The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development

Splenic marginal zone lymphoma (SMZL) is a B cell malignancy of unknown pathogenesis, and thus an orphan of targeted therapies. By integrating whole-exome sequencing and copy-number analysis, we show that the SMZL exome carries at least 30 nonsilent gene alterations. Mutations in NOTCH2, a gene required for marginal-zone (MZ) B cell development, represent the most frequent lesion in SMZL, accounting for ～20% of cases. All NOTCH2 mutations are predicted to cause impaired degradation of the NOTCH2 protein by eliminating the C-terminal PEST domain, which is required for proteasomal recruitment. Among indolent B cell lymphoproliferative disorders, NOTCH2 mutations are restricted to SMZL, thus representing a potential diagnostic marker for this lymphoma type. In addition to NOTCH2, other modulators or members of the NOTCH pathway are recurrently targeted by genetic lesions in SMZL; these include NOTCH1, SPEN, and DTX1. We also noted mutations in other signaling pathways normally involved in MZ B cell development, suggesting that deregulation of MZ B cell development pathways plays a role in the pathogenesis of ～60% SMZL. These findings have direct implications for the treatment of SMZL patients, given the availability of drugs that can target NOTCH, NF-κB, and other pathways deregulated in this disease.     

Cannabinoid receptor 2 positions and retains marginal zone B cells within the splenic marginal zone

Specialized B cells residing in the splenic marginal zone (MZ) continuously survey the blood for antigens and are important for immunity to systemic infections. However, the cues that uniquely attract cells to the MZ have not been defined. Previous work demonstrated that mice deficient in cannabinoid receptor 2 (CB2) have decreased numbers of MZ B cells but it has been unclear whether CB2 regulates MZ B cell development or positioning. We show that MZ B cells are highly responsive to the CB2 ligand 2-arachidonylglycerol (2-AG) and that CB2 antagonism rapidly displaces small numbers of MZ B cells to the blood. Antagonism for longer durations depletes MZ B cells from the spleen. In mice deficient in sphingosine-1-phosphate receptor function, CB2 antagonism causes MZ B cell displacement into follicles. Moreover, CB2 overexpression is sufficient to position B cells to the splenic MZ. These findings establish a role for CB2 in guiding B cells to the MZ and in preventing their loss to the blood. As a consequence of their MZ B cell deficiency, CB2-deficient mice have reduced numbers of CD1d-high B cells. We show that CB2 deficiency results in diminished humoral responses to a CD1d-restricted systemic antigen.     

Unusual direct phycoerythrin labeling of B-cells from a splenic marginal zone lymphoma

Flow cytometry is the most widely used method for lymphocyte subset characterization. Two types of antibodies, directly labeled with fluorochrome, are currently used for immunological diagnosis of B-cell lymphoproliferation: monoclonal antibodies against leukocyte differentiation antigens and polyclonal antibodies against immunoglobulins and light chains. In this study is described the case of a patient with an uncommon immunophenotyping of a B-cell lymphoproliferative disorder. B-cells from peripheral blood and from bone marrow reacted positively with all the tested phycoerythrin (PE)-conjugated antibodies, including the isotypic control. So we thought about a B-cell proliferation carrying a surface receptor recognizing PE: these B-cells were directly labeled with streptavidin-PE, indeed. Moreover, the immunodots from the patient were able to fix the streptavidin-PE. Finally, this unusual immunophenotyping was solved by using antibodies labeled with other fluorochromes than PE.     

脾边缘带淋巴瘤的特点及护理

脾边缘带淋巴瘤 (splenicmarginalzonelymphoma,SMZL)是“WHO2 0 0 0造血和淋巴组织分类”中正式确定的一个新独立类型[1] 。是原发于脾脏的低度恶性B细胞淋巴瘤 ,好发于老年。由于报告的病例数很少 ,对该病的认识还不全面 ,国内仅有 1例报告对临床及肿瘤细胞的特征进行了阐述 ,为提高对本病特征的认识和护理水平 ,现将我院近期收治的 1例患者的治疗及护理报告如下。病例介绍患者 ,男 ,75岁。发热伴脾大 2个月 ,于 2 0 0 2年 12月 14日入院。患者入院前 2个月无明显诱因出现间断低热、乏力 ,左季肋部发胀 ,无呼吸道及消化道等症状。 1个…     

Whole-genome sequencing in personalized therapeutics

Eleven years since the initial drafts of the human genome were published, we have begun to see the first examples of the application of whole-genome sequencing to personalized diagnosis and therapeutics. The exponential decline in sequencing costs and the constant improvement in these technologies promise to further advance the use of a patient's full genetic profile in the clinic. However, realizing the potential benefit of such sequencing will require a concerted effort by science, medicine, law, and management. In this review, we discuss current approaches to decoding the 6 billion-letter genetic code of a whole genome in a clinical context, give current examples of translating this information into therapy-guiding knowledge, and list the challenges that will need to be surmounted before these powerful data can be fully exploited to forward the goals of personalized medicine.     

Follicular lymphoma presenting like marginal zone lymphoma: A case report

BACKGROUNDFollicular lymphoma (FL), a common type of indolent lymphoma, carries markers of the germinal center, and the rearrangement of the BCL-2 gene is regarded as an initiating event and a hallmark of the neoplasm. When FL has marginal zone differentiation, some marginal zone features are carried by the neoplasm.CASE SUMMARYA 54-year-old male with lymphadenopathy, splenomegaly and hyperlymphocytosis was diagnosed with FL with marginal zone differentiation. The tumor demonstrated different features in the bone marrow (BM) compared with the follicle of the lymph node (LN). Some component of the neoplasm mimicked marginal zone lymphoma, such as infiltrating the marginal zone of the LN, displaying a monocytoid shape and lacking the expression of CD10 in the BM. The diagnosis of FL was made due to the concurrent detection of BCL-2 rearrangement in the LN and BM.CONCLUSIONDiscordant pathological features in LN and BM could mislead diagnosis. When clinical and pathological manifestations are confusing in diagnosis, typical genetic abnormalities are decisive.     

结内边缘区B细胞淋巴瘤临床病理观察

目的 提高对结内边缘区B细胞淋巴瘤（NMZL）的认识。方法 对1例结内舰进行临床、病理组织学和免疫组化观察，复习相关文献。结果 患者男性，71岁，腹股沟淋巴结肿大起病。组织病变有突出的单核样B细胞增生和反滤泡结构，晚期呈弥漫性结节状和大细胞化，瘤细胞表达成熟B细胞免疫表型：CD20、CD79a（＋），CD5、CD10和CD23（-），bel-2（＋）。历时6年，行23个疗程化疗，病情反复复发，终致累及全身淋巴结、骨髓和外周血。结论 NMZL．为少见的独立实体，原发于淋巴结的低度恶性B细胞淋巴瘤。临床表现为外周淋巴结肿大，惰性经过。     

结内边缘区B细胞淋巴瘤临床病理学分析

目的 探讨原发结内边缘区B细胞淋巴瘤(NMZL)临床病理学特点.方法 对22例NMZL患者淋巴结活检组织采用HE、免疫组织化学(En Vision二步法)染色,观察其形态及免疫表型特点,其中9例患者标本采用间期荧光原位杂交技术(FISH)检测t(11;18)(q21;q21)及t(14;18)(q32;q21),并对部分病例进行随访.结果 22例NMZL患者中位年龄62(16-77)岁,男女比例为1.2:1.22例患者中肿瘤累及部位以颈部淋巴结最为常见(11例),其后依次为腋下(9例)、腹股沟(7例)、颌下(6例)、纵隔(4例)、锁骨上(2例)及腹膜后淋巴结(1例).Ann Arbor分期:13例(59%)为I/Ⅱ期,9例(4l%)为Ⅲ/Ⅳ期.免疫表型检测显示所有患者标本肿瘤细胞均一致强表达CD20,不表达CD3e、CD10、CyelinD1、CD21、CD23、Bc1-6.CD5及Bc1-2阳性率分别为39%(18例中有7例)、30%(10例中有3例).FISH检测结果显示2例患者存在t(11;18),1例患者同时存在t(11;18)及t(14;18).13例患者获完整随访资料,随访时间为6-44个月,其中3例死亡,3年累积生存率为67%.结论 NMZL好发于中老年人,临床主要表现为多发淋巴结肿大,很少累及结外器官,临床分期较早,诊断时需结合临床相关检查及病理学改变综合分析,尤其是存在t(11;18)及t(14;18)的病例.     

Macrophages control the retention and trafficking of B lymphocytes in the splenic marginal zone

The marginal zone of the spleen is a precisely ordered region that contains specialized subsets of B lymphocytes and macrophages. Disruption of the negative signaling inositol phosphatase, SH2-containing inositol-5-phosphatase 1 (SHIP), results in the loss of marginal zone B cells (MZBs) with reorganization of marginal zone macrophages (MZMOs) to the red pulp of the spleen. This primary macrophage defect, as revealed by selectively depleting SHIP in myeloid cells shows that MZMOs are specifically required for the retention of MZBs. The MZMO phenotype was reverted in SHIP/Bruton's tyrosine kinase (Btk) double knockout mice, thus identifying the Btk activating pathway as an essential component being regulated by SHIP. Furthermore, we identified a direct interaction between the MARCO scavenger receptor on MZMOs and MZBs. Activation or disruption of this interaction results in MZB migration to the follicle. The migration of the MZMOs was further studied after the response to Staphylococcus aureus, which induced MZMOs to move into the red pulp while MZBs migrated into the follicular zone. The marginal zone is therefore a dynamic structure in which retention and trafficking of B cells requires specific macrophage-B cell interactions.     

原发性皮肤边缘区B细胞淋巴瘤临床病理特征

目的 探讨原发皮肤边缘区B细胞淋巴瘤(PCMZL)的临床和病理学特征,诊断和鉴别诊断.方法 对2例PCMZL和1例皮肤淋巴组织增生(CLP)病例进行临床特征、组织形态学、免疫表型及PCR IgH基因重排分析.结果 免疫组化示2例PCMZL的小淋巴细胞CD20和CD79(卅),bcL-2、BOB.1和Oct-2(++),MUM-1(+),CD5、CD10、bel-6和CD23(-);浆细胞CD138、MUM-1(++),限制性表达轻链kappa.1例CLP的小淋巴细胞CD20、CD3和bcl-2(++),MUMl(+);浆细胞同时表达K及λ.IgH扩增2例PCMZL呈单克隆性,1例CLP显示多克隆性.结论 PCMZL属MALT-L家族,形态学上肿瘤细胞由异源性小淋巴细胞组成,免疫学上显示后生发中心标记.浆细胞轻链限制性和B细胞抗原受体基因克隆性重排对诊断有非常重要的帮助.     

90例原发胃肠道黏膜相关淋巴组织结外边缘区B细胞淋巴瘤患者临床特征与预后分析

目的 了解原发胃肠道黏膜相关淋巴组织结外边缘区B细胞淋巴瘤(MALT淋巴瘤)患者临床特征及预后情况.方法 回顾性分析90例原发胃肠道MALT淋巴瘤患者资料,对患者临床特征和相关预后因素进行分析.结果 90例患者中胃内起病者78例,非胃内起病者12例.国际预后指数(IPI)评分0～2分者80例,3～5分者10例.与胃内起病者比较,非胃内起病者多为IPI 3～5分的高危患者(7.7％对33.3％,P=0.025)、幽门螺旋杆菌(Hp)感染率显著降低(50.0％对87.2％,P＜0.01).IPI评分0～2分的低危患者可选择抗Hp治疗、手术、放疗及化疗等治疗,其中化疗可提高患者无进展生存(PFS)率.接受化疗的高危患者3年总生存(OS)率达100.0％.单因素分析结果显示,ECOG评分(P=0.006)、Musshoff分期(P=0.008)、IPI评分(P=0.000)、LDH水平(P=0.019)和是否接受化疗(P=0.026)是影响患者PFS率的相关因素.多因素分析结果显示IPI评分(3～5分)(OR=8.325,95％ CI 3.171～21.853,P=0.000)和是否接受化疗(OR=0.319,95％CI0.121～0.838,P=0.020)是影响患者PFS率的独立预后因素,ECOG评分(≥2分)是影响患者OS率的独立预后因素(OR=5.092,95％CI1.005～25.788,P=0.049).结论 原发胃肠道MALT淋巴瘤是一种低度恶性的淋巴瘤,以低危患者多见,多数患者可获得长期生存.低危患者可选择放疗或抗Hp治疗作为起始治疗方案,高危患者应选择化疗.     

喉部及软腭黏膜相关淋巴组织结外边缘区淋巴瘤1例

<正>患者男,76岁,声音嘶哑半年余;吸烟史30年。查体：咽部轻度充血。实验室检查未见明显异常。喉镜：声门左侧1.7cm×2.2cm×3.0cm肿物,表面光滑,右杓状会厌襞肿胀。颈部CT于左杓状会厌襞、前庭襞及声襞见1.7cm×2.1cm×3.1cm黏膜下边缘清晰等密度肿物（图1A）,侵犯会厌前间隙,下达声门区、上凸向会厌谿、右凸向喉前庭,增强扫描动脉期轻度强化（图1B）、静脉期中度均匀强化;声门裂、喉室、喉前庭及双侧梨状隐窝变窄,邻近喉部骨性支架未见明显破坏;右杓状会厌襞肿胀（图1B）;双侧软腭弥漫肿胀（图1C）,增强后中度均匀强化（图1D、1E）。     

肝脏原发黏膜相关淋巴组织结外边缘区淋巴瘤一例

患者女,59岁,因"间断性右上腹胀痛2周"于2020年8月26日入兰大二院,无发热、寒战,无恶心、呕吐,无腹泻、便秘.查体:全身皮肤黏膜、巩膜无黄染,浅表淋巴结未扪及肿大.右上腹轻度压痛,腹部触及包块,腹式呼吸减弱,无腹壁静脉曲张.实验室检查,甲胎蛋白(alpha fetoprotein,AFPAFP)、癌胚抗原(ca...