Digestive and Liver Disease
Volume 42, Issue 9 , Pages 597-605, September 2010

Familial pancreatic cancer in Italy. Risk assessment, screening programs and clinical approach: A position paper from the Italian Registry

  • Marco Del Chiaro

      Affiliations

    • Division of General and Transplant Surgery, Pisa University Hospital, Via Paradisa, 2, 56124 Cisanello, Pisa, Italy
    • Corresponding Author InformationCorresponding author. Tel.: +39 050996926.
    • ,
  • Alessandro Zerbi

      Affiliations

    • Pancreatic Surgery Section, Department of Surgery, IRCCS Istituto Clinico Humanitas, Rozzano, Milan, Italy
    • ,
  • Gabriele Capurso

      Affiliations

    • Digestive and Liver Disease Unit, University “La Sapienza”, Rome, Italy
    • ,
  • Giuseppe Zamboni

      Affiliations

    • Department of Pathology, University of Verona, Italy
    • ,
  • Patrick Maisonneuve

      Affiliations

    • European Institute of Oncology, Milan, Italy
    • ,
  • Silvano Presciuttini

      Affiliations

    • University of Pisa, Department of Biology, Italy
    • ,
  • Paolo Giorgio Arcidiacono

      Affiliations

    • Division of Gastroenterology and Gastrointestinal Endoscopy, Vita-Salute San Raffaele University, Milan, Italy
    • ,
  • Lucia Calculli

      Affiliations

    • Department of Radiology, University of Bologna, Italy
    • ,
  • Massimo Falconi

      Affiliations

    • Surgical and Gastroenterological Department, University of Verona, Italy

Received 7 April 2010; accepted 22 April 2010. published online 03 June 2010.

Article Outline

Abstract 

In Italy, pancreatic cancer is the fifth leading cause of tumor related death with about 7000 new cases per year and a mortality rate of 95%. In a recent prospective epidemiological study on the Italian population, a family history was found in about 10% of patients suffering from a ductal adenocarcinoma of the pancreas (PDAC). A position paper from the Italian Registry for Familial Pancreatic Cancer was made to manage these high-risk individuals. Even though in the majority of high-risk individuals a genetic test to identify familial predisposition is not available, a screening protocol seems to be reasonable for subjects who have a >10-fold greater risk for the development of PDAC. However this kind of screening should be included in clinical trials, performed in centers with high expertise in pancreatic disease, using the least aggressive diagnostic modalities.

Keywords: Family history, Pancreas, Surveillance protocol

 

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1. Introduction 

In Italy, pancreatic cancer is the fifth leading cause of tumor related death [1] with about 7000 new cases per year and a mortality rate of 95% [2]. In a recent prospective epidemiological study on the Italian population, a family history was found in about 10% of patients suffering from a ductal adenocarcinoma of the pancreas (PDAC) [3]. Similar rates have been reported in other studies. In this population subset at risk for PDAC, different surveillance programs have been proposed in order to achieve an early diagnosis of the disease. However, as yet there is not a “gold standard” as regards inclusion criteria and screening modalities.

In April 2007, a National Registry for Familial Pancreatic Cancer was instituted by the Italian Association for the Study of the Pancreas (AISP) (www.cancropancreas.org). One of the most important missions of the Registry was to define a position statement for both the definition of risk and the establishment of a surveillance protocol for people with a family history of pancreatic cancer in Italy. To accomplish this task, a consensus meeting was held in Pisa (Pisa Expert Consensus Statement on Familial Pancreatic Cancer) (see Acknowledgments) in June 2009. The working group formulated 4 main topic areas, each of these in turn containing numerous questions. The answers to these questions were discussed and approved during the consensus conference and are herein reported, constituting the aim of this paper.

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2. Definition of non-genetic and genetic risk for pancreatic cancer 

2.1. Which are the non-genetic risk factors? 

Most cases of PDAC are caused by non-genetic (environmental) risk factors as summarized in Table 1 [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37]. Many of them, such as smoking and overweight, may be controlled by a definite health policy, with the potential of saving lives, and eventually reducing costs as a result of curing PDAC. Smoking is by far the major environmental risk factor for PDAC. Smoking causes a 75% increase in the risk of developing PDAC, and explains at least 25% of all PDAC cases [4]. The risk is dose and time related, with former smokers still at risk for at least 10 years after quitting smoking. It has been calculated that if all smokers would quit, the number of new cases of pancreatic cancer in the EU could be reduced by at least 15% [5]. Smoking is also associated with an higher risk of cancer and a younger age of onset, in sporadic cases [6], [7], in subjects with family history of pancreatic cancer [8], and those with hereditary or chronic pancreatitis [9], [10].

Table 1. Non-genetic factors consistently associated with an increased risk of pancreatic ductal adenocarcinoma (PDAC).
Risk factor for PDACEstimated OR compared to non-exposedaReferences
Smoking1.75[4], [5], [7]
Overweight/obesity1.12 per increased 5kg/m2[12], [13], [14], [15], [16], [17]
Heavy alcohol drinking1.2[7], [8], [11], [18], [19]
Type I diabetes2[23]
Long standing Type II diabetes1.5[24]
New onset Type II diabetes2[24], [25]
Chronic pancreatitis14[10], [27]
Exposure to nickel1.9[28]
Previous gastric ulcer1.8[29], [30]

aThe reported odds ratio are estimated data obtained from the literature, taking into account the highest quality evidence when available (i.e. meta-analyses or large cohort studies).

However, these non-genetic risk factors, as pointed out in Table 1, are associated with only a moderately increased risk of developing PDAC. For this reason, it is currently accepted that a screening program is not worthwhile for subjects with non-genetic risk factors, even if it may have some role in reducing the overall risk for individuals at “hereditary” risk for PDAC.

2.2. Which conditions/hereditary syndromes increase the risk of pancreatic cancer and by how much? 

Although the genetic defect responsible for the majority of cases of familial pancreatic cancer (FPC) has not yet been detected, there is a growing list of germline diseases which markedly increase the risk of PDAC [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59] (Table 2). These syndromes are primarily defined by a clinical phenotype, with pancreatic cancer not being the leading one, and include familial atypical multiple mole melanoma (FAMMM), Peutz–Jeghers syndrome (PJS), hereditary pancreatitis (HP), hereditary non-polyposis colorectal carcinoma (HNPCC), familial breast and ovarian cancer (FBOC), cystic fibrosis (CF), familial adenomatous polyposis (FAP), ataxia telangiectasia (AT) and Fanconi anemia (FA). Most of the diseases are inherited in an autosomal dominant pattern except for CF, AT and FAN, which are autosomal recessive diseases. In contrast, the term FPC is used in the context of families having at least two first-degree relatives with PDAC in the absence of an accumulation of other cancers or diseases which are known to be familial. Other conditions such as Multiple Endocrine Neoplasia Type 1 (MEN-1), Von Hippel-Lindau disease (VHL) and rarer conditions, such as neurofibromatosis type 1 and tuberous sclerosis, have been associated with endocrine tumors of the pancreas.

Table 2. Genetic factors consistently associated with an increased risk of pancreatic ductal adenocarcinoma (PDAC).
Individuals, SyndromeGene (Chrom. locus)Relative riskRisk by age 70Cancer at other sitesReferences
None–10.5%None

Exocrine pancreatic tumors
Familial pancreatic cancerUnknown None[38]
1 or more first-degree relative(s) 9.04%
1 first-degree relative 4.52%
2 first-degree relatives 6.43%
3 or more first-degree relatives 3216%

Northwest U.S. cohort (Seattle Cohort)PALLD (4q32–34)>100>50%None[39], [40]
Breast and ovarian cancer syndromes (FBOC)BRCA2 (13q12.3)3.5–105%Breast, ovary, prostate[41]
BRCA1 (17q21)2.31%Breast, ovary, prostate, peritoneum, skin, lung[42]
Hereditary non-polyposis colon cancer (HNPCC) or Lynch Syndrome IIMSH2 MLH1 MSH6 PMS PMS2 (2p22–p21, 3p21.3)4.7<5%Colorectal, endometrium, stomach, ovary, ureter, renal, pelvis, biliary tract, brain[43], [44], [45]
Familial adenomatous polyposis (FAP)APC (5q21–q22)4.52%Ampullary cancer[46], [47]
Cystic fibrosis (CF)CFTR (7q31.2)5.3<5%Digestive cancers[48]
Hereditary pancreatitis (HP)PRSS1 (7q35)50–7040%None[49], [50]
Familial atypical multiple mole melanoma (FAMMM)CDKN2A/P16 (9p21)34–3917%Melanoma, breast[51], [52]
Peutz–Jeghers syndrome (PJS)LKB1/STK11 (19p)13230–60%Gastroesophageal, small bowel, colorectal and breast[53]
Fanconi anemia (FA)FA (multiple incl. 3p22–26, 9p13, 9q22.3, 16q24.3)UnknownUnknownAcute myeloid leukemia, head and neck cancer[54], [55]
Ataxia telangiectasia (AT)ATM (11q22.3)3UnknownBreast cancer[56]
Li-Fraumeni syndrome (LFS1)TP53 (17p13.1)UnknownUnknownMultiple tumors[57]

Endocrine pancreatic tumors
Von Hippel-Lindau syndrome (VHL)VHL (3p25)Unknown5–17%Multiple tumors[58]
Multiple Endocrine Neoplasia Type 1 (MEN)MEN1 (11q13)Unknown68%Parathyroid, anterior pituitary[59]

While no more than 5–10% of all pancreatic cancers are diagnosed at an early age (<50 years), the proportion of early onset PDAC is much higher in familial or hereditary pancreatic cancer [60]. Among pancreatic cancer families, the risk of developing PDAC is higher in younger subjects and could be modified by other non-genetic risk factors, such as exposure to tobacco [8], [61]. Not only do smokers have a two- to three-fold greater risk of developing the disease as compared to non-smokers, but they generally develop the disease at an earlier age.

A statistical model with associated software (PancPRO) has recently been developed for estimating the probability that an individual carries a mutation in a major susceptibility gene (or gene effect), based on his or her family history of PDAC, and for further estimating the probability of developing PDAC in his or her future years [62]. PancPRO was formulated by extending the Bayesian modeling framework developed for BRCAPRO, trained using published data, and validated using independent prospective data on 961 families enrolled in the National Familial Pancreas Tumor Registry, including 26 individuals who developed incidental pancreatic cancer during follow-up. The results may give useful information about an individual's pancreatic cancer risk before he or she decides to undergo invasive screening and for researchers to enroll individuals at high-risk for screening and genetic studies.

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3. Pre-neoplastic lesions of the pancreas 

3.1. Which pancreatic lesions are precancerous? What kind of evolution do they have and at what stage are they detectable? What is their prognosis? 

Different non-invasive precursor lesions can give rise to invasive carcinoma of the pancreas [63]. The early detection of these lesions offers the potential of reducing mortality. The careful study of surgically resected pancreata from patients with a strong family history of PDAC has demonstrated that many patients had multifocal, microscopic pancreatic intraepithelial neoplasms (PanINs), associated with potentially clinically detectable lobulocentric atrophy. The other two well-known precursor lesions are mass-forming lesions: intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs). Their clinical detection and treatment can interrupt the progression to invasive cancer and might potentially save lives [64].

Pancreatic intraepithelial neoplasia (PanIN): a microscopic papillary or flat non-invasive epithelial neoplasm arising in the small pancreatic ducts, usually <5mm in diameter. PanINs are characterized by columnar to cuboidal cells with varying amounts of mucin and degrees of cytologic and architectural atypia [65]. PanIN lesions (including lesions which were formerly called ductal non-papillary or papillary hyperplasia), characteristically occurring in the intralobular ducts, are clinically silent. Early lesions, PanIn-1A and PanIN-1B, show minimal cytological and architectural atypia. PanIn-2 lesions show mild to moderate cytological and architectural atypia with frequent papillary formation. PanIN-3 lesions are characterized by severe cytological and architectural atypia. The immunohistochemical profile shows positivity for MUC1, for gastric foveolar mucin MUC5AS and pyloric gland mucin MUC6, and negativity for intestinal mucin MUC2 and intestinal differentiation marker CDX2 [66], [67]. Cyclin D1 and cycloxigenase-2 (COX-2) are unregulated; the sonic hedgehog pathway is activated and over expressed with the progression of the PanIN grade of atypia [67], [68], [69].

The evidence of the neoplastic nature of PanINs derives from many observations: (i) post-mortem studies have shown an increased prevalence of PanINs with age as well as an increased cancer rate [70], (ii) strong association with invasive cancer in the resected specimen [71] and (iii) their presence in pancreata surgically resected from patients with a strong family history of pancreatic cancer [72]. PanIN lesions have been integrated into a tumor progression model for ductal carcinoma which links the morphological changes in the duct epithelium with genetic alterations. Early genetic alterations include telomerase shortening and KRAS2 activation; intermediate alterations include the inactivation of the tumor suppressor gene p16/CDKN2A and late alterations are the inactivation of the TP53 and DPC4/SMAD4 tumor suppressor gene [65]. The possibility of clinically identifying even low-grade PanINs depends on their association with secondary lobular parenchymal atrophy, the only lesion which can be preoperatively detected with endoscopic ultrasound [72].

Intraductal papillary mucinous neoplasms (IPMNs): they represent a heterogeneous group of neoplasms, classified as “main duct type” when they arise in the main pancreatic duct, as “branch duct type” when they arise in the secondary branches of the main duct and “combined type” when they involve both the main and branch ducts. IPMNs are classified into three grades of dysplasia using the histological system which is similar to that used for PanINs and MCNs. They are also divided into at least four cell types on the basis of their morphology and mucin immunophenotype: (i) MUC2+, CDX2+ intestinal type with a good prognosis, (ii) MUC2−/CDX2−/MUC1+ pancreatobiliary type with a poorer prognosis, (iii) MUC5AC+/MUC6+ and MUC1−/MUC2−/CDX2− gastric foveolar type with frequent involvement of branch ducts and (iv) MUC1+/MUC2+/CDX2− oncocytic types which are not yet well characterized clinically. The invasive component, present in approximately one-third of cases, shows either a tubular or a mucinous invasive component. The tubular invasive pattern resembles conventional ductal carcinoma while the mucinous pattern shows the features of colloid (mucinous non-cystic) carcinoma. While MUC2+ intestinal IPMNs can be considered precursors of MUC2+ mucinous non-cystic carcinoma, characterized by a good prognosis, MUC2−/MUC1+ pancreatobiliary IPMNs appear to have a close relationship to aggressive tubular carcinoma [73], [74]. The progression from benign IPMNs to malignancy can be radiologically detected, considering either an increase in the diameter of the main duct or the cyst, or the emergence of a mural nodule [75].

Interestingly, IPMNs can be associated with familial syndromes. They have been detected in asymptomatic members of familial pancreatic cancer kindred [76], in patients with Peutz–Jeghers syndrome (PJS), with inactivation of the STK11/LKB1 gene [77] and in association with familial adenomatous polyposis (FAP) [78]. These findings highlight the fact that, in these patients, screening for curable pancreatic neoplasia may be possible.

Mucinous cystic neoplasms (MCNs): they almost exclusively affect women, predominantly involve the tail of the pancreas, do not communicate with the ductal system and are usually accompanied by the characteristics of ovarian-type stroma [63], [79], [80]. Invasive carcinoma is present in approximately one-third of patients, and usually resembles common ductal adenocarcinoma. Patients with invasive MCNs are significantly older than patients with non-invasive MCNs (10–15 years older). As in the development of ductal carcinomas, KRAS2 mutations are early events while TP53 and DPC4/SMAD4 inactivation is a relatively late genetic alteration in the progression of non-invasive to invasive MCNs [81], [82]. MCNs can be detected early by computed tomography (CT), magnetic resonance imaging (MRI) or endoscopic ultrasound (EUS).

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4. Sensibility and specificity of available diagnostic tools 

4.1. Which lesions can be detected by CT scan and MRI? What is their sensitivity and specificity? What is the risk for the patient when undergoing these exams? 

No reports are available regarding the possibility of detecting PanIN lesions using CT scans or magnetic resonance (MRI). However, CT and MRI have an important role in detecting small pancreatic tumors in high-risk individuals or other pre-neoplastic lesions, such as IPMNs or MCNs. It should be noted that, in the last few years, there has been an improvement in imaging technology, such as the development of 64-slice multi-detector CT (MDCT) scans and 3T MRI scanners which can detect a small tumor in an asymptomatic patient population [83]. Today, with CT and MRI, it is possible to detect solid lesions greater than 1cm, indirect signs (such as black and white sign) in cases of lesions less than 1cm in diameter and cystic lesions equal to or greater than 3mm [84], [85], [86]. CT is the technique of choice for detecting pancreatic cancer because it is widely available. Findings of altered pancreatic attenuation or a focal mass with or without pancreatic duct dilatation or isolated pancreatic duct dilatation with an abrupt transition should be considered suspicious for pancreatic cancer on CT [87]. In patients with a suspected pancreatic mass not satisfactorily identified on a high quality MDCT exam, MRI imaging may be considered as a second-line imaging modality [88]. The sensitivity of MRI can be increased by the use of secretin administration for the study of the pancreatic ducts (MRCP); duct distension achieved after secretin administration improves both the quality of the examination and lesion detection [87]. Although the role of MRI in assessing pancreatic malignancy is evolving, some factors contribute in limiting its use as a first-line diagnostic tool for this purpose. They are mainly related to the need for patient cooperation to reduce motion and breathing artefacts which can severely compromise the quality of the examination. Other limits are the reduced availability of the technique at least in Italy and its inherent costs. Currently, MRI is used in patients with an inconclusive CT diagnosis or in suspected masses without contour deformity of the pancreas. MRI can also be considered an alternative preoperative staging exam in patients with allergies to iodinated contrast agents and in patients with renal insufficiency. A meta-analysis has revealed a sensitivity of 84% for MRI versus 91% for helical CT in detecting PDAC [84]. In patients under 40 years of age, the risk of excessive radiation exposure due to repeated screening CT studies remains a valid concern. Therefore, non-ionizing radiation benefits and the superior contrast resolution of MRI imaging can also be utilized for screening high-risk individuals, eventually in association with other low invasive modalities. However, CT and MRI can also be considered complementary examinations in the screening of high-risk subjects. In fact, CT is the gold standard for evaluating solid tumors of the pancreas and for defining, for example, the wall characteristics of cystic lesions. On the other hand, MRI is the best tool for defining the characteristics of the pancreatic ducts and communication between the cystic lesions and the main duct.

4.2. Which lesions can be detected by EUS? What is its sensitivity and specificity? What is the risk related to the procedure? 

Endoscopic ultrasound (EUS) has emerged as an extremely powerful imaging modality for studying pancreatic diseases, either inflammatory or tumoral. This evidence makes it a good candidate as a screening modality. In several studies, EUS has shown a high sensitivity and specificity, and a negative predictive value for pancreatic malignancy. Some comparative studies with helical and multi-detector helical CT have shown superior results for EUS, both in detecting small pancreatic tumors and in staging the tumor and the regional lymph nodes in patients who have potentially resectable PDAC [89], [90]. In experienced hands, EUS can detect pancreatic neoplasms as small as 5mm [91]. In a review, Hunt and Faigel pooled data from four studies, comparing the accuracy of EUS and dual phase helical CT in the evaluation of PDAC [92]. They noted that EUS detected more tumors (97% versus 73%, respectively), it was more accurate in determining tumor resectability (91% versus 73%, respectively), and more sensitive in detecting vascular involvement (91% versus 64%, respectively). However, newer and more sophisticated multiphase helical CT scans have shown better accuracy in detecting small cancers. DeWitt et al. compared EUS with MDCT for detecting and staging PDAC and concluded that EUS was significantly superior for tumor detection (98% versus 86%, respectively), but equivalent for nodal staging and assessment respectability [93]. Furthermore, EUS-guided fine needle aspiration (EUS-FNA) has emerged as an effective technique for the histologic diagnosis of cancer and a means for detecting dysplasia in precancerous lesions [94], [95]. There is currently no evidence that PanINs can be diagnosed by imaging tests, even if a recent study by Brune et al. [72] suggests that morphologic changes in the pancreatic parenchyma adjacent to PanIN lesions may be detectable by EUS. They demonstrated that multifocal PanINs are frequently associated with lobulocentric forms of pancreatic parenchymal atrophy, which is detectable by EUS.

An EUS-based screening program was first proposed by Brentnall et al. [40], reporting a small prospective cohort study in 14 high-risk patients. The study compared a CT-based approach to one using both EUS and endoscopic cholangio-pancreatography (ERCP). In this study, every patient with an abnormal EUS and ERCP who opted for a tissue diagnosis had precancerous changes in the pancreas (PanIN 2 and 3). Canto and colleagues have reported their experience with EUS-based screening in a prospective controlled study [76]. Seventy-eight high-risk patients and 149 control patients were studied. If the EUS was abnormal, EUS-FNA and ERCP were performed. They demonstrated a high prevalence of chronic pancreatitis-like changes (72% by EUS and 68% by ERCP) which were significantly more common and severe in high-risk patients as compared to control subjects, and were related neither to alcohol intake nor age [96]. In addition, 10% of the high-risk patients treated by subtotal pancreatectomy had precursor lesions for PDAC consisting of IPMNs. The chronic pancreatitis changes in high-risk individuals suggest a link between chronic pancreatitis and PDAC. The EUS features of chronic pancreatitis should be carefully studied during screening because these abnormalities can be confusing, thus interfering with the accurate identification of early pancreatic neoplasms. These experiences provide convincing evidence that intensive EUS-based screening can detect PDAC and its early precursor lesions. However, the cost-effectiveness of screening is unknown. Rulyak et al. used a decision analysis to compare one-time screening for PDAC with EUS to no screening in a hypothetical cohort of 100 members of FPC kindred [97]. They demonstrated that endoscopic screening of high-risk family members appears to increase patient life expectancy in a cost-effective manner, although testing should be limited to centers specializing in pancreatic disorders.

Moreover, EUS complications are infrequent in high volume centers and the perforation rate is usually considered similar to standard upper GI endoscopy (<0.03%). EUS-FNA-related complications consist in pancreatitis, haemorrhage, and infection [98]. The reported pancreatitis rate is between 0 and 2% [99], [100], [101] and the bleeding rate varies from 0 to 1.3% [102], [103], [104], [105]. The procedure is a considered at ‘low-risk’ for infectious complications, and antibiotic prophylaxis is indicated only when mucinous cystic lesions are involved [106], [107], [108], [109]. In a recent large series, no deaths were reported [99], [100], [101], [102], [103], [104], [105], [106], [107].

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5. Definition of high-risk populations, screening modalities and therapeutic decisions 

Following the first reports on FPC, many surveillance programs were developed around the world for individuals with a family history of pancreatic cancer. However, today a “gold standard” protocol is not available.

The actual goal in the screening of FPC is the possibility of detecting precursor lesions, such as PanIN 3, mucinous cystadenomas, IPMNs, or early stage cancer. Since PDAC is frequently a systemic disease at the moment of the diagnosis, some data suggest that a small (early) lesion [91] without lymph nodes metastases [108] is associated with a better prognosis.

The first report of an FPC surveillance program comes from Washington University [40]. This study included three families with a strong history of PDAC. The aim was to detect pancreatic cancer precursor lesions (PanINs) using EUS and ERCP. The EUS signs arousing suspicion of PanINs were: no specific gland changes (similar to those due to chronic pancreatitis and alcohol consumption). The ERCP signs arousing suspicion were an irregular duct, and the narrowing, dilatation or poor filling of the pancreatic ducts. In all patients with an abnormal EUS and ERCP who underwent a biopsy, the specimens included pancreatic cancer precursor lesions (PanIN 2 and 3). Another study, published by the same group [110], on a large cohort of 43 patients from 24 families reported the use of EUS as the first diagnostic approach. ERCP was used for patients with EUS abnormalities. Twelve patients with imaging abnormalities were referred to surgical biopsy and PanIN 2 and 3 were found in all of them. All patients were treated by total pancreatectomy; the resection specimens had no evidence of cancer but, all of the cases revealed widespread precancerous (PanIN) lesions.

Another early surveillance program was done at Johns Hopkins University. The first approach was represented by EUS and CT scan; an ERCP was performed in case of doubtful lesions at EUS. This protocol was reserved mostly for high-risk individuals (≥3 affected relatives). From the first series of 38 patients evaluated, two of the six pancreatic masses detected were neoplastic (one adenocarcinoma and one IPMN); the other four masses were benign lesions [111]. In a more recent series [76], the same group analyzed the results of a prospective study comparing 78 high-risk patients (72 from FPC kindred and 6 PJS) and 149 control patients. Ten percent of the high-risk patients had histologically confirmed neoplasia (6 patients had a benign IPMN, 1 had an IPMN which progressed to invasive cancer and 1 had a PanIN).

Today, many screening protocols are available throughout the world; the most important are reported in Table 3 [112].

Table 3. The most widely used screening protocols available throughout the world.
CenterJohns HopkinsEUROPACWashington UniversityGerman Case Collection of FPC
Inclusion criteria1: ≥2 first-degree relatives with PDAC1: 2 first-degree relatives with PDAC1: 2 or more first-degree relatives with PDAC1: Two first-degree relatives with PDAC
2: PJS2: 3 or more relatives with PDAC2: 1 first-degree relative diagnosed with PDAC before 50 years of age
3: Families with mutations that can lead to PDAC (for example BRCA2 mutations) if a first- or second-degree relative had PDAC3: 2 or more second degree relatives with PDAC, one before 50 years of age

Screening modalitiesBaseline EUS/CT scan. If EUS was abnormal, EUS-fine-needle aspiration and ERCP are performedBaseline EUS/CT scan and ERCP with aspiration of pancreatic juice. Screening for K-ras mutations in the pancreatic juice.EUS. If abnormal or alarming symptoms, ERCP should also be performed. Pancreatic tumor-markers, such as CA19-9 and CEA are always measured in serumEUS. If abnormal or alarming symptoms, ERCP should also be performed. Pancreatic tumor-markers, such as CA19-9 and CEA are always measured in serum. Screening for mutations: Everyone: BRCA2 and p16 mutations. Family history of pancreatitis: PRSS1 mutations. Family history of Peutz–Jeghers syndrome: LKBI mutations. Family history of _2 cases with HNPCC also mismatch repair gene mutations

Age for Inclusion1: PJS at least 30 yrs oldAt 40 years of age10 years before the youngest in the family developed PDAC, but not later than 50 years of age5 years before the youngest in the family developed PDAC, but not later than 50 years of age
2: FPC≥40 yrs or 10 years younger than the age of youngest relative with pancreatic cancer

Screening intervalHigh-risk subjects with an abnormal EUS who did not have surgery were offered follow-up EUS/FNA and CT scan within 3–6 months to assess the stability of the abnormalities. All patients were offered repeated EUS within 1 year from the baseline evaluation1: K-ras mutations in pancreatic juice: EUS/CT scan and ERCP with PJ aspiration every yearYearly. If ERCP is required but normal, EUS is repeated within 3–12 monthsYearly. If ERCP is required but normal EUS is repeated within 3–12 months
2: K-ras mutations EUS/CT scan and ERCP with PJ aspiration every third year

PDAC: pancreatic ductal adenocarcinoma; PJS: Peutz–Jeghers syndrome; EUS: endoscopic ultrasound; PJ: pancreatic juice;

5.1. Who should participate in a surveillance program? 

According to a recently published paper from the Fourth International Symposium of Inherited Diseases of the Pancreas [113], a surveillance program should be recommended for patients who have a >10-fold greater risk for the development of PDAC. Several conditions are reported in this paper and in the literature which are associated with a 10-fold greater risk of developing pancreatic cancer. However, today, there are also mathematical models [62] to calculate the risk. In Table 4, the inclusion criteria we suggest for the screening of pancreas cancer are reported.

Table 4. Inclusion criteria for the screening program of pancreatic ductal adenocarcinoma (PDAC) in high-risk individuals.
≥3 first degree, second degree, third degree relatives with PDAC in the same lineage
Mutation carrier for BRCA2, BRCA1 or p16 with at least one first-degree or second-degree relative with PDAC
A verified germline carrier, of a PJS kindred
2 relatives in the same lineage (directly connected) affected with PDAC, at least one a first-degree relative of the candidate
An affected individual with hereditary pancreatitis
Subject with a 10-fold greater risk, using PancPRO software

5.2. When to begin a surveillance program? 

In the absence of clear indications from the literature on this topic, it seems reasonable to start at 45 years of age or 15 years earlier than the earliest occurrence of pancreatic cancer in the family, whatever the age. No benefit seems to be evident for an earlier screening for heavy smokers with respect to non-smokers [114].

5.3. Screening frequency 

There is no consensus on the frequency of a screening program. However, yearly screening seems to be the most suitable approach. A more aggressive protocol can be used for patients with a particularly strong risk or with a not completely negative evaluation at the last screening.

5.4. What kind of screening for FPC? 

Despite the fact that this issue is the one most debated, the majority of the Centers involved in FPC surveillance programs use EUS as the first imaging approach for screening. The advantages of EUS are its high sensitivity and the possibility of taking a bioptic sample. However, CT scans and ERCP are used and are also proposed in combination with EUS. Few data are available for MRCP. This technique seems to be very promising in the detection of both ductal and parenchymal lesions. In its conclusions, the paper from the Fourth International Symposium of Inherited Diseases of the Pancreas [113] strongly suggests that high-risk individuals should participate in a surveillance program, emphasizing that the screening should be performed by a Center with experience in the specific pathology. The working group also feels that screening programs should be carried out in centers with experience in pancreatic diseases. Screening protocols, mostly based on the use of EUS and MRCP, are recommended. More aggressive protocols including ERCP or the extensive use of CT should be avoided in healthy individuals who have only a statistical risk of cancer, such as subjects with a family history of pancreatic cancer. Moreover the opinion of the working group strongly emphasizes that high-risk individuals should follow a suitable lifestyle in order to reduce the risk of pancreatic cancer (avoid smoking, healthy diet high in fruits and vegetables, regular exercise, weight reduction if necessary and an increased intake of vitamin D).

5.5. Indications for surgery in high-risk individuals 

Making decisions regarding the treatment of subjects at high-risk for PDAC is as yet a topic on which there is little consensus. Only a few reports are available based on limited numbers; however, some indications can be given based on their findings.

If individuals considered at high-risk for the development of PDAC are asymptomatic with a negative screening, surgery is useless. In fact, it would involve all the risks and complications of the surgery with a high chance of removing a still healthy organ. Thus, a prophylactic pancreatectomy cannot be recommended in this setting. On the other hand, sometimes these individuals can show significant findings at screening exams. In this latter case, two different approaches can be followed. The first one, outlined by the studies of the Seattle group, suggests performing surgical procedures aimed at removing all pancreatic tissue in patients showing significant signs or histological findings compatible with dysplasia of the pancreatic ducts (PanIN-2 or 3) [40], relying on their role as precursors of PDAC [115]. The second approach, supported by the group of Johns Hopkins, is based on the early diagnosis of nodular or cystic pancreatic lesions and their removal through partial resections (pancreaticoduodenectomy or distal pancreatectomy) [111], [116].

According to Seattle's approach (also sustained by the Heidelberg group) [117], the goal is to remove all “precancerous” lesions involving the pancreatic ducts due to the demonstrated multicentricity of dysplastic areas. The indicated treatment is then a total pancreatectomy. Considering the relevance of the resection, the young average age of the patients undergoing surgery (approximately 40 years), and the difficulty of demonstrating these types of lesions through imaging, it has recently been suggested that a laparoscopic distal pancreatectomy be performed in patients with a positive screening and, only after the assessment of the histological examination of the surgical specimen, to subsequently proceed with a laparotomic completion of the pancreatectomy [118].

On the other hand, the approach of the Johns Hopkins group, also supported by the University of Cincinnati [119], is aimed at the removal of nodular or cystic lesions demonstrated by US-guided biopsies, by performing “typical” partial resections. Indications for surgery in this group of high-risk patients are quite extensive; they encompass cystic lesions smaller than 1cm, those arising from secondary ducts and even lesions without histology strongly suggestive of IPMNs. This aggressive attitude is also supported by observations which show an increased growth rate and the degeneration of IPMNs in this type of population and its association with PanIN [111], [116].

While choosing one or the other approach, we have to consider that a total pancreatectomy, even if performed in a high-volume Center, is not free from risk. In fact, it is frequently performed on young patients who are exposed to serious adverse events mostly related to glycemic control failure and its sequelae. Moreover, it is still unclear whether the lesions described will evolve to neoplasia or how long this will take. If a total pancreatectomy is performed, the possibility of pancreatic islet auto transplantation must be excluded due to seeding risk. In the literature, the case of a patient who needed to undergo pancreas transplantation is reported [120]. However, even in individuals without predisposition, the onset of PDAC in the pancreatic remnant has been reported after partial pancreatic resection for lesions with a histological finding showing severe ductal dysplasia [76].

At the moment, it remains very difficult to precisely define the best therapeutic approach for patients known to be at high-risk for developing PDAC, showing evidence of some alterations in the pancreatic parenchyma at imaging and/or pathology. The answer will come only from detailed prospective data collections, aimed at classifying the different types of pancreatic lesions and at recording not only the survival of these patients but also the timing and modalities of the development of pancreatic cancer.

A special mention should be reserved for individuals at high-risk for PDAC and affected by IPMNs. According to a recent paper [121], in these individuals, the surgical approach to branch duct IPMNs should be different from those suggested by the International guidelines on IPMNs: lesions less than 3cm in diameter without worrisome features, should be considered for surgery because they are potentially more aggressive in comparison to sporadic IPMNs [122].

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6. Conclusions 

Each year in Italy, about 700 new cases of PDAC with a “hereditary” origin occur. Given the aggressive nature of PDAC, a screening protocol for high-risk individuals seems to be appropriate. However, the majority of the high-risk individuals are healthy subjects with only a statistical risk of developing pancreatic cancer. In fact, the gene/s responsible for FPC has/have not yet been identified. The Italian Registry for Familial Pancreatic Cancer suggests developing a screening protocol for high-risk individuals; the modalities proposed are reported in Table 5.

Table 5. Recommendations from the Italian Association for the Study of the Pancreas (AISP) for screening in individuals at high-risk for pancreatic ductal adenocarcinoma (PDAC).
Inclusion Criteria for a Screening Program≥3 first, second, third-degree relatives with PDAC in the same lineage
Known mutation carrier for BRCA1, BRCA2 or p16, with at least one first-degree or second-degree relative with PDAC
A member, ideally a verified germline carrier, of a PJS kindred
Two relatives in the same lineage (directly connected) affected with PDAC, at least one a first-degree relative of the candidate
An affected individual with hereditary pancreatitis
A subject with at least a 10-fold greater PancPro risk of developing PDAC with respect to the general population

Screening modalitiesExclusive or complementary use of EUS, MRI
CT scan can be used but the radiologic risk should be considered

Start of screeningAt 45 years of age
15 years prior to the earliest age at which PDAC has occurred in the family

Timing for ScreeningYearly
More frequently in high-risk patients (for example, patients with not completely negative tests)

Target lesion for screeningSmall solid tumor
IPMN
MCN
PanIN (?)

PreventionAvoid smoking
Weight reduction if necessary
Healthy diet high in fruit and vegetables
Regular exercise
Increase intake of vitamin D
Perform abdominal US in patient with a recent onset of diabetes

SurgeryResection should be considered only for patients with “macroscopic” lesions, such as IPMNs, MCNs or solid tumors
The extent of resection remains controversial (total pancreatectomy vs. partial pancreatectomy)
The indication for surgery for IPMNs should be different (more aggressive) with respect to the International Guidelines due to the more aggressive nature in patients with a strong family history of PDAC

PJS: Peutz–Jeghers syndrome; EUS: endoscopic ultrasound; MRI: magnetic resonance; IPMN: intraductal papillary mucinous neoplasm; MCN: mucinous cystic neoplasm; PanIN: pancreatic intraepithelial neoplasia; US: ultrasound.

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Conflict of interest 

The authors declare that they have no conflict of interest.

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Acknowledgements 

The authors thank Claudio Bassi (Verona), Ugo Boggi (Pisa), Riccardo Casadei (Bologna), Gianfranco Delle Fave (Rome), Luca Frulloni (Verona), Rossella Graziani (Verona), Alberto Larghi (Rome), Massimiliano Muttignani (Rome), Michele Reni (Milan), Generoso Uomo (Naples) for their active participation at the meeting as experts, for their suggestions to the working group members and for their contribution to the present paper.

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PII: S1590-8658(10)00163-5

doi:10.1016/j.dld.2010.04.016

Digestive and Liver Disease
Volume 42, Issue 9 , Pages 597-605, September 2010

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