Clinical background
Uveal melanoma is a malignant neoplasm that arises from neuroectodermal melanocytes within the choroid, ciliary body, or iris, and it is the most common primary malignant intraocular neoplasm. Uveal melanoma can cause flashes, floaters, and other visual symptoms, but it is most often asymptomatic and discovered on routine eye examination ( Box 47.1 ). These tumors can range from minimally to darkly pigmented, usually grow slowly, and invade through the sclera to involve the orbit ( Figure 47.1 ). Uveal melanomas have a strong tendency to metastasize hematogenously to the liver and other organs. Despite advances in diagnosis and treatment in recent decades, the mortality rates have not exhibited a commensurate improvement. Uveal melanoma occurs in about 4–5 per million individuals in the USA, and it is much more common in Caucasians than in individuals of African and Asian descent. Men are at slightly higher risk than women, and the peak incidence occurs in patients between the age of 50 and 60, although individuals of any age can be affected.
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Melanocytic tumor of choroid, ciliary body, or iris
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Choroidal and ciliary body tumors usually larger than iris tumors
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Often asymptomatic and discovered on routine eye exam
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Unilateral and unifocal in almost all patients
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Strong tendency to metastasize hematogenously to the liver and other organs
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Much more common in Caucasians
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Men are at slightly higher risk
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Common features include subretinal fluid, orange pigment (lipofuscin), and mushroom-like shape due to eruption through Bruch’s membrane
The differential diagnosis includes uveal nevus, melanocytoma, metastasis, congenital hypertrophy of the retinal pigment epithelium, circumscribed choroidal hemangioma, hemorrhagic detachment, and/or disciform scarring of the choroid or the retinal pigment epithelium, choroidal osteoma, choroidal detachment, uveal effusion, posterior nodular scleritis, choroidal granuloma, toxoplasmic retinochoroiditis, retinal detachment, retinoschisis, neurilemoma, leiomyoma, and combined hamartoma of the retina and retinal pigment epithelium, leiomyoma, intraocular foreign body, medulloepithelioma, pigment epithelial adenoma, or adenocarcinoma.
Treatment options include observation, local microsurgical tumor resection, diode laser hyperthermia, plaque radiotherapy, charged particle radiotherapy, stereotactic radiotherapy, and enucleation. Complications of radiotherapy, the most frequently used treatment option, include cataract, dry eye, radiation retinopathy and optic neuropathy, neovascular glaucoma, vitreous hemorrhage, and local tumor recurrence. Factors that influence therapeutic decision include patient age, overall health, visual status of the affected and unaffected eyes, tumor size and location, extrascleral tumor extension, systemic metastasis, and patient preference.
Pathology
Uveal melanomas are composed of transformed melanocytes arising from the uveal tract of the eye, which includes the choroid, ciliary body, and iris. The histopathologic classification originally proposed by Callender included six categories based on cell morphology: spindle A, spindle B, fascicular, mixed spindle and epithelioid, and necrotic. Subsequently, a modified classification was developed in which tumors are classified as spindle, mixed, or epithelioid ( Figure 47.2 ). Tumors containing mostly spindle cells have a more favorable prognosis than those composed of epithelioid cells. Other histopathologic features associated with poor outcome include greater mean nuclear size, greater mean and standard deviation of the nucleolar area, scleral invasion, higher mitotic index, greater tumor pigmentation, and extracellular matrix patterns ( Box 47.2 ).
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Increased patient age
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Larger tumor size
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Ciliary body involvement
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Juxtapapillary location
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Extrascleral extension
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Epithelioid cell type
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Increased pigmentation
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Extracellular matrix patterns
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Lymphocyte infiltration
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Macrophage infiltration
Etiology
Caucasian ancestry is the most important risk factor for uveal melanoma. Skin freckling, light iris, and light hair color have been linked to uveal melanoma. However, iris freckles, iris nevi, and choroidal nevi have not been convincingly linked to uveal melanoma. Another systemic risk factor is oculo(dermal) melanocytosis. Although there have been reports of familial clustering of uveal melanoma, clear mendelian inheritance is rare. Germline BRCA2 mutations are present in up to 3% of uveal melanoma patients. Mutations in the p16INK4a tumor suppressor are extremely rare in uveal melanoma. There is a weak epidemiologic association between uveal melanoma and ultraviolet light. Arc welding is one of few occupational exposures that is associated with uveal melanoma, but there have been too few reported cases to establish reliable risk estimates.
Pathophysiology
The hallmark features of cancer cells include proliferation independent of normal growth signals, continued proliferation beyond normal replicative limits, resistance to apoptosis, recruitment of a tumor blood supply, and metastasis to other locations. The molecular mechanisms governing these characteristics have been found to be defective in uveal melanoma ( Box 47.3 ).
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Abnormal proliferation resulting from mutations that circumvent normal cell cycle control
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Acquisition of immortality by overexpressing telomerase and derailing the DNA damage response
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Evasion of cell death by disrupting apoptotic pathways
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Recruitment of a blood supply by expressing angiogenic molecules
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Metastasis to distant organs
Proliferation independent of normal growth signals
Cell proliferation is normally regulated through extracellular signals, such as growth (mitogenic) factors and extracellular matrix interactions. Cell surface receptors transmit these signals to intracellular signaling cascades that converge upon the nucleus to activate the transcription of genes involved in cell cycle progression. Growth factors such as stem cell factor, transforming growth factor-β and hepatocyte growth factor/scatter factor, and growth factor receptors such as the insulin-like growth factor receptor-1 (IGFR1), the KIT oncogene, and the epidermal growth factor receptor, have been shown to be aberrantly expressed in uveal melanoma ( Figure 47.3 ). The mitogen-activated protein kinase (MAPK)/mitogen extracellular kinase (MEK)/extracellular signal-related kinase (ERK) signaling pathway, which is a major conduit for transfer of growth signals to the nucleus, is constitutively activated by oncogenic mutations in KIT, RAS, NRAS, or BRAF in cutaneous melanomas and many other cancers. However, such mutations are extremely rare in uveal melanoma. Nevertheless, this pathway is constitutively activated in uveal melanoma, suggesting that unidentified mutations in this pathway are present. Alterations in nuclear cell cycle proteins provide further evidence for disrupted mitogenic signaling in uveal melanoma. The retinoblastoma tumor suppressor (Rb) is a key cell cycle inhibitor that couples cell cycle exit with differentiation in melanocytes. Phosphorylation of Rb by cyclin-dependent kinase-4 (Cdk4), which is activated by its binding partner cyclin D, blocks the tumor suppressor activity of Rb. Aberrant phosphorylation of Rb in differentiating melanocytes allows them to re-enter the cell cycle and proliferate. Almost all uveal melanomas show evidence of such inappropriate phosphorylation of Rb, either through overexpression of cyclin D or silencing of the Cdk4 inhibitor p16Ink4a. The cyclin D overexpression appears to result from constitutive activation of the MAPK/MEK/ERK pathway.
Sustained proliferation beyond normal replicative limits
Even in the context of abnormal proliferation, cells have a second level of defense against malignant transformation in the form of senescence. With each cell division, the lengths of the telomeres at the ends of chromosomes become shorter. After a finite number of cell divisions, the telomeres become shorted to a critical length where they trigger a DNA damage response that drives the cell permanently out of the cell cycle and into a senescence state. This mechanism likely accounts for the arrest in growth that is observed in benign tumors. Tumors that progress to a fully malignant state must overcome this senescence mechanism. One way in which tumors do this is by stopping the erosion of telomeres through upregulation of telomerase, the enzyme that maintains telomere length. Telomerase activity is upregulated in at least 90% of uveal melanomas ( Figure 47.3 ). Another way that tumors can bypass the senescence mechanism is to disrupt the DNA damage response, such as by mutation of the p53 pathway, which triggers cell cycle arrest or apoptosis in response to DNA damage. While p53 is rarely mutated in uveal melanoma, the DNA damage response is defective in most tumors, as evidenced by defective downstream signaling to Bax, p21, Bcl-XL, and other p53 targets. Functional inhibition of p53 is due at least in part to overexpression of HDM2, an inhibitor of p53 that targets it for degradation. Targeted blockade of HDM2 induces apoptosis in uveal melanoma cells.
Resistance to apoptosis
Since p53 can trigger apoptosis in response to DNA damage and other oncogenic insults, functional blockade of the p53 pathway described above also conveys resistance to apoptosis ( Figure 47.3 ). The Bcl2 protein and IGFR1 are expressed at high levels in many uveal melanomas and provide additional antiapoptotic activity. Constitutive activation of the phosphatidylinositol 3-kinase (PI3K) survival pathway is yet another mechanism commonly used by uveal melanoma cells to avert apoptosis. The phosphatase with tensin homology (PTEN) tumor suppressor protein, which is a negative regulator of the PI3K pathway, is silenced in over 76% of uveal melanomas. Consistent with these findings, PTEN expression is associated with increased genomic aneuploidy.
Recruitment of a tumor blood supply
Complex patterns of extracellular matrix deposition within uveal melanomas have been convincingly linked to metastasis and poor systemic outcome. However, the biological nature of these patterns remains controversial. They have been suggested to represent “vasculogenic mimicry,” a hypothetical phenomenon in which tumor cells may form embryonic-like blood-conveying channels. While these structures can convey fluid, they do not typically contain red blood cells, so it seems unlikely that they represent the major conduits for tumor blood flow. Another possibility is that these “vascular mimicry patterns” represent basement membrane-like extracellular matrix material deposited by highly aggressive uveal melanoma cells that have acquired epithelial-like characteristics. It seems more likely that endothelial-lined neovasculature provides most tumor blood flow, as supported by the expression of angiogenic factors such as vascular endothelial growth factor (VEGF), endoglin, and angiopoietin-2, and the staining of tumor blood vessels with endothelial markers in uveal melanoma ( Figure 47.3 ).
Metastasis
There are many steps in the metastatic process, including disengagement from local cell–cell and cell–matrix adhesive restraints, resistance to anoikis (detachment-induced apoptosis), migration and invasion into nearby tissues, vascular intravasation, embolization and extravasation, and modulation of and proliferation at the secondary site. The relative importance of each step varies between cancer types. For example, disengagement from adhesive interactions is of paramount importance in the progression of cutaneous melanoma, because cutaneous melanocytes are enmeshed within the epithelium through E-cadherin-mediated cell–cell adhesions with surrounding keratinocytes. In order for these melanoma cells to metastasize, they must first downregulate E-cadherin to dissociate from the epithelium, then invade through the underlying basement membrane and migrate to lymphatics and blood vessels. Uveal melanoma cells do not face these boundaries to metastatic progression. They do not have to contend with an epithelium or basement membrane, nor do they have to migrate far to encounter blood vessels since they arise within the highly vascular uveal tract. Thus, the rate-limiting step in metastasis is likely to be different in cutaneous and uveal melanomas as a result of their differing local environments. The factors that determine whether a given uveal melanoma will spawn clinically significant metastatic disease are not known, but indirect evidence from clinical observations and genetic studies allows us to make some reasonable predictions.
Uveal melanomas metastasize almost exclusively by the hematogenous route, and the liver is the predominant secondary site. Many patients develop fatal metastatic disease even after successful treatment of the ocular tumor, and this survival rate has not changed in the past four decades despite improvements in local treatment. Most patients experience a delay of months to years from ocular diagnosis to the detection of metastatic disease, suggesting the presence of subclinical micrometastasis and a period of dormancy following ocular treatment. Indeed, it has been calculated from tumor doubling times that most micrometastasis occurs up to 5 years prior to ocular diagnosis. Circulating melanoma cells can be demonstrated in peripheral blood from about 90% of uveal melanoma patients, including many that never develop metastatic disease. Taken together, these observations suggest that uveal melanoma cells commonly gain access to the circulation, so this is probably not rate-limiting in metastasis. Rather, the key events in metastasis appear to occur later, such as survival in the circulation, extravasation, and successful colonization of the secondary site. Uncovering the rate-limiting events in metastasis will shed light on the phenomenon of tumor dormancy and suggest novel treatment approaches in high-risk patients.
To date, most research on the metastatic process in uveal melanoma has been through indirect genetic studies. In recent years, these studies have led to a paradigm shift in our understanding of uveal melanoma and its propensity for metastasis. Clinical and pathologic risk factors for metastasis, such as tumor size, location, and cell type, form a continuous spectrum from low risk to high risk with no discrete stages, which was assumed for many years to mean that the risk for metastasis is also a continuous scale from low risk to high risk. However, it is now clear that there are two major forms of uveal melanoma based on molecular/genetic features that differ markedly in their metastatic capacity. Monosomy 3 (loss of one copy of chromosome 3) has been shown to be strongly associated with metastasis independently of other prognostic factors. The dichotomous, rather than continuous, nature of this chromosomal abnormality supports the idea that metastatic risk represents a discontinuous, bimodal trait. This possibility has been further confirmed by high-density microarray-based gene expression profiling in primary tumor specimens. Whereas chromosomal analysis provides only a one-dimensional marker, gene expression profiling provides a highly dimensional biological “snapshot” of the transcriptional activity of the entire tumor. Based on gene expression profile, uveal melanomas form two distinct groups, which we refer to as class 1 and class 2. About half of tumors fall into each class. This gene expression-based classification has been independently validated by other groups, and it predicts metastasis more accurately than clinical and pathologic risk factors, and even monosomy 3. We have identified a set of only three genes that accurately predicts metastatic risk and have optimized the testing platform for polymerase chain reaction-based assay that can be performed on a routine basis on primary tumor tissue and paraffin-embedded archival tissue. An international study is now underway to validate the predictive accuracy of this state-of-the-art prognostic assay ( Box 47.4 ).
