Review with novel markers facilitates precise categorization of 41 cases of diagnostically challenging, “undifferentiated small round cell tumors”. A clinicopathologic, immunophenotypic and molecular analysis

Abstract Background Despite extensive immunohistochemical (IHC) and molecular studies combined with morphologic findings, a group of round/ovoid cell tumors histologically similar to Ewing sarcomas (ES) but lacking EWSR1 -rearrangements may remain unclassifiable. Design We retrospectively analyzed 41 Ewing-like tumors (formalin-fixed, paraffin-embedded) previously determined as negative or non-informative for EWSR1 -rearrangements by FISH and/or RT-PCR. A new histopathology revision and additional IHC and molecular analyses were carried out in order to investigate whether additional IHC and/or molecular testing in combination with the morphological findings may help in reaching a definitive diagnosis. Results Almost all the tumors ( n  = 40) involved soft tissue and/or bone and half the patients died of disease. In the archival cases all diagnoses were Ewing sarcoma (ES), Ewing-like sarcoma (ELS), myoepithelial tumor and undifferentiated sarcoma (US). In the new review all the tumors were re-classified as, ES ( n  = 16), Ewing-like tumor with EWSR1 rearrangement and amplification and possible EWSR1-NFATC2 gene fusion (n = 1), CIC -rearranged sarcomas or undifferentiated sarcoma, most consistent with CIC -rearranged sarcoma ( n  = 7), sarcoma with BCOR-alteration or undifferentiated sarcoma, consistent with BCOR-associated sarcoma ( n  = 3), neuroblastoma ( n  = 2), unclassifiable neoplasm with neuroblastic differentiation ( n  = 1), malignant rhabdoid tumor (n = 2), lymphoblastic lymphoma ( n  = 1), clear cell sarcoma of the gastrointestinal tract ( n  = 1), small cell carcinoma (n = 1), sclerosing rhabdomyosarcoma ( n  = 1), desmoplastic small round cell tumor (n = 1), malignant peripheral sheath nerve tumor ( n  = 1), poorly-differentiated synovial sarcoma ( n  = 1), Possible gastrointestinal stromal tumor/GIST with predominant round cells (n = 1) and possible SMARCA4-deficient-sarcoma (n = 1). NKX2.2, ETV4 and BCOR immunoreactivity was observed in all ES, CIC -rearranged sarcomas and sarcomas with BCOR alteration, respectively. CIC -rearrangement by FISH was observed in many of the CIC -rearranged sarcomas. Conclusion Our analysis of 41 Ewing-like tumors confirms that there may be a significant pathological and IHC overlap among Ewing-like tumors, with prognostic and therapeutic impacts. Additional IHC (NKX2.2, ETV4 and BCOR) and molecular studies including FUS , CIC or BCOR analysis may support the final diagnosis when FISH or RT-PCR fail to detect EWSR1 -rearrangements. Any molecular findings should always be interpreted in relation to the specific clinical and pathological context.