Prognosis of operated hepatocellular carcinoma developed on non-cirrhotic liver

The incidence of primary liver cancers, and particularly hepatocellular carcinoma (HCC), is increasing throughout the world. The vast majority of HCCs develop on cirrhotic livers (CLs) (CL HCC) or livers chronically infected by hepatotropic viruses, mainly hepatitis B virus (HBV) and hepatitis C virus (HCV) (1). As HCC occurring on non-HBV non-HCV non-CL (NCL) HCC occurs much less frequently, its management is less established than for CL HCC. Consequently, many clinicians might confuse the prognosis and management of NCL HCC with the one of CL HCC. It is however demonstrated that NCL HCCs behave differently than CL HCCs. Their prognostic factors and sensibility to systemic therapy are different, added to the fact that NCLs can undergo major resections allowing curative surgical management or even systemic therapies that are not even possible in CL HCCs due to the failing function of the CL. The established criteria for liver transplantation of CL HCCs, including the famous Milan criteria, have no role in NCL HCC management (2-4). The Barcelona Clinic Liver Cancer (BCLC) strategy for prognosis prediction and treatment recommendation also concerns only CL HCCs; and should not be used for NCL HCCs (5).

It is therefore of the outmost importance to specifically study NCL HCCs. Due to the rarity of this cancer, it is also necessary to merge experiences of large expert liver centers to build strong scientific evidence allowing better management of patients suffering from NCL HCC. Despite the unavoidable bias linked to the retrospective nature of their study, this paper by Maulat et al. is an important step, as by grouping 11 French major liver surgery centers, they were able to review the largest series of operated NCL HCC patients so far (n=467), with a median follow-up 30 months (6). The results of this operated series are better than expected in CL HCCs, with a median overall survival (OS) of 88 months and a median recurrence-free survival (RFS) of 28 months. Amongst the preoperative prognostic factors, the number of HCC nodules (>2) and the size of the largest nodule (>10 cm) were determined as significant preoperative prognostic factors for decreased RFS after surgical resection with curative intent. In the population of NCL HCC patients with good RFS prognosis based on these preoperative prognostic factors, the pathology report of the resection specimen was also a very important, as microvascular invasion (median RFS: 25 months) or poor/moderate differentiation (median RFS: 33 months) decreased RFS to one-third of the one of patients with well-differentiated NCL HCCs (median RFS: 88 months) (6). These decreased RFSs were correlated to decreased OS. In total 209 patients (44%) developed recurrence in the follow-up period, half of them confined to the liver, and one-third of the recurrences were further managed with curative intent.

These results first confirm the fact that patients with operated NCL HCC should be carefully followed after surgery, as recurrence might occur in half of the patients and as it is likely that early detection of this recurrence might allow a better chance of curative management, especially if it occurs within a healthy liver that can undergo a second resection surgery (7). Secondly, this study allows to preoperatively determine which NCL HCC patients have a higher risk of recurrence after surgery. In this French series, the NCL HCC patients with three or more nodules had a median RFS of 10 months and a 5-year RFS of 5%, meaning that nearly all of them develop recurrence after surgery with curative-intent (6). In the group of patients with an HCC size >10 cm and one or two nodules, the 5-year RFS was also quite poor at 30%. These high-risk patients might be considered for inclusion in future prospective studies on the role of neoadjuvant therapy before liver resection, with maybe a combination of locoregional chemo- or radio-embolization for decreasing the risk of intrahepatic HCC recurrence and systemic immunotherapy for lowering the risk of extrahepatic HCC spread. This study also confirmed that poorly or moderately differentiated NCL HCCs or HCCs with microvascular invasion, information that is often only available postoperatively, are at high-risk of postoperative recurrence. These patients might also be considered in future prospective studies on the role of adjuvant therapies including combination immunotherapies. Finally, as two-thirds of the NCL HCC recurrences are not amenable to curative surgical management, there is also a place for future studies on systemic therapies in these recurrent patients, as their usually normally functioning livers allow them to better tolerate the potential severe side effects of these therapies.

HCC on NCLs is rare and could be considered as a neglected disease with a rising incidence. To improve the management of NCL HCC patients, it is necessary that large expert centers merge their experience in prospective studies evaluating the interests of different therapeutic strategies. This study by Maulat et al. allowed to determine a population of NCL HCC patients who might benefit from multimodal management with neoadjuvant or postoperative therapies to improve the overall results. These results should be confirmed by prospective studies, which are difficult to conduct, as NCL HCCs are rare. New therapies, including combination immunotherapies, should be rigorously tested in this particular population (8). However, until now, surgery is the only treatment of NCL HCCs with curative intent, and long-term cancer-free survival can be obtained even with very large tumors (9). In complicated cases or when the expected functional reserve of the future liver remnant (FLR) is insufficient, curative resection might be rendered possible by portal and hepatic vein embolization to induce preoperative FLR hypertrophy (10). As suggested, liver transplantation might also be considered in patients with unresectable NCL HCC without vascular or lymph node involvement (11).

In the Maulat et al. retrospective series of 467 patients operated on in France between 2010 and 2018, alcohol consumption and metabolic syndrome were detected as risk factors for HCC in one-third and one-fourth of the cases, respectively (6). With the rising incidence of metabolic syndrome and of metabolic dysfunction-associated steatohepatitis (MASH) throughout the world (12), it is likely that challenges in the management of NCL HCCs will be faced more frequently by liver cancer centers. Therefore, including these patients in prospective studies or registries should be strongly encouraged to improve outcomes in patients with NCL HCCs. Postoperative NCL HCC recurrences are frequent and deserve to be detected early to offer patients a chance on repeated surgical resection.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-155/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Villanueva A. Hepatocellular Carcinoma. N Engl J Med 2019;380:1450-62. [Crossref] [PubMed]
2. Schielke A, Meurisse N, Lamproye A, et al. Selection criteria for liver transplantation in patients with hepatocellular carcinoma. Eastern and western experiences, and perspectives for the future. Acta Gastroenterol Belg 2019;82:314-8. [PubMed]
3. Adler M, De Pauw F, Vereerstraeten P, et al. Outcome of patients with hepatocellular carcinoma listed for liver transplantation within the Eurotransplant allocation system. Liver Transpl 2008;14:526-33. [Crossref] [PubMed]
4. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693-9. [Crossref] [PubMed]
5. Reig M, Forner A, Rimola J, et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol 2022;76:681-93. [Crossref] [PubMed]
6. Maulat C, Truant S, Hobeika C, et al. Prognostication algorithm for non-cirrhotic non-B non-C hepatocellular carcinoma-a multicenter study under the aegis of the French Association of Hepato-Biliary Surgery and liver Transplantation. HepatoBiliary Surg Nutr 2023;12:192-204. [Crossref] [PubMed]
7. Herrero A, Toubert C, Bedoya JU, et al. Management of hepatocellular carcinoma recurrence after liver surgery and thermal ablations: state of the art and future perspectives. HepatoBiliary Surg Nutr 2024;13:71-88. [Crossref] [PubMed]
8. Rimassa L, Finn RS, Sangro B. Combination immunotherapy for hepatocellular carcinoma. J Hepatol 2023;79:506-15. [Crossref] [PubMed]
9. Bihain C, Delwaide J, Meunier P, et al. Successful multimodal management of a large hepatocellular carcinoma in a non-cirrhotic liver: a case report. Acta Chir Belg 2024;124:229-33. [Crossref] [PubMed]
10. Heil J, Korenblik R, Heid F, et al. Preoperative portal vein or portal and hepatic vein embolization: DRAGON collaborative group analysis. Br J Surg 2021;108:834-42. [Crossref] [PubMed]
11. Mergental H, Adam R, Ericzon BG, et al. Liver transplantation for unresectable hepatocellular carcinoma in normal livers. J Hepatol 2012;57:297-305. [Crossref] [PubMed]
12. Gao F, Chen G, Byrne CD, et al. Metabolic dysfunction-associated fatty liver disease and hepatocellular carcinoma: present and future. HepatoBiliary Surg Nutr 2023;12:945-8. [Crossref] [PubMed]