Summary Background The distinct somatic mutations that define clinical and histopathological heterogeneity in cutaneous melanoma could be dependent on host susceptibility to exogenous factors like ultraviolet radiation. Objectives Firstly, to characterize patients with cutaneous melanoma clinically and pathologically based on the mutational status of BRAF, NRAS and TERT promoter. Secondly, to elucidate the modified features due to the presence of TERT promoter mutations over the background of either BRAF or NRAS mutations. Methods We performed a retrospective study on 563 patients with melanoma by investigating somatic mutations in BRAF, NRAS and TERT promoter. Results We observed co‐occurrence of TERT promoter mutations with BRAF and NRAS mutations in 26.3% and 6.9% of melanomas, respectively. Multivariate analysis showed an independent association between BRAF mutations and a decreased presence of cutaneous lentigines at the melanoma site, and an increased association with the presence of any MC1R polymorphism. We also observed an independent association between TERT promoter mutations and increased tumour mitotic rate. Co‐occurrence of BRAF and TERT promoter mutations was independently associated with occurrence of primary tumours at usually sun‐exposed sites, lack of histological chronic sun damage in surrounding unaffected skin at the melanoma site, and increased tumour mitotic rate. Co‐occurrence of NRAS and TERT promoter mutations was independently associated with increased tumour mitotic rate. The presence of TERT promoter together with BRAF or NRAS mutations was associated with statistically significantly worse survival. Conclusions The presence of TERT promoter mutations discriminates BRAF‐ and NRAS‐mutated tumours and indicates a higher involvement of ultraviolet‐induced damage and tumours with worse melanoma‐specific survival than those without any mutation. These observations refine classification of patients with melanoma based on mutational status.

IMPORTANCEThe lymphatic and the hematogenous pathways have been proposed for disease progression in cutaneous melanoma, but association with recurrence has not been studied separately to date.OBJECTIVE To identify the risk factors associated with lymphatic and hematogenous metastasis.

IMPORTANCE Lentigo maligna (LM) presents an invasive component in up to 20% of biopsied cases, but to date the histologic features useful in detecting this invasive component have not been described. Some histologic characteristics are hypothesized to contribute to the progression of LM invasion. OBJECTIVE To identify the histologic characteristics associated with lentigo maligna melanoma (LMM) in patients with LM diagnosed by a partial diagnostic biopsy. DESIGN, SETTING, AND PARTICIPANTSA retrospective cross-sectional study of patients treated between January 1, 2000, and December 31, 2017, was conducted in a referral oncology center in València, Spain. Data and specimens of patients (n = 96) with a diagnosis of primary cutaneous melanoma in the form of either LM or LMM who had undergone surgical treatment, a complete histologic examination of the whole tumor, and an initial diagnostic partial biopsy of LM were included in the study. Histologic assessment was blinded to the presence of an invasive component.INTERVENTIONS All biopsy specimens were evaluated for the presence of certain histologic characteristics.MAIN OUTCOMES AND MEASURES Comparisons between invasive samples and samples without an invasive component were performed. The differences in the distribution of variables between the groups were assessed using the χ 2 and Fisher exact tests, and the degree of association of the relevant variables was quantified by logistic regression models. A classification and regression tree analysis was performed to rank the variables by importance. RESULTSIn total, 96 patients had sufficient histologic material that could be evaluated. The patients were predominantly male (56 [58.3%]) and had a mean (SD) age at diagnosis of 72 (12) years. Of these patients, 63 (65.6%) had an LM diagnosis and 33 (34.4%) had an LMM diagnosis (an invasive component). The histologic variables associated with the presence of an invasive component were melanocytes forming rows (odds ratio [OR], 11.5; 95% CI, 1.4-94.1; P = .02), subepidermal clefts (OR, 2.8; 95% CI, 1.0-7.9; P = .049), nests (OR, 3.0; 95% CI, 1.1-8.6; P = .04), and a lesser degree of solar elastosis (OR, 0.4; 95% CI, 0.1-1.1; P = .07). A classification and regression tree analysis of the relevant histologic features was able to accurately identify lentigo maligna with an invasive component (LMM) in more than 60% of patients.CONCLUSIONS AND RELEVANCE These findings may be useful in classifying early LM specimens at higher risk of invasion, which may eventually be relevant in identifying the most appropriate management for LM.

Survival predictions are currently determined on the basis of NRAS/BRAF mutations, even though TERT promoter mutations have been recently associated with a poor prognosis in stage I-II melanomas. Usually, it is not recommended to perform a mutational test on primary melanoma, as the results do not always reflect the mutational status of metastases. In particular, trunk melanomas have been reported to have an unfavourable prognosis. A series of 105 advanced melanoma patients were analysed by TERT promoter Sanger sequencing. Univariate/multivariate binary logistic regression models were performed using progression to a visceral site as the dependent variable and patient/tumour characteristics as covariates. Performance of the model was assessed in an external independent primary melanoma patients’ dataset. Male gender (odds ratio (OR), 344; 95% CI, 1.12–10.6; p = 0.031), AJCC (American Joint Committee on Cancer) classification (OR, 022; 95% CI, 0.07–0.67; p = 0.008), SLNB (Sentinel Lymph Node Biopsy) status (OR, 3.05; 95% CI, 1.06–8.78; p = 0.039) and TERT-mutated trunk lesions (OR, 3.78; 95% CI, 1.35–10.6; p =  0.011) were significantly associated with the risk of developing a visceral spreading as first site of progression using multivariate logistic regression analysis. These results were confirmed in the external validation control group. Therefore, in trunk primary melanomas, due to their high risk of progression to visceral sites, we encourage somatic TERT mutation analysis at diagnosis to identify those patients who would potentially benefit from a more intensive follow-up protocol and a prompt initiation of therapy.