Abstract

Poorly differentiated round cell tumors of the skin are extremely rare and may present as a diagnostic challenge when encountered by the practicing dermatopathologist. Their histologic differential encompasses a wide array of entities including cutaneous involvement by lymphoma, Merkel cell carcinoma, melanoma, as well as various classes of sarcomas such as rhabdomyosarcomas and undifferentiated round cell sarcomas. The latest edition of the World Health Organization (WHO) Classification of Soft Tissue and Bone Tumours includes Ewing sarcoma/primitive neuroectodermal tumor (PNET), round cell sarcoma with EWSR1-non-ETS fusions, CIC-rearranged sarcomas, and sarcomas with BCOR genetic alterations in this latter group of sarcomas. While BCOR sarcomas predominantly arise in the bone or deep in the soft tissue and are virtually never encountered on skin biopsy, the others can arise superficially. Here, we describe four cases of superficial tumors that adopt a poorly differentiated round cell morphology. We compare and contrast their histology on H&E sections, their immunohistochemical staining patterns, and the results of either fluorescent in situ hybridization (FISH) testing or next generation sequencing (NGS) fusion panels performed on the different cases. We review the diagnostic use and clinical implications of the various molecular alterations identified including CIC-DUX4 fusions, EWSR1 gene rearrangement, and GLI1 gene amplification. Finally, we discuss the potential pitfalls when encountering round cell tumors in the skin, our diagnostic approach, and additional clinical considerations.