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 journalArticle

83 Citations (Scopus)

Abstract

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
Volume27
Issue number12
DOIs
StatePublished - Dec 2003
Externally publishedYes

Fingerprint

Chronic Pancreatitis
Neoplasms
Adenocarcinoma
Pancreas
Smoking
History
Tumor Suppressor Genes
Pancreatic Neoplasms

Keywords

  • Chronic pancreatitis
  • p16
  • PanIN
  • Smad4

ASJC Scopus subject areas

  • Anatomy
  • Pathology and Forensic Medicine

Cite this

p16 Inactivation in Pancreatic Intraepithelial Neoplasias (PanINs) Arising in Patients with Chronic Pancreatitis. / Rosty, Christophe; Geradts, Joseph; Sato, Norihiro; Wilentz, Robb E.; Roberts, Helen; Sohn, Taylor; Cameron, John L.; Yeo, Charles J.; Hruban, Ralph H.; Goggins, Michael.

In: American Journal of Surgical Pathology, Vol. 27, No. 12, 12.2003, p. 1495-1501.

Research output: Contribution to journalArticle

Rosty, C, Geradts, J, Sato, N, Wilentz, RE, Roberts, H, Sohn, T, Cameron, JL, Yeo, CJ, Hruban, RH & Goggins, M 2003, 'p16 Inactivation in Pancreatic Intraepithelial Neoplasias (PanINs) Arising in Patients with Chronic Pancreatitis', American Journal of Surgical Pathology, vol. 27, no. 12, pp. 1495-1501. https://doi.org/10.1097/00000478-200312000-00001
Rosty, Christophe ; Geradts, Joseph ; Sato, Norihiro ; Wilentz, Robb E. ; Roberts, Helen ; Sohn, Taylor ; Cameron, John L. ; Yeo, Charles J. ; Hruban, Ralph H. ; Goggins, Michael. / p16 Inactivation in Pancreatic Intraepithelial Neoplasias (PanINs) Arising in Patients with Chronic Pancreatitis. In: American Journal of Surgical Pathology. 2003 ; Vol. 27, No. 12. pp. 1495-1501.
@article{c8ed247ef8984131a4a037492b26eaf0,
title = "p16 Inactivation in Pancreatic Intraepithelial Neoplasias (PanINs) Arising in Patients with Chronic Pancreatitis",
abstract = "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.",
keywords = "Chronic pancreatitis, p16, PanIN, Smad4",
author = "Christophe Rosty and Joseph Geradts and Norihiro Sato and Wilentz, {Robb E.} and Helen Roberts and Taylor Sohn and Cameron, {John L.} and Yeo, {Charles J.} and Hruban, {Ralph H.} and Michael Goggins",
year = "2003",
month = "12",
doi = "10.1097/00000478-200312000-00001",
language = "English (US)",
volume = "27",
pages = "1495--1501",
journal = "American Journal of Surgical Pathology",
issn = "0147-5185",
publisher = "Lippincott Williams and Wilkins",
number = "12",

}

TY - JOUR

T1 - p16 Inactivation in Pancreatic Intraepithelial Neoplasias (PanINs) Arising in Patients with Chronic Pancreatitis

AU - Rosty, Christophe

AU - Geradts, Joseph

AU - Sato, Norihiro

AU - Wilentz, Robb E.

AU - Roberts, Helen

AU - Sohn, Taylor

AU - Cameron, John L.

AU - Yeo, Charles J.

AU - Hruban, Ralph H.

AU - Goggins, Michael

PY - 2003/12

Y1 - 2003/12

N2 - 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.

AB - 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.

KW - Chronic pancreatitis

KW - p16

KW - PanIN

KW - Smad4

UR - http://www.scopus.com/inward/record.url?scp=0345724812&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0345724812&partnerID=8YFLogxK

U2 - 10.1097/00000478-200312000-00001

DO - 10.1097/00000478-200312000-00001

M3 - Article

C2 - 14657708

AN - SCOPUS:0345724812

VL - 27

SP - 1495

EP - 1501

JO - American Journal of Surgical Pathology

JF - American Journal of Surgical Pathology

SN - 0147-5185

IS - 12

ER -