Persistent cutaneous hyperpigmentation after tyrosine kinase inhibition with imatinib for GIST
Doru T Alexandrescu MD1, Constantin A Dasanu MD PhD2, Haleh Farzanmehr MD3, C Lisa Kauffman MD1
Dermatology Online Journal 14 (7): 7

1. Georgetown Dermatology, Washington, DC. mddoru@hotmail.com
2. Oncologist, Seattle, Washington
3. Department of Pathology, Washington Hospital Center, Washington, DC


Abstract

Imatinib mesylate, a tyrosine kinase inhibitor targeting the Bcr-Abl protein, c-kit (KIT) and the platelet-derived growth factor receptors (PDGFR), is an important part of the therapeutic armamentarium used in chronic myelogenous leukemia and gastrointestinal stromal tumors. A multitude of dermatological toxicities occur with the clinical use of this drug, ranging from various acute rashes to Steven-Johnson syndrome. Hyperpigmentation of the skin is a less frequent side effect. This phenomenon may be linked to alterations in the c-kit signaling pathway, which plays an important role in melanogenesis. A similar cutaneous phenotypic expression is manifested in families carrying congenital tyrosine II domanin mutations of c-kit. We present a unique case of long-term persistent hyperpigmentation that occured after the treatment with imatinib and describe the possible pathogenetic mechanisms involved. Elucidation of the mechanisms of action of imatinib in the skin may open future directions for the treatment of pigmentary disorders.



Introduction

Imatinib mesylate (Gleevec, STI571, Novartis Pharmaceuticals) is a tyrosine kinase inhibitor in wide clinical use in chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST) that target the BCR-ABL protein in CML, c-kit (KIT), and platelet-derived growth factor receptors. In clinical trials with imatinib mesylate, common side effects of nausea, emesis, diarrhea, periorbital edema, fluid retention, and myelosuppression have been documented [1]. Dermatological side effects include a pruritic maculopapular exanthem, follicular mucinosis, erythroderma, graft-versus-host-like-disease, a mycosis fungoides-like reaction, small vessels vasculitis, generalized exanthematous pustulosis, Stevens-Johnson syndrome, a pityriasis rosea-like eruption, Sweet syndrome, edema, and a lichenoid eruption [2, 3]. The most common alterations of the skin, superficial edema and rash, were observed in 48 percent and 12.7 percent of patients, respectively [4].

Although hypopigmentation of the skin has been recognized as a frequent and predictable effect of imatinib, only one report mentions hyperpigmentation of the integument [4]. We describe a unique case of persistent hyperpigmentation after treatment with imatinib and present the pathogenetic mechanisms that might have led to this development. Such an occurrence is important for understanding the cellular mechanisms of action of imatinib in the skin.


Case report

A 50-year-old African American man without any significant past medical history presented with abdominal discomfort in May 2003 and was diagnosed with anemia and an extrinsic tumor attached to the stomach. Multiple liver metastases including a necrotic lesion requiring drainage were present at the time of diagnosis. Biopsy of the tumor revealed a spindle-cell sarcoma that was unresponsive to an initial course of combination chemotherapy. A second biopsy taken from one of the liver nodules revealed cells with hypochromatic pleomorphic nuclei showing positivity for S100, but negative for chromogranin, TTF1, melanoma markers and HPAP. C-kit (CD117) was positive. The histological findings were compatible with metastatic gastrointestinal stromal (GIST) tumor.


Figure 1A Figure 1B
Figure 1A. A symmetrical maculopapular exanthem with areas of confluence developed during administration of imatinib distributed in a patchy fashion on the extremities, abdomen, trunk, back, and neck. The eruption was accompanied by cutaneous edema and mild pruritus; it was most severe on the distal extremities and bilateral scapular areas, where it presented with formation of confluent erythematous plaques.
Figure 1B. The face and scalp were spared. A dark-brown hyperpigmentation pattern started to develop in a non-overlapping pattern with the original lesions and progressed, reaching a maximum of intensity two months after discontinuation of imatinib. Hyperpigmented macules were observed on the anterior chest and abdomen in a midline confluent distribution and on the extremities (distal more than proximal).

Treatment with imatinib mesylate 600 mg orally daily was commenced in June 2003. Within 8 weeks the patient noticed the development of generalized erythema and edema. A symmetrical pruritic maculopapular exanthem with areas of confluence developed on his extremities, abdomen, trunk, back, and neck. This eruption was most pronounced on the distal extremities and bilateral scapulae, where it formed confluent erythematous plaques. The face and scalp were spared (Fig. 1A). After discontinuation of imatinib the rash improved markedly; this prompted the treatment to be resumed in August 2005 at a reduced dose of 300 mg daily. The same cutaneous eruption recurred in the same distribution within a few days after restarting imatinib, which prompted permanent discontinuation of the drug. Although the plaques began to improve within 1 week, reticulate dark-brown hyperpigmentation started to develop in a non-overlapping pattern with the original lesions and progressed reaching a maximum of intensity in October 2005, At this time hyperpigmented macules were observed on the anterior chest and abdomen in a midline confluent distribution; on the extremities distal areas were more affected than proximal (Fig. 1B). The pruritus asscociated with the initial morbiliform eruption decreased substantially and was present only occasionally in association with the hyperpigmented areas. Histologically, the pigmented lesions demonstrated an increase in basal melanin pigment and a mild perivascular lymphohistiocytic infiltrate. Prominent melanin pigment incontinence and presence of melanophages at the periphery of the superficial capillaries were noted (Figs. 2A & 2B). The patient did not have any significant sun exposure and did not use systemic steroids during the course of his disease.


Figure 2A Figure 2B
Figure 2. Two punch biopsies were obtained from the patient's back, one from a hyperpigmanted patch (A), and the other from uninvolved skin (B). The biopsy from the affected area shows lentiginous elongation of the rete ridges and a mild increase in basal melanin pigment. The dermis contains a mild superficial perivascular and interstitial lymphohistiocytic infiltrate with prominent melanin pigment incontinence and melanophages at the periphery of the superficial capillaries (A). Biopsy of normal skin revealed perivascular inflammation and pigment incontinence, but to a much lesser degree than the hyperpigmented areas (B).

A normal thyroid profile and no clinical signs of endocrine dysfunction were found during the medical evaluation. No hirsutism or nail abnormalities were present. In November 2005, as a result of enlargement of his liver metastases, the patient was started on sunitinib maleate (SU11248). The residual dark brown and grey hyperpigmentation has persisted during 3 years of clinical follow-up.


Discussion

KIT activation appears to be a central tumorigenic event in the development of GISTs, in which c-KIT gene mutations are identified in 60-90 percent of cases. An important insight in the association of hyperpigmentation with the occurence of GIST tumors is provided by the analysis of individuals with germ-line mutations in KIT. Seven families comprising less than 40 individuals have been described in which germ-line mutations in KIT resulted in a constitutive activation of the KIT receptor. The clinical manifestations consist of hyperpigmentation, urticaria pigmentosa, dysphagia, and the occurrence of GIST tumors [5].

It is not known whether different germ-line mutations in KIT lead to various clinical syndromes. Hyperpigmentation has been observed in three out of seven families, which had the 559delV, V559A (two families), and W557R mutation of c-kit [5]. The presence of urticaria along with the other characteristics of this genetic syndrome is not surprising because systemic mastocytosis, a disease often associated with significant urticaria, has been linked to disturbances in c-kit, and is amenable to imatinib in cases of non-resistant mutations [6]. Although imatinib has not been reported to cause urticaria pigmentosa, it represents an effective treatment for this condition in patients with systemic mastocytosis who present with c-kit mutations.

It has been suggested that individuals with germ-line mutations in the tyrosine kinase I domain develop GIST, but not hyperpigmentation or urticaria pigmentosa [7], whereas mutations in the tyrosine kinase II domain of the protein may be associated with non-malignant manifestations such as dysphagia [7, 8]. However, if we analyze the cases summarized by Isozaki et al. it is apparent that all the families that manifested hyperpigmentation as a component of their genetic syndrome presented a juxta-membrane (JM) alteration. Variable clinical penetrance or intervention of other genetic or phenotypical factors is suggested by the presence of various combinations of GIST, hyperpigmentation, and dysphagia in the most recently reported family [7]; a few individuals display all 3 manifestations.

We hypothesize that imatinib exacerbated a genetic predisposition to cutaneous hyperpigmentation; this may also explain its persistence. This may have been related to a mutation in the c-kit gene, or a variant of the kinase, which is activated rather than being inhibited by imatinib. Such a mutation may present as one of the familial genetic alterations described above and may have had incomplete penetrance or may represent a sporadic event. However, our patient had no other family members with any of the features of the syndrome. Considering that the median age at diagnosis of patients in affected families is 57 (range, 18 to 71), it is still possible that a familial syndrome may be apparent in his siblings or offspring in the future. The long delay between the diagnosis of GIST and occurrence of hyperpigmentation, as well as a lack of concordance between the severity of the 2 processes, argues against a main direct causation of hyperpigmentation by the tumor through a genetic or paraneoplastic effect. An alternative explanation may consist of a different effect of imatinib that simulates the signaling resulting from a JM alteration.

A clinical paradox of imatinib causing both hypo- and hyperpigmentation appears also to relate to the inhibition of c-kit and PDGFR receptors [9]. Hypopigmentation of the skin was observed in the majority of patients who experienced pigment changes due to imatinib. It usually develops within the first month of treatment and is accompanied by the development of other signs of skin toxicity. Imatinib-induced hypopigmentation in a series of 6 patients was reversible and potentially dose related [1]. In fact, all 5 patients studied by Brazzelli et al. developed a gradual long-term lightening of the skin, which reached statistical significance, as measured by a precise chromametric method [10]. Hyperpigmentation of the skin appears to be a much more rare event with only a few patients being reported to date [4]. Hyperpigmentation has been observed occasionally in the nails, in the absence of cutaneous changes [11], and in the teeth [12]. These changes appear to be dose-related and manifest in all skin phototypes; they have been reported to be reversible with discontinuation of the drug [11].

It is currently not known how imatinib can induce both loss of pigment and darkening of the skin in different patients. Changes in cutaneous photosensitivity consisting in both hypo- and hypersensitivity have been observed with imatinib and have been attributed to an interference with the molecular pathways involved in the response to UV stress [13]. Pigmentation in melanocytes was associated with c-kit signaling with resultant activation of the tyrosine kinases involved in melanogenesis, such as tyrosinase (TYR) and tyrosinase-related protein 1 (TYRP-1). The signal transmission is thought to be intermediated through downstream activation of the MAP kinase Erk-2, that phosphorylates the microphtalmia transcription factor (MTF), a basic helix-loop-helix leucine zipper. This results in modulation of pigment production through an effect on the tyrosine pigmentation gene promoter and expression of genes essential for melanocyte survival and development [1, 14].

Other medications received by the patient during the course of his disease (dialudid, promethazine, acetaminophen, and benadryl) are not associated with hyperpigmentation and have been used intermittently with no exacerbation or new occurrence of hyperpigmentation during their use. The possibility of a post-inflammatory hyperpigmentation in our patient secondary to the acute inflammation in the original erythematous eruption needs to be considered, but is not substantiated by the different location and pattern of hyperpigmentation compared to the initial distribution of the rash. The time relationship between administration of imatinib and the onset of rash during the 2 treatment courses, as well as the absence of other iatrogenic, paraneoplastic, or endocrinologic causes, makes the etiology of the persistent hyperpigmentation in our patient to be very likely an effect of the biological properties of imatinib mesylate.

The persistent hyperpigmentation may be due to increased basal melanin pigment, dermal melanin pigment incontinence, and chronic inflammation. We can speculate that imatinib caused diffuse overstimulation of melanogenesis in the skin. How the same drug can produce both hypopigmentation and darkening in the skin is unclear, but a possible explanation may reside in its binding to different receptors in the skin, some with activator, and others with inhibitory effects on melnogenesis. More studies are necessary to elucidate the effects of c-kit and PDGFR inhibition through imatinib to the skin.

Acknowledgement: The authors would like to thank Dr. Gary Peck for his useful suggestions and comments on our manuscript.

References

1. Tsao AS, Kantarjian H, Cortes J, O'Brien S, Talpaz M. Imatinib mesylate causes hypopigmentation in the skin. Cancer. 2003;98:2483-7. PubMed

2. Ayirookuzhi SJ, Ma L, Ramshesh P, Mills G. Imatinib-induced sweet syndrome in a patient with chronic myeloid leukemia. Arch Dermatol. 2005;14:368-70. MID: 15781678

3. Pascual JC, Matarredona J, Miralles J, Conesa V, Borras-Blasco J. Oral and cutaneous lichenoid reaction secondary to imatinib: report of two cases. Int J Dermatol. 2006;45:1471-3. PubMed

4. Arora B, Kumar L, Sharma A, Wadhwa J, Kochupillai V. Pigmentary changes in chronic myeloid leukemia patients treated with imatinib mesylate. Ann Oncol. 2004;15:358-9. PubMed

5. Robson ME, Glogowski E, Sommer G, Antonescu CR, Nafa K, Maki RG et al. Pleomorphic characteristics of a germ-line KIT mutation in a large kindred with gastrointestinal stromal tumors, hyperpigmentation, and dysphagia. Clin Cancer Res. 2004;10:1250-4. PubMed

6. Gotlib J. KIT mutations in mastocytosis and their potential as therapeutic targets. Immunol Allergy Clin North Am. 2006;26:575-92. PubMed

7. Isozaki K, Terris B, Belghiti J, Schiffmann S., Hirota S, Vanderwinden JM. Germline-activating mutation in the kinase domain of KIT gene in familial gastrointestinal stromal tumors. Am. J. Pathol. 2000;157:1581-1585. PubMed

8. Hirota S, Nishida T, Isozaki ., Taniguchi M, Nishikawa K, Ohashi A, et al. Familial gastrointestinal stromal tumors associated with dysphagia and novel type germline mutation of KIT gene. Gastroenterology. 2002;122:1493-1499. PubMed

9. Valeyrie L, Bastuji-Garin S, Revuz J, Bachot N, Wechsler J, Berthaud P, Tulliez M, Giraudier S. Adverse cutaneous reactions to imatinib (STI571) in Philadelphia chromosome-positive leukemias: a prospective study of 54 patients. J Am Acad Dermatol. 2003;48:201-6. PubMed

10. Brazzelli V, Prestinari F, Barbagallo T, Rona C, Orlandi E, Passamonti F, et al. A long-term time course of colorimetric assessment of the effects of imatinib mesylate on skin pigmentation: a study of five patients. J Eur Acad Dermatol Venereol. 2007;21:384-7. PubMed

11. Prabhash K, Biswas G, Prasad N, Karant N, Sastry PS, Parikh PM. Imatinib-induced nail hyperpigmentation in chronic myeloid leukemia. Indian J Dermatol Venereol Leprol. 2006;72:63-4. PubMed

12. Singh N, Bakhshi S. Imatinib-induced dental hyperpigmentation in childhood chronic myeloid leukemia. J Pediatr Hematol Oncol. 2007;29:208-9. PubMed

13. Robert C, Soria JC, Spatz A, Le Cesne A, Malka D, Pautier P, et al. Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol. 2005;6:491-500. PubMed

14. Hemesath TJ, Price ER, Takemoto C, Badalian T, Fisher DE. MAP kinase links the transcription factor Microphthalmia to c-Kit signalling in melanocytes. Nature. 1998;391:298-301. PubMed

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Title:

Persistent cutaneous hyperpigmentation after tyrosine kinase inhibition with imatinib for GIST

Journal Issue:

Dermatology Online Journal, 14(7)

Author:

Alexandrescu, Doru T;
Dasanu, Constantin A;
Farzanmehr, Haleh;
Kauffman, C Lisa

Publication Date:

2008

Publication Info:

Dermatology Online Journal, UC Davis

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