Yasutoshi Hida

Strong expression of a longevity-related protein, SIRT1, in Bowen’s disease

The class III histone deacetylase (HDAC), SIRT1, is a mammalian homologue of the Saccharomyces cerevisiae chromatin-silencing factor Sir2 that regulates longevity. SIRT1 regulates cell survival via deacetylation of p53 and forkhead transcription factors, and overexpression of SIRT1 is reported to be essential for cell growth and survival in some kinds of cancer. To elucidate the role of SIRT1 in human skin carcinogenesis, we have examined SIRT1 protein expression in 20 cases each of squamous cell carcinoma (SCC), basal cell carcinoma (BCC), Bowen’s disease (BD), and actinic keratosis (AK) by immunohistochemical analysis. Overexpression of SIRT1 is frequently observed in all kinds of non-melanoma skin cancers included in this study. In particular, strong expression was observed in all cases of BD. In addition, no obvious difference between AK and SCC was observed in the expression of SIRT1, suggesting that overexpression of SIRT1 may have some relevance to the early stage of skin carcinogenesis. We suppose that SIRT1 could be one of the critical targets for future therapy with the aim of inhibiting cell proliferation and promoting apoptosis in non-melanoma skin cancers.

Lack of somatic mutation in the PTEN gene in squamous cell carcinomas of human skin

The tumor suppressor gene PTEN is deleted and/or mutated in a variety of tumors and the susceptibility gene for Cowden disease. Loss of heterozygosity of chromosome 10q23, where PTEN resides, in squamous cell carcinomas (SCCs) of human skin and the association of SCC with Cowden disease were reported previously. In the present study, we screened for mutations of PTEN in SCCs by polymerase chain reaction single strand conformation polymorphism analysis to examine whether PTEN is involved in the carcinogenesis of SCC. None of 21 SCCs showed somatic mutations in the coding regions of PTEM. Instead the same allelic variation was detected in two cases without any clinical features of Cowden disease. Our results indicate that inactivation of PTEN does not play an important role in the carcinogenesis of SCC.

A novel PTEN mutation in a Japanese patient with Cowden disease

Cowden disease (CD) is an autosomal dominant syndrome characterized by multiple hamartomatous lesions and an increased risk for malignancies. Recent evidence has indicated that the PTEN gene, encoding a protein tyrosine phosphatase, is the CD susceptibility gene. However, another line of evidence has suggested that CD might be genetically heterogeneous. Clinical features of CD are variable, and there are interfamilial differences in the expression of skin lesions . Therefore, information on PTEN mutations in CD patients should be accumulated to clarify the genotype–phenotype correlation. In the present study, we found heterozygous germline mutations of PTEN in all of three Japanese patients with CD examined, indicating no genetic heterogeneity among our patients. The mutations included two non‐sense mutations of R335X and R130X, and a mis‐sense mutation of C136R. To the best of our knowledge, the C136R mutation has not previously been reported in CD patients. This novel mutation was located outside the core motif of the phosphatase domain of PTEN protein, where most of the missense mutations previously reported in CD patients were clustered. Mucocutaneous manifestations were far fewer in the patient with this mutation than in the patients with nonsense mutations. Whether the phenotypic difference in mucocutaneous features was due to the different mutations remains unclear.

Diltiazem-associated photodistributed hyperpigmentation : Report of two Japanese cases and published work review

Scherschum et al. proposed diltiazem‐associated photodistributed hyperpigmentation as a novel type of drug‐induced photosensitive lichenoid eruption. The characteristic clinical features were slate‐gray reticulated hyperpigmentation on sun‐exposed areas, while lichenoid dermatitis with prominent pigmentary incontinence was noted histologically. Although the clinical and histological features were similar to those of lichen planus pigmentosus, the histological features did not show either compact hyperkeratosis or wedge‐shaped hypergranulosis, which are typical histological features of lichen planus. We describe two Japanese cases of diltiazem‐associated photodistributed hyperpigmentation, who were successfully treated with topical tacrolimus, and review the published work.

Primary dermal melanoma: A case report and molecular characterization.

Swetter et al. proposed primary dermal melanoma (PDM) as a distinct entity based on an excellent prognosis. The histopathological features of PDM are extremely similar to those of metastatic melanoma or clear cell sarcoma (CCS). We describe a 38‐year‐old woman with a subcutaneous tumor in her left thigh. Physical and imaging examinations showed no evidence of metastatic melanoma. The lesion showed obvious strong expression of KIT by immunohistochemistry, but no EWS‐ATF1 fusion transcript specific for CCS was detected by reverse transcription polymerase chain reaction. In further analyses of KIT expression in other tumors, three of four primary melanomas (75%) and six of 12 metastatic melanomas (50%) were moderately or strongly positive, however, both the primary and metastatic lesions of CCS tested negative. We believe this to be a case of PDM, and emphasize the distinctiveness of PDM.

Activation of fibroblast growth factor receptor 3 and oncogene-induced senescence in skin tumours.

Background  The activation of oncogenes is an important step in tumorigenesis, and recently, oncogene‐induced senescence (OIS) was proposed as a critical barrier against malignant transformation in normal primary cells.

Malignant acanthosis nigricans with enhanced expression of fibroblast growth factor receptor 3.

Sir, Fibroblast growth factor receptor 3 (FGFR3) belongs to the transmembrane tyrosine kinase receptors (1). Con-stitutive activating FGFR3 germline mutations cause genetic syndromes with acanthosis nigricans (AN) (2–5). In addition to hereditary forms of AN, some sporadic forms are known. Among these, the lesions linked with malignancy are called malignant acanthosis nigricans (MAN), which are more severe and more extensive than other sporadic forms of AN. We describe here two cases of MAN and examine the role of the FGFR3 signalling pathway in MAN. PATIENTS AND METHODS Case 1. A 68-year-old Japanese man presented in October 1999 with a 4-month history of darkening and thickening of the skin on his face, neck, axillae, groin, hands and feet. On physical examination he had velvety hyperpigmented plaques on the face (Fig. 1) neck, axillae, groin, and dorsal and palmar aspects of his hands and feet. Soft papillomas and warty nodules studded the affected surface. Thickening and papillation without hyperpigmentation was evident on the lips, gingiva, and hard plate. A skin biopsy specimen taken from his axillae revealed hyperkeratosis and mild acanthosis with dermal papillomatosis. A gastroscopy showed a Borrmann type 4 tumour located in the cardiac part of the stomach, and histological examination revealed a poorly differentiated adenocarcinoma. We diagnosed this case as MAN. He underwent a palliative gastrectomy in November 1999, because the gastric cancer had directly invaded the diaphragm, and his para-aortic lymph nodes were swollen. His skin improved after the operation, but subsequently worsened again with the development of metastatic lesions. He died in April 2000 with peritoneal dissemination. Case 2. A 70-year-old Japanese man presented in January 2004 with a 4-month history of darkening and thickening of the skin on his face. On physical examination, he had velvety hyperpigmented plaques on the face neck, axillae, and dorsal aspects of his hands. Soft papillomas and warty nodules studded the affected surface. His oral mucosa gradually became diffusely thick, and both palms became diffusely hyperkeratotic. A gastroscopy showed a Borrmann type 1 tumour located in the greater curvature of the stomach, and histological examination revealed a poorly differentiated adenocarcinoma. This case was also diagnosed as MAN. He underwent a total gastrectomy for the proximal gastric cancer in March 2004. He received Tegafur after the operation. His abdominal lesions currently remain in remission 4 years after surgical removal. His skin lesions have been improving since the operation. In order to elucidate …

A case of epidermolysis bullosa acquisita with unusual clinical features

A 30‐year‐old woman developed epidermolysis bullosa acquisita (EBA) with unusual clinical features. Initially, only prurigo‐like nodules were seen, which lasted for > 2 years and then blisters appeared. Eruptions resembling the rash in systemic lupus erythematosus were also seen on the face. Histopathological examination of a biopsy specimen revealed subepidermal blisters containing eosinophils and neutrophils. Direct immunofluorescence examination, indirect immunofluorescence examination using skin split with 1 mol/L sodium chloride, and immunoblotting analysis using extracts of normal human dermis gave results compatible with EBA. This case shows that EBA can present with nodular lesions as seen in pemphigoid nodularis or epidermolysis bullosa pruriginosa.

Relapsing polychondritis associated with psoriasis vulgaris and alopecia areata

ejd.2011.1437 Auteur(s) : Kazutoshi Murao kmurao@clin.med.tokushima-u.ac.jp, Yasutoshi Hida, Mayumi Minato, Yoshiaki Kubo, Seiji Arase Department of Dermatology, University of Tokushima Graduate School, 15-18-3 Kuramoto-cho, Tokushima City 770-8503, Japan Relapsing polychondritis (RP) is a rare disease manifesting as recurring episodes of inflammation in cartilaginous tissues throughout the body, especially involving the ear and nose. RP is considered an autoimmune disease, and can be associated [...]

Coexistence of X-linked ichthyosis and Nagashima-type palmoplantar keratosis: A case report

Dear Editor, X-linked ichthyosis (XLI) is an X-linked recessive disorder characterized by desquamation of large brown scales on the limbs and trunk, while the palms and soles are spared. XLI is caused by a deficiency in steroid sulfatase (STS) activity due to STS gene mutations. Nagashima-type palmoplantar keratosis (NPPK) is an autosomal recessive disorder characterized by hyperkeratosis and erythema on the palms and soles extending to the dorsum of the hands and feet, inner wrists and Achilles tendon area. NPPK is also characterized by a whitish spongy change in affected areas upon exposure to water. Recently, homozygous or compound heterozygous loss-of-function mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, have been identified as causative genes of NPPK. Here, we report the first case of both XLI and NPPK, which seems to be a coincidence. A 9-year-old boy presented with scaly skin on the extremities and trunk (Fig. 1a,b). He also had mental retardation, epilepsy, hyperactivity and scoliosis. His older brother, grandfather and grandfather’s brother also had scaly skin (Fig. 1c). Histopathological examination showed hyperkeratosis and a normal granular layer in the epidermis. Fluorescence in situ hybridization analysis using an LSI STS Spectrum Red/ DXZ1 Spectrum Green (Abbott Molecular, Des Plaines, IL, USA) probe showed no red fluorescent spot, suggesting deletion of the STS gene. An approximately 1.7-Mb deletion containing six RefSeq genes, including full-length STS, was detected by chromosomal microarray analysis (Fig. 1d). Based on these findings, we diagnosed him as having XLI. Subsequently, we noticed well-demarcated diffuse palmoplantar hyperkeratosis and mild erythema that extended to the dorsum of the hands and feet, inner wrists and Achilles tendon area (Fig. 1e,f). Mild hyperkeratotic lesions on the knees were also observed (Fig. 1a). The affected skin showed a whitish spongy change within 10 min of exposure to water (Fig. 1g,h). His parents were non-consanguineous and no relatives were affected by palmoplantar keratosis (Fig. 1c). Direct sequencing of SERPINB7, as previously reported, revealed a heterozygous nonsense mutation (c.796C>T: p.Arg266Ter), but no pathogenic mutations were detected in another allele except for single nucleotide polymorphisms in introns or 30-untranslated regions (rs2689399, rs1625353, rs2658459, rs1720858 and rs374963251). Gross deletion of SERPINB7 was not detected by chromosomal microarray analysis. His mother had the same heterozygous c.796C>T mutation but palmoplantar hyperkeratosis was not seen. Palmoplantar hyperkeratosis is an unusual clinical feature for XLI. Thus, we made a diagnosis of NPPK based on typical clinical features. Obvious mutations of SERPINB7 in both alleles have not been detected in all NPPK cases. Because his mother with the same heterozygous mutation shows no abnormal features in her palmoplantar regions, a novel SERPINB7 mutation in another allele may be present outside the analyzed regions such as deep introns or regulatory regions in the present case. Further examinations using additional techniques are needed to detect such mutations. The eruptions of NPPK can be overlooked if they are accompanied by other dermatoses as in our case and atopic dermatitis. Dermatologists should pay attention to characteristic lesions of NPPK in such cases.