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An immunohistochemical panel of insulin-like growth factor II mRNA-binding protein 3 (IMP3), enhancer of zeste homolog 2 (EZH2), and p53 is useful for a diagnosis in bile duct biopsy

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Abstract

Bile duct biopsy is being increasingly performed in number for a definite diagnosis of cholangiocarcinoma. However, difficulties are associated with a histopathological diagnosis because of the limited small amount of specimen obtained and crash artifact. The aim of the present study was to identify useful diagnostic immunohistochemical markers in bile duct biopsy that support a histological diagnosis. Fifty-one bile duct biopsy samples, including 26 samples taken from patients with cholangiocarcinoma, 11 with intraductal papillary neoplasm of the bile duct (IPNB), and 14 with benign bile duct lesions, were examined. Histology and the immunohistochemical expression of insulin-like growth factor II mRNA-binding protein 3 (IMP3), enhancer of zeste homolog 2 (EZH2), and p53 were assessed. They were then evaluated for their usefulness as diagnostic markers of malignancy. The diagnostic sensitivity and accuracy of the institutional histological diagnosis were 53.8% and 70.0%, respectively. The diagnostic sensitivity and accuracy of IMP3, EZH2, and p53 were 69.2% and 80.0%, 76.9% and 85.0%, and 50.0% and 67.5%, respectively. Immunohistochemical staining for EZH2; the combination of either 2 of IMP3, EZH2, and p53; or the combination of IMP3, EZH2, and p53 significantly increased sensitivity and accuracy over those of the institutional histological diagnosis (p<0.05). In conclusion, an immunohistochemical panel consisting of IMP3, EZH2, and p53 increases the diagnostic sensitivity and accuracy of bile duct biopsy for the diagnosis of cholangiocarcinoma.

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All data generated or analyzed during the present study were included in the published article.

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References

  1. Dumonceau JM, Delhaye M, Charette N, Farina A (2020) Challenging biliary strictures: pathophysiological features, differential diagnosis, diagnostic algorithms, and new clinically relevant biomarkers - part 1. Ther Adv Gastroenterol 13:1756284820927292. https://doi.org/10.1177/1756284820927292

    Article  CAS  Google Scholar 

  2. Kawashima H, Itoh A, Ohno E, Miyahara R, Ohmiya N, Tanaka T, Shimoyama Y, Nakamura S, Ebata T, Nagino M, Goto H, Hirooka Y (2013) Diagnostic and prognostic value of immunohistochemical expression of S100P and IMP3 in transpapillary biliary forceps biopsy samples of extrahepatic bile duct carcinoma. J Hepatobiliary Pancreat Sci 20:441–447. https://doi.org/10.1007/s00534-012-0581-z

    Article  PubMed  Google Scholar 

  3. Singhi AD, Nikiforova MN, Chennat J, Papachristou GI, Khalid A, Rabinovitz M, Das R, Sarkaria S, Ayasso MS, Wald AI, Monaco SE, Nalesnik M, Ohori NP, Geller D, Tsung A, Zureikat AH, Zeh H, Marsh JW, Hogg M, Lee K, Bartlett DL, Pingpank JF, Humar A, Bahary N, Dasyam AK, Brand R, Fasanella KE, McGrath K, Slivka A (2020) Integrating next-generation sequencing to endoscopic retrograde cholangiopancreatography (ERCP)-obtained biliary specimens improves the detection and management of patients with malignant bile duct strictures. Gut 69:52–61. https://doi.org/10.1136/gutjnl-2018-317817

    Article  CAS  PubMed  Google Scholar 

  4. De Bellis M, Sherman S, Fogel EL, Cramer H, Chappo J, McHenry L Jr, Watkins JL, Lehman GA (2002) Tissue sampling at ERCP in suspected malignant biliary strictures (part 1). Gastrointest Endosc 56:552–561. https://doi.org/10.1067/mge.2002.128132

    Article  PubMed  Google Scholar 

  5. de Bellis M, Sherman S, Fogel EL, Cramer H, Chappo J, McHenry L Jr, Watkins JL, Lehman GA (2002) Tissue sampling at ERCP in suspected malignant biliary strictures (part 2). Gastrointest Endosc 56:720–730. https://doi.org/10.1067/mge.2002.129219

    Article  PubMed  Google Scholar 

  6. Levy M, Lin F, Xu H, Dhall D, Spaulding BO, Wang HL (2010) S100P, von Hippel-Lindau gene product, and IMP3 serve as a useful immunohistochemical panel in the diagnosis of adenocarcinoma on endoscopic bile duct biopsy. Hum Pathol 41:1210–1219. https://doi.org/10.1016/j.humpath.2010.01.014

    Article  CAS  PubMed  Google Scholar 

  7. Sasaki M, Sato Y (2017) Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is a marker that predicts presence of invasion in papillary biliary tumors. Hum Pathol 62:152–159. https://doi.org/10.1016/j.humpath.2016.12.028

    Article  CAS  PubMed  Google Scholar 

  8. Gao Y, Yang M, Jiang Z, Woda BA, Mercurio AM, Qin J, Huang X, Zhang F (2014) IMP3 expression is associated with poor outcome and epigenetic deregulation in intrahepatic cholangiocarcinoma. Hum Pathol 45:1184–1191. https://doi.org/10.1016/j.humpath.2014.01.016

    Article  CAS  PubMed  Google Scholar 

  9. 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. https://doi.org/10.1016/j.humpath.2012.12.020

    Article  CAS  PubMed  Google Scholar 

  10. Peng DF, Kanai Y, Sawada M, Ushijima S, Hiraoka N, Kitazawa S, Hirohashi S (2006) DNA methylation of multiple tumor-related genes in association with overexpression of DNA methyltransferase 1 (DNMT1) during multistage carcinogenesis of the pancreas. Carcinogenesis 27:1160–1168. https://doi.org/10.1093/carcin/bgi361

    Article  CAS  PubMed  Google Scholar 

  11. Riener MO, Fritzsche FR, Clavien PA, Pestalozzi BC, Probst-Hensch N, Jochum W, Kristiansen G (2009) IMP3 expression in lesions of the biliary tract: a marker for high-grade dysplasia and an independent prognostic factor in bile duct carcinomas. Hum Pathol 40:1377–1383. https://doi.org/10.1016/j.humpath.2009.01.024

    Article  CAS  PubMed  Google Scholar 

  12. Saito Y, Kanai Y, Nakagawa T, Sakamoto M, Saito H, Ishii H, Hirohashi S (2003) Increased protein expression of DNA methyltransferase (DNMT) 1 is significantly correlated with the malignant potential and poor prognosis of human hepatocellular carcinomas. Int J Cancer 105:527–532. https://doi.org/10.1002/ijc.11127

    Article  CAS  PubMed  Google Scholar 

  13. Jacobs JJ, Kieboom K, Marino S, DePinho RA, van Lohuizen M (1999) The oncogene and polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397:164–168

    Article  CAS  Google Scholar 

  14. Valk-Lingbeek ME, Bruggeman SW, van Lohuizen M (2004) Stem cells and cancer; the polycomb connection. Cell 118:409–418

    Article  CAS  Google Scholar 

  15. Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, Ghosh D, Sewalt RG, Otte AP, Hayes DF, Sabel MS, Livant D, Weiss SJ, Rubin MA, Chinnaiyan AM (2003) EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci U S A 100:11606–11611

    Article  CAS  Google Scholar 

  16. Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, Ghosh D, Pienta KJ, Sewalt RG, Otte AP, Rubin MA, Chinnaiyan AM (2002) The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419:624–629

    Article  CAS  Google Scholar 

  17. Sasaki M, Matsubara T, Yoneda N, Nomoto K, Tsuneyama K, Sato Y, Nakanuma Y (2013) Overexpression of enhancer of zeste homolog 2 and MUC1 may be related to malignant behaviour in intraductal papillary neoplasm of the bile duct. Histopathology 62:446–457. https://doi.org/10.1111/his.12016

    Article  PubMed  Google Scholar 

  18. Nakanuma Y, Curado M, Fransceschi S, Gores G, Paradis V, Sripa B, Tsui W, Wee S (2010) Intrahepatic cholagiocarcinoma. In: Bosman F, Carneiro F, Hruban H, Theise N (eds) WHO classification of tumours of the digestive system, 4th edn. IARC, Lyon, pp 217–227

    Google Scholar 

  19. Sasaki M, Nakanuma Y, Kim Y (1996) Characterization of apomicin expression in intrahepatic cholangio-carcinomas and their precursor lesions: an immunohistochemical study. Hepatology 24:1074–1078

    Article  CAS  Google Scholar 

  20. Sasaki M, Yamaguchi J, Itatsu K, Ikeda H, Nakanuma Y (2008) Over-expression of polycomb group protein EZH2 relates to decreased expression of p16 INK4a in cholangiocarcinogenesis in hepatolithiasis. J Pathol 215:175–183

    Article  CAS  Google Scholar 

  21. Yamaguchi J, Sasaki M, Harada K, Zen Y, Sato Y, Ikeda H, Itatsu K, Yokoyama Y, Ando H, Ohta T, Kubota A, Shimizu K, Nimura Y, Nagino M, Nakanuma Y (2009) Papillary hyperplasia of the gallbladder in pancreaticobiliary maljunction represents a senescence-related lesion induced by lysolecithin. Lab Investig 89:1018–1031. https://doi.org/10.1038/labinvest.2009.65

    Article  CAS  PubMed  Google Scholar 

  22. Zen Y, Sasaki M, Fujii T, Chen TC, Chen MF, Yeh TS, Jan YY, Huang SF, Nimura Y, Nakanuma Y (2006) Different expression patterns of mucin core proteins and cytokeratins during intrahepatic cholangiocarcinogenesis from biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct--an immunohistochemical study of 110 cases of hepatolithiasis. J Hepatol 44:350–358

    Article  CAS  Google Scholar 

  23. Hsu M, Sasaki M, Igarashi S, Sato Y, Nakanuma Y (2013) KRAS and GNAS mutations and p53 overexpression in biliary intraepithelial neoplasia and intrahepatic cholangiocarcinomas. Cancer 119:1669–1674. https://doi.org/10.1002/cncr.27955

    Article  CAS  PubMed  Google Scholar 

  24. Nakanuma Y, Sasaki M, Sato Y, Ren X, Ikeda H, Harada K (2009) Multistep carcinogenesis of perihilar cholangiocarcinoma arising in the intrahepatic large bile ducts. World J Hepatol 1:35–42. https://doi.org/10.4254/wjh.v1.i1.35

    Article  PubMed  PubMed Central  Google Scholar 

  25. Wang HL, Kim CJ, Koo J, Zhou W, Choi EK, Arcega R, Chen ZE, Wang H, Zhang L, Lin F (2017) Practical immunohistochemistry in neoplastic pathology of the gastrointestinal tract, liver, biliary tract, and pancreas. Arch Pathol Lab Med 141:1155–1180. https://doi.org/10.5858/arpa.2016-0489-RA

    Article  CAS  PubMed  Google Scholar 

  26. Kobel M, Reuss A, du Bois A, Kommoss S, Kommoss F, Gao D, Kalloger SE, Huntsman DG, Gilks CB (2010) The biological and clinical value of p53 expression in pelvic high-grade serous carcinomas. J Pathol 222:191–198. https://doi.org/10.1002/path.2744

    Article  CAS  PubMed  Google Scholar 

  27. Burnett AS, Quinn PL, Ajibade DV, Peters SR, Ahlawat SK, Mahmoud OM, Chokshi RJ (2019) Design of an immunohistochemistry biomarker panel for diagnosis of pancreatic adenocarcinoma. Pancreatology 19:842–849. https://doi.org/10.1016/j.pan.2019.08.007

    Article  CAS  PubMed  Google Scholar 

  28. Senoo J, Mikata R, Kishimoto T, Hayashi M, Kusakabe Y, Yasui S, Yamato M, Ohyama H, Sugiyama H, Tsuyuguchi T, Yoshitomi H, Ohtsuka M, Maeda J, Ota S, Nakatani Y, Kato N (2018) Immunohistochemical analysis of IMP3 and p53 expression in endoscopic ultrasound-guided fine needle aspiration and resected specimens of pancreatic diseases. Pancreatology 18:176–183. https://doi.org/10.1016/j.pan.2017.12.010

    Article  CAS  PubMed  Google Scholar 

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Funding

The present study was supported in part by a Grant-in Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports and Science and Technology of Japan (18K06985).

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  1. Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan

    Motoko Sasaki & Yasunori Sato

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  1. Motoko Sasaki
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  2. Yasunori Sato
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Contributions

Study conception and design were performed by Motoko Sasaki. Material preparation and data collection and analysis were performed by Motoko Sasaki and Yasunori Sato. The first draft of the manuscript was written by Motoko Sasaki and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Motoko Sasaki.

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The Ethics Committee of Kanazawa University approved the present study. The work described herein was conducted in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans.

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Sasaki, M., Sato, Y. An immunohistochemical panel of insulin-like growth factor II mRNA-binding protein 3 (IMP3), enhancer of zeste homolog 2 (EZH2), and p53 is useful for a diagnosis in bile duct biopsy. Virchows Arch 479, 697–703 (2021). https://doi.org/10.1007/s00428-021-03132-3

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  • DOI: https://doi.org/10.1007/s00428-021-03132-3

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