PHF1::TFE3-positive fibromyxoid sarcoma? Report of 2 cases and review of 13 cases of PHF1::TFE3-positive ossifying fibromyxoid tumor in the literature

Abstract Objectives Ossifying fibromyxoid tumor (OFMT) is a rare soft tissue neoplasm of uncertain histogenesis. Most OFMTs have benign behavior, and many harbor gene fusions involving the PHD finger protein 1 (PHF1), such as EP400::PHF1, MEAF6::PHF1, EPC1::PHF1, and PHF1::TFE3. The PHF1::TFE3 fusion is unique because PHF1 is at 5ʹ instead of residing at 3ʹ in the other fusions. In this study, we describe 2 cases of OFMT harboring PHF1::TFE3 fusions and review 13 published cases. Methods Two cases of PHF1::TFE3-positive OFMT were investigated using RNA Next-Generation Sequencing and immunohistochemistry. Results Most (12/15) of the PHF1::TFE3 OFMTs we studied were located at proximal and distal extremities, with a multinodular growth pattern. Only 1 case (1/10) had a shell of bone at the periphery. Areas morphologically similar to sclerosing epithelioid fibrosarcoma or low-grade fibromyxoid sarcoma were found in 8 of 12 (66.7%) cases. Eleven cases (11/15 [73.3%]) were regarded as malignant based on more than 2/50 high-power field mitotic figures, increased cellularity, or the presence of necrosis. Among the 9 cases with follow-up data, 2 patients died of disease (with metastases), 1 patient is alive with metastases, and 1 patient had multiple local recurrences. Conclusions Because PHF1 is located at 3ʹ in all the PHF1 fusions in OFMTs except PHF1::TFE3, the different driver molecular alterations suggest that OFMTs with 3ʹ-PHF1 fusions and OFMTs with PHF1::TFE3 are different tumors. Immunohistochemistry confirmed TFE3 expression in all PHF1::TFE3 OFMTs. Because PHF1::TFE3-positive OFMTs have increased mitotic figures and tumor cellularity, with a high rate of metastasis, using the name PHF1::TFE3 positive fibromyxoid sarcoma may be appropriate.