GLP3

(Glypican 3)
Assessments
Characteristics
Nature: GLP3 is a membrane proteoglycan, 60-70 kDa (core protein only), encoded by a gene on Chr Xq26, one of six members of the GLP family, which together with the syndecan family represent the major groups of cell surface heparin sulphate proteoglycans. Function and occurrence: GLPs play a vital role in developmental morphogenesis by modifying cell signaling pathways thus contributing to cellular proliferation and tissue growth. GLPs are regulators for the Wnt and Hedgehog cell signaling pathways, and for fibroblast growth factor and bone morphogenic protein signaling. GLPs are oncofetal proteins, i.e., they are expressed in embryonic structures (such as liver and intestine), but undetectable in the corresponding normal adult structures but re-expressed in malignant tumors developed from these structures. In normal adult tissues only placental syncytiotrophoblast and villus core mesenchymal cells are GLP3 positive.
Neoplasms
+: >90% positive, +/-: 50-90% positive, -/+: 10 - >50% positive, -(+): 1-<10% positive, -: <1% positive, ?: conflicting evidence or insufficient information. + GLP3 is detected in almost all cases of choriocarcinoma, yolk sac tumour, hepatoblastoma, and atypical teratoid/rhabdoid tumor. +/- GLP3 is detected in most cases of hepatocellular carcinoma (HCC) (70-90%), especially in low differentiated tumors, where it is a negative prognostic factor. Acinar pancreatic carcinoma and Merkel cell carcinoma also express GLP3 in most cases. -/+ GLP3 is less frequently detected in dysplastic liver cell nodule (where focal positivity may indicate HCC development), squamous cell carcinoma (esophagus, anus), gastroentestinal adenocarcinomas, ovarian carcinomas, especially clear cell carcinoma (30%), in embryonal carcinoma (15%, often focal), Wilms’ tumor (40%), and alveolar and embryonal rhabomyosarcoma (30%). [-] GLP3 is not detected in liver focal nodular hyperplasia or liver cell adenoma (focal positivity may indicate HCC development), ovarian sex cord stromal tumor, seminoma/dysgerminoma, and also not in carcinomas and sarcomas apart from the above mentioned.
Application
GLP3 is an important marker for the identification of HCC (+/-) vs. liver cell adenoma (-), focal nodular hyperplasia (-), cholangiocellular carcinoma (-) and metastatic carcinoma of the liver (-). GLP3 is also relevant as a sensitive (though not specific) marker for yolk sac tumour (+) vs. clear cell carcinoma (-/+) and embryonal carcinoma (-/+).
Controls
Placenta is recommended as positive tissue control for GLP3. Virtually all syncytiotrophoblasts and cytotrophoblasts must show a moderate to strong predominantly cytoplasmic but also membranous staining reaction. Dispersed villous stromal cells must show an at least weak cytoplasmic staining reaction. Appendix can be used as negative tissue control. The vast majority of epithelial cells must be negative. Dispersed basal epithelial cells can show a weak cytoplasmic staining reaction.
Selected references
Fujiwara M, Kwok S, Yano H, Pai RK. Arginase-1 is a more sensitive marker of hepatic differentiation than HepPar-1 and glypican-3 in fine-needle aspiration biopsies. Cancer Cytopathol. 2012 Aug 25;120(4):230-7. doi: 10.2002/cncy.21190.Epub 2012 Mar 20. PubMed PMID: 22434791. He H, Fang W, Liu X, Weiss LM, Chu PG. Frequent expression of glypican-3 in Merkel cell carcinoma: an immunohistochemical study of 55 cases. Appl Immunohistochem Mol Morphol. 2009 Jan;17(1):40-6. doi: 10.1097/PAI.0b013e31817b67d1. PubMed PMID: 18813128. Kandil D, Leiman G, Allegretta M, Evans M. Glypican-3 protein expression in primary and metastatic melanoma: a combined immunohistochemistry and immunocytochemistry study. Cancer. 2009 Aug 25;117(4):271-8. doi:10.2002/cncy.20032. PubMed PMID: 19517479. Mounajjed T, Zhang L, Wu TT. Glypican-3 expression in gastrointestinal and pancreatic epithelial neoplasms. Hum Pathol. 2013 Apr;44(4):542-50. doi: 10.1016/j.humpath.2012.06.016. Epub 2012 Oct 15. PubMed PMID: 23079207. Preda O, Nicolae A, Aneiros-Fernández J, Borda A, Nogales FF. Glypican 3 is a sensitive, but not a specific, marker for the diagnosis of yolk sac tumours.Histopathology. 2011 Jan;58(2):312-4; author reply 314-5. doi:10.1111/j.1365-2559.2010.03735.x. Epub 2011 Jan 24. PubMed PMID: 21255065. Rabban JT, Zaloudek CJ. A practical approach to immunohistochemical diagnosis of ovarian germ cell tumours and sex cord-stromal tumours. Histopathology. 2013 Jan;62(1):71-88. doi: 10.1111/his.12052. Review. PubMed PMID: 23240671. Thway K, Selfe J, Missiaglia E, Fisher C, Shipley J. Glypican-3 is expressed in rhabdomyosarcomas but not adult spindle cell and pleomorphic sarcomas. J Clin Pathol. 2011 Jul;64(7):587-91. doi: 10.1136/jclinpath-2011-200071. Epub 2011 Apr 14. PubMed PMID: 21493758. Timek DT, Shi J, Liu H, Lin F. Arginase-1, HepPar-1, and Glypican-3 are the most effective panel of markers in distinguishing hepatocellular carcinoma from metastatic tumor on fine-needle aspiration specimens. Am J Clin Pathol. 2012 Aug;138(2):203-10. doi: 10.1309/AJCPK1ZC9WNHCCMU. PubMed PMID: 22904131. Trinh DT, Shibata K, Hirosawa T, Umezu T, Mizuno M, Kajiyama H, Kikkawa F.Diagnostic utility of CD117, CD133, SALL4, OCT4, TCL1 and glypican-3 in malignant germ cell tumors of the ovary. J Obstet Gynaecol Res. 2012 May;38(5):841-8. doi:10.1111/j.1447-0756.2011.01798.x. Epub 2012 Mar 26. PubMed PMID: 22448662. Zhang L, Liu H, Sun L, Li N, Ding H, Zheng J. Glypican-3 as a potential differential diagnosis marker for hepatocellular carcinoma: a tissue microarray-based study. Acta Histochem. 2012 Oct;114(6):547-52. doi:10.1016/j.acthis.2011.10.003. Epub 2011 Nov 26. PubMed PMID: 22119409.
09.12.14 - SN/MV/LE