Enhancer of zeste homologue 2 (EZH2) is a reliable immunohistochemical marker to differentiate malignant and benign hepatic tumors

Diagnostic Pathology

Péter Nagy¹  Zsuzsa Schaff⁴  Krisztina Schlachter⁴  Judit Halász⁴  Zoltán Pávai³  Sándor Paku²  Csaba Bödör¹  Edina Bugyik¹  Katalin Dezső¹  Szofia Hajósi-Kalcakosz¹ 

[1] First Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllõi út 26, Budapest, H-1085, Hungary;Tumor Progression Research Group, Joint Research Organization of the Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary;Department of Anatomy and Embriology, University of Medicine and Pharmacy, Targu Mures, Romania;Second Department of Pathology, Semmelweis University, Budapest, Hungary

关键词: Hepatocellular adenoma;    Metastasis;    Hepatoblastoma;    Cholangiocarcinoma;    Hepatocellular carcinoma;    EZH2;    Immunohistochemistry;   

Others  :  808029
DOI  :  10.1186/1746-1596-7-86

 received in 2012-05-23, accepted in 2012-07-18,  发布年份 2012

【 摘 要 】

Background

The immunohistochemical demonstration of Enhancer of zeste homologue 2 (EZH2) proved to be a useful marker in several tumor types. It has been described to distinguish reliably hepatocellular carcinomas from liver adenomas and other benign hepatocellular lesions. However, no other types of malignant liver tumors were studied so far.

Methods

To evaluate the diagnostic value of this protein in hepatic tumors we have investigated the presence of EZH2 by immunohistochemistry in hepatocellular carcinomas and other common hepatic tumors.

EZH2 expression was examined in 44 hepatocellular carcinomas, 23 cholangiocarcinomas, 31 hepatoblastomas, 16 other childhood tumor types (rhabdomyosarcoma, neuroblastoma, Wilms’ tumor and rhabdoid tumor), 17 metastatic liver tumors 24 hepatocellular adenomas, 15 high grade dysplastic nodules, 3 biliary cystadenomas, 3 biliary hamartomas and 3 Caroli’s diseases.

Results

Most of the malignant liver tumors were positive for EZH2, but neither of the adenomas, cirrhotic/dysplastic nodules, reactive and hamartomatous biliary ductules stained positively.

Conclusions

Our immunostainings confirm that EZH2 is a sensitive marker of hepatocellular carcinoma, but its specificity is very low, since almost all the investigated malignant liver tumors were positive regardless of their histogenesis. Based on these results EZH2 is a sensitive marker of malignancy in hepatic tumors. In routine surgical pathology EZH2 could be most helpful to diagnose cholangiocarcinomas, because as far as we know this is the first marker to distinguish transformed and reactive biliary structures. Although hepatoblastomas also express EZH2, the diagnostic significance of this observation seems to be quite limited whereas, the structurally similar, other blastic childhood tumors are also positive.

Virtual Slides

The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1173195902735693

【 授权许可】

   
2012 Hajósi-Kalcakosz et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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【 参考文献 】

• [1]As L, Sormunen RT, Tsui WMS: Hep Par 1 and selected antibodies in the immunohistochemical distinction of hepatocellular carcinoma from cholangiocarcinoma, combined tumors and metastatic carcinoma. Histopathology 1998, 33:319-324.
• [2]Shousha S, Gadir F, Peston D, Bansi D, Thillainaygam AV, Murray-Lyon IM: CD10 immunostaining of bile canaliculi in liver biopsies:change of staining pattern with the development of cirrhosis. Histopathology 2004, 45:335-342.
• [3]Wee A: Diagnostic utility of immunohistochemistry in hepatocellular carcinoma, its variants and their mimics. Appl Immunohistochem Mol Morphol. 2006, 14:266-272.
• [4]Kojiro M, Wanless IR, Alves V, et al.: Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. Hepatology 2009, 49:658-664.
• [5]Di Tommaso L, Destro A, Seok JY, et al.: The application of markers (HSP70 GPC3 and GS) in liver biopsies is useful for detection of hepatocellular carcinoma. J Hepatol 2009, 50:746-754.
• [6]Di Tommaso L, Destro A, Fabbris V, et al.: Diagnostic accuracy of clathrin heavy chain staining in a marker panel for the diagnosis in small hepatocellular carcinoma. Hepatology 2011, 53:1549-1557.
• [7]Kandil DH, Cooper K: Glypican-3 a novel diagnostic marker for hepatocellular carcinoma and more. Adv Anat Pathol 2009, 16:125-129.
• [8]Abdul-Al HM, Makhlouf HR, Wang G, Goodman ZS: Glypican-3 expression in benign liver tissue with active hepatitis C: implications for the diagnosis of hepatocellular carcinoma. Hum Pathol 2008, 39:209-212.
• [9]Dezső K, Halász J, Bisgaard HC, et al.: Delta-like protein (DLK) is a novel immunohistochemical marker for human hepatoblastomas. Virchows Arch. 2008, 452:443-448.
• [10]Patsenker E, Wilkens L, Banz V, et al.: The ανβ6 integrin is a highly specific immunohistochemical marker for cholangiocarcinoma. J Hepatol 2009, 52:362-369.
• [11]Cai M, Tong Z, Zheng F, et al.: EZH2 protein: a promising immunomarker for the detection of hepatocellular carcinomas in liver needle biopsies. Gut 2011, 60:967-976.
• [12]Ryutaro A, Tetsuhiro C, Satoru M, et al.: The polycomb group gene product Ezh2 regulates proliferation and differentiation of murine hepatic stem/progenitor cells. J Hepatology. 2010, 52:854-863.
• [13]Tsang DPF, Cheng ASL: Epigenetic regulation of signaling pathways in cancer: Role of the histone methyltransferase EZH2. J Gastroenterol Hepatol 2011, 26:19-27.
• [14]Wang H, Albadine R, Magheli A, et al.: Increased EZH2 protein expression is associated with invasive urothelial carcinoma of the bladder. Urol Oncol 2011. Epub ahead of print
• [15]Yamada A, Fujii S, Daiko H, Nishimura M, Chiba T, Ochiai A: Aberrant expressions of EZH2 is associated with a poor outcome and P53 alteration in squamous cell carcinoma of the esophagus. Int J Oncol 2011, 38:345-353.
• [16]Matsukawa Y, Semba S, Kato H, Ito A, Yanagihara K, Yokozaki H: Expression of the enhancer of zeste homolog 2 is correlated with poor prognosis in human gastric cancer. Cancer Sci. 2006, 97:484-491.
• [17]Orzan F, Pellegatta S, Poliani L, et al.: Enhancer of zeste homolog 2 (EZH2) is up-regulated in malignant gliomas and in glioma stem-like cells. Neuropathol Appl Neurobiol 2011, 37:381-394.
• [18]Wagener N, Macher-Goeppinger S, Pritsch M, et al.: Enhancer of zeste homolog 2 (EZH2) expression is an independent prognostic factor in renal cell carcinoma. BMC Cancer. 2010, 10:524. BioMed Central Full Text
• [19]Kikuchi J, Kinoshita I, Shmizu Y, et al.: Distinctive expression of the polycomb group proteins Bmi1 polycomb ring finger oncogene and enhancer of zeste homolog 2 in nonsmall cell lung cancers and their clinical and clinicopathologic significance. Cancer 2010, 116:3015-3024.
• [20]Wang CG, Ye YJ, Yuan J, Liu FF, Zhang H, Wang S: EZH2 and STAT6 expression profiles are correlated with colorectal cancer stage and prognosis. World J Gastroenterol 2010, 16:2421-2427.
• [21]Gonzalez ME, DuPrie ML, Krueger H, et al.: Histone methyltransferase EZH2 induces Akt-dependent genomic instability and BRCA1 inhibition in breast cancer. Cancer Res 2011, 71:2360-2370.
• [22]Edmondson HA, Steiner PE: Primary carcinoma of the liver. Cancer 1954, 7:462-503.
• [23]Chen Y, Lin MC, Yao H, et al.: Lentivirus-mediated RNA interference targeting enhancer of zeste homolog 2 inhibits hepatocellular carcinoma growth through dowregulation of stathmin. Hepatology 2007, 46:200-208.
• [24]Yonemitsu Y, Imazeki F, Chiba T, et al.: Distinct expression of polycomb group proteins EZH2 and BMI1 in hepatocellular carcinoma. Hum Pathol 2009, 40:1304-1311.
• [25]Sasaki M, Ikeda H, Itatsu K, et al.: The overexpression of of polycomb group proteins Bmi1 and EZH2 is associated with the progression and aggressive biological behavior of hepatocellular carcinoma. Lab Invest. 2008, 88:873-882.
• [26]Leung-Kuen Au S, Chak-Lui Wong C, Man-Fong Lee J, et al.: Enhancer of zeste homolog 2 (EZH2) epigenetically silences multiple tumor suppressor miRNAs to promote liver cancer metastasis. Hepatology 2012. Epub ahead of print
• [27]Zucman-Rossi J, Jeannot E, Tran Van Nhieu J, et al.: Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC. Hepatology 2006, 43:515-524.
• [28]Németh Z, Szász AM, Tátrai P, et al.: Claudin-1,-2,-3,-4,-7.-8, and −10 protein expression in biliary tract cancers. J Histochem Cytochem 2009, 57:113-121.
• [29]Richter GH, Plehm S, Fasan A, et al.: EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiation. Proc Natl Acad Sci USA 2009, 106:5324-5329.
• [30]Venneti S, Le P, Martinez D, et al.: Malignant rhabdoid tumors express stem cell factors, which relate to the expression of EZH2 and Id proteins. Am J Surg Path 2011, 35:1463-1472.
• [31]Pirrotta V: Polycombing the genome: PcG, trxG, and chromatin silencing. Cell 1998, 93:333-336.
• [32]Hayden A, Johnson PW, Packham G, Crabb SJ: S-adenosylhomocysteine hydrolase inhibition by 3-deazaneplanocin A analogues induces anti-cancer effects in breast cancer cell lines and synergy with both histone deacetylase and HE2 inhibition. Breast Cancer Res Treat. 2011, 127:109-119.