Osimertinib-associated erythema dyschromicum perstans–like eruption: A case series

Erythema dyschromicum perstans (EDP), which is frequently referred to as ashy dermatosis, is a form of acquired hyperpigmentation characterized by symmetrical, asymptomatic, slate-gray, and brown macules and patches. It occurs most often in patients with dark pigmented skin and can appear in any age group, sex, or time of year.¹ The primary etiology is unknown, although infection, drugs, and genetic predispositions have been suggested as potential contributory factors.1, 2, 3 Although the rash is not painful or deleterious to physical health, its appearance is often extremely distressing to patients, and a better understanding of its etiology would be extremely helpful in better managing the condition and alleviating its morbidity.¹

Osimertinib is a third-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) used to treat malignancies driven by specific oncogenic EGFR mutations. It is the first-line treatment for patients with metastatic non–small cell lung cancer with acquired EGFR-TKI resistance whose tumors have EGFR exon 19 deletions and 21 L858R mutations.⁴ Patients undergoing osimertinib therapy develop a variety of adverse cutaneous side effects, including acneiform eruptions, xerosis, and paronychia.⁵ There have been reports of pigmentary changes associated with osimertinib as well, though this appears to be a less common or underreported phenomenon.6, 7, 8 We report the case series of 3 further patients who developed EDP-like eruptions while receiving treatment with osimertinib, highlighting the potential association between this medication and a condition that, in many ways, mimics this poorly understood primary dermatosis. All patients gave consent for the publication of patient photographs and medical information to be published in print and online and with the understanding that this information may be publicly available.

Case reports

Case 1

A 56-year-old man (Fitzpatrick skin type IV) with stage IV lung adenocarcinoma treated with osimertinib 80 mg oral daily presented for evaluation of dyspigmentation. The patient noted development of an asymptomatic and progressive hyperpigmented rash that began 1 to 2 months after the initiation of osimertinib. He reported that it initially had some pink and itchy components but rapidly progressed to diffusely distributed dark lesions. Physical examination revealed gray-brown oval macules and patches coalescing into large patches on his face, neck, trunk, arms, and legs (Fig 1). The patient had no additional skin toxicity related to his osimertinib treatment.

Fig 1.

Slate-gray hyperpigmentation patches found on the (A) trunk, (B) front and back of legs, (C) both arms, and (D) neck of patient 1.

A 4-mm punch biopsy on the left forearm was performed, which demonstrated postinflammatory hyperpigmentation, showing melanophages in the upper dermis and sparse lymphocytic infiltrate (Fig 2). The clinical and histopathologic findings supported the diagnosis of an EDP-like eruption. After discussing the etiology and potential options for therapy, the patient declined treatment.

Fig 2.

Melanophages in upper dermis and sparse lymphocytic infiltrate of patient 1. (Hematoxylin-eosin stain; original magnification: ×200.)

Case 2

A 63-year-old man (Fitzpatrick skin type IV) with stage IV lung adenocarcinoma was initially treated with osimertinib 80 mg oral daily for approximately 24 months. This was increased to 160 mg daily due to progression of disease, and 3 months later, the patient was noted to have developed a hyperpigmented rash on his back (Fig 3). Brown to gray-brown patches on the middle portion of the back were noted. The patient also developed fingernail paronychia favored to be related to his osimertinib treatment. Biopsy analysis was not performed, but the patient’s history and physical examination findings were believed to be consistent with EDP-like dyspigmentation. Skin-directed therapy was discussed with the patient and family, but was deferred.

Fig 3.

Slate-gray hyperpigmented patch on the back of patient 2.

Case 3

A 63-year-old man (Fitzpatrick skin type IV) with stage IV (cT1c, cN2, cM1) adenocarcinoma of the lung receiving osimertinib 80 mg oral daily presented for evaluation of dyspigmentation, which developed 28 months after initiating osimertinib therapy (Fig 4). Dark blue-gray macules and patches were seen in the bilateral thighs, lower back, and abdomen. He had no other skin toxicity from his osimertinib treatment.

Fig 4.

Slate-gray hyperpigmented patch on the lower portion of the back of patient 3.

A 4-mm punch biopsy was performed on the back (Fig 5). There was sparse superficial perivascular and focally perifollicular lymphocytic infiltrate. Lymphocytes were present at the dermoepidermal junction with numerous melanophages within the papillary dermis. These clinical and histopathologic findings were believed to be consistent with EDP-like dyspigmentation. Treatment with superpotent topical steroids and calcineurin inhibitors was initiated, with neither improvement nor progression of the condition after 2 months; treatment is ongoing at this time. Systemic treatments, including oral retinoids and glucocorticoids, were discussed with the patient, but he elected to defer systemic therapy.

Fig 5.

Sparse superficial perivascular and focally perifollicular lymphocytic infiltrate at dermoepidermal junction and malanophages within the papillary dermis of patient 3. (Hematoxylin-eosin stain; original magnification: ×200.)

Discussion

Treatment for advanced-stage epithelial cancers, such as non–small cell lung adenocarcinomas, often involves EGFR inhibitor therapy. However, these treatments are associated with adverse cutaneous events. In patients treated with osimertinib, a third-generation EGFR-TKI, 40% of patients report rashes and acne, 20% dry skin, and 25% nail onycholysis.⁵ First generation EGFR-TKIs, such as gefitinib, have been associated with lichen planus pigmentosus–like eruptions.⁹ However, pigmentary changes following treatment with osimertinib have only recently been reported in the literature.6, 7, 8 We report 3 cases of osimertinib-associated EDP-like eruption, with similar characteristic slate-gray hyperpigmentation, and diverse histopathologic findings that recapitulate the varied potential histopathology of primary EDP.

In a case series conducted by Ransohoff et al,⁶ 8 patients on EGFR-TKIs, including 6 patients receiving osimertinib, received a diagnosis of EDP after >6 months of receiving therapy. Two other individual case reports have also documented osimertinib-induced EDP in which asymptomatic slate-gray hyperpigmentation was observed after 6 to 24 months of osimertinib therapy.^7,8 Limited responses to topical steroids, photoprotection, calcineurin inhibitors, and topical bleaching creams were noted.

The etiology of EDP is not well understood. EDP has been associated with multiple medications, including amiodarone, proton pump inhibitors, chlorothalonil, ethambutol, and fluoxetine,1, 2, 3 but more commonly occurs in the absence of any clear inciting medication. Epidermal growth factors, which bind to EGFRs, have been shown to reduce inflammation-induced melanogenesis and hyperpigmentation.¹⁰ Additionally, EGFR inhibitors increase infiltration of inflammatory cells in the skin by unblocking chemokine production and enhancing chemotaxis.¹¹ It is possible that a combination of increased inflammation from drug antigens, stimulation of the immune response by EGFR-TKIs, and inflammation-induced melanogenesis may be partially responsible for the EDP-like presentation in these patients.

There is no standard for treatment of EDP.¹ Although removal of a suspected offending agent may be useful, this may not be possible in oncology patients given the need for continued disease control. Various topical, systemic, and procedure therapies have been trialed with variable levels of improvement in patients.¹

It is important to note that, although the association of osimertinib with EDP-like dyspigmentation has been observed in this report and previous series,6, 7, 8 true causation is extremely difficult to establish given the nature of both the condition and the implicated medication. Formal criteria for establishing causation of drug reactions, such as the Naranjo Adverse Drug Reaction Probability Score, rely on observation of reaction remittance with withdrawal of medication and recurrence on readministration,¹² which is impossible to assess in this instance as the medications were essential and not discontinued. With the data available, all our patients have a score of 3 by this criterion, consistent with a “possible adverse drug reaction.”

An alternate hypothesis that these patients developed primary EDP while coincidentally being treated with osimertinib is possible. EDP is considered a rare disease in the general population, and a lack of reliable epidemiologic data on its prevalence makes it impossible at this time to ascertain whether the condition is enriched in patients receiving osimertinib. It is our hope that future diligent reporting of pigmentary changes in patients with cancer receiving this or other agents will help to establish or refute the observed association between osimertinib and EDP-like dyspigmentation.

Significantly, association between EGFR-TKIs and erythema dyschromicum perstans–like dyspigmentation offers a potential window into the mechanistic understanding of this previously poorly understood disease. It is possible that disruption of EGFR signaling may contribute or predispose to development of EDP in a way that has yet to be elucidated. It is notable that, of all EGFR-TKIs used in the treatment of non–small cell lung cancer, osimertinib is by far the most widely associated in the literature with dyspigmentation,6, 7, 8 although this may also be in part due to its wide use.

Of note, some toxicities of EGFR inhibitors, such as acneiform eruption, have been associated with improved oncologic outcomes in patients with lung cancer.¹³ At this time, there is not enough data from the limited cases reported to comment on whether EDP-like dyspigmentation has prognostic significance.

Disorders of pigmentation greatly impact quality of life, and drug-induced pigmentation is associated with lower patient adherence to medication regimens.^14,15 Moreover, the experience of cancer treatment is stressful and anxiety inducing, and the appearance of dramatic new skin findings can be alarming to patients, or worse, seen as a potential sign of poor outcomes. On the other side of the stethoscope, oncologists faced with a patient with unexplained skin changes may experience similar uncertainties about the safety of continuing a given antineoplastic regimen. The role of the dermatologist, in this instance, is to provide diagnostic clarity, prognostication, and reassurance to patients and oncologists alike. To that end, this case series serves to support the theory that EGFR inhibition with osimertinib may contribute to EDP-like discoloration, which is extremely difficult to treat, but is neither dangerous to the patient’s physical health nor an indication to pause or modify therapy.

Conclusion

This case series presents 3 cases of EDP-like dyspigmentation associated with osimertinib therapy, contributing considerably to a growing body of evidence associating therapeutic EGFR inhibition with hyperpigmentation mimicking this poorly understood primary dermatosis. Dermatologists and oncologists should be clinically aware of this uncommon cutaneous adverse effect so that it can be promptly diagnosed and patients appropriately counseled. In the future, better understanding of this observed association may also serve to improve our understanding of a notoriously poorly understood primary dermatosis, and potentially reveal pathways for more effective treatment.

Conflicts of interest

Dr Tattersall has received consulting fees from OnQuality Pharmaceuticals. Drs Gutierrez and Meehan and authors Oh and Martinez have no conflicts to disclose.