A Comprehensive Comparative Analysis of the Histomorphological Features of ALK-Rearranged Lung Adenocarcinoma Based on Driver Oncogene Mutations: Frequent Expression of Epithelial-Mesenchymal Transition Markers than Other Genotype

et al. (2013) A Comprehensive Comparative Analysis of the Histomorphological Features of ALK-Rearranged Lung Adenocarcinoma Based on Driver Oncogene Mutations: Frequent Expression of Epithelial-Mesenchymal Transition Markers than Other Genotype. PLoS ONE 8(10): e76999. doi:10.1371/journal.pone.0076999 A Comprehensive Comparative Analysis of the Histomorphological Features of ALK -Rearranged Lung Adenocarcinoma Based on Driver Oncogene Mutations: Frequent Expression of Epithelial-Mesenchymal Transition Markers than Other Genotype Hyojin Kim 0 Se Jin Jang 0 Doo Hyun Chung 0 Seol Bong Yoo 0 Pingli Sun 0 Yan Jin 0 Kyung 0 Han Nam 0 Jin-Ho Paik 0 Jin-Haeng Chung 0 Alfredo Fusco, Consiglio Nazionale delle Ricerche (CNR), Italy 0 1 Department of Pathology, Seoul National University Bundang Hospital , Seongnam , Republic of Korea, 2 Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea, 3 Department of pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea, 4 Department of Pathology, Presbyterian Medical Center , Jeonju , Republic of Korea Molecular classification of lung cancer correlates well with histomorphological features. However, specific histomorphological features that differentiate anaplastic lymphoma kinase (ALK)-rearranged tumors from ALK-negative tumors have not been fully evaluated. Eighty ALK-rearranged and 213 ALK-negative (91 epidermal growth factor receptor-mutated; 29 K-rasmutated; 93 triple-negative) resected lung adenocarcinomas were analyzed for several histomorphological parameters and histological subtype. ALK-rearranged tumors were associated with younger age at presentation, frequent nodal metastasis, and higher stage of disease at diagnosis. ALK-rearranged tumors were more likely to show a solid predominant pattern than ALK-negative tumors (43.8%; 35/80; p,0.001). Unlike ALK-negative tumors, a lepidic predominant pattern was not observed in ALK-rearranged tumors (p,0.001). In multivariate analysis, the most significant morphological features that distinguished ALK-rearranged tumors from ALK-negative tumors were cribriform formation (odds ratio [OR], 3.253; p = 0.028), presence of mucin-containing cells (OR, 4.899; p = 0.008), close relationship to adjacent bronchioles (OR, 5.361; p = 0.001), presence of psammoma bodies (OR, 4.026; p = 0.002), and a solid predominant pattern (OR, 13.685; p = 0.023). ALK-rearranged tumors exhibited invasive histomorphological features, aggressive behavior and frequent expression of epithelial-mesenchymal transition markers (loss of E-cadherin and expression of vimentin) compared with other genotype (p = 0.015). Spatial proximity between bronchus and ALK-rearranged tumors and frequent solid histologic subtype with p63 expression may cause diagnostic difficulties to differentiate squamous cell carcinoma in the small biopsy, whereas p40 was rarely expressed in ALK-rearranged adenocarcinoma. Knowledge of these features may improve the diagnostic accuracy and lead to a better understanding of the characteristic behavior of ALK-rearranged tumors. - Adenocarcinoma of the lung is the most common histological type of primary lung cancer [1] and is a heterogeneous tumor with diverse molecular, clinical, and pathological characteristics. Identification of molecular driver mutations and their therapeutic implications in lung adenocarcinoma have become an important area of research as evidenced by the abundance of genomic, mutational, and proteomic profiling studies. [2,3] Many studies have shown correlations between morphological features and molecular alterations in lung adenocarcinoma. Previous reports have investigated the association between epidermal growth factor receptor (EGFR) mutations and specific histological subtypes of adenocarcinoma such as lepidic (formerly known as nonmucinous bronchioloalveolar carcinoma), papillary, and micropapillary patterns.[47] In contrast, KRAS mutation status has been shown to be significantly associated with solid and invasive mucinous adenocarcinoma subtypes. [8,9] Therefore, these findings raise the fundamental question of whether morphological features reflect the presence of molecular alterations. The presence of anaplastic lymphoma kinase (ALK) gene rearrangement in lung adenocarcinomas is the best predictor of response to crizotinib, an ALK tyrosine kinase inhibitor. [10,11] Fluorescence in situ hybridization (FISH) has been established as the gold standard method for the detection of ALK rearrangement in lung adenocarcinoma. The Food and Drug Administration approved crizotinib with a companion diagnostic FISH test for ALK-rearranged non-small cell lung cancer (NSCLC). Several studies have investigated the predictive value of pathological and morphological features in detecting ALK-rearranged tumors; however, the results of these studies have been inconsistent because of the limited number of ALK-rearranged tumors. [1216] Solid signet-ring cell subtypes and cribriform pattern have been associated with ALK rearrangement in lung adenocarcinoma. [12,15] A few studies have reported a positive histological correlation with ALK rearrangement in lung adenocarcinoma using the new International Association for the Study of Lung Cancer, American Thoracic Society and European Respiratory Society (IASLC/ATS/ERS) classification that was published in 2011. [16,17] However, the comparative analysis of these histomorphological features and subtypes of ALK-rearranged lung adenocarcinoma based on driver oncogene mutations has not been clearly established in lung adenocarcinoma. The aim of this study was 1) to evaluate the clinicopathological and histological features of 80 cases of ALK-rearranged resected lung adenocarcinomas, 2) to compare these features with those of ALK-negative tumors expressing well-known driver mutations associated with lung adenocarcinoma, and 3) to investigate the correlation between molecular subtype and histological features of lung adenocarcinoma based on the new IASLC/ATS/ERS classification. Materials and Methods Case Selection This study was approved by the Institutional Review Board at Seoul National University Bundang Hospital. Written informed consent was specifically waived by the approving IRB in this study. A total of 80 surgically resected lung adenocarcinoma specimens harboring ALK-rearrangement were retrieved from the files of Seoul National University Affiliated Hospitals and the Asian Medical Center between January 2004 and June 2011. In addition, 213 ALK-negative resected adenocarcinoma specimens obtained from patients diagnosed between March 2009 and March 2010 were included in the study. Of the 213 ALK-negative tumors, 91 were EGFR-mutated, 29 were K-ras-mutated, and 93 were triple-negative (TN; wild-type EGFR, K-ras, and ALK). Patients who had a previous history of cancer, presurgical chemotherapy or radiotherapy were excluded. All cases were classified according (...truncated)