BRONCHIOLOALVEOLAR LUNG CARCINOMAS: K-ras MUTATIONS ARE CONSTANT EVENTS IN THE MUCINOUS SUBTYPE

Abstract

Bronchioloalveolar carcinoma (BAC) is a form of peripheral lung adenocarcinoma growing as a single layer of malignant cells along the walls of terminal airways. The existence of BAC as a separate clinico‐pathological entity has been a matter of controversy, mainly because its histogenesis is uncertain and it is not easily distinguishable from conventional lung adenocarcinoma (CLA). Three subtypes of BAC have been described using histological and cytological criteria: mucinous, non‐mucinous, and sclerosing. The clinical behaviour of BAC appears to be dependent on the histological subtype. The different morphological patterns and clinical outcome of the subtypes of BAC suggest that their biological behaviour may be different from one another and from CLA. This study has investigated 58 BACs (10 mucinous, 40 non‐mucinous, and 8 sclerosing) and 50 control CLAs for mutations at codon 12 of the K‐ras oncogene. Twenty‐one (36 per cent) BACs and 13 (26 per cent) CLAs showed K‐ras mutations. A clear association (P<0·0001) between K‐ras mutations and the mucinous type of BAC was observed: all 10 mucinous tumours examined were scored positive for mutations in the K‐ras gene, while only 9 (23 per cent) of the 40 non‐mucinous and 2 (25 per cent) of the 8 sclerosing BACs were found to be positive. The frequency of ras mutations in non‐mucinous BAC, sclerosing BAC, and CLA was not statistically different. Our data indicate that BACs are a heterogeneous group of lung tumours and that the mucinous form might represent a biological entity separate from both the other two BAC types and CLA.

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.…”

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

“…Our findings confirm the previous association of KRAS mutations with mucinous BAC. 35 Furthermore, multiple studies have suggested that EGFR mutations and KRAS mutations are almost always mutually exclusive in NSCLC. 11,12,24 -26,36 Our finding that mucinous differentiation correlates with the presence of KRAS mutations and the absence of EGFR mutations further strengthens this hypothesis.…”

Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells

“…Polymerase chain reaction analysis of K-ras sequence in the MIAPaCa-2 cell line In order to demonstrate a possible mutation of K-ras sequence, the mutational analysis of the codon 12 of the K-ras gene was performed in MIAPaCa-2 cells by oligodeoxynucleotide hybridisation, as described previously (Marchetti et al, 1996). Briefly, as a negative control the CLONE cell line (ATCC), derived from a normal human corneal epithelium, was analysed, while as a positive control a sample of human lung adenocarcinoma with mutation at codon 12 (GGT-TGT, Gly-Cys) was used.…”