Skip to main content
SpringerLink
Log in

Relationships Between Indices of Tumor Aggressiveness in Hepatocellular Carcinoma

  • Invited Paper
  • Published:
Journal of Gastrointestinal Cancer Aims and scope Submit manuscript

Abstract

Background

Hepatocellular carcinoma (HCC) aggressiveness factors include serum levels of alpha-fetoprotein (AFP), maximum tumor diameter (MTD), tumor multifocality, and presence of portal vein thrombosis (PVT).

Aims

The interdependence of these factors has not been closely studied.

Methods

A large HCC database was examined for the presence of patients with PVT and multifocality and was analyzed retrospectively for the relationship of these 2 parameters to each other and to MTD and survival.

Results

Multifocality was found to increase with increase in MTD in the whole cohort and especially in patients with PVT. PVT also increased with increasing MTD. Neither increases in multifocality nor in PVT depended on elevated serum AFP levels, although they each increased with higher AFP levels. PVT increased in monofocal tumors as MTD increased but increased further in multifocal tumors.

Conclusions

Multifocality and PVT appear to be separate processes, each increasing with increase in MTD and AFP levels. The data support the hypothesis that in hepatocarcinogenesis, various factors cause increase in MTD, that in turn causes increased multifocality and PVT, which are non-co-dependent. However, both multifocality and PVT mechanisms involve both HCC cell growth and invasiveness, multifocality in liver parenchyma, and PVT in the portal vein.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

PVT:

Macroscopic portal vein thrombosis

MTD:

Maximum tumor diameter

RRR:

Relative risk ratio

RRR(se):

Standard error of RRR

Rf.:

Reference category

KM:

Kaplan–Meier

HR:

Hazard ratio

References

  1. Sherman CB, Behr S, Dodge JL, Roberts JP, Yao FY, Mehta N. Distinguishing tumor from bland portal vein thrombus in liver transplant candidates with hepatocellular carcinoma: the A-VENA criteria. Liver Transpl. 2019;25(2):207–16.

    Article  Google Scholar 

  2. Taylor CR. Computed tomography in the evaluation of the portal venous system. J Clin Gastroenterol. 1992;14:167–72.

    Article  CAS  Google Scholar 

  3. Rossi S, Ghittoni G, Ravetta V, et al. Contrast-enhanced ultrasonography and spiral computed tomography in the detection and characterization of portal vein thrombosis complicating hepatocellular carcinoma. Eur Radiol. 2008;18:1749–56.

    Article  Google Scholar 

  4. Tublin ME, Dodd GD 3rd. Baron RL Benign and malignant portal vein thrombosis: differentiation by CT characteristics. AJR Am J Roentgenol. 1997;168:719–23.

    Article  CAS  Google Scholar 

  5. Carr BI, Guerra V, Giannini EG, et al. A liver index and its relationship to indices of HCC aggressiveness. J Intergr Oncol. 2016;5:178. https://doi.org/10.4172/2329-6771.1000169. (PMID: 28580457).

    Article  Google Scholar 

  6. Carr BI, Guerra V, Donghia R et al. Changes in hepatocellular carcinoma aggressiveness characteristics with an increase in tumor diameter. Internat J Biol Markers 2021; Feb. https://doi.org/10.1177/1724600821996372

  7. Akkiz H, Carr BI, Kuran S, et al. Macroscopic portal vein thrombosis in HCC patients. Canad J Gastroenterol Hepatol. 2018;13:3120185. https://doi.org/10.1155/2018/3120185.

    Article  Google Scholar 

  8. Carr BI, Guerra V, Donghia R, Yilmaz SJ. Trends in tumor indices in relation to increased hepatocellular carcinoma size: evidence for tumor evolution as a function of growth. Gastrointest Cancer. 2020;51(4):1215–9. https://doi.org/10.1007/s12029-020-00530-9. (Epub 2020 Oct 2).

    Article  CAS  Google Scholar 

  9. Ventura Y, Carr BI, Kori I, Guerra V, Shibolet O. Analysis of aggressiveness factors in hepatocellular carcinoma patients undergoing transarterial chemoembolization. World J Gastroenterol. 2018;24:1641–9.

    Article  Google Scholar 

  10. Pancoska P, Carr BI. Macro- and micro-environmental factors in clinical hepatocellular cancer. Semin Oncol. 2014;41:185–94.

    Article  CAS  Google Scholar 

  11. Carr BI, Guerra V, Giannini EG et al. Italian Liver Cancer Group. Significance of platelet and AFP levels and liver function parameters for HCC size and survival. Int J Biol Markers. 2014 Sep 30;29(3):e215–23. https://doi.org/10.5301/jbm.5000064 (PMID: 24526315).

  12. Carr BI, Lin CY. Lu SN Platelet-related phenotypic patterns in hepatocellular carcinoma patients. Semin Oncol. 2014;41(3):415–21. https://doi.org/10.1053/j.seminoncol.2014.04.001. (Epub 2014 Apr 23 PMID: 25023358).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Akkiz H, Carr BI, Yalçın KK, et al. Characteristics of hepatocellular carcinoma aggressiveness factors in turkish patients. Oncology. 2018;94(2):116–24.

    Article  CAS  Google Scholar 

  14. Carr BI, Guerra V, Giannini EG, et al. A liver index and its relationship to indices of HCC aggressiveness. J Integr Oncol. 2016;5:178. https://doi.org/10.4172/2329-6771.1000178. (Epub 2016 Sep 5 PMID: 28580457).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Carr BI, Guerra V. A hepatocellular carcinoma aggressiveness index and its relationship to liver enzyme levels. Oncology. 2016;90:215–20.

    Article  CAS  Google Scholar 

  16. Carr BI, Guerra V, Giannini EG, Farinati F. An HCC Aggressiveness Index and blood GTP, bilirubin and platelet levels. Integrative Oncology. 2016;5:172. https://doi.org/10.4172/2329-6771.1000172.

    Article  Google Scholar 

  17. Okuda K, Ohtsuki T, Obata H, et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Cancer. 1985;56:918–28.

    Article  CAS  Google Scholar 

  18. Zhao JJ, Yan T, Zhao H, Zhou JG, et al. Evaluation of eight different clinical staging systems associated with overall survival of chinese patients with hepatocellular carcinoma. Chin Med J (Engl). 2015;128:316–21.

    Article  Google Scholar 

  19. Memon K, Kulik LM, Lewandowski RJ, Wang E, et al. Comparative study of staging systems for hepatocellular carcinoma in 428 patients treated with radioembolization. J Vasc Interv Radiol. 2014;25:1056–66.

    Article  Google Scholar 

  20. Carr BI, Irish W, Federle MP. Chemoembolization for unresectable hepatocellular carcinoma in patients with or without portal vein thrombosis. Hepatogastroenterology. 2010;57:1375–81.

    PubMed  Google Scholar 

  21. Kishi N, Kanayama N, Hirata T, et al. Preoperative stereotactic body radiotherapy to portal vein tumour thrombus in hepatocellular carcinoma: clinical and pathological analysis. Sci Rep. 2020;10:4105. https://doi.org/10.1038/s41598-020-60871-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Abouchaleh N, Gabr A, Ali R, et al. 90 Y Radioembolization for locally advanced hepatocellular carcinoma with portal vein thrombosis: long-term outcomes in a 185-patient cohort. J Nucl Med. 2018;59:1042–8.

    Article  CAS  Google Scholar 

  23. Federico P, Petrillo A, Giordano P, et al. Immune checkpoint inhibitors in hepatocellular carcinoma: current status and novel perspectives. Cancers (Basel). 2020;12(10):3025. https://doi.org/10.3390/cancers12103025 (PMID: 33080958).

    Article  CAS  Google Scholar 

  24. Kalasekar SM, Garrido-Laguna I, Evason KJ. Immune checkpoint inhibitors in novel combinations for hepatocellular carcinoma hepatology. 2021 Jan 12. doi: https://doi.org/10.1002/hep.31706. Online ahead of print. (PMID: 33434363)

  25. Pinter M, Jain RK, Duda DG. The current landscape of immune checkpoint blockade in hepatocellular carcinoma: a review. JAMA Oncol. 2021 Jan 1;7(1):113–123. doi: https://doi.org/10.1001/jamaoncol.2020.3381. (PMID: 33090190).

  26. Wong JSL, Kwok GGW, Tang V et al. Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors. Immunother Cancer. 2021 Feb;9(2):e001945. https://doi.org/10.1136/jitc-2020-001945.

  27. Casak SJ, Donoghue M, Fashoyin-Aje L, et al. FDA approval summary: atezolizumab plus bevacizumab for the treatment of patients with advanced unresectable or metastatic hepatocellular carcinoma. Clin Cancer Res. 2020 Nov 2. https://doi.org/10.1158/1078-0432.CCR-20-3407. Online ahead of print. (PMID: 33139264).

  28. Refolo MG, Messa C, Guerra V, Carr BI, D'Alessandro R. Inflammatory mechanisms of HCC development  Cancers (Basel). 2020;12:3–641. https://doi.org/10.3390/cancers12030641. (PMID: 32164265)

  29. Leslie M. Cell biology. Beyond clotting: the powers of platelets. Science. 2010;328:562–564. https://doi.org/10.1126/science.328.5978.562.

  30. Chen W, Jiang J, Wang PP, et al. Identifying hepatocellular carcinoma driver genes by integrative pathway crosstalk and protein interaction network. DNA Cell Biol. 2019;38:1112–1124.

  31. Zucman-Rossi J, Villanueva A, Nault JC, Llovet JM. The genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology. 2015;149:1226–39.

    Article  CAS  Google Scholar 

  32. Guo L, Kuroda N, Toi M, et al. Increased expression of platelet-derived endothelial cell growth factor in human hepatocellular carcinomas correlated with high Edmondson grades and portal vein tumor thrombosis. Oncol Rep. 2001;8:871–6.

    CAS  PubMed  Google Scholar 

  33. Koike Y, Shiratori Y, Sato S, et al. Des-gamma-carboxy prothrombin as a useful predisposing factor for the development of portal venous invasion in patients with hepatocellular carcinoma: a prospective analysis of 227 patients. Cancer. 2001;91:561–9.

    Article  CAS  Google Scholar 

  34. Gotoh M, Nakatani T, Masuda T, et al. Prediction of invasive activities in hepatocellular carcinomas with special reference to alpha-fetoprotein and des-gamma-carboxyprothrombin. Jpn J Cl Oncol. 2003;33:522–6.

    Article  Google Scholar 

  35. Yamazaki S, Takayama T, Kurokawa T, et al. Next-generation des-r-carboxyprothrombin for immunohistochemical assessment of vascular invasion by hepatocellular carcinoma BMC Surg 2020;20:1–201. https://doi.org/10.1186/s12893-020-008620. (PMID:32928172 PMCID:PMC: 7491115).

  36. Huang X, Fan X, Zhang R, Jiang S, Yang K, Chen S. Systemic inflammation and portal vein thrombosis in cirrhotic patients with gastroesophageal varices. Eur J Gastroenterol Hepatol. 2020;32:401–5.

    Article  CAS  Google Scholar 

  37. Kim JM, Kwon CH, Joh JW, et al. World J Surg Oncol. 2013;23(11):92. https://doi.org/10.1186/1477-7819-11-92. (PMID: 23618082).

    Article  Google Scholar 

  38. Carr BI, Akkiz H, Guerra V, et al. Erythrocyte sedimentation rate and C-reactive protein are markers for tumor aggressiveness and survival in patients with hepatocellular carcinoma. J Clinical Trials. 2020;10:1000428.

    Google Scholar 

  39. Carr BI, Guerra V, Donghia R. portal vein thrombosis and markers of inflammation in hepatocellular carcinoma. J Gastrointest Cancer. 2020;51:1141–7.

    Article  CAS  Google Scholar 

  40. Xu X, Wei X, Ling Q, et al. Identification of two portal vein tumor thrombosis associated proteins in hepatocellular carcinoma: protein disulfide-isomerase A6 and apolipoprotein A-I. J Gastroenterol Hepatol. 2011;26:1787–94.

    Article  CAS  Google Scholar 

  41. Zhou L, Jin Y, Cui QC, Jin KM, Zhou WX, Xing BC. Low expression of PAI-2 as a novel marker of portal vein tumor thrombosis and poor prognosis inhepatocellular carcinoma. World J Surg. 2013;37:608–13.

    Article  Google Scholar 

  42. Nishida N, Arizumi T, Takita M, et al. Quantification of tumor DNA in serum and vascular invasion of human hepatocellular carcinoma. Oncology. 2013;84(Suppl 1):82–7. https://doi.org/10.1159/000345895.

    Article  CAS  PubMed  Google Scholar 

  43. Carr BI, Guerra V, Donghia R et al. Changes in hepatocellular carcinoma aggressiveness characteristics with an increase in tumor diameter. Int J Biol Markers. 2021 Feb 27:1724600821996372. https://doi.org/10.1177/1724600821996372. (Epub ahead of print. PMID: 33641486).

  44. Liao W, Liu W, Liu X et al. Upregulation of FAM83D affects the proliferation and invasion of hepatocellular carcinoma. Oncotarget. 2015;6:24132–47. https://doi.org/10.18632/oncotarget.4432. (PMID: 26125229 PMCID: PMC4695175).

  45. Huang T, Guo YZ, Yue X et al. Cripto-1 promotes tumor invasion and predicts poor outcomes in hepatocellular carcinoma. Carcinogenesis. 2020;4:571–581.

  46. Akiba J, Ogasawara S, Kawahara A, et al. N-myc downstream regulated gene 1 (NDRG1)/Cap43 enhances portal vein invasion and intrahepatic metastasis in human hepatocellular carcinoma. Oncol Rep. 2008;20:1329–35.

    PubMed  Google Scholar 

Download references

Funding

This work was supported in part by NIH grant CA 82723 (B.I.C).

Author information

Authors and Affiliations

  1. Liver Transplant Institute, İnönü University, Bulgurlu Mah, Elazig Yolu 15 km, 44289 Merkez Battalgazi, Malatya, Turkey

    Brian I. Carr & Seai Yilmaz

  2. National Institute of Gastroenterology, S. de Bellis Research Hospital, Bari, Italy

    Vito Guerra & Rossella Donghia

Authors
  1. Brian I. Carr
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vito Guerra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rossella Donghia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seai Yilmaz
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

BIC: concept, ideas, and writing; VG, RD: biostatistics; SY: reviewing.

Corresponding author

Correspondence to Brian I. Carr.

Ethics declarations

Statement of Ethics

This work complies with the guidelines of the World Medical Association, Declaration of Helsinki. This work was approved by each institution’s IRB as documented in the methods section.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Carr, B.I., Guerra, V., Donghia, R. et al. Relationships Between Indices of Tumor Aggressiveness in Hepatocellular Carcinoma. J Gastrointest Canc 52, 1340–1349 (2021). https://doi.org/10.1007/s12029-021-00720-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12029-021-00720-z

Keywords

Search

Navigation