Biomarkers in the Differential Diagnosis of Pancreatic Diseases: Looking for a Compass

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To the Editor:
We read with great interest the recent publication of Pezzilli et al1 evaluating the presence of pancreatic enzyme kinetics in patients with pancreatic cystic lesions and its potential role in differential diagnosis between acute or chronic benign pancreatic diseases and pancreatic malignancies. The striking finding was that abnormally high serum pancreatic amylase and lipase levels were found in less than 50% of patients with mucinous cystic lesions and chronic pancreatitis but in none of the patients with pancreatic adenocarcinoma.1
Current literature reveals many biomarkers, mainly inflammatory, that have been used to differentiate benign from malignant pancreatic disease. Unfortunately, no reliable and efficient biomarker has been established to serve this purpose. As the authors have already established, intraductal papillary mucinous neoplasms have serum vascular endothelial growth factor receptor-2 concentrations, which differ from those in patients with ductal adenocarcinomas.2 Similarly, serum tumor necrosis factor receptor-1 was elevated in patients with intraductal papillary mucinous neoplasms and in those with pancreatic adenocarcinomas, suggesting high apoptotic activity in both groups of patients studied.3 Furthermore, leptin serum determinations have also been suggested to be able to differentiate benign from malignant pancreatic disease.4
Because the apoptotic process seems to be profound in many pancreatic diseases, we wonder whether the authors have ever focused on evaluating both M30 and M65 antigens as markers of differentiation between benign and malignant pancreatic diseases in serum or in ductal fluid. M30 antigen stands for the caspase-cleaved cytokeratin-18 and is used to detect apoptosis in many settings,5 and uncleaved cytokeratin-18, detectable as M65 antigen, is also released from dying cells (due to both apoptosis and necrosis).5 Our group recently demonstrated that the concentrations of M30 and M65 and their ratio differed significantly in severe compared to mild acute pancreatitis, serving as a marker of apoptosis and thus of disease severity.6 This phenomenon and correlation were attenuated after 6 days from the onset of symptoms (unpublished data). In the setting of advanced pancreatic adenocarcinoma, Tas et al7 demonstrated that both serum levels of M30 and M65 were found to be of diagnostic value of the disease without adding any predictive and prognostic value.
Finally, we wonder whether the authors have any data on the value of the S100A8/9 complex, as a novel inflammatory marker, in differentiating benign and malignant pancreatic diseases. The role of the S100A8/9 complex in benign and malignant colorectal diseases is well described with potential diagnostic value,8 but the literature on pancreatic diseases is scarce. Recently, Farkas et al9 demonstrated that the plasma levels of S100A8 and S100A9 were elevated in patients with acute pancreatitis, but a definitive difference between the severe and mild forms of the disease could not be observed. Similarly, Chen et al10 demonstrated that a high expression of either S100A8 or S100A9 predicted a worse disease-free and overall survival in patients with advanced pancreatic cancer. Moreover, moderate to high expression of S100A8 or S100A9 resulted in a median recurrence-free survival of 5.8 months compared with 17.3 months in those patients with low expression.10 Finally, overall median overall survival in patients with and without moderate to high expression of S100A8 or S100A9 was 12.6 months compared with 27 months in patients with low expression of these biomarkers.
All in all, we believe that M30/M65 antigens, as an apoptotic marker, and S100A8/S100A9 complex, as an inflammatory marker, might have a diagnostic role in the differentiation between benign and malignant pancreatic diseases. Literature on their exact role is scarce and inconclusive. Large prospective studies are compulsory to validate a correlation, if any.
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