OBJECTIVETo evaluate the relevance of molecular alterations and histopathological subtypes of lung adenocarcinoma according to 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Lung Adenocarcinoma Classification.

METHODSMutations of epidermal growth factor receptor (EGFR) 18-21 exons (E18-21), KRAS 12/13 codons and EML4-ALK fusion in 212 cases of lung adenocarcinoma which underwent complete tumor resection, were detected by immunohistochemistry, PCR-amplifying and gene sequencing. The relevance of the molecular alterations to histopathological subtypes based on the new classification and 2004 WHO classification were further characterized.

RESULTSMutations of EGFR were observed in 49.6% of lung adenocarcinomas, involving mainly E21 (52.4%, 55/105) and E19 (36.2%, 38/105). Mutations of KRAS were detected in 8% cases of adenocarcinoma, involving mainly codon 12 (15/17). EML4-ALK fusions were found in 6.1% of lung adenocarcinoma, the most common fusion mutation was type V1 (E13; A20) (7/13), followed by type V3a/b (E6a/b; A20) (4/13). Based on the new classification, 7/10 lepidic, 63.2% (48/76) papillary, and 5/8 micropapillary predominant adenocarcinomas harbored EGFR mutations. EGFR mutations showed significant difference among different histological subtypes (P = 0.008). KRAS mutations were most frequently found in invasive mucinous adenocarcinoma (1/2), followed by colloid predominant adenocarcinoma (3/7). There was significant difference of KRAS mutations among different histological subtypes (P = 0.003). EML4-ALK fusions were most frequently found in the solid predominant with mucin production subtype (15.4%, 6/39), followed by colloid predominant adenocarcinoma (1/7), and no significant difference of EML4-ALK fusions was found among different histological subtypes (P = 0.181). Significant TTF-1 overexpression was observed in adenocarcinomas harbored EGFR mutations (P = 0.008), and no or significantly lower level expression of TTF-1 was observed in adenocarcinomas harbored KRAS mutations (P = 0.000). However, there was no association between TTF-1 expression and EML4-ALK fusions (P = 0.274). Based on the 2004 WHO classification, mutations of KRAS (P = 0.002) and EML4-ALK (P = 0.000), rather than EGFR (P = 0.502), showed significant differences among different subtypes. According to both classification systems, the difference of "triple negative" adenocarcinomas was not significant among different subtypes (P = 0.684, P = 0.449, respectively).

CONCLUSIONSThe new classification, combined with TTF-1 immunomarker, can help to predict the molecular alterations of EGFR and KRAS genes, but can not indicate the EML4-ALK fusion in lung adenocarcinoma. Lepidic, papillary, and micropapillary predominant adenocarcinomas with TTF-1 expression are closely related to the presence of EGFR mutation, and invasive mucinous adenocarcinoma, while colloid predominant adenocarcinoma without TTF-1 expression is closely related to the presence of KRAS mutation.