K-ras mutations in pancreatic ductal proliferative lesions.

We read with interest the recent article of DiGiuseppe et a1l regarding the detection of K-ras mutations in the pancreatic ductal epithelium of a patient with a strong family history of pancreatic adenocarcinoma. The patient did not have an invasive carcinoma anywhere within the gland, and the K-ras mutations were found in a lesion the authors described as "papillary mucinous duct hyperplasia" without atypia. While the presence of K-ras mutations in 75% or more of infiltrating pancreatic ductal carcinomas suggests a major role for the K-ras oncogene in pancreatic carcinogenesis, the difficulty of studying the human pancreas at early stages in the genesis of carcinoma has limited our knowledge regarding the point at which K-ras mutations first occur. The findings of several other investigators2-4 indicate that K-ras mutations may occur before the development of invasive carcinoma and may even precede morphologically clear-cut preneoplastic changes within the ductal epithelium. Yanagisawa et a14 have reported the detection of K-ras mutations in ducts showing papillary hyperplasia in the absence of carcinoma elsewhere within the pancreas. There are significant clinical implications to the detection of K-ras mutations at early stages of ductal proliferation, as it has been proposed to examine pancreatic ductal secretions for the presence of K-ras mutations in patients at risk for the development of carcinoma. If the decision to perform a radical surgical procedure on the basis of K-ras mutations is to be made (especially in the absence of a mass), then the true preneoplastic potential of epithelial proliferative lesions exhibiting these mutations must be well established. Clearly, the finding of K-ras mutations in hyperplasia without atypia is very significant and requires replication by other investigators. The report by DiGiuseppe et a1l appears to provide the first independent confirmation of the very early appearance of K-ras mutations reported by Yanagisawa.4 To assess the point during pancreatic carcinogenesis at which molecular alterations first occur, it is critical to have reproducible morphological criteria for the proliferative lesions within the ducts, which precede the development of invasive carcinoma. Unfortunately, there are few studies characterizing the morphological features of preneoplastic ductal lesions.610 These studies are reported by several groups who have not used standardized terminology for the various lesions. In addition, most studies have examined the changes in residual ducts in the pancreas surrounding an invasive carcinoma, making it difficult to assess the temporal relationship of putative precursor lesions to invasive carcinoma. Studies evaluating the potential of a given morphologically defined precursor lesion to progress to invasive carcinoma have not been possible in humans. In a recent study of the ductal proliferative lesions associated with 182 resected ductal adenocarcinomas, Hameed et a11 proposed standardized terminology for ductal proliferative lesions, including simple and papillary hyperplasia, atypical hyperplasia, and carcinoma in situ, analogous to the terminology used for proliferative lesions of the mammary ducts. On a strictly morphological basis, lesions exhibiting only simple or papillary hyperplasia were not regarded as preneoplastic, atypical hyperplasia was felt to be probably preneoplastic, and carcinoma in situ was felt to represent a definite precursor to invasive carcinoma. The lesions illustrated by Yanagisawa et al4 would be classified as simple or papillary hyperplasia in this scheme. We believe that the report by DiGiuseppe et a1l illustrates the difficulties inherent in the morphological assessment of ductal proliferative lesions. While the authors describe the analysis of "papillary mucinous duct hyperplasia" and specifically mention the lack of atypia, the illustration of the lesion (Figure 1A1) reveals pseudostratification of nuclei with loss of polarization, nuclear enlargement and variation in nuclear size, mucin depletion, and early intraepithelial lumen formation (cribriforming). We consider many of these features to be evidence of atypia, and would therefore designate the lesion in question as "atypical hyperplasia," although it falls short of the