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Pancreatic ductal adenocarcinoma (pancreatic cancer, PC) is one of the leading causes of cancer-related mortality worldwide . In the United States, PC ranks fourth in leading causes of cancer deaths among men and women . Most symptomatic patients with PC have advanced, incurable disease at diagnosis. Even in those with apparently resectable tumors, prognosis is poor. Given that outcomes may be better following resection of small invasive cancers, it is hoped that screening and detection of asymptomatic, early, potentially curable PC and its precursors will improve outcomes. Individuals at increased risk for PC based upon family history or an identifiable genetic predisposition are potential targets for selective screening and curative or preventive treatment.
This topic reviews the epidemiology and genetic basis of familial PC and familial PC-associated genetic syndromes, the diagnostic tests used for screening, and the risks and benefits of screening for PC. A more detailed discussion of epidemiology and risk factors for PC, and the clinical evaluation and staging workup of newly diagnosed PC, are addressed separately.
Epidemiology and risk factors
An estimated 10 to 15% of PCs are attributable to genetic causes [3-7]. PC aggregates in some families, and approximately 5 to 10% of individuals with PC have a family history of the disease [6,8].
There are two broad categories of hereditary risk for PC:
- Genetic predisposition syndromes associated with PC (table 1)
- Familial pancreatic cancer (FPC), which is defined as a family with a pair of affected first-degree relatives (parent-child or sibling pair) who do not meet criteria for a known PC-associated genetic predisposition syndrome
The major gene causing most hereditary PC is not yet known. Germline mutations in the BRCA1 and BRCA2 genes are the most commonly associated mutations in FPC, occurring in 13 to 19% of FPC families [9,10]. Next generation sequencing has led to discovery of other genes causing hereditary pancreatic ductal adenocarcinoma: the Partner and Localizer of the Breast Cancer 2 (PALB2) gene and the ataxia-telangiectasia-mutated (ATM) gene [11,12].
In kindreds with FPC, the risk of developing PC ranges from 1.5 to 13% depending upon the number of affected blood relatives [1,10-17]. Cigarette smoking contributes to the risk of PC in patients with hereditary pancreatitis and FPC, and is associated with an earlier PC diagnosis by approximately 20 years [18,19].
Although some studies suggest that patients from affected families present at an earlier age as compared with noninherited disease (especially for individuals with genetic predisposition syndromes, including hereditary pancreatitis), the median age for development of FPC is about the same as that for sporadic PC (about 65 years), and the majority of incident FPC cases arise in individuals age 60 years or older .
Genetic predisposition syndromes
Hereditary pancreatitis is an autosomal dominant disorder that accounts for a small fraction of cases of chronic pancreatitis. Autosomal dominant hereditary pancreatitis is most often associated with mutations in serine protease 1 gene (PRSS1) on chromosome 7q35, which encodes cationic trypsinogen. Rarely, autosomal dominant-appearing hereditary pancreatitis is identified in a kindred that does not have an identifiable PRSS1 mutation.
The majority of affected individuals develop chronic pancreatitis before the age of 20 years and often before the age of five. Chronic inflammation in hereditary pancreatitis leads to accelerated mutation accumulation and clonal expansion required for development of PC . Hereditary pancreatitis is associated with a markedly increased risk of PC, although it accounts for a very small fraction of PC cases [1,13,21]. The magnitude of lifetime risk is estimated to be 25 to 44% (table 2) [13,14]. In one study that included 200 patients with hereditary pancreatis, the cumulative risk of PC in affected family members at 50, 60, and 75 years was 10, 19, and 54%, respectively . The standardized incidence ratio (SIR) compared with the general population was 87 . The risk of PC appears to be highest in smokers, diabetics, and in those with a paternal inheritance pattern [13,14,18].
Inherited cancer susceptibility syndromes
A small but clinically important proportion of PC is associated with mutations in known cancer predisposition genes [22,23]. The inherited cancer susceptibility syndromes and approximate lifetime risk for PC are summarized in the table (table 2).
Hereditary breast cancer: BRCA and PALB2
Hereditary breast and ovarian cancer (HBOC) is characterized by the presence of germline mutations in one of two cancer susceptibility genes, BRCA1 and BRCA2. The risk of PC may be elevated threefold in BRCA1 mutation carriers, but the risk has not been well established, as it is with BRCA2 gene mutations [17,24,25]. In one familial PC registry study, BRCA1 mutations (by full sequencing) were not highly prevalent . In contrast, BRCA2 mutations have been found in as many as 5 to 17% of patients with familial PC [10,27,28]. PC risk in BRCA2 gene mutation carriers is elevated with a relative risk (RR) of 3.5 (1.87-6.58) to 10 [29,30].
BRCA mutations are particularly prevalent among patients of Ashkenazi Jewish origin. An estimated 1.7 to 21% of patients of Ashkenazi Jewish origin who have PC carry aBRCA mutation, many of whom lack a family history of typical BRCA-associated cancers [23,28,31,32]. Because of this, some have suggested that the diagnosis of PC in an Ashkenazi individual should prompt referral for BRCA testing , including the founder BRCA2 gene mutation, 6174delT, that is present in 1% of Ashkenazi Jewish individuals  and 4% of PC patients .
Mutations in the PALB2 gene confer an increased risk of both breast and pancreatic cancer . Approximately 1% of non-BRCA1/BRCA2 deficient familial breast cancers are caused by germline defects in the PALB2 gene. The PALB2 protein binds with BRCA2 protein and stabilizes it in the nucleus; the BRCA2/PALB2 complex is part of the Fanconi Anemia DNA repair pathway that acts in double-stranded DNA repair. PALB2 mutations have been identified in 2.1 to 4.9% of familial PC (FPC) kindreds [8,35,36]. The absolute magnitude of risk for PC in affected individuals is unknown.
Germline mutations in the STK11 gene are associated with Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder in which affected individuals develop hamartomatous polyps of the gastrointestinal tract, pigmented macules on the lips and buccal mucosa, and a variety of gastrointestinal malignancies . Patients with PJS have a dramatically increased risk of developing pancreatic cancer, with an 11 to 36% lifetime risk to age 70 (relative risk 132) [37-39].
Furthermore, both somatic and germline mutations of the STK11 gene have been identified in PC, suggesting that genetic alterations of the STK11 gene may play a causal role in carcinogenesis and that the same gene contributes to the development of both sporadic and familial forms of cancer .
Familial atypical multiple mole and melanoma syndrome
Mutations in the CDKN2A gene (p16 or multiple tumor suppressor-1 gene) characterize the familial atypical multiple mole and melanoma (FAMMM) syndrome, a disorder associated with multiple nevi, cutaneous and ocular malignant melanomas, as well as pancreatic cancers. The variant FAMMM-pancreatic carcinoma syndrome has been identified in families with a specific 19-base-pair deletion in the p16 gene (the p16 Leiden mutation), which is associated with a cumulative risk of pancreatic carcinoma of up to 19% by age 75 [41-46].
Individuals with inherited germline mutations in mismatch repair (MMR) genes, in particular MLH1, MSH2, and MSH6, have Lynch syndrome and are at increased risk of PC [47,48]. In a study of 147 families with MMR gene mutation, of whom 21% had at least one PC within the family, the cumulative risk of PC was 3.7% by age 70 . The PCs that develop in individuals with Lynch syndrome have a characteristic medullary histology. Individuals who have a medullary pancreatic cancer should have their pedigree evaluated to determine if they are a Lynch syndrome kindred .
Ataxia-telangiectasia, which is caused by mutations in the ataxia-telangiectasia-mutated (ATM) gene, is associated with an increased risk of PC, although the lifetime risk is uncertain [12,51].
Familial pancreatic cancer
Familial pancreatic cancer (FPC) is defined as an inherited predisposition to PC that is based upon family clustering in families in which there is at least a pair of first-degree relatives with pancreatic ductal adenocarcinoma in the absence of a known genetic susceptibility syndrome. A specific gene defect responsible for familial pancreatic cancer has not been identified. Segregation models support a rare but dominant susceptibility gene that is carried by approximately 7 in every 1000 individuals .
Prospective analysis of data from a large familial PC registry led to quantitative estimates of PC risk in at-risk relatives [6,20]. In this study, the risk of PC for a member of a FPC family was ninefold higher than for the sporadic pancreatic cancer kindreds . Individuals with an affected first-degree relative had an 18-fold higher risk, and the risk increased with the total number of affected blood relatives. The number of affected relatives with a first-degree relationship to the at-risk individual also increases PC risk (table 2) .
PancPRO is a statistical model for assessing the probability that an individual carries a germline deleterious mutation of a susceptibility gene for PC and the risk of developing a future PC based on the individual’s family history [53,54]. Although this model may represent an accurate predictor of the likelihood of developing a PC in high-risk families, external validation in other populations and consideration of other risk factors is needed to allow improved risk stratification and selection for targeted screening .
Referral for genetic evaluation
A detailed personal and family cancer history (in first- and second-degree relatives), including the type of cancer and age at diagnosis, and ancestry may help identify individuals with a hereditary predisposition to cancer. If the history suggests the possibility of a PC-associated genetic syndrome, patients should be referred for genetic counseling and genetic testing as appropriate.
Definition of high-risk individuals
Individuals should be considered to be at high-risk for hereditary pancreatic adenocarcinoma if they have any of the following:
- Known genetic syndrome associated with pancreatic cancer, including hereditary breast-ovarian cancer syndrome, familial atypical multiple melanoma and mole syndrome, Peutz-Jeghers syndrome, Lynch syndrome, or other gene mutations associated with an increased risk of pancreatic adenocarcinoma
- Two relatives with pancreatic adenocarcinoma, where one is a FDR
- Three or more relatives with pancreatic cancer
- Hereditary pancreatitis
However, only a subset of high-risk individuals are candidates for screening.
Pancreatic cancer screening
The decision to perform screening for PC requires a discussion of the risks, benefits, and lack of definitive data on long-term screening outcomes. The decision should be guided by individual patient values and preferences. Screening should only be performed in patients who are candidates for pancreas surgery. Screening for PC should preferably be performed in the setting of a research protocol at an experienced centers with a multidisciplinary team.
The optimal screening strategy for patients at risk for hereditary PC is not unclear. Guidelines for screening for PC have been published by several guidelines [5,56-59]. Our approach to screening for individuals with hereditary pancreatis and other high-risk conditions is consistent with guidelines from the International Cancer of the Pancreas Screening (CAPS) Consortium (table 3) and The American College of Gastroenterology [5,57].
Candidates for screening
We screen for PC in the following individuals [5,56]:
- First-degree relatives (FDRs) of patients with PC from a FPC family with at least two affected FDRs
- Patients with Peutz-Jeghers syndrome (PJS)
- CDKN2A(p16), BRCA1, BRCA2, PALB2, and Lynch syndrome mutation carriers with one or more affected FDRs
- Patients with hereditary pancreatitis
Screening modality and timing
For most patients, we perform endoscopic ultrasonography (EUS) and/or magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP). This recommendation is based upon a cross-sectional blinded comparison of EUS, MRI, and CT demonstrating comparable frequent detection of pancreatic lesions by EUS and MRI, compared with CT (table 4) .
We base our approach to begin screening on the mean expected age of development of PC and the youngest age of onset of PC in the family [5,56]. We begin screening at age 45 to 50 years, or 10 to 15 years younger than the youngest relative with pancreatic cancer [5,61]. We begin screening for PC in patients with PJS at 30 years . In patients with hereditary pancreatitis, we begin screening at age 40 years. Screening should begin earlier in people who have ever smoked, given that smokers from pancreatic cancer-prone families develop cancer on average a decade earlier than non-smokers.
For patients with a normal pancreas on imaging, repeat pancreatic imaging (EUS and/or MRI/MRCP) can be performed every year, typically alternating EUS and MRCP until a lesion is detected. The age for stopping screening should be individualized based upon each patient’s medical status (eligibility for surgical treatment of detected lesions), life expectancy, and preferences.
Pancreatic surveillance intervals for detected lesions that are thought not to require imminent surgical management are influenced by the size and type of lesion (solid versus cystic), growth rate, and concerning features. The management of pancreatic lesions and intervals for surveillance are as recommended by the CAPS Consortium are outlined in the table (table 3)  and discussed in detail below.
Screening for pancreatic cancer aims to detect early invasive tumors and pre-invasive lesions (intraductal papillary mucinous neoplasms and pancreatic intraepithelial neoplasia) with high-grade neoplastic changes [62-65].
- Intraductal papillary mucinous neoplasms (IPMNs) – IPMNs are potentially malignant intraductal epithelial neoplasms that are grossly visible (>1 cm) and are composed of mucin-producing columnar cells. IPMNs are highly prevalent in individuals with hereditary FPC [63,66]. Over time, IPMNs can develop increasingly dysplastic features (graded as low, intermediate, or high) and eventually transform into invasive adenocarcinoma.
Evidence on the frequency and rate at which IPMNs progress to invasive PC in high-risk individuals as compared with sporadic IPMNs is lacking. In patients with apparently sporadic noninvasive IPMNs, it may take three to five years for a clinically detectable noninvasive lesion to progress to an invasive PC . The risk for progression to high-grade dysplasia (in situ carcinoma) or invasive disease is much higher for main-duct IPMNs than it is for branch-duct IPMNs. On the other hand, among patients with small branch-duct (BD)-IPMN(s) followed for over five years, only 2.4 to 6.9% of these lesions progress to invasive PC [68,69].
The natural history of low-risk IPMNs in high-risk individuals is also not well understood. In fact, some tiny cystic lesions visualized by EUS will be found to be visible PanINs in resected patients [60,70,71]. In the setting of familial PC, the presence of multiple small «imaging» BD-IPMNs may indicate the presence of high-grade PanIN lesions elsewhere in the pancreas .
- Pancreatic intraepithelial neoplasia (PanIN) – PanIN lesions are noninvasive microscopic pancreatic duct neoplasms. These lesions are typically <5 mm in size and too small to be visualized by imaging. Most ductal adenocarcinomas are considered to arise from PanIN, presumably developing as a result of a series of genetic events. However, although PanIN is considered to represent a precursor lesion to invasive ductal adenocarcinoma, it appears that only a small fraction of low-grade PanIN progress to high-grade PanIN and then to invasive cancer. PanIN are more common, more often multifocal, and of a higher grade in patients with hereditary PC [17,62,63].
Diagnostic yield, benefits, and harms
Several studies have evaluated the diagnostic yield of screening [60,70,73-82]. These studies have reported the detection of asymptomatic precursor lesions and PCs at baseline and follow-up in 3.9 to 50% of individuals, depending on whether only resected neoplasms or all pancreatic lesions (resected or not) were used as an end point (table 4) [70,71,73,74,77-79,81,83-86]. Small cysts (BD-IPMNs) are the most common abnormality detected on screening for pancreatic cancer .
The benefits of screening include early detection of invasive pancreatic ductal adenocarcinomas, at a time when they are asymptomatic and more likely to be amenable to potentially curative resection, and identification of high-risk preinvasive neoplasms, such as main-branch IPMNs and high-grade pancreatic intraepithelial neoplasia (PanIN-3) . Screening for pancreatic cancer in high-risk individuals may also be cost effective [87-89]. In one cohort study of 79 high-risk Leiden p16 (CDKN2A) mutation carriers who were screened usingMRI/MRCP, the number needed to be screen to detect and treat one PC was 11 .
Screening for PC in high-risk individuals has not been demonstrated to improve survival [73,74,83,86,90]. Potential harms of screening include procedure-associated complications, particularly for invasive procedures like endoscopic ultrasound. Screening can also cause harm by over-diagnoses, resulting in treatment of non-neoplastic or low-grade neoplastic lesions (serous cystadenomas, low-grade PanIN associated with lobulocentric parenchymal atrophy) [70,76-78,83]. In patients with hereditary pancreatitis, the «background noise» from severe chronic pancreatitis makes PC screening particularly challenging . False-positive cytology from subcentimeter solid indeterminate lesions may also lead to unnecessary surgery and anxiety [73,76].
Is there a role for prophylactic surgery?
Prophylactic surgery is not recommended for an asymptomatic individuals without an identifiable lesion, given the short term risks of pancreatectomy and the metabolic consequences, including permanent exocrine insufficiency and diabetes, which have a detrimental impact on long-term survival.
There is no consensus as to the best imaging method for screening high-risk individuals, and there are few prospective data comparing outcomes from different screening strategies. However, endoscopic ultrasound (EUS) and/or magnetic resonance-based imaging appear to have the highest yield and do not involve ionizing radiation . There is insufficient evidence to support the use of biomarkers for screening for PC.
Several imaging modalities have been evaluated for screening for PC in high-risk individuals.
EUS is one of the most sensitive and specific imaging tests for the pancreas. It allows detection, staging, and tissue sampling of pancreatic neoplasms, including minute lesions.
Furthermore, unlike computed tomography (CT), EUS involves high frequency ultrasound and not ionizing radiation. It typically does not require contrast injection. EUS imaging can also be coupled with collection of pancreatic secretions and/or pancreatic neoplastic tissue (during fine needle aspiration/biopsy) for biomarker analysis. The disadvantage of EUS as a screening modality is that is typically requires sedation and is associated with variability in interpretation of pancreatic abnormalities, even among experts .
MRI and MRCP
Magnetic resonance imaging (MRI) provides complete abdominal imaging of the abdomen and pelvis, unlike EUS. In addition, MRI can detect extra-pancreatic neoplasms, which is a benefit for high-risk individuals. Magnetic resonance cholangiopancreatograph (MRCP) images the fluid-filled pancreatic duct and branches, along with cystic pancreatic lesions and duct communication. Secretin has been injected during MRCP (off-label use in the United States) to improve pancreatic duct imaging and detection of ductal abnormalities [92,93].
The main disadvantages of MRI include the inability to image individuals with implanted metal (such as pacemakers, defibrillators, certain artificial joints and valves) and claustrophobia. Intravenous contrast with gadolinium can also be associated with nephrotoxicity.
CT is a rapid, high-resolution imaging method for visualizing the pancreas, including all abdominal and pelvic organs. It typically requires only two breath-holds for complete imaging and has a more open scanner, unlike MRI, which takes about 45 minutes and has a more enclosed gantry. It is a widely available imaging test, relative to MRI and EUS. The disadvantage of CT is that it involves ionizing radiation (a particular concern in high-risk individuals) and side effect of intravenous contrast injection. Furthermore, CT has a relatively low detection rate for small lesions in the high-risk population [60,71,74,84].
Endoscopic retrograde cholangiopancreatography (ERCP) is not recommended for routine screening and surveillance due to the risk of post-ERCP pancreatitis . Studies examining the benefit of ERCP for screening high-risk individuals are conflicting. In one prospective study of 14 individuals from three FPC families, ERCP identified mild and focal side-branch-duct irregularities, and ectasia and main-duct strictures in all seven patients with an abnormal EUS . All patients with an abnormal ERCP were found to have low-grade dysplasia at pancreatectomy. However, another prospective screening study of 78 individuals at high risk for PC showed that when ERCP was performed routinely for abnormal EUS, it provided no additional clinically relevant information and was associated with a 7% rate of pancreatitis .
Transabdominal ultrasound is not a recommended for pancreas screening and surveillance in a high-risk population due to the relatively low sensitivity for small pancreatic lesions .
Several studies have evaluated the yield of imaging in detecting early PC and preinvasive lesions. However, comparison of the diagnostic yield and accuracy of screening tests is limited by the variability in the study populations, type of screening modalities, and imaging protocols. However, these data suggest that EUS andMRI/MRCP both have limitations based on the underlying lesion but detect more lesions as compared with CT scan.
- In a comparative study of EUS, secretin-enhanced MRI/MRCP, and CT in 225 asymptomatic high-risk individuals (the CAPS3 study), in the 216 screened individuals, EUS and MRI detected significantly more (mostly small cystic) pancreatic lesions as compared with CT (43, 33, and 11%, respectively) . For cystic lesions, MRCP provided the best visualization of cyst communication with the main pancreatic duct.
- In another prospective study, 139 high-risk individuals underwent EUS and MRI for initial screening for pancreatic cancer . Clinically relevant lesions were defined as any solid lesion, cysts ≥3 cm, or cysts with thickened/enhancing cyst walls and/or mural nodules and/or a solid component, main duct IPMNs with main pancreatic duct ≥10 mm, and side branch IPMNs with side duct dilations/cysts >10 mm. A total of 11 clinically relevant lesions were detected by either EUS or MRI in nine high-risk individuals (6%). Six of the 11 were detected by both modalities; two additional lesions were apparent on EUS only (the only two solid lesions that were found on initial screening), and three additional lesions (all three cysts ≥10 mm) were found by MRI only. EUS and MRI detected clinically relevant pancreatic lesions in 6%. These results suggest that both imaging techniques were complementary rather than interchangeable, but that MRI might have important limitations for timely detection of small solid lesions.
Several biomarkers are being evaluated in order to improve early diagnosis of high-grade neoplasms not detectable by imaging and to aid the appropriate selection of high-risk individuals for surveillance versus surgery .
The most useful serum tumor marker for pancreatic cancer is carbohydrate antigen 19-9 (CA 19-9).
There are limited data on the performance characteristics of CA 19-9 in patients at high-risk of PC. In one study of targeted screening of individuals with at least one affected relative with PC, serum CA 19-9 was elevated in 27 of 546 (4.9%). Neoplastic or malignant findings were detected on subsequent EUS in only five patients (0.9%), and only one was a pancreatic adenocarcinoma (0.2%) .
Aberrant expression of microRNAs (MiRNAs; short non-coding segments of RNA that regulate gene expression) are potential diagnostic markers for several solid tumors, including pancreatic cancer [96-99]. Assays for multiple microRNAs performed in combination with CA 19-9 may improve diagnostic accuracy . However, additional studies are needed in high-risk cohorts.
Pancreatic juice and pancreatic cyst fluid
Pancreatic juice collected at the time of ERCP and cyst fluid obtained via an EUS-guided fine needle aspiration can be analyzed for molecular markers. Next generation sequencing can be performed at low cost to detect low frequency mutations in pancreatic juice and pancreatic cyst fluid . Although data are scarce, the genetic alterations (aberrant methylation, mutant oncogene Kras2, inactivated tumor suppressor genes SMAD4 and p53) in familial PC appear to be similar to those detected in sporadic PC . Potential markers include mutant GNAS (specific for IPMNs), mutant KRAS, and mutant TP53 [64,102,103]. In one prospective study of familial PC relatives and controls, mutant TP53 DNA was present in pancreatic juice in 29 of 43 patients with pancreatic ductal adenocarcinoma and four of eight patients with high-grade dysplasia lesions (PanIN3 and high-grade IPMN), but not in any samples from normal or benign disease controls and screened individuals without advanced lesions . Further studies are needed to validate these results.
Management and follow-up of identified lesions
Pancreatic lesions will be detected in up to 42% of high-risk individuals (predominantly relatives of kindreds with familial PC) . Most of these are managed conservatively and do not need surgery. However, there is currently little consensus regarding surgical indications for lesions detected by screening . The few published reports are based on limited numbers of patients [104,105]. For management of pancreatic lesions that are detected on imaging, individualized decision-making for surveillance and treatment within multidisciplinary programs is recommended. However, when pancreatic surgery is necessary, it is best performed at a high-volume specialty center [106,107].
Solid pancreatic lesions
Fewer than 2% of pancreatic lesions detected at baseline screening are solid . In individuals with a solid pancreatic lesion on endoscopic ultrasound (EUS) and/or magnetic resonance imaging (MRI), we perform triple-phase, helical multidetector row (pancreatic protocol) computed tomography (CT) .
Some indeterminate solid lesions identified only by EUS are cancers, but they can be benign lesions, such as non-metastatic pancreatic neuroendocrine tumors or low-grade pancreatic intraepithelial neoplasia (PanIN) with focal associated lobulocentric parenchymal atrophy [60,70,71,74,76]. The decision to perform EUS FNA on solid lesions should be individualized. If the pancreatic lesion can be safely aspirated, and the cytological results might impact patient management, we would perform EUS FNA. The impact is potentially greater for right sided pancreatic lesions requiring Whipple surgery, versus left sided tail lesions that could be readily excised, including minimally invasive approaches. It should be noted that false positive cytological results can lead to unnecessary surgery [71,76].
In patients with a new indeterminate solid lesion that is detected on only one imaging modality, in whom initial EUS-FNA is negative and in whom surgery is not planned, we perform follow-up imaging (EUS and pancreatic protocol CT testing) at three months.
Unambiguous solid lesions (≥1 cm, or seen by multiple imaging modalities) are more ominous, and the threshold for resection is much lower as subcentimeter solid pancreatic lesions can be clinically significant .
Cystic pancreatic lesions
About one-third of individuals have one or more cysts at baseline screening . The prevalence increases by age, with cystic lesions detected in 14% of subjects younger than 50 years old, 34% of subjects 50 to 59 years old, and 53% of subjects 60 to 69 years old . The majority of cystic lesions detected by screening appear to be low-risk branch-duct IPMNs. The majority of such branch duct (BD)-IPMNs remain stable during surveillance [73,74,77,78,83].
The optimal approach to evaluating pancreatic cysts is unclear. Our approach is more conservative as compared to guidelines for sporadic pancreatic cysts, and we do not routinely perform EUS-fine needle aspiration (FNA) [5,108-111]. This is because benign IPMNs may be a marker of a generalized field effect in genetically predisposed individuals as both PanIN3 lesions and high-grade dysplasia and/or main-duct involvement have been found in patients who did not meet Sendai/American Gastroenterological Association (AGA) criteria for surgical resection [60,70,76,80,83,109,110]. EUS-FNA in the clinical management of most pancreatic cysts is limited, given the low accuracy of cytology in cystic lesions and the low volume of cyst fluid aspirated from small cysts (which comprise the majority of detected lesions in high-risk individuals) [112,113].
Surgical resection is indicated in high-risk patients with any of the following:
- Main-duct IPMNs with any one of the following:
- Main pancreatic duct dilation of ≥10 mm
- Mural nodules
- Thickened duct walls
- Intraductal mucin
- BD-IPMN with any one of the following:
- Rapid growth (ie, >5 mm over six months)
- Cysts (suspected BD-IPMNs) with size 2 cm or larger 
- Mural nodules or a solid component
- Main pancreatic duct dilation of ≥10 mm
For patients who do not meet these criteria for surgery, repeat imaging in three months if worrisome features are present . Worrisome features include:
- Thickened or enhancing cyst walls on imaging
- Associated pancreatitis
- Main pancreatic duct size of 5 to 9 mm in diameter
Individuals without worrisome features of malignancy should undergo repeat imaging in 12 months.
Screening/surveillance should be continued until the patient is no longer a surgical candidate.
The extent of surgery (partial versus total pancreatectomy) is driven by the extent of disease (multifocality of lesions, location of dominant lesion) and the patient’s life expectancy and overall health, considered with the risks and benefits of the type of surgery. Multidisciplinary, individualized decision-making is highly recommended .
Main pancreatic duct strictures/dilation without associated lesion
If an indeterminate main pancreatic duct stricture without a mass is detected, repeat imaging should be performed within three months to potentially detect occult neoplasia not visible by EUS, CT, and MRI. ERCP should be avoided as a diagnostic modality for MPD strictures because of the associated risk of pancreatitis [5,70].
Invasive pancreatic cancer
Suspected invasive pancreatic cancers should be resected. However, the surgical approach to high-risk individuals undergoing resection for suspected cancer is controversial. Most experts do not recommend a total pancreatectomy unless necessary to achieve completely negative (R0) resection margin . There is controversy as to what to do if there is PanIN at the surgical margin. Most experts would not pursue additional surgery in this setting , but if PanIN-3 is identified at the margin, follow-up imaging is recommended within six months of surgery and indefinitely because of the risk for new or metachronous pancreatic neoplasms .
Pancreatic neuroendocrine tumors
Well-differentiated neuroendocrine tumors (PanNETs) have been detected within familial PC screening programs [60,70,74]. PanNETs <0.5 cm (microadenomas) are essentially benign lesions. Most surgically-resected PanNETs between 0.5 and 1 cm are cured with resection .
Table 1. Inherited cancer syndromes associated with increased risk of pancreatic cancer
|Syndrome||Gene(s)||Lifetime risk of pancreatic cancer, %||Locus|
|Hereditary breast/ovarian cancer||BRCA2, BRCA1||3 to 5||13q|
|Familial atypical multiple mole melanoma syndrome||CDKN2A||10 to 19||9p|
|Peutz-Jeghers syndrome||STK 11||11 to 36||19p|
|Familial adenomatous polyposis||APC||Unknown||5q|
|Hereditary nonpolyposis colon cancer (Lynch II)||DNA mismatch repair genes||4||2p, 3p, 7p|
|Hereditary pancreatitis||PRSS1, SPINK1||25 to 40||7q, 5q|
Adapted with permission from: Brentnall TA. Management strategies for patients with hereditary pancreatic cancer. Curr Treat Options Oncol 2005; 6:437. Copyright © 2005 Current Medicine.
Table 2. Pancreatic cancer predisposition syndromes and risk of pancreatic cancer
|Group (mutated gene)||Other characteristics||Relative risk for pancreatic cancer||Lifetime risk for pancreatic cancer by age 70 years (incidence)|
|HBOC (BRCA1)||Predisposition to breast, ovarian, prostate cancer||3||1.2%|
|HBOC (BRCA2)||Predisposition to breast, ovarian, prostate cancer, Jewish ancestry in some (refer for gene testing)||3.5 to 10||2 to 5%|
|Familial PC + 1 FDR affected||Pancreatic ductal adenocarcinoma in an individual with one affected FDR (sibling, parent, or child)||4.6|
|Familial PC+ 2 FDR affected (unknown)||Pancreatic ductal adenocarcinoma in an individual with two affected FDRs||6.4|
|Lynch II syndrome (mismatch repair genes MLH1, MSH2, MSH6)||Predisposition to colorectal, endometrial cancer||8.6||3.7%|
|FAMMM (CKDN2A)||Predisposition to melanoma, multiple nevi, atypical moles (autosomal dominant)||13 to 36||10 to 19%|
|Familial PC + 3 FDR affected (unknown)||Pancreatic ductal adenocarcinoma in an individual with three affected FDRs||32|
|Hereditary pancreatitis (PRSS1, SPINK1)||Young-onset pancreatitis (autosomal dominant)||50 to 82||25 to 44%|
|Peutz-Jeghers syndrome (STK11)||132||11 to 66%|
HBOC: hereditary breast ovarian cancer syndrome; BRCA: breast-related cancer; familial PC: familial pancreatic cancer (pancreatic ductal adenocarcinoma) in the absence of a definable high-risk inherited mutation; FDR: first-degree relative; FAMMM: familial atypical multiple mole melanoma syndrome; CDKN: cyclin-dependent kinase inhibitor.
Table 3. International Cancer of the Pancreas Screening (CAPS) consortium consensus on screening for pancreatic cancer in patients with increased risk for familial pancreatic cancer
|Who should be screened?|
|A1||Individuals with three or more affected blood relatives, with at least one affected FDR, should be considered for screening.|
|A2||Individuals with at least two affected FDR with PC, with at least one affected FDR, should be considered for screening once they reach a certain age.|
|A3||Individuals with two or more affected blood relatives with PC, with at least one affected FDR, should be considered for screening.|
|A4||All Peutz-Jeghers syndrome patients should be screened, regardless of family history of PC.|
|A5||p16 carriers with one affected FDR should be considered for screening.|
|A6||BRCA2 mutation carriers with one affected FDR should be considered for screening.|
|A7||BRCA2 mutation carriers with two affected family members (no FDR) with PC should be considered for screening.|
|A8||PALB2 mutation carriers with one affected FDR should be considered for screening.|
|A9||Mismatch repair gene mutation carriers (Lynch syndrome) with one affected FDR should be considered for screening.|
|How should high-risk individuals be screened?|
|B1||Initial screening should include (multiple answers allowed):
EUS 83.7%, MRI/MRCP 73.5%, CT 26.5%, abdominal ultrasound 14.3%, ERCP 2.0%.
|B2||When previous screening did not detect an abnormality that met criteria for shortening of the interval or surgical resection, follow-up screening should include (multiple answers allowed):
EUS 79.6%, MRI/MRCP 69.4%, CT 22.4%, abdominal ultrasound 4.1%, ERCP 2.0%.
|B3||Standardized nomenclature should be used to define chronic pancreatitis-like abnormalities.|
|B4||Whenever a cystic lesion is detected, an additional ERCP should not be performed.|
|B5||Patients with a cystic lesion without worrisome features for malignancy should have an imaging test after 6 to 12 months.|
|B6||In case of detection of a solid lesion, CT should also be performed.|
|B7||In case of detection of a solid lesion, ERCP should not be performed.|
|B8||In case of detection of a solid lesion at baseline with an indeterminate diagnosis and not being referred for immediate surgery, imaging should be repeated after three months.|
|B9||In case of detection of a new solid lesion on follow-up with an indeterminate diagnosis and not being referred for immediate surgery, imaging should be repeated after three months.|
|B10||If an indeterminate main pancreatic duct stricture without a mass is detected, repeat imaging should be performed within three months.|
|When should surgery be performed?|
|C1||Screening should only be offered to individuals who are candidates for surgery.|
|C1||Pancreatic resections should be performed at specialty centers (taking into account volume, morbidity and mortality rates, and expertise available).|
|C2||Intraoperatively, further pancreatectomy (up to a possible total) should be performed in patients with otherwise reasonable life expectancy to achieve R0 resection of cancer.|
|C3||Intraoperatively, further pancreatectomy (up to a possible total) should not be performed in a patient with otherwise reasonable life expectancy and no cancer, but with unifocal PanIN-2 in the resected specimen but not at the margin.|
|C4||Postoperatively, further pancreatectomy (up to a possible total) should not be performed in patients with otherwise reasonable life expectancy in a patient without cancer in the resected specimen but with PanIN-2 at margin.|
|C5||Postoperatively, further pancreatectomy (up to a possible total) should not be performed in patients with otherwise reasonable life expectancy in a patient who did not have cancer, but had unifocal PanIN-2 in the resected specimens but not at the margin.|
|C6||Postoperatively, further pancreatectomy (up to a possible total) should not be performed in patients with otherwise reasonable life expectancy in a patient without cancer, but had multifocal PanIN-2 in the resected specimens butnot at the margin.|
|What are the goals of screening? What outcome(s) would be considered a «success»?|
|D1||One of the pathologic lesions that is a potential target for early detection and treatment is resectable carcinoma.|
|D2||One of the pathologic lesions that is a potential target for early detection and treatment is PanINs.|
|D3||One of the pathologic lesions that is a potential target for early detection and treatment is IPMNs.|
|D4||Detection and treatment of multifocal PanIN-3 should be considered a success of a screening/surveillance program.|
|D5||Detection and treatment of IPMN with high-grade dysplasia should be considered a success of a screening/surveillance program.|
|D6||Detection and treatment of invasive cancer-T1N0M0 detected at baseline should be considered a success of a screening program.|
|D7||Detection and treatment of invasive cancer-T1N0M0 detected on follow-up should be considered a success of a screening program.|
|D8||Detection and treatment of invasive cancer >T1N0M0 resectable with margins negative at baseline, should be considered a success of a screening program.|
FDR: first-degree relative; PC: pancreatic cancer; BRCA: breast-related cancer; EUS: endoscopic ultrasound; MRI: magnetic resonance imaging; MRCP: magnetic resonance cholangiopancreatography; CT: computed tomography; ERCP: endoscopic retrograde cholangiopancreatography; PanIN: pancreatic intraepithelial neoplasia; IPMN: intraductal papillary mucinous neoplasms.
Canto MI, Harinck F, Hruban RH, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 2013; 62:339-47. Reproduced with permission from BMJ
Table 4. Diagnostic yield of familial pancreatic cancer screening and surveillance
|Study||High-risk group||Imaging tests||Diagnostic yield*|
|Brentnall 1999; n = 14||FPC||EUS + ERCP + CT||7/14 (50%)¶|
|Kimmey 2002; n = 46Δ||FPC||EUS; ERCP◊||12/46 (26%)¶|
|Canto 2004; n = 38||FPC, PJS||EUS; ERCP◊, EUS-FNA◊, CT◊||2/38 (5.3%)¶|
|Canto 2006; n = 78||FPC, PJS||EUS; CT◊, EUS-FNA◊, ERCP◊||8/78 (10.2%)¶§|
|Poley 2009; n = 44||FPC, BRCA, PJS, CDKN2A, p53, hereditary pancreatitis||EUS; CT◊, MRI◊||10/44 (23%)|
|Langer 2009; n = 76||FPC, BRCA||EUS + MRCP; EUS-FNA◊||1/76 (1.3%)¶§|
|Verna 2010; n = 51||FPC, BRCA, CDKN2A||EUS and/or MRCP||6/51 (12%)¶|
|Ludwig 2011; n = 109||FPC, BRCA||MRCP; EUS◊, EUS-FNA◊||9/109 (8.3%)§|
|Vasen 2011; n = 79||CDKN2A||MRI/MRCP||14/79 (18%)¶|
|Al-Sukhni 2011; n = 262||FPC, BRCA, PJS, CDKN2A, hereditary pancreatitis||MRI; CT◊, EUS◊, ERCP◊||19/262 (7.3)§|
|Schneider 2011¥; n = 72||FPC, BRCA, PALB2||EUS+MRCP||11/72 (15%)§|
|Canto 2012; n = 216||FPC, BRCA, PJS||CT, MRI/MRCP, EUS; ERCP◊||5/216 (2.3%)¶ – 92/216 (42%)|
|Harinck 2015; n = 139||FPC, BRCA, PJS, CDKN2A||MRI, EUS||11/139 (8%)§|
|Vasen 2016; n = 411||FPC, BRCA, PALB2, CDKN2A||MRI, MRCP, EUS||32/411 (7.8%)¶§|
FPC: familial pancreatic cancer; EUS: endoscopic ultrasound; ERCP: endoscopic retrograde cholangiopancreatography; CT: computed tomography; PJS: Peutz-Jeghers syndrome; EUS-FNA: endoscopic ultrasound-guided fine needle aspiration; BRCA: breast-related cancer; CDKN2A: cyclin-dependent kinase inhibitor 2A; MRI: magnetic resonance imaging; MRCP: magnetic resonance cholangiopancreatography; IPMN: intraductal papillary mucinous neoplasms.
* Yield is defined as the detection of any pathologically proven (pre)malignant lesion (≥PanIN2/IPMN and pancreatic adenocarcinoma) and lesions that are morphologically suspicious for branch-duct IPMNs.
¶ Includes only pathologically proven pancreatic neoplasms (histology or cytology).
Δ Continuation of Brentnall 1999, included 14 high-risk individuals from Brentnall 1999.
◊ Test performed only as an additional test for detected abnormalities.
§ Includes baseline and follow-up.
¥ Continuation of Langer 2009, includes high-risk individuals from this series.
Summary and recommendations
- An estimated 10 to 15% of pancreatic ductal adenocarcinomas (pancreatic cancers [PCs]) are attributable to genetic causes. PC aggregates in some families, and approximately 5 to 10% of individuals with PC have a family history of the disease. There are two broad categories of hereditary risk for PC:
- Genetic predisposition syndromes associated with PC (table 1)
- Familial pancreatic cancer (FPC), which is defined as a family with a pair of affected first-degree relatives (FDRs; parent-child or sibling pair) who do not meet criteria for a known PC-associated genetic predisposition syndrome
- A small but clinically important proportion of PC is associated with mutations in known predisposition genes (table 1). However, the gene causing most hereditary PC is not yet known.
- A detailed personal and family cancer history (in first- and second-degree relatives), including the type of cancer and age at diagnosis, and ancestry may help identify individuals with a hereditary predisposition to cancer. If the history suggests the possibility of a PC-associated genetic syndrome, patients should be referred for genetic counseling and genetic testing, as appropriate.
- Screening for PC aims to identify early invasive pancreatic cancers and pre-invasive lesions (intraductal papillary mucinous neoplasms and pancreatic intraepithelial neoplasia) with high-grade neoplastic changes. The benefits of screening include early detection and treatment of invasive pancreatic ductal adenocarcinomas, and identification of high-risk preinvasive neoplasms. However, screening for PC in high-risk individuals has not been demonstrated to improve survival. Other risks associated with screening include procedure related complications, over-diagnosis, and false positives.
- Screening for PC should preferably be performed in the setting of a research protocol at an experienced centers with a multidisciplinary team. Screening is not appropriate for patients who are not surgical candidates.
We screen the following individuals for PC:
- FDRs of patients with PC from a familial PC kindred with at least two affected FDRs
- Patients with Peutz-Jeghers syndrome (PJS)
- CDKN2A(p16), BRCA1, BRCA2, PALB2, and Lynch syndrome mutation carriers with one or more affected FDRs
- Patients with hereditary pancreatitis
- We perform endoscopic ultrasonography (EUS) and/or magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP). We begin screening at age 45 to 50, or 10 to 15 years younger than the youngest relative with pancreatic cancer. In patients with PJS, we begin screening at age 30.
Screening should begin earlier in people who have ever smoked, given that smokers from pancreatic cancer-prone families develop cancer on average a decade earlier than non-smokers.
- In patients with a normal pancreas on imaging, repeat pancreatic imaging (EUS and/or MRI/MRCP) can be performed every one year. We do not perform prophylactic surgery in asymptomatic individuals without an identifiable lesion, given the short-term risks of pancreatectomy and the metabolic consequences, including permanent exocrine insufficiency and diabetes.
- For those with detected lesions, pancreatic surveillance intervals are influenced by the size and type of lesion (solid versus cystic), growth rate, and concerning features (table 3). For management of pancreatic lesions that are detected during screening and surveillance testing, individualized decision-making for surveillance and treatment within multidisciplinary programs is recommended.
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