ABSTRACT: This review summarizes the pathophysiology and clinical presentation of the cutaneous toxicities associated with EGFR inhibition. Such effects include papulopustular reactions, xerosis, pruritus, fissures, nail changes, hair changes, telangiectasias, hyperpigmentation, and mucositis. Most management strategies for these toxicities have been based on anecdotal experience; clinical trials are needed to provide uniform characterization to allow for evidence-based treatment strategies.
The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein consisting of an extracellular ligand-binding domain, a transmembrane region, and an intracellular tyrosine kinase domain, which is found on cells of epithelial origin. EGFR, also known as ErbB1 (HER1), is a member of the ErbB receptor tyrosine kinase family, which includes ErbB2 (HER2/neu), ErbB3, (HER3), and ErbB4 (HER4). Binding of specific natural ligands such as epidermal growth factor (EGF) and transforming growth factor–alpha (TGF-alpha) to the extracellular domain of the receptor results in dimerization of the receptor either with another EGFR (homodimerization) or with another member of the family (heterodimerization), which leads to phosphorylation of intracellular tyrosine kinases and downstream activation of multiple pathways, including ras/raf, JAK/STAT, and mitogen.
This cascade of signal transduction events initiates multiple processes that regulate epidermal proliferation, differentiation, apoptosis, migration, and synthesis of inflammatory chemokines. Consequently, disruption of EGFR pathway signaling leads to a variety of effects, which results in the characteristic clinical manifestations of EGFR inhibitor–induced dermatologic toxicities. Inhibition of EGFR-mediated signaling is achieved with the use of monoclonal antibodies (ie, cetuximab(Drug information on cetuximab) [Erbitux], panitumumab [Vectibix]) that bind the extracellular domain and prevent ligand binding, or with the use of low–molecular-weight agents (ie, erlotinib [Tarceva], lapatinib [Tykerb]) that block adenosine(Drug information on adenosine) triphosphate binding to the intracellular portion of the receptor.
The tolerability profile of EGFR inhibitors does not include many of the severe side effects commonly observed with cytotoxic chemotherapy. However, therapy is affected by unique dermatologic toxicities, the most common of which is a papulopustular reaction (PPR) on the skin, along with other reactions on hair and nails. The manifestation of skin toxicities can lead to dose reductions and cessation of therapy, predispose to serious infections, and may have an impact on quality of life. This review summarizes the pathophysiology and clinical presentation of the cutaneous toxicities associated with EGFR inhibition.
Pathophysiology of EGFR-Associated Cutaneous Toxicities
EGFR plays a role in normal differentiation and development of epidermal keratinocytes, stimulating epidermal growth, inhibiting differentiation, protecting against ultraviolet (UV)-induced damage, inhibiting inflammation, and accelerating wound healing. EGFR is expressed on normal epidermal and follicular keratinocytes, basal layer of the epidermis, outer root sheath of the hair follicle, sebaceous epithelium, eccrine epithelium, dendritic antigen-presenting cells, and various connective tissue cells, with the greatest expression occurring in proliferating and undifferentiated keratinocytes that are located in the basal and suprabasal layers of the epidermis and the outer root sheath of the hair follicle.[2,3] The pathogenesis of EGFR inhibitor–induced toxicities is incompletely characterized but has been shown to involve inflammation due to interference with the follicular and interfollicular epidermal growth signaling pathways. Abundant experimental data suggest that inhibition of EGFR alters keratinocyte proliferation, differentiation, migration, and attachment, thus leading to the multiple cutaneous manifestations.[5,6]
Histologic findings depend on the time course and severity of the reaction, with varying changes ranging from a lymphocytic or mixed inflammatory infiltrate surrounding the upper areas of the dermis, or follicular infundibulum, to suppurative folliculitis, follicle rupture, and epithelial acantholysis.[7,8] Animal studies suggest that the skin reaction may be caused by abnormal follicular keratinization leading to inflammation and direct enhancement of immune response.
Immunohistochemical studies during drug-induced EGFR blockade demonstrate altered expression of key markers in skin. In normal skin differentiation, phosphorylated EGFR is expressed in the basal and suprabasal layers, and MAPK is observed in the basal layer. EGFR blockade leads to cellular abolishment of phosphorylated EGFR and reduced expression of MAPK. Within basal keratinocytes, growth arrest and premature differentiation occurs, with upregulation of cyclin-dependent kinase (CDK)-associated p27 inhibition,[8,10-12] keratin-1 (KRT1), and signal transduction and activation of transcription-3 (STAT3) in the basal layer, markers of differentiation that are normally only observed in the suprabasal layer.[8,10-12] Malik et al reported on the pharmacodynamic effects of an EGFR inhibitor in normal skin tissues collected from patients treated with an EGFR inhibitor in a phase I study.
Along with the release of inflammatory chemokines (as has been shown in vitro), these changes result in recruitment of inflammatory infiltrates and initiate release of cytokines and enzymes that produce keratinocyte apoptosis. These changes are thought to be responsible for many of the cutaneous abnormalities and clinical symptoms, including pain, tenderness, erythema, papulopustules, and periungual inflammation. Bacterial overgrowth and subsequent infections can occur. Eventually, a decrease occurs in the thickness of the stratum corneum, which will lack its characteristic basket-woven configuration and exhibit retained nuclei in a process known as parakeratosis. These histologic changes will manifest clinically as xerosis and flaking.
Patients who have received radiotherapy months to years before EGFR administration tend not to develop a rash in previously irradiated skin with EGFR-inhibitor therapy.[15,16] This condition is likely caused by depletion of EGFR-expressing cells, of resident antigen-presenting cells, or alterations in the microvasculature over irradiated areas. On the other hand, concurrent inhibition of EGFR with irradiation leads to radiosensitization in malignant tissues, an effect that is also observed in normal skin and leads to greater skin toxicity in irradiated sites.
Clinical Manifestations of EGFR Inhibitor Cutaneous Toxicities
Papulopustular Reaction (PPR)
The most frequently observed side effect of EGFR inhibitors is a PPR (Figure 1). The rash is dose-dependent and is observed in 45% to 100% of patients, depending on the agent. It occurs more frequently in the seborrheic areas of the face, neck, shoulders, upper trunk, and scalp. However, the lower back, abdomen, buttocks, arms, and legs can also be involved, with significant tenderness over elbows but with the palms and soles spared. Initially, the lesions consist of erythema, edema, and a warm sensation on the face, followed by follicular papules that may progress to pustules. The pustules may become confluent with lakes of pus that form crusts. Skin necrosis with black eschar and ulceration have been reported.[8,16,18,19] Resolution with telangiectasias occurs once the elevated lesions have resolved.
The PPR usually begins within 2 to 3 days of drug administration and peaks in 2 to 3 weeks. A gradually worsening PPR progressive over several weeks can also occur. Some patients develop spontaneous improvement, even with continuation of therapy. However, a flare-up of the rash may be observed and should be expected with each drug administration. The eruption usually improves with cessation of therapy and gradually disappears after discontinuation of EGFR inhibition, although residual hyperpigmentation, scarring, and xerosis may be observed. No relation to preexisting skin abnormalities such as acne or a history of acne or oily skin has been associated.
Rash associated with EGFR inhibitors is frequently referred to as "acneiform." No clear formation of comedones are noted; therefore, the term acne, or acneiform is incorrect and should not be used.[20-26]
Xerosis and Pruritus
EGFR inhibitor administration results in significant pruritus and development of dry skin with flaking (Figure 2). With continued therapy, dry, scaly, flaking skin appears over the extremities, scalp, and areas associated with PPR. The xerosis may result in chronic asteatoic eczema. Secondary infection with bacteria and fungi may enhance oozing and complicate the clinical picture. The compromised epidermal barrier may predispose to systemic infection and colonization with resistant organisms. Increased skin fragility, bruising, and swelling over the interphalangeal joints have been reported.[8,16,18,19] Fissuring on the fingertips and soles frequently occurs and may lead to significant disability, with burning and tenderness.
The fingertips and toes may develop dry areas with scaling, cracks, or fissures (Figure 3). Painful fissures may develop on the palms, fingertips, toes, and heels. Additionally, perioral fissures and cracks on the lips may be extremely painful.[8,16,18,19]
Nail changes are observed in 10% to 15% of patients and are a late manifestation, usually starting 4 to 8 weeks after initiation of therapy (Figure 4). Paronychia with painful inflammation of the thumbs or great toes is common, but other digits may be involved. The paronychia may mimic ingrown toenail initially, gradually progressing to periungual granulation-type or friable changes with associated erythema, swelling, and fissuring of the lateral folds and/or distal tufts of the fingers. In severe cases, pyogenic granuloma of the nail folds develop. Secondary infections with bacteria such as Staphylococcus aureus or fungi such as Candida albicans commonly develop.[27-29]
After 4 to 8 weeks of treatment with EGFR inhibitors, characteristic changes in the hair may be noted (Figures 5, 6, and 7). Alopecia has been reported, but more commonly, curlier, more brittle hair, with dry pruritic scalp, may be noticed. This condition can be accompanied by increased hair growth and thickness on the extremities. Trichomegaly, curling, and increased growth, with lengthening and rigidity of the eyelashes and thickening and rigidity of the eyebrows, are commonly observed.[30,31] With continued treatment, new hair growth may be noted circumferentially around the eyes. Whereas less frequent shaving of the beard may be noted in men, vellus hairs may develop above the lips in women. In fact, hirsutism has been reported in up to 50% of women who received panitumumab for more than 6 weeks of therapy.
Telangiectasias may be an early event, appearing on the face, behind the ears, on the chest, on limbs, and usually in the vicinity of and associated with early PPR or with subsequent flares that occur with continued drug administration (Figure 8). They may fade with time but with residual hyperpigmentation.[8,16,18,19]
Postinflammatory hyperpigmentation is typically observed after PPR or other inflammatory conditions of the skin, such as eczema or inflamed sebaceous cyst (Figure 9). Sunlight or other UV exposure may aggravate the hyperpigmentation. Notably, darker-skinned individuals treated with EGFR inhibitors may develop hyperpigmentation in areas devoid of previous inflammations.[8,16,18-20]
Mucositis, with aphthous ulcers of the oral and nasal mucosa, has been observed. Vaginal dryness, ulcerations, and secondary infections have also been observed, as has inflammation of the urethra and penile skin.[8,16,18,19]
The cutaneous effects of EGFR inhibitors characterize a unique combination of class-specific side effects consisting of varying degrees of skin changes that include early appearance of erythema, pruritus, acneiform papulopustular eruption, telangiectasia, and xerosis. In addition, nail-fold inflammation, hair changes, hyperpigmentation, and scarring may occur. Presentation of a different toxicity should prompt referral to a dermatologist, as it may indicate an unrelated condition that may not warrant modification or interruption of EGFR inhibitor therapy.
Further research is needed to understand the mechanisms underlying cutaneous toxicities. Because most management strategies for skin toxicities have been based on anecdotal experience, well designed clinical trials are needed to provide uniform classification and characterization, as well as accurate grading that will allow for evidence-based treatment strategies.