Ductal lesions in patients with chronic pancreatitis show K‐ras mutations in a frequency similar to that in the normal pancreas and lack nuclear immunoreactivity for p53

BACKGROUND Chronic pancreatitis (CP) is considered to be a risk factor for the development of pancreatic carcinoma. The detection of K‐ras mutations in the duodenal or pancreatic juice has been held to be a reliable tool for its early diagnosis. However, K‐ras mutations also occur in hyperplastic ductal epithelium, making it difficult to interpret their role in pancreatic carcinogenesis. METHODS The study included 30 resection specimens, 15 from patients with alcoholic CP, and 15 from patients with idiopathic CP. The mean duration of disease was 6.8 years. A total of 429 ductal lesions were classified according to the World Health Organization classification (1996) and microdissected. K‐ras analysis was performed by means of polymerase chain reaction (45 cycles), constant denaturing gel electrophoresis, and sequencing. Immunostaining was performed with antibodies against p53, Ki‐S5, carcinoembryonic antigen, and two types of mucins. RESULTS The 30 specimens demonstrated all types of ductal lesions. Severe cellular atypia was not observed. A total of 429 ductal lesions were analyzed. Approximately 4.4% of the lesions (19 of 429) from 27% of the patients (8 of 30) showed K‐ras mutations, but they were unrelated to the duration or type of CP. Immunostaining for mutated p53 protein always was negative. Increased proliferative activity was noted only in patients with papillary hyperplasia. No patient developed pancreatic carcinoma within a follow‐up period of at least 3 years. CONCLUSIONS Ductal lesions in patients with CP exhibit K‐ras mutations without additional indications of neoplastic transformation such as severe dysplasia or mutated p53 protein. Therefore, for diagnostic and therapeutic purposes, the detection of K‐ras mutations should be supplemented by the demonstration of additional genetic alterations or clinical signs of malignancy. Cancer 2000;88:2495–504. © 2000 American Cancer Society. Ductal lesions in patients with chronic pancreatitis exhibit K‐ras mutations in a frequency similar to that in the normal pancreas but lack other characteristics of neoplastic transformation such as nuclear immunoreactivity for mutated p53 protein or severe cellular atypia. Hence, they do not appear to be high risk lesions for the development of ductal adenocarcinoma.