MUC4-Positive Fibroblastoma: Clinicopathological and Molecular Analysis of 7 Cases

In soft tissue pathology, MUC4 is considered a sensitive and specific immunohistochemical marker for low-grade fibromyxoid sarcoma (LGFMS) and sclerosing epithelioid fibrosarcoma (SEF), which are characterized by FUS/EWSR1 :: CREB3L2/1 fusions. Recently, MUC4-positive fibroblastoma has been proposed as a novel entity, and we herein describe 7 cases that align with this disease concept. These tumors occurred in 7 female patients aged 14 to 60 years, and they were located in the neck (2 cases), temple, arm, chest wall, pharynx, and thigh, with 5 being deep-seated. All tumors were surgically removed. No patients experienced recurrence during follow-up periods of 2 to 113 months. The well-circumscribed tumors comprised hypocellular fibrous tissue, populated by nonatypical spindle cells. Myxoid stroma was absent. Common features included thin-walled patent vessels, extremely long vessels, and mast cells. In some cases, fat entrapment/overgrowth was conspicuous. All tumors tested positive for MUC4 and nuclear β-catenin expression. The tumors were molecularly investigated with fluorescence in situ hybridization, RNA sequencing, DNA panel sequencing, DNA methylation analysis, and/or nanopore sequencing. Genetic analysis showed the absence of FUS/EWSR1 fusions in all 7 cases. All 5 tested tumors harbored APC alterations, with 3 having inactivating mutations and 2 showing copy number loss. DNA methylation profiles of 2 tumors did not match those of any references, including LGFMS or SEF, as indicated by t-SNE. Overall, our study supports the recent proposal of MUC4-positive fibroblastoma as a distinct entity and further delineates its phenotypic and molecular characteristics. These tumors should be distinguished from LGFMS, SEF, desmoid fibromatosis, and other fibrous or fibroadipose tumors.