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Pancreatic cancer (PC) is among the most common tumors of the gastrointestinal system in the world. In the United States and in other industrialized countries, it represents the fourth leading cause of cancer-related mortality. The incidence of PC increases with age and most patients are diagnosed after the age of 50. The overall prognosis of PC is poor. Most tumors are silent and they often present when metastatic. Only less than 15% of patients can undergo surgery, which represents the only potential cure for PC, and less than 10% of patients are alive after 5 years. In this chapter, we present the epidemiology of PC and its most common risk factors.
Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
Hao Liu
Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
Christof Kaltenmeier
Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
*Address all correspondence to: molinarim@upmc.edu
1. Introduction
Worldrwide, pancreatic cancer (PC) is the 12th most common cancer [1] and the fourth leading cause of cancer-related mortality in the United States with estimated 42,500 new cases and 35,000 deaths each year [2] (Figure 1). The age-standardized incidence of PC is 4.9 per 100,000 individuals [1] (Figure 2). There are significant variations in the incidence of PC among different geographical areas (Figure 3). In high-income countries, the incidence of PC is much higher than in low-income countries (11 vs. 3 per 100,000 individuals). PC ranks fifth after colorectal cancer, gastric cancer, hepatic cancer, and esophageal cancer among all gastrointestinal malignancies [3] (Table 1). Over time, the mortality rate for males has decreased by 0.4% while the mortality rate for females has increased by 4.4% [2]. More than 80% of PCs are diagnosed in patients older than 60 and almost 50% have distant metastases at the time of their clinical presentation [3, 4, 5]. Men are more frequently affected than women (Relative Risk (RR) = 1.3) and individuals of African American descent are at a higher risk in comparison to Caucasians (RR = 1.5) [3]. Despite some improvements in early diagnosis, surgical therapy, neoadjuvant therapy, adjuvant therapy and palliative interventions, the overall survival of patients with PC is still quite poor with only 6-9% of all patients being alive after 5 years (Figure 4) [6].
Figure 1.
Estimated age-standardized mortality rates of the most common types of malignancies in 2020 for patients older than 50 years in Canada and in the United States (data from the World Health Organization; https://gco.iarc.fr/).
Figure 2.
Age-standardized incidence of pancreatic cancer in the world (4.9 per 100,000 individuals) and in selected countries with high incidence of the tumor (data from the World Health Organization; https://gco.iarc.fr/).
Figure 3.
Estimated age-standardized incidence of pancreatic cancer in the world for individuals older than 50 years (data from the World Health Organization; https://gco.iarc.fr/).
Type of cancer
Total number
Crude rate
ASR (World)
(%)
All cancers
18,094,716
232.1
190
100
Breast
2,261,419
58.5
47.8
12.5
Lung
2,206,771
28.3
22.4
12.2
Colorectum
1,931,590
24.8
19.5
10.7
Prostate
1,414,259
36
30.7
7.8
Stomach
1,089,103
14
11.1
6
Liver
905,677
11.6
9.5
5
Cervix uteri
604,127
15.6
13.3
3.3
Esophagus
604,100
7.8
6.3
3.3
Thyroid
586,202
7.5
6.6
3.2
Bladder
573,278
7.4
5.6
3.2
Non-Hodgkin lymphoma
544,352
7
5.8
3
Pancreas
495,773
6.4
4.9
2.7
Leukemia
474,519
6.1
5.4
2.6
Kidney
431,288
5.5
4.6
2.4
Corpus uteri
417,367
10.8
8.7
2.3
Lip and oral cavity
377,713
4.8
4.1
2.1
Melanoma of skin
324,635
4.2
3.4
1.8
Ovary
313,959
8.1
6.6
1.7
Brain and central nervous system
308,102
4
3.5
1.7
Larynx
184,615
2.4
2
1
Multiple myeloma
176,404
2.3
1.8
1
Nasopharynx
133,354
1.7
1.5
0.7
Gallbladder
115,949
1.5
1.2
0.6
Oropharynx
98,412
1.3
1.1
0.5
Hypopharynx
84,254
1.1
0.91
0.5
Hodgkin lymphoma
83,087
1.1
0.98
0.5
Testis
74,458
1.9
1.8
0.4
Salivary glands
53,583
0.69
0.57
0.3
Vulva
45,240
1.2
0.85
0.3
Penis
36,068
0.92
0.8
0.2
Kaposi sarcoma
34,270
0.44
0.39
0.2
Mesothelioma
30,870
0.4
0.3
0.2
Vagina
17,908
0.46
0.36
0.1
Table 1.
Estimated number of patients diagnosed with cancer with exclusion of nonmelanoma skin cancer, worldwide in 2020.
All ages, crude, and age-standardized rates per 100,000 individuals (data from the World Health Organization; https://gco.iarc.fr/).
Figure 4.
Estimated age-standardized mortality rate of pancreatic cancer in different parts of the world for individuals older than 50 years (data from the World Health Organization; https://gco.iarc.fr/).
The strongest risk factor for PC is age. The incidence of PC increases significantly after the age of 50 and over 80% of PCs are diagnosed in patients older than 60 [7] (Figure 5).
Figure 5.
Incidence of pancreatic cancer in Canada during the period between 2011 and 2013 per 100,000 individuals stratified by age.
2.1 Smoking
The risk of PC in smokers ranks second to lung cancer [8] and it is proportionate to the frequency (≥30 cigarettes per day: Odds Ratio (OR) = 1.75), duration (≥50 years: OR = 2.13), and cumulative smoking dose (≥40 pack/years: OR = 1.78) [9]. A meta-analysis of 82 studies from 4 continents has shown that cigarette smokers were diagnosed at significantly younger ages and had a 75% increased risk of developing PC in comparison to the regular population [10], and the risk persisted for 5 to 15 years after cessation [11]. In a case–control study of 808 PC patients matched against 808 healthy controls, in comparison to male counterparts, female smokers were at increased risk of developing PC as they suffered from a synergistic interaction between cigarette smoking, diabetes mellitus (OR = 9.3), and family history of PC (OR = 12.8) [12].
2.2 Diabetes
Nearly 80% of PC patients have either frank diabetes or impaired glucose tolerance at the time of their diagnosis [13]. Diabetes is often found concomitantly or during the two years preceding the diagnosis of PC [14]. Several studies have assessed the link between diabetes and PC with conflicting results. A meta-analysis of 11 cohort studies found that the relative risk for diabetic patients was 2.1 (95% CI 1.6–2.8) in comparison to nondiabetic individuals [15]. These findings were supported by another cohort study of 100,000 Danish diabetic patients that found a standardized incidence ratio of 2.1 (95% CI 1.9–2.4) [16]. A large prospective cohort study of 20,475 men and 15,183 women in the United States, has shown that the relative risk of dying from PC adjusted for age, race, history of cigarette smoking, and body mass index (BMI) was proportionate to the severity of diabetes. The RR was 1.65 for post-load plasma glucose levels between 6.7 and 8.8 mmol/L, 1.60 for levels between 8.9 and 11.0 mmol/L, and 2.15 for levels equal or more than 11.1 mmol/L [17]. Diabetes can present as an early manifestation of PC. Approximately 1% of new onset of diabetes in patients older than 50 is linked to PC [18]. Despite these findings, there is no evidence that screening patients for PC when newly diagnosed with diabetes [19] could reduce their mortality risk [5].
It is important to highlight that the link between abnormal glycemia and PC exists only for type II diabetes. A meta-analysis of 36 studies indicated that the OR of PC for patients with type II diabetes was 2.1 [20] while there are no reports showing an association between PC and type I diabetes [21].
Family history of diabetes does not appear to be a risk factor for PC [22]. On the other hand, a recent prospective study found that women with gestational diabetes are at a higher risk of developing PC with an estimated relative risk of 7.1 (95% CI = 2.8–18.0) [23]. Gapstur and colleagues [17] have proposed that high levels of insulin can cause abnormalities in the regulation of the insulin-like growth factor I (IGF1) receptor [19] that down-regulates the IGF binding protein 1, (IGFBP1) [20] causing an increase cell growth in PC cell lines [24, 25].
2.3 Alcohol
The role of alcohol in the predisposition of PC is controversial. Several studies have shown inconsistent findings due to multiple associations between alcohol consumption and other confounders such as cigarette smoking, lower socioeconomic status [26], and history of pancreatitis and diabetes [25]. A recent pooled analysis of 14 cohort studies with a sample of 862,664 individuals has shown a slight positive association between PC and alcohol consumption when larger than 30 gm/day (RR 1.22; 95% CI 1.03–1.45) [27]. On the other hand, a smaller epidemiological European study of 555 patients did not show any association between PC and alcohol consumption [28]. Yet, there is some evidence that compared with light drinkers, men consuming a large amount of hard liquor suffered from 62% increased risk of PC (95% CI 1.24–2.10) [11, 29] but this did not pan out for women and for beer and wine drinkers [29].
Although moderate alcohol consumption is not a risk factor, African Americans seem to be at a significantly higher risk of developing PC after adjusting for their drinking habits suggesting that racial differences play a role [30].
2.4 Pancreatitis
Several studies have shown a positive association between PC and history of pancreatitis. However, the magnitude of this phenomenon remains poorly understood [31, 32]. An international epidemiological study reported that both genders with chronic pancreatitis had an increased risk of developing PC independently from the cause of the disease [32]. A large case–control study indicated that chronic pancreatitis lasting more than 7 years was associated with a higher risk of PC (RR = 2.04; 95% CI 1.53–2.72) [33]. A large Italian study from 1983 to 1992 found similar results reporting that the risk increased after 5 or more years of chronic pancreatitis (RR in the first 4 years = 2.1, RR after 5 years = 6.9) [29]. These findings have been challenged by a more recent international study that showed that the risk was significantly increased only in the early years after the onset of pancreatitis. This observation suggested that pancreatitis might represent a manifestation of PC that becomes apparent only several years later rather than an independent risk factor for PC.
2.5 Hereditary pancreatitis
Hereditary pancreatitis affects 0.3 per 100,000 [34]. In 1996, it was found that hereditary pancreatitis was due to an autosomal dominant defect of the cationic trypsinogen gene (PRSS1) in 7q35 chromosome region [35]. Since then, more than 30 different PRSS1 mutations have been identified and reported in a few families. The risk of developing PC is particularly high for patients affected by hereditary pancreatitis who are at 53 times higher risk of developing the tumor in comparison to individuals without history of hereditary pancreatitis [36]. This observation was confirmed by another study that estimated a 40% cumulative risk of PC in patients with hereditary pancreatitis by the age of 70 [37]. For patients with paternal inheritance of hereditary pancreatitis, the cumulative risk of PC was even higher with a risk of up to 75% [37]. Patients with hereditary pancreatitis have high concentrations of cytokines, reactive oxygen molecules, and pro-inflammatory compounds that can lead to DNA damage, and despite DNA repair systems, these mechanisms seem responsible for the higher risk of genetic mutations leading to PC [33, 38].
2.6 Intraductal papillary mucinous neoplasms
The definition of intraductal papillary mucinous neoplasm (IPMN) is applied to a family of benign pancreatic cysts that can transform into PC [39]. The risk factors and the true incidence of IPMN are still unclear. These cysts produce mucin and are divided into two groups: IPMNs that affect the side branches of the pancreatic ducts and IPMN that affect the main pancreatic duct. Some patients have mixed IPMNs as they have cystic lesions in both the side branch and main pancreatic duct. IPMNs are responsible for 20–30% of PC cases. Current evidence suggests that only IPMNs affecting the main pancreatic duct are at high risk for malignant transformation. A recent meta-analysis [39] of 2411 patients with low-risk IPMNs and 825 patients with high-risk IPMNs has shown that the cumulative incidence of PC was significantly different between the two groups. For low-risk IPMNs, the cumulative incidence of PC was 0.02% at 1 year, 1.4% at 3 years, 3.1% at 5 years, and 7.7% at 10 years. On the other hand, for high-risk IPMNs, the cumulative incidence of PC was 1.9% at 1 year, 5.7% at 3 years, 9.7% at 5 years, and 24.6% at 10 years.
2.7 Genetic predisposition for pancreatic cancer
The presence of genetic predisposing factors for the development of PC has been an area of intense research during the last few decades. Case reports of families with multiple members diagnosed with PC suggest that for some patients, PC might be hereditary [40]. A large population study on twins identified hereditary factors for prostatic, breast, and colorectal cancers, however, this was not detected for PC [41]. A Canadian study on patients with suspected hereditary cancer syndromes found that the standardized incidence of PC was 4.5 (CI 0.54–16.) when cancer affected one 1st degree relative; the standardized incidence increased to 6.4 (CI 1.8–16.4) and 32 (CI 10.4–74.7) when two and three 1st degree relatives were affected, respectively [42]. This translates to an estimated incidence of PC of 41, 58, and 288 per 100,000 individuals, respectively, compared to 9 per 100,000 for the general population [43].
Brentnall et al. [44] and Meckler and colleagues [45] described examples of autosomal dominant PC in individuals presenting at early age (median age 43 years) and with high genetic penetrance (more than 80%). A mutation causing a proline (hydrophobic) to serine (hydrophilic) amino acid change (P239S) within a highly conserved region of the gene encoding paladin (PALLD) was found in all affected family members (family X). Another study has shown that the P239S mutation was only specific for the family X while it was not a common finding in other individuals with suspected familial PC [46]. Currently, genetic predisposition is thought to be responsible for 7–10% of all PC [47]. Genetic factors including germline mutations in p16/CDKN2A [48], BRCA2 [49, 50, 51], and STK 11 [52] genes are thought to increase the risk of PC. The combination of all these known genetic factors accounts for less than 20% of the familial aggregation of PC, suggesting that other genes play a role in the development of familial PC.
A systematic review and meta-analysis of studies on familial PC has shown that individuals with positive family history have nearly two-fold increased risk of developing PC (RR = 1.80, CI 1.48–2.12) [53]. Therefore, families with two or more cases may benefit from a comprehensive risk assessment involving collection of detailed family history information and data regarding other risk factors for PC [54]. A case–control study of PC in two Canadian provinces (Ontario and Quebec) assessed a total of 174 PC cases and 136 healthy controls. Information regarding the ages and sites of cancer was taken in 966 first-degree relatives of PC patients and for 903 first-degree relatives of the control group. PC was the only malignancy in excess in relatives of patients with PC, compared to the control group (RR = 5, p = 0.01). The lifetime risk of PC was 4.7% for the first-degree relatives and the risk was 7.2% for relatives of patients diagnosed before the age of 60 [55].
Besides the isolated aggregation of PC in some families, several other hereditary disorders predispose the development of PC in known familial cancer conditions [56]. These include hereditary pancreatitis, Peutz-Jeghers syndrome (STK11 mutation), familial atypical multiple mole melanoma (FAMMM mutation), familial breast cancer (BRCA1, BRCA2, PALB2, CDKN2A, ATM mutations) and ovarian cancer, Li-Fraumeni syndrome (TP53 mutation), Fanconi anemia, ataxia-telangiectasia, familial adenomatous polyposis, cystic fibrosis, and possible hereditary nonpolyposis colon cancer (HNPCC) or Lynch syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM mutations) [4, 54, 57, 58, 59].
2.8 Familial pancreatic cancer registries
As the prognosis of PC is generally poor, there has been a strong interest to detect genes or other markers that could help identify high-risk patients in early stage. Although a precise genetic marker for this scope is not currently available, geneticists and epidemiologists have been profiling traits of high-risk families enrolled in registries established in North America and Europe [60]. Even if there is no standardized definition for familial PC, most authors apply the term to families with at least two first-degree relatives affected by PC in the absence of other predisposing familial conditions [60]. The creation of familial PC registries has been used not only for identification of genetic mutations but also for the screening of high-risk individuals. In selected centers in North America and Europe, screening programs for high-risk individuals have been implemented with the use of endoscopic ultrasound and computed tomography (CT) scan or magnetic resonance imaging (MRI). Such early diagnosis of PC within a comprehensive screening program is hoped to ultimately result in improved survival [61]. The discovery of the genetic bases of inherited PC continues to be an active area of research and in 2001 a multi-center linkage was formed to conduct studies aimed at the localization and identification of PC susceptibility genes (PACGENE) [62]. The complex nature of pedigree data makes it difficult to accurately assess risk based upon the simple counting of the number of affected family members, as it does not adjust for family size, age of onset of PC, and exact relationship between affected family members. Therefore, computer programs have been developed to integrate these complex risk factors and pedigree data. In April 2007 the 1st risk prediction tool for PC, PancPro (https://projects.iq.harvard.edu/bayesmendel/pancpro) was released [63]. This model provides accurate risk assessment for kindreds with familial PC as the receiver operating characteristic (ROC) curve was 0.75, which is considered good for predictive models.
Several studies have explored the relationship between body mass index (BMI) lifestyle, diet, and the risk of PC, but uncertainty regarding the strength of this relationship still exists. A recent case–control study of 841 patients and 754 healthy controls showed that individuals with BMI of 25–29.9 had an OR of 1.67 (95% CI = 1.20–2.34) in comparison to obese patients (BMI of ≥30) who had an OR of 2.58 (95% CI = 1.70–3.90) independently of their diabetes status [64]. The duration of being overweight was significantly longer among patients with PC than among controls. Being obese or overweight, particularly in early adulthood, resulted in earlier onset of PC (age at presentation of PC was 61 years for overweight patients and 59 years for obese) when compared to the median age of diagnosis being 64 in the general population [65]. A few studies reported that central weight gain measured by waist circumference and/or waist-to-hip ratio had a statistically significant increased risk compared to those with peripheral weight gain (RR = 1.45, 95% CI 1.02–2.07) [66, 67]. All the known risk factors for PC are summarized in Table 2.
The role of screening for PC is not recommended for asymptomatic average-risk individuals [68, 69] as it is estimated that it would generate more harm than good. With an incidence of only 1.6% of individuals developing PC during their lifetime, Lucas et al. [68] estimated that even with an ideal screening tool with 99% sensitivity and 99% specificity, 1000 false positive results would be generated when the test is applied to 100,000 individuals. Current guidelines recommend that only healthy individuals with at least a 5% or higher risk of developing PC should be considered for screening programs [70] at age 50, or 10 years younger than the earliest diagnosis of PC in the family. These individuals must have two or more blood relatives diagnosed with PC with at least one affected first-degree relative [70, 71].
Guidelines also recommend that individuals with germline mutations in the genes listed above should consider screening beginning at age 50, or 10 years younger than the earliest pancreatic cancer diagnosis in the family, if they have a family history of PC. Some experts have recommended that all individuals with germline mutations in STK11 (which causes Peutz-Jeghers syndrome) or CDKN2A (which causes familial atypical multiple mole melanoma [FAMMM] syndrome), ATM, BRCA1, BRCA2, CDKN2A, PALB2, PRSS1, STK11, TP53, and the Lynch syndrome mismatch repair genes undergo screening for PC regardless of their family history. Peutz-Jeghers syndrome patients are recommended to begin screening at ages 30 to 35. FAMMM syndrome patients are recommended to begin screening for PC at age 40. Magnetic resonance imaging (MRI) or endoscopic ultrasound (EUS) is the two radiological modalities recommended for the screening of patients considered at increased risk of developing PC.
PC is among the most common malignancies of the gastrointestinal system. Its incidence increases after the age of 50. Most patients diagnosed with PC have advanced disease at the time of their presentation. Age, cigarette smoking, alcohol abuse, chronic pancreatitis, and genetic factors are well-known predisposing factors for PC. Screening protocols for PC in the general population are not recommended as the incidence of PC is relatively low. The use of screening programs for high-risk patients is still under investigation.
References
1.International WCRF. Pancreatic Cancer Statistics. 2022. Available from: https://www.wcrf.org/cancer-trends/pancreatic-cancer-statistics/#:~:text=pancreatic%20cancer%20data-,Pancreatic%20cancer%20is%20the%2012th%20most%20common%20cancer%20worldwide.,most%20common%20cancer%20in%20women [Accessed: October 2, 2022]
2.Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA: A Cancer Journal for Clinicians. 2009;59(4):225-249
3.Shaib YH, Davila JA, El-Serag HB. The epidemiology of pancreatic cancer in the United States: Changes below the surface. Alimentary Pharmacology & Therapeutics. 2006;24(1):87-94
4.Ghadirian P, Lynch HT, Krewski D. Epidemiology of pancreatic cancer: An overview. Cancer Detection and Prevention. 2003;27(2):87-93
5.Lowenfels AB, Maisonneuve P. Epidemiology and risk factors for pancreatic cancer. Best Practice & Research. Clinical Gastroenterology. 2006;20(2):197-209
6.Rawla P, Sunkara T, Gaduputi V. Epidemiology of pancreatic cancer: Global trends, etiology and risk factors. World Journal of Oncology. 2019;10(1):10-27
7.Lin RT, Chen PL, Yang CY, Yeh CC, Lin CC, Huang WH, et al. Risk factors related to age at diagnosis of pancreatic cancer: A retrospective cohort pilot study. BMC Gastroenterology. 2022;22(1):243
8.Neugut AI, Ahsan H, Robinson E. Pancreas cancer as a second primary malignancy. A population-based study. Cancer. 1995;76(4):589-592
9.Lynch SM, Vrieling A, Lubin JH, Kraft P, Mendelsohn JB, Hartge P, et al. Cigarette smoking and pancreatic cancer: A pooled analysis from the pancreatic cancer cohort consortium. American Journal of Epidemiology. 2009;170(4):403-413
10.Brand RE, Greer JB, Zolotarevsky E, Brand R, Du H, Simeone D, et al. Pancreatic cancer patients who smoke and drink are diagnosed at younger ages. Clinical Gastroenterology and Hepatology. 2009;7(9):1007-1012
11.Iodice S, Gandini S, Maisonneuve P, Lowenfels AB. Tobacco and the risk of pancreatic cancer: A review and meta-analysis. Langenbeck's Archives of Surgery. 2008;393(4):535-545
12.Hassan MM, Bondy ML, Wolff RA, Abbruzzese JL, Vauthey JN, Pisters PW, et al. Risk factors for pancreatic cancer: Case-control study. The American Journal of Gastroenterology. 2007;102(12):2696-2707
13.Permert J, Ihse I, Jorfeldt L, von Schenck H, Arnqvist HJ, Larsson J. Pancreatic cancer is associated with impaired glucose metabolism. The European Journal of Surgery. 1993;159(2):101-107
14.Gullo L, Pezzilli R, Morselli-Labate AM. Diabetes and the risk of pancreatic cancer. The New England Journal of Medicine. 1994;331(2):81-84
15.Everhart J, Wright D. Diabetes mellitus as a risk factor for pancreatic cancer. A meta-analysis. JAMA. 1995;273(20):1605-1609
16.Wideroff L, Gridley G, Mellemkjaer L, Chow WH, Linet M, Keehn S, et al. Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark. Journal of the National Cancer Institute. 1997;89(18):1360-1365
17.Gapstur SM, Gann PH, Lowe W, Liu K, Colangelo L, Dyer A. Abnormal glucose metabolism and pancreatic cancer mortality. Journal of the American Medical Association. 2000;283(19):2552-2558
18.Chari ST, Leibson CL, Rabe KG, Ransom J, de Andrade M, Petersen GM. Probability of pancreatic cancer following diabetes: A population-based study. Gastroenterology. 2005;129(2):504-511
19.Ogawa Y, Tanaka M, Inoue K, Yamaguchi K, Chijiiwa K, Mizumoto K, et al. A prospective pancreatographic study of the prevalence of pancreatic carcinoma in patients with diabetes mellitus. Cancer. 2002;94(9):2344-2349
20.Huxley R, Ansary-Moghaddam A, Berrington de Gonzalez A, Barzi F, Woodward M. Type-II diabetes and pancreatic cancer: A meta-analysis of 36 studies. British Journal of Cancer. 2005;92(11):2076-2083
21.Yalniz M, Pour PM. Diabetes mellitus: A risk factor for pancreatic cancer? Langenbeck's Archives of Surgery. 2005;390(1):66-72
22.Silverman DT, Schiffman M, Everhart J, Goldstein A, Lillemoe KD, Swanson GM, et al. Diabetes mellitus, other medical conditions and familial history of cancer as risk factors for pancreatic cancer. British Journal of Cancer. 1999;80(11):1830-1837
23.Perrin MC, Terry MB, Kleinhaus K, Deutsch L, Yanetz R, Tiram E, et al. Gestational diabetes as a risk factor for pancreatic cancer: A prospective cohort study. BMC Medicine. 2007;5:25
24.Fisher WE, Boros LG, Schirmer WJ. Insulin promotes pancreatic cancer: Evidence for endocrine influence on exocrine pancreatic tumors. The Journal of Surgical Research. 1996;63(1):310-313
25.Lowenfels AB, Maisonneuve P, Cavallini G, Ammann RW, Lankisch PG, Andersen JR, et al. Pancreatitis and the risk of pancreatic cancer. International pancreatitis study group. The New England Journal of Medicine. 1993;328(20):1433-1437
26.Jiao L, Silverman DT, Schairer C, Thiebaut AC, Hollenbeck AR, Leitzmann MF, et al. Alcohol use and risk of pancreatic cancer: The NIH-AARP diet and health study. American Journal of Epidemiology. 2009;169(9):1043-1051
27.Genkinger JM, Spiegelman D, Anderson KE, Bergkvist L, Bernstein L, van den Brandt PA, et al. Alcohol intake and pancreatic cancer risk: A pooled analysis of fourteen cohort studies. Cancer Epidemiology, Biomarkers & Prevention. 2009;18(3):765-776
28.Rohrmann S, Linseisen J, Vrieling A, Boffetta P, Stolzenberg-Solomon RZ, Lowenfels AB, et al. Ethanol intake and the risk of pancreatic cancer in the European prospective investigation into cancer and nutrition (EPIC). Cancer Causes & Control. 2009;20(5):785-794
29.Fernandez E, La Vecchia C, Porta M, Negri E, d'Avanzo B, Boyle P. Pancreatitis and the risk of pancreatic cancer. Pancreas. 1995;11(2):185-189
30.Silverman DT, Brown LM, Hoover RN, Schiffman M, Lillemoe KD, Schoenberg JB, et al. Alcohol and pancreatic cancer in blacks and whites in the United States. Cancer Research. 1995;55(21):4899-4905
31.Bansal P, Sonnenberg A. Pancreatitis is a risk factor for pancreatic cancer. Gastroenterology. 1995;109(1):247-251
32.Karlson BM, Ekbom A, Josefsson S, McLaughlin JK, Fraumeni JF Jr, Nyren O. The risk of pancreatic cancer following pancreatitis: An association due to confounding? Gastroenterology. 1997;113(2):587-592
33.Farrow B, Evers BM. Inflammation and the development of pancreatic cancer. Surgical Oncology. 2002;10(4):153-169
34.Weiss FU. Pancreatic cancer risk in hereditary pancreatitis. Frontiers in Physiology. 2014;5:70
35.Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nature Genetics. 1996;14(2):141-145
36.Whitcomb DC, Applebaum S, Martin SP. Hereditary pancreatitis and pancreatic carcinoma. Annals of the New York Academy of Sciences. 1999;880:201-209
37.Lowenfels AB, Maisonneuve P, DiMagno EP, Elitsur Y, Gates LK Jr, Perrault J, et al. Hereditary pancreatitis and the risk of pancreatic cancer. International hereditary pancreatitis study group. Journal of the National Cancer Institute. 1997;89(6):442-446
38.Hingorani SR, Wang LF, Multani AS, Combs C, Deramaudt TB, Hruban RH, et al. Trp53(R172H) and KraS(G12D) cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 2005;7(5):469-483.
39.Choi SH, Park SH, Kim KW, Lee JY, Lee SS. Progression of Unresected Intraductal papillary mucinous neoplasms of the pancreas to cancer: A systematic review and meta-analysis. Clinical Gastroenterology and Hepatology. 2017;15(10):1509-20 e4
40.Hruban RH, Petersen GM, Goggins M, Tersmette AC, Offerhaus GJ, Falatko F, et al. Familial pancreatic cancer. Annals of Oncology. 1999;10(Suppl. 4):69-73
41.O'Brien JM. Environmental and heritable factors in the causation of cancer: Analyses of cohorts of twins from Sweden, Denmark, and Finland, by P. Lichtenstein, N.V. holm, P.K. Verkasalo, A. Iliadou, J. Kaprio, M. Koskenvuo, E. Pukkala, A. Skytthe, and K. Hemminki. N Engl J med 343:78-84, 2000. Survey of Ophthalmology. 2000;45(2):167-168
42.Lilley M, Gilchrist D. The hereditary spectrum of pancreatic cancer: The Edmonton experience. Canadian Journal of Gastroenterology. 2004;18(1):17-21
43.Klein AP, Brune KA, Petersen GM, Goggins M, Tersmette AC, Offerhaus GJ, et al. Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Research. 2004;64(7):2634-2638
44.Brentnall TA, Bronner MP, Byrd DR, Haggitt RC, Kimmey MB. Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancer. Annals of Internal Medicine. 1999;131(4):247-255
45.Meckler KA, Brentnall TA, Haggitt RC, Crispin D, Byrd DR, Kimmey MB, et al. Familial fibrocystic pancreatic atrophy with endocrine cell hyperplasia and pancreatic carcinoma. The American Journal of Surgical Pathology. 2001;25(8):1047-1053
46.Zogopoulos G, Rothenmund H, Eppel A, Ash C, Akbari MR, Hedley D, et al. The P239S palladin variant does not account for a significant fraction of hereditary or early onset pancreas cancer. Human Genetics. 2007;121(5):635-637
47.Lynch HT, Fitzsimmons ML, Smyrk TC, Lanspa SJ, Watson P, McClellan J, et al. Familial pancreatic cancer: Clinicopathologic study of 18 nuclear families. The American Journal of Gastroenterology. 1990;85(1):54-60
48.Goldstein AM, Fraser MC, Struewing JP, Hussussian CJ, Ranade K, Zametkin DP, et al. Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. The New England Journal of Medicine. 1995;333(15):970-974
49.Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein CL, Petersen GM, et al. Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Research. 1996;56(23):5360-5364
50.Hahn SA, Greenhalf B, Ellis I, Sina-Frey M, Rieder H, Korte B, et al. BRCA2 germline mutations in familial pancreatic carcinoma. Journal of the National Cancer Institute. 2003;95(3):214-221
51.Murphy KM, Brune KA, Griffin C, Sollenberger JE, Petersen GM, Bansal R, et al. Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: Deleterious BRCA2 mutations in 17%. Cancer Research. 2002;62(13):3789-3793
52.Su GH, Hruban RH, Bansal RK, Bova GS, Tang DJ, Shekher MC, et al. Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers. The American Journal of Pathology. 1999;154(6):1835-1840
53.Permuth-Wey J, Egan KM. Family history is a significant risk factor for pancreatic cancer: Results from a systematic review and meta-analysis. Familial Cancer. 2009;8(2):109-117
54.Shi C, Hruban RH, Klein AP. Familial pancreatic cancer. Archives of Pathology & Laboratory Medicine. 2009;133(3):365-374
55.Ghadirian P, Liu G, Gallinger S, Schmocker B, Paradis AJ, Lal G, et al. Risk of pancreatic cancer among individuals with a family history of cancer of the pancreas. International Journal of Cancer. 2002;97(6):807-810
56.Bartsch DK, Kress R, Sina-Frey M, Grutzmann R, Gerdes B, Pilarsky C, et al. Prevalence of familial pancreatic cancer in Germany. International Journal of Cancer. 2004;110(6):902-906
57.Bartsch DK. Familial pancreatic cancer. The British Journal of Surgery. 2003;90(4):386-387
58.Landi S. Genetic predisposition and environmental risk factors to pancreatic cancer: A review of the literature. Mutation Research. 2009;681(2-3):299-307
59.van der Heijden MS, Yeo CJ, Hruban RH, Kern SE. Fanconi anemia gene mutations in young-onset pancreatic cancer. Cancer Research. 2003;63(10):2585-2588
60.Rieder H, Sina-Frey M, Ziegler A, Hahn SA, Przypadlo E, Kress R, et al. German national case collection of familial pancreatic cancer - clinical-genetic analysis of the first 21 families. Onkologie. 2002;25(3):262-266
61.Hruban RH, Canto MI, Yeo CJ. Prevention of pancreatic cancer and strategies for management of familial pancreatic cancer. Digestive Diseases. 2001;19(1):76-84
62.Petersen GM, de Andrade M, Goggins M, Hruban RH, Bondy M, Korczak JF, et al. Pancreatic cancer genetic epidemiology consortium. Cancer Epidemiology, Biomarkers & Prevention. 2006;15(4):704-710
63.Wang W, Chen S, Brune KA, Hruban RH, Parmigiani G, Klein AP. PancPRO: Risk assessment for individuals with a family history of pancreatic cancer. Journal of Clinical Oncology. 2007;25(11):1417-1422
64.Li D, Morris JS, Liu J, Hassan MM, Day RS, Bondy ML, et al. Body mass index and risk, age of onset, and survival in patients with pancreatic cancer. Journal of the American Medical Association. 2009;301(24):2553-2562
65.Patel AV, Rodriguez C, Bernstein L, Chao A, Thun MJ, Calle EE. Obesity, recreational physical activity, and risk of pancreatic cancer in a large U.S. cohort. Cancer Epidemiology, Biomarkers & Prevention. 2005;14(2):459-466
66.Larsson SC, Permert J, Hakansson N, Naslund I, Bergkvist L, Wolk A. Overall obesity, abdominal adiposity, diabetes and cigarette smoking in relation to the risk of pancreatic cancer in two Swedish population-based cohorts. British Journal of Cancer. 2005;93(11):1310-1315
67.Berrington de Gonzalez A, Spencer EA, Bueno-de-Mesquita HB, Roddam A, Stolzenberg-Solomon R, Halkjaer J, et al. Anthropometry, physical activity, and the risk of pancreatic cancer in the European prospective investigation into cancer and nutrition. Cancer Epidemiology, Biomarkers & Prevention. 2006;15(5):879-885
68.Lucas AL, Kastrinos F. Screening for pancreatic cancer. JAMA. 2019;322(5):407-408
69.Tracer H, Sanou A. Screening for pancreatic cancer. American Family Physician. 2019;100(12):771-772
70.Henrikson NB, Bowles EJA, Blasi PR, Morrison CC, Nguyen M, Pillarisetty VG, et al. Screening for pancreatic cancer: Updated evidence report and systematic review for the US preventive services task force. JAMA. 2019;322(5):445-454
71.Canto MI, Harinck F, Hruban RH. International cancer of the pancreas screening (CAPS) consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut. 2014;63(1):178
Written By
Michele Molinari, Hao Liu and Christof Kaltenmeier
Submitted: 30 November 2022Reviewed: 03 January 2023Published: 25 January 2023
Open access peer-reviewed chapter
