FISH patterns of ROS1, MET, and ALK with a correlation of ALK immunohistochemistry in lung cancer: a case for introducing ALK immunohistochemistry ‘Equivocal’ interpretation category in the Ventana anti?ALK (D5F3) CDx assay ? A tertiary cancer center experience

Background: Mutations in ROS1, ALK, and MET genes are targetable alterations in non-small cell lung cancer (NSCLC). They can be evaluated by different techniques, most commonly fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Methods: We explored the prevalence of ROS1, ALK, MET mutations, discuss clinicopathological associations and FISH signal patterns on 413 consecutive cases of EGFR negative lung carcinoma from March 2016 to April 2017 using FISH for ALK, ROS1, and MET along with ALK (D5F3) IHC. Results: ROS1 gene rearrangement, ALK positivity (IHC and/or FISH), and MET amplification were seen in 18/358 (5%) cases, 76/392 cases (19.4%), and 10/370 (2.7%) cases, respectively. ALK FISH and ALK IHC were positive in 51/300 (17%) and 58/330 cases (17.57%), respectively, while 8/330 (2.4%) cases were ALK IHC “equivocal” of which 3/8 (37.5%) were ALK FISH positive. Of ALK FISH and IHC co-tested cases, 43/238 (18.07%) cases were positive by both techniques, while 15/43 (34.88%) of ALK positive cases showed discordant ALK FISH and IHC results. All ROS1 rearranged and MET amplified cases were adenocarcinoma. Signet ring cell histology was associated with 78.57% likelihood of being either ALK or ROS1 positive. Genomic heterogeneity was seen in 30% of MET amplified cases. Conclusions: ALK/ROS1/MET gene alterations were found in 25.18% of NSCLC cases. An ALK IHC “equivocal” interpretation category should be incorporated into practice. Atypical patterns of ROS1 and genomic heterogeneity need to be evaluated further for any clinical relevance.

Evolving Cancer Classification in the Era of Personalized Medicine: A Primer for Radiologists

Traditionally tumors were classified based on anatomic location but now specific genetic mutations in cancers are leading to treatment of tumors with molecular targeted therapies. This has led to a paradigm shift in the classification and treatment of cancer. Tumors treated with molecular targeted therapies often show morphological changes rather than change in size and are associated with class specific and drug specific toxicities, different from those encountered with conventional chemotherapeutic agents. It is important for the radiologists to be familiar with the new cancer classification and the various treatment strategies employed, in order to effectively communicate and participate in the multi-disciplinary care. In this paper we will focus on lung cancer as a prototype of the new molecular classification.