Hepatocellular carcinoma a retrospective clinico-pathologic and immunohistochemical study of 15 cases

Open access


Hepatocellular carcinoma (HCC) is the fifth most frequently diagnosed cancer worldwide, and the third most frequent oncological cause of death. Being detected at an advanced, non-resectable stage, HCC is associated with a low 5-year survival and poor prognosis. Recently some studies have demonstrated that the prognosis of HCC correlates to various molecular markers. In this view, we have studied here the immunohistochemical reactivity of 15 HCC cases diagnosed in the last three years for some biomarkers with prognostic value such as p53, alpha-fetoprotein (AFP) and CXCR4, in correlation with the major clinicopathological parameters of these patients. In our casuistry the most prevalent architectural pattern was the trabecular (53.4%), followed by the pseudoglandular pattern (20%), while the less common diagnosed were the solid and pleomorphic variants. More than 80% of these tumors were well to moderate differentiated; developed in the six decade, twice more common in men and diagnosed in advance stages (80% of cases in stages ≥III). Markers such as CK18, CK7 and CEA were usefully in order to certify the primary liver origin and the hepatocellular differentiation of these tumors. Moreover, biomarkers as p53, AFP and CXCR4 were positive especially in more advance stages suggesting the possibility of their utilization as prognostic factors and in the therapeutically stratification of such patients.

1. Bosch FX, Ribes J, Cléries R, Díaz M. Epidemiology of hepatocellular carcinoma. Clin Liver Dis. 2005;9:191-211.

2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69-90.

3. Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol. 2009;27:1485-91.

4. Bosetti C, Levi F, Boffetta P, Lucchini F, Negri E, La Vecchia C. Trends in mortality from hepatocellular carcinoma in Europe, 1980-2004. Hepatology. 2008;48:137-45.

5. Vălean S, Armean P, Resteman S, Nagy G, Mureşan A, Mircea PA. Cancer mortality in Romania, 1955-2004. Digestive sites: esophagus, stomach, colon and rectum, pancreas, liver, gallbladder and biliary tree. J. Gastrointestin Liver Dis. 2008;17(1):9-14.

6. Blachier M, Leleu H, Peck-Radosavljevic M, Valla DC, Roudot-Thoraval F. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol. 2013;58(3):593-608.

7. Llovet JM, Bruix J. Novel advancements in the management of hepatocellular carcinoma in 2008. J Hepatol. 2008;48 Suppl 1: S20-S37.

8. Behne T, Copur MS. Biomarkers for hepatocellular carcinoma. Int J Hepatol. 2012:859076.

9. Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO classification of tumours of the Digestive System 4th edn. IARC Press, Lyon, 2010:322-6.

10. Remmele W, Stegner HE. Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe. 1987;8:138-40.

11. Guo RP, Zhong C, Shi M, Zhang CQ, Wei W, Zhang YQ, et al. Clinical value of apoptosis and angiogenesis factors in estimating the prognosis of hepatocellular carcinoma. J Cancer Res Clin Oncol. 2006;132(9):547-55.

12. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557-76.

13. Mittal S, El-Serag HB. Epidemiology of Hepatocellular Carcinoma: Consider the Population. J Clin Gastroenterol. 2013. (Epub ahead of print)

14. Yu MW, Chang HC, Chang SC, Liaw YF, Lin SM, Liu CJ, et al. Role of reproductive factors in hepatocellular carcinoma: Impact on hepatitis B- and C-related risk. Hepatology. 2003;38:1393-400.

15. Abbruzzese JL, Abbruzzese MC, Lenzi R, Hess KR, Raber MN. Analysis of a diagnostic strategy for patients with suspected tumors of unknown origin. J Clin Oncol. 1995;8:2094-103.

16. Burt AD, Portmann BC, Ferrell LD. MacSween’s Pathology of the Liver. 5th ed. 2007: 771-87.

17. Lau SK, Prakash S, Geller SA, Alsabeh R. Comparative immunohistochemical profile of hepatocellular carcinoma, cholangiocarcinoma, and metastatic adenocarcinoma.Hum Pathol. 2002;33:1175-81.

18. Johnson DE, Herndier BG, Medeiros LJ, Warnke RA, Rouse RV. The diagnostic utility of the keratin profiles of hepatocellular carcinoma and cholangiocarcinoma. Am J Surg Pathol. 1988;12(3):187-97.

19. Kakar S, Gown AM, Goodman ZD, Ferrell LD. Best practices in diagnostic immunohistochemistry: hepatocellular carcinoma versus metastatic neoplasms. Arch Pathol Lab Med. 2007;131(11):1648-54.

20. Heukamp LC , Fischer HP, Schirmacher P, Chen X, Breuhahn K, Nicolay C, et al. Podocalyxin-like protein 1 expression in primary hepatic tumours and tumour-like lesions. Histopathology. 2006;49(3):242-7.

21. Saad RS, Luckasevic TM, Noga CM, Johnson DR, Silverman JF, Liu YL. Diagnostic value of HepPar1, pCEA, CD10, and CD34 expression in separating hepatocellular carcinoma from metastatic carcinoma in fine-needle aspiration cytology. Diagn Cytopathol. 2004;30(1):1-6.

22. Balaton AJ, Nehama-Sibony M, Gotheil C, Callard P, Baviera EE. Distinction between hepatocellular carcinoma, cholangiocarcinoma, and metastatic carcinoma based on immunohistochemical staining for carcinoembryonic antigen and for cytokeratin 19 on paraffin sections. J Pathol. 1988;156(4):305-10.

23. Bonetti F, Chilosi M, Pisa R, Novelli P, Zamboni G, Menestrina F. Epithelial membrane antigen expression in cholangiocarcinoma. An useful immunohistochemical tool for differential diagnosis with hepatocarcinoma. Virchows Arch A Pathol Anat Histopathol. 1983;401:307-13.

24. Chu PG, Ishizawa S, Wu E, Weiss LM. Hepatocyte antigen as a marker of hepatocellular carcinoma: an immunohistochemical comparison to carcinoembryonic antigen, CD10, and alpha-fetoprotein. Am J Surg Pathol. 2002;26(8):978-88.

25. Imoto M, Nishimura D, Fukuda Y, Sugiyama K, Kumada T, Nakano S. Immunohistochemical detection of afetoprotein, carcinoembryonic antigen, and ferritin in formalin- paraffin sections from hepatocellular carcinoma. Am J Gastroenterol. 1985;80(11):902-6.

26. Wee A. Diagnostic utility of immunohistochemistry in hepatocellular carcinoma, its variants and their mimics. Appl Immunohistochem Mol Morphol. 2006;14(3):266-72.

27. El-Serag HB, Mason AC, Key C. Trends in survival of patients with hepatocellular carcinoma between 1977 and 1996 in the United States. Hepatology. 2001;33(1):62-5.

28. Simard EP, Ward EM, Siegel R, Jemal A. Cancers with increasing incidence trends in the United States: 1999 through 2008. CA Cancer J Clin. 2012;62:118-28.

29. Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology. 2008;48:1312-27.

30. Qin LX, Tang ZY. Recent progress in predictive biomarkers for metastatic recurrence of human hepatocellular carcinoma: a review of the literature J Cancer Res Clin Oncol. 2004;130(9):497-513.

31. Hayashi H, Sugio K, Matsumata T, Adachi E, Takenaka K, Sugimachi K. The clinical signiWcance of p53 gene mutation in hepatocellular carcinoma from Japan. Hepatology. 1995;22(6):1702-7.

32. Naka T, Toyota N, Kaneko T, Kaibara N. Protein expression of p53, p21WAF1, and Rb as prognostic indicators in patients with surgically treated hepatocellular carcinoma. Anticancer Res. 1998;18(1B):555-64.

33. Qin LF, Ng IO. Expression of p27(KIP1) and p21(WAF1/CIP1) in primary hepatocellular carcinoma: clinicopathologic correlation and survival analysis. Hum Pathol. 2001;32(8):778-84.

34. Schöniger-Hekele M, Hänel S, Wrba F, Müller C. Hepatocellular carcinoma--survival and clinical characteristics in relation to various histologic molecular markers in Western patients. Liv Liver Int. 2005;25(1):62-9.

35. Sung CO, Yoo BC, Koh KC, Cho JW, Park CK. Prognostic significance of p53 overexpression after hepatic resection of hepatocellular carcinoma. Korean J Gastroenterol. 2005;45(6):425-30.

36. Terris B, Laurent-Puig P, Belghitti J, Degott C, Hénin D, Fléjou JF. Prognostic influence of clinicopathologic features, DNAploidy, CD44H and p53 expression in a large series of resected hepatocellular carcinoma in France. Int J Cancer. 1997;74(6):614-9.

37. Tseng PL, Tai MH, Huang CC, Wang CC, Lin JW, Hung CH, et al. Overexpression of VEGF is associated with positive p53 immunostaining in hepatocellular carcinoma (HCC) and adverse outcome of HCC patients. J Surg Oncol. 2008 Oct 1;98(5):349-57.

38. Kao WY, Su CW, Chau GY, Lui WY, Wu CW, Wu JC. A comparison of prognosis between patients with hepatitis B and C virus- related hepatocellular carcinoma undergoing resection surgery. World J Surg. 2011;35(4):858-67.

39. Zhou J, Yan T, Bi X, Zhao H, Huang Z, Zhang Y, et al. Evaluation of seven different staging systems for alphafetoprotein expression in hepatocellular carcinoma after hepatectomy. Tumour Biol. 2013;34(2):1061-70.

40. Changchien CS, Chen CL, Yen YH, Wang JH, Hu TH, Lee CM, et al. Analysis of 6381 hepatocellular carcinoma patients in southern Taiwan: prognostic features, treatment outcome, and survival. J Gastroenterol. 2008;43(2):159-70.

41. Japan LCSGi. Survey and follow-up study of primary liver cancer in Japan - report 11. Kanzo. 1995;36:208-18.

42. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology. 1998;28(3):751-5.

43. Hu KQ, Kyulo NL, Lim N, Elhazin B, Hillebrand DJ, Bock T. Clinical significance of elevated alpha-fetoprotein (AFP) in patients with chronic hepatitis C, but not hepatocellular carcinoma. Am J Gastroenterol. 2004;99(5):860-5.

44. Yen YH, Changchien CS, Wang JH, Kee KM, Hung CH, Hu TH, et al. A modified TNM-based Japan Integrated Score combined with AFP level may serve as a better staging system for early-stage predominant hepatocellular carcinoma patients. Dig Liver Dis. 2009;41(6):431-41.

45. Ueland J, Yuan A, Marlier A, Gallagher AR, Karihaloo A. A novel role for the chemokine receptor cxcr4 in kidney morphogenesis: an in vitro study. Dev Dyn. 2009;238(5):1083-91.

46. Xiang ZL, Zeng ZC, Tang ZY, Fan J, Zhuang PY, Liang Y, et al. Chemokine receptor CXCR4 expression in hepatocellular carcinoma patients increases the risk of bone metastases and poor survival. BMC Cancer. 2009;9:176.

47. Li N, Guo W, Shi J, Xue J, Hu H, Xie D, et al. Expression of the chemokine receptor CXCR4 in human hepatocellular carcinoma and its role in portal vein tumor thrombus. J Exp Clin Cancer Res. 2010;29:156.

Revista Romana de Medicina de Laborator

Romanian Journal of Laboratory Medicine

Journal Information

IMPACT FACTOR 2018: 0,800
5-year IMPACT FACTOR: 0,655

CiteScore 2017: 0.31

SCImago Journal Rank (SJR) 2018: 0.194
Source Normalized Impact per Paper (SNIP) 2018: 0.306


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 216 159 7
PDF Downloads 81 67 7