The significance of p53 mutations and
DNA aneuploidy in
carcinoma cells has been investigated on the basis of a multi-step development theory of
carcinogenesis. It has, however, not been determined whether these alterations can be used as diagnostic markers for the early detection of bronchial
squamous cell carcinoma (BSqCC). To address this problem, we topographically investigated p53 alterations and
DNA aneuploidy in 24 X-ray-negative, early BSqCC patients with various preneoplastic lesions and in 25 non-
carcinoma patients with preneoplastic lesions. Bronchial lesions (n=88) were morphologically classified as
hyperplasia (HP, n=5), squamous
metaplasia (SM, n=23), low-grade dysplasia (LGD, n=14), high-grade dysplasia (HGD, n=11),
intraepithelial carcinoma including '
carcinoma in situ' (CIS) (IEC, n=15), and microinvasive
carcinoma (MIC, n=20). Immunohistochemistry for the p53
protein and image cytometry for
DNA ploidy detection were performed in serial sections of each lesion. Overexpression of p53
protein was detected in 36, 73, and 65% of the HGD, IEC, and MIC lesions, respectively.
Aneuploid DNA profiles were found only in
carcinoma lesions, 33% in IEC and 85% in MIC. The topographical analysis revealed two types of early BSqCCs, one with adjacent preneoplastic lesions (sequential type, n=8) and another without such lesions (de novo type, n=16). The p53
protein was frequently overexpressed in both types (sequential type, 79%; de novo type, 62%). In the sequential type, however, the p53
protein was overexpressed in HGD lesions that were directly adjacent to p53-overexpressing
carcinoma lesions without exception. The present topographical study suggests that p53 mutations play an important role in the
carcinogenesis of BSqCC and that p53-overexpressing HGD lesions in sequential types should be regarded as 'truly' preneoplastic lesions that actually develop into
carcinomas. In addition, our study demonstrated that
DNA aneuploidy might occur at times after p53 alteration with increasing frequency, as invasive growth begins. Such combination analysis of p53 immunohistochemistry and nuclear
DNA ploidy in routine histology may contribute to estimates of malignant potential in preneoplastic and intraepithelial squamous lesions and provide additional information for early detection of BSqCC.