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

Atypical lymphoplasmacytic and immunoblastic proliferation: A Systematic Review Reviewed

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

Authorship：Last 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

T-cell receptor gamma gene rearrangement analysis of classic Hodgkin lymphoma using a BIOMED-2 assay: a paraffin-embedded tissue analysis of one hundred cases. Reviewed

Katsuyoshi Takata, Tomoko Miyata-Takata, Asami Nishikori, Tomoka Haratake, Yasuharu Sato

Journal of clinical and experimental hematopathology : JCEH 64 ( 2 ) 138 - 143 2024

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

In the new WHO classifications of haematolymphoid tumours (WHO-HAEM5), classic Hodgkin lymphoma (cHL) is categorized into B-cell lymphoid proliferations and lymphomas. Although the majority of Hodgkin Reed-Sternberg (HRS) cells are of germinal center B-cell origin with some defects of B-cell transcription factors, they rarely express T-cell antigens or cytotoxic molecules. Clonality analyses on cHL samples using BIOMED-2 have been reported by several groups; however, those studies were only focused on Ig regions, including IgH, Ig-kappa, and Ig-lambda, and TCR-γ clonality analysis of cHL has not yet been explored. Here, we investigated TCR-γ gene rearrangement for one hundred cases using a PCR-based method. Four of one hundred (4%) cases showed TCR-γ clonal peaks. Of these, three were at an advanced stage and one patient died of the disease. To clarify whether HRS cells showed T-cell clonality or not, we performed PCR analysis using DNAs of microdissected HRS cells. Three samples showed identical clonal peaks with bulk specimens. Our results indicate that cHL is a heterogeneous disease of mainly B-cell and rarely T-cell origin with a special phenotype. Further molecular studies are warranted.

DOI： 10.3960/jslrt.24027

Frequent CDKN2B/P15 and DAPK1 methylation in duodenal follicular lymphoma is related to duodenal reactive lymphoid hyperplasia. Reviewed

Katsuyoshi Takata, Tomoko Miyata-Takata, Yasuharu Sato

Journal of clinical and experimental hematopathology : JCEH 64 ( 2 ) 129 - 137 2024

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

Duodenal type follicular lymphoma (DFL), a rare entity of follicular lymphoma (FL), is clinically indolent and is characterized by a low histological grade compared with nodal follicular lymphoma (NFL). Our previous reports revealed that DFL shares characteristics of both NFL and mucosa-associated lymphoid tissue (MALT) lymphoma in terms of clinical and biological aspects, suggesting its pathogenesis may involve antigenic stimulation. In contrast to NFL, the genomic methylation status of DFL is still challenging. Here, we determined the methylation profiles of DNAs from patients with DFL (n = 12), NFL (n = 10), duodenal reactive lymphoid hyperplasia (D-RLH) (n = 7), nodal reactive lymphoid hyperplasia (N-RLH) (n = 5), and duodenal samples from normal subjects (NDU) (n = 5) using methylation specific PCR of targets previously identified in MALT lymphoma (CDKN2B/P15, CDKN2A/P16, CDKN2C/P18, MGMT, hMLH-1, TP73, DAPK, HCAD). DAPK1 was frequently methylated in DFL (9/12; 75%), NFL (9/10; 90%), and D-RLH (5/7; 71%). CDKN2B/P15 sequences were methylated in six DFL samples and in only one NFL sample. Immunohistochemical analysis showed that p15 expression inversely correlated with methylation status. Genes encoding other cyclin-dependent kinase inhibitors (CDKN2A/P16, CDKN2C/P18) were not methylated in DFL samples. Methylation of the genes of interest was not detected in DNAs from D-RLH, except for DAPK1, and the difference in the extent of methylation between NDU and D-RLH was statistically significant (P = 0.013). Our results suggest that D-RLH serves as a reservoir for the development of DFL and that methylation of CDKN2B/P15 plays an important role in this process.

DOI： 10.3960/jslrt.24020

Primary Thyroid Lymphoma: Clinical Factors Predicting the Possibility of Diffuse Large B-Cell Lymphoma. Reviewed International journal

Akifumi Kariya, Tomoyasu Tachibana, Yasushi Hiramatsu, Yoji Wani, Jun-Ya Matsumoto, Chieko Furukawa, Asuka Sato, Yuto Naoi, Yorihisa Orita, Yasuharu Sato, Mizuo Ando

Ear, nose, & throat journal 1455613231218130 - 1455613231218130 2023.12

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

Aims: Among primary thyroid lymphomas (PTLs), diffuse large B-cell lymphoma (DLBCL) has a poorer prognosis than other indolent lymphomas such as mucosa-associated lymphoid tissue (MALT) or follicular lymphoma (FL). However, the clinical differences between DLBCL and indolent lymphoma remain unclear. Therefore, this retrospective study on PTL was aimed at investigating the clinical differences between DLBCL and indolent lymphomas and identifying the factors differentiating DLBCL from indolent lymphomas. Materials and Methods: Medical records of 28 patients diagnosed with PTL and treated at our institution between 2005 and 2022 were retrospectively analyzed. Data on the following clinical variables were extracted: sex, age, symptoms (pain and dysphagia), ultrasonographic appearance patterns, the presence of airway stenosis on computed tomography and laryngeal endoscopy, blood test results, disease stage, and pathological diagnosis. Results: In all, 13 patients were histologically diagnosed with DLBCL, 12 with MALT lymphoma, and 3 with FL. Significant differences in disease-specific survival rates were evident between the DLBCL and indolent lymphoma groups (68.2 vs 100%, P = .043). High lactate dehydrogenase levels (>230 U/mL) and airway stenosis were observed only in patients with DLBCL. Multivariate analysis identified that the presence of a linear echoic strand pattern and the absence of an echoic nodular pattern on ultrasound were independently associated with DLBCL (P = .0497 and .012, respectively). Conclusion: DLBCL can cause airway stenosis. The linear echogenic strand pattern and the absence of a nodular pattern should be recognized as predictive factors of DLBCL.

DOI： 10.1177/01455613231218130

Pediatric IgG4-related disease: a descriptive review. Reviewed International journal

Satoshi Hara, Misaki Yoshida, Hajime Sanada, Yasunori Suzuki, Yasuharu Sato, Ichiro Mizushima, Mitsuhiro Kawano

Expert review of clinical immunology 1 - 23 2023.10

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

INTRODUCTION: IgG4-related disease (IgG4-RD) is an immune-mediated systemic fibroinflammatory condition characterized by serum IgG4 elevation and IgG4-positive plasma cell infiltration into various organs. It generally occurs in elderly males. Pediatric cases have been reported, albeit rarely, accordingly lack of recognition of such cases could delay therapeutic intervention leading to poorer outcomes. AREAS COVERED: The present review is a descriptive review of all published case reports, cohort studies, and reviews of pediatric IgG4-RD listed in PubMed. Characteristics of pediatric IgG4-RD were clarified, including sex, organ involvement, serological and histological findings, and treatment. We assessed how many published cases met current classification and comprehensive diagnostic criteria. EXPERT OPINION: The characteristics of pediatricIgG4-RD differed from adult IgG4-RD in terms of sex and involved organs. There was no clear male dominance in numbers of cases, and surface organ involvement such as ophthalmic diseases were more common in the pediatric IgG4-RD. Organ involvement tended to be indolent and unilateral, causing difficulty in definitively diagnosing pediatric IgG4-RD. Only about 20% of published cases met IgG4-RD classification or comprehensive diagnostic criteria. Physicians should be careful in diagnosing pediatric IgG4-RD after excluding mimickers. International collaboration toward high-quality evidence to support diagnosis and treatment of pediatric IgG4-RD is advised.

DOI： 10.1080/1744666X.2023.2274358

Near-infrared photoimmunotherapy for salivary duct carcinoma. Reviewed International journal

Takuma Makino, Yasuharu Sato, Kensuke Uraguchi, Yuto Naoi, Yujiro Fukuda, Mizuo Ando

Auris, nasus, larynx 2023.9

Language：English

In Japan, near-infrared photoimmunotherapy (NIR-PIT) was introduced in 2021 as a treatment option for unresectable recurrent head and neck cancer. The treatment targets the epidermal growth factor receptor (EGFR), which is overexpressed in 80-90 % of head and neck squamous cell carcinoma (HNSCC). NIR-PIT should theoretically show therapeutic efficacy if EGFR is expressed, even in nonsquamous cell carcinomas (non-SCC). To the best of our knowledge, there are no case reports of NIR-PIT for non-SCC. We performed NIR-PIT in a patient with non-SCC of the head and neck region. After performing two NIR-PIT treatments, small free clusters of residual tumor cells were observed. Immunostaining in this specimen revealed EGFR expression in residual tumor cells. The residual tumor cells had been irradiated sufficiently to achieve necrosis. It is suggested that not only laser irradiation and expression of EGFR but also other factors are involved in the efficacy of this treatment. Further investigation for these other factors is warranted.

DOI： 10.1016/j.anl.2023.09.006

Distribution and clinical impact of molecular subtypes with Dark Zone signature of DLBCL in a Japanese real-world study. Reviewed International journal

Tomohiro Urata, Yusuke Naoi, Aixiang Jiang, Merrill Boyle, Kazutaka Sunami, Toshi Imai, Yuichiro Nawa, Yasushi Hiramatsu, Kazuhiko Yamamoto, Soichiro Fujii, Isao Yoshida, Tomofumi Yano, Ryota Chijimatsu, Hiroyuki Murakami, Kazuhiro Ikeuchi, Hiroki Kobayashi, Katsuma Tani, Hideki Ujiie, Hirofumi Inoue, Shuta Tomida, Akira Yamamoto, Takumi Kondo, Hideaki Fujiwara, Noboru Asada, Hisakazu Nishimori, Keiko Fujii, Nobuharu Fujii, Ken-Ichi Matsuoka, Keisuke Sawada, Shuji Momose, Jun-Ichi Tamaru, Asami Nishikori, Yasuharu Sato, Tadashi Yoshino, Yoshinobu Maeda, David W Scott, Daisuke Ennishi

Blood advances 2023.8

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

The distribution and clinical impact of cell-of-origin (COO) subtypes of diffuse large B-cell lymphoma (DLBCL) outside Western countries remain unknown. Recent literature also suggests that there is an additional COO subtype associated with the germinal center dark zone, that warrants wider validation to generalize clinical relevance. Here, we assembled a cohort of Japanese patients with untreated DLBCL and determined the refined COO subtypes, that include the dark zone signature (DZsig), using the NanoString DLBCL90 assay. To compare the distribution and clinical characteristics of the molecular subtypes, we used a dataset from the cohort of BC Cancer (BCC) (n = 804). Of the 1050 patients where DLBCL90 assay was successfully performed in our cohort, 35%, 45%, and 6% of patients were identified to be germinal center B-cell-like (GCB)-DLBCL, activated B-cell-like (ABC)-DLBCL, and DZsigpos-DLBCL, respectively, with the highest prevalence of ABC-DLBCL differing significantly from that of BCC (P < 0.001). GCB-DLBCL, ABC-DLBCL, and DZsigpos-DLBCL were associated with two-year overall survival rates of 88%, 75%, and 66%, respectively (P < 0.0001), with patients of the DZsigpos-DLBCL having the poorest prognosis. In contrast, GCB-DLBCL without DZsig showed excellent outcomes following rituximab-containing immunochemotherapy. DZsigpos-DLBCL was associated with the significant enrichment of tumors with CD10 expression, concurrent MYC/BCL2 expression, and depletion of microenvironmental components (all P < 0.05). These results provide evidence of the distinct distribution of clinically relevant molecular subtypes in Japanese DLBCL and that refined COO, as measured by the DLBCL90 assay, is a robust prognostic biomarker that is consistent across geographical areas.

DOI： 10.1182/bloodadvances.2023010402

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 63 ( 1 ) 25 - 31 2023.1

A Case of Adolescent-onset TAFRO Syndrome with Malignant Nephrosclerosis-like Lesions. Reviewed

Yuki Nakayama, Hiroki Mizuno, Naoki Sawa, Tatsuya Suwabe, Masayuki Yamanouchi, Daisuke Ikuma, Eiko Hasegawa, Junichi Hoshino, Akinari Sekine, Yuki Oba, Kei Kono, Keiichi Kinowaki, Kenichi Ohashi, Kodai Suzuki, Yasuharu Sato, Akira Shimizu, Yutaka Yamaguchi, Yoshifumi Ubara

Internal medicine (Tokyo, Japan) 62 ( 15 ) 2223 - 2229 2022.12

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

A 16-year-old Japanese girl developed a fever, thrombocytopenia, and renal dysfunction. Treatment was started with steroids, but cervical lymphadenopathy and ascites developed. A lymph node biopsy indicated TAFRO syndrome. The patient's renal function deteriorated, and dialysis was started. Refractory hypertension and subsequent encephalopathy developed. Treatment was started with an anti-IL-6 receptor antibody and an anti-CD20 monoclonal antibody. A kidney biopsy showed malignant nephrosclerosis-like microangiopathy and glomerular collapse due to narrowing of the small arteries. The majority of TAFRO syndrome cases are adult-onset, with glomerular microangiopathy. To our knowledge, this is the first report of adolescent-onset TAFRO syndrome presenting with malignant nephrosclerosis-like lesions associated with hypertension.

DOI： 10.2169/internalmedicine.0529-22

Utility of renal biopsy in differentiating idiopathic multicentric Castleman disease from IgG4-related disease. Reviewed

Miharu Kawanishi, Fumika Kamei, Hirotaka Sonoda, Masafumi Oba, Shohei Fukunaga, Masahiro Egawa, Takashi Koyama, Yasuharu Sato, Kazuaki Tanabe, Takafumi Ito

CEN case reports 12 ( 2 ) 242 - 248 2022.11

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

Idiopathic multicentric Castleman disease (iMCD) is a subtype of human herpesvirus type 8 (HHV-8)-related Castleman disease that causes multi-organ damage, including kidney damage due to polyclonal lymphoproliferation and interleukin (IL)-6-induced cytokine storm. However, its renal pathological findings are unclear. We report the case of a woman in her 80 s who was diagnosed with iMCD based on renal pathological findings. Five years ago, hypergammaglobulinemia was detected, and her renal function declined. Renal biopsy revealed plasma cells infiltrating the stroma. Immunostaining revealed numerous IgG4-positive plasma cells. The serum IgG4 level was high, and she was initially diagnosed with IgG4-related disease (IgG4-RD) and treated with steroids. However, the therapeutic effect was poor. On re-examination, computed tomography revealed lymphadenopathy around the aorta and spleen. Renal histopathology showed numerous IL-6-positive plasma cells. Anemia and C-reactive protein (CRP) positivity persisted despite steroid administration. HHV-8 was negative, and polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes syndrome was not suspected. Thus, iMCD was diagnosed. Based on previous reports, there is no significant difference in IgG4 levels between iMCD and IgG4-RD, and IgG4-positive plasma cell infiltrates were observed in iMCD-affected organs. Therefore, it may be difficult to distinguish iMCD from IgG4-RD. In this case, high-serum IL-6 and CRP were observed, which are usually not seen in IgG4-RD but are common findings in iMCD, leading to the diagnosis. Patients with deep lymphadenopathy may be diagnosed with iMCD based on renal pathological findings. Renal biopsy is recommended for patients with suspected iMCD and decreased renal function.

DOI： 10.1007/s13730-022-00751-w

Clinical characteristics and outcomes of Castleman disease: a multicenter Consortium study of 428 patients with 15-year follow-up. Reviewed International journal

Wanying Liu, Qingqing Cai, Tiantian Yu, Paolo Strati, Frederick B Hagemeister, Qiongli Zhai, Mingzhi Zhang, Ling Li, Xiaosheng Fang, Jianyong Li, Ruifang Sun, Shanxiang Zhang, Hanjin Yang, Zhaoming Wang, Wenbian Qian, Noriko Iwaki, Yasuharu Sato, Eric Oksenhendler, Zijun Y Xu-Monette, Ken H Young, Li Yu

American Journal of Cancer Research 12 ( 9 ) 4227 - 4240 2022.10

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

Castleman disease (CD) has been reported as a group of poorly understood lymphoproliferative disorders, including unicentric CD (UCD) and idiopathic multicentric CD (iMCD) which are human immunodeficiency virus (HIV) negative and human herpes virus 8 (HHV-8) negative. The clinical and independent prognostic factors of CD remain poorly elucidated. We retrospectively collected the clinical information of 428 patients with HIV and HHV-8 negative CD from 12 large medical centers with 15-year follow-up. We analyzed the clinicopathologic features of 428 patients (248 with UCD and 180 with iMCD) with a median age of 41 years. The histology subtypes were hyaline-vascular (HV) histopathology for 215 patients (56.58%) and plasmacytic (PC) histopathology for 165 patients (43.42%). Most patients with UCD underwent surgical excision, whereas the treatment strategies of patients with iMCD were heterogeneous. The outcome for patients with UCD was better than that for patients with iMCD, 5-year overall survival (OS) rates were 95% and 74%, respectively. In further analysis, a multivariate analysis using a Cox regression model revealed that PC subtype, hepatomegaly and/or splenomegaly, hemoglobin ≤ 80 g/L, and albumin ≤ 30 g/L were independent prognostic factors of CD for OS. The model of iMCD revealed that age > 60 years, hepatomegaly and/or splenomegaly, and hemoglobin ≤ 80 g/L were independent risk factors. In UCD, single-factor analysis identified two significant risk factors: hemoglobin ≤ 100 g/L and albumin ≤ 30 g/L. Our study emphasizes the distinction of clinical characteristics between UCD and iMCD. The importance of poor risk factors of different clinical classifications may direct more precise and appropriate treatment strategies.

Neuropeptide Y Antagonizes Development of Pulmonary Fibrosis Through IL-1β Inhibition. Reviewed International journal

Junko Itano, Akihiko Taniguchi, Satoru Senoo, Noboru Asada, Yuka Gion, Yuria Egusa, Lili Guo, Naohiro Oda, Kota Araki, Yasuharu Sato, Shinichi Toyooka, Katsuyuki Kiura, Yoshinobu Maeda, Nobuaki Miyahara

American journal of respiratory cell and molecular biology 67 ( 6 ) 654 - 665 2022.9

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

Neuropeptide Y, a 36-amino acid residue polypeptide, distributed throughout the nervous system, acts on various immune cells in many organs, including the respiratory system. However, little is known about its role in the pathogenesis of pulmonary fibrosis. This study was performed to determine the effects of neuropeptide Y on pulmonary fibrosis. Neuropeptide Y-deficient and wild-type mice were intratracheally administered bleomycin. Inflammatory cells, cytokine levels, and morphological morphometry of the lungs were analyzed. Serum neuropeptide Y levels were also measured in idiopathic pulmonary fibrosis patients and healthy controls. Neuropeptide Y-deficient mice exhibited significantly enhanced pulmonary fibrosis and higher IL-1β levels in the lungs compared to wild-type mice. Exogenous neuropeptide Y treatment suppressed the development of bleomycin-induced lung fibrosis and decreased IL-1β levels in the lungs. Moreover, IL-1β neutralization in neuropeptide Y-deficient mice attenuated the fibrotic changes. Neuropeptide Y decreased IL-1β release, and Y1 receptor antagonists inhibited IL-1β release and induced epithelial mesenchymal transition in human alveolar epithelial cells. Patients with idiopathic pulmonary fibrosis had lower neuropeptide Y and greater IL-1β levels in the serums compared to healthy controls. Neuropeptide Y expression was mainly observed around bronchial epithelial cells in human idiopathic pulmonary fibrosis lungs. These data suggest that neuropeptide Y plays a protective role against pulmonary fibrosis by suppressing IL-1β release and manipulating the neuropeptide Y-Y1 receptor axis could be a potential therapeutic strategy for delaying disease progression.

DOI： 10.1165/rcmb.2021-0542OC

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

Asami Nishikori, Midori 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

Authorship：Last author,　Corresponding author 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 < 0.001, respectively). Pleural effusion and ascites were less common in the IPL group (p < 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

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

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

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

9p24.1 Genetic Alteration and PD-L1 Expression Are Characteristic of De Novo and Methotrexate-associated Epstein-Barr Virus-positive Hodgkin Lymphoma, But Not Methotrexate-associated Hodgkin-like Lesions. Reviewed International journal

Sawako Shiraiwa, Yara Yukie Kikuti, Joaquim Carreras, Yusuke Kondo, Ken Ohmachi, Yoshiaki Ogawa, Hiroshi Kawada, Shinji Sato, Yuka Gion, Yasuharu Sato, Naoya Nakamura, Kiyoshi Ando

The American journal of surgical pathology 46 ( 8 ) 1017 - 1024 2022.8

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

Although the alteration of the 9p24.1 chromosome locus and PD-L1 overexpression is found in nodular sclerosis classic Hodgkin lymphoma, whether these aberrations occur in CHL and Hodgkin-like lesion (HLL) of methotrexate-associated lymphoproliferative disorder (MTX-CHL and MTX-HLL) is unknown. We compared the clinicopathologic features, the genomic status of the 9p24.1 locus and PD-L1 expression in a series of 34 patients including 17 with Epstein-Barr virus-positive de novo CHL, 7 with MTX-CHL, 10 with MTX-HLL using an immunofluorescence in situ hybridization method and immunohistochemistry. The proportions of cells with 9p24.1 genetic alteration in CD30-positive Hodgkin/Reed-Sternberg cells of de novo CHL, MTX-CHL and MTX-HLL were 55%, 68%, and 24%, respectively. The positive rates of PD-L1 measured by immunohistochemical H-scores of de novo CHL, MTX-CHL and MTX-HLL were 142±38, 157±75, and 70±42, respectively. Alteration of the 9p24.1 gene and expression of PD-L1 protein were correlated with all 3 diseases (correlation coefficient, 0.731). Both alteration of the 9p24.1 gene and overexpression of PD-L1 protein were observed in Epstein-Barr virus-positive de novo CHL and MTX-CHL but not in MTX-HLL. In conclusion, MTX-CHL has similar pathogenesis-like de novo CHL, but MTX-HLL seems to be a different disease from de novo CHL and MTX-CHL.

DOI： 10.1097/PAS.0000000000001899

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

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

EJHaem 3 ( 3 ) 748 - 753 2022.8

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

Castleman disease (CD) is a rare lymphoproliferative disorder with multiple subtypes. Thrombocytopenia, anasarca, fever, reticulin fibrosis or renal insufficiency, and organomegaly (TAFRO) syndrome can occur in the context of CD. The study evaluated worldwide public awareness of CD and TAFRO syndrome using Google Trends data between 2015 and 2021. Our results showed that global public interest steadily grew until late 2019, at a small but significant rate of 1.1% per month from the 1st to 57th month (1/2015-9/2019). The increase coincided with a peak in the United States and Japan, but the search volume decreased at a rate of 1.3% per month after that time. No clear trend changes were noted throughout the study period with the search term "TAFRO." However, the search volume significantly increased during the time period at a rate of 4.8% (confidence interval [CI]: 2.8, 6.8) and 4.7% (CI: 2.7, 6.8) per month in Japan and worldwide, respectively. There was an insufficient search volume for "TAFRO" in the United States to perform the analysis. Most searches on "TAFRO" stemmed from Japan, suggesting considerable geographical disparity in the awareness of TAFRO syndrome. Further efforts are crucial to raise the awareness of CD and TAFRO syndrome among physicians and the general public, primarily in non-USA and Japanese countries.

DOI： 10.1002/jha2.459

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jha2.459

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

Authorship：Lead author,　Corresponding author Language：Japanese Publisher：(一社)日本病理学会

キャッスルマン病は、リンパ節の病理像で特徴づけられており、いくつかの亜型が存在するヘテロな疾患単位である。原型は限局性で全身症状の乏しい単心性キャッスルマン病(UCD)であったが、その後、病変が多発し全身症状を呈する多中心性キャッスルマン病(MCD)が報告された。MCDはさらにKSHV/HHV8の感染状態によって分類され、陰性例は特発性MCD(iMCD)と定義されている。本項では、キャッスルマン病の歴史を振り返り、各亜型の臨床および病理学的特徴について述べる。(著者抄録)

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

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

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

Distinct disease-specific Tfh cell populations in two different fibrotic diseases: IgG4-related disease and Kimura's disease. Reviewed International journal

Ryusuke Munemura, Takashi Maehara, Yuka Murakami, Risako Koga, Ryuichi Aoyagi, Naoki Kaneko, Atsushi Doi, Cory A Perugino, Emanuel Della-Torre, Takako Saeki, Yasuharu Sato, Hidetaka Yamamoto, Tamotsu Kiyoshima, John H Stone, Shiv Pillai, Seiji Nakamura

The Journal of allergy and clinical immunology 2022.5

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

BACKGROUND: How T follicular (Tfh) cells contribute to many different B-cell class-switching events during T cell-dependent immune responses has been unclear. Diseases with polarized isotype switching offer a unique opportunity for the exploration of Tfh subsets. Secondary and tertiary lymphoid organs (SLOs and TLOs) in patients with elevated tissue expression levels of IgE (Kimura's disease, KD) and those of IgG4 (IgG4-related disease, IgG4-RD) can provide important insights regarding cytokine expression by Tfh cells. OBJECTIVE: To identify disease-specific Tfh cell subsets in SLOs and TLOs expressing IL-10 or IL-13 and thus identify different cellular drivers of class switching in two distinct types of fibrotic disorders: allergic fibrosis (driven by type 2 immune cells) and inflammatory fibrosis (driven by cytotoxic T lymphocytes). METHODS: Single-cell RNA-sequencing, in situ sequencing, and multi-color immunofluorescence analysis was used to investigate B cells, Tfh cells and infiltrating type 2 cells in lesion tissues from patients with KD or IgG4-RD. RESULTS: Infiltrating Tfh cells in TLOs from IgG4-RD were divided into six main clusters. We encountered abundant infiltrating IL-10-expressing LAG3+ Tfh cells in patients with IgG4-RD. Furthermore, we found that infiltrating AID+CD19+B cells expressing IL-4, IL-10, and IL-21 receptors correlated with IgG4 expression. In contrast, we found that infiltrating IL-13-expressing Tfh cells were abundant in affected tissues from patients with KD. Moreover, we observed few infiltrating IL-13-expressing Tfh cells in tissues from patients with IgG4-RD, despite high serum levels of IgE (but low IgE in the disease lesions). Cytotoxic T cells were abundant in IgG4-RD, and in contrast Type 2 immune cells were abundant in KD. CONCLUSIONS: This single-cell dataset revealed a novel subset of IL10+LAG3+Tfh cells infiltrating the affected organs of IgG4-RD patients. In contrast, IL13+Tfh cells and type 2 immune cells infiltrated those of KD patients.

DOI： 10.1016/j.jaci.2022.03.034

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

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

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

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

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

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

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 : JCEH 2022.3

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

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

The fine-needle aspiration cytology and clinical findings of Kikuchi-Fujimoto disease in pediatric patients: a retrospective clinical study. Reviewed International journal

Yuto Naoi, Tomoyasu Tachibana, Yoji Wani, Machiko Hotta, Katsuya Haruna, Yasutoshi Komatsubara, Kazunori Kuroda, Soichiro Fushimi, Tami Nagatani, Yuko Kataoka, Kazunori Nishizaki, Yasuharu Sato, Mizuo Ando

Acta oto-laryngologica 142 ( 3-4 ) 1 - 5 2022.3

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

BACKGROUND: Histological evaluation of lymph node is crucial for the definitive diagnosis of Kikuchi-Fujimoto disease (KFD). However, lymph node biopsy under local anesthesia is often difficult in pediatric patients. OBJECTIVES: We evaluated cytological findings for pediatric patients with prolonged cervical lymphadenitis clinically suggestive of KFD and investigated the clinical characteristics of patients diagnosed with KFD by fine-needle aspiration cytology (FNAC). METHODS: This retrospective clinical study included 58 Japanese pediatric patients with cervical lymphadenitis who underwent FNAC. RESULTS: Cytological diagnosis was KFD for 22 and suspicion of KFD for 11 patients. The remaining 25 patients were diagnosed with non-specific lymphadenitis (NSL). Tenderness was independently associated with a higher frequency of both KFD in narrow and broad senses, compared with NSL (p = .009; p = .038). The percentage of patients who underwent FNAC within 28 days from symptom onset tended to be higher among patients with KFD in a narrow sense than those with NSL (p = .052). CONCLUSION: This study indicated that the period from symptom onset to FNAC (<28 days) and the symptom of tenderness were associated with the cytological diagnosis of KFD.

DOI： 10.1080/00016489.2022.2040744

CD30-targeted therapy induces apoptosis of inflammatory cytokine-stimulated synovial fibroblasts and ameliorates collagen antibody-induced arthritis in mice. Reviewed International journal

Minami Matsuhashi, Keiichiro Nishida, Misa Sakamoto, Yuka Gion, Aki Yoshida, Takayuki Katsuyama, Ryuichi Nakahara, Yoshihisa Nasu, Yoshinori Matsumoto, Yasuharu Sato, Toshifumi Ozaki

Inflammation research : official journal of the European Histamine Research Society ... [et al.] 71 ( 2 ) 215 - 226 2022.2

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

OBJECTIVE: It has been reported that levels of soluble CD30 in serum and joint fluid are significantly elevated in patients with rheumatoid arthritis (RA). This study aimed to investigate whether CD30 could be a therapeutic target for RA. METHODS: The expression and localization of CD30 were examined by immunohistochemical and double immunofluorescence staining on synovial tissue samples obtained from patients with RA or osteoarthritis (OA) during surgery. Changes in CD30 expression of fibroblast-like synoviocytes (FLS) from RA patients with or without TNFα and IL-1β stimulation were examined by the polymerase chain reaction (PCR) and flow cytometry. Collagen antibody-induced arthritis (CAIA) was created in DBA/1 mice, and the therapeutic effect of brentuximab vedotin (BV) was examined by clinical score, histological findings and measurement of serum levels of SAA, IL-6, and TNFα. RESULTS: CD30 expression was significantly higher in samples from patients with RA than from those with OA. Double immunofluorescence showed a low rate of co-localization of CD30 with CD20 or CD90, but a high rate of co-localization of CD30 and CD138. CD30 mRNA expression was upregulated 11.7-fold in FLS following stimulation by inflammatory cytokines. The clinical scores of CAIA mice were significantly lower following both BV treatments, however, the histological scores of CAIA mice were significantly lower only following treatment with high dose BV (70 mg/kg). CONCLUSIONS: CD30 was expressed on immunocompetent cells in synovial tissue from RA patients and in cytokine-stimulated FLS in vitro. High dose BV (70 mg/kg) showed significant therapeutic effects in ameliorating inflammation and joint destruction in CAIA mice, but low dose BV (30 mg/kg) was insufficient.

DOI： 10.1007/s00011-021-01537-z

Clinicopathologic Analysis of Sinonasal Inverted Papilloma, with Focus on Human Papillomavirus Infection Status Reviewed

Munechika Tsumura, Seiichiro Makihara, Asami Nishikori, Yuka Gion, Toshiaki Morito, Shotaro Miyamoto, Tomoyuki Naito, Kensuke Uraguchi, Aiko Oka, Tomoyasu Tachibana, Yorihisa Orita, Shin Kariya, Mitsuhiro Okano, Mizuo Ando, Yasuharu Sato

Diagnostics 12 ( 2 ) 454 - 454 2022.2

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

Sinonasal inverted papilloma (SNIP) can recur; however, the factors related to tumor recurrence remain unclear. This study aimed to analyze risk factors, including human papillomavirus (HPV) infection, as well as other factors associated with SNIP recurrence. Thirty-two patients who were diagnosed with SNIP and underwent surgery between 2010 and 2019 were enrolled: 24 men and 8 women, with a mean age of 59.2 years. The mean follow-up was 57.3 months. Demographics and information about history of smoking, diabetes mellitus (DM), hypertension, allergic rhinitis, alcohol consumption, tumor stage, surgical approach, and recurrence were reviewed retrospectively. Specimens were investigated using polymerase chain reaction to detect HPV DNA (high-risk subtypes: 16, 18, 31, 33, 35, 52b, and 58; low-risk subtypes: 6 and 11). Seven patients (21.9%) experienced recurrence. HPV DNA was detected in five (15.6%) patients (high-risk subtypes, n = 2; low-risk subtypes, n = 3). Patients with recurrence of SNIP had a higher proportion of young adults and displayed higher rates of HPV infection, DM, and advanced tumor stage than those without recurrence. HPV infection, young adulthood, DM, and advanced tumor stage could be associated with a high recurrence rate, which suggests that patients with these risk factors could require close follow-up after surgery.

DOI： 10.3390/diagnostics12020454

Investigation of IgG4-positive cells in idiopathic multicentric Castleman disease and validation of the 2020 exclusion criteria for IgG4-related disease. Reviewed International journal

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

Pathology international 72 ( 1 ) 43 - 52 2022.1

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

Patients with plasma cell type idiopathic multicentric Castleman disease (PC-iMCD) often show elevated serum IgG4 levels and IgG4-positive cell infiltration in tissues due to overproduction of interleukin-6, and may meet the diagnostic criteria for IgG4-related disease (IgG4-RD). Although PC-iMCD has been listed as a major exclusion disease for IgG4-RD, distinguishing between these diseases is challenging due to a lack of highly specific diagnostic biomarkers. In 2020, we proposed exclusion criteria of IgG4-RD mimickers. In this paper, we validated the accuracy of the criteria in excluding one of the mimickers, PC-iMCD, from IgG4-RD. Validation was performed on 57 PC-iMCD patients (39 presenting lymph node lesions and 19 with lung lesions) and 29 IgG4-RD patients (22 presenting lymph node lesions and seven with lung lesions). According to our results, 20.5% of the PC-iMCD patients with lymph node lesions and 42.1% of those with lung lesions met the diagnostic criteria for IgG4-RD. All these patients with PC-iMCD were excluded from a diagnosis of IgG4-RD by the proposed criteria. Additionally, 6.9% of IgG4-RD patients met the exclusion criteria. Thus, if the exclusion criteria are met, diagnosis should be made based on a combination of findings including organ distribution of disease, response to steroid therapy, and other pathological findings.

DOI： 10.1111/pin.13185

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/pin.13185

PD-L1 expression is associated with the spontaneous regression of patients with methotrexate-associated lymphoproliferative disorders. Reviewed International journal

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 11 ( 2 ) 417 - 432 2022.1

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

BACKGROUND: Most patients with methotrexate-associated lymphoproliferative disorder (MTX-LPD) show diffuse large B-cell lymphoma (DLBCL) or classic Hodgkin lymphoma (CHL) types. Patients with MTX-LPD often have spontaneous remission after MTX discontinuation, but chemotherapeutic intervention is frequently required in patients with CHL-type MTX-LPD. In this study, we examined whether programmed cell death-ligand 1 (PD-L1) expression levels were associated with the prognosis of MTX-LPD after MTX discontinuation. METHODS: A total of 72 Japanese patients diagnosed with MTX-LPD were clinicopathologically analyzed, and immunohistochemical staining of PD-L1 was performed in 20 DLBCL-type and 24 CHL-type MTX-LPD cases to compare with the clinical course. RESULTS: PD-L1 was expressed in 5.0% (1/20) of patients with DLBCL-type MTX-LPD, whereas it was expressed in 66.7% (16/24) of the patients with CHL-type MTX-LPD in more than 51% of tumor cells. Most CHL-type MTX-LPD patients with high PD-L1 expression required chemotherapy owing to exacerbations or relapses after MTX discontinuation. However, no significant differences in clinicopathologic findings at diagnosis were observed between PD-L1 high- and low-expression CHL-type MTX-LPD. CONCLUSION: PD-L1 expression was significantly higher in patients with CHL-type than DLBCL-type MTX-LPD, suggesting the need for chemotherapy in addition to MTX discontinuation in CHL-type MTX-LPD patients to achieve complete remission. No association was observed between PD-L1 expression levels and clinical findings at diagnosis, suggesting that PD-L1 expression in tumor cells influences the pathogenesis of CHL-type MTX-LPD after MTX discontinuation.

DOI： 10.1002/cam4.4462

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/cam4.4462

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

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

Authorship：Last author,　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

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 ) 2021.11

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

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

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 International journal

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

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 34 ( 11 ) 2085 - 2086 2021.11

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

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

Diagnostics (Basel, Switzerland) 11 ( 11 ) 2008 - 2008 2021.10

Authorship：Last author,　Corresponding author Language：English 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

Validated international definition of the thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly clinical subtype (TAFRO) of idiopathic multicentric Castleman disease. Reviewed International journal

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 van Rhee, Yasuharu Sato

American journal of hematology 96 ( 10 ) 1241 - 1252 2021.10

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

Thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly (TAFRO) syndrome is a heterogeneous entity manifesting with a constellation of symptoms described above that can occur in the context of idiopathic multicentric Castleman disease (iMCD) as well as infectious diseases, malignancies, and rheumatologic disorders. So, iMCD-TAFRO is an aggressive subtype of iMCD with TAFRO syndrome and often hyper-vascularized lymph nodes. Since we proposed diagnostic criteria of iMCD-TAFRO in 2016, we have accumulated new insights on the disorder and additional cases have been reported worldwide. In this systematic review and cohort analysis, we established and validated a definition for iMCD-TAFRO. First, we searched PubMed and Japan Medical Abstracts Society databases using the keyword "TAFRO" to extract cases. Patients with possible systemic autoimmune diseases and hematologic malignancies were excluded. Our search identified 54 cases from 50 articles. We classified cases into three categories: (1) iMCD-TAFRO (TAFRO syndrome with lymph node histopathology consistent with iMCD), (2) possible iMCD-TAFRO (TAFRO syndrome with no lymph node biopsy performed and no other co-morbidities), and (3) TAFRO without iMCD or other co-morbidities (TAFRO syndrome with lymph node histopathology not consistent with iMCD or other comorbidities). Based on the findings, we propose an international definition requiring four clinical criteria (thrombocytopenia, anasarca, fever/hyperinflammatory status, organomegaly), renal dysfunction or characteristic bone marrow findings, and lymph node features consistent with iMCD. The definition was validated with an external cohort (the ACCELERATE Natural History Registry). The present international definition will facilitate a more precise and comprehensive approach to the diagnosis of iMCD-TAFRO.

DOI： 10.1002/ajh.26292

Transformation to diffuse large B-cell lymphoma with germinal center B-cell like subtype and discordant light chain expression in a patient with Waldenström macroglobulinemia/lymphoplasmacytic lymphoma. Reviewed

Hiroki Kobayashi, Noboru Asada, Yuria Egusa, Tomoka Ikeda, Misa Sakamoto, Masaya Abe, Daisuke Ennishi, Masahiro Sakata, Akinobu Takaki, Soichiro Kawahara, Yusuke Meguri, Hisakazu Nishimori, Nobuharu Fujii, Ken-Ichi Matsuoka, Yasuharu Sato, Tadashi Yoshino, Yoshinobu Maeda

International journal of hematology 114 ( 3 ) 401 - 407 2021.9

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

Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare indolent B-cell neoplasm, and a gain-of-function mutation in the myeloid differentiation primary response 88 (MYD88), L265P, is a commonly recurring mutation in patients with WM/LPL. Histological transformation of WM/LPL to an aggressive lymphoma such as diffuse large B-cell lymphoma (DLBCL) is rare, and transformed DLBCL has a worse prognosis than de novo DLBCL, partly because transformed DLBCL is mostly classified as non-germinal center B-cell-like (non-GCB) subtype. We herein describe a 75-year-old man with DLBCL with a history of WM/LPL. DLBCL in this patient showed the GCB subtype, and the light chain restriction of DLBCL was different from that of the antecedent WM/LPL, indicating that the two types of lymphoma cells had distinctive origins. However, DLBCL in this patient harbored the MYD88 L265P mutation, and polymerase chain reaction and Sanger sequencing of the DLBCL and WM/LPL for immunoglobulin heavy chain gene rearrangement suggested a clonal relationship between the two lymphomas. Since the outcome of transformed DLBCL is worse than for de novo DLBCL, it is important to evaluate the clonal relationship between primary WM/LPL and the corresponding transformed DLBCL, even if the DLBCL expresses a GCB subtype or discordant light chain restriction.

DOI： 10.1007/s12185-021-03157-z

Exacerbation of pulmonary cryptococcosis associated with enhancement of Th2 response in the postpartum period. Reviewed International journal

Shota Miyoshi, Naohiro Oda, Yuka Gion, Takahiro Taki, Reo Mitani, Ichiro Takata, Akihiko Taniguchi, Yasuharu Sato, Nobuaki Miyahara

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 27 ( 8 ) 1248 - 1250 2021.8

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

Cryptococcosis is an invasive mycosis that has become increasingly prevalent in immunocompromised patients. Pregnant women are also one of the risk populations for cryptococcosis. Reversal of Th2 to Th1 response following resolution of immunosuppression during the postpartum period can lead to overt clinical manifestations of a previously silent infection, resembling an immune reconstitution inflammatory syndrome. Here, we report a case of a 30-year-old woman who had an exacerbation of pulmonary cryptococcosis in the postpartum period mimicking an immune reconstitution inflammatory syndrome. In the present case, chest computed tomography showed multiple small nodules on the day of the delivery; however, pulmonary cryptococcosis, which was subclinical during pregnancy, rapidly worsened to mass-like consolidation at one month after the delivery. Pathohistological examination of the lung specimen showed lung parenchyma infiltration with histiocytes and numerous lymphocytes without granulomatous formations, and a small number of yeast-like organisms consistent with Cryptococcus without capillary involvement. Immunohistochemical staining showed predominance of CD3+ cells and CD4+ cells over CD8+ cells. In addition, GATA3+ cells dominated over T-bet + cells. These data suggested exacerbation of pulmonary cryptococcosis associated with enhancement of Th2 response in the postpartum period.

DOI： 10.1016/j.jiac.2021.03.025

The 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD. Reviewed International journal

Hisanori Umehara, Kazuichi Okazaki, Shigeyuki Kawa, Hiroki Takahashi, Hiroshi Goto, Shoko Matsui, Nobukazu Ishizaka, Takashi Akamizu, Yasuharu Sato, Mitsuhiro Kawano

Modern rheumatology 31 ( 3 ) 529 - 533 2021.5

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

IgG4-related disease (IgG4-RD) is a fascinating clinical entity first reported in this century in Japan, and includes a wide variety of diseases, such as formerly named Mikulicz's disease (MD), autoimmune pancreatitis (AIP), interstitial nephritis, prostatitis and retroperitoneal fibrosis. The Japanese IgG4 team organized by the Ministry of Health, Labor and Welfare (MHLW) of Japan has published the first criteria, comprehensive diagnostic (CD) criteria for IgG-RD 2011. Thereafter, IgG4-RD has been accepted widely and many cases have been reported from all over the world. Several problems have arisen in clinical practice, however, including the difficulty obtaining biopsy samples, and the sensitivity and specificity in cut off level of serum IgG4 and impaired immunostaining of IgG4. Given these situations, the Japanese IgG4 team has updated the 2011 comprehensive diagnostic criteria for IgG4-RD and propose the 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD, which consists of 3 domains; 1) Clinical and radiological features, 2) Serological diagnosis and 3) Pathological diagnosis. In addition, the new pathological diagnosis is composed by three sub-items including storiform fibrosis and obliterative phlebitis.

DOI： 10.1080/14397595.2020.1859710

Nodal EBV-positive polymorphic B cell lymphoproliferative disorder with plasma cell differentiation: clinicopathological analysis of five cases. Reviewed International journal

Akira Satou, Tetsuya Tabata, Yuka Suzuki, Yasuharu Sato, Ippei Tahara, Kunio Mochizuki, Naoki Oishi, Taishi Takahara, Tadashi Yoshino, Toyonori Tsuzuki, Shigeo Nakamura

Virchows Archiv : an international journal of pathology 478 ( 5 ) 969 - 976 2021.5

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

Plasma cell differentiation (PCD) is frequently observed in some entities of non-Hodgkin B cell lymphoma, including both low-grade and high-grade lymphomas. However, except for plasmablastic lymphoma and primary effusion lymphoma, EBV+ B cell lymphoproliferative disorder (LPD) with PCD has not been well addressed due to its rarity. We clinicopathologically examined five cases of nodal EBV+ polymorphic B cell LPD with PCD (PBLPD-PCD) initially diagnosed as polymorphic EBV+ diffuse large B cell lymphoma, not otherwise specified (DLBCL-NOS) with PCD (n = 3) and methotrexate-associated B cell LPD (MTX-associated B-LPD) (n = 2). One case had a concomitant brain lesion which was clinically diagnosed as EBV-related encephalitis. This patient received therapy with vidarabine, and both the brain lesion and the nodal EBV+ PBLPD-PCD lesions disappeared. Another case was characterized by Mott cell differentiation. This case was the first reported case of EBV+ B cell lymphoma or LPD with Mott cell differentiation. The two cases of MTX-associated B cell LPD which arose in patients with rheumatoid arthritis spontaneously regressed after MTX cessation. TCRγ and IGH PCR analysis was performed in four cases. Two cases had TCRγ rearrangements, but no IGH rearrangements. The other two cases had no rearrangements in these genes. We concluded that nodal EBV+ PBLPD-PCD is rare, with heterogeneous characteristics. PCR analysis revealed that nodal EBV+ PBLPD-PCD may have only TCR clonality and no IGH clonality. Considering the partial or complete loss of CD20 expression on the tumor cells, this result may be confusing for accurate diagnosis of EBV+ PBLPD-PCD, and pathologists need to be aware of this phenomenon to avoid misdiagnosis.

DOI： 10.1007/s00428-020-02967-6

Diagnostic Utility of SOX4 Expression in Adult T-Cell Leukemia/Lymphoma. Reviewed International journal

Atsuko Nasu, Yuka Gion, Yoshito Nishimura, Asami Nishikori, Misa Sakamoto, Yuria Egusa, Azusa Fujita, Tadashi Yoshino, Yasuharu Sato

Diagnostics (Basel, Switzerland) 11 ( 5 ) 2021.4

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

Differentiation between adult T-cell leukemia/lymphoma (ATLL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), is often challenging based on pathological findings alone. Although serum anti-HTLV-1 antibody positivity is required for ATLL diagnosis, this information is often not available at the time of pathological diagnosis. Therefore, we examined whether the expression of SOX4 and p16 would be helpful for differentiating the two disease entities. We immunohistochemically examined SOX4 and p16 expression (which have been implicated in ATLL carcinogenesis) in 11 ATLL patients and 20 PTCL-NOS patients and classified them into four stages according to the percentage of positive cells. Among the ATLL cases, 8/11 (73%) were SOX4-positive, while only 2/20 (10%) PTCL-NOS cases expressed SOX4. The mean total score was 4.2 (standard deviation (SD): 0.61) in the ATLL group and 0.50 (SD: 0.46) in the PTCL-NOS group (p < 0.001). Positive expression of p16 was noted in 4/11 (36%) patients with ATLL and 3/20 (15%) patients with PTCL-NOS, with mean total scores of 1.9 (SD: 0.64) and 0.70 (SD: 0.48) in the ATLL and PTCL-NOS groups, respectively (p = 0.141). These results suggest that SOX4 may be strongly expressed in ATLL compared to PTCL-NOS cases. Therefore, it may be helpful to perform immunohistochemical staining of SOX4 when pathologists face challenges discriminating between ATLL and PTCL-NOS.

DOI： 10.3390/diagnostics11050766

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

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

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

PD-L1 expression in tongue squamous cell carcinoma Reviewed

Naoki Akisada, Kohei Nishimoto, Soshi Takao, Yuka Gion, Hidenori Marunaka, Tomoyasu Tachibana, Takuma Makino, Kentaro Miki, Yusuke Akagi, Munechika Tsumura, Tomohiro Toji, Tadashi Yoshino, Kazunori Nishizaki, Yorihisa Orita, Yasuharu Sato

Medical Molecular Morphology 54 ( 1 ) 52 - 59 2021.3

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Purpose: Immune checkpoint proteins programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are important therapeutic targets for head and neck cancer. This large-scale case study aimed to analyze tongue squamous cell carcinomas (SCCs) and evaluate the correlation between PD-L1 expression and clinical prognosis. So far, this study is the largest case study on PD-L1 expression in tongue SCCs. Methods: This is a case–control study that analyzed 121 tongue SCCs. Paraffin-embedded sections and clinical data were obtained retrospectively and immunohistochemistry with PD-L1 was performed. Results: 11.6% contained ≥ 50% of PD-L1-positive cells, 57.1% of these cases had a poor prognosis with nodal metastasis. Among cases of T1/2 primary lesions with nodal metastasis, cases of high PD-L1 expression had a significantly shorter disease-free survival than cases of no PD-L1 expression (p = 0.018). The hazard ratio for high PD-L1 expression was 3.21 (95 per cent CI, 1.26–8.72) compared with no PD-L1 expression after adjusting for other factors. Conclusions: These data indicate that PD-L1 upregulation in tongue SCCs is associated with a more advanced stage and shorter disease-free survival. PD-1/PD-L1 inhibitors might hence constitute potential adjuvant therapy for tongue SCCs with PD-L1 upregulation.

DOI： 10.1007/s00795-020-00261-7

Other Link： http://link.springer.com/article/10.1007/s00795-020-00261-7/fulltext.html

Correction to: PD-L1 expression in tongue squamous cell carcinoma.

Naoki Akisada, Kohei Nishimoto, Soshi Takao, Yuka Gion, Hidenori Marunaka, Tomoyasu Tachibana, Takuma Makino, Kentaro Miki, Yusuke Akagi, Munechika Tsumura, Tomohiro Toji, Tadashi Yoshino, Kazunori Nishizaki, Yorihisa Orita, Yasuharu Sato

Medical molecular morphology 54 ( 1 ) 68 - 68 2021.3

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

In the original publication of the article an affiliation should be added to the first author “Naoki Akisada” as given below:5Departments of Otolaryngology Head and Neck Surgery,Okayama University Graduate School of Medicine,Dentistry and Pharmaceutical Sciences, Okayama 700‑8558,Japan

DOI： 10.1007/s00795-020-00270-6

Comment on: HHV-8-negative multicentric Castleman disease patients with serological, histopathological and imaging features of IgG4-related disease: reply. Reviewed International journal

Mitsuhiro Kawano, Yasuharu Sato, David C Fajgenbaum

Rheumatology (Oxford, England) 60 ( 2 ) e76-e77 2021.2

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

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

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

HHV-8-negative multicentric Castleman disease patients with serological, histopathological and imaging features of IgG4-related disease. Reviewed International journal

Mitsuhiro Kawano, Satoshi Hara, Akihiro Yachie, Dai Inoue, Yasuharu Sato, David C Fajgenbaum

Rheumatology (Oxford, England) 60 ( 1 ) e3-e4 2021.1

Follow-up with serum IgG4-monitoring in 8 patients with IgG4-related disease diagnosed by a lacrimal gland mass. Reviewed

Toshihiko Matsuo, Takehiro Tanaka, Yasuharu Sato, Hitomi Kataoka, Mayu Uka, Daisuke Ennishi, Tomofumi Yano

Journal of clinical and experimental hematopathology : JCEH 61 ( 1 ) 10 - 21 2021

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

The diagnostic criteria for IgG4-related disease were previously published and serum IgG4 measurement has been reimbursed by national health insurance in Japan since 2012. Eight patients diagnosed with IgG4-related disease based on lacrimal gland masses were retrospectively reviewed. The 8 patients were 3 men and 5 women ranging in age from 52 to 77 (median, 63) years at the initial visit and their follow-up period ranged from 0.25 to 11 (median, 7) years. Bilateral and unilateral involvement were noted in 4 patients each; 2 on the right side and 2 on the left side in those with unilateral involvement. Serum IgG4 was high in 5 of 8 patients at the initial visit. Five patients with no systemic signs were followed without treatment, whereas oral steroids were administered and tapered in the other 3 patients who exhibited systemic signs. One patient with a history of radiation for MALT lymphoma in bilateral lacrimal glands developed IgG4-related disease in the left lacrimal gland 10 years later and was followed without treatment. Nine years later, her serum IgG4 level increased to 1500 mg/dL and paracardiac lesions, found on positron emission tomography, were confirmed to be MALT lymphoma by needle biopsy, leading to systemic chemotherapy. The other 7 patients had neither local recurrence nor additional systemic signs. Serum IgG4 monitoring may be useful to detect systemic complications in IgG4-related ophthalmic disease and markedly high serum IgG4 levels may indicate new lymphoma at other sites.

DOI： 10.3960/jslrt.20048

IgG4 Expression in Patients with Eosinophilic Otitis Media Reviewed

Masahiro Takahashi, Aiko Oka, Shin Kariya, Yuka Gion, Yasuharu Sato, Satoshi Iwasaki, Shogo Oyamada, Atsushi Matsubara, Mitsuhiro Okano

ORL 83 ( 3 ) 167 - 171 2021

Publishing type：Research paper (scientific journal) Publisher：S. Karger AG

<b><i>Objective:</i></b> Eosinophilic otitis media (EOM) is an intractable middle ear disease recognized by an eosinophil enriched middle ear effusion and mucosa. Although precise pathogenesis of EOM remains unclear, it is characterized by type 2 inflammation. Since IgG4 is an IgG subclass induced by type 2 cytokines such as IL-4 and IL-13, we sought to characterize and compare local IgG4 expression in patients with and without EOM. <b><i>Methods:</i></b> Twelve patients with bilateral profound hearing loss, 9 of which underwent a cochlear implant surgery, were enrolled in this study (6 with EOM and 6 without EOM). The surgical specimens were harvested during surgery and were subjected to IgG4 immunostaining. <b><i>Result:</i></b> The middle ear mucosa showed the presence of a large number of IgG4-positive cells in patients with EOM, which was significantly higher than that in patients without EOM. <b><i>Conclusion:</i></b> Local IgG4 expression was observed in patients with EOM in comparison to those without EOM, suggesting that IgG4 contributes to EOM pathogenesis.

DOI： 10.1159/000512726

Differential diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma and other indolent lymphomas, including mantle cell lymphoma. Reviewed

Tadashi Yoshino, Takehiro Tanaka, Yasuharu Sato

Journal of clinical and experimental hematopathology : JCEH 60 ( 4 ) 124 - 129 2020.12

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

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) accounts for approximately 1% of all lymphomas in our department. In this article, we describe the differential diagnosis of CLL/SLL from other indolent lymphomas, with special reference to follicular lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, and mantle cell lymphoma, although the latter is considered to be aggressive. CLL/SLL often exhibits proliferation centers, similar to follicular lymphoma. Immunohistological examination can easily distinguish these two lymphomas. The most important characteristic of CLL/SLL is CD5 and CD23 positivity. Mantle cell lymphoma is also CD5-positive and there are some CD23-positive cases. Such cases should be carefully distinguished from CLL/SLL. Some marginal zone lymphomas are also positive for CD5 and such cases are often disseminated. Lymphoplasmacytic lymphoma should also be a differential diagnosis for CLL/SLL. It frequently demonstrates MYD88 L265P, which is a key differential finding. By immunohistological examination, the expression of lymphoid enhancer-binding factor 1 is specific for CLL/SLL and can be a good marker in the differential diagnosis.

DOI： 10.3960/jslrt.19041

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

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

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

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 2020.12

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

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

Treatment outcomes of IgG4-producing marginal zone B-cell lymphoma: a retrospective case series. Reviewed

Yuichi Sumii, Noboru Asada, Yasuharu Sato, Koh-Ichi Ohshima, Masanori Makita, Yusuke Yoshimoto, Yuka Sogabe, Kenji Imajo, Yusuke Meguri, Daisuke Ennishi, Hisakazu Nishimori, Nobuharu Fujii, Ken-Ichi Matsuoka, Tadashi Yoshino, Yoshinobu Maeda

International journal of hematology 112 ( 6 ) 780 - 786 2020.12

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

IgG4-producing marginal zone B-cell lymphomas (MZLs) have been recently proposed as a subtype of MZLs. Despite the abundant literature on pathophysiological features of this type of lymphoma, only a few retrospective studies pertaining to the treatment outcomes have been reported, and its prognosis remains unclear. We retrospectively analyzed seven patients with IgG4-producing MZLs diagnosed at our institute, with specific reference to treatment and outcomes. The median age was 69.0 years (55-79), and all were males. The median follow-up period was 66.6 months (8-121). All patients had localized disease; four patients had tumors of the ocular adnexa, whereas two had retroperitoneal tumors. Five patients were treated with irradiation (30 Gy/15 fr) (n = 4) or surgery (n = 1), resulting in tumor reduction. Two patients were treated by chemotherapy or irradiation. Among them, one commenced rituximab monotherapy, which led to an inadequate reduction of the tumor. Subsequent irradiation induced complete response (CR). The other patient experienced repeated relapses during follow-up and finally achieved CR by combination chemotherapy. Treatment was well tolerated in all cases, and none of the patients showed disease progression at the last follow-up visit. Our results indicate that the standard treatments for MZLs are generally appropriate for IgG4-producing MZL.

DOI： 10.1007/s12185-020-02968-w

Insufficient evidence exists to use histopathologic subtype to guide treatment of idiopathic multicentric Castleman disease. Reviewed International journal

David C Fajgenbaum, David Wu, Aaron Goodman, Raymond Wong, Amy Chadburn, Sunita Nasta, Gordan Srkalovic, Sudipto Mukherjee, Heather Leitch, Raj Jayanthan, Simone Ferrero, Yasuharu Sato, Steve Schey, Angela Dispenzieri, Eric Oksenhendler, Pier Luigi Zinzani, Mary Jo Lechowicz, Christian Hoffmann, Naveen Pemmaraju, Adam Bagg, Alexander Fossa, Megan S Lim, Frits van Rhee

American journal of hematology 95 ( 12 ) 1553 - 1561 2020.12

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

Idiopathic multicentric Castleman disease (iMCD) is a rare immunologic disorder characterized by systemic inflammation, multicentric lymphadenopathy, and organ dysfunction. Enlarged lymph nodes demonstrate a spectrum of characteristic but variable histopathologic features historically categorized into hyaline vascular (HV) (or hypervascular [HyperV] more recently), plasmacytic, or "mixed." Though the etiology is unknown, a pro-inflammatory cytokine storm, often involving interleukin-6 (IL-6), contributes to pathogenesis. Anti-IL-6 therapy with siltuximab is the only FDA- or EMA-approved treatment based on efficacy and safety in multiple studies. Importantly, no patients considered to have HV histopathology achieved the primary endpoint in the Phase II study. NCCN currently recommends siltuximab first-line for iMCD, except for patients considered to have HV histopathology. We investigated whether histopathologic subtype should guide siltuximab treatment decisions. Secondary analyses of clinical trial and real-world data revealed similar clinical benefit across histopathologic subtypes. Notably, only 18 of 79 patients in the Phase II study were consistently classified into histopathologic subtype by three independent review panels, demonstrating limited reliability to guide treatment decisions. Real-world data further demonstrate siltuximab's effectiveness in patients considered to have HV (or HyperV). Though histopathology is a critical component for diagnosis, there is insufficient evidence to guide treatment based solely on lymph node histopathologic subtype.

DOI： 10.1002/ajh.25992

Deletion of BART miRNA-encoding cluster in Epstein-Barr virus DNA in classic Hodgkin lymphoma. Reviewed International journal

Akihiro Kawatsuki, Takuro Igawa, Tomohiro Urata, Takehiro Tanaka, Yasuharu Sato, Tadashi Yoshino

Pathology international 70 ( 12 ) 1032 - 1033 2020.12

Methotrexate-Associated Lymphoproliferative Disorders Mimicking Granulomatosis With Polyangiitis: A Radiological Diagnostic Challenge. Reviewed International journal

Tomoyasu Tachibana, Tomoaki Sasaki, Yoji Wani, Yasutoshi Komatsubara, Kazunori Kuroda, Yuto Naoi, Yuka Gion, Yorihisa Orita, Kazunori Nishizaki, Yasuharu Sato

Ear, nose, & throat journal 101 ( 8 ) 145561320970685 - 145561320970685 2020.11

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

Methotrexate-associated lymphoproliferative disorders (MTX-LPD) frequently involve the extranodal organs throughout the body. Among the extranodal occurrences of MTX-LPD, pulmonary involvement is most frequent. In contrast, there are only a few reports of MTX-LPD in the nasal cavity or paranasal sinuses. Moreover, there are no previous reports of MTX-LPD mimicking granulomatosis with polyangiitis (GPA) in imaging examinations. We describe a case of a 53-year-old woman with MTX-LPD mimicking GPA in the nasal cavity and lungs. She complained of left nasal obstruction and discharge, general fatigue, and continual fever for 2 months. The patient had been diagnosed with rheumatoid arthritis and received methotrexate (MTX) for over 10 years. Contrast-enhanced computed tomography revealed unenhanced masses in the nasal cavity and multiple masses with cavitary changes in the bilateral lungs, suggesting GPA. However, histological examination of the nasal lesion and a history of MTX treatment indicated a diffuse large B-cell lymphoma type MTX-LPD. Two weeks after MTX withdrawal, prominent improvements in both lesions were observed. Complete regression of the nasal lesion was observed 3 months after discontinuation of MTX. Thus, MTX-LPD may mimic GPA in imaging examinations.

DOI： 10.1177/0145561320970685

Application of Lip Biopsy for the Histological Diagnosis of Immunoglobulin G4-Related Disease. Reviewed International journal

Tomoyasu Tachibana, Yorihisa Orita, Yoji Wani, Yasutoshi Komatsubara, Kazunori Kuroda, Yuto Naoi, Yuka Gion, Takuma Makino, Kazunori Nishizaki, Yasuharu Sato

Ear, nose, & throat journal 101 ( 8 ) 145561320971932 - 145561320971932 2020.11

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

We describe the case of a 51-year-old woman with immunoglobulin G4-related disease (IgG4-RD) diagnosed using lip biopsy. She reported having bilateral submandibular nodules for a month. Magnetic resonance imaging showed diffuse swelling in the bilateral submandibular glands (SMGs), suggesting inflammatory changes. Laboratory data revealed an elevated level of serum IgG4. Fine needle aspiration cytology of the SMG showed a considerable number of lymphocytes with degeneration but did not demonstrate specific findings for a definitive diagnosis of IgG4-RD. Lip biopsy was performed, and a biopsy specimen from the labial salivary gland showed abundant lymphoplasmacytic infiltration with a large number of IgG4-positive cells. The patient was diagnosed with IgG4-RD based on histological and laboratory findings. Findings of further examinations revealed that the patient had autoimmune pancreatitis, confirming our diagnosis. Four months after prednisolone administration, improvement of the submandibular and pancreatic lesions was observed. One year after the initial presentation, the serum IgG4 level was normalized. In cases of IgG4-RD with salivary gland involvement, lip biopsy might be one of the options for the histological diagnosis of IgG4-RD.

DOI： 10.1177/0145561320971932

A Novel Predictive Model for Idiopathic Multicentric Castleman Disease: The International Castleman Disease Consortium Study. Reviewed International journal

Li Yu, Menghan Shi, Qingqing Cai, Paolo Strati, Fredrick Hagemeister, Qiongli Zhai, Ling Li, Xiaosheng Fang, Jianyong Li, Ruifang Sun, Shanxiang Zhang, Hanjin Yang, Zhaoming Wang, Wenbin Qian, Noriko Iwaki, Yasuharu Sato, Lu Zhang, Jian Li, Eric Oksenhendler, Zijun Y Xu-Monette, Ken H Young

The oncologist 25 ( 11 ) 963 - 973 2020.11

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

BACKGROUND: Patients with multicentric Castleman disease (MCD) who are negative for human immunodeficiency virus and human herpesvirus 8 are considered to have idiopathic MCD (iMCD). The clinical presentation of iMCD varies from mild constitutional symptoms to life-threatening symptoms or death. The treatment strategy varies from "watchful waiting" to high-dose chemotherapy. This diverse clinical presentation calls for a classification stratification system that takes into account the severity of the disease. SUBJECTS, MATERIALS, AND METHODS: We analyzed the clinical, laboratory, and pathologic abnormalities and treatment outcomes of 176 patients with iMCD (median follow-up duration 12 years) from the U.S. and China to better understand the characteristics and prognostic factors of this disease. This discovery set of iMCD results was confirmed from the validation set composed of additional 197 patients with iMCD organized from The International Castleman Disease Consortium. RESULTS: Using these data, we proposed and validated the iMCD international prognostic index (iMCD-IPI), which includes parameters related to patient characteristics (age > 40 years), histopathologic features (plasma cell variant), and inflammatory consequences of iMCD (hepatomegaly and/or splenomegaly, hemoglobin <80 g/L, and pleural effusion). These five factors stratified patients according to their performance status and extent of organ dysfunction into three broad categories: low risk, intermediate risk, and high risk. The iMCD-IPI score accurately predicted outcomes in the discovery study cohort, and the results were confirmed on the validation study cohort. CONCLUSION: This study represents the largest series of studies on patients with iMCD in the field and proposed a novel risk-stratification model for iMCD-IPI that could be used to guide risk-stratified treatment strategies in patients with iMCD. IMPLICATIONS FOR PRACTICE: Patients with idiopathic multicentric Castleman disease (iMCD) can benefit from care based on clinical symptoms and disease severity. This study in 176 patients with iMCD constructed an iMCD-IPI score based on five clinical factors, including age >40 years, plasmacytic variant subtype, hepatomegaly and/or splenomegaly, hemoglobin <80 g/L, and pleural effusion, and stratified patients into three risk categories: low risk, intermediate risk, and high risk. The predictive value was validated in an independent set of 197 patients with iMCD from The International Castleman Disease Consortium. The proposed novel model is valuable for predicting clinical outcome and selecting optimal therapies using clinical parameters.

DOI： 10.1634/theoncologist.2019-0986

Pathological evaluation of radiotherapy and concomitant intraarterial cisplatin for maxillary sinus cancer. Reviewed International journal

Takuma Makino, Tomoyasu Tachibana, Shin Kariya, Yusuke Matsui, Hidenobu Matsuzaki, Shohei Fujimoto, Yorihisa Orita, Kuniaki Katsui, Takao Hiraki, Yasuharu Sato, Susumu Kanazawa, Kazunori Nishizaki

Auris, nasus, larynx 47 ( 5 ) 881 - 886 2020.10

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

OBJECTIVE: Since 2010, we have mainly performed surgical treatment following radiotherapy and concomitant intraarterial cisplatin (RADPLAT) for locally advanced maxillary sinus cancer (MSC). The present study investigated treatment results and pathological evaluations following RADPLAT for MSC. METHODS: Pathological response to RADPLAT was evaluated using surgical specimens. Pathological response was graded in accordance with the classification method that Shimosato reported in 1964, as grade V (no tumor cells remain in any of section), grade IV, III, II, I, and 0. Five-year overall and disease-specific survival rates were estimated using Kaplan-Meier methods. Univariate analyses of correlations between recurrence of MSC and other clinicopathological parameters were evaluated using the chi-square or Fisher's exact tests. RESULT: 19 patients were enrolled in this study, 5 patients showed T3 disease and 14 had T4 disease. One patient demonstrated local recurrence and 3 patients experienced distant metastasis. The 5-year overall survival rate was 67.1% (T3, 50.0%; T4, 69.6%), and the 5-year disease-specific survival rate was 81.9% (T3, 100%; T4, 76.0%). Histological response was categorized as grade V in 9 cases. No significant risk factors for residual cancer were identified. CONCLUSION: Our study suggested that RADPLAT not only has a low risk of side effects, but also could represent an effective procedure for locally advanced MSC by pathological evaluation. Increasing the therapeutic intensity of RADPLAT might provide an effective modality to avoid highly invasive surgery.

DOI： 10.1016/j.anl.2020.04.004

Clinicopathological significance of CD79a expression in classic Hodgkin lymphoma. Reviewed

Akio Sakatani, Takuro Igawa, Takeshi Okatani, Megumu Fujihara, Hideki Asaoku, Yasuharu Sato, Tadashi Yoshino

Journal of clinical and experimental hematopathology : JCEH 60 ( 3 ) 78 - 86 2020.9

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

Classic Hodgkin lymphoma (CHL) is a lymphoid neoplasia characterized by the presence of large tumor cells, referred to as Hodgkin and Reed-Sternberg (HRS) cells, originating from B-cells in an inflammatory background. As the clinical significance of B-cell markers has yet to be fully elucidated, this study aimed to clarify the clinicopathological significance of CD79a in 55 patients with CHL. They were immunohistochemically divided into two groups, comprising of 20 CD79a-positive and 35 CD79a-negative patients. There was no significant correlation between CD79a and CD20 expression (rs = 0.125, P = 0.362). CD79a-positive patients were significantly older at onset (P = 0.011). There was no significant correlation between CD79a-positivity and clinical stage (P = 0.203), mediastinal involvement (P = 0.399), extranodal involvement (P = 0.749), or laboratory findings, including serum levels of lactate dehydrogenase (P = 1) and soluble interleukin-2 receptor (P = 0.251). There were significant differences in overall survival (OS) (P = 0.005) and progression-free survival (PFS) (P = 0.007) between CD79a-positive and CD79a-negative patients (5-year OS: 64.6% and 90.5%; 5-year PFS: 44.0% and 76.6%, respectively). Five patients in whom the majority (> 80%) of HRS cells expressed CD79a consisted of 4 males and 1 female aged between 52 and 81 years; 4 of them were in a limited clinical stage. We concluded that CD79a-positive CHL may have unique clinicopathological features.

DOI： 10.3960/jslrt.20010

Primary human herpesvirus 8-negative effusion-based lymphoma: a large B-cell lymphoma with favorable prognosis. Reviewed International journal

Daisuke Kaji, Yasunori Ota, Yasuharu Sato, Koji Nagafuji, Yasunori Ueda, Masataka Okamoto, Yasushi Terasaki, Naoko Tsuyama, Kosei Matsue, Tomohiro Kinoshita, Go Yamamoto, Shuichi Taniguchi, Shigeru Chiba, Koichi Ohshima, Koji Izutsu

Blood advances 4 ( 18 ) 4442 - 4450 2020.9

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

Primary effusion-based lymphoma (EBL) presents as a malignant effusion in a body cavity. The clinicopathologic features and prognosis of primary human herpesvirus 8 (HHV8)-negative EBL remain unclear. We therefore conducted a retrospective study of 95 patients with EBL, regardless of HHV8 status, in Japan. Of 69 patients with EBL tested for HHV8, a total of 64 were negative. The median age of patients with primary HHV8-negative EBL at diagnosis was 77 years (range, 57-98 years); all 58 tested patients were negative for HIV. Primary HHV8-negative EBL was most commonly diagnosed in pleural effusion (77%). Expression of at least 1 pan B-cell antigen (CD19, CD20, or CD79a) was observed in all cases. According to the Hans algorithm, 30 of the 38 evaluated patients had nongerminal center B-cell (non-GCB) tumors. Epstein-Barr virus-encoded small RNA was positive in 6 of 45 patients. In 56 of 64 HHV8-negative patients, systemic therapy was initiated within 3 months after diagnosis. Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) or CHOP-like regimens with or without rituximab (n = 48) were the most common primary treatments. The overall response and complete response rates were 95% and 73%, respectively. Three patients did not progress without systemic treatment for a median of 24 months. With a median 25-month follow-up, the 2-year overall survival and progression-free survival rates were 84.7% and 73.8%. Sixteen patients died; 12 were lymphoma-related deaths. Thus, most EBL cases in Japan are HHV8-negative and affect elderly patients. The non-GCB subtype is predominant. Overall, primary HHV8-negative EBL exhibits a favorable prognosis after anthracycline-based chemotherapy.

DOI： 10.1182/bloodadvances.2020002293

Clinical characteristics of subglottic cancer: emphasis on therapeutic management strategies for stage II subglottic cancer. Reviewed International journal

Yasutoshi Komatsubara, Tomoyasu Tachibana, Yorihisa Orita, Takuma Makino, Kazunori Kuroda, Yuto Naoi, Yuko Kataoka, Yasuharu Sato, Shin Kariya, Kazunori Nishizaki

Acta oto-laryngologica 140 ( 9 ) 773 - 778 2020.9

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

Background: Subglottic cancer (SGC) is extremely rare, as most laryngeal cancers are localized to the glottic region. Accordingly, the clinical characteristics of SGC have not been well characterized.Objectives: In the current study, SGCs were clinically evaluated, and the outcomes of radiotherapy (RT) in patients with stage II SGC were assessed.Materials and Methods: Medical data derived from 11 patients with SGC, who were treated at our hospital between 1995 and 2019, were retrospectively reviewed.Results: In our department SGC accounted for 3.9% of the 280 laryngeal cancer patients treated during the study period. At the time of SGC diagnosis, 9 (81.8%) had stage II cancer, 1 had stage III cancer, and 1 had stage IV cancer. Stage II SGC patients treated with concurrent chemoradiotherapy (CCRT) showed a significantly higher local control rate (p = .026) and laryngeal dysfunction free rate (p = .026) than those treated with RT alone. Salvage surgery, performed in 4 patients whose disease was not locally controlled with CCRT/RT, was successful in 3 patients.Conclusion: As a treatment strategy for stage II SGC, CCRT is an acceptable initial treatment for laryngeal function and preservation while salvage surgery is effective for recurrence after CCRT/RT treatment.

DOI： 10.1080/00016489.2020.1767303

Clinicopathologic analysis of gastric mucosa-associated lymphoid tissue lymphoma with or without c-Met expression. Reviewed

Rika Omote, Yuka Gion, Shizuma Omote, Akira Tari, Takehiro Tanaka, Asami Nishikori, Tadashi Yoshino, Yasuharu Sato

Medical molecular morphology 53 ( 3 ) 149 - 155 2020.9

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

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach is mainly associated with Helicobacter pylori infection, and H. pylori eradication therapy is often effective. However, 20-30% of the cases of MALT lymphoma are resistant to the eradication therapy, and translocation of the API2-MALT1 gene is often found in these cases. Most cases without translocation of API2-MALT1 are localized to the stomach, whereas some cases with this translocation are a more advanced stage of MALT lymphoma that spreads to other organs. The c-Met receptor is a prognostic factor involved in infiltration and metastasis in many malignant tumors, including gastric, pancreatic, lung, and kidney cancer. In the present study, the expression of c-Met in 43 cases of gastric MALT lymphomas was immunohistochemically examined and compared with clinicopathological factors. To elucidate the significance of c-Met in MALT lymphoma, the expression intensity of c-Met in 22 API2-MALT1 translocation-positive and 21 API2-MALT1 translocation-negative cases was scored, compared, and examined. The immunohistochemistry analysis revealed strong staining for c-Met in 21 API2-MALT1 translocation-positive cases and in 1 translocation-negative case (P = 0.00). This result indicates the relationship between strong expression of c-Met and the progression of MALT lymphoma with API2-MALT1 gene translocation.

DOI： 10.1007/s00795-019-00241-6

Comparison of the Hybrid Capture II Method with a PCR-Based Screening Method Using a Carboxyfluorescein-Labeled Primer for Detecting Human Papillomavirus in Cervicovaginal Liquid-Based Cytology Reviewed

Yusuke Saiki, Yuka Gion, Asami Nishikori, Yoshiaki Norimatsu, Yasuharu Sato

Journal of Molecular Pathology 1 ( 1 ) 9 - 18 2020.9

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

Objective: Human papillomaviruses (HPVs) are DNA viruses, of which over 120 types have been identified. The main screening methods for HPV-DNA include the hybrid capture II (HC-II) and polymerase chain reaction (PCR) assays. Liquid-based cytology (LBC) is a high-quality technique developed to improve the diagnostic reliability of traditional Papanicolaou tests (Pap tests). However, relatively few studies have compared the efficacy of PCR and HC-II assays using cervicovaginal LBC specimens. In this study, we conducted a comparative analysis with results derived from the HC-II assay to assess whether a PCR-based assay using a novel carboxyfluorescein (FAM)-labeled primer could be applied to cervicovaginal LBC specimens. Methods and Results: We analyzed 59 specimens diagnosed as atypical squamous cells of undetermined significance (ASCUS) by Pap tests. After extracting DNA from cervicovaginal LBC specimens, we performed PCR using a FAM-labeled consensus primer, and then conducted fragment analysis to confirm the results. The value of the kappa statistic measuring the agreement between the PCR and HC-II results was 0.8557, or “almost perfect agreement.” Conclusion: Our novel HPV-PCR assay can be successfully applied to cervicovaginal LBC specimens for the detection of HPV subtypes.

DOI： 10.3390/jmp1010003

Clinicopathological differential diagnosis of IgG4-related disease: A historical overview and a proposal of the criteria for excluding mimickers of IgG4-related disease. Reviewed International journal

Akira Satou, Kenji Notohara, Yoh Zen, Shigeo Nakamura, Tadashi Yoshino, Kazuichi Okazaki, Yasuharu Sato

Pathology international 70 ( 7 ) 391 - 402 2020.7

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

IgG4-related disease (RD) is a relatively new entity, which was first proposed in 2001. Since then, clinical and pathological characteristics of the disease have been investigated. As IgG4-RD has been studied extensively, the diagnostic criteria for IgG4-RD of each organ and the comprehensive diagnostic criteria for IgG4-RD have also been developed. However, one of the biggest challenges in the field is distinguishing between IgG4-RD and mimickers, which show overlapping features with IgG4-RD. It is now known that some non-IgG4-RDs may meet the diagnostic criteria of IgG4-RD and can be misdiagnosed as IgG4-RD. However, accurate diagnosis is crucial, as the treatments for IgG4-RD and those for other diseases that may be misdiagnosed as IgG4-RD are different. This prompted us to create and propose comprehensive exclusion criteria for IgG4-RD. In this review, we have described the comprehensive exclusion criteria for IgG4-RD, with a historical overview of the disease. These exclusion criteria were recently created by the Research Program for Intractable Disease of the Ministry of Health, Labor, and Welfare of Japan, All Japan IgG4 team, to support correct and accurate diagnosis of IgG4-RD.

DOI： 10.1111/pin.12932

MACC1 expression is an indicator of recurrence in early-stage glottic cancer. Reviewed International journal

Takuma Makino, Yorihisa Orita, Yuka Gion, Tomoyasu Tachibana, Soshi Takao, Hidenori Marunaka, Kentaro Miki, Naoki Akisada, Yusuke Akagi, Tadashi Yoshino, Kazunori Nishizaki, Yasuharu Sato

Japanese journal of clinical oncology 50 ( 4 ) 392 - 398 2020.4

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

BACKGROUND: Metastasis-associated in colon cancer 1 (MACC1) has been reported to be an independent indicator of poor prognoses in some kinds of cancer due to disease metastasis or recurrence. We investigated the correlation between MACC1 expression and the prognosis of glottic cancer. METHODS: Paraffin-embedded, early-stage (I or II) glottic cancer specimens (n = 52) were immunohistochemically analyzed to explore MACC1 expression. The clinical records associated with each case were also examined. Recurrence-free survival (RFS) was estimated using the Kaplan-Meier method, and between-group RFS differences were assessed using the log-rank test. The multivariate analyses were evaluated using the Cox's proportional-hazard model. RESULTS: Patients were treated with only radiotherapy (RT) (n = 37, including 18 with T1 disease and 19 with T2 disease), or with chemoradiotherapy (CRT) (n = 15, including 1 with T1 disease and 14 with T2 disease). Eleven patients demonstrated local recurrence and two patients experienced cervical lymph node recurrence. Tumor specimens were MACC1-positive in 9 of the 13 (69.2%) patients with local or neck recurrence, and 7 of the 11 (63.6%) patients with local recurrence. The RFS rate of patients who were treated with only RT was significantly lower than that of patients who were treated with CRT (P = 0.0243). The RFS rate was significantly lower in cases with MACC1 expression than in those without MACC1 expression (P = 0.0003). Multivariate analysis revealed that MACC1 expression was an independent risk factor of local recurrence (P = 0.0016). CONCLUSION: MACC1 is an independent indicator of recurrence related to RFS in early-stage glottic cancer.

DOI： 10.1093/jjco/hyz206

Hemosiderin deposition in lymph nodes of patients with plasma cell-type Castleman disease. Reviewed

Yanyan Han, Takuro Igawa, Kyohei Ogino, Asami Nishikori, Yuka Gion, Tadashi Yoshino, Yasuharu Sato

Journal of clinical and experimental hematopathology : JCEH 60 ( 1 ) 1 - 6 2020.3

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

Plasma cell-type Castleman disease (PCD) is a rare idiopathic atypical lymphoproliferative disorder. It is difficult to differentiate between PCD and IgG4-related disease (IgG4-RD) based on histology alone. As PCD often presents with abundant hemosiderin deposition, lymph node lesions obtained from 22 PCD patients and 12 IgG4-RD patients were analyzed using Prussian blue staining to clarify whether hemosiderin deposition is effective in distinguishing between these two diseases. The analysis disclosed that hemosiderin was more densely deposited in PCD than in IgG4-RD. The median number of Prussian blue-positive cells ± standard deviation (SD) in PCD and IgG4-RD cases was 13 ± 36 cells/3HPFs and 4 ± 8 cells/3HPFs (P = 0.034), respectively. In addition, we analyzed the relationship between hemosiderin deposition and levels of serum interleukin (IL)-6, serum C-reactive protein (CRP), and anemia-related biomarkers. We found that hemosiderin deposition was significantly correlated with the level of serum CRP (P = 0.045); however, no significant correlation was observed between hemosiderin deposition and serum IL-6 levels (P = 0.204). A non-significant positive correlation was observed between hemosiderin deposition and serum hemoglobin levels (P=0.09). Furthermore, no significant correlation was observed between hemosiderin deposition and serum iron levels (P = 0.799). In conclusion, hemosiderin deposition characteristically observed in PCD may be related to the inflammatory aggressiveness of the disease and could be used for its differential diagnosis.

DOI： 10.3960/jslrt.19037

Serum IgG4 as a biomarker reflecting pathophysiology and post-operative recurrence in chronic rhinosinusitis. Reviewed International journal

Oka A, Ninomiya T, Fujiwara T, Takao S, Sato Y, Gion Y, Minoura A, Haruna SI, Yoshida N, Sakuma Y, Izuhara K, Ono J, Taniguchi M, Haruna T, Higaki T, Kariya S, Koyama T, Takabayashi T, Imoto Y, Sakashita M, Kidoguchi M, Nishizaki K, Fujieda S, Okano M

Allergology international : official journal of the Japanese Society of Allergology 69 ( 3 ) 417 - 423 2020.1

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

BACKGROUND: Type 2 chronic rhinosinusitis (CRS), especially eosinophilic CRS (ECRS), is an intractable upper airway inflammatory disease. Establishment of serum biomarkers reflecting the pathophysiology of CRS is desirable in a clinical setting. As IgG4 production is regulated by type 2 cytokines, we sought to determine whether serum IgG4 levels can be used as a biomarker for CRS. METHODS: Association between the serum IgG4 levels and clinicopathological factors was analyzed in 336 CRS patients. Receiver operating characteristics (ROC) analysis was performed to determine the cut-off value of serum IgG4 levels that can be used to predict the post-operative recurrence. RESULTS: Serum IgG4 levels were significantly higher in patients with moderate to severe ECRS versus those with non to mild ECRS. The levels were also significantly higher in asthmatic patients and patients exhibiting recurrence after surgery compared to controls. ROC analysis determined that the best cut-off value for the serum IgG4 level to predict the post-operative recurrence was 95 mg/dL. The corresponding sensitivity and specificity were 39.7% and 80.5%, respectively. When we combined the two cut-off values for the serum IgG4 and periostin, patients with high serum levels of either IgG4 or periostin exhibited a high post-operative recurrence (OR: 3.95) as compared to patients having low serum levels of both IgG4 and periostin. CONCLUSIONS: The present results demonstrate that the serum IgG4 level is associated with disease severity and post-operative course in CRS. In particular, the combination of serum IgG4 and periostin could be a novel biomarker that predicts post-operative recurrence.

DOI： 10.1016/j.alit.2019.12.004

Clinical significance of cytoplasmic IgE-positive mast cells in eosinophilic chronic rhinosinusitis Reviewed International journal

Gion Y, Okano M, Koyama Y, Oura T, Nishikori A, Orita Y, Tachibana T, Marunaka H, Makino T, Nishizaki K, Sato Y

Int J Mol Sci 7 ( 21 ) 2020

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

Cross-linking of antigen-specific IgE bound to the high-affinity IgE receptor (FcεRI) on the surface of mast cells with multivalent antigens results in the release of mediators and development of type 2 inflammation. FcεRI expression and IgE synthesis are, therefore, critical for type 2 inflammatory disease development. In an attempt to clarify the relationship between eosinophilic chronic rhinosinusitis (ECRS) and mast cell infiltration, we analyzed mast cell infiltration at lesion sites and determined its clinical significance. Mast cells are positive for c-kit, and IgE in uncinated tissues (UT) and nasal polyps (NP) were examined by immunohistochemistry. The number of positive cells and clinicopathological factors were analyzed. Patients with ECRS exhibited high levels of total IgE serum levels and elevated peripheral blood eosinophil ratios. As a result, the number of mast cells with membranes positive for c-kit and IgE increased significantly in lesions forming NP. Therefore, we classified IgE-positive mast cells into two groups: membrane IgE-positive cells and cytoplasmic IgE-positive cells. The amount of membrane IgE-positive mast cells was significantly increased in moderate ECRS. A positive correlation was found between the membrane IgE-positive cells and the radiological severity score, the ratio of eosinophils, and the total serum IgE level. The number of cytoplasmic IgE-positive mast cells was significantly increased in moderate and severe ECRS. A positive correlation was observed between the cytoplasmic IgE-positive cells and the radiological severity score, the ratio of eosinophils in the blood, and the total IgE level. These results suggest that the process of mast cell internalization of antigens via the IgE receptor is involved in ECRS pathogenesis.

DOI： 10.3390/ijms21051843

Clinical and Pathological Characteristics of IgG4-Related Periaortitis/Periarteritis and Retroperitoneal Fibrosis Diagnosed Based on Experts' Diagnosis. Reviewed

Ichiro Mizushima, Satomi Kasashima, Yasunari Fujinaga, Kenji Notohara, Takako Saeki, Yoh Zen, Dai Inoue, Motohisa Yamamoto, Fuminari Kasashima, Yasushi Matsumoto, Eisuke Amiya, Yasuharu Sato, Kazunori Yamada, Yukako Domoto, Shigeyuki Kawa, Mitsuhiro Kawano, Nobukazu Ishizaka

Annals of vascular diseases 12 ( 4 ) 460 - 472 2019.12

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

IgG4-related disease is a systemic disease, characterized by elevation of serum IgG4 and, histopathologically, massive infiltration of IgG4+ lymphocyte and plasma cell infiltration, storiform fibrosis, causing enlargement, nodules or thickening. It may affect various organs simultaneously or metachronously. Here we analyzed the clinical and pathological characteristics of 99 patients diagnosed with IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis. Of 99 patients (women/men, 15/84; mean age 67.3±9.5 years), 33 were diagnosed based on the histopathological findings of perivascular/retroperitoneal lesions, 50 were diagnosed based on the characteristic imaging findings of perivascular/retroperitoneal lesions and the presence of definitive IgG4-related disease in other organ(s), and the remaining 16 patients were diagnosed by experts based on the characteristic imaging findings of perivascular/retroperitoneal legions, serological findings, response to glucocorticoid treatment, and/or the presence of suspected IgG4-related disease in other organ(s). According to the new organ-specific criteria proposed by experts, 73 (73.7%) diagnoses were categorized to be definitive, and 6 (6.1%) and 17 (17.2%) diagnoses were categorized to be probable and possible, respectively. Further analyses are needed to clarify the optimal diagnostic and therapeutic strategy of IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis. (This is a translation of J Jpn Coll Angiol 2018; 58: 117-129.).

DOI： 10.3400/avd.oa.19-00085

Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling. Reviewed International journal

Yosaku Watatani, Yasuharu Sato, Hiroaki Miyoshi, Kana Sakamoto, Kenji Nishida, Yuka Gion, Yasunobu Nagata, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Lanying Zhao, Yotaro Ochi, Yasuhide Takeuchi, June Takeda, Hiroo Ueno, Yasunori Kogure, Yusuke Shiozawa, Nobuyuki Kakiuchi, Tetsuichi Yoshizato, Masahiro M Nakagawa, Yasuhito Nanya, Kenichi Yoshida, Hideki Makishima, Masashi Sanada, Mamiko Sakata-Yanagimoto, Shigeru Chiba, Ryota Matsuoka, Masayuki Noguchi, Nobuhiro Hiramoto, Takayuki Ishikawa, Junichi Kitagawa, Nobuhiko Nakamura, Hisashi Tsurumi, Tatsuhiko Miyazaki, Yusuke Kito, Satoru Miyano, Kazuya Shimoda, Kengo Takeuchi, Koichi Ohshima, Tadashi Yoshino, Seishi Ogawa, Keisuke Kataoka

Leukemia 33 ( 12 ) 2867 - 2883 2019.12

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

Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) is a diagnosis of exclusion, being the most common entity in mature T-cell neoplasms, and its molecular pathogenesis remains significantly understudied. Here, combining whole-exome and targeted-capture sequencing, gene-expression profiling, and immunohistochemical analysis of tumor samples from 133 cases, we have delineated the entire landscape of somatic alterations, and discovered frequently affected driver pathways in PTCL, NOS, with and without a T-follicular helper (TFH) cell phenotype. In addition to previously reported mutational targets, we identified a number of novel recurrently altered genes, such as KMT2C, SETD1B, YTHDF2, and PDCD1. We integrated these genetic drivers using hierarchical clustering and identified a previously undescribed molecular subtype characterized by TP53 and/or CDKN2A mutations and deletions in non-TFH PTCL, NOS. This subtype exhibited different prognosis and unique genetic features associated with extensive chromosomal instability, which preferentially affected molecules involved in immune escape and transcriptional regulation, such as HLA-A/B and IKZF2. Taken together, our findings provide novel insights into the molecular pathogenesis of PTCL, NOS by highlighting their genetic heterogeneity. These results should help to devise a novel molecular classification of PTCLs and to exploit a new therapeutic strategy for this group of aggressive malignancies.

DOI： 10.1038/s41375-019-0473-1

Hepatic Campylobacter jejuni infection in patients with Castleman-Kojima disease (idiopathic multicentric Castleman disease with thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome). Reviewed International journal

Chihiro Kageyama, Takuro Igawa, Yuka Gion, Noriko Iwaki, Tetsuya Tabata, Takehiro Tanaka, Eisei Kondo, Hajime Sakai, Koichi Tsuneyama, Kazuhiro Nomoto, Hiroko Noguchi, Tadashi Yoshino, Kenji Yokota, Yasuharu Sato

Pathology international 69 ( 10 ) 572 - 579 2019.10

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

Castleman-Kojima disease, also known as idiopathic multicentric Castleman disease with TAFRO syndrome (iMCD-TAFRO), is a recently recognized systemic inflammatory disorder with a characteristic series of clinical symptoms, including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O). Patients with iMCD-TAFRO often develop severe abdominal pain, elevated alkaline phosphatase levels, and systemic inflammation, but the etiological factors are unknown. To investigate the potential role of bacterial infection in the pathogenesis of iMCD-TAFRO, we performed polymerase chain reaction (PCR) for the bacterial 16S rRNA gene with DNA extracted from liver specimens of three patients with iMCD-TAFRO, four patients with amyotrophic lateral sclerosis, and seven patients with inflammatory conditions. Sequencing of the PCR product showed 99% DNA sequence identity with Campylobacter jejuni in all three patients with iMCD-TAFRO and in two patients with inflammatory conditions. Immunohistochemical and electron microscopy analyses could not identify C. jejuni in patients with iMCD-TAFRO. The findings indicated that C. jejuni infection is not the pathological cause of iMCD-TAFRO; however, this ubiquitous bacterium may play a role in uncontrolled systemic hypercytokinemia, possibly through the development of cross-reactive autoantibodies.

DOI： 10.1111/pin.12856

The efficacy of OK-432 sclerotherapy on thyroglossal duct cyst and the influence on a subsequent surgical procedure. Reviewed International journal

Tomoyasu Tachibana, Shin Kariya, Yorihisa Orita, Takuma Makino, Takenori Haruna, Yuko Matsuyama, Yasutoshi Komatsubara, Yuto Naoi, Michihiro Nakada, Yoji Wani, Soichiro Fushimi, Machiko Hotta, Katsuya Haruna, Tami Nagatani, Yasuharu Sato, Kazunori Nishizaki

Acta oto-laryngologica 139 ( 9 ) 788 - 792 2019.9

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

Background: Although there are studies regarding the efficacy of OK-432 sclerotherapy on thyroglossal duct cyst (TDC), its effects on surgical procedure following this therapy have not been properly described. Objectives: The present study aimed to delineate the prognostic factors of OK-432 sclerotherapy in patients with TDC and investigate its influence on subsequent surgical procedure and the histological characteristics in patients with poor response to OK-432 sclerotherapy. Material and methods: We conducted a retrospective analysis of the medical records of 20 TDC patients treated with OK-432 sclerotherapy. Results: Of the 20 patients, OK-432 sclerotherapy was effective in 5 patients (25.0%). OK-432 showed a lower effective rate in multilocular cysts (9.1%) than in unilocular cysts (44.4%), although not significantly. Five cases were treated with surgery following OK-432 sclerotherapy. There was no significant difference in the operating time and the amount of bleeding between patients with and without OK-432 sclerotherapy. From the results of the histological examination of the cyst wall, two cases had stratified squamous epithelium and two cases showed the absence of lymphocyte infiltration. Conclusion and significance: OK-432 sclerotherapy is an acceptable initial treatment for TDC, especially in unilocular cysts, because of lack of influence on surgical procedure.

DOI： 10.1080/00016489.2019.1633019

Focus on immunodeficiency-associated lymphoproliferative disorders. Invited Reviewed

Sato Y

J Clin Exp Hematop. 59 ( 2 ) 64 - 71 2019.8

Clinical and biochemical characteristics of patients having general symptoms with increased serum IgG4. Reviewed International journal

Kou Hasegawa, Yoshihisa Hanayama, Mikako Obika, Tomoko Miyoshi, Hiroko Ogawa, Eisei Kondo, Hitomi Kataoka, Yasuharu Sato, Fumio Otsuka

Modern rheumatology 30 ( 4 ) 721 - 728 2019.8

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

Objective: To differentiate patients with IgG4-related diseases (RD) from patients with other hyper IgG4 conditions who visit general medicine department.Methods: Fifty-six patients with high serum IgG4 levels (>135 mg/dL) were classified into three groups based on the final diagnosis: definite and possible IgG4-RD and others. Clinical and laboratory characteristics of the three groups of patients were retrospectively analyzed.Results: Major manifestations were renal dysfunction and general malaise, while thirst was the most frequent symptom in the definite group, in which submandibular glands and lymph nodes were likely to be affected. Biopsy of minor salivary glands was the least diagnostic for IgG4-RD despite the high frequency of biopsy. In the definite group, serum levels of IgG4 and IgG, IgG4/IgG ratio and basophil number were increased, while serum levels of CRP, IgA and complements were decreased. A negative correlation between serum levels of IgG4 and IgM was found in the definite group.Conclusion: The results indicated that in patients with renal dysfunction, malaise, thirst or weight loss, measurements of the levels of basophils, immunoglobulins and complements are helpful for diagnosing IgG4-RD. Considering distribution of affected tissues and localization of diagnostic biopsies, physical examination and laboratory workup are required for early diagnosis.

DOI： 10.1080/14397595.2019.1642291

A review of EBV-positive mucocutaneous ulcers focusing on clinical and pathological aspects. Invited Reviewed

Tomoka Ikeda, Yuka Gion, Tadashi Yoshino, Yasuharu Sato

Journal of clinical and experimental hematopathology 59 ( 2 ) 64 - 71 2019.8

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

Epstein-Barr virus (EBV)-positive mucocutaneous ulcers (EBVMCUs) were first described as a lymphoproliferative disorder in 2010. Clinically, EBVMCUs are shallow, sharply circumscribed, unifocal mucosal or cutaneous ulcers that occur in immunosuppressed patients, including those with advanced age-associated immunosenescence, iatrogenic immunosuppression, primary immune disorders, and HIV/AIDS-associated immune deficiencies. In general, patients exhibit indolent disease progression and spontaneous regression. Histologically, EBVMCUs are characterized by the proliferation of EBV-positive, variable-sized, atypical B-cells. According to conventional histopathologic criteria, EBVMCUs may diagnosed as lymphomas. However, EBVMCUs are recognized as pseudomalignant lesions because they spontaneously regress without anti-cancer treatment. Therefore, overtreatment must be carefully avoided and multilateral differentiation is important. In this article, we reviewed previously reported EBVMCUs focusing on their clinical and pathological aspects in comparison with other EBV-positive B-cell neoplasms.

DOI： 10.3960/jslrt.18039

Methotrexate-associated lymphoproliferative disorders of T-cell phenotype: clinicopathological analysis of 28 cases. Reviewed International journal

Akira Satou, Tetsuya Tabata, Hiroaki Miyoshi, Kei Kohno, Yuka Suzuki, Daisuke Yamashita, Kazuyuki Shimada, Tomonori Kawasaki, Yasuharu Sato, Tadashi Yoshino, Koichi Ohshima, Taishi Takahara, Toyonori Tsuzuki, Shigeo Nakamura

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 32 ( 8 ) 1135 - 1146 2019.7

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

Methotrexate-associated lymphoproliferative disorders are categorized as "other immunodeficiency-associated lymphoproliferative disorders in the WHO classification. Methotrexate-associated lymphoproliferative disorder is mainly a B-cell lymphoproliferative disorders or Hodgkin lymphoma type, whereas T-cell lymphoproliferative disorders are relatively rare (4-8%). Only a small number of methotrexate-associated T-cell lymphoproliferative disorders have been detailed thus far. Because of the rarity, methotrexate-associated T-cell lymphoproliferative disorder has not been well studied and its clinicopathological characteristics are unknown. A total of 28 cases of methotrexate-associated T-cell lymphoproliferative disorders were retrospectively analyzed. Histologically and immunohistochemically, they were divided into three main types: angioimmunoblastic T-cell lymphoma (n = 19), peripheral T-cell lymphoma, NOS (n = 6), and CD8+ cytotoxic T-cell lymphoma (n = 3). Among the 28 cases, only one CD8+ cytotoxic T-cell lymphoma case was Epstein-Barr virus-positive. The other 27 cases were negative for Epstein-Barr virus on tumor cells, but scattered Epstein-Barr virus-infected B-cells were detected in 24 cases (89%), implying the reactivation of Epstein-Barr virus caused by immunodeficient status of the patients. After the diagnosis of methotrexate-associated T-cell lymphoproliferative disorder, methotrexate was immediately withdrawn in 26 cases. Twenty (77%) cases presented with spontaneous regression. Compared to methotrexate-associated B-cell lymphoproliferative disorder, patients with methotrexate-associated T-cell lymphoproliferative disorder had a significantly higher proportion of males (p = 0.035) and presence of B-symptoms (p = 0.036), and lower proportion of Epstein-Barr virus+ tumor cells (p < 0.001). Although the difference was not significant, the methotrexate-associated T-cell lymphoproliferative disorder also had more frequent spontaneous regression (p = 0.061). In conclusion, methotrexate-associated T-cell lymphoproliferative disorder was divided into three main types: angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, NOS, and CD8+ cytotoxic T-cell lymphoma. Angioimmunoblastic T-cell lymphoma was the most common type. Methotrexate-associated T-cell lymphoproliferative disorder was characterized by a high rate of spontaneous regression after methotrexate cessation. Epstein-Barr virus positivity was relatively rare in methotrexate-associated T-cell lymphoproliferative disorder, significantly less frequent than methotrexate-associated B-cell lymphoproliferative disorder, suggesting different pathogenesis.

DOI： 10.1038/s41379-019-0264-2

Activated M2 Macrophages Contribute to the Pathogenesis of IgG4-Related Disease via Toll-like Receptor 7/Interleukin-33 Signaling. Reviewed International journal

Noriko Ishiguro, Masafumi Moriyama, Katsuhiro Furusho, Sachiko Furukawa, Takuma Shibata, Yusuke Murakami, Akira Chinju, A S M Rafiul Haque, Yuka Gion, Miho Ohta, Takashi Maehara, Akihiko Tanaka, Masaki Yamauchi, Mizuki Sakamoto, Keita Mochizuki, Yuko Ono, Jun-Nosuke Hayashida, Yasuharu Sato, Tamotsu Kiyoshima, Hidetaka Yamamoto, Kensuke Miyake, Seiji Nakamura

Arthritis & rheumatology (Hoboken, N.J.) 72 ( 1 ) 166 - 178 2019.7

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

OBJECTIVE: IgG4-related disease (IgG4-RD) is a unique inflammatory disorder in which Th2 cytokines promote IgG4 production. In addition, recent studies have implicated the Toll-like receptor (TLR) pathway. This study was undertaken to examine the expression of TLRs in salivary glands (SGs) from patients with IgG4-RD. METHODS: SGs from 15 patients with IgG4-RD, 15 patients with Sjögren's syndrome (SS), 10 patients with chronic sialadenitis, and 10 healthy controls were examined histologically. TLR family gene expression (TLR-1 through TLR-10) was analyzed by DNA microarray in the submandibular glands (SMGs). Up-regulation of TLRs was confirmed in SGs from patients with IgG4-RD. Finally, the phenotype of human TLR-7 (huTLR-7)-transgenic C57BL/6 mice was assessed before and after stimulation with TLR agonist. RESULTS: In patients with IgG4-RD, TLR-4, TLR-7, TLR-8, and TLR-9 were overexpressed. Polymerase chain reaction validated the up-regulation of TLR-7 in IgG4-RD compared with the other groups. Immunohistochemical analysis confirmed strong infiltration of TLR-7-positive cells in the SGs of patients with IgG4-RD. Double immunohistochemical staining showed that TLR-7 expression colocalized with CD163+ M2 macrophages. After in vitro stimulation with a TLR-7 agonist, CD163+ M2 macrophages produced higher levels of interleukin-33 (IL-33), which is a Th2-activating cytokine. In huTLR-7-transgenic mice, the focus and fibrosis scores in SMGs, pancreas, and lungs were significantly higher than those in wild-type mice (P < 0.05). Moreover, the concentration of serum IgG, IgG1, and IL-33 in huTLR-7-transgenic mice was distinctly increased upon stimulation with a TLR-7 agonist (P < 0.05). CONCLUSION: TLR-7-expressing M2 macrophages may promote the activation of Th2 immune responses via IL-33 secretion in IgG4-RD.

DOI： 10.1002/art.41052

KRAS mutations in tongue squamous cell carcinoma Reviewed

Yusuke Akagi, Tomoyasu Tachibana, Yorihisa Orita, Yuka Gion, Hidenori Marunaka, Takuma Makino, Kentaro Miki, Naoki Akisada, Tadashi Yoshino, Kazunori Nishizaki, Yasuharu Sato

Acta Oto-Laryngologica 139 ( 7 ) 647 - 651 2019.7

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

Background: p16 (p16) expression in tongue cancer (TC) is reportedly not associated with human papilloma virus (HPV). Mutations of KRAS in cancer cells are most frequently observed within codon 12. However, few reports have investigated the association between KRAS mutations and p16 status in TC. Objectives: This study aimed to evaluate the influence of KRAS mutations on TC. Methods: Clinical records and surgically resected specimens of 85 TC patients were analyzed. Tumor samples were analyzed for mutations of KRAS located within codons 12 and 13. p16 staining was performed and considered positive in cases with moderate to strong nuclear and cytoplasmic staining. Results: Positive p16 staining was observed in 10 cases (11.8%). A KRAS mutation was detected in one case (1.2%). The case with KRAS mutation showed negative p16 staining. Despite being at an early stage, the patient died of lung metastasis at 43 months from initial treatment. Conclusions and Significance:KRAS mutations are not associated with p16 expression in TC and may predict poor prognosis in TC patients. Further analysis of mutations in regions other than codons 12 and 13 of KRAS will be necessary to determine the relationship between KRAS mutations and prognosis of this disease. INK4a

DOI： 10.1080/00016489.2019.1610574

Spontaneous closure of traumatic tympanic membrane perforation following long-term observation Reviewed

Tomoyasu Tachibana, Shin Kariya, Yorihisa Orita, Takuma Makino, Takenori Haruna, Yuko Matsuyama, Yasutoshi Komatsubara, Yuto Naoi, Michihiro Nakada, Yohei Noda, Yasuharu Sato, Kazunori Nishizaki

Acta Oto-Laryngologica 139 ( 6 ) 487 - 491 2019.6

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

Background: Traumatic tympanic membrane perforation (TTMP) is usually managed conservatively because most close spontaneously within a few months. Nevertheless, spontaneous closure of TTMP during long-term observation has not been well described in the literature. Objectives: The present study investigated factors associated with spontaneous closure of TTMP, and the characteristics of cases exhibiting spontaneous closure following long-term observation. Materials and Methods: The medical records of 40 patients with TTMP who visited the authors’ hospital were retrospectively reviewed. Results: Spontaneous closure was observed in 27 (67.5%) patients. The healing period was <2 weeks in 6 cases, <4 weeks in 9, <3 months in 5, <6 months in 3, and ≥6 months in 4. All four cases in which spontaneous closure took ≥6 months exhibited a sign of spontaneous closure at 6 months following injury. Perforation in contact with the malleus was associated with a lower frequency of spontaneous closure. Conclusions and Significance: In TTMP, surgery should be considered in patients who exhibit perforation in contact with the malleus. However, it has also been suggested that long-term observation may be a viable treatment option when a sign of spontaneous closure is observed within 6 months following injury.

DOI： 10.1080/00016489.2019.1592225

Virome capture sequencing does not identify active viral infection in unicentric and idiopathic multicentric Castleman disease. Reviewed International journal

Christopher S Nabel, Stephen Sameroff, Dustin Shilling, Daisy Alapat, Jason R Ruth, Mitsuhiro Kawano, Yasuharu Sato, Katie Stone, Signe Spetalen, Federico Valdivieso, Michael D Feldman, Amy Chadburn, Alexander Fosså, Frits van Rhee, W Ian Lipkin, David C Fajgenbaum

PloS one 14 ( 6 ) e0218660 2019.6

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

Castleman disease (CD) describes a spectrum of heterogeneous disorders defined by characteristic lymph node histopathology. Enlarged lymph nodes demonstrating CD histopathology can occur in isolation (unicentric CD; UCD) sometimes accompanied by mild symptoms, or at multiple sites (multicentric CD, MCD) with systemic inflammation and cytokine-driven multi-organ dysfunction. The discovery that Kaposi sarcoma herpesvirus/human herpesvirus (HHV)-8 drives MCD in a subset of patients has led to the hypotheses that UCD and MCD patients with negative HHV-8 testing by conventional methods may represent false negatives, or that these cases are driven by another virus, known or unknown. To investigate these hypotheses, the virome capture sequencing for vertebrate viruses (VirCapSeq-VERT) platform was employed to detect RNA transcripts from known and novel viruses in fresh frozen lymph node tissue from CD patients (12 UCD, 11 HHV-8-negative MCD [idiopathic MCD; iMCD], and two HHV-8-positive MCD) and related diseases (three T cell lymphoma and three Hodgkin lymphoma). This assay detected HHV-8 in both HHV-8-positive cases; however, HHV-8 was not found in clinically HHV-8-negative iMCD or UCD cases. Additionally, no novel viruses were discovered, and no single known virus was detected with apparent association to HHV-8-negative CD cases. Herpesviridae family members, notably including Epstein-Barr virus (EBV), were detected in 7 out of 12 UCD and 5 of 11 iMCD cases with apparent correlations with markers of disease severity in iMCD. Analysis of a separate cohort of archival formalin-fixed, paraffin-embedded lymph node tissue by In situ hybridization revealed significantly fewer EBV-positive cells in UCD and iMCD compared to tissue from HHV-8-positive MCD and EBV-associated lymphoproliferative disorder. In an additional cohort, quantitative testing for EBV by PCR in peripheral blood during disease flare did not detect systemic EBV viremia, suggesting detection lymph node tissue is due to occult, local reactivation in UCD and iMCD. This study confirms that HHV-8 is not present in UCD and iMCD patients. Further, it fails to establish a clear association between any single virus, novel or known, and CD in HHV-8-negative cases. Given that distinct forms of CD exist with viral and non-viral etiological drivers, CD should be considered a group of distinct and separate diseases with heterogeneous causes worthy of further study.

DOI： 10.1371/journal.pone.0218660

包括的遺伝学的特性分析により明らかになった非特定型末梢T細胞リンパ腫における分子的異質性(Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling) Reviewed

綿谷陽作, 佐藤康晴, 三好寛明, 坂本佳奈, 西田賢司, 祇園由佳, 坂田麻実子, 中村信彦, 平本展大, 白石友一, 宮野悟, 真田昌, 千葉滋, 石川隆之, 鶴見寿, 竹内賢吾, 大島孝一, 吉野正, 小川誠司, 片岡圭亮

日本リンパ網内系学会会誌 59 113 - 113 2019.5

Significance of IgG4-positive cells in severe eosinophilic chronic rhinosinusitis Reviewed

Takahisa Koyama, Shin Kariya, Yasuharu Sato, Yuka Gion, Takaya Higaki, Takenori Haruna, Tazuko Fujiwara, Akira Minoura, Soshi Takao, Yorihisa Orita, Kengo Kanai, Masami Taniguchi, Kazunori Nishizaki, Mitsuhiro Okano

Allergology International 68 ( 2 ) 216 - 224 2019.4

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

Background: IgG4 production is regulated by type 2 (IL-4 and IL-13) and regulatory (IL-10) cytokines involved in the pathophysiology of chronic rhinosinusitis (CRS). We sought to determine the pathophysiological characteristics of IgG4-positive cells in sinonasal tissues in CRS, especially eosinophilic CRS (ECRS). Methods: IgG4-positive cells in uncinate tissues (UT) and nasal polyps (NP) were examined by immunohistochemistry. Associations between the number of IgG4-positive cells and clinicopathological factors were analyzed. Receiver operating characteristics (ROC) analysis was performed to determine the cut-off value of IgG4-positive cells in tissue that can predict the post-operative course. Results: IgG4 was mainly expressed in infiltrating plasma and plasmacytoid cells, and the number of IgG4-positive cells was significantly higher in NP, especially those from severe ECRS patients, than in UT. In CRS patients, the number of IgG4-positive cells significantly and positively correlated with blood and tissue eosinophilia, radiological severity, and serum level of total IgE. The number of infiltrating IgG4-positive cells was significantly higher in patients with a poor post-operative course (sustained sinus shadow 6 months after surgery) than in those with a good one. The number of IgG4-positive cells in NP could discriminate patients with a good or a poor post-operative course (area under the curve: 0.769). Also, 73.3% sensitivity and 82.5% specificity were achieved when the cut-off value was set at 17 cells/high-power field. Conclusions: Our results suggest that the local expression of IgG4 on cells may be used as a biomarker that reflects the pathophysiology of CRS, including the post-operative course.

DOI： 10.1016/j.alit.2018.09.002

Up-regulation of activation-induced cytidine deaminase and its strong expression in extra- germinal centres in IgG4-related disease Reviewed

Yuka Gion, Mai Takeuchi, Rei Shibata, Katsuyoshi Takata, Tomoko Miyata-Takata, Yorihisa Orita, Tomoyasu Tachibana, Tadashi Yoshino, Yasuharu Sato

SCIENTIFIC REPORTS 9 ( 1 ) 761 2019.1

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

Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a systemic disorder involving benign mass formation due to fibrosis and intense lymphoplasmacytosis; the chronic inflammation associated with the disease might also contribute to oncogenesis. Activation-induced cytidine deaminase (AID), normally expressed in germinal centre activated B-cells, is an enzyme that edits DNA/RNA and induces somatic hypermutation and Ig class switching. AID expression is strictly controlled under physiological conditions; however, chronic inflammation and some infectious agents induce its up-regulation. AID is overexpressed in various cancers and may be important in chronic inflammation-associated oncogenesis. We examined AID expression in IgG4-related sialadenitis (n = 14), sialolithiasis (nonspecific inflammation, n = 13), and normal submandibular glands (n = 13) using immunohistochemistry and quantitative real-time polymerase chain reaction (qPCR). Immunohistochemistry revealed significantly more AID-expressing cells in IgG4-related sialadenitis than in sialolithiasis or normal submandibular gland samples (P = 0.02 and P < 0.01, respectively); qPCR yielded similar results. Thus, AID was significantly more up-regulated and had higher expression in extra-germinal centres in IgG4-RD than in non-specific inflammation or normal conditions. This report suggests that IgG4-RD has several specific causes of AID up-regulation in addition to inflammation. Furthermore, chronic inflammation-associated AID-mediated oncogenesis is possible in IgG4-RD.

DOI： 10.1038/s41598-018-37404-x

Young adult patients with squamous cell carcinoma of the tongue strongly express p16 without human papillomavirus infection Reviewed

Tomoyasu Tachibana, Yorihisa Orita, Yuka Gion, Kentaro Miki, Kana Ikegami, Hidenori Marunaka, Takuma Makino, Yusuke Akagi, Naoki Akisada, Munechika Tsumura, Toshihiro Ito, Tadashi Yoshino, Kazunori Nishizaki, Yasuharu Sato

Acta Oto-Laryngologica 139 ( 1 ) 80 - 84 2019.1

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

Background: Long-term smoking and drinking are known to contribute to the onset of tongue cancer (TC). However, the increasing incidence of TC in younger adults has been suggested to be associated with other factors. Objectives: The present study investigated the relationship between TC and human papillomavirus (HPV) infection. Material and methods: Clinical records and surgically resected specimens from 86 patients (<40-years-old, n = 12; ≥40-years-old, n = 74) with TC were analyzed. Strong nuclear and cytoplasmic p16 staining was considered positive. HPV DNA (high-risk subtypes: 16, 18, 31, 33, 35, 52b, and 58; low-risk subtypes: 6 and 11) was detected using consensus primer-mediated polymerase chain reaction. Results: Strong p16 expression was observed in 10 (11.6%) patients. HPV DNA was detected in 9 (10.5%) patients (high-risk subtypes, n = 2; low-risk subtypes, n = 7). Strong p16 expression was observed more frequently among younger adults than among older adults (33.3% vs. 8.1%; p =.045). p16 staining did not correlate with the detection of HPV DNA (correlation coefficient, 0.113; p =.300). Conclusions and significance: In TC, p16 expression was not associated with HPV infection, suggesting that it may be caused by a different mechanism.

DOI： 10.1080/00016489.2018.1541506

Factors that prolong the duration of recovery in acute rhinosinusitis with orbital complications. Reviewed International journal

Tomoyasu Tachibana, Shin Kariya, Yorihisa Orita, Michihiro Nakada, Takuma Makino, Takenori Haruna, Yuko Matsuyama, Yasutoshi Komatsubara, Yuto Naoi, Yasuharu Sato, Kazunori Nishizaki

Acta oto-laryngologica 139 ( 1 ) 52 - 56 2019

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

BACKGROUND: Regarding prognostic factors of acute rhinosinusitis (ARS) with orbital complications, there are few studies including adult cases. OBJECTIVES: The present study aims to delineate prognostic factors of ARS with orbital complications. MATERIAL AND METHODS: We conducted a retrospective analysis of medical records of 21 patients (6 pediatric and 15 adult patients) with ARS with orbital complications. The duration of recovery was defined as the time from initial diagnosis to complete resolution of local findings and all symptoms. Orbital complications due to postoperative cysts or mycosis were excluded. RESULTS: Twenty-one patients comprised 11 males and 10 females. Chandler's classification showed group I in 4, group II in 8, and group III in 9. None of six pediatric patients required any surgical intervention, whereas five adult patients (23.8%) underwent surgical intervention. The average period of recovery was 8.1 days. In univariate analysis, the duration of recovery was significantly longer among adult cases (p < .01) and cases with Chandler's groups II-III (p = .019). In multivariate analysis, adult patients had a significantly longer duration of recovery than pediatric patients (p = .027). CONCLUSION AND SIGNIFICANCE: The present study suggested that ARS with orbital complications may have prolonged clinical course in adults.

DOI： 10.1080/00016489.2018.1539516

Frequent structural variations involving programmed death ligands in Epstein-Barr virus-associated lymphomas. Reviewed International journal

Keisuke Kataoka, Hiroaki Miyoshi, Seiji Sakata, Akito Dobashi, Lucile Couronné, Yasunori Kogure, Yasuharu Sato, Kenji Nishida, Yuka Gion, Yuichi Shiraishi, Hiroko Tanaka, Kenichi Chiba, Yosaku Watatani, Nobuyuki Kakiuchi, Yusuke Shiozawa, Tetsuichi Yoshizato, Kenichi Yoshida, Hideki Makishima, Masashi Sanada, Masahiro Onozawa, Takanori Teshima, Yumiko Yoshiki, Tadao Ishida, Kenshi Suzuki, Kazuyuki Shimada, Akihiro Tomita, Motohiro Kato, Yasunori Ota, Koji Izutsu, Ayako Demachi-Okamura, Yoshiki Akatsuka, Satoru Miyano, Tadashi Yoshino, Philippe Gaulard, Olivier Hermine, Kengo Takeuchi, Koichi Ohshima, Seishi Ogawa

Leukemia 33 ( 7 ) 1687 - 1699 2019

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

Viral infection induces potent cellular immunity and activated intracellular signaling, which may dictate the driver events involved in immune escape and clonal selection of virus-associated cancers, including Epstein-Barr virus (EBV)-positive lymphomas. Here, we thoroughly interrogated PD-L1/PD-L2-involving somatic aberrations in 384 samples from various lymphoma subtypes using high-throughput sequencing, particularly focusing on virus-associated lymphomas. A high frequency of PD-L1/PD-L2-involving genetic aberrations was observed in EBV-positive lymphomas [33 (22%) of 148 cases], including extranodal NK/T-cell lymphoma (ENKTL, 23%), aggressive NK-cell leukemia (57%), systemic EBV-positive T-cell lymphoproliferative disorder (17%) as well as EBV-positive diffuse large B-cell lymphoma (DLBCL, 19%) and peripheral T-cell lymphoma-not otherwise specified (15%). Predominantly causing a truncation of the 3'-untranslated region, these alterations represented the most prevalent somatic lesions in ENKTL. By contrast, the frequency was much lower in EBV-negative lymphomas regardless of histology type [12 (5%) of 236 cases]. Besides PD-L1/PD-L2 alterations, EBV-positive DLBCL exhibited a genetic profile distinct from EBV-negative one, characterized by frequent TET2 and DNMT3A mutations and the paucity of CD79B, MYD88, CDKN2A, and FAS alterations. Our findings illustrate unique genetic features of EBV-associated lymphomas, also suggesting a potential role of detecting PD-L1/PD-L2-involving lesions for these lymphomas to be effectively targeted by immune checkpoint blockade.

DOI： 10.1038/s41375-019-0380-5

A Long-term Survival after Surgical Treatment for Atypical Aortic Coarctation Complicating Takayasu Arteritis with Inactive Disease at the Diagnosis: An Appropriately Treated Autopsy Case. Reviewed

Yoshida M, Zoshima T, Hara S, Mizushima I, Fujii H, Yamada K, Sato Y, Harada K, Kawano M

Intern Med. 58 ( 15 ) 2241 - 2246 2019

Expression of T-cell receptor signalling pathway components in extranodal NK/T-cell lymphoma

Tomoko Miyata-Takata, Shih-Sung Chuang, Katsuyoshi Takata, Tomohiro Toji, Yoshinobu Maeda, Yasuharu Sato, Tadashi Yoshino

Histopathology 73 ( 6 ) 1030 - 1038 2018.12

Language：English Publishing type：Research paper (scientific journal) Publisher：Blackwell Publishing Ltd

Aims: Although the neoplastic cells of extranodal natural killer (NK)/T-cell lymphoma (ENKTL) usually do not express T-cell antigens, the T-cell receptor (TCR) gene might be rearranged and TCR protein expressed. The aim is to elucidate the expression of the downstream TCR pathway components and their importance in ENKTL. Methods and results: We used formalin-fixed paraffin-embedded tissues from 91 ENKTL samples to immunohistochemically characterise the expression of TCR pathway components. The following proteins were variably expressed: ZAP70 (94%
83/88), GRAP2/GADS (68%
60/88), DOK2 (42%
38/90), LCK (35%
31/88), and ITK (10%
9/90). When these tumours were classified as being of T lineage (16%), NK lineage (45%), or indeterminate lineage (38%), the GRAP2/GADS expression rate was higher in T lineage tumours (versus NK, P = 0.0073
versus indeterminate, P = 0.00082). GRAP2/GADS-positive NK lineage tumours more frequently expressed DOK2 (P = 0.0073), and were more often confined to the nasal areas (P = 0.014). Furthermore, when these tumours were immunophenotypically classified into a T signature (42%) or NK signature (58%), the expression rates of GRAP2/GADS and ITK were higher in T signature tumours (P = 0.00074 and P = 0.067, respectively), whereas that of LCK was higher in NK-signature tumours (P = 0.10). Conclusions: Although some ENTKL cases were polyclonal for TCR rearrangement and others lacked TCR expression, we speculate that the TCR pathway might be functioning in ENKTLs. A T signature versus a NK signature might be better for delineating the physiology of ENKTL than cellular lineage. Furthermore, ITK may represent a potential therapeutic target for patients with ITK-expressing tumours.

DOI： 10.1111/his.13728

Computed Tomography Findings for Diagnosing Follicular Thyroid Neoplasms. Reviewed

Takuma Makino, Yorihisa Orita, Tomoyasu Tachibana, Hidenori Marunaka, Kentaro Miki, Naoki Akisada, Yusuke Akagi, Yoshiyuki Usui, Yasuharu Sato, Tadashi Yoshino, Kazunori Nishizaki

Acta medica Okayama 72 ( 6 ) 577 - 581 2018.12

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

Since no diagnostic method has been established to distinguish follicular thyroid carcinoma (FTC) from follicular thyroid adenoma (FTA), surgery has been the only way to reach a diagnosis of follicular neoplasm. Here we investigated the computed tomography (CT) features of follicular neoplasms, toward the goal of being able to identify specific CT features allowing the preoperative differentiation of FTC from FTA. We retrospectively analyzed the cases of 205 patients who underwent preoperative CT of the neck and were histopathologically diagnosed with FTC (n=31) or FTA (n=174) after surgery between January 2002 and June 2016 at several hospitals in Japan. In each of these 205 cases, non-enhanced and contrast-enhanced CT images were obtained, and we analyzed the CT features. On univariate analysis, inhomogeneous features of tumor lesions on contrast-enhanced CT were more frequently observed in FTC than in FTA (p=0.0032). A multivariate analysis identified inhomogeneous features of tumor lesions on contrast-enhanced CT images as an independent variable indicative of FTC (p=0.0023). CT thus offers diagnostic assistance in distinguishing FTC from FTA.

DOI： 10.18926/AMO/56375

Recent progress in follicular lymphoma in Japan and characteristics of the duodenal type

Tadashi Yoshino, Katsuyoshi Takata, Takehiro Tanaka, Yasuharu Sato, Akira Tari, Hiroyuki Okada

PATHOLOGY INTERNATIONAL 68 ( 12 ) 665 - 676 2018.12

Language：English Publisher：WILEY

The incidence of lymphoma has rapidly increased over the last 40 years in Japan, following a trend that is very similar to that of breast cancer. In particular, the relative frequency of follicular lymphoma (FL) has reached that in Western countries. Given its indolence, a "watch-and-wait" approach is often applied to FL patients. We have shown that FL is often detected in the second portion of the duodenum and has a distinct follicular dendritic cell distribution and heavy chain variable usage similar to mucosa-associated lymphoid tissue (MALT) lymphoma. Although the t(14;18)(q32;q21) frequency is the same as in the nodal subtype of FL, there are also ongoing mutations, immunopositivity for cluster of differentiation 10 and B-cell lymphoma (BCL)6, and overexpression of BCL2. Gene expression profiling has shown that it is more similar to gastric MALT lymphoma than to nodal FL. Duodenal-type FL lacks the activation-induced cytidine deaminase (AID) expression observed in nodal ones, although this may be compensated for by BTB domain and CNC homolog 2. Based on these findings, duodenal-type FL has been included in the Revised 4th edition of the World Health Organization classification published in late 2017.

DOI： 10.1111/pin.12733

The efficacy and safety of anti-interleukin-6 receptor monoclonal blockade in a renal transplant patient with Castleman disease: early post-transplant outcome. Reviewed International journal

Masatoshi Matsunami, Yoshifumi Ubara, Keiichi Sumida, Yoichi Oshima, Masahiko Oguro, Kazuya Kinoshita, Kiho Tanaka, Yuki Nakamura, Keiichi Kinowaki, Kenichi Ohashi, Takeshi Fujii, Takuro Igawa, Yasuharu Sato, Yasuo Ishii

BMC nephrology 19 ( 1 ) 263 - 263 2018.10

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

BACKGROUND: Multicentric Castleman disease (MCD) is an uncommon lymphoproliferative disease characterized by systemic inflammatory reactions associated with the dysregulated production of interleukin-6 (IL-6). In patients with MCD, renal involvement is uncommon, with only one report published regarding kidney transplantation (KTx) to treat end-stage renal disease (ESRD) secondary to MCD. Recent clinical observations have shown that IL-6 production is implicated in allograft rejection, while IL-6 receptor blockade (with tocilizumab [TCZ]) reduces alloantibody generation and thereby improves graft survival; however, the efficacy and safety of TCZ in MCD patients undergoing KTx is still unknown. CASE PRESENTATION: Herein, we describe the case of a 50-year-old man with MCD who received living-donor KTx for ESRD. Post-operative immunosuppression consisted of a triple-drug regimen (tacrolimus, mycophenolate mofetil and methylprednisolone) with TCZ that was administered intravenously every 2 weeks. At 17 months post-transplantation, the patient remains asymptomatic, and the allograft pathology has shown no evidence of rejection and no development of de novo donor-specific antibody (DSA). CONCLUSIONS: To our knowledge, this is the second reported case of an MCD patient with ESRD who underwent successful KTx. TCZ safely supported the patient during the perioperative period, and this drug may be useful for blocking the generation of donor-specific antibodies and reducing the risk of rejection episodes. KTx in combination with TCZ is thus considered a viable treatment option for ESRD due to MCD.

DOI： 10.1186/s12882-018-1065-4

Serum soluble interleukin-2 receptor as a biomarker in immunoglobulin G4-related disease Reviewed

Tomohiro Handa, Shoko Matsui, Hajime Yoshifuji, Yuzo Kodama, Hiroshi Yamamoto, Seijiro Minamoto, Yuko Waseda, Yasuharu Sato, Keishi Kubo, Tsuneyo Mimori, Tsutomu Chiba, Toyohiro Hirai, Michiaki Mishima

Modern Rheumatology 28 ( 5 ) 838 - 844 2018.9

Publishing type：Research paper (scientific journal)

© 2017, © 2017 Japan College of Rheumatology. Objectives: Serum soluble interleukin-2 (IL-2) receptor (sIL-2R) might reflect disease activity in immunoglobulin G4-related disease (IgG4-RD). We aimed to elucidate the clinical significance of blood markers, including sIL-2R, in patients with IgG4-RD. Methods: We enrolled 59 patients with IgG4-RD and investigated the association between blood markers (white blood cells, C-reactive protein, sIL-2R, IgG, IgG4, IgE, total hemolytic complement), and clinical indices. Results: At baseline, serum sIL-2R (Rs = 0.532, p <.001) and IgG4 (Rs = 0.545, p <.001) levels showed significant correlation to the number of organs involved. During follow-up period (median, 70 months; range, 7–195 months), 40 patients were treated with corticosteroids. Receiver operating characteristic (ROC) analysis showed that baseline sIL-2R levels most accurately predicted patients requiring glucocorticoid treatment (area under the ROC curve, 0.807). Among the 46 patients who improved, sIL-2R and IgG4 levels decreased in 42 and 41 patients, respectively. Among them, serum sIL-2R levels decreased to a normal range in 42 patients (91%), whereas IgG4 levels normalized in 19 (41%). Conclusion: The serum sIL-2R level is a potential biomarker for IgG4-RD that may reflect the number of involved organs and may predict patients requiring glucocorticoid treatment.

DOI： 10.1080/14397595.2017.1416739

Gastrointestinal manifestation of immunoglobulin G4-related disease: clarification through a multicenter survey Reviewed

Kenji Notohara, Terumi Kamisawa, Kazushige Uchida, Yoh Zen, Mitsuhiro Kawano, Satomi Kasashima, Yasuharu Sato, Masahiro Shiokawa, Takeshi Uehara, Hajime Yoshifuji, Hiroko Hayashi, Koichi Inoue, Keisuke Iwasaki, Hiroo Kawano, Hiroyuki Matsubayashi, Yukitoshi Moritani, Katsuhiko Murakawa, Yoshio Oka, Masatoshi Tateno, Kazuichi Okazaki, Tsutomu Chiba

Journal of Gastroenterology 53 ( 7 ) 845 - 853 2018.7

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Tokyo

Background: Several reports on immunoglobulin (Ig)G4-related disease (IgG4-RD) with gastrointestinal involvement (IgG4-related gastrointestinal disease
IgG4-GID) have been published, although this entity has not been fully established clinicopathologically. Thus, we carried out a multicenter survey. Methods: Patients with possible IgG4-GID who underwent resection were collected. Histologic slides were reevaluated, and eight cases with diffuse lymphoplasmacytic infiltration but without numerous neutrophils, granulations or epithelioid granulomas were further analyzed. Results: Overall, the IgG4 counts (87–345/high-power field) and IgG4/IgG-positive ratio were high (44–115%). The demographic findings included advanced age among the patients (55–80 years) and male preponderance (six cases). Six lesions (five gastric, one esophageal), consisting of lymphoplasmacytic infiltration with neural involvement in the muscularis propria and/or bottom-heavy plasmacytosis in the gastric mucosa, were histologically regarded as highly suggestive of IgG4-RD. Storiform fibrosis and obliterative phlebitis were found in two cases, and the former gave rise to a 7-cm-sized inflammatory pseudotumor (IPT) in one case. Ulceration and carcinoma co-existed in three and two lesions, respectively. All the patients had other organ involvement (OOI), and serum IgG4 levels were markedly elevated (four of five patients). The remaining two cases with gastric IPTs featuring reactive nodular fibrous pseudotumor or nodular lymphoid hyperplasia were regarded as possible cases of IgG4-RD because of the histologic findings and lack of OOI. Conclusions: IgG4-GID is found in the setting of IgG4-RD, often with ulceration or cancer. Characteristic histologic findings are observed in the muscularis propria and gastric mucosa. Cases with IPT may be heterogeneous, and there may be mimickers of IgG4-GID.

DOI： 10.1007/s00535-017-1420-4

Overexpression of folate receptor alpha is an independent prognostic factor for outcomes of pancreatic cancer patients Reviewed

Shizuma Omote, Katsuyoshi Takata, Takehiro Tanaka, Tomoko Miyata-Takata, Yoshiyuki Ayada, Mai Noujima-Harada, Rika Omote, Tetsuya Tabata, Yasuharu Sato, Tatsuya Toyokawa, Hironari Kato, Takahito Yagi, Hiroyuki Okada, Tadashi Yoshino

Medical Molecular Morphology 51 ( 4 ) 1 - 7 2018.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Tokyo

Pancreatic cancer has a poor prognosis
hence, novel prognostic markers and effective therapeutic targets should be identified. We aimed to evaluate folate receptor alpha (FR-α) expression in pancreatic cancer and examine its association with clinicopathological features. We utilized tissue samples from 100 primary pancreatic cancer patients who underwent surgery. FR-α was expressed in 37 of 100 cases (37%). The FR-α-positive group (median, 18.8 months) had a significantly poorer prognosis than the FR-α-negative group [median 21.3 months
HR 1.89 (1.12–3.12)
P = 0.017]. These groups were not significantly different regarding progression-free survival (P = 0.196). Furthermore, other serum tumor markers including CA19-9 (mean, 186 vs. 822 U/ml
P = 0.001), Dupan-2 (286 vs. 1133 U/ml
P = 0.000), and Span-1 (69.7 vs. 171.9 U/ml
P = 0.006) were significantly downregulated in the FR-α-positive group. CA19-9 was another prognostic factor, in addition to FR-α, and patient prognosis showed clear stratification curves with the expression of these two molecules. Along with CA19-9, FR-α expression was an independent prognostic factor for the overall survival. FR-α and CA19-9 helped predict patient prognosis based on stratification curves.

DOI： 10.1007/s00795-018-0197-8

Prognostic factors and importance of recognition of adult croup Reviewed

Tomoyasu Tachibana, Yorihisa Orita, Takuma Makino, Yasutoshi Komatsubara, Yuko Matsuyama, Yuto Naoi, Michihiro Nakada, Yasuharu Sato, Kazunori Nishizaki

Acta Oto-Laryngologica 138 ( 6 ) 579 - 583 2018.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Taylor and Francis Ltd

Objectives: Croup, or laryngotracheobronchitis, is a common disease in childhood. On the other hand, to our knowledge, there are only 14 cases in six English literatures describing adult croup (AC). The clinical features of AC have not been well known. Methods: We conducted a retrospective analysis of medical records of 18 patients with AC during the period from 2008 to 2016. Results: None of the 18 patients required an urgent airway intervention. Univariate analysis indicated that the duration of symptoms was significantly longer in patients with cough (p &lt
.01) and younger patients (age &lt
60, p =.037). The duration of subglottic edema was significantly longer in female (p =.035), patients with high levels of CRP (≥1 mg/dL, p =.049), and patients with cough symptom (p =.035). Conclusions: Female, young age (&lt
60 years), the symptom of cough, and high levels of CRP should be recognized as signs of prolonged AC. It is important to confirm the diagnosis of AC by laryngoscopic examination, which also help to avoid airway intervention.

DOI： 10.1080/00016489.2017.1422140

Neck metastasis in patients with T1-2 supraglottic cancer Reviewed

Tomoyasu Tachibana, Yorihisa Orita, Hidenori Marunaka, Sei-ichiro Makihara, Misato Hirai, Yuka Gion, Kana Ikegami, Kentaro Miki, Takuma Makino, Yasuyuki Noyama, Yasutoshi Komatsubara, Miyuki Kimura, Tadashi Yoshino, Kazunori Nishizaki, Yasuharu Sato

Auris Nasus Larynx 45 ( 3 ) 540 - 545 2018.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier Ireland Ltd

Objectives: Unlike glottic cancer, supraglottic cancer often presents with neck metastases. This different might be attributable to the location of the primary lesion. This study aimed to clarify the relationships between the sublocation of T1-2 supraglottic cancer, human papillomavirus (HPV) infection, neck metastasis, and prognosis of supraglottic cancer. Methods: This retrospective clinical study investigated 55 Japanese patients with T1-2 supraglottic cancer treated between 1994 and 2015. Results: Of 55 patients with T1-2 supraglottic cancer, neck metastasis was present at initial diagnosis in 14 patients (25.5%). Presence of neck metastasis was the only factor associated with worse prognosis of T1-2 supraglottic cancer (p = 0.004). In multivariate analysis, age &lt
70 years (p = 0.033) and sublocation of the primary lesion in the superior epilaryngeal portion (p = 0.017) were significantly associated with presence of neck metastasis in multivariate analysis. Twelve (27.9%) of 43 patients showed positive results for human papillomavirus infection. However, human papillomavirus infection was not associated with prognosis, presence of neck metastasis, or primary lesion sublocation in T1-2 supraglottic cancer. Conclusion: Relatively young patients with supraglottic cancer at the superior epilaryngeal portion are more likely to show neck metastasis. Human papillomavirus infection was not associated with frequency of neck metastasis.

DOI： 10.1016/j.anl.2017.06.002

Diffuse large B-cell lymphoma of the lacrimal sac arising from a patient with IgG4-related disease Reviewed

Hidenori Marunaka, Yorihisa Orita, Tomoyasu Tachibana, Kentaro Miki, Takuma Makino, Tadashi Yoshino, Kazunori Nishizaki, Yasuharu Sato

Modern Rheumatology 28 ( 3 ) 559 - 563 2018.5

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：Taylor and Francis Ltd

A rare case of diffuse large B-cell lymphoma (DLBCL) possibly induced by IgG4-related disease is described. A 78-year-old woman was presented with a mass of the right lacrimal sac that extended to the inferior nasal meatus through the nasolacrimal duct. Pathological diagnosis was DLBCL with diffuse distribution of IgG4 + cells in the background of this lesion. The chronic inflammatory state of IgG4-related disease could have caused the development of DLBCL.

DOI： 10.3109/14397595.2015.1131353

Gastrointestinal follicular lymphoma: Current knowledge and future challenges Invited Reviewed

Katsuyoshi Takata, Tomoko Miyata-Takata, Yasuharu Sato, Masaya Iwamuro, Hiroyuki Okada, Akira Tari, Tadashi Yoshino

Pathology International 68 ( 1 ) 1 - 6 2018.1

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

The gastrointestinal (GI) tract is the most commonly involved site of extranodal follicular lymphoma (FL). GI-FL shows very indolent clinical behavior and localized at GI tract without any progression or transformation compared to nodal FL. The most frequently involved site of the GI tract was the duodenum followed by the jejunum and ileum, and only 15% of FL arising in the second part of the duodenum were localized there without scattered very small daughter lesions in other GI tract examined by double-balloon endoscopy. The typical macroscopic appearance of GI-FL was multiple white nodules. Microscopically, neoplastic cells were small- to medium-sized lymphoid cells and formed neoplastic follicles. Most of the cases (&gt
95%) were histologically Grade 1 to 2 (low grade). Several pathological and molecular characteristics were seen in GI-FL (especially duodenal FL) compared with nodal FL: immunoglobulin heavy chain deviation to VH4 and VH5
memory B-cell immunophenotype
and molecular features shared by mucosa-associated lymphoid tissue lymphoma. Considering the pathological and molecular uniqueness of this disease, GI-FL should be separately managed from nodal FL.

DOI： 10.1111/pin.12621

Expression of T-cell Receptor Signaling Pathway Components in Extranodal NK/T-cell Lymphoma Reviewed

Tomoko Takata, Katsuyoshi Takata, Shih-Sung Chuang, Yasuharu Sato, Tadashi Yoshino

LABORATORY INVESTIGATION 98 559 - 559 2018

Factors in glucocorticoid regimens associated with treatment response and relapses of IgG4-related disease: a multicentre study. Reviewed International journal

Mirei Shirakashi, Hajime Yoshifuji, Yuzo Kodama, Tsutomu Chiba, Motohisa Yamamoto, Hiroki Takahashi, Kazushige Uchida, Kazuichi Okazaki, Tetsuya Ito, Shigeyuki Kawa, Kazunori Yamada, Mitsuhiro Kawano, Shintaro Hirata, Yoshiya Tanaka, Masafumi Moriyama, Seiji Nakamura, Terumi Kamisawa, Shoko Matsui, Hiroto Tsuboi, Takayuki Sumida, Motoko Shibata, Hiroshi Goto, Yasuharu Sato, Tadashi Yoshino, Tsuneyo Mimori

Scientific reports 8 ( 1 ) 10262 - 10262 2018

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

Glucocorticoids (GC) are effective for treating IgG4-related disease (IgG4-RD); however, relapse is often observed. We conducted a retrospective multicentre study to investigate risk factors in GC regimens associated with relapses of IgG4-RD. Data on 166 patients with definitive IgG4-RD diagnosis were collected from 12 institutions. Comprehensive surveillance of clinical backgrounds and GC regimens as well as multivariate analysis of factors associated with treatment responses and relapses was performed. To determine the initial maximal GC dose, the patients were stratified into three groups depending on the initial prednisolone (PSL) dosage: <0.39, 0.4-0.69 and >0.7 mg/kg/day. The multivariate analysis extracted the disease duration and reduction speed of initial GC dose. Patients treated with initial GC <0.39 or >0.7 mg/kg/day of PSL showed higher relapse rates than those treated with 0.4-0.69 mg/kg/day. The relapse rates were significantly higher in patients with fast reduction of the initial dose (>0.4 mg/day) than in patients with slow reduction (<0.4 mg/day). To avoid relapse, 0.4-0.69 mg/kg/day of initial PSL with slow reduction speed (<0.4 mg/day) is needed in the early treatment of IgG4-RD.

DOI： 10.1038/s41598-018-28405-x.

Mast Cells Exhibiting Strong Cytoplasmic Staining for IgE and High Affinity IgE Receptor are Increased in IgG4-Related Disease. Reviewed International journal

Kenji Nishida, Yuka Gion, Mai Takeuchi, Takehiro Tanaka, Tatsuki R Kataoka, Tadashi Yoshino, Yasuharu Sato

Scientific reports 8 ( 1 ) 4656 - 4656 2018

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

Immunoglobulin G4 (IgG4)-related disease is characterized by elevated serum IgG4 levels and increased numbers of IgG4-positive cells. However, its pathogenesis is not fully understood. We previously suggested that mast cells may play an important role in IgG4-related disease. In this study, we confirmed the characteristics of mast cells in IgG4-related lymphadenopathy by using immunohistochemistry and dual immunofluorescence. We analyzed 23 cases of IgG4-related lymphadenopathy and compared them with 23 cases of non-specific lymphoid hyperplasia. The majority of patients with IgG4-related lymphadenopathy had cervical lesions with involvement of other organs. Immunohistologically, mast cells with strong cytoplasmic staining for immunoglobulin E and high affinity immunoglobulin E receptor were significantly increased in IgG4-related lymphadenopathy as compared to those in non-specific lymphoid hyperplasia (mean: 3.83 ± 3.99 cells per high power field and 7.14 ± 8.21 cells per high power field, respectively; P = 0.007 and P = 0.011). In addition, dual immunofluorescence assay showed that immunoglobulin E and high affinity immunoglobulin E receptor staining exhibited a cytoplasmic granular pattern in IgG4-related lymphadenopathy, suggesting internalization of the antibodies and receptors. Our findings showed that mast cell activation might be involved in the pathogenesis of IgG4-related disease.

DOI： 10.1038/s41598-018-23043-9.

Laryngeal squamous cell papilloma is highly associated with human papillomavirus Reviewed

Yorihisa Orita, Yuka Gion, Tomoyasu Tachibana, Kana Ikegami, Hidenori Marunaka, Seiichiro Makihara, Yasuhiko Yamashita, Kentaro Miki, Takuma Makino, Naoki Akisada, Yusuke Akagi, Miyuki Kimura, Tadashi Yoshino, Kazunori Nishizaki, Yasuharu Sato

Japanese Journal of Clinical Oncology 48 ( 4 ) 350 - 355 2018

Publishing type：Research paper (scientific journal)

Objective: To delineate the association between characteristics of adult-onset laryngeal squamous cell papilloma and human papillomavirus (HPV) infection. Methods: Clinical records and paraffin-embedded specimens of 77 papilloma patients who had been treated between 1998 and 2014 were collected. Of the 77 cases, 34 were identified in the larynx, 28 in the oral cavity and 15 in the oropharynx. Specimens were investigated by polymerase chain reaction (PCR) to detect HPV 6, 11, 16, 18, 31, 33, 35, 52b and 58, and immunohistochemical (IHC) staining for anti-p16 antibody. Results: In 21 cases (61.8%) with laryngeal squamous cell papilloma, various types of HPV were detected: 14 cases (41.2%) were positive of high-risk HPV, 18 (52.9%) were positive of low-risk HPV and 11 (32.4%) were positive of both high-risk HPV and low-risk HPV. Younger patients (<60 years) showed a higher rate of HPV infection than older patients. Among the 34 cases with laryngeal papilloma, no malignant transformation was observed during the study period. With IHC staining, positive expression of p16 was observed in 20 cases (58.8%). HPV infection and p16-expression were associated with the pathological finding of koilocytosis. Only four cases (14.3%) showed HPV-positivity in the oral cavity, and none of the 15 oropharyngeal cases were positive for HPV, and none of the oral cavity and oropharyngeal cases showed koilocytosis. Results of HPV-PCR and p16-IHC staining were significantly correlated each other. Conclusions: HPV infection is frequently associated with laryngeal squamous cell papilloma, and koilocytosis is a characteristic pathological finding. To the best of our knowledge, this is the first report which have described infections with multiple HPV types in laryngeal papilloma. INK4a

DOI： 10.1093/jjco/hyy009.

A20 (TNFAIP3) Alterations in Primary Intestinal Diffuse Large B-cell Lymphoma Reviewed

Masayoshi Fujii, Katsuyoshi Takata, Shih-Sung Chuang, Tomoko Miyata-Takata, Midori Ando, Yasuharu Sato, Tadashi Yoshino

ACTA MEDICA OKAYAMA 72 ( 1 ) 23 - 30 2018

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

The gastrointestinal (GI) tract is the most frequently involved site of extranodal non-Hodgkin lymphomas, and diffuse large B-cell lymphoma (DLBCL) is the most common subtype occurring in the GI tract. TNFAIP3 (A20) genetic alterations were reported to be involved in DLBCL's pathogenesis and a portion of GI-DLBCL cases harbor this alteration. However, the frequency and clinicopathological relations focusing on small and large intestinal DLBCL are unclear. Here, we examined A20 deletion and protein expression and analyzed the clinicopathological features of 52 cases of primary intestinal DLBCL. The most frequently involved site was the ileocecal region (75%), followed by small bowel (13.5%) and large intestine. Immunohistochemically, the ileocecal cases expressed BCL6 (p=0.027) and MUM1 (p=0.0001) significantly more frequently than the small intestinal cases. Six of 47 cases (13%) had A20 heterozygous deletion, whereas all 6 heterozygously deleted cases had detectable A20 protein expression. In summary, A20 abnormality was less prevalent among intestinal DLBCLs with some discordancy between gene deletion and protein expression. Although the A20 alteration status did not affect any clinicopathological characteristics in this series, further studies exploring alterations of A20 and other NF-kappa B components in primary intestinal DLBCL are needed.

Characteristic Distribution Pattern of CD30-positive Cytotoxic T Cells Aids Diagnosis of Kikuchi-Fujimoto Disease Reviewed

Tetsuya Tabata, Katsuyoshi Takata, Tomoko Miyata-Takata, Yasuharu Sato, Shin Ishizawa, Tomoyoshi Kunitomo, Keina Nagakita, Nobuhiko Ohnishi, Kohei Taniguchi, Mai Noujima-Harada, Yoshinobu Maeda, Mitsune Tanimoto, Tadashi Yoshino

Applied Immunohistochemistry and Molecular Morphology 26 ( 4 ) 274 - 282 2018

Language：English Publishing type：Research paper (scientific journal) Publisher：Lippincott Williams and Wilkins

Introduction: Histiocytic necrotizing lymphadenitis (or Kikuchi-Fujimoto disease) frequently occurs in Asian young adult females and typically presents as cervical lymphadenopathy with unknown etiology. Although large immunoblasts frequently appear in Kikuchi-Fujimoto disease, the diffuse infiltration of these cells can cause difficulty in establishing a differential diagnosis from lymphoma. In such cases, CD30 immunostaining may be used
however, the extent or distribution pattern of CD30-positive cells in Kikuchi-Fujimoto disease remains largely unknown. Here we investigated the expression of CD30 and its clinicopathologic significance. Materials and Methods: We investigated 30 Kikuchi-Fujimoto disease and 16 control [6, systemic lupus erythematosus (SLE)
10, reactive lymphoid hyperplasia (RLH)] cases. Results: The number of CD30-positive cells in Kikuchi-Fujimoto disease was significantly more than that in SLE and RLH, and majority of these cells were located around necrotic areas. Moreover, double immunohistochemical staining showed these CD30-positive cells to be CD8-positive cytotoxic T cells, suggesting that activated cytotoxic T cells around necrotic areas are a characteristic feature of this disease. Clinicopathologic analysis showed that cases with abundant CD30-positive cells were predominantly female with only mild symptoms and normal laboratory data. Conclusions: In Kikuchi-Fujimoto disease cases, CD30-positive cytotoxic T cells were abundant around necrotic areas
this histologic feature may be helpful to differentiate this disease from SLE and RLH.

DOI： 10.1097/PAI.0000000000000411

TAFRO syndrome Invited Reviewed

Igawa T, Sato Y

Hematol Oncol Clin N Am 107 - 118 2018

International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease. Reviewed

Blood 132 ( 20 ) 2115 - 2124 2018

IgG4陽性形質細胞の集簇を認めた鼻腔底Reactive lymphoid hyperplasia症例

金井健吾, 岡野光博, 折田頼尚, 野山和廉, 檜垣貴哉, 春名威範, 假谷伸, 小山貴久, 大道亮太郎, 佐藤康晴, 安藤翠, 平田裕二, 西崎和則

日本鼻科学会会誌 56 ( 4 ) 619 - 624 2017.12

Language：Japanese Publisher：(一社)日本鼻科学会

Reactive lymphoid hyperplasia(RLH)は、組織学的に胚中心を伴うリンパ濾胞の反応性過形成を示し、個々のリンパ球の異型が少なくpolyclonalな増殖を認めるものと定義される。今回我々は、IgG4陽性形質細胞の集簇を認めた鼻腔底RLHの一例を経験した。症例は69歳女性。主訴は左鼻腔腫瘤、右難聴。右難聴で近医受診した際に、左鼻腔底前方に隆起性病変を認めた。唾液腺腫脹や鼻症状は認めなかった。IgG4値は45.5mg/dlと正常範囲内であった。2度の生検を施行し悪性リンパ腫の可能性も否定できず、摘出術を施行した。病理組織所見は、HE染色では、粘膜上皮下に著明なリンパ球・形質細胞の浸潤を認め、リンパ濾胞の過形成を伴っていた。免疫染色では、濾胞間に多数のIgG4陽性形質細胞を認め、400倍1視野あたり100個を超え、IgG4/IgG陽性細胞比は40%を超えていた。しかし、線維化の所見や高IgG4血症を認めず、包括診断基準に照らしIgG4関連疾患には合致しなかった。摘出後、約1年を経過するが、再発所見を認めていない。今後、病変の再発や悪性転化する可能性も考えられることから、治療後も厳重な経過観察を行う必要があると考えられる。(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J01675&link_issn=&doc_id=20180122310011&doc_link_id=10.7248%2Fjjrhi.56.619&url=https%3A%2F%2Fdoi.org%2F10.7248%2Fjjrhi.56.619&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

A Multi-Organ Inflammatory Condition with Features of Idiopathic Multicentric Castleman's Disease and IgG4-Related Disease: An Unrecognized Mimicker of IgG4-RD

Zachary S. Wallace, Yasuharu Sato, Kazuichi Okazaki, Judith Ferry, Hisanori Umehara, Aliyah Sohani, Mitsuhiro Kawano, Nancy Harris, Yoshiya Tanaka, Cory A. Perugino, Satoshi Kubo, James Stone, Robert Colvin, Tsutomu Chiba, John H. Stone, Yoh Zen

ARTHRITIS & RHEUMATOLOGY 69 2017.10

Clinicopathological analysis of primary central nervous system NK/T cell lymphoma: rare and localized aggressive tumour among extranasal NK/T cell tumours Reviewed

Tomoko Miyata-Takata, Katsuyoshi Takata, Seiichi Kato, Lei-Ming Hu, Mai Noujima-Harada, Shih-Sung Chuang, Yasuharu Sato, Yoshinobu Maeda, Tadashi Yoshino

HISTOPATHOLOGY 71 ( 2 ) 287 - 295 2017.8

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

AimsThe central nervous system (CNS) is a rare primary site of non-Hodgkin lymphoma. Although direct invasion of nasal natural killer (NK)/T cell tumours into CNS is reported occasionally, primary CNS NK/T cell lymphoma is extremely rare, and the clinicopathological features of primary CNS NK/T cell lymphoma remain largely unknown.
Methods and resultsWe identified four cases from our consultation files and analysed the clinicopathological features. Three were immunocompetent and one was immunosuppressed. There were three males and one female and their ages ranged from 21 to 77 years (median: 46 years). Radiotherapy was rendered for all patients, and methotrexate was administered to two patients. The overall survival was 4-29 months (median, 19 months) for the three immunocompetent patients. Neoplastic cells exhibited medium to large atypical nuclei. Angiocentric growth and necrosis were observed. The immunophenotype was typical of NK cell tumours: CD3 epsilon, 100%; CD56, 67%; CD5, 50%; cytotoxic molecules, 100%; Epstein-Barr virus encoded small RNA (EBER), 100% and T cell receptor (TCR)- or , 0%. No TCR-gene rearrangements were detected. Reviewing 10 additional cases from the literature and comparing with extranasal NK/T cell lymphoma of the more frequent origins (skin or gastrointestinal tract), primary CNS NK/T cell lymphoma was diagnosed at an earlier stage without B symptoms but exhibited aggressive clinical behaviours.
ConclusionsAlthough extremely rare, primary CNS NK/T cell lymphoma does occur and should always be included in the differential diagnosis and we should apply relevant markers routinely in conjunction with exploring the patient background. The accumulation of cases is indispensable to establish an effective treatment strategy for this rare and aggressive malignancy.

DOI： 10.1111/his.13223

Extranodal Marginal Zone B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissue with Plasma Cell Differentiation: Periodic Acid-Schiff Reaction-Positive Dutcher Body is a Diagnostic Clue to Distinguish it from Plasmacytoma Reviewed

Atsuko Nasu, Takuro Igawa, Hiaki Sato, Hiroyuki Yanai, Tadashi Yoshino, Yasuharu Sato

DIAGNOSTIC CYTOPATHOLOGY 45 ( 6 ) 547 - 551 2017.6

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

We herein report a case of primary parotid extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) with Dutcher bodies. An 82-year-old man presented with a 4 cm x 2.5 cm mass in the left parotid region. Positron emission tomography/computed tomography (PET/CT) showed localized abnormal fluorodeoxyglucose (FDG) uptake in the left parotid gland and lymph nodes of the left cervical region. Fine needle aspiration (FNA) cytology of the left parotid gland showed lymphoplasmacytoid cells with periodic acid-Schiff (PAS)-positive Dutcher bodies. A subsequent excisional biopsy showed sheets of small- to medium-sized neoplastic B cells with abundant IgM in the cytoplasm as detected by immunohistochemistry. A diagnosis of stage II MALT lymphoma was made, but the patient did not receive therapeutic intervention. As previously reported, Dutcher bodies are mainly observed in B-cell neoplasms with IgM production. Because these characteristic intranuclear inclusions can be easily observed by PAS staining, the presence of PAS reaction-positive Dutcher bodies in FNA cytology can serve as a clue to differentially diagnose MALT lymphoma from plasmacytoma. (C). 2017 Wiley Periodicals, Inc.

DOI： 10.1002/dc.23691

Clinicopathological analysis of methotrexate-associated lymphoproliferative disorders: Comparison of diffuse large B-cell lymphoma and classical Hodgkin lymphoma types Reviewed

Yuka Gion, Noriko Iwaki, Katsuyoshi Takata, Mai Takeuchi, Keiichiro Nishida, Yorihisa Orita, Tomoyasu Tachibana, Tadashi Yoshino, Yasuharu Sato

CANCER SCIENCE 108 ( 6 ) 1271 - 1280 2017.6

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

Patients with rheumatoid arthritis often develop methotrexate-associated lymphoproliferative disorders (MTX-LPD) during MTX treatment. MTX-LPD occasionally regresses spontaneously after simply discontinuing MTX treatment. In patients without spontaneous regression, additional chemotherapy is required to avoid disease progression. However, the differences between spontaneous and non-spontaneous regression have yet to be elucidated. To clarify the factors important for spontaneous regression, we analyzed the clinicopathological features of 51 patients with rheumatoid arthritis who developed MTX-LPD (diffuse large B-cell lymphoma [DLBCL]-type [n = 34] and classical Hodgkin lymphoma [CHL]-type [n = 17]). We examined the interval from MTX discontinuation to the administration of additional chemotherapy. The majority of DLBCL-type MTX-LPD patients (81%) exhibited remission with MTX discontinuation alone. In contrast, the majority of CHL-type MTX-LPD patients (76%) required additional chemotherapy. This difference was statistically significant (P = 0.001). However, overall survival was not significantly different between DLBCL-type and CHL-type (91% vs 94%, respectively; P > 0.05). Thus, the morphological differences in the pathological findings of MTX-LPD may be a factor for spontaneous or non-spontaneous regression after discontinuation of MTX.

DOI： 10.1111/cas.13249

Frequent downregulation of BTB and CNC homology 2 expression in Epstein-Barr virus-positive diffuse large B-cell lymphoma Reviewed

Mai Noujima-Harada, Katsuyoshi Takata, Tomoko Miyata-Takata, Hiroaki Sakurai, Kazuhiko Igarashi, Etsuro Ito, Keina Nagakita, Kohei Taniguchi, Nobuhiko Ohnishi, Shizuma Omote, Tetsuya Tabata, Yasuharu Sato, Tadashi Yoshino

CANCER SCIENCE 108 ( 5 ) 1071 - 1079 2017.5

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

Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell lymphoma subtype, and the Epstein-Barr virus (EBV)-positive subtype of DLBCL is known to show a more aggressive clinical behavior than the EBV-negative one. BTB and CNC homology 2 (BACH2) has been highlighted as a tumor suppressor in hematopoietic malignancies; however, the role of BACH2 in EBV-positive DLBCL is unclear. In the present study, BACH2 expression and its significance were studied in 23 EBV-positive and 43 EBV-negative patient samples. Immunohistochemistry revealed BACH2 downregulation in EBV-positive cases (P < 0.0001), although biallelic deletion of BACH2 was not detected by FISH. Next, we analyzed the contribution of BACH2 negativity to aggressiveness in EBV-positive B-cell lymphomas using FL-18 (EBV-negative) and FL-18-EB cells (FL-18 sister cell line, EBV-positive). In BACH2-transfected FL-18-EB cells, downregulation of phosphorylated transforming growth factor--activated kinase 1 (pTAK1) and suppression in p65 nuclear fractions were observed by Western blot analysis contrary to non-transfected FL-18-EB cells. In patient samples, pTAK1 expression and significant nuclear p65, p50, and p52 localization were detected immunohistochemically in BACH2-negative DLBCL (P < 0.0001, P = 0.006, and P = 0.001, respectively), suggesting that BACH2 downregulation contributes to constitutive activation of the nuclear factor-B pathway through TAK1 phosphorylation in BACH2-negative DLBCL (most EBV-positive cases). Although further molecular and pathological studies are warranted to clarify the detailed mechanisms, downregulation of BACH2 may contribute to constitutive activation of the nuclear factor-B pathway through TAK1 activation.

DOI： 10.1111/cas.13213

様々な悪性リンパ腫におけるPD-L1/PD-L2ゲノム異常

片岡圭亮, 三好寛明, 坂田征士, 土橋映仁, 木暮泰寛, 佐藤康晴, 加藤元博, 伊豆津宏二, 吉野正, 竹内賢吾, 大島孝一, 小川誠司

日本臨床分子医学会学術総会プログラム・抄録集 54回 63 - 63 2017.4

Immunohistochemical analysis of IgA expression differentiates IgG4-related disease from plasma cell-type Castleman disease Reviewed

Akihiro Manabe, Takuro Igawa, Mai Takeuchi, Yuka Gion, Tadashi Yoshino, Yasuharu Sato

MEDICAL MOLECULAR MORPHOLOGY 50 ( 1 ) 34 - 41 2017.3

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

Plasma cell-type Castleman disease (PCD) is often encountered when differentiating IgG4-related disease (IgG4-RD). Given that serum IgA is often elevated in Castleman disease, we investigated whether IgA expression levels in histological specimens can be used to differentiate between the two diseases. Lymph node lesions obtained from 12 IgG4-RD and 11 PCD patients were analysed by immunohistochemistry with anti-IgG, -IgG4, and -IgA antibodies. In addition to all 12 cases of IgG4-RD, 8/11 cases (72.7 %) of PCD also met the diagnostic criteria of IgG4-RD (serum IgG4135 mg/dl and IgG4/IgG-positive cells40 %). IgA-positive cells were sparsely and densely distributed in IgG4-RD and PCD cases, respectively. The median number of IgA-positive cells +/- SD in all 12 cases of IgG4-RD was 31 +/- 37 cells per three high-powered fields (3HPFs) (range 4-118 cells/3HPFs). In contrast, the median number of IgA-positive cells, which was significantly higher in all 11 cases of PCD, was 303 +/- 238 cells/3HPFs (range 74-737 cells/3HPFs) (P < 0.001). In conclusion, our findings indicate that in cases where serum analysis-based data are unavailable, anti-IgA immunostaining can be used for differential diagnosis of IgG4-RD.

DOI： 10.1007/s00795-016-0145-4

Elevated serum interferon gamma-induced protein 10 kDa is associated with TAFRO syndrome Reviewed

Noriko Iwaki, Yuka Gion, Eisei Kondo, Mitsuhiro Kawano, Taro Masunari, Hiroshi Moro, Koji Nikkuni, Kazue Takai, Masao Hagihara, Yuko Hashimoto, Kenji Yokota, Masataka Okamoto, Shinji Nakao, Tadashi Yoshino, Yasuharu Sato

SCIENTIFIC REPORTS 7 164 - 173 2017.2

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

Multicentric Castleman disease (MCD) is a heterogeneous lymphoproliferative disorder. It is characterized by inflammatory symptoms, and interleukin (IL)-6 contributes to the disease pathogenesis. Human herpesvirus 8 (HHV-8) often drives hypercytokinemia in MCD, although the etiology of HHV-8-negative MCD is idiopathic (iMCD). A distinct subtype of iMCD that shares a constellation of clinical features including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O) has been reported as TAFRO-iMCD, however the differences in cytokine profiles between TAFRO-iMCD and iMCD have not been established. We retrospectively compared levels of serum interferon gamma-induced protein 10 kDa (IP-10), platelet-derived growth factor (PDGF)-AA, interleukin (IL)-10, and other cytokines between 11 cases of TAFRO-iMCD, 6 cases of plasma cell type iMCD, and 21 healthy controls. During flare-ups, patients with TAFRO-iMCD had significantly higher serum IP-10 and tended to have lower PDGF-AA levels than the other 2 groups. In addition, serum IL-10, IL-23, and vascular endothelial growth factor-A were elevated in both TAFRO-iMCD and iMCD. Elevated serum IP-10 is associated with inflammatory diseases including infectious diseases. There was a strong correlation between high serum IP-10 and the presence of TAFRO-iMCD, suggesting that IP-10 might be involved in the pathogenesis of TAFRO-iMCD.

DOI： 10.1038/srep42316

A multicenter phase II prospective clinical trial of glucocorticoid for patients with untreated IgG4-related disease Reviewed

Yasufumi Masaki, Shoko Matsui, Takako Saeki, Hiroto Tsuboi, Shintaro Hirata, Yasumori Izumi, Taiichiro Miyashita, Keita Fujikawa, Hiroaki Dobashi, Kentaro Susaki, Hisanori Morimoto, Kazutaka Takagi, Mitsuhiro Kawano, Tomoki Origuchi, Yoko Wada, Naoki Takahashi, Masanobu Horikoshi, Hiroshi Ogishima, Yasunori Suzuki, Takafumi Kawanami, Haruka Kawanami Iwao, Tomoyuki Sakai, Yoshimasa Fujita, Toshihiro Fukushima, Masatoshi Saito, Ritsuro Suzuki, Yuko Morikawa, Tadashi Yoshino, Shigeo Nakamura, Masaru Kojima, Nozomu Kurose, Yasuharu Sato, Yoshiya Tanaka, Susumu Sugai, Takayuki Sumida

MODERN RHEUMATOLOGY 27 ( 5 ) 849 - 854 2017

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS LTD

Objective: Although glucocorticoids are effective for patients with IgG4-related disease, the treatment has not yet been standardized. Therefore, the treatment strategy should be established.
Patients and methods: Patients who fulfilled the comprehensive diagnostic criteria for definite IgG4-related disease were started on prednisolone (0.6mg/ kg body weight) with the dose reduced every two weeks. The subsequent maintenance dose and need for prednisolone were determined for individual patients. The primary endpoint was the complete remission (CR) rate at one year. Secondary end-points included overall response rate (ORR), the maintenance dose, the relapse rate, and adverse events.
Results: This study enrolled 61 patients. After clinicopathological review, three patients were excluded, and one, 13, and 44 patients were diagnosed with probable, possible, and definite IgG4-related disease, respectively. Of the 44 patients with definite IgG4-RD, 29 (65.9%) achieved CR, and the ORR was 93.2%. No patient was refractory to primary treatment. The most frequent adverse events were glucose intolerance. Six patients relapsed.
Conclusions: Glucocorticoid treatment is usually effective for patients with IgG4-RD, and we should examine the possibility of other disorders when a patient is glucocorticoid refractory. Some patients are misdiagnosed, making central clinicopathological review of diagnosis very important in conducting clinical studies.

DOI： 10.1080/14397595.2016.1259602

A possible new morphological variant of mantle cell lymphoma with plasma-cell type Castleman disease-like features Reviewed

Takuro Igawa, Rika Omote, Hiaki Sato, Kohei Taniguchi, Katsuya Miyatani, Tadashi Yoshino, Yasuharu Sato

PATHOLOGY RESEARCH AND PRACTICE 213 ( 11 ) 1378 - 1383 2017

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER GMBH, URBAN & FISCHER VERLAG

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by overexpression of cyclin Dl resulting from t(11;14)(q13;q32) translocation. Herein, we report 3 cases of MCL with features of plasma cell type Castleman disease (CD). The 3 patients were all men, ranging from 51 to 74 years in age, and they all presented with systemic lymphadenopathy with anemia, hypoalbuminemia, elevated serum levels of C-reactive protein, and polyclonal hypergammaglobulinemia. Lymph node biopsy specimens of the 3 cases showed histological features of plasma cell-type CD, including atrophic germinal centers and interfollicular plasmacytosis, with no light chain restriction. However, flow cytometric analysis demonstrated an abnormal B-cell population with CD5 expression, and further analysis using cyclin Dl immunostaining highlighted a neoplastic component that was restricted to the mantle zone. These neoplastic cells were immunohistochemically positive for CD20, CD5, and SOX11, and negative for CD3, CD10, and HHV8. The Ki67 index was low. All patients were finally diagnosed with MCL. This rare type of MCL can be misdiagnosed clinically and histologically as CD. Therefore, it is important to recognize this rare type of MCL, and careful examination is required using both histological and flow cytometric analyses.

DOI： 10.1016/j.prp.2017.09.015

Tumor-Associated Macrophages in the Development of 4-Nitroquinoline-1-Oxide-Induced Tongue Squamous Cell Carcinoma in a Mouse Model Reviewed

Kentaro Miki, Yorihisa Orita, Yuka Gion, Soshi Takao, Kyotaro Ohno, Mai Takeuchi, Toshihiro Ito, Akira Minoura, Tomoyasu Tachibana, Hidenori Marunaka, Takuma Makino, Akihiro Matsukawa, Kazunori Nishizaki, Tadashi Yoshino, Yasuharu Sato

ONCOLOGY 93 ( 3 ) 204 - 212 2017

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

Objective: We aimed to determine the distribution of tumor-associated macrophages (TAMs) in the development of tongue squamous cell carcinoma (SCC) and to elucidate the role of TAMs in the progression of tongue SCC. Methods: The expression of the macrophage markers nitric oxide synthase, Retnla, and mannose receptor 1 in the development of tongue SCC was longitudinally observed using real-time quantitative polymerase chain reaction. Additionally, an immunohistochemical study using an anti-mannose receptor (MR) antibody was performed. Results: The numbers of both of M1 and M2 macrophages in the tongues of mice treated with 4-nitroquinoline-1-oxide (4NQO) were significantly lower compared with those of normal tongues. The cyclo-oxygenase-2 (COX-2) inhibitor did not prevent cancer progression and did not affect the total number of macrophages in the tongues of 4NQO-treated mice. In the immunohistochemical studies, MR staining was observed in lymphangio-endothelium in the subepithelial area of the tongues. The staining intensity of the MR was significantly stronger in the 4NQO-treated mice compared with that in control mice and 4NQO-treated mice treated with the COX-2 inhibitor. Conclusion: TAMs may not contribute to the development of 4NQO-induced tongue SCC. MR expression is associated with the progression of 4NQO-induced tongue SCC. (C) 2017 S. Karger AG, Basel

DOI： 10.1159/000477301

Multicentric Castleman's disease with multiple hepatic mass lesions mimicking malignant liver tumors Reviewed

UEKI Toshimitsu, NASUNO Masaru, KAIUME Hiroko, HIROSHIMA Yuki, SUMI Masahiko, WATANABE Masahide, INOUE Dai, MASAKI Yasufumi, SATO Yasuharu, KOJIMA Masaru, KOBAYASHI Hikaru

Rinsho Ketsueki 58 ( 6 ) 630 - 636 2017

Language：Japanese Publisher：The Japanese Society of Hematology

<p>Multicentric Castleman's disease (MCD) is a rare, non-malignant lymphoproliferative disorder. We report a case of MCD with multiple liver masses. A 26-year-old woman presented with asymptomatic anemia and hypoalbuminemia. Laboratory tests detected high CRP levels and findings indicative of polyclonal gammopathy. Abdominal CT revealed multiple hepatic large masses (≤10 cm) and partial calcification in the right lobe. Multiple enlarged lymph nodes were also identified in the cardiophrenic angle and porta hepatis. We suspected hepatic malignancy, but pathological examinations of the liver and lymph nodes demonstrated polyclonal plasma cell infiltration and fibrosis. IL-6 staining was positive for plasma cell infiltration of lymph nodes. A few plasma cells were positive for IgG4, and tests for HIV and HHV-8 were negative. Serum IL-6 and plasma VEGF levels were both elevated (45 and 536 pg/ml, respectively). The patient was diagnosed with plasma cell type MCD. We started treatment with PSL 1 mg/kg/day, which led to improvement of anemia, hypoalbuminemia, and high CRP levels. Marginal regression of liver masses was also observed. At the last follow-up, the patient had been progression-free for 18 months. To our knowledge, this is the first report of a plasma cell type MCD with liver masses.</p>

DOI： 10.11406/rinketsu.58.630

Other Link： http://search.jamas.or.jp/link/ui/2017370560

Clinicopathological analysis of primary central nervous system NK/T-cell lymphoma: rare and localised aggressive tumour among extranasal NK/T-cell tumours.

Miyata-Takata T, Takata K, Kato S, Hu LM, Noujima-Harada M, Chuang SS, Sato Y, Maeda Y, Yoshino T

0 ( 0 ) 0-0 2017

The role of bacteriological studies in the management of peritonsillar abscess

Tomoyasu Tachibana, Yorihisa Orita, Soshi Takao, Yuya Ogawara, Yuko Matsuyama, Aiko Shimizu, Iku Fujisawa, Michihiro Nakada, Yasuharu Sato, Kazunori Nishizaki

Journal of Otolaryngology of Japan 120 ( 5 ) 772 - 773 2017

The role of bacteriological studies in the management of peritonsillar abscess Reviewed

Tomoyasu Tachibana, Yorihisa Orita, Soshi Takao, Yuya Ogawara, Yuko Matsuyama, Aiko Shimizu, Iku Abe-Fujisawa, Michihiro Nakada, Yasuharu Sato, Kazunori Nishizaki

AURIS NASUS LARYNX 43 ( 6 ) 648 - 653 2016.12

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI LTD

Objective: Since most patients with peritonsillar abscess (PTA) can be successfully treated with surgical drainage and empirical antibiotic therapy, routine bacteriologic studies for all patients with PTA may be unnecessary. This study tried to evaluate which patients with PTA should certainly undergo bacteriologic studies.
Methods: Hundred consecutive patients with PTA were treated and underwent culture tests of purulent contents obtained by surgical drainage between April 2008 and December 2013.
Results: In 62 of the 100 patients, 71 pathogenic bacteria were identified; 61 (86%) were Gram-positive cocci (GPC), 8 (11%) were Gram-negative rods (GNR), and 6 (8%) were anaerobes. Normal flora were isolated in 27 patients, and culture results were negative in 11 patients. Although not significant, primary (without prior antibiotic therapy) case (odds ratio (OR) = 2.19; 95% CI, 0.95-5.05) and laryngeal edema (OR = 2.04; 95% CI, 0.82-5.03) showed a tendency of associations with detection of pathogenic bacteria. After taking into account interactions between smoking habit and laryngeal edema, the covariate-adjusted OR for non-smokers with laryngeal edema was significant and showed a strong relationship (OR = 7.43; 95% confidence interval, 1.05-52.73) compared to non-smokers without laryngeal edema.
Conclusion: Although empirical antibiotic therapy was effective for most of the PTA patients, bacteriologic studies might be indispensable for the patients with laryngeal edema considering the failure of the first treatments. Particularly, the culture tests may be useful for non-smokers with laryngeal edema. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.anl.2016.01.009

IgG4-producing lymphoma arising in a patient with IgG4-related disease Reviewed

Takuro Igawa, Toshiaki Hayashi, Kazuya Ishiguro, Yumiko Maruyama, Mai Takeuchi, Katsuyoshi Takata, Tadashi Yoshino, Yasuharu Sato

MEDICAL MOLECULAR MORPHOLOGY 49 ( 4 ) 243 - 249 2016.12

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

We herein report a case in which an IgG4-producing lymphoma arose in a patient with a previous diagnosis consistent with an IgG4-related disease. A 43-year-old man presented with enlarged cervical lymph nodes and was treated with steroids and radiation for what was initially assumed to be Kimura's disease, although the lesions were later histologically re-diagnosed as IgG4-related lymphadenopathy. Fourteen years later, when the patient was 58-years-old, he presented with retroperitoneal fibrosis and swollen lymph nodes. The suspicious lesions were not histologically examined as the patient did not give consent. However, the serum IgG4 concentration was high (1400 mg/dL) and he was clinically diagnosed with systemic IgG4-related disease. Although steroid administration reduced the size of the lesions, tapering the dose finally resulted in systemic, prominently enlarged lymph nodes. Analysis of the biopsy specimen revealed that these multiple lymph node lesions were marginal zone B cell lymphomas that themselves expressed IgG4. Complete remission was achieved after a total of six courses of chemotherapy including rituximab. This case suggests that the infiltrating IgG4-expressing cells observed in IgG4-related disease can clonally expand to malignant lymphomas.

DOI： 10.1007/s00795-016-0139-2

Molecular Heterogeneity in Peripheral T-Cell Lymphoma Not Otherwise Specified Revealed By Comprehensive Mutational Profiling

Yosaku Watatani, Yasuharu Sato, Kenji Nishida, Hiroaki Miyoshi, Yuichi Shiraishi, Kenichi Chiba, Tanaka Hiroko, Hiroo Ueno, Nobuyuki Kakiuchi, Yusuke Shiozawa, Tetsuichi Yoshizato, Kenichi Yoshida, Masashi Sanada, Satoru Miyano, Koichi Ohshima, Tadashi Yoshino, Seishi Ogawa, Keisuke Kataoka

BLOOD 128 ( 22 ) 2016.12

Structural Variations Involving Programmed Death Ligands in B-Cell and T-Cell Lymphomas

Keisuke Kataoka, Hiroaki Miyoshi, Yasunori Kogure, Yasuharu Sato, Kenji Nishida, Yuichi Shiraishi, Hiroko Tanaka, Kenichi Chiba, Yosaku Watatani, Yusuke Shiozawa, Kenichi Yoshida, Masashi Sanada, Motohiro Kato, Satoru Miyano, Koji Izutsu, Kengo Takeuchi, Tadashi Yoshino, Koichi Ohshima, Seishi Ogawa

BLOOD 128 ( 22 ) 2016.12

CD10 down expression in follicular lymphoma correlates with gastrointestinal lesion involving the stomach and large intestine Reviewed

Nobuhiko Ohnishi, Katsuyoshi Takata, Tomoko Miyata-Takata, Yasuharu Sato, Akira Tari, Yuka Gion, Mai Noujima-Harada, Kohei Taniguchi, Tetsuya Tabata, Keina Nagakita, Shizuma Omote, Hiroyuki Takahata, Masaya Iwamuro, Hiroyuki Okada, Yoshinobu Maeda, Hiroyuki Yanai, Tadashi Yoshino

CANCER SCIENCE 107 ( 11 ) 1687 - 1695 2016.11

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Follicular lymphoma (FL) shows co-expression of B-cell lymphoma 2 (BCL2) and CD10, whereas downexpression of CD10 is occasionally experienced in gastrointestinal (GI) FL with unknown significance. Gastrointestinal FL is a rare variant of FL, and its similarity with mucosa-associated lymphoid tissue lymphoma was reported. We investigated the clinicopathological and genetic features of CD10 downexpressed (CD10(down)) GI-FL. The diagnosis of CD10(down) FL was carried out with a combination of pathological and molecular analyses. The incidence of CD10(down) GI-FL was shown in 35/172 (20.3%) cases, which was more frequent than nodal FL (3.5%, P < 0.001). The difference was additionally significant between GI-FL and nodal FL when the analysis was confined to primary GI-FL (55.2% vs 3.5%, P < 0.001). Compared to CD10(+) GI-FL, CD10(down) GI-FL significantly involved the stomach or large intestine (P = 0.015), and additionally showed the downexpression of BCL6 (P < 0.001). The follicular dendritic cell meshwork often showed a duodenal pattern in the CD10(down) group (P = 0.12). Furthermore, a lymphoepithelial lesion was observed in 5/12 (40%) gastric FL cases, which indicated caution in the differentiation of mucosa-associated lymphoid tissue lymphoma. Molecular analyses were undertaken in seven cases of CD10(down) GI-FL, and an identical clone was found between CD10(down) follicles and CD10(+)BCL2(+) neoplastic follicles. In the diagnosis of cases with CD10(down) BCL2(+) follicles, careful examination with molecular studies should be carried out.

DOI： 10.1111/cas.13031

Regulatory T cells function at the early stage of tumor progression in a mouse model of tongue squamous cell carcinoma Reviewed

Kentaro Miki, Yorihisa Orita, Yuka Gion, Soshi Takao, Kyotaro Ohno, Mai Takeuchi, Toshihiro Ito, Hiroyuki Hanakawa, Tomoyasu Tachibana, Hidenori Marunaka, Takuma Makino, Akira Minoura, Akihiro Matsukawa, Kazunori Nishizaki, Tadashi Yoshino, Yasuharu Sato

CANCER IMMUNOLOGY IMMUNOTHERAPY 65 ( 11 ) 1401 - 1410 2016.11

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

The objective of this study was to observe the distribution of regulatory T cells (Tregs) in the development of tongue squamous cell carcinoma (SCC) and to determine the role of Tregs in the progression of tongue SCC. A mouse model of 4-nitroquinoline-1-oxide (4NQO)-induced-tongue SCC was established. The expression of Forkhead box P3 (Foxp3), interleukin 10, transforming growth factor-beta, chemokine CC motif ligands 17, 20, and CC chemokine receptor 4 was determined using real-time quantitative polymerase chain reaction. Foxp3 expression was also analyzed using immunohistochemistry. The results were compared with those of control mice and of 4NQO-treated mice treated with a cyclooxygenase-2 (COX-2) inhibitor. Well to moderately differentiated tongue SCC was induced in all of the experimental mice. The amount of Tregs of the experimental mice was over 10 times as much as control mice at the early stage of tumor progression. COX-2 inhibitor did not prevent the progression of tongue SCC and did not reduce the total amount of Tregs. Tregs function at the early stage of the development of tongue SCC, and it may be effective to suppress Tregs at the early stage of tumor progression for the treatment and/or prevention of tongue SCC.

DOI： 10.1007/s00262-016-1902-x

Protocadherin gamma A3 is expressed in follicular lymphoma irrespective of BCL2 status and is associated with tumor cell growth Reviewed

Xueyan Zhang, Katsuyoshi Takata, Wei Cui, Tomoko Miyata-Takata, Yasuharu Sato, Mai Noujima-Harada, Tadashi Yoshino

MOLECULAR MEDICINE REPORTS 14 ( 5 ) 4622 - 4628 2016.11

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Protocadherin genes (PCDHs) have been suggested to act as tumor suppressor genes in various tumor types. Previous studies have demonstrated the upregulation of certain PCDH-gamma subfamily genes in nodal and duodenal follicular lymphoma (FL) using gene expression analyses. However, the mechanisms and associated molecular function of PCDH-gamma subfamily gene upregulation in FL remain to be elucidated. The present study examined the expression of PCDHGA3, an upregulated PCDH-gamma gene subfamily member, in B-cell lymphoma 2 (BCL2)-positive and-negative FL, and evaluated its association with tumor cell proliferation in an FL-derived cell line. Immunohistochemical analysis demonstrated that the majority of FL grade 1-2 samples (19/20; 95%) and over half of grade 3A FL samples (5/9; 56%) were PCDHGA3-positive, whereas only 1/17 reactive lymphoid hyperplasia samples was positive. Notably, this positivity was widely observed in samples of BCL2-negative FL (13/15; 87%) and FL with diffuse area (10/10; 100%). The FL-derived cell line FL18 exhibited strong PCDHGA3 expression, similar to the patient samples, and its proliferation was suppressed by PCDHGA3 gene knockdown. Genes expressed concomitantly with PCDHGA3 were selected from gene expression data, and TNFRSF6B, a member of the tumor necrosis factor receptor superfamily, was among the top five most strongly correlated genes. Coexpression of TNFRSF6B and PCDHGA3 was observed immunohistochemically in FL18 cells, suggesting potential cooperation in tumor cell maintenance. In conclusion, the results of the present study indicated that PCDHGA3 was expressed in FL irrespective of BCL2 status and grading and was associated with cell proliferation. Further studies involving molecular genetic analyses are required to elucidate the mechanisms underlying the activity of PCDHGA3 in FL.

DOI： 10.3892/mmr.2016.5808

A case of IgG4-related lymphadenopathy, pericarditis, coronary artery periarteritis and luminal stenosis Reviewed

Ryoto Hourai, Masatoshi Miyamura, Ryunosuke Tasaki, Akiko Iwata, Yoshihiro Takeda, Hideaki Morita, Nobuharu Hanaoka, Jun Tanigawa, Kensaku Shibata, Atsushi Takeshita, Mitsuhiro Kawano, Yasuharu Sato, Yoshinobu Hirose, Nobukazu Ishizaka

HEART AND VESSELS 31 ( 10 ) 1709 - 1713 2016.10

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

Immunoglobulin G4 (IgG4)-related disease is an emerging new clinicopathological disorder that is characterized by elevation of serum IgG4 levels and histological findings of IgG4-positive plasmacytic infiltration. IgG4-related disease may appear synchronously or metachronously in a wide variety of organs. The current patient was found to have pericardial effusion and retroperitoneal fibrosis. He was subsequently diagnosed with coronary artery stenosis. F-18-FDG positron emission tomography showed enhanced FDG uptake in lymph nodes as well as pericardial and peri-aortic tissue. Histopathology of the mediastinal lymph node showed the infiltration of numerous IgG4-positive cells, leading to the diagnosis of IgG4-related lymphadenopathy with pericardial and periarterial involvement.

DOI： 10.1007/s00380-016-0794-1

Clinical and Laboratory Features of IgG4-Related Retroperitoneal Fibrosis/Periarteritis in Japan: Retrospective Multicenter Study of 99 Cases

Ichiro Mizushima, Satomi Kasashima, Motohisa Yamamoto, Takako Saeki, Kazunori Yamada, Dai Inoue, Fuminori Kasashima, Yasushi Matsumoto, Eisuke Amiya, Kenji Notohara, Yasuharu Sato, Yoh Zen, Shigeyuki Kawa, Mitsuhiro Kawano, Nobukazu Ishizaka

ARTHRITIS & RHEUMATOLOGY 68 2016.10

Distribution and components of interstitial inflammation and fibrosis in IgG4-related kidney disease: analysis of autopsy specimens Reviewed

Satoshi Hara, Mitsuhiro Kawano, Ichiro Mizushima, Kenichi Harada, Takuma Takata, Takako Saeki, Yoshifumi Ubara, Yasuharu Sato, Michio Nagata

HUMAN PATHOLOGY 55 164 - 173 2016.9

Language：English Publishing type：Research paper (scientific journal) Publisher：W B SAUNDERS CO-ELSEVIER INC

IgG4-related kidney disease (IgG4-RKD) occasionally progresses to chronic renal failure and is pathologically characterized by IgG4-positive lymphoplasmacyte-rich tubulointerstitial nephritis with storiform fibrosis (bird's-eye pattern fibrosis). Although radiology reveals a heterogeneous distribution of affected areas in this disease, their true distribution within the whole kidney is still unknown because of difficulty in estimating this from needle biopsy samples. Using 5 autopsy specimens, the present study histologically characterized the distribution and components of interstitial inflammation and fibrosis in IgG4-RKD. Interstitial lymphoplasmacytic infiltration or fibrosis was observed in a variety of anatomical locations such as intracapsular, subcapsular, cortical, perivascular, and perineural regions heterogeneously in a patchy distribution. They tended to be more markedly accumulated around medium- and small-sized vessels. Storiform fibrosis was limited to the cortex. Immunostaining revealed nonfibrillar collagens (collagen IV and VI) and fibronectin predominance in the cortical lesion, including storiform fibrosis. In contrast, fibril-forming collagens (collagen I and 111), collagen VI, and fibronectin were the main components in the perivascular lesion. In addition, a-smooth muscle actin positive myofibroblasts were prominently accumulated in the early lesion and decreased with progression, suggesting that myofibroblasts produce extracellular matrices forming a peculiar fibrosis. In conclusion, perivascular inflammation or fibrosis of medium- and small-sized vessels is a newly identified pathologic feature of IgG4-RKD. Because storiform fibrosis contains mainly nonfibrillar collagens, "interstitial fibrosclerosis" would be a suitable term to reflect this. The relation between the location and components of fibrosis determined in whole kidney samples provides new clues to the pathophysiology underlying IgG4-RKD. (C) 2016 The Authors. Published by Elsevier Inc.

DOI： 10.1016/j.humpath.2016.05.010

Kikuchi-Fujimoto disease: evaluation of prognostic factors and analysis of pathologic findings Reviewed

Hidenori Marunaka, Yorihisa Orita, Tomoyasu Tachibana, Kentaro Miki, Takuma Makino, Yuka Gion, Kazunori Nishizaki, Tadashi Yoshino, Yasuharu Sato

ACTA OTO-LARYNGOLOGICA 136 ( 9 ) 944 - 947 2016.9

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS LTD

Conclusion: In Kikuchi-Fujimoto disease (KFD), a low ratio of blastic cells (<70%) in lymph node specimens and absence of atypical lymphocytes in peripheral blood are predictive of a protracted clinical course. Objectives: Since KFD is a self-limiting disorder that does not require any specific management, prognostic factors have received little attention. The present study identified clinical and pathological factors that may affect the period from onset to cure of KFD. Methods: This retrospective study investigated 43 KFD patients who underwent lymph node biopsy diagnosed by immunohistochemical staining at Okayama University Hospital and Okayama Medical Center from January 2001 to December 2013. Results: Mean total period from onset to cure was 6 months (median =9.4 months; range =1-37 months). Low ratios of blastic cell proliferation area (<70%) in lymph node specimens (p=0.011) and absence of atypical lymphocytes in peripheral blood (p=0.026) were associated with a relatively long duration of KFD.

DOI： 10.3109/00016489.2016.1164895

Clinicopathological features of 49 primary gastrointestinal diffuse large B-cell lymphoma cases; comparison with location, cell-of-origin, and frequency of MYD88 L265P Reviewed

Keina Nagakita, Katsuyoshi Takata, Kohei Taniguchi, Tomoko Miyata-Takata, Yasuharu Sato, Akira Tari, Nobuhiko Ohnishi, Mai Noujima-Harada, Shizuma Omote, Naoya Nakamura, Masaya Iwamuro, Yoshinobu Maeda, Hiroyuki Okada, Mitsune Tanimoto, Tadashi Yoshino

PATHOLOGY INTERNATIONAL 66 ( 8 ) 444 - 452 2016.8

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

The gastrointestinal (GI) tract is the most common primary site of extranodal diffuse large B-cell lymphoma (DLBCL), with approximately one-third of extranodal DLBCL occurring in the GI tract. We investigated the clinicopathological features and immunohistochemically-assessed cell-of-origin of 49 GI DLBCL cases (stomach, 24; small intestine, 10; colon, 15) and also examined the presence of MYD88 L265P as recently this mutation has been frequently identified in ABC-like DLBCL, particularly in extranodal sites. Small intestinal DLBCL was characterized by the preponderance of women (P = 0.041) and elevated LDH (P = 0.002) and soluble interleukin-2 receptor (P = 0.033). Small intestinal DLBCL more frequently showed anemia (P = 0.031) and elevated CRP (P = 0.029) than gastric DLBCL. ABC-like phenotype was seen in 71.4 % cases (stomach, 79 %; small intestine, 70 %; colon, 60 %). MYD88 L265P was detected in 6.1 % cases; all were primary gastric DLBCL with ABC-like phenotype but had no distinct clinicopathological features. In conclusion, GI DLBCL had different clinicopathological features according to the primary site especially in the small intestine. Also, MYD88 L265P had little involvement in GI DLBCL compared with other extranodal DLBCLs, suggesting that its pathogenesis might be different from that of organs with a high frequency of MYD88 L265P.

DOI： 10.1111/pin.12439

Multicentric Castleman Disease With Tubulointerstitial Nephritis Mimicking IgG4-related Disease Two Case Reports Reviewed

Takeshi Zoshima, Kazunori Yamada, Satoshi Hara, Ichiro Mizushima, Masakazu Yamagishi, Kenichi Harada, Yasuharu Sato, Mitsuhiro Kawano

AMERICAN JOURNAL OF SURGICAL PATHOLOGY 40 ( 4 ) 495 - 501 2016.4

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Multicentric Castleman disease is a benign lymphoproliferative disorder with heterogenous clinical symptoms and involves systemic organs in addition to lymph nodes. Elevated serum IgG4 levels and IgG4-positive plasma cell (IgG4+PC) infiltrates have been reported in lymph nodes, lung and skin in some multicentric Castleman disease cases, resembling IgG4-related disease (IgG4-RD) histologically. However, no report has been available regarding IgG4+PC infiltration in the kidneys of multicentric Castleman disease. Here, we report 2 cases of multicentric Castleman disease complicated by IgG4-related disease (IgG4-RD) histologically. However, there has been no report published on PC-rich tubulointerstitial nephritis, lymphadenopathy, with numerous IgG4+PC infiltration, and elevated serum IgG4 levels, mimicking IgG4-RD. The blood examinations revealed systemic inflammation and elevated C-reactive protein and interleukin-6 levels. Corticosteroid therapy was partially effective in both cases, and combination therapy of corticosteroid and tocilizumab was needed in both cases. Moreover, after triple therapy with corticosteroid, rituximab and cyclophosphamide were used in 1 case to tame the severe inflammation. The present cases suggest that if continuously elevated serum C-reactive protein levels and partial corticosteroid responsiveness are encountered, multicentric Castleman disease should be considered rather than IgG4-RD as a differential diagnosis even if serum IgG4 is elevated and IgG4+PCs infiltrate systemic organs.

DOI： 10.1097/PAS.0000000000000575

Glottic cancer in patients without complaints of hoarseness Reviewed

Tomoyasu Tachibana, Yorihisa Orita, Hidenori Marunaka, Seiichiro Makihara, Misato Hirai, Kentaro Miki, Yuya Ogawara, Hisashi Ishihara, Yuko Matsuyama, Iku Abe-Fujisawa, Aiko Shimizu, Yasuharu Sato, Kazunori Nishizaki

HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK 38 E316 - E320 2016.4

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Background. Few studies have investigated the clinical characteristics of patients with glottic cancer without hoarseness.
Methods. This retrospective clinical study investigated 371 patients with glottic cancer.
Results. Thirty-two of the 371 patients (8.6%) with glottic cancer first presented to hospitals with complaints other than hoarseness. Although proportions of stage I and T1 disease were significantly higher among patients without hoarseness than among those with hoarseness (p = .0036 and p = .0004, respectively), survival curves showed no significant differences between groups (p = .1334).
Conclusion. Patients with glottic cancer without complaints of hoarseness were diagnosed at an earlier stage than those with hoarseness. Accumulation of more cases may lead to better survival of patients with glottic cancer without hoarseness compared to those with hoarseness. Checking the larynx of patients without hoarseness or encouraging internists to check the larynx when performing gastroscopic or respiratory examinations may lead to improvement of glottic cancer prognosis. (C) 2015 Wiley Periodicals, Inc.

DOI： 10.1002/hed.23992

Castleman's diseaseに類似した組織像を呈するMantle cell lymphomaの2症例

表梨華, 佐藤康晴, 高田尚良, 吉野正

日本病理学会会誌 105 ( 1 ) 557 - 557 2016.4

Frequent MYD88 L265P and CD79B Mutations in Primary Breast Diffuse Large B-Cell Lymphoma Reviewed

Kohei Taniguchi, Katsuyoshi Takata, Shih-Sung Chuang, Tomoko Miyata-Takata, Yasuharu Sato, Akira Satou, Yuko Hashimoto, Maiko Tamura, Keina Nagakita, Nobuhiko Ohnishi, Mai Noujima-Harada, Tetsuya Tabata, Yara Yukie Kikuti, Yoshinobu Maeda, Naoya Nakamura, Mitsune Tanimoto, Tadashi Yoshino

AMERICAN JOURNAL OF SURGICAL PATHOLOGY 40 ( 3 ) 324 - 334 2016.3

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare disease comprising < 3% of extranodal lymphomas. It frequently reveals an activated B-cell (ABC)-like phenotype. ABC-like DLBCL was reported to have gain-of-function mutations in MYD88, CD79B, CARD11, and TNFAIP3, resulting in constitutive activation of the NF kappa B pathway. Because of the rare occurrence of PB-DLBCL, the frequency of MYD88 and CD79B mutations is still unknown. We used Sanger sequencing to study these mutations from 46 breast DLBCL cases and also investigated the associated clinicopathologic factors. MYD88 L265P was confirmed by allele-specific polymerase chain reaction and compared with the Sanger sequencing results. MYD88 L265P and CD79B mutations were detected in 27/46 (58.7%) and 11/33 (33.3%) cases, respectively. Twenty-eight of 46 cases met the criteria for PB-DLBCL, and the latter 18 cases were further classified as clinical breast DLBCL (CLB-DLBCL). The frequency of MYD88 L265P and CD79B mutations was 16/28 (57.1%) and 9/23 (39.1%), respectively, in PB-DLBCL and 11/18 (61.1%) and 2/10 (20%), respectively, in CLB-DLBCL. When the cutoff value was set at Delta Ct <= 1, the result of allele-specific polymerase chain reaction for MYD88 corresponded to those of the Sanger sequence at 92.6% sensitivity and 100% specificity. According to Choi's algorithm, 16/27 (59.3%) demonstrated an ABC-like phenotype in PB-DLBCL, and 15/18 (83.3%) demonstrated an ABC-like phenotype in CLB-DLBCL. In conclusion, MYD88 L265P and CD79B mutations were frequently detected in PB-DLBCL, and they may be key molecules associated with PB-DLBCL lymphomagenesis. Further analysis will be required to clarify the mechanism of its pathogenesis.

DOI： 10.1097/PAS.0000000000000592

Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric Castleman disease Reviewed

Noriko Iwaki, David C. Fajgenbaum, Christopher S. Nabel, Yuka Gion, Eisei Kondo, Mitsuhiro Kawano, Taro Masunari, Isao Yoshida, Hiroshi Moro, Koji Nikkuni, Kazue Takai, Kosei Matsue, Mitsutoshi Kurosawa, Masao Hagihara, Akio Saito, Masataka Okamoto, Kenji Yokota, Shinichiro Hiraiwa, Naoya Nakamura, Shinji Nakao, Tadashi Yoshino, Yasuharu Sato

AMERICAN JOURNAL OF HEMATOLOGY 91 ( 2 ) 220 - 226 2016.2

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

Multicentric Castleman disease (MCD) describes a heterogeneous group of disorders involving systemic inflammation, characteristic lymph node histopathology, and multi-organ dysfunction because of pathologic hypercytokinemia. Whereas Human Herpes Virus-8 (HHV-8) drives the hypercytokinemia in a cohort of immunocompromised patients, the etiology of HHV-8-negative MCD is idiopathic (iMCD). Recently, a limited series of iMCD cases in Japan sharing a constellation of clinical features, including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O) has been described as TAFRO syndrome. Herein, we report clinicopathological findings on 25 patients (14 males and 11 females; 23 Japanese-born and two US-born), the largest TAFRO syndrome case series, including the first report of cases from the USA. The median age of onset was 50 years old (range: 23-72). The frequency of each feature was as follows: thrombocytopenia (21/25), anasarca (24/25), fever (21/25), organomegaly (25/25), and reticulin fibrosis (13/16). These patients frequently demonstrated abdominal pain, elevated serum alkaline phosphatase levels, and acute kidney failure. Surprisingly, none of the cases demonstrated marked hypergammoglobulinemia, which is frequently reported in iMCD. Lymph node biopsies revealed atrophic germinal centers with enlarged nuclei of endothelial cells and proliferation of endothelial venules in interfollicular zone. 23 of 25 cases were treated initially with corticosteroids; 12 patients responded poorly and required further therapy. Three patients died during the observation period (median: 9 months) because of disease progression or infections. TAFRO syndrome is a unique subtype of iMCD that demonstrates characteristic clinicopathological findings. Further study to clarify prognosis, pathophysiology, and appropriate treatment is needed. (C) 2015 Wiley Periodicals, Inc.

DOI： 10.1002/ajh.24242

DNA Microarray Analysis of Submandibular Glands in IgG4-Related Disease Indicates a Role for MARCO and Other Innate Immune-Related Proteins Reviewed

Miho Ohta, Masafumi Moriyama, Takashi Maehara, Yuka Gion, Sachiko Furukawa, Akihiko Tanaka, Jun-Nosuke Hayashida, Masaki Yamauchi, Noriko Ishiguro, Yurie Mikami, Hiroto Tsuboi, Mana Iizuka-Koga, Shintaro Kawano, Yasuharu Sato, Tamotsu Kiyoshima, Takayuki Sumida, Seiji Nakamura

MEDICINE 95 ( 7 ) e2853 2016.2

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

IgG4-related disease (IgG4-RD) is a novel systemic disease entity characterized by elevated serum IgG4 and tissue infiltration of IgG4-positive plasma cells accompanied by severe fibrosis. Although recent studies demonstrated that innate immune cells including monocytes and macrophages might promote local fibrosis and IgG4 production, the pathological mechanism remains unclear. In this study, we sought to identify the disease-associated genes, especially innate immune molecules.
Gene expression was analyzed by DNA microarray in submandibular glands (SMGs) from patients with IgG4-RD (n=5), chronic sialoadenitis (CS) (n=3), and controls (n=3). Differentially expressed genes (DEGs) were validated by real-time polymerase chain reaction (PCR) and immunohistochemical staining in IgG4-RD (n=18), CS (n=4), Sjogren syndrome (n=11), and controls (n=10).
Gene expression patterns in the 3 groups were quite different from each other by the pvclust method and principal components analysis. In IgG4-RD, 1028 upregulated genes and 692 downregulated genes were identified as DEGs (P<0.05). Gene Ontology (GO) term analysis indicated that the upregulated DEGs in IgG4-RD encoded proteins involved in T/B cell activation and chemotaxis. PCR validated significantly higher expression of macrophage receptor with collagenous structure (MARCO), a pattern-recognition receptor, in IgG4-RD compared with the other groups (P<0.01). Immunohistochemical analysis confirmed that the expression pattern of MARCO was similar to that of the M2 macrophage marker CD163.
MARCO was identified as a disease-associated molecule in IgG4-RD by DNA microarray. Moreover, M2 macrophages might contribute to the initiation of IgG4-RD via MARCO.

DOI： 10.1097/MD.0000000000002853

Characteristic distribution of inflammatory lesions in IgG4-related kidney disease: Findings from autopsy case series Reviewed

Satoshi Hara, Mitsuhiro Kawano, Ichiro Mizushima, Kenichi Harada, Takuma Takata, Takako Saeki, Yoshifumi Ubara, Yasuharu Sato, Michio Nagata

IgG4-Related Kidney Disease 187 - 191 2016.1

Language：English Publishing type：Part of collection (book) Publisher：Springer Japan

IgG4-related tubulointerstitial nephritis (TIN) reveals specific histologies such as storiform (“bird’s-eye pattern”) fibrosis, regional lesion distribution, and extension of inflammation into and beyond the renal capsule, all of which clearly serve to distinguish IgG4-related TIN from non-IgG4-related TIN. However, the histological extent of IgG4-related TIN in the kidney remains unclear, largely because histological analyses of IgG4-related TIN to date have been based generally only on renal needle biopsy specimens. We histologically analyzed five autopsy specimens of IgG4-related TIN cases. The lymphoplasmacytic infiltration or fibrosis was mainly located in the cortex and perivasculature. Notably, inflammation or fibrosis generally appeared prominently around the interlobar, arcuate and interlobular arteries or veins. In addition, all specimens included various stages of fibrosis in the same kidneys. Storiform fibrosis (bird’s-eye pattern fibrosis) was limited to the cortex. These results indicate that inflammation or fibrosis is predominantly located in the renal cortex and perivasculature in IgG4-related TIN. Of note is that the lesions showed a predilection to develop around medium- and small-sized arteries in addition to forming nodular lesions in the renal cortex.

DOI： 10.1007/978-4-431-55687-9_16

Multicentric castleman’s disease mimicking IgG4-related disease: A case report Reviewed

Eiko Hasegawa, Akinari Sekine, Jun-Ichi Inenaga, Takeshi Fujii, Kenichi Ohashi, Yasuharu Sato, Yoshifumi Ubara

IgG4-Related Kidney Disease 293 - 301 2016.1

Language：English Publishing type：Part of collection (book) Publisher：Springer Japan

A 63-year-old Japanese man was admitted to our hospital for the evaluation of hypergammaglobulinemia, lymphadenopathy, interstitial lung disease and nephritis. His serum level of IgG and IgG4 were 8198 mg/dL and 3360 mg/dL, respectively. Renal biopsy revealed focal interstitial nephritis with IgG4 positive plasma cells, with an IgG4/IgG ratio of &gt
0.6. Inguinal lymph node biopsy showed hyperplasia of the lymphoid follicles with prominent infiltration of mature plasma cells between normal germinal centers. Immunostaining showed that the IgG4-positive plasma cells were prominent, and the IgG4/IgG ratio within the lymph node was &gt
0.8. Although these findings were consistent with IgG4-related disease (IgG4-RD), other laboratory findings such as high serum concentrations of C-reactive protein, interleukin-6, IgA, and IgM, as well as positive staining of the lymph node for IgA and IL-6, suggested multicentric Castleman’s disease (MCD). Following unsuccessful therapy with glucocorticoids, treatment with an anti-interleukin-6 receptor monoclonal antibody (tocilizumab) exerted disease control. Understanding the crucial differences between MCD and IgG4-RD may contribute to understanding the pathogenesis of both diseases.

DOI： 10.1007/978-4-431-55687-9_26

Anti-high mobility group box 1 monoclonal antibody improves ischemia/reperfusion injury and mode of liver regeneration after partial hepatectomy Reviewed

Masahiro Sugihara, Hiroshi Sadamori, Masahiro Nishibori, Yasuharu Sato, Hiroshi Tazawa, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Nobuoka, Masashi Utsumi, Kyotaro Ohno, Takeshi Nagasaka, Tadashi Yoshino, Hideo Kohka Takahashi, Takahito Yagi, Toshiyoshi Fujiwara

AMERICAN JOURNAL OF SURGERY 211 ( 1 ) 179 - 188 2016.1

Language：English Publishing type：Research paper (scientific journal) Publisher：EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC

BACKGROUND: The purpose of this study is to determine the effects of anti-high mobility group box 1 (HMGB1) monoclonal antibody (mAb) on ischemia/reperfusion injury (IRI) and the mode of liver regeneration.
METHODS: Rats underwent 70% hepatectomy with IRI caused by clamping the hepatoduodenal ligament for 20 minutes, followed by the administration of anti-HMGB1 mAb immediately before declamping the hepatoduodenal ligament. Five animals were used for each time point. We then evaluated IRI, regeneration parameters and the status of HMGB1 in remnant livers.
RESULTS: The anti-HMGB1 mAb significantly ameliorated the degree of IRI in the remnant livers in association with the downregulation of HMGB1 protein. The ratio of Ki67-positive hepatocytes at 48 hours after 70% hepatectomy was significantly improved. Mean hepatocyte size was significantly reduced and cyclin-dependent kinase inhibitor 1 expression was significantly attenuated.
CONCLUSIONS: Anti-HMGB1 mAb ameliorated IRI and improved the mode of liver regeneration after IRI followed by 70% hepatectomy in rats. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.amjsurg.2015.06.025

Peripheral T-Cell Lymphoma, Not Otherwise Specified and Concurrent Seminoma in Testis. Reviewed

Kitagawa J, Goto N, Shibata Y, Nakamura N, Nakamura H, Kanemura N, Hara T, Takata K, Sato Y, Yoshino T, Tsurumi H

Journal of Clinical and Experimental Hematopathology 55 ( 3 ) 169 - 174 2016

A condition closely mimicking IgG4-related disease despite the absence of serum IgG4 elevation and IgG4-positive plasma cell infiltration Reviewed

Satoshi Hara, Mitsuhiro Kawano, Ichiro Mizushima, Kazunori Yamada, Kentaro Fujita, Kenichi Harada, Masami Matsumura, Masakazu Yamagishi, Yasuharu Sato, Yutaka Yamaguchi, Yasuni Nakanuma, Michio Nagata

MODERN RHEUMATOLOGY 26 ( 5 ) 784 - 789 2016

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

We describe a 74-year-old Japanese man with systemic fibroinflammatory conditions closely resembling those of immunoglobulin G4-related disease (IgG4-RD). Radiology and histology showed characteristics of IgG4-related tubulointerstitial nephritis, despite normal serum IgG4 value and scanty IgG4-positive plasma cell infiltration in each organ. This case suggests that a condition closely mimicking IgG4-RD may develop without IgG4-positive plasma cells and those exceptional cases should also be taken into account in the differential diagnosis of IgG4-RD.

DOI： 10.3109/14397595.2014.916836

Ocular adnexal marginal zone lymphoma arising in a patient with IgG4-related ophthalmic disease. Reviewed International journal

Kenji Nishida, Yuka Sogabe, Ayako Makihara, Akemi Senoo, Hisanori Morimoto, Mai Takeuchi, Yuka Gion, Tadashi Yoshino, Yasuharu Sato

Modern rheumatology 29 ( 2 ) 1 - 5 2016

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

A 41-year-old man was diagnosed with immunoglobulin G4-related disease (IgG4-RD) in both eyelids 4 years ago and exhibited good response to steroid therapy. However, rapid swelling of the right eyelid lesion was recently observed. As IgG4-RD progression was suspected, biopsy was performed. Although the histology was consistent with IgG4-RD, the infiltrating large atypical lymphoid cells showed immunoglobulin light-chain restriction and IgH gene rearrangement. Consequently, he was diagnosed with extranodal marginal zone lymphoma with abundant IgG4-positive cells.

DOI： 10.1080/14397595.2016.1216733

Elevation of serum interleukins 8, 4, and 1 beta levels in patients with gastrointestinal low-grade B-cell lymphoma Reviewed

Tomoko Miyata-Takata, Katsuyoshi Takata, Tomohiro Toji, Naoe Goto, Senji Kasahara, Takeshi Takahashi, Akira Tari, Mai Noujima-Harada, Takafumi Miyata, Yasuharu Sato, Tadashi Yoshino

SCIENTIFIC REPORTS 5 18434 2015.12

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Proinflammatory cytokines that are produced by helper T cells (Th) regulate immune reactions, facilitate class switching of B cells, and prolong the lifespan of B and T cells. Eradication therapy using antibiotics is sometimes effective against gastrointestinal (GI) malignant lymphoma, suggesting that the tumor development or progression is affected by the inflammatory microenvironment. In the present study, serum samples from 148 patients with various subtypes of malignant lymphoma were tested for 11 proinflammatory Th1/Th2 cytokines. In the comparison by subtype or GI lesions, serum interleukin (IL)-8 (P= 6.7E-05), IL-4 (P = 7.5E-05), and IL-10 (P = 0.0043) levels showed significant differences among subtypes, being particularly elevated in follicular lymphomas (FL) and mucosa-associated lymphoid tissue (MALT) lymphomas. Serum IL-8 levels were elevated in GI-FL and MALT lymphomas, and serum IL-4 and IL-10 levels were elevated in MALT lymphomas. These findings show that GI low-grade B-cell lymphoma could develop against the background of an inflammatory microenvironment. Thus, these cytokines may be useful as diagnostic markers and could provide new insights into tumor development.

DOI： 10.1038/srep18434

Human immunodeficiency virus-positive secondary syphilis mimicking cutaneous T-cell lymphoma Reviewed

Michiko Yamashita, Yoshiyuki Fujii, Keiji Ozaki, Yoshio Urano, Masami Iwasa, Shingen Nakamura, Shiro Fujii, Masahiro Abe, Yasuharu Sato, Tadashi Yoshino

DIAGNOSTIC PATHOLOGY 10 2015.10

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Malignant syphilis or lues maligna is a severe form of secondary syphilis that was commonly reported in the pre-antibiotic era, and has now reemerged with the advent of the human immunodeficiency virus (HIV) epidemic. However, the characteristic histopathological findings of malignant syphilis remain controversial. The aim of this case report was to clarify the clinical and histopathological findings of HIV-positive malignant secondary syphilis. A Japanese man in his forties complained of fever, skin lesions, headache, and myalgia without lymphadenopathy during the previous 4 weeks. The skin lesions manifested as erythematous, nonhealing, ulcerated papules scattered on his trunk, extremities, palm, and face. Although the skin lesions were suspected to be cutaneous T-cell lymphomas on histological analyses, they lacked T-cell receptor J gamma rearrangement; moreover, immunohistochemical analyses confirmed the presence of spirochetes. The patient was administered antibiotics and anti-retroviral therapy, which dramatically improved the symptoms. On the basis of these observations of the skin lesions, we finally diagnosed the patient with HIV-associated secondary syphilis that mimicked cutaneous T-cell lymphoma. The patient's systemic CD4+ lymphocyte count was very low, and the infiltrate was almost exclusively composed of CD8+ atypical lymphocytes; therefore, the condition was easily misdiagnosed as cutaneous lymphoma. Although the abundance of plasma cells is a good indicator of malignant syphilis on skin histological analyses, in some cases, the plasma cell count may be very low. Therefore, a diagnosis of malignant secondary syphilis should be considered before making a diagnosis of primary cutaneous peripheral T-cell lymphoma or lymphoma associated with HIV infection.

DOI： 10.1186/s13000-015-0419-5

Spontaneous regression of plasmablastic lymphoma in an elderly human immunodeficiency virus (HIV)-negative patient Reviewed

Takuro Igawa, Yasuharu Sato, Hotaka Kawai, Eisei Kondo, Mai Takeuchi, Tomoko Miyata-Takata, Katsuyoshi Takata, Tadashi Yoshino

DIAGNOSTIC PATHOLOGY 10 2015.10

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

Plasmablastic lymphoma (PBL) is an aggressive lymphoma commonly associated with human immunodeficiency virus (HIV) infection. Herein we describe a rare case of PBL that spontaneously regressed. An 80-year-old man was referred to our hospital owing to an exophytic gingival tumor in the right maxillary second molar region. He had no significant past medical history, and a screening test for HIV was negative. Imaging showed that the tumor measured 26 x 23 x 16 mm and was confined in the alveolar bone. The tumor was histologically comprised of highly proliferative immunoblastic cells positive for CD138 and Epstein-Barr virus (EBV)-encoded RNA. Monoclonal IgH chain gene rearrangement was detected via polymerase chain reaction. After biopsy and diagnosis of PBL, the tumor began to decrease in size and had apparently disappeared at the time of surgery. There was no histological evidence of a residual lesion in the surgical specimen. In conclusion, a minority of immunosenescence-associated PBLs in the elderly should be recognized as a unique clinicopathological entity distinct from common aggressive PBL.

DOI： 10.1186/s13000-015-0421-y

Clinicopathologic Analysis of 6 Lymphomatoid Gastropathy Cases Expanding the Disease Spectrum to CD4(-) CD8(+) Cases Reviewed

Katsuyoshi Takata, Mai Noujima-Harada, Tomoko Miyata-Takata, Koichi Ichimura, Yasuharu Sato, Takafumi Miyata, Keishi Naruse, Toshiyuki Iwamoto, Akira Tari, Taro Masunari, Hiroshi Sonobe, Hiroyuki Okada, Masaya Iwamuro, Kohichi Mizobuchi, Yuka Gion, Tadashi Yoshino

AMERICAN JOURNAL OF SURGICAL PATHOLOGY 39 ( 9 ) 1259 - 1266 2015.9

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Lymphomatoid gastropathy, which was first reported in 2010, is a rare NK-cell proliferation of cyCD3(+), CD4(-), CD5(-), CD8(-), CD56(+) phenotypes with unknown etiology. The diagnosis is challenging, as there is histopathologic similarity to malignant lymphoma. In the 2010 report on 10 cases, all lesions were located in the stomach, and all regressed without any therapy. In the present study, we analyzed 6 cases of lymphomatoid gastropathy by investigating the clinicopathologic, immunohistochemical, and molecular findings. Endoscopic and morphologic appearances of all cases were consistent with previous reports, but 2 cases showed previously unreported unique immunophenotypes of CD4(-)CD8(+). Three of 6 patients underwent lower gastrointestinal examination (1 case underwent double-balloon endoscopic examination), but no patient had lesions in the lower gastrointestinal tract. No obvious difference of histology was found between the cases of CD4-CD8-typical phenotype and ones of CD4(-)CD8(+) phenotype. Both cases had similar clinical behavior as the other 4 cases, implying that the spectrum of the disease is broader than initially thought. Careful clinical and endoscopic follow-up is required for the diagnosis of lymphomatoid gastropathy, and additional case studies and molecular studies are warranted to further investigate the pathophysiology of this peculiar benign mimic of lymphoma.

DOI： 10.1097/PAS.0000000000000443

Serum level of soluble interleukin-2 receptor correlates with CD25 expression in patients with T lymphoblastic lymphoma Reviewed

Tomohiro Toji, Katsuyoshi Takata, Yasuharu Sato, Tomoko Miyata-Takata, Eiko Hayashi, Toshiyuki Habara, Yoshinobu Maeda, Mitsune Tanimoto, Tadashi Yoshino

JOURNAL OF CLINICAL PATHOLOGY 68 ( 8 ) 622 - 627 2015.8

Language：English Publishing type：Research paper (scientific journal) Publisher：BMJ PUBLISHING GROUP

Acute lymphoblastic leukaemia/lymphoma (ALL/LBL) is an aggressive form of non-Hodgkin's lymphoma (NHL) affecting B-cells or T-cells, respectively. The serum level of soluble interleukin-2 receptor (sIL-2R) is known to reflect the immune activity and tumour volume in aggressive NHL; however, the release of sIL-2R in LBL has not been extensively studied. Further, the relationship between sIL-2R release and the expression level of IL-2R alpha subunit (CD25) remains unknown.
In the present study, we examined the serum level of sIL-2R in 23 patients with T lymphoblactic lymphoma (T-LBL) and compared these with the levels in 20 patient with T acute lymphoblastic leukaemia (T-ALL), 40 patients with diffuse large B-cell lymphoma (DLBCL) and 40 patients with peripheral T-cell lymphoma (PTCL), not otherwise specified. The release of sIL-2R into the serum in patients with T-LBL was significantly lower than that for T-ALL, DLBCL and PTCL (p<0.001).
Immunohistochemistry revealed that CD25 expression was correlated with the serum level of sIL-2R in T-LBL (p=0.0069), whereas no correlation was found to exist between serum sIL-2R levels and CD25 expression in patients with DLBCL (p=0.348) and PTCL (p=0.266). Furthermore, double immunohistochemical analysis revealed that CD25-positive cells were also found to be Foxp3-positive non-neoplastic T-cells. In conclusion, CD25-positive non-neoplastic T-cells in T-LBL are presumed to be the primary source of sIL-2R, and the low number of cells present results in a lower level of sIL-2R released into the serum compared with the other aggressive and highly aggressive lymphomas.

DOI： 10.1136/jclinpath-2015-202934

A subset of ocular adnexal marginal zone lymphomas may arise in association with IgG4-related disease Reviewed

Kyotaro Ohno, Yasuharu Sato, Koh-ichi Ohshima, Katsuyoshi Takata, Tomoko Miyata-Takata, Mai Takeuchi, Yuka Gion, Tomoyasu Tachibana, Yorihisa Orita, Toshihiro Ito, Steven H. Swerdlow, Tadashi Yoshino

SCIENTIFIC REPORTS 5 13539 2015.8

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

We previously suggested a relationship between ocular immunoglobulin (Ig)G4-related disease (IgG4-RD) and marginal zone lymphomas (MZLs). However, the cytokine background associated with these disorders and whether it differs between ocular adnexal MZLs with (IgG4-associated MZL) and without (IgG4-negative MZL) numerous IgG4(+) plasma cells are unknown. In this study, we identified the mRNA expression pattern of Th2 and regulatory T-cell (Treg) cytokines in IgG4-RD and in IgG4-associated MZL and IgG4-negative MZL using real-time polymerase chain reaction analysis. Ocular IgG4-RD and IgG4-associated MZL exhibited significantly higher expression ratios of interleukin (1Q-4/beta-actin, IL-10/beta-actin, IL-13/beta-actin, transforming growth factor (TGF) beta 1/beta-actin, and FOXP3/beta-actin than did IgG4-negative MZL (p < 0.05). This finding further supports our prior observations that a significant subset of ocular MZLs arises in the setting of IgG4-RD. Furthermore, the presence of a different inflammatory background in IgG4-negative MZLs suggests that IgG4-associated MZLs may have a different pathogenesis. Immunoglobulin (Ig)G4-related

DOI： 10.1038/srep13539

Aggressive Garcin's syndrome by acquired cystic disease of kidney-related renal cell carcinoma in a long-term hemodialytic patient Reviewed

Yuko Kawahara, Kentaro Deguchi, Kota Sato, Nozomi Hishikawa, Syoichiro Kono, Yasuyuki Ohta, Toru Yamashita, Eiko Hayashi, Yasuharu Sato, Koji Abe

JOURNAL OF THE NEUROLOGICAL SCIENCES 355 ( 1-2 ) 216 - 218 2015.8

Cytokeratin-positive fibroblastic reticular cell tumor with follicular dendritic cell features : A case report and review of the literature Reviewed

Naoe Goto, Hisashi Tsurumi, Tsuyoshi Takami, Manabu Futamura, Kasumi Morimitsu, Katsuyoshi Takata, Yasuharu Sato, Tadashi Yoshino, Seiji Adachi, Koshiro Saito, Mitsunori Yamakawa

American Journal of Surgical Pathology 39 ( 4 ) 573 - 580 2015.3

Language：English Publisher：Lippincott Williams and Wilkins

Fibroblastic reticular cell (FRC) neoplasms, which are one of the histiocyte tumor types, are very rare. Here we report a cytokeratin (CK)-positive FRC neoplasm having features of follicular dendritic cells in a 54-year-old woman with right axillary lymph node swelling. The resected lymph node showed multiple nodular aggregations simulating and replacing normal follicles. The tumor cells had a uniform, large and oval to polygonal shape, abundant cytoplasm, and various sizes of nuclei with central eosinophilic nucleoli and coarse nuclear chromatin. They were positive for CK AE1/AE3+CAM5.2, CK7, tenascin C, l-caldesomone, and CD21, weakly positive for S100, and negative for CD1a. Ultrastructurally, the tumor cells had long interdigitating microvillus-like cell processes and oval to elongated vesicular nuclei. In addition, the intercellular spaces contained accumulations of collagen, and some tumor cells had desmosomal-like junctions. These findings suggest that the present case is a CK-positive FRC tumor with follicular dendritic cell features.

DOI： 10.1097/PAS.0000000000000362

葉酸レセプターαは膵癌において高率に発現し予後不良な経過を示す

綾田善行, 平部顕子, 加藤光晴, 高田尚良, 高田友子, 佐藤康晴, 柳井広之, 吉野正

日本病理学会会誌 104 ( 1 ) 516 - 516 2015.3

Interleukin 13-positive mast cells are increased in immunoglobulin G4-related sialadenitis Reviewed

Mai Takeuchi, Kyotaro Ohno, Katsuyoshi Takata, Yuka Gion, Tomoyasu Tachibana, Yorihisa Orita, Tadashi Yoshino, Yasuharu Sato

SCIENTIFIC REPORTS 5 2015.1

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

Interleukin (IL)-13 is a T helper 2 (Th2) cytokine that plays important roles in the pathogenesis of asthma. IL-13 induces hypersensitivity of the airways, increased mucous production, elevated serum immunoglobulin (Ig) E levels, and increased numbers of eosinophils. Many patients with IgG4-related disease have allergic backgrounds and show elevated serum IgE levels and an increase in the number of eosinophils. Upregulation of Th2/regulatory T (Treg) cytokines, including IL-13, has been detected in affected tissues of patients with IgG4-related disease. We previously reported that mast cells might be responsible for the production of the Th2/Treg cytokines IL-4, IL-10, and transforming growth factor (TGF)-beta 1 in IgG4-related disease. In this study, immunohistochemical analysis showed increased numbers of IL-13-positive mast cells in IgG4-related disease, which suggests that mast cells also produce IL-13 and contribute to elevation of serum IgE levels and eosinophil infiltration in IgG4-related disease.

DOI： 10.1038/srep07696

Diffuse large B-cell lymphoma of the lacrimal sac arising from a patient with IgG4-related disease. Reviewed International journal

Hidenori Marunaka, Yorihisa Orita, Tomoyasu Tachibana, Kentaro Miki, Takuma Makino, Tadashi Yoshino, Kazunori Nishizaki, Yasuharu Sato

Modern rheumatology 28 ( 3 ) 559 - 563 2015

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

A rare case of diffuse large B-cell lymphoma (DLBCL) possibly induced by IgG4-related disease is described. A 78-year-old woman was presented with a mass of the right lacrimal sac that extended to the inferior nasal meatus through the nasolacrimal duct. Pathological diagnosis was DLBCL with diffuse distribution of IgG4 + cells in the background of this lesion. The chronic inflammatory state of IgG4-related disease could have caused the development of DLBCL.

DOI： 10.3109/14397595.2015.1131353

How long should we continue S-1 as adjuvant chemotherapy for squamous cell carcinoma of the head and neck? Reviewed

Misato Hirai, Yorihisa Orita, Soshi Takao, Tomoyasu Tachibana, Hidenori Marunaka, Seiichiro Makihara, Kentaro Miki, Yasuyuki Noyama, Sayaka Fuji, Akiko Torigoe, Yasuharu Sato, Kazunori Nishizaki

ACTA OTO-LARYNGOLOGICA 135 ( 10 ) 1079 - 1085 2015

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS LTD

Conclusion: It appears that patients with SCCHN should be recommended to take S-1 for more than 1 year and, if possible, more than 2 years, as adjuvant chemotherapy for SCCHN. Objectives: There is no established consensus on the duration of administration of S-1 as adjuvant chemotherapy for squamous cell carcinoma of the head and neck (SCCHN). Since it might be difficult to undergo prospective randomized study to identify the optimal duration of the administration period of S-1 without a standard, the authors have undergone a retrospective clinical study to decide the tentative standard of therapeutic duration of S-1 as adjuvant chemotherapy for SCCHN. Methods: The clinical records of 89 patients with SCCHN who underwent adjuvant chemotherapy with S-1 were investigated. Results: The median duration of S-1 administration as adjuvant chemotherapy for SCCHN was 7 months (range = 0.1-58 months). Disease-free survivals (DFSs) were generally longer when S-1 administration periods were longer. After adjusting for prognostic factors, S-1 administration periods of 24 months or longer showed significantly lower hazard ratios (HRs) than 0-12 months.

DOI： 10.3109/00016489.2015.1049664

HHV8-Negative Body Cavity-Based Lymphoma Is Mature Large B-Cell Lymphoma That Affects Elderly and Displays Favorable Prognosis: A Multi-Center Retrospective Study of 50 Patients in Japan

Daisuke Kaji, Yasunori Ota, Yasuharu Sato, Koji Nagafuji, Masataka Okamoto, Yasushi Terasaki, Naoko Tsuyama, Tomohiro Kinoshita, Shuichi Taniguchi, Koichi Ohshima, Koji Izutsu

BLOOD 124 ( 21 ) 2014.12

Prognostic factors and effects of early surgical drainage in patients with peritonsillar abscess Reviewed

Tomoyasu Tachibana, Yorihisa Orita, Iku Abe-Fujisawa, Yuya Ogawara, Yuko Matsuyama, Aiko Shimizu, Michihiro Nakada, Yasuharu Sato, Kazunori Nishizaki

JOURNAL OF INFECTION AND CHEMOTHERAPY 20 ( 11 ) 722 - 725 2014.11

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

Peritonsillar abscess is a frequently encountered otorhinolaryngological emergency, but the characteristics of patients with this disease have not been described in detail. The objective of this study was to delineate prognostic factors associated with peritonsillar abscess and the effects of early surgical drainage for the treatment of peritonsillar abscess. We conducted a retrospective analysis of the medical records of 240 consecutive patients with PTA during the period from 2007 to 2013. Univariate analysis indicated that the period between symptom onset and relief was significantly longer in patients with high levels of C-reactive protein (CRP) (>8.53 mg/dL, p = 0.0073) and without early surgical drainage of pus (p < 0.0001). Multivariate analysis identified both of these values as independently associated with longer duration of symptoms (high CRP, P < 0.0001; no early drainage, P < 0.0001). Univariate analysis indicated that the duration between symptom onset and complete recovery from the disease was significantly longer with age >= 40 years (P = 0.0004), no history of recurrent tonsillitis (P = 0.022), high CRP level (P = 0.0017), and no early surgical drainage of the abscess (P = 0.0014). Multivariate analysis identified older age (P = 0.0004), high CRP level (P = 0.0001), and no early drainage (P < 0.0001) as independently associated with longer duration between symptom onset and complete recovery. Early surgical drainage of the abscess is important for the treatment of peritonsillar abscess. Patients >40 years old with peritonsillar abscess and high CRP levels should be recognized as a high-risk group. (C) 2014, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jiac.2014.07.018

A case of diffuse large B-cell lymphoma transformed from primary duodenal follicular lymphoma Reviewed

Tomoko Miyata-Takata, Katsuyoshi Takata, Yasuharu Sato, Kohei Taniguchi, Yuka Takahashi, Nobuya Ohara, Tadashi Yoshino

PATHOLOGY INTERNATIONAL 64 ( 10 ) 527 - 532 2014.10

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Primary intestinal follicular lymphoma (FL) is a variant of FL characterized by frequent duodenal involvement and a very indolent clinical behavior without therapy. Unlike nodal FL, there have been no reports of histologic transformation (HT) or death attributable to primary intestinal FL. Here, we report the first case of primary duodenal FL showing HT. A Grade 1 FL in the duodenum was incidentally detected in a 73-year-old man. A watch-and-wait strategy was adopted because the disease was stage IE. Six months later, bone marrow involvement was suspected. The intestinal lesions had not changed during the first year since the initial diagnosis. Sixty-two months after the initial diagnosis, a biopsy specimen showed diffuse large B-cell lymphoma (DLBCL). A perforation of the intestine occurred before chemotherapy was started. Partial resection was performed and subsequent chemotherapy was administered. The clone of the initial FL and DLBCL were identical according to PCR analysis, indicating that the primary intestinal FL had transformed into DLBCL. Although HT is rare, it could occur in some patients with primary intestinal FL. Based on this case, it may be necessary to re-evaluate the clinical watch-and-wait strategy for primary intestinal FL in some patients.

DOI： 10.1111/pin.12197

Does HMGB1 predict occult neck lymph node metastasis in early tongue carcinoma? A case-control study of 26 patients Reviewed

H. Hanakawa, Y. Orita, Y. Sato, M. Takeuchi, S. Takao, K. Ohno, T. Kohno, N. Iwaki, H. Marunaka, R. Tamamura, M. Nishibori, H. Nagatsuka, K. Nishizaki, T. Yoshino

JOURNAL OF LARYNGOLOGY AND OTOLOGY 128 ( 10 ) 926 - 931 2014.10

Language：English Publishing type：Research paper (scientific journal) Publisher：CAMBRIDGE UNIV PRESS

Objective: This study examined whether the occurrence of late neck metastasis in early tongue squamous cell carcinoma can be predicted by evaluating HMGB1 (high mobility group box 1) expression in the primary lesion.
Methods: A case-control study was conducted. The cases comprised 10 patients with late neck metastasis. The controls consisted of 16 patients without recurrence. All were examined immunohistochemically for HMGB1 protein expression. The odds ratio for late neck metastasis in relation to HMGB1 was estimated.
Results: Results for HMGB1 were dichotomised into positive staining scores (score, 5-7) and negative scores (0-4). Six cases (60 per cent) and four controls (25 per cent) were HMGB1-positive. Although no significant result was seen, compared with HMGB1-negative patients the odds ratio for late neck metastasis in HMGB1-positive patients was 3.8 (95 per cent confidence interval, 0.6-26.5) after adjusting for other factors.
Conclusion: In the present study, immunohistochemical study of HMGB1 in early tongue squamous cell carcinoma did not appear to be very useful for predicting occult neck metastasis. Further study is necessary to clarify the relationship between HMGB1 expression and late neck metastasis in early tongue squamous cell carcinoma.

DOI： 10.1017/S0022215114001819

Mantle cell lymphoma with a unique pattern of CD5 expression: a case report with review of the literatures Reviewed

Toshiki Yamada, Naoe Goto, Hisashi Tsurumi, Katsuyoshi Takata, Yasuharu Sato, Tadashi Yoshino, Hisataka Moriwaki, Yusuke Kito, Tamotsu Takeuchi, Hitoshi Iwata

MEDICAL MOLECULAR MORPHOLOGY 47 ( 3 ) 169 - 175 2014.9

Language：English Publisher：SPRINGER JAPAN KK

Mantle cell lymphoma (MCL) is a unique subtype of B-cell non-Hodgkin's lymphoma characterized by chromosomal translocation t(11;14)(q13;q32), positive CD5, and nuclear cyclin D1 overexpression with unfavorable prognosis. We report herein a case of MCL in a 73-year-old male diagnosed with diffuse large B-cell lymphoma (ileal tumor) at another hospital, who subsequently relapsed with CD5-negative MCL. At the 1st relapse, he developed neck lymph node swelling, of which biopsy showed proliferation of atypical large pleomorphic cells with CD5-negativity by both immunohistochemistry and flow cytometry. At the 2nd relapse, he again developed an ileal tumor, of which biopsy showed positivity for CD5, CD20, and cyclin D1. In MCL, CD5-negative expression has sometimes been reported as having pleomorphic and blastoid variants. The present case was also histologically the pleomorphic type, but the CD5 expression changed from negative at the onset and the 1st relapse to positive at the 2nd relapse. This is a rare and interesting case because of the different expression of CD5 at all stage. This phenomenon made the diagnosis of MCL difficult.

DOI： 10.1007/s00795-013-0060-x

Detection of T-cell receptor gamma gene rearrangement in paraffin-embedded T or natural killer/T-cell lymphoma samples using the BIOMED-2 protocol Reviewed

Tomoko Miyata-Takata, Katsuyoshi Takata, Sachiko Yamanouchi, Yasuharu Sato, Mai Harada, Takashi Oka, Takehiro Tanaka, Yoshinobu Maeda, Mitsune Tanimoto, Tadashi Yoshino

LEUKEMIA & LYMPHOMA 55 ( 9 ) 2161 - 2164 2014.9

Language：English Publishing type：Research paper (scientific journal) Publisher：INFORMA HEALTHCARE

While the use of polymerase chain reaction (PCR)-based clonality analysis of formalin-fixed paraffin-embedded (FFPE) tissue has recently become widespread, the detection sensitivity for lymphoma subtypes using FFPE samples is not well known. Here, we analyzed T-cell receptor gamma chain (TCRG) gene rearrangement clonality in 100 cases of T-or natural killer (NK)/T-cell lymphoma and examined detection sensitivity according to lymphoma subtype. Clonality was detected in approximately 80% of the major T-cell lymphoma subtypes: peripheral T-cell lymphoma, not otherwise specified, 84% (21/25 cases); angioimmunoblastic T-cell lymphoma, 71% (15/21 cases); and adult T-cell leukemia/lymphoma, 80% (8/10 cases). The number of clonal peaks differed according to subtype. TCRG gene rearrangement was not detected in 63 cases of B-cell lymphoma or reactive lesions. Thus, clonality analysis can effectively and reliably detect TCRG gene rearrangement in T-cell lymphoma cases and could, therefore, be a useful diagnostic tool in routine practice.

DOI： 10.3109/10428194.2013.871634

Regulatory T-cell infiltration in tongue squamous cell carcinoma

Hiroyuki Hanakawa, Yorihisa Orita, Yasuharu Sato, Mai Takeuchi, Kyotaro Ohno, Yuka Gion, Kiyoaki Tsukahara, Ryo Tamamura, Toshihiro Ito, Hitoshi Nagatsuka, Kazunori Nishizaki, Tadashi Yoshino

ACTA OTO-LARYNGOLOGICA 134 ( 8 ) 859 - 864 2014.8

Language：English Publishing type：Research paper (scientific journal) Publisher：INFORMA HEALTHCARE

Conclusion: In tongue squamous cell carcinoma (SCC), high levels of regulatory T-cell (Treg) infiltration in tumor nests are observed in the cases with poor prognosis. Objectives: The role of Tregs in head and neck cancers remains unclear. The aim of this study was to observe the distribution of Tregs in different stages of tongue SCC and estimate the effects on prognosis. Methods: Thirty-four cases with tongue SCC were examined immunohistochemically for CD4, CD8, and Forkhead box P3 (Foxp3). Immunoreactive cells were counted in cancer stroma and nest regions, and relationships between cell numbers and disease-free survival rates were analyzed. Results: In the 34 cases, univariate analysis for disease-free survival indicated high-level infiltration of Tregs (CD4(+)Foxp3+) into both cancer nests and stroma and presence of helper T (CD4(+)Foxp3-) cells in cancer stroma as potential predictors of significantly worse prognosis. In early-stage cases (stage I/II), high-level infiltration of Tregs in cancer nests correlated significantly with poor disease- free survival rate. Multivariate analysis for disease-free survival found no independent variables.

DOI： 10.3109/00016489.2014.918279

T helper 2 and regulatory T-cell cytokine production by mast cells: a key factor in the pathogenesis of IgG4-related disease

Mai Takeuchi, Yasuharu Sato, Kyotaro Ohno, Satoshi Tanaka, Katsuyoshi Takata, Yuka Gion, Yorihisa Orita, Toshihiro Ito, Tomoyasu Tachibana, Tadashi Yoshino

MODERN PATHOLOGY 27 ( 8 ) 1126 - 1136 2014.8

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

IgG4-related disease is a systemic disorder with unique clinicopathological features and uncertain etiological features and is frequently related to allergic disease. T helper 2 and regulatory T-cell cytokines have been reported to be upregulated in the affected tissues; thus, the production of these cytokines by T helper 2 and regulatory T cells has been suggested as an important factor in the pathogenesis of IgG4-related disease. However, it is not yet clear which cells produce these cytokines in IgG4-related disease, and some aspects of the disorder cannot be completely explained by T-cell-related processes. To address this, we analyzed paraffin-embedded sections of tissues from nine cases of IgG4-related submandibular gland disease, five cases of submandibular sialolithiasis, and six cases of normal submandibular gland in order to identify potential key players in the pathogenesis of IgG4-related disease. Real-time polymerase chain reaction analysis confirmed the significant upregulation of interleukin (IL)4, IL10, and transforming growth factor beta 1 (TGF beta 1) in IgG4-related disease. Interestingly, immunohistochemical studies indicated the presence of mast cells expressing these cytokines in diseased tissues. In addition, dual immunofluorescence assays identified cells that were double-positive for each cytokine and for KIT, which is expressed by mast cells. In contrast, the distribution of T cells did not correlate with cytokine distribution in affected tissues. We also found that the mast cells were strongly positive for IgE. This observation supports the hypothesis that mast cells are involved in IgG4-related disease, as mast cells are known to be closely related to allergic reactions and are activated in the presence of elevated non-specific IgE levels. In conclusion, our results indicate that mast cells produce T helper 2 and regulatory T-cell cytokines in tissues affected by IgG4-related disease and possibly have an important role in disease pathogenesis.

DOI： 10.1038/modpathol.2013.236

Clinicopathological analysis of 17 primary cutaneous T-cell lymphoma of the gamma delta phenotype from Japan

Yuka Takahashi, Katsuyoshi Takata, Seiichi Kato, Yasuharu Sato, Naoko Asano, Tetsuro Ogino, Kimio Hashimoto, Yukie Tashiro, Shogo Takeuchi, Taro Masunari, Yasushi Hiramatsu, Yoshinobu Maeda, Mitsune Tanimoto, Tadashi Yoshino

CANCER SCIENCE 105 ( 7 ) 912 - 923 2014.7

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Primary cutaneous gamma delta T-cell lymphoma (PCGD-TCL) is an aggressive lymphoma consisting of clonal proliferation of mature activated gamma delta T-cells of a cytotoxic phenotype. Because primary cutaneous gamma delta T-cell lymphoma is a rare disease, there are few clinicopathological studies. In addition, T-cell receptor (TCR) gamma delta cells are typically immunostained in frozen sections or determined by TCR beta negativity. We retrospectively analyzed 17 primary cutaneous T-cell lymphomas of the gamma delta phenotype (CTCL-gamma delta) in a clinicopathological and molecular study using paraffin-embedded sections. Among 17 patients, 11 had CTCL-gamma delta without subcutaneous panniculitis-like T-cell lymphoma (SPTCL) features and six had CTCL-gamma delta with SPTCL features. Immunophenotypically, some significant differences were found in CD8 and CD56 positivity between our patient series of CTCL-gamma delta patients with SPTCL features and SPTCL-gamma delta patients described in the previous literature. A univariate analysis of 17 CTCL-gamma delta patients showed that being more than 60 years old, presence of visceral organ involvement, and small-to-medium cell size were poor prognostic factors. In addition, the 5-year overall survival rate was 42.4% for the CTCL-gamma delta patients without SPTCL features and 80.0% for those with SPTCL features. Consequently, there was a strikingly significant difference in overall survival among SPTCL, CTCL-gamma delta with SPTCL features and CTCL-gamma delta without SPTCL features (P = 0.0005). Our data suggests that an indolent subgroup may exist in CTCL-gamma delta. Studies on more cases, including those from other countries, are warranted to delineate the clinicopathological features and the significance in these rare lymphomas.

DOI： 10.1111/cas.12439

Epstein-Barr Virus-infected Cells in IgG4-related Lymphadenopathy With Comparison With Extranodal IgG4-related Disease

Mai Takeuchi, Yasuharu Sato, Hiroshi Yasui, Hiroaki Ozawa, Kyotaro Ohno, Katsuyoshi Takata, Yuka Gion, Yorihisa Orita, Tomoyasu Tachibana, Tomoo Itoh, Naoko Asano, Shigeo Nakamura, Steven H. Swerdlow, Tadashi Yoshino

AMERICAN JOURNAL OF SURGICAL PATHOLOGY 38 ( 7 ) 946 - 955 2014.7

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

IgG4-related lymphadenopathy with increased numbers of Epstein-Barr virus (EBV)-infected cells has been reported but not fully described. We analyzed 31 cases of IgG4-related lymphadenopathy and 24 cases of extranodal IgG4-related diseases for their possible relationship with EBV. Other types of reactive lymph nodes (22) and angioimmunoblastic T-cell lymphoma (AITL) (10) were also studied for comparison. EBV-encoded RNA (EBER) in situ hybridization revealed EBER+ cells in 18 of 31 cases (58%) of IgG4-related lymphadenopathy. Increased EBER+ cells were found in only 4 of 22 (18.1%) non-IgG4-related reactive lymphoid hyperplasia in patients of a similar age (P = 0.002) and in only 5 of 24 (21%) extranodal IgG4-related biopsies (P = 0.006). Interestingly, all patients with EBER+ progressively transformed germinal center-type IgG4-related lymphadenopathy had systemic lymphadenopathy and/or extranodal involvement. AITL also is associated with EBV, and IgG4-related lymphadenopathy sometimes mimics the morphology of AITL; however, the number of IgG4(+) cells in AITL was significantly less than that in IgG4-related lymphadenopathy (P < 0.001). Increased numbers of regulatory T cells are seen in IgG4-related disease; however, there was not a significant difference between the EBER+ and EBER- cases. In conclusion, the presence of increased numbers of EBV-infected cells in IgG4-related lymphadenopathy, compared with other reactive lymphadenopathy or extranodal IgG4-related disease, suggests that there may be a relationship at least between nodal IgG4-related disease and EBV. It is important to avoid overdiagnosing these cases as malignant lymphomas or EBV-related lymphoproliferative disorders.

DOI： 10.1097/PAS.0000000000000206

Low-grade B-cell lymphoma presenting primarily in the bone marrow

Kayoko Iwatani, Katsuyoshi Takata, Yasuharu Sato, Tomoko Miyata-Takata, Noriko Iwaki, Wei Cui, Seiko Sawada-Kitamura, Hiroshi Sonobe, Maiko Tamura, Katsuhiko Saito, Katsuya Miyatani, Rie Yamasaki, Ichiro Yamadori, Nobuharu Fujii, Yasushi Terasaki, Yoshinobu Maeda, Mitsune Tanimoto, Naoya Nakamura, Tadashi Yoshino

HUMAN PATHOLOGY 45 ( 7 ) 1379 - 1387 2014.7

Language：English Publishing type：Research paper (scientific journal) Publisher：W B SAUNDERS CO-ELSEVIER INC

Cases of low-grade B-cell lymphoma presenting primarily in the bone marrow are rare, and its clinicopathology remains unclear. We retrospectively examined patients with low-grade B-cell lymphoma presenting primarily in the bone marrow. Fourteen patients met the inclusion criteria, including 5 with lymphoplasmacytic lymphoma (LPL), 3 with chronic lymphocytic leukemia/small lymphocytic lymphoma, 2 with follicular lymphoma (FL), and 4 with low-grade B-cell lymphoma not otherwise specified (LGBCL-NOS). The median age was 69.5 years (range, 42-89 years), and a slight male predominance was noted (9 men and 5 women, 1.8: 1). Immunohistochemically, all cases were positive for CD20. One case was positive for CD138. Both cases of FL were positive for CD10 and B-cell lymphoma 2 (BCL-2), and immunoglobulin heavy locus (IgH)/B-cell lymphoma 2 rearrangement was observed by fluorescence in situ hybridization. The myeloid differentiation primary response gene (88) leucine to proline mutation was observed in 3 of 5 LPL, 1 of 2 FL, and 2 of 4 LGBCL-NOS patients. Paraproteinemia was observed in 10 patients; IgM and IgG paraproteinemia were observed in 6 and 3 patients, respectively. In this patient series, 3 patients had died at a median follow-up of 36.5 months; the cause of death of 1 LPL patient was malignant lymphoma itself. Thus, low-grade B-cell lymphoma presenting primarily in the bone marrow has various subtypes, and approximately one-third of the patients had LGBCL-NOS. The immunophenotypic features and myeloid differentiation primary response gene (88) leucine to proline mutation data of LGBCL-NOS suggested that some cases present with characteristics similar to those of LPL or marginal zone lymphoma. (C) 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2014.02.010

Duodenal follicular lymphoma: Comprehensive gene expression analysis with insights into pathogenesis

Katsuyoshi Takata, Motohiko Tanino, Daisuke Ennishi, Akira Tari, Yasuharu Sato, Hiroyuki Okada, Yoshinobu Maeda, Naoe Goto, Hiroshi Araki, Mai Harada, Midori Ando, Masaya Iwamuro, Mitsune Tanimoto, Kazuhide Yamamoto, Randy D. Gascoyne, Tadashi Yoshino

CANCER SCIENCE 105 ( 5 ) 608 - 615 2014.5

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Follicular lymphoma (FL) of the gastrointestinal tract, particularly duodenal follicular lymphoma (DFL), is a rare variant of FL with indolent clinical behavior, and this disease is included in the 2008 World Health Organization classification system. In contrast to nodal follicular lymphoma (NFL), DFL occurs most frequently in the second part of the duodenum, lacks follicular dendritic cell meshworks and has memory B-cell characteristics. However, its molecular pathogenesis is still unclear. In the present study, we examined 10 DFL, 18 NFL and 10 gastric MALT lymphoma samples using gene expression analysis. Quantitative RT-PCR experiments and immunohistochemical analysis for 72 formalin-fixed, paraffin-embedded tissues from an independent series, including 32 DFL, 19 gastric MALT lymphoma and 27 NFL samples, were performed for validation of microarray data. Gene expression profiles of the three lymphoma types were compared using 2918 differentially expressed genes (DEG) and results suggested that DFL shares characteristics of MALT lymphoma. Among these DEG, CCL20 and MAdCAM-1 were upregulated in DFL and MALT but downregulated in NFL. In contrast, protocadherin gamma subfamily genes were upregulated in DFL and NFL. Quantitative RT-PCR and immunohistochemical studies demonstrated concordant results. Double immunofluorescence studies revealed that CCL20 and CCR6 were co-expressed in both DFL and MALT. We hypothesize that increased expression of CCL20 and MAdCAM-1 and co-expression of CCL20 and CCR6 may play an important role in tumorigenesis.

DOI： 10.1111/cas.12392

CHARACTERISTIC PATHOLOGY OF IgG4-RELATED KIDNEY DISEASE

Nagata Michio, Hara Satoshi, Mizushima Ichiro, Kawano Mitsuhiro, Saeki Takako, Ubara Yoshifumi, Ohara Nobuya, Sato Yasuharu, Yamada Kazunori, Nakashima Hitoshi, Nishi Shinichi, Yamaguchi Yutaka, Hisano Satoshi, Yamanaka Nobuaki, Saito Takao

NEPHROLOGY 19 11 - 12 2014.5

Novel and simple prognostic index for nasal natural killer/T- cell lymphoma

Hiroyuki Hanakawa, Yorihisa Orita, Yasuharu Sato, Soshi Takao, Hidenori Marunaka, Tokiwa Morishita, Yasuhiko Yamashita, Yasutaka Hori, Shuhei Domae, Ikuo Inokuchi, Seiko Akagi, Eisei Kondo, Noriko Iwaki, Kana Motomiya, Hirokazu Okumura, Tadashi Yoshino, Kazunori Nishizaki

HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK 36 ( 4 ) 551 - 556 2014.4

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

BackgroundFew studies have investigated the prognostic factors for nasal natural killer (NK)/T-cell lymphoma.
MethodsThis was a retrospective multicenter clinical study. The clinical records of 36 patients with nasal NK/T-cell lymphoma who had been first treated between 1996 and 2011 were collected from 12 hospitals.
ResultsHigh serum levels of C-reactive protein (1.0 mg/dL), lactate dehydrogenase (350 IU/L), and soluble interleukin-2 receptor (sIL-2R; 600 U/mL) were associated with worse prognosis. A prognostic score was devised by totaling the number of these 3 predictors: 0 or 1 = score 0; and 2 or 3 = score 1. As for tumor invasion, local invasion beyond the nasal cavity was associated with poor prognosis, and a prognostic score was devised as: tumor restricted to nasal cavity, yes = score 0; no = score 1. A novel prognostic index (NPI) was established based on these scores from 0 to 2. Disease-specific survival rates at 5 years were: 90.0% for NPI = 0; 29.3% for NPI = 1; and 0.0% for NPI = 2.
ConclusionOur NPI is valid for anticipating prognosis of nasal NK/T-cell lymphoma. (c) 2013 Wiley Periodicals, Inc. Head Neck36: 551-556, 2014

DOI： 10.1002/hed.23322

Leriche operation for parotid gland pathology

Yorihisa Orita, Toshiaki Ogawara, Ryutaro Endo, Sayaka Fuji, Kentaro Miki, Misato Hirai, Yohei Noda, Hidenori Marunaka, Tomoyasu Tachibana, Yasuharu Sato, Kazunori Nishizaki

ACTA OTO-LARYNGOLOGICA 134 ( 4 ) 413 - 415 2014.4

Systemic IgG4-related disease with extensive peripheral nerve involvement that progressed from localized IgG4-related lymphadenopathy: an autopsy case

Masayoshi Fujii, Yasuharu Sato, Nobuya Ohara, Kenji Hashimoto, Haruhiko Kobashi, Yoshinobu Koyama, Tadashi Yoshino

DIAGNOSTIC PATHOLOGY 9 ( 1 ) 41 2014.2

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

A 77-year-old man, with a lengthy medical history of chronic dysuria, constipation, hypertension, myocardial infarction, and a submandibular lymphadenopathy that was excised 3 years ago, was hospitalized due to elevated liver enzyme levels. He demonstrated hypergammaglobulinemia, hyperproteinemia, high levels of IgG and IgG4, eosinophilia, sclerosing cholangitis, and retroperitoneal fibrosis. He was diagnosed with IgG4-related disease (IgG4-RD). While hospitalized, he had several episodes of syncope while standing and was diagnosed with autonomic nerve dysfunction. Thirty days after hospitalization, he died of nonocclusive mesenteric ischemia (NOMI). Post-mortem, his submandibular lymphadenopathy lesion was diagnosed with progressively transformed germinal center (PTGC)-type IgG4-related lymphadenopathy. At autopsy, small and large intestines showed mucosal necrosis and the wall muscles of the transverse to sigmoid colon were necrotic. The sigmoid colon was fibrotic and infiltrated with numerous IgG4(+) plasma cells and eosinophils; infiltration into Auerbach's plexus was also observed. The IgG4-RD lesions were also detected in the mesentery of the sigmoid colon, retroperitoneal soft tissue, abdominal aorta, liver, extrahepatic bile duct, bilateral lungs, bilateral kidneys, urinary bladder, prostate, epicardium, bilateral coronary arteries, and lymph nodes. Interestingly, infiltration into the lesions was most notable around the peripheral nerves in every organ. Thus, this case describes an IgG4-RD that progressed from PTGC-type IgG4-related lymphadenopathy to systemic IgG4-RD, suggesting that IgG4-RD may affect many organs through peripheral nerve involvement. Virtual slide: The virtual slides for this article can be found here: http://www.diagnosticpathology. diagnomx.eu/ vs/ 9995992971155224.

DOI： 10.1186/1746-1596-9-41

Lymph node lesions Reviewed

Yasuharu Sato, Tadashi Yoshino

Igg4-Related Disease 187 - 193 2014.1

Language：English Publishing type：Part of collection (book) Publisher：Springer Japan

Pathological examination of involved tissue occupies an extremely important place in establishing the diagnosis of IgG4-related disease (IgG4-RD). However, the histological picture in IgG4-RD can vary significantly from organ to organ in this disease even while adhering to basic tenets. Consequently, the pathological diagnosis of this condition is often challenging even in the setting of adequate tissue specimens. This is particularly true with regard to the assessment of lymph nodes in patients who may have IgG4-RD. The diagnosis of IgG4-related lymphadenopathy is complicated owing to a great histological diversity. At least five histological subtypes have already been identified. Lymph node biopsies are often performed because of suspicion that the lymphadenopathy might reflect a malignant lymphoma or other lymphoproliferative disorder. In general, if the IgG4+/IgG+ plasma cell ratio is ≥40 %, the possibility of IgG4-RD is high, but cases of patients with diagnosis other than IgG4-RD who fulfill this criterion are well described in the literature. In practice, patients with hyper-interleukin (IL)-6 syndromes such as multicentric Castleman’s disease, rheumatoid arthritis, and other immune-mediated conditions frequently show lymph node involvement and often fulfill the diagnostic criteria for IgG4-RD. For this reason, it is important that the diagnosis of IgG4-RD relies not only on the pathological findings, but be the result of a careful clinicopathologic collaboration that considers the overall clinical context and appropriate serologic (in particular, serum IL-6, C-reactive protein, IgG4 concentration) and radiologic data as well.

DOI： 10.1007/978-4-431-54228-5_27

IgG4-related disease involving the sclera

Kyotaro Ohno, Yasuharu Sato, Koh-ichi Ohshima, Katsuyoshi Takata, Midori Ando, Lamia Abd Al-Kader, Noriko Iwaki, Mai Takeuchi, Yorihisa Orita, Tadashi Yoshino

MODERN RHEUMATOLOGY 24 ( 1 ) 195 - 198 2014.1

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

A 49-year-old female patient previously treated for scleritis and uveitis-induced cataract in the right eye presented with a subretinal white lesion in the same eye. With a preliminary diagnosis of choroidal tumor, enucleation of the eyeball was performed in accordance with the patient's request. Histologic and immunohistologic examinations were consistent with immunoglobulin G4-related disease. The case demonstrates that it is important to consider IgG4-related disease in the differential diagnosis of an intraocular tumor.

DOI： 10.3109/14397595.2013.852842

Characteristic ultrasound features of mucosa-associated lymphoid tissue lymphoma of the salivary and thyroid gland

Yorihisa Orita, Yasuharu Sato, Nobuhiko Kimura, Hidenori Marunaka, Tomoyasu Tachibana, Yasuhiko Yamashita, Hiroyuki Hanakawa, Tadashi Yoshino, Kazunori Nishizaki

ACTA OTO-LARYNGOLOGICA 134 ( 1 ) 93 - 99 2014.1

Language：English Publishing type：Research paper (scientific journal) Publisher：INFORMA HEALTHCARE

Conclusion: The characteristic ultrasound appearance of mucosa-associated lymphoid tissue (MALT) lymphoma of the head and neck provides diagnostic information regarding masses or swellings in the head and neck region. Objectives: There are only a few reports about ultrasound features of malignant lymphoma (ML) of the head and neck. We have noticed that the ultrasound appearances of cases with MALT lymphoma resembled each other even when the appearances of other images like computed tomography were absolutely different. The objective of this study was to delineate the reliability of this characteristic ultrasound appearance of MALT lymphoma of the head and neck. Methods: The ultrasound examinations of 30 patients with histopathologically proven primary ML of the head and neck (15 cases of MALT) were reviewed. The ultrasound results of each case were independently compared to the results of the histopathological examination. Results: Two ultrasound patterns were observed for MALT lymphoma. The first was characterized by a marked hypoechoic area with interspersed linear echogenic strands (linear echogenic strands pattern), and the second was characterized by multiple, relatively large, hypoechoic segments (segmental pattern). Histopathologically, these patterns could be explained on the basis of the expansion of lymphoma cells demarcated by narrow or wide fibrous bands.

DOI： 10.3109/00016489.2013.831994

A condition closely mimicking IgG4-related disease despite the absence of serum IgG4 elevation and IgG4-positive plasma cell infiltration.

Hara S, Kawano M, Mizushima I, Yamada K, Fujita K, Harada K, Matsumura M, Yamagishi M, Sato Y, Yamaguchi Y, Nakanuma Y, Nagata M

Modern Rheumatology 2014

Simultaneous immunostaining with anti-S100P and anti-SV40 antibodies revealed the origin of BK virus-infected decoy cells in voided urine samples.

Ariyasu S, Yanai H, Sato M, Shino Y, Taniguchi K, Yamadori I, Miki Y, Sato Y, Yoshino T, Takahashi K

Cytopathology 26 ( 4 ) 250 - 255 2014

IgG4-related renal disease: clinical and pathological characteristics

Naoto Kuroda, Tomoya Nao, Hideo Fukuhara, Takashi Karashima, Keiji Inoue, Yoshinori Taniguchi, Mai Takeuchi, Yoh Zen, Yasuharu Sato, Kenji Notohara, Tadashi Yoshino

INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 7 ( 9 ) 6379 - 6385 2014

Language：English Publisher：E-CENTURY PUBLISHING CORP

IgG4-related disease is a recently established systemic condition. Tubulointerstitial nephritis is the most common renal manifestation. Glomerular lesions, particularly membranous glomerulonephritis, can develop simultaneously. Some patients present with serological renal dysfunction associated with elevated IgG or IgE levels and hypocomplementemia, while others are incidentally found to have abnormalities in kidneys on imaging. A majority of patients with IgG4-related kidney disease have similar lesions at other anatomical sites, which help us to suspect this condition. Serum IgG4 elevation (>135 mg/dL) is the most, although not entirely, specific marker for the diagnosis. Imaging findings varies from small nodules to bilateral diffuse abnormalities. In addition to the renal parenchyma, the renal pelvis and perirenal adipose tissue can be affected. Histological features include dense lymphoplasmacytic infiltration, storiform or "bird's eye" fibrosis (highlighted by PAM stain), and IgG4-positive plasma cell infiltration (>10 cells/high-power field and IgG4/IgG-positive cell ratio >40%). Immune complex deposition is detectable in the tubular basement membrane by immunofluorescence and/or electron microscopy. Patients usually respond well to corticosteroids, but highly active diseases may require other immunosuppressive therapies. Further investigations will be required to fully understand pathophysiology underlying this emerging condition.

Pathology of follicular lymphoma.

Takata K, Miyata-Takata T, Sato Y, Yoshino T

Jornal of Clinical Experimental Hematopathology 54 ( 1 ) 3 - 9 2014

Time-lag between symptom onset and laboratory findings in patients with subacute thyroiditis Reviewed

Tachibana T, Orita Y, Ogawara Y, Matsuyama Y, Abe I, Nakada M, Sato Y, Nishizaki K

Auris Nasus Larynx 41 ( 4 ) 369 - 372 2014

Publishing type：Research paper (scientific journal)

Objective: The objective of this study was to delineate the frequency of delayed diagnosis in cases of subacute thyroiditis (SAT) and intervals between onset of clinical symptoms and appearance of abnormal laboratory findings. Methods: We reviewed the medical records of 27 patients (7 men and 20 women) with SAT who visited our hospital between 2007 and 2013. Results: On presentation to the hospital, 5 of 27 SAT cases (18.5%) showed normal laboratory findings. Among these 5 cases, the mean interval between symptom onset and thyrotropin (TSH) suppression was 6.3 weeks, and the mean interval to elevation of fT4 was 6.7 weeks. The longest interval from symptom onset to appearance of an abnormal laboratory finding was 11 weeks. Conclusion: Sometimes time-lag exists between onset of clinical symptoms and the appearance of abnormal laboratory findings in patients with SAT. The possibility of this disease should not be excluded from the differential diagnoses for patients with clinical symptoms consistent with SAT but showing normal laboratory findings. © 2013 Elsevier Ireland Ltd.

DOI： 10.1016/j.anl.2013.11.003

Mucosa-associated lymphoid tissue lymphoma of the thyroid with abundant IgG4-positive plasma cells

Kentaro Miki, Yorihisa Orita, Yasuharu Sato, Iwao Sugitani, Misato Noyama, Sayaka Fuji, Shuhei Domae, Soichiro Nose, Kazuo Hamaya, Tadashi Yoshino, Kazunori Nishizaki

AURIS NASUS LARYNX 40 ( 6 ) 587 - 590 2013.12

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI LTD

A case of thyroidal mucosa-associated lymphoid tissue (MALT) lymphoma mimicking IgG4-related disease is described. A 54-year-old male presented with acute swelling of the anterior neck. Anaplastic thyroid carcinoma (ATC), malignant lymphoma (ML), or acute deterioration of Hashimoto's thyroiditis were initially suspected, and an emergent tracheostomy was required for progressive airway obstruction; a simultaneous biopsy from the thyroid tissue was performed. Histopathologically, the lesion consisted of sclerotic fibrosis and diffuse and dense infiltration by small lymphoid cells without atypia and plasma cells, many of which were IgG4-positive. Blood examination also revealed high serum IgG4 levels. Riedel's thyroiditis was suspected. However, despite medical treatments, a firm swelling of the thyroid still remained. In an in situ hybridization study, IgG4-negative plasma cells showed immunoglobulin light-chain restriction (kappa-monotype), and immunoglobulin heavy (IgH) chain gene monoclonal re-arrangement was detected by polymerase chain reaction. The lesion was finally diagnosed as MALT lymphoma. When IgG4-related disease is suspected, it is important to thoroughly exclude other possibilities. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.anl.2012.12.004

Cutting needle biopsy combined with imrnunohistochemical study of myeloperoxidase for the diagnosis of histiocytic necrotizing lymphadenitis

Hiroyuki Hanakawa, Yorihisa Orita, Yasuharu Sato, Mai Takeuchi, Kyotaro Ohno, Noriko Iwaki, Toshihiro Ito, Kazunori Nishizaki, Tadashi Yoshino

ACTA OTO-LARYNGOLOGICA 133 ( 12 ) 1328 - 1332 2013.12

Language：English Publishing type：Research paper (scientific journal) Publisher：INFORMA HEALTHCARE

Conclusion: Cutting needle biopsy (CNB) combined with immunohistochemical study of myeloperoxidase (MPO) is a useful minimally invasive diagnostic procedure for histiocytic necrotizing lymphadenitis (HNL). Objectives: HNL is mainly diagnosed by pathological findings of open surgical biopsy (OSB) specimens. Recently the appearance of anti-MPO positive histiocytes has been reported as a highly specific pathological diagnosis for HNL. Considering the cosmetic impact and burden on the patients, we performed CNB combined with immunohistochemical study of MPO for the diagnosis of HNL. Few studies have reported the utility of this method in the diagnosis of HNL. Methods: A retrospective study was conducted using clinical data from 20 HNL patients. Results: CNB was performed in 8 patients and OSB in 13 (OSB after CNB in 1). MPO-positive histiocytes were observed in all of the 20 cases. The accuracy of the diagnoses was finally confirmed by the clinical courses in all cases.

DOI： 10.3109/00016489.2013.824112

Factors that make it difficult to diagnose cervical tuberculous lymphadenitis

Tomoyasu Tachibana, Yorihisa Orita, Masayoshi Fujisawa, Michihiro Nakada, Yuya Ogawara, Yuko Matsuyama, Iku Abe, Yasuharu Sato, Koichi Uesaka, Kazunori Nishizaki

JOURNAL OF INFECTION AND CHEMOTHERAPY 19 ( 6 ) 1015 - 1020 2013.12

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

Cervical tuberculous lymphadenitis is mainly diagnosed by analyzing tissue samples obtained by fine-needle aspiration (FNA). However, some cases remain diagnostic challenges even after polymerase chain reaction analysis of FNA specimens. To delineate differences between cases that are relatively easy to diagnose and those for which diagnosis is difficult, 22 patients with cervical tuberculous lymphadenitis were studied retrospectively. FNA tissues were used to diagnose 14 cases (group A), whereas excisional biopsy was required for accurate diagnosis of 8 cases (group B). These two groups were compared with regard to results of blood examinations, ultrasound appearance, and various other procedures required to reach the final diagnosis. The results indicated that diagnosis of cervical tuberculous lymphadenitis was more difficult for patients with lower white blood cell counts, lower serum C-reactive protein levels, and absence of lymph node fusion or abscess formation on ultrasonography. The possibility of tuberculosis as a cause of cervical lymphadenopathy should always be considered, even when the presenting symptoms are not typical of this disease.

DOI： 10.1007/s10156-013-0615-8

Nestin is a wide-spectrum abluminal cell marker of salivary gland tumors

Hiroyuki Yanai, Yasuharu Sato, Hitoshi Nagatsuka, Tadashi Yoshino

PATHOLOGY INTERNATIONAL 63 ( 10 ) 496 - 501 2013.10

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Nestin is an intermediate filament that was first identified in neural progenitor cells. It is expressed in various cell types in the nervous system as well as in other systems. In the present study, we investigated nestin expression in non-neoplastic salivary gland tissue and in salivary gland tumors. In non-neoplastic salivary glands, nestin expression was observed in only a few abluminal cells. In contrast, diffuse nestin staining was observed in the abluminal cells of pleomorphic adenoma (11 of 11 cases), basal cell adenoma (7 of 7 cases), and epithelial-myoepithelial carcinoma (2 of 2 cases). The stromal cells in basal cell adenoma also expressed nestin. In adenoid cystic carcinoma (6 of 7 cases) and polymorphous low-grade adenocarcinoma (3 of 3 cases), nestin positive cells were observed focally. Nestin was not detected in Warthin tumor (6 cases), classical acinic cell carcinoma (2 cases), mucoepidermoid carcinoma (5 cases), or salivary duct carcinoma (4 cases). Because the nestin expression pattern in each histological salivary gland tumor type is unique, nestin could be a very useful abluminal cell marker for the diagnosis of salivary gland tumors.

DOI： 10.1111/pin.12103

B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma without mediastinal disease: mimicking nodular sclerosis classical Hodgkin lymphoma

Noriko Iwaki, Yasuharu Sato, Toshiro Kurokawa, Yoshinobu Maeda, Kyotaro Ohno, Mai Takeuchi, Katsuyoshi Takata, Yorihisa Orita, Shinji Nakao, Tadashi Yoshino

MEDICAL MOLECULAR MORPHOLOGY 46 ( 3 ) 172 - 176 2013.9

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma (BCLu-DLBCL/CHL), also known as gray-zone lymphoma, has overlapping clinical and biological characteristics of both diffuse large B-cell lymphoma and classical Hodgkin lymphoma (CHL). These lymphomas are typically associated with mediastinal disease, and extranodal involvement is rare. In the present report, we describe a case of a 78-year-old woman with BCLu-DLBCL/CHL found to have extranodal lesions and no evidence of mediastinal disease. Although biopsy specimens were histologically similar to nodular sclerosis CHL, the tumor cells were positive for CD30 and mature B-cell markers, such as CD20, CD79a, PAX5, BOB.1, and OCT-2, but negative for CD15. Furthermore, the patient had extranodal lesions and an increased level of soluble IL-2 receptor. These findings are unusual in CHL. Therefore, we diagnosed the patient with BCLu-DLBCL/CHL. She received adriamycin, bleomycin, vincristine, and dacarbazine therapy and exhibited partial response. Some cases without mediastinal disease, such as our case, have been reported; however, these cases are rare and further studies are required.

DOI： 10.1007/s00795-013-0038-8

Distinct morphologic, phenotypic, and clinical-course characteristics of indolent peripheral T-cell lymphoma

Eiko Hayashi, Katsuyoshi Takata, Yasuharu Sato, Yukie Tashiro, Yoshiro Tachiyama, Seiko Sawada-Kitamura, Yasushi Hiramatsu, Shun Sugiguchi, Soichiro Nose, Mitsuyoshi Hirokawa, Midori Ando, Lamia Abd Mader, Yoshinobu Maeda, Mitsune Tanimoto, Tadashi Yoshino

HUMAN PATHOLOGY 44 ( 9 ) 1927 - 1936 2013.9

Language：English Publishing type：Research paper (scientific journal) Publisher：W B SAUNDERS CO-ELSEVIER INC

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) consists of a heterogeneous group of lymphomas. Patients. generally show an aggressive clinical course and very poor outcome. Although the 2008 World Health Organization classification of PTCL-NOS includes 3 variants, low-grade lymphoma is not Included. Of 277 PTCL-NOS cases recorded in our consultation files, we examined the clinicopathologic characteristics of 10 patients with T-cell lymphomas composed of small-sized cells with slight nuclear atypia. Eight patients showed extranodal involvement (5 patients, spleen; 3 patients, thyroid), and 5 patients were at clinical stage I or II. Histologically, all samples presented diffuse infiltrate of small lymphoid cells, with few mitotic figures. Immunohistologically, all samples were positive for CD3, and CD:20 Was detected in 5 samples. All samples showed a low Ki-67 labeling index (mean, 1.05%), and 7 samples were positive for central memory T-cell markers. Clonal T-cell receptor gamma chain and/or alpha-beta chain gene rearrangements were detected in all 10 patients. Five patients received chemotherapy, whereas for 3 patients, treatment consisted only of observation following surgical resection of the spleen or thyroid. Nine patients were alive at a median follow-up time of 19.5 months, whereas 1 patient died of an unrelated disease. The present study strongly indicates that T-cell lymphoma with small-sized lymphoma cells and a low Ki-67 labeling index is a distinct variant. Recognition of this novel lymphoma subtype, which should not be defined merely as PTCL-NOS, should be seriously considered. Crown Copyright (C) 2013 Published by Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2013.03.002

Large Ulceration of the Oropharynx Induced by Methotrexate-Associated Lymphoproliferative Disorders

Hiroyuki Hanakawa, Yorihisa Orita, Yasuharu Sato, Kinya Uno, Kazunori Nishizaki, Tadashi Yoshino

ACTA MEDICA OKAYAMA 67 ( 4 ) 265 - 269 2013.8

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

We present a case of a 67-year-old Japanese man with a serious oropharyngeal ulceration that at first seemed to be destructive malignant lymphoma or oropharyngeal carcinoma. We suspected methotrexate (MTX)-associated lymphoproliferative disorder (LPD) induced by MTX treatment for rheumatoid arthritis (RA). About 3 weeks after simple discontinuation of MTX, complete regression of the disease was observed, confirming our diagnosis.

DOI： 10.18926/AMO/51072

十二指腸濾胞性リンパ腫はAIDの発現を欠くがBACH2の発現を有しmemory B細胞としての性質を有する

高田尚良, 佐藤康晴, 中村直哉, 徳中摩美, 三木由香里, 菊池イアーラ幸江, 五十嵐和彦, 伊藤悦郎, 張替秀雄, 加藤省一, 林詠子, 岡剛史, 星井嘉信, 田利晶, 岡田裕之, Mohamad Abd Alkader Lamia, 前田嘉信, 谷本光音, 木下朝博, 吉野正

岡山医学会雑誌 125 ( 2 ) 103 - 107 2013.8

Duodenal follicular lymphoma lacks AID but expresses BACH2 and has memory B-cell characteristics (vol 26, pg 22, 2013)

Katsuyoshi Takata, Yasuharu Sato, Naoya Nakamura, Mami Tokunaka, Yukari Miki, Yara Yukie Kikuti, Kazuhiko Igarashi, Etsuro Ito, Hideo Harigae, Seiichi Kato, Eiko Hayashi, Takashi Oka, Yoshinobu Hoshii, Akira Tari, Hiroyuki Okada, Lamia Abd Al-Kader, Yoshinobu Maeda, Mitsune Tanimoto, Tomohiro Kinoshita, Tadashi Yoshino

MODERN PATHOLOGY 26 ( 8 ) 1152 - 1152 2013.8

De novo CD5-positive diffuse large B-cell lymphomas show high specificity for cyclin D2 expression

Takuro Igawa, Yasuharu Sato, Katsuyoshi Takata, Noriko Iwaki, Takehiro Tanaka, Naoko Asano, Yoshinobu Maeda, Yorihisa Orita, Naoya Nakamura, Shigeo Nakamura, Tadashi Yoshino

DIAGNOSTIC PATHOLOGY 8 ( 1 ) 81 2013.5

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

D cyclins positively regulate the cell cycle and mediate the pathogenesis of some lymphomas. Cyclin D1 overexpression is the hallmark of mantle cell lymphoma, whereas cyclins D2 and D3 are reportedly not as specific to certain lymphomas as cyclin D1. In this study, cyclin D2 was found to be overexpressed in 98% of de novo CD5-positive diffuse large B-cell lymphomas (DLBCLs) (50/51) and in 28% of CD5-negative DLBCLs (14/51). A statistically significant difference was observed between these two groups (p<0.0001). In contrast, no statistical difference was found in the cyclin D3 expression between CD5-positive (18/51) and CD5-negative (24/51) DLBCLs (p=0.23). Based on these findings, cyclin D2 is therefore considered to be closely associated with de novo CD5-positive DLBCLs. This insight may be useful for overcoming the inferior survival of this aggressive lymphoma. Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1382856320966453

DOI： 10.1186/1746-1596-8-81

Clinicopathologic analysis of IgG4-related skin disease

Yasuharu Sato, Mai Takeuchi, Katsuyoshi Takata, Kyotaro Ohno, Noriko Iwaki, Yorihisa Orita, Naoe Goto, Akira I. Hida, Toshiyuki Iwamoto, Naoko Asano, Toshihiro Ito, Hiroyuki Hanakawa, Hiroyuki Yanai, Tadashi Yoshino

Modern Pathology 26 ( 4 ) 523 - 532 2013.4

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

IgG4-related disease is a recently recognized systemic syndrome characterized by mass-forming lesions with lymphoplasmacytic infiltration, increase in the number of IgG4 + cells in affected tissues and elevation of serum IgG4 levels. In 2009, we were the first to report skin lesions in patients with IgG4-related disease, but no large case series has been reported and clinicopathological findings remain unclear. To clarify these features, we herein report 10 patients (9 men and 1 woman
median age, 64 years
age range, 46-81 years) with IgG4-related skin disease. All patients had erythematous and itchy plaques or subcutaneous nodules on the skin of the head and neck, particularly in the periauricular, cheek, and mandible regions, except for one patient, whose forearm and waist skin were affected. In addition, eight patients had extracutaneous lesions: these were found on the lymph nodes in six patients, the lacrimal glands in three patients, the parotid glands in three patients, and the kidney in one patient. Histologically examined extracutaneous lesions were consistent with IgG4-related disease
five of six lymph node lesions showed progressively transformed germinal centers-type IgG4-related lymphadenopathy. Cases of IgG4-related skin disease were classified into two histological patterns: those exhibiting a nodular dermatitis pattern and those with a subcutaneous nodule pattern. The infiltrate was rich in plasma cells, small lymphocytes, and eosinophils
the majority of the plasma cells were IgG4 +. The IgG4 + cell count was 49-396 per high-power field (mean±s.d., 172±129), with an IgG4 +/IgG + cell ratio ranging from 62 to 92%. Serum IgG4 levels were elevated in all examined patients. In conclusion, patients with IgG4-related skin disease had uniform clinicopathology. Lesions were frequently present on the skin of the periauricular, cheek, and mandible regions, and were frequently accompanied by IgG4-related lymphadenopathy. © 2013 USCAP, Inc. All rights reserved.

DOI： 10.1038/modpathol.2012.196

Clinicopathologic Analysis of Localized Nasal/Paranasal Diffuse Large B-Cell Lymphoma

Hiroko Toda, Yasuharu Sato, Katsuyoshi Takata, Yorihisa Orita, Naoko Asano, Tadashi Yoshino

PLoS ONE 8 ( 2 ) e57677 2013.2

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

Diffuse large B-cell lymphoma (DLBCL) comprises 2 molecularly distinct subgroups of non-germinal center B-cell-like (non-GCB) and germinal center B-cell-like (GCB) DLBCLs, with the former showing relatively poor prognosis. In the present study, we analyzed the clinicopathological features of 39 patients with localized nasal/paranasal DLBCL. Immunohistochemistry-based subclassification revealed that 11 patients (28%) were of the GCB-type according to Hans' algorithm and 11 (28%) were of the GCB-type according to Choi's algorithm. According to both Hans' and Choi's algorithms, the non-GCB type was predominant. Nevertheless, prognosis was good. Overall survival did not differ significantly between the GCB and non-GCB subgroups (Hans' algorithm: p = 0.57, Choi's algorithm: p = 0.99). Furthermore, the prognosis of localized nasal/paranasal DLBCL was better than that of other localized extranodal DLBCLs. The prognosis of extranodal DLBCL is usually considered poorer than that of nodal DLBCL. However, in our study, no difference was noted between patients with localized nasal/paranasal DLBCL and patients with localized nodal DLBCL. In conclusion, although the non-GCB subtype is thought to show poor prognosis, in our study, the prognosis for localized nasal/paranasal DLBCL patients was good irrespective of subclassification. © 2013 Toda et al.

DOI： 10.1371/journal.pone.0057677

Elevated serum interferon γ-induced protein 10 kDa is associated with TAFRO syndrome Reviewed

Iwaki N, Gion Y, Kondo E, Kawano M, Masunari T, Moro H, Nikkuni K, Takai K, Hagihara M, Hashimoto Y, Yokota K, Okamoto M, Nakao S, Yoshino T, Sato Y

Scientific Report 13 ( 7 ) 42316 - 42323 2013.2

Ectopic hamartomatous thymoma is distinct from lipomatous pleomorphic adenoma in lacking PLAG1 aberration

Peir-In Liang, Chien-Feng Li, Yasuharu Sato, Victor Kwan Min Lee, Armita Bahrami, Shih-Sung Chuang

Histopathology 62 ( 3 ) 518 - 522 2013.2

Duodenal follicular lymphoma lacks AID but expresses BACH2 and has memory B-cell characteristics

Katsuyoshi Takata, Yasuharu Sato, Naoya Nakamura, Mami Tokunaka, Yukari Miki, Yara Yukie Kikuti, Kazuhiko Igarashi, Etsuro Ito, Hideo Harigae, Seiichi Kato, Eiko Hayashi, Takashi Oka, Yoshinobu Hoshii, Akira Tari, Hiroyuki Okada, Abd Alkader Lamia Mohamad, Yoshinobu Maeda, Mitsune Tanimoto, Tomohiro Kinoshita, Tadashi Yoshino

Modern Pathology 26 ( 1 ) 22 - 31 2013.1

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

We have reported previously that duodenal follicular lymphoma (FL) is distinct from nodal FL and showed more resemblance to mucosa-associated lymphoid tissue lymphoma, and that FL frequently involved the duodenal second portion. In the present study, we examined duodenal FLs and gastric/colonic FLs to clarify the clinicopathological and immunological differences between the tumor types. We analyzed 8 samples of gastric FL, 17 of duodenal ones, and 5 of colonic/rectal ones, and characterized them by immunohistochemistry, immunogenotyping, and histology. Gastric and colonic FLs presented in submucosal to subserosal areas, whereas duodenal ones presented in the mucosal to submucosal layers. Immunohistochemical analysis revealed that duodenal FLs exhibited the following phenotypes: CD10 (+), B-cell lymphoma 2 (BCL-2) (+), BCL-6 (+), activation-induced cytidine deaminase (AID) (-), BACH2 (+), CD27 (+), MUM-1 (-), Blimp-1 (-), and loose CD21 network (duodenal pattern). Gastric/colonic FLs exhibited the following phenotypes: CD10 (+), BCL-2 (+), BCL-6 (+), AID (+), BACH2 (+), CD27 (-), MUM-1 (-), Blimp-1 (-), and a dense CD21 network (nodal pattern). Expression of AID and CD27 in lymphoma cells and the CD21 network pattern were considerably different between duodenal FLs and gastric/colonic ones. Moreover, in situ hybridization revealed that, in the duodenal FLs, BACH2 was expressed at the periphery of the tumor follicle and tumor villi. The number of immunoglobulin heavy-chain variable domains VH4 and VH5 were higher in duodenal follicular lymphomoas than in gastric FLs. The lymphoma cells of duodenal FLs are different from those of gastric/colonic FLs, and duodenal FL is distinct even within the gastrointestinal tract. Somatic hypermutation in immunoglobulin genes and CD27 expression are hallmarks of memory B cells. We suggest that duodenal FL cells are in the memory B-cell stage, and require BACH2 instead of AID for ongoing mutation. © 2013 USCAP, Inc.

DOI： 10.1038/modpathol.2012.127

Cervical lymph node extirpation for the diagnosis of malignant lymphoma

Yorihisa Orita, Soichiro Nose, Yasuharu Sato, Kentaro Miki, Shuhei Domae, Misato Hirai, Yasuyuki Noyama, Kazuo Hamaya, Norio Kasai, Kazunori Nishizaki, Tadashi Yoshino

SURGERY TODAY 43 ( 1 ) 67 - 72 2013.1

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

Lymph node enlargement in the neck is a common presentation of malignant lymphoma (ML) and requires tissue sampling for accurate diagnosis. Although delayed diagnosis may be critical for some patients, unnecessary biopsy should be avoided wherever possible. This study examined the process for determining the necessity to perform a biopsy and evaluated the value of an open biopsy as a diagnostic tool to enable definite subclassification of the disease.
The subjects included 20 patients with suspected ML who underwent cervical lymph node extirpation at Okayama Saiseikai general hospital between 2007 and 2010. The decision to perform a biopsy was made based on the results of sonographic evaluation, fine needle aspiration cytology (FNAC), and serum levels of lactate dehydrase (LDH) and soluble interleukin-2 receptor (sIL-2r).
The diagnosis was ML in 15 patients (75%), Castleman's disease in 1 (5%), and benign lymphadenopathy in 4 (20%).
A lymph node biopsy remains the gold standard for the diagnostic evaluation of ML. Sonographic evaluation combined with serum levels of LDH and sIL-2r is useful in determining the need for biopsy. Many of the cases of ML where it was difficult to determine whether a biopsy should be performed were relatively low grade and critical conditions could be avoided by close observation of the patient.

DOI： 10.1007/s00595-012-0149-1

Time-lag between symptom onset and laboratory findings in patients with subacute thyroiditis.

Tachibana T, Orita Y, Ogawara Y, Matsuyama Y, Abe I, Nakada M, Sato Y, Nishizaki K

Auris Nasus Larynx 54 ( 1 ) 3 - 9 2013

A Case of IgG4-Related Dacryoadenitis that Regressed Without Systemic Steroid Administration

OHSHIMA Koh-ichi, SATO Yasuharu, YOSHINO Tadashi

The journal of the Japanese Society of Lymphoreticular Tissue research 53 ( 1 ) 53 - 56 2013

Language：English Publisher：The Japanese Society for Lymphoreticular Tissue Research

There are no reports on the effect of anti-allergic agents against IgG4-related disease. We herein report a case of IgG4-related dacryoadenitis that is believed to have regressed due to the administration of anti-allergic agents. A 57-year-old woman consulted us because of bilateral temporal upper eyelid swelling and induration. She had also been suffering from allergic rhinitis and allergic conjunctivitis for 20 years. We performed an incisional biopsy of the lesion. With respect to the pathology, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue type was strongly suspected. On obtaining consent from the patient, follow-up alone was to be continued without radiation therapy. In addition to the observation of lacrimal gland lesions, the administration of epinastine hydrochloride at a dosage of 20 mg/day and 0.01% betamethasone eye drops twice a day to both eyes was commenced in order to treat both allergic rhinitis and allergic conjunctivitis. The lacrimal gland lesion decreased in size over time, becoming predominantly normal 7 years after the commencement of agent administration. We therefore re-examined the blood and pathology specimens. As a result, the serum IgG4 level was found to have increased to 540 mg/dl, while IgG4/IgG was 36.2%. The pathological diagnosis was revised to IgG4-related dacryoadenitis. The hypotheses of spontaneous remission and/or the effect of epinastine hydrochloride administration can be proposed regarding the mechanism by which the lacrimal gland lesion decreased in size. [J Clin Exp Hematop 53(1): 53-56, 2013]

DOI： 10.3960/jslrt.53.53

Other Link： http://search.jamas.or.jp/link/ui/2014163923

A Case of Conjunctival Follicular Lymphoma Mimicking Mucosa-Associated Lymphoid Tissue Lymphoma

AL-KADER Lamia Abd, SATO Yasuharu, TAKATA Katsuyoshi, OHSHIMA Koh-ichi, SOGABE Yuka, FUJII Kazuhiro, IWAKI Noriko, YOSHINO Tadashi

The journal of the Japanese Society of Lymphoreticular Tissue research 53 ( 1 ) 49 - 52 2013

Language：English Publisher：The Japanese Society for Lymphoreticular Tissue Research

Ocular adnexal lymphoma may involve the eyelids, conjunctiva, orbital tissue, or lacrimal structures. The majority are non-Hodgkin's B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) lymphoma type. Follicular lymphomas represent a small percentage of ocular adnexa lymphomas, particularly in Japan. We report a 68-year-old female patient who presented with a salmon pink patch-like lesion of the left conjunctiva, suspected of being (MALT) lymphoma. However, histologic and immunohistologic examinations were consistent with follicular lymphoma. This case demonstrates the importance of considering such rare lymphomas when making a diagnosis of ocular adnexal lymphoid neoplasms. [J Clin Exp Hematop 53(1): 49-52, 2013]

DOI： 10.3960/jslrt.53.49

Other Link： http://search.jamas.or.jp/link/ui/2014163922

A20 (TNFAIP3) deletion in Epstein-Barr virus-associated lymphoproliferative disorders/lymphomas. International journal

Midori Ando, Yasuharu Sato, Katsuyoshi Takata, Junko Nomoto, Shigeo Nakamura, Koichi Ohshima, Tamotsu Takeuchi, Yorihisa Orita, Yukio Kobayashi, Tadashi Yoshino

PloS one 8 ( 2 ) e56741 2013

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

A negative regulator of the nuclear factor (NF)-κB pathway, A20 (TNFAIP3), is inactivated in several types of lymphomas; particularly in diffuse large B-cell lymphoma (DLBCL), classical Hodgkin's lymphoma, and extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue. These findings suggest that the NF-κB activation is related to A20 inactivation. Recently, A20 inactivation has also been observed in Epstein-Barr virus (EBV)-related lymphomas; however, this occurrence has not been well investigated. Moreover, NF-κB is a key molecule in activated B-cell-like (ABC)-type DLBCL; EBV-associated DLBCL is of the ABC type. Therefore, we focused on A20 deletions in EBV-associated lymphoproliferative disorders/lymphomas. Using fluorescent in situ hybridization analysis, A20 deletions were identified in 4 of 13 samples from patients with pyothorax-associated lymphoma (PAL) (31%), 3 of 20 samples from nasal-type NK/T cell lymphomas (NKTLs) (15%), 1 of 8 samples of EBV-positive DLBCL of the elderly (DLBCL-e) (13%), but not in any of the 11 samples from individuals with methotrexate-related lymphoproliferative disorder (MTX-LPD) (0%). Among the samples with A20 deletions, EBV latent membrane protein 1 (LMP-1) expression was detected in all 4 of the PAL samples with A20 deletions and in the DLBCL-e sample with an A20 deletion, but not in any of the 3 NKTL samples. This finding indicated that A20 deletions were not directly related to the EBV latency pattern of lymphomas, although such deletions might be related to the diagnostic category. Immunohistologically, the A20 protein was absent in 2 (15%) of the 13 PAL samples, 1 (9%) of 11 MTX-LPD samples, and in none of the 20 NKTL (0%) or 8 DLBCL-e samples. In conclusion, A20 deletion and/or dysfunctional expression are frequently associated with PALs, and A20 abnormalities may be related to the pathogenesis of PAL.

DOI： 10.1371/journal.pone.0056741

Usefulness of Immunoglobulin Light-Chain Restriction on Immunocytochemical Double Staining for the Cytological Diagnosis of B Cell Non-Hodgkin's Lymphoma

Yasumasa Shimoura, Yasuharu Sato, Katsuyoshi Takata, Yorihisa Orita, Satoko Nakamura, Shyouhei Mano, Tadashi Yoshino

ACTA CYTOLOGICA 57 ( 1 ) 84 - 90 2013

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

Objective: We examined the usefulness of light-chain restriction (LCR) on immunocytochemical double staining (IDS) for cytological diagnosis. Study Design: We investigated LCR on IDS in 40 patients with proliferative lymphatic disorders (23 with B cell lymphoma, 13 with reactive lymphoid lesions, 2 with T cell lymphoma and 2 with Hodgkin's lymphoma). In addition, the results of flow cytometry (FCM) were compared in 34 of these patients. Results: On IDS, LCR was detected in 21 of 23 patients (91.3%) with B cell lymphoma. On FCM, it was detected in 15 of 21 patients (71.4%) with B cell lymphoma. Neither IDS nor FCM showed LCR in any patients with reactive lesions, T cell lymphoma or Hodgkin's lymphoma. Conclusion: IDS facilitated the detection of LCR with a single specimen under morphological observation. The application of this procedure may improve the accuracy of cytological diagnosis. Copyright 2012 S. Karger AG, Basel

DOI： 10.1159/000342475

Atypical hyaline vascular-type castleman's disease with thrombocytopenia, anasarca, fever, and systemic lymphadenopathy. Reviewed

Noriko Iwaki, Yasuharu Sato, Katsuyoshi Takata, Eisei Kondo, Kyotaro Ohno, Mai Takeuchi, Yorihisa Orita, Shinji Nakao, Tadashi Yoshino

Journal of clinical and experimental hematopathology : JCEH 53 ( 1 ) 87 - 93 2013

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

Recently, atypical Castleman's disease (CD) was reported in Japan. This disease is considered as TAFRO syndrome or non-idiopathic plasmacytic lymphadenopathy (IPL), a constellation of clinical symptoms, namely, thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly without hyper-γ-globulinemia. Histopathologically, this disease is similar to hyaline vascular (HV)-type CD. Here, we present a 43-year-old Japanese woman meeting the clinical criteria of TAFRO syndrome who was successfully treated with combined corticosteroid therapy. She showed a rapidly progressive course of thrombocytopenia, systemic lymphadenopathy, fever, anasarca, and increase in acute inflammatory proteins without hyper-γ-globulinemia. Lymph node biopsy was performed and revealed HV-type CD without human herpes virus 8 infection, which was clinicopathologically compatible with non-IPL. The association of these atypical features with well-known multicentric Castleman's disease (MCD), namely, HV-type histology with systemic lymphadenopathy, marked thrombocytopenia even with a high level of interleukin-6, and increased acute inflammatory proteins without hyper-γ-globulinemia, suggests that TAFRO syndrome as presented in our case is a novel entity, which may have been diagnosed as MCD in the past. To define this novel entity more clearly and to demonstrate its etiology, further nationwide surveys of this syndrome and MCD are needed.

DOI： 10.3960/jslrt.53.87

Clinicopathological characteristics of human epidermal growth factor receptor 2-positive Barrett's adenocarcinoma

Takehiro Tanaka, Atsushi Fujimura, Koichi Ichimura, Hiroyuki Yanai, Yasuharu Sato, Katsuyohi Takata, Hiroyuki Okada, Seiji Kawano, Shunsuke Tanabe, Tadashi Yoshino

WORLD JOURNAL OF GASTROENTEROLOGY 18 ( 43 ) 6263 - 6268 2012.11

Language：English Publishing type：Research paper (scientific journal) Publisher：BAISHIDENG PUBL GRP CO LTD

AIM: To compare the clinicopathological characteristics of human epidermal growth factor receptor 2 (HER2)-positive and HER2-negative Barrett's adenocarcinoma in Japan.
METHODS: We performed immunohistochemical analysis of HER2 in 30 samples taken from patients with Barrett's adenocarcinoma and dual color in situ hybridization in cases showing 2+ reactions. We compared the clinicopathological characteristics of HER2-positive and HER2-negative patients.
RESULTS: HER2 positivity was identified in 8 (27%) carcinoma samples. We found that HER2 expression was associated with p53 overexpression (100% vs 52.6% in pT1 tumor; 100% vs 54.5% in all stage tumor, P < 0.05) and protruding lesions at the early disease stage. There was no association between the mucin phenotype of the carcinomas and prognosis. HER2 expression and low clinical stage were unexpectedly different between Barrett's adenocarcinoma patients and gastric cancer patients, but the macroscopic features may be associated with earlier diagnosis in these patients.
CONCLUSION: Our results suggest that HER2-positive Barrett's adenocarcinomas are associated with p53 overexpression and lesion protrusion at the early disease stage. (C) 2012 Baishideng. All rights reserved.

DOI： 10.3748/wjg.v18.i43.6263

Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations

John H. Stone, Arezou Khosroshahi, Vikram Deshpande, John K. C. Chan, J. Godfrey Heathcote, Rob Aalberse, Atsushi Azumi, Donald B. Bloch, William R. Brugge, Mollie N. Carruthers, Wah Cheuk, Lynn Cornell, Carlos Fernandez-Del Castillo, Judith A. Ferry, David Forcione, Guenter Kloeppel, Daniel L. Hamilos, Terumi Kamisawa, Satomi Kasashima, Shigeyuki Kawa, Mitsuhiro Kawano, Yasufumi Masaki, Kenji Notohara, Kazuichi Okazaki, Ji Kon Ryu, Takako Saeki, Dushyant Sahani, Yasuharu Sato, Thomas Smyrk, James R. Stone, Masayuki Takahira, Hisanori Umehara, George Webster, Motohisa Yamamoto, Eunhee Yi, Tadashi Yoshino, Giuseppe Zamboni, Yoh Zen, Suresh Chari

ARTHRITIS AND RHEUMATISM 64 ( 10 ) 3061 - 3067 2012.10

Consensus statement on the pathology of IgG4-related disease

Vikram Deshpande, Yoh Zen, John K. Chan, Eunhee E. Yi, Yasuharu Sato, Tadashi Yoshino, Guenter Kloeppel, J. Godfrey Heathcote, Arezou Khosroshahi, Judith A. Ferry, Rob C. Aalberse, Donald B. Bloch, William R. Brugge, Adrian C. Bateman, Mollie N. Carruthers, Suresh T. Chari, Wah Cheuk, Lynn D. Cornell, Carlos Fernandez-Del Castillo, David G. Forcione, Daniel L. Hamilos, Terumi Kamisawa, Satomi Kasashima, Shigeyuki Kawa, Mitsuhiro Kawano, Gregory Y. Lauwers, Yasufumi Masaki, Yasuni Nakanuma, Kenji Notohara, Kazuich Okazaki, Ji Kon Ryu, Takako Saeki, Dushyant V. Sahani, Thomas C. Smyrk, James R. Stone, Masayuki Takahira, George J. Webster, Motohisa Yamamoto, Giuseppe Zamboni, Hisanori Umehara, John H. Stone

MODERN PATHOLOGY 25 ( 9 ) 1181 - 1192 2012.9

Language：English Publisher：NATURE PUBLISHING GROUP

IgG4-related disease is a newly recognized fibro-inflammatory condition characterized by several features: a tendency to form tumefactive lesions in multiple sites; a characteristic histopathological appearance; and-often but not always-elevated serum IgG4 concentrations. An international symposium on IgG4-related disease was held in Boston, MA, on 4-7 October 2011. The organizing committee comprising 35 IgG4-related disease experts from Japan, Korea, Hong Kong, the United Kingdom, Germany, Italy, Holland, Canada, and the United States, including the clinicians, pathologists, radiologists, and basic scientists. This group represents broad subspecialty expertise in pathology, rheumatology, gastroenterology, allergy, immunology, nephrology, pulmonary medicine, oncology, ophthalmology, and surgery. The histopathology of IgG4-related disease was a specific focus of the international symposium. The primary purpose of this statement is to provide practicing pathologists with a set of guidelines for the diagnosis of IgG4-related disease. The diagnosis of IgG4-related disease rests on the combined presence of the characteristic histopathological appearance and increased numbers of IgG4(+) plasma cells. The critical histopathological features are a dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis. We propose a terminology scheme for the diagnosis of IgG4-related disease that is based primarily on the morphological appearance on biopsy. Tissue IgG4 counts and IgG4:IgG ratios are secondary in importance. The guidelines proposed in this statement do not supplant careful clinicopathological correlation and sound clinical judgment. As the spectrum of this disease continues to expand, we advocate the use of strict criteria for accepting newly proposed entities or sites as components of the IgG4-related disease spectrum. Modern Pathology (2012) 25, 1181-1192; doi:10.1038/modpathol.2012.72; published online 18 May 2012

DOI： 10.1038/modpathol.2012.72

Pathological findings of infraorbital nerve enlargement in IgG4-related ophthalmic disease

Yuka Sogabe, Katsuya Miyatani, Rieko Goto, Gengo Ishii, Koh-ichi Ohshima, Yasuharu Sato

JAPANESE JOURNAL OF OPHTHALMOLOGY 56 ( 5 ) 511 - 514 2012.9

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

We report a case of bilateral infraorbital nerve enlargement (IONE) associated with immunoglobulin (Ig)G4-related ophthalmic disease and describe the associated histopathologic findings.
An otherwise healthy 59-year-old man presented with bilateral exophthalmos and right visual disturbance. Orbital magnetic resonance imaging showed bilateral IONE and a soft tissue mass in the right orbit. Excisional biopsy in the left infraorbital canal was performed. Histopathologic assessment revealed IgG4-related disease involving the epineurium of the infraorbital nerve. The patient received systemic steroid therapy, to which he responded well.
IONE in IgG4-related ophthalmic disease is due to IgG4-related disease involving the epineurium.

DOI： 10.1007/s10384-012-0170-3

Association between IgG4-related disease and progressively transformed germinal centers of lymph nodes

Yasuharu Sato, Dai Inoue, Naoko Asano, Katsuyoshi Takata, Hideki Asaoku, Yoshinobu Maeda, Toshiaki Morito, Hirokazu Okumura, Shin Ishizawa, Shoko Matsui, Takayoshi Miyazono, Tamotsu Takeuchi, Naoto Kuroda, Yorihisa Orita, Kiyoshi Takagawa, Masaru Kojima, Tadashi Yoshino

MODERN PATHOLOGY 25 ( 7 ) 956 - 967 2012.7

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Progressively transformed germinal centers is a benign condition of unknown pathogenesis characterized by a distinctive variant form of reactive follicular hyperplasia in lymph nodes. We recently reported Ig G4-related disease in progressively transformed germinal centers. However, no large case series has been reported and clinicopathologic findings remain unclear. Here, we report 40 Japanese patients (28 men, 12 women; median age, 56 years) with progressively transformed germinal centers of the lymph nodes who fulfilled the histological diagnostic criteria for IgG4-related disease (IgG4(+) progressively transformed germinal centers), with asymptomatic localized lymphadenopathy involving the submandibular nodes in 24, submandibular and cervical nodes in 14, cervical nodes only in 1, and cervical and supraclavicular nodes in 1. In all, 16 (52%) of 31 examined patients had allergic disease. Histologically, the lymph nodes demonstrated uniform histological findings, namely marked follicular hyperplasia with progressively transformed germinal centers, and localization of the majority of IgG4(+) plasma cells in the germinal centers. Serum IgG4, serum IgE and peripheral blood eosinophils were elevated in 87%, 92% and 53% of examined patients, respectively. Eighteen patients subsequently developed extranodal lesions (including five who developed systemic disease), which on histological examination were consistent with IgG4-related disease. IgG4(+) progressively transformed germinal centers presents with uniform clinicopathological features of asymptomatic localized submandibular lymphadenopathy, which persists and/or relapses, and sometimes progresses to extranodal lesions or systemic disease. Nine patients were administered steroid therapy when the lesions progressed, to which all responded well. We suggest that IgG4+ progressively transformed germinal centers should be included in the IgG4-related disease spectrum. Modern Pathology (2012) 25, 956-967; doi:10.1038/modpathol.2012.54; published online 6 April 2012

DOI： 10.1038/modpathol.2012.54

The usefulness of infraorbital nerve enlargement on MRI imaging in clinical diagnosis of IgG4-related orbital disease

Koh-ichi Ohshima, Yuka Sogabe, Yasuharu Sato

JAPANESE JOURNAL OF OPHTHALMOLOGY 56 ( 4 ) 380 - 382 2012.7

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER TOKYO

To investigate the frequency of infraorbital nerve enlargement (IONE) in orbital lymphoproliferative disorders, and to show that IONE can contribute to the clinical diagnosis of IgG4-related orbital diseases (IgG4-ROD).
71 cases in which orbital lymphoproliferative disorders were diagnosed at Okayama Medical Center and Mitoyo General Hospital from April, 2004 to March, 2011 were investigated. The male-to-female ratio was 39:32, and the age range 27-87 years old (average age 64.1 years). Whenever the coronal section of the infraorbital nerve was larger than that of the optic nerve on MRI, it was defined as IONE.
The breakdown of the 71 cases was: 45 cases of non-Hodgkin lymphoma, 16 cases of IgG4-ROD, 5 cases of reactive lymphoid hyperplasia, and 5 cases of idiopathic orbital inflammation. Of these, a total of 9 cases had IONE. The incidence of IONE was compared between the IgG4-ROD patient group and the non-IgG4-ROD patient group and was significantly higher in the IgG4-ROD patient group (p < 0.0001).
If IONE is observed in a case of orbital lymphoproliferative disorders on MRI, then it is highly possible that such a case is IgG4-ROD.

DOI： 10.1007/s10384-012-0151-6

Minimally Invasive Procedure for Accurate Diagnosis of Mucosa-associated Lymphoid Tissue Lymphoma of the Head and Neck

Yorihisa Orita, Yasuharu Sato, Eisei Kondo, Hisashi Ishihara, Haruka Hirai, Hiroyuki Hanakawa, Tomoo Onoda, Takuro Igawa, Ryusuke Saito, Kazunori Nishizaki, Tadashi Yoshino

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 42 ( 4 ) 325 - 330 2012.4

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

Sonography-guided cutting needle biopsy for the diagnosis of malignant lymphoma has recently come into wide use. However, surgery is sometimes unavoidable for the diagnosis of malignant lymphoma, particularly for low-grade malignant lymphoma such as extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, because cutting needle biopsy offers limited diagnostic accuracy for low-grade malignant lymphoma. Of course, unnecessary invasive procedures like open biopsy should be avoided wherever possible, given the cosmetic problems and burden on the patient. We tried to diagnose malignant lymphoma using the combination of cutting needle biopsy, flow cytometry and polymerase chain reaction to identify monoclonal rearrangement of immunoglobulin heavy chain genes. We have used this method in two cases in whom malignant lymphoma was suspected in the head and neck region, allowing diagnosis of mucosa-associated lymphoid tissue lymphoma in both cases. One case involved a 23-year-old woman with mucosa-associated lymphoid tissue lymphoma in the parotid glands, and the other involved a 77-year-old man with mucosa-associated lymphoid tissue lymphoma in the thyroid. The combination of cutting needle biopsy, flow cytometry and immunoglobulin heavy chain gene rearrangement testing might offer a useful alternative to open biopsy for the diagnosis of mucosa-associated lymphoid tissue lymphoma. We recommend this procedure, particularly for young women or patients with poor performance status in whom malignant lymphoma is suspected.

DOI： 10.1093/jjco/hys011

Cutaneous multicentric Castleman's disease mimicking IgG4-related disease

Mai Takeuchi, Yasuharu Sato, Katsuyoshi Takata, Keita Kobayashi, Kyotaro Ohno, Noriko Iwaki, Yorihisa Orita, Tadashi Yoshino

PATHOLOGY RESEARCH AND PRACTICE 208 ( 12 ) 746 - 749 2012

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER GMBH, URBAN & FISCHER VERLAG

Castleman's disease, an uncommon lymphoproliferative disorder, can be difficult to differentiate from immunoglobulin (Ig) G4-related disease. The latter is typically characterized by elevated serum IgG4 levels and abundant IgG4-positive cells. However, multicentric Castleman's disease can also have elevated serum IgG4 levels and even fulfill the histological diagnostic criteria for IgG4-related disease. We present a case of cutaneous multicentric Castleman's disease mimicking IgG4-related disease. A 55-year-old Japanese woman developed erythematous and brown plaques on her back. Skin biopsy revealed regressive follicles with interfollicular plasmacytosis, and many plasma cells were positive for IgG4 (mean 263.67 +/- 79.19, range 214-355 per high power field). The IgG4-/IgG-positive cell ratios were 35.6%, 36.2%, and 48.4%, respectively, with an average of 40.6%, thus fulfilling the histological diagnostic criteria for IgG4-related disease. Furthermore, serum IgG4 level was significantly elevated (1490 mg/dl; normal range: 4.8-105 mg/dl). However, laboratory findings of anemia, hypoalbuminemia, polyclonal gammaglobulinemia, high C-reactive protein level, and elevated serum interleukin-6 level were consistent with hyper-IL-6 syndrome. Hence, the diagnosis of cutaneous multicentric Castleman's disease was made. In conclusion, IgG4-related disease cannot be differentiated from hyper-IL-6 syndromes on histology alone. Instead, laboratory analyses are necessary to distinguish between the two diseases. (c) 2012 Elsevier GmbH. All rights reserved.

DOI： 10.1016/j.prp.2012.09.006

IgG4-related lymphadenopathy Invited Reviewed

Yasuharu Sato, Tadashi Yoshino

International Journal of Rheumatology 2012 572539 2012

Language：English

Lymphadenopathy is frequently observed in patients with immunoglobulin G4-related disease (IgG4-RD) and sometimes appears as the first manifestation of the disease. The diagnosis of IgG4-related lymphadenopathy is complicated owing to a great histological diversity, with at least 5 histological subtypes. Indeed, lymph node biopsy may be performed under the suspicion that the lymphadenopathy is a malignant lymphoma or other lymphoproliferative disorder. The diagnosis of IgG4-RD is characterized by both elevated serum IgG4 (135mg/dL) and histopathological features, including a dense lymphoplasmacytic infiltrate rich in IgG4 + plasma cells (IgG4 +/IgG + plasma cell ratio 40%). However, patients with hyper-interleukin (IL-) 6 syndromes such as multicentric Castlemans disease, rheumatoid arthritis, and other immune-mediated conditions frequently show lymph node involvement and often fulfill the diagnostic criteria for IgG4-RD. Owing to these factors, IgG4-RD cannot be differentiated from hyper-IL-6 syndromes on the basis of histological findings alone. Laboratory analyses are crucial to differentiate between the 2 diseases. Hyper-IL-6 syndromes are characterized by elevated serum levels of IgG, IgA, IgM, and C-reactive protein (CRP)
thrombocytosis
anemia
hypoalbuminemia
hypocholesterolemia. In contrast, IgG4-RD does not share any of these characteristics. Therefore, the diagnosis of IgG4-RD requires not only pathological findings but also clinical and laboratory analyses. © 2012 Yasuharu Sato and Tadashi Yoshino.

DOI： 10.1155/2012/572539

Germinal center B-cell-like versus non-germinal center B-cell-like as important prognostic factor for localized nodal DLBCL.

Toshiyuki Habara, Yasuharu Sato, Katsuyoshi Takata, Noriko Iwaki, Hirokazu Okumura, Hiroshi Sonobe, Takehiro Tanaka, Yorihisa Orita, L. A. Al-Kader, Naoko Asano, Daisuke Ennishi, Tadashi Yoshino

Journal of clinical and experimental hematopathology : JCEH 52 ( 2 ) 91 - 99 2012

Publishing type：Research paper (scientific journal)

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma. Although many investigations have been performed on the prognostic factors of DLBCL, no reports have focused on localized nodal DLBCL. We examined the prognostic significance of 39 Japanese patients with localized nodal DLBCL with special reference to the germinal center B-cell-like (GCB) versus non-germinal center B-cell-like (NGCB) types. The median age was 65 years with 23 males and 16 females. Using Hans algorithm of immunohistochemistry, 18 patients (46%) exhibited GCB type and 21 (54%) exhibited NGCB type. Twenty-nine patients (74%) presented with disease in the neck (neck group) and 10 (26%) had disease in non-neck regions (non-neck group). Comparing Hans, Choi, and Muris algorithms, patients with GCB type showed statistically significant progression-free survival (PFS) only with Hans algorithm (P = 0.022, P = 0.100, and P = 0.130, respectively). Patient survival analyses revealed that GCB-type patients by Hans algorithm had a better PFS (P = 0.012), and neck-group patients had better PFS and overall survival (OS) (P = 0.018 and P = 0.012, respectively). Univariate analysis revealed that only neck vs. non-neck exhibited a significant difference in terms of OS (P = 0.026). Multivariate analysis revealed that GCB type by Hans algorithm and neck vs. non-neck were significantly different in terms of PFS (P = 0.025 and P = 0.033, respectively). Therefore, the subclassifications of GCB type vs. NGCB type and neck vs. non-neck are important predictive prognostic factors in localized nodal DLBCL.

DOI： 10.3960/jslrt.52.91

Ocular Adnexal IgG4-Producing Mucosa-Associated Lymphoid Tissue Lymphoma Mimicking IgG4-Related Disease

SATO Yasuharu, OHSHIMA Koh-ichi, TAKATA Katsuyoshi, HUANG Xingang, CUI Wei, OHNO Kyotaro, YOSHINO Tadashi

The journal of the Japanese Society of Lymphoreticular Tissue research 52 ( 1 ) 51 - 55 2012

Language：English Publisher：The Japanese Society for Lymphoreticular Tissue Research

IgG4-related disease is a recently proposed clinical entity with several unique clinicopathological features. A chronic inflammatory state with marked fibrosis, which can often be mistaken for malignancy, especially by clinical imaging analyses, unifies these features. In the present report, we describe a case of IgG4-producing mucosa-associated lymphoid tissue lymphoma mimicking IgG4-related disease. The patient was a 55-year-old male who was being followed for right orbital tumor over 1.5 years. The lesion had recently increased in size, so a biopsy was performed. Histologically, the lesion was consistent with IgG4-related disease ; however, IgG4⁺ plasma cells showed immunoglobulin light-chain restriction and immunoglobulin heavy chain gene rearrangement was detected in the lesion. Therefore, the lesion was diagnosed as IgG4-producing mucosa-associated lymphoid tissue lymphoma. In conclusion, in histological diagnosis of IgG4-related disease, it is important to examine not only IgG4-immunostain but also immunoglobulin light-chain restriction. [J Clin Exp Hematopathol 52(1) : 51-55, 2012]

DOI： 10.3960/jslrt.52.51

Other Link： http://search.jamas.or.jp/link/ui/2013247916

Rheumatoid Lymphadenopathy with Abundant IgG4^+ Plasma Cells : A Case Mimicking IgG4-Related Disease

ASANO Naoko, SATO Yasuharu

The journal of the Japanese Society of Lymphoreticular Tissue research 52 ( 1 ) 57 - 61 2012

Language：English Publisher：The Japanese Society for Lymphoreticular Tissue Research

Immunoglobulin (Ig) G4-related disease is a recently confirmed clinical entity with several unique clinicopathological features. Here we report a case of rheumatoid lymphadenopathy mimicking IgG4-related disease. The patient was a 63-year-old woman who had been treated for rheumatoid arthritis (RA) for six years. The patient noted cervical lymphadenopathy. Upon radiological examination, systemic lymphadenopathy was detected, and enlarged right brachial lymph node biopsy was performed. Histologically, the lymph node showed marked follicular hyperplasia and interfollicular plasmacytosis without eosinophil infiltration. Although the histological findings were compatible with rheumatoid lymphadenopathy, numerous plasma cells were IgG4⁺ (IgG4⁺/IgG⁺ plasma cell ratio > 50%). However, laboratory findings revealed elevation of C-reactive protein level, polyclonal hyper-γ-globulinemia, anemia, and hypoalbuminemia. These findings were compatible with hyper-interleukin (IL)-6 syndrome, namely, RA. It is known that hyper-IL-6 syndromes, such as multicentric Castleman's disease, RA, and other autoimmune diseases, fulfill the histological diagnostic criteria for IgG4-related disease. Therefore, hyper-IL-6 syndromes and IgG4-related disease cannot be differentially diagnosed by immunohistochemical staining alone. In conclusion, rheumatoid lymphadenopathy sometimes occurs with abundant IgG4⁺ plasma cells, which is required for the differential diagnosis of IgG4-related disease. [J Clin Exp Hematopathol 52(1) : 57-61, 2012]

DOI： 10.3960/jslrt.52.57

Other Link： http://search.jamas.or.jp/link/ui/2013247917

IgG4-related perineural disease

Dai Inoue, Yoh Zen, Yasuharu Sato, Hitoshi Abo, Hiroshi Demachi, Akio Uchiyama, Toshifumi Gabata, Osamu Matsui

International Journal of Rheumatology 2012 572539 2012

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

Aims. To elucidate characteristics of IgG4-related disease involving the peripheral nervous system. Methods. Retrospective review of 106 patients with IgG4-related disease identified 21 peripheral nerve lesions in 7 patients. Clinicopathological and radiological features were examined. Results. Peripheral nerve lesions were commonly identified in orbital or paravertebral area, involving orbital (n=9), optic (n=4), spinal (n=7), and great auricular nerves (n=1). The predominant radiological feature was a distinct perineural soft tissue mass, ranging 8 to 30mm in diameter. Histologically, the epineurium was preferentially involved by massive lymphoplasmacytic infiltration rich in IgG4 plasma cells. All lesions were neurologically asymptomatic and steroid-responsive at the first presentation, but one recurrent lesion around the optic nerve caused failing vision. Conclusion. IgG4-related disease of the peripheral nervous system is characterized by orbital or paravertebral localization, perineural mass formation, and rare neurologic symptoms. The term IgG4-related perineural disease seems appropriate to describe this entity. © Copyright 2012 Dai Inoue et al.

DOI： 10.1155/2012/401890

Germinal center B-cell-like diffuse large B-cell lymphoma of the duodenum is associated with t(14;18) translocation

Maiko Tamura, Katsuyoshi Takata, Yasuharu Sato, Naoya Nakamura, Yara Yukie Kikuti, Koichi Ichimura, Takehiro Tanaka, Akira Tari, Yoshinobu Maeda, Mitsune Tanimoto, Hiroyuki Okada, Tadashi Yoshino

PATHOLOGY INTERNATIONAL 61 ( 12 ) 742 - 748 2011.12

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Diffuse large B-cell lymphoma (DLBCL) rarely involves the duodenum, and its clinicopathological characteristics have not been well elucidated. We performed clinicopathological examinations and identified 15 patients with duodenal DLBCL using 18 gastric or colonic DLBCL as a control. Eleven of the 15 patients (73%) were subclassified by immunohistochemical analysis according to the Choi algorithm as germinal center B-cell-like (GCB) type, whereas the 18 control gastric and colonic DLBCL were predominantly subclassified as activated B-cell-like (ABC) type. The classifications according to organ involvement were statistically significant (P= 0.011 and P= 0.035). Macroscopically, the GCB lesions were varied, while all ABC lesions were ulcerative. Fluorescence in situ hybridization analysis revealed a higher frequency of t(14;18) translocation in patients with duodenal DLBCL (3 of 13) as compared with non-duodenal gastrointestinal tract DLBCL (0 of 18), however, the difference was not significant (P = 0.064). Furthermore, the three patients with t(14;18) translocations were classified as GCB. In addition, overall survival of patients was statistically different between those with and without t(14;18) translocation (P= 0.040). In conclusion, duodenal DLBCL predominantly exhibits GCB-type tumors and the frequency of t(14;18) translocation appears to be higher in duodenal GCB-type DLBCL compared to non-duodenal tumors.

DOI： 10.1111/j.1440-1827.2011.02748.x

Nodal follicular lymphoma without complete follicular dendritic cell networks is related to localized clinical stage

Wei Cui, Lisha Che, Yasuharu Sato, Xingang Huang, Katsuyoshi Takata, Yorihisa Orita, Naoe Goto, Yoshinobu Maeda, Mitsune Tanimoto, Tadashi Yoshino

PATHOLOGY INTERNATIONAL 61 ( 12 ) 737 - 741 2011.12

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Follicular lymphoma is the most common low-grade lymphoma and it frequently presents with a systemic disease, often showing advanced clinical stage (III/IV). The lymphoma cells are usually growing associated with follicular dendritic cell (FDC) networks. Abnormal FDC networks have been reported in duodenal follicular lymphoma, in which cases exhibit lower clinical stages than the nodal cases. In the present study, we analyzed the FDC network distribution pattern of 242 nodal follicular lymphomas by immunohistochemistry. Out of the 242 cases, 27 cases (11%) demonstrated an atypical pattern of FDC networks, in which the CD21 staining totally or partially disappeared in the neoplastic follicles. Furthermore, we compared the clinical data of these 27 cases and 58 typical FDC network cases of follicular lymphoma. We found that in the typical cases, 52 out of 58 patients (90%) showed advanced clinical stage (III or IV), whereas 10 of 27 (37%) atypical FDC network cases showed localized clinical stage (I or II) (P < 0.01). In conclusion, nodal follicular lymphoma with total loss or partially disrupted FDC networks therefore show a lower clinical stage.

DOI： 10.1111/j.1440-1827.2011.02736.x

Cyclin D2 is overexpressed in proliferation centers of chronic lymphocytic leukemia/small lymphocytic lymphoma

Takuro Igawa, Yasuharu Sato, Katsuyoshi Takata, Soichiro Fushimi, Maiko Tamura, Naoya Nakamura, Yoshinobu Maeda, Yorihisa Orita, Mitsune Tanimoto, Tadashi Yoshino

CANCER SCIENCE 102 ( 11 ) 2103 - 2107 2011.11

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

The D cyclins are important cell cycle regulatory proteins involved in the pathogenesis of some lymphomas. Cyclin D1 overexpression is a hallmark of mantle cell lymphoma, whereas cyclins D2 and D3 have not been shown to be closely associated with any particular subtype of lymphoma. In the present study, we found that cyclin D2 was specifically overexpressed in the proliferation centers (PC) of all cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) examined (19/19). To examine the molecular mechanisms underlying this overexpression, we immunohistochemically examined the expression of nuclear factor (NF)-kappa B, p15, p16, p18, and p27 in the PC of six patients. Five cases showed upregulation of NF-kappa B expression, which is known to directly induce cyclin D2 by binding to the promoter region of CCND2. All six PC examined demonstrated downregulation of p27 expression. In contrast, upregulation of p15 expression was detected in five of six PC examined. This discrepancy suggests that unknown cell cycle regulatory mechanisms involving NF-kappa B-related pathways are also involved, because NF-kappa B upregulates cyclin D2 not only directly, but also indirectly through c-Myc, which is believed to downregulate both p27 and p15. In conclusion, cyclin D2 is overexpressed in the PC of CLL/SLL and this overexpression is due, in part, to the upregulation of NF-kappa B-related pathways. (Cancer Sci 2011; 102: 2103-2107)

DOI： 10.1111/j.1349-7006.2011.02046.x

Review of acquired cystic disease-associated renal cell carcinoma with focus on pathobiological aspects Reviewed

Naoto Kuroda, Chisato Ohe, Shuji Mikami, Ondrej Hes, Michal Michal, Matteo Brunelli, Guido Martignoni, Yasuharu Sato, Tadashi Yoshino, Yoshiyuki Kakehi, Taro Shuin, Gang-Hong Lee

HISTOLOGY AND HISTOPATHOLOGY 26 ( 9 ) 1215 - 1218 2011.9

Language：English Publisher：F HERNANDEZ

Acquired cystic disease (ACD)-associated renal cell carcinoma (RCC) is a recently established entity. In this article, we introduce the general view of this new entity. Macroscopically, the disease exclusively occurs in ACD and may arise as a dominant mass or non-dominant masses. Histologically, the tumor is characterized by a microcystic pattern, neoplastic cells with an eosinophilic or oncocytic cytoplasm and frequent intratumoral oxalate crystal deposition. Prominent nucleoli of tumor cells are often observed. Immunohistochemically, neoplastic cells are generally positive for AMACR but negative for cytokeratin 7. Ultrastructurally, neoplastic cells contain abundant mitochondria in the cytoplasm. Genetically, the gain of chromosomes 3, 7, 17 and abnormality of the sex chromosome were frequently observed in several studies. In conclusion, ACD-associated RCC may be widely recognized as a distinct entity in the near future because this tumor is morphologically and genetically different from other renal tumor entities that have been previously established.

Immunoglobulin G4-related lymphadenopathy with inflammatory pseudotumor-like features Reviewed

Yasuharu Sato, Masaru Kojima, Katsuyoshi Takata, Xingang Huang, Eiko Hayashi, Akihiro Manabe, Yukari Miki, Tadashi Yoshino

MEDICAL MOLECULAR MORPHOLOGY 44 ( 3 ) 179 - 182 2011.9

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER TOKYO

Immunoglobulin (Ig) G4-related disease has been recently described. This disease affects various organs, including lymph nodes. We describe the case of a 52-year-old Japanese man with IgG4-related lymphadenopathy with inflammatory pseudotumor (IPT)-like features. Five years ago, the patient noticed a painless mass in the mandible but did not consult a doctor. Recently, he noted that the mass had increased in size and consulted an oral surgeon in the hospital. Excisional biopsy was performed for diagnosis. Histopathological examination revealed that most of the enlarged lymph node was occupied by the hyalinized tissue. A few residual lymphoid follicles with hyperplastic germinal centers and infiltration of plasma cells and eosinophils were observed. Most of the plasma cells expressed IgG4, and the ratio of IgG4-positive cells to IgG-positive cells was 57.1%. These findings were consistent with IgG4-related lymphadenopathy. In conclusion, pathologists should consider IgG4-related lymphadenopathy when diagnosing a lesion with IPT-like features.

DOI： 10.1007/s00795-010-0525-0

BCL2、C-MYC、BCL6転座を有するtriple-hit lymphomaの3例

鈴木優子, 増成太郎, 二宮貴一朗, 益田加奈, 田村朋季, 木村耕介, 園部宏, 佐藤康晴, 吉野正, 瀬崎伸夫

臨床血液 52 ( 9 ) 1194 - 1194 2011.9

Primary gastrointestinal follicular lymphoma involving the duodenal second portion is a distinct entity: A multicenter, retrospective analysis in Japan

Katsuyoshi Takata, Hiroyuki Okada, Naoki Ohmiya, Shotaro Nakamura, Yasuhiko Kitadai, Akira Tari, Taiji Akamatsu, Hiroki Kawai, Shu Tanaka, Hiroshi Araki, Takashi Yoshida, Hirokazu Okumura, Hogara Nishisaki, Tamotsu Sagawa, Norihiko Watanabe, Nobuyoshi Arima, Noritaka Takatsu, Masanao Nakamura, Shunichi Yanai, Hiroyasu Kaya, Toshiaki Morito, Yasuharu Sato, Hisataka Moriwaki, Choitsu Sakamoto, Yasumasa Niwa, Hidemi Goto, Tsutomu Chiba, Takayuki Matsumoto, Daisuke Ennishi, Tomohiro Kinoshita, Tadashi Yoshino

CANCER SCIENCE 102 ( 8 ) 1532 - 1536 2011.8

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

We conducted a multicenter, retrospective study to determine the anatomical distribution and prognostic factors of gastrointestinal (GI) follicular lymphoma (FL). This study included 125 patients with stage I and II(1) GI-FL. Of the 125 patients, the small intestine was examined in 70 patients, with double-balloon endoscopy and/or capsule endoscopy. The most frequently involved GI-FL site was the duodenal second portion (DSP) (81%), followed by the jejunum (40%); 85% of patients with involvement of the DSP also had jejunal or ileal lesions. The absence of abdominal symptoms and macroscopic appearance of multiple nodules were significantly present in the DSP-positive group. During a median follow up of 40 months, six patients showed disease progression. Patients with involvement of the DSP had better progression-free survival (PFS) than those without such involvement (P = 0.001). A multivariate analysis revealed that male sex, the presence of abdominal symptoms, and negative involvement of the DSP were independently associated with poor PFS. In conclusion, most patients with GI-FL have duodenal lesions associated with multiple jejunal or ileal lesions. Gastrointestinal follicular lymphomas involving the DSP might be a distinct entity showing a favorable clinical course. (Cancer Sci 2011; 102: 1532-1536)

DOI： 10.1111/j.1349-7006.2011.01980.x

[Frequent inactivation of A20 through gene mutation in B-cell lymphomas]. Reviewed

Kato M, Sanada M, Kato I, Sato Y, Takita J, Takeuchi K, Niwa A, Chen Y, Nakazaki K, Nomoto J, Asakura Y, Akatsuka M, Hayashi Y, Mori H, Igarashi T, Kurokawa M, Chiba S, Mori S, Ishikawa Y, Okamoto K, Tobinai K, Nakagama H, Nakahata T, Yoshino T, Kobayashi Y, Ogawa S

[Rinsho ketsueki] The Japanese journal of clinical hematology 52 ( 6 ) 313 - 319 2011.6

Follicular variant of peripheral T-cell lymphoma mimicking follicular lymphoma: A case report with a review of the Literature

Naoe Goto, Hisashi Tsurumi, Michio Sawada, Nobuhiro Kanemura, Takeshi Hara, Senji Kasahara, Yusuke Kito, Katsuyoshi Takada, Yasuharu Sato, Tadashi Yoshino, Hisataka Moriwaki, Tsuyoshi Takami

PATHOLOGY INTERNATIONAL 61 ( 5 ) 326 - 330 2011.5

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Peripheral T-cell lymphoma (PTCL) with a follicular growth pattern is very rare. Herein, a case of follicular variant of PTCL in a 50-year-old man who complained of tonsillar and generalized lymph node swelling is reported. The resected tonsil revealed a vague nodular growth pattern of atypical cells, medium to large in size, with abundant pale cytoplasm. The lymphoma cells were CD3+ CD4+ CD5+ CD8- CD10+ CD56- CD57- BCL6+ PD-1+ CXCL13+ and were associated with a meshwork of CD21+ follicular dendritic cells. Molecular studies revealed clonal rearrangement of the T-cell receptor gamma chain gene but not of the immunoglobulin gene. Cytogenetic analysis disclosed a complex abnormality in 18 of 20 cells with the exclusion of t(5; 9). These findings suggest that the present case is a follicular variant of PTCL derived from follicular T-helper cells.

DOI： 10.1111/j.1440-1827.2011.02656.x

Downregulation of the B-cell receptor signaling component CD79b in plasma cell myeloma: A possible post transcriptional regulation

Xingang Huang, Katsuyoshi Takata, Yasuharu Sato, Takehiro Tanaka, Kouichi Ichimura, Maiko Tamura, Takashi Oka, Tadashi Yoshino

PATHOLOGY INTERNATIONAL 61 ( 3 ) 122 - 129 2011

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

The CD79 molecule, encoded by the CD79a and CD79b genes, is a signaling unit of the B-cell receptor complex, which transmits signals of B-cell activation, growth, and differentiation. They are B-cell-specific and expressed at most stages of B-cell development. Although plasma cells have been believed to lack these gene products, the regulation of CD79 expression in plasma cells is still controversial. In particular, the regulation of CD79b expression remains unclear. We sought to examine CD79b expression in normal and neoplastic plasma cells by immunohistochemical analysis. Out of the 23 clinical samples and 11 cell lines of plasma cell myeloma (PCM), none of the clinical samples and only 1 of 11 cell lines expressed CD79b immunohistologically, whereas non-neoplastic plasma cells in reactive hyperplastic lymph nodes exhibited loss of CD79b protein expression. This finding is quite different from our previous report on CD79a. Not only immunocytochemistry, but also RT-PCR and Western blot analysis of PCM cell lines gave identical results. Interestingly, we detected mRNA transcripts of CD79b in PCM cell lines, although protein translation was lacking. These findings suggest that expression of CD79b is downregulated in both plasma cells and plasma cell myeloma, and this process is possibly under post transcriptional regulation.

DOI： 10.1111/j.1440-1827.2010.02634.x

Multicentric Castleman's disease with abundant IgG4-positive cells: a clinical and pathological analysis of six cases

Yasuharu Sato, Masaru Kojima, Katsuyoshi Takata, Toshiaki Morito, Kohichi Mizobuchi, Takehiro Tanaka, Dai Inoue, Hideyuki Shiomi, Haruka Iwao, Tadashi Yoshino

JOURNAL OF CLINICAL PATHOLOGY 63 ( 12 ) 1084 - 1089 2010.12

Language：English Publishing type：Research paper (scientific journal) Publisher：B M J PUBLISHING GROUP

Background Differentiation between multicentric Castleman's disease and systemic immunoglobulin (Ig) G4-related lymphadenopathy is sometimes difficult. It has been suggested that measurement of the IgG4-/IgG-positive cell ratio is useful for the differential diagnosis of the two diseases. However, the authors present a detailed report of six patients with multicentric Castleman's disease with abundant IgG4-positive cells (IgG4-/IgG-positive cell ratio, >40%).
Results In the present series, the patients showed systemic lymphadenopathy, polyclonal hypergammaglobulinaemia and elevated serum interleukin-6 (IL-6) and C-reactive protein levels. Further, anaemia, hypoalbuminaemia, hypocholesterolaemia and thrombocytosis were observed. These findings were consistent with those of multicentric Castleman's disease. Although five patients showed elevated serum IgG4 levels, only two patients showed an increased serum IgG4/IgG ratio. However, the two patients showed highly elevated serum IgG4 levels, but the serum IgG4/IgG ratios were, although increased, not very high. Also, a patient with increased serum IgG4/IgG ratio showed a good response to antihuman IL-6 receptor monoclonal antibody (tocilizumab). Histologically, the germinal centres were mostly small and regressive, and frequently penetrated by hyalinised blood vessels, and there was no eosinophil infiltration. These findings were different from those of IgG4-related lymphadenopathy.
Conclusions The authors conclude that multicentric Castleman's disease sometimes occurs with abundant IgG4-positive cells and elevated serum IgG4 levels. Therefore, the two diseases cannot be differentially diagnosed by immunohistochemical staining alone. Laboratory findings, especially IL-6 level, C-reactive protein level and platelet count, are important for the differential diagnosis of the two diseases.

DOI： 10.1136/jcp.2010.082958

Epstein-Barr virus-associated primary central nervous system lymphomas in immunocompetent elderly patients: analysis for latent membrane protein-1 oncogene deletion and EBNA-2 strain typing

Yasuo Sugita, Mizuhiko Terasaki, Daisuke Niino, Koichi Ohshima, Arakawa Fumiko, Minoru Shigemori, Yasuharu Sato, Naoko Asano

JOURNAL OF NEURO-ONCOLOGY 100 ( 2 ) 271 - 279 2010.11

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

Epstein-Barr virus (EBV) has been implicated in the pathogenesis of primary central nervous system lymphomas (PCNLs) in immunocompetent hosts. To investigate the role of EBV in the pathogenesis of PCNLs in immunocompetent hosts, this study assessed six PCNL cases (elderly male immunocompetent patients; age a parts per thousand yen60 years) histologically and immunohistochemically, and an EBV genetic study was performed. Histologically, all cases were diagnosed as diffuse large B-cell lymphoma with extensive necrosis. In all six cases, PCNL cells showed immunohistochemical positivity for latent membrane protein 1 (LMP-1) and Epstein-Barr nuclear 2 (EBNA2). Lymphoma cells also showed positive signals for EBV-encoded small RNAs (EBERs) on in-situ hybridization. EBV subtyping-PCR analysis demonstrated that one case was EBNA 2B type and the other five cases were EBNA 2A type, and two cases were EBV wild-type and four cases showed 30-bp LMP-1 deletion by PCR analysis. It is therefore possible that LMP gene deletion or EBNA-2 strain type are important in the tumorigenesis of EBV-positive PCNLs. In addition, EBV-positive PCNLs in immunocompetent hosts may be related to immunological deterioration derived from the aging process.

DOI： 10.1007/s11060-010-0191-z

A duodenal follicular lymphoma associated with the lesion mimicking MALT lymphoma in terminal ileum and Bauhin valve

Akira Tari, Yasuharu Sato, Hideki Asaoku, Masaki Kunihiro, Akira Fukumoto, Shinji Tanaka, Megumu Fujihara, Tadashi Yoshino

MEDICAL MOLECULAR MORPHOLOGY 43 ( 3 ) 174 - 177 2010.9

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER TOKYO

This is a case report of a 66-year-old woman who consulted us with a 1-week history of postprandial epigastric discomfort and dyspepsia. Upper and lower gastrointestinal endoscopy and double-balloon enteroscopy revealed lesions in three parts: a swelling with a shallow depression in the ampulla of Vater, flat and rough nodules in the jejunum, and a mixture of lymphoid polyposis and rough surface of follicular lymphoma of the terminal ileum and Bauhin valve. The histological, immunophenotypic, and molecular findings of the duodenal lesion confirmed the diagnosis of follicular lymphoma. We initially diagnosed the ileal lesion as MALT lymphoma immunohistochemically. However, Southern blot hybridization analysis for immunoglobulin heavy chain gene rearrangement showed identical monoclonal bands in both the duodenal and ileal lesions. The molecular cytogenetic studies were also positive for the 14;18 translocation in both lesions. Therefore, the true diagnosis of this ileal lesion should be a follicular lymphoma with marginal zone differentiation. Primary follicular lymphomas of gastrointestinal tract were suggested to have intermediate features between nodal follicular lymphoma and MALT lymphoma. This case is an important clue to prove the similarity of follicular lymphoma of gastrointestinal tract to MALT lymphoma and will be crucial in considering the therapeutic strategy.

DOI： 10.1007/s00795-009-0477-4

IgG4-related disease: Historical overview and pathology of hematological disorders

Yasuharu Sato, Kenji Notohara, Masaru Kojima, Katsuyoshi Takata, Yasufumi Masaki, Tadashi Yoshino

PATHOLOGY INTERNATIONAL 60 ( 4 ) 247 - 258 2010.4

Language：English Publisher：WILEY-BLACKWELL

IgG4-related diseases comprise a recently recognized systemic syndrome characterized by mass-forming lesions in mainly exocrine tissue that consist of lymphoplasmacytic infiltrates and sclerosis. There are numerous IgG4-positive plasma cells in the affected tissues, and the serum IgG4 level is increased in these patients. The present study describes the history, autoimmune pancreatitis (AIP), IgG4-related lymphadenopathy and lymphomagenesis based upon ocular adnexal IgG4-related disease. Lymphoplasmacytic sclerosing pancreatitis, a prototypal histological type of AIP, is now recognized as a systemic IgG4-related disease. Lymph node lesions can be subdivided into at least five histological subtypes, and systemic IgG4-related lymphadenopathy should be distinguished from multicentric Castleman's disease. Interleukin-6 and CRP levels are abnormally high in multicentric Castleman's disease, but are normal in the majority of systemic IgG4-related lymphadenopathy. Ocular adnexal IgG4-related disease frequently involves bilateral lacrimal glands swelling, and obliterative phlebitis is rare. Moreover, some malignant lymphomas, especially mucosa-associated lymphoid tissue lymphoma, arise from ocular adnexal IgG4-related disease. In addition, IgG4-producing lymphoma also exists.

DOI： 10.1111/j.1440-1827.2010.02524.x

Immunoglobulin G4 (IgG4)-Positive or -Negative Ocular Adnexal Benign Lymphoid Lesions in Relation to Systemic Involvement

MATSUO Toshihiko, ICHIMURA Kouichi, SATO Yasuharu, TANIMOTO Yasushi, KIURA Katsuyuki, KANAZAWA Sou, OKADA Toshiaki, YOSHINO Tadashi

The journal of the Japanese Society of Lymphoreticular Tissue research 50 ( 2 ) 129 - 142 2010

Language：English Publisher：The Japanese Society for Lymphoreticular Tissue Research

The purpose of this study is to determine the relationship of ocular adnexal benign or reactive lymphoid hyperplasia, including orbital pseudotumor, with immunoglobulin G4 (IgG4)-related diseases. Medical charts of 9 consecutive patients with ocular adnexal benign lymphoid lesions, seen in the Department of Ophthalmology, Okayama University Hospital, were reviewed, and pathological sections were restained immunohistochemically for IgG4-, IgG-, and CD138-positive plasma cells. The diagnosis of IgG4-positive lesions was based on 10 or more IgG4-positive plasma cells in a high-power field and greater than 40% ratios of IgG4-positive plasma cells/CD138-positive plasma cells and IgG4-positive plasma cells/IgG-positive plasma cells. IgG4-positive lesions were determined as absent in 5 patients (4 with bilateral lacrimal/orbital lesions and one with a unilateral conjunctival lesion), none of whom showed systemic manifestations. In contrast, IgG4-positive lesions were present in 4 patients (3 with bilateral lacrimal/orbital lesions and one with a unilateral lacrimal/orbital lesion), who showed systemic manifestations : one with Hashimoto thyroiditis, one with IgG4-positive bilateral interstitial lung disease and hepatic inflammatory pseudotumor, one with bilateral interstitial lung disease, and one with systemic lymphadenopathy and antiphospholipid syndrome. In conclusion, IgG4-positive ocular adnexal benign lymphoid lesions might be used as a benchmark for the probable presence of other systemic lymphoid lesions.

DOI： 10.3960/jslrt.50.129

Other Link： http://search.jamas.or.jp/link/ui/2011254628

BAFF-R is Expressed on B-cell Lymphomas Depending on their Origin, and its Related to Proliferation Index of Nodal Diffuse Large B-cell Lymphomas

TAKAHATA Hiroyuki, OHARA Nobuya, ICHIMURA Kouichi, TANAKA Takehiro, SATO Yasuharu, MORITO Toshiaki, TAKATA Katsuyoshi, KOJIMA Masaru, KOBATA Tetsuji, YOSHINO Tadashi

The journal of the Japanese Society of Lymphoreticular Tissue research 50 ( 2 ) 121 - 127 2010

Language：English Publisher：The Japanese Society for Lymphoreticular Tissue Research

B-cell activating factor receptor (BAFF-R) is one of three known receptors for BAFF. BAFF-R is required for B-cell maturation and survival. We tried to determine the normal pattern of BAFF-R expression in non-neoplastic and neoplastic B- and T-cells. We used immunohistochemistry to evaluate the expression pattern of BAFF-R in non-neoplastic and neoplastic lymphoid tissues of routinely fixed paraffin-embedded samples, and examined the relationships among BAFF-R and expressions of CD10, bcl-6, MUM-1, and MIB-1. BAFF-R expression was detected on B-cells of the mantle zones, some cells within germinal centers, and scattered cells in the interfollicular areas of reactive lymph nodes. BAFF-R expression was only found in B-cell lymphoma (60/120, positive samples/examined samples), but not in T/NK cell lymphoma (0/10) or Hodgkin lymphoma (0/10). The proportions were as follows : follicular lymphoma (14/16), diffuse large B-cell lymphoma (DLBCL) (27/61), mantle cell lymphoma (4/4), and Burkitt lymphoma (0/4). According to Hans' criteria, DLBCLs were subclassified into germinal center B-cell-like (GCB) and non-germinal center B-cell-like (non-GCB) types. Interestingly, in nodal lymphomas, in the GCB subgroup (n=12), 9 of 12 (75%) were positive for BAFF-R, while 6 of 20 (30%) were positive in the non-GCB subgroup (n=20) (p < 0.05). In addition, expression of BAFF-R related to lower MIB-1 index was associated with GCB-type DLBCL. In conclusion, BAFF-R was only found in some B-cell lymphomas, which was closely associated with the expression pattern in normal counterparts, although BAFF-R expression on follicular lymphoma is different from that on germinal center cells, which is similar to bcl-2. BAFF-R was rather specifically related to low growth activity of GCB-type DLBCL of nodal origin.

DOI： 10.3960/jslrt.50.121

Other Link： http://search.jamas.or.jp/link/ui/2011254627

BAFF-R is expressed on B-cell lymphomas depending on their origin, and is related to proliferation index of nodal diffuse large B-cell lymphomas.

Hiroyuki Takahata, Nobuya Ohara, Kouichi Ichimura, Takehiro Tanaka, Yasuharu Sato, Toshiaki Morito, Katsuyoshi Takata, Masaru Kojima, Tetsuji Kobata, Tadashi Yoshino

Journal of clinical and experimental hematopathology : JCEH 50 ( 2 ) 121 - 127 2010

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

B-cell activating factor receptor (BAFF-R) is one of three known receptors for BAFF. BAFF-R is required for B-cell maturation and survival. We tried to determine the normal pattern of BAFF-R expression in non-neoplastic and neoplastic B- and T-cells. We used immunohistochemistry to evaluate the expression pattern of BAFF-R in non-neoplastic and neoplastic lymphoid tissues of routinely fixed paraffin-embedded samples, and examined the relationships among BAFF-R and expressions of CD10, bcl-6, MUM-1, and MIB-1. BAFF-R expression was detected on B-cells of the mantle zones, some cells within germinal centers, and scattered cells in the interfollicular areas of reactive lymph nodes. BAFF-R expression was only found in B-cell lymphoma (60/120, positive samples/examined samples), but not in T/NK cell lymphoma (0/10) or Hodgkin lymphoma (0/10). The proportions were as follows : follicular lymphoma (14/16), diffuse large B-cell lymphoma (DLBCL) (27/61), mantle cell lymphoma (4/4), and Burkitt lymphoma (0/4). According to Hans' criteria, DLBCLs were subclassified into germinal center B-cell-like (GCB) and non-germinal center B-cell-like (non-GCB) types. Interestingly, in nodal lymphomas, in the GCB subgroup (n=12), 9 of 12 (75%) were positive for BAFF-R, while 6 of 20 (30%) were positive in the non-GCB subgroup (n=20) (p &lt
0.05). In addition, expression of BAFF-R related to lower MIB-1 index was associated with GCB-type DLBCL. In conclusion, BAFF-R was only found in some B-cell lymphomas, which was closely associated with the expression pattern in normal counterparts, although BAFF-R expression on follicular lymphoma is different from that on germinal center cells, which is similar to bcl-2. BAFF-R was rather specifically related to low growth activity of GCB-type DLBCL of nodal origin.

DOI： 10.3960/jslrt.50.121

Chronic sclerosing pyelitis with an increased number of IgG4-positive plasma cells

Naoto Kuroda, Shoichiro Nakamura, Katsushi Miyazaki, Kaori Inoue, Masahiko Ohara, Keiko Mizuno, Yasuharu Sato, Tadashi Yoshino

MEDICAL MOLECULAR MORPHOLOGY 42 ( 4 ) 236 - 238 2009.12

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER TOKYO

IgG4-related disease has been recently described. This disease occurs in various anatomic locations including pancreas, biliary tract, liver, retroperitoneum, kidney, breast, lung, thyroid gland, prostate, salivary gland, lacrimal gland, and lymph node. In this article, we report the first case of IgG4-related disease arising in the renal pelvis. A 49-year-old Japanese woman was found to show left hydronephrosis by a medical checkup. Histological examination of the renal pelvic tumor showed IgG4-related disease. Her postoperative serum IgG4 was elevated, and this was compatible with IgG4-related disease. Systemic examination showed swelling of major and minor salivary glands and the lacrimal glands, and biopsy of the minor salivary gland revealed the finding of IgG4-related disease. Finally, pathologists and clinicians should be aware of the possibility that the renal pelvis may be involved in IgG4-related systemic disease.

DOI： 10.1007/s00795-008-0425-8

Aberrations of Genes Regulating NF Kappa B Pathway in B-Cell Malignant Lymphoma Reviewed

Kato Motohiro, Sanada Masashi, Kato Itaru, Sato Yasuharu, Takita Junko, Kawahata Ryoichiro, Takeuchi Kengo, Niwa Akira, Chen Yuyan, Nakazaki Kumi, Nomoto Junko, Asakura Yoshitaka, Akatsuka Yoshiki, Hayashi Yasuhide, Igarashi Takashi, Kurokawa Mineo, Chiba Shigeru, Mori Shigeo, Ishikawa Yuichi, Okamoto Koji, Tobinai Kensei, Nakagama Hitoshi, Nakahata Tatsutoshi, Yoshino Tadashi, Kobayashi Yukio, Ogawa Seishi

BLOOD 114 ( 22 ) 401 - 401 2009.11

Frequent downregulation or loss of CD79a expression in plasma cell myelomas: potential clue for diagnosis. International journal

Takehiro Tanaka, Kouichi Ichimura, Yasuharu Sato, Katsuyoshi Takata, Toshiaki Morito, Maiko Tamura, Eisaku Kondo, Nobuya Ohara, Hiroyuki Yanai, Masaharu Sakai, Satoru Takahashi, Tadashi Yoshino

Pathology international 59 ( 11 ) 804 - 8 2009.11

Language：English

Plasma cell myeloma is a frequent hematogeneous disorder that occurs mainly in older people. Not only bone marrow smears but also clots and/or biopsied specimens are often taken for confirmation of pathological diagnosis. Some specimens show sheet-like plasma cell proliferation associated with immunoglobulin monotype on immunohistology, which readily leads to diagnosis, but many samples do not clearly show light-chain restriction. The aim of the present study was therefore to examine CD79a expression because some samples had reduced expression or none at all. The immunoreactivity of CD79a was categorized into three groups: positive, weakly positive and negative, compared with scattering non-neoplastic plasma cells in the same specimen. Out of 100 specimens of plasma cell myeloma, 48% were positive for CD79a, 15% were weakly positive, and 37% were negative. In contrast, overexpression of cyclinD1 was detected in 26% of examined samples. CD79a-negative cases had a significantly lower percentage of positive staining for cyclinD1 than CD79a-positive or weakly positive cases. Clinicopathological data showed that CD79a-negative expression was associated with decreased platelet numbers in patients. The present study indicates that downregulation or loss of CD79a and/or overexpression of cyclin D1, observed in 59% of neoplastic plasma cell samples, could provide a strong diagnostic clue without regard to the results of immunoglobulin light-chain restriction.

DOI： 10.1111/j.1440-1827.2009.02448.x

Duodenal and nodal follicular lymphomas are distinct: the former lacks activation-induced cytidine deaminase and follicular dendritic cells despite ongoing somatic hypermutations. International journal

Katsuyoshi Takata, Yasuharu Sato, Naoya Nakamura, Yara Yukie Kikuti, Koichi Ichimura, Takehiro Tanaka, Toshiaki Morito, Maiko Tamura, Takashi Oka, Eisaku Kondo, Hiroyuki Okada, Akira Tari, Tadashi Yoshino

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 22 ( 7 ) 940 - 9 2009.7

Language：English

Although most follicular lymphomas are believed to be of nodal origin, they sometimes originate from the duodenum. We have reported that the latter differ from nodal follicular lymphomas in having lower clinical stages and uniformly low histological grades, along with variable region of immunoglobulin heavy chain gene (VH) usage that is more similar to mucosa-associated lymphoid tissue (MALT) lymphomas. Little is known, however, about whether they possess other characteristics of nodal follicular lymphomas, particularly ongoing mutations with follicular dendritic cells. We examined 17 cases for which PCR identified the monoclonal bands of the immunoglobulin gene. The duodenal cases showed ongoing mutations, but they lacked activation-induced cytidine deaminase (AID) expression, a statistically significant difference from the nodal cases (P<0.001), and their follicular dendritic cell networks were disrupted. Moreover, not only were VH deviations observed but also they used very restricted VH genes. Although the mechanisms of ongoing mutation without AID and follicular dendritic cell were not clarified, restricted VH usage strongly suggested that antigen stimulation was involved, and that was similar to MALT lymphomas. In conclusion, duodenal follicular lymphomas were shown to be unique, in that they had ongoing hypermutations such as nodal cases, but the mechanisms involved in the hypermutation were quite different; furthermore, restricted VH usage suggested a strong similarity to the antigen-dependent origin of MALT lymphomas.

DOI： 10.1038/modpathol.2009.51

Serum soluble interleukin-2 receptor level and immunophenotype are prognostic factors for patients with diffuse large B-cell lymphoma

Toshiaki Morito, Megumu Fujihara, Hideki Asaoku, Akira Tari, Yasuharu Sato, Kouichi Ichimura, Takehiro Tanaka, Katsuyoshi Takata, Maiko Tamura, Tadashi Yoshino

CANCER SCIENCE 100 ( 7 ) 1255 - 1260 2009.7

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL PUBLISHING, INC

Diffuse large B-cell lymphoma is the most common form of non-Hodgkin lymphoma. Although many studies have attempted to identify prognostic factors, most have focused on conventionally treated patients. The influence of anti-CD20 antibody (rituximab) should be considered now. We evaluated the prognostic significance of serum soluble interleukin-2 receptor levels and germinal center B-cell-like or non-germinal center B-cell like subgroups in 80 patients with diffuse large B-cell lymphoma, who had been treated with rituximab. Serum soluble interleukin-2 receptor levels ranged from 322 to 39900 U/mL (median 1365 U/mL). Sixteen (20%) were germinal center B-cell-like subgroups, and the remainder (80%) non-germinal center B-cell-like. Survival analysis associated lower serum soluble interleukin-2 receptor level and germinal center B-cell-like phenotype with better overall survival (P = 0.015), whereas multivariate analysis, including International Prognostic Index factors, revealed that only higher performance status score and higher serum lactate dehydrogenase levels significantly affected survival. However, serum soluble interleukin-2 receptor levels were elevated in patients with higher International Prognostic Index scores as well as in the non-germinal center B-cell-like subgroup. Serum soluble interleukin-2 receptor levels, International Prognostic Index, and subphenotypes were strongly correlated with each other. Our study showed that soluble interleukin-2 receptor is quite useful and may serve as a substitute for the International Prognostic Index, especially for patients undergoing treatment. Moreover, the differentiation between the germinal center B-cell-like and non-germinal center B-cell-like phenotypes is also useful for predicting patients with diffuse large B-cell lymphoma, even among those treated with rituximab. (Cancer Sci 2009; 100: 1255-1260)

DOI： 10.1111/j.1349-7006.2009.01167.x

Frequent inactivation of A20 in B-cell lymphomas

Motohiro Kato, Masashi Sanada, Itaru Kato, Yasuharu Sato, Junko Takita, Kengo Takeuchi, Akira Niwa, Yuyan Chen, Kumi Nakazaki, Junko Nomoto, Yoshitaka Asakura, Satsuki Muto, Azusa Tamura, Mitsuru Iio, Yoshiki Akatsuka, Yasuhide Hayashi, Hiraku Mori, Takashi Igarashi, Mineo Kurokawa, Shigeru Chiba, Shigeo Mori, Yuichi Ishikawa, Koji Okamoto, Kensei Tobinai, Hitoshi Nakagama, Tatsutoshi Nakahata, Tadashi Yoshino, Yukio Kobayashi, Seishi Ogawa

NATURE 459 ( 7247 ) 712 - U118 2009.6

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

A20 is a negative regulator of the NF-kappa B pathway and was initially identified as being rapidly induced after tumour-necrosis factor-alpha stimulation(1). It has a pivotal role in regulation of the immune response and prevents excessive activation of NF-kappa B in response to a variety of external stimuli(2-7); recent genetic studies have disclosed putative associations of polymorphic A20 (also called TNFAIP3) alleles with autoimmune disease risk(8,9). However, the involvement of A20 in the development of human cancers is unknown. Here we show, using a genome-wide analysis of genetic lesions in 238 B-cell lymphomas, that A20 is a common genetic target in B-lineage lymphomas. A20 is frequently inactivated by somatic mutations and/or deletions in mucosa-associated tissue lymphoma (18 out of 87; 21.8%) and Hodgkin's lymphoma of ;nodular sclerosis histology (5 out of 15; 33.3%), and, to a lesser extent, in other B-lineage lymphomas. When re-expressed in a lymphoma-derived cell line with no functional A20 alleles, wildtype A20, but not mutant A20, resulted in suppression of cell growth and induction of apoptosis, accompanied by down-regulation of NF-kappa B activation. The A20-deficient cells stably generated tumours in immunodeficient mice, whereas the tumorigenicity was effectively suppressed by re-expression of A20. In A20-deficient cells, suppression of both cell growth and NF-kappa B activity due to re-expression of A20 depended, at least partly, on cell-surface-receptor signalling, including the tumour-necrosis factor receptor. Considering the physiological function of A20 in the negative modulation of NF-kappa B activation induced by multiple upstream stimuli, our findings indicate that uncontrolled signalling of NF-kappa B caused by loss of A20 function is involved in the pathogenesis of subsets of B-lineage lymphomas.

DOI： 10.1038/nature07969

Systemic IgG4-related lymphadenopathy: a clinical and pathologic comparison to multicentric Castleman's disease

Yasuharu Sato, Masaru Kojima, Katsuyoshi Takata, Toshiaki Morito, Hideki Asaoku, Tamotsu Takeuchi, Kohichi Mizobuchi, Megumu Fujihara, Kazuya Kuraoka, Tokiko Nakai, Kouichi Ichimura, Takehiro Tanaka, Maiko Tamura, Yuriko Nishikawa, Tadashi Yoshino

MODERN PATHOLOGY 22 ( 4 ) 589 - 599 2009.4

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

IgG4-related disease sometimes involves regional and/or systemic lymph nodes, and often clinically and/or histologically mimics multicentric Castleman's disease or malignant lymphoma. In this study, we examined clinical and pathologic findings of nine patients with systemic IgG4-related lymphadenopathy. None of these cases were associated with human herpes virus-8 or human immunodeficiency virus infection, and there was no T-cell receptor or immunoglobulin gene rearrangement. Histologically, systemic IgG4-related lymphadenopathy was classified into two types by the infiltration pattern of IgG4-positive cells: interfollicular plasmacytosis type and intra-germinal center plasmacytosis type. The interfollicular plasmacytosis type showed either Castleman's disease-like features or atypical lymphoplasmacytic and immunoblastic proliferation-like features. By contrast, the intra-germinal center plasmacytosis type showed marked follicular hyperplasia, and infiltration of IgG4-positive cells mainly into the germinal centers, and some cases exhibited features of progressively transformed germinal centers. Interestingly, eight of our nine (89%) cases showed eosinophil infiltration in the affected lymph nodes, and examined patients showed high elevation of serum IgE. Laboratory examinations revealed elevation of serum IgG4 and soluble interleukin-2 receptors. However, the levels of interleukin-6, C-reactive protein, and lactate dehydrogenase were within normal limits or only slightly elevated in almost all patients. One patient showed a high interleukin-6 level whereas C-reactive protein was within the normal limit. Autoantibodies were examined in five patients and detected in four. Compared with the previously reported cases of multicentric Castleman's disease, our patients with systemic IgG4-related lymphadenopathy were significantly older and had significantly lower C-reactive protein and interleukin-6 levels. In conclusion, in our systemic IgG4-related lymphadenopathy showed pathologic features only partially overlapping those of multicentric Castleman's disease, and serum data (especially C-reactive protein and interleukin-6) are useful for differentiating the two. Our findings of eosinophil infiltration in the affected tissue and elevation of serum IgE may suggest an allergic mechanism in the pathogenesis of systemic IgG4-related lymphadenopathy.

DOI： 10.1038/modpathol.2009.17

Patients with localized primary non-tonsillar oral diffuse large B-cell lymphoma exhibit favorable prognosis despite a non-germinal center B-cell-like phenotype

Yasuharu Sato, Naoko Onishi, Toshiaki Morito, Katsuyoshi Takata, Kohichi Mizobuchi, Hitoshi Nagatsuka, Kouichi Ichimura, Takehiro Tanaka, Maiko Tamura, Tadashi Yoshino

CANCER SCIENCE 100 ( 1 ) 42 - 46 2009.1

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL PUBLISHING, INC

Diffuse large B-cell lymphomas are detected frequently in the oral cavity. Although tonsillar lymphomas have been rather well characterized, lymphomas originating from non-tonsillar regions, such as the gingiva, palate, and tongue, have not been well studied. We examined the pathology of clinical samples obtained from 21 patients with localized primary non-tonsillar oral diffuse large B-cell lymphoma. Immunohistological examination of CD10, Bcl-6, and MUM1 determined that 17 of 21 (81%) samples exhibited non-germinal center B-cell type, an increased proportion of non-germinal center B-cell type compared with previous reports in samples of tonsillar origin (P < 0.05). The four remaining samples exhibited germinal center B-cell type, although one sample expressed MUM1. Follow-up clinical survival data were obtained from the 17 patients over a range from 4 to 173 months (mean 52 months). All patients were treated with chemotherapies, irradiation, or surgical resection. Sixteen patients achieved complete remission and two patients relapsed, but no patient has died of disease. Extranodal diffuse large B-cell lymphomas of non-germinal center B-cell type are generally characterized by poor prognosis, regardless of localized disease. Interestingly, our results indicate that, unlike similar lymphomas of tonsillar origin, localized primary non-tonsillar oral diffuse large B-cell lymphomas exhibit favorable prognosis, suggesting that these lymphomas may be clinicopathologically distinct. (Cancer Sci 2009; 100: 42-46).

DOI： 10.1111/j.1349-7006.2008.00995.x

Genome-Wide Analysis of B Cell Non-Hodgkin's Lymphoma Disclosed Frequent Involvement of Genes in NFkB Pathway Reviewed

Kato Motohiro, Nakazaki Kumi, Sato Yasuharu, Takeuchi Kengo, Sanada Masashi, Asakura Yoshitaka, Muto Satsuki, Chen Yuyan, Takita Junko, Hayashi Yasuhide, Igarashi Takashi, Watanabe Toshiki, Tobinai Kensei, Ishikawa Yuichi, Mori Shigeo, Kurokawa Mineo, Yoshino Tadashi, Kobayashi Yukio, Ogawa Seishi

BLOOD 112 ( 11 ) 300 2008.11

IgG4-producing marginal zone B-cell lymphoma

Yasuharu Sato, Katsuyoshi Takata, Kouichi Ichimura, Takehiro Tanaka, Toshiaki Morito, Maiko Tamura, Tadashi Yoshino

INTERNATIONAL JOURNAL OF HEMATOLOGY 88 ( 4 ) 428 - 433 2008.11

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

IgG4-related disease is a recently proposed clinical entity with several unique clinicopathological features. A chronic inflammatory state with marked fibrosis, which can often be mistaken for malignancy, especially by clinical imaging analyses, unifies these features. Little is known about lymphomagenesis in the context of IgG4-related disease, we recently first reported the ocular adnexal marginal zone B-cell lymphomas arising from IgG4-related disease. To the best of our knowledge, no existing study has ever established the neoplastic potential of IgG4-producing cells. In the present report, we describe the first IgG4-producing lymphoma. The patient was a 72-year-old male who was being followed for an asbestos-related pleural plaque. During follow-up, computed tomography revealed bilateral renal masses and multiple swollen retroperitoneal lymph nodes. A retroperitoneal lymph node biopsy was performed. Histologically, the interfollicular areas were expanded by medium to large plasmacytoid cells. These plasmacytoid cells showed nuclear pleomorphism and had prominent Russell bodies. Immunohistochemistry and double immunofluorescence staining of these cells revealed IgG4 positivity and monotypic lambda-light chain predominance. A portion of these cells were partially positive for CD20, negative for CD3, and somewhat faintly positive for CD138. In addition, serum IgG4 was elevated. Southern blot analysis of the lymph node specimen detected immunoglobulin heavy chain gene rearrangement. The present study indicates that, not only can malignant lymphomas occur in the setting of IgG4-related disease, but IgG4-producing cells can also be neoplastic.

DOI： 10.1007/s12185-008-0170-8

Ocular adnexal IgG4-related disease has uniform clinicopathology. International journal

Yasuharu Sato, Koh-ichi Ohshima, Kouichi Ichimura, Masakazu Sato, Ichiro Yamadori, Takehiro Tanaka, Katsuyoshi Takata, Toshiaki Morito, Eisaku Kondo, Tadashi Yoshino

Pathology international 58 ( 8 ) 465 - 70 2008.8

Language：English

IgG4-related disease is a recently proposed clinical entity with several unique clinicopathological features. Ocular adnexal IgG4-related disease, however, has not well been clarified. The purpose of the present study was to examine 21 patients (10 men, 11 women; age range, 39-86 years) with ocular adnexal IgG4-related disease. In 17 out of 21 patients (81%), the lacrimal glands were involved and bilateral lacrimal gland swelling was frequently observed (n = 12; 70.6%). In contrast, the conjunctiva was not involved in any of the patient. Histology was uniform with marked lymphoplasmacytic infiltration admixed with dense fibrosis, similar to previous reports of IgG4-related disease. Immunostaining detected numerous aggregates of IgG4-positive plasma cells. Serum IgG4 was higher than normal in 10 of the 13 patients tested, although it was measured after treatment in almost all cases. Interestingly, immunoglobulin heavy chain gene rearrangement was detected in two of 17 patients (12%) examined. The present results show that ocular adnexal IgG4-related disease has uniform clinicopathology: that is, disease involving the bilateral lacrimal glands with lymphoid hyperplasia and fibrosis, but not the conjunctiva. And presence of immunoglobulin heavy chain gene rearrangement suggests the possibility of B-cell lymphoma arising in a background of IgG4-related chronic inflammation.

DOI： 10.1111/j.1440-1827.2008.02257.x

Duodenal follicular lymphomas share common characteristics with mucosa-associated lymphoid tissue lymphomas

Y. Sato, K. Ichimura, T. Tanaka, K. Takata, T. Morito, H. Sato, Y. Sato, E. Kondo, H. Yanai, N. Ohara, T. Oka, T. Yoshino

JOURNAL OF CLINICAL PATHOLOGY 61 ( 3 ) 377 - 381 2008.3

Language：English Publishing type：Research paper (scientific journal) Publisher：B M J PUBLISHING GROUP

Background: Follicular lymphomas occasionally arise in the extra-nodal organs and are frequently found in the duodenum. They are often localised tumours with multiple polyps around the ampulla of Vater.
Aims: To examine a IgH/bcl-2 hybrid gene and VH gene to investigate the nature of the lymphoma cells and how they differ from nodal follicular lymphomas and MALT lymphomas.
Methods: Of 40 patients reported previously, 35 with duodenal follicular lymphoma were studied in detail with respect to clinicopathological characteristics.
Results: 37/40 patients were in clinical stage I (n= 30) or stage II (n= 7). Clonal immunoglobulin gene rearrangement was detected in 53.3% of examined cases, and rearrangement of IgH/bcl-2 gene at the major break point was detected in 27% of cases. Three of 8 examined cases were VH4 (38%); 2 out of them were VH4-34. As VH4 deviation is one of the common characteristics of MALT lymphomas and 2/3 were identical, duodenal follicular lymphomas have a similar aetiology to MALT lymphomas. Clinical course was also similar to that of MALT lymphomas.
Conclusions: Results suggest that duodenal follicular lymphomas have intermediate characteristics of MALT lymphomas and nodal follicular lymphomas.

DOI： 10.1136/jcp.2007.049825

HHV-8/KSHV-Negative and CD20-Positive Primary Effusion Lymphoma Successfully Treated by Pleural Drainage Followed by Chemotherapy Containing Rituximab

Yasushi Terasaki, Hirokazu Okumura, Katsuhiko Saito, Yasuharu Sato, Tadashi Yoshino, Ryo Ichinohasama, Youichi Ishida

INTERNAL MEDICINE 47 ( 24 ) 2175 - 2178 2008

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC INTERNAL MEDICINE

The present patient was diagnosed as having human herpes virus-8 (HHV-8)/Kaposi sarcoma herpes virus (KSHV)-negative and CD20-positive primary effusion lymphoma (PEL) of the right-sided pleural effusion. After pleural drainage, malignant cells disappeared spontaneously in a small amount of the remaining pleural effusion without chemotherapy. The patient was treated with six cycles of chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone. He has been in complete remission for more than 22 months. It is suggested that effusion drainage followed by chemotherapy containing rituximab is a potential treatment strategy for patients with HHV-8/KSHV-negative and CD20-positive PEL.

DOI： 10.2169/internalmedicine.47.1565

ラット中脳動脈閉塞・再灌流モデルにおける抗 HMGB1 単クローン抗体の治療効果

劉克約, 森秀治, 高橋英夫, 友野靖子, 和気秀徳, 菅家徹, 佐藤康晴, 平賀憲人, 足立尚登, 吉野正, 西堀正洋

岡山医学会雑誌 120 ( 3 ) 271 - 277 2008

Synchronous Pulmonary MALT Lymphoma and Pulmonary Adenocarcinoma after Metachronous Gastric MALT Lymphoma and Gastric Adenocarcinoma

Eiki Ichihara, Masahiro Tabata, Nagio Takigawa, Yumilko Sato, Eisaku Kondo, Motoi Aoe, Katsuyuki Kiura, Mitsune Tanimoto

JOURNAL OF THORACIC ONCOLOGY 3 ( 11 ) 1362 - 1363 2008

Anti-high mobility group box1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats

Keyue Liu, Shuji Mori, Hideo Takahashi, Yasuko Tornono, Hidenori Wake, Toru Kanke, Yasuharu Sato, Norihito Hiraga, Naoto Adati, Tadashi Yoshino, Masahiro Nishibori

JOURNAL OF PHARMACOLOGICAL SCIENCES 106 129P - 129P 2008

Anti-high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats

Keyue Liu, Shuji Mori, Hideo K. Takahashi, Yasuko Tomono, Hidenori Wake, Toru Kanke, Yasuharu Sato, Norihito Hiraga, Naoto Adachi, Tadashi Yoshino, Masahiro Nishibori

FASEB JOURNAL 21 ( 14 ) 3904 - 3916 2007.12

Language：English Publishing type：Research paper (scientific journal) Publisher：FEDERATION AMER SOC EXP BIOL

The high mobility group box-1 (HMGB1), originally identified as an architectural nuclear protein, exhibits an inflammatory cytokine- like activity in the extracellular space. Here we show that treatment with neutralizing anti- HMGB1 monoclonal antibody ( mAb; 200 mu g, twice) remarkably ameliorated brain infarction induced by 2- h occlusion of the middle cerebral artery in rats, even when the mAb was administered after the start of reperfusion. Consistent with the 90% reduction in infarct size, the accompanying neurological deficits in locomotor function were significantly improved. Anti- HMGB1 mAb inhibited the increased permeability of the blood- brain barrier, the activation of microglia, the expression of TNF-alpha and iNOS, and suppressed the activity of MMP- 9, whereas it had little effect on blood flow. Intracerebroventricular injection of HMGB1 increased the severity of infarction. Immunohistochemical study revealed that HMGB1 immunoreactivity in the cell nuclei decreased or disappeared in the affected areas, suggesting the release of HMGB1 into the extracellular space. These results indicate that HMGB1 plays a critical role in the development of brain infarction through the amplification of plural inflammatory responses in the ischemic region and could be an outstandingly suitable target for the treatment. Intravenous injection of neutralizing anti- HMGB1 mAb provides a novel therapeutic strategy for ischemic stroke.

DOI： 10.1096/fj.07-8770com

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