Was Lymphovascular Invasion Associated With Increased Odds of Early Distant Metastasis in Soft Tissue Sarcoma?

BACKGROUND: Soft tissue sarcomas are a heterogeneous group of malignancies with varied clinical outcomes. Existing prognostic calculators do not capture their complete risk profile. Lymphovascular invasion, a well-known adverse prognostic marker in several other cancers, has been proposed as a risk factor in soft tissue sarcoma. However, whether it is associated with outcomes independent of and incremental to established clinicopathologic variables remains unclear.

QUESTIONS/PURPOSES: (1) Is lymphovascular invasion independently associated with distant metastatic disease, local recurrence, and overall survival? (2) Does lymphovascular invasion improve the classification of patients with distant metastasis beyond established clinicopathologic associated factors? (3) Which clinicopathologic characteristics are associated with the detection of lymphovascular invasion in a resected soft tissue sarcoma specimen?

METHODS: Between March 1993 and December 2025, subspecialty surgeons at two urban referral centers treated 1196 patients with primary soft tissue sarcomas. The exclusion criteria were as follows: no primary resection (11% [134]), metastatic at presentation (8% [92]), missing follow-up data (7% [84]), ineligible histology (1% [6]), and undocumented lymphovascular invasion status (20% [235]). After applying the inclusion and exclusion criteria, 645 patients were analyzed. Undocumented patients were not found to have worse outcomes than those with known lymphovascular invasion status; nevertheless, two sensitivity analyses were performed. The first analysis coded all missing patients as negative, and the second analysis imputed the lymphovascular invasion status for these patients. The presence of lymphovascular invasion was determined histologically, with 7% (42 of 645) of patients testing positive. We evaluated survivorship using a Kaplan-Meier analysis and identified independently associated factors using multivariable Fine-Gray competing risks regression and Cox proportional hazards testing. The classification performance of adding lymphovascular invasion to a baseline clinicopathologic model was assessed using the Akaike information criterion (AIC), time-dependent area under the curve (AUC), Brier scores, decision curve analysis, and calibration curves. Logistic regression was used to identify characteristics associated with lymphovascular invasion positivity.

RESULTS: After controlling for potentially confounding variables such as tumor size, chemotherapy, tumor grade, and positive margins, the presence of lymphovascular invasion was independently associated with distant metastasis (SHR 3.13 [95% confidence interval (CI) 1.88 to 5.21]; p < 0.001). Lymphovascular invasion was not independently associated with increased odds of local recurrence, although an initial association was borderline in the primary cohort (SHR 2.04 [95% CI 1.00 to 4.21]; p = 0.05), this signal was lost after excluding tumor bed excisions (SHR 1.61 [95% CI 0.73 to 3.52]; p = 0.24). Lymphovascular invasion was not independently associated with overall survival (HR 0.77 [95% CI 0.43 to 1.37]; p = 0.37). The model with lymphovascular invasion added an explicit incremental contribution to the classification value using the AIC, time-dependent AUC, and Brier scores, even though the absolute gain in discrimination remains modest. For the time-dependent AUC, at 2 years there was an increase of 3.1% (0.70 to 0.73 [95% CI 0.01 to 0.06]; p = 0.02), and at 5 years there was an increase of 2.3% (0.70 to 0.73 [95% CI 0.001 to 0.04]; p = 0.04) when adding lymphovascular invasion to the baseline model. Leiomyosarcoma histology (OR 7.44 [95% CI 2.90 to 19.1]; p < 0.001) and positive surgical margins (OR 2.54 [95% CI 1.21 to 5.18]; p = 0.01) were independently associated with higher odds of lymphovascular invasion positivity, but liposarcoma histology decreased the odds (OR 0.19 [95% CI 0.03 to 0.68]; p = 0.03).

CONCLUSION: Lymphovascular invasion was independently associated with distant metastatic progression in patients with soft tissue sarcoma. Although the absolute gain in discrimination with the addition of lymphovascular invasion was modest and is not sufficient to guide treatment decisions, we now increase the frequency of chest CT for the first 5 years after surgery among patients with lymphovascular invasion. We believe that the cost-benefit of increased surveillance is justified in this setting, although future studies should evaluate this more formally. In our cohort, lymphovascular invasion was not consistently independently associated with local recurrence and was not associated with survival. These findings support consistent reporting of lymphovascular invasion, further evaluation of its incorporation into soft tissue sarcoma prognostic models to refine early metastatic risk stratification, and more frequent chest CTs for the first 5 years after surgery in patients with lymphovascular invasion.

LEVEL OF EVIDENCE: Level III, therapeutic study.