Rare Sarcomas With Shared Genes Follow Two Very Different Paths, Study Finds

Two ultra-rare soft-tissue cancers that look like close molecular cousins behave so differently in patients that researchers are now questioning whether they belong on a single biological spectrum at all. Low-grade fibromyxoid sarcoma, a tumour with a deceptively bland appearance under the microscope, and sclerosing epithelioid fibrosarcoma, a far more aggressive entity, both carry recurrent rearrangements of the FUS or EWSR1 genes and frequently express the protein MUC4. Yet a new study from a Portuguese national sarcoma reference centre shows that the clinical trajectories of these tumours diverge sharply, with nearly all recurrences and metastases concentrated in the more aggressive end of the spectrum.

The research, published in Frontiers in Oncology, reviewed twenty consecutive patients treated between August 2013 and May 2024 at the Instituto Português de Oncologia do Porto Francisco Gentil, a comprehensive cancer centre that serves as a national reference centre for soft-tissue sarcomas and a member of the European Reference Network EURACAN. The cohort comprised eleven patients with low-grade fibromyxoid sarcoma, six with sclerosing epithelioid fibrosarcoma, and three with hybrid tumours displaying overlapping histological features of both entities. Every diagnosis was validated by a pathologist with dedicated sarcoma expertise, and the team collected detailed clinical, pathological and molecular data from electronic medical records.

The molecular work relied on two complementary techniques. Fluorescence in situ hybridisation, using break-apart probes, detects rearrangements of the FUS and EWSR1 genes, while a targeted next-generation sequencing panel screens for the specific fusion transcripts that result when these genes splice onto partner genes such as CREB3L1 and CREB3L2. Molecular analysis produced informative results in nineteen of the twenty patients, and FUS or EWSR1 rearrangements were identified in sixteen of them. FUS rearrangements predominated overall, appearing in twelve patients, and were found exclusively in low-grade fibromyxoid sarcomas and hybrid tumours. EWSR1 rearrangements, by contrast, were confined entirely to the sclerosing epithelioid fibrosarcoma group.

That near-complete molecular exclusivity is one of the study’s most striking findings. Among patients tested by sequencing, the FUS::CREB3L2 fusion characterised the FUS-rearranged tumours, while the EWSR1-rearranged sclerosing epithelioid fibrosarcomas harboured either EWSR1::CREB3L1 or EWSR1::CREB3L2 fusions. The authors argue that this pattern argues against a true biological continuum between the two entities, instead supporting relatively distinct molecular profiles within a related tumour spectrum. Hybrid tumours, which share greater molecular overlap with low-grade fibromyxoid sarcoma, nonetheless behaved clinically more like the aggressive end of the spectrum, a discrepancy that carries real implications for how patients are risk-stratified.

MUC4, a protein detected by immunohistochemistry and widely regarded as a highly sensitive and specific diagnostic marker for these tumours, was positive in thirteen of the twenty cases. The lower overall positivity rate of sixty-five percent, driven mainly by the low-grade fibromyxoid sarcoma subgroup, likely reflects methodological factors rather than a true reduction in diagnostic sensitivity, according to the authors. Retrospective binary scoring over a prolonged inclusion period, combined with the focal nature of MUC4 expression in some low-grade tumours, may have understated its presence. The marker remains a cornerstone of diagnosis in a family of cancers so rare that few pathologists encounter more than a handful of cases in a career.

Treatment in the cohort was overwhelmingly surgical. Nineteen of the twenty patients underwent curative-intent resection, with complete excision and negative margins achieved in fifteen cases. Radiotherapy was used selectively: one patient received radical-intent treatment and three received adjuvant radiotherapy, delivered with modern techniques such as volumetric modulated arc therapy or three-dimensional conformal radiotherapy to total doses of 66 to 70 Gy. Only one patient, a case of sclerosing epithelioid fibrosarcoma that had already spread to bone at diagnosis, received systemic therapy, progressing through doxorubicin, an etoposide and ifosfamide combination, and finally the kinase inhibitor pazopanib, each discontinued for progressive disease. The limited role of chemotherapy mirrors the modest benefit conventional sarcoma regimens have shown against these tumours.

After a median follow-up of sixty-five months, the outcomes split cleanly along histological lines. Local recurrence occurred in only two patients, one with sclerosing epithelioid fibrosarcoma and one with a hybrid tumour, at a median of thirty-two months after initial treatment. Distant metastases developed in three patients, all with sclerosing epithelioid fibrosarcoma or hybrid histology, and the median time to metastatic spread was a startlingly short six months. Every one of these events was associated with adverse pathological features, including high cellularity, nuclear atypia and elevated mitotic counts, and the two metastasising sclerosing epithelioid fibrosarcomas also carried EWSR1 rearrangements. Not a single patient with pure low-grade fibromyxoid sarcoma relapsed during the study period.

Survival figures underscore the same divide. At last follow-up, all eleven patients with low-grade fibromyxoid sarcoma and all three with hybrid tumours were alive, the hybrid patient who developed lung metastases having been rendered disease-free by complete metastasectomy. One patient with sclerosing epithelioid fibrosarcoma died of disease progression, making it the sole disease-related death in the cohort and leaving overall survival at ninety-five percent. Median overall survival was not reached during the study window, which extended to January 2026. The authors caution, however, that the small number of events limits statistical power and that these observations should be treated as hypothesis-generating rather than definitive prognostic evidence.

The findings align closely with larger international datasets. A French nationwide registry study of 330 patients published in the European Journal of Cancer found metastases present at diagnosis in thirty percent of sclerosing epithelioid fibrosarcomas versus four percent of low-grade fibromyxoid sarcomas, while a twenty-seven-institution international study reported in the American Journal of Surgical Pathology confirmed the more indolent behaviour of the low-grade entity. The Portuguese series, though small, contributes something the larger studies often lack: systematic and concordant testing by both fluorescence in situ hybridisation and next-generation sequencing, a median follow-up exceeding five years, and multidisciplinary diagnostic validation at a European reference centre, a setting under-represented in the existing literature.

The practical message for clinicians is one of vigilance calibrated to risk. The authors suggest that hybrid tumours be managed clinically as high-risk, in line with sclerosing epithelioid fibrosarcoma, irrespective of their predominant molecular profile, and that sclerosing epithelioid fibrosarcomas showing adverse features, such as more than four mitoses per ten high-power fields, hypercellularity, nuclear atypia, necrosis or dedifferentiation, warrant close and sustained surveillance. Long-term follow-up remains essential, as documented recurrences and metastases in these tumours can emerge years or even decades after the initial diagnosis, meaning the sixty-five-month median follow-up of this study may not capture the full natural history. Because no single centre can accumulate meaningful numbers of such rare cancers, the researchers emphasise that collaborative multicentre efforts with consistent molecular assessment will be vital to refine prognostic stratification and, ultimately, to guide the development of targeted therapies for a group of tumours whose genetics are now far better mapped than their treatment options.

Subject of Research: Clinical and molecular behaviour of low-grade fibromyxoid sarcoma and sclerosing epithelioid fibrosarcoma across a spectrum of ultra-rare soft-tissue sarcomas

Article Title: Low-grade fibromyxoid and sclerosing epithelioid fibrosarcoma: distinct behaviour in the same spectrum of ultra-rare sarcomas

Article References: Castanheira, B., Soldin, I., Vieira, J., Afonso, M., Conde, S., Moreira, A., & Abreu, M. H. (2026). Low-grade fibromyxoid and sclerosing epithelioid fibrosarcoma: distinct behaviour in the same spectrum of ultra-rare sarcomas. Frontiers in Oncology, 16, Article 1943496. https://doi.org/10.3389/fonc.2026.1943496

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1943496

Keywords: low-grade fibromyxoid sarcoma, sclerosing epithelioid fibrosarcoma, sarcoma, FUS, EWSR1, MUC4, gene fusions, hybrid tumours, ultra-rare cancer, metastasis, EURACAN, next-generation sequencing