Expression of glypican 3 in placental site trophoblastic tumor

Robin J Ou-Yang,Pei Hui,Debra L Zynger,Ximing J Yang

doi:10.1186/1746-1596-5-64

Abstract

BackgroundGlypican-3 (GPC3) is a membrane-bound heparan sulfate proteoglycan that functions in embryonic cell growth and differentiation and is highly expressed in the placenta. GPC3 is mutated in Simpson-Golabi-Behmel syndrome, which is characterized by tissue overgrowth and an increased risk of embryonal malignancies. GPC3 has also been implicated in sporadic cancer, particularly hepatocellular carcinoma, for which it has been shown to be a useful diagnostic marker. Although GPC3 expression has been studied in non-neoplastic placental tissue, its presence in gestational trophoblastic diseases has not been previously explored. The purpose of this study was to investigate the immunohistochemical expression of GPC3 in placental site trophoblastic tumor (PSTT), a very rare gestational trophoblastic neoplasm which may be morphologically confused with non-trophoblastic tumors, and to assess its possible utility as a diagnostic marker.MethodsFifteen cases of PSTT, as well as samples from placental site nodule (PSN) (n = 2), leiomyosarcoma (n = 1), leiomyoma (n = 1), invasive cervical squamous cell carcinoma (n = 7) and endometrial adenocarcinoma (n = 11) were examined. Immunoreactivity was semi-quantitatively evaluated as negative (0, < 5% of cells stained), focally positive (1+, 5-10% of cells stained), positive (2+, 11-50% of cells stained) or diffusely positive (3+, > 50% of cells stained). Staining intensity for each subtype was graded from 0 to 3 and a mean intensity was calculated.ResultsEighty percent of PSTT (12/15) were immunoreactive for GPC3 (0, 20; 1+, 20%; 2+, 40%; 3+, 20%) with a mean intensity of 1.3. Stronger, predominately cytoplasmic staining was seen in larger multi- and mononucleated cells with smaller mononucleate cells showing weak muddy cytoplasmic staining. Both PSN cases were positive (1+, 50%; 2+, 50%) and two of nine invasive cervical squamous cell carcinomas showed staining (0, 57%; 1+, 29%; 2+, 14%), predominately in a basal distribution. Other uterine tumors and non-neoplastic tissues were negative.ConclusionsIdentification of GPC3 in PSTT and PSN is consistent with the derivation of these lesions from intermediate trophoblasts, which have been described to express GPC3. GPC3 may be a useful adjunct immunohistochemical marker in differentiating PSTT from non-trophoblastic tumors.

Highlights

Glypican-3 (GPC3) is a membrane-bound heparan sulfate proteoglycan that functions in embryonic cell growth and differentiation and is highly expressed in the placenta
Like all heparan sulfate proteoglycans, glypicans consist of a core protein, to which are attached two heparan sulfate glycosaminoglycan polysaccharide chains
In tissues with no adult expression, GPC3 may act as an oncofetal protein, and tumors derived from these tissues have increased levels of GPC3 mRNA, with protein studies limited to the first three [7,10,11,12,13]

Summary

Introduction

Glypican-3 (GPC3) is a membrane-bound heparan sulfate proteoglycan that functions in embryonic cell growth and differentiation and is highly expressed in the placenta. Like all heparan sulfate proteoglycans, glypicans consist of a core protein, to which are attached two heparan sulfate glycosaminoglycan polysaccharide chains. The variability within these chains determines binding specificity with different ligands, such as growth factors and chemokines, which triggers intracellular signaling. In tissues with no adult expression, GPC3 may act as an oncofetal protein, and tumors derived from these tissues have increased levels of GPC3 mRNA (hepatocellular carcinoma, hepatoblastoma, Wilms tumor, neuroblastoma, and rhabdomyosarcoma), with protein studies limited to the first three [7,10,11,12,13]. GPC3 in particular has been shown to increase Wnt signaling in hepatocellular carcinoma via interaction between Wnt and GPC3 core protein [4]

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