A distinct cutaneous reaction to sorafenib and a multikinase inhibitor

A 52-year-old, white male with metastatic renal cancer presented to our clinic with an exquisitely painful papulopustular eruption of the face, scalp, and neck of 4 week's duration, associated with alopecia of his scalp and eyebrows. He described a new onset “sandpaper-like” aspect to his skin. Concurrently, the patient developed painful bullous lesions of his palm and soles. He was undergoing treatment with sorafenib (600 mg/day) for his malignancy, initiated 2 months prior. Physical examination revealed a follicular papulopustular eruption predominantly of the head and neck (Fig. 1), with fewer lesions localized to the genital area. Many of the larger lesions expressed a malodorous purulent discharge. A diffuse eruption of spiny, filiform, follicular hyperkeratoses covered the patient's scalp (2, 3), trunk, and abdomen. Nonscarring alopecia of the scalp and eyebrows was present, along with hyperkeratosis overlying pressure points of his palms and soles. Follicular papulopustular eruption predominantly of the head and neck Spiny, filiform, follicular hyperkeratoses Spiny, filiform, follicular hyperkeratoses (closer view) Biopsy of a hyperkeratotic papule of his scalp revealed dilated hair follicles (comedone like) with orthokeratotic hyperkeratosis and a mild polymorphous infiltrate including lymphocytes, histiocytes, plasma cells, and a few eosinophils. The specimen also revealed squamous metaplasia of many eccrine ducts. The patient noted an improvement of the inflammatory papules and pustules with oral tetracycline combined with topical erythromycin, metronidazole, benzyl peroxide, and fluocinonide cream. Rapid clearance of the spiny papules was noted shortly following the regular application of a urea-based cream. At this point, treatment with sorafenib was suspended for a planned surgery. Similar lesions reappeared shortly after reinstitution of his treatment. Research in molecular biology has led to the development of specific molecules targeting the epidermal growth factor receptor (EGFR) and several other unrelated signaling pathways. Recently, cutaneous reactions to EGFR inhibitors have been described in the dermatology literature. Common cutaneous adverse reactions to EGFR inhibitors include acneiform eruption, xerosis, and paronychia.1 Sorafenib (BAY 43-9006, Nexavar®, Bayer, Toronto, Ontario, Canada) is one of the new-generation oral small-molecule kinase inhibitor targeting both tumor cells and tumor vasculature, not primarily related to EGFR. It inhibits the kinase activity of both C-Raf and B-Raf, which are encoded by oncogenes. It also targets the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-B and kit).2 Since December 2005, the FDA has approved its use for treatment of metastatic renal cell cancer. The most common dermatological adverse events seen with sorafenib in a phase-3 study were reported as “rash” and “hand-foot skin reactions”.3 An acneiform eruption was also reported with the use of sorafenib in combination with an EGFR inhibitor.4 Less common cutaneous adverse events are subungueal splinter hemorrhages and erythemato-squamous eruptions of the nasofacial area.5 Sorafenib-induced erythema multiforme,6 keratoacanthomas,7 and inflammation of actinic keratosis8 have also been described. Hyperkeratotic spicules of the face, scalp, palms, and soles have been described in the setting of various clinical entities such as monoclonal gammopathy.9 While the hyperkeratotic spicules in our case clinically resemble these lesions, histopathology demonstrated a comedone-like follicular dilatation consistent with an acneiform process. This unique presentation of hyperkeratotic spicules, in addition to the severe papulopustular eruption following the initiation and reinstitution of sorafenib therapy, strongly implicates this drug as the causal agent. To our knowledge, this very distinct sorafenib-induced eruption has not yet been described in the literature.

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