Sarcomatoid Differentiation as a Predictor of Recurrence in Intermediate- and High-Risk RCC: Implications for Adjuvant Immunotherapy Selection.

[BACKGROUND] Adjuvant pembrolizumab improves survival in clear cell renal cell carcinoma (ccRCC) at elevated recurrence risk. However, broad application may lead to overtreatment. Sarcomatoid differentiation, a histologic feature associated with poor prognosis, is not currently used to guide adjuvant decisions.

[OBJECTIVE] To evaluate whether sarcomatoid differentiation can refine patient selection for adjuvant immunotherapy in intermediate- and high-risk ccRCC.

[METHODS] Retrospective analysis of 136 patients with localized/locally advanced ccRCC who underwent nephrectomy (2000-2023) meeting modified KEYNOTE-564 criteria. Recurrence-free survival (RFS) and predictive factors were analyzed using Kaplan-Meier estimates, logistic regression, and Cox models. Clinical utility was assessed via the number needed to treat (NNT) and cost-effectiveness modeling.

[RESULTS] At median follow-up of 55 months, recurrence occurred in 26 patients (19.1%). Sarcomatoid differentiation was significantly associated with recurrence (HR = 2.31; 95% CI, 1.03-5.18; P = .042). Among intermediate-risk patients, those with sarcomatoid features had 50.0% recurrence versus 16.7% without (P = .007). number needed to treat (NNT) improved from 5 (treating all) to 2 (treating sarcomatoid-positive only). Combining sarcomatoid status and ECOG 0 allowed 39.1% of patients to avoid therapy with 7.0% recurrence rate. This strategy could theoretically save $11.4 million USD.

[CONCLUSIONS] Sarcomatoid differentiation was independently associated with recurrence and may help inform adjuvant therapy decisions. Selective immunotherapy based on histologic features may optimize outcomes while avoiding overtreatment.