Assuntos
Nevo , Neoplasias Cutâneas , Humanos , Neoplasias Cutâneas/patologia , Nevo/patologia , DermoscopiaRESUMO
BACKGROUND: Cutaneous melanoma shows high variability regarding clinicopathological presentation, evolution and prognosis. METHODS: Next generation sequencing was performed to analyze hotspot mutations in different areas of primary melanomas (MMp) and their paired metastases. Clinicopathological features were evaluated depending on the degree of variation of the BRAFV600E mutant allele frequency (MAF) in MMp. RESULTS: In our cohort of 14 superficial spreading, 10 nodular melanomas and 52 metastases, 17/24 (71%) melanomas had a BRAFV600E mutation and 5/24 (21%) had a NRASQ61 mutation. We observed a high variation of BRAFV600E MAF (H-BRAFV600E) in 7/17 (41%) MMp. The H-BRAFV600E MMp were all located on the trunk, had lower Breslow and mitotic indexes and predominantly, a first nodal metastasis. Regions with spindled tumor cells (Spin) and high lymphocytic infiltrate (HInf) were more frequent in the H-BRAFV600E patients (4/7; 57%), whereas regions with epithelial tumor cells (Epit) and low lymphocytic infiltrate (LInf) were predominant (6/10; 60%) and exclusive in the low BRAFV600E MAF variation tumors (L-BRAFV600E). The H-BRAFV600E/Spin/HInf MMp patients had better prognostic features and nodal first metastasis. CONCLUSIONS: The H-BRAFV600E MMp were located on the trunk, had better prognostic characteristics, such as lower Breslow and mitotic indexes as well as high lymphocytic infiltrate.
RESUMO
BRAF/V600E mutation and other cell growth/growth-control mechanisms are involved in naevogenesis and melanomagenesis. Immunoexpression of BRAF/V600E and other molecules (p16, phosphatase and tensin homologue (PTEN), Ki67, hTERT and Cav3.1 and 3.2 calcium channels) were investigated in 80 histopatho-logically and dermoscopically classified acquired naevi. Regarding BRAF/V600E, dysplastic naevi showed lower immunostaining than common naevi, which was significant in comparison with intradermal naevi, which showed the highest BRAF/V600E histoscore. Junctional naevi showed the lowest BRAF/V600E levels. Globular/cobblestone and reticular dermoscopic patterns were consistently associated with high and low BRAF/V600E immunoexpression, respectively, but Zalaudek's peripheral globule pattern (CR/PG) showed the highest BRAF/V600E immunoexpression. Among global patterns, the previously not investigated multicomponent pattern showed the lowest BRAF/V600E immunoexpression. Regarding the remaining biomarkers, new immunohistochemical features were found, in particular p16 and PTEN low expression in multicomponent pattern; and Ki67, hTERT and Cav.3.1 high expression in CR/PG. In conclusion, histopathology and dermoscopy provide complementary information regarding the biology of melanocytic naevi.
Assuntos
Canais de Cálcio Tipo T , Nevo Pigmentado , Neoplasias Cutâneas , Biomarcadores , Dermoscopia , Humanos , PTEN Fosfo-Hidrolase , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
Melanoma is a malignant neoplasia that is highly resistant to chemotherapy and radiotherapy and is associated with poor prognosis in advanced stage. Targeting melanoma that harbors the common BRAFV600E mutation with kinase inhibitors, such as vemurafenib, reduces tumor burden, but these tumors frequently acquire resistance to these drugs. We previously proposed that T-type calcium channel (TTCC) expression may serve as a biomarker for melanoma progression and prognosis, and we showed that TTCC blockers reduce migration and invasion rates because of autophagy blockade only in BRAFV600E-mutant melanoma cells. Here, we demonstrated that high expression of the TTCC Cav3.1 isoform is related to autophagic status in vemurafenib-resistant BRAFV600E-mutant melanoma cells and human biopsies, and in silico analysis revealed an enrichment of Cav3.1 expression in post-treatment melanomas. We also demonstrated that the TTCC blocker mibefradil induces apoptosis and impairs migration and invasion via inhibition of autophagy in resistant melanoma cells and mouse xenograft models. Moreover, we identified an association between PTEN status and Cav3.1 expression in these cells as a marker of sensitivity to combination therapy in resistant cells. Together, our results suggest that TTCC blockers offer a potential targeted therapy in resistant BRAFV600E-mutant melanoma and a therapeutic strategy to reduce progression toward BRAF inhibitor resistance.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/metabolismo , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Melanoma/genética , Melanoma/patologia , Camundongos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Vemurafenib/farmacologia , Vemurafenib/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The incidence of lentigo maligna (LM), in situ (LM) or invasive (lentigo maligna melanoma, LMM), has increased during the last decades. Due to functional or cosmetic outcomes, optimal treatment with surgical excision may not be appropriate in some cases. We tried less invasive therapy, immunocryosurgery, as a single treatment for LM or combined with surgery for LMM, with better aesthetic results. Three patients with LM or LMM not amenable to complete surgical excision were selected. LMM patients underwent limited surgical resection of the invasive area. Subsequently, a combined treatment with topical imiquimod and cryosurgery was performed. The LM patient received immunocryosurgery directly. All of them were free of local and systemic disease at 48, 42 and 41 months after discontinuation of therapy. We consider that immunocryosurgery is an alternative option for LM or even for LMM (after removal of the invasive tissue with narrow margins) in poor surgical candidates, with good therapeutic, functional and cosmetic results.
Assuntos
Criocirurgia/métodos , Sarda Melanótica de Hutchinson/terapia , Imunoterapia/métodos , Melanoma/terapia , Neoplasias Cutâneas/terapia , Adjuvantes Imunológicos/uso terapêutico , Administração Cutânea , Idoso , Idoso de 80 Anos ou mais , Aminoquinolinas/uso terapêutico , Biópsia , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Criocirurgia/efeitos adversos , Procedimentos Cirúrgicos Dermatológicos/efeitos adversos , Procedimentos Cirúrgicos Dermatológicos/métodos , Feminino , Humanos , Sarda Melanótica de Hutchinson/patologia , Imiquimode , Imunoterapia/efeitos adversos , Melanoma/patologia , Pele/patologia , Creme para a Pele/uso terapêutico , Neoplasias Cutâneas/patologiaRESUMO
The worldwide incidence of malignant melanoma is increasing. The number of pigmented naevi and amount of solar exposure are important risk factors. The aim of this study was to characterize a paediatric population (from Lleida, Catalonia, Spain) in terms of phenotype, sun behaviour and naevi prevalence. Data on the numbers and distributions of acquired naevi in 369 children, aged 4, 8 and 14 years, were collected and correlated with age, sex, skin phototype and environmental factors (annual/lifetime intermittent and chronic sun exposure, sunburns and sunscreen use). The density of naevi increased with age. Boys had more naevi on the trunk and girls had more naevi on the legs. Children with light skin phototype had more naevi. A higher level of accumulated sun exposure correlated with a higher number of naevi in children with non-adequate sunscreen use. In conclusion, several risk factors associated with naevi density and distribution were found, as previously reported by others. Multivariate analysis confirmed a protective role of sunscreen in the development of acquired melanocytic naevi.
Assuntos
Neoplasias Induzidas por Radiação/epidemiologia , Neoplasias Induzidas por Radiação/prevenção & controle , Nevo Pigmentado/epidemiologia , Nevo Pigmentado/prevenção & controle , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/prevenção & controle , Luz Solar/efeitos adversos , Protetores Solares/uso terapêutico , Adolescente , Fatores Etários , Distribuição de Qui-Quadrado , Criança , Estudos Transversais , Relação Dose-Resposta à Radiação , Feminino , Humanos , Masculino , Análise Multivariada , Neoplasias Induzidas por Radiação/diagnóstico , Nevo Pigmentado/diagnóstico , Razão de Chances , Prevalência , Fatores de Proteção , Fatores de Risco , Fatores Sexuais , Neoplasias Cutâneas/diagnóstico , Pigmentação da Pele , Espanha/epidemiologia , Fatores de TempoRESUMO
Primary acute cutaneous infections caused by Serratia marcescens are extremely unusual. Nevertheless, Serratia infections are especially frequent in chronic granulomatous disease, which is a primary immunodeficiency that affects phagocytic cells of the innate immune system. We report a young man without history of infections, who developed multiple dermal abscesses on a leg with chronic lymphoedema attributed to S marcescens. Laboratory investigations showed a delayed partial neutrophilic oxidative function. It is remarkable that the patient did not have any other infections during childhood, when most of the innate immune deficiencies are diagnosed, and he had no history of granulomatous lesions. We hypothesize that the delayed neutrophilic oxidative function could be explained by a partial neutrophilic oxidative function, which could be enough to maintain the patient asymptomatic until this infection.