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Regression of B‐RAF inhibitor associated keratoacanthomas by acitretin – how do retinoids act on the RAF/MEK/ERK‐signaling pathway?

Vemurafenib belongs to the class I RAF(rat fibrosarcoma)-selective inhibitors, and is available for the treatment of metastatic B-RAF-V600E-positive malignant melanoma. Frequently observed cutaneous side effects include follicular hyperkeratosis, UVA-induced phototoxic reactions, alopecia, itching and plantar hyperkeratosis [1]. Up to 31 % of patients treated with Vemurafenib develop keratoacanthoma (KA) and other squamous-cell carcinomas (SCC) [1]. Excision with histologic examination constitutes the first-line therapy, however, in cases of multiple KA or anatomically complex locations, alternative therapeutic options are needed. We herein describe the regression of a B-RAF inhibitor associated keratoacanthoma located at the upper eye lid under systemic therapy with acitretin. A 31-year old female patient with metastatic occult malignant melanoma (left-sided cervical and hilar lymph node metastasis, multiple pulmonary metastases stage IV (AJCC 2009), B-RAF-positive/c-KIT-negative following palliative surgical left cervical tumor debulking) developed, at 47d after initiation of chemotherapy with Vemurafenib (960 mg b.i.d./p.o.), a growing cutaneous tumor on the left upper eye Clinical Letter lid. Clinically, a compact erythematous tumor, 5 mm × 7 mm in size, with a centrally located hemorrhagic incrustation, was found on the left upper eye lid (Figure 1). Due to its rapid growth and clinical morphology, the tumor was classified as KA. The patient refused surgical excision. Two month after treatment with Vemurafenib had been initiated (day 57), Acitrecin 25 mg b.i.d./p.o. was started after a pregnancy had been excluded, and with the patient on contraception. After 26 days of treatment with Acitretin, the KA, which had intermittently atrophied, detached from the left upper eyelid (Figures 2, 3). Treatment with retinoids was continued for another nine days and discontinued after that. Staging after 5-month therapy with Vemurafenib showed a partial remission according to the current RECIST (Response Evaluation Criteria in Solid Tumors, version 1.1) criteria. Retinoids (Acitretin, Isotretinoin, Bexaroten, Alitretinoin) are synthetic derivatives of all-trans retinoic acid commonly used to treat keratosis or inflammatory dermatoses. Due to their antineoplastic effects, retinoids are used in immunosuppressed patients for the prevention of nonmelanocytic skin cancer [2]. More than 30 years ago, the first reports of a successful retinoid therapy of solitary KA were published [3, 4]. In the meantime a number of research groups including ours have shown that synthetic retinoids may be used to effectively treat RAF inhibitor-associated KA [5]. The exact mechanism of action remains to be elucidated. The genetic profile of RAF inhibitor-associated KA and SCC seems to differ from that found in sporadic forms, especially with regard to activating HRAS (Harvey rat sarcoma) mutations [6–8]. HRAS mutations have been assigned a prominent role in tumorigenesis [6]. Oberholzer et al. assumed that RAF inhibitors