Neoplasia

or spindle cells, usually with melanin granules in the cytoplasm. The nuclei of these cells are typically oblong or ovoid with a bland appearance and indistinct nucleoli. Less commonly, epithelioid nevus cells may be present. A variety of growth patterns and cytologic appearances is possible, but cellular atypia and significant mitotic activity are not present. The nevus cells are present as an aggregate within the stroma and occasionally are also present in a plaquelike distribution on the surface of the iris. Occasionally, the cells may extend into the adjacent angle structures.

Melanoma

Melanomas arising in the iris tend to follow a nonaggressive clinical course compared to posterior (ciliochoroidal) melanomas. The majority of iris melanomas occur in the inferior sectors of the iris (see Chapter 17, Fig 17-3). The lesions can be quite vascularized and may occasionally cause spontaneous hyphema.

Iris melanomas are composed of spindle melanoma cells, epithelioid melanoma cells, or a combination of these. Histologically, spindle cells possess plump, spindle-shaped nuclei that have a coarse, granular appearance and prominent nucleoli. These cells are the equivalent of spindle-B cells in posterior melanoma (see the “Melanoma” section under Choroid and Ciliary Body). Epithelioid cells are polyhedral in shape, with large, round nuclei that have a clumped chromatin pattern and prominent eosinophilic nucleoli. Both types of cells tend to have a high nuclear-to-cytoplasmic ratio. The cytoplasm of melanoma cells can range from lightly to heavily pigmented. Typically, they grow as a solid mass in the stroma, sometimes with a surface plaque. Occasionally, iris melanomas may demonstrate satellite lesions or a diffuse growth pattern that replaces normal stroma (Fig 12-11). The modified Callender classification for posterior melanomas (see the discussion later in the chapter) is not applicable to iris melanomas in terms of prognostic significance.

Although iris melanomas may grow in a locally aggressive fashion, they rarely metastasize. One exception occurs when melanomas grow to diffusely involve the entire iris stroma. In such cases, the melanoma may extend posteriorly into the chamber angle and involve the ciliary body.

Figure 12-11 A, Clinical appearance of iris melanoma. The pigmented tumor is seen between 10:30 and 1:00. B, Gross appearance of pigmented iris mass (between arrows). C, Low magnification shows the iris melanoma completely replacing the normal iris stroma, extending into the anterior chamber, touching the posterior cornea, and occluding the angle. D, Histology of iris melanoma shows numerous plump epithelioid melanoma cells containing prominent nucleoli (arrowheads).

(Courtesy of Hans E. Grossniklaus, MD.)

Choroid and Ciliary Body

Nevus

Most nevi of the uveal tract occur in the choroid (see Chapter 17, Fig 17-2). One review of 100 nevi showed that fewer than 6% involved the ciliary body; the remainder were present in the choroid. Four types of nevus cells have been described. They are

plump polyhedral: abundant cytoplasm filled with pigment and a small, round to oval nucleus with bland appearance

slender spindle (Fig 12-12): cytoplasm contains scant pigment and a small, dark, elongated nucleus

plump fusiform dendritic: morphology is intermediate between plump polyhedral and slender spindle

balloon cells: abundant, foamy cytoplasm that lacks pigment and has a bland nucleus

Depending on the size and location of the nevus, it may exert nonspecific effects on adjacent ocular tissues. The associated choriocapillaris may become compressed or obliterated, and drusen

may be seen overlying the nevus. Less commonly, localized serous detachments of the overlying RPE or neurosensory retina develop.

Most choroidal nevi remain stationary over long periods of observation. However, the presence of nevus cells associated with some melanomas supplies evidence that melanomas may arise from choroidal nevi.

Melanocytoma

The melanocytoma is a specific type of uveal tract nevus (magnocellular nevus) that warrants separate consideration. These jet-black lesions may occur anywhere in the uveal tract, but they most commonly appear in the peripapillary region (see Chapter 17, Fig 17-12).

Histologically, a melanocytoma is composed of plump polyhedral cells with small nuclei and abundant cytoplasm. Because the nevus cells are so heavily pigmented, it is usually necessary to obtain bleached sections to accurately study the cytologic features. Areas of cystic degeneration or necrosis may be observed.

Melanoma

Melanoma arising from the ciliary body and choroid is the most common primary intraocular malignancy in adults. When this tumor achieves significant size, it may extend beyond its site of origin (ie, from the choroid to the ciliary body and vice versa). Unlike iris melanomas, ciliary body and choroidal melanomas exhibit similar features and are usually considered to be the same type of tumor, with similar histologic features and prognostic implications.

Figure 12-14 Compared with spindle-A cells, spindle-B cells demonstrate a higher nuclear-to-cytoplasmic ratio; more coarsely granular chromatin; and plumper, large nuclei. Nucleoli are prominent and mitoses are present, though not in large numbers. Tumors composed of a mix of spindle-A and spindle-B cells are designated spindle cell melanomas.

Nasreen A. Syed, MD.)

Figure 12-15 Epithelioid melanoma cells. Cells resemble epithelium because of abundant eosinophilic cytoplasm and enlarged oval to polygonal nuclei. Epithelioid melanoma cells often lack cohesiveness and demonstrate marked pleomorphism, including the formation of multinucleated tumor giant cells. Nuclei have a conspicuous nuclear membrane, very coarse chromatin, and large nucleoli. (Courtesy of Nasreen A. Syed, MD.)

Melanomas typically start as dome-shaped lesions and, as they grow and break through the Bruch membrane, they acquire a mushroom or collar-button shape (Fig 12-16). Less commonly, choroidal lesions may grow in a diffuse pattern, replacing normal choroid without achieving significant height. In the ciliary body, the equivalent of the diffuse pattern is the ring melanoma, in which the tumor extends for the entire circumference of the ciliary body (Figs 12-17, 12-18).

Figure 12-16 Choroidal melanoma with rupture through the Bruch membrane. A, Gross appearance. B, Microscopic appearance. Note the subretinal fluid (SRF) adjacent to the tumor.

Figure 12-17 Some melanomas grow in a diffuse placoid fashion, replacing normal choroid, without achieving significant height (arrows). Note the eosinophilic proteinaceous material (asterisks) interposed between the retina and the tumor, corresponding to exudative retinal detachment overlying the tumor.

Figure 12-18 By definition, a ring melanoma (asterisks) follows the major arterial circle of the iris circumferentially around the eye.

Choroidal melanomas may also cause serous detachments of the overlying and adjacent retina, with subsequent degenerative changes in the outer segments of the photoreceptors (Fig 12-19). Melanomas may extend through scleral emissary channels to gain access to the episcleral surface and the orbit (Fig 12-20). Less commonly, aggressive melanomas may directly invade the underlying sclera or overlying retina (see Fig 12-19). Direct invasion of the anterior chamber may lead to secondary glaucoma. In addition, tumor necrosis may lead to the liberation of melanin pigment, which can then gain access to the anterior chamber and angle, causing a type of secondary glaucoma called melanomalytic glaucoma.

Several factors that can be identified on pathologic examination have been significantly correlated with survival in patients with choroidal and ciliary body melanomas. The 2 most important variables associated with survival are

the size of the largest tumor dimension in contact with the sclera the cell type making up the tumor

Figure 12-19 Invasion of neurosensory retina by melanoma (arrows). Note the atrophy of overlying outer retina, cystoid edema, and intraretinal hemorrhage.

Figure 12-20 A, Note the melanoma cells tracking along scleral emissary canals (arrows). B, Melanoma is found within the vortex vein (arrows). C, Some melanomas (arrows) track along the outer sheaths of posterior ciliary vessels (asterisks) and nerves.

The modified Callender classification is used for the cytologic classification of uveal melanomas:

spindle cell melanoma epithelioid melanoma

mixed-cell type (mixture of spindle and epithelioid cells)

Occasionally, a melanoma undergoes extensive necrosis, which precludes classification.

Spindle cell melanoma has the best prognosis, and epithelioid melanoma the worst. Melanomas of mixed-cell type have an intermediate prognosis. Some authors have suggested that survival following enucleation decreases with increasing proportions of epithelioid cells in mixed-cell melanomas. Totally necrotic melanomas assume the same prognosis as 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, the scheme is difficult to reproduce, even among experienced ophthalmic pathologists. This difficulty arises because the cytologic features of the melanoma cells reflect a continuous spectrum.

Cytomorphometric measurements of melanoma cells have been studied. One such measurement is the mean of the 10 largest melanoma cell nucleoli (MLN). This parameter has been shown to correlate well with mortality after enucleation. The correlation with morphometry is enhanced further when combined with the largest dimension of scleral contact by tumor.

Intrinsic tumor extravascular matrix patterns have also been studied and shown to have prognostic significance. Tumors containing more complex extravascular matrix patterns such as closed loops or networks (3 loops located back-to-back) are associated with an increased incidence of subsequent metastases (Fig 12-21).

Cytogenetic studies of uveal melanoma have shown that approximately half of uveal melanomas demonstrate monosomy of chromosome 3. A smaller proportion demonstrates changes in chromosome 8, with either gain or loss of a chromosome. Monosomy 3 and trisomy 8 are associated with increased mortality from the tumor. A commercially available test using gene expression profiling allows prognostic classification of uveal melanoma tumors. The test requires a small amount of fresh or paraffin-embedded tissue and classifies these tumors as either Class 1 (low metastatic potential) or Class 2 (high metastatic potential).

Figure 12-21 Extravascular matrix patterns in uveal melanoma. A, Closed loop (L). B, Network: 3 or more back-to-back

loops. (Courtesy of Nasreen A. Syed, MD.)

Other factors associated with an increased mortality rate include extrascleral extension, anterior or juxtapapillary location of the tumor, and the presence of tumor-infiltrating lymphocytes. Invasion through the Bruch membrane does not affect survival.

Lymphatic spread of ciliary body and choroidal melanomas is rare. Metastases almost invariably result from the hematogenous spread of melanoma to the liver. The reason for the propensity of melanomas to spread to the liver is unknown, although more than 95% of tumor-related deaths have liver involvement. In as many as one-third of tumor-related deaths, the liver is the sole site of metastasis.

Some types of uveal melanomas show biologic 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 are almost always of mixed-cell type, and they may grow circumferentially without becoming significantly elevated. Diffuse choroidal melanomas similarly have a poor prognosis.

See Chapter 17. Also see the appendix for the American Joint Committee on Cancer (AJCC) staging form for uveal melanoma.