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Abstract

Melanoma and clear cell sarcoma (CCS) share significant histologic and immunohistochemical similarities. The key to distinguishing between these two entities lies in their molecular underpinnings. Melanoma of sun-exposed sites has a variable genetic landscape, but cumulative mutations typically result in a “common denominator” pattern of DNA copy number changes (e.g., amplifications or deletions) on the whole-chromosome or chromosomal arm level. In contrast, CCS is known for harboring a specific translocation: t(12;22)(q13;q12), which results in the EWSR1-ATF1 fusion gene. Here we report two cases of melanoma with morphologic and immunochemical profiles overlapping with clear cell sarcoma (CCS) that also carried alterations of the EWSR1 region on chromosome 22— one of which has not been documented in the context of melanoma previously. Case 1 is that of an 81-year-old male who presented with an ulcerated, 3.4 cm plaque on the left lower leg and case 2 is that of a 55-year-old male with an ulcerated, 5 cm left heel mass. Both cases showed histology concerning for a deeply invasive melanoma versus clear cell sarcoma and had immunohistochemical profiles compatible with melanocytic differentiation. Molecular studies revealed chromosome 22 alterations at the EWSR1 locus in both cases—an amplification for case 1, and a translocation with fusion partner of uncertain significance (EWSR1:: KIAA1671) for case 2—neither of which was a defining molecular alteration for clear cell sarcoma. Awareness of these possible pitfalls involving chromosome 22 alterations in the differential diagnosis of melanoma versus clear cell sarcoma is essential for accurate diagnosis.