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Outside the Lab Oncology, Biochemistry and molecular biology, Clinical care

Friend or Foe?

A lot of the press around pancreatic cancer focuses on the difficulty in detecting early-stage disease and in treating advanced forms. As a result, most research focuses on ways to detect more cancers earlier in the disease, and on how to improve subsequent interventions. But not every pancreatic cyst we detect is a precursor to cancer.

Unfortunately, the currently available methods for distinguishing between harmless and precancerous pancreatic cysts are very poor. Although detecting the cysts gives us the opportunity to prevent or intervene early, there’s also a risk that patients may undergo significant surgery – with a mortality rate of up to 2 percent in high-volume centers (1) and even more elsewhere (2) – without actually needing it. Recent studies have shown that the accuracy of cyst fluid carcinoembryonic antigen (CEA), currently considered the gold standard for differentiating mucinous cystic neoplasms from other cysts, is only 63 percent (3). But if we could reliably identify benign (serous) cysts and intraductal papillary mucinous neoplasms (IPMNs) with high-grade dysplasia or early invasive adenocarcinoma, we could determine which patients needed which interventions – and significantly impact patient care.

Combination is key

At the moment, we examine pancreatic cysts by endoscopic ultrasound-guided biopsy, aspirating fluid directly from the cyst and then testing it for the presence of malignant cells or proteins associated with cancer. But fewer than two-thirds of cyst fluid CEA tests are accurate, and surgical series have only reinforced the issues. In some cases, over 20 percent of resected cysts were found to be entirely benign (4), while in others up to 78 percent of branch duct IPMNs harbored only low- or intermediate-grade dysplasia (5). It seemed clear to us that a better system was needed.

The word “system” is appropriate here, because we believe that the solution doesn’t lie in a single test. To get all of the relevant information, it’s important to evaluate a combination of tests reflecting various features. We began our investigations by using molecular markers to identify the cyst type – which worked very well for some cysts (like solid-pseudopapillary neoplasms), but not quite as well in others (like IPMNs). So, to fill in the blanks, we combined them with clinical features like the presence of a dilated main pancreatic duct. Overall, our multicenter retrospective study (6) incorporated 130 patients with resected pancreatic cystic neoplasms, 74 of whom were later determined not to have needed surgery. Our panel of molecular markers correctly identified 67 of those patients – which could have reduced the amount of unnecessary surgery by 91 percent. After adding in the clinical features, our testing was able to classify cyst type with 90 to 100 percent sensitivity and 92 to 98 percent specificity. That’s a significant improvement in the overall accuracy of testing, and could mean a significant decrease in the number of patients undergoing risky operations they don’t truly need.

Fighting false-positives

The testing still has limitations, though – this is a preliminary paper, so both the molecular markers and the clinical features we identified need to be validated in a larger series before being used in clinical practice. We’re currently completing a large multicenter trial, the data from that trial should be available next year. My personal opinion is that the markers will be available in clinical practice towards the end of 2016. When they reach the clinic, we hope that they will provide additional information for pathologists, improving our ability to both correctly classify the type of cyst and detect the presence of high-grade dysplasia or invasive cancer.

We’ve previously demonstrated that there’s a large window of opportunity for detecting and treating pancreatic neoplasms before they progress beyond the point of curability (7). We have both imaging and molecular methods for detecting curable lesions – and different research groups are making great strides forward in those areas (see “Tapping a Rich Vein”). But what we haven’t had to date is a good way of distinguishing between benign and precursor lesions, meaning that a false-positive result can lead to unnecessary and potentially harmful treatment in over one-fifth of cases. We hope that our system of molecular markers and clinical features will improve the accuracy of screening and help doctors make the best decisions for each individual patient.

Anne Marie Lennon is associate professor of medicine and surgery at the Johns Hopkins University School of Medicine, and the director of the Multidisciplinary Pancreatic Cyst Clinic and an attending gastroenterologist at the Johns Hopkins Hospital, Baltimore, USA.

Mission: Impossible by Michael Schubert

Tapping a Rich Vein by Christopher Chapman

New Ab-ilities in Imaging by Michael Schubert

Surprising Subtypes by Michael Schubert

(Chemo)resistance Is Futile by Michael Schubert

Breaching Cancer’s Defenses by Ingunn Stromnes

An Epigenetic Epiphany by Michael Schubert

Building a Better Mousetrap by Michael Schubert

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  1. JL Cameron et al., “One thousand consecutive pancreaticoduodenectomies”, Ann Surg, 244, 10–15 (2006). PMID: 16794383.
  2. RF de Wilde et al., “Impact of nationwide centralization of pancreaticoduodenectomy on hospital mortality”, Br J Surg, 99, 404–410 (2012). PMID: 22237731.
  3. M Al-Haddad et al., “Performance characteristics of molecular (DNA) analysis for the diagnosis of mucinous pancreatic cysts”, Gastrointest Endosc, 79, 79–87 (2014). PMID: 23845445.
  4. NP Valsangkar et al., “851 resected cystic tumors of the pancreas: a 33-year experience at the Massachusetts General Hospital”, Surgery, 152, S4–S12 (2012). PMID: 22770958.
  5. K Sahora et al., “Branch duct intraductal papillary mucinous neoplasms: does cyst size change the tip of the scale? A critical analysis of the revised international consensus guidelines in a large single-institutional series”, Ann Surg, 258, 466–475 (2013). PMID: 24022439.
  6. S Springer et al., “A combination of molecular markers and clinical features improve the classification of pancreatic cysts”, Gastroenterology, 149, 1501–1510 (2015). PMID: 26253305.
  7. AM Lennon et al., “The early detection of pancreatic cancer: what will it take to diagnose and treat curable pancreatic neoplasia?” Cancer Res, 74, 3381–3389 (2014). PMID: 24924775.
About the Author
Anne Marie Lennon

Anne Marie Lennon is associate professor of medicine and surgery at the Johns Hopkins University School of Medicine, and the director of the Multidisciplinary Pancreatic Cyst Clinic and an attending gastroenterologist at the Johns Hopkins Hospital, Baltimore, USA.

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