Stage IIB-IIC cutaneous melanomas carry a substantial risk of recurrence and disease-related mortality despite complete surgical excision, highlighting the need for reliable prognostic biomarkers. We retrospectively analyzed 153 patients with stage IIB-IIC cutaneous melanoma who underwent surgery at the Instituto Valenciano de Oncología between May 2000 and August 2024. Recurrence-free survival (RFS), disease-free survival (DFS), and overall survival (OS) were estimated using Kaplan-Meier methods. Associations between clinicopathologic and molecular characteristics and survival outcomes were assessed by log-rank test and Cox proportional hazards models. At a median follow-up of 81.6 months, median RFS, DFS, and OS were 43, 31, and 50 months, respectively. In univariate analyses, both telomerase reverse transcriptase (TERT) promoter mutations [hazard ratio = 0.38, 95% confidence interval (CI) = 0.18-0.8, P  = 0.008] and the absence of melanocortin-1 receptor (MC1R) variants (hazard ratio = 0.38, 95% CI = 0.16-0.91, P  = 0.024) were significantly associated with RFS. In multivariate analyses, only TERT promoter mutations remained an independent predictor of both RFS (hazard ratio = 0.44, 95% CI = 0.20-0.96, P  = 0.038) and DFS (hazard ratio = 0.47, 95% CI = 0.24-0.93, P  = 0.030). Patients harboring TERT promoter mutations exhibited significantly poorer survival outcomes compared with those with wild-type TERT promoter status. Combined analysis supported the contrasting prognostic roles of TERT and MC1R. Our findings identify TERT promoter mutations as an independent prognostic factor and suggest a potential protective role of MC1R variants in stage IIB-IIC cutaneous melanoma.

Background/Objectives: Acral (AM) and mucosal melanomas (MM) have certain genetic similarities compared to non-acral cutaneous melanomas and share a restricted influence of UV radiation in their etiology. Yet, AM and MM arise in quite different locations from a histological perspective. This study aimed to report differences between AM and MM for the most prominently mutated genes in melanoma: BRAF, NRAS, KIT, and TERT promoter. Methods: We conducted a retrospective, single-center study including 152 patients diagnosed with AM (n = 121) or MM (n = 31) at the Fundación Instituto Valenciano de Oncología between 2000 and 2024. Clinical and histopathological data were collected, and mutational analyses of BRAF, NRAS, KIT, and the TERT promoter were performed using targeted sequencing. Results: MM presented with significantly greater Breslow thickness and higher rates of hematogenous metastasis compared to AM. While BRAF, NRAS, and TERT promoter mutations were similarly distributed between subtypes, KIT mutations were significantly more frequent in MM (33% vs. 12.3%; p = 0.043) and exhibited a broader mutational spectrum. Survival outcomes were poorer in MM, with lower 5- and 10-year survival rates compared to AM. Discussion: Despite shared UV-independent biology, AM and MM differ in clinically and molecularly meaningful ways. The higher prevalence and diversity of KIT mutations in MM suggest subtype-specific oncogenic mechanisms and potential therapeutic implications. These findings support a more refined classification of UV-independent melanomas based on anatomical and molecular distinctions.

BACKGROUND:The use of targeted therapies, such as BRAF/MEK inhibitors, has led to a considerable increase in melanoma-specific survival rates; however, prolonged responses remain uneven and uncertain. Moreover, there is a lack of reliable biomarkers that can predict the type and duration of the response. This study aimed to determine whether pTERT mutations affect progression-free survival and overall survival in melanoma patients treated with BRAF/MEK inhibitors. MATERIALS AND METHODS:This study employed a retrospective observational design. We included 77 patients with metastatic BRAF (V600) mutated melanoma treated with BRAF/MEK inhibitors. The data analysis included only patients with known pTERT mutation status (WT, -124C>T, -146C>T, and -138_139 CC>TT) and clinical variables collected at two different centers. Progression-free survival and overall survival were determined using Kaplan-Meier curves and Cox regression models. RESULTS:A multivariate analysis with 56-month follow-up suggested a decreased melanoma overall survival with BRAF (V600K) mutation (hazard ratio [HR] 2.2; 95% confidence interval [CI] 1.2-4.0; p = 0.016), the Stage M1c/M1d (HR 3.3; 95% CI 1.7-6.5; p = 0.001), ECOG ≥ 1 (HR 3.6; 95% CI 1.9-6.7; p = 0.001) and not having the -138_139 CC>TT pTERT mutation (HR 3.2; 95% CI 1.0-10.5; p = 0.052). CONCLUSION:These findings suggest that the tandem -138_139 CC>TT, a less frequent pTERT mutation subtype, may be associated with a trend toward improved prognosis in patients with metastatic melanoma treated with BRAF/MEK inhibitors. However, due to the limited sample size, this study is essentially an exploratory investigation. It requires independent validation with a larger sample to determine the effect of TERT promoter mutations, together with other clinical parameters, on treatment response to BRAF/MEK inhibitors.

Cancer remains a leading cause of mortality in developed countries, with advancements in targeted therapies, antibody-drug conjugates (ADCs), and immunotherapy significantly improving patient survival. However, these treatments often result in cutaneous adverse effects (AEs), impacting the skin, mucosa, hair, and nails. This expert consensus statement provides a comprehensive overview of the mechanisms behind these skin toxicities, their clinical manifestations, and the importance of rapid diagnosis and treatment. The spectrum of skin toxicities ranges from mild reactions such as xerosis and pruritus to severe, potentially life-threatening conditions such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). This statement underlines the need for healthcare professionals to work in multidisciplinary teams, use standardized classification systems such as the Common Terminology Criteria for AEs (CTCAE) v5.0, educate patients on preventive measures, and establish clinical management guidelines to mitigate these AEs. By understanding the pathophysiological mechanisms and implementing effective management strategies such as photoprotection, gentle hygiene, emollients, prophylactic antibiotics, or specific hair and nail care, the quality of life for cancer patients can be significantly improved, ensuring continuity of oncologic treatment and improving overall survival.

BACKGROUND:Further studies are required to support the clinical value of paraffin-embedded microscopically controlled surgery (MCS) in lentigo maligna (LM) and lentigo maligna melanoma (LMM). METHODS:This is a retrospective observational study to review histologically confirmed LM and LMM cases treated definitively and exclusively with paraffin-embedded MCS, specifically, staged excision, with at least ≥ 6 months follow-up if recurrence was absent. RESULTS:One hundred and ninety-four patients were eligible for inclusion, with a median age of 72.5 years. Most cases were primary tumors (82%). Tumors were predominantly located on the face (167, 86.1%), especially on the cheek (73, 37.6%). Most of the cases were LM (141, 72.7%). LMMs had a median Breslow thickness of 0.48 mm and were mainly T1a (38, 71.7%) (8th edition of the AJCC staging system). Dermoscopy was routinely utilized to delineate the tumor border prior to surgery, and in 29 cases (15.0%), Wood's lamp was also employed. All patients achieved negative margins with paraffin-embedded MCS. After a global median follow-up of 34 months, seven patients (3.6%) had LR. LRR was higher in LMM (4/53, 7.5%) than LM (3/141, 2.1%) (p = 0.09). The restricted mean survival time (RMST) at 36 months was 36.0 months for LM and 34.9 months for LMM. LMM patients tended to have LR earlier-on average, 1.1 months sooner in the first 36 months than LM patients (p = 0.13). Given the low number of events (n = 7), multivariable survival modeling was not used to prevent unstable or overfitted estimates. CONCLUSIONS:Paraffin-embedded MCS provides accurate margin control and low LRR for LM and LMM.

Introduction: Seborrheic keratoses (SK) are common benign epidermal tumors. Their pathogenesis is unknown, and no pathological significance is ascribed to them, although they could be part of paraneoplastic syndromes, in addition to presenting a variety of somatic mutations. SKs are associated with increased age, family history, and sun-exposure. Methods: This study aimed to analyze if SK was related to DNA repair genes polymorphisms and analyze if any epidemiological, clinical or environmental characteristics could modify their prevalence. It was conducted an epidemiological, analytical, observational, cross-sectional, retrospective case-control study. Both univariate and multivariate logistic regression models were used to evaluate which characteristics were associated with having >50 SKs versus <10. Results: A total of 294 patients with melanoma were studied, 270 (91.8%) having had less than 10 SKs, while 24 (8.2%) >50 SKs. Of all the polymorphisms studied, only rs25487 in XRCC1 reached statistical significance (OR = 3.56; 95% CI 1.36-9.33; p = 0.01). In addition, an increasing age (OR = 1.07; 95% CI 1.03-1.11; p = 0.001) and the phototype (III-V vs. I-II) (OR = 0.28; 95% CI 0.12-0.68; p = 0.005) were related to the presence of >50 SK. Conclusion: We identified that increasing age, having a phototype I-II, and the existence of the rs25487 polymorphism could be associated with the occurrence of KS.

Introduction: Complete lymph node dissection (CLND) was the standard practice for patients with melanoma and a positive sentinel lymph node biopsy (SLNB) until the results of two clinical trials published in 2016 and 2017 demonstrated that it did not improve melanoma-specific survival (MSS). However, it continues to be performed in some scenarios. No studies have ever been published on lymph node management after a positive SLNB in the routine clinical practice in our setting. Objectives: To determine the evolution of the indication for CLND in patients with a positive SLNB, as well as the characteristics associated with its performance. Material and methods: We conducted a multicenter retrospective observational study with patients with skin melanoma and positive sentinel lymph nodes diagnosed from 2017 through 2022 at 8 Spanish centers and 1 Italian center. Results: A total of 430 patients were included, 54% men, with 323 (75.1%) aged between 45 and 80 years. A total of 133 cases (31%) exhibited Breslow thickness >4 mm, 206 cases (49%) were ulcerated, and in 213 cases (55.7%), lymph node metastasis was >1 mm. Isolated lymphadenectomy or followed by adjuvant therapy was performed in 146 patients (34.1%). After multivariate logistic regression, the factors associated with the performance of CLND were the acral lentiginous melanoma histological subtype, lymph node metastasis size >1 mm, extracapsular spread, and the participant hospital. Age >80 years was inversely associated. Conclusion: While the frequency of CLND in patients with melanoma and positive SLNB has decreased, the indication for systemic adjuvant therapy in these patients has increased. However, CLND is still indicated in patients with high-risk characteristics. (c) 2024 AEDV. Published by Elsevier Espana, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

INTRODUCTION:Since the field of dermatopathology is not an exact science, it is subject to personal subjectivity, which sometimes causes disagreements on the diagnosis and assessment of some histological features. In the case of melanoma, some variables such as regression are associated with low interobserver agreement. On the contrary, other variables such as the measurement of Breslow thickness show high reproducibility. OBJECTIVE:The main objective of our study was to investigate multiple features of 60 consecutive cases of melanoma to establish interobserver reproducibility. METHODS AND MAIN RESULTS:We conducted an observational and descriptive study at Hospital de Manises, Valencia, Spain, IVO Foundation, Valencia, Spain, and Hospital 12 de Octubre, Madrid, Spain. The mean level of agreement of all study variables was moderate (Cohen's kappa coefficient statistic=0.5). The highest agreement corresponded to polypoid morphology, pigmentation, ulceration, and solar elastosis. On the other hand, the lowest level agreement was reached for the presence of cellular pleomorphism and tumor necrosis. CONCLUSIONS:Our mean level of agreement was moderate, which reflects that some of the measured characteristics such as cellular pleomorphism or the presence of necrosis cannot be used for future studies or must be redefined and their reproducibility, reestablished. When conducting a research study, it is necessary to analyze the study variables to demonstrate their validity to measure or classify a certain feature. It is also advisable to warrant that that the variables are reproducible to be able to use them for other studies or in the routine clinical practice.

The arrival of immunotherapy has revolutioned the management of patients with metastatic Merkel cell carcinoma (MCC). We conducted an observational, retrospective study of 14 cases treated with avelumab. The response rate was 57%: complete response was reached in 29% of patients, and partial responses in 29%. The drug proved effective in 83% (5/6) of the patients with a single metastatic site. However, the disease progressed in 75% (3/4) of the patients with bone metastases. PD1-L expression, MCC polyomavirus (MCPyV) positivity, and an impaired neutrophil-to-lypmhocyte ratio (NLR) could not be associated with responses to the therapy. Avelumab is an effective and safe drug for the management of advanced MCC, and its effectiveness appears to be impacted by the number and location of metastases. (c) 2024 Published by Elsevier Espana, S.L.U. on behalf of AEDV. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

INTRODUCTION:The neutrophil-to-lymphocyte ratio (NLR) is a critical biomarker of the immune system that plays an important role in predicting the outcome of various malignant tumors, including skin cancer. This study aimed to evaluate an NLR cutoff that could help better predict the prognosis of patients with localized melanoma. MATERIALS AND METHODS:We designed a retrospective, longitudinal, observational study of 988 patients with localized melanoma for whom NLR levels were collected at baseline. To evaluate the prognostic value of NLR, the patients were divided into two groups: > 4.8 vs. ≤ 4.8. We analyzed the association between increased NLR levels and clinical and pathological variables using Pearson's chi-squared test and Fisher's exact test. Univariate and multivariate Cox proportional hazards models were built using stepwise backward selection to evaluate the association between NLR values and melanoma-specific survival (MSS); NLR values and distant metastasis-free survival (DMFS). Kaplan-Meier survival curves were used to illustrate the difference in survival outcomes between the two groups. RESULTS:An NLR level of > 4.8 was associated with male sex, melanoma located on the head or neck, a mitotic index of > 5 mitoses/mm2, ulceration, worse MSS (hazard ratio [HR] 3.2, 95% confidence interval [CI] 1.8-5.9; p < 0.001) and a higher probability of developing distant metastasis (HR 2.0, 95% CI 1.1-3.7; p = 0.034). CONCLUSIONS:We identified an NLR level of 4.8 as the best cutoff to distinguish patients with localized melanoma (stages I and II) who are at an increased risk of death due to melanoma (MSS) and of developing distant metastasis (DMFS).

Background: Angiosarcomas (ASs) represent a heterogeneous and highly aggressive subset of tumors that respond poorly to systemic treatments and are associated with short progression-free survival (PFS) and overall survival (OS). The aim of this study was to develop and validate an immune-related prognostic model—termed the AS score—using data from two independent sarcoma cohorts. Methods: A prognostic model was developed using a previously characterized cohort of 25 angiosarcoma samples. Candidate genes were identified via the Maxstat algorithm (Maxstat v0.7-25 for R), combined with log-rank testing. The AS score was then computed by weighing normalized gene expression levels according to Cox regression coefficients. For external validation, transcriptomic data from TCGA Sarcoma cohort (n = 253) were analyzed. The Immunoscore—which reflects the tumor immune microenvironment—was inferred using the ESTIMATE package (v1.0.13) in R. All statistical analyses were performed in RStudio (v 4.0.3). Results: Four genes—IGF1R, MAP2K1, SERPINE1, and TCF12—were ultimately selected to construct the prognostic model. The resulting AS score enabled the classification of angiosarcoma cases into two prognostically distinct groups (p = 0.00012). Cases with high AS score values, which included both cutaneous and non-cutaneous forms, exhibited significantly poorer outcomes, whereas cases with low AS scores were predominantly cutaneous. A significant association was observed between the AS score and the Immunoscore (p = 0.025), with higher Immunoscore values found in high-AS score tumors. Validation using TCGA sarcoma cohort confirmed the prognostic value of both the AS score (p = 0.0066) and the Immunoscore (p = 0.0029), with a strong correlation between their continuous values (p = 2.9 × 10−8). Further survival analysis, integrating categorized scores into four groups, demonstrated robust prognostic significance (p = 0.00021). Notably, in tumors with a low Immunoscore, AS score stratification was not prognostic. In contrast, among cases with a high Immunoscore, the AS score effectively distinguished outcomes (p < 0.0001), identifying a subgroup with poor prognosis but potential sensitivity to immunotherapy. Conclusions: This combined classification using the AS score and Immunoscore has prognostic relevance in sarcoma, suggesting that angiosarcomas with an immunologically active microenvironment (high Immunoscore) and poor prognosis (high AS score) may be prime candidates for immunotherapy and this approach warrants prospective validation.

BACKGROUND:Vitamin D deficiency associates with the risk of developing many diseases, including cancer. At the molecular level, vitamin D appears to have an antineoplastic effect. However, the role of vitamin D deficiency in cancer pathogenesis remains unelucidated and numerous studies have resulted in discordant results. This study aimed to determine whether vitamin D deficiency during melanoma diagnosis increases the risk of developing non-cutaneous second primary cancers (SPC).MATERIALS AND METHODS:A retrospective study on 663 patients diagnosed with melanoma between 1 January 2011 and 31 October 2022. The effect of each variable on the development of a subsequent non-cutaneous cancer was performed using Kaplan-Meier curves and differences were assessed by log-rank tests. Cox proportional hazard univariate and multivariate models were used to quantify the effect of each variable in the time to develop a non-cutaneous neoplasia.RESULTS:Out of 663 patients, 34 developed a non-cutaneous SPC. There was no statistically significant association between vitamin D levels and non-cutaneous SPC development (log-rank, p=0.761). Age>60 years, stage III/IV, and nodular melanoma subtype were significantly associated with the development of a SPC. After multivariate analysis, only age>60 years (HR 3.4; HR CI 95%: 1.5-7.6) and nodular melanoma subtype (HR 2.2; HR CI 95%: 1.0-4.8) were included in the final model.CONCLUSIONS:Our results suggest that vitamin D deficiency is not associated with an increased risk of developing non-cutaneous SPC in melanoma patients. However, age over 60 years and nodular melanoma subtype increase the risk for non-cutaneous SPC development.

Introducción La disección ganglionar completa (DGC) era la práctica estándar en pacientes con melanoma y biopsia selectiva del ganglio centinela (BSGC) positiva hasta que, en 2016 y 2017 se publicaron los resultados de dos ensayos clínicos que no demostraron que mejorase la supervivencia específica por melanoma (SEM). Sin embargo, continúa realizándose en algunos escenarios. No existen estudios que recojan el manejo ganglionar tras BSGC positivo en la práctica clínica en nuestro medio. Objetivos Determinar la evolución de la indicación de la DGC en pacientes con BSGC positiva, así como las características que se asocian a su realización. Material y métodos Estudio observacional retrospectivo multicéntrico que incluye pacientes con melanoma cutáneo y ganglio centinela positivo diagnosticados entre los años 2017-2022 en ocho centros españoles y uno italiano. Resultados Se incluyeron 430 pacientes, 54% hombres, 358 (75,1%) tenían entre 45-80 años, de ellos, 133 casos (31%) presentaban un Breslow>4mm, 206 casos (49,1%) estaban ulcerados, en 213 casos (55,7%) la metástasis ganglionar era>1mm. Se realizó la linfadenectomía aislada o seguida de adyuvancia en 146 pacientes (34,1%). Tras una regresión logística multivariante, los factores asociados a la realización de DGC fueron el subtipo histológico melanoma lentiginoso acral (MLA), un tamaño de metástasis ganglionar>1mm, la extensión extracapsular y el hospital participante. La edad>80 años se asoció inversamente. Conclusión Mientras que ha disminuido la frecuencia de realización de la DGC en pacientes con melanoma y BSGC positiva, ha aumentado la indicación del tratamiento sistémico adyuvante en estos pacientes. Sin embargo, se sigue indicando la DGC en pacientes con características de alto riesgo.

Combined Merkel cell carcinoma (MCC) and squamous cell carcinoma (SCC) have classically been regarded as more aggressive than conventional, pure, Merkel cell polyomavirus (MCPyV)-positive MCC. It is still unknown whether combined MCC and SCC are more aggressive than pure, MCPyV-negative MCC, and the origin of both the SCC and MCC elements of these combined tumors has not been elucidated. The main objective of this systematic review was to assess whether combined MCC and SCC tumors are associated with a worse prognosis than pure MCC; the secondary goals were the characterization of the clinical and histopathological features of these combined neoplasms. A total of 38 studies, including 152 patients, were selected for review. In total, 76% of the cases were MCPyV-negative, whereas 4% were MCPyV-positive. The most frequent histopathological pattern was that of an SCC in situ combined with a dermal MCC (36%), followed by both an in situ and invasive SCC combined with a dermal MCC (20%). Forty-seven percent of all cases fitted in the morphology of the so-called “collision tumors”. Three combined MCC cases that would fit in the morphological category of collision tumors presented both squamous and neuroendocrine elements in their respective nodal metastases. The mean overall survival was 36 months, comparable to that of pure, MCPyV-negative MCC. This review found similarly aggressive behavior for combined MCC and SCC and pure, MCPyV-negative MCC. Preliminary data strongly suggest that all MCPyV-negative MCC tumors, whether combined or pure, are part of a common spectrum.