眼附属器淋巴组织增生性病变的临床病理和分子遗传学特征及其意义

目的 分析眼附属器淋巴组织增生性病变的临床病理特点,探讨其分子遗传学特征及其意义.方法 收集1995-2007年37例眼附属器淋巴组织增生性病变石蜡组织标本(其中5例为反应性增生性病变,32例为淋巴瘤),依据2001年WHO肿瘤分类标准对32例淋巴瘤标本重新诊断分类.采用IgH、MALT1、bcl-6、c-Mye、bcl-2、CCND1、bcl-10、FOXP1双色分离重排探针、IgH/bcl-2双色融合易位探针和18号染色体着丝粒探针,利用间期荧光原位杂交(FISH)的方法 检测眼附属器淋巴组织增生性病变的分子遗传学特点.结果 32例淋巴瘤均为非霍奇金B细胞淋巴瘤.其中,黏膜相关淋巴组织结外边缘区B细胞淋巴瘤(MALT)淋巴瘤28例(87.5%),滤泡性淋巴瘤2例,弥漫性大B细胞淋巴瘤2例.60.7%(17/28)的眼附属器MALT淋巴瘤携带分子遗传学异常.其中,IgH基因断裂1例,但未找到与其发生相互易位的伙伴基因;基因3拷贝者16例,其中MALT1基因、bcl-6基因和c-Myc基因3拷贝的发生率分别为25%(7/28)、43%(12/28)和7%(2/28).16例基因3拷贝病例中,两种基因3拷贝合并存在者5例,其中bcl-6基因合并MALT1基因3拷贝者4例,bcl-6基因合并c-Myc基因3拷贝者1例.进一步研究显示,MALT1基因3拷贝者均存在18号染色体三体.2例滤泡性淋巴瘤都携带t(14;18)(q32;q21)/IgH-bcl-2.2例弥漫性大B细胞淋巴瘤均存在遗传学异常,1例表现为bcl-6基因3拷贝合并18号染色体三体,另1例表现为bcl-6基因3拷贝合并IgH和c-Myc基因双断裂.5例反应性淋巴组织增牛性标本均未见分子遗传学异常.结论 MALT淋巴瘤是眼附属器最常见的淋巴瘤类型;间期FISH有助于淋巴组织增生性病变的良恶性鉴别及淋巴瘤的分类;MALTI基因3拷贝者由18号染色体三体所致;18号染色体三体和bcl-6基因3拷贝(可能为3号染色体三体所致)是眼附属器MALT淋巴瘤常见的分子遗传学异常.     

胃肠道黏膜相关边缘区B细胞淋巴瘤和弥漫性大B细胞淋巴瘤中API2-MALT1融合基因表达的差异

目的 比较t(11;18)(q21;q21)/API2-MALX1融合基因在胃肠道黏膜相关边缘区B细胞淋巴瘤(MALN淋巴瘤)和弥漫性大B细胞淋巴瘤(DLBCL)中的发生情况,探讨t(11;18)(q21;q21)与胃肠道MALT淋巴瘤和DLBCL间演进的关系.方法 收集57例胃肠道MALT淋巴瘤(包括38例胃和19例肠),32例胃肠道DLBCL(包括28例胃和4例肠)和7例胃DLBCL同时合并MALT淋巴瘤成分,用荧光原位杂交(FISH)检测API2-MALT1融合基因.使用的探针包括API2-MALT1双色融合易位探针和MALT1双色分离重排探针.结果 在MALT淋巴瘤中有21.1%(12/57,包括10例胃和2例肠)发现API2-MALT1融合基因,而在32例DLBCL和7例DLBCL与MALT淋巴瘤混合的病例中均未检测出API2-MALT1融合基因.两组经统计学比较差异有统计学意义(X~2=9.383,P=0.001).结论 API2-MALT1融合基因是MALT淋巴瘤中特异的遗传学异常,而不见于DLBCL或DLBCL与MAIX淋巴瘤共存的病例中,提示至少在胃肠道API2-MALT1阳性的MALT淋巴瘤一般不会发生大细胞转化,而胃肠道DLBCL可能为原发或由t(11;18)阴性的部分MALT淋巴瘤转化而来.     

不同部位黏膜相关淋巴组织结外边缘区B细胞淋巴瘤中染色体的异常及其意义

目的 探讨不同部位黏膜相关淋巴组织结外边缘区B细胞淋巴瘤(MALT淋巴瘤)中t(11;18)/APl2-MALT1、t(1;14)/IgH-bcl-10、t(14;18)/IgH-MALT1和其他遗传学异常的发生情况及其意义.方法 收集196例不同部位的MALT淋巴瘤,包括胃53例[其中9例有弥漫性大B细胞淋巴瘤(DLBCL)成分]、眼眶50例、涎腺20例、肺20例、肠17例、皮肤17例、肝脏8例、甲状腺5例和其他部位6例(包括舌根2例,胰腺、喉、声带和肾脏各1例),用荧光原位杂交(FISH)分别检测APl2-MALT1、bel-10、MALT1和IgH基因的异常.结果 在196例MALT淋巴瘤中,APl2-MALT1融合基因共检出25例(12.8%).但是在不同部位,阳性率差异有统计学意义(P=0.002):从高到低依次为肺(45.0%,9/20)、不伴DLBCL成分的胃MALT淋巴瘤(22.7%,10/44)、涎腺(15.0%,3/20)、肠2/17、眼眶2.0%(1/50).而在伴DLBCL成分的胃MALT淋巴瘤、皮肤、甲状腺、肝脏和其他散发部位均未发现APl2-MALT1融合基因.在196例中,1例肺MALT淋巴瘤同时显示IgH基因和MALT1基因异常,可能是t(14;18)/IgH-MALT1异常.3例(2例不伴DLBCL成分的胃和1例肺)同时显示IgH基因和bcl-10基因异常,可能是t(1;14)/IgH-bcl-10异常.此外,用MALT1基因探针检测中,6例(2例涎腺、2例肝脏、1例伴DLBCL成分的胃和1例甲状腺)可能为18号染色体3体;3例(2例胃和1例肠)为MALT1基因扩增.结论 在MALT淋巴瘤中特异性的染色体异常发生率较低,但在不同部位,这些异常发生率存在差异.该现象提示发生在不同部位的MALT淋巴瘤,尽管组织形态学特点类似,但可能具有不同的发病机制.     

t(11;18)染色体易位对于胃黏膜相关淋巴组织淋巴瘤的预后价值

目的 探讨t(11;18)(q21;q21)染色体易位对于胃黏膜相关淋巴组织(mucosal associated lymphoid tissue,MALT)淋巴瘤预后意义.方法 采用回顾性方法对1994年1月至2004年6月间,经术后病理明确诊断的36例MALT淋巴瘤患者进行随访,同时采用间期荧光原位杂交技术检测患者保存的石蜡手术标本有无t(11;18)(q21;q21)染色体易位.结果 36例患者中15例检出t(11;18)(q21;q21)染色体易位,阳性率为41.67％;35例随访至2010年3月,总的中位生存期87个月,伴有t(11;18)(q21;q21)染色体易位者的中位生存期为43个月,无t(11;18)(q21;q21)染色体易位者的中位生存期为130个月,两组之间差异有统计学意义(x2 =29.57,P＜0.01).结论 t(11;18)(q21;q21)染色体易位是MALT淋巴瘤的重要预后因素.     

API2-MALT1融合基因变异体在粘膜相关淋巴组织结外边缘区B细胞淋巴瘤中的分布及凋亡的关系

目的探讨API2-MALT1融合基因变异体在粘膜相关淋巴组织结外边缘区B细胞淋巴瘤(extranodal marginal zone B—cell lymphoma of mucosa—associated lymphoid tissue，MALT)中的分布特点及其转录与肿瘤凋亡的关系。方法将逆转录-聚合酶链反应和巢式聚合酶链式反应结合，检测62例不同部位MALT淋巴瘤中API2-MALT1融合基因的多种变异体；通过TdT介导脱氧核苷酸缺口末端标记技术进行肿瘤细胞的原位凋亡检测；通过逆转录-聚合酶链反应和免疫组化染色检测API2的mRNA和蛋白水平。结果62例MALT淋巴瘤中28例检出API2-MALT1融合基因(45．16％)，为变异体A1446-M1123或A1446-M814，但未检出A1446-M541和A1446-M1150。A1446-M1123(18／28)的检出明显多于A1446-M814(10／28)。融和基因转录在甲状腺MALT淋巴瘤中检出最低，在其它部位的分布无差异。在API2-MALT1^ 组(API2-MALT1mRNA表达阳性组)肿瘤凋亡水平明显高于API2-MALT1^-组(API2-MALT1mRNA表达阴性组)，API2的mRNA和蛋白水平低于阴性组。A1446-M1123^ 与A1446-M814^ 病例之间凋亡和API2的变化无差异。结论MALT淋巴瘤中t(11；18)(q21；q21)的发生有部位差异，A1446-M1123可能是中国人MALT淋巴瘤中API2-MALT1融合基因变异体的主要类型。API2-MALT1融合基因转录与MALT淋巴瘤的凋亡水平和API2的变化有关。     

结外B细胞淋巴瘤组织中API2-MALT1融合基因的检测及其意义

目的了解API2-MALT1融合基因mRNA多种变异体在多个部位黏膜相关淋巴组织结外边缘区B细胞淋巴瘤（MALT淋巴瘤）、结外弥漫大B细胞淋巴瘤（DLBCL）以及桥本甲状腺炎中的分布特征,探讨t（11;18）（q21;q21）与上述淋巴瘤的临床病理特征和预后的关系及意义。方法收集手术切除的MALT淋巴瘤62例（肺10例、胃31例、肠9例及甲状腺12例）、DLBCL32例（胃16例、肠13例和甲状腺3例）及桥本甲状腺炎8例标本,通过逆转录聚合酶链反应（RT-PCR）检测所有病例的API2-MALT1 mRNA,5例淋巴结反应性增生作为阴性对照。根据检测结果将94例淋巴瘤分为API2-MALT1阳性及阴性组,比较两组的临床病理特征和生存率（随访6-120个月）。结果94例淋巴瘤中39例检出API2-MALT1 mRNA（MALT淋巴瘤28例,结外DLBCL 11例）。8例桥本甲状腺炎及阴性对照组均未检出融合基因。共检出A1446-M814和A1446-M1123两种变异体,以后者多见。融合基因mRNA检出率在甲状腺淋巴瘤最低,而在肺、胃肠较高。与阴性组相比,阳性组临床分期较早,浸润程度较轻、复发率较低,5年生存率较高。结论API2-MALT1融合基因mRNA在MALT淋巴瘤和结外DLBCL中都可被检出,而在桥本甲状腺炎中未检出。MALT1基因在1123bp断点较高的发生率可能是国人API2-MALT1形成时的一个特点;表达API2-MALT1融合基因的B细胞淋巴瘤具有更加惰性的临床过程和较好的存活情况,将其视为同一谱系更能体现其发展。     

胃B细胞淋巴瘤API2-MALT1融合基因表达与幽门螺杆菌感染的相关性

目的 探讨胃MALT淋巴瘤和弥漫性大B细胞淋巴瘤演进中t(11;18)(t121;q21)与幽门螺杆菌(HP)感染的关系,以及检测AP12-MALT1融合基因的意义。方法47例胃淋巴瘤病例(MALT淋巴瘤31例,弥漫性大B细胞淋巴瘤16例),经复查诊断后,用RT—PCR和巢式PCR,检测肿瘤组织中AP12-MALT1融合基因的表达,用半巢式PCR和特殊染色检查HP感染情况。根据淋巴瘤类型及融合基因检测结果将病例分组,观察各组病例HP感染的差异。结果47例胃淋巴瘤中20例AP12-MALT1融合基因mRNA检测阳性,包括16例MALT淋巴瘤和4例弥漫大B细胞淋巴瘤。HP感染检出率：AP12-MALT1阳性组为25％(5／20),AP12-MALT1阴性组25．92％(7／27)。统计学分析表明两组间差异无显著性。2例AP12-MALT1融合基因检测阴性的胃MALT淋巴瘤病例经抗HP治疗后病情稳定。结论胃MALT淋巴瘤和DLBCL中AP12-MALT1 mRNA表达与胃淋巴瘤HP感染无明显相关,AP12-MALT1融合基因可能成为胃MALT淋巴瘤抗HP治疗效果不良的预测因子。     

黏膜相关淋巴组织淋巴瘤诊断进展

黏膜相关淋巴组织(mucosa-associated lymphoid tissue,MALT)淋巴瘤是起源于生发中心后边缘区记忆B细胞,常发生于黏膜获得性淋巴组织的淋巴瘤。MALT淋巴瘤组织学形态多样,缺乏特异性的免疫表型,诊断较困难,目前主要采用排除性的诊断方法。随着分子病理学技术快速发展,鉴别诊断手段日益增多,如采用PCR技术检测MALT淋巴瘤Ig基因重排,荧光原位杂交技术检测MALT淋巴瘤中Ig H基因断裂以及t(11;18)(q21;q21)、t(1;14)(p22;q32)、t(14;18)(q32;q21)、t(3;14)(p14;q32)4种独特的染色体改变等。该文对MALT淋巴瘤的病因学、临床病理学特征、遗传学特征等研究进展进行综述,探讨其对MALT淋巴瘤诊断及鉴别诊断、治疗和预后判断的临床意义。     

荧光原位杂交技术在淋巴瘤诊断中的价值

目的 探讨荧光原位杂交(FISH)检测在淋巴瘤诊断中的价值,为淋巴瘤的准确诊断提供依据.方法 以前瞻性非随机分组模式,采用三组IgH/bcl-2、IgH/CCNDl、API2/MALT1探针,对临床初诊为淋巴瘤的74例活检新鲜样本的瘤细胞进行FISH,检测其相应t(14;18)、t(11;14)及t(11;18)染色体易位,将检测结果与组织病理诊断进行比较评价.结果 74例中8例(10.8%)检测到染色体易位,分别为t(14;18)和t(11;14)各4例.62例组织病理诊断为淋巴瘤者中7例检测到染色体易位,分别为t(14;18)3例(组织病理诊断2例为滤泡性淋巴瘤、1例为结节硬化型霍奇金淋巴瘤);t(11;14)4例(组织病理诊断2例为套细胞淋巴瘤、1例滤泡性淋巴瘤,1例小淋巴细胞淋巴瘤).在组织病理未诊断为淋巴瘤的12例中,仅检测到1例t(14;18),而其组织形态显示为淋巴组织增生活跃,经FISH检测更正诊断为滤泡性淋巴瘤.25例弥漫性大B细胞淋巴瘤未检测到t(14;18).在其他有基因数目异常者56例(75.7%)中恶性病变52例(92.9%),与4例(7.1%)良性病变比较,病变性质与基因数目异常之间差异有统计学意义(P=0.011).结论 FISH技术检测淋巴瘤特异的遗传学异常对于复核组织病理诊断、鉴别其类型、亚型及病变的良、恶性有重要参考价值.     

无t(14;18)染色体易位滤泡性淋巴瘤中BCL-2蛋白表达的变异

滤泡性淋巴瘤(FL)的遗传学特征为t(14;18)(q32;q21)染色体易位,导致肿瘤细胞BCL-2基因重排,BCL-2蛋白过表达。部分BCL-2蛋白阳性表达的FL中缺乏t(14;18)染色体易位,也有少数FL同时缺乏BCL-2蛋白表达及t(14;18)染色体易位。     

MALT1, BCL10 and FOXP1 in salivary gland mucosa-associated lymphoid tissue lymphomas

In view of the certain anatomic site-dependent frequency of chromosomal translocations involved in extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) pathogenesis, 17 salivary gland MALT lymphoma cases were analyzed for MALT1 and FOXP1 translocations. B cell CLL/lymphoma 10 (BCL10) and forkhead box PA (FOXP1) protein expression were studied by immunohistochemistry and translocations identified using fluorescence in situ hybridization (FISH)-specific probes FOXP1, t(11;18)(q21;q21)/API2-MALT1 and t(14;18)(q32;q21)/IgH-MALT1. None of the 11 analyzed cases showed FOXP1 rearrangement or amplification. The t(11;18) was present in five of 13 cases and the t(14;18) in three of 13 cases. MALT1 translocations were mostly mutually exclusive except in a single case. FOXP1 protein expression showed differences in the proportion of tumor cells with nuclear expression but not in their intensity, with the exception of one case where very intense nuclear staining was noted. BCL10 nuclear expression was present in four of 17 cases, two of which lacked t(11;18). Our results suggest that MALT1-specific translocations and FOXP1 rearrangements are not commonly involved in pathogenesis. A case with strong FOXP1 protein expression indicates the possibility that the upregulation of FOXP1 expression is significant in a small subset of salivary gland MALT lymphomas. Also a single case in which both MALT1 translocations were present indicates that these are not always mutually exclusive.     

Mucosa-associated lymphoid tissue lymphoma: molecular pathogenesis and clinicopathological significance

Mucosa-associated lymphoid tissue (MALT) lymphoma is a low-grade tumor closely associated with chronic inflammation such as that of Helicobacter pylori gastritis, Sjogren's syndrome, and Hashimoto's thyroiditis. Tumor regression by H. pylori eradication alone is well known in gastric MALT lymphoma, but some tumors occur in the absence of pre-existing chronic inflammation. The understanding of MALT lymphoma biology has significantly improved, and recurrent cytogenetic alterations have been detected. These include the trisomies 3 and 18, and the translocations t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), and t(3;14)(p14.1;q32). At least some of these alterations result in the constitutive activation of the nuclear factor (NF)-kappaB pathway, and may exert anti-apoptotic action. Apoptosis inhibitor 2-MALT lymphoma-associated translocation 1 (API12-MALT1) fusion, resulting from t(11;18)(q21;q21), is specific to, and is the most common in, MALT lymphomas, and its clinicopathological significance has been studied extensively. The focus of the present review is on the recent progress made in elucidating MALT lymphomagenesis and its clinicopathological impact, especially in terms of the effect of API2-MALT1 fusion on this unique tumor.     

T(14;18)(q32;q21) involving MALT1 and IGH genes in an extranodal diffuse large B-cell lymphoma

Two translocations involving the MALT1 gene have been described in extranodal marginal zone B-cell lymphomas of MALT type. A t(11;18)(q21;q21) involving API2 and MALT1 occurs in a subset of MALT lymphomas but with only rare exception is absent in diffuse large B-cell lymphomas (DLBCL), even at MALT sites. More recently, a t(14;18)(q32;q21) involving IGH and MALT1 has been described in nongastric extranodal MALT lymphomas. This translocation is indistinguishable from the IGH-BCL2 translocation by using classical cytogenetics. We report the IGH-MALT1 translocation in a cutaneous DLBCL as shown by classical cytogenetics and molecular cytogenetic analysis. This is the first report of an IGH-MALT1 translocation in DLBCL. These findings indicate that MALT1 translocations are not restricted to indolent-appearing lymphomas, provide further evidence that API2-MALT1 and IGH-MALT1 translocations exhibit biologic differences, have implications regarding the pathogenesis of some extranodal DLBCL, and emphasize that a t(14;18)(q32;q21) cannot be assumed to reflect a BCL2 translocation.     

MALT lymphoma with t(14;18)(q32;q21)/IGH-MALT1 is characterized by strong cytoplasmic MALT1 and BCL10 expression

Mucosa-associated lymphoid tissue (MALT) lymphoma is specifically associated with t(11;18)(q21;q21), t(1;14)(p22;q32) and t(14;18)(q32;q21). t(11;18)(q21;q21) fuses the N-terminus of the API2 gene to the C-terminus of the MALT1 gene and generates a functional API2-MALT1 product. t(1;14)(p22;q32) and t(14;18)(q32;q21) bring the BCL10 and MALT1 genes respectively to the IGH locus and deregulate their expression. The oncogenic activity of the three chromosomal translocations is linked by the physiological role of BCL10 and MALT1 in antigen receptor-mediated NFkappaB activation. In this study, MALT1 and BCL10 expression was examined in normal lymphoid tissues and 423 cases of MALT lymphoma from eight sites, and their expression was correlated with the above translocations, which were detected by molecular and molecular cytogenetic methods. In normal B-cell follicles, both MALT1 and BCL10 were expressed predominantly in the cytoplasm, high in centroblasts, moderate in centrocytes and weak/negative in mantle zone B-cells. In MALT lymphoma, MALT1 and BCL10 expression varied among cases with different chromosomal translocations. In 9/9 MALT lymphomas with t(14;18)(q32;q21), tumour cells showed strong homogeneous cytoplasmic expression of both MALT1 and BCL10. In 12/12 cases with evidence of t(1;14)(p22;q32) or variants, tumour cells expressed MALT1 weakly in the cytoplasm but BCL10 strongly in the nuclei. In all 67 MALT lymphomas with t(11;18)(q21;q21), tumour cells expressed weak cytoplasmic MALT1 and moderate nuclear BCL10. In MALT lymphomas without the above translocations, both MALT1 and BCL10, in general, were expressed weakly in the cytoplasm. Real-time quantitative RT-PCR showed a good correlation between MALT1 and BCL10 mRNA expression and underlining genetic changes, with t(14;18)(q32;q21)- and t(1;14)(p22;q32)-positive cases displaying the highest MALT1 and BCL10 mRNA expression respectively. These results show that MALT1 expression pattern is identical to that of BCL10 in normal lymphoid tissues but varies in MALT lymphomas, with high cytoplasmic expression of both MALT1 and BCL10 characterizing those with t(14;18)(q32;q21).     

MALT lymphoma: many roads lead to nuclear factor-κb activation

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma is characterized genetically by several recurrent, but mutually exclusive, chromosome translocations. To date, it has been shown that at least the oncogenic products of t(1;14)(p22;q32)/BCL10-IGH, t(14;18)(q32;21)/IGH-MALT1 and t(11;18)(q21;q21)/API2-MALT1 activate the nuclear factor (NF)-κB activation pathway. Recently, A20, an essential global NF-κB inhibitor, was found to be inactivated by somatic deletion and/or mutation in translocation-negative MALT lymphomas. However, these genetic abnormalities alone are not sufficient for malignant transformation and thus need to cooperate with other factors in MALT lymphomagenesis. Recent studies have shown steady, exciting progresses in our understanding of the biological functions of BCL10, MALT1 and A20 in the regulation of the NF-κB activation pathways and the biology of lymphocytes. This review discusses the implication of these recent advances in the molecular pathogenesis of MALT lymphoma, and explores how the above genetic abnormalities cooperate with immunological stimulation in the development of lymphoma.     

API2-MALT1 fusion gene in colorectal lymphoma.

The API2-MALT1 fusion gene was originally identified from a t(11;18)(q21;q21) translocation, a specific chromosomal abnormality that is found in mucosa-associated lymphoid tissue (MALT) lymphoma. Gastric MALT lymphomas positive for the API2-MALT1 fusion gene do not respond to Helicobacter pylori-eradication therapy, but otherwise, the incidence and clinicopathological behavior of colorectal MALT lymphoma with this genetic abnormality are unclear. We examined the API2-MALT1 fusion by multiplex RT-PCR method in 47 cases of MALT lymphoma and 13 cases of diffuse large B-cell lymphoma and evaluated the relevance of API2-MALT1 positivity to the clinical and pathological features. The mean ages of MALT lymphoma and diffuse large B-cell lymphoma patients were 65 (range, 37-87 y) and 58 (range, 14-85 y) years, respectively. API2-MALT1 fusion genes were detected in seven cases (15%) of MALT lymphoma and one case (8%) of diffuse large B-cell lymphoma. In MALT lymphomas, the tumor size in API2-MALT1-positive cases was 62 +/- 39 mm (mean +/- SD), statistically larger than that in API2-MALT1-negative cases (25 +/- 19 mm; P <.01). The API2-MALT1-positive cases demonstrated more advanced clinical stages and a male predominance, compared with API2-MALT1-negative cases. Thus, API2-MALT1-positive tumors should be cared for as a more aggressive subgroup and be followed for a longer time.