Tetsuo Nagatani

Guidelines for the management of cutaneous lymphomas (2011): A consensus statement by the Japanese Skin Cancer Society - Lymphoma Study Group

In 2010, the first Japanese edition of guidelines for the management of cutaneous lymphoma was published jointly by the Japanese Dermatological Association (JDA) and the Japanese Skin Cancer Society (JSCS) – Lymphoma Study Group. Because the guidelines were revised in 2011 based on the most recent data, we summarized the revised guidelines in English for two reasons: (i) to inform overseas clinicians about our way of managing common types of cutaneous lymphomas such as mycosis fungoides/Sézary syndrome; and (ii) to introduce Japanese guidelines for lymphomas peculiar to Asia, such as adult T‐cell leukemia/lymphoma and extranodal natural killer/T‐cell lymphoma, nasal type. References that provide scientific evidence for these guidelines have been selected by the JSCS – Lymphoma Study Group. These guidelines, together with the degrees of recommendation, have been made in the context of limited medical treatment resources, and standard medical practice within the framework of the Japanese National Health Insurance system.

Phase I/II study of the oral retinoid X receptor agonist bexarotene in Japanese patients with cutaneous T-cell lymphomas

Safety, tolerability, pharmacokinetics and efficacy of bexarotene, a novel retinoid X receptor (RXR)‐selective retinoid, were evaluated in Japanese patients with stage IIB–IVB and relapsed/refractory stage IB–IIA cutaneous T‐cell lymphomas (CTCL). This study was conducted as a multicenter, open‐label, historically controlled, single‐arm phase I/II study. Bexarotene was p.o. administrated once daily at a dose of 300 mg/m2 for 24 weeks in 13 patients, following an evaluation of safety and tolerability for 4 weeks at a dose of 150 mg/m2 in three patients. Eight of 13 patients (61.5%) with an initial dose of 300 mg/m2 met the response criteria using the modified severity‐weighted assessment tool (mSWAT) at 24 weeks or discontinuation. Dose‐limiting toxic effects (DLT) were present in four of 13 patients (31%) at a dose of 300 mg/m2: two neutropenia, one abnormal hepatic function and one hypertriglyceridemia. No DLT was observed in patients received 150 mg/m2 bexarotene. In the 13 patients at 300 mg/m2, common drug‐related adverse events (AE) included hypothyroidism (92%), hypercholesterolemia (77%), leukopenia or neutropenia (39%), nasopharyngitis or anemia (31%). The treatment‐related grade 3 AE included hypertriglyceridemia (4/16 patients, 25%), increased alanine aminotransferase, increased aspartate aminotransferase, dyslipidaemia, leukopenia and neutropenia (1/16 patients, 6%), and one of 16 patients experienced grade 4 hypertriglyceridemia. No patients discontinued bexarotene due to the AE during the study, but dose reduction or suspension was required. Bexarotene was shown to be well tolerated at 300 mg/m2 once daily and effective in Japanese patients with CTCL.

Prevalence of Autoantibodies and the Efficacy of Immunotherapy for Autoimmune Cerebellar Ataxia.

OBJECTIVEnAutoimmune cerebellar ataxias were recently reported to be treatable. However, the proportion of patients with cortical cerebellar atrophy of unknown etiology with autoimmune-associated cerebellar ataxia and the actual effectiveness of immunotherapy in these diseases remain unknown.nnnMETHODSnWe measured the level of autoantibodies (including anti-gliadin antibody, anti-glutamic acid decarboxylase (GAD) antibody, and anti-thyroid antibody) in 58 Japanese patients with cerebellar ataxia, excluding those with multiple system atrophy, hereditary spinocerebellar ataxia, cancer, or those who were receiving phenytoin, and the efficacy of immunotherapy was assessed.nnnRESULTSnThirty-one of 58 (53%) patients were positive for anti-GAD antibody, anti-gliadin antibody, or anti-thyroid antibody. Seven of the 12 anti-gliadin antibody-positive patients, three of the four anti-GAD antibody-positive patients, and three of the six anti-thyroid antibody-positive patients responded well to immunotherapy, indicating that 59% of patients with ataxia-associated antibody-positive cerebellar ataxia undergoing immunotherapy responded well.nnnCONCLUSIONnSome patients with cerebellar ataxia have autoimmune conditions and diagnosing autoimmune cerebellar ataxia is therefore an important component in the care of patients with this disease entity.

A Case of Cutaneous T Cell Pseudolymphoma in a Patient with Helicobacter pylori Infection

Cutaneous pseudolymphomas (CPL) are benign cutaneous lymphoproliferative infiltrations of various origin, including among others bacterial infections, viral infections and drugs . Helicobacter pylori has been frequently founded in the stomach of patients with MALT lymphoma. In January 2001, a 43-year-old man was referred to our department because of a 1-month history of itchy erythematous patches, plaques and flat tumors on his body. Histological examination revealed nodular infiltrations composed of lymphocytes, plasma cells and histiocytes with exocytosis of lymphocytes within the epidermis. Molecular analysis of rearrangement of T cell receptor and immunoglobulin heavy-chain genes did not reveal monoclonality. Based on these clinical, laboratory and histopathological data, a diagnosis of cutaneous T cell pseudolymphoma (CTPL) was made. The patient was anti-H. pylori antibody-positive, and was treated with anti-H. pylori combination with the result that all of the tumors had disappeared by January 2002. The patient has maintained complete response up to the last follow-up visit in December 2005.

Hidradenoma papilliferum of the vulva in association with an anogenital mammary‐like gland

Hidradenoma papilliferum (HP) is a benign adnexal neoplasm which preferentially develops in the anogenital region of women. Although the origin of HP was previously thought to be an apocrine sweat gland, recent studies have suggested that it may derive from the anogenital mammary‐like gland (MLG). In this paper, we present a 43‐year‐old Japanese woman with hidradenoma papilliferum of the vulva. The lesion developed 7 years prior to her visit, and clinically appeared as a skin‐colored cystic nodule. Histopathological examination revealed that the neoplasm was formed by the tubular structures consisting of two types of pleomorphic cells, columnar cells in the luminal layer and cuboidal cells in the basal layer. Further, the surgical specimen contained a wide, divergent, lobular ductal structure located in the vicinity of the neoplastic lesion, which was consistent with MLG.

Primary breast carcinoma en cuirasse derived from invasive lobular carcinoma: the first case report.

Dear Editor, Carcinoma en cuirasse (CEC) preferentially arises in association with the cutaneous involvement of breast carcinomas. A large percentage of cases of breast CECs are secondary (recurrent) lesions following a breast operation, while 0.6– 10% of the cases are primary lesions, i.e., the first manifestation of the breast carcinoma. Herein we report an unusual case of primary breast CEC and discuss the importance of E-cadherin immunohistochemistry for their histopathological classification. A 60-year-old Japanese woman with no remarkable medical history visited our hospital complaining of an unusual eruption on her right breast that slowly increased in size over 35 years. A physical examination revealed a keloid-like erythematous plaque around the right nipple (Fig. 1a). An MRI scan demonstrated an irregular mass on the right mammary gland directly extending to the overlying skin. No other neoplastic lesions were found by CT screening. The findings of the skin biopsy corresponded histologically to the “Indian file” pattern, which consists of dermal changes with a proliferation of thickened collagen bundles and infiltration of a small number of atypical neoplastic cells with linear arrangement between collagen bundles (Fig. 1b,c). Immunohistochemistry showed that the atypical cells were positive for the estrogen receptor (Fig. 1d) and

Comparative analysis of methicillin-resistant Staphylococcus aureus isolated from outpatients of dermatology unit in hospitals and clinics

Community-onset methicillin-resistant Staphylococcus aureus (CO-MRSA) is a causative agent of intractable skin infections. In general, clinical symptoms of hospital outpatients with skin infections are severer than those of clinic patients. Hence, molecular epidemiological features of the CO-MRSA strains from hospital outpatients are predicted to be different from those of clinic patients. Here, we conducted a comparative analysis for CO-MRSA isolates from outpatients with impetigo in hospitals and clinics located in the same district of Tokyo, Japan. Incidence of MRSA infection was higher in hospital outpatients (21.5%, 20/93 isolates) than in clinic patients (14.5%, 121/845 isolates). The resistance rate to clindamycin, which is a common topical antimicrobial agent in dermatology, in the isolates from hospital outpatients (60.0%) was higher than those from clinic patients (31.4%). Proportion of the staphylococcal cassette chromosome (SCC) mec type II, which is a representative type of hospital-acquired MRSA in Japan, in the isolates from hospital outpatients (65.0%) was significantly higher than those from clinic patients (30.6%) (Pxa0<xa00.01). Multilocus sequence typing showed that the clonal complex 89-SCCmec type II (CC89-II) clone, which exhibits clindamycin resistance, was the most predominant (55.0%) in the isolates from hospital outpatients. On the other hand, all CC8-IV, CC121-V, and CC89-V clones accounted for 60% in clinic patients were susceptible to clindamycin. Our findings suggested that the clindamycin-resistant CC89-II CO-MRSA clone might be more related to skin infections in hospital outpatients than clinic patients.

Patient delay in skin cancer: Influence of clinical characteristics and questionnaire results.

gosity (LOH). A 29-year-old Japanese man presented with several painful bluish skin nodules that had appeared 12 years earlier. The patient had epilepsy but was otherwise healthy. Although his mother also had epilepsy, no family members had GVM. Physical examination revealed aggregations of bluish nodules, each of which was approximately 5 mm in diameter, on the left forearm, left lower back and right thigh (Fig. 1a). A biopsy of a back lesion revealed GVM (Fig. 1b,c). Subsequently, we performed sequence analysis of the GLMN gene using DNA samples taken from both peripheral blood and formalin-fixed paraffin-embedded enucleated GVM tissue without using microdissection to isolate pure glomus cell populations after obtaining informed consent, with approval of the ethics committee of Kurume University. Heterozygous and homozygous mutations (c.1150_1151delAG) were identified in exon 13 from peripheral blood DNA and skin lesion DNA, respectively (Fig. 1d). LOH in the skin lesion DNA was identified by microsatellite marker studies using D1S2766, D1S435, D1S2868 and D1S495 around the GLMN locus (Fig. 1e). LOH was determined if the ratio of blood sample ratio (the ratio of peak height of two alleles) to tumor sample ratio was less than 0.67 or more than 1.35. A GLMN mutation has been found in 162 families to date. There are 40 different mutations, and c.157_161del is the most frequent mutation found in 44.4% patients. Only two families had c.1150_1151delAG. Most of the index patients (143/162; 88%), who had GLMN mutations, had a family history of GVM; the remaining 19 patients were considered sporadic. Because our patient did not have a family history, the patient was likely to be a sporadic case. Glomuvenous malformation is confined to limited skin areas. The expressivity of the phenotype is variable for the same mutation. Not all family members harboring a mutation are affected. Considering these facts, a second-hit somatic mutation may be necessary in addition to a germline mutation. In 2002, one case with the 980delCAGAA somatic mutation in a lesion in a patient harboring an inherited large genomic deletion in the GLMN gene was reported. However, in 2011, no second-hit somatic mutation was identified in an Italian family. Recently, 16 somatic second-hit mutations were identified in 28 GVMs. Among 16 mutations, 12 mutations were not intragenic but were acquired uniparental isodisomy (aUPID) on 1p. Interestingly, the breakpoint of each aUPID was located near the centromere at 1p13.1-1p12. In that study, six samples with an inherited mutation of c.3951G>A, c.107dup, c.157_161del, c.395-1G>C or c.743dup demonstrated LOH, and four out of these six samples had 1p aUPID. Although our case showed another LOH in c.1150_1151delAG, no data was available with regard to 1p aUPID. Our case added some legitimacy to the second-hit somatic mutation hypothesis.

Spontaneous multiple eruptive milia in a 91-year-old man.

Dear Editor, Milia (singular: milium) are small, superficial keratinous cysts. There are primary and secondary forms of milia. Primary milia, derived from the lower infundibulum of vellus hairs, develop preferentially on the face of newborns and on the eyelid, cheeks and genitalia of children or adults. By contrast, secondary milia, derived from eccrine ducts or epidermis, occur following trauma such as burns, subepidermal blistering diseases, radiotherapy, or topical use of glucocorticoids and 5-fluorouracil. Multiple eruptive milia are an unusual variant of primary milia, presenting sudden onset and lesions that are more extensive in number and distribution than would be expected in “common” primary milia. The etiology is uncertain. The condition falls into three categories, namely, cases which: (i) occur spontaneously, without a known cause or association; (ii) are the result of autosomal dominant transmission; and (iii) form a component of genodermatosis. A 96-year-old Japanese man presented with asymptomatic, multiple small papules on the neck, which began to develop 4 weeks prior to his visit. The papules were 1–2 mm in diameter and white or yellow in coloration (Fig. 1a). Family history was not relevant. There were no medical problems associated with the lesions. The histopathology revealed small keratinfilled cysts lined with stratified epithelium located in the superficial dermis (Fig. 1b). A sebaceous gland was found attached to the cystic lesions, which indicated that the cysts might have been derived from hair follicles. Further, solar elastosis spreading to the cystic lesion was observed in the reticular dermis. Based on these facts, we made the diagnosis of spontaneous multiple eruptive milia. The patient did not require any treatment. Spontaneous multiple eruptive milia is a rare condition. To our knowledge, only 11 cases, aged 2–96 years (Table 1), have hitherto been reported in English-language publications. Our case represents the oldest individual in whom this condition was found to occur. Spontaneous multiple eruptive milia seem to develop either in the elderly over 60 years of age (four cases) or in juveniles under 20 years of age (six cases). One case was documented in a 48-year-old. Interestingly, three of four elderly cases were male, while juvenile cases were evenly divided between males and females. No clear difference was found in the localization of lesions between elderly and juvenile cases. A neck lesion was described in only one case, besides the present one. Some authors have hypothesized that sunlight may play a role in the pathogenesis of multiple eruptive milia because the lesions preferentially develop in sun-exposed areas. In our case, histopathological findings of the neck lesions revealed solar elastosis. However, this may not be etiological but rather an accidental association because milia were not found on the face. In a case with lesions occurring in non-sun-exposed areas, the authors hypothesized that external stimuli, such as friction or rubbing, might have caused the invagination of epidermal cells and resulted in multiple eruptive milia. Moreover, the case of an elderly male patient with diabetic nephropathy suggested the possibility that chronic renal failure may be related causally to multiple eruptive milia. Despite such conjectures, a clear cause of spontaneous multiple milia still Table 1. Reported cases of spontaneous multiple eruptive milia in English-language publications

A case of cellular neurothekeoma

Contributions: RS Akin, co-primary author, research and diagnosis; RH Cook-Norris, co-primary author, research and diagnosis; MJ Wells, Correspondence, research, paper reviewer and diagnosis; CL Stetson, Chairman Department of Dermatology, Dermatopathology consultant, and reviewer; F Levent, author, contributed to research; RW Scott, author, primary care physician, paper reviewer, Varma SK, author, reviewer, endocrinology consultant.