[Relevance of molecular alterations in histopathologic subtyping of lung adenocarcinoma based on 2011 International Multidisciplinary Lung Adenocarcinoma Classification].

OBJECTIVE: To 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.
METHODS: Mutations 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.
RESULTS: Mutations 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).
CONCLUSIONS: The 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.