Melanotic Lesions of the Eye
Charleen T. Chu, M.D., Ph.D.
Division of Neuropathology
University of Pittsburgh
chu@np.awing.upmc.edu
April 2002
Copyright ©2002 CT Chu
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
– Neuroepithelium of embryonic optic cup

Stromal melanocytes
– 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
Iris
© 2002 CT Chu
© 2002 CT Chu
Ciliary Body
© 2002 CT Chu
© 2002 CT Chu
Retina and choroid
© 2002 CT Chu
RPE and Choroidal Melanocytes
Pigment epithelium
QuickTime™ and a
Photo - JPEG decompressor
are needed to see this picture.
Stromal melanocytes
Modified from Yanoff & Fine,
©1996 Mosby-Times Mirror Int.
Bruch’s
membrane
Case 1
58 year old
man with
serous
detachment of
the retina
What might be
the most relevant
prognostic
feature?
A
B
C
Case 1
© 2002 CT Chu
© 2002 CT Chu
Choroidal Melanoma, Spindle B Type
with transcleral extension along an
emissary channel (vortex vein)
Choroidal Melanoma
Most common intraocular tumor
 Classic mushroom shape - rupture into vitreous


LIVER
If metastatic - tend to go to _________.

Prognosis
–
–
–
–
Largest dimension, particularly along base
Extension into canal of Schlemm, emissary channels
Cytology
Location
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

<< Modified from Yanoff & Fine,
©1996 Mosby-Times Mirror Int.
Epithelioid
Spindle A - grooves
© 2002 CT Chu
Spindle B - nucleoli
© 2002 CT Chu
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
© 2002 CT Chu
© 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
Spindle only - 22% death rate
Necrotic, mixed, epithelioid - 62% death rate
– Infarcted tumors can cause significant ocular
inflammation >> misdiagnosis in “blind painful
eyes”
Uveal melanoma - location
Tumors of the iris - ______
better prognosis
 Tumors of the posterior temporal pole better prognosis
_______
 Tumors of the ciliary body and the
worse prognosis
peripheral choroid - ______

Early detection
Proximity to meshwork and
related structures
Anterior ciliary
artery, venous
drainage from
meshwork, ciliary
nerves
Vortex vein
© 2002 CT Chu
Short and long
posterior ciliary
arteries
Modified from Apple & Rabb, Ocular
Pathology, © 1998 Mosby-Year Book
Epibulbar Mass
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Photo - JPEG decompressor
are needed to see this picture.
Modified from Yanoff & Fine,
©1996 Mosby-Times Mirror Int.
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
Images modified from Yanoff & Fine,
©1996 Mosby-Times Mirror Int.
QuickTime™ and a
Photo - JPEG decompressor
are needed to see this picture.
Nerve with associated
melanocytes
Melanoma exiting
through anterior scleral
canal
Pigment spots of the sclera
People with dark irises
 Located 3-4 mm from the limbus
 Collections of melanocytes associated
with:

– Anterior ciliary vessel
– Intrascleral nerve loop of Axenfeld

Conjunctiva remains freely mobile over the
pigment spot and nerve remains painful after
anesthesia
Case 3
80 year old woman
 Corneal transplant
 Expulsive choroidal hemorrhage

© 2002 CT Chu
Case 3
© 2002 CT Chu
Case 3
© 2002 CT Chu
Your diagnosis?


What if this was a 55 year old African
American man?
What if this lesion measured 16 x 10 mm?
What if I told you this is then classic
location for this tumor?
QuickTime™ and a
Photo - JPEG decompressor
are needed to see this picture.
Modified from Yanoff & Fine,
©1996 Mosby-Times Mirror Int.
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 darkskinned individuals
 In contrast, uveal melanomas are 15
times more likely to occur in Caucasians
 Benign lesion with low malignant
potential

– 15% will enlarge over time, can locally
infiltrate choroid and optic nerve beyond
lamina cribosa

Caveat: choroidal melanomas can invade optic disc
QuickTime™ and a
Photo - JPEG decompressor
are needed to see this picture.
Modified from Yanoff & Fine, Ocular Pathology ©1996
Mosby-Times Mirror Int.
Multiple iris nevi
associated with NF2
(Lisch Nodules)
Modified from Okazaki & Scheithauer, Slide Atlas of
Neuropathology © 1991 Gower Medical Pub.
Case 4
Orbital exenteration
for morpheaform BCC
© 2002 CT Chu
© 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
© 2002 CT Chu
© 2002 CT Chu
Reactive hyperplasia of the
RPE
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

© 2002 CT Chu
© 2002 CT Chu
Neoplastic transformation of uveal epithelia is very rare.
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 Solitary, dendritic cells,
jxns, coarse granules (melanin fine dusty granules
and lipofuscin)
Always darkly pigmented
(except albinos)
Reactive proliferations
Vary in size, number,
and melanin content
Neoplastic proliferation
Adenoma/adenocarcinoma
Nevus, Melanoma
Case 5

46 year old
man with a
cystic
conjunctival
lesion
© 2002 CT Chu
Compound cystic melanocytic
nevus of the conjunctiva
Modified from Yanoff & Fine,
©1996 Mosby-Times Mirror Int.
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
– Can have “feeder vessels”

Inflammed nevus of puberty - nevus
enlarges because of lymphoplasmacytic
infiltration +/- germinal centers
– DDx lymphoid tumor, regressing melanoma
Warning signs
Overwhelming majority of nevi stable
 But 20-25% melanomas arise from nevi

– 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
–Junctional component should end with
subepithelial component (except in children - early phase
of maturation from junctional to compound)
© 2002 CT Chu
© 2002 CT Chu
Case 5
© 2002 CT Chu


72 year old man with pigmented areas on the conjunctiva.
Status post multiple biopsies
© 2002 CT Chu
Images modified from Yanoff & Fine, ©1996 Times Mirror Int.
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
© 2002 CT Chu
© 2002 CT Chu
© 2002 CT Chu
© 2002 CT Chu
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
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

Spread via ipsilateral preauricular,
submandibular, or cervical lymph nodes
DDX - extraocular extension of uveal tumor, metastasis
© 2002 CT Chu
•
© 2002 CT
Chu
S-100
© 2002 CT Chu
© 2002 CT Chu
Secondary melanosis
Radiation
 Addison’s, Pregnancy
 Arsenic, Thorazine
 Chronic conjunctivitis
 “Racial” melanosis


Pathologically, how
do these differ from
primary melanosis?
Nonproliferative conditions with increased
melanin transfer to keratinocytes