Faculty Profiles - YAMAMOTO HIDETAKA

Papers - YAMAMOTO HIDETAKA

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Dedifferentiated liposarcoma of the spermatic cord with a hemangioendothelioma-like component: a case report and review of the literature. Reviewed International journal

Shinji Okano, Hidetaka Yamamoto, Shinji Kono, Hiroshi Fujii, Ken Shirabe, Yoshihiko Maehara, Yoshinao Oda

Pathology, research and practice 209 ( 9 ) 596 - 604 2013.9

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

Atypical lipomatous tumor or well-differentiated liposarcoma/dedifferentiated liposarcoma (DDLPS) is the most frequent subtype of malignant adipocytic tumor. This tumor typically presents in late adult life, most commonly in the retroperitoneum, extremities, or spermatic cord. It has been reported that the dedifferentiated component consists mainly of high-grade sarcoma, including undifferentiated pleomorphic sarcoma, fibrosarcoma, and myxofibrosarcoma, and it has been recently reported that the dedifferentiated component can be also made up of a low-grade sarcomatous component. Therefore, the dedifferentiated areas exhibit a wide morphological spectrum that commonly includes fibroblastic/myofibroblastic and fibrohistiocytic tumors but very rarely includes vascular tumors. We present here the first reported case of DDLPS with a hemangioendothelioma-like component in the spermatic cord.

DOI： 10.1016/j.prp.2013.06.014

Clinicopathological features of primary leiomyosarcoma of the gastrointestinal tract following recognition of gastrointestinal stromal tumours. Reviewed International journal

Hidetaka Yamamoto, Mizuki Handa, Taro Tobo, Nokitaka Setsu, Kohei Fujita, Yumi Oshiro, Yumi Mihara, Yasuji Yoshikawa, Yoshinao Oda

Histopathology 63 ( 2 ) 194 - 207 2013.8

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

AIMS: We aimed to elucidate the clinicopathological and immunohistochemical features of leiomyosarcoma (LMS) of the gastrointestinal (GI) tract. METHODS AND RESULTS: We encountered seven cases of GI-LMS in the colon (n = 4), rectum (n = 1), jejunum (n = 1) and stomach (n = 1). They ranged from 1 to 25 cm (median, 8.5 cm) in size and had high mitotic counts (median 38 per 50 high-power fields). Morphologically, the tumours were composed mainly of spindle cells with eosinophilic cytoplasm and various degrees of nuclear atypia and pleomorphism. Immunohistochemically, the tumours were positive for α-smooth muscle actin (86%), muscle-specific actin (71%), desmin (86%), calponin (71%), h-caldesmon (57%) and smoothelin (71%). All were negative for KIT, CD34, protein kinase C theta and DOG1. Local recurrence and distant metastasis occurred in one and three patients, respectively. We then reviewed 55 cases of GI-LMS from the era following the recognition of gastrointestinal stromal tumours. Among 29 of 55 cases for whom follow-up information was available, the estimated 5-year overall survival rate was 51.6%; tumour size ≥5 cm was correlated significantly with shorter overall survival time (P = 0.0016), while mitotic count (≥50 or ≥100 per 50 high-power fields) proved to be no prognostic factor. CONCLUSIONS: GI-LMSs have distinctive clinicopathological and immunohistochemical features and exhibit aggressive biological behaviour.

DOI： 10.1111/his.12159

Low-grade central osteosarcoma arising from bone infarct. Reviewed International journal

Makoto Endo, Tatsuya Yoshida, Hidetaka Yamamoto, Takeaki Ishii, Nokitaka Setsu, Kenichi Kohashi, Tomoya Matsunobu, Yukihide Iwamoto, Yoshinao Oda

Human pathology 44 ( 6 ) 1184 - 9 2013.6

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

Bone infarct-associated sarcoma is a rare sarcoma, accounting for less than 1% of all bone sarcomas. Its histology usually reflects a high-grade sarcoma, such as malignant fibrous histiocytoma of bone or conventional osteosarcoma. Low-grade sarcoma arising from bone infarct has not been described well in the literature. Here, we present a 17-year follow-up of a female patient with bone infarct in her right humerus, from which a low-grade central osteosarcoma developed during follow-up. A histologic diagnosis of low-grade central osteosarcoma was confirmed by immunohistochemical expression of MDM2 and CDK4. She underwent a wide resection surgery. As of 4 years after surgery, she has remained free of any evidence of recurrence or metastasis. Here, we present clinical and pathologic findings of our case in detail and discuss the differential diagnoses of this extremely rare condition.

DOI： 10.1016/j.humpath.2012.11.011

Fascin-1 overexpression and miR-133b downregulation in the progression of gastrointestinal stromal tumor. Reviewed International journal

Hidetaka Yamamoto, Kenichi Kohashi, Aya Fujita, Yoshinao Oda

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 26 ( 4 ) 563 - 71 2013.4

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

MicroRNAs (miRNAs) are small, non-coding RNAs that are up- or downregulated in several types of cancer, and have an important role in the tumorigenesis and progression. To better understand the role of aberrantly expressed miRNAs and their target genes affecting the biology of gastrointestinal stromal tumor (GIST), we performed miRNA array in 19 cases of GIST, and found that several miRNAs, including miR-133b, were downregulated in high-grade GISTs. Subsequently, quantitative real-time reverse transcription-PCR revealed that fascin-1 mRNA was upregulated in accordance with miR-133b downregulation in high-grade GIST; this result was consistent with a previous report showing that fascin-1 might be a direct target of miR-133b. We then examined the fascin-1 protein expression by immunohistochemical staining in 147 cases of GIST, and found that fascin-1 overexpression was significantly correlated with shorter disease-free survival time and several aggressive pathological factors, including tumor size, mitotic counts, risk grade, blood vessel invasion and mucosal ulceration. Our results suggest that downregulation of miR-133b and overexpression of fascin-1 may have an important role in the progression of GIST, and that fascin-1 may be a useful biomarker to predict the aggressive behavior.

DOI： 10.1038/modpathol.2012.198

Glypican 3 expression in tumors with loss of SMARCB1/INI1 protein expression. Reviewed International journal

Kenichi Kohashi, Tetsuya Nakatsura, Yoshiaki Kinoshita, Hidetaka Yamamoto, Yuichi Yamada, Tatsuro Tajiri, Tomoaki Taguchi, Yukihide Iwamoto, Yoshinao Oda

Human pathology 44 ( 4 ) 526 - 33 2013.4

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

Glypican 3 (GPC3), a membrane-bound heparin sulfate proteoglycan, is mutated in Simpson-Golabi-Behmel syndrome, characterized by tissue overgrowth and an increased risk of embryonal malignancies such as Wilms tumor. Malignant rhabdoid tumor (MRT), originally described as a rhabdomyosarcomatoid variant of Wilms tumor, is a tumor with loss of SMARCB1/INI1 protein expression. We analyzed the frequency of GPC3 protein expression, GPC3 mRNA, and serum-soluble GPC3 levels in 71 cases of tumors with loss of SMARCB1/INI1 protein expression, including 14 MRTs, 48 epithelioid sarcomas (ES) (proximal-type, 21; distal-type, 27), 4 extraskeletal myxoid chondrosarcomas, and 5 pediatric undifferentiated soft-tissue sarcomas. We found that GPC3 overexpression of more than 10% of the labeling index was recognized in 6 (42.9%) MRTs, 1 (2.1%) proximal-type ES, and 3 (60%) pediatric undifferentiated soft-tissue sarcomas (MRT vs ES, P = .0003). All the remaining cases revealed GPC3-absent expression of less than 1% of the labeling index. The median values of GPC3 mRNA in the GPC3-absent expression group and overexpression group were 10.2 and 309, respectively, with a statistically significant difference between these 2 groups (P = .004). However, there was no statistically significant difference in the prognoses of these 2 groups of MRT (P = .99). In analyzable cases of small-number MRT and pediatric undifferentiated soft-tissue sarcoma, there is no significant correlation between GPC3 immunoreactivity and serum-soluble GPC3 level. Therefore, evaluation of GPC3 immunoexpression may be a useful diagnostic tool to distinguish ES from MRT, especially extrarenal MRT. It was suggested that MRTs with GPC3 overexpression may become a new target of GPC3 immunotherapy.

DOI： 10.1016/j.humpath.2012.06.014

Fibrocartilaginous mesenchymoma arising in the pubic bone: a case report. Reviewed International journal

Yusuke Takahashi, Yoshinao Oda, Hidetaka Yamamoto, Takeaki Ishii, Nokitaka Setsu, Makoto Endo, Shuichi Matsuda, Yukihide Iwamoto

Pathology international 63 ( 4 ) 226 - 9 2013.4

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

Fibrocartilaginous mesenchymoma (FCM) of the bone is a rare tumor, with only 21 reported cases since 1984. It usually occurs in the long bones of children and adolescents, but in this case, the tumor arose in the pubic bone. The pathological diagnosis of FCM can be challenging, and the treatment should be a wide resection because of its locally aggressive behavior. Histologically, our tumor was composed of a lobular proliferation of spindle cells juxtaposed to the cartilaginous tissue, lacking cytological atypia. Enchondral ossification was observed at the periphery of the cartilaginous nodules, and hypertrophic chondrocytes was recognized, reminiscent of an epiphyseal plate. Intralesional resection followed by phenol and ethanol cauterization was performed in place of the usual wide resection. We report a case of FCM arising in a rare anatomical site, the pubic bone, successfully treated by intralesional resection. One year after the surgery, the patient is free of disease.

DOI： 10.1111/pin.12052

Spindle-cell carcinoma of the hypopharynx presenting with a pedunculated appearance: CT and MR features. Reviewed

Masato Yonezawa, Hidetake Yabuuchi, Yoshio Matsuo, Takeshi Kamitani, Hideki Shiratsuchi, Hidetaka Yamamoto, Hiroshi Honda

Japanese journal of radiology 31 ( 3 ) 211 - 4 2013.3

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

Spindle-cell carcinoma (SPCC) is a rare tumor that presents biphasic components: squamous-cell carcinoma and sarcomatous features without any differentiation. We present a case of SPCC of the hypopharynx in a 60-year-old man. A well-demarcated mass occupying the hypomesopharynx and presenting a pedunculated appearance was observed originating from the lateral wall of left piriform sinus. High signal intensity on T2-weighted magnetic resonance (MR) images corresponded to the myxoid matrix of the tumor on MR pathologic correlation.

DOI： 10.1007/s11604-012-0170-8

Epithelial and cartilaginous differentiation in clear cell chondrosarcoma. Reviewed International journal

Suguru Matsuura, Takeaki Ishii, Makoto Endo, Yusuke Takahashi, Nokitaka Setsu, Hidetaka Yamamoto, Sadafumi Tamiya, Yukihide Iwamoto, Yoshinao Oda

Human pathology 44 ( 2 ) 237 - 43 2013.2

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

Clear cell chondrosarcoma is a rare cartilaginous bone tumor, and little is known about its pathology. We investigated the immunohistochemical expression profiles of cytokeratins (CAM5.2, AE1/AE3, CK7, CK8, CK18, and CK20), epithelial membrane antigen, SRY (sex-determining region Y)-box 9, type II collagen, runt-related transcription factor 2, and osteocalcin in clear cell chondrosarcoma and compared them with those in chondroblastoma, conventional chondrosarcoma, and osteosarcoma. Of 5 cases of clear cell chondrosarcoma, 3 demonstrated positive staining for AE1/AE3 and some form of cytokeratin in the clear cell component. Of the 5 cases, 4 strongly expressed SRY (sex-determining region Y)-box 9 in the clear cell component but weakly expressed it in the cartilaginous component. Of the 5 cases of clear cell chondrosarcoma, 3 expressed runt-related transcription factor 2 in both the clear cell and cartilaginous components, but no expression of osteocalcin was detected. In chondroblastoma, 8 of 13 cases expressed AE1/AE3, and other cytokeratins, such as CK7 (4/13), CK8 (6/13), CK18 (8/13), and CK20 (3/13), demonstrated a similar staining extensity pattern between the cellular and cartilaginous components. Clear cell chondrosarcoma and chondroblastoma have similar immunohistochemical features in that they both express epithelial and chondrogenetic markers. On the other hand, tumor cells of clear cell chondrosarcoma have no osteoblastic immunohistochemical expression in comparison with chondroblastoma.

DOI： 10.1016/j.humpath.2012.05.012

Prognostic significance of AKT/mTOR and MAPK pathways and antitumor effect of mTOR inhibitor in NF1-related and sporadic malignant peripheral nerve sheath tumors. Reviewed International journal

Makoto Endo, Hidetaka Yamamoto, Nokitaka Setsu, Kenichi Kohashi, Yusuke Takahashi, Takeaki Ishii, Kei-ichiro Iida, Yoshihiro Matsumoto, Michiyuki Hakozaki, Mikiko Aoki, Hiroshi Iwasaki, Yoh Dobashi, Kenichi Nishiyama, Yukihide Iwamoto, Yoshinao Oda

Clinical cancer research : an official journal of the American Association for Cancer Research 19 ( 2 ) 450 - 61 2013.1

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

PURPOSE: Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma with poor prognosis. MPNSTs occur frequently in patients with neurofibromatosis type 1 (NF1), in which NF1 gene deficiency leads to Ras hyperactivation. Ras activation causes the subsequent activation of the AKT/mTOR and Raf/MEK/ERK pathways and regulates cellular functions. However, the activation profiles of the AKT/mTOR and MAPK pathways in MPNSTs are poorly understood. The purposes of this study are to examine the correlation between the activation of these pathways and clinicopathologic or prognostic factors and to identify candidate target molecules in MPNST. Moreover, we assessed the antitumor effects of the inhibitor of candidate target. EXPERIMENTAL DESIGN: Immunohistochemistry was conducted to evaluate the activation profiles of AKT/mTOR and MAPK pathways using 135 tumor specimens. Immunohistochemical expressions were confirmed by Western blotting. Then, an in vitro study was conducted to examine the antitumor effect of the mTOR inhibitor on MPNST cell lines. RESULTS: Phosphorylated-AKT (p-AKT), p-mTOR, p-S6RP, p-p70S6K, p-4E-BP1, p-MEK1/2, and p-ERK1/2 expressions were positive in 58.2%, 47.3%, 53.8%, 57.1%, 62.6%, 93.4%, and 81.3% of primary MPNSTs, respectively. Positivity for each factor showed no difference between NF1-related and sporadic MPNSTs. Univariate prognostic analysis revealed that p-AKT, p-mTOR, and p-S6RP expressions were associated with poor prognosis. Furthermore, activation of each p-mTOR and p-S6RP was an independent poor prognostic factor by multivariate analysis. mTOR inhibition by Everolimus showed antitumor activity on MPNST cell lines in vitro. CONCLUSION: mTOR inhibition is a potential treatment option for both NF1-related and sporadic MPNSTs.

DOI： 10.1158/1078-0432.CCR-12-1067

Phosphorylation of signal transducer and activator of transcription 3 in soft tissue leiomyosarcoma is associated with a better prognosis. Reviewed International journal

Nokitaka Setsu, Kenichi Kohashi, Makoto Endo, Hidetaka Yamamoto, Sadafumi Tamiya, Yusuke Takahashi, Yuichi Yamada, Takeaki Ishii, Shuichi Matsuda, Ryohei Yokoyama, Yukihide Iwamoto, Yoshinao Oda

International journal of cancer 132 ( 1 ) 109 - 15 2013.1

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

Signal transducer and activator of transcription (STAT) 3 mediates a broad range of biological processes, including cell survival and proliferation, and STAT3 has generally been regarded as a pro-oncogenic transcription factor. We investigated the phosphorylation status of STAT3 and the protein expression of the suppressor of cytokine signaling 3 (SOCS3) by immunohistochemistry in 145 formalin-fixed, paraffin-embedded samples of soft tissue leiomyosarcoma (LMS), including 129 primary tumors. Eight benign soft tissue smooth muscle tumors were also examined. Thirteen frozen LMS samples, which were paired with normal tissue samples, were assessed by Western blot analysis for the phosphorylation of STAT3 and SOCS3 expression. Immunohistochemical study showed that the phosphorylation of STAT3 was not a major event in LMS (37%). Moreover, phosphorylated STAT3 (pSTAT3) expression was significantly correlated with a better prognosis. Overexpression of SOCS3 was recognized in 52% of the cases and negatively correlated with pSTAT3 expression. Among the benign tumors, 63 and 25% were positive for pSTAT3 and SOCS3, respectively. Immunoblotting detected pSTAT3 in all tumor samples, but at lower levels than in non-neoplastic tissue. SOCS3 was detected in 92% (12 out of 13) of tumor tissues, but in none of the normal tissues. Contrary to the previous investigations of many other malignant tumors, STAT3 was inactivated in most LMS cases, likely owing to SOCS3 overexpression. STAT3 might not contribute to the progression of soft tissue LMS, and the phosphorylation status of STAT3 has the potential to be a favorable prognostic marker of LMS.

DOI： 10.1002/ijc.27655

Correlations between apparent diffusion coefficient values and prognostic factors of breast cancer. Reviewed

Takeshi Kamitani, Yoshio Matsuo, Hidetake Yabuuchi, Nobuhiro Fujita, Michinobu Nagao, Mikako Jinnouchi, Masato Yonezawa, Yuzo Yamasaki, Eriko Tokunaga, Makoto Kubo, Hidetaka Yamamoto, Takashi Yoshiura, Hiroshi Honda

Magnetic resonance in medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine 12 ( 3 ) 193 - 9 2013

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

PURPOSE: We investigated possible correlations between apparent diffusion coefficient (ADC) values and prognostic factors of breast cancer. METHODS: We retrospectively evaluated 81 patients who underwent magnetic resonance (MR) imaging of the breast and were diagnosed pathologically with invasive ductal carcinoma (IDC) not otherwise specified with invasive foci one cm or larger. We excluded ductal carcinoma in situ and IDC with invasive foci smaller than one cm because small lesions decrease the reliability of signal intensity of diffusion-weighted imaging (DWI). We also excluded special type cancers. We used t-test to compare the mean ADC values of cancers of Stage pT1 (≤2 cm) versus pT2 or 3 (>2 cm), cancers with versus without vascular invasion, axillary lymph node (N)-positive versus N-negative cancers, estrogen receptor (ER)-positive versus ER-negative cancers, and progesterone receptor (PgR)-positive versus PgR-negative cancers. We analyzed correlations between the ADC value with nuclear grade (NG) and human epidermal growth factor receptor 2 (HER2) score by rank test using Spearman's correlation coefficient. RESULTS: The mean ADC value was significantly higher for N-positive (n=28; 0.97 ± 0.20 × 10(-3) mm(2)/s) than N-negative cancers (n=53; 0.87 ± 0.17 × 10(-3) mm(2)/s) (P=0.017); significantly lower for ER-positive (n=63; 0.88 ± 0.15 × 10(-3) mm(2)/s) than ER-negative cancers (n=18; 1.01 ± 0.21 × 10(-3) mm(2)/s) (P=0.005); and significantly lower for PgR-positive (n=47; 0.88 ± 0.16 × 10(-3) mm(2)/s) than PgR-negative cancers (n=34; 0.95 ± 0.18 × 10(-3) mm(2)/s) (P=0.048). Tumor size, vascular invasion, NG, and HER2 status showed no significant correlation with ADC values. CONCLUSION: ADC values were higher for N-positive and ER-negative breast cancers than N-negative and ER-positive cancers.

Inhibin-α and synaptophysin immunoreactivity in synovial sarcoma with granular cell features. Reviewed International journal

Nokitaka Setsu, Kenichi Kohashi, Makoto Endo, Hidetaka Yamamoto, Yoshihiro Ohishi, Kazunobu Sueyoshi, Yukihide Iwamoto, Masazumi Tsuneyoshi, Toru Motoi, Arisa Kumagai, Yoshinao Oda

Human pathology 43 ( 6 ) 850 - 7 2012.6

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

We recognized immunoreactivity for the α subset of inhibin and synaptophysin in synovial sarcomas with granular cell features. Histologic findings of 90 cases of synovial sarcoma were reviewed. Two (2.2%) of the 90 cases had granular cell features, showing sheet or nested proliferation of characteristic epithelioid cells with abundant eosinophilic and granular cytoplasm, in addition to the typical spindle cell component. The 2 cases were both female (aged 86 and 76 years). The tumors were located in the foot and the retroperitoneum and measured 3.5 and 14 cm in maximum diameter. Reverse transcriptase polymerase chain reaction analysis revealed SS18-SSX1 transcripts in both cases. SS18 gene rearrangement was detected in granular cells as well as spindle cells by chromogenic in situ hybridization. Immunohistochemistry found the granular cells to be positive for inhibin-α in both cases and for synaptophysin in 1 case, whereas spindle cells were not. Thirty-six cases (20 monophasic fibrous, 11 biphasic, and 5 poorly differentiated synovial sarcomas) were additionally examined for comparison; they showed no immunoreactivity for inhibin-α or synaptophysin. This is the first report of immunoreactivity for inhibin-α and synaptophysin in synovial sarcoma. These immunohistochemical findings might be characteristic of synovial sarcomas with granular cell features.

DOI： 10.1016/j.humpath.2011.07.012

HER-2/neu gene amplification in carcinoma ex pleomorphic adenoma in relation to progression and prognosis: a chromogenic in-situ hybridization study. Reviewed International journal

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

Histopathology 60 ( 6B ) E131-42 2012.5

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

AIMS: The aim of this study was to investigate the potential role of HER-2/neu in the stepwise progression of carcinoma ex pleomorphic adenoma (CXPA) and to evaluate its prognostic significance in CXPA. METHODS AND RESULTS: We examined HER2 overexpression and HER2 amplification by immunohistochemistry and chromogenic in-situ hybridization in 31 cases of CXPA with ductal differentiation (eight intraductal, five intracapsular, and 18 extracapsular) and seven cases of atypical pleomorphic adenoma (PA). HER2 overexpression and HER2 amplification were found in 17 (54.8%) and 12 (38.7%) of the 31 CXPA cases, respectively. HER2 amplification was more prevalent in extracapsular CXPAs (9/18 cases; 50%) than intracapsular CXPAs (1/5 cases; 20%), intraductal CXPAs (2/8 cases; 25%), or atypical PAs (0/7 case; 0%). The status of HER2 amplification was essentially retained from the intraductal to the extracapsular component in individual extracapsular CXPAs. In addition, HER2 amplification was significantly associated with a worse prognosis (shorter disease-free survival time and shorter overall survival time) among extracapsular CXPAs (each P < 0.05). CONCLUSIONS: These results suggest that HER2 may play an important role in the progression of CXPA, and that HER2 amplification may be an additional prognostic indicator of CXPA.

DOI： 10.1111/j.1365-2559.2012.04201.x

The Akt/mammalian target of rapamycin pathway is activated and associated with adverse prognosis in soft tissue leiomyosarcomas. Reviewed International journal

Nokitaka Setsu, Hidetaka Yamamoto, Kenichi Kohashi, Makoto Endo, Shuichi Matsuda, Ryohei Yokoyama, Kenichi Nishiyama, Yukihide Iwamoto, Yoh Dobashi, Yoshinao Oda

Cancer 118 ( 6 ) 1637 - 48 2012.3

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

BACKGROUND: The Akt/mammalian target of rapamycin (mTOR) pathway mediates cell survival and proliferation and contributes to tumor progression. Soft tissue leiomyosarcoma continues to show poor prognosis, and little is known about its mechanisms of tumor progression. Here the authors investigated the significance of activation of the Akt/mTOR pathway in soft tissue leiomyosarcomas. METHODS: The phosphorylation status of Akt, mTOR, S6, and the eukaryotic translation initiation factor 4E-binding protein (4E-BP1) and the protein expression of phosphatase and tensin homologue (PTEN) were assessed by immunohistochemistry in 145 formalin-fixed paraffin-embedded samples of soft tissue leiomyosarcoma including 129 primary tumors. The expression of phosphorylated Akt and mTOR in comparison with their total forms was assessed by Western blot analysis in 13 frozen samples, which were paired with normal tissue samples. Moreover, 39 frozen tumor samples were analyzed for PIK3CA and AKT1 gene mutation. RESULTS: Immunohistochemically, phosphorylated forms of Akt, mTOR, S6, and 4E-BP1 were positive in 78.3%, 72.6%, 74.5%, and 70.5% of the samples, respectively. These results were correlated with each other, and associated with higher mitotic activity and adverse prognosis. Decreased expression of PTEN was recognized in only 19.7% and had no statistically significant correlation with Akt or other molecules. Immunoblotting showed a high degree of Akt and mTOR phosphorylation in tumor samples compared with that in non-neoplastic tissue. Mutational analysis failed to reveal any PIK3CA or AKT1 mutations around the hot spots. CONCLUSIONS: The Akt/mTOR pathway was activated in most cases of soft tissue leiomyosarcoma and associated with worse clinical behavior and aggressive pathological findings.

DOI： 10.1002/cncr.26448

Expression level of the mitotic checkpoint protein and G2-M cell cycle regulators and prognosis in gastrointestinal stromal tumors in the stomach. Reviewed International journal

Aya Fujita, Hidetaka Yamamoto, Masakazu Imamura, Norimoto Nakamura, Yoshihiko Maehara, Masazumi Tsuneyoshi, Yoshinao Oda

Virchows Archiv : an international journal of pathology 460 ( 2 ) 163 - 9 2012.2

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

The biological behavior of gastrointestinal stromal tumors (GISTs) ranges from benign to malignant, and the risk of an adverse outcome is correlated with the location of the primary tumor, tumor size, and mitotic counts. Cell cycle regulators are potentially associated with the tumorigenesis and progression of GISTs. Checkpoint with forkhead and ring finger (CHFR) functions as an important checkpoint protein in the early to mid-prophase to regulate mitosis. In this study, we evaluated the expression of CHFR and several cell cycle regulators, including cyclin A, cyclin B1, cdc2, and cdk2, by immunohistochemical staining in 53 cases of primary gastric GISTs, and compared the immunohistochemical results with the clinicopathological factors or the GIST risk grades as modified by Miettinen et al. Of the 53 cases, 18 (34%) showed decreased nuclear CHFR expression. Decreased CHFR expression was correlated with higher mitotic counts [>5/50 high-power fields (HPFs)] (p = 0.039) and a high-risk grade (p = 0.0475), but not with expression of other cell cycle regulators. Higher cyclin A labeling index (LI, >1.5%), cyclin B1 LI (>0.25%), cdc2 LI (>1.16%), Ki-67 LI (>4.9%), mitotic counts (>5/50 HPF) and high-risk grade were each associated with shorter disease-free survival (p = 0.0017, p = 0.003, p = 0.0471, p = 0.002, p < 0.001, and p = 0.0017, respectively). Our results suggest that modified risk grade and increased expression of G2-M regulators such as cyclin A, cyclin B1, and cdc2 are useful for predicting the biological behavior of gastric GISTs. In addition, decreased CHFR expression may play a role in increased proliferative activity of higher grade GISTs.

DOI： 10.1007/s00428-011-1181-z

Clinical significance of pathologic staging of progression in carcinoma ex pleomorphic adenoma: A comparison with current t classification for salivary cancer

Kazuki Hashimoto, Hidetaka Yamamoto, Hideki Shiratsuchi, Satoshi Toh, Torahiko Nakashima, Yuichiro Higaki, Yoshinao Oda, Shizuo Komune

Japanese Journal of Head and Neck Cancer 38 ( 1 ) 50 - 55 2012

Publishing type：Research paper (scientific journal)

Although pathologic progression stage on the basis of the extent of capsular invasion has been considered to be a useful prognostic indicator for carcinoma ex pleomorphic adenoma (CXPA), this pathologic factor is not adopted in the T-factor of the current TMN classification for salivary cancer. In this study, we examined the pathologic progression stage in 31 cases of CXPA, and evaluated its clinical and prognostic significance in CXPA, with a comparison with the current T-classification. Among the cases in category pT1 and 2, 25% and 50% showed invasion beyond the capsule of preexisting pleomorphic adenoma, 25% and 30% developed distant metastasis after surgery, and 25% and 20% eventually died of cancer, respectively. In contrast, 41.7% of the cases in category pT3 were histopathologically non-invasive carcinoma, and none of them developed local recurrence or distant metastasis. Moreover, noninvasive or minimally invasive CXPAs showed excellent prognoses, regardless of their sizes or strategies for postoperative adjuvant therapy. In addition, pathologic progression stage was a more useful prognostic indicator in CXPA than the current T-classification regarding disease-free and overall survival rates. These results demonstrate that appropriate postoperative treatment and clinical follow-up based on the pathologic progression staging is important for patients with CXPA.

DOI： 10.5981/jjhnc.38.50

Sclerosing variant of perivascular epithelioid cell tumor in the female genital organs. Reviewed International journal

Yuichi Yamada, Hidetaka Yamamoto, Yoshihiro Ohishi, Kenichi Nishiyama, Masao Fukuhara, Toshiaki Saitou, Masazumi Tsuneyoshi, Yoshinao Oda

Pathology international 61 ( 12 ) 768 - 72 2011.12

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

Perivascular epithelioid cell tumor (PEComas), other than angiomyolipoma, clear cell 'sugar' tumor of the lung, and lymphangioleiomyomatosis, is an uncommon mesenchymal neoplasm that arises in the soft tissue and visceral organs. We report herein two cases of sclerosing PEComa; a distinctive variant of PEComa, which is characterized by extensive stromal hyalinization, occurring in the uterus and broad ligament. The patients were 34- and 51-year-old females with no family history of tuberous sclerosis complex. Macroscopically, the tumors had white to gray cut surfaces and were microscopically composed of predominantly spindle- to polygon-shaped cells with clear to slightly eosinophilic cytoplasm and pleomorphic nuclei focally arranged in a perivascular pattern, accompanied by marked stromal hyalinization. These tumor cells were immunohistochemically positive for HMB45 and α-smooth muscle actin. Although this variant of PEComa is very rare, this entity should be considered as a potential primary neoplasm of the female genital organs.

DOI： 10.1111/j.1440-1827.2011.02737.x

Diagnostic performance in differentiation of breast lesion on digital mammograms: comparison among hard-copy film, 3-megapixel LCD monitor, and 5-megapixel LCD monitor Reviewed

Takeshi Kamitani, Hidetake Yabuuchi, Yoshio Matsuo, Taro Setoguchi, Shuji Sakai, Takashi Okafuji, Shunya Sunami, Masamitsu Hatakenaka, Nobuhide Ishii, Makoto Kubo, Eriko Tokunaga, Hidetaka Yamamoto, Hiroshi Honda

CLINICAL IMAGING 35 ( 5 ) 341 - 345 2011.9

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

We compared observer performance of digital mammography among hard-copy readings and soft-copy readings using 3-megapixel (3M) and 5-megapixel (5M) liquid crystal display (LCD) monitors. Five experienced radiologists assessed 80 mammograms of 40 cancers and 40 benign lesions. There were no significant differences among the average A(z) of three modalities and among the kappa values for intra- and interobserver agreement. The soft-copy reading using the 3M LCD monitor took a slightly longer time, although there were no significant differences. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.clinimag.2010.08.015

KIT-negative gastrointestinal stromal tumor of the abdominal soft tissue: a clinicopathologic and genetic study of 10 cases. Reviewed International journal

Hidetaka Yamamoto, Aya Kojima, Shigenori Nagata, Yasuhiko Tomita, Satsuki Takahashi, Yoshinao Oda

The American journal of surgical pathology 35 ( 9 ) 1287 - 95 2011.9

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

Gastrointestinal stromal tumor (GIST) typically occurs in the gastrointestinal (GI) tract, and expresses KIT protein that is associated with KIT or platelet-derived growth factor receptor-α (PDGFRA) gene mutation. Extragastrointestinal stromal tumors (EGISTs) are a minor subset of GIST that occurs in the soft tissue outside the GI tract, and in very rare cases, these tumors can be KIT negative. We examined the clinicopathologic and molecular characteristics of 10 cases of KIT-negative EGIST by using immunohistochemical staining and gene mutation analysis. The tumors occurred in the omentum (n=5), mesentery (n=2), retroperitoneum (n=1), pelvic cavity (n=1), and not otherwise specified regions of the abdominal cavity (n=1). They ranged from 4 to 33 cm (median, 15 cm) in maximum diameter with relatively low mitotic counts (median, 3.5 per 50 high-power fields). Morphologically, most cases were of epithelioid cell (n=9) or mixed epithelioid and spindle cell (n=1) type, accompanied by variable amounts of myxoid stroma. By immunohistochemical staining, the tumors were positive for CD34 (80%), protein kinase C (PKC) θ (90%), and discovered on GIST-1 (DOG1) (90%), but were negative for KIT (0%). The majority of the examined cases (7 of 9 cases; 78%) had PDGFRA mutations in exon 12 (n=1) or exon 18 (n=6). One case (11%) had a mutation in KIT exon 11, and the remaining 1 had no mutation in either KIT or PDGFRA. Distant metastasis and local recurrence occurred in 1 (10%) and 2 (20%) patients, respectively, and adverse outcome was correlated with larger (>10 cm) tumor size and high mitotic counts (>5/50 high-power fields). Therefore, KIT-negative EGISTs can be characterized by preferential omental origin, epithelioid cell type, low mitotic activity, and mutation of the PDGFRA gene, and these features are similar to those of KIT-negative gastric GISTs. As KIT-negative EGISTs should be considered to be a potential abdominal soft tissue neoplasm, immunohistochemical staining panel and molecular analysis are necessary not only to confirm the diagnosis but also to determine the therapeutic strategy.

DOI： 10.1097/PAS.0b013e3182206f15

Secondary resistance of extra-gastrointestinal stromal tumors to imatinib mesylate: report of a case. Reviewed

Koji Ando, Eiji Oki, Masahiko Sugiyama, Yan Zhao, Aya Kojima, Hidetaka Yamamoto, Yoichi Yamashita, Hiroshi Saeki, Akinobu Taketomi, Masaru Morita, Yoshihiro Kakeji, Shunichi Tsujitani, Yoshihiko Maehara

Surgery today 41 ( 9 ) 1290 - 3 2011.9

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

Extra-gastrointestinal stromal tumors (EGISTs) that do not originate in the digestive tract are rare. We report a case of multiple EGISTs, which was monitored closely by KIT gene mutation analysis and other investigations. The patient was a 52-year-old man in whom multiple tumors in the abdominal cavity were diagnosed as EGISTs. Immunohistochemical analysis revealed positive staining for c-kit; however, no mutations were found in the KIT gene. The tumors decreased in size remarkably following treatment with imatinib mesylate, but after 2 years of this treatment, multiple liver metastases and some regrowth of the abdominal masses were found simultaneously. The liver metastasis and the abdominal masses were excised, and further analysis of the KIT gene revealed the same mutation in exon 11 in the KIT gene in the metastatic tumors. We speculate that the treatment might have triggered development of the imatinib mesylate-resistant clone, which may have existed in the primary lesion as a KIT gene mutant. This report provides valuable insight into the mechanisms of recurrent GISTs after treatment with imatinib mesylate.

DOI： 10.1007/s00595-010-4477-8

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