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Podoplanin expression in the cyst wall correlates with the progression of intraductal papillary mucinous neoplasm

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Abstract

A thickened, enhanced cyst wall on imaging examinations is one of the “worrisome features” described in the consensus guidelines for management of intraductal papillary mucinous neoplasm of the pancreas (IPMN). Podoplanin (PDPN) expression by cancer-associated fibroblasts is known to be an indicator of poor prognosis in some types of cancer. We performed immunohistochemical staining for alpha-smooth muscle actin (α-SMA) in IPMN lesions and determined the pathological wall thickness by measuring the thinnest and thickest α-SMA-positive parts of the wall of the largest cyst in each case, and the mean of these two values was recorded as the wall thickness. The thickness of the pathological wall increased with progression from IPMN with low-grade dysplasia to IPMN with an invasive carcinoma. The pathological wall was thicker in IPMN with main duct involvement, nongastric-type IPMN, and IPMN with mural nodules. We also stained for PDPN and assessed the thickness of cyst wall staining as for α-SMA. The thickness of the PDPN-positive cyst wall varied in a pattern similar to the thickness of the α-SMA-positive pathological cyst wall. PDPN-positive stromal fibroblasts in the invasive component of IPMN-IC were evaluated as a ratio to α-SMA-positive fibroblasts. A high ratio (>50 %) of PDPN-positive stromal fibroblasts was a predictor of poor outcome. PDPN expression in the cyst wall correlates with the progression of IPMN. PDPN may be a significant prognostic marker of IPMN-IC.

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Abbreviations

PDPN:

Podoplanin

IPMN:

Intraductal papillary mucinous neoplasm of the pancreas

IPMN-L:

IPMN with low-grade dysplasia

IPMN-I:

IPMN with intermediate-grade dysplasia

IPMN-H:

IPMN with high-grade dysplasia

IPMN-IC:

IPMN with an associated invasive carcinoma

PB:

Pancreatobiliary

HE:

Hematoxylin and eosin

References

  1. Adsay NV, Fukushima N, Furukawa T et al (2010) Intraductal neoplasms of the pancreas. In: Bosman FT, Carneiro F, Hruban RH et al (eds) WHO classification of tumours of the digestive system, 4th edn. IARC Press, Lyon, pp 304–313

    Google Scholar 

  2. Takaori K (2007) Current understanding of precursors to pancreatic cancer. J Hepatobiliary Pancreat Surg 14:217–223

    Article  PubMed  Google Scholar 

  3. Farrell JJ, Fernandez-del Castillo C (2013) Pancreatic cystic neoplasms: management and unanswered questions. Gastroenterology 144:1303–1315

    Article  PubMed  Google Scholar 

  4. Distler M, Kersting S, Niedergethmann M, Aust DE, Franz M, Ruckert F, Ehehalt F, Pilarsky C, Post S, Saeger HD, Grutzmann R (2013) Pathohistological subtype predicts survival in patients with intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Ann Surg 258:324–330

    Article  PubMed  Google Scholar 

  5. Mino-Kenudson M, Fernandez-del Castillo C, Baba Y et al (2011) Prognosis of invasive intraductal papillary mucinous neoplasm depends on histological and precursor epithelial subtypes. Gut 60:1712–1720

    Article  PubMed Central  PubMed  Google Scholar 

  6. Tanaka M, Fernandez-del Castillo C, Adsay V et al (2012) International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology 12:183–197

    Article  PubMed  Google Scholar 

  7. Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6:392–401

    Article  CAS  PubMed  Google Scholar 

  8. Polanska UM, Orimo A (2013) Carcinoma-associated fibroblasts: non-neoplastic tumour-promoting mesenchymal cells. J Cell Physiol 228:1651–1657

    Article  CAS  PubMed  Google Scholar 

  9. Cirri P, Chiarugi P (2011) Cancer associated fibroblasts: the dark side of the coin. Am J Cancer Res 1:482–1497

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Kawase A, Ishii G, Nagai K, Ito T, Nagano T, Murata Y, Hishida T, Nishimura M, Yoshida J, Suzuki K, Ochiai A (2008) Podoplanin expression by cancer associated fibroblasts predicts poor prognosis of lung adenocarcinoma. Int J Cancer 123:1053–1059

    Article  CAS  PubMed  Google Scholar 

  11. Kitano H, Kageyama S, Hewitt SM, Hayashi R, Doki Y, Ozaki Y, Fujino S, Takikita M, Kubo H, Fukuoka J (2010) Podoplanin expression in cancerous stroma induces lymphangiogenesis and predicts lymphatic spread and patient survival. Arch Pathol Lab Med 134:1520–1527

    CAS  PubMed  Google Scholar 

  12. Pula B, Jethon A, Piotrowska A, Gomulkiewicz A, Owczarek T, Calik J, Wojnar A, Witkiewicz W, Rys J, Ugorski M, Dziegiel P, Podhorska-Okolow M (2011) Podoplanin expression by cancer-associated fibroblasts predicts poor outcome in invasive ductal breast carcinoma. Histopathology 59:1249–1260

    Article  PubMed  Google Scholar 

  13. Wicki A, Lehembre F, Wick N, Hantusch B, Kerjaschki D, Christofori G (2006) Tumor invasion in the absence of epithelial-mesenchymal transition: podoplanin-mediated remodeling of the actin cytoskeleton. Cancer Cell 9:261–272

    Article  CAS  PubMed  Google Scholar 

  14. Honma M, Minami-Hori M, Takahashi H, Iizuka H (2012) Podoplanin expression in wound and hyperproliferative psoriatic epidermis: regulation by TGF-beta and STAT-3 activating cytokines, IFN-gamma, IL-6, and IL-22. J Dermatol Sci 65:134–140

    Article  CAS  PubMed  Google Scholar 

  15. Morimatsu K, Aishima S, Yamamoto H, Hayashi A, Nakata K, Oda Y, Shindo K, Fujino M, Tanaka M, Oda Y (2013) Insulin-like growth factor II messenger RNA-binding protein-3 is a valuable diagnostic and prognostic marker of intraductal papillary mucinous neoplasm. Hum Pathol 44:1714–1721

    Article  CAS  PubMed  Google Scholar 

  16. Furukawa T, Kloppel G, Volkan Adsay N, Albores-Saavedra J, Fukushima N, Horii A, Hruban RH, Kato Y, Klimstra DS, Longnecker DS, Luttges J, Offerhaus GJ, Shimizu M, Sunamura M, Suriawinata A, Takaori K, Yonezawa S (2005) Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study. Virchows Arch 447:794–799

    Article  PubMed  Google Scholar 

  17. Aishima S, Nishihara Y, Iguchi T, Taguchi K, Taketomi A, Maehara Y, Tsuneyoshi M (2008) Lymphatic spread is related to VEGF-C expression and D2-40-positive myofibroblasts in intrahepatic cholangiocarcinoma. Mod Pathol 21:256–264

    Article  CAS  PubMed  Google Scholar 

  18. Cuzick J (1985) A Wilcoxon-type test for trend. Stat Med 4:87–90

    Article  CAS  PubMed  Google Scholar 

  19. Shields MA, Dangi-Garimella S, Redig AJ, Munshi HG (2012) Biochemical role of the collagen-rich tumour microenvironment in pancreatic cancer progression. Biochem J 441:541–552

    Article  CAS  PubMed  Google Scholar 

  20. Rodriguez JR, Salvia R, Crippa S, Warshaw AL, Bassi C, Falconi M, Thayer SP, Lauwers GY, Capelli P, Mino-Kenudson M, Razo O, McGrath D, Pederzoli P, Fernández-Del Castillo C (2007) Branch-duct intraductal papillary mucinous neoplasms: observations in 145 patients who underwent resection. Gastroenterology 133:72–79, quiz 309-310

    Article  PubMed Central  PubMed  Google Scholar 

  21. Bassi C, Crippa S, Salvia R (2008) Intraductal papillary mucinous neoplasms (IPMNs): is it time to (sometimes) spare the knife? Gut 57:287–289

    Article  PubMed  Google Scholar 

  22. Hwang DW, Jang JY, Lee SE, Lim CS, Lee KU, Kim SW (2012) Clinicopathologic analysis of surgically proven intraductal papillary mucinous neoplasms of the pancreas in SNUH: a 15-year experience at a single academic institution. Langenbecks Arch Surg 397:93–102

    Article  PubMed  Google Scholar 

  23. Kim KW, Park SH, Pyo J, Yoon SH, Byun JH, Lee MG, Krajewski KM, Ramaiya NH (2014) Imaging features to distinguish malignant and benign branch-duct type intraductal papillary mucinous neoplasms of the pancreas: a meta-analysis. Ann Surg 259:72–81

    Article  PubMed  Google Scholar 

  24. Rautou PE, Levy P, Vullierme MP, O’Toole D, Couvelard A, Cazals-Hatem D, Palazzo L, Aubert A, Sauvanet A, Hammel P, Hentic O, Rebours V, Pelletier AL, Maire F, Ruszniewski P (2008) Morphologic changes in branch duct intraductal papillary mucinous neoplasms of the pancreas: a midterm follow-up study. Clin Gastroenterol Hepatol 6:807–814

    Article  PubMed  Google Scholar 

  25. Ideno N, Ohtsuka T, Kono H, Fujiwara K, Oda Y, Aishima S, Ito T, Ishigami K, Tokunaga S, Ohuchida K, Takahata S, Nakamura M, Mizumoto K, Tanaka M (2013) Intraductal papillary mucinous neoplasms of the pancreas with distinct pancreatic ductal adenocarcinomas are frequently of gastric subtype. Ann Surg 258:141–151

    Article  PubMed  Google Scholar 

  26. Nakamura A, Horinouchi M, Goto M, Nagata K, Sakoda K, Takao S, Imai K, Kim YS, Sato E, Yonezawa S (2002) New classification of pancreatic intraductal papillary-mucinous tumour by mucin expression: its relationship with potential for malignancy. J Pathol 197:201–210

    Article  PubMed  Google Scholar 

  27. 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 15:1087–1095

    Article  PubMed  Google Scholar 

  28. Okabayashi T, Shima Y, Kosaki T, Sumiyoshi T, Kozuki A, Iiyama T, Takezaki Y, Kobayashi M, Nishimori I, Ogawa Y, Hanazaki K (2013) Invasive carcinoma derived from branch duct-type IPMN may be a more aggressive neoplasm than that derived from main duct-type IPMN. Oncol Lett 5:1819–1825

    PubMed Central  PubMed  Google Scholar 

  29. Van Laethem JL, Resibois A, Rickaert F et al (1997) Different expression of transforming growth factor beta 1 in pancreatic ductal adenocarcinoma and cystic neoplasms. Pancreas 15:41–47

    Article  PubMed  Google Scholar 

  30. Shindo K, Aishima S, Ohuchida K, Fujiwara K, Fujino M, Mizuuchi Y, Hattori M, Mizumoto K, Tanaka M, Oda Y (2013) Podoplanin expression in cancer-associated fibroblasts enhances tumor progression of invasive ductal carcinoma of the pancreas. Mol Cancer 12:168

    Article  PubMed Central  PubMed  Google Scholar 

  31. Hoshino A, Ishii G, Ito T, Aoyagi K, Ohtaki Y, Nagai K, Sasaki H, Ochiai A (2011) Podoplanin-positive fibroblasts enhance lung adenocarcinoma tumor formation: podoplanin in fibroblast functions for tumor progression. Cancer Res 71:4769–4779

    Article  CAS  PubMed  Google Scholar 

  32. Okada K, Hirabayashi K, Imaizumi T, Matsuyama M, Yazawa N, Dowaki S, Tobita K, Ohtani Y, Tanaka M, Inokuchi S, Makuuchi H (2010) Stromal thrombospondin-1 expression is a prognostic indicator and a new marker of invasiveness in intraductal papillary-mucinous neoplasm of the pancreas. Biomed Res 31:13–19

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by a Grant-in-Aid from the Japan Society for the Promotion of Science (JSPS) fellows. We thank Edanz Group Japan for English language editing.

Conflict of interest

The authors declare that they have no competing interests.

Author information

Authors and Affiliations

  1. Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan

    Koji Shindo, Shinichi Aishima, Minoru Fujino, Yusuke Mizuuchi, Masami Hattori & Yoshinao Oda

  2. Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan

    Kenoki Ohuchida, Takao Ohtsuka, Kazuhiro Mizumoto & Masao Tanaka

  3. Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan

    Kenoki Ohuchida

  4. Medical Information Center, Kyushu University Hospital, Fukuoka, 812-8582, Japan

    Shoji Tokunaga

  5. Cancer Center, Kyushu University Hospital, Fukuoka, 812-8582, Japan

    Kazuhiro Mizumoto

  6. Japan Society for the Promotion of Science, Tokyo, Japan

    Koji Shindo & Yusuke Mizuuchi

Authors
  1. Koji Shindo
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  2. Shinichi Aishima
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Corresponding author

Correspondence to Yoshinao Oda.

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Online Resource Fig. 1

Immunohistochemical staining of normal pancreatic duct. (a) Normal pancreatic ducts had α-SMA-positive cells sparsely. (b) PDPN was negative in the normal pancreatic ducts. (c) Lymphatic vessels were positive for PDPN without exception, and used as a positive control. Original magnification: (a,b) × 40 (c) × 100 (GIF 698 kb)

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Shindo, K., Aishima, S., Ohuchida, K. et al. Podoplanin expression in the cyst wall correlates with the progression of intraductal papillary mucinous neoplasm. Virchows Arch 465, 265–273 (2014). https://doi.org/10.1007/s00428-014-1610-x

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  • DOI: https://doi.org/10.1007/s00428-014-1610-x

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