Clonality and K- ras mutation analyses of epithelia in intraductal papillary mucinous tumor and mucinous cystic tumor of the pancreas

Abstract

Histological criteria for subclassification of intraductal papillary mucinous tumor (IPMT) and mucinous cystic tumor (MCT) of the pancreas remain ambiguous in the absence of apparent invasion or metastasis. To elucidate this issue, we evaluated clonality and K- ras mutations in 11 cystic tumors of the pancreas from female patients, including 7 IPMTs and 4 MCTs. The analyses were performed on DNA from laser microdissected epithelia showing different degrees of atypia as well as normal-appearing epithelia (NAE) in the individual tumors. The grades of atypia were classified into three groups on conventional hematoxylin-eosin staining. Clonality was assessed using the methylation-induced polymorphic inactivation of the X-linked phosphoglycerate kinase gene. The incidence of monoclonality increased with the grades of atypia: 27% for NAE, 43% for grade 1, and 100% for grades 2 and 3. In three of four MCTs, foci of NAE were polyclonal, while monoclonality was seen in each one of grades 1 and 2. The frequency of K- ras mutation depended on the grades of atypia: 0% for NAE, 29% for grade 1, 50% for grade 2, and 75% for grade 3. Polyclonal epithelia were devoid of K- ras mutation in 92% of sites, while monoclonality was associated with both wild and mutational types in an approximately equal ratio. Both IPMT and MCT seem to arise from polyclonal epithelia and to be replaced by monoclonal neoplastic cells as they undergo dysplastic changes and K- ras mutation. These data suggest that the monoclonal expansion precedes K- ras mutation.

Integration of KRAS testing in the diagnosis of pancreatic cystic lesions: a clinical experience of 618 pancreatic cysts

“…[18][19][20][21][22] Consistent with previous studies, the prevalence of KRAS mutations in IPMNs was 67%. In contrast, only 14% of MCNs harbored a KRAS mutation.…”

Characterization of gene expression in mucinous cystic neoplasms of the pancreas using oligonucleotide microarrays

“…In addition, better knowledge of the molecular alterations that give rise to MCNs could help in the management of patients with these neoplasms. Because MCNs are uncommon and usually only contain a small number of neoplastic cells, molecular studies are difficult and as a result information about these neoplasms has largely been derived from immunohistochemical studies of proteins such as p53 (Thompson et al, 1999;Zamboni et al, 1999;Yoshizawa et al, 2002), mucin proteins (Luttges et al, 2002), markers of gastric or intestinal differentiation (Zamboni et al, 1999), as well as protein expression patterns within the 'ovarian-type' stroma (Fukushima and Mukai, 1997;Izumo et al, 2003). In contrast, much more is known about the genetic and epigenetic alterations involved in the development of pancreatic ductal adenocarcinomas, IPMNs and pancreatic intraepithelial neoplasms (PanINs).…”

Cystic pancreatic lesions: Can we diagnose them accurately what to look for? FNA marker molecular analysis resection, surveillance, or endoscopic treatment?

“…Mucinous cystic neoplasms frequently contain mutations of the K-ras oncogene and p53 tumor suppressor gene, and the frequency of these mutations increases with increasing degrees of dysplasia in the neoplasm [11]. The frequency of K-ras mutation in mucinous cystic neoplasms is linearly related to the grades of atypia [12]. However, the degree of atypia in IPMT does not seem to correlate with the presence of k-ras mutations.…”