Velocidad de crecimiento tumoral: Definición del valor pronóstico en el carcinoma epidermoide cutáneo y en el melanoma

La incidencia del cáncer de piel se ha incrementado exponencialmente en los últimos años debido en parte a la mayor longevidad de la población general a nivel mundial, y en parte atribuible a la modificación del comportamiento social con respecto a la exposición solar con un predominio de un patrón de exposición intenso vacacional desde mediados del siglo XX. Dentro de los diferentes cánceres de piel clasificados en base a la tasa de frecuencia/mortalidad global, el melanoma maligno (MM) y el carcinoma epidermoide cutáneo (CEC) son los más relevantes en el campo de la Dermatología. En los últimos años se han producido grandes avances en la capacidad de predecir el pronóstico y en el tratamiento del MM, y en menor medida del CEC. A pesar de todos los grandes avances en el campo de la investigación básica y translacional, y de los grandes esfuerzos en campañas de prevención social, se ha observado que la incidencia de MM de espesor elevado se ha mantenido estable a lo largo del tiempo, así como la mortalidad. Esto se ha atribuido a la existencia de un grupo de tumores que tienen una tasa elevada de crecimiento que dificulta su diagnóstico precoz y que condiciona una mayor agresividad biológica. Este hecho también se constata desde el punto de vista clínico en el que se observan tumores que han sido detectados de forma relativamente rápida pero que se diagnostican con espesores elevados. Lo mismo ocurre con el CEC, en los que aún teniendo en cuenta los factores pronósticos conocidos, el comportamiento no siempre es predecible y por el contrario parece correlacionarse con la impresión clínica del tumor que crece rápidamente. En el presente trabajo se pretendió evaluar un marcador biológico y dinámico en el cáncer, como es la velocidad de crecimiento tumoral, como parámetro pronóstico de ambas tumoraciones. El estudio de esta variable, sugerida como de mal pronóstico en la literatura relacionada con ambos tumores, permitiría esclarecer la agresividad tumoral clínica y definir biológicamente a la tumoración a fin de caracterizar de una forma más certera ambos tipos de cáncer y con ello mejorar tanto su orientación pronóstica como su actitud terapéutica. Las conclusiones obtenidas a partir de la presente tesis fueron las siguientes: Primera conclusión El melanoma de crecimiento rápido (MCR) es un tumor que típicamente se presenta en el tronco y las regiones acrales de pacientes de edades mayores a los 65 años, sin mostrar predilección por sexo y sin relación con la exposición solar intensa intermitente. Histológicamente, son tumores de mayor espesor tumoral, con una mayor frecuencia de ulceración, un mayor índice mitótico y una mayor frecuencia de afectación del ganglio centinela. Segunda conclusión La velocidad de crecimiento modificada (VCm) es un factor pronóstico independiente del melanoma maligno (MM) principalmente para la supervivencia global, con un valor incluso superior al del índice mitótico. Esto último sugiere que el crecimiento clínico del tumor refleja una agresividad tumoral que no puede ser exclusivamente medida con los factores pronósticos universalmente aceptados del MM. Tercera conclusión Una proporción significativa de casos de MCR(26,5%) portan mutaciones en NRAS. Los MM con mutaciones en NRAS muestran un comportamiento más agresivo que siguen mecanismos probablemente no relacionados con los factores clínico-patológicos pronósticos actualmente bien establecidos. Cuarta conclusión Las mutaciones patogénicas en el promotor de TERT podrían explicar, al menos en parte, la agresividad tumoral del MCR. Su relación se ve modificada por la presencia de un polimorfismo frecuente (rs2853669) en el propio promotor. Quinta conclusión La frecuencia y la severidad de las alteraciones de la respiración durante el sueño en el síndrome de apnea del sueño (SAOS) se asocian de forma independiente con el MCR. A su vez, la gravedad del SAOS se correlaciona con un mayor espesor tumoral, un mayor índice mitótico, y una mayor frecuencia de ulceración, Sexta conclusión La VCm se comporta como un factor pronóstico independiente en el carcinoma epidermoide cutáneo (CEC) que permite su inclusión, junto con la tasa de mitosis y la edad del paciente en un modelo predictivo para definir la probabilidad de adenopatía en el CEC

Intermittent Hypoxia Is Associated With High Hypoxia Inducible Factor-1α but Not High Vascular Endothelial Growth Factor Cell Expression in Tumors of Cutaneous Melanoma Patients

Epidemiological associations linking between obstructive sleep apnea and poorer solid malignant tumor outcomes have recently emerged. Putative pathways proposed to explain that these associations have included enhanced hypoxia inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) cell expression in the tumor and altered immune functions via intermittent hypoxia (IH). Here, we examined relationships between HIF-1α and VEGF expression and nocturnal IH in cutaneous melanoma (CM) tumor samples. Prospectively recruited patients with CM tumor samples were included and underwent overnight polygraphy. General clinical features, apnea-hypopnea index (AHI), desaturation index (DI4%), and CM characteristics were recorded. Histochemical assessments of VEGF and HIF-1α were performed, and the percentage of positive cells (0, 75%) was blindly tabulated for VEGF expression, and as 0, 0-5.9, 6.0-10.0, >10.0% for HIF-1α expression, respectively. Cases with HIF-1α expression >6% (high expression) were compared with those 75% of cells was compared with those with <75%. 376 patients were included. High expression of VEGF and HIF-1α were seen in 88.8 and 4.2% of samples, respectively. High expression of VEGF was only associated with increasing age. However, high expression of HIF-1α was significantly associated with age, Breslow index, AHI, and DI4%. Logistic regression showed that DI4% [OR 1.03 (95% CI: 1.01-1.06)] and Breslow index [OR 1.28 (95% CI: 1.18-1.46)], but not AHI, remained independently associated with the presence of high HIF-1α expression. Thus, IH emerges as an independent risk factor for higher HIF-1α expression in CM tumors and is inferentially linked to worse clinical CM prognostic indicators.IA is supported by SEPAR (086/2014 and 595/2017). MM-G is supported by the Instituto de Salud Carlos III (PI16/01772) and cofinanced by the European Development Regional Find “A way to achieve Europe” (ERDF) and SEPAR (211/2012). ER-F is the recipient of a postdoctoral fellowship from “Fundación Científica de la Asociación Española Contra el Cáncer” and supported by FMM-2013/0075 of “Fundación Mutua Madrileña.” JR-P is supported by FIS 2014/1737 from the Spanish Ministry of Health. RF is supported in part by the Spanish Ministry of Economy and Competitiveness—Instituto de Salud Carlos III (FIS-PI14/00004); DG is supported by National Institutes of Health grant 1R01HL130984 and by the Herbert T. Abelson Chair in Pediatrics

Obesity attenuates the effect of sleep apnea on active TGF-ss 1 levels and tumor aggressiveness in patients with melanoma

Active transforming growth factor-β1 (TGF-β1), a cytokine partially regulated by hypoxia and obesity, has been related with poor prognosis in several tumors. We determine whether obstructive sleep apnea (OSA) increases serum levels of active TGF-β1 in patients with cutaneous melanoma (CM), assess their relationship with melanoma aggressiveness and analyze the factors related to TGF-β1 levels in obese and non-obese OSA patients. In a multicenter observational study, 290 patients with CM were underwent sleep studies. TGF-β1 was increased in moderate-severe OSA patients vs. non-OSA or mild OSA patients with CM. In OSA patients, TGF-β1 levels correlated with mitotic index, Breslow index and melanoma growth rate, and were increased in presence of ulceration or higher Clark levels. In CM patients, OSA was associated with higher TGF-β1 levels and greater melanoma aggressiveness only in non-obese subjects. An in vitro model showed that IH-induced increases of TGF-β1 expression in melanoma cells is attenuated in the presence of high leptin levels. In conclusion, TGF-β1 levels are associated with melanoma aggressiveness in CM patients and increased in moderate-severe OSA. Moreover, in non-obese patients with OSA, TGF-β1 levels correlate with OSA severity and leptin levels, whereas only associate with leptin levels in obese OSA patients

Intermittent hypoxia is associated with high hypoxia inducible factor-1α but not high vascular endothelial growth factor cell expression in tumors of cutaneous melanoma patients

Epidemiological associations linking between obstructive sleep apnea and poorer solid malignant tumor outcomes have recently emerged. Putative pathways proposed to explain that these associations have included enhanced hypoxia inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) cell expression in the tumor and altered immune functions via intermittent hypoxia (IH). Here, we examined relationships between HIF-1α and VEGF expression and nocturnal IH in cutaneous melanoma (CM) tumor samples. Prospectively recruited patients with CM tumor samples were included and underwent overnight polygraphy. General clinical features, apnea-hypopnea index (AHI), desaturation index (DI4%), and CM characteristics were recorded. Histochemical assessments of VEGF and HIF-1α were performed, and the percentage of positive cells (0, 75%) was blindly tabulated for VEGF expression, and as 0, 0-5.9, 6.0-10.0, >10.0% for HIF-1α expression, respectively. Cases with HIF-1α expression >6% (high expression) were compared with those 75% of cells was compared with those with <75%. 376 patients were included. High expression of VEGF and HIF-1α were seen in 88.8 and 4.2% of samples, respectively. High expression of VEGF was only associated with increasing age. However, high expression of HIF-1α was significantly associated with age, Breslow index, AHI, and DI4%. Logistic regression showed that DI4% [OR 1.03 (95% CI: 1.01-1.06)] and Breslow index [OR 1.28 (95% CI: 1.18-1.46)], but not AHI, remained independently associated with the presence of high HIF-1α expression. Thus, IH emerges as an independent risk factor for higher HIF-1α expression in CM tumors and is inferentially linked to worse clinical CM prognostic indicators

Prevalence of BRAF and NRAS mutations in fast-growing melanomas (Letter to the Editor)

Dear Sir, About one-fourth of melanomas grow very quickly. The so-called fast-growing melanomas (FGMs) increase in thickness by 0.5 millimeters or more per month (Grob et al., 2002; Liu et al., 2006). FGMs are defined based on tumor growth rate (GR) which is calculated based on Breslow thickness and self-reported information from the patient about the time taken for the melanoma to develop (Grob et al., 2002; Martorell-Calatayud et al., 2011). FGMs have a worse prognosis and present mostly in elderly patients with fewer nevi and fewer freckles and at the trunk or acral sites (Liu et al., 2006; Martorell- Calatayud et al., 2011)