Positive Surgical Margins in Clear Cell Renal Cell Carcinoma: Prognostic Impact and Implications for Risk Stratification and Adjuvant Therapy

<b>Objectives:</b> To evaluate the prognostic impact of positive surgical margins (PSMs) after partial or radical nephrectomy for clear cell renal cell carcinoma (ccRCC) across AJCC stages and assess its relevance to adjuvant therapy eligibility, given that landmark trials excluded patients with PSMs. <b>Methods</b>: We conducted a retrospective study using the National Cancer Database, including 171,151 ccRCC patients treated with partial or radical nephrectomy (2004-2020). Patients receiving systemic therapy or with missing key data were excluded. OS was analyzed using Kaplan-Meier curves, log-rank tests, and multivariable Cox regression. Subgroup analyses compared T2 G2/G3 PSM vs. T2 G4 negative surgical margin (NSM) (N0/Nx M0) and assessed PSM impact within KEYNOTE-564 risk groups. <b>Results</b>: PSMs were present in 5.9% of patients and independently predicted worse OS (HR 1.43; <i>p</i> < 0.001). No OS difference was observed in AJCC stage I (<i>p</i> = 0.54), while stages II (<i>p</i> = 0.001), III, and IV (<i>p</i> < 0.001) showed poorer survival with PSMs. OS in patients with T2 G2/G3 tumors and PSMs was comparable to those with T2 G4 and NSMs (<i>p</i> = 0.69). Within the KEYNOTE-564 risk population, PSMs were associated with a 62% increased risk of death (HR 1.62; <i>p</i> < 0.001). <b>Conclusions</b>: PSMs are independently associated with worse OS in ccRCC. Their prognostic impact varies across AJCC stages, supporting the use of margin status to refine risk models, guide surveillance, and consider PSM patients for adjuvant trials.