Inflammation and Carcinogenesis in the Pancreas and Biliary Tract: Mechanisms and Practice

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Among the diseases treated by gastroenterologists, those involving the pancreas and the biliary tract are often the most challenging. However, recent advances in our knowledge of disease mechanisms, new diagnostic modalities, and progress in describing the natural history of disease have led to the promise of new and more successful treatments. This is true of inflammatory as well as neoplastic processes that involve the pancreas and biliary tract. In May 2009, scientists and clinical investigators representing the Japanese Society of Gastroenterology and the American Gastroenterology Association met in Sapporo, Japan, to present and discuss their work at the Inflammation and Carcinogenesis in the Pancreas and Biliary Tract: Mechanism and Practice symposium. In this supplement to Clinical Gastroenterology and Hepatology, we provide summaries of presentations that ranged from molecular pathology to studies of anatomic variations that cause disease and new imaging modalities that help to discriminate between benign and malignant processes. The following comments summarize some of the highlights included in this supplement.

Advances have been seen in studies of pancreatic inflammation and pancreatic cancer. Studies of acute pancreatitis suggest that a group with intermediate severity, between mild and severe pancreatitis, have a distinct clinical course that is characterized by a high incidence of local complications, but rare mortality. Conditions associated with acute metabolic acidosis, such as mitochondrial dysfunction or diabetic ketoacidosis, appear to predispose to developing acute pancreatitis. Thus, an acute acid load could sensitize the pancreas or worsen disease through mechanisms involving the acinar cell and inflammatory pathways. A population-based study from Japan examining the natural history of acute pancreatitis showed that the risk of progression to chronic pancreatitis was greatest in those with alcohol-associated disease. Interestingly, in this series, extent of pancreatic necrosis at presentation affected the risk of developing chronic disease.

Autoimmune pancreatitis (AIP) has become a well-recognized entity with many of the key studies performed by investigators in Japan. However, the natural history of this disease remains unclear. Serum immune markers, such as immune complex assayed by the monoclonal rheumatoid factor method (IC-mRF) and the immunoglobulin G4 levels, may reflect disease activity and be useful as a therapeutic guide. It appears that some patients with AIP can progress to chronic pancreatitis. Two issues are raised with respect to AIP and pancreatic cancer: (1) what is the best way to distinguish AIP from pancreatic cancer, and (2) are subjects with AIP at increased risk of developing cancer? To separate AIP from cancer, 2 diagnostic paradigms have been proposed: one from Japan and the other from the United States. However, neither has been validated prospectively. Whether patients with AIP are at increased risk for developing pancreatic cancer remains unclear.

Although the relationship between AIP and pancreatic cancer is uncertain, there is a consensus that subjects with chronic pancreatitis are at risk for this neoplasm. Data from Japan suggest that the presence of chronic pancreatitis substantially (10–15 y) reduces life expectancy. The most common cause of death in subjects with chronic pancreatitis is malignancy and, most often, pancreatic cancer. Preliminary studies suggest that specific mutations in the SPINK gene are associated strongly with increased pancreatic cancer risk in subjects with chronic pancreatitis. If confirmed, this could have implications for cancer surveillance in subjects with chronic pancreatitis. Both chronic inflammation and pancreatic fibrosis, hallmarks of chronic pancreatitis, appear to be linked to pancreatic cancer development. In recent years, an important role for activated pancreatic stellate cells and extracellular matrix proteins in creating a milieu that promotes cancer development has emerged. Several studies have suggested that a significant fraction of pancreatic stellate cells may arise from a bone-marrow precursor. Other studies have suggested that although pancreatic carcinoma has a ductal phenotype, it might arise from acinar cell precursors. Some of the most common mutations associated with pancreatic adenocarcinoma are those producing K-ras. Notably, the biologic activity of K-ras, and not the presence of the mutant protein, may be the most important factor in determining its neoplastic effects. A key factor in the development of chronic pancreatitis and pancreatic cancer is cigarette smoking, acting in part through its effects on inflammation. Obesity, possibly by creating a proinflammatory state, is another important risk factor for the developing pancreatic cancer. Because there usually is little that can be done to treat pancreatic cancer, measures that reduce the risk of developing disease need more emphasis.

Differentiating between benign and malignant pancreatic lesions often presents one of the greatest challenges to gastroenterologists. This includes evaluating the malignant potential of cystic lesions, differentiating AIP from cancer, detecting cancer in the setting of chronic pancreatitis, and identifying pancreatic endocrine tumors. Newer approaches that use combinations of biomarkers, detailed structural analysis using high-resolution endoscopic ultrasonography and blood flow analysis, and elastography, promise to increase the sensitivity and specificity for identifying pancreatic neoplasms.

Both inflammatory processes and neoplasia of the biliary tract can be difficult to diagnose and to manage. Biliary cancer is much less common than pancreatic cancer and its molecular characteristics are just being described. However, several markers, including specific mucins and matrix metalloproteinases, as well as proteins encoded by the connective tissue growth factor gene, appear to provide prognostic information. Similar to pancreatic cancer, interactions between stellate cells and extracellular matrix proteins may modulate biliary cancer growth. The development of a rat model of biliary cancer that closely mimics human disease holds strong promise for advancing studies of this malignancy. Some conditions, such as congenital dilation of the biliary tract, are known to predispose to the development of biliary malignancy. Another condition associated with an increase of both bile duct and gallbladder malignancy is pancreaticobiliary maljunction. In subjects with this anomaly, the pancreatic and bile ducts join proximal to entering the duodenal wall, proximal to the sphincter of Oddi. Often this anomaly is associated with a long common channel and the bidirectional reflux of biliary and pancreatic duct content. Prophylactic surgery, to prevent biliary cancers, is recommended in these patients. Finally, the diagnosis and treatment of biliary strictures, both benign and malignant, is challenging. However, the use of endoscopic ultrasonography, direct visualization, and biopsy of the common bile duct and advanced molecular markers promises to improve diagnostic accuracy. Treatment of biliary strictures using percutaneous stenting, endoscopic stents, and phototherapy can be used to treat biliary strictures; the latter is reserved for neoplastic disease.

The advances highlighted in this supplement should interest both investigators and those involved in the clinical management of patients with pancreatic and biliary diseases. Most of these summaries provide state-of-the-art commentaries related to specific clinic issues. The editors and participants hope that the contents of this supplement also will stimulate interest in these topics and advance the pace of both clinical and basic research.