Histological Types And Significance Of Bronchial And Bronchiolo-alveolar Epithelial Dysplasia

ObjectivesLung carcinoma is the commonest fatal malignancy worldwide, with an incidence which has increased steadily over recent decades. The incidence and mortality rates of lung carcinoma are the highest of all carcinoma types for both males and females in some areas in China and worldwide. However, the exact causes and natural progression of lung carcinoma are still matters of speculation and not fully elucidated. Experiments have demonstrated that bronchial and alveolar epithelial cells undergo multiple morphologic and molecular changes as part of the malignant transformation into lung carcinoma. However, only squamous dysplasia of bronchial epithelial cell and atypical adenomatous hyperplasia of bronchiolo-alveolar cell have been deeply investigated and have been cited as pre-invasive lesions in the World Health Organization (WHO) histologic classification of lung and pleural tumors. Currently, it is not known how non-squamous cell carcinoma (non-SCC) originating from central bronchial epithelial cell and peripherally located SCC develop. Furthermore, unlike SCC, the precursor/pre-invasive lesions of bronchogenic non-SCC are still not well understood.Methods and Materials114 primary lung carcinomas and 18 non-tumoral lung specimens were resected at Second Affiliated Hospital of Zhejiang University School of Medicine from February 2000 to November 2001. Consecutive tissue blocks of 3-4mm thickness were dissected from the proximal bronchial resection margin to the peripheral macroscopic bronchiole and all tissue blocks were subjected to pathological examination. Histologic observation and immunostaining with a panel of antibodies against cytokeratins (7, 8, 10/13, 17, 18), SurfactantApoproteinA, Thyroid transcription factor 1, Chromogranin A, Synaptophysin, p53, Ki-67, and bcl-2 on 53 histologic sections from 26 lung specimens were carried out with the following objectives: (a) to further characterize histological types of bronchial and bronchiolo-alveolar epithelial dysplasia;(b) to investigate the quality of bronchial and bronchiolo-alveolar epithelial dysplasia. Criteria for synthetic evaluating on bronchial epithelial dysplasia of whole lung specimen was set up for the purpose of evaluating relationships of extent and grade of bronchial epithelial dysplasia to bronchogenic carcinoma and multifocal primary lung carcinomas, and amounts of bronchiolo-alveolar epithelial atypical adenomatous hyperplasia was calculated for the purpose of evaluatinge its relationship to bronchiolo-alveolar cell carcinoma. The following statistical tests were applied, where appropriate: McNemar's Test, the Kappa measure of agreement, the Mann-Whitney U-test (for 2 independent groups), the Kruskal-Wallis one-way non-parametric ANOVA (for >2 independent groups) and the Spearman Rank Correlation Test, to analyze the possible correlations of bronchial epithelial dysplasia to bronchogenic carcinoma, and of atypical adenomatous hyperplasia to bronchiolo-alveolar carcinoma;The threshold significance level used was P<0.05 (two-tailed). By single strand length polymorphism microsatellite instability analysis, the possibility of multifocal origin of multifocal primary lung carcinoma was demonstrated.ResultsThere are four histologic patterns of bronchial epithelial dysplasia (basal cell dysplasia, columnar cell dysplasia, bronchial epithelial dysplasia with transitional differentiation and squamous dysplasia) and two histologic types for bronchiolo-alveolar epithelial dysplasia (atypical adenomatous hyperplasia and squamous dysplasia). These subtypes were further characterized by immunohistochemistry as follows. Basal cell dysplasia was generally positive for cytokeratin 17, focally positive for cytokeratin 10/13, and negative for cytokeratin 7, 8, 18. Columnar cell dysplasia was generally positive for cytokeratin 7, 8, 18, and negative for cytokeratin 10/13, cytokeratin 17. Bronchial epithelial dysplasia with transitional differentiation had a heterogeneous, diverse immunohistochemical profile. All types of bronchial epithelial dysplasia were negative for Surfactant Apoprotein A, Thyroid Transcription Factor 1, Chromogranin A and Synaptophysin. Atypical adenomatous hyperplasia was positive for Surfactant Apoprotein A and Thyroid Transcription Factor 1, focally positive for cytokeratin 7, 8, 18, and negative for cytokeratin 10/13 and cytokeratin 17. Squamous dysplasia was positive for cytokeratin 10/13, focally positive for cytokeratin 17, and negative for cytokeratin 7, 8, 18, Surfactant Apoprotein A and Thyroid Transcription Factor 1. Abnormal expression of p53 was found in 69.05% of bronchial epithelial dysplasia and abnormal expression of Ki-67 was found in 92.85%. Cells positive for p53 existed singly, while positivity for Ki-67 was diffuse. 3 foci in 3 foci of atypical adenomatous hyperplasias detected were positive for Ki-67 and 2 foci in 3 foci of atypical adenomatous hyperplasias detected were positive for p53. Bronchial epithelial dysplasia was evaluated as low-grade or high-grade based on the degree of cell/nuclear atypia and disorder of cell arrangement. Synthetic evaluating ofbronchial epithelial dysplasia was evaluated as three grades based on extent and grade of bronchial epithethial dysplasia: Grade 0 had normal bronchial epithelium with or without simple hyperplasia, or occasionally with small foci of low-grade dysplasia;Grade 1 had bronchial epithelium with extensive low-grade dysplasia (lacking any foci of high-grade dysplasia), or showed foci of low-grade dysplasia with small groups of cells (several or dozens) exhibiting high-grade dysplasia;and Grade 2 had extensive low-grade dysplasia plus variable foci of high-grade dysplasia. As a result, there were 51 cases which were evaluated as grade 0, 55 cases were evaluated as grade 1, and 26 cases were evaluated as grade 2. By McNemar's Test, the Kappa measure of agreemant, the Mann-Whitney U-test, the Kruskal-Wallis one-way non-parametric ANOVA and the Spearman Rank Correlation Test, Synthetic evaluating grade of bronchial epithelial dysplasia was positively correlated with the incidence of bronchogenic carcinoma and multifocal primary lung carcinoma (p<0.05).Bronchiolo-alveolar atypical adenomatous hyperplasia were found in 26 cases with amounts of 1 to 15 foci. Atypical adenomatous hyperplasia was positively correlated with bronchiolo-alveolar epithelial carcinoma (p<0.05). Squamous dyaplasia were found in three cases.By single strand length polymorphism microsatellite markers analysis on three cases of multifocal primary lung carcinoma, it was shown that two primary lung carcinoma in all three cases have different molecular genetic changes.The extent and grade of bronchial epithelial dysplasia (synthetic evaluating grade) in smoker were higher significantly than in non-smoker, and with age, the incidence of bronchial epithetlial dysplasia increased significantly.Conclusionsi. Bronchial epithelial cells can develop into various types and degrees ofdysplasia with abnormal/ambiguous cell differentiation synchronously and metachronously, with characteristic cytokeratin expression immunohistochemically. Bronchial epithelial dysplasia can be graded into low-grade and high-grade based on the degree of nuclear atypia and irregularity of cell arrangement. Bronchiolo-alveolar epithelial cell can develop multifocal atypical adenomatous hyperplasia or squamous dysplasia synchronously and metachronously. These types of bronchial epithelial dysplasia and bronchiolo-alveolar epithelial atypical adenomatous hyperplasia frequently showed abnormal expressions of p53 and Ki-67, so they likely represent a pre-neoplastic process.ii. Bronchial epithelial dysplasia showed distributive features: high-grade bronchial epithelial dysplasia generally occurred in bronchial epithelium with extensive low-grade bronchial epithelial dysplasia and was rarely seen in bronchial epithelium almost having normal bronchial epithelium. It was indicated statistically that the extent and grade of bronchial epithelial dysplasia (synthetic evaluating grade ) was positively correlated with bronchogenic carcinoma and multifocal primary lung carcinoma;and that bronchiolo-alveolar epithelial atypical adenomatous hyperplasia was positively correlated with bronchiolo-alveolar cell carcinoma. These results suggested that bronchogenic carcinoma might develop from extensive and high grade bronchial epithelial dysplasia, and bronchiolo-alveolar carcinoma may develop from bronchiolo-alveolar atypical adenomatous hyperplasia.iii. Extent and grade of bronchial epithelial dysplasia (synthetic evaluating grade) were positively correlated statistically with bronchogenic carcinoma and multifocal primary lung carcinoma, so assessment of extent and grade of bronchial epithelial dysplasia (synthetic evaluating grade) may significantlypredispose an individual to the development of bronchogenic carcinoma and multifocal primary lung carcinoma.iv. Cigarette smoking was positively correlated with extent and grade of bronchial epithelial dyaplasia (synthetic evaluating grade). The incidence of bronchial epithelial dysplasia increased significantly with age.