Painful nipple hyperkeratosis secondary to vemurafenib

Vemurafenib is a selected BRAF kinase inhibitor approved for treating metastatic or unresectable melanoma, which has numerous cutaneous side effects unfortunately, including three previously reported cases of asymptomatic areola and/or nipple hyperkeratosis. We present the first case of painful bilateral nipple hyperkeratosis secondary to vemurafenib in an 84‐year‐old woman. She was successfully treated with tretinoin 0.05% cream that allowed her to comfortably continue treatment. With increased awareness of this condition, we found a second case of asymptomatic nipple hyperkeratosis secondary to vemurafenib in our clinic. As this medication gains acceptance for treatment of metastatic melanoma, it is imperative that dermatologists are aware of this potentially uncomfortable side effect that can result in decreased compliance and impaired quality of life.     

A case of vemurafenib-induced keratosis pilaris-like eruption

Vemurafenib, a selective BRAF kinase inhibitor, is a new anti-cancer drug recently proven to improve survival in patients with metastatic melanoma harboring the BRAF V600E mutation. BRAF is one of three RAF kinases (ARAF, BRAF, CRAF) involved in the MAP kinase pathway. Mutations in BRAF are reported to be present in 40 to 70 percent of melanomas and in lower frequencies in various other malignancies. The BRAF V600E mutation is a specific valine to glutamic acid single substitution that constitutes 80 to 90 percent of reported BRAF mutations. Successful treatment of metastatic melanoma with vemurafenib is not without significant adverse effects. The most common toxic effects of this drug include rash, arthralgia, and fatigue. Less commonly, cases of follicular cystic lesions, keratoacanthoma, and squamous cell carcinoma have also been described. We report a case of a patient with metastatic melanoma treated with vemurafenib, who developed diffuse follicular hyperkeratosis resembling keratosis pilaris. To our knowledge, this is the first reported case of a keratosis pilaris-like side effect of vemurafenib.     

Vemurafenib‐Induced Neutrophilic Panniculitis in a Child with a Brainstem Glioma

Neutrophilic panniculitis is a rare adverse effect of therapy with selective BRAF inhibitors. We report a case of neutrophilic panniculitis in a 15‐year‐old girl receiving treatment with vemurafenib for a brainstem glioma. Clinicians should be aware of this rare but important side effect of vemurafenib. This is the first report of neutrophilic panniculitis in a child treated with vemurafenib.     

Nevoid hyperkeratosis of the nipple and areola: a distinct entity

Although nevoid hyperkeratosis of the nipple and areola was initially described in 1923, there are only case reports or reviews about it; no large series have been documented to date. The clinical features of the reported cases in the literature are not uniform, and it is questioned whether nevoid hyperkeratosis of the nipple and areola is a distinct clinicopathologic entity or a clinical presentation of various dermatoses. We describe 7 cases with hyperkeratotic nevoid lesions localized on the nipple and areola with different clinical features. None of them had any other associated dermatologic or systemic disease. Histopathologic examination was performed in 6 patients. Four of them had common histopathologic features suggesting a distinct entity, namely, nevoid hyperkeratosis of the nipple and areola; 2 of them had histopathologic features consistent with seborrheic keratosis. Seborrheic keratosis presents as sharply demarcated papules or plaques, whereas nevoid hyperkeratosis of the nipple or areola presents as a plaque diffusely involving the nipple or the areola.     

Bilateral areolar leiomyomas in a patient undergoing BRAF inhibition therapy for melanoma

BRAF inhibition therapy, used to treat melanomas with BRAF mutations, is associated with both neoplastic and non‐neoplastic cutaneous side effects including squamous cell carcinomas, warty dyskeratomas, verrucous keratoses, photosensitivity and widespread eruptions that present histopathologically as acantholytic dyskeratosis. We report a case of a patient undergoing BRAF inhibition therapy for disseminated melanoma with a V600E mutation who developed bilateral areolar leiomyomas, one of which was biopsied and the other of which resolved after discontinuation of vemurafenib therapy. To our knowledge, this is the first reported case of a mesenchymal neoplasm developing in association with BRAF inhibition therapy.     

Dabrafenib-induced neutrophilic panniculitis in a child undergoing dual BRAF-MEK inhibitor therapy for glioblastoma multiforme

BRAF inhibitor-induced neutrophilic panniculitis is a rare event that is well-characterized in adults undergoing therapy for metastatic melanoma. To date, there are very few reports of this event in children undergoing BRAF inhibitor therapy for low-grade gliomas, all of which were seen with vemurafenib. We report a case of dabrafenib-induced neutrophilic panniculitis in a 9-year-old girl that manifested within several weeks of initiating dual BRAF-MEK inhibitor therapy for glioblastoma multiforme. This case highlights neutrophilic panniculitis as a side effect of dabrafenib in children and serves as a reminder to consider cutaneous side effects of BRAF inhibitors as they are increasingly used to treat children with primary brain tumors.     

Nevoid hyperkeratosis of the nipple and areola: treatment of two patients with topical calcipotriol.

Nevoid hyperkeratosis of the nipple and areola, which is characterized by verrucous thickening and pigmentation of the nipple or areola, is a rare condition. Different therapeutic options have been used with varying results, but there is no uniformly effective treatment. We describe two patients with hyperkeratosis of the nipple and areola who responded well to topical calcipotriol ointment.     

Hyperkeratosis of the nipple and areola

Hyperkeratosis of the nipple and areola is a rare condition. We report two cases of hyperkeratosis of the nipple and areola occurring in men with no underlying endocrinopathy or synthetic estrogenic drug therapy. Both patients demonstrated prompt resolution of the hyperkeratosis of the nipples with a keratolytic gel. Because our cases were not associated with ichthyosis or epidermal nevus, they best fit into the category of nevoid hyperkeratosis of the nipples.     

Nevoid hyperkeratosis of the areola misinterpreted as mycosis fungoides

Nevoid hyperkeratosis of the nipple and areola is a benign condition with fewer than 70 cases reported in the literature. We report a case of unilateral nevoid hyperkeratosis of the areola with intraepidermal lymphocytes that resembled Pautrier's microabscesses on histological examination. This is the third report of mycosis fungoides-like changes in nevoid hyperkeratosis of the nipple and areola. In addition, this is the first case to present immunohistochemical and T-cell gene rearrangement studies of the intraepidermal lymphocytes. This case highlights a potential histopathological pitfall in the diagnosis of nevoid hyperkeratosis of the nipple and areola.     

Vemurafenib‐induced toxic epidermal necrolysis: possible cross‐reactivity with other sulfonamide compounds

Vemurafenib is a newly licensed target‐directed medication. It has been proven to improve the survival of patients with metastatic melanoma and the BRAF^V600E mutation; however, adverse cutaneous reactions are frequent. Few cases of life‐threatening severe cutaneous adverse reactions (SCARs) induced by vemurafenib have been reported. Dabrafenib, another selective BRAF inhibitor, has been licensed recently as an alternative drug with the same indications. From a molecular point of view, both vemurafenib and dabrafenib contain a sulfonamide group; cross‐reactivity to sulfonamide compounds has been reported in allergic patients. We report on a patient with vemurafenib‐induced toxic epidermal necrolysis (TEN). In vitro analysis of lymphocyte reactivity to vemurafenib showed positive results, confirming drug causality. In addition, lymphocytes from the patient reacted to dabrafenib and to the antibiotic sulfonamide drug sulfamethoxazole. Moreover, lymphocytes from two patients with cutaneous adverse reactions to sulfamethoxazole also reacted to vemurafenib and dabrafenib in vitro. These data strongly suggest that there might be clinical cross‐reactivity between BRAF inhibitors and sulfonamides in some patients. Thus, precautions should be taken to avoid sulfonamide drugs as much as possible in patients showing serious hypersensitivity reactions to vemurafenib and vice versa.     

Vemurafenib: an unusual UVA‐induced photosensitivity

Vemurafenib is a new‐targeted therapy approved for the treatment of patients with V600E BRAF‐mutant metastatic melanoma. Among the cutaneous adverse events reported, the photosensitivity is frequently experienced. We aimed to characterize more deeply the mechanism leading to this photosensitivity as well as the corresponding UV spectrum. Phototests showed that the phototoxicity was UVA‐dependent since from normal value prior to vemurafenib treatment, the UVA‐minimal erythema dose decreased in 17 of 18 patients (94.4%) while the minimal erythema dose remained unchanged. Furthermore, a vemurafenib‐induced erythema appeared quickly during the UVA exposure contrarily to what is observed with a conventional drug‐induced phototoxicity showing an erythema 12–24 h after the phototesting. Vitamin PP concentration decreased, and porphyrin level significantly increased after 2 months of vemurafenib. Our study confirms the high risk of vemurafenib‐induced photosensitivity and indicates that it is possibly vitamin PP‐ and porphyrin dependent.     

Vemurafenib‐induced interface dermatitis manifesting as radiation‐recall and a keratosis pilaris‐like eruption

Vemurafenib is a specific inhibitor of the V600E mutated BRAF protein kinase used for the treatment of unresectable or metastatic melanoma harboring this mutation. Multiple predictable side effects have been described with use of this targeted therapy, and implicate BRAF and mitogen activated protein kinase (MAPK) signaling pathways in their pathogenesis. Herein, we report the novel finding of an interface dermatitis in radiation recall and a keratosis pilaris‐like clinical reaction in a patient treated with vemurafenib.     

Cutaneous adverse events associated with vemurafenib in patients with metastatic melanoma: practical advice on diagnosis,prevention and management of the main treatment‐related skin toxicities

Until recently, no effective treatment was available for patients with metastatic malignant melanoma, and median overall survival was little more than 6 months with the current standard of care, dacarbazine. In 2012, the first specific BRAF mutation inhibitor, vemurafenib, was licensed for the monotherapy of adults with BRAF V600 mutation‐positive unresectable or metastatic melanoma. Like other targeted therapies, vemurafenib is associated with a predictable pattern of adverse events, including skin toxicities. We review the most common cutaneous adverse events associated with vemurafenib, based on data from clinical trials, and our own experiences of treating patients in trials and clinical practice. Overall, these toxicities are not preventable, but they rarely necessitate permanent treatment discontinuation and are generally manageable with dose modification and supportive care. We provide a treatment algorithm offering guidance on the most appropriate approach to managing the main skin toxicities to help clinicians unfamiliar with this novel agent to become confident in using vemurafenib effectively in the management of patients with metastatic melanoma.     

Nevoid hyperkeratosis of the nipple and/or areola: a report of two cases and a review of the literature

Nevoid hyperkeratosis of the nipple and/or areola is a rare and idiopathic disorder with fewer than 50 cases reported in the literature. We report two cases, discuss the clinical and histological findings, and review the literature pertaining to its pathogenesis and therapy. It is hoped that, through this report, nevoid hyperkeratosis of the nipple and/or areola becomes a more recognizable and reported entity, thereby stimulating future studies regarding its pathogenesis and therapy.     

Acute kidney injury in patients with severe rash on vemurafenib treatment for metastatic melanomas

Vemurafenib, a selective BRAF (v‐raf murine sarcoma viral oncogene homologue B1) kinase inhibitor, is a new targeted biotherapy that improves survival in patients with metastatic melanomas harbouring the BRAF V600E mutation. However, this drug has significant dermatological adverse effects. We report a new severe cutaneous reaction to this drug associated with acute kidney injury (AKI). Four patients presented a generalized grade 3 (Common Terminology Criteria for Adverse Events) erythematous eruption with hyperkeratosis pilaris, 5–14 days after the introduction of vemurafenib. These symptoms were associated with AKI in all cases and transitory hypereosinophilia in two cases. Vemurafenib treatment was stopped in three patients and the dose was reduced in the fourth, leading to a gradual improvement of skin symptoms and renal function. Positron‐emission tomography scans showed a complete response in three cases and a major response in one case. Vemurafenib was reintroduced at a lower dose, without a relapse of the rash, but renal function again deteriorated. Thus, we report a cluster of four cases of AKI associated with similar, severe, grade 3 cutaneous drug reactions related to vemurafenib.     

Unilateral nevoid hyperkeratosis of the nipple: a report of two cases

Nevoid hyperkeratosis of the nipple and areola is an unusual condition. Two female patients aged 31 and 18 years presented with chronic unilateral warty lesions of the nipple. One patient had difficulty in breastfeeding from the affected side. A skin biopsy showed acanthosis, hyperkeratosis, papillomatosis and lymphocytic infiltrate in the dermis. There was no significant improvement with topical tretinoin cream in both the patients.     

Nevoid hyperkeratosis of the areola with histopathological features mimicking mycosis fungoides.

Hyperkeratosis of the areola is a rare benign condition of unknown etiology characterized by slowly growing verrucous thickening and brown pigmentation of the areola or/and the nipple. It may be presented as isolated nevoid form or associated with other skin diseases. We described a 21-year-old woman with characteristic lesions of nevoid hyperkeratosis in both areolas but with histopathological findings resembling mycosis fungoides. Cutaneous lesions have remained unchanged after two years of follow-up.     

双侧巨大型乳头乳晕角化过度症

报告1例双侧巨大型乳头乳晕角化过度症。患者女，24岁。乳晕褐色斑10年，加重半年。患者自幼左侧乳头看不见。体格检查：双侧乳晕粗糙、增厚，呈乳头瘤样增生，右侧尤为明显。组织病理检查示表皮乳头瘤样增生，皮突延长并融合。诊断：乳头乳晕角化过度症。     

Case of vemurafenib‐induced Sweet's syndrome

Vemurafenib is a targeted therapy that has become standard treatment for patients with advanced melanoma with a V600E BRAF mutation. It has been associated with frequent skin toxicity, including photosensitivity, rash and squamous cell carcinomas. We present an 83‐year‐old woman with an advanced V600E BRAF‐mutant melanoma who developed a severe skin rash and fatigue after taking vemurafenib. The dose was reduced from 960 to 720 to 480 mg twice a day; however, she was subsequently admitted to the hospital with fever, chills, fatigue, confusion and a diffuse skin eruption. She then developed hypoxia and acute renal failure that required hemodialysis. A biopsy of her skin lesions revealed a neutrophilic dermatitis with papillary dermal edema, consistent with Sweet's syndrome. Her symptoms resolved upon discontinuation of vemurafenib and treatment with prednisone. This constellation of symptoms and clinical course are consistent with drug‐induced Sweet's syndrome caused by vemurafenib.