title: Detection of ALK translocation in non-small cell lung carcinoma (NSCLC) and its clinicopathological significance using the Ventana immunohistochemical staining method: a single-center large-scale investigation of 1, 504 Chinese Han patients.
abstract: 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.
authors.affiliation: Department of Pathology, Cancer Hospital.
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Pathology, Cancer Hospital.
authors.forename: Yun
authors.initials: Y
authors.lastname: Ling
authors.affiliation: Department of Pathology, Cancer Hospital.
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
authors.affiliation: Internal Department, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China.
authors.forename: Di
authors.initials: D
authors.lastname: Ma
authors.affiliation: Department of Pathology, Cancer Hospital.
authors.forename: Xuemin
authors.initials: X
authors.lastname: Xue
authors.affiliation: Department of Pathology, Cancer Hospital.
authors.forename: Bingning
authors.initials: B
authors.lastname: Wang
authors.affiliation: Internal Department, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China.
authors.forename: Junling
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pathology, Cancer Hospital.
authors.forename: Jianming
authors.initials: J
authors.lastname: Ying
keywords: Anaplastic lymphoma kinase (ALK) rearrangements; clinicopathological analysis; fully automated immunohistochemistry (IHC); targeted therapy