Tumor Biology

, Volume 36, Issue 8, pp 6255–6263 | Cite as

Vascular invasion in hepatitis B virus-related hepatocellular carcinoma with underlying cirrhosis: possible associations with ascites and hepatitis B viral factors?

  • Chuan Chen
  • Dong-Ping Chen
  • Yan-Yan Gu
  • Liang-Hao Hu
  • Dan Wang
  • Jin-Huan Lin
  • Zhao-Shen Li
  • Jing Xu
  • Ge Wang
Research Article

Abstract

Vascular invasion is one of the most important prognostic factors for patients with hepatocellular carcinoma (HCC). The objective of the current, retrospective study was to determine the associations of ascites and hepatitis B viral factors (HBeAg and anti-HBe status and HBV DNA levels), as well as tumor-related factors (size, tumor number, grade, and location) with micro- or macroscopic vascular invasion in patients with HCC that developed as a result of hepatitis B virus (HBV)-related cirrhosis. A total of 336 consecutive patients were included. Potential factors associated with micro- or macroscopic vascular invasion were analyzed by logistic regression. Ascites were more commonly detected in patients with micro- or macroscopic vascular invasion, and the presence of ascites was independently associated with vascular invasion. Among patients with mild-to-moderate or severe ascites, the odds ratio for macroscopic vascular invasion was 4.83 (95 % confidence interval [CI] 2.29–10.16) and 11.87 (95 % CI 4.53–31.07), respectively. Similarly, the presence of ascites was associated with microscopic vascular invasion (OR 5.00; 95 % CI 1.23–20.31). In contrast, hepatitis B viral factors were not significantly associated with vascular invasion. The presence of ascites was associated with vascular invasion in patients with HBV-related cirrhotic HCC. Thus, patients with ascites, vascular invasion should be considered and more frequent surveillance should be performed after curative treatment.

Keywords

Ascites Hepatitis B virus Liver cirrhosis Hepatocellular carcinoma Neoplasm invasiveness 

Abbreviations

AFP

α-Fetoprotein

Anti-HBe

Antibody to hepatitis B e antigen

CI

Confidence interval

HBeAg

Hepatitis B e antigen

HBV

Hepatitis B virus

HCC

Hepatocellular carcinoma

References

  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90. doi: 10.3322/caac.20107.CrossRefPubMedGoogle Scholar
  2. 2.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29. doi: 10.3322/caac.21208.CrossRefPubMedGoogle Scholar
  3. 3.
    El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76. doi: 10.1053/j.gastro.2007.04.061.CrossRefPubMedGoogle Scholar
  4. 4.
    Guan YS, Ahmad Al-Shatouri M, He Q, Liu WM. Hepatocellular carcinoma: carcinogenesis, establishment, progression, and therapies. Biomed Res Int. 2014;2014:706142. doi: 10.1155/2014/706142.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127:S35–50.CrossRefPubMedGoogle Scholar
  6. 6.
    Anzola M. Hepatocellular carcinoma: role of hepatitis B and hepatitis C viruses proteins in hepatocarcinogenesis. J Viral Hepat. 2004;11:383–93. doi: 10.1111/j.1365-2893.2004.00521.x.CrossRefPubMedGoogle Scholar
  7. 7.
    Ishikawa T, Ichida T, Yamagiwa S, Sugahara S, Uehara K, Okoshi S, et al. High viral loads, serum alanine aminotransferase and gender are predictive factors for the development of hepatocellular carcinoma from viral compensated liver cirrhosis. J Gastroenterol Hepatol. 2001;16:1274–81.CrossRefPubMedGoogle Scholar
  8. 8.
    Wei L. Natural history of chronic hepatitis B virus infection: what determines prognosis after cirrhotic decompensation? J Gastroenterol Hepatol. 2008;23:1631–2. doi: 10.1111/j.1440-1746.2008.05576.x.CrossRefPubMedGoogle Scholar
  9. 9.
    Fattovich G. Natural history and prognosis of hepatitis B. Semin Liver Dis. 2003;23:47–58. doi: 10.1055/s-2003-37590.CrossRefPubMedGoogle Scholar
  10. 10.
    Jonas S, Bechstein WO, Steinmuller T, Herrmann M, Radke C, Berg T, et al. Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology. 2001;33:1080–6. doi: 10.1053/jhep.2001.23561.CrossRefPubMedGoogle Scholar
  11. 11.
    Senkerikova R, Frankova S, Sperl J, Oliverius M, Kieslichova E, Filipova H, et al. Incidental hepatocellular carcinoma: risk factors and long-term outcome after liver transplantation. Transplant Proc. 2014;46:1426–9. doi: 10.1016/j.transproceed.2014.03.010.CrossRefPubMedGoogle Scholar
  12. 12.
    Hsieh CH, Wei CK, Yin WY, Chang CM, Tsai SJ, Wang LY, et al. Vascular invasion affects survival in early hepatocellular carcinoma. Mol Clin Oncol. 2015;3:252–6. doi: 10.3892/mco.2014.420.PubMedGoogle Scholar
  13. 13.
    Sumie S, Nakashima O, Okuda K, Kuromatsu R, Kawaguchi A, Nakano M, et al. The significance of classifying microvascular invasion in patients with hepatocellular carcinoma. Ann Surg Oncol. 2014;21:1002–9. doi: 10.1245/s10434-013-3376-9.CrossRefPubMedGoogle Scholar
  14. 14.
    Figueras J, Ibanez L, Ramos E, Jaurrieta E, Ortiz-de-Urbina J, Pardo F, et al. Selection criteria for liver transplantation in early-stage hepatocellular carcinoma with cirrhosis: results of a multicenter study. Liver Transpl. 2001;7:877–83. doi: 10.1053/jlts.2001.27856.CrossRefPubMedGoogle Scholar
  15. 15.
    Pawlik TM, Delman KA, Vauthey JN, Nagorney DM, Ng IO, Ikai I, et al. Tumor size predicts vascular invasion and histologic grade: implications for selection of surgical treatment for hepatocellular carcinoma. Liver Transpl. 2005;11:1086–92. doi: 10.1002/lt.20472.CrossRefPubMedGoogle Scholar
  16. 16.
    Shirabe K, Toshima T, Kimura K, Yamashita Y, Ikeda T, Ikegami T, et al. New scoring system for prediction of microvascular invasion in patients with hepatocellular carcinoma. Liver Int. 2014;34:937–41. doi: 10.1111/liv.12459.CrossRefPubMedGoogle Scholar
  17. 17.
    Suh SW, Lee KW, Lee JM, You T, Choi Y, Kim H, et al. Prediction of aggressiveness in early-stage hepatocellular carcinoma for selection of surgical resection. J Hepatol. 2014;60:1219–24. doi: 10.1016/j.jhep.2014.01.027.CrossRefPubMedGoogle Scholar
  18. 18.
    Kim BK, Han KH, Park YN, Park MS, Kim KS, Choi JS, et al. Prediction of microvascular invasion before curative resection of hepatocellular carcinoma. J Surg Oncol. 2008;97:246–52. doi: 10.1002/jso.20953.CrossRefPubMedGoogle Scholar
  19. 19.
    Esnaola NF, Lauwers GY, Mirza NQ, Nagorney DM, Doherty D, Ikai I, et al. Predictors of microvascular invasion in patients with hepatocellular carcinoma who are candidates for orthotopic liver transplantation. J Gastrointest Surg. 2002;6:224–32. discussion 232.CrossRefPubMedGoogle Scholar
  20. 20.
    Hsu C-Y, Lee Y-H, Huang Y-H, Hsia C-Y, Su C-W, Lin H-C, et al. Ascites in patients with hepatocellular carcinoma: prevalence, associated factors, prognostic impact, and staging strategy. Hepatol Int. 2013;7:188–98. doi: 10.1007/s12072-011-9338-z.CrossRefPubMedGoogle Scholar
  21. 21.
    Chen LP, Li C, Wang C, Wen TF, Yan LN, Li B. Risk factors of ascites after hepatectomy for patients with hepatocellular carcinoma and hepatitis B virus-associated cirrhosis. Hepatogastroenterology. 2012;59:292–5. doi: 10.5754/hge11399.CrossRefPubMedGoogle Scholar
  22. 22.
    Lee SS, Shin HS, Kim HJ, Lee SJ, Lee HS, Hyun KH, et al. Analysis of prognostic factors and 5-year survival rate in patients with hepatocellular carcinoma: a single-center experience. Korean J Hepatol. 2012;18:48–55. doi: 10.3350/kjhep.2012.18.1.48.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Lencioni R, Bartolozzi C, Caramella D, Paolicchi A, Carrai M, Maltinti G, et al. Treatment of small hepatocellular carcinoma with percutaneous ethanol injection. Analysis of prognostic factors in 105 Western patients. Cancer. 1995;76:1737–46.CrossRefPubMedGoogle Scholar
  24. 24.
    Savastano S, Miotto D, Casarrubea G, Teso S, Chiesura-Corona M, Feltrin GP. Transcatheter arterial chemoembolization for hepatocellular carcinoma in patients with Child’s grade A or B cirrhosis: a multivariate analysis of prognostic factors. J Clin Gastroenterol. 1999;28:334–40.CrossRefPubMedGoogle Scholar
  25. 25.
    Dvorchik I, Carr BI. A simple prognostic scoring system for patients with unresectable hepatocellular carcinoma treated by chemo-embolization. Cancer Detect Prev. 2007;31:154–60. doi: 10.1016/j.cdp.2007.02.003.CrossRefPubMedGoogle Scholar
  26. 26.
    Ikai I, Hatano E, Hasegawa S, Fujii H, Taura K, Uyama N, et al. Prognostic index for patients with hepatocellular carcinoma combined with tumor thrombosis in the major portal vein. J Am Coll Surg. 2006;202:431–8. doi: 10.1016/j.jamcollsurg.2005.11.012.CrossRefPubMedGoogle Scholar
  27. 27.
    Sun HC, Zhang W, Qin LX, Zhang BH, Ye QH, Wang L, et al. Positive serum hepatitis B e antigen is associated with higher risk of early recurrence and poorer survival in patients after curative resection of hepatitis B-related hepatocellular carcinoma. J Hepatol. 2007;47:684–90. doi: 10.1016/j.jhep.2007.06.019.CrossRefPubMedGoogle Scholar
  28. 28.
    Kim WR, Gores GJ. Recurrent hepatocellular carcinoma: it’s the virus. J Clin Oncol. 2013;31:3621–2. doi: 10.1200/JCO.2013.51.8381.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Jang JW, Choi JY, Bae SH, Yoon SK, Woo HY, Chang UI, et al. The impact of hepatitis B viral load on recurrence after complete necrosis in patients with hepatocellular carcinoma who receive transarterial chemolipiodolization: implications for viral suppression to reduce the risk of cancer recurrence. Cancer. 2007;110:1760–7. doi: 10.1002/cncr.22984.CrossRefPubMedGoogle Scholar
  30. 30.
    Urata Y, Kubo S, Takemura S, Uenishi T, Kodai S, Shinkawa H, et al. Effects of antiviral therapy on long-term outcome after liver resection for hepatitis B virus-related hepatocellular carcinoma. J Hepatobiliary Pancreat Sci. 2012;19:685–96. doi: 10.1007/s00534-011-0489-z.CrossRefPubMedGoogle Scholar
  31. 31.
    DiMaio CJ, Krishnan S, Roayaie S. EUS-guided ethanol ablation for management of metastatic hepatocellular carcinoma. J Interv Gastroenterol. 2014;4(1):13–14. doi: 10.7178/jig.138.
  32. 32.
    Chong CC, Wong GL, Lai PB. Impact of antiviral therapy on post-hepatectomy outcome for hepatitis B-related hepatocellular carcinoma. World J Gastroenterol. 2014;20:6006–12. doi: 10.3748/wjg.v20.i20.6006.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Verslype C, Rosmorduc O, Rougier P, Group EGW. Hepatocellular carcinoma: ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23 Suppl 7:vii41–8. doi: 10.1093/annonc/mds225.CrossRefPubMedGoogle Scholar
  34. 34.
    Shyamala K, Girish HC, Murgod S. Risk of tumor cell seeding through biopsy and aspiration cytology. J Int Soc Prev Community Dent. 2014;4:5–11. doi: 10.4103/2231-0762.129446.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Supriya M, Denholm S, Palmer T. Seeding of tumor cells after fine needle aspiration cytology in benign parotid tumor: a case report and literature review. Laryngoscope. 2008;118:263–5. doi: 10.1097/MLG.0b013e318158f718.CrossRefPubMedGoogle Scholar
  36. 36.
    Huang C, Sheng Y, Jia J, Chen L. Identification of melanoma biomarkers based on network modules by integrating the human signaling network with microarrays. J Cancer Res Ther. 2014;10 Suppl:C114–124. doi: 10.4103/0973-1482.145816.
  37. 37.
    Pawlik TM, Gleisner AL, Anders RA, Assumpcao L, Maley W, Choti MA. Preoperative assessment of hepatocellular carcinoma tumor grade using needle biopsy: implications for transplant eligibility. Ann Surg. 2007;245:435–42. doi: 10.1097/01.sla.0000250420.73854.ad.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Stigliano R, Burroughs AK. Should we biopsy each liver mass suspicious for HCC before liver transplantation?–no, please don’t. J Hepatol. 2005;43:563–8. doi: 10.1016/j.jhep.2005.07.015.CrossRefPubMedGoogle Scholar
  39. 39.
    Malek NP, Schmidt S, Huber P, Manns MP, Greten TF. The diagnosis and treatment of hepatocellular carcinoma. Dtsch Arztebl Int. 2014;111:101–6. doi: 10.3238/arztebl.2014.0101.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Fitzmorris P, Shoreibah M, Anand BS, Singal AK. Management of hepatocellular carcinoma. J Cancer Res Clin Oncol. 2014. doi: 10.1007/s00432-014-1806-0.PubMedGoogle Scholar
  41. 41.
    Sotiropoulos GC, Tagkalos E, Fouzas I, Vernadakis S, Mathe Z, Treckmann J, et al. Liver transplantation for hepatocellular carcinoma using extended criteria donor grafts. Transplant Proc. 2012;44:2730–3. doi: 10.1016/j.transproceed.2012.09.021.CrossRefPubMedGoogle Scholar
  42. 42.
    Yao FY, Ferrell L, Bass NM, Bacchetti P, Ascher NL, Roberts JP. Liver transplantation for hepatocellular carcinoma: comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TNM criteria. Liver Transpl. 2002;8:765–74. doi: 10.1053/jlts.2002.34892.CrossRefPubMedGoogle Scholar
  43. 43.
    You Z, Chen LP, Ye H. Predictors of microvascular invasion in patients with solitary small hepatitis B related hepatocellular carcinoma. Pak J Med Sci. 2014;30:331–4.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Lim KC, Chow PK, Allen JC, Chia GS, Lim M, Cheow PC, et al. Microvascular invasion is a better predictor of tumor recurrence and overall survival following surgical resection for hepatocellular carcinoma compared to the Milan criteria. Ann Surg. 2011;254:108–13. doi: 10.1097/SLA.0b013e31821ad884.CrossRefPubMedGoogle Scholar
  45. 45.
    Thuluvath PJ. Vascular invasion is the most important predictor of survival in HCC, but how do we find it? J Clin Gastroenterol. 2009;43:101–2. doi: 10.1097/MCG.0b013e318191e64f.CrossRefPubMedGoogle Scholar
  46. 46.
    McHugh PP, Gilbert J, Vera S, Koch A, Ranjan D, Gedaly R. Alpha-fetoprotein and tumour size are associated with microvascular invasion in explanted livers of patients undergoing transplantation with hepatocellular carcinoma. HPB (Oxford). 2010;12:56–61. doi: 10.1111/j.1477-2574.2009.00128.x.CrossRefGoogle Scholar
  47. 47.
    Kuiper JJ, de Man RA, van Buuren HR. Review article: management of ascites and associated complications in patients with cirrhosis. Aliment Pharmacol Ther. 2007;26 Suppl 2:183–93. doi: 10.1111/j.1365-2036.2007.03482.x.CrossRefPubMedGoogle Scholar
  48. 48.
    Nguyen VX, Nguyen CC, De Petris G, Sharma VK, Das A. Confocal endomicroscopy (CEM) improves efficiency of Barrett surveillance. J Interv Gastroenterol. 2012;2(2):61-65. doi: 10.4161/jig.22175.
  49. 49.
    Lee YH, Hsu CY, Huang YH, Hsia CY, Chiou YY, Su CW, et al. Vascular invasion in hepatocellular carcinoma: prevalence, determinants and prognostic impact. J Clin Gastroenterol. 2014;48:734–41. doi: 10.1097/MCG.0b013e3182a8a254.CrossRefPubMedGoogle Scholar
  50. 50.
    Xu J, Shi J, Wang YP, Lin Y, Chen YX, Lu J, et al. Milder liver cirrhosis and loss of serum HBeAg do not imply lower risk for hepatocellular carcinoma development in HBV-related cirrhosis. Med Sci Monit. 2009;15:Cr274–9.PubMedGoogle Scholar
  51. 51.
    Kim HY, Park JW, Joo J, Kim H, Woo SM, Lee WJ, et al. Worse outcome of sorafenib therapy associated with ascites and Child-Pugh score in advanced hepatocellular carcinoma. J Gastroenterol Hepatol. 2013;28:1756–61. doi: 10.1111/jgh.12310.CrossRefPubMedGoogle Scholar
  52. 52.
    Chan KM, Lee CF, Wu TJ, Chou HS, Yu MC, Lee WC, et al. Adverse outcomes in patients with postoperative ascites after liver resection for hepatocellular carcinoma. World J Surg. 2012;36:392–400. doi: 10.1007/s00268-011-1367-1.CrossRefPubMedGoogle Scholar
  53. 53.
    Hsu SJ, Huang HC. Management of ascites in patients with liver cirrhosis: recent evidence and controversies. J Chin Med Assoc. 2013;76:123–30. doi: 10.1016/j.jcma.2012.11.005.CrossRefPubMedGoogle Scholar
  54. 54.
    Gines P, Cardenas A. The management of ascites and hyponatremia in cirrhosis. Semin Liver Dis. 2008;28:43–58. doi: 10.1055/s-2008-1040320.CrossRefPubMedGoogle Scholar
  55. 55.
    Wang L, Liu X, Wang H, Wang S. Correlation of the expression of vascular endothelial growth factor and its receptors with microvessel density in ovarian cancer. Oncol Lett. 2013;6:175–80. doi: 10.3892/ol.2013.1349.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Yabushita H, Shimazu M, Noguchi M, Kishida T, Narumiya H, Sawaguchi K, et al. Vascular endothelial growth factor activating matrix metalloproteinase in ascitic fluid during peritoneal dissemination of ovarian cancer. Oncol Rep. 2003;10:89–95.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Chuan Chen
    • 1
  • Dong-Ping Chen
    • 2
  • Yan-Yan Gu
    • 3
  • Liang-Hao Hu
    • 4
  • Dan Wang
    • 4
  • Jin-Huan Lin
    • 4
  • Zhao-Shen Li
    • 4
  • Jing Xu
    • 2
  • Ge Wang
    • 1
  1. 1.Cancer Center, Research Institute of Surgery, Daping HospitalThird Military Medical UniversityChongqingChina
  2. 2.Department of Nephrology, Changzheng HospitalSecond Military Medical UniversityShanghaiChina
  3. 3.Department of Nutrition, Changzheng HospitalSecond Military Medical UniversityShanghaiChina
  4. 4.Department of Gastroenterology, Changhai HospitalSecond Military Medical UniversityShanghaiChina

Personalised recommendations