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Figure 2. Histopathologic Findings

A B

C D A, Black-brown deposits in the upper and deep (hematoxylin-, original magnification ×10). B, Panoramic view in which deposits are positively stained in superficial and deep layers (Perls stain, original magnification ×4). C, Interstitial and perivascular deposits positively stained with this argent technique (Masson-Fontana stain, original magnification ×40). D, Deposits corresponding to an exogenous material inside lysosomes of fibroblasts (ultrastructural study).

confined to scars or sites with previous or Author Affiliations: Department of , Hospital Universitario de trauma. In type 2, blue-gray pigmentation occurs within pre- Guadalajara, Spain (Lorente, Ballano, Juanes, Pastor); Department of , Hospital Universitario de Guadalajara, Spain (Cuevas). viously normal-appearing , especially in the lower legs and Corresponding Author: Mónica Lorente, MD, Donantes de Sangre s/n, E-19002 forearms. Type 3 is characterized by the presence of diffuse Guadalajara, Spain ([email protected]; [email protected]). brownish discoloration of sun-exposed areas. Histopathologi- Published Online: July 3, 2013. cally, types 1 and 2 demonstrate pigment granules in the der- doi:10.1001/jamadermatol.2013.4365. mis, concentrated around vasculature within macrophages, Conflict of Interest Disclosures: None reported. and, in type 2, around myoepithelial cells as well. Perls stain- Additional Contributions: Special thanks to Miguel Angel Martínez, MD, ing is positive in type 1. In type 2, both Perls and Masson- Hospital 12 de Octubre, Madrid, for ultrastructural study. Fontana stainings are positive. In type 3, there is increased 1. Liu HH. Safety profile of the fluoroquinolones: focus on levofloxacin. Drug in basal keratinocytes with subjacent dermal mela- Saf. 2010;33(5):353-369. nophages without the presence of iron. Only Masson- 2. López-Pestaña A, Tuneu A, Lobo C, Zubizarreta J, Eguino P. Blue-black Fontana is positive in this type.4 pigmentation of legs and arms in a 68-year-old woman. Arch Dermatol. 2007;143(11):1441-1446. Ultrastructural observations have confirmed that the clini- 3. Le Cleach L, Chosidow O, Peytavin G, et al. Blue-black pigmentation cal coloration is a result of a minocycline derivative chelated of the legs associated with pefloxacin therapy. Arch Dermatol. with iron that is stored within the lysosomes of macro- 1995;131(7):856-857. phages. To our knowledge, there are no reports of cutaneous 4. Bowen AR, McCalmont TH. The histopathology of subcutaneous pigmentation due to rifampicin. Our patient’s symptoms and minocycline pigmentation. J Am Acad Dermatol. 2007;57(5):836-839. the histologic findings were similar to those described for mi- 5. Green D, Friedman KJ. Treatment of minocycline-induced cutaneous nocycline pigmentation type 2 and previous cases associated pigmentation with the Q-switched Alexandrite laser and a review of the literature. J Am Acad Dermatol. 2001;44(2)(suppl):342-347. with levofloxacin and pefloxacin. The course of the pigmentation is unknown, but it tends to fade if levofloxacin treatment is discontinued. Months or Eltrombopag-Associated years are necessary to achieve resolution, although in some We report 2 cases of cutaneous hyperpigmentation with cases the pigmentation can be permanent. Treatment with Q- eltrombopag, a novel thrombopoietin receptor agonist. switched laser has been reported with successful results.5 Report of Cases | Case 1. A 69-year-old white woman with re- Mónica Lorente, MD fractory acute myelogenous leukemia (AML) was referred to der- Adrián Ballano, MD matology for skin graying. Treatment with eltrombopag, 300 Adriana Juanes, MD mg/d, was initiated in a clinical trial.1 After 3 months, the pa- Maria Antonia Pastor, MD tient’s husband and clinical team noted gray hyperpigmenta- Jesús Cuevas, MD tion predominantly affecting the face (Figure 1A). She had re-

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Figure 1. Images From Case 1

A B

C D

A, Clinical photograph of patient 1 demonstrates subtle gray discoloration of the magnification ×600). C and D, This pigment was highlighted by face compared with the patient’s hands. B, Histopathologic image Fontana-Masson stain (C) (original magnification ×600) and stained weakly demonstrates brown granules of pigmentation (hematoxylin-eosin, original positive with (D) (original magnification ×600).

ceived cytarabine and daunorubicin 10 weeks prior to In addition to deep neutrophilic inflammation, there was eltrombopag and sirolimus and mitoxantrone 5 weeks prior to prominent pigment deposition in the mid to deep dermis stain- eltrombopag. The hands, nails, sclera, and mucosa were unin- ing positive with both Fontana-Masson and Prussian blue stains volved. Histopathologic examination of preauricular skin dem- (Figure 2). The pigmentation remained stable 3 months into onstrated mild inflammation and focal dermal pigment that eltrombopag therapy. The patient, her husband, and the on- stained positive with Fontana-Masson and weakly positive with cology team believed that she was notably darker than before Prussian blue (Figure 1B-D). The pigmentation remained stable beginning eltrombopag treatment, and on comparison with a over the subsequent 8 months during eltrombopag treatment. family photograph, the patient’s skin was believed to be darker than baseline by the dermatology team. Case 2. A 66-year-old woman of mixed white, African, and Na- tive American descent with refractory AML developed dark- Discussion | Eltrombopag is a novel, nonpeptide thrombopoi- ening of her skin during treatment with eltrombopag. She had etin receptor agonist approved for treatment of chronic idio- received cytarabine and daunorubicin 3 months prior to ini- pathic (ITP). It has also recently been tiating a clinical trial with eltrombopag. Two months after start- approved for the treatment of C associated ing eltrombopag therapy, the dermatology consult team was thrombocytopenia2 and is currently being used in clinical trials called to evaluate subcutaneous nodules clinically sugges- for AML and myelodysplastic syndromes. Reported cutaneous tive of Sweet syndrome. At that time she was noted to have a adverse effects have been minimal. Pruritic exanthema have diffuse dusky complexion involving her face, arms, and legs. been reported in 3 patients taking eltrombopag, 25 to 50 mg/d, A of a subcutaneous nodule on her leg was performed. for ITP.3 In vitro studies suggest a theoretical phototoxic effect

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Figure 2. Histopathologic Images From Case 2 With Diffuse Pigment Deposition

A B

C D

A, Low magnification demonstrates pigmentation throughout the dermis and in (hematoxylin-eosin, original magnification ×600) that stain strongly positive superficial subcutaneous (hematoxylin-eosin, original magnification with Fontana-Masson (C) (original magnification ×600) and Prussian blue ×40). B-D, Higher magnification shows multiple foci of brown fine granules (B) (original magnification ×600).

of eltrombopag; however, a clinical study of eltrombopag, 300 those agents. Additionally,the lack of inflammation or mg/d (75 mg 4 times daily) for 6 days, failed to show increased in the skin, along with the presence of both and photosensitivity.4 To our knowledge, this is the first report of Fontana-Masson–positive material, supports a drug-associated cutaneous hyperpigmentation associated with eltrombopag. hyperpigmentation rather than postinflammatory hyperpigmen- Numerous medications are associated with drug-induced tation. The hyperpigmentation in case 1 appeared photodistrib- hyperpigmentation, including minocycline, amiodarone, and uted, which, along with the superficial pigmentary deposits, may chemotherapeutic agents including novel targeted therapies.5,6 implicate phototoxic effects in the . The pathogenesis behind medication-associated hyperpigmen- We describe the novel finding of cutaneous hyperpigmen- tation remains unclear. Some attribute increased melanin dep- tation associated with eltrombopag and the associated patho- osition (measured by Fontana-Masson staining) to increased logic findings. Further investigation is needed to better char- melanin production stimulated directly by the medication or acterize this phenomenon. indirectly by inflammation related to the medication. Like- wise, hemosiderin deposition (seen with Prussian blue stain- Inbal Braunstein, MD ing) is postulated to arise from red blood cell leakage (1) from Karolyn A. Wanat, MD direct vessel damage caused by the drug, (2) secondary to in- Rosalie Elenitsas, MD flammation related to the drug or (3) due to deposition of spe- XiaoWei Xu, MD, PhD cific pigments related to the drug.6 Noelle Frey, MD Although some of the other chemotherapeutic agents used Misha Rosenbach, MD previously in the patients have been associated with hyperpig- mentation, the onset of the clinical graying in our patients oc- Author Affiliations: Department of Dermatology, Perelman School of Medicine, curred more than 10 weeks after discontinuing treatment with University of Pennsylvania, Philadelphia (Braunstein, Wanat, Elenitsas, Xu,

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Rosenbach); Department of Pathology and Laboratory Medicine, University of of Becker nevus has been approximated to be about 4:1, al- Pennsylvania, Philadelphia (Elenitsas, Xu); Department of Hematology and though it may well be underdiagnosed in women owing to less , Perelman School of Medicine, University of Pennsylvania, Philadelphia (Frey). intense pigmentation and milder or even absent hypertricho- sis. An association with soft-tissue defects is common, mani- Corresponding Author: Inbal Braunstein, MD, 3600 Spruce St, 2 Maloney, 2 Hospital of the University of Pennsylvania, Philadelphia, PA 19103 festing most frequently as breast hypoplasia. Danarti et al de- ([email protected]). fined a Becker nevus syndrome as the coincidence of Becker Published Online: July 24, 2013. nevus and ipsilateral breast hypoplasia, scoliosis, spina bi- doi:10.1001/jamadermatol.2013.5107. fida, or ipsilateral limb hypoplasia. Becker nevi of the lower Conflict of Interest Disclosures: None reported. extremity are exceedingly rare. Additional Contributions: We are indebted to Katie Dawson, MD, and the team from GlaxoSmithKline for helpful comments. Report of a Case | We report the case of a 31-year-old woman from 1. Abramson Center of the University of Pennsylvania. A phase I/II study of the United Arab Emirates who presented with a that had eltrombopag in elderly patients with AML. http://www.clinicaltrials.gov/ct2/show /NCT01113502?term=eltrombopag+and+AML&rank=4. Accessed February 7, 2013. been present since birth but darkened during adolescence. Fol- 2. Saleh MN, Bussel JB, Cheng G, et al; EXTEND Study Group. Safety and lowing a cesarean section 1 year before presentation, she ob- efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: served a reduction in girth of the left leg. She also complained results of the long-term, open-label EXTEND study. Blood. 2013;121(3):537-545. of pain on exercise. Examination showed hyperpigmentation 3. Meyer SC, Rovó A, Tsakiris DA, Scherer K, Tichelli A, Holbro A. Severe and lipoatrophy involving the entire left lower extremity, ex- cutaneous toxicity related to eltrombopag. Br J Haematol. 2013;160(3):412-414. tending from the left lumbar region to the ankle (Figure). The 4. Bowen CJ, Lobb KM, Park JW, Sanderson B, Ferguson J. Eltrombopag (75 lesion’s margins were irregular with satellite macules, remi- mg) does not induce photosensitivity: results of a clinical pharmacology trial. Photodermatol Photoimmunol Photomed. 2010;26(5):243-249. niscent of an archipelago. The circumferences of the left and 5. Susser WS, Whitaker-Worth DL, Grant-Kels JM. Mucocutaneous reactions to right thighs were 56 and 68 cm, respectively. There was only chemotherapy. J Am Acad Dermatol. 1999;40(3):367-400. minimal hypertrichosis, and that was restricted to the ventral 6. Dereure O. Drug-induced skin pigmentation: epidemiology, diagnosis and aspect of the left thigh. The patient underwent 7.5-MHz so- treatment. Am J Clin Dermatol. 2001;2(4):253-262. nography, which revealed thinning of the subcutis of the left side (1.04 cm) compared with the right side (2.57 cm). Histo- Becker Nevus of the Leg With Lipoatrophy pathologic analysis showed increased melanin production with Becker nevus presents most commonly as a patchy hyperpig- pronounced pigmentation of the basal cell layer. mentation with dark hairs on the upper arms or the shoulder The patient desired to improve the cosmetic appearance girdle of male patients. Its prevalence has been determined at of the affected leg, which required extensive plastic . 0.52 percent in a large cohort of male French military recruits This, again, was declined by the patient, and she was lost to between the ages of 17 and 26 years.1 The male to female ratio follow-up for 3 years.

Figure. Dark Pigmentation and Lipoatrophy Extending From the Hip to the Ankle

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Front (A) and posterior (B) views.

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