# Histopathology and Genetic Biomarkers of Choroidal Melanoma
## 3 Histopathological Features  
Grossly, an enucleated eye shows the presence of a frequently pigmented, dome- or mushroom-shaped, mass protruding into the posterior segment (Figure 1). Hemorrhages, signs of extrascleral invasion and secondary retinal detachment may be identified in some cases. In 1931 [PERSON] [4] proposed the first classification of CM identifying six types of melanoma based on their cellular composition and included: (1) spindle A, (2) spindle B, (3) fascicular, (4) mixed, (5) epithelelioid, and (6) necrotic. In this classification, (1) spindle A cells are fusiform, cohesive and have a slender nucleus with fine nuclear chromatin, a small or indistinct basophilic nucleolus and have a longitudinal fold in the nucleus related to invagination of the nuclear membrane; (2) spindle B cells are fusiform cohesive and have plumper spindle or cigar-like nuclei, coarser chromatin, and a more prominent basophilic or eosinophil nucleolus; (3) fascicular choroidal melanomas have a histopathological pattern reminiscent of schwanoma and therefore characterized by nuclei arranged in columnsperpendicular to a central vessel or spindle cells arranged in bundles with palisading of nuclei; (4) the mixed type is composed of spindle cells and epithelelioid cells that are non-cohesive, larger, polygonal cells with an abundant, glassy cytoplasm, distinct cell border and large, round nucleus with marginated coarse chromatin; (5) melanomas composed exclusively of the previously described epithelelioid cells and (6) the last group is composed of tumors too necrotic to be classified. In this first classification, patients with mixed, epithelelioid and necrotic choroidal melanomas have a much worse prognosis than those with tumors of the spindle A, spindle B or fascicular types [5]. However, this first classification was difficult to interpret and apply by pathologists that requested a more reproducible classification with objective criteria. Considering this, it was decided to eliminate the division of spindle cell tumors into type A and type B because tumors are usually composed of a mixture of these two cell types and, more important, no differences in prognosis were observed. CMs originally reported as fascicular were reclassified as spindle-cell type or mixed-cell type [6]. It was also decided to include a smaller type of epithelelioid cells with less cytoplasm and a small nucleus than the classical epithelelioid cell described by [PERSON] [7]. These small epithelelioid cells have large eosinophilic nucleoli and lack cohesiveness as classical epithelelioid cells and have a worse prognosis. Currently, the American Joint Committee of Cancer (AJCC) classification [8] recognizes three cell types: (i) spindle cell (usually composed of an admixture of spindle A and spindle B cells) (Figure 2); (ii) epithelelioid cell (Figure 3); and (iii) mixed cell type (Figure 4). According to this classification, spindle cell melanoma is composed of spindle cells in \(\geq\)90% of the tumor, and epithelelioid cell melanoma is composed of epithelelioid cells in \(\geq\)90% of the tumor; all other tumors are mixed cell melanomas. Other rare variants of choroidal melanomas include: (1) diffuse melanoma characterized by the involvement of at least one-quarter of the uveal tract [9]; (2) clear cell melanoma composed of tumor cells with oval, centrally located nuclei and clear cell cytoplasm due to the dissolution of glycogen granules during fixation [10]; (3) balloon cell melanoma characterized of cells with abundant cytoplasm containing multiple vacuoles that stain for lipids [11]. The pigmentation of CMs usually varies from heavily pigmented to amelanotic cases. Lymphocytic infiltration in CMs is not as frequent as in cutaneous melanoma and two types of infiltration, patchy or diffuse, are reported [12] (Figure 5). As reported in the literature [13], lymphocytic infiltration is usually associated with a better prognosis in many cancer types, such as cutaneous melanoma, nonsmall cell lung cancer, and breast cancer.