ROS1 immunohistochemistry for detection of ROS1-rearranged lung adenocarcinomas
Lynette M Sholl1, Heather Sun, Mohit Butaney
1*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.
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.
Insights
Immunohistochemistry (IHC) for ROS1 protein is a sensitive and specific screening tool for detecting ROS1 gene rearrangements in lung adenocarcinoma. This method effectively identifies patients who may benefit from targeted therapies like crizotinib.
Area of Science:
- Oncology
- Molecular Pathology
- Genetics
Background:
- ROS1 gene rearrangements occur in 1-2% of lung adenocarcinomas.
- These rearrangements predict response to crizotinib, a targeted therapy.
- Fluorescence in situ hybridization (FISH) detects ROS1 rearrangements, but immunohistochemistry (IHC) offers a promising alternative screening method.
Purpose of the Study:
- To evaluate the correlation between ROS1 IHC and FISH for detecting ROS1 rearrangements in lung adenocarcinoma.
- To describe the clinicopathologic features of lung tumors with ROS1 rearrangements.
Main Methods:
- ROS1 IHC (clone D4D6) was performed on lung adenocarcinoma tissue sections.
- A validation cohort (n=53) compared IHC with ROS1 break-apart FISH.
- A screening cohort (n=167) used IHC for initial screening, with FISH for confirmation.
Main Results:
- ROS1 IHC showed 100% sensitivity and 92% specificity for detecting ROS1 rearrangements by FISH.
- In the validation cohort, 11% of cases were positive by both IHC and FISH.
- In the screening cohort, 1.2% of cases showed strong ROS1 IHC positivity, confirmed by FISH.
Conclusions:
- ROS1 IHC is a highly sensitive and specific screening tool for identifying ROS1 rearrangements in lung adenocarcinoma.
- This IHC approach can effectively identify patients with ROS1-rearranged tumors who may benefit from targeted therapies.
