Home > Information for Physicians > Basic Science
Molecular Profiling for IPMN/IPMC
Intraductal papillary mucinous neoplasms (IPMN) are pancreatic precancerous lesions composed of dilated main or branch ducts lined by mucin producing atypical epithelium, which usually proliferates in a papillary fashion .
Based on their increasing architectural and nuclear atypia IPMN are divided into three groups: intraductal papillary mucinous adenoma (IPMA), borderline IPMN (IPMB), and intraductal papillary mucinous carcinoma (IPMC) .
According to the absence or presence of neoplastic cells invading the pancreatic tissue surrounding the involved ducts, IPMC are separated into invasive and noninvasive types .
IPMN are precancerous lesions and disclose a progression pattern similar to the "adenoma-carcinoma sequence" in colorectal cancer [3-6].
Most IPMN are slow growing and less aggressive compared with conventional ductal adenocarcinoma. Borderline lesions and carcinoma are accompanied by less atypical lesions in the vicinity, and transition from adenoma to adenocarcinoma has been described.
The overall incidence of invasive carcinoma associated with an IPMN is 20% to 40%  and invasiveness seems to be the strongest prognostic factor .
The prognosis of patients with non-invasive IPMN consisting of adenoma, adenocarcinoma in situ, or minimally invasive adenocarcinoma is excellent, and the 5 year survival rate was reported to be 77% to 100% [4, 8-10].
However, invasive IPMC that macroscopically involves the pancreatic parenchyma comprises 16% to 43% of all IPMN lesions, and the 5 year survival rate for patients with these lesions varied widely from 0% to 64% in several reported series [4, 8, 9, 11-13].
A significant proportion of the patients with completely resected noninvasive IPMN may develop pancreatic adenocarcinoma in the pancreatic remnant and die of disseminated disease. Other studies have also reported recurrences of invasive carcinoma in completely resected noninvasive IPMN [5, 6], some of which demonstrated only moderate dysplasia (borderline IPMN).
The genetic progression of IPMN/IPMC has not been completely defined. IPMN/IPMC are known to harbor mutations of KRAS [14, 15], p16 , p53 , and DPC4/SMAD4/MADH4 , but the prevalence of the mutations is lower than in ductal pancreatic adenocarcinoma.
In fact, Dpc4/Smad4/Madh4 expression in IPMN is virtually normal unless associated with invasive ductal adenocarcinoma .
Our team has shown the STK11/LKB1 is more frequently inactivated in IPMN/IPMC than PanIN/PDA [19, 20].
Oncogenic PIK3CA plays an important role in the tumorigenesis of IPMN/IPMC, but not in PanIN/PDA .
Oncogenic BRAF is involved in the tumorigenesis of IPMN/IPMC, but at a much lower frequency than KRAS and PIK3CA [22, 23].
We also have reported that EGFR and ERBB2 (HER2) mutations are very infrequent in IPMN/IPMC, suggesting the limited possibility of targeting mutated ERBB2 and EGFR for therapy of these lesions .
KRAS, BRAF and PIK3CA, however, could represent interesting targets for future therapies in these lesions.
- Hruban RH, Takaori K, Klimstra DS, Adsay NV, Albores-Saavedra J, Biankin AV, Biankin SA, Compton C, Fukushima N, Furukawa T (2004) An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol 28(8):977-987
- Kloppel G SE, Longnecker DS (1996) Histological Typing of Tumours of the Exocrine Pancreas. New York
- D'Angelica M, Brennan MF, Suriawinata AA, Klimstra D, Conlon KC (2004) Intraductal papillary mucinous neoplasms of the pancreas: an analysis of clinicopathologic features and outcome. Ann Surg 239(3):400-408
- Sohn TA, Yeo CJ, Cameron JL, Hruban RH, Fukushima N, Campbell KA, Lillemoe KD (2004) Intraductal papillary mucinous neoplasms of the pancreas: an updated experience. Ann Surg 239(6):788-797; discussion 797-789
- Adsay NV, Conlon KC, Zee SY, Brennan MF, Klimstra DS (2002) Intraductal papillary-mucinous neoplasms of the pancreas: an analysis of in situ and invasive carcinomas in 28 patients. Cancer, 94(1):62-77
- Salvia R, Fernandez-del Castillo C, Bassi C, Thayer SP, Falconi M, Mantovani W, Pederzoli P, Warshaw AL (2004) Main-duct intraductal papillary mucinous neoplasms of the pancreas: clinical predictors of malignancy and long-term survival following resection. Ann Surg 239(5):678-685; discussion 685-677
- Adsay NV, Merati K, Andea A, Sarkar F, Hruban RH, Wilentz RE, Goggins M, Iocobuzio-Donahue C, Longnecker DS, Klimstra DS (2002) The dichotomy in the preinvasive neoplasia to invasive carcinoma sequence in the pancreas: differential expression of MUC1 and MUC2 supports the existence of two separate pathways of carcinogenesis. Mod Pathol 15(10):1087-1095
- Raimondo M, Tachibana I, Urrutia R, Burgart LJ, DiMagno EP (2002) Invasive cancer and survival of intraductal papillary mucinous tumors of the pancreas. Am J Gastroenterol 97(10):2553-2558
- Maire F, Hammel P, Terris B, Paye F, Scoazec JY, Cellier C, Barthet M, O'Toole D, Rufat P, Partensky C (2002) Prognosis of malignant intraductal papillary mucinous tumours of the pancreas after surgical resection. Comparison with pancreatic ductal adenocarcinoma. Gut 51(5):717-722.
- Hermanova M, Lukas Z, Nenutil R, Brazdil J, Kroupova I, Kren L, Pazourkova M, Ruzicka M, Dite P (2004) Amplification and overexpression of HER-2/neu in invasive ductal carcinomas of the pancreas and pancreatic intraepithelial neoplasms and the relationship to the expression of p21(WAF1/CIP1). Neoplasma 51(2):77-83
- Yamao K, Ohashi K, Nakamura T, Suzuki T, Shimizu Y, Nakamura Y, Horibe Y, Yanagisawa A, Nakao A, Nimuara Y (2000) The prognosis of intraductal papillary mucinous tumors of the pancreas. Hepatogastroenterology 47(34):1129-1134
- Chari ST, Yadav D, Smyrk TC, DiMagno EP, Miller LJ, Raimondo M, Clain JE, Norton IA, Pearson RK, Petersen BT (2002) Study of recurrence after surgical resection of intraductal papillary mucinous neoplasm of the pancreas. Gastroenterology 123(5):1500-1507
- Nakagohri T, Konishi M, Inoue K, Tanizawa Y, Kinoshita T (2004) Invasive carcinoma derived from intraductal papillary mucinous carcinoma of the pancreas. Hepatogastroenterology 51(59):1480-1483
- Z'Graggen K, Rivera JA, Compton CC, et al. Prevalence of activating K-ras mutations in the evolutionary stages of neoplasia in intraductal papillary mucinous tumors of the pancreas. Ann Surg 1997; 226(4):491-8; discussion 498-500.
- Sessa F, Solcia E, Capella C, Bonato M, Scarpa A, Zamboni G, et al. Intraductal papillary-mucinous tumours represent a distinct group of pancreatic neoplasms: an investigation of tumour cell differentiation and K-ras, p53 and c-erbB-2 abnormalities in 26 patients. Virchows Arch 1994;425:357-367.
- Moore PS, Orlandini S, Zamboni G, Capelli P, Rigaud G, Falconi M, et al. Pancreatic tumours: molecular pathways implicated in ductal cancer are involved in ampullary but not in exocrine nonductal or endocrine tumorigenesis. Br J Cancer 2001;84:253-262.
- Iacobuzio-Donahue CA, Klimstra DS, Adsay NV, Wilentz RE, Argani P, Sohn TA, 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;157:755-761.
- Biankin AV, Biankin SA, Kench JG, Morey AL, Lee CS, Head DR, 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;50:861-868.
- Su GH, Hruban RH, Bansal RK, Bova GS, Tang DJ, Sheker MC, Westerman AM, Entius MM, Goggins M, Yeo CJ, Kern SE. Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers. American Journal of Pathology 1999; 154:1835-1840.
- Sahin F, Maitra A, Argani P, Sato N, Maehara N, Montgomery E, Goggins M, Hruban RH, Su GH. Loss of Stk11/Lkb1 expression in pancreatic and biliary neoplasms. Modern Pathology 2003, 16:686-91.
- Schönleben F, Qiu W, Ciau NT, Ho DJ, Li X, Allendorf JD, Remotti HE, Su GH. PIK3CA mutations in intraductal papillary mucinous neoplasm/carcinoma (IPMN/IPMC) of the pancreas. Clinical Cancer Research 2006, 12:3851-5.
- Schönleben F, Qiu W, Bruckman KC, Ciau NT, Li X, Lauerman MH, Frucht H, Chabot JA, Allendorf JD, Remotti HE, Su GH. BRAF and KRAS gene mutations in intraductal papillary mucinous neoplasm/carcinoma (IPMN/IPMC) of the pancreas. Cancer Letters 2007 May 8; 249(2):242-8. Epub 2006 Nov 9.
- Schönleben F, Qiu W, Remotti HE, Hohenberger W, Su GH. PIK3CA, KRAS, and BRAF mutations in intraductal papillary mucinous neoplasm/carcinoma (IPMN/C) of the pancreas. Langenbecks Arch Surg 2008, 393(3):289-96.
- Schönleben F, Allendorf JD, Qiu W, Li X, Ho D J, Ciau NT, Fine RL, Chabot JA, Remotti HE, Su GH. Mutational analyses of multiple oncogenic pathways in intraductal papillary mucinous neoplasms of the pancreas. Pancreas 2008, 36: 168-72.
If you plan to refer a patient to the Pancreas Center, please fill out our contact form so we know how best to communicate with you.
> Referring Physician Contact Form