Histologic Response to Neoadjuvant Therapy Is Not Predictive of Favorable Outcomes in High-grade Pleomorphic Soft...

The College of American Pathologists recommends reporting the histologic response of soft tissue sarcomas (STS) to neoadjuvant therapy, presumably as an assessment of chemosensitivity and a prognostic indicator, despite lack of evidence of clinical utility as such. This study examines whether extent of neoadjuvant therapy effect in STS is a favorable prognostic factor for disease-free survival. Extent of tumor necrosis and stromal hyalinization/fibrosis were determined in 143 high-grade, nonmetastatic, pleomorphic STS of the extremity or trunk. Multivariable nonlinear Cox proportional hazard regression was used to evaluate the prognostic impact of tumor necrosis and fibrosis. Cross-model comparisons of regression coefficients from nested parametric survival models were used to investigate possible effects of multicollinearity (inverse correlation) between tumor necrosis and fibrosis. Increasing tumor necrosis after neoadjuvant therapy (with or without adjusting for fibrosis) was associated with increased hazard ratios. In contrast, hazard ratios for increasing tumor fibrosis did not significantly change when unadjusted for necrosis, but were similar to necrosis after adjusting for tumor necrosis. This suggests that tumor fibrosis evolves as a reparative response to regional tumor necrosis, a conclusion supported by evidence that extent of tumor fibrosis was positively correlated with interval between initiation of neoadjuvant therapy and surgical resection. Increasing amounts of tumor necrosis observed in STS after neoadjuvant therapy are not indicative of a good therapeutic response or better prognosis. Instead, tumor necrosis simply reflects higher histologic grade and biological aggressiveness. Stromal hyalinization/fibrosis is not an independent prognostic factor either, and likely represents organization of prior tumor necrosis.