91 Novel Low-Grade Fibroblastic Neoplasm with Co-Expression of MUC4 and Beta-catenin: Clinicopathologic and Molecular Characterization of Eight Cases

Document Type

Conference Proceeding

Publication Date

3-24-2025

Publication Title

Lab Invest

Keywords

beta catenin, mucin 4, adult, chromosome 5q, clinical article, conference abstract, controlled study, desmoid tumor, diagnosis, DNA methylation, DNA sequencing, exon, familial adenomatous polyposis, family history, fasciculation, female, fibroblast, fibroma, fibromatosis, fluorescence in situ hybridization, follow up, gene fusion, histology, human, human tissue, immunophenotyping, male, mast cell, metastasis, RNA sequencing, spindle cell carcinoma, young adult

Abstract

Disclosures: Nika Tavberidze: None; Lawrence Jennings: None; Drew Duckett: None; Michael Volek: None; Borislav Alexiev: None; Claire Castaneda: None; Paul Weisman: None; Eliza Kapinski: None; Alexandra Isaacson: None; Christian Keller: None; Karen Fritchie: None; Darya Buehler: None Background: To date, MUC4 immunostain has been a highly specific marker in separating low-grade fibromyxoid sarcoma (LGFMS) from its known fibroblastic mimics, including desmoid fibromatosis. Here, we present clinicopathologic, molecular genetic, and epigenetic features of a novel low-grade fibroblastic neoplasm showing co-expression of MUC4 and nuclear beta-catenin by IHC. Design: Eight spindle cell neoplasms with co-expression of MUC4 and nuclear beta-catenin were analyzed by RNA/DNA sequencing and DNA methylation profiling. A control group of sporadic (CTNNB1 exon 3 mutated) and familial adenomatous polyposis (FAP)-related desmoid fibromatoses were stained with MUC4. Results: The tumors occurred in 5F and 3M patients (median age 25 years; range 17-60) without personal or family history of FAP, as masses of deep axial or appendicular soft tissue (7) and lung (1), with a mean size of 8.6 cm (range 2.5-10). The tumors uniformly consisted of short, banal fibroblasts in a loosely fascicular or storiform pattern within a densely collagenous stroma containing compressed vessels and scattered mast cells. All cases with evaluable margins (7/7) showed sharp circumscription with minimal or no peripheral infiltration. Strong, diffuse MUC4 and nuclear beta-catenin co-expression was present in all cases (8/8) while 9 sporadic and 8 FAP-associated desmoid fibromatoses were negative for MUC4 (0/17). RNA sequencing revealed no gene fusions in all 6 cases tested; the remaining 2 cases were negative for FUS and FUS/EWSR1 rearrangements by FISH, respectively. Preliminary DNA sequencing showed a pathogenic APC mutation in 1 of 2 cases tested (6 not yet completed) and no CTNNB1 mutations in 4 of 4 cases tested. Four tumors analyzed by DNA methylation profiling formed a distinct cluster separate from desmoid fibromatosis and LGFMS on unsupervised clustering. Of those, the methylation array showed recurrent chromosome 5q deletions in 3 cases; the last case had inconclusive findings. Seven cases were resected with negative (1), positive (3) and unspecified (3) final margins. No recurrences or metastasis have been reported (mean follow-up of 11.6 months (range 2-38)). [Formula presented] [Formula presented] Conclusions: Low-grade fibroblastic neoplasms with MUC4 and beta-catenin co-expression appear to be a unique fibroblastic tumor with a DNA methylation signature distinct from desmoid fibromatosis and LGFMS even though they overlap by histology and immunophenotype. Long-term follow-up is needed to determine the biologic potential of this novel neoplasm.

Volume

105

Issue

3

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