Faculty Profiles - SATO Yasuharu

Papers - SATO Yasuharu

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[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

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