Up until the mid-1990s, physicians knew little about the relationship between pancreatic cysts and pancreatic cancer. But collaborative research conducted by gastroenterologists, surgeons, radiologists, and pathologists at the Massachusetts General Hospital Digestive Healthcare Center has led to a much greater understanding of pancreatic cystadenomas and what makes some cysts progress to cancer. These advances are opening up new therapies to target this deadly cancer early on, when it is most treatable.

Physician-researchers discover keys to understanding pancreatic cysts

17/May/2010

Pancreatic Cysts in the Population

Gross pathology of a resected serous cystadenoma demonstrating a microcystic structure. Serous cystadenomas are benign, but may enlarge over time.

As many as 2 percent of American adults have pancreatic cysts. These lesions are particularly common in older people. It’s estimated that 9 percent of people ages 80 and older have such cysts.

Most pancreatic cysts are found serendipitously during a computed tomography (CT) scan or ultrasound test to evaluate another chest or abdominal condition.

The two main classifications of pancreatic cysts include the following:

  • Serous cystadenomas, which are made of multiple thin-walled cysts that cluster together like a honeycomb. These cysts tend to be benign and are not associated with precancer.
  • Mucinous cystadenomas, which have a distinct appearance and are composed of distinct cystic compartments that vary in diameter and contain a clear, viscous fluid. Research shows these lesions have a tendency to progress to pancreatic cancer.

Mass General researchers were the first to detail the distinctions between these two types of cysts in a 2004 New England Journal of Medicine report titled “Cystic Neoplasms of the Pancreas.” The authors described how the cysts could be differentiated by CT findings, endoscopic ultrasound images, and cytology studies from biopsies.

Identifying Cysts that Pose the Greatest Threat

Brugge W, et al. (2004). Gastroenterol, 126(5): 1330-36.

Targeting patients with mucinous cystadenomas has been the focus of many investigations at the hospital’s Digestive Healthcare Center. In recent years, gastroenterologists have worked closely with scientists in Mass General’s Department of Cytology and Chemistry to develop assays for tumor markers and cytologic analysis. As a result, physicians can now make a tissue diagnosis of a mucinous cystadenoma and detect early evidence of malignant degeneration. Specifically, physicians have developed a test that tracks levels of carcinoembryonic antigen (CEA), which tends to be elevated in the cyst fluid of patients with premalignant, mucinous cysts of the pancreas. CEA levels are not elevated in patients with serous cysts of the pancreas. Mass General physicians published their research supporting the accuracy of CEA testing over other methods for determining premalignancy in pancreatic cysts in a 2004 report in Gastroenterology.

Once a mucinous cyst has been identified, physicians can use imaging and other methods to monitor the patient for early signs of cancer. In this regard, a new test based on DNA analysis of cyst fluid can help uncover early warning signs of pancreatic cancer.

So far, the most important mutation that physicians have discovered is on the KRAS gene. The KRAS gene is critical to the body’s production of the K-Ras protein, which is involved in regulating cell division. KRAS gene mutations are found only in mucinous cysts and not in serous cysts. These mutations, along with other DNA markers, suggest malignancy in pancreatic cysts. Recently, the Mass General team published findings from their work with DNA markers in the June 2009 issue of Cancer Cytopathology.

Other Predictors of Malignancy

Besides these markers, physicians have also identified demographic factors that seem to raise a patient’s risk of developing a pancreatic malignancy.

A recent report published in the January 15, 2010 issue of Alimentary Pharmacology and Therapeutics looked at imaging studies and biopsy findings from 153 patients with pancreatic cysts. Data revealed that older patients, particularly men, have the highest probability of cyst malignancy and may benefit from the most aggressive management. Specifically, they need close follow-up with ultrasound and MRI to detect cystic changes that could signal cancer.

Key Points

  • Pancreatic cysts can represent an early malignancy in the pancreas.
  • There are two main types of pancreatic cysts. Mucinous cystadenomas can be premalignant. Serous cystadenomas are usually benign.
  • Physicians can differentiate between benign and premalignant pancreatic cysts using the tumor marker CEA. Cyst fluid CEA is elevated in patients with premalignant mucinous cysts of the pancreas. Physicians can use CEA to identify patients with mucinous cysts. Of those, cytologic analysis can be conducted to determine malignant or premalignant cysts.
  • Physicians are now using CEA and DNA markers in the fluid cytology, obtained through a new test called cyst fluid analysis, to determine which cysts will develop into cancer. So far, the most important mutation that physicians have discovered is on the KRAS gene. The KRAS gene is critical to the body’s production of the K-Ras protein, which is involved in regulating cell division. KRAS gene mutations are found only in mucinous cysts and not in serous cysts.
  • Another recent study by Mass General physicians has identified several clinical predictors of malignancy in patients with pancreatic cysts. Older patients, particularly men, seem to have the highest probability of cyst malignancy and may benefit from the most aggressive management.
  • A large, multicenter prospective trial led by Mass General physician-researchers found that injecting alcohol into pancreatic cysts eliminated 33 percent of cysts.
  • In other research, physicians at Mass General have demonstrated the utility of endoscopic ultrasound-guided fine needle aspiration (EUS FNA) for diagnosing solid tumors of the pancreas.

Managing Patients with Premalignancies

Patients with premalignant conditions may be treated one of several ways. Typically, these lesions can be resected surgically, particularly if they are causing symptoms such as pain from pancreatitis. Lesions in the head of the pancreas can be removed with a Whipple resection.

However, resections for cysts in the head of the pancreas can pose greater risks to the patient. Some patients, such as elderly adults with multiple comorbidities, may not be candidates for surgery. These patients may be offered a new treatment involving ethyl alcohol injections being tested at the Digestive Healthcare Center.

During this therapy, a gastroenterologist injects alcohol into the lining of the mucinous cyst, where researchers believe the malignancy develops. A multicenter prospective trial led by Mass General physician-researchers found that injecting alcohol into pancreatic cysts reduced the size of the cysts after six months. In one-third of patients treated by alcohol injection, the cysts resolved. The results of this trial, known as the EUS-Guided Pancreatic Injection of Cyst (EPIC) Trial, were published in the October 2009 issue of Gastrointestinal Endoscopy. If further studies prove that this is an effective treatment, physicians would have a much less invasive therapy to ablate cysts, compared with surgery. Unpublished results from a follow-up of EPIC patients suggest that cysts do not return, and the therapy has good durability.

Other Pancreatic Cancer Advances

Solid tumors of the pancreas are also an active area of interest at the hospital’s Digestive Healthcare Center. A recent report published in the January 2010 issue of Gastrointestinal Endoscopy, led by gastroenterologists at Mass General, demonstrated the utility of using endoscopic ultrasound-guided fine needle aspiration (EUS FNA) for diagnosing solid tumors of the pancreas.

This large study of 559 patients found that EUS FNA had a 77 percent accuracy rate for detecting pancreatic adenocarcinoma. Test accuracy improved to 93 percent when atypical and suspicious samples were considered positive.

Selected References

  • Brugge W, Lauwers G, Sahani D, Fernandez-del Castillo C, Warshaw A. (2004). Cystic neoplasms of the pancreas. N Engl J Med, 351(12): 1218-26.
  • Brugge W, Lewandrowski K, Lee-Lewandrowski E, Centeno B, Szydlo T, Regan S, Fernandez-del Castillo C, Warshaw A. (2004). Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterol, 126(5): 1330-36.
  • DeWitt J, McGreevy K, Schmidt C, Brugge W. (2009). EUS-guided ethanol versus saline solution lavage for pancreatic cysts: a randomized, double-blind study. Gastrointest Endosc, 70(4): 710-23.
  • Huang E, Turner B, Fernandez-del Castillo C, Brugge W, Hur C. (2010). Pancreatic cystic lesions: clinical predictors of malignancy in patients undergoing surgery. Aliment Pharmacol Ther, 31(2): 285-94.
  • Shen J, Brugge W, Dimaio C, Pitman M. (2009). Molecular analysis of pancreatic cyst fluid: a comparative analysis with current practice of diagnosis. Cancer Cytopathol, 117(3): 217-27.
  • Turner B, Cizginer S, Agarwal D, Yang J, Pitman M, Brugge W. (2010). Diagnosis of pancreatic neoplasia with EUS and FNA: a report of accuracy. Gastrointest Endosc, 71(1): 91-98.

Contributors

William R. Brugge, MD

  • Director of GI Endoscopy, Massachusetts General Hospital Gastrointestinal Unit
  • Professor of Medicine, Harvard Medical School
  • wbrugge@partners.org

Massachusetts General Hospital Digestive Healthcare Center

The Massachusetts General Hospital Digestive Healthcare Center is a collaborative practice of gastroenterologists, endoscopists, surgeons, radiologists, pathologists, hepatologists, oncologists, and radiation oncologists dedicated to the prevention, diagnosis, treatment, and management of digestive diseases. The Digestive Healthcare Center offers a full range of medical and surgical treatments for digestive diseases, including conditions of the esophagus, stomach, small and large intestines, liver, gallbladder, pancreas, and colon.