ES12.01 Multiple Lung Nodules

Abstract

Advanced imaging techniques resulted in increased detection of multiple tumors of the lung. Distinguishing synchronous primary lung cancers from intrapulmonary metastases (separate nodules) is important because treatments are very different. In addition, patients with independent primary tumors are expected to have better prognosis. Staging of such tumors as independent primary tumors or intrapulmonary metastases is often challenging, particularly in squamous cell carcinomas. Martini and Melamed modified criteria were used as the main approach for many decades with the idea that morphology of metastases should match the primary tumor, while different morphology supports classification of tumors as unrelated separate primaries. The 8th edition of the AJCC staging of the lung cancer pretty much has replaced this classification by establishing a multidisciplinary approach to these tumors as a standard of care and by promoting the tools such as comprehensive histologic assessment, imaging studies and molecular characterization either by CGH or biomarker testing. Comprehensive histologic assessment is based on the 2015 WHO classification of lung cancers and includes determination of the main histologic tumor type, quantitative subtyping particularly of lung adenocarcinomas, and assessment of cytologic and stromal characteristics. This approach can be relatively easily applied in lung adenocarcinomas, while squamous cell carcinoma remains a great challenge. A recent study conducted by the IASLC Pathology committee showed a good agreement (κ score 0.60) among thoracic pathologists in the histologic assessment of independent primary tumors from intrapulmonary metastasis. Despite a good agreement, there were cases with split opinions supporting a need for ancillary studies. Over the past decade many studies reported different molecular approaches to analysis of multiple lung tumor nodules including DNA microsatellite analysis, CGH/aCHG and most recently next generation sequencing. The data from published reports indicate a highly variable percentage of multifocal tumors identified as clonally related (up to 70%). Discrepancy between clinical and molecular classification of originally presumed cases of multiple primary lung cancers ranged in different series from 18% to 30%. Recent recommendations for routine molecular profiling of lung adenocarcinoma resulted in a widespread use of targeted mutational profiling for oncogenic mutations (i.e. EGFR, KRAS, BRAF etc) and gene rearrangements (i.e.ALK, ROS1) which results can be used in staging of multiple lung cancers. A different mutation profile in oncogenic mutations strongly indicates two separate primary tumors. However, the presence of a common driver mutation does not necessarily indicate tumors of similar origin. Therefore, limited molecular panels may not be sufficient in some cases. The detection of shared identical breakpoints by whole genome sequencing has been recently proposed as potentially more accurate and specific for lineage determination than the analysis of driver mutations alone. Also whole exome and whole genome sequencing approaches have been reported, but these assays may be technically challenging and turnaround time may not be suitable for routine clinical use.