FOS and FOSB Immunohistochemistry and Molecular Testing Reveal Novel Patterns in Proliferative Fasciitis and Myositis, FOSB Rearrangement in Proliferative Funiculitis, and FOSL1 :: RELA Fusion in Pediatric Proliferative Fasciitis.

Proliferative fasciitis (PFA) and proliferative myositis (PM) are related benign neoplasms that show large ganglion-like neoplastic cells and harbor recurrent FOS fusions. Proliferative funiculitis (PFU) is a benign mesenchymal lesion of the spermatic cord, with small ganglion-like cells and unknown etiology. Ischemic fasciitis (IFA) is a possibly reactive lesion that shows cytomorphologic overlap with PFA/PM. Here, we assessed FOS and FOSB immunohistochemistry (IHC) in PFA (adult and pediatric), PM, PFU, and IFA. Diffuse nuclear FOS expression was detected in adult PFA (15/26 cases; 58%) and PM (6/10; 60%), while FOSB was consistently negative (19 adult PFA, 5 PM). FOS FISH demonstrated rearrangement in only 4 of 12 tested adult PFA/PM, all of which were FOS-positive by IHC. A FOS fusion ( FOS::TSHZ2 ) was detected in only 1 of 9 adult PFA/PM (11%) tested by RNA sequencing (RNAseq); 5 tumors without detected FOS fusions by RNAseq were FOS-positive by IHC. The pediatric PFA lacked expression of FOS (all 9 tumors) and FOSB (4 tested tumors) by IHC. Compared with FOS-positive PFA/PM, pediatric PFA and adult FOS-negative PFA/PM were more frequently cellular, and pediatric tumors were less infiltrative. DNA sequencing demonstrated FOSL1 :: RELA fusions in 2 of 5 tested pediatric PFAs, both in infants. Six of 18 PFU (33%) expressed FOS and/or FOSB by IHC. FISH demonstrated FOSB rearrangement in 1 of 6 PFU, while all 6 tested PFU were negative for FOS rearrangement. Nine of 20 IFA (45%) expressed FOS and/or FOSB; 2 tested tumors were negative for FOS or FOSB fusions by RNAseq. We conclude that about 60% of adult PFA/PM strongly express FOS, and 5 of these tumors were proven to harbor FOS rearrangements, including a novel FOS :: TSHZ2 fusion. Some PFU and pediatric PFA harbored alterations in related genes FOSB and FOSL1 , respectively. RNAseq and FISH might have imperfect sensitivity for FOS alterations in PFA/PM, likely due to the low relative neoplastic cell content in these tumor types.