Chronic Pancreatitis Is Malignant Driver

Chronic pancreatitis is a progressive inflammatory disease with irreversibly functional and morphological changes caused by various etiological factors（Liao et al.2013）.Recent investigation on 2008 patients with chronic pancreatitis shows that its incidence in China is increasing（13/100,000）（Wang et al.2009）.Given that inflammation is one of the major risk factor for carcinogenesis，chronic pancreatitis patients would be more susceptible to pancreatic cancer.However，it was Lowenfels and colleagues，who published an international cohort study on clarification of the nature of the risk in 1993（Lowenfels et al.1993）.In their multicenter cohort study，2015 chronic pancreatitis cases were enrolled and 56 cancers were identified during a mean follow-up of 7.4 years.The standardized incidence ratio was 14.4 and the risk of developing pancreatic cancer，20 years after diagnosis，was as high as 4%.Similar studies further confirmed the increased cancer risk in chronic pancreatitis patients，which underlines the significance of differential diagnosis between chronic pancreatitis and pancreatic cancer（Bansal and Sonnenberg 1995）.

Hereditary pancreatitis represents the best model to dissect the causal link between chronic pancreatitis and pancreatic cancer.Epidemiological and experimental analyses show that hereditary pancreatitis ranks the strongest known risk factor for pancreatic cancer（Schneider and Whitcomb 2002）.By the age of 70 years old，40%of patients with hereditary pancreatitis will develop pancreatic tumors（Lowenfels et al.1997）.Genetic studies identified germ-line mutations in the PRSS1 gene and CFTR gene as leading causes to hereditary pancreatitis.One important question was whether these genes actually oncogenes for development of sporadic pancreatic carcinomas.To address this question，Hengstler et al.analyzed genomic DNA in pancreatic tissue for R122H mutations in the trypsinogen gene from 34 patients and corresponding normal tissue from 28 of these individuals.No mutations were found（Hengstler et al.2000）.Malats et al.have also shown that the incidence of mutations of CFTR gene in sporadic pancreatic cancers were similar to that in healthy controls（Malats et al.2001）.These studies suggest that PRSS1 and CFTR gene mutations are not directly associated with the development of pancreatic cancer.Interestingly，hereditary pancreatitis arises mainly during or soon after childhood，which means that those patients with hereditary pancreatitis will endure chronic inflammation with onset of an early age（Raimondi et al.2009）.Though mutations in PRSS1 and CFTR genes do not directly contribute to pancreatic cancer development and progression，the high-risk inflammation milieu caused by them may play important roles in this regard.(https://www.daowen.com)

Histopathologically，pancreatic cancer contains two compartments as major components of pancreatic cancer，the malignant ductal cells and the surrounding stromal cells，with the latter accounts for 90%of total tumor mass（Neesse et al.2011）.Previous studies establish that the stroma formation was initiated and sustained by the out-of-control inflammation，and recent studies from genetic mouse models indicate that inflammation induced by pancreatitis will significantly promote pancreatic tumor formation（Carriere et al.2009；Gidekel Friedlander et al.2009；Guerra et al.2007；Morris et al.2010）.Though it is evident that chronic pancreatitis is a significant risk factor in inducing cellular transformation and pancreatic carcinogenesis，detailed mechanisms underlying the progression from chronic pancreatitis to pancreatic cancer remain to be explored（Kong et al.2012）.