Abstract
Purpose of review
In current clinical practice, the diagnosis and management of pancreatic cystic lesions (PCLs) are based on guidelines that combine clinical and imaging findings. These guidelines usefully identify a large category of low-risk PCLs that do not require treatment. However, they have limited accuracy for diagnosis of advanced neoplasia in worrisome and high-risk PCLs. Novel molecular markers that can accurately detect advanced neoplasia in PCLs can transform the care of patients with PCLs. We reviewed the recent medical literature on molecular diagnostics of PCLs and summarized molecular biomarkers assayed in cyst fluid, pancreatic juice, and blood.
Recent findings
Several studies have been recently published describing promising early results in genetic, epigenetic, and protein biomarkers from cyst fluid to help in both histologic diagnosis and detection of advanced neoplasia. The majority of studies have been completed using opportunistically collected archival cyst fluid and few report validation in independent sample sets. Results of ongoing multicenter prospective validation studies are awaited and will help define the best combination of cyst fluid molecular markers. In multifocal PCLs communicating with the pancreatic ductal system, a pancreatic juice biomarker is likely to be less invasive and more informative. Novel biomarkers in pancreatic juice and blood are in early phases of study.
Summary
The field of molecular diagnostic biomarkers for PCLs is rapidly evolving with several promising candidate markers being prospectively evaluated. In the near future, these novel molecular markers, combined with advances in imaging technology, will transform clinical decision-making in the management of PCLs and improve patient outcomes.
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Abbreviations
- PCL:
-
Pancreatic cystic lesion
- SCA:
-
Serous cystadenoma
- IPMN:
-
Intraductal papillary mucinous neoplasms
- MCN:
-
Mucinous cystic neoplasms
- HGD:
-
High-grade dysplasia
- LGD:
-
Low-grade dysplasia
- EUS:
-
Endoscopic ultrasound
- CT:
-
Computed tomography
- MRI:
-
Magnetic resonance imagining
- CEA:
-
Carcinoembryonic antigen
- VEGF:
-
Vascular endothelial growth factor
- SCN:
-
Serous cystic neoplasms
- AUC:
-
Area under curve
- MUC:
-
Mucins
- FNA:
-
Fine-needle aspiration
- miRNA:
-
MicroRNAs
- PGE2 :
-
Prostaglandin E2
- PDAC:
-
Pancreatic ductal adenocarcinoma
- HMGA2:
-
High-mobility group A2 protein
- CA 19-9:
-
Carbohydrate antigen 19-9
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Smith-Bindman R, Miglioretti DL, Larson EB. Rising use of diagnostic medical imaging in a large integrated health system. Health Aff (Millwood). 2008;27(6):1491–502. https://doi.org/10.1377/hlthaff.27.6.1491.
Brenner DJ, Hall EJ. Computed tomography--an increasing source of radiation exposure. N Engl J Med. 2007;357(22):2277–84. https://doi.org/10.1056/NEJMra072149.
Zerboni G, Signoretti M, Crippa S, Falconi M, Arcidiacono PG, Capurso G. Systematic review and meta-analysis: prevalence of incidentally detected pancreatic cystic lesions in asymptomatic individuals. Pancreatology. 2019;19(1):2–9. https://doi.org/10.1016/j.pan.2018.11.014.
Moris M, Bridges MD, Pooley RA, Raimondo M, Woodward TA, Stauffer JA, et al. Association between advances in high-resolution cross-section imaging technologies and increase in prevalence of pancreatic cysts from 2005 to 2014. Clin Gastroenterol Hepatol. 2016;14(4):585–593.e3. https://doi.org/10.1016/j.cgh.2015.08.038.
de Jong K, Nio CY, Hermans JJ, Dijkgraaf MG, Gouma DJ, van Eijck CH, et al. High prevalence of pancreatic cysts detected by screening magnetic resonance imaging examinations. Clin Gastroenterol Hepatol. 2010;8(9):806–11. https://doi.org/10.1016/j.cgh.2010.05.017.
European Study Group on Cystic Tumours of the Pancreas. European evidence-based guidelines on pancreatic cystic neoplasms. Gut. 2018;67(5):789–804. https://doi.org/10.1136/gutjnl-2018-316027.
Elta GH, Enestvedt BK, Sauer BG, Lennon AM. ACG clinical guideline: diagnosis and management of pancreatic cysts. Am J Gastroenterol. 2018;113(4):464–79. https://doi.org/10.1038/ajg.2018.14.
Tanaka M, Fernández-Del Castillo C, Kamisawa T, Jang JY, Levy P, Ohtsuka T, et al. Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas. Pancreatology. 2017;17(5):738–53. https://doi.org/10.1016/j.pan.2017.07.007.
Vege SS, Ziring B, Jain R, Moayyedi P. Clinical Guidelines Committee; American Gastroenterology Association. American Gastroenterological Association Institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. Gastroenterology. 2015;148(4):819–22. https://doi.org/10.1053/j.gastro.2015.01.015.
ASGE Standards of Practice Committee, Muthusamy VR, Chandrasekhara V, Acosta RD, Bruining DH, Chathadi KV, et al. The role of endoscopy in the diagnosis and treatment of cystic pancreatic neoplasms. Gastrointest Endosc. 2016;84(1):1–9. https://doi.org/10.1016/j.gie.2016.04.014.
Correa-Gallego C, Ferrone CR, Thayer SP, Wargo JA, Warshaw AL, Fernández-Del CC. Incidental pancreatic cysts: do we really know what we are watching? Pancreatology. 2010;10(2–3):144–50. https://doi.org/10.1159/000243733.
Salvia R, Malleo G, Marchegiani G, Pennacchio S, Paiella S, Paini M, et al. Pancreatic resections for cystic neoplasms: from the surgeon’s presumption to the pathologist’s reality. Surgery. 2012;152(3 Suppl 1):S135–42. https://doi.org/10.1016/j.surg.2012.05.019.
de Pretis N, Mukewar S, Aryal-Khanal A, Bi Y, Takahashi N, Chari S. Pancreatic cysts: diagnostic accuracy and risk of inappropriate resections. Pancreatology. 2017;17(2):267–72. https://doi.org/10.1016/j.pan.2017.01.002.
Scheiman JM, Hwang JH, Moayyedi P. American Gastroenterological Association technical review on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. Gastroenterology. 2015;148(4):824–48.e22. https://doi.org/10.1053/j.gastro.2015.01.014.
Pelaez-Luna M, Chari ST, Smyrk TC, Takahashi N, Clain JE, Levy MJ, et al. Do consensus indications for resection in branch duct intraductal papillary mucinous neoplasm predict malignancy? A study of 147 patients. Am J Gastroenterol. 2007;102(8):1759–64. https://doi.org/10.1111/j.1572-0241.2007.01224.x.
Del Chiaro M, Segersvärd R, Pozzi Mucelli R, Rangelova E, Kartalis N, Ansorge C, et al. Comparison of preoperative conference-based diagnosis with histology of cystic tumors of the pancreas. Ann Surg Oncol. 2014;21(5):1539–44. https://doi.org/10.1245/s10434-013-3465-9.
• Mukewar S, de Pretis N, Aryal-Khanal A, Ahmed N, Sah R, Enders F, et al. Fukuoka criteria accurately predict risk for adverse outcomes during follow-up of pancreatic cysts presumed to be intraductal papillary mucinous neoplasms. Gut. 2017;66(10):1811–7. https://doi.org/10.1136/gutjnl-2016-311615 Large cohort study demonstrating that the vast majority of PCLs do not progress to cancer.
Majumder S, Philip NA, Singh Nagpal SJ, Takahashi N, Mara KC, Kendrick ML, et al. High-grade dysplasia in resected main-duct intraductal papillary mucinous neoplasm (MD-IPMN) is associated with an increased risk of subsequent pancreatic cancer. Am J Gastroenterol. 2019;114(3):524–9. https://doi.org/10.1038/s41395-018-0403-2.
Singhi AD, Zeh HJ, Brand RE, Nikiforova MN, Chennat JS, Fasanella KE, et al. American Gastroenterological Association guidelines are inaccurate in detecting pancreatic cysts with advanced neoplasia: a clinicopathologic study of 225 patients with supporting molecular data. Gastrointest Endosc. 2016;83(6):1107–1117.e2. https://doi.org/10.1016/j.gie.2015.12.009.
Goh BK, Lin Z, Tan DM, Thng CH, Khor CJ, Lim TK, et al. Evaluation of the Fukuoka consensus guidelines for intraductal papillary mucinous neoplasms of the pancreas: results from a systematic review of 1,382 surgically resected patients. Surgery. 2015;158(5):1192–202. https://doi.org/10.1016/j.surg.2015.03.021.
Brugge WR, Lewandrowski K, Lee-Lewandrowski E, Centeno BA, Szydlo T, Regan S, et al. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology. 2004;126(5):1330–6.
• Tanaka M, Heckler M, Liu B, Heger U, Hackert T, Michalski CW. Cytologic analysis of pancreatic juice increases specificity of detection of malignant IPMN-a systematic review. Clin Gastroenterol Hepatol. 2019. https://doi.org/10.1016/j.cgh.2018.12.034 First contemporary meta-analysis looking into all available clinical biomarkers determining many currently available biomarkers have a low or very low quality of evidence.
Oppong KW, Dawwas MF, Charnley RM, Wadehra V, Elamin K, White S, et al. EUS and EUS-FNA diagnosis of suspected pancreatic cystic neoplasms: is the sum of the parts greater than the CEA? Pancreatology. 2015;15(5):531–7. https://doi.org/10.1016/j.pan.2015.08.001.
Oh SH, Lee JK, Lee KT, Lee KH, Woo YS, Noh DH. The combination of cyst fluid carcinoembryonic antigen, cytology and viscosity increases the diagnostic accuracy of mucinous pancreatic cysts. Gut Liver. 2017;11(2):283–9. https://doi.org/10.5009/gnl15650.
Gaddam S, Ge PS, Keach JW, Mullady D, Fukami N, Edmundowicz SA, et al. Suboptimal accuracy of carcinoembryonic antigen in differentiation of mucinous and nonmucinous pancreatic cysts: results of a large multicenter study. Gastrointest Endosc. 2015;82(6):1060–9. https://doi.org/10.1016/j.gie.2015.04.040.
Kadayifci A, Al-Haddad M, Atar M, et al. The value of KRAS mutation testing with CEA for the diagnosis of pancreatic mucinous cysts. Endosc Int Open. 2016;4(4):E391–6. https://doi.org/10.1055/s-0042-101755.
Moris M, Raimondo M, Woodward TA, Skinner V, Arcidiacono PG, Petrone MC, et al. Diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration cytology, carcinoembryonic antigen, and amylase in intraductal papillary mucinous neoplasm. Pancreas. 2016;45(6):870–5. https://doi.org/10.1097/MPA.0000000000000559.
van der Waaij LA, van Dullemen HM, Porte RJ. Cyst fluid analysis in the differential diagnosis of pancreatic cystic lesions: a pooled analysis. Gastrointest Endosc. 2005;62(3):383–9. https://doi.org/10.1016/s0016-5107(05)01581-6.
•• Singhi AD, McGrath K, Brand RE, Khalid A, Zeh HJ, Chennat JS, et al. Preoperative next-generation sequencing of pancreatic cyst fluid is highly accurate in cyst classification and detection of advanced neoplasia. Gut. 2018;67(12):2131–41. https://doi.org/10.1136/gutjnl-2016-313586 Next-generation sequencing demonstrating high accuracy in diagnosing mucinous cysts and advanced neoplasia in IPMNs.
Faias S, Duarte M, Albuquerque C, da Silva JP, Fonseca R, Roque R, et al. Clinical impact of KRAS and GNAS analysis added to CEA and cytology in pancreatic cystic fluid obtained by EUS-FNA. Dig Dis Sci. 2018;63(9):2351–61. https://doi.org/10.1007/s10620-018-5128-y.
•• Springer S, Wang Y, Dal Molin M, Masica DL, Jiao Y, Kinde I, et al. A combination of molecular markers and clinical features improve the classification of pancreatic cysts. Gastroenterology. 2015;149(6):1501–10. https://doi.org/10.1053/j.gastro.2015.07.041 Landmark study demonstrating the role of cyst fluid molecular markers for diagnosis of PCL subtype.
Carr RA, Yip-Schneider MT, Dolejs S, Hancock BA, Wu H, Radovich M, et al. Pancreatic cyst fluid vascular endothelial growth factor A and carcinoembryonic antigen: a highly accurate test for the diagnosis of serous cystic neoplasm. J Am Coll Surg. 2017. https://doi.org/10.1016/j.jamcollsurg.2017.05.003.
Maker AV, Katabi N, Gonen M, DeMatteo R, D’Angelica MI, Fong Y, et al. Pancreatic cyst fluid and serum mucin levels predict dysplasia in intraductal papillary mucinous neoplasms of the pancreas. Ann Surg Oncol. 2011;18(1):199–206. https://doi.org/10.1245/s10434-010-1225-7.
Tomishima K, Sai JK, Kanazawa R, Miura H, Shimizu R, Sato K, et al. Impact of MUC1 expression on the progression of intraductal papillary mucinous neoplasm with worrisome features during follow-up. Pancreas. 2017;46(9):1127–32. https://doi.org/10.1097/MPA.0000000000000902.
Sinha J, Cao Z, Dai J, Tang H, Partyka K, Hostetter G, et al. A gastric glycoform of MUC5AC is a biomarker of mucinous cysts of the pancreas. PLoS One. 2016;11(12):e0167070. https://doi.org/10.1371/journal.pone.0167070.
Bick BL, Enders FT, Levy MJ, Zhang L, Henry MR, Abu Dayyeh BK, et al. The string sign for diagnosis of mucinous pancreatic cysts. Endoscopy. 2015;47(7):626–31. https://doi.org/10.1055/s-0034-1391484.
Park WG, Wu M, Bowen R, Zheng M, Fitch WL, Pai RK, et al. Metabolomic-derived novel cyst fluid biomarkers for pancreatic cysts: glucose and kynurenine. Gastrointest Endosc. 2013;78(2):295–302.e2. https://doi.org/10.1016/j.gie.2013.02.037.
Zikos T, Pham K, Bowen R, Chen AM, Banerjee S, Friedland S, et al. Cyst fluid glucose is rapidly feasible and accurate in diagnosing mucinous pancreatic cysts. Am J Gastroenterol. 2015;110(6):909–14. https://doi.org/10.1038/ajg.2015.148.
• Carr RA, Yip-Schneider MT, Simpson RE, Dolejs S, Schneider JG, Wu H, et al. Pancreatic cyst fluid glucose: rapid, inexpensive, and accurate diagnosis of mucinous pancreatic cysts. Surgery. 2018;163(3):600–5. https://doi.org/10.1016/j.surg.2017.09.051 Study demonstrating that low cyst fluid glucose can differentiate between mucinous and non-mucinous PCLs.
Wang QX, Xiao J, Orange M, Zhang H, Zhu YQ. EUS-guided FNA for diagnosis of pancreatic cystic lesions: a meta-analysis. Cell Physiol Biochem. 2015;36(3):1197–209. https://doi.org/10.1159/000430290.
Gillis A, Cipollone I, Cousins G, Conlon K. Does EUS-FNA molecular analysis carry additional value when compared to cytology in the diagnosis of pancreatic cystic neoplasm? A systematic review. HPB (Oxford). 2015;17(5):377–86. https://doi.org/10.1111/hpb.12364.
Ridtitid W, DeWitt JM, Schmidt CM, Roch A, Stuart JS, Sherman S, et al. Management of branch-duct intraductal papillary mucinous neoplasms: a large single-center study to assess predictors of malignancy and long-term outcomes. Gastrointest Endosc. 2016;84(3):436–45. https://doi.org/10.1016/j.gie.2016.02.008.
• Hata T, Dal Molin M, Hong SM, Tamura K, Suenaga M, Yu J, et al. Predicting the grade of dysplasia of pancreatic cystic neoplasms using cyst fluid DNA methylation markers. Clin Cancer Res. 2017;23(14):3935–44. https://doi.org/10.1158/1078-0432.CCR-16-2244 Study demonstrating the role of cyst fluid methylated DNA for detecting advanced neoplasia.
•• Majumder S, Taylor WR, Yab TC, Berger CK, Dukek BA, Cao X, et al. Novel methylated DNA markers discriminate advanced neoplasia in pancreatic cysts: marker discovery, tissue validation, and cyst fluid testing. Am J Gastroenterol. 2019. https://doi.org/10.14309/ajg.0000000000000284 Cyst fluid methylated DNA markers to predict advanced neoplasia in PCLs, pilot and independent validation using pre-specified cutoffs.
Bartels CL, Tsongalis GJ. MicroRNAs: novel biomarkers for human cancer. Clin Chem. 2009;55(4):623–31. https://doi.org/10.1373/clinchem.2008.112805.
Matthaei H, Wylie D, Lloyd MB, Dal Molin M, Kemppainen J, Mayo SC, et al. miRNA biomarkers in cyst fluid augment the diagnosis and management of pancreatic cysts. Clin Cancer Res. 2012;18(17):4713–24. https://doi.org/10.1158/1078-0432.CCR-12-0035.
Farrell JJ, Toste P, Wu N, Li L, Wong J, Malkhassian D, et al. Endoscopically acquired pancreatic cyst fluid microRNA 21 and 221 are associated with invasive cancer. Am J Gastroenterol. 2013;108(8):1352–9. https://doi.org/10.1038/ajg.2013.167.
Utomo WK, Looijenga LH, Bruno MJ, Hansen BE, Gillis A, Biermann K, et al. A microRNA panel in pancreatic cyst fluid for the risk stratification of pancreatic cysts in a prospective cohort. Mol Ther Nucleic Acids. 2016;5:e350. https://doi.org/10.1038/mtna.2016.61.
•• Das KK, Geng X, Brown JW, Morales-Oyarvide V, Huynh T, Pergolini I, et al. Mino-Kenudson M. Cross validation of the monoclonal antibody Das-1 in identification of high-risk mucinous pancreatic cystic lesions, Gastroenterology. 2019. https://doi.org/10.1053/j.gastro.2019.05.014. Cyst fluid protein biomarker with high sensitivity and specificity for diagnosing advanced neoplasia.
Yip-Schneider MT, Carr RA, Wu H, Schmidt CM. Prostaglandin E(2): a pancreatic fluid biomarker of intraductal papillary mucinous neoplasm dysplasia. J Am Coll Surg. 2017;225(4):481–7. https://doi.org/10.1016/j.jamcollsurg.2017.07.521.
DiMaio CJ, Weis-Garcia F, Bagiella E, Tang LH, Allen PJ. Pancreatic cyst fluid concentration of high-mobility group A2 protein acts as a differential biomarker of dysplasia in intraductal papillary mucinous neoplasm. Gastrointest Endosc. 2016;83(6):1205–9. https://doi.org/10.1016/j.gie.2015.09.020.
Al Efishat MA, Attiyeh MA, Eaton AA, Gönen M, Prosser D, Lokshin AE, et al. Multi-institutional validation study of pancreatic cyst fluid protein analysis for prediction of high-risk intraductal papillary mucinous neoplasms of the pancreas. Ann Surg. 2018;268(2):340–7. https://doi.org/10.1097/SLA.0000000000002421.
Hata T, Dal Molin M, Suenaga M, Yu J, Pittman M, Weiss M, et al. Cyst fluid telomerase activity predicts the histologic grade of cystic neoplasms of the pancreas. Clin Cancer Res. 2016;22(20):5141–51.
Sadakari Y, Kanda M, Maitani K, Borges M, Canto MI, Goggins M. Mutant KRAS and GNAS DNA concentrations in secretin-stimulated pancreatic fluid collected from the pancreatic duct and the duodenal lumen. Clin Transl Gastroenterol. 2014;5:e62. https://doi.org/10.1038/ctg.2014.14.
Takano S, Fukasawa M, Kadokura M, Shindo H, Takahashi E, Hirose S, et al. Next-generation sequencing revealed TP53 mutations to be malignant marker for intraductal papillary mucinous neoplasms that could be detected using pancreatic juice. Pancreas. 2017;46(10):1281–7. https://doi.org/10.1097/MPA.0000000000000931.
Eshleman JR, Norris AL, Sadakari Y, Debeljak M, Borges M, Harrington C, et al. KRAS and guanine nucleotide-binding protein mutations in pancreatic juice collected from the duodenum of patients at high risk for neoplasia undergoing endoscopic ultrasound. Clin Gastroenterol Hepatol. 2015;13(5):963–9.e4. https://doi.org/10.1016/j.cgh.2014.11.028.
Yu J, Sadakari Y, Shindo K, Suenaga M, Brant A, Almario JAN, et al. Digital next-generation sequencing identifies low-abundance mutations in pancreatic juice samples collected from the duodenum of patients with pancreatic cancer and intraductal papillary mucinous neoplasms. Gut. 2017;66(9):1677–87. https://doi.org/10.1136/gutjnl-2015-311166.
Mateos RN, Nakagawa H, Hirono S, Takano S, Fukasawa M, Yanagisawa A, et al. Genomic analysis of pancreatic juice DNA assesses malignant risk of intraductal papillary mucinous neoplasm of pancreas. Cancer Med. 2019. https://doi.org/10.1002/cam4.2340.
Kisiel JB, Raimondo M, Taylor WR, Yab TC, Mahoney DW, Sun Z, et al. New DNA methylation markers for pancreatic cancer: discovery, tissue validation, and pilot testing in pancreatic juice. Clin Cancer Res. 2015;21(19):4473–81. https://doi.org/10.1158/1078-0432.CCR-14-2469.
• Majumder S, Raimondo M, Taylor WR, Yab TC, Berger CK, Dukek BA, et al. Methylated DNA in pancreatic juice distinguishes patients with pancreatic cancer from controls. Clin Gastroenterol Hepatol. 2019. https://doi.org/10.1016/j.cgh.2019.07.017 Case-control study validating pancreatic juice as a potential target for detecting advanced neoplasia.
Yamakawa K, Masuda A, Nakagawa T, Shiomi H, Toyama H, Takenaka M, et al. Evaluation of efficacy of pancreatic juice cytology for risk classification according to international consensus guidelines in patients with intraductal papillary mucinous neoplasm; a retrospective study. Pancreatology. 2019;19(3):424–8. https://doi.org/10.1016/j.pan.2019.02.013.
• Berger AW, Schwerdel D, Costa IG, Hackert T, Strobel O, Lam S, et al. Detection of hot-spot mutations in circulating cell-free DNA from patients with intraductal papillary mucinous neoplasms of the pancreas. Gastroenterology. 2016;151(2):267–70. https://doi.org/10.1053/j.gastro.2016.04.034 Promising application of systemic blood biomarker for detection of IPMNs.
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Shounak Majumder could receive potential future royalties because Mayo Clinic has licensed intellectual property to Exact Sciences (Madison, WI).
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de la Fuente, J., Majumder, S. Molecular Diagnostics and Testing for Pancreatic Cysts. Curr Treat Options Gastro 18, 158–171 (2020). https://doi.org/10.1007/s11938-020-00270-6
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DOI: https://doi.org/10.1007/s11938-020-00270-6