Faculty Profiles - YAMAMOTO HIDETAKA

Papers - YAMAMOTO HIDETAKA

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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

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