melanotic lesions of the eye charleen t. chu, m.d., ph.d. division of neuropathology university of...

Melanotic Lesions of the Eye

Charleen T. Chu, M.D., Ph.D.Division of Neuropathology

University of [email protected]

April 2002

Copyright ©2002 CT Chu

mailto:[email protected]







Pigmented Cells of the Eye

Eyelid and Conjunctiva– Neural crest derived melanocytes

Uvea (“grape”) or tunica vasculosa

– Middle layer of the globe– Iris, ciliary body, choroid

– Epithelial and stromal compartments

Uvea (“grape”)

Evisceration specimen

Melanin producing cells - Embryology

Pigmented epithelia

Stromal melanocytes

– Neuroepithelium of embryonic optic cup

– Neural crest - similar to those found in skin

Migration of neural crest derived stromal melanocytes continues after birth

2-4 weeks - Invagination of optic cup

Images modified from Apple & Rabb, Ocular Pathology 5th ed, © 1998 Mosby-Year Book

Ciliary Body

© 2002 CT Chu

© 2002 CT Chu

© 2002 CT Chu

Retina and choroid

RPE and Choroidal Melanocytes

QuickTime™ and aPhoto - JPEG decompressor

are needed to see this picture.

Modified from Yanoff & Fine, ©1996 Mosby-Times Mirror Int.

Bruch’s membrane

Pigment epithelium

Stromal melanocytes

Case 158 year old man with serous detachment of the retina

What might be the most relevant prognostic feature?

AB

C

Case 1

© 2002 CT Chu

© 2002 CT Chu

Choroidal Melanoma, Spindle B Typewith transcleral extension along an

emissary channel (vortex vein)

Choroidal Melanoma Most common intraocular tumor Classic mushroom shape - rupture into vitreous If metastatic - tend to go to _________.

Prognosis– Largest dimension, particularly along base– Extension into canal of Schlemm, emissary channels– Cytology– Location

LIVER

DDx: Diffuse uveal thickening?

DDx Diffuse Uveal Thickening

Diffuse, flat melanoma of the choroid Metastatic carcinoma Lymphoid/leukemic infiltrates Sympathetic uveitis Vogt-Koyanagi-Harada syndrome Phacoanaphylactic uveitis

Spindle A - grooves

<< Modified from Yanoff & Fine, ©1996 Mosby-Times Mirror Int.

© 2002 CT Chu

Spindle B - nucleoli © 2002 CT Chu

Epithelioid

Case 2

84 year old woman with blind eye and 2 week history of eye pain and inflammation.

Mass detected by ultrasound

FNA performed

Case 2

© 2002 CT Chu

Necrotic Choroidal Melanoma (with residual epithelioid and spindle A cells)

and Transcleral Extension

Choroidal Melanoma - cytology

Spindle A, Spindle B, Epithelioid, Necrotic– Most are mixed– Significant epithelioid component - worse prognosis

– Infarcted tumors can cause significant ocular inflammation >> misdiagnosis in “blind painful eyes”

Spindle only - 22% death rate

Necrotic, mixed, epithelioid - 62% death rate

Uveal melanoma - location Tumors of the iris - ______ prognosis Tumors of the posterior temporal pole -

_______ prognosis Tumors of the ciliary body and the

peripheral choroid - ______ prognosis

Early detection

Proximity to meshwork and related structures

better

better

worse

© 2002 CT Chu

Modified from Apple & Rabb, Ocular Pathology, © 1998 Mosby-Year Book

Anterior ciliary artery, venous drainage from meshwork, ciliary nerves

Vortex vein

Short and long posterior ciliary arteries

Epibulbar Mass




DDx of Pigmented Epibulbar Masses

Conjunctival nevus or melanoma Extraocular extension of uveal melanoma Foreign body “Pigment spots of the sclera”

– Recurrent nerve loop of Axenfeld Hematoma



Melanoma exiting through anterior scleral canal

Images modified from Yanoff & Fine, ©1996 Mosby-Times Mirror Int.

Nerve with associated melanocytes

Pigment spots of the sclera People with dark irises Located 3-4 mm from the limbus Collections of melanocytes associated

with:

Conjunctiva remains freely mobile over the pigment spot and nerve remains painful after anesthesia

– Anterior ciliary vessel– Intrascleral nerve loop of Axenfeld

Case 3 80 year old woman Corneal transplant Expulsive choroidal hemorrhage

© 2002 CT Chu

Case 3

© 2002 CT Chu

Your diagnosis?

What if this lesion measured 16 x 10 mm?

What if this was a 55 year old African American man?



What if I told you this is then classic location for this tumor?


Melanocytoma

(Magnocellular Nevus)

Bleached slide - H&E

What special technique might be helpful for demonstrating benign cytology?

Image courtesy of Bruce Shields, presented EOPS ‘99

Suspect melanocytoma

Maximally pigmented Uniform, polyhedral cells Low N/C ratio Typically affect inferior temporal aspect of optic disc

(but can occur anywhere in uvea and sclera)

Skin tone of patient

Melanocytoma - Clinical Characteristics 10 times more likely to occur in dark-

skinned individuals In contrast, uveal melanomas are 15

times more likely to occur in Caucasians Benign lesion with low malignant

potential

Caveat: choroidal melanomas can invade optic disc

– 15% will enlarge over time, can locally infiltrate choroid and optic nerve beyond lamina cribosa



Modified from Yanoff & Fine, Ocular Pathology ©1996 Mosby-Times Mirror Int.

Modified from Okazaki & Scheithauer, Slide Atlas of Neuropathology © 1991 Gower Medical Pub.

Multiple iris nevi associated with NF2 (Lisch Nodules)

© 2002 CT Chu

Case 4

Orbital exenteration for morpheaform BCC

© 2002 CT Chu

RPE hypertrophy Melanotic RPE nevus, benign “melanoma” of

the RPE of Reese and Jones Round or oval, jet black, flat lesion Can be surrounded by halo or contain punched

out yellow, depigmented patches Hypertrophy of RPE cells, increase in size of

melanosomes May be associated with Gardner’s syndrome -

4 or more RPE hamartomas early marker 5q21

Reactive hyperplasia of the RPE

© 2002 CT Chu

© 2002 CT Chu

Reactive PE Proliferation Pseudoneoplastic proliferations

– “Invasion” of neural retina

– Intravitreal extension of papillary cords and nests of pigmented and nonpigmented epithelia with abundant BM material

– “Fuchs’ adenoma” - of pars plicata

Drusen Metaplasia

– Fibrous - macular scarring in ARMD– Osseus

Reactive PE Proliferation

TRAUMA LONG-STANDING OCULAR

INFLAMMATION LONG-STANDING DIABETES Retinitis pigmentosa Homocystinuria Ringschwiele or demarcation line

Neoplastic transformation of uveal epithelia is very rare.

© 2002 CT Chu © 2002 CT Chu

What type(s) of neoplasms arise from pigmented uveal epithelia?

Pleomorphic Adenoma, Adenocarcinoma of the ciliary body

Tubulo-papillary or vacuolated solid pattern, Variable pigmentaion Nuclear atypia common, mitoses rare Vimenin, S-100, low MW keratins, Sparse stroma (BM and hyaluronic acid) CA - histologic dx, locally invasive, rare

extrascleral extension, and no distant mets

Images courtesy of Barbara Streeten (presented EOPS’99)

PAS

Pigment epithelia Stromal melanocytes

Optic cup Neural crest

Present at birth Develops after birth

Cuboidal epithelial cells, tight jxns, coarse granules (melanin and lipofuscin)

Solitary, dendritic cells, fine dusty granules

Always darkly pigmented (except albinos)

Vary in size, number, and melanin content

Reactive proliferations Neoplastic proliferation

Adenoma/adenocarcinoma Nevus, Melanoma

Compound cystic melanocytic nevus of the conjunctiva


Conjunctival Nevi

Junctional Compound Subepithelial

Blue Congenital melanocytosis (African & Asian)

– Melanosis oculi - ipsilateral conj & uveal– Nevus of Ota - ipsilateral skin, conj & uveal

Melanocytic nevus 50% associated with epithelial buds & cysts

– Cysts may be so prominent to simulate lymphangioma clinically

Inflammed nevus of puberty - nevus enlarges because of lymphoplasmacytic infiltration +/- germinal centers– DDx lymphoid tumor, regressing melanoma

– Can have “feeder vessels”

Warning signs Overwhelming majority of nevi stable But 20-25% melanomas arise from nevi

–Junctional component should end with subepithelial component (except in children - early phase of maturation from junctional to compound)

– Nevi rare in palpebral and forniceal conj.– Base of nevus does not encroach the cornea– Cysts tend to be uniformly distributed; look

closely are regions where solid tissue obliterates cysts at one end of lesion

– Pagetoid spread of melanocytes

Primary Acquired Melanosis with Marked Atypia (Stage IB2)

PAM IB vs. Junctional nevus

May be identical histologically Basilar hyperplasia, basilar nesting, and

intraepithelial nesting can be seen in both Pagetoid spread is not seen in nevus PAM - > 30 year old, mean age is 40-47

Caveat: Conjunctival melanomas can arise in teenagers

PAM

Unilateral, middle-aged or elderly white pts.

Can wax and wane in size, pigmentation Need to evert eyelids to chart extent of

involvement, does not respect cornea Extends beyond palpebral fissure, in

contrast to lentigo/freckle (sun exposure)

PAM Staging

IA without atypia IB with atypical melanocytic hyperplasia

– 1. Mild to moderate– 2. Severe (“melanoma in situ”)

IIA with superficially invasive melanoma IIB with invasive melanoma (>1.5 mm)

Primary acquired melanosis PAM without atypia (IA)

– 8% recurrence– 0 progressed to melanoma

PAM with atypia (IB)– 61% recurrence

• incomplete excision, involvement of cornea

– 46% progression to malignant melanoma• 20% if mild atypia, basilar hyperplasia pattern • 90% if atypical melanocytes distant from jxn (nests or pagetoid)• 75% if epithelioid cells

Primary acquired melanosis PAM with superficially invasive

melanoma (< 1.5 mm) (IIA)– Generally nonlethal if excised– Jakobiec et al. suggest cut off of 0.8 mm

PAM with invasive melanoma (IIB)– Generally lethal

• Pagetoid growth pattern - more sensitive than tumor thickness

• Unfavorable location (palpebral, forniceal, caruncle, invasion of cornea)

• > 5 mitoses/10 HPF, lack of inflammation

Potential pitfalls for overcalling invasion

Bulbous basilar nests simulating invasion Melanophages - central or eccentric nuclei

without nucleoli after bleaching Tangential sectioning

– surgeon may submit fixed on a cucumber slice

– corneal margin, deep margin, other margins

Pseudoglands and epithelial cysts– Goblet cells or compressed rim of keratinocytes

Goblet cells can take up melanin

Spread via

Conjunctival melanomas 75% associated with PAM

– Confused with nevus, SCC, can simultaneously involve conj and lid skin

– Usually progress within 6 yrs. Not after 10. 20-25% associated with compound nevus

DDX - extraocular extension of uveal tumor, metastasis

Spread via ipsilateral preauricular, submandibular, or cervical lymph nodes

Secondary melanosis

Radiation Addison’s, Pregnancy Arsenic, Thorazine Chronic conjunctivitis “Racial” melanosis

Nonproliferative conditions with increased melanin transfer to keratinocytes

Pathologically, how do these differ from primary melanosis?

melanotic lesions of the eye charleen t. chu, m.d., ph.d. division of neuropathology university of...

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