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Figure. Clinical Image of Pityriasis Rosea Box. Proposed Diagnostic Criteria for Pityriasis Roseaa

A patient is diagnosed as having pityriasis rosea if: 1. On at least one occasion or clinical encounter, he/she has all the essential clinical features and at least one of the optional clinical features, and 2. On all occasions or clinical encounters related to the eruption, he/ she does not have any of the exclusional clinical features. The essential clinical features are: 1. Discrete circular or oval lesions, 2. Scaling on most lesions, and 3. Peripheral collarette scaling with central clearance on at least two lesions. The optional clinical features are: 1. Truncal and proximal limb distribution, with less than 10% of lesions distal to mid-upper-arm and mid-thigh, 2. Orientation of most lesions along skin cleavage lines, and 3. A herald patch (not necessarily the largest) appearing at least Skin lesions present on the groin, genitals, and pubic mound show multiple oval, two days before eruption of other lesions, noted from patient sharply defined, coalescent, scaly, annular plaques surrounded by erythema. history or from clinical observation. The exclusional clinical features are: Approximately 20% of patients present with atypical or vari- 1. Multiple small vesicles at the center of 2 or more lesions, ant forms of PR, which are less readily recognized than typical 2. Two or more lesions on palmar or plantar skin surfaces, and 3. Clinical or serologic evidence of secondary syphilis. eruptions and may pose a diagnostic challenge.2,3 The mor- phologic characteristics of the eruption may be papular, ve- a This outline was first published by Chuh and Zawar6 and is reproduced here sicular, purpuric or hemorrhagic, or urticarial. Very small le- with permission. sions will be observed in papular PR, and PR with enormous plaques is known as pityriasis rosea gigantea of Darier. A mor- phologic variant characterized by atypical large patches that tend to be few in number and coalescent has been described. 2. Chuh A, Zawar V, Lee A. Atypical presentations of pityriasis rosea: case In this variant, commonly referred to as pityriasis circinata et presentations. J Eur Acad Dermatol Venereol. 2005;19(1):120-126. marginata of Vidal or limb-girdle PR, the eruption generally ap- 3. Brzezinski P, Sinjab AT. Pityriasis rosea in a 12-month-old infant. Our Dermatol pears in the axillae, the groin, or both, with the trunk and ex- Online. 2012;3(2):119-122. 4,5 tremities usually spared. A simple classification for atypical 4. Chukwudi NL. Comment: does pityriasis rosea koebnerize? Our Dermatol pityriasis rosea has been proposed by Chuh and Zawar (Box).6 Online. 2013;4(2):191. In our patient, the eruption fulfills all 3 essential clinical 5. Zawar V, Jerajani H, Pol R. Current trends in pityriasis rosea. Expert Rev features (discrete annular lesions, scaling, and peripheral col- Dermatol. 2010;5(3):325-333. larette scaling with central clearance on at least 2 lesions), all 6. Chuh A, Zawar V. Case reports and studies on pityriasis rosea: from number of patients to meta-analyses and diagnostic criteria. Our Dermatol Online.2012; 3 optional clinical features (relative truncal distribution, ori- 3(2):141-142. entation along skin cleavage lines, and herald patch), and none of the exclusional clinical features. This case has clinical fea- Cutaneous Hemophagocytosis After Alemtuzumab tures of localized PR, papular PR, and pityriasis circinata et mar- Injection in a Patient With Sézary Syndrome ginata of Vidal. It should also be noted that the involvement Alemtuzumab, a CD52 monoclonal antibody, is increasingly of penile and scrotal skin is rarely reported in PR. Physicians used for treating advanced cutaneous T-cell lymphomas in- should be aware of the wide spectrum of PR variants so that cluding Sézary syndrome (SS). While injection site reactions appropriate management and reassurance can be offered. are common, the finding of localized cutaneous hemophagocytosis at the injection site without systemic hemophagocy- Piotr Brzezinski, MD, PhD tosis is rare. Anca Chiriac, MD, PhD Report of a Case | A woman in her 60s presented with a 2-year his- Author Affiliations: Dermatological Clinic, Sixth Military Support Unit, Ustka, Poland (Brzezinski); Department of Dermatology, Nicolina Medical Center, Iasi, tory of SS (clinical stage IVA [T4NXM0B2]). After multiple regi- Romania (Chiriac). mens failed, she was treated with subcutaneous alemtuzumab Corresponding Author: Piotr Brzezinski, MD, PhD, Department of injections (10 mg each) thrice weekly for 10 weeks and experi- Dermatology, Sixth Military Support Unit, os Ledowo 1N, 76-270 Ustka, Poland enced complete remission. However, her disease recurred 7 ([email protected]). months after therapy was completed. She restarted treatment Published Online: July 30, 2014. doi:10.1001/jamadermatol.2013.10505. with alemtuzumab and 1 month later developed large, tender, Conflict of Interest Disclosures: None reported. indurated plaques on the left lower abdomen and right thigh at 1. Chuh AA, Lee A, Molinari N. Case clustering in pityriasis rosea: a multicenter epidemiologic study in primary care settings in Hong Kong. Arch Dermatol. her injection sites (Figure, A). Analysis of a right thigh biopsy 2003;139(4):489-493. specimen (Figure, B) showed a deep dermal and subcutaneous

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Figure. Clinical and Pathologic Images From a Case of Cutaneous Hemophagocytosis After Subcutaneous Alemtuzumab Injection

A B

A, Clinical image of erythematous to brown indurated plaque on right lateral thigh following subcutaneous injection with alemtuzumab. B, Pathologically, a deep dermal infiltrate consisting of histiocytes, neutrophils, extravasated erythrocytes, and scattered atypical lymphocytes was present; histiocytes with phagocytosed neutrophils, lymphocytes, and erythrocytes were seen (hemophagocytosis; arrowheads) (hematoxylin-eosin, original magnification ×400).

infiltrate of lymphocytes, histiocytes, and neutrophils consis- papular eruption. In virus-induced cases, the cutaneous tent with injection site reaction. Numerous histiocytes contained appearance may reflect the underlying cause. Typical histo- phagocytosed lymphocytes, erythrocytes, and/or neutrophils pathologic characteristics include a dermal perivascular lym- without features of vasculitis or vasculopathy. Immunohisto- phohistiocytic infiltrate, nuclear debris, extravasated eryth- chemical analysis showed a normal CD4:CD8 ratio of 3:1. The re- rocytes, and, rarely, hemophagocytosis in skin lesions.1 sults of blood tests and in situ hybridization assays for Epstein- We describe herein a case of localized cutaneous hemo- Barr virus (EBV)–encoded RNA and EBV DNA were negative. phagocytosis in an injection site reaction without evident sys- The dose of alemtuzumab was decreased, and then the full temic involvement. To our knowledge, only 4 cases of cutane- dose was resumed with dexamethasone premedication, and ous hemophagocytosis have been previously reported, with an finally alemtuzumab therapy was discontinued altogether ow- underlying condition identified in 3 of these 4 cases (lymphoma, ing to persistent, painful injection site reaction. The indu- autoimmune disease).2,3 A viral trigger was suspected but not rated erythematous plaques slowly resolved under treat- confirmed in the fourth case. In all cases, there was no evidence ment with clobetasol, 0.05%, ointment. The patient of extracutaneous hemophagocytosis, with the isolated skin subsequently started a clinical trial of therapeutic PI-3 (phos- findings possibly representing a form of leukocytoclastic vas- phatidylinositide 3) kinase inhibitor. culitis. Features of vasculitis were not identified in our case. Peripheral T-cell lymphomas (PTCLs) have also been asso- Discussion | Hemophagocytosis (the engulfment of erythro- ciated with development of HPS. Reactivation of EBV is thought cytes, their precursors, and occasionally white blood cells by to play a role, although it is unclear whether EBV-infected ma- typically benign histiocytes) involves multiple sites (spleen, lignant T cells initiate HPS or if latent EBV infection predis- bone marrow, lymph nodes), usually in association with he- poses to HPS.4 The development of HPS was reported in 2 of mophagocytic syndrome (HPS). Characterized by high fever, 14 patients with relapsed or refractory PTCL treated with ale- cytopenias, liver dysfunction, and coagulopathy, HPS can oc- mtuzumab and was attributed to EBV reactivation in the set- cur primarily (eg, inherited defects of cellular toxic effects) or ting of PTCL.5 Alemtuzumab has never been linked to HPS in secondarily (infections, autoimmune/rheumatologic dis- mycosis fungoides or SS and chronic lymphocytic leukemia eases, and malignant conditions, particularly lymphomas).1 (CLL). Recent data have shown that soluble CD52 detected in Secondary HPS may result from dysfunctional cytotoxic T and plasma of patients with CLL can form immune complexes with natural killer cells, leading to excess cytokine production and alemtuzumab.6 However, an underlying immune complex– uncontrolled activation of lymphocytes and histiocytes.1 mediated mechanism seems unlikely in our case in which the Cutaneous findings are seen in 6% to 65% of HPS cases. reaction was localized to the injection site and there was no vas- Clinically, most present with a nonspecific maculopapular cular damage. Hemophagocytic syndrome in PTCL is thought eruption, with occasional purpura, erythroderma, and edema.1 to result from cytokine release (interferon-γ, tumor necrosis fac- Skin findings may be specific to the underlying malignant con- tor, and interleukin-1) by activated reactive and malignant T dition (eg, cutaneous lymphoma), manifestations of reactive cells. While our patient was EBV-negative, we speculate that HPS (ie, jaundice and purpura), or a nonspecific maculo- the alemtuzumab injections induced a similar but localized hy-

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percytokine response from reactive and possibly malignant T suppressive therapy included prednisone, mycophenolate cells, resulting in focal cutaneous hemophagocytosis. mofetil, and sirolimus. Eight years after his first transplantation, but only a few months after he began sirolimus treatment, Sarah I. Jawed, BA he developed left upper extremity lymphedema on the same arm Klaus Busam, MD as the arteriovenous fistula (AVF) used for dialysis. The lymph- Xuan Wang, MD, PhD edema was still present at last follow-up (Figure). Complemen- Steven Horwitz, MD tary studies such as Doppler ultrasonography and magnetic reso- Christiane Querfeld, MD, PhD nance angiography showed normal findings, and the lymphedema could not be attributed to any cause other than si- Author Affiliations: Dermatology Service, Department of Medicine, Memorial rolimus. The AVF was tied off; sirolimus treatment was discon- Sloan-Kettering Cancer Center, New York, New York (Jawed, Querfeld); Weill Cornell Medical College, New York, New York (Jawed, Busam, Wang, Horwitz, tinued; and he began acupressure treatment (an alternative medi- Querfeld); Department of Pathology, Memorial Sloan-Kettering Cancer Center, cine technique based on the application of physical pressure is New York, New York (Busam, Wang); Lymphoma Service, Department of to trigger points) with some improvement of lymphedema. Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York (Horwitz). Corresponding Author: Christiane Querfeld, MD, PhD, Dermatology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 160 E 53rd Patient 2. A woman in her 40s developed chronic renal failure St, New York, NY 10022 ([email protected]). secondary to polycystic renal disease and required renal trans- Published Online: July 16, 2014. doi:10.1001/jamadermatol.2013.10615. plantation. Her medical history was relevant for hypertension, Conflict of Interest Disclosures: None reported. hiatal hernia, and temporal lobe epilepsy. Her immunosuppres- 1. Fardet L, Galicier L, Vignon-Pennamen MD, et al. Frequency, clinical features sive therapy included prednisone, mycophenolate mofetil, and and prognosis of cutaneous manifestations in adult patients with reactive tacrolimus. This treatment regimen was changed to prednisone haemophagocytic syndrome. Br J Dermatol. 2010;162(3):547-553. and sirolimus when she developed polyomavirus nephritis a year 2. Valentín SM, Montalván E, Sánchez JL. Perivascular hemophagocytosis: report after transplantation. One year after sirolimus was added to her of 2 cases and review of the literature. Am J Dermatopathol. 2010;32(7):716-719. regimen, she developed chronic lymphedema in her right breast 3. Draper NL, Morgan MB. Dermatologic perivascular hemophagocytosis: a report of two cases. Am J Dermatopathol. 2007;29(5):467-469. and forearm, the same side of her body as her former AVF.No ax- 4. Yao M, Cheng AL, Su IJ, et al. Clinicopathological spectrum of illary lymph nodes were found. Mammography, magnetic reso- haemophagocytic syndrome in Epstein-Barr virus-associated peripheral T-cell nance imaging, skin biopsies of the breast, Doppler ultrasonog- lymphoma. Br J Haematol. 1994;87(3):535-543. raphy,and tumor markers assays were repeatedly performed, and 5. Enblad G, Hagberg H, Erlanson M, et al. A pilot study of alemtuzumab all findings were normal. After malignancy was ruled out, her (anti-CD52 monoclonal antibody) therapy for patients with relapsed or chemotherapy-refractory peripheral T-cell lymphomas. Blood. 2004;103(8): chronic lymphedema could not be attributed to any cause other 2920-2924. than sirolimus. It did not improve during a follow-up of 5 years. 6. Albitar M, Do KA, Johnson MM, et al. Free circulating soluble CD52 as a Unfortunately, the patient died 8 years after transplantation due tumor marker in chronic lymphocytic leukemia and its implication in therapy to primary central nervous system lymphoma. with anti-CD52 antibodies. Cancer. 2004;101(5):999-1008.

Chronic Lymphedema in Renal Transplant Recipients Discussion | Adverse effects of mTOR (mammalian target of rapa- Under Immunosuppression With Sirolimus: mycin) inhibitors include hyperlipidemia, thrombocytopenia, Presentation of 2 Cases lymphocele, hernia, delayed wound healing, thrombotic micro- angiopathy, interstitial pneumonitis, angioedema, edema of the Report of Cases | Patient 1. A man in his 40s developed chronic eyelids, and acneiform eruptions. Chronic lymphedema is very renal failure secondary to glomerulonephritis and required re- rare, and only a few cases have been described in the literature.1-3 nal transplantation. Thirteen years later, he required retrans- To relate this adverse event to the drug, it is necessary to exclude plantation. His medical history was relevant for hypertension, other causes of lymphedema. Therefore a negative family his- dyslipidemia, and severe ischemic heart disease. His immuno- tory for lymphedema, no evidence of underlying neoplasm, and

Figure. Left Lower Arm Lymphedema

Lymphedema in patient 1 developed a few months after sirolimus treatment was begun.

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