Faculty Profiles - YAMAMOTO HIDETAKA

Papers - YAMAMOTO HIDETAKA

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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

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