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Hepatocellular carcinoma (HCC) is the seventh most common cancer worldwide and the third most common cause of cancer-related deaths; the number of new cases per year is approaching 750,000.1 The magnitude of the incidence of HCC has discouraged any attempts to apply liver transplantation (LT) as the prevailing curative therapy for HCC worldwide because of the limited sources of donated organs (deceased and living donors) and the poor access to sophisticated health care systems in some geographical areas. If these limitations continue to prevail throughout the world, any attempt to significantly reduce HCC-related mortality rates through the application of LT will be delusional. International experiences have confirmed, however, the potential of LT to definitively cure HCC because it presents a unique opportunity to remove both the tumor (HCC is associated with 695,000 deaths per year1) and the underlying cirrhosis. Despite its limited access, LT has become the standard of care for patients with small HCCs and the main driving force for alternative strategies offered to patients with intermediate HCCs. In 1996, a prospective cohort study defined restrictive selection criteria that led to superior survival for transplant patients in comparison with any other previous experience with transplantation or other options for HCC.2 Since then, these selection criteria have become universally known as the Milan criteria (MC) in recognition of their origin. Ever since their adoption in clinical practice, the MC have helped doctors to single out early-stage HCC as a prognostic category of cancer presentation that is amenable to curative treatments. After their implementation, the favorable posttransplant outcomes that were observed in cohort series were so convincing that the MC immediately became the standard of care for early HCC, and further validation by randomized controlled trials (RCTs) was prevented. After the passage of approximately a decade, researchers began to challenge the MC with other proposals designed to capture those patients not meeting the MC who could achieve similar posttransplant survival rates through the expansion of the accepted tumor limits for transplant eligibility. None of these expanded criteria have become the new reference standard for selecting LT candidates with HCC; any broadening of the selection criteria for transplantation is inevitably hampered by severe restrictions in donor availability. Consequently, the MC remain the benchmark for any transplant strategy involving patients with HCC and the cornerstone for decision making for other patients at any stage. Surprisingly, no systematic review of the available experiences with the MC has been published yet; the suboptimal quality of the literature and the poor application of evidence-based principles has prevented this exercise. The aim of this study was to fill the gap through a systematic review of the available evidence on the MC and the related issue of the position of LT in the treatment algorithm for HCC. AFP, alpha-fetoprotein; CI, confidence interval; df, degrees of freedom; HCC, hepatocellular carcinoma; LT, liver transplantation; MC, Milan criteria; MELD, Model for End-Stage Liver Disease; mVI, microvascular invasion; NA, not applicable; n/n, number of studies/number of patients; NOS, Newcastle-Ottawa scale; RCT, randomized controlled trial; TACE, transarterial chemoembolization. For the literature review, analysis, and discussion, the MC were defined as follows: a single HCC nodule with a maximum size of 5 cm or as many as 3 nodules with the largest not exceeding 3 cm and no macrovascular invasion.2 Is the posttransplant survival of patients influenced by the MC when they are assessed at the time of the explant pathology examination? Do the boundaries of the MC correlate with a reduced likelihood of detecting 2 pathology surrogates of tumor behavior: microvascular invasion (mVI) and poor differentiation (grade 3)? In addition, we also probed the literature to answer less stringent questions (eg, the role of pretransplant treatments in patients meeting or not meeting the MC at the time of wait listing). A review of the literature in English was performed with various search terms. A PubMed-, Embase-, and Scopus-based search strategy was used that combined text, keywords, and Medical Subject Headings terms for titles and abstracts. Manual cross-referencing was also used to find more relevant articles. This part of the search strategy was not restricted by date. The following search terms were used in various combinations: Milan criteria, primary liver cancer, primary liver tumor, hepatoma, hepatocellular carcinoma, HCC, BCLC A, T1-T2, tumor size, tumor number, tumor burden, metastatic disease and metastases of HCC, transplantation, liver transplantation, liver substitution, orthotopic liver transplantation, OLT, LT, living donor liver transplantation, deceased donor liver transplantation, survival, overall survival, recurrence-free survival, RFS, disease-free survival, DFS, prognosis, death, recurrence, tumor relapse, time to recurrence, time to relapse, and TTR. Because of the large quantity of reports including the use of the MC in the setting of HCC management, case studies and reviews that were not focused specifically on the MC were not considered. Abstracts were selected according to the inclusion-exclusion criteria and the review methodology, which are outlined in Table 1 and Fig. 1, whereas studies lacking explant pathology data (which were used to check for adherence to the MC) were not entered into the meta-analysis (exclusion code G). Review methodology. The classification proposed by the Oxford Centre for Evidence-Based Medicine was used to rank each publication in the particular subset of prognosis-oriented studies.3, 4 This methodology, in combination with a quality assessment scale for case-control and cohort studies proposed by the Newcastle-Ottawa group [ie, the Newcastle-Ottawa scale (NOS)],5 allowed a comprehensive review of the current evidence. The ranking of the studies and the assumptions were made specifically in terms of prognosis according to practice and the literature search; for this purpose, the MC were considered a prognostic covariate rather than a therapeutic covariate. Accordingly, in the Oxford Centre for Evidence-Based Medicine scheme, specific grading criteria for assigning levels of evidence are used to discriminate prognosis-oriented studies from therapy-oriented studies; the latter consist of systematic reviews of RCTs (including meta-analyses), whereas the former include case-control and cohort studies.3-5 The allocation of each study to the predefined categories was independently performed by 2 reviewers who were trained in the field of transplantation and HCC. All cases of possible inconsistencies between the reviewers were discussed so a shared judgment of the study's final allocation could be reached. The studies were selected and then ranked with the Oxford Centre for Evidence-Based Medicine classification and the NOS quality assessment; hazard ratio estimates, which were extracted from sufficiently powered individual studies, were combined for the meta-analysis with the generic inverse variance method according to a random effect model. Meta-analysis techniques were also used for aggregating frequency data for the distribution of pathology surrogates (ie, mVI and tumor grading) across individual studies. For this analysis, the Mantel-Haenszel random effect method was applied, and the odds ratio was the investigated association measure. Presuming an excess of variability (heterogeneity) in the study results, we used the random effect models to produce more conservative estimates of the significance of treatment effects in comparison with estimates from fixed effect models. Calculations were performed with RevMan 5 (Cochrane Information Management System, Copenhagen, Denmark).6 P values below the conventional 5% threshold were considered statistically significant. The first Web search resulted in a total of 1864 references; 1466 references were discarded as irrelevant because of the abstract title. Another 308 references were discarded because they did not comply with a predefined list of inclusion and exclusion criteria, which are outlined in Table 1 and Fig. 1. Studies describing LT outcomes with respect to the MC or using the MC as the reference standard for intraseries comparisons (n = 48). More heterogeneous studies describing the MC as a major determinant for the prognosis of patients with HCC undergoing LT (deceased donor LT, living donor LT, salvage transplantation, or pediatric transplantation) versus patients undergoing resection or other combined therapies (n = 42). In order to generate the meta-analysis, another cut to 25 references was necessary; 65 of the 90 studies were discarded according to exclusion codes G to J (Fig. 1). The stratification of the studies with a prognosis-oriented analysis revealed that 65 of the 90 studies (72%) reached an intermediate level of evidence (grade 2); only 17% of the studies were solid enough for grade 1b evidence, and the remaining studies were positioned at suboptimal levels (grades 4 and 5). In general, there was a significant correlation between the Oxford Centre for Evidence-Based Medicine level of evidence and the NOS-determined quality of the studies, even after quality adjustments were made to avoid overestimations of non-RCTs7-9 (for a summary of the stratification of the studies, see Table 2). The 90 studies, which spanned 15 years,2, 10-98 included 17,780 patients; only 1612 patients qualified for level 1b studies, and 16,043 qualified for level 2 studies. Presumably, this sample size represented less than 10% of the total number of patients who underwent transplantation for HCC and a negligible fraction of the potential transplant candidates with HCC who were observed during the same period. An unavoidable overestimation of the exact number of patients collected by the data pooling may have occurred because of the possible overlapping effect of patients recruited to multicenter studies. However, the aforementioned assumptions are confirmed by the estimated number of potential candidates with HCC who could benefit from LT, that is, more than 20,000 per year in the United States alone; this number far exceeds the number of deceased donors per year in the United States (8000). Having established the limits of the representativeness of the sampling and the suboptimal level of the evidence, we present the results, which are ordered in accordance with the predetermined endpoints, in the following sections. The current widespread acceptance of LT candidacy via the MC indicates the general acceptance of the reliability of these criteria in comparison with the pioneering days when the MC were not in place and LT for HCC was considered barely palliative.99 Indeed, in 9 studies, patients with chronic hepatitis and cirrhosis who met the MC and underwent LT for HCC achieved posttransplant survival rates comparable to those of patients with nontumor indications for LT. Although they were not designed to specifically address a survival equivalence between LT patients within the MC and LT patients with nontumor indications, 4 prospective cohort studies (level 1b)2, 10, 11, 13 and 5 retrospective cohort studies29, 32, 39, 45, 46 (level 2b) reported 5-year survival rates of 65% to 78% for patients meeting the MC and 68% to 87% for patients with nontumor indications. The European Liver Transplant Registry, the Organ Procurement and Transplantation Network, and the Australian and New Zealand Liver Transplant Registry100-102 have confirmed survival rates of 70% to 82% for patients with nontumor indications. Incidentally, these studies did not compare patients within the MC who were treated with transplantation and patients to whom nontransplant therapies were offered. However, other noncomparative studies have reported that the 5-year survival rates of HCC patients have improved with time, and these improvements started with the implementation of the MC in the clinical practice.103 Since the path of LT for HCC was reopened in 1996, a few prospective studies and several retrospective cohort studies based on intraseries comparisons (ie, lacking external validation) have shown significant improvements in the survival rates of patients undergoing LT for HCC within the MC versus patients with HCC beyond the MC (level of evidence 2b). An analysis of the results of LT for patients exceeding the MC is beyond the scope of the present review because any comparisons with extended criteria are biased by the fact that no prospective studies or RCTs of indications for LT for HCC beyond the MC have ever been conducted. However, the significant deterioration in survival that is observed when the MC limits are exceeded should be outlined; the 5-year survival rates of these patients are as low as 46% to 60%. The meta-analysis included 19 studies2, 15, 16, 19, 26, 33, 35, 39, 40, 42, 46, 48, 53-55, 57, 63, 67, 84 that used different methodologies to compare the overall survival of patients meeting the MC and patients exceeding the criteria at the time of the explant pathology examination; 3949 patients were also stratified by the graft origin (deceased or living donors). As outlined in Fig. 2, the hazard ratio of 1.68 [95% confidence interval (CI) = 1.39-2.03] confirmed the significantly increased posttransplant survival expected for patients meeting the MC versus patients beyond the MC. In fact, the MC qualified as the benchmark for LT prognostication in patients with HCC despite the significant heterogeneity in the hazard ratios reported by or derived from the different series because all the studies showed similar trends in favor of patients meeting the MC. When the studies were split according to the type of transplant, the hazard ratio for patients exceeding the MC was 1.76 (95% CI = 1.45-2.15) in the deceased donor category, but it was only 1.28 (with a lower confidence interval limit of 0.86) in the living donor category. This was presumably due to the shortening of the waiting time and the acceleration of transplantation with living donation versus deceased donation (the so-called Meta-analysis of the 19 studies the overall survival of patients with HCC meeting the MC and patients with HCC exceeding the MC at the time of the explant pathology The studies are stratified by the graft type (deceased or living HCCs that the MC during the time on the waiting list are not the only an prognosis when patients not the MC. the tumor the the prognosis, even the magnitude of this covariate could not be further in this meta-analysis because of the significant heterogeneity of the HCCs exceeding the MC in the collected studies. studies have that the of outcomes after LT be to in the size and number of HCCs in patients selected for there are no studies of the of LT with respect to the MC. The of that are with LT is to the for living donor LT is even to the available there is evidence to the MC as the main for the prognosis after LT. the of the tumor size and number, the MC the most for HCC with respect to allocation for An of the of this is the current graft allocation for patients with cirrhosis and HCC in the large of to the Model for End-Stage Liver liver are with only to patients meeting the MC at the time of pretransplant (ie, United for Organ category In addition, because the potential benefit for patients with HCC meeting the MC is similar to the potential benefit for patients with the use of donor organs for candidates with HCC meeting the MC is In this the MC remain the benchmark for any other prognostic criteria proposed for the use of LT in patients with cirrhosis and HCC. A relevant to outcomes for patients meeting the MC is the of the criteria to patients for LT HCCs have favorable to size and number respect to patients exceeding the MC, posttransplant pathology of from patients meeting the MC have revealed reduced rates of and surrogates of tumor as mVI, and level 1b studies2, 15, 2 level and 13 level 33, 39, 40, 42, 48, have confirmed the likelihood of detecting mVI, grade 3 and as the tumor size and number beyond the MC. In patients with HCCs meeting the MC, mVI is at a of 10% to are at a of to and are at a of to For patients not meeting the MC, the rates of mVI and grade 3 and 4 significantly and rates of of tumor and poor have been in patients exceeding the MC, as patients meeting the of 84 even a significant of patients meeting the of criteria are meeting the MC as 26, 48, 63, frequency data for mVI and tumor in patients meeting or not meeting the MC, and a meta-analysis of the odds ratios was performed (Fig. Meta-analysis of the studies the frequency of tumor than 2 and the of mVI studies in common with in patients with HCC meeting the MC and patients with HCC exceeding the MC. the of mVI and were investigated in this meta-analysis (Fig. The fact that only 1 frequency data for related to the MC any meta-analysis for the covariate. to the MC was significantly associated with a reduced frequency of tumor than 2 and a reduced of mVI, as shown by odds ratio estimates of (95% CI = and (95% CI = (Fig. results the common that the size and number limits of the MC a of early-stage HCCs with a low of in comparison with expanded indications. to the available the of early and early HCCs for transplant candidacy some because of the current and the prognostication of as a of tumor the metastatic potential mVI are and are the of HCC patients meeting the MC through size and number be considered a for the inclusion of patients with less HCCs on the LT waiting is evidence that patients meeting the MC have a lower of from the waiting list due to disease or in comparison with patients from large in and the United States have confirmed that most patients with early-stage HCC within the MC not experience significant of their cancer for approximately 1 year after they the waiting the of due to cancer in patients meeting the MC at the time of and is as as no treatment is however, therapies during the waiting or are to reduce the into the of to In general, the as the waiting time in the case of HCC patients who are for more than 3 the is than that observed for patients with Although there is no posttransplant in patients within the MC who are for transplantation, the available evidence NOS = 35, indicates that patients within the MC who are treated they are on the waiting list with for single nodules 3 or transarterial for HCCs 3 cm or with a have reduced rates in comparison with Although no RCTs have confirmed to 65% of the HCC patients on the Organ Procurement and Transplantation waiting list treatments. Although data for the subset of patients meeting the MC are not evidence that pretransplant treatments are of the tumor to from the list and to In a study using a and restrictive was shown to be in comparison with no therapy for patients within the MC (ie, United for Organ who were waiting for transplantation, when the time to transplantation was therapies during the LT waiting for patients with HCC are to be in the Although the level of evidence is the current clinical practice of patients with HCCs within the MC who are for LT for the specific of the therapies may the of the disease and may the between observed and expected rates of disease The of data and the of evidence not any the of posttransplant survival for patients within the MC who pretransplant some effects be from experiences with The pretransplant of HCCs for LT because they to the MC at no deterioration in survival to have occurred for patients considered to the MC in different This may be with the fact that the MC outcomes for patients within the limits rather than outcomes for patients exceeding The of the of and selecting patients with more HCCs for transplantation as as the MC are As a of fact, pathology of from find significantly more HCC nodules versus with mVI versus In comparison with patients with HCCs exceeding the criteria, patients with HCCs meeting the MC have levels within lower 63, In with the role of as a prognostic than a for HCC, levels of have been with a deterioration in the prognosis of patients with to the MC category, even a is Although the of the evidence is by the suboptimal quality NOS = and the limited number of 35, in clinical practice a and for more HCCs within the MC. In some values or are for patients for no evidence for a of to LT as the most treatment for HCC any individual strategies liver As a of fact, an increased number of treatment options are proposed for HCC each it is is proposed according to the or potential for The practice of treatment that for LT in patients with HCC should not be This is the first systematic review the of the MC as an prognostic the outcomes of LT for the treatment of HCC. A comprehensive search of the literature based on stringent selection criteria a list of 90 studies of quality from 1864 In addition, a meta-analysis of 25 sufficiently powered studies allowed the of hazard ratios that significantly the prognostic of the MC and their to capture HCCs favorable The has allowed the prognostic of MC to with a lower grade of evidence in comparison with RCTs were prevented for HCC by the in the posttransplant survival rates observed since the implementation of MC and those of HCCs meeting the MC have been confirmed to be a prognostic category associated with outcomes after LT 5-year survival of at This has the of the MC into transplant indications, and The MC are major of the prognosis of patients undergoing LT for HCC. meeting the MC achieve survival similar to those of patients with The results of LT for patients meeting the MC should be the benchmark for any of expanded criteria, which are associated with an increased of outcomes in comparison with conventional indications (Fig. 2). The MC a subset of patients with a significantly lower of tumor than 2 and mVI (Fig. more of prognosis using techniques are the MC in combination with the of levels remain a and for selecting patients with less HCCs more for LT. treatment strategies for patients with HCCs within the MC who are for LT are for the specific of the of patients from the transplant waiting the effect of therapies on survival is not treatment lacking prospective and predetermined not indications beyond the MC and should not be