Expression Of HIF-1α And P53 In Bronchioloalveolar Carcinoma And Mixed Adenocarcinma And Their Significance

Backgroud and objectBronchioloalveolar carcinoma is classified as a subtype of lung carcinoma. In 1999 and 2004, the World Health Organization defines BAC as lesions with lepidic growth without stromal, vascular and pleural invasion.According to this strict definition, BAC is carcinoma in situ.Serious pathological analysis of the lesion should be conducted to exclude infiltration and metastases after operation so that the lesion can be diagnosed as BAC.Recent studies reveal that BAC accounts for only 3%-5%of all lung cancers.However,many BACs have had areas of infiltrations and metastases or mixed other types of lung cancer.According to the WHO criteria of classification of lung cancer,these lesions are regarded as lung adenocarcinoma with bronchioloalveolar features,which are also considered as mixed subtype of lung adenocarcinoma.Many researches have showed that lung adenocarcinoma follows multiprocedures and multisteps from atypical adenomatous hyperplasia(AAH) to BAC to ADWBF.According to this theory, BAC and ADWBF act as two important stages in the process of lung adenocarcinoma development in essence.It is very significant to reveal the mechanism of lung adenocarcinoma origin and development by means of comparative analysis of difference in aspects of molecular biology and protein expression between BAC and ADWBF. Rapid proliferation of human solid tumors cause hypoxia and anoxia that result in increased expression of hypoxia inducible factor-11α(HIF-1α).Studies reveal that HIF-1αoverexpression existed in most of human solid tumors which related to the capacity of invasion of carcinoma. HIF-1αplays an important role in tumor origin and development.P53 is tumor suppressor gene which encodes wild type P53 protein that can inhibit tumor proliferation.The mutation and protein expression alteration of P53 can cause tumor progression to some extent.Researches showed that P53 mutation can be detected in over 70% of small cell lung cancer and 50% of NSCLC that reveal the important role of P53 in lung cancer development. In this study,we detect HIF-1 and P53 expression in two groups of BAC and ADWBF by immunohistochemisty(IHC) to reveal different expression, correlation in the two groups and significance as well as provide a new therapy strategy for lung cancer.Materials and MethodsIn this retrospective study,386 cases of confirmed lung adenocarcinom were retrieved from the files of department of Thoracic Surgery, Provincial Hospital affiliated to Shandong University between 2003 and 2009. According to the WHO diagnosis standard of 1999, there were 32 cases of bronchioloalveolar carcinoma(BAC), which account for 8.5% of the diagnosed lung adenocarcinom, and 69 cases of adenocarcinoma with bronchioloalveolar features(ADWBF),which account for 17.9%. All of the 101cases(38 males and 63 females) were free of chemotherapy or radiotherapy before surgery. The age ranged from 34 to75 years; the median age at surgery was 56.3±1.0. According to TNM staging:stageⅠ85.1% (n=86), stageⅡ5.9%(n=6), stageⅢ8.9%(n=9), and all of the BAC cases belonged to stageⅠ. The expression of P53 and HIF-1αin tumor tissues were detemined by SP immunohistochemical method. Two pathologists evaluated immunohistochemistry under microscope. Results for P53 protein were classified as follows:Only crisp nuclear staining was accepted as positive. Here is the quantity of nuclear staining grades:<10%, negative; 10-30%,+; 30-50%,++;≥50%,+++, the staining cell nucleus which were more than 10% were defined as positive ones. The results for HIF-1αprotein were classified as follows:-, no staining;+,nuclear staining in less than 1% of cells;++,nuclear staining in<10% of cells and/or with weak cytoplasmic staining;+++, nuclear staining in 10%-50% of cells and/or with distinct cytoplasmic staining;++++, nuclear Staining in more than 50% of cells and/or with strong cytoplasmic staining. The scores which were more than (++) were defined as positive ones. Different expression analysis of HIF-la and P53 between the two groups were determined by Chi Square test respectively and the correlation of HIF-la and P53 was determined by Chi Square test and Pearson coefficient of continency was calculated then.Results1. Statistical analysis showed significant difference existed in gender and tumor size between BAC and ADWBF(P<0.05)2 Positive rates of P53 and HIF-la in BAC and ADWBF groups were 25.0% (8/32) and 49.3%(34/69),6.3%(2/32) and 26.1%(18/69) respectively, showing statistical difference between the two groups (P<0.05)3 There was a positive correlation between p53 and HIF-la expression in 101 tumor tissues (P=0.001<0.05) r=0.338.ConclusionThe expression rates of P53 and HIF-la in ADWBF groups were higher than those in BAC group,showing us that ADWBF is much more malignant and invasive. The results provide us theoretical evidence that HIF-la and P53 play facilitative roles in lung adenocarcinoma progression.