Faculty Profiles - NAKAGURO Masato

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

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

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

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