Upper gastrointestinal cancers: Are all carcinomas truly carcinomas?

20 Background: Poorly differentiated cancer of the upper GI tract is a challenging diagnosis for the pathologist, who will rely on a positive cytokeratin immunostaining to confirm the epithelial origin of the tumor. Being confronted with a highly unusual case (a poorly differentiated esophageal “carcinoma” with immunophenotypic and genetic sarcoma-like features, arising in the background of high grade Barrett dysplasia), we retrospectively investigated whether other cancer cases displayed the same unusual features. Methods: 34 poorly differentiated GI cancers were selected based on availability of FFPE. All cases were investigated by (1) immunohistochemistry for selected carcinoma and sarcoma markers (prekeratin, NCAM, vimentin, CD99) and by (2) FISH for presence/absence of abnormalities of 2 genes, SYT and EWS, that are frequently rearranged in synovial and Ewing’s sarcoma respectively. Results: 6/34 cases displayed an aberrant immunophenotype, with expression of NCAM, vimentin, and/or CD99. FISH revealed a substantial number (9/34) of SYT and EWS related anomalies: 1 EWS rearrangements, 1 SYT rearrangements, 1 SYT and 1 EWS focal amplification, and 4 aneuploidies. While EWS and SYT are (mostly) fused to ERG or SSX1/2 in Ewing’s and synovial sarcoma respectively, these genes were found to be intact in our EWS and SYT rearranged cases. Conclusions: Our data show that SYT & EWS abnormalities are recurrently occurring in poorly differentiated GI cancers that are (mis?)diagnosed as carcinomas. While EWS rearrangement has previously been described in cancer types other than Ewing’s sarcoma, SYT rearrangement was so far thought to be exclusive to the diagnosis of synovial sarcoma. In addition, EWS/SYT abnormalities in our series seemed to target cancers that are at risk of not responding well to the conventional chemoradiotherapy regimen. Of interest, the one “carcinoma” patient that started this study went into complete remission after being administered a sarcoma targeted therapy. We also infer from our results that good histologic assessment of GI cancers is essential for clinical trials aiming at targeted therapy, as not all carcinomas may present true carcinomas.