Immunohistochemical and Molecular Testing for the Diagnosis of Primary Cutaneous Ewing Sarcoma: A Comprehensive Review

Primary cutaneous Ewing Sarcoma (PCES) is a rare superficial subtype of Ewing sarcoma that typically presents above the fascia and is associated with a relatively favorable prognosis compared to its deep soft tissue and osseous counterparts. This review, conducted by the American Society of Dermatopathology Appropriate Use Criteria Committee Soft Tissue Subgroup, focuses on the ancillary diagnostic methodologies for PCES. This work provides an overview of current immunohistochemical, cytogenetic, and molecular tests used to support a diagnosis of PCES. A total of 37 articles were reviewed, identifying 140 confirmed superficial cases: 26 from case reports and 114 from 10 retrospective studies (ranging from 1 to 56 cases). Immunohistochemically, CD99 demonstrated a positive membranous staining rate of 100% in PCES when reported. While NKX2.2 and PAX7 have not been widely tested in PCES, data from the broader sarcoma literature indicate NKX2.2 sensitivity ranging from 92.7% to 100%, and specificity from 85% to 87.5%. PAX7 showed sensitivity of 90% to 99% and a specificity of 83%. Molecularly, EWSR1 rearrangement by FISH was detected in 57 of 64 tested PCES cases (89%). Next-Generation Sequencing (NGS) revealed EWSR1::FLI1 rearrangement in all three tested PCES cases (100%). In conclusion, the accurate diagnosis of PCES requires a comprehensive approach, integrating detailed morphologic assessment with immunohistochemical studies and potentially cytogenetics/molecular assays.