Next Article in Journal
Unveiling Myelodysplastic Syndromes: Exploring Pathogenic Mechanisms and Therapeutic Advances
Previous Article in Journal
Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer: A Nationwide Analysis of Eligibility, Utilization, and Outcomes
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 17
Issue 3
10.3390/cancers17030507
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Communication

Evolving Indications for Liver Transplantation for Hepatocellular Carcinoma Following the Milan Criteria

by
Takashi Kokudo
* and
Norihiro Kokudo
National Center for Global Health and Medicine, Tokyo 162-8655, Japan
*
Author to whom correspondence should be addressed.
Cancers 2025, 17(3), 507; https://doi.org/10.3390/cancers17030507
Submission received: 16 December 2024 / Revised: 28 January 2025 / Accepted: 30 January 2025 / Published: 3 February 2025
(This article belongs to the Section Transplant Oncology)
Review Reports Versions Notes

Simple Summary

Since their introduction in the 1990s, the Milan criteria have been the gold standard of indication for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC). Nevertheless, several institutions have reported wider indication criteria for LT with comparable survival outcomes. This paper summarizes the recent indications for LT for HCC through a literature review.

Abstract

Background/Objectives: Since their introduction in the 1990s, the Milan criteria have been the gold standard of indication for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC). Nevertheless, several institutions have reported wider indication criteria for LT with comparable survival outcomes. Methods: This paper summarizes the recent indications for LT for HCC through a literature review. Results: There are several criteria expanding the Milan criteria, which can be subdivided into the “based on tumor number and size only”, “based on tumor number and size plus tumor markers”, and “based on tumor differentiation” groups, with the outcomes being comparable to those of patients included within the Milan criteria. Besides the tumor size and number, which are included in the Milan criteria, recent criteria included biomarkers and tumor differentiation. Several retrospective studies have reported microvascular invasion (MVI) as a significant risk factor for postoperative recurrence, highlighting the importance of preoperatively predicting MVI. Several studies attempted to identify preoperative predictive factors for MVI using tumor markers or preoperative imaging findings. Patients with HCC who are LT candidates are often treated while on the waiting list to prevent the progression of HCC or to reduce the measurable disease burden of HCC. The expanding repertoire of chemotherapeutic regiments suitable for patients with HCC should be further investigated. Conclusions: There are several criteria expanding Milan criteria, with the outcomes being comparable to those of patients included within the Milan criteria.

1. Introduction

Liver transplantation (LT) is the theoretically ideal treatment modality for hepatocellular carcinoma (HCC) to avoid recurrence [1,2]. Nevertheless, recurrence occurs even after LT, and the prognosis is dismal in patients with post-transplant recurrence [3]. Hence, the selection criteria of the recipient are essential to take complete advantage of the therapeutic benefits of LT.
The Milan criteria are the most well-known size and number criteria, and first reported in 1996 [4]. The criteria were a tumor measuring ≤ 5 cm in diameter in patients with a single HCC, and no more than three tumor nodules each measuring ≤ 3 cm in diameter in patients with multiple tumors. After the turn of the century, multiple new expanded criteria were reported with acceptable survival outcomes (Table 1) [5]. In this review, we provide an overview of the reported criteria for LT in patients with HCC.
The Milan criteria depend on morphological parameters, and provide an opportunity for LT to only 30% of the patients with HCC [6]. Nevertheless, various observations have demonstrated that there are patients with tumors that are beyond the Milan criteria who have favorable outcomes after LT [7]. The idea of expanding beyond the Milan criteria spread rapidly among the transplant community [5].
Two types of LT are performed worldwide. The first one is deceased donor liver transplantation (DDLT), which is primarily performed in Western countries. Conversely, living donor liver transplantation (LDLT) is a major modality because of the shortage of deceased donors in the East [8]. Because LDLT has donor risks, the transplantation criteria should be stricter than those for DDLT [9].
Table 1. Summary of the eligibility criteria for liver transplantation in hepatocellular carcinoma.
Table 1. Summary of the eligibility criteria for liver transplantation in hepatocellular carcinoma.
Eligibity CriteriaYearCriteria
Based on tumor number and size only
Milan [4]1996
  • Single tumor ≤ 5 cm
  • ≤3 tumors, all ≤ 3 cm
UCSF [10]2001
  • Single tumor ≤ 6.5 cm
  • ≤3 tumors, all ≤ 4.5 cm
Total tumor diameter ≤ 8 cm
5-5 rule [11]2007
  • Tumor number ≤ 5
  • Maximum diameter ≤ 5 cm
Up-to-seven [12]2009Sum of the size of the largest tumor [in cm] and the number of tumors ≤ 7
Based on number and size, plus tumor markers
Kyoto [13]2007
  • Tumor number ≤ 10
Maximum diameter ≤ 5 cm
Serum DCP level ≤ 400 mAU/mL
French AFP model [14]2012Score (model including tumor size, tumor number, and AFP level) ≤ 2
TTV/AFP [15]2015TTV ≤ 115 cm3 and AFP level ≤ 400 ng/mL
Metroticket 2.0 [16]2018Sum of the size of the largest tumor [in cm] and the number of tumors ≤ 7 + AFP level < 200 ng/mL
Sum of the size of the largest tumor [in cm] and the number of tumors ≤ 5 + AFP level 200–400 ng/mL
Sum of the size of the largest tumor [in cm] and the number of tumors ≤ 4 + AFP level 400–1000 ng/mL
5-5-500 rule [17]2019
  • Tumor size ≤ 5 cm in diameter
  • Tumor number ≤ 5
  • AFP level ≤ 500 ng/mL
Based on tumor differentiation
Toronto [18]2011Any size or number without
  • extrahepatic disease
  • vascular invasion
  • poorly differentiated
Tumor
Extended Toronto [19]2016Any size or number without
systemic cancer-related symptoms
  • extrahepatic disease
vascular invasion
  • poorly differentiated
tumor
Abbreviations: AFP, alpha-fetoprotein; UCSF, University of California San Francisco; BCLC, Barcelona Clinic Liver Cancer; DCP, des-gamma-carboxy prothrombin; TTV, total tumor volume.

2. Expanding the Milan Criteria by Tumor Size

After the report of the Milan criteria, Yao et al. reported the University of California San Francisco (UCSF) criteria in 2001, where in the tumor size was expanded as follows: solitary tumor ≤ 6.5 cm, or three or fewer nodules with the largest lesion measuring ≤ 4.5 cm, and the total tumor diameter measuring ≤ 8 cm [10]. These patients had survival rates of 90% and 75.2% at 1 and 5 years, respectively, after LT, compared to a 50% 1-year survival rate for patients with tumors exceeding these limits (p = 0.0005). These criteria expanded the Milan criteria by tumor size, but still preserved excellent survival after LT.

3. Expanding the Milan Criteria by Tumor Number

The limit of tumor number is three in the Milan criteria, and several reports have extended this limit. The relatively well-known criteria for tumor number are the so-called “Up-To-Seven” criteria [12], in which the inclusion criterion was “HCC with seven as the sum of size of the largest tumor (in cm) and the number of tumors”. This criterion was also reported by Mazzaferro V, who initially proposed the Milan criteria. Besides this report, the Tokyo group expanded the tumor number to five [11]. The criteria reported by the Tokyo group are based on LDLT; however, they reported that recurrence-free survival rates at 3 years for patients fulfilling the criteria and for those exceeding the criteria were 94% and 50%, respectively, and concluded that the indication for HCC might be expanded from the Milan criteria with equivalent outcomes.

4. Expanding the Milan Criteria by Biomarkers

In addition to tumor number and size, several biomarkers have been used to evaluate tumor aggressiveness. Alpha-fetoprotein (AFP) is the most widely used biomarker for HCC, and it was added to several criteria. Mazzaferro V also reported a Metroticket 2.0 model that included not only tumor size and number, but also serum AFP level [16]. The model identified patients who survived for 5 years after liver transplantation with an accuracy of 0.721 (95% confidence interval, 0.648−0.793%), which was higher than the predictive abilities of the Milan, UCSF, and Up-To-Seven7 criteria (p < 0.001). The French AFP model also included the serum AFP level [14]. Toso C et al. reported criteria that included total tumor volume and AFP level [15]. The Japanese nationwide survey also reported a 5-5-500 rule, including the serum AFP level [17]. The Kyoto group developed criteria using protein induced by vitamin K absence or antagonist-II (PIVKA-II), also known as des-gamma-carboxy prothrombin (DCP) levels [13].

5. Expanding the Milan Criteria by Tumor Differentiation

DuBay et al. reported the Toronto criteria in 2011, according to which a pretransplant tumor biopsy is performed, and irrespective of the tumor size and number, LT could be performed for patients with HCC not poorly differentiated on biopsy [18]. These innovative criteria expand the indication of liver transplantation (LT) regardless of the tumor number and size, although tumor biopsy before LT should be performed. The same group reported extended Toronto criteria in 2016, which included the absence of cancer-related symptoms [19]. The criteria required tumor biopsy to select patients for LT.

6. Impact of Microvascular Invasion in Patients with HCC

Several retrospective studies have reported microvascular invasion (MVI) as a significant risk factor for postoperative recurrence [20,21,22,23]. Therefore, predicting MVI preoperatively is important in both LT and liver resection because of its high risk of recurrence. Several studies have attempted to identify preoperative predictive factors for MVI using tumor markers or preoperative imaging findings [24,25,26]. The reported preoperative imaging findings include computed tomography (CT) [27], contrast-enhanced magnetic resonance imaging (MRI) [28,29,30,31], and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) [31,32].
Peng et al. [33] constructed a radionics nomogram using CT images to predict MVI in patients with HCC related to hepatitis B virus (HBV). They found that the radionics nomogram, as a noninvasive preoperative prediction method, demonstrated favorable predictive accuracy for the MVI status in patients with HBV-related HCC.
Three MRI features were reported to be independently associated with MVI, viz., arterial peritumoral enhancement, non-smooth tumor margin, and peritumoral hypointensity in the hepatobiliary phase [29]. Shirabe et al. proposed a new scoring system for predicting MVI, which consisted of tumor size, serum DCP levels, and the maximum standardized uptake value on FDG-PET [24].
Compared with CT/MRI, ultrasound (US) is radiation-free, easy to implement, and simple to use for liver examinations. Hu et al. [34] reported a US-based radionics score for the preoperative prediction of MVI. They found AFP level, tumor size, and radionics score as independent predictors of MVI. The radionics nomogram demonstrated better performance in detecting MVI than the clinical nomogram.
High glucose consumption by the tumor cell microenvironment, including that in HCC, can be reflected in FDG-PET. Although the efficiency of tumor detection is affected by liver cirrhosis and a high background signal, a recent study [35] reported that the FDG-PET/CT radionics signature was an independent biomarker for MVI estimation.

7. Bridging Therapy Before LT

Patients with HCC who are listed for LT are often treated while on the waiting list to prevent the progression of HCC or reduce the measurable disease burden of HCC [36,37]. This strategy is applied to patients who do not fulfill the criteria. Table 2 summarizes the techniques used for bridging or downstaging [38]. Despite the lack of data from randomized controlled trials, the recent European guidelines recommend neoadjuvant therapies to reduce the dropout risk due to tumor progression [39]. The recent guidelines from the American Association for the Study of Liver Diseases also suggest bridging therapy [40]. Transarterial chemoembolization (TACE) shows good outcome while on the waiting list with an excellent outcome after LT, with the 1-, 2-, and 5-year survival rates being 98%, 98%, and 93%, respectively [41].
Table 2. Summary of bridging therapies before liver transplantation in hepatocellular carcinoma.
Table 2. Summary of bridging therapies before liver transplantation in hepatocellular carcinoma.
Bridging TherapyYearFirst Author5-Year Survival After Transplantation
TACE [41]2003Graziadei IW93%
Radioembolization [42]2006Kulik LM27% *
RFA [43]2005Lu DS76% *
SBRT [44]2017Sapisochin G75%
Resection [45]2003Belghiti J61%
Immunotherapy [46]2024Tabrizian P85% *
* 3-year survival. Abbreviations: TACE, transarterial chemoembolization; RFA, radiofrequency ablation; SBRT, stereotactic body radiotherapy.
Radioembolization with yttrium-90 microspheres has been shown to limit tumor progression and dropout from LT [42]. Kulik et al. reported that 23% of the patients were successfully downstaged and underwent LT after treatment. The 1-, 2-, and 3-year survival rates in these patients were 84%, 54%, and 27%, respectively.
Radiofrequency ablation (RFA) has been reported as a bridging therapy, with the 1- and 3-year post-transplantation survival rates being 85% and 76%, respectively [43]. Lu et al. concluded that percutaneous RFA is an effective bridging therapy to LT for patients with compensated liver function and safely accessible tumors.
There is limited experience with stereotactic body radiotherapy (SBRT) as a bridging therapy; however, one study compared SBRT with TACE or RFA and found similar results among the groups [44]. The 1-, 3-, and 5-year survival rates from the time of transplantation were 83%, 75%, and 75% in the SBRT group compared to 96%, 75%, and 69% in the TACE group and 95%, 81%, and 73% in the RFA group, respectively (p = 0.7).
Another strategy may be used for selected patients with small tumors and adequate liver function, which consists of initial surgical tumor resection followed by close surveillance and “salvage” transplantation if tumor recurrence or deterioration of liver function occurs. A retrospective study of patients with HCC undergoing LT compared with patients subjected to initial resection and then LT reported that the postoperative course and overall survival were not different [45]. The study concluded that, in selected patients, liver resection before transplantation does not increase the morbidity or impair long-term survival after LT. Therefore, liver resection before transplantation can be integrated into the treatment strategy for HCC.
Immune checkpoint inhibitor (ICI) is recommended as a first- and second-line treatment for unresectable or advanced HCC [40]. A recent study reported the safety and outcomes of neoadjuvant immunotherapy before LT, with a 3-year post-LT survival rate of 85% [46]. Graft rejection is the major concern with pretransplant ICI use. In their series, 16.7% of patients experienced rejection; however, no deaths occurred secondary to graft rejection. They concluded that patient with HCC who received ICI pre-LT showed favorable survival and safety outcomes, justifying continued use.

8. Discussion

This review has summarized the criteria for LT for patients with HCC. The initial Milan criteria were reported in 1996, which were subsequently expanded by several centers, with the outcomes being comparable to those of patients included within the Milan criteria. Besides tumor size and number, which are included in the Milan criteria, recent criteria included biomarkers such as AFP and tumor differentiation.
The relatively well-known criteria that included AFP is the Metroticket 2.0 model proposed by Mazzaferro et al. [16]. The efficiency of this model depends on the inclusion of AFP in the equation predicting post-transplantation prognosis in HCC. HCC results in a “double prognosis” depending on two major components, viz., tumor burden and liver function. This implies that it is difficult to determine cancer-specific outcomes in such patients, considering the impact of nontumoral conditions on patient performance status, eligibility to therapies, risk of de novo tumors, and ultimately survival. The liver function status should be considered to determine the indication of LT. In Italy, the model for end-stage liver disease score is used as the criteria for LT [47].
The presence of MVI in patients with HCC is a significant prognostic factor after LT [20]. Therefore, it is important to predict MVI before HCC treatment. If MVI presence is anticipated, the patient might not be a good candidate for LT, considering the high incidence of HCC recurrence after LT. From this viewpoint, the prediction of MVI is essential to determine therapeutic modalities. Because MVI has also a significant risk of recurrence after liver resection [48], there have been several attempts to predict MVI preoperatively [33,34,35]. However, since the preoperative prediction of MVI is difficult, including MVI in the indication criteria would have limited value.
Bridging therapy is an attractive strategy to perform locoregional treatments to bring patients whose tumor burden does not fulfill the criteria [49]. In a prospective, uncontrolled study, tumor downstaging was beneficial, with the post-transplantation outcomes being comparable to those of patients included within the criteria [50]. As shown in Table 2, TACE, radioembolization, RFA, SBRT, and surgical resection are the reported bridging therapies before LT [41,42,43,44,45,46]. Prospective trials investigating tumor downstaging as a tool to expand the conventional criteria for LT are required and would be a future direction of expanding the indication of HCC before LT.
Considering the shortage of deceased donor organ pool and the ethical difficulty with living donors, it is necessary to develop ideal criteria that can be universally used. Although the Milan criteria are the most commonly used criteria, there is increasing evidence that they can be expanded with comparable outcomes. Adding biomarkers may be a promising direction to appropriately transplant organs to the appropriate recipient. Future studies will be required for developing ideal criteria for LT to prevent post-transplant recurrence. Bridging therapy is another approach to bring patients whose tumor burden does not fulfill the criteria; however, several studies are limited by the small sample size and short follow-up duration [50,51,52,53,54]. Future prospective trials would be required to clarify the benefit of bridging therapy.
The current European Association for the Study of the Liver guidelines and the American Association for the Study of Liver Diseases (AASLD) guidelines recommend the Milan criteria for the indication of LT [55,56]. In the AASLD criteria, the UCSF criteria, total tumor volume cutoff of 115 cm, Up-To-Seven criteria, extended Toronto criteria, and Kyoto criteria are also proposed as the expanded criteria [56]. In the guidelines for the Asia–Pacific region, the Milan criteria are also proposed and the expanded criteria are considered limited due to the scarcity of the donor pool [57].

9. Conclusions

There are several criteria expanding Milan criteria, with the outcomes being comparable to those of patients included within the Milan criteria. Besides tumor size and number, which are included in the Milan criteria, recent criteria included biomarkers and tumor differentiation.

Author Contributions

T.K. have performed conceptualization; methodology; writing—review and editing; supervision, N.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Ethical review and approval were waived for this study because this article is a literature review.

Informed Consent Statement

Patient consent was waived because this article is a literature review.

Data Availability Statement

There is no new data created for this paper.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Lee, K.K.; Kim, D.G.; Moon, I.S.; Lee, M.D.; Park, J.H. Liver transplantation versus liver resection for the treatment of hepatocellular carcinoma. J. Surg. Oncol. 2010, 101, 47–53. [Google Scholar] [CrossRef] [PubMed]
  2. Facciuto, M.E.; Koneru, B.; Rocca, J.P.; Wolf, D.C.; Kim-Schluger, L.; Visintainer, P.; Klein, K.M.; Chun, H.; Marvin, M.; Rozenblit, G.; et al. Surgical treatment of hepatocellular carcinoma beyond Milan criteria. Results of liver resection, salvage transplantation, and primary liver transplantation. Ann. Surg. Oncol. 2008, 15, 1383–1391. [Google Scholar] [CrossRef] [PubMed]
  3. Badwei, N. Challenges related to clinical decision-making in hepatocellular carcinoma recurrence post-liver transplantation: Is there a hope? World J. Transplant. 2024, 14, 96637. [Google Scholar] [CrossRef]
  4. Mazzaferro, V.; Regalia, E.; Doci, R.; Andreola, S.; Pulvirenti, A.; Bozzetti, F.; Montalto, F.; Ammatuna, M.; Morabito, A.; Gennari, L. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N. Engl. J. Med. 1996, 334, 693–699. [Google Scholar] [CrossRef] [PubMed]
  5. Ince, V.; Sahin, T.T.; Akbulut, S.; Yilmaz, S. Liver transplantation for hepatocellular carcinoma: Historical evolution of transplantation criteria. World J. Clin. Cases 2022, 10, 10413–10427. [Google Scholar] [CrossRef] [PubMed]
  6. Lingiah, V.A.; Niazi, M.; Olivo, R.; Paterno, F.; Guarrera, J.V.; Pyrsopoulos, N.T. Liver Transplantation Beyond Milan Criteria. J. Clin. Transl. Hepatol. 2020, 8, 69–75. [Google Scholar] [CrossRef] [PubMed]
  7. Cascales-Campos, P.; Martinez-Insfran, L.A.; Ramirez, P.; Ferreras, D.; Gonzalez-Sanchez, M.R.; Sanchez-Bueno, F.; Robles, R.; Pons, J.A.; Capel, A.; Parrilla, P. Liver Transplantation in Patients with Hepatocellular Carcinoma Outside the Milan Criteria After Downstaging: Is It Worth It? Transplant. Proc. 2018, 50, 591–594. [Google Scholar] [CrossRef]
  8. Shukla, A.; Vadeyar, H.; Rela, M.; Shah, S. Liver Transplantation: East versus West. J. Clin. Exp. Hepatol. 2013, 3, 243–253. [Google Scholar] [CrossRef] [PubMed]
  9. Sugawara, Y.; Makuuchi, M. Advances in adult living donor liver transplantation: A review based on reports from the 10th anniversary of the adult-to-adult living donor liver transplantation meeting in Tokyo. Liver Transpl. 2004, 10, 715–720. [Google Scholar] [CrossRef] [PubMed]
  10. Yao, F.Y.; Ferrell, L.; Bass, N.M.; Watson, J.J.; Bacchetti, P.; Venook, A.; Ascher, N.L.; Roberts, J.P. Liver transplantation for hepatocellular carcinoma: Expansion of the tumor size limits does not adversely impact survival. Hepatology 2001, 33, 1394–1403. [Google Scholar] [CrossRef] [PubMed]
  11. Sugawara, Y.; Tamura, S.; Makuuchi, M. Living donor liver transplantation for hepatocellular carcinoma: Tokyo University series. Dig. Dis. 2007, 25, 310–312. [Google Scholar] [CrossRef]
  12. Mazzaferro, V.; Llovet, J.M.; Miceli, R.; Bhoori, S.; Schiavo, M.; Mariani, L.; Camerini, T.; Roayaie, S.; Schwartz, M.E.; Grazi, G.L.; et al. Predicting Survival After Liver Transplantation in Patients with Hepatocellular Carcinoma Beyond the Milan Criteria: A Retrospective, Exploratory Analysis. Lancet Oncol. 2009, 10, 35–43. [Google Scholar] [CrossRef] [PubMed]
  13. Takada, Y.; Ito, T.; Ueda, M.; Sakamoto, S.; Haga, H.; Maetani, Y.; Ogawa, K.; Ogura, Y.; Oike, F.; Egawa, H.; et al. Living donor liver transplantation for patients with HCC exceeding the Milan criteria: A proposal of expanded criteria. Dig. Dis. 2007, 25, 299–302. [Google Scholar] [CrossRef]
  14. Duvoux, C.; Roudot-Thoraval, F.; Decaens, T.; Pessione, F.; Badran, H.; Piardi, T.; Francoz, C.; Compagnon, P.; Vanlemmens, C.; Dumortier, J.; et al. Liver transplantation for hepatocellular carcinoma: A model including alpha-fetoprotein improves the performance of Milan criteria. Gastroenterology 2012, 143, 986–994. [Google Scholar] [CrossRef] [PubMed]
  15. Toso, C.; Meeberg, G.; Hernandez-Alejandro, R.; Dufour, J.F.; Marotta, P.; Majno, P.; Kneteman, N.M. Total tumor volume and alpha-fetoprotein for selection of transplant candidates with hepatocellular carcinoma: A prospective validation. Hepatology 2015, 62, 158–165. [Google Scholar] [CrossRef] [PubMed]
  16. Mazzaferro, V.; Sposito, C.; Zhou, J.; Pinna, A.D.; De Carlis, L.; Fan, J.; Cescon, M.; Di Sandro, S.; Yi-Feng, H.; Lauterio, A.; et al. Metroticket 2.0 Model for Analysis of Competing Risks of Death After Liver Transplantation for Hepatocellular Carcinoma. Gastroenterology 2018, 154, 128–139. [Google Scholar] [CrossRef]
  17. Shimamura, T.; Akamatsu, N.; Fujiyoshi, M.; Kawaguchi, A.; Morita, S.; Kawasaki, S.; Uemoto, S.; Kokudo, N.; Hasegawa, K.; Ohdan, H.; et al. Expanded living-donor liver transplantation criteria for patients with hepatocellular carcinoma based on the Japanese nationwide survey: The 5-5-500 rule—A retrospective study. Transpl. Int. 2019, 32, 356–368. [Google Scholar] [CrossRef] [PubMed]
  18. DuBay, D.; Sandroussi, C.; Sandhu, L.; Cleary, S.; Guba, M.; Cattral, M.S.; McGilvray, I.; Ghanekar, A.; Selzner, M.; Greig, P.D.; et al. Liver transplantation for advanced hepatocellular carcinoma using poor tumor differentiation on biopsy as an exclusion criterion. Ann. Surg. 2011, 253, 166–172. [Google Scholar] [CrossRef] [PubMed]
  19. Sapisochin, G.; Goldaracena, N.; Laurence, J.M.; Dib, M.; Barbas, A.; Ghanekar, A.; Cleary, S.P.; Lilly, L.; Cattral, M.S.; Marquez, M.; et al. The extended Toronto criteria for liver transplantation in patients with hepatocellular carcinoma: A prospective validation study. Hepatology 2016, 64, 2077–2088. [Google Scholar] [CrossRef] [PubMed]
  20. Rodríguez-Perálvarez, M.; Luong, T.V.; Andreana, L.; Meyer, T.; Dhillon, A.P.; Burroughs, A.K. A systematic review of microvascular invasion in hepatocellular carcinoma: Diagnostic and prognostic variability. Ann. Surg. Oncol. 2013, 20, 325–339. [Google Scholar] [CrossRef] [PubMed]
  21. Chen, Z.H.; Zhang, X.P.; Wang, H.; Chai, Z.T.; Sun, J.X.; Guo, W.X.; Shi, J.; Cheng, S.Q. Effect of microvascular invasion on the postoperative long-term prognosis of solitary small HCC: A systematic review and meta-analysis. HPB 2019, 21, 935–944. [Google Scholar] [CrossRef] [PubMed]
  22. Nitta, H.; Allard, M.A.; Sebagh, M.; Ciacio, O.; Pittau, G.; Vibert, E.; Sa Cunha, A.; Cherqui, D.; Castaing, D.; Bismuth, H.; et al. Prognostic Value and Prediction of Extratumoral Microvascular Invasion for Hepatocellular Carcinoma. Ann. Surg. Oncol. 2019, 26, 2568–2576. [Google Scholar] [CrossRef]
  23. Xu, X.; Zhang, H.L.; Liu, Q.P.; Sun, S.W.; Zhang, J.; Zhu, F.P.; Yang, G.; Yan, X.; Zhang, Y.D.; Liu, X.S. Radiomic analysis of contrast-enhanced CT predicts microvascular invasion and outcome in hepatocellular carcinoma. J. Hepatol. 2019, 70, 1133–1144. [Google Scholar] [CrossRef]
  24. Shirabe, K.; Toshima, T.; Kimura, K.; Yamashita, Y.; Ikeda, T.; Ikegami, T.; Yoshizumi, T.; Abe, K.; Aishima, S.; Maehara, Y. New scoring system for prediction of microvascular invasion in patients with hepatocellular carcinoma. Liver Int. 2014, 34, 937–941. [Google Scholar] [CrossRef] [PubMed]
  25. Kim, N.R.; Bae, H.; Hwang, H.S.; Han, D.H.; Kim, K.S.; Choi, J.S.; Park, M.S.; Choi, G.H. Preoperative Prediction of Microvascular Invasion with Gadoxetic Acid-Enhanced Magnetic Resonance Imaging in Patients with Single Hepatocellular Carcinoma: The Implication of Surgical Decision on the Extent of Liver Resection. Liver Cancer 2023, 13, 181–192. [Google Scholar] [CrossRef] [PubMed]
  26. Imai, K.; Yamashita, Y.I.; Yusa, T.; Nakao, Y.; Itoyama, R.; Nakagawa, S.; Okabe, H.; Chikamoto, A.; Ishiko, T.; Baba, H. Microvascular invasion in small-sized hepatocellular carcinoma: Significance for outcomes following hepatectomy and radiofrequency ablation. Anticancer. Res. 2018, 38, 1053–1060. [Google Scholar]
  27. Lv, K.; Cao, X.; Du, P.; Fu, J.Y.; Geng, D.Y.; Zhang, J. Radiomics for the detection of microvascular invasion in hepatocellular carcinoma. World J. Gastroenterol. 2022, 28, 2176–2183. [Google Scholar] [CrossRef] [PubMed]
  28. Cho, E.S.; Choi, J.Y. MRI features of hepatocellular carcinoma related to biologic behavior. Korean J. Radiol. 2015, 16, 449–464. [Google Scholar] [CrossRef] [PubMed]
  29. Lee, S.; Kim, S.H.; Lee, J.E.; Sinn, D.H.; Park, C.K. Preoperative gadoxetic acid-enhanced MRI for predicting microvascular invasion in patients with single hepatocellular carcinoma. J. Hepatol. 2017, 67, 526–534. [Google Scholar] [CrossRef] [PubMed]
  30. Kim, H.; Park, M.S.; Choi, J.Y.; Park, Y.N.; Kim, M.J.; Kim, K.S.; Choi, J.S.; Han, K.H.; Kim, E.; Kim, K.W. Can microvessel invasion of hepatocellular carcinoma be predicted by pre-operative MRI? Eur. Radiol. 2009, 19, 1744–1751. [Google Scholar] [CrossRef] [PubMed]
  31. Ahn, S.Y.; Lee, J.M.; Joo, I.; Lee, E.S.; Lee, S.J.; Cheon, G.J.; Han, J.K.; Choi, B.I. Prediction of microvascular invasion of hepatocellular carcinoma using gadoxetic acid-enhanced MR and (18)F-FDG PET/CT. Abdom. Imaging 2015, 40, 843–851. [Google Scholar] [CrossRef]
  32. Kornberg, A.; Freesmeyer, M.; Barthel, E.; Jandt, K.; Katenkamp, K.; Steenbeck, J.; Sappler, A.; Habrecht, O.; Gottschild, D.; Settmacher, U. 18F-FDG-uptake of hepatocellular carcinoma on PET predicts microvascular tumor invasion in liver transplant patients. Am. J. Transpl. 2009, 9, 592–600. [Google Scholar] [CrossRef]
  33. Peng, J.; Zhang, J.; Zhang, Q.; Xu, Y.; Zhou, J.; Liu, L. A radiomics nomogram for preoperative prediction of microvascular invasion risk in hepatitis B virus-related hepatocellular carcinoma. Diagn. Interv. Radiol. 2018, 24, 121–127. [Google Scholar] [CrossRef] [PubMed]
  34. Hu, H.T.; Wang, Z.; Huang, X.W.; Chen, S.L.; Zheng, X.; Ruan, S.M.; Xie, X.Y.; Lu, M.D.; Yu, J.; Tian, J.; et al. Ultrasound-based radiomics score: A potential biomarker for the prediction of microvascular invasion in hepatocellular carcinoma. Eur. Radiol. 2019, 29, 2890–2901. [Google Scholar] [CrossRef]
  35. Li, Y.; Zhang, Y.; Fang, Q.; Zhang, X.; Hou, P.; Wu, H.; Wang, X. Radiomics analysis of [18F]FDG PET/CT for microvascular invasion and prognosis prediction in very-early- and early-stage hepatocellular carcinoma. Eur. J. Nucl. Med. Mol. Imaging 2021, 48, 2599–2614. [Google Scholar] [CrossRef] [PubMed]
  36. Kulik, L.; Heimbach, J.K.; Zaiem, F.; Almasri, J.; Prokop, L.J.; Wang, Z.; Murad, M.H.; Mohammed, K. Therapies for patients with hepatocellular carcinoma awaiting liver transplantation: A systematic review and meta-analysis. Hepatology 2018, 67, 381–400. [Google Scholar] [CrossRef]
  37. Mazzaferro, V.; Citterio, D.; Bhoori, S.; Bongini, M.; Miceli, R.; De Carlis, L.; Colledan, M.; Salizzoni, M.; Romagnoli, R.; Antonelli, B.; et al. Liver transplantation in hepatocellular carcinoma after tumour downstaging (XXL): A randomised, controlled, phase 2b/3 trial. Lancet Oncol. 2020, 21, 947–956. [Google Scholar] [CrossRef] [PubMed]
  38. Santopaolo, F.; Lenci, I.; Milana, M.; Manzia, T.M.; Baiocchi, L. Liver transplantation for hepatocellular carcinoma: Where do we stand? World J. Gastroenterol. 2019, 25, 2591–2602. [Google Scholar] [CrossRef]
  39. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J. Hepatol. 2018, 69, 182–236. [Google Scholar] [CrossRef] [PubMed]
  40. Heimbach, J.K.; Kulik, L.M.; Finn, R.S.; Sirlin, C.B.; Abecassis, M.M.; Roberts, L.R.; Zhu, A.X.; Murad, M.H.; Marrero, J.A. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 2018, 67, 358–380. [Google Scholar] [CrossRef] [PubMed]
  41. Graziadei, I.W.; Sandmueller, H.; Waldenberger, P.; Koenigsrainer, A.; Nachbaur, K.; Jaschke, W.; Margreiter, R.; Vogel, W. Chemoembolization followed by liver transplantation for hepatocellular carcinoma impedes tumor progression while on the waiting list and leads to excellent outcome. Liver Transpl. 2003, 9, 557–563. [Google Scholar] [CrossRef]
  42. Kulik, L.M.; Atassi, B.; van Holsbeeck, L.; Souman, T.; Lewandowski, R.J.; Mulcahy, M.F.; Hunter, R.D.; Nemcek, A.A., Jr.; Abecassis, M.M.; Haines, K.G., 3rd; et al. Yttrium-90 microspheres (TheraSphere) treatment of unresectable hepatocellular carcinoma: Downstaging to resection, RFA and bridge to transplantation. J. Surg. Oncol. 2006, 94, 572–586. [Google Scholar] [CrossRef] [PubMed]
  43. Lu, D.S.; Yu, N.C.; Raman, S.S.; Lassman, C.; Tong, M.J.; Britten, C.; Durazo, F.; Saab, S.; Han, S.; Finn, R.; et al. Percutaneous radiofrequency ablation of hepatocellular carcinoma as a bridge to liver transplantation. Hepatology 2005, 41, 1130–1137. [Google Scholar] [CrossRef] [PubMed]
  44. Sapisochin, G.; Barry, A.; Doherty, M.; Fischer, S.; Goldaracena, N.; Rosales, R.; Russo, M.; Beecroft, R.; Ghanekar, A.; Bhat, M.; et al. Stereotactic body radiotherapy vs. TACE or RFA as a bridge to transplant in patients with hepatocellular carcinoma. An intention-to-treat analysis. J. Hepatol. 2017, 67, 92–99. [Google Scholar] [CrossRef]
  45. Belghiti, J.; Cortes, A.; Abdalla, E.K.; Régimbeau, J.M.; Prakash, K.; Durand, F.; Sommacale, D.; Dondero, F.; Lesurtel, M.; Sauvanet, A.; et al. Resection prior to liver transplantation for hepatocellular carcinoma. Ann. Surg. 2003, 238, 885–892. [Google Scholar] [CrossRef] [PubMed]
  46. Tabrizian, P.; Holzner, M.; Ajmera, V.; Kim, A.K.; Zhou, K.; Schnickel, G.T.; Torosian, K.; Hoteit, M.; Marino, R.; Li, M.; et al. Intention-to-treat outcomes of patients with hepatocellular carcinoma receiving immunotherapy before liver transplant: The multicenter VITALITY study. J. Hepatol. 2024, in press. [Google Scholar] [CrossRef] [PubMed]
  47. Ravaioli, M.; Lai, Q.; Sessa, M.; Ghinolfi, D.; Fallani, G.; Patrono, D.; Di Sandro, S.; Avolio, A.; Odaldi, F.; Bronzoni, J.; et al. Impact of MELD 30-allocation policy on liver transplant outcomes in Italy. J. Hepatol. 2022, 76, 619–627. [Google Scholar] [CrossRef] [PubMed]
  48. Fuster-Anglada, C.; Mauro, E.; Ferrer-Fàbrega, J.; Caballol, B.; Sanduzzi-Zamparelli, M.; Bruix, J.; Fuster, J.; Reig, M.; Díaz, A.; Forner, A. Histological predictors of aggressive recurrence of hepatocellular carcinoma after liver resection. J. Hepatol. 2024, 81, 995–1004. [Google Scholar] [CrossRef] [PubMed]
  49. Yao, F.Y.; Kerlan, R.K., Jr.; Hirose, R.; Davern, T.J., 3rd; Bass, N.M.; Feng, S.; Peters, M.; Terrault, N.; Freise, C.E.; Ascher, N.L.; et al. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: An intention-to-treat analysis. Hepatology 2008, 48, 819–827. [Google Scholar] [CrossRef] [PubMed]
  50. Ravaioli, M.; Grazi, G.L.; Piscaglia, F.; Trevisani, F.; Cescon, M.; Ercolani, G.; Vivarelli, M.; Golfieri, R.; D’Errico Grigioni, A.; Panzini, I.; et al. Liver transplantation for hepatocellular carcinoma: Results of down-staging in patients initially outside the Milan selection criteria. Am. J. Transplant. 2008, 8, 2547–2557. [Google Scholar] [CrossRef] [PubMed]
  51. Yao, F.Y.; Mehta, N.; Flemming, J.; Dodge, J.; Hameed, B.; Fix, O.; Hirose, R.; Fidelman, N.; Kerlan, R.K., Jr.; Roberts, J.P. Downstaging of hepatocellular cancer before liver transplant: Long-term outcome compared to tumors within Milan criteria. Hepatology 2015, 61, 1968–1977. [Google Scholar] [CrossRef] [PubMed]
  52. De Luna, W.; Sze, D.Y.; Ahmed, A.; Ha, B.Y.; Ayoub, W.; Keeffe, E.B.; Cooper, A.; Esquivel, C.; Nguyen, M.H. Transarterial chemoinfusion for hepatocellular carcinoma as downstaging therapy and a bridge toward liver transplantation. Am. J. Transpl. 2009, 9, 1158–1168. [Google Scholar] [CrossRef] [PubMed]
  53. Barakat, O.; Wood, R.P.; Ozaki, C.F.; Ankoma-Sey, V.; Galati, J.; Skolkin, M.; Toombs, B.; Round, M.; Moore, W.; Mieles, L. Morphological features of advanced hepatocellular carcinoma as a predictor of downstaging and liver transplantation: An intention-to-treat analysis. Liver Transpl. 2010, 16, 289–299. [Google Scholar] [CrossRef]
  54. Chapman, W.C.; Majella Doyle, M.B.; Stuart, J.E.; Vachharajani, N.; Crippin, J.S.; Anderson, C.D.; Lowell, J.A.; Shenoy, S.; Darcy, M.D.; Brown, D.B. Outcomes of neoadjuvant transarterial chemoembolization to downstage hepatocellular carcinoma before liver transplantation. Ann. Surg. 2008, 248, 617–625. [Google Scholar] [CrossRef] [PubMed]
  55. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma. J. Hepatol. 2025, 82, 315–374. [Google Scholar] [CrossRef] [PubMed]
  56. Singal, A.G.; Llovet, J.M.; Yarchoan, M.; Mehta, N.; Heimbach, J.K.; Dawson, L.A.; Jou, J.H.; Kulik, L.M.; Agopian, V.G.; Marrero, J.A.; et al. AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology 2023, 78, 1922–1965. [Google Scholar] [CrossRef] [PubMed]
  57. Lau, G.; Obi, S.; Zhou, J.; Tateishi, R.; Qin, S.; Zhao, H.; Otsuka, M.; Ogasawara, S.; George, J.; Chow, P.K.H.; et al. APASL clinical practice guidelines on systemic therapy for hepatocellular carcinoma-2024. Hepatol. Int. 2024, 18, 1661–1683. [Google Scholar] [CrossRef] [PubMed]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Kokudo, T.; Kokudo, N. Evolving Indications for Liver Transplantation for Hepatocellular Carcinoma Following the Milan Criteria. Cancers 2025, 17, 507. https://doi.org/10.3390/cancers17030507

AMA Style

Kokudo T, Kokudo N. Evolving Indications for Liver Transplantation for Hepatocellular Carcinoma Following the Milan Criteria. Cancers. 2025; 17(3):507. https://doi.org/10.3390/cancers17030507

Chicago/Turabian Style

Kokudo, Takashi, and Norihiro Kokudo. 2025. "Evolving Indications for Liver Transplantation for Hepatocellular Carcinoma Following the Milan Criteria" Cancers 17, no. 3: 507. https://doi.org/10.3390/cancers17030507

APA Style

Kokudo, T., & Kokudo, N. (2025). Evolving Indications for Liver Transplantation for Hepatocellular Carcinoma Following the Milan Criteria. Cancers, 17(3), 507. https://doi.org/10.3390/cancers17030507

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Article metric data becomes available approximately 24 hours after publication online.
Back to TopTop