascularization (Rubeosis Iridis)
Choroidal Folds
Heterochromia
Macular Degeneration
Dystrophies
Iris Nevus Syndrome
Chandler’s Syndrome
Essential Iris Atrophy
Iridoschisis
Choroidal Dystrophies
Tumors
Epithelial
Muscular
Vascular
Osseous
Melanomatous
Leukemic and Lymphomatous (See Chapter 14)
Other Tumors
Secondary Neoplasms
Uveal Edema (Uveal Detachment; Uveal Hydrops)
Types
Bibliography
Normal Anatomy
Congenital and Developmental Defects
Systemic Diseases
Atrophies and Degenerations
Dystrophies
Tumors
Uveal Edema
10 Lens
Normal Anatomy
General Information
Congenital Anomalies
Introduction
Mittendorf’s Dot
Congenital Aphakia
Congenital Duplication of Lens
Fleck Cataract
Anterior Polar Cataract
Posterior Polar Cataract
Anterior Lenticonus (Lentiglobus)
Posterior Lenticonus (Lentiglobus)
Other Congenital Cataracts
Capsule (Epithelial Basement Membrane)
General Reactions
Exfoliation of the Lens Capsule
Pseudoexfoliation Syndrome (Pseudoexfoliation of Lens Capsule, Exfoliation Syndrome, Basement Membrane Exfoliation Syndrome, Fibrillopathia Epitheliocapsularis) (Figs. 10.8–10.11)
Epithelium
Proliferation and Migration of Epithelium
Anterior Subcapsular Cataract (ASC) (Figs. 10.12–10.15)
Posterior Subcapsular Cataract (PSC) (Figs. 10.16 and 10.17; see Fig. 10.15)
Elschnig’s Pearls (see Fig. 5.15)
Degeneration and Atrophy of the Epithelium
Cortex and Nucleus (Lens Cells or “Fibers”)
Cortex (“Soft Cataract”)
Nucleus (“Hard Cataract”)
Age-Related (Senile) Cataracts
Secondary Cataracts
Intraocular Disease
Trauma
Toxic
Endocrine, Metabolic, and Others
Complications of Cataracts
Glaucoma
Phacoanaphylactic Endophthalmitis
Ectopic Lens
Congenital
Bibliography
Normal Anatomy
General Information
Congenital Anomalies
Capsule
Epithelium
Cortex and Nucleus
Secondary Cataracts
Complications of Cataracts
Ectopic Lens
11 Neural (Sensory) Retina
Normal Anatomy
Congenital Anomalies
Albinism (Fig. 11.4)
Grouped Pigmentation (Bear Tracks)
Coloboma
Retinal Dysplasia
Lange’s Fold
Congenital Nonattachment of the Retina
Neural Retinal Cysts
Myelinated (Medullated) Nerve Fibers
Oguchi’s Disease
Foveomacular Abnormalities
Leber’s Congenital Amaurosis
Inherited Retinal Arteriolar Tortuosity
Vascular Diseases
Definitions
Retinal Ischemia
Causes
Complications of Retinal Ischemia
Histology of Retinal Ischemia
Retinal Hemorrhagic Infarction (Fig. 11.12)
Causes and Risk Factors of Hemorrhagic Infarction
Types of Hemorrhagic Infarction
Complications of Hemorrhagic Infarction
Histology of Retinal Hemorrhagic Infarction (see Fig. 11.12)
Hypertensive and Arteriolosclerotic Retinopathy
Hemorrhagic Retinopathy
Exudative Retinopathy
Diabetes Mellitus
Coats’ Disease, Leber’s Miliary Aneurysms, and Retinal Telangiectasia
Idiopathic Macular Telangiectasia (Idiopathic Juxtafoveolar Retinal Telangiectasis)
Retinal Arterial and Arteriolar Macroaneurysms
Sickle-Cell Disease
Eales’ Disease (Primary Perivasculitis of the Retina)
Retinopathy of Prematurity
Hemangioma of the Retina
Hereditary Hemorrhagic Telangiectasia (Rendu–Osler–Weber Disease)
Disseminated Intravascular Coagulation
Inflammations
Nonspecific Retinal Inflammations
Specific Retinal Inflammations (see Chapters 2–4)
Injuries
Degenerations
Definitions
Microcystoid Degeneration
Degenerative Retinoschisis
Secondary Microcystoid Degeneration and Retinoschisis
Paving Stone (Cobblestone) Degeneration (Peripheral Chorioretinal Atrophy; Equatorial Choroiditis)
Peripheral Retinal Albinotic Spots
Myopic Retinopathy
Macular Degeneration
Idiopathic Serous Detachment of the RPE (Fig. 11.25)
Idiopathic Central Serous Choroidopathy (Central Serous Retinopathy; Central Angiospastic Retinopathy) (see Fig. 11.25)
Drusen
Dry Age-Related Macular Degeneration (Dry, Atrophic, or Senile Atrophic Macular Degeneration)
Age-Related Exudative Macular Degeneration (Exudative, Wet, or Senile Disciform Macular Degeneration; Kuhnt–Junius Macular Degeneration)
Congenital Hypotrichosis With Juvenile Macular Degeneration (CHWJMD)
Exudative Macular Degeneration Secondary to Focal Choroiditis (Juvenile Disciform Degeneration of the Macula)
Idiopathic Polypoidal Choroidal Vasculopathy
Cystoid Macular Edema (Irvine–Gass Syndrome)
Toxic Retinal Degenerations
Postirradiation Retinopathy
Bone Marrow Transplant Retinopathy
Cancer-Associated Retinopathy (Paraneoplastic Syndrome; Paraneoplastic Retinopathy; Paraneoplastic Photoreceptor Retinopathy; Melanoma-Associated Retinopathy)
Idiopathic Macular Holes
Light Energy Retinopathy
Traumatic Retinopathy
Hereditary Primary Retinal Dystrophies
Definitions
X-Linked Retinoschisis (Juvenile Retinoschisis, Vitreous Veils; Congenital Vascular Veils; Cystic Disease of the Retina; Congenital Retinal Detachment)
Choroidal Dystrophies
Stargardt’s Disease (Fundus Flavimaculatus)
Dominant Drusen of Bruch’s Membrane (Doyne’s Honeycomb Dystrophy; Malattia Lèventinese; Hutchinson–Tay Choroiditis; Guttate Choroiditis; Holthouse–Batten Superficial Choroiditis; Family Choroiditis; Crystalline Retinal Degeneration; Iridescent Crystals of the Macula; Hyaline Dystrophies)
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)
Dominant Progressive Foveal Dystrophy
Dominant Cystoid Macular Dystrophy (DCMD)
Fenestrated Sheen Macular Dystrophy
North Carolina Macular Dystrophy
Familial Internal Limiting Membrane Dystrophy
Central Pigmentary Sheen Dystrophy
Cone–Rod Dystrophy
Annular Macular Dystrophy (Benign Concentric Annular Macular Dystrophy)
Retinitis Punctata Albescens (Albipunctate Dystrophy; Fundus Albipunctatus; Panretinal Degeneration)
Central Retinitis Pigmentosa (Central Retinopathia Pigmentosa; Retinopathia Pigmentosa Inversa; Retinitis Pigmentosa Inversa; Pericentral Pigmentary Retinopathy)
Retinitis Pigmentosa (Retinopathia Pigmentosa; Pigmentary Degeneration of the Retina)
Clumped Pigmentary Retinal Dystrophy (Clumped Pigmentary Retinal Degeneration)
Hereditary Pigmented Paravenous Chorioretinal Atrophy
Pigment Epithelial Dystrophy
Central Areolar Pigment Epithelial Dystrophy
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)
Bietti’s Crystalline Dystrophy (Bietti’s Tapetoretinal Degeneration With Marginal Corneal Dystrophy, Crystalline Retinopathy)
Sorsby Fundus Dystrophy (Sorsby’s Pseudoinflammatory Macular Dystrophy; Hereditary Macular Dystrophy)
Autosomal-Dominant Occult Macular Dystrophy
Unilateral Retinal Pigment Epithelial Dysgenesis (URPED)
Recessive Retinopathy Consequent on Mutant G-Protein β Subunit 3 (GNB3)
Martinique Crinkled Retinal Pigment Epitheliopathy (MCRPE)
Hereditary Secondary Retinal Dystrophies
Angioid Streaks
Sjögren–Larsson Syndrome (S-LS)
Mucopolysaccharidoses
Mucolipidoses
Sphingolipidoses
Other Lipidoses
Disorders of Carbohydrate Metabolism
Primary Hyperoxaluria (Primary Oxalosis; Fig. 11.43)
Osteopetrosis
Homocystinuria
Systemic Diseases Involving the Retina
Hereditary Secondary Retinal Dystrophies
Diabetes Mellitus
Hypertension and Arteriolosclerosis
Collagen Diseases
Blood Dyscrasias
Demyelinating Diseases
Tumors
Glia
Phakomatoses
Retinal Pigment Epithelium
Retinoblastoma and Pseudogliomas
Neural Retinal Metastases (Fig. 11.49)
Neural Retinal Detachment
Definitions
Major Causes
Classification of Neural Retinal Detachment
Predisposing Factors to Neural Retinal Detachment
Pathologic Changes After Neural Retinal Detachment
Pathologic Complications After Neural Retinal Detachment Surgery
Bibliography
Normal Anatomy
Congenital Anomalies
Vascular Disease
Inflammation
Degenerations
Hereditary Primary Retinal Dystrophies
Hereditary Secondary Retinal Dystrophies
Systemic Diseases Involving the Retina
Tumors
Retinal Detachment
12 Vitreous
Normal Anatomy
Congenital Anomalies
Persistent Primary Vitreous
Persistent Fetal Vasculature (PFV; Persistent Hyperplastic Primary Vitreous [PHPV])
Inflammation
Acute
Chronic
Vitreous Adhesions
Post Nonsurgical and Surgical Trauma
Postinflammation
Idiopathic
Vitreous Opacities
Hyaloid Vessel Remnants
Acquired Vitreous Strands and Floaters
Inflammatory Cells
Red Blood Cells
Iridescent Particles
Tumor Cells
Pigment Dust
Cysts
Retinal Fragments
Traumatic Avulsion of Vitreous Base
Vitreous Detachment
Proteinaceous Deposits
Amyloid
Familial Exudative Vitreoretinopathy (FEVR)
Autosomal-Dominant Vitreoretinochoroidopathy (ADVIRC; Peripheral Annular Pigmentary Dystrophy of the Retina)
Autosomal-Dominant Neovascular Inflammatory Vitreoretinopathy (ADNIV)
Erosive Vitreoretinopathy
Knobloch Syndrome
Vitreous Hemorrhage
Definitions
Causes
Complications
Bibliography
Normal Anatomy
Congenital Anomalies
Vitreous Adhesions
Vitreous Opacities
Vitreous Hemorrhage
13 Optic Nerve
Normal Anatomy
Congenital Defects and Anatomic Variations
Aplasia
Hypoplasia
Dysplasia
Anomalous Shape of Optic Disc and Cup
Congenital Crescent or Conus
Congenital (Familial) Optic Atrophies
Coloboma (Table 13.1)
Myopia
Optic Disc Edema
General Information (Fig. 13.7; see Fig. 13.22)
Causes
Pseudopapilledema
Histology of Optic Disc Edema
Optic Neuritis
Causes
Histology of Optic Neuritis
Optic Atrophy
Causes
Histology of Optic Atrophy
Injuries
Tumors
Primary
Secondary
Bibliography
Normal Anatomy
Congenital Defects and Anatomic Variations
Optic Disc Edema
Optic Neuritis
Optic Atrophy
Tumors
14 Orbit
Normal Anatomy
Exophthalmos
Developmental Abnormalities
Developmental Abnormalities of Bony Orbit
Microphthalmos With Cyst
Cephaloceles
Congenital Alacrima
Orbital Inflammation
Acute
Chronic
Injuries
Penetrating Wounds
Nonpenetrating Wounds
Vascular Disease
Primary
Part of Systemic Disease
Ocular Muscle Involvement in Systemic Disease
Graves’ Disease (Fig. 14.10)
Myasthenia Gravis (MG)
Myotonic Dystrophy (Myotonia Dystrophica; Steinert’s Disease)
Myotonia Congenita (Thomsen’s Disease)
Mitochondrial Myopathies
Dermatomyositis
Neoplasms and Other Tumors
Primary Orbital Tumors
Secondary Orbital Tumors
Bibliography
Normal Anatomy
Exophthalmos
Developmental Abnormalities
Orbital Inflammation
Injuries
Vascular Disease
Ocular Muscle Involvement in Systemic Disease
Tumors: Choristoma
Tumors: Hamartomas
Tumors: Mesenchymal–Vascular
Tumors: Mesenchymal–Fatty
Tumors: Mesenchymal–Fibrous–Histiocytic
Tumors: Mesenchymal–Muscle
Tumors: Mesenchymal–Cartilage
Tumors: Mesenchymal–Bone
Tumors: Neural
Tumors: Miscellaneous
Tumors: Epithelial of Lacrimal Gland
Tumors: Reticuloendothelial System
Tumors: Inflammatory Pseudotumor
Tumors: Malignant Lymphoma
Tumors Leukemia
Tumors: Monoclonal and Polyclonal Gammopathies
Secondary Tumors
15 Diabetes Mellitus
Natural History
Ocular Surface Disease
Intraocular Changes
Lens
Iris
Ciliary Body and Choroid
Retinal Vasculature in Normal Subjects and Diabetic Patients
Neural Retina
Vitreous
Optic Nerve
Bibliography
Natural History
Ocular Surface Disease
Lens
Ciliary Body and Choroid
Retina
Vitreous
Optic Nerve
16 Glaucoma
Normal Anatomy (Figs. 16.1–16.3)
Introduction
Normal Outflow
Hypersecretion
Impaired Outflow
Congenital Glaucoma (Table 16.3)
Primary Glaucoma (Closed- and Open-Angle)
Secondary Angle-Closure Glaucoma
Causes
Secondary Open-Angle Glaucoma
Tissue Changes Caused by Elevated Intraocular Pressure
Cornea (Figs. 16.26–16.28; See Also Fig. 8.49A,B)
Anterior-Chamber Angle
Iris
Ciliary Body
Lens
Sclera
Neural Retina (Fig. 16.31)
Optic Nerve
Bibliography
Normal Anatomy
Introduction
Impaired Outflow: Congenital Glaucoma
Impaired Outflow: Primary Closed-Angle
Impaired Outflow: Primary Open-Angle
Impaired Outflow: Secondary Closed-Angle
Impaired Outflow-Secondary Open-Angle
Tissue Changes Caused by Elevated Intraocular Pressure
17 Ocular Melanocytic Tumors
Normal Anatomy
Ocular Melanocytes
Melanotic Tumors of Eyelids
Ephelis (Freckle)
Lentigo
Nevus
Malignant Melanoma
Melanotic Tumors of Conjunctiva
Ephelis (Freckle)
Lentigo
Nevus
Primary Acquired Melanosis (PAM; Figs. 17.15 and 17.16; see also Table 17.2)
Primary Malignant Melanoma of Conjunctiva (Fig. 17.17; see also Fig. 17.16)
Lesions That May Simulate Primary Conjunctival Nevus or Malignant Melanoma
Melanotic Tumors of Pigment Epithelium of Iris, Ciliary Body, and Retina
Reactive Tumors
Nonreactive Tumors
Acquired Neoplasms
Melanotic Tumors of the Uvea
Iris
Ciliary Body and Choroid
Melanotic Tumors of the Optic Disc and Optic Nerve
Melanocytoma (Magnocellular Nevus of the Nerve Head)
Malignant Melanoma
Melanotic Tumors of the Orbit
Bibliography
Melanocytic Tumors of the Eyelids
Melanocytic Tumors of Conjunctiva
Melanocytic Tumors of Pigment Epithelium of Iris, Ciliary Body, and Retina
Melanocytic Tumors of the Uvea: Iris
Melanocytic Tumors of the Uvea: Ciliary Body and Choroid
Melanocytic Tumors of the Orbit
18 Retinoblastoma and Simulating Lesions
Retinoblastoma
General Information
Heredity
Clinical Features
Histology
Prognosis
Overview
Lesions Simulating Retinoblastoma (Pseudoglioma)
General Information
Leukokoria (Box 18.1)
Discrete Retinal or Chorioretinal Lesions
Bibliography
Retinoblastoma—General Information
Retinoblastoma—Heredity
Retinoblastoma—Clinical Features
Retinoblastoma—Histology
Retinoblastoma—Prognosis
Lesions Simulating Retinoblastoma (Pseudoglioma)—General Information
Lesions Simulating Retinoblastoma (Pseudoglioma)—Leukokoria: Introduction
Lesions Simulating Retinoblastoma (Pseudoglioma)—Leukokoria: Persistent Fetal Vasculature
Lesions Simulating Retinoblastoma (Pseudoglioma)—Leukokoria: Retinal Dysplasia
Lesions Simulating Retinoblastoma (Pseudoglioma)—Leukokoria: Retinopathy of Prematurity
Lesions Simulating Retinoblastoma (Pseudoglioma)—Leukokoria: Coats’ Disease
Lesions Simulating Retinoblastoma (Pseudoglioma)—Leukokoria: Incontinentia Pigmenti
Lesions Simulating Retinoblastoma (Pseudoglioma)—Leukokoria: Other Causes
Index
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
R
S
T
U
V
W
X
Z

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.

vi

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

viii

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.)

22

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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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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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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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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187

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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189

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

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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.

Lid Manifestations of Systemic Dermatoses or Disease

















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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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).

Cysts, Pseudoneoplasms, and Neoplasms

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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CHAPTER 6  Skin and Lacrimal Drainage System

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,

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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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CHAPTER 6  Skin and Lacrimal Drainage System

(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

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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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A

CHAPTER 6  Skin and Lacrimal Drainage System

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

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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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CHAPTER 6  Skin and Lacrimal Drainage System

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

225



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

229

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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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).

233

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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CHAPTER 6  Skin and Lacrimal Drainage System

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

235

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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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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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

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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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CHAPTER 7  Conjunctiva

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

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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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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

313

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CHAPTER 8  Cornea and Sclera

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

316

CHAPTER 8  Cornea and Sclera

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

317

Dystrophies and Simulating Disorders



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

320

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



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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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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.)



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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.













329

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.)

333

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

335

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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).

337

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.)

338











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.

339

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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CHAPTER 8  Cornea and Sclera

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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CHAPTER 8  Cornea and Sclera

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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CHAPTER 8  Cornea and Sclera

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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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

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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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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.

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Evans CJ, Davidson AE, Carnt N, et al: Genotype-phenotype correlation for TGFBI corneal dystrophies identifies p.(G623D) as a novel cause of epithelial basement membrane dystrophy, Invest Ophthalmol Vis Sci 57:5407–5414, 2016. Han KE, Choi SI, Kim TI, et al: Pathogenesis and treatments of TGFBI corneal dystrophies, Prog Retin Eye Res 50:67–88, 2016. Hassan H, Thaung C, Ebenezer ND, et al: Severe Meesmann’s epithelial corneal dystrophy phenotype due to a missense mutation in the helix-initiation motif of keratin 12, Eye (Lond) 27:367–373, 2013. He J, Bazan HE: Corneal nerve architecture in a donor with unilateral epithelial basement membrane dystrophy, Ophthalmic Res 49:185–191, 2013. Kaza H, Barik MR, Reddy MM, et al: Gelatinous drop-like corneal dystrophy: a review, Br J Ophthalmol 101:10–15, 2017. Kojima Y, Inoue T, Hori Y, et al: Unilateral variant of late-onset lattice corneal dystrophy with the pro501thr mutation in the TGFBI gene without deposits in the unaffected cornea using confocal microscopy, Cornea 32:1396–1398, 2013. Lakshminarayanan R, Chaurasia SS, Murugan E, et al: Biochemical properties and aggregation propensity of transforming growth factor-induced protein (TGFBIp) and the amyloid forming mutants, Ocul Surf 13:9–25, 2015. Magalhaes Ode A, Rymer S, Marinho DR, et al: Optical coherence tomography image in gelatinous drop-like corneal dystrophy: case report, Arq Bras Oftalmol 75:356–357, 2012. Morantes S, Evans CJ, Valencia AV, et al: Spectrum of clinical signs and genetic characterization of gelatinous drop-like corneal dystrophy in a Colombian family, Cornea 35:1141–1146, 2016. Ogasawara M, Matsumoto Y, Hayashi T, et al: KRT12 mutations and in vivo confocal microscopy in two Japanese families with Meesmann corneal dystrophy, Am J Ophthalmol 157:93–102, e101, 2014. Oliver VF, van Bysterveldt KA, Cadzow M, et al: A COL17a1 splice-altering mutation is prevalent in inherited recurrent corneal erosions, Ophthalmology 123:709–722, 2016. Pole C, Sise A, Joag M, et al: High-resolution optical coherence tomography findings of Lisch epithelial corneal dystrophy, Cornea 35:392–394, 2016. Shukla AN, Cruzat A, Hamrah P: Confocal microscopy of corneal dystrophies, Semin Ophthalmol 27:107–116, 2012. Suri K, Kosker M, Duman F, et al: Demographic patterns and treatment outcomes of patients with recurrent corneal erosions related to trauma and epithelial and bowman layer disorders, Am J Ophthalmol 156:1082–1087, e1082, 2013. Tsujikawa M: Gelatinous drop-like corneal dystrophy, Cornea 31(Suppl 1):S37–S40, 2012. Vincent AL, Markie DM, De Karolyi B, et al: Exclusion of known corneal dystrophy genes in an autosomal dominant pedigree of a unique anterior membrane corneal dystrophy, Mol Vis 15:1700–1708, 2009. Vincent AL, Markie DM, de Karolyi B, et al: Exclusion of known corneal dystrophy genes in an autosomal dominant pedigree of a unique anterior membrane corneal dystrophy, Mol Vis 15:1700–1708, 2009.

Dystrophies: Stromal Acar BT, Bozkurt KT, Duman E, et al: Bilateral cloudy cornea: is the usual suspect congenital hereditary endothelial dystrophy or stromal dystrophy? BMJ Case Rep 2016:2016. Aldave AJ, Rosenwasser GO, Yellore VS, et al: Linkage of posterior amorphous corneal dystrophy to chromosome 12q21.33 and

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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.

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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.

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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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v r

s B

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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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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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B

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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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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

369

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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CHAPTER 9  Uvea

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

570

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.

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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.

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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