Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Mod Pathol. 2013 Oct;26(10):1307-19. doi: 10.1038/modpathol.2013.74. Epub 2013 Apr 26.
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 histopathological 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 histological patterns (lepidic, acinar, papillary, micropapillary, solid, and mucinous), several other histological 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±s.d. for the amount of solid pattern in KRAS+ carcinomas was 27±34% compared with 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 with EGFR+ (2/35; 6%; P<0.001) and KRAS-/EGFR- (21/82; 26%; P=0.022) 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 cytological atypia, hobnail cytology, TTF-1 expression, and never/light smoking history. In conclusion, extended molecular and clinicopathological 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 morphological 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.
KRAS 突变定义了一组具有临床特征的肺腺癌患者，其特征为吸烟史、对 EGFR 靶向治疗的耐药性和不良预后。KRAS 突变的肺腺癌是否也具有独特的组织病理学特征尚不清楚。我们通过基于高灵敏度质谱的基因分型（Sequenom）和基于 PCR 的大小测定法检测了 180 例切除的肺腺癌中的 KRAS 和 EGFR 突变。所有肿瘤均评估了标准组织学模式（贴壁型、腺泡型、乳头状、微乳头状、实体型和黏液型）、其他几种组织学和临床参数以及 TTF-1 的免疫组织化学表达。在 180 例癌中，63 例（35%）有 KRAS 突变（KRAS+），35 例（19%）有 EGFR 突变（EGFR+），82 例（46%）无突变（KRAS-/EGFR-）。在 KRAS+癌中，实性生长模式明显更为常见：KRAS+癌中实性模式的平均值±标准差为 27±34%，而 EGFR+癌中为 3±10%（P<0.001），KRAS-/EGFR-癌中为 15±27%（P=0.033）。此外，在 KRAS+（28/63；44%）中至少局灶性（≥20%）的实性成分比 EGFR+（2/35；6%；P<0.001）和 KRAS-/EGFR-（21/82；26%；P=0.022）癌中更常见。KRAS 突变也在黏液型癌中过度表达，并且与肿瘤浸润白细胞和更重的吸烟史显著相关。EGFR 突变与非黏液性非实性模式相关，特别是贴壁型和乳头状，无坏死，无细胞学异型性，鞋钉状细胞，TTF-1 表达，从不/轻度吸烟史。总之，对肺腺癌的扩展分子和临床病理分析揭示了 KRAS 突变与实体组织学和肿瘤浸润性炎症细胞之间的新关联，并扩展了先前认识到的 KRAS 和 EGFR 突变的几种形态和临床关联。最近已经证明，实体生长模式是肺腺癌侵袭性行为的强有力预测因子，这可能是这些肿瘤中与 KRAS 突变相关的不良预后的基础。
