Histological heterogeneity of Ewing’s sarcoma/PNET: an immunohistochemical analysis of 415 genetically confirmed cases with clinical support

Abstract

Ewing's sarcoma (ES)/peripheral neuroectodermal tumor (PNET) are malignant neoplasms affecting children and young adults. We performed a study to typify the histological diversity and evaluate antibodies that may offer diagnostic/prognostic support. In total, 415 cases of genetically confirmed paraffin-embedded ES/PNET were analyzed on whole sections and in tissue microarrays. This study confirms the structural heterogeneity of ES/PNET, distinguishing three major subtypes: conventional ES (280 cases); PNET (53 cases); and atypical ES/PNET (80), including large cells, vascular-like patterns, spindle pattern, and adamantinoma-like configuration. All cases presented positivity for at least three of the four tested antibodies (CD99, FLI1, HNK1, and CAV1). CAV1 appeared as a diagnostic immunomarker of ES/PNET being positive in CD99-negative cases. Hence, the immunohistochemical analysis confirmed the diagnostic value of all four antibodies, which together cover more than 99% of the tumors, independently of the histological variety. The univariate analysis for survival revealed atypical ES as the only histological parameter apparently associated with less favorable clinical outcome, particularly in the subgroup of patients treated with surgery. In conclusion, the diagnosis of atypical ES is a challenge for the pathologist and needs support from molecular techniques to perform an optimal differential diagnosis with other small round cell tumors.

Evaluation of NKX2-2 expression in round cell sarcomas and other tumors with EWSR1 rearrangement: imperfect specificity for Ewing sarcoma

“…Rare histologic variants of Ewing sarcoma include atypical 'large-cell,' 'vascular-like,' 'adamantinoma-like,' spindle cell and sclerosing. 4,5,16 Ewing sarcoma is characterized by reciprocal chromosomal translocation and gene rearrangement involving the Ewing sarcoma breakpoint region 1 (EWSR1) at 22q12 and FLI1 at 11q24 in 85-90% of cases. 17 This rearrangement creates the oncogenic transcription factor EWSR1-FLI1, whereby the transactivation domain of EWSR1, a ubiquitously expressed member of unknown function in the TET family, is fused to the DNA-binding domain of FLI1, a member in the ETS family.…”

“…In conjunction with histomorphology and molecular techniques, immunohistochemical markers such as CD99 and FLI-1 have been used for the diagnosis of Ewing sarcoma, [4][5][6] albeit with suboptimal specificities. CD99 (MIC2 gene product, recognized by the monoclonal antibody O13) is a surface glycoprotein in normal thymic T lymphocytes and an extremely sensitive marker for Ewing sarcoma; however, its expression is also observed in neuroendocrine carcinoma, lymphoma, synovial sarcoma, rhabdomyosarcoma, and mesenchymal chondrosarcoma.…”

“…CD99 (MIC2 gene product, recognized by the monoclonal antibody O13) is a surface glycoprotein in normal thymic T lymphocytes and an extremely sensitive marker for Ewing sarcoma; however, its expression is also observed in neuroendocrine carcinoma, lymphoma, synovial sarcoma, rhabdomyosarcoma, and mesenchymal chondrosarcoma. [4][5][6] A member of the ETS family and a marker of endothelial differentiation, FLI-1 appears less sensitive for Ewing sarcoma than CD99 and is also expressed in various other round cell tumors including neuroblastoma, lymphoma, synovial sarcoma, rhabdomyosarcoma, desmoplastic small round cell tumor, Merkel cell carcinoma, and small cell carcinoma. 7 NKX2-2, a homeodomain-containing transcription factor involved in neuronal development and glial/neuroendocrine differentiation, 8,9 is a downstream target of EWSR1-FLI1 oncogenic signaling in Ewing sarcoma.…”

Adamantinoma-Like Ewing Sarcoma Mimicking Basal Cell Adenocarcinoma of the Parotid Gland: A Case Report and Review of the Literature

“…Aside from these, 9-20 % of tumors may demonstrate variant morphologies [5,6], which include: large cell ES, ES/PNET with hemangioendothelial features, synovial sarcoma-like ES, sclerosing ES and adamantinoma-like ES. Adamantinomalike ES (AES) is quite rare, particularly in pure form.…”

“…However, as their name would indicate their appearance is reminiscent of adamantinoma; specifically, tumors tend to have a nested appearance and peripheral palisading as well as desmoplasia. Furthermore, AES also express cytokeratins and 'basal' markers like p63, unlike the classic Ewing sarcoma [5][6][7][8]. This variant morphology can be treacherously difficult to recognize in sites such as salivary gland where primary basaloid neoplasms are far more common.…”