Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
권호 표지
DOI QR코드

DOI QR Code

Roles of Combined Glypican-3 and Glutamine Synthetase in Differential Diagnosis of Hepatocellular Lesions

  • Published : 2015.06.26
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and thirdly leading cause of cancer-related death worldwide. The estimated risk of hepatocellular carcinoma is 15 to 20 times as high among persons infected with HCV as it is among those who are not infected, with most of the excess risk limited to those with advanced hepatic fibrosis or cirrhosis. Glypican3 (GPC3) plays a key role in relation to signaling with growth factors, regulating the proliferative activity of cancer cells. Glutamine synthetase (GS) catalyzes the synthesis of glutamine from glutamate and ammonia in the mammalian liver. GS was suggested as a specific marker for tracing cell lineage relationships during hepatocarcinogenesis. In normal liver, GS expression is seen in pericentral hepatocytes, but not by midzonal or periportal hepatocytes. In HCC, strong and diffuse GS expression in seen in tumor cells. Results: Glypican3 immunopositvity was highly specific and sensitive indicator for hepatocellular carcinoma as well as glutamine synthetase which was found to be a sensitive and specific indicator for development of hepatocellular carcinoma when compared to cirrhosis, liver cell dyspalsia and metastatic carcinomas. Statistical analysis revealed a significant association between GPC3 and GS with tumor size (P=0.003, p=0.006, respectively). Diffuse staining significantly associated with large tumor size while, focal and mixed staining was detected more with small tumor size. Studying the relation with tumor grade also revealed significant association between diffuse GPC3 and GS staining with high tumor grade. Diffuse staining was detected in 91.7% and 100% respectively of poorly differentiated specimens and only in 33.3% and 22.2% of well differentiated specimens. Conclusions: While using GPC3 and GS to screen for premalignant hepatic lesions remains controversial, our data suggest that GPC3 and GS may be a reliable diagnostic immunomarkers to distinguish HCC from benign hepatocellular lesions. However, negative immunostaining should not exclude the diagnosis of HCC.

Keywords

References

  1. Anatelli F, Chuang ST, Yang XJ, Wang HL (2008). Value of Glypican 3 immunostaining in the diagnosis of hepatocellular carcinoma on needle biopsy. Am J Clin Pathol, 130, 219-23. https://doi.org/10.1309/WMB5PX57Y4P8QCTY
  2. Abdelgawad IA, Mossallam GI, Radwan NH, Elzawahry HM, Elhifnawy NM (2013). Can Glypican 3 be diagnostic for early hepatocellular carcinoma among egyptian patients? Asian Pac J Cancer Prev, 14, 7345-9. https://doi.org/10.7314/APJCP.2013.14.12.7345
  3. Abouzied MM, Eltahir HM, Fawzy MA, et al (2015). Estimation of leucine aminopeptidase and 5-Nucleotidase increases alpha-fetoprotein sensitivity in human hepatocellular carcinoma cases. Asian Pac J Cancer Prev, 16, 959-63. https://doi.org/10.7314/APJCP.2015.16.3.959
  4. Bello BD, Rosa L, Campanini N, et al (2010). Glutamine synthetase immunostaining correlates with pathologic features of hepatocellular carcinoma and better survival after radiofrequency thermal ablation. Clin Cancer Res, 16, 2157. https://doi.org/10.1158/1078-0432.CCR-09-1978
  5. Capurro M, Wanless IR, Sherman M, et al (2003). Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma. Gastroenterology, 125, 89-97. https://doi.org/10.1016/S0016-5085(03)00689-9
  6. Christa L, Simon MT, Flinois JP, et al (1994). Overexpression of glutamine synthetase in human primary liver cancer. Gastroenterology, 106, 1312-20. https://doi.org/10.1016/0016-5085(94)90024-8
  7. Coston WM, Loera S, Lau SK, et al (2008). Distinction of hepatocellular carcinoma from benign hepatic mimickers using Glypican-3 and CD34 immunohistochemistry. Am J Surg Pathol, 32, 433-44. https://doi.org/10.1097/PAS.0b013e318158142f
  8. Di Tommaso L, Franchi G, Park YN, et al (2007). Diagnostic value of HSP70, Glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis. Hepatology, 45, 725-34. https://doi.org/10.1002/hep.21531
  9. Donato F, Tagger A, Gelatti U, et al (2002). Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am J Epidemiol, 155, 323-31. https://doi.org/10.1093/aje/155.4.323
  10. Evason K, Grenert JP, Ferrell LD, Kakar S (2013). Immunohistochemical classification of hepatic adenomas and atypical hepatocellular neoplasms: correlation with clinicopathologic characteristics and chromosomal abnormalities. Mod Pathol, 44, 750-8.
  11. Hsu HC, Cheng W, Lai PL (1997). Cloning and expression of a developmentally regulated transcript MXR7 in hepatocellular carcinoma: biological significance and temporospatial distribution. Cancer Res, 57, 5179-84.
  12. Ismail S, Mayah W, Battia HE, et al (2015). Plasma nuclear factor kappa b and serum peroxiredoxin 3 in early diagnosis of hepatocellular carcinoma. Asian Pac J Cancer Prev, 16, 1657-66. https://doi.org/10.7314/APJCP.2015.16.4.1657
  13. Kandil DH, Cooper K (2009). Glypican-3: a novel diagnostic marker for hepatocellular carcinoma and more. Adv Anat Pathol, 16, 125-9. https://doi.org/10.1097/PAP.0b013e3181992455
  14. Lagana SM, Moreira RK, Remotti HE, Bao F (2013). Glutamine synthetase, heat shock protein-70, and glypican-3 in intrahepatic cholangiocarcinoma and tumors metastatic to liver. Appl Immunohistochem Mol Morphol, 21, 254-7.
  15. Libbrecht L, Severi T, Cassiman D, et al (2006). Glypican-3 expression distinguishes small hepatocellular carcinomas from cirrhosis, dysplastic nodules, and focal nodular hyperplasia-like nodules. Am J Surg Pathol, 30, 1405-11. https://doi.org/10.1097/01.pas.0000213323.97294.9a
  16. Long J, Wang H, Lang ZW, et al (2011). Expression level of glutamine synthetase is increased in hepatocellular carcinoma and liver tissue with cirrhosis and chronic hepatitis B. Hepatol Int, 5, 698-706. https://doi.org/10.1007/s12072-010-9230-2
  17. Pan Z, Chen C, Long H, et al (2013). Overexpression of gpc3 inhibits hepatocellular carcinoma cell proliferation and invasion through induction of apoptosis. Mol Medicine Reports, 7, 969-974. https://doi.org/10.3892/mmr.2013.1279
  18. Rangaswami H, Bulbule A, Kundu GC (2006). Osteopontin: Role in cell signaling and cancer progression. Trends Cell Biol, 16, 79-87. https://doi.org/10.1016/j.tcb.2005.12.005
  19. Shafizadeh N, Ferrell LD, Kakar S (2008). Utility and limitations of glypican-3 expression for the diagnosis of hepatocellular carcinoma at both ends of the differentiation spectrum. Mod Pathol, 21, 1011-8. https://doi.org/10.1038/modpathol.2008.85
  20. Suzuki M, Sugimoto K, Tanaka J, et al (2010). Up-regulation of glypican-3 in human Hepatocellular carcinoma. Anti Cancer Res, 30, 5055-62.
  21. Tremosini S, Forner A, Boix L, et al (2012). Prospective validation of an immunohistochemical panel (glypican 3, heat shock protein 70 and glutamine synthetase) in liver biopsies for diagnosis of very early hepatocellular carcinoma. Gut, 61, 1481-7. https://doi.org/10.1136/gutjnl-2011-301862
  22. Wang F, Jing X, Wang T, et al (2012). Differential diagnostic value of GPC3-CD34 combined staining in small liver nodules with diameter less than 3 cm. Am J Clin Pathol, 137, 937-45. https://doi.org/10.1309/AJCP0KZZ5DSIGMNY
  23. Weng LL, Xiang JF, Lin JB, et al (2014). Asparagus polysaccharide and gum with hepatic artery embolization induces tumor growth and inhibits angiogenesis in an orthotopic hepatocellular carcinoma model. Asian Pac J Cancer Prev, 15, 10949-55.
  24. Yamauchi N, Watanabe A, Hishinuma M, et al (2005). The glypican 3 oncofetal protein is a promising diagnostic marker for hepatocellular carcinoma. Modern Pathology, 18, 1591-8. https://doi.org/10.1038/modpathol.3800436
  25. Yan B, Wei JJ, Qian YM, et al (2011). Expression and clinicopathologic significance of glypican 3 in hepatocellular carcinoma. An Diagnostic Pathol, 15, 162-9. https://doi.org/10.1016/j.anndiagpath.2010.10.004
  26. Yip YC, Wang FH, Vong HT, Zhang M, Wen JM (2011). Significance of glypican-3 immunohistochemistry in diagnosis of hepatocellular carcinoma. Zhonghua Bing Li Xue Za Zhi, 40, 626-9.
  27. Zaakook M, Ayoub M, Abu Sinna E, El-Sheikh S (2013). Role of glypican-3 immunocytochemistry in differentiating hepatocellular carcinoma from metastatic carcinoma of the liver utilizing fine needle aspiration cytology. J Egyptian Nat Cancer Inst, 25, 173-180. https://doi.org/10.1016/j.jnci.2013.07.004
  28. Zou ZQ, Ding YP, Long B, et al (2010). Gpc-3 is a notable diagnostic, prognostic and a latent targeted therapy marker in hepatocellular carcinoma. Hepatogastroenterology, 57, 102-3, 1285-90.

Cited by

  1. Specificities of Human Hepatocellular Carcinoma Developed on Non-Alcoholic Fatty Liver Disease in Absence of Cirrhosis Revealed by Tissue Extracts 1H-NMR Spectroscopy vol.7, pp.4, 2017, https://doi.org/10.3390/metabo7040049
  2. mTOR Activation in Liver Tumors Is Associated with Metabolic Syndrome and Non-Alcoholic Steatohepatitis in Both Mouse Models and Humans vol.10, pp.12, 2018, https://doi.org/10.3390/cancers10120465