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Introduction

Epidermal growth factor receptor (EGFR) is a member of the of the EGFR family proteins, which consists of at least four receptor tyrosine kinases: EGFR, human epidermal growth factor receptor (HER)2, HER3 and HER4.

The EGFR family regulates the tyrosine kinase signaling pathway, which is responsible for cell cycle progression, division and differentiation. EGFR has been found to be overexpressed in certain types of solid tumors, such as colon, pancreas, lung and breast tumors, and leads to the dysregulation of cell growth (1).

Therapeutic agents with two main anti-EGFR mechanisms are used in clinical practice: Low molecular-weight tyrosine kinase inhibitors that compete with adenosine triphosphate (ATP) for binding with the tyrosine kinase portion of a mutant EGFR receptor, and monoclonal antibodies directed against the ligand-binding extracellular domain (1).

Agents targeting EGFR comprise some of the most extensively used drugs in the treatment of several common solid tumors (2). Gefitinib is an orally selective tyrosine kinase inhibitor of EGFR. Gefitinib and erlotinib were the first EGFR tyrosine kinase inhibitors to be approved by the US Food and Drug Administration for the treatment of advanced non-small cell lung carcinoma (NSCLC) (3).

Although these agents do not exhibit many of the classic side effects of cytotoxic chemotherapy, they are associated with unpleasant cutaneous toxicities, which can affect treatment compliance, as well as the quality of life of the patient (2,4). Papulopustular acne-like eruption is the most common cutaneous adverse event (5) with an incidence rate of 55% (1). Xerosis, pruritus, desquamation, eczematous eruptions, teleangectasia, hyperpigmentation, trichomegalia, alopecia and nail alterations have also been reported (6–8). The present case report describes an atypical skin reaction in a patient treated with gefitinib.

Case report

The present study reports the case of a 73-year old woman suffering from advanced NSCLC, who developed a squamous, crusted eruption on her face after 4 weeks of treatment with gefitinib. The patient had been initially diagnosed with advanced lung adenocarcinoma in March 2013 and treated with gefinib at the Unit of Medical Oncology of the Veneto Institute of Oncology (Padua, Italy). The patient had never smoked and her initial symptoms were a persistent dry cough and a dull low back pain, which was unresponsive to corticosteroid therapy. A computed tomography (CT) scan revealed the presence of a mass in the left inferior lobe of the lung (average diameter, 5 cm), which was found by histopathological examination to be a primary adenocarcinoma of the lung. Further examinations with positron emission tomography/CT revealed metastases in locoregional lymph nodes, bones and pleura. Magnetic resonance imaging (MRI) of the lumbar spine demonstrated secondary neoplastic lesions in multiple locations: D12, L2, L4, S1, S2 and the sacral right wing. The brain CT scan was negative. According to the TNM classification and staging system (9), lung adenocarcinoma stage IV was diagnosed and the EGFR mutation status (in-frame deletion of E746–750 in exon 19) was determined. The presence of an EGFR mutation-positive neoplasm was thus identified, and oral treatment with gefitinib was initiated at a dose of 250 mg once daily. After 4 weeks of treatment with gefitinib, the patient visited the Dermatology Unit (Department of Medicine, University of Padua, Padua, Italy) in May 2013, presenting with a squamous-crusted eruption on her face (Fig. 1). The patient exhibited yellowish exophytic squamous-crusted lesions with sharp edges and an erythematous base. She had not previously applied topical products to the lesions, reported sun exposure or contact with aeroallergens, taken any other medications, or complained of fever, nausea, diarrhoea, abdominal pain or fatigue. The patient reported a weight loss of 3 kg during the last month prior to her visit to the hospital.

Figure 1. (A) Squamous-crusted eruption on the face of a 73-year old woman, who was undergoing oral treatment with gefitinib at an dose of 250 mg once daily. (B) A yellowish exophytic squamous-crusted lesion with sharp edges and an erythematous base on the forehead of the patient.

Dermatoscopic examination did not reveal abnormalities in the lesions, thus excluding the diagnosis of squamous cell carcinoma or seborrheic keratosis. The cutaneous swab was positive for Staphylococcus aureus. Complete blood count and liver and kidney function tests were normal, serum carcinoembryonic antigen was elevated (1,300 ng/ml) and an enzyme-linked immunosorbent assay for autoantibodies against desmogleins 1 and 3 was negative.

Treatment with gefitinib was discontinued and a systemic and topical antibiotic therapy was administered instead. The patient was treated with 100 mg minocyclin (2 tablets/day) orally, and with rifamycin topically (twice a day for 1 month).

Two weeks later, the patient returned to the Unit exhibiting an almost complete resolution of the lesions (Fig. 2), and therefore gefitinib treatment (250 mg once daily) was resumed. Despite the gefitinib treatment, the disease progressed, leading to the mortality of the patient 2 months after resuming the treatment. Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.

Figure 2. Almost complete resolution of the lesions on the face of the patient after 2 weeks of oral treatment with 100 mg minocyclin (2 tablets/day) and topical treatment with rifamycin.

Discussion

EGFR inhibitors are widely used in monotherapy, or in combination with chemotherapy and/or radiotherapy, for the treatment of advanced solid cancers, such as NSCLC, squamous cell carcinoma of the head and neck, and colorectal and pancreatic cancer (10).

Among EGFR inhibitors, gefitinib is generally preferred because of its greater tolerability (2), despite the adverse events that are commonly reported, such as diarrhea, fatigue, nausea, elevated transaminase and skin rash (11). The most common adverse effects associated with EGFR inhibitors involve the skin. Several skin complications have been described, with the most frequent being an inflammatory papulopustular rash occurring within the first 2–4 weeks of treatment (12). The papulopustular eruption is usually distributed in the seborrheic areas and the primary lesions are follicular papules and pustules. Comedones are rarely observed (13). Histopathologically, a T-cell infiltrate around the follicular infundibulum is observed, which is associated with a suppurative folliculitis (14). Dry skin is very commonly observed in patients receiving treatment with EGFR inhibitors; vaginal dryness and itching, perineal dryness and blepharitis have been reported (15). The second most frequent systemic adverse effect of EGFR inhibitors is diarrhea, whose development can be associated with skin rash (16). Other cutaneous adverse reactions include paronychia, mucositis and hair changes, such as scalp alopecia, curling of the hair and facial hypertrichosis (17). Nail alterations are generally observed between weeks 4 and 8 from the initiation of gefitinib (13). The big toe is often affected by paronychia, which can be very painful if pyogenic granuloma of the nail fold develops (17). The combination of the papulopustular eruption, xerosis and nail and hair alterations along with pruritus is specific for this class of agents. The term PRIDE syndrome (papulopustules and/or paronychia, regulatory abnormalities of hair growth, itching, dryness caused by epidermal growth factor inhibitors) has been proposed for EGFR inhibitor-associated cutaneous complications (18,19). Gefitinib-induced skin lesions usually occur on the face, scalp and upper chest and back, but can be observed anywhere (16). The skin rash, particularly when it occurs on the face, can affect the quality of life of the patient, and it may even result in a modification or discontinuation of their treatment. Furthermore, a high prevalence of cutaneous bacterial infections has been reported among patients with dermatological toxic effects following treatment with EGFR inhibitors (20). Other reported skin complications associated with gefitinib treatment are small-vessel vasculitis (21), psoriasis (22) and necrolytic migratory erythema (23).

To the best of our knowledge, the present study reports the first case of a squamous-crusted eruption on the face of a patient undergoing treatment with gefitinib. The epidermal alterations that this patient exhibited could have been the result of the activation of both innate and acquired immunity (16), leading to the production of cytokines acting on keratinocyte proliferation. A role of EGFR in the control of skin inflammation has been proposed on the basis of the observation that mice with an epidermis-restricted dominant negative EGFR mutation display an abundant inflammatory infiltrate in their skin, formed by macrophages, lymphocytes and granulocytes, starting 4–6 days after birth and progressively aggravating with the passage of time (24). Mascia et al (25) demonstrated that pharmacological blockade of EGFR boosted the expression of monocytes, dendritic cells and the T-cell chemoattractants chemokine (C-C motif) ligand (CCL)2 and CCL5, as well as the T-cell-selective chemokine (C-X-C motif) ligand (CXCL)10, while it markedly impaired the expression of granulocyte-macrophage colony-stimulating factor and CXCL8. These molecular events are dependent upon the concentration of the EGFR inhibitor, documenting the existence of an EGFR-driven regulatory mechanism during the keratinocyte response to inflammatory triggers (16). A strong upregulation of CCL2 and CCL5, but also of CCL27 and CXCL14, was found in the lesional skin of patients with cancer, who were undergoing treatment with EGFR inhibitors (26,27). Finally, upregulated transcripts of tumor necrosis factor-α and interleukin-1β, as well as CCL2, CCL5, CCL11 and CCL22, were detected in the skin and circulation of mouse models with EGFR ablation in the epidermis during their first week of life, prior to infiltration by immune cell populations (27,28).

Due to the lack of clarity concerning the etiology of the skin rash, there are no evidence-based recommendations for treating it. Prophylactic treatments with local or systemic antibiotics, such as minocycline, have been recommended (13,29), and it is plausible that the effect of minocycline on gefitinib-induced skin complications is mediated by its anti-inflammatory activities (30).

Further studies are required in order to explain the mechanisms through which EGFR-targeting agents, such as gefitinib, induce cutaneous reactions. Additional studies may facilitate a more natural approach to the treatment of these dermatologic adverse effects and provide more information concerning the physiological role of EGFR in the skin immune system. Informing the patients about the nature of these unpleasant skin side effects may restore their faith in the use of EGFR-targeted cancer treatments and help to ensure compliance.

References