Risk of pancreatic ductal adenocarcinoma in chronic pancreatitis

Chronic pancreatitis has been proposed as an independent risk factor for the development of pancreatic cancer in a number of important studies.^1–3 Problems with methodology however, such as patient selection, ascertainment bias, small patient numbers, and stringency of patient selection have been major criticisms, leading some authors to believe that the risk of pancreatic cancer in chronic pancreatitis is confounded by other risk factors such as smoking.⁴ The study presented by Malka and colleagues⁵ in this issue of Gut has addressed some of these considerations, in that it has prospectively followed a cohort of 373 patients with proven chronic pancreatitis, defined by stringent criteria, over a median of 9.2 years [see page 849]. The high incidence of pancreatic calcification (83%), elective surgery (60%), diabetes mellitus (54%), pseudocysts (46%), and venous occlusive disease (21%) leave little room for doubt that this is a true cohort of patients with chronic pancreatitis. Patients with pancreatic cancer were confirmed histologically in all cases and careful consideration was given to patients that were lost to follow up. The results of the study suggest a significantly overall increased risk of pancreatic cancer (standardised incidence ratio 26.7) in chronic pancreatitis.

The majority of patients in this study had alcoholic pancreatitis (85%); patients with chronic pancreatitis however are a heterogeneous group, with chronic pancreatitis of other aetiologies having a much greater risk for the development of pancreatic cancer. Hereditary pancreatitis, an autosomal dominant disease presenting in childhood that is histologically identical to chronic pancreatitis of other aetiologies, has a 53-fold increased risk for the development of pancreatic cancer.⁶ The risk of developing pancreatic cancer in chronic pancreatitis is also related to the age of the patient. Whether this is a reflection of the age per se or the duration of chronic pancreatitis is unclear. Lowenfels et al, in a study of 1552 patients with chronic pancreatitis, found a marked independent increase in pancreatic cancer with age such that the relative risk for the development of pancreatic cancer was more than three times greater for a patient over the age of 60 years compared with younger patients.² In a similar study in patients with hereditary pancreatitis, the risk of pancreatic cancer was negligible below the age of 40 years but increased greatly with age such that the overall lifetime risk to aged 70 was 40%.⁶

Cigarette consumption is an important consideration in any study evaluating cancer risk, particularly in chronic pancreatitis where a high proportion of patients smoke. A number of studies have identified smoking as an independent variable in the development of pancreatic cancer, and demonstrated that there is a relationship to the number of cigarettes consumed.^7,8 In a multivariate analysis of 497 patients with hereditary pancreatitis, smoking was found to independently double the risk of pancreatic cancer and accounted for approximately 25–30% of all pancreatic tumours. Pancreatic cancer also developed some 20 years earlier in smokers compared with non-smokers, suggesting that smoking compounds the risk of pancreatic cancer in chronic pancreatitis.⁹

Leaving epidemiological studies aside, there is some biological evidence supporting the development of chronic pancreatitis to pancreatic ductal adenocarcinoma. Ductal dysplasia, which is relatively common in chronic pancreatitis, has been demonstrated in the pancreas of patients with pancreatic cancer. More importantly, there is a stepwise progression from mild to severe dysplasia within the pancreatic ducts¹⁰ suggesting a temporal relationship of these ductal lesions and pancreatic cancer. Molecular analysis of pancreatic ductal lesions, similar to those found in chronic pancreatitis, has demonstrated identical molecular lesions as those found in infiltrating ductal adenocarcinomas of the pancreas. K-ras mutations have been described in ductal lesions with minimal atypia and as such are “early” genetic events in carcinogenesis.^11–13 Mutations in the p16 gene occur at a later stage in carcinogenesis. Yamano et al showed loss of heterogeneity of the p16 loci in 13% of histologically low grade pancreatic ductal lesions compared with 90% of high grade lesions.¹⁴ Loss of expression of p16, another tumour suppressor gene thought to be important in the development of pancreatic cancer, was found in 60/126 microdissected intraductal lesions. More significantly, loss of expression of p16 was seen in atypical lesions three times more often than non-atypical lesions, suggesting that loss of p16 expression occurs more frequently in higher grade duct lesions.¹⁵ Loss of expression of p16 and another tumour suppressor gene SMAD4 have also been seen in pancreatic ductal lesions, but unlike K-ras and p16, these mutations are seen in lesions with significant atypia or carcinoma in situ.^16,17 A more direct link may lie in the chronic activation of trypsinogen and activation by trypsin of the matrix metalloproteinase matrilysin (MMP-7),¹⁸ increased activity of which is now recognised as one of the earliest events in the molecular pathogenesis of pancreatic cancer.¹⁹

Further confirmation of chronic pancreatitis as a risk factor for pancreatic cancer is important from a clinical prospective, particularly with respect to screening. It is clear that unstructured screening of all patients with chronic pancreatitis is unlikely to be of benefit as existing tests are not sufficiently sensitive or specific to result in patients with cancer being detected with the required positive and negative predictive values to enable screening to be effective. It is apparent however that there are subsets of patients with chronic pancreatitis where their individual risk of pancreatic cancer may be sufficiently high to justify screening. Given also that there appears to be a progression of molecular mutations in patients with developing pancreatic cancer, screening using a combination of imaging and molecular tests may be justified in older (>40–50 years) patients with the non-inherited as well as the inherited forms of chronic pancreatitis.²⁰