Updated on 2025/05/06

写真a

 
KARUBE Kennosuke
 
Organization
Graduate School of Medicine Program in Integrated Medicine Advanced Medical Science Professor
Graduate School
Graduate School of Medicine
Undergraduate School
School of Medicine Department of Medicine
Title
Professor

Degree 1

  1. Doctor of Medicine ( 2006.3   Kyushu University ) 

 

Papers 45

  1. Extranodal marginal zone B-cell lymphoma with LP-like cells: indication of the link between MALT and nodular lymphocyte predominant Hodgkin lymphoma Open Access

    Karube Kennosuke, Tsuzuki Megumi, Iwakoshi Akari, Murakami Yoshiko, Nishimura Rieko

    Journal of Clinical and Experimental Hematopathology   Vol. 65 ( 1 ) page: 81 - 83   2025.3

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    Language:English   Publisher:Japanese Society of Lymphoma Research  

    DOI: 10.3960/jslrt.24079

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  2. New classifications of B-cell neoplasms: a comparison of 5th WHO and International Consensus classifications

    Karube, K; Satou, A; Kato, S

    INTERNATIONAL JOURNAL OF HEMATOLOGY   Vol. 121 ( 3 ) page: 331 - 341   2025.3

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    Language:English   Publisher:International Journal of Hematology  

    In 2024, the World Health Organization (WHO) launched a new classification of lymphoid neoplasms, a revision of the previously used Revised 4th Edition of their classification (WHO-4R). However, this means that two classifications are now in simultaneous use: the 5th Edition of the WHO classification (WHO-5) and the International Consensus Classification (ICC). Instead of a comprehensive review of each disease entity, as already described elsewhere, this review focuses on revisions made in both the WHO-5 and ICC from WHO-4R and discrepancies between them regarding B-cell neoplasms. Similarities include cutaneous marginal zone lymphoma, cold agglutinin disease, non-primary effusion lymphoma-type effusion-based lymphoma, and gray zone lymphoma. Differences include plasma cell neoplasms, high-grade B-cell lymphoma (double hit lymphoma), follicular lymphoma, LPD with immune deficiency and dysregulation, extranodal large B-cell lymphoma, transformations of indolent B-cell lymphomas, and diffuse large B-cell lymphoma, not otherwise specified. Understanding the similarities and differences between the two latest classifications will aid daily diagnostic practice and future research on lymphoid neoplasms.

    DOI: 10.1007/s12185-024-03781-5

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  3. The Phenotypic Landscape of Anaplastic Large Cell Lymphoma Supports a New Molecular Classification: An LLMPP Study

    Acuna, JG; Dasari, S; Rimsza, L; Scott, D; Hu, GH; Shi, M; Campo, E; Chan, W; Cook, J; Inghirami, G; Jaffe, E; Morin, R; Raess, P; Rosenwald, A; Savage, K; Staudt, L; Wright, G; Amador, C; Delabie, J; Farinha, P; Greiner, T; Iqbal, J; Hilton, L; Ondrejka, S; Ott, G; Pittaluga, S; Slack, G; Song, J; Wang, HW; Aljudi, A; Ansell, S; Cornejo, CB; Cerhan, J; Chen, WA; de Leval, L; Gru, A; Jaye, D; Jiang, LY; Kahl, B; Karube, K; Ko, Y; Mou, ER; Maurer, M; Medeiros, LJ; Miranda, R; Oishi, N; Perry, A; Satou, A; Wang, XJ; Wilcox, R; Wu, XJ; Yoshino, T; Zeng, Y; Feldman, A

    LABORATORY INVESTIGATION   Vol. 105 ( 3 ) page: 30 - 31   2025.3

  4. Imaging features and consideration of progression pattern of diffuse hemispheric gliomas, H3 G34-mutant Open Access

    Kibe, Y; Chalise, L; Ohka, F; Motomura, K; Nakahara, N; Aoki, K; Deguchi, S; Shiba, Y; Takeuchi, K; Iwami, K; Yamaguchi, J; Shimizu, H; Maeda, S; Takido, Y; Yamamoto, R; Okuno, Y; Sakai, A; Karube, K; Saito, R

    ACTA NEUROPATHOLOGICA COMMUNICATIONS   Vol. 13 ( 1 ) page: 43   2025.2

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    Language:English   Publisher:Acta Neuropathologica Communications  

    Diffuse hemispheric glioma H3 G34-mutant (DHG) has been identified as a distinct pediatric-type high-grade glioma, according to the World Health Organization (WHO) classification of central nervous system tumors. Widely accepted treatment options include surgery, radiation, and conventional chemotherapy. However, the efficacy of the surgical resection remains unclear. Although there are some reports, a comprehensive understanding of the clinical characteristics, pathogenesis, and outcomes of DHG is insufficient to evaluate the efficacy of maximal tumor resection. We retrospectively analyzed nine cases of DHG, focusing on imaging features and progression patterns. Initial Magnetic Resonance Imaging (MRI) revealed T2/FLAIR high lesions with minimal or no contrast enhancement in all cases. The lesions exhibited T2/FLAIR hyperintensities and focal diffusion restriction in the deep white matter, with most showing high methionine accumulation, suggesting deep white matter infiltration at the time of diagnosis. The extent of white matter infiltration in tumor resection cases was significantly negatively correlated with the extent of resection (EOR). In addition, cases with EOR of 90% or more had significantly longer progression-free survival (PFS) and overall survival (OS). However, achieving an EOR of 90% or more was possible in fewer than half of the cases, primarily in those with relatively limited white matter involvement. Histopathological findings of the tumor obtained by initial resection and autopsy revealed extensive deep white matter infiltration, with one patient demonstrating tumor invasion into the brainstem at death. Our study highlights early deep white matter infiltration of DHGs, complicating surgical resection, and potentially contributing to a poor prognosis. While EOR may influence survival to some extent, residual lesions extensively infiltrate the white matter and eventually invade the brainstem and contralateral brain, thereby contributing to mortality. These findings underscore the challenges of managing DHGs and emphasize the need for further research on effective therapeutic strategies, particularly to understand and target their unique progression patterns.

    DOI: 10.1186/s40478-025-01945-w

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  5. The fifth edition of the WHO classification of mature T cell, NK cell and stroma-derived neoplasms

    Attygalle, AD; Karube, K; Jeon, YK; Cheuk, W; Bhagat, G; Chan, JKC; Naresh, KN

    JOURNAL OF CLINICAL PATHOLOGY   Vol. 78 ( 4 ) page: 217 - 232   2025.2

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    Language:English   Publisher:Journal of Clinical Pathology  

    The fifth edition of the WHO Classification of Haematolymphoid Tumors (WHO-HAEM5) introduces significant advancements in the understanding and diagnosis of mature T cell and NK cell, and stroma-derived neoplasms, and incorporates molecular and genetic data/findings accrued over the past years. The classification has been reorganised using a hierarchical system, employed across the fifth edition of the WHO classification of tumours of all organ systems. This review highlights recent developments, evolving concepts, and key updates since the revised fourth edition (WHO-HAEM4R). It enumerates the minimal/essential criteria necessary for diagnosis and classification, constituting not only the importance of clonality analysis in the workup of certain T cell neoplasms and the detection of infectious agents and specific genetic alterations in a subset of entities but also the applicability of these criteria in resource-constrained settings. 'Stroma-derived neoplasms of lymphoid tissues discussed in this review is a new category introduced in HAEM5 that encompasses mesenchymal tumours occurring exclusively in lymph nodes and spleen and mesenchymal dendritic cell neoplasms previously classified as 'histiocytic/dendritic cell neoplasms'.

    DOI: 10.1136/jcp-2025-210074

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  6. Coactivation of innate immune suppressive cells induces acquired resistance against combined TLR agonism and PD-1 blockade

    Nishinakamura, H; Shinya, S; Irie, T; Sakihama, S; Naito, T; Watanabe, K; Sugiyama, D; Tamiya, M; Yoshida, T; Hase, T; Yoshida, T; Karube, K; Koyama, S; Nishikawa, H

    SCIENCE TRANSLATIONAL MEDICINE   Vol. 17 ( 785 ) page: eadk3160   2025.2

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    Language:English   Publisher:Science Translational Medicine  

    Immune checkpoint blockade therapy has been successfully applied in clinical settings as a standard therapy for many cancer types, but its clinical efficacy is restricted to patients with immunologically hot tumors. Various strategies to modify the tumor microenvironment (TME), such as Toll-like receptor (TLR) agonists that can stimulate innate immunity, have been explored but have not been successful. Here, we show a mechanism of acquired resistance to combination treatment consisting of an agonist for multiple TLRs, OK-432 (Picibanil), and programmed cell death protein 1 (PD-1) blockade. Adding the TLR agonist failed to convert the TME from immunogenically cold to hot and did not augment antitumor immunity, particularly CD8+ T cell responses, in multiple animal models. The failure was attributed to the coactivation of innate suppressive cells, such as polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) expressing CXCR2, through high CXCL1 production by macrophages in the TME upon OK-432 treatment. A triple combination treatment with OK-432, PD-1 blockade, and a CXCR2 neutralizing antibody overcame the resistance induced by PMN-MDSCs, resulting in a stronger antitumor effect than that of any dual combinations or single treatments. The accumulation of PMN-MDSCs was similarly observed in the pleural effusions of patients with lung cancer after OK-432 administration. We propose that successful combination cancer immunotherapy intended to stimulate innate antitumor immunity requires modulation of unwanted activation of innate immune suppressive cells, including PMN-MDSCs.

    DOI: 10.1126/scitranslmed.adk3160

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  7. A case of severe immune-related adverse events, myocarditis with myositis, and myasthenia gravis overlap syndrome following adjuvant nivolumab administration for muscle-invasive bladder cancer

    Kamikawa, H; Matsukawa, Y; Nishii, H; Naito, Y; Obara, K; Sahashi, K; Morimoto, R; Matsuo, K; Ishida, S; Inoue, S; Miyagi, S; Sakakibara, A; Katsuno, M; Karube, K; Akamatsu, S

    NAGOYA JOURNAL OF MEDICAL SCIENCE   Vol. 87 ( 1 ) page: 156 - 162   2025.2

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    Language:English   Publisher:Nagoya Journal of Medical Science  

    Herein, we present a case of severe immune-related adverse events (irAEs), myocarditis with myositis, and myasthenia gravis overlap syndrome (IM3OS) in a patient receiving an immune checkpoint inhibitor (ICI), as adjuvant therapy after surgery for muscle-invasive bladder cancer. An 80-year-old woman who had undergone a total cystectomy for bladder cancer presented with ptosis, diplopia, and paralysis 18 days after receiving nivolumab, an anti-programmed cell death-1 (PD-1) monoclonal antibody, as adjuvant therapy for the first time. Initial testing revealed positive findings on the ice pack test; elevated troponin, creatine kinase, and aldolase levels; and an abnormal electrocardiogram, suggesting that the patient had developed ICI-related myocarditis, myositis, and myasthenia gravis. Despite treatment with intravenous immunoglobulin (IVIG) and high-dose corticosteroids, her condition worsened, leading to a complete atrioventricular block. After cardiac pacemaker insertion and intensive treatment with repeated high-dose corticosteroids, IVIG, plasma exchange, and tacrolimus, left ventricular function and myositis symptoms improved. However, the patient developed a respiratory infection and renal failure, leading to death on day 99. Although ICIs are considered relatively safe with few side effects, they can cause serious complications and lead to death. In particular, when severe irAEs occur in multiple organs, such as IM3OS, the prognosis is poor. Although IM3OS has no specific diagnostic biomarker, making early detection difficult, clinicians should always pay attention to patient symptoms when using ICI and evaluate other pathologies with IM3OS when conditions such as myositis or myocarditis are suspected. Further research is needed to elucidate the pathophysiology and risk factors of IM3OS.

    DOI: 10.18999/nagjms.87.1.156

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  8. 第1土曜特集 ゲノム解析時代の血液腫瘍学 ホジキンリンパ腫の遺伝子異常と臨床的意義

    加留部 謙之輔

    医学のあゆみ   Vol. 292 ( 1 ) page: 111 - 115   2025.1

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    Publisher:医歯薬出版  

    DOI: 10.32118/ayu292010111

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  9. Spheroid culture to select theoretical therapeutic drugs in intravascular large B-cell lymphoma Open Access

    Takai, M; Shimada, K; Furukawa, K; Yamaga, Y; Yoshiyama, S; Kagaya, Y; Suzuki, T; Hayashi, K; Shimada, S; Karube, K; Kiyoi, H

    CANCER SCIENCE   Vol. 116 ( 1 ) page: 214 - 225   2025.1

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    Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal large B-cell lymphoma that is characterized by the proliferation of lymphoma cells in the lumina of small vessels. Recent progress uncovering the genetic characteristics associated with MYD88/CD79B mutations has stimulated interest in the use of drugs targeting B-cell receptor signaling, including Bruton's tyrosine kinase. However, difficulties in culturing ex vivo IVLBCL cells has hampered research on the development of novel therapies. In the present study, we demonstrated the establishment of an ex vivo culture system of IVLBCL cells obtained from patient-derived xenograft (PDX) models. The spheroid culture enabled us to culture IVLBCL PDX cells for more than 10 days and to explore the efficacy of drug treatments acting on these cells. We found that carfilzomib and ibrutinib were effective for treating IVLBCL in ex vivo experiments and conducted in vivo analyses to assess the efficacy of these drugs. Although the efficacy of carfilzomib was difficult to confirm due to its toxicity in our models, ibrutinib showed comparable efficacy to a standard combination of chemotherapy drugs. Together, our data provide a new culture method for IVLBCL PDX cells and a rationale for translating ibrutinib to clinical use in IVLBCL patients.

    DOI: 10.1111/cas.16310

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  10. Clinicopathological significance of genomic alterations in lymphomas

    Karube, K

    CANCER SCIENCE   Vol. 116   page: 29 - 29   2025.1

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  11. Recent progress in pathological understanding of adult T-cell leukemia/ lymphoma in the new classification era Open Access

    Karube, K; Sakihama, S; Takatori, M; Morichika, K; Tamaki, T; Wada, N; Fukushima, T

    LEUKEMIA RESEARCH   Vol. 148   page: 107634   2025.1

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    Language:English   Publisher:Leukemia Research  

    Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell lymphoma caused by Human T-cell leukemia virus type 1 (HTLV-1) infection. Although the 5th Edition of the WHO classification (WHO-5) did not make drastic changes regarding the disease concept of ATLL from the revised 4th Edition of the WHO classification (WHO-4R), WHO-5 newly introduced the essential and desirable diagnostic criteria, namely, “neoplastic lymphoid cell proliferation with mature T-cell phenotype; proven HTLV-1 carriership” and "identification of monoclonal integration of HTLV-1", respectively. To satisfy the desirable criteria, a new diagnostic method using a combination of HBZ-ISH and tax-PCR was introduced for the identification of the HTLV-1 in addition to the conventionally used Southern blot hybridization, especially in the case when only FFPE specimens are available. Morphologically, pleomorphic- and anaplastic large cell-type, account for most cases, while minor variants, ATLL with dermatopathic reaction, angioimmunoblastic T-cell lymphoma-like variant, and classic Hodgkin lymphoma-like variant, should also be noted as diagnostic pitfalls. Phenotypically, about 80 % of ATLL cases show a typical phenotype of CD3 + CD4 +CD25 +CCR4 +, while about 10 % show atypical phenotypes such as T follicular helper cell-like one. Many genetic abnormalities, mainly associated with the TCR signaling pathway, are observed, and most are more frequent in the aggressive type than in the indolent type, except for STAT3, indicating the heterogeneous pathogenic process of ATLL. In this review, we present the latest findings on molecular pathogenesis and histopathological findings of ATLL in the era of the new classification of lymphomas, serving as a basis for future research and classification.

    DOI: 10.1016/j.leukres.2024.107634

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  12. Primary large B-cell lymphoma of the central nervous system: A reappraisal of CD5-positive cases based on clinical, pathological, and molecular evaluation

    Yamada, S; Satou, A; Tsuyuki, Y; Iba, S; Okumura, Y; Ishikawa, E; Ito, H; Kogure, Y; Goto, N; Tanikawa, M; Shimada, K; Tsukamoto, T; Karube, K; Yokoo, H; Kataoka, K; Tomita, A; Mase, M; Nakamura, S

    PATHOLOGY INTERNATIONAL   Vol. 75 ( 1 ) page: 11 - 20   2025.1

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    Language:English   Publisher:Pathology International  

    CD5 expression is seen in 5%–10% of de novo diffuse large B-cell lymphomas (DLBCLs). Primary large B-cell lymphoma of the central nervous system (PCNS-LBCL) also exhibits CD5 expression in a minority of cases, however, clinicopathological and molecular features remain largely unclarified. Here we present the clinical, molecular, and pathological features of 11 CD5-positive (+) PCNS-LBCL cases, occupying 6.7% of all 165 PCNS-LBCLs diagnosed in our institutions. While CD5+ systemic DLBCL has been recognized as a distinctive subgroup showing an aggressive clinical course, no obvious differences were found between CD5+ and CD5-negative subgroups among the present CNS patients clinically. MYD88 p.L265P and CD79B p.Y196 mutations were detected in eight (73%) and seven (64%) cases, respectively, supporting previous reports. Notably, the microenvironmental immune cells were universally PD-L1/CD274-positive, and the higher levels tended to present favorable overall survival, as already evidenced in the PCNS-LBCL series. In contrast, neoplastic PD-L1/CD274 expression was undetectable in all cases. Indeed, no structural variations or copy number alterations involving PD-1 ligands were detected by targeted-capture sequencing and fluorescence in situ hybridization. While further studies are warranted, we may have confirmed similarity between PCNS-LBCLs and intravascular large B-cell lymphomas from a molecular standpoint.

    DOI: 10.1111/pin.13496

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  13. Development of Adult T-Cell Leukemia/Lymphoma During Treatment with PD-L1 Inhibitor for Lung Cancer

    Fujioka Hikari, Kikuchi Kentaro, Nakahara Takumi, Yoshioka Satoshi, Kawai Rina, Kajitani Maki, Ishizuka Mana, Akiyama Masaya, Tanaka Yutaro, Kobayashi Ayako, Sato Ken, Karube Kennosuke, Tanaka Goh, Kohyama Tadashi

    Internal Medicine   Vol. advpub ( 0 )   2025

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    Language:English   Publisher:The Japanese Society of Internal Medicine  

    <p>Advancements in immunotherapy, the phenomenon of hyperprogression in cancer patients, have garnered increasing attention. We herein report a case of acute adult T-cell leukemia/lymphoma (ATL) that developed after administration of the PD-L1 inhibitor durvalumab in a patient with lung cancer. Although the patient was a carrier of human T-cell leukemia virus type 1 (HTLV-1), this was unknown prior to durvalumab treatment. <i>HTLV-1 bZIP factor</i> was detected in formalin-fixed lymph node tissue, confirming the diagnosis of ATL. Our findings suggest a potential association between immune checkpoint inhibition and ATL development in HTLV-1 carriers. </p>

    DOI: 10.2169/internalmedicine.5114-24

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  14. A case of myoepithelioma-like tumor of the vulvar region showing infiltrative growth to the dermis

    Naito Yu, Yanagida Eriko, Noto Yuki, Ando Takuro, Kawano Tasuku, Karube Kennosuke

    Japanese Journal of Diagnostic Pathology   Vol. 42 ( 2 ) page: 139 - 145   2025

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    Language:Japanese   Publisher:The Japanese Society of Pathology  

    <p>We report a case of myoepithelioma-like tumor of the vulvar region (MELTVR). A woman in her 60s had a 2cm subcutaneous tumor on the perineum. Histologically, the tumor extended from the subcutaneous tissue to the dermis. The tumor consisted of the proliferation of spindle-shaped and epithelioid cells with abundant myxoid stroma. The histology resembled that of soft tissue myoepithelioma;however, immunohistochemically, AE1/AE3 showed very focal and weak positivity, CAM5.2, S-100, and GFAP were negative, and <i>EWSR1</i> gene rearrangement was absent. Additional immunohistochemical evaluation was performed, and the diagnosis of MELTVR was confirmed based on the expression of Estrogen receptor and complete loss of SMARCB1 expression. The infiltrative proliferation into the dermis was a characteristic feature of this case. In addition, we report on MELTVR from the perspective of tumors that show loss of SMARCB1 expression, along with a discussion of the literature.</p>

    DOI: 10.69281/jspjjdp.2024_09_0037

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  15. A lymph node lesion of hyper IL-6 syndrome mimicking plasmacytoma, IgG4-related disease, and Castleman disease Open Access

    Matsui Kenta, Imai Hiroshi, Kobayashi Toshiaki, Mizutani Minoru, Nishimura Midori Filiz, Sato Yasuharu, Karube Kennosuke, Okada Manato, Usui Miki, Kawakami Keiki, Murata Tetsuya

    Journal of Clinical and Experimental Hematopathology   Vol. 64 ( 4 ) page: 307 - 312   2024.12

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    <p>A 72-year-old male patient presented fatigue, anemia, elevated total protein, IgG, IgG4, IL-6, and vascular endothelial growth factor (VEGF) levels. Initial diagnostics suspected multiple myeloma. A plane computed tomography (CT) scan showed pneumonia and the enlargement of generalized lymph nodes. A lymph node biopsy revealed a mix of immature and mature plasma cells, significant IgG4-positive cells, and IL-6-secreting plasma cells, mimicking plasmacytoma, IgG4-related disease, and Castleman disease, ultimately leading to a diagnosis of hyper IL-6 syndrome. Treatment with antibiotics improved the patient’s condition without the need for additional therapies, including tocilizumab.</p>

    DOI: 10.3960/jslrt.24039

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  16. Dual phenotypes in recurrent astrocytoma, IDH-mutant; coexistence of IDH-mutant and IDH-wildtype components: a case report with genetic and epigenetic analysis Open Access

    Yamaguchi, J; Ohka, F; Seki, M; Motomura, K; Deguchi, S; Shiba, Y; Okumura, Y; Kibe, Y; Shimizu, H; Maeda, S; Takido, Y; Yamamoto, R; Nakamura, A; Karube, K; Saito, R

    ACTA NEUROPATHOLOGICA COMMUNICATIONS   Vol. 12 ( 1 ) page: 169   2024.10

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    Mutations in the isocitrate dehydrogenase (IDH) gene are recognized as the key drivers in the oncogenesis of astrocytoma and oligodendroglioma. However, the significance of IDH mutation in tumor maintenance and malignant transformation has not been elucidated. We encountered a unique case of IDH-mutant astrocytoma that, upon malignant transformation, presented two distinct intratumoral components: one IDH-wildtype and one IDH-mutant. The IDH-wild-type component exhibited histological findings similar to those of small cell-type glioblastoma with a higher Ki-67 index than the IDH-mutant component. Despite their genetic divergence, both components exhibited similar comprehensive methylation profiles within the CpG island and were classified into methylation class of “Astrocytoma, IDH-mutant; High Grade” by the German Cancer Center (DKFZ) classifier v11.4. Phylogenetic analysis demonstrated that the IDH-wildtype component emerged as a subclonal component of the primary tumor. Detailed molecular analyses revealed that the loss of the IDH mutation was induced by the hemizygous loss of the entire arm of chromosome 2, on which IDH1 gene is located. Notably, the IDH-wild-type subclones uniquely acquired CDKN2A/B homozygous deletion and PDGFRA amplification, which is a marker of the aggressive phenotype of astrocytoma, IDH-mutant. Because these genetic abnormalities can drive oncogenic pathways, such as the PI3K/AKT/mTOR and RB signaling pathway, IDH-mutant gliomas that acquired these mutations were no longer dependent on the initial driver mutation, the IDH mutation. Molecular analysis of this unique case provides insight that in a subset of astrocytoma, IDH-mutant that acquired these genetic abnormalities, IDH mutation may not play a pivotal role in tumor growth and acquisition of these genetic abnormalities may contribute to the acquisition of resistance to IDH inhibitors.

    DOI: 10.1186/s40478-024-01879-9

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  17. Testicular large B-cell lymphoma is genetically similar to PCNSL and distinct from nodal DLBCL Open Access

    Rivas-Delgado, A; López, C; Clot, G; Nadeu, F; Grau, M; Frigola, G; Bosch-Schips, J; Radke, J; Ishaque, N; Alcoceba, M; Tapia, G; Luizaga, L; Barcena, C; Kelleher, N; Villamor, N; Baumann, T; Muntañola, A; Sancho-Cia, JM; García-Sancho, AM; Gonzalez-Barca, E; Matutes, E; Brito, JA; Karube, K; Salaverria, I; Enjuanes, A; Wiemann, S; Heppner, FL; Siebert, R; Climent, F; Campo, E; Giné, E; López-Guillermo, A; Beà, S

    HEMASPHERE   Vol. 8 ( 10 ) page: e70024   2024.10

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    Testicular large B-cell lymphoma (TLBCL) is an infrequent and aggressive lymphoma arising in an immune-privileged site and has recently been recognized as a distinct entity from diffuse large B-cell lymphoma (DLBCL). We describe the genetic features of TLBCL and compare them with published series of nodal DLBCL and primary large B-cell lymphomas of the CNS (PCNSL). We collected 61 patients with TLBCL. We performed targeted next-generation sequencing, copy number arrays, and fluorescent in situ hybridization to assess chromosomal rearrangements in 40 cases with available material. Seventy percent of the cases showed localized stages. BCL6 rearrangements were detected in 36% of cases, and no concomitant BCL2 and MYC rearrangements were found. TLBCL had fewer copy number alterations (p < 0.04) but more somatic variants (p < 0.02) than nodal DLBCL and had more frequent 18q21.32-q23 (BCL2) gains and 6q and 9p21.3 (CDKN2A/B) deletions. PIM1, MYD88L265P, CD79B, TBL1XR1, MEF2B, CIITA, EP300, and ETV6 mutations were more frequent in TLBCL, and BCL10 mutations in nodal DLBCL. There were no major genetic differences between TLBCL and PCNSL. Localized or disseminated TLBCL displayed similar genomic profiles. Using LymphGen, the majority of cases were classified as MCD. However, we observed a subgroup of patients classified as BN2, both in localized and disseminated TLBCL, suggesting a degree of genetic heterogeneity in the TLBCL genetic profile. TLBCL has a distinctive genetic profile similar to PCNSL, supporting its recognition as a separate entity from DLBCL and might provide information to devise targeted therapeutic approaches.

    DOI: 10.1002/hem3.70024

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  18. Standardization of CD30 immunohistochemistry staining among three automated immunostaining platforms Reviewed Open Access

    Masafumi Seki 1, Akira Satou 2, Renji Funato 1, Tomoko Tamaki 3, Naoki Wada 3 4, Norihiro Nakada 5, Hirofumi Matsumoto 5, Iwao Nakazato 6, Eriko Wada 2, Kaneko Sakurai 2, Toyonori Tsuzuki 2, Kennosuke Karube 1

    Pathology International   Vol. 74 ( 9 ) page: 530 - 537   2024.9

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

    DOI: 10.1111/pin.13472

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  19. Small cell pattern of ALK-negative anaplastic large cell lymphoma with double-hit rearrangements of <i>DUSP22</i> and <i>TP63</i>

    Niiyama-Uchibori, Y; Mizutani, S; Tsukamoto, T; Okamoto, H; Ide, D; Onishi, A; Kato, D; Fujino, T; Shimira, Y; Miyagawa-Hayashino, A; Konishi, E; Karube, K; Nannya, Y; Kuroda, J

    EJHAEM   Vol. 5 ( 4 ) page: 798 - 801   2024.8

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  20. Comparison of genomic alterations in Epstein-Barr virus-positive and Epstein-Barr virus-negative diffuse large B-cell lymphoma Open Access

    Liu, F; Tian, SF; Liu, Q; Deng, YF; He, QY; Shi, QY; Chen, G; Xu, XL; Yuan, JY; Nakamura, S; Karube, K; Wang, Z

    CANCER MEDICINE   Vol. 13 ( 4 ) page: e6995   2024.2

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    Background: Epstein–Barr virus (EBV)-positive diffuse large B-cell lymphoma (EBV-posDLBCL) is an aggressive B-cell lymphoma that often presents similar morphological and immune phenotype features to that of EBV-negative DLBCL (EBV-negDLBCL). Aims and Methods: To better understand their difference in genomic landscape, we performed whole-exome sequencing (WES) of EBV-posDLBCL and EBV-negDLBCL. Results: This analysis revealed a new mutational signature 17 (unknown) and signature 29 (smoking) in EBV-posDLBCL as well as a specific mutational signature 24 (associated with aflatoxin) in EBV-negDLBCL. Compared with EBV-negDLBCL, more somatic copy number alterations (CNAs) and deletions were detected in EBV-posDLBCL (p = 0.01). The most frequent CNAs specifically detected in EBV-posDLBCL were gains at 9p24.1 (PDL1 and JAK2), 8q22.2-q24.23 (DEPTOR and MYC), and 7q31.31-q32.2 (MET), which were validated in additional EBV-posDLBCL cases. Overall, 53.7% (22/41) and 62.9% (22/35) of the cases expressed PD-L1 and c-MET, respectively, in neoplastic cells, whereas only 15.4% (4/26) expressed c-MYC. Neoplastic c-MET expression was positively correlated with PD-L1 (p < 0.001) and MYC expression (p = 0.016). However, EBV-posDLBCL cases did not show any differences in overall survival between PD-L1-, c-MET-, or c-MYC-positive and -negative cases or between age-related groups. Analysis of the association between somatic mutation load and EBV status showed no difference in the distribution of tumor mutant burden between the two lymphomas (p = 0.41). Recurrent mutations in EBV-posDLBCL implicated several genes, including DCAF8L1, KLF2, and NOL9, while in EBV-negDLBCL, ANK2, BPTF, and CNIH3 were more frequently mutated. Additionally, PIM1 is the most altered gene in all the WES-detected cases. Conclusions: Our results confirm that genomic alteration differs significantly between EBV-posDLBCL and EBV-negDLBCL, and reveal new genetic alterations in EBV-posDLBCL. The positive correlation of c-MET and PD-L1/c-Myc expression may be involved in the pathogenesis of EBV-posDLBCL, which is should be explored prospectively in trials involving MET-directed therapies.

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  21. 症例 肝紫斑病のEOB-MRI所見:2例報告

    佐東 征記, 安座間 喜明, 木村 隆, 上里 安範, 加留部 謙之輔, 伊良波 祥子, 樋口 佳代子, 西江 昭弘

    臨床放射線   Vol. 69 ( 1 ) page: 123 - 130   2024.1

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    DOI: 10.18888/rp.0000002621

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  22. Follicular lymphoma with Epstein-Barr virus-associated transformation: A case report and review of the literature Open Access

    Tsuyuki Yuta, Karube Kennosuke

    Journal of Clinical and Experimental Hematopathology   Vol. 64 ( 2 ) page: 144 - 148   2024

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    <p>Follicular lymphoma (FL) is a common type of B-cell lymphoma, accounting for about 20% of all lymphomas. Although FL is primarily characterized by an indolent clinical course, histological transformation (HT) remains one of the significant challenges in managing patients with FL. Here, we present a case of FL with partial large-cell transformation due to Epstein-Barr Virus (EBV) arising in a 50-year-old Japanese woman with no known immunodeficiency. Immunohistochemical studies revealed that medium-sized FL cells expressed CD20, CD10, BCL2, and BCL6, whereas large cells were positive for CD20, and MUM1. In situ hybridization (ISH) revealed large cells to be positive for EBV-encoded small RNA (EBER) and further immunohistochemical investigation demonstrated EBER+ cells to express latent membrane protein 1 (LMP1). The Ki-67 index was about 30% in FL cells, and over 70% in large cells. Fluorescence in situ hybridization for <i>BCL2</i> combined with EBER-ISH identified <i>BCL2</i> rearrangement in both EBV-infected large cells and EBV-uninfected FL cells, suggesting these two components were clonally related. These findings indicate that EBV contributes to the transformation of FL. As far as the authors could find, only four previous cases of FL development to EBV-positive aggressive lymphoma have been reported. Further studies are needed to clarify the role of EBV in the HT of FL.</p>

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  23. <i>MYD88</i> mutation-positive indolent B-cell lymphoma with CNS involvement: Bing–Neel syndrome mimickers Open Access

    Takeda Kenichiro, Okazaki Shoichiro, Minami Rintaro, Ichiki Akihumi, Yamaga Yusuke, Nakajima Kosei, Kitamura Kunio, Karube Kennosuke, Nishiyama Takahiro

    Journal of Clinical and Experimental Hematopathology   Vol. 64 ( 3 ) page: 252 - 260   2024

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    <p><i>MYD88</i> p.L265P mutation occurs in over 90% of Waldenström’s macroglobulinemia (WM), which is characterized by lymphoplasmacytic lymphoma (LPL) with monoclonal IgM. WM requires careful diagnosis due to overlapping features with other B-cell malignancies. Bing–Neel syndrome (BNS), a rare complication of WM, involves central nervous system (CNS) invasion. This report describes two cases of morphologically low-grade B-cell lymphoma in the bone marrow accompanied by the presence of a large B-cell lymphoma in the brain and a common <i>MYD88</i> p.L265P mutation, which were eventually established as BNS mimickers. Although the two components in these cases showed the same identical light-chain restriction, different immunoglobulin heavy-chain rearrangement peaks indicated distinct lymphoma stem cells for CNS and bone marrow lesions. These clinical cases emphasize the challenges in diagnosing BNS. Based on the findings, biopsy is recommended for accurate identification of the clonal relationship and <i>MYD88</i> mutation status.</p>

    DOI: 10.3960/jslrt.24033

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  24. Extranodal NK/T-cell lymphoma with localized relapse in bone marrow of lower leg detected using PET-CT Open Access

    Nakamura Takahisa, Tatetsu Hiro, Higuchi Yusuke, Endo Shinya, Shiraishi Shinya, Kawanaka Koichi, Imakane Daisuke, Sonoda Miyu, Furuta Rie, Shichijo Takafumi, Honda Yumi, Karube Kennosuke, Mikami Yoshiki, Nosaka Kisato, Matsuoka Masao, Yasunaga Jun-ichirou

    Journal of Clinical and Experimental Hematopathology   Vol. 64 ( 1 ) page: 45 - 51   2024

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    <p>Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is a rare subtype of non-Hodgkin lymphoma (NHL) with poor prognosis, particularly in relapsed or refractory patients. Thus, timely detection of relapse and appropriate disease management are crucial. We present two patients with ENKTL, wherein positron emission tomography-computed tomography (PET-CT) with total-body coverage after induction therapy, detected newly relapsed regions in the bone marrow of the lower leg prior to progression. Case 1: A 47-year-old woman with nasal obstruction, showing 18F-fluoro-deoxyglucose (FDG) uptake in the nasal cavity (Lugano stage IE). After induction therapy (RT-2/3 DeVIC), PET-CT revealed abnormal uptake only in the right fibula. Case 2: A 68-year-old man with a skin nodule/ulcer and an enlarged right inguinal lymph node was diagnosed with advanced ENKTL. A PET-CT scan revealed abnormal uptake in the subcutaneous mass of the right medial thigh, lymph nodes, and descending colon (Lugano stage IV). After induction therapy, PET-CT revealed new abnormal uptake only in the left tibia. In both patients, CT-guided biopsy confirmed ENKTL recurrence. Moreover, PET-CT with whole-body coverage was useful for the timely assessment of relapse and detection of asymptomatic bone involvement. This approach allowed for modifications to treatment strategies in certain patients.</p>

    DOI: 10.3960/jslrt.23046

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  25. Gene Expression Profiling Reveals Two Overarching Types of Anaplastic Large Cell Lymphoma with Distinct Targetable Biology: An LLMPP Study

    Feldman, AL; Dasari, S; Rimsza, LM; Scott, DW; Oishi, N; Amador, C; Campo, E; Chan, WC; Cook, JR; Delabie, J; Farinha, P; Fu, K; Greiner, TC; Inghirami, G; Iqbal, J; Jaffe, ES; Ondrejka, SL; Ott, G; Pittaluga, S; Raess, P; Rosenwald, A; Savage, KJ; Slack, G; Slager, SL; Song, JY; Staudt, LM; Wright, G; Wang, HW; Zeng, Y; Yoshino, T; Wu, XJ; Wilcox, RA; Wang, XJ; Satou, A; Perry, AM; Miranda, R; Medeiros, LJ; Maurer, MJ; Mou, E; Ko, YH; Karube, K; Kahl, BS; Jiang, LY; Jaye, DL; de Leval, L; Chen, WN; Chapman-Fredricks, JR; Cerhan, JR; Barrionuevo, C; Ansell, SM; Aljudi, A

    BLOOD   Vol. 142   2023.11

  26. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue of pleural origin

    Urano, Y; Karube, K; Shiraki, Y

    PATHOLOGY INTERNATIONAL   Vol. 73 ( 11 ) page: 560 - 562   2023.11

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  27. Masqueraded mastocytosis with prominent crystal-storing histiocytic infiltration Open Access

    Karube, K; Takeuchi, K

    BLOOD   Vol. 142 ( 16 ) page: 1404 - 1404   2023.10

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    DOI: 10.1182/blood.2023021961

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  28. 症例 子宮体癌との鑑別を要した異型ポリープ状腺筋腫の1例

    川上 由香, 伊良波 裕子, 下地 裕子, 青木 陽一, 玉城 智子, 加留部 謙之輔, 西江 昭弘

    臨床放射線   Vol. 68 ( 10 ) page: 1001 - 1005   2023.10

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    DOI: 10.18888/rp.0000002481

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  29. The 5th edition of The World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms (vol 36, pg 1720, 2022) Open Access

    Alaggio, R; Amador, C; Anagnostopoulos, I; Attygalle, AD; Araujo, IBD; Berti, E; Bhagat, G; Borges, AM; Boyer, D; Calaminici, M; Chadburn, A; Chan, JKC; Cheuk, W; Chng, WJ; Choi, JK; Chuang, SS; Coupland, SE; Czader, M; Dave, SS; de Jong, D; Di Napoli, A; Du, MQ; Elenitoba-Johnson, KS; Ferry, J; Geyer, J; Gratzinger, D; Guitart, J; Gujral, S; Harris, M; Harrison, CJ; Hartmann, S; Hochhaus, A; Jansen, PM; Karube, K; Kempf, W; Khoury, J; Kimura, H; Klapper, W; Kovach, AE; Kumar, S; Lazar, AJ; Lazzi, S; Leoncini, L; Leung, N; Leventaki, V; Li, XQ; Lim, MS; Liu, WP; Louissaint, A ; Marcogliese, A; Medeiros, LJ; Michal, M; Miranda, RN; Mitteldorf, C; Montes-Moreno, S; Morice, W; Nardi, V; Naresh, KN; Natkunam, Y; Ng, SB; Oschlies, I; Ott, G; Parrens, M; Pulitzer, M; Rajkumar, SV; Rawstron, AC; Rech, K; Rosenwald, A; Said, J; Sarkozy, C; Sayed, S; Saygin, C; Schuh, A; Sewell, W; Siebert, R; Sohani, AR; Suzuki, R; Tooze, R; Traverse-Glehen, A; Vega, F; Vergier, B; Wechalekar, AD; Wood, B; Xerri, L; Xiao, WB; Akinola, NO; Akkari, Y; Allende, LM; Aozasa, K; Araujo, I; Arcaini, L; Ardeshna, KM; Asano, N; Attarbaschi, A; Bacon, CM; Barrans, SL; Batchelor, T; Battistella, M; Baughn, LB; Behdad, A; Berentsen, S; Bianchi, G; Bledsoe, J; Borchmann, P; Bower, M; Buldini, B; Burger, JA; Burkhardt, B; Cassaday, RD; Cazzaniga, G; Cerf-Bensussan, N; Cesarman, E; Chandy, M; Chapman, JR; Chapuy, B; Chen, XY; Cheng, CL; Chiattone, C; Chiorazzi, N; Cook, LB; Cooper, WA; Corboy, GP; Cowan, AJ; Cozzolino, I; Cree, IA; d'Amore, ESG; Davies, AJ; Deckert, M; Delabie, J; Demicco, EG; Deshpande, V; Diepstra, A; Dierickx, D; Dunleavy, K; Eichhorst, B; Ennishi, D; Fajgenbaum, DC; Farinha, P; de Larrea, CF; Fisher, KE; Fitzgibbon, J; Flanagan, M; Fromm, J; Garcia, JF; Geddie, WR; Gertz, M; Gopal, A; Gopal, S; Greipp, PT; Gru, A; Gupta, R; Hansmann, ML; Hebeda, KM; Herfarth, K; Herling, M; Hermine, O; Khe, HX; Hodge, J; Hu, SM; Huang, YH; Hung, YP; Hunger, S; Inaba, H; Inagaki, H; Iqbal, J; Ishitsuka, K; Iwaki, N; Iwatsuki, K; Jain, N; Jeon, YK; Kadin, M; Kaji, S; Kakkar, A; Karadimitris, A; Kataoka, K; Kato, S; Kersten, MJ; Ketterling, RP; Kim, JE; Kratz, CP; Kridel, R; Kristinsson, S; Küppers, R; Kuzu, I; Kwong, YL; Lacasce, A; Lamant-Rochaix, L; Lamy, T; Landgren, O; Laskar, S; Laskin, WB; Lenz, G; Li, SY; Di Li, G; Lin, P; Locatelli, F; Lorsbach, RB; Lossos, I; Loughran, TP Jr; Macon, WR; Maleszewski, JJ; Malhotra, P; Marafioti, T; Maruyama, D; Marx, A; Mbulaiteye, SM; Meignin, V; Mejstrikova, E; Michelow, P; Miettinen, M; Miles, RR; Miyoshi, H; Molina, TJ; Mollejo, M; Momose, S; Mori, T; Morice, WG; Nadel, B; Nagai, H; Nagane, M; Nair, R; Nakamura, N; Nakazawa, A; Nasr, S; Nicholson, AG; Nicolae, A; Ohgami, RS; Oishi, N; Olson, TS; Ortonne, N; Paiva, B; Pan-Hammarström, Q; Parihar, M; Paulli, M; Petersen, A; Picarsic, J; Pileri, A; Pimpinelli, N; Plaza, JA; Rabin, KR; Raderer, M; Rai, K; Randen, U; Rao, H; Robson, A; Rochford, R; Rosenquist, R; Rossi, D; Rossi, ED; Rule, S; Rymkiewicz, G; Sabattini, E; Saha, V; Sakata-Yanagimoto, M; Sander, CA; Sangueza, JM; Sangüeza, OP; Santucci, M; Sato, Y; Satou, A; Schafernak, KT; Schmitt, F; Semenzato, G; Sengar, M; Shanafelt, T; Shimada, K; Slack, GW; Slager, S; Soffietti, R; Solomon, DA; Stamatopoulos, K; Steidl, C; Stilgenbauer, S; Sukswai, N; Takeuchi, K; Tallini, G; Tamaru, J; Tan, SY; Tembhare, P; Tiacci, E; Tokura, Y; Tournilhac, O; Treon, S; Truemper, L; Tsukasaki, K; van Rhee, F; Varghese, A; Vermeer, MH; Vielh, P; Walker, B; Wang, M; Wang, HY; Wang, Z; Watanabe, T; Weigert, O; Wein-Stock, D; Whittaker, SJ; Willemze, R; Woessmann, W; Wu, CJ; Yamaguchi, M; Yamamoto, H; Yamashita, D; Yang, SM; Yang, DT; Yasuda, T; Yin, WH; Zen, Y; Zhao, S; Zhao, WL

    LEUKEMIA   Vol. 37 ( 9 ) page: 1944 - 1951   2023.9

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    Correction to: Leukemia, published online 22 June 2022 At the time of original publication, there was an incomplete listing of contributing authors and their institutions. This revision corrects those omissions.

    DOI: 10.1038/s41375-023-01962-5

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  30. Prognostic impact of highly solid component in early-stage solid lung adenocarcinoma Open Access

    Kato, T; Iwano, S; Hanamatsu, Y; Nakaguro, M; Emoto, R; Okado, S; Sato, K; Noritake, O; Nakanishi, K; Kadomatsu, Y; Ueno, H; Ozeki, N; Nakamura, S; Fukumoto, K; Takeuchi, T; Karube, K; Matsui, S; Chen-Yoshikawa, TF

    QUANTITATIVE IMAGING IN MEDICINE AND SURGERY   Vol. 13 ( 9 ) page: 5641 - +   2023.9

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    Background: Based on computed tomography (CT) findings of lung cancer, solid nodules have a much worse prognosis than subsolid nodules, even if the nodules are subcentimeter in size. There is, however, no systematic method for determining the prognosis of solid tumors on CT. This study aimed to discover the prognostic factor of early-stage solid lung adenocarcinoma using three-dimensional CT volumetry. Methods: Patients with pathological stage I solid lung adenocarcinoma who underwent complete resection between 2007 and 2012 were selected in this retrospective study. Clinicopathological data and preoperative multidetector CT findings, such as tumor size on the two-dimensional axial image, three-dimensional tumor volume between -600 and 199 HU, and three-dimensional solid volume between 0 and 199 HU, which corresponded to highly solid components, were compared between recurrence and non-recurrence. Furthermore, these radiological values were compared to pathological invasive volume (PIV). Results: During this time, 709 patients had their lung cancer completely removed. From this cohort, 90 patients with pathological stage I solid lung adenocarcinoma were selected. In addition, recurrence was found in 26 patients (28.9%). Although two-dimensional axial image, serum carcinoembryonic antigen (CEA) level, and SUVmax on 18F fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/ CT) did not differ statistically between recurrent and non-recurrent patients, three-dimensional tumor and solid tumor volume did. Multivariate analysis indicated that three-dimensional solid tumor volume [hazard ratio: 2.440; 95% confidence interval (CI): 1.110-5.361, P=0.026] and epidermal growth factor receptor (EGFR) mutation (hazard ratio: 4.307; 95% CI: 1.328-13.977, P=0.015) were significantly associated with disease-free survival (DFS). When three-dimensional tumor and solid tumor volume were compared to PIV, three-dimensional solid tumor volume (3,091 mm3 on average) showed a highly similar value with PIV (2,930 mm3 on average), whereas three-dimensional tumor volume (6,175 mm3 on average) was significantly larger than PIV (P<0.001). Conclusions: In patients with early-stage solid lung adenocarcinoma, the measurement of threedimensional solid tumor volume, which is correlated with PIV, accurately predicted the postoperative outcome.

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  31. Diagnostic Utility of STAT6 and pSTAT6 Immunohistochemistry for Distinguishing Classic Hodgkin Lymphoma and Peripheral T-Cell Lymphoma With Hodgkin and Reed-Sternberg-like Cells

    Satou, A; Takahara, T; Yamashita, D; Seki, M; Kato, S; Tanioka, F; Tsuyuki, T; Wada, E; Sakurai, K; Karube, K; Tsuzuki, T; Nakamura, S

    AMERICAN JOURNAL OF SURGICAL PATHOLOGY   Vol. 47 ( 8 ) page: 897 - 906   2023.8

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    Peripheral T-cell lymphomas (PTCLs), particularly nodal lymphomas of T-follicular helper cell origin, may include Hodgkin/Reed-Sternberg (HRS)-like cells in their microenvironment. These HRS-like cells are morphologically indistinguishable from HRS cells of classic Hodgkin lymphoma (CHL). Therefore, PTCLs with HRS-like cells pose a differential diagnosis vis-à-vis CHL. A previous study reported that, in contrast to HRS cells, programmed death-ligand 1 (PD-L1) expression is rare in HRS-like cells of PTCLs and suggested that PD-L1 immunohistochemistry is useful to differentiate HRS cells and HRS-like cells. In this study, we analyzed 21 patients with PTCL with HRS-like cells and 34 patients with CHL and assessed the diagnostic utility of STAT6, pSTAT6, and pSTAT3 immunohistochemistry in distinguishing HRS cells from HRS-like cells. In addition, we also performed PD-L1 immunohistochemistry to reconfirm its utility in distinguishing the 2 diseases. Compared with HRS cells in CHLs, HRS-like cells in PTCLs showed significantly less positivity for STAT6 (9.6% vs. 70%, P<0.001), pSTAT6 (9.6% vs. 70%, P<0.001), and PD-L1 (9.6% vs. 85%, P<0.001). Thus, we reconfirmed the diagnostic utility of PD-L1 immunohistochemistry in distinguishing CHLs from PTCLs with HRS-like cells. In contrast, both HRS-like and HRS cells were highly associated with pSTAT3 expression, with no significant difference in positive cell frequency (86% vs. 91%, P=0.66). On the basis of these findings, we conclude that, in addition to PD-L1, STAT6 and pSTAT6 immunohistochemistry are helpful diagnostic tools to distinguish CHLs from PTCLs with HRS-like cells.

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  32. A Comprehensive Study of the Immunophenotype and its Clinicopathologic Significance in Adult T-Cell Leukemia/Lymphoma Open Access

    Tamaki, T; Karube, K; Sakihama, S; Tsuruta, Y; Awazawa, R; Hayashi, M; Nakada, N; Matsumoto, H; Yagi, N; Ohshiro, K; Nakazato, I; Kitamura, S; Nishi, Y; Miyagi, T; Yamaguchi, S; Nakachi, S; Morishimaj, S; Masuzakij, H; Takahashik, K; Fukushimac, T; Wadaa, N

    MODERN PATHOLOGY   Vol. 36 ( 8 ) page: 100169   2023.8

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    Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell tumor caused by human T-lymphotropic virus type 1 (HTLV-1). The typical ATLL immunophenotypes are described in the 2017 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues (positive: CD2, CD3, CD5, CD4, and CD25; negative: CD7, CD8, and cytotoxic markers; and partially positive: CD30, CCR4, and FOXP3). However, limited studies are available on the expression of these markers, and their mutual relationship remains unknown. Furthermore, the expression status of novel markers associated with T-cell lymphomas, including Th1 markers (T-bet and CXCR3), Th2 markers (GATA3 and CCR4), T follicular helper markers (BCL6, PD1, and ICOS), and T-cell receptor (TCR) markers, and their clinicopathologic significance is unclear. In this study, we performed >20 immunohistochemical stains in 117 ATLL cases to determine the comprehensive immunophenotypic profile of ATLL, which were compared on the basis of clinicopathologic factors, including morphologic variants (pleomorphic vs anaplastic), biopsy locations, treatments, Shimoyama classification-based clinical subtype, and overall survival. CD3+/CD4+/CD25+/CCR4+ was considered a typical immunophenotype of ATLL, but approximately 20% of cases did not conform to this pattern. Simultaneously, the following new findings were obtained: (1) most cases were negative for TCR-β and TCR-δ (104 cases, 88.9%), indicating the usefulness of negative conversion of TCR expression to provide differentiation from other T-cell tumors; (2) the positivity of CD30 and CD15 and the negativity of FOXP3 and CD3 were significantly associated with anaplastic morphology; and (3) atypical cases, such as T follicular helper marker-positive (12 cases, 10.3%) and cytotoxic molecule-positive cases (3 cases, 2.6%), were identified. No single markers could predict the overall survival among patients with acute/lymphoma subtypes of ATLL. The results of this study illustrate the diversity of ATLL phenotypes. In T-cell tumors occurring in HTLV-1 carriers, the possibility of ATLL should not be eliminated even when the tumor exhibits an atypical phenotype, and the confirmation of HTLV-1 in the tissue is recommended.

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  33. Intravascular Large B-Cell Lymphoma Genomic Profile Is Characterized by Alterations in Genes Regulating NF-κB and Immune Checkpoints Open Access

    Gonzalez-Farre, B; Ramis-Zaldivar, JE; de Anta, NC; Rivas-Delgado, A; Nadeu, F; Salmeron-Villalobos, J; Enjuanes, A; Karube, K; Balague, O; Cobo, F; Kelleher, N; Victoria, I; Veloza, L; Teixido, C; Gine, E; Lopez-Guerra, M; Quintanilla-Martinez, L; Lopez-Guillermo, A; Salaverria, I; Campo, E

    AMERICAN JOURNAL OF SURGICAL PATHOLOGY   Vol. 47 ( 2 ) page: 202 - 211   2023.2

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    Intravascular large B-cell lymphoma (IVLBCL) is an uncommon lymphoma with an aggressive clinical course characterized by selective growth of tumor cells within the vessels. Its pathogenesis is still uncertain and there is little information on the underlying genomic alterations. In this study, we performed a clinicopathologic and next-generation sequencing analysis of 15 cases of IVLBCL using a custom panel for the detection of alterations in 68 recurrently mutated genes in B-cell lymphomagenesis. Six patients had evidence of hemophagocytic syndrome. Four patients presented concomitantly a solid malignancy. Tumor cells outside the vessels were observed in 7 cases, 2 with an overt diffuse large B-cell cell lymphoma. In 4 samples, tumor cells infiltrated lymphatic vessel in addition to blood capillaries. Programmed death-ligand 1 (PD-L1) was positive in tumor cells in 4 of 11 evaluable samples and in macrophages intermingled with tumor cells in 8. PD-L1 copy number gains were identified in a higher proportion of cases expressing PD-L1 than in negative tumors. The most frequently mutated gene was PIM1 (9/15, 60%), followed by MYD88 L265P and CD79B (8/15, 53% each). In 6 cases, MYD88 L265P and CD79B mutations were detected concomitantly. We also identified recurrent mutations in IRF4, TMEM30A, BTG2, and ETV6 loci (4/15, 27% each) and novel driver mutations in NOTCH2, CCND3, and GNA13, and an IRF4 translocation in 1 case each. The mutational profile was similar in patients with and without evidence of hemophagocytic syndrome and in cases with or without dissemination of tumor cells outside the vessels. Our results confirm the relevance of mutations in B-cell receptor/nuclear factor-κB signaling and immune escape pathways in IVLBCL and identify novel driver alterations. The similar mutational profile in tumors with extravascular dissemination suggests that these cases may also be considered in the spectrum of IVLBCL.

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  34. The correlation between HTLV-1 and Whipple's disease in a Japanese population: A case series

    Furugen Tomonori, Kinjo Tetsu, Hokama Akira, Furukawa Kojiro, Karube Kennosuke

      Vol. 42 ( 1-4 ) page: 21 - 28   2023

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    Purpose: Whippleʼs disease (WD) is a rare systemic disease caused by Tropheryma whipplei. It is predominantly diagnosed in middle-aged Caucasian men, and its association with immunosuppression and human leukocyte antigen (HLA)-B27 has been discussed; however, these studies are limited to western countries. Herein, we analyzed five WD cases and eight previously described WD cases in the Japanese population.
    Results: None of the patients were under immunosuppressive treatment or HLA-B27-positive. In 10/13 cases checking anti-HTLV-1 antibody, 6/10 (60%) cases were carriers of human T-cell leukemia virus type 1 (HTLV-1). All patients were treated with antibiotics, and their symptoms diminished promptly. The prognosis for these cases was excellent, and one patient developed the smoldering type adult T-cell leukemia/lymphoma, but no progression to aggressive type adult T-cell leukemia/lymphoma was observed.
    Conclusion: These findings probably support the findings that the immunosuppressive effect of HTLV-1 triggers WD in Japanese patients. It is recommended to evaluate the presence of HTLV-1 antibody in the blood of WD patients in HTLV-1 endemic areas for the clarification of the accurate pathogenesis and appropriate clinical follow-up. Ryukyu Med. J., 42 (1~4) 21~28, 2023

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  35. Genomic profiling for clinical decision making in lymphoid neoplasms Open Access

    de Leval, L; Alizadeh, AA; Bergsagel, PL; Campo, E; Davies, A; Dogan, A; Fitzgibbon, J; Horwitz, SM; Melnick, AM; Morice, WG; Morin, RD; Nadel, B; Pileri, SA; Rosenquist, R; Rossi, D; Salaverria, I; Steidl, C; Treon, SP; Zelenetz, AD; Advani, RH; Allen, CE; Ansell, SM; Chan, WC; Cook, JR; Cook, LB; D'Amore, F; Dirnhofer, S; Dreyling, M; Dunleavy, K; Feldman, AL; Fend, F; Gaulard, P; Ghia, P; Gribben, JG; Hermine, O; Hodson, DJ; Hsi, ED; Inghirami, G; Jaffe, ES; Karube, K; Kataoka, K; Klapper, W; Kim, WS; King, RL; Ko, YH; LaCasce, AS; Lenz, G; Martin-Subero, J; Piris, MA; Pittaluga, S; Pasqualucci, L; Quintanilla-Martinez, L; Rodig, SJ; Rosenwald, A; Salles, GA; San-Miguel, J; Savage, KJ; Sehn, LH; Semenzato, G; Staudt, LM; Swerdlow, SH; Tam, CS; Trotman, J; Vose, JM; Weigert, O; Wilson, WH; Winter, JN; Wu, CJ; Zinzani, PL; Zucca, E; Bagg, A; Scott, DW

    BLOOD   Vol. 140 ( 21 ) page: 2193 - 2227   2022.11

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    With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies.

    DOI: 10.1182/blood.2022015854

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  36. INFANT WITH NEUROBLASTOMA STAGE 4S REQUIRING LIVING DONOR LIVER TRANSPLANTATION

    Yamamori, A; Muramatsu, H; Wakamatsu, M; Kataoka, S; Tsuyuki, Y; Nishio, N; Shimoyama, Y; Karube, K; Ogura, Y; Takahashi, Y

    PEDIATRIC BLOOD & CANCER   Vol. 69   2022.11

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  37. Acute type adult T-cell leukemia cells proliferate in the lymph nodes rather than in peripheral blood

    Mizuguchi, M; Takatori, M; Sakihama, S; Yoshita-Takahashi, M; Imaizumi, N; Takahashi, Y; Hasegawa, H; Karube, K; Fukushima, T; Nakamura, M; Tanaka, Y

    CANCER GENE THERAPY   Vol. 29 ( 11 ) page: 1570 - 1577   2022.11

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    A massive increase in the number of mature CD4+ T-cells in peripheral blood (PB) is a defining characteristic of acute type of adult T-cell leukemia (ATL). To date, the site of proliferation of ATL cells in the body has been unclear. In an attempt to address this question, we examined the expression of the proliferation marker, Ki-67, in freshly isolated ATL cells from PB and lymph nodes (LNs) of patients with various types of ATL. Our findings reveal that LN-ATL cells display higher expression of the Ki-67 antigen than PB-ATL cells in acute type patients. The gene expression of T-cell quiescence regulators such as Krüppel-like factor 2/6 and forkhead box protein 1 was substantially high in acute type PB-ATL cells. The expression of human telomerase reverse transcriptase, which is involved in T-cell expansion, was significantly low in PB-ATL cells from acute type patients, similar to that in normal resting T-cells. These findings suggest that ATL cells proliferate in the LNs rather than in PB.

    DOI: 10.1038/s41417-022-00475-0

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  38. Wide excision alone for elderly patients aged &gt; 70 years old with soft tissue sarcomas Open Access

    Aoki, Y; Tome, Y; Oshiro, H; Katsuki, R; Tamaki, T; Wada, N; Karube, K; Nishida, K

    MEDICINE   Vol. 101 ( 36 ) page: e30127   2022.9

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    The purpose of the present study was to clarify clinical outcomes of elderly patients with soft tissue sarcoma who underwent surgery neither with neoadjuvant nor adjuvant chemotherapy. The median follow-up period was 46.3 (range 6.7-99.0) months. All patients underwent surgical resections. R0 margins were achieved in 24 cases (92.3%) and R1 margins in 2 cases (7.7%). The 1-, 2-, and 5-year sarcoma-specific survival (SSS) rates were 92.3%, 88.5%, and 83.8%, respectively. Multivariate analysis showed no significant risk factors for SSS. No significant relationship of histological grades and local recurrences (P =.56) or distant metastases (P =.54) was shown. In the current study, we observed a comparable survival ratio, despite no neoadjuvant or adjuvant chemotherapies performed. Tumor resections with adequate margins might, at least in part, have contributed to the decent survival ratio regardless of histological grade. Twenty-six consecutive patients aged ≥ 70 years, who underwent surgical resections of soft tissue sarcoma between January 2013 and December 2019, were included. SSS were analyzed by the Kaplan-Meier method, and the relationships between SSS and clinical parameters were evaluated by Cox proportional hazards analysis.

    DOI: 10.1097/MD.0000000000030127

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  39. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms Open Access

    Alaggio, R; Amador, C; Anagnostopoulos, I; Attygalle, AD; Araujo, IBD; Berti, E; Bhagat, G; Borges, AM; Boyer, D; Calaminici, M; Chadburn, A; Chan, JKC; Cheuk, W; Chng, WJ; Choi, JK; Chuang, SS; Coupland, SE; Czader, M; Dave, SS; de Jong, D; Du, MQ; Elenitoba-Johnson, KS; Ferry, J; Geyer, J; Gratzinger, D; Guitart, J; Gujral, S; Harris, M; Harrison, CJ; Hartmann, S; Hochhaus, A; Jansen, PM; Karube, K; Kempf, W; Khoury, J; Kimura, H; Klapper, W; Kovach, AE; Kumar, S; Lazar, AJ; Lazzi, S; Leoncini, L; Leung, N; Leventaki, V; Li, XQ; Lim, MS; Liu, WP; Louissaint, A ; Marcogliese, A; Medeiros, LJ; Michal, M; Miranda, RN; Mitteldorf, C; Montes-Moreno, S; Morice, W; Nardi, V; Naresh, KN; Natkunam, Y; Ng, SB; Oschlies, I; Ott, G; Parrens, M; Pulitzer, M; Rajkumar, SV; Rawstron, AC; Rech, K; Rosenwald, A; Said, J; Sarkozy, C; Sayed, S; Saygin, C; Schuh, A; Sewell, W; Siebert, R; Sohani, AR; Tooze, R; Traverse-Glehen, A; Vega, F; Vergier, B; Wechalekar, AD; Wood, B; Xerri, L; Xiao, WB

    LEUKEMIA   Vol. 36 ( 7 ) page: 1720 - 1748   2022.7

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    We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms.

    DOI: 10.1038/s41375-022-01620-2

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  40. Spindle cell tumor with histiocytic and myogenic marker expression in the lymph node of a human T-cell leukemia virus type 1 carrier

    Kubo, T; Hirayama, Y; Sakihama, S; Kikuchi, T; Hirohashi, Y; Tsujiwaki, M; Karube, K; Hasegawa, T; Torigoe, T

    PATHOLOGY RESEARCH AND PRACTICE   Vol. 234   page: 153935   2022.6

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    Carriers of oncogenic human T-cell leukemia virus type 1 (HTLV-1) can develop adult T-cell leukemia/lymphoma (ATLL). While an increasing number of animal models of HTLV-1 infection have revealed that malignant tumors with a histiocytic phenotype can arise, they have not been reported in humans. Here, we present a 79-year-old female HTLV-1 carrier who presented with a swollen lymph node. Histological examination revealed that the lymph node was replaced with a malignant spindle cell tumor, but not ATLL. Immunohistochemical analysis indicated that the tumor was positive for histiocytic (CD68 and CD163) and myogenic (α-smooth muscle actin, desmin, and caldesmon) markers, suggesting some differential diagnoses. We could not reach a definitive diagnosis under the current notion of the disease entity. In addition, we could not provide an exact causal relationship between HTLV-1 infection and the development of the current tumor. Nevertheless, this tumor may be a human counterpart of murine HTLV-1-related histiocytic tumors. Curiously, the tumor showed a good response to chemotherapy with the combination of cyclophosphamide, vincristine, and prednisone, a standard approach for ATLL. This case might represent a novel entity of an HTLV-1-related malignant tumor. Further accumulation of case reports will certainly contribute to our understanding of human HTLV-1-related disease and the mechanism of viral oncogenesis.

    DOI: 10.1016/j.prp.2022.153935

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  41. Genetic Alterations in Adult T-Cell Leukemia/Lymphoma: Novel Discoveries with Clinical and Biological Significance Open Access

    Sakihama, S; Karube, K

    CANCERS   Vol. 14 ( 10 )   2022.5

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    Adult T-cell leukemia/lymphoma (ATLL) is a refractory T-cell neoplasm that develops in human T-cell leukemia virus type-I (HTLV-1) carriers. Large-scale comprehensive genomic analyses have uncovered the landscape of genomic alterations of ATLL and have identified several altered genes related to prognosis. The genetic alterations in ATLL are extremely enriched in the T-cell receptor/nuclear factor-κB pathway, suggesting a pivotal role of deregulation in this pathway in the transformation of HTLV-1-infected cells. Recent studies have revealed the process of transformation of HTLV-1-infected cells by analyzing longitudinal samples from HTLV-1 carriers and patients with overt ATLL, an endeavor that might enable earlier ATLL diagnosis. The latest whole-genome sequencing study discovered 11 novel alterations, including CIC long isoform, which had been over-looked in previous studies employing exome sequencing. Our study group performed the targeted sequencing of ATLL in Okinawa, the southernmost island in Japan and an endemic area of HTLV-1, where the comprehensive genetic alterations had never been analyzed. We found associations of genetic alterations with HTLV-1 strains phylogenetically classified based on the tax gene, an etiolog-ical virus factor in ATLL. This review summarizes the genetic alterations in ATLL, with a focus on their clinical significance, geographical heterogeneity, and association with HTLV-1 strains.

    DOI: 10.3390/cancers14102394

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  42. Elevation of the Plasma Levels of TNF Receptor 2 in Association with Those of CD25, OX40, and IL-10 and HTLV-1 Proviral Load in Acute Adult T-Cell Leukemia Open Access

    Kato, M; Imaizumi, N; Tanaka, R; Mizuguchi, M; Hayashi, M; Miyagi, T; Uchihara, J; Ohshiro, K; Todoroki, J; Karube, K; Masuzaki, H; Tanaka, Y; Fukushima, T

    VIRUSES-BASEL   Vol. 14 ( 4 )   2022.4

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    Adult T-cell leukemia/lymphoma (ATL) cells express TNF receptor type-2 (TNFR2) on their surface and shed its soluble form (sTNFR2). We previously reported that sTNFR2 levels were highly elevated in the plasma of patients with acute ATL. To investigate whether its quantitation would be helpful for the diagnosis or prediction of the onset of acute ATL, we examined the plasma levels of sTNFR2 in a large number of specimens obtained from a cohort of ATL patients and asymptomatic human T-cell leukemia virus type 1 (HTLV-1) carriers (ACs) and compared them to those of other candidate ATL biomarkers (sCD25, sOX40, and IL-10) by enzyme-linked immunosorbent assays (ELISA) and HTLV-1 proviral loads. We observed that sTNFR2 levels were significantly elevated in acute ATL patients compared to ACs and patients with other types of ATL (chronic, smoldering, and lymphoma). Importantly, sTNFR2 levels were significantly correlated with those of sCD25, sOX40, and IL-10, as well as proviral loads. Thus, the present study confirmed that an increase in plasma sTNFR2 levels is a biomarker for the diagnosis of acute ATL. Examination of plasma sTNFR2 alone or in combination with other ATL biomarkers may be helpful for the diagnosis of acute ATL.

    DOI: 10.3390/v14040751

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  43. Blastic plasmacytoid dendritic cell neoplasm with prominent intracytoplasmic vacuoles: A challenging diagnosis

    Karube, K; Nakada, N; Sakamoto, K; Takeuchi, K

    PATHOLOGY INTERNATIONAL   Vol. 72 ( 3 ) page: 211 - 213   2022.3

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    DOI: 10.1111/pin.13201

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  44. Follicular T-cell lymphoma successfully treated with long-term corticosteroid

    TATETSU Hiro, IMAKANE Daisuke, NOSAKA Kisato, KARUBE Kennosuke, HONDA Yumi, HIGUCHI Yusuke, YASUNAGA Jun-ichirou, MIKAMI Yoshiki, MATSUOKA Masao

    Rinsho Ketsueki   Vol. 63 ( 11 ) page: 1497 - 1502   2022

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    Language:Japanese   Publisher:The Japanese Society of Hematology  

    <p>Follicular T-cell lymphoma (FTCL) is a rare disease, recently defined in the revised WHO classification Tumours of Haematopoietic and lymphoid tissues (4th edition). Although angioimmunoblastic T-cell lymphoma (AITL) and FTCL share similar T follicular helper (TFH) cell immunophenotypes and gene mutations, the clinical course of FTCL is not well characterized. Herein, we report the case of a 91-year-old woman with FTCL, who was successfully treated with corticosteroid. The patient, who had systemic lymphadenopathy and splenomegaly, was first diagnosed with necrotizing lymphadenitis. Re-biopsy was performed because of her persistent lymphadenopathy, which revealed FTCL. She was treated with corticosteroid because of her advanced age, poor performance, edema, and pleural effusion. After administering 100 mg prednisone, her condition improved and was discharged with prednisone tapering. Six-month positron emission tomography-computed tomography (PET-CT) scan showed complete metabolic remission. With a low dose of prednisone (6-10 mg), she remained disease-free for >3 years. Thus, these findings suggest that corticosteroid treatment is effective in some patients with peripheral T-cell lymphoma of TFH origin, including FTCL.</p>

    DOI: 10.11406/rinketsu.63.1497

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  45. The Positivity of Phosphorylated STAT3 Is a Novel Marker for Favorable Prognosis in Germinal Center B-Cell Type of Diffuse Large B-Cell Lymphoma

    Morichika, K; Karube, K; Sakihama, S; Watanabe, R; Kawaki, M; Nishi, Y; Nakachi, S; Okamoto, S; Takahara, T; Satou, A; Shimada, S; Shimada, K; Tsuzuki, T; Fukushima, T; Morishima, S; Masuzaki, H

    AMERICAN JOURNAL OF SURGICAL PATHOLOGY   Vol. 45 ( 6 ) page: 832 - 840   2021.6

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    On the basis of immunohistochemistry, diffuse large B-cell lymphoma (DLBCL) is categorized as a germinal center B-cell (GCB) or non-GCB subtype. Recent integrated genomic analyses have highlighted the importance of the JAK-STAT3 pathway in the molecular pathogenesis of DLBCL. However, its relevance to clinical outcomes remains controversial. Therefore, we evaluated the extent of the nuclear expression of phosphorylated STAT3 (pSTAT3), a surrogate marker of signal transducer and activator of transcription 3 (STAT3) activation, by immunohistochemistry. We also analyzed the potential relationship between pSTAT3 positivity (defined as ≥ 40% positive neoplastic cells) and clinicopathologic characteristics in 294 patients with DLBCL. pSTAT3 was detected in 122 patients (42%), with a higher rate in the non-GCB subtype than in the GCB subtype (57% vs. 28%, P < 0.001). Factors potentially activating STAT3, MYD88L265P, and Epstein-Barr virus-encoded small RNA were identified in the pSTAT3-positive non-GCB subtype, whereas the pSTAT3-positive GCB subtype often showed STAT3 mutations and lacked EZH2 mutations and the rearrangements of BCL2 and MYC. Multivariate analyses revealed that the pSTAT3-positive GCB subtype showed a favorable prognosis (HR: 0.17; 95% confidence interval, 0.04-0.7; P = 0.014). These findings suggest that pSTAT3 positivity may have a unique impact on the clinicopathologic characteristics of DLBCL, making it a promising novel marker for the favorable prognosis of patients with the GCB subtype.

    DOI: 10.1097/PAS.0000000000001691

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Books 1

  1. リンパ腫アトラス

    中村 直哉, 大島 孝一 , 加留部 謙之輔, 竹内 賢吾, 三好 寛明

    文光堂  2025  ( ISBN:9784830604973

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    Language:Japanese

    CiNii Books

KAKENHI (Grants-in-Aid for Scientific Research) 2

  1. 新規病態:HTLV-1陽性HRS細胞を伴う成人T細胞白血病/リンパ腫の統合的解析

    Grant number:23K27384  2023.4 - 2027.3

    科学研究費助成事業  基盤研究(B)

    加留部 謙之輔, 石塚 賢治, 加藤 光次, 福島 卓也, 佐藤 賢文, 下田 和哉

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    Authorship:Principal investigator 

    Grant amount:\18460000 ( Direct Cost: \14200000 、 Indirect Cost:\4260000 )

    申請者らが同定したHTLV-1関連の新規病態である Adult T-cell leukemia/lymphoma with HTLV-1 infected HRS-like cells (ATLL-HH)に関し
    て、腫瘍細胞及び腫瘍微小環境の両面から詳細な解析を行い、ATLL、CHLとの差異を明らかにする。具体的には臨床病理学的特徴の把握、網羅
    的遺伝子解析、シングルセル解析を組み合わせて解析し、ひいてはATLL-HHの診断、治療の向上につなげることを目的とする。
    HTLV-1を組織学的に同定するHBZ-ISHの技術は確立しており、症例の同定は問題なく行うことができた。現時点で18例まで症例集積が進んでおり、それらに関しては典型的ATLLとCHLの中間の予後が示唆されている。その他の特徴的な臨床病理学的所見の有無について、より症例数を蓄積し解析を今後も進めていく。nCounterによるFFPE検体を用いたbulkでの遺伝子発現解析では、ATLL-HHは典型的ATLLよりもCHLに近い遺伝子発現プロファイルを持つことが示唆された。ATLL-HHが形態的に類似するCHLと同様の腫瘍微小環境を有することを示唆する結果であると考えている。
    ほぼ計画当初に予想された通りのペースで研究が進んでいます。
    RNAレベルでの遺伝子発現解析の結果を、FFPE検体での免疫染色により、蛋白質レベルでもvalidationする予定である。免疫染色の抗体選定、条件検討は終了しており、各施設から未染標本を取り寄せることでスムーズに解析を行うことができる。以上の手法を通して、ATLL-HH、CHL、ATLLにおける腫瘍微小環境の違いに関して、網羅的遺伝子解析を併用して詳細を明らかにしたいと考えている。

  2. A new diagnostic algorithm using biopsy specimens in adult T-cell leukemia/lymphoma: combination of RNA in situ hybridization and quantitative PCR for HTLV-1

    Grant number:19K07438  2019.4 - 2022.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Karube Kennosuke

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    Authorship:Principal investigator 

    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

    Histopathological distinction between adult T-cell leukemia/lymphoma (ATLL) and other T-cell neoplasms is often challenging. Here we developed a new diagnostic algorithm for the accurate diagnosis of ATLL using FFPE samples. This method combines two HTLV-1 detection assays, namely, ultrasensitive RNA in situ hybridization using RNAscope for HTLV-1 bZIP factor (HBZ-RNAscope), and quantitative PCR targeting the tax gene (tax-qPCR). As a result, tax-qPCR had a higher ATLL identification rate than HBZ-RNAscope (88% [52/59], and 63% [39/62], respectively). However, HBZ-RNAscope clearly visualized the localization of HTLV-1-infected tumor cells and its identification rate increased to 94% (17/18) when the analysis was limited to samples up to 2 years old, indicating its usefulness in the daily diagnosis. This method is expected to replace Southern blot hybridization (SBH) and increase the accuracy of the diagnosis of ATLL.