In adults, most intraocular tumors arise from, or involve the uveal tract, the eye’s middle coat composed of the stroma of the iris, ciliary body, and choroid. The uvea tract is highly vascular and pigmented. The pigment is contained within the cytoplasm of dendritic uveal melanocytes, which are derived embryologically from the neural crest (Fig. 11-1). A similar number of uveal melanocytes are present in lightly and heavily pigmented eyes. Increasing intensity of uveal pigmentation (and eye color) is caused by a corresponding increase in the size and number of melanin pigment granules or melanosomes in the cytoplasm of the melanocytes. The pigment may protect against the development of uveal tumors, because uveal malignant melanoma occurs most often in patients with blue eyes and is rare in heavily pigmented individuals.

The choroidal vessels occasionally undergo hamartomatous proliferation forming hemangiomas, and the rich vascular supply of the posterior choroid explains that region’s predilection for blood-borne metastases.

Uveal melanoma is the most common primary malignant intraocular neoplasm in adults in Europe and the United States. On a worldwide basis, retinoblastoma actually is the most common primary intraocular tumor. Kivelä has estimated that there are ˜8,000 cases of retinoblastoma yearly in the world compared to 7,000 cases of melanoma. Uveal melanoma is a tumor with a definite predilection for fair-skinned, blue-eyed Europeans. Approximately two third of uveal melanomas arise in Caucasians of European descent who comprise ˜13% of the world’s population. In contrast, Han Chinese and Bengalis comprise one fourth of the world’s population, yet have only 8% of the uveal melanomas. Uveal melanomas are relatively rare; about 1,800 tumors occur yearly in the United States. The annual age-adjusted incidence in the United States is about 6 cases per 1 million population.

Uveal melanomas arise from the dendritic melanocytes of the uvea, the middle pigmented and vascularized coat of the eye, which includes the iris, ciliary body, and the choroid (Fig. 11-1B). Choroidal melanomas are most common. More than 90% are choroidal tumors. Uveal melanoma affects both sexes equally. Although pediatric and even rare congenital cases have been reported, uveal melanoma generally occurs in older persons. The mean age of patients eligible for treatment in the Collaborative Ocular Melanoma Study (COMS) was 59 years. Less than 0.8% of cases occur in patients less than age 20 years. Older patients tend to have larger tumors and are more likely to die from their tumors after enucleation.

As noted above, race is an important predisposing factor for uveal melanoma. In the United States, the incidence of uveal melanoma in White patients is 8.5 times greater than the incidence in African Americans. The tumor is also relatively uncommon in Latin America and Asia. The incidence of uveal melanoma in the United States is 25 times greater than that in Taiwan, that is, 0.28 per million versus 7 per million.

Caucasian patients who have congenital ocular or oculodermal melanocytosis (nevus of Ota) (Fig. 5-29) are especially at risk to develop uveal malignant melanoma. The tumor is spawned by a diffuse nevus of the uvea, which is evident clinically as hyperchromic heterochromia iridum. Affected patients often have slate-gray epibulbar pigmentation and a bluish discoloration of adnexal skin as well. It has been estimated that about 1 in 400 white patients with oculodermal melanocytosis will develop uveal melanoma in their lifetime. This risk is about 25 times greater than the risk in unaffected patients. Patients with uveal melanoma associated with oculodermal melanocytosis have double the risk for metastasis compared to those without melanocytosis. Melanomas have developed in young patients with Ota nevus. Ocular and oculodermal melanocytosis are relatively common in Asians but do not appear to predispose them to melanoma. Melanoma also can arise in patients who have the combination of ocular melanocytosis and nevus flammeus called phacomatosis pigmentovascularis.

Uveal melanomas occasionally arise from localized uveal nevi, but the estimated incidence of malignant transformation is quite low. Uveal melanoma has been reported in patients with neurofibromatosis type I, the dysplastic nevus or familial atypical mole melanoma syndrome, and the BAP1 cancer syndrome. Uveal melanoma can arise in patients who have a rare paraneoplastic syndrome called benign diffuse uveal melanocytic proliferation or BDUMP syndrome. The tumor’s propensity for blue-eyed individuals and the inferior exposed part of the iris suggests that exposure to ultraviolet light could be a predisposing factor.

The clinical signs and symptoms of uveal malignant melanoma depend largely on the location of the tumor and the extent of the disease when the patient initially seeks medical attention. Most posterior uveal melanomas present with painless visual loss. Visual symptoms are caused most often by serous and/or solid detachment of the retina. Other mechanisms of visual loss include physical obscuration of the fovea by overhanging tumor, cystoid macular edema, cataracts caused by expanding ciliary body tumors, and rarely vitreous hemorrhage, which usually develops when tumors erode through the retina. Melanomas occasionally are found in asymptomatic patients during routine ophthalmologic examinations. Iris melanomas may present as an enlarging pigmented blemish or a change in eye color (heterochromia iridum) (Fig. 8-21). Other tumors present with unilateral glaucoma. Anterior segment melanomas cause secondary glaucoma by directly seeding or infiltrating the aqueous outflow pathways. Posterior segment tumors usually cause secondary closed-angle glaucoma through a pupillary block mechanism or by stimulating iris neovascularization. Infarcted or extensively necrotic tumors can cause prominent inflammatory signs that can mimic orbital cellulitis (Fig. 11-5). Advanced cases with extrascleral tumor extension into the orbit may present with ocular proptosis. Unsuspected melanomas occasionally are found when blind painful glaucomatous eyes with opaque media are examined pathologically. Before the advent of ultrasonography, as many as 10% of blind painful eyes were said to harbor previously undiagnosed tumors. Care should be taken to exclude the presence of an occult tumor preoperatively if ocular evisceration is planned (Fig. 11-6). Distant metastases usually are not evident when the tumor is first detected and treated.

Melanomas initially arise in the uveal stroma. In early cases of choroidal melanoma, the profile of the sectioned tumor is oval or almond shaped, and its tissue usually appears relatively cohesive after fixation (Fig. 11-8A). Although some melanomas diffusely infiltrate the uvea, most uveal melanomas are relatively well-circumscribed tumors with distinct margins. In many cases, the growing melanoma perforates the Bruch membrane and enters the subretinal space where
its apical portion typically assumes a spherical shape that often is likened to a mushroom or collar button (Figs. 11-7, 11-8B,D and 11-9). If a choroidal tumor has a mushroom configuration, one can be reasonably certain that it is a uveal melanoma. There are exceptions to this rule, but they are exceedingly rare. Dilated blood vessels typically are found in the mushrooming head of the tumor (Figs. 11-7D and 11-9). The ruptured ends of the Bruch membrane exert a compressive cinch-like effect on the waist of the tumor causing vascular congestion in its apex. Rupture of the Bruch membrane was present in 87.7% of 1,527 large- or medium-sized melanomas examined in the COMS. Retinal invasion was present in nearly half (49.1%), and tumor cells were found in the vitreous body in one fourth. About 3% of melanomas diffusely thicken the choroid without forming an elevated mass. These diffuse melanomas usually are of mixed cell type are more likely to infiltrate the sclera and invade the optic nerve or orbit (Figs. 11-10 and 11-11E). Delayed diagnosis or misdiagnosis is common.

In the COMS, choroidal melanomas were classified as small, medium, and large based on the tumor’s largest basal diameter (LTD). Small choroidal melanomas measure <10 mm in LTD and appear as a focal discoid or oval area of choroidal thickening. Medium-sized melanomas measure 11 to 15 mm, and large tumors are more than 15 mm in largest basal tumor diameter. Size is an important prognostic feature in uveal melanoma.

Choroidal melanomas typically cause an exudative serous detachment of the overlying and adjacent retina. Large tumors may cause total retinal detachment (Figs. 11-8B,D and 11-9). The detached retina typically shows photoreceptor atrophy and microcystoid retinal degeneration. The RPE on the surface of the tumor undergoes atrophy and proliferation forming drusenoid material and occasionally a plaque of metaplastic fibrous tissue. Many tumors infiltrate the overlying retina. The melanoma may perforate the retina in exceptional cases, causing vitreous hemorrhage and tumor seeding of the vitreous and the inner retinal surface. Large tumors may totally fill the globe. Eventually, some melanomas extend extraocularly through the sclera and invade the orbit (Fig. 11-11C,E). Secondary glaucoma is often present in eyes with advanced


or neglected tumors. Uveal melanomas vary markedly in their pigment content. Some tumors are totally amelanotic. Other maximally pigmented tumors appear jet black grossly and must be bleached before they can be interpreted histopathologically. Varying degrees of pigmentation typically are found within a single tumor. The cut surface of some tumors has a marbleized appearance. Clumps of orange pigment are found on the surface of many melanomas (Fig. 11-12). The orange pigment comprises either aggregates of macrophages that have ingested lipofuscin pigment and melanin from the damaged RPE or detached RPE cells termed RPE macrophages (Fig. 11-12C,D). The pigment generally is thought to be a clinical marker for an actively growing tumor and can be highlighted with FAF.

Ciliary body melanomas are less common than choroidal tumors and tend to have a more spherical shape (Fig. 11-8C). Ciliary body tumors may be larger when they are first detected because they remain hidden behind the iris and often remain asymptomatic because they cause late retinal detachment. Ciliary body melanomas can deform the crystalline lens and cause unilateral cataract. Occasionally, they can invade the anterior chamber and present with iris heterochromia and secondary glaucoma. The glaucoma is caused by seeding of the trabecular meshwork by tumor cells or by circumferential tumor growth around the angle (ring melanoma). Patients with ciliary body involvement have a poorer prognosis.

The biologic spectrum of uveal melanoma cells comprises bland spindle A melanoma cells at one end and wildly anaplastic epithelioid cells at the other (Fig. 11-13). The term spindle cell is derived from the fusiform or spindled configuration of the cells’ cytoplasmic outline. Spindle cells are bipolar in shape, and many have long tapering processes that occasionally are visible when individual pigmented cells are seen in a largely amelanotic tumor. Spindle cells grow in a syncytial fashion and form interweaving fascicles of parallel oriented cells (Fig. 11-14A,B). The cells can be pigmented or nonpigmented.

There are two types of spindle cells, spindle A and spindle B, which are distinguished by their nuclear characteristics. Spindle A nuclei are cigar-shaped and have finely
dispersed chromatin (Fig. 11-14A). Many spindle A cells have a longitudinally oriented chromatin stripe caused by a fold in the nuclear membrane. If a nucleolus is present, it usually is inconspicuous. The nuclei of spindle B cells tend to be plumper and more oval in shape and have coarser chromatin and distinct nucleoli (Fig. 11-14B).

Epithelioid melanoma cells comprise the poorly differentiated end of the cytologic spectrum. Uveal melanomas that contain epithelioid cells have a poorer prognosis. The term epithelioid, which means “epithelial-like,” reflects the superficial resemblance of the tumor cells to simple epithelial cells. Epithelioid cells have abundant cytoplasm and are often polygonal in shape (Fig. 11-14C). They have distinct cytoplasmic margins, are poorly cohesive, and do not grow as a syncytium. The nuclei of epithelioid cells typically are round or oval in shape, and they often appear vesicular due to margination or clumping of chromatin along the inner side of the nuclear membrane. Epithelioid melanoma cells also have prominent nucleoli that are often large and reddish-purple in color. The large nucleoli are often visible at lower magnification. Variants of epithelioid cells include wildly anaplastic tumor giant cells (Figs. 11-13G-I and 11-15) and relatively uniform small epithelioid cells (Fig. 11-16A).

During histopathologic assessment, melanoma cells are classified by their nuclear characteristics. Spindleshaped cells that have epithelioid nuclei occasionally are encountered; such cells are classified as epithelioid. In recent years, the term intermediate cell has been used more and more. Intermediate cells have nuclear characteristics that are intermediate between spindle B and epithelioid. For example, one might apply the term intermediate cell to a spindle B cell that has a nucleus that is somewhat large and has a fairly prominent nucleolus.

Occasionally, spindle cells in a uveal melanoma are arranged radially around vessels or perpendicular to

fibrovascular septa (vasocentric pattern), or their nuclei form rows that resemble the Verocay bodies or the Antoni A pattern seen in schwannoma (Verocay pattern). Melanomas are called fascicular if these patterns dominate (Fig. 11-16B). Fascicular melanoma was a separate category in the Callender initial classification that was dropped from McLean’s 1983 modification.

Varying degrees of necrosis may be found (Fig. 11-5C). Necrosis tends to be more prominent in rapidly growing high-grade tumors, or tumors that have had prior brachytherapy, and may produce inflammatory signs clinically. The necrosis may be patchy and focal, or may involve extensive parts, or even all of the tumor. Aggregates of melanophages typically are found in the necrotic areas. Total infarction of the tumor (and other intraocular structures) may occur in eyes with severe secondary closed-angle glaucoma. As mentioned above, melanocytoma is especially prone to spontaneous necrosis. The latter diagnosis should always be considered when a totally necrotic, heavily pigmented tumor is found.

Choroidal melanomas produce abnormalities in the overlying RPE including atrophy, hyperplasia, and the formation of drusen and drusenoid material. The overlying retina often shows photoreceptor loss and may develop cystoid edema. The latter tends to be more common over slower growing lesions, especially choroidal hemangiomas. After the Bruch membrane has ruptured, the vessels located in the mushrooming head of the tumor are often quite prominent, reflecting vascular stagnation caused by the compression at the waist of the tumor (Fig. 11-9). Aggregates of macrophages that have ingested PAS-positive lipofuscin pigment and melanin from the damaged RPE or perhaps detached RPE cells can be found in the subretinal fluid (Fig. 11-12). These are evident ophthalmoscopically as clumps of orange pigment that serve as a clinical marker for an actively growing neoplasm.

Uveal melanomas are placed into four categories based on their cytology. Tumors composed entirely of spindle A cells or even blander nevus cells are classified as spindle cell nevi. Tumors composed of a mixture of malignant spindle A and spindle B cells are called spindle melanomas. Melanomas of mixed cell type contain a mixture of spindle and epithelioid melanoma cells (Fig. 11-14D). Some laboratories specify the predominant cell type found in a mixed cell melanoma, for example, reporting mixed cell, predominantly spindle if only a few epithelioid cells are present. Epithelioid melanomas are composed predominantly of epithelioid cells. They are relatively rare and have the poorest prognosis. Most medium- and large-sized melanomas contain a mixture of spindle and epithelioid cells. Eighty-six percent of the posterior melanomas in the COMS histopathology study were classified as mixed cell type; 8% were of spindle cell type and 5% were epithelioid. The association between cytology and mortality is known as the Callender classification (see section on “Prognostic Factors” below).

About one half of patients with choroidal and ciliochoroidal malignant melanomas eventually die from their tumors. Because the eye and orbit lack lymphatics, uveal melanoma spreads via the bloodstream. Hematogenous metastasis to the liver occurs most often; more than 90% of cases with metastatic melanoma have liver metastases, and they are the first metastases detected in 80% (Fig. 11-17B). For this reason, liver enzymes and hepatic imaging are used clinically to monitor patients for recurrence. Other common sites of metastatic uveal melanoma include the lung (24%) and bone (16%). Multiple sites are found in 87%. Micrometastases in the liver are not evident clinically and may remain dormant for many years.

Grossniklaus examined biopsies of liver tissue from patients dying from metastatic uveal melanoma and found that they contained three stages of metastases. Stage I metastases, which were most common, comprised small clusters of tumor cells measuring <50 µm in diameter that were present in the sinusoids of the liver. Based on size, stage II and III metastases were defined as 51 to 500 µm and >500 µm, respectively. The architecture of stage II metastases mimicked the surrounded hepatic parenchyma, while stage III metastases showed either a lobular or portal growth pattern. The mean vascular density and mitotic index of the metastases increased with increasing size. Stage I metastases were not vascularized and showed little mitotic activity, consistent with small, apparently dormant micrometastases.

It is now generally believed that metastasis already has occurred in many cases before the melanoma is diagnosed and treated. Unfortunately, once distant metastases are manifest clinically, therapy generally is ineffective. More than 50% of patients who have metastatic uveal melanoma die within 1 year. In recent years, there has been an effort to identify prognostic factors that could identify patients at high risk for metastatic disease who hopefully might benefit from prophylactic chemo- or immunotherapy (Fig. 11-18). These include factors evident on routine clinical examination, factors disclosed by routine histopathologic evaluation, and powerful new factors that require special testing. Prognostic factors evident on clinical examination include the size of the tumor and the presence or absence of ciliary body involvement and extraocular extension. These three clinical factors are used to prognostically stratify uveal melanomas in the American Joint Committee on Cancer (AJCC) Cancer Staging Manual. Tumor size is particularly important. In the seventh edition of the AJCC Cancer Staging Manual, melanomas are divided into four size categories based on their largest basal diameter and thickness in millimeters. Tumors >18 mm in diameter are class 4. Tumors that involve the ciliary body have a poor prognosis, as do tumors that have extended out of the eye.

Other aspects of tumor size that typically are measured and recorded by ophthalmic pathologists include the size of the melanoma’s transillumination shadow and the dimensions of the tumor on the cut surface of the globe. Both are measured during gross dissection of the eye. In addition, the tumor’s largest basal diameter and height are measured on the glass slide at the time of microscopic evaluation.

In addition to tumor size, ciliary body involvement, and extraocular extension, prognostic factors evident on routine histopathologic examination include the cytologic characteristics of the tumor cells (cell type or Callender classification) discussed above, mitotic activity, and the presence of vascular mimicry patterns (i.e., vascular loops and networks) and tumor-infiltrating lymphocytes and macrophages.

Cell type or the Callender classification refers to the relationship between mortality and the characteristic of the melanoma’s cells. This association initially was reported in 1931 by Major George Russel Callender who examined a series of cases on file in the Registry of Ophthalmic Pathology at the Army Medical Museum in Washington, DC. Callender observed that melanomas were composed of two types of spindle cells that he designated spindle A and B and less differentiated epithelioid cells. He found that tumors that contained epithelioid cells had a poorer prognosis. Ian McLean and his coworkers at the Armed Forces Institute of Pathology modified the Callender original classification in 1978.

In actuality, uveal melanoma represents a biological spectrum (Fig. 11-13). The appearance of morphology of the melanoma cells evolves as mutations accumulate, and the cells become progressively less differentiated. The Callender classification is an attempt to pigeonhole this biologic spectrum.

The presence or absence of epithelioid cells is an extremely important prognostic factor in uveal melanoma. McLean reviewed a series of 3,432 cases of malignant melanoma of the choroid and ciliary body on file in the AFIP’s Registry of Ophthalmic Pathology and found that 56% were mixed cell tumors composed of a mixture of spindle and epithelioid cells. The 15-year mortality of patients with melanomas of mixed cell type was three times that of patients whose tumors were composed solely of spindle cells. Tumor size, measured as the largest tumor diameter (LTD), was also highly correlated with mortality.

The modified Callender classification remains an important and reliable prognosticator of mortality from uveal melanoma. Tumor mortality is greater if uveal melanomas contain epithelioid cells (epithelioid melanomas or mixed epithelioid/spindle cell type). The 5-year mortality of uveal melanomas that contain epithelioid cells is 42%. At 15 years, death from metastatic melanoma increases to 63%. The prognosis of spindle cell tumors is much better; 90% survive 5 years and 72% survive 15 years. Although rare fatal spindle A melanomas have been reported, most tumors composed entirely of spindle A cells are thought to be benign spindle cell nevi.

Cell type remains one of prognostic mainstays of surgical pathologists because assessment is relatively rapid and requires no special stains or equipment. However, determination of cell type is highly subjective, and diagnostic accuracy can vary with the expertise and experience of the pathologist. A masked study showed that even experienced ophthalmic pathologists disagree about their classification of individual tumor cells. Secondly, uveal melanoma’s biological spectrum, which includes extremely bland spindle A melanoma cells at one end and highly anaplastic epithelioid cells at the other, includes only three diagnostic categories, spindle, mixed, or epithelioid, and tumors in a single category, for example, mixed cell type, can vary significantly in their apparent degree of differentiation.

The limitations of the Callender classification prompted a search for more objective and reliable criteria for the histopathological assessment of the malignant potential of uveal melanomas. Gamel and coworkers showed that certain nucleolar parameters, most notably the inverse of the standard deviation of the area of the nucleolus and a second simpler objective method of nucleolar assessment based on the measurement of the 10 largest nucleoli (MTLN), were useful predictors of death from metastatic melanoma. Although these techniques more accurately predicted survival after enucleation using morphological data contained within routine histologic slides, they were not widely adopted because they were labor intensive and relatively time consuming and required special expertise and equipment.

Other attempts to make the assessment of cell type more objective and quantitative include counting the number of epithelioid cells and intermediate cells in 40 high-power fields (HPFs). (The mitotic activity of uveal melanoma is routinely assessed by counting the number of mitotic figures in 40 HPFs.)

As noted above, tumor size is an important prognostic factor. Large melanomas have a poorer prognosis than medium- and small-sized melanomas. Tumor size generally is recorded as the largest tumor diameter or LTD measured at the base. The 5-year survival of small (<10 mm), medium (10 to 15 mm), and large (>15 mm) melanomas are 86%, 66%, and 56%, respectively. These survival rates drop to 76%, 51%, and 41% at 10 years and 70%, 43%, and 35% at 15 years. Smaller melanomas are more likely to be spindle cell tumors. Furthermore, they are more likely to have disomy of chromosome 3 and a more favorable class I gene expression profile.

Certain extracellular matrix patterns within uveal melanomas that initially were termed microvascular patterns have been shown to be prognostic indicators for death from metastatic melanoma. The so-called vascular loops and networks composed of back-to-back loops encircling microdomains of tumor are the vascular mimicry patterns that are strongly associated with death from metastatic melanoma (Fig. 11-18F). The term vasculogenic mimicry looping matrix patterns has been applied to these patterns in recent publications.

Other prognostic factors, which have been shown by multivariant statistical analysis to be less important, include mitotic activity, extraocular tumor extension, necrosis, pigmentation, anterior location, and lymphocytic infiltration. Paradoxically, the prognosis of heavily pigmented tumors may be slightly poorer.

Ocular pathologists routinely assess the mitotic activity of uveal melanoma by counting the number of mitotic figures in 40 high-power (“high dry”) microscopic fields. Forty fields are counted because most uveal melanomas contain relatively few mitoses, that is, only 5 or 10 per 40 HPF. Not unexpectedly, patients whose tumors have more mitoses have a poorer prognosis.

About 8% of 1,527 enucleated globes with uveal melanoma evaluated in the COMS had some degree of extrascleral extension on histopathologic examination (Figs. 11-11 and 11-18C). Although direct scleral infiltration occurs in some cases, melanomas typically extend out of the eye through the emissarial canals of vessels and nerves in the sclera or via the lumina of the vortex veins (Fig. 11-11A,B). Unlike retinoblastoma, uveal melanoma rarely invades the optic nerve. Coupland and Damato found that extraocular spread correlates with increased mortality because it is associated with increased tumor malignancy and, in the case of posterior tumors, more advanced disease.

The presence of tumor-infiltrating lymphocytes is associated with decreased survival (Fig. 11-18G). De la Cruz et al. examined 1,078 cases of uveal melanoma with known survival and found that 12.4% harbored 100 or more lymphocytes per 20 high-power (×400) microscopic fields. The survival rate at 15 years was 36.7% for patients in the high lymphocytic group and 69.6% for patients in the low lymphocytic group. This seemingly counterintuitive observation is explained by the fact that extraocular dissemination of tumor cells is a requisite for stimulation of a T-lymphocyte-mediated immune response. The latter reflects the eye’s status as an immunologically privileged site.

The number of tumor-infiltrating CD68-positive macrophages infiltrating the tumor is another prognostic factor (Fig. 11-18H). Tumor infiltration by M2-type macrophages, the main type found in uveal melanoma, is associated with decreased survival. Tumors with monosomy of chromosome 3 contain a greater number of M2 macrophages than tumors with disomy of chromosome 3. M2-type macrophages are alternatively activated macrophages that promote angiogenesis and have anti-inflammatory properties.

The most powerful prognostic indicators of uveal melanoma require special testing. These include the presence of certain nonrandom chromosomal abnormalities in the tumor cells and the tumor’s gene expression profile (Fig. 11-18I). Uveal melanomas harbor recurrent nonrandom chromosomal abnormalities that include monosomy 3, trisomy 8, and structural or numerical abnormalities of chromosome 6. Loss of chromosome 3 and gains in chromosome 8 are associated with metastatic death. Monosomy 3 has been shown to be a significant predictor of poor prognosis in uveal melanoma. In one study, 57% of patients with monosomy 3 had developed metastases at 3 years, compared to none of the patients with disomy 3. Chromosomal 3 abnormalities have been identified using a variety of techniques including fluorescent in situ hybridization (FISH), multiplex ligation-dependent probe amplification and DNA amplification, and microsatellite assay.

Harbour and coworkers initially examined the expression of genes in uveal melanomas using microarray
technology and found that they fell into two classes that differed markedly in survival (Fig. 11-18J). Their gene expression profile of class I tumors resembles melanocytes. They are low grade and have less than a 5% incidence of metastasis. In contrast, the risk for metastasis in patients who have class II melanomas is >90%. The gene expression profile of class II melanomas resembles primitive neural or ectodermal stem cells. These tumors typically contain epithelioid cells and have monosomy of chromosome 3 and vascular mimicry patterns. They are characterized by downregulation of neural crest and melanocyte-specific genes and upregulation of epithelial genes. Recently, a subclass of class I termed class IB has been recognized. Affected patients develop late metastases. Tumors with gene expression profile 1B harbor mutations in the preferentially expressed antigen in melanoma (PRAME) gene. Gene expression profiling (GEP) of uveal melanomas currently is available as a proprietary test that assesses tumor class by examining 13 genes. The test’s proponents believe that it is the most accurate prognostic marker for melanoma mortality and metastasis, but this remains controversial.

Many centers are now submitting specimens for GEP testing. Others rely on monosomy 3, which can be assessed using several methods. The use of these powerful ancillary tests is somewhat controversial because there currently is no effective treatment for metastatic uveal melanoma. Patients at risk for metastatic disease can be identified, but clinicians currently have no effective treatment to offer them. Many patients want to know their prognosis, however, and those in the low-risk categories can be reassured and followed less rigorously. In addition, GEP can exclude patients at low risk for metastasis from clinical trials investigating new therapeutic agents. Inclusion of class I patients would bias the results of such studies.

The mitogen-activated protein kinase pathway (MAP-K) is activated in 86% of uveal melanomas. In most melanocytic lesions, the oncogenic mutations in the MAP-K signaling pathway are located in BRAF and NRAS1. BRAF stands for (v-raf murine sarcoma viral oncogene homolog B1). Sixty-four percent of cutaneous melanomas have activating mutations in BRAF and 90% of these are the V600E mutation in which there is replacement of the normal valine at position 600 in the molecule by glutamic acid. The 600 E mutation is the target for the BRAF enzyme inhibitor vemurafenib, which successfully controls melanoma that harbor this mutation, albeit for a short period time. Unfortunately, BRAF mutations are rare in uveal melanoma, but they do occur in conjunctival melanoma.

Mutations in GNAQ/GNA11 are an alternate route to MAP kinase activation in uveal melanoma. GNAQ stands for guanine nucleotide-binding protein G(q) subunit alpha. This gene encodes a guanine nucleotide-binding protein that couples the seven transmembrane domain receptor to activation of phospholipase C-beta. GNAQ/GNA11 mutations have been found in 83% of blue nevi and 46% of uveal melanomas. They appear to be an early event since they are also present in blue nevi and the nevus of Ota. GNAQ/GNA11 mutations also activate YAP in the Hippo pathway, which may be inhibited by verteporfin.

Inactivating mutations in the BAP1 gene play an important role in the metastasis of uveal melanoma. BAP1 stands for breast cancer 1, early onset (BRCA1)—associated protein-1 gene. BAP1 mutations are found in 84% of class II melanomas. The BAP1 gene is located on chromosome 3, and the inactivating mutations are thought to be disclosed by loss of chromosome 3 in tumors with monosomy 3. An autosomal dominantly inherited familial cancer syndrome is caused by mutations in BAP1. Patients with the BAP1 cancer syndrome develop uveal melanomas, mesotheliomas, and benign atypical melanocytic skin tumors. These BAP1-mutated atypical intradermal tumor (MBAITS) are biphasic nevus-like lesions. They contain a conventional junctional, compound, or intradermal component composed of small BAP1-positive melanocytes and an adjacent dermal lesion composed of BAP1-negative epithelioid melanocytes.

Most melanocytic lesions of the iris are benign nevi or low-grade spindle cell tumors (Figs. 11-19, 11-20, 11-21, 11-22). About half of the adult population has small nonprogressive iris nevi called freckles (Fig. 11-19). Larger pigmented iris lesions initially should be observed for growth. In one series, only 6.5% enlarged during a 5-year observation period. Clinical features that suggest that a pigmented iris tumor is a melanoma include large size, documented growth, elevated intraocular pressure, hyphema, and tumor vascularity. Other risk factors for malignant transformation include a diffuse gross pattern and ectropion iridis. Subsequently, Shields and coworkers analyzed 1,611 patients with iris nevus to determine factors predictive of growth into melanoma. In that series, 8% had transformed into melanoma in 15 years. That paper included an ABCDEF mnemonic that listed risk factors for malignant transformation. They included: A = age, young (<40 years), B = blood in the anterior chamber (hyphema), C = clock hour (mass located inferiorly), D = diffuse configuration and F = feathery margins. Diffuse growth pattern and hyphema were the most powerful risk factors.

The mean age of patients with iris melanomas is about 10 years younger (age 43 years) than the age of patients with posterior segment melanomas. The prognosis of iris melanoma is also relatively favorable compared to tumors of the posterior segment. Shields studied 169 patients with histologically confirmed iris melanoma and found that distant metastases developed in 5% at 10-year follow-up. In that series, metastases were more likely to develop in older patients whose tumors involved the angle or iris

root and had elevated intraocular pressure and extraocular extension. The relatively small size of most iris melanomas probably is a major factor in their good prognosis. The majority are low-grade spindle cell melanomas as well. Iris melanomas that contain epithelioid cells occasionally are encountered however (Figs. 11-20B and 11-21).

Diffuse iris melanomas that cause hyperchromic heterochromia iridis and secondary glaucoma are a rare but clinically important group of iris tumors (Fig. 8-21). Many diffuse iris melanomas are higher-grade tumors that contain epithelioid cells, which are poorly cohesive and prone to aqueous dispersal. Patients are often misdiagnosed clinically and undergo filtering surgery for glaucoma. The latter invariably fails and puts patients at greater risk for extraocular extension and metastasis. Multicentric tapioca melanoma is a variant of diffuse iris melanoma whose cells form nodular aggregates on the anterior surface of the iris reminiscent of the appearance of the pearl form of tapioca used to make tapioca pudding (Fig. 11-22). Pigmented tumors of the iris pigment epithelium are exceedingly rare (Fig. 11-23).