Immune-Adjusted Nodal Risk Classification After Neoadjuvant Immunotherapy for Resectable Head and Neck Cutaneous Squamous Cell Carcinoma.

BACKGROUND: Conventional nodal staging may inadequately capture posttreatment biology after neoadjuvant immunotherapy for head and neck cutaneous squamous cell carcinoma (HNcSCC). We developed an immune-adjusted nodal risk classification integrating residual viable nodal burden, residual extranodal extension (rENE), and nodal pathological response. METHODS: This single-center retrospective cohort included 82 patients with resectable HNcSCC who received at least two cycles of neoadjuvant immunotherapy followed by surgery. Residual positive lymph nodes contained viable tumor. rENE was categorized as microscopic or macroscopic, and residual viable tumor percentage was assessed in the largest residual nodal metastasis. Disease-free survival (DFS) was primary; overall survival (OS) was secondary. Prognostic performance was compared with conventional ypN stage and iN-core. RESULTS: After a median follow-up of 31.6 months, 24 DFS events and 14 deaths occurred. Nodal pathological complete response was observed in 27 patients (32.9%). Residual nodal burden showed a nonlinear association with DFS, supporting cutoffs of 0, 1, 2-3, and ≥4 residual positive lymph nodes. The final iN-risk classification defined iN-low, iN-intermediate, and iN-high groups, comprising 39 (47.6%), 22 (26.8%), and 21 (25.6%) patients, respectively. Three-year DFS decreased stepwise across groups (91.2%, 70.8%, and 25.9%; log-rank P < 0.001). Compared with iN-low disease, iN-high disease was independently associated with inferior DFS (hazard ratio 13.42; 95% confidence interval 3.85-46.77) and OS (hazard ratio 20.86; 95% confidence interval 2.65-164.34). The iN-risk model showed higher C-indexes for DFS and OS. CONCLUSIONS: An immune-adjusted nodal risk classification based on viable residual nodal disease, rENE extent, and nodal response may improve risk stratification after neoadjuvant immunotherapy for resectable HNcSCC.