27 Young-Onset Renal Cell Carcinoma: Distinct Survival Dynamics in a Competing Risks Framework

Abstract

Abstract Background Young-onset renal cell carcinoma (RCC), defined as onset ≤46 years, is associated with distinct clinicopathologic features, including associations with hereditary syndromes and distinct oncologic behavior. We compared clinicopathologic variables and survival dynamics in a competing risks framework between young- and older-onset RCC patients. Methods We retrospectively reviewed a tertiary cancer center database of patients with RCC who underwent partial or radical nephrectomy between 2015 and 2024. Patients were categorized as young-onset (≤46 years) and older-onset (>46 years) based on age at surgery. Patients with non-RCC primary malignancies, metastatic disease to the kidney from a non-renal primary, or incomplete clinical data were excluded. Outcomes included recurrence-free survival (RFS), overall survival (OS), metastasis-free survival (MFS), and cumulative incidence of RCC-related death and death from other causes. Descriptive statistics summarize clinicopathologic variables. The Chi-squared/Fisher’s test and the Wilcoxon rank sum test were used for intergroup comparisons. The Kaplan-Meier method and log-rank tests were used to estimate RFS, OS, and MFS. Cumulative incidence functions evaluated RCC-specific and competing-cause mortality. Multivariable Cox proportional hazards models identified predictors of OS and RFS. Results From a total of 976 patients, 812 met the inclusion criteria, of which 109 (13%) were categorized as young-onset and 703 (87%) as older-onset. Overall, the median age at surgery was 62 years (IQR 53.5, 69.0), most patients were male (65%), non-Hispanic (65%), and white (74%). Young-onset patients were more likely to be Hispanic (49% vs. 29%, p < 0.001) and less likely to experience any-grade perioperative complications (4% vs. 15%, p = 0.002) or receive adjuvant therapy (17% vs. 26%, p = 0.03). OS differed significantly between groups (log‑rank p = 0.01), with young‑onset patients demonstrating higher 5‑year OS (92.4% vs 80.9%). In multivariable analysis, clinical T2 stage (HR 2.46 [95% CI 1.53, 3.97], p < 0.001), clinical T3 stage (HR 2.94 [95% CI 1.24, 6.97], p = 0.02), and an ASA IV score (HR 4.74 [95% CI 1.82, 12.4], p = 0.001) were associated with worse OS, while obesity (HR 0.50 [95% CI 0.32, 0.79], p = 0.002) was associated with improved OS. In competing-risks analyses, we observed a higher cumulative incidence of RCC-specific mortality in the older-onset cohort at 1 and 5 years (1.6% and 5.4%) than in the young-onset cohort (0% and 1.3%), although this difference was not statistically significant (p = 0.06, Gray’s test). The cumulative incidence of non‑RCC mortality was significantly higher in the older-onset cohort at 1 and 5 years (3.6% and 14%) compared to the young-onset cohort (0.97% and 6.3%). Five-year RFS and MFS did not vary significantly between cohorts (p = 0.07 and 0.22, respectively). Clinical T2 stage (HR 2.81 [95% CI 1.64, 4.83], p < 0.001) was associated with worse RFS. In exploratory analyses, among older-onset patients, obese individuals (BMI ≥30) demonstrated higher OS at both 1 year (95.5% vs 94.3%) and 5 years (84.7% vs 78.1%) compared to non-obese patients (p = 0.006). Conclusions Young-onset RCC patients demonstrated higher OS, largely driven by lower competing non-RCC mortality, with comparable RFS and MFS compared to patients with older-onset RCC. Paradoxically, obesity was associated with improved OS, particularly among older-onset patients, suggesting a potential role of metabolic reserve in this group.