Figure 1: picture depicting the face of the patient
Diagnostic Assessment
 On dermoscopy, an irregular dark brown pigmentation network is seen in a pseudo reticular pattern, along with hypopigmented areas in between with a few areas of erythema. Patient did not give consent for biopsy from the representative areas. So, further histological examination and  confirmation by various staining procedures[ Hematoxylin-Eosin, Fontana- Masson, Peris Prussian Blue, Alcian Blue] could not be done.  Based on the above-mentioned clinical  findings and diagnostic tests, a diagnosis of Imatinib-induced melasma-like pigmentation was made.
Therapeutic Intervention
 The patient was initiated  on topical depigmenting agents, sunscreen, and topical corticosteroids to address the hyperpigmentation, coupled with strict photoprotective measures for comprehensive management.
Follow-up and Outcomes
The patient is currently under our care, continuing  imatinib therapy with us at the same dose as the patient is having good response to primary disease at this dose and attending regular follow-up appointments at the dermatology clinic showing symptomatic improvement. Hyperpigmentaion over mandibular areas and lateral aspect of face has started resolving after 5th follow up in dermatology clinic. She is still improving in other areas of face. Overall , she  is having 25% subjective response in hyperpigmentary changes yet.
 
Discussion
Imatinib belongs to a new class of anti-cancer drugs that target the tyrosine kinase receptor. Its systemic side effects are less severe than those seen with other cytotoxic drugs. The most common toxicities are nausea, myalgia, skin rashes and edema. Among the dermatological side effects, maculopapular rash is the most common. Other side effects include xerosis, photosensitivity, angular cheilitis, psoriasiform rash and pigmentary changes. Rarer side effects include acute generalized exanthematous pustulosis, urticaria, lichenoid reaction and painful oral erosions.[9] Among the pigmentary changes seen with this drug, hypopigmentation has been most commonly reported. On the contrary, there are only a few case reports of imatinib-induced hyperpigmentation in the available literature . Pigmentation associated with imatinib has been described not only in the skin but also involving the palatal mucosa, nails, teeth, hair, and gums.[2,9,11,12,13] In one series, 3.6% of patients were found to have imatinib-induced pigmentation.[10]  Imatinib mesylate, a tyrosine kinase inhibitor hinders the oncogenic   fusion protein BCR-ABL, which promotes the growth of leukemic cell in chronic myeloid leukemia (CML) causes  by activating the tyrosine kinase pathway abnormally. Additionally, c-kit and platelet-derived growth factor (PDGF), which function via the tyrosine kinase pathway, are inhibited by imatinib. Imatinib is also useful in treating dermatofibrosarcoma protuberans and gastrointestinal stromal tumors (GIST) because c-kit is crucial in the pathophysiology of both of these diseases.  Melanocytes depend on PDGF and C-kit receptors, which are crucial for functions like melanocyte migration, survival, proliferation, and differentiation in the melanin production  pathway. As a result of imatinib's inhibition of the c-kit and PDGF pathways of the melanocytes, hypopigmentation is a predictable and dose-dependent side effect.[3]However, the cause of hyperpigmentation needs to be clarified. The paradoxical activation of melanocytes, drug-induced basal cell degeneration, and drug metabolite accumulation that chelates melanin are potential causes of this.[3]
The pathophysiology of targeted anticancer therapy-induced dpAEs appears to be multifactorial, and remains poorly understood.[16] Pigmentary changes associated with imatinib, a tyrosine kinase inhibitor, are well documented in the literature, with the most commonly described clinical phenotype being reversible, dose-related hypopigmentation.[15] Interestingly, paradoxical cases of imatinib-associated hyperpigmentation have also been described  although the mechanisms underlying these differential reactions remain unclear.[17]
 Dai J et al found that the overall incidence of  depigmentary adverse events in patients exposed to targeted anticancer therapies is high—skin, 17.7% and hair, 21.5%.[17] The targeted agents imatinib, cabozantinib, nivolumab, pazopanib, pembrolizumab, sorafenib, and sunitinib appeared to be the most common culprits.[17]
Kagimoto et al. [2] described a case with imatinib-induced violaceous-gray pigmentation on the face, neck, and trunk that, upon histopathologic investigation, revealed characteristics indicative of a lichenoid response pattern. Three examples of grey-blue pigmentation of the palate in CML patients receiving imatinib therapy were reported by Li et al. [1] Histology revealed dermal deposition of tiny, dark-brown, spherical granules. Both the Prussian blue and Fontana-Masson stains produced positive results on the granules. They therefore hypothesized that imatinib-induced pigmentation was caused by the deposition of a drug metabolite that chelates melanin and iron, much like the metabolites produced by other drugs like minocycline and anti-malarial drugs.[1] While melanin incontinence was missing and the pigmented foci were not stained by Prussian blue in the current case, the pigmentation was caused by an increase in the number and activity of melanocytes in the epidermis.
Similar to the previously reported instances, in this patient, the pigmentation first emerged after 2 months from the start of imatinib 600 mg/day. The fact that our patient is still receiving imatinib therapy may be to blame for the pigmentation's persistence.  Dermatological adverse effects of imatinib encompass various conditions like pruritic or itchy rash,  maculopapular exanthem, follicular mucinosis or follicle inflammation, erythroderma or skin redness, graft-versus-host-like reactions, mycosis fungoides-like reaction, small vessel vasculitis, generalized exanthematous pustulosis, Stevens-Johnson syndrome, pityriasis rosea-like eruption, Sweet syndrome, edema, and a lichenoid eruption.[3]
In 54 CML patients receiving imatinib therapy, Valeyrie et al.'s prospective study  documented a case with both  hypopigmentation and hyperpigmentation[ cutaneous side effects] .[4] The individuals who were of ethnically pigmented backgrounds had a higher frequency of hypopigmentation, they observed. In their case series, they found one instance of cheek hypo and hyperpigmentation caused by imatinib.
Although hypopigmentation  is common  with imatinib therapy,  cutaneous hyperpigmentation has only been observed in a small number of individuals undergoing this treatment upto to date. Sometimes, hyperpigmentation was also seen in the nails, teeth, and palate. [5,6].
 In a case series by Ghunawat et al,[14] Patients developed melasma-like pigmentation present predominantly on the forehead and convexities of the cheeks at a mean interval of 3 months after starting therapy. All other causes of pigmentation were ruled out. Of note, Case 3 also developed extrafacial melasma on the forearms. Drugs that have been reported to cause melasma-like pigmentation include oral contraceptive pills, hormone replacement therapy, drugs causing phototoxic and photo-allergic reactions and anti-epilepsy medications. No morphological differences were noted between melasma-like pigmentation due to imatinib, and melasma. The patients were advised about sun protection and were counseled regarding the reversible nature of the pigmentation. One of the patients (case 1) was started on modified Kligman's regimen (0.5% tretinoin + 4% hydroquinone + 0.1% fluocinolone acetonide) along with broad spectrum sunscreen due to his cosmetic worry. An improvement of 30% in Melasma Area and Severity Index (MASI) was noted after 6 weeks of therapy. The patient was lost to follow up after that. Imatinib was not stopped in any patient.[14]  Informing the patients about the possibility of these side effects can increase compliance to therapy. Further insight into the mechanisms of the pigmentary alterations caused by this drug is required for better treatment/prevention of these manifestations.[14] Current management strategies focus on pre-emptive approaches and patient education rather than symptom management, because termination of drug exposure typically leads to resolution of the dpAEs.[17] Patients should also be advised to use appropriate UV protection, as individuals who experience hypopigmentation may be at an increased risk for photosensitivity disorders .[17]There is an urgent need to educate patients and healthcare providers and develop effective management strategies.[17].  To the best of our knowledge, 30 cases of well documented imatinib related hyperpigmentation were described in literature and included in our review.18 [ Table 2]18