Recurrent FOS rearrangement in proliferative fasciitis/proliferative myositis

Proliferative fasciitis (PF) and proliferative myositis (PM) are rare benign soft tissue lesions, usually affecting the extremities of middle-aged or older adults. Presenting as poorly circumscribed masses, they histologically show bland spindle cell proliferation in a myxoid to fibrous background and a hallmark component of large epithelioid "ganglion-like" cells in various numbers, which may lead to their misdiagnosis as sarcoma. PF/PM has been long considered as reactive, akin to nodular fasciitis; however, its pathogenesis has remained unknown. In this study, we analyzed the FOS status in 6 PF/PMs (5 PFs and 1 PM). Five PF/PMs occurred in adults, all showing diffuse strong expression of c-FOS primarily in the epithelioid cells, whereas spindle cell components were largely negative. Using fluorescence in situ hybridization (FISH), all 5 c-FOS-immunopositive tumors showed evidence of FOS gene rearrangement in the epithelioid cells. RNA sequencing in 1 case detected a FOS-VIM fusion transcript, which was subsequently validated by reverse transcriptase-polymerase chain reaction, Sanger sequencing, and VIM FISH. The one pediatric PF case lacked c-FOS expression and FOS rearrangement. c-FOS immunohistochemistry was negative in 45 cases of selected mesenchymal tumor types with epithelioid components that may histologically mimic PF/PM, including pleomorphic sarcoma with epithelioid features and epithelioid sarcoma. Recurrent FOS rearrangement and c-FOS overexpression in PF/PM suggested these lesions to be neoplastic. FOS abnormality was largely restricted to the epithelioid cell population, clarifying the histological composition of at least 2 different cell types. c-FOS immunohistochemistry may serve as a useful adjunct to accurately distinguish PF/PM from mimics.