Progressive genomic alterations in intraductal papillary mucinous tumours of the pancreas and morphologically similar lesions of the pancreatic ducts

Abstract

Intraductal papillary mucinous tumours (IPMTs) of the pancreas are rare neoplasms characterized by a prominent intraductal component, and by malignant potential. Little data exists concerning numerical chromosome aberrations in IPMTs. The biological significance of mucinous epithelial changes (mucinous hyperplasia) in small branching ducts adjacent to IPMTs also remains unclear. From a series of 12 IPMTs, we investigated by interphase cytogenetics 22 foci with mucinous hyperplasia, 27 foci with borderline lesions, and 11 samples with either intraductal (CIS) or invasive carcinoma. Chromosome 6 loss was detected in areas with mucinous hyperplasia (36.3%), borderline lesions (96.3%), and CIS/invasive carcinoma (100%). Similar losses, indicating clonal progression, were found for chromosome 17 (18.2%, 81.5%, and 100%), and for chromosome 18 (0%, 18.5%, and 100%). Quantitative analysis showed a significant intraductal expansion of cell clones harbouring these numerical aberrations within the spectrum of IPMTs. Mucinous epithelial changes in 11 resection samples with chronic pancreatitis showed monosomy 6 (36%) and monosomy 17 (27%). Conversely, areas with low-grade pancreatic intraepithelial neoplasia (PanIN-1), obtained from eight surgical specimens with ductal adenocarcinoma, showed monosomies for chromosome 6, 17, and 18 (100%, 87%, and 50%, respectively). We conclude that monosomies, as defined by FISH analysis, are frequent in both IPMTs and mucinous hyperplasia of pancreatic ducts adjacent to IPMTs. Monosomy 6 may represent an early event in the stepwise accumulation of genomic mutations necessary for the neoplastic transformation of pancreatic duct epithelia, whereas loss of chromosome 18 may be implicated in the progression of borderline to malignant IPMT. The detection of complex chromosomal aberrations in mucinous epithelial changes, and the quantitative expansion of monosomic cell clones in pancreatic ducts, provide evidence for a continuum between hyperplastic and dysplastic epithelial changes.

Fascin overexpression in intraductal papillary mucinous neoplasms (adenomas, borderline neoplasms, and carcinomas) of the pancreas, correlated with increased histological grade

“…29,30 The fact that PanINs show fascin upregulation correlated with histological grade increased our interest in fascin expression in IPMNs, because PanINs and IPMNs share the following fundamental characteristics: 5,6 inherently intraductal; composed predominantly of columnar, mucin-producing cells that may grow in a flat configuration or may produce papillae; exhibit a range of cytologic and architectural atypia (mild, moderate and severe); recognized as precursors to Fascin expression in IPMNs of the pancreas H Yamaguchi et al invasive adenocarcinoma; and sequentially accumulate similar genetic alterations with increasing cytoarchitectural atypia. [43][44][45] We showed that fascin overexpression in IPMNs was correlated with increased histological grade by immunohistochemical analysis, followed by a supporting molecular experiment that showed upregulation of fascin mRNA. We consider that fascin upregulation would be a relatively early event in the progression of IPMN, because of the finding that fascin expression was significantly and almost equally greater in borderline neoplasms (86%) and carcinomas (88%) than in adenomas (51%).…”

S100A6 Is Increased in a Stepwise Manner during Pancreatic Carcinogenesis: Clinical Value of Expression Analysis in 98 Pancreatic Juice Samples

“…IPMN and chronic pancreatitis samples frequently show changes in expression of tumor-related genes similar to those in pancreatic cancers (24)(25)(26)(27). Thus, to determine whether S100A6 is differentially expressed between pancreatic cancer, nonmalignant IPMN, and chronic pancreatitis, we did laser microdissection to isolate IDC cells, nonmalignant IPMN cells, PAE cells, and normal epithelial cells and quantified S100A6 expression in each cell type with one-step quantitative real-time RT-PCR with gene-specific priming.…”

Fluorescence In Situ Hybridization to Visualize Genetic Abnormalities in Interphase Cells of Acinar Cell Carcinoma, Ductal Adenocarcinoma, and Islet Cell Carcinoma of the Pancreas

“…An assortment of genetic procedures have been attempted to investigate pancreatic cancer, including family history studies, 1 conventional cytogenetic techniques, 10 interphase FISH, [11][12][13] comparative genomic hybridization, 14 RNA expression analyses, 15, 16 and evaluation of sequence variations. 17 These studies implicate a variety of point mutations and chromosomal anomalies in most, if not all, patients with pancreatic cancer.…”