title: ROS1 immunohistochemistry for detection of ROS1-rearranged lung adenocarcinomas.
abstract: 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.
authors.affiliation: *Department of Pathology, Brigham and Women's Hospital †Lowe Center for Thoracic Oncology ‡Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, MA.
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Sholl
authors.forename: Heather
authors.initials: H
authors.lastname: Sun
authors.forename: Mohit
authors.initials: M
authors.lastname: Butaney
authors.forename: Chengsheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D005260:Female; D015321:Gene Rearrangement; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000737:chemistry* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011237:Predictive Value of Tests; D011505:Protein-Tyrosine Kinases / Q000032:analysis* / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000032:analysis* / Q000235:genetics*; D015203:Reproducibility of Results
chemical_list: D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human