Proliferation, c-myc, and cyclin D1 expression in diffuse alveolar damage:Potential roles in pathogenesis and implications for prognosis

In this study, we compared expression of DNA topoisomerase II alpha, a mark er of cellular proliferation, c-myc, and cyclin D1 in lung biopsy specimens showing diffuse alveolar damage (DAD) with control lung tissues. We subseq uently correlated DNA topoisomerase Do, c-myc, and cyclin D1 expression wit h survival. We hypothesized that poor outcome may correlate with a higher p roliferation index, and that c-myc and cyclin D1 activation are potentially important regulators of both proliferation and apoptosis in DAD. Immunohis tochemical stains for c-myc, cyclin D1, and DNA topoisomerase II alpha were performed on 10 cases of DAD (15 cases for DNA topoisomerase Do) and 10 co ntrol lungs. A proliferation index for each case was calculated by dividing the number of nuclei expressing DNA topoisomerase II alpha by the total nu mber of nuclei counted. The percentages of alveolar pneumocytes and interst itial cells staining positively for c-myc and cyclin D1were estimated. The average proliferation index (DNA topoisomerase II alpha index) in DAD (0.16 +/- 0.06, n = 15) was significantly greater than in control lungs (0.00 +/ - 0.01, n = 10) (P < .0001). The average proliferation index of patients wi th DAD who died of respiratory failure (0.18 +/- 0.05, n = 9) was significa ntly greater than the average proliferation index of patients whose respira tory disease resolved or stabilized (0.11 +/- 0.05, n = 5) (P < .03). Expre ssion of c-myc in alveolar pneumocytes and interstitial cells was more inte nse and slightly more widespread in cases of DAD compared with control lung s. In 9 of 10 cases of DAD, cyclin D1 expression was present in up to 30% o f alveolar pneumocytes and up to 10% of interstitial cells. No staining for cyclin D1 was present in control lungs. These results show that the prolif eration index in DAD potentially correlates with patient survival. Furtherm ore, enhanced expression of c-myc and cyclin D1 may contribute to dysregula tion of cellular proliferation and apoptosis observed in DAD. HUM PATHOL 30 :1050-1057.