Clinicopathological Study On Molecular Markers In Bronchioloalveolar Carcinoma And Adenocarcinoma Of The Lung

Objective: To find different expression of multi-molecular markers in pure BACs, carcinomas with interstitial sclerosis and central scar, and conventional adenocarcinomas of the lung in order to assist correct pathologic diagnosis of bronchioloalveolar carcinoma (BAC).Methords:1180 cases of lung cancer were collected and reviewed from the archives of the Department of Pathology, Chinese PLA General Hospital during the time period from 2004 to 2006. The definite diagnosis of BAC based on 2004 WHO classification of lung tumors was made by two pathologists. Immunohistochemistry was applied on tumor tissue microarray to test the expression of different molecular markers in pure BACs, carcinomas with interstitial sclerosis and central scar, and conventional adenocarcinomas as well. Fluorescent in situ hybridization (FISH) and DNA sequencing were performed to detect EGFR gene amplification and mutations of exons 19, 21 in pure BACs, carcinomas with interstitial sclerosis and central scar, and conventional adenocarcinomas as well.Results: Of 1180 lung carcinomas 165 cases were initially diagnosed as BAC. A particular problem is that it is hard to distinguish scar from interstitial sclerosis. After reevalutation asisted by multi-molecular markers,the definit diagnoses of BAC were only 57 cases. The incidence of BAC between female and male was similar. The expression of Ki67, c-myc and EGFR showed no statistical significant difference between carcinomas with interstitial sclerosis and central scar and pure BAC (P>0.05), while showed significant difference with conventional adenocarcinomas (P<0.05). The cellular adhesion molecules E-cadherin,β-catenin and tumor suppressor gene P53 in carcinomas with interstitial sclerosis and central scar presented intermediate level of expression compared with pure BACs and conventional adenocarcinomas (P>0.05). Conventional adenocarcinoma had higher EGFR amplification compared with pure BAC and carcinomas with interstitial sclerosis and central scar (P<0.05). There was no significant difference in BAC and carcinomas with interstitial sclerosis and central scar(P>0.05). EGFR gene ammplification was correlated with EGFR protein expression. EGFR mutation in carcinomas with interstitial sclerosis and central scar had no significant difference compared with pure BACs and conventional adenocarcinomas (P>0.05). The difference of EGFR mutation in gender and age was not found. Based on discriminant analysis, 39 cases with BAC histology mixed with interstitial sclerosis or central scar were reevaluated. 30 cases were reclassified as sclerosing BAC, 9 cases as adenocarcinomas, mixed subtype..Conclusions: 1.The expression of different molecular markers in pure BACs, carcinomas with interstitial sclerosis and central scar, and conventional adenocarcinmas can help in differential diagnosis. The application of Ki67 and EGFR is useful in distinguishing BACs from adenocarcinomas mixed subtype. Some of lung carcinomas with interstitial sclerosis or central scar belong to sclerosing BAC, while others may be the adenocarcinomas mixed subtype. 2. The results of EGFR amplification and gene mutation also indicate that lung carcinomas with interstitial sclerosis or central scar do not always equel to adenocarcinomas, some belong to sclerosing BACs.