Nodular fasciitis may present as a nonspecific soft-tissue lesion that mimics sarcoma or other neoplasms, and molecular testing may help support the diagnosis in challenging cases, according to a retrospective case series published in Pathology. Accurate recognition is clinically important because misdiagnosis can lead to unnecessary aggressive treatment for what is generally a benign, self-limiting lesion.
Researchers reviewed 29 cases of nodular fasciitis diagnosed over 9 years at a single institution. The cohort had a mean age of 33.5 years, ranged from 9 to 63 years, and showed no sex predominance.
Nineteen cases had nonspecific clinical or radiologic presentations or histologic features that raised diagnostic concern. The remaining 10 cases had more typical presentations, including superficial masses in young or middle-aged patients with clinicopathologic findings compatible with nodular fasciitis.
Among the 19 nonspecific cases, suspected diagnoses included nerve sheath tumors and sarcoma. Five cases involved unusual sites, including deep-seated, intraneural, and juxta-articular lesions.
Histopathologic findings were compatible with nodular fasciitis in all cases, although variability in cellularity, stromal features, and lesion location contributed to diagnostic uncertainty. Immunohistochemistry was described as nonspecific and primarily useful for excluding malignant differential diagnoses rather than confirming nodular fasciitis. Most tested tumors showed smooth muscle actin positivity, and all tested cases were negative for desmin.
Fluorescence in situ hybridization (FISH) for ubiquitin-specific peptidase 6 (USP6) rearrangement was performed in 18 of the 19 nonspecific cases and was positive in 15 cases. Three cases had negative or inconclusive FISH results. Next-generation sequencing (NGS) identified USP6 gene fusions in all four subsequently tested cases, including the three with negative or inconclusive FISH findings.
The researchers noted that FISH interpretation may be technically challenging and suggested that senescence-related signal loss in older lesions may contribute to false-negative findings. Two technically analyzable FISH-negative cases had relatively long preoperative durations of 6 and 8 months, respectively.
NGS was ultimately performed in seven cases overall and identified MYH9::USP6 fusions in four tumors and rare fusion partners in three tumors: MIR22HG, CTNNB1, and SRSF3. The researchers framed these findings within the broader concept of USP6-associated neoplasia, a group of lesions linked by shared USP6-driven molecular mechanisms despite variable anatomic presentations.
All three rare-fusion tumors showed relatively high cellularity and osteoclast-like giant cells — histologic features traditionally associated with “young” nodular fasciitis lesions — despite relatively long preoperative durations of 8 to 12 months. The researchers suggested these features may reflect underlying tumor biology rather than lesion age alone.
Patients with rare fusion partners also tended to be younger than those with MYH9::USP6 fusions, although the difference was not statistically significant.
One tumor harbored a CTNNB1::USP6 fusion, a finding the researchers distinguished from the CTNNB1 exon 3 mutations classically associated with desmoid fibromatosis, another spindle-cell lesion frequently included in the differential diagnosis. The identified translocation instead involved exon 1 and was interpreted as consistent with the promoter-swapping mechanism typical of USP6-associated neoplasms.
Prior reports have also described rare USP6-rearranged tumors with more aggressive clinical behavior, predominantly involving atypical fusion partners, although no such cases were identified in this series.
The mean preoperative duration was 4.5 months among patients with available data, excluding interval-censored cases. No tumors showed progression or recurrence during available follow-up, although follow-up duration was not systematically reported.
The researchers emphasized that negative or ambiguous FISH results should not exclude nodular fasciitis when histologic findings remain suggestive and said NGS-based testing may be useful in diagnostically challenging cases.
The findings should be interpreted cautiously because the study was retrospective, single-center, and included a small number of rare-fusion cases. The results do not establish prognostic differences by fusion subtype or define recurrence risk.
The researchers reported no conflicts of interest and disclosed use of ChatGPT/OpenAI to improve readability and language, with subsequent researcher review and editing.
Source: Pathology