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 Table of Contents  
EDITORIAL
Year : 2018  |  Volume : 7  |  Issue : 5  |  Page : 289-292

Pancreatic cystic neoplasms in 2018: The final cut


1 Digestive and Liver Disease Unit, S. Andrea Hospital, Rome; Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
2 Digestive and Liver Disease Unit, S. Andrea Hospital, Rome, Italy
3 Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy

Date of Submission16-May-2018
Date of Acceptance27-Jul-2018
Date of Web Publication15-Oct-2018

Correspondence Address:
Dr. Gabriele Capurso
Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan
Italy
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/eus.eus_48_18

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How to cite this article:
Capurso G, Vanella G, Arcidiacono PG. Pancreatic cystic neoplasms in 2018: The final cut. Endosc Ultrasound 2018;7:289-92

How to cite this URL:
Capurso G, Vanella G, Arcidiacono PG. Pancreatic cystic neoplasms in 2018: The final cut. Endosc Ultrasound [serial online] 2018 [cited 2018 Nov 18];7:289-92. Available from: http://www.eusjournal.com/text.asp?2018/7/5/289/243368




  Introduction: Pancreatic Cystic Lesions: High Prevalence and Low Evidence Top


The incidental diagnosis of pancreatic cystic lesions (PCLs) is increasing, being a significant health-care problem and economic burden. Indeed, up to 10% of the adult population has PCLs occasionally detected when undergoing procedures such as computed tomography scan and magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography. Anyway, the prevalence of PCLs increases with age, approaching 50%[1] in the elderly. Notably, the majority of these lesions are intraductal papillary mucinous neoplasms (IPMNs) with a potential premalignant significance. In this context, there is the need to develop evidence-based and cost-effective guidelines based on the solid data to guide the clinical process. Unfortunately, while the number of published original research articles on the topic is increasing, the quality of the evidence is low. While the number of hits on PubMed for the search terms “IPMN or IPMT or Intraductal Papillary Mucinous Neoplasms” is equal to 2326 in April 2018, with original studies increasing from 103 in 2007 to 183 in 2017, only 4 of >2000 articles are randomized controlled trials (RCTs). In this scenario, there are probably no other health disorders so prevalent and potentially relevant for which evidence is so low. An attempt to summarize the best available evidence for the clinical management of PCLs has been made by experts in the field with the preparation of several guidelines.[2],[3],[4],[5],[6],[7],[8],[9] The present paper will discuss critical issues and limitations of current guidelines in the management of PCLs and will highlight novel findings potentially leading to an improvement of the current scenario.


  Correct Diagnosis of Pancreatic Cystic Lesions: More Complicated Than it Seems Top


The main limitation of most available data on IPMNs is that they are obtained in surgical series, and applying their results to nonsurgical cohorts represents a typical spectrum bias, like when the performance of a diagnostic test obtained in a certain clinical settings is wrongly applied to another, while each setting has a different mix of patients. However, the cultural journey of IPMNs has recently switched from the analysis of surgical series to the follow-up of cystic lesions stratified according to noninvasive morphological imaging. In this view, the correct initial diagnosis and stratification of malignant potential are crucial issues. However, when preoperative assessment and postoperative histology of PCLs have been compared, a surprising high rate of misdiagnosis was observed.[10],[11],[12],[13],[14],[15],[16] Most patients with PCLs receive MRI as first-line investigation, with EUS with fine-needle aspiration, and evaluation of intracystic fluid being employed as second-line tests when diagnosis is uncertain or malignant behavior is suspected. As the accuracy of these tests remains suboptimal, novel EUS-based technologies are under evaluation.

Contrast harmonic EUS has preliminary shown to strongly increase specificity and positive predictive value for malignancy when used for evaluating mural nodules detected at basal EUS; quantitative evaluation of echo intensity changes through time-intensity curve analysis may further stratify between IPMN with low- or intermediate-grade dysplasia and those with high-grade dysplasia or invasive carcinoma.[17] Needle-based confocal laser endomicroscopy returns real-time cellular and architectural imaging and has demonstrated a high positive predictive value when detecting typical patterns of mucinous or nonmucinous cystic lesions; however, in the absence of such patterns, sensitivity remains suboptimal but may be increased through the contemporary use of cystoscopy through SpyGlass probe.[18] Anyway, the diagnostic gain is limited by the lack of standardization and by the reported rate of adverse events.

The need to overcome the low accuracy of traditional cystic aspiration sampling has led to the development of a through-the-needle biopsy forceps allowing histological evaluation of cystic walls, septa, or nodules. In one preliminary study, this histopathological evaluation has proved similar to traditional (but including routine molecular analysis) cystic fluid evaluation in differentiating between mucinous and nonmucinous cysts and in detecting high-risk cysts but superior in differentiating between IPMNs and MCNs.[19]

Molecular biomarkers obtained in either tissues, duodenal aspirates, cystic fluid, or serum have been evaluated for their potential ability to differentiate between different PCLs and between degrees of dysplasia. In particular, in a recent study, mutations of KRAS/GNAS in the cystic fluid were reported to have a sensitivity of 89% and specificity of 100% for the diagnosis of mucinous lesions, and the combinations of KRAS/GNAS mutations with those of TP53/PIK3CA/PTEN a 89% sensitivity and 100% specificity for the diagnosis of advanced neoplasia.[20] However, apart from KRAS and GNAS mutations, the use of such “molecular signatures” in predicting cyst behavior is still not recommended,[5] and an “ideal perfect potion” with a compromise between sensibility and specificity does not exist.


  Surgical Indication: Is it Just a Question Of Millimeters? Top


When referring to the indication for surgery of asymptomatic PCLs, the main differences between existing guidelines are about the thresholds of pancreatic cyst and Wirsung duct diameters. When referring to branch-duct IPMNs (BD-IPMNs), the new European guidelines[5] do not consider the size of the peripheral cyst among factors representing an absolute indication for surgery, while a size of 40 mm represents a relative indication, to be considered with patients' features. Previous guidelines[2],[4] consider a diameter >30 mm as a “worrisome feature” requiring further investigation or eventually a surgical indication in young individuals. The American Gastroenterological Association (AGA) guidelines[3] consider cyst size >30 mm an indication to perform EUS only in the presence of at least another high-risk feature (i.e., dilated Wirsung duct or the presence of a solid component). In any case, the size of a BD-IPMN per se should not be considered as an absolute indication for surgery.

As far as regards the diameter of the Wirsung duct, the cutoff of 10 mm is an indication for surgery according with the European, Italian, and International Association of Pancreatology (IAP) guidelines,[2],[4],[5] while the AGA ones[3] generically mention “Wirsung duct dilation.” The European guidelines also include a diameter above 5 mm among “relative indications” for surgery because there are studies reporting a high rate of malignancies with Wirsung duct >5 mm and calculating the best cutoff at 7 mm.[21],[22]

Intuitively, the larger is the diameter of the Wirsung duct the higher is the risk of malignancy, but as the rate of IPMN patients with a dilation >10 mm is rather small, the fraction of patients carrying that risk is limited. This is why this risk factor turns out to be nonsignificant in some published series, with the category of 5–9 mm being more relevant.[23],[24]

Furthermore, data supporting these different policies are obtained in retrospective surgical series with all inherent biases. Even more, it is unclear how this delicate “millimeters' cutoff” should be measured, given the reported low agreement between MRI and EUS in reporting the size of both BD-IPMNs and Wirsung duct.[25]

There are few publications comparing available guidelines for their accuracy in providing a correct indication for surgery. Interestingly, the rate of overtreatment, which is around 80% with the IAP and European guidelines, is only 56% when employing the AGA criteria, but the latter is also the only guidelines missing 11% of cases with high-grade dysplasia or cancer compared to 0% with IAP or European ones.[26] This stresses the importance of relying on factors other than the characteristics of the cyst. Among these, family history of pancreatic cancer does not seem to substantially increase the risk.[27] Research efforts should be focused in creating a combined set of variables including not only “cyst factors” (such as size) but also “patients' variables” (e.g., smoking and family history) and possibly “molecular/genetic markers” to better predict cyst behavior.


  Is it Possible to Personalize the Follow-up of Intraductal Papillary Mucinous Neoplasms? Top


If one optimistically takes for granted that we are sufficiently accurate in stratifying the malignant potential of a PCL, the question becomes how long are we going to follow-up patients for whom we did not recommend resection? Several papers have demonstrated that malignant potential of low-risk BD-IPMNs is generally low but increases over time,[28] and a significant proportion of this progression appears beyond 5 years from diagnosis,[29] thus making it questionable to interrupt the follow-up at a defined interval. While waiting for further data on long-term follow-up of conservatively managed cohorts, fitness for surgery must be considered the only significant parameter limiting follow-up length.[5]

We are improving our ability in stratifying the malignant potential of one cyst, but we almost grope in the dark when we are required to define how to adapt that risk to different categories of patients. In this individualized balance, fitness for surgery and life expectancy of a patient and location of the cyst (determining the type and invasiveness of pancreatic resection) can become as important as cyst morphological appearance. It has been demonstrated that patients with advanced age or comorbidities are more likely to die from their fragility (or eventually from the pancreatic resection) rather than from the cancerization of their IPMN.[30] The shaping role of the Charlson comorbidity index in the decisional process has been explored by some authors,[31] confirming that factors beyond cyst features have a definite impact on the risk of death. However, to date, no validated nomogram integrates patient- and cyst-related factors in tailoring prognosis and management, and guidelines are fundamentally “cyst-centric.” Future efforts in the area of PCL research should concentrate on realizing well-conducted RCTs comparing different strategies and on combining patients' environmental and genetic characteristics with morphological and molecular features of the cyst to establish the most appropriate management of these common lesions. Given the low annual risk of malignant transformation in most IPMNs,[32] these studies need both multicentric efforts and long follow-up intervals to record a sufficient number of significant events.

Conflict of interest

There are no conflicts of interest.



 
  References Top

1.
Kromrey ML, Bülow R, Hübner J, et al. Prospective study on the incidence, prevalence and 5-year pancreatic-related mortality of pancreatic cysts in a population-based study. Gut 2018;67:138-45.  Back to cited text no. 1
    
2.
Italian Association of Hospital Gastroenterologists and Endoscopists, Italian Association for the Study of the Pancreas, Buscarini E, Pezzilli R, Cannizzaro R, et al. Italian consensus guidelines for the diagnostic work-up and follow-up of cystic pancreatic neoplasms. Dig Liver Dis 2014;46:479-93.  Back to cited text no. 2
    
3.
Vege SS, Ziring B, Jain R, et al. American Gastroenterological Association Institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. Gastroenterology 2015;148:819-22.  Back to cited text no. 3
    
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Tanaka M, Fernández-Del Castillo C, Kamisawa T, et al. Revisions of International Consensus Fukuoka Guidelines for the management of IPMN of the pancreas. Pancreatology 2017;17:738-53.  Back to cited text no. 4
    
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European Study Group on Cystic Tumours of the Pancreas. European evidence-based guidelines on pancreatic cystic neoplasms. Gut 2018;67:789-804.  Back to cited text no. 5
    
6.
Wang Y, Chai N, Feng J, et al. A prospective study of endoscopic ultrasonography features, cyst fluid carcinoembryonic antigen, and fluid cytology for the differentiation of small pancreatic cystic neoplasms. Endosc Ultrasound 2017. [Epub ahead of print].  Back to cited text no. 6
    
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Hussain I, Ang TL. Cystic pancreatic lymphangioma diagnosed with endoscopic ultrasound-guided fine needle aspiration. Endosc Ultrasound 2017;6:136-9.   Back to cited text no. 7
    
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Zhang W, Linghu E, Chai N, et al. New criteria to differentiate between mucinous cystic neoplasm and serous cystic neoplasm in pancreas by endoscopic ultrasound: A preliminarily confirmed outcome of 41 patients. Endosc Ultrasound 2017;6:116-22.  Back to cited text no. 8
    
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Dalal KS, DeWitt JM, Sherman S, et al. Endoscopic ultrasound characteristics of pancreatic lymphoepithelial cysts: A case series from a large referral center. Endosc Ultrasound 2016;5:248-53.  Back to cited text no. 9
    
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Correa-Gallego C, Ferrone CR, Thayer SP, et al. Incidental pancreatic cysts: Do we really know what we are watching? Pancreatology 2010;10:144-50.  Back to cited text no. 10
    
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Del Chiaro M, Segersvärd R, Pozzi Mucelli R, et al. Comparison of preoperative conference-based diagnosis with histology of cystic tumors of the pancreas. Ann Surg Oncol 2014;21:1539-44.  Back to cited text no. 11
    
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Korenblit J, Tholey DM, Tolin J, et al. Effect of the time of day and queue position in the endoscopic schedule on the performance characteristics of endoscopic ultrasound-guided fine-needle aspiration for diagnosing pancreatic malignancies. Endosc Ultrasound 2016;5:78-84.  Back to cited text no. 12
    
13.
Saftoiu A, Vilmann P, Bhutani MS. The role of contrast-enhanced endoscopic ultrasound in pancreatic adenocarcinoma. Endosc Ultrasound 2016;5:368-72.  Back to cited text no. 13
    
14.
Palazzo M. Role of contrast harmonic endoscopic ultrasonography in other pancreatic solid lesions: Neuroendocrine tumors, autoimmune pancreatitis and metastases. Endosc Ultrasound 2016;5:373-6.  Back to cited text no. 14
    
15.
Nemakayala D, Patel P, Rahimi E, et al. Use of quantitative endoscopic ultrasound elastography for diagnosis of pancreatic neuroendocrine tumors. Endosc Ultrasound 2016;5:342-5.  Back to cited text no. 15
    
16.
Mohammad Alizadeh AH, Shahrokh S, Hadizadeh M, et al. Diagnostic potency of EUS-guided FNA for the evaluation of pancreatic mass lesions. Endosc Ultrasound 2016;5:30-4.   Back to cited text no. 16
    
17.
Polkowski M. Endoscopic ultrasonography for pancreatic cystic lesions: Let's enhance it. Endoscopy 2016;48:4-6.  Back to cited text no. 17
    
18.
Krishna SG, Brugge WR, Dewitt JM, et al. Needle-based confocal laser endomicroscopy for the diagnosis of pancreatic cystic lesions: An international external interobserver and intraobserver study (with videos). Gastrointest Endosc 2017;86:644-54.e2.  Back to cited text no. 18
    
19.
Zhang ML, Arpin RN, Brugge WR, et al. Moray micro forceps biopsy improves the diagnosis of specific pancreatic cysts. Cancer Cytopathol 2018;126:414-20.  Back to cited text no. 19
    
20.
Singhi AD, McGrath K, Brand RE, et al. Preoperative next-generation sequencing of pancreatic cyst fluid is highly accurate in cyst classification and detection of advanced neoplasia. Gut 2017. pii: gutjnl-2016-313586.  Back to cited text no. 20
    
21.
Hackert T, Fritz S, Klauss M, et al. Main-duct intraductal papillary mucinous neoplasm: High cancer risk in duct diameter of 5 to 9 mm. Ann Surg 2015;262:875-80.  Back to cited text no. 21
    
22.
Sugimoto M, Elliott IA, Nguyen AH, et al. Assessment of a revised management strategy for patients with intraductal papillary mucinous neoplasms involving the main pancreatic duct. JAMA Surg 2017;152:e163349.  Back to cited text no. 22
    
23.
Petrone MC, Magnoni P, Pergolini I, et al. Long-term follow-up of low-risk branch-duct IPMNs of the pancreas: Is main pancreatic duct dilatation the most worrisome feature? Clin Transl Gastroenterol 2018;9:158.  Back to cited text no. 23
    
24.
Robles EP, Maire F, Cros J, et al. Accuracy of 2012 International Consensus Guidelines for the prediction of malignancy of branch-duct intraductal papillary mucinous neoplasms of the pancreas. United European Gastroenterol J 2016;4:580-6.  Back to cited text no. 24
    
25.
Uribarri-Gonzalez L, Keane MG, Pereira SP, et al. Agreement among magnetic resonance imaging/magnetic resonance cholangiopancreatography (MRI-MRCP) and endoscopic ultrasound (EUS) in the evaluation of morphological features of branch duct intraductal papillary mucinous neoplasm (BD-IPMN). Pancreatology 2018;18:170-5.  Back to cited text no. 25
    
26.
Lekkerkerker SJ, Besselink MG, Busch OR, et al. Comparing 3 guidelines on the management of surgically removed pancreatic cysts with regard to pathological outcome. Gastrointest Endosc 2017;85:1025-31.  Back to cited text no. 26
    
27.
Mukewar SS, Sharma A, Phillip N, et al. Risk of pancreatic cancer in patients with pancreatic cysts and family history of pancreatic cancer. Clin Gastroenterol Hepatol 2018;16:1123-300.  Back to cited text no. 27
    
28.
Del Chiaro M, Ateeb Z, Hansson MR, et al. Survival analysis and risk for progression of intraductal papillary mucinous neoplasia of the pancreas (IPMN) under surveillance: A Single-institution experience. Ann Surg Oncol 2017;24:1120-6.  Back to cited text no. 28
    
29.
Crippa S, Pezzilli R, Bissolati M, et al. Active surveillance beyond 5 years is required for presumed branch-duct intraductal papillary mucinous neoplasms undergoing non-operative management. Am J Gastroenterol 2017;112:1153-61.  Back to cited text no. 29
    
30.
Vanella G, Crippa S, Archibugi L, et al. Meta-analysis of mortality in patients with high-risk intraductal papillary mucinous neoplasms under observation. Br J Surg 2018;105:328-38.  Back to cited text no. 30
    
31.
Kwok K, Chang J, Duan L, et al. Competing risks for mortality in patients with asymptomatic pancreatic cystic neoplasms: Implications for clinical management. Am J Gastroenterol 2017;112:1330-6.  Back to cited text no. 31
    
32.
Crippa S, Capurso G, Cammà C, et al. Risk of pancreatic malignancy and mortality in branch-duct IPMNs undergoing surveillance: A systematic review and meta-analysis. Dig Liver Dis 2016;48:473-9.  Back to cited text no. 32
    




 

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