Does detection of K-ras mutations in pancreatic juice influence clinical decision making?

O'Mahony, Seamus; Sreedharan, Aravamuthan

European Journal of Gastroenterology & Hepatology:
Leading Articles
Abstract

The majority of patients with pancreatic cancer harbour mutations in the K-ras gene. This oncogene may be detected in material obtained at endoscopic retrograde cholangiopancreatography (ERCP), such as bile and pancreatic juice. Since a formal tissue diagnosis may be difficult to establish in pancreatic cancer, detection of K-ras in these materials is an attractive approach to diagnosis. A variety of molecular techniques has been used to detect K-ras, and frequency of the mutation may vary between different populations. In this issue of the European Journal of Gastroenterology and Hepatology, Boadas et al. collected pancreatic juice following secretin stimulation at the time of ERCP, and detected K-ras in 44% of patients with pancreatic cancer. They found the mutation in 16% of patients with chronic pancreatitis. Presence of the mutation, therefore, is not specific enough to recommend its use in the clinical diagnosis of pancreatic cancer. Chronic pancreatitis patients with the mutation may be at higher risk of developing pancreatic cancer than those patients without the mutation, but there is no clear consensus on management and follow-up of these patients.

*  Most patients with pancreatic cancer harbour mutations in the K-ras gene.

*  K-ras mutations may be detected in materials obtained endoscopically, such as bile, pancreatic juice, pancreatic brushings, and duodenal aspirate; positivity for the oncogene in these materials varies enormously.

*  K-ras mutations may also be detected in a significant minority of patients with chronic pancreatitis; this limits the clinical usefulness of K-ras as a diagnostic marker for pancreatic cancer.

*  Chronic pancreatitis patients with K-ras may be at increased risk of developing pancreatic cancer.

Author Information

Centre for Digestive Diseases, The General Infirmary at Leeds, Leeds, UK

Received 22 May 2001

Correspondence to Dr Seamus O'Mahony, Gastroenterology Unit, The General Infirmary at Leeds, Great George Street, Leeds LS1 3EX, UK Tel: +44 (0)113 392 6733; fax: +44 (0)113 392 6968; e-mail: seamuso@ulth.northy.nhs.uk

Article Outline

Most (> 90%) pancreatic adenocarcinomas harbour mutations in codon 12 of the K-ras gene [1]. Many studies have reported detection of the oncogene in material obtained during endoscopic retrograde cholangiopancreatography (ERCP) in patients with pancreatic cancer. K-ras mutations have been detected in bile [2], pancreatic juice [3], pancreatic brushings [4], and duodenal aspirates [5]. This approach to diagnosis of pancreatic cancer is attractive, as tissue diagnosis is otherwise difficult and invasive. In our region, for example, a formal tissue diagnosis is established in only one-third of patients with pancreatic cancer [2].

The sensitivity of molecular diagnosis on material obtained at ERCP varies enormously. We detected K-ras mutations in bile in 50% of patients with pancreatic cancer [2]; van Laethem et al. [4] reported a prevalence of 83% in pancreatic brushings; and in this issue of the European Journal of Gastroenterology and Hepatology, Boadas et al. [6] detected the mutation in secretin-stimulated pancreatic juice in 44% of pancreatic cancer patients. We used bile because it was easy to collect following biliary stenting, and because collection did not add significantly to procedure duration. Collection of pancreatic juice following secretin stimulation probably takes a little longer, whilst carrying out pancreatic brushings is likely to double the duration of the procedure. In our experience in the UK, when patients with pancreatic cancer come for ERCP, the primary objective is to establish biliary drainage by stent insertion. In our series, less than 50% of patients with pancreatic cancer had a pancreatogram, as most endoscopists would proceed to stent insertion if the bile duct is cannulated first. The Belgian group [4] carry out ERCP under general anaesthesia, which allows for a more leisurely approach, and is likely to facilitate procedures such as pancreatic duct brushings.

Initial enthusiasm for molecular diagnosis on material obtained at ERCP has been tempered by the detection of K-ras mutations in patients with chronic pancreatitis. Pancreatic cancer may be difficult to distinguish from chronic pancreatitis, as chronic pancreatitis is associated with both ductal and parenchymal changes that can mimic pancreatic cancer. As chronic pancreatitis is therefore the main differential diagnosis in patients with suspected pancreatic cancer, detection of K-ras mutations is unlikely to play a significant role as a diagnostic marker of pancreatic cancer. Furthermore, the evidence that presence of the mutation identifies those patients with chronic pancreatitis who are at particular risk of developing pancreatic cancer is conflicting. Boadas et al. diagnosed pancreatic cancer in one patient with chronic pancreatitis and K-ras, but this diagnosis was established after only 1 month of follow-up. Furthermore, another chronic pancreatitis patient without the mutation went on to develop pancreatic cancer.

Cytology (biliary and pancreatic, aspiration and brushings) has proved disappointing in the diagnosis of pancreatic cancer. Boadas et al. reported positive cytology in only 27% of pancreatic cancer patients. The combination of cytology and K-ras increased the ‘diagnostic’ rate to 50%. Although cytology has a poor sensitivity, it has a high specificity, and will therefore continue to play a role in the clinical diagnosis of pancreatic cancer. Although cytology was positive in only 27% of this series, other groups have reported much higher sensitivities, particularly when pancreatic brushings are used [7].

This study raises a number of questions: (1) does the presence of K-ras in material obtained at ERCP have a role to play in diagnosis of pancreatic cancer or clinical decision making? Boadas et al. concluded that ‘when a K-ras mutation is present in pancreatic juice, in patients without chronic pancreatitis, pancreatic cancer is highly suspected.’ We would concur with this conclusion, with the caveat that the most likely alternative diagnosis in patients with suspected pancreatic cancer is chronic pancreatitis. (2) Are patients with chronic pancreatitis and K-ras at higher risk of developing pancreatic cancer than chronic pancreatitis patients without K-ras? Van Laethem [8] and Barthelemy et al. [9] followed up patients with chronic pancreatitis and K-ras, and both studies detected two cancers over the follow-up period. By contrast, a Japanese study [10] of 54 patients detected no cancers in 20 patients over a mean follow-up period of 78 months. (3) How should we manage patients with chronic pancreatitis in whom K-ras mutations have been detected? The approach of Boadas et al. seems sensible and pragmatic, although there is little evidence as yet that such an approach is likely to detect early cancer. Should these patients undergo regular surveillance with ERCP and brush/aspiration cytology? Van Laethem [8] has commented that only long-term prospective studies will answer this question, and such a study has been initiated by the Brussels group. The significance of K-ras in chronic pancreatitis has not, therefore, been defined clearly, and detection of the mutation may lead to anxiety for both patient and clinician, without clear consensus on follow-up and treatment.

The presence of K-ras mutations in pancreatic juice (and other material obtained at ERCP) is not specific enough to justify its use in clinical practice. Other tumour markers, such as p53 [11] and telomerase [12] may, in combination with K-ras, increase the specificity, but further studies are required to define the role of combinations of tumour markers in the diagnosis of pancreatic cancer.

We conclude that K-ras is biologically significant but, at present, not clinically useful in the diagnosis of pancreatic cancer.

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© 2001 Lippincott Williams & Wilkins, Inc.