Ryoko Takayama

Ber-EP4 is a useful marker for follicular germinative cell differentiation of cutaneous epithelial neoplasms.

Ber‐EP4 is a monoclonal antibody that recognizes 34‐kDa and 39‐kDa non‐covalently linked glycopolypeptides expressed by most human epithelial cells and carcinomas. In this study, we performed immunohistochemical staining of 31 cases of basal cell carcinoma (BCC); 20 cases of trichoblastoma (TB), including ten cases of nodular type, eight cases of cribriform type (trichoepithelioma) and two cases of columnar type (desmoplastic trichoepithelioma); 16 cases of actinic keratosis (AK); and 10 cases each of Bowen’s disease, poroma and seborrheic keratosis. Six cases of BCC and AK were co‐lesions of both neoplasms. In normal skin tissue, Ber‐EP4 reacted positively with the secretory portion of eccrine glands and follicular germinative cells at the lower end of catagen hairs. Neoplastic cells in 97% of cases with BCC reacted positively with Ber‐EP4 in at least 5% of neoplastic cells. Those in 90% with nodular type TB and 50% with trichoepithelioma also reacted positively in at least 5% of neoplastic cells. No cases of poroma, seborrheic keratosis, AK or Bowen’s disease were immunohistochemically positive for Ber‐EP4 in neoplastic cells. In all six cases with co‐lesions of BCC and AK, neoplastic cells of BCC reacted positively with Ber‐EP4 and those of AK were negative. Immunohistochemical examination using the Ber‐EP4 antibody is a useful tool for diagnosing neoplasms with follicular germinative differentiation, such as TB, TE or BCC, and for differentiating those from squamous cell carcinoma in situ, poroma or seborrheic keratosis.

Effective treatment by glycolic acid peeling for cutaneous manifestation of familial generalized acanthosis nigricans caused by FGFR3 mutation

Acanthosis nigricans (AN) can occur as a cutaneous manifestation of genetic diseases, one of which is associated with activating mutations of the fibroblast growth factor receptor 3 gene (FGFR3).

Lumican as a novel marker for differential diagnosis of Bowen disease and actinic keratosis.

Abstract:Lumican, a member of the small leucine-rich proteoglycan family, regulates the assembly and diameter of collagen fibers in the extracellular matrix of various tissues. Lumican expression correlates with pathological conditions, including skin fragility, corneal opacification, and corneal and cardiac wound healing. Lumican is overexpressed in tumor cells, including in the breast, colorectal, neuroendocrine cell, uterine cervical, and pancreatic cancers. Lumican expression also correlates with the growth and metastasis of various malignancies. For example, lumican expression is lower in the dermis of malignant melanoma cases than in early-stage melanomas. However, the expression patterns and roles of lumican in nonmelanoma skin cancer have not been elucidated. In this study, we used immunohistochemistry and in situ hybridization to examine the expression patterns of lumican in normal skin, Bowen disease, and actinic keratosis. In normal skin, lumican was expressed in the collagen fibers in the dermis, acrosyringium, follicular epithelium, and sebocytes but not in epidermal keratinocytes. In Bowen disease, lumican was expressed in 34 (91.8%) of 37 patients. Notably, all cases of actinic keratosis were negative for lumican. These findings suggest that lumican plays an important role in the pathogenesis of Bowen disease and actinic keratosis and might be useful as an adjunct to the diagnosis for subtypes of 2 diseases: bowenoid actinic keratosis and Bowen disease in sun-exposed areas.

Expression of lumican in hidroacanthoma simplex and clonal-type seborrheic keratosis as a potent differential diagnostic marker.

Abstract:Lumican, a member of the small leucine-rich proteoglycan family, regulates the assembly and diameter of collagen fibers in the extracellular matrix of various tissues. The lumican expression correlates with pathological conditions and the growth and metastasis of various malignancies. In cutaneous neoplasms, the lumican expression is lower in advanced-stage malignant melanomas that invade the dermis than in early-stage melanomas. Furthermore, we have recently reported that the expression pattern of lumican is different from that of actinic keratosis and the Bowen disease. Lumican is positive in the poroid cells of intraepidermal sweat ducts; therefore, we examined the expression patterns of lumican in acanthotic-type seborrheic keratosis and Pinkus-type poroma followed by clonal-type seborrheic keratosis and hidroacanthoma simplex. The neoplastic cells of acanthotic-type seborrheic keratosis exhibited positive immunostaining in only 1 of 31 cases (3.23%), whereas the poroid cells of Pinkus-type poroma exhibited positive immunoreactivity in 26 of 28 patients (92.8%). In the hidroacanthoma simplex cases, lumican was expressed in poroid cells forming intraepidermal nests in 22 of 28 patients (78.6%), whereas the neoplastic cells in most cases of clonal-type seborrheic keratosis were negative for lumican. In some seborrheic keratosis cases that were positive for lumican in neoplastic cells, lumican was observed in squamoid cells but not in basaloid cells. Therefore, it is necessary to evaluate the immunoreactivity of lumican in seborrheic keratosis and in basaloid cells. These findings suggest that lumican is a potent differential diagnostic marker that distinguishes hidroacanthoma simplex from clonal-type seborrheic keratosis.

Arteriovenous malformation manifested after subclavian central venous catheterization

Dear Editor, Arteriovenous malformation (AVM) is a vascular malformation composed of multiple vascular dysplastic channels called a “nidus”, which shunts blood from the arterial system to the venous one. Histopathologically, AVM contains many vessels of varying size, including thick-walled arteries and thinwalled veins, with normal proliferation of endothelial cells. Vascular malformations are rheologically subdivided into fastflow and slow-flow types. The fast-flow group includes AVM and arteriovenous fistula (AVF). The presence of a nidus differentiates AVM from AVF in which an artery directly communicates with a vein. AVM is commonly present at birth in a quiescent stage. The aberrant vascular growth is triggered by a variety of stimuli such as hormonal changes during puberty or pregnancy, thrombosis or infection. AVM can also emerge after trauma in adults. Herein, we describe a case of AVM that manifested after subclavian central venous catheterization (CVC). A 74-year-old woman presented with a 20-year history of a reddish violaceous plaque over the right clavicular region. Six years prior to the first notice, she had undergone right subclavian CVC during the perioperative period of hysterectomy for myoma uteri. She did not have any other significant medical history or trauma. On clinical examination, a 12 cm 9 10 cm lesion with an indurated violaceous telangiectatic surface was located over the right clavicular region (Fig. 1a). Magnetic

Immunoglobulin G4-related disease and its skin manifestations

Immunoglobulin G4‐related disease (IgG4‐RD) is a systemic inflammatory condition characterized by tissue infiltration with IgG4+ plasma cells and an elevated serum IgG4 level. It usually occurs in middle‐aged or older patients, with male predominance, and can involve multiple organs synchronously or metachronously. Patients with IgG4‐RD generally respond to steroid therapy. IgG4‐related skin lesions are typically erythematous and itchy plaques, subcutaneous nodules, or papules like prurigo nodularis located on the head and neck areas. Histologically, lymphoplasmacytic infiltrates with abundant IgG4+ plasma cells are seen in the dermis and/or subcutaneous tissue. The skin condition of IgG4‐RD does not necessarily exhibit infiltration of IgG4+ plasma cells, which is a prerequisite for IgG4‐related skin disease, but such skin lesions without infiltration by IgG4+ plasma cells can be included in the skin manifestations of IgG4‐RD.

Case of basal cell carcinoma with ductal differentiation.

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Tenosynovial Giant Cell Tumor Arising on the Scapular Region

Tenosynovial giant cell tumor (TSGCT) is a benign soft tissue tumor arising from the synovial membrane that composes the lining of joints, tendons and bursae. TSGCT is a common tumor occurring in the hands and fingers, and also consecutively in the knees, ankles, feet and hips. It is rarely found in the scapular region. To the best of our knowledge, only 2 cases arising on the upper back have been reported. This report presents the case of a 44-year-old Japanese female with a TSGCT arising on her right scapular region.

Abstract 5531: Lumican as a novel differential diagnostic maker for Bowen's disease and actinic keratosis

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL BACKGROUND: Lumican is a member of the small leucine-rich proteoglycan (SLRP) family and regulates the assembly and diameter of collagen fibrils in the extracellular matrix in human tissue. Mice homozygous for a null mutation in lumican display corneal opacification and skin laxity. Recent studies have shown that lumican is expressed in various types of malignant tumors including breast, colorectal, and pancreatic cancer, and osteosarcoma and malignant melanoma, and that it plays an important role in the growth of tumors. However, little has been studied about the expression pattern and role of lumican in non-melanoma skin cancer. In this study, we examined the expression levels of lumican in in situ lesions of squamous cell carcinoma (SCC) of the skin, actinic keraotsis and Bowens disease, to discover whether lumican can be used as a novel differential diagnostic marker for such skin tumors, particularly for bowenoid actinic keratosis and Bowens disease in sun-exposed areas of the body. Bowenoid actinic keratosis and Bowens disease are often difficult to distinguish in both the clinical setting and commonly prepared pathological specimens. Furthermore, invasive SCC arising in actinic keratosis is considered low-risk clinically, while Bowens disease with invasion is considered high-risk. Thus, it is important to distinguish between actinic keratosis and Bowens disease, and reliable differential markers for these diseases are required.METHOD: Twenty-nine cases of actinic keratosis, including 4 of the bowenoid sub-type, and 37 cases of Bowens disease, including 6 in sun-exposed areas of the body, were selected from among patients undergoing surgical resection at the Department of Dermatology at the Nippon Medical School from 2006 to 2010. We evaluated lumican expression and mRNA in these cases using immunohistochemistry and in situ hybridization analysis, respectively. RESULTS: Immunohistochemical analysis indicated that Lumican was expressed in 34 of 37 patients with Bowens disease (91.8%), but was not detected in any of the cases of actinic keratosis. In situ hybridization analysis revealed that lumican mRNA was expressed in the cytoplasm of immunohistochemically lumican-positive tumor cells in Bowens disease. CONCLUSION: These findings suggest that lumican plays an important role in the pathogenesis of Bowens disease and will be a useful marker for the differential diagnosis between Bowens disease and actinic keratosis, particularly for bowenoid actinic keratosis and Bowens disease occurring in sun-exposed areas of the body. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5531. doi:1538-7445.AM2012-5531

Abstract 1421: The stem cell marker nestin is a novel therapeutic target to suppress tumor growth and invasion of malignant melanoma

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL BACKGROUND: Nestin, a class VI intermediate filament protein, was first described as a neural stem cell/progenitor cell marker expressed during central nervous system development. Recently, nestin was detected in various neoplasms such as glioblastomas, gastrointestinal stromal tumors, prostate cancers, breast cancers, pancreatic cancers and malignant melanomas. An abundance of nestin has been identified in metastatic sites and the dermal parts of nodular melanomas, and the expression level of nestin has relevance to poor prognosis in malignant melanomas. These findings suggest that nestin plays important roles in the invasion of melanoma cells. Furthermore, recent studies have shown that nestin is one of the cancer stem cell markers in melanomas. Therefore, we hypothesized that nestin may be a novel therapeutic target for malignant melanomas. In this study, we used a silencing strategy to clarify the effectiveness of nestin-targeting therapy in malignant melanomas. METHODS: To determine the expression patterns of nestin, we performed immunohistochemical analysis of nestin in human melanoma tissues. Next, we stably knocked down nestin expression in A375 human malignant melanoma cells by short hairpin RNA (shRNA) transfection in vitro. We also transfected sham vectors to A375 cells as negative controls. Cell proliferation, invasion, morphology, and sphere-forming ability were compared with nestin-shRNA-transfected cells (Sh) and sham cells (Sc). RESULTS: Immunohistochemical staining demonstrated that nestin was strongly expressed in melanoma cells in the invasive front of human melanoma tissues. Reduced expression level of nestin mRNA and protein in Sh cells was confirmed by quantitative RT-PCR, western blot and immunocytochemical analyses. Sh and Sc cells did not show characteristic morphological differences; however, stress fiber formation of F-actin was markedly increased in Sh cells. Cell growth of Sh cells was slower than that of Sc cells at 48 hrs as determined by cell counts and MTT assay. On the cell invasion assay using a modified Boyden chamber coated with matrigel on the inner surface of the inserts, the invasion of Sh cells was significantly attenuated in comparison with that of Sc cells. Sphere-forming ability using ultra-low attachment plates supplemented with EGF and FGF-2 showed that Sh cells formed fewer spheres than Sc cells. CONCLUSION: Nestin is expressed in melanoma cells at the invasive front of melanoma tissues, and decreased expression level of nestin inhibits the growth and invasion of melanoma cells. Furthermore, nestin regulates the functions of cancer stem cells of malignant melanoma as determined by sphere-forming ability. Our findings imply that nestin is a promising novel therapeutic target in malignant melanomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1421. doi:10.1158/1538-7445.AM2011-1421