nach oben

Erschienen in:

01.02.2012 | Original Article—Liver, Pancreas, and Biliary Tract

Different subtypes of intraductal papillary mucinous neoplasm in the pancreas have distinct pathways to pancreatic cancer progression

verfasst von: Dai Mohri, Yoshinari Asaoka, Hideaki Ijichi, Koji Miyabayashi, Yotaro Kudo, Motoko Seto, Miki Ohta, Motohisa Tada, Yasuo Tanaka, Tsuneo Ikenoue, Keisuke Tateishi, Hiroyuki Isayama, Fumihiko Kanai, Noriyoshi Fukushima, Minoru Tada, Takao Kawabe, Masao Omata, Kazuhiko Koike

Erschienen in: Journal of Gastroenterology | Ausgabe 2/2012

Einloggen, um Zugang zu erhalten

Abstract

Background

Intraductal papillary mucinous neoplasm (IPMN) is recognized as a precursor lesion to pancreatic cancer, a unique pathological entity. IPMN has subtypes with different clinical characteristics. However, the molecular mechanisms of cancer progression from IPMN remain largely unknown. In this study we examined the differences in genetic alteration(s) among the IPMN subtypes.

Methods

Surgically resected IPMNs (n = 25) were classified into four subtypes by hematoxylin and eosin (H&E) and mucin immunostaining. Mutations in KRAS, BRAF, and PIK3CA genes and expression of CDKN2A, TP53, SMAD4, phospho-ERK, and phospho-SMAD1/5/8 proteins were examined.

Results

There were 11 gastric, 11 intestinal, one pancreatobiliary, and two oncocytic types in this study. We then compared the two major subtypes, gastric-type and intestinal-type IPMN. Gastric-type IPMN showed a significantly higher incidence of KRAS mutations (9/11, 81.8%) compared with intestinal type (3/11, 27.3%; p < 0.05), although the intestinal type showed a higher grade of dysplasia than gastric type (p < 0.01). All cases with KRAS mutations showed phospho-ERK immunostaining. In contrast, intestinal type (9/11, 81.8%) showed more frequent SMAD1/5/8 phosphorylation compared with gastric-type IPMN (3/11, 27.3%; p < 0.05%).

Conclusions

There may be distinct mechanisms of pancreatic cancer progression in the different subtypes of IPMN. In particular, KRAS mutation and bone morphogenetic protein-SMAD signaling status may be crucial diverging steps for the two representative pathways to pancreatic cancer in IPMN patients.

Carpelan-Holmström M, Nordling S, Pukkala E, Sankila R, Lüttges J, Klöppel G, et al. Does anyone survive pancreatic ductal adenocarcinoma? A nationwide study re-evaluating the data of the Finnish Cancer Registry. Gut. 2005;54:385–7.PubMedCrossRef

Warshaw A, Fernández-del Castillo C. Pancreatic carcinoma. N Engl J Med. 1992;326:455–65.PubMedCrossRef

Rosewicz S, Wiedenmann B. Pancreatic carcinoma. Lancet. 1997;349:485–9.PubMedCrossRef

Bardeesy N, DePinho R. Pancreatic cancer biology and genetics. Nat Rev Cancer. 2002;2:897–909.PubMedCrossRef

Hruban RH, Takaori K, Klimstra DS, Adsay NV, Albores-Saavedra J, Biankin AV, Biankin SA, 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.PubMedCrossRef

Adsay N, Merati K, Andea A, Sarkar F, Hruban R, Wilentz R, et al. 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. 2002;15:1087–95.PubMedCrossRef

Tada M, Kawabe T, Arizumi M, Togawa O, Matsubara S, Yamamoto N, et al. Pancreatic cancer in patients with pancreatic cystic lesions: a prospective study in 197 patients. Clin Gastroenterol Hepatol. 2006;4:1265–70.PubMedCrossRef

Ohashi K, Murakami F, Maruyama M. Four cases of the mucin-producing cancer of the pancreas on specific findings of the papilla of Vater. Prog Dig Endosc. 1982;20:348–51.

Lüttges J, Zamboni G, Longnecker D, Klöppel 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;25:942–8.PubMedCrossRef

10.

Yonezawa S, Taira M, Osako M, Kubo M, Tanaka S, Sakoda K, et al. MUC-1 mucin expression in invasive areas of intraductal papillary mucinous tumors of the pancreas. Pathol Int. 1998;48:319–22.PubMedCrossRef

11.

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;197:201–10.PubMedCrossRef

12.

Furukawa T, Klöppel G, Volkan Adsay N, Albores-Saavedra J, Fukushima N, Horii A, et al. Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study. Virchows Arch. 2005;447:794–9.PubMedCrossRef

13.

Adsay N, Merati K, Basturk O, Iacobuzio-Donahue C, Levi E, Cheng J, 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.PubMedCrossRef

14.

Ban S, Naitoh Y, Mino-Kenudson M, Sakurai T, Kuroda M, Koyama I, 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.PubMedCrossRef

15.

Z’graggen K, Rivera J, Compton C, Pins M, Werner J, Fernández-del Castillo C, 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;226:491–8. (discussion 498-500).PubMedCrossRef

16.

Satoh K, Shimosegawa T, Moriizumi S, Koizumi M, Toyota T. K-ras mutation and p53 protein accumulation in intraductal mucin-hypersecreting neoplasms of the pancreas. Pancreas. 1996;12:362–8.PubMedCrossRef

17.

Satoh K, Sawai T, Shimosegawa T, Koizumi M, Yamazaki T, Mochizuki F, et al. The point mutation of c-Ki-ras at codon 12 in carcinoma of the pancreatic head region and in intraductal mucin-hypersecreting neoplasm of the pancreas. Int J Pancreatol. 1993;14:135–43.PubMed

18.

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;425:357–67.PubMedCrossRef

19.

Tada M, Omata M, Ohto M. Ras gene mutations in intraductal papillary neoplasms of the pancreas. Analysis in five cases. Cancer. 1991;67:634–7.PubMedCrossRef

20.

Schönleben F, Qiu W, Bruckman K, Ciau N, Li X, Lauerman M, et al. BRAF and KRAS gene mutations in intraductal papillary mucinous neoplasm/carcinoma (IPMN/IPMC) of the pancreas. Cancer Lett. 2007;249:242–8.PubMedCrossRef

21.

Biankin A, Biankin S, Kench J, Morey A, Lee C, Head D, 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.PubMedCrossRef

22.

Abe K, Suda K, Arakawa A, Yamasaki S, Sonoue H, Mitani K, et al. Different patterns of p16INK4A and p53 protein expressions in intraductal papillary-mucinous neoplasms and pancreatic intraepithelial neoplasia. Pancreas. 2007;34:85–91.PubMedCrossRef

23.

Takahashi H, Oda T, Hasebe T, Aoyagi Y, Kinoshita T, Konishi M, et al. Biologically different subgroups of invasive ductal carcinoma of the pancreas: Dpc4 status according to the ratio of intraductal carcinoma components. Clin Cancer Res. 2004;10:3772–9.PubMedCrossRef

24.

Schönleben F, Qiu W, Ciau N, Ho D, Li X, Allendorf J, et al. PIK3CA mutations in intraductal papillary mucinous neoplasm/carcinoma of the pancreas. Clin Cancer Res. 2006;12:3851–5.PubMedCrossRef

25.

Jaffee E, Hruban R, Canto M, Kern S. Focus on pancreas cancer. Cancer Cell. 2002;2:25–8.PubMedCrossRef

26.

Ishimura N, Yamasawa K, Karim Rumi M, Kadowaki Y, Ishihara S, Amano Y, et al. BRAF and K-ras gene mutations in human pancreatic cancers. Cancer Lett. 2003;199:169–73.PubMedCrossRef

27.

Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304:554.PubMedCrossRef

28.

Tanaka M, Chari S, Adsay V, Fernandez-del Castillo C, Falconi M, Shimizu M, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology. 2006;6:17–32.PubMedCrossRef

29.

Tanaka Y, Kanai F, Tada M, Asaoka Y, Guleng B, Jazag A, et al. Absence of PIK3CA hotspot mutations in hepatocellular carcinoma in Japanese patients. Oncogene. 2006;25:2950–2.PubMedCrossRef

30.

Shao R, Kato N, Lin L, Muroyama R, Moriyama M, Ikenoue T, et al. Absence of tyrosine kinase mutations in Japanese colorectal cancer patients. Oncogene. 2007;26:2133–5.PubMedCrossRef

31.

Ohta M, Sugimoto T, Seto M, Mohri D, Asaoka Y, Tada M, et al. Genetic alterations in colorectal cancers with demethylation of insulin-like growth factor II. Hum Pathol. 2008;39:1301–8.PubMedCrossRef

32.

Andrejevic-Blant S, Kosmahl M, Sipos B, Klöppel G. Pancreatic intraductal papillary-mucinous neoplasms: a new and evolving entity. Virchows Arch. 2007;451:863–9.PubMedCrossRef

33.

Naoki K, Chen T, Richards W, Sugarbaker D, Meyerson M. Missense mutations of the BRAF gene in human lung adenocarcinoma. Cancer Res. 2002;62:7001–3.PubMed

34.

Davies H, Bignell G, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.PubMedCrossRef

35.

Karnoub A, Weinberg R. Ras oncogenes: split personalities. Nat Rev Mol Cell Biol. 2008;9:517–31.PubMedCrossRef

36.

Chadwick B, Willmore-Payne C, Tripp S, Layfield L, Hirschowitz S, Holden J. Histologic, immunohistochemical, and molecular classification of 52 IPMNs of the pancreas. Appl Immunohistochem Mol Morphol. 2009;17:31–9.PubMedCrossRef

37.

Nakata K, Nagai E, Ohuchida K, Aishima S, Hayashi A, Miyasaka Y, et al. REG4 is associated with carcinogenesis in the ‘intestinal’ pathway of intraductal papillary mucinous neoplasms. Mod Pathol. 2009;22:460–8.PubMedCrossRef

38.

Barros R, Pereira B, Duluc I, Azevedo M, Mendes N, Camilo V, et al. Key elements of the BMP/SMAD pathway co-localize with CDX2 in intestinal metaplasia and regulate CDX2 expression in human gastric cell lines. J Pathol. 2008;215:411–20.PubMedCrossRef

39.

Adsay N, Pierson C, Sarkar F, Abrams J, Weaver D, Conlon K, et al. Colloid (mucinous noncystic) carcinoma of the pancreas. Am J Surg Pathol. 2001;25:26–42.PubMedCrossRef

40.

Uehara H, Nakaizumi A, Ishikawa O, Iishi H, Tatsumi K, Takakura R, et al. Development of ductal carcinoma of the pancreas during follow-up of branch duct intraductal papillary mucinous neoplasm of the pancreas. Gut. 2008;57:1561–5.PubMedCrossRef

41.

Fernández-del Castillo C, Adsay N. Intraductal papillary mucinous neoplasms of the pancreas. Gastroenterology. 2010;139:708–13.PubMedCrossRef

Titel: Different subtypes of intraductal papillary mucinous neoplasm in the pancreas have distinct pathways to pancreatic cancer progression
verfasst von: Dai Mohri
Yoshinari Asaoka
Hideaki Ijichi
Koji Miyabayashi
Yotaro Kudo
Motoko Seto
Miki Ohta
Motohisa Tada
Yasuo Tanaka
Tsuneo Ikenoue
Keisuke Tateishi
Hiroyuki Isayama
Fumihiko Kanai
Noriyoshi Fukushima
Minoru Tada
Takao Kawabe
Masao Omata
Kazuhiko Koike
Publikationsdatum: 01.02.2012
Verlag: Springer Japan
Erschienen in: Journal of Gastroenterology / Ausgabe 2/2012
Print ISSN: 0944-1174
Elektronische ISSN: 1435-5922
DOI: https://doi.org/10.1007/s00535-011-0482-y

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

25.04.2024 | Hypotonie | Nachrichten

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Different subtypes of intraductal papillary mucinous neoplasm in the pancreas have distinct pathways to pancreatic cancer progression

Abstract

Background

Methods

Results

Conclusions

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

Viel Bewegung in der Parkinsonforschung

Adjuvante Immuntherapie verlängert Leben bei RCC

Update Innere Medizin

Springer Medizin

Abstract

Background

Methods

Results

Conclusions

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 2/2012

Development of a new immunoassay for the accurate determination of anti-infliximab antibodies in inflammatory bowel disease

Detectability of colorectal neoplasia with fluorine-18-2-fluoro-2-deoxy-d-glucose positron emission tomography and computed tomography (FDG-PET/CT)

Usefulness of miriplatin as an anticancer agent for transcatheter arterial chemoembolization in patients with unresectable hepatocellular carcinoma

The inflammatory network in the gastrointestinal tumor microenvironment: lessons from mouse models

Impedance-pH reflux patterns can differentiate non-erosive reflux disease from functional heartburn patients

Comparisons of symptoms reported by elderly and non-elderly patients with GERD

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

Viel Bewegung in der Parkinsonforschung

Adjuvante Immuntherapie verlängert Leben bei RCC

Update Innere Medizin