Imatinib-induced Extensive Hyperpigmentation in a Case of Chronic Myeloid Leukemia.

Imatinib, a tyrosine kinase inhibitor, is well known to cause hypopigmentation because of its inhibitory effect on melanocytes. Herewith we report a case of chronic myeloid leukemia who developed extensive hyperpigmentation following imatinib therapy.

What was known?

Hypopigmentation is a predictable adverse effect of imatinib mesylate because of its inhibition of melanocytic activity.

Introduction

Imatinib mesylate, a tyrosine kinase inhibitor, plays a pivotal role in the management of chronic myeloid leukemia. There are a multitude of cutaneous adverse reactions due to imatinib that have been reported. Although hypopigmentation is a predictable sequelae following imatinib therapy, hyperpigmentation is unusual. We report a case of extensive hyperpigmentation in a case of chronic myeloid leukemia following treatment with imatinib.

Case Report

A 60-year-old female was referred to the dermatology clinic with complaints of extensive hyperpigmentation involving the face, neck, chest and forearms. She was already diagnosed with chronic myeloid leukemia and was being treated with imatinib mesylate 400 mg daily. The patient showed good improvement in the hematological parameters. However, 6 months after the imatinib therapy, she started noticing hyperpigmentation initially on her face followed by chest and extensor aspect of the forearms. The extent of involvement of skin by the hyperpigmentation was progressively increasing. There was no pigmentation or active skin lesions on these sites prior to this. There was no history of photosensitivity. Her thyroid profile was normal. She was not on any other medications.

On examination, there were brownish hyperpigmented macules involving the forehead, malar and mandibular areas of the face. The pigmentation was more marked on the lateral aspect of the face than on the centrofacial area. There was sparing of the upper and lower eyelids and the nasolabial folds [Figures 1 and 2]. The pigmentation also involved the neck, upper chest and the extensor aspect of forearms [Figures 3 and 4]. The palms, soles and nails were normal. The buccal mucosa and teeth were uninvolved.

Figure 1

Hyperpigmentation of the face seen from the front

Figure 2

Hyperpigmentation of the face seen involving the lateral part (malar and mandibular areas) than the centrofacial aspect

Figure 3

Pigmentation involving the neck and upper chest

Figure 4

Hyperpigmentation involving the extensor aspect of the forearm

Histopathological examination of the skin biopsy specimen taken from the hyperpigmented lesion on the forearm showed increased melanocyte density in the epidermis which was highlighted by the Masson-Fontana stain. There was no evidence of basal layer vacuolar degeneration, melanin incontinence or lichenoid infiltrate in the dermis.

The patient was treated with modified Kligman's regimen and sunscreens. She was also advised strict photoprotective measures. But she did not show any improvement in the pigmentation. The patient is continuing the imatinib therapy till date. She was under follow-up in dermatology clinic for 2 years since the onset of the pigmentation.

Discussion

Imatinib mesylate is a tyrosine kinase inhibitor. It inhibits the fusion product BCR-ABL which acts through the tyrosine kinase pathway to cause proliferation of leukemic cells in chronic myelogenous leukemia (CML). Imatinib also inhibits c-kit and platelet-derived growth factor (PDGF) which acts through the tyrosine kinase pathway. Moreover, c-kit plays a pivotal role in the pathogenesis of dermatofibrosacrcoma protuberans and gastrointestinal stromal tumor (GIST), therefore imatinib is effective in these conditions as well.[1]

C-kit and PDGF receptors are present in the melanocytes, the activation of which plays an essential role in the melanogenesis pathway, namely melanocyte migration, survival, proliferation and differentiation.[2] Thus, hypopigmentation is a predictable and dose-dependent adverse effect of imatinib as it inhibits the c-kit and PDGF pathways of the melanocyes. But the reason behind hyperpigmentation needs to be elucidated. This could be due to the following reasons: Paradoxical stimulation of melanocytes, drug-induced basal cell degeneration,[34] and deposition of drug metabolite that chelates melanin.[5]

In the case reported by Alexandrescu et al.,[3] the reason behind the imatinib-induced hyperpigmentation of skin was attributed to the melanin incontinence and increased melanocytes in the epidermis. Similarly, Kagimoto et al.[4] reported a case of imatinib-induced violaceous-gray pigmentation on face, neck and trunk which on histopathologic examination showed features suggestive of a lichenoid reaction pattern.

Li et al.[5] reported three cases of grey-blue pigmentation of palate in CML patients on imatinib therapy which on histopathology showed deposition of fine, dark-brown, spherical granules in the dermis. The granules stained positively for both Fontana-Masson and Prussian blue stains. Thus, they postulated imatinib-induced pigmentation to be due to deposition of a drug metabolite which chelates melanin and iron similar to that caused by other medications such as minocycline and anti-malarial medications. Whereas in the present case, the pigmentation was due to the increased number and activity of melanocytes in the epidermis, melanin incontinence was absent and Prussian blue did not stain the pigmented foci. In this patient, the pigmentation appeared 6 months after the initiation of imatinib which was akin to the previously reported case. The persistence of pigmentation in our patient could be because of her continuing the imatinib therapy.

The reported dermatological adverse effects of imatinib include pruritic maculopapular exanthem, follicular mucinosis, erythroderma, graft-versus-host-like-disease, mycosis fungoides-like reaction, small vessels vasculitis, generalized exanthematous pustulosis, Stevens-Johnson syndrome, pityriasis rosea-like eruption, Sweet syndrome, edema, and lichenoid eruption.[3] Valeyrie et al.[6] prospectively studied the cutaneous adverse reactions in 54 patients of CML on imatinib therapy. They noticed the hypopigmentation to be more common an incidence in the ethnically pigmented patients. One case of both hypo and hyperpigmention of the cheek due to imatinib was observed in their case series.

Hypopigmentation of the skin has been recognized as a frequent and predictable effect of imatinib while cutaneous hyperpigmentation is reported only in a few patients till date. Hyperpigmentation had occasionally been observed in the nails, teeth and palate too.[78910] Han et al.[11] have reported a patient with GIST who had repigmentation of vitiligo lesions following imatinib therapy.

We have reported this case for the unusual nature of hyperpigmentation due to imatinib mesylate.

What is new?

The occurrence of extensive hyperpigmentation following imatinib mesylate administration in this patient is paradoxical to its effect on melanocytes.