Pancreatic adenocarcinoma pathology: Changing "landscape"

Journal of Gastrointestinal Oncology

Volumn 6, Issue 4, 2015, Pages 358-374

  Brosens, Lodewijk A A ^a,b   Hackeng, Wenzel M ^a,b   Offerhaus, Johan ^a   Hruban, Ralph H ^b   Wood, Laura D ^b  

^a UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

^b JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Genetics; Intraductal papillary mucinous neoplasm (IPMN); Pancreatic cancer; Pancreatic intraepithelial neoplasia (PanIN); Precursor lesions

Indexed keywords

ADVANCED CANCER; CANCER DIAGNOSIS; CANCER GENETICS; CANCER GROWTH; CANCER PATIENT; CANCER PROGNOSIS; CANCER STAGING; CANCER SURGERY; CANCER SURVIVAL; CARCINOGENESIS; EARLY DIAGNOSIS; HISTOPATHOLOGY; HUMAN; INTRADUCTAL PAPILLARY MUCINOUS TUMOR; MUCINOUS CYSTIC NEOPLASM; NEXT GENERATION SEQUENCING; NONHUMAN; OVERALL SURVIVAL; PANCREAS ADENOCARCINOMA; PANCREAS ADENOMA; PANCREAS RESECTION; PRECANCER; REVIEW; SURVIVAL RATE; SURVIVAL TIME;

EID: 84995750489     PISSN: 20786891     EISSN: 2219679X     Source Type: Journal    
DOI: 10.3978/j.issn.2078-6891.2015.032     Document Type: Review

References (109)

1. Vincent A, Herman J, Schulick R, et al. Pancreatic cancer. Lancet 2011;378:607-20.
2. Hruban RH, Takaori K, Canto M, et al. Clinical importance of precursor lesions in the pancreas. J Hepatobiliary Pancreat Surg 2007;14:255-63.
3. Hruban RH, Goggins M, Parsons J, et al. Progression model for pancreatic cancer. Clin Cancer Res 2000;6:2969-72.
4. Matthaei H, Schulick RD, Hruban RH, et al. Cystic precursors to invasive pancreatic cancer. Nat Rev Gastroenterol Hepatol 2011;8:141-50.
5. Biankin AV, Waddell N, Kassahn KS, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 2012;491:399-405.
6. Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008;321:1801-6.
7. Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 2010;467:1114-7.
8. Wu J, Jiao Y, Dal Molin M, 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;108:21188-93.
9. Wu J, Matthaei H, Maitra A, et al. Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci Transl Med 2011;3:92ra66.
10. Iacobuzio-Donahue CA. Genetic evolution of pancreatic cancer: lessons learnt from the pancreatic cancer genome sequencing project. Gut 2012;61:1085-94.
11. Yachida S, Iacobuzio-Donahue CA. Evolution and dynamics of pancreatic cancer progression. Oncogene 2013;32:5253-60.
12. Iacobuzio-Donahue CA, van der Heijden MS, Baumgartner MR, et al. Large-scale allelotype of pancreaticobiliary carcinoma provides quantitative estimates of genome-wide allelic loss. Cancer Res 2004;64:871-5.
13. Kowalski J, Morsberger LA, Blackford A, et al. Chromosomal abnormalities of adenocarcinoma of the pancreas: identifying early and late changes. Cancer Genet Cytogenet 2007;178:26-35.
14. Jones S, Hruban RH, Kamiyama M, et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 2009;324:217.
15. Roberts NJ, Jiao Y, Yu J, et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov 2012;2:41-6.
16. Zhen DB, Rabe KG, Gallinger S, et al. BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genet Med 2014. [Epub ahead of print].
17. Hearle N, Schumacher V, Menko FH, et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res 2006;12:3209-15.
18. Kastrinos F, Mukherjee B, Tayob N, et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA 2009;302:1790-5.
19. Hruban RH, Takaori K, Klimstra DS, et al. An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol 2004;28:977-87.
20. Brune K, Abe T, Canto M, et al. Multifocal neoplastic precursor lesions associated with lobular atrophy of the pancreas in patients having a strong family history of pancreatic cancer. Am J Surg Pathol 2006;30:1067-76.
21. Konstantinidis IT, Vinuela EF, Tang LH, et al. Incidentally discovered pancreatic intraepithelial neoplasia: what is its clinical significance? Ann Surg Oncol 2013;20:3643-7.
22. Shi C, Klein AP, Goggins M, et al. Increased Prevalence of Precursor Lesions in Familial Pancreatic Cancer Patients. Clin Cancer Res 2009;15:7737-43.
23. van Heek NT, Meeker AK, Kern SE, et al. Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia. Am J Pathol 2002;161:1541-7.
24. Kanda M, Matthaei H, Wu J, et al. Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology 2012;142:730-733.e9.
25. Löhr M, Klöppel G, Maisonneuve P, et al. Frequency of K-ras mutations in pancreatic intraductal neoplasias associated with pancreatic ductal adenocarcinoma and chronic pancreatitis: a meta-analysis. Neoplasia 2005;7:17-23.
26. Hruban RH, Adsay NV, Albores-Saavedra J, et al. Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations. Cancer Res 2006;66:95-106.
27. Matthaei H, Wu J, Dal Molin M, et al. GNAS sequencing identifies IPMN-specific mutations in a subgroup of diminutive pancreatic cysts referred to as "incipient IPMNs". Am J Surg Pathol 2014;38:360-3.
28. Wilentz RE, Geradts J, Maynard R, et al. Inactivation of the p16 (INK4A) tumor-suppressor gene in pancreatic duct lesions: loss of intranuclear expression. Cancer Res 1998;58:4740-4.
29. Wilentz RE, Iacobuzio-Donahue CA, Argani P, et al. Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res 2000;60:2002-6.
30. Lüttges J, Galehdari H, Bröcker V, et al. Allelic loss is often the first hit in the biallelic inactivation of the p53 and DPC4 genes during pancreatic carcinogenesis. Am J Pathol 2001;158:1677-83.
31. Schutte M, Hruban RH, Geradts J, et al. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res 1997;57:3126-30.
32. Sato N, Ueki T, Fukushima N, et al. Aberrant methylation of CpG islands in intraductal papillary mucinous neoplasms of the pancreas. Gastroenterology 2002;123:365-72.
33. Murphy SJ, Hart SN, Lima JF, et al. Genetic alterations associated with progression from pancreatic intraepithelial neoplasia to invasive pancreatic tumor. Gastroenterology 2013;145:1098-1109.e1.
34. Matthaei H, Hong SM, Mayo SC, et al. Presence of pancreatic intraepithelial neoplasia in the pancreatic transection margin does not influence outcome in patients with R0 resected pancreatic cancer. Ann Surg Oncol 2011;18:3493-9.
35. Brugge WR, Lauwers GY, Sahani D, et al. Cystic neoplasms of the pancreas. N Engl J Med 2004;351:1218-26.
36. Tanaka M, Fernández-del Castillo C, Adsay V, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology 2012;12:183-97.
37. de Jong K, Nio CY, Hermans JJ, et al. High prevalence of pancreatic cysts detected by screening magnetic resonance imaging examinations. Clin Gastroenterol Hepatol 2010;8:806-11.
38. Laffan TA, Horton KM, Klein AP, et al. Prevalence of unsuspected pancreatic cysts on MDCT. AJR Am J Roentgenol 2008;191:802-7.
39. Schnelldorfer T, Sarr MG, Nagorney DM, et al. Experience with 208 resections for intraductal papillary mucinous neoplasm of the pancreas. Arch Surg 2008;143:639-46; discussion 646.
40. Shimizu Y, Yamaue H, Maguchi H, et al. Predictors of malignancy in intraductal papillary mucinous neoplasm of the pancreas: analysis of 310 pancreatic resection patients at multiple high-volume centers. Pancreas 2013;42:883-8.
41. Furukawa T, Hatori T, Fujita I, et al. Prognostic relevance of morphological types of intraductal papillary mucinous neoplasms of the pancreas. Gut 2011;60:509-16.
42. Lafemina J, Katabi N, Klimstra D, et al. Malignant progression in IPMN: a cohort analysis of patients initially selected for resection or observation. Ann Surg Oncol 2013;20:440-7.
43. Kang MJ, Lee KB, Jang JY, et al. Evaluation of clinical meaning of histological subtypes of intraductal papillary mucinous neoplasm of the pancreas. Pancreas 2013;42:959-66.
44. Fritz S, Klauss M, Bergmann F, et al. Pancreatic main-duct involvement in branch-duct IPMNs: an underestimated risk. Ann Surg 2014;260:848-55; discussion 855-6.
45. Aso T, Ohtsuka T, Matsunaga T, et al. "High-risk stigmata" of the 2012 international consensus guidelines correlate with the malignant grade of branch duct intraductal papillary mucinous neoplasms of the pancreas. Pancreas 2014;43:1239-43.
46. Furukawa T, Klöppel G, Volkan Adsay N, et al. Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study. Virchows Arch 2005;447:794-9.
47. Adsay NV, Merati K, Basturk O, et al. Pathologically and biologically distinct types of epithelium in intraductal papillary mucinous neoplasms: delineation of an "intestinal" pathway of carcinogenesis in the pancreas. Am J Surg Pathol 2004;28:839-48.
48. Ban S, Naitoh Y, Mino-Kenudson M, et al. Intraductal papillary mucinous neoplasm (IPMN) of the pancreas: its histopathologic difference between 2 major types. Am J Surg Pathol 2006;30:1561-9.
49. Kitazono I, Higashi M, Kitamoto S, et al. Expression of MUC4 mucin is observed mainly in the intestinal type of intraductal papillary mucinous neoplasm of the pancreas. Pancreas 2013;42:1120-8.
50. Basturk O, Khayyata S, Klimstra DS, et al. Preferential expression of MUC6 in oncocytic and pancreatobiliary types of intraductal papillary neoplasms highlights a pyloropancreatic pathway, distinct from the intestinal pathway, in pancreatic carcinogenesis. Am J Surg Pathol 2010;34:364-70.
51. Adsay NV, Merati K, Nassar H, et al. Pathogenesis of colloid (pure mucinous) carcinoma of exocrine organs: Coupling of gel-forming mucin (MUC2) production with altered cell polarity and abnormal cell-stroma interaction may be the key factor in the morphogenesis and indolent behavior of colloid carcinoma in the breast and pancreas. Am J Surg Pathol 2003;27:571-8.
52. Nakamura A, Horinouchi M, Goto M, et al. New classification of pancreatic intraductal papillary-mucinous tumour by mucin expression: its relationship with potential for malignancy. J Pathol 2002;197:201-10.
53. Terada T, Ohta T, Sasaki M, et al. Expression of MUC apomucins in normal pancreas and pancreatic tumours. J Pathol 1996;180:160-5.
54. Liszka L, Pajak J, Zielińska-Pajak E, et al. Intraductal oncocytic papillary neoplasms of the pancreas and bile ducts: a description of five new cases and review based on a systematic survey of the literature. J Hepatobiliary Pancreat Sci 2010;17:246-61.
55. Yamaguchi H, Shimizu M, Ban S, et al. Intraductal tubulopapillary neoplasms of the pancreas distinct from pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol 2009;33:1164-72.
56. Amato E, Molin MD, Mafficini A, et al. Targeted next-generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas. J Pathol 2014;233:217-27.
57. Dal Molin M, Matthaei H, Wu J, et al. Clinicopathological correlates of activating GNAS mutations in intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Ann Surg Oncol 2013;20:3802-8.
58. Yamaguchi H, Kuboki Y, Hatori T, et al. Somatic mutations in PIK3CA and activation of AKT in intraductal tubulopapillary neoplasms of the pancreas. Am J Surg Pathol 2011;35:1812-7.
59. Komatsu H, Tanji E, Sakata N, et al. A GNAS mutation found in pancreatic intraductal papillary mucinous neoplasms induces drastic alterations of gene expression profiles with upregulation of mucin genes. PLoS One 2014;9:e87875.
60. Parvanescu A, Cros J, Ronot M, et al. Lessons from McCune-Albright syndrome-associated intraductal papillary mucinous neoplasms:: GNAS-activating mutations in pancreatic carcinogenesis. JAMA Surg 2014;149:858-62.
61. de Lau W, Peng WC, Gros P, et al. The R-spondin/Lgr5/ Rnf43 module: regulator of Wnt signal strength. Genes Dev 2014;28:305-16.
62. Wall I, Schmidt-Wolf IG. Effect of Wnt inhibitors in pancreatic cancer. Anticancer Res 2014;34:5375-80.
63. Jiang X, Hao HX, Growney JD, et al. Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. Proc Natl Acad Sci U S A 2013;110:12649-54.
64. Wada K. p16 and p53 gene alterations and accumulations in the malignant evolution of intraductal papillarymucinous tumors of the pancreas. J Hepatobiliary Pancreat Surg 2002;9:76-85.
65. Baas IO, Hruban RH, Offerhaus GJ. Clinical applications of detecting dysfunctional p53 tumor suppressor protein. Histol Histopathol 1999;14:279-84.
66. Abe K, Suda K, Arakawa A, et al. Different patterns of p161NK4A and p53 protein expressions in intraductal papillary-mucinous neoplasms and pancreatic intraepithelial neoplasia. Pancreas 2007;34:85-91.
67. Biankin AV, Biankin SA, Kench JG, et al. Aberrant p16(INK4A) and DPC4/Smad4 expression in intraductal papillary mucinous tumours of the pancreas is associated with invasive ductal adenocarcinoma. Gut 2002;50:861-8.
68. Iacobuzio-Donahue CA, Klimstra DS, Adsay NV, et al. Dpc-4 protein is expressed in virtually all human intraductal papillary mucinous neoplasms of the pancreas: comparison with conventional ductal adenocarcinomas. Am J Pathol 2000;157:755-61.
69. Schönleben F, Qiu W, Remotti HE, et al. PIK3CA, KRAS, and BRAF mutations in intraductal papillary mucinous neoplasm/carcinoma (IPMN/C) of the pancreas. Langenbecks Arch Surg 2008;393:289-96.
70. Garcia-Carracedo D, Turk AT, Fine SA, et al. Loss of PTEN expression is associated with poor prognosis in patients with intraductal papillary mucinous neoplasms of the pancreas. Clin Cancer Res 2013;19:6830-41.
71. Brosens LA, van Hattem WA, Jansen M, et al. Gastrointestinal polyposis syndromes. Curr Mol Med 2007;7:29-46.
72. Sato N, Rosty C, Jansen M, et al. STK11/LKB1 PeutzJeghers gene inactivation in intraductal papillary-mucinous neoplasms of the pancreas. Am J Pathol 2001;159:2017-22.
73. Hashimoto Y, Murakami Y, Uemura K, et al. Telomere shortening and telomerase expression during multistage carcinogenesis of intraductal papillary mucinous neoplasms of the pancreas. J Gastrointest Surg 2008;12:17-28; discussion 28-9.
74. Jang KT, Lee KT, Lee JG, et al. Immunohistochemical expression of Sonic hedgehog in intraductal papillary mucinous tumor of the pancreas. Appl Immunohistochem Mol Morphol 2007;15:294-8.
75. Dal Molin M, Hong SM, Hebbar S, et al. Loss of expression of the SWI/SNF chromatin remodeling subunit BRG1/SMARCA4 is frequently observed in intraductal papillary mucinous neoplasms of the pancreas. Hum Pathol 2012;43:585-91.
76. House MG, Guo M, Iacobuzio-Donahue C, et al. Molecular progression of promoter methylation in intraductal papillary mucinous neoplasms (IPMN) of the pancreas. Carcinogenesis 2003;24:193-8.
77. Hong SM, Omura N, Vincent A, et al. Genome-wide CpG island profiling of intraductal papillary mucinous neoplasms of the pancreas. Clin Cancer Res 2012;18:700-12.
78. Lubezky N, Loewenstein S, Ben-Haim M, et al. MicroRNA expression signatures in intraductal papillary mucinous neoplasm of the pancreas. Surgery 2013;153:663-72.
79. Caponi S, Funel N, Frampton AE, et al. The good, the bad and the ugly: a tale of miR-101, miR-21 and miR-155 in pancreatic intraductal papillary mucinous neoplasms. Ann Oncol 2013;24:734-41.
80. Gironella M, Seux M, Xie MJ, et al. Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development. Proc Natl Acad Sci U S A 2007;104:16170-5.
81. Meng F, Henson R, Wehbe-Janek H, et al. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 2007;133:647-58.
82. Nakahara O, Takamori H, Iwatsuki M, et al. Carcinogenesis of intraductal papillary mucinous neoplasm of the pancreas: loss of microRNA-101 promotes overexpression of histone methyltransferase EZH2. Ann Surg Oncol 2012;19 Suppl 3:S565-71.
83. Kuroki H, Hayashi H, Okabe H, et al. EZH2 is associated with malignant behavior in pancreatic IPMN via p27Kip1 downregulation. PLoS One 2014;9:e100904.
84. Aso T, Ohtsuka T, Tamura K, et al. Elevated expression level of microRNA-196a is predictive of intestinal-type intraductal papillary mucinous neoplasm of the pancreas. Pancreas 2014;43:361-6.
85. Lahat G, Lubezky N, Loewenstein S, et al. Epithelial-tomesenchymal transition (EMT) in intraductal papillary mucinous neoplasm (IPMN) is associated with high tumor grade and adverse outcomes. Ann Surg Oncol 2014;21 Suppl 4:S750-7.
86. Wang J, Paris PL, Chen J, et al. Next generation sequencing of pancreatic cyst fluid microRNAs from low grade-benign and high grade-invasive lesions. Cancer Lett 2015;356:404-9.
87. Abue M, Yokoyama M, Shibuya R, et al. Circulating miR-483-3p and miR-21 is highly expressed in plasma of pancreatic cancer. Int J Oncol 2015;46:539-47.
88. Kanda M, Sadakari Y, Borges M, et al. Mutant TP53 in duodenal samples of pancreatic juice from patients with pancreatic cancer or high-grade dysplasia. Clin Gastroenterol Hepatol 2013;11:719-30.e5.
89. Rhim AD, Thege FI, Santana SM, et al. Detection of circulating pancreas epithelial cells in patients with pancreatic cystic lesions. Gastroenterology 2014;146:647-51.
90. Morimatsu K, Aishima S, Yamamoto H, et al. Insulin-like growth factor II messenger RNA-binding protein-3 is a valuable diagnostic and prognostic marker of intraductal papillary mucinous neoplasm. Hum Pathol 2013;44:1714-21.
91. Rebours V, Le Faouder J, Laouirem S, et al. In situ proteomic analysis by MALDI imaging identifies ubiquitin and thymosin-β4 as markers of malignant intraductal pancreatic mucinous neoplasms. Pancreatology 2014;14:117-24.
92. Das KK, Xiao H, Geng X, et al. mAb Das-1 is specific for high-risk and malignant intraductal papillary mucinous neoplasm (IPMN). Gut 2014;63:1626-34.
93. Erdogan D, Lamers WH, Offerhaus GJ, et al. Cystadenomas with ovarian stroma in liver and pancreas: an evolving concept. Dig Surg 2006;23:186-91.
94. Erdogan D, Kloek J, Lamers WH, et al. Mucinous cystadenomas in liver: management and origin. Dig Surg 2010;27:19-23.
95. Zamboni G, Fukushima N, Hruban RH, et al. Mucinous cystic neoplasms of the pancreas. In: Bosman FT, Carneiro F, Hruban RH, et al, editors. WHO Classification of tumors of the digestive system. 4th ed. Lyon: IARC, 2010:300-3.
96. Zamboni G, Scarpa A, Bogina G, et al. Mucinous cystic tumors of the pancreas: clinicopathological features, prognosis, and relationship to other mucinous cystic tumors. Am J Surg Pathol 1999;23:410-22.
97. Kosmahl M, Pauser U, Peters K, et al. Cystic neoplasms of the pancreas and tumor-like lesions with cystic features: a review of 418 cases and a classification proposal. Virchows Arch 2004;445:168-78.
98. Yamao K, Yanagisawa A, Takahashi K, et al. Clinicopathological features and prognosis of mucinous cystic neoplasm with ovarian-type stroma: a multi-institutional study of the Japan pancreas society. Pancreas 2011;40:67-71.
99. Wilentz RE, Albores-Saavedra J, Zahurak M, et al. Pathologic examination accurately predicts prognosis in mucinous cystic neoplasms of the pancreas. Am J Surg Pathol 1999;23:1320-7.
100. Crippa S, Salvia R, Warshaw AL, et al. Mucinous cystic neoplasm of the pancreas is not an aggressive entity: lessons from 163 resected patients. Ann Surg 2008;247:571-9.
101. Fukushima N, Fukayama M. Mucinous cystic neoplasms of the pancreas: pathology and molecular genetics. J Hepatobiliary Pancreat Surg 2007;14:238-42.
102. Lüttges J, Feyerabend B, Buchelt T, et al. The mucin profile of noninvasive and invasive mucinous cystic neoplasms of the pancreas. Am J Surg Pathol 2002;26:466-71.
103. Jimenez RE, Warshaw AL, Z'graggen K, et al. Sequential accumulation of K-ras mutations and p53 overexpression in the progression of pancreatic mucinous cystic neoplasms to malignancy. Ann Surg 1999;230:501-9; discussion 509-11.
104. Iacobuzio-Donahue CA, Wilentz RE, Argani P, et al. Dpc4 protein in mucinous cystic neoplasms of the pancreas: frequent loss of expression in invasive carcinomas suggests a role in genetic progression. Am J Surg Pathol 2000;24:1544-8.
105. Garcia-Carracedo D, Chen ZM, Qiu W, et al. PIK3CA mutations in mucinous cystic neoplasms of the pancreas. Pancreas 2014;43:245-9.
106. Kim SG, Wu TT, Lee JH, et al. Comparison of epigenetic and genetic alterations in mucinous cystic neoplasm and serous microcystic adenoma of pancreas. Mod Pathol 2003;16:1086-94.
107. Fukushima N, Sato N, Prasad N, et al. Characterization of gene expression in mucinous cystic neoplasms of the pancreas using oligonucleotide microarrays. Oncogene 2004;23:9042-51.
108. Kanda M, Knight S, Topazian M, et al. Mutant GNAS detected in duodenal collections of secretin-stimulated pancreatic juice indicates the presence or emergence of pancreatic cysts. Gut 2013;62:1024-33.
109. Sadakari Y, Kanda M, Maitani K, et al. 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.