The etiology of pancreatic cancer is unknown. Its origins are believed by many to be multifactorial, likely involving a complex interplay between genes and environmental factors. With various studies demonstrating the heritability of certain forms of pancreatic cancer 1, genetic factors have been suggested and are continuing to be refined 2-3. Increasingly, family history is a well-recognized risk factor, which confers a 1.5 to 13 fold higher risk of developing pancreatic cancer when compared to the general population 4. Further evidence for a genetic contribution to pancreatic cancer lies in the identification of the BRCA2 gene as a major disease susceptibility allele on chromosome 13q12.3 5. While the genetics of pancreatic cancer are not homogeneous, its subsequent development has been associated with a single base pair deletion in codon 1982 of exon 11 (6174delT) of the BRCA 2 gene 6. In addition, a germline mutation in the p16 tumor suppressor gene has been shown to confer a significant increase in risk for the development of pancreatic cancer 7-8. Other research has focused on investigating environmental risk factors that may contribute to pancreatic cancer 9-11, such as smoking, which carries an associated odds ratio ranging from 1.75 to 2.13 12. Even so, the precise influence each brings to bear and the proportionate impact of genetic and environmental risk factors remains indeterminate. Few studies have ascertained paradigms of inherited susceptibility, which may help substantiate the association between genetic and environmental origins of pancreatic cancer.
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Clinical advances have been made on many fronts. Still, the 5-year survival rate for pancreatic cancer remains approximately 5.5% 13. Estimates from the National Cancer Institute (NCI) suggest that 42, 470 were diagnosed with this neoplasm in the last calendar year (2009). Of these, 35,240 were expected to succumb to their diagnosis, making pancreatic cancer the fourth leading cause of cancer related deaths in the United States 22 , With an age-adjusted incidence rate of 11.7 per 100,000 person-years and a lifetime risk of 1 in 76, its preponderance is almost equal between the genders 13. In order to impact patient survival, two of our greatest diagnostic challenges thus remain: 1) the early recognition of patients at risk for the development of pancreatic cancer, and 2) the judicious employ of sensitive screening techniques in appropriate populations.
The identification of populations with shared disease associations is crucial in this regard. Patients with the hamartomatous polyposis Peutz-Jeghers syndrome have been classified as such due to a germline mutation in the STK11/LKB1 gene 14. Unfortunately, other, similar populations have not been convincingly demonstrated. An epiphenomen in the inflammatory bowel disease (IBD) population deserves further consideration, however. Characterized by immune dysregulation and phenotypic features reflecting the sequelae of acute and chronic intestinal inflammation, IBD and its colorectal cancer risks have been well described 15-23. Interestingly, its extra-intestinal manifestations have also been linked to cancers of hepatobiliary origin. A total of 75-90% of patients with PSC have concurrent IBD. However, only 4% of patients with IBD have or go on to develop PSC. In either situation, it is known to beget overt cholangiocarcinoma in 3.3-36.4% of cases24 Perhaps because of the common embryological origin of the pancreato-biliary system, a Swedish study recently demonstrated that individuals with PSC, already at increased risk for the evolution of a biliary neoplasm, also incur a 14-fold increased risk of developing pancreatic cancer 25. In like manner, we investigate the relationship of pancreatic cancer arising de novo in the IBD population and hypothesize a shared association between the two conditions.
A retrospective cohort study was conducted using a statewide, population-based hospital electronic medical records database in conjunction with a statewide cancer registry affiliated with the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program.
The University of Utah Health Sciences Center Electronic Data Warehouse was searched to identify patients assigned International Classification of Diseases, Ninth Revision (ICD-9) codes for Crohn's disease and ulcerative colitis (UC) from January 1996, to December 2006.
The number of clinical encounters for each identified IBD case within the cohort was also captured. This was done in an attempt to increase the accuracy of diagnosis. Clinical encounters were noted as a single occurrence, two occurrences, or three or more occurrences with the corresponding ICD-9 code for Crohn's disease or ulcerative colitis within the hospital database system. Incident pancreatic cases in the IBD cohort were identified by cross-referencing cancer incidence data collected by the Utah Cancer Registry (UCR), a National Cancer Institute SEER program registry. Identities of UUHCS patients in the cohort were linked to pancreatic cancer cases reported to the UCR through the Utah Population Database (UPDB). All identified cases of pancreatic cancer underwent thorough chart review to confirm a prior diagnosis of IBD. Specific attention to pre-existing medical conditions predisposing a patient to pancreatic cancer was also previously noted. United States Census Bureau data for total and age- and sex-specific yearly state population estimates were used for population-based analyses (US Census 2000).
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Approvals to conduct this study were obtained from the University of Utah Institutional Review Board as well as the UCR and UPDB governing boards.
Data were obtained from the University of Utah Health Sciences Center (UUHSC) Data Warehouse, a resource that has tracked all inpatient and outpatient encounters within the University of Utah health care system since 1996. It now contains more that 1.4 million patient records, while incorporating demographic variables, payer status, dates of service, admission and discharge administrative details, and diagnostic and procedural coding [REFERENCE]. Diagnostic and procedural coding is typically done by the patient provider or by a certified professional hospital coder and is consistent with the International Classification of Diseases, Ninth Revision-9 (ICD-9) system.
The Utah Cancer Registry is a population-based cancer registry that has been part of a statewide cancer registry program since 1966, but includes cancer records dating back to 1952 [REFERENCE]. In 1973, the UCR was incorporated into the SEER Program, a prerequisite of which being that all cancers except basal and squamous cell cancers of the skin be included in the Registry and includes data up until 2007. [REFERENCE]. As one of the SEER sites, the UCR must follow meticulous procedures to guarantee the fidelity of its data. The UCR is legally directed to gather and safeguard data on all patients with cancer diagnosed in the state, including primary tumor site, histology, patient age at diagnosis, tumor stage, tumor grade, duration of patient survival, and treatment and follow-up data 25-26. Every documented cancer case compels the inclusion of a pathology report with follow-up achieved through annual review of hospital records and hospital site visits [REFERENCE].
The UPDB is a computerized data repository consisting of demographic and genealogic data representing the population of Utah 27-28. The database is comprised by a majority of families living in Utah, with a distinctive accent on genealogical records of the founders of Utah and their descendents 29-30. The initial record set incorporated data for approximately 1.6 million Utah pioneers and their descendents. Currently, it is expanded to their posterity using Utah vital statistics data, and now embraces over 7.1 million individuals. Some pedigrees now extend to 11 generations, linking back to the original settlers in the State of Utah. The genealogical data in the UPDB has been record-linked to other statewide data resources, including the UCR and Utah death certificates dating back to 1904 25, 31. It currently integrates annual updates from the Utah Department of Health for births, deaths, marriages, and divorces, as well as records from the Utah Driver's License Division, in addition to information from the UCR (http://www.huntsman-cancer.org/groups/ppr/index.html). Several studies using genealogical data in the UPDB linked to the UCR have characterized familial cancer tendencies and syndromes 27, 31-33.
There are currently over 86,000 SEER registry records that have been linked to the geneology records in the UPDB22. Approximately 60% of cancer records in the UCR link to a UPDB geneology record; record linking rates are slightly lower for females due to name changes that reduce the probability of successful linkage19 Linkage of UCR information to the UPDB genealogy records occurred in August 2003, and includes cancer cases since 1966 [REFERENCE].
Patients in the IBD cohort were tracked from the date of IBD diagnosis to December 2006, or until a diagnosis of pancreatic cancer was rendered. The date of IBD diagnosis was assumed to be the date an ICD-9 code corresponding to either ulcerative colitis or Crohn's disease appeared in the UUHCS electronic medical record. Only cancer diagnoses that occurred 30 days after the diagnosis of IBD were included in incidence rate calculations. Descriptive statistics were provided for gender and age of IBD diagnosis. The standardized incidence rate (SIR) for pancreatic cancer in the IBD cohort was calculated relative to age- and gender-specific pancreatic cancer incidence rates for the population of Utah obtained from publicly available UCR / SEER data.
The expected number of pancreatic cancer cases for the IBD cohort was calculated by multiplying the person years in each gender and / or age group by the corresponding rate of the reference population of Utah pancreatic cases. The sum was then calculated over all of the strata.
The Standardized Incidence Rate was defined as the ratio of observed to expected pancreatic cancer cases and can be found by dividing the observed by expected columns from Table 2. These ratios were confirmed by Poisson regression and the Genmod procedure in the Statistical Analysis System (SAS), version 9.2 to obtain age-adjusted SIRs and 95% confidence intervals. By using the logarithm of person years as the offset variable in the Genmod procedure, the variations in the number of person years in each time period was controlled. An SIR greater than 1.0 denotes a higher incidence rate for the specific age or gender IBD subgroup when compared to the corresponding Utah incidence rate.
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During the 10-year study period, we identified a cohort of 2877 distinct adult cases of IBD within the University of Utah Health Care System. Median follow-up was ___years, representing ____person-years of follow-up. Of this group, 939 had Crohn's disease (32.6%), 1668 had ulcerative colitis (58%), and 270 had indeterminate colitis (9.4%). Ages at diagnosis ranged from 20 to 94 years with a median age of 45.4 years (Table 1). In the Crohn's disease subgroup, 42% of cases had a single encounter bearing ICD-9 codes 555.0-555.9 within our hospital database, while 43% had more than 3 such clinical encounters. In the cadre of patients with ulcerative colitis, 48% of cases had a single encounter registering ICD-9 codes 556.0-556.9 within our hospital database, while 38% of all cases had more than 3 clinical encounters bearing the requisite ICD-9 codes.
Expected frequencies of pancreatic cancer in Utah totaled 9 cases per 100,000 person- years. In the IBD cohort, 12 pancreatic adenocarcinoma cases were identified, five of which were excluded from the calculation of the standardized incidence ratio because the cancer diagnosis preceded the diagnosis of IBD. The remaining 7 pancreatic cancer cases were thoroughly reviewed and occurred during 15,784 person-years of follow-up. None of the index cases had an a priori history of chronic pancreatitis, diabetes, smoking, or familial syndromes predisposing them to the development of pancreatic cancer.
The SIR for pancreatic cancer for our IBD cohort was 3.364 (95% CI 1.60-7.05). All of the incident cases of pancreatic cancer occurred in the ulcerative colitis group; none were identified among Crohn's disease patients. For the ulcerative colitis cohort, 7 cases of pancreatic cancer occurred during 10, 046 years of follow-up. The ages of patients with IBD who later developed pancreatic cancer ranged from 49.0 to 74.6 years at the time of their IBD diagnosis with a median age of 64.9 years. Subsequent diagnosis of pancreatic cancer occurred at a median age of 66.8 years (range 50.2-80.7 years). The interval between diagnosis of IBD and pancreatic cancer for the 7 incident cases included in our analysis ranged from 435 to 2242 days (1.19-6.14 years) with a median time to pancreatic cancer diagnosis of 4.37 years.
The SIR in the ulcerative colitis cohort was 4.854 (95% CI 2.31-10.19) (Table 2). All 7 observed cases of pancreatic cancer were males and occurred in the ulcerative colitis group only. The SIR for males with ulcerative colitis and pancreatic cancer was 6.22 (95% CI 2.96-13.06).
Inflammatory bowel disease denotes a group of intestinal disorders characterized by acute and chronic intestinal inflammation and a predilection for the development of colorectal and intestinal neoplasia 15-23. Major IBD disorders include ulcerative colitis and Crohn's disease, the pathophysiology of which are not clearly understood. Studies have suggested that the clinical manifestations of the disease represent the sequelae of a dysfunctional immune system 34-35. Other factors implicated in the etiology of IBD are genetic and environmentally based 34-35. In North America, incidence rates of IBD are estimated to range from 2.2 to 14.3 cases per 100,000 person-years for ulcerative colitis and 3.1 to 14.6 cases per 100,000 person-years for Crohn's disease. Similarly, the prevalence rates range from 37 to 246 cases per 100,000 persons and 26 to 199 cases per 100,000 persons for ulcerative colitis and Crohn's disease, respectively 34. A male preponderance in patients with IBD is thought to exist (2.5:1, male to female ratio) with a median age of onset of 41 years [REFERENCE]. Evidence for its heritability is illustrated by its predilection to occur in families at a rate of 2-13 times higher than the general population [REFERENCE]
For reasons also unknown, some individuals with IBD express extra-intestinal manifestations of their disease which are unmistakably coupled with, but may appear independently of, IBD activity. One main hepatobiliary manifestation of IBD is primary sclerosing cholangitis (PSC), a chronic, stricturing disorder of the biliary tree occurring in 75-90% of IBD patients. In this setting, it is hypothesized that increases in intestinal inflammation and permeability lead to episodes of portal bacteremia and increased biliary lithocolic acid exposure [REFERENCE]. Compounded by an immune-mediated assault on the biliary epithelium, it is believed that repetitive bouts of ductal injury [REFERENCE] place patients with PSC at increased risk for developing cancers of the liver and biliary tree, most notably, cholangiocarcinoma [REFERENCE]. While it is plausible that a host of environmental phenomenon can influence the development of PSC and biliary neoplasia, both have been known to occur de novo in members of large IBD kindreds [REFERENCE]. What's more, PSC and cholangiocarcinoma have been known to appear years after colectomy in IBD patients [REFERENCE]. These facts provide justification for a complex theory of inheritance linking biliary neoplasia, PSC, and IBD.
Perhaps similarly, PSC has also been associated with the development of pancreatic cancer. For example, in a Swedish study of 604 PSC patients, the risk of pancreatic cancer was 14 times greater than that of the general population 24, an observation made more pertinent given the shared embryologic anlage of the pancreas and biliary tree. Beginning in the fourth week after conception, the epithelium of the foregut expands outward from the alimentary canal into the dorsal and ventral mesenteries, respectively. During this time, an enlargement known as the hepatic diverticulum materializes in the ventral wall of the distal foregut (duodenum). The foregut endoderm of this diverticulum evolves into the biomass of the liver and the epithelial lining of the biliary tree. The ventral pancreatic primordium emerges during the fifth week, either as an outgrowth of the hepatic diverticulum or independently from the duodenum, in due course maturing into the uncinate process and most of the head of the pancreas [REFERENCE-Don't know how to cite-Neas, John F. Digestive System Development. In Anatomy and Physiology 3rd Ed Embryology Atlas (online publication-Pearson Higher Education, editor Benjamin Cummings)-accessed February 8, 2010]. Given what is known regarding the embryological origins of the pancreato-hepatobiliary systems, a shared susceptibility for pancreatic neoplasia in those with IBD can be inferred given the relationship of PSC to both IBD and pancreatic malignancy.
For pancreatic cancer, our results indicate an age- and gender-adjusted SIR of 3.364 in patients with IBD along with an SIR of 4.854 in the UC subgroup, suggesting that individuals with IBD in the State of Utah are at a 3- to almost 5-fold increased risk of developing pancreatic cancer when compared to the general population. With the association observed almost exclusively in males, an X-linked form of inheritance cannot be excluded. Given the few early indicators of illness in pancreatic cancer, the relevance of these findings is clear. With the exception of smoking and family history, there are no attributes that accurately differentiate at risk patients for early detection efforts. By affording clinicians additional opportunities for early screening, the emergence of inflammatory bowel disease as a predictive marker for the development of pancreatic neoplasia represents a quantum advance in the early detection of the disease..
In the context of these results, it should be noted that the association between IBD and pancreatic cancer in this study was confirmed in the 12 incident pancreatic cancer cases by manual chart review. Interestingly, all cases of pancreatic cancer occurred in males within the ulcerative colitis group and none were found to have concomitant primary sclerosing cholangitis. Although the number of incident pancreatic cancer cases was small, the lower confidence interval was not near unity, indicating that chance alone is an unlikely explanation for the result. Chance is further mitigated when considering that five additional cases of concomitant pancreatic cancer and IBD were excluded from our analysis because in each case, the cancer diagnosis preceded that of the IBD diagnosis. With the most recent Utah Cancer Registry data extending only to 2007, also excluded from the analysis were ___additional cases of contemporaneous IBD / pancreatic cancer identified at UUHSC between the years 2007-2009, cases which would almost certainly strengthen these observations still further.
Detection bias is important in cohort studies and occurs when one group is followed more closely than another, leading to an outcome being diagnosed more frequently, but not because it truly occurred more often in that group. For our purposes, the increase in pancreatic cancer cases observed in the IBD population may simply be a function of the increased medical surveillance afforded to the typical IBD patient. Loss to follow-up is also important, often leading to bias as well. In this study, all cohort members were assumed to be followed to the end of 2006, when in fact, some may have died or moved away from Utah before the end of follow-up. By potentially overestimating person-time at risk while underestimating the SIR, this assumption would not undermine the link between pancreatic cancer and IBD in this particular case. Another limitation is the lack of specificity in classifying IBD patients using ICD-9 codes. While there may be some patients who were designated as having IBD when, in fact, they had evidence of colonic ischemia, motility disorders, or a self-limiting illness such as infectious colitis, these errors should be randomly distributed across the population and thus, should not affect results to a significant degree. Nevertheless, in an effort to characterize the veracity of this approach, we examined the number of clinical encounters for each case identified. In each instance, a clinical encounter corresponded to a case bearing one of the requisite ICD-9 codes associated with IBD. In the ulcerative colitis subgroup, for example, 48% of the cases had 1 documented clinical encounter, while in 38% of cases, more than 3 clinical encounters were noted. In the Crohn's disease subgroup, 42% of cases had 1 clinical encounter, while 58% had two or more clinical encounters associated with that diagnosis. By assuming that a certain percentage of patients with a single clinical encounter of IBD were ultimately misdiagnosed, the net effect of this group's inclusion into calculations of SIRs would tend to underestimate the true association between IBD and pancreatic cancer.
. Another limitation of the study was the inability to reliably quantify intensity and duration of exposure to risk factors such as smoking, ethanol use, and diet through chart review alone. Smoking, in particular, has been implicated as a risk factor for pancreatic cancer [REFERENCE] and would be a potential confounding influence if recognized in association with both IBD and pancreatic cancer. As before, a systematic chart review was conducted to demonstrate an absence of smoking in all of the incident pancreatic cancer cases, although we do acknowledge that limited documentation does not preclude previous smoking exposure. With the penchant to induce neoplasia in certain individuals [REFERENCE], the increased use of immunomodulatory drugs in recent years in the treatment of refractory IBD can obfuscate matters still further. Again, the use of these agents by incident pancreatic cancer patients was excluded by comprehensive review of the medical record. Finally, diets rich in saturated fats, red, or processed meats, and high amounts of refined carbohydrates have been associated with increases in pancreatic cancer risk [REFERENCE]. As a comprehensive dietary history is not typically available for each patient, we do not discount the possibility that dietary composition could have influenced the number of incident cases ultimately identified in this study.
Complementing earlier work reporting an increase in extra-intestinal malignancies within the UC population, these results should not be viewed in isolation 36. Adding to their relevance are recent findings identifying common variants at new loci associated with the development of IBD 37-39, areas where loss of heterozygosity and novel homozygous deletions have been linked with increases in pancreatic tumorogenesis. Noteworthy are copy number variations at 10q22 involving the membrane cytoskeletal protein vinculin 40 and that at 1p36 involving the transcription factor RUNX3 40 amongst others that may also be involved 41-43[REFERENCES: 4) Cancer Res. 2006. Jan 15; 66 (2): 898-906]. Clearly, scrutiny is needed in multi-member families with the two diseases for linkage studies in order to confirm loci promoting an amplified vulnerability to pancreatic cancer.
With extensive family histories, combined with information from UUHSC medical records and statewide vital records, the UPDB allows for the discovery of large pedigrees and the calculation of population-based risks of diseases, like in the present study [REFERENCE]. However, as a derivative of the modern population of the State of Utah, results obtained from the UPDB most likely reflect populations of white, Northern European descent, 27, 31[REFERENCE: 3) Jorde LB. same reference as above] and may be less generalizable to populations of dissimilar genetic backgrounds. Nonetheless, the study population was founded over a relatively short period of time (1847-1868) by individuals with unique genetic backgrounds and extensive ancestry with relatively little inbreeding. [1) Niazi T. et al. Utah population database: a tool to study…Neurosurg Focus 28: (1): E1, 2010., 2) Cannon-Albright LA. Utah family-based analysis: past, present and future. Hum Hered 65: 209-220, 2008., 3) Jorde LB. Inbreeding in the Utah Mormons: an evaluation…Ann Hum Genet 54: 339-355, 1989]. As members of the Church of Jesus Christ of Latter Day Saints (LDS), many of their descendents continue to abide by its proscriptions against the consumption of coffee, tea, alcohol, and tobacco, which allows for the study of the shared association between pancreatic cancer and other diseases in a population with few confounding factors.
Resultantly, the more than three- and almost-five-fold excess rate of pancreatic cancer observed among patients with inflammatory bowel disease in this study classifies IBD as a potential harbinger for the development of pancreatic cancer, an association that could certainly impact the delivery of care in terms of additional screening opportunities. Given the claim that IBD could be associated with pancreatic, as well as hepatobiliary neoplasia, the invocation of a wider field effect would imply that similar genetic and environmental factors influence the development of both of these malignancies. As well, a strong genetic contribution to this phenotype should reveal a higher rate of expression of pancreatic cancer in relatives of IBD patients than that seen in a control population. As such, future studies await the identification of high-risk pedigrees with IBD in significant excess in order to identify predisposition genes responsible for the observed phenotypes. The association between IBD and pancreatic cancer, therefore, underscores the need for continued research in both fields.
Table 1. Characteristics of Inflammatory Bowel Disease Cohort
Table 2. Age-adjusted Standardized Incidence Ratios for IBD and Pancreatic Cancer
# of PC Cases
95% Confidence Limits
Type of IBD:
PC - Pancreatic cancer; IBD - Inflammatory Bowel Disease; IC - Indeterminate colitis