Glypican 3

Synonyms: GLP3

by Jan Klos

Background

The glypicans are a family of 6 members of heparin sulfate proteoglycan. They are extracellular proteins, bound to the cell surface by a glycophosphatidylinositol. Glypicans are predominantly expressed during growth and development. They show modulatory activity on growth regulators signaling through interactions with a number of growth and morphogenic factors. Mutations of GPC3 gene (coding for Glypican 3 and localized to Xq26) cause a rare X-linked overgrowth syndrome (Simpson-Golabi-Behmel syndrome) characterized by numerous craniofacial, skeletal and genitourinary anomalies. Patients with this syndrome have also an increased risk for a number of malignancies including neuroblastoma, gonadoblastoma, Wilms` tumor, hepatoblastoma and hepatocellular carcinoma.

Positive staining in normal tissues

Trophoblast and wide spectrum of fetal tissues, but has limited expression in adult tissues (gastric glands, kidney tubules).

Positive staining in tumors

Hepatocellular carcinoma including its variants, hepatoblastoma, yolk sac tumor, choriocarcinoma, malignant rhabdoid tumor, Wilms` tumor, neuroblastoma, liposarcoma, squamous cell carcinoma of the lung, small cell neuroendocrine carcinomas including Merkel cell carcinoma, around 50% of bile duct adenocarcinoma including gallbladder adenocarcinoma, acinic cell carcinoma of the pancreas and clear cell  carcinoma  of the ovary are reported positive in decreasing frequency. Rhabdomyosarcoma is stained positive in about 1/3 of the cases.  Few cases in many other tumor categories are also found positive (positivity found in 10,3% among different tumors (347/3353 cases) and in 76 out of 139 different tumor categories in a large TMA study). GLP3 is also considered a potential target for immunotherapy for hepatocellular carcinoma.

Staining pattern

Staining pattern is variable: cytoplasmic often diffuse, sometimes with enhancement in Golgi region, membranous or combined.

Control tissue

Placenta

Application

Recommended to use in the panel as a sensitive but not specific marker.

  • Sensitive marker of yolk sac tumor (closely to 100% positive staining) vs. embryonal carcinoma (negative staining).    Cave! Weak positivity in immature elements of teratoma and clear cell carcinoma of the ovary (20-60%) has been reported.
  • Part of the panel diagnosing proliferations of trophoblast also as a component of mixed germ cell tumors (80-100% positive staining).
  • Hepatoblastoma (together with Hepatocyte antigen).
  • Hepatocellular carcinoma (together with CD34, Hepatocyte antigen) – seems to be more sensitive than Hepatocyte antigen in poorly differentiated variants (60-80% of positivity reported).
  • Differential diagnosis of adenoma and regenerative nodules (both negative) from hepatocellular carcinoma (positive) in the liver. Cave! Some positivity with high grade hepatocyte dysplasia and positive staining in virus hepatitis are reported.
  • Differential diagnosis of metastatic adenocarcinoma/cholangiocarcinoma vs. hepatocellular carcinoma in the panel with EP-CAM/EMA/mCEA.
  • Confirming hepatoid differentiation in adenocarcinoma (with Hepatocyte antigen).
  • Supporting diagnosis of squamous cell carcinoma (>50% positive) in lung (in panel with CK5/6 and p63) vs. adenocarcinoma (<10% positive).
  • Minority of immature teratomas may show positivity in primitive stroma, fetal type glands, neuroepithelium, primitive tubules and cartilage anlage.
  • About 1/3 of squamous cell carcinomas from different locations are positive.

Selected references

  1. Abdul-Al HM1, Makhlouf HR, Wang G, et al. Glypican-3 expression in benign liver tissue with active hepatitis C: implications for the diagnosis of hepatocellular carcinoma. Hum Pathol. 2008;39:209-212.
  2. Baumhoer D1, Tornillo L, Stadlmann S, et  al. Glypican 3 expression in human nonneoplastic, preneoplastic, and neoplastic tissues:a tissue microarray analysis of 4,387 tissue samples. Am J Clin Pathol. 2008 Jun;129(6):899-906.
  3. Hishinuma M1, Ohashi KI, Yamauchi N, et al. Hepatocellular oncofetal protein, glypican 3 is a sensitive marker for alpha-fetoprotein-producing gastric carcinoma. Histopathology. 2006 Nov;49(5):479-86.
  4. https://app.immunoquery.com/engine/abpanel?abs=Glypican-3
  5. Kakar S1, Gown AM, Goodman ZD, et al. Best practices in diagnostic immunohistochemistry: hepatocellular carcinoma versus metastatic neoplasms. Arch Pathol Lab Med. 2007 Nov;131(11):1648-54.
  6. Kandil DH1, Cooper K. Glypican-3: a novel diagnostic marker for hepatocellular carcinoma and more. Adv Anat Pathol. 2009 Mar;16(2):125-9. doi: 10.1097/PAP.0b013e3181992455.
  7. Luo W1, Ren Z2, Gao S2, et al. Clinical correlation of calpain-1 and glypican-3 expression with gallbladder carcinoma. Oncol Lett. 2016 Feb;11(2):1345-1352. Epub 2016 Jan 7.
  8. 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. PMID: 23079207.
  9. Nogales FF1, Preda O, Nicolae A. Yolk sac tumours revisited. A review of their many faces and names. Histopathology. 2012 Jun;60(7):1023-33. doi: 10.1111/j.1365-2559.2011.03889.x. Epub 2011 Oct 18.
  10. Shimizu Y1,2, Suzuki T1, Yoshikawa T.1  Next-Generation Cancer Immunotherapy Targeting Glypican-3. Front Oncol. 2019 Apr 10;9:248. doi: 10.3389/fonc.2019.00248. eCollection 2019.
  11. Shirakawa H1, Kuronuma T, Nishimura Y, et al. Glypican-3 is a useful diagnostic marker for a component of hepatocellular carcinoma in human liver cancer. Int J Oncol. 2009 Mar;34(3):649-56.
  12. Thway K1, Selfe J, Missiaglia E, et al. 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.