Men With Rare Limb Sarcoma Face Higher Odds of Incomplete First Surgery, Study Finds

A rare cancer of smooth muscle tissue has become the unlikely centerpiece of a new debate about how sex shapes the earliest moments of surgical cancer care. In a retrospective study of 79 patients treated at a German tertiary sarcoma center, researchers report that men with leiomyosarcoma of the extremities were far more likely than women to undergo an initial operation that left tumor cells behind under the microscope — a so-called R1 resection — and consequently to need a second, salvage operation to clean the tumor bed. The findings, published in Frontiers in Oncology, are deliberately framed by their authors as hypothesis-generating rather than proof of inequity, but they spotlight a question that has received surprisingly little attention: does a patient’s sex influence where, and how completely, the first cut is made?

The study, led by Pia Weskamp and Christoph Wallner of the Sarcoma Center at BG University Hospital Bergmannsheil, Ruhr University Bochum, drew on an institutional registry of patients with histologically confirmed extremity leiomyosarcoma who underwent their first therapeutic resection between January 2000 and December 2015 and were ultimately treated at the index center. Of 82 registry records, three were excluded because their initial surgery predated 2000, leaving 31 women and 48 men. All diagnoses were confirmed by specialist sarcoma pathologists and reviewed by a multidisciplinary tumor board, and truncal, retroperitoneal, and head-and-neck primaries were excluded to keep the analysis entity-specific. The team chose initial margin status — R1 versus the microscopically complete R0 — as the primary endpoint precisely because it captures the quality of the first operation before any subsequent surgery can blur the picture.

The headline numbers are striking. Initial R1 resection occurred in 34 of 46 men, or 73.9 percent, compared with 13 of 29 women, or 44.8 percent — an absolute difference of 29.1 percentage points, with a risk ratio of 1.65 and a nominal P value of 0.015. Men were also far more likely to have had their first operation somewhere other than the sarcoma center: 72.3 percent versus 41.4 percent for women, a 31-point gap. And they more often required re-excision of the tumor bed, 82.6 percent versus 50.0 percent. When the researchers cross-tabulated the sequence of events, the pattern became even clearer: among patients with known location and margin status, R1 followed 37 of 44 outside-center resections but only 9 of 29 index-center resections. Every one of the 47 patients with an initial R1 margin went on to re-excision.

Crucially, the study did not stop at raw percentages. Because men in the cohort also carried a different recorded tumor profile — 64.6 percent had tumors recorded as smaller than 5 centimeters, versus 35.5 percent of women, and men’s tumors were less often deep to the fascia — the investigators used Firth penalized logistic regression, a technique designed for small samples where conventional models can fail, to see how the sex association held up under adjustment. The unadjusted male-sex odds ratio for initial R1 was 3.37. After accounting for age and anatomic site it barely moved, to 3.41. But adding recorded tumor size dropped it to 2.54, and adding depth brought it down further to 2.43 — an estimate whose 95 percent confidence interval, spanning 0.82 to 7.41, comfortably included the null.

To translate those odds ratios into something clinically digestible, the team turned to Bayesian marginal standardization, expressing the association as an absolute difference in R1 probability. Standardizing over age and site yielded a male-female gap of 29.5 percentage points. But once recorded size and depth entered the model, the fully standardized difference shrank to 16.6 points, with a 95 percent credible interval running from minus 2.5 to plus 37.4 — a range compatible with a small excess in women, no difference at all, or a substantial excess in men. The authors are emphatic that this interval should not be read as evidence of a residual sex effect; it is a measure of how much genuine uncertainty remains in a cohort of this size.

Why might smaller, more superficial tumors be overrepresented among men who fared worse at first surgery? The researchers point to a plausible recognition-and-referral mechanism. Small or superficial sarcomas can masquerade as benign lumps, generating less clinical suspicion and potentially altering the entire downstream cascade — imaging, biopsy, referral, and the choice of where the first operation happens. That phenotype matches what larger multicenter studies of unplanned sarcoma excision have reported, including a 728-patient European cohort in which unplanned excision was associated with smaller, superficial tumors and a borderline male-sex association, and a Japanese registry study that linked unplanned excision to male sex as well. Neither prior study, however, isolated a single sarcoma entity the way this analysis does.

The authors are unusually candid about the limits of causal language. They constructed a directed acyclic graph during revision to lay out competing biological, social, diagnostic, and selection mechanisms, while stressing that the graph was not prespecified and is not a validated causal model. Recorded sex, they note, may mark incompletely measured biological and social processes but says nothing about gender identity, health literacy, or help-seeking behavior. Tumor size and depth need not be confounders at all — they could lie on the very pathways linking sex-related processes to surgical management. And a critical structural limitation looms over the whole enterprise: patients whose outside-center R0 surgery succeeded were never referred and never entered the cohort. Conditioning on tertiary-center treatment in this way can induce spurious associations through selection, potentially changing even the direction of the observed sex difference.

What about consequences for patients? Here the picture is more reassuring, with an important caveat. Definitive R0 resection was ultimately achieved in all 79 patients, and exploratory survival analyses showed no meaningful differences: five-year overall survival was 77.3 percent after initial R1 versus 79.3 percent after R0, with wide confidence intervals that cannot establish equivalence. Local recurrence, interestingly, trended the other way — 35.5 percent in women versus 14.6 percent in men — a contrast the authors cannot fully explain given the small number of events. The main burden of an incomplete first operation, they argue, is the additional surgery itself: re-excising a previously operated tumor bed can demand wider tissue removal and extra reconstructive or radiotherapeutic treatment, even when the oncological endpoint is eventually salvaged.

The team also probed whether calendar time explained the pattern, splitting the cohort into 2000–2007 and 2008–2015 eras. Adding an era term barely changed the pooled sex estimate, but the crude differences were notably larger in the earlier period — the outside-center gap was 48.4 percentage points in 2000–2007 versus 13.3 points in 2008–2015 — hinting, though not proving, that centralization of sarcoma care and growing referral awareness may have narrowed whatever gap existed. With strata this small, the authors warn, no firm conclusion about temporal trends is possible.

Where does this leave patients and clinicians? The study’s contribution is an exploratory, entity-specific description of how men and women with the same rare tumor entered surgical care differently, with honest quantification of the uncertainty surrounding that difference. The authors explicitly state that the findings do not establish inequity, differential access to specialist care, biological causation, or mediation, and they call for prospective multicenter studies that capture patients from first clinical assessment — recording diagnostic sequence, measurement provenance, planned versus unplanned surgery, and social and geographic context. Until such data exist, the message is less about blame and more about vigilance: any soft-tissue lump, in any patient, deserves an imaging-and-biopsy pathway that treats a possible sarcoma seriously before the first scalpel moves.

Subject of Research: Sex-associated differences in initial surgical margins, treatment location, and re-excision in extremity leiomyosarcoma

Article Title: Sex-associated differences in initial resection location, margin status, and re-excision in extremity leiomyosarcoma: a retrospective tertiary-center cohort study

Article References: Weskamp, P., Schmidt, S. V., Drysch, M., Reinkemeier, F., Dadras, M., Lehnhardt, M., Puscz, F., & Wallner, C. (2026). Sex-associated differences in initial resection location, margin status, and re-excision in extremity leiomyosarcoma: a retrospective tertiary-center cohort study. Frontiers in Oncology, 16, Article 1980400. https://doi.org/10.3389/fonc.2026.1980400

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1980400

Keywords: leiomyosarcoma, soft tissue sarcoma, surgical margins, R1 resection, re-excision, sex differences, referral patterns, tertiary sarcoma center, retrospective cohort study, Bayesian standardization, Firth logistic regression, selection bias