Abstract

Background & Aims: Individuals with a strong family history of pancreatic cancer and persons with Peutz-Jeghers syndrome (PJS) have an increased risk for pancreatic cancer. This study screened for early pancreatic neoplasia and compared the pancreatic abnormalities in high-risk individuals and control subjects. Methods: High-risk individuals with PJS or a strong family history of pancreatic cancer were prospectively evaluated with baseline and 12-month computed tomography (CT) scan and endoscopic ultrasonography (EUS). If EUS was abnormal, EUS–fine-needle aspiration and endoscopic retrograde cholangiopancreatography (ERCP) were performed. Surgery was offered to patients with potentially neoplastic lesions. Radiologic findings and pathologic diagnoses were compared. Patients undergoing EUS and/or ERCP for benign non-pancreatic indications were concurrently enrolled as control subjects. Results: Seventy-eight high-risk patients (72 from familial pancreatic cancer kindreds, 6 PJS) and 149 control patients were studied. To date, 8 patients with pancreatic neoplasia have been confirmed by surgery or fine-needle aspiration (10% yield of screening); 6 patients had 8 benign intraductal papillary mucinous neoplasms (IPMNs), 1 had an IPMN that progressed to invasive ductal adenocarcinoma, and 1 had pancreatic intraepithelial neoplasia. EUS and CT also diagnosed 3 patients with 5 extrapancreatic neoplasms. At EUS and ERCP abnormalities suggestive of chronic pancreatitis were more common in high-risk patients than in control subjects. Conclusions: Screening EUS and CT diagnosed significant asymptomatic pancreatic and extrapancreatic neoplasms in high-risk individuals. IPMN should be considered a part of the phenotype of familial pancreatic cancer. Abnormalities suggestive of chronic pancreatitis are identified more commonly at EUS and ERCP in high-risk individuals. Background & Aims: Individuals with a strong family history of pancreatic cancer and persons with Peutz-Jeghers syndrome (PJS) have an increased risk for pancreatic cancer. This study screened for early pancreatic neoplasia and compared the pancreatic abnormalities in high-risk individuals and control subjects. Methods: High-risk individuals with PJS or a strong family history of pancreatic cancer were prospectively evaluated with baseline and 12-month computed tomography (CT) scan and endoscopic ultrasonography (EUS). If EUS was abnormal, EUS–fine-needle aspiration and endoscopic retrograde cholangiopancreatography (ERCP) were performed. Surgery was offered to patients with potentially neoplastic lesions. Radiologic findings and pathologic diagnoses were compared. Patients undergoing EUS and/or ERCP for benign non-pancreatic indications were concurrently enrolled as control subjects. Results: Seventy-eight high-risk patients (72 from familial pancreatic cancer kindreds, 6 PJS) and 149 control patients were studied. To date, 8 patients with pancreatic neoplasia have been confirmed by surgery or fine-needle aspiration (10% yield of screening); 6 patients had 8 benign intraductal papillary mucinous neoplasms (IPMNs), 1 had an IPMN that progressed to invasive ductal adenocarcinoma, and 1 had pancreatic intraepithelial neoplasia. EUS and CT also diagnosed 3 patients with 5 extrapancreatic neoplasms. At EUS and ERCP abnormalities suggestive of chronic pancreatitis were more common in high-risk patients than in control subjects. Conclusions: Screening EUS and CT diagnosed significant asymptomatic pancreatic and extrapancreatic neoplasms in high-risk individuals. IPMN should be considered a part of the phenotype of familial pancreatic cancer. Abnormalities suggestive of chronic pancreatitis are identified more commonly at EUS and ERCP in high-risk individuals. See CME exam on page 665 and editorial on page 684. See CME exam on page 665 and editorial on page 684. Pancreatic cancer is a deadly disease, with an overall 5-year relative survival of only 4.6%.1Ries L, Eisner M, Kosary C, et al. SEER Cancer Statistics Review, 1975-2002. National Cancer Institute 2005. Available at http://seer.cancer.gov/csr/1975_2002/, based on November 2004 SEER data submission, posted to the SEER web site.Google Scholar One of the reasons for the poor outcome is the advanced stage at which most of the carcinomas are diagnosed and the very high rate of unresectability in nearly all symptomatic patients. When curative resection is attempted, the best reported 5-year survival rate for pancreatic adenocarcinomas in the head is still only 26%.2Yeo C.J. Cameron J.L. Lillemoe K.D. et al.Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients.Ann Surg. 1995; 221: 721-733Crossref PubMed Scopus (959) Google Scholar Nearly all survivors have early stage disease.3Cleary S.P. Gryfe R. Guindi M. et al.Prognostic factors in resected pancreatic adenocarcinoma analysis of actual 5-year survivors.J Am Coll Surg. 2004; 198: 722-731Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar Japanese investigators reported a 4-year survival rate of 78% in resected stage 1 ductal adenocarcinomas 2 mm, without color flow or Doppler signal, with posterior acoustic enhancement). Lesions such as nodules or masses were measured in 2 dimensions and described according to shape, border, echogenicity, heterogeneity, and location. The pancreatic parenchyma and duct were also assessed for changes of chronic pancreatitis by using standard EUS criteria.20Catalano M.F. Lahoti S. Geenen J.E. et al.Prospective evaluation of endoscopic ultrasonography, endoscopic retrograde pancreatography, and secretin test in the diagnosis of chronic pancreatitis.Gastrointest Endosc. 1998; 48: 11-17Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar, 21Sahai A.V. Zimmerman M. Aabakken L. et al.Prospective assessment of the ability of endoscopic ultrasound to diagnose, exclude, or establish the severity of chronic pancreatitis found by endoscopic retrograde cholangiopancreatography.Gastrointest Endosc. 1998; 48: 18-25Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar, 22Wiersema M.J. Hawes R.H. Lehman G.A. et al.Prospective evaluation of endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography in patients with chronic abdominal pain of suspected pancreatic origin.Endoscopy. 1993; 25: 555-564Crossref PubMed Scopus (307) Google Scholar, 23Hollerbach S. Klamann A. Topalidis T. et al.Endoscopic ultrasonography (EUS) and fine-needle aspiration (FNA) cytology for diagnosis of chronic pancreatitis.Endoscopy. 2001; 33: 824-831Crossref PubMed Scopus (119) Google Scholar All parenchymal changes were categorized as focal (with location) or diffuse. The pancreatic parenchyma was also assessed for calcification, lobularity,20Catalano M.F. Lahoti S. Geenen J.E. et al.Prospective evaluation of endoscopic ultrasonography, endoscopic retrograde pancreatography, and secretin test in the diagnosis of chronic pancreatitis.Gastrointest Endosc. 1998; 48: 11-17Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar, 22Wiersema M.J. Hawes R.H. Lehman G.A. et al.Prospective evaluation of endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography in patients with chronic abdominal pain of suspected pancreatic origin.Endoscopy. 1993; 25: 555-564Crossref PubMed Scopus (307) Google Scholar and the presence of echogenic foci20Catalano M.F. Lahoti S. Geenen J.E. et al.Prospective evaluation of endoscopic ultrasonography, endoscopic retrograde pancreatography, and secretin test in the diagnosis of chronic pancreatitis.Gastrointest Endosc. 1998; 48: 11-17Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar, 21Sahai A.V. Zimmerman M. Aabakken L. et al.Prospective assessment of the ability of endoscopic ultrasound to diagnose, exclude, or establish the severity of chronic pancreatitis found by endoscopic retrograde cholangiopancreatography.Gastrointest Endosc. 1998; 48: 18-25Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar and echogenic strands.20Catalano M.F. Lahoti S. Geenen J.E. et al.Prospective evaluation of endoscopic ultrasonography, endoscopic retrograde pancreatography, and secretin test in the diagnosis of chronic pancreatitis.Gastrointest Endosc. 1998; 48: 11-17Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar, 21Sahai A.V. Zimmerman M. Aabakken L. et al.Prospective assessment of the ability of endoscopic ultrasound to diagnose, exclude, or establish the severity of chronic pancreatitis found by endoscopic retrograde cholangiopancreatography.Gastrointest Endosc. 1998; 48: 18-25Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar The main pancreatic duct diameter was measured in the head, body (at level of the portal vein–superior mesenteric vein confluence), and tail. In addition, the pancreatic ductal system was assessed for ductal dilation, visible side branches, echogenic ductal walls, irregularity of the main duct, and intraductal calcification. The endosonographer evaluated 9 EUS features that have been associated with chronic pancreatitis (echogenic foci, echogenic strands, lobularity, main ductal dilation, visible side branches, echogenic duct walls, duct irregularity, cysts, and stones).21Sahai A.V. Zimmerman M. Aabakken L. et al.Prospective assessment of the ability of endoscopic ultrasound to diagnose, exclude, or establish the severity of chronic pancreatitis found by endoscopic retrograde cholangiopancreatography.Gastrointest Endosc. 1998; 48: 18-25Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar, 22Wiersema M.J. Hawes R.H. Lehman G.A. et al.Prospective evaluation of endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography in patients with chronic abdominal pain of suspected pancreatic origin.Endoscopy. 1993; 25: 555-564Crossref PubMed Scopus (307) Google Scholar Chronic pancreatitis was rated as “absent to equivocal” if there were <3 of 9 features21Sahai A.V. Zimmerman M. Aabakken L. et al.Prospective assessment of the ability of endoscopic ultrasound to diagnose, exclude, or establish the severity of chronic pancreatitis found by endoscopic retrograde cholangiopancreatography.Gastrointest Endosc. 1998; 48: 18-25Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar, 22Wiersema M.J. Hawes R.H. Lehman G.A. et al.Prospective evaluation of endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography in patients with chronic abdominal pain of suspected pancreatic origin.Endoscopy. 1993; 25: 555-564Crossref PubMed Scopus (307) Google Scholar present, and chronic pancreatitis was rated as “present” if ≥3 of 9 features were present. This approach is associated with an accuracy of 85% or greater for diagnosis of chronic pancreatitis when using ERCP as the reference standard.21Sahai A.V. Zimmerman M. Aabakken L. et al.Prospective assessment of the ability of endoscopic ultrasound to diagnose, exclude, or establish the severity of chronic pancreatitis found by endoscopic retrograde cholangiopancreatography.Gastrointest Endosc. 1998; 48: 18-25Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar, 22Wiersema M.J. Hawes R.H. Lehman G.A. et al.Prospective evaluation of endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography in patients with chronic abdominal pain of suspected pancreatic origin.Endoscopy. 1993; 25: 555-564Crossref PubMed Scopus (307) Google Scholar The overall EUS grade of chronic pancreatitis was also assessed by using a previously reported classification, which uses the type of parenchymal and ductal EUS features of chronic pancreatitis rather than the number.23Hollerbach S. Klamann A. Topalidis T. et al.Endoscopic ultrasonography (EUS) and fine-needle aspiration (FNA) cytology for diagnosis of chronic pancreatitis.Endoscopy. 2001; 33: 824-831Crossref PubMed Scopus (119) Google Scholar The normal pancreas has a homogeneous echotexture with a thin and anechoic main pancreatic duct.20Catalano M.F. Lahoti S. Geenen J.E. et al.Prospective evaluation of endoscopic ultrasonography, endoscopic retrograde pancreatography, and secretin test in the diagnosis of chronic pancreatitis.Gastrointest Endosc. 1998; 48: 11-17Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar, 21Sahai A.V. Zimmerman M. Aabakken L. et al.Prospective assessment of the ability of endoscopic ultrasound to diagnose, exclude, or establish the severity of chronic pancreatitis found by endoscopic retrograde cholangiopancreatography.Gastrointest Endosc. 1998; 48: 18-25Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar, 22Wiersema M.J. Hawes R.H. Lehman G.A. et al.Prospective evaluation of endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography in patients with chronic abdominal pain of suspected pancreatic origin.Endoscopy. 1993; 25: 555-564Crossref PubMed Scopus (307) Google Scholar If the EUS was abnormal (ie, focal lesion such as mass, nodule, or cyst or at least 3 of 9 EUS features of chronic pancreatitis present), EUS-guided fine-needle aspiration (FNA) was performed at the same procedure by using an electronic video curved linear array echoendoscope (Olympus GF-UCT1409-AL5; Olympus Corporation, Inc) and a 22-gauge ultrasound aspiration needle (Wilson-Cook, Winston-Salem, NC; GIP Mediglobe, Tempe, AZ). Aspirates were first obtained from pancreatic lesions, and then the pancreatic parenchyma was systematically sampled for the specimen bank as part of ongoing collaborative translational studies on novel biomarkers for pancreatic neoplasia. Pancreatic fine-needle aspirates were assessed by an on-site cytopathologist and technician and routinely processed. Aspirates were also independently assessed by an experienced cytopathologist (S.Z.A.) unaware of the clinical and radiologic findings. High-risk individuals with abnormal EUS also underwent dual phase, multi-detector, spiral CT scan of the abdomen and pelvis with the standard protocol for pancreatic imaging at the Johns Hopkins Hospital. Patients were given 1000 mL of water 15–20 minutes before the study and injected with 120 mL of Omnipaque-350 at an injection rate of 3 mL/s. CT scans were performed on a Siemens Volume Zoom, 16-detector multi-slice scanner (Siemens Medical Solutions USA, Inc, Malvern, PA) by using 1-mm collimation with 1.25-mm slice thickness reconstructed at 1-mm intervals. All studies were reviewed with 3-dimensional volume rendering supplemented with maximum intensity projection. CT scans were interpreted by an experienced CT radiologist (E.F.) who was unaware of the EUS or ERCP findings. All high-risk subjects with an abnormal EUS were offered ERCP. ERCP was usually scheduled on a separate visit from the EUS. A single experienced endoscopist (A.K.) performed ERCP by using a videoduodenoscope (JF-140, JF-160; Olympus America) and fluoroscopy. The pancreatic duct was selectively cannulated with a triple lumen wire-guided catheter and a glidewire, and, if necessary, a small amount of contrast was injected to verify the location of the position in the pancreatic duct. The pancreatic ductal system was opacified with full-strength contrast with careful injection and magnification of fluoroscopic images to fill the primary and secondary ducts completely. The presence of saccules (saccular or grape-like deformities of the pancreatic ducts24Brentnall T.A. Bronner M.P. Byrd D.R. et al.Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancer.Ann Intern Med. 1999; 131: 247-255Crossref PubMed Scopus (318) Google Scholar) and grade of chronic pancreatitis were assessed by using the Cambridge classification.25Axon A.T. Endoscopic retrograde cholangiopancreatography in chronic pancreatitis Cambridge classification.Radiol Clin North Am. 1989; 27: 39-50PubMed Google Scholar Chronic pancreatitis-like changes of the ducts were classified as absent, mild (more than 3 dilated side branches with normal main duct), moderate (abnormal main duct and side branches), or severe (large cavity, ductal stone or filling defect, duct obstruction or stricture, gross irregularity). Other duodenal, ampullary, and pancreatic ductal abnormalities such as extrusion of mucin, pancreas divisum, and communicating cysts were noted. Patients who were suspected of having a pancreatic neoplasm because of a mass, cystic lesion, or nodule detected on imaging studies or because of severe dysplasia in their EUS-guided pancreatic fine-needle aspirates were referred to an experienced pancreatic surgeon (C.J.Y.). The risk and benefits of surgical treatment as well as the alternative option of close follow-up and repeat imaging and cytologic sampling were also discussed with the patient and family. Patients proceeding with surgery had a subtotal pancreatectomy (either pylorus-sparing Whipple procedure or distal pancreatectomy with or without splenectomy), depending on the distribution of lesions or abnormalities in preoperative imaging tests. All patients were called by telephone within 7 days after EUS and ERCP to assess for post-procedure complications. High-risk subjects with an abnormal EUS who did not have surgery were offered follow-up EUS/FNA and CT scan within 3–6 months to assess the stability of the abnormalities. All patients were offered repeat EUS within 1 year from the baseline evaluation. Pancreatic surgical specimens were assessed for neoplastic lesions by an experienced pathologist (R.H.H.) with expertise in pancreatic pathology. IPMNs were defined as neoplasms with tall, columnar, mucin-containing epithelium with or without papillary proliferations and extensively involving the main pancreatic ducts or major side branches. The IPMNs were also classified into main d