Pancreatitis as a risk for pancreatic cancer

Pancreatitis as a risk for pancreatic cancer

Hematol Oncol Clin N Am 17 (2003) 647 – 661 Pancreatitis as a risk for pancreatic cancer David C. Whitcomb, MD, PhDa,b,c,*, Katherine Pogue-Geile, Ph...

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Hematol Oncol Clin N Am 17 (2003) 647 – 661

Pancreatitis as a risk for pancreatic cancer David C. Whitcomb, MD, PhDa,b,c,*, Katherine Pogue-Geile, PhDa a

Department of Medicine, University of Pittsburgh, UPMC Presbyterian, Mezzanine Level, C Wing, 200 Lothrop Street, Pittsburgh, PA 15213, USA b Department of Cell Biology and Physiology, and Human Genetics, University of Pittsburgh, UPMC Presbyterian, Mezzanine Level, C Wing, 200 Lothrop Street, Pittsburgh, PA 15213, USA c VA Pittsburgh Health Care System, Pittsburgh, PA 15240, USA

It is time to change the way we think about pancreatic cancer. Only a few years ago, this cancer epitomized the depths of mystery, ignorance, and hopelessness that cynics of cancer research expenditures highlighted. The past few years, however, featured the gradual unmasking of this enigmatic cancer. Now that preneoplastic lesions have been identified [1], and the progression of genetic mutations necessary for pancreatic adenocarcinoma development has been outlined, new animal models are available specifically to test the most basic of hypotheses [2]. In addition, clinicoepidemiologic studies, especially with hereditary pancreatitis (HP) families, have identified high-risk, very high-risk, and ultra high-risk groups for pancreatic cancer [3– 5]. These kindreds allow for the identification of key risk factors (eg, tobacco smoking [6]) and could provide the right population for testing screening and preventative strategies. Within this broad context, the present chapter focuses on the evidence that chronic inflammation in chronic pancreatitis increases the risk of pancreatic cancer, how this might impact the pathway to carcinogenesis, the increased risk of having germline oncogenic mutations, and the importance of environmental factors in accelerating the oncogenic process. For the clinician, reducing the risk of pancreatic cancer in these patients is essential, and cancer screening strategies must be considered.

Reprinted with permission from Gastroenterology Clinics of North America 2002;31(2):663 – 78. This work was supported by Grant DK54709 from the National Institutes of Health, and by a grant from the National Pancreas Foundation, Wexford, PA. * Corresponding author. Department of Medicine, University of Pittsburgh, UPMC Presbyterian, Mezzanine Level, C Wing, 200 Lothrop Street, Pittsburgh, PA 15213, USA. E-mail address: [email protected] (D.C. Whitcomb). 0889-8588/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved. doi:10.1016/S0889-8588(03)00017-0


D.C. Whitcomb, K. Pogue-Geile / Hematol Oncol Clin N Am 17 (2003) 647–661

Pancreatic cancer arises from all forms of chronic pancreatitis A number of epidemiologic studies conducted during the 1990s have produced convincing evidence that pancreatic cancer arises from all forms of chronic pancreatitis. Review of the evidence for this assertion is warranted. Evidence that chronic pancreatitis increases the risk of pancreatic cancer The association between chronic pancreatitis and cancer has been confirmed in a number of epidemiological studies. During the 1980s, two small casecontrol studies noted an increased yet insignificant number of pancreatic cancers among patients with chronic pancreatitis [7,8]. Between 1990 and 1993, three studies noted a small but significant increased risk of pancreatic cancer in patients with chronic pancreatitis [9 – 11]. In 1993, Lowenfels et al [12] published the results of the International Pancreatitis Study Group’s multicenter historical cohort study of 2015 subjects with chronic pancreatitis. These subjects were recruited from clinical centers in six countries. A total of 56 cancers were identified among these patients during a mean follow-up of 7.4 ± 6.2 years. The expected number of cases of cancer calculated from country specific incidence data and adjusted for age and sex was 0.150. For subjects with a minimum of 5 years of follow-up, the standardized incidence ratio was 14.4. The cumulative risk of pancreatic cancer in subjects with chronic pancreatitis for 10 and 20 years was 1.8% and 4.0%, respectively. Furthermore, the risk of pancreatic cancer was independent of the underlying cause of chronic pancreatitis. Thus, the risk of pancreatic cancer in patients with chronic pancreatitis appeared to far exceed any other known risk factor, including cigarette smoking (relative risk from 8 studies varied from 1.2 to 3.1 [13]. Subsequently, five additional studies demonstrated a significant risk of pancreatic cancer in patients with chronic pancreatitis [14 – 18]. In each of the major epidemiologic studies cited above, pancreatic cancer seemed to arise from the chronic pancreatitis of several etiologies beside alcoholic chronic pancreatitis. This led to focused studies to determine if the incidence of pancreatic cancer was elevated in cystic fibrosis (CF), tropical pancreatitis, or HP. Evidence that CF increases the risk of pancreatic cancer If chronic pancreatitis increases the risk of pancreatic cancer, then pancreatic cancer should be clearly evident among the many patients with CF. Because the pathology of CF encompasses numerous organ systems, and most patients died well before the age of 20 years, pancreatic cancer was, however, seldom witnessed. By the 1990s, the vigilance of physicians dedicated to improving the pulmonary and nutritional challenges of CF patients began paying off with many patients reaching adulthood. But with increasing age, pancreatic cancer, digestive tract cancers, and other tumors were increasingly noted and concern emerged that CF might increase the risk and incidence of these neoplasms. The

D.C. Whitcomb, K. Pogue-Geile / Hematol Oncol Clin N Am 17 (2003) 647–661


concern of increased risk was addressed in 1991 by Neglia et al [19] who initially reported that no increased risk of cancer could be demonstrated among 712 patients with CF. In 1993, however, Sheldon et al [20] reported two cases of pancreatic cancer (0.008 expected) and one case of adenocarcinoma of the terminal ileum ( < 0.001 expected) among 412 subjects with CF. The increased incidence of digestive tract cancers, but not cancer in general, was then confirmed by Neglia among 28,511 CF patients in the United States and Canada (risk ratio 6.5) and Europe (risk ratio 6.4) [21]. These digestive tract cancers were observed predominately in the third decade of life (ie, in the oldest CF patients) and involved the esophagus, small and large intestines, stomach, liver, biliary tract, pancreas, and rectum. Again, only two pancreatic cancers were identified, but pancreatic cancers at this age are exceedingly rare, resulting in an odds ratio of 31.5 compared with controls [21]. Among the other cancers, only esophageal cancer and melanoma had odds ratios of greater than 10 with cystic fibrosis. The small but statistically increased number of pancreatic cancers reported in patients with CF should be viewed with great concern in light of the pattern of cancer development in patients with HP [3,4,22]. Indeed, the incidence of pancreatic cancer in HP rises sharply, almost exponentially, after age 50 [3,4,6]. Thus, as a cohort of CF patients begins to reach this milestone, we must pay close attention to this potential problem. Fortunately, patients with CF rarely smoke cigarettes, which is the only known risk factor in those with HP that can currently be modified. Evidence that tropical pancreatitis increases the risk of pancreatic cancer Tropical pancreatitis (TP) is a form of idiopathic chronic pancreatitis seen in tropical Asia and Africa characterized by abdominal pain, intraductal pancreatic calculi, and diabetes mellitus in young nonalcoholic individuals. Recently, we identified pancreatitis-causing mutations [23,24] in the serine protease inhibitor, Kazal type 1 (SPINK1) gene (also known as pancreatic secretory trypsin inhibitor; PSTI), in a significant subset of patients with tropical pancreatitis in Bangladesh [25], suggesting that a major underlying predisposing factor is genetic. More information on the etiology of TP is likely in the near future. The link between TP and pancreatic cancer is strong. The incidence of pancreatic cancer in India is about 10% of the incidence in the United States [26]. For example, the pancreatic cancer burden in India for 2001 was estimated at 14,230 cases [26], whereas in the United States the burden is closer to 29,000 cases. The incidence of pancreatic cancer among adult patients with TP is striking, however. For example, in 1992 Augustine and Ramesh [27] reported 22 pancreatic cancers among 266 patients with TP over an 8-year period (8.3%). In this cohort, the risk was highest after age 40, and patients with TP often had features of dysplasia as well as cancer in resected pancreatic specimens. In 1994 Chari et al [14] reported that over a 4.5-year period 24 of 185 patients with TP died, and that 6 (25%) died of pancreatic cancer. The average age of onset was 45 ± 7 years, and the relative risk compared with those without TP was 100. Other


D.C. Whitcomb, K. Pogue-Geile / Hematol Oncol Clin N Am 17 (2003) 647–661

reports confirm these observations [28]. Thus, current evidence suggests that the risk of pancreatic cancer is very high in patients with long-standing TP. Evidence that HP increases the risk of pancreatic cancer HP represents a condition with an inherited predisposition to recurrent attacks of typical acute pancreatitis, frequent progression to typical chronic pancreatitis, 80% phenotypic penetrance, and trait transmission in an autosomal dominant pattern [29 – 32]. The disease is caused by gain-of-function mutations in the cationic trypsinogen gene (UniGene symbol; PRSS1) in about 60% of cases [29,33 – 35]. One of the most striking features of HP is the very high incidence of pancreatic cancer beginning 30 –40 years after the onset of pancreatitis [4,6,22]. A link between HP and pancreatic cancer was suspected for some time. For example, Miller et al [36] noted that 2 of the 22 patients followed with HP died of pancreatic cancer, and Leger et al [37] reported that 6 of 24 patients with HP developed adenocarcinoma of the pancreas. In addition, Malik et al [38] reported 1 out of 9 patients with HP developed pancreatic cancer, and Kattwinkel et al [31] reported 8 of 54 family members in 3 large kindreds with HP died of pancreatic cancer. Similar high incidences of pancreatic cancer in HP families have been reported by others [39 –43]. In 1997 Lowenfels et al [4] reported the results of an international study designed to formally address this issue. During 8,550 person years of HP patient observation, 8 cases of pancreatic cancer were observed against a background expected number of 0.15 (relative risk 53). The estimated accumulated risk of pancreatic cancer to age 70 in these families is about 40% [4]. These studies have been confirmed and extended [3,22,44]. A striking gene-environment interaction was noted related to tobacco smoking (see also below). The age- and sex-adjusted odds ration was doubled by tobacco smoking (OR 2.1; 95% CI, 0.7– 6.1), and the median age of diagnosis of pancreatic cancer was 20 years earlier in the smokers [6]. Taken together, the evidence is very strong for a connection between HP and pancreatic cancer.

Pathways to carcinogenesis Development of pancreatic cancer in any individual requires a progressive series of genetic events typically occurring within pancreatic duct cells [45,46]. The genetic events must alter a critical group of genes that have been broadly categorized as oncogenes, those that promote cell growth, and tumor suppressor genes that normally suppress cell growth and division. Mutations in the oncogene K-ras and in the tumor suppressor genes p53, p16, DPC4 have been detected in a majority of pancreatic tumors [45]. As the number of mutations accumulates in the cells progressing toward adenocarcinoma, the morphology acquires the characteristics of more aggressive tumors. However the exact sequence of

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mutation development, if necessary, and the complete repertoire of critical mutations have yet to be discovered [45 – 50]). Specific genes that are known to be mutated in ductal pancreatic adenocarcinoma can be divided into four groups based on the frequency with which they can be detected. The k-ras codon 12 and the p16 gene alterations are found in more than 90% of pancreatic cancers [51 – 54]. These mutations appear to occur early as they are often detected in preneoplastic lesions and may be found in patients with chronic pancreatitis [55 –58]. The frequency of k-ras mutation is approximately 90% in all ductal pancreatic adenocarcinomas, and nearly 100% in typical ductal adenocarcinoma cancer [52,53,59]. The p16 gene product is also frequently altered or lost through nucleotide deletions, mutations, and epigenetic alterations including methylation that alters gene expression [60]. The fact that the p16 and k-ras mutations occur early, and that they are in the overwhelming majority of tumors, suggests that these mutations are necessary but not sufficient for pancreatic cancer development. A second group of genes in which mutations that occur in approximately 50% of those tumors examined include the p53 (50 – 75%) and DPC4 (55%) [61,62]. The third group includes germline mutations, including those in the BRCA2 gene. Mutations in the BRCA2 gene occur in 7 –10% of pancreatic cancer tumors [63]. A fourth group that includes a group of genes mutated in 5% or less of pancreatic tumors include the LKB1/STK11 and MKK4, the transforming growth factor-beta receptors I or II, and the retinoblastoma (RB1) genes [62,64 – 67]. Evidence that other genes playing a role in pancreatic cancer emerge from examination of nonrandom changes in chromosomal material. Karyotype analysis of pancreatic cancers has revealed nonrandom chromosomal rearrangements of chromosomes 7 and 20, trisomy and monosomy of 18 and, and chromosomal gains of 1q, 3q, 8q, 11q, and 19q [68 – 70]. Other genomic regions that become repeatedly duplicated include 6q, 19q, and 20q [63,71 – 73]. Nonrandom chromosomal rearrangements of chromosomes may indicate that the regulation or the sequence of a particular gene or sets of genes has been disrupted in a manner that contributes to oncogenesis. Amplification of a specific chromosomal region may indicate the presence of an oncogene(s). Other regions of the genome that require additional analysis are regions of the genome that are frequently lost during tumor development. Some of these regions have been shown to contain tumor suppressor genes in a variety of different cancers. In pancreatic cancer, genomic regions that have been shown to be deleted frequently in pancreatic tumors include 1p, 3p, 6p, 6q, 8p, 9p, 10q, 12q 13q, 17p, 18p, 18q, 21q, and 22q [69]. Four of these 14 loci contain one of the known pancreatic cancer tumor suppressor genes described above. They include CDKN2A (p16) at 9p21, Tumor protein p53 (TP53) at 17p13, BRCA2 at 13q12-13, and DPC4 at 18q21 [63,74,75]. Evidence suggests, however, that there are at least two tumor suppressor genes at the DPC4 locus [74]. Based on this evidence, there may be 11 or more undiscovered tumor suppressor genes yet to be identified. This assumption, and the fact that there are at least three other nonrandom chromosomal rearrangements that occur in pancreatic cancer, suggests that numerous genes play a role in pancreatic cancer.


D.C. Whitcomb, K. Pogue-Geile / Hematol Oncol Clin N Am 17 (2003) 647–661

Carcinogenesis in chronic pancreatitis As the pathway from normal ductal epithelium to pancreatic cancer becomes clear, we can begin to investigate the accelerated pathway from chronic pancreatitis to pancreatic cancer. The first question is whether cationic trypsinogen mutations or Cystic fibrosis transmembrane conductance regulator (CFTR) mutations represent key steps in the carcinogenesis pathway. The second question is whether chronic pancreatic inflammation per se promotes mutations and chromosomal deletions in known oncogenes. At least two studies investigated common pancreatitis-associated mutations in the trypsinogen gene or CFTR gene in patients with apparently sporadic pancreatic cancer. Hengsler et al [76] analyzed genomic DNA for R122H mutations in the trypsinogen gene in pancreatic cancer samples from 34 patients and corresponding normal tissue from 28 of these individuals. No mutations were found. These data suggest that underlying trypsinogen gene mutations are uncommon in sporadic pancreatic cancers, and that trypsinogen R122H mutations are unlikely to be an important step in carcinogenesis. Malats et al [77] investigated the possibility that common CFTR mutations were a risk factor for sporadic pancreatic cancers. The incidence of deltaF508 mutation and the 5T allele variant was similar to controls, however. Again, the presence of these pancreatic disease-associated mutations is unlikely to be an important step in pancreatic cancer development. Although these two studies have limitations in size and scope, they suggest that pancreatitis-associated genes are in themselves not important in sporadic carcinogenesis. The increased risk of pancreatic cancer is likely through a different mechanism. Does chronic pancreatic inflammation per se facilitate development of key mutations or loss of chromosomal material? Substantial experimental data is becoming available, especially with respect to K-ras mutations. These mutations are generally not seen in normal pancreatic tissue and were thought to be specific for pancreatic cancer [52,53,59]. Numerous reports suggest, however, that K-ras mutations are also common in chronic pancreatitis [56 –58,78,79]. Indeed, the K-ras in patients with chronic pancreatitis may be localized to areas of the duct with hyperplasia [80], suggesting focal progression toward carcinogenesis. Ductal dysplasia also appears to be increased in TP. Augustine and Ramesh [27] observed dysplasia in two of five resected specimens in patients with TP and cancer, whereas no dysplasia was seen in sporadic pancreatic cancers. Thus, focal areas of dysplasia, possibly harboring K-ras mutations, frequently arise within the context of chronic pancreatitis. The mechanism remains to be determined, however.

Gene – gene interactions Epidemiology studies and studies in families with HP and pancreatic cancer syndromes may provide some additional clues to possible mechanism for the

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increased risk of carcinogenesis seen in all forms of long-standing chronic pancreatitis. Although it is reasonable to assume that the inflammatory condition of the pancreas contributes to an environmental milieu that increases the risk of developing cancer, these data suggests that other germline genetic factors may also play a role in the increased risk of pancreatic cancer among patients with pancreatitis. There is growing evidence from familial and epidemiologic studies that a variety of nonspecific oncogenes, tumor suppressor genes, or pancreatic cancer genes may predispose individuals to pancreatic cancer [81 –84]. For example, Silverman et al [85] recently reported the remarkable findings of a populationbased case-control study of pancreatic cancer. In this study of 484 cases and 2099 controls, 21% of cases compared with 13% of controls reported a first-degree relative with at least one type of cancer. The risk was associated with cancers of the pancreas (OR = 3.2), colon (OR = 1.7), and ovary (OR = 5.3), but not endometrium (OR = 1.5) or breast (OR = 1.3). These cancers are also common in the hereditary nonpolyposis colon cancer (HNPCC) syndrome. The risk and incidence of pancreatic cancer is exceptionally high, 18 –57 fold, among at-risk first-degree relatives in familial PC kindreds [81] and may be even higher in other families [86]. These observations suggest that some pancreatic cancer predisposing gene mutations are common within the United States, and that some result in very high risk of pancreatic cancer. Several observations from the Pittsburgh-Midwest Multicenter Pancreatic Study Group Hereditary Pancreatitis Study [29] suggest that other germline mutations may also play a role in the etiology of pancreatic cancer in patients with HP. The first observation is that many of the subjects with HP, and pancreatic cancers appear to be clustered within a subset of families, and several cases suggested vertical transmission of the pancreatic cancer trait [44]. If the high pancreatic cancer risk in HP were caused by inflammation alone, we would anticipate widespread and randomly distributed pancreatic cancer throughout the HP families. Although the number of HP-associated pancreatic cancers is relatively small, the number of pancreatic cancers in family members without hereditary pancreatitis appears to be high. In our families the incidence of a positive family history among all the HP-pancreatic cancers was nearly 50% (10 out of 21). These observations suggests that an inherited mutation that causes pancreatitis (eg, PRSS1 R122H) results in a chronically inflamed pancreatic environment that increases the penetrance of other germline mutation and promotes oncogenesis of the pancreas. A large number of well-defined syndromes have pancreatic cancer as a major feature [82,87]. HNPCC is an autosomal dominant disorder caused by mutations in the mismatch repair genes, in particular MLH1, MSH2, and MSH6. Park et al [88] found that cancer at an early age and pancreatic cancer were independent predictive factors of germline mutations in MLH1, MSH2, and MSH6 in the Korean subset of families, but not in Dutch families. Germline mutations in BRCA2 have been shown in 5% – 10% of sporadic pancreatic cancer cases [63] and ares associated with a relative risk of 3.51 [89]. Germline mutations in p16


D.C. Whitcomb, K. Pogue-Geile / Hematol Oncol Clin N Am 17 (2003) 647–661

predispose to melanoma and pancreatic cancer (the FAMMM syndrome) [90], and genetic mutations in STK11/LKB1 to pancreatic cancer in patients with the Peutz-Jeghers Syndrome (PJS) [64]. These examples demonstrate that multiple germline mutations predispose to pancreatic cancer. The hypothesis that any of these mutations are responsible for accelerating carcinogenesis in chronic pancreatitis remains to be proven, however.

Gene-environment interactions The high risk of pancreatic cancer in patients with chronic pancreatitis implies an accelerated accumulation of cancer-causing mutations. Although inheritance of oncogenic germline mutations likely plays some role in the process (ie, the person is born with the first ‘‘hit’’), environmental factors must be carefully considered, especially because they represent risk-reducing preventative targets. Most of the work in this area focused on sporadic pancreatic cancers. In these studies, the probability that common occupational exposures significantly increase the risk of pancreatic cancer appears minimal. For example, a recent population-based case-control study based on death certificates from 63,097 persons dying from pancreatic cancer and 252,386 controls from 24 US states failed to identify industrial or occupational exposure as a major contributor to the etiology of pancreatic cancer [91]. Likewise, a population-based casecontrol study of pancreatic cancer diagnosed in Atlanta (GA), Detroit (MI), and 10 New Jersey counties identified only mild risk or protection from dietary factors [92]. A number of studies have shown, however, that smoking increases the risk of pancreatic cancer about twofold [3,13]. Thus, common environmental factors appear to play a minor role in the development of pancreatic cancer. But these factors may be amplified in the context of chronic pancreatic inflammation. Cigarette smoking is the most significant environmental risk factor in pancreatic cancer. Recent evidence suggests that cigarette smoking and a positive family history of pancreatic cancer are synergistic. Schenk et al [93] examined the relative risk in smokers and in families with a positive family history of pancreatic cancer and found that each of these factors approximately doubled the risk of pancreatic cancer. The increased relative risk (RR) was 2.49 (95% confidence intervals, CI, 1.32– 4.49) for a positive family history, and 2.04 (95% CI, 2.18 –31.07) for individuals who had ever smoked. The RR of pancreatic cancer from smoking was dramatically increased to 8.23 among relatives of proband diagnosed with pancreatic cancer before age 60. This synergism between a HP, pancreatic cancer, and smoking has also been reported [3,4,6]. Smoking doubles the risk of cancer among these very high-risk patients and reduces the age of onset by about 20 years. Alcohol consumption is another environmental factor that impacts the pancreas and potentially increases risk of pancreatic cancer because alcohol is clearly associated with neoplasms of the digestive tract [94]. Studies investigating the

D.C. Whitcomb, K. Pogue-Geile / Hematol Oncol Clin N Am 17 (2003) 647–661


risk of pancreatic cancer with alcohol consumption have reported conflicting results, however. In the Iowa Women’s Health Study, a prospective cohort study of 33,976 postmenopausal Iowa women, the relative risks of pancreatic cancer increased with the amount of alcohol consumed (Ptrend = 0.11) after adjustment for age, smoking status, and pack-years of smoking [95]. Recently, Talamini et al [96] reported a cohort study of Italian men to determine the relationship between alcohol consumption, cigarette smoking, chronic pancreatitis, and pancreatic cancer. Six hundred thirty patients with chronic pancreatitis developed 12 pancreatic cancers. This group was compared with 69 patients with pancreatic cancer in the absence of chronic pancreatitis and 700 random controls. Patients with chronic pancreatitis drank significantly more alcohol than patients with pancreatic cancer or control patients. Smoking was an independent risk factor for chronic pancreatitis (odds ratio 17; 95% CI 13– 24) and pancreatic cancer (OR 5; 95% CI 3– 9), but the risk of cancer was not associated with alcohol consumption. Thus, alcohol may play a small role in accelerating the carcinogenesis process in the pancreas, but the independent effect appears to be small. The combined effect of tobacco smoking and alcohol consumption increases the risk of pancreatitis synergistically and thereby increases the risk of pancreatic cancer. Taken together, general environmental factors do not appear to play a major role in the progression of chronic pancreatitis to pancreatic cancer, with the exception of cigarette smoking. Other more specific and important environmental factors will likely be identified in the future.

Risk reduction strategies Risk factor determination for pancreatic cancer provides opportunities for preventing, delaying, or early identification of pancreatic cancer in patients. Inherited genetic factors cannot be altered, but identification of patients at high risk of pancreatic cancer affords the opportunity to eliminate or reduce other risks. For example, patients in families with a history of HP, pancreatic cancer, HNPCC, BRACA II mutations, and other syndromes associated with pancreatic cancer should neither smoke cigarettes nor drink alcohol. Dietary factors play a small but perhaps significant role in altering risk for pancreatic cancer. Attention to these factors, however, may reduce the overall risk of pancreatic cancer in individual patients. Although the results of epidemiological studies investigating different populations often conflict, obesity and excessive caloric intake increase risk, whereas consumption of foods such as fruits and vegetables reduce risk [92,97,98]. Thus, additional advice for patients at high risk of pancreatic cancer could include the reduction of caloric intake and the addition of more fruits and vegetables to their diets. Future risk reduction and preventative strategies will likely include chemoprevention [99] or vaccination [100]. Researches in these areas are in their infancy, however, and no recommendations can yet be given.


D.C. Whitcomb, K. Pogue-Geile / Hematol Oncol Clin N Am 17 (2003) 647–661

Recommendations for screening Many patients with chronic pancreatitis, and especially chronic HP, are concerned about the high risk of pancreatic cancer. These concerns are shared by health care providers, and raise questions about screening and early detection of premalignant lesions or early cancers, as well as recommendations for effective therapy. The pancreas is difficult to evaluate, however, by current imaging modalities, especially in the context of chronic pancreatitis, and it is the premalignant lesion rather than established cancers that physicians prefer to identify. Furthermore, the only current therapy is pancreatectomy, which is associated with significant early and late mortality and morbidity. In an effort to provide some guidelines for physicians caring for patients with HP, a consensus conference was sponsored by the International Association of Pancreatologists during the Third International Symposium on Inherited Diseases of the Pancreas [5] held in Milan, Italy, on March 5 –7, 2001. The consensus document has been published [101] and is available free of charge at or In summary, it was the unanimous opinion of the consensus conference that screening should be offered to patients with HP  age 40. Optimally, screening should be done at medical centers expert in the care of patients with HP with state-of-the-art imaging technology [101]. In addition, screening should be considered yearly and within the context of multicenter protocols assessing the efficacy of endoscopic ultrasound (EUS) or multiphasic helical CT or MRI/MRCP in conjunction with standardized collection and storage of blood/serum and pancreatic juice for future analysis [101]. The experts recognize the limitation of EUS to identify suspicious lesions in the contest of chronic pancreatitis, and therefore no recommendation of the modality of screening was reached [101]. Several investigators also argued for the use of endoscopic retrograde cholangiopancreatography (ERCP) because it facilitates detection and sampling of ductal pancreatic dysplasia/malignancy while allowing optimal collection of pancreatic juice [101]. Other investigators feel, however, that the same objectives can be accomplished with lower morbidity and mortality through EUS with needle biopsy of suspicious lesions and aspiration of duodenal contents following secretin stimulation. Thus, the need for screening and counseling is recognized, but the mode and timing remain matters for future research.

Summary Chronic pancreatitis clearly predisposes to pancreatic cancer, with early onsetlong duration chronic pancreatitis from cystic fibrosis, TP, and HP conferring the highest risk. Chronic pancreatitis is not a critical step, however, but rather one of several conditions that accelerate the accumulation of critical genetic mutations and chromosomal losses necessary for carcinogenesis. Indeed, other germline mutations, environmental factors such as tobacco smoking and alcohol consump-

D.C. Whitcomb, K. Pogue-Geile / Hematol Oncol Clin N Am 17 (2003) 647–661


tion, or dietary factors may also accelerate the pathway to carcinogenesis, and may be synergistic with the conditions created by chronic pancreatitis. Because patients with chronic pancreatitis are at high risk of pancreatic cancer, the physician is faced with decisions on how to manage this risk. Discontinuing smoking and alcohol consumption, and perhaps dietary modification are obvious recommendations for risk reduction. If, however, the patient is older and already in a very high-risk category (eg, long-standing HP), then screening for cancers must be considered. Inclusion in multicenter trials is recommended, and information on ongoing studies can be obtained through the office of Dr. Whitcomb, or as posted on

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