OBSERVATION Disappearance of Lentigines in a Patient Receiving Imatinib Treatment for Familial Gastrointestinal Stromal Tumor Syndrome

Tracy Campbell, MD; Lesley Felsten, MD; Julie Moore, MD

Background: Gastrointestinal stromal tumors (GISTs) tumor load. Three months after treatment initiation, the harbor gain-of-function mutations of the c-kit tyrosine patient noted a decrease in the number of pigmented kinase receptor. Imatinib mesylate is an inhibitor of c-kit lesions, lightening of the skin in her genital area, and gray- and is indicated in the treatment of chronic myeloid leu- ing of her terminal hair. kemia and GISTs. Reported adverse effects of imatinib include , , and hyper- Conclusions: The potential association between a spe- pigmentation. Although the exact mechanism by which cific genetic mutation and pigmentation changes sec- these occur is unclear, it is likely that inhibition of c-kit ondary to imatinib therapy may account for the variety leads to downstream inhibition of the tyrosinase gene pro- in presentation of this potential side effect. Further ge- moter and thus to inhibition of pigment production. netic studies paired with -specific or c-kit– specific stains of affected tissue are warranted to better Observations: A 45-year-old woman with a history of understand the relationship between the genetic muta- multiple dysplastic nevi and lentigines was diagnosed as tion and the effect of imatinib on pigmentation. having familial GIST syndrome. Treatment with im- atinib mesylate was started in an attempt to decrease the Arch Dermatol. 2009;145(11):1313-1316

ASTROINTESTINAL STRO- cases of familial GIST syndrome exhibit mal tumors (GISTs) are anticipation, meaning that the syndrome the most common mes- manifests earlier with each consecutive enchymal tumors of the generation.3 gastrointestinal tract and Most GISTs—both sporadic and famil- originate from the interstitial cells of Ca- ial types—harbor gain-of-function muta- G1 jal. Interstitial cells of Cajal are part of the tions of the c-kit tyrosine kinase recep- autonomic nervous system found in the tor. Those who do not harbor this mutation wall of the gastrointestinal tract and are have a mutated PDGF receptor alpha the “pacemakers” of the human digestive (PDGFRA) gene or an unknown muta- tract. Symptoms of GISTs include abdomi- tion.4 Both c-kit (location 4q12; OMIM nal discomfort, pain, and bleeding into the *164920) and PDGFRA (location 4q12; gastrointestinal tract that can manifest as OMIM *173490) are tyrosine kinase re- melena and anemia.2 The patient de- ceptors for growth factors that are acti- scribed herein has been documented to vated in normal tissues. C-kit and its li- have familial GIST syndrome, an ex- gand stem cell factor (SCF) regulate the tremely rare autosomal dominant condi- development, migration, and survival of tion that predisposes the patient to devel- , interstitial cells of Cajal, and oping GISTs throughout her lifetime. With many other types of cells.5 The c-kit mu- only 24 families reported to date, pa- tation in exon 11 causes most GISTs be- tients who carry the mutation in familial cause it promotes continued activation of GIST syndrome have a greater than 90% the receptor, which can lead to an in- lifetime risk of developing 1 or more creased cellular proliferation, decreased Author Affiliations: Rush GISTs.3 Despite the tendency for mul- apoptosis, and ultimately neoplasia.5,6 University Medical Center, Chicago, Illinois. Dr Campbell tiple tumors to develop in the gastroin- It is currently believed that c-kit and its is now with the Department of testinal tract, patients with familial GIST ligand SCF regulate the development and 7 , UC (University of syndrome may have less of a tendency for survival of melanocytes. Through a se- California) Davis Medical metastasis, and the clinical course has been ries of kinase activation and phosphory- Center, Sacramento. described as relatively indolent.3 Some lation reactions, the combination of c-kit

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 Figure 2. Back before treatment with imatinib mesylate. The rectangle highlights the prominence of the lentigines; the labels highlight individual lentigines and include a scale marked in millimeters and centimeters.

to have 3 additional small gastric tumors consistent with GIST. Because of a family history significant for GIST in her mother and multiple intestinal “sarcomas” in her ma- ternal grandmother, genetic studies were performed and confirmed a c-kit mutation on exon 11. She was subse- quently diagnosed as having familial GIST syndrome. In February 2006, the patient started treatment with imatinib mesylate (Gleevec; Novartis Pharmaceuticals Figure 1. Left palm before treatment with imatinib mesylate. Corp, East Hanover, New Jersey), 400 mg/d, in an at- tempt to decrease the tumor load. Three months after treatment initiation, the patient noticed a decrease in the and its ligand SCF activates the tyrosinase gene pro- number of pigmented lesions on both palms (Figure 3), moter and thus initiates pigment production.7 Specific lightening of the skin in her genital area, and graying of hypopigmentary disorders, such as and piebald- her pubic hair, eyebrows, and scalp hair. She also expe- ism, have been known to be associated with c-kit muta- rienced some nausea, weight loss, and periorbital edema. tions.8 One patient reported that her vitiligo became more Physical examination results showed a decreased num- extensive after being treated for chronic myeloid leuke- ber of brown macules on her trunk (Figure 4). Her mia with the c-kit inhibitor imatinib.9 This association palms, soles, and face had very few pigmented lesions, suggests that altering the function of c-kit maybere- and there was diffuse lightening of her labia minora sponsible for impaired pigment production. pudendi. Biopsy specimens were taken from her right deltoid REPORT OF A CASE and right lower back, where lentigines had been previ- ously. Hematoxylin-eosin and Melan-A immunohisto- A 45-year-old woman with a history of multiple dysplas- chemical staining of both specimens showed underac- tic nevi and lentigines presented to the dermatology clinic tive melanocytes at the basal layer (Figures 5), which at Rush University Medical Center in 2001 for a full skin were identified with the help of a dermatopathologist. Fon- examination. On physical examination she was found to tana-Masson staining revealed only subtle focal mela- have medium brown flat macules that were too numer- nin pigmentation (Figure 6). Unfortunately, Melan-A ous to count and that were generalized to the entire cu- and hematoxylin-eosin cannot stain the activity of me- taneous surface with involvement of the palms and soles lanocytes. Immunostaining with anti–TRP-1 (anti- (Figure 1 and Figure 2). Also of significance was a dif- tyrosinase antibodies) would have been more informa- fuse darkening of her labia minora pudendi. There was tive; however, that stain was unavailable. no oral or anal pigmentation. Since then, she has been For the first 2 years after her diagnosis, the patient un- followed up by photographic surveillance every 6 months derwent computed tomography every 3 months, endo- for dysplastic nevi. scopic ultrasonography every 4 months, positron emis- In November 2005, the patient had a 6.2-cm mass re- sion tomography every 6 months, and colonoscopy every moved from her colon and was diagnosed as having a 8 months. At her last follow-up visit, the patient re- GIST. Regional lymph node biopsy specimens taken at ported continuing treatment at the Dana-Farber/ the time of surgery were negative for malignancy. Two Brigham and Women’s Cancer Center in Boston, Mas- months after the tumor resection, she underwent endo- sachusetts, where she receives counseling, monitoring, scopic ultrasonography and endoscopy and was found and treatment and is involved in clinical trials for famil-

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 Figure 5. Melan-A staining of lentigines showing numerous underactive melanocytes, which appear in red at the basal layer (original magnification ϫ20).

Figure 3. Left palm during treatment with imatinib mesylate.

Figure 6. Fontana-Masson staining reveals subtle focal pigmentation and highlights the underactive melanocytes (original magnification ϫ20).

some abnormality in chronic myeloid leukemia). In addition to bcr-abl, imatinib has inhibitory effects on the PDGF receptor and c-kit.10 In familial GIST syndrome, imatinib induces apoptosis, and imatinib is currently in- Figure 4. Back during treatment with imatinib mesylate. The rectangle dicated for the treatment of c-kit–positive GISTs that can- highlights the disappearance of the lentigines. not be removed surgically and/or have spread to other parts of the body.7 Although the effectiveness of ima- ial GIST syndrome. The patient seemed to be doing very tinib in the treatment of GISTs has yet to be defined, our well with imatinib therapy and stated that the graying of interest in this drug lies in its potential role to induce her terminal hair, the lightening of the skin in her geni- pigment changes. tal area, and the decrease in the number of pigmented As stated herein, imatinib has been shown to have in- lesions had stabilized. The patient had no evidence of new hibitory effects on c-kit,10 the receptor believed to play a GIST foci or metastasis. regulatory role in melanocyte development and sur- vival.7 In vitro studies have shown that the number of COMMENT melanocytes with high tyrosinase activity (an indica- tion of high pigment production activity) decreases af- Imatinib is one of the treatments currently available for ter treatment with imatinib.11 Parallel in vitro studies of GISTs. Imatinib is a tyrosine kinase inhibitor that inhib- fibroblasts have shown a 50% decrease in melanocyte pro- its bcr-abl tyrosine kinase (the constitutive abnormal ty- liferation after treatment with imatinib.11 Because fibro- rosine kinases encoded by the Philadelphia chromo- blasts secrete SCF, it is thus thought that imatinib may

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 inhibit pigment production through direct inhibition of Author Contributions: All authors had full access to all c-kit–mediated gene activation and indirect inhibition of the data in the study and take responsibility for the in- SCF production.11 tegrity of the data and the accuracy of data analysis. Study There have been many reports of patients developing concept and design: Campbell. Acquisition of data: Camp- pigmentary abnormalities after imatinib therapy. Spe- bell, Felsten, and Moore. Analysis and interpretation of data: cifically, patients have experienced localized, patchy, or Campbell and Felsten. Drafting of the manuscript: Camp- diffuse hypopigmentation and depigmentation12 that ap- bell, Felsten, and Moore. Critical revision of the manu- pears to be dose dependent and generally reversible on script for important intellectual content: Campbell. discontinuation of therapy.13,14 Although less common, Financial Disclosure: None reported. patchy has also been reported sec- 15,16 ondary to treatment with imatinib. However, not all REFERENCES patients experience pigmentary changes in response to imatinib, and not all experience it to the same degree. 1. Carballo M, Roig I, Aguilar F, et al. Novel c-KIT germline mutation in a family The effect of imatinib on cellular response may be spe- with gastrointestinal stromal tumors and cutaneous hyperpigmentation. Am J cific to the c-kit mutation in the individual. In a study of Med Genet A. 2005;132(4):361-364. patients with c-kit–positive melanocytic tumors, it was 2. Detailed guide: gastrointestinal stromal tumors (GIST): what are the risk factors for gastrointestinal stromal tumors? 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Shibusawa Y, Tamura A, Mochiki E, Kamisaka K, Kimura H, Ishikawa O. C-kit cal response to imatinib compared with patients harbor- mutation in generalized lentigines associated with gastrointestinal stromal tumor. ing different mutations.18 Dermatology. 2004;208(3):217-220. 6. Miettinen M, Lasota J. Gastrointestinal stromal tumors: review on morphology, Further genetic studies paired with melanocyte- molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. specific or c-kit–specific stains of affected tissue would 2006;130(10):1466-1478. be beneficial to our understanding of the pathogenesis 7. Tsao AS, Kantarjian H, Cortes J, O’Brien S, Talpaz M. Imatinib mesylate causes behind imatinib-induced pigment changes. Specifically, hypopigmentation in the skin. Cancer. 2003;98(11):2483-2487. 8. Dippel E, Haas N, Grabbe J, Schadendorf D, Hamann K, Czarnetzki BM. Expres- the dopa reaction would provide information as to the sion of the c-kit receptor in hypomelanosis: a comparative study between piebald- density and distribution of epidermal melanocytes, and ism, depigmentosus and vitiligo. Br J Dermatol. 1995;132(2):182-189. the c-kit monoclonal antibody stain would help identify 9. Legros L, Cassuto J-P, Ortonne J-P. Imatinib mesilate (Glivec): a systemic de- tissues that are c-kit positive. pigmenting agent for extensive vitiligo? Br J Dermatol. 2005;153(3):691-692. Our patient is unique in that hypopigmentation spe- 10. Gleevec [package insert]. East Hanover, NJ; Novartis Pharmaceuticals Corp; 2006. 11. Cario-Andre´ M, Ardilouze L, Pain C, Gauthier Y, Mahon FX, Taieb A. Imatinib me- cifically targeted her lentigines in addition to general- silate inhibits melanogenesis in vitro [letter]. Br J Dermatol. 2006;155(2):493- ized hypopigmentation. Because little is known about fa- 494. milial GIST syndrome and imatinib’s role in this disease, 12. Grossman WJ, Wilson DB. Hypopigmentation from imatinib mesylate (Gleevec). the molecular basis for the disappearance of pigment re- J Pediatr Hematol Oncol. 2004;26(3):214. 13. Talwar V, Doval DC, Bhatia K. Imatinib mesylate induced skin hypopigmentation mains elusive. One theory is that the lentigines are part [letter]. J Assoc Physicians India. 2007;55:527. of her familial GIST syndrome and therefore harbor the 14. Sharma A, Vora A, Bhutani M. Generalized hypopigmentation due to imatinib: a same mutation that makes both interstitial cells of Cajal fairness boon? Indian J Dermatol Venereol Leprol. 2005;71(1):45-46. and melanocytes susceptible to imatinib therapy via the 15. Alexandrescu D, Dasanu C, Farzanmehr H, Kauffman L. Persistent cutaneous hy- c-kit pathway. Furthermore, it is possible that the di- perpigmentation after tyrosine kinase inhibition with imatinib for GIST. Derma- tol Online J. 2008;14(7):7. http://dermatology.cdlib.org/147/case_report/gleevec verse variation in pigmentary response for those treated _hyperpigmentation/doru.html. Accessed August 5, 2008. with imatinib can be explained by the presence of dif- 16. Mcpherson T, Sherman V, Turner R. Imatinib-associated hyperpigmentation, a ferent c-kit mutations in different patients. side effect that should be recognized. J Eur Acad Dermatol Venereol. 2009; 23(1):82-83. 17. Alexis JB, Martinez AE, Lutzky J. An immunohistochemical evaluation of c-kit Accepted for Publication: April 14, 2009. (CD-117) expression in malignant melanoma, and results of imatinib mesylate (Gleevec) therapy in three patients. Melanoma Res. 2005;15(4):283-285. Correspondence: Tracy Campbell, MD, Department of 18. Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib re- Dermatology, UC Davis Medical Center, 3301 C St, Ste sponse in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 1300, Sacramento, CA 95816 ([email protected]). 2003;21(23):4342-4349.

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