ALK阳性间变性大细胞淋巴瘤临床病理研究进展

约半数的间变性大细胞淋巴瘤（ALCL）病人中存在间变性淋巴瘤激酶（ALK）基因异常，ALK蛋白的异常激活使ALK阳性ALCL具有其典型的临床病理特征，并为ALK阳性ALCL的治疗提供新的靶点，提示ALK阳性ALCL的淋巴瘤可归类为一独立病种。     

ALK-ALCL合并嗜血细胞综合征一例报告并文献复习

间变大细胞淋巴瘤(anaplastic large cell lymphoma,ALCL)是一种恶性程度高且异质性明显的T细胞淋巴瘤,约占成人非霍奇金淋巴瘤的3%及儿童淋巴瘤的10%~20%[1]。1985年Stein等[2]发现ALCL以多形性大细胞增殖为主及高表达CD30(Ki-1),其最常见的染色体异常是t(2;5)(p23;q35),即2号染色体上的间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)基因和5号染色体上的核磷蛋白(nucleophosmin,NPM)基因融合产生了融合基因NPM-ALK。     

间变性大细胞淋巴瘤中ALK与clusterin的表达及其临床病理意义

背景与目的：间变性淋巴瘤激酶（ALK）是系统性间变性大细胞淋巴瘤（ALCL）较为特异的标志,近来研究发现一种新的蛋白clusterin在ALCL中也有较高的表达率,其可能在ALCL的发展中起作用,并对诊断和治疗具有潜在价值.本研究探讨ALCL中ALK及clusterin蛋白表达特点、相互关系及临床病理意义.方法：应用免疫组织化学EnVision法检测90例淋巴瘤组织中ALK及clusterin蛋白表达,其中包括47例ALCL及对照组周围T细胞淋巴瘤非特殊型（PTCL-u）22例,经典型霍奇金淋巴瘤（CHL）21例.结果：ALK在ALCL、PTCL和CHL中的阳性率分别为60%（28/47）、0和0;clusterin在三者中的阳性率分别81%（38/47）、27%（6/22）和14%（3/21）,ALK和clusterin在ALCL的阳性率均显著高于PTCL和CHL的阳性率（P＜0.05）,clusterin在ALK阴性的ALCL中的阳性率为68%（13/19）,也显著高于PTCL和CHL的阳性率（P＜0.05）.ALK阳性的ALCL中位年龄20岁（3～70岁）,显著低于ALK阴性者（P＜0.05）,阴性中位年龄48岁（4～71岁）,ALK阳性与否与发生部位、性别无关（P＞0.05）.clusterin的表达与否与年龄、部位和性别均无关（P＞0.05）.结论：ALK在ALCL中的特异性表达对其诊断、鉴别诊断并可能对临床预后判断具有重要价值.clusterin作为一新的分子标志物,在ALCL中的相对特异性高表达对ALCL的诊断、特别是对ALK阴性的ALCL与PTCL和CHL的鉴别诊断将具有重要意义.     

间变性大细胞淋巴瘤一例并文献复习

 目的　巩固对间变性大细胞淋巴瘤（ALCL）的定义、诊断、临床表现及治疗、预后的认识。方法　对1例ALCL患者的临床表现、实验室、影像学检查及治疗进行回顾。结果　通过对文献资料的复习,进一步学习和巩固了ALCL的定义、诊断、临床表现和相关治疗及进展,预后相关因素。结论　ALCL是一种具有特殊免疫表型和临床特点的非霍奇金淋巴瘤（NHL）,治疗方案尚无统一,间变性淋巴瘤激酶（ALK）为最重要预后影响因素。 【关键词】　间变性大细胞淋巴瘤;　淋巴瘤,非霍奇金;　肿瘤;　CD30 德国物理学家Stein等[1]1985年首次提出了"间变性大细胞淋巴瘤"（anaplastic large cell lymphoma,ALCL）的命名。其具有独特的病理学改变和生物学行为,是一种高度恶性肿瘤,为非霍奇金淋巴瘤（NHL）的一种特殊的罕见类型。现报道一例我科诊断的全身多发的ALCL,结合文献讨论如下。 无     

42例初治原发系统性间变大细胞淋巴瘤临床特点分析

目的:分析42例初治原发系统性间变大细胞淋巴瘤（ALCL）临床特点。方法:回顾性分析2012年1月至2016年12月河南省肿瘤医院淋巴瘤病区42例初治原发系统性ALCL住院病人的临床资料,根据是否表达间变性淋巴瘤激酶(anaplastic lymphoma kinase ALK)分为ALK＋组和ALK－组。根据临床特征数据的类型,分别采用秩和检验、卡方检验和Student's t检验比较各组临床特征的差异。结果:ALK＋组ALCL患者年龄低于ALK－组患者,差异有统计学意义（P＜0.05）;ALK＋组患者外周血PLT、Ann Arbor分期Ⅲ-Ⅳ比例和EMA表达比例高于ALK－组患者,差异有统计学意义（P均＜0.05）。结论:与ALK－ALCL患者相比,ALK＋ALCL患者年龄较小,有较高的外周血PLT,Ann Arbor分期多为Ⅲ-Ⅳ,有高的EMA表达。     

间变性大细胞淋巴瘤的形态学及免疫表型与诊断预后的相关性

目的：研究间变性大细胞淋巴瘤（ALCL）的临床病理特点和免疫表型，提高该疾病的早期诊断，并比较ALK＋与ALK-在临床表现、治疗和预后的不同点。方法：对原诊断为ALCL的20例病例重新行组织学观察和免疫组织化学染色（ABC法）并复习相关文献。结果：20例中15例属于T／Null细胞表型，结合免疫组化诊断为ALCL。15例ALCL均强烈表达CD30；ALK阳性者9例，ALK的表达与患者性别，免疫分型、组织分型、临床分期无相关性；而与患者年龄及化疗敏感性具有相关性（P〈0．05）。其余5例为B细胞表型（CD20强阳性），结合新的淋巴瘤分类标准，被诊断为弥漫性大B细胞淋巴瘤（DLBCL）。结论：间变性大细胞淋巴瘤中具有标志性的大细胞出现CD30、ALK和EMA阳性时，对ALCL的诊断具有重要价值；ALK＋ALCL与ALK-ALCL在遗传特征，临床表现及治疗预后的不同，使其作为一种新的病理类型被提出具有合理性。     

c-myc在间变性大细胞淋巴瘤中的表达及其意义

目的 探讨c-myc在系统性间变性大细胞淋巴瘤(ALCL)中蛋白表达和基因异常与临床病理特征、免疫组织分型的关系.方法 选取ALCL患者87例,应用免疫组织化学EnVision法检测c-mvc、间变性淋巴瘤激酶(ALK)、CD3、CD10、CD20、CD30、EMA的蛋白表达情况;应用荧光原位杂交(FISH)技术检测c-myc和ALK基因异常情况;统计分析c-myc蛋白表达和基因异常与各临床病理参数间的关系.结果 免疫组织化学结果:87例ALCL中,ALK阳性者54例(62.1％),c-myc阳性者27例(31.0％),c-myc和ALK蛋白联合表达20例(23.0％).c-myc蛋白表达率、c-myc和ALK蛋白联合表达率随ALCL临床分期的增加而升高,且在国际预后指数(IPI)高危组中表达率高于低危组(P＜0.05).FISH检测结果:87例ALCL中,50例(57.5％)发现ALK基因的易位,19例(21.8％)发现ALK基因的多拷贝.所有患者均未发现c-myc基因的易位,但19例(21.8％)检测到c-myc基因的多拷贝.c-myc基因多拷贝的发生率在ALK蛋白阳性和阴性组中差异无统计学意义(P＞0.05),在c-myc蛋白阳性和阴性组中发生率差异有统计学意义(P＜0.05),在IPI高危组中发生率高于低危组(P＜0.05).结论 c-myc蛋白表达及基因异常与ALCL临床分期、IPI相关,可作为判断ALCL恶性程度和预测预后的指标.     

间变大细胞淋巴瘤的分子生物学特点和临床特征分析

间变大细胞淋巴瘤(ALCL)是非霍奇金淋巴瘤的一个亚型.间变淋巴瘤激酶(ALK)融合基因及其表达产物是ALCL的特征性改变,也是ALCL的发病基础.根据ALK的表达,可将ALCL分为原发全身ALK+的ALCL、原发全身ALK-的ALCL和原发皮肤的ALCL.虽然ALCL属于侵袭性淋巴瘤,但目前的临床研究显示,ALCL的预后优于其他类型的侵袭性淋巴瘤,特别是ALK+的ALCL.鉴于该病的发病率较低,需要地区间的研究协作来探索标准的治疗方案.     

维布妥昔单抗治疗淋巴瘤的研究进展

霍奇金淋巴瘤（Hodgkin lymphoma,HL ）、间变性大细胞淋巴瘤（anaplastic large cell lymphoma,ALCL）及其他淋巴瘤中均有不同程度的CD30表达。维布妥昔单抗（Brentuximab vedotin,BV）作为一种针对CD30的抗体⁃药物偶联物,使淋巴瘤治疗的取得重要进展。BV目前已被批准用于治疗复发性HL和ALCL,以及HL的移植后维持治疗,并且已被证明对其他表达CD30的淋巴瘤有效。本文就BV在HL、ALCL和其他淋巴瘤中的研究进展进行综述。     

T细胞淋巴瘤中MUM1蛋白的表达及其与细胞增殖的关系

目的：探讨T细胞淋巴瘤中MUM1蛋白的表达及其与肿瘤细胞增殖的关系。方法：收集诊断及分型均明确的T细胞淋巴瘤患者的石蜡包埋组织58例,其中T淋巴母细胞性淋巴瘤/白血病（precursor Tlymphoblastic lymphoma/leukemia,T-LBL/L）9例、间变性大细胞淋巴瘤（anaplastic large Tcell lymphoma,ALCL）12例和外周T细胞性淋巴瘤（peripheral Tcell lymphoma,PTL）37例。另选2例反应性增生性淋巴结炎组织作对照。应用免疫组织化学法检测各组织中MUM1蛋白、ki-67的表达,并分析肿瘤组织中MUM1蛋白表达与ki-67增殖指数的关系。结果：1例T-LBL/L（1/9,11.11%）、9例ALCL（9/12,75.0%）和26例PTL（26/37,70.27%）组织中MUM1蛋白的表达呈阳性。MUM1蛋白在T-LBL/L中的阳性表达率明显低于ALCL组和PTL组（P〈0.05）,而在ALCL与PTL间的差别无统计学意义（P〉0.05）。MUM1蛋白阳性病例的ki-67增殖指数（53.61±23.83）%与MUM1阴性组（53.27±21.23）%相比,其差异无统计学意义（P〉0.05）。结论：MUM1蛋白在T细胞淋巴瘤中的表达可能与细胞活化有关,与肿瘤细胞的增殖可能无直接关系。     

Anaplastic large cell lymphoma: one or more entities among T‐cell lymphoma?

Anaplastic large cell lymphoma (ALCL) is a subtype of peripheral T‐cell lymphoma (PTCL) first described in 1985 as a lymphoid malignancy characterized by marked cellular pleomorphism, propensity to grow cohesively, tendency to invade lymph node sinuses and diffuse expression of CD30 1 . The discovery of the t(2;5), involving the anaplastic lymphoma kinase (ALK) gene on chromosome 2 and the nucleophosmin (NPM) gene on chromosome 5 in the majority of systemic ALCL, has soon pointed out that ALCL is a clinically and biologically heterogeneous disease. While ALK‐positive (ALK+) ALCL is usually characterized by onset in children and young adults and better prognosis, epidemiology, poor outcome and possibly genetic defects of ALK‐negative (ALK?) ALCL suggest that this neoplasms should be considered an independent pathological entity. The aim of this review is to illustrate clinical features, histology, immunophenotype, genetics and biology of ALCL and discuss possible relationship(s) among different T‐non‐Hodgkin lymphoma (T‐NHL). Copyright © 2009 John Wiley & Sons, Ltd.     

Quantitative PCR detection of NPM/ALK fusion gene and CD30 gene expression in patients with anaplastic large cell lymphoma--residual disease monitoring and a correlation with the disease status

Anaplastic large cell lymphoma (ALCL) represents a heterogeneous group of malignant lymphoproliferative diseases with a consistent expression of the cytokine receptor CD30. ALCL is frequently associated with a NPM/ALK fusion gene which is found in up to 75% of pediatric ALCLs. Real-time quantitative RT-PCR (RQ-RT-PCR) of NPM/ALK and CD30 gene expression was employed to analyze minimal residual disease (MRD) in 10 patients with NPM/ALK positive ALCL in 79 follow-up bone marrow (BM) and/or peripheral blood (PB) samples. In all BM samples from relapses and/or closely before a relapse, BM samples revealed NPM/ALK and CD30 positivity in at least one of the iliac BM trephines. Five out of nine relapses were preceded or were accompanied by minimally half log increased NPM/ALK levels in the BM. We found that RQ-RT-PCR of the CD30 expression is not suitable for MRD detection--only two relapses were accompanied by an increase of the CD30 level above a level which was detected in BM/PB samples from healthy individuals. RQ-RT-PCR of NPM/ALK expression is a promising and rapid approach for monitoring MRD.     

B and CTL responses to the ALK protein in patients with ALK-positive ALCL

Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) has a good prognosis compared to ALK-negative ALCL, possibly as a result of the immune recognition of the ALK proteins. The aim of our study was to investigate the presence of both a B and cytotoxic T cell (CTL) response to ALK in ALK-positive ALCL. We confirmed the presence of an antibody response to ALK in all 9 ALK-positive ALCL patients investigated. An ELISpot assay was used to detect a gamma-interferon (IFN) T cell response after short term culture of mononuclear blood cells with 2 ALK-derived HLA-A*0201 restricted peptides: ALKa and ALKb. A significant gamma-IFN response was identified in all 7 HLA-A*0201-positive ALK-positive ALCL patients but not in ALK-negative ALCL patients (n = 2) or normal subjects (n = 6). CTL lines (>95% CD8-positive) raised from 2 ALK-positive ALCL patients lysed ALK-positive ALCL derived cell lines in a MHC-Class I restricted manner. This is the first report of both a B cell and CTL response to ALK in patients with ALK-positive ALCL. This response persisted during long-term remission. The use of modified vaccinia virus Ankara (MVA) to express ALK is also described. Our findings are of potential prognostic value and open up therapeutic options for those ALK-positive patients who do not respond to conventional treatment.     

The NPM-ALK oncoprotein abrogates CD30 signaling and constitutive NF-kappaB activation in anaplastic large cell lymphoma

NPM-ALK characterizes anaplastic large cell lymphoma (ALCL), as does the high expression of CD30, a feature shared with H-RS cells of classic Hodgkin's lymphoma. In H-RS cells, ligand-independent signaling by overexpressed CD30 drives constitutive NF-kappaB activation, which is absent in ALCL cells. Here we show that NPM-ALK impedes CD30 signaling and NF-kappaB activation, dependent on both ALK kinase activity and the N-terminal NPM domain. NPM-ALK transduction into H-RS cell lines abrogates recruitment and aggregation of TRAF proteins, inducing an ALCL-like morphology and phenotype. TRAF2 associates with NPM-ALK at a consensus binding motif located in the kinase domain. Thus, NPM-ALK abrogates CD30-driven NF-kappaB activation and can also induce an ALCL phenotype, distinguishing ALCL cells from H-RS cells of T cell origin.     

间变性大细胞淋巴瘤的ALK和c-myc基因研究

 目的　探讨间变性大细胞淋巴瘤（ALCL）中间变性淋巴瘤激酶（ALK）基因与c-myc基因的分子遗传学改变。方法　收集原发系统性ALCL石蜡包埋组织标本72例,利用间期荧光原位杂交（FISH）技术检测ALCL肿瘤组织中ALK和c-myc基因结构与数目的变化。结果　72例ALCL中,ALK阳性者42例,40例存在涉及ALK基因的染色体易位,其中17例同时伴有ALK基因的多拷贝;ALK阴性的30例均未发现ALK基因的易位,但其中14例存在ALK基因的多拷贝。ALK基因多拷贝的发生率在ALK阳性与 阴性组中的差异无统计学意义（P＞0.05）。72例病例中,均未发现涉及c-myc基因的染色体易位,但其中24例存在c-myc基因的多拷贝。结论　大部分ALCL伴有ALK基因的异常（75.0 %）。以涉及ALK基因的染色体易位最为多见（55.6 %）,ALK基因多拷贝也是ALCL较为常见的遗传学改变（43.1 %）。前者只出现于ALK阳性ALCL中,后者既可出现在ALK阳性也可出现在ALK阴性的ALCL中。ALCL中不见或罕见涉及c-myc基因的染色体易位,但c-myc基因多拷贝的现象较为常见（33.3 %）。     

富于粒细胞的间变性大细胞淋巴瘤(附六例报道并文献复习)

目的　探讨间变性大细胞淋巴瘤 (ALCL)的一种新类型—富于粒细胞的ALCL的临床病理特点。方法　收集 6例本院及会诊病例 ,免疫组化ABC法证实为ALCL ,使用抗体包括CD45,CD3 ,CD45RO,CD2 0 ,CD79,CD3 0 ,ALK1,EMA ,CD15,S -10 0 ,CD68,CD1a,均为DAKO产品。结果　 6例均原发于淋巴结 ,其中 1例为B细胞性 ,5例为T细胞性 ,强表达CD3 0 ,不表达CD15,组织学特点为在肿瘤细胞间有大量的嗜中性粒细胞和 (或 )嗜酸性粒细胞浸润 ,局部形成小脓肿。结论　富于粒细胞的ALCL具有独特的组织学特点 ,可能是ALCL一种新亚型 ,但临床应与Langerhans细胞组织细胞增生症 (LCH) ,霍奇金淋巴瘤 (HL) ,T细胞淋巴瘤及急性化脓性炎症鉴别。     

p53 gene mutations are uncommon but p53 is commonly expressed in anaplastic large-cell lymphoma.

Anaplastic large-cell lymphoma (ALCL), as defined in the World Health Organization, is a heterogeneous category in which a subset of cases is associated with the t(2;5)(p23;q35) or variant translocations resulting in overexpression of anaplastic lymphoma kinase (ALK). p53 has not been assessed in currently defined subsets of ALCL tumors. In this study, we assessed ALK+ and ALK- ALCL tumors for p53 gene alterations using PCR, single-strand conformation polymorphism and direct sequencing methods. We also immunohistochemically assessed ALCL tumors for p53 expression. Three of 36 (8%) ALCL tumors (1/14 ALK+, 2/22 ALK-) with adequate DNA showed p53 gene mutations. By contrast, p53 was overexpressed in 36 of 55 (65%) ALCL tumors (16 ALK+, 20 ALK-). p21, a target of p53, was expressed in 15 of 31 (48%) ALCL tumors including seven of 15 (47%) p53-positive tumors. p21 expression in a subset of ALCL suggests the presence of functional p53 protein. Apoptotic rate was significantly higher in p53-positive than p53-negative tumors (mean 2.78 vs 0.91%, P = 0.0003). We conclude that the p53 gene is rarely mutated in ALK+ and ALK- ALCL tumors. Nevertheless, wild-type p53 gene product is commonly overexpressed in ALCL and may be functional in a subset of these tumors.