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Syringocystadenocarcinoma papilliferum (SCACP) is a very rare cutaneous adnexal neoplasm. SCACP presents histologic variability, and it is difficult to establish the diagnosis from a punch biopsy. SCACP has an overall configuration similar to that of syringocystadenoma papilliferum (SCAP). When we diagnose SCACP, the histologic features of SCAP can be contributing and immunohistochemical staining is useful. Our case shows the histologic variability of SCACP and the pitfalls of a punch biopsy for the diagnosis of SCACP.

SummaryBackground In extramammary Paget's disease (EMPD), Paget cells are sometimes detected outside the clinical border (subclinical extension). The spreading pattern of Paget cells in subclinical extension, however, remains unclear. In addition, the macroscopic appearances of lesions accompanied by subclinical extension are totally unknown. Objectives To characterize the spreading pattern of Paget cells as well as the macroscopic appearance of lesions of EMPD with subclinical extension. Methods Nineteen patients with primary anogenital EMPD underwent mapping biopsies and excisional surgeries, then biopsy samples were taken at the periphery of well-demarcated lesions. Samples were transparentized and subjected to whole-mount immunostaining with anti-cytokeratin 7 antibody to label Paget cells. The histological border was evaluated in three dimensions by two-photon microscopy. The shape and location of the histological border were compared with those of the clinical border. Results In 21 samples taken at the lesion where subclinical extension was not shown by mapping biopsy, the shape and location of the histological border were almost identical to those of the clinical border. Two samples, however, exhibited small foci of Paget cells outside the clinical border, showing subclinically extended satellite lesions. In the two samples taken at the lesions where subclinical extension was shown by mapping biopsy, a continuous arrangement of Paget cells extending beyond the clinical border was identified. Subclinically extended Paget cells were detected solely outside hypopigmented patches with erythema. Conclusions In EMPD, at least two patterns of subclinical extension exist: continuous and satellite lesions. Subclinical extension might exist preferentially outside hypopigmented patches with erythema. This article is protected by copyright. All rights reserved.

Although nivolumab is associated with a significant improvement in overall survival and progression-free survival, only 20 to 40% of patients experience long-term benefit. It is therefore of great interest to identify a predictive marker of clinical benefit for nivolumab. To address this issue, the frequencies of CD4+ T cell subsets (Treg, Th1, Th2, Th9, Th17 and Th22), CD8+ T cells, and serum cytokine levels (IFNγ, IL-4, IL-9, IL-10, TGF-β) were assessed in 46 patients with melanoma. Eighteen patients responded to nivolumab, and the other 28 patients did not. An early increase in Th9 cell counts during the treatment with nivolumab was associated with an improved clinical response. Before the first nivolumab infusion, the responders displayed elevated serum concentrations of TGF-β compared to non-responders. Th9 induction by IL-4 and TGF-β was enhanced by PD-1/PD-L1 blockade in vitro. The role of IL-9 in disease progression was further assessed using a murine melanoma model. In vivo IL-9 blockade promoted melanoma progression in mice using an autochthonous mouse melanoma model, and the cytotoxic ability of murine melanoma-specific CD8+ T cells was enhanced in the presence of IL-9 in vitro. These findings suggest that Th9 cells, which produce IL-9, play an important role in the successful treatment of melanoma patients with nivolumab. Th9 cells therefore represent a valid biomarker to be further developed in the setting of anti-PD-1 therapy.

Summary Background ‘FOXP3+ regulatory T cells’ (Tregs) are reported to be increased in tumour-bearing hosts including patients with melanoma, leading to tumour immune suppression. However, this idea is challenged by recent evidence that the ‘FOXP3+ Treg’ fraction in fact contains activated ‘nonregulatory’ T cells. Also, FOXP3+ T cells are reported to have functionally and kinetically distinct subsets. Objectives To investigate whether either or both of regulatory and ‘nonregulatory’ FOXP3+ T cells are perturbed in patients with melanoma. Methods FOXP3+ T cells were classified into three subsets, namely CD45RO+FOXP3low nonregulatory T cells, CD45RO+FOXP3high effector Tregs, and CD45RO−FOXP3low naive Tregs, according to their expression levels of FOXP3 and CD45RO. The percentage and cytokine production of these FOXP3+ T-cell subsets were assessed by flow cytometry. Results Both regulatory and nonregulatory T cells were increased in patients with melanoma. Moreover, we found three unexpected perturbations in FOXP3+ T-cell subsets: (i) patients with melanoma showed higher frequencies of FOXP3low nonregulatory T cells, which decreased and normalized after tumour removal; (ii) FOXP3low naive Tregs containing higher frequencies of interferon-γ+ cells increased with tumour progression; and (iii) CD45RO+FOXP3high effector Tregs were pronouncedly infiltrated around tumour tissues. Conclusions These findings demonstrate that patients with melanoma have distinct and differential perturbation of both regulatory and nonregulatory FOXP3+ T cells. The degree of perturbation is associated with tumour burden and progression, suggesting that the perturbation reflects fundamental pathophysiological processes in patients with melanoma. The presented analysis provides a practical approach to investigate the immunological environment of cancer patients.

症例は30代女性。右足関節の悪性軟部組織腫瘍にて当院整形外科で化学療法中であった。右足底の色素斑が拡大してきたという主訴で当科を紹介受診した。経過観察したところ1カ月間で色素斑は5.5×5.5mm大から7.0×5.5mmと拡大し, 色調も初診時に比べ濃淡差を認めるようになった。ダーモスコピーでは皮丘パターンを示しており悪性黒色腫を疑った。足底の色素斑を全摘生検したところ病理組織は単純黒子であった。色素斑は化学療法により生じたものであると推測された。

A wild type keratin 9 (K9) cDNA and a point mutated keratin 9 cDNA were injected subcutaneously into mouse skin. The hemagglutinin tag staining of the wild type K9 cDNA injected specimens mainly showed a homogeneous pattern, whereas the point mutated K9 cDNA injected specimens mainly showed a granular pattern in the suprabasal cells. Double staining of K9 and the endogenous keratin revealed the incorporation of de novo synthesized K9 into the keratin network. These results demonstrate that (1) a naked DNA transfection into mouse skin can detect the pathogenic changes of point mutated keratin in vivo and (2) the keratin 9 mutation disrupts the keratin network formation in the suprabasal cells in vivo.

We report a 36-year-old woman with complex regional pain syndrome (CRPS) type 1 presenting with extensive skin necrosis of the left arm. The patient cooled her arm with ice packs to ease severe pain due to CRPS, in spite of repeated cautions against frostbite injury. The regions of skin necrosis corresponded with the sites where she had applied ice packs. We considered that the severe skin necrosis in our case was due to a self-induced frostbite injury.

We describe the first reported instances of juvenile xanthogranuloma (JXG) in dizygotic twins. They had characteristic skin lesions and subcutaneous nodules as well as hepatomegaly, anemia, and thrombocytopenia. These extracutaneous symptoms improved in 5 months, coincident with the resolution of the skin lesions. Although most patients with JXG have only cutaneous symptoms, some show such dramatic extracutaneous manifestations that the possibility of malignant disease is occasionally the principle concern. It is therefore necessary to make a precise diagnosis based on specific immunohistochemical and ultrastructural findings, and to evaluate for other organ involvement, including hematologic abnormalities.

This study was performed to elucidate whether xeroderma pigmentosum complementation group A (XPA) carrier has DNA repair abnormality against sun-exposure and ultraviolet (UV)-mimetic chemical carcinogen 4-nitroquinoline 1- oxide (4NQO). Here we report three sporadic cases of XP that were defined as group A by genetic complementation test as well as polymerase chain reaction (PCR) analysis to detect the point mutation in the responsible gene for XPA. DNA repair analyses in the skin fibroblasts revealed that the cells from the patients were much more sensitive to UV and 4NQO and had extremely low UV-induced unscheduled DNA synthesis (UDS) than control cells, whereas the cells from the carriers (heterozygotes of XP) had sensitivity to UV and 4NQO and levels of UV-induced UDS similar to normal cells. These results indicate that the obligate heterozygotes, despite having a mutated allele in XPA complementing gene demonstrated by PCR, have no DNA repair abnormality after UV irradiation and UV-mimetic 4NQO treatment. Our observations imply that XPA heterozygotes do not have higher risk of skin cancers than normal subjects based on their DNA repair abnormality.

We report a case of malignant melanoma (MM) derived from cerebriform intradermal naevus (CIN) in a 66-year-old Japanese man. The patient had cutis verticis gyrata (CVG) on the posterior area of the scalp at birth. He noticed a dome-shaped nodule at the centre of the CVG at 66 years of age. Histopathological examination found a nodule of MM arising within an extensive area of intradermal naevus. There was no metastasis to lymph nodes or other organs. To our knowledge, only two cases of CIN in which MM had later developed have been reported. We estimated that the incidence of melanoma from CIN including our case is 4.5% (3 of 67 reported cases), which seems to be comparable to the frequency of malignant alteration of giant pigmented naevi. This suggests that pathological examination is recommended for CVG, and once pathological diagnosis of CIN is confirmed, long clinical follow-ups are necessary for detecting development of MM.

Malignant melanoma usually shows resistance to a standard chemotherapy regimen. A useful in vitro method to evaluate individual chemosensitivity is required to select effective anti-cancer drugs. This study aimed to establish in vitro tumor response testing for malignant melanoma. We determined the chemosensitivity of primary cultured melanoma cells using the collagen gel droplet-embedded culture drug sensitivity test (CD-DST). Nineteen tests were carried out for 15 cases of malignant melanoma. Primary cultured melanoma cells in collagen gel droplets were exposed to anti-cancer drugs, including cisplatin, adriamycin, dacarbazine, nimustine and vincristine. After a 7-day incubation in a serum-free medium, living melanoma cells in a collagen droplet were detected by image analysis after staining with Neutral red reagent. In vitro drug exposure conditions were determined to reproduce the value of the plasma area under the time-drug concentration curve in vivo. The rate of evaluation of the primary culture of melanoma cells was 78.9% (15/19 tests). The chemosensitivity of cisplatin, adriamycin, dacarbazine, nimustine and vincristine was 15, 62, 0, 0 and 62%, respectively. Dacarbazine was not suitable for CD-DST due to its prodrug characteristics. The CD-DST method was able to evaluate the chemosensitivity of malignant melanoma to anti-cancer drugs in vitro. This method can also be applied to estimate the efficacy of newly developed anti-cancer drugs in vitro.

A 57-year-old Japanese man with tumor-stage mycosis fungoides suddenly presented multiple small papules on the right chest. Histopathology of a biopsy specimen from the papules revealed medium-to-large pleomorphic lymphoid cells throughout the entire dermis but not in the epidermis, and the large cells expressed CD30 antigen. These newly-developed papules underwent spontaneous remission in the following 3 months. We reviewed the reported cases of mycosis fungoides, which showed CD30-positive large cell transformation and those of CD30-positive lymphoproliferative disorders associated with mycosis fungoides.

ejd.2013.2159 Auteur(s) : Kenji Sakurai beautifulskyblue58@yahoo.co.jp, Teruasa Murata, Mizue Yamamoto, Satoshi Kore-eda Department of Dermatology, Tenri Hospital, 200 Mishima-cho, Tenri, Nara 632-8552, Japan A 73-year-old Japanese woman visited our hospital mainly with complaints of fever, general malaise and multiple subcutaneous nodules. She had a 10-year history of rheumatoid arthritis (RA) and had been treated with oral methotrexate (MTX), 8 mg/week for the past 6 years. At the initial [...]

a 64-year-old woman with a 4-year history of pruritic erythema was admitted to our hospital because of aggravation of the erythema that did not respond to 20 mg/ day oral prednisolone. The patient had had malignant thymoma and myasthenia gravis for 12 years, together with recurrent oral herpes infection for several years. In spite of thymectomy, chemotherapy, and radiation therapy, malignant thymoma was disseminated to the thoracic cavity and no more treatment options could be utilized on admission. The patient presented with erythema that was scaly, mildly keratotic, and distributed over the face, body trunk, and extremities (Fig. 1a). The patient reported severe pruritus. Biopsy specimen of the erythema revealed superficial perivascular dermatitis with parakeratosis, hypogranulosis, dyskeratosis with satellite cell necrosis, mild acanthosis, and vacuolar change in the epidermis, and moderate infiltration of lymphocytes in the upper dermis (Fig. 1b). Direct immunofluorescence was negative (data not shown). Immunohistochemistry revealed that there were more CD8+ T cells than CD4+ T cells infiltrated in the epidermis and dermis (Fig. 1c, d). Differential diagnoses included psoriasis, lichen planus, pityriasis rosea, lichenoid drug eruption, pityriasis lichenoides chronica, and thymoma-associated GVHD-like erythroderma. psoriasis was ruled out by the presence of dyskeratosis, and parakeratosis is not usually observed in lichen planus. The clinical course was too long for pityriasis rosea, and lichenoid drug eruption could be ruled out because of the absence of eosinophils in the dermis. Furthermore, pityriasis lichenoides chronica is not usually pruritic and the eruptions are more oval than those of our case. Based on the characteristic distribution and clinical features of the erythema and pathological findings, a diagnosis of thymoma-associated GVHD-like erythroderma was made. potent topical steroid (clobetasol propionate 0.05%), systemic steroid (prednisolone 2 mg/kg/day), and cyclosporine (5 mg/kg/day) were prescribed for 2 weeks, but did not control the erythema (Fig. s1; available from http://www.medicaljournals.se/acta/content/?d oi=10.2340/00015555-1577). Intriguingly, after the initiation of oral acyclovir (15 mg/kg/day) for exacerbated oral herpes infection, the erythema began to subside. acyclovir was then switched to valacyclovir hydrochloride (15 mg/kg/day). Incidentally, we detected a high level of CMV antigenemia of up to 1,564 cells/slide, although it was only 11 cells/slide 6 months previously. The patient did not report any symptoms of retinitis, pneumonia, or colitis, thus we administered ganciclovir (5 mg/kg/day) and discontinued valacyclovir. The erythema recurred when prednisolone was tapered to 0.75 mg/kg/day; therefore, prednisolone was increased up to 1 mg/kg/day, which was not successful. Next, broadband ultraviolet Reactivation of Herpes Simplex Virus and Cytomegalovirus in a Case of Thymoma-associated Graft-versus-host Disease-like Erythroderma

ejd.2012.1705 Auteur(s) : Satoshi Nakamizo, Akiko Arakawa arakawa@kuhp.kyoto-u.ac.jp, Akihiko Kitoh, Satoshi Kore-Eda, Atsushi Utani, Yoshiki Miyachi Department of Dermatology, Kyoto School of Medicine, 54 Shogoin-Kawara, Sakyo, Kyoto 606-8507, Japan Muir-Torre syndrome (MTS) is a cancer susceptibility syndrome, defined as the association of sebaceous tumor and internal malignancy [1]. Tumors in MTS are characterized by the accumulation of microsatellite instability (MSI) in a repeated sequence [...]

To detail the histogenetic relationship between basal cell carcinoma (BCC) and hair follicles, a monoclonal antibody, coded as MMKB-1 and established from immunization of mice by human basal cell carcinoma (BCC) tissues, was immunohistochemically studied in tissues of BCC and squamous cell carcinoma (SCC) of the skin, as well as in normal human skin tissues. On 1M-NaCl-split normal human skin tissues, it reacted against both the epidermal and the dermal sides of the basement membrane zone (BMZ). This monoclonal antibody reacted to the BMZ and intercellular space (ICS) of the solid, superficial, and fibrosing types of BCC cell nests, but, in SCC tumor cell nests, it reacted exclusively to the BMZ. Immunoelectron microscopic studies revealed that the corresponding antigen of the monoclonal antibody was distributed in the hemidesmosomes and the anchoring fibrils along the BMZ of the normal human skin and the desmosomes of the BCC cell nest. The monoclonal antibody also reacted to the ICS of the lower outer root sheath and hair matrix. We discussed the histogenesis of BCC and hair follicles, referring to the results of the staining patterns of MMKB-1 monoclonal antibody and to other studies suggesting a histogenetic relationship between BCC and hair follicles.

ejd.2011.1295 Auteur(s) : Yuka MASUNO1, Yumi MATSUMURA1 yumatsu@kuhp.kyoto-u.ac.jp, Mayumi KATOH1, Akiko ARAKAWA1, Satoshi KORE-EDA1, Takayuki ISHIKAWA2, Yoshiki MIYACHI1 1 Department of Dermatology, 2 Department of Haematology, Kyoto University Medical School, 54 Shogoin-Kawahara-cho, Sakyo-ku Kyoto 606-8507, Japan Eosinophilic, polymorphic, and pruritic eruption associated with radiotherapy (EPPER) – first described by Rueda et al. in 1999 [1] – has been described in cancer patients [...]

Auteur(s) : Yuichiro Endo1, Miki Tanioka1,2, Reiko Taki1, Satoshi Kore-Eda1, Atsushi Utani1, Yoshiki Miyachi1 1Department of Dermatology, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan 2Fukui Red Cross Hospital Actinomyces are gram-positive, non-acid fast anaerobic bacteria that are normal inhabitants of the oral cavity and intestinal tract, but acquire pathogenicity through invasion of breached or necrotic tissue [1-6]. The most common pathogen is Actinomyces israelii. [...]

Sir, Eccrine angiomatous hamartoma (EAH) is a rare benign hamartoma of eccrine glands and blood vessels. It most commonly develops before adulthood as a single, slowgrowing lesion on the extremities. We describe here a case of adult-onset EAH with generalized multiple hairy reddish-brown indurated plaques with a rapidly progressive course. As the lesions showed histopathological findings such as an increase in mature eccrine glands and blood vessels, the diagnosis was determined to be EAH. This case was observed carefully because the lesion had characteristics not only of a hamartoma but also of a tumour.

To detail the histogenetic relationship between basal cell carcinoma (BCC) and hair follicles, we immunohistochemically compared BCC cells to follicular matrix cells and follicular bulge cells using a panel of monoclonal antibodies against melanocytes, cytokeratins, subepidermal extracellular matrix components, and bullous pemphigoid (BP) sera, as well as using electron microscopy. Cytokeratin expression patterns were not consistent with the variety in types of cytokeratins and in cases of BCC. The distribution of some extracellular matrix components was not only linear along the interfaces of BCC tumor nests and stroma, and follicular matrix and follicular papilla; granular deposits were also seen in the stroma and follicular papilla, whereas they were only linearly distributed along the follicular bulge. The BP antigens and integrin alpha 6, which were absent in BCC and follicular matrix, were expressed in the follicular bulge area. Electron microscopically, hemidesmosomes were poorly organized in these three tissues, but the lamina densa was incomplete in BCC and follicular matrix, whereas the lamina densa in the follicular bulge area was continuous. These morphologic similarities between BCC and follicular matrix cells, and coexistence of melanocytes in the BCC tumor nest strongly suggest the differentiation of BCC toward the follicular matrix cells.

Summary Immunofluorescence microscopy of epidermodermal junction components in serial cryosections from the perilesional skin of a patient with generalized atrophic benign epidermolysis bullosa (GABEB) showed broken line-like staining of both BPAG2 (180-kDa bullous pemphigoid antigen) and uncein (antigen of 19-DEJ-l monoclonal antibody), whereas integrin α6 and laminin 5 were continuously expressed along the basement membrane zone. Immunoelectron microscopy revealed a mosaic distribution of the BPAG2/uncein positive and negative cells. BPAG2, a candidate protein of GABEB, probably has a close connection with uncein, an anchoring filament component.

We present the case of a 69-year-old woman with type 2 diabetes mellitus who developed severe insulin resistance associated with insulin injections into a subcutaneous mass formed by repeated injections into the same site over many years. The patient (height, 150 cm; weight, 79 kg; BMI, 35.1 kg/m2) was admitted to Tenri Hospital with severe insulin resistance. She was undergoing insulin therapy since 56 years of age. Her glycemic control was fair until 63 years of age, after which it worsened and necessitated an increase in her insulin dose. This led to a 15-kg increase in body weight. On admission, her insulin regimen comprised a single injection of 33 units of neutral protamine Hagedorn insulin at bedtime and three daily injections of 33 units of premixed human insulin (70/30) before each meal. …

We report a case of focal dermal hypoplasia (FDH) with multiple giant papillomas on nonperimucosal areas. The patient had had cribriform hyperpigmented and depigmented plaques on the trunk and extremities since birth. There were also hypoplastic skin lesions on the right arm, left elbow and right thigh. The multiple giant papillomas began to appear, when she was 22 years old, on the trunk and extremities. Cryotherapy was effective in controlling them.

Pleomorphic blisters, including tense bullae and annularly arranged vesicles around the erythema as well as erosive eruptions in the oral cavity, appeared on a 61-year-old woman 5 years after surgery for cholangiocellular carcinoma. A biopsy specimen from the oral cavity showed intraepidermal blisters, and those from skin lesions showed subepidermal blisters with infiltrates of eosinophils and neutrophils. The early-stage vesicles showed infiltrates along the epidermal-dermal junction, where electron microscopy disclosed disruption of the lamina densa, basal cells remaining on the dermis, and acantholytic keratinocytes among the infiltrates, but there was no cleavage of the epidermal-dermal junction at the lamina lucida. Direct immunofluorescence studies showed immune deposition at the intercellular space (ICS) and along the basement membrane zone (BMZ). Indirect immunofluorescence studies confirmed coexistence of IgG class anti-ICS and anti-BMZ antibodies. Although this case showed immunohistochemical features of bullous pemphigoid, the presence of suprabasal cleavage in the oral mucosa, acantholytic cells in the blister cavity, the deposition of IgG at the ICS of the perilesional epidermis, and circulating anti-ICS antibodies strongly suggested that this case was primarily pemphigus. The strong inflammation along the epidermal-dermal junction due to unknown factors may have modified the clinical appearance and the histopathology.

ejd.2012.1827 Auteur(s) : Chisa Nakashima otsukamn@kuhp.kyoto-u.ac.jp, Atsushi Otsuka, Hiroko Sonobe, Akihiko Kitoh, Mayumi Kato, Satoshi Kore-Eda, Yoshiki Miyachi, Kenji Kabashima Department of Dermatology, Kyoto University School of Medicine, 54 Shogoin-Kawara Sakyo, Kyoto 606-8507, Japan Lichen planus (LP) is a chronic dermatosis and is idiopathic or associated with underlying systemic diseases, such as hepatitis C virus [1]. LP can involve skin, genital mucosa, hair follicles, and nails. In [...]

• Background.— The gene responsible for the xeroderma pigmentosum (XP) group A gene was recently identified and isolated. Preliminary study with fibroblasts from patients with XP group A revealed that most of the Japanese patients with XP group A have a point mutation at the 3′ splice acceptor site of intron 3. This mutation site in the XP group A—complementing gene can be recognized by a restriction enzyme, Alw NI. This article describes the usefulness of the polymerase chain reaction diagnosis on XP group A. Observations.— We tried a polymerase chain reaction diagnosis on genomic DNA from a sporadic case of XP group A and this child's parents. Alw NI restriction fragment length polymorphism of the polymerase chain reaction product showed three bands for his father's and mother's DNA, one corresponding to normal and two corresponding to a point-mutated gene, respectively. A DNA sample from our patient showed two fragments indicating that only he has the mutated gene. Conclusions.— This study demonstrated that we can know that this patient has group A XP without a complementation test that needs a lot of time. Moreover, our study revealed that we can detect the hidden mutated XP group A—complementing gene in the pedigree in which there is no patient with XP. Furthermore, it may be available soon for prenatal diagnosis. ( Arch Dermatol. 1992;128:971-974)