Eye

8 January 2005, copyright (c) 2004-2005 PathologyOutlines.com, LLC

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Table of contents

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

General

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

 

Primary references

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

University of Utah

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

 

Normal anatomy

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)

 

Autopsy findings

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

 

Trisomy 13

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

 

Trisomy 21

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

 

Congenital rubella syndrome

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

Grossing

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

 

Ataxia-telangiectasia

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

 

Cysts of conjunctiva

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

 

Dermoid tumor of conjunctiva

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

 

Dysplasia of conjunctiva

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

 

Lymphoma of conjunctiva

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)

 

Melanoma of conjunctiva

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

 

Myxoma of conjunctiva

Treatment: local excision

Gross: smooth, fleshy, gelatinous

 

Nevi of conjunctiva

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

 

Papilloma of conjunctiva

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

 

Pinguecula

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)

 

Pterygium

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

 

Sarcoidosis of conjunctiva

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

Normal anatomy and histology

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)

 

Grossing corneal specimens

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)

 

Acanthamoeba keratitis

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

 

Actinic band keratopathy

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

 

Aphakic bullous keratopathy

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

 

Blood staining

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

 

Bullous keratopathy

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

 

Calcific band keratopathy

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)

 

Chronic actinic keratopathy

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

 

Corneal dystrophy

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

 

Fuchs endothelial dystrophy

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)

 

Graft failure

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

 

Herpes simplex keratitis

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

 

Infectious keratitis

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

 

Keratoconus

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

 

Keratomalacia

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

 

Limbus-general

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

 

Pannus

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

 

Transplantation of cornea

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

 

Ulceration of cornea

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

General

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

Chalazion of eyelid

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 (demodicosis)

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+)

 

Molluscum contagiosum

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

 

Prototheca

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

 

Pyogenic granuloma of eyelid

Post-traumatic or post-surgical

Gross: red, fleshy, often pedunculated

Micro: inflammatory lesion composed of granulation tissue with mixed inflammatory infiltrate

 

Silica granuloma of eyelid

Noncaseating, composed of epithelioid cells, multinucleated giant cells and birefringent silica crystals, surrounded by fibrosis

 

Stye

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

Eyelid tumors-general

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

Adenocarcinoma of eyelid

Malignant sweat gland tumor, often mucinous

Similar to adenocystic carcinoma of skin at other sites

Local recurrences are common, rarely distant metastases

 

Sebaceous gland adenoma

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

 

Sebaceous gland carcinoma

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