Melanoma
The most common primary intraocular malignancy in adults is melanoma arising from the ciliary body and/or choroid. When this type of tumor grows to a significant size, it may extend beyond its site of origin (ie, from the choroid to the ciliary body and vice versa). Ciliary body and choroidal melanomas exhibit overlapping clinical features with similar prognostic implications and may be referred to collectively as posterior uveal melanomas.
Histologically, posterior uveal melanomas are composed of spindle cells and/or epithelioid melanoma cells (Figs 12-17, 12-18, 12-19). Less commonly, balloon cells similar to those seen in choroidal nevi may be present. Spindle cell melanoma consists primarily of spindle-B melanoma cells (see Fig 12-18). It may also contain spindle-A cells (see Fig 12-17); however, a tumor consisting entirely of spindle-A cells is considered a nevus.
The cytoplasmic melanin content in melanoma cells can vary considerably. The mitotic rate in posterior uveal melanomas tends to be quite low, and mitotic counts by the pathologist typically require 40 high-power fields. These tumors may exhibit variable amounts of necrosis.
Choroidal melanomas typically start as dome-shaped lesions and, as they grow and break through Bruch membrane, they acquire a mushroom or collar-button shape (Fig 12-20). Tumors may involve both the choroid and the ciliary body in some cases (ciliochoroidal melanoma), and it may be difficult to determine where the lesion originated. Less commonly, choroidal lesions grow in a diffuse pattern, replacing normal choroid without achieving significant height (Fig 12-21). In the ciliary body, tumors usually grow in a fashion similar to that of their choroidal counterparts. Likewise, there is a ciliary equivalent of the diffuse pattern seen in the choroid, known as a ring melanoma, in which the tumor extends for the entire circumference of the ciliary body (Fig 12-22).
Choroidal melanomas may cause serous detachments of the overlying and adjacent retina, with subsequent degenerative changes in the outer segments of the photoreceptors (see Figs 12-20B, 12-21). Melanoma may extend through the scleral emissary canals to gain access to the episcleral surface and the orbit (extrascleral tumor extension) (Fig 12-23). Less commonly, melanoma may directly invade the underlying sclera or overlying retina (Fig 12-24). Direct invasion of the anterior chamber or mechanical blockage of the chamber due to anterior iris displacement may lead to secondary glaucoma (Fig 12-25). In addition, tumor necrosis may lead to the dispersion of melanin in the anterior chamber and angle. The trabecular meshwork becomes obstructed by histiocytes that have ingested this pigment, causing a type of secondary glaucoma called melanomalytic glaucoma (see Chapter 7, Fig 7-14).
Histologic prognostic factors Several factors that can be identified via pathologic examination have been significantly correlated with survival in patients with posterior uveal melanoma. The most important histologic variables statistically associated with patient survival are
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tumor cell type (modified Callender classification)
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size of tumor in contact with the sclera (greatest basal dimension of tumor)
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direct extraocular extension
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tumor location (eg, ciliary body)
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complexity of extravascular matrix patterns and high microvascular density
Posterior uveal melanomas are classified by cell type via the modified Callender classification:
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spindle cell melanoma: >90% spindle cells
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epithelioid melanoma: >90% epithelioid cells
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mixed-cell type: mixture of spindle and epithelioid cells
Cell type, defined with the modified Callender classification, has one of the highest associations with survival. Spindle cell melanoma has the best prognosis; epithelioid melanoma, the worst. Melanomas of mixed-cell type have an intermediate prognosis. Some authors have suggested that, in mixed-cell melanoma, survival following enucleation decreases with increasing proportions of epithelioid cells. In rare cases, a melanoma undergoes extensive necrosis, which precludes classification. The prognosis for completely necrotic melanomas is the same as that for mixed-cell melanomas.
The modified Callender classification has some disadvantages. First, there is continuing controversy about the minimum number of epithelioid cells needed for a melanoma to be classified as mixed-cell type. Second, tumor classification can vary between pathologists, even with experienced ophthalmic pathologists, because the cytologic features of melanoma represent a continuous spectrum.
Tumor size is a factor that is also strongly associated with patient survival. In general, larger tumors are associated with poor survival. Many studies use greatest basal dimension and greatest tumor thickness to classify tumors based on size. These measurements can be obtained clinically for many tumors with the use of ultrasonography. Methodical measurements of tumor size are obtained on pathologic examination of tumors that are treated with enucleation. In studies of uveal melanomas that have been enucleated, 10 mm is often used as the cutoff for stratification by size to evaluate prognosis. Most studies have demonstrated that tumor size is an independent risk factor for patient survival and that the larger the tumor, the worse the survival rate. The American Joint Committee on Cancer (AJCC) staging system, commonly used for staging uveal melanoma, stratifies tumor size into 4 categories; these are described in Chapter 17.
Extrascleral extension of tumor is another factor that correlates with prognosis for survival. Extrascleral extension may be classified as macroscopic (ie, extension that can be detected clinically or by ultrasonography and, for enucleated eyes, seen on gross examination) or as microscopic (extension seen only under the microscope in enucleated specimens). The AJCC staging system categorizes extrascleral extension as present or not present; if extension is present, the largest diameter of the extrascleral component is categorized as 5 mm or less, or as greater than 5 mm in greatest dimension. In general, extrascleral extension, particularly macroscopic extension, is associated with less favorable survival.
Yet another prognostic factor that correlates with survival is the location of posterior uveal melanoma. Tumors with a scleral base 1 mm or less from the optic disc (juxtapapillary) have a less favorable prognosis. Posterior uveal melanomas with any ciliary body involvement are also associated with a worse prognosis.
Intrinsic tumor extravascular matrix patterns have prognostic significance. This is a feature that is difficult to assess without histologic evaluation. Tumors demonstrating more-complex extravascular matrix patterns, such as closed loops or networks (3 or more back-to-back loops), are associated with a higher rate of subsequent metastases (Fig 12-26).
Many other histologic factors have some association with survival and/or rate of metastasis. The mean diameter of the 10 largest melanoma cell nucleoli (MLN) correlates well with mortality after enucleation. However, because of the time-intensive nature of calculating this particular variable, it is not often included in pathology reports. High microvascular density is associated with an increased rate of subsequent metastases; this association is as strong as, if not stronger than, that of MLN and extravascular matrix patterns, and is relevant given that the mode of metastasis is overwhelmingly hematogenous. The presence of a large number of tumor-infiltrating lymphocytes and/or histiocytes is associated with a higher metastatic rate as well. It is important to note that invasion through Bruch membrane is not associated with a decrease in survival rates.
Metastases almost invariably result from the hematogenous spread of melanoma to the liver; in more than 95% of tumor-related deaths there is liver involvement. In as many as one-third of tumor-related deaths, the liver is the sole site of metastasis.
Some types of posterior uveal melanomas exhibit biological behavior that cannot be predicted according to the criteria just discussed. Survival rates of patients with diffuse ciliary body melanomas (ring melanoma) are particularly poor. These relatively flat tumors, which are almost always of mixed-cell type, may grow circumferentially without becoming significantly elevated. Diffuse choroidal melanomas have a similarly poor prognosis.
Cytogenetic studies of posterior uveal melanoma have shown that mutually exclusive mutations in GNAQ and GNA11 are an initiating event in the development of uveal melanomas and nevi from melanocytes. Approximately half of uveal melanomas demonstrate monosomy of chromosome 3; a smaller proportion shows gain or loss of a chromosome in chromosomes 1, 6, or 8. Tumors with monosomy 3, especially when associated with gains in 8q, are associated with increased mortality.
Molecular analysis of posterior uveal melanomas by gene expression profiling provides a prognostic classification of uveal melanoma. The analysis, which requires a small amount of fresh or paraffin-embedded tissue, classifies these tumors as follows: class 1A (low metastatic potential), class 1B (intermediate metastatic potential), or class 2 (high metastatic potential). Gene expression profiling analyzes the status of several genes within the tumor. One of these genes is BAP1 (BRCA1-associated protein-1). Mutations leading to inactivation of this gene within the tumor are associated with a higher rate of metastasis. Expression of mRNA by the PRAME gene in tumors may also be associated with rate of metastasis, but this needs to be validated in further studies. Identification of the genetic alterations in uveal melanoma is important not only for prognostication but also in the development of potential targeted therapies for posterior uveal melanoma.
See Chapter 17 for further discussion of posterior uveal melanomas.
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Coupland SE, Lake SL, Zeschnigk M, Damato BE. Molecular pathology of uveal melanoma. Eye (Lond). 2013;27(2):230–242.
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Field MG, Durante MA, Anbunathan H, et al. Punctuated evolution of canonical genomic aberrations in uveal melanoma. Nat Commun. 2018;9(1):116.
Excerpted from BCSC 2020-2021 series: Section 4 - Ophthalmic Pathology and Intraocular Tumors. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.