Mucinous Differentiation Correlates with Absence of EGFR Mutation and Presence of KRAS Mutation in Lung Adenocarcinomas with Bronchioloalveolar Features

Abstract

Somatic mutations in the epidermal growth factor receptor gene (EGFR) are detected in a subset of lung adenocarcinomas, particularly bronchioloalveolar carcinoma (BAC) and adenocarcinoma with bronchioloalveolar features (AWBF), and correlate with clinical response to tyrosine kinase inhibitors (TKIs). In contrast, lung adenocarcinomas refractory to TKIs often have activating mutations in KRAS but lack EGFR mutations. Some adenocarcinomas have mucinous histology, but the clinical and molecular significance of the mucinous pattern is less well studied. We analyzed 43 BAC and AWBF tumors submitted for EGFR mutation testing to identify histopathological features that predicted EGFR or KRAS mutations. EGFR mutations were detected in 14 of 30 (47%) nonmucinous tumors, whereas 0 of 13 mucinous tumors harbored an EGFR mutation (P ‫؍‬ 0.003). Missense mutations in KRAS codon 12 were detected in six of seven (86%) mucinous adenocarcinomas but only 3 of 18 (17%) nonmucinous adenocarcinomas (P ‫؍‬ 0.003). Thus, in BAC/AWBF mucinous differentiation was significantly correlated with the absence of EGFR mutation and presence of KRAS mutation, suggesting that mucinous BACs/AWBFs are unlikely to respond to TKIs. Therefore, our data suggest that EGFR sequence analysis could be avoided in BAC/AWBF when true mucinous morphology is identified, avoiding the associated testing costs. (J Mol Diagn 2007, 9

Clinicopathological predictors of EGFR/KRAS mutational status in primary lung adenocarcinomas

“…38 Most importantly, statistical analysis failed to show any significance of this subtype. Similar to Finberg et al, 37 we found a strong correlation of mucinous differentiation in mixed subtypes of adenocarcinomas and KRAS mutations. 40 Marchetti et al 50 showed the same correlation in mucinous types of bronchioloalveolar carcinoma.…”

“…35,36 In contrast, mucinous differentiation was associated with KRAS mutations in some studies. 37,38 This variety of morphological interpretations reflects the lack of consistency in the interpretation of the World Health Organization criteria for classifications of lung tumors. Furthermore, different types of samples, including surgical resection and cytology specimens, were used for morphological analysis.…”

Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases

“…8 In this new classification (Table 1) there are several major changes for surgically resected tumors: (1) the term bronchioloalveolar carcinoma (BAC) is no longer used and the growth pattern of BAC is referred to as lepidic pattern; (2) adenocarcinoma in situ is proposed for small (r3 cm) solitary adenocarcinomas with pure lepidic growth lacking invasion; (3) minimally invasive adenocarcinoma (MIA) is proposed for small (r3 cm) lepidic predominant tumors with r0.5 cm of invasion; (4) invasive adenocarcinomas are now classified according to the predominant subtype after performing comprehensive histological subtyping with semiquantitative assessment of each subtype in 5% increments; 4 (5) micropapillary adenocarcinoma is added as a major subtype because of its poor prognostic significance in multiple studies of early stage lung adenocarcinoma; [9][10][11] (6) former mucinous BACs are now classified as invasive mucinous adenocarcinomas recognizing that most of these tumors will have invasive components, less expression of TTF-1, frequent KRAS mutations, characteristic CT finding primarily of consolidation rather than ground glass opacities, worse prognosis than non-mucinous lepidic predominant adenocarcinomas and lack of responsiveness to tyrosine kinase inhibitors; [12][13][14][15][16][17][18][19] and (7) clear cell and signet ring adenocarcinoma are recognized to represent cytological changes that occur in multiple histological subtypes rather than in separate histological subtype. 20,21 We sought to explore the prognostic significance of this classification in a large series of surgically resected stage I lung adenocarcinomas.…”

EGFR, KRAS, and BRAF mutational profiles of female patients with micropapillary predominant invasive lung adenocarcinoma

“…EGFR and KRAS mutations were observed in 10%-30% of cases, with a higher frequency of EGFR mutations being found in Asians, in people who had no history of smoking, and in nonmucinous tumors (5). However, it has been found that the level of KRAS mutation is associated with smoking, being non-Asian, and invasive mucinous adenocarcinoma (19). A BRAF mutation rate of 1.9% was reported in nonsmokers with adenocarcinoma (18).…”