Diverse cutaneous side effects associated with BRAF inhibitor therapy: a clinicopathologic study

Abstract

Background: Vemurafenib, a novel selective small molecule inhibitor of BRAF, has recently been shown to be effective in the treatment of melanomas harboring the BRAF V600E mutation. Similar to the broad-spectrum RAF inhibitor sorafenib, vemurafenib induces development of squamous cell carcinomas and keratoacanthomas as a side effect of therapy.

Objective: We sought to detail additional cutaneous adverse effects of vemurafenib and a similar BRAF inhibitor, dabrafenib.

Methods: We evaluated the clinical and histologic feature of skin side effects developing on vemurafenib or dabrafenib therapy in 14 patients.

Results: Eight patients developed one or more squamous cell carcinomas, and 11 patients formed benign verrucous keratoses. Eight patients developed single lesions and/or widespread eruptions with histopathologic findings of acantholytic dyskeratosis, consistent with warty dyskeratomas and Darier- or Grover-like rashes, respectively. One patient developed palmoplantar hyperkeratosis, and darkening of existing nevi and new nevi within 2 months of starting vemurafenib. Side effects presented as early as 1 week after beginning therapy, with a mean time of onset of 12.6 weeks in our cohort.

Limitations: This study was limited by the small number of cases, all from a single institution.

Conclusion: Selective BRAF inhibitor therapy is associated with the development of malignant and benign growths, including keratoacanthoma-like squamous cell carcinomas, warty dyskeratomas, and verrucous keratoses, along with widespread eruptions with histologic features of acantholytic dyskeratosis. Given the potential for malignant lesions to develop on treatment, awareness of potential adverse effects of these agents is necessary, and a low threshold for biopsy of new growths is recommended.

Fig 1

Warty dyskeratoma (case 1). A, New keratotic papules on chest. B, Biopsy specimen demonstrating acantholysis and dyskeratosis, consistent with warty dyskeratoma. (Hematoxylin-eosin stain; original magnification: ×200.)

Fig 2

Acantholytic dyskeratosis resembling Darier disease (case 2). A, Eruption of crusted papules on trunk. B, Biopsy specimen demonstrating prominent acantholytic dyskeratosis. (Hematoxylin-eosin stain; original magnification: ×200.)

Fig 3

Squamous cell carcinoma (SCC) (case 3). A, Multiple eruptive nodules on forearm. B, Histopathologic examination reveals well-differentiated SCC with keratoacanthoma-like features. (Hematoxylin-eosin stain; original magnification: ×20.)

Fig 4

Verrucous keratosis (case 4). A, Multiple verrucous papules on face. B, Biopsy specimen of facial papule reveals hyperkeratosis, acanthosis, and papillomatosis in absence of viral changes, all features of verrucous keratosis. (Hematoxylin-eosin stain; original magnification: ×40.)

Fig 5

Eruptive nevi and darkening nevi (case 4). A, New nevi on palm developing on treatment with vemurafenib, and focal palmar hyperkeratosis. B, Nevi on trunk, which darkened after initiation of vemurafenib.