Composite diffuse large B-cell lymphoma and CD20-positive peripheral T-cell lymphoma

Composite lymphoma is defined as two or more distinct types of lymphoma in a single anatomical site. Among various combinations, composite B-cell and T-cell non-Hodgkin's lymphomas (CBTL) are very infrequent. Herein we describe a 66-year-old female with CBTL presenting with lymphadenopathy, multiple bone lesions and an epidural tumor. Light microscopic examination of a biopsied cervical node revealed a dual population of lymphoid cells: sheets of large cells admixed with medium-sized cells. The large cells expressed B-cell markers and showed immunoglobulin light chain restriction, consistent with diffuse large B-cell lymphoma (DLBCL). The medium-sized cells were positive for CD20 as well as T-cell markers. Because polymerase chain reaction amplification showed monoclonal rearrangement of the T-cell receptor β chain gene, this population was compatible with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS). We therefore made a diagnosis of composite DLBCL and CD20-positive PTCL-NOS. Complete remission was achieved after six cycles of R-CHOP regimen (rituximab, doxorubicin, vincristine, cyclophosphamide and prednisolone). This is the first report of CD20-positive PTCL-NOS associated with composite lymphoma. Moreover, a literature review of composite DLBCL and PTCL-NOS indicates that this rare clinical entity may be featured by efficacy of systemic chemotherapy in spite of prevalent extranodal lesions.     

Differential expression of Toll-like receptors in follicular lymphoma,diffuse large B-cell lymphoma and peripheral T-cell lymphoma

Although Toll-like receptors (TLRs) in mammals are well-known to play important roles in innate immunity, newer roles for the TLRs have suggested that cells with aberrant TLR expression may have a survival advantage over normal cells. Lymphocytes are one of a small number of cell types that express many of the TLRs, suggesting that abnormal TLR levels/signaling may potentially influence the progression of malignant lymphomas. Thus, frozen samples of 51 lymph nodes from patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL) were analyzed for the expression of TLR1 to 9 using quantitative real-time PCR, and compared to those in reactive lymphadenopathy (RL) samples. TLR2 was over-expressed in both DLBCL and PTCL but not in FL when compared to RL. TLR1 and TLR4 expression was up-regulated in PTCL, while TLR8 was highly expressed in DLBCL. Although TLR5 showed lower expression in FL, expression of TLR3, TLR6, TLR7 and TLR9 did not vary significantly between different lymphoma subtypes. Double immunostaining revealed an increase in the number of TLR2 and/or TLR8 expressing lymphoma cells in DLBCL. In PTCL, TLR2 and TLR4 expression was localized to neoplastic T cells. TLR expression is highly variable among lymphoma subtypes. However, despite this some significant differences exist that may prove useful in the development of novel therapeutic strategies.     

Comparative clinicopathological study of primary CNS diffuse large B-cell lymphoma and intravascular large B-cell lymphoma

Primary CNS diffuse large B-cell lymphoma (CNS DLBCL) is confined to the CNS, and constitutes a distinct entity. In the present study a series of 40 Japanese patients with CNS DLBCL who presented with neurological, but not systemic symptoms, was reviewed. Median survival was 18.7 months. CD5, CD10, Bcl-6, MUM-1, and Bcl-2 were positive in 30%, 10%, 84%, 100%, and 93% of patients, respectively. All CD10-negative patients had non-germinal center B-cell type. There was no significant difference in survival among the immunophenotypic subgroups. CNS DLBCL appeared to be homogenous as a group, which prompted the comparison with another distinct extranodal entity, intravascular large B-cell lymphoma (IVLBCL) in Japanese patients. CNS DLBCL patients did not differ in age, sex, or immunophenotype, including CD5 positivity, from IVLBCL patients, but were significantly less likely to have poor prognostic parameters than IVLBCL patients: the international prognostic index score was low or low–intermediate in 86% of CNS DLBCL patients and high or high–intermediate in 98% of IVLBCL patients. Notably, despite this difference, their survival curves almost overlapped. The present study highlights the issue of clinical distinctiveness of aggressive extranodal lymphomas, the peculiar migration and localization of which should be further clarified.     

p52 Activation in monomorphic B-cell posttransplant lymphoproliferative disorder/diffuse large B-cell lymphoma without BAFF-R expression

Posttransplantation lymphoproliferative disorders (PTLD) are associated with Epstein-Barr virus (EBV) and activate the NF-κB pathway. B-cell activating factor (BAFF) modulates cell growth and survival in non-Hodgkin's lymphomas. However, there are few studies of EBV, BAFF/BAFF-R signaling, and NF-κB1 and NF-κB2 pathway activation in PTLD. Diffuse large B-cell lymphomas (DLBCL) in two different clinical contexts, immunocompetent patients (DLBCL/IC; n = 30) or posttransplantation solid-organ recipients (DLBCL/PTLD; n = 21), were characterized histogenically as germinal center (GC) or non-germinal center (NGC). Expression of BAFF, BAFF-R, and NF-κB proteins p50 and p52 and the presence or absence of EBV were compared in these clinical contexts. Regardless of the GC or NGC pattern of DLBCL, BAFF-R was expressed in 37% of DLBCL/IC but in only 4.8% of DLBCL/PTLD. p52 was expressed in DLBCL/PTLD/NGC (12 of 19 cases) as compared with DLBCL/IC/NGC (0 of 18 cases). This pattern might be related to the presence of EBV and latent membrane protein 1 because p52 expression was observed primarily in EBV-positive DLBCL/PTLD cases expressing latent membrane protein 1. Thus, the activation profile or NGC pattern of DLBCL/PTLD was not associated with BAFF/BAFF-R expression, whereas nuclear p52 related to NF-κB2 pathway activation might be linked to EBV.     

信号通路在弥漫性大B细胞淋巴瘤发病过程中的作用

弥漫性大B细胞淋巴瘤(DLBCL)是最常见的一种B细胞恶性肿瘤,约占成人非霍奇金淋巴瘤的30%～40%.依据肿瘤细胞起源大致可将DLBCL分为生发中心B细胞型(GCB型)及非生发中心B细胞型(非GCB型).B细胞发育过程中,多种信号通路精确地调控其细胞周期、增殖、分化及凋亡,以达到平衡,确保B细胞的正常发育及成熟.     

弥漫大B细胞淋巴瘤基因表达谱的研究进展

弥漫大B细胞淋巴瘤（DLBCL）是最常见的一类淋巴瘤,占非霍奇金淋巴瘤的30％左右。DLBCL的临床表现、形态学、免疫表型及遗传学特征极具异质性,越来越多的证据表明其可能并不是一个真正独立的病种。最新的WHO淋巴造血组织肿瘤分类列出了DLBCL的一些形态学亚型,但这种形态学分型不仅与预后的关系尚存在争议,而且诊断的可重复性差,所以实际应用价值不大。大多数DLBCL患者经过化学治疗后可以获得缓解,但半数患者仍在短期内复发并死亡。国际预后指数（international prognostic index,IPI）是通过年龄、功能状态、血清乳酸脱氢酶水平、累及结外部位的数量以及肿瘤临床分期等5个临床特征对患者进行评分,具有相当的预后判断价值。     

发生于非特殊型外周T细胞淋巴瘤后的EB病毒阳性弥漫性大B细胞淋巴瘤一例

患者女,70岁.因自觉右耳后肿块3个月、持续低热1个多月于2008年7月入院.起病以来,患者纳差、乏力,体重明显减轻.体检:全身浅表淋巴结肿大.CT示双侧颈部、耳后、腋下、纵隔、腹股沟可触及多发肿大的淋巴结.实验室检查:红细胞3.38×1012/L,血小板计数96×109/L.骨髓涂片:骨髓增生活跃,粒系增生活跃,嗜酸细胞比例增高.取右腋下淋巴结活检.     

发生于非特殊型外周T细胞淋巴瘤后的EB病毒阳性弥漫性大B细胞淋巴瘤一例

患者女,70岁.因自觉右耳后肿块3个月、持续低热1个多月于2008年7月入院.起病以来,患者纳差、乏力,体重明显减轻.体检:全身浅表淋巴结肿大.CT示双侧颈部、耳后、腋下、纵隔、腹股沟可触及多发肿大的淋巴结.实验室检查:红细胞3.38×1012/L,血小板计数96×109/L.骨髓涂片:骨髓增生活跃,粒系增生活跃,嗜酸细胞比例增高.取右腋下淋巴结活检.     

bcl-6基因5'非编码区突变与弥漫性大B细胞淋巴瘤生发中心亚型的相关性

目的 分析弥漫性大B细胞淋巴瘤(DLBCL)中bcl-6基因5'非编码区突变频率及与其生发中心B细胞(GCB)型的相关性.方法 对60例DLBCL行套式PCR检测t(14;l8)易位,并经免疫组织化学EnVision两步法进行GCB和非GCB分子分型.PCR扩增bcl-6主要突变区,测序检测突变位点.结果 60例中7例(11.7%)发生t(14;18)易位,为主要断裂点发生转位;联合免疫组织化学分析和t(14;18)易位检测,筛选出GCB型18例和非GCB型42例;5'非编码区总突变率为20.0%(12/60),GCB型突变率为7/18,非GCB型突变率为11.9%(5/42);+363和+469位点频繁发生突变.结论 DLBCL的bcl-65'非编码区发生突变频率较国外低,突变多发生于GCB型中.t(14;18)易位检测有助于DLBCL的分子分型.     

EBV-associated diffuse large B-cell lymphoma in a psoriatic treated with methotrexate

Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is a lymphoid proliferation or lymphoma in a patient immunosuppressed with MTX, which is usually administered for treating autoimmune diseases. The majority of MTX-LPD cases develop in patients with rheumatoid arthritis and occasionally with psoriasis who had been treated with MTX. Here, we report on a 50-year-old Taiwanese male with severe psoriasis, who received high doses of MTX. The patient developed EBV-positive MTX-LPD at nodal and extranodal sites. The diffuse and polymorphic lymphoid infiltrate consisted predominantly of immunoblasts and plasmablasts expressing B-cell markers, CD138, Epstein-Barr virus (EBV)-LMP1, and EBNA2, and these were monotypic for kappa light chain. The tumor cells were also positive for EBV by in situ hybridization. These findings indicated a type III latency infection of EBV. The patient died of progressive disease after 19 months. A review of the previously reported cases shows that MTX-LPD, in association with psoriasis, occurs in middle-aged males. The tumors are diffuse large B-cell lymphomas with immunoblastic morphology, and frequently show plasmacytic differentiation.     

发生于非特殊型外周T细胞淋巴瘤后的EB病毒阳性弥漫性大B细胞淋巴瘤一例

患者女,70岁.因自觉右耳后肿块3个月、持续低热1个多月于2008年7月入院.起病以来,患者纳差、乏力,体重明显减轻.体检:全身浅表淋巴结肿大.CT示双侧颈部、耳后、腋下、纵隔、腹股沟可触及多发肿大的淋巴结.实验室检查:红细胞3.38×1012/L,血小板计数96×109/L.骨髓涂片:骨髓增生活跃,粒系增生活跃,嗜酸细胞比例增高.取右腋下淋巴结活检.     

Sequential development of diffuse large B-cell lymphoma in a patient with angioimmunoblastic T-cell lymphoma

Lymphoma of different histologic type can occur in the same patient. Here, we describe a 64-year-old male patient with angioimmunoblastic T-cell lymphoma (AITL) who subsequently developed diffuse large B-cell lymphoma (DLBCL). At the time of initial diagnosis, histologic examination of a left inguinal lymph node of the patient and a monoclonal pattern of TCRβ gene rearrangement showed typical features of AITL, and there was no evidence of a monoclonal B-cell population. Twenty-six months later, he had generalized lymphadenopathy and organs involvement by DLBCL. A monoclonal IgH gene rearrangement proved de novo development of secondary B-cell lymphoma and excluded relapse of a primary composite lymphoma. The in situ hybridization analysis showed Epstein-Barr-encoded RNA (EBER) sporadic positivity in sample collected from AITL but extensive positivity in the immunoblasts collected from DLBCL. Our observation supports the hypothesis that Epstein-Barr virus (EBV) is etiologically related to AITL in this case. Clonal expansion of EBV-associated DLBCL is a secondary event in AITL via EBV infection or reactivation.     

Expression of c-FLIP is primarily detected in diffuse large B-cell lymphoma and Hodgkin's lymphoma and correlates with lack of caspase 8 activation

AIMS: Inhibition of apoptosis is important in the pathogenesis of lymphomas. c-FLIP, a regulator of caspase 8-mediated apoptosis, plays an important role in protecting normal B and T cells from apoptosis and possibly also in lymphomas. Because of contradictory reports about immunohistochemical detection of c-FLIP expression, the aim was to test the specificity of four antibodies in c-FLIP-transfected cells and subsequently to investigate expression of c-FLIP in different types of lymphoma. METHODS AND RESULTS: Two of four antibodies were specific. In primary lymphomas c-FLIP expression was restricted to Hodgkin's lymphomas (> 90%) and diffuse large B-cell lymphomas (44%). Burkitt lymphomas and indolent B-cell lymphomas were negative in all cases. No expression was detected in primary T-cell lymphomas, although expression was observed in one relapsed ALK+ anaplastic large cell lymphoma. Expression of c-FLIP was inversely correlated with caspase 8 activation. CONCLUSIONS: c-FLIP is important in escape of B cells from apoptosis during normal follicle centre cell reaction and may thus be an important early event in the development of B-cell-derived lymphomas. Moreover, non-specific staining of frequently used antibodies might explain discrepancies in different reports of c-FLIP expression.     

Comparative immunohistochemical analysis of pediatric Burkitt lymphoma and diffuse large B-cell lymphoma

Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) account for nearly all pediatric nonlymphoblastic B-cell lymphomas. Because clinical behavior, prognosis, and response to therapy might differ, diagnostic accuracy is important. Morphologic examination often is sufficient, but occasionally, diagnostic ancillary studies are required. In adults, immunophenotyping is useful; however, pediatric data are limited. We characterized the immunohistochemical expression of 6 proteins (c-myc, CD10, bcl-6, bcl-2, CD138, and MIB-1) in pediatric BL (33 cases) and DLBCL (20 cases) with classic morphologic features. Significant differences in c-myc (BL, 30/33 [91%] vs DLBCL, 5/20 [25%]; P < .0001), bcl-2 (BL, 1/25 [4%] vs DLBCL, 7/19 [37%]; P < .02), and mean MIB-1 (BL, 99% vs DLBCL, 56%; P < .0001) expression were observed. There were no significant differences for CD10 (100% expression in BL and DLBCL), bcl-6 (BL, 23/33 [70%] vs DLBCL, 15/20 [75%]), or CD138 (no expression). Thus, pediatric BL and DLBCL have distinctive immunohistochemical profiles, and staining for c-myc, MIB-1, and bcl-2 might be useful in morphologically difficult cases.     

Oligoclonality of a "composite" gastric diffuse large B-cell lymphoma with areas of marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type

We analyzed a case of oligoclonal Helicobacter pylori-associated, primary gastric diffuse large B-cell lymphoma (DLBCL) with areas of extranodal marginal zone B-cell lymphoma (MZBL) of mucosa-associated lymphoid tissue (MALT) type in a 61-year-old male patient. The patient had two separate tumors, in the corpus and in the antrum, each showing two morphologically distinct components (DLBCL and MZBL of MALT type). To determine the clonal relationship between the large- and small-cell components, we microdissected four samples from morphologically distinct tumor components at both tumor sites. PCR analysis revealed rearranged immunoglobulin heavy chain (IgH) genes of different sizes in three of the four microdissected samples. Cloning and sequencing of the PCR products displayed different IgH gene rearrangements in the two small cell components of the antrum and the corpus. A third genuinely differently rearranged IgH gene was found in the large-cell components of both antrum and corpus. Our results suggest that in primary gastric DLBCL with areas of MZBL of MALT type, the small-cell component may comprise more than one tumor clone. Furthermore, the large-cell component may evolve independently from coexisting MZBL.     

Expression and significance of leptin receptor,p-STAT3 and p-AKT in diffuse large B-cell lymphoma

We investigated the expression and clinical significance of leptin receptor (OBR), p-STAT3 and p-AKT in patients with diffuse large B-cell lymphoma (DLBCL) by immunohistochemical analysis. Immunohistochemistry revealed high expression of OBR, p-STAT3 and p-AKT in 45.0% (36/80), 28.8% (23/80) and 18.8% (15/80) cases of DLBCL, respectively, and minimal staining in 100% (20/20) cases of RLH (P < 0.05). Compared with GCB group, the non-GCB group had higher p-STAT3 expression rate (21/57 vs. 2/23, P < 0.01). The expression of OBR was positively related with that of p-STAT3 and p-AKT in DLBCL patients (P < 0.05). Our data suggest that OBR stimulates the JAK/STAT and PI3K/AKT signaling pathway and induces the phosphorylation of STAT3 and AKT. This may be involved in carcinogenesis and prognosis of DLBCL. The specific inhibitions could interfere in the combination of leptin with OBR and obstruct the JAK/STAT and PI3K/AKT signaling pathways, which could lead to new research and treatment strategies for DLBCL treatment.