Gastrointestinal Oncology - part 3 docx

20 years. The roles of other potential risk factors such as race, gender, diet, or occupa- tion have yet to be examined in the familial setting. Nonetheless, all patients with a family history of pancreatic cancer should be advised not to smoke. IDENTIFICATION OF PATIENTS AT RISK FOR FAMILIAL PANCREATIC CANCER The identification of patients at increased risk for familial pancreatic cancer can be challenging because familial aggregation of pancreatic cancer may be influenced by a number of factors, including chance, family size, shared environmental exposures, and incomplete gene penetrance. For example, a shared environmental factor could hypo- thetically result in multiple first-degree relatives with pancreatic cancer. Conversely, if a parent with a pancreatic cancer gene with complete penetrance has 4 children, there is a 6.25% chance that none of the children will be affected. If this hypothetical gene is also incompletely penetrant, the chance that no offspring will be affected is even greater. Furthermore, it can be difficult or impossible to obtain accurate family history data for such a rapidly and uniformly fatal disease, and the clinician is often unable to elicit an accurate family history for more than one or two generations of a family. For these reasons, there is currently no clear consensus on the definition of familial pancreatic cancer. However, families known to segregate mutations associated with cancer syndromes and those patients with hereditary pancreatitis should be considered at increased risk. It also appears that the absolute number of affected first-degree relatives is correlated with increased cancer risk, and most experts would agree the families that 74 Chapter 5 Figure 5-1. Earlier onset and increased risk of pancreatic cancer in members of familial pancreatic cancer kindreds who smoke. (Reprinted from Gastroenterology, Vol. 124(5), 1292-9, Rulyak SJ, et al, Risk factors for the development of pancreatic cancer in familial pancreatic cancer kindreds, Copyright 2003, with permission from the American Gastroenterological Association.) Ch05.qxd 4/8/2005 10:23 AM Page 74 include 2 or more first degree relatives with pancreatic cancer should be considered to have familial pancreatic cancer until proven otherwise. Families that include multiple second-degree relatives with pancreatic cancer and/or those with an unusually young age of onset (<50 years of age) may also be at increased risk, although these criteria are more controversial. These latter criteria may be most useful in evaluating small families and/or those with limited family history data. It is important for the clinician to recognize that the risk to an individual patient varies by both the number and relationship of affected relatives. For example, a patient whose mother and brother have been diagnosed with pancreatic cancer is likely to be at much higher risk of developing pancreatic cancer than if his or her uncle or first cousin were affected. Table 5-4 gives criteria that may prompt a clinician to consider the diagnosis of familial pancreatic cancer, although it is important to emphasize that estimation of risk for an individual patient is likely to be imprecise and that listed criteria have not been validated prospectively. Identification and Management of Familial Pancreatic Cancer 75 Table 5-4 C RITERIA FOR THE I DENTIFICATION OF P ATIENTS AT R ISK FOR I NHERITED P ANCREATIC C ANCER Increased Risk for Inherited Pancreatic Cancer 1. Patients with 2 or more first- degree relatives with pancreatic cancer 2. Patients known to harbor mutations that result in cancer syndromes associated with pancreatic cancer • Familial breast cancer (BRCA2) • Familial atypical multiple mole melanoma syndrome (CDKN2A) • Peutz-Jeghers syndrome (STK 11) • Familial adenomatous polyposis (APC) • Patients with hereditary pancreatitis* Possibly Increased Risk for Inherited Pancreatic Cancer 1. Individuals with one first-degree relative and one or more second-degree relative(s) diagnosed with pancreatic cancer 2. Individuals with one first-degree relative diagnosed with pancreatic cancer at an early age (under the age of 50) 3. Individuals with 2 or more second-degree relatives with pancreatic cancer, one of whom developed it at an early age 4. Patients meeting clinical criteria for one of the above cancer syndromes without a clearly defined mutation 5. Members of HNPCC families *Endoscopic screening is of uncertain utility as the findings of chronic pancreatitis are sim- ilar to the findings of dysplasia. Ch05.qxd 4/8/2005 10:23 AM Page 75 SCREENING FOR PANCREATIC CARCINOMA IN FAMILIAL PANCREATIC CANCER Pancreatic cancer is most often asymptomatic until it has progressed to an incurable stage. The nearly uniform lethality of pancreatic cancer is in part due to the lack of an acceptable screening test for pancreatic cancer. At present, there are no adequate radiographic, endoscopic, or laboratory tests for use in population-based pancreatic cancer screening. However, the risk of familial pancreatic cancer approaches 50% in some kindreds, and methods for early detection of pancreatic cancer and precancer in such families are clearly needed. The goal of such strategies is to identify family members with pancreatic dysplasia or very early pancreatic cancers before they progress to invasive disease. D YSPLASIA AS A P RECURSOR TO P ANCREATIC C ANCER The discovery of a dysplastic precursor lesion has been critical to the development of screening and surveillance tests for other gastrointestinal cancers including those arising in the colon, esophagus, and stomach. Pancreatic adenocarcinomas also appear to arise from dysplasia, which is more correctly referred to as PanIN. There are different grades of PanIN, which appear to represent a continuum of neoplastic progression (Figure 5- 2). PanIN-1 is also referred to as intraepithelial ductal hyperplasia and is characterized by elongation of epithelial cells with abundant supranuclear mucin (PanIN-1A), sometimes with papillary architecture (PanIN-1B). PanIN-2, or LGD, is defined by nuclear abnormalities including enlargement and crowding, hyperchromatism, and stratification. PanIN-3, also referred to as HGD or carcinoma in-situ, is characterized by papillary projections, loss of nuclear polarity, nuclear atypia, and mitoses. The prevalence of PanIN in the general population is currently unknown, but a recent study of a referral population of familial pancreatic cancer kindreds suggests that the prevalence of PanIN- 2 and PanIN-3 may be as high as 34% if stringent criteria are used to select family members for screening. 76 Chapter 5 Figure 5-2. Histology of PanIN. (A) PanIN-1 (open arrow) is characterized by elongation of epithelial cells with abundant supranuclear mucin and PanIN-2 (solid arrow) is defined by nuclear abnormalities including enlargement and crowding, hyperchromatism, and stratification. (B) In PanIN-3, there are lush papillary projections, loss of nuclear polarity, and nuclear atypia with mitoses. (Photomicrographs courtesy of Dr. Teresa Brentnall.) For a full-color version, see page CA-IV of the Color Atlas. A B Ch05.qxd 4/8/2005 10:23 AM Page 76 There are several important limitations in the literature regarding PanIN lesions and their progression to cancer. First, the absolute risk of pancreatic cancer in patients with pancreatic dysplasia has yet to be determined, as does the prevalence of PanIN in the general population. Second, the time course for progression from PanIN to cancer is as yet unknown. In one series of 3 patients who underwent pancreatic surgery for non- malignant indications and were found to have dysplasia at the resection margins, all patients progressed to cancer within 10 years. Clearly, larger studies of the natural history of PanIN are needed to confirm this finding. Finally, it is important to note that the accurate pathologic diagnosis of PanIN can be difficult. In one study, interobserver agreement among expert gastrointestinal pathologists was found to be only fair for PanIN 1 and PanIN 3 (kappa=0.43 and kappa=0.42, respectively) and poor for PanIN 2 lesions (kappa=0.14). Accurate diagnosis of PanIN is critical because PanIN is a multifocal or diffuse process and total pancreatectomy is necessary to ensure removal of all dysplastic tissue. It is likely that the accuracy of PanIN diagnoses will improve as pathologists accrue additional experience with this lesion. While the natural history of pancreatic dysplasia is difficult to study and incompletely characterized, PanIN represents a curable precursor lesion and thus it is possible that effective screening tests can be developed. Potential screening methods may involve the use of imaging modalities such as endoscopy or radiography. Ultimately, a biomark- er in serum or pancreatic juice may be most attractive option for screening. PanINs share many of the molecular genetic alterations found in adenocarcinomas. Because these molecular alterations appear to be acquired in a step-wise fashion, it may eventually be possible to detect the highest risk precursor lesions shortly before cancer develops. E NDOSCOPIC A PPROACHES FOR S CREENING Endoscopic techniques have been used to detect PanIN or early pancreatic cancer, and endoscopic screening protocols for high-risk members of familial pancreatic cancer kindreds are ongoing at several institutions in the United States and abroad. At present, EUS appears to be the most promising screening test for identifying pancreatic dysplasia and early pancreatic cancer because it is relatively non-invasive and has the ability to discriminate subtle abnormalities in the pancreatic parenchyma. The pancreatic abnormalities on EUS that are associated with dysplasia are the same findings that are present on EUS in patients with chronic pancreatitis. These changes include the presence of hyperechoic strands, hyperechoic foci, lobules (sometimes referred to as hypoechoic nodules), echogenic pancreatic duct walls, and irregularity of the pancreatic duct (Figure 5-3). Several of these findings have been reported to be more common in relatives of patients with pancreatic cancer compared to controls undergoing EUS for another indi- cation (Table 5-5). More importantly, Brentnall and colleagues have shown that these findings can be used to identify members of familial pancreatic kindreds with histopathologically-confirmed PanIN on pancreatic biopsy specimens. The findings seen on EUS should not be mistaken to represent endosonographic imaging of PanIN lesions, as EUS does not permit resolution of cellular details. Instead, these findings should be thought of as endoscopic markers associated with dysplasia. These changes may represent inflammation, fibrosis, or fatty replacement of the pancreas associated with PanIN, although the precise anatomic correlates of these findings have yet to be determined. One important limitation of EUS in screening is that identical findings can be found in patients with chronic pancreatitis, patients who consume alcohol, and occasionally in otherwise healthy adults undergoing EUS for other indications. Identification and Management of Familial Pancreatic Cancer 77 Ch05.qxd 4/8/2005 10:23 AM Page 77 ERCP may also have utility in detecting pancreatic dysplasia, although few would advocate this as a first-line screening test given the potential for complications, including pancreatitis. As with EUS findings, the ERCP findings associated with dysplasia can also be seen in patients with chronic pancreatitis. However, in selected members of familial pancreatic cancer kindreds without clinical evidence for pancreatitis, several ERCP findings have been associated with dysplasia. These include irregularity of main 78 Chapter 5 Figure 5-3. EUS findings associated with pancreatic dysplasia in familial pancreatic cancer kindreds. Radial imaging of the pancreas reveals hyperechoic strands (small arrows) and hypoechoic lobules (larger arrows) in a patient subse- quently diagnosed with PanIN 3. (Image courtesy of Dr. Michael Kimmey.) Table 5-5 F INDINGS OF EUS E XAMINATIONS OF M EMBERS OF F AMILIES W ITH 3 OR M ORE M EMBERS W ITH P ANCREATIC C ANCER ( N =30) C OMPARED TO C ONTROLS U NDERGOING EUS FOR O THER I NDICATIONS ( N =103) Finding FPC relatives (%) Controls (%) p-value Nodules* 46 1 0.0001 Prominent septae 33 10 0.003 Dilated side branch 33 14 0.03 Echogenic foci 70 52 0.09 Echogenic strands 67 48 0.09 Mass 10 2 0.08 Irregular main duct 17 7 0.14 Echogenic duct wall 7 4 0.62 *These findings, also known as "lobules," are multifocal hypoechoic areas throughout the pancreatic parenchyma measuring between 2 mm and 8 mm. The term lobule is used to distinguish these findings from those of a discrete mass lesion within the pancreas Adapted from Jagannath S, et al. Endoscopic ultrasound abnormalities in at-risk relatives from familial pancreatic cancer kindreds: a prospective, controlled pilot cohort study. Gastrointest Endosc. 2002;56(Suppl):S120. Ch05.qxd 4/8/2005 10:23 AM Page 78 pancreatic duct or side branches, ectasia of pancreatic duct side branches, sacculations of pancreatic ducts, and early acinarization of pancreatic head during pancreatic duct injec- tion with inability to completely fill the pancreatic tail (Figure 5-4). ERCP should be used primarily as a confirmatory test when abnormalities on EUS are identified, although one potential advantage of ERCP is ability to obtain pure pancreatic juice or pancreatic duct brushings, which may provide material for screening if an accurate molecular screening assay can be developed. It is important to emphasize that the use of endoscopic screening tests in familial pancreatic cancer is a field under development, and all screening should be conducted in the context of an approved clinical protocol. R ADIOGRAPHIC A PPROACHES FOR S CREENING If the goal of a screening program is to detect PanIN, it is unlikely that currently available radiographic imaging modalities such as helical CT or magnetic resonance cholangiopancreatography (MRCP) have the ability to resolve either the histopatholog- ic abnormalities seen in PanIN or the fibroinflammatory changes detected with EUS. However, improvements in technology may eventually allow detection of pancreatic cancers at a very early stage where the potential of cure is reasonable. However, until the clinical utility of radiographic tests is demonstrated, their use outside of research protocol is inadvisable unless patients report symptoms that warrant cross-sectional imaging. M OLECULAR A PPROACHES TO S CREENING The detection of molecular alterations in either blood or pancreatic juice may have the potential for the early detection of pancreatic cancer or PanIN. Mutations in k-ras have been the most widely studied of these alterations. While k-ras can be detected in pancreatic juice, pancreatic brushings, or fine needle aspirates of the pancreas, none of these assays have adequate specificity for the diagnosis of adenocarcinoma or dysplasia because k-ras mutation are also present in benign conditions, including chronic pancreatitis. p53 mutations can also be detected in pancreatic juice. However, p53 mutations appear to be a late event in pancreatic carcinogenesis and these mutations are absent in up to 50% of adenocarcinomas, thereby limiting sensitivity for the detection of pancreatic cancers or dysplasia. Mutations in CDKN2A (p16) and SMAD4 (DPC4) can be Identification and Management of Familial Pancreatic Cancer 79 Figure 5-4. ERCP findings associated with pancreatic dysplasia in familial pancreatic cancer kindreds. Markedly abnormal pancreatogram reveals an irregular, dilated main pancreatic duct with multiple side branch sacculations within the pancreatic head. (Image courtesy of Dr. Michael Kimmey.) Ch05.qxd 4/8/2005 10:23 AM Page 79 identified from pancreatic juice, but one recent study suggests that testing for these mutations adds little additional diagnostic information to the detection of K-ras. It is possible that combinations of screening markers may improve the accuracy of molecular testing for pancreatic cancers. There has been one study to suggest that combining assays for K-ras and p53 may improve diagnostic accuracy for pancreatic adenocarcinoma. However, no published studies have utilized combinations of molecular tests for the diagnosis of PanIN lesions. Telomere dysfunction is another promising molecular marker for screening of familial pancreatic cancer kindreds because it is an early and nearly ubiquitous alteration in PanIN. Telomere length shortening has been reported to be present in 96% in PanIN specimens. Assays of telomere length currently require histologically normal tissue as a control, and such tissue cannot be readily obtained by sampling pancreatic juice or by fine needle aspiration because PanIN is a diffuse and frequently multifocal process. However, telomerase activity is a surrogate for telomere shortening, and preliminary reports suggest that telomerase activity can be determined from either pancreatic juice or fine needle aspirates. It is important to recognize that telomere dysfunction is presently not only seen in low grade dysplasia (PanIN-2) and high grade dysplasia (PanIN-3), but also in pancreatic duct hyperplasia (PanIN-1). Therefore, any potential assay for telomere dysfunction is likely to have high sensitivity but low specificity for the diagnosis of dysplasia, although sensitivity is arguably the most important feature of a screening assay. If a suitable assay for telomere dysfunction can be developed, it may be most useful to select a subset of patients who warrant more intensive screening with EUS or other modalities. In patients with a family history suggestive of one of the defined cancer syndromes that result in pancreatic cancer, testing for germline mutations may represent an important tool for identifying family members at risk for pancreatic cancer. The yield of rou- tine testing of familial pancreatic cancer kindreds for most of these mutations is likely to be low. One exception may be testing for BRCA2, as recent studies suggest that up to 19% of familial pancreatic cancer kindreds may harbor a BRCA2 mutation in the absence of a family history of breast or ovarian cancer. However, future studies to confirm the prevalence of BRCA2 mutations among familial pancreatic cancer kindreds are needed before such testing can be widely recommended. As the pathways that lead to pancreatic adenocarcinoma are better understood, molecular approaches may assume an increasing role in screening and surveillance of high-risk family members. With the advent of proteomic technology, it is likely that newer markers with improved sensitivity and specificity will become available. While molecular techniques hold great promise, there are presently few studies to suggest that testing for single molecular genetic alterations or combinations thereof have utility in clinical detection of PanIN or early pancreatic cancer. As with other screening modalities, their use should be restricted to investigational protocols. APPROACH TO PATIENTS WITH A FAMILY HISTORY OF PANCREATIC CANCER The management of members of familial pancreatic cancer kindreds presents a for- midable challenge to the clinician because clinical experience with screening among high-risk pancreatic cancer patients is limited and currently evolving. However, several centers across the United States have initiated protocols to study the role of screening 80 Chapter 5 Ch05.qxd 4/8/2005 10:23 AM Page 80 and surveillance for high-risk family members, and early results from these studies are promising. One protocol using endoscopic screening has been developed at the University of Washington Medical Center in Seattle. To date, 73 patients from 50 different familial pancreatic cancer kindreds have been enrolled and follow-up extends to 9 years. From this cohort, 9 patients have been diagnosed with PanIN 3 and 7 have been diagnosed with PanIN 2. Thirteen of these patients have elected to undergo total pancreatectomy, with no operative deaths. Most importantly, no patient enrolled in the protocol has developed pancreatic cancer while under surveillance. While these results are encouraging, it must be emphasized that experience with endoscopic screening is limited, and endoscopic tests such as EUS are operator depend- ent. Therefore, screening with EUS should only be entertained in patients at greatest risk for pancreatic dysplasia, and patients should be well-informed, active participants in the decision to proceed with screening. The findings of EUS should be corroborated by other studies, including ERCP and ultimately laparoscopic biopsy of the pancreatic tail, prior to proceeding with total pancreatectomy. Finally, it cannot be overemphasized that the natural history of pancreatic dysplasia is uncertain and the performance characteris- tics of endoscopic tests such as EUS and ERCP have yet to be determined. However, a recent decision analysis that assumed a 90% sensitivity of EUS for dysplasia suggested that a strategy employing EUS to screen members of familial pancreatic cancer kindreds is cost-effective, although the benefit appears to be limited to patients with a pre-test probability of pancreatic dysplasia of 16% or greater. In all patients with a family history of pancreatic cancer, evaluation should begin with a careful history and physical examination in order to determine if alarm symptoms such as abdominal or back pain, diarrhea, weight loss, or recent onset diabetes are present. A history of smoking, alcohol consumption, or occupational exposures should also be elicited. All patients with a family history of pancreatic cancer should be counseled not to smoke. A careful family history should be obtained in order to construct a detailed family pedigree, which can then be used to select patients who may be candi- dates for screening. Patients with 2 or more first-degree family members diagnosed with pancreatic cancer are considered at increased risk of pancreatic cancer, as are patients who are known to harbor a germline mutation associated with pancreatic cancer. Patients with less compelling family histories may also be at increased risk of pancreatic cancer, although the utility of screening in such patients is far less certain. Table 5-4 lists proposed criteria for pancreatic cancer risk stratification, with the understanding that such criteria have yet to be prospectively validated. Patients with hereditary or acquired chronic pancreatitis represent a particular challenge, because the EUS and ERCP findings in patients with these conditions are indistinguishable from the findings of dysplasia. Therefore, endoscopic screening patients with chronic pancreatitis cannot be widely recommended, although experience with this population of patients is limited. Once a patient is deemed to be at increased risk for pancreatic cancer, extensive counseling regarding the uncertainties about the natural history of PanIN and lack of clearly validated methods for screening and surveillance for pancreatic neoplasia should then be undertaken. Counseling must include a frank discussion about the outcome of screening if abnormalities are uncovered, specifically total pancreatectomy. In patients with family histories suggestive of a known cancer syndrome, genetic counseling and mutational analysis should be considered. Patients who remain interested after a thor- ough discussion of risks and benefits are then offered screening. Identification and Management of Familial Pancreatic Cancer 81 Ch05.qxd 4/8/2005 10:23 AM Page 81 The algorithm used at the University of Washington for screening patients who meet criteria for familial pancreatic cancer is shown in Figure 5-5. Interested patients are offered EUS as the initial screening test, beginning either at the age of 50 years or 10 years prior to the earliest age at which pancreatic cancer was diagnosed in an affected family member. If EUS is abnormal and there is no recent history of alcohol use, the patient is then offered ERCP to confirm the pancreatic abnormalities noted on EUS. However, if the patient actively consumes alcohol, he or she is advised to abstain from alcohol for 6 months and the EUS is repeated to confirm that abnormalities persist. If both EUS and ERCP display characteristic abnormalities, the patient is referred for 82 Chapter 5 Figure 5-5. Approach to screening for pancreatic cancer in familial pancreatic cancer kindreds. Ch05.qxd 4/8/2005 10:23 AM Page 82 laparascopic distal pancreatectomy to confirm the presence of dysplasia. Patients with high-grade dysplasia (PanIN-3) are advised to undergo completion total pancreatectomy, which is required to ensure removal of all dysplastic tissue. Postoperatively, these patients require lifelong pancreatic enzyme replacement and close follow-up by a dia- betologist for diabetes mellitus. Experience with the management of patients with LGD (PanIN-2) limited, and patients are offered the choice of pancreatectomy or continued close surveillance. To date, several patients with PanIN-2 have elected to undergo pancreatectomy, while others have chosen to continue surveillance with EUS and/or ERCP. Patients with normal findings on EUS are advised to undergo repeat examination on a yearly basis, as at least one case of progression from a normal EUS to cancer in less than 12 months has occurred. It remains to be determined whether the surveillance interval may be lengthened after several normal examinations. Patients with an abnormal EUS examination but normal findings at ERCP are recommended to undergo repeat EUS in 1 year with close comparison of findings. Patients with progression of endosonographic changes undergo repeat ERCP, with laparoscopic biopsy reserved for patients with abnormalities on ERCP. However, if the abnormal EUS findings are stable in such patients, the examination is repeated on a yearly basis. CONCLUSION Approximately 10% of pancreatic cancers are inherited. A number of genetic syndromes can predispose mutation carriers to pancreatic cancer, including FAP, FAMMM, Peutz-Jeghers syndrome, hereditary breast/ovarian cancer syndrome, hereditary pancreatitis, and possibly HNPCC. However, the gene or genes involved in the majority of inherited pancreatic cancers have yet to be determined, although the molecular pathways of pancreatic tumorigenesis are beginning to be better understood. Smoking appears to be an important modifier of familial pancreatic cancer risk, but the role of other environmental factors in such families has yet to be determined. Screening and surveillance protocols using endoscopic techniques such as EUS and ERCP have been developed, but their use should be restricted to approved research protocols. Molecular genetic testing may have the greatest potential for screening and surveillance, although tests with improved sensitivity and specificity will need to be developed. Most importantly, what is learned from familial pancreatic cancer kindreds will have important implications for screening and prevention of pancreatic cancer in the general population. BIBLIOGRAPHY Banke MG, Mulvihill JJ, Aston CE. Inheritance of pancreatic cancer in pancreatic cancer- prone families. Med Clin North Am. 2000;84(3):677-690. Brat DJ LK, Yeo CJ, Warfield PB, Hruban RH. Progression of pancreatic intraductal neo- plasias to infiltrating adenocarcinoma of the pancreas. Am J Surg Pathol. 1998;22:163- 169. Brentnall TA, Bronner MP, Byrd DR, Haggitt RC, Kimmey MB. Early diagnosis and treat- ment of pancreatic dysplasia in patients with a family history of pancreatic cancer. Ann Intern Med. 1999;131(4):247-255. Eberle MA, Pfutzer R, Pogue-Geile KL, et al. A new susceptibility locus for autosomal dom- inant pancreatic cancer maps to chromosome 4q32-34. Am J Hum Genet. 2002;70(4): 1044-1048. Identification and Management of Familial Pancreatic Cancer 83 Ch05.qxd 4/8/2005 10:23 AM Page 83 [...]... cancer in the Peutz-Jeghers syndrome N Engl J Med 1987 ;31 6:151 1-1 514 Giardiello FM, Offerhaus GJ, Lee DH, et al Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis Gut 19 93; 34(10): 139 4-1 39 6 Goldstein AM, Fraser MC, Struewing JP, et al Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations N Engl J Med 1995 ;33 3(15): 97 0-9 74 Goldstein AM,... 1995;222: 63 8-6 45 Lillemoe KD, Cameron JL, Hardacre JM, et al Is prophylactic gastrojejunostomy indicated for unresectable periampullary cancer? A prospective randomized trial Ann Surg 1999; 230 :32 2 -3 28;discussion 32 8 -3 30 Lillemoe KD, Cameron JL, Kaufman HS, et al Chemical splanchnicectomy in patients with unresectable pancreatic cancer A prospective randomized trial Ann Surg 19 93; 217: 44 7-4 55;discussion 45 6-4 47... outcomes in 235 patients Ann Surg 1999;229:69 3- 6 98;discussion 69 8-7 00 Lim JE, Chien MW, Earle CC Prognostic factors following curative resection for pancreatic adenocarcinoma: a population-based, linked database analysis of 39 6 patients Ann Surg 20 03; 237 :7 4-8 5 Lin PW, Lin YJ Prospective randomized comparison between pylorus-preserving and standard pancreaticoduodenectomy Br J Surg 1999;86:60 3- 6 07 Loftus... and Pancreatic Neoplasia 89 Table 6-2 SURGICAL RESULTS FOR PATIENTS UNDERGOING PANCREATICODUODENECTOMY FOR PANCREATIC CARCINOMA Author Yeo Sohn Conlon Richter Billingsley Year No of patients Morbitity (%) Mortality (%) 5-year survival Median survival (months) 1999 650 – 1.4 – 20 2000 564 31 2 .3 17 17 2001 409 54 3 – 17.2 20 03 194 30 3 25 – 20 03 462 45.9 9 .3 – – mimic so-called mucinous cystic neoplasm... 1970; 130 :104 9-1 0 53 104 Chapter 6 Gullo L, Pezzilli R, Morselli-Labate AM Diabetes and the risk of pancreatic cancer Italian Pancreatic Cancer Study Group N Engl J Med 1994 ;33 1:8 1-8 4 Gunaratnam NT, Sarma AV, Norton ID, Wiersema MJ A prospective study of EUS-guided celiac plexus neurolysis for pancreatic cancer pain Gastrointest Endosc 2001;54 :31 632 4 Harada N, Wiersema MJ, Wiersema LM Endosonography-guided... 1998;85:19 9-2 01 Richter A, Niedergethmann M, Sturm JW, et al Long-term results of partial pancreaticoduodenectomy for ductal adenocarcinoma of the pancreatic head: 25-year experience World J Surg 20 03; 27 :32 4 -3 29 Rivera JA, Fernandez-del Castillo C, Pins M, et al Pancreatic mucinous ductal ectasia and intraductal papillary neoplasms A single malignant clinicopathologic entity Ann Surg 1997;225: 63 7-6 44;discussion... Natl Cancer Inst 2001; 93( 8):64 0-6 44 Schutte M, Hruban RH, Geradts J, et al Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas Cancer Res 1997;57 :31 2 6 -3 130 Tersmette AC, Petersen GM, Offerhaus GJ, et al Increased risk of incident pancreatic cancer among first-degree relatives of patients with familial pancreatic cancer Clin Cancer Res 2001;7: 73 8-7 44 van der Heijden... pathologic analysis J Gastrointest Surg 1999 ;3: 23 3- 2 43 Chou FF, Sheen-Chen SM, Chen YS, Chen MC, Chen CL Postoperative morbidity and mortality of pancreaticoduodenectomy for periampullary cancer Eur J Surg 1996;162: 47 7-4 81 Clarke DL, Thomson SR, Madiba TE, Sanyika C Preoperative imaging of pancreatic cancer: a management-oriented approach J Am Coll Surg 20 03; 196:11 9-1 29 Conlon KC, Labow D, Leung D, et al... experience Gut 1999;44:72 0-7 26 Yeo CJ The Whipple procedure in the 1990s Adv Surg 1999 ;32 :27 1 -3 03 Yeo CJ, Sohn TA, Cameron JL, Hruban RH, Lillemoe KD, Pitt HA Periampullary adenocarcinoma: analysis of 5-year survivors Ann Surg 1998;227:82 1-8 31 Yeo TP, Hruban RH, Leach SD, et al Pancreatic cancer Curr Probl Cancer 2002;26:17 6-2 75 Zerbi A, Balzano G, Patuzzo R, et al Comparison between pylorus-preserving and Whipple... prospective controlled study Lancet 2000 ;35 6:19 0-1 93 Adler DG, Baron TH Endoscopic palliation of malignant gastric outlet obstruction using self-expanding metal stents: experience in 36 patients Am J Gastroenterol 2002;97:7278 Alazraki N Imaging of pancreatic cancer using fluorine-18 fluorodeoxyglucose positron emission tomography J Gastrointest Surg 2002;6: 13 6-1 38 Billingsley KG, Hur K, Henderson WG, . 2002;62( 13) :37 8 9 -3 7 93. Neglia JP, FitzSimmons SC, Maisonneuve P, et al. The risk of cancer among patients with cystic fibrosis. Cystic Fibrosis and Cancer Study Group. N Engl J Med. 1995 ;33 2:49 4-4 99 Med. 1995 ;33 3(15): 97 0-9 74. Goldstein AM, Struewing JP, Chidambaram A, Fraser MC, Tucker MA. Genotype-pheno- type relationships in U.S. melanoma-prone families with CDKN2A and CDK4 mutations 1999; 131 (4):24 7-2 55. Eberle MA, Pfutzer R, Pogue-Geile KL, et al. A new susceptibility locus for autosomal dom- inant pancreatic cancer maps to chromosome 4q3 2 -3 4. Am J Hum Genet. 2002;70(4): 104 4-1 048. Identification

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