p16 Inactivation in Pancreatic Intraepithelial Neoplasias (PanINs) Arising in Patients with Chronic Pancreatitis

Christophe Rosty, Joseph Geradts, Norihiro Sato, Robb E. Wilentz, Helen Roberts, Taylor Sohn, John L. Cameron, Charles J. Yeo, Ralph H. Hruban, Michael Goggins

Research output: Contribution to journalArticlepeer-review

88 Scopus citations


Patients with long-standing chronic pancreatitis are thought to be at increased risk of developing pancreatic ductal adenocarcinoma, but the mechanism for this increased risk is unknown. Since increasing evidence supports the notion that infiltrating pancreatic ductal adenocarcinomas arise from pancreatic intraepithelial lesions (PanINs), we sought to determine if patients with chronic pancreatitis harbor PanINs with alterations in tumor suppressor genes that are associated with infiltrating pancreatic ductal adenocarcinoma. We identified 122 patients with a diagnosis of chronic pancreatitis and 29 patients with a well-differentiated pancreatic endocrine tumor that underwent pancreatic surgery at the Johns Hopkins Hospital from 1985 to 1999. PanINs from each resection specimen were identified, graded, counted, and correlated with smoking and alcohol history. The expression patterns of p 16 and Smad4 were determined in a subset of PanINs by immunohistochemistry, and the pattern of labeling compared with that seen in PanINs associated with infiltrating adenocarcinoma of the pancreas as identified in prior studies, and to PanINs associated with pancreatic endocrine tumor. Duct lesions were present in 80 of the 122 pancreata with chronic pancreatitis (66%). Of 405 duct lesions identified in the chronic pancreatitis group, 7.6% were reactive changes, 65.5% were PanIN-1A, 18% were PanIN-1B, 7.4% were PanIN-2, and 1.5% were PanIN-3. Within the pancreatic endocrine tumor group, 22 PanINs were identified: 15 PanIN-1A, 4 PanIN-1B, and 3 PanIN-2. There were significantly fewer high-grade PanINs in the pancreata with chronic pancreatitis than in pancreata with pancreatic adenocarcinoma (P < 0.0001). Within the chronic pancreatitis group, the 80 patients with PanINs were significantly older than the 42 patients without PanINs (mean age 57.0 ± 14.1 years vs. 50.9 ± 14.7 years, P = 0.01). Smoking history was not associated with PanIN prevalence or grade, but patients who reported a history of excessive alcohol consumption had fewer Pan-INs (25 of 44 harbored PanINs, 57%) than those who did not (54 of 74, 73%, P = 0.07). In the chronic pancreatitis group, 0% of PanIN-1A, 11% of the PanIN-1B, 16% of the PanIN-2, and 40% of the PanIN-3 lesions showed loss of p16 expression, whereas all of the PanINs from patients with an pancreatic endocrine tumor retained p 16 expression. All of the PanINs analyzed from patients with chronic pancreatitis retained normal Smad4 expression. We conclude that a significant minority of PanINs arising in patients with chronic pancreatitis show loss of p16 expression. This alteration, common to pancreatic cancer-associated PanINs, may contribute to the predisposition of patients with chronic pancreatitis to develop pancreatic ductal adenocarcinoma.

Original languageEnglish (US)
Pages (from-to)1495-1501
Number of pages7
JournalAmerican Journal of Surgical Pathology
Issue number12
StatePublished - Dec 2003


  • Chronic pancreatitis
  • PanIN
  • Smad4
  • p16

ASJC Scopus subject areas

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine


Dive into the research topics of 'p16 Inactivation in Pancreatic Intraepithelial Neoplasias (PanINs) Arising in Patients with Chronic Pancreatitis'. Together they form a unique fingerprint.

Cite this