The Prognostic Value of Clinical and Pathological Response to Neoadjuvant Therapy in Metastatic Renal Cell Carcinoma Undergoing Cytoreductive Nephrectomy: A Systematic Review and Clinical Implications

Background: In the immunotherapy era, cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) is increasingly performed after neoadjuvant immune checkpoint inhibitor (ICI)-based therapy. Examination of the nephrectomy specimen may capture the depth of treatment-induced tumor clearance more accurately than size-based radiological criteria alone. However, pathological reporting is highly heterogeneous across studies: residual viable tumor (RVT), necrosis, pT stage, and binary downstaging have all been used, limiting reproducible cross-study comparison. We aimed to characterize this heterogeneity, assess its implications for evidence synthesis, and propose a pragmatic framework for qualitative interpretation. Methods: PRISMA-compliant systematic review of studies reporting pathological response and oncological outcomes in mRCC patients undergoing CN after neoadjuvant systemic therapy (PROSPERO CRD420251154068). A qualitative synthesis was performed. A three-category Pathological Response Category (PRC) framework is proposed to harmonize heterogeneous metrics. Results: Seven retrospective studies (n = 408) were included. Pathological reporting metrics were inconsistent across all studies, preventing formal meta-analysis. Nevertheless, across cohorts reporting survival outcomes, deeper pathological response was directionally associated with more favorable oncologic outcomes. A discordance between radiological and pathological response was observed, including near-complete tumor clearance in patients classified as radiologically stable, reflecting the non-size-based mechanisms of ICI-induced tumor killing. Conclusions: The central finding of this review is not that pathological response predicts survival—which is expected—but that current pathological reporting in the mRCC surgical setting is too heterogeneous to quantify the frequency, depth, or prognostic significance of that response in a reproducible way. Prospective adoption of standardized pathological reporting protocols is the most critical next step for this field.