MUC4-positive Fibroblastoma: A Distinctive Hyalinized Spindle Cell Neoplasm With Aberrant Nuclear Beta-catenin Expression and Frequent Biallelic Inactivation of APC.

Among soft tissue tumors, MUC4 is expressed in low-grade fibromyxoid sarcoma and sclerosing epithelioid fibrosarcoma, and is regarded as a specific and sensitive marker for these malignant entities. These tumors are driven by oncogenic fusions involving FUS or EWSR1 as a 5' partner and CREB3L1 or CREB3L2 as a 3' partner. In this study, we describe the clinicopathologic and molecular features of a distinctive fibroblastic soft tissue neoplasm characterized by consistent co-expression of MUC4 and beta-catenin, and frequent underlying APC inactivation without evidence of EWSR1 or FUS rearrangements. Fifteen hyalinized spindle cell neoplasms with MUC4 and aberrant nuclear beta-catenin co-expression were identified from our institutional archives. The cohort comprised 15 adult patients (6 female, 9 male) with a median age of 40 years (range: 20 to 61). Tumors arose in the extremities (n=9), trunk (n=5), and retroperitoneum (n=1), with a median size of 8.5 cm (range: 2.8 to 18.0 cm). The tumors consisted of a hypocellular proliferation of spindled-to-stellate fibroblastic cells in a variably hyalinized collagenous stroma. No atypia, fascicular growth, or myxoid stroma was present. Targeted DNA sequencing was successfully performed on 8 tumors. In addition, 8 tumors underwent FISH testing to assess for FUS and/or EWSR1 rearrangement. In the majority of tumors, DNA sequencing demonstrated APC inactivation (7/8; 88%). In 6 of these cases, 2 concurrent deleterious APC alterations were present, indicative of biallelic inactivation. No rearrangements involving FUS or EWSR1 were identified by NGS and/or FISH. Clinical follow-up data were available for 4 patients, with no local recurrences or metastases reported, including 1 patient followed for 8 years. No patients had a known history of familial adenomatous polyposis. We describe a novel fibroblastic soft tissue neoplasm characterized by co-expression of MUC4 and beta-catenin and frequent underlying APC inactivation, for which we propose the name "MUC4-positive fibroblastoma."