Papers - Nishimura Midori Filiz

International Consensus Histopathological Criteria for Subtyping Idiopathic Multicentric Castleman Disease Based on Machine Learning Analysis Reviewed International coauthorship

Midori Filiz Nishimura, Tomoka Haratake, Yoshito Nishimura, Asami Nishikori, Remi Sumiyoshi, Hideki Ujiie, Yuri Kawahara, Tomohiro Koga, Masao Ueki, Dorottya Laczko, Eric Oksenhendler, David C. Fajgenbaum, Frits van Rhee, Atsushi Kawakami, Yasuharu Sato

American Journal of Hematology   2025.6

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Authorship：Lead author   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/ajh.27743

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The involvement of PI3K–Akt signaling in the clinical and pathologic findings of iMCD-TAFRO and NOS subtypes Reviewed

Tomoka Haratake, Midori Filiz Nishimura, Asami Nishikori, Michael V. Gonzalez, Daisuke Ennishi, You Cheng Lai, Sayaka Ochi, Manaka Tsunoda, David C. Fajgenbaum, Frits van Rhee, Shuji Momose, Yasuharu Sato

Modern Pathology   100782 - 100782   2025.4

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

DOI： 10.1016/j.modpat.2025.100782

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Kikuchi‐Fujimoto disease: investigating comprehensive clinicopathological features and risk factors for recurrence Reviewed

Midori Filiz Nishimura, Chikako Sakao, Yuka Kurokawa, Yoshito Nishimura, Asami Nishikori, Hidetaka Yamamoto, Yasuharu Sato

Histopathology   2025.2

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Authorship：Lead author,　Corresponding author   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/his.15427

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Clinicopathological and Gene Expression Analysis of Hyaline Vascular Castleman Disease

Midori Filiz Nishimura, Yoshito Nishimura, Yuika Iwamoto, Tomoka Haratake, Hideki Ujiie, Asami Nishikori, Thomas M. Habermann, Angela Dispenzieri, Yasuharu Sato

Blood   144 ( Supplement 1 )   3301 - 3301   2024.11

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Publishing type：Research paper (scientific journal)   Publisher：American Society of Hematology  

Introduction:

Hyaline-vascular type unicentric Castleman disease (HV-UCD) is a classic variant of Castleman disease, characterized by localized lymph node hyperplasia. Due to its rarity, there have been few systematic reports summarizing its clinicopathological features globally. Also, its pathogenesis remains unelucidated. The present study aims to provide a detailed clinicopathological and transcriptomic analysis of HV-UCD to enhance the understanding of its underlying mechanisms at a molecular level.

Methods:

We conducted a clinicopathological analysis of 51 HV-UCD cases and performed whole transcriptome analysis on frozen lymph node specimens from four cases. Differentially expressed genes (DEGs) and Gene Ontology (GO) analyses were performed to identify significant pathways and biological processes involved in HV-UCD, with reactive lymphoid hyperplasia as control.

Results:

The mean age of HV-UCD patients was 42.8 years, with no significant gender differences. The most common sites involved were the abdominal cavity (n = 18, 35.3%), mediastinum (n = 11, 21.6%), and retroperitoneum (n = 9, 17.6%), with an average size of the lesions being 4.8 cm. Histologically, 33.3% of cases exhibited “dysplastic follicular dendritic cells (dFDCs)” characterized by multinucleation or large nuclei within and outside follicles, positive for follicular dendritic cells (FDC) markers. DEGs analysis compared to reactive lymphoid hyperplasia revealed significant upregulation of genes related to FDCs and angiogenesis. Notably, the placental growth factor (PGF), a proangiogenic factor and a member of the VEGF family, demonstrated significant overexpression. GO analysis identified significant enrichment of genes involved in angiogenesis, cell adhesion, tissue architecture, and humoral immunity.

Discussion:

This large cohort of HV-UCD cohort provides potentially novel clinicopathological insights. Gene expression analysis demonstrated increased expression of FDC-related genes, suggesting a pivotal role of FDCs in HV-UCD pathogenesis. The differences in the gene profiles related to angiogenesis may contribute to the distinct mechanisms and histological features of HV-UCD and iMCD-TAFRO, where HV-UCD is associated with hyalinization of vascular walls and iMCD-TAFRO is characterized by angiogenesis with endothelial cell swelling.

Conclusion:

The present results suggest the crucial role of FDCs in HV-UCD pathogenesis from the molecular features. Currently, there are no objective diagnostic markers for HV-UCD. Identifying these markers may lead to a clearer understanding of the disease pathophysiology and improve diagnostic accuracy for HV-UCD. Further investigation is warranted to verify the findings.

DOI： 10.1182/blood-2024-200298

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Transcriptome analysis of the cytokine storm-related genes among the subtypes of idiopathic multicentric Castleman disease. Reviewed

Asami Nishikori, Midori Filiz Nishimura, Shuta Tomida, Ryota Chijimatsu, Himawari Ueta, You Cheng Lai, Yuri Kawahara, Yudai Takeda, Sayaka Ochi, Tomoka Haratake, Daisuke Ennishi, Naoya Nakamura, Shuji Momose, Yasuharu Sato

Journal of clinical and experimental hematopathology : JCEH   2024.10

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society for Lymphoreticular Tissue Research  

Idiopathic multicentric Castleman disease (iMCD) is a type of Castleman disease unrelated to the Kaposi sarcoma-associated herpesvirus/human herpesvirus type 8 (KSHV/HHV8) infection. Presently, iMCD is classified into iMCD-IPL (idiopathic plasmacytic lymphadenopathy), iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly), and iMCD-NOS (not otherwise specified). The most common treatment for iMCD is using IL-6 inhibitors; however, some patients resist IL-6 inhibitors, especially for iMCD-TAFRO/NOS. Nevertheless, since serum IL-6 levels are not significantly different between the iMCD-IPL and iMCD-TAFRO/NOS cases, cytokines other than IL-6 may be responsible for the differences in pathogenesis. Herein, we performed a transcriptome analysis of cytokine storm-related genes and examined the differences between iMCD-IPL and iMCD-TAFRO/NOS. The results demonstrated that counts per million of STAT2, IL1R1, IL1RAP, IL33, TAFAIP1, and VEGFA (P < 0.001); STAT3, JAK2, MAPK8, IL17RA, IL18, TAFAIP2, TAFAIP3, PDGFA, VEGFC, CXCL10, CCL4, and CXCL13 (P < 0.01); and STAT1, STAT6, JAK1, MAPK1, MAPK3, MAPK6, MAPK7, MAPK9, MAPK10, MAPK11, MAPK12, MAPK14, NFKB1, NFKBIA, NFKBIB, NFKBIZ, MTOR, IL10RB, IL12RB2, IL18BP, TAFAIP6, TNFAIP8L1, TNFAIP8L3, CSF2RBP1, PDGFB, PDGFC, and CXCL9 (P < 0.05) were significantly increased in iMCD-TAFRO/NOS. Particularly, upregulated IL33 expression was demonstrated for the first time in iMCD-TAFRO/NOS. Thus, inflammatory signaling, such as JAK-STAT and MAPK, may be enhanced in iMCD-TAFRO/NOS and may be a cytokine storm.

DOI： 10.3960/jslrt.24061

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Hematopoietic stem cell–derived Tregs are essential for maintaining favorable B cell lymphopoiesis following posttransplant cyclophosphamide Reviewed

Yuichi Sumii, Takumi Kondo, Shuntaro Ikegawa, Takuya Fukumi, Miki Iwamoto, Midori Filiz Nishimura, Hiroyuki Sugiura, Yasuhisa Sando, Makoto Nakamura, Yusuke Meguri, Takashi Matsushita, Naoki Tanimine, Maiko Kimura, Noboru Asada, Daisuke Ennishi, Yoshinobu Maeda, Ken-ichi Matsuoka

JCI Insight   8 ( 8 )   2023.4

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Publishing type：Research paper (scientific journal)   Publisher：American Society for Clinical Investigation  

DOI： 10.1172/jci.insight.162180

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Historical and pathological overview of Castleman disease. Invited Reviewed

Midori Filiz Nishimura, Yoshito Nishimura, Asami Nishikori, Tadashi Yoshino, Yasuharu Sato

Journal of clinical and experimental hematopathology : JCEH   2022.4

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Castleman disease consists of several lymphoproliferative subtypes that share some histological features in the lymph nodes. On the other hand, numerous clinical findings and etiologies make the disease challenging to understand. The origin of the disease is the hyaline vascular-type unicentric Castleman disease (UCD), first reported by Benjamin Castleman et al. in 1954. Although UCD is characterized by localized lesions and lack of symptoms, multicentric Castleman disease (MCD) with multiple lesions and systemic symptoms was reported by Frizzera in 1983. MCD is further divided according to KSHV/HHV8 infection status. In KSHV/HHV8-related MCD, viral infection signals lead to excessive cytokine production, and cause clinical and pathologic abnormalities. Some cases of plasma cell-type KSHV/HHV8-negative MCD can be found in association with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-proteins, and skin changes), which is a paraneoplastic syndrome. The others are idiopathic MCD, which are currently considered a heterogeneous group of diseases with overlapping pathological and clinical features. In this article, we summarize the historical evolution of Castleman disease to help understand the disease concept. We also review the latest ideas and definitions of the subtypes within the MCD spectrum and summarize the histopathological findings.

DOI： 10.3960/jslrt.21036

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Primary Gastrointestinal T-Cell Lymphoma and Indolent Lymphoproliferative Disorders: Practical Diagnostic and Treatment Approaches Reviewed International journal

Midori Filiz Nishimura, Yoshito Nishimura, Asami Nishikori, Tadashi Yoshino, Yasuharu Sato

Cancers   13 ( 22 )   5774 - 5774   2021.11

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Primary gastrointestinal (GI) T-cell neoplasms are extremely rare heterogeneous disease entities with distinct clinicopathologic features. Given the different prognoses of various disease subtypes, clinicians and pathologists must be aware of the key characteristics of these neoplasms, despite their rarity. The two most common aggressive primary GI T-cell lymphomas are enteropathy-associated T-cell lymphoma and monomorphic epitheliotropic intestinal T-cell lymphoma. In addition, extranodal natural killer (NK)/T-cell lymphoma of the nasal type and anaplastic large cell lymphoma may also occur in the GI tract or involve it secondarily. In the revised 4th World Health Organization classification, indolent T-cell lymphoproliferative disorder of the GI tract has been incorporated as a provisional entity. In this review, we summarize up-to-date clinicopathological features of these disease entities, including the molecular characteristics of primary GI T-cell lymphomas and indolent lymphoproliferative disorders. We focus on the latest treatment approaches, which have not been summarized in existing reviews. Further, we provide a comprehensive review of available literature to address the following questions: How can pathologists discriminate subtypes with different clinical prognoses? How can primary GI neoplasms be distinguished from secondary involvement? How can these neoplasms be distinguished from non-specific inflammatory changes at an early stage?

DOI： 10.3390/cancers13225774

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Clinical and Pathological Characteristics of Hyaline-Vascular Type Unicentric Castleman Disease: A 20-Year Retrospective Analysis Reviewed

Midori Filiz Nishimura, Yoshito Nishimura, Asami Nishikori, Yukina Maekawa, Kanna Maehama, Tadashi Yoshino, Yasuharu Sato

Diagnostics   11 ( 11 )   2008 - 2008   2021.10

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Authorship：Lead author   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

The first case of hyaline vascular type of unicentric Castleman disease (HV-UCD) was reported more than six decades ago. Since patients with HV-UCD are often asymptomatic and this condition is generally discovered incidentally on imaging tests, most of the previous reports were of mediastinal origin detected by chest radiography. In recent years, improved access to imaging modalities has provided new insights in the diagnosis of this condition. In this study, we reviewed the detailed clinical and pathological findings of 38 HV-UCD cases (20 males and 18 females, mean age: 42.8 years). The most common site involved was the abdominal cavity (34.2%), followed by mediastinum (23.7%) and retroperitoneum (15.8%). In the abdominal cavity, mesenteric origin was the most common. The mean size of masses was 4.8 cm. Pathologically, thick hyalinized collagen fibers surrounding large blood vessels and calcification were observed (81.6% and 23.7%, respectively). Multinucleated giant cells resembling Warthin–Finkeldey cell were also observed in occasional cases (23.7%). This is a unique paper that summarizes detailed clinical and pathological findings of a large series of a rare disease. The clinical information presented in this paper is more plausible than previous views and is useful for accurate diagnosis and understanding of the disease.

DOI： 10.3390/diagnostics11112008

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Validated International Definition of the TAFRO clinical subtype of idiopathic multicentric Castleman disease Reviewed International coauthorship

Yoshito Nishimura, David C. Fajgenbaum, Sheila K. Pierson, Noriko Iwaki, Asami Nishikori, Mitsuhiro Kawano, Naoya Nakamura, Koji Izutsu, Kengo Takeuchi, Midori Filiz Nishimura, Yoshinobu Maeda, Fumio Otsuka, Kazuyuki Yoshizaki, Eric Oksenhendler, Frits Rhee, Yasuharu Sato

American Journal of Hematology   96 ( 10 )   1241 - 1252   2021.7

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

DOI： 10.1002/ajh.26292

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/ajh.26292

Pulmonary Manifestations of Plasma Cell Type Idiopathic Multicentric Castleman Disease: A Clinicopathological Study in Comparison with IgG4-Related Disease. Reviewed International journal

Midori Filiz Nishimura, Takuro Igawa, Yuka Gion, Sakura Tomita, Dai Inoue, Akira Izumozaki, Yoshifumi Ubara, Yoshito Nishimura, Tadashi Yoshino, Yasuharu Sato

Journal of personalized medicine   10 ( 4 )   2020.12

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Plasma cell type idiopathic multicentric Castleman disease (PC-iMCD) occasionally manifests as parenchymal lung disease. This study aimed to elucidate the detailed clinicopathological features of lung lesions in PC-iMCD and compare the findings with those in immunoglobulin (Ig) G4-related disease (IgG4-RD), the most difficult differential diagnosis of PC-iMCD. We analyzed the clinicopathological findings and immunohistochemical expression patterns of interleukin-6 (IL-6) and Igs in lung specimens from 16 patients with PC-iMCD and 7 patients with IgG4-RD. Histologically, pulmonary PC-iMCD could not be differentiated from IgG4-RD based on lesion distribution patterns, the number of lymphoid follicles and obliterative vasculitis, or fibrosis types. The eosinophil count was higher in the IgG4-RD group than in the PC-iMCD group (p = 0.004). The IgG4/IgG-positive cell ratio was significantly higher in the IgG4-RD group (p < 0.001). The IgA-positive cell count and IL-6 expression intensity were higher in the PC-iMCD group than in the IgG4-RD group (p < 0.001). Based on these findings, we proposed a new diagnostic approach to differentiate lung lesions of PC-iMCD and IgG4-RD. Our approach can be utilized to stratify patients with suspected lung-dominant PC-iMCD to identify candidates for strong immunosuppressive treatment, including IL-6 blockade, at an early stage.

DOI： 10.3390/jpm10040269

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Spontaneous Complete Regression of Aleukaemic Cutaneous Myeloid Sarcoma without Progression to Leukaemia Over a Long-term Follow-up Period Reviewed

Hiromi HIGAKI-MORI, Nanako YAMADA, Kanae OZAKI, Midori Filiz NISHIMURA, Yuichi YOSHIDA

Acta Dermato-Venereologica   2025.2

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DOI： 10.2340/actadv.v105.42339

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Computed tomography findings of idiopathic multicentric Castleman disease subtypes. Reviewed

Toshihiro Iguchi, Asami Nishikori, Yasuharu Sato, Midori Filiz Nishimura, Noriko Iwaki, Katsuhide Kojima, Takashi Asahara, Fumio Otsuka, Yoshinobu Maeda, Takao Hiraki

Journal of clinical and experimental hematopathology : JCEH   64 ( 4 )   292 - 296   2024.12

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This study retrospectively evaluated the computed tomography (CT) findings of idiopathic multicentric Castleman disease (iMCD) at a single center and compared the CT findings of iMCD-TAFRO with those of iMCD-non-TAFRO. CT images obtained within 30 days before diagnostic confirmation were reviewed for 20 patients with iMCD (8 men and 12 women, mean age 52.8 ± 12.3 years, range 25-74 years). Twelve patients were diagnosed with iMCD-TAFRO, five with iMCD-idiopathic plasmacytic lymphadenopathy, and three with iMCD-not otherwise specified. CT images revealed anasarca and lymphadenopathy in all 20 patients. The iMCD-TAFRO group showed significantly higher frequencies of ascites (100% vs. 37.5%, P = 0.004), gallbladder wall edema (75.0% vs. 12.5%, P = 0.020), periportal collar (91.7% vs. 25.0%, P = 0.004), and anterior mediastinal lesions (non-mass-forming infiltrative lesions) (66.7% vs. 12.5%, P = 0.028). Para-aortic edema tended to be more frequent in patients with the iMCD-TAFRO group (83.3% vs. 37.5%, P = 0.062), while the absence of anterior mediastinal lesions tended to be more frequent in the iMCD-non-TAFRO group (16.7% vs. 62.5%, P = 0.062). These CT findings may have clinical implications for improving the accuracy and speed of iMCD diagnosis and differentiating iMCD-TAFRO from other subtypes.

DOI： 10.3960/jslrt.24053

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A lymph node lesion of hyper IL-6 syndrome mimicking plasmacytoma, IgG4-related disease, and Castleman disease. Reviewed

Kenta Matsui, Hiroshi Imai, Toshiaki Kobayashi, Minoru Mizutani, Midori Filiz Nishimura, Yasuharu Sato, Kennosuke Karube, Manato Okada, Miki Usui, Keiki Kawakami, Tetsuya Murata

Journal of clinical and experimental hematopathology : JCEH   64 ( 4 )   307 - 312   2024.12

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

A 72-year-old male patient presented fatigue, anemia, elevated total protein, IgG, IgG4, IL-6, and vascular endothelial growth factor (VEGF) levels. Initial diagnostics suspected multiple myeloma. A plane computed tomography (CT) scan showed pneumonia and the enlargement of generalized lymph nodes. A lymph node biopsy revealed a mix of immature and mature plasma cells, significant IgG4-positive cells, and IL-6-secreting plasma cells, mimicking plasmacytoma, IgG4-related disease, and Castleman disease, ultimately leading to a diagnosis of hyper IL-6 syndrome. Treatment with antibiotics improved the patient's condition without the need for additional therapies, including tocilizumab.

DOI： 10.3960/jslrt.24039

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Discrepancy of Hans' criteria for clonally related nodal and pericardiac fluid diffuse large B-cell lymphoma with MYD88 L265P mutation. Reviewed

Toshiki Terao, Yumiko Sato, Yoshiaki Kuroda, Tomoka Haratake, Midori Filiz Nishimura, Yasuharu Sato, Shoichi Kuyama

Journal of clinical and experimental hematopathology : JCEH   2024.12

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

A 79-year-old Japanese woman presented with exertional dyspnea. She had cardiac tamponade and urgent pericardial drainage was performed. Pathological findings from the pericardial fluid revealed non-germinal center B-cell (non-GCB) pericardial large B-cell lymphoma (CD10-, BCL6+, and MUM1+). Although a diagnosis of fluid overload-associated large B-cell lymphoma was considered, GCB nodal diffuse large B-cell lymphoma (CD10+, BCL6+, and MUM1+) was discovered through needle biopsy of the enlarged left axillary lymph node. Despite the two lymphomas exhibiting different expression levels of CD10, polymerase chain reaction assessing IgH gene rearrangement suggested a clonal relationship between them. Additionally, MYD88 L265P mutation was confirmed using Sanger sequencing in both samples, suggesting the MCD type. Our case highlights a discrepancy between the Hans' criteria and the gene expression profile-based cell of origin.

DOI： 10.3960/jslrt.24050

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Clinicopathological Features of Kikuchi-Fujimoto Disease: Retrospective Observational Study

Yoshito Nishimura, Midori Filiz Nishimura, Chikako Sakao, Asami Nishikori, Thomas M. Habermann, Angela Dispenzieri, Yasuharu Sato

Blood   144 ( Supplement 1 )   5371 - 5371   2024.11

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Publishing type：Research paper (scientific journal)   Publisher：American Society of Hematology  

Introduction:

Kikuchi-Fujimoto disease (KFD), is a rare inflammatory disease of unknown etiology, typically presenting with transient fever and cervical lymphadenopathy. It is recently classified as a tumor-like lesion in the World Health Organization Classification 5th Edition. There are few large-scale studies on patient demographics and clinical course. This study aims to report detailed clinicopathological features of KFD.

Methods:

We reviewed 112 cases of KFD diagnosed at Okayama University Department of Pathology and Oncology, Okayama, Japan between 2012 and 2022. Patients who were diagnosed with autoimmune diseases or bacterial/tuberculous lymphadenitis after the initial presentation as KFD were excluded.

Results:

The average age of the included cases was 29.4 years (range:6 to 77 years) with slight female predominance (n = 51/115, 44.3% for male; n = 61/115, 53.0% for female). For the included cases of 30 years or older, there were more females than males. The cervical lymph nodes were the most commonly affected sites (85%). For the 70 patients who had complete follow-up data available in the electric medical records, the recurrence rate was 23%, without a difference between males and females. Laboratory tests demonstrated significantly lower complement 4 (C4) levels (p = 0.038) and a higher rate of positive antinuclear antibodies (p = 0.007) in the relapsed cases than in the cases without documented recurrence. The mean number of days prior to confirm the diagnosis was 71.5 days. Among the representative lymph node histology classification, proliferative type was the most common (n = 75; 77%), followed by necrotizing (n = 22; 22%), and xanthomatous (n = 1; 1%). The patients with necrotizing type had significantly enlarged lymph nodes (p = 0.047) and longer duration of symptoms (p = 0.009) compared to the proliferating type.

Discussion:

The present study provides data from a large KFD cohort to provide comprehensive clinicopathological information to date. While KFD is known to predominantly affect female, there were considerably more males up to age 30 than females, Being young and adolescent male KFD patients was associated with atypical features. Future studies are warranted to confirm the findings noted in the results, to clarify clinicopathological differences in the male young adolescent KFD, and further characterize the classical female KFD cases, including histological features, treatment responses, and association with autoimmune or malignant hematology conditions.

Conclusion:

In this study, we analyzed a large number of KFD cases and clarified characteristics. The comprehensive clinicopathological features provided by the present results may be useful in elucidating the pathogenesis and predicting the clinical course of such clinically challenging cases, including association with autoimmune diseases and its long-term outcomes.

DOI： 10.1182/blood-2024-200286

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A case of adult T-cell leukemia/lymphoma showing CD8 positive and CD25 negative by immunohistochemistry Reviewed

Kengo Atsumi, Minoru Matsumoto, Michiko Yamashita, Midori Filiz Nishimura, Yasuharu Sato, Yoshimi Bando, Hisanori Uehara

Japanese Journal of Diagnostic Pathology   41 ( 4 )   349 - 354   2024.10

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Atypical lymphoplasmacytic and immunoblastic proliferation: A Systematic Review Reviewed International coauthorship

Nishimura Midori Filiz, Takahashi Toshiaki, Takaoka Kensuke, Macapagal Sharina, Wannaphut Chalothorn, Nishikori Asami, Toda Hiroko, Nishimura Yoshito, Sato Yasuharu

Journal of Clinical and Experimental Hematopathology   64 ( 2 )   97 - 106   2024.6

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Authorship：Lead author   Language：English   Publisher：The Japanese Society for Lymphoreticular Tissue Research  

Atypical lymphoplasmacytic and immunoblastic proliferation (ALPIBP) was first reported in 1984 as characteristic histological findings in lymph nodes associated with autoimmune diseases, but it has not been clearly defined to date. To summarize the histological characteristics and clinical diagnoses associated with ALPIBP, we searched MEDLINE and EMBASE for all peer-reviewed articles using keywords including “atypical lymphoplasmacytic and immunoblastic lymphadenopathy” from their inception to December 27, 2023. We also summarized the courses of three cases with a pathological diagnosis of ALPIBP. Nine articles with 52 cases were included. Among the total of 55 cases, including the three from our institution, the median age of the cases was 63.5 years with a female predominance (69.5%). Lymphadenopathy was generalized in 65.6% and regional in 34.4% of cases. RA (24.4%), SLE (24.4%), and autoimmune hemolytic anemia (20.0%), were common clinical diagnoses. A combination of cytotoxic chemotherapy was used in 15.6% of cases due to the suspicion of malignancy. Nodal T-follicular helper cell lymphoma, angioimmunoblastic type, methotrexate-associated lymphoproliferative disorders, and IgG4-related diseases were listed as important diseases that need to be pathologically differentiated from ALPIBP. This review summarizes the current understanding of the characteristics of ALPIBP. Given that underrecognition of ALPIBP could lead to overdiagnosis of hematological malignancy and unnecessary treatment, increased awareness of the condition in pathologists and clinicians is crucial.

DOI： 10.3960/jslrt.24007

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Copy Number Analysis of 9p24.1 in Classic Hodgkin Lymphoma Arising in Immune Deficiency/Dysregulation Reviewed

Kumiko Ohsawa, Shuji Momose, Asami Nishikori, Midori Filiz Nishimura, Yuka Gion, Keisuke Sawada, Morihiro Higashi, Michihide Tokuhira, Jun-ichi Tamaru, Yasuharu Sato

Cancers   2024.3

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DOI： 10.3390/cancers16071298

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Diagnostic challenges of the idiopathic plasmacytic lymphadenopathy (IPL) subtype of idiopathic multicentric Castleman disease (iMCD): Factors to differentiate from IgG4-related disease Reviewed International coauthorship

Asami Nishikori, Midori Filiz Nishimura, David C Fajgenbaum, Yoshito Nishimura, Kanna Maehama, Tomoka Haratake, Tetsuya Tabata, Mitsuhiro Kawano, Naoya Nakamura, Shuji Momose, Remi Sumiyoshi, Tomohiro Koga, Hidetaka Yamamoto, Frits van Rhee, Atsushi Kawakami, Yasuharu Sato

Journal of Clinical Pathology   2024.2

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Publishing type：Research paper (scientific journal)  

DOI： 10.1136/jcp-2023-209280

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Ectopic Breast Cancer Arising within an Axillary Lymph Node. Reviewed

Kei Toshima, Tadahiko Shien, Midori Filiz Nishimura, Yoko Suzuki, Shogo Nakamoto, Maya Uno, Ryo Yoshioka, Takahiro Tsukioki, Yuko Takahashi, Takayuki Iwamoto, Tsuguo Iwatani, Hiroyuki Yanai

Acta medica Okayama   78 ( 1 )   89 - 93   2024.2

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Language：English  

We report our experience with the diagnosis and treatment of an ectopic breast cancer arising within an axillary lymph node. The patient was a 65-year-old woman diagnosed breast cancer and axillary lymph node metastasis. We performed a partial mastectomy and axillary lymph node dissection. Postoperative pathology revealed no malignant lesions in the breast; however, a nodule in one of axillary lymph nodes had mixed benign and malignant components, leading to a diagnosis of invasive ductal carcinoma derived from ectopic mammary tissue. This case represents a very rare form of breast cancer, and the malignancy was difficult to distinguish from metastasis.

DOI： 10.18926/AMO/66676

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Analysis of Notch1 protein expression in methotrexate-associated lymphoproliferative disorders Reviewed

Okatani Takeshi, Nishimura Midori Filiz, Egusa Yuria, Yoshida Sayako, Nishimura Yoshito, Nishikori Asami, Yoshino Tadashi, Yamamoto Hidetaka, Sato Yasuharu

Journal of Clinical and Experimental Hematopathology   64 ( 1 )   1 - 9   2024

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society for Lymphoreticular Tissue Research  

Methotrexate (MTX)-associated lymphoproliferative disorder (MTX-LPD) is a lymphoproliferative disorder in patients treated with MTX. The mechanism of pathogenesis is still elusive, but it is thought to be a complex interplay of factors, such as underlying autoimmune disease activity, MTX use, Epstein-Barr virus infection, and aging. The NOTCH genes encode receptors for a signaling pathway that regulates various fundamental cellular processes, such as proliferation and differentiation during embryonic development. Mutations of NOTCH1 have been reported in B-cell tumors, including chronic lymphocytic leukemia/lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma (DLBCL). Recently, it has also been reported that NOTCH1 mutations are found in post-transplant lymphoproliferative disorders, and in CD20-positive cells in angioimmunoblastic T-cell lymphoma, which might be associated with lymphomagenesis in immunodeficiency. In this study, to investigate the association of NOTCH1 in the pathogenesis of MTX-LPD, we evaluated protein expression of Notch1 in nuclei immunohistochemically in MTX-LPD cases [histologically DLBCL-type (n = 24) and classical Hodgkin lymphoma (CHL)-type (n = 24)] and de novo lymphoma cases [DLBCL (n = 19) and CHL (n = 15)]. The results showed that among MTX-LPD cases, the expression of Notch1 protein was significantly higher in the DLBCL type than in the CHL type (P < 0.001). In addition, among DLBCL morphology cases, expression of Notch1 tended to be higher in MTX-LPD than in the de novo group; however this difference was not significant (P = 0.0605). The results showed that NOTCH1 may be involved in the proliferation and tumorigenesis of B cells under the use of MTX. Further research, including genetic studies, is necessary.

DOI： 10.3960/jslrt.23038

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Other Link： https://www.jstage.jst.go.jp/article/jslrt/64/1/64_23038/_pdf

Multiple Glomus tumor that developed in the lower leg of one side: A case report Reviewed

Takahiro Tokuda, Tomohiro Fujiwara, Ayana Kondo, Toshiyuki Kunisada, Eiji Nakata, Midori Filiz Nishimura, Hiroyuki Yanai, Toshihumi Ozaki

The Journal of the Chugoku-Shikoku Orthopaedic Association   35 ( 1 )   47 - 51   2023.7

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Comparison of serum sIL-2R and LDH levels in patients with intravascular large B-cell lymphoma and patients with advanced stage diffuse large B-cell lymphoma Reviewed

Yuki Hirami, Midori Filiz Nishimura, Tomohiro Urata, Michiko Morimoto, Yukina Maekawa, Tadashi Yoshino, Yoshito Nishimura, Yasuharu Sato

Journal of Clinical and Experimental Hematopathology   Advance online publication   2023.2

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society for Lymphoreticular Tissue Research  

DOI： 10.3960/jslrt.22043

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Idiopathic Plasmacytic Lymphadenopathy Forms an Independent Subtype of Idiopathic Multicentric Castleman Disease Reviewed International journal

Asami Nishikori, Midori Filiz Nishimura, Yoshito Nishimura, Fumio Otsuka, Kanna Maehama, Kumiko Ohsawa, Shuji Momose, Naoya Nakamura, Yasuharu Sato

International Journal of Molecular Sciences   23 ( 18 )   10301 - 10301   2022.9

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：{MDPI} {AG}  

Idiopathic multicentric Castleman disease (iMCD) is a type of Castleman disease that is not related to KSHV/HHV8 infection. Currently, iMCD is classified into iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly) and iMCD-NOS (not otherwise specified). The former has been established as a relatively homogeneous disease unit that has been recently re-defined, while the latter is considered to be a heterogeneous disease that could be further divided into several subtypes. In 1980, Mori et al. proposed the concept of idiopathic plasmacytic lymphadenopathy (IPL), a disease presenting with polyclonal hypergammaglobulinemia and a sheet-like proliferation of mature plasma cells in the lymph nodes. Some researchers consider IPL to be a part of iMCD-NOS, although it has not been clearly defined to date. This is the first paper to analyze iMCD-NOS clinicopathologically, to examine whether IPL forms a uniform disease unit in iMCD. Histologically, the IPL group showed prominent plasmacytosis and the hyperplasia of germinal centers, while the non-IPL group showed prominent vascularity. Clinically, the IPL group showed significant thrombocytosis and elevated serum IgG levels compared to the non-IPL group (p = 0.007, p &lt; 0.001, respectively). Pleural effusion and ascites were less common in the IPL group (p &lt; 0.001). The IPL group was more likely to have an indolent clinical course and a good response to the anti-IL-6 receptor antibody, while the non-IPL counterpart frequently required more aggressive medical interventions. Thus, the IPL group is a clinicopathologically uniform entity that forms an independent subtype of iMCD.

DOI： 10.3390/ijms231810301

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Clinicopathological Characteristics of Gastric IgG4-related Disease: Systematic Scoping Review. Reviewed International journal

Haruki Sawada, Torrey Czech, Krixie Silangcruz, Landon Kozai, Adham Obeidat, Eric Andrew Wien, Midori Filiz Nishimura, Asami Nishikori, Yasuharu Sato, Yoshito Nishimura

Journal of gastroenterology and hepatology   2022.8

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BACKGROUND: Gastric IgG4-related disease (IgG4-RD) can mimic malignancy, submucosal tumors (SMT), and ulcers, leading to over-triage and unnecessary medical interventions such as gastrectomy. The variability in the clinicopathological presentation of IgG4-related disease is not yet well defined, posing a diagnostic challenge. METHODS: Following the PRISMA Extension for Scoping Reviews, we searched MEDLINE and EMBASE for all peer-reviewed articles using keywords including"gastritis," "stomach," "gastrointestinal stromal tumor," and "IgG4-RD" from their inception to December 28, 2021. RESULTS: 39 articles, including two observational studies and 42 cases, were included in the systematic review. While bottom-heavy lymphoplasmacytic mucosal infiltration is a characteristic finding of gastric IgG4-RD, it was only present in less than half of the patients in the observational studies. Patients with Gastric IgG4-RD were more likely to be diagnosed with gastrointestinal stromal tumor (GIST), gastric cancer, or peptic ulcer disease and their clinical course involved resection (51.3%) or even gastrectomy. Diagnosis of gastric IgG4-RD was most frequently made by post-operative pathological analysis. CONCLUSION: This systematic review summarizes the current understanding of the characteristics of gastric IgG4-RD. Increased awareness of gastric IgG4-RD as a differential diagnosis of gastric SMT or ulcers among clinicians is crucial in order to reduce unnecessary high-risk, invasive interventions.

DOI： 10.1111/jgh.15980

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キャッスルマン病の歴史と病理 Invited Reviewed

佐藤 康晴, 錦織 亜沙美, 前濱 かんな, 西村 碧フィリーズ

診断病理   39 ( 3 )   167 - 172   2022.7

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Language：Japanese   Publisher：(一社)日本病理学会  

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Clinical characteristics and outcomes of IgG4-positive marginal zone lymphoma: Systematic scoping review Reviewed International journal

Yoshito Nishimura, Eric Andrew Wien, Midori Filiz Nishimura, Asami Nishikori, Yasuharu Sato, Fumio Otsuka

Pathology International   2022.6

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Immunoglobulin G4 (IgG4)-positive marginal zone lymphoma (MZL) is rare and undefined. It is unclear whether IgG4-positive MZLs have as favorable an outcome as MZLs in general. Also, correlation with IgG4-related disease (IgG4-RD) and IgG4-positive MZLs is unknown. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews, we searched MEDLINE and EMBASE for all peer-reviewed articles using keywords including"IgG4" and "marginal zone lymphoma" from their inception to February 20, 2022. Twenty-two articles, including six observational studies and 24 cases from 16 case reports and case series, were included. Only one study had a comparative group, and the other five were exploratory observational studies. IgG4-positive MZLs commonly occurred in males (83.3%). It primarily involved ocular adnexa (41.7%) and skin (29.2%). Only 29.2% had concurrent IgG4-RD, and no expiration was noted. While most cases were treated with excision, resection, or clinical observation, 21.7% received rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone as a first-line treatment. This systematic review summarizes the current understanding of the characteristics of IgG4-positive MZLs. While there seems to be IgG4-RD-related and de novo IgG4-positive MZLs, future research needs to clearly define MZL with polyclonal IgG4-positive cells and IgG4-producing lymphoma. Further studies are critical to clarifying long-term prognosis and optimal surveillance planning.

DOI： 10.1111/pin.13251

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Global public awareness of Castleman disease and TAFRO syndrome between 2015 and 2021: A Google Trends analysis Reviewed

Yoshito Nishimura, Midori Filiz Nishimura, David C. Fajgenbaum, Frits van Rhee, Yasuharu Sato, Fumio Otsuka

eJHaem   3 ( 3 )   748 - 753   2022.4

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

DOI： 10.1002/jha2.459

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International definition of iMCD-TAFRO: future perspectives. Invited Reviewed

Yoshito Nishimura, Midori Filiz Nishimura, Yasuharu Sato

Journal of clinical and experimental hematopathology : JCEH   2022.4

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Since thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly (TAFRO) syndrome was first proposed in 2010, there has been considerable progress in this area, particularly regarding its association with idiopathic multicentric Castleman disease (iMCD). TAFRO syndrome is a heterogeneous category with a constellation of symptoms that can develop in the setting of infection, rheumatologic disorder, malignancy, and iMCD. Now, iMCD with TAFRO symptoms is subtyped as iMCD-TAFRO. However, confusion between TAFRO syndrome and iMCD-TAFRO remains. In this article, we discuss the current understanding and future research agenda of TAFRO syndrome and iMCD-TAFRO from the perspective of its new validated international definition.

DOI： 10.3960/jslrt.21037

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Idiopathic multicentric Castleman disease with positive antiphospholipid antibody: atypical and undiagnosed autoimmune disease? Reviewed

Yoshito Nishimura, Asami Nishikori, Haruki Sawada, Torrey Czech, Yuki Otsuka, Midori Filiz Nishimura, Hiroki Mizuno, Naoki Sawa, Shuji Momose, Kumiko Ohsawa, Fumio Otsuka, Yasuharu Sato

Journal of Clinical and Experimental Hematopathology   2022

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society for Lymphoreticular Tissue Research  

Idiopathic multicentric Castleman disease (iMCD) is a systemic disorder characterized by systemic inflammation and organ dysfunction associated with an increase in pro-inflammatory cytokines. Some patients with iMCD are positive for autoantibodies, although their significance and relationship with specific associated autoimmune diseases are unclear. This study retrospectively analyzed the clinicopathological features of iMCD patients focusing on autoantibodies. Among 63 iMCD patients in our database, 19 were positive for at least one autoantibody. Among the 19, we identified five with plasma cell type (PC)-iMCD lymph node histopathology and positive anti-phospholipid antibodies. These patients were likely to have thrombocytopenia, anasarca, fever, reticulin fibrosis or renal insufficiency, organomegaly (TAFRO) symptoms, and thrombotic events. The present study suggests that patients with undiagnosed or atypical autoimmune diseases, including anti-phospholipid syndrome (APS), were treated for iMCD. APS may present with thrombocytopenia or even multi-organ failure, which overlap with clinical presentations of iMCD. Due to differences in the treatment regimen and follow-up, recognition of the undiagnosed autoimmune disease process in those suspected of iMCD is essential. Our study highlights the importance of complete exclusion of differential diagnoses in patients with iMCD in their diagnostic workup.

DOI： 10.3960/jslrt.21038

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Cytopathological Findings of Secretory Carcinoma of the Salivary Gland and the Diagnostic Utility of Giemsa Staining Reviewed International journal

Yuria Egusa, Midori Filiz Nishimura, Satoko Baba, Kengo Takeuchi, Takuma Makino, Tomoyasu Tachibana, Asami Nishikori, Azusa Fujita, Hiroyuki Yanai, Yasuharu Sato

Diagnostics   11 ( 12 )   2284 - 2284   2021.12

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Secretory carcinoma is a salivary gland neoplasm first described as a mammary analogue secretory carcinoma by Skalova et al. in 2010 and redesignated as a secretory carcinoma in the 2017 World Health Organization Classification of Head and Neck Tumors. Secretory carcinoma diagnosis is reliant on specific cytological and histological findings and the detection of an ETV6-NTRK3 fusion gene. Here, we examined the clinical and cytopathological features of four cases of secretory carcinoma occurring in three males and a female, aged between 39 and 74 years. All four tumors involved the parotid gland, and were found to have the ETV6-NTRK3 fusion gene. Fine-needle aspiration-based cytology smears of all tumors displayed papillary and/or dendritic pattern clusters, some of which were associated with blood vessels. The neoplastic cells displayed enlarged nuclei with fine chromatin and small, distinct, single nucleoli. Furthermore, several neoplastic cells with a characteristic vacuolated cytoplasm were identified in each specimen. Giemsa staining revealed cytoplasmic vacuolation, intracytoplasmic metachromatic secretions and/or various sized metachromatic granules, and a background of metachromatic mucin in all four specimens. Given this, we conclude that these cytological findings, especially those of the Giemsa staining, might be helpful in the diagnosis of secretory carcinoma.

DOI： 10.3390/diagnostics11122284

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PD‐L1 expression is associated with the spontaneous regression of patients with methotrexate‐associated lymphoproliferative disorders Reviewed

Yuka Gion, Misato Doi, Yoshito Nishimura, Tomoka Ikeda, Midori Filiz Nishimura, Misa Sakamoto, Yuria Egusa, Asami Nishikori, Azusa Fujita, Noriko Iwaki, Naoya Nakamura, Tadashi Yoshino, Yasuharu Sato

Cancer Medicine   2021.11

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

DOI： 10.1002/cam4.4462

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Investigation of IgG4‐positive cells in idiopathic multicentric Castleman disease and validation of the 2020 exclusion criteria for IgG4‐related disease Reviewed

Asami Nishikori, Midori Filiz Nishimura, Yoshito Nishimura, Kenji Notohara, Akira Satou, Masafumi Moriyama, Seiji Nakamura, Yasuharu Sato

Pathology International   2021.11

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Authorship：Lead author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1111/pin.13185

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Epstein-Barr virus-positive mucocutaneous ulcer is characterized by relatively low serum soluble IL-2 receptor levels regardless of methotrexate use; Reply to Ramia de Cap and Michaels Reviewed

Tomoka Ikeda, Yuka Gion, Yoshito Nishimura, Asami Nishikori, Midori Filiz Nishimura, Tadashi Yoshino, Yasuharu Sato

Modern Pathology   2021.8

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

DOI： 10.1038/s41379-021-00892-w

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Other Link： https://www.nature.com/articles/s41379-021-00892-w

Upregulated Expression of Activation-Induced Cytidine Deaminase in Ocular Adnexal Marginal Zone Lymphoma with IgG4-Positive Cells Reviewed International journal

Asami Nishikori, Yoshito Nishimura, Rei Shibata, Koh-ichi Ohshima, Yuka Gion, Tomoka Ikeda, Midori Filiz Nishimura, Tadashi Yoshino, Yasuharu Sato

International Journal of Molecular Sciences   22 ( 8 )   2021.4

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Immunoglobulin G4-related disease (IgG4-RD) is a systemic disorder characterized by tissue fibrosis and intense lymphoplasmacytic infiltration, causing progressive organ dysfunction. Activation-induced cytidine deaminase (AID), a deaminase normally expressed in activated B-cells in germinal centers, edits ribonucleotides to induce somatic hypermutation and class switching of immunoglobulin. While AID expression is strictly controlled under physiological conditions, chronic inflammation has been noted to induce its upregulation to propel oncogenesis. We examined AID expression in IgG4-related ophthalmic disease (IgG4-ROD; n = 16), marginal zone lymphoma with IgG4-positive cells (IgG4+ MZL; n = 11), and marginal zone lymphoma without IgG4-positive cells (IgG4- MZL; n = 12) of ocular adnexa using immunohistochemical staining. Immunohistochemistry revealed significantly higher AID-intensity index in IgG4-ROD and IgG4+ MZL than IgG4- MZL (p < 0.001 and = 0.001, respectively). The present results suggest that IgG4-RD has several specific causes of AID up-regulation in addition to inflammation, and AID may be a driver of oncogenesis in IgG4-ROD to IgG4+ MZL.

DOI： 10.3390/ijms22084083

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Epstein–Barr Virus-Positive Mucocutaneous Ulcer: A Unique and Curious Disease Entity Reviewed International journal

Tomoka Ikeda, Yuka Gion, Yoshito Nishimura, Midori Filiz Nishimura, Tadashi Yoshino, Yasuharu Sato

International Journal of Molecular Sciences   22 ( 3 )   2021.1

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Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) was first described as a lymphoproliferative disorder in 2010. EBVMCU is a unifocal mucosal or cutaneous ulcer that often occurs after local trauma in patients with immunosuppression; the patients generally have a good prognosis. It is histologically characterized by proliferating EBV-positive atypical B cells accompanied by ulcers. On the basis of conventional pathologic criteria, EBVMCU may be misdiagnosed as EBV-positive diffuse large B-cell lymphoma or other lymphomas. However, its prognosis differs from that of EBV-associated lymphomas, in that patients with EBVMCU frequently show spontaneous regression or complete remission without chemotherapy. Therefore, EBVMCU is now recognized as a low-grade malignancy or a pseudo-malignant lesion. Avoiding unnecessary chemotherapy by distinguishing EBVMCU from other EBV-associated lymphomas will reduce the burden and unnecessary harm on patients. On the basis of these facts, EBVMCU was first described as a new clinicopathological entity by the World Health Organization in 2017. In this review, we discuss the clinicopathological characteristics of previously reported EBVMCU cases, while focusing on up-to-date clinical, pathological, and genetic aspects.

DOI： 10.3390/ijms22031053

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Triple-negative pleomorphic lobular carcinoma and expression of androgen receptor: Personal case series and review of the literature. Reviewed International journal

Kohei Taniguchi, Shinichi Takada, Masako Omori, Takuro Igawa, Midori Filiz Nishimura, Toshiaki Morito, Kouichi Ichimura, Tadashi Yoshino

PloS one   15 ( 7 )   e0235790   2020.6

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Pleomorphic lobular carcinoma (PLC) is a histological variant of invasive lobular carcinoma (ILC) and is associated with worse prognosis than classical ILC. It exhibits a greater degree of cellular atypia and pleomorphism and is occasionally accompanied with apocrine morphology. We investigated the immunohistochemical characteristics of samples from 31 Japanese patients with PLC to elucidate the clinicopathological characteristics of PLC including androgen receptor (AR) immunoreactivity. The surrogate molecular subtypes were luminal A-like, luminal B-like, luminal B-like/HER2, HER2-type, and triple-negative in 5, 4, 3, 5, and 14 cases, respectively. AR was positive in 92.8% (13/14) of the triple-negative PLC cases and 100% (10/10) of the non-triple-negative PLC cases. Disease-specific survival was worse in patients with histological grade 3 PLCs than in those with histological grade 2 PLCs (p = 0.007). However, there was no significant difference in the progression-free survival between the two groups (p = 0.152). No other clinicopathological characteristics were associated with prognosis. These results reveal that PLC exhibits various surrogate molecular subtypes and that the triple-negative subtype frequently expresses AR. The observed molecular apocrine differentiation implicates that triple-negative PLC can be categorized into the luminal AR subtype. Furthermore, AR-targeted therapy might be useful for patients with triple-negative PLC.

DOI： 10.1371/journal.pone.0235790

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Clinicopathological analysis of 34 Japanese patients with EBV-positive mucocutaneous ulcer. Reviewed International journal

Tomoka Ikeda, Yuka Gion, Misa Sakamoto, Tomoyasu Tachibana, Asami Nishikori, Midori Filiz Nishimura, Tadashi Yoshino, Yasuharu Sato

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc   33 ( 12 )   2437 - 2448   2020.6

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Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) is a unifocal mucosal or cutaneous ulcer that is histologically characterized by proliferating EBV-positive atypical B cells. While EBVMCU demonstrates a histology similar to that of EBV-positive diffuse large B-cell lymphoma (DLBCL), their clinical behavior differs. Thus, characterizing distinguishing features of EBVMCU and EBV-positive DLBCL is critical. To identify unique characteristics between EBVMCU and lymphoma, we analyzed the clinicopathological and genetic features of 34 Japanese patients with EBVMCU and compared them to those of 24 EBV-positive DLBCL patients and 25 EBV-negative DLBCL patients. All patients with EBVMCU had localized ulcerative lesions, and 31 patients (91%) were using immunosuppressants, such as methotrexate (MTX) or hydroxycarbamide. All patients that were followed up with exhibited good prognosis following immunosuppressant reduction or chemotherapy. In addition, 17 EBV-positive DLBCL patients, and 15 EBV-negative DLBCL patients, received chemotherapy (P < 0.001, P < 0.001, respectively). Our data showed that EBVMCU did not increase indicators associated with lymphoma prognosis, such as soluble interleukin 2 receptor (sIL-2R) and lactate dehydrogenase (LDH) compared to those in the EBV-positive DLBCL or EBV-negative DLBCL groups (sIL-2R, P < 0.001, P = 0.025; LDH, P = 0.018, P = 0.038, respectively). However, histologically, EBVMCU exhibited EBV-positive, variable-sized, atypical B-cell proliferation. Thus, EBVMCU was histologically classified as: (1) polymorphous; (2) large cell-rich; (3) classic Hodgkin lymphoma-like; and (4) mucosa-associated lymphoid tissue lymphoma-like. Moreover, genetic analysis showed that immunoglobin heavy chain (IGH) gene rearrangement did not differ significantly between EBVMCU and EBV-positive DLBCL (44% vs. 32%; P = 0.377), or between EBVMCU and EBV-negative DLBCL (44% vs. 58%; P = 0.280). Therefore, it is difficult to distinguish EBVMCU from EBV-positive DLBCL using only pathological and genetic findings, suggesting that clinical information is important in accurately distinguishing between EBVMCU and EBV-positive DLBCL.

DOI： 10.1038/s41379-020-0599-8

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