Pulmonary Fibrosis and Carcinoma of the Lung : An Analysis of Genetic Abnormalities of Honeycombed Lesion and IPF-Related Lung Carcinoma.

我们研究了特发性肺纤维化(IPF)中肺癌高发的机制。首先，对一例肺间质纤维化合并肺癌的临床病理特征进行了研究，发现肺癌与肺间质纤维化的蜂窝军团在地形学上有密切关系。第二，形态计量学结果显示，在患有肺癌的蜂窝状IPF军团的上皮细胞成分中，鳞状化生显著频繁。而伴与不伴肺癌的IPF中Ki-67和P53的标记指数及鳞状化生中细胞异型性的分级无明显差异。由于基因异常的模式可能反映肿瘤的发展过程，我们通过RT-PCR检测FHIT基因异常，并通过亚硫酸氢盐处理和聚合酶链式反应来检测p16启动子区的甲基化状态。甲基化频率在IPF相关肺癌中显著升高，但在IPF合并肺癌的鳞状化生中未观察到，其组织直接从切片中剥离。这些结果提示，p16基因甲基化在IPF的癌变过程中是一个相对较晚的事件，在IPF合并肺癌的患者中可能存在共同的鳞状化生和癌的遗传基础。为了评估这一假设，我们调查了参与芳香胺加工的酶的遗传多态。结果表明，在无肺癌的IPF患者中，能力减退类型明显增多，证实了IPF患者肺癌发生率较高的遗传基础。未来的研究应该集中在肺癌的IPF、蜂窝状军团化生上皮中的遗传异常以及包括DNA修复基因多态性在内的遗传学基础上。

We investigated a mechanism underlying the high frequency of lung carcinomas in idiopathic pulmonary fibrosis (IPF). Firstly, the study of a clinico-pathologic features of IPF with lung carcinomas demonstrated that the carcinomas showed a topographically intimate relationship with the honeycombed legion in IPF. Second, the morphometry revealed that squamous metaplasia was significantly frequent among epithelial cell components of the honeycombed legions of IPF with lung carcinoma. However, the labeling indexes of Ki-67 and p53 or the gardes of cellular atypia in squamous metaplasia were not different in IPF with or without lung carcinomas. Since the pattern of genetic abnormalities might reflect the development process of a carcinoma, we evaluated FHIT gene abnormality by RT-PCR and methylation status of p16 promoter regions by bisulfite treatment and PCR. The frequency of methylation was significantly higher in IPF-related lung carcinomas, but was not observed in squamous metaplasia in IPF with lung carcinoma, the tissue of which was dissected directly from the slides. These results suggest that methylation of p16 is relatively a late event in the carcinogenesis in IPF, and that there might be some genetic basis commonly underlying squamous metaplasia and carcinoma in The IPF-patients with lung carcinomas. To evaluate this hypothesis, we investigated genetic polymorphism of the enzymes, which are involved in the processing of aromatic amines. As a result, a decreased ability type was significantly frequent in IPF without lung carcinomas, confirming that there might be a genetic basis for the high frequency of lung carcinomas in IPF. Future studies should focus on both aspects in IPF with lung carcinomas, genetic abnormalities in metaplastic epithelia of the honeycombed legion and genetic basis including polymorphism of DNA repair genes.