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Primary references, normal anatomy, autopsy findings, trisomy 13, trisomy 21, congenital rubella syndrome
Conjunctiva
Grossing, normal anatomy/histology, acquired melanosis, actinic keratosis, ataxia-telangiectasia, carcinoma in situ, cysts, dermoid tumor, dysplasia, ephelis, graft versus host disease, inflammatory disorders, lymphoid hyperplasia, lymphoma, malignant fibrous histiocytoma, melanoma, mucoepidermoid carcinoma, myxoma, nevi, ocular cicatricial pemphigoid, papilloma, pinguecula, pterygium, sarcoidosis, spindle cell carcinoma, squamous cell carcinoma, trachoma
Miscellaneous: tumor features to report, TNM staging for carcinoma, TNM staging for melanoma
Cornea
Normal anatomy/histology, grossing, acanthamoeba, actinic band keratopathy, aphakic bullous keratopathy, blood staining, bullous keratopathy, calcific band keratopathy, chronic active keratopathy, corneal dystrophy, epithelial ingrowth, Fuchs dystrophy, graft failure, herpes simplex keratitis, infectious keratitis, keratoconus, keratomalacia, limbus, nonspecific responses, pannus, pseudoexfoliation syndrome, rheumatoid arthritis, transplant, ulceration, tumor features to report
Eyelid
Inflammatory disorders: chalazion, mites, molluscum contagiosum, necrobiotic xanthogranuloma, Prototheca, pseudorheumatoid nodules, pyogenic granuloma, silica granuloma, stye
Tumors: general
Adnexal tumors: adenocarcinoma, sebaceous gland adenoma, sebaceous gland carcinoma, sweat gland carcinoma, syringoma, trichilemmal cell tumor, trichilemmoma, trichoepithelioma, trichofolliculoma
Melanocytic tumors: melanoma, melanosis oculi, nevi, nevus of Ota
Other tumors: actinic keratosis, amyloidosis, basal cell carcinoma, cysts, dermoid cyst, hemangioma, Kaposi sarcoma, keratoacanthoma, Merkel cell carcinoma, metastases to eyelid, myxoma, neurofibroma, pilomatricoma, port wine stain, seborrheic keratosis, squamous papilloma, squamous cell carcinoma, xanthelasma
Miscellaneous: tumor features to report, TNM staging for carcinoma
Glaucoma
General, congenital glaucoma, primary glaucoma, secondary glaucoma, degenerative changes
Globe
General, grossing, inflammation, lymphoma, metastases, phthisis bulbi, Sturge-Weber syndrome, trauma
Lacrimal duct/gland
General, adenoid cystic carcinoma, dacryoadenitis, dacrocystitis/canaliculitis, dacryoliathiasis, malignant mixed tumor, melanoma, Mikulicz’s disease, mucocele, oncocytoma, papilloma, pleomorphic adenoma, squamous cell carcinoma, TNM staging for carcinoma of lacrimal gland
Lens and vitreous humor
General, Alport’s syndrome, cataract, dislocation, persistent hyperplastic primary vitreous, phacoanaphylactic endophthalmitis, prosthetic intraocular lens, pseudoexfoliation, vitreous pathology
Orbit and optic nerve
General, alveolar soft parts sarcoma, anterior ischemic optic neuropathy, coloboma, dermoid cyst, drusen, dysthyroid ophthalmopathy, fibrous histiocytoma, giant cell angiofibroma, glioma of optic nerve, granulocytic sarcoma, hemangioblastoma, hemangioma, hemangiopericytoma, idiopathic sclerosing inflammation, inflammatory processes, inflammatory pseudotumor, lymphangioma, lymphoma, meningioma, metastases to orbit, mucocele, neurofibroma, optic atrophy, papilledema, rhabdomyosarcoma, Schnabel cavernous degeneration of optic nerve, schwannoma, shaken baby syndrome, solitary fibrous tumor, temporal arteritis, Wegener’s granulomatosis, TNM staging for sarcoma of orbit
Retina
General, adenocarcinoma, astrocytic tumor, Behcet’s disease, central retinal artery occlusion, central retinal vein occlusion, CMV, Coats’ disease, cystic macular edema, detachment, diabetes, hemangioblastoma, hypertension, lattice degeneration, macular degeneration, massive retinal gliosis, pleomorphic xanthoastrocytoma, retinal dysplasia, retinitis pigmentosa, retinoblastoma, retrolental fibroplasia, sickle cell retinopathy, toxoplasmosis, tuberous sclerosis, visceral larva migrans, von Hippel-Lindau disease, Wyburn-Mason syndrome
Miscellaneous: tumor features to report-retinoblastoma, TNM for retinoblastoma
Uvea (iris, choroid and ciliary body), limbus and sclera
Choroid-general, ciliary body-general, iris-general, sclera-general, adenoma of pigmented ciliary epithelium, aniridia, anterior chamber cleavage syndrome, blue sclera, coloboma, diffuse uveal melanocytic proliferation, Fuchs’ adenoma, herpes zoster, hypertensive changes, idiopathic solitary granuloma, iris pigment epithelial cyst, juvenile xanthogranuloma, leiomyoma, Lisch nodules, medulloepithelioma, melanoma, mesenchymoma, nevi, post-traumatic uveitis, rubeosis iridis, sarcoidosis, scleritis, senile scleral plaques, sympathetic uveitis, uveitis
Miscellaneous: tumor features to report, TNM for uveal melanoma
AJCC Cancer Staging Manual (6th Ed)
American Journal of Surgical Pathology (AJSP), March 1977 to December 2004
Archives of Pathology and Laboratory Medicine (Archives), January 1976 to December 2004
Human Pathology (Hum Path), March 1970 to October 2004
Modern Pathology (Mod Path), January 1988 to December 2004
Rosai, J: Ackerman’s Surgical Pathology (9th Ed); 2004
Sternberg, S: Diagnostic Surgical Pathology (4th Ed); Lippincott Williams & Wilkins, 2004
Sternberg, S: Histology for Pathologists (2nd Ed); Lippincott Williams & Wilkins, 1997
Robbins and Cotran: Pathologic Basis of Disease (7th Ed); Elsevier, Inc., 2004
Journal search terms: eye, conjunctiva, choroid, ciliary body, cornea, eyelid, globe, iris, lacrimal, lens, orbit, retina, uvea, vitreous
Please refer to these primary references for more detailed discussions and photographs
Anterior chamber: between iris and cornea; contains Schlemm’s canal and trabecular meshwork
Bruch’s membrane: see uvea (choroid)
Canaliculi: see lacrimal duct/gland
Caruncle: see conjunctiva
Choriocapillaris: see uvea (choroid)
Choroid: see below
Ciliary body: see below
Conjunctiva: see below
Cornea: see below
Episclera: see sclera
Eyelid: see below
Fornix: see conjunctiva
Fovea centralis: see retina
Globe: eyeball itself plus intraocular tissues
Intraocular tissues: uveal tract (iris, choroid and ciliary body), retina, lens and vitreous
Iris: see below
Lacrimal gland: see below
Lacrimal sac: see lacrimal duct/gland
Lamina cribrosa: see orbit and optic nerve
Lens: see below
Limbus: see below
Macula: see retina
Macula lutea: see retina
Nasolacrimal duct: see lacrimal duct/gland
Optic nerve: see below
Orbit: see below
Palpebral fissure: longitudinal opening between the upper and lower eyelids
Pars plicata: see uvea (ciliary body)
Plica semilunaris: see conjunctiva
Posterior chamber: between lens and iris
Puncta: see lacrimal duct/gland
Pupil: see uvea (iris)
Retina: see below
Schlemm’s canal: see uvea (limbus)
Sclera: see below
Trabecular meshwork: see uvea (limbus)
Trochlea: see orbit and optic nerve
Uvea: see below
Vitreous humor: see below
Zonule: see uvea (ciliary body)
Most common findings are diabetic retinopathy (14%), age related macular degeneration (5%), melanoma of uvea or choroid, metastatic carcinoma
Rare findings are retinitis pigmentosa
References: Archives 2001;125:1193
Almost all patients have severe ocular abnormalities
80% have microphthalmos (abnormally small eyes), cyclopean synophthalmus (fused eyes), colobomas (defective formation of iris and ciliary body), cataracts or persistent hyperplastic primary vitreous
75% have retinal dysplasia (tubular and rosette-like structures)
65% have cartilage within coloboma
60% have anterior chamber dysgenesis (defective development of cornea, iris or anterior chamber angle), often associated with congenital glaucoma
Less severe than trisomy 13
Hypertelorism (wide spaced eyes), lid abnormalities (oblique, arched palpebral fissures), epicanthus (vertical fold of skin on either side of nose), ectropion and eversion of upper eyelid
Also keratoconus (may be due to knuckle rubbing) and retinal dysplasia
Iris is speckled due to Brushfield spots (ringlike foci of iris hypoplasia surrounded by normal stroma)
Cataracts develop at age 15+ years
Also esotropia, myopia, hyperemic optic disc, retinal pigment epithelial atrophy, prominent whitened choroidal vessels, chronic blepharoconjunctivitis
Associated with cataracts, iris abnormalities, retinopathy, congenital glaucoma, microphthalmos
Cataracts are due to retention of cell nucleus in lens cells
Rubella virus can survive within these cells for years; surgery on these infants may cause uveitis or endophthalmitis, due to release of virus
Iris abnormalities include poorly developed dilator muscle and necrotic-appearing epithelium; granulomatous inflammation is common; iris looks leathery since it doesn't dilate normally
Rubella retinopathy consists of alternating atrophy and hypertrophy of retinal pigment epithelium (salt and pepper appearance); may have subretinal neovascularization
Conjunctiva
Specimens are thin, tend to fold when placed in fixative
Surgeon should spread lesion onto filter paper, allow to dry for a few seconds, then place in specimen container
Relevant landmarks should be labeled
Don’t place specimens on sponges, which expand in fixative and distort specimen
Normal anatomy/histology of conjunctiva
Thin mucous membrane lining inner eyelid (tarsal or palpebral portion) and anterior surface of ocular globe (bulbar portion)
Has 2-5 layers of columnar cells resting on continuous basal lamina
Contains goblet cells and melanocytes
Has rich lymphatic channels connecting to parotid and submandibular nodes
Has protective function and also allows eyelids to move smoothly over globe
Bulbar conjunctiva: portion covering anterior surface of sclera and surface epithelium of cornea; nonkeratinizing squamous epithelium; goblet cells more common in inferior and nasal parts, particularly near fornix
Caruncle: small fleshy nodular prominence in nasal portion of interpalpebral fissure (inner angle of eye); lined by conjunctival epithelium and containing cutaneous adnexal structures
Fornix: portion of conjunctiva covering cornea; pseudostratified columnar epithelium rich in goblet cells; contains accessory lacrimal tissue, ductules of main lacrimal gland and lymphoid follicles; site of sarcoid granulomas
Palpebral (tarsal) conjunctiva: lines interior of eyelid; becomes papillary with allergic or bacterial conjunctivitis
Plica semilunaris (semilunar fold): arc shaped fold of conjunctiva just lateral to caruncle; may be a vestigial nictitating membrane of lower species; contains abundant goblet cells and rarely cartilage
Regional lymph nodes: preauricular (parotid), submandibular and cervical
Positive stains: CK19
Negative stains: CK3
References: Hum Path 1997;28:1348 (cytokeratin)
Acquired melanosis of conjunctiva
Also called primary acquired melanosis, melanoma in situ
Unilateral, melanocytic proliferative lesion of conjunctiva
Usually ages 40+ years, whites
May be associated with Addison’s disease
Cases without atypia don’t progress to melanoma; 46% with atypia do progress to melanoma; 90% progress to melanoma if nests or pagetoid spread of atypical cells; however disease is variable within same conjunctiva (Hum Path 1985;16:129)
Treatment: excision or cryotherapy
Gross: diffuse granular conjunctival pigmentation, usually of bulbar conjunctiva, also cornea, palpebral conjunctiva, eyelid skin
Micro: increase in basal melanocytes with variable atypia
References: Mod Path 1991;4:253 (“all these cases are melanoma in situ”)
Actinic keratosis of conjunctiva
Gross: thickened conjunctiva with leukoplakia
Micro: mild atypia of epithelium, variable degenerative changes in substantia propria; normal polarity, normal maturation
A phakoma with telangiectatic blood vessels in conjunctiva
Carcinoma in situ of conjunctiva
May present as complication of pterygium or pinguecula
Also called conjunctival intraepithelial neoplasia
Due to solar radiation or other irritation
Treatment: cryotherapy or topical chemotherapy is preferable to surgery to preserve goblet cells and lacrimal gland ductules and prevent a painful dry eye that may compromise vision
Gross: leukoplakia or fleshy mass with increased vascularity
Micro: full thickness changes including loss of epithelial polarity, cytologic atypia, pleomorphism and mitotic figures; no extension of atypical cells beyond basal lamina of conjunctival epithelium; resembles dysplastic changes in cervix, Bowen’s disease or Paget’s disease of skin
DD: dysplasia
Dermoid cysts: lined by stratified squamous epithelium and containing cutaneous adnexae
Inclusion cysts: one or two cell lining of non-keratinized epithelium containing goblet cells; usually post-traumatic
A type of choristoma, often at limbus
May be associated with colobomas of iris and ciliary body, Goldenhar syndrome (ocular dermoid tumors, extra-auricular appendages, vertebral anomalies) or organoid nevus syndrome (also called linear nevus sebaceous of Jadassohn, Solomon syndrome)
Gross: bulbar tumors are firm, localized, elevated, opaque masses at limbus, near cornea
Micro: solid choristoma mass (different from orbital dermoid cyst) with surface epithelium resembling epidermis and dermis and containing a few hairs overlying thick bundles of collagen, which make up bulk of mass
Dermolipomas: abundant adipose tissue but minimal skin adnexae, usually in upper outer fornix
Complex choristoma: cartilage, lacrimal tissue, smooth muscle, adipose tissue, neural tissue
Lesions intermediate between papilloma and carcinoma in situ
Also called conjunctival intraepithelial neoplasia
Associated with HPV 16
Ephelis or freckle of conjunctiva
Congenital pigmentation, does not evolve into melanoma
Graft versus host disease of conjunctiva
Keratinization may be present after bone marrow transplant
Also changes in cornea, choroid and lacrimal gland
Inflammatory disorders of conjunctiva
Usually not biopsied
Associated with reduction in goblet cells, causing reduction in surface mucin, so aqueous portion of tears does not adhere to corneal epithelium, leading to dry eye and corneal ulceration
Chronic conjunctivitis: numerous goblet cells and papillary folds; isolated islands of epithelium may form retention cysts that calcify; late changes are epithelial atrophy, keratinization and stromal scarring; note that lymphocytes are common within normal conjunctiva
Granulomatous conjunctivitis: with necrosis - tuberculosis, cat-scratch fever, tularemia; without necrosis - syphilis, foreign bodies, sarcoidosis; other - fungi, acid-fast bacilli
Ligneous conjunctivitis: “ligneous” means resembling wood; chronic pseudomembranous conjunctivitis with woody induration of eyelid and tarsal conjunctiva and pseudomembrane on tarsal conjunctiva; membrane contains large hyaline masses containing fibrin and immunoglobulin but resembling amyloid; due to mutations in plasminogen PLG gene at 6q26; pseudomembrane recurs after excision
Liesegang rings: rings of precipitated iron and calcium in conjunctiva and eyelid, associated with inflammation, necrosis, fibrosis or cysts (AJSP 1987;11:598)
Pseudomembranous conjunctivitis: rare, due to Streptococcus, Klebsiella, Chlamydia, adenovirus, toxic epidermal necrolysis, graft versus host disease, plasminogen mutation (see ligneous conjunctivitis above); case report with graft versus host disease (Hum Path 1996;27:307)
Sjogren’s syndrome: epithelial metaplasia with decreased goblet cells and polymorphic stromal infiltrate (in cornea); see also Mikulicz’s disease
Lymphoid hyperplasia of conjunctiva
Well differentiated, somewhat pleomorphic lymphocytes with occasional plasma cells, macrophages, eosinophils and follicles with germinal centers
Follicles usually contain tingible body macrophages (containing apoptotic debris) and mitotic activity
Often hyperplastic vessels
Usually indolent MALT lymphomas, may be preceded by apparent reactive lymphoid hyperplasia
Difficult to predict malignant potential; often remains an isolated lesion
Diagnosis: fresh tissue for flow cytometry or gene rearrangement studies, immunohistochemistry (light chain restriction)
Gross: salmon colored mass or masses
Micro: typical for MALT lymphoma with well differentiated, monoclonal small B lymphocytes
Molecular: MALT may have t(14;18)(q32;q21) involving IgH and MALT1 genes; B cell clonality in 55% of MALT and 60% of diffuse large B cell lymphomas (Mod Path 2001;14:641)
References: AJSP 1998;22:201 (CD5+, localized, low grade MALT lymphoma)
Malignant fibrous histiocytoma of conjunctiva
Case report in black patient with xeroderma pigmentosum at early age (Archives 1991;115:910)
Very rare
Due to acquired melanosis, nevi or no apparent precursor lesion
Usually fair-complexioned individuals age 40+ years
Prognosis related to subsite and size - excellent if small, localized and bulbar; intermediate if diffuse and bulbar; poor if fornix or caruncle
Prognosis not related to nature of initial lesion, although acquired melanosis cases are often multicentric
Metastasis to parotid or submandibular lymph nodes; metastasis uncommon if primary tumor less than 1.5 cm
May extend directly into orbit, eyelids, sinuses
Overall mortality 26%
Treatment: local excision or radical surgery, depending on extent of disease
References: Hum Path 1985;16:136
Mucoepidermoid carcinoma of conjunctiva
More likely to invade eye and orbit
Resembles squamous cell carcinoma but with mucus secreting cells and intraepithelial mucin
Positive stains: Alcian blue, Hales colloidal iron, mucicarmine
Treatment: local excision
Gross: smooth, fleshy, gelatinous
Common in conjunctiva; seldom invade cornea or appear in fornix or over palpebral conjunctiva
May be observed at birth or later
May enlarge and become more pigmented at puberty
See also Nevus of Ota below
Gross: discrete, flat or slightly elevated lesions in interpalpebral zone near limbus; 1/3 are amelanotic
Micro: small round nevus cells with junctional or compound features (almost never dermal nevi), often with solid and prominent cystic inclusions of conjunctival epithelium and chronic inflammatory infiltrate; rarely Spitz nevi
Ocular cicatricial pemphigoid of conjunctiva
Mucocutaneous autoimmune disorder
Usually age 50+, more common in women
50% of cases involve conjunctiva, but 10 years+ after onset of cutaneous or other mucosal disease
May be a paraneoplastic syndrome from nonocular carcinoma
Should submit tissue for immunofluorescent studies
Diagnosis: linear deposition of IgA and IgG along conjunctival basal lamina
Micro: early - epithelial erosions and bullae; late - epithelial and stromal scarring, perivascular lymphocytes and plasma cells
Also called squamous papilloma
Common
In children, are often bilateral and recur after excision, HPV 6/11 often present
In adults, usually solitary and unilateral, may clinically resemble squamous cell carcinoma
Probably lack malignant potential
Due to actinic damage, usually in fissure between upper and lower eyelids
Gross: pedunculated, papillary or mulberry surface on conjunctiva with prominent surface vessels
Micro: exophytic growth of papillary, well differentiated acanthotic keratinized squamous epithelial cells supported by prominent fibrovascular core; also koilocytosis, inflammation
DD: basal cell carcinoma
Common bilateral degenerative process associated with sun damage and age
Not progressive
Usually not biopsied
May cause uneven distribution of tear film, leading to focal dehydration and saucer like depression in corneal tissue (“dellen”)
Treatment: excision for cosmetic reasons or to remove mild irritation
Gross: elevated yellow lesion (due to solar elastosis) in bulbar conjunctiva in interpalpebral region near nasal limbus; conjunctiva is atrophic or thickened
Micro: band of subepithelial actinic elastosis with variable hyalinization and calcification; may have epithelium acanthosis or dyskeratosis resembling carcinoma; may have foreign body giant cell reaction around elastotic material (actinic granuloma)
Bilateral, asymmetric fibrovascular lesion similar to pinguecula but which extends onto nasal cornea and interferes with vision; doesn’t cross pupil and doesn’t pose significant threat to vision
Recurs, but doesn’t undergo malignant transformation
May cause mild astigmatism
Treatment: excision for cosmetic reasons or to remove mild irritation
Micro: fibrovascular connective tissue that migrates onto cornea, dissecting into plane of Bowman membrane; similar to pinguecula but with corkscrew configuration of individual collagen fibers; also variable acute and chronic inflammatory infiltrate and vascular congestion; may cause atrophy, thickening or dysplasia of adjacent corneal epithelium
Conjunctival involvement in 25-38% of sarcoidosis patients; other ocular involvement includes eyelid, lacrimal gland, uvea
Conjunctival biopsy is often performed to diagnose sarcoidosis; should do step sections through entire specimen since granulomas may be focal
Micro: noncaseating granulomas without microorganisms
DD: tuberculosis, cat scratch fever and tularemia (all with extensive necrosis); syphilis, foreign body
Spindle cell carcinoma of conjunctiva
Rare, but more aggressive than squamous cell carcinoma
Positive stains: keratin
EM: desmosomes, tonofibrils
DD: sarcoma
Squamous cell carcinoma of conjunctiva
Rare, but more common than basal cell carcinoma at this site
In US, precancerous lesions are excised, so invasive carcinoma is uncommon
May invade anterior chamber of globe or orbit; only rarely causes death
Treatment: excision of superficial tumors, radical surgery for deeply invasive tumors
Gross: papillary or exophytic mass, often at limbus; occasionally jet black resembling melanoma (in heavily pigmented individuals)
Micro: atypia throughout full thickness of epithelium (conjunctival intraepithelial neoplasia) with individual tumor cells or nests extending into underlying stroma; epithelium may be keratinized; deeply invasive tumors have adenosquamous (mucoepidermoid) features
Trachoma (inclusion conjunctivitis)
Major cause of blindness outside US
Caused by Chlamydia trachomatis; causes scarring of corneal tissue
Stage I: conjunctival inflammatory infiltrates (lymphoid follicles and diffuse infiltrates); followed by pannus formation (fibrovascular tissue in conjunctival and corneal stroma) with Chlamydia elementary bodies and larger basophilic initial bodies seen; also lymphocytes, plasma cells, neutrophils
Stage II: florid inflammation, more follicles, epithelial thickening, severe pannus; macrophages with ingested debris (Leber cells) in conjunctiva
Stage III: scarring, no follicles, cicatricial entropion (inversion of upper lid), misdirected lashes (trichiasis)
Stage IV: arrest of disease due to entropion and trichiasis but with continuing corneal damage, infection
Miscellaneous
Tumor features to report-conjunctiva
Histologic type
Degree of differentiation
Precise anatomic location-bulbar by quadrant, palpebral (superior or inferior), fornix (superior or inferior), caruncle, plica semilunaris, limbus, cornea
Tumor size
Involvement of corneal stroma, episclera, orbital fat
Involvement (noninvolvement) of other tissues present
Margins (deep and lateral, minimum clearance)
Presence of angiolymphatic, perineural, intraocular or intraorbital invasion
Presence of ulceration
For melanomas, also indicate thickness (from top of epithelium using ocular micrometer) and mitotic activity
References: AJSP 2003;27:999
TNM staging for carcinoma of the conjunctiva
Applies to clinical and pathologic staging
Note: excludes melanoma and malignancies other than carcinoma
Primary tumor (T)
TX: primary tumor cannot be assessed
T0: no evidence of primary tumor
Tis: carcinoma in situ
T1: tumor 5 mm or less in greatest dimension
T2: tumor more than 5 mm in greatest dimension, without invasion of adjacent structures
T3: tumor invades adjacent structures, excluding the orbit
T4: tumor invades the orbit with or without further extension
T4a: tumor invades orbital soft tissues, without bone invasion
T4b: tumor invades bone
T4c: tumor invades adjacent paranasal sinuses
T4d: tumor invades brain
Regional lymph nodes (N)
NX: regional lymph nodes cannot be assessed
N0: no regional lymph node metastasis
N1: regional lymph node metastasis
Distant metastasis (M)
MX: distant metastasis cannot be assessed
M0: no distant metastasis
M1: distant metastasis
Stage grouping
No stage grouping is presently recommended by AJCC
TNM staging for melanoma of the conjunctiva
Primary tumor (T) - Pathologic staging
pTX: primary tumor cannot be assessed
pT0: no evidence of primary tumor
pT1: tumor of bulbar conjunctiva confined to epithelium
pT2: tumor of bulbar conjunctiva not more than 0.8 mm in thickness with invasion of the substantia propria (stroma of cornea)
pT3: tumor of bulbar conjunctiva more than 0.8 mm in thickness with invasion of the substantia propria or tumors involving the palpebral or caruncular conjunctiva
pT4: tumor invades eyelid, globe, orbit, sinuses or central nervous system
Primary tumor (T) - Clinical staging
TX: primary tumor cannot be assessed
T0: no evidence of primary tumor
T1: tumor of bulbar conjunctiva
T2: tumor of bulbar conjunctiva with corneal extension
T3: tumor extending into conjunctival fornix, palpebral conjunctiva or caruncle
T4: tumor invades eyelid, globe, orbit, sinuses or central nervous system
Regional lymph nodes (N)
NX: regional lymph nodes cannot be assessed
N0: no regional lymph node metastasis
N1: regional lymph node metastasis
Distant metastasis (M)
MX: distant metastasis cannot be assessed
M0: no distant metastasis
M1: distant metastasis
Stage grouping
No stage grouping is presently recommended by AJCC
Cornea
Wider than tall (11.7 mm horizontally vs. 10.6 mm vertically)
Cornea and overlying tear film are major refractive surface of eye, not the lens
6 distinct layers (outside to inside):
(1) outer epithelium: stratified squamous, nonkeratinized, 5 layers thick centrally, thicker peripherally
(2) epithelial basal lamina (basement membrane): highlighted with PAS stain
(3) Bowman’s membrane: most anterior stroma; acellular, made of collagen fibers, does not regenerate; 8-14 microns thick
(4) stroma: also called substantia propria, no blood vessels or lymphatics; 90% of cornea’s thickness
Note: normally see stromal lamellae separated by clefts, a processing artifact; absence of clefts is caused by stroma edema, due to damage of "endothelium"; with edema, get corneal clouding (fibrils are normally separated by glycoprotein and mucoprotein which makes cornea transparent)
(5) Descemet’s [pronounced DEZMET’s] membrane: a true basal lamina produced by underlying corneal endothelial cells, gets thicker with age (10-12 microns in adults), does not regenerate, site of copper deposition in Kayser-Fleisher ring of Wilson’s disease
(6) “endothelium”: single layer of very flat cells, does not regenerate, keeps cornea dehydrated, neural crest origin; does not line blood vessels or lymphatic spaces
Hasall-Henle bodies (warts): focal excrescences that form on peripheral Descemet’s membrane with normal aging
Myopia: eye too long for its refractive power
Hyperopia: eye too short for its refractive power
Laser assist in situ keratomileusis (LASIK): sculpt cornea and change its refractive properties to eliminate need for glasses
Positive stains: CK3
Negative stains: CK19
References: Hum Path 1997;28:1348 (cytokeratin)
Don't pick up with forceps
Bisect at center with sharp razor to see papillary excrescences or other lesions of interest
Embed "on edge"
Routine stains are hematoxylin & eosin and PAS (highlights basal lamina)
Rare but serious complication of contact lenses due to contamination of contact lens cleaning systems
Organisms are ubiquitous protozoa in soil and fresh water
Infections wax and wane, may infiltrate cornea along corneal nerve and cause pain
Micro: stromal neutrophils, necrotic tissue; amoebic cysts and trophozoites identifiable with H&E, highlighted with GMS, PAS
DD: fungal or herpetic keratitis
Extensive solar elastosis in superficial layers of corneal collagen in band-like area of interpalpebral fissure
Due to chronic high levels of ultraviolet light
Gross: yellow due to solar elastosis
Secondary endothelial compensation, often after cataract extraction (with or without an intraocular lens)
Resembles Fuchs dystrophy; causes severe visual loss and astigmatism
Micro: corneal edema with bullae between corneal epithelium and Bowman’s membrane; late changes are replacement of bullous cavity with fibrous tissue; no/attenuated endothelium
Due to chronic anterior chamber hemorrhage or hyphema, caused by trauma or increased intraocular pressure
Hemoglobin and other red blood cell breakdown products may diffuse into and stain cornea
May eventually clear, beginning in periphery
Micro: small pink-brown globules or spheres in corneal lamellae
Injury to endothelium (does not regenerate), which normally pumps fluid out from corneal stroma, leads to chronic edema of stroma and epithelium, subepithelial bullae, pain, eventually diffuse scarring and reduced vision
Causes include immunologic rejection of corneal endothelium, Fuchs dystrophy, implantation of prosthetic intraocular lens
Called aphakic bullous keratopathy (see above) if after cataract extraction
Micro: intraepithelial vesicles, bullae between epithelium and Bowman’s layer, fewer endothelial cells than normal, increased corneal thickness with loss of normal artifactual clefts between collagen lamellae
Due to chronic inflammation, calcium and phosphate disorders
May complicate chronic uveitis, especially in patients with juvenile rheumatoid arthritis
Gross: brown staining material in anterior cornea within palpebral fissure
Micro: calcium deposition in Bowman’s layer and superficial corneal stroma; may be associated pannus formation
Positive stains: calcium (von Kossa stain)
Also called climatic droplet keratopathy or spheroidal degeneration
Initially involves periphery of cornea, increases in severity and incidence with age
Associated with long term exposure to excessive ultraviolet light
Micro: amorphous globules of protein accumulate in superficial stroma of interpalpebral portion of cornea
DD: other disorders produce similar globules
Heterogeneous group of inherited, bilateral, symmetric corneal disorders
Most common is Fuchs dystrophy; also macular, lattice and granular corneal dystrophy
Cause severe visual loss reparable by corneal transplantation
Site of damage and types of dystrophy:
Epithelium: Meesman dystrophy; microcystic, map dot and fingerprint dystrophy
Bowman’s layer and superficial stroma: granular corneal dystrophy type III; Thiel-Behnke dystrophy; familial subepithelial amyloidosis
Stroma: granular corneal dystrophy types I and II, macular corneal dystrophy, central stromal crystalline dystrophy
Endothelium: Fuchs dystrophy (see below), posterior polymorphous dystrophy, congenital hereditary endothelial dystrophy
Central stromal crystalline dystrophy: also called Schnyder corneal dystrophy, disease maps to 1p34-p32, crystals of cholesterol ester in anterior stroma
Congenital hereditary endothelial dystrophy: autosomal dominant (maps to 20q12-q13.1) or autosomal recessive; edematous epithelium with lack of Bowman’s layer, thickened stroma and Descemet’s membrane, diminished number of endothelial cells
Familial subepithelial amyloidosis: also called primary gelatinous droplike dystrophy, Bowman’s layer and superficial stroma dystrophy; autosomal recessive, usually due to mutation in M1S1 gene at 1p, has subepithelial amyloid deposits that contain lactoferrin
Fleck dystrophy: also called speckled, cloudy dystrophy; subepithelial and stromal amyloid deposits, autosomal dominant, maps to 2q35, stains with colloidal iron and Alcian blue
Granular corneal dystrophy type I: stromal dystrophy, autosomal dominant, usually due to R555W mutation in TGFB1 gene at 5q31, discrete deposits of mutated protein appear red with Masson trichrome stain
Granular corneal dystrophy type II: also called Avellino corneal dystrophy; autosomal dominant, due to R124H mutation in TGFB1 gene at 5q31, corneal deposits similar to granular corneal dystrophy type I plus amyloid
Granular corneal dystrophy type III: also called Reis-Bucklers dystrophy, Bowman’s layer and superficial stroma dystrophy; autosomal dominant, due to R124L mutation in TGFB1 gene at 5q31
Lattice dystrophy: irregular linear subepithelial and stromal amyloid deposits, normal Descemet’s membrane and endothelium; birefringent amyloid with Congo Red stain
Lattice type I: autosomal dominant, usually due to R124C mutation in TGFB1 at 5q31, lesions limited to cornea; often recurrent epithelial erosions and subepithelial amyloid or collagenous plaques
Lattice type II: autosomal dominant, mutation in GSN gene at 9q34, associated with familial amyloid polyneuropathy; amyloid is derived from fragment of mutated gelsolin
Lattice type III: autosomal recessive, amyloid deposits thicker than in types I and II, identity of amyloid unknown
Lattice type IIIA: autosomal dominant, amyloid deposits resemble type III, mutation in TGFB1 gene at 5q31
Macular corneal dystrophy: autosomal recessive, due to mutation in CHST6 gene at 16q22.1, deficiency in carbohydrate sulfotransferase, causes deposits of low sulfated keratan sulfate-related glycosaminoglycan throughout stroma, Descemet’s membrane and endothelium; also corneal guttae; deposits are positive for colloidal iron and Alcian blue
Macular type I - no/low serum keratan sulfate; keratocytes don’t react to keratan sulfate antibodies
Macular type IA - no/low serum keratan sulfate; keratocytes DO react to keratan sulfate antibodies
Macular type II - normal serum keratan sulfate; keratocytes DO react to keratan sulfate antibodies
Meesmann’s dystrophy: epithelium dystrophy, autosomal dominant, mutation in keratin KRT3 (12q) or KRT12 gene (17q), intraepithelial microcysts
Microcystic, map dot and fingerprint dystrophy: epithelium dystrophy with nonspecific features, intraepithelial basement membrane and microcysts
Posterior polymorphous dystrophy: endothelial dystrophy, autosomal dominant (may be due to mutation in COL8A2 at 1p34.3-p32.3), or autosomal recessive; may also map to 20q12-q13; abnormal Descemet’s membrane; has multilayered epithelial cells in posterior cornea
Thiel-Behnke dystrophy: transmission EM shows subepithelial “curly” fibers; due to R555Q mutation in TGFB1 gene at 5q31 or 10q23-q24; focal loss of epithelial basement membrane and Bowman’s layer
DD: amyloid due to trauma; keratoconus, trachoma, uveitis, retrolental fibroplasia, sympathetic ophthalmia, glaucoma
Epithelial ingrowth into cornea
Occurs after penetrating corneal injury (trauma, surgery)
Epibulbar squamous epithelium grows through wound into anterior chamber of eye, and may replace corneal epithelium and cause bullous keratopathy
May cause intractable glaucoma if epithelium invades trabecular meshwork
Micro: squamous epithelium in cornea instead of single layered corneal epithelium
Positive stains: keratin
Type of primary endothelial dystrophy or endothelial decompensation
Most common endothelial dystrophy and common indication for corneal transplantation in US
Damage (decompensation) to endothelium, which normally pumps out fluid from corneal stroma, leads to chronic edema of stroma and epithelium, pain from rupture of epithelial bullae, eventually diffuse scarring and reduced vision
Women ages 50+; some cases are autosomal dominant, some cases are due to mutation in COL8A2 at 1p34.3-p32.3
Gross: bilateral, often asymmetric
Micro: corneal edema and cysts due to endothelial damage with paucity of endothelial cells and thickening of Descemet’s membrane; epithelium is separated from Bowman's membrane; papillary excrescences (guttae) in middle of cornea (must bisect cornea at equator and embed at equator to see); if severe, may see edema of basal cells, bullae formation and pannus formation (fibrovascular ingrowth between Bowman’s layer and epithelium)
DD: interstitial keratitis (inconspicuous ghost vessels in most posterior corneal stroma)
Most corneal transplants are successful and provide long term improvement in visual acuity
Matching of donor and recipient tissue is not necessary for corneal transplants, since no lymphatics or blood vessels in corneal stroma
Graft failure may be due to surgical damage of endothelium, immunologic rejection (uncommon) or recurrence of dystrophy
Micro: fibrosis, vascularization, inflammatory cell infiltrate; full thickness scars from prior surgery are present at edge of specimen; 50% have fibrous retrocorneal membrane
Most common cause of corneal ulcers; usually unilateral, may recur
Usually HSV1
Diagnosis: difficult in recurrent cases, may need EM, PCR, ISH or immunohistochemistry since cultures are usually negative and inclusions are rarely identified
Micro: diffuse epithelial edema, causing bullae between epithelium and Bowman’s layer; also patchy loss of Bowman’s membrane, irregular epithelium, infiltration of anterior stroma by lymphocytes and plasma cells with stromal fibrosis and neovascularization; severe cases have granulomatous reaction surrounding Descemet’s membrane; herpetic inclusions are rare
Contact lens wearers are susceptible to Pseudomonas and Acanthamoeba (see above)
Keratitis caused by microfilaria of Onchocerca volvulus is the leading cause of blindness worldwide, outside US
Granulomatous keratitis: due to HSV1, leprosy, juvenile xanthogranuloma, sarcoidosis
Micro: similar histologic findings for all organisms - destruction of corneal epithelium, Bowman’s layer and stroma; necrosis and prominent neutrophils; discontinuities of Descemet’s membrane with corneal perforation; crystal-like stromal opacities with Streptococcus viridans; may need special stains to detect organisms
Common, incidence of 1 per 2000
Congenital ectasia of central cornea, usually identified by age 9 years; usually bilateral
Associated with Down’s syndrome, Marfan’s syndrome and atopic disorders
Progresses until fibrosis decreases vision
May have sudden rupture of Descemet’s membrane, allowing aqueous humor to enter corneal stroma, causing corneal hydrops and sudden worsening of vision
Causes scarring and astigmatism which cannot be corrected by glasses; may be corrected by rigid contact lenses
Treatment: corneal transplantation
Gross: wrinkled corneal button after transplantation, cornea is cone shaped; often has Fleischer ring (brown, stainable intraepithelial iron arc surrounds conical portion of cornea)
Micro: thinning and fibrosis of cornea, numerous breaks in Bowman’s layer, no inflammation or vascularization
Severe form of Vitamin A deficiency with diffuse, severe keratinization of mucous membrane epithelia, including corneal and conjunctiva epithelia (xerophthalmia)
Leading cause of blindness in developing world
Associated with secondary bacterial infection, corneal ulceration/necrosis, which causes corneal perforation and panophthalmitis
Junction of peripheral cornea and anterior sclera
Not a distinct anatomic site
Composed of conjunctiva (epithelium and stroma), cornea and scleral stroma, episclera, Tenon’s capsule (fibrous tissue that covers the globe)
Contains trabecular meshwork and Schlemm’s canal
Site of incisions for surgery on anterior eye
Descemet’s membrane terminates at limbus and gives rise to Schwalbe’s ring; 15% have prominent area of thickening at this site
Trabecular meshwork: with Schlemm’s canal, are apparatus for removal of aqueous from eye; collection of finely branching and delicately pigmented connective tissue bands; lining cells are continuous with corneal endothelium; posteriorly, trabecular meshwork extends to scleral connective tissue called scleral spur
Schlemm’s canal: anterior and superficial to trabecular meshwork; endothelial lined venous canal that completely encircles limbus; separated from trabecular meshwork by thin connective tissue and separate endothelial linings
Nonspecific responses in cornea
Corneal edema may lead to intraepithelial vesicles and bullae between epithelium and Bowman’s layer
Aberrant basal lamina may develop within corneal epithelium in response to some injuries
Collagenous tissue (pannus) may accumulate between corneal epithelium and Bowman’s layer
Blood vessels may be present in superficial or deep stroma after inflammatory conditions (normally cornea is avascular)
Irregular thickening of Descemet’s membrane occurs with aging
Due to chronic inflammation in eye
Micro: proliferation of fibrovascular tissue under epithelium in anterior cornea
Pseudoexfoliation syndrome in cornea
Common systemic degenerative condition with extracellular deposition of distinctive fibrillar material on surfaces of cornea and other structures lining anterior and posterior chambers
Associated with cataract and glaucoma
May be a connective tissue disorder
References: Hum Path 1996;27:1255
Rheumatoid arthritis in cornea
May have spontaneous thinning of corneal stroma, more common at periphery of cornea, but central thinning more often causes perforation
Keratoplasty (corneal transplantation): produces button 8 mm in diameter
Indications for keratoplasty: primary and secondary endothelial decompensation (dystrophy), fibrosis, vascularization, keratoconus, failed prior grafts, interstitial keratitis
Penetrating keratoplasty: full thickness corneal graft, 8 mm in diameter
Lamellar keratoplasty: partial thickness corneal graft
Donor corneal scleral rim: want to check for endothelial damage
Due to any process that causes uneven distribution of the tear film across cornea
Bacterial ulcers often destroy epithelium and Bowman’s layer with variable stromal destruction; due to Staphylococcus aureus, Streptococcus pneumoniae, E. coli, Klebsiella, Pseudomonas
Complications include corneal perforation and scarring
Fungal ulcers occur 8-15 days after trauma, usually involving vegetative matter; due to Candida, Aspergillus, Cephalosporium, Fusarium; satellite lesions are also present
Micro: eosinophils and granulomas with fungal infection
Tumor features to report-cornea
Precise anatomic location-limbus by clock hour
Histologic type
Tumor size
Involvement (noninvolvement) of other tissues present
Margins (minimum clearance)
Angiolymphatic invasion
Presence of ulceration
Eyelid
Specimens received are often from cosmetic blepharoplasty or other reparative surgery, with no abnormalities
Other lesions are similar to those in skin
Creates tear film via accessory lacrimal glands embedded above fibrous tarsus of eyelid; helps to protect and lubricate the globe
Tumors may prevent complete closure of eyelid, leading to exposure and ulceration of cornea
Anatomy:
Has cutaneous and conjunctival portion
Palpebral (tarsal) conjunctiva lines interior of eyelid; is very thin; is continuous with bulbar conjunctiva that covers the sclera; becomes papillary with allergic or bacterial conjunctivitis
Gray line: junction between palpebral and bulbar conjunctiva
Contains eccrine and apocrine glands (glands of Moll) and sebaceous glands
Sebaceous glands (Meibomian glands within eyelid fibrous tarsus and glands of Zeis associated with eyelashes) create lipid layer of tear film, which retards evaporation of tears
Muscular layer is composed primary of orbicularis oculi muscle
Eyelid inflammatory disorders
Very common
Deep seated lipogranuloma that develops near meibomian glands or glands of Zeis
Probably due to obstruction and nonspecific inflammation (blepharitis), leading to discharge of sebaceous material into surrounding tissue and resulting intense granulomatous inflammatory reaction
May erupt through conjunctival surface of eyelid
Initial specimens are often not submitted for pathologic examination, but recurrences suggest sebaceous carcinoma and should be examined
Treatment: curettage
Micro: multiple foci of granulomatous inflammation with microabscesses and multinucleated giant cells; center of granulomas may contain small fat globules
DD: sarcoidosis, tuberculosis, fungi
Mites commonly found within hair follicles (Demodex folliculorum) or sebaceous glands (Demodex brevis)
Usually incidental findings that don’t incite an inflammatory reaction
Increase with age (100% at age 70+)
Poxvirus that produces small nodules on eyelid
Treatment: excision if on eyelid margin to prevent infection of ocular surface
Gross: multiple raised skin nodules with umbilicated centers
Micro: lobules of acanthotic epithelium that surround intracytoplasmic eosinophilic inclusion bodies (molluscum bodies), which become larger at they reach the superficial epithelium
Necrobiotic xanthogranuloma with paraproteinemia
Multiple nodules or plaques in periorbital areas and elsewhere in body
Patients always have IgG paraprotein dysproteinemia
Micro: granulomas with collagen necrobiosis, foamy macrophages, Touton giant cells
Case report of 5 year old Chinese girl in Taiwan with Prototheca wickerhamii in eyelid (Archives 1987;111:737)
Treatment: ketoconazole
Micro: symmetrically arranged endospores
Pseudorheumatoid nodules of eyelid
Also called deep granuloma annulare
May involve eyelid and eyebrow
Post-traumatic or post-surgical
Gross: red, fleshy, often pedunculated
Micro: inflammatory lesion composed of granulation tissue with mixed inflammatory infiltrate
Noncaseating, composed of epithelioid cells, multinucleated giant cells and birefringent silica crystals, surrounded by fibrosis
Also called hordeolum, chalazion (by some)
Acute suppurative inflammation of sebaceous glands or follicles of eyelid
Usually due to Staphylococcal infection
Internal - affects meibomian glands; external - affects glands of Moll or Zeis and adjacent hair follicles and cilia
Treatment: medical
Tumors
Consist of epithelial tumors originating in skin and conjunctival surfaces (squamous cell and basal cell carcinoma), glandular tumors originating from sebaceous, sweat and apocrine glands and hair follicles
Also lymphoid and melanocytic tumors
Occasionally Kaposi’s sarcoma, fibrous histiocytoma and other sarcomas
Regional lymph nodes are pre-tarsal and post-tarsal plexuses, which are anastamosed
Lateral 2/3 of upper eyelid and lateral 1/3 of lower eyelid drain into preauricular nodes; remaining lymphatics drain into submandibular nodes
Local extension includes soft tissue of orbit, lacrimal gland and globe
Metastases to cervical, axillary and mediastinal lymph nodes, lung, liver and other viscera
Eyelid adnexal tumors
Malignant sweat gland tumor, often mucinous
Similar to adenocystic carcinoma of skin at other sites
Local recurrences are common, rarely distant metastases
Also called sebaceous cell adenoma
Arise from cutaneous sebaceous glands, glands of Zeis (surrounding eyelashes at lid margin) or meibomian glands (in tarsus) or sebaceous glands of caruncle
Solitary adenomas: rarely biopsied, may be curetted as likely chalazion with disposal of tissue
Recurrent tumors should be examined histologically to rule out malignancy
Also called sebaceous cell carcinoma
Commonly misdiagnosed as chalazion or chronic blepharoconjunctivitis
1-3% of eyelid malignancies in US
75% women, mean age 61 years, range 28-82 years
10% are multicentric
May arise after radiation therapy for retinoblastoma
1/3 recur, 25% die of metastases (parotid and submandibular nodes), may spread to lacrimal drainage system and nasopharynx
Intraepithelial (pagetoid) spread to adjacent structures is common
Poor prognostic factors: orbital or vascular invasion, bilateral involvement of eyelids, poorly differentiated or multicentric tumors, large size, infiltrative pattern, pagetoid spread
Case reports: fatal tumor after radiation therapy for bilateral retinoblastoma (AJSP 1978;2:305)
Micro: nesting, comedonecrosis or papillary patterns; morphology varies from well differentiated to anaplastic; often pagetoid spread or carcinoma in situ
Well differentiated: contain cells with foamy, finely vacuolated cytoplasm and distinct cell borders; better differentiat