Undifferentiated round cell sarcomas of the skin

Undifferentiated round cell sarcomas are a heterogenous group of bone/soft tissue neoplasms characterized by relatively monotonous small blue round cell morphology, with high nuclear/cytoplasmic ratio and unspecific or overlapping immunohistochemical findings. According to the WHO Classification of Tumors of Soft tissue and Bone, this group includes Ewing sarcoma, CIC-rearranged sarcoma, sarcoma with BCOR genetic alterations, and round cell sarcoma with EWSR1::non-ETS fusions. Although they are quite rare in cutaneous/subcutaneous localization, they should always be included in the differential diagnosis of poorly differentiated round cell cutaneous tumors. Among them, subcutaneous/cutaneous Ewing sarcoma and superficial CIC- rearranged sarcoma are the most common entities and distinction between them is extremely important, as Ewing sarcoma has a significantly better prognosis, particularly in the superficial location, as opposed to CIC-rearranged sarcoma which is a highly aggressive sarcoma with a poor clinical outcome. Molecular analysis is required for diagnostic confirmation, and it includes FISH, standard sequencing-based methods and recently also DNA methylation profiling. This article provides a summary on contemporary knowledge regarding undifferentiated cutaneous round cell sarcomas, with an emphasis on characteristic histologic and immunohistochemical features as well as diagnostic pitfalls, including differential diagnosis and potential false-negative results in molecular assays.