Duct changes and K-ras mutations in the disease-free pancreas: analysis of type, age relation and spatial distribution

Abstract

Recent molecular studies have suggested that hyperplastic duct lesions of the pancreas are potential precursors of pancreatic ductal carcinoma. This study examines the type, distribution, age-related incidence and K-ras codon 12 mutation rate of duct lesions in the normal pancreas. Postmortem pancreases from 140 patients were screened for the presence of mucinous cell hypertrophy (MHT), ductal papillary hyperplasia (DPH), adenomatoid ductal hyperplasia (ADH), and squamous metaplasia (SQM). Microdissected cell samples were analyzed for K-ras codon 12 mutations by polymerase chain reaction amplification of exon 1 of the K-ras gene, combined with constant denaturing gel electrophoresis, and analyzed by sequencing. Of the 140 specimens 114 showed duct lesions. The lesions were evenly distributed throughout the pancreas. They were more common beyond the age of 40. MHT was present in 68%, DPH in 36%, ADH in 40%, and SQM in 36% of the cases. K-ras mutations were found in 19 samples from 15 out of 79 pancreases (18%), including all types of duct lesions and a variant of ADH with dense stroma. 67% of the K-ras-positive specimens showed the transition GGT to GAT (8) or GTT (5). Hyperplastic/metaplastic duct changes of the pancreas increase with age, but their distribution pattern in the pancreas differs from that of ductal carcinomas.

Adenomatoid Tumor of the Pancreas: A Case Report with Comparison of Histology and Aspiration Cytology

“…However these lesions characteristically have fascicular and storiform arrangements and lack the tubular structures commonly seen in adenomatoid tumors. Defined by CD34 and bcl-2 immunopositivity, this immunoprofile is inconsistent with mesothelial origin and that of our lesion (13). Solitary fibrous tumors also lack a significant inflammatory component (12).…”

Transcriptome analysis of microdissected pancreatic intraepithelial neoplastic lesions

“…The progressive accumulation of morphological changes and the presence of typical mutations strongly argue for (Luttges et al, 1999;Hruban et al, 2001b), strongly suggesting that the risk of progression to invasive carcinoma is very low for PanIN-1. Together, these results indicate that PanIN-2 rather than PanIN-1B represents the earliest truly preneoplastic lesion in the pancreas.…”

“…PanINs are believed to progress from flat (PanIN-1A) and papillary lesions (PanIN-1B) without dysplasia, to papillary lesions with dyplasia (PanIN-2), to carcinoma in situ (PanIN-3). PanINs, especially the intermediate and higher grade lesions, display a number of genetic abnormalities also observed in invasive cancers, including mutations of the KRAS, CDKN2A/p16INK4A, BRCA2, TP53 and SMAD4 genes (Wilentz et al, 1998Luttges et al, 1999Luttges et al, , 2001Goggins et al, 2000;Wilentz et al, 2000;Luttges et al, 2001), which is suggestive of their neoplastic potential Luttges et al, 2001). However, efforts to develop molecular screening approaches based on the detection of some of these molecular alterations have so far been of limited success (see Vimalachandran et al, 2004 for an overview).…”

Clonality and field cancerization in intraductal papillary-mucinous tumors of the pancreas

“…24,25,33,47,48 Although K-ras muta- tions are found in ductal hyperplasias and probably play an important role in pancreatic carcinogenesis, it also has been suggested that K-ras mutations have a limited role and that only a small fraction of hyperplastic lesions with mutated K-ras progresses to carcinoma (Ͻ 1%). 25,47,49 Nevertheless, K-ras mutation is an early key event leading to later genetic alterations, including inactivation of the p16 tumor-suppressor gene. 47,48 Multiple distinct K-ras mutations reportedly were identified among different hyperplasias in 47-50% of patients with ductal adenocarcinoma, 33,47 and 6 -12% of patients with carcinoma had multiple, distinct mutations, 47,50 adding molecular support for field (multicentric) cancerization.…”