研究者詳細 - 中黒　匡人

Prognostic scores for patients with salivary adenoid cystic carcinoma without lymph node metastasis 査読有り国際誌

Shimoda, H; Teshima, M; Murase, T; Nagao, T; Kusafuka, K; Nakaguro, M; Urano, M; Taguchi, K; Yamamoto, H; Kano, S; Tada, Y; Tsukahara, K; Okami, K; Onitsuka, T; Fujimoto, Y; Kawakita, D; Sakurai, K; Hanai, N; Nagao, T; Kawata, R; Hato, N; Nibu, K; Inagaki, H

ORAL ONCOLOGY 145 巻頁： 106491 - 106491 2023年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Oral Oncology

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 査読有り

Bishop, JA; Weinreb, I; van Vliet, C; Leslie, C; Utsumi, Y; Aishima, S; Shiraishi, J; Koyama, M; Nara, Y; Kimura, M; Palsgrove, D; Kuo, YJ; Gilbert, R; Gagan, J; Nakaguro, M; Nagao, T

AMERICAN JOURNAL OF SURGICAL PATHOLOGY 47 巻 ( 10 ) 頁： 1176 - 1185 2023年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：American Journal of Surgical Pathology

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 査読有り国際誌

Hirai, H; Nakaguro, M; Tada, Y; Saigusa, N; Kawakita, D; Honma, Y; Kano, S; Tsukahara, K; Ozawa, H; Okada, T; Okami, K; Yamazaki, K; Sato, Y; Urano, M; Kajiwara, M; Utsumi, Y; Shimura, T; Fushimi, C; Shimizu, A; Kondo, T; Imanishi, Y; Sakai, A; Sato, Y; Togashi, T; Hanazawa, T; Matsuki, T; Yamazaki, K; Nagao, T

VIRCHOWS ARCHIV 483 巻 ( 3 ) 頁： 367 - 379 2023年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Virchows Archiv

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 査読有り

Kato, T; Iwano, S; Hanamatsu, Y; Nakaguro, M; Emoto, R; Okado, S; Sato, K; Noritake, O; Nakanishi, K; Kadomatsu, Y; Ueno, H; Ozeki, N; Nakamura, S; Fukumoto, K; Takeuchi, T; Karube, K; Matsui, S; Chen-Yoshikawa, TF

QUANTITATIVE IMAGING IN MEDICINE AND SURGERY 13 巻 ( 9 ) 頁： 5641 - + 2023年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Quantitative Imaging in Medicine and Surgery

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 査読有り国際誌

Taniguchi, N; Satou, A; Ito, T; Nakaguro, M; Tsuzuki, T

PATHOLOGY INTERNATIONAL 73 巻 ( 7 ) 頁： 317 - 322 2023年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Pathology International

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 49 巻 ( 2 ) 頁： 193 - 193 2023年5月

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 49 巻 ( 2 ) 頁： 193 - 193 2023年5月

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 49 巻 ( 2 ) 頁： 193 - 193 2023年5月

頭頸部癌 49 巻 ( 2 ) 頁： 193 - 193 2023年5月

本態性血小板血症が潜在し診断に難渋した脾臓の結節状髄外造血の1例

稲垣公太, 柴田淳平, 荘加道太, 藤竹信一, 禰宜田政隆, 伊藤真文, 中黒匡人

日本消化器外科学会雑誌 56 巻 ( 3 ) 頁： 173 - 179 2023年3月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人日本消化器外科学会

症例は72歳の男性で，検診で脾腫および脾臓内腫瘤を指摘された．過誤腫，炎症性偽腫瘍，悪性リンパ腫，sclerosing angiomatoid nodular transformation（SANT）が考えられたが，悪性疾患を除外できず，腹腔鏡下脾臓摘出術を施行した．術後に血小板増多および偽性高カリウム血症を呈した．後にJAK2-V617F遺伝子変異を伴う本態性血小板血症，骨髄線維症と診断された．病理組織検査では，限局性結節状髄外造血と診断された．髄外造血はいくつかの血液疾患に続発し，全身に造血腫瘤として現れることもあるが，脾臓限局性に結節状の腫瘤を形成することはまれである．血液疾患の既往のない患者において，髄外造血を鑑別に挙げ診断するのは非常に困難であるが，脾臓の限局性結節状腫瘤の鑑別には血液疾患の潜在や髄外造血も念頭におき治療戦略を決定する必要がある．

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 査読有り

CiNii Research

Papillary variant of adenoid cystic carcinoma of the maxillary sinus 査読有り国際誌

Shiraishi, J; Hatano, M; Funakoshi, I; Murata, Y; Maeshima, A; Ito, F; Morinaga, S; Nakaguro, M

PATHOLOGY INTERNATIONAL 73 巻 ( 3 ) 頁： 141 - 143 2023年3月

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

LABORATORY INVESTIGATION 103 巻 ( 3 ) 頁： S1061 - S1062 2023年3月

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 112 巻 ( 1 ) 頁： 204 - 204 2023年3月

NKX3.1 Expression in Salivary Gland "Intraductal" Papillary Mucinous Neoplasm: A Low-Grade Subtype of Salivary Gland Mucinous Adenocarcinoma 査読有り国際誌

Nakaguro, M; Sadow, PM; Hu, R; Hattori, H; Kuwabara, K; Tsuzuki, T; Urano, M; Nagao, T; Faquin, WC

HEAD & NECK PATHOLOGY 16 巻 ( 4 ) 頁： 1114 - 1123 2022年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Head and Neck Pathology

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 査読有り国際誌

Kohsaka, S; Tada, Y; Ando, M; Nakaguro, M; Shirai, Y; Ueno, T; Kojima, S; Hirai, H; Saigusa, N; Kano, S; Tsukahara, K; Togashi, T; Ozawa, H; Kondo, T; Okami, K; Takahashi, H; Kawakita, D; Fushimi, C; Suzuki, T; Shimizu, A; Okamoto, I; Okada, T; Sato, Y; Imanishi, Y; Watanabe, Y; Sakai, A; Ebisumoto, K; Sato, Y; Urano, M; Honma, Y; Yamazaki, K; Ueki, Y; Hanazawa, T; Saito, Y; Shimura, T; Nagao, T; Mano, H

NPJ PRECISION ONCOLOGY 6 巻 ( 1 ) 頁： 82 - 82 2022年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：npj Precision Oncology

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