Differences in cutaneous melanoma survival between the 7th and 8th edition of the American Joint Committee on Cancer (AJCC). A multicentric population-based study.

BACKGROUND: The 8th edition of the AJCC manual for melanoma includes many changes leading to major substage migrations, which could lead to important clinical reassessments. OBJECTIVES: To evaluate the differences and prognostic value of the 8th AJCC classification in comparison with the 7th edition. METHODS: Clinical and histopathological data were retrieved from five melanoma referral centers including 7815 melanoma patients diagnosed between January 1998 and December 2018. All patients were reclassified and compared using the 7th and 8th classifications of the AJCC. Sankey plots were used to evaluate the migration of patients between the different versions. The primary outcome was overall survival (OS), and curves based on the Kaplan-Meier method were used to investigate survival differences between the 7th and 8th editions. RESULTS: The number of patients classified as stages IB, IIIA, and IIIB decreased while the patients classified as stages IA and IIIC increased notably. Migration analysis showed that many patients in group I were understaged whereas a significant percentage of patients in group III were upstaged. Indirect OS analysis showed a loss in the linearity in the AJCC 8th edition and the groups tended to overlap. Direct OS analysis between groups and versions of the AJCC showed a better prognosis within the new stage III patients, with no effect on those in stages I and II. CONCLUSION: The 8th AJCC edition represents an important change in the classification of patients. We observe that the main migratory changes occur in stage I and III, that severity linearity is lost and groups overlap, and that a more advanced stage does not mean a worse prognosis.

TERT promoter mutation subtypes and survival in stage I and II melanoma patients.

Mutations within the promoter of gene encoding telomerase reverse transcriptase subunit are frequent in many cancers including melanoma. Previously, the TERT promoter mutations were shown to associate with markers of poor outcome and reduced survival in patients with primary melanoma. In this study, we investigated the impact of the subtypes of TERT mutations on disease-free and melanoma-specific survival in 287 patients with stage I/II nonacral melanoma. Our results showed that of the three TERT promoter mutation subtypes, in multivariate models, the -138/-139 CC > TT tandem mutation associated with worst disease-free and melanoma-specific survival. In particular, in combination with BRAF/NRAS mutations, the -138/-139 CC > TT TERT promoter mutation associated with statistically significant poor disease-free and melanoma-specific survival with hazard ratios of 6.04 (95% CI 2.03-17.94, p = 0.001) and 12.59 (95% CI 2.18-72.70, p = 0.005), respectively. In contrast to the survival data, luciferase assays showed that the highest activity was observed in experiments with a promoter construct with -124 C > T mutation followed by the -138/-139 CC > TT and -146 C > T mutations, which showed similar activity. Based on previous reports, we speculate that the tandem mutation probably leads to greater genomic instability than the common TERT promoter mutations, hence the association with worst survival. However, the results from the study are only preliminary with limited patient data, therefore, require a cautious interpretation. The observations in this study, if confirmed, could have implications for melanoma patients treated with MAP-kinase inhibitors.