研究者詳細 - 中黒　匡人

Intraductal carcinoma of the salivary gland with NCOA4-RET: expanding the morphologic spectrum and an algorithmic diagnostic approach. 査読有り国際誌

Fisch AS, Laklouk I, Nakaguro M, Nosé V, Wirth LJ, Deschler DG, Faquin WC, Dias-Santagata D, Sadow PM

Human pathology 114 巻頁： 74 - 89 2021年8月

The Diagnostic Utility of RAS Q61R Mutation-specific Immunohistochemistry in Epithelial-Myoepithelial Carcinoma 査読有り国際誌

Nakaguro, M; Tanigawa, M; Hirai, H; Yamamoto, Y; Urano, M; Takahashi, RH; Sukeda, A; Okumura, Y; Honda, S; Tasaki, K; Shimizu, A; Tsukahara, K; Tada, Y; Matsubayashi, J; Faquin, WC; Sadow, PM; Nagao, T

AMERICAN JOURNAL OF SURGICAL PATHOLOGY 45 巻 ( 7 ) 頁： 885 - 894 2021年7月

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

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 査読有り国際誌

Yagi, H; Nakaguro, M; Ito, M; Okumura, Y; Takahashi, S; Aoshima, Y; Enomoto, Y; Meguro, S; Kawasaki, H; Kosugi, I; Shimoyama, Y; Ogawa, H; Tateyama, H; Iwashita, T

PATHOLOGY INTERNATIONAL 71 巻 ( 7 ) 頁： 453 - 462 2021年7月

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

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 査読有り国際誌

Ichikawa, D; Yamashita, K; Okuno, Y; Muramatsu, H; Murakami, N; Suzuki, K; Kojima, D; Kataoka, S; Hamada, M; Taniguchi, R; Nishikawa, E; Kawashima, N; Narita, A; Nishio, N; Hama, A; Kasai, K; Mizuno, S; Shimoyama, Y; Nakaguro, M; Okita, H; Kojima, S; Nakazawa, A; Takahashi, Y

NPJ GENOMIC MEDICINE 6 巻 ( 1 ) 頁： 49 - 49 2021年6月

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

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 An Unrecognized Bronchial Counterpart of the Salivary Gland Tumor With Frequent BRAF V600E Mutations 査読有り国際誌

Nakaguro, M; Mino-Kenudson, M; Urano, M; Ogawa, I; Honda, Y; Hirai, H; Tanigawa, M; Sukeda, A; Kajiwara, N; Ohira, T; Ikeda, N; Mikami, Y; Tada, Y; Ikeda, JI; Matsubayashi, J; Faquin, WC; Sadow, PM; Nagao, T

AMERICAN JOURNAL OF SURGICAL PATHOLOGY 45 巻 ( 5 ) 頁： 662 - 671 2021年5月

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

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 39 巻 ( 臨増 ) 頁： 26 - 31 2021年4月

Pathological evaluation of tumor grade for salivary adenoid cystic carcinoma: A proposal of an objective grading system 査読有り国際誌

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

CANCER SCIENCE 112 巻 ( 3 ) 頁： 1184 - 1195 2021年3月

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

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. 査読有り国際誌

Nakaguro M, Nagao T

Surgical pathology clinics 14 巻 ( 1 ) 頁： 97 - 109 2021年3月

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

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査読有り

中黒匡人, 長尾俊孝

病理と臨床 39 巻 ( 2 ) 頁： 195 - 197 2021年2月

Gastrointestinal tract metastasis of lung cancer: The PD-L1 expression and correlated clinicopathological variables 査読有り国際誌

Ishikawa, E; Nakaguro, M; Nakamura, M; Yamamura, T; Sawada, T; Mizutani, Y; Maeda, K; Furukawa, K; Shimoyama, Y; Kawashima, H; Fujishiro, M

PATHOLOGY INTERNATIONAL 71 巻 ( 1 ) 頁： 33 - 41 2021年1月

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

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 査読有り

Koga R., Hashimoto N., Yokota T., Nakaguro M., Kohno K., Nakamura S., Takeuchi I., Hontani H.

Proceedings of SPIE - The International Society for Optical Engineering 11792 巻 2021年

記述言語：英語掲載種別：研究論文（国際会議プロシーディングス）出版者・発行元：Proceedings of SPIE - The International Society for Optical Engineering

We proposed a method that detects DLBCL (Diffuse Large B-Cell Lymphoma) regions from a H&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&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 査読有り

Koga R., Hashimoto N., Yokota T., Nakaguro M., Kohno K., Nakamura S., Takeuchi I., Hontani H.

Proceedings of SPIE - The International Society for Optical Engineering 11792 巻 2021年

記述言語：英語掲載種別：研究論文（国際会議プロシーディングス）出版者・発行元：Proceedings of SPIE - The International Society for Optical Engineering

We propose a method to transfer a given pathology image stained by some immunostaining to a H&E stained one. When one construct a classifier that estimates the subtype of malignant lymphoma from a given H&E stained pathology image, one needs a set of training H&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&E stained ones, you can easily obtain a set of virtually H&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&E stained ones.

DOI： 10.1117/12.2590720