Faculty Profiles - NAKAGURO Masato

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

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

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

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

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