The uvea of the eye is a
vascular tunic comprised of the iris, ciliary body, and choroid. Located
between the sclera and the retina, the uvea contains dendritic pigmented
melanocytes which have the potential to give rise to malignant melanoma. Patients
with choroidal melanoma typically present as adults with painless monocular vision
loss, while a cataract or glaucoma may be the presenting feature of an anterior
segment melanoma. Approximately half of patients with choroidal and ciliochoroidal
melanomas eventually die from their tumors. Prognosis is better in cases
localized to the iris, presumably because they are recognized earlier.
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| Uveal melanom on right, melanin pigment in middle, and atropic retina on left |
Most uveal melanomas produce
at least some melanin pigment. For amelanotic cases, confirmatory
immunohistochemical stains for melanoma, such as SOX10 and HMB45, may be helpful. Many uveal
melanomas perforate Bruch membrane, enter the subretinal space, and invade the
retina (see image), resulting in
cystic atrophy of the overlying retina.
Although a small percentage
of melanomas diffusely infiltrate the uvea, the vast majority are
well-circumscribed. The presence of distinct margins allows for accurate
assessment of tumor size. Measurement of largest tumor diameter (LTD) at the
base has prognostic significance.
Histologic assessment of
uveal melanoma requires subtyping based on the predominance of particular
morphologic cell types: spindle type A, spindle type B, and epitheloid. This
cytomorphologic subtyping schema is known as the modified Callender
classification, after a system originated in 1931 by Dr. George Russel
Callender and then modified in 1978. Spindle type A cells have elongated
nuclei, inapparent nucleoli, scant cytoplasm, and indistinct cell borders.
Spindle type B cells have
oval nuclei with identifiable nucleoli and moderate cytoplasmic volume.
Epithelioid cells are
larger, with rounded nuclei, prominent nucleoli, and distinct cell borders.
Patients with pure spindle tumors have the best prognosis. Indeed, tumors
composed entirely of spindle A cells are better classified as benign spindle
cell nevi. On the other end of the spectrum, tumors composed purely of epithelioid
cells have the worst prognosis. Those with a mix of spindle and epithelioid
cell types, which represent the majority of cases, have an intermediate
prognosis.
In addition to basal LTD and
cytologic phenotype, other histologic features shown to have some negative
prognostic implication include: lymphocytic infiltration, macronucleoli, elevated mitotic count, looping
vascular networks, and extrascleral extension.
Although the histomorphology
of cutaneous and uveal melanomas can be similar, genetic tumorigenesis differs.
Early mutations in BRAF characterize cutaneous melanoma while mutations in GNAQ
and GNA11 are typical of uveal melanomas. Chromosomal and genetic features also
impact prognosis. Monosomy for chromosome 3 indicates a worse prognosis. Gene
expression profiling using RT-PCR has emerged as a method of stratifying
patients according to risk for metastatic death, and has been reported to be
prognostically superior to clinical and histopathologic features. Uveal
melanomas naturally cluster into two groups according to expression of thirteen
different genes. Class 1 melanomas tend not to metastasize, while Class 2
melanomas have a high risk of metastasis. Not unexpectedly, Class 2 tumors tend
to exhibit epithelioid cytomorphology and monosomy for chromosome 3. Elevated
expression of the PRAME (preferentially expressed antigen in melanoma) gene on
chromosome 22 is an additional indicator of increased risk for metastasis.
Increased PRAME expression has been shown to identify the small percentage of
Class 1 uveal melanomas that metastasize as well as indicate a shorter time to
metastasis for Class 2 tumors.
Therapeutic options such as brachytherapy and focused radiation may obviate the need for enucleation in smaller tumors. For those who undergo enucleation, long-term surveillance includes monitoring liver enzymes as well as hepatic imaging, as the liver is the metastatic site first discovered in 80% of cases. More than half of patients who have metastatic uveal melanoma die within one year.
