Differential Diagnosis Between Pancreatic Cancer...
Chronic pancreatitis and pancreatic cancer are two distinct diseases with entirely different prognosis.However，it is a great challenge to discriminate them from each other in many cases.Several reasons contribute to this challenge.First，just like chronic pancreatitis tissues which are mostly made of fibrosis，more than 90%of pancreatic tumor mass is also made of the stroma element.Fine needle aspiration，the most commonly used technique to sample a pancreatic mass，usually could not obtain the tissue containing pancreatic cells.Second，there are too many common pathways dysregulated among chronic pancreatitis and pancreatic cancer tissues，such as reactive oxygen species，Hedgehog，NF-κB，and etc.At the present time，none of the global proteomic studies have identified cancer-specific proteins（Goggins 2005）.Third，as chronic pancreatitis patients are more susceptible to develop into pancreatic cancer，the chronic pancreatitis patients are frequently followed up.However，even using the most advanced techniques，one cannot exclude the existence of malignant cells hidden within a chronic inflammatory mass（Cote et al.2013）.
It is generally accepted that stroma formation is a critical hallmark characteristic for pancreatic cancer，and the transformation of pancreatic cells usually occur in inflamed tissues（Xie and Xie 2015）.Most previous cancer biomarker studies using modem technologies are methodologically flawed as they compare samples from cancer patients with those of healthy，inflammation-free people（Morcos et al.2013）.An accurate and non-invasive test to differentiate pancreatic cancer from chronic pancreatitis would be extremely helpful to detect pancreatic cancer at an early stage and help physicians to make the right treatment decisions and prolong patients’survival.
Protein Biomarkers CA19-9 is the most widely used tumor maker for pancreatic cancer，and its sensitivity is～80%，while only about 55%for small and resectable cancers（＜3 cm）（Ballehaninna and Chamberlain 2011）.Disappointingly，in high-risk，asymptomatic individuals harboring IPMNs or high-grade PanINs，serum CA19-9 is often normal（Maitra and Hruban 2008）.Furthermore，chronic pancreatitis tissues also exhibit high positive rates of CA19-9 expression（Shi et al.2014）.These data showed that CA1 9-9 is not an optimal biomarker to detect those non-malignant pancreatic tumors，nor is suitable to distinguish pancreatic cancer from chronic pancreatitis and other nonneoplastic pancreatic diseases.Recent efforts have been devoted to those markers with capacity to distinguish pancreatic cancer from chronic pancreatitis cases，and have identified a list of markers with potential clinical application（Crnogorac-Jurcevic et al.2005）.For example，using quantitative RT-PCR and immunohistochemistry to analyze the expression of UHRF1，ATP7A and aldehyde oxidase 1 in combination could potentially provide an additional useful diagnostic tool for fineneedle aspirated or cytological specimens obtained during endoscopic procedures（Crnogorac-Jurcevic et al.2005）.PAM4 is a monoclonal antibody expressed by 90%of PDAC，as well as the precursor lesions PanIN and intraductal papillary mucinous neoplasm，and shows high specificity for PDAC and precursor lesions versus benign，nonneoplastic pancreatic tissues.Interestingly，approximately 80%of chronic pancreatitis patients are negative for circulating PAM4 antigen，which highlights PAM4's potential use in differential diagnosis between chronic pancreatitis and pancreatic cancer（Shi et al.2014）.(https://www.daowen.com)
DNA and RNA biomarkers Early studies indicate that human plasma are rich in nuclease，so that DNA and RNA fragments could not be stably detected as markers for cancer detection and diagnosis（Kong et al.2011）.However，recent studies show that DNA and RNA molecules could also serve as markers with potential clinical applications.For example，KRAS2 mutations in codon 12 could stably be detected in circulating deoxyribo nucleic acid，and its positive rate is significantly higher in pancreatic cancer than in chronic pancreatitis patients（47%vs.13%）.A combined normal serum CA19-9 and absence of circulating KRAS2 mutations may significantly increase the differential diagnosis efficacy between chronic pancreatitis and pancreatic cancer（Maire et al.2002）.
microRNAs microRNAs（miRNAs）are endogenous，small，non-coding RNAs that repress the expression of target mRNAs.More than 1500 mature human miRNA sequences are listed in the miRNA database（Kozomara and Griffiths-Jones 2014）.These sequences play important roles in virtually all biological pathways in mammals and other multicellular organisms（Berezikov 2011）.Despite their subtle effects on individual targets，miRNAs are responsible for the modulation of multiple signaling pathways involved in cell growth，proliferation，differentiation，motility，and apoptosis（Kang et al.2016）.In fact，a number of miRNAs are located in fragile regions of the human genome that are associated with cancer development，and dysregulated miRNAs play crucial roles in tumor initiation，progression，and metastasis and are often associated with diagnosis，prognosis，and response to therapy（Rachagani et al.2015）.
There are many miRNAs that play important roles in pancreatic cancer development and progression，including miR-494（Li et al.2014）.Our recent study has suggested that miRNAs could be stably detected in plasma and may serve as good markers for pancreatic cancer diagnosis（Kong et al.2011）.Among seven miRNAs evaluated in our study，miR-21 is able to distinguish pancreatic cancer from chronic pancreatitis and healthy patients；whereas miR-155 and miR-196a are able to differentiate sera with diseased pancreas（pancreatic cancer/chronic pancreatitis）from normal pancreas.Further quantitation of miRNAs in whole blood from pancreatic cancer，chronic pancreatitis and healthy controls has identified two panels of microRNAs with potential to distinguish pancreatic cancer patients from chronic pancreatitis and healthy controls（Schultz et al.2014）.