Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

Gray zone lymphoma (GZL), a B-cell lymphoma with features intermediate between large B-cell lymphoma (LBCL) and classic Hodgkin lymphoma (cHL), is a rare and poorly defined entity. Alongside GZL, a subset of Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) has been described with polymorphic/GZL-like morphology (polymorphic-EBV-L). To fill the important gap in our understanding of the pathogenic process underlying these entities, we performed a gene expression study of a large international cohort of GZL and polymorphic-EBV-L, combined with cHL and primary mediastinal large B-cell lymphoma (PMBCL) cases. In an unsupervised principal component analysis, GZL cases presented with intermediate scores in a spectrum between cHL and PMBCL, whereas polymorphic-EBV-L clustered distinctly. The main biological pathways underlying the GZL spectrum were related to cell cycle, reflecting tumor cell content, and extracellular matrix signatures related to the cellular tumor microenvironment. Differential expression analysis and phenotypic characterization of the tumor microenvironment highlighted the predominance of regulatory macrophages in GZL compared with cHL and PMBCL. Two distinct subtypes of GZL were distinguishable that were phenotypically reminiscent of PMBCL and DLBCL, and we observed an association of PMBCL-type GZL with clinical presentation in the "thymic" anatomic niche. In summary, gene expression profiling (GEP) enabled us to add precision to the GZL spectrum, describe the biological distinction compared with polymorphic-EBV-L, and distinguish cases with and without thymic involvement as 2 subgroups of GZL, namely PMBCL-like and DLBCL-like GZL.

DOI： 10.1182/bloodadvances.2020001923

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CELL PRESS  

Follicular lymphomas (FLs) are slow-growing, indolent tumors containing extensive follicular dendritic cell (FDC) networks and recurrent EZH2 gain-of-function mutations. Paradoxically, FLs originate from highly proliferative germinal center (GC) B cells with proliferation strictly dependent on interactions with T follicular helper cells. Herein, we show that EZH2 mutations initiate FL by attenuating GC B cell requirement for T cell help and driving slow expansion of GC centrocytes that become enmeshed with and dependent on FDCs. By impairing T cell help, mutant EZH2 prevents induction of proliferative MYC programs. Thus, EZH2 mutation fosters malignant transformation by epigenetically reprograming B cells to form an aberrant immunological niche that reflects characteristic features of human FLs, explaining how indolent tumors arise from GC B cells.

DOI： 10.1016/j.ccell.2020.04.004

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Hodgkin lymphoma is characterized by an extensively dominant tumor microenvironment (TME) composed of different types of noncancerous immune cells with rare malignant cells. Characterization of the cellular components and their spatial relationship is crucial to understanding cross-talk and therapeutic targeting in the TME. We performed single-cell RNA sequencing of more than 127,000 cells from 22 Hodgkin lymphoma tissue specimens and 5 reactive lymph nodes, profiling for the first time the phenotype of the Hodgkin lymphoma-specific immune microenvironment at single-cell resolution. Single-cell expression profiling identified a novel Hodgkin lymphoma-associated subset of T cells with prominent expression of the inhibitory receptor LAG3, and functional analyses established this LAG3(+) T-cell population as a mediator of immunosuppression. Multiplexed spatial assessment of immune cells in the microenvironment also revealed increased LAG3(+) T cells in the direct vicinity of MHC class II-deficient tumor cells. Our findings provide novel insights into TME biology and suggest new approaches to immune-checkpoint targeting in Hodgkin lymphoma.SIGNIFICANCE: We provide detailed functional and spatial characteristics of immune cells in classic Hodgkin lymphoma at single-cell resolution. Specifically, we identified a regulatory T-cell-like immunosuppressive subset of LAG3(+) T cells contributing to the immune-escape phenotype. Our insights aid in the development of novel biomarkers and combination treatment strategies targeting immune checkpoints.

DOI： 10.1158/2159-8290.CD-19-0680

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Integrative analysis in patients with diffuse large B-cell lymphoma uncovers that biallelic mutations on TMEM30A are associated with a favorable outcome and enhanced sensitivity to CD47 blockade.Transmembrane protein 30A (TMEM30A) maintains the asymmetric distribution of phosphatidylserine, an integral component of the cell membrane and 'eat-me' signal recognized by macrophages. Integrative genomic and transcriptomic analysis of diffuse large B-cell lymphoma (DLBCL) from the British Columbia population-based registry uncovered recurrent biallelic TMEM30A loss-of-function mutations, which were associated with a favorable outcome and uniquely observed in DLBCL. Using TMEM30A-knockout systems, increased accumulation of chemotherapy drugs was observed in TMEM30A-knockout cell lines and TMEM30A-mutated primary cells, explaining the improved treatment outcome. Furthermore, we found increased tumor-associated macrophages and an enhanced effect of anti-CD47 blockade limiting tumor growth in TMEM30A-knockout models. By contrast, we show that TMEM30A loss-of-function increases B-cell signaling following antigen stimulation-a mechanism conferring selective advantage during B-cell lymphoma development. Our data highlight a multifaceted role for TMEM30A in B-cell lymphomagenesis, and characterize intrinsic and extrinsic vulnerabilities of cancer cells that can be therapeutically exploited.

DOI： 10.1038/s41591-020-0757-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

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DOI： 10.1182/blood-2019-127375

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

We performed a genomic, transcriptomic, and immunophenotypic study of 347 patients with diffuse large B-cell lymphoma (DLBCL) to uncover the molecular basis underlying acquired deficiency of MHC expression. Low MHC-II expression defines tumors originating from the centroblast-rich dark zone of the germinal center (GC) that was associated with inferior prognosis. MHC-II-deficient tumors were characterized by somatically acquired gene mutations reducing MHC-II expression and a lower amount of tumor-infiltrating lymphocytes. In particular, we demonstrated a strong enrichment of EZH2 mutations in both MHC-I- and MHC-II-negative primary lymphomas, and observed reduced MHC expression and T-cell infiltrates in murine lymphoma models expressing mutant Ezh2(Y)(641). Of clinical relevance, EZH2 inhibitors significantly restored MHC expression in EZH2-mutated human DLBCL cell lines. Hence, our findings suggest a tumor progression model of acquired immune escape in GC-derived lymphomas and pave the way for development of complementary therapeutic approaches combining immunotherapy with epigenetic reprogramming.SIGNIFICANCE: We demonstrate how MHC-deficient lymphoid tumors evolve in a cell-of-origin-specific context. Specifically, EZH2 mutations were identified as a genetic mechanism underlying acquired MHC deficiency. The paradigmatic restoration of MHC expression by EZH2 inhibitors provides the rationale for synergistic therapies combining immunotherapies with epigenetic reprogramming to enhance tumor recognition and elimination.

DOI： 10.1158/2159-8290.CD-18-1090

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

Despite receiving rituximab-combined chemotherapy, follicular lymphoma (FL) patients often suffer tumor recurrence and understand that the cause of relapse in FL would thus significantly ameliorate the tumor therapeutics. In the present study, we show that TRA-1-60-expressing cells are a unique population in FL, converge to the conventional stem cell marker Oct3/4 and ALDH1-positive population, and resist current B-lymphoma agents. TRA-1-60 expression was observed in scattered lymphoma cells in FL tissues only as well as in resting B-lymphocytes inside germinal centers. Retrospective comparison between recurrent and cognate primary tissues showed that the number of TRA-1-60-positive cells from rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP)-treated FL had increased relative to primary tissue, a finding corroborated by assays on different rituximab-treated FL cell lines, FL-18 and DOHH2, wherein TRA-positive cell numbers increased over 10-fold compared to the untreated sample. Concordantly, scanty TRA-1-60-positive FL-18 cells implanted s.c. into mice evinced potent tumor-initiating capacity in vivo, where tumors were 12-fold larger in volume (P = 0.0021 < 0.005) and 13-fold heavier in weight (P = 0.0015 < 0.005) compared to those xenografted from TRA-negative cells. To explain these results, gene expression profiling and qPCR analysis indicated that TRA-1-60-positive cells defined a distinct population from that of TRA-negative cells, with upregulation of multiple drug transporters and therapeutic resistance genes. Hence, TRA-1-60-expressing cells in FL are considered to be vigorously intractable against conventional therapeutic agents, which may explain its refractory recurrence.

DOI： 10.1111/cas.13870

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

Aims Although the neoplastic cells of extranodal natural killer (NK)/T-cell lymphoma (ENKTL) usually do not express T-cell antigens, the T-cell receptor (TCR) gene might be rearranged and TCR protein expressed. The aim is to elucidate the expression of the downstream TCR pathway components and their importance in ENKTL. Methods and results We used formalin-fixed paraffin-embedded tissues from 91 ENKTL samples to immunohistochemically characterise the expression of TCR pathway components. The following proteins were variably expressed: ZAP70 (94%; 83/88), GRAP2/GADS (68%; 60/88), DOK2 (42%; 38/90), LCK (35%; 31/88), and ITK (10%; 9/90). When these tumours were classified as being of T lineage (16%), NK lineage (45%), or indeterminate lineage (38%), the GRAP2/GADS expression rate was higher in T lineage tumours (versus NK, P = 0.0073; versus indeterminate, P = 0.00082). GRAP2/GADS-positive NK lineage tumours more frequently expressed DOK2 (P = 0.0073), and were more often confined to the nasal areas (P = 0.014). Furthermore, when these tumours were immunophenotypically classified into a T signature (42%) or NK signature (58%), the expression rates of GRAP2/GADS and ITK were higher in T signature tumours (P = 0.00074 and P = 0.067, respectively), whereas that of LCK was higher in NK-signature tumours (P = 0.10). Conclusions Although some ENTKL cases were polyclonal for TCR rearrangement and others lacked TCR expression, we speculate that the TCR pathway might be functioning in ENKTLs. A T signature versus a NK signature might be better for delineating the physiology of ENKTL than cellular lineage. Furthermore, ITK may represent a potential therapeutic target for patients with ITK-expressing tumours.

DOI： 10.1111/his.13728

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Language：English   Publisher：NATURE PUBLISHING GROUP  

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The gastrointestinal (GI) tract is the most commonly involved site of extranodal follicular lymphoma (FL). GI-FL shows very indolent clinical behavior and localized at GI tract without any progression or transformation compared to nodal FL. The most frequently involved site of the GI tract was the duodenum followed by the jejunum and ileum, and only 15% of FL arising in the second part of the duodenum were localized there without scattered very small daughter lesions in other GI tract examined by double-balloon endoscopy. The typical macroscopic appearance of GI-FL was multiple white nodules. Microscopically, neoplastic cells were small- to medium-sized lymphoid cells and formed neoplastic follicles. Most of the cases (>95%) were histologically Grade 1 to 2 (low grade). Several pathological and molecular characteristics were seen in GI-FL (especially duodenal FL) compared with nodal FL: immunoglobulin heavy chain deviation to VH4 and VH5; memory B-cell immunophenotype; and molecular features shared by mucosa-associated lymphoid tissue lymphoma. Considering the pathological and molecular uniqueness of this disease, GI-FL should be separately managed from nodal FL.

DOI： 10.1111/pin.12621

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

AimsThe central nervous system (CNS) is a rare primary site of non-Hodgkin lymphoma. Although direct invasion of nasal natural killer (NK)/T cell tumours into CNS is reported occasionally, primary CNS NK/T cell lymphoma is extremely rare, and the clinicopathological features of primary CNS NK/T cell lymphoma remain largely unknown.Methods and resultsWe identified four cases from our consultation files and analysed the clinicopathological features. Three were immunocompetent and one was immunosuppressed. There were three males and one female and their ages ranged from 21 to 77 years (median: 46 years). Radiotherapy was rendered for all patients, and methotrexate was administered to two patients. The overall survival was 4-29 months (median, 19 months) for the three immunocompetent patients. Neoplastic cells exhibited medium to large atypical nuclei. Angiocentric growth and necrosis were observed. The immunophenotype was typical of NK cell tumours: CD3 epsilon, 100%; CD56, 67%; CD5, 50%; cytotoxic molecules, 100%; Epstein-Barr virus encoded small RNA (EBER), 100% and T cell receptor (TCR)- or , 0%. No TCR-gene rearrangements were detected. Reviewing 10 additional cases from the literature and comparing with extranasal NK/T cell lymphoma of the more frequent origins (skin or gastrointestinal tract), primary CNS NK/T cell lymphoma was diagnosed at an earlier stage without B symptoms but exhibited aggressive clinical behaviours.ConclusionsAlthough extremely rare, primary CNS NK/T cell lymphoma does occur and should always be included in the differential diagnosis and we should apply relevant markers routinely in conjunction with exploring the patient background. The accumulation of cases is indispensable to establish an effective treatment strategy for this rare and aggressive malignancy.

DOI： 10.1111/his.13223

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

Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell lymphoma subtype, and the Epstein-Barr virus (EBV)-positive subtype of DLBCL is known to show a more aggressive clinical behavior than the EBV-negative one. BTB and CNC homology 2 (BACH2) has been highlighted as a tumor suppressor in hematopoietic malignancies; however, the role of BACH2 in EBV-positive DLBCL is unclear. In the present study, BACH2 expression and its significance were studied in 23 EBV-positive and 43 EBV-negative patient samples. Immunohistochemistry revealed BACH2 downregulation in EBV-positive cases (P < 0.0001), although biallelic deletion of BACH2 was not detected by FISH. Next, we analyzed the contribution of BACH2 negativity to aggressiveness in EBV-positive B-cell lymphomas using FL-18 (EBV-negative) and FL-18-EB cells (FL-18 sister cell line, EBV-positive). In BACH2-transfected FL-18-EB cells, downregulation of phosphorylated transforming growth factor--activated kinase 1 (pTAK1) and suppression in p65 nuclear fractions were observed by Western blot analysis contrary to non-transfected FL-18-EB cells. In patient samples, pTAK1 expression and significant nuclear p65, p50, and p52 localization were detected immunohistochemically in BACH2-negative DLBCL (P < 0.0001, P = 0.006, and P = 0.001, respectively), suggesting that BACH2 downregulation contributes to constitutive activation of the nuclear factor-B pathway through TAK1 phosphorylation in BACH2-negative DLBCL (most EBV-positive cases). Although further molecular and pathological studies are warranted to clarify the detailed mechanisms, downregulation of BACH2 may contribute to constitutive activation of the nuclear factor-B pathway through TAK1 activation.

DOI： 10.1111/cas.13213

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Follicular lymphoma (FL) shows co-expression of B-cell lymphoma 2 (BCL2) and CD10, whereas downexpression of CD10 is occasionally experienced in gastrointestinal (GI) FL with unknown significance. Gastrointestinal FL is a rare variant of FL, and its similarity with mucosa-associated lymphoid tissue lymphoma was reported. We investigated the clinicopathological and genetic features of CD10 downexpressed (CD10(down)) GI-FL. The diagnosis of CD10(down) FL was carried out with a combination of pathological and molecular analyses. The incidence of CD10(down) GI-FL was shown in 35/172 (20.3%) cases, which was more frequent than nodal FL (3.5%, P < 0.001). The difference was additionally significant between GI-FL and nodal FL when the analysis was confined to primary GI-FL (55.2% vs 3.5%, P < 0.001). Compared to CD10(+) GI-FL, CD10(down) GI-FL significantly involved the stomach or large intestine (P = 0.015), and additionally showed the downexpression of BCL6 (P < 0.001). The follicular dendritic cell meshwork often showed a duodenal pattern in the CD10(down) group (P = 0.12). Furthermore, a lymphoepithelial lesion was observed in 5/12 (40%) gastric FL cases, which indicated caution in the differentiation of mucosa-associated lymphoid tissue lymphoma. Molecular analyses were undertaken in seven cases of CD10(down) GI-FL, and an identical clone was found between CD10(down) follicles and CD10(+)BCL2(+) neoplastic follicles. In the diagnosis of cases with CD10(down) BCL2(+) follicles, careful examination with molecular studies should be carried out.

DOI： 10.1111/cas.13031

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare disease comprising < 3% of extranodal lymphomas. It frequently reveals an activated B-cell (ABC)-like phenotype. ABC-like DLBCL was reported to have gain-of-function mutations in MYD88, CD79B, CARD11, and TNFAIP3, resulting in constitutive activation of the NF kappa B pathway. Because of the rare occurrence of PB-DLBCL, the frequency of MYD88 and CD79B mutations is still unknown. We used Sanger sequencing to study these mutations from 46 breast DLBCL cases and also investigated the associated clinicopathologic factors. MYD88 L265P was confirmed by allele-specific polymerase chain reaction and compared with the Sanger sequencing results. MYD88 L265P and CD79B mutations were detected in 27/46 (58.7%) and 11/33 (33.3%) cases, respectively. Twenty-eight of 46 cases met the criteria for PB-DLBCL, and the latter 18 cases were further classified as clinical breast DLBCL (CLB-DLBCL). The frequency of MYD88 L265P and CD79B mutations was 16/28 (57.1%) and 9/23 (39.1%), respectively, in PB-DLBCL and 11/18 (61.1%) and 2/10 (20%), respectively, in CLB-DLBCL. When the cutoff value was set at Delta Ct <= 1, the result of allele-specific polymerase chain reaction for MYD88 corresponded to those of the Sanger sequence at 92.6% sensitivity and 100% specificity. According to Choi's algorithm, 16/27 (59.3%) demonstrated an ABC-like phenotype in PB-DLBCL, and 15/18 (83.3%) demonstrated an ABC-like phenotype in CLB-DLBCL. In conclusion, MYD88 L265P and CD79B mutations were frequently detected in PB-DLBCL, and they may be key molecules associated with PB-DLBCL lymphomagenesis. Further analysis will be required to clarify the mechanism of its pathogenesis.

DOI： 10.1097/PAS.0000000000000592

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Proinflammatory cytokines that are produced by helper T cells (Th) regulate immune reactions, facilitate class switching of B cells, and prolong the lifespan of B and T cells. Eradication therapy using antibiotics is sometimes effective against gastrointestinal (GI) malignant lymphoma, suggesting that the tumor development or progression is affected by the inflammatory microenvironment. In the present study, serum samples from 148 patients with various subtypes of malignant lymphoma were tested for 11 proinflammatory Th1/Th2 cytokines. In the comparison by subtype or GI lesions, serum interleukin (IL)-8 (P= 6.7E-05), IL-4 (P = 7.5E-05), and IL-10 (P = 0.0043) levels showed significant differences among subtypes, being particularly elevated in follicular lymphomas (FL) and mucosa-associated lymphoid tissue (MALT) lymphomas. Serum IL-8 levels were elevated in GI-FL and MALT lymphomas, and serum IL-4 and IL-10 levels were elevated in MALT lymphomas. These findings show that GI low-grade B-cell lymphoma could develop against the background of an inflammatory microenvironment. Thus, these cytokines may be useful as diagnostic markers and could provide new insights into tumor development.

DOI： 10.1038/srep18434

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Lymphomatoid gastropathy, which was first reported in 2010, is a rare NK-cell proliferation of cyCD3(+), CD4(-), CD5(-), CD8(-), CD56(+) phenotypes with unknown etiology. The diagnosis is challenging, as there is histopathologic similarity to malignant lymphoma. In the 2010 report on 10 cases, all lesions were located in the stomach, and all regressed without any therapy. In the present study, we analyzed 6 cases of lymphomatoid gastropathy by investigating the clinicopathologic, immunohistochemical, and molecular findings. Endoscopic and morphologic appearances of all cases were consistent with previous reports, but 2 cases showed previously unreported unique immunophenotypes of CD4(-)CD8(+). Three of 6 patients underwent lower gastrointestinal examination (1 case underwent double-balloon endoscopic examination), but no patient had lesions in the lower gastrointestinal tract. No obvious difference of histology was found between the cases of CD4-CD8-typical phenotype and ones of CD4(-)CD8(+) phenotype. Both cases had similar clinical behavior as the other 4 cases, implying that the spectrum of the disease is broader than initially thought. Careful clinical and endoscopic follow-up is required for the diagnosis of lymphomatoid gastropathy, and additional case studies and molecular studies are warranted to further investigate the pathophysiology of this peculiar benign mimic of lymphoma.

DOI： 10.1097/PAS.0000000000000443

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Primary cutaneous, extranodal natural killer/T-cell lymphoma, nasal type (PC-ENKTL), is a rare Epstein-Barr virus (EBV)-associated neoplasm with poorly defined clinicopathologic features. We performed a multinational retrospective study of PC-ENKTL and CD56-positive EBV-negative peripheral T-cell lymphoma (PC-CD56+PTCL) in Asia in an attempt to elucidate their clinicopathologic features. Using immunohistochemistry for T-cell receptors (TCRs), in situ hybridization for EBV, and TCR gene rearrangement, we classified 60 tumors into 51 with PC-ENKTL (20 of NK-cell, 17 T-cell, and 14 indeterminate lineages) and 9 with PC-CD56+PTCL. Tumors of T-cell origin accounted for 46% of PC-ENKTLs with half of these cases being TCR-silent. As compared with T-lineage tumors, PC-ENKTLs of NK-cell lineage had more frequent involvement of regional lymph nodes and more frequently CD8-negative and CD56-positive. Cases of PC-ENKTL showed more frequent tumor necrosis, younger age, and a higher frequency of CD16 and CD30 expression than cases of PC-CD56+PTCL. CD56-positive T-lineage PC-ENKTL tumors (n=8) had more localized disease in the TNM (tumor-node-metastasis) staging and were more often of gamma delta T-cell origin compared with cases of PC-CD56+PTCL (n=9). PC-ENKTLs and PC-CD56+PTCLs were equally aggressive, with a 5-year overall survival rate of 25%. Tumor necrosis and CD16 expression may serve as useful surrogates for differentiating PC-ENKTL from PC-CD56+PTCL. A single lesion, an elevated lactate dehydrogenase level, and the presence of B symptoms were independent poor prognostic factors for PC-ENKTL in multivariate analysis. Further studies with more cases are warranted to delineate the clinicopathologic features and significance of EBV in these rare lymphomas.

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Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer, often associated with Merkel cell polyomavirus (MCPyV). Recently, immunoglobulin (Ig) expression was reported in MCC, thereby suggesting that B cells might be their cellular ancestors. We tested 30 MCCs (20 MCPyV-positive and 10 MCPyV-negative) using immunohistochemistry for the expressions of IgG, IgA, IgM, Ig kappa, Ig lambda, terminal desoxynucleotidyl transferase, paired box gene 5 (PAX5), octamer transcription factor-2 (Oct-2), and sex-determining region Y-box 11 (SOX11). We performed in situ hybridization for Ig kappa-mRNA or Ig lambda-mRNA and Ig heavy chain (IgH) gene rearrangement (IgH-R) analyses. The expressions of PAX5, TdT, Oct-2, and SOX11 were not significantly different between MCPyV-positive and MCPyV-negative MCCs. At least 1 of IgG, IgA, IgM, or Ig kappa was expressed in MCPyV-positive (14/20, 70%) and none in MCPyV-negative MCCs (P = 0.0003). There was a higher tendency for Ig kappa-mRNA expression (7/19, using in situ hybridization) and IgH-R (10/20, using polymerase chain reaction) in MCPyV-positive than in MCPyV-negative MCCs (0/10 and 2/10, respectively), thus suggesting a different Ig production pattern and pathogenesis between the 2 types of MCC. Ig expression or IgH-R in MCPyV-positive MCCs might be associated with MCPyV gene integration or expression in cancer cells but do not necessarily suggest a B-cell origin for MCCs. IgH expression or IgH-R nonsignificantly correlated with improved prognosis. However, these might be important factors that influence the survival of neoplastic cells and might allow the development of novel therapies for patients with MCPyV-positive MCCs.

DOI： 10.1097/PAS.0000000000000279

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Concurrent chemoradiotherapy has become one of the standard management approaches for newly diagnosed localized nasal natural killer (NK)/T-cell lymphoma (NKTCL). Few data are available on the prognostic biomarkers of NKTCL among patients treated with concurrent chemoradiotherapy. To evaluate the prognostic significance of immunophenotypic biomarkers for patients treated with concurrent chemoradiotherapy, latent membrane protein 1 (LMP1), cutaneous lymphocyte antigen (CLA) and cell origin were examined in samples from 32 patients who were enrolled in the Japan Clinical Oncology Group 0211 trial and treated with concurrent chemoradiotherapy. LMP1 and CLA were positive in 66% (19/29) and 29% (9/31) of the cases examined, respectively. The median follow-up duration was 68months (range, 61-94). The patients with LMP1-positive tumors showed a better overall survival (OS) than the patients with LMP1-negative tumors (hazard ratio, 0.240; 95% confidence interval [CI], 0.057-1.013; 80% CI, 0.093-0.615; P=0.035). All five patients with LMP1-negative tumors who experienced disease progression died of lymphoma, and both patients with local failure had LMP1-negative tumors. There was no significant difference in OS according to CLA expression. A total of 27 (84%) cases were of NK-cell origin, two were of T-cell origin and three were of T-cell origin. In contrast to those with tumors of NK-cell origin, all five patients with NKTCL of T-cell origin were alive without relapse at the last follow up. Our results indicate that LMP1 expression is a favorable prognostic marker and suggest that a T-cell origin of the tumor may be a favorable prognostic marker for patients with localized NKTCL treated with concurrent chemoradiotherapy.

DOI： 10.1111/cas.12526

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INFORMA HEALTHCARE  

While the use of polymerase chain reaction (PCR)-based clonality analysis of formalin-fixed paraffin-embedded (FFPE) tissue has recently become widespread, the detection sensitivity for lymphoma subtypes using FFPE samples is not well known. Here, we analyzed T-cell receptor gamma chain (TCRG) gene rearrangement clonality in 100 cases of T-or natural killer (NK)/T-cell lymphoma and examined detection sensitivity according to lymphoma subtype. Clonality was detected in approximately 80% of the major T-cell lymphoma subtypes: peripheral T-cell lymphoma, not otherwise specified, 84% (21/25 cases); angioimmunoblastic T-cell lymphoma, 71% (15/21 cases); and adult T-cell leukemia/lymphoma, 80% (8/10 cases). The number of clonal peaks differed according to subtype. TCRG gene rearrangement was not detected in 63 cases of B-cell lymphoma or reactive lesions. Thus, clonality analysis can effectively and reliably detect TCRG gene rearrangement in T-cell lymphoma cases and could, therefore, be a useful diagnostic tool in routine practice.

DOI： 10.3109/10428194.2013.871634

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Primary cutaneous gamma delta T-cell lymphoma (PCGD-TCL) is an aggressive lymphoma consisting of clonal proliferation of mature activated gamma delta T-cells of a cytotoxic phenotype. Because primary cutaneous gamma delta T-cell lymphoma is a rare disease, there are few clinicopathological studies. In addition, T-cell receptor (TCR) gamma delta cells are typically immunostained in frozen sections or determined by TCR beta negativity. We retrospectively analyzed 17 primary cutaneous T-cell lymphomas of the gamma delta phenotype (CTCL-gamma delta) in a clinicopathological and molecular study using paraffin-embedded sections. Among 17 patients, 11 had CTCL-gamma delta without subcutaneous panniculitis-like T-cell lymphoma (SPTCL) features and six had CTCL-gamma delta with SPTCL features. Immunophenotypically, some significant differences were found in CD8 and CD56 positivity between our patient series of CTCL-gamma delta patients with SPTCL features and SPTCL-gamma delta patients described in the previous literature. A univariate analysis of 17 CTCL-gamma delta patients showed that being more than 60 years old, presence of visceral organ involvement, and small-to-medium cell size were poor prognostic factors. In addition, the 5-year overall survival rate was 42.4% for the CTCL-gamma delta patients without SPTCL features and 80.0% for those with SPTCL features. Consequently, there was a strikingly significant difference in overall survival among SPTCL, CTCL-gamma delta with SPTCL features and CTCL-gamma delta without SPTCL features (P = 0.0005). Our data suggests that an indolent subgroup may exist in CTCL-gamma delta. Studies on more cases, including those from other countries, are warranted to delineate the clinicopathological features and the significance in these rare lymphomas.

DOI： 10.1111/cas.12439

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

Follicular lymphoma (FL) of the gastrointestinal tract, particularly duodenal follicular lymphoma (DFL), is a rare variant of FL with indolent clinical behavior, and this disease is included in the 2008 World Health Organization classification system. In contrast to nodal follicular lymphoma (NFL), DFL occurs most frequently in the second part of the duodenum, lacks follicular dendritic cell meshworks and has memory B-cell characteristics. However, its molecular pathogenesis is still unclear. In the present study, we examined 10 DFL, 18 NFL and 10 gastric MALT lymphoma samples using gene expression analysis. Quantitative RT-PCR experiments and immunohistochemical analysis for 72 formalin-fixed, paraffin-embedded tissues from an independent series, including 32 DFL, 19 gastric MALT lymphoma and 27 NFL samples, were performed for validation of microarray data. Gene expression profiles of the three lymphoma types were compared using 2918 differentially expressed genes (DEG) and results suggested that DFL shares characteristics of MALT lymphoma. Among these DEG, CCL20 and MAdCAM-1 were upregulated in DFL and MALT but downregulated in NFL. In contrast, protocadherin gamma subfamily genes were upregulated in DFL and NFL. Quantitative RT-PCR and immunohistochemical studies demonstrated concordant results. Double immunofluorescence studies revealed that CCL20 and CCR6 were co-expressed in both DFL and MALT. We hypothesize that increased expression of CCL20 and MAdCAM-1 and co-expression of CCL20 and CCR6 may play an important role in tumorigenesis.

DOI： 10.1111/cas.12392

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) consists of a heterogeneous group of lymphomas. Patients. generally show an aggressive clinical course and very poor outcome. Although the 2008 World Health Organization classification of PTCL-NOS includes 3 variants, low-grade lymphoma is not Included. Of 277 PTCL-NOS cases recorded in our consultation files, we examined the clinicopathologic characteristics of 10 patients with T-cell lymphomas composed of small-sized cells with slight nuclear atypia. Eight patients showed extranodal involvement (5 patients, spleen; 3 patients, thyroid), and 5 patients were at clinical stage I or II. Histologically, all samples presented diffuse infiltrate of small lymphoid cells, with few mitotic figures. Immunohistologically, all samples were positive for CD3, and CD:20 Was detected in 5 samples. All samples showed a low Ki-67 labeling index (mean, 1.05%), and 7 samples were positive for central memory T-cell markers. Clonal T-cell receptor gamma chain and/or alpha-beta chain gene rearrangements were detected in all 10 patients. Five patients received chemotherapy, whereas for 3 patients, treatment consisted only of observation following surgical resection of the spleen or thyroid. Nine patients were alive at a median follow-up time of 19.5 months, whereas 1 patient died of an unrelated disease. The present study strongly indicates that T-cell lymphoma with small-sized lymphoma cells and a low Ki-67 labeling index is a distinct variant. Recognition of this novel lymphoma subtype, which should not be defined merely as PTCL-NOS, should be seriously considered. Crown Copyright (C) 2013 Published by Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2013.03.002

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DOI： 10.1038/modpathol.2013.118

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

We have reported previously that duodenal follicular lymphoma (FL) is distinct from nodal FL and showed more resemblance to mucosa-associated lymphoid tissue lymphoma, and that FL frequently involved the duodenal second portion. In the present study, we examined duodenal FLs and gastric/colonic FLs to clarify the clinicopathological and immunological differences between the tumor types. We analyzed 8 samples of gastric FL, 17 of duodenal ones, and 5 of colonic/rectal ones, and characterized them by immunohistochemistry, immunogenotyping, and histology. Gastric and colonic FLs presented in submucosal to subserosal areas, whereas duodenal ones presented in the mucosal to submucosal layers. Immunohistochemical analysis revealed that duodenal FLs exhibited the following phenotypes: CD10 (+), B-cell lymphoma 2 (BCL-2) (+), BCL-6 (+), activation-induced cytidine deaminase (AID) (-), BACH2 (+), CD27 (+), MUM-1 (-), Blimp-1 (-), and loose CD21 network (duodenal pattern). Gastric/colonic FLs exhibited the following phenotypes: CD10 (+), BCL-2 (+), BCL-6 (+), AID (+), BACH2 (+), CD27 (-), MUM-1 (-), Blimp-1 (-), and a dense CD21 network (nodal pattern). Expression of AID and CD27 in lymphoma cells and the CD21 network pattern were considerably different between duodenal FLs and gastric/colonic ones. Moreover, in situ hybridization revealed that, in the duodenal FLs, BACH2 was expressed at the periphery of the tumor follicle and tumor villi. The number of immunoglobulin heavy-chain variable domains VH4 and VH5 were higher in duodenal follicular lymphomoas than in gastric FLs. The lymphoma cells of duodenal FLs are different from those of gastric/colonic FLs, and duodenal FL is distinct even within the gastrointestinal tract. Somatic hypermutation in immunoglobulin genes and CD27 expression are hallmarks of memory B cells. We suggest that duodenal FL cells are in the memory B-cell stage, and require BACH2 instead of AID for ongoing mutation. Modern Pathology (2013) 26, 22-31; doi:10.1038/modpathol.2012.127; published online 17 August 2012

DOI： 10.1038/modpathol.2012.127

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

We conducted a multicenter, retrospective study to determine the anatomical distribution and prognostic factors of gastrointestinal (GI) follicular lymphoma (FL). This study included 125 patients with stage I and II1 GI-FL. Of the 125 patients, the small intestine was examined in 70 patients, with double-balloon endoscopy and/or capsule endoscopy. The most frequently involved GI-FL site was the duodenal second portion (DSP) (81%), followed by the jejunum (40%); 85% of patients with involvement of the DSP also had jejunal or ileal lesions. The absence of abdominal symptoms and macroscopic appearance of multiple nodules were significantly present in the DSP-positive group. During a median follow up of 40 months, six patients showed disease progression. Patients with involvement of the DSP had better progression-free survival (PFS) than those without such involvement (P = 0.001). A multivariate analysis revealed that male sex, the presence of abdominal symptoms, and negative involvement of the DSP were independently associated with poor PFS. In conclusion, most patients with GI-FL have duodenal lesions associated with multiple jejunal or ileal lesions. Gastrointestinal follicular lymphomas involving the DSP might be a distinct entity showing a favorable clinical course. (Cancer Sci 2011; 102: 1532-1536)

DOI： 10.1111/j.1349-7006.2011.01980.x

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Epstein-Barr virus (EBV)+ nodal T- and NK-cell lymphoma (EBV+ nPTCL) is a peripheral T-cell lymphoma (PTCL) that presents as a primary nodal disease with T-cell phenotype and EBV harboring on tumor cells. To date, the genetic aspect of EBV+ nPTCL has not been fully investigated. In this study, whole-exome and/or genome sequencing was performed on 22 cases of EBV+ nPTCL. TET2 (68%) and DNMT3A (32%) were observed to be the most frequently mutated genes whose presence was associated with poor overall survival (p = 0.004). The RHOA p.Gly17Val mutation was identified in two patients who had TET2 and/or DNMT3A mutations. In four patients with TET2/DNMT3A alterations, blood cell-rich tissues (bone marrow [BM] or spleen) were available as paired normal samples. Three out of these four cases had at least one identical TET2/DNMT3A mutation in the BM or spleen. Additionally, the whole part of the EBV genome was sequenced and structural variations (SVs) were found frequent among the EBV genomes (63%). The most frequently identified type of SV was deletion. In one patient, four pieces of human chromosome 9, including PD-L1 were identified to be tandemly incorporated into the EBV genome. The 3'-untranslated region of PD-L1 was truncated, causing a high-level of PD-L1 protein expression. Overall, the frequent TET2 and DNMT3A mutations in EBV+ nPTCL seem to be closely associated with clonal hematopoiesis and, together with the EBV genome deletions, may contribute to the pathogenesis of this intractable lymphoma.

DOI： 10.1182/bloodadvances.2023012019

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

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DOI： 10.1182/blood-2019-131450

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Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.SABCS18-3480

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Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2019-3765

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC CLINICAL ONCOLOGY  

PurposeHigh-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) has a poor outcome after standard chemoimmunotherapy. We sought to understand the biologic underpinnings of HGBL-DH/TH with BCL2 rearrangements (HGBL-DH/TH-BCL2) and diffuse large B-cell lymphoma (DLBCL) morphology through examination of gene expression.Patients and MethodsWe analyzed RNA sequencing data from 157 de novo germinal center B-cell-like (GCB)-DLBCLs, including 25 with HGBL-DH/TH-BCL2, to define a gene expression signature that distinguishes HGBL-DH/TH-BCL2 from other GCB-DLBCLs. To assess the genetic, molecular, and phenotypic features associated with this signature, we analyzed targeted resequencing, whole-exome sequencing, RNA sequencing, and immunohistochemistry data.ResultsWe developed a 104-gene double-hit signature (DHITsig) that assigned 27% of GCB-DLBCLs to the DHITsig-positive group, with only one half harboring MYC and BCL2 rearrangements (HGBL-DH/TH-BCL2). DHITsig-positive patients had inferior outcomes after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy compared with DHITsig-negative patients (5-year time to progression rate, 57% and 81%, respectively; P < .001), irrespective of HGBL-DH/TH-BCL2 status. The prognostic value of DHITsig was confirmed in an independent validation cohort. DHITsig-positive tumors are biologically characterized by a putative non-light zone germinal center cell of origin and a distinct mutational landscape that comprises genes associated with chromatin modification. A new NanoString assay (DLBCL90) recapitulated the prognostic significance and RNA sequencing assignments. Validating the association with HGBL-DH/TH-BCL2, 11 of 25 DHITsig-positive-transformed follicular lymphomas were classified as HGBL-DH/TH-BCL2 compared with zero of 50 in the DHITsig-negative group. Furthermore, the DHITsig was shared with the majority of B-cell lymphomas with high-grade morphology tested.ConclusionWe have defined a clinically and biologically distinct subgroup of tumors within GCB-DLBCL characterized by a gene expression signature of HGBL-DH/TH-BCL2. This knowledge has been translated into an assay applicable to routinely available biopsy samples, which enables exploration of its utility to guide patient management.

DOI： 10.1200/JCO.18.01583

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a systemic disorder involving benign mass formation due to fibrosis and intense lymphoplasmacytosis; the chronic inflammation associated with the disease might also contribute to oncogenesis. Activation-induced cytidine deaminase (AID), normally expressed in germinal centre activated B-cells, is an enzyme that edits DNA/RNA and induces somatic hypermutation and Ig class switching. AID expression is strictly controlled under physiological conditions; however, chronic inflammation and some infectious agents induce its up-regulation. AID is overexpressed in various cancers and may be important in chronic inflammation-associated oncogenesis. We examined AID expression in IgG4-related sialadenitis (n = 14), sialolithiasis (nonspecific inflammation, n = 13), and normal submandibular glands (n = 13) using immunohistochemistry and quantitative real-time polymerase chain reaction (qPCR). Immunohistochemistry revealed significantly more AID-expressing cells in IgG4-related sialadenitis than in sialolithiasis or normal submandibular gland samples (P = 0.02 and P < 0.01, respectively); qPCR yielded similar results. Thus, AID was significantly more up-regulated and had higher expression in extra-germinal centres in IgG4-RD than in non-specific inflammation or normal conditions. This report suggests that IgG4-RD has several specific causes of AID up-regulation in addition to inflammation. Furthermore, chronic inflammation-associated AID-mediated oncogenesis is possible in IgG4-RD.

DOI： 10.1038/s41598-018-37404-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Pancreatic cancer has a poor prognosis; hence, novel prognostic markers and effective therapeutic targets should be identified. We aimed to evaluate folate receptor alpha (FR-) expression in pancreatic cancer and examine its association with clinicopathological features. We utilized tissue samples from 100 primary pancreatic cancer patients who underwent surgery. FR- was expressed in 37 of 100 cases (37%). The FR--positive group (median, 18.8 months) had a significantly poorer prognosis than the FR--negative group [median 21.3 months; HR 1.89 (1.12-3.12); P=0.017]. These groups were not significantly different regarding progression-free survival (P=0.196). Furthermore, other serum tumor markers including CA19-9 (mean, 186 vs. 822U/ml; P=0.001), Dupan-2 (286 vs. 1133U/ml; P=0.000), and Span-1 (69.7 vs. 171.9U/ml; P=0.006) were significantly downregulated in the FR--positive group. CA19-9 was another prognostic factor, in addition to FR-, and patient prognosis showed clear stratification curves with the expression of these two molecules. Along with CA19-9, FR- expression was an independent prognostic factor for the overall survival. FR- and CA19-9 helped predict patient prognosis based on stratification curves.

DOI： 10.1007/s00795-018-0197-8

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Language：English   Publisher：WILEY  

The incidence of lymphoma has rapidly increased over the last 40 years in Japan, following a trend that is very similar to that of breast cancer. In particular, the relative frequency of follicular lymphoma (FL) has reached that in Western countries. Given its indolence, a "watch-and-wait" approach is often applied to FL patients. We have shown that FL is often detected in the second portion of the duodenum and has a distinct follicular dendritic cell distribution and heavy chain variable usage similar to mucosa-associated lymphoid tissue (MALT) lymphoma. Although the t(14;18)(q32;q21) frequency is the same as in the nodal subtype of FL, there are also ongoing mutations, immunopositivity for cluster of differentiation 10 and B-cell lymphoma (BCL)6, and overexpression of BCL2. Gene expression profiling has shown that it is more similar to gastric MALT lymphoma than to nodal FL. Duodenal-type FL lacks the activation-induced cytidine deaminase (AID) expression observed in nodal ones, although this may be compensated for by BTB domain and CNC homolog 2. Based on these findings, duodenal-type FL has been included in the Revised 4th edition of the World Health Organization classification published in late 2017.

DOI： 10.1111/pin.12733

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Language：English   Publisher：AMER SOC HEMATOLOGY  

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DOI： 10.1182/blood-2018-99-112010

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DOI： 10.1182/blood-201S-99-113516

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

Nodal cytotoxic molecule (CM)-positive peripheral T-cell lymphoma (CTL) has recently been recognized as a clinicopathologically distinct disease. To further characterize this disease, here we compared 58 patients with Epstein-Barr virus (EBV)-negative CTL to 48 patients with EBV-positive CTL. The two groups did not differ in histopathology, T-cell receptor (TCR) expression or rearrangement incidences, or survival curves. However, patients with EBV-negative CTL less frequently showed hepatic involvement (P = .007), B symptoms (P = .020), hemophagocytosis (P = .024), and detectable CD4 (P = .002) and CD5 (P = .009). Univariate and multivariate analyses identified three factors that independently predicted favorable survival, onset age <60 years (P = .002), CD5 expression (P = .002), and mixed morphology (P = .013), TCR was not an independent predictor (P = .30), but was strongly linked with long survivorship among patients younger than 60 years old. A prognostic model incorporating these factors worked well for prognostic delineation, independently of the International Prognostic Index (P = .007 vs P = .082) and Prognostic Index for PTCL (P = .020 vs P = .15). Moreover, this constellation of findings indicated two nodal indolent diseases: CD5(+)TCR (n = 13), and CD5(+) NK-cell type lacking TCR expression or clonal TCR rearrangement (n = 4). The survival curves for these two groups were significantly superior to others (n = 29, P < .001). These diseases appear to be unique in their indolent clinical behavior, and should be managed differently from other diseases.

DOI： 10.1111/cas.13652

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

Background and AimFew reports have demonstrated the effectiveness of treatments for intestinal follicular lymphoma (FL) because of the limited number of patients who undergo comprehensive small intestinal examinations. This study compared the efficacy of rituximab-combined chemotherapy in patients with asymptomatic and low tumor burden (LTB) intestinal FL, according to the criteria of the Groupe d'Etude des Lymphomes Folliculaires, with that of a watch and wait (W&W) approach.MethodsThe endoscopic examination for entire gastrointestinal tracts was performed in 29 Japanese patients with intestinal FL. These patients had CD21-positive follicular dendritic cells arranged in a duodenal pattern. In a prospective, two-center, open-label trial, this study evaluated the efficacy of rituximab-combined chemotherapy ([cyclophosphamide, doxorubicin, vincristine, and prednisone] or [cyclophosphamide, vincristine, and prednisone]) and prolonged treatment with rituximab (R-Chemo+prolongedR) in 14 patients and compared their outcomes with those of 15 patients managed with a W&W approach.ResultsFour patients managed with the W&W plan showed worsening macroscopic findings, lesion area enlargement, or clinical stage progression but stayed on this plan because they had LTB and experienced no changes in bowel function. In the R-Chemo+prolongedR group, all patients achieved complete remission; recurrence occurred in one patient, who was subsequently managed with the W&W plan because of LTB. There were no significant differences in progression-free survival between the two groups (P=0.1045). Overall survival was 100% in both groups.ConclusionsThe prognoses of patients with asymptomatic intestinal FL and LTB who were managed with a W&W strategy were comparable with those of patients receiving R-Chemo+prolongedR.

DOI： 10.1111/jgh.14100

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

Primary mediastinal large B-cell lymphoma (PMBCL) is a distinct subtype of diffuse large B-cell lymphoma thought to arise from thymic medullary B cells. Gene mutations underlying the molecular pathogenesis of the disease are incompletely characterized. Here, we describe novel somatic IL4R mutations in 15 of 62 primary cases of PMBCL (24.2%) and in all PMBCL-derived cell lines tested. The majority of mutations (11/21; 52%) were hotspot single nucleotide variants in exon 8, leading to an I242N amino acid change in the transmembrane domain. Functional analyses establish this mutation as gain of function leading to constitutive activation of the JAK-STAT pathway and upregulation of downstream cytokine expression profiles and B cell-specific antigens. Moreover, expression of I242N mutant IL4R in a mouse xenotransplantation model conferred growth advantage in vivo. The pattern of concurrent mutations within the JAK-STAT signaling pathway suggests additive/synergistic effects of these gene mutations contributing to lymphomagenesis. Our data establish IL4R mutations as novel driver alterations and provide a strong preclinical rationale for therapeutic targeting of JAK-STAT signaling in PMBCL.

DOI： 10.1182/blood-2017-09-808907

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Introduction:Histiocytic necrotizing lymphadenitis (or Kikuchi-Fujimoto disease) frequently occurs in Asian young adult females and typically presents as cervical lymphadenopathy with unknown etiology. Although large immunoblasts frequently appear in Kikuchi-Fujimoto disease, the diffuse infiltration of these cells can cause difficulty in establishing a differential diagnosis from lymphoma. In such cases, CD30 immunostaining may be used; however, the extent or distribution pattern of CD30-positive cells in Kikuchi-Fujimoto disease remains largely unknown. Here we investigated the expression of CD30 and its clinicopathologic significance.Materials and Methods:We investigated 30 Kikuchi-Fujimoto disease and 16 control [6, systemic lupus erythematosus (SLE); 10, reactive lymphoid hyperplasia (RLH)] cases.Results:The number of CD30-positive cells in Kikuchi-Fujimoto disease was significantly more than that in SLE and RLH, and majority of these cells were located around necrotic areas. Moreover, double immunohistochemical staining showed these CD30-positive cells to be CD8-positive cytotoxic T cells, suggesting that activated cytotoxic T cells around necrotic areas are a characteristic feature of this disease. Clinicopathologic analysis showed that cases with abundant CD30-positive cells were predominantly female with only mild symptoms and normal laboratory data.Conclusions:In Kikuchi-Fujimoto disease cases, CD30-positive cytotoxic T cells were abundant around necrotic areas; this histologic feature may be helpful to differentiate this disease from SLE and RLH.

DOI： 10.1097/PAI.0000000000000411

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Language：English   Publisher：NATURE PUBLISHING GROUP  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Most high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements are aggressive B-cell lymphomas. Occasional double-hit follicular lymphomas have been described but the clinicopathological features of these tumors are not well known. To clarify the characteristics of double-hit follicular lymphomas, we analyzed 10 cases of double-hit follicular lymphomas and 15 cases of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements for clinicopathological and genome-wide copy-number alterations and copy-neutral loss-of-heterozygosity profiles. For double-hit follicular lymphomas, the median age was 67.5 years (range: 48-82 years). The female/male ratio was 2.3. Eight patients presented with advanced clinical stage. The median follow-up time was 20 months (range: 1-132 months). At the end of the follow-up, 8 patients were alive, 2 patients were dead including 1 patient with diffuse large B-cell lymphoma transformation. Rearrangements of MYC/BCL2, MYC/BCL6, and MYC/BCL2/BCL6 were seen in 8, 1, and 1 cases, respectively. The partner of MYC was IGH in 6 cases. There were no cases of histological grade 1, 4 cases of grade 2, 5 cases of grade 3a, and 1 case of grade 3b. Two cases of grade 3a exhibited immunoblast-like morphology. Immunohistochemistry demonstrated 9 cases with >= 50% MYC-positive cells. There was significant difference in MYC intensity (P=0.00004) and MIB-1 positivity (P=0.001) between double-hit follicular lymphomas and high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements. The genome profile of double-hit follicular lymphomas was comparable with conventional follicular lymphomas (GSE67385, n=198) with characteristic gains of 2p25.3-p11.1, 7p22.3-q36.3, 12q11-q24.33, and loss of 18q21.32-q23 (P < 0.05). In comparison with high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements, double-hit follicular lymphomas had fewer copy-number alterations and minimal common region of gain at 2p16.1 (70%), locus also significant against conventional follicular lymphomas (P=0.0001). In summary, double-hit follicular lymphomas tended to be high-grade histology, high MYC protein expression, high MYC/IGH fusion, and minimal common region of gain at 2p16.1. Double-hit follicular lymphomas seemed to be a different disease from high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements and have an indolent clinical behavior similar to follicular lymphomas without MYC rearrangement.

DOI： 10.1038/modpathol.2017.134

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

The gastrointestinal (GI) tract is the most frequently involved site of extranodal non-Hodgkin lymphomas, and diffuse large B-cell lymphoma (DLBCL) is the most common subtype occurring in the GI tract. TNFAIP3 (A20) genetic alterations were reported to be involved in DLBCL's pathogenesis and a portion of GI-DLBCL cases harbor this alteration. However, the frequency and clinicopathological relations focusing on small and large intestinal DLBCL are unclear. Here, we examined A20 deletion and protein expression and analyzed the clinicopathological features of 52 cases of primary intestinal DLBCL. The most frequently involved site was the ileocecal region (75%), followed by small bowel (13.5%) and large intestine. Immunohistochemically, the ileocecal cases expressed BCL6 (p=0.027) and MUM1 (p=0.0001) significantly more frequently than the small intestinal cases. Six of 47 cases (13%) had A20 heterozygous deletion, whereas all 6 heterozygously deleted cases had detectable A20 protein expression. In summary, A20 abnormality was less prevalent among intestinal DLBCLs with some discordancy between gene deletion and protein expression. Although the A20 alteration status did not affect any clinicopathological characteristics in this series, further studies exploring alterations of A20 and other NF-kappa B components in primary intestinal DLBCL are needed.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FRONTIERS MEDIA SA  

In lymphocytes, immune receptor signals induce the rapid nuclear translocation of preformed cytosolic NFAT proteins. Along with co-stimulatory signals, persistent immune receptor signals lead to high levels of NFATc1/alpha A, a short NFATc1 isoform, in effector lymphocytes. Whereas NFATc1 is not expressed in plasma cells, in germinal centers numerous centrocytic B cells express nuclear NFATc1/alpha A. When overexpressed in chicken DT40 B cells or murine WEHI 231 B cells, NFATc1/alpha A suppressed their cell death induced by B cell receptor signals and affected the expression of genes controlling the germinal center reaction and plasma cell formation. Among those is the Prdm1 gene encoding Blimp-1, a key factor of plasma cell formation. By binding to a regulatory DNA element within exon 1 of the Prdm1 gene, NFATc1/alpha A suppresses Blimp-1 expression. Since expression of a constitutive active version of NFATc1/alpha A interfered with Prdm1 RNA expression, LPS-mediated differentiation of splenic B cells to plasmablasts in vitro and reduced immunoglobulin production in vivo, one may conclude that NFATc1/alpha A plays an important role in controlling plasmablast/plasma cell formation.

DOI： 10.3389/fimmu.2018.00032

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Language：Japanese   Publisher：WILEY  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

To evaluate the usefulness of colonoscopy for the detection of ileal involvement in patients with intestinal follicular lymphoma, seventeen patients with intestinal follicular lymphoma who underwent colonoscopy and biopsy sampling from the terminal ileum were enrolled. The patients were divided into 2 groups: cases with ileal involvement (n=6) and cases without ileal involvement (n=11). Patients' clinical backgrounds were compared between the two groups. Subsequently, 10 board-certified endoscopists independently evaluated the endoscopic pictures and determined whether the ileum was involved with follicular lymphoma. Infiltration of follicular lymphoma cells were identified in 6 patients (35.3%). Cases with positive ileal involvement were diagnosed with follicular lymphoma at a younger age than were cases without ileal involvement (55.4 +/- 7.4 vs. 68.1 +/- 10.3 years, p=0.011). Macroscopically, in patients with ileal involvement, there were multiple polypoid elevations smaller than 5 mm in 4 cases, single polypoid elevation smaller than 5 mm in 1 case, and single polypoid elevation larger than 5 mm in 1 case. In patients without ileal involvement, there were no lesions in the terminal ileum in 7 cases, and multiple polypoid elevations smaller than 5 mm were seen in 4 cases. The accuracy of the macroscopic evaluation by 10 board-certified endoscopists was 68.8%. Colonoscopy is particularly recommended during the initial workup of patients with follicular lymphoma diagnosed at age <= 60 years. The diagnosis of ileal involvement based on morphology alone is difficult; thus, biopsy and pathologic diagnosis are required for accurate diagnosis.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Among extranodal NK/T-cell lymphoma of nasal type (NKTL), the extranasal variant (ENKTL) is known to have a worse prognosis with advanced clinical stage than the nasal variant of NKTL. However, detailed clinicopathological features of the localized extranasal disease have not been well documented in English literature. Here, we described the clinicopathological profiles of 14 patients with stage I ENKTL, including 7 in the skin, 5 in the gastrointestinal tract, and 2 in the central nervous system, highlighting the distinctiveness of the first. The 7 primary cutaneous (PCNKTL) cases were characterized by an older onset age (median, 76 versus 53 years, P = .012) and a more favorable clinical course (P = .041) compared with 17 patients with stages II-IV ENKTL that showed cutaneous involvement. The skin lesions in the PCNKTL group were distributed in the face or neck (n = 4) and limbs (n = 3) but not the trunk, which was most frequently affected (60%, P = .017) in the latter group. Furthermore, the stage I cutaneous disease showed a female predominance (male-female, 2:5 versus 7:0; P = .021) and a significantly more favorable survival compared with the noncutaneous stage I ENKTL (P = .037). These results suggest that PCNKTL constitute a distinct subgroup in the nasal-type lymphoma spectrum. (C) 2017 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2017.08.025

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Primary gastrointestinal anaplastic large cell lymphoma (GI-ALCL) is rare. We report eight new cases. The median age was 61.5 years (range 10-88), most frequently involving the stomach (n = 3) and small intestine (n = 4). The neoplastic hallmark cells in all cases expressed CD30. Anaplastic lymphoma kinase (ALK) protein was expressed in two cases (25%). By in situ hybridisation, all cases were negative for Epstein-Barr virus and for DUSP22/IRF4 gene translocation. At a median follow-up time of 37.5 months, four patients died of disease, one was alive with disease, and three were disease-free. Our literature review showed that GI-ALCL occurred mainly in older patients and was characterised by a low rate of ALK expression, a high rate of T-cell lineage, and a frequent occurrence in the small intestine. Incorporating our two ALK(+) GI-ALCL cases together with the four cases in the literature, the median age was 34 years (range 10-56), with four (67%) cases in the small intestine. The six patients were all alive with a median follow-up of 21 months. The 5-year overall survival of our six patients with ALK(-) GI-ALCL was 40%, in contrast to 100% with ALK(+) GI-ALCL. The prognosis for ALK -GI-ALCL was poor, while that for the ALK+ counterparts was good.

DOI： 10.1016/j.pathol.2017.05.007

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

AimsEpstein-Barr virus-positive (EBV+) intestinal T/natural killer (NK) cell lymphoma (ITNKL) is an uncommon tumour with an extremely aggressive clinical behaviour. However, the clinicopathological characteristics of this tumour, including T cell receptor (TCR) phenotype and the patient's background, remain unknown. The aim of this study was to elucidate the detailed clinicopathological profile of EBV+ ITNKL.Methods and resultsWe enrolled 12 patients with EBV+ ITNKL without nasal involvement into the study. All patients were characterized by involvement of the small intestine with concurrent lesions of the large intestine in two patients. Seven patients (58%) had Lugano stages IIE/IV disease and eight (67%) were categorized as high-intermediate/high-risk according to the Prognostic Index for PTCL (PIT). Three patients (25%) with an age of onset of less than 50 years had chronic active EBV infection (CAEBV). Five CD56-positive patients (42%) had a poorer prognosis than those without CD56 expression (P = 0.008). NK cell-type lymphoma defined by the absence of any TCR expression or clonal TCR- rearrangement was found in six patients (50%). Interestingly, EBV+ intra-epithelial lymphocytosis was observed in one case with a background of CAEBV.ConclusionsThis study is the first to shed light on the significant heterogeneity of EBV+ ITNKL and its relationship with CAEBV, especially in patients younger than 50 years of age. These observations will provide a guide for diagnostic and therapeutic approaches in routine practice.

DOI： 10.1111/his.13172

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

Patients with rheumatoid arthritis often develop methotrexate-associated lymphoproliferative disorders (MTX-LPD) during MTX treatment. MTX-LPD occasionally regresses spontaneously after simply discontinuing MTX treatment. In patients without spontaneous regression, additional chemotherapy is required to avoid disease progression. However, the differences between spontaneous and non-spontaneous regression have yet to be elucidated. To clarify the factors important for spontaneous regression, we analyzed the clinicopathological features of 51 patients with rheumatoid arthritis who developed MTX-LPD (diffuse large B-cell lymphoma [DLBCL]-type [n = 34] and classical Hodgkin lymphoma [CHL]-type [n = 17]). We examined the interval from MTX discontinuation to the administration of additional chemotherapy. The majority of DLBCL-type MTX-LPD patients (81%) exhibited remission with MTX discontinuation alone. In contrast, the majority of CHL-type MTX-LPD patients (76%) required additional chemotherapy. This difference was statistically significant (P = 0.001). However, overall survival was not significantly different between DLBCL-type and CHL-type (91% vs 94%, respectively; P > 0.05). Thus, the morphological differences in the pathological findings of MTX-LPD may be a factor for spontaneous or non-spontaneous regression after discontinuation of MTX.

DOI： 10.1111/cas.13249

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

The human herpes virus, Epstein-Barr virus (EBV), is a known oncogenic virus and plays important roles in life-threatening T/NK-cell lymphoproliferative disorders (T/NK-cell LPD) such as hypersensitivity to mosquito bite (HMB), chronic active EBV infection (CAEBV), and NK/T-cell lymphoma/leukemia. During the clinical courses of HMB and CAEBV, patients frequently develop malignant lymphomas and the diseases passively progress sequentially. In the present study, gene expression of CD16((-))CD56((+))-, EBV(+) HMB, CAEBV, NK-lymphoma, and NK-leukemia cell lines, which were established from patients, was analyzed using oligonucleotide microarrays and compared to that of CD56(bright)CD16(dim/-) NK cells from healthy donors. Principal components analysis showed that CAEBV and NK-lymphoma cells were relatively closely located, indicating that they had similar expression profiles. Unsupervised hierarchal clustering analyses of microarray data and gene ontology analysis revealed specific gene clusters and identified several candidate genes responsible for disease that can be used to discriminate each category of NK-LPD and NK-cell lymphoma/leukemia.

DOI： 10.1080/10428194.2017.1304762

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Language：English   Publisher：JAPANESE SOC LYMPHORETICULAR TISSUE RESEARCH  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

HER2 is a receptor tyrosine kinase and its upregulation via activating mutations or amplification has been identified in some malignant tumors, including lung cancers. Because HER2 can be a therapeutic target in HER2-driven malignancies, it is important to understand the molecular mechanisms of HER2 activation. In the current study, we identified that cytokeratin 19 (KRT19) binds to HER2 at the inside face of plasma membrane. HER2 and KRT19, which were concurrently introduced to a human embryonic kidney 293 T cells, revealed an association with each other and resulted in phosphorylation of HER2 with the subsequent activation of a downstream Erk-associated pathway. A binding assay revealed that both the NH2-terminal head domain of KRT19 and the COOH-terminal domain of HER2 were essential for their binding. To investigate the impact of the interaction between HER2 and KRT19 in lung cancer, we examined their expressions and localizations in lung cancers. We found that KRT19 was highly expressed in HER2-positive lung cancer cells, and KRT19 and HER2 were co-localized at the cell membrane. In conclusion, we found that KRT19 intracellularly binds to HER2, playing a critical role in HER2 activation.

DOI： 10.1038/srep39557

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

We herein report a case in which an IgG4-producing lymphoma arose in a patient with a previous diagnosis consistent with an IgG4-related disease. A 43-year-old man presented with enlarged cervical lymph nodes and was treated with steroids and radiation for what was initially assumed to be Kimura's disease, although the lesions were later histologically re-diagnosed as IgG4-related lymphadenopathy. Fourteen years later, when the patient was 58-years-old, he presented with retroperitoneal fibrosis and swollen lymph nodes. The suspicious lesions were not histologically examined as the patient did not give consent. However, the serum IgG4 concentration was high (1400 mg/dL) and he was clinically diagnosed with systemic IgG4-related disease. Although steroid administration reduced the size of the lesions, tapering the dose finally resulted in systemic, prominently enlarged lymph nodes. Analysis of the biopsy specimen revealed that these multiple lymph node lesions were marginal zone B cell lymphomas that themselves expressed IgG4. Complete remission was achieved after a total of six courses of chemotherapy including rituximab. This case suggests that the infiltrating IgG4-expressing cells observed in IgG4-related disease can clonally expand to malignant lymphomas.

DOI： 10.1007/s00795-016-0139-2

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Language：English   Publisher：AMER SOC HEMATOLOGY  

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DOI： 10.1182/blood.V128.22.4122.4122

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

Protocadherin genes (PCDHs) have been suggested to act as tumor suppressor genes in various tumor types. Previous studies have demonstrated the upregulation of certain PCDH-gamma subfamily genes in nodal and duodenal follicular lymphoma (FL) using gene expression analyses. However, the mechanisms and associated molecular function of PCDH-gamma subfamily gene upregulation in FL remain to be elucidated. The present study examined the expression of PCDHGA3, an upregulated PCDH-gamma gene subfamily member, in B-cell lymphoma 2 (BCL2)-positive and-negative FL, and evaluated its association with tumor cell proliferation in an FL-derived cell line. Immunohistochemical analysis demonstrated that the majority of FL grade 1-2 samples (19/20; 95%) and over half of grade 3A FL samples (5/9; 56%) were PCDHGA3-positive, whereas only 1/17 reactive lymphoid hyperplasia samples was positive. Notably, this positivity was widely observed in samples of BCL2-negative FL (13/15; 87%) and FL with diffuse area (10/10; 100%). The FL-derived cell line FL18 exhibited strong PCDHGA3 expression, similar to the patient samples, and its proliferation was suppressed by PCDHGA3 gene knockdown. Genes expressed concomitantly with PCDHGA3 were selected from gene expression data, and TNFRSF6B, a member of the tumor necrosis factor receptor superfamily, was among the top five most strongly correlated genes. Coexpression of TNFRSF6B and PCDHGA3 was observed immunohistochemically in FL18 cells, suggesting potential cooperation in tumor cell maintenance. In conclusion, the results of the present study indicated that PCDHGA3 was expressed in FL irrespective of BCL2 status and grading and was associated with cell proliferation. Further studies involving molecular genetic analyses are required to elucidate the mechanisms underlying the activity of PCDHGA3 in FL.

DOI： 10.3892/mmr.2016.5808

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Successful bronchial healing after a bronchoplastic procedure mainly depends on bronchial circulation at the anastomostic site. We developed a bronchial fluorescein angiography (B-FAG) technique for visualizing circulation on the bronchial surface. The technique was evaluated in animals.Fluorescein was used as a contrast agent and an autofluorescence imaging (AFI) bronchoscope as a detector. The left main pulmonary artery (PA) and main bronchus of 10 pigs were isolated. After transection of the left main bronchus and bronchial arteries and re-anastomosis of the bronchus, the pigs were randomly divided into two groups: the PA- group (n = 5), in which the pulmonary artery was transected; and the PA+ group (n = 5), in which the pulmonary artery was preserved. Following intravenous injection of fluorescein, the distal anastomotic site was observed for 30 min with autofluorescence imaging bronchoscopy. Bronchial specimens sampled 2 days after the surgical intervention were histologically evaluated.In the PA- group, there was no fluorescein enhancement in the distal bronchus throughout the observation time. However, enhancement, which turned the bronchial surface from magenta to bright green, was clearly observed in less than 207 +/- 102.5 s in the PA+ group. The enhancement status detected by bronchial fluorescein angiography was related to the extent of tissue damage, as was proven histologically in the acute healing stage.Bronchial fluorescein angiography clearly visualized the circulatory status promptly after the anastomosis procedure at the central bronchus. This technique is a potentially practical approach to predict ischaemic airway complications following bronchial anastomosis.

DOI： 10.1093/icvts/ivw210

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The Polycomb repressive complex-2 members (EZH2, EED, SUZ12 and EZH1) are important regulators of haematopoiesis, cell cycle and differentiation. Over expression of EZH2 has been linked to cancer metastases and poor prognosis. Detailed information on the expression of other members in normal and neoplastic lymphoid tissue remains to be elucidated. Immunohistochemical and immunofluorescent analyses of 156 samples from haematopoietic neoplasms patients and 27 haematopoietic cell lines were used.B-cell neoplasms showed a significant over-expression of EZH2, EED and SUZ12 in the aggressive subtypes compared to the indolent subtypes and normal tissue (p = 0.000-0.046) while expression of EZH1 was decreased in mantle cell lymphoma compared to normal tissue (p = 0.011). T/NK-cell neoplasms also showed significant over expression of EZH2, EED and SUZ12 (p = 0.000-0.002) and decreased expression of EZH1 (p = 0.001) compared to normal cells. EZH2 and EZH1 have opposite expression patterns both in normal and neoplastic lymphoid tissues as well as an opposite relation to Ki-67. These results were supported by western blotting analyses. Immunofluorescent staining revealed a difference in the intracellular localisation of EZH1 compared to other members.These evidences suggest that EZH2 and EZH1 are important in the counter-balancing mechanisms controlling proliferation/resting of lymphoid cells. The disruption of the balanced EZH2/EZH1 ratio may play important roles in the pathogenesis of lymphomas.

DOI： 10.1016/j.pathol.2016.05.002

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

The gastrointestinal (GI) tract is the most common primary site of extranodal diffuse large B-cell lymphoma (DLBCL), with approximately one-third of extranodal DLBCL occurring in the GI tract. We investigated the clinicopathological features and immunohistochemically-assessed cell-of-origin of 49 GI DLBCL cases (stomach, 24; small intestine, 10; colon, 15) and also examined the presence of MYD88 L265P as recently this mutation has been frequently identified in ABC-like DLBCL, particularly in extranodal sites. Small intestinal DLBCL was characterized by the preponderance of women (P = 0.041) and elevated LDH (P = 0.002) and soluble interleukin-2 receptor (P = 0.033). Small intestinal DLBCL more frequently showed anemia (P = 0.031) and elevated CRP (P = 0.029) than gastric DLBCL. ABC-like phenotype was seen in 71.4 % cases (stomach, 79 %; small intestine, 70 %; colon, 60 %). MYD88 L265P was detected in 6.1 % cases; all were primary gastric DLBCL with ABC-like phenotype but had no distinct clinicopathological features. In conclusion, GI DLBCL had different clinicopathological features according to the primary site especially in the small intestine. Also, MYD88 L265P had little involvement in GI DLBCL compared with other extranodal DLBCLs, suggesting that its pathogenesis might be different from that of organs with a high frequency of MYD88 L265P.

DOI： 10.1111/pin.12439

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

Esophagogastroduodenoscopy revealed small duodenal lesions in a 56-year-old Japanese man and a 92-year-old Japanese woman with stage IV follicular lymphoma. Magnifying endoscopy examination revealed tiny white deposits in the second duodenal portion of the former patient and slightly enlarged duodenal villi in the latter. In both cases, biopsy revealed infiltration of follicular lymphoma cells and incipient formation of neoplastic follicles. Here, we discuss the usefulness of magnifying endoscopy and narrow-band imaging for the detection of small duodenal lesions in follicular lymphoma cases.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE PHARMACOLOGICAL SOC  

Acute respiratory distress syndrome (ARDS) is a severe respiratory failure caused by acute lung inflammation. Recently, the receptor for advanced glycation end-products (RAGE) has attracted attention in the lung inflammatory response. However, the function of soluble form of RAGE (sRAGE), which is composed of an extracellular domain of RAGE, in ARDS remains elusive. Therefore, we investigated the dynamics of pulmonary sRAGE and the effects of exogenous recombinant human sRAGE (rsRAGE) under intratracheal lipopolysaccharide (LPS)-induced lung inflammation. Our result revealed that RAGE was highly expressed on the alveolar type I epithelial cells in the healthy rat lung including sRAGE isoform sized 45 kDa. Under LPS-induced injured lung, the release of sRAGE into the alveolar space was increased, whereas the expression of RAGE was decreased with alveolar disruption. Treatment of the injured lung with rsRAGE significantly suppressed the lung edema, the neutrophils infiltration, the release of high mobility group box-1 (HMGB1), and the expressions of TNF-alpha, IL-1 beta and iNOS. These results suggest that the alveolar release of sRAGE may play a protective role against HMGB1 as well as exogenous pathogenassociated molecular patterns. Supplementary therapy with sRAGE may be an effective therapeutic strategy for ARDS. (C) 2016 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license.

DOI： 10.1016/j.jphs.2016.02.005

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Language：English   Publisher：(一社)日本病理学会  

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CANCER INTELLIGENCE LTD  

An 82-year-old Japanese man presented with a gastric involvement of peripheral T-cell lymphoma, not otherwise specified. Although gastrointestinal lesions were not detected on computed tomography, oesophagogastroduodenoscopy revealed a slight elevation of the gastric mucosa, with changes in mucosal colour and the presence of abnormal microvessels. This led to the prompt detection of gastric involvement in lymphoma. This case highlights the usefulness of detailed observation of the gastric mucosa for the endoscopic detection of gastric involvement of peripheral T-cell lymphoma.

DOI： 10.3332/ecancer.2016.625

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Glioblastoma multiforme (GBM) is the most common malignant brain tumor with a median survival time about one year. Invasion of GBM cells into normal brain is the major cause of poor prognosis and requires dynamic reorganization of the actin cytoskeleton, which includes lamellipodial protrusions, focal adhesions, and stress fibers at the leading edge of GBM. Therefore, we hypothesized that inhibitors of actin polymerization can suppress GBM migration and invasion. First, we adopted a drug repositioning system for screening with a pyrene-actin-based actin polymerization assay and identified fluvoxamine, a clinically used antidepressant. Fluvoxamine, selective serotonin reuptake inhibitor, was a potent inhibitor of actin polymerization and confirmed as drug penetration through the blood-brain barrier (BBB) and accumulation of whole brain including brain tumor with no drug toxicity. Fluvoxamine inhibited serum-induced ruffle formation, cell migration, and invasion of human GBM and glioma stem cells in vitro by suppressing both FAK and Akt/mammalian target of rapamycin signaling. Daily treatment of athymic mice bearing human glioma-initiating cells with fluvoxamine blocked tumor cell invasion and prolonged the survival with almost same dose of anti-depressant effect. In conclusion, fluvoxamine is a promising anti-invasive treatment against GBM with reliable approach.

DOI： 10.1038/srep23372

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

Objective: There is no consensus regarding the best treatment for intestinal follicular lymphoma (FL). We used watch and wait for patients with intestinal FL with low-tumor-burden (LTB) criteria and without mass formation causing bowel obstruction. We investigated the overall survival (OS) and time to treatment required (TTR). Methods: Thirty-three intestinal FL patients [clinical stage (CS) I:16, II1:0, II2:7, IV:10; median observation period: 45.5 months, range: 13-110 months] were diagnosed via endoscopy. Detailed clinical and pathological examinations were performed, and neoplastic process behavior was monitored. Results: All of the 33 patients were WHO grade 1. FL lesions in the digestive tract were found frequently in the second-fourth portion of the duodenum in 91% of the patients; 87% of those patients had lesions in a broader area including the small intestine. Two patients had an enlargement of the area of the lesions and a worsening of the macroscopic findings. Three patients had CS progression; however, these remained within the indication for watch and wait. Two patients with transformation into diffuse large B-cell lymphoma received rituximab and chemotherapy, which led to complete remission. The OS was 100%. The time to treatment required (TTR) was 49 months in one patient and 37 months in one patient. Conclusion: Intestinal FL in CS I-IV with broad infiltration of the digestive tract meeting the criteria for LTB had a remarkably slow course. This study suggests that watch and wait is appropriate for the treatment of LTB intestinal FL even in the era of rituximab.

DOI： 10.3109/00365521.2015.1087589

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background:Primary cutaneous T-cell lymphomas (CTCL) are heterogenous extranodal non-Hodgkin lymphomas including a few distinct and provisional entities. Compared with the West, Asian populations have a relatively higher frequency of nonmycosis fungoides CTCL. Primary cutaneous extranodal natural killer/T-cell lymphoma (PC-ENKTL) is distinct from other CTCL by the presence of EBV association.Method:In our recent retrospective Asian study of PC-ENKTL, we identified 5 cases initially misdiagnosed as various CTCL. We fully characterized these cases with immunohistochemistry, EBV in situ hybridization, and clonality study for T-cell receptor (TCR) gamma-chain gene (TRG).Results:The 5 patients included 3 males and 2 females with a median age of 45. All tumors were positive for EBER. Two cases were clonal for TRG gene rearrangement but without expression of beta F1 or TCR-gamma (TCR-silent T-cell origin), 1 tumor expressed TCR-gamma (gamma delta T-cell origin), and the remaining 2 were polyclonal for TRG and negative for TCR expression (NK-cell origin). On the basis of the initial diagnoses (2 as peripheral T-cell lymphoma, unspecified, 2 as primary cutaneous anaplastic large-cell lymphoma, and 1 as subcutaneous panniculitis-like T-cell lymphoma), all patients received CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy with additional radiotherapy in 3. All patients experienced persistent disease or relapse despite treatment in a mean duration of 8.8 months (range, 1 to 12 mo).Conclusions:PC-ENKTL is rare and aggressive. These cases strongly demonstrate the importance of consultation/referral to experienced hematopathologists and the inclusion of EBER in the initial diagnostic work-up for patients with nonmycosis fungoides CTCL to avoid erroneous diagnosis and subsequent inadequate treatment of the patients.

DOI： 10.1097/PAI.0000000000000162

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

The purpose of this study was to determine the prevalence of lymphoid hyperplasia in the lower gastrointestinal tract and its role in patients undergoing colonoscopic examinations, particularly focusing on any allergic predisposition.A database search performed at the Department of Gastroenterology at Onomichi Municipal Hospital identified seven patients with lymphoid hyperplasia in the large intestine (i.e., cecum, colon, and/or rectum). Data regarding the endoscopic, biological, and pathological examinations performed and the allergic histories for each patient were retrospectively reviewed from the clinical records.Median age of the patients (four males, three females) was 50 years. Lymphoid hyperplasia was seen in the cecum (n = 5), ascending colon (n = 2), and transverse colon (n = 1). Six patients (85.7 %) had one of the allergic airway diseases: allergic rhinoconjunctivitis for pollen (n = 3), bronchial asthma (n = 1), infantile asthma (n = 1), or allergic bronchitis (n = 1). Drug allergy (n = 3) and urticaria (n = 2) were also found. All seven patients had one or more allergic diseases; however, none had a history of food allergy. Blood tests for allergens revealed that six patients (85.7 %) had positive reactions to inherent allergens, whereas only one patient had a positive reaction to food allergens.Our results indicate that lymphoid hyperplasia in the large intestine may be associated with allergic airway diseases rather than with food allergies; thus, its presence may be useful to detect patients with underlying airway hyperreactivity.

DOI： 10.1007/s00384-015-2392-6

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Language：English   Publisher：BAISHIDENG PUBLISHING GROUP INC  

Due to an increasing incidence and more frequent recognition by endoscopists, gastrointestinal follicular lymphoma has been established as a variant of follicular lymphoma. However, due to its rarity, there are no established guidelines on the optimal diagnostic strategy for patients with primary gastrointestinal follicular lymphoma or secondary gastrointestinal involvement of systemic follicular lymphoma. This review offers an overview and pitfalls to avoid during the initial diagnostic workup of this disease entity. Previously reported case reports, case series, and retrospective studies are reviewed and focus on the disease's endoscopic and histological features, the roles of computed tomography and positron emission tomography scanning, the clinical utility of the soluble interleukin-2 receptor, and the possible pathogenesis.

DOI： 10.3748/wjg.v22.i4.1674

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Objective Due to their rarity, the endoscopic features and clinical backgrounds of colorectal follicular lymphoma lesions have not yet been fully investigated. The aim of this study was to reveal the characteristics of this disease entity.Methods A database search performed at the Department of Pathology of our institute identified 12 follicular lymphoma patients with involvement in the cecum, colon, and/or rectum. Data regarding the endoscopic, radiological, biological, and pathological examinations performed were retrospectively reviewed from their clinical records.Results The mean age of the patients (5 men, 7 women) was 58.7 years. Five patients were classified as being Lugano system stage I, while the other seven patients were stage IV. In all of the patients, colorectal follicular lymphoma presented with papular (n=4), polypoid (n=4), and flat elevated lesions (n=4). No erosions or ulcers were seen in any of the lesions. The initial pathological diagnoses included extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (n=2) and colitis/proctitis with infiltration of inflammatory cells (n=3), in addition to the correct diagnosis of follicular lymphoma (n=7).Conclusion Colorectal involvement of follicular lymphoma shows no erosions or ulcers. These lesions could be macroscopically observed as papular, polypoid and flat elevated lesions. Making a correct diagnosis of this disease based on the findings of biopsied samples is sometimes challenging. In such cases, multiple biopsies and/or endoscopic mucosal resection is required, in addition to appropriate consultation with pathologists.

DOI： 10.2169/internalmedicine.55.5393

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：HINDAWI LTD  

A 70-year-old woman presented with follicular lymphoma involving the stomach, duodenum, jejunum, bone, and lymph nodes. Esophagogastroduodenoscopy revealed multiple depressed lesions in the stomach. Examination with magnifying endoscopy showed branched abnormal vessels along with gastric pits, which were irregularly shaped but were preserved. The second case was a 45-year-old man diagnosed with stage II 1 follicular lymphoma with duodenal, ileal, and colorectal involvement, as well as lymphadenopathy of the mesenteric lymph nodes. Esophagogastroduodenoscopy performed six years after the diagnosis revealed multiple erosions in the gastric body and angle. Magnifying endoscopic observation with narrow-band imaging showed that the gastric pits were only partially preserved and were destroyed in most of the stomach. Branched abnormal vessels were also seen. Pathological features were consistent with follicular lymphoma in both cases. The structural differences reported between the two cases appear to reflect distinct pathologies. Disappearance of gastric pits in the latter case seems to result from loss of epithelial cells, probably due to chronic inflammation. In both cases, branched abnormal vasculature was observed. These two cases suggest that magnified observations of abnormal branched microvasculature may facilitate endoscopic detection and recognition of the extent of gastric involvement in patients with follicular lymphoma.

DOI： 10.1155/2016/2082698

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Language：Japanese   Publisher：Okayama Medical Association  

A 63-year-old Japanese woman was diagnosed with duodenal follicular lymphoma. The initial esophagogastroduodenoscopic examination with magnifying observation revealed opaque white spots and enlarged whitish villi. Nine months later, esophagogastroduodenoscopy showed that the size of the lymphoma lesion decreased, and only opaque white spots were visible. The histological analysis of biopsy samples obtained during the initial endoscopy examination showed both neoplastic follicles and an inter-follicular infiltration of lymphoma cells, whereas the biopsy samples obtained at the endoscopy performed 9 months later showed only neoplastic follicle formation. These results suggest that the magnifying endoscopic features may reflect the underlying pathological mechanisms : enlarged whitish villi are probably due to lymphoma cell infiltration in the inter-follicular area, and opaque white spots are probably caused by neoplastic follicle formation.

DOI： 10.4044/joma.128.111

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Other Link： http://search.jamas.or.jp/link/ui/2016396171

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOC LYMPHORETICULAR TISSUE RESEARCH  

Concurrent seminoma andm alignant lymphoma of the testis is rare. We present a case of concurrent seminoma and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) in a 54-year-oldm an who complainedof painless left testicular enlargement. Radical left orchiectomy was performed. Macroscopically, the tumor (4.0 x 3.0 cm) was creamy, soft, and homogeneous, and microscopic evaluation revealed an alveolar structure of large cells that formeds heets, as well as colonization by other abnormal cells in a 1.0 x 1.0 cm area. The portion of the tumor comprising large abnormal cells was diagnosed as a seminoma, which was positive for c-kit by immunohistochemistry; the other portion was diagnosed as CD3/CD8, TIA, and granzyme B-positive PTCL-NOS. These two portions were clearly differentiated from one another. The patient received CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) therapy and a chieved complete response for 50 months. To our knowledge, this is the first reportedcase of synchronous advanced seminoma and PTCL.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

A 41-year-old woman was diagnosed with duodenal follicular lymphoma. She had no other lesions and was assigned to a "watch and wait" policy. Swelling of the inguinal lymph nodes appeared 45 months later, and rituximab monotherapy resulted in complete remission. However, follicular lymphoma recurred in the stomach, rectum and mesenteric and external iliac lymph nodes 81 months after the therapy. The patient received rituximab monotherapy again and has remained in complete remission in the fifteenth year after the initial diagnosis. This case suggests the usefulness of rituximab monotherapy in the long-term management of intestinal follicular lymphoma.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Enteropathy-associated T-cell lymphoma (EATL) is a rare primary T-cell lymphoma of the digestive tract. EATL is classified as either Type I, which is frequently associated with and thought to arise from celiac disease and is primarily observed in Northern Europe, and Type II, which occurs de novo and is distributed all over the world with predominance in Asia. The pathogenesis of EATL in Asia is unknown. We aimed to clarify the histological and genomic profiles of EATL in Japan in a homogeneous series of 20 cases. The cases were characterized by immunohistochemistry, high-resolution oligonucleotide microarray, and fluorescence in situ hybridization (FISH) at five different loci: 1q21.3 (CKS1B), 6q16.3 (HACE1), 7p22.3 (MAFK), 9q33.3 (PPP6C), and 9q34.3 (ASS1, CARD9) using formalin-fixed paraffin-embedded sections. The histological appearance of EATL ranged from medium-to large-sized cells in 13 cases (65%), small-to medium-sized cells in five cases (25%), and medium-sized in two cases (10%). The immunophenotype was CD2(+) (60%), CD3 epsilon(+) (100%), CD4(+) (10%), CD7(+) (95%), CD8(+) (80%), CD56(+) (85%), TIA-1(+) (100%), Granzyme B+ (25%), T-cell receptor (TCR)beta(+) (10%), TCR gamma(+) (35%), TCR gamma delta(+) (50%), and double negative for TCR (six cases, 30%). All cases were EBER-. The genomic profile showed recurrent copy number gains of 1q32.3, 4p15.1, 5q34, 7q34, 8p11.23, 9q22.31, 9q33.2, 9q34.13, and 12p13.31, and losses of 7p14.1. FISH showed 15 patients (75%) with a gain of 9q34.3 with good correlation with array comparative genomic hybridization. EATL in Japan is characterized by non-monomorphic cells with a cytotoxic CD8(+) CD56(+) phenotype similar to EATL Type II. The genomic profile is comparable to EATL of Western countries, with more similarity to Type I (gain of 1q and 5q) rather than Type II (gain of 8q24, including MYC). The 9q34.3 gain was the most frequent change confirmed by FISH irrespective of the cell origin of alpha beta-T-cells and gamma delta-T-cells.

DOI： 10.1038/modpathol.2015.85

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Plasmablastic lymphoma (PBL) is an aggressive lymphoma commonly associated with human immunodeficiency virus (HIV) infection. Herein we describe a rare case of PBL that spontaneously regressed. An 80-year-old man was referred to our hospital owing to an exophytic gingival tumor in the right maxillary second molar region. He had no significant past medical history, and a screening test for HIV was negative. Imaging showed that the tumor measured 26 x 23 x 16 mm and was confined in the alveolar bone. The tumor was histologically comprised of highly proliferative immunoblastic cells positive for CD138 and Epstein-Barr virus (EBV)-encoded RNA. Monoclonal IgH chain gene rearrangement was detected via polymerase chain reaction. After biopsy and diagnosis of PBL, the tumor began to decrease in size and had apparently disappeared at the time of surgery. There was no histological evidence of a residual lesion in the surgical specimen. In conclusion, a minority of immunosenescence-associated PBLs in the elderly should be recognized as a unique clinicopathological entity distinct from common aggressive PBL.

DOI： 10.1186/s13000-015-0421-y

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Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2015-48

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMJ PUBLISHING GROUP  

Acute lymphoblastic leukaemia/lymphoma (ALL/LBL) is an aggressive form of non-Hodgkin's lymphoma (NHL) affecting B-cells or T-cells, respectively. The serum level of soluble interleukin-2 receptor (sIL-2R) is known to reflect the immune activity and tumour volume in aggressive NHL; however, the release of sIL-2R in LBL has not been extensively studied. Further, the relationship between sIL-2R release and the expression level of IL-2R alpha subunit (CD25) remains unknown.In the present study, we examined the serum level of sIL-2R in 23 patients with T lymphoblactic lymphoma (T-LBL) and compared these with the levels in 20 patient with T acute lymphoblastic leukaemia (T-ALL), 40 patients with diffuse large B-cell lymphoma (DLBCL) and 40 patients with peripheral T-cell lymphoma (PTCL), not otherwise specified. The release of sIL-2R into the serum in patients with T-LBL was significantly lower than that for T-ALL, DLBCL and PTCL (p<0.001).Immunohistochemistry revealed that CD25 expression was correlated with the serum level of sIL-2R in T-LBL (p=0.0069), whereas no correlation was found to exist between serum sIL-2R levels and CD25 expression in patients with DLBCL (p=0.348) and PTCL (p=0.266). Furthermore, double immunohistochemical analysis revealed that CD25-positive cells were also found to be Foxp3-positive non-neoplastic T-cells. In conclusion, CD25-positive non-neoplastic T-cells in T-LBL are presumed to be the primary source of sIL-2R, and the low number of cells present results in a lower level of sIL-2R released into the serum compared with the other aggressive and highly aggressive lymphomas.

DOI： 10.1136/jclinpath-2015-202934

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

We previously suggested a relationship between ocular immunoglobulin (Ig)G4-related disease (IgG4-RD) and marginal zone lymphomas (MZLs). However, the cytokine background associated with these disorders and whether it differs between ocular adnexal MZLs with (IgG4-associated MZL) and without (IgG4-negative MZL) numerous IgG4(+) plasma cells are unknown. In this study, we identified the mRNA expression pattern of Th2 and regulatory T-cell (Treg) cytokines in IgG4-RD and in IgG4-associated MZL and IgG4-negative MZL using real-time polymerase chain reaction analysis. Ocular IgG4-RD and IgG4-associated MZL exhibited significantly higher expression ratios of interleukin (1Q-4/beta-actin, IL-10/beta-actin, IL-13/beta-actin, transforming growth factor (TGF) beta 1/beta-actin, and FOXP3/beta-actin than did IgG4-negative MZL (p < 0.05). This finding further supports our prior observations that a significant subset of ocular MZLs arises in the setting of IgG4-RD. Furthermore, the presence of a different inflammatory background in IgG4-negative MZLs suggests that IgG4-associated MZLs may have a different pathogenesis. Immunoglobulin (Ig)G4-related

DOI： 10.1038/srep13539

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

The importance of enteroscopy examinations to investigate the entire length of the small intestines has been emphasized in follicular lymphoma patients with intestinal involvement. The aim of the present study was to determine the current state of enteroscopy examinations, including the performance rate, and the prevalence of small intestinal lesions in a patient population in Japan. A retrospective multicenter survey of 17 institutions collected the case information of 110 follicular lymphoma patients with gastrointestinal involvement. The results of the enteroscopy examinations were reviewed, and in order to identify potential factors affecting the performance rate of enteroscopy, patient gender, age at lymphoma diagnosis, histopathological grade, clinical stage, the date of the initial diagnosis and the annual volume of enteroscopy at the institution were compared between the patients who underwent one or more enteroscopy procedures and the patients who did not undergo enteroscopy. A total of 34 patients (30.9%) underwent enteroscopy, and 24 of these (70.6%) presented with involvement in the jejunum and/or ileum. It was found that more patients diagnosed in recent years and more patients treated at an ultra-high volume institution (101 enteroscopy examinations/year) underwent an enteroscopy. In conclusion, although the prevalence of small intestinal lesions was high (70.6%) in the follicular lymphoma patients presenting with intestinal involvement, the performance rate of enteroscopy was only 30.9%, and thus the majority of the patients have not undergone enteroscopy examinations. Further investigation is required to define the clinical significance of enteroscopy at the initial diagnostic work-up and during the follow-up period of these patients.

DOI： 10.3892/ol.2015.3251

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Language：Japanese   Publisher：(一社)日本リンパ網内系学会  

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Language：Japanese   Publisher：(一社)日本リンパ網内系学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Among Epstein-Barr virus (EBV)-positive cytotoxic T/NK-cell lymphoma, there are only a few reports on the clinicopathologic features of patients with primary nodal presentation (nodal EBV+ cytotoxic T-cell lymphoma [CTL]). Here, we compared the clinicopathologic profiles of 39 patients with nodal EBV+ CTL with those of 27 cases of "extranasal" NK/T-cell lymphoma of nasal type (ENKTL), especially addressing their T-cell receptor (TCR) phenotype. Histologically, 22 of 39 nodal EBV+ CTL cases (56%) were unique in having centroblastoid appearance, which was contrasted with the lower incidence of this feature in ENKTL (15%, P - 0.001). In contrast, pleomorphic appearance was more frequently seen in ENKTL than in nodal EBV+ CTL (67% vs. 23%, P = 0.001). Thirty-three of 39 nodal EBV+ CTL cases (85%) were of T-cell lineage on the basis of TCR expression and/or TCR gamma gene rearrangement; in detail, 18 cases (46%) were TCR gamma positive (alpha beta T), 5 (13%) were TCR gamma and/or delta positive (gamma delta T), and 10 (26%) were TCR-silent type with clonal TCRg gene rearrangement but no expression of TCR beta, gamma, or delta. These results were clearly contrasted by a lower incidence of T-cell lineage in ENKTL (7 cases, 26%, P < 0.001). Notably, the survival time of the 5 nodal lymphoma patients with gamma delta T-cell phenotype was within 3 months, which was inferior to those of alpha beta T and TCR-silent types (P = 0.003), and 3 of those with available clinical information were all found to be associated with autoimmune diseases. These data suggest that nodal EBV+ CTL is distinct from ENKTL.

DOI： 10.1097/PAS.0000000000000323

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Fibroblastic reticular cell (FRC) neoplasms, which are one of the histiocyte tumor types, are very rare. Here we report a cytokeratin (CK)-positive FRC neoplasm having features of follicular dendritic cells in a 54-year-old woman with right axillary lymph node swelling. The resected lymph node showed multiple nodular aggregations simulating and replacing normal follicles. The tumor cells had a uniform, large and oval to polygonal shape, abundant cytoplasm, and various sizes of nuclei with central eosinophilic nucleoli and coarse nuclear chromatin. They were positive for CK AE1/AE3 + CAM5.2, CK7, tenascin C, l-caldesomone, and CD21, weakly positive for S100, and negative for CD1a. Ultrastructurally, the tumor cells had long interdigitating microvillus-like cell processes and oval to elongated[GRAPHICS]vesicular nuclei. In addition, the intercellular spaces contained accumulations of collagen, and some tumor cells had desmosomal-like junctions. These findings suggest that the presentcase is a CK-positive FRC tumor with follicular dendritic cell features.

DOI： 10.1097/PAS.0000000000000362

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Language：English   Publisher：(一社)日本病理学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

The sensitivity and specificity of magnified endoscopic features for differentiating follicular lymphoma from other diseases with duodenal whitish lesions have never been investigated. Here we compared the magnified endoscopic features of duodenal follicular lymphoma with those of other whitish lesions. We retrospectively reviewed the cases of patients with follicular lymphoma (n = 9), lymphangiectasia (n = 7), adenoma (n = 10), duodenitis (n = 4), erosion (n = 1), lymphangioma (n = 1), and hyperplastic polyp (n = 1). The magnified features of the nine follicular lymphomas included enlarged villi (n = 8), dilated microvessels (n = 5), and opaque white spots of various sizes (n = 9). The lymphangiectasias showed enlarged villi, dilated microvessels, and white spots, but the sizes of the white spots were relatively homogeneous and their margin was clear. Observation of the adenoma and duodenitis revealed only whitish villi. Although the lymphangioma was indistinguishable from the follicular lymphomas by magnified features, it was easily diagnosed based on the macroscopic morphology. In conclusion, magnified endoscopic features, in combination with macroscopic features, are useful for differentiating follicular lymphomas from other duodenal diseases presenting whitish lesions.

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Language：English   Publisher：BIOMED CENTRAL LTD  

We propose Langerhans cell histiocytosis (LCH) is an inflammatory process that is prolonged by mutations. We hypothesize that Merkel cell polyomavirus (MCPyV) infection triggers an interleukin-1 (IL-1) activation loop that underlies the pathogenesis of LCH. Langerhans cells (LCs) are antigen presenting cells in the skin. When LCs encounter exogenous antigens, they migrate from the epidermis into draining lymphoid tissues to initiate T-cell activity. It has been proposed that LC migration-related factors, including E-cadherin, matrix metalloproteinase, and Notch ligand induce LCH activity. We found that the tyrosine phosphatase SHP-1, which binds IL-1 receptor-associated kinase 1, is expressed at a significantly higher level in LCH affecting multiple organ systems (MS-LCH) than in LCH affecting a single organ system (SS-LCH). IL-1 stimulates T helper 17 cells and their signature cytokine IL-17 had been a matter of controversy. We detected higher levels of IL-17A receptor expression in MS-LCH than in SS-LCH and proposed an IL-17 endocrine model that could settle the controversy. IL-1 is the first cytokine secreted in response to sensitizers and promotes LC migration from sentinel tissues. Myeloid differentiation primary response 88 (MyD88), downstream of the IL-1 receptor, has functions in both RAS signaling and inflammation, leading to human cell transformation. In 2010, an activating mutation in the B-rapidly accelerated fibrosarcoma gene (BRAF) V600E was found in LCH. This BRAF mutation induces phosphorylation of the extracellular signal-regulated kinase (ERK) that may play an important role with MyD88 in LCH pathogenesis. However, phosphorylated ERK (pERK) is rapidly dephosphorylated by dual specificity phosphatase 6 (DUSP6), and limited proliferation is predicted in BRAF mutant cells. MyD88 binds pERK via its D-domain, thereby preventing pERK-DUSP6 interaction and maintaining ERK in an active, phosphorylated state. We detected MCPyV-DNA in the peripheral blood cells of two out of three patients with LCH in high-risk organs but not in those of patients with LCH in non-high-risk organs (0/12; P = .029). MCPyV infection can trigger precursor LCH cells with BRAF mutation to produce IL-1; the IL-1 loop is amplified in all LCH subclasses. Our model indicates both BRAF mutation and IL-1 loop regulation as potential therapeutic targets.

DOI： 10.1186/s12964-015-0092-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Interleukin (IL)-13 is a T helper 2 (Th2) cytokine that plays important roles in the pathogenesis of asthma. IL-13 induces hypersensitivity of the airways, increased mucous production, elevated serum immunoglobulin (Ig) E levels, and increased numbers of eosinophils. Many patients with IgG4-related disease have allergic backgrounds and show elevated serum IgE levels and an increase in the number of eosinophils. Upregulation of Th2/regulatory T (Treg) cytokines, including IL-13, has been detected in affected tissues of patients with IgG4-related disease. We previously reported that mast cells might be responsible for the production of the Th2/Treg cytokines IL-4, IL-10, and transforming growth factor (TGF)-beta 1 in IgG4-related disease. In this study, immunohistochemical analysis showed increased numbers of IL-13-positive mast cells in IgG4-related disease, which suggests that mast cells also produce IL-13 and contribute to elevation of serum IgE levels and eosinophil infiltration in IgG4-related disease.

DOI： 10.1038/srep07696

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

A 60-year-old Japanese man was diagnosed with systemic follicular lymphoma with duodenal, jejunal, and ileal involvement. The duodenal lesion showed typical endoscopic features with multiple whitish granules. Chemotherapy with bendamustine and rituximab was administered, and complete remission was confirmed by CT scanning and positron emission tomography scanning. Although the duodenal granular lesions did not completely disappear, magnifying observation for the remaining lesions showed no evidence of residual lymphoma. Complete remission was pathologically confirmed by biopsy examinations. This case suggests the usefulness of magnifying observation in evaluating the effects of treatment for duodenal follicular lymphoma lesions.

DOI： 10.2169/internalmedicine.54.4390

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

Primary intestinal follicular lymphoma (FL) is a variant of FL characterized by frequent duodenal involvement and a very indolent clinical behavior without therapy. Unlike nodal FL, there have been no reports of histologic transformation (HT) or death attributable to primary intestinal FL. Here, we report the first case of primary duodenal FL showing HT. A Grade 1 FL in the duodenum was incidentally detected in a 73-year-old man. A watch-and-wait strategy was adopted because the disease was stage IE. Six months later, bone marrow involvement was suspected. The intestinal lesions had not changed during the first year since the initial diagnosis. Sixty-two months after the initial diagnosis, a biopsy specimen showed diffuse large B-cell lymphoma (DLBCL). A perforation of the intestine occurred before chemotherapy was started. Partial resection was performed and subsequent chemotherapy was administered. The clone of the initial FL and DLBCL were identical according to PCR analysis, indicating that the primary intestinal FL had transformed into DLBCL. Although HT is rare, it could occur in some patients with primary intestinal FL. Based on this case, it may be necessary to re-evaluate the clinical watch-and-wait strategy for primary intestinal FL in some patients.

DOI： 10.1111/pin.12197

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Language：English   Publisher：SPRINGER JAPAN KK  

Mantle cell lymphoma (MCL) is a unique subtype of B-cell non-Hodgkin's lymphoma characterized by chromosomal translocation t(11;14)(q13;q32), positive CD5, and nuclear cyclin D1 overexpression with unfavorable prognosis. We report herein a case of MCL in a 73-year-old male diagnosed with diffuse large B-cell lymphoma (ileal tumor) at another hospital, who subsequently relapsed with CD5-negative MCL. At the 1st relapse, he developed neck lymph node swelling, of which biopsy showed proliferation of atypical large pleomorphic cells with CD5-negativity by both immunohistochemistry and flow cytometry. At the 2nd relapse, he again developed an ileal tumor, of which biopsy showed positivity for CD5, CD20, and cyclin D1. In MCL, CD5-negative expression has sometimes been reported as having pleomorphic and blastoid variants. The present case was also histologically the pleomorphic type, but the CD5 expression changed from negative at the onset and the 1st relapse to positive at the 2nd relapse. This is a rare and interesting case because of the different expression of CD5 at all stage. This phenomenon made the diagnosis of MCL difficult.

DOI： 10.1007/s00795-013-0060-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

IgG4-related disease is a systemic disorder with unique clinicopathological features and uncertain etiological features and is frequently related to allergic disease. T helper 2 and regulatory T-cell cytokines have been reported to be upregulated in the affected tissues; thus, the production of these cytokines by T helper 2 and regulatory T cells has been suggested as an important factor in the pathogenesis of IgG4-related disease. However, it is not yet clear which cells produce these cytokines in IgG4-related disease, and some aspects of the disorder cannot be completely explained by T-cell-related processes. To address this, we analyzed paraffin-embedded sections of tissues from nine cases of IgG4-related submandibular gland disease, five cases of submandibular sialolithiasis, and six cases of normal submandibular gland in order to identify potential key players in the pathogenesis of IgG4-related disease. Real-time polymerase chain reaction analysis confirmed the significant upregulation of interleukin (IL)4, IL10, and transforming growth factor beta 1 (TGF beta 1) in IgG4-related disease. Interestingly, immunohistochemical studies indicated the presence of mast cells expressing these cytokines in diseased tissues. In addition, dual immunofluorescence assays identified cells that were double-positive for each cytokine and for KIT, which is expressed by mast cells. In contrast, the distribution of T cells did not correlate with cytokine distribution in affected tissues. We also found that the mast cells were strongly positive for IgE. This observation supports the hypothesis that mast cells are involved in IgG4-related disease, as mast cells are known to be closely related to allergic reactions and are activated in the presence of elevated non-specific IgE levels. In conclusion, our results indicate that mast cells produce T helper 2 and regulatory T-cell cytokines in tissues affected by IgG4-related disease and possibly have an important role in disease pathogenesis.

DOI： 10.1038/modpathol.2013.236

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Cases of low-grade B-cell lymphoma presenting primarily in the bone marrow are rare, and its clinicopathology remains unclear. We retrospectively examined patients with low-grade B-cell lymphoma presenting primarily in the bone marrow. Fourteen patients met the inclusion criteria, including 5 with lymphoplasmacytic lymphoma (LPL), 3 with chronic lymphocytic leukemia/small lymphocytic lymphoma, 2 with follicular lymphoma (FL), and 4 with low-grade B-cell lymphoma not otherwise specified (LGBCL-NOS). The median age was 69.5 years (range, 42-89 years), and a slight male predominance was noted (9 men and 5 women, 1.8: 1). Immunohistochemically, all cases were positive for CD20. One case was positive for CD138. Both cases of FL were positive for CD10 and B-cell lymphoma 2 (BCL-2), and immunoglobulin heavy locus (IgH)/B-cell lymphoma 2 rearrangement was observed by fluorescence in situ hybridization. The myeloid differentiation primary response gene (88) leucine to proline mutation was observed in 3 of 5 LPL, 1 of 2 FL, and 2 of 4 LGBCL-NOS patients. Paraproteinemia was observed in 10 patients; IgM and IgG paraproteinemia were observed in 6 and 3 patients, respectively. In this patient series, 3 patients had died at a median follow-up of 36.5 months; the cause of death of 1 LPL patient was malignant lymphoma itself. Thus, low-grade B-cell lymphoma presenting primarily in the bone marrow has various subtypes, and approximately one-third of the patients had LGBCL-NOS. The immunophenotypic features and myeloid differentiation primary response gene (88) leucine to proline mutation data of LGBCL-NOS suggested that some cases present with characteristics similar to those of LPL or marginal zone lymphoma. (C) 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2014.02.010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

IgG4-related lymphadenopathy with increased numbers of Epstein-Barr virus (EBV)-infected cells has been reported but not fully described. We analyzed 31 cases of IgG4-related lymphadenopathy and 24 cases of extranodal IgG4-related diseases for their possible relationship with EBV. Other types of reactive lymph nodes (22) and angioimmunoblastic T-cell lymphoma (AITL) (10) were also studied for comparison. EBV-encoded RNA (EBER) in situ hybridization revealed EBER+ cells in 18 of 31 cases (58%) of IgG4-related lymphadenopathy. Increased EBER+ cells were found in only 4 of 22 (18.1%) non-IgG4-related reactive lymphoid hyperplasia in patients of a similar age (P = 0.002) and in only 5 of 24 (21%) extranodal IgG4-related biopsies (P = 0.006). Interestingly, all patients with EBER+ progressively transformed germinal center-type IgG4-related lymphadenopathy had systemic lymphadenopathy and/or extranodal involvement. AITL also is associated with EBV, and IgG4-related lymphadenopathy sometimes mimics the morphology of AITL; however, the number of IgG4(+) cells in AITL was significantly less than that in IgG4-related lymphadenopathy (P < 0.001). Increased numbers of regulatory T cells are seen in IgG4-related disease; however, there was not a significant difference between the EBER+ and EBER- cases. In conclusion, the presence of increased numbers of EBV-infected cells in IgG4-related lymphadenopathy, compared with other reactive lymphadenopathy or extranodal IgG4-related disease, suggests that there may be a relationship at least between nodal IgG4-related disease and EBV. It is important to avoid overdiagnosing these cases as malignant lymphomas or EBV-related lymphoproliferative disorders.

DOI： 10.1097/PAS.0000000000000206

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Invasive candidiasis has increased as nosocomial infection recently in cancer patients who receive systemic chemotherapy, and the timely risk assessment for developing such specific infection is crucial. Especially in those concomitantly with hypopituitarism, febrile neutropenia with candidiasis can cause severe stress and lead potentially to sudden fatal outcome when the temporal steroid coverage for the adrenal insufficiency is not fully administered. We report a 72-year-old male case diagnosed as non-small-cell lung cancer, Stage IIIA. He had received a steroid replacement therapy for the prior history of hypophysectomy due to pituitary adenoma with hydrocortisone of 3.3 mg/day, equivalent to prednisolone of 0.8 mg/day. This very small dosage of steroid was hardly supposed to weaken his immune system, but rather potentially led to an inappropriate supplementation of his adrenal function, assuming that the serum sodium and chlorine levels decreased. On Day 6 of second cycle of chemotherapy with carboplatin and paclitaxel, he developed sudden febrile neutropenia, septic shock and ileus, leading to death. After his death, the venous blood culture on Day 7 detected Candida albicans. Autopsy findings showed a massive necrotizing enterocolitis with extensive Candida invasion into submucous tissue. In conclusion, this case may suggest that (i) immediate initiation of antifungal therapy soon after the careful risk assessment of Candida infection and (ii) adequate administration of both basal steroid replacement therapy and temporal steroid coverage for febrile neutropenia might have improved his fatal outcome.

DOI： 10.1093/jjco/hyu019

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Langerhans cell (LC) sarcoma (LCS) is a high-grade neoplasm with overtly malignant cytologic features and an LC phenotype. We very recently suggested that LC behaves as a reservoir for common dermotropic Merkel cell polyomavirus (MCPyV) and determined the relationship between LC histiocytosis (LCH), which has an underlining oncogenic capacity, and MCPyV as a trigger for a reactive process rather than a neoplastic process. We propose LC to be a reservoir for MCPyV and hypothesize that some LCS subtypes may be related to the MCPyV agent.Findings: We examined seven LCS tissues using multiplex quantitative PCR (Q-PCR) and immunohistochemistry with anti MCPyV large-T (LT) antigen antibody. High viral loads of MCPyV DNA sequences (viral load = relative levels of MCPyV) were detected (0.328-0.772 copies/cell (Merkel cell carcinoma (MCC) = 1.0)) using Q-PCR in 43% (3/7) tissues, but LT antigen expression was not observed (0/7).Conclusions: Frequent MCPyV-DNA amplification suggests that LCS in some patients may be related to MCPyV infection. Moreover, the higher viral load of LCS (median, 0.453 copies/cell) than low load of LCH (0.003, median of 12 cases) (P < 0.01) may suggest a virally induced tumorigenic process in some LCS. Although the absence of LT antigen expression may indicate a different role for MCPyV in this pathology, some subtypes of LCS may develop in the background of MCPyV-infected LC. To the best of our knowledge, this is the first report on the relationship between MCPyV and LCS. The recent discovery of MCPyV opened new therapeutic avenues for MCC. These data open novel possibilities for therapeutic interventions against LCS.

DOI： 10.1186/1750-9378-9-15

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

The purpose of this study was to reveal the diagnostic accuracy of initial pathologic assessment of biopsied samples in patients with gastrointestinal follicular lymphoma lesions. A total of 48 patients with follicular lymphoma (Lugano system stage I: n = 30; II1: n = 4; II2: n = 4; IV: n = 10) with gastrointestinal involvement who underwent endoscopic biopsy were enrolled and retrospectively reviewed. Nine (18.8%) of the 48 patients were not appropriately diagnosed as having follicular lymphoma at the initial biopsy. The initial pathological diagnosis included extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (n = 4), necrotic tissue (n = 2), duodenitis (n = 1), or suspected lymphoma of unspecified subtype (n = 2). The reasons for these inappropriate diagnoses were insufficient histopathologic analysis lacking CD10 and BCL2 staining (n = 7) and unsuitable biopsy samples taken from erosions or ulcers that contained scanty lymphoma cells or no lymphoid follicles (n = 2). In conclusion, incomplete histopathologic analysis and unsuitable biopsy samples are pitfalls in the diagnosis of gastrointestinal follicular lymphoma. (c) 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.anndiagpath.2013.12.006

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：European Institute of Oncology  

An 80-year-old Japanese male was diagnosed with pulmonary adenocarcinoma. The patient exhibited extensive extra pulmonary involvement in the bone, adrenal gland, abdominal lymph nodes, and sigmoid colon. A single course of chemotherapy with carboplatin and pemetrexed was administered as the first-line treatment. Subsequently, the patient received pemetrexed monotherapy. Two months after the diagnosis, rapid regression of the metastatic tumour in the sigmoid colon was observed. Based on the findings of CT scanning and colonoscopic examination, tumour-bowel fistulisation was considered to be a cause of the rapid regression. This case report illustrates a tumour-bowel fistula of a colonic metastatic tumour in a patient with lung cancer. Radiographic and endoscopic features of the rare manifestation are presented. © the authors
licensee ecancermedicalscience.

DOI： 10.3332/ecancer.2014.412

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Objectives: Establish a correlation between serum soluble interleukin 2 receptor (sIL-2R) levels and clinical characteristics of follicular lymphoma patients with gastrointestinal involvement.Design and methods: Patients (n = 44) presenting with follicular lymphoma lesions in the gastrointestinal tract were enrolled into the study and divided into 2 groups based on sIL-2R levels (normal vs. elevated). Clinical characteristics were also analyzed between groups.Results: Patients with elevated sIL-2R levels likely had systemic follicular lymphoma involvement (Ann Arbor system staging IIIES/IV or Lugano system staging II-2/IV), involvement of 5 or more nodal areas, and presentation of bulky tumors in the gastrointestinal tract. These patients also presented a high Follicular Lymphoma International Prognostic Index (FLIPI) score, suggestive of poor prognosis. No differences were found among other clinical characteristics including sex, age at lymphoma diagnosis, histological grade, LDH levels, bone marrow involvement, hemoglobin levels, and identification of tracer accumulation in gastrointestinal lesions by positron-emission tomography scanning.Conclusions: sIL-2R levels can be used as an independent prognostic index in follicular lymphoma patients based on the correlation with the FLIPI score. Moreover, since high sIL-2R levels were associated with a large tumor bulk, sIL-2R may serve as a good indicator for monitoring disease relapse or progression. (C) 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

DOI： 10.1016/j.clinbiochem.2013.11.026

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

A 49-year-old female patient previously treated for scleritis and uveitis-induced cataract in the right eye presented with a subretinal white lesion in the same eye. With a preliminary diagnosis of choroidal tumor, enucleation of the eyeball was performed in accordance with the patient's request. Histologic and immunohistologic examinations were consistent with immunoglobulin G4-related disease. The case demonstrates that it is important to consider IgG4-related disease in the differential diagnosis of an intraocular tumor.

DOI： 10.3109/14397595.2013.852842

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Langerhans cell histiocytosis (LCH) is a group of granulomatous disorders in which abnormal Langerhans cells proliferate as either a localized lesion in a single bone or disseminated disease involving two or more organs or systems. Because the different LCH forms exhibit significantly elevated levels of inflammatory molecules, including pro-inflammatory cytokines and tissue-degrading enzymes, we investigated for a possible viral trigger in LCH pathogenesis. We looked for Merkel cell polyomavirus (MCPyV) in peripheral blood cells and tissues using quantitative real-time PCR and immunohistochemistry staining with anti-MCPyV large T-antigen antibody. Our findings revealed elevated amounts of MCPyV DNA in the peripheral blood cells of 2 of 3 patients affected by LCH with high-risk organ involvement (RO+) and absence of MCPyV DNA in the blood cells in all 12 LCH-RO-patients (P = .029). With lower viral loads (0.002-0.033 copies/cell), an elevated number of MCPyV DNA sequences was detected in 12 LCH tissues in comparison with control tissues obtained from patients with reactive lymphoid hyperplasia (0/5; P = .0007), skin diseases not related to LCH in children younger than 2 years (0/11; P = .0007), or dermatopathic lymphadenopathy (5/20; P = .0002). The data, including frequent but lower viral loads and low large-T antigen expression rate (2/13 LCH tissues), suggest that development of LCH as a reactive rather than a neoplastic process may be related to MCPyV infection. (C) 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2013.05.028

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Language：English   Publisher：JAPAN SOC INTERNAL MEDICINE  

DOI： 10.2169/internalmedicine.53.2433

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

A 69-year-old man underwent endoscopic mucosal resection of a solitary polyp located in the cecum. After the procedure, a fecal mass and appendiceal orifice appeared under the cut surface. A diagnosis of reactive lymphoid hyperplasia was made based on the results of an immunostaining analysis, which revealed a segregated population of T cells and B cells in multiple lymphoid follicles. The aggregation of adipocytes forming a lipomatous area and granulation tissue was also observed. We speculate that the compaction of the fecal mass in the appendix triggered mucosal inflammation, resulting in the formation of the polyp, which concealed both the feces and appendiceal orifice.

DOI： 10.2169/internalmedicine.53.1635

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Publisher：Hindawi Publishing Corporation  

DOI： 10.1155/2014/549248

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

A 30-year-old female patient presented with intestinal Epstein-Barr virus (EBV)-positive cytotoxic T-cell lymphoma (EBV+ CTL), which was surgically resected. Fourteen years later, she returned to our hospital with hypersensitivity to mosquito bites and was diagnosed with chronic active EBV infection-associated T/NK-cell lymphoproliferative disorder (CAEBV/TNK-LPD). She developed systemic EBV+ CTL at age 47 years during the 2.5-year clinical course of CAEBV/TNK-LPD, despite multiagent chemotherapy and allogeneic stem cell transplantation. Afterward, she had a rapidly deteriorating clinical course and died at age 48 years. The immunophenotype of the EBV+ CTL was consistently a CD3, CD8, and cytotoxic molecule-positive type with the same clonality in polymerase chain reaction analysis of T-cell receptor-gamma chain gene rearrangement. This is the first reported case of EBV+ CTL preceding the clinical presentation of CAEBV/TNK-LPD. The present case was unique in suggesting a close relationship between EBV+ CTL and chronic active EBV infection. (C) 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2013.05.025

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Polycomb group (PcG) proteins are important for the regulation of hematopoiesis by regulating chromatin compaction and silencing genes related to differentiation and cell cycle. Overexpression of enhancer of zeste homologue 2 (Ezh2) and Bmi-1/PCGF4 has been implicated in solid organ cancers, while Mel-18/PCGF2 has been reported as a tumor suppressor. Detailed expression profiles of PcG proteins and their diagnostic significance in malignant lymphomas are still unknown. In this study, we analyzed the expression levels of Ezh2, Bmi-1, Mel-18, and Ki67 in 197 Hodgkin's and non-Hodgkin's lymphoma patient samples and in lymphoma cell lines using immunohistochemistry, fluorescent immunocytochemistry, and Western blotting. Immunohistochemical staining showed that Ezh2 expression was significantly increased in aggressive compared to indolent subtypes of B cell neoplasms (P = 0.000-0.030), while no significant differences in Bmi-1 expression were found between these subtypes. Compared to the normal counterpart, T cell lymphomas showed significant overexpression of Bmi-1 (P = 0.011) and Ezh2 (P = 0.000). The Ki67 labeling index showed a positive correlation with Ezh2 expression in B cell lymphomas (correlation coefficient (Co) = 0.983, P = 0.000) and T/NK cell lymphomas (Co = 0.629, P = 0.000). Fluorescent immunohistochemical staining showed coexpression of Ezh2 and Ki67 in the same tumor cells, indicating that Ezh2 expression correlates with cell proliferation. Both B and T/NK cell neoplasms showed low expression of Mel-18 and high expression of both Bmi-1 and Ezh2. In conclusion, in aggressive lymphoma variants, Ezh2 is strongly expressed and polycomb repressive complex PRC1.4 dominates over PRC1.2. Coexpression of Bmi-1 and Ezh2 is a characteristic of aggressive lymphomas. Ezh2 correlates with the proliferation and aggressive nature of non-Hodgkin's lymphomas.

DOI： 10.1007/s00428-013-1428-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SCIENTIFIC PUBLISHERS INDIA  

A Japanese man in his mid-60s reported having a subcutaneous mass for a period of 8 months, after which it gradually enlarged in size and was surgically extirpated. The resected tumor was 10 x 8 mm in size, and the cut surface was smooth, solid, and whitish. Histological analysis revealed the presence of medium to large lymphoid cells that had proliferated to form a solid mass. The diffuse proliferating cells stained positive for CD20, CD79a, and CD5, but were negative for CD3, CD30, and CD10, and the MIB-1 index was very high. On the basis of these findings, the tumor was diagnosed as cutaneous CD5(+) diffuse large B cell lymphoma. Interestingly, detailed analysis revealed elastophagocytosis, with scattered, fragmented elastic fibers engulfed by macrophages that were intermixed with tumor cells. These macrophages were mostly multinucleated giant cells, apparently forming part of a foreign body-type reaction. Elastic fiber staining clearly revealed positively stained fragmented fibers in the cytoplasm of the macrophages, which were densely positive for CD68, in sharp contrast to the CD68-negative tumor cells. The final diagnosis was cutaneous CD5(+) diffuse large B cell lymphoma exhibiting unusual elastophagocytosis. The patient's clinical course was good, and the tumor disappeared completely after 3 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy with radiation.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma (BCLu-DLBCL/CHL), also known as gray-zone lymphoma, has overlapping clinical and biological characteristics of both diffuse large B-cell lymphoma and classical Hodgkin lymphoma (CHL). These lymphomas are typically associated with mediastinal disease, and extranodal involvement is rare. In the present report, we describe a case of a 78-year-old woman with BCLu-DLBCL/CHL found to have extranodal lesions and no evidence of mediastinal disease. Although biopsy specimens were histologically similar to nodular sclerosis CHL, the tumor cells were positive for CD30 and mature B-cell markers, such as CD20, CD79a, PAX5, BOB.1, and OCT-2, but negative for CD15. Furthermore, the patient had extranodal lesions and an increased level of soluble IL-2 receptor. These findings are unusual in CHL. Therefore, we diagnosed the patient with BCLu-DLBCL/CHL. She received adriamycin, bleomycin, vincristine, and dacarbazine therapy and exhibited partial response. Some cases without mediastinal disease, such as our case, have been reported; however, these cases are rare and further studies are required.

DOI： 10.1007/s00795-013-0038-8

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Language：Japanese   Publisher：Japan Gastroenterological Endoscopy Society  

The purpose of this study was to determine the endoscopic features of duodenal involvement in mantle cell lymphoma. Eleven patients with multiple protruding lesions were analyzed in this study. Macroscopically, multiple minute polyploid lesions, verrucous lesions, the mixed type of multiple minute polyploid lesions and verrucous lesions and submucosal tumor-like lesions were observed in 3, 3, 2 and 3 cases respectively. The multiple tiny polyploid lesions were not associated with erosive changes. Meanwhile, all verrucous lesions and submucosal tumor-like lesions presented with an erosive surface except for one verrucous lesion. In order to diagnose mantle cell lymphoma as early as possible, lesions in the duodenum presenting these endoscopic findings need to be biopsied.

DOI： 10.11280/gee.55.2167

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DOI： 10.4044/joma.125.103

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Other Link： http://ousar.lib.okayama-u.ac.jp/50806

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

The basic region-leucine zipper (bZip) factor BTB, CNC homology 2 (BACH2) is known to have important roles in class switch recombination and somatic hypermutation (SHM) of the immunoglobulin (Ig) gene. In this study, we investigated the relationship between the expression of BACH2 and the status of SHM of the Ig heavy chain gene variable region (IgHV) for SHM in diffuse large B-cell lymphoma (DLBCL). We examined 20 cases of DLBCL, 13 of which were germinal center B-cell (GCB) DLBCL and 7 were non-GCB DLBCL. Seven cases were negative, 6 were positive (cytoplasmic expression) and 7 were strongly positive (both nuclear and cytoplasmic expression) for BACH2. Confirmed mutation (CM) was identified in 8 cases and the CM index (number of confirmed mutations per 10 subclones) was distributed from 0 to 5. A CM index of 7 strongly positive (over-expression) cases with BACH2 were distributed from 0 to 5, and that of 7 negative and 6 positive cases were distributed from 0 to 1. Over-expression of BACH2 was statistically related to CM index (P = 0.008). In conclusion, over-expression of BACH2 is critical for ongoing SHM of IgHV in DLBCL, and our data suggest that BACH2 may play an essential role for SHM of the Ig gene in B-cell lymphoma.

DOI： 10.1111/pin.12076

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Language：English   Publisher：The Japanese Society for Lymphoreticular Tissue Research  

Ocular adnexal lymphoma may involve the eyelids, conjunctiva, orbital tissue, or lacrimal structures. The majority are non-Hodgkin's B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) lymphoma type. Follicular lymphomas represent a small percentage of ocular adnexa lymphomas, particularly in Japan. We report a 68-year-old female patient who presented with a salmon pink patch-like lesion of the left conjunctiva, suspected of being (MALT) lymphoma. However, histologic and immunohistologic examinations were consistent with follicular lymphoma. This case demonstrates the importance of considering such rare lymphomas when making a diagnosis of ocular adnexal lymphoid neoplasms. [<I>J Clin Exp Hematop 53(</I><I>1): 49-52,</I> <I>2013</I>]

DOI： 10.3960/jslrt.53.49

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Language：English   Publisher：W B SAUNDERS CO-ELSEVIER INC  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

D cyclins positively regulate the cell cycle and mediate the pathogenesis of some lymphomas. Cyclin D1 overexpression is the hallmark of mantle cell lymphoma, whereas cyclins D2 and D3 are reportedly not as specific to certain lymphomas as cyclin D1. In this study, cyclin D2 was found to be overexpressed in 98% of de novo CD5-positive diffuse large B-cell lymphomas (DLBCLs) (50/51) and in 28% of CD5-negative DLBCLs (14/51). A statistically significant difference was observed between these two groups (p<0.0001). In contrast, no statistical difference was found in the cyclin D3 expression between CD5-positive (18/51) and CD5-negative (24/51) DLBCLs (p=0.23). Based on these findings, cyclin D2 is therefore considered to be closely associated with de novo CD5-positive DLBCLs. This insight may be useful for overcoming the inferior survival of this aggressive lymphoma. Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1382856320966453

DOI： 10.1186/1746-1596-8-81

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We herein describe the case of a 40-year-old Japanese male who was admitted to our hospital because of a continuous remittent fever lasting 1 month. He fulfilled the items of the classification criteria for the diagnosis of systemic lupus erythematosus (SLE). The administration of 20 mg per day of oral prednisolone completely diminished his clinical symptoms. However, his renal biopsy performed 1 day after the admission showed marked pathognomonic characteristics. Not only did his glomeruli show class I lupus nephritis with mesangial depositions of IgG, IgA, C3, and C1q, but also tubulointerstitial nephritis with marked T-lymphocyte infiltration. These infiltrated T cells partly had nuclear atypia. The patient was positive for human T cell leukemia virus type 1 (HTLV-1) antibodies. Furthermore, clonal rearrangements of T cell receptor-gamma chain gene was detected in the DNA extracted from his kidney sections by the polymerase chain reaction (PCR) method. A second renal biopsy 6 months after the prednisolone treatment showed that the infiltrating T lymphocytes had markedly diminished. This is the first case report of lupus nephritis class I with tubulointerstitial nephritis, which might include oncogenic T lymphocytes, in an HTLV-1 positive patient.

DOI： 10.1007/s13730-012-0044-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

IgG4-related disease is a recently recognized systemic syndrome characterized by mass-forming lesions with lymphoplasmacytic infiltration, increase in the number of IgG4(+) cells in affected tissues and elevation of serum IgG4 levels. In 2009, we were the first to report skin lesions in patients with IgG4-related disease, but no large case series has been reported and clinicopathological findings remain unclear. To clarify these features, we herein report 10 patients (9 men and 1 woman; median age, 64 years; age range, 46-81 years) with IgG4-related skin disease. All patients had erythematous and itchy plaques or subcutaneous nodules on the skin of the head and neck, particularly in the periauricular, cheek, and mandible regions, except for one patient, whose forearm and waist skin were affected. In addition, eight patients had extracutaneous lesions: these were found on the lymph nodes in six patients, the lacrimal glands in three patients, the parotid glands in three patients, and the kidney in one patient. Histologically examined extracutaneous lesions were consistent with IgG4-related disease; five of six lymph node lesions showed progressively transformed germinal centers-type IgG4-related lymphadenopathy. Cases of IgG4-related skin disease were classified into two histological patterns: those exhibiting a nodular dermatitis pattern and those with a subcutaneous nodule pattern. The infiltrate was rich in plasma cells, small lymphocytes, and eosinophils; the majority of the plasma cells were IgG4(+.) The IgG4(+) cell count was 49-396 per high-power field (mean +/- s.d., 172 +/- 129), with an IgG4(+)/IgG(+) cell ratio ranging from 62 to 92%. Serum IgG4 levels were elevated in all examined patients. In conclusion, patients with IgG4-related skin disease had uniform clinicopathology. Lesions were frequently present on the skin of the periauricular, cheek, and mandible regions, and were frequently accompanied by IgG4-related lymphadenopathy. Modern Pathology (2013) 26, 523-532; doi:10.1038/modpathol.2012.196; published online 23 November 2012

DOI： 10.1038/modpathol.2012.196

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：EDITORIAL OFFICE GUT & LIVER  

The representative endoscopic features of primary intestinal follicular lymphoma are well known as small whitish polypoid nodules, but a magnified view has only been described in a few case reports. Herein, we report a case with intestinal follicular lymphoma in which magnifying endoscopy with narrow band imaging was helpful for prompt diagnosis. A 57-year-old Japanese woman underwent surveillance esophagogastroduodenoscopy. The endoscopic examination revealed confluent whitish granules in the duodenum, distinct from the nodules or polyps that are typical findings of intestinal follicular lymphoma. Magnifying endoscopy visualized whitish enlarged villi, and narrow band imaging emphasized an elongated and coiled vascular pattern. Based on these features, intestinal follicular lymphoma was highly suspected, and subsequent histological study confirmed the diagnosis. This case demonstrates that magnifying endoscopy with narrow band imaging was useful for the detection and prompt diagnosis of intestinal follicular lymphoma. The pathological features of intestinal follicular lymphoma are also discussed. (Gut Liver 2013;7:258-261)

DOI： 10.5009/gnl.2013.7.2.258

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Diffuse large B-cell lymphoma (DLBCL) comprises 2 molecularly distinct subgroups of non-germinal center B-cell-like (non-GCB) and germinal center B-cell-like (GCB) DLBCLs, with the former showing relatively poor prognosis. In the present study, we analyzed the clinicopathological features of 39 patients with localized nasal/paranasal DLBCL. Immunohistochemistry-based subclassification revealed that 11 patients (28%) were of the GCB-type according to Hans' algorithm and 11 (28%) were of the GCB-type according to Choi's algorithm. According to both Hans' and Choi's algorithms, the non-GCB type was predominant. Nevertheless, prognosis was good. Overall survival did not differ significantly between the GCB and non-GCB subgroups (Hans' algorithm: p = 0.57, Choi's algorithm: p = 0.99). Furthermore, the prognosis of localized nasal/paranasal DLBCL was better than that of other localized extranodal DLBCLs. The prognosis of extranodal DLBCL is usually considered poorer than that of nodal DLBCL. However, in our study, no difference was noted between patients with localized nasal/paranasal DLBCL and patients with localized nodal DLBCL. In conclusion, although the non-GCB subtype is thought to show poor prognosis, in our study, the prognosis for localized nasal/paranasal DLBCL patients was good irrespective of subclassification.

DOI： 10.1371/journal.pone.0057677

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A negative regulator of the nuclear factor (NF)-kappa B pathway, A20 (TNFAIP3), is inactivated in several types of lymphomas; particularly in diffuse large B-cell lymphoma (DLBCL), classical Hodgkin's lymphoma, and extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue. These findings suggest that the NF-kappa B activation is related to A20 inactivation. Recently, A20 inactivation has also been observed in Epstein-Barr virus (EBV)-related lymphomas; however, this occurrence has not been well investigated. Moreover, NF-kappa B is a key molecule in activated B-cell-like (ABC)-type DLBCL; EBV-associated DLBCL is of the ABC type. Therefore, we focused on A20 deletions in EBV-associated lymphoproliferative disorders/lymphomas. Using fluorescent in situ hybridization analysis, A20 deletions were identified in 4 of 13 samples from patients with pyothorax-associated lymphoma (PAL) (31%), 3 of 20 samples from nasal-type NK/T cell lymphomas (NKTLs) (15%), 1 of 8 samples of EBV-positive DLBCL of the elderly (DLBCL-e) (13%), but not in any of the 11 samples from individuals with methotrexate-related lymphoproliferative disorder (MTX-LPD) (0%). Among the samples with A20 deletions, EBV latent membrane protein 1 (LMP-1) expression was detected in all 4 of the PAL samples with A20 deletions and in the DLBCL-e sample with an A20 deletion, but not in any of the 3 NKTL samples. This finding indicated that A20 deletions were not directly related to the EBV latency pattern of lymphomas, although such deletions might be related to the diagnostic category. Immunohistologically, the A20 protein was absent in 2 (15%) of the13 PAL samples, 1 (9%) of 11 MTX-LPD samples, and in none of the 20 NKTL (0%) or 8 DLBCL-e samples. In conclusion, A20 deletion and/or dysfunctional expression are frequently associated with PALs, and A20 abnormalities may be related to the pathogenesis of PAL.

DOI： 10.1371/journal.pone.0056741

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

Langerhans cell histiocytosis (LCH) is a lymphoproliferative disorder consisting of abnormal Langerhans cell-like cells and other lymphoid cells. LCH presents as either a multisystem LCH (LCH-MS) or a single-system LCH (LCH-SS). Currently, neither the pathogeneses nor the factors that define these disease subclasses have been elucidated. The interleukin (IL)-17A autocrine LCH model and IL-17A-targeted therapies have been proposed and have engendered much controversy. Those authors showed high serum IL-17A levels in LCH and argued that serum IL-17A-dependent fusion activities in vitro, rather than serum IL-17A levels, correlated with LCH severity (i.e. the IL-17A paradox). In contrast, others could not confirm the IL-17A autocrine model. So began the controversy on IL-17A, which still continues. We approached the IL-17A controversy and the IL-17A paradox from a new perspective in considering the expression levels of IL-17A receptor (IL-17RA). We detected higher levels of IL-17RA protein expression in LCH-MS (n = 10) as compared to LCH-SS (n = 9) (P = 0.041) by immunofluorescence. We reconfirmed these data by re-analyzing GSE16395 mRNA data. We found that serum levels of IL-17A were higher in LCH (n = 38) as compared to controls (n = 20) (P = 0.005) with no significant difference between LCH subclasses. We propose an IL-17A endocrine model and stress that changes in IL-17RA expression levels are important for defining LCH subclasses. We hypothesize that these IL-17RA data could clarify the IL-17A controversy and the IL-17A paradox. As a potential treatment of LCH-MS, we indicate the possibility of an IL-17RA-targeted therapy.

DOI： 10.1007/s00428-012-1360-6

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A 69-year-old Japanese female was diagnosed with primary intestinal follicular lymphoma. Esophagogastroduodenoscopy with high-definition imaging revealed not only the typical feature of whitish polyps of up to 2 mm in diameter in the duodenal second and third portions, but also more detailed morphology, such as enlarged whitish villi and tiny whitish depositions. These findings appeared to reflect the pathological structures; infiltration of lymphoma cells into the villi were probably seen as enlargement of the villi, and the formation of lymphoid follicles were shown as opaque white spots or tiny white depositions. Thus, the above features might contribute to the distinct diagnosis of intestinal follicular lymphoma. This case indicates that routine esophagogastroduodenoscopy can visualize microsurface structures, which can be pathognomonic and help to diagnose intestinal follicular lymphoma, even without magnifying endoscopy.

DOI： 10.4253/wjge.v5.i1.34

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

Objective: We examined the usefulness of light-chain restriction (LCR) on immunocytochemical double staining (IDS) for cytological diagnosis. Study Design: We investigated LCR on IDS in 40 patients with proliferative lymphatic disorders (23 with B cell lymphoma, 13 with reactive lymphoid lesions, 2 with T cell lymphoma and 2 with Hodgkin's lymphoma). In addition, the results of flow cytometry (FCM) were compared in 34 of these patients. Results: On IDS, LCR was detected in 21 of 23 patients (91.3%) with B cell lymphoma. On FCM, it was detected in 15 of 21 patients (71.4%) with B cell lymphoma. Neither IDS nor FCM showed LCR in any patients with reactive lesions, T cell lymphoma or Hodgkin's lymphoma. Conclusion: IDS facilitated the detection of LCR with a single specimen under morphological observation. The application of this procedure may improve the accuracy of cytological diagnosis. Copyright 2012 S. Karger AG, Basel

DOI： 10.1159/000342475

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

A 73-year-old Japanese man with synchronous follicular lymphoma and adenocarcinoma of the stomach underwent curative surgical resection. The follicular lymphoma lesion was preoperatively diagnosed as extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) according to biopsy samples. However, postoperative pathological evaluations revealed components of CD10-positive and CD10-negative lymphoma cells within the lymphoma lesion. This case highlights the potential difficulty of diagnosing gastric follicular lymphoma. In such cases, conducting repeat pathological examinations of biopsy samples or resected specimens is required to obtain a correct diagnosis of follicular lymphoma.

DOI： 10.2169/internalmedicine.52.7948

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Recently, atypical Castleman's disease (CD) was reported in Japan. This disease is considered as TAFRO syndrome or non-idiopathic plasmacytic lymphadenopathy (IPL), a constellation of clinical symptoms, namely, thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly without hyper-γ-globulinemia. Histopathologically, this disease is similar to hyaline vascular (HV)-type CD. Here, we present a 43-year-old Japanese woman meeting the clinical criteria of TAFRO syndrome who was successfully treated with combined corticosteroid therapy. She showed a rapidly progressive course of thrombocytopenia, systemic lymphadenopathy, fever, anasarca, and increase in acute inflammatory proteins without hyper-γ-globulinemia. Lymph node biopsy was performed and revealed HV-type CD without human herpes virus 8 infection, which was clinicopathologically compatible with non-IPL. The association of these atypical features with well-known multicentric Castleman's disease (MCD), namely, HV-type histology with systemic lymphadenopathy, marked thrombocytopenia even with a high level of interleukin-6, and increased acute inflammatory proteins without hyper-γ-globulinemia, suggests that TAFRO syndrome as presented in our case is a novel entity, which may have been diagnosed as MCD in the past. To define this novel entity more clearly and to demonstrate its etiology, further nationwide surveys of this syndrome and MCD are needed.

DOI： 10.3960/jslrt.53.87

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：S. Karger AG  

Among duodenal tumors, lymphangioma is relatively infrequent. In this case report, we describe the case of a 65-year-old Japanese man with duodenal lymphangioma diagnosed by esophagogastroduodenoscopy. Endoscopically, the tumor appeared as a soft submucosal tumor with white spots. When the white spots were grasped by biopsy forceps, milky liquid exuded from the tumor. Additionally, observation by a magnifying endoscope with narrow-band imaging revealed elongated microvessels on the surface. We speculated that this feature was formed because the duodenal villi were dilated and the microvessels were stretched due to the retention of chyle. These endoscopic findings are key features in the diagnosis of duodenal lymphangioma.

DOI： 10.1159/000351831

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Publisher：Hindawi Publishing Corporation  

DOI： 10.1155/2013/930918

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Language：English   Publisher：AMER SOC HEMATOLOGY  

DOI： 10.1182/blood.V120.21.5107.5107

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BAISHIDENG PUBL GRP CO LTD  

AIM: To investigate the capacity for 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) to evaluate patients with gastrointestinal lesions of follicular lymphoma.METHODS: This retrospective case series consisted of 41 patients with follicular lymphoma and gastrointestinal involvement who underwent 18F-FDG-PET and endoscopic evaluations at ten different institutions between November 1996 and October 2011. Data for endoscopic, radiological, and biological examinations performed were retrospectively reviewed from clinical records. A semi-quantitative analysis of 18F-FDG uptake was performed for each involved area by calculating the maximum standardized uptake value (SUVmax). Based on the positivity of 18F-FDG uptake in the gastrointestinal lesions analyzed, patients were subdivided into two groups. To identify potential predictive factors for 18F-FDG positivity, these two groups were compared with respect to gender, age at diagnosis of lymphoma, histopathological grade, pattern of follicular dendritic cells, mitotic rate, clinical stage, soluble interleukin-2 receptor levels detected by 18F-FDG-PET, lactate dehydrogenase (LDH) levels, hemoglobin levels, bone marrow involvement, detectability of gastrointestinal lesions by computed tomography (CT) scanning, and follicular lymphoma international prognostic index (FLIPI) risk.RESULTS: Involvement of follicular lymphoma in the stomach, duodenum, jejunum, ileum, cecum, colon, and rectum was identified in 1, 34, 6, 3, 2, 3, and 6 patients, respectively. No patient had esophageal involvement. In total, 19/41 (46.3%) patients exhibited true-positive 18F-FDG uptake in the lesions present in their gastrointestinal tract. In contrast, false-negative 18F-FDG uptake was detected in 24 patients (58.5%), while false-positive 18F-FDG uptake was detected in 5 patients (12.2%). In the former case, 2/19 patients had both 18F-FDG-positive lesions and 18F-FDG-negative lesions in the gastrointestinal tract. In patients with 18F-FDG avidity, the SUVmax value of the involved gastrointestinal tract ranged from 2.6 to 17.4 (median: 4.7). For the 18F-FDG-negative (n = 22) and -positive (n = 19) groups, there were no differences in the male to female ratios (10/12 vs 4/15, P = 0.186), patient age (63.6 +/- 2.4 years vs 60.1 +/- 2.6 years, P = 0.323), presence of histopathological grade 1 vs 2 (20/2 and 17/2, P = 1.000), follicular dendritic cell pattern (duodenal/nodal: 13/5 vs 10/3, P = 1.000), mitotic rate (low/ partly high, 14/1 vs 10/3, P = 0.311), clinical stage according to the Ann Arbor system (stages I E and II E/other, 15/7 vs 15/4, P = 0.499), clinical stage according to the Lugano system (stages I and II-1/other, 14/8 vs 14/5, P = 0.489), soluble interleukin-2 receptor levels (495 +/- 78 vs 402 +/- 83, P = 0.884), LDH levels (188 +/- 7 vs 183 +/- 8, P = 0.749), hemoglobin levels (13.5 +/- 0.3 vs 12.8 +/- 0.4, P = 0.197), bone marrow involvement (positive/negative, 1/8 vs 1110, P = 1.000), detectability by CT scanning (positive/negative, 1/16 vs 4/13, P = 0.335), and FLIPI risk (low risk/other, 16/6 vs 13/6, P = 0.763), respectively in each case.CONCLUSION: These findings indicate that it is not feasible to predict 18F-FDG-avidity. Therefore, 18F-FDG-PET scans represent a complementary modality for the detection of gastrointestinal involvements in follicular lymphoma patients, and surveillance of the entire gastrointestinal tract by endoscopic examinations is required. (C) 2012 Baishideng. All rights reserved.

DOI： 10.3748/wjg.v18.i44.6427

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BAISHIDENG PUBL GRP CO LTD  

AIM: To compare the clinicopathological characteristics of human epidermal growth factor receptor 2 (HER2)-positive and HER2-negative Barrett's adenocarcinoma in Japan.
METHODS: We performed immunohistochemical analysis of HER2 in 30 samples taken from patients with Barrett's adenocarcinoma and dual color in situ hybridization in cases showing 2+ reactions. We compared the clinicopathological characteristics of HER2-positive and HER2-negative patients.
RESULTS: HER2 positivity was identified in 8 (27%) carcinoma samples. We found that HER2 expression was associated with p53 overexpression (100% vs 52.6% in pT1 tumor; 100% vs 54.5% in all stage tumor, P &lt; 0.05) and protruding lesions at the early disease stage. There was no association between the mucin phenotype of the carcinomas and prognosis. HER2 expression and low clinical stage were unexpectedly different between Barrett's adenocarcinoma patients and gastric cancer patients, but the macroscopic features may be associated with earlier diagnosis in these patients.
CONCLUSION: Our results suggest that HER2-positive Barrett's adenocarcinomas are associated with p53 overexpression and lesion protrusion at the early disease stage. (C) 2012 Baishideng. All rights reserved.

DOI： 10.3748/wjg.v18.i43.6263

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Progressively transformed germinal centers is a benign condition of unknown pathogenesis characterized by a distinctive variant form of reactive follicular hyperplasia in lymph nodes. We recently reported Ig G4-related disease in progressively transformed germinal centers. However, no large case series has been reported and clinicopathologic findings remain unclear. Here, we report 40 Japanese patients (28 men, 12 women; median age, 56 years) with progressively transformed germinal centers of the lymph nodes who fulfilled the histological diagnostic criteria for IgG4-related disease (IgG4(+) progressively transformed germinal centers), with asymptomatic localized lymphadenopathy involving the submandibular nodes in 24, submandibular and cervical nodes in 14, cervical nodes only in 1, and cervical and supraclavicular nodes in 1. In all, 16 (52%) of 31 examined patients had allergic disease. Histologically, the lymph nodes demonstrated uniform histological findings, namely marked follicular hyperplasia with progressively transformed germinal centers, and localization of the majority of IgG4(+) plasma cells in the germinal centers. Serum IgG4, serum IgE and peripheral blood eosinophils were elevated in 87%, 92% and 53% of examined patients, respectively. Eighteen patients subsequently developed extranodal lesions (including five who developed systemic disease), which on histological examination were consistent with IgG4-related disease. IgG4(+) progressively transformed germinal centers presents with uniform clinicopathological features of asymptomatic localized submandibular lymphadenopathy, which persists and/or relapses, and sometimes progresses to extranodal lesions or systemic disease. Nine patients were administered steroid therapy when the lesions progressed, to which all responded well. We suggest that IgG4+ progressively transformed germinal centers should be included in the IgG4-related disease spectrum. Modern Pathology (2012) 25, 956-967; doi:10.1038/modpathol.2012.54; published online 6 April 2012

DOI： 10.1038/modpathol.2012.54

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Language：English   Publisher：The Japanese Society for Lymphoreticular Tissue Research  

IgG4-related disease is a recently proposed clinical entity with several unique clinicopathological features. A chronic inflammatory state with marked fibrosis, which can often be mistaken for malignancy, especially by clinical imaging analyses, unifies these features. In the present report, we describe a case of IgG4-producing mucosa-associated lymphoid tissue lymphoma mimicking IgG4-related disease. The patient was a 55-year-old male who was being followed for right orbital tumor over 1.5 years. The lesion had recently increased in size, so a biopsy was performed. Histologically, the lesion was consistent with IgG4-related disease ; however, IgG4<SUP>+</SUP> plasma cells showed immunoglobulin light-chain restriction and immunoglobulin heavy chain gene rearrangement was detected in the lesion. Therefore, the lesion was diagnosed as IgG4-producing mucosa-associated lymphoid tissue lymphoma. In conclusion, in histological diagnosis of IgG4-related disease, it is important to examine not only IgG4-immunostain but also immunoglobulin light-chain restriction. [<I>J Clin Exp Hematopathol 52(1</I><I>) : 51-55, 2012</I>]

DOI： 10.3960/jslrt.52.51

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DOI： 10.1158/1538-7445.AM2012-3132

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Accurate diagnosis of lymphoma includes the assessment of lineage-specific markers. Hematopoietic and lymphoid tissues express PAX5 exclusively in pro-B-cell to mature B-cell stages. However, some mature PAX5+ T-cell lymphomas have been reported. We report three cases of primary cutaneous CD30+ T-cell lymphoproliferative disorders (LPDs) with PAX5 expression: one cutaneous anaplastic large cell lymphoma (ALCL) and two cases of lymphomatoid papulosis (LyP). The three patients were 26 years old and female, 75 years old and female, and 65 years old and male. In all cases, Hodgkin's and Reed-Sternberg-like large lymphoid cells were present, positive for CD30, fascin, and PAX5, and negative for CD3, CD4, CD8, CD20, CD45RO, CD56, cytotoxic markers, and Epstein-Barr virus. The ALCL was accompanied by lymphadenopathy; the patient died of progressive disease 5 months after diagnosis. The LyP cases were localized in the skin with spontaneous regression. One case was diagnosed during pregnancy, transformed to ALCL, and ended in death 32 months after diagnosis despite multi-agent chemotherapy. This study is the first to address the clinical significance of PAX5+ primary cutaneous CD30+ T-cell LPDs. These cases were distinct regarding PAX5 expression and a relatively aggressive clinical course versus conventional primary cutaneous CD30+ T-cell LPDs.

DOI： 10.1111/j.1440-1827.2011.02784.x

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Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2012-1034

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

A 52-year-old Japanese woman was diagnosed with primary follicular lymphoma of the duodenum that was curatively resected by pancreatoduodenectomy. She remained in complete remission until 11 years after the surgery, when multiple enlarged intra-abdominal lymph nodes were demonstrated by computed tomography scans and positron emission tomography scans. Two years later, jejunal lesions were detected by endoscopy, and biopsy samples confirmed a recurrence of follicular lymphoma. This case indicates that primary gastrointestinal follicular lymphoma has a potential of relapse after an extended period of time, and thus patients must be followed up for over 10 years after complete remission.

DOI： 10.2169/internalmedicine.51.7060

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER GMBH  

Castleman's disease, an uncommon lymphoproliferative disorder, can be difficult to differentiate from immunoglobulin (Ig) G4-related disease. The latter is typically characterized by elevated serum IgG4 levels and abundant IgG4-positive cells. However, multicentric Castleman's disease can also have elevated serum IgG4 levels and even fulfill the histological diagnostic criteria for IgG4-related disease. We present a case of cutaneous multicentric Castleman's disease mimicking IgG4-related disease. A 55-year-old Japanese woman developed erythematous and brown plaques on her back. Skin biopsy revealed regressive follicles with interfollicular plasmacytosis, and many plasma cells were positive for IgG4 (mean 263.67 +/- 79.19, range 214-355 per high power field). The IgG4-/IgG-positive cell ratios were 35.6%, 36.2%, and 48.4%, respectively, with an average of 40.6%, thus fulfilling the histological diagnostic criteria for IgG4-related disease. Furthermore, serum IgG4 level was significantly elevated (1490 mg/dl; normal range: 4.8-105 mg/dl). However, laboratory findings of anemia, hypoalbuminemia, polyclonal gammaglobulinemia, high C-reactive protein level, and elevated serum interleukin-6 level were consistent with hyper-IL-6 syndrome. Hence, the diagnosis of cutaneous multicentric Castleman's disease was made. In conclusion, IgG4-related disease cannot be differentiated from hyper-IL-6 syndromes on histology alone. Instead, laboratory analyses are necessary to distinguish between the two diseases. (c) 2012 Elsevier GmbH. All rights reserved.

DOI： 10.1016/j.prp.2012.09.006

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Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma. Although many investigations have been performed on the prognostic factors of DLBCL, no reports have focused on localized nodal DLBCL. We examined the prognostic significance of 39 Japanese patients with localized nodal DLBCL with special reference to the germinal center B-cell-like (GCB) versus non-germinal center B-cell-like (NGCB) types. The median age was 65 years with 23 males and 16 females. Using Hans algorithm of immunohistochemistry, 18 patients (46%) exhibited GCB type and 21 (54%) exhibited NGCB type. Twenty-nine patients (74%) presented with disease in the neck (neck group) and 10 (26%) had disease in non-neck regions (non-neck group). Comparing Hans, Choi, and Muris algorithms, patients with GCB type showed statistically significant progression-free survival (PFS) only with Hans algorithm (P = 0.022, P = 0.100, and P = 0.130, respectively). Patient survival analyses revealed that GCB-type patients by Hans algorithm had a better PFS (P = 0.012), and neck-group patients had better PFS and overall survival (OS) (P = 0.018 and P = 0.012, respectively). Univariate analysis revealed that only neck vs. non-neck exhibited a significant difference in terms of OS (P = 0.026). Multivariate analysis revealed that GCB type by Hans algorithm and neck vs. non-neck were significantly different in terms of PFS (P = 0.025 and P = 0.033, respectively). Therefore, the subclassifications of GCB type vs. NGCB type and neck vs. non-neck are important predictive prognostic factors in localized nodal DLBCL.

DOI： 10.3960/jslrt.52.91

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Hindawi Limited  

A 52-year-old Japanese woman who was eventually diagnosed with primary follicular lymphoma of the duodenum showed atypical endoscopic features, namely, erosions with peripheral whitish edematous mucosa. Initial biopsy specimens taken from the erosions revealed insufficient numbers of lymphoma cells for histological diagnosis. Subsequent biopsy specimens from the peripheral mucosa containing the whitish enlarged villi showed infiltration of the lymphoma cells forming lymphoid follicles, which led us to the appropriate diagnosis. This case indicates that endoscopists should take biopsy samples from the peripheral mucosa with whitish enlarged villi rather than erosions in the rare instances that erosions appear as the main macroscopic feature of intestinal follicular lymphoma. Copyright © 2012 Keiko Takeuchi et al.

DOI： 10.1155/2012/582607

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

Diffuse large B-cell lymphoma (DLBCL) rarely involves the duodenum, and its clinicopathological characteristics have not been well elucidated. We performed clinicopathological examinations and identified 15 patients with duodenal DLBCL using 18 gastric or colonic DLBCL as a control. Eleven of the 15 patients (73%) were subclassified by immunohistochemical analysis according to the Choi algorithm as germinal center B-cell-like (GCB) type, whereas the 18 control gastric and colonic DLBCL were predominantly subclassified as activated B-cell-like (ABC) type. The classifications according to organ involvement were statistically significant (P= 0.011 and P= 0.035). Macroscopically, the GCB lesions were varied, while all ABC lesions were ulcerative. Fluorescence in situ hybridization analysis revealed a higher frequency of t(14;18) translocation in patients with duodenal DLBCL (3 of 13) as compared with non-duodenal gastrointestinal tract DLBCL (0 of 18), however, the difference was not significant (P = 0.064). Furthermore, the three patients with t(14;18) translocations were classified as GCB. In addition, overall survival of patients was statistically different between those with and without t(14;18) translocation (P= 0.040). In conclusion, duodenal DLBCL predominantly exhibits GCB-type tumors and the frequency of t(14;18) translocation appears to be higher in duodenal GCB-type DLBCL compared to non-duodenal tumors.

DOI： 10.1111/j.1440-1827.2011.02748.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Follicular lymphoma is the most common low-grade lymphoma and it frequently presents with a systemic disease, often showing advanced clinical stage (III/IV). The lymphoma cells are usually growing associated with follicular dendritic cell (FDC) networks. Abnormal FDC networks have been reported in duodenal follicular lymphoma, in which cases exhibit lower clinical stages than the nodal cases. In the present study, we analyzed the FDC network distribution pattern of 242 nodal follicular lymphomas by immunohistochemistry. Out of the 242 cases, 27 cases (11%) demonstrated an atypical pattern of FDC networks, in which the CD21 staining totally or partially disappeared in the neoplastic follicles. Furthermore, we compared the clinical data of these 27 cases and 58 typical FDC network cases of follicular lymphoma. We found that in the typical cases, 52 out of 58 patients (90%) showed advanced clinical stage (III or IV), whereas 10 of 27 (37%) atypical FDC network cases showed localized clinical stage (I or II) (P < 0.01). In conclusion, nodal follicular lymphoma with total loss or partially disrupted FDC networks therefore show a lower clinical stage.

DOI： 10.1111/j.1440-1827.2011.02736.x

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

The D cyclins are important cell cycle regulatory proteins involved in the pathogenesis of some lymphomas. Cyclin D1 overexpression is a hallmark of mantle cell lymphoma, whereas cyclins D2 and D3 have not been shown to be closely associated with any particular subtype of lymphoma. In the present study, we found that cyclin D2 was specifically overexpressed in the proliferation centers (PC) of all cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) examined (19/19). To examine the molecular mechanisms underlying this overexpression, we immunohistochemically examined the expression of nuclear factor (NF)-kappa B, p15, p16, p18, and p27 in the PC of six patients. Five cases showed upregulation of NF-kappa B expression, which is known to directly induce cyclin D2 by binding to the promoter region of CCND2. All six PC examined demonstrated downregulation of p27 expression. In contrast, upregulation of p15 expression was detected in five of six PC examined. This discrepancy suggests that unknown cell cycle regulatory mechanisms involving NF-kappa B-related pathways are also involved, because NF-kappa B upregulates cyclin D2 not only directly, but also indirectly through c-Myc, which is believed to downregulate both p27 and p15. In conclusion, cyclin D2 is overexpressed in the PC of CLL/SLL and this overexpression is due, in part, to the upregulation of NF-kappa B-related pathways. (Cancer Sci 2011; 102: 2103-2107)

DOI： 10.1111/j.1349-7006.2011.02046.x

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Language：English   Publisher：(一社)日本癌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

Immunoglobulin (Ig) G4-related disease has been recently described. This disease affects various organs, including lymph nodes. We describe the case of a 52-year-old Japanese man with IgG4-related lymphadenopathy with inflammatory pseudotumor (IPT)-like features. Five years ago, the patient noticed a painless mass in the mandible but did not consult a doctor. Recently, he noted that the mass had increased in size and consulted an oral surgeon in the hospital. Excisional biopsy was performed for diagnosis. Histopathological examination revealed that most of the enlarged lymph node was occupied by the hyalinized tissue. A few residual lymphoid follicles with hyperplastic germinal centers and infiltration of plasma cells and eosinophils were observed. Most of the plasma cells expressed IgG4, and the ratio of IgG4-positive cells to IgG-positive cells was 57.1%. These findings were consistent with IgG4-related lymphadenopathy. In conclusion, pathologists should consider IgG4-related lymphadenopathy when diagnosing a lesion with IPT-like features.

DOI： 10.1007/s00795-010-0525-0

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Language：Japanese   Publisher：(一社)日本リンパ網内系学会  

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Language：English   Publisher：W B SAUNDERS CO-ELSEVIER INC  

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Language：Japanese   Publisher：(一社)日本病理学会  

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

The CD79 molecule, encoded by the CD79a and CD79b genes, is a signaling unit of the B-cell receptor complex, which transmits signals of B-cell activation, growth, and differentiation. They are B-cell-specific and expressed at most stages of B-cell development. Although plasma cells have been believed to lack these gene products, the regulation of CD79 expression in plasma cells is still controversial. In particular, the regulation of CD79b expression remains unclear. We sought to examine CD79b expression in normal and neoplastic plasma cells by immunohistochemical analysis. Out of the 23 clinical samples and 11 cell lines of plasma cell myeloma (PCM), none of the clinical samples and only 1 of 11 cell lines expressed CD79b immunohistologically, whereas non-neoplastic plasma cells in reactive hyperplastic lymph nodes exhibited loss of CD79b protein expression. This finding is quite different from our previous report on CD79a. Not only immunocytochemistry, but also RT-PCR and Western blot analysis of PCM cell lines gave identical results. Interestingly, we detected mRNA transcripts of CD79b in PCM cell lines, although protein translation was lacking. These findings suggest that expression of CD79b is downregulated in both plasma cells and plasma cell myeloma, and this process is possibly under post transcriptional regulation.

DOI： 10.1111/j.1440-1827.2010.02634.x

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER GMBH, URBAN & FISCHER VERLAG  

Lymphomatoid gastropathy (LyGa) is a new evolving pathological entity that has been introduced recently. It is designated to describe CD56-positive atypical gastric lymphoid proliferation, mimicking NK/T cell lymphomas, that shows an indolent clinical course with spontaneous regression. We here present our experience with one new case diagnosed and treated in our hospital. An annual upper endoscopic check-up of a 50-year-old male with an unremarkable past history revealed a small reddish lesion on the posterior wall of the gastric angle. Endoscopic biopsy showed atypical cells of NK-cell lineage expressing CD56, CD16, CD3, perforin, and TIA-1, but not CD4, CD5, and CD8. Epstein-Barr virus encoded RNA was negative. The lesion regressed spontaneously after one month without treatment, but recurred two years later in a different site of the stomach with spontaneous regression again one month later. The recurrence of lymphomatoid gastropathy is very rare and should be diagnosed carefully to distinguish it from the aggressive lymphoma. (C) 2011 Elsevier GmbH. All rights reserved.

DOI： 10.1016/j.prp.2011.09.012

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMJ PUBLISHING GROUP  

Background Differentiation between multicentric Castleman's disease and systemic immunoglobulin (Ig) G4-related lymphadenopathy is sometimes difficult. It has been suggested that measurement of the IgG4-/IgG-positive cell ratio is useful for the differential diagnosis of the two diseases. However, the authors present a detailed report of six patients with multicentric Castleman's disease with abundant IgG4-positive cells (IgG4-/IgG-positive cell ratio, >40%).Results In the present series, the patients showed systemic lymphadenopathy, polyclonal hypergammaglobulinaemia and elevated serum interleukin-6 (IL-6) and C-reactive protein levels. Further, anaemia, hypoalbuminaemia, hypocholesterolaemia and thrombocytosis were observed. These findings were consistent with those of multicentric Castleman's disease. Although five patients showed elevated serum IgG4 levels, only two patients showed an increased serum IgG4/IgG ratio. However, the two patients showed highly elevated serum IgG4 levels, but the serum IgG4/IgG ratios were, although increased, not very high. Also, a patient with increased serum IgG4/IgG ratio showed a good response to antihuman IL-6 receptor monoclonal antibody (tocilizumab). Histologically, the germinal centres were mostly small and regressive, and frequently penetrated by hyalinised blood vessels, and there was no eosinophil infiltration. These findings were different from those of IgG4-related lymphadenopathy.Conclusions The authors conclude that multicentric Castleman's disease sometimes occurs with abundant IgG4-positive cells and elevated serum IgG4 levels. Therefore, the two diseases cannot be differentially diagnosed by immunohistochemical staining alone. Laboratory findings, especially IL-6 level, C-reactive protein level and platelet count, are important for the differential diagnosis of the two diseases.

DOI： 10.1136/jcp.2010.082958

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Language：English   Publisher：The Japanese Society for Lymphoreticular Tissue Research  

B-cell activating factor receptor (BAFF-R) is one of three known receptors for BAFF. BAFF-R is required for B-cell maturation and survival. We tried to determine the normal pattern of BAFF-R expression in non-neoplastic and neoplastic B- and T-cells. We used immunohistochemistry to evaluate the expression pattern of BAFF-R in non-neoplastic and neoplastic lymphoid tissues of routinely fixed paraffin-embedded samples, and examined the relationships among BAFF-R and expressions of CD10, bcl-6, MUM-1, and MIB-1. BAFF-R expression was detected on B-cells of the mantle zones, some cells within germinal centers, and scattered cells in the interfollicular areas of reactive lymph nodes. BAFF-R expression was only found in B-cell lymphoma (60/120, positive samples/examined samples), but not in T/NK cell lymphoma (0/10) or Hodgkin lymphoma (0/10). The proportions were as follows : follicular lymphoma (14/16), diffuse large B-cell lymphoma (DLBCL) (27/61), mantle cell lymphoma (4/4), and Burkitt lymphoma (0/4). According to Hans' criteria, DLBCLs were subclassified into germinal center B-cell-like (GCB) and non-germinal center B-cell-like (non-GCB) types. Interestingly, in nodal lymphomas, in the GCB subgroup (n=12), 9 of 12 (75%) were positive for BAFF-R, while 6 of 20 (30%) were positive in the non-GCB subgroup (n=20) (p < 0.05). In addition, expression of BAFF-R related to lower MIB-1 index was associated with GCB-type DLBCL. In conclusion, BAFF-R was only found in some B-cell lymphomas, which was closely associated with the expression pattern in normal counterparts, although BAFF-R expression on follicular lymphoma is different from that on germinal center cells, which is similar to bcl-2. BAFF-R was rather specifically related to low growth activity of GCB-type DLBCL of nodal origin.

DOI： 10.3960/jslrt.50.121

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Other Link： http://search.jamas.or.jp/link/ui/2011254627

Language：English   Publisher：WILEY  

IgG4-related diseases comprise a recently recognized systemic syndrome characterized by mass-forming lesions in mainly exocrine tissue that consist of lymphoplasmacytic infiltrates and sclerosis. There are numerous IgG4-positive plasma cells in the affected tissues, and the serum IgG4 level is increased in these patients. The present study describes the history, autoimmune pancreatitis (AIP), IgG4-related lymphadenopathy and lymphomagenesis based upon ocular adnexal IgG4-related disease. Lymphoplasmacytic sclerosing pancreatitis, a prototypal histological type of AIP, is now recognized as a systemic IgG4-related disease. Lymph node lesions can be subdivided into at least five histological subtypes, and systemic IgG4-related lymphadenopathy should be distinguished from multicentric Castleman's disease. Interleukin-6 and CRP levels are abnormally high in multicentric Castleman's disease, but are normal in the majority of systemic IgG4-related lymphadenopathy. Ocular adnexal IgG4-related disease frequently involves bilateral lacrimal glands swelling, and obliterative phlebitis is rare. Moreover, some malignant lymphomas, especially mucosa-associated lymphoid tissue lymphoma, arise from ocular adnexal IgG4-related disease. In addition, IgG4-producing lymphoma also exists.

DOI： 10.1111/j.1440-1827.2010.02524.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Aberrant CpG island methylation contributes to the pathogenesis of various malignancies. However, little is known about the association of epigenetic abnormalities with multistep tumorigenic events in adult T cell leukemia/lymphoma (ATLL). To determine whether epigenetic abnormalities induce the progression of ATLL, we analyzed the methylation profiles of the SHP1, p15, p16, p73, HCAD, DAPK, hMLH-1, and MGMT genes by methylation specific PCR assay in 65 cases with ATLL patients. The number of CpG island methylated genes increased with disease progression and aberrant hypermethylation in specific genes was detected even in HTLV-1 carriers and correlated with progression to ATLL. The CpG island methylator phenotype (CIMP) was observed most frequently in lymphoma type ATLL and was also closely associated with the progression and crisis of ATLL. The high number of methylated genes and increase of CIMP incidence were shown to be unfavorable prognostic factors and correlated with a shorter overall survival by Kaplan-Meyer analysis. The present findings strongly suggest that the multistep accumulation of aberrant CpG methylation in specific target genes and the presence of CIMP are deeply involved in the crisis, progression, and prognosis of ATLL, as well as indicate the value of CpG methylation and CIMP for new diagnostic and prognostic biomarkers. (Am J Pathol 2010, 176:402-415; DOI: 10.2353/ajpath.2010.090236)

DOI： 10.2353/ajpath.2010.090236

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Language：English   Publisher：SPANDIDOS PUBL LTD  

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

Plasma cell myeloma is a frequent hematogeneous disorder that occurs mainly in older people. Not only bone marrow smears but also clots and/or biopsied specimens are often taken for confirmation of pathological diagnosis. Some specimens show sheet-like plasma cell proliferation associated with immunoglobulin monotype on immunohistology, which readily leads to diagnosis, but many samples do not clearly show light-chain restriction. The aim of the present study was therefore to examine CD79a expression because some samples had reduced expression or none at all. The immunoreactivity of CD79a was categorized into three groups: positive, weakly positive and negative, compared with scattering non-neoplastic plasma cells in the same specimen. Out of 100 specimens of plasma cell myeloma, 48% were positive for CD79a, 15% were weakly positive, and 37% were negative. In contrast, overexpression of cyclinD1 was detected in 26% of examined samples. CD79a-negative cases had a significantly lower percentage of positive staining for cyclinD1 than CD79a-positive or weakly positive cases. Clinicopathological data showed that CD79a-negative expression was associated with decreased platelet numbers in patients. The present study indicates that downregulation or loss of CD79a and/or overexpression of cyclin D1, observed in 59% of neoplastic plasma cell samples, could provide a strong diagnostic clue without regard to the results of immunoglobulin light-chain restriction.

DOI： 10.1111/j.1440-1827.2009.02448.x

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Language：English   Publisher：WILEY-LISS  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

Aberrant DNA hypermethylation is an important mechanism for the inactivation of tumor-related genes in human tumors. Gastric mucosa-associated lymphoid tissue (MALT) lymphomas arise from Helicobacter pylori-associated chronic gastritis: most patients are H. pylori-positive and eradication therapy is highly effective. In the present study, we used methylation-specific PCR to analyze the DNA methylation status of 11 tumor-related genes (Kip2, p16, hMLH-1, p15, p73, MGMT, DAPK, MINT1, MINT2, MINT31 and HCAD) in 21 specimens of MALT lymphoma, 5 specimens of MALT lymphoma with large cell component (high-grade MALT lymphoma), 15 specimens of diffuse large B-cell lymphoma (DLBCL), 8 specimens of complete remission of MALT lymphoma after eradication therapy, 5 specimens with no evidence of malignancy and PBMCs from 10 healthy donors. The average number of methylated genes was significantly greater in gastric lymphomas as compared to normal controls (P<0.001). The CpG island methylator phenotype (CIMP) was observed in 93.3% (14/15) of DLBCLs, 100% (5/5) of high-grade MALT lymphomas and 61.9% (13/21) of MALT lymphomas; in contrast, CIMP was not found in the control group (0%). The average number of methylated genes and the CIMP incidence significantly increased with H. pylori infection. Furthermore, aberrant CpG methylation of specific genes, such as p16, MGMT and MINT31, was consistently associated with H. pylori infection. These findings strongly suggest that H. pylori infection causes the aberrant DNA hypermethylation of specific genes and induces CIMP, which is an important epigenetic mechanism for the development and progression of gastric MALT lymphoma; additionally, our findings provide new epigenetic markers.

DOI： 10.3892/ijo_00000366

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background. Human mesenchymal stem cells (hMSCs) are multipotent stem cells found in the adult bone marrow that have the capacity to differentiate into various mesenchymal cell types. The hMSCs may provide a potential therapy to restore damaged tissues or organs of mesenchymal origin; however, a drawback is their limited life span in vitro.Methods. We immortalized normal hMSCs with retrovirally transmitted human telomerase reverse transcriptase cDNA. One of the immortalized clones (YKNK-12) was established, and the biological characteristics were investigated in vitro and in vivo.Results. YKNK-12 cells were capable of differentiating adipocytes, osetoblasts, and chondrocytes. Osteogenically differentiated YKNK-12 cells produced significant levels of growth factors BMP4, BMP6, FGF6, FGF7, transforming growth factor-beta 1, and transforming growth factor-beta 3..Microcomputer tomography T and soft X-ray assays showed an excellent calvarial bone healing in mice after transplantation of osteogenically differentiated YKNK-12 cells. These cells expressed human-specific osteocalcin and increased the gene expression of runt-related transcription factor 2, alkaline phosphatase, osteocalcin, and osterix in the bone regenerating area. YKNK-12 cell transplant corrected the bone defect without inducing any adverse effects.Conclusions. We conclude that hMSCs immortalized by transduction with human telomerase reverse transcriptase may provide an unlimited source of cells for therapeutic use in bone regeneration.

DOI： 10.1097/TP.0b013e3181ae5ba2

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

Diffuse large B-cell lymphoma is the most common form of non-Hodgkin lymphoma. Although many studies have attempted to identify prognostic factors, most have focused on conventionally treated patients. The influence of anti-CD20 antibody (rituximab) should be considered now. We evaluated the prognostic significance of serum soluble interleukin-2 receptor levels and germinal center B-cell-like or non-germinal center B-cell like subgroups in 80 patients with diffuse large B-cell lymphoma, who had been treated with rituximab. Serum soluble interleukin-2 receptor levels ranged from 322 to 39900 U/mL (median 1365 U/mL). Sixteen (20%) were germinal center B-cell-like subgroups, and the remainder (80%) non-germinal center B-cell-like. Survival analysis associated lower serum soluble interleukin-2 receptor level and germinal center B-cell-like phenotype with better overall survival (P = 0.015), whereas multivariate analysis, including International Prognostic Index factors, revealed that only higher performance status score and higher serum lactate dehydrogenase levels significantly affected survival. However, serum soluble interleukin-2 receptor levels were elevated in patients with higher International Prognostic Index scores as well as in the non-germinal center B-cell-like subgroup. Serum soluble interleukin-2 receptor levels, International Prognostic Index, and subphenotypes were strongly correlated with each other. Our study showed that soluble interleukin-2 receptor is quite useful and may serve as a substitute for the International Prognostic Index, especially for patients undergoing treatment. Moreover, the differentiation between the germinal center B-cell-like and non-germinal center B-cell-like phenotypes is also useful for predicting patients with diffuse large B-cell lymphoma, even among those treated with rituximab. (Cancer Sci 2009; 100: 1255-1260)

DOI： 10.1111/j.1349-7006.2009.01167.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Although most follicular lymphomas are believed to be of nodal origin, they sometimes originate from the duodenum. We have reported that the latter differ from nodal follicular lymphomas in having lower clinical stages and uniformly low histological grades, along with variable region of immunoglobulin heavy chain gene (VH) usage that is more similar to mucosa-associated lymphoid tissue (MALT) lymphomas. Little is known, however, about whether they possess other characteristics of nodal follicular lymphomas, particularly ongoing mutations with follicular dendritic cells. We examined 17 cases for which PCR identified the monoclonal bands of the immunoglobulin gene. The duodenal cases showed ongoing mutations, but they lacked activation-induced cytidine deaminase (AID) expression, a statistically significant difference from the nodal cases (P<0.001), and their follicular dendritic cell networks were disrupted. Moreover, not only were VH deviations observed but also they used very restricted VH genes. Although the mechanisms of ongoing mutation without AID and follicular dendritic cell were not clarified, restricted VH usage strongly suggested that antigen stimulation was involved, and that was similar to MALT lymphomas. In conclusion, duodenal follicular lymphomas were shown to be unique, in that they had ongoing hypermutations such as nodal cases, but the mechanisms involved in the hypermutation were quite different; furthermore, restricted VH usage suggested a strong similarity to the antigen-dependent origin of MALT lymphomas. Modern Pathology (2009) 22, 940-949; doi: 10.1038/modpathol.2009.51; published online 24 April 2009

DOI： 10.1038/modpathol.2009.51

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Language：Japanese   Publisher：(一社)日本リンパ網内系学会  

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Language：Japanese   Publisher：The Japanese Society of Hematology  

We report a case of extranodal CD20-positive peripheral T-cell lymphoma (PTCL). A 59-year-old man was admitted because of a right testicular mass in April 2006. CT scan revealed bilateral adrenal masses and he underwent right orchiectomy. The enlarged testis showed diffuse infiltration of large CD20-positive lymphocytes with slight CD3-positive cells. These cells were negative for CD10 and showed a high MIB-1 index. The pathological diagnosis was diffuse large B-cell lymphoma. He received R-CHOP, but developed brain involvement. He received whole brain radiotherapy following high-dose methotrexate, but he died of disease progression in August 2007. At autopsy, lymphoma cells were definitely positive for CD3 and negative for CD20. Monoclonal TCR gamma gene rearrangement was detected in the brain specimen without IgH rearrangement by PCR. The testicular tumor also showed the same clonal bands. Immunohistochemical re-evaluation of the testis showed CD20+, CD79a-, PAX5-, MUM1-, CD3 p+, CD5 p+, CD4-, CD8-, CD7 p+, granzyme B+, and TIA1+. Based on the clinical course and immunohistology, we finally diagnosed this case as extranodal PTCL-nos (not otherwise specified) with aberrant CD20 expression, which is extremely rare. The detection of gene rearrangement, plural immunohistochemical markers and knowledge of the possibility of CD20+ PTCL-nos are necessary for such cases.

DOI： 10.11406/rinketsu.50.413

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Other Link： http://search.jamas.or.jp/link/ui/2009352393

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

IgG4-related disease sometimes involves regional and/or systemic lymph nodes, and often clinically and/or histologically mimics multicentric Castleman's disease or malignant lymphoma. In this study, we examined clinical and pathologic findings of nine patients with systemic IgG4-related lymphadenopathy. None of these cases were associated with human herpes virus-8 or human immunodeficiency virus infection, and there was no T-cell receptor or immunoglobulin gene rearrangement. Histologically, systemic IgG4-related lymphadenopathy was classified into two types by the infiltration pattern of IgG4-positive cells: interfollicular plasmacytosis type and intra-germinal center plasmacytosis type. The interfollicular plasmacytosis type showed either Castleman's disease-like features or atypical lymphoplasmacytic and immunoblastic proliferation-like features. By contrast, the intra-germinal center plasmacytosis type showed marked follicular hyperplasia, and infiltration of IgG4-positive cells mainly into the germinal centers, and some cases exhibited features of progressively transformed germinal centers. Interestingly, eight of our nine (89%) cases showed eosinophil infiltration in the affected lymph nodes, and examined patients showed high elevation of serum IgE. Laboratory examinations revealed elevation of serum IgG4 and soluble interleukin-2 receptors. However, the levels of interleukin-6, C-reactive protein, and lactate dehydrogenase were within normal limits or only slightly elevated in almost all patients. One patient showed a high interleukin-6 level whereas C-reactive protein was within the normal limit. Autoantibodies were examined in five patients and detected in four. Compared with the previously reported cases of multicentric Castleman's disease, our patients with systemic IgG4-related lymphadenopathy were significantly older and had significantly lower C-reactive protein and interleukin-6 levels. In conclusion, in our systemic IgG4-related lymphadenopathy showed pathologic features only partially overlapping those of multicentric Castleman's disease, and serum data (especially C-reactive protein and interleukin-6) are useful for differentiating the two. Our findings of eosinophil infiltration in the affected tissue and elevation of serum IgE may suggest an allergic mechanism in the pathogenesis of systemic IgG4-related lymphadenopathy.

DOI： 10.1038/modpathol.2009.17

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

Diffuse large B-cell lymphomas are detected frequently in the oral cavity. Although tonsillar lymphomas have been rather well characterized, lymphomas originating from non-tonsillar regions, such as the gingiva, palate, and tongue, have not been well studied. We examined the pathology of clinical samples obtained from 21 patients with localized primary non-tonsillar oral diffuse large B-cell lymphoma. Immunohistological examination of CD10, Bcl-6, and MUM1 determined that 17 of 21 (81%) samples exhibited non-germinal center B-cell type, an increased proportion of non-germinal center B-cell type compared with previous reports in samples of tonsillar origin (P < 0.05). The four remaining samples exhibited germinal center B-cell type, although one sample expressed MUM1. Follow-up clinical survival data were obtained from the 17 patients over a range from 4 to 173 months (mean 52 months). All patients were treated with chemotherapies, irradiation, or surgical resection. Sixteen patients achieved complete remission and two patients relapsed, but no patient has died of disease. Extranodal diffuse large B-cell lymphomas of non-germinal center B-cell type are generally characterized by poor prognosis, regardless of localized disease. Interestingly, our results indicate that, unlike similar lymphomas of tonsillar origin, localized primary non-tonsillar oral diffuse large B-cell lymphomas exhibit favorable prognosis, suggesting that these lymphomas may be clinicopathologically distinct. (Cancer Sci 2009; 100: 42-46).

DOI： 10.1111/j.1349-7006.2008.00995.x

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

The objective of our study was to investigate the clinicopathological features of the currently ill-defined subtype of primary cutaneous T-cell lymphoma of unspecified type (CTCLU) with a cytotoxic phenotype and no Epstein-Barr virus (EBV) association. A series of 27 patients with CTCLU (median age 49 years; range 25-87 years; 18 men) was reviewed. Performance status scores above 1 (7%), clinical stages above 2 (15%), B symptoms (26%), extracutaneous involvement (30%), and a fatal course within 1 year of diagnosis (19%) were observed infrequently. The International Prognostic Index was high or high to intermediate in 11%, and the Prognostic Index for Peripheral T-cell Lymphoma unspecified was above group 2 in 22%. Notably, the rates of spontaneous regression and T-cell receptor gene rearrangements by polymerase chain reaction analysis were seen in 26 and 17% of our cases, respectively. Histologically, 22 patients had subcutaneous involvement of whom eight showed a lethal clinical course, and five patients without subcutaneous involvement were all survivors. Immunophenotypical and morphological features allowed us to subclassify our cases according to the following four categories: (1) epidermotropic CD8(+) T-cell lymphoma (n = 5); (2) cutaneous gamma/delta T-cell lymphoma (n = 8); (3) cutaneous alpha/beta pleomorphic T-cell lymphoma (n = 8); and (4) cutaneous medium/large pleomorphic T-cell lymphoma, not otherwise specified (n = 6). All four of these groups of lymphomas exhibited a relatively favorable clinical course compared to previous reports. However, epidermotropic CD8(+) T-cell lymphoma appeared to be unique with a higher ratio (80%) of spontaneous regression, a lower ratio (40%) of subcutaneous involvement, and a more favorable clinical course than the other three subcategories. (Cancer Sci 2009; 100: 33-41).

DOI： 10.1111/j.1349-7006.2008.01000.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

IgG4-related disease is a recently proposed clinical entity with several unique clinicopathological features. A chronic inflammatory state with marked fibrosis, which can often be mistaken for malignancy, especially by clinical imaging analyses, unifies these features. Little is known about lymphomagenesis in the context of IgG4-related disease, we recently first reported the ocular adnexal marginal zone B-cell lymphomas arising from IgG4-related disease. To the best of our knowledge, no existing study has ever established the neoplastic potential of IgG4-producing cells. In the present report, we describe the first IgG4-producing lymphoma. The patient was a 72-year-old male who was being followed for an asbestos-related pleural plaque. During follow-up, computed tomography revealed bilateral renal masses and multiple swollen retroperitoneal lymph nodes. A retroperitoneal lymph node biopsy was performed. Histologically, the interfollicular areas were expanded by medium to large plasmacytoid cells. These plasmacytoid cells showed nuclear pleomorphism and had prominent Russell bodies. Immunohistochemistry and double immunofluorescence staining of these cells revealed IgG4 positivity and monotypic lambda-light chain predominance. A portion of these cells were partially positive for CD20, negative for CD3, and somewhat faintly positive for CD138. In addition, serum IgG4 was elevated. Southern blot analysis of the lymph node specimen detected immunoglobulin heavy chain gene rearrangement. The present study indicates that, not only can malignant lymphomas occur in the setting of IgG4-related disease, but IgG4-producing cells can also be neoplastic.

DOI： 10.1007/s12185-008-0170-8

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

To investigate the role of an activating epidermal growth factor receptor (EGFR) mutation in lung cancer, we generated transgenic mice expressing the delE748-A752 mutant version of mouse EGFR driven by the SP-C promoter, which is equivalent to the delE746-A750 mutation found in lung cancer patients. Strikingly, the mice invariably developed multifocal lung adenocarcinomas of varying sizes at between 5 and 6 weeks of age, and they died from tumor progression approximately 2 months later if left untreated. Daily oral administration of the EGFR tyrosine kinase inhibitor (TKI) gefitinib (5 mg/kg/day) reduced the total and phosphorylation levels of EGFR to those in wild-type mouse lung tissue; in addition, it abrogated tumor growth within 1 week and prolonged survival to > 30 weeks. Interestingly, phosphorylated ErbB2, ErbB3, and thyroid transcriptional factor-1 increased in the transgenic mice compared with those in wild-type mice. They might play some roles in tumors progression in the transgenic mice. This model will be useful for studying the mechanisms of carcinogenesis, chemoprevention, and acquired resistance to EGFR TKIs in lung cancer patients carrying activating EGFR mutations.

DOI： 10.1111/j.1349-7006.2008.00875.x

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

IgG4-related disease is a recently proposed clinical entity with several unique clinicopathological features. Ocular adnexal IgG4-related disease, however, has not well been clarified. The purpose of the present study was to examine 21 patients (10 men, 11 women; age range, 39-86 years) with ocular adnexal IgG4-related disease. In 17 out of 21 patients (81%), the lacrimal glands were involved and bilateral lacrimal gland swelling was frequently observed (n = 12; 70.6%). In contrast, the conjunctiva was not involved in any of the patient. Histology was uniform with marked lymphoplasmacytic infiltration admixed with dense fibrosis, similar to previous reports of IgG4-related disease. Immunostaining detected numerous aggregates of IgG4-positive plasma cells. Serum IgG4 was higher than normal in 10 of the 13 patients tested, although it was measured after treatment in almost all cases. Interestingly, immunoglobulin heavy chain gene rearrangement was detected in two of 17 patients (12%) examined. The present results show that ocular adnexal IgG4-related disease has uniform clinicopathology: that is, disease involving the bilateral lacrimal glands with lymphoid hyperplasia and fibrosis, but not the conjunctiva. And presence of immunoglobulin heavy chain gene rearrangement suggests the possibility of B-cell lymphoma arising in a background of IgG4-related chronic inflammation.

DOI： 10.1111/j.1440-1827.2008.02257.x

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Language：Japanese   Publisher：(一社)日本リンパ網内系学会  

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

A 79-year-old man presented with back pain. Chest CT scan showed elevated nodular lesions in the right parietal pleurae with pleural effusion. There were no intrapulmonary or mediastinal abnormalities. Under local anesthesia, right thoracoscopy and subsequent thoracoscopic pleural resection were performed using an insulation-tipped diathermic knife (IT-knife). The resected pleura, 2.2 cm in diameter, had a rough granular surface. Lymphoid cells histologically infiltrated diffusely into the pleura. They were composed of centrocyte-like and monocytoid cells. On immunohistochemistry they were found to be positive for Bcl2, CD20, CD45RB and CD79a, but negative for CD3, CD5, CD10 and cyclin D1. EBV-encoded small RNA-1 (EBER-1) in situ hybridization was negative. A diagnosis of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) arising in the pleura was therefore made. To the authors' knowledge this is the first case in which IT-knife was used for diagnosis of a pleural lesion. This large, single-piece, only slightly crushed pleural specimen, enabled study of histopathological findings (listed here) that could not have been obtained on conventional biopsy: (i) lack of apparent evidence of plasmacytic differentiation; (ii) no recognition of lymphoid follicles; (iii) mesothelial cells not infiltrated by lymphoma cell clusters; (iv) thin layer of hyperplastic mesothelial cells continuously covering the surface; and (v) no proliferation of fibroblast-like submesothelial cells.

DOI： 10.1111/j.1440-1827.2008.02220.x

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：B M J PUBLISHING GROUP  

Background: Follicular lymphomas occasionally arise in the extra-nodal organs and are frequently found in the duodenum. They are often localised tumours with multiple polyps around the ampulla of Vater.
Aims: To examine a IgH/bcl-2 hybrid gene and VH gene to investigate the nature of the lymphoma cells and how they differ from nodal follicular lymphomas and MALT lymphomas.
Methods: Of 40 patients reported previously, 35 with duodenal follicular lymphoma were studied in detail with respect to clinicopathological characteristics.
Results: 37/40 patients were in clinical stage I (n= 30) or stage II (n= 7). Clonal immunoglobulin gene rearrangement was detected in 53.3% of examined cases, and rearrangement of IgH/bcl-2 gene at the major break point was detected in 27% of cases. Three of 8 examined cases were VH4 (38%); 2 out of them were VH4-34. As VH4 deviation is one of the common characteristics of MALT lymphomas and 2/3 were identical, duodenal follicular lymphomas have a similar aetiology to MALT lymphomas. Clinical course was also similar to that of MALT lymphomas.
Conclusions: Results suggest that duodenal follicular lymphomas have intermediate characteristics of MALT lymphomas and nodal follicular lymphomas.

DOI： 10.1136/jcp.2007.049825

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Language：Japanese   Publisher：Okayama Medical Association  

DOI： 10.4044/joma.119.323

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Other Link： http://ousar.lib.okayama-u.ac.jp/13229

Language：English   Publisher：(一社)日本リンパ網内系学会  

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Language：Japanese   Publisher：(株)東京医学社  

消化管濾胞性リンパ腫の治療への奏効率は高い。再燃も比較的高率に認められるが長期予後が得られている。watch and wait例も相当数認められ、一部は増悪しているが生存率への影響は少ない。本邦における多施設共同研究では、Lugano臨床病期stage I、II1 125例において、経過観察期間中央値40ヵ月(6〜148ヵ月)で原病死例はなく、6例(5%)が増悪した(初期治療:watch and wait 3例、rituximabを含んだ多剤併用化学療法2例、rituximab単独1例)。5年全生存率および無増悪生存率は100%および93%であった。生命予後を規定するのは、びまん性大細胞型リンパ腫への転化であり、転化率は10〜17%/5年、転化後の全生存率は中央値1.2〜4年と報告されている。限局期例が多い消化管濾胞性リンパ腫での検討は、いまだ不十分である。(著者抄録)

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Other Link： http://search.jamas.or.jp/link/ui/2015223707

Language：Japanese   Publisher：(一社)日本病理学会  

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Language：Japanese   Publisher：(一社)日本病理学会  

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J-GLOBAL

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DOI： 10.11477/mf.1403114146

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DOI： 10.3960/jslrt.54.3

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Language：Japanese   Publisher：(一社)日本病理学会  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本リンパ網内系学会  

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Language：Japanese   Publisher：(一社)日本病理学会  

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Other Link： http://search.jamas.or.jp/link/ui/2012209506

DOI： 10.1007/s10165-012-0758-y

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Other Link： http://search.jamas.or.jp/link/ui/2011313170

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Language：English   Publisher：日本癌学会  

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Other Link： http://search.jamas.or.jp/link/ui/2011011051

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Other Link： http://search.jamas.or.jp/link/ui/2009228487

Language：Japanese   Publisher：(一社)日本病理学会  

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DOI： 10.11477/mf.1403101403

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Other Link： http://search.jamas.or.jp/link/ui/2008118326

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DOI： 10.11477/mf.1403101150

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