EGFR inhibitor-induced cut-like skin lesions of the fingers

Abstract

Cetuximab and osimertinib are epidermal growth factor receptors (EGFRs) inhibitors used in the treatment of several malignancies. These agents have been associated with several skin lesions, the most common being papulopustular acneiform rash involving the face, neck, chest and back. Herein, we describe a unique toxic effect of these agents involving the fingertips and lateral aspects of fingers in a small patient series. The lesions presented approximately 4 weeks into treatment were cut-like and caused local discomfort/pain. Application of a colloidal solution allowed for partial resolution of these lesions in one patient, while discontinuation of the drug led to the disappearance of the lesions in another. Thus, we call for awareness of this unique skin toxicity with the use of EGFR inhibitors in patients with cancer.

Background

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase involved in the pathophysiology of several cancers. Hence, it represents a logical target for anticancer therapy. Currently, two classes of EGFR inhibitors are currently in use in the anticancer armamentarium: monoclonal antibodies that target the extracellular ligand-binding domain and tyrosine kinase inhibitors (TKIs) that target the intracellular domain. These agents are associated with the development of a papulopustular acneiform rash. Herein, we describe a unique skin effect documented in two patients treated with these agents.

Case presentation 1

A 68-year-old man presented for follow-up with complaints of ‘painful cuts’ on the tips and lateral aspects of his fingers. He had been receiving treatment for metastatic, K-ras unmutated colon cancer with bilateral lung and pericardial metastasis.

He was initially diagnosed with tumour node metastasis (TNM) stage I sigmoid colon cancer, and treated with segmental colonic resection, without any adjuvant chemotherapy. Five years later, he presented with malignant pericardial effusion and pericardial tamponade. A CT scan showed bilateral lung lesions, mediastinal lymph node involvement and lymphangitic carcinomatosis, consistent with biopsy-proven stage IV disease. Initial chemotherapy regimen consisted of 5-fluorouracil-oxaliplatin-bevacizumab. Subsequent positron emission tomography (PET)/CT showed improved lung metastases, but persistent lymphangitic carcinomatosis.

Subsequently, he received 5-fluorouracil-irinotecan-cetuximab for a period of 5 months. After 2 weeks of therapy, the patient reported a typical acneiform rash involving the face, trunk and back. Four weeks into treatment, he noticed cut-like lesions on the lateral aspects of several fingers. These lesions caused significant pain and discomfort. The patient denied any recent trauma or self-induced harm. On physical examination, multiple linear erosions were seen on the lateral aspects of fingers bilaterally (figure 1). Overlying the face, trunk and upper back were scattered painful comedones and tender erythematous papules. There was no evidence of xerosis observed elsewhere on the body. Restaging scans showed continued improvement of lung metastases but persistent lymphangitic spread, prompting discontinuation of cetuximab. Shortly thereafter, the patient noticed disappearance of the cut-like lesions and resolution of the acneiform rash.

Figure 1.

Linear erosions present on the lateral aspect of two different fingers.

Case presentation 2

A 61-year-old woman diagnosed with TNM stage IV EGFR mutated lung adenocarcinoma presented for follow-up. During examination, painful cut-like skin lesions were observed on her fingertips that were not present on previous visits.

At presentation, the patient had a right upper lobe nodule, a right perihilar mass and right-sided pleural effusion. She received several consecutive single-agent regimens including erlotinib, gemcitabine and pemetrexed, after which only minimal disease was detected. Subsequent PET/CT showed increased size of the right perihilar mass. Rebiopsy was consistent with relapsed disease, and mutation T790M was positive. The patient was started on osimertinib. One month into treatment, the patient returned for follow-up with a moderate pain in her fingertips caused by new cut-like lesions. In addition, she noted pain and dryness near the nailbeds of several fingers. The first skin lesion was discovered earlier in the week, after which this condition progressed to involvement of multiple fingers. These cut-like lesions led to significant distress and difficulty with activities of daily living. The patient denied self-infliction of wounds, history of physical abuse or trauma to the hands. Physical examination revealed several circa 1 cm linear ulcers on the palmar aspects of several fingers, some of which had overlying crust formation (figure 2). Dry, scaly patches from xerosis were present in multiple interdigital spaces of both hands. Application of oatmeal colloidal solution did allow for partial response of these lesions. Since the onset of treatment, the cut-like lesions remained relatively stable as the patient continued oral osimertinib therapy.

Figure 2.

Multiple linear ‘cut-like’ lesions present on the ventral aspect of multiple fingertips.

Outcome and follow-up for case 1

The patient was on cetuximab for a total of 5 months of therapy. After seeing progression of his cancer on repeat scans, he was subsequently discontinued from this regimen and his lesions resolved in the coming weeks. Unfortunately, not long after discontinuing this therapy, the patient passed away.

Outcome and follow-up for case 2

The patient was started in osimertinib and is currently still receiving active treatment. The lesions continue to be bothersome to the patient, however, the patient’s lesions are well controlled with colloidal oatmeal solution treatments.

Discussion

Cetuximab is a monoclonal antibody that targets the extracellular ligand-binding domain of the EGFR receptor. One of the mechanisms of action is thought to be antibody-dependent cell-mediated cytotoxicity.¹ While this agent targets cancer cells, bystanders that also express the receptor can be affected, leading to disruption of the normal skin architecture and, conceivably, to the cut-like lesions seen in our first patient.

Small molecule TKIs, such as osimertinib, target the intracellular domain of EGFR receptors. Skin toxicity could be due to complex effects on keratinocyte growth and differentiation.² Keratinocytes are the predominant cells within the epidermis and provide a protective barrier against the outside environment. In addition, they are capable to produce several proinflammatory mediators. Disruption of their normal function can lead to increased production of chemokines, which in turn may attract leucocytes, ultimately resulting in an inflammatory response. As surrounding tissue becomes inflamed, it is likely that the cells within the skin layer may transition into apoptosis, leading to the cut-like lesions witnessed in our patients. It could be theorised that the natural dryness of those areas of the fingers could have predisposed them to these lesions that initially began as xerosis.

EGFR inhibitors have been associated with various skin toxicities. The most common effect, occurring in up to 80% of patients, is a pustular acneiform rash involving the face, neck, chest and back.³ Other dermatological toxicities include xerosis, skin desquamation, paronychia and eczema. Although the precise mechanisms by which these reactions occur are not known, they are believed to be related to some immunological factors.¹ Of note, a paper by Sadeghi et al⁴ published in 2016 described cut-like lesions with the TKI erlotinib, which were resembling our patients’ skin lesions.

In the skin, EGFR is expressed by basal keratinocytes, sebocytes, the outer root sheath and some endothelial cells, and is thought to play a role in the normal differentiation of keratinocytes and vessels of the dermis.⁵ We hypothesise that EGF(R) inhibition may contribute to a minor vascular impairment. In addition, the abnormal immune response consisting of increased inflammatory cell and various chemoattractants may have resulted in recruitment of leucocytes, enzyme release, apoptosis and tissue damage, thus leading to the cut-like lesions in our patients. Furthermore, skin dryness might represent an additional culprit in the pathogenesis of these skin lesions.

Naranjo scores for the association of cetuximab and osimertinib with these lesions were 7 and 6, respectively. Based on this finding, it is likely that these lesions were caused by aforementioned agents. In both patients, the cuts emerged at approximately 4 weeks of treatment and in the first case, resolved shortly after discontinuation of therapy. In addition, the patients experienced other side effects already established with EGFR inhibitors such as classical acneiform rash and xerosis, respectively. Of note, cystic acneiform rash affects the hair follicles. When intact, these cysts are filled with purulent and/or serosanguinous fluid and appear as white bumps measuring several millimetres in diameter.⁶ Cessation of the offending agent will usually lead to resolution of acne-like lesions in subsequent weeks.^{3 4 6}

Various providers should be on the lookout for the described above cut-like lesions in patients receiving treatment with EGFR inhibitors. They might represent fissures that occur in hand dermatitis triggered by the long-term use of EGFR inhibitors. Due to their appearance and associated discomfort, local therapy is warranted.⁷ Seldom, dermatological evaluation may be required. As seen in case 2, regular use of oatmeal lotion treatments improved to a certain extent the symptoms and appearance of the lesions. Other skin emollients and topical corticosteroids may also be helpful.

In conclusion, we would like to make the medical community aware that patients receiving active treatment with EGFR inhibitors may report this unique skin toxicity. While patients should be offered reassurance and local therapy, their providers are expected to avoid unnecessary referrals to dermatology, psychiatry or a costly diagnostic work-up.

Learning points.

• Cetuximab and osimertinib are epidermal growth factor receptors (EGFRs) inhibitors commonly used in the treatment of several malignancies.

• EGFR inhibitors are commonly associated with various skin toxicities, including an acneiform rash involving the face, neck, chest and back.

• A unique toxic effect of EGFR inhibitors was noted in two cases presenting with ‘cut-like’ lesions of the tips and lateral aspect of multiple fingers.

• Application of a colloidal oatmeal solution allowed for partial resolution of these lesions.