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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. Resumen: Antecedentes: El déficit de vitamina D se asocia con un mayor riesgo de padecer varias enfermedades, incluido el cáncer. Molecularmente, esta parece tener un efecto antineoplásico. Sin embargo, el papel que juega en la patogénesis del cáncer no está bien esclarecido y hay resultados dispares en los estudios publicados. El objetivo del presente fue determinar si unos niveles de vitamina D deficientes en el momento del diagnóstico del melanoma aumentaba el riesgo de desarrollar un cáncer no cutáneo (CNC). Material y método: Se diseñó un estudio retrospectivo de 663 pacientes diagnosticados de melanoma entre el 1 de enero de 2011 y el 31 de octubre de 2022. El efecto de cada una de las variables seleccionadas en el desarrollo de un CNC durante el seguimiento tras el diagnóstico del melanoma se realizó mediante el estudio de supervivencia con el método de Kaplan-Meier y las diferencias se evaluaron con la prueba de los rangos logarítmicos. Se elaboraron modelos uni y multivariados de riesgos proporcionales de Cox para cuantificar el efecto de cada valor de las variables de estudio en el tiempo para desarrollar un CNC. Resultados: De los 663 pacientes, 34 desarrollaron un CNC tras el melanoma. No hubo diferencias estadísticamente significativas entre los grupos definidos por los niveles de vitamina D (log-rank, p = 0,761). Sin embargo, una edad > 60, el estadio III/IV, y el tipo nodular se asociaron significativamente al desarrollo de un CNC. Tras el análisis multivariado, solo la edad > 60 (hazard ratio [HR] 3,4; intervalo de confianza [IC] 95% HR:1,5-7,6) y el subtipo nodular de melanoma (HR 2,2; IC 95% HR:1,0-4,8) se mantuvieron en el modelo predictivo final. Conclusiones: Nuestros resultados sugieren que unos niveles de vitamina D deficientes en el diagnóstico de melanoma no se asocian a un mayor riesgo de desarrollar un CNC. Sin embargo, en una edad > 60 y el subtipo nodular sí que aumentan el riesgo de desarrollar un CNC.

Resumen: El melanoma sobre nevus azul o melanoma ex-blue nevus es una variedad de melanoma peculiar que tiene un perfil genético diferente al del resto de los melanomas cutáneos y sorprendentemente superponible al perfil del melanoma uveal. Aunque puede aparecer de novo, el melanoma ex-blue nevus se suele desarrollar sobre un nevus azul previo o sobre una melanocitosis dérmica. No todas las lesiones nodulares desarrolladas sobre un nevus azul o una melanocitosis dérmica son melanomas, y los hallazgos clínicos e histológicos pueden ser insuficientes para llegar a un diagnóstico de certeza. Así, cobran relevancia estudios adicionales, como la hibridación genómica comparada, pues la presencia de aberraciones cromosómicas favorece el diagnóstico de malignidad. Es de especial utilidad el estudio del gen BAP1, cuya pérdida de expresión orienta a melanoma en este espectro de lesiones. Presentamos 3 casos del espectro nevus azul a melanoma ex-blue nevus con estudios de biología molecular. Abstract: Melanoma arising in blue nevus, also known as melanoma ex blue nevus, is a specific form of melanoma whose genetic profile is different to that of other cutaneous melanomas and surprisingly similar to that of uveal melanoma. Although melanoma ex blue nevus can appear de novo, it usually arises in a preexisting blue nevus or dermal melanocytosis. Not all nodular lesions arising in association with blue nevus or dermal melanocytosis are melanomas, however, and because clinical and histologic findings may be insufficient for a definitive diagnosis, additional studies such as comparative genomic hybridization are important. Detection of chromosomal aberrations supports a diagnosis of malignancy. Studies of the BAP1 gene are particularly useful in this setting because loss of expression is indicative of melanoma. We present 3 cases on the spectrum of blue nevus to melanoma ex blue nevus that were studied using molecular biology techniques.

Resumen: Antecedentes: El déficit de vitamina D se asocia con un mayor riesgo de padecer varias enfermedades, incluido el cáncer. Molecularmente, esta parece tener un efecto antineoplásico. Sin embargo, el papel que juega en la patogénesis del cáncer no está bien esclarecido y hay resultados dispares en los estudios publicados. El objetivo del presente fue determinar si unos niveles de vitamina D deficientes en el momento del diagnóstico del melanoma aumentaba el riesgo de desarrollar un cáncer no cutáneo (CNC). Material y método: Se diseñó un estudio retrospectivo de 663 pacientes diagnosticados de melanoma entre el 1 de enero de 2011 y el 31 de octubre de 2022. El efecto de cada una de las variables seleccionadas en el desarrollo de un CNC durante el seguimiento tras el diagnóstico del melanoma se realizó mediante el estudio de supervivencia con el método de Kaplan-Meier y las diferencias se evaluaron con la prueba de los rangos logarítmicos. Se elaboraron modelos uni y multivariados de riesgos proporcionales de Cox para cuantificar el efecto de cada valor de las variables de estudio en el tiempo para desarrollar un CNC. Resultados: De los 663 pacientes, 34 desarrollaron un CNC tras el melanoma. No hubo diferencias estadísticamente significativas entre los grupos definidos por los niveles de vitamina D (log-rank, p = 0,761). Sin embargo, una edad > 60, el estadio III/IV, y el tipo nodular se asociaron significativamente al desarrollo de un CNC. Tras el análisis multivariado, solo la edad > 60 (hazard ratio [HR] 3,4; intervalo de confianza [IC] 95% HR:1,5-7,6) y el subtipo nodular de melanoma (HR 2,2; IC 95% HR:1,0-4,8) se mantuvieron en el modelo predictivo final. Conclusiones: Nuestros resultados sugieren que unos niveles de vitamina D deficientes en el diagnóstico de melanoma no se asocian a un mayor riesgo de desarrollar un CNC. Sin embargo, en una edad > 60 y el subtipo nodular sí que aumentan el riesgo de desarrollar un CNC. Abstract: 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.

Melanoma arising in blue nevus, also known as melanoma ex blue nevus, is a specific form of melanoma whose genetic profile is different to that of other cutaneous melanomas and surprisingly similar to that of uveal melanoma. Although melanoma ex blue nevus can appear de novo, it usually arises in a pre-existing blue nevus or dermal melanocytosis. Not all nodular lesions arising in association with blue nevus or dermal melanocytosis are melanomas, however, and because clinical and histologic findings may be insufficient for a definitive diagnosis, additional studies such as comparative genomic hybridization are important. Detection of chromosomal aberrations supports a diagnosis of malignancy. Studies of the BAP1 gene are particularly useful in this setting because loss of expression is indicative of melanoma. We present 3 cases on the spectrum of blue nevus to melanoma ex blue nevus that were studied using molecular biology techniques. Resumen: El melanoma sobre nevus azul o melanoma ex-blue nevus es una variedad de melanoma peculiar que tiene un perfil genético diferente al del resto de los melanomas cutáneos y sorprendentemente superponible al perfil del melanoma uveal. Aunque puede aparecer de novo, el melanoma ex-blue nevus se suele desarrollar sobre un nevus azul previo o sobre una melanocitosis dérmica. No todas las lesiones nodulares desarrolladas sobre un nevus azul o una melanocitosis dérmica son melanomas, y los hallazgos clínicos e histológicos pueden ser insuficientes para llegar a un diagnóstico de certeza. Así, cobran relevancia estudios adicionales, como la hibridación genómica comparada, pues la presencia de aberraciones cromosómicas favorece el diagnóstico de malignidad. Es de especial utilidad el estudio del gen BAP1, cuya pérdida de expresión orienta a melanoma en este espectro de lesiones. Presentamos tres casos del espectro nevus azul a melanoma ex-blue nevus con estudios de biología molecular.

Resumen: Introducción: La vitamina D tiene un rol fundamental en múltiples vías metabólicas, incluidas vías implicadas en la proliferación celular y la respuesta inmune. Sus niveles han mostrado una asociación con el riesgo de desarrollar el melanoma cutáneo y su pronóstico. El objetivo de este estudio fue evaluar si los niveles séricos de vitamina D influyen en el pronóstico del melanoma. Materiales y métodos: Estudio de cohorte retrospectivo, observacional, longitudinal y analítico en 286 pacientes con diagnóstico histológico de melanoma, en los que se midieron los niveles séricos de vitamina D en el momento del diagnóstico. Se analizó la relación entre los niveles de vitamina D y las características epidemiológicas, clínicas y patológicas de los pacientes, y el efecto de la vitamina D en la supervivencia global de los pacientes. Mediante un bucle iterativo se encontró el punto de corte de los niveles séricos de vitamina D de 9,25 ng/mL para su relación con la supervivencia. Resultados: Un nivel bajo de vitamina D (

Resumen: Debido a las particularidades anatómicas clínicas e histológicas del aparato ungueal, y a las dificultades inherentes a la obtención y procesado de las biopsias ungueales, el estudio de las lesiones melanocíticas subungueales no suele ser una tarea sencilla. Además, en el caso de las lesiones melanocíticas subungueales de la edad pediátrica, hay que añadir las peculiaridades de las características clínicas y epidemiológicas propias de esta edad. En la infancia, muchos de los signos clínicos que son considerados de alarma en el adulto no han demostrado tener la misma validez, y no existe un claro consenso respecto a cuándo realizar una biopsia ungueal para descartar patología melanocítica maligna. Esto, unido al carácter excepcional del melanoma subungueal pediátrico, hacen que en la mayoría de los casos se recomiende exclusivamente la observación y el seguimiento. Por otro lado, las lesiones melanocíticas subungueales pediátricas pueden mostrar características histopatológicas atípicas, sin que ello implique un comportamiento clínico agresivo. El melanoma subungueal es una entidad excepcional, con solo 21 casos descritos hasta la fecha. Cabe destacar que ninguno de los casos de melanoma subungueal pediátrico descritos hasta la fecha presentó afectación metastásica visceral, ni tampoco ocasionó la muerte del paciente, y que el diagnóstico es controvertido en muchos de ellos. Por todo ello, y teniendo en cuenta la significativa mayor frecuencia de lesiones melanocíticas benignas subyacentes a melanoniquias longitudinales en la edad pediátrica, así como las peculiaridades clínicas de las mismas, el manejo de estas lesiones debe ser diferente al de las melanoniquias del adulto, siendo la observación la actitud más adecuada en la gran mayoría de los casos. Abstract: The study of subungual melanocytic lesions can present challenges because of the clinical and histologic characteristics of the nail unit and the difficulty of performing nail biopsies and processing specimens. These lesions can be even more challenging in children due to differences in clinical and epidemiological profiles between the adult and pediatric populations. Many of the clinical features of subungual melanocytic lesions that would raise alarm in an adult do not have the same implications in children. Consensus is also lacking on when a nail biopsy is needed to rule out malignancy in the pediatric setting. In view of these considerations and the rarity of subungual melanoma in childhood, the recommended approach in most cases is a watch-and-wait strategy. Subungual melanocytic lesions in children may also show atypical histopathologic features that are not necessarily associated with aggressive behavior. Subungual melanoma is very rare in childhood, with just 21 cases described to date. None of the patients developed visceral metastasis or died as a result and the diagnosis was controversial in many of the cases. Considering the above and the significantly higher frequency and particular characteristics of longitudinal melanonychia with a benign etiology in children, subungual melanocytic lesions should be managed differently in this setting than in adults. In most cases, a watch-and-wait approach is the most appropriate strategy.

Introduction: Vitamin D plays a fundamental role in many metabolic pathways, including those involved in cell proliferation and the immune response. Serum levels of this vitamin have been linked to melanoma risk and prognosis. This study aimed to assess the prognostic value of vitamin D serum level in melanoma. Material and methods: Retrospective, observational, longitudinal, and analytical study of 286 patients with a histologic diagnosis of melanoma in whom serum levels of vitamin D were measured at the time of diagnosis. We analyzed associations between serum level and epidemiologic and clinical variables and pathology findings; we also analyzed the influence of vitamin D on overall survival. An iterative loop was used to identify a vitamin D serum level to test for its an association with survival. Results: A vitamin D level less than 9.25 ng/mL was associated with a histologic finding of ulceration. After a median follow-up period of 39.4 months, 24 patients (8.4%) had died. The cutoff of 9.25 ng/mL was associated with lower overall survival according to both the Kaplan–Meier curves and multivariate Cox regression analysis. Conclusion: Vitamin D levels less than 9.25 ng/mL are associated with ulceration in melanoma and serve as an independent prognostic factor for overall survival in this disease. Resumen: Introducción: La vitamina D tiene un rol fundamental en múltiples vías metabólicas, incluidas vías implicadas en la proliferación celular y la respuesta inmune. Sus niveles han mostrado una asociación con el riesgo de desarrollar el melanoma cutáneo y su pronóstico. El objetivo de este estudio fue evaluar si los niveles séricos de vitamina D influyen en el pronóstico del melanoma. Materiales y métodos: Estudio de cohorte retrospectivo, observacional, longitudinal y analítico en 286 pacientes con diagnóstico histológico de melanoma, en los que se midieron los niveles séricos de vitamina D en el momento del diagnóstico. Se analizó la relación entre los niveles de vitamina D y las características epidemiológicas, clínicas y patológicas de los pacientes, y el efecto de la vitamina D en la supervivencia global de los pacientes. Mediante un bucle iterativo se encontró el punto de corte de los niveles séricos de vitamina D de 9,25 ng/mL para su relación con la supervivencia. Resultados: Un nivel bajo de vitamina D (

The study of subungual melanocytic lesions can present challenges because of the clinical and histologic characteristics of the nail unit and the difficulty of performing nail biopsies and processing specimens. These lesions can be even more challenging in children due to differences in clinical and epidemiological profiles between the adult and pediatric populations. Many of the clinical features of subungual melanocytic lesions that would raise alarm in an adult do not have the same implications in children. Consensus is also lacking on when a nail biopsy is needed to rule out malignancy in the pediatric setting. In view of these considerations and the rarity of subungual melanoma in childhood, the recommended approach in most cases is a watch-and-wait strategy. Subungual melanocytic lesions in children may also show atypical histopathologic features that are not necessarily associated with aggressive behavior. Subungual melanoma is very rare in childhood, with just 21 cases described to date. None of the patients developed visceral metastasis or died as a result and the diagnosis was controversial in many of the cases. Considering the above and the significantly higher frequency and particular characteristics of longitudinal melanonychia with a benign etiology in children, subungual melanocytic lesions should be managed differently in this setting than in adults. In most cases, a watch-and-wait approach is the most appropriate strategy. Resumen: Debido a las particularidades anatómicas clínicas e histológicas del aparato ungueal, y a las dificultades inherentes a la obtención y procesado de las biopsias ungueales, el estudio de las lesiones melanocíticas subungueales no suele ser una tarea sencilla. Además, en el caso de las lesiones melanocíticas subungueales de la edad pediátrica, hay que añadir las peculiaridades de las características clínicas y epidemiológicas propias de esta edad. En la infancia, muchos de los signos clínicos que son considerados de alarma en el adulto no han demostrado tener la misma validez, y no existe un claro consenso respecto a cuándo realizar una biopsia ungueal para descartar patología melanocítica maligna. Esto, unido al carácter excepcional del melanoma subungueal pediátrico, hacen que en la mayoría de los casos se recomiende exclusivamente la observación y el seguimiento. Por otro lado, las lesiones melanocíticas subungueales pediátricas pueden mostrar características histopatológicas atípicas, sin que ello implique un comportamiento clínico agresivo. El melanoma subungueal es una entidad excepcional, con solo 21 casos descritos hasta la fecha. Cabe destacar que ninguno de los casos de melanoma subungueal pediátrico descritos hasta la fecha presentó afectación metastásica visceral, ni tampoco ocasionó la muerte del paciente, y que el diagnóstico es controvertido en muchos de ellos. Por todo ello, y teniendo en cuenta la significativa mayor frecuencia de lesiones melanocíticas benignas subyacentes a melanoniquias longitudinales en la edad pediátrica, así como las peculiaridades clínicas de las mismas, el manejo de estas lesiones debe ser diferente al de las melanoniquias del adulto, siendo la observación la actitud más adecuada en la gran mayoría de los casos.

Background: Biosynthetic porcine type I collagen dressing is useful to close ulcers and secondary intention healing of surgical cancer wounds., Objective: To identify factors associated with the healing time of such wounds., Methods: We conducted a retrospective observational study of patients on oncological dermatological surgery in a cancer center. Healing time was studied based on age, sex, personal history of comorbidities, usual medication, anatomical location, type of surgery performed and size of the defect. Statistical analysis was performed using the ANOVA test and logistic regression., Results: A total of 306 patients were included with a median age of 73 years (62.4%, men). The statistically significantly characteristics associated with a healing time ≤ 66 days were location-auricle, nose, inner canthus, hand, retroauricular region and nail bed-use of the Mohs technique and defect sizes ≤ 5.28 cm 2 ., Limitations: This is a retrospective study from a single center., Conclusion: The use of biosynthetic porcine type I collagen dressings for the definitive closure of dermatological surgical cancer wounds seems particularly suitable for small defects of the inner canthus of the eye, hand, auricle, nose, forehead, retroauricular region, and nail bed., (Copyright © 2025. Publicado por Elsevier España, S.L.U.)

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 >4mm, 206 cases (49%) were ulcerated, and in 213 cases (55.7%), lymph node metastasis was >1mm. 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 >1mm, 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., (Copyright © 2024 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

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 2 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 358 (75.1%) aged between 45 and 80 years. A total of 133 cases (31%) exhibited Breslow thickness > 4mm, 206 cases (49.1%) were ulcerated, and in 213 cases (55.7%), lymph node metastasis was > 1mm. 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 > 1mm, 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., (Copyright © 2024 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

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., (Copyright © 2024 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Differences in survival according to the pTERT mutation subtypes (-124C > T, -146C > T, and tandem -138_139CC > TT) have been observed. The present study aimed to describe the clinical as the histopathological and molecular cutaneous melanoma features according to the presence of the three most prevalent pTERT mutation subtypes (-124C > T, -146C > T, and tandem -138_139CC > TT). A retrospective cross-sectional study including 684 patients was designed, and a Partial Least-Squares Discriminant Analysis (PLS-DA) was performed. After the PSL-DA, it was observed that the tandem -138_139CC > TT subtype differs from the other subtypes. The model demonstrated that the -124C > T and the -138_139 CC > TT subtypes were associated with fast-growing melanomas (OR 0.5, CI 0.29-0.86, p = .012) and with Breslow >2 mm (OR 0.6, CI 0.37-0.97, p = .037), compared to the -146C > T mutation. Finally, the -124C > T appeared to be more associated with the presence of TILs (non-brisk) than the -146C > T (OR 0.6, CI 0.40-1.01, p = .05). These findings confirmed that the -124C > T and the tandem -138_139 CC > TT subtypes are both highly associated with the presence of features of aggressiveness; however, only the -124C > T was highly associated with TILs. This difference could explain the worse survival rate associated with the tandem -138_139CC > TT mutations., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A great portion of cutaneous melanoma's diagnoses nowadays is attributed to thin tumors with up to 1 mm in Breslow thickness (hereafter thin CMs), which occasionally metastasize. The objective of this study was to identify thin CM's metastatic patterns from a topographical and chronological standpoint. A total of 204 cases of metastatic thin CMs from five specialized centers were included in the study, and corresponding data were collected (clinical, epidemiological, histopathological information of primary tumor and the number, anatomical site, and time intervals of their progressions). First progressions occurred locally, in regional lymph nodes, and in a distant site in 24%, 15% and 61% of cases, respectively, with a median time to first progression of 3.10 years (IQR: 1.09-5.24). The median elapsed time between the first and second progression and between the second and third progression was 0.82 (IQR: 0.34-1.97) and 0.49 (IQR: 0.21-2.30) years, respectively, while the median survival time was about 4 years since first progression. Furthermore, the sequences of locations and time intervals of the progressions were associated with the clinicopathological and demographic features of the primary tumors along with the features of the preceding progressions. In conclusion, the findings of this study describe the natural history of thin CMs, thus highlighting the necessity to identify subgroups of thin CMs at a higher risk for metastasis and contributing to the optimization of the management and follow-up of thin CM patients.

Background: Acral location of melanomas is associated with poor survival. It can be due, at least in part, to the fact that acral lentiginous melanoma, a distinct melanoma subtype, has a particular biological profile and a bad clinical behavior. However, since almost 50% of acral melanomas are not of acral lentiginous melanoma subtype, the worse clinical behavior could also be attributable to the intrinsic characteristics of the location., Objective: This study aimed to investigate if melanomas of the lower limb excluding acral lentiginous melanoma differ by location., Methods: This retrospective, observational study recruited patients from an oncology referral center in Spain. We included 285 patients with superficial spreading and nodular melanomas of the lower limb. We compare melanomas by site, clinical and pathological characteristics, and the differences by location of disease-free and melanoma-specific survival by the Kaplan-Meier method and Cox proportional hazard method., Results: Patients with melanomas on the foot, compared to those on the rest of the limb, were older and reported having suffered less sunburns; the melanoma more frequently appeared in areas that had been rarely sun exposed, were more frequently of nodular type, presented thicker tumors, with more ulceration, less regression, and more advanced stage of the disease. Foot location increased the risk of relapse and decreased melanoma-specific survival., Conclusion: Melanoma development in foot is less related to sun exposure and is associated with pathological features that can account for the worse prognosis and poorer survival., (© 2022 S. Karger AG, Basel.)

Background: KIT mutations are primarily associated with acral and mucosal melanoma, and have been reported to show higher prevalence in chronic sun-damaged (CSD) than non-CSD melanomas., Objectives: To investigate the prevalence of KIT mutations in melanoma according to subtype, and determine the clinical role of such mutations., Materials & Methods: We present results from a study of a Spanish population of 492 melanomas, classified according to the latest World Health Organization (WHO) guidelines. We analysed the mutational status of KIT and correlated with different clinical variables related to sun exposure and family history., Results: KIT mutations were significantly more frequent in acral (3/36; 8.3%) and mucosal (4/8; 50%) melanomas than non-acral cutaneous melanomas. No significant difference was observed in KIT mutational status between CSD and non-CSD melanomas., Conclusion: Our results suggest that KIT mutations in melanoma tumours are unrelated to the development of nevi or chronic sun damage, but their presence is associated with aggressive melanomas which show ulceration, vascular invasiveness, and increased Breslow thickness. These findings are consistent with those reported by The Cancer Genome Atlas network.

According to the divergent pathway model, cutaneous melanoma comprises a nevogenic group with a propensity to melanocyte proliferation and another one associated with cumulative solar damage (CSD). While characterized clinically and epidemiologically, the differences in the molecular profiles between the groups have remained primarily uninvestigated. This study has used a custom gene panel and bioinformatics tools to investigate the potential molecular differences in a thoroughly characterized cohort of 119 melanoma patients belonging to nevogenic and CSD groups. We found that the nevogenic melanomas had a restricted set of mutations, with the prominently mutated gene being BRAF . The CSD melanomas, in contrast, showed mutations in a diverse group of genes that included NF1 , ROS1 , GNA11 , and RAC1 . We thus provide evidence that nevogenic and CSD melanomas constitute different biological entities and highlight the need to explore new targeted therapies.

Background: Some studies have suggested a relationship between type 2 diabetes mellitus (T2DM) and increased incidence of melanoma. Efforts are under way to identify preventable and treatable factors associated with greater melanoma aggressiveness, but no studies to date have examined the relationship between T2DM and the aggressiveness of cutaneous melanoma at diagnosis., Objectives: To explore potential associations between T2DM, glycaemic control and metformin treatment and the aggressiveness of cutaneous melanoma., Methods: We conducted a cross-sectional multicentric study in 443 patients diagnosed with cutaneous melanoma. At diagnosis, all patients completed a standardized protocol, and a fasting blood sample was extracted to analyse their glucose levels, glycated haemoglobin concentration and markers of systemic inflammation. Melanoma characteristics and aggressiveness factors [Breslow thickness, ulceration, tumour mitotic rate (TMR), sentinel lymph node (SLN) involvement and tumour stage] were also recorded., Results: The mean (SD) age of the patients was 55·98 (15·3) years and 50·6% were male. The median Breslow thickness was 0·85 mm. In total, 48 (10·8%) patients were diagnosed with T2DM and this finding was associated with a Breslow thickness > 2 mm [odds ratio (OR) 2·6, 95% confidence interval (CI) 1·4-4·9; P = 0·004)] and > 4 mm (OR 3·6, 95% CI 1·7-7·9; P = 0·001), TMR > 5 per mm 2 (OR 4·5, 95% CI 1·4-13·7; P = 0·009), SLN involvement (OR 2·3, 95% CI 1-5·7; P = 0·038) and tumour stages III-IV (vs. I-II) (OR 3·4, 95% CI 1·6-7·4; P = 0·002), after adjusting for age, sex, obesity, alcohol intake and smoking habits. No significant associations emerged between glycated haemoglobin levels, metformin treatment and melanoma aggressiveness., Conclusions: T2DM, rather than glycaemic control and metformin treatment, is associated with increased cutaneous melanoma aggressiveness at diagnosis., (© 2021 British Association of Dermatologists.)

The large-scale implementation of primary and secondary skin cancer prevention strategies in recent decades has led to an increase in the diagnosis of thin melanomas and a decrease in the mean thickness of tumours diagnosed. The number of newly diagnosed thick melanomas, however, has remained stable. To investigate associations between melanoma thickness, clinical presentation and demographic and phenotypic characteristics. The study is based on a cross-sectional study of 1,459 patients with melanoma from a dermatology department at a tertiary hospital in Spain between 2000 and 2017. We analysed associations between median Breslow thickness and demographic, phenotypic, and clinical characteristics, including the method of melanoma detection. Age ≥ 70 years (regression coefficient [RC] =  1.2, 95% CI: 1.1-1.3; p  <  0.001), male sex (RC  =  0.9, 95% CI: 0.8-0.9; p  <  0.001), symptom-based detection (RC  =  1.3, 95% CI: 1.1-1.4; p  <  0.001), and a history of sunburn at the melanoma site (RC  =  0.9, 95% CI: 0.8-0.9; p  =  0.04) were all associated with thicker tumours. Melanomas on the lower extremities, by contrast, were significantly thinner (RC  =  0.9, 95% CI: 0.8-0.9; p = 0.04). Thick melanomas occur preferentially in older men and show changes such as bleeding or an increase in volume or colour. This information should be incorporated into health training and education programs to design better prevention strategies and minimize diagnostic delays.

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., Competing Interests: Conflict of interest statement The authors state no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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., (© 2020 British Association of Dermatologists.)

Background: The incidence of cutaneous melanoma, an important global public health problem, has been increasing over the last several decades., Objectives: In order to decrease melanoma-related mortality, ways to communicate and implement the correct methods for conducting primary and secondary prevention measures (such as early detection via self-examination) should be investigated., Materials and Methods: An observational, cross-sectional, retrospective study consisting of 409 patients diagnosed with cutaneous melanoma was conducted. An online questionnaire was created to evaluate knowledge levels, attitudes, and adherence to primary preventive measures and to skin self-examination practices., Results: The results revealed that even when 43% of the patients perform cutaneous self-examinations, only half of them fully followed the recommendations. Patients aged <45 years, female, with a I-II phototype, with an intermediate/high level of education, and with a history of NMSC were more likely to have an adequate degree of knowledge. Moreover, patients aged <45 years and with an adequate degree of knowledge more frequently showed an adequate adherence to the primary prevention measures. Finally, patients aged 45-60 years and with an adequate degree of knowledge presented a good adherence to the self-skin examination measures., Limitations: Possible limitations of this study were memory bias through the influence of age within the study population, and bias due to a greater proportion of subjects with a high education level., Conclusion: Within the population of patients with melanoma, a high percentage of patients do not rigorously follow the recommended prevention measures. Our study highlights the need to implement awareness in this population to improve the prevention of cutaneous cancer., (© 2021 S. Karger AG, Basel.)

Background : Sentinel lymph node (SLN) status is recognized as the most important prognostic factor for patients with cutaneous melanoma. However, sometimes it is not possible to identify SLN. The phenomenon of non-identification of SLN and its prognostic role have not been thoroughly evaluated in melanoma literature. The objective of this study was to identify which patient or tumor variables may be associated to non-identification of SLN and to evaluate the prognostic role of non-identification of SLN. Methods : Observational retrospective study of 834 cutaneous melanoma patients who underwent SLN biopsy at Instituto Valenciano de Oncología. Results : Forty-two patients (5%) presented non-identification of SLN. Patients with age at diagnosis of ≥ 64 years, obesity (BMI ≥ 30), and head and neck localization were at higher risk of non-identification of SLN. Non-identified SLN patients had worse nodal disease-free survival with respect to negative SLN patients, but not worse melanoma-specific survival. Conclusions : Our findings suggest a need to follow-up patients with non-identified SLN in the same way as patients with positive SLN.

Locoregional lymph node recurrences of primary trunk melanoma can occur in basins not identified during sentinel lymph node biopsy. However, the factors associated with recurrences in non-sentinel lymph node basins are unknown. To evaluate these factors, this observational retrospective study examined the patterns of first lymph node recurrence and the factors associated with recurrence in non-sentinel lymph node basins. A total of 305 patients with primary trunk melanoma who had undergone sentinel lymph node biopsy from 2000 to 2015 were evaluated. Twenty-three patients presented locoregional lymph node recurrence; 8 of which (34.8%) were in non-sentinel lymph node basins. Non-sentinel lymph node recurrences were more frequent in patients with positive sentinel lymph nodes and in those patients whose number of tumour-involved nodes was > 3. These results suggest that clinical examination and ultrasound surveillance should be performed on all potential lymph node drainage basins of trunk melanomas.

Introduction: Sentinel lymph node (SLN) biopsy is useful for the prognostic stratification of patients with thick melanoma. Identifying which variables are associated with SLN involvement and establishing risk in different subgroups of patients could be useful for guiding the indication of SLN biopsy. The value of complete lymph node dissection (CLND) in patients with a positive SLN biopsy is currently under debate., Materials and Methods: To identify factors associated with SLN involvement in thick melanoma we performed a multicentric retrospective cohort study involving 660 patients with thick melanoma who had undergone SLN biopsy. To analyze the role of CLND in thick melanoma patients with a positive SLN biopsy, we built a multivariate Cox proportional hazards model for melanoma-specific survival (MSS) and disease-free survival (DFS) and compared 217 patients who had undergone CLND with 44 who had not., Results: The logistic regression analysis showed that age, histologic subtype, ulceration, microscopic satellitosis, and lymphovascular invasion were associated with nodal disease. The CHAID (Chi-squared Automatic Interaction Detection) decision tree showed ulceration to be the most important predictor of lymphatic involvement. For nonulcerated melanomas, the histologic subtype lentigo maligna melanoma was associated with a low rate of SLN involvement (4.3%). No significant differences were observed for DFS and MSS between the CLND performed and not-performed groups. Nodal status on CLND was associated with differences in DFS and MSS rates., Conclusion: We identified subgroups of thick melanoma patients with a low likelihood of SLN involvement. CLND does not offer survival benefit, but provides prognostic information., Competing Interests: Declaration of competing interest None., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

The aim of this study is to evaluate the relation between 25-hydroxyvitamin D levels at diagnosis and pathological characteristics in primary invasive melanoma. A cross-sectional study was designed based on a series of 204 consecutive patients diagnosed of invasive melanomas in the 2013-2017 period at a single institution. 25-hydroxyvitamin D serum levels at diagnosis were assessed, and three groups were defined by vitamin D status: deficiency, insufficiency, and sufficiency. Clinical and pathological characteristics were compared between the groups by Chi-square test. Logistic regression models were performed to evaluate the association between vitamin D status and Breslow thickness, ulceration, and tumor mitotic rate. A significant association between vitamin D levels at diagnosis and location, tumor mitotic rate, and ulceration was found; and a borderline association with Breslow thickness and BMI. Deficient levels were found in 7.8% of patients and increased the risk of presenting ulcerated tumors [odds ratio: 6.8 (95% confidence interval: 1.5-29.7; P = 0.012)] and with a tumor mitotic rate greater than 1 mitosis/mm [odds ratio: 6.0 (95% confidence interval: 1.4-25.1; P = 0.014)]. A marginal increased risk of tumor thickness greater than 1 mm was also observed [odds ratio: 3.7 (95% confidence interval: 1.0-13.9; P = 0.057)]. Our study suggests a role of vitamin D levels in melanoma aggressiveness and raises the question as to whether vitamin D levels should be monitored, or even supplemented, in people with low yearly sun exposure.

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 Participants: A 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 χ2 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., Results: In 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.

Importance: The 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., Design, Setting, and Participants: This retrospective cohort study included 1177 patients with malignant melanoma treated at Instituto Valenciano de Oncología, València, Spain. Data were retrieved from the melanoma database from January 1, 2000, through December 31, 2015, and analyzed from June 1 to 30, 2018., Exposure: Malignant melanoma at stages I to II., Main Outcomes and Measures: Analyses of survival free of lymphatic and hematogenous metastasis were performed using Kaplan-Meier curves and Cox proportional hazards regression., Results: For the 1177 patients included in the study analysis (51.1% women; median age at diagnosis, 55 years [interquartile range, 42-68 years), median follow-up was 75 months (interquartile range, 33-121 months); 108 (9.2%) developed lymphatic metastasis, and 108 (9.2%) developed hematogenous metastasis. In the multivariate analysis, being older than 55 years (hazard ratio [HR], 1.9; 95% CI, 1.2-3.1), tumor in the head/neck (HR, 1.7; 95% CI, 1.0-2.9) and acral locations (HR, 2.4; 95% CI, 1.3-4.5), greater Breslow thickness (HR for >4.00 mm, 5.4; 95% CI, 2.4-12.4), and presence of vascular invasion (HR, 3.2; 95% CI, 0.9-10.6) were associated with lymphatic spreading. Hematogenous metastasis was associated with greater Breslow thickness (HR for >4.00 mm, 10.4; 95% CI, 3.6-29.7), the absence of regression (HR, 0.1; 95% CI, 0.0-1.0), TERT promoter mutations (HR, 2.9; 95% CI, 1.5-5.7), and BRAF mutations (HR, 1.9; 95% CI, 1.1-3.6)., Conclusions and Relevance: Risk factors associated with lymphatic and hematogenous metastasis differ. Follow-up and adjuvant treatment strategies may therefore need to be adapted to individual clinical, histopathologic, and molecular characteristics.

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.