ROS1 immunohistochemistry for detection of ROS1-rearranged lung adenocarcinomas

Am J Surg Pathol. 2013 Sep;37(9):1441-9. doi: 10.1097/PAS.0b013e3182960fa7.


ROS1 gene rearrangements are reported in 1% to 2% of lung adenocarcinomas (ACAs) and are associated with response to the multitargeted tyrosine kinase inhibitor crizotinib. ROS1 rearrangements can be detected using fluorescence in situ hybridization (FISH); however, immunohistochemistry (IHC) for ROS1 protein is a promising alternate screening modality. In this study, we examine the correlation between ROS1 IHC and FISH and describe the clinicopathologic characteristics of ROS1-rearranged lung tumors. ROS1 IHC was performed using clone D4D6 on whole-tissue sections. In a validation cohort, IHC was compared with ROS1 break-apart FISH in 53 cases of lung ACA enriched for an absence of known genetic alterations and never-smoking status. In a screening cohort, we performed ROS1 IHC on 167 consecutive cases of lung ACA from a routine molecular diagnostic practice and confirmed positive results by FISH. In the validation cohort, 6 cases (11%) were both FISH and IHC positive. One FISH-negative case was strongly ROS1 IHC positive. All IHC-negative cases were FISH negative. In the screening cohort, 2 of 167 (1.2%) had strong, diffuse ROS1 protein expression; a rearrangement was confirmed by FISH in both. ROS1-translocated tumors were wild type for EGFR, KRAS, and ALK and commonly had solid growth with mucinous/cribriform features and psammomatous calcification. ROS1 protein expression in tumor cells is 100% sensitive and 92% specific for ROS1 rearrangements by FISH. ROS1 IHC is an effective screening tool for this rare but clinically important subset of lung ACAs.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Adenocarcinoma / chemistry*
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / mortality
  • Adenocarcinoma / pathology
  • Adenocarcinoma of Lung
  • Adult
  • Aged
  • Aged, 80 and over
  • Biopsy
  • Female
  • Gene Rearrangement*
  • Genetic Predisposition to Disease
  • Humans
  • Immunohistochemistry*
  • In Situ Hybridization, Fluorescence
  • Lung Neoplasms / chemistry*
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • Male
  • Middle Aged
  • Phenotype
  • Predictive Value of Tests
  • Protein-Tyrosine Kinases / analysis*
  • Protein-Tyrosine Kinases / genetics*
  • Proto-Oncogene Proteins / analysis*
  • Proto-Oncogene Proteins / genetics*
  • Reproducibility of Results


  • Proto-Oncogene Proteins
  • Protein-Tyrosine Kinases
  • ROS1 protein, human