Skip to main content
SpringerLink
Log in

Ancillary Studies in the Cytologic Diagnosis of Pancreatico-biliary Lesions

  • Chapter
  • First Online:
Pancreas and Biliary Tract Cytohistology

Part of the book series: Essentials in Cytopathology ((EICP,volume 28))

  • 712 Accesses

Abstract

Pancreatico-biliary pathology includes a broad spectrum of neoplastic diseases, such as pancreatic ductal adenocarcinoma (PDACA) and its precursor lesions, cholangiocarcinoma (ChACA), neuroendocrine and acinar tumors, and solid pseudopapillary neoplasm (SPN). Differentiating these entities from one another may be challenging by morphologic analysis alone, especially when examining the small quantities of material inherent to cytologic specimens. Fortunately, the advent of next-generation sequencing (NGS) and other novel methods of genetic, epigenetic, and proteomic characterization has facilitated the development of a broad range of molecular and other ancillary techniques for diagnostic, prognostic, and predictive evaluation of pancreatico-biliary lesions. Ancillary studies are particularly important in the subset of cases for which cytomorphologic analysis provides a result that is equivocal or insufficient to guide clinical management. In some cases, clinical management requires that pathologists differentiate among several diagnostic entities. In others, pathologists must simply identify the presence of dysplasia or malignancy. Different ancillary tests provide pathologists with different information, and selection of the correct ancillary test may be critical for patient care. Ancillary tests typically have been validated separately for evaluation of specimens collected from solid lesions, cystic lesions, and pancreatic and bile duct strictures. This chapter discusses ancillary methods for the diagnosis of pancreatic ductal adenocarcinoma and cholangiocarcinoma in both fine needle aspiration biopsy and pancreatico-biliary duct fluid, washing, and brushing specimens. Ancillary studies for the diagnosis of other neoplasms are also discussed, as well as precursor lesions of pancreatic ductal adenocarcinoma.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Cancer Genome Atlas Research Network. Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell. 2017;32(2):185–203.e13.

    Article  CAS  Google Scholar 

  2. Murphy KM, Brune KA, Griffin C, Sollenberger JE, Petersen GM, Bansal R, et al. Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. Cancer Res. 2002;62(13):3789–93.

    CAS  PubMed  Google Scholar 

  3. Al-Sukhni W, Rothenmund H, Borgida AE, Zogopoulos G, O’Shea AM, Pollett A, et al. Germline BRCA1 mutations predispose to pancreatic adenocarcinoma. Hum Genet. 2008;124(3):271–8.

    Article  CAS  PubMed  Google Scholar 

  4. Jones S, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW, et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009;324(5924):217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Roberts NJ, Jiao Y, Yu J, Kopelovich L, Petersen GM, Bondy ML, et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2012;2(1):41–6.

    Article  CAS  PubMed  Google Scholar 

  6. Zhen DB, Rabe KG, Gallinger S, Syngal S, Schwartz AG, Goggins MG, et al. BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genet Med. 2015;17(7):569–77.

    Article  CAS  PubMed  Google Scholar 

  7. Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518(7540):495–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Farshidfar F, Zheng S, Gingras MC, Newton Y, Shih J, Robertson AG, et al. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-Mutant molecular profiles. Cell Rep. 2017;18(11):2780–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Layfield LJ, Ehya H, Filie AC, Hruban RH, Jhala N, Joseph L, et al. Utilization of ancillary studies in the cytologic diagnosis of biliary and pancreatic lesions: the Papanicolaou Society of Cytopathology guidelines for pancreatobiliary cytology. Diagn Cytopathol. 2014;42(4):351–62.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Wilentz RE, Iacobuzio-Donahue CA, Argani P, McCarthy DM, Parsons JL, Yeo CJ, et al. Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res. 2000;60(7):2002–6.

    CAS  PubMed  Google Scholar 

  11. Liu H, Shi J, Anandan V, Wang HL, Diehl D, Blansfield J, et al. Reevaluation and identification of the best immunohistochemical panel (pVHL, Maspin, S100P, IMP-3) for ductal adenocarcinoma of the pancreas. Arch Pathol Lab Med. 2012;136(6):601–9.

    Article  PubMed  Google Scholar 

  12. Argani P, Iacobuzio-Donahue C, Ryu B, Rosty C, Goggins M, Wilentz RE, et al. Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE). Clin Cancer Res. 2001;7(12):3862–8.

    CAS  PubMed  Google Scholar 

  13. Agarwal B, Ludwig OJ, Collins BT, Cortese C. Immunostaining as an adjunct to cytology for diagnosis of pancreatic adenocarcinoma. Clin Gastroenterol Hepatol. 2008;6(12):1425–31.

    Article  PubMed  Google Scholar 

  14. Ali A, Brown V, Denley S, Jamieson NB, Morton JP, Nixon C, et al. Expression of KOC, S100P, mesothelin and MUC1 in pancreatico-biliary adenocarcinomas: development and utility of a potential diagnostic immunohistochemistry panel. BMC Clin Pathol. 2014;14:35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Dim DC, Jiang F, Qiu Q, Li T, Darwin P, Rodgers WH, et al. The usefulness of S100P, mesothelin, fascin, prostate stem cell antigen, and 14–3-3 sigma in diagnosing pancreatic adenocarcinoma in cytological specimens obtained by endoscopic ultrasound guided fine-needle aspiration. Diagn Cytopathol. 2014;42(3):193–9.

    Article  PubMed  Google Scholar 

  16. Zhu L, Liu Y, Chen G. Diagnostic value of mesothelinin pancreatic cancer: a meta-analysis. Int J Clin Exp Med. 2014;7(11):4000–7.

    PubMed  PubMed Central  Google Scholar 

  17. Furuhata A, Minamiguchi S, Shirahase H, Kodama Y, Adachi S, Sakurai T, et al. Immunohistochemical antibody panel for the differential diagnosis of pancreatic ductal carcinoma from gastrointestinal contamination and benign pancreatic duct epithelium in endoscopic ultrasound-guided fine-needle aspiration. Pancreas. 2017;46(4):531–8.

    Article  CAS  PubMed  Google Scholar 

  18. McCarthy DM, Maitra A, Argani P, Rader AE, Faigel DO, Van Heek NT, et al. Novel markers of pancreatic adenocarcinoma in fine-needle aspiration: mesothelin and prostate stem cell antigen labeling increases accuracy in cytologically borderline cases. Appl Immunohistochem Mol Morphol. 2003;11(3):238–43.

    Article  CAS  PubMed  Google Scholar 

  19. Ezzat NE, Tahoun NS, Ismail YM. The role of S100P and IMP3 in the cytologic diagnosis of pancreatic adenocarcinoma. J Egypt Natl Canc Inst. 2016;28(4):229–34.

    Article  PubMed  Google Scholar 

  20. Sweeney J, Rao R, Margolskee E, Goyal A, Heymann JJ, Siddiqui MT. Immunohistochemical staining for S100P, SMAD4, and IMP3 on cell block preparations is sensitive and highly specific for pancreatic ductal adenocarcinoma. Journal of the American Society of Cytopathology. 2018;7(6):318–23.

    Article  PubMed  Google Scholar 

  21. Levy MJ, Oberg TN, Campion MB, Clayton AC, Halling KC, Henry MR, et al. Comparison of methods to detect neoplasia in patients undergoing endoscopic ultrasound-guided fine-needle aspiration. Gastroenterology. 2012;142(5):1112–21.

    Article  PubMed  Google Scholar 

  22. Ribeiro A, Peng J, Casas C, Fan YS. Endoscopic ultrasound guided fine needle aspiration with fluorescence in situ hybridization analysis in 104 patients with pancreatic mass. J Gastroenterol Hepatol. 2014;29(8):1654–8.

    Article  CAS  PubMed  Google Scholar 

  23. de Biase D, Visani M, Acquaviva G, Fornelli A, Masetti M, Fabbri C, et al. The role of next-generation sequencing in the cytologic diagnosis of pancreatic lesions. Arch Pathol Lab Med. 2018;142(4):458–64.

    Article  PubMed  Google Scholar 

  24. Kameta E, Sugimori K, Kaneko T, Ishii T, Miwa H, Sato T, et al. Diagnosis of pancreatic lesions collected by endoscopic ultrasound-guided fine-needle aspiration using next-generation sequencing. Oncol Lett. 2016;12(5):3875–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Valero V, Saunders TJ, He J, Weiss MJ, Cameron JL, Dholakia A, et al. Reliable detection of somatic mutations in fine needle aspirates of pancreatic cancer with next-generation sequencing: implications for surgical management. Ann Surg. 2016;263(1):153–61.

    Article  PubMed  Google Scholar 

  26. Young G, Wang K, He J, Otto G, Hawryluk M, Zwirco Z, et al. Clinical next-generation sequencing successfully applied to fine-needle aspirations of pulmonary and pancreatic neoplasms. Cancer Cytopathol. 2013;121(12):688–94.

    Article  CAS  PubMed  Google Scholar 

  27. Gleeson FC, Kerr SE, Kipp BR, Voss JS, Minot DM, Tu ZJ, et al. Targeted next generation sequencing of endoscopic ultrasound acquired cytology from ampullary and pancreatic adenocarcinoma has the potential to aid patient stratification for optimal therapy selection. Oncotarget. 2016;7(34):54526–36.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Hayashi H, Kohno T, Ueno H, Hiraoka N, Kondo S, Saito M, et al. Utility of assessing the number of mutated KRAS, CDKN2A, TP53, and SMAD4 genes using a targeted deep sequencing assay as a prognostic biomarker for pancreatic cancer. Pancreas. 2017;46(3):335–40.

    Article  CAS  PubMed  Google Scholar 

  29. Deftereos G, Finkelstein SD, Jackson SA, Ellsworth EM, Krishnamurti U, Liu Y, et al. The value of mutational profiling of the cytocentrifugation supernatant fluid from fine-needle aspiration of pancreatic solid mass lesions. Mod Pathol. 2014;27(4):594–601.

    Article  CAS  PubMed  Google Scholar 

  30. Khalid A, Dewitt J, Ohori NP, Chen JH, Fasanella KE, Sanders M, et al. EUS-FNA mutational analysis in differentiating autoimmune pancreatitis and pancreatic cancer. Pancreatology. 2011;11(5):482–6.

    Article  PubMed  Google Scholar 

  31. Steele CW, Oien KA, McKay CJ, Jamieson NB. Clinical potential of microRNAs in pancreatic ductal adenocarcinoma. Pancreas. 2011;40(8):1165–71.

    Article  CAS  PubMed  Google Scholar 

  32. Ali S, Saleh H, Sethi S, Sarkar FH, Philip PA. MicroRNA profiling of diagnostic needle aspirates from patients with pancreatic cancer. Br J Cancer. 2012;107(8):1354–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hong TH, Park IY. MicroRNA expression profiling of diagnostic needle aspirates from surgical pancreatic cancer specimens. Ann Surg Treat Res. 2014;87(6):290–7.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Brand RE, Adai AT, Centeno BA, Lee LS, Rateb G, Vignesh S, et al. A microRNA-based test improves endoscopic ultrasound-guided cytologic diagnosis of pancreatic cancer. Clin Gastroenterol Hepatol. 2014;12(10):1717–23.

    Article  CAS  PubMed  Google Scholar 

  35. Shi C, Klimstra DS. Pancreatic neuroendocrine tumors: pathologic and molecular characteristics. Semin Diagn Pathol. 2014;31(6):498–511.

    Article  PubMed  Google Scholar 

  36. Wood LD, Hruban RH. Genomic landscapes of pancreatic neoplasia. J Pathol Transl Med. 2015;49(1):13–22.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Pea A, Hruban RH, Wood LD. Genetics of pancreatic neuroendocrine tumors: implications for the clinic. Expert Rev Gastroenterol Hepatol. 2015;9(11):1407–19.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Hackeng WM, Hruban RH, Offerhaus GJ, Brosens LA. Surgical and molecular pathology of pancreatic neoplasms. Diagn Pathol. 2016;11(1):47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331(6021):1199–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yachida S, Vakiani E, White CM, Zhong Y, Saunders T, Morgan R, et al. Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. Am J Surg Pathol. 2012;36(2):173–84.

    Article  PubMed  PubMed Central  Google Scholar 

  41. La Rosa S, Sessa F, Capella C. Acinar Cell carcinoma of the pancreas: overview of clinicopathologic features and insights into the molecular pathology. Front Med (Lausanne). 2015;2:41.

    Google Scholar 

  42. Abraham SC, Wu TT, Klimstra DS, Finn LS, Lee JH, Yeo CJ, et al. Distinctive molecular genetic alterations in sporadic and familial adenomatous polyposis-associated pancreatoblastomas : frequent alterations in the APC/beta-catenin pathway and chromosome 11p. Am J Pathol. 2001;159(5):1619–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Abraham SC, Wu TT, Hruban RH, Lee JH, Yeo CJ, Conlon K, et al. Genetic and immunohistochemical analysis of pancreatic acinar cell carcinoma: frequent allelic loss on chromosome 11p and alterations in the APC/beta-catenin pathway. Am J Pathol. 2002;160(3):953–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Weksberg R, Shuman C, Beckwith JB. Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2010;18(1):8–14.

    Article  PubMed  Google Scholar 

  45. Jiao Y, Yonescu R, Offerhaus GJ, Klimstra DS, Maitra A, Eshleman JR, et al. Whole-exome sequencing of pancreatic neoplasms with acinar differentiation. J Pathol. 2014;232(4):428–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Furlan D, Sahnane N, Bernasconi B, Frattini M, Tibiletti MG, Molinari F, et al. APC alterations are frequently involved in the pathogenesis of acinar cell carcinoma of the pancreas, mainly through gene loss and promoter hypermethylation. Virchows Arch. 2014;464(5):553–64.

    Article  CAS  PubMed  Google Scholar 

  47. Chmielecki J, Hutchinson KE, Frampton GM, Chalmers ZR, Johnson A, Shi C, et al. Comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes. Cancer Discov. 2014;4(12):1398–405.

    Article  CAS  PubMed  Google Scholar 

  48. Tanaka Y, Kato K, Notohara K, Hojo H, Ijiri R, Miyake T, et al. Frequent beta-catenin mutation and cytoplasmic/nuclear accumulation in pancreatic solid-pseudopapillary neoplasm. Cancer Res. 2001;61(23):8401–4.

    CAS  PubMed  Google Scholar 

  49. Abraham SC, Klimstra DS, Wilentz RE, Yeo CJ, Conlon K, Brennan M, et al. Solid-pseudopapillary tumors of the pancreas are genetically distinct from pancreatic ductal adenocarcinomas and almost always harbor beta-catenin mutations. Am J Pathol. 2002;160(4):1361–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Burford H, Baloch Z, Liu X, Jhala D, Siegal GP, Jhala N. E-cadherin/beta-catenin and CD10: a limited immunohistochemical panel to distinguish pancreatic endocrine neoplasm from solid pseudopapillary neoplasm of the pancreas on endoscopic ultrasound-guided fine-needle aspirates of the pancreas. Am J Clin Pathol. 2009;132(6):831–9.

    Article  CAS  PubMed  Google Scholar 

  51. La Rosa S, Franzi F, Marchet S, Finzi G, Clerici M, Vigetti D, et al. The monoclonal anti-BCL10 antibody (clone 331.1) is a sensitive and specific marker of pancreatic acinar cell carcinoma and pancreatic metaplasia. Virchows Arch. 2009;454(2):133–42.

    Article  PubMed  CAS  Google Scholar 

  52. Hosoda W, Sasaki E, Murakami Y, Yamao K, Shimizu Y, Yatabe Y. BCL10 as a useful marker for pancreatic acinar cell carcinoma, especially using endoscopic ultrasound cytology specimens. Pathol Int. 2013;63(3):176–82.

    Article  CAS  PubMed  Google Scholar 

  53. Comper F, Antonello D, Beghelli S, Gobbo S, Montagna L, Pederzoli P, et al. Expression pattern of claudins 5 and 7 distinguishes solid-pseudopapillary from pancreatoblastoma, acinar cell and endocrine tumors of the pancreas. Am J Surg Pathol. 2009;33(5):768–74.

    Article  PubMed  Google Scholar 

  54. Yasumoto M, Hamabashiri M, Akiba J, Ogasawara S, Naito Y, Taira T, et al. The utility of a novel antibody in the pathological diagnosis of pancreatic acinar cell carcinoma. J Clin Pathol. 2012;65(4):327–32.

    Article  PubMed  Google Scholar 

  55. Singhi AD, Lilo M, Hruban RH, Cressman KL, Fuhrer K, Seethala RR. Overexpression of lymphoid enhancer-binding factor 1 (LEF1) in solid-pseudopapillary neoplasms of the pancreas. Mod Pathol. 2014;27(10):1355–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Guo Y, Yuan F, Deng H, Wang HF, Jin XL, Xiao JC. Paranuclear dot-like immunostaining for CD99: a unique staining pattern for diagnosing solid-pseudopapillary neoplasm of the pancreas. Am J Surg Pathol. 2011;35(6):799–806.

    Article  PubMed  Google Scholar 

  57. Larghi A, Capurso G, Carnuccio A, Ricci R, Alfieri S, Galasso D, et al. Ki-67 grading of nonfunctioning pancreatic neuroendocrine tumors on histologic samples obtained by EUS-guided fine-needle tissue acquisition: a prospective study. Gastrointest Endosc. 2012;76(3):570–7.

    Article  PubMed  Google Scholar 

  58. Hasegawa T, Yamao K, Hijioka S, Bhatia V, Mizuno N, Hara K, et al. Evaluation of Ki-67 index in EUS-FNA specimens for the assessment of malignancy risk in pancreatic neuroendocrine tumors. Endoscopy. 2014;46(1):32–8.

    PubMed  Google Scholar 

  59. Weynand B, Borbath I, Bernard V, Sempoux C, Gigot JF, Hubert C, et al. Pancreatic neuroendocrine tumour grading on endoscopic ultrasound-guided fine needle aspiration: high reproducibility and inter-observer agreement of the Ki-67 labelling index. Cytopathology. 2014;25(6):389–95.

    CAS  PubMed  Google Scholar 

  60. Diaz Del Arco C, Diaz Perez JA, Ortega Medina L, Sastre Valera J, Fernandez Acenero MJ. Reliability of Ki-67 determination in FNA samples for grading pancreatic neuroendocrine tumors. Endocr Pathol. 2016;27(4):276–83.

    Article  CAS  PubMed  Google Scholar 

  61. Ozaslan E, Demir S, Karaca H, Guven K. Evaluation of the concordance between the stage of the disease and Ki-67 proliferation index in gastroenteropancreatic neuroendocrine tumors. Eur J Gastroenterol Hepatol. 2016;28(7):836–41.

    Article  PubMed  CAS  Google Scholar 

  62. Diaz Del Arco C, Esteban Lopez-Jamar JM, Ortega Medina L, Diaz Perez JA, Fernandez Acenero MJ. Fine-needle aspiration biopsy of pancreatic neuroendocrine tumors: correlation between Ki-67 index in cytological samples and clinical behavior. Diagn Cytopathol. 2017;45(1):29–35.

    Article  PubMed  Google Scholar 

  63. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):501–13.

    Article  CAS  PubMed  Google Scholar 

  65. Phan AT, Halperin DM, Chan JA, Fogelman DR, Hess KR, Malinowski P, et al. Pazopanib and depot octreotide in advanced, well-differentiated neuroendocrine tumours: a multicentre, single-group, phase 2 study. Lancet Oncol. 2015;16(6):695–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hobday TJ, Qin R, Reidy-Lagunes D, Moore MJ, Strosberg J, Kaubisch A, et al. Multicenter Phase II trial of Temsirolimus and Bevacizumab in pancreatic neuroendocrine tumors. J Clin Oncol. 2015;33(14):1551–6.

    Article  CAS  PubMed  Google Scholar 

  67. Nodit L, McGrath KM, Zahid M, Jani N, Schoedel KE, Ohori NP, et al. Endoscopic ultrasound-guided fine needle aspirate microsatellite loss analysis and pancreatic endocrine tumor outcome. Clin Gastroenterol Hepatol. 2006;4(12):1474–8.

    Article  CAS  PubMed  Google Scholar 

  68. Kubota Y, Kawakami H, Natsuizaka M, Kawakubo K, Marukawa K, Kudo T, et al. CTNNB1 mutational analysis of solid-pseudopapillary neoplasms of the pancreas using endoscopic ultrasound-guided fine-needle aspiration and next-generation deep sequencing. J Gastroenterol. 2015;50(2):203–10.

    Article  CAS  PubMed  Google Scholar 

  69. Sigel CS, Krauss Silva VW, Reid MD, Chhieng D, Basturk O, Sigel KM, et al. Assessment of cytologic differentiation in high-grade pancreatic neuroendocrine neoplasms: a multi-institutional study. Cancer Cytopathol. 2018;126(1):44–53.

    Article  CAS  PubMed  Google Scholar 

  70. Basturk O, Coban I, Adsay NV. Pancreatic cysts: pathologic classification, differential diagnosis, and clinical implications. Arch Pathol Lab Med. 2009;133(3):423–38.

    PubMed  Google Scholar 

  71. Wu J, Jiao Y, Dal Molin M, Maitra A, de Wilde RF, Wood LD, et al. Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proc Natl Acad Sci U S A. 2011;108(52):21188–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wu J, Matthaei H, Maitra A, Dal Molin M, Wood LD, Eshleman JR, et al. Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci Transl Med. 2011;3(92):92ra66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Amato E, Molin MD, Mafficini A, Yu J, Malleo G, Rusev B, et al. Targeted next-generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas. J Pathol. 2014;233(3):217–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Habbe N, Koorstra JB, Mendell JT, Offerhaus GJ, Ryu JK, Feldmann G, et al. MicroRNA miR-155 is a biomarker of early pancreatic neoplasia. Cancer Biol Ther. 2009;8(4):340–6.

    Article  CAS  PubMed  Google Scholar 

  75. Lubezky N, Loewenstein S, Ben-Haim M, Brazowski E, Marmor S, Pasmanik-Chor M, et al. MicroRNA expression signatures in intraductal papillary mucinous neoplasm of the pancreas. Surgery. 2013;153(5):663–72.

    Article  PubMed  Google Scholar 

  76. Hong SM, Kelly D, Griffith M, Omura N, Li A, Li CP, et al. Multiple genes are hypermethylated in intraductal papillary mucinous neoplasms of the pancreas. Mod Pathol. 2008;21(12):1499–507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hong SM, Omura N, Vincent A, Li A, Knight S, Yu J, et al. Genome-wide CpG island profiling of intraductal papillary mucinous neoplasms of the pancreas. Clin Cancer Res. 2012;18(3):700–12.

    Article  CAS  PubMed  Google Scholar 

  78. Leung KK, Ross WA, Evans D, Fleming J, Lin E, Tamm EP, et al. Pancreatic cystic neoplasm: the role of cyst morphology, cyst fluid analysis, and expectant management. Ann Surg Oncol. 2009;16(10):2818–24.

    Article  PubMed  Google Scholar 

  79. 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.

    Article  CAS  PubMed  Google Scholar 

  80. 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.

    Article  PubMed  Google Scholar 

  81. Rockacy M, Khalid A. Update on pancreatic cyst fluid analysis. Ann Gastroenterol. 2013;26(2):122–7.

    PubMed  PubMed Central  Google Scholar 

  82. Ngamruengphong S, Lennon AM. Analysis of pancreatic cyst fluid. Surg Pathol Clin. 2016;9(4):677–84.

    Article  PubMed  PubMed Central  Google Scholar 

  83. 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.

    Article  PubMed  Google Scholar 

  84. Linder JD, Geenen JE, Catalano MF. Cyst fluid analysis obtained by EUS-guided FNA in the evaluation of discrete cystic neoplasms of the pancreas: a prospective single-center experience. Gastrointest Endosc. 2006;64(5):697–702.

    Article  PubMed  Google Scholar 

  85. Snozek CL, Mascarenhas RC, O’Kane DJ. Use of cyst fluid CEA, CA19–9, and amylase for evaluation of pancreatic lesions. Clin Biochem. 2009;42(15):1585–8.

    Article  CAS  PubMed  Google Scholar 

  86. Cizginer S, Turner BG, Bilge AR, Karaca C, Pitman MB, Brugge WR. Cyst fluid carcinoembryonic antigen is an accurate diagnostic marker of pancreatic mucinous cysts. Pancreas. 2011;40(7):1024–8.

    Article  CAS  PubMed  Google Scholar 

  87. Soyer OM, Baran B, Ormeci AC, Sahin D, Gokturk S, Evirgen S, et al. Role of biochemistry and cytological analysis of cyst fluid for the differential diagnosis of pancreatic cysts: a retrospective cohort study. Medicine (Baltimore). 2017;96(1):e5513.

    Article  CAS  Google Scholar 

  88. Ajaj Saieg M, Munson V, Colletti S, Nassar A. Impact of pancreatic cyst fluid CEA levels on the classification of pancreatic cysts using the Papanicolaou Society of Cytology Terminology System for Pancreaticobiliary cytology. Diagn Cytopathol. 2017;45(2):101–6.

    Article  PubMed  Google Scholar 

  89. Thornton GD, McPhail MJ, Nayagam S, Hewitt MJ, Vlavianos P, Monahan KJ. Endoscopic ultrasound guided fine needle aspiration for the diagnosis of pancreatic cystic neoplasms: a meta-analysis. Pancreatology. 2013;13(1):48–57.

    Article  CAS  PubMed  Google Scholar 

  90. de Jong K, Poley JW, van Hooft JE, Visser M, Bruno MJ, Fockens P. Endoscopic ultrasound-guided fine-needle aspiration of pancreatic cystic lesions provides inadequate material for cytology and laboratory analysis: initial results from a prospective study. Endoscopy. 2011;43(7):585–90.

    Article  PubMed  Google Scholar 

  91. Luttges J, Zamboni G, Longnecker D, Kloppel G. The immunohistochemical mucin expression pattern distinguishes different types of intraductal papillary mucinous neoplasms of the pancreas and determines their relationship to mucinous noncystic carcinoma and ductal adenocarcinoma. Am J Surg Pathol. 2001;25(7):942–8.

    Article  CAS  PubMed  Google Scholar 

  92. Luttges J, Feyerabend B, Buchelt T, Pacena M, Kloppel G. The mucin profile of noninvasive and invasive mucinous cystic neoplasms of the pancreas. Am J Surg Pathol. 2002;26(4):466–71.

    Article  CAS  PubMed  Google Scholar 

  93. Nakamura A, Horinouchi M, Goto M, Nagata K, Sakoda K, Takao S, et al. New classification of pancreatic intraductal papillary-mucinous tumour by mucin expression: its relationship with potential for malignancy. J Pathol. 2002;197(2):201–10.

    Article  PubMed  Google Scholar 

  94. Jabbar KS, Verbeke C, Hyltander AG, Sjovall H, Hansson GC, Sadik R. Proteomic mucin profiling for the identification of cystic precursors of pancreatic cancer. J Natl Cancer Inst. 2014;106(2):djt439.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Lewandrowski KB, Southern JF, Pins MR, Compton CC, Warshaw AL. Cyst fluid analysis in the differential diagnosis of pancreatic cysts. A comparison of pseudocysts, serous cystadenomas, mucinous cystic neoplasms, and mucinous cystadenocarcinoma. Ann Surg. 1993;217(1):41–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Lee LS, Banks PA, Bellizzi AM, Sainani NI, Kadiyala V, Suleiman S, et al. Inflammatory protein profiling of pancreatic cyst fluid using EUS-FNA in tandem with cytokine microarray differentiates between branch duct IPMN and inflammatory cysts. J Immunol Methods. 2012;382(1–2):142–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Yip-Schneider MT, Wu H, Dumas RP, Hancock BA, Agaram N, Radovich M, et al. Vascular endothelial growth factor, a novel and highly accurate pancreatic fluid biomarker for serous pancreatic cysts. J Am Coll Surg. 2014;218(4):608–17.

    Article  PubMed  Google Scholar 

  98. Lee LS, Bellizzi AM, Banks PA, Sainani NI, Kadiyala V, Suleiman S, et al. Differentiating branch duct and mixed IPMN in endoscopically collected pancreatic cyst fluid via cytokine analysis. Gastroenterol Res Pract. 2012;2012:247309.

    PubMed  PubMed Central  Google Scholar 

  99. Maker AV, Katabi N, Qin LX, Klimstra DS, Schattner M, Brennan MF, 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(6):1502–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Schmidt CM, Yip-Schneider MT, Ralstin MC, Wentz S, DeWitt J, Sherman S, et al. PGE(2) in pancreatic cyst fluid helps differentiate IPMN from MCN and predict IPMN dysplasia. J Gastrointest Surg. 2008;12(2):243–9.

    Article  PubMed  Google Scholar 

  101. 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.

    Article  PubMed  Google Scholar 

  102. Barresi L, Tarantino I, Traina M, Granata A, Curcio G, Azzopardi N, et al. Endoscopic ultrasound-guided fine needle aspiration and biopsy using a 22-gauge needle with side fenestration in pancreatic cystic lesions. Dig Liver Dis. 2014;46(1):45–50.

    Article  PubMed  Google Scholar 

  103. Shakhatreh MH, Naini SR, Brijbassie AA, Grider DJ, Shen P, Yeaton P. Use of a novel through-the-needle biopsy forceps in endoscopic ultrasound. Endosc Int Open. 2016;4(4):E439–42.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Zhang ML, Arpin RN, Brugge WR, Forcione DG, Basar O, Pitman MB. Moray micro forceps biopsy improves the diagnosis of specific pancreatic cysts. Cancer Cytopathol. 2018;126(6):414–20.

    Article  CAS  PubMed  Google Scholar 

  105. Nagata K, Horinouchi M, Saitou M, Higashi M, Nomoto M, Goto M, et al. Mucin expression profile in pancreatic cancer and the precursor lesions. J Hepato-Biliary-Pancreat Surg. 2007;14(3):243–54.

    Article  Google Scholar 

  106. Terris B, Dubois S, Buisine MP, Sauvanet A, Ruszniewski P, Aubert JP, et al. Mucin gene expression in intraductal papillary-mucinous pancreatic tumours and related lesions. J Pathol. 2002;197(5):632–7.

    Article  CAS  PubMed  Google Scholar 

  107. Khalid A, Zahid M, Finkelstein SD, LeBlanc JK, Kaushik N, Ahmad N, et al. Pancreatic cyst fluid DNA analysis in evaluating pancreatic cysts: a report of the PANDA study. Gastrointest Endosc. 2009;69(6):1095–102.

    Article  PubMed  Google Scholar 

  108. Reid MD, Lewis MM, Willingham FF, Adsay NV. The evolving role of pathology in new developments, classification, terminology, and diagnosis of pancreatobiliary neoplasms. Arch Pathol Lab Med. 2017;141(3):366–80.

    Article  PubMed  Google Scholar 

  109. Al-Haddad M. Role of emerging molecular markers in pancreatic cyst fluid. Endosc Ultrasound. 2015;4(4):276–83.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Maker AV, Carrara S, Jamieson NB, Pelaez-Luna M, Lennon AM, Dal Molin M, 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(2):243–53.

    Article  PubMed  Google Scholar 

  111. Khalid A, McGrath KM, Zahid M, Wilson M, Brody D, Swalsky P, et al. The role of pancreatic cyst fluid molecular analysis in predicting cyst pathology. Clin Gastroenterol Hepatol. 2005;3(10):967–73.

    Article  CAS  PubMed  Google Scholar 

  112. Al-Haddad M, DeWitt J, Sherman S, Schmidt CM, LeBlanc JK, McHenry L, et al. Performance characteristics of molecular (DNA) analysis for the diagnosis of mucinous pancreatic cysts. Gastrointest Endosc. 2014;79(1):79–87.

    Article  PubMed  Google Scholar 

  113. Al-Haddad MA, Kowalski T, Siddiqui A, Mertz HR, Mallat D, Haddad N, et al. Integrated molecular pathology accurately determines the malignant potential of pancreatic cysts. Endoscopy. 2015;47(2):136–42.

    PubMed  Google Scholar 

  114. Singhi AD, Nikiforova MN, Fasanella KE, McGrath KM, Pai RK, Ohori NP, et al. Preoperative GNAS and KRAS testing in the diagnosis of pancreatic mucinous cysts. Clin Cancer Res. 2014;20(16):4381–9.

    Article  CAS  PubMed  Google Scholar 

  115. Rosenbaum MW, Jones M, Dudley JC, Le LP, Iafrate AJ, Pitman MB. Next-generation sequencing adds value to the preoperative diagnosis of pancreatic cysts. Cancer Cytopathol. 2017;125(1):41–7.

    Article  CAS  PubMed  Google Scholar 

  116. Jones M, Zheng Z, Wang J, Dudley J, Albanese E, Kadayifci A, et al. Impact of next-generation sequencing on the clinical diagnosis of pancreatic cysts. Gastrointest Endosc. 2016;83(1):140–8.

    Article  PubMed  Google Scholar 

  117. 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.

    Article  CAS  PubMed  Google Scholar 

  118. Shen J, Brugge WR, Dimaio CJ, Pitman MB. Molecular analysis of pancreatic cyst fluid: a comparative analysis with current practice of diagnosis. Cancer. 2009;117(3):217–27.

    PubMed  Google Scholar 

  119. Toll AD, Kowalski T, Loren D, Bibbo M. The added value of molecular testing in small pancreatic cysts. JOP. 2010;11(6):582–6.

    PubMed  Google Scholar 

  120. Sawhney MS, Devarajan S, O’Farrel P, Cury MS, Kundu R, Vollmer CM, et al. Comparison of carcinoembryonic antigen and molecular analysis in pancreatic cyst fluid. Gastrointest Endosc. 2009;69(6):1106–10.

    Article  PubMed  Google Scholar 

  121. Talar-Wojnarowska R, Pazurek M, Durko L, Degowska M, Rydzewska G, Smigielski J, et al. A comparative analysis of K-ras mutation and carcinoembryonic antigen in pancreatic cyst fluid. Pancreatology. 2012;12(5):417–20.

    Article  CAS  PubMed  Google Scholar 

  122. Mertz H. K-ras mutations correlate with atypical cytology and elevated CEA levels in pancreatic cystic neoplasms. Dig Dis Sci. 2011;56(7):2197–201.

    Article  CAS  PubMed  Google Scholar 

  123. Panarelli NC, Sela R, Schreiner AM, Crapanzano JP, Klimstra DS, Schnoll-Sussman F, et al. Commercial molecular panels are of limited utility in the classification of pancreatic cystic lesions. Am J Surg Pathol. 2012;36(10):1434–43.

    Article  PubMed  Google Scholar 

  124. Nikiforova MN, Khalid A, Fasanella KE, McGrath KM, Brand RE, Chennat JS, et al. Integration of KRAS testing in the diagnosis of pancreatic cystic lesions: a clinical experience of 618 pancreatic cysts. Mod Pathol. 2013;26(11):1478–87.

    Article  CAS  PubMed  Google Scholar 

  125. 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.

    Article  Google Scholar 

  126. Winner M, Sethi A, Poneros JM, Stavropoulos SN, Francisco P, Lightdale CJ, et al. The role of molecular analysis in the diagnosis and surveillance of pancreatic cystic neoplasms. JOP. 2015;16(2):143–9.

    PubMed  Google Scholar 

  127. DeWitt JM, Al-Haddad M, Sherman S, LeBlanc J, Schmidt CM, Sandrasegaran K, et al. Alterations in cyst fluid genetics following endoscopic ultrasound-guided pancreatic cyst ablation with ethanol and paclitaxel. Endoscopy. 2014;46(6):457–64.

    Article  PubMed  Google Scholar 

  128. Ryu JK, Matthaei H, Dal Molin M, Hong SM, Canto MI, Schulick RD, et al. Elevated microRNA miR-21 levels in pancreatic cyst fluid are predictive of mucinous precursor lesions of ductal adenocarcinoma. Pancreatology. 2011;11(3):343–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Wang J, Paris PL, Chen J, Ngo V, Yao H, Frazier ML, et al. Next generation sequencing of pancreatic cyst fluid microRNAs from low grade-benign and high grade-invasive lesions. Cancer Lett. 2015;356(2 Pt B):404–9.

    Article  CAS  PubMed  Google Scholar 

  130. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Vincent A, Omura N, Hong SM, Jaffe A, Eshleman J, Goggins M. Genome-wide analysis of promoter methylation associated with gene expression profile in pancreatic adenocarcinoma. Clin Cancer Res. 2011;17(13):4341–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Chai SM, Herba K, Kumarasinghe MP, de Boer WB, Amanuel B, Grieu-Iacopetta F, et al. Optimizing the multimodal approach to pancreatic cyst fluid diagnosis: developing a volume-based triage protocol. Cancer Cytopathol. 2013;121(2):86–100.

    Article  CAS  PubMed  Google Scholar 

  135. Ryan ME, Baldauf MC. Comparison of flow cytometry for DNA content and brush cytology for detection of malignancy in pancreaticobiliary strictures. Gastrointest Endosc. 1994;40(2 Pt 1):133–9.

    Article  CAS  PubMed  Google Scholar 

  136. Rumalla A, Baron TH, Leontovich O, Burgart LJ, Yacavone RF, Therneau TM, et al. Improved diagnostic yield of endoscopic biliary brush cytology by digital image analysis. Mayo Clin Proc. 2001;76(1):29–33.

    Article  CAS  PubMed  Google Scholar 

  137. Baron TH, Harewood GC, Rumalla A, Pochron NL, Stadheim LM, Gores GJ, et al. A prospective comparison of digital image analysis and routine cytology for the identification of malignancy in biliary tract strictures. Clin Gastroenterol Hepatol. 2004;2(3):214–9.

    Article  PubMed  Google Scholar 

  138. Hamada S, Satoh K, Hirota M, Kanno A, Ishida K, Umino J, et al. Calcium-binding protein S100P is a novel diagnostic marker of cholangiocarcinoma. Cancer Sci. 2011;102(1):150–6.

    Article  CAS  PubMed  Google Scholar 

  139. Agrawal S, Kuvshinoff BW, Khoury T, Yu J, Javle MM, LeVea C, et al. CD24 expression is an independent prognostic marker in cholangiocarcinoma. J Gastrointest Surg. 2007;11(4):445–51.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Javle MM, Tan D, Yu J, LeVea CM, Li F, Kuvshinoff BW, et al. Nuclear survivin expression predicts poor outcome in cholangiocarcinoma. Hepato-Gastroenterology. 2004;51(60):1653–7.

    PubMed  Google Scholar 

  141. Swierczynski SL, Maitra A, Abraham SC, Iacobuzio-Donahue CA, Ashfaq R, Cameron JL, et al. Analysis of novel tumor markers in pancreatic and biliary carcinomas using tissue microarrays. Hum Pathol. 2004;35(3):357–66.

    Article  CAS  PubMed  Google Scholar 

  142. Tascilar M, Offerhaus GJ, Altink R, Argani P, Sohn TA, Yeo CJ, et al. Immunohistochemical labeling for the Dpc4 gene product is a specific marker for adenocarcinoma in biopsy specimens of the pancreas and bile duct. Am J Clin Pathol. 2001;116(6):831–7.

    Article  CAS  PubMed  Google Scholar 

  143. Zhao H, Davydova L, Mandich D, Cartun RW, Ligato S. S100A4 protein and mesothelin expression in dysplasia and carcinoma of the extrahepatic bile duct. Am J Clin Pathol. 2007;127(3):374–9.

    Article  CAS  PubMed  Google Scholar 

  144. Karamitopoulou E, Tornillo L, Zlobec I, Cioccari L, Carafa V, Borner M, et al. Clinical significance of cell cycle- and apoptosis-related markers in biliary tract cancer: a tissue microarray-based approach revealing a distinctive immunophenotype for intrahepatic and extrahepatic cholangiocarcinomas. Am J Clin Pathol. 2008;130(5):780–6.

    Article  CAS  PubMed  Google Scholar 

  145. Ayaru L, Stoeber K, Webster GJ, Hatfield AR, Wollenschlaeger A, Okoturo O, et al. Diagnosis of pancreaticobiliary malignancy by detection of minichromosome maintenance protein 5 in bile aspirates. Br J Cancer. 2008;98(9):1548–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Levy M, Lin F, Xu H, Dhall D, Spaulding BO, Wang HL. S100P, von Hippel-Lindau gene product, and IMP3 serve as a useful immunohistochemical panel in the diagnosis of adenocarcinoma on endoscopic bile duct biopsy. Hum Pathol. 2010;41(9):1210–9.

    Article  CAS  PubMed  Google Scholar 

  147. Tretiakova M, Antic T, Westerhoff M, Mueller J, Himmelfarb EA, Wang HL, et al. Diagnostic utility of CD10 in benign and malignant extrahepatic bile duct lesions. Am J Surg Pathol. 2012;36(1):101–8.

    Article  PubMed  Google Scholar 

  148. Lau SK, Prakash S, Geller SA, Alsabeh R. Comparative immunohistochemical profile of hepatocellular carcinoma, cholangiocarcinoma, and metastatic adenocarcinoma. Hum Pathol. 2002;33(12):1175–81.

    Article  PubMed  Google Scholar 

  149. Komuta M, Spee B, Vander Borght S, De Vos R, Verslype C, Aerts R, et al. Clinicopathological study on cholangiolocellular carcinoma suggesting hepatic progenitor cell origin. Hepatology. 2008;47(5):1544–56.

    Article  CAS  PubMed  Google Scholar 

  150. Nishihara Y, Aishima S, Hayashi A, Iguchi T, Fujita N, Taketomi A, et al. CD10+ fibroblasts are more involved in the progression of hilar/extrahepatic cholangiocarcinoma than of peripheral intrahepatic cholangiocarcinoma. Histopathology. 2009;55(4):423–31.

    Article  PubMed  Google Scholar 

  151. Stewart CJ, Burke GM. Value of p53 immunostaining in pancreatico-biliary brush cytology specimens. Diagn Cytopathol. 2000;23(5):308–13.

    Article  CAS  PubMed  Google Scholar 

  152. Hart J, Parab M, Mandich D, Cartun RW, Ligato S. IMP3 immunocytochemical staining increases sensitivity in the routine cytologic evaluation of biliary brush specimens. Diagn Cytopathol. 2012;40(4):321–6.

    Article  PubMed  Google Scholar 

  153. Tokumitsu T, Sato Y, Yamashita A, Moriguchi-Goto S, Kondo K, Nanashima A, et al. Immunocytochemistry for Claudin-18 and Maspin in biliary brushing cytology increases the accuracy of diagnosing pancreatobiliary malignancies. Cytopathology. 2017;28(2):116–21.

    Article  CAS  PubMed  Google Scholar 

  154. Kipp BR, Barr Fritcher EG, Pettengill JE, Halling KC, Clayton AC. Improving the accuracy of pancreatobiliary tract cytology with fluorescence in situ hybridization: a molecular test with proven clinical success. Cancer Cytopathol. 2013;121(11):610–9.

    Article  PubMed  Google Scholar 

  155. Rizvi S, Eaton J, Yang JD, Chandrasekhara V, Gores GJ. Emerging technologies for the diagnosis of perihilar cholangiocarcinoma. Semin Liver Dis. 2018;38(2):160–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Kipp BR, Stadheim LM, Halling SA, Pochron NL, Harmsen S, Nagorney DM, et al. A comparison of routine cytology and fluorescence in situ hybridization for the detection of malignant bile duct strictures. Am J Gastroenterol. 2004;99(9):1675–81.

    Article  PubMed  Google Scholar 

  157. Moreno Luna LE, Kipp B, Halling KC, Sebo TJ, Kremers WK, Roberts LR, et al. Advanced cytologic techniques for the detection of malignant pancreatobiliary strictures. Gastroenterology. 2006;131(4):1064–72.

    Article  PubMed  Google Scholar 

  158. Barr Fritcher EG, Kipp BR, Slezak JM, Moreno-Luna LE, Gores GJ, Levy MJ, et al. Correlating routine cytology, quantitative nuclear morphometry by digital image analysis, and genetic alterations by fluorescence in situ hybridization to assess the sensitivity of cytology for detecting pancreatobiliary tract malignancy. Am J Clin Pathol. 2007;128(2):272–9.

    Article  PubMed  Google Scholar 

  159. Levy MJ, Baron TH, Clayton AC, Enders FB, Gostout CJ, Halling KC, et al. Prospective evaluation of advanced molecular markers and imaging techniques in patients with indeterminate bile duct strictures. Am J Gastroenterol. 2008;103(5):1263–73.

    Article  PubMed  PubMed Central  Google Scholar 

  160. Fritcher EG, Kipp BR, Halling KC, Oberg TN, Bryant SC, Tarrell RF, et al. A multivariable model using advanced cytologic methods for the evaluation of indeterminate pancreatobiliary strictures. Gastroenterology. 2009;136(7):2180–6.

    Article  PubMed  Google Scholar 

  161. Smoczynski M, Jablonska A, Matyskiel A, Lakomy J, Dubowik M, Marek I, et al. Routine brush cytology and fluorescence in situ hybridization for assessment of pancreatobiliary strictures. Gastrointest Endosc. 2012;75(1):65–73.

    Article  PubMed  Google Scholar 

  162. Gonda TA, Glick MP, Sethi A, Poneros JM, Palmas W, Iqbal S, et al. Polysomy and p16 deletion by fluorescence in situ hybridization in the diagnosis of indeterminate biliary strictures. Gastrointest Endosc. 2012;75(1):74–9.

    Article  PubMed  Google Scholar 

  163. Boldorini R, Paganotti A, Sartori M, Allegrini S, Miglio U, Orsello M, et al. Fluorescence in situ hybridisation in the cytological diagnosis of pancreatobiliary tumours. Pathology. 2011;43(4):335–9.

    Article  PubMed  Google Scholar 

  164. Eaton JE, Barr Fritcher EG, Gores GJ, Atkinson EJ, Tabibian JH, Topazian MD, et al. Biliary multifocal chromosomal polysomy and cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol. 2015;110(2):299–309.

    Article  PubMed  PubMed Central  Google Scholar 

  165. Bangarulingam SY, Bjornsson E, Enders F, Barr Fritcher EG, Gores G, Halling KC, et al. Long-term outcomes of positive fluorescence in situ hybridization tests in primary sclerosing cholangitis. Hepatology. 2010;51(1):174–80.

    Article  CAS  PubMed  Google Scholar 

  166. Barr Fritcher EG, Kipp BR, Voss JS, Clayton AC, Lindor KD, Halling KC, et al. Primary sclerosing cholangitis patients with serial polysomy fluorescence in situ hybridization results are at increased risk of cholangiocarcinoma. Am J Gastroenterol. 2011;106(11):2023–8.

    Article  PubMed  Google Scholar 

  167. Barr Fritcher EG, Voss JS, Jenkins SM, Lingineni RK, Clayton AC, Roberts LR, et al. Primary sclerosing cholangitis with equivocal cytology: fluorescence in situ hybridization and serum CA 19–9 predict risk of malignancy. Cancer Cytopathol. 2013;121(12):708–17.

    Article  PubMed  CAS  Google Scholar 

  168. Navaneethan U, Njei B, Venkatesh PG, Vargo JJ, Parsi MA. Fluorescence in situ hybridization for diagnosis of cholangiocarcinoma in primary sclerosing cholangitis: a systematic review and meta-analysis. Gastrointest Endosc. 2014;79(6):943–50.e3.

    Article  PubMed  Google Scholar 

  169. Barr Fritcher EG, Voss JS, Brankley SM, Campion MB, Jenkins SM, Keeney ME, et al. An optimized set of fluorescence in situ hybridization probes for detection of pancreatobiliary tract cancer in cytology brush samples. Gastroenterology. 2015;149(7):1813–24.e1.

    Article  CAS  PubMed  Google Scholar 

  170. Young MR, Wagner PD, Ghosh S, Rinaudo JA, Baker SG, Zaret KS, et al. Validation of biomarkers for early detection of pancreatic cancer: summary of the alliance of pancreatic cancer consortia for biomarkers for early detection workshop. Pancreas. 2018;47(2):135–41.

    Article  PubMed  PubMed Central  Google Scholar 

  171. 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.

    Article  CAS  PubMed  Google Scholar 

  172. Yang J, Li S, Li J, Wang F, Chen K, Zheng Y, et al. A meta-analysis of the diagnostic value of detecting K-ras mutation in pancreatic juice as a molecular marker for pancreatic cancer. Pancreatology. 2016;16(4):605–14.

    Article  CAS  PubMed  Google Scholar 

  173. Hata T, Ishida M, Motoi F, Yamaguchi T, Naitoh T, Katayose Y, et al. Telomerase activity in pancreatic juice differentiates pancreatic cancer from chronic pancreatitis: a meta-analysis. Pancreatology. 2016;16(3):372–81.

    Article  CAS  PubMed  Google Scholar 

  174. 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.

    Article  CAS  PubMed  Google Scholar 

  175. Kanda M, Sadakari Y, Borges M, Topazian M, Farrell J, Syngal S, et al. Mutant TP53 in duodenal samples of pancreatic juice from patients with pancreatic cancer or high-grade dysplasia. Clin Gastroenterol Hepatol. 2013;11(6):719–30.e5.

    Article  CAS  PubMed  Google Scholar 

  176. Sturm PD, Rauws EA, Hruban RH, Caspers E, Ramsoekh TB, Huibregtse K, et al. Clinical value of K-ras codon 12 analysis and endobiliary brush cytology for the diagnosis of malignant extrahepatic bile duct stenosis. Clin Cancer Res. 1999;5(3):629–35.

    CAS  PubMed  Google Scholar 

  177. Kipp BR, Fritcher EG, Clayton AC, Gores GJ, Roberts LR, Zhang J, et al. Comparison of KRAS mutation analysis and FISH for detecting pancreatobiliary tract cancer in cytology specimens collected during endoscopic retrograde cholangiopancreatography. J Mol Diagn. 2010;12(6):780–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Ohori NP, Fowler MH, Swalsky PA, Pal R, Thompson J, Finkelstein SD. Comparative molecular analysis of loss of heterozygosity in adenocarcinoma in bile duct brushings and corresponding surgical pathology specimens. Cancer. 2003;99(6):379–84.

    Article  CAS  PubMed  Google Scholar 

  179. Khalid A, Pal R, Sasatomi E, Swalsky P, Slivka A, Whitcomb D, et al. Use of microsatellite marker loss of heterozygosity in accurate diagnosis of pancreaticobiliary malignancy from brush cytology samples. Gut. 2004;53(12):1860–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Finkelstein SD, Bibbo M, Loren DE, Siddiqui AA, Solomides C, Kowalski TE, et al. Molecular analysis of centrifugation supernatant fluid from pancreaticobiliary duct samples can improve cancer detection. Acta Cytol. 2012;56(4):439–47.

    Article  CAS  PubMed  Google Scholar 

  181. Gonda TA, Viterbo D, Gausman V, Kipp C, Sethi A, Poneros JM, et al. Mutation profile and fluorescence in situ hybridization analyses increase detection of malignancies in biliary strictures. Clin Gastroenterol Hepatol. 2017;15(6):913–9.e1.

    Article  CAS  PubMed  Google Scholar 

  182. Dudley JC, Zheng Z, McDonald T, Le LP, Dias-Santagata D, Borger D, et al. Next-generation sequencing and fluorescence in situ hybridization have comparable performance characteristics in the analysis of pancreaticobiliary brushings for malignancy. J Mol Diagn. 2016;18(1):124–30.

    Article  CAS  PubMed  Google Scholar 

  183. Parsi MA, Li A, Li CP, Goggins M. DNA methylation alterations in endoscopic retrograde cholangiopancreatography brush samples of patients with suspected pancreaticobiliary disease. Clin Gastroenterol Hepatol. 2008;6(11):1270–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Andresen K, Boberg KM, Vedeld HM, Honne H, Jebsen P, Hektoen M, et al. Four DNA methylation biomarkers in biliary brush samples accurately identify the presence of cholangiocarcinoma. Hepatology. 2015;61(5):1651–9.

    Article  CAS  PubMed  Google Scholar 

  185. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Prachayakul V, Kanchanapermpoon J, Thuwajit C, Boonyaarunnate T, Pongpaibul A, Chobson P, et al. DNA methylation markers improve the sensitivity of endoscopic retrograde cholangiopancreatography-based brushing cytology in extrahepatic cholangiocarcinoma. Technol Cancer Res Treat. 2017;16(6):1252–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ. Cholangiocarcinoma—evolving concepts and therapeutic strategies. Nat Rev Clin Oncol. 2018;15(2):95–111.

    Article  CAS  PubMed  Google Scholar 

  188. Olaizola P, Lee-Law PY, Arbelaiz A, Lapitz A, Perugorria MJ, Bujanda L, et al. MicroRNAs and extracellular vesicles in cholangiopathies. Biochim Biophys Acta. 2018;1864(4 Pt B):1293–307.

    Article  CAS  Google Scholar 

  189. Li L, Masica D, Ishida M, Tomuleasa C, Umegaki S, Kalloo AN, et al. Human bile contains microRNA-laden extracellular vesicles that can be used for cholangiocarcinoma diagnosis. Hepatology. 2014;60(3):896–907.

    Article  CAS  PubMed  Google Scholar 

  190. Shigehara K, Yokomuro S, Ishibashi O, Mizuguchi Y, Arima Y, Kawahigashi Y, et al. Real-time PCR-based analysis of the human bile microRNAome identifies miR-9 as a potential diagnostic biomarker for biliary tract cancer. PLoS One. 2011;6(8):e23584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Voigtlander T, Gupta SK, Thum S, Fendrich J, Manns MP, Lankisch TO, et al. MicroRNAs in serum and bile of patients with primary Sclerosing cholangitis and/or cholangiocarcinoma. PLoS One. 2015;10(10):e0139305.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  192. Liang Z, Liu X, Zhang Q, Wang C, Zhao Y. Diagnostic value of microRNAs as biomarkers for cholangiocarcinoma. Dig Liver Dis. 2016;48(10):1227–32.

    Article  CAS  PubMed  Google Scholar 

  193. Ge X, Wang Y, Nie J, Li Q, Tang L, Deng X, et al. The diagnostic/prognostic potential and molecular functions of long non-coding RNAs in the exosomes derived from the bile of human cholangiocarcinoma. Oncotarget. 2017;8(41):69995–70005.

    Article  PubMed  PubMed Central  Google Scholar 

  194. Keane MG, Huggett MT, Chapman MH, Johnson GJ, Webster GJ, Thorburn D, et al. Diagnosis of pancreaticobiliary malignancy by detection of minichromosome maintenance protein 5 in biliary brush cytology. Br J Cancer. 2017;116(3):349–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Navaneethan U, Parsi MA, Lourdusamy V, Bhatt A, Gutierrez NG, Grove D, et al. Volatile organic compounds in bile for early diagnosis of cholangiocarcinoma in patients with primary sclerosing cholangitis: a pilot study. Gastrointest Endosc. 2015;81(4):943–9.e1.

    Article  PubMed  Google Scholar 

  196. Alvaro D, Macarri G, Mancino MG, Marzioni M, Bragazzi M, Onori P, et al. Serum and biliary insulin-like growth factor I and vascular endothelial growth factor in determining the cause of obstructive cholestasis. Ann Intern Med. 2007;147(7):451–9.

    Article  PubMed  Google Scholar 

  197. Navaneethan U, Lourdusamy V, Gk Venkatesh P, Willard B, Sanaka MR, Parsi MA. Bile proteomics for differentiation of malignant from benign biliary strictures: a pilot study. Gastroenterol Rep (Oxf). 2015;3(2):136–43.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Weill-Cornell Medicine, New York Presbyterian Hospital, New York, NY, USA

    Jonas J. Heymann

Authors
  1. Jonas J. Heymann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jonas J. Heymann .

Editor information

Editors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Weill-Cornell Medicine, NewYork Presbyterian Hospital, New York, NY, USA

    Abha Goyal

  2. Department of Pathology and Laboratory Medicine, Weill-Cornell Medicine, NewYork Presbyterian Hospital, New York, NY, USA

    Rema Rao

  3. Department of Pathology and Laboratory Medicine, Weill-Cornell Medicine, New York Presbyterian Hospital, New York, NY, USA

    Momin T. Siddiqui

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Heymann, J.J. (2019). Ancillary Studies in the Cytologic Diagnosis of Pancreatico-biliary Lesions. In: Goyal, A., Rao, R., Siddiqui, M. (eds) Pancreas and Biliary Tract Cytohistology. Essentials in Cytopathology, vol 28. Springer, Cham. https://doi.org/10.1007/978-3-030-22433-2_12

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-22433-2_12

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-22432-5

  • Online ISBN: 978-3-030-22433-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation