Atypical EWSR1 alterations in gastrointestinal melanoma mimicking clear cell sarcoma: a diagnosis resolved by integrated molecular profiling

Background In cases where tumors share histological and immunohistochemical features, molecular studies can assist in achieving a definitive diagnosis. Next generation sequencing (NGS)-based molecular profiling helps identify characteristic genetic alterations associated with specific cancer types and mutational signatures such as tumor mutational burden (TMB). Gene fusions, present in approximately 30–50% of sarcoma cases, are especially valuable for distinguishing sarcoma from other solid tumors. However, atypical rearrangements in promiscuous genes such as EWSR1 may complicate interpretation. Case description Here we present the molecular workup of a gastrointestinal mass with a differential diagnosis of clear cell sarcoma or melanoma using DNA- and RNA-based solid tumor NGS panels and fluorescence in situ hybridization (FISH). No EWSR1 :: ATF1 or EWSR1 :: CREB1 fusions were identified by NGS; however, EWSR1 copy number gain and atypical EWSR1 fusion events were detected, representing potential diagnostic pitfalls. A high TMB (99.3 muts/Mb) and pathogenic somatic variants in BRAF , NF1 and TP53 ultimately supported a diagnosis of melanoma. Conclusions In the context of complex genomic architecture and atypical EWSR1 rearrangements, where single assays may fail to detect unusual but diagnostically critical alterations, integrating DNA-based NGS with an RNA-based fusion panel yields a more reliable molecular profile. The identification of a high TMB and multiple established somatic mutations ultimately facilitated the diagnosis of melanoma over clear cell sarcoma, despite overlapping histological and immunohistochemical features.