PRAME as a Diagnostic Adjunct in Clear Cell Sarcoma

Clear cell sarcoma (CCS) is a rare soft tissue neoplasm characterized by melanocytic differentiation and recurrent EWSR1 rearrangements. Owing to its overlapping morphology and immunophenotype with malignant melanoma (MM), distinction between these entities can be challenging, particularly in small biopsies or metastatic settings. Preferentially Expressed Antigen in Melanoma (PRAME) has emerged as a valuable marker in melanocytic pathology; however, its utility in CCS remains to be fully elucidated. We conducted a retrospective analysis of 26 CCS cases from 2 sarcoma referral centers, assessing PRAME immunohistochemistry (IHC) alongside a validation cohort of 120 cutaneous melanomas. Clinicopathologic features, EWSR1 rearrangement status, and survival data were reviewed. The patient cohort (65.4% female) had a mean age of 36.1±15.4 years, with most tumors arising in the extremities. The mean tumor diameter was 4.9±2.8 cm. PRAME was negative in 25/26 (96.2%) CCS cases, with only one case showing focal weak staining. Nineteen CCS cases demonstrated EWSR1 gene rearrangement on molecular analysis. In contrast, PRAME was positive in 110/120 melanomas (91.7%), displaying diffuse (80%) or focal (11.7%) staining. Our findings indicate that PRAME is almost uniformly absent in CCS, in sharp contrast to its strong and prevalent expression in melanoma. PRAME immunohistochemistry may therefore serve as a useful and cost-effective adjunct in the differential diagnosis of melanocytic soft tissue tumors. In an appropriate morphologic and clinical context, the absence of PRAME expression supports a diagnosis of CCS over melanoma, particularly when molecular confirmation of EWSR1 rearrangement is unavailable or inconclusive.