RESUMO
Cutaneous adverse events (cAEs) are reported in 90% of all patients on selective BRAF inhibitors and contribute significantly to patient morbidity. Two weeks after initiating vemurafenib for metastatic melanoma, our patient developed a pruritic eruption with numerous, 1-2 mm pink hyperkeratotic follicular papules over his trunk and upper extremities. A biopsy demonstrated squamous metaplasia of the eccrine ducts with irregular hyperplasia of hair follicles sparing the interfollicular epidermis. Diffuse adnexal metaplasia is a novel and unusual cutaneous response to vemurafenib. The patient was started on acitretin 10 mg daily with improvement of the eruption after 4 weeks. We report an unusual cAE of vemurafenib selectively targeting the adnexal epithelium with relative sparing of the interfollicular epidermis. Interval improvement was noted after 4 weeks of acitretin, which is an effective therapeutic option for patients with cAEs involving squamous hyperplasia secondary to vemurafenib. Our case illustrates the particular sensitivity of the adnexal epithelium for vemurafenib-induced dysfunction in proliferation and differentiation, providing the basis for common cAEs observed on this medication.
Assuntos
Toxidermias/etiologia , Glândulas Écrinas/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Indóis/efeitos adversos , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Sulfonamidas/efeitos adversos , Acitretina/uso terapêutico , Idoso , Biópsia , Proliferação de Células/efeitos dos fármacos , Toxidermias/diagnóstico , Toxidermias/tratamento farmacológico , Glândulas Écrinas/patologia , Células Epiteliais/patologia , Humanos , Ceratolíticos/uso terapêutico , Masculino , Melanoma/secundário , Metaplasia , Neoplasias Cutâneas/patologia , Resultado do Tratamento , VemurafenibRESUMO
BACKGROUND: Vemurafenib has been approved for the treatment of patients with advanced BRAF(V600E)-mutant melanoma. This report by the Vemurafenib Dermatology Working Group presents the characteristics of dermatologic adverse events (AEs) that occur in vemurafenib-treated patients, including cutaneous squamous cell carcinoma (cuSCC). METHODS: Dermatologic AEs were assessed from three ongoing trials of BRAF(V600E) mutation-positive advanced melanoma. Histologic central review and genetic characterization were completed for a subset of cuSCC lesions. RESULTS: A total of 520 patients received vemurafenib. The most commonly reported AEs were dermatologic AEs, occurring in 92%-95% of patients. Rash was the most common AE (64%-75% of patients), and the most common types were rash not otherwise specified, erythema, maculopapular rash, and folliculitis. Rash development did not appear to correlate with tumor response. Photosensitivity occurred in 35%-63% of patients, and palmar-plantar erythrodysesthesia (PPE) occurred in 8%-10% of patients. The severity of rash, photosensitivity, and PPE were mainly grade 1 or 2. In all, 19%-26% of patients developed cuSCC, mostly keratoacanthomas (KAs). The majority of patients with cuSCC continued therapy without dose reduction after resection. Genetic analysis of 29 cuSCC/KA samples demonstrated HRAS mutations in 41%. CONCLUSIONS: Dermatologic AEs associated with vemurafenib treatment in patients with melanoma were generally manageable with supportive care measures. Dose interruptions and/or reductions were required in <10% of patients.
Assuntos
Indóis/efeitos adversos , Indóis/uso terapêutico , Melanoma/tratamento farmacológico , Segunda Neoplasia Primária/induzido quimicamente , Dermatopatias/induzido quimicamente , Neoplasias Cutâneas/tratamento farmacológico , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Segunda Neoplasia Primária/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Vemurafenib , Adulto JovemRESUMO
BACKGROUND: Cutaneous squamous-cell carcinomas and keratoacanthomas are common findings in patients treated with BRAF inhibitors. METHODS: We performed a molecular analysis to identify oncogenic mutations (HRAS, KRAS, NRAS, CDKN2A, and TP53) in the lesions from patients treated with the BRAF inhibitor vemurafenib. An analysis of an independent validation set and functional studies with BRAF inhibitors in the presence of the prevalent RAS mutation was also performed. RESULTS: Among 21 tumor samples, 13 had RAS mutations (12 in HRAS). In a validation set of 14 samples, 8 had RAS mutations (4 in HRAS). Thus, 60% (21 of 35) of the specimens harbored RAS mutations, the most prevalent being HRAS Q61L. Increased proliferation of HRAS Q61L-mutant cell lines exposed to vemurafenib was associated with mitogen-activated protein kinase (MAPK)-pathway signaling and activation of ERK-mediated transcription. In a mouse model of HRAS Q61L-mediated skin carcinogenesis, the vemurafenib analogue PLX4720 was not an initiator or a promoter of carcinogenesis but accelerated growth of the lesions harboring HRAS mutations, and this growth was blocked by concomitant treatment with a MEK inhibitor. CONCLUSIONS: Mutations in RAS, particularly HRAS, are frequent in cutaneous squamous-cell carcinomas and keratoacanthomas that develop in patients treated with vemurafenib. The molecular mechanism is consistent with the paradoxical activation of MAPK signaling and leads to accelerated growth of these lesions. (Funded by Hoffmann-La Roche and others; ClinicalTrials.gov numbers, NCT00405587, NCT00949702, NCT01001299, and NCT01006980.).
Assuntos
Carcinoma de Células Escamosas/genética , Genes ras , Indóis/uso terapêutico , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Neoplasias Cutâneas/genética , Sulfonamidas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma de Células Escamosas/tratamento farmacológico , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Indóis/administração & dosagem , Masculino , Camundongos , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Sulfonamidas/administração & dosagem , VemurafenibRESUMO
Exophytic neoplasms arise rarely in neurotrophic ulcers of leprosy. When such a lesion does develop, it has clinical resemblance to an indolent and locally invasive epithelioma cuniculatum, may invade deeply, and may metastasize. The case described showed deep invasion and extensive involvement of bone. Exophytic neoplasms in neurotrophic ulcers of leprosy should be considered to be squamous-cell carcinomas, not epitheliomata cuniculata, because of their potential for rapid, deep invasion and metastases.