Mazzaferro and colleagues published their trial in 1996 and revealed a remarkable survival benefit for the patient within their criteria (Table 1) (4). It remains the reference for novel criteria based on the tumor burden, which are currently being developed. In chronological order, right after MC, Llovet and colleagues published their trial known as the Barcelona Criteria (11). They have selected the candidates for transplant, with a single tumor ≤7 cm, or 3 tumors ≤5 cm, or 5 tumors ≤3 cm. The 5-year overall survival rates were over 50%.

Two years after the Barcelona Criteria, Yao and colleagues published the University of California, San Francisco (UCSF) Criteria in 2001 (12). Their criteria include patients with a single tumor ≤6.5 cm or ≤3 lesions with the largest one ≤4.5 cm, and total tumor diameter ≤8 cm for LT. Their trial revealed 73% of 5-year overall survival (OS) and 81% of 5-year disease-free survival (DFS) (12).

In 2007, Sugawara et al. published the Tokyo University series (13). Up to 5 nodules with a maximum tumor size of ≤5 cm in diameter were considered acceptable candidates for living donor liver transplantation (LDLT) in their study. 1-year and 3-year survival rates were completely similar to those within MC; 97% and 94%, respectively. In the same year, 2007, Jonas et al. from Germany published their extended criteria outcomes (14). Multiple HCC nodes were considered acceptable up to a diameter of the largest node of 6 cm and a total tumor diameter (TTD) of 15 cm for their study. Rates of 3-year survival and recurrence-free survival were 68% and 64%, respectively.

Mazzaferro and colleagues published their extended criteria “Up-to7” in 2009 (15). Their criteria include the size and number of the tumors. The results were obtained from a retrospective analysis of 1,556 LT patients, showing a group of patients with an estimated 5-year OS in the absence of microvascular invasion (MiVI); seven being the result of the sum of size (in cm) and number of tumors for any given HCC. This included all combinations of a given HCC from one nodule up to 6 cm in size (1 + 6) to many tumors fulfilling seven as the sum of size plus number (2 tumors up to 5 cm, 3 tumors up to 4 cm, 4 tumors up to 3 cm, 5 tumors up to 2 cm). This group of patients had 71.2% 5-year OS rates similar to outcomes of patients wMC. On the other hand, for patients with MiVI, the 5-year overall survival rates decreased to 48.1%. In the analysis for the microvascular invasion rates, the estimated tumor size for no microvascular invasion was 30 mm and 45 mm for patients with microvascular invasion (p < 0.001). This result has proposed a possible relation between tumor size and the presence of MiVI.

DuBay and colleagues from the University of Toronto published the extended Toronto Criteria in 2011 (16). The Toronto criteria do not limit the size or number of the tumor, but it should not have any vascular invasion, extrahepatic disease, or cancer-related symptoms, and the biopsy can not be poorly differentiated. The 5-year survival outcomes revealed 68% rates.

Xu and colleagues revealed the Hangzhou Criteria in 2008 from China (17). They reviewed a total of 6,012 HCC patients; of those, 1,352 cases were bMC but within the extended Hangzhou Criteria. Their criteria were: total tumor diameter (TTD) ≤8 cm; or TTD >8 cm, well and moderate differentiation, and preoperative AFP level ≤100 ng/ml. The reported 1-year, 3-year, and 5-year OS rates were 83.1%, 67%, and 59.8%, respectively. They also had a second study group in their trial with AFP levels of 100–400 ng/ml and the same tumor size. This group of patients had worse overall and DFS rates. This demonstrates the effect of AFP level on predicting the prognosis of LT.

Duvuox and colleagues published the French-AFP model in 2012 (18). The tumor diameters were divided into three groups: ≪3cm, 3–6 cm, >6 cm, and the number of tumors was divided into two groups: 1–3, and ≥4, in the model. The AFP values were also divided into three groups: <100, 100–1,000, and >1,000. The risk assessment was calculated by the points, varying from zero to four. In this study, it was claimed that the French-AFP model could achieve comparable or even better results than MC in predicting recurrence and survival times. It has also been interpreted that increased AFP levels are associated with vascular invasion and loss of differentiation and are a good tool for predicting tumor behavior. Moreover, it has been stated that AFP provides better prognostic information than tumor diameter and number (18).

Toso and colleagues investigated 6,478 patients who underwent LT and published their extended criteria as “total tumor volume and AFP” (TTV-AFP) criteria proposed the following rules: tumor volume <115 cm³ and AFP levels under 400 ng/ml in 2015. They presented 75% of 4-year OS rates for the patients within their criteria (19). Toso et al. have already published the “Total tumor volume” criteria in 2008, and they determined the cut-off values of the tumor volumes from their previous study (20).

The Metroticket 2.0 model includes AFP levels in the algorithm, showing an individualized increase in the risk of death following LT proportional to increased AFP levels (21). Nine years after the publication of the Up-to-7 criteria, Mazzaferro and colleagues published the Metroticket 2.0 in 2018. By the combination of Italian and Chinese data with 1,359 patients, Mazzaferro and colleagues aimed to determine the risk factors affecting the survival rates of patients with HCC. In addition to the Up-to-7 criteria, they prompted AFP levels as a risk factor in their trial. The Milan Criteria's rate of 70% for 5-year overall survival led to determining the extended criteria for Metroticket. In conclusion, they recommended performing LT for patients with HCC with the following features; AFP should be <200 ng/ml and the sum of the number and size of tumors (in centimeters) should not exceed 7; if the level of AFP 200–400 ng/ml, the sum of the number and size of tumors should be ≤5; if the level of AFP 400–1,000 ng/ml, the sum of the number and size of tumors should be ≤4.

The Japanese Liver Transplantation Society proposed the 5-5-500 Model for LT candidates in 2019 (22). The model includes patients with the number of lesions <5, tumor size ≤5 cm, and AFP levels ≤500 ng/ml. Their results proposed a 19% increase in patients to be candidates for LT when compared with MC. The new criteria provided the 7.3% 5-year recurrence rate and +70% 5-year OS rate.

Kaido and colleagues published the current Kyoto Criteria results (23). Their criteria involve a combination of tumor number ≤10, maximal diameter of each tumor ≤5 cm, and serum des-gamma-carboxy prothrombin (DCP) levels ≤400 mAU/ml. 198 HCC patients were enrolled in the study. 147 of them were within the Kyoto criteria, and 49 of them exceeded the criteria. The 5-year OS rates were 82% and 42%, respectively. The 5-year recurrence rates were 4% and 51%, respectively. The 5-year overall survival rates were similar for both wMC (n = 118) and bMC (n = 80) groups. The patients were divided into three groups: wMC/Kyoto in (n = 105), bMC/Kyoto in (n = 42), and bMC/Kyoto out (n = 36). The overall survival rates were similar in the wMC/Kyoto in and the bMC/Kyoto in groups. The bMC/Kyoto out group had the worst 5-year survival rates. Also, the same group had the worst 5-year DFS rates.

In 2016, Lee and colleagues developed a model to predict tumor recurrence after LDLT for HCC, with the well-known name, MoRAL (24). They used the serum AFP and serum protein induced by vitamin K absence-II (PIVKA-II) levels to calculate risk stratifications for HCC recurrence. They showed that the serum AFP levels were significantly associated with the maximal tumor size. In this study, serum AFP and serum PIVKA levels were used to calculate the MoRAL score. The higher MoRAL score (>314,8) has been shown to be a risk factor for higher tumor recurrence. Interestingly, the patients wMC with a high MoRAL revealed a significantly higher risk of recurrence than those bMC with a low MoRAL score. At a cutoff value of 314,8, the MoRAL score provided significant discrimination functions on tumor recurrence in both the wMC and the bMC cohorts (24).

In 2017, Halazun and colleagues updated their previously presented MORAL study (25). A total of 339 HCC patients were enrolled in the study. The neutrophil to lymphocyte ratio (NLR) was measured from the immediate routine pretransplant labs by dividing the neutrophil count by the lymphocyte count. NLR 5 was considered the cutoff level; a level of 5 and above was considered elevated. The AFP 200 level was considered the cutoff level. In the multivariate analysis, the largest tumor size >3 cm, >200 AFP levels, and NLR >5 were detected as preoperative risk factors for DFS rates. Patients were examined in 3 separate risk groups according to their MORAL scores. The 5-year DFS rate of the low-risk group was found to be 98.6%. The medium-risk group reached 69.8% and the high-risk group reached 55.8% DFS values.

Sasaki and colleagues from the Cleveland Clinic developed the Hazard Associated with Liver Transplantation for Hepatocellular Carcinoma (HALT-HCC) score in 2017 (26). Unlike other models, the general health status of the recipient was also included in the calculation. This study showed that the tumor morphology (TBS), AFP levels, and the recipient MELD-Na were significantly associated with overall survival by the multivariable analysis. The TBS was a tumor morphological score, consisting of maximum tumor diameter and tumor number, but it represents tumor morphology in a single, continuous fashion, similar to the total tumor volume for this trial.

In 2021, Goldberg and colleagues published the Liver Transplant Expected Survival (LiTES) HHC score (27). There were 6,502 HCC patients in this cohort, and 6,224 (95,7%) were wMC. The 1-, 3-, 5-, and 10-year survival rates were 92.5%, 83.8%, 76.2%, and 60.1% respectively. The patients were divided into three groups: the top 25% LiTES score, 25%–75% LiTES score, and the bottom 25% LiTES score, and compared with other well-known risk models. The LiTES score was calculated by the following variables: bilirubin levels, international normalized ratios, estimated glomerular filtration rate, chronic kidney disease, age, diabetes, and the etiology of the LT.

In this study, liver transplant patients who underwent transplantation at Koç University Organ Transplantation Center between September 2018 and July 2024 were retrospectively analyzed. The study included patients in the adult age group who were diagnosed with hepatocellular carcinoma based on definitive pathology reports. Patients with HCC-CCC mixed tumors and those in the pediatric age group with HCC were excluded from the study. Patients were divided into two groups based on their pathological results: within the Milan Criteria (wMC) and beyond the Milan Criteria (bMC). Preoperative features, intraoperative and postoperative outcomes were compared. Overall survival and disease-free survival rates were compared between the groups. This study was approved by the Institutional Review Board (Project No: KA25/48-18.02.2025).

Statistical analysis was performed using SPSS statistical software (Version 25.0, SPSS Inc., Chicago, IL, United States). Continuous variables that were normally distributed were described as the mean ± standard deviation (p > 0.05) based on the Kolmogorov–Smirnov or Shapiro–Wilk tests (n < 30). Non-normally distributed continuous variables were described as the median. Comparisons between groups were evaluated using the Mann–Whitney U test. The categorical variables between groups were analyzed using the Chi-square test or Fisher's Exact Test. Kaplan–Meier survival curves were generated to compare overall and disease-free survival rates between the wMC and bMC groups. The log-rank test was used to compare survival distributions between groups. The association of the variables with overall survival and disease-free survival was analyzed using the Cox proportional hazard model. A retrospective power analysis was performed to examine the reliability of the results.

A total of 279 liver transplants (LT) were performed at Koç University Hospital Organ Transplant Center during the study period. According to pathological results, hepatocellular carcinoma (HCC) was diagnosed in 54 patients. Six patients had mixed hepatocellular carcinoma-cholangiocellular carcinoma (HCC-CCC) tumors. Three patients were in the pediatric age group. Patients with HCC-CCC mixed tumors and those in the pediatric age group with HCC were excluded from the study. The median follow-up time was 49 (2-76) months. The mean age was 57.9 ± 15.5 years. Among the 45 HCC patients, 23 (51.1%) were within the Milan Criteria, with a mean age of 57.7 ± 8.8 years. The remaining 22 patients (48.9%) were beyond the Milan Criteria, with a mean age of 58.3 ± 7.9 years (p = 0.663). The mean body mass index (BMI) was 23.7 ± 6.2. Among the 45 adult patients with HCC, 39 were male, and 6 were female. In the wMC group, 21 (91.3%) patients were male, while 18 (81.8%) male patients were in the bMC group (p = 0.414). Thirty-eight cases underwent living donor liver transplant (LDLT), and 7 received deceased donor liver transplant (DDLT). A total of 38 patients received a right lobe graft from living donors, while 7 patients received deceased donor grafts, including 2 with a split right graft and 5 with a full graft. The distributions of donor and graft types were similar between the groups. Although AFP levels appeared higher in the bMC group, no statistically significant difference was found between the two groups (Table 2). The tumor count and total tumor diameter were statistically higher in the bMC group, as expected. No statistically significant difference was found in the distribution of tumor differentiation.

Microvascular invasion (MiVI) was detected in 17 patients, with 4 patients (17.4%) in the wMC group and 13 patients (59.1%) in the bMC group showing MiVI (p = 0.006). Among all patients, macrovascular invasion (MaVI) was observed in only one patient, who was in the bMC group (p = 0.489).

The MELD scores were similar in both groups, with the wMC group having a median MELD score of 13 (range 6–29) and the bMC group having a median MELD score of 11 (range 6–26) (p = 0.985). Child scores were also comparable. The median Child score for the wMC group was 7 (range 5–11), while for the bMC group it was 6 (range 5–10) (p = 0.476). The distribution of preoperative ascites presence and severity was also similar between the two groups. Warm and cold ischemia times, ICU length of stay, total length of stay, and mortality rates were also comparable between the two groups (Table 2).

Bridging procedures were performed before liver transplantation in five patients. Of these, one patient underwent RFA, three underwent TACE, and one patient received both TACE and TARE.

Survival analyses were conducted for both groups. The 1-year, 3-year, and 5-year overall survival (OS) rates and disease-free survival (DFS) rates were statistically similar between the two groups (p > 0.05) (Table 3). Kaplan–Meier survival curves are shown in Figures 1, 2. Perioperative mortality was observed in one patient in the bMC group due to intra-abdominal sepsis. The second mortality in the bMC group was due to disease progression on postoperative day (POD) 375. The third mortality in the bMC group occurred due to cardiac decompensation on POD 1,679. The first mortality in the wMC group was due to disease progression on POD 707. The second mortality in the wMC group was due to chronic rejection on POD 961.

Recurrence occurred in four patients. In the wMC group, one patient developed lung metastasis on POD 463. In the bMC group, one patient developed vertebral metastasis on POD 168, and two patients had liver recurrences on PODs 483 and 1,254. Pathological examination of the explanted specimens from the four patients who developed recurrence revealed no evidence of microvascular invasion.

Post-hoc power analysis based on tumor count and total tumor diameter revealed a study power of 89% within a 95% confidence interval. Moreover, the post-hoc power calculated based on the survival analyisis results was to be found 71%.