Molecular testing identified ubiquitin-specific peptidase 6 (USP6) rearrangements in all clinically non-specific cases of nodular fasciitis in a 29-patient series, the researchers reported.

Nodular fasciitis often presents as a non-specific soft-tissue lesion that can mimic more aggressive tumors. In this series, 19 of 29 cases (66%) did not initially raise clinical suspicion for nodular fasciitis and/or showed alarming histologic features. Five cases involved atypical locations, including deep, intraneural, and juxta-articular sites.

Methods and Findings

The researchers conducted a retrospective, single-institution analysis of 29 patients over nine years. Diagnoses were confirmed using histopathology, immunohistochemistry, and molecular testing when indicated. Nineteen cases were classified as non-specific presentations and 10 as typical presentations based on clinical and radiologic features.

Among the 19 non-specific cases, molecular testing was performed in 14 because of inconclusive morphology or clinicopathological discordance. Fluorescence in situ hybridization and next-generation sequencing were used to detect USP6 rearrangements, a hallmark of nodular fasciitis, although detection rates may vary depending on testing method.

USP6 rearrangements were identified across all 19 non-specific cases through a combination of molecular testing approaches. Fluorescence in situ hybridization detected rearrangements in 15 of 18 tested cases (83%), whereas next-generation sequencing confirmed rearrangements in cases with negative or ambiguous fluorescence in situ hybridization findings.

Three cases with inconclusive or negative fluorescence in situ hybridization results were resolved by next-generation sequencing, which identified USP6 gene fusions in each case.

Among seven cases analyzed with next-generation sequencing, three rare fusion partners—MIR22HG, CTNNB1, and SRSF3—were identified. These cases were characterized by moderate to high cellularity and the presence of osteoclast-like multinucleated giant cells.

Patients with these atypical fusions were younger on average (23 years) compared with those with the more common MYH9::USP6 fusion (40 years).

Clinical Context

The mean age across the cohort was 34 years, with no sex predominance, and the mean preoperative duration was 4.5 months.

In the non-specific group, lesions were most commonly suspected to represent nerve sheath tumors (seven cases) or sarcoma (four cases).

Five cases (27%) occurred in atypical locations, including deep soft tissue and intraneural sites, and presented with symptoms such as pain or neurologic deficits rather than superficial masses.

Histologic features were consistent with nodular fasciitis across all cases, whereas immunohistochemistry showed non-specific patterns.

Limitations

The study was limited by its small sample size and single-institution, retrospective design.

Conclusion

The findings highlight the role of molecular diagnostics in evaluating patients with soft-tissue lesions that lack classic features of nodular fasciitis.

“This knowledge may improve diagnostic confidence for pathologists and aid in the recognition of nodular fasciitis in challenging cases,” the researchers wrote.

Disclosures

The researchers reported no conflicts of interest. The study was funded by internal resources of the Institute of Pathology of the Technical University of Munich.

Source: Pathology