Abstract

A 79-year-old male presented with a 6-week history of a brown-black discoloration under his right index fingernail, initially thought to be a subungual hematoma. The lesion progressed into a nodule, raising concerns of subungual squamous cell carcinoma, pyogenic granuloma, onychopapilloma, or verruca. Histologic examination of the subsequent biopsy showed nodules of malignant hyaline cartilage juxtaposed with variably nested epithelioid cells exhibiting enlarged pleomorphic nuclei and prominent cherry-red nucleoli. By immunohistochemistry, the tumor cells were diffusely positive for S100, SOX10, and PRAME and negative for Melan-A and HMB45, while exhibiting complete loss of p16. The findings were diagnostic of subungual melanoma with cartilaginous differentiation. Further analysis by next-generation sequencing and SNP-microarray uncovered complex chromosomal aberrations, including deletion of CDKN2A and copy number gains of RICTOR, a gene previously linked to melanoma therapy resistance. Additionally, a heterozygous deletion in chromosome 11p11.2 containing the EXT2 locus was detected. The tumor had a low mutational burden of 6 mutations/MB. Notably, loss of function alterations in EXT2 have been implicated in the development of solitary and multiple hereditary osteochondromas and chondrosarcoma. Cartilaginous differentiation is exceedingly rare in melanoma, typically occurring in the subunguum of middle-aged adults with nail dystrophy or trauma. While the mechanism is poorly understood, it has been suggested that melanoma cells may induce sarcomatous proliferation of pluripotent connective tissue stromal cells or may directly differentiate into mesenchymal tumor cells. Further research is needed to explore whether EXT2 or related genes contribute to this phenotypic switch.