Journal of Clinical and Experimental Hematopathology
Online ISSN : 1880-9952
Print ISSN : 1346-4280
ISSN-L : 1346-4280
Volume 54 , Issue 1
Showing 1-12 articles out of 12 articles from the selected issue
Highlights: Focus on Indolent Lymphoma
Commentary
Review Article
  • Katsuyoshi Takata, Tomoko Miyata-Takata, Yasuharu Sato, Tadashi Yoshin ...
    Type: Review Article
    2014 Volume 54 Issue 1 Pages 3-9
    Published: 2014
    Released: June 18, 2014
    JOURNALS FREE ACCESS
    Follicular lymphoma (FL) is a heterogeneous disease, and there are many different subgroups, such as in terms of age of onset, involved organ (especially extranodal sites such as gastrointestinal tract) and genetic abnormality. Grade 3B is currently regarded as a distinct entity by molecular genetic analyses, but the independence of Grade 3A remains unclear. Variations of clinical course are known in FL. Some cases are very indolent, but others are not. The latter cases show histological transformation to diffuse large B-cell lymphoma (DLBCL) (high-grade transformation) and an aggressive course. Histological transformation to DLBCL is reported to occur in about 30-40% of patients, at a rate of about 3% each year. However, it reaches a plateau at about 16 years, so the stratification of patients in whom transformation would or would not occur is very important for the therapeutic strategy. From genome-wide analysis by next-generation sequencing, EZH2, CREBBP and MLL2, which are histone-modifying genes, have been shown to be frequently mutated in FL and to have an important role in lymphomagenesis. IGH-BCL2 translocation and CREBBP mutations are early events, whereas MLL2 and TNFSFR14 mutations represent late events during disease evolution. In the 2008 WHO classification, three new variants: (1) pediatric follicular lymphoma, (2) primary intestinal follicular lymphoma and (3) in situ follicular lymphoma, are included. Pathologists and clinicians should consider these new developments when deciding on the diagnostic and therapeutic strategy. [J Clin Exp Hematop 54(1): 3-9, 2014]
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  • Seiji Sakata, Naoko Tsuyama, Kengo Takeuchi
    Type: Review Article
    2014 Volume 54 Issue 1 Pages 11-22
    Published: 2014
    Released: June 18, 2014
    JOURNALS FREE ACCESS
    Indolent B-cell lymphomas include follicular lymphoma (FL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and marginal zone lymphomas (MZLs). They are a diverse group of disorders with different clinical, morphological, immunophenotypic and genetic features. However, because of several histological similarities, such as in cell size and nodular structure, it may sometimes be difficult to differentiate them and to make a definitive diagnosis. In this review article, we summarize the histopathology of indolent B-cell neoplasms excluding FL and including hairy cell leukemia, and briefly mention recent genetic findings useful for their differential diagnosis. In addition, a provisional subtype of low-grade B-cell lymphoma, “prolymphocytic/paraimmunoblastic lymphoma”, is described. [J Clin Exp Hematop 54(1): 11-22, 2014]
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  • Wataru Kishimoto, Momoko Nishikori
    Type: Review Article
    2014 Volume 54 Issue 1 Pages 23-30
    Published: 2014
    Released: June 18, 2014
    JOURNALS FREE ACCESS
    t(14;18) translocation has been recognized as a genetic hallmark of follicular lymphoma (FL), but it is now known that additional genetic aberrations are required for the development of FL. With recent advances in the technology for DNA analysis, recurrent gene aberrations such as TNFRSF14, EPHA7, EZH2, CREBBP, EP300, MLL2 and MEF2B have been identified. A few t(14;18)-positive B cells can be detected in healthy individuals, and these B cells are reported to have their own biological features that are closely associated with the pathogenesis of FL. On the other hand, FL is characterized by a unique microenvironment. Further understanding of the pathogenesis of FL is expected to contribute to the development of novel treatment approaches for this disease. [J Clin Exp Hematop 54(1): 23-30, 2014]
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  • Koji Izutsu
    Type: Review Article
    2014 Volume 54 Issue 1 Pages 31-37
    Published: 2014
    Released: June 18, 2014
    JOURNALS FREE ACCESS
    Follicular lymphoma (FL) is the most common subtype of indolent lymphomas. Several lines of evidence suggest that the prognosis of patients with FL has improved since the introduction of rituximab, although cure cannot be achieved. Although the treatment paradigm for FL has changed over the past decade with the introduction of rituximab and other agents, there is still no standard therapy to fit all patients. Instead, treatment decisions are made taking into consideration disease status (stage, tumor burden, and presence of symptoms) and patient factors including patient preferences. Rituximab-containing chemotherapy such as R-CHOP, R-CVP, and bendamustine plus rituximab is usually recommended for symptomatic patients. However, optimal rituximab-containing chemotherapy has not been established. Rituximab maintenance is one of the post-induction options for patients responding to first-line chemoimmunotherapy. For patients without symptoms and low-tumor burden, both expectant management (watchful waiting) and rituximab monotherapy are reasonable options. A very limited proportion of patients with FL are diagnosed at stage I with rigorous staging using bone marrow biopsy and whole-body imaging with computed tomography (CT) and/or positron emission tomography/CT. Although local radiotherapy has been the standard approach for these patients, its role is being questioned. Patients with FL who achieve remission eventually relapse and require salvage therapy. The salvage regimen should be chosen taking into account previous treatment and its response duration. Moreover, the presence of histological transformation should be assessed. [J Clin Exp Hematop 54(1): 31-37, 2014]
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Review Article
  • Sung Won Kim
    Type: Review Article
    2014 Volume 54 Issue 1 Pages 39-47
    Published: 2014
    Released: June 18, 2014
    JOURNALS FREE ACCESS
    The definitive management of advanced follicular lymphoma (FL) remains controversial due to various treatment options, including watchful waiting, single-agent or combination chemotherapy, monoclonal antibody, and radioimmunotherapy. These options can provide prolonged progression-free survival. However, they cannot cure advanced FL. Allogeneic hematopoietic stem cell transplantation (allo-SCT) remains the sole curative therapy for FL. Allo-SCT has had a major impact with the use of reduced-intensity conditioning regimens because of its lower associated nonrelapse mortality compared with myeloablative regimens. Autologous SCT (auto-SCT) shows high response rates and extends progression-free survival in patients with chemosensitive relapse. In the rituximab era, however, associated comorbidities, risk of secondary cancers, and presence of refractory disease have become problematic in the auto-SCT population. On the basis of results from large-scale randomized trials, upfront auto-SCT is not recommended. Novel conditioning regimens including radioimmunotherapy followed by either auto-SCT or allo-SCT are likely to show efficacy even in chemorefractory disease. Consequently, the optimal timing for SCT remains a matter of opinion, except for patients in first remission. However, the outcomes of allo-SCT and auto-SCT keep on improving. Physicians should note that there is no therapy with a track record equivalent to that of SCT for relapsed or refractory FL. [J Clin Exp Hematop 54(1): 39-47, 2014]
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  • Akira Sakai, Noriaki Yoshida
    Type: Review Article
    2014 Volume 54 Issue 1 Pages 49-57
    Published: 2014
    Released: June 18, 2014
    JOURNALS FREE ACCESS
    Interkeukin-2 receptor (IL-2R) is comprised of three different subunits (α, β, and γ chain) and is expressed on B cells and NK cells besides T cells. CD25 is also known as the IL-2Rα chain on cell membranes, while soluble IL-2R (sIL-2R) is generated by the proteolytic cleavage of the IL-2Rα chain. Levels of sIL-2R in sera are monitored as a marker of disease activity in patients with lymphoma. However, elevated serum sIL-2R levels are also found in inflammatory diseases, such as infectious diseases. Levels of sIL-2R in sera are thought to reflect tumor burden in adult T-cell leukemia/lymphoma due to the expression of CD25 on tumor cells. Conversely, sIL-2R is thought to be mainly derived from activated T cells infiltrating tumor tissues in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) because lymphoma cells except for a subtype of DLBCL are mainly negative for CD25. Matrix metalloproteinase-9, a protease capable of cleaving the membrane bound IL-2Rα chain, is mainly produced by tissue-associated macrophages. Increased macrophages in tumor tissues are reported to be associated with poor prognosis, especially in Hodgkin's lymphoma. We found increased macrophages in DLBCL and FL compared with reactive lymphoid hyperplasia as well as a positive correlation between the levels of sIL-2R in sera and the number of macrophages in tumor tissues in FL and extranodal DLBCL. [J Clin Exp Hematop 54(1): 49-57, 2014]
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Original Article
  • Yoichi Saito, Yoshihiro Komohara, Daisuke Niino, Hasita Horlad, Koji O ...
    Type: Original Article
    2014 Volume 54 Issue 1 Pages 59-65
    Published: 2014
    Released: June 18, 2014
    JOURNALS FREE ACCESS
    Adult T-cell leukemia/lymphoma (ATLL) is endemic in southwestern Japan, the Caribbean basin, and parts of central Africa, and is considered to be caused by long-term infection with human T-cell leukemia virus type I. CD204 is a scavenger receptor that is overexpressed on alternatively activated macrophages and is known to be overexpressed in tumor-associated macrophages (TAMs). CD206 is also considered a marker of alternatively activated macrophages. However, no studies have investigated CD206 and TAMs. In the present study, we investigated the significance of CD204+ and CD206+ TAMs in ATLL tissue samples. We also investigated the correlations with the Ki-67 labeling index (Ki-67LI) and the number of CD31+ vessels. We found that the number and ratio of CD204+ TAMs were closely associated with the Ki-67LI, which reflects lymphoma cell proliferation. The number of CD31+ vessels was not correlated with the number or ratio of CD204+ and CD206+ TAMs. The number and ratio of CD204+ and CD206+ TAMs, number of CD31+ vessels, and the Ki-67LI were not associated with the clinical outcome of patients with ATLL. Although further studies are necessary to uncover the detailed mechanisms of CD204 and lymphoma proliferation, these data may provide novel insight into the pathogenesis of ATLL. [J Clin Exp Hematop 54(1): 59-65, 2014]
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  • Ikuo Matsuda, Yukihiro Imai, Seiichi Hirota
    Type: Original Article
    2014 Volume 54 Issue 1 Pages 67-73
    Published: 2014
    Released: June 18, 2014
    JOURNALS FREE ACCESS
    Lymphomas are malignant neoplasms composed of lymphoid cells at various developmental stages and lineages. Recent advances in comprehensive genomic analyses in acute myeloid leukemia have revealed prevalent mutations in regulators of epigenetic phenomena including global DNA methylation status. The examples include mutations in isocitrate dehydrogenase 1 (IDH1), IDH2, and ten-eleven translocation 2. These mutations are proposed to inhibit conversion of 5-methylcytosine (5 mC) to 5-hydroxymethylcytosine (5 hmC), leading to global accumulation of 5 mC. These changes in global DNA methylation status can be visualized immunohistochemically using specific antibodies against 5 mC and 5 hmC. We examined the global DNA methylation status of B-cell lymphomas and that of their normal counterparts by immunohistochemistry for 5 mC and 5 hmC. Non-tumor lymphoid cells inside germinal centers (GC) in reactive lymphoid hyperplasia (RLH) were stained positive for 5 mC, but they were negative for 5 hmC. Similarly, follicular lymphomas, whose postulated normal counterparts are centrocytes in GCs, were 5 mC-positive but 5 hmC-negative by immunohistochemistry. This immunostaining pattern was also observed in Burkitt lymphoma. In contrast, non-tumor lymphoid cells in mantle zones were stained positive for 5 mC as well as for 5 hmC. Likewise, most mantle cell lymphomas, whose postulated normal counterparts are mantle zone B cells in RLH, were stained positive for 5 mC as well as for 5 hmC. This immunostaining pattern was also observed in chronic lymphocytic leukemia/small lymphocytic lymphoma. These results suggest that, in terms of 5 mC/5 hmC immunohistochemistry, B-cell lymphomas with different histological subtypes are associated with distinct global DNA methylation statuses that resemble those of their postulated normal counterparts. [J Clin Exp Hematop 54(1): 67-73, 2014]
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  • Tsugumi Satoh, Ryuichi Wada, Nobuhisa Yajima, Tadaatsu Imaizumi, Sorok ...
    Type: Original Article
    2014 Volume 54 Issue 1 Pages 75-84
    Published: 2014
    Released: June 18, 2014
    JOURNALS FREE ACCESS
    Classical Hodgkin lymphoma (CHL) is a B-cell neoplasm characterized by Hodgkin and Reed-Sternberg (HRS) cells. Its prevalence exhibits a bimodal pattern of peaking in young adults and the elderly. There is an association with Epstein-Barr virus (EBV) infection in about 50% of cases of CHL of the elderly, and the outcome of these patients is unfavorable. It is not well known how the latent infection of EBV is involved in the pathophysiology of CHL of the elderly. To address this issue, we examined the tumor microenvironment (TME) and the expression of molecules related to EBV infection in HRS cells in 10 EBV-positive CHL and 7 EBV-negative CHL patients older than 50 years. In EBV-positive CHL, we found an increased population of FOXP3+ cells, while that of granzyme B+ cells was reduced, compared with those in EBV-negative CHL. The expression of inhibitory chemokine CCL20 was increased in EBV-positive HRS cells compared with that in EBV-negative HRS cells. In addition, despite increased expression of a pattern recognition receptor, RIG-I, in intracellular innate immunity, there was no evidence of interferon regulatory factor 3 activation or interferon-ß induction in EBV-positive HRS cells in CHL of the elderly. The disease recurred frequently (50%) in EBV-positive CHL. The current study thus suggests the possibility that the latent infection of EBV alters the expression of chemokines and the innate immunity response in HRS cells and modulates TME to an immunosuppressive state, which may account for the unfavorable disease course in CHL of the elderly. [J Clin Exp Hematop 54(1): 75-84, 2014]
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Case Study
  • Anne Bauters, Moshe Rogosnitzky, Eric Hachulla, Marie Christine Copin, ...
    Type: Case Study
    2014 Volume 54 Issue 1 Pages 85-88
    Published: 2014
    Released: June 18, 2014
    JOURNALS FREE ACCESS
    This is the first report of an early association between elevated fibrinogen and asymptomatic unicentric Castleman's disease (CD). A 49-year-old asymptomatic female who was serving as a normal control in an unrelated study was incidentally found to have significantly elevated levels of plasma fibrinogen. Upon further investigation with computer tomography scans and magnetic resonance imaging, the woman was found to have a mobile mass in the abdominal region which was surgically removed. Based on histological analysis, a diagnosis of CD was made. At four-month follow-up, no additional signs of CD were present and fibrinogen levels returned to the normal range. This report, therefore, signifies the importance for physicians to consider unicentric CD in the differential diagnosis when patients present with elevated levels of plasma fibrinogen. Awareness of this diagnostic possibility may lead to increased early diagnosis of CD before symptoms become apparent, and provide a marker candidate for CD activity that may assist in monitoring treatment success. [J Clin Exp Hematop 54(1): 85-88, 2014]
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Letter to the Editor
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