Faculty Profiles - SATO Yasuharu

Papers - SATO Yasuharu

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

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 : an official journal of the United States and Canadian Academy of Pathology, Inc 100782 - 100782 2025.4

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Idiopathic multicentric Castleman disease is a rare lymphoproliferative disorder that is clinically classified into idiopathic plasmacytic lymphadenopathy (IPL); thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO); and not otherwise specified (NOS). Although each subtype shows varying degrees of hypervascularity, no statistical data on the degree of vascularization have been reported. Additionally, the mechanisms underlying vascularization in each clinical subtype are poorly understood. Here, we aimed to clarify these mechanisms by evaluating the histopathological characteristics of each clinical subtype across 37 patients and performing a whole-transcriptome analysis focusing on angiogenesis-related gene expression. Histologically, TAFRO and NOS exhibited a significantly higher degree of vascularization than IPL (IPL vs TAFRO: p < 0.001, IPL vs NOS: p = 0.002). In addition, the germinal centers (GCs) were significantly more atrophic in TAFRO than in IPL. In TAFRO and NOS, "whirlpool vessels" in GCs were seen in most cases (TAFRO: 9/9, 100%, NOS: 6/8, 75%), but not in IPL (IPL vs TAFRO: p < 0.001, IPL vs NOS: p = 0.007). Likewise, immunostaining for Ets-related gene revealed higher levels in endothelial cells of GCs in TAFRO than in IPL (p = 0.014), and TAFRO and NOS were associated with a significantly higher number of endothelial cells in interfollicular areas compared to that in IPL (TAFRO vs IPL: p < 0.001, NOS vs IPL: p = 0.002). Gene expression analysis revealed that the PI3K-Akt signaling pathway was significantly enriched in the TAFRO and NOS (TAFRO/NOS) groups. This pathway, which may be activated by vascular endothelial growth factor A and some integrins, is known to affect angiogenesis by increasing vascular permeability, which may explain the clinical manifestations of anasarca and/or fluid retention in TAFRO/NOS. These results suggest that the PI3K-Akt pathway plays an important role in the pathogenesis of TAFRO/NOS.

DOI： 10.1016/j.modpat.2025.100782

Differential diagnosis between pleomorphic adenoma and carcinoma ex pleomorphic adenoma: focus on clinical and MR findings. Reviewed International journal

Asuka Sato, Tomoyasu Tachibana, Yuichiro Kanie, Minami Kakiuchi, Akifumi Kariya, Chieko Furukawa, Yuto Naoi, Yasuharu Sato, Mizuo Ando

Acta oto-laryngologica 1 - 5 2025.4

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

BACKGROUND: In parotid tumors, preoperative differential diagnosis between pleomorphic adenoma (PA) and carcinoma ex pleomorphic adenoma (CXPA) remains challenging. OBJECTIVES: The present study aimed to evaluate the clinical characteristics of CXPA and PA and to identify factors associated with the differential diagnosis of these conditions. MATERIAL AND METHODS: We reviewed the medical records of 6 CXPA and 127 PA patients treated surgically at our institution between 2008 and 2024. RESULT: Univariate analysis revealed significant differences in spontaneous pain (p = .044), facial nerve palsy (p = .045), and subjective enlargement (p < .01) between the CXPA and PA patients. Magnetic resonance imaging (MRI) revealed that the proportions of masses with ill-defined margins, localization in the deep lobe, and low apparent diffusion coefficient (ADC) were significantly higher in patients with CXPA than in those with PA (p < .01, p = .048, and p < .01, respectively). Multivariate analysis identified that spontaneous pain and masses with ill-defined margins were associated with CXPA (p = .047 and p = .013, respectively). CONCLUSION: Spontaneous pain and masses with ill-defined margins could be suggestive of CXPA rather than PA. Low ADC levels indicate the possibility of CXPA.

DOI： 10.1080/00016489.2025.2480687

Exploring the Clinical Diversity of Castleman Disease and TAFRO Syndrome: A Japanese Multicenter Study on Lymph Node Distribution Patterns. Reviewed International journal

Mizuna Otsuka, Tomohiro Koga, Remi Sumiyoshi, Shoichi Fukui, Yuko Kaneko, Takayuki Shimizu, Atsushi Katsube, Shingo Yano, Yasufumi Masaki, Makoto Ide, Hajime Yoshifuji, Masayasu Kitano, Yasuharu Sato, Naoki Sawa, Hiroaki Niiro, Naoya Nakamura, David C Fajgenbaum, Frits van Rhee, Atsushi Kawakami

American journal of hematology 100 ( 4 ) 592 - 605 2025.4

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

Individuals diagnosed with Castleman disease (CD) and TAFRO syndrome (characterized by thrombocytopenia, anasarca, fever, bone marrow fibrosis, and organomegaly) displays a wide range of clinical symptoms, including varying patterns of lymph node enlargement, systemic inflammation, and impaired organ function. Some patients may present with both CD and TAFRO syndrome concurrently. A retrospective study conducted across multiple centers in Japan examined 321 cases to determine if the quantity and position of swollen lymph nodes could forecast the clinical progression and intensity of these conditions. Interestingly, the study revealed that patients with TAFRO syndrome exhibited lymphadenopathy across all ranges of lymph node region counts. Moreover, no specific clinical patterns were associated with the number of affected lymph node regions in CD patients, regardless of whether they also had TAFRO syndrome. These results enhance our understanding of the clinical variability in CD and TAFRO syndrome, suggesting that a comprehensive clinical evaluation, rather than relying solely on lymph node count, is crucial for effectively managing these conditions. Additional studies are required to establish reliable diagnostic markers and to predict disease severity at the time of diagnosis, ultimately improving patient outcomes.

DOI： 10.1002/ajh.27612

Kikuchi-Fujimoto disease: investigating comprehensive clinicopathological features and risk factors for recurrence. Reviewed International journal

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

Histopathology 2025.2

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

AIMS: Kikuchi-Fujimoto disease (KFD) is a rare disease that typically manifests with fever and cervical lymphadenopathy. Little is known about the risk factors associated with recurrence and their correlation with clinicopathologic features. METHODS AND RESULTS: We analysed 112 patients with KFD, predominantly female (61/112, 54.5%), with an average age of 29.4 years. The incidence was higher in males up to the age of 20 and higher in females from their 30s onwards. Of the 70 patients with follow-up data, 23% experienced recurrence. Recurrence was associated with lower C4 levels (P = 0.038) and higher antinuclear antibody (ANA) rates (P = 0.007) compared to transient disease. The mean duration of symptoms was 71.5 days. Lymph node histology in 98 cases (excluding 14 needle biopsy specimens) was classified into three patterns: proliferative (n = 75, 77%), necrotizing (n = 22, 22%), and xanthomatous (n = 1, 1%). The necrotizing pattern associated with significantly enlarged lymph nodes (P = 0.047) and a longer symptom duration (P = 0.009) than the proliferating pattern. The number of CD4-positive lymphocytes was significantly lower in the necrotizing type than in the proliferative type (P < 0.001). CONCLUSION: These results indicated that low C4 levels and positive ANA were associated with KFD recurrence. Although the aetiology of KFD remains elusive, given that some cases develop autoimmune disease, the results suggest that patients with recurrent KFD represent an intermediate status between those with transient KFD and those with overt autoimmune disease. The comprehensive clinicopathological findings of this study may be useful for elucidating its pathogenesis and predicting the clinical course.

DOI： 10.1111/his.15427

Effect of D-amino acid metabolic enzyme deficiency on cancer development-diffuse large B-cell lymphoma onset and gene expression analyses in DASPO-knockout mice. Reviewed International journal

Yusuke Nakade, Yasunori Iwata, Kenichi Harada, Yasuharu Sato, Masashi Mita, Kenji Hamase, Ryuichi Konno, Mayo Hayashi, Taku Kobayashi, Yuta Yamamura, Tadashi Toyama, Atsushi Tajima, Takashi Wada

Amino acids 57 ( 1 ) 4 - 4 2024.12

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

The relationship between D-AA metabolic enzymes and cancer development remains unclear. We aimed to investigate this relationship using mice deficient in D-AA-related metabolic enzymes. We examined mice lacking these enzymes for approximately 900 days and the effects of altered D-AA metabolism on cancer development based on lifespan, pathological findings, and gene expression. The lifespan of female DASPO -knockout (DASPO-/-) mice was shorter than that of the other group mice; furthermore, these mice showed tumor-like masses in the liver, spleen, and small intestine. A pathological diagnosis of diffuse large B-cell lymphoma (DLBCL) was made. RNA sequencing of the liver samples showed specific alterations in the expression of 71 genes in DASPO-/- mice compared with that in wild-type B6 mice; RGS 1, MTSS1, and SMARCD 1 were identified as DLBCL-related genes. Patients with DLBCL exhibiting low DASPO expression demonstrated a shorter survival period than those showing high expression. However, the role of DASPO in DLBCL development is unclear. Therefore, future research should focus on B cells. DASPO may serve as novel biomarkers and therapeutic targets in cancer.

DOI： 10.1007/s00726-024-03426-1

Late onset paediatric dacryoadenitis associated with SARS-CoV-2 confirmed by histological analysis. Reviewed International journal

Koji Yokoyama, Yasuharu Sato, Yuka Suimon, Satoru Kase

BMJ case reports 17 ( 12 ) 2024.12

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

We report a case of chronic dacryoadenitis associated with SARS-CoV-2, confirmed by histological analysis. A previously healthy school-aged boy was admitted to the paediatric department with a 1 month history of both eyebrow swelling and very mild pain in the upper parts of both eyelids. Gadolinium-enhanced T1-weighted MRI revealed enlargement of both lacrimal glands. Clinicopathological analysis confirmed bilateral chronic dacryoadenitis. Topical steroids were given, resulting in slow resolution over 2 months, and clinical stability at 10 months. The patient had experienced mild respiratory symptoms and tested positive for SARS-CoV-2 antigen via PCR testing, diagnosed as SARS-CoV-2, 3 months prior to the onset of dacryoadenitis. Inflammatory cells around the lacrimal gland demonstrated immunoreactivity for SARS-CoV-2 nucleocapsid protein. However, PCR testing of lacrimal fluid for SARS-CoV-2 was negative. This case illustrates protean complications and suggests a probable pathogenetic mechanism of dacryoadenitis associated with SARS-CoV-2.

DOI： 10.1136/bcr-2023-257615

Erythema Nodosum Secondary to CD5-Positive Diffuse Large B-Cell Lymphoma as a Paraneoplastic Symptom: A Case Report. Reviewed International journal

Masaya Abe, Kyotaro Ohno, Yuki Nakagawa, Yasuharu Sato, Hiroyuki Sugiura

Case reports in oncology 17 ( 1 ) 1094 - 1102 2024.12

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

INTRODUCTION: Erythema nodosum (EN) is the most common form of panniculitis. EN can be idiopathic or secondary to an underlying systemic disease, infection, drug use, or tumor. CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is a relapsed and refractory lymphoma, and further understanding of its pathology is required. We report a case of newly diagnosed CD5+ DLBCL with concomitant EN. Within the scope of our search, there were no reports of CD5+ DLBCL complicated with EN. CASE PRESENTATION: A 79-year-old woman experienced swelling, warmth, redness, and pain in both legs and a mass lesion on the right side of the back at almost the same time. The respective lesions were diagnosed as EN and CD5+ DLBCL by biopsy. With chemotherapy, the lymphoma and EN improved in parallel courses. The patient has completed scheduled chemotherapy, and there has been no recurrence of swelling in the legs or mass on the right side of the back. DISCUSSION: The lymphoma and EN developed simultaneously and followed a parallel clinical course after chemotherapy, suggesting that EN was a paraneoplastic symptom of CD5+ DLBCL. Recognizing and treating underlying malignancies in patients presenting with EN is crucial.

DOI： 10.1159/000540913

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

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

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

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

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

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 2024.11

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

Clinical profile of IgG4-related disease in Japan based on the rare disease data registry. Reviewed International journal

Motohisa Yamamoto, Masatoshi Kanda, Ichiro Mizushima, Atsushi Kanno, Takeji Umemura, Tsukasa Ikeura, Yuzo Kodama, Hiroaki Dobashi, Yoshiya Tanaka, Atsushi Masamune, Masafumi Moriyama, Takako Saeki, Shoko Matsui, Tomoki Origuchi, Yasufumi Masaki, Masanori Asada, Hisanori Umehara, Hiroshi Seno, Itaru Naitoh, Satoshi Yamamoto, Eisuke Iwasaki, Kensuke Kubota, Shiroh Tanoue, Takayoshi Nishino, Hiroto Tsuboi, Yasushi Matsumoto, Hiroyuki Isayama, Hiroshi Goto, Kenji Notohara, Kazushige Uchida, Ken Kawabe, Kazunori Yamada, Satomi Kasashima, Masayuki Takahira, Yasuharu Sato, Izumi Kawachi, Izumi Yamaguchi, Kazuichi Okazaki, Seiji Nakamura, Fumihiko Matsuda, Hideki Ishikawa, Mitsuhiro Kawano

Immunological medicine 1 - 11 2024.11

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

We started a registry for cases of immunoglobulin (Ig)G4-related disease (IgG4-RD) in December 2019 to clarify the clinical profile of IgG4-RD. In this study, clinical information from 854 cases registered by February 16, 2024 was analyzed from multiple perspectives. Diagnosis of IgG4-RD was made in 808 cases, comprising 638 definite, 38 probable, and 132 possible. The mean ± SD age at time of enrollment of the 808 cases was 67.9 ± 11.3 years, with 68.8% being male. The pancreas was the most frequently affected organ (49.8%), followed by the submandibular glands (46.2%) and lacrimal glands (30.6%). This study reconfirmed the pancreas and head-and-neck region as major affected areas in IgG4-RD. Clinically, submandibular adenitis and autoimmune pancreatitis often occur together in the same patient, but no association between the two organs was observed in our analysis. Regarding diagnosis, the comprehensive diagnostic criteria were most commonly used (63.6%). Storiform fibrosis and phlebitis obliterans were detected at different frequencies in different organs. In summary, this registry study identified clinical, imaging, hematologic, and pathologic findings in 808 Japanese patients with IgG4-RD. The frequency of affected organs and their characteristic pathological findings will be particularly useful for future practice.

DOI： 10.1080/25785826.2024.2430812

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

Authorship：Last author,　Corresponding author 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

免疫染色にてCD8陽性,CD25陰性を示した成人T細胞白血病リンパ腫の1例 Reviewed

厚美憲吾, 松本穣, 山下理子, 西村碧フィリーズ, 佐藤康晴, 坂東良美, 上原久典

診断病理 41 ( 4 ) 349 - 354 2024.10

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

症例はヒトT細胞白血病ウイルス1型(HTLV-1)キャリアの70歳代男性。腫大した鼠経リンパ節生検が行われた。組織像では,濾胞間でびまん性に増殖する小から中型,一部大型のリンパ球様細胞を認めた。免疫染色で中型細胞はCD3陽性,CD8陽性,CD25陰性を示し,他のCD8陽性T細胞リンパ腫との鑑別に難渋したが,CD7の減弱,CCR4の陽性像,HTLV-1プロウイルスDNAの増幅を認め,ATLLの診断に至った。ATLLにはCD8陽性例があり,病勢に伴ってCD7が減弱することを認識しておく必要がある。(著者抄録)

Renal cell carcinoma preceded by a rheumatoid‑like paraneoplastic syndrome: A case report Reviewed

Yusuke Yoshimura, Tatsuya Suwabe, Katsuyuki Miki, Takayoshi Yokoyama, Kei Kono, Keiichi Kinowaki, Ikuma Kato, Yoji Nagashima, Asami Nishikori, Yasuharu Sato, Shigekazu Kurihara, Yuki Oba, Hiroki Mizuno, Akinari Sekine, Masayuki Yamanouchi, Manabu Kamiyama, Yasuo Ishii, Yuki Nakamura, Yoshifumi Ubara, Naoki Sawa

Oncology Letters 28 ( 4 ) 2024.7

Lymphocyte-variant hypereosinophilic syndrome with dense IgG4-positive plasma cell infiltration of lymph nodes. Reviewed International journal

Hidenori Amaike, Ken Nagahata, Masatoshi Kanda, Hiroyuki Nakamura, Hiromi Fujita, Hiroaki Shima, Yasuharu Sato, Hiroki Takahashi

International journal of rheumatic diseases 27 ( 6 ) e15206 2024.6

Co-occurrence of Epstein-Barr virus-positive nodal T/NK-cell lymphoma and nodal T-follicular helper cell lymphoma of different clonal origins: An autopsy case report. Reviewed International journal

Daisuke Hoshi, Nami Migita, Shin Ishizawa, Yasuharu Sato, Koichi Yamamura, Etsuko Kiyokawa

Pathology international 2024.4

Language：English

Nodal T-follicular helper cell lymphoma (TFHL) is a subset of T-cell lymphoma and frequently co-occurs with Epstein-Barr virus (EBV)-positive B-cell lymphoma but not with T/NK-cell lymphoma. Recently, a new entity with a worse prognosis, called EBV-positive nodal T/NK-cell lymphoma (NTNKL) has been established. Here, we report an autopsy case of synchronous multiple lymphomas, including TFHL and NTNKL. The patient was a 78-year-old female admitted with pneumonia. Although pneumonic symptoms were improved, fever, pancytopenia, and disseminated intravascular coagulation emerged, implicating lymphoma. She died on the 21st hospital day without a definitive diagnosis. The autopsy revealed the enlargement of multiple lymph nodes throughout her body. Histological analysis revealed three distinct regions in the left inguinal lymph node. The first region consists of small-sized lymphocytes with T-follicular helper phenotype and extended follicular dendritic cell meshwork, indicating TFHL. The second region included EBV-positive large B cells. The third region comprised EBV-positive large cells with cytotoxic T/NK cell phenotype, indicating NTNKL. Clonality analysis of the first and the third regions showed different patterns. Since various hematopoietic malignancies progress from common clonal hematopoiesis according to existing literature, this case may help to understand TFHL and NTNKL.

DOI： 10.1111/pin.13425

EBV+ nodal T/NK-cell lymphoma associated with clonal hematopoiesis and structural variations of the viral genome. Reviewed International journal

Seiichi Kato, Motoharu Hamada, Akinao Okamoto, Daisuke Yamashita, Hiroaki Miyoshi, Haruto Arai, Akira Satou, Yuka Gion, Yasuharu Sato, Yuta Tsuyuki, Tomoko Miyata-Takata, Katsuyoshi Takata, Naoko Asano, Emiko Takahashi, Koichi Ohshima, Akihiro Tomita, Waki Hosoda, Shigeo Nakamura, Yusuke Okuno

Blood advances 2024.3

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

Epstein-Barr virus (EBV)+ nodal T- and NK-cell lymphoma (EBV+ nPTCL) is a peripheral T-cell lymphoma (PTCL) that presents as a primary nodal disease with T-cell phenotype and EBV harboring on tumor cells. To date, the genetic aspect of EBV+ nPTCL has not been fully investigated. In this study, whole-exome and/or genome sequencing was performed on 22 cases of EBV+ nPTCL. TET2 (68%) and DNMT3A (32%) were observed to be the most frequently mutated genes whose presence was associated with poor overall survival (p = 0.004). The RHOA p.Gly17Val mutation was identified in two patients who had TET2 and/or DNMT3A mutations. In four patients with TET2/DNMT3A alterations, blood cell-rich tissues (bone marrow [BM] or spleen) were available as paired normal samples. Three out of these four cases had at least one identical TET2/DNMT3A mutation in the BM or spleen. Additionally, the whole part of the EBV genome was sequenced and structural variations (SVs) were found frequent among the EBV genomes (63%). The most frequently identified type of SV was deletion. In one patient, four pieces of human chromosome 9, including PD-L1 were identified to be tandemly incorporated into the EBV genome. The 3'-untranslated region of PD-L1 was truncated, causing a high-level of PD-L1 protein expression. Overall, the frequent TET2 and DNMT3A mutations in EBV+ nPTCL seem to be closely associated with clonal hematopoiesis and, together with the EBV genome deletions, may contribute to the pathogenesis of this intractable lymphoma.

DOI： 10.1182/bloodadvances.2023012019

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

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

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

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

AIMS AND METHODS: Idiopathic multicentric Castleman disease (iMCD) is currently considered to be classified into three clinical subtypes, including idiopathic plasmacytic lymphadenopathy (IPL), thrombocytopaenia, anasarca, fever, reticulin fibrosis/renal dysfunction, organomegaly (TAFRO) and not otherwise specified (NOS). Among the three, iMCD-IPL closely mimics IgG4-related disease (IgG4-RD). In diagnosing IgG4-RD, it is sometimes challenging to distinguish iMCD-IPL patients that also meet the histological diagnostic criteria for IgG4-RD. In this study, we focused on the number of IgG4-positive cells in the lymph nodes and analysed the relationship with laboratory findings to distinguish iMCD-IPL from IgG4-RD. Thirty-nine patients with iMCD-IPL and 22 patients with IgG4-RD were included. RESULTS: Among the cases considered to be iMCD-IPL, 33.3% (13/39) cases also met the histological diagnostic criteria for IgG4-RD and serum IgG4 levels were not different between the two groups. However, the serum IgG4/IgG ratio was significantly higher in IgG4-RD, with a cut-off value of 19.0%. Additionally, a significant positive correlation between serum IgG levels and the number of IgG4-positive cells was observed in iMCD-IPL (p=0.001). The serum IgG cut-off value for distinguishing iMCD-IPL meeting histological criteria for IgG4-RD from other iMCD-IPL was 5381 mg/dL. CONCLUSIONS: iMCD-IPL cases with high serum IgG levels (>5000 mg/dL) were likely to meet the diagnostic criteria for IgG4-RD because of the numerous IgG4-positive cells observed. A combination of clinical presentations, laboratory values including the serum IgG4/IgG ratios and histological analysis is crucial for diagnosis of IgG4-RD and iMCD-IPL.

DOI： 10.1136/jcp-2023-209280

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

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

Journal of clinical and experimental hematopathology : JCEH 2024.1

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

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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