KRAS mutations are associated with solid growth pattern and tumor-infiltrating leukocytes in lung adenocarcinoma

KRAS mutations define a clinically-distinct subgroup of lung adenocarcinoma patients, characterized by smoking history, resistance to EGFR-targeted therapies, and adverse prognosis. Whether KRAS- mutated lung adenocarcinomas also have distinct histopathologic features is not well established. We tested 180 resected lung adenocarcinomas for KRAS and EGFR mutations by high-sensitivity mass spectrometry-based genotyping (Sequenom) and PCR-based sizing assays. All tumors were assessed for the proportion of standard histologic patterns (lepidic, acinar, papillary, micropapillary, solid and mucinous), several other histologic and clinical parameters, and TTF-1 expression by immunohistochemistry. Among 180 carcinomas, 63 (35%) had KRAS mutations (KRAS+), 35 (19%) had EGFR mutations (EGFR+), and 82 (46%) had neither mutation (KRAS-/EGFR-). Solid growth pattern was significantly over-represented in KRAS+ carcinomas: the mean ± standard deviation for the amount of solid pattern in KRAS+ carcinomas was 27 ± 34% compared to 3 ± 10% in EGFR+ (P<0.001) and 15 ± 27% in KRAS-/EGFR- (P=0.033) tumors. Furthermore, at least focal (>20%) solid component was more common in KRAS+ (28/63; 44%) compared to EGFR+ (2/35; 6%; P<0.001) and KRAS-/EGFR- (21/82; 26%; P=0.012) carcinomas. KRAS mutations were also over-represented in mucinous carcinomas, and were significantly associated with the presence of tumor-infiltrating leukocytes and heavier smoking history. EGFR mutations were associated with non-mucinous non-solid patterns, particularly lepidic and papillary, lack of necrosis, lack of cytologic atypia, hobnail cytology, TTF-1 expression, and never/light smoking history. In conclusion, extended molecular and clinicopathologic analysis of lung adenocarcinomas reveals a novel association of KRAS mutations with solid histology and tumor-infiltrating inflammatory cells, and expands on several previously recognized morphologic and clinical associations of KRAS and EGFR mutations. Solid growth pattern was recently shown to be a strong predictor of aggressive behavior in lung adenocarcinomas, which may underlie the unfavorable prognosis associated with KRAS mutations in these tumors.