CANCER SURVEILLANCE OF PATIENTS FROM FAMILIAL PANCREATIC CANCER KINDREDS

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Pancreatic cancer is the fourth leading cause of cancer death in the United States, and its incidence is rising. At the time of diagnosis, 96% to 99% of patients are incurable and have a less than 1-year median survival.20, 33 Hereditary factors are important in the risk of pancreatic cancer, and in some patients, the risk of cancer approaches 50%.8, 23 As the importance of hereditary cancer syndromes is appreciated, physicians are taking note of family history and discovering patients who have multiple relatives with pancreatic cancer. Some genes have been identified that are associated with hereditary pancreatic cancer, such as BRCA2 and p16, and additional genes will soon be discovered.11, 12, 13, 14, 16, 24, 34

Although molecular genetics has expanded knowledge of the genetic basis for familial pancreatic cancer, there are few data about the clinical management of these patients. Prophylactic surgery in patients who are gene carriers, but do not yet have cancer, is fraught with complications, including postoperative death. Early experience with prophylactic pancreatectomy, before the development of a surveillance program, led to the death of a patient postoperatively from acute respiratory distress.8 Although the patient was a gene carrier, she did not yet have cancer or precancer. This anecdote further illustrates that not all gene carriers get cancer because some pedigrees reveal incomplete penetrance.12, 16 The ideal solution is to identify pancreatic neoplasia before it is invasive, reserving the risk and morbidity of pancreatectomy for those who are one step away from cancer.

The precursor lesion to pancreatic cancer is believed to be pancreatic dysplasia, also termed pancreatic intraductal neoplasia grades II and III and atypical ductal hyperplasia of the pancreas.6, 15, 17, 18, 21 Dysplastic epithelium shares many features with cancer, histologically and genetically, but it has not yet become invasive. Pancreatic dysplasia is typically multifocal, is present in at least 50% of pancreata that contain invasive adenocarcinoma, and implies a high risk for progression to cancer.17, 19 Animal models have shown dysplasia to be part of the hyperplasia-dysplasia-carcinoma sequence in the pancreas.29 Dysplasia was found incidentally in three patients who underwent partial pancreatic resection, all of whom subsequently developed cancer in the remaining pancreas within 1.5 to 10 years.2

Until recently, methods had not been described for the detection of pancreatic dysplasia or for the surveillance of patients who are at high risk for the development of pancreatic cancer, such as those with a strong family history.3, 4 Traditional modalities for evaluating patients with suspected pancreatic adenocarcinoma include endoscopic retrograde cholangiopancreatography (ERCP), helical computed tomography (CT) scanning, transabdominal ultrasound and endoscopic ultrasound (EUS), and serum tumor markers. These methods of diagnosis are typically used for diagnosis after pancreatic cancer has developed; the role of these conventional tests in the diagnosis of pancreatic dysplasia is just beginning to be discovered. General guidelines for the surveillance of pancreatic dysplasia have previously been published and are based on experience at the University of Washington that now includes 25 patients from multiple familial pancreatic cancer kindreds.4 Eight of these 25 patients have now undergone pancreatectomy based on the surveillance studies outlined below; all 8 have had evidence of dysplasia (neoplastic change that is precancerous) without invasive carcinoma. None of the remaining patients have developed cancer while under surveillance.

Section snippets

WHO IS AT RISK

Although there are few studies to define who is at risk for familial pancreatic cancer, it may be possible to obtain guidance from the preliminary data that are available and the experience with other familial gastrointestinal cancer syndromes.7, 25 First, there are data to support that even one family member with pancreatic cancer has a 5% to 10% risk of harboring an occult BRCA2 mutation that would predispose other related family members to cancer.12, 16, 28 This mutation appears to have low

HISTORY AND PHYSICAL EXAMINATION

The first job in evaluating patients is to obtain as many clues from the history and physical examination as possible. Common presenting symptoms include epigastric pain radiating through to the back, a history of loose stools or steatorrhea, diabetes, and weight loss. Occasionally, patients have lower abdominal pain; this symptom coupled with diarrhea may lead to evaluation of the colon rather than the pancreas. Most patients are completely asymptomatic and have an unremarkable physical

FAMILY HISTORY

Valuable information can be obtained from the history of affected family members. Often, these affected members are deceased, but spouses or other family members frequently remember symptoms and events. The following key questions should be addressed:

  • What are the ages of affected family members at the time of diagnosis? By looking at the age that the family members developed cancer, important information is gained for determining when to start surveillance in remaining relatives. In

SURVEILLANCE

Surveillance (Fig. 1) should be performed in centers that have experience in the surveillance of familial pancreatic cancer kindreds. Imaging modalities of the pancreas include EUS, ERCP, and spiral CT scanning. The first two tests appear to be quite useful, whereas the last-mentioned appears to be ineffective for surveillance.4 The commonest EUS changes include heterogeneous parenchyma with 1- to 2-mm echogenic foci scattered throughout; hypoechoic nodules and distinct masses are other

TREATMENT

Treatment for patients with a strong family history of pancreatic cancer who have abnormal EUS and ERCP is total pancreatectomy. Partial pancreatectomy is not recommended because the dysplasia is usually multifocal and widespread, and the whole pancreas is at risk. For the same reason, the author's group has not performed islet cell isolation and autotransplantation—it is possible that neoplastic cells could be reintroduced at the time of autotransplantation. As noted earlier, in new kindreds,

FUTURE CONSIDERATIONS

The first prospective surveillance of 14 patients from hereditary pancreatic cancer kindreds has been performed.4 Seven of 14 patients were referred for pancreatectomy on the basis of abnormal EUS and ERCP findings, and all 7 had pancreatic dysplasia at pancreatectomy. Such studies provide optimism that early intervention is possible; however, a larger cohort of patients needs to be studied to verify these preliminary results. The role of magnetic resonance cholangiopancreatography and positron

SUMMARY

The family history can be used to determine which family members warrant surveillance and when to start it. Surveillance should be started at least 1 decade before the earliest age of pancreatic cancer in the family. EUS is the basic, least-invasive surveillance tool; however, findings are similar to those seen in chronic pancreatitis. All patients who have a positive EUS or who have symptoms warrant ERCP. Changes on ERCP of ductal stricturing and clubbed or saccular side branches are

ACKNOWLEDGMENTS

The author thanks friends and colleagues Michael Kimmey, for his uncommon good sense and valuable insights, and Mary Bronner, for her remarkable prowess as a pathologist and wide-ranging excellence as a scientist.

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      Citation Excerpt :

      If the patient is symptomatic or has a history of pancreatitis, alcohol abuse, or cholelithiasis, which can influence the EUS findings, ERCP should be performed in addition to the EUS. Total pancreatectomy would be considered if suspicious changes are detected on ERCP.53 Such surveillance is best performed at a center specializing in the endoscopy and pancreatic pathology.

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    Address reprint requests to Teresa A. Brentnall, MD, Division of Gastroenterology, Box 356424, University of Washington Medical Center, 1959 NE Pacific Street, Seattle, WA 98195

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    Department of Medicine, Division of Gastroenterology, University of Washington Medical Center, Seattle, Washington

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    Copyright © 2000 W. B. Saunders Company. Published by Elsevier Inc. All rights reserved.