5.1.1. Introduction

Obstructive jaundice is the most common presenting symptom in people with pancreatic cancer, although it is to be noted that most people presenting with jaundice do not actually have pancreatic cancer.

There is currently uncertainty about the most accurate technique for diagnosing the disease in people with obstructive jaundice. CT scans are commonly used to diagnose pancreatic cancer in this group of people, however it is not always possible for the CT scan to visualise the cancer that is causing the obstruction. Ultrasound is another technique which can identify pancreatic cancer. MRI and fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT) are both increasingly being used but their diagnostic accuracy in this group of people is not clearly understood. Whether histology and cytology are needed to make the diagnosis of pancreatic cancer in someone with obstructive jaundice is uncertain, with some centres operating on imaging alone. There is also variation in practice as to how the histology and cytology are obtained. The role of cancer antigen 10-9 (CA 19-9) in combination with imaging is not defined.

In the group of people thought not suitable for resection based on imaging, brushing the duct (for cytology) at the time of ERCP and stenting is common. Where this does not confirm a diagnosis, endoscopic ultrasound (EUS) and fine needle aspiration (FNA) is usually done. However there are still a small group of people in whom the imaging is highly suggestive of malignancy but the cytology/histology does not confirm, leaving the question of what to do next.

Guidance is needed on the most effective diagnostic pathway to identify pancreatic cancer in people who have jaundice.

5.1.1.1. Review protocol summary

The review protocol summary used for this question can be found in Table 17. Full details of the review protocol can be found in Appendix C.

Table 17

Clinical review protocol summary for the review of most effective diagnostic pathway for people with suspected pancreatic cancer who have jaundice.

5.1.2. Description of Clinical Evidence

Six observational studies (n=806) - 1 multicentre prospective cohort study (n=159) and five single-centre retrospective cohort studies (n=647) - were included in the review. A summary of the included studies is presented in Table 18.

One study (n=47) reported on the diagnostic accuracy of spiral CT. This study was carried out in the USA and included patients with obstructive jaundice with a suspicion of pancreatic cancer (Agarwal et al. 2004).

One study (n=47) reported on the diagnostic accuracy of EUS. This study was carried out in the USA and included patients with obstructive jaundice with a suspicion of pancreatic cancer (Agarwal et al. 2004).

Five studies (n=691) reported on the diagnostic accuracy of EUS-FNA based cytology (Agarwal et al. 2004; Kim et al. 2015; Oppong et al. 2010; Ross et al. 2008; Tummala et al. 2013). All studies included patients with obstructive jaundice with a suspicion of pancreatic cancer. One study was conducted in the UK (Oppong et al. 2010), whilst the remaining 4 studies were conducted in the USA.

One prospective multicentre UK study (n=393) – known as PET-PANC - reported on the diagnostic accuracy of MDCT and FDG-PET/CT (Ghaneh et al. 2018) in patients with obstructive jaundice and a suspicion of pancreatic cancer. The main aim of the latter study was to assess - in a multicentre setting and using a standardised protocol - whether the addition of FDG-PET/CT to MDCT, which is standard practice in the UK, provides tangible diagnostic and staging benefits. Two studies (n=89) reported on the diagnostic accuracy of ERCP + brushings of biliary strictures (Oppong et al. 2010; Ross et al. 2008). Both studies included patients with obstructive jaundice with a suspicion of pancreatic. One study was conducted in the UK (Oppong et al. 2010), with the other study conducted in the USA (Ross et al. 2008).

All included studies reported on diagnostic accuracy outcome measures, whilst only 2 studies reported adverse effects or complications. Positive and likelihood ratios were calculated, where appropriate, from the raw diagnostic test accuracy data or the estimated sensitivity and specificity of the studies to enable evaluation of the relevant tests. The QUADAS-2 checklist was used to evaluate the risk of bias and indirectness (applicability) of the studies.

Further information about the search strategy can be found in Appendix D. See study selection flow chart in Appendix E, single and multiple test ROC curves and forest plots in Appendix H, summary of Risk of Bias in Appendix J, study evidence tables in Appendix F and list of excluded studies in Appendix G.

5.1.3. Summary of included studies

A summary of the studies that were included in this review is presented in Table 18.

Table 18

Summary of included studies.

5.1.4. Clinical evidence profile

The clinical evidence profiles for this review question are presented in Table 19 to Table 22.

Table 19

Summary of clinical evidence for CT to detect malignancy in people with jaundice.

Table 20

Summary of clinical evidence for EUS to detect malignancy in people with jaundice.

Table 21

Summary of clinical evidence for EUS-FNA cytology to detect malignancy in people with jaundice.

Table 22

Summary of clinical evidence for ERCP + brushings of biliary strictures to detect malignancy in people with jaundice.

Table 23

Summary of clinical evidence for FDG-PET/CT to detect malignancy in people with jaundice.

5.1.5. Economic evidence

A literature review of published cost effectiveness analyses did not identify any relevant studies for this topic. Although there were potential implications for resource use associated with making recommendations in this area, other topics in the guideline were agreed as a higher economic priority. Consequently, bespoke economic modelling was not done for this topic.

5.1.6. Evidence Statements

5.1.7. Recommendations

1.

For people with obstructive jaundice and suspected pancreatic cancer, offer a pancreatic protocol CT scan before draining the bile duct.

2.

If the diagnosis is still unclear, offer fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT) and/or endoscopic ultrasound (EUS) with EUS-guided tissue sampling.

3.

Take a biliary brushing for cytology if:

• endoscopic retrograde cholangiopancreatography (ERCP) is being used to relieve the biliary obstruction and
• there is no tissue diagnosis.

5.1.8. Evidence to recommendations

5.1.9. References

• Agarwal B, Abu-Hamda E, Molke KL et al. (2004) Endoscopic ultrasound-guided fine needle aspiration and multidetector spiral CT in the diagnosis of pancreatic cancer. American Journal of Gastroenterology 99(5): 844–50 [PubMed: 15128348]
• Ghaneh P, Hanson R, Titman A et al. (2018) PET-PANC: multicentre prospective diagnostic accuracy and health economic analysis study of the impact of combined modality ¹⁸fluorine-2-fluoro-2-deoxy-d-glucose positron emission tomography with computed tomography scanning in the diagnosis and management of pancreatic cancer. Health Technology Assessment 22(7) [PMC free article: PMC5817411] [PubMed: 29402376]
• Kim JJ, Walia S, Lee SH et al. (2015) Lower yield of endoscopic ultrasound-guided fine-needle aspiration in patients with pancreatic head mass with a biliary stent. Digestive diseases and sciences 60(2): 543–549 [PubMed: 25245115]
• Oppong K, Raine D, Nayar M et al. (2010) EUS-FNA versus biliary brushings and assessment of simultaneous performance in jaundiced patients with suspected malignant obstruction. Journal of the Pancreas 11(6): 560–567 [PubMed: 21068487]
• Ross WA, Wasan SM, Evans DB et al. (2008) Combined EUS with FNA and ERCP for the evaluation of patients with obstructive jaundice from presumed pancreatic malignancy. Gastrointestinal endoscopy 68(3): 461–466 [PubMed: 18384788]
• Tummala P, Munigala S, Eloubeidi MA et al. (2013) Patients with obstructive jaundice and biliary stricture±mass lesion on imaging: prevalence of malignancy and potential role of EUS-FNA. Journal of clinical gastroenterology 47(6): 532–537 [PubMed: 23340062]

5.2.1. Introduction

The availability and use of imaging, both ultrasound and CT, continues to increase in clinical practice and, as a consequence, incidental lesions are detected with increasing frequency. Incidental lesions in the pancreas, both solid and cystic, in asymptomatic people are a common finding. There is no consensus as to the most appropriate pathway to establish an accurate diagnosis in this patient group.

Pancreatic CT scanning is regarded as the mainstay of the imaging pathway, but the role of pancreatic MRI and FDG-PET/CT, although not well defined, is increasing.

In addition, the role of both cytology and histology and the best method of obtaining tissue to confirm the diagnosis has not been established. Imaging may also reveal metastatic disease, which could be sampled to help establish the diagnosis.

Guidance is needed on the most effective diagnostic pathway to identify pancreatic cancer in people who have a pancreatic abnormality on imaging.

5.2.1.1. Review protocol summary

The review protocol summary used for this question can be found in Table 24. Full details of the review protocol can be found in Appendix C.

Table 24

Clinical review protocol summary for the review of the most effective diagnostic pathway for people with suspected pancreatic cancer who do not have jaundice but have a pancreatic abnormality on imaging.

5.2.2. Description of clinical evidence

Twenty-one articles reporting a total of 32 datasets were identified: 3 of these were RCTs (Bang et al. 2012; Lee et al. 2014; Ramesh et al. 2015), 13 were prospective cohort studies (Bournet et al. 2015; Bournet et al. 2009; Fabbri et al. 2011; Harewood & Wiersema 2002; Iglesias-Garcia et al. 2007; Kliment et al. 2010; Krishna et al. 2009; Mishra et al. 2006; Seicean et al. 2016; Strand et al. 2014; Touchefeu et al. 2009; Wakatsuki et al. 2005; Wittman et al. 2006) and 5 were retrospective cohort studies (Fritscher-Ravens et al. 2002; Hikichi et al. 2009; Tamm et al. 2007; Yang et al. 2015; Yusuf et al. 2009). A summary of the included studies is presented in Table 25.

The majority of the studies examined the diagnostic test accuracy of EUS-FNA for detecting malignancy in patients with suspected pancreatic cancer due to a solid lesion identified through previous imaging (e.g. EUS, CT, MRI, ERCP). The majority of the studies reported sensitivity and specificity, as well as positive/negative predictive value. Three articles (Hikichi et al. 2009; Ramesh et al. 2015; Yusuf et al. 2009) contributed two sets of data to the review on EUS-FNA. The majority of the studies also used a composite ‘gold standard’ reference test generally comprised of histo-/cyto-pathology from surgery, and subsequent clinical and imaging follow-up results. The majority of the studies also reported that there were no procedure-related adverse events, serious or otherwise. No studies were found that examined percutaneous liver biopsy, laparoscopy + biopsy.

One single centre retrospective cohort study (n=117) examined the diagnostic accuracy of multidetector CT (Tamm et al. 2007) in detecting malignancy in solid lesions initially identified through imaging.

Two single centre cohort studies (n=330) – 1 prospective (n=213; Krishna et al. 2009) and 1 retrospective (n=117; Tamm et al. 2007) - examined the diagnostic accuracy of EUS in detecting malignancy in solid lesions initially identified through imaging. The sample in Krishna et al. (2009) had a low prevalence of malignant lesions (0.52) and included 15% patients whose lesions were revealed to be cystic by EUS-FNA.

Twenty-two datasets (n=2869) from 19 studies - 3 RCTs (Bang et al. 2012; Lee et al. 2014; Ramesh et al. 2015) and 16 (11 prospective and 5 retrospective) cohort studies - examined the diagnostic accuracy of EUS-FNA in detecting malignancy in solid lesions initially identified through imaging (Bournet et al. 2009, ²⁰¹⁵; Fabbri et al. 2011; Fritscher-Ravens et al. 2002; Harewood & Wiersema 2002; Hikichi et al. 2009; Iglesias-Garcia et al. 2007; Kliment et al. 2010; Krishna et al. 2009; Mishra et al. 2006; Seicean et al. 2016; Tamm et al. 2007; Touchefeu et al. 2009; Wakatsuki et al. 2005; Wittman et al. 2006; Yusuf et al. 2009). The majority of these studies used a 22-gauge needle to extract a cytological specimen. The number of included studies (≥4) allowed a meta-analysis of the diagnostic test accuracy data to be performed, which produces a summary point estimate of the sensitivity and specificity of EUS-FNA. Although there was not sufficient data to examine heterogeneity for covariates such as needle type and type of reference test, a subgroup analysis by type of study (RCT/prospective cohort vs retrospective cohort) was conducted.

Four studies (n=158) - 2 RCTs (Bang et al. 2012; Lee et al. 2014) and 2 prospective cohort studies (Strand et al. 2014; Wittman et al. 2006) - examined the diagnostic accuracy of EUS-core biopsy in detecting malignancy in solid lesions initially identified through imaging. The number of included studies (≥4) allowed a meta-analysis of the diagnostic test accuracy data to be performed, which produces a summary point estimate of the sensitivity and specificity of EUS-core biopsy. The two RCTs, which randomised participants to receive either EUS-FNA or EUS-core, both used fine biopsy (ProCore) needles (EUS-FNB), whilst the cohort studies used either FNB (Strand et al. 2014) or trucut (Wittman et al. 2006) biopsy needles (EUS-TNB).

One prospective cohort study (n=36) examined the diagnostic accuracy of combining EUS-FNA with EUS-Core (Wittman et al. 2006).

One multicentre retrospective cohort study (n=60) examined the diagnostic accuracy of percutaneous US-guided core in detecting malignancy in solid lesions initially identified through imaging (Yang et al. 2015).

One multicentre retrospective cohort study (n=15) examined the diagnostic accuracy of percutaneous US-guided FNA + core in detecting malignancy in solid lesions initially identified through imaging (Yang et al. 2015).

Positive and likelihood ratios were calculated, where appropriate, from the raw diagnostic test accuracy data or the estimated sensitivity and specificity of the studies to enable evaluation of the relevant tests. The QUADAS-2 checklist was used to evaluate the risk of bias and indirectness (applicability) of the studies.

5.2.3. Summary of included studies

A summary of the studies that were included in this review is presented in Table 25.

Table 25

Summary of included studies.

5.2.4. Clinical evidence profile

The clinical evidence profiles for this review question are presented in Table 26 to Table 33.

5.2.4.1. Computed tomography

Table 26

Summary of clinical evidence for computed tomography to detect malignancy in people without jaundice but who have a pancreatic abnormality on imaging.

5.2.4.2. Endoscopic ultrasonography (EUS)

5.2.4.2.1. EUS

Table 27

Summary of clinical evidence for EUS to detect malignancy in people without jaundice but who have a pancreatic abnormality on imaging.

5.2.4.2.2. EUS-FNA

Table 28

Summary of clinical evidence for EUS-FNA to detect malignancy in people without jaundice but who have a pancreatic abnormality on imaging.

Table 29

Pooled sensitivity and specificity of EUS-FNA by type of study.

5.2.4.2.3. EUS-Core (FNB or TNB)

Table 30

Summary of clinical evidence for EUS-guided core biopsy (FNB or trucut) to detect malignancy in people without jaundice but who have a pancreatic abnormality on imaging.

5.2.4.2.4. EUS-FNA + Core

Table 31

Summary of clinical evidence for EUS-FNA + Core to detect malignancy in people without jaundice but who have a pancreatic abnormality on imaging.

Percutaneous ultrasonography

5.2.4.2.5. Percutaneous US-guided Core

Table 32

Summary of clinical evidence for percutaneous US-guided core to detect malignancy in people without jaundice but who have a pancreatic abnormality on imaging.

5.2.4.2.6. Percutaneous US-guided FNA + Core

Table 33

Summary of clinical evidence for percutaneous US-guided FNA + core to detect malignancy in people without jaundice but who have a pancreatic abnormality on imaging.

5.2.5. Economic evidence

A literature review of published cost effectiveness analyses did not identify any relevant studies for this topic. Although there were potential implications for resource use associated with making recommendations in this area, other topics in the guideline were agreed as a higher economic priority. Consequently, bespoke economic modelling was not done for this topic.

5.2.6. Evidence statements

5.2.7. Recommendations

4.

Offer a pancreatic protocol CT scan to people with pancreatic abnormalities but no jaundice.

5.

If the diagnosis is still unclear, offer fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT) and/or EUS with EUS-guided tissue sampling.

6.

If cytological or histological samples are needed, offer EUS with EUS-guided tissue sampling.

5.2.8. Evidence to recommendations

5.2.9. References

• Bang JY, Hebert-Magee S, Trevino J et al. (2012) Randomized trial comparing the 22-gauge aspiration and 22-gauge biopsy needles for EUS-guided sampling of solid pancreatic mass lesions. Gastrointestinal Endoscopy 76(2): 321–327 [PMC free article: PMC4148209] [PubMed: 22658389]
• Bournet B, Selves J, Grand D et al. (2015) Endoscopic Ultrasound–guided Fine-Needle Aspiration Biopsy Coupled with a KRAS Mutation Assay Using Allelic Discrimination Improves the Diagnosis of Pancreatic Cancer. Journal of Clinical Gastroenterology 49(1): 50–56 [PubMed: 24798941]
• Bournet B, Souque A, Senesse P et al. (2009) Endoscopic ultrasound-guided fine-needle aspiration biopsy coupled with KRAS mutation assay to distinguish pancreatic cancer from pseudotumoral chronic pancreatitis. Endoscopy 41(06): 552–557 [PubMed: 19533561]
• Fabbri C, Polifemo AM, Luigiano C et al. (2011) Endoscopic ultrasound-guided fine needle aspiration with 22-and 25-gauge needles in solid pancreatic masses: a prospective comparative study with randomisation of needle sequence. Digestive and Liver Disease 43(8): 647–652 [PubMed: 21592873]
• Fritscher-Ravens A, Brand L, Knöfel WT et al. (2002) Comparison of endoscopic ultrasound-guided fine needle aspiration for focal pancreatic lesions in patients with normal parenchyma and chronic pancreatitis. The American Journal of Gastroenterology, 97(11): 2768–2775 [PubMed: 12425546]
• Ghaneh P, Hanson R, Titman A et al. (2018) PET-PANC: multicentre prospective diagnostic accuracy and health economic analysis study of the impact of combined modality ¹⁸fluorine-2-fluoro-2-deoxy-d-glucose positron emission tomography with computed tomography scanning in the diagnosis and management of pancreatic cancer. Health Technology Assessment 22(7) [PMC free article: PMC5817411] [PubMed: 29402376]
• Harewood GC and Wiersema MJ (2002) Endosonography-guided fine needle aspiration biopsy in the evaluation of pancreatic masses. The American Journal of Gastroenterology 97(6): 1386–1391 [PubMed: 12094855]
• Hikichi T, Irisawa A, Bhutani MS et al. (2009) Endoscopic ultrasound-guided fine-needle aspiration of solid pancreatic masses with rapid on-site cytological evaluation by endosonographers without attendance of cytopathologists. Journal of Gastroenterology 44(4): 322–328 [PubMed: 19274426]
• Iglesias-Garcia J, Dominguez-Munoz E, Lozano-Leon A et al. (2007) Impact of endoscopic ultrasound-guided fine needle biopsy for diagnosis of pancreatic masses. World Journal of Gastroenterology 13(2): 289 [PMC free article: PMC4065960] [PubMed: 17226911]
• Kliment M, Urban O, Cegan M et al. (2010) Endoscopic ultrasound-guided fine needle aspiration of pancreatic masses: the utility and impact on management of patients. Scandinavian Journal of Gastroenterology 45(11): 1372–1379 [PubMed: 20626304]
• Krishna NB, LaBundy JL, Saripalli S et al. (2009) Diagnostic value of EUS-FNA in patients suspected of having pancreatic cancer with a focal lesion on CT scan/MRI but without obstructive jaundice. Pancreas 38(6): 625–630 [PubMed: 19506529]
• Lee YN, Moon JH, Kim HK et al. (2014) Core biopsy needle versus standard aspiration needle for endoscopic ultrasound-guided sampling of solid pancreatic masses: a randomized parallel-group study. Endoscopy 46(12): 1056–1062 [PubMed: 25098611]
• Mishra G, Zhao Y, Sweeney J et al. (2006) Determination of qualitative telomerase activity as an adjunct to the diagnosis of pancreatic adenocarcinoma by EUS-guided fine-needle aspiration. Gastrointestinal Endoscopy 63(4): 648–654 [PubMed: 16564867]
• Ramesh J, Bang JY, Hebert-Magee S et al. (2015) Randomized trial comparing the flexible 19G and 25G needles for endoscopic ultrasound-guided fine needle aspiration of solid pancreatic mass lesions. Pancreas 44(1): 128–133 [PMC free article: PMC4272223] [PubMed: 25232713]
• Seicean A, Gheorghiu M, Zaharia T et al. (2016) Performance of the Standard 22G Needle for Endoscopic Ultrasound-guided Tissue Core Biopsy in Pancreatic Cancer. Journal of Gastrointestinal Liver Disease 25(2): 213–218 [PubMed: 27308653]
• Strand DS, Jeffus SK, Sauer BG et al. (2014) EUS – guided 22 – gauge fine – needle aspiration versus core biopsy needle in the evaluation of solid pancreatic neoplasms. Diagnostic Cytopathology 42(9): 751–758 [PubMed: 24550162]
• Tamm EP, Loyer EM, Faria SC et al. (2007) Retrospective analysis of dual-phase MDCT and follow-up EUS/EUS-FNA in the diagnosis of pancreatic cancer. Abdominal Imaging 32(5): 660–667 [PubMed: 17712589]
• Touchefeu Y, Le Rhun M, Coron E et al. (2009) Endoscopic ultrasound – guided fine – needle aspiration for the diagnosis of solid pancreatic masses: the impact on patient – management strategy. Alimentary Pharmacology & Therapeutics 30(10): 1070–1077 [PubMed: 19735232]
• Wakatsuki T, Irisawa A, Bhutani MS et al. (2005) Comparative study of diagnostic value of cytologic sampling by endoscopic ultrasonography – guided fine – needle aspiration and that by endoscopic retrograde pancreatography for the management of pancreatic mass without biliary stricture. Journal of Gastroenterology and Hepatology 20(11): 1707–1711 [PubMed: 16246190]
• Wittmann J, Kocjan G, Sgouros SN et al. (2006) Endoscopic ultrasound-guided tissue sampling by combined fine needle aspiration and trucut needle biopsy: a prospective study. Cytopathology 17(1): 27–33 [PubMed: 16417562]
• Yang RY, Ng D, Jaskolka JD et al. (2015) Evaluation of percutaneous ultrasound-guided biopsies of solid mass lesions of the pancreas: a center’s 10-year experience. Clinical Imaging 39(1): 62–65 [PubMed: 25043532]
• Yusuf TE, Ho S, Pavey DA et al. (2009) Retrospective analysis of the utility of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in pancreatic masses, using a 22-gauge or 25-gauge needle system: a multicenter experience. Endoscopy 41(05): 445–448 [PubMed: 19418399]

5.3.1. Introduction

The diagnosis of pancreatic cysts continues to increase in frequency as more people undergo cross sectional imaging.

The morphological identification of a cyst is straightforward on both MRI and CT but the identification of the exact nature of the cystic lesion continues to present diagnostic difficulty.

Three broad groups of cystic lesions can be identified; definitely malignant, definitely benign and indeterminate. There are features on imaging that suggest a cyst is suspicious in nature, but often these are not definitive.

The presence of mucin within the cyst and the measurement of markers such as Carcinoembryonic antigen (CEA) and amylase can help determine whether a lesion is benign or pre-malignant, and the role of cytology and histology is important.

Several diagnostic pathways have been suggested within the literature but there remains inconsistency within the UK as to the most effective method for diagnosis.

Guidance is needed on the most effective diagnostic pathway to identify cysts at high risk of malignancy in people with pancreatic cysts.

5.3.1.1. Review protocol summary

The review protocol summary used for this question can be found in Table 34. Full details of the review protocol can be found in Appendix C.

Table 34

Clinical review protocol summary for the review of most effective diagnostic pathway to identify the cyst(s) at high risk of pancreatic malignancy.

5.3.2. Description of Clinical Evidence

Thirty-five publications were included in this review: 2 of these were systematic reviews (Cao et al. 2016; Zhu et al. 2017), 6 were prospective cohort studies (Brugge et al. 2004; Cizginer et al. 2011; Frossard et al. 2003; Ghaneh et al. 2007; Pitman et al. 2013; Sperti et al. 2005), and 27 of them were retrospective cohort studies (Ardengh et al. 2007; Gaddam et al. 2015; Gerke et al. 2006; Hirono et al. 2012; Jang et al. 2014; Jin et al. 2015; Kamata et al. 2016; Kim et al. 2012; Kim et al. 2015; Lee et al. 2001; Linder et al. 2006; Moris et al. 2016; Nagashio et al. 2014; Nara et al. 2009; Oh et al. 2014; Oppong et al. 2015; Othman et al. 2012; Pais et al. 2007; Park et al. 2011; Pitman et al. 2010; Smith et al. 2016; Song et al. 2007; Sperti et al. 2001; Takanami et al. 2011; Talar-Wojnarowska et al. 2013; Wu et al. 2007; Zhang et al. 2010). A summary of the included studies is presented in Table 36.

Fourteen studies examined the diagnostic accuracy of cyst fluid analysis, cytology or imaging for distinguishing between mucinous cystic neoplasms (MCNs; including IPMNs) and non-mucinous cystic neoplasms (NMCNs) of the pancreas (Brugge et al. 2004; Cizginer et al. 2011; Frossard et al. 2003; Gaddam et al. 2015; Jin et al. 2015; Linder et al. 2006; Moris et al. 2016; Nagashio et al. 2014; Oh et al. 2014; Oppong et al. 2015; Park et al. 2011; Pitman et al. 2010; Song et al. 2007; Zhang et al. 2010).

Twenty studies examined the diagnostic accuracy of cyst fluid analysis, cytology or imaging for distinguishing between benign and potentially malignant or malignant pancreatic cystic lesions (PCLs) (Ardengh et al. 2007; Cao et al. 2016; Gerke et al. 2006; Ghaneh et al. 2018; Hirono et al. 2012; Jang et al. 2014; Kamata et al. 2016; Kim et al. 2012; Kim et al. 2015; Lee et al. 2011; Nara et al. 2009; Othman et al. 2012; Pais et al. 2007; Pitman et al. 2013; Smith et al. 2016; Sperti et al. 2001, Sperti et al. 2005; Takanami et al. 2011; Talar-Wojnarowska et al. 2013; Wu et al. 2007).

One study (Park et al. 2011) examined the diagnostic accuracy of cyst fluid analysis, cytology or imaging for distinguishing between both (i) MCNs and NMCNs and (ii) benign and potentially malignant PCLs.

One of the systematic reviews (Cao et al. 2016) aimed to evaluate the diagnostic value of serum CA 19-9 in identifying malignant PCLs and included 13 studies (n=1437). The other systematic review (Zhu et al. 2017) evaluated the morbidity and mortality associated with EUS-FNA for the diagnosis of PCLs, and included 40 studies (n=5147). Both systematic reviews were assessed as being of high methodological quality, but included very low to moderate quality evidence. See Table 36 for more details of the included studies.

Positive and likelihood ratios were calculated, where appropriate, from the raw diagnostic test accuracy data or the estimated sensitivity and specificity of the studies to enable evaluation of the relevant tests. The QUADAS-2 tool was used for assessing risk of bias and indirectness of included studies.

Further information about the search strategy can be found in Appendix D. See study selection flow chart in Appendix E, single and multiple test ROC curves and forest plots in Appendix H, summary of QUADAS-2 study quality evaluations in Appendix J, study evidence tables in Appendix F and list of excluded studies in Appendix G.

5.3.2.1. CEA

5.3.2.1.1. Cystic fluid CEA

Thirteen studies (n=1542) examined the diagnostic accuracy of cyst fluid CEA: 2 of these were prospective cohort studies (Brugge et al. 2004; Cizginer et al. 2011), whilst the remaining 11 were retrospective cohort studies. The median number of patients was 112 (range 52-226).

Nine studies focused on distinguishing between MCNs and NMCNs (Brugge et al. 2004; Cizginer et al. 2011; Gaddam et al. 2015; Jin et al. 2015; Linder et al. 2006; Moris et al. 2016; Nagashio et al. 2014; Oppong et al. 2015; Oh et al. 2014). One study examined the diagnostic accuracy of CEA for distinguishing between both types of cystic lesions (Park et al. 2011). The cut-off value of cystic fluid CEA used to differentiate pancreatic MCNs and NMCNs ranged from 5 to 6000 ng/ml, and were categorised as detailed in Table 35:

Table 35

Studies on cystic fluid CEA by cut-off level.

Three studies evaluated the diagnostic accuracy of cyst fluid CEA for distinguishing between benign from potentially malignant and malignant PCLs (Hirono et al. 2012; Othman et al. 2012; Talar-Wojnarowska et al. 2013). The cut-off value of cystic fluid CEA used to differentiate benign from malign cysts ranged from 30 to 6000 ng/ml, and were categorised as follow:

• 30-70 ng/ml: Hirono et al. 2012; Talar-Wojnarowska et al. 2013
• 6000 ng/ml: Othman et al. 2012

5.3.2.1.2. Serum CEA

One retrospective study (n= 85) conducted in Taiwan evaluated serum levels of CEA for the differential diagnosis of pancreatic cystadenoma (benign PLC) or cystadenocarcinoma (malign PLC) (Wu et al. 2007).

5.3.3. Summary of included studies

A summary of the studies that were included in this review is presented in Table 36

Table 36

Summary of included studies.

5.3.4. Clinical evidence profile

The clinical evidence profiles for this review are presented in Table 39 to Table 54

5.3.4.1. Cystic fluid or serum CEA

5.3.4.1.1. Cystic fluid CEA

Table 37

Summary of clinical evidence for meta-analyses of cystic fluid CEA to distinguish between mucinous cystic and non-mucinous cystic neoplasms of the pancreas.

Table 38

Summary of clinical evidence for other studies on cystic fluid CEA at various cut-offs to distinguish between mucinous cystic and non-mucinous cystic neoplasms of the pancreas.

Table 39

Summary of clinical evidence for studies on cystic fluid CEA to distinguish between (potentially) malignant and benign pancreatic cystic lesions.

5.3.4.1.2. Serum CEA

Table 40

Summary of clinical evidence for studies on serum CEA to distinguish between benign and (potentially) malignant pancreatic cystic lesions.

5.3.4.2. Cystic fluid or serum CA 19-9

5.3.4.2.1. Cystic fluid CA 19-9

Table 41

Summary of clinical evidence for meta-analysis of cystic fluid CA 19-9 to distinguish between mucinous cystic and non-mucinous cystic neoplasms of the pancreas.

5.3.4.2.2. Serum CA 19-9

Table 42

Summary of clinical evidence for studies on serum CA 19-9 to distinguish between malignant and benign pancreatic cystic lesions.

5.3.4.3. Cytology: EUS-FNA

Table 43

Summary of clinical evidence for meta-analysis of EUS-FNA cytology to distinguish between mucinous cystic and non-mucinous cystic neoplasms of the pancreas.

Table 44

Summary of clinical evidence for meta-analysis of EUS-FNA cytology to distinguish between malignant and benign pancreatic cystic lesions.

5.3.4.4. Imaging: CT

Table 45

Summary of clinical evidence for studies on computed tomography to distinguish between mucinous cystic and non- mucinous cystic neoplasms of the pancreas.

Table 46

Summary of clinical evidence for meta-analysis of computed tomography to distinguish between malignant and benign pancreatic cystic lesions.

5.3.4.5. Imaging: EUS

Table 47

Summary of clinical evidence for meta-analysis of EUS to distinguish between mucinous cystic and non-mucinous cystic neoplasms of the pancreas.

Table 48

Summary of clinical evidence for studies on EUS to distinguish between malignant and benign pancreatic cystic lesions.

5.3.4.6. Imaging: EUS-FNA

Table 49

Summary of clinical evidence for studies on EUS-FNA to distinguish between mucinous cystic and non-mucinous cystic neoplasms of the pancreas.

5.3.4.7. Imaging: FDG-PET/CT

Table 50

Summary of clinical evidence for studies on FDG-PET/CT to distinguish between (potentially) malignant and benign pancreatic cystic lesions.

5.3.4.8. Imaging: MRI

Table 51

Summary of clinical evidence for meta-analysis of MRI to distinguish between mucinous cystic and non-mucinous cystic neoplasms of the pancreas.

Table 52

Summary of clinical evidence for studies on MRI to distinguish between (potentially) malignant and benign pancreatic cystic lesions.

5.3.5. Economic evidence

A literature review of published cost effectiveness analyses did not identify any relevant studies for this topic. Although there were potential implications for resource use associated with making recommendations in this area, other topics in the guideline were agreed as a higher economic priority. Consequently, bespoke economic modelling was not done for this topic.

5.3.6. Evidence statements

5.3.7. Recommendations

7.

Offer a pancreatic protocol CT scan or magnetic resonance cholangiopancreatography (MRI-MRCP) to people with pancreatic cysts. If more information is needed after one of these tests, offer the other one.

8.

Refer people with any of these high-risk features for resection:

• obstructive jaundice with cystic lesions in the head of the pancreas
• enhancing solid component in the cyst
• a main pancreatic duct that is 10 mm diameter or larger.

9.

Offer EUS after CT and MRI-MRCP if more information on the likelihood of malignancy is needed, or if it is not clear whether surgery is needed.

10.

Consider fine-needle aspiration during EUS if more information on the likelihood of malignancy is needed.

11.

When using fine-needle aspiration, perform carcinoembryonic antigen (CEA) assay in addition to cytology if there is sufficient sample.

12.

For people with cysts that are thought to be malignant, follow the recommendations on staging.

5.3.8. Evidence to recommendations

5.3.9. References

• Ardengh JC, Lopes CV, de Lima LF et al. (2007) Diagnosis of pancreatic tumors by endoscopic ultrasound-guided fine-needle aspiration. World Journal of Gastroenterology 13(22): 3112–6 [PMC free article: PMC4172620] [PubMed: 17589929]
• Brugge WR, Lewandrowski K, Lee-Lewandrowski E et al. (2004) Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology 126(5): 1330–6 [PubMed: 15131794]
• Cao S, Hu Y, Gao X et al. (2016) Serum Carbohydrate Antigen 19-9 in Differential Diagnosis of Benign and Malignant Pancreatic Cystic Neoplasms: A Meta-Analysis. PLoS One 11(11): e0166406 [PMC free article: PMC5105948] [PubMed: 27835676]
• Cizginer S, Turner BG, Bilge AR et al. (2011) Cyst fluid carcinoembryonic antigen is an accurate diagnostic marker of pancreatic mucinous cysts. Pancreas 40(7): 1024–8 [PubMed: 21775920]
• Frossard JL, Amouyal P, Amouyal G et al. (2003) Performance of endosonography-guided fine needle aspiration and biopsy in the diagnosis of pancreatic cystic lesions. American Journal of Gastroenterology 98(7): 1516–24 [PubMed: 12873573]
• Gaddam S, Ge PS, Keach JW et al. (2015) Suboptimal accuracy of carcinoembryonic antigen in differentiation of mucinous and nonmucinous pancreatic cysts: results of a large multicenter study. Gastrointestinal Endoscopy 82(6): 1060–9 [PubMed: 26077458]
• Gerke H, Jaffe TA, Mitchell RM et al. (2006) Endoscopic ultrasound and computer tomography are inaccurate methods of classifying cystic pancreatic lesions. Digestive and Liver Disease 38(1): 39–44 [PubMed: 16314152]
• Ghaneh P, Hanson R, Titman A et al. (2018) PET-PANC: multicentre prospective diagnostic accuracy and health economic analysis study of the impact of combined modality ¹⁸fluorine-2-fluoro-2-deoxy-d-glucose positron emission tomography with computed tomography scanning in the diagnosis and management of pancreatic cancer. Health Technology Assessment 22(7) [PMC free article: PMC5817411] [PubMed: 29402376]
• Hirono S, Tani M, Kawai M et al. (2012) The carcinoembryonic antigen level in pancreatic juice and mural nodule size are predictors of malignancy for branch duct type intraductal papillary mucinous neoplasms of the pancreas. Annals of Surgery 255(3): 517–22 [PubMed: 22301608]
• Jang KM, Kim SH, Min JH et al. (2014) Value of diffusion-weighted MRI for differentiating malignant from benign intraductal papillary mucinous neoplasms of the pancreas. American Journal of Roentgenology 203(5): 992–1000 [PubMed: 25341136]
• Jin DX, Small AJ, Vollmer CM et al. (2015) A lower cyst fluid CEA cut-off increases diagnostic accuracy in identifying mucinous pancreatic cystic lesions. Journal of Pancreas 16(3): 271–7
• Kamata K, Kitano M, Omoto S et al. (2016) Contrast-enhanced harmonic endoscopic ultrasonography for differential diagnosis of pancreatic cysts. Endoscopy 48(1): 35–41 [PubMed: 26605974]
• Kim JH, Eun HW, Park HJ et al. (2012) Diagnostic performance of MRI and EUS in the differentiation of benign from malignant pancreatic cyst and cyst communication with the main duct. European Journal of Radiology 81(11): 2927–35 [PubMed: 22227264]
• Kim SH, Lee JM, Lee ES et al. (2015) Intraductal papillary mucinous neoplasms of the pancreas: Evaluation of malignant potential and surgical resectability by using MR imaging with MR cholangiography. Radiology 274(3): 723–33 [PubMed: 25302831]
• Lee HJ, Kim MJ, Choi JY et al. (2011) Relative accuracy of CT and MRI in the differentiation of benign from malignant pancreatic cystic lesions. Clinical Radiology 66: 315–21, 2011 [PubMed: 21356393]
• Linder JD, Geenen JE, Catalano MF (2006) Cyst fluid analysis obtained by EUS-guided FNA in the evaluation of discrete cystic neoplasms of the pancreas: A prospective single-center experience. Gastrointestinal Endoscopy 64(5): 697–702 [PubMed: 17055859]
• Moris M, Raimondo M, Woodward TA et al. (2016) Diagnostic Accuracy of Endoscopic Ultrasound-Guided Fine-Needle Aspiration Cytology, Carcinoembryonic Antigen, and Amylase in Intraductal Papillary Mucinous Neoplasm. Pancreas 45(6): 870–5 [PubMed: 26646270]
• Nagashio Y, Hijioka S, Mizuno N et al. (2014) Combination of cyst fluid CEA and CA 125 is an accurate diagnostic tool for differentiating mucinous cystic neoplasms from intraductal papillary mucinous neoplasms. Pancreatology 14(6): 503–9 [PubMed: 25458668]
• Nara S, Onaya H, Hiraoka N et al. (2009) Preoperative evaluation of invasive and noninvasive intraductal papillary-mucinous neoplasms of the pancreas: clinical, radiological, and pathological analysis of 123 cases. Pancreas 38(1): 8–16 [PubMed: 18665010]
• Oh HC, Kang H, Brugge WR (2014) Cyst fluid amylase and CEA levels in the differential diagnosis of pancreatic cysts: a single-center experience with histologically proven cysts. Digestive Diseases and Sciences 59(12): 3111–6 [PubMed: 24965184]
• Oppong KW, Dawwas MF, Charnley RM et al. (2015) EUS and EUS-FNA diagnosis of suspected pancreatic cystic neoplasms: Is the sum of the parts greater than the CEA? Pancreatology 15(5): 531–7 [PubMed: 26375415]
• Othman MO, Patel M, Dabizzi E, et al. (2012) Carcino embryonic antigen and long-term follow-up of mucinous pancreatic cysts including intraductal papillary mucinous neoplasm. Digestive and Liver Disease 44: 844–8 [PubMed: 22789399]
• Pais SA, Attasaranya S, Leblanc JK et al. (2007) Role of endoscopic ultrasound in the diagnosis of intraductal papillary mucinous neoplasms: correlation with surgical histopathology. Clinical Gastroenterology and Hepatology 5(4): 489–95 [PubMed: 17350894]
• Park WG, Mascarenhas R, Palaez-Luna M et al. (2011) Diagnostic performance of cyst fluid carcinoembryonic antigen and amylase in histologically confirmed pancreatic cysts. Pancreas 40(1): 42–5 [PMC free article: PMC3005131] [PubMed: 20966811]
• Pitman MB, Genevay M, Yaeger K et al. (2010) High-grade atypical epithelial cells in pancreatic mucinous cysts are a more accurate predictor of malignancy than “positive” cytology. Cancer Cytopathology 118(6): 434–40 [PubMed: 20931638]
• Pitman MB, Yaeger KA, Brugge WR et al. (2013) Prospective analysis of atypical epithelial cells as a high-risk cytologic feature for malignancy in pancreatic cysts. Cancer Cytopathology 121(1): 29–36 [PubMed: 23132817]
• Smith AL, Abdul-Karim FW, Goyal A (2016) Cytologic categorization of pancreatic neoplastic mucinous cysts with an assessment of the risk of malignancy: A retrospective study based on the Papanicolaou Society of Cytopathology guidelines. Cancer Cytopathology 124(4): 285–93 [PubMed: 26618476]
• Song SJ, Lee JM, Kim YJ et al. (2007) Differentiation of intraductal papillary mucinous neoplasms from other pancreatic cystic masses: comparison of multirow-detector CT and MR imaging using ROC analysis. Journal of Magnetic Resonance Imaging 26(1): 86–93 [PubMed: 17659551]
• Sperti C, Pasquali C, Chierichetti F et al. (2001) Value of 18-fluorodeoxyglucose positron emission tomography in the management of patients with cystic tumors of the pancreas. Annals of Surgery 234(5): 675–80 [PMC free article: PMC1422093] [PubMed: 11685032]
• Sperti C, Pasquali C, Decet G et al. (2005) F-18-fluorodeoxyglucose positron emission tomography in differentiating malignant from benign pancreatic cysts: a prospective study. Journal of Gastrointestinal Surgery 9(1): 22–8 [PubMed: 15623441]
• Takanami K, Hiraide T, Tsuda M et al. (2011) Additional value of FDG FDG-PET/CT to contrast-enhanced CT in the differentiation between benign and malignant intraductal papillary mucinous neoplasms of the pancreas with mural nodules. Annals of Nuclear Medicine 25(7): 501–10 [PubMed: 21537945]
• Talar-Wojnarowska R, Pazurek M, Durko L et al. (2013) Pancreatic cyst fluid analysis for differential diagnosis between benign and malignant lesions. Oncology Letters 5(2): 613–616 [PMC free article: PMC3573134] [PubMed: 23420052]
• Wu H, Yan LN, Cheng NS et al. (2007) Role of cystic fluid in diagnosis of the pancreatic cystadenoma and cystadenocarcinoma. Hepatogastroenterology 54(79): 1915–8 [PubMed: 18251127]
• Zhang S, Defrias DV, Alasadi R et al. (2010) Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA): experience of an academic centre in the USA. Cytopathology 21(1): 35–43 [PubMed: 19843142]
• Zhu H, Jiang F, Zhu J et al. (2017) Assessment of morbidity and mortality associated with EUS-guided FNA for pancreatic cystic lesions: A System Review and Meta-Analysis. Digestive Endoscopy Feb 20

5.4.1. Introduction

There are three main groups of people who are at a high risk of developing pancreatic cancer:

1. those with familial pancreatic cancer
2. those with hereditary pancreatitis
3. those with hereditary tumour predisposition syndromes

People with hereditary pancreatitis have a 70 fold increased risk of pancreatic cancer. The life time risk is 35-40% and rises with age. People with familial pancreatic cancer have a life time risk of 30-50% which rises with age.

Guidance is needed on the most effective monitoring protocol to ensure early diagnosis in people with an inherited high risk of pancreatic cancer.

5.4.1.1. Review protocol summary

The review protocol summary used for this question can be found in Table 58. Full details of the review protocol can be found in Appendix C.

Table 53

Clinical review protocol summary for the review of most effective monitoring protocol for adults with an inherited high risk of pancreatic cancer.

5.4.2. Description of clinical evidence

Eighteen articles were identified: 17 of these concerned screening/surveillance programs, whilst 1 was a secondary study that reported on the psychological burden/quality of life of participating in 1 of these screening programs. All 17 of the primary studies reported diagnostic yield (early diagnosis). A summary of the included studies is presented in Table 54.

Seventeen studies (n=2661) were identified that evaluated the diagnostic performance of screening and/or surveillance programs for adults with an inherited ‘high’ risk of pancreatic cancer: 5 prospective cohort studies (Canto et al. 2006; Chang et al. 2017; Potjer et al. 2013; Vasen et al. 2016; Verna et al. 2010), 1 retrospective review of a prospective cohort study (Nocholson et al. 2015), and 11 case series (Al-Sukhni et al. 2012; Bartsch et al. 2016; Canto et al. 2004; Canto et al. 2012; Del Chiaro et al. 2015; Harinck et al. 2016; Kimmey et al. 2002; Ludwig et al. 2011; Poley et al. 2009; Sud et al. 2014; Zubarik et al. 2011). The majority of the studies included familial pancreatic cancer (FPC), which was typically defined as an individual that has two or more relatives with pancreatic cancer. In addition, all of the studies (with the exception of Canto et al. 2012 and Harinck et al. 2016) consisted of an initial test(s) and, given an abnormal result, subsequent imaging or other tests. The most common initial test (11 studies) was MRI/MRCP, or MRI combined with EUS±FNA, whilst the most common subsequent test was EUS±FNA. Only two studies (Canto et al. 2006; Canto et al. 2012) used CT as part of the initial screening test and in both cases this was in combination with other tests (EUS and/or MRI). One multicentre prospective study (n=546; Zubarik et al. 2011) used serum CA 19-9 as the initial test and EUS-FNA given an abnormal result (values >37 U/ml). Data on the diagnostic yield and adverse events of screening/surveillance programs is not amenable to a meta-analysis or depiction using forest plots (however see Nicholson et al. 2015 below). Therefore a narrative summary and table listing the relevant results have been presented.

One retrospective review of a prospective cohort study (n=60; Nicholson et al. 2015) examined the incidence of post-ERCP pancreatitis with and without prophylaxis in people with familial pancreatic cancer or hereditary pancreatitis.

One interrupted time series study (n=152; Konings et al. 2016) examined participants enrolled in the annual surveillance program reported in Harinck et al. 2016 (see above). Although this secondary study did not report health-related quality of life, it reported change on the Cancer Worry scale and the HADS-Anxiety and HADS–Depression scales and so was included.

The QUADAS-2 checklist was used to evaluate the risk of bias and applicability (indirectness) of the screening/surveillance studies. Due to the type of data (diagnostic yield) reported, the criteria of inconsistency and imprecision were not evaluated for these studies, and the quality of each study was therefore rated individually. A narrative summary of the evidence is presented. The GRADE risk of bias tool was used to evaluate 1 study that reported post-ERCP pancreatitis with and without prophylaxis.

Further information about the search strategy can be found in Appendix D. See study selection flow chart in Appendix E, forest plots in Appendix H, summary of QUADAS-2 study quality evaluations in Appendix J, study evidence tables in Appendix F and list of excluded studies in Appendix G.

5.4.3. Summary of included studies

A summary of the studies that were included in this review is presented in Table 54.

Table 54

Summary of included studies.

5.4.4. Clinical evidence profile

5.4.4.1. Screening/surveillance studies

5.4.4.1.1. Narrative summary of evidence

The majority of the 17 studies were in adults with familial pancreatic cancer, the majority of which also included relatively small numbers of individuals with identified germline mutations such as BRCA, p16 or p53. The majority of the participants were female, ranging from 55% to 75% of the samples (approximately 60% female across 15 studies). One study did not report patient characteristics, and in 1 study this information was unclear. Nine studies were conducted in the USA/Canada, 6 in Europe (2 of which were international multicentre studies), and 1 in Taiwan. Only 1 study was conducted in the UK (Nicholson et al. 2015).

The most common initial screening test in the 17 published studies was MRI/MRCP with or without additional EUS (8 studies), whilst the most common test given an abnormal initial result was EUS±FNA (10 studies). Three screening programs did not use a subsequent test given an abnormal result. Fifteen of the articles included only individuals with at least a 5% or more increased risk of pancreatic cancer compared to those in the normal population, whilst two of the studies included individuals at ‘average’ risk of pancreatic cancer.

The diagnostic yield reported in the identified screening/surveillance studies varied widely, ranging from 0.9% to 39%, depending on the type of malignant or premalignant lesion identified, the population and reference test (e.g. surgical pathology only) employed, whether additional tests were conducted given initial abnormal results, and whether results included baseline results only or included follow up.

Of the 2661 individuals at risk, 2418 were screened: 41 (1.7%) of these were diagnosed with pancreatic cancer, resulting in an overall screening efficiency of 59 screened individuals to detect 1 case of pancreatic cancer. If individuals with premalignant lesions are included (i.e. those with IPMN and/or PanIN≥2), 145 individuals (including those with pancreatic cancer) were identified, resulting in a screening efficiency of 6.0% (1 malignant or premalignant lesions for every 17 individuals at risk screened). This suggests that screening high- and moderate- individuals at risk for malignant lesions only will be both costly and time consuming and that screening programs should include premalignant lesions.

Only 1 study (Vasen et al. 2016), which evaluated the diagnostic yield of MRI/MRCP, reported overall survival (a 5-year overall survival of 24% for the CDKN2A/p16 cohort with pancreatic ductal adenocarcinoma). Very few adverse events as a result of participating in the screening/surveillance programs were reported in the 13 studies that reported procedure-related complications. The majority of these were reported in 1 study (Canto et al. 2006) or were related to post-ERCP pancreatitis. Although no studies were found that reported health-related quality of life, there was 1 secondary study (Konings et al. 2016) related to participation in the screening/surveillance program reported in Harinck et al. 2016 (comprising EUS and MRI), that reported significant decreases in worry associated with having cancer (approximately 0.5 point decrease on the Cancer Worry Scale) for every year enrolled in the program. However, participants in this study reported no significant change in depression and anxiety.

The risk of bias and indirectness for each study was generally low for both quality measures with the exception of 2 studies (Canto et al. 2012; Ludwig et al. 2011) both of which had an unclear risk of bias. Overall, the majority of the studies were of ‘high’ quality (rated as ++), with the aforementioned 2 studies rated as ‘low’ (+) quality. Generally it was not clear whether the reference test(s) was interpreted without knowledge of the index test(s) results.

A summary of the evidence for this review question is presented in Table 55.

Table 55

Summary of evidence and quality evaluation.

5.4.4.2. ERCP with prophylaxis versus ERCP only

Table 56

Summary clinical evidence profile for ERCP with prophylaxis versus ERCP only on reducing post-ERCP pancreatitis in people at high risk of pancreatic cancer.

5.4.5. Economic evidence

A literature review of published cost effectiveness analyses did not identify any relevant studies for this topic. Although there were potential implications for resource use associated with making recommendations in this area, other topics in the guideline were agreed as a higher economic priority. Consequently, bespoke economic modelling was not done for this topic.

5.4.6. Evidence Statements

5.4.7. Recommendations

13.

Ask people with pancreatic cancer if any of their first-degree relatives has had it. Address any concerns the person has about inherited risk.

14.

Offer surveillance for pancreatic cancer to people with:

• hereditary pancreatitis and a PRSS1 mutation
• BRCA1, BRCA2, PALB2, or CDKN2A (p16) mutations, and one or more first-degree relatives with pancreatic cancer
• Peutz–Jeghers syndrome.

15.

Consider surveillance for pancreatic cancer for people with:

• 2 or more first-degree relatives with pancreatic cancer, across 2 or more generations
• Lynch syndrome (mismatch repair gene [MLH1, MSH2, MSH6, or PMS2] mutations) and any first-degree relatives with pancreatic cancer.

16.

Consider an MRI-MRCP or EUS for pancreatic cancer surveillance in people without hereditary pancreatitis.

17.

Consider a pancreatic protocol CT scan for pancreatic cancer surveillance in people with hereditary pancreatitis and a PRSS1 mutation.

18.

Do not offer EUS to detect pancreatic cancer in people with hereditary pancreatitis.

5.4.8. Evidence to recommendations

5.4.9. Research recommendations

1.

Research should be undertaken to evaluate the most clinically effective and cost effective initial surveillance tests, additional tests and frequency of surveillance that produce the greatest diagnostic yield and overall surveillance efficiency.

At the present time we do not know what the best initial surveillance and subsequent tests are, nor the frequency of the surveillance that will produce the best diagnostic yield for people with an inherited high risk of pancreatic cancer, whilst maintaining quality of life. These will depend upon the accuracy of the tests available, the level of risk and the rate at which the risk materialises.

Individuals with an inherited risk of pancreatic cancer have a highly variable risk dependent on their particular genotype, each with a widely differing levels of risk, or the particular phenotype each also with a variable level of risk. In each case there is a threshold of risk and frequency of testing that would need to be determined to make surveillance effective.

5.4.10. References

• Al-Sukhni W, Borgida A, Rothenmund H et al. (2012) Screening for pancreatic cancer in a high-risk cohort: an eight-year experience. Journal of Gastrointestinal Surgery 16(4): 771–783 [PubMed: 22127781]
• Bartsch DK, Slater EP, Carrato A et al. (2016) Refinement of screening for familial pancreatic cancer. Gut 65(8): 1314–1321 [PubMed: 27222532]
• Canto MI, Goggins M, Hruban RH et al. (2006) Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study. Clinical Gastroenterology and Hepatology 4(6): 766–781 [PubMed: 16682259]
• Canto MI, Goggins M, Yeo CJ et al. (2004). Screening for pancreatic neoplasia in high-risk individuals: an EUS-based approach. Clinical Gastroenterology and Hepatology 2(7): 606–621 [PubMed: 15224285]
• Canto, MI, Harink, F, Hruban, RH et al. (2013). International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 62(3): 339–347 [PMC free article: PMC3585492] [PubMed: 23135763]
• Canto MI, Hruban RH, Fishman EK et al. (2012) Frequent detection of pancreatic lesions in asymptomatic high-risk individuals. Gastroenterology 142(4): 796–804. [PMC free article: PMC3321068] [PubMed: 22245846]
• Chang MC, Wu CH, Yang SH et al. (2017) Pancreatic cancer screening in different risk individuals with family history of pancreatic cancer-a prospective cohort study in Taiwan. American Journal of Cancer Research 7(2): 357 [PMC free article: PMC5336508] [PubMed: 28337383]
• Del Chiaro M, Verbeke CS, Kartalis N et al. (2015) Short-term Results of a Magnetic Resonance Imaging–Based Swedish Screening Program for Individuals at Risk for Pancreatic Cancer. JAMA Surgery 150(6): 512–518 [PubMed: 25853369]
• Harinck F, Konings IC, Kluijt I et al. (2016) A multicentre comparative prospective blinded analysis of EUS and MRI for screening of pancreatic cancer in high-risk individuals. Gut 65(9): 1505–1513 [PubMed: 25986944]
• Kimmey MB, Bronner MP, Byrd DR et al. (2002) Screening and surveillance for hereditary pancreatic cancer. Gastrointestinal Endoscopy 56(4): S82–S86 [PubMed: 12297755]
• Konings IC, Sidharta GN, Harinck, F et al. (2015) Repeated participation in pancreatic cancer surveillance by high – risk individuals imposes low psychological burden. Psycho – Oncology 25(8): 971–978 [PubMed: 26632416]
• Ludwig E, Olson SH, Bayuga S et al. (2011) Feasibility and yield of screening in relatives from familial pancreatic cancer families. The American Journal of Gastroenterology 106(5): 946–954 [PMC free article: PMC3683863] [PubMed: 21468009]
• Nicholson JA, Greenhalf W, Jackson R et al. (2015) Incidence of post-ERCP pancreatitis from direct pancreatic juice collection in hereditary pancreatitis and familial pancreatic cancer before and after the introduction of prophylactic pancreatic stents and rectal diclofenac. Pancreas 44(2): 260–265 [PubMed: 25438071]
• Poley JW, Kluijt I, Gouma DJ et al. (2009) The yield of first-time endoscopic ultrasonography in screening individuals at a high risk of developing pancreatic cancer. The American Journal of Gastroenterology 104(9): 2175–2181 [PubMed: 19491823]
• Potjer TP, Schot I, Langer P et al. (2013) Variation in precursor lesions of pancreatic cancer among high-risk groups. Clinical Cancer Research 19(2): 442–449. [PubMed: 23172884]
• Sud A, Wham D, Catalano M et al. (2014) Promising outcomes of screening for pancreatic cancer by genetic testing and endoscopic ultrasound. Pancreas 43(3): 458–461 [PubMed: 24622079]
• Vasen H, Ibrahim I, Ponce CG et al. (2016) Benefit of surveillance for pancreatic cancer in high-risk individuals: outcome of long-term prospective follow-up studies from three European expert centers. Journal of Clinical Oncology 34(17): 2010–2019 [PubMed: 27114589]
• Verna EC, Hwang C, Stevens PD et al. (2010) Pancreatic cancer screening in a prospective cohort of high-risk patients: a comprehensive strategy of imaging and genetics. Clinical Cancer Research 16(20): 5028–5037 [PubMed: 20876795]
• Zubarik R, Gordon SR, Lidofsky, SD et al. (2011) Screening for pancreatic cancer in a high-risk population with serum CA 19-9 and targeted EUS: a feasibility study. Gastrointestinal Endoscopy 74(1): 87–95 [PubMed: 21704809]