Wiley Acta Medica Okayama 0361-8609 100 4 2025 Exploring the Clinical Diversity of Castleman Disease and TAFRO Syndrome: A Japanese Multicenter Study on Lymph Node Distribution Patterns 592 605 EN Mizuna Otsuka Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences Tomohiro Koga Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences Remi Sumiyoshi Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences Shoichi Fukui Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences Yuko Kaneko Division of Rheumatology, Department of Internal Medicine Keio University School of Medicine Tokyo Japan Takayuki Shimizu Division of Hematology, Department of Medicine, Keio University School of Medicine Atsushi Katsube Division of Clinical Oncology and Hematology, Department of Internal Medicine, The Jikei University School of Medicine Shingo Yano Division of Clinical Oncology and Hematology, Department of Internal Medicine, The Jikei University School of Medicine Yasufumi Masaki Department of Hematology and Immunology, Kanazawa Medical University Makoto Ide Department of Hematology, Takamatsu Red Cross Hospital Hajime Yoshifuji DDepartment of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University Masayasu Kitano Department of Collagen Disease and Rheumatology, Sumitomo Hospital Yasuharu Sato Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Naoki Sawa Nephrology Center and Department of Rheumatology, Toranomon Hospital Kajigaya Hiroaki Niiro Department of Clinical Immunology and Rheumatology/Infectious Disease, Kyushu University Hospital Naoya Nakamura Department of Pathology, Tokai University School of Medicine David C. Fajgenbaum Center for Cytokine Storm Treatment & Laboratory, University of Pennsylvania Frits van Rhee Myeloma Center, University of Arkansas for Medical Sciences Atsushi Kawakami Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences 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. No potential conflict of interest relevant to this article was reported.

Japanese Society for Lymphoreticular Tissue Research Acta Medica Okayama 1346-4280 66 2 2026 RHOA G17V mutation analysis redirecting diagnosis: nodal T-follicular helper cell lymphoma with classic Hodgkin lymphoma feature 122 129 EN Rio Yamada Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Midori Filiz Nishimura Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Asami Nishikori Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Takuya Fukumi Department of Hematology, Okayama City Hospital Kumiko Ohsawa Department of Pathology, Saitama Medical Center, Saitama Medical University Shuji Momose Department of Pathology, Saitama Medical Center, Saitama Medical University Yasuharu Sato Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Nodal T-follicular helper cell lymphoma (nTFHL) may present with Hodgkin/Reed–Sternberg (HRS)-like cells and can morphologically mimic classic Hodgkin lymphoma (CHL), although these entities are usually distinguishable. We report an unusual case showing marked morphologic and molecular overlap with CHL, creating a diagnostic challenge but ultimately considered biologically consistent with nTFHL. An 81-year-old woman presented with stage IV disease involving the bone marrow and markedly elevated serum soluble interleukin-2 receptor levels. Excisional lymph node biopsy revealed scattered HRS cells in a T-cell–rich background, with strong CD30 and PD-L1 expression and weak PAX5 positivity, findings consistent with CHL. Fluorescence in situ hybridization demonstrated copy-number alterations at the 9p24.1 locus in HRS cells, further supporting molecular features characteristic of CHL. However, the presence of two T-follicular helper markers, detection of the RHOA p.Gly17Val (G17V) mutation, and oligoclonal T-cell receptor rearrangements with shared peaks in lymph node and bone marrow indicated an underlying nTFHL. The differential therapeutic response also supported a diagnosis of nTFHL, which could not have been established on morphology alone. In this case, although the HRS cells displayed morphological, immunophenotypic, and molecular features highly suggestive of CHL, the biological nature of the lesion was consistent with nTFHL. Compared with previously reported cases of nTFHL with HRS-like cells, this case more closely resembled CHL and may represent a distinct subset best described as “nTFHL with CHL features,” a concept warranting greater recognition among pathologists and clinicians. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 1572-1000 58 2026 Pathological features of residual head and neck cancer after near-infrared photoimmunotherapy: implications of an unfavorable tumor immune microenvironment 105422 EN Takuma Makino Department of Otolaryngology - Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuharu Sato Department of Hematopathology, Okayama University Graduate School of Health Sciences Asami Nishikori Department of Hematopathology, Okayama University Graduate School of Health Sciences Yuto Naoi Department of Otolaryngology - Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mizuo Ando Department of Otolaryngology - Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Purpose: Near-infrared photoimmunotherapy has been approved in Japan for unresectable locally advanced or recurrent head and neck cancer. While this therapy theoretically induces selective necrosis of epidermal growth factor receptor-expressing tumor cells following administration of cetuximab sarotalocan sodium and irradiation with 690-nm light, residual disease is not uncommon in clinical practice. The mechanisms underlying such persistence remain poorly understood. Methods: We examined two patients with head and neck squamous cell carcinoma who underwent salvage resection due to residual disease after four cycles of near-infrared photoimmunotherapy. Resected specimens were subjected to histopathological evaluation, including immunohistochemistry for epidermal growth factor receptor, cluster of differentiation 8, programmed cell death protein 1, and forkhead box P3 proteins. Results: In both cases, residual tumor cells were predominantly localized in the superficial mucosal layers, while deeper layers were replaced by fibrosis. All residual tumors retained expression of epidermal growth factor receptor. Lymphocytic infiltration was sparse, with scattered cluster of differentiation 8-positive cells but few programmed cell death protein 1-positive or forkhead box P3-positive lymphocytes. These findings suggest that the tumor microenvironment surrounding residual tumors may have been unfavorable for the induction of robust antitumor immune responses. Conclusion: Residual tumors after near-infrared photoimmunotherapy can occur despite adequate laser irradiation and epidermal growth factor receptor expression. Our observations imply that insufficient immune activation within the tumor microenvironment may contribute to treatment resistance. Further characterization of the post-photoimmunotherapy tumor microenvironment will be essential to better understand treatment mechanisms and to optimize therapeutic efficacy. No potential conflict of interest relevant to this article was reported.

Ferrata Storti Foundation (Haematologica) Acta Medica Okayama 1592-8721 111 5 2025 Distinct interleukin-6 production in IPL and TAFRO subtypes of idiopathic multicentric Castleman disease 1705 1715 EN Asami Nishikori Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Midori Filiz Nishimura Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Yoshito Nishimura Division of Hematology/Oncology, Mayo Clinic Rio Yamada Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Tomoka Haratake Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Daisuke Ennishi Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama, Japan; Department of Hematology and Oncology, Okayama University Hospital Ryota Chijimatsu Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama, Japan; Department of Hematology and Oncology, Okayama University Hospital Toshihiro Ito Department of Immunology, Nara Medical University Tomohiro Koga Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences Sayaka Ochi Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Yuri Kawahara Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Himawari Ueta Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Yudai Takeda Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Michael V. Gonzalez Center for Cytokine Storm Treatment and Laboratory, Department of Medicine, Perelman School of Medicine, University of Pennsylvania David C. Fajgenbaum Center for Cytokine Storm Treatment and Laboratory, Department of Medicine, Perelman School of Medicine, University of Pennsylvania Frits Van Rhee University of Arkansas for Medical Sciences Shuji Momose Department of Pathology, Saitama Medical Center, Saitama Medical University Yasuharu Sato Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder characterized by systemic inflammation and lymphadenopathy. Two major clinical subtypes, idiopathic plasmacytic lymphadenopathy (iMCD-IPL) and iMCD with thrombocytopenia, anasarca, fever, renal dysfunction/reticulin fibrosis, and organomegaly (iMCD-TAFRO), have distinct pathophysiological mechanisms. While interleukin-6 (IL-6) is known to be elevated in iMCD, differences in the sources of IL-6 production between subtypes remain unclear. We examined the source of IL-6 production and its transcriptional regulation across iMCD subtypes using immunohistochemistry, in situ hybridization, and gene expression profiling. Immunohistochemistry and in situ hybridization revealed that plasma cells were the predominant IL-6-expressing cells in iMCD-IPL, whereas vascular endothelial cells expressed IL-6 in iMCD-TAFRO. Plasma cells exhibited stronger IL-6 protein expression in iMCD-IPL than in iMCD-TAFRO. Gene expression analysis revealed upregulation of XBP1, MZB1, DERL3, SSR4, FKBP11, FKBP2, PIM2, RABAC1, and SDF2L1 in iMCD-IPL, implicating endoplasmic reticulum stress and plasma cell differentiation in IL-6 dysregulation. Our findings suggest that XBP1-mediated IL-6 production may contribute to the pathogenesis of iMCD-IPL, potentially explaining its favorable responses to IL-6 blockade therapy. In contrast, IL-6 production in iMCD-TAFRO may be predominantly from vascular endothelial cells, suggesting that elevated serum IL-6 is a secondary phenomenon of the cytokine storm in this subtype. Future studies should clarify how proteomics and gene expression profiling could inform subtype-specific therapeutic strategies in iMCD. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 0309-0167 2026 Clinicopathological and transcriptomic profiles of 101 patients with diffuse large B-cell lymphoma/high-grade B-cell lymphoma with double-hit MYC and BCL2 or BCL6 and triple hit EN Masashi Miyaoka Department of Pathology, School of Medicine, Tokai University Joaquim Carreras Department of Pathology, School of Medicine, Tokai University Yara Yukie Kikuti Department of Pathology, School of Medicine, Tokai University Haruka Ikoma Department of Pathology, School of Medicine, Tokai University Shunsuke Nagase Department of Pathology, School of Medicine, Tokai University Atsushi Ito Department of Pathology, School of Medicine Tokai University Isehara Japan Makoto Orita Department of Pathology, School of Medicine, Tokai University Hiroshi Kawada Department of Hematology, School of Medicine, Tokai University Rika Sakai Department of Medical Oncology, Kanagawa Cancer Center Yasuharu Sato Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Midori Filiz Nishimura Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Kunihiro Tsukasaki Department of Hematology, International Medical Center, Saitama Medical University Shuji Momose Department of Pathology, Saitama Medical Center, Saitama Medical University Yoshihiro Kameoka Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine Masahiro Yoshida Department of Hematology, Osaka City General Hospital Akira Satou Department of Surgical Pathology, Aichi Medical University Hospital Seiichi Kato Center for Clinical Pathology, Fujita Health University Hospital Naoki Oishi Department of Pathology, University of Yamanashi Akio Saito Department of Hematology, NHO Shibukawa Medical Center Ken Sadahira Division of Hematology, Kawasaki Municipal Kawasaki Hospital Yohei Masugi Department of Pathology, School of Medicine, Tokai University Naoya Nakamura Department of Pathology, School of Medicine, Tokai University Aims: Diffuse large B-cell lymphoma/high-grade B-cell lymphoma (DLBCL/HGBCL) with MYC and BCL2 rearrangements (double-hit lymphoma with BCL2, DHL-BCL2) is a mature aggressive B-cell lymphoma that also includes concurrent triple hit with BCL6 translocation (TH). DHL with MYC and BCL6 (DH-BCL6) can also occur. The differences among these three DLBCL/HGBCL subtypes have not yet been definitively determined. Methods and Results: This study characterized the clinicopathological features and transcriptomic profiles of a series of 101 cases of DLBCL/HGBCL that were subclassified according to MYC, BCL2 and BCL6 FISH data, including cell-of-origin (COO)-like, molecular high-grade (MHG)-like and double-hit/dark-zone (DHIT/DZsig)-like signatures. DLBCL/HGBCL-DH-BCL2 was characterized by higher HGBCL morphology, CD10 positivity, GCB Hans's, GCB COO and MHG molecular subtype. DLBCL/HGBCL-TH had higher LDH levels and worse overall survival. DLBCL/HGBCL-DH-BCL6 had higher MUM1 expression, non-GCB Hans', ABC/Unclassified COO, non-MHG and low DHIT/DZ signatures. Transcriptomic analysis showed that DLBCL/HGBCL-DH-BCL2 and DLBCL/HGBCL-TH were close but separated from DLBCL/HGBCL-DH-BCL6. Gene set enrichment analysis (GSEA) revealed different levels of enrichment between the subtypes. Conclusions: DLBCL/HGBCL-DH-BCL6 differs from the DLBCL/HGBCL-DH-BCL2, and the DLBCL/HGBCL-TH is associated with the worst survival. Analysis of all three genes of MYC, BCL2 and BCL6 is recommended in the context of DLBCL/HGBCL diagnosis. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 1092-9134 81 2026 The diagnostic utility and frequency of CD56 expression in plasma cell myeloma 152587 EN Midori Imai Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Asami Nishikori Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Tomoka Haratake Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Midori Filiz Nishimura Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Rio Yamada Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Syoma Kato Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Mizuha Tabe Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Hiroyuki Yanai Department of Diagnostic Pathology, Okayama University Hospital Hidetaka Yamamoto Department of Pathology and Oncology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yasuharu Sato Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Plasma cell myeloma (PCM) is a hematological malignancy characterized by systemic proliferation of neoplastic plasma cells within the bone marrow. Diagnosis requires clinical findings and immunohistochemical staining, including CD138, CD79a, cyclin D1, immunoglobulin κ (Igκ), and λ (Igλ). However, CD79a and cyclin D1 have limited sensitivity and specificity, and Igκ/Igλ assessment is often difficult due to overstaining. Therefore, more reliable antibodies are needed to accurately diagnose PCM. In this study, we examined the diagnostic utility of CD56 expression in PCM. We retrospectively performed immunostaining for CD138, CD56, CD79a, cyclin D1, Igκ, and Igλ in bone marrow samples from 116 patients with PCM. CD56 expression was observed in 85/116 cases (73.3 %), CD79a was downregulated in 46/116 cases (39.7 %), and cyclin D1 expression was observed in 42/116 cases (36.2 %). The expression of CD56 was significantly higher than that of CD79a and cyclin D1 (both p < 0.001). The combination of two antibodies resulted in the highest detection rate when combining CD56 and CD79a (105/116, 90.5 %), which was significantly higher than the detection rates of CD56 and cyclin D1 (93/116, 80.2 %) and CD79a and cyclin D1 (75/116, 64.7 %) (both p < 0.001). In contrast, lymphoplasmacytic lymphoma and marginal zone lymphoma lacked CD56 and cyclin D1 expression. Furthermore, in cases where light chain restriction was undetectable (11/116, 9.5 %), all could be diagnosed as PCM based on CD56, CD79a, and cyclin D1. Among these, CD56 showed the highest detection rate (8/11, 72.7 %). These findings highlight CD56 as a helpful marker for PCM diagnosis and support further clinical research. No potential conflict of interest relevant to this article was reported.

Japanese Society for Lymphoreticular Tissue Research Acta Medica Okayama 1346-4280 64 4 2024 Computed tomography findings of idiopathic multicentric Castleman disease subtypes 292 296 EN Toshihiro Iguchi Department of Radiological Technology, Faculty of Health Sciences, Okayama University Asami Nishikori Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Yasuharu Sato Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Midori Filiz Nishimura Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Noriko Iwaki Department of Hematology, National Cancer Center Hospital Katsuhide Kojima Department of Radiology, Okayama University Hospital Takashi Asahara Department of Radiological Technology, Faculty of Health Sciences, Okayama University Fumio Otsuka Department of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yoshinobu Maeda Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Takao Hiraki Department of Radiology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University 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. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 1572-1000 54 2025 Near-infrared photoimmunotherapy for recurrent cancer at the base of the tongue 104719 EN Takuma Makino Department of Otolaryngology - Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Asami Nishikori Department of Hematopathology, Okayama University Graduate School of Health Sciences Yasuharu Sato Department of Hematopathology, Okayama University Graduate School of Health Sciences Yuto Naoi Department of Otolaryngology - Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Junya Matsumoto Department of Otolaryngology - Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shohei Fujimoto Department of Otolaryngology - Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mizuo Ando Department of Otolaryngology - Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Near-infrared photoimmunotherapy (NIR-PIT) is a novel therapeutic approach that targets epidermal growth factor receptor (EGFR). In NIR-PIT, administration of cetuximab sarotalocan sodium is followed by laser irradiation of the affected area, which theoretically should induce tumor cell death. However, residual tumors are occasionally observed. This study investigated factors that influence the therapeutic efficacy of NIR-PIT in cases of recurrence of cancer at the base of the tongue. Six patients undergoing 11 treatment cycles were analyzed, focusing on the puncture interval of cylindrical diffusers and the expression of EGFR in tumors. The results demonstrated that a puncture interval of ≤12 mm significantly enhanced therapeutic efficacy, with one case achieving complete response. EGFR expression was positive in all cases and expression score showed no significant change between before and after treatment. These findings suggest that puncture interval plays a critical role in therapeutic outcomes, whereas EGFR expression may not directly influence treatment efficacy. No potential conflict of interest relevant to this article was reported.

BMJ Acta Medica Okayama 2632-6140 7 1 2025 Reversible cerebral vasoconstriction syndrome in idiopathic multicentric Castleman disease under treatment with tocilizumab e000923 EN Naoya Kamimura Department of Neurology, Yokohama City University Medical Center Naohisa Ueda Department of Neurology, Yokohama City University Medical Center Katsuo Kimura Department of Neurology, Yokohama City University Medical Center Asami Nishikori Yasuharu Sato Hitaru Kishida Department of Neurology, Yokohama City University Medical Center Fumiaki Tanaka Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine Background Idiopathic multicentric Castleman disease (iMCD) is a rare polyclonal lymphoproliferative disorder characterised by systemic inflammation resulting from overproduction of interleukin 6 (IL-6). While iMCD primarily affects the lymph nodes and related tissues, it can also rarely involve the central nervous system. Case presentation We report the case of a 58-year-old female patient with at least a 3-year history of iMCD, who experienced acute thunderclap headaches due to reversible cerebral vasoconstriction syndrome (RCVS). RCVS occurred 3 months after initiating treatment with tocilizumab, a humanised anti-IL-6 receptor monoclonal antibody, and was accompanied by focal cortical subarachnoid haemorrhage (SAH). Elevated IL-6 levels were found in both serum and cerebrospinal fluid. MR angiography revealed multiple diffuse stenotic lesions in the bilateral middle and posterior cerebral arteries, which, along with bilateral cerebral oedema, resolved within 3 months. The diffuse nature of the cerebral vasospasm and the presence of bilateral brain oedema suggested that cerebral vasospasm was due to RCVS rather than SAH. Conclusions In patients with Castleman disease, RCVS may occur due to IL-6-dependent chronic cerebral vascular inflammation, either as a primary condition or as a complication of tocilizumab treatment. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 0361-8609 2025 International Consensus Histopathological Criteria for Subtyping Idiopathic Multicentric Castleman Disease Based on Machine Learning Analysis EN Midori Filiz Nishimura Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Tomoka Haratake Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Yoshito Nishimura Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Asami Nishikori Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Remi Sumiyoshi The Research Program for Intractable Disease by Ministry of Health, Labor and Welfare, Castleman Disease, TAFRO and Related Ddisease Research Group Hideki Ujiie Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Yuri Kawahara Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Tomohiro Koga The Research Program for Intractable Disease by Ministry of Health, Labor and Welfare, Castleman Disease, TAFRO and Related Ddisease Research Group Masao Ueki School of Information and Data Sciences, Nagasaki University Dorottya Laczko Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania Eric Oksenhendler Department of Clinical Immunology, Hôpital Saint-Louis David C. Fajgenbaum Center for Cytokine Storm Treatment and Laboratory, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania Frits van Rhee Myeloma Center, University of Arkansas for Medical Sciences Atsushi Kawakami The Research Program for Intractable Disease by Ministry of Health, Labor and Welfare, Castleman Disease, TAFRO and Related Ddisease Research Group Yasuharu Sato Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder classified into three recognized clinical subtypes―idiopathic plasmacytic lymphadenopathy (IPL), TAFRO, and NOS. Although clinical criteria are available for subtyping, diagnostically challenging cases with overlapping histopathological features highlight the need for an improved classification system integrating clinical and histopathological findings. We aimed to develop an objective histopathological subtyping system for iMCD that closely correlates with the clinical subtypes. Excisional lymph node specimens from 94 Japanese iMCD patients (54 IPL, 28 TAFRO, 12 NOS) were analyzed for five key histopathological parameters: germinal center (GC) status, plasmacytosis, vascularity, hemosiderin deposition, and “whirlpool” vessel formation in GC. Using hierarchical clustering, we visualized subgroups and developed a machine learning-based decision tree to differentiate the clinical subtypes and validated it in an external cohort of 12 patients with iMCD. Hierarchical cluster analysis separated the IPL and TAFRO cases into mutually exclusive clusters, whereas the NOS cases were interspersed between them. Decision tree modeling identified plasmacytosis, vascularity, and whirlpool vessel formation as key features distinguishing IPL from TAFRO, achieving 91% and 92% accuracy in the training and test sets, respectively. External validation correctly classified all IPL and TAFRO cases, confirming the reproducibility of the system. Our histopathological classification system closely aligns with the clinical subtypes, offering a more precise approach to iMCD subtyping. It may enhance diagnostic accuracy, guide clinical decision-making for predicting treatment response in challenging cases, and improve patient selection for future research. Further validation of its versatility and clinical utility is required. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 0893-3952 38 8 2025 The Involvement of PI3K–Akt Signaling in the Clinical and Pathological Findings of Idiopathic Multicentric Castleman Disease–Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis, and Organomegaly and Not Otherwise Specified Subtypes 100782 EN Tomoka Haratake Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Midori Filiz Nishimura Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Asami Nishikori Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Michael V. Gonzalez Center for Cytokine Storm Treatment and Laboratory, Department of Medicine, Perelman School of Medicine, University of Pennsylvania Daisuke Ennishi Center for Comprehensive Genomic Medicine, Okayama University Hospital You Cheng Lai Department of Medical Biotechnology and Laboratory Science, Chang Gung University Sayaka Ochi Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Manaka Tsunoda Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences David C. Fajgenbaum Center for Cytokine Storm Treatment and Laboratory, Department of Medicine, Perelman School of Medicine, University of Pennsylvania Frits van Rhee Center for Cytokine Storm Treatment and Laboratory, Department of Medicine, Perelman School of Medicine, University of Pennsylvania Shuji Momose Department of Pathology, Saitama Medical Center, Saitama Medical University Yasuharu Sato Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences 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 < .001; IPL vs NOS, P = .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 < .001; IPL vs NOS, P = .007). Likewise, immunostaining for Ets-related gene revealed higher levels in endothelial cells of GCs in TAFRO than in IPL (P = .014), and TAFRO and NOS were associated with a significantly higher number of endothelial cells in interfollicular areas compared with that in IPL (TAFRO vs IPL, P < .001; NOS vs IPL, P = .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. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 0361-8609 96 10 2021 Validated international definition of the thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly clinical subtype (TAFRO) of idiopathic multicentric Castleman disease 1241 1252 EN Yoshito Nishimura Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences David C. Fajgenbaum Center for Cytokine Storm Treatment & Laboratory, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania Sheila K. Pierson Center for Cytokine Storm Treatment & Laboratory, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania Noriko Iwaki Hematology/Respiratory Medicine, Kanazawa University Graduate School of Medical Science Asami Nishikori Division of Pathophysiology, Okayama University Graduate School of Health Sciences Mitsuhiro Kawano Department of Rheumatology, Kanazawa University Graduate School of Medical Science Naoya Nakamura Department of Pathology, Tokai University School of Medicine Koji Izutsu Department of Hematology, National Cancer Center Hospital Kengo Takeuchi Department of Pathology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research Midori Filiz Nishimura Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Fumio Otsuka Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kazuyuki Yoshizaki Department of Organic Fine Chemicals, Institute of Scientific and Industrial Research, Osaka University Eric Oksenhendler Department of Clinical Immunology, Hôpital Saint-Louis Frits van Rhee Myeloma Center, University of Arkansas for Medical Sciences Yasuharu Sato Division of Pathophysiology, Okayama University Graduate School of Health Sciences 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. No potential conflict of interest relevant to this article was reported.

Japanese Society for Lymphoreticular Tissue Research Acta Medica Okayama 1346-4280 64 2 2024 Atypical lymphoplasmacytic and immunoblastic proliferation: A Systematic Review 97 106 EN Midori Filiz Nishimura Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Toshiaki Takahashi Department of Medicine, John A. Burns School of Medicine, University of Hawai’i Kensuke Takaoka Department of Medicine, John A. Burns School of Medicine, University of Hawai’i Sharina Macapagal Department of Medicine, John A. Burns School of Medicine, University of Hawai’i Chalothorn Wannaphut Department of Medicine, John A. Burns School of Medicine, University of Hawai’i Asami Nishikori Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Hiroko Toda Department of Pathology, Chugoku Central Hospital Yoshito Nishimura Department of Medicine, John A. Burns School of Medicine, University of Hawai’i Yasuharu Sato Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences 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. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 0309-0167 2025 Kikuchi‐Fujimoto disease: investigating comprehensive clinicopathological features and risk factors for recurrence EN Midori Filiz Nishimura Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Chikako Sakao Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Yuka Kurokawa Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Yoshito Nishimura Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Asami Nishikori Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Hidetaka Yamamoto Department of Pathology and Oncology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yasuharu Sato Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences 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. No potential conflict of interest relevant to this article was reported.

Japanese Society for Lymphoreticular Tissue Research Acta Medica Okayama 1346-4280 64 4 2024 Transcriptome analysis of the cytokine storm-related genes among the subtypes of idiopathic multicentric Castleman disease 297 306 EN Asami Nishikori Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Midori Filiz Nishimura Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Shuta Tomida Center for Comprehensive Genomic Medicine, Okayama University Hospital Ryota Chijimatsu Center for Comprehensive Genomic Medicine, Okayama University Hospital Himawari Ueta Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences You Cheng Lai Department of Medical Biotechnology and Laboratory Science, Chang Gung University Yuri Kawahara Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Yudai Takeda Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Sayaka Ochi Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Tomoka Haratake Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Daisuke Ennishi Center for Comprehensive Genomic Medicine, Okayama University Hospital Naoya Nakamura Department of Pathology, Tokai University School of Medicine Shuji Momose Department of Pathology, Saitama Medical Center, Saitama Medical University Yasuharu Sato Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences 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. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 2072-6694 16 7 2024 Copy Number Analysis of 9p24.1 in Classic Hodgkin Lymphoma Arising in Immune Deficiency/Dysregulation 1298 EN Kumiko Ohsawa Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Shuji Momose Department of Pathology, Saitama Medical Center, Saitama Medical University Asami Nishikori Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Midori Filiz Nishimura Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Yuka Gion Department of Medical Technology, Faculty of Health Sciences, Ehime Prefectural University of Health Sciences Keisuke Sawada Department of Pathology, Saitama Medical Center, Saitama Medical University Morihiro Higashi Department of Pathology, Saitama Medical Center, Saitama Medical University Michihide Tokuhira Department of Hematology, Japan Community Health Care Organization Saitama Medical Center Jun-Ichi Tamaru Department of Pathology, Saitama Medical Center, Saitama Medical University Yasuharu Sato Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences A subset of patients with rheumatoid arthritis receiving methotrexate develop immune deficiencies and dysregulation-associated lymphoproliferative disorders. Patients with these disorders often exhibit spontaneous regression after MTX withdrawal; however, chemotherapeutic intervention is frequently required in patients with classic Hodgkin lymphoma arising in immune deficiency/dysregulation. In this study, we examined PD-L1 expression levels and 9p24.1 copy number alterations in 27 patients with classic Hodgkin lymphoma arising from immune deficiency/dysregulation. All patients demonstrated PD-L1 protein expression and harbored 9p24.1 copy number alterations on the tumor cells. When comparing clinicopathological data and associations with 9p24.1 copy number features, the copy gain group showed a significantly higher incidence of extranodal lesions and clinical stages than the amplification group. Notably, all cases in the amplification group had latency type II, while 6/8 (75%) in the copy gain group had latency type II, and 2/8 (25%) had latency type I. Thus, a subset of the copy-gain group demonstrated more extensive extranodal lesions and higher clinical stages. This finding speculates the presence of a genetically distinct subgroup within the group of patients who develop immune deficiencies and dysregulation-associated lymphoproliferative disorders, which may explain certain characteristic features. No potential conflict of interest relevant to this article was reported.

Japanese Society for Lymphoreticular Tissue Research Acta Medica Okayama 1346-4280 64 1 2024 Analysis of Notch1 protein expression in methotrexate-associated lymphoproliferative disorders 1 9 EN Takeshi Okatani Department of Pathology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Midori Filiz Nishimura Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Yuria Egusa Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Sayako Yoshida Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Yoshito Nishimura Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Asami Nishikori Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Tadashi Yoshino Department of Pathology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Hidetaka Yamamoto Department of Pathology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yasuharu Sato Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences 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. No potential conflict of interest relevant to this article was reported.

American Society of Hematology Acta Medica Okayama 2473-9529 7 24 2023 Distribution and clinical impact of molecular subtypes with dark zone signature of DLBCL in a Japanese real-world study 7459 7470 EN Tomohiro Urata Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yusuke Naoi Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Aixiang Jiang British Columbia Cancer, Centre for Lymphoid Cancer Merrill Boyle British Columbia Cancer, Centre for Lymphoid Cancer Kazutaka Sunami Department of Hematology, NHO Okayama Medical Center Toshi Imai Department of Hematology and Blood Transfusion, Kochi Health Sciences Center Yuichiro Nawa Division of Hematology, Ehime Prefectural Central Hospital Yasushi Hiramatsu Department of Hematology and Oncology, Japanese Red Cross Society Himeji Hospital Kazuhiko Yamamoto Department of Hematology and Oncology, Okayama City Hospital Soichiro Fujii Department of Hematology, Japanese Red Cross Okayama Hospital Isao Yoshida Department of Hematologic Oncology, NHO Shikoku Cancer Center Tomofumi Yano Department of Internal Medicine, Okayama Rosai Hospital Ryota Chijimatsu Center for Comprehensive Genomic Medicine, Okayama University Hospital Hiroyuki Murakami Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiro Ikeuchi Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiroki Kobayashi Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuma Tani Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hideki Ujiie Center for Comprehensive Genomic Medicine, Okayama University Hospital Hirofumi Inoue Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science Shuta Tomida Center for Comprehensive Genomic Medicine, Okayama University Hospital Akira Yamamoto Department of Hematology and Oncology, Okayama University Hospital Takumi Kondo Department of Hematology and Oncology, Okayama University Hospital Hideaki Fujiwara Department of Hematology and Oncology, Okayama University Hospital Noboru Asada Department of Hematology and Oncology, Okayama University Hospital Hisakazu Nishimori Department of Hematology and Oncology, Okayama University Hospital Keiko Fujii Department of Hematology and Oncology, Okayama University Hospital Nobuharu Fujii Department of Hematology and Oncology, Okayama University Hospital Ken-ichi Matsuoka Department of Hematology and Oncology, Okayama University Hospital Keisuke Sawada Department of Pathology, Saitama Medical Center, Saitama Medical University Shuji Momose Department of Pathology, Saitama Medical Center, Saitama Medical University Jun-ichi Tamaru Department of Pathology, Saitama Medical Center, Saitama Medical University Asami Nishikori Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Yasuharu Sato Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Tadashi Yoshino Department of Pathology, Okayama University Yoshinobu Maeda Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences David W. Scott British Columbia Cancer, Centre for Lymphoid Cancer Daisuke Ennishi Department of Hematology and Oncology, Okayama University Hospital 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 (DZ) 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, which include the DZ signature (DZsig), using the NanoString DLBCL90 assay. To compare the distribution and clinical characteristics of the molecular subtypes, we used a data set from the cohort of British Columbia Cancer (BCC) (n = 804). Through the 1050 patient samples on which DLBCL90 assay was successfully performed in our cohort, 35%, 45%, and 6% of patients were identified to have germinal center B-cell–like (GCB) DLBCL, activated B-cell–like (ABC) DLBCL, and DZsig-positive (DZsigpos) DLBCL, respectively, with the highest prevalence of ABC-DLBCL, differing significantly from the BCC result (P < .001). GCB-DLBCL, ABC-DLBCL, and DZsigpos-DLBCL were associated with 2-year overall survival rates of 88%, 75%, and 66%, respectively (P < .0001), with patients with DZsigpos-DLBCL having the poorest prognosis. In contrast, GCB-DLBCL without DZsig showed excellent outcomes after 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 < .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. No potential conflict of interest relevant to this article was reported.

Japanese Society for Lymphoreticular Tissue Research Acta Medica Okayama 1346-4280 63 1 2023 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 25 31 EN Yuki Hirami Department of Nursing, Okayama University Graduate School of Health Sciences Midori Filiz Nishimura Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Tomohiro Urata Department of Hematology and Oncology, Okayama University Hospital Michiko Morimoto Department of Nursing, Okayama University Graduate School of Health Sciences Yukina Maekawa Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Tadashi Yoshino Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yoshito Nishimura Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yasuharu Sato Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Intravascular large B-cell lymphoma (IVL) is a rare type of lymphoma characterized by tumor growth selectively within the vessels. The 5th edition of the World Health Organization classification defines IVL as a large B-cell lymphoma, the same as diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS). Since the clinical manifestations of IVL are nonspecific, the diagnosis is time-consuming, and the course is often fatal. Serum soluble interleukin-2 receptor (sIL-2R) and serum lactate dehydrogenase (LDH) levels are known to be elevated in a variety of lymphomas. However, the mechanism of sIL-2R elevation in B-cell lymphomas is not fully understood. In this study, we analyzed the serum level of laboratory findings, including sIL-2R and LDH, as well as the presence of B symptoms in 39 patients with IVL, and compared them with 56 patients with stage IV DLBCL. Both sIL-2R and LDH levels were significantly higher in IVL than in DLBCL (p = 0.035 andp = 0.002, respectively). In IVL, there were no significant differences in both sIL-2R and LDH levels between patients with and without B symptoms (p = 0.206 andp = 0.441, respectively). However, in DLBCL, both sIL-2R and LDH levels were significantly higher in the presence of B symptoms (p = 0.001 andp < 0.001, respectively). The high sIL-2R and LDH levels in IVL may be related to the peripheral blood microenvironment, but further studies are needed to verify this. No potential conflict of interest relevant to this article was reported.

American Thoracic Society Acta Medica Okayama 1044-1549 67 6 2022 Neuropeptide Y Antagonizes Development of Pulmonary Fibrosis through IL-1β Inhibition 654 665 EN Junko Itano Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Akihiko Taniguchi Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Satoru Senoo Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Noboru Asada Department of Hematology and Oncology, Okayama University Hospital Yuka Gion Department of Medical Technology, Okayama University Graduate School of Health Sciences Yuria Egusa Department of Medical Technology, Okayama University Graduate School of Health Sciences Lili Guo Department of Medical Technology, Okayama University Graduate School of Health Sciences Naohiro Oda Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kota Araki Department of General Thoracic Surgery, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuharu Sato Department of Medical Technology, Okayama University Graduate School of Health Sciences Shinichi Toyooka Department of General Thoracic Surgery, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuyuki Kiura Department of Allergy and Respiratory Medicine, Okayama University Hospital Yoshinobu Maeda Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Nobuaki Miyahara Department of Allergy and Respiratory Medicine, Okayama University Hospital Neuropeptide Y (NPY), 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 NPY on pulmonary fibrosis. NPY-deficient and wild-type mice were intratracheally administered bleomycin. Inflammatory cells, cytokine concentrations, and morphological morphometry of the lungs were analyzed. Serum NPY concentrations were also measured in patients with idiopathic pulmonary fibrosis and healthy control subjects. NPY-deficient mice exhibited significantly enhanced pulmonary fibrosis and higher IL-1 beta concentrations in the lungs compared with wild-type mice. Exogenous NPY treatment suppressed the development of bleomycin-induced lung fibrosis and decreased IL-1 beta concentrations in the lungs. Moreover, IL-1 beta neutralization in NPY-deficient mice attenuated the fibrotic changes. NPY decreased IL-1 beta release, and Y1 receptor antagonists inhibited IL-1 beta release and induced epithelial-mesenchymal transition in human alveolar epithelial cells. Patients with idiopathic pulmonary fibrosis had lower NPY and greater IL-1 beta concentrations in the serums compared with healthy control subjects. NPY expression was mainly observed around bronchial epithelial cells in human idiopathic pulmonary fibrosis lungs. These data suggest that NPY plays a protective role against pulmonary fibrosis by suppressing IL-1 beta release, and manipulating the NPY-Y1 receptor axis could be a potential therapeutic strategy for delaying disease progression. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 1422-0067 23 18 2022 Idiopathic Plasmacytic Lymphadenopathy Forms an Independent Subtype of Idiopathic Multicentric Castleman Disease 10301 EN Asami Nishikori Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Midori Filiz Nishimura Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Yoshito Nishimura Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Fumio Otsuka Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kanna Maehama Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences Kumiko Ohsawa Department of Pathology, Saitama Medical Center, Saitama Medical University Shuji Momose Department of Pathology, Saitama Medical Center, Saitama Medical University Naoya Nakamura Department of Pathology, Tokai University School of Medicine Yasuharu Sato Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences 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. No potential conflict of interest relevant to this article was reported.

The Japanese Society for Lymphoreticular Tissue Research Acta Medica Okayama 1346-4280 2022 Historical and pathological overview of Castleman disease 21036 EN Midori Filiz Nishimura Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yoshito Nishimura Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Asami Nishikori Division of Pathophysiology, Okayama University Graduate School of Health Sciences Tadashi Yoshino Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yasuharu Sato Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences 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, cndocrinopathy, M-protcins, 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. No potential conflict of interest relevant to this article was reported.

The Japanese Society for Lymphoreticular Tissue Research Acta Medica Okayama 1346-4280 2022 Idiopathic multicentric Castleman disease with positive antiphospholipid antibody: atypical and undiagnosed autoimmune disease? 21038 EN Yoshito Nishimura Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Asami Nishikori Division of Pathophysiology, Okayama University Graduate School of Health Sciences Haruki Sawada Department of Medicine, University of Hawaii Torrey Czech Department of Medicine, University of Hawaii Yuki Otsuka Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Midori Filiz Nishimura Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Hiroki Mizuno Nephrology Center, Toranomon Hospital Kajigaya Naoki Sawa Nephrology Center, Toranomon Hospital Kajigaya Shuji Momose Department of Pathology, Saitama Medical Center, Saitama Medical University Kumiko Ohsawa Division of Pathophysiology, Okayama University Graduate School of Health Sciences Fumio Otsuka Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuharu Sato Division of Pathophysiology, Okayama University Graduate School of Health Sciences 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. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 2075-4418 12 2 2022 Clinicopathologic Analysis of Sinonasal Inverted Papilloma, with Focus on Human Papillomavirus Infection Status 454 EN Munechika Tsumura Department of Otolaryngology Head and Neck Surgery, Kagawa Rosai Hospital Seiichiro Makihara Department of Otolaryngology Head and Neck Surgery, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Okayama University Asami Nishikori Division of Pathophysiology, Graduate School of Health Sciences, Okayama University Yuka Gion Division of Pathophysiology, Graduate School of Health Sciences, Okayama University Toshiaki Morito Shotaro Miyamoto Department of Otolaryngology Head and Neck Surgery, Kagawa Rosai Hospital Tomoyuki Naito Department of Otorhinolaryngology, Kagawa Prefectural Central Hospital Kensuke Uraguchi Department of Otolaryngology Head and Neck Surgery, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Okayama University Aiko Oka Department of Otorhinolaryngology, School of Medicine, International University of Health and Welfare Tomoyasu Tachibana Department of Otolaryngology, Japanese Red Cross Society Himeji Hospital Yorihisa Orita Department of Otolaryngology Head and Neck Surgery, Graduate School of Medicine, Kumamoto University Shin Kariya Department of Otolaryngology Head and Neck Surgery, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Okayama University Mitsuhiro Okano Department of Otorhinolaryngology, School of Medicine, International University of Health and Welfare Mizuo Ando Department of Otolaryngology Head and Neck Surgery, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Okayama University Yasuharu Sato Department of Pathology, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Okayama University 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. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 2075-4418 11 12 2021 Cytopathological Findings of Secretory Carcinoma of the Salivary Gland and the Diagnostic Utility of Giemsa Staining 2284 EN Yuria Egusa Division of Pathophysiology, Okayama University Graduate School of Health Sciences Midori Filiz Nishimura Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Satoko Baba Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research Kengo Takeuchi Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research Takuma Makino Department of Otolaryngology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomoyasu Tachibana Department of Otolaryngology, Japanese Red Cross Society Himeji Hospital Asami Nishikori Division of Pathophysiology, Okayama University Graduate School of Health Sciences Azusa Fujita Division of Pathophysiology, Okayama University Graduate School of Health Sciences Hiroyuki Yanai Department of Diagnostic Pathology, Okayama University Hospital Yasuharu Sato Division of Pathophysiology, Okayama University Graduate School of Health Sciences Secretory carcinoma is a salivary gland neoplasm first described as a mammary analogue secretory carcinoma by Skalova 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. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 2072-6694 13 22 2021 Primary Gastrointestinal T-Cell Lymphoma and Indolent Lymphoproliferative Disorders: Practical Diagnostic and Treatment Approaches 5774 EN Midori Filiz Nishimura Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yoshito Nishimura Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Asami Nishikori Division of Pathophysiology, Okayama University Graduate School of Health Sciences Tadashi Yoshino Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yasuharu Sato Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Simple Summary: It is challenging for pathologists to diagnose primary gastrointestinal T-cell neoplasms. Besides the rarity of the diseases, the small biopsy material makes it more difficult to differentiate between non-neoplastic inflammation and secondary involvement of extra gastrointestinal lymphoma. Since this group of diseases ranges from aggressive ones with a very poor prognosis to indolent ones that require caution to avoid overtreatment, the impact of the diagnosis on the patient is enormous. Although early treatment of aggressive lymphoma is essential, the treatment strategy is not well established, which is a problem for clinicians. This review provides a cross-sectional comparison of histological findings. Unlike previous reviews, we summarized up-to-date clinically relevant information including the treatment strategies as well as practical differential diagnosis based on thorough literature review. Abstract: 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? No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 2075-4418 11 11 2021 Clinical and Pathological Characteristics of Hyaline-Vascular Type Unicentric Castleman Disease: A 20-Year Retrospective Analysis 2008 EN Midori Filiz Nishimura Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yoshito Nishimura Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Asami Nishikori Division of Pathophysiology, Okayama University Graduate School of Health Sciences Yukina Maekawa Division of Pathophysiology, Okayama University Graduate School of Health Sciences Kanna Maehama Division of Pathophysiology, Okayama University Graduate School of Health Sciences Tadashi Yoshino Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yasuharu Sato Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences 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. No potential conflict of interest relevant to this article was reported.

WILEY Acta Medica Okayama 2045-7634 2021 00 2021 PD-L1 expression is associated with the spontaneous regression of patients with methotrexate-associated lymphoproliferative disorders 1 EN Yuka Gion Division of Pathophysiology, Okayama University Graduate School of Health Sciences Misato Doi Division of Clinical Laboratory, Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital Yoshito Nishimura Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomoka Ikeda Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Midori Filiz Nishimura Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Misa Sakamoto Division of Pathophysiology, Okayama University Graduate School of Health Sciences Yuria Egusa Division of Pathophysiology, Okayama University Graduate School of Health Sciences Asami Nishikori Division of Pathophysiology, Okayama University Graduate School of Health Sciences Azusa Fujita Division of Pathophysiology, Okayama University Graduate School of Health Sciences Noriko Iwaki Department of Hematology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University Naoya Nakamura Department of Pathology, Tokai University School of Medicine Tadashi Yoshino Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuharu Sato Division of Pathophysiology, Okayama University Graduate School of Health Sciences 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. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 2075-4418 11 5 2021 Diagnostic Utility of SOX4 Expression in Adult T-Cell Leukemia/Lymphoma 766 EN Atsuko Nasu Division of Pathophysiology, Okayama University Graduate School of Health Sciences Yuka Gion Division of Pathophysiology, Okayama University Graduate School of Health Sciences Yoshito Nishimura Department of General Medicine, Okayama University Hospital Asami Nishikori Division of Pathophysiology, Okayama University Graduate School of Health Sciences Misa Sakamoto Division of Pathophysiology, Okayama University Graduate School of Health Sciences Yuria Egusa Division of Pathophysiology, Okayama University Graduate School of Health Sciences Azusa Fujita Division of Pathophysiology, Okayama University Graduate School of Health Sciences Tadashi Yoshino Department of Pathology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Yasuharu Sato Division of Pathophysiology, Okayama University Graduate School of Health Sciences 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. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 1422-0067 22 8 2021 Upregulated Expression of Activation-Induced Cytidine Deaminase in Ocular Adnexal Marginal Zone Lymphoma with IgG4-Positive Cells 4083 EN Asami Nishikori Division of Pathophysiology, Okayama University Graduate School of Health Sciences Yoshito Nishimura Department of General Medicine, Okayama University Hospital Rei Shibata Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Koh-Ichi Ohshima Department of Ophthalmology, National Hospital Organization Okayama Medical Center Yuka Gion Division of Pathophysiology, Okayama University Graduate School of Health Sciences Tomoka Ikeda Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Midori Filiz Nishimura Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Tadashi Yoshino Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yasuharu Sato Division of Pathophysiology, Okayama University Graduate School of Health Sciences 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. No potential conflict of interest relevant to this article was reported.

Japanese Society for Lymphoreticular Tissue Research Acta Medica Okayama 1346-4280 61 1 2021 Follow-up with serum IgG4-monitoring in 8 patients with IgG4-related disease diagnosed by a lacrimal gland mass 10 20 EN Toshihiko Matsuo Okayama University Graduate School of Interdisciplinary Science and Engineering in Health Systems Takehiro Tanaka Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yasuharu Sato Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Hitomi Kataoka Department of General Medicine, Okayama University Hospital Mayu Uka Department of Radiology, Okayama University Hospital Daisuke Ennishi Department of Hematology/Oncology, Okayama University Hospital Tomofumi Yano Department of Internal Medicine, Okayama Rosai Hospital 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. No potential conflict of interest relevant to this article was reported.

Japanese Society for Lymphoreticular Tissue Research Acta Medica Okayama 1346-4280 60 4 2020 Differential diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma and other indolent lymphomas, including mantle cell lymphoma 124 129 EN Tadashi Yoshino Department of Pathology, Okayama University Graduate School Takehiro Tanaka Department of Pathology, Okayama University Graduate School Yasuharu Sato Department of Pathology, Okayama University Graduate School 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. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 1422-0067 22 3 2021 Epstein-Barr Virus-Positive Mucocutaneous Ulcer: A Unique and Curious Disease Entity 1053 EN Tomoka Ikeda Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuka Gion Division of Pathophysiology, Okayama University Graduate School of Health Sciences Yoshito Nishimura Department of General Medicine, Okayama University Hospital Midori Filiz Nishimura Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tadashi Yoshino Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuharu Sato Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences 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. No potential conflict of interest relevant to this article was reported.

The Japanese Society for Lymphoreticular Tissue Research Acta Medica Okayama 1346-4280 60 1 2020 Hemosiderin deposition in lymph nodes of patients with plasma cell-type Castleman disease 1 6 EN Yanyan Han Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Takuro Igawa Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kyohei Ogino Department of Pathology, Fukuyama City Hospital Asami Nishikori Division of Pathophysiology, Okayama University Graduate School of Health Sciences Yuka Gion Division of Pathophysiology, Okayama University Graduate School of Health Sciences Tadashi Yoshino Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yasuharu Sato Division of Pathophysiology, Okayama University Graduate School of Health Sciences 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. No potential conflict of interest relevant to this article was reported.

The Japanese Society for Lymphoreticular Tissue Research Acta Medica Okayama 1346-4280 60 3 2020 Clinicopathological significance of CD79a expression in classic Hodgkin lymphoma 78 86 EN Akio Sakatani Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences akuro Igawa Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Takeshi Okatani Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Megumu Fujihara Department of Pathology, Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital Hideki Asaoku Department of Hematology, Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital Yasuharu Sato Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Tadashi Yoshino Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences 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. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 2075-4426 10 4 2020 Pulmonary Manifestations of Plasma Cell Type Idiopathic Multicentric Castleman Disease: A Clinicopathological Study in Comparison with IgG4-Related Disease 269 EN Midori Filiz Nishimura Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Takuro Igawa Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yuka Gion Division of Pathophysiology, Okayama University Graduate School of Health Sciences Sakura Tomita Department of Pathology, Tokai University School of Medicine Dai Inoue Department of Radiology, Kanazawa University Graduate School of Medical Sciences Akira Izumozaki Department of Radiology, Kanazawa University Graduate School of Medical Sciences Yoshifumi Ubara Nephrology Center, Toranomon Hospital Kajigaya Yoshito Nishimura Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Tadashi Yoshino Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yasuharu Sato Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences 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. No potential conflict of interest relevant to this article was reported.

Springer Nature Acta Medica Okayama 0893-3952 33 12 2020 Clinicopathological analysis of 34 Japanese patients with EBV-positive mucocutaneous ulcer 2437 2448 EN Tomoka Ikeda Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuka Gion Okayama University Graduate School of Health Sciences Misa Sakamoto Okayama University Graduate School of Health Sciences Tomoyasu Tachibana Department of Otolaryngology, Japanese Red Cross Society Himeji Hospital Asami Nishikori Okayama University Graduate School of Health Sciences Midori Filiz Nishimura Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tadashi Yoshino Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuharu Sato Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences 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. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 1422-0067 21 5 2020 Clinical Significance of Cytoplasmic IgE-Positive Mast Cells in Eosinophilic Chronic Rhinosinusitis 1843 EN Yuka Gion Division of Pathophysiology, Okayama University Graduate School of Health Sciences Mitsuhiro Okano Department of Otolaryngology of Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takahisa Koyama Department of Otolaryngology of Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tokie Oura Division of Pathophysiology, Okayama University Graduate School of Health Sciences Asami Nishikori Division of Pathophysiology, Okayama University Graduate School of Health Sciences Yorihisa Orita Department of Otolaryngology, Head and Neck Surgery, Kumamoto University Graduate School Tomoyasu Tachibana Department of Otolaryngology, Japanese Red Cross Society Himeji Hospital Hidenori Marunaka Department of Otolaryngology of Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takuma Makino Department of Otolaryngology of Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazunori Nishizaki Department of Otolaryngology of Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuharu Sato Division of Pathophysiology, Okayama University Graduate School of Health Sciences Cross-linking of antigen-specific IgE bound to the high-affinity IgE receptor (Fc epsilon RI) on the surface of mast cells with multivalent antigens results in the release of mediators and development of type 2 inflammation. Fc epsilon RI 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. No potential conflict of interest relevant to this article was reported.

Japanese Society for Lymphoratic Tissue Research Acta Medica Okayama 1346-4280 59 2 2019 Highlights: Focus on Immunodeficiency-Associated Lymphoproliferative Disorders 46 47 EN Yasuharu Sato Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University No potential conflict of interest relevant to this article was reported.

Japanese Society for Lymphoratic Tissue Research Acta Medica Okayama 1346-4280 59 2 2019 A review of EBV-positive mucocutaneous ulcers focusing on clinical and pathological aspects 64 6471 EN Tomoka Ikeda Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuka Gion Division of Pathophysiology, Okayama University Graduate School of Health Sciences Tadashi Yoshino Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuharu Sato Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences 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. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 13238930 2020 Serum IgG4 as a biomarker reflecting pathophysiology and post-operative recurrence in chronic rhinosinusitis EN Aiko Oka Department of Otorhinolaryngology, International University of Health and Welfare Graduate School of Medicine Takahiro Ninomiya Department of Otorhinolaryngology Head & Neck Surgery, Faculty of Medical Sciences, University of Fukui Tazuko Fujiwara Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Soshi Takao Department of Epidemiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuharu Sato Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yuka Gion Division of Pathophysiology, Okayama University Graduate School of Health Sciences Akira Minoura Department of Hygiene, Public Health and Preventive Medicine, Showa University School of Medicine Shin-ichi Haruna Department of Otorhinolaryngology, Head & Neck Surgery, Dokkyo Medical University Naohiro Yoshida Department of Otolaryngology, Jichi Medical University Saitama Medical Center Yasunori Sakuma Department of Otorhinolaryngology, Yokohama City Medical Center Kenji Izuhara Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School Junya Ono Shino-Test Co., Ltd. Masami Taniguchi Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital Takenori Haruna Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takaya Higaki Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shin Kariya Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takahisa Koyama Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tetsuji Takabayashi Department of Otorhinolaryngology Head & Neck Surgery, Faculty of Medical Sciences, University of Fukui Yoshimasa Imoto Department of Otorhinolaryngology Head & Neck Surgery, Faculty of Medical Sciences, University of Fukui Masafumi Sakashita Department of Otorhinolaryngology Head & Neck Surgery, Faculty of Medical Sciences, University of Fukui Masanori Kidoguchi Department of Otorhinolaryngology Head & Neck Surgery, Faculty of Medical Sciences, University of Fukui Kazunori Nishizaki Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shigeharu Fujieda Department of Otorhinolaryngology Head & Neck Surgery, Faculty of Medical Sciences, University of Fukui Mitsuhiro Okano Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences 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. No potential conflict of interest relevant to this article was reported.

Nature Publishing Group Acta Medica Okayama 2045-2322 9 2019 Up-regulation of activation-induced cytidine deaminase and its strong expression in extra- germinal centres in IgG4-related disease 761 EN Yuka Gion Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mai Takeuchi Department of Pathology, Kurume University School of Medicine Rei Shibata Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuyoshi Takata Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomoko Miyata-Takata Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yorihisa Orita Department of Otolaryngology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomoyasu Tachibana Department of Otolaryngology, Himeji Red Cross Hospital Tadashi Yoshino Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuharu Sato Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences 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. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 13238930 68 2 2019 Significance of IgG4-positive cells in severe eosinophilic chronic rhinosinusitis 216 224 EN Takahisa Koyama Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shin Kariya Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuharu Sato Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuka Gion Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takaya Higaki Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takenori Haruna Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tazuko Fujiwara Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akira Minoura Department of Public Health, Showa University School of Medicine Soshi Takao Department of Epidemiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yorihisa Orita Department of Otolaryngology-Head and Neck Surgery, Kumamoto University Kengo Kanai Department of Otorhinolaryngology-Head & Neck Surgery, Kagawa Prefectural Central Hospital Masami Taniguchi Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital Kazunori Nishizaki Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mitsuhiro Okano Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences 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. No potential conflict of interest relevant to this article was reported.

BioMed Central Acta Medica Okayama 1746-1596 8 2013 De novo CD5-positive diffuse large B-cell lymphomas show high specificity for cyclin D2 expression 81 EN Takuro Igawa Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuharu Sato Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsuyoshi Takata Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Noriko Iwaki Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takehiro Tanaka Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Naoko Asano Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshinobu Maeda Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yorihisa Orita Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Naoya Nakamura Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shigeo Nakamura Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tadashi Yoshino Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences 　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. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 0046-8177 45 7 2014 Low-grade B-cell lymphoma presenting primarily in the bone marrow 1379 1387 EN 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 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. No potential conflict of interest relevant to this article was reported.

Public Library Science Acta Medica Okayama 1932-6203 8 2 2013 A20 (TNFAIP3) Deletion in Epstein-Barr Virus-Associated Lymphoproliferative Disorders/Lymphomas EN Midori Ando Yasuharu Sato Katsuyoshi Takata Junko Nomoto Shigeo Nakamura Koichi Ohshima Tamotsu Takeuchi Yorihisa Orita Yukio Kobayashi Tadashi Yoshino A negative regulator of the nuclear factor (NF)-kappa B 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-kappa B 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-kappa B 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 the13 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. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 0046-8177 44 9 2013 Distinct morphologic, phenotypic, and clinical-course characteristics of indolent peripheral T-cell lymphoma 1927 1936 EN 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 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. No potential conflict of interest relevant to this article was reported.

Public Library Science Acta Medica Okayama 1932-6203 8 2 2013 Clinicopathologic Analysis of Localized Nasal/Paranasal Diffuse Large B-Cell Lymphoma EN Hiroko Toda Yasuharu Sato Katsuyoshi Takata Yorihisa Orita Naoko Asano Tadashi Yoshino 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. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 67 4 2013 Large Ulceration of the Oropharynx Induced by Methotrexate-Associated Lymphoproliferative Disorders 265 269 EN Hiroyuki Hanakawa Yorihisa Orita Yasuharu Sato Kinya Uno Kazunori Nishizaki Tadashi Yoshino Case Report 10.18926/AMO/51072 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. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 125 2 2013 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memoryB細胞としての性質を有する 103 107 EN 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 Mohamado Yoshinobu Maeda Mitsune Tanimoto Tomohiro Kinoshita Tadashi Yoshino No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 0001-5547 57 1 2013 Usefulness of Immunoglobulin Light-Chain Restriction on Immunocytochemical Double Staining for the Cytological Diagnosis of B Cell Non-Hodgkin's Lymphoma 84 90 EN Yasumasa Shimoura Yasuharu Sato Katsuyoshi Takata Yorihisa Orita Satoko Nakamura Shyouhe Mano Tadashi Yoshino 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. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 122 1 2010 IgG4 関連疾患 77 79 EN Yasuharu Sato Tadashi Yoshino No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 2009 Patients with localized primary non-tonsillar oral diffuse large B-cell lymphoma exhibit favorable prognosis despite a non-germinal center B-cell-like phenotype EN Yasuharu Sato No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 120 3 2008 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 271 277 EN Keyue Liu Shuji Mori Hideo Takahashi Yasuko Tomono Hidenori Wake Toru Kanke Yasuharu Sato Norihito Hiraga Naoto Adachi Tadashi Yoshino Masahiro Nishibori No potential conflict of interest relevant to this article was reported.