2 microns
6
This electron micrograph shows a dermal fibroblast with prominent crystalline inclusions within the cytoplasm and some smaller inclusions forming within lysosomes (magnification ×8000).
Discussion | Cystinosis is caused by the accumulation of free cystine within lysosomes.1 Cystine is derived from protein degradation within the lysosome and is normally trans- ported through the lysosomal membrane to the cytosol where it is transformed into cysteine and reused.5 In cysti- nosis, a mutation in the CTNS gene (on chromosome 17p13),6 which encodes cystinosin, leads to a defect in the transport system. The low solubility of cystine leads to the precipita- tion of intracellular needle-shaped crystals as lysosomal cys- tine levels rise.3 The accumulation of cystine in various tis- sues in the body has been known to cause renal failure as well as extrarenal effects leading to ocular, hepatic, thyroid, pancreatic, muscular, dental, gonadal, and neurologic tissue damage.1,3
However, we know of only 3 prior reports of cutaneous ac- cumulation of cystine crystals in patients with cystinosis. The first 2 published reports described subcutaneous infiltration of a palpable amorphous material with skin atrophy and tel- angiectasia mimicking premature aging2 and scattered small erythematous hyperkeratotic macules and papules on sun- exposed areas.3 The third published report involved normal- appearing skin on the forearms of patients with infantile cys- tinosis examined with in vivo reflectance confocal microscopy.4 To our knowledge, the present case report is the first to de- scribe multiple skin-colored, dome-shaped, firm facial pap- ules in a patient with long-term cystinosis.
A definitive diagnosis of cystinosis can be made based on an elevated cystine content in peripheral blood leukocytes.1 Early detection of cystinosis is crucial because early treat- ment with oral cysteamine improves growth and survival, pre- vents hypothyroidism, reduces ocular impairment, and can
preserve renal function.1 Given the improved prognosis for pa- tients with cystinosis who receive renal transplantation and/or cysteamine therapy, the prevalence of extrarenal effects, in- 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 (michael.stevens@sickkids.ca).
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 and premature skin ageing in cystinosis. Lancet. 1998;352(9138):1444-1445.
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 of the skin: a noninvasive means of assessing body cystine accumulation in infantile cystinosis. J Am Acad Dermatol. 2013;68(4):e111-e116.
5. Gahl WA, Bashan N, Tietze F, Bernardini I, Schulman JD. Cystine transport is defective in isolated leukocyte lysosomes from patients with cystinosis. Science. 1982;217(4566):1263-1265.
6. Town M, Jean G, Cherqui S, et al. A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis. Nat Genet. 1998;18 (4):319-324.
Subacute Cutaneous Lupus Erythematosus Induced by Mitotane
Drug-induced subacute cutaneous lupus erythematosus (DISCLE) presents similar clinical and serological characteris- tics to idiopathic SCLE. The following report describes a case of DISCLE induced by mitotane.
Case Report | A woman in her 60s was diagnosed with a non- functioning stage II right adrenocortical carcinoma (ACC) and began treatment with mitotane (300 mg, 3 times daily) with supplementary hydrocortisone (200 mg/d). One month later, she had developed an itchy eruption without systemic involve- ment and she was referred for dermatologic consult.
She presented with a widespread papulosquamous erup- tion, predominantly on the upper chest and upper back (Figure 1) as well on the extensor surfaces of both arms. No ma- lar erythema was present. She had no history of photosensi- tivity. DISCLE was suspected, and a blood test and a skin bi- opsy of 1 lesion on her back were performed. Laboratory findings revealed only a mild elevation of liver enzymes. An- tinuclear antibody, anti-Ro/SSA, and anti-La/SSB findings were all negative. The skin biopsy specimen revealed a superficial and perivascular infiltrate accompanied by a vacuolization of
the dermoepidermal membrane along with some necrotic ke- ratinocytes (Figure 2A). An iron colloidal stain revealed a large mucin deposit in both papillary and reticular dermis (Figure 2B). These histological results were compatible with lupus erythematosus.
Mitotane treatment was suspended, and the lesions im- proved gradually until complete resolution within 3 weeks. Mi- totane treatment was not resumed because no signs of ACC re- currence were observed in a computed tomographic study at 1-year follow-up.
Discussion | DISCLE was first described by Reed et al1 in 1985. It is a now rare drug-related lupus that presents similar clinical
A papulosquamous eruption is seen distributed along the back.
and serological characteristics to idiopathic SCLE.2 Lesions are usually papulosquamous or annular polycyclic.2,3 No specific diagnostic criteria have been proposed, although certain guide- lines have been laid out, such as the absence of clinical indi- cators for lupus erythematosus prior to administering the drug and complete clinical resolution after ending drug treatment. 4
Several different groups of drugs have been associated with DISCLE, including calcium channel blockers, ß-blockers, di- uretics, antifungals, and more recently, chemotherapeutics and immunomodulators. Among chemotherapeutics, pyrimi- dine analogue drugs (fluorouracil, capecitabine, and gem- citabine), mitosis inhibitors (docetaxel, paclitaxel), anthracy- clines (doxorubicin with cyclophosphamide), and antiestrogens (tamoxifen) have been reported to induce DISCLE.3 The mean 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, diarrhea, nausea, 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- nomenon could trigger an autoimmune reaction.5
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).
Our patient developed a skin eruption that was clinically and histologically compatible with SCLE after 1 month of mi- totane therapy, which resolved after treatment with the drug was stopped. Although test results for serological antibodies were negative, she met some of the guideline conditions for drug-induced LE,4 sufficient to diagnose DISCLE according to our criteria.
In conclusion, we report the first case to our knowledge of DISCLE induced by mitotane. It is important for the clini- cian to enquire about drug intake history when evaluating pa- tients presenting with SCLE.
Ander Mayor-Ibarguren, MD María Concepción Roldán-Puchalt, MD Cristina Gómez-Fernández, MD Fátima Albízuri-Prado, MD Cristina Álvarez-Escola, MD
Author Affiliations: Department of Dermatology, La Paz Hospital, Madrid, Spain (Mayor-Ibarguren, Gómez-Fernández, Albízuri-Prado); Department of Endocrinology, La Paz Hospital, Madrid, Spain (Roldán-Puchalt, Álvarez-Escola).
Corresponding Author: Ander Mayor-Ibarguren, MD, Department of Dermatology, La Paz Hospital, Paseo de la Castellana 261, Z.C 28046 Madrid, Spain (andermayor@gmail.com).
Published Online: October 7, 2015. doi:10.1001/jamadermatol.2015.2702.
Conflict of Interest Disclosures: None reported.
Additional Contributions: We are indebted to the patient for allowing us to use this material for scientific purposes. We would also like to thank John Turcany, language services consultant, for language corrections. Mr Turcany received no compensation for his contributions beyond that received in the normal course of his employment.
1. Reed BR, Huff JC, Jones SK, Orton PW, Lee LA, Norris DA. Subacute cutaneous lupus erythematosus associated with hydrochlorothiazide therapy. Ann Intern Med. 1985;103(1):49-51.
2. Marzano AV, Vezzoli P, Crosti C. Drug-induced lupus: an update on its dermatologic aspects. Lupus. 2009;18(11):935-940.
3. Lowe GC, Henderson CL, Grau RH, Hansen CB, Sontheimer RD. A systematic 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: Including anti-tumour necrosis factor and interferon induced. Lupus. 2014;23 (6):545-553.
5. Wiznia LE, Subtil A, Choi JN. Subacute cutaneous lupus erythematosus induced by chemotherapy: gemcitabine as a causative agent. JAMA Dermatol. 2013;149(9):1071-1075.
6. Terzolo M, Daffara F, Ardito A, et al. Management of adrenal cancer: a 2013 update. J Endocrinol Invest. 2014;37(3):207-217.
Metastatic Cutaneous Apocrine Adenocarcinoma Treated With a Combination of Pertuzumab-Based Targeted Therapy and Taxane Chemotherapy: A Case Report
There is no effective treatment for metastatic cutaneous apo- crine carcinoma (CAC). In some cases of CAC, human epider- mal growth factor receptor 2 (HER2) is overexpressed.1,2 We report the case of a patient with metastatic CAC for whom a combination of the anti-HER2 humanized monoclonal anti- bodies with taxane chemotherapy was effective.
Report of a Case | A man in his 50s presented with an asymp- tomatic erythematous tumor and lymph nodes fused with the
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right chest wall, axillary artery, and vein of the right axilla. (Figure 1A). A skin biopsy performed from a specimen of the axilla revealed that atypical tumor cells had proliferated in the dermis to the subcutis (Figure 2A). Immunohistochemically, these tumor cells were positive for gross cystic disease fluid protein 15 and HER2 (immunohistochemical score of 3+) (Figure 2B and C) and negative for mammaglobin and estro- gen and progesterone receptors. From these findings, we di- agnosed the tumor as CAC. Computed tomography (CT) re- vealed fused lymph nodes in the right axilla, which infiltrated the right chest wall, axillary artery, and vein. The CT findings enabled us to determine that there was no surgical indica- tion. Therefore, considering that the tumor cells strongly ex- pressed HER2, we administered the combination of pertu- zumab and trastuzumab, which are HER2 inhibitors, with taxane chemotherapy according to the treatment of HER2- positive metastatic breast cancer (MBC).3-5 These drugs were intravenously administered every 3 weeks. Pertuzumab and trastuzumab were administered at fixed dosages of 420 mg and 6 mg/kg, respectively, and docetaxel was administered at a dos- age of 75 mg/m2. After 7 cycles of this combination therapy, erythematous lesions and fused lymph nodes dramatically de- creased (Figure 1B). At this point, we determined that it was possible for the patient to undergo surgical treatment. We per- formed a wide local excision of the primary lesion and re- gional lymph node dissection, and the defect was recon- structed using the latissimus dorsi musculocutaneous flap (Figure 1C). Pathological results showed that there were vi- able tumor cells in dissected lymph nodes; however, the ac- cessory mammary gland was not identified. Additional radio- therapy was administered on the right axilla with a total dose of 60 Gy, and subsequent trastuzumab monotherapy was ad- ministered. Following 11 cycles of this monotherapy, CT showed complete response (CR). At the last follow-up, 11 months af- ter surgical treatment, the patient was disease free.
Discussion | The National Comprehensive Cancer Network guidelines recommend the combination of pertuzumab and trastuzumab with docetaxel as a preferred option for first- line treatment of patients with HER2-positive MBC.3 In gen- eral, CAC has a histological similarity to the apocrine subtype of breast cancer. Therefore, if patients with metastatic CAC have 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- nation than when used alone because these 2 agents bind to different HER2 epitopes and provide a comprehensive signal- ing blockade.6 According to a randomized clinical trial of pa- tients with HER2-positive MBC,4,5 the combination of pertu- zumab and trastuzumab with docetaxel compared with placebo and trastuzumab with docetaxel significantly improved both progression-free and overall survival. Therefore, the addi- tion of pertuzumab plays an important role in the improve- ment of outcomes for patients with HER2-positive MBC. How- ever, with regard to HER2-positive metastatic CAC, to our knowledge, there are no reports of therapy with pertuzumab. In the present case, the tumor cells dramatically regressed with the combination of pertuzumab and trastuzumab with