Publication date: Mar 21, 2025

AJCC 8th edition substaging might be suboptimal for predicting melanoma progression. Using it to select stage II patients for adjuvant immunotherapy risks overtreating low-risk stage IIB/IIC patients and undertreating high-risk stage IIA patients. Prognostic capability of tumor-infiltrating lymphocytes (TILs) is unclear in stage II melanoma. To evaluate AJCC substaging and TIL scoring as predictors of progression in stage II melanoma. Retrospective cohort study of 366 SLN(-) stage II melanoma patients from four UK hospitals (2004-2017), with long-term follow-up. 23% of melanomas progressed (median 9. 5-year follow-up). Among those, 41. 5% were stage IIA, 41. 5% IIB, and 17. 1% IIC. TIL scoring independently predicted progression risk (non-brisk vs brisk: OR 0. 298,p=0. 009; non-brisk vs absent: OR 0. 436,p=0. 049) and PFS. Non-brisk TILs, present in 80% of progressing tumors, denoted high risk. TIL scoring split patients into high and low risk across substages: stage IIA patients with non-brisk TILs had similar 5-year PFS to stage IIB/IIC patients with absent/brisk TILs. Retrospective study design and unknown generalizability. Stage II melanoma progression is poorly predicted by AJCC 8 substage. TIL scoring offers improved risk stratification across substages and could serve as a cost-effective method to better identify patients who may benefit from adjuvant immunotherapies.

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