Clinicopathological Predictors of Recurrence in Resected Stage IIB-IIIB Melanoma: The Prognostic Impact of Stage IIC in a Real-World Cohort

Background: Patients with stage IIB–IIIB cutaneous melanoma remain at substantial risk of recurrence despite complete surgical resection. Accurate risk stratification is essential to optimize patient selection for adjuvant therapy and surveillance strategies. We aimed to evaluate the clinicopathological and molecular factors associated with recurrence in a real-world cohort of high-risk melanoma patients. Methods: We retrospectively analyzed 97 patients with stage IIB–IIIB cutaneous melanoma treated at a single tertiary referral center. Clinicopathological characteristics, molecular features, treatment-related variables, and sentinel lymph node (SLN) pathological characteristics were evaluated. Recurrence-free survival (RFS) was estimated using the Kaplan–Meier method. Independent prognostic factors were identified using multivariable Cox proportional hazards regression. Results: After a median follow-up of 88 months, 31 patients (32.0%) developed recurrence. Stage IIC showed the highest recurrence rate in the cohort (52.4%), compared with 25% in stage IIIA and 31.4% in stage IIIB. Consistently, in the multivariable analysis, compared with stage IIB, only stage IIC remained independently associated with worse recurrence-free survival (hazard ratio [HR] = 3.57, 95% confidence interval [CI]: 1.08–11.82; p = 0.037), whereas neither stage IIIA nor stage IIIB differed significantly from stage IIB. Female sex was independently associated with a lower risk of recurrence (HR 0.33, 95% CI 0.14–0.79; p = 0.012). Although BRAF V600E-mutated tumors showed higher recurrence rates and shorter recurrence-free survival in univariable analyses, BRAF V600E status was not independently associated with recurrence in the multivariable model (p = 0.250). Higher lymphoid infiltration density was associated with improved RFS in univariable analysis, although this finding was limited by substantial missing data and non-standardized pathological assessment. Conclusions: In this exploratory retrospective analysis, female sex and stage IIC were independently associated with RFS. These findings should be interpreted cautiously given the small sample size, limited number of recurrence events, and incomplete availability of some clinicopathological and molecular variables. The prognostic associations observed for BRAF V600E status and lymphoid infiltration, as well as the analyses according to adjuvant treatment, should be considered exploratory and hypothesis-generating. The unfavorable outcomes observed in stage IIC disease support growing evidence that this subgroup represents a biologically aggressive form of melanoma despite the absence of regional nodal involvement. Our findings do not challenge the validity of the AJCC staging system but suggest that clinically relevant heterogeneity may exist within established AJCC stage groups.