Surgical resection for hepatocellular carcinoma in cirrhotic patients with clinically significant portal hypertension: a multidisciplinary team decision

At the beginning of the 21st century, in a global attempt to guide and organize the treatment of hepatocellular carcinoma (HCC), which had reached 7th place as the most frequent cancer due to the historical coincidence of three confluent pandemics worldwide (alcoholism, obesity and viral hepatitis), several HCC classification proposals arose, among them, the one elaborated by Llovet et al., members of the Liver Unit of Barcelona Clinic Hospital, who published the first version of the Barcelona Clinic Liver Cancer (BCLC) in 1999. The BCLC model was a concise and orderly manual to guide prognosis and treatment, based on cancer stage and various functional parameters, interpreting the best evidence published at that time and extending a previous system by Kunio Okuda (1921–2003). The BCLC model also proposes several early stages, in which some potentially curative procedures should have greater efficacy and achieve longer disease-free survival (1).

Within a few years, this model, due to its great practical utility and simplicity, achieved worldwide success and was endorsed and adopted in its later versions by the European Association for the Study of the Liver (EASL) in 2001 and by the American Association for the Study of Liver Diseases (AASLD) in 2005. However, it was clear from the outset that the BCLC paradigm might allow HCC multidisciplinary tumor boards (MTBs) to select only a handful of patients for liver resection (LR) due, and not only, to the high recurrence rates detected in early publications after LR, but also, as a consequence of its exclusion criteria [e.g., clinically significant portal hypertension (CSPH) >10 mmHg].

Meanwhile, in 1969 and in parallel with the Western model, a national HCC registry was founded by the Liver Cancer Study Group of Japan (LCSGJ) (2), who developed a treatment algorithm, finally published by the Japan Society of Hepatology in 2007 (3). Despite certain radical differences (e.g., conceptualization of anatomic liver partitioning, useful biomarkers for follow-up, anatomical portal vein-based surgical resection), many MTB working under the discipline of the BCLC paradigm, both in Eastern and Western centers and with access to the state of the art in liver surgical technology (e.g. intraoperative 3D navigation, minimally invasive surgery, invasive hemodynamic and thromboelastography-based coagulation monitoring) considered this alternative source of information as an opportunity to explore LR in Child-Pugh class A patients with CSPH in the group of HCC non-susceptible candidates for liver transplantation (4).

In addition, another niche of LR candidates with CSPH subsequently emerged, paradoxically in high-volume centers with otherwise successful liver transplant programs, in a so-called waiting list crisis. Due to the nature of this limited resource, those tensions in organ supply and demand were noted by an increase in dropouts, as well as a higher rate of HCC progression within the enlisted patients. A combination of factors caused this situation, such as a >30% proportion of HCC within the waiting list, an overproportion of priority patients with a model for end-stage liver disease (MELD) score >30, and a median time to transplant of >6 months. Among the solutions, a two-stage procedural strategy—LR followed by transplantation (also known as secondary salvage liver transplantation)—was proposed (5-7). Another way to balance the distribution of organs was to assign exception points to patients with HCC listed. Finally, in the medium term, increasing the national donation rate was another part of the solution (e.g., in 2005, Spain reached 35 organ donors per million population).

As expected, and after two long decades, a few centers working independently in two continents (Asia and Europe), in different time frames and feeding from the same academic sources, challenged the BCLC notion that HCC and Child-Pugh class A patients with CSPH undergoing LR would end up with a high burden of morbidity and mortality. This historical period is analyzed by Aliseda and collaborators, from the Hepatopancreatobiliary and Liver Transplantation Unit of the Clínica Universidad de Navarra (8), through a robust meta-analysis selecting only high-quality prospective and matched cohort studies, mostly single-center cohorts.

Their conclusions are straightforward, firstly, the confirmation that LR in patients with surrogate indirect signs of portal hypertension is not associated with an increased risk of postoperative morbidity and mortality.

Secondly, in the group in which direct measurement of CSPH was performed, it is indisputable that a small group of patients presented complications after LR (mainly treatable ascites) although most patients were successfully treated during a short hospital stay (9).

Finally, a new version of the EASL guidelines was published in 2018 (10) (much more extensive and complex, 54 pages and 636 references), which does not exclude LR with CSPH, yet insists on proclaiming that CSPH carries a >30% morbidity penalty. However, despite the search for the ideal HCC patient undergoing LR, even within the BCLC Stage A group (Child-Plug class A with CSPH), there is enormous inter-patient heterogeneity (e.g., total liver volume, intraparenchymal vascular variations, serum marker expression, tumor burden and its distribution, degree of CSPH and indocyanine green clearance test, spatial mapping of hepatic fibrotic deposition, genetic profile). This group of patients needs further clarification and analysis from the surgical standpoint.

For now, and by way of conclusion, this reflects the evolution and progress of the technological landscape (and I will add also the surgical planning labscape) of current HCC treatment, especially after so many clinical trials with immune checkpoint inhibitors, targeted therapies and immunotherapy, where a simple approach is no longer possible. Pending further hierarchization and prioritization of treatments and quality control of the decision-making process, the MDT is essential to personalize consistently single or combined treatments for individual patients, with the aim of improving their overall survival.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article has undergone external peer review.

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-224/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-224/coif). The author has no conflicts of interest to declare.

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References

1. Llovet JM, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999;19:329-38. [Crossref] [PubMed]
2. Eguchi S, Kanematsu T, Arii S, et al. Recurrence-free survival more than 10 years after liver resection for hepatocellular carcinoma. Br J Surg 2011;98:552-7. [Crossref] [PubMed]
3. Kudo M, Okanoue TJapan Society of Hepatology. Management of hepatocellular carcinoma in Japan: consensus-based clinical practice manual proposed by the Japan Society of Hepatology. Oncology 2007;72:2-15. [Crossref] [PubMed]
4. Ishizawa T, Hasegawa K, Aoki T, et al. Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma. Gastroenterology 2008;134:1908-16. [Crossref] [PubMed]
5. Poon RT, Fan ST, Lo CM, et al. Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation. Ann Surg 2002;235:373-82. [Crossref] [PubMed]
6. Belghiti J, Cortes A, Abdalla EK, et al. Resection prior to liver transplantation for hepatocellular carcinoma. Ann Surg 2003;238:885-92; discussion 892-3. [Crossref] [PubMed]
7. Molina V, Sampson-Dávila J, Ferrer J, et al. Benefits of laparoscopic liver resection in patients with hepatocellular carcinoma and portal hypertension: a case-matched study. Surg Endosc 2018;32:2345-54. [Crossref] [PubMed]
8. Aliseda D, Zozaya G, Martí-Cruchaga P, et al. The Impact of Portal Hypertension Assessment Method on the Outcomes of Hepatocellular Carcinoma Resection: A Meta-Analysis of Matched Cohort and Prospective Studies. Ann Surg 2024;280:46-55. [Crossref] [PubMed]
9. Cortese S, Tellado JM. Impact and outcomes of liver resection for hepatocellular carcinoma in patients with clinically significant portal hypertension. Cir Cir 2022;90:579-87. [PubMed]
10. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 2018;69:182-236. [Crossref] [PubMed]