Novel Case of a Molecularly Confirmed Low-Grade Fibromyxoid Sarcoma of the Floor of the Mouth and Literature Review

TL;DR

This paper reports the first confirmed case of a rare mouth tumor using molecular testing and highlights the importance of accurate diagnosis and long-term monitoring.

Contribution

First molecularly confirmed case of LGFMS in the floor of the mouth with a FUS::CREB3L2 fusion.

Findings

Molecular testing confirmed a FUS::CREB3L2 fusion in a rare LGFMS case in the mouth.

The patient showed no recurrence after 1 year with no detectable circulating tumor DNA.

The case underscores the need for aggressive local control and long-term surveillance for LGFMS.

Abstract

Low-grade fibromyxoid sarcoma (LGFMS) is a deceptively bland spindle cell neoplasm with malignant potential, most commonly arising in the extremities and trunk, and limited to at least 110 cases in the head and neck. This report describes the first molecularly confirmed LGFMS of the floor of the mouth demonstrating a FUS::CREB3L2 gene fusion.

An 18-year-old male presented with a painless floor of mouth mass of 1-year duration that was clinically suspected to represent a ranula. The mass was subjected to excisional biopsy. Histological examination was salient for an infiltrating proliferation of bland spindle cells arranged in whorled patterns within a collagenous stroma with focal myxoid change.

Immunohistochemical analysis revealed diffuse MUC4 expression, narrowing the diagnosis. Targeted RNA sequencing identified a FUS::CREB3L2 fusion involving FUS exon 6 and CREB3L2 exon 5, confirming LGFMS. At 1-year follow-up, the patient showed no clinical evidence of disease and no detectable circulating tumor DNA.

This case highlights the critical role of molecular testing in the diagnosis of LGFMS and emphasizes the importance of appropriate management strategies, including aggressive local control and long-term surveillance, given the tumor’s risk of late recurrence and distant metastasis.

The online version contains supplementary material available at 10.1007/s12105-026-01888-1.

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