Faculty Profiles - NAKAGURO Masato

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 Vol. 145 page： 106491 - 106491 2023.10

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

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

Palisading Adenocarcinoma Reviewed

Justin A. Bishop, Ilan Weinreb, Chris van Vliet, Connull Leslie, Yoshitaka Utsumi, Shinichi Aishima, Junichi Shiraishi, Masamichi Koyama, Yoshiharu Nara, Masatomo Kimura, Doreen Palsgrove, Ying-Ju Kuo, Ralph Gilbert, Jeffrey Gagan, Masato Nakaguro, Toshitaka Nagao

American Journal of Surgical Pathology Vol. 47 ( 10 ) page： 1176 - 1185 2023.10

Language：English Publishing type：Research paper (scientific journal) Publisher：Ovid Technologies (Wolters Kluwer Health)

Adenocarcinoma, not otherwise specified (NOS) is a heterogenous group of salivary gland tumors that likely contains distinct tumors that have not yet been characterized. Indeed, in recent years, cases previously diagnosed as adenocarcinoma, NOS have been recategorized into novel tumor designations such as secretory carcinoma, microsecretory adenocarcinoma, and sclerosing microcystic adenocarcinoma. We sought to describe a distinctive, hitherto-undescribed salivary gland tumor encountered in the authors’ practices. Cases were pulled from the surgical pathology archives of the authors’ institutions. Histologic, immunohistochemical, and clinical findings were tabulated, and targeted next-generation sequencing was performed on all cases. Nine cases were identified, arising in 8 women and 1 man ranging from 45 to 74 years (mean, 56.7 y). Seven tumors (78%) arose in the sublingual gland, while 2 (22%) arose in the submandibular gland. The cases shared a distinctive morphologic appearance. They were biphasic, with ducts scattered among a predominant polygonal cell with round nuclei, prominent nucleoli, and pale eosinophilic cytoplasm. These cells were arranged as trabeculae and palisaded as pseudorosettes around hyalinized stroma and vessels, resembling a neuroendocrine tumor. Four of the cases were well-circumscribed, while the remaining 5 showed infiltrative growth including perineural invasion in 2 (22%) and lymphovascular invasion in 1 (11%). Mitotic rates were low (mean, 2.2/10 HPFs); necrosis was absent. By immunohistochemistry, the predominant cell type was strongly positive for CD56 (9 of 9) and variably positive for pan-cytokeratin (AE1/AE3) (7 of 9) with patchy S100 (4 of 9), but negative for synaptophysin (0 of 9) and chromogranin (0 of 9), while the ducts were strongly positive for pan-cytokeratin (AE1/AE3) (9 of 9) and CK5/6 (7 of 7). Next-generation sequencing did not reveal any fusions or obvious driver mutations. All cases were resected surgically, with external beam radiation also done in 1 case. Follow-up was available in 8 cases; there were no metastases or recurrences after 4 to 160 months (mean, 53.1 mo). A dual population of scattered ducts with a predominance of CD56-positive neuroendocrine-like cells characterizes a unique salivary gland tumor which is often encountered in the sublingual glands of women, for which we propose the term “palisading adenocarcinoma.” Although the tumor was biphasic and had a neuroendocrine-like appearance, it lacked convincing immunohistochemical evidence of myoepithelial or neuroendocrine differentiation. Although a subset showed unequivocally invasive growth, this tumor appears to behave in an indolent manner. Moving forward, recognition of palisading adenocarcinoma and its separation from other salivary adenocarcinomas, NOS will facilitate a better understanding of the characteristics of this previously unrecognized tumor.

DOI： 10.1097/PAS.0000000000002091

Prognostic value and clinicopathological roles of the tumor immune microenvironment in salivary duct carcinoma. Reviewed International journal

Hideaki Hirai, Masato Nakaguro, Yuichiro Tada, Natsuki Saigusa, Daisuke Kawakita, Yoshitaka Honma, Satoshi Kano, Kiyoaki Tsukahara, Hiroyuki Ozawa, Takuro Okada, Kenji Okami, Keisuke Yamazaki, Yukiko Sato, Makoto Urano, Manami Kajiwara, Yoshitaka Utsumi, Tomotaka Shimura, Chihiro Fushimi, Akira Shimizu, Takahito Kondo, Yorihisa Imanishi, Akihiro Sakai, Yuichiro Sato, Takafumi Togashi, Toyoyuki Hanazawa, Takashi Matsuki, Kazuto Yamazaki, Toshitaka Nagao

Virchows Archiv : an international journal of pathology Vol. 483 ( 3 ) page： 367 - 379 2023.9

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

Salivary duct carcinoma (SDC) is an aggressive type of salivary gland carcinoma. Recently, immunotherapies targeting immune checkpoints, including PD1, PD-L1, CTLA4, and LAG3, have had a considerable prognostic impact on various malignant tumors. The implementation of such immune checkpoint inhibitor (ICI) therapies has also been attempted in cases of salivary gland carcinoma. The tumor immune microenvironment (TIME) is implicated in tumorigenesis and tumor progression and is closely associated with the response to ICI therapies. However, the TIME in SDC has not been fully explored. We examined the immunohistochemical expression of CD8, FOXP3, PD1, PD-L1, CTLA4, LAG3, and mismatch repair (MMR) proteins, tumor-infiltrating lymphocytes (TILs), and microsatellite instability (MSI) status in 175 cases of SDC. The associations between these TIME-related markers and the clinicopathological factors and prognosis were evaluated. An elevated expression of CD8, FOXP3, PD1, CTLA4, and LAG3 was associated with more aggressive histological features and an advanced N and/or M classification, elevated Ki-67 index, and poor prognosis. Furthermore, cases with a high PD-L1 expression exhibited more aggressive histological features and adverse clinical outcomes than those with a low expression. Alternatively, there was no significant correlation between TILs and clinicopathological factors. No SDC cases with an MSI-high status or MMR deficiency were found. The coexistence of both an immunostimulatory and immunosuppressive TIME in aggressive SDC might play a role in the presence of T-cell exhaustion. The contribution of multiple immune escape pathways, including regulatory T cells and immune checkpoints, may provide a rationale for ICI therapy, including combined PD1/CTLA4 blockade therapy.

DOI： 10.1007/s00428-023-03598-3

Prognostic impact of highly solid component in early-stage solid lung adenocarcinoma Reviewed

Taketo Kato, Shingo Iwano, Yuki Hanamatsu, Masato Nakaguro, Ryo Emoto, Shoji Okado, Keiyu Sato, Osamu Noritake, Keita Nakanishi, Yuka Kadomatsu, Harushi Ueno, Naoki Ozeki, Shota Nakamura, Koichi Fukumoto, Tamotsu Takeuchi, Kennosuke Karube, Shigeyuki Matsui, Toyofumi Fengshi Chen-Yoshikawa

Quantitative Imaging in Medicine and Surgery Vol. 13 ( 9 ) page： 5641 - + 2023.9

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

Background: Based on computed tomography (CT) findings of lung cancer, solid nodules have a much worse prognosis than subsolid nodules, even if the nodules are subcentimeter in size. There is, however, no systematic method for determining the prognosis of solid tumors on CT. This study aimed to discover the prognostic factor of early-stage solid lung adenocarcinoma using three-dimensional CT volumetry. Methods: Patients with pathological stage I solid lung adenocarcinoma who underwent complete resection between 2007 and 2012 were selected in this retrospective study. Clinicopathological data and preoperative multidetector CT findings, such as tumor size on the two-dimensional axial image, three-dimensional tumor volume between -600 and 199 HU, and three-dimensional solid volume between 0 and 199 HU, which corresponded to highly solid components, were compared between recurrence and non-recurrence. Furthermore, these radiological values were compared to pathological invasive volume (PIV). Results: During this time, 709 patients had their lung cancer completely removed. From this cohort, 90 patients with pathological stage I solid lung adenocarcinoma were selected. In addition, recurrence was found in 26 patients (28.9%). Although two-dimensional axial image, serum carcinoembryonic antigen (CEA) level, and SUVmax on 18F fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/ CT) did not differ statistically between recurrent and non-recurrent patients, three-dimensional tumor and solid tumor volume did. Multivariate analysis indicated that three-dimensional solid tumor volume [hazard ratio: 2.440; 95% confidence interval (CI): 1.110-5.361, P=0.026] and epidermal growth factor receptor (EGFR) mutation (hazard ratio: 4.307; 95% CI: 1.328-13.977, P=0.015) were significantly associated with disease-free survival (DFS). When three-dimensional tumor and solid tumor volume were compared to PIV, three-dimensional solid tumor volume (3,091 mm3 on average) showed a highly similar value with PIV (2,930 mm3 on average), whereas three-dimensional tumor volume (6,175 mm3 on average) was significantly larger than PIV (P<0.001). Conclusions: In patients with early-stage solid lung adenocarcinoma, the measurement of threedimensional solid tumor volume, which is correlated with PIV, accurately predicted the postoperative outcome.

DOI： 10.21037/qims-23-36

Adenocarcinoma arising in branchioma with a KRAS and TP53 mutation. Reviewed International journal

Natsuki Taniguchi, Akira Satou, Takanori Ito, Masato Nakaguro, Toyonori Tsuzuki

Pathology international Vol. 73 ( 7 ) page： 317 - 322 2023.7

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

Branchioma is a rare benign neoplasm occurring in the lower neck. Occurrence of malignant neoplasms arising in branchioma is extremely rare. Here, we report a case of adenocarcinoma arising in branchioma. A 62-year-old man had a right supraclavicular mass measuring 7.5 cm in diameter. The tumor contained an adenocarcinoma component encapsulated in a benign branchioma component. The adenocarcinoma component consisted of high- and low-grade components, with the former accounting for 80% of the adenocarcinoma. The high-grade component was immunohistochemically characterized by diffuse strong p53 expression, while the low-grade component and branchioma component were negative for p53. Targeted sequencing analysis for the branchioma and adenocarcinoma components revealed that the adenocarcinoma component harbored pathogenic mutations in KRAS and TP53. No definitive oncogenic drivers were detected in the branchioma component. Based on these immunohistochemical and molecular findings, we suggest that the KRAS mutation contributed to the pathogenesis of the adenocarcinoma, and the TP53 mutation played a key role in the transition from low-grade to high-grade adenocarcinoma.

DOI： 10.1111/pin.13346

唾液腺腺様嚢胞癌におけるMYB/MYBL1遺伝子関連異常の検索

唾液腺腺様嚢胞癌cN0/pN0症例における予後スコアの作成

下田光, 手島直則, 村瀬貴幸, 長尾俊孝, 草深公秀, 中黒匡人, 浦野誠, 田口健一, 山元英崇, 加納里志, 多田雄一郎, 塚原清彰, 大上研二, 鬼塚哲郎, 藤本保志, 川北大介, 櫻井一生, 花井信広, 長尾徹, 河田了, 羽藤直人, 丹生健一, 稲垣宏

頭頸部癌 Vol. 49 ( 2 ) page： 193 - 193 2023.5

唾液腺腺様嚢胞癌におけるMYB/MYBL1遺伝子関連異常の検索

上田佳緒璃, 村瀬貴幸, 川北大介, 長尾俊孝, 草深公秀, 中黒匡人, 浦野誠, 山元英崇, 田口健一, 加納里志, 多田雄一郎, 塚原清彰, 大上研二, 鬼塚哲郎, 藤本保志, 櫻井一生, 花井信広, 長尾徹, 河田了, 羽藤直人, 丹生健一, 稲垣宏

頭頸部癌 Vol. 49 ( 2 ) page： 193 - 193 2023.5

唾液腺腺様嚢胞癌cN0/pN0症例における予後スコアの作成

頭頸部癌 Vol. 49 ( 2 ) page： 193 - 193 2023.5

頭頸部癌 Vol. 49 ( 2 ) page： 193 - 193 2023.5

A Case of Nodular Extramedullary Hematopoiesis of the Spleen with Latent Essential Thrombocythemia That Was Difficult to Diagnose

Inagaki Kota, Shibata Junpei, Shoka Michita, Fujitake Shinichi, Negita Masataka, Ito Masafumi, Nakaguro Masato

The Japanese Journal of Gastroenterological Surgery Vol. 56 ( 3 ) page： 173 - 179 2023.3

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japanese Society of Gastroenterological Surgery

<p>A 72-year-old man was found to have splenomegaly and an intrasplenic mass in a medical examination. Hamartoma, inflammatory pseudotumor, and sclerosing angiomatoid nodular transformation (SANT) were included as differential diagnoses, but malignant disease could not be ruled out; therefore, laparoscopic splenectomy was performed. A postoperative peripheral blood test showed extreme thrombocytosis and pseudo-hyperkalemia. Thereafter, the patient was diagnosed with essential thrombocythemia and myelofibrosis, with a mutant JAK2-V617F gene. The pathological diagnosis was focal nodular extramedullary hematopoiesis (EMH). EMH sequentially occurs in many hematological disorders, and sometimes presents as hematopoietic masses at several sites; however, presentation as a nodular mass localized in the spleen is rare. It is extremely difficult to diagnose EMH in patients without a past medical history of hematological disorders. However, for a focal nodular mass of the spleen, it is important to determine the treatment strategy with consideration of potential hematological diseases and extramedullary hematopoiesis.</p>

DOI： 10.5833/jjgs.2021.0155

Salivary Duct Carcinoma Ex Basal Cell Adenoma or Epithelial-myoepithelial Carcinoma: Alternative Histo-molecular Pathways of Salivary Duct Carcinoma Formation Reviewed

CiNii Research

Papillary variant of adenoid cystic carcinoma of the maxillary sinus. Reviewed International journal

Junichi Shiraishi, Mami Hatano, Izumi Funakoshi, Yuya Murata, Arafumi Maeshima, Fumihiro Ito, Shojiroh Morinaga, Masato Nakaguro

Pathology international Vol. 73 ( 3 ) page： 141 - 143 2023.3

Nakaguro, M; Faquin, W; Sadow, P; Urano, M; Tada, Y; Nagao, T

LABORATORY INVESTIGATION Vol. 103 ( 3 ) page： S1061 - S1062 2023.3

HER2検査の新たなパラダイム唾液腺癌HER2検査の解説

長尾俊孝, 浦野誠, 中黒匡人, 山元英崇

日本病理学会会誌 Vol. 112 ( 1 ) page： 204 - 204 2023.3

NKX3.1 Expression in Salivary Gland "Intraductal" Papillary Mucinous Neoplasm: A Low-Grade Subtype of Salivary Gland Mucinous Adenocarcinoma. Reviewed International journal

Masato Nakaguro, Peter M Sadow, Rong Hu, Hikaru Hattori, Kyoko Kuwabara, Toyonori Tsuzuki, Makoto Urano, Toshitaka Nagao, William C Faquin

Head and neck pathology Vol. 16 ( 4 ) page： 1114 - 1123 2022.12

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

BACKGROUND: Salivary gland intraductal papillary mucinous neoplasm (SG IPMN) is a recently proposed entity characterized by a papillary-cystic proliferation of mucin-producing cells. Because of overlapping histologic features and a clonal AKT1 p.E17K variant, SG IPMN has been presumed to be a precursor or a low-grade subtype of mucinous adenocarcinoma. NKX3.1 is a tumor suppressor gene located on chromosome 8p and is a known immunohistochemical marker of prostate epithelium and mucinous acinar cells of the intraoral salivary glands. METHODS: We retrieved 12 SG IPMN cases, and performed histologic and genetic analysis. Given the association of SG IPMN with mucinous acinar cells, we also investigated the performance of NKX3.1 as a marker of this tumor entity. RESULTS: Diffuse and strong NKX3.1 expression was observed in all SG IPMN cases (12/12, 100%) as well as in normal mucinous acinar cells. In contrast, mucoepidermoid carcinoma and pancreatic IPMN cases as well as normal serous acinar cells were negative for NKX3.1. Genetically, 11 of 12 cases (92%) harbored an AKT1 p.E17K variant. A novel PTEN frameshift deletion (p.G36Dfs*18) was detected in the other single case. At least one of the histologic features implying malignant tumors, such as severe cellular atypia, brisk mitotic activity, high Ki-67 proliferating index, lymphovascular invasion, and lymph node metastasis, was detected in 6 SG IPMN cases (50%). CONCLUSION: The findings suggest that SG IPMN is a low-grade subtype of mucinous adenocarcinoma which may be derived from mucinous acinar cells of the minor salivary gland.

DOI： 10.1007/s12105-022-01471-4

Identification of novel prognostic and predictive biomarkers in salivary duct carcinoma via comprehensive molecular profiling. Reviewed International journal

Shinji Kohsaka, Yuichiro Tada, Mizuo Ando, Masato Nakaguro, Yukina Shirai, Toshihide Ueno, Shinya Kojima, Hideaki Hirai, Natsuki Saigusa, Satoshi Kano, Kiyoaki Tsukahara, Takafumi Togashi, Hiroyuki Ozawa, Takahito Kondo, Kenji Okami, Hideaki Takahashi, Daisuke Kawakita, Chihiro Fushimi, Takayoshi Suzuki, Akira Shimizu, Isaku Okamoto, Takuro Okada, Yuichiro Sato, Yorihisa Imanishi, Yoshihiro Watanabe, Akihiro Sakai, Koji Ebisumoto, Yukiko Sato, Makoto Urano, Yoshitaka Honma, Keisuke Yamazaki, Yushi Ueki, Toyoyuki Hanazawa, Yuki Saito, Tomotaka Shimura, Toshitaka Nagao, Hiroyuki Mano

NPJ precision oncology Vol. 6 ( 1 ) page： 82 - 82 2022.11

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

Molecular targets and predictive biomarkers for prognosis in salivary duct carcinoma (SDC) have not been fully identified. We conducted comprehensive molecular profiling to discover novel biomarkers for SDC. A total of 67 SDC samples were examined with DNA sequencing of 464 genes and transcriptome analysis in combination with the clinicopathological characteristics of the individuals. Prognostic biomarkers associated with response to combined androgen blockade (CAB) treatment were explored using mRNA expression data from 27 cases. Oncogenic mutations in receptor tyrosine kinase (RTK) genes or genes in the MAPK pathway were identified in 55 cases (82.1%). Alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway were identified in 38 cases (56.7%). Interestingly, patient prognosis could be predicted using mRNA expression profiles, but not genetic mutation profiles. The risk score generated from the expression data of a four-gene set that includes the ADAMTS1, DSC1, RNF39, and IGLL5 genes was a significant prognostic marker for overall survival in the cohort (HR = 5.99, 95% confidence interval (CI) = 2.73-13.1, p = 7.8 × 10-6). Another risk score constructed from the expression of CD3E and LDB3 was a strong prognostic marker for progression-free survival for CAB treatment (p = 0.03). Mutations in RTK genes, MAPK pathway genes, and PI3K/AKT pathway genes likely represent key mutations in SDC tumorigenesis. The gene expression profiles identified in this study may be useful for stratifying patients who are good candidates for CAB treatment and may benefit from additional systemic therapies.

DOI： 10.1038/s41698-022-00324-1