title: Expression of ROS1 predicts ROS1 gene rearrangement in inflammatory myofibroblastic tumors.
abstract: Inflammatory myofibroblastic tumor is a distinctive, rarely metastasizing mesenchymal neoplasm composed of fascicles of spindle cells with a prominent inflammatory infiltrate. Roughly 50% of inflammatory myofibroblastic tumors harbor ALK receptor tyrosine kinase gene rearrangements. Such tumors are usually positive for ALK by immunohistochemistry. The molecular pathogenesis of ALK-negative inflammatory myofibroblastic tumors is largely unknown. A recent study identified rearrangements of ROS1 (another tyrosine kinase receptor) in a subset of ALK-negative inflammatory myofibroblastic tumors. Immunohistochemistry for ROS1 has been shown to correlate with ROS1 rearrangement in lung adenocarcinomas. The purpose of this study was to determine whether immunohistochemistry for ROS1 could predict ROS1 rearrangement in inflammatory myofibroblastic tumor. In total, 30 inflammatory myofibroblastic tumors were evaluated, including 21 ALK-positive tumors (10 confirmed to harbor ALK rearrangements, with TPM3, CLTC, RANPB2, and FN1 fusion partners) and 9 ALK-negative tumors (including 2 known to harbor ROS1 rearrangements). Immunohistochemistry was performed on whole tissue sections following pressure cooker antigen retrieval using a rabbit anti-ROS1 monoclonal antibody. The results were scored as 'positive' or 'negative,' and the pattern of staining was recorded. Three ALK-negative inflammatory myofibroblastic tumors (including both tumors with known ROS1 rearrangements) showed immunoreactivity for ROS1, whereas all ALK-positive inflammatory myofibroblastic tumors were negative for ROS1. One ROS1-positive inflammatory myofibroblastic tumor (with YWHAE-ROS1 fusion) showed strong, diffuse cytoplasmic and nuclear staining; one case (with TFG-ROS1 fusion) showed weak, diffuse and dot-like cytoplasmic staining; and one case (fusion partner unknown) showed moderate, diffuse and dot-like cytoplasmic staining. Expression of ROS1 correlates with ROS1 gene rearrangement in inflammatory myofibroblastic tumor. These findings suggest that immunohistochemistry for ROS1 may be useful to support the diagnosis of a subset of inflammatory myofibroblastic tumors and may select some clinically aggressive cases for targeted therapy directed against ROS1.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Hornick
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Sholl
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Dal Cin
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Merrida A
authors.initials: MA
authors.lastname: Childress
authors.affiliation: 1] Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA [2] Department of Medicine, Vanderbilt University School of Medicine and Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Lovly
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D015321:Gene Rearrangement; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007249:Inflammation; D008297:Male; D008875:Middle Aged; D047708:Myofibroma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012983:Soft Tissue Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human