EWSR1::POU2AF3 (COLCA2) sarcomas are a recently identified group of undifferentiated round/spindle cell neoplasms with a predilection for the head and neck region. Herein, we report our experience with 8 cases, occurring in 5 men and 3 women (age range, 37-74 years; median, 60 years). Tumors involved the head/neck (4 cases), and one each the thigh, thoracic wall, fibula, and lung. Seven patients received multimodal therapy; 1 patient was treated only with surgery. Clinical follow-up (8 patients; range, 4-122 months; median, 32 months) showed 5 patients with metastases (often multifocal, with a latency ranging from 7 to 119 months), and 3 of them also with local recurrence. The median local recurrence-free and metastasis-free survival rates were 24 months and 29 months, respectively. Of the 8 patients, 1 died of an unknown cause, 4 were alive with metastatic disease, 1 was alive with unresectable local disease, and 2 were without disease. The tumors were composed of 2 morphologic subgroups: (1) relatively bland tumors consisting of spindled to stellate cells with varying cellularity and fibromyxoid stroma (2 cases) and (2) overtly malignant tumors composed of nests of "neuroendocrine-appearing" round cells surrounded by spindled cells (6 cases). Individual cases in the second group showed glandular, osteogenic, or rhabdomyoblastic differentiation. Immunohistochemical results included CD56 (4/4 cases), GFAP (5/8), SATB2 (4/6), keratin (AE1/AE3) (5/8), and S100 protein (4/7). RNA sequencing identified EWSR1::POU2AF3 gene fusion in all cases. EWSR1 gene rearrangement was confirmed by fluorescence in situ hybridization in 5 cases. Our findings confirm the head/neck predilection and aggressive clinical behavior of EWSR1::POU2AF3 sarcomas and widen the morphologic spectrum of these rare lesions to include relatively bland spindle cell tumors and tumors with divergent differentiation.

Department for Human Genetics University Hospitals Leuven KU Leuven Leuven Belgium

Department of Anatomical Pathology Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung City Taiwan

Department of General Medical Oncology University Hospitals Leuven Leuven Cancer Institute Leuven Belgium; Department of Oncology KU Leuven Laboratory of Experimental Oncology Leuven Belgium

Department of Internal Medicine Maastricht University Medical Center Maastricht The Netherlands

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota; Department of Pathology Indiana University School of Medicine Indianapolis Indiana

Department of Pathology Charles University Faculty of Medicine in Plzeň Czech Republic; Bioptical Laboratory Ltd Plzeň Czech Republic

Department of Pathology Charles University Faculty of Medicine in Plzeň Czech Republic; Medical Laboratory CSD Ltd Kyiv Ukraine

Department of Pathology GROW School for Oncology and Developmental Biology Maastricht University Medical Center Maastricht The Netherlands

Department of Pathology Hacettepe University Ankara Turkey

Department of Pathology The Johns Hopkins Medical Institutions Baltimore Maryland

Department of Pathology University Hospitals Leuven KU Leuven Leuven Belgium

Institute of Pathology Friedrich Alexander University Erlangen Nürnberg University Hospital Erlangen Germany

Section of Histopathology Department of Pathology and Laboratory Medicine Aga Khan University Hospital Karachi Pakistan

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