Faculty Profiles - NAKAGURO Masato

Papers - NAKAGURO Masato

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Comprehensive Next Generation Sequencing Reveals that Purported Primary Squamous Cell Carcinomas of the Parotid Gland are Genetically Heterogeneous.

Bishop JA, Nakaguro M, Weinreb I, Palsgrove D, Rooper LM, Vandergriff TW, Carlile B, Sorelle JA, Gagan J, Nagao T

Head and neck pathology Vol. 18 ( 1 ) page： 106 2024.10

Multiple subcutaneous reactive angioendotheliomatosis in a patient with antiphospholipid syndrome. Reviewed International journal

Takashi Yokoyama, Masato Nakaguro, Mariko Ogawa-Momohara, Yoshihisa Nakano, Ryo Fukaura, Takuya Takeichi, Yoshinao Muro, Masashi Akiyama

Clinical and experimental dermatology 2024.8

Initial Tumor Size and Narrow-Band Image Findings Estimate Growth Speed in Duodenal Tumors. Reviewed International journal

Takashi Hirose, Naomi Kakushima, Yoshiyuki Minami, Satoshi Furune, Eri Ishikawa, Tsunaki Sawada, Keiko Maeda, Takeshi Yamamura, Kazuhiro Furukawa, Masanao Nakamura, Masato Nakaguro, Hiroki Kawashima

Digestive diseases (Basel, Switzerland) page： 1 - 10 2024.7

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

INTRODUCTION: Recently, the detection of superficial non-ampullary duodenal epithelial tumors (SNADETs) including adenomas and superficial duodenal carcinomas has increased. Various endoscopic treatment methods have also been reported for SNADETs, but there are few reports on the natural history. The aim of this study was to analyze factors related to tumor growth and determine the characteristics of SNADETs which need early therapeutic intervention. METHODS: A single-center, retrospective study was performed on the medical records of 309 patients with SNADETs who underwent endoscopic or surgical resection between January 2010 and May 2021. Of these, 41 patients who were followed up for more than 1 year by endoscopy were analyzed. The primary outcome was an analysis of the tumor growth speed. Secondary outcomes were the relationship between the tumor growth speed and mucin phenotype, tumor size and findings of magnifying endoscopy with narrow-band imaging (M-NBI). RESULTS: The observation period was 24 months (13-182). Tumor growth speed was 1.1 mm/year (0-21.6). Tumor diameter ≥10 mm at first detection (p = 0.004; odds ratio 19.5 [2.03-186.96]) and mixed type by M-NBI (p = 0.036; odds ratio 9.69 [1.05-89.88]) were identified as risk factors of tumors growing at a rate of ≥3 mm/year. There was no statistically significant difference in the speed of tumor growth between the different mucin immunohistochemical phenotypes. CONCLUSION: Initial tumor size and findings of M-NBI are useful to predict tumor growth and consider early intervention.

DOI： 10.1159/000540544

The clinicopathological and prognostic significance of autonomic nerves in salivary duct carcinoma. Reviewed International journal

Manami Kajiwara, Hideaki Takahashi, Masato Nakaguro, Daisuke Kawakita, Hideaki Hirai, Yoshitaka Utsumi, Makoto Urano, Yukiko Sato, Kiyoaki Tsukahara, Satoshi Kano, Kenji Okami, Hiroyuki Ozawa, Keisuke Yamazaki, Takuro Okada, Akira Shimizu, Kenji Hanyu, Akihiro Sakai, Mayu Yamauchi, Mariko Sekimizu, Toyoyuki Hanazawa, Yuki Saito, Yushi Ueki, Yoshitaka Honma, Tomoyuki Arai, Sho Iwaki, Koji Yamamura, Yorihisa Imanishi, Yuichiro Sato, Yuichiro Tada, Toshitaka Nagao

Virchows Archiv : an international journal of pathology Vol. 485 ( 3 ) page： 439 - 452 2024.7

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

Many researchers have focused on the role of the autonomic nervous system in the tumor microenvironment. Autonomic nerves include the sympathetic and parasympathetic nerves, which are known to induce cancer growth and metastasis. However, in salivary duct carcinoma (SDC), a rare and highly malignant tumor, the issue should be investigated from both biological and therapeutic perspectives. We explored the clinicopathological and prognostic implications of the autonomic nerves in 129 SDCs. Immunohistochemistry was performed to determine the nature of each nerve using antibodies against S100, tyrosine hydroxylase (TH) as a sympathetic marker, and vesicular acetylcholine transporter (VAChT) as a parasympathetic marker. The area of each marker-positive nerve was digitized and evaluated quantitatively. Double immunofluorescence for TH and VAChT was performed in selected cases. The expression of the secreted neurotrophins was also examined. S100-positive nerves were present in the cancer tissue in 94 of 129 cases (72.9%). Among them, TH-positive sympathetic nerves and/or VAChT-positive parasympathetic nerves were identified in 92 cases (97.9%), and 59 cases (62.8%) had TH/VAChT-co-expressing nerves. Double immunofluorescence revealed a mosaic pattern of sympathetic and parasympathetic fibers in co-expressing nerve bundles. The presence of autonomic nerves, regardless of their area, was significantly associated with aggressive histological features, advanced T/N classification, and a poor prognosis, with shorter disease-free and overall survival. There was an association between some tumor immune microenvironment-related markers and the autonomic nerve status, but not the latter and the secreted neurotrophin expression. This study suggests that autonomic nerves might play a role in the progression of SDC.

DOI： 10.1007/s00428-024-03873-x

症例病変部毛包内に毛包虫を認めたMorbihan病の1例 Reviewed

竹内想, 武市拓也, 中黒匡人, 秋山真志

皮膚科の臨床 Vol. 66 ( 8 ) page： 1145 - 1148 2024.7

The differential diagnosis of lymphoepithelial lesion of the salivary gland. Reviewed International journal

Makoto Urano, Masato Nakaguro

Seminars in diagnostic pathology Vol. 41 ( 4 ) page： 190 - 196 2024.7

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

The differential diagnosis of salivary gland lesions with epithelial components and lymphoid stroma is often challenging. Salivary gland carcinoma with tumor-associated lymphoid proliferation, tumors composed of both epithelial and lymphoid components, lymphoid neoplasms in the salivary gland, and inflammatory lesions are all included in this category. It encompasses inflammatory lesions and neoplastic lesions. With the exception of Warthin tumors, these lesions are rare, making them more difficult to diagnose. Carcinoma showing thymus-like elements has recently been reported in the salivary gland. Similar to thymic carcinoma, tumor cells are positive for CD5 and are accompanied by T lymphocytes.

DOI： 10.1053/j.semdp.2024.04.004

High-grade salivary carcinomas: A current insight on diagnostic pathology and the key to clinical decision making. Reviewed International journal

Yoshitaka Utsumi, Masato Nakaguro, Yuichiro Tada, Toshitaka Nagao

Seminars in diagnostic pathology Vol. 41 ( 4 ) page： 197 - 206 2024.7

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

High-grade carcinomas of the salivary glands are a group of several tumor entities with highly malignant histologic appearances, and have an aggressive biological behavior accompanied by poor a prognosis. In general, they require more intensive treatment than low- or intermediate-grade carcinomas. High-grade salivary carcinomas are rare and the microscopic features often overlap between different tumor types, making an appropriate diagnosis challenging in daily practice settings. However, with recent rapid advances in molecular pathology and molecular-targeted therapy in this field, there is a growing need to properly classify tumors, rather than just diagnosing the cases as "high-grade carcinomas". This leads to specific treatment strategies. In this article, we review representative high-grade salivary gland carcinomas, including salivary duct carcinoma and its histologic subtypes, high-grade mucoepidermoid carcinoma, solid-type adenoid cystic carcinoma, and high-grade transformation of low- or intermediate-grade carcinomas, and discuss their differential diagnoses and clinical implications. Other rare entities, such as neuroendocrine carcinoma, NUT carcinoma, and metastatic carcinoma, should also be considered before diagnosing high-grade carcinoma, NOS. Of these tumors, salivary duct carcinoma has received the most attention because of its strong association with androgen deprivation and anti-HER2 therapies. Other tumor-type-specific treatments include anti-TRK therapy for high-grade transformation of secretory carcinoma, but further therapeutic options are expected to be developed in the future. It should be emphasized that detailed histological evaluation with adequate sampling, in addition to the effective use of molecular ancillary tests, is of the utmost importance for a suitable diagnosis.

DOI： 10.1053/j.semdp.2024.04.002

Diagnostic clues and pitfalls in salivary gland fine-needle aspiration cytology. Reviewed International journal

Masato Nakaguro

Seminars in diagnostic pathology Vol. 41 ( 4 ) page： 207 - 211 2024.7

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

Salivary gland tumors (SGT) display morphological diversity and pose diagnostic challenges. Preoperative fine needle aspiration cytology (FNAC) is a minimally invasive and efficient diagnostic test. However, due to the limited sample size, the final diagnosis may not be established based on FNAC alone. Although cytomorphology and architecture are usually preserved on FNAC, morphologic changes specific to FNAC can complicate the diagnosis. The Milan System for Reporting Salivary Gland Cytopathology categorizes complex FNAC interpretations. Because the cytological diagnosis is closely linked to the histological diagnosis, a multidimensional approach considering the possibility of several differential diagnoses is necessary. From the standpoint of treatment, distinguishing high-grade malignancy from low-grade malignancy is more important than distinguishing malignancy from benign tumors.

DOI： 10.1053/j.semdp.2024.04.003

Clearing the clouds of uncertainty: Foreword for the special issue "Diagnostic pitfalls of salivary gland tumor pathology". Reviewed International journal

Masato Nakaguro

Seminars in diagnostic pathology Vol. 41 ( 4 ) page： 163 - 164 2024.7

Endoscopic Diagnosis of Epithelial Subtypes of Superficial Non-Ampullary Duodenal Epithelial Tumors using Magnifying Narrow-Band Imaging. Reviewed International journal

Yoshiyuki Kurata, Takashi Hirose, Naomi Kakushima, Masato Nakaguro, Yuki Okumura, Hitoshi Tanaka, Mitsuhiro Fujishiro, Hiroki Kawashima

Digestive diseases (Basel, Switzerland) Vol. 42 ( 5 ) page： 399 - 406 2024.5

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

INTRODUCTION: Superficial non-ampullary duodenal epithelial tumors (SNADETs) include low-grade adenoma (LGA) and high-grade adenoma or carcinoma (HGA/Ca) and are classified into two different epithelial subtypes, gastric-type (G-type) and intestinal-type (I-type). We attempted to distinguish them by endoscopic characteristics including magnifying endoscopy with narrow-band imaging (M-NBI). METHODS: Various endoscopic and M-NBI findings of 286 SNADETs were retrospectively reviewed and compared between G- and I-types and histological grades. M-NBI findings were divided into four patterns based on the following vascular patterns; absent, network, intrastructural vascular (ISV), and unclassified. Lesions displaying a single pattern were classified as mono-pattern and those displaying multiple patterns as mixed-pattern. Lesions showing CDX2 positivity were categorized as I-types and those showing MUC5AC or MUC6 positivity were categorized as G-types based on immunohistochemistry. RESULTS: Among 286 lesions, 23 (8%) were G-type and 243 (85%) were I-type. More G-type lesions were located oral to papilla (91.3 vs. 45.6%, p < 0.001), and had protruding morphology compared to those of I-types (65.2 vs. 14.4%, p < 0.001). The major M-NBI pattern was ISV in G-type (78.2 vs. 26.3%, p < 0.001), and absent for I-type (0 vs. 34.5%, p = 0.003). Three endoscopic characteristics; location oral to papilla, protruding morphology, and major M-NBI pattern (ISV) were independent predictors for G-type. Mixed-pattern was more common in HGA/Ca than LGA for I-type (77.0 vs. 58.8%, p = 0.01); however, there was no difference for those in G-type. CONCLUSION: Endoscopic findings including M-NBI are useful to differentiate epithelial subtypes.

DOI： 10.1159/000539308

唾液腺導管癌におけるHER2低発現の臨床的意義

加納里志, 川北大介, 花澤豊行, 塚原清彰, 岡田拓朗, 大上研二, 山崎恵介, 齊藤裕毅, 小澤宏之, 植木雄志, 本間義崇, 中黒匡人, 長尾俊孝, 多田雄一郎

頭頸部癌 Vol. 50 ( 2 ) page： 137 - 137 2024.5

Prognostic Significance of p16/CDKN2A in Salivary Duct Carcinoma: A Multi-institutional Study(タイトル和訳中) Reviewed

井上和成, 平井秀明, 梶原真奈美, 内山由貴, 山本善也, 長尾俊孝, 塚原清彰, 清水顕, 羽生健治, 多田雄一郎, 中黒匡人

東京医科大学雑誌 Vol. 82 ( 2 ) page： 232 - 233 2024.4

Does Salivary Hybrid Carcinoma Exist? Histomorphologic and Molecular Analyses of 9 Salivary Hybrid Carcinoma Cases Reviewed

Nakaguro, M; Matsuki, T; Nakamura, H; Nakamura, S; Utsumi, Y; Kano, S; Kawakita, D; Hanazawa, T; Nakajima, K; Yagi, H; Tada, Y; Nagao, T

LABORATORY INVESTIGATION Vol. 104 ( 3 ) page： S1341 - S1342 2024.3

Keratocystoma: A Distinctive Salivary Gland Neoplasm Characterized by RUNX2 Rearrangements. Reviewed International journal

Justin A Bishop, Masato Nakaguro, Makoto Urano, Yoshinari Yamamoto, Yoshitaka Utsumi, Rong Li, Ilan Weinreb, Yoji Nagashima, Chiraag Gangahar, Katsushige Yamashiro, Kimio Hashimoto, Lisa M Rooper, Brian Carlile, Richard C Wang, Jeffrey Gagan, Toshitaka Nagao

The American journal of surgical pathology Vol. 48 ( 3 ) page： 317 - 328 2024.3

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

Keratocystoma is a rare salivary gland lesion that has been reported primarily in children and young adults. Because of a scarcity of reported cases, very little is known about it, including its molecular underpinnings, biological potential, and histologic spectrum. Purported to be a benign neoplasm, keratocystoma bears a striking histologic resemblance to benign lesions like metaplastic Warthin tumor on one end of the spectrum and squamous cell carcinoma on the other end. This overlap can cause diagnostic confusion, and it raises questions about the boundaries and definition of keratocystoma as an entity. This study seeks to utilize molecular tools to evaluate the pathogenesis of keratocystoma as well as its relationship with its histologic mimics. On the basis of targeted RNA sequencing (RNA-seq) results on a sentinel case, RUNX2 break-apart fluorescence in situ hybridization (FISH) was successfully performed on 4 cases diagnosed as keratocystoma, as well as 13 cases originally diagnosed as tumors that morphologically resemble keratocystoma: 6 primary squamous cell carcinomas, 3 metaplastic/dysplastic Warthin tumors, 2 atypical squamous cysts, 1 proliferating trichilemmal tumor, and 1 cystadenoma. RNA-seq and/or reverse transcriptase-PCR were attempted on all FISH-positive cases. Seven cases were positive for RUNX2 rearrangement, including 3 of 4 tumors originally called keratocystoma, 2 of 2 called atypical squamous cyst, 1 of 1 called proliferating trichilemmal tumor, and 1 of 6 called squamous cell carcinoma. RNA-seq and/or reverse transcriptase-PCR identified IRF2BP2::RUNX2 in 6 of 7 cases; for the remaining case, the partner remains unknown. The cases positive for RUNX2 rearrangement arose in the parotid glands of 4 females and 3 males, ranging from 8 to 63 years old (mean, 25.4 years; median, 15 years). The RUNX2 -rearranged cases had a consistent histologic appearance: variably sized cysts lined by keratinizing squamous epithelium, plus scattered irregular squamous nests, with essentially no cellular atypia or mitotic activity. The background was fibrotic, often with patchy chronic inflammation and/or giant cell reaction. One case originally called squamous cell carcinoma was virtually identical to the other cases, except for a single focus of small nerve invasion. The FISH-negative case that was originally called keratocystoma had focal cuboidal and mucinous epithelium, which was not found in any FISH-positive cases. The tumors with RUNX2 rearrangement were all treated with surgery only, and for the 5 patients with follow-up, there were no recurrences or metastases (1 to 120 months), even for the case with perineural invasion. Our findings solidify that keratocystoma is a cystic neoplastic entity, one which appears to consistently harbor RUNX2 rearrangements, particularly IRF2BP2::RUNX2 . Having a diagnostic genetic marker now allows for a complete understanding of this rare tumor. They arise in the parotid gland and affect a wide age range. Keratocystoma has a consistent morphologic appearance, which includes large squamous-lined cysts that mimic benign processes like metaplastic Warthin tumor and also small, irregular nests that mimic squamous cell carcinoma. Indeed, RUNX2 analysis has considerable promise for resolving these differential diagnoses. Given that one RUNX2 -rearranged tumor had focal perineural invasion, it is unclear whether that finding is within the spectrum of keratocystoma or whether it could represent malignant transformation. Most important, all RUNX2 -rearranged cases behaved in a benign manner.

DOI： 10.1097/PAS.0000000000002169

唾液腺導管癌171例におけるPLAG1,HMGA2再構成の有無の検討とその分子病理学的特徴に関する比較検討

八木春奈, 山本善也, 内海由貴, 浦野誠, 多田雄一郎, 長尾俊孝, 中黒匡人

日本病理学会会誌 Vol. 113 ( 1 ) page： 349 - 349 2024.2

HER2低発現の唾液腺導管癌に対する臨床病学的検討

加納里志, 花澤豊行, 塚原清彰, 川北大介, 岡田拓朗, 大上研二, 山崎恵介, 小澤宏之, 齊藤祐毅, 植木雄志, 中黒匡人, 長尾俊孝, 多田雄一郎

日本唾液腺学会誌 Vol. 63 page： 30 - 31 2023.11

唾液腺混成癌は存在するのか? 9例の唾液腺混成癌の形態学的および遺伝子解析

中黒匡人, 松木崇, 中村ハルミ, 加納里志, 川北大介, 花澤豊行, 中島広聖, 内海由貴, 八木春奈, 多田雄一郎, 長尾俊孝

日本唾液腺学会誌 Vol. 63 page： 28 - 29 2023.11

唾液腺導管癌の臨床解析唾液腺導管癌多施設共同研究会からの報告

山村晃司, 齊藤祐毅, 川北大介, 加納里志, 花澤豊行, 塚原清彰, 岡田拓朗, 大上研二, 山崎恵介, 小澤宏之, 植木雄志, 中黒匡人, 長尾俊孝, 多田雄一郎

日本唾液腺学会誌 Vol. 63 page： 31 - 32 2023.11

唾液腺導管癌におけるp16/CDKN2Aの予後因子としての意義多施設共同研究

井上和成, 内海由貴, 山本善也, 平井秀明, 花澤豊行, 加納里志, 塚原清彰, 川北大介, 岡田拓朗, 大上研二, 山崎恵介, 小澤宏之, 齊藤祐毅, 植木雄志, 中黒匡人, 多田雄一郎, 長尾俊孝

日本唾液腺学会誌 Vol. 63 page： 25 - 26 2023.11

唾液腺導管癌ではLAT1発現が抗AR療法の治療効果予測因子となり得る

平井秀明, 梶原真奈美, 内海由貴, 山本善也, 花澤豊行, 加納里志, 塚原清彰, 川北大介, 岡田拓朗, 大上研二, 山崎恵介, 小澤宏之, 齊藤祐毅, 植木雄志, 中黒匡人, 多田雄一郎, 長尾俊孝

日本唾液腺学会誌 Vol. 63 page： 29 - 30 2023.11

唾液腺導管癌171例におけるPLAG1,HMGA2再構成の有無の検討とその分子病理学的特徴と予後に関する比較検討

八木春奈, 山本善也, 内海由貴, 浦野誠, 多田雄一郎, 長尾俊孝, 中黒匡人

日本唾液腺学会誌 Vol. 63 page： 26 - 27 2023.11

耳下腺角化嚢胞腫(ケラトシストーマ)2例の臨床病理学的・遺伝子学的解析

浦野誠, 中黒匡人, Bishop JA, 長尾俊孝

日本唾液腺学会誌 Vol. 63 page： 37 - 37 2023.11

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 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

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

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

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Vol. 36 ( 10 ) page： 100274 - 100274 2023.10

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

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

DOI： 10.1016/j.modpat.2023.100274

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

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

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

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

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

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

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

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

唾液腺導管癌における自律神経(交感神経・副交感神経)の臨床・分子病理学的意義

梶原真奈美, 高橋秀聡, 川北大介, 平井秀明, 内海由貴, 浦野誠, 中黒匡人, 佐藤由紀子, 塚原清彰, 加納里志, 大上研二, 小澤宏之, 富樫孝文, 岡田拓朗, 多田雄一郎, 長尾俊孝

日本唾液腺学会誌 Vol. 62 page： 38 - 39 2022.11

唾液腺多型腺癌の臨床病理学的・遺伝学的検討多施設共同研究

宮部悟, 福村元洋, 石橋謙一郎, 中黒匡人, 長尾俊孝, 浦野誠, 谷川真希, 平井秀明, 菊池建太郎, 矢田直美, 杉田好彦, 山元英崇, 大内知之, 草深公秀, 小川郁子, 多田雄一郎, 高田隆, 森永正二郎, 前田初彦, 長尾徹

日本唾液腺学会誌 Vol. 62 page： 35 - 35 2022.11

唾液腺導管癌の癌免疫微小環境の臨床病理学的特徴とその予後に関する検討

平井秀明, 川北大介, 梶原真奈美, 内海由貴, 浦野誠, 中黒匡人, 佐藤由紀子, 塚原清彰, 加納里志, 大上研二, 小澤宏之, 富樫孝文, 岡田拓朗, 山崎一人, 多田雄一郎, 長尾俊孝

日本唾液腺学会誌 Vol. 62 page： 41 - 42 2022.11

唾液腺導管癌における自律神経(交感神経・副交感神経)の臨床・分子病理学的意義

梶原真奈美, 高橋秀聡, 川北大介, 平井秀明, 内海由貴, 浦野誠, 中黒匡人, 佐藤由紀子, 塚原清彰, 加納里志, 大上研二, 小澤宏之, 富樫孝文, 岡田拓朗, 多田雄一郎, 長尾俊孝

日本唾液腺学会誌 Vol. 62 page： 38 - 39 2022.11

基底細胞腺腫あるいは上皮筋上皮癌由来唾液腺導管癌新たな唾液腺導管癌発生の経路

安藤知美, 八木春奈, 浦野誠, 多田雄一郎, 長尾俊孝, 中黒匡人

日本唾液腺学会誌 Vol. 62 page： 44 - 44 2022.11

細胞診ガイドライン(唾液腺)改訂の要点

長尾俊孝, 浦野誠, 加藤拓, 河原明彦, 駄阿勉, 谷川真希, 中黒匡人, 三宅真司, 山元英崇

日本臨床細胞学会雑誌 Vol. 61 ( Suppl.2 ) page： 465 - 465 2022.10

Examination of Abnormal Alpha-synuclein Aggregates in the Enteric Neural Plexus in Patients with Ulcerative Colitis. Reviewed International journal

Noriaki Gibo, Tomonari Hamaguchi, Yasuo Miki, Takeshi Yamamura, Masato Nakaguro, Mikako Ito, Masanao Nakamuara, Hiroki Kawashima, Masaaki Hirayama, Yoshiki Hirooka, Koichi Wakabayashi, Kinji Ohno

Journal of gastrointestinal and liver diseases : JGLD Vol. 31 ( 3 ) page： 290 - 300 2022.9

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

BACKGROUND AND AIMS: Parkinson's disease (PD) is the second most neurodegenerative disease after Alzheimer's disease. Accumulating knowledge points to the notion that abnormal aggregation of alpha-synuclein (αSyn) starts in the gut and ascends to the substantia nigra via the vagus nerve in about a half of PD patients. Epidemiological studies revealed that ulcerative colitis (UC) increases a risk for PD 1.3 to 1.8-folds. However, it remains unknown whether αSyn is abnormally aggregated in the enteric neurons in UC patients. METHODS: We first inspected and optimized the immunostaining protocols with an anti-phosphorylated αSyn antibody, pSyn#64, using the brain and the gut of eight autopsied cases (five with PD and three without PD). Then, we examined abnormal αSyn aggregation in the enteric neurons in 23 and 18 colectomized patients with and without UC, respectively. Five or more sections were stained for αSyn in each of 87 and 25 paraffin- embedded blocks in patients with and without UC, respectively. RESULTS: Ten different protocols of epitope exposure appropriately stained aggregated αSyn in the brain, but only complete lack of epitope exposure stained aggregated αSyn in the colon with low background. Abnormal αSyn aggregates, which was confirmed by co-localization of p62, in the enteric neurons were detected in a single patient with UC but not in any patients without UC. CONCLUSIONS: Omission of epitope exposure enabled us to immunostain aggregated αSyn in the colon by pSyn#64 with low nonspecific staining, but the number of 23 UC patients was not high enough to discern whether abnormal αSyn aggregation in the colonic neural plexus was increased in UC or not.

DOI： 10.15403/jgld-4313

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

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

Journal of Oral Pathology & Medicine Vol. 51 ( 8 ) page： 710 - 720 2022.9

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

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

DOI： 10.1111/jop.13336

Survival benefit of HER2-targeted or androgen deprivation therapy in salivary duct carcinoma. Reviewed International journal

Daisuke Kawakita, Toshitaka Nagao, Hideaki Takahashi, Satoshi Kano, Yoshitaka Honma, Hideaki Hirai, Natsuki Saigusa, Kohei Akazawa, Kaori Tani, Hiroya Ojiri, Kiyoaki Tsukahara, Hiroyuki Ozawa, Kenji Okami, Takahito Kondo, Takafumi Togashi, Chihiro Fushimi, Tomotaka Shimura, Akira Shimizu, Isaku Okamoto, Takuro Okada, Yorihisa Imanishi, Yoshihiro Watanabe, Kuninori Otsuka, Akihiro Sakai, Koji Ebisumoto, Yuichiro Sato, Keisuke Yamazaki, Yushi Ueki, Toyoyuki Hanazawa, Yuki Saito, Mizuo Ando, Takashi Matsuki, Masato Nakaguro, Yukiko Sato, Makoto Urano, Yoshitaka Utsumi, Shinji Kohsaka, Takashi Saotome, Yuichiro Tada

Therapeutic advances in medical oncology Vol. 14 page： 17588359221119538 - 17588359221119538 2022.9

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

Background: The efficacy and safety of human epidermal growth factor receptor 2 (HER2)-targeted therapy and androgen deprivation therapy (ADT) for locally advanced or recurrent or metastatic (LA/RM) salivary duct carcinoma (SDC) have been reported in prospective studies. However, the survival benefit of these therapies to conventional therapy remains controversial, and whether HER2-targeted therapy or ADT should be chosen in HER2- and androgen receptor (AR)-positive SDC patients remains unknown. Methods: Overall, 323 LA/RM SDC patients treated at seven institutions between August 1992 and June 2020 were retrospectively enrolled. The primary aim was to analyze the effect of HER2-targeted therapy and ADT on overall survival from the diagnosis of LA/RM disease to death from any cause (OS1). The secondary indicators included the overall response rate (ORR), clinical benefit rate (CBR), overall survival from therapy initiation for LA/RM disease (OS2), progression-free survival (PFS), time to second progression (PFS2), duration of response (DoR), and duration of clinical benefit (DoCB) of HER2-targeted therapy or ADT as first-line therapy for HER2-positive/AR-positive SDC. Results: Patients treated with HER2-targeted therapy or ADT had longer OS1 than those treated without these therapies (Median OS1: historical control, 21.6 months; HER2-targeted therapy, 50.6 months; ADT, 32.8 months; HER2-targeted therapy followed by ADT, 42.4 months; and ADT followed by HER2-targeted therapy, 45.2 months, p < 0.001). Among HER2-positive/AR-positive SDC patients, although HER2-targeted therapy had better ORR, CBR, and PFS than those of ADT as first-line therapy, we found no significant differences between HER2-targeted therapy and ADT regarding OS2, PFS2, DoR, and DoCB. Conclusion: Patients treated with HER2-targeted therapy and ADT showed longer survival in LA/RM SDC. HER2-targeted therapy can be recommended prior to ADT for HER2-positive/AR-positive SDC. It is warranted to establish a biomarker that could predict the efficacy of clinical benefit or better response in ADT.

DOI： 10.1177/17588359221119538

今月の話題唾液腺腫瘍の病理診断における遺伝子異常の代替的免疫染色マーカー

中黒匡人, 長尾俊孝

病理と臨床 Vol. 40 ( 9 ) page： 0940 - 0944 2022.9

Microsatellite instability-high is rare events in refractory pediatric solid tumors. Reviewed International journal

Taro Yoshida, Hideki Muramatsu, Manabu Wakamatsu, Rieko Taniguchi, Daisuke Ichikawa, Masato Nakaguro, Atsushi Natsume, Yoshiyuki Takahashi

Pediatric hematology and oncology Vol. 39 ( 5 ) page： 468 - 474 2022.8

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

Microsatellite instability (MSI)-high status is associated with good responsiveness to immune checkpoint inhibitors. Although MSI-high status has been actively investigated in pediatric brain tumors, studies of other pediatric solid tumors are lacking. Among 334 consecutive pediatric patients with solid tumors, we retrospectively analyzed formalin-fixed paraffin-embedded tumor tissues of 36 of 74 patients (49%) who died of disease. We assessed the MSI status in these tissues using five multiplexed markers. The results revealed that none of the patients had an MSI-high status. These results indicate that MSI-high status is a rare event in pediatric patients with refractory/relapsed solid tumors.Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2021.1998266.

DOI： 10.1080/08880018.2021.1998266

Subtype classification of malignant lymphoma using immunohistochemical staining pattern Reviewed International journal

Noriaki Hashimoto, Kaho Ko, Tatsuya Yokota, Kei Kohno, Masato Nakaguro, Shigeo Nakamura, Ichiro Takeuchi, Hidekata Hontani

International Journal of Computer Assisted Radiology and Surgery Vol. 17 ( 7 ) page： 1379 - 1389 2022.7

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

Abstract

Purpose

For the image classification problem, the construction of appropriate training data is important for improving the generalization ability of the classifier in particular when the size of the training data is small. We propose a method that quantitatively evaluates the typicality of a hematoxylin-and-eosin (H&E)-stained tissue slide from a set of immunohistochemical (IHC) stains and applies the typicality to instance selection for the construction of classifiers that predict the subtype of malignant lymphoma to improve the generalization ability.

Methods

We define the typicality of the H&E-stained tissue slides by the ratio of the probability density of the IHC staining patterns on low-dimensional embedded space. Employing a multiple-instance-learning-based convolutional neural network for the construction of the subtype classifier without the annotations indicating cancerous regions in whole slide images, we select the training data by referring to the evaluated typicality to improve the generalization ability. We demonstrate the effectiveness of the instance selection based on the proposed typicality in a three-class subtype classification of 262 malignant lymphoma cases.

Results

In the experiment, we confirmed that the subtypes of typical instances could be predicted more accurately than those of atypical instances. Furthermore, it was confirmed that instance selection for the training data based on the proposed typicality improved the generalization ability of the classifier, wherein the classification accuracy was improved from 0.664 to 0.683 compared with the baseline method when the training data was constructed focusing on typical instances.

Conclusion

The experimental results showed that the typicality of the H&E-stained tissue slides computed from IHC staining patterns is useful as a criterion for instance selection to enhance the generalization ability, and this typicality could be employed for instance selection under some practical limitations.

DOI： 10.1007/s11548-021-02549-0

Other Link： https://link.springer.com/article/10.1007/s11548-021-02549-0/fulltext.html

Non-sebaceous lymphadenoma-like mucoepidermoid carcinoma: A case report. Reviewed International journal

Shinnichi Sakamoto, Mutsumi Miyauchi, Toshinori Ando, Megumu Fujihara, Masato Nakaguro, Toshitaka Nagao, Ikuko Ogawa

Pathology international Vol. 72 ( 7 ) page： 371 - 375 2022.7

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

Non-sebaceous lymphadenoma is a rare benign salivary gland tumor comprised of non-sebaceous epithelial cells and lymphoid tissue. Although its clinicopathological features have been described, its histogenesis and genetic background have not yet been elucidated. MAML2 rearrangement and the resultant CRTC1/3-MAML2 fusion gene are well-known specific genetic changes in mucoepidermoid carcinoma. Here, we present a case of lymphoepithelial tumor characterized by histomorphology of the non-sebaceous lymphadenoma and CRTC1-MAML2 fusion gene. The patient was an 83-year-old woman with an 8-year history of a solid, well-circumscribed tumor in the parotid gland. Histologically, the tumor was surrounded by thin fibrous connective tissue and was composed of tubular-cystic and solid nests of epithelial cells equally distributed in the lymphoid tissue. The histological features were suggestive of non-sebaceous lymphadenoma. Although the histomorphology was not consistent with mucoepidermoid carcinoma, a diagnosis of non-sebaceous lymphadenoma-like mucoepidermoid carcinoma was made based on the presence of the CRTC1-MAML2 fusion gene. The histological features alone could not establish the diagnosis, and ancillary molecular analysis was required.

DOI： 10.1111/pin.13236

増刊号結果の読み方がよくわかる!　耳鼻咽喉科検査ガイド Ⅵ.頭頸部腫瘍の検査融合遺伝子

中黒匡人

耳鼻咽喉科・頭頸部外科 Vol. 94 ( 5 ) page： 218 - 223 2022.4

Predictors of Failure of Mitral Valve Repair Using Artificial Chordae. Reviewed International journal

Masato Mutsuga, Yuji Narita, Yoshiyuki Tokuda, Wataru Uchida, Hideki Ito, Sachie Terazawa, Masato Nakaguro, Akihiko Usui

The Annals of thoracic surgery Vol. 113 ( 4 ) page： 1136 - 1143 2022.4

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

BACKGROUND: We investigated predictors of failure of mitral valve repair (MVr) using expanded polytetrafluoroethylene (ePTFE) and its durability in the long term in a single institution. METHODS: Four hundred twenty-one consecutive patients with primary mitral valve disease underwent MVr using artificial chordae (group A, n = 304) and suture repair (group S, n = 117) at our institution from January 2002 to April 2020. A comparison study was performed to examine the long-term outcomes, reoperation rate, and risk factors for reoperation. RESULTS: One hospital death and 5 late deaths occurred in group S, and 20 late deaths occurred in group A. The reoperation rates were similar: group A, n = 8 (2.6%); and group S, n = 6 (5%). The major cause of reoperation was ruptured ePTFE (CV-4, n = 1; CV-5, n = 6) in group A, and suture rupture in group S. Reoperation was performed after a median of 88 months for ruptured ePTFE, and 26 months for group S. The rate of ePTFE rupture was 1.8% with CV-5 and 0.2% with CV-4. Risk factors for reoperation included postoperative arrhythmia, urgent operation, no annular ring, ruptured ePTFE, and suture rupture. The rates of freedom from reoperation and actuarial mitral valve survival rates at 5, 10, and 15 years were 99%, 95%, and 93% and 96%, 91%, and 89%, respectively, in group A; and 96%, 91%, and 91% and 95%, 94%, and 94%, respectively, in group S. CONCLUSIONS: The long-term surgical outcomes of MVr using both techniques were feasible. Over the long term, the ePTFE rupture rate of CV-5 was higher than that of CV-4.

DOI： 10.1016/j.athoracsur.2021.04.084

CDKN2A/B Loss in High-Grade Transformation of Salivary Gland Carcinoma: High-Grade Malignant Potential in Histologically Low-Grade Component Reviewed

Nakaguro, M; Faquin, W; Snuderl, M; Baloch, Z; Cantley, R; Compton, M; Ely, K; Holmes, B; Hu, R; Kerr, D; Montone, K; Nishino, M; Pantanowitz, L; Rossi, E; Nagao, T; Sadow, P

MODERN PATHOLOGY Vol. 35 ( SUPPL 2 ) page： 894 - 895 2022.3

CDKN2A/B Loss in High-Grade Transformation of Salivary Gland Carcinoma: High-Grade Malignant Potential in Histologically Low-Grade Component Reviewed

Nakaguro, M; Faquin, W; Snuderl, M; Baloch, Z; Cantley, R; Compton, M; Ely, K; Holmes, B; Hu, R; Kerr, D; Montone, K; Nishino, M; Pantanowitz, L; Rossi, E; Nagao, T; Sadow, P

LABORATORY INVESTIGATION Vol. 102 ( SUPPL 1 ) page： 894 - 895 2022.3

The Role of the EZH2 and H3K27me3 Expression as a Predictor of Clinical Outcomes in Salivary Duct Carcinoma Patients: A Large-Series Study With Emphasis on the Relevance to the Combined Androgen Blockade and HER2-Targeted Therapy Reviewed International journal

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

Frontiers in Oncology Vol. 11 page： 779882 - 779882 2022.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Frontiers Media SA

<sec><title>Objective</title>Salivary duct carcinoma (SDC) is a highly aggressive and uncommon tumor arising not only <italic>de novo</italic> but also in pleomorphic adenoma. Androgen receptor (AR)- and HER2-targeted therapy have recently been introduced for SDC as promising treatment options; however, no predictive biomarkers have yet been established. EZH2 and H3K27me3 are closely linked to the development and progression of various cancers, and EZH2 is also expected to be a desirable therapeutic target. We therefore explored the clinicopathological and prognostic implications of EZH2 and H3K27me3 in a large cohort of SDC patients, focusing on their impact on the therapeutic efficacy of AR- or HER2-targeted therapy.

</sec><sec><title>Materials and Methods</title>The EZH2 and H3K27me3 immunohistochemical expression and <italic>EZH2</italic> Y646 gain-of-function mutation status were examined in 226 SDCs, and the relationship with the clinicopathological factors as well as clinical outcomes were evaluated within the three groups depending on the treatment: AR-targeted (combined androgen blockade with leuprorelin acetate and bicalutamide; 89 cases), HER2-targeted (trastuzumab and docetaxel; 42 cases), and conventional therapy (112 cases).

</sec><sec><title>Results</title>EZH2 and H3K27me3 were variably immunoreactive in most SDCs. A positive correlation was found between the expression of EZH2 and H3K27me3. The EZH2 expression in the SDC component was significantly higher than that in the pre-existing pleomorphic adenoma component. <italic>EZH2</italic> Y646 was not identified in any cases. EZH2-high cases more frequently had an advanced clinical stage and aggressive histological features than EZH2-low cases. An EZH2-high status in patients treated with AR-targeted therapy was associated with a significantly shorter progression-free and overall survival as well as a lower objective response rate and clinical benefit rate. In addition, a H3K27me3-high status in patients treated with AR-targeted therapy was related to a shorter overall survival. Conversely, there was no association between the EZH2 and H3K27me3 expression and the clinical outcomes in the conventional or HER2-targeted therapy groups.

</sec><sec><title>Conclusions</title>A high expression of EZH2 and H3K27me3 in SDC might be a predictor of a poor efficacy of AR-targeted therapy. Our data provide new insights into the role of EZH2 and H3K27me3 in therapeutic strategies for SDC.

</sec>

DOI： 10.3389/fonc.2021.779882

NR4A3 Immunostain Is a Highly Sensitive and Specific Marker for Acinic Cell Carcinoma in Cytologic and Surgical Specimens. Reviewed International journal

Kartik Viswanathan, Shaham Beg, Bing He, Taotao Zhang, Richard Cantley, Daniel J Lubin, Qiuying Shi, Zahra Maleki, Saeed Asiry, Rema Rao, Nora Katabi, Masato Nakaguro, William C Faquin, Peter M Sadow, Momin T Siddiqui, Theresa Scognamiglio

American journal of clinical pathology Vol. 157 ( 1 ) page： 98 - 108 2022.1

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

OBJECTIVES: Salivary gland acinic cell carcinoma (AciCC) has recognizable cytomorphologic features that can overlap with benign and malignant entities, creating a diagnostic challenge. AciCC harbors a t(4;9) translocation increasing nuclear receptor subfamily 4 group A member 3 (NR4A3) expression, detectable by immunohistochemistry (IHC) on surgical resection (SR). NR4A3 IHC cytology data are limited. Here, we examine NR4A3 IHC on smears, cell blocks (CBs), and SRs of AciCC and its mimickers. METHODS: Our cohort comprised AciCC (including high-grade transformation), secretory carcinoma, mucoepidermoid carcinoma (MEC), Warthin tumor, pleomorphic adenoma (PA), cellular PA, carcinoma ex-PA, oncocytic carcinoma, oncocytoma, and nodular oncocytosis. NR4A3 IHC (Santa Cruz Biotechnology and Origene antibodies) was positive if more than 5% tumor cells showed nuclear staining. RESULTS: Among CBs, 90% of AciCC cases and none of the mimickers expressed NR4A3. Among SRs, 100% of AciCC cases showed diffuse NR4A3, whereas one high-grade MEC expressed focal NR4A3. Concordance was 95% with two antibody clones. Sensitivity, specificity, positive predictive value, and negative predictive value were 90%, 100%, 100%, and 94.7% for CBs and 100%, 98.8%, 92.3%, and 100% for SRs, respectively. NR4A3 immunostaining was demonstrable on smears from an AciCC case. CONCLUSIONS: NR4A3 IHC can be a robust diagnostic tool to identify AciCC, especially for cytology specimens.

DOI： 10.1093/ajcp/aqab099

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

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

Cancer Cytopathology Vol. 130 ( 1 ) page： 30 - 40 2022.1

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

BACKGROUND: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) is a risk-stratification reporting system that was introduced in 2018. The objective of this multi-institutional study was to evaluate the utility of the MSRSGC in Japan. METHODS: In total, 1608 fine-needle aspiration samples with matching histologic diagnoses were retrieved from 12 large institutions in Japan. The diagnostic categories of the MSRSGC were assigned prospectively or retrospectively, and the results were compared with the histologic diagnoses. RESULTS: The cases were classified as follows: nondiagnostic, 18.1%; non-neoplastic, 4.1%; atypia of undetermined significance, 11.5%; neoplasm-benign, 43.7%; salivary gland neoplasm of uncertain malignant potential, 9.6%; suspicious for malignancy, 3.6%; and malignant, 9.4%. The risk of neoplasm and the risk of malignancy in each MSRSGC category were as follows: nondiagnostic, 72.9% and 13.4%, respectively; non-neoplastic, 15.2% and 9.1%, respectively; atypia of undetermined significance, 77.9% and 24.9%, respectively; neoplasm-benign, 99% and 1.8%, respectively; salivary gland neoplasm of uncertain malignant potential, 94.8% and 37%, respectively; suspicious for malignancy, 100% and 89.7%, respectively; and malignant, 100% and 99.3%, respectively. The accuracy of the MSRSGC for diagnosing neoplasms was 97.8%, and its accuracy for diagnosing malignancy was 97.3%. Institutions that used Romanowsky-stained preparations had lower nondiagnostic rates and lower risks of neoplasm and malignancy in the non-neoplastic category. CONCLUSIONS: The MSRSGC is useful for risk stratification and quality control. Widespread use of the MSRSGC would improve the accuracy of salivary gland cytology and lead to better patient care in Japan.

DOI： 10.1002/cncy.22505

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/cncy.22505

Clinicopathologic Analysis of Primary Adrenal Diffuse Large B-Cell Lymphoma: A Reappraisal of 23 Japanese Patients Based on EBV Association and PD-L1 Expression in Tumor Cells. Reviewed International journal

Tasuku Kawano, Yuta Tsuyuki, Yuka Suzuki, Kazuyuki Shimada, Seiichi Kato, Taishi Takahara, Mayuko Mori, Masato Nakaguro, Ayako Sakakibara, Shigeo Nakamura, Akira Satou

The American journal of surgical pathology Vol. 45 ( 12 ) page： 1606 - 1615 2021.12

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

Primary adrenal diffuse large B-cell lymphoma (PA-DLBCL) is rare. We investigate 23 Japanese patients with PA-DLBCL to understand the clinicopathologic features and biological behavior of this disease. The 17 males and 6 females had a median age of 74 years (range: 40 to 86 y). Tumor cells harbored Epstein-Barr virus-encoded small RNA (EBER) in 9 (39%) samples, including samples from the 2 patients with methotrexate-associated B-cell lymphoproliferative disorder. Programmed cell death ligand 1 (PD-L1) expression was detected in tumor cells of 6 (26%) samples, including 1 EBER+ and 5 EBER- samples. Four (17%) patients exhibited an intravascular proliferating pattern, and all 4 patient samples showed positive staining for PD-L1 in tumor cells. Among those patients, 3 showed intravascular proliferating pattern accompanied by a diffuse extravascular proliferation of tumor cells, and 1 patient was diagnosed with intravascular large B-cell lymphoma. We divided the 23 patients into 3 groups: EBER+ (n=9, 39%), EBER-PD-L1+ (n=5, 22%), and EBER-PD-L1- (n=9, 39%). A comparison of the outcomes among the 3 groups showed significant differences in overall survival (P=0.034). The EBER+ group had the worst prognosis, and the EBER-PD-L1- group had the best prognosis. We also compared the outcomes among the 3 groups that received rituximab-containing chemotherapies. Both the overall survival and progression-free survival were significantly different among these groups (P<0.001 and P=0.002, respectively). In conclusion, we evaluated 3 types of PA-DLBCL and found that each had unique clinical, pathologic, and prognostic features. Our results suggested that immune senescence, iatrogenic immunodeficiency, and immune evasion contribute to the development of PA-DLBCL.

DOI： 10.1097/PAS.0000000000001809

Microsecretory Adenocarcinoma of Salivary Glands: An Expanded Series of 24 Cases. Reviewed International journal

Justin A Bishop, Dipti P Sajed, Ilan Weinreb, Brendan C Dickson, Elizabeth A Bilodeau, Abbas Agaimy, Alessandro Franchi, Syed Ali Khurram, Philip Da Forno, Juliana Robledo, John R Kalmar, Sarah Aguirre, Jeffrey F Krane, Jose Luis Tapia, Katalin Kiss, Kitrina Cordell, Molly Rosebush, A William Barrett, Dolphine Oda, Adel Assaad, Toshitaka Nagao, Fumi Kawakami, Masato Nakaguro, Ismail Zahir, Kristina Wakeman, Stephan Ihrler, Jacinthe Chenevert, Yi-Ling Lin, William H Westra, Jeffrey Gagan, Lisa M Rooper

Head and neck pathology Vol. 15 ( 4 ) page： 1192 - 1201 2021.12

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

Microsecretory adenocarcinoma (MSA) is a recently described salivary gland tumor with a characteristic histologic and immunophenotypic profile and recurrent MEF2C-SS18 fusions. Because only six cases of MSA have been published, its complete clinicopathologic spectrum is unclear, and its biologic behavior has not been documented. Here, we present an updated and expanded experience of 24 MSA cases. All cases of MSA were obtained from the authors' files. Immunohistochemistry for S100, SOX10, p63, p40, SMA, calponin, and mammaglobin was performed. Molecular analysis was performed by targeted RNA sequencing, SS18 break apart fluorescence in situ hybridization, and/or reverse transcriptase polymerase chain reaction for MEF2C-SS18 fusion. Clinical follow-up was obtained from medical records. A total of 24 MSA cases were collected, from 13 women and 11 men, ranging from 17 to 83 years (mean 49.5 years). The vast majority (23 of 24) arose in the oral cavity, with the palate (n = 14) and buccal mucosa (n = 6) as the most frequent subsites. Tumors showed consistent histologic features including: (1) microcystic tubules, (2) flattened intercalated duct-like cells, (3) monotonous oval hyperchromatic nuclei, (4) abundant basophilic luminal secretions, (5) fibromyxoid stroma, and (6) circumscribed borders with subtle infiltration. The tumors were very consistently positive for S100 (24 of 24), p63 (24 of 24), and SOX10 (14 of 14) and negative for p40 (0 of 21), calponin (0 of 12) and mammaglobin (0 of 16), while SMA (4 of 20) was variable. MEF2C-SS18 fusion was demonstrated in 21 of 24 cases; in the remaining 3 cases with insufficient RNA, SS18 break apart FISH was positive. Treatment information was available in 17 cases, all of which were managed with surgery only. In 14 cases with follow-up (1-216 months, mean 30), no cases recurred or metastasized. MSA is a distinct salivary gland neoplasm with remarkably consistent clinical, histologic, immunophenotypic, and genetic features that generally behaves in an indolent manner following surgery alone. These observations solidify MSA as a unique, low-grade salivary gland carcinoma that warrants inclusion in the next version of the WHO classification of head and neck tumors.

DOI： 10.1007/s12105-021-01331-7

唾液腺導管癌におけるPTEN欠損とその臨床病理学的意義多施設共同研究

山本善也, 平井秀明, 三枝奈津季, 浦野誠, 中黒匡人, 佐藤由紀子, 塚原清彰, 加納里志, 近藤貴仁, 大上研二, 小澤宏之, 富樫孝文, 川北大介, 多田雄一郎, 長尾俊孝

日本唾液腺学会誌 Vol. 61 page： 43 - 44 2021.11

唾液腺導管癌においてEZH2高発現は複合アンドロゲン遮断療法の効果不良予測因子になりうる

平井秀明, 三枝奈津季, 浦野誠, 中黒匡人, 佐藤由紀子, 塚原清彰, 加納里志, 近藤貴仁, 大上研二, 小澤宏之, 富樫孝文, 川北大介, 多田雄一郎, 長尾俊孝, SDC多施設共同研究会

日本唾液腺学会誌 Vol. 61 page： 48 - 49 2021.11

唾液腺導管癌においてEZH2高発現は複合アンドロゲン遮断療法の効果不良予測因子になりうる

平井秀明, 三枝奈津季, 浦野誠, 中黒匡人, 佐藤由紀子, 塚原清彰, 加納里志, 近藤貴仁, 大上研二, 小澤宏之, 富樫孝文, 川北大介, 多田雄一郎, 長尾俊孝, SDC多施設共同研究会

日本唾液腺学会誌 Vol. 61 page： 48 - 49 2021.11

唾液腺導管癌におけるPTEN欠損とその臨床病理学的意義多施設共同研究

山本善也, 平井秀明, 三枝奈津季, 浦野誠, 中黒匡人, 佐藤由紀子, 塚原清彰, 加納里志, 近藤貴仁, 大上研二, 小澤宏之, 富樫孝文, 川北大介, 多田雄一郎, 長尾俊孝

日本唾液腺学会誌 Vol. 61 page： 43 - 44 2021.11

唾液腺導管内乳頭粘液性腫瘍におけるNKX3.1免疫染色の有用性

八木春奈, 中黒匡人, 浦野誠, 長尾俊孝, Faquin William C., Sadow Peter M

日本唾液腺学会誌 Vol. 61 page： 45 - 45 2021.11

非脂腺型リンパ腺腫様粘表皮癌の1例

坂本真一, 安藤俊範, 宮内睦美, 藤原恵, 中黒匡人, 長尾俊孝, 小川郁子

日本唾液腺学会誌 Vol. 61 page： 54 - 54 2021.11

Oncocytic Intraductal Carcinoma of Salivary Glands: A Distinct Variant with TRIM33-RET Fusions and BRAF V600E mutations. Reviewed International journal

Justin A Bishop, Masato Nakaguro, Rumeal D Whaley, Kanako Ogura, Hiroshi Imai, Israa Laklouk, William C Faquin, Peter M Sadow, Jeffrey Gagan, Toshitaka Nagao

Histopathology Vol. 79 ( 3 ) page： 338 - 346 2021.9

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

AIMS: Salivary gland intraductal carcinoma (IDC) is a complex ductal neoplasm surrounded by a layer of myoepithelial cells. Recent insights have shown that there are 3 different types: intercalated duct-like, with frequent NCOA4-RET fusions; apocrine, with salivary duct carcinoma-like mutations; and mixed intercalated duct-like/apocrine with RET fusions including TRIM27-RET. In addition, an oncocytic IDC was described, but it remains unclear if it represents a fourth variant or simply oncocytic metaplasia of another IDC type. METHODS AND RESULTS: Six IDCs with oncocytic changes were retrieved from the authors' archives, from 3 men and 3 women ranging from 45-75 years (mean, 63). Five arose in the parotid, with one in an accessory parotid gland. Four patients with follow-up were free of disease after 1-23 months. Several immunostains (S100, mammaglobin, androgen receptor, p63/p40) and molecular tools (RNA sequencing, RET fluorescence in situ hybridization, BRAF V600E VE1 immunohistochemistry and Sanger sequencing) were performed. Histologically, tumors were variably cystic with solid intracystic nodules often difficult to recognize as intraductal. In all, tumor ducts were positive for S100 and mammaglobin, negative for androgen receptor, and completely surrounded by myoepithelial cells positive for p63/p40. Molecular analysis revealed TRIM33-RET in 2/6, NCOA4-RET in 1/6, and BRAF V600E in 2/6 cases. One case had no identifiable alterations. CONCLUSIONS: Oncocytic IDC shares similarities with intercalated duct-like IDC. While additional verification is needed, the oncocytic variant appears to be sufficiently unique to be regarded now as the fourth distinct subtype of IDC. Because of its indolent nature, oncocytic IDC should be distinguished from histologic mimickers.

DOI： 10.1111/his.14296

Intraductal carcinoma of the salivary gland with NCOA4-RET: expanding the morphologic spectrum and an algorithmic diagnostic approach. Reviewed International journal

Adam S Fisch, Israa Laklouk, Masato Nakaguro, Vânia Nosé, Lori J Wirth, Daniel G Deschler, William C Faquin, Dora Dias-Santagata, Peter M Sadow

Human pathology Vol. 114 page： 74 - 89 2021.8

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

After the publication of the 2017 World Health Organization Classification of Head and Neck Tumours, there has been increasing interest in the classification of newly categorized intraductal carcinomas. Intraductal carcinoma (IC) is an indolent tumor, typically arising in the parotid gland, with an intact myoepithelial layer and a cystic, papillary, often cribriform architecture. Early studies of IC identified a heterogeneous group of molecular alterations driving neoplasia, and recent studies have defined three primary morphological/immunohistochemical variants, subsequently linking these morphologic variants with defined molecular signatures. Although studies to date have pointed toward distinct molecular alterations after histological classification, this study used a novel approach, focusing primarily on six cases of IC with NCOA4-RET gene rearrangement as determined by next-generation sequencing and describing the spectrum of clinicopathologic findings within that molecularly-defined group, among them a unique association between the NCOA4-RET fusion and hybrid variant IC and the first case of IC arising in association with a pleomorphic adenoma. RET-rearranged IC show histological and immunohistochemical overlap with the more widely recognized secretory carcinoma, including low-grade morphology, a lumen-forming or microcystic growth pattern, and co-expression of S100, SOX10, and mammaglobin, findings undoubtedly leading to misdiagnosis. Typically regarded to have ETV6-NTRK3 fusions, secretory carcinomas may alternatively arise with RET fusions as well. Adding our cohort of six NCOA4-RET fusion-positive IC compared with four cases of secretory carcinoma with ETV6-RET fusions and a single case of fusion-negative IC with salivary duct carcinoma-like genetics, we propose a diagnostic algorithm that integrates histological elements, including atypia and invasiveness, and the likelihood of specific molecular alterations to increase diagnostic accuracy in what can be a very subtle diagnosis with important clinical implications.

DOI： 10.1016/j.humpath.2021.05.004

The Diagnostic Utility of RAS Q61R Mutation-specific Immunohistochemistry in Epithelial-Myoepithelial Carcinoma. Reviewed International journal

Masato Nakaguro, Maki Tanigawa, Hideaki Hirai, Yoshinari Yamamoto, Makoto Urano, Reisuke H Takahashi, Aoi Sukeda, Yuki Okumura, Shogo Honda, Koichiro Tasaki, Akira Shimizu, Kiyoaki Tsukahara, Yuichiro Tada, Jun Matsubayashi, William C Faquin, Peter M Sadow, Toshitaka Nagao

The American journal of surgical pathology Vol. 45 ( 7 ) page： 885 - 894 2021.7

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

Epithelial-myoepithelial carcinoma (EMC) is a rare salivary gland cancer characterized by biphasic tubular structures composed of inner ductal and outer clear myoepithelial cells. Because of its histologic variety and overlap of histologic features with other salivary gland tumors, there are broad differential diagnoses. The HRAS Q61R mutation has been reported to be frequent in and specific to EMC. We evaluated the usefulness of RAS Q61R mutant-specific immunohistochemical (IHC) staining for detecting this genetic alteration in EMC. We investigated 83 EMC cases and 66 cases of salivary gland tumors with an EMC-like component, including pleomorphic adenoma, adenoid cystic carcinoma, basal cell adenoma/adenocarcinoma, and myoepithelial carcinoma. Sanger sequencing was performed for HRAS, KRAS, and NRAS. The diffuse and membranous/cytoplasmic RAS Q61R IHC expression was observed in 65% of EMC cases, in which all cases harbored the HRAS Q61R mutation. IHC-positive cases were present only in de novo EMCs (54/76 cases, 71%) but not in EMCs ex pleomorphic adenoma. The immunoreactivity was almost always restricted to the myoepithelial cells. Conversely, all EMC cases lacking the HRAS Q61R mutation were negative on IHC. In addition, only 3% of EMC-like tumors showed the abovementioned immunopositivity. None of the cases examined carried KRAS or NRAS mutations. IHC for RAS Q61R is highly sensitive and specific for detecting the HRAS Q61R mutation in EMC. Since significant immunopositivity was almost exclusively identified in nearly two thirds of EMCs but seldom in the histologic mimics, the IHC of RAS Q61R is a useful tool for diagnosing EMC in general pathology laboratories.

DOI： 10.1097/PAS.0000000000001673

Difference in the distribution of tumor-infiltrating CD8+ T cells and FOXP3+ T cells between micronodular thymoma with lymphoid stroma and micronodular thymic carcinoma with lymphoid stroma. Reviewed International journal

Haruna Yagi, Masato Nakaguro, Masafumi Ito, Yuki Okumura, Seishiro Takahashi, Yoichiro Aoshima, Yasunori Enomoto, Shiori Meguro, Hideya Kawasaki, Isao Kosugi, Yoshie Shimoyama, Hiroshi Ogawa, Hisashi Tateyama, Toshihide Iwashita

Pathology international Vol. 71 ( 7 ) page： 453 - 462 2021.7

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

Micronodular thymoma with lymphoid stroma (MNT) is a rare thymic epithelial neoplasm subtype characterized by a micronodular tumor cell growth pattern and abundant lymphoid stroma. Micronodular thymic carcinoma with lymphoid stroma (MNCA) is considered as a malignant counterpart of MNT and exhibits a growth pattern similar to that of MNT but has histologic features reminiscent of thymic squamous cell carcinoma, such as cytologic atypia and CD5 and CD117 immunoexpression. Although both MNT and MNCA are characterized by abundant lymphoid stroma, it remains unknown whether there are differences in infiltrating lymphocytes between MNT and MNCA. We analyzed the immune microenvironment profile in eight MNT and three MNCA cases. The cell density of CD8-positive T cells was significantly higher in MNT than in MNCA, whereas that of FOXP3-positive T cells was significantly higher in MNCA than in MNT. There was no significant difference in the cell density of programmed death protein 1-positive T cells and programmed death ligand 1 expression between the MNT and MNCA cases. Our findings indicated that the immune microenvironment of MNCA differed from that of MNT and, compared with the T-cell profile of MNT, that of MNCA was more suppressive to patients' antitumor immune response.

DOI： 10.1111/pin.13099

Integrated diagnosis based on transcriptome analysis in suspected pediatric sarcomas. Reviewed International journal

Daisuke Ichikawa, Kyoko Yamashita, Yusuke Okuno, Hideki Muramatsu, Norihiro Murakami, Kyogo Suzuki, Daiei Kojima, Shinsuke Kataoka, Motoharu Hamada, Rieko Taniguchi, Eri Nishikawa, Nozomu Kawashima, Atsushi Narita, Nobuhiro Nishio, Asahito Hama, Kenji Kasai, Seiji Mizuno, Yoshie Shimoyama, Masato Nakaguro, Hajime Okita, Seiji Kojima, Atsuko Nakazawa, Yoshiyuki Takahashi

NPJ genomic medicine Vol. 6 ( 1 ) page： 49 - 49 2021.6

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

Pediatric solid tumors are a heterogeneous group of neoplasms with over 100 subtypes. Clinical and histopathological diagnosis remains challenging due to the overlapping morphological and immunohistochemical findings and the presence of atypical cases. To evaluate the potential utility of including RNA-sequencing (RNA-seq) in the diagnostic process, we performed RNA-seq in 47 patients with suspected pediatric sarcomas. Histopathologists specialized in pediatric cancer re-evaluated pathological specimens to reach a consensus diagnosis; 42 patients were diagnosed with known subtypes of solid tumors whereas 5 patients were diagnosed with undifferentiated sarcoma. RNA-seq analysis confirmed and refined consensus diagnoses and further identified diagnostic genetic variants in four of the five patients with undifferentiated sarcoma. Genetic lesions were detected in 23 patients, including the novel SMARCA4-THOP1 fusion gene and 22 conventional or recently reported genetic events. Unsupervised clustering analysis of the RNA-seq data identified a distinct cluster defined by the overexpression of rhabdomyosarcoma-associated genes including MYOG and CHRNG. These findings suggest that RNA-seq-based genetic analysis may aid in the diagnosis of suspected pediatric sarcomas, which would be useful for the development of stratified treatment strategies.

DOI： 10.1038/s41525-021-00210-y

Sialadenoma Papilliferum of the Bronchus Reviewed International journal

Masato Nakaguro, Mari Mino-Kenudson, Makoto Urano, Ikuko Ogawa, Yumi Honda, Hideaki Hirai, Maki Tanigawa, Aoi Sukeda, Naohiro Kajiwara, Tatsuo Ohira, Norihiko Ikeda, Yoshiki Mikami, Yuichiro Tada, Jun-Ichiro Ikeda, Jun Matsubayashi, William C. Faquin, Peter M. Sadow, Toshitaka Nagao

American Journal of Surgical Pathology Vol. 45 ( 5 ) page： 662 - 671 2021.5

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

Sialadenoma papilliferum (SP) is a rare benign tumor of the salivary glands, and only 3 unequivocal cases of SP arising in the bronchus have been reported. We herein describe the histomorphologic and molecular features of 4 bronchial SP cases and discuss the differential diagnosis of this entity and the relationship with its clinicopathologic mimics, in particular, glandular papilloma and mixed squamous cell and glandular papilloma (GP/MP). We encountered 2 male and 2 female patients with bronchial SP (mean: 66.8 y old). All 4 tumors arose in the central bronchus and were characterized by a combination of surface exophytic endobronchial papillary proliferation and a submucosal multicystic component with complex architecture. The neoplastic epithelium consisted predominantly of nonciliated stratified columnar cells with ciliated, squamous, and mucinous cells present focally. While 2 tumors (50%) harbored a BRAF V600E mutation by molecular and immunohistochemical analysis, similar to GP/MP, no KRAS, HRAS, AKT1, or PIK3CA mutations were detected in any of the cases. Two patients were treated with limited resection, while 2 patients underwent lobectomy based on the diagnosis of adenocarcinoma or possible squamous cell carcinoma in situ in the preoperative biopsy. All survived without recurrence or metastasis for 23 to 122 months after treatment. SP can develop in the central bronchus as the bronchial counterpart of the salivary gland tumor and should be considered in the differential diagnosis of endobronchial tumors. In addition, some histologic resemblance and frequent BRAF V600E mutation raise the possibility of SP and GP/MP being on the same disease spectrum.

DOI： 10.1097/PAS.0000000000001657

【治療方針を変える病理所見診療ガイドラインと治療戦略】(第1部)臓器別唾液腺

中黒匡人, 長尾俊孝

病理と臨床 Vol. 39 ( 臨増 ) page： 26 - 31 2021.4

Pathological evaluation of tumor grade for salivary adenoid cystic carcinoma: A proposal of an objective grading system. Reviewed 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 Vol. 112 ( 3 ) page： 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

Epithelial-Myoepithelial Carcinoma. Reviewed International journal

Masato Nakaguro, Toshitaka Nagao

Surgical pathology clinics Vol. 14 ( 1 ) page： 97 - 109 2021.3

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

Epithelial-myoepithelial carcinoma is an uncommon low-grade salivary gland carcinoma. It is classically characterized by biphasic tubular structures composed of inner eosinophilic ductal cells and outer clear myoepithelial cells. In addition, epithelial-myoepithelial carcinoma sometimes shows various histologic features, including a cribriform pattern, basaloid appearance, and sebaceous differentiation. Because clear myoepithelial cells are also noted in other benign and malignant salivary gland tumors, the histologic variety and similarity with other tumor entities make the diagnosis of epithelial-myoepithelial carcinoma challenging. A recent analysis revealed that HRAS hotspot point mutations are specifically identified in epithelial-myoepithelial carcinoma and the assessment of given genes facilitate the correct diagnosis.

DOI： 10.1016/j.path.2020.10.002

唾液腺における高悪性度転化癌と混成癌 Reviewed

中黒匡人, 長尾俊孝

病理と臨床 Vol. 39 ( 2 ) page： 195 - 197 2021.2

Gastrointestinal tract metastasis of lung cancer: The PD-L1 expression and correlated clinicopathological variables. Reviewed International journal

Eri Ishikawa, Masato Nakaguro, Masanao Nakamura, Takeshi Yamamura, Tsunaki Sawada, Yasuyuki Mizutani, Keiko Maeda, Kazuhiro Furukawa, Yoshie Shimoyama, Hiroki Kawashima, Mitsuhiro Fujishiro

Pathology international Vol. 71 ( 1 ) page： 33 - 41 2021.1

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

The gastrointestinal tract is a rare site for metastatic lung cancer. Programmed cell death-ligand 1 (PD-L1) expression in lung cancer is a biomarker for the response to anti-PD-1/PD-L1 therapy. We investigated clinicopathological features and PD-L1 expression in 25 gastrointestinal metastatic tumors from the lung and primary adenocarcinoma of the small bowel. The small bowel was the most common site (16/25; 64%) of gastrointestinal tract lung cancer metastasis. A total of 19 (76%) of the gastrointestinal metastasis showed PD-L1 expression in ≥5% of tumor cells, with 14 (56%) showing high expression levels (≥50%). In contrast, 21 (84%) expressed PD-L1 in ≥5% immune cells, including 4 (16%) showing a high expression levels (≥50%). The PD-L1 expression on tumor cells and immune cells in primary lung cancer and corresponding gastrointestinal metastasis was concordant in 13 (68%) and 11 (58%) of the 19 paired cases, respectively. Small-bowel metastasis of lung cancer was characterized by a higher incidence of perforation (31% vs. 0%), ulcerated mass (83% vs. 60%), and neoplastic PD-L1 expression (75% vs. 0%) compared to primary small-bowel adenocarcinoma. Gastrointestinal metastasis from lung cancer might be a potential target for immune checkpoint inhibitor therapy, given its high expression of PD-L1.

DOI： 10.1111/pin.13048

Stain transfer for automatic annotation of malignant lymphoma regions in H&E stained whole slide histopathology images Reviewed

Ryoichi Koga, Noriaki Hashimoto, Tatsuya Yokota, Masato Nakaguro, Kei Kohno, Shigeo Nakamura, Ichiro Takeuchi, Hidekata Hontani

Proceedings of SPIE - The International Society for Optical Engineering Vol. 11792 2021

Language：English Publishing type：Research paper (international conference proceedings) Publisher：SPIE

We propose a method to transfer a given pathology image stained by some immunostaining to a H&amp
E stained one. When one construct a classifier that estimates the subtype of malignant lymphoma from a given H&amp
E stained pathology image, one needs a set of training H&amp
E stained whole slide images in which the tumor regions are annotated. The annotation is not easy and requires large human resources. Here, it is known that some immunostaining stains only some specific tumor cells and the tumor region detection from the immunostained images is straightforward. It means once you transfer the immunostained images to H&amp
E stained ones, you can easily obtain a set of virtually H&amp
E stained images with annotation of tumor regions. In this manuscript, we report on the proposed method and experimental results of stain transfer from CD20 stained images to H&amp
E stained ones.

DOI： 10.1117/12.2590720

Detection of DLBCL regions in H&E stained whole slide pathology images using Bayesian U-Net Reviewed

Ryoichi Koga, Noriaki Hashimoto, Tatsuya Yokota, Masato Nakaguro, Kei Kohno, Shigeo Nakamura, Ichiro Takeuchi, Hidekata Hontani

Proceedings of SPIE - The International Society for Optical Engineering Vol. 11792 2021

Language：English Publishing type：Research paper (international conference proceedings) Publisher：SPIE

We proposed a method that detects DLBCL (Diffuse Large B-Cell Lymphoma) regions from a H&amp
E stained whole slide pathology image by measuring the size of each nucleus. It is known that DLBCL cells would have about 2 to 3 times larger nuclei than typical lymphocytes. One can hence detect DLBCL regions by detecting every cell nucleus in a given H&amp
E stained pathology image and describing the spatial distribution of the large nuclei. For the detection of cell nuclei, we employ a U-Net and a Bayesian U-Net. We describe the details of the proposed method and report the experimental results, which demonstrate the proposed method works well in the DLBCL regions.

DOI： 10.1117/12.2590719

Immunostaining With Immunoglobulin G Subclass Antibody Cocktail for Diagnosis of Type 1 Autoimmune Pancreatitis. Reviewed International journal

Rie Nakata, Takeshi Uehara, Mai Iwaya, Shiho Asaka, Shota Kobayashi, Mitsutoshi Sugano, Kayoko Higuchi, Yukiko Kusama, Koh Nakazawa, Masato Nakaguro, Mikiko Kobayashi, Ayako Tateishi, Mutsuki Makino, Kenji Kawaguchi, Toshitaka Maejima, Keiko Ishii, Kenji Sano, Hisashi Shimojo, Atsushi Hori, Toshiaki Otsuki, Hideaki Hamano, Shigeyuki Kawa, Hiroyoshi Ota

International journal of surgical pathology Vol. 28 ( 8 ) page： 844 - 849 2020.12

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

BACKGROUND.: Immunoglobulin (Ig) G4-related diseases (RDs) are systemic diseases in which serum IgG4 levels are frequently elevated. They can cause diffuse or focal tumor formation, organ swelling, and tissue thickening in organs infiltrated by IgG4
+
plasma cells. The diagnostic criteria for IgG4-RDs include an IgG4/IgG ratio >40%, but counting IgG+ cells can be difficult because of the weakness of IgG staining density. We hypothesized that an antibody cocktail of mixed IgG1, IgG2, IgG3, and IgG4 (AC-IgG) might give immunohistochemistry results comparable with those of IgG in IgG4-RD. METHODS.: We compared AC-IgG reactivity with IgG expression in type 1 autoimmune pancreatitis (AIP), a representative IgG4-RD. We compared immunohistochemistry results using AC-IgG and IgG-only in 10 cases of AIP. The coefficient of variation (Cv) was used to analyze differences between AC-IgG and IgG findings in AIP by 13 board-certified pathologists. RESULTS.: Although mean values for IgG+ cells did not significantly differ between AC-IgG (34.3; range = 27.4-37.1) and IgG (30.0; range = 23.0-45.6; P = .6254), Cv was lower for AC-IgG (33.4%) than for IgG (51.4%; regression equation; y[IgG] = 0.988x + 0.982; correlation coefficient = 0.907). The data showed that the results of both methods were largely consistent. CONCLUSION.: AC-IgG could replace IgG to count IgG+ cells because of its lower Cv.

DOI： 10.1177/1066896920924781

Microsatellite Instability-High is Rare Events in Refractory Pediatric Solid Tumors Reviewed

Yoshida, T; Muramatsu, H; Wakamatsu, M; Taniguchi, R; Ichikawa, D; Nakaguro, M; Natsume, A; Takahashi, Y

PEDIATRIC BLOOD & CANCER Vol. 67 2020.12

Fine needle aspiration of salivary gland carcinomas with high-grade transformation: A multi-institutional study of 22 cases and review of the literature. Reviewed International journal

Masato Nakaguro, William C Faquin, Zubair W Baloch, Richard L Cantley, Margaret L Compton, Kim A Ely, Brittany J Holmes, Rong Hu, Darcy A Kerr, Kathleen T Montone, Michiya Nishino, Liron Pantanowitz, Esther Diana Rossi, Peter M Sadow

Cancer cytopathology Vol. 129 ( 4 ) page： 318 - 325 2020.11

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

BACKGROUND: High-grade transformation (HGT) is a rare process whereby conventional low- to intermediate-grade salivary gland carcinomas (SGC) transform into high-grade, poorly or undifferentiated malignancies with focal or complete loss of their conventional histomorphologic features. Because tumors with HGT are associated with a worse prognosis than their conventional counterparts, preoperative recognition of HGT may be of benefit for optimal patient management. Using a multi-institutional approach, we describe the largest fine needle aspiration (FNA) cohort of salivary gland carcinomas with HGT. METHODS: The archives of 9 large academic medical centers were searched, and 22 cases of SGC with HGT were identified by surgical excision accompanied by preoperative FNA. Clinical and cytomorphologic features were retrospectively reviewed. RESULTS: The male-to-female ratio was 14:8, and the mean patient age was 60.2 years. The average tumor size was 3.6 cm, and 19 cases were from the parotid gland. Acinic cell carcinoma with HGT was the most common tumor subtype, comprising 12 cases with HGT, followed by adenoid cystic carcinoma, secretory carcinoma, and other subtypes. Eighteen cases were classified as malignant; however, a specific diagnosis of HGT was not made. Sixteen cases contained a high-grade cytologic component, and 7 cases had a mixture of both conventional and high-grade components retrospectively. CONCLUSIONS: SGC with HGT should be considered in the differential diagnosis of a salivary gland aspirate exhibiting high-grade cytomorphologic features. The presence of distinct tumor populations, conventional and high-grade, should prompt consideration of HGT, especially when the conventional component is acinic cell carcinoma or adenoid cystic carcinoma.

DOI： 10.1002/cncy.22388

Solitary fibrous tumor/hemangiopericytoma treated with temozolomide plus bevacizumab: a report of four cases and literature review. Reviewed

Osamu Maeda, Fumiharu Ohka, Satoshi Maesawa, Ayumu Matsuoka, Tomoya Shimokata, Ayako Mitsuma, Hiroshi Urakawa, Shota Nakamura, Yoshie Shimoyama, Masato Nakaguro, Toshihiko Wakabayashi, Yuichi Ando

Nagoya journal of medical science Vol. 82 ( 4 ) page： 631 - 644 2020.11

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

Solitary fibrous tumor/hemangiopericytoma (SFT/HPC) is a rare tumor derived from mesenchymal tissue. Although standard chemotherapy for SHT/HPC has not been established, temozolomide plus bevacizumab (TMZ+Bev) therapy for SFT/HPC has been reported. The effectiveness and safety of TMZ+Bev (temozolomide 150 mg/m2 orally on days 1-7 and days 15-21 and bevacizumab 5 mg/kg intravenously on day 8 and day 22 on a 28-day cycle), which was administered from December 2013 until April 2019 to four patients with SFT/HPC, were retrospectively analyzed. Four patients with SFT/HPC received TMZ+Bev. The age of the patients ranged from 41 to 75 years. Two were male, and the primary tumor sites were the meninges in three patients and the pleura in one. One achieved partial response; the others, stable disease (SD). The progression-free survival time ranged from 9.4 to 29.6 months according to RECIST v1.1. One patient died 59 months after using TMZ+Bev, and the others survived for 17 to 64 months. All patients experienced Grade 3 or higher lymphopenia, and three had Grade 3 or higher leukopenia and neutropenia. One patient subsequently received doxorubicin; another, pazopanib. TMZ+Bev therapy for SFT/HPC is safe and effective for maintaining long-term SD.

DOI： 10.18999/nagjms.82.4.631

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

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

International journal of clinical oncology Vol. 25 ( 10 ) page： 1774 - 1785 2020.10

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

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

DOI： 10.1007/s10147-020-01731-9

Other Link： http://link.springer.com/article/10.1007/s10147-020-01731-9/fulltext.html

Salivary duct carcinoma: Updates in histology, cytology, molecular biology, and treatment. Reviewed International journal

Masato Nakaguro, Yuichiro Tada, William C Faquin, Peter M Sadow, Lori J Wirth, Toshitaka Nagao

Cancer cytopathology Vol. 128 ( 10 ) page： 693 - 703 2020.10

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

Salivary duct carcinoma (SDC) is an aggressive subtype of primary salivary gland carcinoma, often with an advanced stage at presentation and high rates of metastasis and recurrence. It most commonly arises in the parotid gland of older men and microscopically resembles high-grade breast ductal carcinoma. While 50 years have lapsed since the first report of this entity, recent intensive studies have shed light on its biologic, genetic, and clinical characteristics. The diagnosis of SDC is aided by the immunohistochemical expression of androgen receptor (AR) coupled with its characteristic histomorphology. Fine-needle aspiration typically reveals cytologic features of high-grade carcinoma, and ancillary studies using cell block material can facilitate the specific diagnosis of SDC. In surgical specimens, certain histologic features are important prognostic factors, including nuclear pleomorphism, mitotic counts, vascular invasion, and the morphology at the invasion front. Several clinical studies have shown promising results using targeted therapy for AR and human epidermal growth factor receptor 2 (HER2), and the latest version of the National Comprehensive Cancer Network guidelines recommends the evaluation of AR and HER2 status before treatment. Recent molecular analyses have revealed multiple heterogeneous alterations in well-known oncogenes and tumor suppressor genes, including TP53, HRAS, PIK3CA, PTEN, and BRAF. Clinical trials of drugs targeting these genes may broaden the treatment options for SDC in the near future.

DOI： 10.1002/cncy.22288

Microsecretory adenocarcinoma of the hard palate: A case report of a recently described entity. Reviewed International journal

Fumi Kawakami, Toshitaka Nagao, Yumi Honda, Junki Sakata, Ryoji Yoshida, Hideki Nakayama, Seijiro Inoue, Mika Kitajima, Osamu Ikeda, Masato Nakaguro, Yoshiki Mikami

Pathology international Vol. 70 ( 10 ) page： 781 - 785 2020.10

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

We report a case of microsecretory adenocarcinoma of the hard palate. The patient is a 37-year-old woman with a 15 mm submucosal tumor, which was incidentally found by her primary care dentist, in her hard palate. Preoperative magnetic resonance imaging revealed a tumor exhibiting high signal on T2-weighted image, which was gradually enhanced on dynamic study. Histologically, the tumor border was ill-defined without fibrous capsule and adjoined minor salivary gland with permeative infiltration at the tumor periphery. The tumor comprised intercalated duct-like cells with polygonal narrow eosinophilic to clear cytoplasm and small, uniform oval nuclei. These cells formed small infiltrative microcysts, tubules and fascicular cords collecting pale basophilic secretions and small vacuoles setting in an abundant fibromyxoid stroma. The tumor cells were positive for CK AE1+AE3, S-100 protein, and p63, while are completely negative for p40, alpha-SMA, and calponin. The MEF2C-SS18 fusion was identified by reverse transcriptase-polymerase chain reaction followed by Sanger sequencing. The combination of characteristic histology, immunophenotype, and presence of MEF2C-SS18 fusion indicated the diagnosis of microsecretory adenocarcinoma of the hard palate, an entity described only recently. Post-operative course was uneventful and there was no evidence of disease at 4 months after surgery.

DOI： 10.1111/pin.12987

Color information from linked color imaging is associated with invasion depth and vascular diameter in superficial esophageal squamous cell carcinoma

Kenichi Kobayashi, Ryoji Miyahara, Kohei Funasaka, Kazuhiro Furukawa, Tsunaki Sawada, Keiko Maeda, Takeshi Yamamura, Takuya Ishikawa, Eizaburo Ohno, Masanao Nakamura, Hiroki Kawashima, Masato Nakaguro, Yuki Okumura, Yoshiki Hirooka, Mitsuhiro Fujishiro

Gastroenterological Endoscopy Vol. 62 ( 9 ) page： 1624 - 1633 2020.9

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japan Gastroenterological Endoscopy Society

Objectives: Accurate diagnosis of invasion depth is important for reliable treatment of esophageal squamous cell carcinoma (ESCC), but it is limited to the muscularis mucosae to slight submucosal invasion (MM/SM1). The diagnostic accuracy of invasion depth is unsatisfactory and remains to be improved. We aimed to investigate the association between the color of the superficial ESCC and invasion depth using linked color imaging (LCI) under light-emitting diode (LED) light sources. Methods: Lesions diagnosed as superficial ESCC were observed using white light imaging and then by LCI. The color values were calculated using Commission Internationale de l’Eclariage - L＊a＊b＊ color space, and the color difference was calculated according to invasion depth. The vascular diameters and vascular angles of the intrapapillary capillary loops were pathologically analyzed. Their correlation with mucosal color was also investigated by LCI. Results: In all, 52 lesions from 48 patients were analyzed. On the basis of invasion depth, the color difference between the normal mucosa and the lesion was larger in the MM/SM1 or deeper group than in the epithelium and the lamina propria mucosa (EP/LPM) group using LCI (P=0.025). The vascular diameter was positively correlated with the b＊ color value (correlation coefficient=0.302, P=0.033). Conclusion: Observation using LCI under LED light sources may improve the endoscopic diagnosis of the invasion depth of superficial ESCC. Further research is needed to validate its usefulness.

DOI： 10.11280/gee.62.1624

表在型食道扁平上皮癌におけるLinked Color Imagingで観察される色情報と深達度および血管径との相関に関する検討 Reviewed

小林健一, 宮原良二, 舩坂好平, 古川和宏, 澤田つな騎, 前田啓子, 山村健史, 石川卓也, 大野栄三郎, 中村正直, 川嶋啓揮, 中黒匡人, 奥村結希, 廣岡芳樹, 藤城光弘

Gastroenterological Endoscopy Vol. 62 ( 9 ) page： 1624 - 1633 2020.9

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：(一社)日本消化器内視鏡学会

【背景】食道扁平上皮癌の治療方針決定に正確な深達度診断が重要であるが,MM/SM1の正診率は低く解決すべき課題となっている.本研究の目的はLED光源を用いたLCIにおける食道表在癌に対する色と深達度の関連性について検討することである.【方法】表在型食道癌と診断された病変に対し白色光につづいてLCIで観察を行った.色合いの評価についてはCIE-L*a*b*空間を用いて色値を算出し,深達度ごとの癌部と非癌部の色差を算出した.血管径およびintrapapillary capillary loopの分岐角を病理的に算出し,色合いとの相関を検討した.【結果】48症例52病変が登録された.深達度別の正常と病変部の色差において,MM/SM1以深群ではEP/LPM群に比べて有意に色差が大きかった(P=0.025).血管径はb*値と弱い正の相関を認めた(相関係数=0.302,P=0.033).【結論】LED光源を用いたLCI観察は,表在型食道癌における深達度診断の向上に有用である可能性があるが,その有用性を示すのにはさらなる検討が必要である.(著者抄録)

The clinicopathological significance of the adipophilin and fatty acid synthase expression in salivary duct carcinoma. Reviewed International journal

Hideaki Hirai, Yuichiro Tada, Masato Nakaguro, Daisuke Kawakita, Yukiko Sato, Tomotaka Shimura, Kiyoaki Tsukahara, Satoshi Kano, Hiroyuki Ozawa, Kenji Okami, Yuichiro Sato, Chihiro Fushimi, Akira Shimizu, Isaku Okamoto, Soichiro Takase, Takuro Okada, Hiroki Sato, Yorihisa Imanishi, Kuninori Otsuka, Yoshihiro Watanabe, Akihiro Sakai, Koji Ebisumoto, Takafumi Togashi, Yushi Ueki, Hisayuki Ota, Natsuki Saigusa, Hideaki Takahashi, Mizuo Ando, Makoto Urano, Toyoyuki Hanazawa, Toshitaka Nagao

Virchows Archiv : an international journal of pathology Vol. 477 ( 2 ) page： 291 - 299 2020.8

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

Salivary duct carcinoma (SDC) is an aggressive, uncommon tumor histologically comparable to high-grade mammary ductal carcinoma. SDCs are usually androgen receptor (AR)-positive and often HER2-positive. Recently, therapies targeting these molecules for SDC have attracted attention. Lipid metabolism changes have been described in association with biological behavior in various cancers, although no such relationship has yet been reported for SDC. We therefore analyzed the clinicopathological relevance of the immunohistochemical expression of adipophilin (ADP) and fatty acid synthase (FASN), representative lipid metabolism-related proteins, in 147 SDCs. ADP and FASN were variably immunoreactive in most SDCs (both 99.3%), and the ADP and FASN expression was negatively correlated (P = 0.014). ADP-positive (≥ 5%) SDCs more frequently exhibited a prominent nuclear pleomorphism and high-Ki-67 labeling index than those ADP-negative (P = 0.013 and 0.011, respectively). In contrast, a high FASN score, calculated by the staining proportion and intensity, (≥ 120) was correlated with the high expression of AR and FOXA1 (P < 0.001 and = 0.003, respectively). The ADP and FASN expression differed significantly among the subtypes based on biomarker immunoprofiling, as assessed by the AR, HER2, and Ki-67 status (P = 0.017 and 0.003, respectively). A multivariate analysis showed that ADP-positive expression was associated with a shorter overall and progression-free survival (P = 0.018 and 0.003, respectively). ADP was associated with an aggressive histopathology and unfavorable prognosis, and FASN may biologically interact with the AR signaling pathway in SDC. ADP may, therefore, be a new prognostic indicator and therapeutic target in SDC.

DOI： 10.1007/s00428-020-02777-w

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

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

Head & neck Vol. 42 ( 8 ) page： 1721 - 1727 2020.8

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

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

DOI： 10.1002/hed.26081

Steroid-responsive recurrent tumefactive demyelination with multiple petechial hemorrhages along non-displaced medullary veins. Reviewed International journal

Takashi Tsuboi, Yumiko Harada, Masashi Suzuki, Takashi Ando, Naoki Atsuta, Fumiharu Ohka, Kazuhito Takeuchi, Toshiaki Taoka, Shigeo Ohba, Masato Nakaguro, Masato Abe, Ichiro Nakashima, Mari Yoshida, Masahisa Katsuno

Clinical neurology and neurosurgery Vol. 193 page： 105764 - 105764 2020.6

A familial case of alveolar capillary dysplasia with misalignment of the pulmonary veins: the clinicopathological features and unusual glomeruloid endothelial proliferation. Reviewed International journal

Akiko Kitano, Masato Nakaguro, Seiichi Tomotaki, Shintaro Hanaoka, Masahiko Kawai, Akiko Saito, Masahiro Hayakawa, Yoshiyuki Takahashi, Hidenori Kawasaki, Takahiro Yamada, Masahiko Ikeda, Tetsuo Onda, Kazutoshi Cho, Hironori Haga, Atsuko Nakazawa, Sachiko Minamiguchi

Diagnostic pathology Vol. 15 ( 1 ) page： 48 - 48 2020.5

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

BACKGROUND: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare disorder of pulmonary vascular abnormality with persistent pulmonary hypertension of the newborn. The symptom usually presents within hours after birth, leading to an early demise. Heterozygous de novo point mutations and genomic deletions of the FOXF1 (forkhead box F1) gene or its upstream enhancer have been identified in most patients with ACD/MPV. Most cases of ACD/MPV are sporadic; however, familial cases are also reported in 10% of patients. CASE PRESENTATION: We herein report a case of familial ACD/MPV that showed unusual glomeruloid proliferation of endothelial cells. In this family, three of the four siblings died within two to 3 days after birth because of persistent pulmonary hypertension and respiratory failure. Only the second child remains alive and healthy. An autopsy was performed for the third and fourth children, resulting in a diagnosis of ACD/MPV based on the characteristic features, including misalignment of smaller pulmonary veins and lymphangiectasis. In both of these children, glomeruloid endothelial proliferation of vessels was noted in the interlobular septa. The vessels were immunohistochemically positive for D2-40, CD31, Factor VIII, and ERG, suggestive of differentiation for both lymphatic and blood vessels. CONCLUSIONS: Unusual glomeruloid endothelial proliferation was observed in a familial ACD/MPV case. This histologic feature has not been described previously in ACD/MPV or any other pulmonary disease. Although the histogenesis of this histologic feature is unclear, this finding may suggest that ACD/MPV is a compound vascular and lymphovascular system disorder that exhibits various histologic features.

DOI： 10.1186/s13000-020-00972-6

Enhanced performance of the Milan System for Reporting Salivary Gland Cytopathology: Point of view from an Asian country. Reviewed International journal

Kayoko Higuchi, Makoto Urano, Masato Nakaguro

Cancer cytopathology Vol. 128 ( 5 ) page： 305 - 306 2020.5

Prognostic Implication of Histopathologic Indicators in Salivary Duct Carcinoma: Proposal of a Novel Histologic Risk Stratification Model. Reviewed International journal

Masato Nakaguro, Yukiko Sato, Yuichiro Tada, Daisuke Kawakita, Hideaki Hirai, Makoto Urano, Tomotaka Shimura, Kiyoaki Tsukahara, Satoshi Kano, Hiroyuki Ozawa, Kenji Okami, Yuichiro Sato, Chihiro Fushimi, Akira Shimizu, Soichiro Takase, Takuro Okada, Hiroki Sato, Yorihisa Imanishi, Kuninori Otsuka, Yoshihiro Watanabe, Akihiro Sakai, Koji Ebisumoto, Takafumi Togashi, Yushi Ueki, Hisayuki Ota, Natsuki Saigusa, Hideaki Takahashi, Mizuo Ando, Toyoyuki Hanazawa, Toshitaka Nagao

The American journal of surgical pathology Vol. 44 ( 4 ) page： 526 - 535 2020.4

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

Salivary duct carcinoma (SDC) is a rare, aggressive malignancy that histologically resembles high-grade mammary duct carcinoma. Because of the rarity of this entity, data verifying the association between histologic features and patient survival are limited. We conducted a comprehensive histologic review of 151 SDC cases and performed an analysis of the association between various histomorphologic parameters and the clinical outcome with the aim of developing a histologic risk stratification model that predicts the prognosis of SDC patients. A multivariate analysis revealed that prominent nuclear pleomorphism (overall survival [OS]: P=0.013; progression-free survival [PFS]: P=0.019), ≥30 mitoses/10 HPF (PFS: P=0.013), high tumor budding (OS: P=0.011; PFS: P<0.001), and high poorly differentiated clusters (OS: P<0.001; PFS: P<0.001) were independent prognostic factors. Patients with vascular invasion demonstrated a marginally significant association with shorter PFS (P=0.064) in a multivariate analysis. We proposed a 3-tier histologic risk stratification model based on the total number of positive factors among 4 prognostically relevant parameters (prominent nuclear pleomorphism, ≥30 mitoses/10 HPF, vascular invasion, and high poorly differentiated clusters). The OS and PFS of patients with low-risk (0 to 1 point) (23% of cases), intermediate-risk (2 to 3 points) (54% of cases), and high-risk (4 points) (23% of cases) tumors progressively deteriorated in this order (hazard ratio, 2.13 and 2.28, and 4.99 and 4.50, respectively; Ptrend<0.001). Our histologic risk stratification model could effectively predict patient survival and may be a useful aid to guide clinical decision-making in relation to the management of patients with SDC.

DOI： 10.1097/PAS.0000000000001413

【免疫組織化学実践的な診断・治療方針決定のために】(第3部)腫瘍の鑑別に用いられる抗体(各臓器別) 唾液腺 Reviewed

中黒匡人, 長尾俊孝

病理と臨床 Vol. 38 ( 臨増 ) page： 84 - 93 2020.4

唾液腺導管癌におけるEZH2蛋白発現の臨床病理学的意義

平井秀明, 多田雄一郎, 川北大介, 中黒匡人, 三枝奈津季, 長尾俊孝

日本病理学会会誌 Vol. 109 ( 1 ) page： 290 - 290 2020.3

唾液腺導管癌におけるEZH2蛋白発現の臨床病理学的意義

平井秀明, 多田雄一郎, 川北大介, 中黒匡人, 三枝奈津季, 長尾俊孝

日本病理学会会誌 Vol. 109 ( 1 ) page： 290 - 290 2020.3

Syncytial variant of classic Hodgkin lymphoma: Four cases diagnosed with the aid of CD274/programmed cell death ligand 1 immunohistochemistry. Reviewed International journal

Kei Kohno, Ayako Sakakibara, Akari Iwakoshi, Masaki Hasegawa, Shiro Adachi, Eri Ishikawa, Yuka Suzuki, Satoko Shimada, Masato Nakaguro, Yoshie Shimoyama, Taishi Takahara, Emiko Takahashi, Akiko Ohashi, Akira Satou, Seiichi Kato, Naoko Asano, Shigeo Nakamura

Pathology international Vol. 70 ( 2 ) page： 108 - 115 2020.2

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

Although several reports have highlighted neoplastic PD-L1 (nPD-L1) expression in classic Hodgkin lymphoma (CHL), some have addressed associations between its expression and detailed histopathologic features. Here we describe four cases of syncytial variant of CHL (SV-CHL), with and without Epstein-Barr virus (EBV) association, and highlight the diagnostic utility of PD-L1 (clone SP142) immunohistochemistry. The patients were a 61-year-old male, 45-year-old male, 85-year-old female, and 89-year-old female. All presented with cervical or axillary lymphadenopathy, which on biopsy had the established histopathologic features of SV-CHL with a biphasic pattern of cohesive sheets of large tumor cells and typically scattered distribution of Hodgkin and Reed-Stenberg (HRS) cells. These tumor cells showed identical immunophenotypic findings for CD15, CD30, Fascin, PAX5, OCT2, BOB1 and EBV harboring, regardless of location. The exception was absent or decreased expression of nPD-L1 from tumor cells in the confluent sheets, contrasting with HRS cell positivity in typical areas of CHL. These findings offer the first suggestion of possible downregulation of nPD-L1 expression in association with the histopathologic progression of CHL. The results may be relevant for recognizing 'confluent' sheets in the diagnostic workup for SV-CHL.

DOI： 10.1111/pin.12888

Histopathological evaluation of minor salivary gland papillary-cystic tumours: focus on genetic alterations in sialadenoma papilliferum and intraductal papillary mucinous neoplasm. Reviewed International journal

Masato Nakaguro, Makoto Urano, Ikuko Ogawa, Hideaki Hirai, Yoshinari Yamamoto, Hiroshi Yamaguchi, Maki Tanigawa, Jun Matsubayashi, Hiroshi Hirano, Junji Shibahara, Yuichiro Tada, Toyonori Tsuzuki, Yasuo Okada, Yuichiro Sato, Kenichiro Ikeda, Aoi Sukeda, Yumi Honda, Yoshiki Mikami, Toshitaka Nagao

Histopathology Vol. 76 ( 3 ) page： 411 - 422 2020.2

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

AIMS: Minor salivary gland tumours showing a predominant papillary-cystic structure are rare, and constitute a mixture of various types of neoplasm; thus, the histopathological assessment of these tumours poses a significant diagnostic challenge. We aimed to delineate the histological characteristics of these tumours and further mutational aspects with a particular focus on sialadenoma papilliferum (SP) and intraductal papillary mucinous neoplasm (IPMN). METHODS AND RESULTS: We retrieved 28 papillary-cystic tumours of the minor salivary glands, and performed histological re-evaluation and mutation analyses of several key oncogenes. The histological classifications were as follows: SP (n = 10), SP-like intraductal papillary tumour (SP-IPT) (n = 2), IPMN (n = 9), intraductal papilloma, cystadenoma, and cystadenocarcinoma (two, three and two respectively). Whereas SP typically consisted of a combination of exophytic squamous epithelium and endophytic intraductal papillary infoldings, SP-IPT lacked the exophytic component. SP and SP-IPT frequently harboured BRAF V600E mutations (75.0%), which were identified in both squamous and ductal components. IPMN was characterised by a well-demarcated cystic lesion filled exclusively with a papillary proliferation of mucinous cells and a high rate of AKT1 E17K mutations (88.9%). Intraductal papillomas were unilocular cystic lesions with intraluminal papillary growth of bland columnar cells. In contrast, both cystadenomas and cystadenocarcinomas showed a multicystic appearance with a papillary configuration. Cystadenocarcinomas invaded the surrounding tissue and were composed of markedly atypical tumour cells. CONCLUSION: The appropriate interpretation of histological findings and specific genetic alterations (e.g. BRAF V600E and AKT1 E17K in SP and IPMN) would be useful for the correct diagnosis of minor salivary gland papillary-cystic tumours.

DOI： 10.1111/his.13990

Diagnostic utility of programmed cell death ligand 1 (clone SP142) in mediastinal composite lymphoma: A report of two cases. Reviewed International journal

Ayako Sakakibara, Kei Kohno, Akari Iwakoshi, Suzuko Moritani, Aya Fujishiro, Katsuyuki Kito, Yuka Suzuki, Satoko Shimada, Masato Nakaguro, Yoshie Shimoyama, Taishi Takahara, Emiko Takahashi, Akiko Ohashi, Akira Satou, Seiichi Kato, Naoko Asano, Shigeo Nakamura

Pathology international Vol. 70 ( 2 ) page： 116 - 122 2020.2

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

Composite lymphoma is a well-known diagnostic entity exhibiting the synchronous occurrence of two or more distinct types of lymphomas in the same specimen. Here we report two patients, a 14-year-old female (Case 1) and a 45-year-old male (Case 2), with mediastinal composite lymphoma, comprising nodular sclerosis classic Hodgkin lymphoma (NSCHL) and primary mediastinal large B-cell lymphoma (PMBL). Both patients had a mediastinal mass, and manifested two different histologic components in the same biopsy, one characteristic of NSCHL and the other PMBL. The NSCHL areas included Hodgkin and Reed-Sternberg (HRS) cells with typical immunophenotypic features (CD30-positive and CD20-negative), whereas the sheets of large tumor cells characteristic of PMBL were strongly and uniformly CD20-positive. Interestingly, although both cases showed neoplastic PD-L1 (nPD-L1) positivity on the HRS cells of NSCHL, they differed regarding nPD-L1 expression on the PMBL tumor cells. In Case 1, the nPD-L1-negative PMBL component was anatomically situated outside the NSCHL lesion. On the other hand, in Case 2, the nPD-L1-positive PMBL component was characterized by transitional or continuous areas with the NSCHL component. These findings suggested that nPD-L1 expression may define two subtypes of PMBL that are more similar to or distinct from classic Hodgkin lymphoma.

DOI： 10.1111/pin.12891

唾液腺腫瘍における遺伝子異常と病理診断 Invited

中黒匡人, 長尾俊孝

病理と臨床 Vol. 38 ( 1 ) page： 79-83 2020.1

Giant cell myocarditis with central diabetes insipidus: A case report. Reviewed

Shogo Yamaguchi, Akinori Sawamura, Masato Nakaguro, Yoshie Shimoyama, Ryota Morimoto, Hiroo Kato, Yoshihito Arao, Hideo Oishi, Tomoaki Haga, Tasuku Kuwayama, Tsuyoshi Yokoi, Hiroaki Hiraiwa, Toru Kondo, Takahiro Okumura, Toyoaki Murohara

Journal of cardiology cases Vol. 21 ( 1 ) page： 8 - 11 2020.1

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

A 51-year-old male, previously diagnosed with central diabetes insipidus due to lymphocytic hypophysitis, presented with fever and dyspnea for 1 week. On arrival, he exhibited hypotension (85/60 mmHg) and sinus tachycardia (110 bpm). His electrocardiogram revealed mild ST elevation on V2-V4. Echocardiography indicated a near-normal (50%) left ventricular ejection fraction (LVEF), although the inferior wall of the left ventricle exhibited severe hypokinesis. Fulminant myocarditis and circulatory insufficiency were suspected, and treatment with dobutamine, 3 μg/kg/min, was started. His LVEF gradually decreased to 20%. On day 17, he developed cardiogenic shock due to ventricular tachycardia and underwent peripheral venous-arterial extracorporeal membrane oxygenation and intra-aortic balloon pumping. Although he did not exhibit polyuria, intravenous vasopressin infusion (0.5 U/h) was performed to maintain normonatremia. Endomyocardial biopsy results revealed the infiltration of scattered giant cells (GCs) and extensive lymphocytes. Despite immunosuppressive therapy (methylprednisolone and cyclosporine), his cardiac function did not recover. On day 36, he received a biventricular assist device; however, he died on day 47 due to the progression of sepsis and multiple organ failure. We speculate that a deficient expression of programmed cell death protein-1 was the cause of both GC myocarditis and lymphocytic hypophysitis. <Learning objective: We describe a fatal case of fulminant giant cell myocarditis complicated by central diabetes insipidus due to lymphocytic hypophysitis. Normonatremia was maintained with intravenous vasopressin 0.5 U/h, and circulatory status was maintained with mechanical circulatory support. We speculate that T-cell programmed cell death protein 1 dysregulation was the common cause of the two disorders.>.

DOI： 10.1016/j.jccase.2019.08.011

Color information from linked color imaging is associated with invasion depth and vascular diameter in superficial esophageal squamous cell carcinoma. Reviewed International journal

Kenichi Kobayashi, Ryoji Miyahara, Kohei Funasaka, Kazuhiro Furukawa, Tsunaki Sawada, Keiko Maeda, Takeshi Yamamura, Takuya Ishikawa, Eizaburo Ohno, Masanao Nakamura, Hiroki Kawashima, Masato Nakaguro, Yuki Okumura, Yoshiki Hirooka, Mitsuhiro Fujishiro

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society Vol. 32 ( 1 ) page： 65 - 73 2020.1

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

OBJECTIVES: Accurate diagnosis of invasion depth is important for reliable treatment of esophageal squamous cell carcinoma (ESCC), but it is limited to the muscularis mucosae to slight submucosal invasion (MM/SM1). The diagnostic accuracy of invasion depth is unsatisfactory and remains to be improved. We aimed to investigate the association between the color of the superficial ESCC and invasion depth using linked color imaging (LCI) under light-emitting diode (LED) light sources. METHODS: Lesions diagnosed as superficial ESCC were observed using white light imaging and then by LCI. The color values were calculated using Commission Internationale de l'Eclariage - L*a*b* color space, and the color difference was calculated according to invasion depth. The vascular diameters and vascular angles of the intrapapillary capillary loops were pathologically analyzed. Their correlation with mucosal color was also investigated by LCI. RESULTS: In all, 52 lesions from 48 patients were analyzed. On the basis of invasion depth, the color difference between the normal mucosa and the lesion was larger in the MM/SM1 or deeper group than in the epithelium and the lamina propria mucosa (EP/LPM) group using LCI (P = 0.025). The vascular diameter was positively correlated with the b* color value (correlation coefficient = 0.302, P = 0.033). CONCLUSION: Observation using LCI under LED light sources may improve the endoscopic diagnosis of the invasion depth of superficial ESCC. Further research is needed to validate its usefulness. (UMIN000024615).

DOI： 10.1111/den.13469

Calculating the Tumor Nuclei Content for Comprehensive Cancer Panel Testing. Reviewed International journal

Masashi Mikubo, Katsutoshi Seto, Atsuko Kitamura, Masato Nakaguro, Yukinori Hattori, Nagako Maeda, Tatsuhiko Miyazaki, Kazuko Watanabe, Hideki Murakami, Tetsuya Tsukamoto, Tetsuya Yamada, Shiro Fujita, Katsuhiro Masago, Shakti Ramkissoon, Jeffrey S Ross, Julia Elvin, Yasushi Yatabe

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Vol. 15 ( 1 ) page： 130 - 137 2020.1

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

Comprehensive genetic panel testing generally requires that the analyzed tissues have a percent tumor nuclei (%TN) content of 20% or more to achieve assay performance comparable to the validated specifications. Pathologists play a crucial role in ensuring that the optimal results are achieved by accurately assigning %TN content of the available specimens and selecting the best material to submit for sequencing. This study addresses the issues in evaluating %TN, such as intraobserver variability, and examines whether focused training and feedback can improve pathologist performance. Nine referring institution pathologists (all board-certified and working at the core institute and the alignment hospitals under the National Cancer Genome scheme) evaluated 18 tumors that had been subjected to comprehensive genetic panel testing with the FoundationOne CDx assay. The %TN estimates provided by referring institution pathologists were compared with two standards: %TN assigned by the tumor sequencing institution's pathologist (a board-certified pathologist at Foundation Medicine, Inc.) and the computational %TN estimated from the mutant allele frequencies after sequencing was completed. The pathologists generally overestimated %TN in the first pretraining round of the evaluation, and the differences in the averaged %TN from the tumor sequencing institution and computational standards were statistically significant. However, the posttraining second-round results became significantly concordant with the standards. This study suggests that %TN content is empirically overestimated but the evaluation skill can be improved by providing a training and feedback program.

DOI： 10.1016/j.jtho.2019.09.081

唾液腺腫瘍における遺伝子異常と病理診断

中黒匡人, 長尾俊孝

病理と臨床 Vol. 38 ( 1 ) page： 79 - 83 2020.1

Multi-scale Domain-adversarial Multiple-instance CNN for Cancer Subtype Classification with Unannotated Histopathological Images Reviewed

Noriaki Hashimoto, Daisuke Fukushima, Ryoichi Koga, Yusuke Takagi, Kaho Ko, Kei Kohno, Masato Nakaguro, Shigeo Nakamura, Hidekata Hontani, Ichiro Takeuchi

2020 IEEE/CVF Conference on Computer Vision and Pattern Recognition (CVPR) page： 3851 - 3860 2020

Genetic Diagnosis Based on a Comprehensive Fusion Gene Analysis of Pediatric Malignant Solid Tumors Reviewed

Daisuke Ichikawa, Hideki Muramatsu, Yusuke Okuno, Motoharu Hamada, Rieko Taniguchi, Eri Nishikawa, Nozomu Kawashima, Atsushi Narita, Nobuhiro Nishio, Yoshie Shimoyama, Masato Nakaguro, Shigeo Nakamura, Seiji Kojima, Atsuko Nakazawa, Yoshiyuki Takahashi

PEDIATRIC BLOOD & CANCER Vol. 66 page： S61 - S61 2019.12

唾液腺導管癌における脂質関連蛋白発現の臨床病理学的意義 Reviewed

平井秀明, 多田雄一郎, 中黒匡人, 川北大介, 佐藤由紀子, 志村智隆, 塚原清彰, 加納里志, 小澤宏之, 大上研二, 佐藤雄一郎, 伏見千宙, 清水顕, 高瀬総一郎, 岡田拓朗, 佐藤宏樹, 今西順久, 大塚邦憲, 渡部佳弘, 酒井昭博, 戎本浩史, 富樫孝文, 植木雄志, 太田久幸, 三枝奈津季, 高橋秀聡, 安藤瑞生, 浦野誠, 花澤豊行, 長尾俊孝

日本唾液腺学会誌 Vol. 60 page： 24 - 25 2019.11

がんパネルシーケンスにおける病理所見と遺伝子変異頻度から判定した腫瘍細胞核含有量の比較 Reviewed

真砂勝泰, 瀬戸克年, 北村淳子, 中黒匡人, 服部行紀, 前田永子, 宮崎龍彦, 渡邊和子, 村上秀樹, 塚本徹哉, 山田鉄也, 藤田史郎, 谷田部恭

肺癌 Vol. 59 ( 6 ) page： 918 - 918 2019.11

BK virus-associated viruria and viremia in a patient with lymphangioleiomyomatosis after lung re-transplantation: A case report and review of the literature on BK virus infection post-lung transplantation. Reviewed International journal

Junya Okumura, Yoshio Nakahara, Masato Nakaguro, Yuichiro Shindo, Tetsunari Hase, Keiko Wakahara, Naozumi Hashimoto, Yoshinori Hasegawa

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy Vol. 25 ( 10 ) page： 820 - 824 2019.10

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

The BK virus (BKV) is a member of the polyomaviridae family of DNA viruses. BKV reactivates under a highly immunosuppressed state and causes renal dysfunction. In renal transplant patients, BKV infection leads to tubular impairment and loss of transplanted kidney grafts. However, few studies have reported on the relationship between BKV and lung transplantation. Adjustment of the dosage of immunosuppressants is needed in some cases, but the treatment method has not been established. Here, we report a case of BKV-associated viruria and viremia in a patient with lymphangioleiomyomatosis (LAM) after lung re-transplantation. A 44-year-old female refractory LAM patient who had undergone lung re-transplantation 3 months earlier was diagnosed with BKV-associated viruria and viremia. Urine cytology indicated decoy cells and the urine and serum polymerase chain reaction test was positive for BKV. As scheduled after re-transplantation surgery, immunosuppressive drugs were progressively reduced. This patient was considered to have experienced spontaneous BKV-associated viremia and viruria. Review of the literature suggested that 17%-42% of BKV-associated viruria cases have been reported after lung transplantation, but cases of BKV-associated nephropathy are rarely reported. Based on the present case, doctors involved in lung transplantation should monitor patients for BKV infection. Decoy cell monitoring by urine cytology is a useful screening method in the follow-up observation after lung transplantation. Early-stage interventions may prevent BKV-associated nephropathy even in patients who have developed BKV viremia, and sirolimus can be administered to patients with histories of BKV infection if they are carefully monitored.

DOI： 10.1016/j.jiac.2019.04.002

ちょっと気になる胆・膵画像ティーチングファイルから(第43回) 術前診断が困難であった膵lymphangiomaの1例 Reviewed

小川浩, 竹原康雄, 長縄慎二, 高見秀樹, 中黒匡人

胆と膵 Vol. 40 ( 10 ) page： 841 - 844 2019.10

Fatal case of TAFRO syndrome associated with over-immunosuppression: a case report and review of the literature. Reviewed

Takaharu Matsuhisa, Noriyuki Takahashi, Masato Nakaguro, Motoki Sato, Eri Inoue, Shiho Teshigawara, Yukihiro Ozawa, Takeshi Kondo, Shigeo Nakamura, Juichi Sato, Nobutaro Ban

Nagoya journal of medical science Vol. 81 ( 3 ) page： 519 - 528 2019.8

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

TAFRO syndrome is a novel disease concept characterized by Thrombocytopenia, Anasarca, myeloFibrosis, Renal dysfunction, Organomegaly, multiple lymphadenopathy and a histopathological pattern of atypical Castleman's disease. A 58-year-old man was diagnosed as TAFRO syndrome by clinical and histopathological findings. After receiving intensive immunosuppressive therapy, his thrombocytopenia and anasarca had not improved. He developed complications such as methicillin-resistant Staphylococcus aureus sepsis, gastrointestinal bleeding, peritonitis caused by Stenotrophomonas maltophilia, gastrointestinal perforation, and disseminated candidiasis resulting in death. Autopsy revealed disseminated candidiasis and hemophagocytic lymphohistiocytosis, with no evidence of TAFRO syndrome. During treatment, we regarded his lasting thrombocytopenia and anasarca as insufficient control of TAFRO syndrome. However, the autopsy revealed that thrombocytopenia was caused by secondary hemophagocytic lymphohistiocytosis caused by over-immunosuppression. We reviewed the published literature to identify indicators of adequate treatment, which suggested improvement of platelet count and anasarca several weeks after initial therapy. This indicated that we could not depend on the platelet count and anasarca in acute medical care after initial treatment. We should treat TAFRO syndrome based on patients' clinical status and obviate the risk of treatment-related complications caused by over-immunosuppression.

DOI： 10.18999/nagjms.81.3.519

Diagnostic Significance of HRAS Mutations in Epithelial-Myoepithelial Carcinomas Exhibiting a Broad Histopathologic Spectrum. Reviewed International journal

Makoto Urano, Masato Nakaguro, Yoshinari Yamamoto, Hideaki Hirai, Maki Tanigawa, Natsuki Saigusa, Akira Shimizu, Kiyoaki Tsukahara, Yuichiro Tada, Kouhei Sakurai, Madoka Isomura, Yuki Okumura, Hiroshi Yamaguchi, Jun Matsubayashi, Toshitaka Nagao

The American journal of surgical pathology Vol. 43 ( 7 ) page： 984 - 994 2019.7

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

Epithelial-myoepithelial carcinoma (EMC) is a rare salivary gland tumor that is histologically characterized by biphasic tubular structures composed of inner ductal and outer clear myoepithelial cells. Because of its histologic variety, it is sometimes challenging to make an accurate diagnosis, and useful ancillary tests are essential for this purpose. We investigated 87 cases of EMC arising in the major and minor salivary glands and seromucinous glands in the nasal cavity or bronchus to describe the histologic features and mutation status of selected key oncogenes. Classic EMC accounted for 40.2% of all cases. Other cases showed various growth patterns and cytologic features in addition to the typical histology; cribriform patterns, a basaloid appearance, and sebaceous differentiation were relatively common (17.2% to 18.4%), whereas oncocytic/apocrine, papillary-cystic, double-clear, squamous, psammomatous, Verocay-like, and high-grade transformation were rare. HRAS mutations were found in 82.7% of EMCs and were concentrated in codon 61. There was no significant correlation between the HRAS mutation status and the histology. No EMC ex pleomorphic adenoma cases had HRAS mutations. PIK3CA and/or AKT1 mutations were the second most frequent mutations (20.7%, 6.5%, respectively) and almost always cooccurred with HRAS mutations. It is noteworthy that the HRAS mutation was not identified in any salivary gland tumor entities manifesting EMC-like features, including adenoid cystic carcinoma, pleomorphic adenoma, basal cell adenoma/adenocarcinoma, and myoepithelial carcinoma. We conclude that HRAS mutations are a frequent tumorigenic gene alteration in EMC, despite its histologic diversity. This study provides further insight into strategies for diagnosing EMC and discriminating it from its mimics.

DOI： 10.1097/PAS.0000000000001258

A case of human pancreatic eurytremiasis Reviewed

Ogawa Hiroshi, Takehara Yasuo, Naganawa Shinji, Yamaguchi Junpei, Nakaguro Masato

ABDOMINAL RADIOLOGY Vol. 44 ( 4 ) page： 1213-1216 2019.4

Acrodermatitis continua of Hallopeau with dense infiltration of IgG<sub>4</sub> -positive cells in the lesional dermis. Reviewed International journal

Ogawa-Momohara M, Muro Y, Nakaguro M, Takeichi T, Kono M, Akiyama M

The British journal of dermatology Vol. 180 ( 4 ) page： 941 - 942 2019.4

Utility of linked color imaging for endoscopic diagnosis of early gastric cancer. Reviewed International journal

Toshihisa Fujiyoshi, Ryoji Miyahara, Kohei Funasaka, Kazuhiro Furukawa, Tsunaki Sawada, Keiko Maeda, Takeshi Yamamura, Takuya Ishikawa, Eizaburo Ohno, Masanao Nakamura, Hiroki Kawashima, Masato Nakaguro, Masahiro Nakatochi, Yoshiki Hirooka

World journal of gastroenterology Vol. 25 ( 10 ) page： 1248 - 1258 2019.3

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

BACKGROUND: Linked color imaging (LCI) is a method of endoscopic imaging that emphasizes slight differences in red mucosal color. AIM: To evaluate LCI in diagnostic endoscopy of early gastric cancer and to compare LCI and pathological findings. METHODS: Endoscopic images were obtained for 39 patients (43 lesions) with early gastric cancer. Three endoscopists evaluated lesion recognition with white light imaging (WLI) and LCI. Color values in Commission Internationale de l'Eclairage (CIE) 1976 L*a*b* color space were used to calculate the color difference (ΔE) between cancer lesions and non-cancer areas. After endoscopic submucosal dissection, blood vessel density in the surface layer of the gastric epithelium was evaluated pathologically. The identical region of interest was selected for analyses of endoscopic images (WLI and LCI) and pathological analyses. RESULTS: LCI was superior for lesion recognition (P < 0.0001), and ΔE between cancer and non-cancer areas was significantly greater with LCI than WLI (29.4 vs 18.6, P < 0.0001). Blood vessel density was significantly higher in cancer lesions (5.96% vs 4.15%, P = 0.0004). An a* cut-off of ≥ 24 in CIE 1976 L*a*b* color space identified a cancer lesion using LCI with sensitivity of 76.7%, specificity of 93.0%, and accuracy of 84.9%. CONCLUSION: LCI is more effective for recognition of early gastric cancer compared to WLI as a result of improved visualization of changes in redness. Surface blood vessel density was significantly higher in cancer lesions, and this result is consistent with LCI image analysis.

DOI： 10.3748/wjg.v25.i10.1248

The Immunohistochemical Features of Ectopic Hamartomatous "Thymoma" are Different from Those of Spindle Cell Thymoma Reviewed

Okumura Yuki, Matsubayashi Jun, Nakanishi Hayao, Nagao Toshitaka, Nakamura Shigeo, Nakaguro Masato

MODERN PATHOLOGY Vol. 32 page： . 2019.3

The Immunohistochemical Features of Ectopic Hamartomatous "Thymoma" are Different from Those of Spindle Cell Thymoma Reviewed

Okumura Yuki, Matsubayashi Jun, Nakanishi Hayao, Nagao Toshitaka, Nakamura Shigeo, Nakaguro Masato

LABORATORY INVESTIGATION Vol. 99 page： . 2019.3

Proposal for a new classification for perihilar cholangiocarcinoma based on tumour depth Reviewed

Shinohara K., Ebata T., Shimoyama Y., Nakaguro M., Mizuno T., Matsuo K., Nagino M.

BRITISH JOURNAL OF SURGERY Vol. 106 ( 4 ) page： 427 - 435 2019.3

High Rate of BRAF V600E Mutation in Sialadenoma Papilliferum and Its Diagnostic Significance Reviewed

Nakaguro Masato, Urano Makoto, Ogawa Ikuko, Yamamoto Yoshinari, Yokotsuka Mayumi, Nagao Toshitaka

MODERN PATHOLOGY Vol. 32 page： . 2019.3

Diagnostic Yield of HRAS Mutations in Epithelial-Myoepithelial Carcinoma Exhibiting a Broad Histopathological Spectrum Reviewed

Urano Makoto, Nakaguro Masato, Hirai Hideaki, Tanigawa Maki, Tsukahara Kiyoaki, Tada Yuichiro, Nagao Toshitaka

MODERN PATHOLOGY Vol. 32 page： . 2019.3

Diagnostic Yield of HRAS Mutations in Epithelial-Myoepithelial Carcinoma Exhibiting a Broad Histopathological Spectrum Reviewed

Urano Makoto, Nakaguro Masato, Hirai Hideaki, Tanigawa Maki, Tsukahara Kiyoaki, Tada Yuichiro, Nagao Toshitaka

LABORATORY INVESTIGATION Vol. 99 page： . 2019.3

High Rate of BRAF V600E Mutation in Sialadenoma Papilliferum and Its Diagnostic Significance Reviewed

Nakaguro Masato, Urano Makoto, Ogawa Ikuko, Yamamoto Yoshinari, Yokotsuka Mayumi, Nagao Toshitaka

LABORATORY INVESTIGATION Vol. 99 page： . 2019.3

画像診断と病理膵上皮内腫瘍性病変

小川浩, 岩野信吾, 長縄慎二, 中黒匡人

画像診断 Vol. 39 ( 2 ) page： 142 - 143 2019.1

The high expression of FOXA1 is correlated with a favourable prognosis in salivary duct carcinomas: a study of 142 cases. Reviewed International journal

Makoto Urano, Hideaki Hirai, Yuichiro Tada, Daisuke Kawakita, Tomotaka Shimura, Kiyoaki Tsukahara, Satoshi Kano, Hiroyuki Ozawa, Kenji Okami, Yuichiro Sato, Chihiro Fushimi, Akira Shimizu, Soichiro Takase, Takuro Okada, Hiroki Sato, Yorihisa Imanishi, Kuninori Otsuka, Yoshihiro Watanabe, Akihiro Sakai, Koji Ebisumoto, Takafumi Togashi, Yushi Ueki, Hisayuki Ota, Yukiko Sato, Natsuki Saigusa, Masato Nakaguro, Toyoyuki Hanazawa, Toshitaka Nagao

Histopathology Vol. 73 ( 6 ) page： 943 - 952 2018.12

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

AIMS: Salivary duct carcinoma (SDC) is an uncommon, aggressive tumour that, histologically, resembles high-grade mammary ductal carcinoma, and is characterised by the expression of androgen receptor (AR). The androgen signalling pathway, a potential therapeutic target, can be regulated by FOXA1. This study aimed to evaluate the clinicopathological implications of FOXA1 in SDC. METHODS AND RESULTS: We examined the relationship between the immunoexpression of FOXA1 and FOXA1 mutations and clinicopathological factors, including the biomarker status and clinical outcome, in 142 SDCs. FOXA1 was expressed in 128 SDCs (90.1%); the immunoexpression was heterogeneous. SDCs with a higher FOXA1 labelling index (LI) (≥20%) more frequently showed less advanced tumors on T classification (P = 0.002). FOXA1 LI was correlated positively with the AR expression value (r = 0.430, P < 0.001). PI3K and p-mTOR positivity, and intact-PTEN, were associated with a higher FOXA1 LI. Twenty-two of 121 SDCs (18.2%) harboured FOXA1 gene mutations at the flanking regions in and around the forkhead DNA binding domain; however, the given gene mutation and the expression of FOXA1 were not significantly correlated. A multivariate analysis revealed that SDCs with a higher FOXA1 LI were associated with longer overall survival and progression-free survival (P = 0.029 and 0.016, respectively). CONCLUSIONS: In SDC, FOXA1, which may biologically interact with the AR and PI3K signalling pathways, is a putative biomarker that may be associated with a favourable prognosis. Further studies are needed to apply the findings to the development of targeted personalised therapy for patients with SDC.

DOI： 10.1111/his.13706

Neuroendocrine cells associated with endocrine mucin-producing sweat gland carcinoma - a potential precursor lesion? Reviewed

Kawasaki T, Kubota T, Arai E, Ichihara S, Yata K, Nakaguro M, Kuroda M, Katoh R, Takahashi M, Horibe K, Naoe T, Hasebe T

VIRCHOWS ARCHIV Vol. 473 page： S182 2018.9

Low-grade intraductal carcinoma of the salivary gland with prominent oncocytic change: a newly described variant. Reviewed International journal

Nakaguro M, Urano M, Suzuki H, Yamada K, Sakaguchi A, Ogura K, Matsumoto T, Ono N, Asato T, Mikami Y, Imai H, Nagao T

Histopathology Vol. 73 ( 2 ) page： 314 - 320 2018.8

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

AIMS: Low-grade intraductal carcinoma (LG-IDC) is a clinically indolent malignant tumour of the salivary glands. Because of its rarity, the histological variants of LG-IDC have not been well characterised. Herein, we describe five LG-IDC cases with prominent oncocytic change in the major salivary glands. METHODS AND RESULTS: We examined five cases, three males and two females (mean age = 63 years), of LG-IDC with oncocytic change. The sites affected by LG-IDC were the parotid and submandibular glands. The lesions were macroscopically unilocular or multilocular cysts with a solid tumour arising from the cyst wall. Smaller tumour cell nests were also observed. As with classic LG-IDC, the cyst wall was surrounded by myoepithelial cells with no invasive component. The tumour cells had abundant oncocytic cytoplasm and proliferated in a low-papillary, tubular or cribriform pattern. Immunohistochemically, the tumour cells were diffusely positive for pan-cytokeratin, S100, mammaglobin and antimitochondria antibody, and were negative for androgen receptor and gross cystic disease fluid protein-15. Unlike classic LG-IDC, some of these cases demonstrated focal invagination of myoepithelial cells in the intraductal tumour. CONCLUSION: Oncocytic LG-IDC should be recognised as a histologically unique variant of LG-IDC. Awareness of this entity is important to avoid erroneous diagnosis and inappropriate treatment for histological mimics.

DOI： 10.1111/his.13517

β-catenin (CTNNB1) mutation and LEF1 expression in sinonasal glomangiopericytoma (sinonasal-type hemangiopericytoma) Reviewed

Yuka Suzuki, Shu Ichihara, Tomonori Kawasaki, Hiroyuki Yanai, Satoshi Kitagawa, Yoshie Shimoyama, Shigeo Nakamura, Masato Nakaguro

Virchows Archiv Vol. 473 ( 2 ) page： 235 - 239 2018.8

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

Sinonasal glomangiopericytoma (SN-GPC) is an uncommon mesenchymal tumor with myoid differentiation. Recently, mutations in exon 3 of the gene coding for β-catenin (CTNNB1) and its nuclear expression were discovered in SN-GPC. β-catenin protein is a key regulatory molecule of the canonical Wnt signaling pathway. The expression of β-catenin target proteins is not well characterized in SN-GPC. We examined three SN-GPCs by immunohistochemistry and CTNNB1 mutation analysis. All cases expressed nuclear β-catenin. We identified CTNNB1 exon 3 mutations in two analyzable cases. Lymphoid enhancer-binding factor 1 (LEF1), a protein downstream from β-catenin, was also expressed in all cases. Our results further characterized the activation of the Wnt signaling pathway caused by CTNNB1 exon 3 mutation and suggest the utility of LEF1 immunohistochemistry in the differential diagnosis of SN-GPC.

DOI： 10.1007/s00428-018-2370-9

Immunohistochemical assessment of the diagnostic utility of PD-L1: a preliminary analysis of anti-PD-L1 antibody (SP142) for lymphoproliferative diseases with tumour and non-malignant Hodgkin-Reed-Sternberg (HRS)-like cells. Reviewed International journal

Ayako Sakakibara, Kei Kohno, Ahmed E Eladl, Teerada Klaisuwan, Eri Ishikawa, Yuka Suzuki, Satoko Shimada, Masato Nakaguro, Yoshie Shimoyama, Taishi Takahara, Seiichi Kato, Naoko Asano, Shigeo Nakamura, Akira Satou

Histopathology Vol. 72 ( 7 ) page： 1156 - 1163 2018.6

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

AIMS: The programmed death 1 (PD1)/PD1 ligand (PD-L1) axis plays an important role in tumour cells escape from immune control. PD-L1 immunohistochemistry is a useful predictor of immunotherapy response, but is still not used widely in the diagnostic setting. Here we describe results using PD-L1 immunohistochemistry during routine diagnostics in lymphoma. METHODS AND RESULTS: Ninety-one lymphoproliferative disease cases sharing tumour and non-malignant Hodgkin-Reed-Sternberg (HRS)-like cells with and without Epstein-Barr virus (EBV) association were investigated by immunohistochemistry for PD-L1 (clone SP142). PD-L1 expression was present in more than 5% of tumour or non-malignant HRS-like cells in 100% of EBV+ classical (C) Hodgkin lymphoma (HL) (n = 10) and EBV-negative nodular sclerosis CHL (n = 8); 40% of EBV+ diffuse large B cell lymphoma, not otherwise specified (DLBCL-NOS) (n = 20); and 4% of nodal peripheral T cell lymphoma of follicular helper T cell type (PTCL-TFH) (n = 22). In contrast, nodular lymphocyte-predominant HL (n = 4), lymphocyte-rich CHL (n = 6), EBV+ hyperplasia (n = 8), plasmablastic lymphoma (n = 3) and anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (n = 5) seldom exhibited PD-L1 in their large cells. Assessing PD-L1 positivity in tumour and non-malignant large cells was helpful in differentiating between CHL versus nodal PTCL-TFH (P < 0.0001) or EBV+ DLBCL-NOS (P = 0.0052) and between EBV+ DLBCL-NOS versus nodal PTCL-TFH (P = 0.0052), with PD-L1 expression indicating the first diagnosis in each of those sets. CONCLUSION: Immunohistochemical evaluation of PD-L1 expression in tumour and non-malignant HRS-like large cells may be useful for assessing either immune escape or immunodeficiency in their pathogenesis.

DOI： 10.1111/his.13475

Late-Onset Fulminant Myocarditis With Immune Checkpoint Inhibitor Nivolumab Reviewed

Shogo Yamaguchi, Ryota Morimoto, Takahiro Okumura, Yuta Yamashita, Tomoaki Haga, Tasuku Kuwayama, Tsuyoshi Yokoi, Hiroaki Hiraiwa, Toru Kondo, Yuki Sugiura, Naoki Watanabe, Naoaki Kano, Kei Kohno, Kenji Fukaya, Akinori Sawamura, Kenji Yokota, Hideki Ishii, Masato Nakaguro, Masashi Akiyama, Toyoaki Murohara

Canadian Journal of Cardiology Vol. 34 ( 6 ) page： 812.e1 - 812.e3 2018.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier Inc.

A 60-year-old man was diagnosed with melanoma. After receiving 13 infusions of nivolumab, he had fulminant myocarditis. The myocardial biopsy specimen revealed extensive lymphocytic infiltration, interstitial edema, and myocardial necrosis, with predominant CD4+, CD8+, CD20− and programmed death-1− markers. Programmed death-1 ligand 1 (PD-L1) was predominantly expressed on the surface of the damaged myocardium. Although it is reported that myocarditis induced by the human anti-programmed death-1 inhibitor nivolumab therapy rarely occurred at &gt
2 months use in clinical trials, this case showed that even if at a late phase, long-term use of immune checkpoint inhibitors might to lead immune-related adverse events including myocarditis.

DOI： 10.1016/j.cjca.2018.03.007

Anaplastic variant of diffuse large B-cell lymphoma with hallmark cell appearance: Two cases highlighting a broad diversity in the diagnostics. Reviewed International journal

Ayako Sakakibara, Kei Kohno, Naoto Kuroda, Kenji Yorita, Nirmeen A Megahed, Ahmed E Eladl, Teerada Daroontum, Eri Ishikawa, Yuka Suzuki, Satoko Shimada, Masato Nakaguro, Yoshie Shimoyama, Akira Satou, Seiichi Kato, Yasushi Yatabe, Naoko Asano, Shigeo Nakamura

Pathology international Vol. 68 ( 4 ) page： 251 - 255 2018.4

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

The anaplastic variant of diffuse large B-cell lymphoma (A-DLBCL) is morphologically defined but remains an enigmatic disease in its clinicopathologic distinctiveness. Here, we report two cases involving Japanese women aged 59 years, both with A-DLBCL with the hallmark cell appearance and both indistinguishable from common and giant cell-rich patterns, respectively, of anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma. Case 1 was immunohistochemically positive for CD20, CD79a and OCT-2 but not for the other pan-B-cell markers, CD30 and ALK. Case 2 showed CD20 and CD30 positivity for 50% and 20% of tumor cells in addition to strong expression of p53 and MYC. Both were positive for fascin without Epstein-Barr virus association. Our cases provide additional support for the earlier reports that A-DLBCL exhibits clinicopathologic features distinct from ordinal diffuse large B-cell lymphoma (DLBCL), and documented its broader morphologic diversity than previously recognized. They also shed light on the unique feature of absent expression of pan-B-cell markers except for CD20 and CD79a, suggesting that A-DLBCL may biologically mimic a gray zone or intermediate lymphoma between DLBCL and classic Hodgkin lymphoma.

DOI： 10.1111/pin.12653

Promoter hypomethylation of SKI in autoimmune pancreatitis Reviewed

Yasuhiro Kinugawa, Takeshi Uehara, Kazuyuki Matsuda, Yukihiro Kobayashi, Tomoyuki Nakajima, Hideaki Hamano, Shigeyuki Kawa, Kayoko Higuchi, Noriko Hosaka, Satoshi Shiozawa, Hiroki Ishigame, Toshitsugu Nakamura, Yasuhiro Maruyama, Koh Nakazawa, Masato Nakaguro, Kenji Sano, Hiroyoshi Ota

Pathology Research and Practice Vol. 214 ( 4 ) page： 492 - 497 2018.4

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

The relationship between methylation abnormality and autoimmune pancreatitis (AIP)—a representative IgG4-related disease—has not yet been elucidated. We identified SKI might have a significant methylation abnormality in AIP through methylation array analysis using the Illumina Infinium Human Methylation 450K BeadChip array, and investigated the relationship of SKI with AIP clinicopathological features. The methylation rate of SKI was assessed by quantitative SYBR green methylation-specific PCR, and the degree of SKI expression in tissue specimens was assessed by immunohistochemistry in 10 AIP cases, 14 cases of obstructive pancreatitis area in pancreatic ductal adenocarcinoma (PDA) without a history of AIP, and 9 normal pancreas (NP) cases. The SKI methylation ratio was significantly lower in AIP than in PDA and NP. Additionally, the immunohistochemical staining-index (SI) score for SKI was significantly higher in AIP than NP, although there was no significant difference between AIP and PDA. There was a strong negative correlation between SI score and SKI methylation ratio, and between the serum concentrations of IgG4 and the SKI methylation ratio. There was a moderate positive correlation between the serum concentrations of IgG4 and SI. SKI is thought to be an oncogene indicating that SKI hypomethylation and carcinogenesis might be linked to AIP. Furthermore, the correlation between serum concentrations of IgG4 and SKI methylation levels suggest SKI might be involved in the pathogenesis of AIP. However, the role of SKI has not been clearly elucidated. Further studies are needed to understand further the function of SKI.

DOI： 10.1016/j.prp.2018.03.005

唾液腺腫瘍WHO分類2017・新規の組織型を理解する導管内癌の疾患概念と診断

中黒匡人, 長尾俊孝

日本病理学会会誌 Vol. 107 ( 1 ) page： 553 - 553 2018.4

Beta-Catenin Expression and a CTNNB1 Mutation in Basal Cell Adenoma and Basal Cell Adenocarcinoma Reviewed

Nakaguro Masato, Urano Makoto, Nagao Toshitaka

LABORATORY INVESTIGATION Vol. 98 page： 482 - 482 2018.3

Beta-Catenin Expression and a CTNNB1 Mutation in Basal Cell Adenoma and Basal Cell Adenocarcinoma Reviewed

Nakaguro Masato, Urano Makoto, Nagao Toshitaka

MODERN PATHOLOGY Vol. 31 page： 482 - 482 2018.3

基底細胞腺腫と基底細胞腺癌はbeta-cateninの発現とCTNNB1遺伝子の変異を伴う

中黒匡人, 浦野誠, 長尾俊孝

日本唾液腺学会誌 Vol. 58 page： 30 - 30 2017.11

In vivo histological diagnosis for gastric cancer using endocytoscopy Reviewed

Issei Tsurudome, Ryoji Miyahara, Kohei Funasaka, Kazuhiro Furukawa, Masanobu Matsushita, Takeshi Yamamura, Takuya Ishikawa, Eizaburo Ohno, Masanao Nakamura, Hiroki Kawashima, Osamu Watanabe, Masato Nakaguro, Akira Satou, Yoshiki Hirooka, Hidemi Goto

WORLD JOURNAL OF GASTROENTEROLOGY Vol. 23 ( 37 ) page： 6894 - 6901 2017.10

Language：English Publishing type：Research paper (scientific journal) Publisher：BAISHIDENG PUBLISHING GROUP INC

AIM
To examine usefulness of virtual biopsy using endocytoscopy by comparing the in vivo endocytoscopic and histopathological images of gastric cancers.
METHODS
Endocytoscopy was performed in 30 patients with early gastric cancer. Of these, 26 patients showed well differentiated adenocarcinomas, while 4 patients showed poorly differentiated adenocarcinomas (including one signet ring cell carcinoma). Cancerous and non-cancerous areas were observed after double staining with 0.05% crystal violet and 0.1% methylene blue. The endocytoscopic images obtained were evaluated by an expert endoscopist and an expert pathologist without knowledge of patient clinical data, and endocytoscopic and histopathological diagnoses were compared.
RESULTS
The endocytoscopic images of the cancerous area were assessed as evaluable in 25 (83.3%) and 27 (90%) patients by endoscopist A and pathologist B, respectively, and those of the non-cancerous area as evaluable in 28 (93.3%) and 23 (76.7%) patients by the endoscopist and pathologist, respectively. The sensitivity, specificity, and diagnostic accuracy of gastric cancer diagnosis using evaluable endocytoscopic images were 88.0% and 92.9%, and 90.6% by endoscopist A, and 88.9% and 91.3%, and 90.0% by pathologist B, respectively. Evaluation of the diagnostic concordance rate between the endoscopist and the pathologist by inter-observer agreement calculation revealed no significant difference between the two observers. The inter-observer agreement (kappa-value) for endocytoscopic diagnosis was 0.745.
CONCLUSION
Endocytoscopy is useful for the differentiation of cancerous from non-cancerous gastric mucosa, making it a promising tool for virtual biopsy.

DOI： 10.3748/wjg.v23.i37.6894

Clinicopathologic study on metachronous double cholangiocarcinomas of perihilar and subsequent distal bile duct origin Reviewed

Kentaro Shinohara, Yoshie Shimoyama, Tomoki Ebata, Yukihiro Yokoyama, Takashi Mizuno, Masato Nakaguro, Masato Nagino

SURGERY Vol. 162 ( 1 ) page： 84 - 93 2017.7

Language：English Publishing type：Research paper (scientific journal) Publisher：MOSBY-ELSEVIER

Background. Despite an increasing number of long-term survivors after the resection of perihilar cholangiocarcinoma, metachronous carcinoma in the remnant distal bile duct has not been well documented because of its rarity. The aim of this study was to clarify the feasibility of operative resection and the pathologic features for metachronous double cholangiocarcinomas.
Methods. Between 2003 and 2013, 6 patients underwent resections for both a primary perihilar cholangiocarcinoma and a metachronous distal cholangiocarcinoma. Their medical records were retrospectively reviewed.
Results. At a median of 42 months (range, 19-138 months) after the hepatectomy, a metachronous distal cholangiocarcinoma was detected by follow-up computed tomography and, interestingly, no symptoms were observed. Despite severe adhesions, a pancreatoduodenectomy was undertaken in all patients; there were no serious complications, and the procedure resulted in an R0 resection. Although 2 patients died of the disease after the second operation, the remaining 4 patients are now alive with (n = 1) or without recurrence. A pathologic survey showed that 4 patients had changes of biliary intraepithelial neoplasia-2/3 around their primary and metachronous lesions. The primary and metachronous cholangiocarcinomas showed histologic similarity in 4 of the 6 patients and immunohistochemical concordance in 3 of the 6 patients.
Conclusion. Pancreatoduodenectomy for metachronous distal cholangiocarcinoma can lead to a favorable prognosis. Careful observation after the resection of perihilar cholangiocarcinoma is,mandatory to detect this potentially curable disease. Pathologically, some of the multicentric cholangiocarcinomas present histologic and immunohistochemical similarities.

DOI： 10.1016/j.surg.2016.12.034

改めて見直す唾液腺腫瘍における免疫染色の実践的な臨床病理学的意義唾液腺腫瘍病理診断における汎用マーカーS-100蛋白の有用性とピットフォール

中黒匡人, 長尾俊孝

日本病理学会会誌 Vol. 106 ( 1 ) page： 574 - 574 2017.3

Adenocarcinoma arising in urinary bladder endocervicosis. Reviewed

Nakaguro M, Tsuzuki T, Shimada S, Taki T, Tsuchiyama M, Kitamura A, Suzuki Y, Nakano Y, Ono K.

Pathol Int Vol. 66 ( 2 ) page： 108-113 2016.2

Nucleolar protein PES1 is a marker of neuroblastoma outcome and is associated with neuroblastoma differentiation. Reviewed

Nakaguro M, Kiyonari S, Kishida S, Cao D, Murakami-Tonami Y, Ichikawa H, Takeuchi I, Nakamura S, Kadomatsu K.

Cancer Sci. page： 12598 2014.12

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