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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 differentiated cells are usually in center of nests, often near tarsus and meibomian glands

Anaplastic: often scant cytoplasm with indistinct vacuoles; central necrosis, pagetoid involvement of overlying skin

Positive stains: Oil Red O (on frozen sections)

DD: basal cell carcinoma (less pleomorphic, has peripheral palisading), chalazion (clinically), ocular cicatricial pemphigoid

References: AJSP 1984;8:597

Sweat gland carcinoma of eyelid

Case reports of in situ and invasive sweat gland carcinomas with endocrine differentiation (AJSP 1997;21:1501)

Micro: resemble solid papillary carcinoma of breast

Syringoma of eyelid

Usually young women with multiple lesions

Micro: comma shaped lesions

Trichilemmal cell tumor of eyelid

Also called pilar cyst

Micro: cyst composed of dense keratin without a granular cell layer

Trichilemomma of eyelid

Originates from outer hair sheath

Benign

May involve eyelid or eyebrow

Micro: glycogen rich cells

Trichoepitheiloma of eyelid

Sporadic or autosomal recessive

Multiple epidermal inclusion like cysts plus rudimentary hair follicles

Trichofolliculoma of eyelid

Solitary large cyst with hair in center

Eyelid melanocytic tumors

Melanoma of eyelid

Rare; may originate from nevus, acquired melanosis or de novo

Poor prognosis due to early metastasis via lymphatics or bloodstream

Sentinel lymph node biopsy has been used for melanoma of eyelid

Micro: resembles skin tumors more than globe tumors; spindled or epithelioid cells with marked atypia and invasion into dermis

Melanosis oculi of eyelid

Also called ocular melanocytosis

Rare congenital anomaly with variable hyperpigmentation of conjunctiva, episclera, sclera, uveal tract, possibly optic nerve

May be variant of nevus of Ota

Associated with ocular melanoma

Nevi of eyelid

On cutaneous or conjunctival surface, commonly on lid margin

Usually junctional (nests of nevus cells at border of epidermis and dermis) or compound (nests at junction and within dermis); usually acquired

Rarely give rise to melanoma

Micro: nevus cells with bland nuclei; may be multinucleated; no/rare atypia, no/rare mitotic figures

Nevus of Ota in eyelid

Also called congenital oculodermal melanosis

More common in Orientals and blacks

A form of extrasacral mongolian spot involving the distribution of the first and second branches of trigeminal nerve in face

Diffuse and deeply seated melanocytic lesion

Slight risk of uveal melanoma if skin of eyelid or periorbital area is affected

Eyelid other tumors

Actinic keratosis of eyelid

Gross: thickened or raised red-brown lesions

Micro: acanthosis or hyperkeratosis, with atypia of squamous cell layer but normal polarity and maturation; basophilic degeneration of dermal collagen

Amyloidosis of eyelid

May present as a mass, without systemic disease

Perivascular deposits are characteristic of systemic disease

Basal cell carcinoma of eyelid

Very common; 90% of eyelid malignancies; probably secondary to sunlight

Rarely invades orbit or nose

Arise from cutaneous surface of eyelid (usually lower lid and medial canthus), only rarely from conjunctiva

Frozen section review of margins is helpful in reducing recurrence

Excision is important to preserve vision, since tumors may prevent proper eyelid closure and cause corneal exposure and ulceration

Case reports: 34 year old woman with recurrent eyelid tumor, bony metastases, meningeal carcinomatosis and death (Hum Path 1985;16:530)

Gross: ulcerated, pigmented, superficial or sclerosing

Micro subtypes: nodular and nodular-ulcerative (anastomosing nests and cords of proliferative epidermal basal cells with minimal cytoplasm, dark nuclei and nuclear palisading at periphery), cystic (central necrosis with cystic spaces), multicentric, morphea (infiltrates into dermis as branching cords of cells within a dense stroma; margins are difficult to assess clinically)

DD: conjunctival papilloma

Cysts of eyelid

Common, represent 1/3 of eyelid lesions

Cysts below are benign; excision is curative

Dermoid cyst: see below

Keratinous cyst (epidermal inclusion cyst): most common eyelid cyst; either congenital, post-traumatic or post-surgical; lined by squamous epithelium and contains laminated keratin; marked foreign-body giant cell reaction if cyst ruptures; no dermal appendages

Hidrocystoma (sudoriferous cyst): arise from eyelid sweat glands; thin-walled transparent vesicles at margin of lid, lined by atrophic cuboidal or flattened epithelial cells containing watery fluid or with an empty lumen (“sudoriferous” means carrying or producing sweat); lined by 1-2 layers of flattened cuboidal cells

Apocrine hidrocystoma: lined by double layer of columnar cells with eosinophilic cytoplasm, papillary projections and apocrine snouts; develop from obstructed ducts of glands of Moll, are often multiple at eyelid margin

Dermoid cyst of eyelid

Usually upper eyelid along brow margin

May represent intraorbital mass that is pushed forward

Often attached to periosteum of bony orbital rim

Gross: soft, nontender, round/oval, 1 cm or less

Micro: lined by well differentiated epidermis and dermis, lumen filled with keratinous debris, hair, sebum; may have foreign body inflammatory reaction if cyst ruptures

DD: phakomatous choristoma (lower eyelid of infants, very rare, don’t recur even if incompletely resected, derived from lens tissue, Archives 1989;113:1175)

Hemangioma of eyelid

Small lesion of eyelid or large lesion extending into orbit

Capillary type (“strawberry marks”) usually arise congenitally or in early infancy, and are considered hamartomas

80-90% regress spontaneously by age 5 years

Micro: numerous small capillaries lined by plump endothelial cells

Kaposi’s sarcoma of eyelid

Develops in eyelid or conjunctiva of AIDS patients

Appears purple in eyelid due to deep location in dermis, but red in conjunctiva since superficial

Gross: thickening of conjunctiva

DD: hemorrhage

Keratoacanthoma of eyelid

May involute spontaneously, or exhibit aggressive behavior with perineural invasion

Merkel cell carcinoma of eyelid

Resembles skin tumor

Usually upper eyelid

Often presents as large, nontender, red or violet mass

Metastases to eyelid

Often from lung, breast or kidney

Metastatic lobular carcinoma of breast may have histiocytoid features and mimic inflammation

Myxoma of eyelid

Rare

May be part of Carney syndrome (spotty pigmentation of skin, overactive endocrine glands, myxoma of heart)

Neurofibroma of eyelid

Sporadic or part of neurofibromatosis type 1

May be present at birth, but show accelerated growth during childhood

Neurofibromatosis (facial features): often multiple tumors causing marked facial asymmetry, neurofibroma of orbit and glioma of optic nerve

Micro: increased mast cells

Pilomatricoma of eyelid

Also known as calcifying epithelioma of Malherbe

Benign

Micro: basaloid and ghost cells

Port wine stain

Also called nevus flammeus

Type of facial hemangioma

Sturge-Weber syndrome: ipsilateral port wine stain, choroid hemangioma, glaucoma and meningeal hemangioma

Seborrheic keratosis of eyelid

Gross: elevated irregular lesions, often crusty or greasy appearing; often pigmented

Micro: acanthosis with marked hyperkeratosis and keratin-filled cysts; also increased pigmentation in basal layer; no atypia

Squamous papilloma

Gross: resemble skin tags

Micro: acanthotic epithelium with hyperkeratosis, papillary projections with inner fibrovascular core

Squamous cell carcinoma of eyelid

10% of carcinomas in eyelid

Usually lower lid

Rarely are adenoid (pseudoglandular)

Rarely invade eye or orbit or metastasize

Gross: elevated and thickened areas of eyelid, may be ulcerated or friable

Micro: invasion of malignant squamous cells into dermis; cells are large and eosinophilic with marked atypia; often abnormal deep keratinization, may have keratin pearls

DD: pseudoepitheliomatous hyperplasia, keratoacanthoma, inverted follicular keratosis, seborrheic keratosis, actinic keratosis, papilloma

Xanthelasma of eyelid

Usually not associated with systemic problems

Removed for cosmetic reasons

Yellow plaques on medial eyelids of men/women ages 40+ years

Appear in younger patients with familial hypercholesterolemia

Micro: large, pale, fat-laden histiocytes within dermis

Miscellaneous eyelid

Tumor features to report-eyelid

Precise anatomic location-upper or lower eyelid, medial or lateral canthus

Histologic type and differentiation

Tumor size(s) and gland of origin (Meibomian vs. Zeis)

Presence of infiltrative growth pattern

Presence of pagetoid spread

Involvement (noninvolvement) of other tissues present

Margins (minimum clearance); includes conjunctival margins and resection margin of optic nerve if specimen includes the globe

Angiolymphatic invasion

Perineural invasion

Presence of ulceration

For melanomas, indicate thickness and mitotic activity

TNM staging for carcinoma of the eyelid

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 of any size, not invading the tarsal plate or, at the eyelid margin, 5 mm or less in greatest dimension

T2: tumor invades tarsal plate or, at the eyelid margin, more than 5 mm but not more than 10 mm in greatest dimension

T3: tumor involves full eyelid thickness or, at the eyelid margin, more than 10 mm in greatest dimension

T4: tumor invades adjacent structures, which includes bulbar conjunctiva, sclera and globe, soft tissues of the orbit, perineural space, bone and periosteum of the orbit, nasal cavity and paranasal sinuses, and 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

Glaucoma

General

Diverse etiologies, causes widespread degeneration of ocular tissue

Defined as optic neuropathy with distinct excavation of optic nerve head and incremental loss of visual field sensitivity

Almost always due to increased intraocular pressure (due to impaired outflow of aqueous humor), which causes optic nerve damage and degenerative changes below

Normal circulation of aqueous humor: aqueous humor is produced by pars plicata of ciliary body, discharged into posterior chamber, flows between lens and iris, through pupil, into anterior chamber, then through trabecular meshwork (in deep layers of peripheral cornea just in front of angle of anterior chamber), into Schlemm’s canal, leaves eye via plexus of intrascleral and episcleral veins along limbus

Congenital glaucoma

Increased intraocular pressure due to malformation of tissues in anterior chamber angle

Causes: hereditary (incomplete separation of iris root from trabeculae, retention of embryonic membrane), congenital rubella syndrome

Unilateral congenital glaucoma is associated with neurofibromatosis type 1 (Recklinghausen’s disease) or Sturge-Weber syndrome

DD: anterior chamber cleavage syndrome (see above, more obvious architectural distortion of iris and angle of anterior chamber)

Primary glaucoma

Primary means no known antecedent disease

Either open angle (chronic simple) or angle closure type

Angle refers to angle of anterior chamber formed by junction of uveal tract with corneoscleral coat, an important site of aqueous drainage

Primary open angle glaucoma: most common form of glaucoma; due to degenerative changes in trabecular meshwork and connective tissue of Schlemm’s canal; insidious process, usually does not produce pain or require enucleation; some patients have mutations in trabecular meshwork inducible glucocorticoid response gene (TIGR, GLC1A), which produces myocilin, found in trabecular meshwork, other anterior segment tissue and optic nerve

Primary angle closure glaucoma: due to anatomic or physiologic abnormalities of tissue and anterior chamber that predispose to blockage of outflow channels by iris root, often in patients with hyperopia; increased posterior chamber pressure also bows iris forward and occludes trabecular meshwork; increased pressure on lens damages its epithelium with minute anterior subcapsular opacities (glaukomflecken); multiple attacks may cause extensive anterior synechia and pain and lead to enucleation

Trabeculectomy: excision of 1 mm or smaller fragment of trabecular meshwork to enhance drainage of aqueous from eye; must embed specimen in paraffin using dissecting microscope

Secondary glaucoma

Due to known or suspected antecedent disease, such as trauma, inflammation, tumor or malformation

May be open or closed angle

Common sites of obstruction are pupil and angle of anterior chamber

Causes:

(a) formation of pupillary membranes due to organization of hemorrhage or exudates or posterior synechiae secondary to iritis

(b) peripheral anterior synechiae (adhesions between root of iris and peripheral cornea)

(c) particulate matter clogging passages (red blood cells after hemorrhage; white blood cells after uveitis; lens proteins; iris pigment epithelial granules; melanoma or other tumor cells)

(d) epithelial downgrowth from conjunctiva or cornea after trauma, fibrous downgrowth due to corneal wound

(e) rubeosis iridis (see below)

(f) blunt trauma with retrodisplacement of iris root insertion and atrophy of ciliary body

(g) surface ocular vascular malformations that increase pressure on surface of eye, such as Sturge-Weber syndrome or arterialization in episcleral veins due to fistula

Melanomalytic glaucoma: a type of secondary open angle glaucoma in melanoma patients with pigment laded macrophages that clog the trabecular meshwork

Degenerative changes caused by glaucoma

Enlargement of globe (buphthalmos) or cornea (megalocornea) if childhood onset; atrophy of retinal ganglion cell layer and reduction of nerve fiber and inner nuclear layers, with preservation of rods and cones and outer nuclear layer

Also degeneration of nerve fibers near optic disc, causing cupping (deep excavation) of optic disc, posterior bowing of lamina cribrosa, severe atrophy of optic nerve

May have accumulation of hyaluronic acid in optic nerve (Hales colloidal iron+, Alcian blue+)

Also scleral ectasia in equatorial regions with blue color

Gross: white and atrophic optic nerve with deep cupping and extreme nasal displacement of vessels

Micro: compression of tissues of lamina cribrosa and extensive cupping with posterior bowing; also gliosis of optic nerve, retinal atrophy or loss of ganglion cell layer.

Globe

General

Defined as eyeball itself plus intraocular tissues

Dimensions: anterior-posterior 24 mm, vertical and horizontal dimensions are 23 to 23.5 mm

Six extraocular muscles: 4 rectus and 2 oblique muscles

Equator: midway between anterior and posterior poles

Specimen is the result of enucleation, performed because eye is nonfunctional, painful, unsightly, infectious, contains neoplasm, post-trauma (may be removed to prevent sympathetic uveitis) or has chronic glaucoma

Globe usually intact but free of extraocular muscles and orbital fat

Globe may be eviscerated, with only fragments available for microscopic study

Initial pathologic processes may be obscured by subsequent pathologic processes

Grossing globe

- Fix in formalin for 24 hours before sectioning; do not open the eye, cut windows into the sclera or inject fixative into the vitreous

- Wash in running tap water for 1 hour or more; optionally place in 60% ethyl alcohol for a few more hours

- Review summary of clinical history and results of ophthalmologic examination prior to sectioning

- Measure dimensions of the eye (anterior-posterior, horizontal, vertical)

- Measure length of optic nerve

- Measure cornea (horizontal and vertical)

- Look for sites of trauma (accidental or surgical)

- Orient globe based on (a) cornea is wider than tall, (b) optic nerve distance to limbus (junction of cornea and sclera) is less medially than laterally (i.e. optic nerve is medial to posterior pole), (c) superior oblique muscle inserts in upper outer quadrant of posterior globe (d) inferior oblique muscle has muscular insertion in lower outer quadrant of sclera and fibers run posteriorly and medially

- Transilluminate globe to find tumor and cut accordingly; can use a substage microscope lamp in a dark room; rotate globe over light, mark abnormal shadows on sclera with indelible pencil

- Take Xray before opening globe if foreign body or retinoblastoma is suspected

- If choroidal melanoma is suspected, sample at least one vortex vein from each of four quadrants

- use sharp razor to cut, holding globe with nondominant hand, cornea down against cutting block and blade between thumb and middle finger of dominant hand; open eye with sawing motion from back to front

- If no tumor, cut globe at superior and inferior edges of iris in horizontal plane from back to front (5 mm above and below the optic nerve, missing the lens); quick freeze first in liquid nitrogen to minimize artifacts

- If tumor is present, modify the plane of section so tumor will be included in the slab

- Examine interior of globe

- Examine the ~ 8 mm disc shaped slab, which should contain cornea, pupil, lens, optic nerve

- Obtain cross section of optic nerve

Describing globe:

Measure dimensions of the eye (anterior-posterior, horizontal, vertical)

Measure length of optic nerve

Measure cornea (horizontal and vertical)

Examine eye surface for gross evidence of extraocular extension of tumor

Describe the following:

Corneal clarity

Shape and diameter of pupil

Color of iris, lesions

Presence of lens

Anterior chamber depth, configuration of anterior chamber angle

Condition of ciliary body, lens, choroid, retina, vitreous body, optic disc

Presence of foreign bodies (in traumatic specimens)

For tumors, describe location, dimensions, minimum clearance, presence of ulceration, color, consistency, hemorrhage or necrosis, ocular structures involved, extension into optic nerve

Transillumination findings

Sections to obtain in globe:

Entire eye slab

Other abnormal areas

Surgical margin of optic nerve or cut surface of optic nerve as it enters eye

One vortex vein from each quadrant for melanoma

Inflammation of globe

Acute inflammation

Causes: usually infectious (bacteria or fungi, usually post-traumatic, also from intravenous drug use or hematogenous spread of infection); noninfectious cause is massive necrosis of uveal melanoma or metastatic carcinoma; cataract surgery may cause mild endophthalmitis due to Propionibacterium acnes

Initially endophthalmitis (affects intraocular contents including vitreous humor but not sclera or cornea) - massive purulent reaction in anterior and vitreous chambers; later panophthalmitis (involvement of retina, choroid, sclera or orbit)

Panophthalmitis exposes orbit to microorganisms but endophthalmitis does not

Late complication is phthisis bulbi (see below)

Chronic inflammation (nongranulomatous)

Usually uveitis (see below)

Granulomatous inflammation

Toxoplasmosis, tuberculosis, syphilis, nematodiasis, CMV, sarcoidosis, collagen vascular diseases

Often cannot determine etiology

Diagnostic lesions often found in retina, vitreous or sclera

Lymphoma of globe

Rare; usually associated with extraocular disease, often in CNS

May involve optic nerve

Primary intraocular lymphomas: considered a component of primary CNS lymphoma; are usually diffuse large B cell lymphomas with IgH heavy chain gene rearrangements; some cases in HIV1 negative patients may be related to Toxoplasma gondii infection (Mod Path 2001;14:995)

Metastases to globe

Metastatic carcinoma common but asymptomatic (breast, lung, GI tract)

Also metastatic melanoma or sarcoma; rarely carcinoid (Hum Path 1982;13:459)

Most common site is posterior choroid, which is diffusely thickened on both sides of optic nerve

Metastases to eye often suggests extremely short survival, and treatment is usually palliative radiation therapy

Phthisis bulbi

Degenerative change of globe involving all tissues; usually takes several years to develop

Often due to accidental or post-surgical trauma; also found in eyes removed for blindness, pain, glaucoma, inflammation

Due to reduced production of aqueous humor, causing reduced intraocular pressure (hypotony) and shrinkage of globe; also due to organization of inflammatory exudate

Degenerative changes and degree of shrinkage are variable in different tissues; may be calcification and ossification with bone marrow

Note: must decalcify globe

Micro: typically disorganization of intraocular contents, opaque media, corneal scars, exudate in anterior and posterior chambers, advanced cataracts, destruction of vitreous, scleral thickening, cyclitic membrane extends from one ciliary body behind the lens to the other ciliary body, complete detachment of retina; also ossification or bone formation

Usually histology does not disclose initial condition leading to phthisis bulbi; occasionally occult melanoma or lymphoma is found

Sturge-Weber syndrome

Also called encephalotrigeminal angiomatosis

May have choroidal hemangioma and ipsilateral glaucoma

Trauma to globe

Common cause of enucleation, if no potential for visual recovery exists

Surgeon may want to know if retina is extruded through wound

Common sites of rupture are junction of cornea and sclera or posterior to insertion of rectus muscles where sclera is thinnest

Trauma may cause hyphema (blood in anterior chamber) with associated corneal blood staining, separation of ciliary body from iris (iridodialysis) or sclera (cyclodialysis), cataracts, retinal detachment or choroidal rupture

Search for metal, vegetation or cilia

Globe may contain iron (siderosis) or copper (chalcosis)

Other secondary changes are fibrosis, secondary glaucoma, sympathetic ophthalmia, phacoanaphylactic endophthalmitis, post contusion angle deformity, fibrous downgrowth, epithelial downgrowth or granulomatous inflammation in response to foreign body

Lacrimal duct/gland

Lacrimal duct/gland - general

Lacrimal gland located in superiotemporal aspect of orbit, not palpable

Contributes secretions to tear film including IgA

Accessory lacrimal glands are embedded above fibrous tarsus of eyelid and in conjunctival fornix

Serous with minor mucinous component; larger ducts have myoepithelial layer

Normally may have lymphocytes and plasma cells

Drainage apparatus is composed of puncta, canaliculi, lacrimal sac and nasolacrimal duct

Puncta: opening in medial aspect of eyelid where tear fluid drains

Canaliculi (lacrimal duct): tubular structures 0.5 mm in diameter where puncta drains; nonkeratinizing squamous epithelium surrounded by fibrous tissue

Lacrimal sac: merging of canaliculi, encased by bones of orbit; stratified columnar epithelium with goblet cells

Nasolacrimal duct: drains lacrimal sac, 1 cm long, connects to inferior meatus of nose; stratified columnar epithelium with goblet cells

Lacrimal duct disorders often cause epiphora (tears flow over lid margin onto cheek), induration, inflammation of lower eyelid

Tumors tend to displace eye downward, because adjacent orbit restricts growth

Tumors are difficult to resect completely, leading to high recurrence rate

Lacrimal gland is considered a minor salivary gland for tumor reporting

Regional lymph nodes are preauricular (parotid), submandibular and cervical

Adenoid cystic carcinoma of lacrimal gland

20-30% of lacrimal gland tumors; most common malignant tumor of lacrimal gland

Aggressive, may infiltrate eyelid or brain

Micro: basaloid growth with cribriform change; relatively bland cytology; perineural invasion, focal tumor necrosis

Dacryoadenitis

Inflammation of lacrimal gland due to obstruction of lacrimal ducts by dacryoliths

Dacrocystitis / canaliculitis

Canaliculitis: inflammation of lacrimal duct

Dacrocystitis: inflammation of lacrimal sac

Often obscure origin; may be due to inflammatory spread from nose or conjunctiva

Acute or chronic inflammation with suppurative, granulomatous or necrotizing features

Fistulous tracts may form to skin below eyelid near base of nose

Acute: ducts filled with purulent exudate

Chronic: lacrimal canal narrows due to inflammatory thickening, epithelial hyperplasia

Dacryolithiasis

Stone (dacryolith) in lacrimal canal

Probably due to low grade inflammation, including mycoses (Arachnia propionica)

Micro: laminated concretions in lacrimal sac; may contain degenerating epithelial cells and neutrophils, often fungi

Malignant mixed tumor

5-10% of lacrimal gland tumors

Case reports: lacrimal gland tumor developing after 8 recurrences of pleomorphic adenoma over 32 years (AJSP 1979;3:457)

Melanoma of lacrimal sac

Extremely rare

Case report with surrounding melanosis (Archives 1997;121:517)

Mikulicz’s disease

Lymphocytic infiltration and formation of lymphoepithelial lesions

Most common cause of Mikulicz’s syndrome

Mikulicz’s syndrome

Chronic dacryoadenitis associated with enlargement of salivary glands; causes include Mikulicz’s disease, sarcoidosis, tuberculosis, syphilis, mumps, lymphoma, leukemia, Graves’ disease

Sjogren’s syndrome

Usually postmenopausal women

Mikulicz’s disease, with failure of lacrimal and conjunctival secretions and keratoconjunctivitis sicca

Mucocele of lacrimal sac

Complication of chronic inflammation of lacrimal sac, with distention of sac due to low grade obstructive lesion or hypersecreting mucosa

Cyst contents may be clear, milky, gelatinous, fibrinous or flocculent; may be sterile or infected

Micro: cyst wall is atrophic with degenerative changes; also hyperplasia and chronic inflammatory infiltrate

Oncocytoma of lacrimal duct/sac

Develops in lacrimal sac or caruncle

Usually elderly women

Treatment: excision is curative

Papilloma of lacrimal gland

Similar to conjunctival papilloma

Micro: papillary aggregates of benign transitional epithelial cells with infiltrating neutrophils; may have pseudoepitheliomatous hyperplasia

Pleomorphic adenoma of lacrimal gland

50-60% of lacrimal gland tumors

Resemble salivary gland tumors of same type

Treatment: excisional biopsy with negative margins to prevent recurrence and implantation within the orbit

Micro: usually encapsulated, composed of benign epithelial and myxoid mesenchymal elements; often prominent component of S100+ hyaline cells (presumed myoepithelial origin) with diffuse eosinophilic staining; may have squamous metaplasia, bone, cartilage or fat

Squamous cell carcinoma of lacrimal duct/sac

Uncommon; usually moderately differentiated

Similar to nasal or conjunctival squamous cell carcinoma

Often spreads along surfaces, as well as infiltrating

Lung is most common site for metastases, then bone and remote viscera

Micro: often papillary projections into lumen

TNM staging for carcinoma of the lacrimal gland

Applies to both clinical and pathologic staging

Primary tumor (T)

TX: primary tumor cannot be assessed

T0: no evidence of primary tumor

T1: tumor 2.5 cm or less in greatest dimension, limited to the lacrimal gland

T2: tumor more than 2.5 cm but not more than 5 cm in greatest dimension, limited to the lacrimal gland

T3: tumor invades the periosteum

T3a: tumor not more than 5 cm invades the periosteum of the lacrimal gland fossa

T3b: tumor more than 5 cm in greatest dimension with periosteal invasion

T4: tumor invades the orbital soft tissues, optic nerve or globe with or without bone invasion; tumor extends beyond the orbit to adjacent structures, including 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

Lens and vitreous

General

Most surgical specimens are cataracts or prosthetic intraocular lens

Normal lens is biconvex, behind pupil / iris, in front of vitreous, in posterior chamber

10 mm in diameter by 4-5 mm in width

Usually Gross Examination Only (report as transparent - Yes or No), don’t section

Anterior lens capsule is eosinophilic acellular band overlying single layer of epithelial cells

Lens capsule is strongly PAS+, holds lens in place

Lens has thinner capsule posteriorly, without epithelial cells

Lens in held in place by zonules that connect to pars plicata of ciliary body

Lens normally opacifies with age, due to globules of degenerate lens fibers

Is a closed epithelial system, with lens capsule (epithelium) that totally envelops the lens

Vitreous humor: avascular; extends from lens to sensory retina; contains gel-like material composed of water, protein, hyaluronic acid and “hyalocytes”; gel consistency is due to randomly oriented collagen fibrils; may appear as amorphous material on H&E

Micro: anterior but not posterior lens has single epithelial layer

Alport’s syndrome

Also called hereditary nephritis

Inherited disorder of type IV collagen in basement membranes

Hematuria, progressive nephritis with proteinuria and declining renal function, deafness (55%), ocular abnormalities (15-30%)

Ocular abnormalities: anterior lenticonus (forward central protrusion of anterior surface of lens due to weakness in type IV collagen, relatively specific for Alport’s); also keratoconus, spherophakia (small, spherical lens), myopia, retinal flecks, cataracts, retinitis pigmentosa, amaurosis (blindness without an apparent ocular cause)

Cataract

Defined as progressive opacity of crystalline lens that decreases visual acuity

Usually develops in older individuals, rarely in infancy or childhood

Associated with systemic diseases (galactosemia, diabetes mellitus, Wilson’s disease, atopic dermatitis), corticosteroids, radiation (ultraviolet light or radiation therapy), trauma, glaucoma, uveitis, retinitis pigmentosa, steroids

Age related cataract is due to opacification of lens nucleus, which becomes brown, and distorts perception of blue color

Changes occur in lens nucleus, cortex and subcapsular regions

Nuclear changes due to progressive crosslinking and insolubility of crystalline proteins

Cortical changes begin as small peripheral water clefts and diffuse degenerative changes that coalesce into dense bands of opaque cortical material

Anterior lens epithelial cells may undergo fibrous metaplasia, creating a thick fibrous plaque between the anterior lens capsule and the anterior epithelial cells

Congenital cataract: becomes apparent within first 6 months of life

Posterior subcapsular cataract: migration of lens epithelium posterior to lens equator

Morgagnian cataract: long standing cataract that undergoes liquefaction of lens cortex, with sinking of nucleus into fluid filled sac and clinical brown nucleus

Soemmering’s ring cataract: peripheral donut or ring shape due to loss of lens nucleus and much of anterior and posterior cortex; also proliferating lens epithelial cells in periphery and equatorial region of lens

Treatment: often high frequency sound waves are used to disintegrate the lens (phacoemulsification), then lens contents aspirated and disposed of (not submitted for examination); lens capsule is intact; then placement of prosthetic intraocular lens

Gross: senile cataracts are yellow-brown

Micro: homogenous eosinophilic lens fibers, vacuolization of superficial cortical fibers, extracellular clefts and eosinophilic globules of variable size (morgagnian globules) between lens fibers

Dislocation of lens

Due to Marfan’s syndrome (weakness in zonules, leads to superiotemporal dislocation)

Due to other disruption of zonules causing anterior chamber dislocation

Persistent hyperplastic primary vitreous

Congenital, due to incomplete regression of fetal vasculature of vitreous humor, producing a retrolental mass

Usually unilateral

Associated with small eye, white reflex behind pupil (leukokoria), fibrous tissue behind lens, often cataract

Retina normal or with retinal dysplasia

Micro: dense fibrovascular retrolental mass containing elongated ciliary processes and part of hyaloid vascular system

DD: retinoblastoma (also produces white reflex)

Phacoanaphylactic endophthalmitis

Usually occurs after penetrating injuries to lens

Rarely due to spontaneous rupture of swollen lens with a cataract

Granulomatous reaction may be due to acquired hypersensitivity to lens proteins

May coexist with sympathetic uveitis

Micro: granulomatous inflammation surrounding area of lens perforation, with zonal pattern of central neutrophils around disintegrating lens fibers and peripheral macrophages, epithelioid cells and giant cells; posterior synechiae usually present; usually perivasculitis of retinal vessels; variable plasma cells in iris

Prosthetic intraocular lenses

Made of polymethylmethacrylate

Usually placed in space enclosed by lens capsule

Most have central optical zone (the “optic”) and peripheral extensions that secure the lens within the eye (“haptics”)

Rarely removed due to corneal injury or if they induce inflammation

Gross: flat; entire surface can be examined by light microscopy

Micro: may have adherent multinucleated giant cells, chronic inflammatory cells, fragments of lens capsule or melanin granules

Pseudoexfoliation in lens

Also called exfoliation syndrome

Usually affects those from Scandinavia or Northern Europe

May cause glaucoma

Gross: deposition of white fluffy material on anterior lens capsule, excludes areas corresponding to movement of iris; also deposition on zonules, iris pigment epithelium, ciliary body epithelium and trabecular meshwork

Micro: tiny pink, eosinophilic staining deposits on anterior lens capsule which are perpendicular to edge of lens capsule

Vitreous humor pathology

Hemorrhage (from trauma or retinal neovascularization) causes opacification

Calcium soaps produce particulate matter; called asteroid hyalosis since resembles stars when viewed with ophthalmoscope

Amyloid deposits may reduce vision significantly

Age related collapse may product floaters or detachment from neurosecretory retina

Orbit and optic nerve

Orbit and optic nerve-general

Orbit contains globe and its fibrous covering (Tenon’s capsule), lacrimal gland, optic nerve and its meningeal covering, extraocular muscles, cartilaginous trochlea, blood vessels and delicate fibroadipose connective tissue

Floor of orbit is roof of maxillary sinus

Medial wall of orbit (lamina papyracea) separates orbit from ethmoidal sinuses

Proptosis: forward displacement of eyeball (or other organs), due to any disease that increases orbital contents, since orbit is closed medially, laterally and posteriorly

Exophthalmos: abnormal protrusion of eyeball

Optic nerve: surrounded by meninges and part of the central nervous system; not usually biopsied; often has psammoma bodies or drusen (calcified acellular globular concretions of nerve fibers); site of convergence of one million axons from retinal nerve fiber layer; nerve head accounts for physiologic blind spot in normal visual field; receives blood supply from branches of ophthalmic artery

Lamina cribrosa: site of myelination of optic nerve axons; highlighted with Luxol fast blue or other myelin stains

Trochlea: arc-shaped structure through which tendon of superior oblique muscle passes before insertion upon eyeball; the only cartilaginous structure in normal orbit

Exophthalmos is common symptom of orbital disease, although often due to thyroid disease and not biopsied

Other common causes of exophthalmos are mucocele from paranasal sinus, hemangioma, inflammatory pseudotumor

Tumors should be reported using formats published for their counterpart elsewhere in body

Drainage through submandibular, parotid and cervical lymph nodes through vascular anastomosis

Alveolar soft parts sarcoma of orbit

Indolent, similar to tumor at other sites

May have late metastases

Mean age 23 years, range 1-69 years; 76% women

Micro: organoid pattern outlined by thin-walled capillaries, composed of nests of large polyhedral cells with abundant, finely granular, eosinophilic cytoplasm

Positive stains: PAS+ diastase resistant crystalline structures

DD: paraganglioma, granular cell tumor, metastatic renal cell carcinoma, vascular tumor, alveolar rhabdomyosarcoma, amelanotic melanoma

References: Hum Path 1982;13:569

Anterior ischemic optic neuropathy

Various injuries to optic nerve from ischemia to infarction

May resemble stroke

Coloboma of optic nerve

Unilateral abnormality of optic nerve head, of congenital origin

Complete coloboma may form large hole or posterior protrusion near optic nerve

Micro: large defect with mostly bare sclera, lined by fibrous or glial tissue; may involve retina and choroids along its edges

Dermoid cyst of orbit

Congenital, but may not be clinically evident until age 20 years

Most common in superior temporal orbit; also eyelid

Gross: soft, nontender, round/oval cyst with thickened wall, 1 cm or less; contain yellow, cheesy material

Micro: encapsulated, lined by well differentiated epidermis and dermis, lumen filled with keratinous debris, hair, sebum; may have foreign body inflammatory reaction if cyst ruptures

Drusen

White-yellow irregularities of optic disc, may resemble papilledema

Micro: dark material in optic nerve head anterior to lamina cribrosa; material is acellular and basophilic, often calcified

Positive stains: acid mucopolysaccharides

Dysthyroid ophthalmopathy

Most common cause of orbital disease and exophthalmos

Associated with hyperthyroidism or thyroid-related treatment, although patient may be hyper-, hypo- or euthyroid at the time

Usually bilateral but may be unilateral

Most cases are not biopsied

Gross: marked enlargement of extraocular muscles

Micro: severe edema and chronic inflammation of orbital tissues; degeneration and hyalinization of extraocular muscles, with increase in interstitial connective tissue in muscles and other orbital tissue

Fibrous histiocytoma of orbit

Most common mesenchymal tumor of orbit in adults

Usually upper and nasal orbit

Mean age 43 years

Either benign, locally aggressive or malignant with recurrence rates of 31%, 57% and 64% and 10 year survival rates of 100%, 92% and 23% respectively (Hum Path 1982;13:199)

Treatment: complete surgical excision

Micro: storiform pattern of fibroblast and histiocyte-like cells; variable giant cells

Giant cell angiofibroma of orbit

Has features of solitary fibrous tumor and giant cell fibroblastoma of soft tissue

May be a giant cell rich variant of solitary fibrous tumor

Adults, mean age 45 years; in eyelid close to lacrimal gland or orbit; also posterior mediastinum, upper back, submandibular, parascapular regions

Appears to be a slow growing tumor, with occasional local recurrence

Gross: well circumscribed, nonencapsulated, mean 3 cm

Micro: highly vascular with round/spindle cells, numerous thick-walled vessels, collagenous or myxoid background and floret type multinucleated giant cells lining pseudovascular spaces

Positive stains: CD34, CD99, vimentin, bcl2

References: AJSP 2000;24:971, AJSP 1995;19:1286

Glioma of optic nerve

Relatively rare

Slow growing tumor within orbital segment of optic nerve

Usually ages 0-9 years with symptoms of minimal exophthalmos, optic nerve atrophy or papilledema

Associated with neurofibromatosis type 1

Radiology: thickening of nerve on CT scan; may enlarge optic canal

Treatment: resection for tumors limited to optic nerve; also radiation therapy for more extensive lesions

Gross: small tumors are limited to optic nerve; larger tumors form bulbous enlargement of nerve, often infiltrate pia causing arachnoid thickening

Micro: variable cytology and cellularity, even within same tumor, but usually are low grade pilocytic astrocytomas similar to cerebellar and third ventricle tumors, with round to spindled nuclei and dendrite-like cytoplasmic processes; often Rosenthal fibers (fusiform, cigar-shaped eosinophilic structures within astrocyte cytoplasmic processes, are a nonspecific degenerative change); rarely are hypercellular with brisk mitotic activity, marked pleomorphism, necrosis and vascular proliferation; difficult to differentiate reactive vs. neoplastic resection margins; typically has intense mucinous degeneration with tumor cells in pools of mucin; infiltrating tumor may cause reactive proliferation of arachnoid cells resembling meningioma

Granulocytic sarcoma of orbit

Localized focus of acute myelocytic leukemia

Hemangioblastoma of optic nerve

Case report in 43 year old woman, subsequently determined to have von Hippel-Lindau disease (Hum Path 1994;25:1249)

Hemangioma of orbit

Common; more common than lymphangioma

Usually cavernous, in young adults in retrobulbar space

Benign but slowly progressive; may cause chorioretinal stria or folds

Micro: encapsulated, large cavernous vascular channels or spaces separated by scant connective tissue stroma; spaces lined by single layer of endothelial cells with variable smooth muscle in walls

Infants

Soft, blue, compressible

Diffuse throughout orbit, may extend into eyelids

Usually regress by age 4, difficult to excise

Respond to short course of systemic steroids or radiotherapy

Micro: unencapsulated; usually capillary type with thin walled vessels; may have prominent mitotic activity

Adults

Encapsulated, close to back of eye

Can usually shell out tumors

Micro: usually cavernous type with large, blood filled, endothelium lined channels; thrombi often present, may calcify

Hemangiopericytoma of orbit

Resembles solitary fibrous tumor but prominent vessels

30% recur, 15% metastasize (lung, liver, bone, regional lymph nodes), usually late

Histology does not predict behavior (Hum Path 1982;13:210)

Case reports: 66 year old woman (Archives 2002;126:1555)

Micro: usually encapsulated; random pattern of polygonal and rounded cells with ill defined cytoplasm, variable nucleoli; staghorn vascular pattern and perivascular collagen, dense pericellular reticulin, occasional mitotic figures; must rule out other tumors with this pattern

Positive stains: CD34 (focal or weak), dense pericellular reticulin staining, vimentin; variable XIIIa

Negative stains: EMA, GFAP, S100, keratin, desmin, muscle specific actin, smooth muscle actin

DD: meningiomas (EMA+, complex interdigitating processes and desmosomes by EM, deletions of #22), solitary fibrous tumor (CD34 strongly+), fibrous histiocytoma (predominant storiform pattern; foam cells and giant cells present)

Idiopathic sclerosing inflammation of orbit

Insidious, chronic and progressive fibrosing process

Damages orbital structures by entrapment and mass effect

May have cell mediated pathogenesis, similar to retroperitoneal fibrosis (Mod Path 1993;6:581)

Micro: desmoplasia, sparse lymphocytes (usually T cells), histiocytes, plasma cells, neutrophils, eosinophils

Inflammatory processes of orbit

Usually secondary inflammation due to lesions in adjacent structures

Granulomas are rare; caused by tuberculosis, fungi, sarcoidosis, Wegener’s granulomatosis (multiple confluent granulomas, vasculitis with thrombosis, tissue necrosis)

Inflammatory pseudotumor of orbit

May not be a specific disease process, but due to various causes (paranasal sinus tumors, Rosai-Dorfman disease, inflammatory fibrosclerosis, dysthyroid ophthalmopathy, cholesterol or keratin granulomas, traumatic fat necrosis, prior hemorrhage or abscess)

More common than infectious granulomas

Usually ages 20-49 years with good health and sudden onset of exophthalmos with variable lid or conjunctival edema

Treatment: steroids (alleviate signs and symptoms), excision

Case report: tumor filling vitreous cavity of 50 year old man (Archives 2004;128:e5)

Gross: indurated orbital mass, often surrounding optic nerve and enveloping extraocular muscles

Micro: general - edematous tissue with excessive production of ground substance, chronic inflammatory cells, vascular proliferation and hyperplastic connective tissue; may have periphlebitis with tissue eosinophilia

Inflammatory myofibroblastic tumor: combinations of fibroblasts and myofibroblasts in background of plasma cells and other inflammatory cells

Rosai Dorfman related: large histiocytes, some with lymphocytophagocytosis, lymphocytes and plasma cells, often with prominent fibrosis

Positive stains: inflammatory myofibroblastic tumor - smooth muscle actin, variable ALK

DD: Hodgkin’s lymphoma, temporal arteritis, systemic lupus erythematosus

Lymphangioma of orbit

Usually young children

May wax and wane in size, particularly with upper respiratory infection

May rapidly increase in size due to hemorrhage

Gross: diffuse and poorly outlined

Micro: multiple, irregular lymphatic channels lined by flat endothelial cells; may have large lymphoid aggregates in wall

Lymphoma of orbit

Tumors composed of small lymphocytic proliferations confined to orbit are usually indolent and associated with long survival, even with minimal treatment

MALT lymphoma: uniform and monotonous proliferation of small lymphocytes infiltrating into orbital fat, blood vessels and nerves; may have plasmacytoid features with Dutcher bodies (intranuclear inclusions) and serum paraproteinemia; light chain restriction

Case reports: 5 year old girl with angiocentric orbital lesion with immature NK cell immunophenotype that spontaneously resolved (Hum Path 2001;32:339), NK-T cell lymphoma, nasal type, with distant metastases (Hum Path 2003;34:290)

Positive stains: monotypic immunoglobulins

DD: lymphoid hyperplasia (polymorphic lymphocytes, vascular proliferation, prominent follicles with germinal centers)

Meningioma of orbit

Arise from meninges of optic nerve or extension of cranial meninges; less common than intracranial tumor

Associated with hearing loss, optic atrophy and exophthalmos; also papilledema if arises near inner sphenoidal ridge

Micro: meningothelial pattern of whorled spindle cells, psammoma bodies

DD: exuberant arachnoid hyperplasia, fibrous histiocytoma, solitary fibrous tumor/hemangiopericytoma, metastatic carcinoma, juvenile ossifying fibroma

Metastases to orbit

Rarely is initial manifestation of childhood acute leukemia or adult carcinoma of breast, bronchus, kidney or prostate

Neuroblastoma and carcinoid tumor of lung or small bowel commonly metastasize to orbit (Hum Path 1982;13:459)

Primary embryonal rhabdomyosarcoma or carcinoid tumor of orbit may erroneously be interpreted as metastatic tumor

DD: direct spread from adjacent retinoblastoma, uveal melanoma or paranasal sinus carcinoma

Mucocele of orbit

Due to chronic inflammation of frontal or ethmoid sinus

Lesion erodes sinus wall, produces downward and lateral displacement of globe

Insidious onset with slow and asymptomatic enlargement

Micro: cystic mass lined by ciliated, mucus-secreting columnar epithelium with scarring and inflammation

Neurofibroma of orbit

Usually an expression of neurofibromatosis (also causes neurofibroma of eyelid and glioma of optic nerve)

May grossly deform orbit and eyelid

Optic atrophy

Loss of function of optic nerve with gliosis, loss of capillaries and loss of axonal tissue

Due to damage from within the eye (optic neuritis, papilledema, glaucoma, retina-choroid lesions), to optic nerve or brain (trauma, tumor, demyelinating disorders, hydrocephalus) or congenital (Leber’s optic atrophy)

Gross: white, pale disc

Micro: loss of substance of optic nerve due to degeneration of myelin sheaths and axons; dura appears redundant due to loss of substance; gliosis within nerve

Papilledema

Edema of head of optic nerve, usually bilateral

Due to nerve compression from elevation of cerebrospinal fluid pressure surrounding the nerve

Fundoscopic examination shows swollen optic nerve head with elevation, edema and narrowing of optic cup; also vascular congestion, flame-shaped hemorrhage, exudates, retinal edema

Micro: edematous axons in edematous stroma with vascular congestion

Rhabdomyosarcoma of orbit

Most common orbital sarcoma in childhood

Usually embryonal and alveolar subtypes (alveolar more aggressive)

Often rapid onset of unilateral proptosis

May occur after radiation therapy for retinoblastoma, close to previously irradiated fields

Micro: syncytium of strap cells with abundant eosinophilic cytoplasm; also closely packed small round cells with scanty cytoplasm, coarse nuclear chromatin and increased mitotic activity; many have minimal rhabdomyoblastic differentiation except in occasional mature strap cells with cross striations; alveolar pattern has fibrovascular septa resembling lung alveoli

Tumors in retinoblastoma patients may have rosette-like structures

Positive stains: myogenin, desmin, muscle specific actin (HHF35), vimentin, neurofilament

Negative stains: CD99; Rb in retinoblastoma patients only

References: AJSP 1998;22:1351 (post radiation therapy for bilateral retinoblastoma)

Schnabel cavernous degeneration of optic nerve

Defined as formation of cavernous spaces in retrolaminar portion of proximal optic nerve due to focal loss of myelin and axons and accumulation of hyaluronic acid

Present in < 0.1% of eyes at autopsy; 80% are women, mean age 88 years (range 54-103 years)

Associated with severe vascular anomalies (75%), glaucoma (24%)

Grading of cavernous degeneration: I-clearly present but <10% of diameter of optic nerve at point of most severe involvement; II-10-25%; III-50-75%; IV- >75%

References: Archives 2003;127:1314

Schwannoma of orbit

Uncommon in orbit

Well encapsulated

Treatment: excision

Shaken baby syndrome

Defined as intentional whiplash movement of infant’s head

Can be detected by beta-amyloid precursor protein immunohistochemistry to identify optic nerve damage in optic disk or distal optic nerve

Takes at least 2 hours to develop, staining intensity should exceed background

Also have severe bilateral, often multilayered retinal hemorrhages

Solitary fibrous tumor of orbit

Usually benign, but may be aggressive

See also giant cell angiofibroma, above

Lipomatous hemangiopericytomas may be variants of solitary fibrous tumors (Hum Path 2000;31:1108)

Case reports: t(9;22)(q31;p13) in 58 year old man with orbital tumor (Archives 2000;124:756), myxoid variant (Mod Path 1999;12:463)

Micro: solid with keloid-like collagen and alternating hyper- and hypocellular areas; hemangiopericytoma-like vessels

Positive stains: CD34, bcl2

References: AJSP 1994;18:281

Temporal arteritis

Sudden loss of vision in one eye, low grade fever, loss of appetite, general weakness

May be due to obstruction of posterior ciliary artery

Micro: granulomatous inflammation of arteries with discontinuous and fragmented internal elastic lamina; also arteriosclerosis

Wegener’s granulomatosis of orbit

May present initially or secondarily in orbit

Micro: multiple confluent granulomas, vasculitis with thrombosis, tissue necrosis

TNM staging for sarcoma of the orbit

Includes rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcoma, etc; also lymphoma, plasma cell tumors and melanocytic tumors

Primary tumor (T)

TX: primary tumor cannot be assessed

T0: no evidence of primary tumor

T1: tumor 15 mm or less in greatest dimension

T2: tumor more than 15 mm in greatest dimension without invasion of globe or bony wall

T3: tumor of any size with invasion of orbital tissues or bony walls

T4: tumor invasion of globe or periorbital structure, such as eyelids, temporal fossa, nasal cavity and paranasal 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

Retina

Retina-general

Embryologic derivative of diencephalon, responds to injury via gliosis

Composed of neurons and glial cells

Lines inside surface of eye posterior to ora serrata

Neurons give rise to retinoblastoma, glial cells to astrocytomas

No lymphatics

Layers from outside in:

(1) retinal pigment epithelium; (2) rods and cones; (3) external limiting membrane; (4) outer nuclear layer; (5) outer plexiform layer; (6) inner nuclear layer; (7) inner plexiform layer; (8) ganglion cell layer; (9) nerve fiber layer; (10) inner limiting membrane; (11) vitreous

Bruch’s membrane: separates choroid from overlying retinal pigment epithelium, is 2-4 microns thick, has 5 distinct layers (basal lamina of overlying retinal pigment epithelium, collagenous layer, elastic fiber-rich layer, collagenous layer and basal lamina of endothelial cells of choriocapillaris), thickens with age, has focal excrescences known as drusen

Retinal pigment epithelium is derived from primary optic vesicle, an outpouching of brain; helps maintain outer segments of photoreceptors (rods and cones); is a monolayer of cells containing intracytoplasmic melanosomes; has phagocytic function that assists in turnover of photoreceptor elements

Rods are cylindrical, cones are longer and thicker; light is converted by photoreceptor cells into electric impulses

Hemorrhage in nerve fiber layer appears in ophthalmoscope as horizontal streaks or flames

Hemorrhage in external retinal layers appears as dots

Fovea centralis: center of macula, slightly depressed, 1.5 mm in diameter, responsible for most visual acuity; lacks blood vessels and rods (relies on choroidal circulation)

Macula: has highest density of photoreceptors and high ganglion cell/photoreceptor ratio; ganglion cells are several layers thick

Macula lutea: yellow specialized portion of retina in posterior pole of eye

Ora serrata: irregular, anterior margin of retina, internal to junction of choroid and ciliary body

Retinal detachment: separation of neurosensory retina (rods and cones) from retinal pigment epithelium

Cysts develop in peripheral retina in everyone age 20+ years

Adenocarcinoma of retinal pigment epithelium

Rare, < 50 cases reported

More common in women

Often diagnosed as atypical choroidal melanoma clinically

Astrocytic tumor of retina

Associated with tuberous sclerosis (57%), neurofibromatosis (14%), no syndromes (29%)

Tuberous sclerosis patients usually have multiple, peripheral retinal tumors with giant astrocytes vs. disc-based tumors in non-tuberous sclerosis patients

Usually benign and extremely rare in retina

Micro: interlacing, spindle-shaped astrocytes

References: Archives 1984;108:160

Behcet’s disease

Obliterative vasculitis of retinal vessels

Central retinal artery occlusion

Causes a sudden, painless loss of vision

Retina is pale and white; may have edema and decreased vascularity; fovea has cherry red spot due to ischemic white retina surrounding normal choroidal blood flow

Micro: usually emboli within central retinal artery; early changes are ischemia of inner layers of retina; late changes are atrophy of inner layers of retina and gliosis

Central retinal vein occlusion

Painless decrease in vision, less severe than central retinal artery occlusion

May be partial/incomplete or complete

Fundoscopy: widespread retinal hemorrhage with swelling and edema

Micro: hemorrhage in all layers of retina with diffuse hemorrhage and ischemic changes

CMV infection

Usually acquired due to immunosuppression from tumors, chemotherapy, transplantation, AIDS

May be congenital

Fundoscopy: retinitis with sharply defined borders; may have brushfire appearance with necrosis and hemorrhage

Micro: coagulative necrosis with secondary choroid inflammation; retinal cells have large intranuclear and small intracytoplasmic inclusion bodies

Coats’ disease

Exudative retinopathy associated with retinal detachment and telangiectatic retinal vessels

Usually unilateral, young children, male predominant

Cystic macular edema

Often after cataract extraction or other surgical procedures

Due to diabetic retinopathy, retinal venous occlusion or other retinal vascular disease, ocular inflammation, drugs, tumor

Xray: stellate pattern on fluorescein angiography

Fundoscopy: honeycomb appearance due to fluid-filled cavities

Micro: exudative fluid in outer plexiform layer is amorphous and eosinophilic or appears as blank spaces

Detachment of retina

Separation of neurosensory retina (rods and cone and more superficial layers) from retinal pigment epithelium

Rhegmatogenous (“due to a rupture or fracture”) detachment: associated with full thickness retinal defect, such as collapse of vitreous, causing traction on retinal internal limiting membrane, causing tears and seepage of vitreous between neurosensory layer and retinal pigment epithelium; treated by relieving vitreous traction

Non-rhegmatogenous detachment: no retinal break; due to significant exudates or conditions causing leakage of fluid from choroidal circulation beneath the retina, such as choroidal tumors and malignant hypertension

Chronic retinal detachment may cause loss of photoreceptor outer segments, gliosis and development of microcystic spaces in detached retina

Micro: early changes are degeneration of outer retinal layers and photoreceptors with subretinal exudates; late changes are disruption and atrophy of retinal architecture with marked gliosis and proliferative vitreoretinopathy

Diabetes mellitus

Common cause of blindness in Western society

Classified as background, preproliferative or proliferative retinopathy

Background retinopathy: initial lesion is capillary microangiopathy

Preproliferative retinopathy: changes of background diabetic retinopathy plus significant venous dilation / beading, cotton wool spots (due to focal infarcts in nerve fiber layer), extensive formation of intraretinal microvascular abnormalities (due to vascular shunts) and extensive ischemia

Proliferative retinopathy: growth of neovascular tissue from inner surface of retina into vitreous; causes retinal detachment, treat with laser photocoagulation; may occur without clinically visible background diabetic retinopathy

Retinopathy is associated with duration of diabetes - 60% at 15 years

May cause rubeosis iridis (neovascularization of iris) and secondary glaucoma

Also causes thickening of basement membrane of pars plicata of ciliary body

Also causes vacuolization of iris pigment epithelium, with glycogen containing vacuoles related to blood glucose level at time of enucleation

Micro:

Background retinopathy: retinal capillary microaneurysms and cotton wool spots (due to hypoxia from microvascular obstructions and nonperfusion) with PAS+ deposits on endothelium, basement membrane thickening, loss of pericytes; also venous anomalies, hemorrhage (flame shaped between fibers of nerve fiber layer), exudates (hard, yellow, waxy protein and lipid of outer plexiform layer appears eosinophilic), edema

proliferative retinopathy: new vessels that sprout from existing vessels on surface of optic nerve head or retina and penetrate the internal limiting membrane of the retina; thickened basement membrane, reduction in number of pericytes (causes microaneurysms and arteriovenous shunts)

Hemangioblastoma

Associated with von Hippel Lindau disease

Most commonly in cerebellum, spinal cord and retina

Positive stains: factor VIII related antigen

Negative stains: GFAP (may be positive in reactive astrocytes)

References: Hum Path 1982;13:13

Hypertension

Retinal arteriolosclerosis causes thickened arteriolar wall; with ophthalmoscope, vessels appear narrow and blood changes from bright red to copper or silver

Since retinal arterioles and veins share a common adventitial sheath, marked arteriolosclerosis may cause compression of vein where both vessels cross

Elschnig’s spots: focal choroidal infarcts due to damage to choroidal vessels

Retinal exudates: due to damage to choriocapillaris (internal layer of choroidal vasculature), with accumulation between neurosensory retina and retinal pigment epithelium and possible detachment

Retinal arteriole damage from malignant hypertension usually accumulates in outer plexiform layer, and resembles macular star with ophthalmoscope; may cause inter-retinal flame-shaped or dot/blot hemorrhages

Infarcts in nerve fiber layer cause “cotton-wool spots”; infarcts are due to occlusion or AIDS related vasculopathy

Chronic hypertension causes onion-skin thickening of vessels

Lattice degeneration of retina

Bilateral condition that involves retina peripherally between ora serrata and equator

Associated with hyperpigmentation, condensed overlying vitreous forming adhesions to margins of lattice degeneration that may cause subsequent retinal detachment

Fundoscopy: circumferential area of involvement with small criss-crossing white lattice lines (thickened hyalinized blood vessels)

Micro: atrophic and thinned retina with superficial gliosis; thickened and hyalinized retinal vessels; overlying liquefaction of vitreous with vitroretinal adhesions at edge of lattice lesion

Macular degeneration

Age related (senile) macular degeneration is the most common cause of irreversible visual loss in US

Causes loss of central portion of vision

May be due to vascular disease in choriocapillaris and retinal pigment epithelium

Non-disciform (atrophic, dry type) causes slow, bilateral visual loss in elderly, with atrophy and degeneration of retinal pigment epithelium and choriocapillaris; also drusen

Disciform (wet, exudative type) is associated with more severe and acute vision loss; often after non-disciform degenerative changes and due to hemorrhagic retinal detachment secondary to neovascularization, as vessels from choriocapillaris penetrate through Bruch’s membrane beneath the retinal pigment epithelium and leak fluid / blood, which organizes into macular scars

Micro: small macular scars

Massive retinal gliosis

Relatively uncommon

Large elevated scar near disc and posterior pole after hemorrhage or inflammation

Pleomorphic xanthoastrocytoma

Retinal tumor similar to tumor of brain and spinal cord

Gross: well circumscribed mass with cystic component

Micro: large pleomorphic cells with eosinophilic cytoplasm, enlarged vesicular nuclei with prominent nucleoli and calcium deposits; also cells with markedly swollen cytoplasm containing lipid, spindled cells and multinucleated cells

Positive stains: GFAP, CD68

References: AJSP 1999;23:79

Retinal dysplasia

Congenital anomaly associated with trisomy 13 (retinal pigment epithelium within optic nerve) or unilateral malformed eye not associated with other anomalies (such as persistent hyperplastic primary vitreous)

Micro: series of straight branching tubes composed of abortive rod and cone layers

References: Archives 1977;101:540

Retinitis pigmentosa

Various inherited retinal disorders that are not actually inflammatory

Common (incidence of 1/3600) with variable inheritance or as part of Refsum’s disease

Usually causes loss of rods and cones to apoptosis and focal proliferation of retinal pigment epithelium

Loss of rods causes early night blindness and restricted visual fields (bilateral loss of peripheral vision)

Loss of cones affects central visual acuity

Retinal atrophy causes constriction of retinal vessels, optic nerve head atrophy and accumulation of retinal pigment around blood vessels

Micro: migration of macrophages and retinal pigment epithelial cells with melanin into retina, particularly around vessels; also atrophy of photoreceptors in retina and choriocapillaris

Retinoblastoma

Most common intraocular tumor of children, with incidence of 1 per 20,000 live births

May be congenital, but not recognized until ages 6 months to 2 years

60% sporadic, 40% familial (autosomal dominant)

Develops in 80-90% of those with mutant alleles in retinoblastoma (Rb) gene at 13q14

Need mutations in both alleles to inactivate Rb gene, a negative growth regulator

Patients with hereditary retinoblastoma have a germline mutation in one allele; develop tumors after somatic mutation in second allele (“second hit”); in sporadic cases, both alleles have somatic mutations

Bilateral in 30% of all cases, 90% of familial cases; some patients with bilateral tumors also have similar tumor of pineal gland, termed “trilateral” retinoblastoma, associated with poor prognosis

White reflex (leukokoria) present in affected eye; also retinal detachment

Tends to invade optic nerve (particularly large exophytic tumors with secondary glaucoma); can invade uveal tract

Distant metastases to cranial vault, skeletal system

Second primaries for familial tumors: 6-20% after 10-20 years, usually osteosarcoma (50% of tumors) and rhabdomyosarcoma, close to irradiated fields; also rhabdoid tumors

5 year survival: 90% if unilateral, slightly less if bilateral

Poor prognostic factors: invasion of optic nerve (report as prelaminar or retrolaminar involvement, with or without resection line involvement), invasion of uveal tract or sclera, seeding of vitreous, involvement of anterior segment; differentiation does not appear to have prognostic value

Treatment: early - radiation therapy, cryopexy, xenon arc photocoagulation; large tumors - enucleation; involvement of optic nerve margin - radiation of orbit and systemic chemotherapy; bilateral tumors - radiation therapy to less affected eye with possible chemotherapy or bilateral radiation; recurrences - photocoagulation, cryotherapy or cobalt disks

Case reports: bladder leiomyosarcoma 47 years after enucleation (but no radiation) of unilateral familial retinoblastoma (Archives 2001;125:1231), sinonasal small cell neoplasm 18 years after radiation therapy (Hum Path 1992;23:896)

Gross: creamy white with chalky areas of calcification and yellow necrotic areas; may grow inward (endophytic) or outward toward choroid (exophytic); rarely are diffusely infiltrative; typically seeds intraocularly

Micro: sheets, trabeculae and nests of small blue cells with scant cytoplasm, hyperchromatic nuclei and scanty stroma; frequent necrosis of tumor cells away from vessels and calcification; also Flexner-Wintersteiner rosettes (cells line up around empty lumen delineated by a distinct eosinophilic circle composed of terminal bars analogous to outer limiting membrane of normal retina); also Homer-Wright rosettes (nuclei are displaced away from lumen), fluerettes (tumor cells arranged side by side which show differentiation towards photoreceptors); frequent Azzopardi phenomena (basophilic deposits around blood vessels, also seen in small cell carcinoma); frequent mitotic figures; variable apoptotic cells

Differentiated retinoblastoma: bipolar-like cells are present

Undifferentiated retinoblastoma: large, anaplastic cells without rosette formation

Retinocytoma: marked photoreceptor differentiation; cells have abundant cytoplasm, less hyperchromatic nuclei; benign, with calcification but without necrosis or mitotic activity

Positive stains: neuron-specific enolase, synaptophysin, S100, Leu7, GFAP, myelin basic protein, p53; high Ki-67

Negative stains: CD99

EM: evidence of photodifferentiation

DD: traumatic retinal detachment, retrolental fibroplasia, persistent hyperplastic primary vitreous, massive retinal gliosis, Coats’ disease, visceral larval migrans, astrocytoma of tuberous sclerosis, medulloepithelioma

Retrolental fibroplasia

Also called retinopathy of prematurity

Previously was leading cause of blindness in US

Occurs in premature infants given oxygen therapy; related to level and duration of oxygen, degree of prematurity at birth, status as carrier for defect in Norrie disease gene

Immature vessels of premature infants are damaged by high or even physiologic oxygen; rarely occurs in term infants

Pathophysiology: oxygen therapy causes vasoconstriction and obliteration of immature retinal vessels in lateral (temporal) retina, which causes ischemia and failure of retina to vascularize; then vasoproliferative phase and angiogenesis; vessels grow into vitreous or leak serum or fluid, 25% have associated scarring, which causes retinal detachment

Sickle cell retinopathy

Either proliferative or nonproliferative; both lead to vascular occlusion

Reduced oxygen tension causes sickling, then microvascular occlusions cause hemorrhages; organization may cause traction and retinal detachment or neovascularization

Toxoplasmosis

Common as an entity, rare in surgical specimens

May be due to reactivation of congenital infection

Diffuse retinal necrosis is associated with AIDS

Fundoscopy: optic nerve appears as “headlight in fog”, leading to large scar

Micro: focal areas of coagulative necrosis in retina, surrounded by granulomatous inflammation of choroid and sclera; scar shows abrupt transition of normal retina to scarring with extension disruption of retina, retinal pigment epithelium and choroid with marked disruption of pigment; cysts of Toxoplasma gondii within necrotic retina

Tuberous sclerosis

Also called Bourneville’s syndrome

A type of phakoma

Phakoma: hamartomatous malformation associated with extraocular lesions as part of a well-defined clinicopathologic syndrome

Micro: glial plaques and nodules in retinal nerve fiber layer, which may simulate retinoblastoma

Visceral larva migrans

A type of nematodiasis (parasitic disease)

Somewhat common in US and Great Britain

Usually produced by Toxocara canis in children ages 3-14 years without systemic disease

Single migrating larva enters eye hematogenously and rests in vitreous or inner surface of retina, with accompanying acute and chronic inflammatory cells and intense eosinophilia

Late changes are scarring, retinal detachment and leukokoria, simulating retinoblastoma

Dead larvae may cause minute granulomas, found with serial sectioning

von Hippel-Lindau disease

Also called angiogliomatosis

Abnormally large tortuous arteries and veins leading to a retinal nodule composed of vascular, endothelial and glial tissue

Associated with retinal detachment and vitreous disturbance

Wyburn-Mason syndrome

A phakoma with arteriovenous shunts of retinal vessels

Miscellaneous

Tumor features to report-retinoblastoma

Tumor location

Number, size and location of lesion(s)

Differentiation (poorly differentiated, Flexner-Wintersteiner rosettes, Homer-Wright rosettes, fleurettes)

Growth pattern (diffuse, unifocal, multifocal)

Extraocular extension or choroidal invasion

Presence or absence of vitreous seeding

Presence of absence of retinal detachment

Invasion into optic nerve (prelaminar, to lamina cribrosa, retrolaminar, posterior resection margin)

Involvement or noninvolvement of other structures submitted

Margins (minimum clearance)

Angiolymphatic invasion

Tumor necrosis, calcification, DNA deposition around blood vessels, anterior chamber seeding, retinal or iris neovascularization

TNM for retinoblastoma

Pathologic classification

Primary tumor (T)

pTX: primary tumor cannot be assessed

pT0: no evidence of primary tumor

pT1: tumor confined to retina, vitreous or subretinal space. No optic nerve or choroidal invasion

pT2: minimal invasion of optic nerve or optic coats

pT2a: tumor invades optic nerve up to, but not through, the level of the lamina cribrosa

pT2b: tumor invades choroid focally

pT2c: tumor invades optic nerve up to, but not through, the level of the lamina cribrosa and invades the choroid focally

pT3: significant invasion of the optic nerve or optic coats

pT3a: tumor invades optic nerve through the level of the lamina cribrosa but not to the line of resection

pT3b: tumor massively invades the choroid

pT3c: tumor invades the optic nerve through the level of the lamina cribrosa but not to the line of resection and massively invades the choroid

pT4: extraocular tumor extension that includes: invasion of optic nerve to the line of resection, invasion of orbit through the sclera, extension both anteriorly or posteriorly into the orbit, extension into the brain, extension into the subarachnoidal space of the optic nerve, extension to the apex of the orbit, extension to but not through the chiasm, or extension into the brain beyond the chiasm

Regional lymph nodes (N)

pNX: regional lymph nodes cannot be assessed

pN0: no regional lymph node metastasis

pN1: regional lymph node metastasis

Distant metastasis (M)

pMX: distant metastasis cannot be assessed

pM0: no distant metastasis

pM1: distant metastasis

pM1a: bone marrow

pM1b: other sites

Stage grouping

No stage grouping is presently recommended

Uvea (iris, choroid and ciliary body), limbus and sclera

Uvea: the vascular middle layer of the eye constituting the iris, ciliary body, and choroid.

Choroid-general

Middle layer of globe between outer sclera and inner retina

Highly vascular but no lymphatics

Extends from ciliary body to optic nerve

Inner aspect is adherent to retinal pigment epithelium; outer surface is loosely attached to overlying sclera

Stroma contains abundant pigmented melanocytes

Choriocapillaris: in innermost choroidal stroma adjacent to Bruch’s membrane, connects with arterial and venous channels from vessels in outer choroidal stroma, to nourish outer retinal layers

Ciliary body-general

Middle segment of uveal tract, between iris and choroid

Composed of pars plicata and pars plana

Holds lens in place

Pars plicata: 70 sagitally oriented folds or ciliary processes that gradually merge with posterior flat pars plana, which merges posteriorly with serrated, anterior border of retina (ora serrata)

Ciliary epithelium composed of inner epithelial layer (nonpigmented, contiguous with aqueous of posterior chamber) and outer epithelial layer (pigmented, unites with retinal pigment epithelium at ora serrata)

Outer epithelial layer overlies PAS+ basal lamina that thickens in diabetes mellitus

Zonules: acellular fibers that attach crests of nonpigmented ciliary epithelium in pars plicata to capsule of crystalline lens

Ciliary body has 3 distinct bundles of smooth muscle, which assist in accommodation; as muscle contacts, ciliary body extends forward, reducing pressure on zonules, enabling lens to become less concave, thereby increasing its refractive power

Iris-general

Thin diaphragm of tissue with central opening (pupil)

Forms boundary of anterior and posterior chamber

Highly textured with folds and crypts

Part of middle layer of eye (also ciliary body and choroid)

Normally rests gently upon lens and bulges slightly forward

Consists of stroma and posterior epithelial lining (two closely apposed epithelial layers, with numerous melanosomes); contains sphincter muscle within stroma that controls pupil

Anterior iris lacks a cellular lining

Color is due to number of stromal melanocytes; blue irises have few stromal melanocytes; brown irises have numerous melanocytes

Blood vessels are usually surrounded by a thick collar of collagen fibers, resembling arteriolosclerosis

Fewer melanosomes and melanocytes in patients with ocular and oculocutaneous albinism

Regulates amount of light reaching pupil; muscles of iris dilate or constrict pupil in response to parasympathetic or sympathetic nerve impulses; normal diameter of pupil is 1-8 mm

Ectropion uveae: fibrovascular tissue on anterior surface of iris everts the papillary margin and pulls pigmented epithelia onto anterior surface of iris

Sclera-general

80% of surface area of eye

Begins at periphery of cornea, extends posteriorly to optic nerve

Relatively rigid; protects eye from trauma and maintains intraocular pressure

Visible anteriorly under transparent conjunctiva; white in adults

Thin areas are at limbus, behind insertion of rectus muscles and at insertion of optic nerve

Composed of episclera, stroma, lamina fusca

Episclera: most superficial part of sclera, located between fibrous structure that envelopes the globe (Tenon’s capsule) and scleral stroma; composed of loose collagen fibers and fibroblasts with numerous vessels, occasional melanocytes and mononuclear white blood cells

Stroma: largest component of sclera, randomly arranged bands of collagen with occasional elastic fibers and fibroblasts; minimal blood vessels except in perforating emissiary canals, accompanied by nerves and scattered melanocytes; rarely contains a prominent nerve in an emissiarial canal near limbus

Lamina fusca: innermost layer of sclera with loose collagen fibers, fibroblasts and scattered melanocytes

Heals poorly due to few blood vessels or fibroblasts

Adenoma of pigmented ciliary epithelium

Case report of tumor causing unilateral cataract (Hum Path 2000;31:882)

Microscopic foam cells are actually artifacts

Aniridia

Congenital absence of all but the root of the iris

Associated with Wilm’s tumor

Anterior chamber cleavage syndrome

Also called iridogoniodysgenesis

Obvious architectural distortion of iris and angle of anterior chamber

Causes congenital glaucoma

Blue sclera

Due to scleritis, thin sclera secondary to high intraocular pressure, osteogenesis imperfecta, congenital melanosis oculi (heavily pigmented congenital nevus of underlying uvea)

Coloboma

Defective formation of iris and ciliary body

Diffuse uveal melanocytic proliferation

Bilateral paraneoplastic syndrome associated with poorly differentiated tumors of uterus and ovary

May lead to blindness

Fuchs’ adenoma

Also called benign ciliary epithelioma, coronal adenoma

Benign tumor of ciliary body

Usually incidental finding in enucleated eye or at autopsy

Micro: interlacing trabeculae of uniform, nonpigmented ciliary epithelial cells, surrounded by amorphous, PAS+ hyaline material

Herpes zoster

Micro: chronic inflammatory infiltrate around posterior ciliary nerves and vessels

Hypertensive changes

Includes intimal thickening due to smooth muscle cell migration, hyaline deposits in subendothelium, degeneration (moth-eaten atrophy and necrosis) of medial smooth muscle cells, recanalization and obstruction

Also thrombotic occlusion or narrowing of choroidal artery in patients with hypertension and diabetes mellitus and either chronic azotemia or renal insufficiency

References: Hum Path 1988;19:99

Idiopathic solitary granuloma of uveal tract

Unilateral, associated with uveal effusion and total retinal detachment

Usually between pars plana ciliaris and equator

Iris pigment epithelial cyst

May arise from posterior iris pigment epithelium or at papillary margin

Usually benign

Attached to iris or free floating; may resemble melanoma

Micro: lined by epithelial cells

Juvenile xanthogranuloma

Iris lesion of young children causing spontaneous hyphema (hemorrhage into anterior chamber) or secondary glaucoma

Associated with similar skin lesions

Leiomyoma

Ciliary body or iris

Lisch nodules

Pigmented iris hamartomas

Associated with neurofibromatosis type 1, also familial angiolipomatosis, a benign condition with no malignant potential (Archives 1999;123:946)

Micro: dome shaped papules on anterior surface of iris, consisting of aggregates of ovoid to round cells

Positive stains: S100, vimentin

DD: iris melanoma, nevi, neurofibromatosis, trauma

Medulloepithelioma

Also called dikytoma

Rare, resembles embryonic retina

Usually arises from ciliary epithelium, rarely from optic nerve or retina

Melanoma of uvea

Most common adult intraocular neoplasm in US and Western Europe (20 per million annually)

8x more likely in whites vs. blacks; rare in Africa and Asia

Arises from pigmented or potentially pigment producing cells of uvea, usually choroid, least commonly in iris

All ages

Associated with malignancies at other sites as a paraneoplastic process; etiology is unclear; probably does not evolve from nevi (found in 10% of all whites)

Usually presents with visual disturbance due to retinal detachment or symptoms from tumor necrosis such as endophthalmitis, intraocular hemorrhage or secondary glaucoma

5 year survival: 90-100% for pure spindle A, 66-75% for spindle B, 50% for spindle B/epithelioid, 25-33% for pure epithelioid; prognosis is based on presence of even a few cells in most aggressive category

Favorable prognostic factors: cell type (see above), small size (lateral extent), iris better than choroid which is better than ciliary body, no extension into sclera, no necrosis, no lymphocytic infiltration, indistinct nucleoli, low MDR1 expression, no looping patterns of PAS+ laminin surrounding packets of tumor cells

Tends to spread through scleral emissary canals, rarely to optic nerve; distant metastases to liver, lung, pleura, brain, bone, skin (resembles blue nevi)

Regional lymph nodes are preauricular (parotid), submandibular and cervical

Treatment: traditionally enucleation; also iridectomy or iridocyclectomy if tumors are small; also thermoradiotherapy, photocoagulation

Melanoma of iris: presents as elevated mass with variable pigmentation, often with distortion of pupil and prominent vessels

Melanoma of choroid: irregular, slate-gray, solid, subretinal tumor that commonly extends through Bruch’s membrane into retina and vitreous, producing retinal detachment, macular edema, choroidal hemorrhage; occasionally spreads along scleral canals into orbit, rarely invades optic nerve

Melanoma of ciliary body: may interfere with accommodation or cause localized cataract

Micro: mixtures of spindle A, spindle B and epithelioid cells

Spindle A: cohesive cells, slender, bland, with indistinct cell borders, scant cytoplasm, small fusiform nuclei and no nucleoli; chromatin arranged in linear axis along central axis; may represent pigmented nevi; appear benign

Spindle B: cohesive cells are larger and more pleomorphic than spindle A with more cytoplasm, large oval nuclei and prominent nucleoli, prominent mitotic activity

Epithelioid: cells are even larger and irregular than spindle B, with abundant cytoplasm and well demarcated cell borders; may be marked enlarged or multinucleated; has large nuclei and very prominent nucleoli; usually less cohesive than spindle A or B

Positive stains: S100, HMB45, vimentin, CAM5.2, p53, bcl2 (Archives 1996;120:497)

Molecular: monosomy 3, trisomy 8q, abnormalities of #6; spindle A are diploid, some spindle B and epithelioid melanomas are aneuploid (Hum Path 1995;26:99)

DD: metastatic carcinoma (if amelanotic), metastatic melanoma, retinal hemorrhage, focal proliferation of retinal pigment epithelium, posterior scleritis, nevi, hemangioma

Mesenchymoma of uveal tract

Very rare

Case report of 21 year old woman with malignant tumor on whole iris, causing intractable glaucoma (Archives 1995;119:844)

Micro: anaplastic tumor with rhabdomyosarcomatous and liposarcomatous characteristics

Nevi of choroid or iris

Common

Detected during ophthalmic exams

Most do not progress; at risk for malignancy if thick or enlarging circumference

Iris nevi are elevated on iris surface

Post-traumatic uveitis

Often granulomatous uveitis that may lead to sympathetic uveitis

DD: lens-induced endophthalmitis (phacoanaphylaxis), foreign bodies, blood in vitreous

Rubeosis iridis

Neovascular membrane on surface of iris

Leads to peripheral anterior synechiae. outflow obstruction and secondary glaucoma

Associated with diabetes, occlusion of central retinal artery/vein or carotid artery, longstanding retinal detachment, chronic uveitis, intraocular tumor

Sarcoidosis in uvea

Systemic granulomatous disease, usually affecting young adult blacks

Uvea involved in 1/3

May cause “mutton-fat” corneal precipitates; also granulomas in choroid, retinal perivascular inflammation with candle wax drippings near retinal vessels and retinal hemorrhages

Patients often have conjunctival granulomas (non-caseating)

Micro: noncaseating granulomas; also asteroid bodies (small, eosinophilic star-shaped inclusions in epithelioid cells) or Schaumann’s bodies (darker ovoid inclusions)

DD: tuberculosis, leprosy, syphilis, tularemia, CMV, varicella zoster virus, fungi, parasites

Scleritis

Necrotizing scleritis may be part of collagen vascular disease (rheumatoid arthritis)

Senile scleral plaques

Just anterior to insertion of lateral or horizontal rectus muscles

Apparently due to accumulated actinic damage from solar radiation

Micro: increased hematoxylinophilia of scleral collagen, decreased stromal cellularity, scleral fibers with corkscrew appearance, calcium deposition, elastosis

References: Hum Path 1991;22:557

Sympathetic uveitis

Also called sympathetic ophthalmia

Rare; injury in one eye causes severe inflammation that may progress to blindness in uninjured as well as injured eye via presumed autoimmune response to retinal antigens

Lesion usually confined to uveal tissues and involving entire uveal tract

Retina may develop perivasculitis; injured lens develops phakogenic endophthalmitis

Treatment: immunosuppressive agents

Micro: diffuse and dense infiltration of choroid by lymphocytes and granulomas; also similar involvement of ciliary body and iris; patchy accumulations of small, irregular pale-staining epithelioid cells (Dalen-Fuchs’ nodules) containing fine melanin granules; moderate eosinophils, rare plasma cells, no neutrophils

Uveitis

Anterior uveitis (iridocyclitis)

Diffuse infiltration by plasma cells, occasionally nodular lymphocytic infiltrates

Associated with obliteration of anterior chamber and adherence of iris to cornea

May be seen in juvenile rheumatoid arthritis

Posterior uveitis (choroiditis, chorioretinitis)

Diffuse, focal or scattered chronic inflammatory infiltrate, often involving retina

May form cyclitic membrane that contracts, leading to detachment of retina and ciliary body

Not painful, so enucleation often not necessary

Enucleation if recurrence leads to adhesions between iris and cornea (anterior synechiae) or iris and anterior surface of lens (posterior synechiae) causing secondary glaucoma

Cause usually cannot be determined; known causes are herpes zoster, Behcet’s disease (obliterative vasculitis of retinal vessels), pneumocystis carinii

Sympathetic uveitis and post-traumatic uveitis are described above

Granulomatous uveitis: may be due to sarcoidosis; also tuberculosis, leprosy, syphilis, tularemia, CMV, varicella zoster virus, fungi, parasites

Miscellaneous

Tumor features to report-uveal tumors

Histologic type

Cell types present (for melanomas)

Precise anatomic location (iris, ciliary body, choroid), relative to clock hour

Tumor size

Extraocular extension

Growth pattern (diffuse, ring, focal)

Dimension of largest diameter in contact with sclera

Color of surface lesion and cut surface of lesion

Involvement or noninvolvement of other structures present

Margins (minimum clearance)

Mitotic figures per 40 high power fields

Presence of absence of 100 tumor infiltrating lymphocytes per 40 high power fields

Presence of matrix rich microcirculation associated loops, networks or parallel with cross linking structures

Angiolymphatic invasion

Presence of retinal detachment or hemorrhage

Involvement of intrascleral emissary channels

For melanomas, indicate thickness and mitotic activity, color of surface lesion

Other features present: drusen, neovascularization, nevi, etc.

References: Archives 2001;125:1177 (uveal melanoma)

TNM for uveal melanoma

Apply to both clinical* and pathologic staging

Primary tumor (T) - all uveal melanomas

TX: primary tumor cannot be assessed

T0: no evidence of primary tumor

Iris

T1: tumor limited to iris

T1a: tumor limited to iris, not more than 3 clock hours in size

T1b: tumor limited to iris, more than 3 clock hours in size

T1c: tumor limited to iris with melanomalytic glaucoma

T2: tumor confluent with or extending into ciliary body or choroid

T2a: tumor confluent with or extending into ciliary body or choroid with melanomalytic glaucoma

T3: tumor confluent with or extending into ciliary body or choroid with scleral extension

T3a: tumor confluent with or extending into ciliary body with scleral extension and melanomalytic glaucoma

T4: tumor with extraocular extension

Melanomalytic glaucoma: a type of secondary open angle glaucoma in melanoma patients with pigment laded macrophages that clog the trabecular meshwork

Ciliary body and choroid

T1*: tumor 10 mm or less in greatest diameter and 2.5 mm or less in greatest height (thickness)

T1a: tumor 10 mm or less in greatest diameter and 2.5 mm or less in greatest height (thickness) without microscopic extraocular extension

T1b: tumor 10 mm or less in greatest diameter and 2.5 mm or less in greatest height (thickness) with microscopic extraocular extension

T1c: tumor 10 mm or less in greatest diameter and 2.5 mm or less in greatest height (thickness) with macroscopic extraocular extension

T2*: tumor 10 mm to 16 mm in greatest basal diameter and between 2.5 and 10 mm in maximum height (thickness)

T2a: tumor 10 mm to 16 mm in greatest basal diameter and between 2.5 and 10 mm in maximum height (thickness) without microscopic extraocular extension

T2b: tumor 10 mm to 16 mm in greatest basal diameter and between 2.5 and 10 mm in maximum height (thickness) with microscopic extraocular extension

T2c: tumor 10 mm to 16 mm in greatest basal diameter and between 2.5 and 10 mm in maximum height (thickness) with macroscopic extraocular extension

T3*: tumor more than 16 mm in greatest diameter or greater than 10 mm in maximum height (thickness) without extraocular extension

T4*: tumor more than 16 mm in greatest diameter or greater than 10 mm in maximum height (thickness) with extraocular extension

*When basal dimension and apical height do not fit this classification, the largest tumor diameter should be used for classification. In clinical practice, the tumor base may be estimated in optic disc diameters (dd) (average: 1 dd = 1.5 mm). The height may be estimated in diopters (average: 3 diopters = 1 mm). Techniques such as ultrasonography, visualization and photography are frequently used to provide more accurate measurements.

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

I : T1-T1c N0 M0

II : T2-T2c N0 M0

III : T3-T4 N0 M0

IV : Any T, N1 M0 or Any T, any N, M1

End of Eye chapter/outline

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