An 84-year-old man presented with decreased visual acuity in his right eye of 8 days duration.
Malignant melanoma, spindle cell type, of choroid and ciliary body
The eye is of normal size and appears unremarkable externally. On transillumination, a mass is visible
inferiorly. Opening the eye reveals a pale tan nodular lesion with focal hemorrhage, basal diameter 12 mm
and elevation 9 mm, arising from the choroid. Tumor has penetrated both choroid and retina and abuts on the
posterior lens surface.
Microscopically, a spindle cell melanoma which is essentially amelanotic is seen. It involves both choroid
and ciliary body but does not extend into anterior chamber or iris. Tumor breaks through Bruch's membrane,
penetrates the retina, and is present on adjacent retina's inner surface. Neoplastic cells are S100
positive and HMB-45 negative. Melanoma is noted in a vortex vein, extending extraocularly within that vein.
Mitoses average 7/40 high power fields.
Primary intraocular melanomas arise in the uveal tract (iris, ciliary body and choroid) and are the most
common primary intraocular malignancy with an annual incidence of 5-8 cases per 1,000,000 people.1
Patients with uveal melanoma are typically between 50 and 70 years of age with less than 2% of cases
occurring in individuals less than 20. Almost all uveal melanomas are unilateral, bilateral tumors
accounting for less than 0.2%. The etiology of uveal melanoma is unknown. Risk factors include race, age,
ocular/oculodermal melanocytosis, neurofibromatosis, uveal nevi, and heredity. Uveal melanomas are rare in
African Americans compared to Caucasians, with an incidence ratio of 1:98.2
Uveal melanomas, usually unilateral3 but occasionally bilateral,4 develop in 1-2% of patients with
ocular/oculodermal melanocytosis. Ocular melanocytosis is defined as increased melanocytic pigmentation
involving uvea, sclera and episclera and is typically congenital, unilateral and diffuse, although bilateral
and sectoral types occur. Microscopically, episclera, sclera and choroid contain hyperpigmented
melanocytes; as well these cells can be identified in iris and anterior chamber angle structures in three
quarters of cases, optic nerve in one third and conjunctiva in approximately 14%.3 Oculodermal
melanocytosis (nevus of Ota) is ocular melanocytosis associated with increased skin pigmentation in the
distribution of the fifth cranial nerve ophthalmic, maxillary and sometimes mandibular divisions. Choroidal
nevi are found in approximately 5-10% of healthy individuals.1 They are a risk factor for melanoma since
occasional lesions thought to be nevi clinically suddenly grow and on enucleation are malignant melanomas.
Neurofibromatosis is associated with an increased risk for uveal melanoma. The roles of the dysplastic
nevus syndrome, ultraviolet irradiation and pregnancy in uveal melanoma development are controversial.
Clinically patients with uveal melanoma typically complain of visual disturbances or have a mass on
examination. Most tumors involve the choroid; iris tumors are the least frequent (3-10%).1 In many
instances, clinical diagnosis results in enucleation or local resection from which a histologic diagnosis is
made; however, fine needle aspiration biopsy has successfully diagnosed anterior and posterior uveal
melanomas5 and occasionally incisional biopsies are employed.
Pathological findings classically regarded as prognostically important include tumor size, tumor location
including location of the anterior margin, cell type, extraocular extension and mitotic rate.
Tumor size is an important prognostic indicator, specifically the largest tumor dimension (either maximum
height or greatest length of scleral contact).6 Measurements taken from the gross specimen can be larger
than those obtained from glass slides6 but both correlate with outcome. Small tumors have a diameter
<10mm or height <3 mm; medium tumors a diameter >10mm but <15 mm or a height <5 mm; large tumors a diameter
>15 mm or height <5 mm; the largest measurement is used to determine the category. Grossly, uveal melanomas
are typically circumscribed, vary from white to dark brown, at times even within the same tumor, and
crescentic, oval, nodular, irregular or mushroom-shaped, the latter in choroidal tumors breaking through
Bruch's membrane. Diffuse flat melanomas also can occur but are rare (3-5%).7 Other rare forms include
multifocal melanomas and anterior ring melanomas.
Tumor location has been assessed with regard to prognosis. Combined ciliary body and choroidal tumors have
a poorer prognosis likely the result of their large size. Iris melanomas, on the other hand, have a much
lower metastatic rate, in the order of 5%, but this too may be due to their generally small size.8 In a
recent series of more than 1500 uveal melanomas, over 96% of medium and large melanomas were located
entirely or partially posterior to the equator, with 34.5% partially in the ciliary body, 7.9% in the
trabecular meshwork and 4.7% in the iris.9 The vast majority of large tumors (82.4%) have an anterior
margin at or anterior to the equator.9
Callender's classification recognized 6 cell types and growth patterns: spindle A, spindle B, epithelioid,
mixed, fascicular and necrotic. Spindle A cells are characterized by fine nuclear chromatin, a nuclear
groove, indistinct nucleoli and indistinct cell borders. Spindle B cells have coarser chromatin and
definite nucleoli with indistinct cell borders. Epithelioid cells are polygonal with well defined cell
borders, less cohesion and large prominent nucleoli. Mixed cell tumors contain both epithelioid and spindle
cells. Fascicular pattern involves palisading of spindle cells. Necrotic tumors have no well-preserved
areas which would allow them to be classified into the other types. Although useful, problems with this
classification arise from lack of interobserver reproducibility, overlap of spindle A cells with nevus
cells, no category for tumors composed of spindle A and B cells which is a frequent occurrence, lack of
prognostic value of the fascicular pattern and no criteria to specify what numbers of a second cell type
would have to be present to classify a tumor as mixed.
The modified Callender classification categorizes tumors as spindle cell, epithelioid cell, mixed cell or
necrotic; mixed and epithelioid cell melanomas often are combined as their outcome is similar. Epithelioid
cells may be small or large. Mixed cell tumors need only contain a small quantity of second cell type and
the presence of even a few epithelioid cells in an otherwise spindle cell tumor alters the prognosis.10
However, the classification still suffers from difficulties in interobserver reproducibility, problems in
distinguishing spindle B from epithelioid cells since there is a morphological continuum between such cells,
and lack of a universally accepted definition of how many epithelioid cells are needed for a mixed cell
tumor (one easily recognizable epithelioid cell per 5 x 400 fields has been suggested)11 or how many
spindle cells are permissible in an epithelioid one. Mixed cell tumors constitute half of posterior uveal
melanomas followed in frequency by spindle cell tumors; pure epithelioid cell tumors are uncommon.12
Mortality for spindle cell tumors is in the order of 27-29%, mixed cell 59-62%, epithelioid 58-81% and
Extraocular extension from tumor invading and penetrating the sclera typically around vessels and nerves
(extension through emissary canals) can be seen grossly and/or microscopically, posteriorly or anteriorly in
approximately 17% of uveal melanomas.13 Such tumors often are large with a prominent component of
epithelioid cells and it is uncertain how much additional prognostic significance the extrascleral extension
has in comparison to tumor size and cell type.13 However, tumors with microscopic to moderate gross
extraocular extension often are given post- enucleation radiotherapy so it is important to note this
finding. Intravascular involvement of vortex veins also may be seen and carries a poor prognosis so these
vessels should be submitted for histology. Tumor can invade optic nerve in approximately 2-7% of cases9
although rarely extensively; a cross section of optic nerve from the resection line should be examined
Mitotic rate has prognostic significance. Uveal melanomas typically have few mitoses and therefore they are
counted over 40 high power fields (x400).12
In the search for better prognostic factors,lymphocytic infiltration, mean nucleolar diameter, and tumor PAS
positive patterns have been examined. 12% of melanomas contain 100 or more lymphocytes, predominantly T
cells, per 20 high power fields (x400); such tumors appear to have a poorer prognosis.14 The
Collaborative Ocular Melanoma Study found epithelioid cell tumors contained more inflammatory cells than
other cell types.9 The mean of the longest nucleoli measured in tumor sections stained with colloidal
silver nitrate stain for nucleolar organizing regions using an ocular micrometer and x1000 magnification
also correlates with poor outcome, although technical modifications have made evaluation easier, this
prognostic predictor is not routinely employed at the present time. 15 Study of PAS positive patterns in
uveal melanomas has shown one closed loop (PAS positive tissue surrounds at least three quarters of a tumor
lobule), networks (3 back to back loops) and parallel arrays with cross linking, correlate with decreased
survival.16, 17 Recently, arcs or arcs with branching and parallel channels have been noted to correlate
with the presence of loops and networks.18 There is some controversy as to whether the PAS positive
structures represent blood vessels or connective tissue19 but general agreement as to the usefulness of
these patterns in separating low from high-risk categories for metastasis.
Cytogenetic analysis of uveal melanoma frequently has shown monosomy 3, gain of 8q material, and 6p
alterations with approximately 70% of individuals with monosomy 3 dying of metastases; the possibility of
two tumor suppressor genes on this chromosome has been raised.20 An ever increasing number of genes and
proteins are being studied in uveal melanoma but none have yet proved useful as routine diagnostic and/or
Complications of uveal melanoma include glaucoma, retinal detachment, intraocular hemorrhage and cystoid
macular edema. Large tumors and iris or iris and ciliary body neoplasms are more likely to be associated
with glaucoma than small or choroidal ones.21,22 For ciliary body tumors, intraocular pressure may
depend on the balance between the tumors' effects on aqueous outflow and production by ciliary body
Treatment of uveal melanoma includes photocoagulation, local resection, plaque or particle beam radiotherapy
and enucleation.1 Exenteration is reserved for cases with marked orbital extension. Enucleation usually
is used for larger tumors or ones that have failed other forms of therapy. Irradiated melanomas, regardless
of the method employed, show histologically increased inflammation, necrosis, fibrosis, balloon cells, and
blood vessel damage with hemorrhage and the same or fewer mitoses in comparison to non-irradiated tumors.23
Overall 5, 10 and 15 year survival rates for uveal melanoma are 65%, 52% and 46% respectively.24
Intraocular lymphatics do not exist; exceedingly rare instances of regional lymph node metastases occurred
only after extraocular spread and invasion of conjunctival lymphatics. Thus uveal melanomas essentially
metastasize hematogenously. Approximately 2-3% of patients with ciliary body and choroidal melanoma,
typically with large tumors, have metastases at the time of diagnosis.1 Common sites of metastatic
disease include the liver (93%), lung (24%) and bone (16%) with multiple sites of involvement in 87% of
patients.25 On histology, metastatic melanomas consist predominantly of epithelioid or unclassifiable
cells regardless of the primary cell type. HMB-45 remains the best marker immunohistochemically with S100
staining approximately 66% of metastases.24 Uveal melanoma may metastasize decades after the primary
tumor was diagnosed.
Although the diagnosis of uveal melanoma usually is straightforward, occasionally both clinically and
microscopically, problems may arise. Differential diagnosis of uveal malignant melanoma includes metastatic
tumors and benign and malignant primary intraocular neoplasms. Metastatic tumors are the most common
malignant intraocular neoplasms and primarily involve the choroid. Patients may be asymptomatic or have
decreased vision.26 Breast (40-47%) and lung (21-30%) carcinomas are the most common tumors to
metastasize intraocularly;26,27 most patients with the former have widespread metastatic disease but
frequently lung carcinoma intraocular spread is detected before the primary is found.26 It should be
noted that occasional uveal melanomas may contain substantial numbers of cells with clear cytoplasm, a
potential source of confusion with metastatic renal cell carcinoma.28 Also, pigmented neuroendocrine
tumors metastatic to uvea may be misdiagnosed as melanoma,29 illustrating the importance of performing
immunohistochemical and other ancillary studies in neoplasms appearing atypical for melanoma. Cutaneous
melanomas may metastasize to uvea but such metastases are often multiple, involve other intraocular tissues
and are typically part of widespread systemic disease.30 Rarely, lymphoma may present as a discrete
uveal mass simulating uveal melanoma.31
Primary ocular tumors which may be confused with malignant melanoma include uveal tract nevi, melanocytoma
(magnocellular nevus),32 adenoma/adenocarcinoma of pigmented ciliary body epithelium,33
leiomyoma/leiomyosarcoma34,35 and melanotic schwannoma,36 as well as reactive and neoplastic retinal
pigment epithelial proliferations.
Occasionally eyes enucleated for uveal malignant melanoma do not have this tumor.9 Simulating lesions
include choroidal nevi, central and peripheral exudative chorioretinopathy, congenital and reactive
hypertrophy of retinal pigment epithelium, hemangiomas, hemorrhage, retinal detachment and choroiditis. On
the other hand, eyes enucleated because of trauma, glaucoma, phthisis, endophthalmitis or painful blindness,
sometimes contain malignant melanoma. Unsuspected uveal malignant melanoma also may be discovered at
autopsy either as an incidental finding37 or in patients with metastases but no apparent primary,
illustrating the importance of examining eyes post mortem.
- Seregard S: Posterior uveal melanoma. The Swedish perspective. Acta Ophthalmol Scand 1996;74:315-329.
- Margo CE, McLean IW: Malignant melanoma of the choroid and ciliary body in black patients. Arch
- Gonder JR, et al: Uveal malignant melanoma with ocular and oculodermal melanocytosis.
- Singh AD, et al: Bilateral primary uveal melanoma. Bad luck or bad genes? Ophthalmology
- Shields JA, et al: Fine-needle aspiration biopsy of suspected intraocular tumors. The 1992
Urwick lecture. Ophthalmology 1993;100:1677-1684.
- Folberg R, et al: Comparison of direct and microslide pathology measurements of uveal melanomas.
Invest Ophthalmol Vis Sci 1985;86:1788-1791.
- Shields CL, et al: Diffuse choroidal melanoma. Clinical features predictive of metastasis.
Arch Ophthalmology 1996;114:956-963.
- Jakobiec FA, Silbert G: Are most iris "melanomas" really nevi? A clinicopathologic study of 189
lesions. Arch Ophthalmol 1981;99:2117-2132.
- Histopathologic characteristics of uveal melanomas in eye enucleated from the collaborative ocular
melanoma study group. COMS report no. 6. Am J Ophthalmol 1998;125:745-766.
- McLean IW, et al: Modifications of Callender's classification of uveal melanoma at the Armed
Forces Institute of Pathology. Am J Ophthalmol 1983;96:502-509.
- Gamel JW, McLean IW: Quantitative analysis of the Callender classification of uveal melanoma cells.
Arch Ophthalmol 1977;95:686-691.
- McLean IW: Prognostic features of uveal malignant melanoma. Ophthalmol Clin N A 1995:8:143-153.
- Seregard S, Kock E: Prognostic indicators following enucleation for posterior uveal melanoma. A
multivariate analysis of long-tern survival with minimized loss to follow-up. Acta Ophthalmol Scand
- de la Cruz PO Jr, Specht CS, McLean IW: Lymphocytic infiltration in uveal malignant melanoma. Cancer
- Moshari A, McLean IW: Uveal melanoma: mean of the longest nucleoli measured on silver-stained
sections. Invest Ophthalmol Vis Sci 2001;42:1160-1163
- Folberg R, et al: The morphologic characteristics of tumor blood vessels as a marker of tumor
progression in primary uveal melanoma: a matched case-control study. Hum Pathol 1992;23:1298-1305.
- Folberg R, et al: The prognostic value of tumor blood vessel morphology in primary uveal
melanoma. Ophthalmology 1993;100:1389-1398.
- Folberg R, et al: Microcirculation patterns other than loops and networks in choroidal and
ciliary body melanomas. Ophthalmology 2001;108:996-1001.
- McDonald DM, Munn L, Jain RK: Vasculogenic mimicry: how convincing, how novel, and how significant?
Am J Pathol 2000;156:383-388.
- Tschentscher F, et al: Partial deletions of the long and short arm of chromosome 3 point to two
tumor suppressor genes in uveal melanoma. Cancer Res 2001;61:3439-3442.
- Yanoff M: Mechanisms of glaucoma in eyes with uveal malignant melanomas. Int Ophthalmol Clin
- Shields MB, Klintworth GK: Anterior uveal melanomas and intraocular pressure. Ophthalmology
- Saornil MA, et al: Histopathologic study of eyes after Iodine I 125 episcleral plaque
irradiation for uveal melanoma. Arch Ophthalmol 1997;115:1395-1400.
- Luyten GPM, et al: Metastatic uveal melanoma. A morphologic and immunohistochemical analysis.
- Assessment of metastatic disease status at death in 435 patients with large choroidal melanoma in the
collaborative ocular melanoma study (COMS). COMS report no.15. Arch Ophthalmol 2001;119:670-676.
- Shields CL, et al: Survey of 520 eye with uveal metastases. Ophthalmology 1997;104:1265-1276.
- Ferry AP, Font RL: Carcinoma metastatic to the eye and orbit. I. A clinicopathologic study of 227
cases. Arch Ophthalmol 1974;93:276-286.
- Clear cell differentiation in choroidal melanoma. COMS report no. 8. Arch Ophthalmol 1997;115:894-898.
- Eagle RC Jr., et al: Choroidal metastasis as the initial manifestation of a pigmented
neuroendocrine tumor. Arch Ophthalmol 2000;118:841-845.
- Fishman ML, Tomaszewski MM, Kuwabara T: Malignant melanoma of the skin metastatic to the eye:
frequency in autopsy series. Arch Ophthalmol 1976;94:1309-1311.
- Fredrick DR, et al: Solitary intraocular lymphoma as an initial presentation of widespread
disease. Arch Ophthalmol 1989;107:395-39.
- Reidy JJ, et al: Melanocytoma: nomenclature, pathogenesis, natural history and treatment. Surv
- Rennie IG, Faulkner MK, Parsons MA: Adenoma of the pigmented ciliary epithelium. Br J Ophthalmol
- Foss AJE, et al: Are most intraocular "leiomyomas" really melanocytic lesions? Ophthalmology
- Shields JA, et al: Observations on seven cases of intraocular leiomyoma. The 1993 Byron
Demorest Lecture. Arch Ophthalmol 1994;112:521-528.
- Shields JA, et al: Melanotic schwannoma of the choroid. Immunohistochemistry and electron
microscopic observations. Ophthalmology 1994;101:843-849.
- Butnoer KJ, Proia AD: Unexpected autopsy findings arising from postmortem ocular examination. Arch
Pathol Lab Med 2001;125:1193-1196.