POU2AF3‐rearranged sarcomas: A novel tumor defined by fusions of EWSR1 or FUS to a gene formerly designated COLCA2

Abstract

Gene fusions involving EWSR1 or FUS as the 5 0 partner have been reported in a diverse array of sarcomas. Here, we characterize the histopathology and genomics of six tumors harboring a gene fusion between EWSR1 or FUS and POU2AF3, an understudied, putative colorectal cancer predisposition gene. Striking morphologic features reminiscent of synovial sarcoma were observed including a biphasic appearance with variable fusiform to epithelioid cytomorphology and staghorn-type vasculature. RNA sequencing demonstrated variable breakpoints in EWSR1/FUS along with similar breakpoints in POU2AF3 that encompassed a 3 0 portion of this gene. For cases in which additional information was available, the behavior of these neoplasms was aggressive with local spread and/or distant metastases. Although further studies are needed to confirm the functional significance of our findings, POU2AF3 fusions to EWSR1 or FUS may define a novel type of POU2AF3-rearranged sarcomas with aggressive, malignant behavior.

Molecular pathology in diagnosis and prognostication of head and neck tumors

“…They affect adult patients and commonly arise in the head and neck, particularly within the sinonasal tract. Their morphological spectrum of these tumors is wide from spindle cells, through biphasic tumors with spindled and round cells with features of neuroendocrine differentiation, to purely round cell tumors with high nuclear grade [110][111][112]. Approximately half of the cases display pancytokeratin positivity [110][111][112], possibly leading to diagnostic confusion with synovial sarcoma.…”

“…Their morphological spectrum of these tumors is wide from spindle cells, through biphasic tumors with spindled and round cells with features of neuroendocrine differentiation, to purely round cell tumors with high nuclear grade [110][111][112]. Approximately half of the cases display pancytokeratin positivity [110][111][112], possibly leading to diagnostic confusion with synovial sarcoma. As EWSR1 fusions with various partners are frequent in soft tissue tumors, FISH analysis of an EWSR1 break is not a sufficient diagnostic test.…”

Molecularly defined sinonasal malignancies: an overview with focus on the current WHO classification and recently described provisional entities

“…Their morphological spectrum ranges from spindle cell proliferation with mild nuclear atypia, through biphasic tumors composed of sheets and fascicles of spindled and round cells with features of neuroendocrine differentiation, to purely round cell tumors with high nuclear grade (Fig. 6 A–D) [ 94 – 96 ]. In addition, some tumors were reported to contain foci of glandular, rhabdomyoblastic, or osteogenic differentiation [ 95 ].…”

“…In addition, some tumors were reported to contain foci of glandular, rhabdomyoblastic, or osteogenic differentiation [ 95 ]. Approximately half of the cases display pan-cytokeratin positivity [ 94 – 96 ], possibly leading to diagnostic confusion with synovial sarcoma. In general, EWSR1 fusions with various partners are frequent in soft tissue tumors and include rare instances of alternative EWSR1::SSX1 fusion in synovial sarcoma [ 97 ], or potential FUS fusion with POU2AF3 instead of EWSR1 [ 96 ].…”

“…Approximately half of the cases display pan-cytokeratin positivity [ 94 – 96 ], possibly leading to diagnostic confusion with synovial sarcoma. In general, EWSR1 fusions with various partners are frequent in soft tissue tumors and include rare instances of alternative EWSR1::SSX1 fusion in synovial sarcoma [ 97 ], or potential FUS fusion with POU2AF3 instead of EWSR1 [ 96 ]. Consequently, FISH detection of an EWSR1 break is not a sufficient diagnostic test.…”