目的:新型全自动免疫组织化学(IHC)检测方法——Ventana间变性淋巴瘤激酶(ALK)-D5F3用于ALK重排的筛查已经于2013年获得中国食品药品监督管理局批准,我们之前的研究揭示了高特异性和敏感性近100%,它的疗效需要在一大群原发性肺腺癌患者中进行评估,并比较ALK(+)和ALK(-)肺腺癌的临床病理特征。
方法:收集1,504例连续手术的中国汉族人群肺腺癌病例,按照2011年肺腺癌多学科分型进行再诊断。采用全自动VentanaALK-D5F3IHC染色并进行二元评分,以评估染色并与临床病理特征相关。包括年龄,性别,分化程度,组织学亚型,淋巴结转移,和临床分期。ALK(+)患者随访,根据NCCN指南,在IV期患者中采用并观察到ALK抑制剂的靶向治疗。
结果:在手术切除的1,504例NSCLC中,有6.6%的人发现了ALK阳性腺癌,且明显小于阴性组(P<0.05)。在ALK(+)病例中以粘液腺癌(28.2%)为主,其次是固体类型(11.7%),特定类型(6.8%),乳头状型(5.6%),腺泡型(5.5%),和麻药类型(3.1%),差异有统计学意义(χ2=42.011,P<0.05)。ALK(+)腺癌有淋巴结转移(10.8%)明显高于无淋巴结转移(4.5%)(χ2=19.809,P<0.05);而ALK(+)在Ⅳ期(20%)明显高于Ⅲ期(12.9%),第二阶段(4.2%),第一阶段(4.5%),0期(χ2=36.068,P<0.05)。多变量逻辑回归显示,患者年龄,AJCC分期,和组织学粘液性亚型与ALK阳性染色相关(OR分别为0.959、1.578、5.036)。68例患者有随访结果,5例初步诊断或进展为IV期的患者从克唑替尼靶向治疗中获益良好.
结论:在6.6%的中国非小细胞肺癌患者中发现了ALK融合蛋白,主要见于年轻人,临床分期较高,粘液性和实性占优势的腺癌。IV期患者的临床试验证实,ALK-D5F3VentanaIHC可用于筛选分子靶向治疗的ALK阳性候选者。
OBJECTIVE: The novel fully automated immunohistochemistry (IHC) assay-Ventana anaplastic lymphoma kinase (ALK)-D5F3 for screening ALK rearrangements has been approved by
China\'s Food and Drug Administration in 2013, our previous study disclosed a highly specificity and sensitivity nearly 100%, and its efficacy needs to be evaluated in a large cohort of primary lung adenocarcinoma patients, and to compare clinicopathological features with ALK (+) and ALK (-) lung adenocarcinoma.
METHODS: A total of 1,504 consecutive surgical lung adenocarcinoma cases of Chinese Han population were collected and re-diagnosed according to the 2011 multidisciplinary classification of lung adenocarcinoma. Fully automated Ventana ALK-D5F3 IHC staining with a binary scoring was adopted to evaluate staining and correlated with clinicopathological characters, including age, sex, differentiation degree, histological subtype, lymph node metastasis, and clinical staging. ALK (+) patients were followed-up, and targeted therapy of ALK-inhibitors was adopted and observed in patients with stage IV according to the NCCN guideline.
RESULTS: ALK positive adenocarcinomas were identified in 6.6% of the surgically resected 1,504 NSCLCs, and significantly younger than the negative group (P<0.05).Mucinous adenocarcinoma (28.2%) was determined to be predominant in ALK (+) cases, followed by the solid type (11.7%), specific type (6.8%), papillary type (5.6%), acinar type (5.5%), and lepidic type (3.1%), and the differences were statistically significant (χ2=42.011, P<0.05). ALK (+) adenocarcinoma with lymph node metastasis (10.8%) were significantly higher than that without lymph node metastasis (4.5%) (χ2=19.809, P<0.05); and ALK (+) in phase IV (20%) was significantly higher than phase III (12.9%), phase II (4.2%), phase I (4.5%), and phase 0 (0) (χ2=36.068, P<0.05). Multivariate logistic regression disclosed that patient age, AJCC staging, and histological mucinous subtype were correlated with ALK positive staining (OR=0.959, 1.578, 5.036, respectively). Sixty eight patients had followed-up results, five patients out of which primarily diagnosed or progressed into Stage IV benefited well from targeted therapy with Crizotinib.
CONCLUSIONS: The ALK fusion protein was seen in 6.6% Chinese NSCLC patients, and mostly seen in younger, clinically higher staging, mucinous and solid predominant adenocarcinoma. Clinical trials in patients of Stage IV confirmed that ALK-D5F3 Ventana IHC is serviceable in screening ALK-positive candidates for molecular targeted therapy.