Faculty Profiles - YAMAMOTO HIDETAKA

Papers - YAMAMOTO HIDETAKA

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Tumor-to-tumor metastasis: lung adenocarcinoma metastasizing to a follicular variant of papillary thyroid carcinoma. Reviewed International journal

Kazuki Hashimoto, Hidetaka Yamamoto, Takafumi Nakano, Minako Oyama, Hideki Shiratsuchi, Torahiko Nakashima, Sadafumi Tamiya, Shizuo Komune, Yoshinao Oda

Pathology international 61 ( 7 ) 435 - 41 2011.7

Language：English Publishing type：Research paper (scientific journal)

Cancer-to-cancer metastasis into a thyroid neoplasm is an uncommon phenomenon with possible diagnostic difficulties. Here, we describe a case of lung adenocarcinoma metastatic into a follicular variant of papillary thyroid carcinoma (FVPTC). A 60-year-old woman with no prior history of malignant neoplasm presented with a nodule in the right lobe of the thyroid gland, some masses in the left lung were found by radiological examination. Histopathological examination of the thyroidectomy specimen demonstrated two different components of carcinoma in a single thyroid nodule; one was FVPTC and the other was high-grade adenocarcinoma. Although both components shared the TTF-1+/CK7+/CK19+/CK20-/SP-A- immunoprofile, only the former was positive for thyroglobulin, and only the latter was positive for CEA. The epidermal growth factor receptor (EGFR) gene mutation at exon21 (L858R) was present only in the latter. The lung biopsy specimen showed cytological, immunohistochemical, and EGFR genotypic features similar to those of the high-grade adenocarcinoma component of the thyroid nodule. These findings resulted in a reliable diagnosis of lung adenocarcinoma metastasizing into an FVPCT and treatment with EGFR-targeted therapy. These results demonstrate that a panel of immunohistochemical staining and molecular analysis is helpful for both diagnosis and appropriate postoperative treatment for a patient with cancer-to-cancer metastasis.

DOI： 10.1111/j.1440-1827.2011.02679.x

Prognostic significance of p14ARF, p15INK4b, and p16INK4a inactivation in malignant peripheral nerve sheath tumors. Reviewed International journal

Makoto Endo, Chikashi Kobayashi, Nokitaka Setsu, Yusuke Takahashi, Kenichi Kohashi, Hidetaka Yamamoto, Sadafumi Tamiya, Shuichi Matsuda, Yukihide Iwamoto, Masazumi Tsuneyoshi, Yoshinao Oda

Clinical cancer research : an official journal of the American Association for Cancer Research 17 ( 11 ) 3771 - 82 2011.6

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: p14(ARF), p15(INK4b), and p16(INK4a) are tumor suppressor genes that are located closely at 9p21 and are often coinactivated by genetic or epigenetic alterations. Malignant peripheral nerve sheath tumor (MPNST) is a rare sarcoma with poor prognosis. However, the prognostic implications of inactivation of p14(ARF), p15(INK4b), and p16(INK4a) in MPNSTs have not been adequately investigated. Here we carried out a genetic, epigenetic, and expression analysis of p14(ARF), p15(INK4b), and p16(INK4a), and clarified the prognostic significance of their inactivation in MPNSTs. EXPERIMENTAL DESIGN: p14(ARF), p15(INK4b), and p16(INK4a) protein expressions were assessed by immunohistochemistry in 129 formalin-fixed samples of MPNST including 85 primary tumors. Thirty-nine samples, for which frozen material was available, were also investigated by Western blotting and quantitative reverse transcription PCR (RT-PCR) to detect p14(ARF), p15(INK4b), and p16(INK4a) protein and mRNA expression, and by multiplex real-time PCR, PCR single strand conformation polymorphism and methylation-specific PCR to detect p14(ARF), p15(INK4b), and p16(INK4a) gene alterations. RESULTS: Immunohistochemically decreased expressions of p14(ARF), p15(INK4b), and p16(INK4a) were observed in 48%, 54%, and 49% of primary MPNSTs, respectively, and were significantly correlated with their concordant mRNA levels. As for gene alterations, homozygous deletion of CDKN2A was detected in one third of the cases. Inactivation of p14(ARF) and p16(INK4a) was associated with poor prognosis by both univariate and multivariate analyses. Furthermore, cases with inactivation of all p14(ARF), p15(INK4b), and p16(INK4a) genes showed the worst prognosis in a combined prognostic assessment. CONCLUSION: A comprehensive analysis of p14(ARF), p15(INK4b), and p16(INK4a) inactivation status provides useful prognostic information in MPNSTs.

DOI： 10.1158/1078-0432.CCR-10-2393

S100P expression in ductal type of carcinoma ex pleomorphic adenoma. Reviewed International journal

Kazuki Hashimoto, Hidetaka Yamamoto, Hideki Shiratsuchi, Torahiko Nakashima, Sadafumi Tamiya, Yuichiro Higaki, Shizuo Komune, Masazumi Tsuneyoshi, Yoshinao Oda

The American journal of surgical pathology 35 ( 3 ) 346 - 55 2011.3

Language：English Publishing type：Research paper (scientific journal)

Pleomorphic adenoma (PA) is known to occasionally progress to carcinoma, but the mechanisms of its malignant transformation have not been fully elucidated. S100P, an EF-hand calcium-binding protein, has recently been proposed as an initiator of carcinogenesis in some kinds of epithelial tumors. In this study, we aimed to elucidate the potential role of S100P in tumorigenesis and stepwise progression of carcinoma ex pleomorphic adenoma (CXPA) with ductal differentiation. In 31 ductal type CXPAs (8 in situ, 5 intracapsular, and 18 extracapsular) and 28 PAs (21 conventional and 7 atypical) of the salivary gland, we examined the protein expression of S100P, androgen receptor (AR), HER2/neu, p53, and Ki-67 by immunohistochemistry. HER2 expression, p53 expression, and the Ki-67 labeling index were higher in CXPAs than in atypical PAs and conventional PAs, whereas the AR expression level was relatively high even in atypical PAs. S100P overexpression was significantly more prevalent in CXPAs (27 cases; 87.1%) than in atypical PAs (2 cases; 28.6%) and conventional PAs (1 case; 4.8%) (P<0.05). High prevalence of S100P expression was observed in each intraductal, extraductal-intracapsular, and extracapsular component of CXPAs. In addition, equivalent, high-level S100P expression was observed in all histologic subtypes of the malignant component of CXPAs. These results indicate that S100P may play an important role in malignant transformation of ductal cells of PA, and that immunohistochemical staining for S100P would be a useful diagnostic marker for identifying the early phase of CXPA, in combination with AR, HER2, p53, and Ki-67.

DOI： 10.1097/PAS.0b013e31820832a6

Sessile serrated adenoma with early neoplastic progression: a clinicopathologic and molecular study. Reviewed International journal

Kohei Fujita, Hidetaka Yamamoto, Takayuki Matsumoto, Minako Hirahashi, Masaki Gushima, Junji Kishimoto, Ken-ichi Nishiyama, Tomoaki Taguchi, Takashi Yao, Yoshinao Oda

The American journal of surgical pathology 35 ( 2 ) 295 - 304 2011.2

Language：English Publishing type：Research paper (scientific journal)

Sessile serrated adenoma (SSA), also referred to as sessile serrated polyp, has been proposed as a precursor lesion to microsatellite unstable carcinoma. However, the mechanism of stepwise progression from SSA to early invasive carcinoma has been unclear. The purpose of this study was to elucidate the histologic characteristics and possible role of p53, β-catenin, BRAF, KRAS, and PIK3CA in the development and progression of SSA. We analyzed 12 cases of SSA with neoplastic progression (SSAN), including 7 cases of intraepithelial high-grade dysplasia (HGD) and 5 cases of submucosal invasive carcinoma, and compared them with 53 SSAs and 66 hyperplastic polyps (HPs) by immunohistochemistry and gene mutation analysis. Histologically, 75% (9 of 12) of SSANs showed tubular or tubulovillous growth patterns rather than serrated ones in the HGD/intramucosal carcinoma component. All 5 SSANs with invasive carcinoma lost their serrated structure and developed increased extracellular mucin in their submucosal carcinoma component, a consistent feature of mucinous adenocarcinoma. Nuclear accumulations of β-catenin and p53 were observed in 50% (6 of 12) and 41.7% (5 of 12) of SSANs, respectively, and were exclusively present in HGD/carcinoma areas. By contrast, neither nuclear β-catenin nor p53 expressions were seen in HPs or SSAs (P<0.0001). BRAF mutations (V600E) were observed in 45.8% (11 of 24) of HPs, 60.9% (14 of 23) of SSAs, and 63.6% (7 of 11) of SSANs, and were equally found in both SSA and carcinoma/HGD areas of the individual SSANs. KRAS exon 1 mutations were uncommon in all 3 groups (4.2%, 4.4%, and 0%, respectively). No mutations of PIK3CA exon 9 or exon 20 were found in any cases that were examined. These findings suggest that BRAF mutations may be associated with the pathogenesis of SSA, but progression to HGD or early invasive carcinoma may be associated with other factors, such as alterations of p53 and β-catenin. In addition, our histologic observations suggest a possible close association between SSAN and mucinous adenocarcinoma.

DOI： 10.1097/PAS.0b013e318205df36

Detection of non-palpable breast cancer in asymptomatic women by using unenhanced diffusion-weighted and T2-weighted MR imaging: comparison with mammography and dynamic contrast-enhanced MR imaging. Reviewed International journal

Hidetake Yabuuchi, Yoshio Matsuo, Shunya Sunami, Takeshi Kamitani, Satoshi Kawanami, Taro Setoguchi, Shuji Sakai, Masamitsu Hatakenaka, Makoto Kubo, Eriko Tokunaga, Hidetaka Yamamoto, Hiroshi Honda

European radiology 21 ( 1 ) 11 - 7 2011.1

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: To compare the detectability of non-palpable breast cancer in asymptomatic women by using mammography (MMG), dynamic contrast-enhanced MR imaging (DCE-MRI) and unenhanced MR imaging with combined diffusion-weighted and T2-weighted images (DWI+T2WI). METHODS: Forty-two lesions in 42 patients with non-palpable breast cancer in asymptomatic women were enrolled. For the reading test, we prepared a control including 13 normal and 8 benign cases. Each imaging set included biplane MMG, DCE-MRI and DWI+T2WI. Five readers were asked to rate the images on a scale of 0 to 100 for the likelihood of the presence of cancer and the BI-RADS category. Confidence level results were used to construct receiver operating characteristic analysis. Sensitivity and specificity were calculated for each technique. RESULTS: DWI+T2WI showed higher observer performances (area under the curve, AUC, 0.73) and sensitivity (50%) for the detection of non-palpable breast cancer than MMG alone (AUC 0.64; sensitivity 40%) but lower than those of DCE-MRI (AUC 0.93; sensitivity 86%). A combination of MMG and DWI+T2WI exhibited higher sensitivity (69%) compared with that of MMG alone (40%). CONCLUSION: DWI+T2WI could be useful in screening breast cancer for patients who cannot receive contrast medium and could be used as a new screening technique for breast cancer.

DOI： 10.1007/s00330-010-1890-8

Heterozygosity loss at 22q and lack of INI1 gene mutation in gastrointestinal stromal tumor. Reviewed International journal

Hidetaka Yamamoto, Kenichi Kohashi, Masazumi Tsuneyoshi, Yoshinao Oda

Pathobiology : journal of immunopathology, molecular and cellular biology 78 ( 3 ) 132 - 9 2011

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: Gastrointestinal stromal tumor (GIST) is characterized by KIT or PDGFRA gene mutation. Although chromosomal losses of 22q are frequent in GIST, it is unclear which tumor suppressor genes might be inactivated in association with such losses. The INI1 gene, located at 22q11.23, is a tumor suppressor gene that is frequently altered in malignant rhabdoid tumor. METHODS: To elucidate the hypothesis that the INI1 gene might be altered along with 22q loss in GIST, we examined the loss of heterozygosity (LOH) at 22q11.23, homozygous deletion and mutation of the INI1 gene, and its gene product expression as well as mutations of KIT and PDGFRA in 27 cases of GIST. RESULTS: Among the 27 informative cases, 19 (70.4%) showed LOH of at least one of the microsatellite markers on 22q11.23. None of the cases (0%) showed homozygous deletion or mutation of the INI1 gene. Immunohistochemically, the INI1 expression was focally reduced in 17/27 (63%) cases, and the INI1 protein level and INI1 mRNA level were each correlated with the presence of 22q11.23 LOH. Although the 22q11.23 LOH was more frequently present in high- than in low-grade tumors, INI1 expression level was not correlated with tumor grade, tumor size, proliferative activity and the expression levels of cyclin D1 and p16INK4a. KIT mutations were found in 18/27 (66.7%) GISTs; however, the KIT genotype was not correlated with the status of LOH at 22q11.23. CONCLUSIONS: The results suggest that 22q11.23 LOH is frequently present in GIST irrespective of KIT genotype and it might play a role in part of the development of GIST. However, the hemiallelic loss of INI1 gene causing reduced expression of INI1 protein probably does not have a major impact in the progression of GIST.

DOI： 10.1159/000323564

Mucin core protein expression in serrated polyps of the large intestine. Reviewed International journal

Kohei Fujita, Minako Hirahashi, Hidetaka Yamamoto, Takayuki Matsumoto, Masaki Gushima, Yoshinao Oda, Junji Kishimoto, Takashi Yao, Mitsuo Iida, Masazumi Tsuneyoshi

Virchows Archiv : an international journal of pathology 457 ( 4 ) 443 - 9 2010.10

Language：English Publishing type：Research paper (scientific journal)

Sessile serrated adenoma (SSA) has been proposed as a precursor to microsatellite-unstable colorectal carcinoma. However, histological criteria dictating how to differentiate serrated lesions have not been completely established, and a histological overlap exists between SSA and hyperplastic polyps (HPs), particularly the microvesicular type. In this study, based on a critical review of histology, we aimed to elucidate the potential utility of the mucin phenotype in the identification of SSA. We evaluated mucin core protein expression (MUC2, MUC5AC, and MUC6) by immunohistochemical stain in 65 cases of microvesicular-type HPs, 51 SSAs, and 72 traditional serrated adenomas (TSAs). SSAs had clinicopathological and morphological features distinct from those of HPs and TSAs. MUC6 was more frequently positive in SSAs (39%) than in TSAs (4%) and HPs (19%) (P < 0.001 and P = 0.0107, respectively). Right-sided HPs more frequently expressed MUC6 than did left-sided HPs (60% vs. 4%, respectively; P < 0.0001), but SSAs and TSAs showed no regional differences. These findings suggest that determination of mucin core protein expression is insufficient for differentiating SSAs from other types of serrated polyps, and that microvesicular-type HPs of the right colon and SSAs may belong to the same mucin spectrum.

DOI： 10.1007/s00428-010-0959-8

Prognostic impact of blood vessel invasion in gastrointestinal stromal tumor of the stomach. Reviewed International journal

Hidetaka Yamamoto, Aya Kojima, Yoshihiro Miyasaka, Masakazu Imamura, Norimoto Nakamura, Takashi Yao, Masazumi Tsuneyoshi, Yoshinao Oda

Human pathology 41 ( 10 ) 1422 - 30 2010.10

Language：English Publishing type：Research paper (scientific journal)

Gastrointestinal stromal tumors have a wide spectrum of biologic behavior, and occasional cases show liver metastases. The modified risk grade based on tumor size and mitotic counts has been proposed to predict the biologic behavior in gastric gastrointestinal stromal tumors. Blood vessel invasion (BVI) is important in the development of metastasis of various kinds of cancer. The aim of this study was to elucidate the potential role of blood vessel invasion in gastric gastrointestinal stromal tumors. Blood vessel invasion was found in 17 of 122 cases (13.9%) of gastrointestinal stromal tumors, and was significantly correlated with larger tumor size, higher mitotic count and higher modified risk grade. Among 83 cases of primary, localized gastric gastrointestinal stromal tumors available for follow-up information, liver metastasis was observed in 14 cases (16.9%). When blood vessel invasion was positive in the primary tumor, liver metastasis occurred in 80% of cases after the initial surgery, indicating that blood vessel invasion was a significant risk factor of liver metastasis (P < .0001). In univariate and multivariate analyses, tumor size (>5 cm), mitotic count (>5/50 high-power fields) and blood vessel invasion (positive) were significantly associated with a shorter period of disease-free survival. Our results suggest that the evaluation of blood vessel invasion may be useful for predicting the risk of liver metastasis and aggressive biologic behavior of gastrointestinal stromal tumors, and may serve as important information for determining the therapeutic strategies including adjuvant molecular target therapy.

DOI： 10.1016/j.humpath.2010.02.013

Reduced expression of SMARCB1/INI1 protein in synovial sarcoma. Reviewed International journal

Kenichi Kohashi, Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Hiroshi Matono, Yukihide Iwamoto, Tomoaki Taguchi, Masazumi Tsuneyoshi

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 23 ( 7 ) 981 - 90 2010.7

Language：English Publishing type：Research paper (scientific journal)

Synovial sarcoma is classified as a tumor of uncertain differentiation, and some synovial sarcomas have rhabdoid cells. In previous studies, all malignant rhabdoid tumors and renal medullary carcinomas, some extraskeletal myxoid chondrosarcomas, almost all epithelioid sarcomas and half of epithelioid malignant peripheral nerve sheath tumors showed a loss of SMARCB1/INI1 protein expression in tumor cells and all of these tumors are also known to have rhabdoid cells. We analyzed the immunohistochemical and mRNA expression of SMARCB1/INI1 in 95 synovial sarcomas (73 monophasic fibrous type, 18 biphasic type and 4 poorly differentiated type) and 30 spindle cell sarcomas (3 adult fibrosarcomas, 7 fibrosarcomas arising in dermatofibrosarcoma protuberans, 10 leiomyosarcomas and 10 malignant peripheral nerve sheath tumors) resembling monophasic fibrous synovial sarcoma. The results have shown that 66 of the 95 synovial sarcoma cases (69%) had reduced SMARCB1/INI1 protein expression, whereas the remaining 29 cases (31%) and all 30 spindle cell sarcomas showed preserved this protein expression. No case with a complete loss of SMARCB1/INI1 protein expression was recognized. The median values of SMARCB1/INI1 mRNA expression in non-tumor skeletal muscle and synovial sarcoma with reduced protein expression were 12.86 and 134.01, respectively, and a statistically significant difference was detected between these two groups (P=0.0000004). However, there was no statistically significant difference of prognosis between the synovial sarcoma group with reduced and that with preserved SMARCB1/INI1 protein expression (P=0.46). Therefore, it was suggested that there is a post-transcriptional SMARCB1/INI1 regulatory mechanism in the tumor cells of synovial sarcoma.

DOI： 10.1038/modpathol.2010.71

Non-mass-like enhancement on contrast-enhanced breast MR imaging: lesion characterization using combination of dynamic contrast-enhanced and diffusion-weighted MR images. Reviewed International journal

Hidetake Yabuuchi, Yoshio Matsuo, Takeshi Kamitani, Taro Setoguchi, Takashi Okafuji, Hiroyasu Soeda, Shuji Sakai, Masamitsu Hatakenaka, Makoto Kubo, Eriko Tokunaga, Hidetaka Yamamoto, Hiroshi Honda

European journal of radiology 75 ( 1 ) e126-32 2010.7

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: To evaluate the diagnostic accuracy of a combination of dynamic contrast-enhanced MR imaging (DCE-MRI) and diffusion-weighted MR imaging (DWI) in characterization of lesions showing non-mass-like enhancement on breast MR imaging and to find the strongest discriminators between carcinoma and benignancy. MATERIALS AND METHODS: We analyzed consecutive MR images in 45 lesions showing non-mass like enhancement in 41 patients. We analyzed lesion size, distribution, internal enhancement, kinetic curve pattern, and apparent diffusion coefficient (ADC) values. We applied univariate and multivariate analyses to find the strongest indicators for malignancy. In a validation study, 22 non-mass-like enhancement lesions in 21 patients were examined. We calculated diagnostic accuracy when we presume category 4b, 4c, and 5 lesions as malignant or high to moderate suspicion for malignancy, and category 4a and 3 as low suspicion for malignancy or benign. RESULTS: Segmental distribution (P=0.018), clumped internal enhancement (P=0.005), and ADC less than 1.3 x 10(-3) mm(2)/s (P=0.047) were the strongest MR indicators of malignancy. In a validation study, sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 87% (13/15), 86% (6/7), 93% (13/14), 75% (6/8) and 86% (19/22), respectively. CONCLUSION: The combination of DCE-MRI and DWI showed high diagnostic accuracy in characterization of non-mass-like enhancement lesions on breast MR images.

DOI： 10.1016/j.ejrad.2009.09.013

Down-regulation of artery in moderately differentiated hepatocellular carcinoma related to tumor development. Reviewed International journal

Nobuhiro Fujita, Shinichi Aishima, Tomohiro Iguchi, Yunosuke Nishihara, Hidetaka Yamamoto, Akinobu Taketomi, Yoshinao Oda, Hiroshi Honda, Masazumi Tsuneyoshi

Human pathology 41 ( 6 ) 838 - 47 2010.6

Language：English Publishing type：Research paper (scientific journal)

Hepatocellular carcinoma develops in a multistep process. Previous studies have revealed changes in blood supply in hepatocellular carcinoma during its carcinogenesis. However, little is known about the relationship between tumor vasculature and the biological behavior of moderately differentiated hepatocellular carcinoma which demonstrates varied degrees of biological behavior. We immunohistochemically assessed intratumoral arterial vessel density (by high-molecular-weight caldesmon and calponin) and microvessel density (by CD34) in 123 cases of moderately differentiated hepatocellular carcinomas, and compared these densities with clinicopathological findings. Arterial vessel density and microvessel density of 19 well-differentiated and 37 poorly differentiated hepatocellular carcinomas were also evaluated. The arterial vessel density of moderately differentiated hepatocellular carcinomas with capsule formation, infiltration to the capsule, portal venous invasion, and high Ki-67 labeling index was lower than that of moderately differentiated hepatocellular carcinomas without these pathological findings (high-molecular-weight caldesmon: P < .0001, P = .0074, P = .0009, P = .0244, calponin: P < .0001, P = .0695, P = .0033, and P = .0155, respectively). The low arterial vessel density group (<10) of moderately differentiated hepatocellular carcinomas tended to show poorer overall survival than the high arterial vessel density group (>or=10) (high-molecular-weight caldesmon: P = .0347, calponin: P = .0404). The arterial vessel density and microvessel density of moderately differentiated hepatocellular carcinomas were significantly higher than those of well-differentiated hepatocellular carcinomas (high-molecular-weight caldesmon: P = .022, calponin: P = .027, CD34: P = .036) and poorly differentiated hepatocellular carcinomas (high-molecular-weight caldesmon, calponin and CD34: P < .0001). The moderately differentiated hepatocellular carcinomas with lower arterial vessel density had more malignant potential than those with higher arterial vessel density. The changes of arterial vessel density in moderately differentiated hepatocellular carcinomas were suggested.

DOI： 10.1016/j.humpath.2009.11.011

Primary gastrointestinal stromal tumor of the liver with PDGFRA gene mutation. Reviewed International journal

Hidetaka Yamamoto, Yuichi Miyamoto, Yunosuke Nishihara, Aya Kojima, Masakazu Imamura, Keiji Kishikawa, Yukari Takase, Keisuke Ario, Yoshinao Oda, Masazumi Tsuneyoshi

Human pathology 41 ( 4 ) 605 - 9 2010.4

Language：English Publishing type：Research paper (scientific journal)

Gastrointestinal stromal tumor is a mesenchymal tumor with KIT or PDGFRA gene mutation, occurring primarily in the stomach and intestine and rarely outside the digestive tract. KIT-negative tumors with epithelioid cell morphology and PDGFRA mutation represent a minor subset of gastrointestinal stromal tumor. Here, we describe a case of gastrointestinal stromal tumor in the liver of a 70-year-old man. The tumor was shown to be completely limited within the liver by radiologic, intraoperative, and pathologic examinations. Histopathologically, the tumor showed epithelioid cell-type morphology and immunohistochemical expression of CD34 and protein kinase C theta but was negative for cytokeratin, EMA, S-100, and HMB-45. KIT protein expression was very faint, and we judged it as negative. Mutation analysis revealed the presence of PDGFRA gene mutation (V561D) at exon 12. These findings are essentially the same as those typically seen in ordinary KIT-negative epithelioid cell-type gastrointestinal stromal tumor of the digestive tract. Although KIT-negative gastrointestinal stromal tumor occurring outside the gastrointestinal tract is very rare, this entity should be considered as a potential primary hepatic neoplasm.

DOI： 10.1016/j.humpath.2009.09.016

Overexpression of A disintegrin and metalloproteinase 28 is correlated with high histologic grade in conventional chondrosarcoma. Reviewed International journal

Suguru Matsuura, Yoshinao Oda, Hiroshi Matono, Teiyu Izumi, Hidetaka Yamamoto, Sadafumi Tamiya, Yukihide Iwamoto, Masazumi Tsuneyoshi

Human pathology 41 ( 3 ) 343 - 51 2010.3

Language：English Publishing type：Research paper (scientific journal)

Low-grade chondrosarcoma and enchondroma are occasionally difficult to differentiate solely by reference to clinicoradiologic and histologic findings. The A disintegrin and metalloproteinases are a new gene family of proteins having a metalloprotease domain with matrix metalloproteinases and play an important role in the chondrocyte development process. Therefore, we analyzed the expression of A disintegrin and metalloproteinases and matrix metalloproteinases in several kinds of cartilaginous bone tumors at the messenger RNA level and immunohistochemical protein level and ascertained their relationships to the histologic degree of malignancy. Reverse transciptase-polymerase chain reaction and real-time quantitative reverse transciptase-polymerase chain reaction of the expression of the A disintegrin and metalloproteinase family in cartilaginous bone tumors demonstrated that A disintegrin and metalloproteinase 28 messenger RNA levels in grade I chondrosarcoma were significantly higher than those in enchondroma (P = .009). Moreover, positive immunoreactivity of A disintegrin and metalloproteinase 28 was observed in 12 (59%) of 22 patients with grade I chondrosarcoma and in 21 (91%) of 23 patients with grade II chondrosarcoma, respectively. In contrast, only 2 (9%) of 21 cases of enchondromas demonstrated positive staining for A disintegrin and metalloproteinase 28. On the other hand, the immunohistochemical expressions of matrix metalloproteinase 9 and matrix metalloproteinase 13 were significantly higher in enchondromas than in normal cartilage tissue; however, there is no statistically different expression between enchondromas and grade I chondrosarcomas. We detected that overexpression of A disintegrin and metalloproteinase 28 was increased according to its histologic grade in conventional chondrosarcoma and could be one of the helpful tools in distinguishing between low-grade chondrosarcoma and enchondroma.

DOI： 10.1016/j.humpath.2009.08.002

Low-grade dedifferentiated liposarcoma of the neck: magnetic resonance imaging and pathological correlation. Reviewed

Makoto Endo, Yoshinao Oda, Katsumi Harimaya, Sadafumi Tamiya, Hidetaka Yamamoto, Kenichi Kohashi, Shuichi Kurihara, Nokitaka Setsu, Suguru Matsuura, Hiroshi Matono, Shuichi Matsuda, Yukihide Iwamoto, Masazumi Tsuneyoshi

Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association 15 ( 1 ) 148 - 52 2010.1

Inflammatory myofibroblastic tumor versus IgG4-related sclerosing disease and inflammatory pseudotumor: a comparative clinicopathologic study. Reviewed International journal

Hidetaka Yamamoto, Hiroshi Yamaguchi, Shinichi Aishima, Yoshinao Oda, Kenichi Kohashi, Yumi Oshiro, Masazumi Tsuneyoshi

The American journal of surgical pathology 33 ( 9 ) 1330 - 40 2009.9

Language：English Publishing type：Research paper (scientific journal)

Inflammatory pseudotumor (IPT) is a heterogeneous group of lesions occurring in various organs, which is histologically characterized by fibroblastic and myofibroblastic proliferation with inflammatory infiltrate. Inflammatory myofibroblastic tumor (IMT) is a neoplastic counterpart of IPT, which shows aberrant expression of ALK and its gene translocation. In contrast, the concept "immunoglobulin (Ig)G4-related IPT" in the lung, liver, and pancreas has recently been proposed as a member of IgG4-related sclerosing disease. In this study, we compared the histopathologic features with an emphasis on IgG4 expression between 22 cases of IMT and 16 cases of IgG4-related sclerosing disease, including chronic sclerosing sialadenitis (n=8), mass-forming autoimmune pancreatitis (n=3), sclerosing cholangitis (n=1), retroperitoneal fibrosis (n=2), and chronic sclerosing dacryoadenitis (n=2). Bland-looking spindle cell proliferation with fibrosis and inflammatory infiltrate of lymphocytes and plasma cells was the common morphologic feature in both lesions. Obstructive phlebitis was observed in all of the IgG4-related sclerosing lesions, but in only 1/22 (4.5%) of IMT. The immunohistochemical expression of ALK was observed in 15/22 (68.2%) of IMT and 0/16 (0%) of IgG4-related sclerosing disease. The number of IgG4-positive plasma cells and the ratio of IgG4+/ IgG+ plasma cells were each significantly lower in IMT than in IgG4-related sclerosing disease [mean 6.4/HPF vs. 178.3/HPF (P<0.0001), 3.0% vs. 67.5% (P<0.0001), respectively]. The results suggest that IgG4 does not play an important role in the pathogenesis of IMT. In addition, the evaluation of IgG4+ plasma cells and the ratio of IgG4+/IgG+ plasma cells and the presence of obstructive phlebitis may be useful for the differential diagnosis between IMT and IgG4-related sclerosing disease.

Neurofibromatosis type 1-related gastrointestinal stromal tumors: a special reference to loss of heterozygosity at 14q and 22q. Reviewed International journal

Hidetaka Yamamoto, Taro Tobo, Mari Nakamori, Masakazu Imamura, Aya Kojima, Yoshinao Oda, Norimoto Nakamura, Tomonari Takahira, Takashi Yao, Masazumi Tsuneyoshi

Journal of cancer research and clinical oncology 135 ( 6 ) 791 - 8 2009.6

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Multiple gastrointestinal stromal tumors (GISTs) rarely occur in patients with neurofibromatosis type 1 (NF-1). In contrast to sporadic GISTs characterized by frequent allelic losses of 1p, 14q and 22q and mutations of KIT or PDGFRA gene with the activation of the downstream RAS-MAPK pathway, the molecular pathogenetic mechanisms of NF-1-related GISTs (NF-1 GISTs) remain unclear. METHODS: Thirty-one GISTs and two foci of Cajal cell hyperplasia (CCH) were obtained from five patients with NF-1. Phospho-MAPK p44/42 expression was examined by immunohistochemical stain. KIT and PDGFRA mutations were analyzed by PCR and direct sequencing methods. Loss of heterozygosity (LOH) was analyzed by PCR-based method with microsatellite markers on 14q and 22q. RESULTS: Immunohistochemical expression of phospho-MAPK p44/42 was frequently found in NF-1 GISTs (23/25 cases, 92%). Neither the KIT nor PDGFRA mutation was detected in 25 NF-1 GISTs and 2 CCH. Among the informative cases, LOH was seen at 14q and 22q in 7/8 (87.5%) and 5/12 (41.7%) NF-1 GISTs, respectively. Such LOH was not detected in CCH, whereas it was detected in small GIST less than 1 cm in diameter. CONCLUSIONS: Our results support that KIT and PDGFRA mutations are very rare events in NF-1 GIST. Rather, activation of the Ras-MAPK pathway associated with the inactivation of the NF1 gene may play an important role in the cell proliferation of NF-1 GIST. Additionally, LOH at 14q and 22q may contribute to the relatively early phase of tumor development of NF-1 GIST.

DOI： 10.1007/s00432-008-0514-z

Close correlation between CXCR4 and VEGF expression and their prognostic implications in nasopharyngeal carcinoma. Reviewed International journal

Yuichi Segawa, Yoshinao Oda, Hidetaka Yamamoto, Hideki Shiratsuchi, Naoya Hirakawa, Shizuo Komune, Masazumi Tsuneyoshi

Oncology reports 21 ( 5 ) 1197 - 202 2009.5

Language：English Publishing type：Research paper (scientific journal)

The CXCL12/CXCR4 pathway, which is involved in biological phenomena such as inflammation, lymphoid homing and regeneration, may play an important role in tumor progression and distant metastasis, especially in organ-selective metastasis. In addition, the CXCL12/CXCR4 pathway has been reported to regulate tumor angiogenesis. In this study, we examined the immunohistochemical expression of CXCR4 and vascular endothelial growth factor (VEGF) in nasopharyngeal carcinoma. CXCR4 and VEGF mRNAs were also assessed by real-time reverse transcription-polymerase chain reaction. Overexpression of CXCR4 and VEGF was observed in 41 (53.9%) and 30 (39.5%) of 76 tumors, respectively. There was a significant positive correlation between immunohistochemical CXCR4 and VEGF expression (p=0.0339). Additionally, immunohistochemical CXCR4 expression was associated with CXCR4 mRNA expression, and immunohistochemical VEGF expression was associated with VEGF mRNA expression (p=0.0040 and p=0.0476, respectively). Furthermore, patients with VEGF-positive tumors had a significantly worse prognosis than patients with VEGF-negative primary tumors (p=0.0044). Our findings suggest that the expression of CXCR4 and VEGF is associated with metastatic progression, and that VEGF expression is a valuable prognostic marker in nasopharyngeal carcinoma.

Infrequent SMARCB1/INI1 gene alteration in epithelioid sarcoma: a useful tool in distinguishing epithelioid sarcoma from malignant rhabdoid tumor. Reviewed International journal

Kenichi Kohashi, Teiyu Izumi, Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Tomoaki Taguchi, Yukihide Iwamoto, Tadashi Hasegawa, Masazumi Tsuneyoshi

Human pathology 40 ( 3 ) 349 - 55 2009.3

Language：English Publishing type：Research paper (scientific journal)

Loss of SMARCB1/INI1 protein expression is considered useful for confirming a histologic diagnosis of malignant rhabdoid tumor. However, loss of SMARCB1/INI1 protein expression has recently been reported in other tumors as well, including a few cases of epithelioid sarcoma. In addition, the histopathologic differences between proximal-type epithelioid sarcoma and malignant rhabdoid tumor have not been conclusively defined. We analyzed SMARCB1/INI1 protein expression in 54 epithelioid sarcoma (proximal-type, 25; distal-type, 29) and examined alterations of the SMARCB1/INI1 gene in the cases lacking protein expression. We found that 19 (76.0%) proximal-type epithelioid sarcoma and 27 (93.1%) distal-type epithelioid sarcoma showed loss of SMARCB1/INI1 protein expression. Analysis of 39 cases with loss of protein expression revealed 4 cases (10.3%) with SMARCB1/INI1 gene alterations at the DNA level (homozygous deletion, 2; 1- or 2-bp deletion, 2) that could have induced the loss of gene products, and all 4 of these were proximal-type epithelioid sarcoma. Epithelioid sarcoma was thus associated with a high frequency of loss of SMARCB1/INI1 protein expression similar to that in malignant rhabdoid tumor. However, the frequency of SMARCB1/INI1 gene alteration at the DNA level in proximal-type epithelioid sarcoma was significantly lower than that in malignant rhabdoid tumor. In addition, the prognosis of patients with malignant rhabdoid tumor is significantly worse than that of patients with proximal-type epithelioid sarcoma (P = .001). Therefore, proximal-type epithelioid sarcoma and malignant rhabdoid tumor are suggested to be distinctive tumors with respect to the mechanism of the loss of SMARCB1/INI1 protein expression. Analysis of alterations in the SMARCB1/INI1 gene may thus be a useful diagnostic tool to distinguish proximal-type epithelioid sarcoma from malignant rhabdoid tumor.

DOI： 10.1016/j.humpath.2008.08.007

VEGF-C and VEGFR-3 in a series of lymphangiomas: is superficial lymphangioma a true lymphangioma? Reviewed International journal

Eijun Itakura, Hidetaka Yamamoto, Yoshinao Oda, Masutaka Furue, Masazumi Tsuneyoshi

Virchows Archiv : an international journal of pathology 454 ( 3 ) 317 - 25 2009.3

Language：English Publishing type：Research paper (scientific journal)

Lymphangiomas are commonly regarded as vascular malformations during embryonic development rather than as true neoplasms. VEGF-C and VEGFR-3 are known to be active in the formation of lymphangiomas. However, the significance of the disorders seems to be obscured by confusing different entities. In 114 lymphangiomas, we investigated the clinicopathological features and the expression of VEGF-C and VEGFR-3. The age of patients with lymphangioma circumscriptum or intraabdominal lymphangioma was significantly higher than in patients with cavernous lymphangioma and in patients with cystic hygroma. In cavernous lymphangioma, the age of female patients was significantly higher than in male patients. Five adult cystic hygromas were identified. VEGF-C was detected in 21 of 58 (36%) cavernous lymphangiomas, ten of 28 (36%) cystic hygromas, 0 of 12 (0%) lymphangioma circumscriptum, and four of ten (40%) intraabdominal lymphangiomas. VEGFR-3 was detected in 43 of 58 (72%) cavernous lymphangiomas, 20 of 28 (71%) cystic hygromas, six of 12 (50%) lymphangiomas circumscriptum, and seven of ten (70%) intraabdominal lymphangiomas. VEGF-C was absent from superficial lymphangiomas associated with cavernous lymphangiomas. In typical cases of cavernous lymphangioma, VEGF-C was strongly expressed, suggesting that these cases possessed proliferative activity. In cystic hygroma and intraabdominal lymphangioma, VEGF-C was limited in its distribution. Superficial lymphangiomas more likely represent from peripheral lymphatic dilatation rather than due to growth factor.

DOI： 10.1007/s00428-008-0720-8

Multifocal metanephric adenoma in childhood. Reviewed International journal

Kenichi Kohashi, Yoshinao Oda, Mari Nakamori, Hidetaka Yamamoto, Sadafumi Tamiya, Taro Toubo, Yoshiaki Kinoshita, Tatsuro Tajiri, Tomoaki Taguchi, Masazumi Tsuneyoshi

Pathology international 59 ( 1 ) 49 - 52 2009.1

Language：English Publishing type：Research paper (scientific journal)

Metanephric adenoma is the most commonly occurring member of the metanephric tumor family, which also includes metanephric adenofibroma and metanephric stromal tumor. According to the World Health Organization classification, however, it is not commonly multifocal. Reported herein is the case of a 9-year-old boy with multifocal metanephric adenoma. Histologically, surgical sections showed multifocal proliferation of small rounded and uniform cells with smooth nuclear contours, scant pale-staining cytoplasm, dark-staining nuclei, and inconspicuous nucleoli: the cells were arranged in sheets and acinal, ductal, glomeruloid, and papillary structures. On immunohistochemistry the tumor cells were positive for vimentin, cytokeratins (CAM5.2, AE1/AE3, and CK18), and WT1, but negative for cytokeratin 7 (CK7) and epithelial membrane antigen (EMA). The Ki-67 labeling index was <1%. In addition, cytogenetic analysis indicated a normal karyotype (46XY). Other histologically similar tumors are papillary renal cell carcinoma and nephroblastoma, and it is necessary to distinguish metanephric adenoma from those tumors because of malignancy. In contrast to those tumors, metanephric adenoma has inconspicuous nucleoli, loss of CK7 and EMA expression, and no mitotic figures. Thus, the histological and immunohistochemical features of the present case were compatible with metanephric adenoma.

DOI： 10.1111/j.1440-1827.2008.02324.x

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