Dermatological Side Effects of Epidermal Growth Factor Receptor Inhibitors: 'PRIDE' Complex.

Epidermal growth factor receptor (EGFR) inhibitor therapy has become the standard treatment for non-small cell lung cancer and head neck malignancy. This class of drug comprises EGFR inhibitors (erlotinib and gefitinib) and monoclonal antibody (cetuximab). Use of this class of drugs has been associated frequently with dermatological side effects termed as PRIDE complex-Papulopustules and/or paronychia, Regulatory abnormalities of hair growth, Itching, Dryness due to EGFR inhibitors. We hereby report the cutaneous side effects of EGFR inhibitor therapy in 15 patients of lung and head/neck cancer. The major clinical findings being acneiform eruption and severe xerosis of skin. Management of these dermatological adverse effects rarely requires discontinuation of targeted therapy and can be managed symptomatically.

What was known?

There has been a rapid increase in use of targeted therapies in cancer treatment, which includes epidermal growth factor receptor inhibitors.

As compared to conventional chemotherapeutic agents, epidermal growth factor receptor inhibitors lacks systemic toxicity.

Introduction

Epidermal growth factor receptor (EGFR), a 170-kd transmembrane glycoprotein, is a member of the type 1 receptor tyrosine kinase (TK) family. The EGFR is physiologically expressed in epithelial tissues and hair follicles, where it contributes to epidermal proliferation, differentiation, and hair growth.[1] EGFR is overexpressed in many solid tumors, where it is involved in tumor growth, cell proliferation, apoptosis, angiogenesis, cell motility, and metastasis.[23] The unique skin reactions due to EGFR inhibitor includes acneiform rash, xerosis, eczema, paronychia, and changes in the hair and nails.[45]

Case Report

Fifteen patients (14 males and 1 female) with a mean age of 53.8 years (range: 41-72 years) were being treated with either EGFR inhibitor or anti-EGFR monoclonal antibody for non-small cell lung cancer (n = 6), Ca. tonsil (n = 3), Ca. buccal mucosa (n = 4), Ca. posterior pharyngeal wall (n = 1), and Ca. pyriform fossa (n = 1). All the patients were referred to our outpatient department from a tertiary cancer hospital located in western India. Table 1 gives the demographic data of the patients who were treated with the above drugs.

Table 1

Clinical features of patient with cutaneous drug reaction secondary to anti-cancer agent

All patients presented to us with the chief complaint of multiple red raised and pus-filled lesions on face, chest, back, shoulder blades, and nape of neck of varying duration of 10 days to 4 weeks. Few of the patients also complained of severe dryness of skin not attributable to seasonal variation along with pruritus. None of the patients complaining of acneiform lesion or dryness was being treated with drugs known to cause these problems, i.e., steroids or HMG CoA reductase inhibitors (Statins), respectively. Skin specimen of appropriate lesion was taken with the help of punch biopsy, fixed in 10% buffered neutral formalin, embedded in paraffin, and stained with hematoxylin and eosin.

Cutaneous examination revealed multiple inflammatory acneiform eruption in the so-called seborrheic pattern. [Figure 1a and b]. Acneiform eruption comprised of multiple discrete erythematous papules and pustules on erythematous base on central chest. Gram smear examination of pustules revealed sterile inflammatory cells. Xerosis of extremities and trunk was seen along with scaling and excoriations [Figure 2a and b]. Two of the patients on cetuximab + paclitaxel (patient number 9 and 10) reported to have paronychia associated with pyogenic granuloma-like granulation tissue [Figure 3]. Routine investigations including complete hemogram, serum biochemistry, and urinalysis were within normal limits.

Figure 1

(a and b) Multiple papules and pustules with erythematous base on central chest and anterior trunk. Note that in contrast to classical acneiform lesions, these are inflammatory and predominantly pustular. Note that the right thoracotomy scar is seen corroborating with surgical removal of lung malignancy

Figure 2

(a and b) Severe xerosis on back, shoulder blades, and deltoid region

Figure 3

(a and b) Paronychia of lateral nail fold with pyogenic granuloma-like lesion (shown by arrow)

Hematoxylin and eosin stained sections of skin specimen showed mixed inflammatory infiltrate comprising neutrophils and lymphocytes around pilosebaceous unit [Figure 4].

Figure 4

Histopathology of skin biopsy from acneiform eruption showing predominantly neutrophilic infiltrate in the dermis with scale crust (H & E ×20)

All patients were given symptomatic treatment in the form of anti-acne lotions (benzoyl peroxide 2.5% wash and 1% clindamycin lotion) as was for inflammatory acne. Xerosis was treated with regular application of moisturizing creams and associated eczema was treated with mid-potent steroid cream (Mometasone furoate cream, 0.1%) and non-sedative anti-histaminics (nsAH) like levocetrizine 5-mg bid for a week. All patients showed good response to symptomatic treatment inspite of continuation of anti-EGFR drugs. Two patients with paronychia and granulation tissue in the nail fold were reassured about benign nature of the condition and were prescribed prophylactic steroid-antifungal lotion and gentamicin eye drops to be applied locally.

Discussion

The underlying mechanisms for various cutaneous adverse effects are poorly understood, but they are most likely linked to inhibition of EGFR in the skin. Effects of EGFR inhibition results in impaired growth and migration of keratinocytes, and inflammatory chemokine expression by these cells. These effects lead to inflammatory cell recruitment and subsequent cutaneous injury, which accounts for the majority of symptoms, including tenderness, papulopustules, and periungual inflammation.[6] Similar inflammatory events may also account for the periungual inflammation and onycholysis, whereas abnormalities in keratinocyte differentiation, i.e., premature expression of keratin 1 and signal transducer and activator of transcription 3 (STAT 3), may explain the impaired stratum corneum leading to xerosis and pruritus.[7]

The overall profile of these drugs has been summarised in Table 2.

Table 2

Drugs belonging to epidermal growth factor receptor inhibitor with their molecular target and indications

This class of drug has entirely different spectrum of adverse reaction consisting of an itchy acneiform papulopustular eruption, telangiectasia, and xerosis. The constellation of cutaneous side effects of EGFR inhibitors have been termed under the acronym ‘PRIDE’ (Papulopustules and/or paronychia, Regulatory abnormalities of hair growth, Itching, Dryness due to EGFR inhibitors).[7] There have been cases of trichomegaly caused by use of EGFR inhibitor.[89] Our case series did not show any such hair growth abnormality.

The pathophysiology of acneiform eruption is poorly understood. EGFR is commonly expressed in the pilosebaceous unit, both in follicular keratinocytes and in sebocytes.[10] It has been postulated that both EGFR overstimulation and inhibition lead to disorganisation of the pilosebaceous unit and influx of proinflammatory sebum into the dermis.[11] The eruption is usually located in the so-called seborrheic areas (rich in sebaceous glands): The face, the neck, the shoulders, the upper trunk (V-shaped), and the scalp [Figure 1]. Microscopically, acneiform lesions show a picture of a neutrophilic folliculitis and perifolliculitis. The acneiform eruption appears in few days after starting treatment with the EGFR inhibitor to reach a maximum after 2-3 weeks. In contrast, classical acneiform eruption caused by other drugs (steroids, phenytoin, vitamin B complex, and isoniazid) is usually monomorphous, non-itchy, and non-inflammatory. Resolution of acneiform eruption can lead to postinflammatory hypermelanosis. Phase II clinical trials of cetuximab in combination with chemotherapy in patients with colorectal cancer, squamous cell carcinoma of the head and neck, or pancreatic cancer have shown that development of the acneiform rash was significantly correlated with response to treatment; grade 3 rash may be especially predictive of response. It is possible that development of acneiform rash may become an important clinical prognostic marker.[12]

Acneiform eruption caused by EGFR inhibitors has been classified by National Cancer Institute Common Terminology Criteria for Adverse Events in 2006[13] [Table 3].

Table 3

Classification of acneiform eruption caused by EGFR inhibitors

Grade I acne reaction can be treated with standard anti-acne agents with anti-inflammatory properties (benzoyl peroxide 2.5% gel or clindamycin 1% gel or metronidazole 0.75% gel). Grade 2 acne can be treated with topical agents as mentioned in grade 1 in addition with oral H1 anti-histaminics, i.e. levocetrizine, loratidine or hydroxyzine for itch and an oral tetracycline (doxycycline, minocycline) who have an additional anti-inflammatory action. Oral retinoids should be used with caution as they have overlapping adverse effects profile with EGFR inhibitors (xerosis, paronychia). Grade 3 reaction can be treated with an oral tetracycline given in full therapeutic doses along with saline compresses. Grade 4 acne, though rare, requires discontinuation of drug and wound care management in a burn unit.[14]

EGFR inhibitors have been shown to cause xerosis with associated asteotic eczema.[15] Older age of patients with malignancy can have an additive effect on dryness caused by this class of drugs. Epidermal growth factor is necessary for maintaining the epithelial barrier function. Accumulation of drug in the eccrine sweat units could lead to disturbance in their secretory function and thereby could explain the dryness of the skin. Severe xerosis with mucosal involvement can sometimes lead to sicca-like syndrome.

Paronychia is another troublesome side effect, reflecting an aberrant vascular response affecting the nail folds.[1617] Inflammation of proximal and lateral nail folds can cause redness, swelling, and sometimes exuberant granulation tissue formation mimicking pyogenic granuloma-like lesion. Toenail paronychia can sometimes be mistaken for onychocryptosis (ingrowing toenail). There is growing trend among cancer care physician to use retinoids as a lifelong treatment for chemoprevention of non-melanoma skin cancer.[18] Oral retinoids may induce xerosis and paronychia, but not acneiform changes.

Paclitaxel was used in combination with cetuximab in seven of our patients; however, no dermatological side effect could be attributed to paclitaxel use as per our observations.

Conclusion

Knowledge of dermatological side effects of EGFR inhibitors will enable the dermatologist and primary care physician to tackle them more efficiently and will allow the medical oncologist to titrate the offending drug in case of severe cutaneous toxicities. In future, there are chances that many patients would be treated with these relatively safe anti-cancer drugs, and many such cases of skin reaction will come into light. Explaining the patients about the harmless nature of this troublesome skin reaction will restore their faith in the treatment and can ensure compliance.

What is new?

Papulopustular eruption is a marker of effectiveness of therapy with epidermal growth factor receptor inhibitor.

Histologically, papulopustular eruptions shows suppurative neutrophilic folliculitis and/or a perifollicular inflammatory infiltrate.

Adverse skin reaction due to EGFR inhibitor therapy can be handled conservatively and does not require cessation of cancer chemotherapy.