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preserve renal function.1 Given the improved prognosis for pa- Figure 2. Biopsy Specimen From a Cutaneous Cystinosis Facial Papule Under Electron Microscopy tients with cystinosis who receive renal transplantation and/or cysteamine therapy, the prevalence of extrarenal effects, in- 2 microns cluding cutaneous manifestations, may become more appar- ent over time. Finally, examination of biopsy specimens un- der electron microscopy may be required to accurately diagnosis cutaneous cystinosis.

Michael S. Stevens, BSc, PT, MD Shachar Sade, MD, MSc, FRCPC Scott Walsh, MD, PhD, FRCPC, DABD

Author Affiliations: Department of Dermatology, University of Toronto, Toronto, Ontario, Canada (Stevens); Department of Pathology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada (Sade); Division of Dermatology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada (Walsh). Corresponding Author: Michael S. Stevens, MD, Department of Dermatology, University of Toronto, 2075 Bayview Ave, Ste M1-700, Toronto, ON M4N 3M5, Canada ([email protected]). Published Online: September 23, 2015. doi:10.1001/jamadermatol.2015.2660. Conflict of Interest Disclosures: None reported. 1. Gahl WA, Thoene JG, Schneider JA. Cystinosis. N Engl J Med. 2002;347(2): 111-121. 2. Guillet G, Sassolas B, Fromentoux S, Gobin E, Leroy JP. Skin storage of cystine This electron micrograph shows a dermal fibroblast with prominent crystalline and premature skin ageing in cystinosis. Lancet. 1998;352(9138):1444-1445. inclusions within the cytoplasm and some smaller inclusions forming within lysosomes (magnification ×8000). 3. Patel R, Andea A, Croitoru A, Huang C. Cutaneous accumulation of cystine crystals in a cystinosis patient. J Am Acad Dermatol. 2010;62(3)(suppl 1): AB26. 4. Chiavérini C, Kang HY, Sillard L, et al. In vivo reflectance confocal microscopy Discussion | Cystinosis is caused by the accumulation of free of the skin: a noninvasive means of assessing body cystine accumulation in cystine within lysosomes.1 Cystine is derived from protein infantile cystinosis. J Am Acad Dermatol. 2013;68(4):e111-e116. degradation within the lysosome and is normally trans- 5. Gahl WA, Bashan N, Tietze F, Bernardini I, Schulman JD. Cystine transport is defective in isolated leukocyte lysosomes from patients with cystinosis. Science. ported through the lysosomal membrane to the cytosol 1982;217(4566):1263-1265. where it is transformed into cysteine and reused.5 In cysti- 6. Town M, Jean G, Cherqui S, et al. A novel gene encoding an integral 6 nosis, a mutation in the CTNS gene (on chromosome 17p13), membrane protein is mutated in nephropathic cystinosis. Nat Genet. 1998;18 which encodes cystinosin, leads to a defect in the transport (4):319-324. system. The low solubility of cystine leads to the precipita- tion of intracellular needle-shaped crystals as lysosomal cys- Subacute Cutaneous Lupus Erythematosus tine levels rise.3 The accumulation of cystine in various tis- Induced by Mitotane sues in the body has been known to cause renal failure as Drug-induced subacute cutaneous lupus erythematosus well as extrarenal effects leading to ocular, hepatic, thyroid, (DISCLE) presents similar clinical and serological characteris- pancreatic, muscular, dental, gonadal, and neurologic tissue tics to idiopathic SCLE. The following report describes a case damage.1,3 of DISCLE induced by mitotane. However, we know of only 3 prior reports of cutaneous ac- cumulation of cystine crystals in patients with cystinosis. The Case Report | A woman in her 60s was diagnosed with a non- first 2 published reports described subcutaneous infiltration functioning stage II right (ACC) and of a palpable amorphous material with skin atrophy and tel- began treatment with mitotane (300 mg, 3 times daily) with angiectasia mimicking premature aging2 and scattered small supplementary (200 mg/d). One month later, erythematous hyperkeratotic macules and papules on sun- she had developed an itchy eruption without systemic involve- exposed areas.3 The third published report involved normal- ment and she was referred for dermatologic consult. appearing skin on the forearms of patients with infantile cys- She presented with a widespread papulosquamous erup- tinosis examined with in vivo reflectance confocal microscopy.4 tion, predominantly on the upper chest and upper back To our knowledge, the present case report is the first to de- (Figure 1) as well on the extensor surfaces of both arms. No ma- scribe multiple skin-colored, dome-shaped, firm facial pap- lar erythema was present. She had no history of photosensi- ules in a patient with long-term cystinosis. tivity. DISCLE was suspected, and a blood test and a skin bi- A definitive diagnosis of cystinosis can be made based on opsy of 1 lesion on her back were performed. Laboratory an elevated cystine content in peripheral blood leukocytes.1 findings revealed only a mild elevation of liver enzymes. An- Early detection of cystinosis is crucial because early treat- tinuclear antibody, anti-Ro/SSA, and anti-La/SSB findings were ment with oral cysteamine improves growth and survival, pre- all negative. The skin biopsy specimen revealed a superficial vents hypothyroidism, reduces ocular impairment, and can and perivascular infiltrate accompanied by a vacuolization of

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the dermoepidermal membrane along with some necrotic ke- and serological characteristics to idiopathic SCLE.2 Lesions are ratinocytes (Figure 2A). An iron colloidal stain revealed a large usually papulosquamous or annular polycyclic.2,3 No specific mucin deposit in both papillary and reticular dermis diagnostic criteria have been proposed, although certain guide- (Figure 2B). These histological results were compatible with lines have been laid out, such as the absence of clinical indi- lupus erythematosus. cators for lupus erythematosus prior to administering the drug Mitotane treatment was suspended, and the lesions im- and complete clinical resolution after ending drug treatment.4 proved gradually until complete resolution within 3 weeks. Mi- Several different groups of drugs have been associated with totane treatment was not resumed because no signs of ACC re- DISCLE, including calcium channel blockers, β-blockers, di- currence were observed in a computed tomographic study at uretics, antifungals, and more recently, chemotherapeutics and 1-year follow-up. immunomodulators. Among chemotherapeutics, pyrimi- dine analogue drugs (, , and gem- Discussion | DISCLE was first described by Reed et al1 in 1985. It citabine), mitosis inhibitors (, ), anthracy- is a now rare drug-related lupus that presents similar clinical clines ( with ), and antiestrogens (tamoxifen) have been reported to induce DISCLE.3 The mean Figure 1. Subacute Cutaneous Lupus Erythematous Eruption time for induction in these cases ranged from 4 to 6 months, presenting with no clinical or serological differences from DISCLE related to other drugs. All the reported cases resolved after discontinuation of treatment with the drug. Photosen- sitivity, a translocation of the Ro/SS-A antigen to the cell sur- face of keratinocytes, or the release of nucleosomes due to apoptosis—all induced by chemotherapeutic drugs—are the main mechanisms proposed as pathogenic triggers for an au- toimmune response.5 Mitotane is an analogue of the insecticide dichlorodiphe- nyltrichloroethane with adrenolytic properties, approved as adjuvant treatment for ACC.6 The most common adverse ef- fects include fatigue, , , and mild elevation of liver enzymes. We conducted a search for cases of DISCLE re- lated to mitotane therapy in the MEDLINE and PubMed data- bases and found no reports. Mitotane cytostatic and cyto- toxic effects lead to an increase in adrenal cell apoptosis, which might lead to a release of nucleosomes. As has been theo- rized with regard to other chemotherapeutic agents, this phe- A papulosquamous eruption is seen distributed along the back. nomenon could trigger an autoimmune reaction.5

Figure 2. Biopsy Specimens From a Lesion on the Back

A Hematoxylin-eosin B Colloidal iron

A, Perivascular infiltration of the dermis is evident, with vacuolar degeneration of the dermoepidermal junction along with some apoptotic keratinocytes and perivascular lymphocyte infiltration (original magnification ×40). B, Colloidal iron stain reveals a noteworthy mucin deposit in the upper and lower dermis (original magnification ×20).

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Our patient developed a skin eruption that was clinically right chest wall, axillary artery, and vein of the right axilla. and histologically compatible with SCLE after 1 month of mi- (Figure 1A). A skin biopsy performed from a specimen of the totane therapy, which resolved after treatment with the drug axilla revealed that atypical tumor cells had proliferated in the was stopped. Although test results for serological antibodies dermis to the subcutis (Figure 2A). Immunohistochemically, were negative, she met some of the guideline conditions for these tumor cells were positive for gross cystic disease fluid drug-induced LE,4 sufficient to diagnose DISCLE according to protein 15 and HER2 (immunohistochemical score of 3+) our criteria. (Figure 2B and C) and negative for mammaglobin and estro- In conclusion, we report the first case to our knowledge gen and receptors. From these findings, we di- of DISCLE induced by mitotane. It is important for the clini- agnosed the tumor as CAC. Computed tomography (CT) re- cian to enquire about drug intake history when evaluating pa- vealed fused lymph nodes in the right axilla, which infiltrated tients presenting with SCLE. the right chest wall, axillary artery, and vein. The CT findings enabled us to determine that there was no surgical indica- Ander Mayor-Ibarguren, MD tion. Therefore, considering that the tumor cells strongly ex- María Concepción Roldán-Puchalt, MD pressed HER2, we administered the combination of pertu- Cristina Gómez-Fernández, MD zumab and trastuzumab, which are HER2 inhibitors, with Fátima Albízuri-Prado, MD according to the treatment of HER2- Cristina Álvarez-Escola, MD positive metastatic breast cancer (MBC).3-5 These drugs were intravenously administered every 3 weeks. Pertuzumab and Author Affiliations: Department of Dermatology, La Paz Hospital, Madrid, trastuzumab were administered at fixed dosages of 420 mg and Spain (Mayor-Ibarguren, Gómez-Fernández, Albízuri-Prado); Department of 6 mg/kg, respectively, and docetaxel was administered at a dos- Endocrinology, La Paz Hospital, Madrid, Spain (Roldán-Puchalt, Álvarez-Escola). ageof75mg/m2. After 7 cycles of this combination therapy, Corresponding Author: Ander Mayor-Ibarguren, MD, Department of Dermatology, La Paz Hospital, Paseo de la Castellana 261, Z.C 28046 Madrid, erythematous lesions and fused lymph nodes dramatically de- Spain ([email protected]). creased (Figure 1B). At this point, we determined that it was Published Online: October 7, 2015. doi:10.1001/jamadermatol.2015.2702. possible for the patient to undergo surgical treatment. We per- Conflict of Interest Disclosures: None reported. formed a wide local excision of the primary lesion and re- Additional Contributions: We are indebted to the patient for allowing us to use gional lymph node dissection, and the defect was recon- this material for scientific purposes. We would also like to thank John Turcany, structed using the latissimus dorsi musculocutaneous flap language services consultant, for language corrections. Mr Turcany received no (Figure 1C). Pathological results showed that there were vi- compensation for his contributions beyond that received in the normal course of his employment. able tumor cells in dissected lymph nodes; however, the ac- 1. Reed BR, Huff JC, Jones SK, Orton PW, Lee LA, Norris DA. Subacute cessory mammary gland was not identified. Additional radio- cutaneous lupus erythematosus associated with hydrochlorothiazide therapy. therapy was administered on the right axilla with a total dose Ann Intern Med. 1985;103(1):49-51. of 60 Gy, and subsequent trastuzumab monotherapy was ad- 2. Marzano AV, Vezzoli P, Crosti C. Drug-induced lupus: an update on its ministered. Following 11 cycles of this monotherapy,CT showed dermatologic aspects. Lupus. 2009;18(11):935-940. complete response (CR). At the last follow-up, 11 months af- 3. Lowe GC, Henderson CL, Grau RH, Hansen CB, Sontheimer RD. A systematic ter surgical treatment, the patient was disease free. review of drug-induced subacute cutaneous lupus erythematosus. Br J Dermatol. 2011;164(3):465-472. 4. Araújo-Fernández S, Ahijón-Lana M, Isenberg DA. Drug-induced lupus: Discussion | The National Comprehensive Cancer Network Including anti-tumour necrosis factor and interferon induced. Lupus. 2014;23 guidelines recommend the combination of pertuzumab and (6):545-553. trastuzumab with docetaxel as a preferred option for first- 5. Wiznia LE, Subtil A, Choi JN. Subacute cutaneous lupus erythematosus line treatment of patients with HER2-positive MBC.3 In gen- induced by chemotherapy: as a causative agent. JAMA Dermatol. eral, CAC has a histological similarity to the apocrine subtype 2013;149(9):1071-1075. of breast cancer. Therefore, if patients with metastatic CAC have 6. Terzolo M, Daffara F, Ardito A, et al. Management of adrenal cancer: a 2013 update. J Endocrinol Invest. 2014;37(3):207-217. overexpression of HER2, HER2 inhibitors, such as pertu- zumab and trastuzumab, are expected to be effective for them. Pertuzumab and trastuzumab are more active in combi- Metastatic Cutaneous Apocrine Adenocarcinoma nation than when used alone because these 2 agents bind to Treated With a Combination of Pertuzumab-Based different HER2 epitopes and provide a comprehensive signal- Targeted Therapy and Taxane Chemotherapy: ing blockade.6 According to a randomized of pa- A Case Report tients with HER2-positive MBC,4,5 the combination of pertu- There is no effective treatment for metastatic cutaneous apo- zumab and trastuzumab with docetaxel compared with placebo crine carcinoma (CAC). In some cases of CAC, human epider- and trastuzumab with docetaxel significantly improved both mal growth factor receptor 2 (HER2) is overexpressed.1,2 We progression-free and overall survival. Therefore, the addi- report the case of a patient with metastatic CAC for whom a tion of pertuzumab plays an important role in the improve- combination of the anti-HER2 humanized monoclonal anti- ment of outcomes for patients with HER2-positive MBC. How- bodies with taxane chemotherapy was effective. ever, with regard to HER2-positive metastatic CAC, to our knowledge, there are no reports of therapy with pertuzumab. Report of a Case | A man in his 50s presented with an asymp- In the present case, the tumor cells dramatically regressed with tomatic erythematous tumor and lymph nodes fused with the the combination of pertuzumab and trastuzumab with

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