Faculty Profiles - SATO Yasuharu

Papers - SATO Yasuharu

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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

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

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

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

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

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

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

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

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

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

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

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