Introduction

Sorafenib is an oral multikinase inhibitor that is currently approved for the treatment of hepatocellular carcinoma, renal cell carcinoma, and thyroid cancer. In addition to frequently occurring alopecia and hand–foot skin reactions, other common adverse skin effects related to sorafenib include desquamative ‘rash’ and erythematous eruption, seborrheic dermatitis-like facial erythema, stomatitis, subungual splinter hemorrhages, and xerosis [1–4]. A unique cutaneous reaction after initiating treatment with sorafenib—a facial acneiform eruption—is described in a man with hepatocellular carcinoma and the characteristics of other patients with this rare sorafenib-induced cutaneous adverse event are reviewed to present the clinical features of these individuals.

Case Report

A 79-year-old Asian man presented for evaluation of facial acneiform lesions of 2½ months duration. He also had experienced scalp and eyebrow hair loss, an itchy facial rash, peeling of his fingertips and painful lesions on feet, and dry skin. His medical history was significant for hepatitis B (genotype B) and he had been receiving entecavir 0.5 mg daily for the past 9 months, since December 2013; his most recent polymerase chain reaction quantitative hepatitis B viral load in August 2014 was <20 (undetectable). He had no exposure to aromatic hydrocarbons.

Four months earlier, in May 2014, his alpha fetoprotein level was elevated (20.8 ng/mL, normal <15 ng/ml). A magnetic resonance imaging exam of his abdomen revealed several hepatic lesions consistent with hepatocellular carcinoma. On June 26, 2014 he was started on sorafenib 400 mg twice daily. Within 6 weeks after initiating treatment with sorafenib, his alpha fetoprotein had decreased to 15 ng/ml.

Within 9 days after starting sorafenib, he noted new lesions on his face and behind his ears. Subsequently, he developed a red facial rash and began to lose hair on his scalp and eyebrows. Shortly thereafter, within a month after initiating treatment, he developed generalized xerosis with hand and foot lesions.

Cutaneous examination of his face showed a chloracne-like eruption consisting predominantly closed comedones not only on his malar cheeks, but also on his ears, preauricular area and postauricular skin. In addition, there were several non-inflammatory small cystic lesions and occasional open comedones. There were no inflammatory papules (Fig. 1).

Fig. 1
figure 1

Distant (a) and closer (b) views of left side of the face of a 79-year-old Asian man show numerous closed comedones and non-inflammatory small cystic lesions on the malar cheeks, the preauricular area and the ears; occasional open comedones are also noted, but are not inflammatory papules. A closer view of the left postauricular area (c) also shows several closed comedones. The lesions appeared 9 days after he started sorafenib (400 mg twice daily) for the treatment of his hepatocellular carcinoma. The morphology and distribution of the facial acneiform lesions mimic those of chloracne

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The forehead, glabella region, and paranasal malar area also showed a pruritic seborrheic dermatitis-like eruption consisting of erythema with superficial scaling on the supraorbital ridges. There was loss of the eyebrows and partial alopecia of the scalp. There was also inflammation of the seborrheic keratoses on his chest and back and xerosis was diffusely present.

Hand–foot skin reaction was also present. Asymptomatic peeling of the distal fingertips was observed. Also, painful hyperkeratotic plaques were present on the plantar pressure areas of both feet.

Topical therapy for the acneiform eruption included topical clindamycin 1% solution twice daily, followed by tretinoin 0.025% cream in the evenings. Desonide 0.05% cream twice daily was initiated for the seborrheic dermatitis-like eruption. Betamethasone dipropionate 0.05% cream (under plastic occlusion in the evening) was applied to the hands and feet twice daily. A moisturizing cream was applied to the body once daily.

The patient returned after 1 month; 10 days earlier his family had decided to discontinue the sorafenib because he was tolerating it poorly. His seborrheic dermatitis-like eruption and facial pruritus had completely cleared and his hand–foot skin reaction was nearly resolved. The chloracne-like facial eruption had partially improved; however, since multiple closed comedones still persisted, his topical therapy with clindamycin solution and tretinoin cream was continued. His oncologist is restaging him and considering other therapeutic options or possibly restarting sorafenib at a lower dose.

Discussion

Sorafenib targets tumor cell angiogenesis and proliferation by inhibiting multiple kinases including c-Kit protein, FMS-like tyrosine kinase 3, platelet-derived growth factor beta, Raf kinase, RET receptor tyrosine kinase, and vascular endothelial growth factor receptors 2 and 3 [2, 5]. The hair, nails, and skin of patients treated with sorafenib are potentially also affected by the drug (Table 1) [2–4, 6–53]. In contrast to a significant percentage—ranging from a reported 24–91%—of patients receiving epidermal growth factor receptor inhibitors (such as cetuximab, erlotinib, and gefitinib) who develop a diffuse papulopustular acneiform eruption, sorafenib-associated acneiform facial eruption has seldom been observed [37–39].

Table 1 Cutaneous adverse events associated with sorafenib
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PubMed was used to search the following terms, separately and in combination: acne, acneiform eruption, chloracne, cutaneous adverse events, hepatocellular carcinoma, renal cell carcinoma, skin side effects, and sorafenib. Inclusion criteria for selecting papers to be reviewed included case reports and studies that described cutaneous and mucosal adverse side effects associated with sorafenib. All papers fulfilling inclusion criteria were reviewed and relevant manuscripts, along with their reference citations, were evaluated.

Several reports discuss acneiform eruptions in patients who have received sorafenib. However, three of the patients had developed epidermal cysts on their face [2, 9, 16]. In addition, a critical review of other studies showed that the observed lesions were either secondary to another drug [42] or may not have actually been acne [40, 41] or were not distinguished from other cutaneous adverse events [43].

To the best of my knowledge, including the patient in this report, a drug-related acneiform facial eruption has only been described in five individuals who were treated with sorafenib (Table 2) [37–39]. The patients include a 42-year-old woman with liver epithelioid hemangioendothelioma and 4 men, ranging from 51 to 79 years of age (median, 58 years old), with either metastatic renal cell carcinoma (3 patients) or hepatocellular carcinoma (1 patient). The dose of sorafenib ranged from 600 mg daily (1 patient) to 800 mg (1 patient for 1 day) twice daily; the other 3 patients were receiving 400 mg twice daily.

Table 2 Characteristics of patients with sorafenib-associated facial acneiform facial eruptions
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Three of the patients had symptoms associated with their acneiform lesions: pain or a burning sensation, pruritus, and an increase in facial oiliness. Three of the patients also had acneiform lesions located on other areas of the body: scalp, neck, axillae and arms, genital area, and the upper back, chest and/or trunk. The facial lesions appeared within 9 days to 8 weeks (median, 4 weeks) after starting treatment with sorafenib; indeed, the patient in this report developed his acneiform eruption within the first 2 weeks after starting sorafenib.

The acneiform lesions appeared as papules and pustules for two of the patients. However, the lesions of the currently reported patient were predominantly monomorphic closed comedones. In addition, similar to two of the other patients whose acneiform eruption consisted of open and closed comedones, his facial lesions also had features in common with those observed in chloracne—particularly the development of lesions behind the ears, the absence of inflammatory papules, and the occurrence of non-inflammatory small cystic lesions [54].

The current patient also had several other drug-related cutaneous reactions: alopecia, hand–foot skin reactions, inflammation of seborrheic keratoses, seborrheic dermatitis-like facial eruption, and generalized xerosis. The 52-year-old man with metastatic renal cell carcinoma sorafenib-related facial acneiform eruption also developed other adverse cutaneous events from the drug including another rarely reported eruption: sandpaper-like skin texture associated with spiny filiform follicular hyperkeratosis [39]. Analogous to patients who have developed papulopustular eruptions after receiving epidermal growth factor receptor inhibitors [55], investigators have suggested that the development of skin eruptions (such as ‘rash’ and hand–foot skin reaction) to sorafenib is associated with successful antitumor activity of the drug [3, 17, 35, 45, 56]. Indeed, similar to other sorafenib-treated patients who developed therapy-associated cutaneous adverse events, the development of drug-induced skin effects in the current patient was associated with a favorable response of his hepatocellular carcinoma to sorafenib: a decrease of his alpha fetoprotein tumor marker.

Four of the patients received topical therapy for their acneiform facial eruption; these included benzoyl peroxide, clindamycin, erythromycin, fluocinonide, isotretinoin, and metronidazole. One patient also received oral tetracycline. Although there was a variable degree of improvement following these interventions, either lowering the sorafenib daily dose or discontinuing the drug was consistently associated with partial or complete resolution of the facial eruption. Indeed, one patient’s lesions cleared when his sorafenib was discontinued for a surgical procedure and subsequently recurred when the drug was restarted.

Conclusion

Sorafenib is an oral multikinase inhibitor associated with the potential development of several cutaneous adverse events in patients treated with the drug. Alopecia and hand–foot reaction were frequently occurring events; indeed, appearance of the latter has been associated with a successful antitumor activity of the drug. In contrast, the development of a facial acneiform eruption was a rarely observed sorafenib-associated side effect that has only been described in five patients—a woman with liver epithelioid hemangioendothelioma, three men with metastatic renal cell carcinoma, and a man with hepatocellular carcinoma. The sorafenib dose ranged from 600 mg daily to 800 mg twice daily; most of the patients were receiving 400 mg twice daily. The eruption typically appeared about 4 weeks after starting sorafenib treatment; however, it was noted as early as 9 days or as late as 2 months after therapy had been initiated. Whereas two of the patients presented with papules and pustules, the other three individuals only had open and closed comedones, the appearance and distribution of which were similar to those observed in persons with chloracne. Topical antibiotics, keratolytics, and retinoids resulted in partial improvement; however, lowering the daily dose or discontinuation of sorafenib promoted progressive improvement or resolution of the facial acneiform eruption.