Abstract
Periampullary carcinomas are a group of rare lesions around the ampulla of Vater including distal bile duct and duodenum and are very different from pancreatic ductal adenocarcinoma clinically and pathologically, but the molecular alterations in these tumours are less known. Genetic alterations of the KRAS oncogenes, tumour suppressor genes p53, p16 and MADH4 (SMAD4/DPC4) and genome maintenance genes (MLHI, MSH2) are commonly altered in pancreatic adenocarcinoma and have also been described in periampullary cancers, although at lower frequencies. To understand the molecular characteristics of non-pancreatic periampullary carcinomas, ampullary cancers can now be further defined accurately into their intestinal and pancreatobiliary subtypes using histomolecular profiling. KRAS mutation, which occurs in most pancreatic cancers, is found to occur less frequently in ampullary (42–52%), biliary (22–23%) and duodenal cancers (32–35%). Mutations are also found in tumour suppressor genes (p53) and are associated with transformation of adenomas and low-grade carcinomas into high-grade carcinomas. Loss of DPC4 occurs late in ampullary carcinogenesis. This study summarizes the current knowledge in molecular aberrations in non-pancreatic periampullary cancers.
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Sarmiento JM, Nagomey DM, Sarr MG, Farnell MB (2001) Periampullary cancers: are there differences? Surg Clin North Am 81(3):543–555
Fernandez-Cruz L (2001) Periampullary carcinoma. In: Holzheimer RG, Mannick JA (eds) Surgical treatment: evidence-based and problem-oriented. W. Zuckschwerdt Verlag GmbH, Munich
Dhir V, Mohandas K (1999) Epidemiology of digestive tract cancers in India IV. Gall bladder and pancreas. Indian J Gastroenterol 18(1):24–28
Kim SG, Chan AO, Wu TT, Issa JP, Hamilton SR, Rashid A (2003a) Epigenetic and genetic alteration in duodenal carcinomas are distinct from biliary and ampullary carcinomas. Gastroenterology 124(5):1300–1310
He J, Ahuja N, Makary MA, Cameron JL, Eckhauser FE, Choti MA et al (2014) 2564 resected periampullary adenocarcinoma at single institution: trends over three decades. HPB 16:83–90
Chen JWC, Bhandari M, Astill DS, Wilson TG, Kow L, Brooke-Smith M et al (2010) Predicting patient survival after pancreaticoduodenectomy for malignancy: histopathological criteria based on perineural infiltration and lymphovascular invasion. HPB 12:101–108
Baczako K, Buchler M, Beger H-G, Kirkpatrick CJ, Haferkamp O (1985) Morphogenesis and possible precursor lesions of invasive carcinoma of the papilla of Vater: epithelial dysplasia and adenoma. Hum Pathol 16:305–310
Ghadirian P, Lynch HT, Krewski D (2003) Epidemiology of pancreatic cancer: an overview. Cancer Detect Prev 27:87–93
Berberat PO, Kunzil BM, Gulbinas A, Ramanauskas T, Kleeff J, Muller MW, Wagner M, Friess H (2009) An audit of outcomes of a series of periampullary carcinomas. Eur J Surg Oncology 35(2):187–191
Macgregor-Das AM, Iacobuzio-Donahue CA (2013) Molecular pathways in pancreatic carcinogenesis. J Surg Oncol 107:8–14
Hingorani SR, Tuveson DA (2003) Ras redux: rethinking how and where Ras acts. Curr Opin Genet Dev 13(1):6–13
Biankin AV, Wadell N, Kassahn KS et al (2012) Pancreatic cancer genomes reveals aberrations aberration in axon guidance pathway genes. Nature 491:399–405
Almoguerra C, Shibata D, Forrester K et al (1988) Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53:549–554
Motojima, Tsunoda T, Kanematsu T, Nagata Y, Urano T, Shiku H (1991) Distinguishing pancreatic carcinoma from other periampullary carcinoma by analysis of mutation in Kirsten-ras oncogene. Ann Surg 214(6):657–662
Chung CH, Wilentz RE, Polak MM, Ramsoekh TB, Noorduyn LA, Gouma DJ (1996) Clinical significance of K-ras oncogene activation in ampullary neoplasms. J Clin Pathol 49(6):460–464
Mikhitarian K, Pollen M, Zhao Z, Shyr Y, Merchant N, Parikh A et al (2014) Epidermal growth factor receptor signaling pathway is frequently altered in ampullary carcinoma at protein and genetic levels. Mod Pathol 27(5):665–674
Schultz NA, Roslind A, Christensen IJ et al (2012a) Frequencies and prognostic role of KRAS and BRAF mutations in patients with localised pancreatic and ampullary adenocarcinoma. Pancreas 41:759–766
Rashid A, Ueki T, Gao YT, Houlihan PS, Wallace C, Wang BS, Shen MC, Deng J, Hsing AW (2002) K-ras mutation, p53 overexpression, and microsatellite instability in biliary tract cancers: a population-based study in China. Clin Cancer Res 8(10):3156–3163
Hsu M, Sasaki M, Igrashi S et al (2013) KRAS and GNAS mutations and P53 overexpression in biliary intraepithelial neoplasia and intrahepatic cholangiocarcinomas. Cancer 119:1669–1674
Fu T, Guzetta AA, Jeschke J et al (2013) KRAS G>A mutation favours poor tumour differentiation but may not be associated with poor prognosis in patients with curatively resected duodenal adenocarcinomas. Int J Cancer 132:2502–2509
Dhillon AS, Meikle S, Peyssonnaux C, Grindlay J, Kaiser C, Steen H et al (2003) Raf-1 mutant that dissociates MEK/extracellular signal-regulated kinase activation from malignant transformation and differentiation but not proliferation. Mol Cell Biol 23:1983–1993. doi:10.1128/MCB.23.6.1983-1993.2003
Aguirre-Ghiso JA, Estrada Y, Liu D, Ossowski L (2003) ERK (MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK). Cancer Res 63:1684–1695
Schönleben F, Qiu W, Allendorf JD, Chabot JA (2009) Molecular analysis of PIK3CA, BRAF, and RAS oncogenes in periampullary and ampullary adenomas and carcinomas. J Gastrointest Surg 13(8):1510–1516
Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253:49–53
Scarpa A, Capelli P, Zamboni G, Oda T, Mukai K, Bonetti F et al (1993) Neoplasia of the ampulla of Vater, Ki-ras and p53 mutations. Am J Pathol 142(4):1163–1172
Diamantis I, Karamitopoulou E, Perentes E, Zimmermann A (1995) p53 protein immunoreactivity in extrahepatic bile duct and gallbladder cancer: correlation with tumor grade and survival. Hepatology 22:774–779
Cheng Q, Luo X, Zhang B, Jiang X, Yi B, Wu M (2007) Distal bile duct carcinomas: prognostic factors after curative surgery. A series of 112 cases. Ann Surg Oncol 14(3):1212–1219
Hong SM, Cho H, Moskaluk CA, Yu E (2007) Zaika AI:p 63 and p73 expression in extrahepatic bile duct carcinoma and their clinical significance. J Mol Histol 38(3):167–175
Maitra A, Hruban RH (2008) Pancreatic cancer. Annual Review Pathol 3:157–188
Oshima M, Okano K, Muraki S, Haba R, Maeba T, Suzuki Y et al (2013) Immunohistochemically detected expression of 3 major genes (CDKN2A/p16, TP53, and SMAD4/DPC4) strongly predicts survival in patients with resectable pancreatic cancer. Ann Surg 258:336–346
Schutte M, Hruban RH, Geradts J, Maynard R, Hilgers W, Rabindran SK et al (1997) Abrogation of the Rb/p16 tumor suppressive pathway in virtually all pancreatic carcinomas. Cancer Res 57:3126–3130
Esposito I, Seiler C, Bergmann F, Kleeff J, Friess H, Schirmacher P (2007) Hypothetical progression model of pancreatic cancer with origin in the centroacinar-acinar compartment. Pancreas 35:212–217
Yuan LW, Tang W, Kokudo N, Seyama Y, Shi YZ, Karako H, Zhao B, Sugawara Y, Nagawa H, Makuuchi M (2005) Disruption of pRbp16INK4 pathway: a common event in ampullary carcinogenesis. Hepato-Gastroenterology 52:55–59
Moore PS, Sipos B, Orlandini S et al (2001) Genetic profile of 22 pancreatic carcinoma cell lines: analysis of K-ras, p53, p16 and DPC4/Smad4. Virchows Arch 439(6):798–802
Tuncer E, Şen türk N, Arici S, Düzcan SE, Demirka NÇ (2011) Expression of p16 protein and cyclin D1 in periampullary carcinomas. Turk Patoloji Derg 27(1):17–22
Hahn SA, Schutte M, Atms H, Moskaluk CA, LT DC, Rozenblum E et al (1996) DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271:350–353
McCarthy DM, Hruban RH, Argani P, Howe JR, Conlon KC, Brennan MF et al (2003) Role of the DPC4 tumor suppressor gene in adenocarcinoma of the ampulla of Vater: analysis of 140 cases. Mod Pathol 16(3):272–278
Nicholas Agoff S, Crispin DA, Bronner MP, Dail DH, Hawes SE, Rodger C (2001) Haggitt, neoplasms of the ampulla of Vater with concurrent pancreatic intraductal neoplasia: a histological and molecular study. Mod Pathol 14(3):139–146
Apple SK, Hecht JR, Lewin DN, Jahromi SA, Grody WW, Nieberg RK (1999) Immunohistochemical evaluation of K-ras, p53, and HER-2/neu expression in hyperplastic, dysplastic, and carcinomatous lesions of the pancreas: evidence for multistep carcinogenesis. Hum Pathol 30:123–129
Perrone G, Santini D, Verzi A, Vincenzi B, Borzomati D, Vecchio F, Coppola R, Antinori A, Magistrelli P, Tonini G, Rabitti C (2006) COX-2 expression in ampullary carcinoma: correlation with angiogenesis process and clinicopathological variables. J Clin Pathol 59:492–496. doi:10.1136/jcp.2005.030098
Kim HJ, Sohn TS, Lee KT et al (2003b) Expression of cyclooxygenase-2 and its correlation with clinicopathologic factors of ampulla of Vater cancer. J Korean Med Sci 18:218–224
Chen L, Tao SF, Zheng YX (2006) Prognostic significance of vascular endothelial growth factors expression and microvessel density in carcinoma of ampulla of vater. Hepato-Gastroenterology 53(67):45–50
Vaziri H, Schachter F, Uchida I et al (1993) Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes. Am J Hum Genet 52:661–667
Burger AM, Bibby MC, Double JA (1997) Telomerase activity in normal and malignant mammalian tissues: feasibility of telomerase as a target for cancer chemotherapy. Br J Cancer 75:516–522
Balcom JH, Keck T, Warshaw AL, Antoniu B, Graeme-Cook F, Fernandez-del Castillo C Telomerase activity in periampullary tumors correlates with aggressive malignancy. Ann Surg 234(3):344–351
Beck F, Tata F, Chawengsaksophak K (2000) Homeobox genes and gut development. BioEssays 22:431–441
Jin T, Drucker DJ (1996) Activation of proglucagon gene transcription through a novel promoter element by the caudal-related homeodomain protein cdx-2/3. Mol Cell Biol 16:19–28
Hansel DE, Maitra A, Lin JW, Goggins M, Argani P, Yeo CJ et al (2005) Expression of the caudal-type homeodomain transcription factors CDX 1/2 and outcome in carcinomas of the ampulla of Vater. J Clin Oncol 23:9
Sessa F, Furlan D, Zampatti C, Carnevali I, Franzi F, Capella C (2007) Prognostic factors for ampullary adenocarcinomas: tumor stage, tumor histology, tumor location, immunohistochemistry and microsatelite instability. Virchows Arch 451(3):649–657
Hwang HW, Mendell JT (2006) MicroRNAs in cell proliferation, cell death, and tumorigenesis. Br J Cancer 94:776–780
Li M, Marin-Muller C, Bharadwaj U et al (2009) MicroRNAs: control and loss of control in human physiology anddisease. World J Surg 33:667–684
Nelson KM, Weiss GJ (2008) MicroRNAs and cancer: past, present, and potential future. Mol Cancer Ther 7:3655–3660
Rachagani S, Kumar S, Batra SK (2010) MicroRNA inpancreatic cancer: pathological, diagnostic and therapeutic implications. Cancer Lett 292:8–16
Farazi TA, Spitzer JI, Morozov P et al (2010) MiRNAs in human cancer. J Pathol 223:102–115
Kalluri Sai Shiva UM, Kuruva MM, Mitnala S, Rupjyoti T, Guduru Venkat R, Botlagunta S, Kandagaddala R, Siddarpuram SP, Sekaran A (2014) MicroRNA profiling in periampullary carcinoma. Pancreatology 14(1):36–47
Schultz NA, Werner J, Willenbrock H, Roslind A, Giese N, Horn T, Demann MWJ, Johansen JS (2012b) MicroRNA expression profiles associated withpancreatic adenocarcinoma and ampullary adenocarcinoma. Mod Pathol 25:1609–1622
Kane MF, Loda M, Gaida GM et al (1997) Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatchrepair–defective human tumor cell lines. Cancer Res 57:808–811
Boland CR (2005) Evolution of the nomenclature for the hereditary colorectal cancer syndromes. Familial Cancer 4:211–218
Achille A, Biasi MO, Zamboni G et al (1997) Cancers of the papilla of Vater: mutator phenotype is associated with good prognosis. Clin Cancer Res 3:1841–1847
Ruemmele P, Dietmaier W, Terracciano L et al (2009) Histopathologic features and microsatellite instability of cancers of the papilla of Vater and their precursor lesions. Am J Surg Pathol 33:691–704
Alderlieste YA, Rauws EA, Mathus-Vliegen EM, Fockens P, Dekker E (2013) Prospective enteroscopic evaluation of jejunal polyposis in patients with familial adenomatous polyposis and advanced duodenal polyposis. Familial Cancer 12(1):51–56
Cordero-Fernandez C, Garzon-Benavides M, Pizarro-Moreno, Garcia-Lozano R, Marques-Galan JL, Lopez Ruiz T (2009) Gastroduodenal involvement in patients with FAP. Prospective study of nature and evolution of polyps: evaluation of treatment and surveillance methods applied. Eur J Gastroenterol Hepatol 21:1161–1167
Basford PJ, Bhandari P (2012) Endoscopic management of nonampullary duodenal polyps. Ther Adv Gastroenterol 5:127–138
Ruo L, Coit DG, Brennan MF, Guillem JG (2002) Long term follow up of patients with familial adenomatous polyposis undergoing pancreaticoduodenal surgery. J Gastrointest Surg 6:671–675
Morpugo E, Vitale GC, Galandiuk S, Kimberling J, Ziegler C, Polk HC (2004) Jr :Clinical characteristics of familial adenomatous polyposis and management of duodenal adenomas. J Gastrointest Surg 8:559–564
Brosens LA, Lacobuzio-Donahue CA, Keller JJ, Hustinx SR, Carvalho R et al (2005) Increased cyclooxygenase-2 expression in duodenal compared with colonic tissues in familial adenomatous polyposis and relationship to the -765G->C COX-2 polymorphism. Clin Cancer Res 11(11):4090–4096
Toyooka M, Konishi M, Kikuchi-Yanoshita R, Iwama T, Miyaki M (1995) Somatic mutation of adenomatous polyposis coli gene in gastroduodenal tumours from patients with familial adenomatous polyposis. Cancse Res 55(14):3165–3170
Bjork J, Akerbant H, Iselius L, Bergman A, Engwall Y, Wahlstrom J et al (2001) Periampullary adenomas and adenocarcinomas in familial adenomatous polyposis. Gastroenterology 121(5):1127–1135
Basile U, Cavallaro G, Polistena A et al (2010) Gastrointestinal and retroperitoneal manifestations of type 1 neurofibromatosis. J Gastrointest Surg 14:186–194
Relles D, Back J, Witkiewcz A et al (2010) Periampullary and duodenal neoplasms in neurofibromatosis type 1: two cases and an updated 20 year review of literature yielding 76 cases. J Gastrointest Surg 14:1052–1061
Costi R, Caruana P, Sarli L et al (2001) Ampullary adenocarcinoma in neurofibromatosis type 1. Case report and literature review. Mod Pathol 14:1169–1174
Le LQ, Parada LF (2007) Tumour microenvironment and neurofibromatosis type 1: connecting the GAPs. Oncogene 26:4609–4616
Kimura W, Futakawa N, Yamagata S, Wada Y, Kuroda A, Muto T, Esaki Y (1994) Different clinicopathologic findings in two histologic types of carcinoma of papilla of Vater. Jpn J Cancer Res 85:161–166
Fischer HP, Zhou H (2004) Pathogenesis of carcinoma of papilla of vater. J Hepabiliary Panreat Surg 11(5):301–309
Paulsen FP, Varoga D, Paulsen AR, Corfield A, Tsokos M (2006) Prognostic value of mucins in the classification of ampullary carcinoma. Hum Pathol 37(2):160–167
Ishimura N, Yamasawa K, Karim Rumi MA, Kadowaki Y, Ishihara S et al (2003) BRAF and K-ras gene mutations in human pancreatic cancers. Cancer Lett 199(2):169–173
Attri J, Srinivasan R, Majumdar S, Radotra BD, Wig J (2005) Alterations of tumor suppressor gene p16 INK4a in pancreatic ductal carcinoma. BMC Gastroenterol 5:22
Iovanna J, Mallmann MC, Gonçalves A, Turrini O, Dagorn JD (2012) Current knowledge on pancreatic cancer. Front Oncol 2:6
Ying H, Dey P, Yao W, Kimmelman AC, Draetta GF et al (2016) Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 30(4):355–385
Troiani T, Martinelli E, Capasso A, Morgillo F, Orditura M, De Vita F, Ciardiello F (2012) Targeting EGFR in pancreatic cancer treatment. Curr Drug Targets 13(6):802–810
Wang Y, Gao J, Li Z, Jin Z, Gong Y, Man X (2007) Diagnostic value of mucins (MUC1, MUC2 and MUC5AC) expression profile in endoscopic ultrasound-guided fine-needle aspiration specimens of the pancreas. Int J Cancer 121:2716–2722
Wang T, Liang YM, Hu P, Cheng YF (2011) Mucins differently expressed in various ampullary adenocarcinomas. Diagn Pathol 6:102. doi:10.1186/1746-1596-6-102
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Tewari, M., Swain, J.R., Dixit, V.K. et al. Molecular Aberrations in Periampullary Carcinoma. Indian J Surg Oncol 8, 348–356 (2017). https://doi.org/10.1007/s13193-017-0645-2
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DOI: https://doi.org/10.1007/s13193-017-0645-2