CD99与ALK蛋白在间变性大细胞淋巴瘤患者中的复合表达及其临床意义

目的 探讨CD99/MIC2与间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)蛋白在间变性大细胞淋巴瘤(anaplastic large cell lymphoma,ALCL)中的复合表达规律及其临床意义.方法 对前期收集的25例有ALK蛋白表达和随访资料的ALCL患者进行回顾性分析,对ALK蛋白表达阳性组及阴性组患者生存时间进行比较;应用免疫组化S-P方法检测后期收集的25例ALCL患者病理组织标本和细胞株Karpas299细胞CD99蛋白和ALK蛋白表达,并进行两种蛋白复合表达分析.结果 前期收集的25例ALCL患者中位生存期在ALK阳性组(17例)为59个月,阴性组(8例)为20个月,阳性组患者的预后优于阴性组(P＜0.05).后期收集的25例ALCL患者标本中,CD99蛋白表达阳性18例(72.0％),阴性7例(28.0％);ALK蛋白表达阳性19例(76.0％),阴性6例(24.0％).在19例ALK阳性ALCL患者中16例(84.2％) CD99蛋白复合表达阳性,6例ALK阴性ALCL患者中,2例(33.3％) CD99蛋白复合表达阳性,两者差异有统计学意义(P＜0.05).CD99和ALK蛋白在Karpas299细胞中呈弥漫阳性表达.结论 CD99蛋白在ALCL患者中高表达,与ALK蛋白在ALCL患者中复合表达率较高,CD99联合ALK蛋白表达可作为ALCL病理诊断和判断预后的辅助指标,尤其对ALK蛋白表达阳性的ALCL患者更具有临床意义.     

ALK阴性的间变性大细胞淋巴瘤中Bcl-2、caspase-3及Ki-67的表达及意义

目的探讨棚（阴性的原发系统性间变性大细胞淋巴瘤（J眦L）中Bel-2、easpase-3及Ki-67的表达及其临床意义。方法收集7例确诊的ALK阴性的ALCL作观察组,应用免疫组织化学S—P法检测Bcl-2、caspase-3及Ki-67的表达,与同期15例ALK阳性AlEL作对照,分析Bcl-2、easpase-3及Ki-67在脚￡阴性的原发系统性间变性大细胞淋巴瘤中的表达与临床、病理形态学特征及生物学特性的关系。结果ALK。AIEL较ALK’ALGL发病年龄高,EMA表达率低,Ki-67、Bcl-2表达高,caspase-3表达率低,差异有统计学意义（P〈0．05）;三者表达无相关性（P〉0．05）。结论AIⅨ阴性ALCL中格-67、Bcl-2高表达,caspase-3低表这,与高度恶性程度有关,三者有望成为ALK阴性AtEL的的生物学标志物,三项联合检测可作为ALCL判断预后的指标以及有可能成为分子靶向治疗的靶点。     

间变性大细胞淋巴瘤中AKT、mTOR途径活化的研究

目的 研究间变性大细胞淋巴瘤(ALCL)患者中间变性淋巴瘤激酶(ALK)及磷酸化AKT(p-AKT)、mTOR(p-mTOR)、4E-BPI(p-4E-BPI)和p70S6K(p-p70S6K)的表达特点、临床意义及相互关系.方法 应用免疫组织化学EnVision法检测ALK蛋白及p-AKT、p-mTOR、p-4E-BP1、p-p70S6K蛋白的表达.结果 81例ALCL患者中有51例(63.0%)表达ALK蛋白,30例(37.0%)不表达,ALK阳性患者预后优于阴性患者(P<0.05).71例患者中54例(76.1%)表达p-AKT,p-AKT的表达与ALK表达相关(P<0.05);57例(80.3%)表达p-mTOR,p-mTOR的表达与ALK、p-AKT表达相关(P<0.05);64例(90.1%)表达p-4E-BP1,66例(93.0%)表达p-p70S6K,p-4E-BP1及p-p70S6K的表达与p-mTOR表达相关(P<0.05),与ALK、磷酸化p-AKT表达无关(P>0.05).p-AKT、P-mTOR、p-4E-BP1及p-p70S6K的表达与预后无关(P>0.05).COX比例风险回归分析表明ALK的表达、体质性症状对患者生存影响有统计学意义(P<0.05),其中,ALK的表达对生存的影响最大.结论 p-AKT、P-mTOR、p-4E-BP1和p-p70S6K在ALCL患者中均有表达,但在ALK阳性患者中表达率显著高于阴性患者.p-AKT、P-mTOR表达与ALK表达相关,提示在ALK阳性ALCL患者中存在AKT/mTOR通路的激活,但无明显的预后意义. 无关(P>0.05).p-AKT、P-mTOR、p-4E-BP1及p-p70S6K的表达与预后无关(P>0.05).COX比例风险回归分 表明ALK的表达、体质性症状对患者生存影响有统计学意义(P<0.05),其中,ALK的表达对生存的影响最大.结论 p-AKT、P-mTOR、p-4E-BP1和p-p70S6K在ALCL患者中均有表达,但在ALK阳性患者中表达率显著高于阴性患者.p-AKT、P-mTOR表达与ALK表达相关,提示在ALK阳性ALCL患者中存在AKT/mTOR通路的激活,但无明显的预后意义. 无关(P>0.05).     

对ALK阴性间变性大细胞淋巴瘤的新认识

ALK阴性的间变性大细胞淋巴瘤(ALK-ALCL)虽然具有和ALK+ ALCL相似的形态学特征,CD30亦呈强阳性,但缺乏相对特异的ALK蛋白表达.近来研究表明,两种ALCL不仅在分子和遗传学水平上存在实质性区别,而且在治疗反应,预后和长期生存等方面,ALK-ALCL远远差于ALK+ ALCL,如ALK-ALCL的受累人群一般为老年人,大部分患者合并B组症状,诊断时已处于疾病晚期,国际预后指数评分较高,常规治疗疗效较差,5年生存率低于49%等.鉴于此,本文对ALK-ALCL的基础细胞形态和组织病理、免疫麦型、细胞遗传学和分子标靶以及诊疗新进展作一综述.     

系统性间变大细胞淋巴瘤临床特征及预后分析

目的:分析系统性间变大细胞淋巴瘤(systemic anaplastic large cell lymphoma,ALCL)的临床病理特征;探讨患者临床、病理特征,尤其是间变淋巴瘤激酶(anaplastic lymphoma kinase, ALK)是否表达与预后的关系。方法:回顾性分析本院43例病理确诊为ALCL患者的临床病理特征、治疗及生存资料。结果:ALK阳性患者及ALK阴性患者在临床特征及治疗方案无显著差异,两组患者无进展生存期(progress free survival,PFS)及总生存期(overall survival,OS)无显著差异。单因素分析提示:患者是否合并噬血细胞综合征(hemophagocytic lymphohistiocytosis, HLH)是PFS及OS的影响因素(P0.05);多因素分析提示:是否合并HLH仍为PFS的独立影响因素(P0.05)。结论:ALK阳性及阴性ALCL患者生存无显著差异,发病时是否合并HLH是影响患者生存的预后因素。     

25例间变性大细胞淋巴瘤的临床分析

间变性大细胞淋巴瘤（anaplastic cell lymphomaALCL）是一种比较少见的恶性肿瘤。由于细胞表面表达ki-1（CD30）抗原，称ki-1阳性大细胞淋巴瘤。继而发现酪氨酸激酶（间变淋巴瘤激酶，anaplastic lymphoma kinase，ALK）的异常与其发生有关，从而对ALCL的实质有了进一步了解。在WHO新的淋巴瘤分类中，ALCL的B细胞型被归为弥漫大B细胞淋巴瘤，现在的ALCL仅指具有T细胞或非T非B细胞表型的淋巴瘤。我们发现25例ALCL患者的临床表现、治疗和预后有一定的差异，现报告如下。     

FOXA2、ALK在肺腺癌组织中的表达及其与临床病理特征、预后的关系

目的 研究叉头框架蛋白A2(FOXA2)、间变性淋巴瘤激酶（ALK）在肺腺癌组织中的表达及其与临床病理特征、预后的关系。方法 收集2014年5月至2017年5月我院确诊并收治的肺腺癌患者117例,取其癌组织及癌旁正常肺组织,采用免疫组化法检测FOXA2、ALK在肺腺癌组织及癌旁正常肺组织中的表达,分析FOXA2、ALK表达水平与肺腺癌临床病理学特征及预后的关系。结果 （1）肺腺癌组织中FOXA2表达阳性率显著低于癌旁正常肺组织,ALK表达阳性率显著高于癌旁正常肺组织,差异具有统计学意义（P<0.05）。（2）肺腺癌组织表达FOXA2与患者性别、年龄、肿瘤直径无显著相关性（P>0.05）,与组织分化程度、TNM分期、淋巴结转移有显著相关性（P<0.05）。肺腺癌组织表达ALK与患者性别、年龄、肿瘤直径、TNM分期、淋巴结转移无显著相关性（P>0.05）,与组织分化程度有显著相关性（P<0.05）。（3）FOXA2阳性表达患者的3年生存率显著高于FOXA2阴性表达患者,差异有统计学意义（P<0.05）。ALK阳性表达患者的3年生存率显著低于ALK阴性表达...     

大细胞间变性淋巴瘤中间变性淋巴瘤激酶基因异常研究进展

间变性淋巴瘤激酶(ALK)基因异常存在于半数以上的大细胞间变性淋巴瘤(ALCL)患者中，其编码的融合蛋白具有酪氨酸激酶活性，ALK蛋白的异常激活被认为与ALCL的发生有关。对ALK基因及其信号转导通路的研究有利于阐明肿瘤的分子病理机制，并为ALCL的治疗提供新的靶点，成为目前研究的热点之一。     

19例间变性大细胞淋巴瘤临床特征分析

目的总结19例间变性大细胞淋巴瘤（ALCL）病例的临床特点和治疗方法。方法回顾性分析2003年3月至2008年1月期间经病理证实的19例ALCL病例的临床特征。结果全组近期疗效：有效（CR＋PR）11例（57．9％）,其中CR4例（21．1％）;全组中位生存期10月,1年生存率为57．9％,2年、3年生存率均为52．6％。结论间变性大细胞淋巴瘤属较少见病例,最佳的治疗方案目前尚无定论。对于ALK阴性、IPI评分高、临床分期较晚、伴有全身症状的患者,目前的治疗方案尚未取得令人满意的效果,需要继续探索。     

大细胞间变性淋巴瘤中间变性淋巴瘤激酶基因异常研究进展

间变性淋巴瘤激酶(ALK)基因异常存在于半数以上的大细胞间变性淋巴瘤(ALCL)患者中,其编码的融合蛋白具有酪氨酸激酶活性,ALK蛋白的异常激活被认为与ALCL的发生有关。对ALK基因及其信号转导通路的研究有利于阐明肿瘤的分子病理机制,并为ALCL的治疗提供新的靶点,成为目前研究的热点之一。     

原发性皮肤间变性大细胞淋巴瘤13例临床病理分析

目的探讨原发性皮肤间变性大细胞淋巴瘤(ALCL)的临床病理形态特征、免疫组化及预后特点。方法对13例原发性皮肤ALCL进行形态学观察,免疫组化标记及随访,并结合相关文献进行讨论。结果 13例原发性皮肤ALCL中,男女之比为1.6∶1,平均年龄47岁。临床表现为皮肤斑块、结节、肿块;组织学形态多样;免疫组化示CD30均(+),大多数CD3和/或CD43(+),部分EMA、GranB和perforin(+),ALK、CKpan、CD20、CD79a、HMB45、CD68、CD15和CD117(-)。13例均经外科手术切除局部病变,再辅助以化疗和∕或放疗;9例随访时间5～55个月,1例死亡。结论原发性皮肤ALCL是低度恶性淋巴瘤,预后相对较好。诊断依赖于组织病理学及免疫组化标记。本病应与弥漫性大B细胞性淋巴瘤、黑色素瘤、低分化腺癌等鉴别。     

Reversal of microRNA-150 silencing disadvantages crizotinib-resistant NPM-ALK(+) cell growth

The regulatory microRNA miR-150 is involved in the development of hemopathies and is downregulated in T-lymphomas, such as anaplastic large-cell lymphoma (ALCL) tumors. ALCL is defined by the presence or absence of translocations that activate the anaplastic lymphoma kinase (ALK), with nucleophosmin-ALK (NPM-ALK) fusions being the most common. Here, we compared samples of primary NPM-ALK(+) and NPM-ALK(–) ALCL to investigate the role of miR-150 downstream of NPM-ALK. Methylation of the MIR150 gene was substantially elevated in NPM-ALK(+) biopsies and correlated with reduced miR-150 expression. In NPM-ALK(+) cell lines, DNA hypermethylation–mediated miR-150 repression required ALK-dependent pathways, as ALK inhibition restored miR-150 expression. Moreover, epigenetic silencing of miR-150 was due to the activation of STAT3, a major downstream substrate of NPM-ALK, in cooperation with DNA methyltransferase 1 (DNMT1). Accordingly, miR-150 repression was turned off following treatment with the DNMT inhibitor, decitabine. In murine NPM-ALK(+) xenograft models, miR-150 upregulation induced antineoplastic activity. Treatment of crizotinib-resistant NPM-ALK(+) KARPAS-299-CR06 cells with decitabine or ectopic miR-150 expression reduced viability and growth. Altogether, our results suggest that hypomethylating drugs, alone or in combination with other agents, may benefit ALK(+) patients harboring tumors resistant to crizotinib and other anti-ALK tyrosine kinase inhibitors (TKIs). Moreover, these results support further work on miR-150 in these and other ALK(+) malignancies.     

Ki-1 lymphoma

ALCL is widely recognized with its broad morphologic and phenotypic spectrum causing controversy in the diagnosis of this peculiar neoplasm. It is now beyond doubt that a significant proportion(64 to 84%) of the cases diagnosed as ALCL is closely associated with the expression of chimeric NPM-ALK protein activated by the (2;5) (p23;q35) chromosomal translocation, which can be detected by anti-p80NPM/ALK or ALK1 antibodies. Recently, some investigators including us asserted that these p80NPM/ALK or ALK1-positive(p80/ALK+) ALCLs represent a distinct genetic entity with occurrence in young patients and a favorable prognosis, and should be differentiated from the p80/ALK- tumors with the relatively aggressive clinical course. The p80/ALK+ lymphomas also revealed the characteristic morphology such as horseshoe-like, kidney-like or doughnut-like nuclei and frequent expression of EMA and cytotoxic molecules. However, these features are shared, though to a lesser degree, by other p80/ALK-negative lymphoid neoplasms. Indeed, it is indicated that cytotoxic ALCL cases may be either p80/ALK positive or negative, suggesting that the cytotoxicity and expression of p80/ALK are independent phenomena among the cases of ALCL of T- and null-cell type. Thus, several areas of disagreement and controversy that surround the diagnosis and categorization of ALCL remain.     

Efficacy of therapy of different variants of anaplastic large T-cell lymphomas

AIM: To compare efficacy of NHL-BFM-90 and CHOP-like courses in the treatment of anaplastic large cell lymphoma (ALCL). MATERIAL AND METHODS: Twenty-two patients with ALCL participated in the study. The diagnosis was made basing on the findings of clinical, device, morphological, immunohistochemical and molecular-genetic examinations with application of a panel of monoclonal antibodies to CD30, ALK, CD3, CD4, CDS, CD7, CD34, CD15, CD68, CD20, CD45RO, CD45RA, Ki-67. 14 cases of 22 were negative by kinase of anaplastic lymphocytes (ALK-) and 8 were positive (ALK+). Mean age of ALK-ALCL patients was 39.6 +/- 4.1 years, of ALK+ALCL patients - 23.4 +/- 2.6 years. 14 patients were treated by the protocol NHL-BFM-90, 8 were initially treated with other schemes (CHOP, MACOP-B, BEACOPP and others). All 14 patients treated according to NHL-BFM-90 had ALCL stages III-IV with B-symptoms. 12 patients who completed treatment by the above protocol achieved complete remission after the forth course, 2 patients failed the treatment. Of 8 ALCL patients treated initially according to other schemes, a complete remission was achieved in 4 patients (2 had stage II). One of 4 patients with remission had recurrence. Four patients who had failed to achieve complete remission died of the disease progression. CONCLUSION: ALCL occurs more frequently in young and middle-aged patients. The disease has an aggressive course with rapid generalization. For such processes it is more preferable to use a modified protocol NHL-BFM-90.     

Primary bone anaplastic lymphoma kinase positive anaplastic large-cell lymphoma: A case report and review of the literature

BACKGROUNDPrimary bone lymphoma (PBL) is an uncommon extranodal disease that represents approximately 1%-3% of lymphomas. Anaplastic lymphoma kinase (ALK) positive anaplastic large-cell lymphoma (ALCL) is an extremely rare type of PBL. The aim of this report is describe the symptoms, diagnosis, and treatment of primary bone ALK-positive ALCL.CASE SUMMARYA 66-year-old man presented to our hospital with neck and shoulder pain and intermittent fever that lasted for 1 mo. After extensive evaluation, positron emission tomography-computed tomography (CT) examination showed multiple osteolytic bone lesions without other sites lesions. CT-guided biopsy of the T10 vertebral body was performed, and the pathology results showed that neoplastic cells were positive for ALK-1, CD30, and CD3. A diagnosis of primary bone ALK positive ALCL was ultimately made. The patient was in partial response after four cycle soft cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, and we planned to repeat the biopsy and radiological examination after completion of the fifth cycle of therapy.CONCLUSIONPrimary bone ALK positive ALCL is a rare disease and physicians should keep in mind that ALCL can present with isolated osseous involvement without nodal involvement, and lymphoma should be considered in the differential diagnosis of primary bone lesions.     

Novel therapeutic options in anaplastic large cell lymphoma: molecular targets and immunological tools

Anaplastic large cell lymphoma (ALCL) is a CD30-positive, aggressive T-cell lymphoma, and about half of the patients with this disease harbor the t(2;5)(p21;q35) translocation. This chromosomal aberration leads to fusion of the NPM gene with the ALK tyrosine kinase, leading to its constitutive activation. To date, treatment options include polychemotherapy (e.g., cyclophosphamide, doxorubicin, vincristine, and prednisone), which is sometimes combined with radiation in the case of bulky disease, leading to remission rates of ～80%. However, the remaining patients do not respond to therapy, and some patients experience chemo-resistant relapses, making the identification of new and better treatments imperative. The recent discovery of deregulated ALK in common cancers such as non-small cell lung cancer and neuroblastoma has reinvigorated industry interest in the development of ALK inhibitors. Moreover, it has been shown that the ALK protein is an ideal antigen for vaccination strategies due to its low expression in normal tissue. The characterization of microRNAs that are deregulated in ALCL will yield new insights into the biology of ALCL and open new avenues for therapeutic approaches in the future. Also, CD30 antibodies that have been tested in ALCL for quite a while will probably find a place in forthcoming treatment strategies.     

Metastasis manners and the underlying mechanisms of ALK and ROS1 rearrangement lung cancer and current possible therapeutic strategies

The rearrangements of anaplastic lymphoma kinase (ALK) and the c-ros oncogene 1 (ROS1) have both been important driving factors in non-small-cell lung cancer (NSCLC). They have already been defined in 3–5% of NSCLC patients. ALK and ROS1 rearrangements are associated with unique clinical and pathological features, especially patients are usually younger, with milder or never smoking history, and adenocarcinoma histology. Also, they have both been found to contribute to the metastasis of NSCLC by cell migration and invasion. It has recently been recognized that the brain can be considered as a primary site for metastasis in cancers with ALK or ROS1 rearrangements. The present review summarizes the current status of NSCLC metastasis and possible mechanisms based on available evidence, and then we list possible therapeutic strategies so that an increase in control of ALK and ROS1 rearrangement of NSCLC metastases by combination therapy can be translated in an increase in overall survival and prognosis.

The rearrangements of anaplastic lymphoma kinase (ALK) and the c-ros oncogene 1 (ROS1) have both been important driving factors in non-small-cell lung cancer (NSCLC).