Predicting recurrence after liver transplantation in patients with hepatocellular carcinoma exceeding the up-to-seven criteria

Abstract

The up-to-seven (Up-to-7) criteria [with 7 being the sum of the size and number of tumors for any given hepatocellular carcinoma (HCC)] have been recently proposed to identify potential candidates for liver transplantation (LT) among patients exceeding the Milan criteria. The aim of this study was to compare the ability of the available pathologic staging systems (the Milan, University of California San Francisco, and Up-to-7 criteria) to predict recurrence. A study population of 479 HCC transplanted patients was identified from prospectively collected databases at Mount Sinai Medical Center (New York, NY) and the University of Padua (Padua, Italy). The best pathologic staging system was identified with log rank, proportion separation index (PSEP), and Cox analyses. Pathologic tumor characteristics (tumor number, tumor size, sum of diameters, macroscopic and microscopic vascular invasion, and grading) were then tested by univariate and multivariate Cox analyses in the prognostic subgroups within and beyond the calculated criteria. The Up-to-7 criteria performed as the best pathologic staging system, the calculated 1-, 3-, and 5-year recurrence probabilities being 4%, 8%, and 14% within the criteria (n = 355) and 22%, 45%, 51% beyond the criteria (n = 124; P < 0.0001) and the calculated PSEP being 0.27 (95% confidence interval = 0.23-0.31). In multivariate analysis, only biological variables (vascular invasion and tumor grade) significantly predicted recurrence beyond the Up-to-7 criteria. A 3-stage pathologic staging system with a potential to be applied in the preoperative setting was thus created: within the Up-to-7 criteria (recurrence rate = 8%), beyond the Up-to-7 criteria without macrovascular invasion and poorly differentiated grade (recurrence rate = 24%), and beyond the Up-to-7 criteria with macrovascular invasion and/or poorly differentiated grade (recurrence rate = 45%). In conclusion, HCC patients within the pathologic Up-to-7 criteria were associated with a low risk of recurrence after LT. Beyond these criteria, however, a significant proportion of patients with a good HCC biological profile had an acceptable risk of recurrence.

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“…18 In another study of 497 patients by D'Amico et al in 2009, histologic grade correlated with HCC recurrence. 26 In our study, univariate analysis showed poor differentiation as an independent factor affecting tumor recurrence and survival (P = .005 [highly significant]). It is not feasible to detect the histologic grade preoperatively except by biopsy.…”

Liver Transplantation for HCC: A Review

“…The Milan group recently reviewed the explant pathological data in 1,556 patients (of the Metroticket project) of which 1,112 were found to have HCC beyond Milan criteria. Despite this, in 283 patients who had the sum of largest tumor diameter in centimeters and number of tumors ≤7 (up to 7 criteria), a 5-year survival of 71% was achieved [17,33]. Faced with low rates of deceased donor liver transplantation (DDLT) and prolonged waiting periods, LDLT is often the only realistic option for patients with HCC in some parts of the world.…”

“…The fundamental questions to be answered are what constitutes an acceptable outcome and how much does extension of criteria impact the non-HCC waiting list. A Markov [35] No gross vascular invasion 1-year DFS 83.7% Lesion <8 cm OR 1-year OS 92.8% Lesion ≥8 cm if AFP ≤400 and well-differentiated 5-year DFS 62.4% 5-year OS 70.7% Padua, Italy [33] Sum of number of lesions and diameter ≤7 cm 1-year recurrence 4% 5-year recurrence 14% mathematical model revealed that unless a 5-year survival of at least 61% could be achieved, performing LT for patients with tumors beyond Milan criteria put other patients without HCC at a risk of dying without LT [37]. This survival rate may increase to 71% in regions with severe organ shortage and reduce to 25% in regions where the shortage is not so acute.…”

Should the liver transplant criteria for hepatocellular carcinoma be different for deceased donation and living donation?

“…16 The prognosis for patients with HCC with highly unfavorable factors (eg, macroscopic vascular invasion) is very poor, so these patients are poor candidates for either DDLT or LDLT outside clinical trials. 11,17,18 Are there reasons to be cautious about preferentially or only offering LDLT for HCC? Yes, there are.…”