Digestive Disease Interventions
DOI: 10.1055/s-0045-1808265
Review Article

New Insights in Diagnosing and Risk-Stratifying Pancreatic Cystic Neoplasms and IPMN

1   Division of Surgical Oncology, Department of Surgery, University of California San Francisco, San Francisco, California
,
Ajay V. Maker
1   Division of Surgical Oncology, Department of Surgery, University of California San Francisco, San Francisco, California
› Author Affiliations
Funding Acknowledgement to the Shorenstein Family Foundation, Baker and Simpson Family Research Fund, Illinois Ventures, and Inner Child Foundation.

Abstract

Pancreatic cystic neoplasms (PCN) comprise a diverse group of lesions with variable malignant potential, requiring accurate diagnosis and risk stratification for appropriate management. Distinguishing mucinous cysts, including intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN), from benign nonmucinous lesions such as serous cystadenomas (SCA) is essential due to their risk of progression to invasive carcinoma. Importantly, IPMN and MCN represent the only radiologically detectable precursors to pancreatic cancer, contributing to 15% of cases. Traditional diagnostic approaches utilize imaging modalities like computed tomography, magnetic resonance imaging, and endoscopic ultrasound (EUS), often supported by cyst fluid analysis through fine-needle aspiration. However, these techniques exhibit limited sensitivity and specificity in identifying malignant transformation. Emerging molecular diagnostics, including analysis of carcinoembryonic antigen, glucose, IL1β, PGE2, and DNA sequencing for mutations such as KRAS and GNAS, show promise in differentiating mucinous cysts and identifying advanced dysplasia. Despite this, clinical integration remains limited. Future efforts focus on noninvasive methods, including plasma-based liquid biopsies, to complement cyst fluid analysis. A comprehensive biomarker panel integrating serum and cyst fluid markers holds the potential to improve early detection, reduce overtreatment, and optimize surgical management of high-risk PCN.



Publication History

Received: 24 January 2025

Accepted: 08 April 2025

Article published online:
19 May 2025

© 2025. Thieme. All rights reserved.

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  • References

  • 1 Gonda TA, Cahen DL, Farrell JJ. Pancreatic cysts. N Engl J Med 2024; 391 (09) 832-843
  • 2 Khoury RE, Kabir C, Maker VK, Banulescu M, Wasserman M, Maker AV. What is the incidence of malignancy in resected intraductal papillary mucinous neoplasms? An analysis of over 100 US institutions in a single year. Ann Surg Oncol 2018; 25 (06) 1746-1751
  • 3 Maker AV, Katabi N, Gonen M. et al. Pancreatic cyst fluid and serum mucin levels predict dysplasia in intraductal papillary mucinous neoplasms of the pancreas. Ann Surg Oncol 2011; 18 (01) 199-206
  • 4 Pollini T, Todeschini L, Maker AV. Pancreas cyst diagnosis and advances in cyst fluid analysis. Surg Clin North Am 2024; 104 (05) 965-974
  • 5 Maker AV. ASO author reflections: improving identification of intraductal papillary mucinous neoplasm patients at risk-current status and the role of IPMN molecular biomarkers. Ann Surg Oncol 2018; 25 (Suppl. 03) 818-819
  • 6 Tulla KA, Maker AV. Can we better predict the biologic behavior of incidental IPMN? A comprehensive analysis of molecular diagnostics and biomarkers in intraductal papillary mucinous neoplasms of the pancreas. Langenbecks Arch Surg 2018; 403 (02) 151-194
  • 7 Maker AV, Carrara S, Jamieson NB. et al. Cyst fluid biomarkers for intraductal papillary mucinous neoplasms of the pancreas: a critical review from the international expert meeting on pancreatic branch-duct-intraductal papillary mucinous neoplasms. J Am Coll Surg 2015; 220 (02) 243-253
  • 8 Pollini T, Wong P, Maker AV. The landmark series: intraductal papillary mucinous neoplasms of the pancreas - from prevalence to early cancer detection. Ann Surg Oncol 2023; 30 (03) 1453-1462
  • 9 Ohtsuka T, Fernandez-Del Castillo C, Furukawa T. et al. International evidence-based Kyoto guidelines for the management of intraductal papillary mucinous neoplasm of the pancreas. Pancreatology 2024; 24 (02) 255-270
  • 10 European Study Group on Cystic Tumours of the Pancreas. European evidence-based guidelines on pancreatic cystic neoplasms. Gut 2018; 67 (05) 789-804
  • 11 Marchegiani G, Pollini T, Andrianello S. et al. Progression vs cyst stability of branch-duct intraductal papillary mucinous neoplasms after observation and surgery. JAMA Surg 2021; 156 (07) 654-661
  • 12 Vilas-Boas F, Ribeiro T, Macedo G. et al. Endoscopic ultrasound-guided through-the-needle biopsy: a narrative review of the technique and its emerging role in pancreatic cyst diagnosis. Diagnostics (Basel) 2024; 14 (15) 1587
  • 13 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 (05) 738-753
  • 14 Tanaka M, Fernández-del Castillo C, Adsay V. et al; International Association of Pancreatology. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology 2012; 12 (03) 183-197
  • 15 Tanaka M, Chari S, Adsay V. et al; International Association of Pancreatology. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology 2006; 6 (1-2): 17-32
  • 16 Pflüger MJ, Jamouss KT, Afghani E. et al. Predictive ability of pancreatic cyst fluid biomarkers: a systematic review and meta-analysis. Pancreatology 2023; 23 (07) 868-877
  • 17 Tacelli M, Celsa C, Magro B. et al. Diagnostic performance of endoscopic ultrasound through-the-needle microforceps biopsy of pancreatic cystic lesions: systematic review with meta-analysis. Dig Endosc 2020; 32 (07) 1018-1030
  • 18 Maker AV, Lee LS, Raut CP, Clancy TE, Swanson RS. Cytology from pancreatic cysts has marginal utility in surgical decision-making. Ann Surg Oncol 2008; 15 (11) 3187-3192
  • 19 Magahis PT, Chhoda A, Berzin TM. et al. Risk of pancreatitis after endoscopic ultrasound-guided fine-needle aspiration of pancreatic cystic lesions: a systematic review and meta-analysis. Am J Gastroenterol 2024; 119 (11) 2174-2186
  • 20 Kwan MC, Pitman MB, Fernandez-Del Castillo C, Zhang ML. Revisiting the performance of cyst fluid carcinoembryonic antigen as a diagnostic marker for pancreatic mucinous cysts: a comprehensive 20-year institutional review. Gut 2024; 73 (04) 629-638
  • 21 Mohan BP, Madhu D, Khan SR. et al. Intracystic glucose levels in differentiating mucinous from nonmucinous pancreatic cysts: a systematic review and meta-analysis. J Clin Gastroenterol 2022; 56 (02) e131-e136
  • 22 Rossi G, Petrone MC, Tacelli M. et al. Glucose and lactate levels are lower in EUS-aspirated cyst fluid of mucinous vs non-mucinous pancreatic cystic lesions. Dig Liver Dis 2024; 56 (05) 836-840
  • 23 Williet N, Caillol F, Karsenti D. et al. The level of glucose in pancreatic cyst fluid is more accurate than carcinoembryonic antigen to identify mucinous tumors: a French multicenter study. Endosc Ultrasound 2023; 12 (04) 377-381
  • 24 Gorris M, Dijk F, Farina A. et al. Validation of combined carcinoembryonic antigen and glucose testing in pancreatic cyst fluid to differentiate mucinous from non-mucinous cysts. Surg Endosc 2023; 37 (05) 3739-3746
  • 25 Smith ZL, Satyavada S, Simons-Linares R. et al. Intracystic glucose and carcinoembryonic antigen in differentiating histologically confirmed pancreatic mucinous neoplastic cysts. Am J Gastroenterol 2022; 117 (03) 478-485
  • 26 Lee JH, Kim Y, Choi JW, Kim YS. KRAS, GNAS, and RNF43 mutations in intraductal papillary mucinous neoplasm of the pancreas: a meta-analysis. Springerplus 2016; 5 (01) 1172
  • 27 Berger AW, Schwerdel D, Costa IG. 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 (02) 267-270
  • 28 Okada T, Mizukami Y, Ono Y. et al. Digital PCR-based plasma cell-free DNA mutation analysis for early-stage pancreatic tumor diagnosis and surveillance. J Gastroenterol 2020; 55 (12) 1183-1193
  • 29 Park MA, Zaw T, Yoder SJ. et al. A pilot study to evaluate tissue- and plasma-based DNA driver mutations in a cohort of patients with pancreatic intraductal papillary mucinous neoplasms. G3 (Bethesda) 2023; 13 (02) jkac314
  • 30 Hata T, Mizuma M, Motoi F. et al. GNAS mutation detection in circulating cell-free DNA is a specific predictor for intraductal papillary mucinous neoplasms of the pancreas, especially for intestinal subtype. Sci Rep 2020; 10 (01) 17761
  • 31 Nitschke C, Tölle M, Walter P. et al. KRAS and GNAS mutations in cell-free DNA and in circulating epithelial cells in patients with intraductal papillary mucinous neoplasms-an observational pilot study. Mol Oncol 2024;
  • 32 Paniccia A, Polanco PM, Boone BA. et al. Prospective, multi-institutional, real-time next-generation sequencing of pancreatic cyst fluid reveals diverse genomic alterations that improve the clinical management of pancreatic cysts. Gastroenterology 2023; 164 (01) 117-133.e7
  • 33 Iyer MK, Shi C, Eckhoff AM, Fletcher A, Nussbaum DP, Allen PJ. Digital spatial profiling of intraductal papillary mucinous neoplasms: toward a molecular framework for risk stratification. Sci Adv 2023; 9 (11) eade4582
  • 34 Iyer MK, Fletcher A, Okoye JO. et al. Spatial transcriptomics of intraductal papillary mucinous neoplasms reveals divergent indolent and malignant states. Clin Cancer Res 2025;
  • 35 Moffitt RA, Marayati R, Flate EL. et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat Genet 2015; 47 (10) 1168-1178
  • 36 Collisson EA, Sadanandam A, Olson P. et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med 2011; 17 (04) 500-503
  • 37 Agostini A, Piro G, Inzani F. et al. Identification of spatially-resolved markers of malignant transformation in intraductal papillary mucinous neoplasms. Nat Commun 2024; 15 (01) 2764
  • 38 Pollini T, Adsay V, Capurso G. et al. The tumour immune microenvironment and microbiome of pancreatic intraductal papillary mucinous neoplasms. Lancet Gastroenterol Hepatol 2022; 7 (12) 1141-1150
  • 39 Maker AV, Katabi N, Qin LX. et al. Cyst fluid interleukin-1beta (IL1beta) levels predict the risk of carcinoma in intraductal papillary mucinous neoplasms of the pancreas. Clin Cancer Res 2011; 17 (06) 1502-1508
  • 40 Maker AV, Hu V, Kadkol SS. et al. Cyst fluid biosignature to predict intraductal papillary mucinous neoplasms of the pancreas with high malignant potential. J Am Coll Surg 2019; 228 (05) 721-729
  • 41 Schmidt CM, Yip-Schneider MT, Ralstin MC. et al. PGE(2) in pancreatic cyst fluid helps differentiate IPMN from MCN and predict IPMN dysplasia. J Gastrointest Surg 2008; 12 (02) 243-249
  • 42 Simpson RE, Yip-Schneider MT, Flick KF, Wu H, Colgate CL, Schmidt CM. Pancreatic fluid interleukin-1β complements prostaglandin E2 and serum carbohydrate antigen 19-9 in prediction of intraductal papillary mucinous neoplasm dysplasia. Pancreas 2019; 48 (08) 1026-1031
  • 43 Arima K, Okabe H, Hashimoto D. et al. The neutrophil-to-lymphocyte ratio predicts malignant potential in intraductal papillary mucinous neoplasms. J Gastrointest Surg 2015; 19 (12) 2171-2177
  • 44 Gemenetzis G, Bagante F, Griffin JF. et al. Neutrophil-to-lymphocyte ratio is a predictive marker for invasive malignancy in intraductal papillary mucinous neoplasms of the pancreas. Ann Surg 2017; 266 (02) 339-345
  • 45 McIntyre CA, Pulvirenti A, Lawrence SA. et al. Neutrophil-to-lymphocyte ratio as a predictor of invasive carcinoma in patients with intraductal papillary mucinous neoplasms of the pancreas. Pancreas 2019; 48 (06) 832-836
  • 46 Sugimachi K, Mano Y, Matsumoto Y. et al. Neutrophil-to-lymphocyte ratio as a predictor of malignancy of intraductal papillary mucinous neoplasms. Anticancer Res 2021; 41 (03) 1663-1669
  • 47 Hernandez S, Parra ER, Uraoka N. et al. Diminished immune surveillance during histologic progression of intraductal papillary mucinous neoplasms offers a therapeutic opportunity for cancer interception. Clin Cancer Res 2022; 28 (09) 1938-1947
  • 48 Bernard V, Semaan A, Huang J. et al. Single-cell transcriptomics of pancreatic cancer precursors demonstrates epithelial and microenvironmental heterogeneity as an early event in neoplastic progression. Clin Cancer Res 2019; 25 (07) 2194-2205
  • 49 Eckhoff AM, Fletcher AA, Landa K. et al. Multidimensional immunophenotyping of intraductal papillary mucinous neoplasms reveals novel T cell and macrophage signature. Ann Surg Oncol 2022; 29 (12) 7781-7788
  • 50 Roth S, Zamzow K, Gaida MM. et al. Evolution of the immune landscape during progression of pancreatic intraductal papillary mucinous neoplasms to invasive cancer. EBioMedicine 2020; 54: 102714
  • 51 Hiraoka N, Onozato K, Kosuge T, Hirohashi S. Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 2006; 12 (18) 5423-5434
  • 52 Kobayashi N, Kubota K, Kato S. et al. FOXP3+ regulatory T cells and tumoral indoleamine 2,3-dioxygenase expression predicts the carcinogenesis of intraductal papillary mucinous neoplasms of the pancreas. Pancreatology 2010; 10 (05) 631-640
  • 53 Li J, Wei T, Ma K. et al. Single-cell RNA sequencing highlights epithelial and microenvironmental heterogeneity in malignant progression of pancreatic ductal adenocarcinoma. Cancer Lett 2024; 584: 216607
  • 54 Ma P, Beatty PL, McKolanis J, Brand R, Schoen RE, Finn OJ. Circulating myeloid derived suppressor cells (MDSC) that accumulate in premalignancy share phenotypic and functional characteristics with MDSC in cancer. Front Immunol 2019; 10: 1401
  • 55 Cescon DW, Bratman SV, Chan SM, Siu LL. Circulating tumor DNA and liquid biopsy in oncology. Nat Cancer 2020; 1 (03) 276-290
  • 56 Krebs MG, Malapelle U, André F. et al. Practical considerations for the use of circulating tumor DNA in the treatment of patients with cancer: a narrative review. JAMA Oncol 2022; 8 (12) 1830-1839
  • 57 Kristensen LS, Jakobsen T, Hager H, Kjems J. The emerging roles of circRNAs in cancer and oncology. Nat Rev Clin Oncol 2022; 19 (03) 188-206
  • 58 Slack FJ, Chinnaiyan AM. The role of non-coding RNAs in oncology. Cell 2019; 179 (05) 1033-1055
  • 59 Sharma GG, Okada Y, Von Hoff D, Goel A. Non-coding RNA biomarkers in pancreatic ductal adenocarcinoma. Semin Cancer Biol 2021; 75: 153-168