Faculty Profiles - YAMAMOTO HIDETAKA

Papers - YAMAMOTO HIDETAKA

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High Prevalence of MYD88 and CD79B Mutations in Primary Sinonasal Diffuse Large B-Cell Lymphoma: Identification of an MCD-like Subtype. Reviewed International journal

Fangli Peng, Takuro Igawa, Tomohiro Urata, Hiroki Kobayashi, Tetsuya Isoda, Sawako Ono, Takehiro Tanaka, Daisuke Ennisshi, Yoshinobu Maeda, Hidetaka Yamamoto

The American journal of surgical pathology 2024.10

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Primary sinonasal diffuse large B-cell lymphoma (PSDLBCL) is a rare aggressive lymphoma. Recently, genetic classification using Next Generation Sequencing (NGS) demonstrated that PSDLBCL largely consists of the MCD genotype, which has a poor prognosis mainly driven by MYD88 L265P and CD79B gene abnormalities. This study investigated the prevalence and clinicopathological significance of MYD88 L265P and CD79B Y196 mutations using droplet digital PCR in 55 patients with PSDLBCL, as well as the translocation of BCL2/BCL6/c-Myc with FISH. We found mutations in MYD88 L265P (29/55, 52.7%) and CD79B Y196 (20/55, 36.4%). The MCD-like subtype, defined by the mutation of MYD88 and/or CD79B, was found in 32 out of 55 cases (58.2%). This subtype largely consists of non-GCB type (31/32, 96.9%; P<0.01) and double-expressor cases (20/32, 62.5%; P=0.01) compared with the MYD88/CD79B co-wild type, with BCL6 translocation in a small subset (2/32, 6.3%) and no translocations of BCL2 (0/32) or c-Myc (0/32). The MCD-like subtype tended to relapse in specific sites such as the central nervous system, testis, and/or skin compared with the co-wild type (P=0.03), showing poorer outcomes in overall survival (P=0.02) and progression-free survival (P=0.01). In conclusion, our study highlights a high prevalence of MYD88 and CD79B mutations in PSDLBCL, identifying an aggressive MCD-like subtype with a distinct relapse pattern. This molecular subclassification can be helpful for both prognostic prediction and therapeutic strategy in patients with PSDLBCL.

DOI： 10.1097/PAS.0000000000002329

Re-evaluation of histopathological factors for the outcome of salivary duct carcinoma patients: A multi-institutional retrospective study of 240 cases in a Japanese cohort. International journal

Kimihide Kusafuka, Eiji Nakatani, Satoshi Baba, Yoshifumi Arai, Matsuyoshi Maeda, Koji Yamanegi, Takayuki Murase, Hiroshi Inagaki, Yoshiro Otsuki, Kensuke Suzuki, Hiroshi Iwai, Yoshiaki Imamura, Shoji Yamanaka, Ichiro Ito, Midori Sato, Morito Kurata, Tsutomu Daa, Tomonori Kawasaki, Ryo Kawata, Yuri Tachibana, Junya Fukuoka, Takashi Suzuki, Hidetaka Yamamoto, Kazumori Arai, Makoto Suzuki

Human pathology 105736 - 105736 2025.2

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

AIMS: Salivary duct carcinoma (SDC) is a relatively common, high-grade salivary gland malignancy that can often occur as a carcinomatous component of carcinoma ex pleomorphic adenoma (CXPA). This study aimed to elucidate the histological factors which are related to the outcome of SDC. METHODS AND RESULTS: We conducted a comprehensive histological review of 240 SDC cases and we analyzed the association between the histomorpholgical parameters and the clinical outcomes to identify new histological prognostic factors. The majority of cases involved the parotid glands (n = 197 cases). SDC showed a marked male predilection (M/F = 5.3:1), and the median age was 66 years-old. This study included 110 de novo cases and 130 CXPA cases. Multivariate analysis revealed that only the pathological stage was significantly associated with overall survival (OS), whereas previously reported histological parameters, such as poorly differentiated clusters, nuclear polymorphism, and mitotic index were not significantly associated with OS and progression-free survival (PFS). Vascular invasion (V [+]) was significantly associated with PFS, and lymphatic invasion was associated with late lymph node metastases. Even in the same pathological stage, V (+) cases always had the worse PFS than V (-) cases. CONCLUSIONS: The histopathological review determined that as distant metastasis relapse was the most important prognostic factor in patients with SDC, V (+) status was also a significant outcome indicator.

DOI： 10.1016/j.humpath.2025.105736

Kikuchi-Fujimoto disease: investigating comprehensive clinicopathological features and risk factors for recurrence. International journal

Midori Filiz Nishimura, Chikako Sakao, Yuka Kurokawa, Yoshito Nishimura, Asami Nishikori, Hidetaka Yamamoto, Yasuharu Sato

Histopathology 2025.2

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

AIMS: Kikuchi-Fujimoto disease (KFD) is a rare disease that typically manifests with fever and cervical lymphadenopathy. Little is known about the risk factors associated with recurrence and their correlation with clinicopathologic features. METHODS AND RESULTS: We analysed 112 patients with KFD, predominantly female (61/112, 54.5%), with an average age of 29.4 years. The incidence was higher in males up to the age of 20 and higher in females from their 30s onwards. Of the 70 patients with follow-up data, 23% experienced recurrence. Recurrence was associated with lower C4 levels (P = 0.038) and higher antinuclear antibody (ANA) rates (P = 0.007) compared to transient disease. The mean duration of symptoms was 71.5 days. Lymph node histology in 98 cases (excluding 14 needle biopsy specimens) was classified into three patterns: proliferative (n = 75, 77%), necrotizing (n = 22, 22%), and xanthomatous (n = 1, 1%). The necrotizing pattern associated with significantly enlarged lymph nodes (P = 0.047) and a longer symptom duration (P = 0.009) than the proliferating pattern. The number of CD4-positive lymphocytes was significantly lower in the necrotizing type than in the proliferative type (P < 0.001). CONCLUSION: These results indicated that low C4 levels and positive ANA were associated with KFD recurrence. Although the aetiology of KFD remains elusive, given that some cases develop autoimmune disease, the results suggest that patients with recurrent KFD represent an intermediate status between those with transient KFD and those with overt autoimmune disease. The comprehensive clinicopathological findings of this study may be useful for elucidating its pathogenesis and predicting the clinical course.

DOI： 10.1111/his.15427

Myeloid Cells Induce Infiltration and Activation of B Cells and CD4+ T Follicular Helper Cells to Sensitize Brain Metastases to Combination Immunotherapy. International journal

Toshifumi Ninomiya, Naoya Kemmotsu, Fumiaki Mukohara, Masaki Magari, Ai Miyamoto, Youki Ueda, Takamasa Ishino, Joji Nagasaki, Tomohiro Fujiwara, Hidetaka Yamamoto, Hidetoshi Hayashi, Kota Tachibana, Joji Ishida, Yoshihiro Otani, Shota Tanaka, Shinichi Toyooka, Isamu Okamoto, Yosuke Togashi

Cancer research 2025.1

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

Brain metastasis (BM) is a poor prognostic factor in cancer patients. Despite showing efficacy in many extracranial tumors, immunotherapy with anti-PD-1 monoclonal antibody (mAb) or anti-CTLA-4 mAb appears to be less effective against intracranial tumors. Promisingly, recent clinical studies have reported that combination therapy with anti-PD-1 and anti-CTLA-4 mAbs has a potent antitumor effect on BM, highlighting the need to elucidate the detailed mechanisms controlling the intracranial tumor microenvironment (TME) to develop effective immunotherapeutic strategies. Here, we analyzed the tumor-infiltrating lymphocytes in murine models of BM that responded to anti-CTLA-4 mAb to anti-PD-1 mAb. Activated CD4+ T follicular helper (TFH) cells with high CTLA-4 expression characteristically infiltrated the intracranial TME, which were activated by the combination anti-CTLA-4 and anti-PD-1 treatment. Loss of TFH cells suppressed the additive effect of CTLA-4 blockade on anti-PD-1 mAb. B cell-activating factor belonging to the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) produced by abundant myeloid cells, particularly CD80hiCD206lo pro-inflammatory M1-like macrophages, in the intracranial TME, induced B cell and TFH cell infiltration and activation. Furthermore, the intracranial TME of patients with non-small cell lung cancer featured TFH and B cell infiltration as tertiary lymphoid structures. Together, these findings provide insights into the immune cell crosstalk in the intracranial TME that facilitates an additive anti-tumor effect of CTLA-4 blockade with anti-PD-1 treatment, supporting the potential of a combination immunotherapeutic strategy for BM.

DOI： 10.1158/0008-5472.CAN-24-2274

唾液腺粘液腺癌の遺伝子異常

中黒匡人, 浦野誠, 八木春奈, 山元英崇, 駄阿勉, 矢田直美, 辻隆裕, 中村康平, 長尾俊孝

日本唾液腺学会誌 64 34 - 34 2024.12

唾液腺粘液腺癌の遺伝子異常

中黒匡人, 浦野誠, 八木春奈, 山元英崇, 駄阿勉, 矢田直美, 辻隆裕, 中村康平, 長尾俊孝

日本唾液腺学会誌 64 34 - 34 2024.12

Spatial dynamics of CD39+CD8+ exhausted T cell reveal tertiary lymphoid structures-mediated response to PD-1 blockade in esophageal cancer. Reviewed International journal

Kenro Tanoue, Hirofumi Ohmura, Koki Uehara, Mamoru Ito, Kyoko Yamaguchi, Kenji Tsuchihashi, Yudai Shinohara, Peng Lu, Shingo Tamura, Hozumi Shimokawa, Taichi Isobe, Hiroshi Ariyama, Yoshihiro Shibata, Risa Tanaka, Hitoshi Kusaba, Taito Esaki, Kenji Mitsugi, Daisuke Kiyozawa, Takeshi Iwasaki, Hidetaka Yamamoto, Yoshinao Oda, Koichi Akashi, Eishi Baba

Nature communications 15 ( 1 ) 9033 - 9033 2024.10

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

Despite the success of immune checkpoint blockade (ICB) therapy for esophageal squamous cell cancer, the key immune cell populations that affect ICB efficacy remain unclear. Here, imaging mass cytometry of tumor tissues from ICB-treated patients identifies a distinct cell population of CD39+PD-1+CD8+ T cells, specifically the TCF1+ subset, precursor exhausted T (CD39+ Tpex) cells, which positively correlate with ICB benefit. CD39+ Tpex cells are predominantly in the stroma, while differentiated CD39+ exhausted T cells are abundantly and proximally within the parenchyma. Notably, CD39+ Tpex cells are concentrated within and around tertiary lymphoid structure (TLS). Accordingly, tumors harboring TLSs have more of these cells in tumor areas than tumors lacking TLSs, suggesting Tpex cell recruitment from TLSs to tumors. In addition, circulating CD39+ Tpex cells are also increased in responders following ICB therapy. Our findings show that this unique subpopulation of CD39+PD-1+CD8+ T cells is crucial for ICB benefit, and suggest a key role in TLS-mediated immune responses against tumors.

DOI： 10.1038/s41467-024-53262-w

The combination of p16 and Rb expression pattern is helpful to predict high-risk HPV infection and the primary site in lymph node metastases of squamous cell carcinoma. Reviewed International journal

Ryosuke Kuga, Hidetaka Yamamoto, Fumiya Narutomi, Misa Suzuki, Rina Jiromaru, Takahiro Hongo, Kazuhisa Hachisuga, Nobuko Yasutake, Kiyoko Kato, Takashi Nakagawa, Yoshinao Oda

Pathology, research and practice 263 155642 - 155642 2024.10

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

Identifying the primary site of metastatic squamous cell carcinoma in lymph nodes can be challenging. An immunohistochemistry (IHC) analysis recently revealed that high-risk human papillomavirus (HR-HPV)-associated oropharyngeal squamous cell carcinomas (OPSCCs) typically show overexpression of p16 protein and a partial loss pattern of Rb. Nevertheless, the status of these markers in metastatic lesions is still unclear. In this study, we examined p16 and Rb expression status by IHC and transcriptionally active HR-HPV infection by mRNA in situ hybridization in paired primary and metastatic SCC lesions. A total of 50 patients with OPSCCs (n=17), hypopharyngeal SCCs (n=16), laryngeal SCCs (n=6), or uterine cervical SCCs (n=11) were enrolled. HR-HPV and p16 were positive in 21/50 (42 %) and 23/50 (46 %) patients, respectively. Primary and metastatic lesions showed concordant results for those three markers in individual patients. Among the p16-positive patients (n=23), HPV-positive cases typically showed a partial loss of Rb (n=20) and, rarely, a complete loss of Rb (n=1), whereas HPV-negative cases showed preserved Rb expression (n=2). All 27 p16-negative cases lacked HPV infection, while preserved expression and complete loss of Rb were observed in 26 and 1 of the p16-negative cases, respectively. Compared to standalone p16, the combination of p16 overexpression and Rb-partial/complete loss showed equally excellent sensitivity and negative predictive value (each 100 %) as well as improved specificity (100 % versus 93.1 %) and positive predictive value (100 % versus 91.3 %). Our results suggest that combining p16 and Rb expression patterns may be helpful in screening for HR-HPV infection in metastatic lymph nodes and in estimating the primary site of SCC.

DOI： 10.1016/j.prp.2024.155642

Clinicopathological Review of Head and Neck Squamous Cell Carcinomas After Neoadjuvant Chemotherapy. Reviewed International journal

Ryosuke Kuga, Kazuki Hashimoto, Hidetaka Yamamoto, Midori Taniguchi, Tomomi Manako, Masanobu Sato, Ryunosuke Kogo, Mioko Matsuo, Yoshinao Oda, Takashi Nakagawa

Anticancer research 44 ( 10 ) 4593 - 4603 2024.10

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

BACKGROUND/AIM: The benefit of neoadjuvant chemotherapy (NAC) in the treatment of head and neck squamous cell carcinoma (HNSCC) remains unclear. PATIENTS AND METHODS: We retrospectively collected 30 patients with HNSCC who had undergone radical resection after NAC. We pathologically evaluated the therapeutic response to NAC, and classified the residual tumor patterns. In addition, we compared the maximum horizontal diameter on pathology with imaging. RESULTS: The residual patterns were categorized as follows: 10 cases of shrunken type, 11 cases of mixed type, and seven cases of fragmented type. The majority of underestimation cases - those cases in which the maximum horizontal diameter measured on post-NAC imaging was less than the pathological size after resection - were multifocal residual lesions, with a tendency for more frequent "positive" or "close" surgical margins. CONCLUSION: The strategy of performing NAC to reduce resection volume is not appropriate, and resection margins should be based on the assessment before NAC.

DOI： 10.21873/anticanres.17289

Breast mucoepidermoid carcinoma with a rare CRTC3–MAML2 fusion Reviewed International journal

Kana Kawaguchi, Hideki Ijichi, Hiroki Ueo, Yuichi Hisamatsu, Sachie Omori, Tomoko Shigechi, Kengo Kawaguchi, Hidetaka Yamamoto, Yoshinao Oda, Makoto Kubo, Tomoharu Yoshizumi

International Cancer Conference Journal 13 ( 4 ) 481 - 487 2024.8

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Mucoepidermoid carcinoma is the most prevalent malignancy in the salivary gland and is sporadic in the breast. Here, we report a case of breast mucoepidermoid carcinoma with a rare CREB-regulated transcription coactivator 3-mastermind-like transcriptional coactivator 2 (CRTC3-MAML2) fusion. A 23-year-old female was admitted to our hospital with a left breast palpable mass. Histologic findings of the core-needle biopsy indicated breast cancer. The section revealed a squamoid tumor-cell proliferation with enlarged nuclei and eosinophilic cytoplasm among smaller intermediate cells and abundant cystic spaces containing secretory materials. The features were compatible with mucoepidermoid carcinoma in low-grade, confirmed by detecting the CRTC3-MAML2 fusion using reverse transcription polymerase chain reaction and direct sequencing. We only administered tamoxifen postoperatively without other adjuvant therapy because her tumor partially expressed hormonal receptors. No signs indicate a recurrence or metastasis in our over 3 year follow-up. The genetic analysis helps in definitively diagnosing breast mucoepidermoid carcinoma, and the treatment strategy should be considered based on the histologic findings.

DOI： 10.1007/s13691-024-00713-2

Other Link： https://link.springer.com/article/10.1007/s13691-024-00713-2/fulltext.html

Expression of Forkhead Box M1 and Anticancer Effects of FOXM1 Inhibition in Epithelioid Sarcoma. Reviewed International journal

Yuichi Shibui, Kenichi Kohashi, Yuko Hino, Akihiko Tamaki, Izumi Kinoshita, Hidetaka Yamamoto, Yasuharu Nakashima, Tatsuro Tajiri, Yoshinao Oda

Laboratory investigation; a journal of technical methods and pathology 104 ( 8 ) 102093 - 102093 2024.8

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

Epithelioid sarcoma (ES) is a rare aggressive sarcoma that, unlike most soft-tissue sarcomas, shows a tendency toward local recurrence and lymph node metastasis. Novel antitumor agents are needed for ES patients. Forkhead box transcription factor 1 (FOXM1) is a member of the Forkhead transcription factor family and is associated with multiple oncogenic functions; FOXM1 is known to be overexpressed and correlated with pathogenesis in various malignancies. In this study, we immunohistochemically analyzed FOXM1 expression levels and their clinical, clinicopathologic, and prognostic significance in 38 ES specimens. In addition, to investigate potential correlations between FOXM1 downregulation and oncologic characteristics, we treated ES cell lines with thiostrepton, a naturally occurring antibiotic that inhibits both small interfering RNA (siRNA) and FOXM1. In the analyses using ES samples, all 38 specimens were diagnosed as positive for FOXM1 by immunohistochemistry. We separated specimens into high (n = 19) and low (n = 19) FOXM1-protein expression groups by staining index score, and into large (n = 12), small (n = 25), and unknown (n = 1) tumor-size groups using a cutoff of 5 cm maximum diameter. Although there were significantly more samples with high FOXM1 expression in the large tumor group (P = .013), there were no significant differences with respect to age (P = 1.00), sex (P = .51), primary site of origin (P = .74), histologic subtypes (P = 1.00), depth (P = .74), or survival rate (P = .288) between the high and low FOXM1-protein expression groups. In the in vitro experiments using ES cell lines, FOXM1 siRNA and thiostrepton successfully downregulated FOXM1 mRNA and protein expression. Furthermore, downregulation of FOXM1 inhibited cell proliferation, drug resistance against chemotherapeutic agents, migration, and invasion and caused cell cycle arrest in the ES cell lines. Finally, cDNA microarray analysis data showed that FOXM1 regulated cIAP2, which is one of the apoptosis inhibitors activated by the TNFα-mediated NF-κB pathway. In conclusion, the FOXM1 gene may be a promising therapeutic target for ES.

DOI： 10.1016/j.labinv.2024.102093

Reappraisal of bone and soft tissue cytopathology classification using the modified Milan system. Reviewed International journal

Masaki Naka, Hidetaka Yamamoto, Kenichi Kohashi, Takeshi Iwasaki, Taro Mori, Miwako Nogami, Fumihiko Ookubo, Kayoko Higuchi, Toru Motoi, Yoshinao Oda

Cancer cytopathology 132 ( 11 ) 696 - 706 2024.7

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: A standardized reporting system for bone and soft tissue tumor cytopathology has not yet been established. The objective of this study was to explore the potential utility of a classification modified from the Milan System for Salivary Gland Cytopathology and compared it with the upcoming World Health Organization (WHO) system for fine-needle aspiration of soft tissue lesions. METHODS: The authors reviewed 285 cytology cases of bone/joint (n = 173) and soft tissue (n = 112) lesions, scoring each within diagnostic categories. The results were compared with histologic diagnoses and the risk of malignancy (ROM) for each category, and diagnostic reliability was analyzed. RESULTS: All 285 cases were successfully classified into one of the following categories: nondiagnostic (6.3%), non-neoplastic (11.9%), atypia of uncertain significance (11.9%), benign neoplasm (5.6%), bone and soft tissue neoplasm of uncertain malignant potential (25.3%), suspicious for malignancy (1.4%), and malignant (37.5%). The ROM was 44.4% (eight of /18 cases) in nondiagnostic, 0% (zero of 34 cases) in non-neoplastic, 32.4% (11 of 34 cases) in atypia of uncertain significance, 0% (zero of 16 cases) in benign neoplasm, 16.7% (12 of 72 cases) in bone and soft tissue neoplasm of uncertain malignant potential, 75.0% (three of four cases) in suspicious for malignancy, and 100% (107 of 107 cases) in malignant categories. Using the WHO system, the proportion and ROM of the benign category (non-neoplastic and benign neoplasm) was 17.5% and 0%, respectively. Among benign and malignant lesions, the diagnostic accuracy, sensitivity, and specificity for detecting malignancy were 99.4%, 100%, and 98.0%, respectively. CONCLUSIONS: The modified Milan system as well as the WHO system may be a useful cytopathologic classification tool for both bone and soft tissue lesions.

DOI： 10.1002/cncy.22888

English version of Japanese Clinical Practice Guidelines 2022 for gastrointestinal stromal tumor (GIST) issued by the Japan Society of Clinical Oncology. Reviewed

Seiichi Hirota, Ukihide Tateishi, Yuji Nakamoto, Hidetaka Yamamoto, Shinji Sakurai, Hirotoshi Kikuchi, Tatsuo Kanda, Yukinori Kurokawa, Haruhiko Cho, Toshirou Nishida, Akira Sawaki, Masato Ozaka, Yoshito Komatsu, Yoichi Naito, Yoshitaka Honma, Fumiaki Takahashi, Hironobu Hashimoto, Midori Udo, Minako Araki, Sumito Nishidate

International journal of clinical oncology 29 ( 6 ) 647 - 680 2024.6

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

The Japan Society of Clinical Oncology Clinical Practice Guidelines 2022 for gastrointestinal stromal tumor (GIST) have been published in accordance with the Minds Manual for Guideline Development 2014 and 2017. A specialized team independent of the working group for the revision performed a systematic review. Since GIST is a rare type of tumor, clinical evidence is not sufficient to answer several clinical and background questions. Thus, in these guidelines, we considered that consensus among the experts who manage GIST, the balance between benefits and harms, patients' wishes, medical economic perspective, etc. are important considerations in addition to the evidence. Although guidelines for the treatment of GIST have also been published by the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO), there are some differences between the treatments proposed in those guidelines and the treatments in the present guidelines because of the differences in health insurance systems among countries.

DOI： 10.1007/s10147-024-02488-1

Hemizygous deletion of CDKN2A/B with p16 immuno-negative and methylthioadenosine phosphorylase retention predicts poor prognosis in IDH-mutant adult glioma Reviewed International journal

Ryosuke Otsuji, Nobuhiro Hata, Hidetaka Yamamoto, Daisuke Kuga, Ryusuke Hatae, Yuhei Sangatsuda, Yutaka Fujioka, Naoki Noguchi, Aki Sako, Osamu Togao, Tadamasa Yoshitake, Akira Nakamizo, Masahiro Mizoguchi, Koji Yoshimoto

Neuro-Oncology Advances 6 ( 1 ) vdae069 2024.5

Language：English Publishing type：Research paper (scientific journal) Publisher：Oxford University Press (OUP)

Abstract

Background

Homozygous deletion of the tumor suppression genes cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) is a strong adverse prognostic factor in IDH-mutant gliomas, particularly astrocytoma. However, the impact of hemizygous deletion of CDKN2A/B is unknown. Furthermore, the influence of CDKN2A/B status in IDH-mutant and 1p/19q-codeleted oligodendroglioma remains controversial. We examined the impact of CDKN2A/B status classification, including hemizygous deletions, on the prognosis of IDH-mutant gliomas.

Methods

We enrolled 101 adults with IDH-mutant glioma between December 2002 and November 2021. CDKN2A/B deletion was evaluated with multiplex ligation-dependent probe amplification (MLPA). Immunohistochemical analysis of p16/MTAP and promoter methylation analysis with methylation-specific MLPA was performed for cases with CDKN2A/B deletion. Kaplan−Meier plots and Cox proportion hazards model analyses were performed to evaluate the impact on overall (OS) and progression-free survival.

Results

Of 101 cases, 12 and 4 were classified as hemizygous and homozygous deletion, respectively. Immunohistochemistry revealed p16-negative and MTAP retention in cases with hemizygous deletion, whereas homozygous deletions had p16-negative and MTAP loss. In astrocytoma, OS was shorter in the order of homozygous deletion, hemizygous deletion, and copy-neutral groups (median OS: 38.5, 59.5, and 93.1 months, respectively). Multivariate analysis revealed hazard ratios of 9.30 (p=0.0191) and 2.44 (p=0.0943) for homozygous and hemizygous deletions, respectively.

Conclusions

CDKN2A/B hemizygous deletions exerted a negative impact on OS in astrocytoma. Immunohistochemistry of p16/MTAP can be utilized to validate hemizygous or homozygous deletions in combination with conventional molecular diagnosis.

DOI： 10.1093/noajnl/vdae069

Squamous cell carcinoma initially occurring on the tongue dorsum: a case series report with molecular analysis. International journal

Sawako Ono, Katsutoshi Hirose, Shintaro Sukegawa, Kyoichi Obata, Masanori Masui, Kazuaki Hasegawa, Ai Fujimura, Katsumitsu Shimada, Satoko Nakamura, Akari Teramoto, Yumiko Hori, Eiichi Morii, Daisuke Motooka, Takuro Igawa, Takehiro Tanaka, Hitoshi Nagatsuka, Satoru Toyosawa, Hidetaka Yamamoto

Diagnostic pathology 19 ( 1 ) 63 - 63 2024.4

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Squamous cell carcinoma (SCC) of the dorsum of the tongue is extremely rare, and it clinically resembles various benign lesions. Somatic mutations in TP53 and some driver genes were implicated in the development of SCC; however, the somatic genetic characteristics of dorsal tongue SCC remain unknown. With a detailed analysis of gene mutations in dorsal tongue SCC, we aimed to better understand its biology. METHODS: Four cases of SCC initially occurring on the tongue dorsum were evaluated for clinical and histological findings and immunohistochemical expression of p53 and p16. Gene mutations were analyzed using next-generation sequencing with a custom panel of driver genes. RESULTS: We retrospectively investigated 557 cases of tongue SCC, and only four cases of SCC initially occurred on the tongue dorsum. The four patients (cases 1-4) were one woman and three men with a mean age of 53.75 years (range: 15-74 years). Histological analysis revealed well-differentiated SCC. Through molecular analysis, we identified pathogenic somatic mutations, namely, TP53 p.C176F (c.527G > T) in case 3 and TP53 p.R282W (c.844 C > T) in case 4. No pathogenic variants were identified in the PI3K/AKT or RAS/RAF pathways. The p53 immunohistochemical examination revealed a wild-type expression pattern in cases 1-3 and strong expression in case 4. The results of p16 immunostaining were negative in all cases. CONCLUSIONS: We described four previously unreported genetic characteristics of dorsal tongue SCC. Somatic TP53 mutations may contribute to the development of a subset of dorsal tongue SCC; however, more cases with genetic analysis need to be accumulated.

DOI： 10.1186/s13000-024-01487-0

Immunohistochemical p16 overexpression and Rb loss correlate with high-risk human papillomavirus infection in endocervical adenocarcinomas. Reviewed International journal

Nobuko Yasutake, Hidetaka Yamamoto, Ryosuke Kuga, Rina Jiromaru, Takahiro Hongo, Yoshihiro Katayama, Kenzo Sonoda, Hideaki Yahata, Kiyoko Kato, Yoshinao Oda

Histopathology 84 ( 7 ) 1178 - 1191 2024.3

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

AIMS: p16 is a sensitive surrogate marker for transcriptionally active high-risk human papillomavirus (HR-HPV) infection in endocervical adenocarcinoma (ECA); however, its specificity is not perfect. METHODS AND RESULTS: We examined p16 and Rb expressions by immunohistochemistry (IHC) and the transcriptionally active HR-HPV infection by mRNA in-situ hybridisation (ISH) with histological review in 108 ECA cases. Thirteen adenocarcinomas of endometrial or equivocal origin (six endometrioid and seven serous carcinomas) were compared as the control group. HR-HPV was detected in 83 of 108 ECA cases (77%), including five HPV-associated adenocarcinomas in situ and 78 invasive HPV-associated adenocarcinomas. All 83 HPV-positive cases showed consistent morphology, p16 positivity and partial loss pattern of Rb. Among the 25 cases of HPV-independent adenocarcinoma, four (16%) were positive for p16, and of these four cases, three of 14 (21%) were gastric type adenocarcinomas and one of 10 (10%) was a clear cell type adenocarcinoma. All 25 HPV-independent adenocarcinomas showed preserved expression of Rb irrespective of the p16 status. Similarly, all 13 cases of the control group were negative for HR-HPV with preserved expression of Rb, even though six of 13 (46%) cases were positive for p16. Compared with p16 alone, the combination of p16 overexpression and Rb partial loss pattern showed equally excellent sensitivity (each 100%) and improved specificity (100 versus 73.6%) and positive predictive values (100 versus 89.2%) in the ECA and control groups. Furthermore, HR-HPV infection correlated with better prognosis among invasive ECAs. CONCLUSIONS: The results suggest that the combined use of p16 and Rb IHC could be a reliable method to predict HR-HPV infection in primary ECAs and mimics. This finding may contribute to prognostic prediction and therapeutic strategy.

DOI： 10.1111/his.15169

DDIT3-amplified or low-polysomic pleomorphic sarcomas without MDM2 amplification: Clinicopathological review and immunohistochemical profile of nine cases. Reviewed International journal

Taro Mori, Takeshi Iwasaki, Hiroki Sonoda, Kengo Kawaguchi, Takumi Tomonaga, Hiroshi Furukawa, Chiaki Sato, Sakura Shiraishi, Kenichi Taguchi, Sadafumi Tamiya, Reiko Yoneda, Yumi Oshiro, Tomoya Matsunobu, Chie Abe, Yusuke Kuboyama, Nozomi Ueki, Kenichi Kohashi, Hidetaka Yamamoto, Yasuharu Nakashima, Yoshinao Oda

Human pathology 145 56 - 62 2024.3

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

Several high-grade pleomorphic sarcoma cases that cannot be classified into any existing established categories have been reported. These cases were provisionally classified into undifferentiated pleomorphic sarcoma (UPS). Some dedifferentiated liposarcoma (DDLS) cases may also have been classified into the UPS category due to the absence of MDM2 amplification or an atypical lipomatous tumor/well-differentiated liposarcoma component. We retrieved and reviewed 77 high-grade pleomorphic sarcoma cases, initially diagnosed as UPS in 66 cases and DDLS in 11 cases. Fluorescence in situ hybridization (FISH) analyses of DDIT3 and MDM2 were performed for available cases. Of the cases successfully subjected to DDIT3 FISH (n = 56), nine (7 UPS and 2 DDLS) showed DDIT3 amplification but no MDM2 amplification. Two UPS cases showed both telomeric (5') and centromeric (3') amplification of DDIT3 or low polysomy of chromosome 12, whereas 5 UPS and 2 DDLS cases showed 5'-predominant DDIT3 amplification. Histopathologically, all cases showed UPS-like proliferation of atypical pleomorphic tumor cells. Immunohistochemically, only one case showed focal nuclear positivity for DDIT3, supporting the previous finding that DDIT3 expression was not correlated with DDIT3 amplification. All three cases with focal MDM2 expression involved 5'-predominant amplification, two of which showed DDLS-like histological features. The majority of cases (7/9) showed decreased expression in p53 staining, suggesting that DDIT3 amplification regulates the expression of TP53 like MDM2. From a clinicopathological perspective, we hypothesize that DDIT3-amplified sarcoma, especially with 5'-predominant amplification, can be reclassified out of the UPS category.

DOI： 10.1016/j.humpath.2024.02.007

Diagnostic challenges of the idiopathic plasmacytic lymphadenopathy (IPL) subtype of idiopathic multicentric Castleman disease (iMCD): Factors to differentiate from IgG4-related disease. Reviewed International journal

Asami Nishikori, Midori Filiz Nishimura, David C Fajgenbaum, Yoshito Nishimura, Kanna Maehama, Tomoka Haratake, Tetsuya Tabata, Mitsuhiro Kawano, Naoya Nakamura, Shuji Momose, Remi Sumiyoshi, Tomohiro Koga, Hidetaka Yamamoto, Frits van Rhee, Atsushi Kawakami, Yasuharu Sato

Journal of clinical pathology 2024.2

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

AIMS AND METHODS: Idiopathic multicentric Castleman disease (iMCD) is currently considered to be classified into three clinical subtypes, including idiopathic plasmacytic lymphadenopathy (IPL), thrombocytopaenia, anasarca, fever, reticulin fibrosis/renal dysfunction, organomegaly (TAFRO) and not otherwise specified (NOS). Among the three, iMCD-IPL closely mimics IgG4-related disease (IgG4-RD). In diagnosing IgG4-RD, it is sometimes challenging to distinguish iMCD-IPL patients that also meet the histological diagnostic criteria for IgG4-RD. In this study, we focused on the number of IgG4-positive cells in the lymph nodes and analysed the relationship with laboratory findings to distinguish iMCD-IPL from IgG4-RD. Thirty-nine patients with iMCD-IPL and 22 patients with IgG4-RD were included. RESULTS: Among the cases considered to be iMCD-IPL, 33.3% (13/39) cases also met the histological diagnostic criteria for IgG4-RD and serum IgG4 levels were not different between the two groups. However, the serum IgG4/IgG ratio was significantly higher in IgG4-RD, with a cut-off value of 19.0%. Additionally, a significant positive correlation between serum IgG levels and the number of IgG4-positive cells was observed in iMCD-IPL (p=0.001). The serum IgG cut-off value for distinguishing iMCD-IPL meeting histological criteria for IgG4-RD from other iMCD-IPL was 5381 mg/dL. CONCLUSIONS: iMCD-IPL cases with high serum IgG levels (>5000 mg/dL) were likely to meet the diagnostic criteria for IgG4-RD because of the numerous IgG4-positive cells observed. A combination of clinical presentations, laboratory values including the serum IgG4/IgG ratios and histological analysis is crucial for diagnosis of IgG4-RD and iMCD-IPL.

DOI： 10.1136/jcp-2023-209280

Analysis of Notch1 protein expression in methotrexate-associated lymphoproliferative disorders. Reviewed

Takeshi Okatani, Midori Filiz Nishimura, Yuria Egusa, Sayako Yoshida, Yoshito Nishimura, Asami Nishikori, Tadashi Yoshino, Hidetaka Yamamoto, Yasuharu Sato

Journal of clinical and experimental hematopathology : JCEH 64 ( 1 ) 1 - 9 2024.1

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

Methotrexate (MTX)-associated lymphoproliferative disorder (MTX-LPD) is a lymphoproliferative disorder in patients treated with MTX. The mechanism of pathogenesis is still elusive, but it is thought to be a complex interplay of factors, such as underlying autoimmune disease activity, MTX use, Epstein-Barr virus infection, and aging. The NOTCH genes encode receptors for a signaling pathway that regulates various fundamental cellular processes, such as proliferation and differentiation during embryonic development. Mutations of NOTCH1 have been reported in B-cell tumors, including chronic lymphocytic leukemia/lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma (DLBCL). Recently, it has also been reported that NOTCH1 mutations are found in post-transplant lymphoproliferative disorders, and in CD20-positive cells in angioimmunoblastic T-cell lymphoma, which might be associated with lymphomagenesis in immunodeficiency. In this study, to investigate the association of NOTCH1 in the pathogenesis of MTX-LPD, we evaluated protein expression of Notch1 in nuclei immunohistochemically in MTX-LPD cases [histologically DLBCL-type (n = 24) and classical Hodgkin lymphoma (CHL)-type (n = 24)] and de novo lymphoma cases [DLBCL (n = 19) and CHL (n = 15)]. The results showed that among MTX-LPD cases, the expression of Notch1 protein was significantly higher in the DLBCL type than in the CHL type (P < 0.001). In addition, among DLBCL morphology cases, expression of Notch1 tended to be higher in MTX-LPD than in the de novo group; however this difference was not significant (P = 0.0605). The results showed that NOTCH1 may be involved in the proliferation and tumorigenesis of B cells under the use of MTX. Further research, including genetic studies, is necessary.

DOI： 10.3960/jslrt.23038

Granzyme K- and amphiregulin-expressing cytotoxic T cells and activated extrafollicular B cells are potential drivers of IgG4-related disease. Reviewed International journal

Risako Koga, Takashi Maehara, Ryuichi Aoyagi, Ryusuke Munemura, Yuka Murakami, Atsushi Doi, Michihito Kono, Hidetaka Yamamoto, Hiroaki Niiro, Tamotsu Kiyoshima, Mika Tanabe, Toshiaki Nakano, Yuta Matsukuma, Mitsuhiro Kawano, John H Stone, Shiv Pillai, Seiji Nakamura, Shintaro Kawano

The Journal of allergy and clinical immunology 153 ( 4 ) 1095 - 1112 2023.12

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

BACKGROUND: IgG4-related disease (IgG4-RD), an example of a type I immune disease, is an immune-mediated fibrotic disorder characterized by dysregulated resolution of severe inflammation and wound healing. However, truly dominant or pathognomonic autoantibodies related to IgG4-RD are not identified. OBJECTIVE: We performed single-cell RNA sequencing (scRNA-seq) and T-cell receptor (TCR) and B-cell receptor (BCR) sequencing to obtain a comprehensive, unbiased view of tissue-infiltrating T- and B-cells. METHODS: We performed unbiased scRNA-seq analysis for the transcriptome and TCR-seq and BCR-seq on sorted CD3+ T- or CD19+ B-cells from affected tissues of patients with IgG4-RD. We also conducted quantitative analyses of CD3+ T and CD19+ B subsets in 68 IgG4-RD and 30 Sjögren's syndrome (SjS) patients. RESULTS: Almost all clonally expanded T cells in these lesions were either Granzyme K (GZMK)-expressing CD4+ cytotoxic T cells (CTLs) or GZMK+CD8+ T cells. These GZMK-expressing CTLs also expressed amphiregulin and TGFβ but did not express immune-checkpoints, and the tissue-infiltrating CD8+ T cells were phenotypically heterogeneous. MKI67+ B cells and IgD-CD27-CD11c-CXCR5- double-negative 3 B cells were clonally expanded and infiltrated affected tissue lesions. GZMK+CD4+ CTLs co-localized with MKI67+ B cells in the extrafollicular area from affected tissue sites. CONCLUSION: The abovementioned cells likely participate in T-B collaborative events, suggesting possible avenues for targeted therapies. Our findings were validated using orthogonal approaches, including multicolor immunofluorescence and the use of comparator disease groups, to support the central role of cytotoxic CD4+ and CD8+ T cells expressing GZMK, amphiregulin, and TGFβ in the pathogenesis of inflammatory fibrotic disorders.

DOI： 10.1016/j.jaci.2023.11.916

Expression of CD5 in salivary gland tumors: an ancillary marker for carcinoma showing thymus-like differentiation (CASTLE) of the major salivary gland. Reviewed International journal

Eiichi Sasaki, Hoshino Terada, Naoki Oishi, Akari Iwakoshi, Katsuhiro Masago, Hirokazu Matsushita, Hidetaka Yamamoto, Nobuhiro Hanai, Hisashi Tateyama

Virchows Archiv : an international journal of pathology 484 ( 6 ) 945 - 950 2023.11

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

Recently, cases of carcinoma showing thymus-like differentiation (CASTLE) occurring in major salivary glands have been identified. To assess the diagnostic value of CD5 immunohistochemistry in distinguishing salivary CASTLE from other types of salivary gland tumors, we evaluated CD5 expression in 109 salivary gland tumors, encompassing 23 different histological types, including salivary CASTLE. In addition, we reviewed 10 previously reported cases of salivary CASTLE. Most salivary CASTLE cases (10/11, 91%) showed strong CD5 expression. In contrast, 104 of 108 (96%) non-salivary CASTLE tumors were negative for CD5, while the remaining four tumors (3.7%), all of which were histologically Warthin tumors, showed focal positivity for CD5 with weak to moderate intensity. In conclusion, the findings in this study support the potential use of CD5 immunohistochemistry for distinguishing salivary CASTLE from other histological types of salivary gland tumors. Aberrant CD5 expression in this tumor may be linked to the tumor microenvironment.

DOI： 10.1007/s00428-023-03701-8

Survival outcomes including salvage therapy of adult head and neck para-meningeal rhabdomyosarcoma: a multicenter retrospective study from Japan Reviewed International journal

Kenji Tsuchihashi, Mamoru Ito, Shuji Arita, Hitoshi Kusaba, Wataru Kusano, Takashi Matsumura, Takafumi Kitazono, Shohei Ueno, Ryosuke Taguchi, Tomoyasu Yoshihiro, Yasuhiro Doi, Kohei Arimizu, Hirofumi Ohmura, Tatsuhiro Kajitani, Kenta Nio, Michitaka Nakano, Kotoe Oshima, Shingo Tamura, Tsuyoshi Shirakawa, Hozumi Shimokawa, Keita Uchino, Fumiyasu Hanamura, Yuta Okumura, Masato Komoda, Taichi Isobe, Hiroshi Ariyama, Taito Esaki, Kazuki Hashimoto, Noritaka Komune, Mioko Matsuo, Keiji Matsumoto, Kaori Asai, Tadamasa Yoshitake, Hidetaka Yamamoto, Yoshinao Oda, Koichi Akashi, Eishi Baba

BMC Cancer 23 ( 1 ) 1046 - 1046 2023.10

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Abstract

Background

Rhabdomyosarcoma is the most common soft tissue sarcoma in children, but rare in adults. Para-meningeal rhabdomyosarcoma in head and neck (PM-HNRMS) is less applicable for surgery due to the anatomic reason. PM-HNRMS has a poor prognosis in children. However, its clinical outcomes remain unclear in adults due to the rarity. Further, there is almost no detailed data about salvage therapy.

Methods

We retrospectively examined the adult patients with PM-HNRMS treated at institutions belonging to the Kyushu Medical Oncology Group from 2009 to 2022. We evaluated the overall survival (OS) and progression-free survival (PFS) of the patients who received a first-line therapy. We also reviewed the clinical outcomes of patients who progressed against a first-line therapy and received salvage therapy.

Results

Total 11 patients of PM-HNRMS received a first-line therapy. The characteristics were as follows: median age: 38 years (range 25 – 63 years), histology (alveolar/spindle): 10/1, and risk group (intermediate/high): 7/4. As a first-line therapy, VAC and ARST0431-based regimen was performed in 10 and 1 patients, respectively. During a first-line therapy, definitive radiation for all lesions were performed in seven patients. The median PFS was 14.2 months (95%CI: 6.0 – 25.8 months): 17.1 months (95%CI: 6.0 – not reached (NR)) for patients with stage I-III and 8.5 months (95%CI: 5.2 – 25.8 months) for patients with stage IV. The 1-year and 3-year PFS rates were 54.5% and 11.3% for all patients. Median OS in all patients was 40.8 months (95%CI: 12.1 months–NR): 40.8 months (95%CI: 12.1 – NR) for patients with stage I-III and NR for patients with stage IV. The 5-year OS rate was 48.5% for all patients. Among seven patients who received salvage therapy, three are still alive, two of whom remain disease-free for over 4 years after completion of the last therapy. Those two patients received multi-modal therapy including local therapy for all detected lesions.

Conclusion

The cure rate of adult PM-HNRMS is low in spite of a first-line therapy in this study. Salvage therapy might prolong the survival in patients who received the multi-modal therapy including local therapy for all detected lesions.

DOI： 10.1186/s12885-023-11528-4

Other Link： https://link.springer.com/article/10.1186/s12885-023-11528-4/fulltext.html

An invasive presentation of parotid lymphadenoma: A first reported case. Reviewed International journal

Hideoki Uryu, Minako Fujiwara, Ryutarou Uchi, Hidetaka Yamamoto, Torahiko Nakashima

Pathology, research and practice 250 154823 - 154823 2023.10

Language：English

Lymphadenoma, a rare benign tumor recognized in the WHO salivary gland tumor classification of 2005, poses diagnostic and treatment challenges due to its rarity and distinct histopathological characteristics. We report a unique case of lymphadenoma in a 45-year-old male patient who presented with a hard, painless tumor in the right parotid gland that had been present since he was 15 years old. Distinctively, MRI and CT imaging revealed signs of infiltration into the surrounding muscle tissues, challenging the traditional notion of lymphadenomas as tumors with clear boundaries. The histopathological examination identified the characteristic epithelial and lymphoid cell proliferation, suggestive of a lymphadenoma. However, the possibility of sebaceous differentiation due to faintly pale cells within the epithelial component was inconclusive. The tumor's invasive nature and the high risk of facial nerve paralysis associated with surgical resection led to the patient's decision against treatment. Findings from this case underline the need for caution in diagnosing lymphadenoma, given its potential to show invasive images and the risks associated with a malignant diagnosis based solely on these images. Furthermore, the observations from this case present new insights into the FDG-PET findings of lymphadenoma, contributing to the overall understanding of this rare tumor's clinical implications. Future studies are warranted to provide more clarity on this condition.

DOI： 10.1016/j.prp.2023.154823

HPV Infection in Squamous Cell Carcinoma of the Hypopharynx, Larynx, and Oropharynx with Multisite Involvement Reviewed International journal

Ryosuke Kuga, Hidetaka Yamamoto, Rina Jiromaru, Takahiro Hongo, Ryuji Yasumatsu, Mioko Matsuo, Kazuki Hashimoto, Midori Taniguchi, Takashi Nakagawa, Yoshinao Oda

American Journal of Surgical Pathology 47 ( 9 ) 955 - 966 2023.9

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

The prevalence and prognostic significance of high-risk human papillomavirus (HR-HPV) have been well-established in oropharyngeal squamous cell carcinoma (OPSCC), but not in hypopharyngeal squamous cell carcinoma (HPSCC) or laryngeal squamous cell carcinoma (LSCC). Moreover, HR-HPV infection in squamous cell carcinoma with multisite involvement has not been examined. To clarify these issues, we retrospectively collected 480 invasive tumors from 467 patients with HPSCC, LSCC, or OPSCC, and comprehensively analyzed the detailed tumor localization, transcriptionally active HR-HPV infection by messenger RNA in situ hybridization, and immunohistochemical staining for p16 and Rb. HR-HPV infection was observed in 115/480 tumors (24%). Human papillomavirus (HPV)-positive cases were closely related with p16 positivity and the partial loss pattern of Rb. HR-HPV was detected in 104 of 161 tumors (64.6%) in the pure OPSCC group and only 1 of 253 tumors (0.4%) in the pure HP/LSCC group; the positive case occurred in the vocal cords. In the multisite-involving combined-type squamous cell carcinoma group, HPV infection was observed in 10/40 (25%) cases, and the 10 HPV-positive cases had OPSCC extending to the larynx or hypopharynx. Among high T-stage (T3/T4) cases of pure OPSCC, HPV-positive cases showed a better prognosis (P=0.0144), whereas the HPV-positive combined OPSCC group did not show a better prognosis (P=0.9428), as compared with HPV-negative counterpart. The results suggest that HR-HPV infection in pure HPSCC and LSCC may be extremely rare. HR-HPV infection seems to be present in a substantial proportion of patients with combined OPSCC and HPSCC/LSCC, but it may not improve prognosis at such advanced disease stages. Confirmation of these points awaits future studies with larger cohorts.

DOI： 10.1097/PAS.0000000000002086

Single-cell transcriptomics reveals granzyme K-expressing cytotoxic Tfh cells in tertiary lymphoid structures in IgG4-RD. Reviewed International journal

Ryuichi Aoyagi, Takashi Maehara, Risako Koga, Ryusuke Munemura, Tadashi Tomonaga, Yuka Murakami, Atsushi Doi, Hidetaka Yamamoto, Tamotsu Kiyoshima, Shintaro Kawano, Seiji Nakamura

The Journal of allergy and clinical immunology 153 ( 2 ) 513 - 520 2023.8

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

BACKGROUND: Germinal center (GC) responses controlled by T follicular helper (Tfh) and T follicular regulatory (Tfr) cells are crucial for the generation of high-affinity antibodies. Acquired immune responses to tissue-released antigens might be mainly induced in tertiary lymphoid organs (TLOs) with GCs in affected tissues. IgG4-related disease (IgG4-RD) demonstrates polarized isotype switching and TLOs in affected tissues. We performed single-cell transcriptomics of tissue-infiltrating T cells from these TLOs to obtain a comprehensive, unbiased view of tissue-infiltrating GC-Tfh cells. OBJECTIVE: To identify GC-Tfh-cell subsets in TLOs in patients with IgG4-RD using single-cell transcriptomics. METHODS: Single-cell RNA sequencing of sorted CD3+ T cells and multicolor immunofluorescence analysis were used to investigate CD4+CXCR5+Bcl6+ GC-Tfh cells in affected lesions from patients with IgG4-RD. RESULTS: Infiltrating CD4+CXCR5+Bcl6+ Tfh cells were divided into 5 main clusters. We detected HLA+ granzyme K+ (GZMK+) Tfh cells with cytotoxicity-associated features in patients with IgG4-RD. We also observed abundant infiltrating Tfr cells with suppressor-associated features in patients with IgG4-RD. These GZMK+ Tfh cells and Tfr cells clustered together in affected tissues from patients with IgG4-RD. CONCLUSIONS: This single-cell data set revealed a novel subset of HLA+GZMK+ cytotoxic Tfh cells infiltrating affected organs in patients with IgG4-RD, suggesting that infiltrating Tfr cells might suppress cytotoxic Tfh cells.

DOI： 10.1016/j.jaci.2023.08.019

Preferential B cell differentiation by combined immune checkpoint blockade for renal cell carcinoma is associated with clinical response and autoimmune reactions. Reviewed International journal

Koki Uehara, Kenro Tanoue, Kyoko Yamaguchi, Hirofumi Ohmura, Mamoru Ito, Yuzo Matsushita, Kenji Tsuchihashi, Shingo Tamura, Hozumi Shimokawa, Taichi Isobe, Yoshihiro Shibata, Hiroshi Ariyama, Risa Tanaka, Hitoshi Kusaba, Hidetaka Yamamoto, Yoshinao Oda, Koichi Akashi, Eishi Baba

Cancer immunology, immunotherapy : CII 72 ( 11 ) 3543 - 3558 2023.8

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

Combined immune checkpoint blockade (ICB) is effective therapy for renal cell carcinoma (RCC). However, the dynamic changes in circulating B cells induced by combined ICB have not been clarified. The present study prospectively examined 22 patients scheduled to receive ICB for unresectable or metastatic RCC between March 2018 and August 2021. Eleven patients received combined therapy with anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab), and the other 11 patients received nivolumab monotherapy. Comprehensive phenotypes of circulating immune cells obtained prior to and after ICB therapy were analyzed by flow cytometry. Although the proportion of naïve B cells among total B cells was significantly decreased, that of switched memory B cells was significantly increased after combined therapy. In responders, the proportion of B cells among peripheral blood mononuclear cells was significantly higher prior to ICB therapy, and the proportion of switched memory B cells among total B cells tended to increase after ICB therapy. Of note, the proportion of plasmablasts among total B cells was significantly increased after ICB therapy in patients who developed severe immune-related adverse events (irAEs), and the proportion of B cells among peripheral blood decreased significantly. Furthermore, in four of five patients who developed immune-related hypophysitis following combined therapy, anti-pituitary antibody was detected in the serum. These results suggested that immune-related hypophysitis was closely related to the increase in circulating plasmablasts. Collectively, this study suggests that combined ICB promotes the differentiation of B cell populations, which is associated with efficient tumor suppression and development of irAEs.

DOI： 10.1007/s00262-023-03505-4

Predicting TERT promoter mutation status using 1H-MR spectroscopy and stretched-exponential model of diffusion-weighted imaging in IDH-wildtype diffuse astrocytic glioma without intense enhancement. Reviewed International journal

Koji Yamashita, Ryusuke Hatae, Kazufumi Kikuchi, Daisuke Kuga, Nobuhiro Hata, Hidetaka Yamamoto, Makoto Obara, Koji Yoshimoto, Kousei Ishigami, Osamu Togao

Neuroradiology 65 ( 8 ) 1205 - 1213 2023.8

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

PURPOSE: Isocitrate dehydrogenase (IDH)-wildtype diffuse astrocytic glioma with telomerase reverse transcriptase (TERT) promoter mutation is defined as glioblastoma by the WHO 2021 criteria, revealing that TERT promotor mutation is highly associated with tumor aggressiveness. The aim of this study was to identify features from MR spectroscopy (MRS) and multi-exponential models of DWI distinguishing wild-type TERT (TERTw) from TERT promoter mutation (TERTm) in IDH-wildtype diffuse astrocytic glioma. METHODS: Participants comprised 25 adult patients with IDH-wildtype diffuse astrocytic glioma. Participants were classified into TERTw and TERTm groups. Point-resolved spectroscopy sequences were used for MRS data acquisition. DWI was performed with 13 different b-factors. Peak height ratios of NAA/Cr and Cho/Cr were calculated from MRS data. Mean apparent diffusion coefficient (ADC), perfusion fraction (f), diffusion coefficient (D), pseudo-diffusion coefficient (D*), distributed diffusion coefficient (DDC), and heterogeneity index (α) were obtained using multi-exponential models from DWI data. Each parameter was compared between TERTw and TERTm using the Mann-Whitney U test. Correlations between parameters derived from MRS and DWI were also evaluated. RESULTS: NAA/Cr and Cho/Cr were both higher for TERTw than for TERTm. The α of TERTw was smaller than that of TERTm, while the f of TERTw was higher than that of TERTm. NAA/Cr correlated negatively with α, but not with other DWI parameters. Cho/Cr did not show significant correlations with any DWI parameters. CONCLUSION: The combination of NAA/Cr and α may have merit in clinical situation to predict the TERT mutation status of IDH-wildtype diffuse astrocytic glioma without intense enhancement.

DOI： 10.1007/s00234-023-03177-y

Evaluation of appropriate conditions for Oncomine DxTT testing of FFPE specimens for driver gene alterations in non-small cell lung cancer. Reviewed International journal

Eiji Iwama, Hidetaka Yamamoto, Fumihiko Okubo, Kayo Ijichi, Ritsu Ibusuki, Yoshimasa Shiaraishi, Yasuto Yoneshima, Kentaro Tanaka, Yoshinao Oda, Isamu Okamoto

Thoracic cancer 14 ( 23 ) 2288 - 2296 2023.8

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

BACKGROUND: The Oncomine Dx Target Test Multi-CDx System (ODxTT) is a next-generation sequencing panel approved as a companion diagnostic for drugs targeted to corresponding gene alterations in non-small cell lung cancer. However, appropriate slide conditions for ODxTT have remained unclear. METHODS: We focused on the production of the number of tumor cells on a formalin-fixed paraffin-embedded (FFPE) section and the number of prepared slides, designated the TS value, and determined a TS value of ≥4000 as a target slide condition for ODxTT. We evaluated the impact of this condition on ODxTT testing with tumor specimens found to have a TS of <4000 (n = 23) or a TS of ≥4000 (n = 142). RESULTS: A positive correlation was apparent between the TS value and the concentrations of both DNA and RNA. Among the 142 samples with a TS of ≥4000, a sufficient concentration of DNA or RNA for ODxTT analysis was achieved in 100% and 98% samples, respectively. Among samples explored for driver gene alterations after determination of the target slide condition (TS ≥4000), most (84.9%) had a TS of ≥4000 and were submitted for ODxTT analysis. CONCLUSION: Our findings indicate that a TS of ≥4000 is a feasible and relevant criterion for ODxTT testing, and its adoption should help to improve the success rate of such testing in clinical practice.

DOI： 10.1111/1759-7714.15014

Prognostic scores for patients with salivary adenoid cystic carcinoma without lymph node metastasis. Reviewed International journal

Hikari Shimoda, Masanori Teshima, Takayuki Murase, Toshitaka Nagao, Kimihide Kusafuka, Masato Nakaguro, Makoto Urano, Ken-Ichi Taguchi, Hidetaka Yamamoto, Satoshi Kano, Yuichiro Tada, Kiyoaki Tsukahara, Kenji Okami, Tetsuro Onitsuka, Yasushi Fujimoto, Daisuke Kawakita, Kazuo Sakurai, Nobuhiro Hanai, Toru Nagao, Ryo Kawata, Naohito Hato, Ken-Ichi Nibu, Hiroshi Inagaki

Oral oncology 145 106491 - 106491 2023.7

Language：English

Adenoid cystic carcinoma (AdCC) of salivary gland grows relatively slowly, but occasionally develops distant metastasis. Although cervical lymph node metastasis (LNM) has been reported as a strong prognostic factor, most of AdCC do not have LNM. In this study, we investigated the prognostic factors to predict disease free survival (DFS), distant metastasis free survival (DMFS), and overall survival (OS) for 175 patients surgically treated for AdCC without LNM, and developed prognostic score (PS) determined as number of positive prognostic factors. The following emerged as significant prognostic factors: positive surgical margin in DFS, pT3/4 and positive surgical margin in DMFS, and positive surgical margin and high-histological grade in OS. 10-year DFS rates were 56.4% in PS0, and 19.1% in PS1 (p < 0.0001). 10-year DMFS rates were 86.3% in PS0, 56.4% in PS1, and 30.7% in PS2 (p < 0.0001). 10-year OS rates were 100% in PS0, 73.3% in PS1, and 38.8% in PS2 (p < 0.0001).

DOI： 10.1016/j.oraloncology.2023.106491

The Landscape of MYB/MYBL1- and Peri-MYB/MYBL1-Associated Rearrangements in Adenoid Cystic Carcinoma. Reviewed International journal

Kaori Ueda, Takayuki Murase, Daisuke Kawakita, Toshitaka Nagao, Kimihide Kusafuka, Masato Nakaguro, Makoto Urano, Hidetaka Yamamoto, Ken-Ichi Taguchi, Satoshi Kano, Yuichiro Tada, Kiyoaki Tsukahara, Kenji Okami, Tetsuro Onitsuka, Yasushi Fujimoto, Kazuo Sakurai, Nobuhiro Hanai, Toru Nagao, Ryo Kawata, Naohito Hato, Ken-Ichi Nibu, Hiroshi Inagaki

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 36 ( 10 ) 100274 - 100274 2023.7

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

Approximately 60% of adenoid cystic carcinoma (AdCC) cases are positive for MYB::NFIB or MYBL1::NFIB, whereas MYB/MYBL1 oncoprotein, a key driver of AdCC, is overexpressed in most cases. Juxtaposition of superenhancer regions in NFIB and other genes into the MYB/MYBL1 locus is an attractive oncogenic hypothesis for AdCC cases, either negative or positive for MYB/MYBL1::NFIB. However, evidence supporting this hypothesis is insufficient. We examined 160 salivary AdCC cases for rearrangements in MYB/MYBL1 loci and peri-MYB/MYBL1 areas (centromeric and telomeric areas of 10 Mb each) using formalin-fixed, paraffin-embedded tumor sections. For the detection of the rearrangements, we employed conventional fluorescence in situ hybridization split and fusion assays and a 5 Mb fluorescence in situ hybridization split assay. The latter is a novel assay that enabled us to detect any possible splits within a 5 Mb distance of a chromosome. We found MYB/MYBL1- and peri-MYB/MYBL1-associated rearrangements in 149/160 patients (93%). AdCC cases positive for rearrangements in MYB, MYBL1, the peri-MYB area, and the peri-MYBL1 area numbered 105 (66%), 20 (13%), 19 (12%), and 5 (3%), respectively. In 24 peri-MYB/MYBL1 rearrangement-positive cases, 14 (58%) were found to have a juxtaposition of the NFIB or RAD51B locus into the MYB/MYBL1 loci. On comparing with a tumor group positive for MYB::NFIB, a hallmark of AdCC, other genetically classified tumor groups had similar features of overexpression of the MYB transcript and MYB oncoprotein as detected by semiquantitative RT-qPCR and immunohistochemistry, respectively. In addition, clinicopathological and prognostic features were similar among these groups. Our study suggests that peri-MYB/MYBL1 rearrangements may be a frequent event in AdCC and may result in biological and clinicopathological consequences comparable to MYB/MYBL1 rearrangements. The landscape of MYB/MYBL1 and peri-MYB/MYBL1 rearrangements shown here strongly suggests that juxtaposition of superenhancers into MYB/MYBL1 or peri-MYB/MYBL1 loci is an alteration that acts as a key driver for AdCC oncogenesis and may unify MYB/MYBL1 rearrangement-positive and negative cases.

DOI： 10.1016/j.modpat.2023.100274

Supramaximal Resection Can Prolong the Survival of Patients with Cortical Glioblastoma: A Volumetric Study Reviewed

Ryosuke Otsuji, Nobuhiro Hata, Yusuke Funakoshi, Daisuke Kuga, Osamu Togao, Ryusuke Hatae, Yuhei Sangatsuda, Yutaka Fujioka, Kosuke Takigawa, Aki Sako, Kazufumi Kikuchi, Tadamasa Yoshitake, Hidetaka Yamamoto, Masahiro Mizoguchi, Koji Yoshimoto

NEUROLOGIA MEDICO-CHIRURGICA 63 ( 8 ) 364 - 374 2023.7

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN NEUROSURGICAL SOC

We aimed to retrospectively determine the resection rate of fluid-attenuated inversion recovery (FLAIR) lesions to evaluate the clinical effects of supramaximal resection (SMR) on the survival of pa-tients with glioblastoma (GBM). Thirty-three adults with newly diagnosed GBM who underwent gross total tumor resection were enrolled. The tumors were classified into cortical and deep-seated groups according to their contact with the cortical gray matter. Pre-and postoperative FLAIR and gadolinium-enhanced T1-weighted imaging tumor volumes were measured using a three-dimensional imaging volume analyzer, and the resection rate was calculated. To evaluate the association between SMR rate and outcome, we subdivided patients whose tumors were totally resected into the SMR and non-SMR groups by moving the threshold value of SMR in 10% increments from 0% and compared their overall survival (OS) change. An improvement in OS was observed when the threshold value of SMR was 30% or more. In the cortical group (n = 23), SMR (n = 8) tended to prolong OS compared with gross total resection (GTR) (n = 15), with the median OS of 69.6 and 22.1 months, respectively (p = 0.0945). Contrastingly, in the deep-seated group (n = 10), SMR (n = 4) significantly shortened OS compared with GTR (n = 6), with median OS of 10.2 and 27.9 months, respectively (p = 0.0221). SMR could help prolong OS in patients with cortical GBM when 30% or more volume reduction is achieved in FLAIR lesions, although the impact of SMR for deep-seated GBM must be validated in larger co-horts.

DOI： 10.2176/jns-nmc.2022-0351

The T2-FLAIR mismatch sign in glioblastoma, isocitrate dehydrogenase wild-type A case report. Reviewed International journal

Shunsuke Nishimura, Koji Yamashita, Osamu Togao, Kazufumi Kikuchi, Daisuke Kuga, Hidetaka Yamamoto, Koji Yoshimoto, Kousei Ishigami

Acta radiologica open 12 ( 6 ) 20584601231184565 - 20584601231184565 2023.6

Language：English

We present a case of the T2-FLAIR mismatch sign in glioblastoma, isocitrate dehydrogenase (IDH)-wild type. The T2-FLAIR mismatch sign is known as a highly specific imaging finding of astrocytoma, IDH-mutant. Meanwhile, IDH-wildtype diffuse astrocytic gliomas with telomerase reverse transcriptase (TERT) promoter mutation in adults are defined as glioblastoma in the 2021 World Health Organization Classification of Tumors of the Central Nervous System, fifth edition (2021 WHO classification), which underscores the importance of molecular information in central nervous system tumors. This indicates even glioblastoma, IDH-wild type may be masquerading as lower-grade glioma in histology. The reasons for the discrepancy between tumors with less aggressive histology and poor prognosis caused by telomerase reverse transcriptase promoter mutation of IDH-wildtype diffuse glioma remain unclear. However, glioblastoma, IDH-wildtype should be considered as a potential differential diagnosis even in patients with the T2-FLAIR mismatch sign in diffuse gliomas.

DOI： 10.1177/20584601231184565

Prognostic implications of the immunohistochemical expression of perilipin 1 and adipophilin in high-grade liposarcoma. Reviewed International journal

Kengo Kawaguchi, Kenichi Kohashi, Taro Mori, Hidetaka Yamamoto, Takeshi Iwasaki, Izumi Kinoshita, Yosuke Susuki, Hiroshi Furukawa, Makoto Endo, Yoshihiro Matsumoto, Yasuharu Nakashima, Yoshinao Oda

Journal of clinical pathology 2023.5

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

AIMS: Liposarcoma is a malignant soft tissue tumour with adipocytic differentiation. Dedifferentiated liposarcoma (DDLS) and myxoid liposarcoma (MLS) are classified as high-grade liposarcomas. Lipid droplet-associated protein (also known as perilipin 1 (PLIN1)) is the predominant perilipin and has utility as a specific marker of adipogenic differentiation. Adipose differentiation-related protein (also known as adipophilin (ADRP)) is ubiquitously expressed in a range of tissues. High ADRP expression is reportedly a poor prognostic factor in several cancer types. However, no previous studies have examined the association between PLIN1 or ADRP expression and prognosis in sarcoma. This study therefore aimed to evaluate the association between PLIN1 or ADRP expression and prognosis in liposarcoma. METHODS: In total, 97 primary resection specimens (53 MLS and 44 DDLS) were examined in this study. PLIN1 and ADRP expression was evaluated by immunohistochemistry. Survival analyses were performed for MLS and DDLS. RESULTS: Of the 53 MLS specimens, 15 (28.3%) exhibited high PLIN1 expression. PLIN1 expression was not observed in DDLS specimens. High PLIN1 expression was significantly associated with increased disease-free survival (DFS) among patients with MLS (p=0.045). Distinct ADRP expression was observed in 13 of 53 (24.5%) MLS specimens and 5 of 44 (11.4%) DDLS specimens. High ADRP expression was associated with shorter overall survival (OS) in MLS (p=0.042) and DFS and shorter OS in DDLS (p=0.024 and p<0.001, respectively). CONCLUSIONS: PLIN1 and ADRP expression is associated with poor prognosis in high-grade liposarcoma.

DOI： 10.1136/jcp-2023-208814

Gastric cancer in Lynch syndrome observed by image-enhanced endoscopy. Reviewed International journal

Keisuke Kawasaki, Shinichiro Kawatoko, Chiaki To, Hidetaka Yamamoto, Takehiro Torisu

Gastrointestinal endoscopy 98 ( 2 ) 259 - 260 2023.5

TRK-inhibitor control of an NTRK-rearranged spindle cell tumor with malignant transformation in an adolescent. Reviewed International journal

Naoko Higuchi, Yuko Honda, Yuhki Koga, Hiroshi Asai, Hiroaki Ono, Wakako Kato, Kentaro Nakashima, Esther De La Cuesta, Toshiaki Tsujino, Hidetaka Yamamoto, Koichi Kusuhara, Masanori Hisaoka, Shouichi Ohga

Pediatric blood & cancer e30379 2023.5

Amide proton transfer (APT) imaging of breast cancers and its correlation with biological status. Reviewed International journal

Takeshi Kamitani, Koji Sagiyama, Yuzo Yamasaki, Takuya Hino, Tatsuhiro Wada, Makoto Kubo, Sayuri Akiyoshi, Hidetaka Yamamoto, Hidetake Yabuuchi, Kousei Ishigami

Clinical imaging 96 38 - 43 2023.4

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

PURPOSE: To assess the usefulness of amide proton transfer (APT) imaging to predict the biological status of breast cancers. METHOD: Sixty-six patients (age range 31-85 years, mean 58.9 years) with histopathologically proven invasive ductal carcinomas of 2 cm or larger in diameter were included in this study. 3D APT weighted imaging was conducted on a 3 T scanner. Mean APT signal intensity (SI) was analyzed in relation to biological subtypes, Ki-67 labeling index, and nuclear grades (NGs). RESULTS: The triple-negative (TN) cancers (n = 10; 2.75 ± 0.42%) showed significantly higher APT SI than the luminal type cancers (n = 48; 1.74 ± 0.83) and HER2 cancers (n = 8; 1.83 ± 0.21) (P = 0.0007, 0.03). APT SI had weakly positive correlation with the Ki-67 labeling index (r = 0.38, P = 0.002). The mean APT SIs were significantly higher for high-Ki-67 (>30%) (n = 31; 2.25 ± 0.70) than low-Ki-67 (≤30%) cancers (n = 35; 1.60 ± 0.79) (P = 0.0007). There was no significant difference in the APT SIs between NG 1-2 (n = 31; 1.71 ± 0.84) and NG 3 (n = 35; 2.08 ± 0.76%) cancers (P = 0.06). CONCLUSIONS: TN and high-Ki-67 breast cancers showed high APT SIs. APT imaging can help to predict the biological status of breast cancers.

DOI： 10.1016/j.clinimag.2023.02.002

High-risk HPV-related squamous cell carcinoma in the temporal bone: a rare but noteworthy subtype. International journal

Takahiro Hongo, Hidetaka Yamamoto, Ryosuke Kuga, Noritaka Komune, Masaru Miyazaki, Nana Akagi Tsuchihashi, Teppei Noda, Nozomu Matsumoto, Yoshinao Oda, Takashi Nakagawa

Virchows Archiv : an international journal of pathology 482 ( 3 ) 539 - 550 2023.3

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

High-risk human papillomavirus (HPV) is a risk factor for the development of several head and neck squamous cell carcinomas (SCCs). However, there have been few reports of high-risk HPV infection in temporal bone squamous cell carcinomas (TBSCCs), and thus the prevalence and clinicopathologic significance of high-risk HPV in TBSCCs are still unclear. We retrospectively collected 131 TBSCCs and analyzed them for transcriptionally active high-risk HPV infection using messenger RNA in situ hybridization; we also assessed the utility of p16-immunohistochemistry (IHC) and Rb-IHC to predict HPV infection. Eighteen (13.7%) of the 131 TBSCCs were positive for p16-IHC, and five of them were positive for high-risk HPV infection (the estimated high-risk HPV positivity rate was 3.8% [5/131]). Interestingly, all five HPV-positive patients were male and had TBSCC on the right side. In the p16-IHC+/HPV+ cases (n = 5), the Rb-IHC showed a partial loss pattern (n = 4) or complete loss pattern (n = 1). In contrast, all p16-IHC-negative cases (n = 113) showed an Rb-IHC preserved pattern. The positive predictive value (PPV) of p16-IHC positivity for high-risk HPV infection was low at 27.8%, while the combination of p16-IHC+/Rb-IHC partial loss pattern showed excellent reliability with a PPV of 100%. The prognostic significance of high-risk HPV infection remained unclear. High-risk HPV-related TBSCC is an extremely rare but noteworthy subtype.

DOI： 10.1007/s00428-023-03497-7

Evaluation of the one-step nucleic acid amplification assay for detecting lymph node metastasis in patients with cervical and endometrial cancer: A multicenter prospective study. International journal

Shinichi Togami, Akihide Tanimoto, Shintaro Yanazume, Hideki Tokunaga, Tomoyuki Nagai, Mika Watanabe, Hideaki Yahata, Kazuo Asanoma, Hidetaka Yamamoto, Tomohito Tanaka, Masahide Ohmichi, Takashi Yamada, Yukiharu Todo, Ryutaro Yamada, Hidenori Kato, Wataru Yamagami, Kenta Masuda, Miho Kawaida, Hitoshi Niikura, Takuya Moriya, Hiroaki Kobayashi

Gynecologic oncology 170 70 - 76 2023.3

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

OBJECTIVE: This multicenter study aimed to evaluate the accuracy of the one-step nucleic acid amplification (OSNA) assay in diagnosing lymph node metastasis (LNM) in patients with cervical and endometrial cancers. METHODS: Surgically removed LNs from patients with cervical and endometrial cancer were sectioned at 2-mm intervals along the short axis direction and alternately examined using the OSNA assay and conventional histopathological examination. Ultrastaging (200-μm LN sections) was performed for metastatic LNs using hematoxylin and eosin staining and immunostaining with an anti-CK19 antibody in cases where the OSNA assay and histopathological examination (performed using 2-mm LN sections) results showed discordance. RESULTS: A total of 437 LNs from 133 patients were included; 61 patients (14%) showed metastasis by histopathological examination, with a concordance rate of 0.979 (95% confidence interval [CI]: 0.961-0.991) with the OSNA assay. The sensitivity and specificity of the OSNA assay were 0.918 (95% CI: 0.819-0.973) and 0.989 (95% CI: 0.973-0.997), respectively. Discordance between the two methods was observed in nine LNs (2.1%), and allocation bias of metastatic foci was identified as the major cause of discordance. CONCLUSIONS: The OSNA assay showed equally accurate detection of LN metastasis as the histopathological examination. We suggest that the OSNA assay may be a useful tool for the rapid intraoperative diagnosis of LN metastasis in patients with cervical and endometrial cancers.

DOI： 10.1016/j.ygyno.2022.12.016

Virtual monochromatic spectral CT imaging in preoperative evaluations for intraductal spread of breast cancer: comparison with conventional CT and MRI.

Yuko Matsuura, Takeshi Kamitani, Koji Sagiyama, Yuzo Yamasaki, Takuya Hino, Makoto Kubo, Hideki Ijichi, Hidetaka Yamamoto, Hidetake Yabuuchi, Kousei Ishigami

Japanese journal of radiology 41 ( 7 ) 733 - 740 2023.2

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

PURPOSE: To investigate the efficacy of virtual monochromatic spectral computed tomography imaging (VMI) in the preoperative evaluation for intraductal spread of breast cancer. MATERIALS AND METHODS: Twenty-four women who underwent spectral CT and were pathologically diagnosed with ductal carcinoma with a ≥ 2-cm noninvasive component were retrospectively enrolled in Group 1. Twenty-two women with 22 lesions pathologically diagnosed with ductal carcinoma in situ or microinvasive carcinoma were enrolled in Group 2. We compared the contrast-to-noise ratios (CNRs) of the lesions on conventional 120-kVp CT images and 40-keV VMIs in Group 1. Two board-certified radiologists measured the maximum diameters of enhancing areas on 120-kVp CT, 40-keV VMI, and MRI in Group 2 and compared with histopathological sizes. RESULTS: The quantitative assessment of Group 1 revealed that the mean ± SD of the CNRs in the 40-keV images were significantly greater than those in the 120-kVp images (5.5 ± 1.9 vs. 3.6 ± 1.5, p < 0.0001). The quantitative assessment of Group 2 demonstrated that the lesion size observed in the conventional 120-kVp CT images by both readers was significantly underestimated as compared to the histopathological size (p = 0.017, 0.048), whereas both readers identified no significant differences between the lesion size measured on 40-keV VMI and the histopathological data. In a comparison with MRI, 40-keV VMI provided measurement within a 10-mm error range in more lesions as compared to the conventional 120-kVp CT. CONCLUSION: VMI improves the evaluation of intraductal spread and is useful for the preoperative evaluations of breast cancer.

DOI： 10.1007/s11604-023-01392-4

The Expression of Insulin-Like Growth Factor II Messenger RNA-Binding Protein 3 Upregulated in Intradural Extramedullary Schwannomas.

Hirofumi Bekki, Yoshihiro Matsumoto, Masato Yoshimoto, Shin Ishihara, Kenichi Kawaguchi, Hidetaka Yamamoto, Yoshinao Oda, Yasuharu Nakashima, Katsumi Harimaya

Spine surgery and related research 7 ( 1 ) 36 - 41 2023.1

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

INTRODUCTION: Tumor size is an important factor in determining the appropriate clinical management of intradural-extramedullary schwannoma. A tumor volume reduction may be achieved by conservative targeted therapy instead of invasive surgery if a molecular event related to tumor size is discovered. Insulin-like growth factor II messenger RNA-binding protein 3 (IMP3), an oncofetal tumor-associated antigen that is expected to be a target for immunotherapy, was focused on in this study. METHODS: The IMP3 status was assessed by immunohistochemistry in 64 samples of intradural-extramedullary schwannoma, and the correlation between IMP3 expression and tumor size was evaluated. RESULTS: Immunohistochemically, high IMP3 expression was observed in ～85% of schwannomas. The maximum tumor diameter of the high IMP3 expression group was significantly larger than that of the low IMP3 expression group (34.3 mm vs 18.5 mm, p=0.002). The receiver operating characteristic curve demonstrated that a maximum tumor diameter of 24 mm was a predictable factor for IMP3 expression (sensitivity, 0.7; 1-specificity, 0.2; area under the curve, 0.82). CONCLUSIONS: Upregulated IMP3 expression was associated with large tumor size, suggesting a possible therapeutic approach.

DOI： 10.22603/ssrr.2022-0063

Prognostic value of nuclear morphometry in myxoid liposarcoma. International journal

Kengo Kawaguchi, Kenichi Kohashi, Takeshi Iwasaki, Takeo Yamamoto, Shin Ishihara, Yu Toda, Hidetaka Yamamoto, Yasuharu Nakashima, Yoshinao Oda

Cancer science 114 ( 5 ) 2178 - 2188 2023.1

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

Myxoid liposarcoma (MLS) accounts for 20%-30% of liposarcoma and the round cell component (RCC) is believed to be a specific poor prognostic factor. However, the RCC assessment criteria are vaguely defined and, therefore, are inconsistently employed by pathologists. In this study, we modified and applied two established grading systems to evaluate nuclear atypia (namely, the World Health Organization / International Society of Urological Pathology and the Fuhrman grading in renal cell carcinoma) in 64 MLS cases. Detailed software-based assessments of the morphology and the cellularity were performed. DNA mutation analysis, comprehensive mRNA expression analysis, and immunohistochemistry were also performed. Our findings revealed that the high nuclear grade group according to the modified Fuhrman grading system exhibited a significantly poor disease-free survival (hazard ratio: 4.43; 95% confidence interval: 0.9-22.6; p = 0.047). On the other hand, the cellularity was significantly higher in the modified Fuhrman high-grade group (p = 0.010 at the percentage of the hypercellular area; p = 0.003 at the maximum cell density), but did not qualify per se as a poor prognostic factor in the survival analyses. Furthermore, the modified Fuhrman high-grade group significantly expressed the cell cycle-related genes (such as FOXM1, PLK1, and CDK1). In conclusion, our analyses suggest that an evaluation focusing on nuclear morphology (rather than on cellular density) can be more reliable in predicting the MLS prognosis.

DOI： 10.1111/cas.15729

Liquid biopsy with multiplex ligation-dependent probe amplification targeting cell-free tumor DNA in cerebrospinal fluid from patients with adult diffuse glioma. International journal

Ryosuke Otsuji, Yutaka Fujioka, Nobuhiro Hata, Daisuke Kuga, Yuhei Sangatsuda, Kosuke Takigawa, Yusuke Funakoshi, Aki Sako, Hidetaka Yamamoto, Akira Nakamizo, Masahiro Mizoguchi, Koji Yoshimoto

Neuro-oncology advances 5 ( 1 ) vdac178 2023

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

BACKGROUND: Copy number alterations (CNAs) are common in diffuse gliomas and have been shown to have diagnostic significance. While liquid biopsy for diffuse glioma has been widely investigated, techniques for detecting CNAs are currently limited to methods such as next-generation sequencing. Multiplex ligation-dependent probe amplification (MLPA) is an established method for copy number analysis in pre-specified loci. In this study, we investigated whether CNAs could be detected by MLPA using patients' cerebrospinal fluid (CSF). METHODS: Twenty-five cases of adult diffuse glioma with CNAs were selected. Cell-free DNA (cfDNA) was extracted from the CSF, and DNA sizes and concentrations were recorded. Twelve samples, which had appropriate DNA sizes and concentrations, were subsequently used for analysis. RESULTS: MLPA could be successfully performed in all 12 cases, and the detected CNAs were concordant with those detected using tumor tissues. Cases with epidermal growth factor receptor (EGFR) amplification, combination of gain of chromosome 7 and loss of chromosome 10, platelet-derived growth factor receptor alpha amplification, cyclin-dependent kinase 4 amplification, and cyclin-dependent kinase inhibitor 2A (CDKN2A) homozygous deletion were clearly distinguished from those with normal copy numbers. Moreover, EGFR variant III was accurately detected based on CNA. CONCLUSIONS: Thus, our results demonstrate that copy number analysis can be successfully performed by MLPA of cfDNA extracted from the CSF of patients with diffuse glioma.

DOI： 10.1093/noajnl/vdac178

Sessile serrated lesion of the rectum in ulcerative colitis observed by image-enhanced endoscopy. International journal

Keisuke Kawasaki, Shinichiro Kawatoko, Hidetaka Yamamoto, Takehiro Torisu

The American journal of gastroenterology 118 ( 5 ) 771 - 771 2022.12

Grading of gliomas using 3D CEST imaging with compressed sensing and sensitivity encoding. International journal

Tatsuhiro Wada, Osamu Togao, Chiaki Tokunaga, Masahiro Oga, Kazufumi Kikuchi, Koji Yamashita, Hidetaka Yamamoto, Masami Yoneyama, Koji Kobayashi, Toyoyuki Kato, Kousei Ishigami, Hidetake Yabuuchi

European journal of radiology 158 110654 - 110654 2022.12

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

PURPOSE: We evaluated the usefulness of three-dimensional (3D) chemical exchange saturation transfer (CEST) imaging with compressed sensing and sensitivity encoding (CS-SENSE) for differentiating low-grade gliomas (LGGs) from high-grade gliomas (HGGs). METHODS: We evaluated 28 patients (mean age 51.0 ± 13.9 years, 13 males, 15 females) including 12 with LGGs and 16 with HGGs, all acquired using a 3 T magnetic resonance (MR) scanner. Nine slices were acquired for 3D CEST imaging, and one slice was acquired for two-dimensional (2D) CEST imaging. Two radiological technologists each drew a region of interest (ROI) surrounding the high-signal-intensity area(s) on the fluid-attenuated inversion recovery image of each patient. We compared the magnetization transfer ratio asymmetry (MTRasym) at 3.5 ppm in the tumors among the (i) single-slice 2D CEST imaging ("2D"), (ii) all tumor slices of the 3D CEST imaging (3Dall), and (iii) a representative tumor slice of 3D CEST imaging (maximum signal intensity [3Dmax]). The relationship between the MTRasym at 3.5 ppm values measured by these three methods and the Ki-67 labeling index (LI) of the tumors was assessed. Diagnostic performance was evaluated with a receiver operating characteristic analysis. The Ki-67LI and MTRasym at 3.5 ppm values were compared between the LGGs and HGGs. RESULTS: A moderate positive correlation between the MTRasym at 3.5 ppm and the Ki-67LI was observed with all three methods. All methods proved a significantly larger MTRasym at 3.5 ppm for the HGGs compared to the LGGs. All methods showed equivalent diagnostic performance. The signal intensity varied depending on the slice position in each case. CONCLUSIONS: The 3D CEST imaging provided the MTRasym at 3.5 ppm for each slice cross-section; its diagnostic performance was also equivalent to that of 2D CEST imaging.

DOI： 10.1016/j.ejrad.2022.110654

Quantitative relaxometry using synthetic MRI could be better than T2-FLAIR mismatch sign for differentiation of IDH-mutant gliomas: a pilot study International journal

Kazufumi Kikuchi, Osamu Togao, Koji Yamashita, Daichi Momosaka, Yoshitomo Kikuchi, Daisuke Kuga, Nobuhiro Hata, Masahiro Mizoguchi, Hidetaka Yamamoto, Toru Iwaki, Akio Hiwatashi, Kousei Ishigami

Scientific Reports 12 ( 1 ) 9197 - 9197 2022.12

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

This study aimed to determine whether quantitative relaxometry using synthetic magnetic resonance imaging (SyMRI) could differentiate between two diffuse glioma groups with isocitrate dehydrogenase (IDH)-mutant tumors, achieving an increased sensitivity compared to the qualitative T2-fluid-attenuated inversion recovery (FLAIR) mismatch sign. Between May 2019 and May 2020, thirteen patients with IDH-mutant diffuse gliomas, including seven with astrocytomas and six with oligodendrogliomas, were evaluated. Five neuroradiologists independently evaluated the presence of the qualitative T2-FLAIR mismatch sign. Interrater agreement on the presence of the T2-FLAIR mismatch sign was calculated using the Fleiss kappa coefficient. SyMRI parameters (T1 and T2 relaxation times and proton density) were measured in the gliomas and compared by the Mann–Whitney U test. Receiver operating characteristic curve analysis was used to evaluate the diagnostic performance. The sensitivity, specificity, and kappa coefficient were 57.1%, 100%, and 0.60, respectively, for the qualitative T2-FLAIR mismatch sign. The two types of diffuse gliomas could be differentiated using a cutoff value of 178 ms for the T2 relaxation time parameter with 100% sensitivity, specificity, accuracy, and positive and negative predictive values, with an area under the curve (AUC) of 1.00. Quantitative relaxometry using SyMRI could differentiate astrocytomas from oligodendrogliomas, achieving an increased sensitivity and objectivity compared to the qualitative T2-FLAIR mismatch sign.

DOI： 10.1038/s41598-022-13036-0

Auxiliary diagnosis of subepithelial lesions by impedance measurement during endoscopic ultrasound guided fine-needle biopsy. International journal

Yosuke Minoda, Mitsuru Esaki, Eikichi Ihara, Shuzaburo Nagatomo, Kei Nishioka, Nao Fujimori, Haruei Ogino, Xiaopeng Bai, Yoshimasa Tanaka, Takatoshi Chinen, Qingjiang Hu, Mitsuhiko Ota, Shinya Umekita, Hidetaka Yamamoto, Yoshihiro Ogawa

Gastrointestinal endoscopy 97 ( 5 ) 977 - 984 2022.11

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

INTRODUCTION: Endoscopic ultrasound guided fine-needle aspiration/biopsy (EUS-FNA/B) is the gold standard for diagnosing subepithelial lesions (SELs); however, its diagnostic ability for SELs <20 mm is low. We developed a new diagnostic method to differentiate between gastrointestinal stromal tumor (GIST) and non-GIST by measuring high-frequency impedance (H-impedance) using an EUS-FNB needle. METHODS: The H-impedance of gastric epithelial neoplasms from 16 cases were measured using a conventional impedance probe to confirm whether H-impedance is clinically useful for assessing cell density (Study 1). The H-impedance values of exposed SELs from 25 cases using the conventional probe (Study 2) and non-exposed SELs from 20 cases using the EUS-FNB needle probe (Study 3) were measured to determine the diagnostic ability of H-impedance for differentiating GISTs from non-GISTs. RESULTS: H-impedance significantly positively correlated with cell density (P=0.030) (Study 1). The H-impedance of GIST (99.5) measured using conventional probe was significantly higher than those of the muscular layer (82.4) and leiomyoma (89.2) (P<0.01) (Study 2). The H-impedance of GIST measured using the EUS-FNB needle was also significantly higher than that of leiomyoma (GIST: 80.2 vs. leiomyoma: 71.8, P=0.015). The diagnostic yield of the impedance method for differentiating GISTs from non-GISTs had 94.4% accuracy, 88.9% sensitivity, 100% specificity, and 0.95 area under the curve. Diagnostic ability was not affected by lesion size (P=0.86) (Study 3). CONCLUSION: Auxiliary differential diagnosis between gastric GISTs and non-GISTs by the H-impedance measurement during EUS-FNB could be a good option especially when the lesion is smaller than 20 mm.

DOI： 10.1016/j.gie.2022.11.022

Expression of SATB2, RUNX2, and SOX9 and possible osteoblastic and chondroblastic differentiation in chondroblastoma. International journal

Yu Toda, Hidetaka Yamamoto, Takeshi Iwasaki, Shin Ishihara, Yoshihiro Ito, Yosuke Susuki, Kengo Kawaguchi, Izumi Kinoshita, Daisuke Kiyozawa, Yuichi Yamada, Kenichi Kohashi, Atsushi Kimura, Toshifumi Fujiwara, Nokitaka Setsu, Makoto Endo, Yoshihiro Matsumoto, Yasuharu Nakashima, Masaaki Mawatari, Yoshinao Oda

Pathology, research and practice 241 154239 - 154239 2022.11

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

Chondroblastoma (CB) is histologically characterized by oval to polygonal-shaped mononuclear neoplastic cells, multinucleated osteoclastic giant cells, and eosinophilic matrix with occasional calcification. Genetically, the majority of CBs harbor H3F3B p.K36M mutation. Despite the historical nomenclature, it has been reported that the matrix of CB is similar to osteoid rather than true cartilage; however, it remains unclear whether neoplastic cells in CB have the potential for osteoblastic differentiation. To clarify this issue, we immunohistochemically examined the expression of osteogenic and chondrogenic markers (SATB2, RUNX2, p63, and SOX9) as well as H3K36M mutant protein in 33 cases of CB. All 33 cases of CB were positive for H3K36M, while SATB2, RUNX2, p63, and SOX9 were expressed in 30/33 (91%), 33/33 (100%), 29/33 (88%), and 31/32 (97%) CB cases, respectively. Our immunohistochemical results suggest that neoplastic cells in CB frequently express both osteogenic and chondrogenic markers and may have an intermediate feature of osteoblastic and chondroblastic nature.

DOI： 10.1016/j.prp.2022.154239

Nuclear expression of AFF2 C-terminus is a sensitive and specific ancillary marker for DEK::AFF2 carcinoma of the sinonasal tract. International journal

Ying-Ju Kuo, James S Lewis Jr, Tra Truong, Yi-Chen Yeh, Rebecca D Chernock, Changwen Zhai, Yun-An Chen, Takahiro Hongo, Chien-Kuan Lee, Qiuying Shi, Jaylou M Velez Torres, Ariana B Geromes, Ying-Hsia Chu, Min-Shu Hsieh, Hidetaka Yamamoto, Ilan Weinreb, Jen-Fan Hang

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 35 ( 11 ) 1587 - 1595 2022.11

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

DEK::AFF2 carcinoma of the sinonasal tract is an emerging entity. The tumor is typically characterized by papillary proliferation of non-keratinizing squamous epithelial cells with monotonous cytologic features, which may mimic other sinonasal tumors. The confirmation of this gene fusion has thus far relied solely on next-generation sequencing, fluorescence in situ hybridization (FISH), or reverse transcription polymerase chain reaction (RT-PCR). This current study aimed to validate an immunohistochemical assay for AFF2 C-terminus as an ancillary marker. We first analyzed publicly available RNA sequencing data of sinonasal tumors from the national center for biotechnology information (NCBI) sequence read archive and identified 3 DEK::AFF2 carcinomas out of 28 sinonasal tumors. The gene expression of AFF2 was significantly higher in the fusion-positive cases compared to the wild-type tumors (p < 0.001), while DEK was not. We then optimized an immunohistochemical assay with an anti-AFF2 C-terminus antibody for ancillary diagnosis. Seventeen DEK::AFF2 carcinomas, including 11 cases with predominantly low-grade morphology and one showing glandular differentiation, as well as 78 DEK FISH-negative sinonasal tumors were evaluated by AFF2 immunohistochemistry (IHC). Sixteen of the 17 DEK::AFF2 carcinomas showed nuclear AFF2 expression in ≥30% of tumor cells, including one decalcified case that failed FISH and RT-PCR confirmation. The one case that was negative for AFF2 IHC in the tumor cells also lacked expression in the internal positive control. It was thus considered a failure of the IHC rather than a truly negative case and was excluded from the statistical analysis. All DEK FISH-negative sinonasal tumors were negative for nuclear AFF2 expression. The nuclear expression of AFF2 IHC showed 100% sensitivity and specificity for DEK::AFF2 carcinoma. Accordingly, AFF2 IHC is a highly sensitive and specific ancillary marker that distinguishes DEK-AFF2 carcinoma from the other sinonasal tumors with overlapping morphological features and may be an especially useful alternative for decalcified specimens.

DOI： 10.1038/s41379-022-01117-4

Mucin-rich traditional serrated adenoma with dysplasia of the rectum observed by magnifying endoscopy. International journal

Keisuke Kawasaki, Shinichiro Kawatoko, Shota Yamamoto, Hidetaka Yamamoto, Takehiro Torisu

Gastrointestinal endoscopy 97 ( 3 ) 599 - 600 2022.10

Surgical resection of a tuberculoma in the diaphragm: a case report. International journal

Asato Hashinokuchi, Mikihiro Kohno, Keisuke Kosai, Yuki Ono, Naoki Haratake, Daiki Shibata, Hidetaka Yamamoto, Tomoyoshi Takenaka, Tomoharu Yoshizumi

Surgical case reports 8 ( 1 ) 198 - 198 2022.10

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

BACKGROUND: Extrapulmonary tuberculosis commonly affects the lymphatic system, nervous system, and gastrointestinal system. Tuberculous infection in the muscle is very rare. Moreover, tuberculous infection in the diaphragm is extremely rare. We herein report a case of tuberculomas in the diaphragm and posterior mediastinum that were successfully diagnosed and treated. CASE PRESENTATION: We encountered a 62-year-old woman with a tuberculoma in the diaphragm. The patient presented with mild dyspnea. Computed tomography showed a mass in the left diaphragm, focal thickening of the posterior mediastinum, and multiple nodules in the lungs. Positron emission tomography-computed tomography showed increased uptake in the left diaphragm mass and thickening of the posterior mediastinum; therefore, we considered the masses to be malignant and planned surgical resection. However, the patient was diagnosed with tuberculosis from a sputum culture, and she was treated with anti-tuberculous therapy. The masses in the diaphragm and posterior mediastinum had become enlarged after 6 months of anti-tuberculous therapy; therefore, the patient underwent resection of both masses. Tuberculous infection was histologically confirmed in each lesion. She was pathologically diagnosed with tuberculous abscesses in the diaphragm and posterior mediastinum and began treatment with anti-tuberculosis drugs. CONCLUSIONS: Preoperative diagnosis of a tuberculoma in the diaphragm is usually difficult, and surgical intervention is important for both diagnosis and treatment.

DOI： 10.1186/s40792-022-01554-y

Efficacy of ultrasound endoscopy with artificial intelligence for the differential diagnosis of non-gastric gastrointestinal stromal tumors. International journal

Yosuke Minoda, Eikichi Ihara, Nao Fujimori, Shuzaburo Nagatomo, Mitsuru Esaki, Yoshitaka Hata, Xiaopeng Bai, Yoshimasa Tanaka, Haruei Ogino, Takatoshi Chinen, Qingjiang Hu, Eiji Oki, Hidetaka Yamamoto, Yoshihiro Ogawa

Scientific reports 12 ( 1 ) 16640 - 16640 2022.10

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

Gastrointestinal stromal tumors (GISTs) are common subepithelial lesions (SELs) and require treatment considering their malignant potential. We recently developed an endoscopic ultrasound-based artificial intelligence (EUS-AI) system to differentiate GISTs from non-GISTs in gastric SELs, which were used to train the system. We assessed whether the EUS-AI system designed for diagnosing gastric GISTs could be applied to non-gastric GISTs. Between January 2015 and January 2021, 52 patients with non-gastric SELs (esophagus, n = 15; duodenum, n = 26; colon, n = 11) were enrolled. The ability of EUS-AI to differentiate GISTs from non-GISTs in non-gastric SELs was examined. The accuracy, sensitivity, and specificity of EUS-AI for discriminating GISTs from non-GISTs in non-gastric SELs were 94.4%, 100%, and 86.1%, respectively, with an area under the curve of 0.98 based on the cutoff value set using the Youden index. In the subanalysis, the accuracy, sensitivity, and specificity of EUS-AI were highest in the esophagus (100%, 100%, 100%; duodenum, 96.2%, 100%, 0%; colon, 90.9%, 100%, 0%); the cutoff values were determined using the Youden index or the value determined using stomach cases. The diagnostic accuracy of EUS-AI increased as lesion size increased, regardless of lesion location. EUS-AI based on gastric SELs had good diagnostic ability for non-gastric GISTs.

DOI： 10.1038/s41598-022-20863-8

Hypopharyngeal dedifferentiated liposarcoma treated by endoscopic submucosal dissection. International journal

Keisuke Kawasaki, Shinichiro Kawatoko, Hidetaka Yamamoto, Takehiro Torisu

Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 55 ( 1 ) 137 - 138 2022.9

Nuclear β-catenin translocation plays a key role in osteoblast differentiation of giant cell tumor of bone. International journal

Atsushi Kimura, Yu Toda, Yoshihiro Matsumoto, Hidetaka Yamamoto, Kenichiro Yahiro, Eijiro Shimada, Masaya Kanahori, Ryunosuke Oyama, Suguru Fukushima, Makoto Nakagawa, Nokitaka Setsu, Makoto Endo, Toshifumi Fujiwara, Tomoya Matsunobu, Yoshinao Oda, Yasuharu Nakashima

Scientific reports 12 ( 1 ) 13438 - 13438 2022.8

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

Denosumab is a game-changing drug for giant cell tumor of bone (GCTB); however, its clinical biomarker regarding tumor ossification of GCTB has not been elucidated. In this study, we investigated the relationship between Wnt/β-catenin signaling and the ossification of GCTB and evaluated whether endogenous nuclear β-catenin expression predicted denosumab-induced bone formation in GCTB. Genuine patient-derived primary GCTB tumor stromal cells exhibited osteoblastic characteristics. Identified osteoblastic markers and nuclear β-catenin translocation were significantly upregulated via differentiation induction and were inhibited by treating with Wnt signaling inhibitor, GGTI-286, or selective Rac1-LEF inhibitor, NSC23766. Furthermore, we reviewed the endogenous ossification and nuclear β-catenin translocation of 86 GCTB clinical samples and elucidated that intra-tumoral ossification was significantly associated with the nuclear translocation. Three-dimensional quantitative analyses (n = 13) of tumoral CT images have revealed that the nuclear β-catenin translocation of naïve GCTB samples was significantly involved with the denosumab-induced tumor ossification. Our findings suggest a close relationship between the nuclear β-catenin translocation and the osteoblastic differentiation of GCTB. Investigations of the nuclear β-catenin in naïve GCTB samples may provide a promising biomarker for predicting the ossification of GCTB following denosumab treatment.

DOI： 10.1038/s41598-022-17728-5

Idiopathic myointimal hyperplasia of mesenteric veins depicted by barium enema examination, and conventional and magnifying colonoscopy.

Keisuke Kawasaki, Shinichiro Kawatoko, Takehiro Torisu, Yusuke Mizuuchi, Toshimi Iura, Hiroshi Ohtani, Katsuki Okamura, Hidetaka Yamamoto, Masafumi Nakamura, Takanari Kitazono

Clinical journal of gastroenterology 15 ( 4 ) 734 - 739 2022.8

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

A 71-year-old man was admitted to our institution complaining of abdominal pain and constipation. Barium enema examination revealed narrowing, cobble stoning, and longitudinal ulcerations in the sigmoid colon and upper rectum. Conventional colonoscopy, magnifying narrow-band imaging endoscopy, and magnifying chromoendoscopy revealed edematous mucosa, longitudinal ulcerations with luminal narrowing, and multiple pseudopolyps. The histologic examination of the biopsy specimens showed thick-walled (arterialized) capillaries and subendothelial fibrin deposits in the mucosa and submucosa. Based on a preoperative diagnosis of idiopathic myointimal hyperplasia of mesenteric veins (IMHMV), he underwent a laparoscopic resection of the sigmoid colon and upper rectum. The histologic examination of the resected specimens showed marked proliferation of venous walls with marked myointimal thickening and luminal occlusion from the submucosa to the mesentery throughout the entire resected tissue section. The final diagnosis was IMHMV.

DOI： 10.1007/s12328-022-01647-z

Salivary Gland Polymorphous Adenocarcinoma: Clinicopathological Features and Gene Alterations in 36 Japanese Patients International journal

Masahiro Fukumura, Kenichiro Ishibashi, Masato Nakaguro, Toshitaka Nagao, Kosuke Saida, Makoto Urano, Maki Tanigawa, Hideaki Hirai, Takahiro Yagyuu, Kentaro Kikuchi, Naomi Yada, Yoshihiko Sugita, Megumi Miyabe, Shogo Hasegawa, Mitsuo Goto, Hidetaka Yamamoto, Tomoyuki Ohuchi, Kimihide Kusafuka, Ikuko Ogawa, Hiroaki Suzuki, Kenji Notohara, Masayuki Shimoda, Yuichiro Tada, Tadaaki Kirita, Takashi Takata, Shojiroh Morinaga, Hatsuhiko Maeda, Saman Warnakulasuriya, Satoru Miyabe, Toru Nagao

Journal of Oral Pathology & Medicine 51 ( 8 ) 710 - 720 2022.7

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

OBJECTIVES: Polymorphous adenocarcinoma (PAC) is a common intraoral minor salivary gland carcinoma in Western countries but is extremely rare in Japan. The current study aimed to characterize the clinicopathological features and status of molecular alterations of PAC-associated genes, such as (e.g., PRKD1/2/3, ARID1A, and DDX3X) in a large cohort of Japanese patients with PAC. MATERIALS AND METHODS: We examined the cases of 36 Japanese patients with salivary gland PAC and 26 cases involving histopathological mimics. To detect gene splits, fluorescence in situ hybridization was carried out for PAC-associated genes. Additionally, we applied a SNaPshot multiplex assay to identify PRKD1 hotspot mutations. RESULTS: This study revealed the indolent clinical course of PAC with a high 10-year overall survival rate (92.9%), accompanied by occasional local recurrences and cervical lymph node metastasis (both 23.3%). Twenty cases (55.6%) of PAC (but none of the mimics) exhibited alterations in at least one PAC-associated gene. Rearrangement of PAC-associated genes and PRKD1 E710D were identified in 17 (47.2%) and 4 (11.1%) cases, respectively; one case showed coexisting PRKD3 split and PRKD1 E710D. In the multivariate analysis, high clinical stage (P=0.0005), the presence of prominent nucleoli (P=0.0003), and ARID1A split positivity (P=0.004) were independent risk factors for disease-free survival. CONCLUSION: Japanese patients with PAC showed clinicopathological features similar to those reported in Western countries. This study disclosed that PAC-associated genetic alterations were common and specific findings in PACs. The diagnostic role and possible prognostic significance of PAC-associated genetic alterations in PACs were suggested.

DOI： 10.1111/jop.13336

Negligible procedure-related dissemination risk of mucosal incision-assisted biopsy for gastrointestinal stromal tumors versus endoscopic ultrasound-guided fine-needle aspiration/biopsy. International journal

Yosuke Minoda, Eikichi Ihara, Soichi Itaba, Yorinobu Sumida, Kazuhiro Haraguchi, Akira Aso, Takahiro Mizutani, Takashi Osoegawa, Mitsuru Esaki, Shuzaburo Nagatomo, Kei Nishioka, Kazumasa Muta, Xiaopeng Bai, Haruei Ogino, Nao Fujimori, Daisuke Tsurumaru, Kenoki Ohuchida, Hu Qingjiang, Eiji Oki, Hidetaka Yamamoto, Yoshihiro Ogawa

Surgical endoscopy 37 ( 1 ) 101 - 108 2022.7

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

BACKGROUND: Mucosal incision-assisted biopsy (MIAB) is a valuable alternative to endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNAB) for sampling gastric subepithelial lesions (SELs). This study aimed to evaluate the potential risk of dissemination and impact on postoperative prognosis associated with MIAB, which has not yet been investigated. METHODS: Study 1: A prospective observational study was conducted to examine the presence or absence and growth rate of tumor cells in gastric juice before and after the procedure in patients with SELs who underwent MIAB (n = 25) or EUS-FNAB (n = 22) between September 2018 and August 2021. Study 2: A retrospective study was conducted to examine the impact of MIAB on postoperative prognosis in 107 patients with gastrointestinal stromal tumors diagnosed using MIAB (n = 39) or EUS-FNAB (n = 68) who underwent surgery between January 2001 and July 2020. RESULTS: In study 1, although no tumor cells were observed in gastric juice in MIAB before the procedure, they were observed in 64% of patients after obtaining samples (P < 0.001). In contrast, no tumor cells were observed in the gastric juice in EUS-FNAB before and after the procedure. In study 2, there was no significant difference in 5-year disease-free survival between MIAB (100%) and EUS-FNAB (97.1%) (P = 0.27). CONCLUSION: MIAB is safe, with little impact on postoperative prognosis, although the procedure releases some tumor cells after damaging the SEL's pseudocapsule.

DOI： 10.1007/s00464-022-09419-z

Real-world Experience With Pembrolizumab for Advanced-stage Head and Neck Cancer Patients: A Retrospective, Multicenter Study. International journal

Takafumi Nakano, Ryuji Yasumatsu, Kazuki Hashimoto, Ryosuke Kuga, Takahiro Hongo, Hidetaka Yamamoto, Mioko Matsuo, Takahiro Wakasaki, Rina Jiromaru, Tomomi Manako, Satoshi Toh, Muneyuki Masuda, Moriyasu Yamauchi, Yuichiro Kuratomi, Masahiko Taura, Toranoshin Takeuchi, Takashi Nakagawa

Anticancer research 42 ( 7 ) 3653 - 3664 2022.7

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

BACKGROUND/AIM: This study investigated the effectiveness of pembrolizumab with or without chemotherapy on advanced-stage head and neck cancer (HNC), including nasopharyngeal, sinonasal cavity and external auditory canal cancer, in a real-world setting. PATIENTS AND METHODS: We retrospectively collected data from 97 HNC patients who were treated with pembrolizumab alone (n=60) or with chemotherapy (n=37), and we investigated the association between clinicopathological findings and treatment response or prognosis. RESULTS: Patients treated with pembrolizumab and chemotherapy had a 1-year overall survival (OS) of 72.8%, objective response rate (ORR) of 48.6%, and serious (≥G3) adverse events (AEs) of 29.7%. Patients treated with pembrolizumab alone had a 1-year OS of 51.9%, ORR of 21.7%, and ≥G3 AEs of 6.7%. Both the ORR and disease control rate (DCR) in the pembrolizumab with chemotherapy group were significantly better than those in the pembrolizumab group (p=0.074 and p=0.00101, respectively). Among patients with distant metastasis, patients on pembrolizumab with chemotherapy achieved significantly better OS than pembrolizumab alone (p=0.0039). Among patients in the pembrolizumab group, both AE-positive and better performance status were associated with longer OS (p=0.011 and p=0.0037, respectively). CONCLUSION: Our real-world experience reinforces the durability and effectiveness of pembrolizumab for HNC patients. Additionally, our results suggest that pembrolizumab with chemotherapy might be recommended for patients with distant metastasis and no prior treatment. Further studies are needed to determine the optimal treatment strategy for HNC.

DOI： 10.21873/anticanres.15854

A clinical analysis of oropharyngeal squamous cell carcinoma: a single-institution's experience. International journal

Rina Jiromaru, Ryuji Yasumatsu, Hidetaka Yamamoto, Ryosuke Kuga, Takahiro Hongo, Takafumi Nakano, Tomomi Manako, Kazuki Hashimoto, Takahiro Wakasaki, Mioko Matsuo, Takashi Nakagawa

European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery 279 ( 7 ) 3717 - 3725 2022.7

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

PURPOSE: We herein report the treatment outcome of oropharyngeal squamous cell carcinoma (OPSCC) at Kyushu University Hospital, the total number of OPSCC cases, and changes in the proportion of human papilloma virus (HPV)-related carcinomas over time. METHOD: We performed a retrospective analysis of 237 cases treated for OPSCC at Kyushu University Hospital between 2013 and 2019. We performed HPV-mRNA in situ hybridization and p16 immunohistochemistry. RESULT: This study included 197 males (82.1%) and 40 females (17.9%). The disease-specific, progression-free and overall survival (OS) were 69%, 62% and 61%, respectively, over the decade-long study period. p16-Immunohistochemistory and highrisk HPV mRNA in situ hybridization were positive in 114 (48.1%) and 105 (44.3%) cases, respectively. The number of HPV-related OPSCC cases increased according to an annual analysis. HPV+ cases had a significantly better prognosis than HPV- cases. In addition, p16+/HPV- cases had a significantly worse prognosis than p16+/HPV+ cases (OS: p = 0.0484). HPV+ OPSCC cases were associated with a younger age (< 60 years old) (p = 0.0429), non-smoker (p = 0.0001), lateral tumor site (< 0.00001), lymphoid metastasis (< 0.0001) and low clinical stage (< 0.0001). CONCLUSION: The frequency of HPV-related OPSCC cases is increasing in Japan as well as worldwide, and such cases are characterized by no smoking habit, a young age, and a good prognosis. Even in p16+ OPSCC, HPV- cases had a poor prognosis, suggesting the importance of accurate HPV determination. To determine the intensity of treatment for HPV-related and non-related OPSCC, it is necessary to accumulate cases for the accurate HPV determination and comparison of treatment effects.

DOI： 10.1007/s00405-021-07236-z

The implicated clinical factors for outcomes in 304 patients with salivary duct carcinoma: Multi-institutional retrospective analysis in Japan. International journal

Kimihide Kusafuka, Yoko Sato, Eiji Nakatani, Satoshi Baba, Matsuyoshi Maeda, Koji Yamanegi, Kaori Ueda, Hiroshi Inagaki, Yoshiro Otsuki, Naoto Kuroda, Kensuke Suzuki, Hiroshi Iwai, Yoshiaki Imamura, Junya Itakura, Shoji Yamanaka, Hideaki Takahashi, Ichiro Ito, Takumi Akashi, Tsutomu Daa, Mei Hamada, Masanori Yasuda, Ryo Kawata, Hidetaka Yamamoto, Yuri Tachibana, Junya Fukuoka, Aya Muramatsu, Kazumori Arai, Makoto Suzuki

Head & neck 44 ( 6 ) 1430 - 1441 2022.6

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

BACKGROUND: Salivary duct carcinoma (SDC) is a high-grade salivary malignancy that frequently occurs as the carcinomatous component of carcinoma ex pleomorphic adenoma. We herein examined the clinical factors affecting outcomes in a large cohort of SDC. METHODS: We selected 304 SDC cases and investigated clinical characteristics and the factors affecting outcomes. RESULTS: The median age of the cases examined was 68 years, the most common primary site was the parotid gland (238 cases), and there was a male predominance (M/F = 5:1). Outcomes were significantly worse when the primary tumor site was the minor salivary glands (SG) than when it was the major SG. Outcomes were also significantly worse in pN(+) cases (161 cases) than in pN0 cases, particularly those with a metastatic lymph node number ≥11. The cumulative incidence of relapse and distant metastases was significantly higher in stage IV cases than in stage 0-III cases. CONCLUSIONS: The absolute number of lymph node metastases, higher stages, and the minor SG as the primary tumor site were identified as factors affecting the outcome of SDC.

DOI： 10.1002/hed.27034

Distinct disease-specific Tfh cell populations in two different fibrotic diseases: IgG4-related disease and Kimura's disease. International journal

Ryusuke Munemura, Takashi Maehara, Yuka Murakami, Risako Koga, Ryuichi Aoyagi, Naoki Kaneko, Atsushi Doi, Cory A Perugino, Emanuel Della-Torre, Takako Saeki, Yasuharu Sato, Hidetaka Yamamoto, Tamotsu Kiyoshima, John H Stone, Shiv Pillai, Seiji Nakamura

The Journal of allergy and clinical immunology 150 ( 2 ) 440 - 455 2022.5

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

BACKGROUND: How T follicular (Tfh) cells contribute to many different B-cell class-switching events during T cell-dependent immune responses has been unclear. Diseases with polarized isotype switching offer a unique opportunity for the exploration of Tfh subsets. Secondary and tertiary lymphoid organs (SLOs and TLOs) in patients with elevated tissue expression levels of IgE (Kimura's disease, KD) and those of IgG4 (IgG4-related disease, IgG4-RD) can provide important insights regarding cytokine expression by Tfh cells. OBJECTIVE: To identify disease-specific Tfh cell subsets in SLOs and TLOs expressing IL-10 or IL-13 and thus identify different cellular drivers of class switching in two distinct types of fibrotic disorders: allergic fibrosis (driven by type 2 immune cells) and inflammatory fibrosis (driven by cytotoxic T lymphocytes). METHODS: Single-cell RNA-sequencing, in situ sequencing, and multi-color immunofluorescence analysis was used to investigate B cells, Tfh cells and infiltrating type 2 cells in lesion tissues from patients with KD or IgG4-RD. RESULTS: Infiltrating Tfh cells in TLOs from IgG4-RD were divided into six main clusters. We encountered abundant infiltrating IL-10-expressing LAG3+ Tfh cells in patients with IgG4-RD. Furthermore, we found that infiltrating AID+CD19+B cells expressing IL-4, IL-10, and IL-21 receptors correlated with IgG4 expression. In contrast, we found that infiltrating IL-13-expressing Tfh cells were abundant in affected tissues from patients with KD. Moreover, we observed few infiltrating IL-13-expressing Tfh cells in tissues from patients with IgG4-RD, despite high serum levels of IgE (but low IgE in the disease lesions). Cytotoxic T cells were abundant in IgG4-RD, and in contrast Type 2 immune cells were abundant in KD. CONCLUSIONS: This single-cell dataset revealed a novel subset of IL10+LAG3+Tfh cells infiltrating the affected organs of IgG4-RD patients. In contrast, IL13+Tfh cells and type 2 immune cells infiltrated those of KD patients.

DOI： 10.1016/j.jaci.2022.03.034

Histological and immunohistochemical features and genetic alterations in the malignant progression of giant cell tumor of bone: a possible association with TP53 mutation and loss of H3K27 trimethylation. International journal

Shin Ishihara, Hidetaka Yamamoto, Takeshi Iwasaki, Yu Toda, Takeo Yamamoto, Masato Yoshimoto, Yoshihiro Ito, Yousuke Susuki, Kengo Kawaguchi, Izumi Kinoshita, Yuichi Yamada, Kenichi Kohashi, Toshifumi Fujiwara, Nokitaka Setsu, Makoto Endo, Yoshihiro Matsumoto, Yuko Kakuda, Yasuharu Nakashima, Yoshinao Oda

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 35 ( 5 ) 640 - 648 2022.5

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

In rare cases, giant cell tumor of bone (GCTB) can undergo primary or secondary malignant transformation to malignant giant cell tumor of bone (MGCTB), but the details of the molecular alterations are still unclear. The present study aimed to elucidate the clinicopathologic and molecular features of MGCTBs based on immunohistochemistry, fluorescence in situ hybridization (FISH) and next generation sequencing (NGS) of nine MGCTBs (five primary and four secondary). Seven (78%) of 9 MGCTBs were immunohistochemically positive for H3.3 G34W. In two (22%) patients, although GCTB components were focally or diffusely positive for H3.3 G34W, their malignant components were entirely negative for H3.3 G34W, which was associated with heterozygous loss of H3F3A by FISH. NGS on four MGCTBs revealed pathogenic mutations in TP53 (n = 3), EZH2 (n = 1) and several other genes. Immunohistochemical analysis of the nine MGCTBs confirmed the p53 nuclear accumulation (n = 5) and loss of H3K27me3 expression (n = 3) and showed that they were mutually exclusive. In addition, four (80%) of five cases of pleomorphic or epithelioid cell-predominant MGCTBs were positive for p53, while three (75%) of four cases of spindle cell-predominant MGCTBs were negative for trimethylation at lysine 27 of histone 3 (H3K27me3). The results suggested that p53 alteration and dysfunction of histone methylation as evidenced by H3K27me3 loss may play an important role in the malignant progression of GCTB, and might contribute to the phenotype-genotype correlation in MGCTB. The combined histologic, immunohistochemical and molecular information may be helpful in part for the diagnosis of challenging cases.

DOI： 10.1038/s41379-021-00972-x

Cyclin-dependent kinase 8 is an independent prognosticator in uterine leiomyosarcoma. International journal

Nobuko Yasutake, Takeshi Iwasaki, Hidetaka Yamamoto, Kenzo Sonoda, Keisuke Kodama, Kaoru Okugawa, Kazuo Asanoma, Hideaki Yahata, Kiyoko Kato, Yoshinao Oda

Pathology, research and practice 235 153920 - 153920 2022.4

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

Cyclin-dependent kinase 8 (CDK8) is associated with the transcriptional mediator complex and regulates several transcription factors implicated in cancer. CDK8 expression is a poor prognostic marker in colon and breast cancer by immunohistochemistry. However, somatic mutations in exon 2 of the RNA polymerase II transcriptional mediator subunit MED12 occur in 7-30% of cases of uterine leiomyosarcoma (ULMS), suggesting that these alterations contribute to tumorigenesis. Public genomic mutation data of 80 patients with ULMS were used for MED12 and CDK8 mutation analysis. The expression of MED12, CDK8 and β-catenin was evaluated by immunohistochemistry in our cohort of 60 patients with ULMS, in addition with MED12 mutation status and survival stage. Univariate analysis was performed using the log-rank test, and Cox regression was used to identify independent prognostic factors. Multivariate Cox regression analysis revealed that advanced stage (p < 0.0001) and high CDK8 expression (p = 0.0014) were independent predictors of poor prognosis. MED12 mutation status was not signiﬁcantly associated with CDK8 expression (p = 0.6873) and DSS (p = 0.8075). In conclusion, our data suggest that CDK8 expression may identify a subset of ULMS patients with a poor prognosis.

DOI： 10.1016/j.prp.2022.153920

Clinical, Radiological, and Histopathological Characteristics of Periosteal Chondrosarcoma with a Focus on the Frequency of Medullary Invasion. International journal

Makoto Nakagawa, Makoto Endo, Yosuke Susuki, Nobuhiko Yokoyama, Akira Maekawa, Akira Nabeshima, Keiichiro Iida, Toshifumi Fujiwara, Nokitaka Setsu, Tomoya Matsunobu, Yoshihiro Matsumoto, Ryohei Yokoyama, Yuichi Yamada, Kenichi Kohashi, Hidetaka Yamamoto, Yoshinao Oda, Yukihide Iwamoto, Yasuharu Nakashima

Journal of clinical medicine 11 ( 7 ) 2022.4

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

Periosteal chondrosarcoma is an extremely rare malignant cartilage-forming tumour that originates from the periosteum and occurs on the surface of bone. Often, it is difficult to distinguish periosteal chondrosarcoma from other tumours, and reports in the literature are scarce. This study aims to investigate the characteristics of periosteal chondrosarcoma, focusing particularly on medullary invasion. Among 33 periosteal cartilaginous tumours, seven patients with pathologically proven periosteal chondrosarcoma were identified retrospectively. The average tumour size was 5.4 cm in the long axis; two tumours were smaller than 3.0 cm. Six tumours were resected with a wide margin, and the remaining tumour had a marginal margin. Histology revealed that six tumours (85.7%) had invaded the medullary cavity; three of these did not show invasion into the medullary cavity on MRI evaluation. Neither local recurrence nor metastasis was observed among these patients. The frequency of invasion of the medullary cavity was higher than that reported previously. The recommended treatment for periosteal chondrosarcoma is resection with an adequate margin. Therefore, surgeons should consider the possibility of medullary invasion when attempting to achieve a histologically negative margin, even if the tumour does not show invasion into the medullary cavity on MRI.

DOI： 10.3390/jcm11072062

Myxoid type and non-myxoid type of intimal sarcoma in large vessels and heart: review of histological and genetic profiles of 20 cases. International journal

Yuichi Yamada, Izumi Kinoshita, Yoshiko Miyazaki, Yuki Tateishi, Yusuke Kuboyama, Takeshi Iwasaki, Kenichi Kohashi, Hidetaka Yamamoto, Shin Ishihara, Yu Toda, Yoshihiro Ito, Yosuke Susuki, Kengo Kawaguchi, Mikiko Hashisako, Yui Yamada-Nozaki, Daisuke Kiyozawa, Taro Mori, Takeo Yamamoto, Kenji Tsuchihashi, Kazumi Kuriwaki, Munenori Mukai, Masataka Kawai, Keiko Suzuki, Hirotake Nishimura, Kenji Bando, Junya Masumoto, Mana Fukushima, Junichi Motoshita, Hiroki Mori, Akira Shiose, Yoshinao Oda

Virchows Archiv : an international journal of pathology 480 ( 4 ) 919 - 925 2022.4

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

Intimal sarcoma is one of the most common and well-known primary malignant neoplasms of the aorta and heart. The authors reviewed cases of intimal sarcoma from histological, immunohistochemical and genetic perspectives. Twenty cases of intimal sarcoma were retrieved. Immunohistochemistry and FISH of MDM2 and PDGFRA genes were performed. All 20 tumours were composed of spindle-shaped, stellate, oval or polygonal tumour cells with irregular hyperchromatic nuclei arranged in a haphazard pattern, accompanied by nuclear pleomorphism and frequent mitotic figures. Other histological findings were as follows: abnormal mitosis in 10 cases (50%), necrosis in 15 cases (75%), myxoid stroma in 12 cases (60%), cartilaginous formation in 1 case (5%), haemorrhage in 12 cases (60%) and fibrinous deposition in 14 cases (70%). The tumours were positive for MDM2 in 16 cases (80%), ERG in 4 cases (20%), alpha-smooth muscle actin in 6 cases (30%), desmin in 5 cases (25%) and AE1/AE3 in 4 cases (20%). Immunohistochemical positivity was focal in each case. Loss of H3K27me3 expression was noted in 2 cases (10%). MDM2 and PDGFRA gene amplifications were detected in 11 cases (55%) and 1 case (5%), respectively. Fisher's exact test revealed a significant correlation between MDM2 gene amplification and myxoid stroma (p = 0.0194). No parameters showed any association with the anatomical location of the tumours. It was suggested that myxoid histology of intimal sarcoma may be associated with MDM2 gene amplification and that intimal sarcoma may be divided into myxoid and non-myxoid types.

DOI： 10.1007/s00428-022-03293-9

Retrospective Study of Cisplatin/Carboplatin, 5-Fluorouracil Plus Cetuximab (EXTREME) for Advanced-stage Salivary Gland Cancer

Takafumi Nakano, Ryuji Yasumatsu, Kazuki Hashimoto, Ryosuke Kuga, Takahiro Hongo, Hidetaka Yamamoto, Mioko Matsuo, Takahiro Wakasaki, Rina Jiromaru, Tomomi Manako, Satoshi Toh, Muneyuki Masuda, Moriyasu Yamauchi, Yuichiro Kuratomi, Hideoki Uryu, Torahiko Nakashima, Akihiro Tamae, Risa Tanaka, Masahiko Taura, Toranoshin Takeuchi, Takamasa Yoshida, Takashi Nakagawa

In vivo (Athens, Greece) 36 ( 2 ) 979 - 984 2022.3

Publishing type：Research paper (scientific journal)

BACKGROUND/AIM: Surgery remains the standard treatment for salivary gland carcinoma (SGC). Our study investigated the association between epidermal growth factor receptor (EGFR) status in recurrent/metastatic SGC and the effectiveness of treatment with cisplatin/carboplatin and 5-fluorouracil plus cetuximab (EXTREME). PATIENTS AND METHODS: We retrospectively collected 19 SGCs from patients treated with the EXTREME regimen. After analyzing EGFR expression and gene copy number gain, we evaluated the correlation between EGFR status and clinicopathological factors and prognosis. RESULTS: EGFR overexpression was detected in 77.8% cases, but not statistically associated with clinicopathological factors or prognosis. EGFR gene copy number gain was detected in 16.7% cases, and statistically positively correlated with lymph node metastasis (p=0.0291). The best overall response was partial response in two cases, stable disease in 15, and progressive disease in one case. The EXTREME regimen was discontinued in all cases. CONCLUSION: Our results suggest that SGCs are positive for EGFR protein expression but the response rate to the EXTREME regimen was unremarkable.

DOI： 10.21873/invivo.12790

Salivary mucoepidermoid carcinoma: histological variants, grading systems, CRTC1/3-MAML2 fusions, and clinicopathological features. International journal

Satsuki Nakano, Yoshihide Okumura, Takayuki Murase, Toshitaka Nagao, Kimihide Kusafuka, Makoto Urano, Hidetaka Yamamoto, Satoshi Kano, Kiyoaki Tsukahara, Kenji Okami, Daisuke Kawakita, Toru Nagao, Nobuhiro Hanai, Hiroshi Iwai, Ryo Kawata, Yuichiro Tada, Ken-Ichi Nibu, Hiroshi Inagaki

Histopathology 80 ( 4 ) 729 - 735 2022.3

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

AIMS: To investigate the histological diversity of salivary mucoepidermoid carcinoma (MEC), its clinicopathological features, and its associations with CRTC1/3-MAML2 fusions. METHODS AND RESULTS: Salivary MEC cases (n = 177) were examined for CRTC1/3-MAML2 fusions, histological variants were classified, and tumours were graded according to four different grading systems. Adverse histological features considered to be unusual in MEC were also investigated. Of the 177 MEC cases, 110 were positive for CRTC1/3-MAML2 fusions. The classical variant was the most frequent in the fusion-positive case group, the fusion-negative case group, and the total case group. The clear/oncocytic variant was the second most frequent in the fusion-positive and total case groups. Oncocytic, Warthin-like and spindle variants were seen in the fusion-positive case group only. Clear cell, sclerosing, mucinous and central variants were seen in both the fusion-positive case group and the fusion-negative case group. No case was classified as a ciliated variant, as a mucoacinar variant, or as a high-grade transformation. As compared with the classical variant, non-classical variants were characterised by frequent CRTC1/3-MAML2 fusions and a low clinical stage in all cases. Of the four histological features considered to be unusual in MEC, marked nuclear atypia, frequent mitoses (>10/10 high-power fields) and extensive necrosis were found independently of the fusion status, and were present in 3-5% of all cases. However, none of the cases showed overt keratinisation. On comparison, the Armed Forces Institute of Pathology and modified Healey grading systems downgraded tumours, the Brandwein system upgraded tumours, and the Memorial Sloan Kettering system provided a moderate means of assessment. CONCLUSION: Recognition of the histological diversity of MEC, its clinicopathological features and its associations with CRTC1/3-MAML2 fusions is helpful for an accurate diagnosis of this carcinoma.

DOI： 10.1111/his.14586

Treatment Efficacy of PD-1 Inhibitor Therapy in Patients With Recurrent and/or Metastatic Salivary Gland Carcinoma. International journal

Kazuki Hashimoto, Ryuji Yasumatsu, Ryosuke Kuga, Takahiro Hongo, Hidetaka Yamamoto, Mioko Matsuo, Takahiro Wakasaki, Rina Jiromaru, Tomomi Manako, Satoshi Toh, Muneyuki Masuda, Moriyasu Yamauchi, Yuichiro Kuratomi, Hideoki Uryu, Torahiko Nakashima, Akihiro Tamae, Risa Tanaka, Masahiko Taura, Toranoshin Takeuchi, Takamasa Yoshida, Takashi Nakagawa

Anticancer research 42 ( 2 ) 981 - 989 2022.2

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

BACKGROUND/AIM: The efficacy of programmed cell death 1 (PD-1) inhibitor therapy for patients with recurrent and/or metastatic salivary gland carcinoma (R/M SGC) remains unclear. PATIENTS AND METHODS: We retrospectively analyzed 36 patients with R/M SGC treated with PD-1 inhibitor. The expression of programmed cell death ligand 1 (PD-L1) and mismatch repair (MMR) proteins was also analyzed. RESULTS: The objective response rate (ORR) was 11.1%. The histopathological subtypes of patients who achieved complete response or partial response were salivary duct carcinoma (SDC) in three patients and poorly differentiated carcinoma in one patient, all of whom showed a positive PD-L1 expression. The expression of MMR proteins was not associated with the efficacy of PD-1 inhibitors. CONCLUSION: Although the efficacy of PD-1 inhibitor therapy in R/M SGC is limited, certain patients may respond and achieve long-term disease control. There is a potential therapeutic effect in SDC patients with positive PD-L1 expression.

DOI： 10.21873/anticanres.15558

Lymphoid and myeloid proliferative disorders associated with inflammatory bowel disease: a clinicopathological study of 15 cases. International journal

Yoshifumi Hori, Hidetaka Yamamoto, Shinichiro Kawatoko, Yui Nozaki, Takehiro Torisu, Koji Kato, Yuhki Koga, Hiroaki Miyoshi, Koichi Ohshima, Yuki Tateishi, Shotaro Nakamura, Takanari Kitazono, Yoshinao Oda

Human pathology 120 88 - 98 2022.2

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

Lymphoproliferative disorder (LPD) can occur in patients with inflammatory bowel disease (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD). On rare occasions, patients with IBD develop myeloid neoplasms; however, the frequency and clinicopathological features of IBD-associated lymphoid and myeloid proliferative disorder (LMPD) in Japanese patients are still unclear. In this study, we reviewed 2474 Japanese patients with IBD and found that LMPD occurred in 12 (0.5%) patients with UC (n = 7) or CD (n = 5). Together with an additional 3 cases, we analyzed a total of 15 cases of LMPD for clinicopathological and histological features. Based on the status of using immunosuppressants such as biologics and immunomodulators, Epstein-Barr virus (EBV) infection, and histopathology, the 15 cases were classified into Group I (high-grade LPD; n = 7), Group II (low-grade LPD; n = 5), and Group III (myeloid neoplasms; n = 3). Most patients in Group I were undergoing strong immunosuppressive therapy, and the LPD lesions corresponded to high-grade B-cell or T cell/natural killer cell lymphoma often with EBV infection. Discontinuation of immunosuppressive drugs alone did not resolve these LPDs; Group I patients required chemotherapy, and eventually 4 of them (57%) died of the tumor. Most cases in Group II were low-grade B-cell lymphoma without EBV infection and had an indolent clinical course with excellent prognosis. All patients in Group III developed acute myeloid leukemia (AML) during the course of CD. Two (67%) of these patients died of AML. Our study suggests that IBD-associated LMPD is very rare but can follow an aggressive clinical course.

DOI： 10.1016/j.humpath.2021.12.010

Clinicopathological and histopathological review of dedifferentiated liposarcoma: a comprehensive study of 123 primary tumours. International journal

Taro Mori, Yuichi Yamada, Izumi Kinoshita, Kenichi Kohashi, Hidetaka Yamamoto, Yoshihiro Ito, Yosuke Susuki, Kengo Kawaguchi, Yasuharu Nakashima, Yoshinao Oda

Histopathology 80 ( 3 ) 538 - 557 2022.2

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

AIMS: Dedifferentiated liposarcoma (DDLS) has varying histopathological features, but their significance for the biological behaviour of this disease has not been fully clarified. The aim of this study was to elucidate the prognostic factors for DDLS by clinicopathologically reviewing a large case series. METHODS AND RESULTS: We clinicopathologically reviewed 123 cases of primary de-novo DDLS without preoperative treatment, including 81 in the internal trunk (internal DDLS) and 42 in peripheral sites (peripheral DDLS). Univariate and multivariate analyses of their features were also performed for all cases, the internal DDLS group, and the peripheral DDLS group. The results showed that, in all three groups, distant metastasis was significantly associated with shorter overall survival (OS) (univariate analysis, P < 0.0001, P = 0.0011, and P = 0.0101, respectively), whereas local recurrence showed no significant effect on prognosis. Histopathologically, a high mitotic count and the presence of round tumour cells were significantly associated with shorter OS in multivariate analysis of the internal DDLS group [respectively: P = 0.0022, hazard ratio (HR) 4.39, 95% confidence interval (CI) 1.71-11.28; and P = 0.0014, HR 7.19, 95% CI 2.14-24.16]. In the peripheral DDLS group, necrosis and high-grade histological components were significantly associated with shorter OS (univariate analysis, P = 0.0068 and P = 0.0174, respectively). CONCLUSIONS: The presence of round tumour cells may be one of the histological factors associated with a worse prognosis of DDLS patients, as previous studies indicated. This study also suggests that distant metastasis may be predictive of prognosis for both internal and peripheral DDLS, rather than local recurrence.

DOI： 10.1111/his.14588

High-risk HPV-related Squamous Cell Carcinoma in the Conjunctiva and Lacrimal sac: Clinicopathologic Characteristics and Diagnostic Utility of p16 and Rb Immunohistochemistry. International journal

Takahiro Hongo, Hidetaka Yamamoto, Mika Tanabe, Ryuji Yasumatsu, Ryosuke Kuga, Yoshiko Miyazaki, Rina Jiromaru, Kazuki Hashimoto, Yuki Tateishi, Koh-Hei Sonoda, Takashi Nakagawa, Yoshinao Oda

The American journal of surgical pathology 46 ( 7 ) 977 - 987 2022.1

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

High-risk human papillomavirus (HPV) infection in conjunctival and lacrimal sac squamous cell carcinomas (SCCs) has been sporadically reported; however, its prevalence, clinicopathologic significance and surrogate markers have not been fully elucidated. Here, we attempted to clarify these questions in Japanese patients with conjunctiva and lacrimal sac SCCs. We retrospectively collected 51 conjunctival SCC and 7 lacrimal sac SCC samples and analyzed them for (1) transcriptionally active high-risk HPV infection using messenger RNA in situ hybridization and (2) protein expressions of p16 and Rb using immunohistochemistry (IHC). Among a total of 58 cases, 25 (43.1%) and 16 (27.6%) tumors were positive for p16-IHC and HPV in situ hybridization, respectively. Ten (19.6%) of the 51 conjunctival SCCs, especially in the palpebral conjunctiva, and 6 (85.7%) of the 7 lacrimal sac SCCs were positive for high-risk HPV. High-risk HPV infection was significantly associated with younger patients, nonkeratinizing SCC histology, p16-positivity and partial loss of Rb expression, but not with recurrence risk. Notably, p16-IHC was not a perfect surrogate marker for high-risk HPV infection; only 64% (16/25) of p16-positive tumors were positive for high-risk HPV. In contrast, the p16+/Rb partial loss pattern was exclusively correlated with high-risk HPV-positivity. The results suggest that the combination of p16 and Rb expression patterns by IHC could be a useful method to predict high-risk HPV infection in conjunctival and lacrimal sac SCCs. HPV infection may be of less prognostic value in this field of cancers.

DOI： 10.1097/PAS.0000000000001857

An Analysis of 20 Cases of Radiation-Associated Sarcoma, Including 4 Cases Treated by Carbon Ion Radiotherapy. International journal

Takahito Negishi, Akira Matsunobu, Makoto Endo, Ryouhei Yokoyama, Shuhei Kusano, Nobuki Furubayashi, Kenichi Taguchi, Yoshiyuki Shioyama, Keiichiro Iida, Toshifumi Fujiwara, Nokitaka Setsu, Yoshihiro Matsumoto, Yasuharu Nakashima, Kenichi Kohashi, Hidetaka Yamamoto, Yoshinao Oda, Motonobu Nakamura

Oncology 100 ( 3 ) 148 - 154 2022

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

INTRODUCTION: Radiation-associated sarcoma (RAS) is one of the most life-threatening complications associated with the treatment of malignant neoplasms. Because all RAS patients have a history of radiotherapy, there have been no effective treatment options when RAS is not completely resected. METHODS: We retrospectively reviewed 20 RAS patients, including 4 unresectable cases treated by carbon ion radiotherapy (CIRT). RESULTS: The primary diseases targeted by radiotherapy included malignant lymphoma (n = 4), cervical cancer (n = 3), pharyngeal cancer (n = 3), breast cancer (n = 2), lung cancer (n = 1), rectal cancer (n = 1), maxillary cancer (n = 1), synovial sarcoma (n = 1), and benign neoplasms (n = 4). The histological diagnoses of RAS included osteosarcoma (n = 8), leiomyosarcoma (n = 3), undifferentiated pleomorphic sarcoma (n = 3), rhabdomyosarcoma (n = 1), angiosarcoma (n = 1), malignant peripheral nerve sheath tumor (n = 1), spindle cell sarcoma NOS (n = 1), and sarcoma not further specified (n = 2). The median survival time from the diagnosis of RAS was 26 months. Eleven patients underwent surgery. Five of these patients achieved a continuous disease free (CDF) status or showed no evidence disease. Four patients underwent CIRT. One of these patients with leiomyosarcoma achieved a CDF status, and the other patient with osteosarcoma achieved a partial response. On the other hand, 2 patients experienced grade 3 toxicities that required surgical treatment. CONCLUSION: RAS originates from various types of diseases that are treated by radiotherapy and shows diverse pathological features. Complete resection achieves a good prognosis. CIRT can be an effective and feasible option for unresectable RAS.

DOI： 10.1159/000521504

Activating HRAS mutation in a case of inverted ductal papilloma of the salivary gland. International journal

Fumio Ide, Yumi Ito, Kentaro Kikuchi, Kazuhito Satomura, Ikuko Ogawa, Hidetaka Yamamoto

Pathology international 71 ( 12 ) 844 - 848 2021.12

Language：English

Inverted ductal papilloma (IDP) is one of the least common benign papillary/cystic neoplasms of the salivary duct system, being characterized histologically by florid hyperplasia of duct-type epithelial cells into a cystic lumen near the orifice with occasional endophytic growth of the surface squamous epithelium along the terminus of the affected excretory duct. Given its rarity, the exact etiology of IDP remains to be defined. We herein present the first evidence of oncogenic HRAS mutation in a case of oral IDP. This finding, together with the frequent and specific BRAF mutations in sialadenoma papilliferum reported in the recent literature, supports an active role of the MAP-kinase cascade in the pathogenesis of benign papillary neoplasms of terminal duct origin.

DOI： 10.1111/pin.13166

Prognostic implication of desmoplastic stroma in synovial sarcoma: A histological review. International journal

Yu Toda, Yuichi Yamada, Kenichi Kohashi, Shin Ishihara, Yoshihiro Ito, Yosuke Susuki, Kengo Kawaguchi, Izumi Kinoshita, Daisuke Kiyozawa, Taro Mori, Yusuke Kuboyama, Yuki Tateishi, Hidetaka Yamamoto, Toshifumi Fujiwara, Nokitaka Setsu, Makoto Endo, Yoshihiro Matsumoto, Yasuharu Nakashima, Masaaki Mawatari, Yoshinao Oda

Pathology, research and practice 228 153668 - 153668 2021.12

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

Synovial sarcoma (SS) is a malignant soft tissue neoplasm harboring SS18-SSX fusion gene and is histologically characterized by spindle cells and epithelial components. Some investigations have demonstrated that desmoplastic reaction (DR) is an independent prognostic factor of cancers. However, it remains unknown whether DR is of predictive value for the prognosis of synovial sarcoma patients. Here, we reviewed the clinical and histological findings of 88 patients with SS. We defined DR as hyalinized collagenous structures and classified the degree of DR as follows: none, mild, moderate, and severe. Overall, 23 SS cases (24%) showed moderate or severe DR histologically. Statistically, the cases with moderate or severe degree of DR showed poorer prognosis than those with no or mild DR (local recurrence: P = 0.0059, distant metastasis: P = 0.0002, tumor death: P = 0.0382). The findings of the study suggest that the DR of synovial sarcoma could be an important prognostic factor.

DOI： 10.1016/j.prp.2021.153668

Alveolar soft part sarcoma of the orbit: A case report. International journal

Takeshi Oda, Kazufumi Kikuchi, Osamu Togao, Shingo Baba, Masahiro Mizoguchi, Mika Tanabe, Mamoru Ito, Hidetaka Yamamoto, Kousei Ishigami, Akio Hiwatashi

Radiology case reports 16 ( 12 ) 3766 - 3771 2021.12

Language：English

Alveolar soft part sarcoma is a rare soft tissue neoplasm that accounts for approximately 1% of all sarcomas and is usually identified in the extremities in adults. The occurrence of alveolar soft part sarcoma in the orbit is extremely rare, estimated at approximately 5% - 15% among all cases of alveolar soft part sarcoma . Here, we present a case of 29-year-old woman with orbital alveolar soft part sarcoma. We describe the magnetic resonance and F-18 2-fluoro-2-deoxy-D-glucose-position emission tomography/computed tomography findings of this case. This young woman had a spindle-shaped mass. A higher signal compared to the extraocular muscle on T1-weighted images, numerous flow voids on T2-weighted images, and intense enhancement could be key findings of this disease.

DOI： 10.1016/j.radcr.2021.09.005

Pathological review of cardiac amyloidosis using autopsy cases in a single Japanese institution. International journal

Yuki Tateishi, Yuichi Yamada, Masato Katsuki, Takuya Nagata, Hidetaka Yamamoto, Kenichi Kohashi, Yutaka Koga, Mikiko Hashisako, Daisuke Kiyozawa, Taro Mori, Yusuke Kuboyama, Ayumi Kakinokizono, Yoshiko Miyazaki, Aina Yamaguchi, Hiroyuki Tsutsui, Toshiharu Ninomiya, Hironobu Naiki, Yoshinao Oda

Pathology, research and practice 227 153635 - 153635 2021.11

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

AIM: Amyloidosis is a systemic or localized disease of protein deposition characterized by amorphous eosinophilic morphology and positivity of Congo Red staining. The typing of amyloidosis is becoming increasingly important because therapeutic agents for each amyloidosis type have been developed. Herein, the authors review the autopsy cases at an institution to reveal the putative Japanese characteristics of each amyloidosis type and evaluate the clinicopathological significance of each type. MATERIALS AND METHODS: A total of 131 autopsy cases of systemic and localized amyloidosis were retrieved for classification by immunohistochemistry. Immunohistochemistry for transthyretin, amyloid A (AA), immunoglobulin light-chain kappa and lambda, and β2-microglobulin was performed for all cases. RESULTS: The 131 amyloidosis cases were classified as follows: 71 cases (54.2%) of transthyretin amyloidosis, 32 cases (24.4%) of AA amyloidosis, 8 cases (6.1%) of light-chain amyloidosis, and 5 cases (3.8%) of β2-microglobulin amyloidosis, along with 15 equivocal cases (11.5%). All cases showed myocardial involvement of amyloidosis. Histopathologically, the transthyretin type was significantly associated with the interstitial and nodular patterns, and with the absence of the perivascular and endocardial patterns. The AA type was significantly associated with the perivascular and endocardial patterns, and with the absence of the nodular pattern. CONCLUSION: The authors revealed the putative characteristics of cardiac amyloidosis in Japan by using autopsy cases. About 90% of amyloidosis cases were successfully classified using only commercially available antibodies.

DOI： 10.1016/j.prp.2021.153635

Carcinoma showing thymus-like differentiation (CASTLE) of the salivary gland: Report of 2 cases of a hitherto under-recognized extrathyroid counterpart. International journal

Hidetaka Yamamoto, Kimihide Kusafuka, Yui Nozaki, Tomohiro Iwasaki, Miwako Nogami, Takahiro Hongo, Ryuji Yasumatsu, Yoshinao Oda

Pathology, research and practice 227 153646 - 153646 2021.11

Language：English

Carcinoma showing thymus-like differentiation (CASTLE) outside the thyroid gland is extremely rare. Here we report two cases of CASTLE of the major salivary gland. The tumors occurred in the parotid gland of a 31-year-old female (Case 1) and in the submandibular gland of a 40-year-old female (Case 2). Both tumors showed a lobulated growth pattern, and were histologically composed of a nested or sheet-like proliferation of carcinoma cells with round- to oval-shaped nuclei, distinct nucleoli and pale eosinophilic cytoplasm, accompanied by various degrees of lymphocytic infiltration. Immunohistochemical staining revealed that the tumors were positive for pan-cytokeratin, p40, CD5, CD117 and bcl-2. In addition, PD-L1 expression was seen in 10-90% of tumor cells. After the initial surgery, Case 1 remained tumor-free for 20 months, while Case 2 suffered lymph node recurrence at 4 months, followed by lung metastasis, which was treated with chemoradiotherapy and anti-PD-1 immune checkpoint inhibitor, resulting in a partial response. The present findings indicate that an extrathyroid counterpart of CASTLE can occur as a primary salivary gland neoplasm. Salivary CASTLEs seem to show a wide range of biological behavior, and long-term follow-up may be needed. Immune checkpoint inhibitor targeting PD-1 might become a promising treatment option in patients with CASTLE; however, further study with a larger number of cases is necessary to establish the optimal therapeutic strategy and prognostic factors for this rare cancer.

DOI： 10.1016/j.prp.2021.153646

Evaluation of MR imaging findings differentiating parotid basal cell adenomas from other parotid tumors. International journal

Yuriko Murayama, Takeshi Kamitani, Koji Sagiyama, Yuzo Yamasaki, Tomoyuki Hida, Yuko Matsuura, Ryuji Yasumatsu, Hidetaka Yamamoto, Hidetake Yabuuchi, Kousei Ishigami

European journal of radiology 144 109980 - 109980 2021.11

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

PURPOSE: To evaluate the usefulness of magnetic resonance imaging (MRI) to differentiate basal cell adenomas (BCAs) from other parotid tumors. METHOD: A total of 136 patients with histologically proven parotid gland tumors (13 BCAs, 66 pleomorphic adenomas [PAs], 30 Warthin tumors [WTs], and 27 parotid cancers [PCs]) who underwent a cervical MRI study between December 2011 and March 2019 were retrospectively enrolled. The MRI findings of the tumors were evaluated by two board-certified radiologists. RESULTS: All 13 of the BCAs showed smooth margins, while 19 of the 27 PCs showed irregular margins (p < 0.0001). Eleven BCAs had some cystic components, and five were cyst-dominant. The BCAs had significantly more cystic components than the PAs (p = 0.0077). The mean apparent diffusion coefficient (ADC) value of the BCAs was 1.21 ± 0.20 × 10-3 mm2/sec, which was equivalent to that of the PCs (1.12 ± 0.25 × 10-3 mm2/sec, p = 0.76), significantly lower than that of the PAs (1.61 ± 0.32 × 10-3 mm2/sec, p < 0.0001), and significantly higher than that of the WTs (0.81 ± 0.19 × 10-3 mm2/sec, p = 0.0004). The plateau time-intensity curve (TIC) was the most common type for both BCAs and PCs, seen in 8 of 12 BCAs and 21 of 26 PCs, with no significant difference between these groups (p = 0.34). CONCLUSIONS: BCA should be considered a possibility when a parotid lesion has smooth margins with an entire capsule and includes a cystic component, even if the TIC and diffusion-weighted MR images suggest a malignant pattern.

DOI： 10.1016/j.ejrad.2021.109980

Does the Use of Peripheral Immune-Related Markers Indicate Whether to Administer Pazopanib, Trabectedin, or Eribulin to Advanced Soft Tissue Sarcoma Patients? International journal

Eijiro Shimada, Makoto Endo, Yoshihiro Matsumoto, Kenji Tsuchihashi, Mamoru Ito, Hitoshi Kusaba, Akira Nabeshima, Tomoya Nawata, Akira Maekawa, Tomoya Matsunobu, Nokitaka Setsu, Toshifumi Fujiwara, Keiichiro Iida, Makoto Nakagawa, Takeshi Hirose, Masaya Kanahori, Ryunosuke Oyama, Taichi Isobe, Hiroshi Ariyama, Kenichi Kohashi, Hidetaka Yamamoto, Yoshinao Oda, Yukihide Iwamoto, Koichi Akashi, Eishi Baba, Yasuharu Nakashima

Journal of clinical medicine 10 ( 21 ) 2021.10

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

Pazopanib, trabectedin, and eribulin are administered for the treatment of soft tissue sarcomas (STSs); however, there is little consensus on which agent should be preferentially used in a clinical setting. This study assessed whether peripheral immune-related markers served as a useful reference when selecting pazopanib, trabectedin, or eribulin. This study included 63 patients who were administered pazopanib, trabectedin, or eribulin for advanced STSs between March 2015 and December 2020. Patients were divided into three groups based on the first drug administered among these three drugs. Differences in overall survival (OS) or progression-free survival (PFS) among the three groups were analyzed. OS showed no significant differences among the drugs administered first. For patients with low neutrophil-to-lymphocyte ratio (NLR), the OS of patients administered pazopanib as the first choice was shorter than the others (hazard ratio [HR] = 9.53, 95% confidence interval [CI] = 1.94-18.13, p = 0.0018). In the low platelet-to-lymphocyte ratio (PLR) subgroup, the OS of the patients administered eribulin for the first choice was longer than that of the others (HR = 0.32, 95%CI = 0.10-0.98, p = 0.046). Therefore, NLR and PLR might be used as prognostic indicators to dictate whether STS patients receive pazopanib, trabectedin, or eribulin.

DOI： 10.3390/jcm10214972

A multi‐institutional study of salivary gland cytopathology: Application of the Milan System for Reporting Salivary Gland Cytopathology in Japan

Kayoko Higuchi, Makoto Urano, Jun Akiba, Miwako Nogami, Yukiya Hirata, Yoko Zukeran, Koki Moriyoshi, Yuichiro Tada, Mana Fukushima, Mariko Obayashi, Shinnichi Sakamoto, Kazuya Kuraoka, Kana Kira, Akihiko Kawahara, Taku Kato, Maki Tanigawa, Masato Nakaguro, Hidetaka Yamamoto, Toshitaka Nagao

Cancer Cytopathology 130 ( 1 ) 30 - 40 2021.9

生物学的製剤使用の患者におけるメトトレキサート関連リンパ腫の後方視的研究(Clinical outcome of methotrexate-associated lymphoproliferative disorders)

原田卓哉, 岩崎浩己, 牟田毅, 浦田慎吾, 坂本愛子, 河野健太郎, 高瀬謙, 宮村知也, 澤部琢哉, 麻奥英毅, 押領司健介, 藤崎智明, 森康雄, 吉本五一, 綾野雅宏, 三苫弘喜, 宮本敏浩, 新納宏昭, 山元英崇, 大城由美, 三好寛明, 大島孝一, 竹下盛重, 加藤光次, 赤司浩一

日本血液学会学術集会 83回 OS1 - 2 2021.9

Genetic and transcriptomic analyses in a rare case of HPV-related oropharyngeal squamous cell carcinoma combined with small cell carcinoma. International journal

Kuniaki Sato, Kazuo Nishiyama, Kenichi Taguchi, Rina Jiromaru, Hidetaka Yamamoto, Akihide Matsunaga, Ryozaburo Nagata, Fumihide Rikimaru, Satoshi Toh, Yuichiro Higaki, Shinya Oda, Takashi Nakagawa, Muneyuki Masuda

Cold Spring Harbor molecular case studies 7 ( 5 ) 2021.8

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

Human papillomavirus (HPV)-related oropharyngeal small cell carcinoma (OPSmCC) is a rare malignancy with aggressive behavior, whereas HPV-related oropharyngeal squamous cell carcinoma (OPSqCC) displays a favorable prognosis. Notably, these two malignancies occasionally arise in an identical tumor. In this case study, we explored the molecular characteristics that distinguishes these two carcinomas employing a rare case of HPV-related oropharyngeal carcinoma (OPC) with the combined histology of SmCC and SqCC. Immunohistochemical analysis and HPV-RNA in situ hybridization (ISH) suggested that both SmCC and SqCC were HPV-related malignancies. Targeted exome sequencing revealed that SmCC and SqCC had no significant difference in mutations of known driver genes. In contrast, RNA sequencing followed by bioinformatic analyses suggested that aberrant transcriptional programs may be responsible for the neuroendocrine differentiation of HPV-related OPC. Compared to SqCC, genes upregulated in SmCC were functionally enriched in inflammatory and immune responses (e.g., arachidonic acid metabolism). We then developed a SmCC-like gene module (top 10 upregulated genes) and found that OPC patients with high module activity showed poor prognosis in The Cancer Genome Atlas (TCGA) and GSE65858 cohort. Gene set enrichment analysis of the SmCC-like gene module suggested its link to MYC proto-oncogene in the TCGA dataset. Taken together, these findings suggest that the SmCC-like gene module may contribute to acquisition of aggressive phenotypes and tumor heterogeneity of HPV-related OPC. The present case study is the first report of genetic and transcriptomic aberrations in HPV-related OPSmCC combined with SqCC.

DOI： 10.1101/mcs.a006102

Clinicopathological and prognostic significance of H3K27 methylation status in malignant peripheral nerve sheath tumor: correlation with skeletal muscle differentiation. International journal

Yoshihiro Ito, Kenichi Kohashi, Makoto Endo, Masato Yoshimoto, Shin Ishihara, Yu Toda, Yosuke Susuki, Kengo Kawaguchi, Hiroshi Furukawa, Yuki Tateishi, Yuichi Yamada, Izumi Kinoshita, Taro Mori, Hidetaka Yamamoto, Yasuharu Nakashima, Yoshinao Oda

Virchows Archiv : an international journal of pathology 479 ( 6 ) 1233 - 1244 2021.8

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

Malignant peripheral nerve sheath tumor (MPNST) is a very aggressive peripheral nerve sheath-derived sarcoma, which is one of the most difficult tumors to diagnose due to its wide spectrum of histological findings and lack of specific immunohistochemical markers. Recently, it has been reported that losses of expression of H3K27me3 and H3K27me2 caused by PRC2 dysfunction may be useful diagnostic markers for MPNST, but there is no consensus on their clinicopathological significance. Here, we investigated the relationship between loss of H3K27 methylation and various parameters and clarified the clinicopathological significance of such loss. We analyzed the clinicopathological and immunohistochemical features in 84 MPNST cases. Complete losses of H3K27me3 and H3K27me2 were observed in 37 (44%) and 29 (35%) cases, respectively. Losses of H3K27me3 and H3K27me2 were significantly correlated with myogenic immunopositivity (H3K27me3 vs. desmin, P = 0.0051; H3K27me3 vs. myogenin, P = 0.0009; H3K27me2 vs. myogenin, P = 0.042). Meanwhile, there were significant correlations between preservation of immunohistochemical neurogenic markers and intact H3K27me3 and H3K27me2 (H3K27me3 vs. S-100 protein, P = 0.0019; H3K27me3 vs. SOX10, P = 0.014; H3K27me2 vs. S-100 protein, P = 0.0011; H3K27me2 vs. SOX10, P = 0.0087). In multivariate analysis, local recurrence, distant metastasis, high FNCLCC grade, and loss of SOX10 expression were independent prognostic factors for overall survival. H3K27me3 and H3K27me2 expression was retained in all 26 cases of rhabdomyosarcoma non-alveolar subtype. In conclusion, we suggest that H3K27me3 and H3K27me2 immunonegativity is useful but not definitive for diagnosing MPNST. Complete loss of H3K27 methylation may be involved in aggressive transdifferentiation from neural differentiation to skeletal muscle differentiation in MPNST.

DOI： 10.1007/s00428-021-03189-0

Effect of the 2013 ASCO-CAP HER2 Testing Guideline on the Management of IHC/HER2 2+ Invasive Breast Cancer. International journal

Mai Yamada, Makoto Kubo, Hidetaka Yamamoto, Nami Yamashita, Masaya Kai, Karen Zaguirre, Kazuhisa Kaneshiro, Akiko Shimazaki, Saori Hayashi, Hitomi Kawaji, Masaki Mori, Yoshinao Oda, Masafumi Nakamura

Anticancer research 41 ( 8 ) 4143 - 4149 2021.8

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

BACKGROUND/AIM: With advances in anti-HER2 treatment and improved prognoses of HER2-positive breast cancer, the American Society of Clinical Oncology and the American Society of Pathologists (ASCO/CAP) have revised the HER2 diagnostic guidelines several times. We examined how to respond clinically to the revisions of the interpretation of the immunohistochemistry (IHC) method. PATIENTS AND METHODS: We re-evaluated 254 patients diagnosed as HER2 IHC equivocal, who underwent fluorescence in situ hybridization (FISH) before and after the IHC diagnostic criteria update in 2013. RESULTS: Twenty of 131 (15.3%) IHC equivocal cases by the ASCO/CAP 2007 guideline were IHC score 3+ and one of 20 (0.76%) was negative for FISH. Five of 123 (4.1%) IHC equivocal cases by the ASCO/CAP 2013 guideline were negative for IHC as per the 2007 guideline and four were positive for FISH. CONCLUSION: After revision of the ASCO/CAP 2013 guideline, 3.3% of HER2-negative cases before the revision should have received anti-HER2 treatment.

DOI： 10.21873/anticanres.15217

Tumor microenvironment in giant cell tumor of bone: evaluation of PD-L1 expression and SIRPα infiltration after denosumab treatment. International journal

Yu Toda, Kenichi Kohashi, Hidetaka Yamamoto, Shin Ishihara, Yoshihiro Ito, Yosuke Susuki, Kengo Kawaguchi, Daisuke Kiyozawa, Dai Takamatsu, Izumi Kinoshita, Yuichi Yamada, Junki Maehara, Atsushi Kimura, Sadafumi Tamiya, Kenichi Taguchi, Tomoya Matsunobu, Yoshihiro Matsumoto, Yasuharu Nakashima, Masaaki Mawatari, Yoshinao Oda

Scientific reports 11 ( 1 ) 14821 - 14821 2021.7

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

Giant cell tumor of bone (GCTB) is an intermediate malignant bone tumor that is locally aggressive and rarely metastasizes. Denosumab, which is a receptor activator of nuclear factor kappa B ligand (RANKL) inhibitor, can be used to treat GCTB. We focused on potential immunotherapy for GCTB and investigated the tumor microenvironment of GCTB. Programmed death-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) expression and signal-regulatory protein alpha (SIRPα), forkhead box P3 (FOXP3), and cluster of differentiation 8 (CD8) infiltration were assessed by immunohistochemical studies of 137 tumor tissues from 96 patients. Of the naive primary specimens, 28% exhibited PD-L1 expression and 39% exhibited IDO1 expression. There was significantly more SIRPα+, FOXP3+, and CD8+ cell infiltration in PD-L1- and IDO1-positive tumors than in PD-L1- and IDO1-negative tumors. The frequency of PD-L1 expression and SIRPα+ cell infiltration in recurrent lesions treated with denosumab was significantly higher than in primary lesions and recurrent lesions not treated with denosumab. PD-L1 expression and higher SIRPα+ cell infiltration were significantly correlated with shorter recurrence-free survival. PD-L1 and SIRPα immune checkpoint inhibitors may provide clinical benefit in GCTB patients with recurrent lesions after denosumab therapy.

DOI： 10.1038/s41598-021-94022-w

PD-L1 expression, tumor-infiltrating lymphocytes, mismatch repair deficiency, EGFR alteration and HPV infection in sinonasal squamous cell carcinoma. International journal

Takahiro Hongo, Hidetaka Yamamoto, Rina Jiromaru, Ryuji Yasumatsu, Ryosuke Kuga, Yui Nozaki, Kazuki Hashimoto, Mioko Matsuo, Takahiro Wakasaki, Akihiro Tamae, Kenichi Taguchi, Satoshi Toh, Muneyuki Masuda, Takashi Nakagawa, Yoshinao Oda

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 34 ( 11 ) 1966 - 1978 2021.7

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

The antitumor efficacies of immune checkpoint inhibitors (ICIs) and the usefulness of potential predictive markers such as programmed death-ligand 1 (PD-L1) expression, density of tumor-infiltrating lymphocytes (TILs) and microsatellite instability (MSI) in sinonasal squamous cell carcinoma (SNSCC) have not been fully elucidated. We retrospectively analyzed 131 SNSCCs with immunohistochemistry for PD-L1 expression, TIL subpopulations and loss of mismatch repair (MMR) proteins as a surrogate for MSI-high. We also comprehensively evaluated the mutual relationships among these immuno-markers, high-risk human papillomavirus (HPV) infection, epidermal growth factor receptor (EGFR) gene status, and KRAS mutation. PD-L1 expression (tumor proportion score ≥ 1%) was detected in 60 (45.8%) SNSCC cases and was significantly associated with worse overall survival (OS) (p = 0.0240). High density of cluster of differentiation 8 (CD8)-positive TILs was significantly associated with better progression-free survival (PFS) (p = 0.0368), and high density of forkhead box protein P3-positive TILs was significantly associated with better PFS and OS (p = 0.0007 and 0.0143, respectively). With respect to the combination of CD8 + TIL and PD-L1 expression, the high-CD8/PD-L1-negative group showed the most favorable prognosis, whereas the low-CD8/PD-L1-positive group showed the worst prognosis. MMR loss was detected in 3 (2.3%) of the 131 cases. HPV infection (6.1%), EGFR mutation (14.5%), EGFR copy number gain (26%), and MMR loss were essentially mutually exclusive; patients in these molecular groups showed significant differences in prognosis but not in the degree of PD-L1 expression or TILs. Among the nine ICI-treated patients, three (33.3%) were responders, and the EGFR-wild type cases (n = 7) showed better clinical responses to an ICI compared to the EGFR-mutant cases (n = 2). Among the patients with residual/recurrent EGFR-wild type tumors (n = 43), ICI treatment significantly improved OS (p = 0.0281). The results suggest that the evaluation of immuno-markers and molecular subclassification may be helpful for prognostic prediction and selecting an individualized therapeutic strategy for patients with SNSCC.

DOI： 10.1038/s41379-021-00868-w

Papillary craniopharyngioma coexisting with an intratumoral abscess in a pediatric patient: A case report and review of the literature. International journal

Katsuhiro Takagi, Kazufumi Kikuchi, Akio Hiwatashi, Osamu Togao, Yuhei Sangatsuda, Daisuke Kuga, Masahiro Mizoguchi, Hidetaka Yamamoto, Toru Iwaki, Kousei Ishigami

Acta radiologica open 10 ( 7 ) 20584601211030661 - 20584601211030661 2021.7

Language：English

Craniopharyngiomas are benign neoplasms with two histological subtypes: adamantinomatous and papillary. Papillary craniopharyngiomas are rare in children, and those with a pituitary abscess within are even rarer. Herein, we present the case of a 14-year-old boy with a papillary craniopharyngioma and a coexisting intratumoral abscess, who was hospitalized for persistent pyrexia, polyuria, and polydipsia. The absence of calcification on computed tomography, high signal intensity inside the tumor on diffusion-weighted imaging, and clinical findings such as fever, a high inflammatory response, and meningitis, as well as short-term morphological changes on imaging, could aid in diagnosis.

DOI： 10.1177/20584601211030661

Programmed Death-Ligand 1 Expression and Tumor-Infiltrating Lymphocytes in Temporal Bone Squamous Cell Carcinoma. International journal

Takahiro Hongo, Ryosuke Kuga, Masaru Miyazaki, Noritaka Komune, Takafumi Nakano, Hidetaka Yamamoto, Kensuke Koike, Kuniaki Sato, Ryunosuke Kogo, Kazuki Nabeshima, Yoshinao Oda, Takashi Nakagawa

The Laryngoscope 131 ( 12 ) 2674 - 2683 2021.6

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

OBJECTIVES/HYPOTHESIS: The tumor immune microenvironment in temporal bone squamous cell carcinoma (TBSCC), including the programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs), has not been established. STUDY DESIGN: Retrospective cohort study. METHODS: We performed immunohistochemistry analyses to retrospectively analyze 123 TBSCC cases for PD-L1 expression and TILs and their prognostic significance. We also evaluated the prognostic correlations between these immunomarkers and the therapeutic responses to chemoradiotherapy (CRT). RESULTS: PD-L1 expression (≥1%) was detected in 62 (50.4%) TBSCC cases and was significantly associated with worse prognosis: progression-free survival (PFS), P < .0001; overall survival (OS), P = .0009. A high density of CD8+ TILs was significantly associated with better prognosis (PFS, P = .0012; OS, P = .0120). In contrast, a high density of Foxp3+ TILs tended to be associated with an unfavorable prognosis (PFS, P = .0148; OS, P = .0850). With regard to the tumor microenvironment subtypes defined by CD8+ TILs and PD-L1 expression, the CD8low /PD-L1+ group showed significantly worse prognosis. Among the 36 neoadjuvant CRT-treated cases, PD-L1 expression was significantly associated with worse OS (P = .0132). Among the 32 CRT-treated cases without surgery, a high density of CD8+ TILs tended to be more highly associated with complete response to CRT compared to a low density of CD8+ TILs (P = .0702). CONCLUSIONS: These results indicate that the evaluation of the tumor immune microenvironment may contribute to the prediction of prognoses and the selection of an individualized therapeutic strategy for patients with TBSCC. LEVEL OF EVIDENCE: 4 Laryngoscope, 2021.

DOI： 10.1002/lary.29689

Alectinib-responsive infantile anaplastic ganglioglioma with a novel VCL-ALK gene fusion. International journal

Shunsuke Yamamoto, Yuhki Koga, Hiroaki Ono, Hironori Goto, Nobuhiro Hata, Hidetaka Yamamoto, Satoshi O Suzuki, Yasunari Sakai, Toru Iwaki, Shouichi Ohga

Pediatric blood & cancer 68 ( 9 ) e29122 2021.5

Histological background of dedifferentiated solitary fibrous tumour. International journal

Yuichi Yamada, Kenichi Kohashi, Izumi Kinoshita, Hidetaka Yamamoto, Takeshi Iwasaki, Masato Yoshimoto, Shin Ishihara, Yu Toda, Yoshihiro Ito, Yuki Kuma, Yui Yamada-Nozaki, Yutaka Koga, Mikiko Hashisako, Daisuke Kiyozawa, Daichi Kitahara, Fumiya Narutomi, Yusuke Kuboyama, Takahito Nakamura, Takeshi Inoue, Munenori Mukai, Yumi Honda, Gouji Toyokawa, Kenji Tsuchihashi, Fumiyoshi Fushimi, Kenichi Taguchi, Kenichi Nishiyama, Sadafumi Tamiya, Yumi Oshiro, Masutaka Furue, Yasuharu Nakashima, Satoshi Suzuki, Toru Iwaki, Yoshinao Oda

Journal of clinical pathology 75 ( 6 ) 397 - 403 2021.5

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

AIMS: Dedifferentiation is a histological phenomenon characterised by abrupt transition of histology to a sarcomatous component with high-grade malignant potential in solitary fibrous tumour (SFT). The authors histologically reviewed SFT cases to reveal the histological background of dedifferentiated SFTs. METHODS: Clinicopathological and histopathological findings of 145 SFT cases were reviewed. Immunohistochemical staining and genetic analysis were also performed. RESULTS: The non-dedifferentiated components showed a cellular component in 45 of 145 (31%), high mitotic rate (≥4/10 high-powered field) in 12 of 145 (8.2%) tumours, necrosis in 7 of 145 (4.8%) tumours, multinodular growth pattern in 39 of 132 (29.5%) available tumours and intratumoural fibrous septa in 37 of 131 (28.2%). Immunohistochemically, the non-dedifferentiated components were positive for CD34 in 128 of 141 (90.7%), bcl-2 in 101 of 133 (75.9%), nuclear pattern of β-catenin in 64 of 127 (50.3%) and p16 in 22 of 140 (15.7%). Loss of Rb protein expression was detected in 17 of 110 (15.4%) cases. Statistically, cellular component, multinodular structure, p16 overexpression and Rb protein loss were significantly associated with dedifferentiation. Moreover, cellular component and multinodular structure were significantly associated with p16 overexpression and Rb protein loss. All the non-deddifferentiated components showed wild type of p53 expression. The dedifferentiated components of all 10 dedifferentiated tumours presented positivity for p16 in 9 of 10 (90%) and mutational type of p53 in 5 of 10 (50%). Loss of Rb protein expression was detected in 6 of 10 (60%). CONCLUSIONS: The authors propose that cellular or multinodular transformation may be associated with dedifferentiation. They also suggest that cellular and multinodular transformation may be associated with p16 overexpression and Rb downregulation.

DOI： 10.1136/jclinpath-2020-207311

Myxoepithelioid tumor with chordoid feature: A clinicopathological, immunohistochemical, and genetic study of 14 cases of SMARCB1/INI1-deficient soft-tissue neoplasm. International journal

Izumi Kinoshita, Kenichi Kohashi, Hidetaka Yamamoto, Yuichi Yamada, Takeshi Inoue, Koichi Higaki, Norihiro Teramoto, Yumi Oshiro, Yasuharu Nakashima, Yoshinao Oda

Histopathology 79 ( 4 ) 629 - 641 2021.5

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

AIMS: Complete loss of SMARCB1/INI1 in soft-tissue tumors such as malignant rhabdoid tumor, epithelioid sarcoma, myoepithelial tumor of soft tissue, and extraskeletal myxoid chondrosarcoma is often associated with high-grade malignancy and poor prognosis. The diagnosis is sometimes challenging due to histological similarities, so careful differential diagnosis is required. Therefore, soft-tissue tumors with complete SMARCB1/INI1 loss could potentially include an unknown entity. METHODS AND RESULTS: We analyzed 160 cases of SMARCB1/INI1-deficient soft-tissue tumor and found 14 cases of tumors not classifiable into already existing categories and having common clinical and histological features. These involved 2 male and 12 female patients, ranging in age from 20 to 61 years. The tumors were located in the the pubo-inguinal region (n=13) and pelvic cavity (n=1). Histologically, the tumors showed relatively uniform epithelioid to spindle-shaped cells with myxoid stroma. All tumors showed immunoreactivity for brachyury, EMA, and PgR, while 12 of 14 cases did for ER. Variable positive staining for alpha-SMA, S-100 protein, and GFAP was seen. NR4A3 and EWSR1 gene rearrangements were not detected in 13 and 11 examined cases, respectively. Clinical follow-up data in the 14 patients showed 13 alive without disease and 1 lost to follow-up; 4 cases developed local recurrence and/or metastases. CONCLUSION: The designation "myxoepithelioid tumor with choroid feature" (METC) was proposed as a tumor with intermediate malignancy controllable by appropriate treatment, including the entity of myoepithelioma-like tumor of the vulvar region. METC is a novel and independent subset histologically, biologically, and clinically distinct from already existing SMARCB1/INI1-deficient soft-tissue tumors.

DOI： 10.1111/his.14393

The forkhead box M1 (FOXM1) expression and antitumor effect of FOXM1 inhibition in malignant rhabdoid tumor. International journal

Yuichi Shibui, Kenichi Kohashi, Akihiko Tamaki, Izumi Kinoshita, Yuichi Yamada, Hidetaka Yamamoto, Tomoaki Taguchi, Yoshinao Oda

Journal of cancer research and clinical oncology 147 ( 5 ) 1499 - 1518 2021.5

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

PURPOSE: Malignant rhabdoid tumor (MRT) is a rare, highly aggressive sarcoma with an uncertain cell of origin. Despite the existing standard of intensive multimodal therapy, the prognosis of patients with MRT is very poor. Novel antitumor agents are needed for MRT patients. Forkhead box transcription factor 1 (FOXM1) is overexpressed and is correlated with the pathogenesis in several human malignancies. In this study, we identified the clinicopathological and prognostic values of the expression of FOXM1 and its roles in the progression of MRT. METHODS: We investigated the FOXM1 expression levels and their clinical significance in 23 MRT specimens using immunohistochemistry and performed clinicopathologic and prognostic analyses. We also demonstrated correlations between the downregulation of FOXM1 and oncological characteristics using small interfering RNA (siRNA) and FOXM1 inhibitor in MRT cell lines. RESULTS: Histopathological analyses revealed that primary renal MRTs showed significantly low FOXM1 protein expression levels (p = 0.032); however, there were no significant differences in other clinicopathological characteristics or the survival rate. FOXM1 siRNA and FOXM1 inhibitor (thiostrepton) successfully downregulated the mRNA and protein expression of FOXM1 in vitro and the downregulation of FOXM1 inhibited cell proliferation, drug resistance to chemotherapeutic agents, migration, invasion, and caused the cell cycle arrest and apoptosis of MRT cell lines. A cDNA microarray analysis showed that FOXM1 regulated FANCD2 and NBS1, which are key genes for DNA damage repair. CONCLUSION: This study demonstrates that FOXM1 may serve as a promising therapeutic target for MRT.

DOI： 10.1007/s00432-020-03438-w

Outcomes of methotrexate-associated lymphoproliferative disorders in rheumatoid arthritis patients treated with disease-modifying anti-rheumatic drugs. International journal

Takuya Harada, Hiromi Iwasaki, Tsuyoshi Muta, Shingo Urata, Aiko Sakamoto, Kentaro Kohno, Ken Takase, Tomoya Miyamura, Takuya Sawabe, Hideki Asaoku, Kensuke Oryoji, Tomoaki Fujisaki, Yasuo Mori, Goichi Yoshimoto, Masahiro Ayano, Hiroki Mitoma, Toshihiro Miyamoto, Hiroaki Niiro, Hidetaka Yamamoto, Yumi Oshiro, Hiroaki Miyoshi, Koichi Ohshima, Morishige Takeshita, Koichi Akashi, Koji Kato

British journal of haematology 194 ( 1 ) 101 - 110 2021.4

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

Recently, the use of targeted synthetic or biological disease-modifying anti-rheumatic drugs (ts/bDMARDs) in addition to conventional synthetic (cs)DMARDs including methotrexate (MTX) for rheumatoid arthritis (RA) has increased. However, whether ts/bDMARDs are associated with the development and clinicopathological features of MTX-associated lymphoproliferative disorder (MTX-LPD) in patients with RA remains unknown. Therefore, we evaluated the clinical outcomes of 121 patients with MTX-LPD. Results showed that prior use of ts/bDMARDs was not associated with the different histopathological subtypes of MTX-LPD. Patients with polymorphic-type LPD had a better event-free survival than those with diffuse large B-cell lymphoma (DLBCL), classical Hodgkin lymphoma and peripheral T-cell lymphoma. The pathological subtype of lymphoma could predict the clinical outcome of MTX-LPD. In patients with DLBCL, the use of tumour necrosis factor-alpha (TNF-α) inhibitors prior to MTX-LPD onset was associated with a higher non-relapse mortality. Further, patients with RA previously treated with Janus kinase (JAK) inhibitors more commonly required chemotherapy than those treated with csDMARDs alone, indicating disease aggressiveness. Hence, special caution should be observed when managing patients with MTX-LPD previously treated with JAK or TNF-α inhibitors for RA.

DOI： 10.1111/bjh.17456

The association between the expression of PD-L1 and CMTM6 in undifferentiated pleomorphic sarcoma. International journal

Shin Ishihara, Takeshi Iwasaki, Kenichi Kohashi, Yuichi Yamada, Yu Toda, Yoshihiro Ito, Yousuke Susuki, Kengo Kawaguchi, Dai Takamatsu, Shinichiro Kawatoko, Daisuke Kiyozawa, Taro Mori, Izumi Kinoshita, Hidetaka Yamamoto, Toshifumi Fujiwara, Nokitaka Setsu, Makoto Endo, Yoshihiro Matsumoto, Yasuharu Nakashima, Yoshinao Oda

Journal of cancer research and clinical oncology 147 ( 7 ) 2003 - 2011 2021.4

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

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is a sarcoma with a poor prognosis. A clinical trial, SARC028, revealed that treatment with anti-PD-1 drugs was effective against UPS. Studies have reported that UPS expresses PD-L1, sometimes strongly (≥ 50%). However, the mechanism of PD-L1 expression in UPS has remained unclear. CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) was identified as a novel regulator of PD-L1 expression. The positive relationship between PD-L1 and CMTM6 has been reported in several studies. The aim of this study was thus to examine CMTM6 expression in UPS and evaluate the relationship between PD-L1 and CMTM6 in this disease. MATERIALS AND METHODS: Fifty-one primary UPS samples were subjected to CMTM6 and PD-L1 immunostaining. CMTM6 expression was assessed using proportion and intensity scores. CMTM6 gene copy number was also evaluated using a real-time PCR-based copy number assay. We also analyzed the mRNA expression and copy number variation of PD-L1 and CMTM6 in The Cancer Genome Atlas (TCGA) data. RESULTS: TCGA data indicated that the mRNAs encoded by genes located around 3p22 were coexpressed with CMTM6 mRNA in UPS. Both proportion and intensity scores of CMTM6 positively correlated with strong PD-L1 expression (≥ 50%) (both p = 0.023). CMTM6 copy number gain increased CMTM6 expression. Patients with UPS with a high CMTM6 intensity score had a worse prognosis for overall survival. CONCLUSIONS: UPS showed variation in CMTM6 copy number and CMTM6 expression. CMTM6 expression was significantly correlated with PD-L1 expression, especially with strong PD-L1 expression.

DOI： 10.1007/s00432-021-03616-4

Salivary Duct Carcinoma With Rhabdoid Features-No or Aberrant Expression of E-cadherin and Genetic Changes in CDH1: Immunohistochemical and Genetic Analyses of 17 Cases. International journal

Kimihide Kusafuka, Hidetaka Yamada, Keiko Ishino, Matsuyoshi Maeda, Koji Yamanegi, Satoshi Baba, Tomoyuki Ohuchi, Hiroshi Inagaki, Hidetaka Yamamoto, Tomohiro Iwasaki, Chinatsu Tsuchiya, Haruhiko Sugimura, Makoto Suzuki

The American journal of surgical pathology 45 ( 4 ) 439 - 449 2021.4

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

Salivary duct carcinoma is a relatively uncommon malignancy of the salivary glands; however, it frequently occurs as a carcinomatous component of carcinoma ex pleomorphic adenoma. We previously reported salivary duct carcinoma with rhabdoid features (SDCRF) as an extremely rare subtype of salivary duct carcinoma, and that it occurred as a salivary counterpart of pleomorphic lobular carcinoma of the breast (PLCB). We collected new cases of SDCRF for this study, in which we examined a total of 17 cases immunohistochemically and genetically. As it is known that PLCB exhibits loss of or aberrant E-cadherin expression and carries nonsense/missense mutations in or deletion of the CDH1 gene, we examined the CDH1 gene status of our SDCRF cases. All of the examined SDCRF cases involved the diffuse proliferation of large ovoid cells with eosinophilic cytoplasm and eccentric nuclei, which displayed reduced cell-cell adhesion. Most cases were positive for pan-cytokeratin, androgen receptor, gross cystic disease fluid protein-15, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1, and WI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4, whereas they were negative for vimentin. No and decreased/cytoplasmic E-cadherin expression was observed in 11 and 4 of 17 cases, respectively, whereas no and decreased/cytoplasmic β-catenin expression were observed in 10 and 5 of 17 cases, respectively. Among the 11 cases that could be genetically analyzed, a nonsense mutation (1 case), missense mutations (6 cases), and insertions (1 case) were detected in the CDH1 gene. In conclusion, we propose that SDCRF is the salivary counterpart of PLCB due to its morphology and immunophenotype, and the genetic status of CDH1.

DOI： 10.1097/PAS.0000000000001672

Brachyury expression in intracranial SMARCB1-deficient tumors: important points for distinguishing poorly differentiated chordoma from atypical teratoid/rhabdoid tumor. International journal

Kenichi Kohashi, Hidetaka Yamamoto, Yuichi Yamada, Izumi Kinoshita, Yoshinao Oda

Human pathology 112 1 - 8 2021.3

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

Loss of SMARCB1 protein expression has recently been identified in a variety of tumor types such as poorly differentiated chordoma (PCh) and malignant rhabdoid tumor (MRT) including atypical teratoid/rhabdoid tumor (AT/RT). PCh is characterized by poorly differentiated epithelioid tumor cells, sheet arrangement, and coexpression of nonepithelial and epithelial markers. Rhabdoid cells are sometimes present. Therefore, the differentiation of these tumors is often difficult. Brachyury is a transcription factor within the T-box family typically expressed in notochord tissue and chordomas. Some studies have reported high specificity and sensitivity of brachyury expression in chordomas. In the present study, we analyzed immunohistochemical brachyury expression in SMARCB1-deficient tumors and discuss important clinicopathological and diagnostic points, especially in cases of intracranial SMARCB1-deficient tumors with brachyury expression. Brachyury and cytokeratin immunoexpression status was examined in 42 formalin-fixed paraffin-embedded SMARCB1-deficient tumor specimens (PCh, 6 cases; extra-central nervous system [CNS] MRT, 26 cases; AT/RT, 10 cases) and 25 cases of conventional chordoma (CCh). All cases of PCh and CCh showed diffuse immunopositivities for cytokeratin 8, pan-cytokeratin, and brachyury. Brachyury immunoexpression was present in 2 extra-CNS MRT (8%) and 5 AT/RT (50%) cases, but immunopositivity was focal not diffuse. Indeed, in almost all cases of AT/RT (cytokeratin 8, 7/10 cases; pan-cytokeratin, 7/10 cases) and extra-CNS MRT (cytokeratin 8, 23/26 cases; pan-cytokeratin, 25/26 cases), fewer than 50% of cells showed immunoreactivity. Although the histological and clinical features of PCh resemble those of AT/RT, semiquantitative evaluations of the degree of brachyury and cytokeratin immunoexpressivity may help to distinguish PCh from AT/RT.

DOI： 10.1016/j.humpath.2021.03.001

Pathological evaluation of tumor grade for salivary adenoid cystic carcinoma: A proposal of an objective grading system. International journal

Naruhiko Morita, Takayuki Murase, Kaori Ueda, Toshitaka Nagao, Kimihide Kusafuka, Masato Nakaguro, Makoto Urano, Ken-Ichi Taguchi, Hidetaka Yamamoto, Satoshi Kano, Yuichiro Tada, Kiyoaki Tsukahara, Kenji Okami, Tetsuro Onitsuka, Yasushi Fujimoto, Daisuke Kawakita, Kazuo Sakurai, Toru Nagao, Nobuhiro Hanai, Ryo Kawata, Naohito Hato, Naoki Otsuki, Ken-Ichi Nibu, Hiroshi Inagaki

Cancer science 112 ( 3 ) 1184 - 1195 2021.3

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

Three pathological grading systems advocated by Perzin/Szanto, Spiro, and van Weert are currently used for adenoid cystic carcinoma (AdCC). In these systems, the amount or presence of the solid tumor component in AdCC specimens is an important index. However, the "solid tumor component" has not been well defined. Salivary AdCC cases (N = 195) were collected after a central pathology review. We introduced a novel criterion for solid tumor component, minAmax (minor axis maximum). The largest solid tumor nest in each AdCC case was histologically screened, the maximum oval fitting the solid nest was estimated, and the length of the minor axis of the oval (minAmax) was measured. The prognostic cutoff for the minAmax was determined using training and validation cohorts. All cases were evaluated for the four grading systems, and their prognostic impact and interobserver variability were examined. The cutoff value for the minAmax was set at 0.20 mm. Multivariate prognostic analyses showed the minAmax and van Weert systems to be independent prognostic tools for overall, disease-free, and distant metastasis-free survival while the Perzin/Szanto and Spiro systems were selected for overall survival but not for disease-free or distant metastasis-free survival. The highest hazard ratio for overall survival (11.9) was obtained with the minAmax system. The reproducibility of the minAmax system (kappa coefficient of 0.81) was scored as very good while those of the other three systems were scored as moderate. In conclusion, the minAmax is a simple, objective, and highly reproducible grading system useful for prognostic stratification for salivary AdCC.

DOI： 10.1111/cas.14790

Pan-tropomyosin receptor kinase immunoreactivity, ETV6-NTRK3 fusion subtypes, and RET rearrangement in salivary secretory carcinoma

Hidetaka Yamamoto, Yui Nozaki, Azusa Sugii, Kenichi Taguchi, Takahiro Hongo, Rina Jiromaru, Masanobu Sato, Takafumi Nakano, Kazuki Hashimoto, Minako Fujiwara, Yoshinao Oda

Human Pathology 109 37 - 44 2021.3

Publishing type：Research paper (scientific journal)

© 2020 Elsevier Inc. Salivary secretory carcinoma (SASC) is frequently associated with ETV6-neurotrophic tyrosine receptor kinase (NTRK) 3 fusion and more rarely with RET, MET, or ALK rearrangement. We aimed to elucidate the potential diagnostic utility of pan-tropomyosin receptor kinase (Trk) immunohistochemistry and its relationship with the fusion gene subtype in SASC. We examined 33 cases of SASC for immunoexpression of pan-Trk, ALK and ROS1, and gene rearrangement of the ETV6, NTRK3, and RET genes using fluorescence in situ hybridization (FISH) and reverse transcription-polymerase chain reaction (RT-PCR). Thirty (90.9%) of 33 SASCs harbored ETV6-NTRK3 fusion gene transcripts by RT-PCR and/or both ETV6 and NTRK3 gene rearrangements by FISH, and 3 cases (9.1%) had RET gene rearrangement. Most NTRK3-rearranged SASCs (27/33 cases; 81.8%) had conventional ETV6 exon 5-NTRK3 exon 15 fusion, whereas 2 cases (6.1%) had both the conventional fusion and a novel ETV6 exon 4-NTRK3 exon 15 fusion variant. In the remaining one case (3%), only FISH revealed both ETV6 and NTRK3 rearrangements, suggesting an ETV6-NTRK3 fusion with an as yet undetermined break point. All 30 SASCs with ETV6-NTRK3 fusion and/or NTRK3 rearrangement showed nuclear and cytoplasmic immunoreactivity for pan-Trk. In contrast, 3 SASCs with RET rearrangement showed negative or only weak cytoplasmic staining for pan-Trk. There was no case harboring ALK and ROS1 rearrangements. All 17 non-SASC tumors were negative for pan-Trk. The results suggest that nuclear and cytoplasmic immunoreactivity for pan-TRK may be helpful to identify ETV6-NTRK3–fused SASCs and to distinguish them from RET-rearranged SASCs and morphological mimics.

DOI： 10.1016/j.humpath.2020.11.017

p16 overexpression and Rb loss correlate with high-risk HPV infection in oropharyngeal squamous cell carcinoma. International journal

Rina Jiromaru, Hidetaka Yamamoto, Ryuji Yasumatsu, Takahiro Hongo, Yui Nozaki, Takafumi Nakano, Kazuki Hashimoto, Takashi Nakagawa, Yoshinao Oda

Histopathology 79 ( 3 ) 358 - 369 2021.1

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

AIMS: p16 is a sensitive surrogate marker for transcriptionally active high-risk human papillomavirus (HR-HPV) infection in oropharyngeal squamous cell carcinoma (OPSCC), but it is not sufficient in all clinical settings. METHODS AND RESULTS: We examined the p16 and Rb expression status in 177 OPSCC cases by immunohistochemistry and the presence of transcriptionally active HR-HPV infection by mRNA in-situ hybridisation. The 177 cases were divided into p16+ /HPV+ (n = 105, 59.3%), p16+ /HPV- (n = 8, 4.5%) and p16- /HPV- (n = 64, 36.2%) groups. The p16+ /HPV- and p16- /HPV- groups had a trend towards worse overall survival (OS) or significantly worse OS than the p16+ /HPV+ group (n = 105) (P = 0.0610, P = 0.0004, respectively). We divided the Rb status into preserved expression (> 90%, n = 68), partial loss (PL) (10-90%, n = 97) and complete loss (CL) (< 10%, n = 12). Among the HPV-positive cases (n = 105), the Rb pattern was typically PL (n = 97, 92.4%) and rarely CL (n = 8, 7.6%), but never preserved expression (0%). In contrast, among the HPV-negative cases (n = 72), the Rb pattern was typically preserved expression (n = 68, 94.4%) and rarely CL (n = 4, 5.6%), but never PL (0%). Compared to p16 alone, the combination of p16 overexpression and Rb-PL/CL showed equally excellent sensitivity (each 100%) and improved specificity (97.2 versus 88.9%) and positive predictive values (98.1 versus 92.9%). CONCLUSIONS: These results suggest that the combined use of p16 and Rb immunohistochemistry could be a reliable, cost-effective method to predict HR-HPV infection in OPSCCs; however, HPV specific testing is necessary on inconclusive cases. We propose a diagnostic algorithm for practical use of these markers.

DOI： 10.1111/his.14337

Comprehensive molecular profiling broadens treatment options for breast cancer patients

Hitomi Kawaji, Makoto Kubo, Nami Yamashita, Hidetaka Yamamoto, Masaya Kai, Atsuko Kajihara, Mai Yamada, Kanako Kurata, Kazuhisa Kaneshiro, Yurina Harada, Saori Hayashi, Akiko Shimazaki, Hitomi Mori, Sayuri Akiyoshi, Eiji Oki, Yoshinao Oda, Eishi Baba, Masaki Mori, Masafumi Nakamura

Cancer Medicine 10 ( 2 ) 529 - 539 2021.1

Publishing type：Research paper (scientific journal)

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. Precision oncology with next generation sequencing (NGS) using tumor tissue with or without blood has begun in Japan. Tumor molecular profiling tests are available, including the OncoGuide™ NCC Oncopanel System and FoundationOne® CDx (F1CDx). Our purpose was to identify potentially actionable genetic alterations in breast cancer with this comprehensive tumor profiling test. We enrolled 115 patients with pathologically diagnosed advanced or metastatic breast cancer. Comprehensive tumor genomic profiling, microsatellite instability, and tumor mutational burden (TMB) were determined using F1CDx. Testing was successful in 109/115 cases (94.8%). Clinically actionable alterations were identified in 76% of advanced breast cancer patients. The most frequent short variants were in TP53 (48.6%), PIK3CA (38.5%), GATA3 (11.0%), PTEN (11.0%), and BRCA1 (10.1%), and structural variants were in ERBB2 (24.8%), MYC (21.1%), RAD21 (21.1%), CCND1 (11.9%), FGF19 (10.1%), and PTEN (10.1%). Regarding human epidermal growth factor receptor (HER)2 status, 106/109 samples (97.2%) were concordant between F1CDx and HER2 testing with immunohistochemistry/fluorescence in situ hybridization. However, ERBB2 amplification was newly detected in four samples and ERBB2 mutations were detected in five HER2-negative breast cancer samples. Oncogenic BRCA mutations were found in three samples with F1CDx among 27 germline testing-negative samples. The mean TMB in all samples was 6.28 mut/Mb and tended to be higher in luminal B and triple-negative breast cancer (mean = 8.1 and 5.9 mut/Mb, respectively) compared with other subtypes. In conclusion, we established a system for precision oncology and obtained preliminary data with NGS as the first step. The information in this clinical sequencing panel will help guide the development of new treatments for breast cancer patients.

DOI： 10.1002/cam4.3619

Clinicopathologic significance of EGFR mutation and HPV infection in sinonasal squamous cell carcinoma Reviewed International journal

Takahiro Hongo, Hidetaka Yamamoto, Rina Jiromaru, Yui Nozaki, Ryuji Yasumatsu, Kazuki Hashimoto, Reiko Yoneda, Azusa Sugii, Kenichi Taguchi, Muneyuki Masuda, Takashi Nakagawa, Yoshinao Oda

American Journal of Surgical Pathology 45 ( 1 ) 108 - 118 2021.1

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

© 2020 Wolters Kluwer Health, Inc. All rights reserved. Sinonasal squamous cell carcinoma (SNSCC) is sometimes associated with high-risk human papillomavirus (HR-HPV) infection and inverted sinonasal papilloma or oncocytic sinonasal papilloma. Frequent mutations of EGFR and KRAS are reported in inverted sinonasal papilloma-related sinonasal squamous cell carcinoma (ISP-SCC) and oncocytic sinonasal papilloma-related SNSCC, respectively. Here, we attempted to determine the prevalence and the prognostic significances of these alterations in SNSCC. We retrospectively collected 146 SNSCCs, including 14 ISP-SCCs, and comprehensively analyzed the HR-HPV infection by human papillomavirus (HPV)-RNA in situ hybridization, EGFR gene copy number gain (CNG) by chromogenic in situ hybridization, and gene mutations in EGFR and KRAS by Sanger sequencing. HR-HPV was detected in 11 cases (7.5%), whereas all 14 ISP-SCCs were negative. EGFR mutations were present in 21 (14.7%) of 143 SNSCCs, including 13/14 (92.9%) ISP-SCCs and 8/129 (6.2%) non-ISP-SCCs (P<0.0001). The majority of EGFR mutations were exon 20 insertions, with the remainder composed of deletions and single-nucleotide substitutions in exons 19 and 20. All of 142 SNSCCs harbored no KRAS mutation. EGFR CNG was detected in 41 (28.1%) of 146 SNSCCs; all of them were HPV negative and 3 had EGFR mutations. Collectively, EGFR mutation, EGFR CNG, and HR-HPV were essentially mutually exclusive, and each subgroup had distinct clinicopathologic features. The HPV-negative/EGFR-mutant group, the HPV-negative/EGFR CNG-positive group, and the triple-negative group had significantly worse prognoses than the HPV-positive group (P=0.0265, 0.0264, and 0.0394, respectively). In conclusion, EGFR mutation may play a pathogenetically important role in some populations of SNSCCs, especially ISP-SCCs. The molecular subclassification of SNSCCs may contribute to prognostic prediction and molecular-targeted precision medicine.

DOI： 10.1097/PAS.0000000000001566

PD-L1 and IDO-1 expression in undifferentiated pleomorphic sarcoma: The associations with tumor infiltrating lymphocytes, dMMR and HLA class I

Shin Ishihara, Yuichi Yamada, Takeshi Iwasaki, Masato Yoshimoto, Yu Toda, Kenichi Kohashi, Hidetaka Yamamoto, Yoshihiro Matsumoto, Yasuharu Nakashima, Yoshinao Oda

Oncology Reports 45 ( 1 ) 379 - 389 2021.1

Publishing type：Research paper (scientific journal)

© 2021 Spandidos Publications. All rights reserved. The prognosis of undifferentiated pleomorphic sarcoma (UPS) is generally unfavorable. Recently, clinical trials such as SARC028 demonstrated the utility of cancer immunotherapy for soft tissue sarcomas. The aim of the present study was to assess the expression of PD-L1 and IDO-1 as prognostic factors and therapeutic targets. A total of 52 primary UPS cases were retrieved and two UPS cell lines were utilized for supplementary analysis. Immunohistochemical staining of anti-PD-L1 (28-8), IDO-1, CD8, CD4, CD3, HLA class I, MSH2, MSH6, MLH1 and PMS2 was carried out. Immunohistochemically, 19 of 52 (36.5%) cases showed PD-L1 expression at least focally (≥1%) and 5 of 52 (9.62%) showed strong PD-L1 expression (≥50%). Overall, 25 of 52 (48.1%) cases expressed IDO-1 (≥1%). Two tumors were evaluated as having deficient mismatch repair and six tumors as having the loss of HLA class I. PD-L1 expression (≥1%) was significantly related to the infiltration of CD8- and CD3-positive lympho- cytes, but strong PD-L1 expression (≥50%) did not present a significant relationship with tumor-infiltrating lymphocytes. IDO-1 expression was also associated with CD8-, CD4-, and CD3-positive lymphocytes. In vitro, both PD-L1 and IDO-1 were induced by IFN-γ stimulation. In survival analysis, strong PD-L1 expression (≥50%) was a significant poor prognostic factor, while IDO-1 expression (≥1%) was a favorable one. In conclusion, UPS was shown to frequently express PD-L1 and IDO-1. It was suggested that PD-L1 expression (≥50%) and IDO-1 expression are poor and favorable prognostic factors of UPS patients, respectively.

DOI： 10.3892/or.2020.7837

Genomic Sequencing of Cancer-related Genes in Sinonasal Squamous Cell Carcinoma and Coexisting Inverted Papilloma. International journal

Ryutaro Uchi, Rina Jiromaru, Ryuji Yasumatsu, Hidetaka Yamamoto, Takahiro Hongo, Tomomi Manako, Kuniaki Sato, Kazuki Hashimoto, Takahiro Wakasaki, Mioko Matsuo, Takashi Nakagawa

Anticancer research 41 ( 1 ) 71 - 79 2021.1

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

BACKGROUND: The genetic basis of sinonasal inverted papilloma (SNIP)-derived squamous cell carcinoma (SCC) has not yet been well characterized. AIM: To characterize the genetic abnormalities of SNIP and SNIP-derived SCC and to uncover their differences. MATERIALS AND METHODS: Mutations of 409 genes were analyzed using amplicon targeted sequencing in a total of six papilloma/carcinoma samples from four patients with SNIP-derived SCC. RESULTS: The genes that were mutated in multiple cases were epidermal growth factor receptor (EGFR) (3/6), cyclin-dependent kinase inhibitor 2A (CDKN2A) (3/6), lysine methyltransferase 2D (KMT2D) (3/6), tumor protein p53 (TP53) (3/6), neurofibromin 1 (NF1) (3/6), phosphodiesterase 4D interacting protein (PDE4DIP) (3/6), cytochrome P450 family 2 subfamily D member 6 (CYP2D6) (2/6), fms-related receptor tyrosine kinase 4 (FLT4) (2/6) and myosin heavy chain 9 (MYH9) (2/6). Of the two cases analyzed in the papilloma-oncology carcinoma pair, one did not have any common mutations; the other showed a staged functional deletion of TP53 during the process of malignant transformation from SNIP to SCC. CONCLUSION: CDKN2A, KMT2D, NF1, PDE4DIP, CYP2D6, FLT4, and MYH9 were identified as candidate novel SNIP-derived SCC-related genes.

DOI： 10.21873/anticanres.14752

Breast metastasis from pelvic high-grade serous adenocarcinoma: a report of two cases. International journal

Yurina Harada, Makoto Kubo, Masaya Kai, Mai Yamada, Karen Zaguirre, Tatsuhiro Ohgami, Hideaki Yahata, Yoshihiro Ohishi, Hidetaka Yamamoto, Yoshinao Oda, Masafumi Nakamura

Surgical case reports 6 ( 1 ) 317 - 317 2020.12

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

BACKGROUND: Metastatic tumors to the breast reportedly account for 0.5% to 2.0% of all malignant breast diseases. Such metastatic tumors must be differentiated from primary breast cancer. Additionally, few reports have described metastases of gynecological cancers to the breast. We herein report two cases of metastasis of pelvic high-grade serous adenocarcinoma to the breast. CASE PRESENTATION: The first patient was a 57-year-old woman with a transverse colon obstruction. Colostomy was performed, but the cause of the obstruction was unknown. We found scattered white nodules disseminated throughout the abdominal cavity and intestinal surface. Follow-up contrast-enhanced computed tomography (CT) showed an enhanced nodule outside the right mammary gland. Core needle biopsy (CNB) of the right breast mass was conducted, and immunohistochemical staining of the mass suggested a high-grade serous carcinoma of female genital tract origin. We diagnosed the patient's condition as breast and lymph node metastasis of a high-grade serous carcinoma of the female genital tract. After chemotherapy for stage IVB peritoneal cancer, tumor reduction surgery was performed. The second patient was a 71-year-old woman with a medical history of low anterior resection for rectal cancer at age 49, partial right thyroidectomy for follicular thyroid cancer at age 53, and left lower lung metastasis at age 57. Periodic follow-up CT showed peritoneal dissemination, cancerous peritonitis, and pericardial effusion, and the patient was considered to have a cancer of unknown primary origin. Contrast-enhanced CT showed an enhanced nodule in the left mammary gland with many enhanced nodules and peritoneal thickening in the abdominal cavity. CNB of the left breast mass was conducted, and immunohistochemical staining of the mass suggested a high-grade serous carcinoma of female genital tract origin. After chemotherapy for stage IVB peritoneal cancer, tumor reduction surgery was performed. CONCLUSIONS: We experienced two rare cases of intramammary metastasis of high-grade serous carcinoma of female genital tract origin. CNB was useful for confirming the histological diagnosis of these cancers that had originated from other organs. A correct diagnosis of such breast tumors is important to ensure quick and appropriate treatment.

DOI： 10.1186/s40792-020-01090-7

Characterization of parotid gland tumors: added value of permeability MR imaging to DWI and DCE-MRI Reviewed International journal

Hidetake Yabuuchi, Takeshi Kamitani, Koji Sagiyama, Yuzo Yamasaki, Tomoyuki Hida, Yuko Matsuura, Takuya Hino, Yuriko Murayama, Ryuji Yasumatsu, Hidetaka Yamamoto

European Radiology 30 ( 12 ) 6402 - 6412 2020.12

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

© 2020, European Society of Radiology. Objectives: To determine added value of permeability MRI in parotid tumor characterization to T2-weighted imaging (T2WI), semi-quantitative analysis of time-intensity curve (TIC), and intra-voxel incoherent motion diffusion-weighted imaging (IVIM-DWI). Methods: This retrospective study was approved by the institutional review board, and the informed consent was waived. Sixty-one parotid tumors in 61 patients were examined using T2WI, IVIM-DWI, and permeability MRI. TIC patterns were categorized as persistent, washout, or plateau. Signal intensity ratio of lesion-to-muscle on T2WI, apparent diffusion coefficients (ADCs), D and f values from IVIM-DWI, and Ktrans, kep, Ve, and Vp values from permeability MRI were measured. Multiple comparisons were applied to determine whether any differences among 4 histopathologic types (pleomorphic adenomas, Warthin’s tumors, other benign tumors, and malignant tumors) existed. Diagnostic accuracy was compared before and after modification diagnosis referring to permeability MRI. In a validation study, 60 parotid tumors in 60 patients were examined. Results: ADC and D values of malignant tumors were significantly lower than those of benign tumors other than Warthin’s tumors, but higher than those of Warthin’s tumors. kep and Vp values of Warthin’s tumors were significantly higher than those of malignant tumors. Multivariate analyses showed that TIC pattern, D, and kep values were suitable parameters. McNemar’s test showed a significant increase of sensitivity (11/12, 92%) and specificity (46/49, 94%) with adding kep. The validation study yielded high sensitivity (14/16, 88%) and specificity (41/44, 93%). Conclusion: Permeability MRI offers added value to IVIM-MRI and semi-quantitative TIC analysis of DCE-MRI in characterization of parotid tumors Key Points: • Permeability MR imaging offers added value in the characterization of parotid gland tumors in combination with semi-quantitative TIC analysis and IVIM analyses with D parameter. • The combination of TIC pattern, D, and kepmight facilitate accurate characterization of parotid gland tumor, thereby avoiding unnecessary surgery for benign tumors or delayed treatment for malignant tumors. • A combination of permeability and diffusion MR imaging can be used to guide the selection of an appropriate biopsy site.

DOI： 10.1007/s00330-020-07004-3

Clinicopathological features and immunohistochemical utility of NTRK-, ALK-, and ROS1-rearranged papillary thyroid carcinomas and anaplastic thyroid carcinomas Reviewed International journal

Yui Nozaki, Hidetaka Yamamoto, Takeshi Iwasaki, Masanobu Sato, Rina Jiromaru, Takahiro Hongo, Ryuji Yasumatsu, Yoshinao Oda

Human Pathology 106 82 - 92 2020.12

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

© 2020 NTRK1/3, ALK, and ROS1 translocations have been reported in a minor subset of papillary thyroid carcinomas (PTCs). We aimed to elucidate the prevalence and clinicopathological characteristics of these gene rearrangements and the utility of immunohistochemistry (IHC) in PTC and anaplastic thyroid carcinoma (ATC). We screened nonradiation-exposed cases of 307 PTCs and 16 ATCs by IHC for pan-Trk, ALK, and ROS1, followed by fluorescence in situ hybridization (FISH). In the PTC group, IHC for pan-Trk, ALK, and ROS1 was positive in 18 cases (5.9%), 1 case (0.3%), and 12 cases (3.9%), respectively. Among the pan-Trk IHC–positive cases (n = 18), 2 cases (11.1%; 0.7% of all PTCs) had NTRK1 or NTRK3 gene rearrangement with conventional PTC histology. The ALK IHC–positive case (n = 1) was the follicular variant of PTC with consistent ALK gene rearrangement. ROS1 gene rearrangement was not detectable in the ROS1 IHC–positive PTCs (0/12) by FISH. Most (approximately 70%) of the pan-Trk or ROS1 IHC–positive/FISH–negative cases had BRAF gene mutation with conventional PTC morphology. In the ATC group, neither ALK nor ROS1 IHC was positive, whereas pan-Trk IHC was positive in 1 case (6.3%) in which NTRK1 gene rearrangement was confirmed by FISH. These results suggest that NTRK, ALK, and ROS1 rearrangements are rare molecular events in nonradiation-exposed Japanese patients with PTC and ATC. Although IHC is not an entirely specific surrogate for these abnormalities and does not serve as a stand-alone companion diagnosis, the combined use of IHC and molecular testing may be helpful for determining promising therapeutic strategies with tyrosine kinase inhibitors.

DOI： 10.1016/j.humpath.2020.09.004

Chronic inflammatory changes and oxidative stress in the background of “pancreatic ductal adenocarcinoma concomitant with intraductal papillary mucinous neoplasm” Reviewed International journal

Ryota Matsuda, Yoshihiro Miyasaka, Yuichi Yamada, Jun Kawata, Kukiko Sakihama, Takeo Yamamoto, Kiyoshi Saeki, Hidetaka Yamamoto, Yoshihiro Ohishi, Yutaka Koga, Masafumi Nakamura, Yoshinao Oda

Virchows Archiv 477 ( 6 ) 799 - 806 2020.12

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

© 2020, Springer-Verlag GmbH Germany, part of Springer Nature. Cases of “pancreatic ductal adenocarcinoma (PDAC) concomitant with intraductal papillary mucinous neoplasm” (IPMN) have multiple PDAC lesions more frequently than cases of “PDAC without IPMN”. However, the mechanism of carcinogenesis in this former disease category remains unknown. The main objective of this work was thus to investigate the effects of chronic inflammation on carcinogenesis in PDAC cases. We selected 31 “PDAC concomitant with IPMN” patients and 58 “PDAC without IPMN” patients and pathologically evaluated their background pancreatic parenchyma. Fibrosis and inflammation scores of background pancreas were higher in “PDAC concomitant with IPMN” than in “PDAC without IPMN” (P < 0.0001 and P < 0.0001, respectively), whereas the fatty infiltration score of background pancreas was high in “PDAC without IPMN” (P = 0.0024). Immunohistochemically, the expression of 8-hydroxy-2′-deoxyguanosine (8-OHDG), an oxidative stress marker, in the background pancreas was high in “PDAC concomitant with IPMN” compared with that in “PDAC without IPMN” (P < 0.0001). Chronic inflammation activates oxidative stress in tissue throughout the pancreas and probably confers susceptibility to tumorigenesis in “PDAC concomitant with IPMN”.

DOI： 10.1007/s00428-020-02844-2

Efficacy of endoscopic ultrasound with artificial intelligence for the diagnosis of gastrointestinal stromal tumors Reviewed

Yosuke Minoda, Eikichi Ihara, Keishi Komori, Haruei Ogino, Yoshihiro Otsuka, Takatoshi Chinen, Yasuo Tsuda, Koji Ando, Hidetaka Yamamoto, Yoshihiro Ogawa

Journal of Gastroenterology 55 ( 12 ) 1119 - 1126 2020.12

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

© 2020, Japanese Society of Gastroenterology. Background: Although endoscopic ultrasound (EUS) is reported to be suitable for determining the layer from which subepithelial lesions (SELs) originate, it is difficult to distinguish gastrointestinal stromal tumor (GIST) from non-GIST using only EUS images. If artificial intelligence (AI) can be used for the diagnosis of SELs, it should provide several benefits, including objectivity, simplicity, and quickness. In this pilot study, we propose an AI diagnostic system for SELs and evaluate its efficacy. Methods: Thirty sets each of EUS images with SELs ≥ 20 mm or < 20 mm were prepared for diagnosis by an EUS diagnostic system with AI (EUS-AI) and three EUS experts. The EUS-AI and EUS experts diagnosed the SELs using solely the EUS images. The concordance rates of the EUS-AI and EUS experts’ diagnoses were compared with the pathological findings of the SELs. Results: The accuracy, sensitivity, and specificity for SELs < 20 mm were 86.3, 86.3, and 62.5%, respectively for the EUS-AI, and 73.3, 68.2, and 87.5%, respectively, for the EUS experts. In contrast, accuracy, sensitivity, and specificity for SELs ≥ 20 mm were 90.0, 91.7, and 83.3%, respectively, for the EUS-AI, and 53.3, 50.0, and 83.3%, respectively, for the EUS experts. The area under the curve for the diagnostic yield of the EUS-AI for SELs ≥ 20 mm (0.965) was significantly higher than that (0.684) of the EUS experts (P = 0.007). Conclusion: EUS-AI had a good diagnostic yield for SELs ≥ 20 mm. EUS-AI has potential as a good option for the diagnosis of SELs.

DOI： 10.1007/s00535-020-01725-4

Prognostic impact of CRTC1/3-MAML2 fusions in salivary gland mucoepidermoid carcinoma: A multiinstitutional retrospective study Reviewed International journal

Yoshihide Okumura, Satsuki Nakano, Takayuki Murase, Kaori Ueda, Daisuke Kawakita, Toshitaka Nagao, Kimihide Kusafuka, Makoto Urano, Hidetaka Yamamoto, Satoshi Kano, Kiyoaki Tsukahara, Kenji Okami, Toru Nagao, Nobuhiro Hanai, Hiroshi Iwai, Ryo Kawata, Yuichiro Tada, Ken Ichi Nibu, Hiroshi Inagaki

Cancer Science 111 ( 11 ) 4195 - 4204 2020.11

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

© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association Mucoepidermoid carcinoma (MEC) is rare, but the most common primary malignancy of the salivary gland and not infrequent in young individuals. CRTC1/3-MAML2 fusions are frequently detected in MEC and are useful as a diagnostic biomarker. However, there has been debate as to whether the fusions have prognostic significance. In this study, we retrospectively collected 153 salivary gland MEC cases from 11 tertiary hospitals in Japan. As inclusion criteria, the MEC patients in this study had curative surgery as the initial treatment, received no preoperative treatment, and had no distant metastasis at the time of the initial surgery. The MEC diagnosis was validated by a central pathology review by five expert salivary gland pathologists. The CRTC1/3-MAML2 fusions were detected using FISH and RT-PCR. In 153 MEC cases, 90 (58.8%) were positive for CRTC1/3-MAML2 fusions. During the follow-up period, 28 (18.3%) patients showed tumor recurrence and 12 (7.8%) patients died. The presence of the fusions was associated with favorable tumor features. Of note, none of the fusion-positive patients died during the follow-up period. Statistical analysis showed that the presence of the fusions was a prognostic indicator of a better overall survival in the total and advanced-stage MEC cohorts, but not in the early-stage MEC cohort. In conclusion, CRTC1/3-MAML2 fusions are an excellent biomarker for favorable overall survival of patients with salivary gland MEC.

DOI： 10.1111/cas.14632

Frequent MN1 gene mutations in malignant peripheral nerve sheath tumor

Izumi Kinoshita, Yuichi Yamada, Kenichi Kohashi, Hidetaka Yamamoto, Takeshi Iwasaki, Shin Ishihara, Yu Toda, Yoshihiro Ito, Yousuke Susuki, Kengo Kawaguchi, Toshio Ichiki, Yuki Sato, Masutaka Furue, Yasuharu Nakashima, Yoshinao Oda

Anticancer Research 40 ( 11 ) 6221 - 6228 2020.11

Publishing type：Research paper (scientific journal)

© 2020 International Institute of Anticancer Research. All rights reserved. Background/aim: Malignant peripheral nerve sheath tumor (MPNST) is a rare soft-tissue tumor, and its diagnosis is usually made histopathologically. The effectiveness of chemotherapy and radiotherapy has not been established. We elucidated prognostic factors, diagnostic markers, and therapeutic targets. Materials and Methods: Cases of MPNST were studied using next-generation sequencing. A total of 24 tumor samples, 11 from von Recklinghausen’s disease-associated MPNST (vRH-MPNST), 11 from sporadic non-vRH MPNST, and two neurofibroma (NF) cases were retrieved, on which next-generation sequencing and survival analysis were performed. Results: We identified NF1 gene mutations, including three mutations in two NFs, and 10 mutations in eight MPNSTs (five vRHMPNSTs and three sporadic MPNSTs). Meningioma 1 (MN1) gene alteration was detected in six cases of vRH-MPNST. It is considered that MN1 gene alteration is related to the tumorigenesis of vRH-MPNST. Conclusion: MN1 gene mutation was detected in more than half of our cases, it may have potential for use as a therapeutic target in vRH-MPNST.

DOI： 10.21873/anticanres.14642

B cell receptor signaling related to resistance to Helicobacter pylori eradication therapy in gastric diffuse large B cell lymphoma. Reviewed International journal

Takehiro Torisu, Shinichi Kawano, Kohta Miyawaki, Hidetaka Yamamoto, Yutaro Ihara, Yuichi Matsuno, Kumiko Torisu, Takeshi Sugio, Kensuke Sasaki, Takashi Shimakawa, Koji Kato, Koichi Akashi, Shotaro Nakamura, Takanari Kitazono

Hematological oncology 39 ( 1 ) 145 - 147 2020.10

PD-L1 and IDO1 expression and tumor-infiltrating lymphocytes in osteosarcoma patients: comparative study of primary and metastatic lesions Reviewed International journal

Yu Toda, Kenichi Kohashi, Yuichi Yamada, Masato Yoshimoto, Shin Ishihara, Yoshihiro Ito, Takeshi Iwasaki, Hidetaka Yamamoto, Yoshihiro Matsumoto, Yasuharu Nakashima, Masaaki Mawatari, Yoshinao Oda

Journal of Cancer Research and Clinical Oncology 146 ( 10 ) 2607 - 2620 2020.10

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

© 2020, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: Programmed death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) are immunosuppressive proteins known to be associated with poor prognosis in various cancers. However, their expression and clinical relevance in osteosarcoma remain unknown. In this study, the relationships of PD-L1 and IDO1 expression with clinicopathological features and prognosis were explored. Methods: The expression of PD-L1, IDO1, CD3, CD4, and CD8 in 112 formalin-fixed, paraffin-embedded tumor tissues collected by biopsy or surgical resection from 56 osteosarcoma patients was evaluated immunohistochemically. Moreover, four osteosarcoma cell lines were evaluated for the effects of IFNγ on PD-L1 and IDO1 mRNA expression by real-time reverse-transcription polymerase chain reaction. Results: In pre-neoadjuvant chemotherapy (NAC) primary specimens, 10 cases (17%) showed PD-L1 expression and 12 (21%) showed IDO1 expression. Six of ten cases (60%) with PD-L1 positivity co-expressed IDO1. In post-NAC metastatic lesions, the frequency of immunoexpression of PD-L1 and IDO1 was increased compared with that in pre-NAC specimens. PD-L1 and/or IDO1 expression was not associated with poor prognosis. PD-L1 immunoexpression was significantly associated with the infiltration of CD3+ T cells, CD4+ T cells, and CD8+ T cells; while, IDO1 immunoexpression was significantly associated with the infiltration of CD3+ T cells and CD4+ T cells. In all osteosarcoma cell lines, PD-L1 and IDO1 expression was upregulated by stimulation with IFNγ. Conclusion: Our results suggest that the PD-L1 and IDO1 immune checkpoint inhibitors may provide clinical benefit in osteosarcoma patients with metastatic lesions after conventional chemotherapy.

DOI： 10.1007/s00432-020-03242-6

The impact of clinicopathological factors on clinical outcomes in patients with salivary gland adenoid cystic carcinoma: a multi-institutional analysis in Japan. Reviewed

Daisuke Kawakita, Takayuki Murase, Kaori Ueda, Satoshi Kano, Yuichiro Tada, Kiyoaki Tsukahara, Kenji Okami, Tetsuro Onitsuka, Yasushi Fujimoto, Takuma Matoba, Kazuo Sakurai, Toru Nagao, Nobuhiro Hanai, Ryo Kawata, Naohito Hato, Ken-Ichi Nibu, Makoto Urano, Ken-Ichi Taguchi, Masato Nakaguro, Kimihide Kusafuka, Hidetaka Yamamoto, Toshitaka Nagao, Hiroshi Inagaki

International journal of clinical oncology 25 ( 10 ) 1774 - 1785 2020.10

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

BACKGROUND: Owing to the low incidence of adenoid cystic carcinoma (AdCC), reliable survival estimates and prognostic factors remained unclarified. METHODS: In this multi-institutional retrospective analysis, we collected 192 AdCC cases, and investigated the impact of clinicopathological factors on clinical outcomes of the patients. All AdCC cases were of salivary gland origin and were surgically treated with curative intent. Diagnoses of AdCC were validated by a central pathology review by expert pathologists. RESULTS: The 5-year overall survival (OS) and disease-free survival (DFS) rates were 92.5 and 50.0%, respectively. Treatment failure occurred in 89 patients (46%) with the distant failures in 65 (34%). Multivariate analysis indicated that pN2 and a pathologically positive surgical margin were independent prognostic factors for both OS and DFS. Histological grade III was an independent prognostic factor for OS. A primary site in the submandibular gland, pT3/4, pN1, and histological grade II were independent prognostic factors for DFS. Postoperative radiation therapy (PORT) improved the locoregional control (LRC) rate. Prophylactic neck dissection was not associated with a better OS or better LRC among patients with cN0. Facial nerve dissection did not improve clinical outcomes in parotid AdCC cases without facial nerve palsy. CONCLUSIONS: A higher TN classification, a pathologically positive surgical margin, and a higher histological grade were associated with a lower OS. PORT improved LRC rates but neck dissection failed to improve clinical outcomes in patients with cN0. As the distant metastasis was frequent, effective systemic therapy is imperative to improve the survival of AdCC patients.

DOI： 10.1007/s10147-020-01731-9

Benign mesenteric lipomatous tumor in a child: a case report and literature review. Reviewed International journal

Naoki Hashizume, Takato Aiko, Suguru Fukahori, Shinji Ishii, Nobuyuki Saikusa, Yoshinori Koga, Naruki Higashidate, Saki Sakamoto, Shiori Tsuruhisa, Hirotomo Nakahara, Hiroko Muta, Hiroaki Miyoshi, Yoshiki Naito, Hidetaka Yamamoto, Yoshinao Oda, Yoshiaki Tanaka, Minoru Yagi

Surgical case reports 6 ( 1 ) 243 - 243 2020.9

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

BACKGROUND: Lipomatous tumors are the most common type of soft-tissue tumors. Benign lipomatous tumors are lipomas and lipoblastoma. We herein report a case of benign mesenteric lipomatous tumor and the largest collection of known benign mesenteric lipomatous tumors in children in the literature. CASE PRESENTATION: A 3-year-old girl presented with repeated dull abdominal pain and left abdominal mass swelling. On a physical examination, the child had a soft, moderately distended left abdomen that was not tender when palpated. Computed tomography and magnetic resonance imaging demonstrated a large fatty mass within the mesentery, measuring approximately 8 × 6 cm. The mass extended from the right upper quadrant to the lower pole of the kidneys. Laparotomy with resection of the mesenteric tumor was performed under general anesthesia. A well-capsuled tumor was a soft, yellow mass and found loosely attached to the mesenterium of the ileum. A histopathological examination demonstrated the lobular proliferation of mature adipocytes. Atypical lipoblasts were not seen. These features are compatible with benign lipomatous tumor, such as lipoma or lipoblastoma with maturation. CONCLUSION: In conclusion, benign mesenteric lipomatous tumors tend to be large in size over 10 cm in longitudinal length. However, resection is well tolerated in the vast majority of cases with benign post-operative courses.

DOI： 10.1186/s40792-020-01020-7

Plasmablastic lymphoma occurring in the vicinity of enterocutaneous fistula in Crohn's disease. Reviewed International journal

Seisho Sato, Makiko Nakahara, Koji Kato, Tomohiko Moriyama, Sae Utsumi, Kensuke Sasaki, Takahiro Shima, Hiroaki Miyoshi, Hidetaka Yamamoto, Masutaka Furue

The Journal of dermatology 47 ( 12 ) e442-e443 2020.9

Amide proton transfer (APT) imaging of parotid tumors: Differentiation of malignant and benign tumors. Reviewed International journal

Takeshi Kamitani, Koji Sagiyama, Osamu Togao, Yuzo Yamasaki, Tomoyuki Hida, Yuko Matsuura, Yuriko Murayama, Ryuji Yasumatsu, Hidetaka Yamamoto, Hidetake Yabuuchi

European journal of radiology 129 109047 - 109047 2020.8

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

PURPOSE: To assess the usefulness of amide proton transfer (APT) imaging in differentiating parotid tumors. MATERIAL AND METHODS: We retrospectively analyzed 43 histopathologically proven parotid solid tumors with diameters ≥2 cm. Twenty-one tumors were benign and 12 tumors were malignant. Two-dimensional APT imaging was performed using a saturation pulse with a duration of 2 s and a saturation power level of 2 μT. For acquiring Z-spectra, the imaging was repeated at 25 saturation frequency offsets from ω = -6 to +6 ppm with a step of 0.5 ppm as well as one scan acquired far off-resonance (-1560 ppm) for signal normalization. For the APT imaging, the asymmetry analysis at 3.5 ppm downfield from the water signal was calculated. The mean APT signal intensity (SI) was compared between the benign and malignant tumors. RESULTS: The mean APT SI was 2.23 ± 0.80 % in the benign tumors and significantly higher at 2.99 ± 0.99 % in the malignant tumors (P = 0.01). A receiver operating curve analysis revealed that the optimal APT SI threshold was 2.40 for distinguishing malignant tumors from benign tumors with an area under the curve of 0.74. The sensitivity, specificity, and accuracy were 83.3%, 61.3%, and 67.4%, respectively. CONCLUSION: The mean APT SI of the malignant parotid tumors was significantly higher than that of the benign parotid tumors.

DOI： 10.1016/j.ejrad.2020.109047

Central pathology review of salivary gland adenoid cystic carcinoma. Reviewed International journal

Kaori Ueda, Takayuki Murase, Toshitaka Nagao, Kimihide Kusafuka, Makoto Urano, Hidetaka Yamamoto, Masato Nakaguro, Ken-Ichi Taguchi, Ayako Masaki, Hideaki Hirai, Daisuke Kawakita, Kiyoaki Tsukahara, Naohito Hato, Toru Nagao, Yasushi Fujimoto, Kazuo Sakurai, Nobuhiro Hanai, Satoshi Kano, Tetsuro Onitsuka, Kenji Okami, Ken-Ichi Nibu, Yuichiro Tada, Ryo Kawata, Hiroshi Inagaki

Head & neck 42 ( 8 ) 1721 - 1727 2020.8

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

BACKGROUND: To assess the role of a central pathology review in the diagnosis of salivary gland adenoid cystic carcinoma (AdCC). METHODS: Surgically resected salivary gland tumors diagnosed as AdCC (n = 219) in 15 reference hospitals in Japan were subjected to a retrospective pathological re-evaluation. RESULTS: After the review, the AdCC diagnosis was revised in 21/219 cases (9.6%). The six benign tumors (2.7%) comprised five basal cell adenomas and one pleomorphic adenoma, and among these six patients, three received postoperative radiotherapy. The remaining 15 malignant tumors (6.8%) comprised nine basal cell adenocarcinomas and six other carcinomas. All revised basal cell adenoma/adenocarcinoma cases were of rare cribriform variants. CONCLUSIONS: A significant proportion of AdCC pathology reports were revised after the central pathology review. It should be emphasized that the greatest attention should be paid in differentiating AdCC from cribriform variant basal cell adenoma/adenocarcinoma, which is very rare in salivary gland tumors.

DOI： 10.1002/hed.26081

Genetic landscape of external auditory canal squamous cell carcinoma. Reviewed International journal

Kuniaki Sato, Noritaka Komune, Takahiro Hongo, Kensuke Koike, Atsushi Niida, Ryutaro Uchi, Teppei Noda, Ryunosuke Kogo, Nozomu Matsumoto, Hidetaka Yamamoto, Muneyuki Masuda, Yoshinao Oda, Koshi Mimori, Takashi Nakagawa

Cancer science 111 ( 8 ) 3010 - 3019 2020.6

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

External auditory canal squamous cell carcinoma (EACSCC) is an extremely rare and aggressive malignancy. Due to its rarity, the molecular and genetic characteristics of EACSCC have not yet been elucidated. To reveal the genetic alterations of EACSCC, we performed whole exome sequencing (WES) on 11 primary tumors, 1 relapsed tumor and 10 noncancerous tissues from 10 patients with EACSCC, including 1 with a rare case of synchronous bilateral EACSCC of both ears. WES of the primary tumor samples showed that the most frequently mutated gene is TP53 (63.6%). In addition, recurrent mutations in CDKN2A, NOTCH1, NOTCH2, FAT1 and FAT3 were detected in multiple samples. The mutational signature analysis of primary tumors indicated that the mutational processes associated with the activation of apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) deaminases are the most common in EACSCC, suggesting its similarity to SCC from other primary sites. Analysis of arm-level copy number alterations detected notable amplification of chromosomes 3q, 5p and 8q as well as deletion of 3p across multiple samples. Focal chromosomal aberrations included amplifications of 5p15.33 (ZDHHC11B) and 7p14.1 (TARP) as well as deletion of 9p21.3 (CDKN2A/B). The protein expression levels of ZDHHC11B and TARP in EACSCC tissues were validated by immunohistochemistry. Moreover, WES of the primary and relapsed tumors from a case of synchronous bilateral EACSCC showed the intrapatient genetic heterogeneity of EACSCC. In summary, this study provides the first evidence for genetic alterations of EACSCC. Our findings suggest that EACSCC mostly resembles other SCC.

DOI： 10.1111/cas.14515

Signet Ring Cell Differentiation in Salivary Duct Carcinoma with Rhabdoid Features: Report of Three Cases and Literature Review. Reviewed International journal

Mayumi Akaki, Akira Ishihara, Kentaro Nagai, Hidekazu Naono, Kenichi Taguchi, Hidetaka Yamamoto, Hiroyuki Tanaka, Hiroaki Kataoka

Head and neck pathology 15 ( 1 ) 341 - 351 2020.6

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

Salivary duct carcinoma with rhabdoid features (SDCRF) is a rare salivary tumor with poor prognosis and is proposed as a salivary counterpart of pleomorphic lobular carcinoma of the breast (PLCB). Here, we report three cases of SDC with rhabdoid features (SDCRF) mimicking PLCB. Pleomorphic adenoma (PA) component was accompanied in all the cases confirming carcinoma ex PA. One patient had frequent rhabdoid features and showed invasive growth into the surrounding tissue. The other two patients had intracapsular tumor but with rhabdoid features. The patients with intracapsular SDCRF survived for > 5 years after surgery with no evidence of recurrence, whereas the patient with extracapsular SDCRF died 10 months after biopsy, and autopsy revealed disseminated metastasis to the central nervous system. Histologically, tumor cells in all three cases resembled PLCB, with a discohesive appearance, abundant cytoplasm, enlarged hyperchromatic nuclei, and similar immunohistochemical profiles, namely loss of membranous E-cadherin, obscured expression of membranous β-catenin, diffuse positivity of androgen receptor, gross cystic disease fluid protein-15, mitochondrial adenosine triphosphate synthase subunit β, MUC1, and INI-1. Estrogen and progesterone receptors were negative, and HER2 immunoreactivities were variable. The tumor cells of extracapsular invasive SDCRF exhibited higher MIB-1 labeling index and more frequent intracytoplasmic lumina than those of intracapsular SDCRF. Ultrastructurally, rhabdoid cells contained intracytoplasmic lumina with microvillous structure, analogous to those reported in PLCB. No intracytoplasmic intermediate filament aggregation was observed. These observations indicate that SDCRF is a salivary counterpart of PLCB and under signet ring cell differentiation.

DOI： 10.1007/s12105-020-01186-4

Retroperitoneal Myxofibrosarcoma: A Controversial Entity. Reviewed International journal

Masato Yoshimoto, Yuichi Yamada, Shin Ishihara, Kenichi Kohashi, Yu Toda, Yoshihiro Ito, Yosuke Susuki, Izumi Kinoshita, Hidetaka Yamamoto, Yasuharu Nakashima, Yoshinao Oda

Pathology, research and practice 216 ( 6 ) 152969 - 152969 2020.6

Primary bone anaplastic large cell lymphoma of lymphohistiocytic variant, ALK-negative: A challenging diagnosis. Reviewed International journal

Kennosuke Karube, Norihiro Nakada, Hidetaka Yamamoto

Pathology international 70 ( 6 ) 376 - 378 2020.6

Clinico-pathological characteristics of primary adrenal lymphomas - potential efficacy of autologous stem cell transplantation. Reviewed International journal

Taisuke Narazaki, Motoaki Shiratsuchi, Takamitsu Matsushima, Mariko Tsuda, Yasuhiro Tsukamoto, Hiroki Muta, Toru Masuda, Daisaku Kimura, Akiko Takamatsu, Hidetaka Yamamoto, Yoshinao Oda, Hiroaki Miyoshi, Koichi Ohshima, Yayoi Matsuda, Ryuichi Sakamoto, Yasuhiro Nakashima, Yoshihiro Ogawa

Leukemia & lymphoma 61 ( 6 ) 1516 - 1518 2020.6

Diagnostic utility of pan-Trk immunohistochemistry for inflammatory myofibroblastic tumours. Reviewed International journal

Hidetaka Yamamoto, Yui Nozaki, Kenichi Kohashi, Izumi Kinoshita, Yoshinao Oda

Histopathology 76 ( 5 ) 774 - 778 2020.4

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

AIMS: Inflammatory myofibroblastic tumour (IMT) is a spindle cell neoplasm of intermediate malignancy, and the diagnosis is often challenging due to the morphological overlap with other spindle cell neoplasms and reactive lesions. More than half of IMTs have the ALK gene rearrangement, and a minor subset have ROS1, NTRK3 or RET gene rearrangements. We sought to determine the potential diagnostic utility of pan-Trk immunohistochemistry for IMTs. METHODS AND RESULTS: We retrospectively examined 40 cases of IMT using immunohistochemistry with a rabbit monoclonal pan-Trk antibody. Gene rearrangement was confirmed by fluorescence in-situ hybridisation and/or reverse transcription-polymerase chain reaction. The IMTs were classified as the ALK (n = 29), ROS1 (n = 2), NTRK3 (n = 2), RET (n = 0) and 'quadruple-negative' (n = 7) genotypes by molecular analyses. Both of the ETV6-NTRK3 fusion-positive cases showed nuclear and cytoplasmic staining for pan-Trk in the majority of tumour cells. None of the ALK, ROS1 or quadruple-negative-type IMTs showed nuclear staining for pan-Trk, but approximately one-third of these IMTs showed focal and weak cytoplasmic staining. One exceptional case of a RANBP2-ALK-positive epithelioid inflammatory myofibroblastic sarcoma (an aggressive variant of IMT) showed moderate cytoplasmic staining for pan-Trk. CONCLUSIONS: These results suggest that pan-Trk immunoreactivity with a nuclear and cytoplasmic staining pattern may be useful to identify ETV6-NTRK3-positive IMTs and may be helpful in selecting patients for Trk-targeted therapy.

DOI： 10.1111/his.14010

HPV-related Sinonasal Carcinoma: Clinicopathologic Features, Diagnostic Utility of p16 and Rb Immunohistochemistry, and EGFR Copy Number Alteration. Reviewed International journal

Rina Jiromaru, Hidetaka Yamamoto, Ryuji Yasumatsu, Takahiro Hongo, Yui Nozaki, Kazuki Hashimoto, Kenichi Taguchi, Muneyuki Masuda, Takashi Nakagawa, Yoshinao Oda

The American journal of surgical pathology 44 ( 3 ) 305 - 315 2020.3

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

The prevalence and prognostic value of human papillomavirus (HPV) infection and epidermal growth factor receptor (EGFR) alteration in sinonasal squamous cell carcinoma (SNSCC) are not known. The reliability of p16 overexpression as a surrogate for HPV infection in SNSCC is also unclear. We investigated the prognostic and diagnostic significances of HPV infection, EGFR alteration, and p16 expression in SNSCC. We analyzed high-risk HPV infection by HPV-RNA in situ hybridization and EGFR gene copy number gain (CNG) by chromogenic in situ hybridization and by determining the protein expressions of p16, Rb, and EGFR by immunohistochemistry in 101 SNSCC cases. HPV infection (n=9, 8.9%) and p16 overexpression (n=15, 14.9%) were associated with better overall survival (P=0.0042 and 0.005, respectively). The HPV cases were located predominantly at the nasal cavity with nonkeratinizing histology and partial loss of Rb. Notably, 40% (6/15) of p16 SNSCCs were HPV. Two of these cases showed complete loss of Rb expression by immunohistochemistry, suggesting a reason for the above discrepancy. EGFR CNG, detected in 30.5% of the SNSCCs, was correlated with EGFR protein overexpression (P=0.0001). HPV infection and EGFR CNG were mutually exclusive. The HPV/EGFR CNG group had significantly better overall survival than the HPV/EGFR CNG and HPV/EGFR CNG groups (P=0.0471 and 0.0343, respectively). Our results suggest that HPV infection is a favorable prognostic marker in SNSCC, but p16 is not a perfect surrogate marker; the Rb expression pattern may improve the diagnostic accuracy. The molecular subclassification of SNSCCs based on HPV infection and EGFR copy number status might provide important information for therapeutic strategies.

DOI： 10.1097/PAS.0000000000001410

Histone H3.3 mutation in giant cell tumor of bone: an update in pathology. Reviewed

Hidetaka Yamamoto, Shin Ishihara, Yu Toda, Yoshinao Oda

Medical molecular morphology 53 ( 1 ) 1 - 6 2020.3

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

Giant cell tumor of bone (GCTB) is a locally aggressive bone tumor that frequently shows local recurrence and occasionally shows malignant transformation to high-grade sarcoma. Histologically, conventional GCTB is composed mainly of three types of cells: mononuclear neoplastic cells with an osteoblastic precursor phenotype, mononuclear histiocytic cells, and osteoclast-like multinucleated giant cells. These cells interact with each other via the RANKL-RANK axis and other mechanisms for tumor formation. The vast majority of GCTBs were recently revealed to harbor H3F3A p.G34W mutation, and a minor subset have H3F3A p.G34L, p.G34M, p.G34R, or p.G34V mutation. H3.3 G34W mutant-specific immunohistochemistry is a highly sensitive and specific surrogate marker for H3F3A p.G34W mutation in GCTB and thus useful for differential diagnoses of histological mimics. H3.3 mutant-specific immunohistochemistry has also contributed to the understanding of the bone-forming ability of neoplastic cells of GCTB and the remarkable new bone formation after treatment with denosumab, an inhibitor of RANKL. In primary and secondary malignant GCTBs, the H3F3A gene allele can be preserved or lost with malignant transformation.

DOI： 10.1007/s00795-019-00238-1

Colorectal diffuse large B-cell lymphoma: molecular subclassification and prognostic significance of immunoglobulin gene translocation. Reviewed International journal

Yoshifumi Hori, Hidetaka Yamamoto, Yui Nozaki, Takehiro Torisu, Minako Fujiwara, Kenichi Taguchi, Kenichi Nishiyama, Shotaro Nakamura, Takanari Kitazono, Yoshinao Oda

Human pathology 96 67 - 78 2020.2

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

Primary colorectal diffuse large B-cell lymphoma (DLBCL) is rare, and its clinicopathological and genetic features are poorly understood. The aim of our study was to elucidate the frequency and prognostic significance of molecular subgroups in colorectal DLBCL. We examined 25 cases of colorectal lymphoma with DLBCL-like morphology and classified them into germinal center B-cell like (GCB)/non-GCB subgroups by immunohistochemistry (IHC) for CD10, bcl-6 and MUM1, or into double-expressor (DE)/non-DE subgroups by IHC for bcl-2 and c-myc. Translocations involving BCL2, BCL6, MYC, IGH, IGK, IGL, and MALT1 were also investigated using break-apart fluorescence in situ hybridization (FISH). The 25 cases were classified into two entities-DLBCL, not otherwise specified (NOS) (n = 23; 92%) and high grade B-cell lymphoma, double hit (n = 2; 8%)-according to the recent WHO classification. None of them showed histological evidence of Epstein-Barr virus infection or high-grade transformation from low grade B-cell lymphoma. Ten cases were GCB-type and four cases were DE-type, but these subtypes did not contribute to clinicopathological differences. Translocations involving BCL2, BCL6, MYC, IGH, IGK, IGL, and MALT1 were detected in 3 (12%), 3 (12%), 10 (40%), 14 (56%), 3 (12%), 3 (12%), and 0 (0%) of 25 cases, respectively. Of note, the presence of IGH translocation was significantly associated with better overall survival (P = .0053) and progression free survival (P = .0259). Similarly, the translocation involving at least one of the IGs (IGH, IGK, and/or IGL) was associated with more favorable prognosis in DLBCLs or even in DLBCL, NOS. This is the first report to reveal that a small subset of colorectal DLBCL corresponds to double-hit lymphoma. In addition, translocations involving at least one of the IGs may be a favorable prognostic factor in colorectal DLBCL. Testing the translocation involving rearrangement of IGs as well as MYC and BCL2/BCL6 may thus be useful for diagnosis and prognosis.

DOI： 10.1016/j.humpath.2019.09.003

Malignant perivascular epithelioid cell tumor mimicking jugular foramen schwannoma: A case report and literature review. Reviewed International journal

Noritaka Komune, Shogo Masuda, Ryuji Yasumatsu, Takahiro Hongo, Rina Jiromaru, Satoshi Matsuo, Osamu Akiyama, Nana Tsuchihashi, Nozomu Matsumoto, Hidetaka Yamamoto, Takashi Nakagawa

Heliyon 6 ( 1 ) e03200 2020.1

Language：English

Background: Perivascular epithelioid cell tumors (PEComas) of the skull base are extremely rare. Here we report the first description of a malignant PEComa mimicking jugular foramen schwannoma and presenting as Collet-Sicard syndrome, and we review the previous literature on PEComas of the head, neck and skull base. Case description: A 29-year-old woman presented with hoarseness, dysphagia, vomiting, and headache. She was first diagnosed with Collet-Sicard syndrome caused by thrombosis of the sigmoid and transverse sinuses. She was treated with anticoagulant therapy, and the hoarseness and paralysis of the accessory nerve improved. Later, at age 31, the hoarseness again worsened. At another hospital, enhanced computed tomography revealed a tumor in the jugular foramen extending to the neck and medially displacing the internal carotid artery. She was referred to our hospital for further examination and was diagnosed with jugular foramen schwannoma causing thrombosis of the sinuses. At the one-year follow-up, the tumor had grown rapidly and had started to surround the internal carotid artery. We therefore performed a tissue biopsy of the tumor in the jugular foramen and neck. Based on pathological analysis, we made a definitive diagnosis of malignant PEComa. Conclusions: It may be extremely challenging to reach an accurate diagnosis of PEComa in the skull-base region, which can cause a delay in treatment initiation. When atypical clinical features for a skull-base tumor are found, we recommend preliminary biopsy to obtain a definitive diagnosis and initiate an appropriate treatment strategy as early as possible.

DOI： 10.1016/j.heliyon.2020.e03200

Activated M2 Macrophages Contribute to the Pathogenesis of IgG4-Related Disease via Toll-like Receptor 7/Interleukin-33 Signaling. Reviewed International journal

Noriko Ishiguro, Masafumi Moriyama, Katsuhiro Furusho, Sachiko Furukawa, Takuma Shibata, Yusuke Murakami, Akira Chinju, A S M Rafiul Haque, Yuka Gion, Miho Ohta, Takashi Maehara, Akihiko Tanaka, Masaki Yamauchi, Mizuki Sakamoto, Keita Mochizuki, Yuko Ono, Jun-Nosuke Hayashida, Yasuharu Sato, Tamotsu Kiyoshima, Hidetaka Yamamoto, Kensuke Miyake, Seiji Nakamura

Arthritis & rheumatology (Hoboken, N.J.) 72 ( 1 ) 166 - 178 2020.1

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

OBJECTIVE: IgG4-related disease (IgG4-RD) is a unique inflammatory disorder in which Th2 cytokines promote IgG4 production. In addition, recent studies have implicated the Toll-like receptor (TLR) pathway. This study was undertaken to examine the expression of TLRs in salivary glands (SGs) from patients with IgG4-RD. METHODS: SGs from 15 patients with IgG4-RD, 15 patients with Sjögren's syndrome (SS), 10 patients with chronic sialadenitis, and 10 healthy controls were examined histologically. TLR family gene expression (TLR-1 through TLR-10) was analyzed by DNA microarray in the submandibular glands (SMGs). Up-regulation of TLRs was confirmed in SGs from patients with IgG4-RD. Finally, the phenotype of human TLR-7 (huTLR-7)-transgenic C57BL/6 mice was assessed before and after stimulation with TLR agonist. RESULTS: In patients with IgG4-RD, TLR-4, TLR-7, TLR-8, and TLR-9 were overexpressed. Polymerase chain reaction validated the up-regulation of TLR-7 in IgG4-RD compared with the other groups. Immunohistochemical analysis confirmed strong infiltration of TLR-7-positive cells in the SGs of patients with IgG4-RD. Double immunohistochemical staining showed that TLR-7 expression colocalized with CD163+ M2 macrophages. After in vitro stimulation with a TLR-7 agonist, CD163+ M2 macrophages produced higher levels of interleukin-33 (IL-33), which is a Th2-activating cytokine. In huTLR-7-transgenic mice, the focus and fibrosis scores in SMGs, pancreas, and lungs were significantly higher than those in wild-type mice (P < 0.05). Moreover, the concentration of serum IgG, IgG1, and IL-33 in huTLR-7-transgenic mice was distinctly increased upon stimulation with a TLR-7 agonist (P < 0.05). CONCLUSION: TLR-7-expressing M2 macrophages may promote the activation of Th2 immune responses via IL-33 secretion in IgG4-RD.

DOI： 10.1002/art.41052

Comparative Study of Myxofibrosarcoma With Undifferentiated Pleomorphic Sarcoma: Histopathologic and Clinicopathologic Review. Reviewed International journal

Masato Yoshimoto, Yuichi Yamada, Shin Ishihara, Kenichi Kohashi, Yu Toda, Yoshihiro Ito, Hidetaka Yamamoto, Masutaka Furue, Yasuharu Nakashima, Yoshinao Oda

The American journal of surgical pathology 44 ( 1 ) 87 - 97 2020.1

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

Myxofibrosarcoma (MFS) is a malignant fibroblastic/myofibroblastic neoplasm with the prominent myxoid area. It has the clinical features of frequent local recurrence and occasional distant metastasis. Morphologically, MFS is occasionally difficult to distinguish from undifferentiated pleomorphic sarcoma (UPS), especially in the case of high-grade MFS. Here, we reviewed clinical and histologic data of 162 MFS cases and 43 UPS cases. MFS was distinguished from UPS with the criterion of 10% myxoid area as a cutoff value. Overall, 52 MFS (34.4%) and 9 UPS (20.9%) cases showed local recurrence, 18 MFS (12.2%) and 19 UPS (44.2%) cases developed distant metastasis, and 13 MFS (9.5%) and 14 UPS (32.6%) cases resulted in tumor-related death. Statistically, MFS had a better prognosis than UPS. Moreover, MFS with less myxoid area had a tendency to present a poorer prognosis. FNCLCC grade was a statistically significant prognostic factor (distant metastasis: P=0.0021, tumor-related death: P=0.0021). Cellularity and nuclear atypia had only a statistical tendency for associations with a poorer prognosis. The overall survival rate of MFS after transformation into a UPS-like condition (<10% myxoid area) was close to that of UPS. It was suggested that MFS is a biologically distinct tumor from UPS, and MFS with less myxoid area had a tendency to present a poorer prognosis. We considered that evaluation of the amount of myxoid area, cellularity, and nuclear atypia may be important as prognostic predictors. MFS may become similar to histologic malignancy of UPS in terms of morphology and biology via local recurrence.

DOI： 10.1097/PAS.0000000000001389

Helper T cell-dominant tertiary lymphoid structures are associated with disease relapse of advanced colorectal cancer. Reviewed International journal

Kyoko Yamaguchi, Mamoru Ito, Hirofumi Ohmura, Fumiyasu Hanamura, Michitaka Nakano, Kenji Tsuchihashi, Shuntaro Nagai, Hiroshi Ariyama, Hitoshi Kusaba, Hidetaka Yamamoto, Yoshinao Oda, Masafumi Nakamura, Koichi Akashi, Eishi Baba

Oncoimmunology 9 ( 1 ) 1724763 - 1724763 2020

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

Tertiary lymphoid structures (TLSs), clusters of immune cells found around tumor tissue, have been shown to be associated with anti-tumor immunity, but the cellular composition within each TLS and whether the cellular composition of a TLS affects a patient's prognosis are poorly understood. In the present study, each TLS was categorized according to its cellular composition determined by a system of multiplex immunohistochemical staining and quantitative analysis, and the correlation between the category and prognosis was examined. Sixty-seven patients with curatively resected stage II/III colorectal cancer (CRC) were enrolled. A TLS, consisting of germinal center B cells, follicular dendritic cells, T helper (Th) cells, B cells, cytotoxic T cells, and macrophages, was confirmed in the tumor tissue of 58 patients (87%). The densities of Th cells and macrophages were significantly higher in relapsed patients than in not-relapsed patients (p = .043 and p = .0076). A higher ratio of Th cells was the most significant independent risk factor for disease relapse on multivariate analysis. The subset increasing in Th cells was GATA3+ Th2. A total of 353 TLSs was divided into five clusters according to immune cell composition. Among them, the Th-rich type TLS was significantly increased (p = .0009) in relapsed patients. These data suggest the possibility that Th cell-dominant composition might disturb the anti-tumor immune response, and the function of each TLS might differ depending on its composition.

DOI： 10.1080/2162402X.2020.1724763

Therapeutic outcomes of 68 cases with oropharyngeal squamous cell carcinoma referring to UICC version 7 and 8

Akihiro Tamae, Masanobu Sato, Hidetaka Yamamoto, Teppei Noda, Kazuo Nishiyama, Koichiro Nakashima, Ryuji Yasumatsu

Japanese Journal of Head and Neck Cancer 46 ( 1 ) 59 - 63 2020

Publishing type：Research paper (scientific journal)

We retrospectively reviewed the records of 68 patients with oropharyngeal squamous cell carcinoma who had undergone initial treatment in the Department of Otolaryngology, Head and Neck Surgery, Hamanomachi Hospital between 2009 and 2017. We compared therapeutic outcomes of p16-positive with p16-negative cases, referring to Unio Internationalis Contra Cancrum（UICC）diagnostic criteria version 7 and 8. Of 68（58.5％）patients, 38 were diagnosed as p16-positive. The 3-year disease-specific survival rate of all patients, p16-positive, and p16-negative patients were 78.5％, 74.1％, and 84.7％, respectively. Referring to UICC version 8, the 3-year disease-specific survival rate（3DSS）of p16-negative patients in each clinical stage was stage Ⅱ: 100％, stageⅢ: 66.7％, and stage Ⅳa: 70.6％, whereas 3DSS of p16-positive patients was stage I: 93.8％, stageⅡ: 83.3％, stageⅢ: 77.1％, and stage Ⅳ: 0％.

DOI： 10.5981/jjhnc.46.59

Clinicopathological review of solitary fibrous tumors: dedifferentiation is a major cause of patient death. Reviewed International journal

Yuichi Yamada, Kenichi Kohashi, Izumi Kinoshita, Hidetaka Yamamoto, Takeshi Iwasaki, Masato Yoshimoto, Shin Ishihara, Yu Toda, Yoshihiro Itou, Yutaka Koga, Mikiko Hashisako, Yui Nozaki, Daisuke Kiyozawa, Daichi Kitahara, Takeshi Inoue, Munenori Mukai, Yumi Honda, Gouji Toyokawa, Kenji Tsuchihashi, Yoshifumi Matsushita, Fumiyoshi Fushimi, Kenichi Taguchi, Sadafumi Tamiya, Yumi Oshiro, Masutaka Furue, Yasuharu Nakashima, Satoshi Suzuki, Toru Iwaki, Yoshinao Oda

Virchows Archiv : an international journal of pathology 475 ( 4 ) 467 - 477 2019.10

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

Solitary fibrous tumor (SFT) is a soft-tissue neoplasm of intermediate malignant potential, presenting a wide histopathological spectrum. Poorer prognosis of hemangiopericytoma of the central nervous system (CNS), hypoglycemic SFT, and dedifferentiation are well-known characters of SFT, but their clinical significance were not demonstrated enough by large-sized study. Here, the clinicopathological features of SFTs are reviewed and the relationship between genetics and clinicopathological features is examined using 145 SFT cases. All cases were STAT6 IHC-positive and/or NAB2-STAT6 fusion gene-positive. Tumor location was classified into three categories: 30 pleuropulmonary, 96 non-pleuropulmonary/non-central nervous system (CNS), and 18 CNS tumors. The tumor developed recurrence in 21 of 93 available cases (22.5%), metastasis in 11 of 93 (11.8%), and tumor death in 9 of 93 (9.6%). Hypoglycemia occurred in 2 primary tumors and 1 metastatic tumor among 63 reviewable cases, and dedifferentiation occurred in 10 cases (6.8%) including 6 primary tumors, 2 recurrent tumors, and 2 metastatic tumors. Recurrence was positively associated with CNS location (p = 0.0109) and hypoglycemia (p = 0.001); metastasis was positively associated with CNS location (p = 0.0231), hypoglycemia (p < 0.0001), and dedifferentiation (p < 0.0001), while metastasis was negatively correlated with pleural location (p = 0.0471). Tumor death was positively associated with male sex (p = 0.0154), larger size (p = 0.0455), hypoglycemia (p < 0.0001), and dedifferentiation (p < 0.0001). Multivariate analysis revealed independent statistical significance of dedifferentiation for overall survival (p = 0.0467). Exon variant of the fusion gene had no statistical correlation with clinical outcome. In conclusion, dedifferentiation is a major prognostic factor of SFT, and specific location such as cerebromeningeal and intra-abdominal site and hypoglycemia also had a high risk for unfavorable prognosis.

DOI： 10.1007/s00428-019-02622-9

Gastric cancer during pregnancy with placental involvement: case report and review of published works. Reviewed International journal

Seiya Oga, Masahiro Hachisuga, Nobuhiro Hidaka, Yasuyuki Fujita, Hiroshi Tomonobe, Hidetaka Yamamoto, Kiyoko Kato

Obstetrics & gynecology science 62 ( 5 ) 357 - 361 2019.9

Language：English

Gastric cancer involving the placenta during pregnancy is rare; however, we present 1 such case in this report. A 31-year-old Japanese woman was referred at 26 weeks of gestation for the evaluation of a swollen left supraclavicular lymph node. Biopsy revealed poorly differentiated adenocarcinoma, and esophagogastroduodenoscopy with biopsy of the stomach confirmed the diagnosis of gastric cancer. Her epigastric and back pain became more pronounced and her general status worsened, and we performed a cesarean delivery at 29 weeks. Microscopic examination of the placental specimen revealed poorly differentiated adenocarcinoma cells diffused into the intervillous space. Postpartum chemotherapy consisted of S-1 plus oxaliplatin. Unfortunately, this treatment was ineffective, and the patient died 3 months after delivery. The infant did well, without clinical or laboratory manifestations of metastasis. In patients with advanced gastric cancer during pregnancy, it is important to perform a microscopic examination of the placenta to evaluate for metastatic involvement.

DOI： 10.5468/ogs.2019.62.5.357

Primary mucoepidermoid carcinoma of the liver with CRTC1-MAML2 fusion: a case report. Reviewed International journal

Jiro Watanabe, Keita Kai, Ken Tanikawa, Mamoru Hiraki, Naohisa Mizukami, Shinichi Aishima, Takafumi Nakano, Hidetaka Yamamoto

Diagnostic pathology 14 ( 1 ) 84 - 84 2019.7

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

BACKGROUND: CRTC1-MAML2 fusion is often detected in low- or intermediate-grade salivary mucoepidermoid carcinoma (MEC), and it is associated with a favorable clinical course. Primary MEC of the liver is an extremely rare, aggressive tumor, and no study has investigated CRTC1-MAML2 fusion. CASE PRESENTATION: A 79-year-old Japanese female presented with an approx. 5-cm hepatic mass lesion. We surgically resected the lesion under the clinical diagnosis of intrahepatic cholangiocarcinoma. The histological and immunohistochemical findings were consistent with high-grade MEC, consisting of squamoid, mucin-producing, and intermediate tumor cells. Our RT-PCR analysis revealed the presence of CRTC1-MAML2 fusion. This fusion gene was further confirmed by direct sequencing. The patient is still alive almost 10 years after the surgery. CONCLUSION: This is the first case report of primary MEC of the liver with CRTC1-MAML2 fusion, with long survival. The present case has significant implications for the entity of primary MEC of the liver which should be distinguished from adenosquamous carcinoma.

DOI： 10.1186/s13000-019-0863-8

Mucosal incision-assisted biopsy versus endoscopic ultrasound-guided fine-needle aspiration with a rapid on-site evaluation for gastric subepithelial lesions: A randomized cross-over study. Reviewed International journal

Takashi Osoegawa, Yosuke Minoda, Eikichi Ihara, Keishi Komori, Akira Aso, Ayako Goto, Soichi Itaba, Haruei Ogino, Kazuhiko Nakamura, Naohiko Harada, Kosuke Makihara, Shinichi Tsuruta, Hidetaka Yamamoto, Yoshihiro Ogawa

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 31 ( 4 ) 413 - 421 2019.7

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

OBJECTIVES: This study aimed to compare the diagnostic yield of mucosal incision-assisted biopsy (MIAB) and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) with a rapid on-site evaluation (ROSE) for gastric subepithelial lesions (SEL) suspected of being gastrointestinal stromal tumors (GIST) with an intraluminal growth pattern. METHODS: This was a prospective randomized, cross-over multicenter study. The primary outcome was the diagnostic yield of EUS-FNA and MIAB. The secondary outcomes were the technical success rate, complication rate, procedure time and biopsy frequency. RESULTS: A total of 47 patients were randomized to the MIAB group (n = 23) and EUS-FNA group (n = 24). There was no significant difference in the diagnostic yield of MIAB and EUS-FNA (91.3% vs 70.8%, P = 0.0746). The complication rates of MIAB and EUS-FNA did not differ to a statistically significant extent. The mean procedure time in the MIAB group was significantly longer than that in the EUS-FNA group (34 vs 26 min, P = 0.0011). CONCLUSIONS: The diagnostic yield of MIAB was satisfactorily as high as EUS-FNA with ROSE for gastric SEL with an intraluminal growth pattern.

DOI： 10.1111/den.13367

Endoscopic features of gastrointestinal stromal tumor in the small intestine. Reviewed International journal

Yutaro Ihara, Takehiro Torisu, Tomohiko Moriyama, Junji Umeno, Atsushi Hirano, Yasuharu Okamoto, Yoshifumi Hori, Hidetaka Yamamoto, Takanari Kitazono, Motohiro Esaki

Intestinal research 17 ( 3 ) 398 - 403 2019.7

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

BACKGROUND/AIMS: Gastrointestinal stromal tumor (GIST) is one of the most common types of submucosal tumors (SMTs). Because of GIST's malignant potential, it is crucial to differentiate it from other SMTs. The present study aimed to identify characteristic endoscopic findings of GISTs in the small intestine. METHODS: We reviewed the clinicopathological and endoscopic findings of 38 patients with endoscopically or surgically resected SMTs in the small intestine. SMTs were classified into GIST and non-GIST groups, and clinicopathological and endoscopic findings were compared between the 2 groups. RESULTS: Fifteen patients had GIST and 23 patients had other types of SMTs in the small intestine. Comparison of the endoscopic findings between the 2 groups revealed that dilated vessels in the surrounding mucosa were significantly more in number in the GIST group than in the non-GIST group (P<0.05). However, there were no other differences in endoscopic findings between the 2 groups. Among patients with GISTs, the presence of dilated vessels in the surrounding mucosa was not associated with bleeding risk, tumor size, or metastasis rate at diagnosis. CONCLUSIONS: Dilated vessels in the surrounding mucosa, identified during balloon-assisted endoscopy, may be a diagnostic indicator for GIST in the small intestine. However, its clinical significance should be further analyzed.

DOI： 10.5217/ir.2018.00161

Corrigendum to "Effects of menstrual cycle on background parenchymal enhancement and detectability of breast cancer on dynamic contrast-enhanced breast MRI: A multicenter study of an Asian population" [Eur. J. Radiol. 110 (2019) 130-135]. Reviewed International journal

Takeshi Kamitani, Hidetake Yabuuchi, Yoshihide Kanemaki, Mitsuhiro Tozaki, Tetsuo Sonomura, Waka Mizukoshi, Waka Nakata, Taro Shimono, Misugi Urano, Toshiko Yamano, Fumi Kato, Megumi Kuchiki, Nobuyuki Shiraga, Hisami Yanagita, Eisuke Katsuda, Masako Kataoka, Ken Yamaguchi, Takuro Horikoshi, Tatsuya Gomi, Miwako Nozaki, Motoi Shiotani, Maki Amano, Hirokazu Saigusa, Shunichi Sadaoka, Hisashi Kamiya, Makoto Kubo, Nami Yamashita, Hidetaka Yamamoto, Hiroshi Honda

European journal of radiology 114 192 - 192 2019.5

Current Update on the Molecular Biology of Cutaneous Sarcoma: Dermatofibrosarcoma Protuberans. Reviewed International journal

Takeshi Iwasaki, Hidetaka Yamamoto, Yoshinao Oda

Current treatment options in oncology 20 ( 4 ) 29 - 29 2019.3

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

OPINION STATEMENT: Cutaneous sarcoma is a group of malignant mesenchymal tumors primarily involving the dermis, and it is characterized by extreme clinicopathological heterogeneity. Although its occurrence rate is rare, dermatofibrosarcoma protuberans (DFSP) is one of the most common types of dermal sarcoma. DFSP grows slowly and tends to relapse locally after inadequate resection. There are various histological variants of DFSP tumors and it often mimics benign lesions such as dermatofibroma and scar, which make accurate diagnosis difficult and delayed, and some cases progress to the stage where the tumor is unresectable. Recent advancements in cancer genetics and molecular biology methods have elucidated the COL1A1-PDGFB fusion gene, some novel fusion gene variants and pathways related to DFSP pathogenesis that have resulted in the evolution of cutaneous sarcoma diagnosis and treatment. For example, some clinical studies have confirmed the efficacy of imatinib methylate, an αPDGFR-targeted therapy for unresectable or metastatic DFSP. The present review summarizes recent updates in DFSP research, diagnostics, and treatment.

DOI： 10.1007/s11864-019-0628-3

Glypican-3 expression in malignant small round cell tumors. Reviewed International journal

Yuichi Shibui, Kina Miyoshi, Kenichi Kohashi, Yoshiaki Kinoshita, Masaaki Kuda, Hidetaka Yamamoto, Tomoaki Taguchi, Yoshinao Oda

Oncology letters 17 ( 3 ) 3523 - 3528 2019.3

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

Malignant small round cell tumors usually progress rapidly and show resistance to chemotherapy, and it is often difficult to make a definitive diagnosis based on their histological morphology. Glypican-3 (GPC3) is a highly tumor-specific antigen, and the overexpression of GPC3 was reported in many pediatric and adult malignancies. In the present study, we investigated the GPC3 expression in pediatric malignant small round cell tumors to assess its role in the differential diagnosis of the tumors. Immunohistochemistry was performed to assess the expression of GPC3 in samples from 84 rhabdomyosarcomas (RMSs; 44 alveolar and 40 embryonal RMSs), 62 Ewing sarcomas (EWSs), 35 neuroblastomas (NBs) and two desmoplastic small round cell tumors (DSRCTs). We performed a reverse transcription-quantitative polymerase chain reaction for GPC3 to determine the GPC3 mRNA expression in samples from 66 frozen tumors (23 RMSs, 28 EWSs and 15 NBs). The serum expression levels of GPC3 were analyzed in pre-operative blood samples from two RMS and eight NB patients. In total, 25% (21/84) of the RMSs and 3% (1/35) of the NBs exhibited a focal expression of GPC3, whereas, the other specimens showed no GPC3 expression. The GPC3 mRNA expression level of the RMSs with positive GPC3 expression (n=6) was significantly higher compared with the RMSs without such expression (n=17). A total of two cases of NB showed high serum levels of GPC3, but neither tumor showed immunoreactivity for GPC3. The immunohistochemical overexpression of GPC3 may be a candidate ancillary parameter in the differential diagnosis of RMS from EWS and DSRCT.

DOI： 10.3892/ol.2019.9976

Posttransplant recipient-derived CD4+ T-cell lymphoproliferative disease in X-linked hyper-IgM syndrome. Reviewed International journal

Yasuaki Hagio, Akira Shiraishi, Masataka Ishimura, Motoshi Sonoda, Katsuhide Eguchi, Hidetaka Yamamoto, Yoshinao Oda, Shouichi Ohga

Pediatric blood & cancer 66 ( 3 ) e27529 2019.3

Recurrence of Biphenotypic Sinonasal Sarcoma With Cerebral Hemorrhaging. Reviewed International journal

Hirotaka Fudaba, Yasutomo Momii, Takashi Hirano, Hidetaka Yamamoto, Minoru Fujiki

The Journal of craniofacial surgery 30 ( 1 ) e1-e2 2019.1

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

Biphenotypic sinonasal sarcoma (BSNS) is a newly classified tumor that is characterized by neural and myogenic differentiation. The authors herein report a rare patient of the recurrence of BSNS with intracranial hemorrhaging and a review of the literature. A 70-year-old man presented with disturbance of consciousness and vomiting blood. He had undergone resection of a sinonasal tumor 11 years earlier and shown no recurrence at his last follow-up 4 years ago. Computed tomography showed cerebral hemorrhaging around a low-density mass that occupied the left frontal base and left ethmoid sinus. Total resection was performed. A histological examination of tumor specimens obtained from the first and the second resections revealed almost the same characteristic morphological features and the patient was diagnosed with BSNS. The lesion was negative for any fusion genes, as previously reported. The long-term progression of BSNS is not clear. This case appears to be the first reported recurrence of BSNS with cerebral hemorrhaging. Biphenotypic sinonasal sarcoma should be considered to need long-term follow-up.

DOI： 10.1097/SCS.0000000000004720

Effects of menstrual cycle on background parenchymal enhancement and detectability of breast cancer on dynamic contrast-enhanced breast MRI: A multicenter study of an Asian population. Reviewed International journal

Takeshi Kamitani, Hidetake Yabuuchi, Yoshihide Kanemaki, Mitsuhiro Tozaki, Tetsuo Sonomura, Waka Mizukoshi, Waka Nakata, Taro Shimono, Misugi Urano, Toshiko Yamano, Fumi Kato, Megumi Kuchiki, Nobuyuki Shiragami, Hisami Yanagita, Eisuke Katsuda, Masako Kataoka, Ken Yamaguchi, Takuro Horikoshi, Tatsuya Gomi, Miwako Nozaki, Motoi Shiotani, Maki Amano, Hirokazu Saigusa, Shunichi Sadaoka, Hisashi Kamiya, Makoto Kubo, Nami Yamashita, Hidetaka Yamamoto, Hiroshi Honda

European journal of radiology 110 130 - 135 2019.1

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

PURPOSE: To evaluate the effect of the menstrual cycle on BPE and cancer detectability in an Asian population. MATERIAL AND METHODS: 266 premenopausal patients with regular menstrual cycles from 24 centers were included, and 176 of them were diagnosed by pathology as having breast cancer. Thirty-five patients were examined in the menstrual phase (days 1-4), 105 in the proliferative phase (days 5-14), and 126 in the secretory phase (days 15-30). Measurement of the following signal intensities (SIs) were obtained: breast tissue on the unaffected side on a pre-contrast image (SI1) and an early-phase image (SI2); the SIs of breast tissue on the affected side on a pre-contrast image (SI3) and an early-phase image (SI4); and the SIs of breast cancer on a pre-contrast image (SI5) and an early-phase image (SI6). We calculated the BPE ratio, i.e., (SI2- SI1)/SI1 and the cancer/background enhancement ratio (C/B) ratio, i.e., (SI6- SI5) / (SI4- SI3). The BPE was classified as minimal, mild, moderate, or marked, and the cancer detectability was classified as excellent, good, or poor independently by two radiologists. RESULTS: The average C/B ratio was 20.1, 15.7, and 9.1 at the menstrual, proliferative, and secretory phases (p < 0.001). BPE was determined as moderate or marked in 0% and 5.4% at the menstrual phase, 10.3% and 11.0% at the proliferative phase, and 17.5% and 21.7% at the secretory phase by the two observers, respectively (p = 0.01, p = 0.01). The detectability of breast cancer was classified as poor in 0% and 0%, 1.4% and 13.0%, and 8.0% and 22.1% at the menstrual, proliferative, and secretory phases by the two observers, respectively (p = 0.07, p = 0.02). CONCLUSION: The menstrual phase and the proliferative phase seem to be suitable for breast MRI of Asian women.

DOI： 10.1016/j.ejrad.2018.11.025

Localized malignant pleural mesothelioma mimicking an anterior mediastinal tumor. Reviewed International journal

Takuya Hino, Takeshi Kamitani, Koji Sagiyama, Yuzo Yamasaki, Isamu Okamoto, Tetsuzo Tagawa, Kayo Ijichi, Hidetaka Yamamoto, Hidetake Yabuuchi, Hiroshi Honda

European journal of radiology open 6 72 - 77 2019

Language：English

Localized malignant pleural mesothelioma (LMPM) is an extremely rare tumor. We report the case of a 40-year-old Japanese male with an LMPM mimicking an anterior mediastinal tumor due to invasion to the anterior mediastinum, and we discuss mainly the differentiation of LMPM from an anterior mediastinal tumor. The present tumor had a long shape along the pleura, and LMPM could be one of the differential diagnoses.

DOI： 10.1016/j.ejro.2019.01.006

"Pancreatic Mucoepidermoid Carcinoma" Is not a Pancreatic Counterpart of CRTC1/3-MAML2 Fusion Gene-related Mucoepidermoid Carcinoma of the Salivary Gland, and May More Appropriately be Termed Pancreatic Adenosquamous Carcinoma With Mucoepidermoid Carcinoma-like Features. Reviewed International journal

Kiyoshi Saeki, Yoshihiro Ohishi, Ryota Matsuda, Naoki Mochidome, Yoshihiro Miyasaka, Hidetaka Yamamoto, Yutaka Koga, Yoshihiko Maehara, Masafumi Nakamura, Yoshinao Oda

The American journal of surgical pathology 42 ( 11 ) 1419 - 1428 2018.11

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

"Mucoepidermoid carcinoma (MEC)" has been accepted as a synonym for pancreatic adenosquamous carcinoma (ASC). Pancreatic ASC can show salivary gland-type MEC-like morphology. CRTC1/3-MAML2 fusion gene is a characteristic molecular feature of MEC of the salivary gland. We conducted this study to clarify whether the pancreatic ASC with salivary gland-type MEC-like morphology (Pan-MEC) is a pancreatic counterpart of salivary gland-type MEC (Sal-MEC). We retrospectively analyzed 37 pancreatic ASCs including 16 Pan-MECs and 21 tumors without MEC-like features (ASC-NOS [not otherwise specified]), and we investigated (1) clinicopathologic features, (2) the presence of CRTC1/3-MAML2 fusion gene by reverse transcription polymerase chain reaction, (3) the presence of rearrangement of MAML2 gene by fluorescence in situ hybridization, and (4) mucin core proteins by immunohistochemistry. We also compared 16 Pan-MECs with 20 Sal-MECs by immunohistochemistry for mucin core protein. There were no significant differences of any clinicopathologic characteristics and survival analysis between the Pan-MECs and ASCs-NOS. Of note, the pancreatic ASCs (including Pan-MEC and ASC-NOS) were significantly more aggressive than conventional pancreatic ductal adenocarcinoma. In addition, all Pan-MECs were histologically high-grade. CRTC1/3-MAML2 fusion gene and MAML2 gene rearrangement were not detected in any ASCs including Pan-MECs. There were significant differences of MUC5AC and MUC6 between the Pan-MECs and Sal-MECs, but no significant differences of mucin core protein between the Pan-MECs and pancreatic ASCs-NOS. Pan-MEC is histologically and biologically high-grade and unrelated to CRTC1/3-MAML2 fusion gene, unlike Sal-MEC which is related to CRTC1/3-MAML2 fusion gene. Pan-MEC is not a pancreatic counterpart of CRTC1/3-MAML2 fusion gene-related Sal-MEC.

DOI： 10.1097/PAS.0000000000001135

A case of primary extraskeletal osteosarcoma of the breast. Reviewed International journal

Kanako Kurata, Keisei Anan, Nami Ishikawa, Kenichiro Koga, Michiyo Saimura, Kazuyoshi Nishihara, Toshimitsu Iwashita, Shoshu Mitsuyama, Sadafumi Tamiya, Hideyuki Watanabe, Yutaka Koga, Hidetaka Yamamoto, Yoshinao Oda, Toru Nakano

Surgical case reports 4 ( 1 ) 121 - 121 2018.9

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

BACKGROUND: Primary sarcomas of the breast are rare and account for less than 1% of all primary breast malignancies. We experienced a case of extraskeletal osteosarcoma of the breast that had a unique clinical course and remarkable findings of mammography and magnetic resonance imaging (MRI). A review of the case reports published in the past few decades showed no reports of a case in which a calcified lesion was followed up three different times on mammography, making this a valuable case report. CASE PRESENTATION: A 52-year-old woman noticed a right breast mass and underwent a breast examination. Mammography showed a 1.5-cm coarse calcified lesion in the upper outer portion of the right breast. Because fine-needle aspiration (FNA) revealed no suspicion of malignancy, she was followed up. Sixteen months later, the tumor grew progressively to 4.5 cm in size with new calcifications that were fine and irregular in shape and density surrounding an enlarged, coarse calcified lesion. Contrast-enhanced magnetic resonance imaging (MRI) showed a high signal intensity in the periphery of the tumor. Extirpation of the tumor was indicated. The pathological findings were extraskeletal osteosarcoma. She underwent additional resection and latissimus dorsi flap reconstruction at the Department of Orthopedic Surgery. CONCLUSION: The present case suggests that mammography findings of a tumor with coarse calcifications that are not typical of benign lesions may be extraskeletal osteosarcoma. A diagnosis must be made as early as possible in order to improve the prognosis of this disease.

DOI： 10.1186/s40792-018-0530-4

An extremely rare case of primary malignancy in giant cell tumor of bone, arising in the right femur and harboring H3F3A mutation. Reviewed International journal

Yoshitane Tsukamoto, Hiroyuki Futani, Takako Kihara, Takahiro Watanabe, Shunsuke Kumanishi, Shohei Matsuo, Seiichi Hirota, Takafumi Ueda, Hidetaka Yamamoto, Shinichi Yoshiya

Pathology, research and practice 214 ( 9 ) 1504 - 1509 2018.9

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

We experienced a case of primary malignancy in giant cell tumor of bone (GCTB), arising in the right femur and harboring H3F3A mutation. A 27-year-old Japanese male without any prior disease history complained of pain in his right hip joint and right lower limb. Radiological images revealed an osteolytic and multicystic lesion existing mainly at the proximal epiphysis of the right femur. Preoperative clinical diagnosis was GCTB, although irregular marginal sclerosis was an atypical radiographic finding for conventional GCTBs. Biopsy sample from the lesion revealed the coexistence of typical GCTB and undifferentiated high-grade round cell sarcoma. Despite of the wide local resection of the tumor with preoperative and postoperative chemotherapy, the patient died of multiple distant metastases of the tumor 9 months after the surgery. Since heterozygous H3F3A c. 103G>T (p. Gly34Trp) mutation was detected not only in the biopsy sample from the primary site with typical GCTB and high-grade sarcoma components but also in the resected material from the metastatic site with only pure high-grade sarcoma component, the tumor was considered originally derived from conventional GCTB and acquire malignant transformation to high-grade sarcoma. Thus, this is an extremely rare case of primary malignancy in GCTB and the first case report of primary malignancy in GCTB proved the presence of H3F3A mutation even in the sarcoma component.

DOI： 10.1016/j.prp.2018.06.015

Leiomyosarcoma of the stomach treated by endoscopic submucosal dissection. Reviewed

Takao Sato, Kazuya Akahoshi, Naru Tomoeda, Norikatsu Kinoshita, Masaru Kubokawa, Kentaro Yodoe, Yuka Hiraki, Masafumi Oya, Hidetaka Yamamoto, Eikichi Ihara

Clinical journal of gastroenterology 11 ( 4 ) 291 - 296 2018.8

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

There have been no reports of primary leiomyosarcoma of the stomach treated by endoscopic submucosal dissection (ESD). We report an extremely rare case of gastric leiomyosarcoma that was successfully treated by ESD. An asymptomatic 74-year-old female underwent esophagogastroduodenoscopy for screening in December 2013. A centrally depressed submucosal tumor 10 mm in diameter was detected at the posterior wall of the upper gastric body. Follow-up esophagogastroduodenoscopy conducted 5 months later showed that the tumor diameter had increased to 15 mm. Endoscopic ultrasound revealed a hypoechoic mass located in the second to the middle of the third layer. Endoscopic ultrasound-guided fine-needle aspiration demonstrated a myogenic tumor. The tumor was completely resected by ESD without complications. Immunohistopathological diagnosis of the resected specimen was gastric leiomyosarcoma derived from the muscularis mucosae, with negative lateral and vertical margins. No local recurrence or metastasis has been detected at 36 months after ESD. This is the first report of gastric leiomyosarcoma treated by ESD in the English language literature.

DOI： 10.1007/s12328-018-0838-4

Overexpression of MTH1 and OGG1 proteins in ulcerative colitis-associated carcinogenesis. Reviewed International journal

Yoshiteru Kumagae, Minako Hirahashi, Katsumi Takizawa, Hidetaka Yamamoto, Masaki Gushima, Motohiro Esaki, Takayuki Matsumoto, Masafumi Nakamura, Takanari Kitazono, Yoshinao Oda

Oncology letters 16 ( 2 ) 1765 - 1776 2018.8

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

Oxidative stress, demonstrated by an accumulation of 8-hydroxy-2'-deoxyguanosine (8-OHdG), results in DNA damage, which is normally repaired by base excision repair enzymes including 8-OHdG DNA glycosylase (OGG1) and human MutY homolog (MUTYH), in addition to nucleotide pool sanitizing enzymes including MutT Homolog 1 (MTH1). Abnormalities of this repair system are present in various cancer types. The present study aimed to elucidate the clinicopathological significance of altered expression levels of inducible nitric oxide synthase (iNOS), 8-OHdG, OGG1, MTH1 and MUTYH in ulcerative colitis (UC) and UC-associated neoplasms. Immunohistochemical staining for these markers and p53 in 23 cases of UC-associated neoplasm (Group A, 14 carcinomas and nine dysplasias), 16 cases of UC without neoplasm (Group B) and 17 cases of normal colon specimens (Group C) was performed. Mutation analyses was conducted for KRAS proto-oncogene, GTPase (K-ras), tumor protein P53 (TP53) and isocitrate dehydrogenase (NADP (+)) 1, cytosolic (IDH1) genes. Immunohistochemically, the iNOS, 8-OHdG, OGG1 and MTH1 expression levels were increased in Groups A and B compared with Group C. The OGG1 and MTH1 expression levels in Group A were also increased compared with Group B. Group A and Group B exhibited increased cytoplasmic expression and decreased nuclear expression of MUTYH compared with Group C. Mutations of K-ras and TP53 were detected in 2/21 (9.5%) and 10/22 (45.5%) cases of Group A, respectively. IDH1 mutation was not detected in any cases. These findings suggest that, as a response to oxidative damage, OGG1 and MTH1 may be upregulated in UC through an inflammatory condition that progresses to cancer formation. Persisting oxidative damage stress may play a role in the pathogenesis of UC-associated tumors.

DOI： 10.3892/ol.2018.8812

Wnt/β-catenin signal alteration and its diagnostic utility in basal cell adenoma and histologically similar tumors of the salivary gland. Reviewed International journal

Masanobu Sato, Hidetaka Yamamoto, Yui Hatanaka, Toshimitsu Nishijima, Rina Jiromaru, Ryuji Yasumatsu, Kenichi Taguchi, Muneyuki Masuda, Takashi Nakagawa, Yoshinao Oda

Pathology, research and practice 214 ( 4 ) 586 - 592 2018.4

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

Differential diagnosis among basal cell adenoma (BCA), basal cell adenocarcinoma (BCAC), adenoid cystic carcinoma (ACC) and pleomorphic adenoma (PA) of the salivary gland can be challenging due to their similar histological appearance. Although frequent nuclear β-catenin expression and CTNNB1 mutations have been reported in BCA, further details of the Wnt/β-catenin signal alterations are unclear. The aim of this study was to assess the diagnostic utility of Wnt/β-catenin signal alteration in BCA and morphological mimics. We performed immunohistochemical staining for β-catenin and mutation analysis for Wnt/β-catenin-related genes (CTNNB1, APC, AXIN1 and AXIN2) in BCA (n = 34), BCAC (n = 3), ACC (n = 67) and PA (n = 31). We also analyzed ACC-specific MYB and MYBL1 gene rearrangements by fluorescence in situ hybridization (FISH). Nuclear β-catenin expression (≥3%) was present in 32/34 cases (94.1%) of BCA, and the nuclear β-catenin labeling index was significantly higher than in other tumor types (p = < 0.0001). In BCA, we found mutations in CTNNB1, APC and AXIN1 genes (41.1%, 2.9% and 8.8%, respectively). In BCAC, nuclear β-catenin expression with CTNNB1 mutation was present in 1/3 cases (33.3%). As for ACC, nuclear β-catenin expression was observed in 3/67 cases (4.4%), but all 3 cases harbored either MYB or MYBL1 gene rearrangement. The results suggest that nuclear β-catenin immunoreactivity with appropriate criteria may be helpful to distinguish BCA from histologically similar tumors. However, a minor subset of ACCs with nuclear β-catenin expression require careful diagnosis. In addition, Wnt/β-catenin signal alteration may play a role in the pathogenesis of BCA and BCAC.

DOI： 10.1016/j.prp.2017.12.016

Insulin-like growth factor II messenger RNA-binding protein-3 is an independent prognostic factor in uterine leiomyosarcoma. Reviewed International journal

Nobuko Yasutake, Yoshihiro Ohishi, Kenichi Taguchi, Yuka Hiraki, Masafumi Oya, Yumi Oshiro, Mari Mine, Takeshi Iwasaki, Hidetaka Yamamoto, Kenichi Kohashi, Kenzo Sonoda, Kiyoko Kato, Yoshinao Oda

Histopathology 72 ( 5 ) 739 - 748 2018.4

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

AIMS: The aim of this study was to identify the prognostic factors of uterine leiomyosarcoma (ULMS). METHODS AND RESULTS: We reviewed 60 cases of surgically resected ULMSs and investigated conventional clinicopathological factors, together with the expression of insulin-like growth factor II messenger RNA-binding protein-3 (IMP3), hormone receptors and cell cycle regulatory markers by immunohistochemistry. Mediator complex subunit 12 (MED12) mutation analysis was also performed. Univariate analyses revealed that advanced stage (P < 0.0001), older age (P = 0.0244) and IMP3 expression (P = 0.0011) were significant predictors of a poor outcome. Multivariate analysis revealed advanced stage (P < 0.0001) and IMP3 (P = 0.0373) as independent predictors of a poor prognosis. Expressions of cell cycle markers and hormone receptors, and MED12 mutations (12% in ULMSs) were not identified as prognostic markers in this study. CONCLUSIONS: IMP3 expression in ULMS could be a marker of a poor prognosis.

DOI： 10.1111/his.13422

SWI/SNF Chromatin-remodeling Complex Status in SMARCB1/INI1-preserved Epithelioid Sarcoma. Reviewed International journal

Kenichi Kohashi, Hidetaka Yamamoto, Yuichi Yamada, Izumi Kinoshita, Tomoaki Taguchi, Yukihide Iwamoto, Yoshinao Oda

The American journal of surgical pathology 42 ( 3 ) 312 - 318 2018.3

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

The SWI/SNF chromatin-remodeling complex, which is composed of evolutionarily conserved core subunits such as SMARCB1/INI1 (INI1), SMARCA4/BRG1 (BRG1), SMARCC1/BAF155 (BAF155), and SMARCC2/BAF170 (BAF170), can be viewed as the prototype of an epigenetic regulator of gene expression that is involved in tumor suppression. Epithelioid sarcoma, which classified as a tumor of uncertain differentiation, shows an almost complete loss of INI1. However, some cases of epithelioid sarcoma have preserved INI1, and the clinicopathologic features of these cases are uncertain. To date, there has been no investigation focused on the SWI/SNF chromatin-remodeling complex in INI1-preserved epithelioid sarcoma cases. First, an investigation of INI1 immunoexpression statuses in 60 formalin-fixed paraffin-embedded epithelioid sarcoma specimens (proximal type, 29 cases; conventional type, 31 cases) was performed. In the available INI1-preserved epithelioid sarcoma cases, we analyzed the BRG1, BAF155, and BAF170 protein expressions. INI1 preservation was observed in 6 of 29 (21%) proximal-type and 2 of 31 (6%) conventional-type epithelioid sarcoma cases. Six cases of INI1-preserved epithelioid sarcomas of proximal type were available for further immunohistochemical study. One proximal type showed loss of BAF170, and 2 proximal-type cases revealed loss of BRG1 with preservation of the other remaining core subunit proteins. One proximal-type case showed a mosaic pattern of BRG1 and loss of BAF155. However, in the remaining 2 proximal-type cases, all core subunit proteins were preserved. Overall, these results suggest that loss of expression of SWI/SNF chromatin-remodeling complex proteins has an important role in tumorigenesis. The remaining 2 INI1-preserved epithelioid sarcoma cases may have had other abnormalities causing dysfunction of SWI/SNF chromatin remodeling.

DOI： 10.1097/PAS.0000000000001011

Diagnostic utility of histone H3.3 G34W, G34R, and G34V mutant-specific antibodies for giant cell tumors of bone. Reviewed International journal

Hidetaka Yamamoto, Takeshi Iwasaki, Yuichi Yamada, Yoshihiro Matsumoto, Hiroshi Otsuka, Masato Yoshimoto, Kenichi Kohashi, Kenichi Taguchi, Ryohei Yokoyama, Yasuharu Nakashima, Yoshinao Oda

Human pathology 73 41 - 50 2018.3

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

Giant cell tumors of bone (GCTBs) are characterized by mononuclear stromal cells and osteoclast-like giant cells; up to 95% have H3F3A gene mutation. The RANKL inhibitor denosumab, when used for the treatment of GCTB, leads to histological changes such as new bone formation and giant cell depletion. Here we assessed the diagnostic utility of immunohistochemical staining with the antibodies against histone H3.3 G34W, G34R and G34V mutant proteins for GCTB and other histologically similar bone and joint lesions. H3.3 G34W, G34R and G34V expressions were detected in mononuclear stromal cells in 47/51 (92%), 1/51 (2%) and 3/51 (6%) cases of primary GCTBs, respectively, in a mutually exclusive manner. All recurrent/metastatic GCTBs (n=14), post-denosumab GCTBs (n=8) and secondary malignant GCTBs (n=2) were positive for H3.3 G34W. The immunohistochemical results were essentially correlated with the H3F3A genotype determined by mutation analysis. In post-denosumab GCTBs, H3.3 G34W expression was seen in immature bone-forming cells. H3.3 G34W, G34R and G34V were negative in 121/122 cases of non-GCTB, including chondroblastoma, osteosarcoma, primary aneurysmal bone cyst and other giant cell-rich lesions. The exception was a single case of undifferentiated high-grade pleomorphic sarcoma that was positive for H3.3 G34W, suggesting the possibility of sarcomatous overgrowth of primary malignant GCTB. Therefore, H3.3 G34W/R/V mutant-specific antibodies are useful surrogate markers for the H3F3A genotype and helpful for the diagnosis of GCTB and its variants. The expression of H3.3 G34W mutant protein in post-denosumab GCTB suggests that neoplastic stromal cells may play a role in new bone formation.

DOI： 10.1016/j.humpath.2017.11.020

Immunohistochemical evaluation of H3K27 trimethylation in malignant peripheral nerve sheath tumors. Reviewed International journal

Hiroshi Otsuka, Kenichi Kohashi, Masato Yoshimoto, Shin Ishihara, Yu Toda, Yuichi Yamada, Hidetaka Yamamoto, Yasuharu Nakashima, Yoshinao Oda

Pathology, research and practice 214 ( 3 ) 417 - 425 2018.3

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

The histological definitive diagnosis of malignant peripheral nerve sheath tumor (MPNST) is quite difficult because the morphological features are not specific and no useful immunohistochemical marker has been identified. Loss-of-function mutations in EED or SUZ12, which encode the core subunit of polycomb repressive complex 2 (PRC2), were reported in MPNSTs, and the mutations were shown to cause inactivation of PRC2, leading to loss of trimethylation of histone H3 at lysine 27 (H3K27me3). Immunohistochemistry of H3K27me3 is expected to be a specific marker for MPNSTs. We evaluated immunohistochemical expression of H3K27me3 in MPNSTs with heterologous components and metachronous cases of MPNSTs. Among 145 MPNST samples, 50 (34.5%) showed complete loss of staining, and 45 (31.0%) showed partial loss of staining. Regarding the backgrounds of MPNSTs, 43 patients of neurofibromatosis type 1 (NF-1)-associated MPNST demonstrated 19 (44.2%) complete and 12 (27.9%) partial loss of H3K27me3. Among MPNSTs with heterologous component, almost all of MPNSTs with epithelioid differentiation (8/9 samples, 88.9%) retained H3K27me3, and malignant Triton tumors without epithelioid component lacked H3K27me3 at high rate (91.7%). Five of 20 metachronous MPNST cases showed significantly reduced expression of H3K27me3 between primary and later-occurring tumors, but in some cases increased expression of H3K27me3 in the clinical course (such as complete loss to partial loss) was observed. If the tumors are recurrent or metastatic, H3K27me3 expression should be reduced or at least maintained because loss of H3K27me3 is due to genetic mutation of EED or SUZ12. MPNSTs, especially those associated with NF-1, can occur in heterochronous and multiple patterns, and the identification of increased expression of H3K27me3 during a patient's clinical course can be helpful for determining whether the tumors are heterochronous, multiple or not. As heterochronous and multiple tumors may show lower malignancy compared to recurrent or metastatic tumors, favorable prognosis may be expected when H3K27me3 expression is increased.

DOI： 10.1016/j.prp.2017.12.015

Histopathological and genetic review of phosphaturic mesenchymal tumours, mixed connective tissue variant. Reviewed International journal

Yuichi Yamada, Izumi Kinoshita, Kohashi Kenichi, Hidetaka Yamamoto, Takeshi Iwasaki, Hiroshi Otsuka, Masato Yoshimoto, Shin Ishihara, Yu Toda, Yuki Kuma, Nokitaka Setsu, Yuki Koga, Yumi Honda, Takeshi Inoue, Hiroyuki Yanai, Kyoko Yamashita, Ichiro Ito, Mitsuru Takahashi, Shouichi Ohga, Masutaka Furue, Yasuharu Nakashima, Yoshinao Oda

Histopathology 72 ( 3 ) 460 - 471 2018.2

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

AIMS: Phosphaturic mesenchymal tumour, mixed connective tissue variant (PMT-MCT), is a tumour of uncertain differentiation, characterised by 'smudgy/grungy' calcification and vitamin D-resistant phosphaturic osteomalacia. Fibroblast growth factor (FGF)23 is recognised as a reliable marker of PMT-MCT, but quantitative evaluation has never been performed. We reviewed cases of tumour-associated osteomalacia or histologically definitive PMT-MCT without osteomalacia using histological, immunohistochemical and genetic methods and evaluated the diagnostic significance of these findings. METHODS AND RESULTS: A total of 19 tumours from 14 cases diagnosed previously as PMT-MCT were retrieved, on which immunohistochemical staining, reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence in-situ hybridisation (FISH) analysis were performed. Histologically, fibrous capsule, calcification and giant cell reaction tended to be observed in soft-tissue PMT-MCT, while PMT-MCT of bone and multiple PMT-MCT showed an infiltrative growth pattern. The immunohistochemical results were as follows: the tumour cells were positive for FGF23 (nine of 12, 75%), FGFR1 (11 of 11, 100%), CD56 (12 of 14, 85.7%) and E26 oncogene homologue (ERG) (5 of 13, 38.4%). The sole malignant tumour was positive for p53. FGF23 mRNA was detected in seven of 14 formalin-fixed paraffin-embedded (FFPE) specimens and all five frozen specimens by RT-PCR. The level of FGF23 mRNA, which was determined by real-time PCR, varied among the phosphaturic cases. Two of 17 tumours were positive for FGFR1 gene rearrangement. CONCLUSIONS: It was considered that PMT-MCT is a histopathological entity with or without phosphaturia, with varying levels of FGF23 mRNA, and with or without fibronectin 1 (FN1)-FGFR1 fusion gene. The authors propose that the histology of PMT-MCT differs depending on its location, such as bone or soft tissue, which could complicate the differential diagnosis.

DOI： 10.1111/his.13377

Clinicopathologic and Molecular Characteristics of Synchronous Colorectal Carcinoma With Mismatch Repair Deficiency. Reviewed International journal

Kayoko Nakano, Hidetaka Yamamoto, Minako Fujiwara, Yutaka Koga, Shinichi Tsuruta, Eikichi Ihara, Eiji Oki, Masafumi Nakamura, Yoshihiro Ogawa, Yoshinao Oda

The American journal of surgical pathology 42 ( 2 ) 172 - 182 2018.2

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

Synchronous colorectal carcinoma (CRC) is a unique disease associated with a high prevalence (∼35%) of microsatellite instability and occasionally with Lynch syndrome. The clinicopathologic and molecular features of synchronous CRC are poorly understood, particularly in Japanese patients. We examined 118 Japanese patients (236 tumors) with synchronous CRC and 117 Japanese patients (117 tumors) with solitary CRC with immunohistochemical staining for TP53 and mismatch repair (MMR) protein (MLH1, MSH2, PMS2, and MSH6) and mutation analyses of KRAS and BRAF genes. The results revealed no significant differences in clinicopathologic, histologic, and molecular findings between the synchronous and solitary CRC groups. Among the 118 synchronous CRC patients, 15 (12.7%) showed loss of MMR protein(s) expression in at least 1 tumor, whereas 103 (87.3%) showed intact expression of all 4 MMR proteins in both tumors. Of note, all patients with MMR deficiency had excellent prognoses. The 15 patients were further subdivided into 2 groups: the Concordant group, with concordant MMR loss (n=9, 7.6%) and the Discordant group, with discordant MMR loss (n=6, 5.1%). The Concordant patients showed concurrent MLH1/PMS2 loss (n=3), concurrent MSH2/MSH6 loss (n=4) and isolated MSH6 loss (n=2) in both tumors, whereas the Discordant patients showed concurrent MLH1/PMS2 loss (n=2), isolated PMS2 loss (n=2) and isolated MSH6 loss (n=2) in a single tumor. On the basis of the MMR expression pattern and BRAF mutation, the Concordant and Discordant groups were suspected to include Lynch syndrome, Lynch-like syndrome and sporadic MLH1 promoter hypermethylated CRC. In addition, KRAS mutation was present in only 1 tumor in a single patient in each group. In conclusion, the frequency of MMR protein deficiency in synchronous CRC in the Japanese population may be lower compared with the reported data from Western populations. MMR protein loss and KRAS and BRAF mutations in synchronous CRCs were heterogenous even in an individual patient.

DOI： 10.1097/PAS.0000000000000947

Cancer-testis antigens are predominantly expressed in uterine leiomyosarcoma compared with non-uterine leiomyosarcoma. Reviewed International journal

Kunio Iura, Kenichi Kohashi, Nobuko Yasutake, Takeaki Ishii, Akira Maekawa, Hirofumi Bekki, Hiroshi Otsuka, Yuichi Yamada, Hidetaka Yamamoto, Yoshihiro Ohishi, Yoshihiro Matsumoto, Yukihide Iwamoto, Yoshinao Oda

Oncology letters 15 ( 1 ) 441 - 446 2018.1

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

Leiomyosarcomas account for ~24% of all adult sarcomas, and develop predominantly either in the uterus [uterine leiomyosarcoma (ULMS)] or in deep soft tissue or the retroperitoneum [non-uterine leiomyosarcoma (NULMS)]. Leiomyosarcomas are relatively chemoresistant tumors, and the prognosis of patients with leiomyosarcomas is poor. Cancer-testis (CT) antigens are considered promising immunotherapeutic targets because of their restricted expression in normal tissue, except in the testis. Little is known about the expression of CT antigens in leiomyosarcomas. In the present study, the protein expression of the CT antigens MAGE family member A (MAGEA)1, MAGEA3, MAGEA4, G antigen 7 (GAGE7) and cancer/testis antigen 1 (NY-ESO-1) in ULMS and NULMS were investigated using immunohistochemistry (IHC), and their expression profiles compared. In ULMS and NULMS, positive expression was observed in 11/32 (31%) and 1/31 (3%; MAGEA1), 15/32 (47%) and 5/31 (16%; MAGEA3), 11/32 (34%) and 3/31 (10%; MAGEA4), 23/32 (72%) and 11/31 (35%; GAGE7) and 3/32 (9%) and 0/31 (0%; NY-ESO-1), respectively. The ULMSs demonstrated significantly higher positive expression of MAGEA1 (P=0.0034), MAGEA3 (P=0.0141), MAGEA4 (P=0.0319) and GAGE7 (P=0.0054) compared with the NULMSs. The ULMSs also had significantly higher IHC scores for MAGEA1 (P=0.0023), MAGEA3 (P=0.0474), MAGEA4 (P=0.011), GAGE7 (P=0.0319) and NY-ESO-1 (P=0.0437). The results of the present study support the potential utility of MAGEA1, MAGEA3, MAGEA4 and GAGE7 in ULMS and GAGE7 in NULMS as immunotherapeutic targets.

DOI： 10.3892/ol.2017.7274

The expansion in lymphoid organs of IL-4+ BATF+ T follicular helper cells is linked to IgG4 class switching in vivo. Reviewed International journal

Takashi Maehara, Hamid Mattoo, Vinay S Mahajan, Samuel Jh Murphy, Grace J Yuen, Noriko Ishiguro, Miho Ohta, Masafumi Moriyama, Takako Saeki, Hidetaka Yamamoto, Masaki Yamauchi, Joe Daccache, Tamotsu Kiyoshima, Seiji Nakamura, John H Stone, Shiv Pillai

Life science alliance 1 ( 1 ) 2018.1

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

Distinct T follicular helper (TFH) subsets that influence specific class-switching events are assumed to exist, but the accumulation of isotype-specific TFH subsets in secondary lymphoid organs (SLOs) and tertiary lymphoid organs has not been hitherto demonstrated. IL-4-expressing TFH cells are surprisingly sparse in human SLOs. In contrast, in IgG4-related disease (IgG4-RD), a disorder characterized by polarized Ig class switching, most TFH cells in tertiary and SLOs make IL-4. Human IL-4+ TFH cells do not express GATA-3 but express nuclear BATF, and the transcriptomes of IL-4-secreting TFH cells differ from both PD1hi TFH cells that do not secrete IL-4 and IL-4-secreting non-TFH cells. Unlike IgG4-RD, IL-4+ TFH cells are rarely found in tertiary lymphoid organs in Sjögren's syndrome, a disorder in which IgG4 is not elevated. The proportion of CD4+IL-4+BATF+ T cells and CD4+IL-4+CXCR5+ T cells in IgG4-RD tissues correlates tightly with tissue IgG4 plasma cell numbers and plasma IgG4 levels in patients but not with the total plasma levels of other isotypes. These data describe a disease-related TFH subpopulation in human tertiary lymphoid organs and SLOs that is linked to IgG4 class switching.

DOI： 10.26508/lsa.201800050

A novel fusion gene CRTC3-MAML2 in hidradenoma: histopathological significance. Reviewed International journal

Yuki Kuma, Yuichi Yamada, Hidetaka Yamamoto, Kenichi Kohashi, Takamichi Ito, Masutaka Furue, Yoshinao Oda

Human pathology 70 55 - 61 2017.12

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

Hidradenoma usually presents as a solitary, slow-growing, and solid or cystic nodular lesion, which arises in various anatomical sites. Its diagnosis is occasionally difficult because the tumor shares histological features with other cutaneous appendage tumors. Recently, CRTC1-MAML2 fusion gene was reported in hidradenomas, with the fusion transcript being demonstrated in approximately 50% of cases. However, limited information is available regarding its clinical significance. Here, we investigated the relationship between the fusion gene and clinicohistopathological features. We reviewed 39 cases histologically diagnosed as hidradenoma. Reverse-transcription polymerase chain reaction (RT-PCR) was performed for all 39 cases, and fluorescence in situ hybridization was also performed for the RT-PCR-negative cases. The 39 tumors included 36 clear cell hidradenomas and 3 poroid hidradenomas. The details of the cellular components were as follows: clear cell-dominant type, 9 cases; polygonal cell-dominant type, 21 cases; and equally mixed type, 9 cases. There were no tumors with apparent mucinous cells. There were 8 tumors with prominent cystic change, 2 of which presented apocrine-like decapitated secretion. CRTC1-MAML2 fusion was detected in 10 of the 39 tumors (26%) and CRTC3-MAML2 fusion in 2 of the 39 (5%) by RT-PCR. MAML2 gene rearrangement was detected in 11 of 27 fusion gene-negative cases by fluorescence in situ hybridization. Moreover, neither the fusion genes nor gene rearrangement was detected in prominent cystic tumors and poroid hidradenomas. We conclude that CRTC1/3-MAML2 fusion gene analysis can be a useful method for diagnosing hidradenoma. Considering the histological and genetic similarity to mucoepidermoid carcinoma, hidradenoma may be a cutaneous counterpart of salivary gland mucoepidermoid carcinoma.

DOI： 10.1016/j.humpath.2017.10.004

Diffuse gastric metastases from salivary duct carcinoma. Reviewed International journal

Yuji Maehata, Yoshifumi Hori, Minako Hirahashi, Hidetaka Yamamoto, Motohiro Esaki

Gastrointestinal endoscopy 86 ( 5 ) 916 - 917 2017.11

The Local Recurrence of Breast Cancer with Squamous Metaplasia and Obvious Histological Heterogeneity. Reviewed International journal

Nami Yamashita, Eriko Tokunaga, Hidetaka Yamamoto, Chikako Shimizu, Kenji Taketani, Yuka Inoue, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara

Anticancer research 37 ( 9 ) 5249 - 5254 2017.9

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

CASE REPORT: We herein report a case of local recurrence of breast cancer with squamous metaplasia and obvious intratumoral and intertumoral heterogeneity. A 39-year-old female patient was diagnosed with T3N2M0 stage IIIB right breast cancer and underwent right total mastectomy and axillar lymph node dissection. At four years after surgery, she became aware of chest wall pain and diagnostic imaging revealed recurrence in the lung, right thoracic wall and sternum. The recurrent lesions remained stable for 18 months with endocrine therapy. Thereafter, the lesion in the right thoracic wall suddenly became enlarged. Moreover, liver metastasis was confirmed on FDG-PET/CT. She underwent right thoracic wall tumor resection. A biopsy was simultaneously performed to obtain a specimen from the site of liver metastasis. Postoperatively, the right chest wall mass showed obvious intratumoral heterogeneity; squamous differentiation with aggressive features and a papillotubular component similar to the primary tumor. The metastatic liver tumor showed similar pathological features to the primary tumor. CONCLUSION: Intratumoral and intertumoral heterogeneity within primary tumors and associated metastatic sites may contribute to treatment failure and drug resistance.

Alteration of PDGFRβ-Akt-mTOR pathway signaling in fibrosarcomatous transformation of dermatofibrosarcoma protuberans. Reviewed International journal

Yuka Hiraki-Hotokebuchi, Yuichi Yamada, Kenichi Kohashi, Hidetaka Yamamoto, Makoto Endo, Nokitaka Setsu, Kuma Yuki, Takamichi Ito, Yukihide Iwamoto, Masutaka Furue, Yoshinao Oda

Human pathology 67 60 - 68 2017.9

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

Dermatofibrosarcoma protuberans (DFSP) is a cutaneous mesenchymal tumor of intermediate malignancy and fibroblastic/myofibroblastic differentiation. Fibrosarcomatous (FS) component is a high-grade component of DFSP. The detailed oncogenic difference between DFSP and FS components is not clear. We thus investigated the Akt-mTOR pathway in both components. We used 65 tumor samples obtained from 65 patients. The phosphorylation of Akt-mTOR pathway proteins (Akt, mTOR, 4EBP1, and S6RP) and PDGFRα/β was assessed by immunohistochemical staining, the results of which were confirmed by Western blotting. The immunohistochemical results were as follows: in ordinary DFSP components, p-PDGFRα-positive tumors were 41.9% (18/43 cases), p-PDGFRβ 55.8% (24/43 cases), p-Akt 51.2% (22/43 cases), p-mTOR 39.5% (17/43 cases), p-4EBP1 46.5% (20/43 cases), and p-S6RP 41.8% (18/43 cases); in DFSP components of FS-DFSP, 52.6% (10/19 cases), 47.4% (9/19 cases), 52.6% (10/19 cases), 36.8% (7/19 cases), 52.6% (10/19 cases), and 52.6% (10/19 cases); and in FS components, 45.5% (10/22 cases), 36.4% (8/22 cases), 72.7% (16/22 cases), 54.5% (12/22 cases), 72.7% (16/22 cases), and 68.2% (15/22 cases), respectively. There were significant positive correlations of the phosphorylation of most of the Akt-mTOR pathway proteins (p-Akt, p-mTOR, p-4EBP1, and p-S6RP) with each other (P < .05). Phospho-PDGFRβ was well correlated with the phosphorylation of Akt-mTOR pathway proteins in DFSP components of ordinary and FS-DFSPs, but these correlations were weaker in FS components. This study suggested the association of activation of Akt-mTOR pathway proteins and PDGFR with the progression of DFSP to FS. The Akt-mTOR pathway is thus a potential therapeutic target in imatinib-resistant DFSP/FS.

DOI： 10.1016/j.humpath.2017.07.001

Soft tissue sarcomas: From a morphological to a molecular biological approach. Reviewed International journal

Yoshinao Oda, Hidetaka Yamamoto, Kenichi Kohashi, Yuichi Yamada, Kunio Iura, Takeaki Ishii, Akira Maekawa, Hirofumi Bekki

Pathology international 67 ( 9 ) 435 - 446 2017.9

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

Recently developed molecular genetic techniques have led to the elucidation of tumor-specific genomic alterations and thereby the reclassification of tumor entities of soft tissue sarcoma. A solitary fibrous tumor-mimicking tumor with the AHRR-NCOA2 gene has been isolated as angiofibroma of soft tissue. As for small round cell sarcomas, novel fusion genes such as CIC-DUX4 and BCOR-CCNB3 have been identified in these tumor groups. SMARCB1/INI1 deficient tumors with round cell morphology are also expected to be reclassified in three types, based on the combination of their morphology and genotype. The identification of the MDM2 gene amplification in pleomorphic sarcomas has extended the entity of dedifferentiated liposarcoma (DDLS). Our recent molecular investigations elucidated candidates for novel therapeutic strategies. Activation of the Akt-mTOR pathway was correlated with poor prognosis or tumor grade in spindle cell sarcomas including malignant peripheral nerve sheath tumor. In vitro and in vivo studies of transcription factor Forkhead Box M1 (FOXM1) demonstrated the close correlation between aggressive biological behavior or chemosensitivity and FOXM1 expression in synovial sarcoma, so far. Finally, in regard to the investigation of cancer-testis antigens, myxoid/round cell liposarcoma and synovial sarcoma showed frequent and high expression of PRAME and NY-ESO-1.

DOI： 10.1111/pin.12565

MAGEA4 expression in bone and soft tissue tumors: its utility as a target for immunotherapy and diagnostic marker combined with NY-ESO-1. Reviewed International journal

Kunio Iura, Kenichi Kohashi, Takeaki Ishii, Akira Maekawa, Hirofumi Bekki, Hiroshi Otsuka, Yuichi Yamada, Hidetaka Yamamoto, Yoshihiro Matsumoto, Yukihide Iwamoto, Yoshinao Oda

Virchows Archiv : an international journal of pathology 471 ( 3 ) 383 - 392 2017.9

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

Cancer-testis (CT) antigens have promise as targets for immunotherapy, because of their restricted expression in tumor or testis tissue. MAGEA4 is both a MAGE family member and a CT antigen, and has attracted attention as a potential immunotherapeutic target. We investigated MAGEA4 expression by immunohistochemistry in bone and soft tissue tumor specimens that consisted of 35 malignant or intermediate and 24 benign histological subtypes, in order to evaluate its possible utility as an immunotherapy target and its potential use as a diagnostic marker when combined with another CT antigen, NY-ESO-1. Among these tumors, MAGEA4 was detected in 82.2% of synovial sarcomas, 67.7% of myxoid liposarcomas, 43.8% of osteosarcomas, 41.4% of angiosarcomas, 24.6% of malignant peripheral nerve sheath tumors (MPNSTs), and 21.4% of chondrosarcomas. NY-ESO-1 expression was found in 88.2% of myxoid liposarcomas, 61.1% of synovial sarcomas, 31.3% of osteosarcomas, 21.4% of pleomorphic liposarcomas, 16.7% of desmoplastic small round cell tumors, and 14.3% of chondrosarcomas. Benign tumors and non-tumorous tissue, except for testis tissue, did not express MAGEA4 or NY-ESO-1. Combined use of MAGEA4 and NY-ESO-1 increased the sensitivity, specificity, positive predictive values, and negative predictive values for distinguishing synovial sarcoma from spindle cell tumors and other mimicking tumors, compared to individual use of MAGEA4 or NY-ESO-1. Our results support the immunotherapy targeting MAGEA4 or NY-ESO-1 can be an ancillary therapy in the above-mentioned tumors, and the potential utility of MAGEA4 as an ancillary diagnostic marker for synovial sarcoma combined with NY-ESO-1.

DOI： 10.1007/s00428-017-2206-z

HIF-1α, MDM2, CDK4, and p16 expression in ischemic fasciitis, focusing on its ischemic condition. Reviewed International journal

Yuichi Yamada, Izumi Kinoshita, Kenichi Kohashi, Hidetaka Yamamoto, Yuki Kuma, Takamichi Ito, Kenji Koda, Atsushi Kisanuki, Manabu Kurosawa, Michiko Yoshimura, Masutaka Furue, Yoshinao Oda

Virchows Archiv : an international journal of pathology 471 ( 1 ) 117 - 122 2017.7

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

Ischemic fasciitis is a benign myofibroblastic lesion, occurring in the sacral region or proximal thigh of elderly or bedridden individuals. The pathogenesis of ischemic fasciitis is thought to be based on ischemic condition; however, it has never been demonstrated. In this study, we examined the expression of ischemia-associated proteins in ischemic fasciitis by immunohistochemical and genetic methods. Specifically, this study aimed to reveal the expression of HIF-1α, MDM2, CDK4, p16, and gene amplification of MDM2 gene. Seven cases of ischemic fasciitis from among the soft-tissue tumors registered at our institution were retrieved. Histopathological findings were as follows: poorly demarcated nodular masses, a proliferation of spindle-shaped fibroblastic or myofibroblastic cells with oval nuclei and eosinophilic or pale cytoplasm, zonal fibrinous deposition, pseudocystic degeneration, granulation-like proliferation of capillary vessels, ganglion-like cells, myxoid or hyalinized stroma, and chronic inflammatory infiltration. Immunohistochemically, the spindle cells were positive for HIF-1α (7/7 cases), MDM2 (4/7 cases), CDK4 (4/7 cases), p16 (7/7 cases), p53 (2/7 case), cyclin D1 (7/7 cases), and alpha-smooth muscle actin (6/7 cases). Neither MDM2 gene amplification nor USP6 gene split signal was detected in any case. Overexpression of the above proteins may be associated with the pathogenic mechanism of ischemic fasciitis. It is noted that the immunohistochemical positivity of MDM2, CDK4, and p16 do not necessarily indicate malignant neoplasm such as dedifferentiated liposarcoma.

DOI： 10.1007/s00428-017-2122-2

Comparison between retroperitoneal leiomyosarcoma and dedifferentiated liposarcoma. Reviewed International journal

Takeaki Ishii, Kenichi Kohashi, Hiroshi Ootsuka, Kunio Iura, Akira Maekawa, Yuichi Yamada, Hirofumi Bekki, Masato Yoshimoto, Hidetaka Yamamoto, Yukihide Iwamoto, Yoshinao Oda

Pathology, research and practice 213 ( 6 ) 634 - 638 2017.6

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

It is important to distinguish between leiomyosarcoma (LMS) and dedifferentiated liposarcoma (DDLS) in the retroperitoneum. The dedifferentiated component of DDLS shows an LMS-like morphology in some cases; thus, detailed evaluation is necessary to achieve an accurate diagnosis. Immunohistochemically, MDM2 and myogenic markers provide clues for the diagnoses. However, immunoreactivity for MDM2 and myogenic markers has not been well studied in retroperitoneal LMS and DDLS. Here, we compared the clinicopathological data of 20 retroperitoneal tumors initially diagnosed as LMS with that of 36 cases of retroperitoneal DDLS and conducted an immunohistochemical study. Four (20%) of the cases initially diagnosed as LMS were immunoreactive for MDM2. Fifteen cases (41.7%) of DDLS showed positive expression of two or more myogenic markers. The patients with LMS with MDM2 overexpression were older than the patients with LMS without MDM2 overexpression (P=0.0328). LMS with MDM2 overexpression showed a worse prognosis than DDLS (P=0.0408). No significant difference in prognosis was found between LMS without MDM2 overexpression and DDLS with myogenic differentiation. In conclusion, we recommend that systemic MDM2 expression analysis be performed in cases of retroperitoneal sarcoma. Overdependence on the expression of myogenic markers could lead to misdiagnosis in distinguishing LMS from DDLS.

DOI： 10.1016/j.prp.2017.04.022

Low-grade intraductal carcinoma (low-grade cribriform cystadenocarcinoma) with tumor-associated lymphoid proliferation of parotid gland. Reviewed International journal

Toshimitsu Nishijima, Hidetaka Yamamoto, Takafumi Nakano, Yui Hatanaka, Ken-Ichi Taguchi, Muneyuki Masuda, Yoshinao Oda

Pathology, research and practice 213 ( 6 ) 706 - 709 2017.6

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

We report a rare case of low-grade intraductal carcinoma with tumor-associated lymphoid proliferation (TALP) in the parotid gland of a 75-year-old woman. Grossly, the tumor was solid and cystic. Histologically, the tumor consisted of a papillary-cystic, micropapillary, or focally cribriform proliferations of epithelial cells with low-grade cytological atypia. The interspaces between the epithelial components were filled with prominent lymphoid stroma and lymphoid follicles, superficially mimicking Warthin tumor. The neoplastic epithelial cells were positive for S100 protein by immunohistochemical staining. There was an attenuated layer of myoepithelial cells all around the epithelial components, indicating a non-invasive (in situ) nature. Although TALP is a rare finding in intraductal carcinoma, it should be considered as a histological variation of this kind of tumor. The relationship between intraductal carcinoma, low-grade cribriform cystadenocarcinoma, low-grade salivary duct carcinoma, and salivary duct carcinoma in situ is also discussed in this report.

DOI： 10.1016/j.prp.2017.02.019

Claudin 6 expression is useful to distinguish myxofibrosarcomas from other myxoid soft tissue tumors. Reviewed International journal

Hirofumi Bekki, Hidetaka Yamamoto, Katsumi Takizawa, Takeshi Iwasaki, Hiroshi Otsuka, Yuichi Yamada, Kenichi Kohashi, Katsumi Harimaya, Yukihide Iwamoto, Yoshinao Oda

Pathology, research and practice 213 ( 6 ) 674 - 679 2017.6

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

Myxofibrosarcoma (MFS) is characterized by abundant myxoid stroma, a wide spectrum of cytological atypia, and frequent local recurrence. Some soft tissue tumors with myxoid stroma can histologically mimic MFS, but have different biological behaviors. Here we sought to identify a useful diagnostic marker for MFS. After our analysis of the gene expression dataset from the Gene Expression Omnibus database, we focused on claudin 6 (CLDN 6). The status of CLDN 6 was assessed by immunohistochemistry in 61 samples of MFS and other (benign) myxoid soft tissue tumors (28 myxoma samples, 12 nodular fasciitis samples), 18 low-grade fibromyxoid sarcoma, 30 myxoid liposarcoma, 29 extraskeletal myxoid chondrosarcoma and 27 dedifferentiated liposarcoma with myxoid feature samples. The correlation between the expression of CLDN 6 and clinicopathological findings in MFS was also investigated. Immunohistochemically, high expression of CLDN 6 was observed in approx. 65% of the MFSs, whereas the benign soft tissue tumors did not show a high expression of CLDN 6. The expression of CLDN 6 in the MFS was significantly higher than those of other tumor specimens. Among the MFSs, the high expression of CLDN 6 was correlated with high FNCLCC grades and high AJCC stages. CLDN 6 may be useful for the differential diagnosis from benign myxoid tumor and for predicting the aggressive biological behavior of MFS.

DOI： 10.1016/j.prp.2016.12.001

Long-term outcomes of type I thyroplasty with silicone implantation: Assessment of excised laryngeal tissue from a patient with secondary hypopharyngeal carcinoma. Reviewed International journal

Kazuo Adachi, Toshiro Umezaki, Toshimitsu Nishijima, Hidetaka Yamamoto, Yoshinao Oda

Auris, nasus, larynx 44 ( 2 ) 245 - 248 2017.4

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

Here we describe the long-term outcomes of type I thyroplasty (TP-I) with silicone block implantation through histopathological assessments in a male patient who underwent pharyngolaryngectomy for secondary hypopharyngeal carcinoma 7 years after silicone implantation. A 66-year-old man presented with esophageal carcinoma and underwent subtotal esophagotomy. Subsequently, his left vocal fold exhibited fixation in a paramedian position, and he underwent TP-I with silicone block implantation 2 years after the primary esophageal surgery. His voice quality improved; however, he developed glottic carcinoma in the right vocal fold 6 months after TP-I and underwent laser cordectomy. Glottic carcinoma recurred 21 months later, and he underwent laser cordectomy again. Five years after the second laser surgery, he underwent pharyngolaryngectomy and neck dissection for hypopharyngeal carcinoma detected in the right pyriform sinus. We histopathologically examined a horizontal section of the resected larynx to assess silicone implant-related changes. Although migration of the silicone implant was not observed, a very mild foreign body reaction occurred around the implant. The patient is currently in remission. Our findings suggest that silicone implants are suitable for TP-I due to their remarkable affinity for human tissue and the low risk of a tissue reaction.

DOI： 10.1016/j.anl.2016.07.007

Histological and immunohistochemical characteristics of undifferentiated small round cell sarcomas associated with CIC-DUX4 and BCOR-CCNB3 fusion genes. Reviewed International journal

Yuichi Yamada, Masaaki Kuda, Kenichi Kohashi, Hidetaka Yamamoto, Junkichi Takemoto, Takeaki Ishii, Kunio Iura, Akira Maekawa, Hirofumi Bekki, Takamichi Ito, Hiroshi Otsuka, Makoto Kuroda, Yumi Honda, Shinji Sumiyoshi, Takeshi Inoue, Naoe Kinoshita, Atsushi Nishida, Kyoko Yamashita, Ichiro Ito, Shizuo Komune, Tomoaki Taguchi, Yukihide Iwamoto, Yoshinao Oda

Virchows Archiv : an international journal of pathology 470 ( 4 ) 373 - 380 2017.4

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

CIC-DUX4 and BCOR-CCNB3 fusion-gene-associated small round cell sarcomas account for a proportion of pediatric small round cell sarcomas, but their pathological features have not been sufficiently clarified. We reviewed a large number of soft tissue tumors registered at our institution, retrieved the cases of unclassified tumors with a small round cell component, and subjected them to histopathological, immunohistochemical, and gene profile analysis. We reviewed 164 cases of unclassified tumors with a small round cell component and analyzed them by RT-PCR and FISH. Tumors positive for a specific fusion-gene were also subjected to histopathological and immunohistochemical examinations. We identified 16 cases of BCOR-CCNB3/CIC-associated (CIC-DUX4 or CIC gene rearrangement-positive) sarcomas. These included seven BCOR-CCNB3 sarcomas and nine CIC-associated sarcomas. Heterogeneous elements included a myxoid spindle cell component in three BCOR-CCNB3 sarcomas and an epithelioid cell component in two CIC-associated sarcomas (one CIC-DUX4-positive and one CIC-DUX4-negative sarcomas). Mitotic activity was low in both heterogeneous components. By immunohistochemistry, in seven BCOR-CCNB3 sarcomas expression of EMA was positive in two cases, of p63 in three, of CD56 in six, of TLE1 in seven, of NKX2.2 in two, of CCNB3 in seven, and of BCOR in six cases (one case could not be tested for BCOR). In nine cases of CIC-associated sarcoma, CD56 was expressed in five, alpha-smooth muscle actin in one, ERG in three, and CD99, WT1 and TLE1 each in eight cases. Both sarcoma types showed not only a small round cell component, but also a myxoid/epithelioid component with low mitotic activity.

DOI： 10.1007/s00428-017-2072-8

A Locally Advanced Breast Cancer that Achieved pCR with Pertuzumab, Trastuzumab and Docetaxel: Case Report. Reviewed International journal

Yuka Inoue, Nami Yamashita, Eriko Tokunaga, Kimihiro Tanaka, Hiroki Ueo, Hiroshi Saeki, Eiji Oki, Hidetaka Yamamoto, Yoshihiko Maehara

Anticancer research 37 ( 4 ) 1917 - 1921 2017.4

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

We herein report a case of locally advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer that achieved a pathological complete response (pCR) with pertuzumab, trastuzumab and docetaxel therapy. A 70-year-old female presented with an elastic hard mass, 5.0 cm in diameter with broad redness and edema of the skin in her right breast. Swollen lymph nodes were also recognized in the right axilla. The pathological diagnosis was invasive ductal carcinoma and its biological character was estrogen receptor (ER)-negative, progesterone receptor (PgR)-negative, HER2 3+ and Ki-67 index 60%. The patient was finally diagnosed with primary unresectable, locally advanced breast cancer and started on pertuzumab, trastuzumab and docetaxel combination therapy. The tumor subsequently reduced in size and, after 4 cycles of this therapy, she underwent surgery. The histopathological examination of the postoperative specimen showed pCR in both the primary tumor and axillary lymph nodes.

Cancer-testis antigen expression in synovial sarcoma: NY-ESO-1, PRAME, MAGEA4, and MAGEA1. Reviewed International journal

Kunio Iura, Akira Maekawa, Kenichi Kohashi, Takeaki Ishii, Hirofumi Bekki, Hiroshi Otsuka, Yuichi Yamada, Hidetaka Yamamoto, Katsumi Harimaya, Yukihide Iwamoto, Yoshinao Oda

Human pathology 61 130 - 139 2017.3

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

Synovial sarcoma (SS) is regarded as a relatively chemosensitive sarcoma, but the prognosis of advanced SSs remains poor. Here we identified highly expressed cancer-testis antigens that could be promising immunotherapy targets for SS, using a previously conducted cDNA microarray, and we assessed the clinicopathological or prognostic relationships of these antigens in SS. We compared the gene expression profiles of 11 SSs with those of 3 normal adipose tissues. Among the up-regulated cancer-testis antigens, we analyzed PRAME, MAGEA1, and MAGEA4 and another cancer-testis antigen (NY-ESO-1) together, by immunohistochemistry and real-time polymerase chain reaction in 108 SSs. Immunohistochemically, NY-ESO-1, PRAME, MAGEA4, and MAGEA1 were positive in 66 (61%), 93 (86%), 89 (82%), and 16 (15%) of 108 SSs, respectively, and 104 (96%) of 108 SSs showed the immunohistochemical expression of at least 1 of NY-ESO-1, PRAME, and MAGEA4. Moreover, the high expression of at least 1 of these 3 antigens was observed in 83% of the SSs. High expression of NY-ESO-1 and MAGEA4 was significantly correlated with the presence of necrosis and advanced clinical stage. The immunohistochemical expression of these cancer-testis antigens was not correlated with prognosis, but the coexpression of NY-ESO-1, PRAME, and MAGEA4 was significantly associated with adverse prognosis. The real-time polymerase chain reaction results were closely related to the immunohistochemical results: NY-ESO-1 (P = .0019), PRAME (P = .039), MAGEA4 (P = .0149), and MAGEA1 (P = .0766). These data support the potential utility of NY-ESO-1, PRAME, and MAGEA4 as immunotherapy targets and ancillary prognostic parameters, suggesting the possible benefit of the combined use of these cancer-testis antigens as an SS immunotherapy target.

DOI： 10.1016/j.humpath.2016.12.006

Duodenal Neoplasms of Gastric Phenotype: An Immunohistochemical and Genetic Study With a Practical Approach to the Classification. Reviewed International journal

Risa Hida, Hidetaka Yamamoto, Minako Hirahashi, Reiko Kumagai, Kenichi Nishiyama, Toshihiro Gi, Motohiro Esaki, Takanari Kitazono, Yoshinao Oda

The American journal of surgical pathology 41 ( 3 ) 343 - 353 2017.3

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

Duodenal neoplasm of gastric phenotype (DNGP) is very rare, and details of its histopathologic, genetic, and biological features are still unclear. Frequent gene mutations in GNAS, KRAS, and APC have been reported in pyloric gland adenomas and fundic gland-type neoplasms (initially reported as low-grade adenocarcinomas) of the stomach. Here we retrospectively analyzed 16 cases of extra-ampullary DNGP (benign to malignant), and we examined the mucin immunoprofile and oncogene mutations (GNAS, KRAS, APC, BRAF, and CTNNB1). The 16 DNGPs were histologically classified into adenomas (5 pyloric gland adenomas and 2 foveolar-type adenomas), neoplasms of uncertain malignant potential (NUMPs, n=6), and invasive adenocarcinomas (n=3). NUMPs consisted of slightly atypical epithelial cells with pale, eosinophilic, or basophilic cytoplasm growing in an anastomosing or branching glandular pattern, often with expansive submucosal extension. In contrast to invasive adenocarcinomas, NUMPs lacked significant nuclear irregularity, desmoplastic stromal reaction, lymphovascular invasion, and metastasis; their features were reminiscent of fundic gland-type neoplasms of the stomach. Immunophenotypically, most of NUMPs were predominantly positive for MUC6 with variable expressions of pepsinogen-I, HKATPase, human gastric mucin, and MUC5AC. Molecular analyses revealed the gene mutations of GNAS in 6 (38%) of 16 DNGPs (4 [57%] adenomas, 1 [16%] NUMP, and 1 [33%] invasive adenocarcinoma) and APC in 4 of 15 (27%) DNGPs: no adenomas, 2 (33%) NUMPs, and 2 (67%) invasive adenocarcinomas. BRAF mutation was present in only 1 (16%) NUMP, and KRAS and CTNNB1 mutations were absent. In conclusion, gastric-phenotype adenomas and NUMPs of the duodenum are similar to their counterparts of the stomach, in terms of histologic, genetic, and clinicopathologic features. We propose the term "NUMP" as an intermediate category between adenoma and definitely invasive adenocarcinoma. Our findings may provide novel insights into the classification of undescribed but distinctive duodenal tumors showing similarity to gastric-phenotype neoplasms of the stomach.

DOI： 10.1097/PAS.0000000000000785

Primary Ewing's Sarcoma of the Sinonasal Tract: A Case Report

Tomoharu Suzuki, Ryuji Yasumatsu, Torahiko Nakashima, Shuji Arita, Hidetaka Yamamoto, Takashi Nakagawa

Case Reports in Oncology 10 ( 1 ) 91 - 97 2017.1

Publishing type：Research paper (scientific journal)

© 2017 The Author(s) Published by S. Karger AG, Basel. A 23-year-old male presented with a 3-month history of left purulent rhinorrhea, progressive nasal obstruction, and intermittent epistaxis. A fiberoptic examination revealed a large vascular polypoid mass completely filling the left nasal cavity. CT and MRI scans showed a large hypervascular mass involving the left nasal airway, maxillary antrum, and the anterior ethmoid cells. There was no bony erosion or contiguous spread, and the remaining sinuses, orbit, and cranial fossa were uninvolved. The patient underwent complete removal of the mass via an external lateral rhinotomy approach. The soft mass was large and vascular. A microscopic analysis revealed an undifferentiated tumor consisting of a solid sheet of small, round blue cells. Mitotic figures were also present. Immunohistochemically, the tumor cells were strongly positive for CD99. Molecular studies using a PCR confirmed the chromosomal translocation of FLI1 (exon 6). These findings were considered diagnostic for Ewing's sarcoma. Postoperatively, the patient was treated with combined chemotherapy and radiotherapy. Adjuvant chemotherapy consisting of vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide (total: 7 cycles) was commenced. He also received radiation therapy for local control (total dose: 50.4 Gy). The patient is currently alive without any evidence of recurrence or metastasis.

DOI： 10.1159/000455040

Cardiac metastasis of squamous cell carcinoma of the thyroid gland with severe disseminated intravascular coagulation: A case report. Reviewed International journal

Tomoyasu Yoshihiro, Kenji Tsuchihashi, Hitoshi Kusaba, Torahiko Nakashima, Teppei Obara, Kenta Nio, Kotoe Takayoshi, Hiroyuki Kodama, Nobuhiro Tsuruta, Hideyuki Kiyohara, Kaori Asai, Eiji Harada, Kenjiro Kamezaki, Takeshi Arita, Masanobu Sato, Hidetaka Yamamoto, Shuji Arita, Hiroshi Ariyama, Keita Odashiro, Yoshinao Oda, Koichi Akashi, Eishi Baba

Molecular and clinical oncology 6 ( 1 ) 91 - 95 2017.1

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

Distant metastasis of primary squamous cell carcinoma (SCC) of the thyroid gland is rare and, to the best of our knowledge, cardiac metastasis has not been reported to date. A 57-year-old man underwent surgery and adjuvant chemoradiotherapy for stage IVA SCC of the thyroid gland. After 3 months, the patient was admitted to the Kyushu University Hospital (Fukuoka, Japan) with subcutaneous hematomas of the left thigh and lower leg, and he was diagnosed with cardiac and mediastinal lymph node metastases of SCC of the thyroid gland with severe disseminated intravascular coagulation (DIC). Echocardiography revealed a mass, 52 mm in greatest diameter, protruding from the interventricular septum towards the right ventricle. Weekly administration of paclitaxel and concurrent irradiation of the cardiac and lymph node metastases were performed. Eighteen days after the initiation of chemoradiotherapy, the DIC and hematomas had significantly improved, and the cardiac metastasis was stable. However, 2 months after admission, the patient developed dyspnea and multiple nodular shadows appeared to be spreading in the subpleura of the lungs bilaterally, which were initially suspected to be pulmonary tumor embolisms. Prednisolone and subsequent administration of lenvatinib were not effective and the patient succumbed to respiratory failure. Severe DIC caused by extremely rare cardiac metastasis of SCC of the thyroid gland was effectively controlled by chemoradiotherapy. However, intensive local control appears to be required for this condition.

DOI： 10.3892/mco.2016.1091

Methotrexate-related lymphoproliferative disorder presenting with severe swelling of the elbow joint

Takashi Hatano, Masanobu Ohishi, Goichi Yoshimoto, Moriyasu Yamauchi, Akira Maekawa, Hidetaka Yamamoto, Yoshinao Oda, Makoto Endo, Hirofumi Bekki, Tomoya Matsunobu, Yasuharu Nakashima, Ken Okazaki, Jun Ichi Fukushi, Akiko Oyamada, Yukihide Iwamoto

JBJS Case Connector 7 ( 3 ) 2017

Publishing type：Research paper (scientific journal)

Case: A patient with rheumatoid arthritis (RA) who was being treated with methotrexate (MTX) therapy presented with severe swelling of the left elbow. Magnetic resonance imaging showed a tumor-like lesion around the elbow joint. Fluorodeoxyglucose positron emission tomography indicated multiple lesions in the lung and the lymph nodes. An open biopsy of a cervical lymph node was performed, and MTX-related lymphoproliferative disorder (MTX-LPD) was diagnosed. After cessation of the MTX therapy, the elbow swelling regressed, and the patient was in remission of MTX-LPD. Conclusion: MTX-LPD should be considered in the differential diagnosis when a patient with RA develops severe joint swelling while on MTX therapy.

DOI： 10.2106/JBJS.CC.17.00002

Phosphorylation of STAT3 in Undifferentiated Pleomorphic Sarcoma Is Correlated with a Favorable Prognosis. Reviewed International journal

Hirofumi Bekki, Kenichi Kohashi, Yuichi Yamada, Kunio Iura, Takeaki Ishii, Akira Maekawa, Hiroshi Otsuka, Hidetaka Yamamoto, Michiyuki Hakozaki, Kazuki Nabeshima, Yukihide Iwamoto, Yoshinao Oda

Pathobiology : journal of immunopathology, molecular and cellular biology 84 ( 3 ) 161 - 169 2017

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

OBJECTIVE: The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays a role in various biological processes. Phosphorylated STAT3 (p-STAT3) functions as a transcriptional factor, and suppressor of cytokine signaling 3 (SOCS3) is a potential inhibitor of STAT3. Here, we analyzed the status of the JAK-STAT pathway in undifferentiated pleomorphic sarcoma (UPS). METHODS: We performed immunohistochemistry in 79 samples of UPS and Western blotting in 10 frozen samples. We also examined alterations in protein expression in the JAK-STAT pathway after the inhibition of phosphorylated Akt (p-Akt) or extracellular signal-regulated kinase (p-Erk) in vitro. RESULTS: Immunohistochemically, p-STAT3 and SOCS3 were positive in 59.7 and 55.8%, respectively. Positivity for p-STAT3 was significantly correlated with a better prognosis (p = 0.0006) and negatively with SOCS3 expression (p = 0.0223). Positivity for SOCS3 was significantly correlated with a worse prognosis (p = 0.0001). Western blotting analysis revealed that p-STAT3 expression was lower in tumor than in normal tissue. In vitro results demonstrated that there was no detectable change in the expression of p-STAT3 regardless of the status of p-Akt or p-Erk. CONCLUSION: p-STAT3 may be a useful prognostic factor for UPS.

DOI： 10.1159/000448524

IgG4-related sclerosing mesenteritis causing bowel obstruction: a case report. Reviewed International journal

Atsushi Abe, Tatsuya Manabe, Nobuyoshi Takizawa, Takashi Ueki, Daisuke Yamada, Kinuko Nagayoshi, Yoshihiko Sadakari, Hayato Fujita, Shuntaro Nagai, Hidetaka Yamamoto, Yoshinao Oda, Masafumi Nakamura

Surgical case reports 2 ( 1 ) 120 - 120 2016.12

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

Sclerosing mesenteritis (SM) is a rare inflammatory and fibrosing disease primarily involving the small-bowel mesentery. Recently, SM was reported to be closely related to IgG4-related disease (IgG4-RD). This report describes a patient with SM associated with IgG4-RD. A 77-year-old woman with a history of surgery for ectopic pregnancy and wound dehiscence presented with intestinal obstruction. Abdominal enhanced computed tomography (CT) revealed an enhanced, radially shaped, oval mass, 3 cm in diameter, with an unclear rim in the mesentery of the distal ileum, which may have involved the distal ileum. To remove the cause of bowel obstruction, the SM was resected completely and the ileum was resected partially. Histologic examination showed that the mass was composed of spindle cells arranged in a fascicular or storiform pattern; moreover, fibrous stroma was observed, with dense lymphoplasmacytic infiltration and lymphoid follicles. Immunohistochemically, numerous IgG4-positive plasma cells were observed, at a density of 253 per high-powered field, and the IgG4/IgG ratio was about 50 %. Elastica van Gieson (EVG) staining also showed obstructive phlebitis. These findings indicated IgG4-related SM. Although the accurate diagnosis of SM remains difficult without histological analysis, IgG4-RD should be included in the differential diagnosis of unknown mesenteric tumors. Identification of IgG4-RD may prevent unnecessary surgery because corticosteroids may be effective in these patients.

Utility of adaptive control processing for the interpretation of digital mammograms. Reviewed International journal

Mikako Jinnouchi, Hidetake Yabuuchi, Makoto Kubo, Eriko Tokunaga, Hidetaka Yamamoto, Hiroshi Honda

Acta radiologica (Stockholm, Sweden : 1987) 57 ( 11 ) 1297 - 1303 2016.11

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

Background Adaptive control processing for mammography (ACM) is a novel program that automatically sets up appropriate image-processing parameters for individual mammograms (MMGs) by analyzing the focal and whole breast histogram. Purpose To investigate whether ACM improves the image contrast of digital MMGs and whether it improves radiologists' diagnostic performance in reading of MMGs. Material and Methods One hundred normal cases for image quality assessment and another 100 cases (50 normal and 50 cancers) for observer performance assessment were enrolled. All mammograms were examined with and without ACM. Five radiologists assessed the intra- and extra-mammary contrast of 100 normal MMGs, and the mean scores of the intra- and extra-mammary contrast were compared between MMGs with and without ACM in both the dense and non-dense group. They classified 100 MMGs into BI-RADS categories 1-5, and were asked to rate the images on a scale of 0 to 100 for the likelihood of the presence of category 3-5 lesions in each breast. Detectability of breast cancer, reading time, and frequency of window adjustment were compared between MMGs with and without ACM. Results ACM improved the intra-mammary contrast in both the dense and non-dense group but degraded extra-mammary contrast in the dense group. There was no significant difference in detectability of breast cancer between MMGs with and without ACM. Frequency of window adjustment without ACM was significantly higher than that with ACM. Reading time without ACM was significantly longer than that with ACM. Conclusion ACM improves the image contrast of MMGs and shortens reading time.

DOI： 10.1177/0284185115586022

Lymphomatoid Granulomatosis: Two Different Phenotypes of Computed Tomography Findings. Reviewed International journal

Torahiko Yamanouchi, Satoshi Kawanami, Takeshi Kamitani, Koji Sagiyama, Yuzo Yamasaki, Yuko Tanaka, Michinobu Nagao, Hidetake Yabuuchi, Naoki Hamada, Tatsuro Okamoto, Hidetaka Yamamoto, Hiroshi Honda

Journal of thoracic imaging 31 ( 6 ) W80-W82 2016.11

Reclassification of rhabdoid tumor and pediatric undifferentiated/unclassified sarcoma with complete loss of SMARCB1/INI1 protein expression: three subtypes of rhabdoid tumor according to their histological features. Reviewed International journal

Kenichi Kohashi, Yukichi Tanaka, Hiroshi Kishimoto, Hidetaka Yamamoto, Yuichi Yamada, Tomoaki Taguchi, Yukihide Iwamoto, Yoshinao Oda

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 29 ( 10 ) 1232 - 42 2016.10

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

Rhabdoid tumor is characterized by rhabdoid cells and shows complete loss of SMARCB1/INI1 protein expression. In existing classifications, the diagnostic synonyms vary depending on the anatomic site: rhabdoid tumors in the central nervous system or extra-central nervous system are, respectively, classified as atypical teratoid/rhabdoid tumor or malignant rhabdoid tumor. In this study, we analyzed the histological, immunohistochemical, microRNA, and clinicopathological statuses of tumors initially diagnosed as malignant rhabdoid tumor (n=33), atypical teratoid/rhabdoid tumor (n=11), and pediatric undifferentiated/unclassified sarcoma (n=8) with complete loss of SMARCB1/INI1 expression, and considered the possibility of their histological reclassification. Our analysis indicated that the tumors could be histologically reclassified into three groups: conventional-type tumors resembling malignant rhabdoid tumor, atypical teratoid/rhabdoid-type tumors resembling atypical teratoid/rhabdoid tumor, and small cell-type tumors resembling malignant lymphoma. The reclassified conventional type was composed of 27 malignant rhabdoid tumors and 9 atypical teratoid/rhabdoid tumors (36 cases). The atypical teratoid/rhabdoid type consisted of six malignant rhabdoid tumors, two atypical teratoid/rhabdoid tumors, and two undifferentiated/unclassified sarcomas (10 cases). The six cases of small cell type were made up of six undifferentiated/unclassified sarcomas. All of the available tumor specimens were positive for vimentin and epithelial marker (EMA, CAM5.2, or AE1/AE3). MicroRNA profiles were not significantly different between the conventional- and small cell-type tumors (Pearson's correlation coefficient: 0.888300 or 0.891388). There was no significant difference in overall survival between atypical teratoid/rhabdoid tumor and malignant rhabdoid tumor (P=0.16). In addition, there were no significant differences in survival between any of the reclassified combinations. In conclusion, we could classify eight tumors initially diagnosed as undifferentiated/unclassified sarcomas into two cases of atypical teratoid/rhabdoid type and six cases of small cell type. We suggest that reclassification of malignant rhabdoid tumors into three groups according to their histologic features rather than the traditional classification by sites of origin would be favorable for their histopathological diagnosis.

DOI： 10.1038/modpathol.2016.106

Mucoepidermoid carcinoma of the breast found during treatment of lymphoma

Minoru Fujino, Daisuke Mori, Michiaki Akashi, Hidetaka Yamamoto, Hitoshi Aibe, Kunishige Matake, Kengo Shirahane

Case Reports in Oncology 9 ( 3 ) 806 - 814 2016.9

Language：English Publishing type：Research paper (scientific journal) Publisher：S. Karger AG

A 71-year-old woman, previously treated for malignant lymphoma, was admitted to our hospital with a tumor in the right breast. The tumor size was 2.0 cm in diameter, and the borderline was unclear. The core needle biopsy material revealed an invasive adenocarcinoma with metaplastic change. Right mastectomy and sentinel lymph node biopsy was performed. Histologically, the tumor was composed of mucus-secreting, epidermoid, and intermediate cells. These findings confirmed the diagnosis as mucoepidermoid carcinoma (MEC) of the breast. MEC is more frequently observed in the salivary glands and occurs rarely in the breast, with an incidence of approximately 0.3% of all breast cancers. Because of the rarity of the disease, the clinicopathological features and clinical outcome have not been fully investigated. The relationship between MEC of the breast and lymphoma are unclear. Here we report a rare case of MEC of the breast.

DOI： 10.1159/000452792

Histological spectrum of angiofibroma of soft tissue: histological and genetic analysis of 13 cases. Reviewed International journal

Yuichi Yamada, Hidetaka Yamamoto, Kenichi Kohashi, Takeaki Ishii, Kunio Iura, Akira Maekawa, Hirofumi Bekki, Hiroshi Otsuka, Kyoko Yamashita, Hiroyuki Tanaka, Tsubasa Hiraki, Munenori Mukai, Atsuko Shirakawa, Yoko Shinnou, Mari Jinno, Hiroyuki Yanai, Kenichi Taguchi, Yoshihiko Maehara, Yukihide Iwamoto, Yosinao Oda

Histopathology 69 ( 3 ) 459 - 69 2016.9

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

AIMS: Angiofibroma of soft tissue (AFST) is a rare soft tissue neoplasm characterized by a fibroblastic cytomorphology and a prominent vascular structure. AFSTs possess a novel fusion gene, i.e. NCOA2-AHRR/AHRR-NCOA2 or GTF2I-NCOA2, providing a useful approach to diagnosing AFST. Morphologically, AFSTs span a wide spectrum, making diagnosis a challenge. The aim of this study was to review AFST cases and to report previously unknown histological features, which we confirmed by genetic analysis. METHODS AND RESULTS: We reviewed 276 cases diagnosed as solitary fibrous tumours/haemangiopericytomas (232 cases), unclassified tumours of fibroblastic differentiation (36 cases), and recently diagnosed AFSTs (eight cases), and retrieved 13 cases compatible with AFST. Immunohistochemical staining was performed for these cases, all 13 of which were analysed by reverse transcription polymerase chain reaction and fluorescence in-situ hybridization. The histological findings were as follows: amianthoid fibres, extravasation of red blood cells, haemosiderin deposition, aggregates of foamy histiocytes, cystic change, necrosis, and haemorrhage. Immunohistochemically, the tumour cells were positive for epithelial membrane antigen (four of 13 cases), desmin (six of 13 cases), CD163 (13 of 13 cases), CD68 (seven of 13 cases), oestrogen receptor (13 of 13 cases), progesterone receptor (three of 13 cases), and STAT6 (one of 13 cases, weak nuclear staining), but they were negative for CD34, α-smooth muscle actin, muscle-specific actin, S100, pan-cytokeratin, MDM2, and CDK4. The AHRR-NCOA2 fusion gene was detected in eight cases, and NCOA2 gene rearrangement in nine cases. CONCLUSION: We revealed the previously unreported histological variation and immunohistochemical findings of AFST, and confirmed them by using genetic methods. The results suggested that AFST should be considered in the diagnosis of fibrous or fibrohistiocytic tumours with the above histological features.

DOI： 10.1111/his.12943

Insulin-like growth factor II messenger RNA-binding protein-3 is an indicator of malignant phyllodes tumor of the breast. Reviewed International journal

Katsumi Takizawa, Hidetaka Yamamoto, Kenichi Taguchi, Shinji Ohno, Eriko Tokunaga, Nami Yamashita, Makoto Kubo, Masafumi Nakamura, Yoshinao Oda

Human pathology 55 30 - 8 2016.9

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

The aim of this study was to elucidate the clinicopathological and prognostic significance of the expressions of insulin-like growth factor II mRNA-binding protein-3 (IMP3) and epidermal growth factor receptor (EGFR) in phyllodes tumors (PTs). Immunohistochemical staining for IMP3 and EGFR was performed in 130 cases of primary PTs (83 benign, 28 borderline, 19 malignant), 34 recurrent/metastatic PTs, and 26 fibroadenomas (FAs). Among the primary tumors, a high expression of IMP3 was significantly more frequently present in malignant PTs (17/19, 89%) than in the FAs (0/26, 0%), benign PTs (0/83, 0%) and borderline PTs (3/28, 11%). The recurrent and metastatic lesions of malignant PTs also showed high IMP3 expression (3/5 [60%] and 6/6 [100%], respectively). Most malignant PTs showed strong IMP3 expression at the interductal area or more diffusely, whereas weak and focal (low) expression of IMP3 was limited to the periductal area in FAs and benign PTs. EGFR overexpression was significantly correlated with tumor grade and high IMP3 expression. Overexpressions of IMP3 and EGFR were significantly associated with shorter periods of metastasis-free and disease-free survival. The results suggest that high expressions of IMP3 and EGFR with a characteristic staining pattern may be helpful for both identifying malignant PT and predicting the prognosis of these tumors.

DOI： 10.1016/j.humpath.2016.04.007

ALK, ROS1 and NTRK3 gene rearrangements in inflammatory myofibroblastic tumours. Reviewed International journal

Hidetaka Yamamoto, Akihiko Yoshida, Kenichi Taguchi, Kenichi Kohashi, Yui Hatanaka, Atsushi Yamashita, Daisuke Mori, Yoshinao Oda

Histopathology 69 ( 1 ) 72 - 83 2016.7

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

AIMS: The aim of this study was to elucidate the pathological features of inflammatory myofibroblastic tumour (IMT) with gene rearrangement other than ALK. METHODS AND RESULTS: We investigated anaplastic lymphoma kinase (ALK), ROS1, ETV6, NTRK3 and RET in 36 cases of IMT by using immunohistochemical (IHC) staining, fluorescence in-situ hybridization, and reverse transcription polymerase chain reaction (RT-PCR). IHC staining showed ALK and ROS1 to be positive in 22 of 36 (61.1%) and two of 36 (5.6%) cases, respectively. In one case with ROS1 positivity, IHC staining showed cytoplasmic and dot-like ROS1 expression, and RT-PCR showed the presence of the TFG-ROS1 fusion transcript. Two cases of pulmonary IMT, in a 7-year-old patient and a 23-year-old patient, had ETV6 rearrangement, and the presence of the ETV6-NTRK3 fusion transcript was confirmed in one case. These tumours were composed of hypocellular myxoid areas and highly cellular areas with rich plasmacytic infiltration; the histological features were different from those of infantile fibrosarcoma. RET rearrangement was not detected. CONCLUSIONS: These results suggest that a subset of ALK-negative IMTs have rearrangement of ROS1, ETV6 or NTRK3 as a possible oncogenic mechanism, and that the detection of these alterations may be of diagnostic value and helpful for determining promising therapeutic strategies.

DOI： 10.1111/his.12910

Bi-cytopenia possibly induced by anti-PD-1 antibody for primary malignant melanoma of the esophagus: A case report. Reviewed International journal

Kyoko Inadomi, Hozumi Kumagai, Shuji Arita, Nobuhiro Tsuruta, Kotoe Takayoshi, Koji Mishima, Shun-Ichiro Ota, Mamoru Tanaka, Yuta Okumura, Kosuke Sagara, Kenta Nio, Michitaka Nakano, Hiroshi Uchi, Hidetaka Yamamoto, Hiroshi Ariyama, Hitoshi Kusaba, Hiroaki Niiro, Yoshinao Oda, Koichi Akashi, Eishi Baba

Medicine 95 ( 29 ) e4283 2016.7

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

BACKGROUND: Anti-programmed cell death 1 antibody nivolumab is a promising agent for various cancers. Immune-related adverse events are recognized; however, bi-cytopenia with nivolumab has not been reported. CASE PRESENTATION: A 73-year-old man was diagnosed with advanced primary malignant melanoma of the esophagus with liver, lung, and lymph node metastases. Previous therapies including dacarbazine and radiation of 39 Gy to the esophageal region were performed, but the liver metastases deteriorated. The patient was then administered nivolumab (2 mg/kg, every 3 weeks). After 3 cycles, the esophageal tumor and lymph nodes showed marked reductions in size, the lung metastases disappeared, and the liver metastases shrank partially. The treatment continued with 7 cycles for 4 months. However, severe anemia and thrombocytopenia appeared in the 6th cycle, and intermittent blood transfusions were required. The patient received high-dose intravenous methylprednisolone therapy for bi-cytopenia, but it was ineffective. Seven months after the initiation of nivolumab, the patient died of tumor. Although the mechanisms of bi-cytopenia were unclear, it could have been induced by nivolumab. CONCLUSION: The present case shows a rare but serious life-threatening bi-cytopenia possibly associated with nivolumab and suggests the importance of awareness of hematological adverse events during nivolumab therapy.

DOI： 10.1097/MD.0000000000004283

Reduced MUTYH, MTH1, and OGG1 expression and TP53 mutation in diffuse-type adenocarcinoma of gastric cardia. Reviewed International journal

Yukiko Kohno, Hidetaka Yamamoto, Minako Hirahashi, Yoshiteru Kumagae, Masafumi Nakamura, Eiji Oki, Yoshinao Oda

Human pathology 52 145 - 52 2016.6

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

The effects of oxidative stress in adenocarcinomas of gastric cardia (AGCs) have not been fully elucidated. With a strict definition of AGC, we examined the immunohistochemical expressions of inducible nitric oxide synthase; 8-hydroxy-deoxyguanosine; and the base excision repair enzymes such as MUTYH, MTH1, and OGG1, and TP53 mutational status. Sixty-three cases of AGC were characterized by younger patient age (P = .0227) and more frequent venous invasion (P = .0106) compared with the adenocarcinomas of pylorus (APs). 8-hydroxy-deoxyguanosine was accumulated (P = .0011), whereas MUTYH (P = .0325) and OGG1 (P = .0007) were decreased, in the AGCs compared with the adjacent mucosa, but these differences were not detected in the APs. Among the AGCs, lower expressions of MUTYH (P = .0013) and MTH1 (P = .0059) were each significantly associated with diffuse-type histology. A lower expression of OGG1 was correlated with higher T-stage (P = .0011), lymphatic invasion (P = .004), and lymph node metastasis (P = .0094). In addition, the presence of TP53 mutation was associated with diffuse-type histology (P = .0153) and a lower level of MUTYH (P = .0221). The AGCs also showed a relatively high rate of a transversion-type mutation of TP53 (50%), whereas all TP53 mutations in the APs were transition type. Age 62years or older (P = .0073), diffuse-type histology (P = .0020), and TP53 mutation (P = .0066) were each associated with worse survival in the AGC patients. Our results indicate that oxidative stress accumulation and a downregulation of base excision repair enzymes may play an important role in the pathogenesis of AGC, in particular diffuse-type AGCs. Diffuse-type AGC might involve molecular pathways different from those of other subsets of gastric cancer.

DOI： 10.1016/j.humpath.2016.01.006

Primary Cardiac T-Cell Lymphoma Localized in the Mitral Valve. Reviewed International journal

Yuma Motomatsu, Yasuhisa Oishi, Shogo Matsunaga, Hirofumi Onitsuka, Hidetaka Yamamoto, Eiko Zaitsu, Yuichi Yamada, Kenichi Kohashi, Yoshinao Oda, Ryuji Tominaga

The Annals of thoracic surgery 101 ( 6 ) 2363 - 5 2016.6

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

Primary cardiac lymphoma is a rare cardiac tumor, and usually originates from B cells and involves the right side of the heart. We present an extremely rare case of primary cardiac T-cell lymphoma involving the mitral valve alone. A 58-year-old woman who was positive for human T-cell leukemia virus 1 underwent mitral valve replacement because of severe mitral regurgitation. The postoperative pathologic diagnosis of the mitral valve was T-cell lymphoma. Further evaluation revealed no malignancy, except for the mitral valve. To the best of our knowledge, this is the first case of primary cardiac T-cell lymphoma localized in the mitral valve.

DOI： 10.1016/j.athoracsur.2015.08.091

Activation of the Akt-mTOR and MAPK pathways in dedifferentiated liposarcomas. Reviewed International journal

Takeaki Ishii, Kenichi Kohashi, Kunio Iura, Akira Maekawa, Hirofumi Bekki, Yuichi Yamada, Hidetaka Yamamoto, Kazuki Nabeshima, Hiroyuki Kawashima, Yukihide Iwamoto, Yoshinao Oda

Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 37 ( 4 ) 4767 - 76 2016.4

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

The Akt/mTOR and MAPK pathways play important roles in modulating cellular function in response to extracellular signals, and they are known to be activated in certain kinds of sarcomas. Few investigations have examined these pathways in dedifferentiated liposarcoma (DDLS), in relation to clinicopathological features. Clinicopathological and immunohistochemical analyses were conducted using 99 DDLS specimens. An in vitro study was also conducted to examine the antitumor effects of an mTOR inhibitor and a MEK inhibitor on two DDLS cell lines. The clinicopathological analyses revealed that the AJCC staging was a significant prognostic factor for overall survival and that the tumor size, depth, and location were significant prognostic factors for event-free survival. Phosphorylated Akt (pAkt), pmTOR, pS6RP, p4E-BP1, pMEK, and pERK expressions were positive in 57.4, 52.4, 71.4, 57.1, 84.1, and 50.8 % of the dedifferentiated component of the 63 primary DDLSs. Positive staining for pmTOR was significantly more frequent in the dedifferentiated component than the well-differentiated component. A univariate prognostic analysis revealed that pmTOR expression was associated with poor prognosis in the tumors in the retroperitoneum/ventral body cavity. The mTOR and MEK inhibitors dose-dependently inhibited the cell proliferation of both DDLS cell lines and decreased the expression of downstream pS6RP and pERK, respectively. The combined use of the two inhibitors enhanced antiproliferative activity. In conclusion, the Akt/mTOR and MAPK pathways were activated in DDLS specimens, and the inhibition of these pathways decreased cell proliferation in DDLS cell lines. Our findings suggest that these pathways could be a therapeutic target for patients with DDLS.

DOI： 10.1007/s13277-015-4232-2

Molecular subclassification determined by human papillomavirus and epidermal growth factor receptor status is associated with the prognosis of oropharyngeal squamous cell carcinoma. Reviewed International journal

Takafumi Nakano, Hidetaka Yamamoto, Torahiko Nakashima, Toshimitsu Nishijima, Masanobu Satoh, Yui Hatanaka, Hideki Shiratsuchi, Ryuji Yasumatsu, Satoshi Toh, Shizuo Komune, Yoshinao Oda

Human pathology 50 51 - 61 2016.4

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

Human papillomavirus (HPV) infection is an indicator of good response to chemoradiotherapy in oropharyngeal squamous cell carcinoma (OPSCC), and epidermal growth factor receptor (EGFR) is a molecular-therapeutic target in head and neck squamous cell carcinoma. Here we investigated the prevalence and prognostic significance of HPV infection and EGFR alteration in OPSCC. We analyzed the presence of high-risk HPV using in situ hybridization, protein expressions of p16 and EGFR using immunohistochemistry, and the EGFR gene copy number gain using chromogenic in situ hybridization (CISH) in 105 cases of OPSCC. The biopsy specimens before chemoradiotherapy were used for these analyses. HPV infection and p16 protein overexpression were detected in 53.3% and 52.4% of the OPSCCs, and each factor was associated with better overall survival (P = .0026 and P = .0026) and nonkeratinizing histology (P = .0002 and P = .0004), respectively. EGFR gene copy number gain (high polysomy or amplification) was detected in 12.4% of the OPSCCs and was correlated with EGFR protein overexpression (P = .0667) and worse overall survival (P < .0001). HPV infection and EGFR gene copy number gain (EGFR CISH positive) were mutually exclusive. The HPV-negative/EGFR CISH-positive OPSCCs had significantly worse overall survival than did the HPV-positive/EGFR CISH-negative OPSCCs and HPV-negative/EGFR CISH-negative OPSCCs (P < .0001 and P < .0001, respectively). The EGFR CISH-negative OPSCCs had favorable prognosis irrespective of HPV infection. Our results suggest that EGFR gene copy number gain-positive tumors represent an HPV-negative, aggressive subgroup of OPSCCs. The molecular subclassification of OPSCCs based on HPV infection and EGFR status may serve as important information for appropriate therapeutic strategy.

DOI： 10.1016/j.humpath.2015.11.001

Intraluminal superior vena cava metastasis from adenosquamous carcinoma of the duodenum: A case report. Reviewed International journal

Kotoe Takayoshi, Hiroshi Ariyama, Shingo Tamura, Shunsuke Yoda, Takeshi Arita, Toshihiro Yamaguchi, Keigo Ozono, Hidetaka Yamamoto, Kyoko Inadomi, Hozumi Kumagai, Mamoru Tanaka, Yuta Okumura, Kosuke Sagara, Kenta Nio, Michitaka Nakano, Shuji Arita, Hitoshi Kusaba, Keita Odashiro, Yoshinao Oda, Koichi Akashi, Eishi Baba

Oncology letters 11 ( 1 ) 605 - 609 2016.1

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

In 2013, a 76-year-old male with a cardiac pacemaker was diagnosed with adenosquamous carcinoma of the duodenum. Subsequently, a pancreatoduodenectomy and lymph node dissection were performed, and 12 cycles of adjuvant chemotherapy (modified FOLFOX6 regimen), which consisted of fluorouracil, leucovorin and oxaliplatin, were administered via a central venous catheter. At 5 months after the completion of adjuvant chemotherapy, the patient experienced the sudden onset of severe pain at the back right of the ear, edema of the right side of the face and right jugular vein dilatation. Computed tomography (CT) revealed filling defects in the superior vena cava (SVC) and right brachiocephalic vein, indicating catheter-induced venous thrombosis. Although the catheter was removed and anti-coagulation therapy, aspiration of the thrombosis and ballooning dilatation were performed immediately, the patient's symptoms were not ameliorated. Notably, histological examination following thrombus aspiration revealed metastatic cancer cells, and fluorodeoxyglucose-positron emission tomography/CT identified metabolically active nodules in the SVC at locations consistent with the initial duodenal tumors detected by CT and in the first thoracic vertebrae. The tumor thrombus rapidly increased in size and resulted in worsening dyspnea. Subsequently, radiotherapy was performed, followed by chemotherapy, which relieved the systemic symptoms and suppressed the tumor growth. Adenosquamous carcinoma of the duodenum is extremely rare, and to the best of our knowledge, intraluminal SVC metastasis as a result of adenosquamous carcinoma of the duodenum has not been reported previously. The placement of a cardiac pacemaker, central venous catheter and tumor cells possessing high metastatic potential are hypothesized to have contributed to this rare case of metastasis.

Dual gain of HER2 and EGFR gene copy numbers impacts the prognosis of carcinoma ex pleomorphic adenoma. Reviewed International journal

Toshimitsu Nishijima, Hidetaka Yamamoto, Takafumi Nakano, Torahiko Nakashima, Ken-ichi Taguchi, Muneyuki Masuda, Jun-ichi Motoshita, Shizuo Komune, Yoshinao Oda

Human pathology 46 ( 11 ) 1730 - 43 2015.11

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

We investigated the potential roles of HER2 and EGFR and evaluated their prognostic significance in carcinoma ex pleomorphic adenoma (CXPA). We analyzed HER2 and EGFR overexpression status using immunohistochemistry (IHC) and gene copy number gain by chromogenic in situ hybridization (CISH) in 50 cases of CXPA (40 ductal-type and 10 myoepithelial-type CXPAs). Salivary duct carcinoma was the most common histologic subtype of malignant component (n = 21). Immunohistochemistry positivity and chromogenic in situ hybridization positivity were closely correlated in both HER2 and EGFR. HER2 CISH positivity (mostly gene amplification) and EGFR CISH positivity (mostly gene high polysomy) were present in 19 (40%) and 21 (44%) cases, respectively, and were each significantly correlated with poor outcome (P = .0009 and P = .0032, respectively). Dual gain of HER2 and EGFR gene copy numbers was present in 11 cases (23%) and was the most aggressive genotype. HER2 CISH positivity was more frequently present in ductal-type CXPAs (47%) than in myoepithelial-type CXPAs (10%), whereas the prevalence of EGFR CISH positivity was similar in both histologic subtypes (42% and 50%, respectively). Our results suggest that HER2 and EGFR gene copy number gains may play an important role in the progression of CXPA, in particular ductal-type CXPAs. HER2 CISH-positive/EGFR CISH-positive tumors may be the most aggressive subgroup in CXPA. The molecular subclassification of CXPA based on the HER2 and EGFR status may be helpful for prognostic prediction and decisions regarding the choice of therapeutic strategy.

DOI： 10.1016/j.humpath.2015.07.014

Successful combination chemotherapy for metastatic inflammatory myofibroblastic tumor: A case report. Reviewed International journal

Kyoko Inadomi, Hozumi Kumagai, Kotoe Takayoshi, Hiroshi Ariyama, Hitoshi Kusaba, Akihiro Nishie, Hidetaka Yamamoto, Ken Takase, Mamoru Tanaka, Kosuke Sagara, Yuta Okumura, Kenta Nio, Michitaka Nakano, Shuji Arita, Yoshinao Oda, Koichi Akashi, Eishi Baba

Oncology letters 10 ( 5 ) 2981 - 2985 2015.11

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

A 64-year-old male presented with increased abdo-minal fullness and fever. Radiological examination revealed moderate ascites, a tumor with a diameter of 12.5 cm in the mesenteric region, as well as multiple tumors in the thoracic and abdominal para-aortic regions and in the left supraclavicular regions. Pathohistological findings of the biopsy specimen revealed atypical spindle cells accompanied by infiltration of lymphocytes. The plasmacytes were positive for CD68, murine double minute 2 and S-100, while they were negative for α-smooth muscle actin, cyclin-dependent kinase 4 and anaplastic lymphoma kinase. Clinically, the patient presented systemic symptoms and laboratory results indicated an elevation in the inflammatory response, while the CT and MRI findings were consistent with an inflammatory myofibroblastic tumor (IMT). Based on the clinical and histological findings, the patient was diagnosed with IMT. In total, 4 cycles of combination chemotherapy with doxorubicin and ifosfamide were administered. Tumor size reduction by 50% was achieved subsequent to the 4th chemotherapy cycle. In conclusion, successful control of this rare metastatic IMT was achieved by systemic chemotherapy.

Elevated expression of HSP90 and the antitumor effect of an HSP90 inhibitor via inactivation of the Akt/mTOR pathway in undifferentiated pleomorphic sarcoma. Reviewed International journal

Hirofumi Bekki, Kenichi Kohashi, Akira Maekawa, Yuichi Yamada, Hidetaka Yamamoto, Katsumi Harimaya, Michiyuki Hakozaki, Kazuki Nabeshima, Yukihide Iwamoto, Yoshinao Oda

BMC cancer 15 804 - 804 2015.10

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

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is a heterogeneous tumor group, and little is known about molecular target therapy for UPS. Heat shock protein 90 (HSP90) is an expressed chaperone that refolds certain denatured proteins under stress conditions. One of these proteins is Akt. The disruption of Akt signaling plays an important role in tumor progression. The present study's purpose was to analyze the HSP90 expression, Akt/mTOR pathway activation and the correlation between HSP90 expression and its pathway activation in UPS. METHODS: The status of HSP90 and the profiles of the Akt/ mTOR pathway were assessed by immunohistochemistry in 79 samples of UPS, and these data were compared with clinicopathological and histopathological findings. The expressions of indicated proteins were assessed by Western blotting in five frozen samples. After treating UPS cells with the HSP90 inhibitor, we assessed the antitumor effect of the inhibitor. RESULTS: Immunohistochemically, phosphorylated Akt (p-Akt), p-mTOR, p-S6RP and p-4EBP were positive in 57.3, 51.9, 54.5 and 57.1% of the UPS samples, respectively. The expressions of those phosphorylated proteins were correlated with each other. HSP90 expression was elevated in 56.4% of the samples and was correlated with p-Akt, p-mTOR and p-S6RP. The immunohistochemical results were confirmed by Western blotting. The HSP90 inhibitor led to decreased viability and invasiveness of the cells and inactivated the AKT/mTOR pathway in vitro. CONCLUSION: Elevated expression of HSP90 is a poor-prognosis factor and is involved in the activation of the Akt/mTOR pathway in UPS. HSP90 inhibition is a potential treatment option for UPS.

DOI： 10.1186/s12885-015-1830-8

Expression of adhesion molecules and epithelial-mesenchymal transition factors in medullary carcinoma of the colorectum. Reviewed International journal

Shunsuke Takahashi, Kenichi Kohashi, Hidetaka Yamamoto, Minako Hirahashi, Reiko Kumagai, Nobuyoshi Takizawa, Kazuhiko Nakamura, Yoshihiko Maehara, Masao Tanaka, Ryoichi Takayanagi, Yoshinao Oda

Human pathology 46 ( 9 ) 1257 - 66 2015.9

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

Medullary carcinoma (MC) of the colorectum is known as a rare variant with favorable prognosis despite its poorly differentiated morphology. The mechanism of its favorable behavior has been unclear. Here, we compared the expressions of adhesion molecules and epithelial-mesenchymal transition (EMT)-related proteins in the central portion and invasive front between 43 MCs and 30 poorly differentiated adenocarcinomas (PDAs). The expressions of membranous E-cadherin (P < .0001), β-catenin (P < .0001) and claudin 1 (P = .0036) were significantly preserved in the invasive front of the MCs compared to those in the invasive front of the PDAs. E-cadherin membranous expression was also significantly preserved in the central portion of the MCs (P = .0178). Nuclear β-catenin expression in both the central portion (P = .0463) and invasive front (P = .0346) of the MCs was significantly less frequent compared to that in the PDAs. Snail (P = .0035) and Twist1 (P = .0463) expressions in the invasive front of the MCs were significantly less frequent compared to the PDAs, suggesting that the EMT phenomenon may occur rarely in colorectal MC. Reduced membranous E-cadherin expression in the MC central portion was significantly correlated with poor clinical outcome (P = .0086). Our immunohistochemical results indicate that preserved adhesion molecule protein and less frequent expression of EMT-related transcription factors in the invasive front contribute to the favorable prognosis of colorectal MCs. We suggest that a reduced expression of E-cadherin in the central portion might be a good biomarker for an unfavorable prognosis in cases of MC.

DOI： 10.1016/j.humpath.2015.05.023

Successful treatment of adult Langerhans cell histiocytosis with intensified chemotherapy. Reviewed

Mariko Minami, Takahiro Shima, Koji Kato, Hidetaka Yamamoto, Kenji Tsuchihashi, Seido Oku, Tomonori Shimokawa, Taro Tochigi, Goichi Yoshimoto, Kenjiro Kamezaki, Katsuto Takenaka, Hiromi Iwasaki, Yoshinao Oda, Toshihiro Miyamoto, Koichi Akashi

International journal of hematology 102 ( 2 ) 244 - 8 2015.8

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

Langerhans cell histiocytosis (LCH) is a rare disease in adults. The treatment strategy for this condition remains controversial. Intensified systemic chemotherapy is required in pediatric patients with the multiple system form of LCH (MS-LCH) for aggressive forms of the disease. Recent clinical trials have shown that intensified chemotherapy for pediatric patients diagnosed with MS-LCH results in improved outcomes. However, whether the feasibility and efficacy of an intensified systemic chemotherapy regimen are also beneficial for adult patients with MS-LCH remains unclear. Here, we report two cases of adult MS-LCH that were successfully treated with an intensified treatment protocol as used in pediatric patients. One patient fully completed the protocol, and has since maintained a complete response (CR) for 2 years following completion of the treatment. The other patient also achieved CR after induction therapy, and is now undergoing maintenance therapy in an outpatient clinic. The cases presented in this study suggest that intensified systemic chemotherapy as used for pediatric patients with MS-LCH is well tolerated and effective for adult patients as well.

DOI： 10.1007/s12185-015-1778-0

Cancer-testis antigens PRAME and NY-ESO-1 correlate with tumour grade and poor prognosis in myxoid liposarcoma. Reviewed International journal

Kunio Iura, Kenichi Kohashi, Yuka Hotokebuchi, Takeaki Ishii, Akira Maekawa, Yuichi Yamada, Hidetaka Yamamoto, Yukihide Iwamoto, Yoshinao Oda

The journal of pathology. Clinical research 1 ( 3 ) 144 - 59 2015.7

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

Myxoid liposarcoma is the second most common liposarcoma. Although myxoid liposarcoma is relatively chemosensitive and thus a good candidate for chemotherapy, cases with relapsed or metastatic disease still have poor outcome. Here, we performed a gene microarray analysis to compare the gene expression profiles in six clinical myxoid liposarcoma samples and three normal adipose tissue samples, and to identify molecular biomarkers that would be useful as diagnostic markers or treatment targets in myxoid liposarcoma. This showed that the cancer-testis antigen PRAME was up-regulated in myxoid liposarcoma. We then performed immunohistochemical, western blotting and real-time polymerase chain reaction analyses to quantify the expression of PRAME and another cancer-testis antigen, NY-ESO-1, in clinical samples of myxoid liposarcoma (n = 93), dedifferentiated (n = 46), well-differentiated (n = 32) and pleomorphic liposarcomas (n = 14). Immunohistochemically, positivity for PRAME and NY-ESO-1 was observed in 84/93 (90%) and 83/93 (89%) of the myxoid liposarcomas, and in 20/46 (43%) and 3/46 (7%) of the dedifferentiated, 3/32 (9%) and 1/32 (3%) of the well-differentiated and 7/14 (50%) and 3/21 (21%) of the pleomorphic liposarcomas, respectively. High immunohistochemical expression of PRAME and/or NY-ESO-1 was significantly correlated with tumour diameter, the existence of tumour necrosis, a round-cell component of >5%, higher histological grade and advanced clinical stage. High PRAME and NY-ESO-1 expression correlated significantly with poor prognosis in a univariate analysis. The myxoid liposarcomas showed significantly higher protein and mRNA expression levels of PRAME and NY-ESO-1 (CTAG1B) than the other liposarcomas. In conclusion, PRAME and NY-ESO-1 (CTAG1B) were expressed in the vast majority of myxoid liposarcomas, and their high-level expression correlated with tumour grade and poor prognosis. Our results support the potential use of PRAME and NY-ESO-1 as ancillary parameters for differential diagnosis and as prognostic biomarkers, and indicate that the development of immunotherapy against these cancer-testis antigens in myxoid liposarcoma would be warranted.

DOI： 10.1002/cjp2.16

Mucinous phenotype and CD10 expression of primary adenocarcinoma of the small intestine. Reviewed International journal

Reiko Kumagai, Kenichi Kohashi, Shunsuke Takahashi, Hidetaka Yamamoto, Minako Hirahashi, Kenichi Taguchi, Kenichi Nishiyama, Yoshinao Oda

World journal of gastroenterology 21 ( 9 ) 2700 - 10 2015.3

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

AIM: To clarify the correlation with phenotypic expression, clinicopathological features, genetic alteration and microsatellite-instability status in small intestinal adenocarcinoma (SIA). METHODS: The cases of 47 patients diagnosed with primary SIAs that were surgically resected at our institution in 1975-2005 were studied. We reviewed clinicopathological findings (age, gender, tumor size, gross appearance, histological morphologic type, invasion depth, lymphatic permeation, venous invasion, and lymph node metastasis), and the immunohistochemical expression of MUC5AC, MUC6, MUC2, CD10, and mismatch-repair (MMR) proteins (MLH1 and MSH2). We analyzed KRAS and BRAF gene mutations, and the microsatellite instability (MSI) status. The immunohistochemical staining of CD10, MUC2, MUC5AC and MUC6 was considered positive when distinct staining in > 5% of the adenocarcinoma cells was recorded. To evaluate of MMR protein expression, we used adjacent normal tissue including lymphoid follicles, inflammatory cells, and stromal cells as an internal positive control. Sections without nuclear staining in the tumor cells were considered to have lost the expression of the respective MMR protein. RESULTS: There were 29 males and 18 females patients (mean age 59.9 years, range: 23-87 years). Tumors were located in the duodenum in 14 cases (30%), the jejunum in 21 cases (45%), and the ileum in 12 cases (25%). A phenotypic expression analysis revealed 20 MUC2-positive tumors (42.6%), 11 MUC5AC-positive (23.4%), 4 MUC6-positive (8.5%), and 7 CD10-positive (14.9%). The tumor sizes of the MUC2(+) tumors were significantly larger than those of the MUC2(-) tumors (mean, 5.7 ± 1.4 cm vs 4.7 ± 2.1 cm, P < 0.05). All three tumors with adenomatous component were positive for MUC2 (P < 0.05). Polypoid appearance was seen significantly more frequently in the CD10(+) group than in the CD10(-) group (P < 0.05). The tumor size was significantly larger in the CD10 (+) group than in the CD10(-) group (mean, 5.9 ± 1.4 cm vs 5.0 ± 2.1 cm, P < 0.05). Of 34 SIAs with successfully obtained MSI data, 4 were MSI-high. Of the 4 SIAs positive for both MUC5AC and MUC2, 3 showed MSI-H (75%) and 3 were mucinous adenocarcinoma (75%). KRAS mutations were detected in 4 SIAs. SIAs had KRAS mutation expressed only MUC2, but were negative for MUC5AC, MUC6 and CD10. CONCLUSION: These findings suggest that the phenotypic expression of SIAs is correlated with their biological behavior, genetic alteration, and MSI status.

DOI： 10.3748/wjg.v21.i9.2700

Malignant solitary fibrous tumor with high-grade nuclear atypia: an alternate entity for the undetermined tumor group. Reviewed International journal

Yuichi Yamada, Kenichi Kohashi, Hirofumi Bekki, Takeaki Ishii, Kunio Iura, Akira Maekawa, Hidetaka Yamamoto, Yukihide Iwamoto, Yoshinao Oda

Pathology, research and practice 211 ( 2 ) 117 - 24 2015.2

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

Recently, a novel fusion transcript, NAB2-STAT6, and its variants have also been reported to be specific diagnostic markers for solitary fibrous tumors (SFTs). In this study, we validated the existence of the NAB2-STAT6 fusion gene in SFTs and examined its relation with the pathological features. Frozen samples from 9 tumors were assessed for fusion gene. The detected fusion genes exhibited large intron sequences and the insertion of unknown and previously unreported sequences. The fusion genes were not detected in the 2 malignant cases with high-grade nuclear atypia, nuclear pleomorphism and necrosis, that was confirmed by multiplex PCR method. In addition, 1 of the 2 NAB2-STAT6 fusion gene-negative tumors showed amplification of the MDM2 and CDK4 genes. It was suggested that a certain proportion of tumors previously diagnosed as malignant SFTs with high-grade nuclear atypia lacking NAB2-STAT6 should be categorized into a special subtype of SFT, which is genetically different from conventional SFTs, and which cannot be apparently distinguished from dedifferentiated liposarcoma or undifferentiated pleomorphic sarcoma.

DOI： 10.1016/j.prp.2014.12.002

ERG and SALL4 expressions in SMARCB1/INI1-deficient tumors: a useful tool for distinguishing epithelioid sarcoma from malignant rhabdoid tumor. Reviewed International journal

Kenichi Kohashi, Yuichi Yamada, Yuka Hotokebuchi, Hidetaka Yamamoto, Tomoaki Taguchi, Yukihide Iwamoto, Yoshinao Oda

Human pathology 46 ( 2 ) 225 - 30 2015.2

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

ERG is immunoexpressed in vascular endothelial tumors, blastic extramedullary myeloid tumors, and tumors with ERG-involved translocation, such as prostate carcinoma or Ewing sarcoma. Recently, ERG immunoexpression was reported in an epithelioid sarcoma, which is a SMARCB1/INI1-deficient tumor, although epithelioid sarcoma is not associated with chromosomal translocations involving ERG and is categorized as a tumor with uncertain differentiation. SALL4 is essential for a proliferation and stabilization of embryonic stem cells. It was reported that SALL4 expression may aid in distinguishing epithelioid sarcoma from malignant rhabdoid tumor. We analyzed the frequency of ERG and SALL4 expressions in 80 SMARCB1/INI1-deficient tumors, including 45 epithelioid sarcomas (conventional-type, 24; proximal-type, 20), 17 malignant rhabdoid tumors, 5 atypical teratoid/rhabdoid tumors, 6 undifferentiated/unclassified sarcomas, 5 myoepithelial tumors, and 4 extraskeletal myxoid chondrosarcomas. We found that ERG expression was present in 18 of the epithelioid sarcomas (41%), including 13 conventional-type (54%) and 5 proximal-type (25%), whereas all 17 of the malignant rhabdoid tumors exhibited negative immunoreactivity. One atypical teratoid/rhabdoid tumor (20%), 1 myoepithelial carcinoma (20%), 1 undifferentiated/unclassified sarcoma (17%), and no extraskeletal myxoid chondrosarcomas (0%) also showed ERG expression. SALL4 expression was recognized in 5 epithelioid sarcomas (11%), 12 malignant rhabdoid tumors (71%), 2 atypical teradoid/rhabdoid tumors (40%), 4 undifferentiated/unclassified sarcomas (67%), 1 myoepithelial tumor (20%), and none of the extraskeletal myxoid chondrosarcomas (0%). Therefore, the evaluation of ERG and SALL4 immunoexpressions may be a useful diagnostic tool to distinguish epithelioid sarcoma, especially proximal type, from malignant rhabdoid tumor.

DOI： 10.1016/j.humpath.2014.10.010

Gastrointestinal stromal tumor: recent advances in pathology and genetics. Reviewed International journal

Hidetaka Yamamoto, Yoshinao Oda

Pathology international 65 ( 1 ) 9 - 18 2015.1

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

The discovery of KIT gene mutation in gastrointestinal stromal tumor (GIST) has provided a paradigm shift in the classification, diagnosis and molecular-targeted therapy of gastrointestinal mesenchymal tumors. There is growing evidence of phenotype-genotype (KIT, platelet-derived growth factor receptor-alpha, succinate dehydrogenase or other driver gene mutation) and genotype-therapeutic (sensitivity to imatinib) correlations in GIST. Risk stratification based on mitotic counts, tumor size and rupture is useful for the prognostication and management of patients with GIST. Blood vessel invasion is a strong indicator of liver metastasis in GIST. In addition, novel biomarkers such as cell-cycle regulators, microRNAs and their targets have been discovered by using high throughput molecular analyses. In contrast, leiomyosarcoma of the gastrointestinal tract has become a very rare entity in the 'KIT' era, and its molecular pathogenetic mechanism is unclear. Recent studies have revealed a wide spectrum of cytological atypia, mitotic counts and biological behavior of gastrointestinal smooth muscle tumors, suggesting the necessity of establishing the criteria for malignancy. Collectively, both classical histopathological procedures and modern molecular investigations are indispensable for the evolution of diagnosis and treatment of GIST and mimics.

DOI： 10.1111/pin.12230

Hyalinizing clear cell carcinoma with EWSR1-ATF1 fusion gene: report of three cases with molecular analyses. Reviewed International journal

Takafumi Nakano, Hidetaka Yamamoto, Toshimitsu Nishijima, Sadafumi Tamiya, Hideki Shiratsuchi, Torahiko Nakashima, Shizuo Komune, Yoshinao Oda

Virchows Archiv : an international journal of pathology 466 ( 1 ) 37 - 43 2015.1

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

Hyalinizing clear cell carcinoma (HCCC) is a low-grade salivary gland carcinoma characterized by clear cells and hyalinized stroma. Recently, the EWSR1-ATF1 fusion gene was found in HCCCs. We herein describe three cases of HCCC identified in one male and two females, ranging in age from 27 to 67 years. The tumors were located in the root of tongue, nasopharynx, and soft palate. They were composed of nested or cord-like proliferations of epithelial cells with clear to pale eosinophilic cytoplasm, embedded in hyalinized and focally fibroedematous stroma. Tumor-associated lymphoid proliferation and pseudoepitheliomatous hyperplasia were also observed in each one case. MAML2 fusions specific to mucoepidermoid carcinoma were not detected in any of the three cases. We found EWSR1-ATF1 in two of three HCCCs using reverse transcription polymerase chain reaction (RT-PCR) with our original primer sets designed to detect the fusion gene transcripts in formalin-fixed paraffin-embedded (FFPE) tissues. EWSR1 rearrangement was also confirmed by fluorescence in situ hybridization (FISH) on FFPE sections in two cases. There was a good concordance between the two methods (two positive cases and one negative case by both RT-PCR and FISH). Therefore, RT-PCR and FISH using FFPE tissue may be ancillary tools to confirm the diagnosis of HCCC.

DOI： 10.1007/s00428-014-1676-5

Hypoxemia due to pulmonary tumor microembolisms from a hepatocellular carcinoma: a case report

YAMASHITA Nobuyuki, TANIMOTO Hironori, YAMAMOTO Hidetaka, NISHIURA Saburo, NOMURA Hideyuki

Nippon Shokakibyo Gakkai Zasshi 112 ( 6 ) 1060 - 1066 2015

Language：Japanese Publisher：The Japanese Society of Gastroenterology

We report a case of pulmonary tumor embolism due to hepatocellular carcinoma (HCC). A woman in her 60s was treated with sorafenib 800 mg daily for HCC with lymph node metastasis. Approximately 50 days after taking sorafenib, she experienced dyspnea and was admitted to the hospital on account of hypoxia. Although her oxygen saturation levels deteriorated, we could find no obvious cause for the hypoxia; despite artificial respiration and oxygenation, she died of respiratory failure on the fourth day of admission. Tissue samples revealed that the HCC cells had infiltrated her lung arterioles; therefore, we concluded that multiple tumor microembolisms from the HCC to the lungs had caused death via respiratory failure. Cases of hypoxia caused by multiple invisible embolisms from HCCs are rarely reported. We believe that infiltration into the lymphatic system may have been related to the development of pulmonary tumor microembolisms.

DOI： 10.11405/nisshoshi.112.1060

Other Link： http://search.jamas.or.jp/link/ui/2015259396

Complete remission of anaplastic thyroid carcinoma after concomitant treatment with docetaxel and radiotherapy. Reviewed International journal

Ichiro Abe, Satoko Karasaki, Yayoi Matsuda, Shohei Sakamoto, Torahiko Nakashima, Hidetaka Yamamoto, Hisaya Kawate, Keizo Ohnaka, Hisashi Nakashima, Kunihisa Kobayashi, Yoshinao Oda, Masatoshi Nomura, Ryoichi Takayanagi

Case reports in endocrinology 2015 726085 - 726085 2015

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

Anaplastic thyroid carcinoma (ATC) although rare is the most lethal form of thyroid cancer. The mortality rate for ATC is very high, with a median survival time of only 5 months; the survival rate at 1 year after diagnosis is <20%. Management of ATC is extremely difficult and rife with uncertainties. Herein, we describe a 75-year-old woman who presented with ATC and was successfully treated using concomitant treatment with docetaxel and high-dose radiotherapy. This case appears to be the first to have been reported in the literature involving complete remission of ATC confirmed by autopsy, suggesting the therapeutic potential of this combination.

DOI： 10.1155/2015/726085

Close correlation between CXCR4 and VEGF expression and frequent CXCR7 expression in rhabdomyosarcoma. Reviewed International journal

Kina Miyoshi, Kenichi Kohashi, Fumiyoshi Fushimi, Hidetaka Yamamoto, Junji Kishimoto, Tomoaki Taguchi, Yukihide Iwamoto, Yoshinao Oda

Human pathology 45 ( 9 ) 1900 - 9 2014.9

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

CXC chemokine receptor 4 (CXCR4) expression is reportedly correlated with both vascular endothelial growth factor (VEGF) expression and poor prognosis in a variety of cancers. Its relation to CXC chemokine receptor 7 (CXCR7) is also noted in several malignancies, including rhabdomyosarcoma (RMS) cell lines. However, the correlations between these chemokine receptors and angiogenic factors have not yet been adequately investigated in RMS clinical specimens. By immunohistochemistry, we assessed CXCR4, CXCR7, CC chemokine receptor 6, CC chemokine receptor 7, VEGF expression, microvessel density, and MIB-1 labeling index in 82 formalin-fixed RMS specimens, including 34 primary alveolar RMS and 44 primary embryonal RMS (ERMS). Twenty-six frozen samples were available for investigation by quantitative reverse transcription polymerase chain reaction to detect the messenger RNA expression levels of these molecules. We also evaluated their significance with respect to clinicopathological factors and patient survival rates. Primary RMS showed high expression of CXCR7 (83.1%) regardless of the histologic subtype. High cytoplasmic CXCR4 and high VEGF expression revealed significant correlations in both ERMS and alveolar RMS (P = .0051 and P = .0003, respectively). By univariate analysis of ERMS cases, the tumors with high VEGF expression showed significantly poor prognoses (P = .0017). High VEGF expression also was the independent adverse prognostic factor for ERMS. Because CXCR4, CXCR7, and VEGF are widely expressed in RMS, the combination of these antagonists may provide a potential target for molecular therapy.

DOI： 10.1016/j.humpath.2014.05.012

Differentiation between benign phyllodes tumors and fibroadenomas of the breast on MR imaging. Reviewed International journal

Takeshi Kamitani, Yoshio Matsuo, Hidetake Yabuuchi, Nobuhiro Fujita, Michinobu Nagao, Satoshi Kawanami, Masato Yonezawa, Yuzo Yamasaki, Eriko Tokunaga, Makoto Kubo, Hidetaka Yamamoto, Hiroshi Honda

European journal of radiology 83 ( 8 ) 1344 - 9 2014.8

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

PURPOSE: The purpose of this study was to determine the factors that contribute to the differentiation between phyllodes tumors (PTs) and fibroadenomas (FAs) on MR imaging. MATERIALS AND METHODS: This retrospective study included 19 PTs and 18 FAs with ≥ 2 cm diameter. The presence or absence of a capsule and internal septum, the extent of lobulation, and the apparent diffusion coefficient (ADC) values were determined. The presence or absence of a cystic component, the time-intensity curve, and the signal intensity on delayed-phase contrast-enhanced T1WI were also evaluated in 31 patients (16 PTs and 17 FAs) who underwent a contrast-enhanced study. RESULTS: Cystic components were seen in 10 of the 16 PTs (63%) and in 4 of the 17 FAs (24%; P=0.03). The PTs showed strong lobulation more frequently compared to the FAs (14/19 [74%] vs. 7/18 [39%], respectively; P=0.04). Though there was no significant difference, PT tended to be heterogeneous more frequently on the delayed phase of the contrast-enhanced T1WI compared to the FA (11/16 [69%] vs. 7/17 [41%], respectively). No significant difference was found in the other findings. CONCLUSIONS: Although PTs and FAs show similar MR findings, the presence of a cystic component, strong lobulation, and heterogeneity on delayed-phase contrast-enhanced T1WI suggests a PT.

DOI： 10.1016/j.ejrad.2014.04.031

A case of gastric plexiform fibromyxoma: radiological and pathological findings. Reviewed

Katsumi Sakamoto, Masakazu Hirakawa, Kazushige Atsumi, Koshi Mimori, Kohei Shibata, Taro Tobo, Hidetaka Yamamoto, Hiroshi Honda

Japanese journal of radiology 32 ( 7 ) 431 - 6 2014.7

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

Plexiform fibromyxoma is a relatively new pathological category that consists of a rare group of non-gastrointestinal stromal tumors with a peculiar plexiform growth pattern. We report a case of gastric plexiform fibromyxoma in a 60-year-old man. Gastroscopic examination revealed a gastric submucosal tumor in the antrum. Magnetic resonance imaging (MRI) showed a nodule with distinct signal hyperintensity on T2-weighted images, with strong enhancement peripherally in the early phase to the entire lesion in the delayed phase. Endoscopic ultrasound-guided fine-needle aspiration cytology was performed, and the cytological diagnosis was spindle cell tumor, so partial gastrectomy was performed under a preoperative diagnosis of GIST. The resected tumor demonstrated plexiform architecture, myxoid stroma, prominent vasculature, and spindle cells, reflecting the characteristic findings on MRI. This is the first report to describe radiological findings for gastric plexiform fibromyxoma.

DOI： 10.1007/s11604-014-0315-z

Differential microRNA expression profiles between malignant rhabdoid tumor and epithelioid sarcoma: miR193a-5p is suggested to downregulate SMARCB1 mRNA expression. Reviewed International journal

Kenichi Kohashi, Hidetaka Yamamoto, Reiko Kumagai, Yuichi Yamada, Yuka Hotokebuchi, Tomoaki Taguchi, Yukihide Iwamoto, Yoshinao Oda

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 27 ( 6 ) 832 - 9 2014.6

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

Malignant rhabdoid tumor and epithelioid sarcoma are classified as tumors of uncertain differentiation. However, it is controversial whether these tumors are distinct entities because they share similar histological and immunohistochemical features such as the existence of rhabdoid cells or complete loss of SMARCB1 protein expression. MicroRNAs are small non-coding RNAs, and it is suggested that knowledge of microRNA expression profiles in cancer may have substantial value for diagnostics. We first analyzed microRNA expression profiles in 13 frozen materials (five malignant rhabdoid tumors, two proximal type epithelioid sarcomas, and six conventional type epithelioid sarcomas) and subsequently examined the specific microRNA expressions in 29 paraffin-embedded materials (8 malignant rhabdoid tumors, 13 proximal type epithelioid sarcomas, and 8 conventional type epithelioid sarcomas) and 13 previously described frozen materials by quantitative RT-PCR. According to the unsupervised hierarchical clustering of microRNA, proximal type epithelioid sarcoma and conventional type epithelioid sarcoma were classified into the same category, whereas malignant rhabdoid tumor was a distinct category from both types of epithelioid sarcoma. In addition, when malignant rhabdoid tumor with SMARCB1 gene alterations and proximal type and conventional type epithelioid sarcoma with no SMARCB1 gene alterations were compared, 56 microRNAs were isolated as being significantly different (ANOVA, P<0.05). Among them, quantitative RT-PCR using frozen and paraffin-embedded materials demonstrated that expression levels of miR193a-5p (P=0.002), which has been suggested to downregulate SMARCB1 mRNA expression, showed statistically different expression levels between malignant rhabdoid tumor and epithelioid sarcoma with no SMARCB1 gene alterations. These results suggest that epithelioid sarcoma, especially proximal type epithelioid sarcoma, and malignant rhabdoid tumor are distinct tumors with respect to the microRNA expression profiles and that miR193a-5p may have an important role in the inhibition of SMARCB1 mRNA expression.

DOI： 10.1038/modpathol.2013.213

Solitary fibrous tumor of the thyroid gland. Reviewed

Yusuke Mizuuchi, Hidetaka Yamamoto, Katsuya Nakamura, Kengo Shirahane, Masae Souzaki, Masao Tanaka, Yoshinao Oda

Medical molecular morphology 47 ( 2 ) 117 - 22 2014.6

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

Solitary fibrous tumor is a spindle cell neoplasm rarely arising in the thyroid gland. We present a 78-year-old man with the diagnosis of solitary fibrous tumor of the thyroid gland resected by subtotal thyroidectomy. Fine needle aspiration cytology via ultrasound guidance demonstrated a hypocellular aspirate that revealed follicular epithelial cells with mild nuclear atypia and scattered spindle cells with bland nuclei. Histologically, the patternless proliferation of spindle cells was seen among collagenous bundles, accompanied by hemangiopericytomatous vessels, and variously dilated follicles with mild atypical cells having slightly enlarged nuclei, indicating adenomatous goiter. The neoplastic spindle cells showed diffuse immunoreactivity to CD34, bcl-2, CD99 and vimentin, but were negative for cytokeratins, calcitonin, TTF-1 and CD5. Although solitary fibrous tumor arising in thyroid gland is rare, this tumor should be included in the differential diagnosis of thyroid spindle cell tumors and also that of adenomatous.

DOI： 10.1007/s00795-013-0056-6

Inflammatory pseudotumor in head and neck. Reviewed International journal

Yuichi Segawa, Ryuji Yasumatsu, Hideki Shiratsuchi, Akihiro Tamae, Teppei Noda, Hidetaka Yamamoto, Shizuo Komune

Auris, nasus, larynx 41 ( 3 ) 321 - 4 2014.6

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

BACKGROUND: Inflammatory pseudotumor (IPT) is a tumefactive lesion characterized by fibroblastic proliferations and a prominent inflammatory component. It behaves as a locally benign or aggressive lesion, clinically and radiologically mimicking a neoplastic process. Numerous entities can be diagnosed as IPT, from reactive lesions to true neoplasms. The diagnosis of IPT requires further elaboration, and IPT should be distinguished from other similar entities such as inflammatory myofibroblastic tumor and IgG4-related sclerosing disease. CASE SUMMARY: We report two cases of IPT arising from the head and neck region. One occurred at the orbit and the other at the parapharyngeal space. Histologically, they showed aggregates of myofibroblasts and inflammatory cells. Immunohistochemically, the number of IgG4-positive cells was less than 40% of the number of IgG positive cells, and the myofibroblastic cells were negative for anaplastic lymphoma kinase. The diagnosis was IPT/not otherwise specified. One patient was treated by systemic administration of corticosteroid and had good response. The other, who was treated by local administration of corticosteroid, partially responded and is currently stable with limited disease. DISCUSSION: IPT has been reported to occur in various anatomical sites, most commonly in the lungs. The incidence in the head and neck area is extremely rare. Treatment of IPT is controversial and may involve corticosteroids or surgical resection, or both. Other chemotherapeutic agents and radiotherapy may be considered in steroid-resistant patients. The pathological subtype, safety of resection, and safety of corticosteroid use must be included in the decision-making process for treatment.

DOI： 10.1016/j.anl.2013.11.002

Activation of the Akt/mammalian target of rapamycin pathway in myxofibrosarcomas. Reviewed International journal

Yusuke Takahashi, Kenichi Kohashi, Yuichi Yamada, Makoto Endo, Nokitaka Setsu, Takeaki Ishii, Hidetaka Yamamoto, Yukihide Iwamoto, Yoshinao Oda

Human pathology 45 ( 5 ) 984 - 93 2014.5

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

The Akt/mammalian target of rapamycin (mTOR) pathway plays important roles in modulating cellular function in response to extracellular signals such as growth factors and cytokines. The Akt/mTOR signaling pathway is activated in certain kinds of sarcomas. Myxofibrosarcoma is a soft tissue sarcoma, characterized by abundant myxoid stroma and frequent local recurrence. Here, we conducted a large-scale examination of the clinicopathological and activation statuses of the Akt/mTOR pathways in myxofibrosarcoma. The phosphorylation status of Akt, mTOR, S6 ribosomal protein, and the eukaryotic translation initiation factor 4E-binding protein, and mitogen-activated protein kinase were assessed by immunohistochemistry in 101 formalin-fixed, paraffin-embedded samples, including 68 primary tumors in myxofibrosarcoma. Immunohistochemical expressions were confirmed by Western blotting with 20 frozen samples, which were paired with normal tissue samples. PIK3CA and AKT1 gene mutations were also analyzed using 12 primary tumor frozen samples. Immunohistochemically, phosphorylations of Akt, mTOR, S6 ribosomal protein, 4E-binding protein, and mitogen-activated protein kinase 1/2 were observed in 64.7%, 45.6%, 42.6%, 63.2%, and 64.7% of samples. Phosphorylated Akt/mTOR pathway proteins were correlated with one another and were also correlated with the phosphorylation of these proteins in the concordant recurrent tumors. Immunoblotting showed a high degree of phosphorylation in tumor samples, compared with that in normal tissue samples. Activation of the Akt/mTOR pathway was correlated with histologic grade and tumor progression. Mutational analysis failed to reveal any PIK3CA or AKT1 mutations around the hot spots. Activation of the Akt/mTOR pathway was associated with histologic malignancy and tumor progression in primary and recurrent myxofibrosarcoma.

DOI： 10.1016/j.humpath.2013.12.012

Successful chemoradiotherapy for undifferentiated malignant neoplasm arising from the left pulmonary artery. Reviewed International journal

Hozumi Kumagai, Kenta Nio, Yuta Okumura, Masato Komoda, Tsuyoshi Shirakawa, Hitoshi Kusaba, Shioto Yasuda, Keita Odashiro, Shuji Arita, Hiroshi Ariyama, Yuichi Yamada, Hidetaka Yamamoto, Yoshinao Oda, Katsumasa Nakamura, Koichi Akashi, Eishi Baba

Case reports in oncology 7 ( 2 ) 484 - 90 2014.5

Language：English

Undifferentiated malignant neoplasms, which occur primarily in the pulmonary artery, are extremely rare and associated with poor outcomes as there is no effective therapy. A 67-year-old woman visited our hospital with complaints of dry cough and dyspnea on exertion. A contrast-enhanced chest computed tomography revealed an intravascular tumor obstructing the left pulmonary artery and a pedunculated lesion extending to the main and right pulmonary artery. Multiple metastases in the lung, bones and bilateral adrenal glands were identified by fluorodeoxyglucose-positron emission tomography. A small sample was obtained by catheter aspiration biopsy of the intravascular tumor, and examination revealed undifferentiated small atypical cells. The tumor was diagnosed as an undifferentiated neoplasm arising from the pulmonary artery based on immunohistochemical findings, including the absence of expressions of organ-specific markers. Systemic chemotherapy (paclitaxel and carboplatin) and concurrent radiation were performed as treatment for the primary tumor. Marked shrinkage of the intravascular tumor was achieved, and no serious adverse events were observed during therapy. Chemotherapy was continued for 5 months, but the patient died because of tumor progression 9 months after the initial diagnosis. Chemoradiotherapy has efficacy against undifferentiated neoplasm of the pulmonary artery.

DOI： 10.1159/000365387

Testicular sex cord-stromal tumor in a boy with 2q37 deletion syndrome. Reviewed International journal

Yasunari Sakai, Ryota Souzaki, Hidetaka Yamamoto, Yuki Matsushita, Hazumu Nagata, Yoshito Ishizaki, Hiroyuki Torisu, Yoshinao Oda, Tomoaki Taguchi, Chad A Shaw, Toshiro Hara

BMC medical genomics 7 19 - 19 2014.4

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

BACKGROUND: 2q37 deletion syndrome is a rare congenital disorder that is characterized by facial dysmorphism, obesity, vascular and skeletal malformations, and a variable degree of intellectual disability. To date, common but variable phenotypes, such as skeletal or digit malformations and obesity, have been associated with the deleted size or affected genes at chromosome 2q37. However, it remains elusive whether 2q37 deletion per se or other genetic factors, such as copy number variations (CNVs), may confer the risk for the tumorigenic condition. CASE PRESENTATION: We report a two-year-old Japanese boy with 2q37 deletion syndrome who exhibited the typical facial appearance, coarctation of the aorta, and a global developmental delay, while lacking the symptoms of brachydactyly and obesity. He developed a sex cord-stromal tumor of the right testis at three months of age. The array comparative genome hybridization analysis identified an 8.2-Mb deletion at 2q37.1 (chr2:234,275,216-242,674,807) and it further revealed two additional CNVs: duplications at 1p36.33-p36.32 (chr1:834,101-2,567,832) and 20p12.3 (chr20:5,425,762-5,593,096). The quantitative PCRs confirmed the heterozygous deletion of HDAC4 at 2q37.3 and duplications of DVL1 at 1q36 and GPCPD1 at 20p12.3. CONCLUSION: This study describes the unique phenotypes in a boy with 2q37 deletion and additional CNVs at 1p36.33-p36.32 and 20p12.3. The data provide evidence that the phenotypic variations and unusual complications of 2q37 deletion syndrome are not simply explained by the deleted size or genes located at 2q37, but that external CNVs may account at least in part for their variant phenotypes. Accumulating the CNV data for chromosomal disorders will be beneficial for understanding the genetic effects of concurrent CNVs on the syndromic phenotypes and rare complications.

DOI： 10.1186/1755-8794-7-19

Activation of the Akt-mTOR pathway and receptor tyrosine kinase in patients with solitary fibrous tumors. Reviewed International journal

Yuichi Yamada, Kenichi Kohashi, Fumiyoshi Fushimi, Yusuke Takahashi, Nokitaka Setsu, Makoto Endo, Hidetaka Yamamoto, Shoji Tokunaga, Yukihide Iwamoto, Yoshinao Oda

Cancer 120 ( 6 ) 864 - 76 2014.3

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

BACKGROUND: Solitary fibrous tumors (SFTs) are soft tissue tumors of intermediate malignancy that rarely metastasize. Although unresectable SFTs are reported to have a poor prognosis, to the authors' knowledge there is currently no effective therapy. Molecular target therapy is a promising approach for patients with unresectable tumors, but knowledge of the molecular biology of SFTs is currently insufficient to support such therapy. The current study investigated the activation of receptor tyrosine kinases (RTKs) and the Akt-mammalian target of rapamycin (Akt-mTOR) pathway in SFTs as therapeutic targets. METHODS: The phosphorylation statuses of Akt-mTOR pathway proteins (p-Akt, p-mTOR, phosphorylated 4E-binding protein [p-4EBP1], and phosphorylated S6 ribosomal protein [p-S6RP]) and RTKs (phosphorylated platelet-derived growth factor receptor-α [p-PDGFRα], p-PDGFRβ, p-c-met, and phosphorylated insulin-like growth factor-1 receptor-β [p-IGF-1Rβ]) were assessed by immunohistochemistry in 66 samples of SFTs, and the data were compared with clinicopathological and histopathological findings. The expression of phosphorylated proteins was assessed by Western blot analysis in 6 frozen samples. RESULTS: The immunohistochemical results were as follows: p-Akt, 56.0% (nuclear and cytoplasmic staining); p-mTOR, 69.6% (nuclear and cytoplasmic staining); p-4EBP1, 80.3% (nuclear and cytoplasmic staining); p-S6RP, 69.6% (cytoplasmic staining); p-PDGFRα, 39.0% (cytoplasmic staining); p-PDGFRβ, 52.0% (cytoplasmic staining); p-c-met, 37.8% (nuclear staining) and 19.6% (cytoplasmic staining); and p-IGF-1Rβ, 16.6% (nuclear staining). Phosphorylation of the Akt-mTOR pathway proteins was correlated with one another except for p-Akt with S6RP. p-PDGFRβ and p-IGF-1Rβ were correlated with p-Akt. Moreover, significant relationships were noted between disease-free survival or overall survival and the presence of hypoglycemia, necrosis, cystic and myxoid degeneration, and atypical findings. CONCLUSIONS: The Akt/mTOR pathway was activated in approximately 50% of the cases of SFTs and was associated with RTKs, which were phosphorylated at different rates. Thus, the Akt-mTOR pathway may be involved in the tumorigenesis of SFTs.

DOI： 10.1002/cncr.28506

Insulin-like growth factor II messenger RNA-binding protein 3 expression in gastrointestinal mesenchymal tumors. Reviewed International journal

Hidetaka Yamamoto, Katsumi Arakaki, Katsuya Morimatsu, Yoko Zaitsu, Aya Fujita, Kenichi Kohashi, Minako Hirahashi, Junichi Motoshita, Yumi Oshiro, Yoshinao Oda

Human pathology 45 ( 3 ) 481 - 7 2014.3

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

Insulin-like growth factor II messenger RNA-binding protein 3 (IMP3) is a recently identified biomarker demonstrated to be useful in diagnosis and prognostic prediction for several kinds of malignant tumors. However, the clinicopathologic and diagnostic value of IMP3 in mesenchymal tumors of the gastrointestinal tract is not clear. In this study, we examined the immunohistochemical expression of IMP3 in gastrointestinal stromal tumor (GIST) (n = 150), malignant melanoma (n = 17), malignant mesothelioma (n = 6), leiomyosarcoma (n = 6), inflammatory myofibroblastic tumor (IMT) (n = 12), desmoid fibromatosis (n = 8), leiomyoma (n = 20), and schwannoma (n = 20). Focal (≥10%) or diffuse (≥50%) expression with strong staining for IMP3 was judged as positive. We found that malignant melanomas (16/17 cases, 94.1%), malignant mesotheliomas (5/6 cases, 83.3%), IMTs (7/12 cases, 58.3%), and leiomyosarcomas (2/6 cases, 33.3%) were positive for IMP3. Among IMTs and leiomyosarcomas, IMP3-positive cases were histologically and/or clinically aggressive subtypes. Other kinds of tumors, including GIST, desmoid fibromatosis, leiomyoma and schwannoma, were essentially negative for IMP3. Our results suggest that IMP3 may be an ancillary tool in identifying aggressive abdominal mesenchymal tumors other than GIST.

DOI： 10.1016/j.humpath.2013.10.010

Spontaneous regression of breast cancer with axillary lymph node metastasis: a case report and review of literature. Reviewed International journal

Eriko Tokunaga, Shinji Okano, Yuichiro Nakashima, Nami Yamashita, Kimihiro Tanaka, Sauri Akiyoshi, Kenji Taketani, Mitsunori Shirouzu, Hidetaka Yamamoto, Masaru Morita, Yoshihiko Maehara

International journal of clinical and experimental pathology 7 ( 7 ) 4371 - 80 2014

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

Spontaneous regression (SR) of cancer is a rare but well-documented biological phenomenon. However, the mechanism remains to be elucidated. We herein report a case of the SR of breast cancer at both the primary site and metastatic axillary lymph node with spontaneously-induced T cell-mediated immunological responses. A 52-year-old female with a lump in the left axilla was diagnosed to have a small breast carcinoma with a distinct axillary lymph node metastasis. During the preoperative systemic examination, she was diagnosed to have severe type 2 diabetes mellitus, was treated with insulin, and the hyperglycemia was normalized after one month. Surgery for left breast cancer was then performed. The postoperative histopathological examination revealed the SR of breast cancer at both the primary site and metastatic axillary lymph node. Immunohistochemical studies revealed that estrogen receptor positive, AE1/AE3-positive ductal carcinoma completely underwent necrosis associated with extensive infiltration of CD3-positive T cells in the tumor nodule in the lymph node. In addition, primary ductal carcinoma cells also underwent single cell necrosis with infiltration of T cells with lymph follicle-like organization of B cells in the mammary gland. The features were suggestive that the tumor eradication in the metastatic lymph node and regression of the primary ductal carcinoma could be due to host T cell response to the ductal carcinoma. As far as we know it is the first report that shows the spontaneous regression of breast cancer, probably due to the spontaneously-induced T cell response.

IgG4-related disease of the ileocecal region mimicking malignancy: A case report. Reviewed International journal

Yukiharu Hiyoshi, Eiji Oki, Yoko Zaitsu, Koji Ando, Shuhei Ito, Hiroshi Saeki, Masaru Morita, Hidetaka Yamamoto, Hideo Baba, Yoshihiko Maehara

International journal of surgery case reports 5 ( 10 ) 669 - 72 2014

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

INTRODUCTION: Immunoglobulin G4-related disease (IgG4-RD) is a systemic disease characterized by chronic fibrosing inflammation with abundant IgG4-positive plasma cells, and responds well to steroids. Previous reports of IgG4-RD have focused on pancreatic and extrapancreatic including the gastrointestinal tract, however, the colonic IgG4-RD is rare. PRESENTATION OF CASE: We herein report the case of a 74-year-old female with edematous wall thickening of the terminal ileum to the lower ascending colon confirmed by several preoperative imaging studies, who underwent right hemi-colectomy for suspected malignant lymphoma. The resected specimen showed an irregular wall thickness with subserosal sclerosis, and the lesion was 10cm in length from the terminal ileum to the ascending colon. The patient was diagnosed with IgG4-RD by pathological examinations, which demonstrated an increased number of IgG4-positive plasma cells (150/HPF), and an elevated IgG4/IgG ratio (50%). DISCUSSION: Gastrointestinal IgG4-RD appears to be difficult to diagnose prior to surgical resection because of its rarity, and the similarity of its features to malignancy. The measurement of the serum IgG4 levels, immunohistochemical examination of biopsy specimens and use of several imaging modalities might help us to diagnose the disease without surgical resection, and this disease can generally be treated with steroid therapy. However, surgical resection for IgG4-RD may still be also necessary for patients with concerns regarding malignancy or with intractable gastrointestinal obstruction caused by this disease. CONCLUSION: Gastrointestinal IgG4-RD often mimics malignancy, and we should therefore consider this disease in the differential diagnosis of colonic lesions in order to optimize the treatment.

DOI： 10.1016/j.ijscr.2014.08.003

Conventional spindle cell-type malignant peripheral nerve sheath tumor arising in a sporadic schwannoma. Reviewed International journal

Makoto Endo, Hidetaka Yamamoto, Katsumi Harimaya, Kenichi Kohashi, Takeaki Ishii, Nokitaka Setsu, Yukihide Iwamoto, Yoshinao Oda

Human pathology 44 ( 12 ) 2845 - 8 2013.12

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

Malignant peripheral nerve sheath tumor is a malignant tumor showing nerve sheath differentiation. Approximately one-half of malignant peripheral nerve sheath tumors arise from a benign peripheral nerve sheath tumor, which is commonly a neurofibroma in patients with neurofibromatosis type 1. Malignant peripheral nerve sheath tumor arising in a sporadic schwannoma of soft tissue is extremely rare. In this condition, malignant cells usually show epithelioid morphology, meeting the diagnostic criteria for epithelioid malignant peripheral nerve sheath tumor. Here, we present an extraordinary case of spindle cell-type malignant peripheral nerve sheath tumor arising in a schwannoma on the back of a 58-year-old woman without neurofibromatosis. The malignant component showed hypercellular spindle cell proliferation with high mitotic activities; in contrast, the benign component showed hypocellular spindle cell proliferation in a palisading pattern and with Verocay bodies. Immunohistochemical S-100 protein staining showed a clear contrast between the malignant (negative) and benign (positive) components, which was useful for differentiating cellular schwannoma. Recognizing this rare condition is helpful in the pathologic diagnosis of schwannoma showing cellular proliferation in part.

DOI： 10.1016/j.humpath.2013.05.021

Ossifying fibromyxoid tumor presenting EP400-PHF1 fusion gene. Reviewed International journal

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

Human pathology 44 ( 11 ) 2603 - 8 2013.11

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

Ossifying fibromyxoid tumor is a rare soft tissue tumor of borderline malignancy and uncertain differentiation. Recently, a novel fusion gene, EP400-PHF1, was discovered in ossifying fibromyxoid tumor; however, its relation to this type of tumor has been uncertain because the EP400-PHF1 fusion gene has been successfully detected in only 1 case. We present an ossifying fibromyxoid tumor case with the EP400-PHF1 fusion gene detected by reverse transcriptase polymerase chain reaction, along with compatible cytogenetic data showing a t(6;12)(p21;q24.3) translocation. Our results suggest that the EP400-PHF1 fusion gene is a reproducible finding in ossifying fibromyxoid tumor.

DOI： 10.1016/j.humpath.2013.04.003

Prognostic impact of the activation status of the Akt/mTOR pathway in synovial sarcoma. Reviewed International journal

Nokitaka Setsu, Kenichi Kohashi, Fumiyoshi Fushimi, Makoto Endo, Hidetaka Yamamoto, Yusuke Takahashi, Yuichi Yamada, Takeaki Ishii, Koichirou Yokoyama, Yukihide Iwamoto, Yoshinao Oda

Cancer 119 ( 19 ) 3504 - 13 2013.10

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

BACKGROUND: The Akt/mammalian target of rapamycin (mTOR) pathway, downstream from phosphatidylinositol 3-kinase (PI3K), mediates cell survival and proliferation. Although this pathway reportedly contributes to the progression of synovial sarcoma, its prognostic impact has not been clarified. METHODS: The authors analyzed clinicopathologic data and phosphorylation status of Akt (a serine/threonine kinase also known as protein kinase B), mTOR, the eukaryotic translation initiation factor 4E binding protein (4E-BP1), and the S6 ribosomal protein by immunohistochemical analysis of 120 formalin-fixed, paraffin-embedded samples and by Western blot analysis of 24 frozen samples from 112 patients with synovial sarcoma. RESULTS: Akt, mTOR, 4E-BP1, and S6 were activated in 76.5%, 67.6%, 59.6%, and 42.6% of samples, respectively. Immunohistochemically positive phosphorylated (p) mTOR (pmTOR) and p4E-BP1 results were correlated with higher mitotic activity, and positive p4E-BP1 results were correlated with greater necrosis. No mutations around the hot spots in the PI3K catalytic subunit α (PI3KCA) and Akt1 genes were observed. In multivariate analysis of clinicopathologic parameters, frequent mitosis was a risk factor for shorter overall survival; and male sex, visceral location, larger tumor size, and frequent mitosis were identified as risk factors for shorter event-free survival. Positive pmTOR and p4E-BP1 results were correlated significantly with shorter overall survival, and positive p4E-BP1 results were correlated with shorter event-free survival in univariate analysis. Positive pAkt results were associated significantly with shorter event-free survival in multivariate analysis. CONCLUSIONS: In this study, the Akt/mTOR pathway was activated and was associated with worse clinical and pathologic behavior in patients with synovial sarcoma. The authors propose that this pathway may have potential as a therapeutic target.

DOI： 10.1002/cncr.28255

Insulin-like growth factor II messenger RNA-binding protein-3 is a valuable diagnostic and prognostic marker of intraductal papillary mucinous neoplasm. Reviewed International journal

Katsuya Morimatsu, Shinichi Aishima, Hidetaka Yamamoto, Akifumi Hayashi, Kohei Nakata, Yasunori Oda, Koji Shindo, Minoru Fujino, Masao Tanaka, Yoshinao Oda

Human pathology 44 ( 9 ) 1714 - 21 2013.9

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

Recently, various studies have shown that insulin-like growth factor II messenger RNA-binding protein-3 (IMP3) is a useful diagnostic marker for malignant lesions and a prognostic marker for poor survival in several kinds of tumors. However, the value of IMP3 as a diagnostic and prognostic marker in intraductal papillary mucinous neoplasm (IPMN) of pancreas has been unclear until now. In this study, we examined IMP3 immunohistochemical expression in 190 resection samples and 15 biopsy samples of IPMN and analyzed the value of IMP3 as a diagnostic and prognostic marker. IMP3 expression was recognized in 71.8% (28/39) of IPMNs with high-grade dysplasia and in 81.3% (26/32) of IPMNs with an associated invasive carcinoma (IPMN-IC), but it was not found in any IPMNs with low-grade dysplasia or in IPMNs with intermediate dysplasia. IMP3 expression was significantly higher in cancerous lesions (IPMN with high-grade dysplasia and IPMN-IC) than in noncancerous lesions (IPMN with low-grade dysplasia and IPMN with intermediate-grade dysplasia), with a sensitivity of 76.1% and a specificity of 100% (P < .001). We also identified a significant difference in IMP3 expression between cancerous lesions and noncancerous lesions in biopsy specimens (P = .027). In IPMN-IC, disease-specific survival was significantly shorter in the high-expression group (>50% tumor staining) than in the low-expression group (≤50% tumor staining; P = .0069). In conclusion, our findings show that IMP3 is a useful diagnostic marker for distinguishing between noncancerous and cancerous lesions and is a valuable prognostic biomarker in IPMN.

DOI： 10.1016/j.humpath.2012.12.020

HER2 and EGFR gene copy number alterations are predominant in high-grade salivary mucoepidermoid carcinoma irrespective of MAML2 fusion status. Reviewed International journal

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

Histopathology 63 ( 3 ) 378 - 92 2013.9

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

AIMS: In this study, we aimed to investigate the molecular mechanisms underlying the development of mucoepidermoid carcinoma (MEC). METHODS AND RESULTS: In 31 cases, we examined the MAML2 fusion status using reverse transcriptase-polymerase chain reaction, and HER2 and EGFR status using immunohistochemistry and chromogenic in-situ hybridization. MAML2 fusions were detected in 15 (57.7%) of 26 MECs analysed, including 11 of 16 (68.8%) low-grade, two of four (50%) intermediate-grade and two of six (33.3%) high-grade MECs. HER2 gene amplification and an increased EGFR gene copy number (with balanced chromosome 7 high-polysomy) were each detected in four of 28 (14.3%) MECs analysed. Irrespective of MAML2 fusion status, all seven high-grade MECs had an increased gene copy number of either HER2 or EGFR, in a mutually exclusive manner, whereas such abnormalities were extremely rare in low- and intermediate-grade MEC. CONCLUSIONS: These results suggest that HER2 or EGFR gene abnormality could play an important role in the development of high-grade MEC, and also in the progression from MAML2 fusion-positive low-/intermediate-grade to high-grade in a subset of MEC. Furthermore, we suggest that high-grade MEC comprises a heterogeneous group of tumours in terms of molecular pathogenesis, in particular MAML2 fusion status.

DOI： 10.1111/his.12183

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

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

Correlation between beta-catenin widespread nuclear expression and matrix metalloproteinase-7 overexpression in sporadic desmoid tumors. Reviewed International journal

Hiroshi Matono, Yoshinao Oda, Mari Nakamori, Sadafumi Tamiya, Hidetaka Yamamoto, Ryohei Yokoyama, Tsuyoshi Saito, Yukihide Iwamoto, Masazumi Tsuneyoshi

Human pathology 39 ( 12 ) 1802 - 8 2008.12

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

Desmoid tumors (desmoid-type fibromatoses) are locally aggressive soft tissue tumors associated with the Wnt/beta-catenin signaling pathway (APC-beta-catenin-Tcf pathway). Matrix metalloproteinase-7, which is one of the target genes of the Wnt/beta-catenin signaling pathway, has been reported to play an important role in tumor progression. We examined the immunohistochemical expression of beta-catenin and matrix metalloproteinase-7 in 72 samples (63 primary and 9 recurrent samples, 63 patients) of sporadic desmoid tumors without familial adenomatous polyposis, and the genetic alteration of the beta-catenin gene in 33 frozen materials (22 primary and 11 recurrent samples, 22 patients). We further examined messenger RNA expression of matrix metalloproteinase 7 by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and compared the results with those of normal skeletal muscles. Immunohistochemically, there was a statistically significant correlation between widespread nuclear expression of beta-catenin and overexpression of matrix metalloproteinase-7 (P < .01 in extra-abdominal desmoid, Fisher test). There were 7 missense point mutations in the 22 primary frozen samples (32%). In the beta-catenin mutated group, matrix metalloproteinase-7 messenger RNA expression was significantly higher than that of the beta-catenin wild-type group (P = .0018, Mann-Whitney U test). Our results suggest that the matrix metalloproteinase-7 gene may be up-regulated by mutated or continuously elevated beta-catenin protein and that the matrix metalloproteinase-7 gene may also be targeted in the Wnt/beta-catenin signaling pathway in sporadic desmoid tumors.

DOI： 10.1016/j.humpath.2008.05.005

Enhanced mass 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, Takashi Okafuji, Takeshi Kamitani, Hiroyasu Soeda, Taro Setoguchi, Shuji Sakai, Masamitsu Hatakenaka, Makoto Kubo, Noriaki Sadanaga, Hidetaka Yamamoto, Hiroshi Honda

Journal of magnetic resonance imaging : JMRI 28 ( 5 ) 1157 - 65 2008.11

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 enhanced mass on breast MR imaging and to find the strongest discriminators between carcinoma and benignancy. MATERIALS AND METHODS: We analyzed consecutive breast MR images in 270 patients; however, 13 lesions in 93 patients were excluded based on our criteria. We analyzed tumor size, shape, margin, internal mass enhancement, kinetic curve pattern, and apparent diffusion coefficient (ADC) values. We applied univariate and multivariate analyses to find the strongest indicators of malignancy and calculate a predictive probability for malignancy. We added the corresponding categories to these prediction probabilities for malignancy and calculated diagnostic accuracy when we consider category 4b, 4c, and 5 lesions as malignant and category 4a, 3, and 2 lesions as benign. In a validation study, 75 enhancing lesions in 71 patients were examined consecutively. RESULTS: Irregular margin, heterogeneous internal enhancement, rim enhancement, plateau time-intensity curve (TIC) pattern, and washout TIC pattern were the strongest indicators of malignancy as well as past studies, and ADC values less than 1.1x10(-3) mm2/s were also the strongest indicators of malignancy. In a validation study, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 92% (56/61), 86% (12/14), 97% (56/58), 71% (12/17), and 91% (68/75), respectively. CONCLUSION: The combination of DWI and DCE-MRI could produce high diagnostic accuracy in the characterization of enhanced mass on breast MR imaging.

DOI： 10.1002/jmri.21570

Alterations of RB1 gene in embryonal and alveolar rhabdomyosarcoma: special reference to utility of pRB immunoreactivity in differential diagnosis of rhabdomyosarcoma subtype. Reviewed International journal

Kenichi Kohashi, Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Tomonari Takahira, Yukiko Takahashi, Tatsuro Tajiri, Tomoaki Taguchi, Sachiyo Suita, Masazumi Tsuneyoshi

Journal of cancer research and clinical oncology 134 ( 10 ) 1097 - 103 2008.10

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

PURPOSE: Rhabdomyosarcoma (RMS), which is the most common pediatric soft tissue sarcoma, is classified into two major histologic subtypes, embryonal RMS (ERMS) and alveolar RMS (ARMS). RMS is occasionally reported to be the second neoplasm of hereditary retinoblastoma. Osteosarcoma is known as the most common second neoplasm of hereditary retinoblastoma, and tumorigenesis of osteosarcoma has been proven in previous studies to be related to the RB gene (RB1) alteration. Therefore, there might be a correlation between the tumorigenesis of RMS and RB1 alteration. METHODS: We examined the RB protein (pRB) expression and RB1 alteration such as allelic imbalance (gain or loss) and homozygous deletion, using immunohistochemistry, microsatellite makers, and quantitative real-time PCR in 57 sporadic RMS. RESULTS: Allelic imbalance was more frequently detected in ERMS (13/27), than in ARMS (3/20) (P = 0.04). Homozygous deletion on the protein-binding pocket domain of RB1 was found in 6 of 27 ERMS and in 2 of 20 ARMS (P = 0.24). Furthermore, immunohistochemical pRB labeling indexes (LI) in 31 ERMS (median value, 31%) were significantly reduced in comparison with those observed in 26 ARMS (median value, 85%) (P < 0.0001). CONCLUSIONS: Our results support the assertion that tumorigenesis of RMS may be associated with RB1 alteration especially in ERMS, as previously reported for osteosarcoma. As for the RB pathway, each subtype of RMS may have a different tumorigenesis. In addition, immunohistochemical pRB LI may have the potential to be a useful ancillary tool in the differential diagnosis of RMS subtypes.

DOI： 10.1007/s00432-008-0385-3

SMARCB1/INI1 protein expression in round cell soft tissue sarcomas associated with chromosomal translocations involving EWS: a special reference to SMARCB1/INI1 negative variant extraskeletal myxoid chondrosarcoma. Reviewed International journal

Kenichi Kohashi, Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Yumi Oshiro, Teiyu Izumi, Tomoaki Taguchi, Masazumi Tsuneyoshi

The American journal of surgical pathology 32 ( 8 ) 1168 - 74 2008.8

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

Several previous studies have demonstrated the lack of SMARCB1/INI1 protein expression in only the malignant rhabdoid tumor (MRT). Several sarcoma groups are associated with a tumor-specific translocation involving EWS. Moreover, the EWS and SMARCB1/INI1 genes are located on the same 22q chromosome. We analyzed the status of SMARCB1/INI1 protein expression in 93 cases of sarcomas associated with chromosomal translocation involving EWS, comprising 52 Ewing's sarcoma/primitive neuroectodermal tumors, 24 extraskeletal myxoid chondrosarcomas (EMCS), 14 clear cell sarcomas of soft tissue, 2 desmoplastic small round cell tumors, and 1 myxoid/round cell liposarcoma. In addition, we analyzed the detailed SMARCB1/INI1 gene alteration in cases, which lacked its protein expression. Consequently, 4 EMCS showed no SMARCB1/INI1 expression, and 2 of these 4 cases revealed homozygous deletion and frameshift mutation of the SMARCB1/INI1 gene, respectively. These cases showed histologic findings compatible with EMCS, according to the most recent WHO classification, but no major fusion gene transcripts were detected. Moreover, 3 out of 4 SMARCB1/INI1 negative variant EMCS disclosed rhabdoid features. Therefore, the lack of SMARCB1/INI1 protein expression may be associated with rhabdoid features. The immunohistochemical result of the SMARCB1/INI expression is not an absolute diagnostic criteria for MRT and careful histologic evaluation is required to make a precise diagnosis of MRT.

DOI： 10.1097/PAS.0b013e318161781a

An unexpected cause of a febrile patient with huge splenomegaly. Reviewed International journal

Atsushi Nonami, Hidetaka Yamamoto, Masafumi Nakamura, Koji Nagafuji, Takanori Teshima

Clinical rheumatology 27 ( 7 ) 941 - 3 2008.7

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

We report an unexpected cause of a febrile patient with huge splenomegaly. A 32-year-old patient with fever and huge splenomegaly was admitted to our hospital. Diagnostic splenectomy revealed that the enlarged spleen adhered strongly to the abdominal organs. Pathologically, the splenic parenchyma showed no malignant cells, and the soft tissue adjacent to the splenic hilum showed a proliferation of fibroblastic or myofibroblastic spindle cells with fibrosis and lymphoplasmacytic infiltration. These findings lead to a diagnosis of peritoneal fibrosis, and an administration of 50 mg/day of prednisolone alleviated all the symptoms. The differential diagnosis of huge splenomegaly with fever usually includes hematolymphoid malignancies and infectious diseases; however, our case was diagnosed as idiopathic retroperitoneal fibrosis. Our case suggests that when we see patients with fever and huge splenomegaly, differential diagnosis should include retroperitoneal fibrosis.

DOI： 10.1007/s10067-008-0856-6

Aggressive invasive micropapillary salivary duct carcinoma of the parotid gland. Reviewed International journal

Hidetaka Yamamoto, Hideoki Uryu, Yuichi Segawa, Masazumi Tsuneyoshi

Pathology international 58 ( 5 ) 322 - 6 2008.5

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

The presence of invasive micropapillary component has been reported to be associated with salivary duct carcinoma and poor outcomes. Herein is described a rare case of invasive micropapillary salivary duct carcinoma of the parotid gland in a 60-year-old man. The micropapillary component was approximately 70% of the area of the tumor. Squamous differentiation was focally seen adjacent to the micropapillary component. On immunohistochemistry the ordinary salivary duct carcinoma component was positive for gross cystic disease fluid protein-15 (GCDFP-15), androgen receptor (AR), and HER2/neu, whereas both micropapillary and squamous components were negative for GCDFP-15 and AR. Immunohistochemical staining for D2-40 highlighted the lymph vessel invasion of tumor cells. This patient developed metastases in the lymph nodes of the neck, and also in the liver, lung, and brain. The lymph nodes and liver metastases had both ordinary salivary duct carcinoma and micropapillary components. The patient died of tumor 11 months after the initial surgical operation. The results support that the presence of micropapillary component is associated with more aggressive behavior of salivary duct carcinoma. It is also important for pathologists to recognize that GCDFP-15 and AR expression can be reduced in micropapillary carcinoma in the differential diagnosis of metastatic tumor.

DOI： 10.1111/j.1440-1827.2008.02231.x

Different expression profiles of Y-box-binding protein-1 and multidrug resistance-associated proteins between alveolar and embryonal rhabdomyosarcoma. Reviewed International journal

Yoshinao Oda, Kenichi Kohashi, Hidetaka Yamamoto, Sadafumi Tamiya, Kimitoshi Kohno, Michihiko Kuwano, Yukihide Iwamoto, Tatsuro Tajiri, Tomoaki Taguchi, Masazumi Tsuneyoshi

Cancer science 99 ( 4 ) 726 - 32 2008.4

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

Nuclear expression of the Y-box-binding protein-1 (YB-1) has been reported to regulate the expression of both P-glycoprotein (P-gp) and major vault protein (MVP), and to regulate proliferative activities in human malignancies. Based on morphology and molecular biology, rhabdomyosarcoma (RMS) can be divided into two major types: embryonal type and the more aggressive alveolar type. Thirty-five cases of embryonal RMS (ERMS) and 28 cases of alveolar RMS (ARMS) were examined immunohistochemically for the nuclear expression of YB-1 and the intrinsic expression of P-gp, multidrug resistance (MDR)-associated protein (MRP) 1, 2, and 3, breast-cancer resistant protein (BCRP) and MVP, and the findings were compared with proliferative activities as evaluated by the MIB-1-labeling index (LI). Moreover, mRNA levels of these MDR-related molecules were assessed using a quantitative reverse transcriptase-PCR method in 18 concordant frozen materials. P-gp expression was more frequently observed ARMS, compared with ERMS (P = 0.0332), whereas immunoreactivity for BCRP was more frequently recognized in ERMS (P = 0.0184). Nuclear expression of YB-1 protein was correlated with P-gp (P = 0.0359) and MVP (P = 0.0044) expression, and a higher MIB-1-labeling index (P = 0.0244) in ERMS, however, in ARMS no such relationships were observed. These immunohistochemical results indicate that different expression profiles of MDR-related molecules and their correlation with YB-1 nuclear expression support the concept that ERMS and ARMS are molecular biologically distinct neoplasms. Apart from ERMS, frequent P-gp expression in ARMS may be independent from YB-1 regulation. However, YB-1 may be a candidate for a molecular target in rhabdomyosarcoma therapy, especially in ERMS.

DOI： 10.1111/j.1349-7006.2008.00748.x

Detection and characterization of vascular endothelial growth factors and their receptors in a series of angiosarcomas. Reviewed International journal

Eijun Itakura, Hidetaka Yamamoto, Yoshinao Oda, Masazumi Tsuneyoshi

Journal of surgical oncology 97 ( 1 ) 74 - 81 2008.1

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

BACKGROUND: Angiosarcomas are malignant mesenchymal neoplasms, including sarcomas of presumptive vascular endothelial origin and sarcomas of probable lymphatic origin. It is, however, often difficult to determine whether they are from blood vascular or lymphatic endothelium. The majority of angiosarcomas are thought to originate from vascular endothelia and spread via bloodstream to lung, but lymphatic metastases can occur. METHODS: We investigated immunohistochemical expression of vascular endothelial growth factors (VEGF-A, VEGF-C) and their receptors (VEGFR-1, VEGFR-2, VEGFR-3) in a series of 34 angiosarcomas. RESULTS: VEGF-A was expressed by 32/34 (94%), VEGF-C by 4/34 (12%), VEGFR-1 by 32/34 (94%), VEGFR-2 by 22/34 (65%), and VEGFR-3 by 27/34 (79%). Patients who expressed low or no VEGFR-2 showed a significantly unfavorable prognosis by log-rank test (P = 0.010) and multivariate analysis (hazard ratio, 5.16; 95% CI, 1.40-19.04; P = 0.014). VEGFR-1 and VEGFR-3 were not significantly associated with patients' prognosis. CONCLUSIONS: VEGF-A and VEGFR-1 were detected in diverse subtypes of angiosarcomas. In cooperation, VEGF-A and VEGF-C are likely to be involved in the development of angiosarcoma associated with lymphedema. VEGF-C expression may cause susceptibility to lymphatic metastasis through tumor lymphangiogenesis. Angiosarcoma of the scalp, which is traditionally considered as a true hemangiosarcoma, may include some cases of lymphatic origin.

Overexpression of inducible nitric oxide synthase and accumulation of 8-OHdG in nasopharyngeal carcinoma

Y. Segawa, Y. Oda, H. Yamamoto, H. Uryu, H. Shiratsuchi, N. Hirakawa, K. Tomita, T. Yamamoto, S. Oda, T. Yamada, S. Komune, M. Tsuneyoshi

Histopathology 52 ( 2 ) 213 - 223 2008.1

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

Aims: Nitric oxide (NO), produced by inducible NO synthase (iNOS), has been suggested to cause oxidative stress, leading to 8-hydroxydeoxyguanosine (8-OHdG) accumulation and subsequent transversion mutation of DNA. The aim was to evaluate iNOS expression and the status of oxidative stress in nasopharyngeal carcinoma (NPC). Methods and results: Seventy-three cases of NPC were investigated to examine the immunohistochemical expression of iNOS, 8-OHdG and latent membrane protein-1 (LMP-1) and Epstein-Barr virus-encoded small RNA (EBER) expression using in situ hybridization. iNOS mRNA expression and p53 gene mutations were also assessed. Overexpression of iNOS, LMP-1 and EBER was observed in 62 (84.9%), 28 (38.4%) and 53 (72.6%) cases respectively. p53 gene mutation was found in 10 of 73 (13.7%) cases. Immunohistochemical iNOS expression was associated with the 8-OHdG labelling index, iNOS mRNA expression and p53 gene alteration (P &lt
0.0001, P = 0.016 and 0.0082 respectively). Conclusions: Our present findings suggest that the expression of iNOS induces oxidative stress in NPC. Although the presence of p53 mutation was associated with iNOS overexpression, the type of acid-base change of p53 was transition, but not transversion, which suggests that the p53 gene is not the direct target of DNA damage by 8-OHdG accumulation. © 2008 The Authors.

DOI： 10.1111/j.1365-2559.2007.02920.x

Circumscribed mass lesions on mammography: dynamic contrast-enhanced MR imaging to differentiate malignancy and benignancy. Reviewed

Takashi Okafuji, Hidetake Yabuuchi, Hiroyasu Soeda, Yoshio Matsuo, Takeshi Kamitani, Shuji Sakai, Masamitsu Hatakenaka, Syoji Kuroki, Eriko Tokunaga, Hidetaka Yamamoto, Hiroshi Honda

Magnetic resonance in medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine 7 ( 4 ) 195 - 204 2008

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

PURPOSE: We evaluated the magnetic resonance (MR) features of breast lesions showing circumscribed mass on mammography to understand the characteristics that differentiate malignancy and benignancy. MATERIALS AND METHODS: Our institutional review board approved the study, and informed consent was waived. Using logistic regression analysis, we examined morphologic and kinetic MR imaging data of 90 breast lesions (43 malignant, 47 benign) that showed circumscribed mass on mammography. RESULTS: Features identified as having high odds for malignancy included: rim enhancement (odds ratio, 70.894; 95% confidence interval (CI), 7.525-667.938); heterogeneous enhancement (odds ratio, 10.839; 95% CI, 1.032-113.856); and washout dynamic pattern (odds ratio, 46.262; 95% CI, 3.716-575.901). Combinations of washout dynamic pattern and either rim or heterogeneous enhancement reflected excessively high prediction probability for malignancy (>0.95), whereas combinations lacking washout dynamic pattern and with either homogeneous enhancement or dark internal septation revealed excessively low prediction probability for malignancy (<0.05). CONCLUSION: Breast cancers with circumscribed mass on mammography could be differentiated from benign masses using internal enhancement and the kinetic pattern of contrast-enhanced breast MR imaging.

Highly aggressive behavior of malignant rhabdoid tumor: a special reference to SMARCB1/INI1 gene alterations using molecular genetic analysis including quantitative real-time PCR. Reviewed International journal

Kenichi Kohashi, Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Teiyu Izumi, Shigeru Ohta, Tomoaki Taguchi, Sachiyo Suita, Masazumi Tsuneyoshi

Journal of cancer research and clinical oncology 133 ( 11 ) 817 - 24 2007.11

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

PURPOSE: SMARCB1/INI1, which negatively regulates cell cycle progression from G0/G1 into the S-phase via the p16INK4a-RB-E2F pathway, has been reported to be inactivated homozygously by deletion and/or mutations in malignant rhabdoid tumor (MRT). In the current study, we investigated the alteration of the SMARCB1/INI1 gene using simple methods, and its gene product at the protein level. Moreover, we investigated the status of hyperphosphorylation in RB protein, known as a key cell cycle molecule. METHODS: Three cell lines and 11 formalin-fixed, paraffin-embedded specimens of MRT were investigated. SMARCB1/INI1 gene alteration was analyzed with simple methods as a quantitative real-time PCR and direct sequencing method. Furthermore, SMARCB1/INI1 and RB protein were immunohistochemically evaluated. RESULTS: In 12 of 14 cases, we detected genetic alterations comprised of nine (including three cell lines) homozygous deletions and three mutations, which can induce abnormal expression of gene products. At the protein level, SMARCB1/INI1 immunohistochemical expressions were not detected in any cases. Twelve out of 14 cases showed high-level (+5) expression of tRB (both hyperphosphorylated and underphosphorylated RB), combined with low-level (+1) expression of uRB (underphosphorylated RB), indicating a high rate of hyperphosphorylation. CONCLUSIONS: We could analyze the SMARCB1/INI1 gene alteration with simple methods, and SMARCB1/INI1 gene alteration was found in 12 of 14 cases. Especially, quantitative real-time PCR was a convenient and accurate method. In addition, a high rate of hyperphosphorylation of RB gene was recognized. These results suggest that the clinically aggressive character of MRT is caused by the inactivation of the SMARCB1/INI1 gene.

Phosphoglyceride crystal deposition disease originating from the myocardium. Reviewed International journal

Fumihiro Shoji, Ichiro Yoshino, Takuro Kometani, Hidetaka Yamamoto, Yoshihiko Maehara

The Journal of thoracic and cardiovascular surgery 134 ( 2 ) 508 - 9 2007.8

Congenital pseudarthrosis of the tibia: analysis of the histology and the NF1 gene. Reviewed

Akio Sakamoto, Tatsuya Yoshida, Hidetaka Yamamoto, Yoshinao Oda, Masazumi Tsuneyoshi, Yukihide Iwamoto

Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association 12 ( 4 ) 361 - 5 2007.7

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

BACKGROUND: Congenital pseudarthrosis of the tibia (CPT) is frequently, but not always, associated with neurofibromatosis type 1 (NF1). Double inactivation of the NF1 gene has been reported to be the pathogenesis of CPT in NF1 cases. METHODS: We analyzed the loss of heterozygosity (LOH) of the NF1 gene in cases of CPT with NF1 to examine whether double inactivation was seen in the case. In addition to morphological analysis, immunoexpression of differentiation markers was examined. RESULTS AND DISCUSSION: The tibia tapered with the zone phenomenon from mature to immature bone with osteoblastic rimming, resembling osteofibrous dysplasia. Osteosclerotic bowed bone with a small number of osteoclasts suggested dysfunction of bone remodeling. Fibrous tissue at the site of pseudarthrosis was associated with the periosteum and demonstrated myofibroblastic differentiation accompanied by massive cartilage formation, suggesting some misdirection during the differentiation of periosteum to myofibroblasts or chondrocytes. LOH of the NF1 gene locus was not seen in fibrous tissue. This result suggests that CPT is not accompanied by double inactivation in every NF1 case.

Detection of COL1A1-PDGFB fusion transcripts and PDGFB/PDGFRB mRNA expression in dermatofibrosarcoma protuberans. Reviewed International journal

Tomonari Takahira, Yoshinao Oda, Sadafumi Tamiya, Koichi Higaki, Hidetaka Yamamoto, Chikashi Kobayashi, Teiyu Izumi, Naomi Tateishi, Yukihide Iwamoto, Masazumi Tsuneyoshi

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 20 ( 6 ) 668 - 75 2007.6

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

Fusion of the collagen type I alpha 1 (COL1A1) gene with the platelet-derived growth factor beta chain (PDGFB) gene has been described in dermatofibrosarcoma protuberans. The abnormal fusion transcripts probably cause PDGFB and its receptor (platelet-derived growth factor receptor beta, PDGFRB) autocrine stimulation and cell proliferation, which are responsible for the development of dermatofibrosarcoma protuberans. A reverse transcription-polymerase chain reaction assay was performed to detect the COL1A1-PDGFB fusion transcripts in 57 samples. In addition, the PDGFB gene amplification and PDGFB/PDGFRB mRNA levels were quantified by a real-time PCR system for the samples in which the fusion transcripts had been successfully detected. The fusion transcripts were detected in 42 of 57 samples. Various exons of the COL1A1 gene were fused in frame with the PDGFB gene; exons 7 and 25 were found to be slightly more frequently involved than the other exons. The PDGFB gene amplification levels varied from 0.6 to 8.3 (mean 2.4) in 42 tumor samples and from 0.4 to 3.0 (mean 1.2) in 20 adjacent normal tissue samples. In the 20 paired samples, the PDGFB gene amplification in the tumor was significantly higher than that in the normal tissue. The presence of PDGFB and PDGFRB mRNAs was demonstrated in 26 and 21 of 26 cases, respectively. The PDGFB and PDGFRB mRNA expression levels showed a good correlation (r=0.76, P<0.0001). These results indicate that the fusion protein, which is processed by the COL1A1-PDGFB transcripts, can serve as a functional ligand for PDGFRB.

A case of an inflammatory myofibroblastic tumor in the lung which expressed TPM3-ALK gene fusion

Y. Kinoshita, T. Tajiri, S. Ieiri, K. Nagata, T. Taguchi, S. Suita, K. Yamazaki, I. Yoshino, Y. Maehara, K. Kohashi, H. Yamamoto, Y. Oda, M. Tsuneyoshi

PEDIATRIC SURGERY INTERNATIONAL 23 ( 6 ) 595 - 599 2007.6

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

We herein describe a 4-year-old boy who after being treated for pneumonia showed an abnormal shadow at the hilus of the right lung on chest X-rays with continued inflammatory findings in his laboratory data. CT and MR investigations suggested the existence of a neoplasm at that site. An open biopsy was thus performed for a definite diagnosis. The histological findings and the expression of TPM3-ALK fusion gene confirmed a diagnosis of an inflammatory myofibroblastic tumor. A right upper and middle lobectomy including the tumor was thus performed for a complete resection. In addition to the histological diagnosis, the detection of the tumor specific fusion gene provided objective evidence in making a diagnosis.

DOI： 10.1007/s00383-006-1821-6

Prognostic significance of angiogenesis in gastrointestinal stromal tumor. Reviewed International journal

Masakazu Imamura, Hidetaka Yamamoto, Norimoto Nakamura, Yoshinao Oda, Takashi Yao, Yoshihiro Kakeji, Hideo Baba, Yoshihiko Maehara, Masazumi Tsuneyoshi

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 20 ( 5 ) 529 - 37 2007.5

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

Angiogenesis is important in the growth and metastasis of various kinds of solid tumors. To investigate the potential role of angiogenesis in gastrointestinal stromal tumor (GIST), an immunohistochemical analysis was performed in 95 cases of GISTs for microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression. MVD was evaluated with immunohistochemical staining for CD31. A high level of MVD was significantly correlated with overexpression of VEGF, tumor location (intestine>stomach), tumor size (> or =5 cm), tumor grade (high>intermediate>low grade) (P=<0.0001, 0.0422, 0.0006, 0.0359, respectively). Of the 70 GISTs analyzed, KIT exon 11 mutations were detected in 45 cases (64.3%) and KIT exon 9 mutations in two cases (2.9%). No mutations were found in KIT exons 13 and 17, and platelet-derived growth factor receptor-alpha exons 12 and 18. Interestingly, VEGF expression level was significantly higher in the non-KIT exon 11 mutant group than in the KIT exon 11 mutant group (P=0.0266). In univariate analysis, tumor grade (high grade), tumor size (> or =5 cm), mitotic count (> or =5/50 high-power fields), Ki-67 labeling index (> or =4.6%), MVD (> or =7.0/0.95 mm(2)) and VEGF expression (high) were significantly associated with a shorter period of disease-free survival (P=<0.0001, 0.0199, 0.0055 0.0027, 0.0028 and 0.0302, respectively). In multivariate analysis, tumor grade and MVD were identified as independent worse prognostic factors (P=0.0007, 0.0152, respectively). In conclusion, our results suggest that the evaluation of MVD and VEGF expression is useful for predicting the aggressive biologic behavior of GIST, and that angiogenesis associated with VEGF may play an important role, at least in part, in the progression of GIST.

Dysadherin expression as a significant prognostic factor and as a determinant of histologic features in synovial sarcoma: special reference to its inverse relationship with E-cadherin expression. Reviewed International journal

Teiyu Izumi, Yoshinao Oda, Tadashi Hasegawa, Yukihiro Nakanishi, Akira Kawai, Hiroshi Sonobe, Tomonari Takahira, Chikashi Kobayashi, Hidetaka Yamamoto, Sadafumi Tamiya, Setsuo Hirohashi, Yukihide Iwamoto, Masazumi Tsuneyoshi

The American journal of surgical pathology 31 ( 1 ) 85 - 94 2007.1

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

Dysadherin is a cancer-associated cell membrane glycoprotein, which down-regulates E-cadherin and promotes metastasis. Synovial sarcoma is a very rare mesenchymal tumor that exhibits an epithelial profile. To confirm the diagnosis of synovial sarcoma, we evaluated several immunohistochemical markers, or detected SYT-SSX fusion gene transcript. We studied the clinicopathologic features in 92 synovial sarcoma patients and also assessed the immunohistochemical expression of dysadherin and E-cadherin to examine their possible association with histologic subtype and biologic behavior. Moreover, among 30 patients, for whom frozen materials were available, dysadherin mRNA expression was examined by reverse transcription-polymerase chain reaction and real-time quantitative reverse transcription-polymerase chain reaction analysis. Dysadherin-positive expression was significantly correlated with E-cadherin-reduced expression (P=0.0004). Dysadherin-positive immunostaining was diffusely observed in the membranes of tumor cells in 30/68 (44%) patients with monophasic fibrous type and in 1/2 (50%) patients with poorly differentiated type. However, in biphasic tumors, dysadherin expression in the fibrous component was not diffusely observed, but often sporadically or focally observed [20/22 (91%) patients]. In addition, dysadherin mRNA expression in monophasic fibrous type was significantly higher than in biphasic type (P=0.0079). Synovial sarcoma patients with dysadherin expression survived for a significantly shorter time than those without dysadherin expression (P=0.0006). Patients with combined dysadherin-positive expression and E-cadherin-reduced expression had a significantly worse prognosis than those with other combinations of dysadherin and E-cadherin expression (P=0.0007). SYT-SSX fusion gene transcript was detected in 39 patients. In our series, SYT-SSX fusion type was found to have no correlation with histologic subtype, prognosis, or dysadherin expression. In multivariate analysis, dysadherin immunopositivity (P=0.0411) was an independent adverse prognostic factor, in addition to a high MIB-1 labeling index (> or =10%). We conclude that E-cadherin dysfunction by dysadherin is associated with reduced E-cadherin expression and morphologic change from epithelioid to spindle phenotype. Dysadherin expression is considered to be one of the determinants of histologic subtype in synovial sarcoma. Moreover, dysadherin expression is an excellent and independent prognostic indicator.

Desmoplastic fibroblastoma (collagenous fibroma) with a specific breakpoint of 11q12. Reviewed

Sakamoto A, Yamamoto H, Yoshida T, Tanaka K, Matsuda S, Oda Y, Tsuneyoshi M, Iwamoto Y

Histopathology 2007

Absence of human herpesvirus-8 and Epstein-Barr virus in inflammatory myofibroblastic tumor with anaplastic large cell lymphoma kinase fusion gene. Reviewed International journal

Hidetaka Yamamoto, Kenichi Kohashi, Yoshinao Oda, Sadafumi Tamiya, Yukiko Takahashi, Yoshiaki Kinoshita, Shin Ishizawa, Masayuki Kubota, Masazumi Tsuneyoshi

Pathology international 56 ( 10 ) 584 - 90 2006.10

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

Inflammatory myofibroblastic tumor (IMT) is clinically and histologically characterized by inflammation. Some populations of IMT have anaplastic large cell lymphoma kinase (ALK) gene rearrangements. Infection with Epstein-Barr virus (EBV) and human herpesvirus-8 (HHV-8) in tumor cells of IMT has been reported; these reports, however, have been limited to ALK-negative IMT. The purpose of the present paper was to evaluate 21 cases of IMT for the presence of EBV and HHV-8. Immunohistochemically, 15 cases were ALK positive and six were negative. Of eight cases analyzed using reverse transcription-polymerase chain reaction, tropomyosin 3 (TPM3)-ALK, TPM4-ALK and clathrin heavy chain-ALK fusion genes were detected in one, two and two cases, respectively. All 21 IMT, irrespective of ALK expression, were negative for EBV by in situ hybridization for EBV-encoded RNA and immunohistochemical stain for latent membrane antigen-1. HHV-8 was also negative in all IMT by PCR for HHV-8 DNA sequence (KS330/233) and immunohistochemical stain for latent nuclear antigen. These results suggest that IMT may be a heterogeneous group in terms of pathogenesis, and EBV and HHV-8 do not play a major role in the pathogenesis of ALK-positive tumor.

Dedifferentiated chondrosarcoma with leukocytosis and elevation of serum G-CSF. A case report. Reviewed International journal

Akio Sakamoto, Hidetaka Yamamoto, Kazuhiro Tanaka, Shuichi Matsuda, Katsumi Harimaya, Yoshinao Oda, Masazumi Tsuneyoshi, Yukihide Iwamoto

World journal of surgical oncology 4 37 - 37 2006.7

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

BACKGROUND: G-CSF is known to function as a hematopoietic growth factor and it is known to be responsible for leukocytosis. G-CSF-producing tumors associated with leukocytosis include various types of malignancies. CASE PRESENTATION: We report the case of a 72-year-old man with dedifferentiated chondrosarcoma characterized by dedifferentiated components of malignant fibrous histiocytoma- or osteosarcoma-like features in addition to conventional chondrosarcoma, arising from his pelvic bone. After hemipelvectomy, when local recurrence and metastasis were identified, leukocytosis appeared and an elevated level of serum granulocyte-colony-stimulating factor (G-CSF) was also recognized. The patient died of multiple organ failure 2 months after surgery. Autopsy specimens showed that the histological specimens of the recurrence and metastasis were dedifferentiated components, without any conventional chondrosarcoma components. G-CSF was expressed only in the dedifferentiated components, not in the chondrosarcoma components, immunohistochemically. CONCLUSION: This is the first report of chondrosarcoma, or any other primary bone tumor, with leukocytosis, probably stimulated by tumor-produced G-CSF from the dedifferentiated components.

Prognostic significance of dysadherin expression in epithelioid sarcoma and its diagnostic utility in distinguishing epithelioid sarcoma from malignant rhabdoid tumor. Reviewed International journal

Teiyu Izumi, Yoshinao Oda, Tadashi Hasegawa, Yukihiro Nakanishi, Hiroshi Iwasaki, Hiroshi Sonobe, Hiroaki Goto, Hidenari Kusakabe, Tomonari Takahira, Chikashi Kobayashi, Ken-Ichi Kawaguchi, Tsuyoshi Saito, Hidetaka Yamamoto, Sadafumi Tamiya, Yukihide Iwamoto, Masazumi Tsuneyoshi

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 19 ( 6 ) 820 - 31 2006.6

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

Dysadherin is a cancer-associated cell membrane glycoprotein, which downregulates E-cadherin and promotes metastasis. We studied the clinicopathological features in 72 cases of epithelioid sarcoma and in six cases of malignant rhabdoid tumor, and also assessed the immunohistochemical expression of dysadherin, E-cadherin and MIB-1 in epithelioid sarcoma and malignant rhabdoid tumor cases. In addition, we compared dysadherin mRNA expression between epithelioid sarcoma and malignant rhabdoid tumor cell lines, using RT-PCR and real-time quantitative RT-PCR analysis. Immunohistochemical dysadherin expression was more frequently observed in proximal-type epithelioid sarcoma (71%) in comparison with distal-type epithelioid sarcoma (36%) (P = 0.037). Furthermore, seven proximal-type epithelioid sarcoma cases mimicking malignant rhabdoid tumor (histologically classified as the large cell type, accompanied by frequent rhabdoid cells and located in deep soft tissue) were all positive for dysadherin (100%), whereas dysadherin expression was not detected at all in any of the true six malignant rhabdoid tumors (0%). Cell lines established from proximal-type epithelioid sarcoma revealed significantly higher levels of dysadherin mRNA expression, compared with the levels seen in malignant rhabdoid tumor cell lines by real-time quantitative RT-PCR (P = 0.0433). Epithelioid sarcoma patients with dysadherin expression survived for a significantly shorter time than those without dysadherin expression (P = 0.001). In multivariate analysis, dysadherin immunopositivity (P = 0.0004) was one of the two independent adverse prognostic factors. We conclude that dysadherin expression in epithelioid sarcoma is a significant poor prognostic factor and that it is a powerful diagnostic marker for distinguishing epithelioid sarcoma, including the proximal-type epithelioid sarcoma, from malignant rhabdoid tumor. In epithelioid sarcoma, especially in proximal-type epithelioid sarcoma, increased cell disadhesion and motility by dysadherin plays an important role to acquire aggressive biological behavior. However, in malignant rhabdoid tumor, cell growth cycle that is regulated by hSNF5/INI1 gene seems to be critical to lethal biological behavior rather than dysadherin.

Nuclear beta-catenin correlates with cyclin D1 expression in spindle and pleomorphic sarcomas but not in synovial sarcoma. Reviewed International journal

Tsuyoshi Saito, Yoshinao Oda, Hidetaka Yamamoto, Ken-Ichi Kawaguchi, Kazuhiro Tanaka, Shuichi Matsuda, Yukihide Iwamoto, Masazumi Tsuneyoshi

Human pathology 37 ( 6 ) 689 - 97 2006.6

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

Nuclear beta-catenin staining in soft tissue sarcomas (STSs) has been shown to correlate with tumor progression as assessed by proliferative activity or poor prognosis. Frequent activation of Wnt signaling pathway has been also shown in synovial sarcoma (SS), suggesting a specific role of this pathway in SS. We examined roles of nuclear beta-catenin staining within soft tissue sarcomas. Immunohistochemical detection of nuclear beta-catenin accumulation correlated with cyclin D1 overexpression in spindle cell and pleomorphic sarcomas (P = .037), and the expression of these proteins evenly distributed throughout each section. In some cases, strong beta-catenin nuclear staining was observed in highly pleomorphic and mitotic cells. Furthermore, tumors with nuclear beta-catenin accumulation showed statistically significant increasing cyclin D1 mRNA expression level compared with those without (P = .023). Cyclin D1 mRNA expression levels were statistically higher in tumors with cyclin D1 overexpression than in tumors without (P = .037), suggesting that cyclin D1 overexpression is due to transcriptional activation. However, these correlations could not be detected in SS. In biphasic SS, beta-catenin nuclear staining was observed in spindle cells, whereas cyclin D1 nuclear staining was seen in glandular areas where beta-catenin kept membranous expression. Mutations in exon 3 of the beta-catenin gene and in the mutation cluster region of adenomatous polyposis coli gene were absent in this series of cases. Thus, cyclin D1 could be considered as one of the targets of the nuclear beta-catenin in spindle cell and pleomorphic sarcomas. A possible association between beta-catenin accumulation and spindle cell morphogenesis may exist in SS.

CXCR4 and VEGF expression in the primary site and the metastatic site of human osteosarcoma: analysis within a group of patients, all of whom developed lung metastasis. Reviewed International journal

Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Shuichi Matsuda, Kazuhiro Tanaka, Ryohei Yokoyama, Yukihide Iwamoto, Masazumi Tsuneyoshi

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 19 ( 5 ) 738 - 45 2006.5

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

The chemokine, CXCL12, and its receptor, CXCR4, have recently been shown to play an important role in metastasis of several kinds of carcinoma. It has also been demonstrated that VEGF regulates both the expression of CXCR4 and invasiveness in breast cancer cell lines. We compared the immunohistochemical expression of CXCR4 and VEGF between the primary site and a concordant pulmonary metastatic site in 30 osteosarcoma patients, all of which had undergone thoracotomy. Microvessel density (MVD) as shown by immunostaining of CD34 and proliferative activity with MIB-1 monoclonal antibody was also evaluated. CXCR4 expression (primary, 33.3% positive vs metastatic, 66.6% positive; P = 0.0097) and MVD (primary, 29.86 +/- 6.87/0.26 mm2 vs metastatic, 43.32 +/- 8.65/0.26 mm2; P = 0.0015) in the metastatic site were both significantly increased compared with those in the primary site, whereas no difference between primary and metastatic sites was observed with regard to VEGF expression. There was a significant positive correlation between immunohistochemical CXCR4 and VEGF expression (P = 0.0269). In total population, the MIB-1-labeling index (LI) was significantly higher in tumors, which showed immunoreactivity for VEGF (MIB-1-LI in VEGF-positive tumors, 24.29 +/- 5.4 vs VEGF-negative tumors, 18.33 +/- 4.16; P = 0.034). Furthermore, those patients with VEGF-positive primary tumors had a significantly worse prognosis compared with the patients with VEGF-negative primary tumors (P = 0.0053). Our results suggested that CXCR4 expression was associated with metastatic progression, and immunohistochemical VEGF expression in the primary site had predictive value for the osteosarcoma patients, who developed lung metastasis.

Aberrant expression of CHFR in malignant peripheral nerve sheath tumors. Reviewed International journal

Chikashi Kobayashi, Yoshinao Oda, Tomonari Takahira, Teiyu Izumi, Kenichi Kawaguchi, Hidetaka Yamamoto, Sadafumi Tamiya, Tomomi Yamada, Yukihide Iwamoto, Masazumi Tsuneyoshi

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 19 ( 4 ) 524 - 32 2006.4

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

Mitotic checkpoint maintains genomic integrity before mitosis. Numerous observations have suggested that mitotic abnormalities produce chromosomal instability and aneuploidy. In MPNST, complex karyotypes showing numerical and structural aberrations have been described. 'Checkpoint with forkhead-associated domain and ring finger' (CHFR) was recently identified as defining a new early mitotic checkpoint. We examined the expression of CHFR in 96 cases of MPNST by immunohistochemical and molecular methods. We found reduced (score, < or = 3) expression of CHFR in 63 out of 96 (66%) cases of MPNST, and such alteration was significantly correlated with a high mitotic count, a high Ki-67-labeling index, and a poor prognosis. In addition, MPNST with normal karyotype showed a strong (score, =5) expression of CHFR. Our results support the assertion that CHFR functions as an inhibitor of tumor proliferation.

Chromosomal aberrations and microsatellite instability of malignant peripheral nerve sheath tumors: a study of 10 tumors from nine patients. Reviewed International journal

Chikashi Kobayashi, Yoshinao Oda, Tomonari Takahira, Teiyu Izumi, Kenichi Kawaguchi, Hidetaka Yamamoto, Sadafumi Tamiya, Tomomi Yamada, Shinya Oda, Kazuhiro Tanaka, Shuichi Matsuda, Yukihide Iwamoto, Masazumi Tsuneyoshi

Cancer genetics and cytogenetics 165 ( 2 ) 98 - 105 2006.3

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

Malignant peripheral nerve sheath tumor (MPNST) is an uncommon soft tissue neoplasm with a poor prognosis, occurring sporadically or associated with neurofibromatosis type 1 (NF1); however, the histogenesis of MPNST remains unclear, especially in sporadic tumors. There are two major forms of genomic instability in human cancer: chromosomal instability (CIN) and microsatellite instability (MSI). An inverse relationship has recently been demonstrated between CIN and MSI in colorectal cancers. CIN and MSI are suggested to be individual pathways, which are involved in the pathogenesis and which may lead to specific clinical and pathological characteristics. To elucidate the chromosomal aberration as a consequence of CIN and MSI status of MPNST, we karyotyped 10 MPNSTs from nine patients, and examined the MSI of seven microsatellite markers using high-resolution fluorescence microsatellite analysis; 2 out of 10 cases (20%) had normal karyotypes, and 8 out of 10 cases (80%) revealed structural and numerical chromosomal aberrations. Three of the 10 cases (30%) showed near triploidy. The most frequent aberration was -22 (40%), followed by +2, +14, -13, -17, and -18 (30% each). An MSI-low status was observed in 30% of cases; the remaining cases showed microsatellite stability. These findings suggest that chromosomal aberration as a consequence of CIN has a greater role in the pathogenesis of MPNST than does that due to MSI.

Malignant perivascular epithelioid cell tumor of the colon: report of a case with molecular analysis. Reviewed International journal

Hidetaka Yamamoto, Yoshinao Oda, Takashi Yao, Toshio Oiwa, Chikashi Kobayashi, Sadafumi Tamiya, Ken-ichi Kawaguchi, Okio Hino, Masazumi Tsuneyoshi

Pathology international 56 ( 1 ) 46 - 50 2006.1

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

Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal neoplasm, and malignant cases are extremely rare. A case of malignant PEComa arising in the colon is described herein. The patient was a 43-year-old Japanese woman without a history of tuberous sclerosis complex. The tumor occurred in the abdominal cavity attached to the serosal side of the descending colon. Histologically, the tumor consisted of sheets or closely packed nests of epithelioid cells with clear or eosinophilic cytoplasms. The tumor cells were positive for HMB-45 but negative for S-100 protein and cytokeratins by immunohistochemical staining. Ki-67 labeling index was 2.9%. Peritoneal dissemination of tumor occurred at 20 months and the patient died of tumor at 38 months after the initial operation. This was considered to be a case of malignant PEComa, based on the histological and clinical features. Tumor cells showed overexpression of cyclin D1 but lacked the loss of heterozygosity of the TSC1 and TSC2 genes. The result suggests that the overexpression of cyclin D1 may play an important role in the tumorigenesis of PEComa. Because PEComas can behave in an aggressive manner, careful follow up is warranted.

DNA hypermethylation status of multiple genes in soft tissue sarcomas. Reviewed International journal

Ken-ichi Kawaguchi, Yoshinao Oda, Tsuyoshi Saito, Hidetaka Yamamoto, Tomonari Takahira, Chikashi Kobayashi, Sadafumi Tamiya, Naomi Tateishi, Yukihide Iwamoto, Masazumi Tsuneyoshi

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 19 ( 1 ) 106 - 14 2006.1

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

The aberrant methylation of promoter CpG islands is known to be a major inactivation mechanism of tumor-related genes. To determine the clinicopathological significance of gene promoter methylation in soft tissue sarcomas, we examined the promoter methylation status of 10 tumor-related genes in 65 soft tissue sarcomas and 19 adjacent non-neoplastic tissues by methylation-specific PCR. The methylation frequencies of tumor-related genes tested in soft tissue sarcomas were 17 (26%) for RASSF1A, 11 (17%) for DAP kinase, 10 (15%) for MGMT, nine (14%) for GSTP1, eight (12%) for PTEN, six (9%) for p16 and hMLH1, five (8%) for hMSH2, two (3%) for p14, and one (2%) for RB. Promoter methylation of these genes was not recognized in non-neoplastic tissues. All those cases of soft tissue sarcoma that had MGMT methylation, with the exception of one case of malignant peripheral nerve sheath tumor, showed large tumor size (> or = 10 cm) or recurrence. Moreover, eight of 10 cases with MGMT methylation revealed high American Joint Committee on Cancer stage. Seven of 10 cases (70%) with MGMT methylation showed a loss of MGMT expression by immunohistochemistry. In addition, MGMT methylation status had a statistically significant correlation with a loss of MGMT expression (P=0.014). In conclusion, although methylation of tumor-related genes was a relatively rare event in soft tissue sarcomas, methylation was tumor-specific. Of 10 tumor-related genes, cases with MGMT methylation had a tendency to be aggressive behavior. Moreover, MGMT methylation was closely associated with a loss of MGMT expression. Although our findings need to be extending to a large series, promoter methylation of tumor-related genes is likely to have an association with the pathogenesis of soft tissue sarcomas. Furthermore, MGMT methylation may be associated with tumor aggressiveness and the inactivation of MGMT gene.

Frequent alteration of p16(INK4a)/p14(ARF) and p53 pathways in the round cell component of myxoid/round cell liposarcoma: p53 gene alterations and reduced p14(ARF) expression both correlate with poor prognosis. Reviewed International journal

Yoshinao Oda, Hidetaka Yamamoto, Tomonari Takahira, Chikashi Kobayashi, Kenichi Kawaguchi, Naomi Tateishi, Yoko Nozuka, Sadafumi Tamiya, Kazuhiro Tanaka, Shuichi Matsuda, Ryohei Yokoyama, Yukihide Iwamoto, Masazumi Tsuneyoshi

The Journal of pathology 207 ( 4 ) 410 - 21 2005.12

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

In myxoid/round cell liposarcoma (MLS/RCLS), the presence of a round cell (RC) component has been reported to correlate with a worse prognosis for the patients. However, little is known about the molecular genetic differences between conventional myxoid (MX) components and RC components in this tumour. The aim of this study was to investigate the possible implications of molecular alterations of G1 to S-phase check-point genes, especially in the RC component. We evaluated the immunohistochemical expression of p53, MDM2, p14 and p16 protein and assessed proliferative activities using MIB-1 in 29 RC components and 81 MX components from 90 cases. Mutation of the p53 gene, amplification of the MDM2 gene, homozygous deletion, methylation status and mutation of the p16(INK4a)/p14(ARF) genes were also investigated, using concordant paraffin-embedded and frozen material. The data were analysed together with clinicopathological factors to assess their prognostic implications in MLS/RCLS. Immunohistochemically, the over-expression of p53 protein (p = 0.01366) and the reduced expression of p14 (p < 0.0001) and p16 (p < 0.0001) proteins were significantly more frequently observed in RC components than in MX components. Reduced expression of p14 protein correlated significantly with hypermethylation of the p14(ARF) gene promoter (p = 0.0176) and over-expression of p53 protein (p = 0.00837). By univariate analysis, reduced expression of p14 and p53 missense mutation were found to reduce the rate of survival significantly (p < 0.05). Multivariate analysis, including clinicopathological factors, revealed that tumour site (p = 0.0251), the presence of an RC component (p = 0.0113), high MIB-1 labelling index (p = 0.0005) and p53 missense mutation (p = 0.0036) were adverse prognostic factors. In MLS/RCLS, reduction of p14 protein expression and p53 mutation were related to poor prognosis. Accordingly, the p14(ARF)/p53 pathway may contribute to the presence of an RC component and malignant progression in this tumour.

Alterations of the RB1 gene in dedifferentiated liposarcoma. Reviewed International journal

Tomonari Takahira, Yoshinao Oda, Sadafumi Tamiya, Hidetaka Yamamoto, Chikashi Kobayashi, Teiyu Izumi, Kensaku Ito, Yukihide Iwamoto, Masazumi Tsuneyoshi

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 18 ( 11 ) 1461 - 70 2005.11

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

Dedifferentiated liposarcoma is a malignant adipocytic neoplasm containing a non-lipogenic sarcoma of variable histological grade that arises against the background of a pre-existing well-differentiated liposarcoma. The phenomenon of dedifferentiation is considered to be time-dependent, but the mechanism is not well known. The retinoblastoma protein, encoded by the RB1 gene located at 13q14, is a key regulator of proliferation, development, and differentiation of certain cell types, including adipocytes. In the current study, we investigated the genetic alterations of the RB1 gene, such as mutation (the essential promoter region and the protein-binding pocket domain; exons 20-24) and methylation of the promoter region, in addition to pRB expression and loss of heterozygosity (LOH) status, in two morphologically distinct areas (non-lipogenic dedifferentiated and well-differentiated components) in 27 patients. As a control, 11 undifferentiated high-grade pleomorphic sarcoma/pleomorphic malignant fibrous histiocytoma samples and 11 well-differentiated liposarcoma samples were also evaluated. Dedifferentiated components showed LOH (15/25; 60%) and abnormal retinoblastoma protein expression (18/27; 66.7%) more frequently than noted in the well-differentiated components (3/24; 12.5% and 9/27; 33.3%, respectively). Five and four out of the 27 dedifferentiated components harbored mutations and promoter methylation, respectively, whereas none of these alterations were seen in the well-differentiated components. These results suggest that retinoblastoma protein has a major role to play in dedifferentiation and that a 'two-hit' mechanism is involved in the altered retinoblastoma protein expression in dedifferentiated liposarcoma.

Microsatellite instability and proliferating activity in sinonasal carcinoma: molecular genetic and immunohistochemical comparison with oral squamous cell carcinoma. Reviewed International journal

Hideoki Uryu, Yoshinao Oda, Hideki Shiratsuchi, Shinya Oda, Hidetaka Yamamoto, Shizuo Komune, Masazumi Tsuneyoshi

Oncology reports 14 ( 5 ) 1133 - 42 2005.11

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

Sinonasal carcinomas arise from the respiratory epithelium that lines the nasal and paranasal cavities, and are histologically composed of either squamous or cylindrical cell carcinoma. However, molecular analysis with the purpose of distinguishing sinonasal carcinomas from other head and neck squamous cell carcinomas (HNSCCs), which arise from squamous epithelium, has been limited. Moreover, a wide range of frequency of microsatellite instability (MSI) in HNSCC has been reported. Using high-resolution fluorescent microsatellite analysis (HFRMA), we studied microsatellite alterations in 34 patients with sinonasal carcinoma. As a control, 24 oral squamous cell carcinomas were used. MSI was detected in 14 patients with sinonasal carcinoma (41%), but not in any with oral squamous cell carcinoma (p=0.002). Furthermore, in sinonasal carcinoma, 11 out of 17 (65%) T1-T3 sinonasal carcinomas demonstrated MSI, whereas only 3 out of 15 (20%) T4 tumors demonstrated MSI. Immunohistochemically, sinonasal carcinoma showed a higher MIB-1-labeling index and more frequently showed cytokeratin 18 expression when compared with oral squamous cell carcinoma. These findings suggest that sinonasal carcinoma and HNSCC have quite different molecular backgrounds regarding carcinogenesis, and the role of MSI is relatively minor in cases of advanced sinonasal carcinoma.

Prognostic significance of expressions of cell-cycle regulatory proteins in gastrointestinal stromal tumor and the relevance of the risk grade. Reviewed International journal

Norimoto Nakamura, Hidetaka Yamamoto, Takashi Yao, Yoshinao Oda, Ken-ichi Nishiyama, Masakazu Imamura, Tomomi Yamada, Hajime Nawata, Masazumi Tsuneyoshi

Human pathology 36 ( 7 ) 828 - 37 2005.7

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

Gastrointestinal stromal tumors (GISTs) have a wide spectrum of biologic behavior ranging from benign to malignant. Risk grading based on tumor size and mitotic counts has been proposed in an effort to predict the adverse outcome of GIST in the literature so far. Recent molecular studies have reported the prognostic values of several parameters, including alteration of cell-cycle regulators. The aim of this study was to elucidate the prognostic values of risk grade and alterations of cell-cycle-related proteins, including Ki-67, cyclin A, cyclin B1, cyclin D1, cyclin E, p16, p21, p27, p53, cdc2, and cdk2, in addition to the conventional factors. Eighty cases of primary c-kit-positive GISTs were classified into 2 cases of very-low-risk grade, 20 cases of low-risk grade, 25 cases of intermediate-risk grade, and 33 cases of high-risk grade. The risk grade was correlated with the presence of metastases and/or recurrence. A high level of Ki-67 and cyclin A expression was correlated with risk grade (P = .0027 and .0441, respectively). Overexpression of G2-M regulators, such as cyclin A, cyclin B1, and cdc2, was associated with the Ki-67 labeling index (LI) (P = .0007, .0475, and .0040, respectively). According to univariate analysis, tumor grade (high risk), tumor size (> or =5 cm), mitotic counts (> or =5/50 high-power fields), Ki-67 LI (> or =4.92%), cyclin A LI (> or =1.61%), and cdc2 LI (> or =1.25%) were all found to be significantly associated with a shorter period of disease-free survival (P = .0001, .0270, .0004, .0001, .0001, and .0011, respectively). According to multivariate analysis, both high Ki-67 LI and high-risk grade were found to be significantly associated with a shorter period of disease-free survival (P = .0083 and .0246, respectively). In conclusion, our results strongly support the hypothesis that Ki-67 LI and risk grade are useful for predicting the aggressive biologic behavior of GISTs. Furthermore, alteration of G2-M regulators, such as cyclin A, cyclin B1, and cdc2, is also a useful marker for predicting aggressive behavior and play an important role, at least in part, in the cell proliferation of GIST.

ATP-binding cassette superfamily transporter gene expression in human soft tissue sarcomas. Reviewed International journal

Yoshinao Oda, Tsuyoshi Saito, Naomi Tateishi, Yoshihiro Ohishi, Sadafumi Tamiya, Hidetaka Yamamoto, Ryohei Yokoyama, Takeshi Uchiumi, Yukihide Iwamoto, Michihiko Kuwano, Masazumi Tsuneyoshi

International journal of cancer 114 ( 6 ) 854 - 62 2005.5

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

The phenomenon of multidrug resistance (MDR) in various malignant neoplasms has been reported as being caused by one or multiple expressions of ATP-binding cassette (ABC) superfamily protein, including P-glycoprotein/multidrug resistance (MDR) 1 and the MDR protein (MRP) family. However, their expression levels and distribution within soft tissue sarcomas remain controversial. In 86 cases of surgically resected soft tissue sarcoma, intrinsic mRNA levels of MDR1, MRP1, MRP2 and MRP3 were assessed using a quantitative reverse transcriptase-PCR (RT-PCR) method. Moreover, immunohistochemical protein expressions of P-glycoprotein (P-gp), MRP1, MRP2, MRP3 and p53 protein were evaluated in concordant paraffin-embedded material. The mRNA expression and immunohistochemical expression of ABC superfamily transporters were compared to clinicopathologic parameters and proliferative activities as evaluated by the MIB-1-labeling index (LI). Among the various histologic types, malignant peripheral nerve sheath tumor (MPNST) showed significantly high levels of MDR1 (p=0.017) and MRP3 (p=0.0384) mRNA expression, compared to the other tumor types. When the immunohistochemical method was compared to the RT-PCR technique to assess ABC transported expression at the protein and mRNA levels, a significantly close relationship was found between the 2 methods (p<0.05). P-gp expression was significantly correlated with large tumor size (> or =5 cm, p=0.041) and high AJCC stage (stages III and IV) (p=0.0365). Furthermore, cases with nuclear expression of p53 revealed significantly higher levels of MDR1 mRNA expression, compared to those with negative immunoreaction for p53 (p=0.0328). Our results suggest that MDR1/P-gp expression may have an important role to play in tumor progression in the cases of soft tissue sarcoma, and p53 may be one of the active regulators of the MDR1 transcript. In addition, the high levels of both MDR1 and MRP3 mRNA expression in MPNST may help to explain the poor response of this tumor to anticancer-drugs.

Genetic and epigenetic alterations of the PTEN gene in soft tissue sarcomas. Reviewed International journal

Ken-ichi Kawaguchi, Yoshinao Oda, Tsuyoshi Saito, Tomonari Takahira, Hidetaka Yamamoto, Sadafumi Tamiya, Yukihide Iwamoto, Masazumi Tsuneyoshi

Human pathology 36 ( 4 ) 357 - 63 2005.4

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

The PTEN/MMAC1 ( PTEN ) gene was identified as a tumor suppressor gene encoding a cytoplasmic protein that controls cellular processes. To investigate the potential role and the alteration of the PTEN gene in soft tissue sarcomas (STSs), we searched for homozygous deletion and promoter hypermethylation in a series of 48 STSs that was composed of malignant fibrous histiocytoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, including 2 cases with a mutation that we previously reported; differential polymerase chain reaction and methylation-specific polymerase chain reaction, respectively, were used for the analyses. Furthermore, to determine whether PTEN gene alterations are involved in the down-regulation of PTEN expression, we examined the expression of PTEN protein in 38 cases in which paraffin-embedded tissues were available for immunohistochemical analysis. In addition to our previous results showing that 2 (4%) of 51 cases had a PTEN mutation, promoter methylation was recognized in 6 (13%) of 48 cases, and homozygous deletion was detected in 1 (2%) of 48 cases in the current study. Of 6 cases with promoter methylation of PTEN gene, 5 were malignant peripheral nerve sheath tumor. Decreased expression of PTEN protein was recognized in 11 (29%) of 38 STS cases. Of 9 cases with PTEN alterations (6 cases with promoter methylation, 2 with mutation, and 1 with homozygous deletion), 3 (33%) showed decreased expression of PTEN protein. Furthermore, decreased expression of the PTEN gene showed a statistically significant correlation with high MIB-1 labeling index in 38 STS cases examined ( P = .0441). In conclusion, promoter methylation and homozygous deletion of the PTEN gene were found to be relatively rare events in cases of STS, as is mutation of the gene. Of 9 cases with a PTEN alteration, 3 (33%) showed a decrease in PTEN expression, indicating that PTEN gene alterations seem to play a minor role in the inactivation of PTEN in these tumors. Furthermore, although a further detailed analysis of a larger number of cases is still necessary, the present results suggest that PTEN expression may be a useful indicator of cell proliferation in patients with STS.

Microsatellite instability and hMLH1 and hMSH2 expression analysis in soft tissue sarcomas. Reviewed International journal

Ken-Ichi Kawaguchi, Yoshinao Oda, Tomonari Takahira, Tsuyoshi Saito, Hidetaka Yamamoto, Chikashi Kobayashi, Sadafumi Tamiya, Shinya Oda, Yukihide Iwamoto, Masazumi Tsuneyoshi

Oncology reports 13 ( 2 ) 241 - 6 2005.2

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

Alterations of the size of microsatellite DNA sequences, namely microsatellite instability (MSI), have been demonstrated in some types of malignancies. We analyzed the MSI of five microsatellite markers in 40 cases of soft tissue sarcoma (STS) using high resolution fluorescent microsatellite analysis. In addition, we examined the expression of hMLH1 and hMSH2 proteins of DNA mismatch repair (MMR) genes by immunohistochemistry, and promoter methylation of the hMLH1 gene by methylation-specific PCR (MSP). MSI was recognized in 10 of 40 STS cases (25%), which consisted of 2 MSH-high (MSI-H) tumors and 8 MSI-low (MSI-L) tumors. A loss of hMLH1 expression was recognized in 7 of 40 STS cases (18%), and loss of hMSH2 expression was recognized in 3 of 40 STS cases (8%). One case showed a loss of both hMLH1 and hMSH2 expression. Promoter hypermethylation of the hMLH1 gene was detected in only 3 of 40 STS cases (8%). Of 10 cases with MSI, 5 (50%) showed a loss of hMLH1 and/or hMSH2 expression. There was a statistically significant correlation between MSI-positive tumors and the loss of hMLH1 and/or hMSH2 expression (p=0.0286). Although the frequency of MSI (25%) or a loss of hMLH1 and/or hMSH2 expression (23%) was relatively low in STS cases, a loss of hMLH1 and/or hMSH2 was recognized in 5 out of 10 MSI-positive cases (50%). These findings suggest that the inactivation of MMR gene expression might be the cause of MSI in STS cases.

Clinical value of serum squamous cell carcinoma antigen in the management of sinonasal inverted papilloma Reviewed

R Yasumatsu, T Nakashima, M Masuda, Y Kuratomi, H Shiratsuchi, N Hirakawa, K Tomita, T Yamamoto, S Komune

HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK 27 ( 1 ) 44 - 48 2005.1

Language：English Publishing type：Research paper (scientific journal) Publisher：JOHN WILEY & SONS INC

Background, Although sinonasal inverted papilloma (IP) is a rare benign tumor, it has a tendency to recur and is sometimes associated with squamous cell carcinoma (SCC). Therefore, postoperative long-term follow-up of these patients is recommended. We previously reported that serum SCC antigen might be a useful tumor marker for sinonasal IP. In this study, we investigated whether serum SCC antigen level has a correlation with disease status and is useful in the early detection of recurrent disease.
Methods. Blood samples for the analysis of serum SCC antigen were taken from 28 IP patients before and after surgical treatment.
Results. Twenty-five (89%) of 28 cases showed evaluated serum SCC antigen levels above the upper limit. This marker level decreased in all cases after surgical resection. Four of these patients had a recurrence. None of the patients with recurrent tumor showed symptoms at the time of detection of their recurrent tumor, and recurrence was discovered from elevated levels of SCC antigen.
Conclusions, Serum SCC antigen level has a correlation with disease status of IP and has a potential to serve as a useful tool for monitoring the course of disease. SCC antigen is a reliable tumor marker in the management of sinonasal IPs. (C) 2004 Wiley Periodicals, Inc.

DOI： 10.1002/hed.20115

Other Link： http://orcid.org/0000-0002-7479-8356

E-cadherin mutation and Snail overexpression as alternative mechanisms of E-cadherin inactivation in synovial sarcoma. Reviewed International journal

Tsuyoshi Saito, Yoshinao Oda, Ken-ichi Kawaguchi, Keishi Sugimachi, Hidetaka Yamamoto, Naomi Tateishi, Kazuhiro Tanaka, Shuichi Matsuda, Yukihide Iwamoto, Marc Ladanyi, Masazumi Tsuneyoshi

Oncogene 23 ( 53 ) 8629 - 38 2004.11

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

We have recently reported frequent E-cadherin gene mutations in synovial sarcoma (SS), suggesting mutational inactivation of E-cadherin as a potential mechanism of spindle cell morphology in SS, a spindle cell sarcoma that shows areas of glandular epithelial differentiaton in some cases (biphasic SS) and only pure spindle cell morphology in most cases (monophasic SS). However, the mechanism of downregulation of E-cadherin in SS remains unknown. To further address this issue, we analysed the mechanisms of E-cadherin silencing in 40 SS. Genetic and epigenetic changes in the E-cadherin gene, and the expression level of its transcriptional repressor Snail were examined by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP), methylation-specific PCR, and real-time quantitative PCR, respectively. Expression of E-cadherin was examined by RT-PCR and immunohistochemistry. We also examined ELF3, a transcription factor associated with epithelial differentiation in SS in a previous cDNA microarray, by RT-PCR. E-cadherin and ELF3 transcripts were detected, respectively, in 27/40 (67.5%) and in 25/40 (62.5%) of SS, and these epithelial-related genes were almost always coexpressed. Hypermethylation of the promoter of the E-cadherin gene was detected in five cases (12.5%) in SS; however, E-cadherin was silenced at mRNA level in only one of the five cases. E-cadherin missense mutations were observed in five cases (12.5%) of SS. In SS, all five cases with E-cadherin missense mutations had the SYT-SSX1 fusion and were monophasic tumors, suggesting a relationship between the SYT-SSX fusion type and E-cadherin missense mutation (P=0.07). E-cadherin mRNA expression in SS was associated with reduced Snail expression level (P=0.03). E-cadherin membranous expression was observed in 14/40 (35.0%) of SS, and was also correlated with SYT-SSX1 fusion type and biphasic histology. ELF3 was confirmed to be more highly expressed in biphasic than monophasic SS by real-time quantitative PCR. These results suggest that in SS the loss of E-cadherin expression occurs either by Snail trans-repression or by inactivating mutations. Thus, E-cadherin downregulation is associated with the loss or absence of glandular epithelial differentiation in certain SS.

Death-associated protein kinase (DAP kinase) alteration in soft tissue leiomyosarcoma: Promoter methylation or homozygous deletion is associated with a loss of DAP kinase expression. Reviewed International journal

Ken-ichi Kawaguchi, Yoshinao Oda, Tsuyoshi Saito, Hidetaka Yamamoto, Tomonari Takahira, Sadafumi Tamiya, Yukihide Iwamoto, Masazumi Tsuneyoshi

Human pathology 35 ( 10 ) 1266 - 71 2004.10

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

The death-associated protein kinase (DAP kinase) was initially identified as a positive mediator of programmed cell death induced by interferon-gamma. To investigate the potential role and the alteration of the DAP kinase gene in soft tissue leiomyosarcoma (LMS), we first searched for homozygous deletion and promoter hypermethylation in 45 LMSs for which genomic DNA was available, using differential PCR and methylation-specific PCR, respectively. Promoter methylation was recognized in 10 of 45 cases (22%), and homozygous deletion was detected in 3 of 45 cases (7%). p53 mutation was detected in 11 of 45 LMS cases (24%). Cases with DAP kinase alteration or p53 mutation showed a close correlation with high French Federation of Cancer Centers grade or with poor prognosis (P = 0.0244, P = 0.0491, respectively). Next, to determine that DAP kinase promoter methylation or homozygous deletion is involved in the down-regulation of DAP kinase expression, we examined the expression of DAP kinase protein by immunohistochemistry. Decreased expression of DAP kinase protein was recognized in 13 of 45 LMS cases (29%). Seven of 13 cases (54%) with decreased expression of DAP kinase protein revealed promoter methylation or homozygous deletion of DAP kinase, and the methylation status or homozygous deletion of its gene showed a close correlation with decreased DAP kinase expression (P = 0.0300). In conclusion, although DAP kinase alteration was relatively rare, DAP kinase alteration and/or p53 mutation may associate with tumor progression in soft-tissue LMSs. Furthermore, although further detailed analyses are necessary, promoter methylation or homozygous deletion status of DAP kinase may present a major alternative mechanism of a loss of or decrease in DAP kinase expression.

Alterations of the p16INK4a/p14ARF pathway in clear cell sarcoma. Reviewed International journal

Tomonari Takahira, Yoshinao Oda, Sadafumi Tamiya, Hidetaka Yamamoto, Kenichi Kawaguchi, Chikashi Kobayashi, Yukihide Iwamoto, Masazumi Tsuneyoshi

Cancer science 95 ( 8 ) 651 - 5 2004.8

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

Clear cell sarcoma (CCS) is a very rare soft tissue sarcoma with a poor prognosis. It has become apparent through immunohistochemical, ultrastructural, and microarray analyses that CCS is a soft tissue melanocytic neoplasm. Alterations in the p16INK4a/p14ARF gene are common in malignant melanoma, which is the prototypical melanocytic neoplasm. In the present study, we performed a clinicopathologic analysis and investigated p16 and cyclin D1 expression by immunohistochemistry in 14 cases. Furthermore, we investigated genetic changes of various tumor suppressor genes and an oncogene, including p16INK4a/p14ARF, p53, beta-catenin, and APC, in 11 cases. The 5-year overall survival rate in all the patients was 33.3%. A high mitotic rate was a significant adverse prognostic factor (P = 0.004). Decreased expression of p16 was observed in 4 (28.6%) of 14 cases. Overexpression of cyclin D1 was observed in 9 cases (64.3%). SSCP analysis followed by DNA direct sequencing revealed point mutations of the p16INK4a gene in 2 of 11 cases (18.2%). In addition, one case with the p14ARF mutation and 2 cases with the p53 mutation were observed. None of the cases harbored mutation of the beta-catenin or APC gene. Homozygous deletion of the p16INK4a/p14ARF gene was detected in one case. Methylation-specific PCR did not reveal hypermethylation of the p16INK4a/p14ARF promoter region in any of the cases. Three cases harbored genetic alterations of the p16INK4a/p14ARF gene (27.3%). All tumors with genetic alterations of the p16INK4a/p14ARF or p53 gene showed a high mitotic rate or tumor necrosis. These alterations were considered to be influential in the poor prognosis of CCS patients.

Low-grade fibromyxoid sarcoma versus low-grade myxofibrosarcoma in the extremities and trunk. A comparison of clinicopathological and immunohistochemical features

Y Oda, T Takahira, K Kawaguchi, H Yamamoto, S Tamiya, S Matsuda, K Tanaka, Y Iwamoto, M Tsuneyoshi

HISTOPATHOLOGY 45 ( 1 ) 29 - 38 2004.7

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING LTD

Aims: Low-grade fibromyxoid sarcoma (LGFMS) is a distinctive variant of fibrosarcoma and has been reported to have metastatic potential despite its low-grade histological findings. Low-grade myxofibrosarcoma (MFS) is an important differential diagnosis of LGMFS, because it shows different biological behaviour. Of 75 MFSs in the extremities and trunk, we defined 22 grade 1 tumours as low-grade MFS according to the French Federation of Cancer Centres grading system and compared the clinicopathological factors and immunohistochemical expression of cell cycle regulators with those of 11 LGFMSs.
Methods and results: The two entities could be distinguished on histological grounds. Low-grade MFS was characterized by the presence of prominent elongated, curvilinear capillaries and pseudolipoblasts, accompanied by an abundant myxoid matrix. It had no extensive solid areas. LGFMS was composed of bland spindle cells arranged in a whorled pattern with alternating myxoid and fibrous stroma. Curvilinear capillaries were not prominent and cytological atypia was absent. No tumour necrosis was observed in any of the 11 LGFMSs, whereas only one case showed tumour necrosis in less than 50% of the tumour in 22 low-grade MFSs. The patients with low-grade MFS were significantly older than those with LGFMS (low-grade MFS average, 60.1 years; LGFMS average, 31.5 years; P < 0.0001) and low-grade MFS occurred more frequently in a superficial location (low-grade MFS 14/20; LGFMS 2/11; P = 0.0077). As for cell cycle regulator expression, the MIB-1 labelling index (LI) (14.76 on average) and cyclin E LI (11.55 on average) in low-grade MFS were significantly higher than those (MIB-1 LI, 4.68 on average; cyclin E LI, 3.38 on average) of LGFMS, while p21 LI (25.53 on average) and p27 LI (42.68 on average) in low-grade MFS were significantly lower than those (p21 LI, 42.74 on average; p27 LI, 57.28 on average) of LGFMS.
Conclusions: We conclude that low-grade MFS and LGFMS are distinctly different clinicopathological entities and the assessment of the immunohistochemical expression of MIB-1, cyclin E, p21 and p27 as well as conventional clinicopathological features may be helpful to distinguish low-grade MFS from LGFMS.

DOI： 10.1111/j.1365-2559.2004.01886.x

Altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma. Reviewed International journal

Yukiko Takahashi, Yoshinao Oda, Ken-Ichi Kawaguchi, Sadafumi Tamiya, Hidetaka Yamamoto, Sachiyo Suita, Masazumi Tsuneyoshi

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 17 ( 6 ) 660 - 9 2004.6

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

Rhabdomyosarcoma is the most commonly occurring soft-tissue sarcoma in children. Some reports have discussed the altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma; however, variable frequencies of occurrence have been noted. In the current study, among 72 cases of rhabdomyosarcoma, the authors evaluated for the expression of p53, MDM2, p16, p21/WAF1, p27, cyclin D1, cyclin E, pRb and E2F-1 protein immunohistochemically and assessed for proliferative activities using MIB-1. We also analyzed the mutation of the p53 gene in 45 cases, the amplification of the MDM2 gene in 18 cases and the mutation of the H-ras gene in 29 cases, using formalin-fixed paraffin-embedded materials. Furthermore, we assessed the correlation between clinicopathologic factors and the results of both immunohistochemical and molecular analyses. Alveolar type affected older patients, and it had a significantly higher mitotic rate compared with the embryonal type (P=0.0226). p53 overexpression was detected in 22 (30.6%) of 72 cases, and 10 (22.2%) of 45 cases had p53 gene abnormalities. As for MDM2, its overexpression was found in nine (12.5%) of 72 cases, and three (16.7%) of 18 cases showed MDM2 amplification. A statistically significant association was observed between immunoreaction for MDM2 and p53 overexpression (P=0.0002), and p53 and MDM2 overexpression was significantly correlated with high MIB-1 labeling indices. E2F-1 labeling indices showed a significantly higher score in alveolar type compared with that seen in embryonal type (P=0.0334), but MIB-1 did not. In conclusion, our study suggests that p53 overexpression may be related to tumor progression because tumors with p53 overexpression have a high proliferative activity in the current study. Alveolar type had a significantly higher both mitotic rate and E2F-1 labeling indices when compared with the embryonal type. The current study is the first report of the correlation of E2F-1 with alveolar rhabdomyosarcoma.

PTEN and other tumor suppressor gene mutations as secondary genetic alterations in synovial sarcoma. Reviewed International journal

Tsuyoshi Saito, Yoshinao Oda, Ken-Ichi Kawaguchi, Tomonari Takahira, Hidetaka Yamamoto, Kazuhiro Tanaka, Shuichi Matsuda, Akio Sakamoto, Yukihide Iwamoto, Masazumi Tsuneyoshi

Oncology reports 11 ( 5 ) 1011 - 5 2004.5

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

Synovial sarcomas (SS) consistently show a characteristic chromosomal translocation, t(X;18)(p11;q11), which usually leads to the formation of 2 chimeric fusion transcripts, SYT-SSX1 and -SSX2. A recent multi-institutional retrospective study revealed that the SYT-SSX fusion type emerged as the only independent significant factor for overall survival in cases of SS. The aims of this study were; i). to investigate the frequency of PTEN gene alteration, ii). to evaluate whether the mutation status in various tumor suppressor genes (TSG) is responsible for the clinical and histologic heterogeneity in SS. Forty-nine cases of SS were examined for the presence of PTEN gene mutation by polymerase chain reaction - single-strand conformation polymorphism followed by DNA direct sequencing. The obtained data was combined with those of previously reported TSG mutations such as p53, adenomatous polyposis coli, and E-cadherin genes. Follow-up was available for 44 patients, and survival analysis was performed according to the mutation status of these TSG. PTEN mutations were detected in 7 cases (14.3%), and all of these were monophasic tumors. More than half of the mutations detected were located in exon 9, which has been shown to play a less important role in PTEN functioning, and the PTEN mutation was not associated with patients' prognosis. Mutations in these TSG other than silent mutations were detected in 20 out of 49 cases (40.8%), although the mutation status in TSG was not associated with overall survival rate in patients with SS. Secondary genetic alterations in these TSG seem to have a less important prognostic impact on patients with SS.

c-kit and PDGFRA mutations in extragastrointestinal stromal tumor (gastrointestinal stromal tumor of the soft tissue). Reviewed International journal

Hidetaka Yamamoto, Yoshinao Oda, Ken-ichi Kawaguchi, Norimoto Nakamura, Tomonari Takahira, Sadafumi Tamiya, Tsuyoshi Saito, Yumi Oshiro, Masayuki Ohta, Takashi Yao, Masazumi Tsuneyoshi

The American journal of surgical pathology 28 ( 4 ) 479 - 88 2004.4

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

Extragastrointestinal stromal tumor (EGIST) is a unique tumor that occurs outside the gastrointestinal tract. EGIST shows a c-kit expression and histologic appearance similar to those of gastrointestinal stromal tumor (GIST). Most GISTs have gain-of-functional mutation of the c-kit gene, and some have mutation of the platelet-derived growth factor receptor-alpha (PDGFRA) gene. However, the frequency of mutation of those genes in EGISTs remains unclear. We examined the clinicopathologic features, prognostic factors, and c-kit and PDGFRA mutation in 39 cases of EGIST. Tumors with high mitotic counts (>or=5/50 high power fields) or a high Ki-67 labeling index (>or=10%) were significantly correlated with worse prognoses. The c-kit mutation was found in the juxtamembrane domain (exon 11) and the extracellular domain (exon 9) in 12 of 29 cases (41.4%) and 2 of 29 cases (6.9%), respectively. The PDGFRA gene mutation was found at the juxtamembrane domain (exon 12) and the tyrosine kinase domain (exon 18) in one case each. The pattern of kit and PDGFRA mutation in EGIST was essentially similar to that in GIST. Our results suggest that the c-kit and PDGFRA mutations play an important role in the tumorigenesis of EGIST. High mitotic counts and a high Ki-67 labeling index may be useful for predicting the aggressive biologic behavior in EGIST. Furthermore, STI-571, targeting c-kit and PDGFR tyrosine kinase, seems to be a possible therapeutic strategy for EGISTs, especially advanced cases.

H-ras mutation is an additional event of sarcomatous transformation in aerodigestive spindle cell carcinoma. Reviewed International journal

Hideki Shiratsuchi, Naoya Hirakawa, Tsuyoshi Saito, Yoshinao Oda, Hidetaka Yamamoto, Kichinobu Tomita, Tomoya Yamamoto, Masazumi Tsuneyoshi

Oncology reports 11 ( 3 ) 597 - 604 2004.3

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

The conversion from a carcinomatous component to a sarcomatous one in spindle cell carcinoma (SPCC) of the upper aerodigestive tract is thought to occur via a series of molecular alterations; however the detailed mechanism is still unknown. We examined mutations at the H-ras and p53 genes in 16 SPCCs of upper aerodigestive tracts using PCR-RFLP, PCR-SSCP and direct sequencing analysis. The two distinct components, sarcomatous and carcinomatous components in SPCC, were analyzed independently. p53 mutations were detected in both components of SPCC (50.0%, 8/16), and those in the sarcomatous component were completely in accordance with those in the carcinomatous one. In contrast, H-ras mutations were detected only in the sarcomatous component (12.5%, 2/16), and not in the carcinomatous one (0%, 0/16). There was a statistically significant difference in prognosis between the patients with the H-ras mutation (n=2) and those without (n=14); the former had poorer prognosis (P=0.0049). Our results seem to suggest that the H-ras mutation is a relatively uncommon event in SPCC; however, the presence of H-ras mutations may be associated with a more malignant potential in SPCC, while actually occurring during the sarcomatous change itself.

Cyclooxygenase 2 is a key enzyme for inflammatory cytokine-induced angiogenesis. Reviewed International journal

Takashi Kuwano, Shintaro Nakao, Hidetaka Yamamoto, Masazumi Tsuneyoshi, Tomoya Yamamoto, Michihiko Kuwano, Mayumi Ono

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 18 ( 2 ) 300 - 10 2004.2

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

Cyclooxygenase1 (COX1) and COX2 mediate the rate-limiting step in arachidonic acid metabolism. Expression of COX2 mRNA and protein is often enhanced in various human cell types by inflammatory cytokines such as interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha). IL-1beta enhanced expression of various prostanoids and this expression was blocked by COX2 selective inhibitors. IL-1beta markedly induced angiogenesis in vitro and in vivo, which was significantly inhibited by COX2 selective inhibitors but not by a vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor. In contrast, COX2 selective inhibitors only partially blocked VEGF-induced angiogenesis. EP2, EP4 (prostaglandin E2 receptors) agonists and thromboxane A2 (TXA2) receptor agonists induced angiogenesis in vitro and in vivo; IL-1beta-induced angiogenesis was blocked by an EP4 antagonist and a TXA2 receptor antagonist. IL-1beta induced much less angiogenesis in cornea of COX2 knockout mice than that of wild-type mice. This is the first report that COX2 and some prostanoids play a key role in IL-1beta-induced angiogenesis.

Microsatellite instability and p53 mutation associated with tumor progression in dermatofibrosarcoma protuberans. Reviewed International journal

Tomonari Takahira, Yoshinao Oda, Sadafumi Tamiya, Hidetaka Yamamoto, Kenichi Kawaguchi, Chikashi Kobayashi, Shinya Oda, Yukihide Iwamoto, Masazumi Tsuneyoshi

Human pathology 35 ( 2 ) 240 - 5 2004.2

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

Dermatofibrosarcoma protuberans (DFSP) is a dermal and subcutaneous tumor categorized as a tumor of intermediate malignancy, and its progression in some cases to fibrosarcoma is well known. However, molecular analysis of tumor progression has been limited. The present study investigated microsatellite instability (MSI) of 7 microsatellite markers through high-resolution microsatellite analysis in addition to a mutational analysis of the p53 gene in 44 tumors in 36 patients. The patients were divided into 2 groups: 9 patients with a fibrosarcomatous component in the primary or recurrent/metastasized tumor, designated as the DFSP+FS group, and the remaining 27 patients, designated as the DFSP group. Cases in which the percentage of markers with an additional peak among the markers successfully analyzed was more than 30% was considered MSI high (MSI-H); cases in which microsatellites were stable at all of the successfully examined markers were considered microsatellite stable (MSS); and the remaining cases were considered MSI low (MSI-L). MSI-H cases were observed more frequently in the DFSP+FS group (4 of 9 cases) than in the DFSP group (1 of 27 cases) (P = 0.028, Fischer's exact test). The MSI status of recurrent or metastatic tumors in both the DFSP+FS and the DFSP groups was the same as that in the corresponding primary neoplasms. Furthermore, there was no difference in MSI status between an ordinary DFSP area and a fibrosarcomatous area in 7 tumors that exhibited both areas. p53 mutational analysis revealed 10 point mutations, composed of 4 missense mutations and 6 silent mutations, in 6 of 36 cases (16.7%). A missense mutation was more frequently observed in the DFSP+FS group (3 of 4) than in the DFSP group (1 of 4). Among 3 cases of a missense mutation in the DFSP+FS group, 2 had a mutation only in a fibrosarcomatous area and 1 had a mutation only in a metastatic tumor progressing to fibrosarcoma. These results suggest that MSI and p53 mutations are involved in tumor progression of DFSP to fibrosarcoma as early and late events, respectively.

Decreased expression of transforming growth factor-beta II receptor is associated with that of p27KIP1 in giant cell tumor of bone: a possible link between transforming growth factor-beta and cell cycle-related protein. Reviewed International journal

Ken-Ichi Kawaguchi, Yoshinao Oda, Tsuyoshi Saito, Hidetaka Yamamoto, Tomonari Takahira, Sadafumi Tamiya, Yukihide Iwamoto, Masazumi Tsuneyoshi

Human pathology 35 ( 1 ) 61 - 8 2004.1

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

Transforming growth factor (TGF)-beta is a potential regulator of cell growth that sends its signals through a heteromeric complex composed of type I and II receptors (IR and IIR). This study examined a correlation between TGF-beta1, TGF-beta-IR and -IIR, and cell cycle-related proteins in giant cell tumor (GCT) of bone, using immunohistochemical and Western blot analysis. First, an immunohistochemical study for TGF-beta1, TGF-beta-IR and -IIR, p27KIP1 (p27), p21WAF1 (p21), cyclin D1, and cyclin E was carried out on 92 cases of GCT of bone; the expression of these proteins was evaluated in multinucleated giant cells (MGCs) and mononucleated stromal cells (MSCs) separately; and proliferative activity was assessed using MIB-1. Next, to confirm our immunohistochemical results, Western blot analysis was performed in 19 cases for which frozen samples were available. Immunoreactivity for TGF-beta-IR and -IIR showed a tendency to be greater in MGCs than in MSCs; however, no differences were observed in TGF-beta1. Cyclin D1 expression was correlated with the occurrence of vascular invasion in both MGCs and MSCs (P = 0.0255 and 0.0183, respectively). The expression of TGF-beta-IIR and p27 was concordantly decreased in both MGSs and MSCs (P = 0.0014 and 0.0317, respectively). The expression for TGF-beta-IIR and p27 in Western blot analysis was related to the results from immunohistochemical analysis, and the expression of TGF-beta-IIR and p27 was concordant in almost all GCT cases. Furthermore, there was a statistically significant inverse relationship between p27 expression and MIB-1 labeling index in MSCs (P = 0.0397). In GCT of bone, TGF-beta-IIR and p27 expression were concordantly decreased; this result supports the possibility that these 2 factors may play an important role in cell proliferation of this tumor. Furthermore, our results provide a possible link between the effects of extracellular growth factors and cell cycle control. In addition, p27 expression may be a useful indicator of cell proliferation in MSCs of this tumor.

A case of breast cholesterol granuloma accompanied by cancer. Reviewed

Chizu Furuhira, Akira Ohshima, Kazuo Shimada, Syoji Kuroki, Kenji Nakano, Mikimasa Ishikawa, Hidetaka Yamamoto, Masao Tanaka

Breast cancer (Tokyo, Japan) 11 ( 2 ) 210 - 3 2004

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

Cholesterol granuloma of the breast is a very rare benign disease with clinical and imaging features that are often indistinguishable from cancer preoperatively. We report a case of breast cholesterol granuloma accompanied by cancer. The patient was a 78-year-old woman who complained of a lump in her right breast. Mammography and ultrasonography showed a well-circumscribed mass. Fine needle aspiration cytology showed many cholesterol crystals and inflammatory cells without malignancy. With a diagnosis of cholesterol granuloma, tumor extirpation was performed. Histopathologic examination revealed cholesterol granuloma together with breast cancer, and additional partial mastectomy was subsequently performed. It is noted that breast cholesterol granuloma could be accompanied by cancer.

Mechanisms of inactivation of the p16INK4a gene in leiomyosarcoma of soft tissue: decreased p16 expression correlates with promoter methylation and poor prognosis. Reviewed International journal

Ken-ichi Kawaguchi, Yoshinao Oda, Tsuyoshi Saito, Hidetaka Yamamoto, Sadafumi Tamiya, Tomonari Takahira, Kimitaka Miyajima, Yukihide Iwamoto, Masazumi Tsuneyoshi

The Journal of pathology 201 ( 3 ) 487 - 95 2003.11

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

The p16INK4a tumour suppressor gene, encoding p16 protein, plays a crucial role in regulation of the G1 cell-cycle phase. To investigate the potential role of p16 in soft tissue leiomyosarcoma (LMS), an immunohistochemical analysis was performed of 77 LMSs for p16 expression. Decreased expression of the p16 protein was identified in 25 of 77 LMSs (32%). Decreased expression of p16 correlated significantly with large tumour size (p=0.0038). In a univariate analysis, large tumour size and decreased expression of p16 were statistically significant adverse prognostic factors (p=0.025 and p=0.0021, respectively). In a multivariate analysis including conventional clinicopathological parameters, decreased expression of p16 protein was revealed as the only independent unfavourable prognostic factor (p=0.012). To elucidate the mechanisms of inactivation of the p16INK4a gene, 49 LMSs for which genomic DNA was available were examined; analysis for homozygous deletion, mutation, and promoter hypermethylation was conducted using differential PCR, PCR-SSCP, and methylation-specific PCR, respectively. Promoter hypermethylation was detected in 11 of 49 LMS cases (22%); homozygous deletion was detected in 3 of 49 cases (6%); and mutation was not recognized in any of the cases studied. Eight of 15 cases (53%) with decreased expression of p16 protein revealed methylation of the p16INK4a gene promoter. Promoter hypermethylation correlated closely with decreased expression and poor prognosis (p=0.0014 and p=0.0088, respectively). These results suggest that decreased expression of p16 protein can be considered as an independent reliable prognostic parameter in patients with soft tissue LMS. Furthermore, promoter methylation was more frequent than either homozygous deletion or mutation in this tumour, and promoter methylation was also shown to have a strong association with inactivation of the p16INK4a gene.

Altered expression of cell cycle regulators in myxofibrosarcoma, with special emphasis on their prognostic implications. Reviewed International journal

Yoshinao Oda, Tomonari Takahira, Kenichi Kawaguchi, Hidetaka Yamamoto, Sadafumi Tamiya, Shuichi Matsuda, Kazuhiro Tanaka, Naoko Kinukawa, Yukihide Iwamoto, Masazumi Tsuneyoshi

Human pathology 34 ( 10 ) 1035 - 42 2003.10

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

Myxofibrosarcoma/myxoid malignant fibrous histiocytoma (MFH) has continued to be considered a distinct entity even after recently published reassessments of pleomorphic sarcomas and MFH. Several cell cycle-regulated proteins have already been screened by immunohistochemistry with the aim of finding the reliable prognostic indicator of soft tissue sarcomas; however, it is still unknown whether their altered expression affects patient survival in myxofibrosarcoma. In this study, we evaluated the expression of p53, MDM2, MIB-1 (Ki-67), p21, p27, p16, cyclin A, cyclin D1, and cyclin E by immunohistochemistry in 45 cases of myxofibrosarcoma. First, we searched for possible clinicopathologic prognostic factors in 61 cases of myxofibrosarcoma for which follow-up data were available. In univariate analysis, large tumor size (> or =5 cm), deeply situated tumor, and high histological grade (grade 2 or 3) significantly decreased survival (log-rank test, P <0.05). Among 43 cases of myxofibrosarcoma for which immunohistochemical findings were available, high MIB-1 labeling index (LI) (cutoffs of 10 and 22.5 on average), high cyclin A LI (cutoffs 10% and 13.8% on average), low p21 LI (cutoffs 10 and 20.7 on average), and reduced abnormal expression of p16 were adverse prognostic factors. In multivariate analysis (Cox proportional hazards model), high mitotic rate (>15/10 high-power fields), p53 immunoreactivity (cutoff 10%), high MIB-1 LI (>22.5), low p21 LI (<20.7), and low p27 LI (<47.8 on average) were independent poor prognostic factors. Our results suggest that reduced expression of p21 could be considered a new parameter to be evaluated, along with classical clinicopathologic prognostic factors, for identifying those at high risk for myxofibrosarcoma.

ALK-positive anaplastic large cell lymphoma of the parotid gland

H Yamamoto, H Shiratsuchi, T Yao, H Uryu, Y Oda, S Tamiya, M Tsuneyoshi

HISTOPATHOLOGY 43 ( 4 ) 397 - 398 2003.10

Possible association between tumor-suppressor gene mutations and hMSH2/hMLH1 inactivation in alveolar soft part sarcoma. Reviewed International journal

Tsuyoshi Saito, Yoshinao Oda, Ken-Ichi Kawaguchi, Tomonari Takahira, Hidetaka Yamamoto, Akio Sakamoto, Sadafumi Tamiya, Yukihide Iwamoto, Masazumi Tsuneyoshi

Human pathology 34 ( 9 ) 841 - 9 2003.9

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

Alveolar soft part sarcoma (ASPS) is a rare soft tissue tumor of unknown origin and pathogenesis. We clinicopathologically analyzed 16 cases of ASPS and screened for the genetic alterations of various tumor-suppressor genes and oncogenes, including p53, adenomatous polyposis coli (APC), E-cadherin, and beta-catenin, in 11 cases of ASPS. We also examined the expression of hMSH2/hMLH1 of DNA mismatch repair genes by immunohistochemistry, and promoter hypermethylation of these DNA mismatch repair genes by methylation-specific polymerase chain reaction (MS-PCR) to elucidate any possible association between mutation status of these genes and inactivation of the hMSH2/hMLH1 genes. Furthermore, microsatellite instability (MSI) analysis and loss of heterozygosity (LOH) on chromosome 5q analysis were used for some cases of ASPS where DNA derived from normal tissue was available. The 5-year overall survival rate for all of the patients in this study was 68.6%. The 5-year overall survival rates for patients presenting with localized ASPS and for patients with distant metastases were 83.3% and 47.6%, respectively. The high nuclear grade of tumor cells was a significantly adverse prognostic factor (P = 0.0085). Single-strand conformation polymorphism analysis followed by DNA direct sequencing revealed 4 point mutations of the p53 gene in 3 of 11 cases (27.3%), composed of 3 missense mutations and 1 silent mutation. In addition, 1 case with the E-cadherin missense mutation and 1 case with the APC missense mutations were observed, respectively. None of the cases harbored mutation of exon 3 of the beta-catenin gene. Loss of expression of the hMSH2 and hMLH1 genes was observed in 2 (18.2%) and 3 (27.3%) of 11 cases, respectively. All 3 cases with loss of hMLH1 gene expression harbored mutations of the p53 gene. There was a statistically significant correlation between the genetic alteration positive in these tumor-suppressor genes and loss of hMLH1 gene expression (P = 0.024). Methylation-specific PCR did not reveal hypermethylation of the hMSH2/hMLH1 promoter region in any of the cases examined. Three of 8 (37.5%) ASPS cases showed low MSI, and 2 of these 3 cases showed immunohistochemical lack of expression for either hMSH2 or hMLH1. LOH on 5q was present in 2 of 6 (33.3%) informative cases, and both cases showed LOH on the D5S346 marker, a microsatellite marker near the APC locus. Thus, inactivation of hMSH2/hMLH1 of DNA mismatch repair genes seems to have an important role to play in the mutagenesis of the tumor-suppressor genes in ASPS.

Mucinous cystic tumor of the pancreas: Immunohistochemical assessment of 'ovarian-type stroma'

Akihiko Izumo, Koji Yamaguchi, Takashi Eguchi, Ken-Ichi Nishiyama, Hidetaka Yamamoto, Hirotoshi Yonemasu, Takashi Yao, Masao Tanaka, Masazumi Tsuneyoshi

Oncology Reports 10 ( 3 ) 515 - 525 2003.5

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

The new histopathological classification of exocrine pancreatic tumors by the World Health Organization, now includes 'ovarian-type stroma' ('OS') in the definition of mucinous cystic tumor of the pancreas (MCT-P). This study investigated the clinicopathological findings of the MCT-P according to WHO classification and scrutinize the function of 'OS' in MCT-P immunohistochemically. Thirty-four cases of MCT-P (28 adenomas, 2 borderline tumors and 4 adenocarcinomas) were examined clinicopathologically. The 'OS' of 34 MCTs-P were studied immunohistochemically and compared with the stroma of 10 mucinous cystic tumors of the ovary (MCTs-O), 10 conventional pancreatic carcinomas and 6 normal ovaries. Almost all 34 MCTs-P were located in the body-tail of the pancreas of middle-aged women. Histologically the 'OS' cells exhibited luteinization in 11/34 (32.4%). Immunohistochemically, both 'OS' cells and the stromal cells in MCT-O showed similar positivity rates
calponin (34/34 and 9/10), h-caldesmon (28/34 and 8/10), α-inhibin (29/34 and 9/10), estrogen-receptor (21/34 and 6/10) and progesterone-receptor (28/34 and 9/10, respectively). Some neoplastic epithelial cells of MCT-P were positive for human chorionic gonadotropin (hCG) (21/34, 61.8%). This study indicates the predominance of MCT in the distal pancreas of middle-aged women. Furthermore, the immunohistochemical and histological results demonstrate that the 'OS' of MCT-P and the stroma of MCT-O share the same characteristics. The results also suggested that the hCG produced by the neoplastic epithelium probably plays an important role in the luteinization of the stroma of MCT-P. We therefore conclude there is a possibility that MCT-P originates from the left remnant primordial gonadal cells which migrated to the pancreatic anlage during the early development of the fetus.

p53 mutation and MDM2 amplification in inflammatory myofibroblastic tumours Reviewed

H Yamamoto, Y Oda, T Saito, A Sakamoto, K Miyajima, S Tamiya, M Tsuneyoshi

HISTOPATHOLOGY 42 ( 5 ) 431 - 439 2003.5

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING LTD

Aims: The pathogenic mechanism and predictive indicators of biological behaviour of inflammatory myofibroblastic tumour are poorly understood. We investigated molecular abnormalities of p53 and MDM2 in order to assess whether these play an important role in pathogenesis, and whether they also contribute to clinicopathological aggressive phenotype in inflammatory myofibroblastic tumour.
Methods and results: We compared the immunohistochemical expression of calponin, h-caldesmon, ALK, and p53 gene mutation and MDM2 gene amplification with clinicopathological findings in 15 cases of inflammatory myofibroblastic tumour. Histologically, cellular atypia was observed in five (33.3%) out of 15 cases. Local recurrences were observed in two (14.3%) of 14 informative cases, but no distant metastasis was observed. The expression of calponin (9/14; 64%) but not h-caldesmon (0/14; 0%) was seen, which suggested myofibroblastic differentiation. ALK expression was seen in eight (53.3%) out of 15 cases, particularly in patients under 40 years old. Nuclear expression of p53 protein was recognized in only one (6.7%) of 15 cases, and polymerase chain reaction single-strand conformation polymorphism followed by direct sequencing revealed p53 gene missense mutations in two (13.3%) of 15 cases. Nuclear expression of MDM2 was seen in four (26.7%) of 15 cases, and the MDM2 gene amplification was observed in two of the four cases.
Conclusion: Inflammatory myofibroblastic tumour shows a wide spectrum of cellular atypia and biological behaviour with p53 and MDM2 expression. However, the alterations in the p53 pathway seem not to play a major role in the pathogenesis of inflammatory myofibroblastic tumour.

DOI： 10.1046/j.1365-2559.2003.01611.x

PTEN/MMAC1 gene mutation is a rare event in soft tissue sarcomas without specific balanced translocations. Reviewed International journal

Tsuyoshi Saito, Yoshinao Oda, Ken-ichi Kawaguchi, Tomonari Takahira, Hidetaka Yamamoto, Sadafumi Tamiya, Kazuhiro Tanaka, Shuichi Matsuda, Akio Sakamoto, Yukihide Iwamoto, Masazumi Tsuneyoshi

International journal of cancer 104 ( 2 ) 175 - 8 2003.3

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

The tumor suppressor gene PTEN/MMAC1 was identified on chromosome 10q23.3, which is homozygously deleted in many human malignancies. The loss of chromosome 10q was also frequently reported in some types of soft tissue sarcomas. Our study was designed to investigate the frequency of PTEN/MMAC1 gene mutation and to evaluate the role of the PTEN/MMAC1 gene in the tumorigenesis of soft tissue sarcomas without specific balanced translocations. We analyzed 51 cases of soft tissue sarcomas without specific balanced translocations for PTEN/MMAC1 mutations by polymerase chain reaction-single strand conformation polymorphism and direct sequencing. Mutations in the PTEN/MMAC1 gene were found in only 2 cases (3.9%). Both tumors with PTEN/MMAC1 mutation were leiomyosarcomas arising from the retroperitoneum and inferior vena cava, respectively. Two of 3 leiomyosarcomas arising from the intra-abdominal cavity examined harbored mutations of this tumor suppressor gene. This result suggests that leiomyosarcomas derived from the intra-abdominal cavity might have different tumorigenesis from those of an extremity or the trunk, from the viewpoint of PTEN/MMAC1 mutation, although PTEN/MMAC1 gene mutations are rare event in these soft tissue sarcomas.

Low-grade fibrosarcoma of the proximal humerus. Reviewed International journal

Tsuyoshi Saito, Yoshinao Oda, Kazuhiro Tanaka, Shuichi Matsuda, Akio Sakamoto, Hidetaka Yamamoto, Yukihide Iwamoto, Masazumi Tsuneyoshi

Pathology international 53 ( 2 ) 115 - 20 2003.2

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

We present the clinical, radiographical and pathological features of low-grade fibrosarcoma of the left proximal humerus in a 23-year-old man in whom it was necessary to distinguish the tumor from desmoplastic fibroma, malignant fibrous histiocytoma and intramedullary well-differentiated osteosarcoma. The patient presented with a 10-day history of pain in his left upper arm sustained when trying to break his fall with his left hand when slipping in the street. Plain radiography revealed an expanding multilobular osteolytic lesion from the proximal metaphysis to the diaphysis of his left humerus, accompanied by a pathological fracture at the distal portion of the lesion. Open biopsy of the lesion was performed twice; however, a conclusive diagnosis could not be obtained. The patient underwent wide excision and prosthetic replacement of the left proximal humerus. Histologically, the resected tumor was composed of both cellular areas and hypocellular areas. Cellular areas revealed a proliferation of bundles of uniform fibroblastic spindle-shaped cells with minimal cellular atypia, mixed with abundant intercellular collagenization. Mitotic figures were occasionally seen. Hypocellular areas showed myxoid features with loose bundles of collagen fibers. The patient demonstrates no evidence of disease 42 months after surgery. It is important to detect the scant atypical cells for the differential diagnosis of low-grade fibrosarcoma and desmoplastic fibroma of bone.

Follicular dendritic cell sarcoma of the neck; a case report and literature review. Reviewed International journal

Torahiko Nakashima, Yuichiro Kuratomi, Hideki Shiratsuchi, Hidetaka Yamamoto, Ryuji Yasumatsu, Tomoya Yamamoto, Sohtaro Komiyama

Auris, nasus, larynx 29 ( 4 ) 401 - 3 2002.10

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

Follicular dendritic cell (FDC) sarcomas, also known as dendritic reticulum cell tumors, are uncommon neoplasms arising from antigen-presenting cells in B-lymphofollicles of nodal and extra-nodal sites. It is considered as an intermediate grade malignancy since it has significant recurrent and metastatic potential. We report a case of FDC sarcoma arising in the neck. A 56-year-old female presented with a left neck tumor. Neck dissection was performed. Microscopically, the tumor showed spindle-shaped stromal cells with large oval and polygonal nuclei. Immunohistologically, the cells were positive for CD21 and CD35, consistent with FDC sarcomas. Adjuvant chemotherapy of cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) was given. Literature review provides the current information for the diagnosis and treatment of this unusual tumor.

Severe pulmonary hypertension in a patient with systemic lupus erythematosus and minimal lupus activity. Reviewed

Nobutoshi Kawamura, Hiroyuki Tsutsui, Kae Fukuyama, Shunji Hayashidani, George Koike, Kensuke Egashira, Yasunobu Abe, Hidetaka Yamamoto, Masazumi Tsuneyoshi, Akira Takeshita

Internal medicine (Tokyo, Japan) 41 ( 2 ) 109 - 12 2002.2

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

Pulmonary hypertension (PH) sometimes occurs in patients with systemic lupus erythematosus (SLE). We report a case of 51-year-old-woman with PH associated with SLE. She had been diagnosed as SLE on the basis of pericardial effusion, hematological disorder, positive antinuclear antibody, and hypocomplementemia. Despite minimal lupus activity, she had marked elevation of pulmonary arterial pressure (101/53 mmHg) and decreased cardiac index (1.5 l/min/m2). Symptoms related to PH were progressive under treatment with oral corticosteroids, oxygen, calcium antagonists, and warfarin. After 17 months of epoprostenol treatment, she died of pulmonary infarction. SLE-associated PH is often severe and progressive even in association with minimal activity.

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