Recurrent hepatocellular carcinoma after transplantation: Use of a pathological score on explanted livers to predict recurrence

Abstract

Milan and University of California at San Francisco (UCSF) criteria are used to select patients with hepatocellular carcinoma (HCC) for liver transplantation (LT). Recurrent HCC is a significant cause of death. There is no widely accepted pathological assessment strategy to predict recurrent HCC after transplantation. This study compares the pathology of patients meeting Milan and UCSF criteria and develops a pathological score and nomogram to assess the risk of recurrent HCC after transplantation. All explanted livers with HCC from our center over the 18-yr period 1985 to 2003 were assessed for multiple pathological features and relevant clinical data were recorded; multivariate analysis was performed to determine features associated with recurrent HCC. Using pathological variables that independently predicted recurrent HCC, a pathological score and nomogram were developed to determine the probability of recurrent HCC. Of 75 cases analyzed, 50 (67%) met Milan criteria, 9 (12%) met only UCSF criteria and 16 (21%) met neither criteria based on explant pathology. There were 20 cases of recurrent HCC and the mean follow-up was 8 yr. Recurrent HCC was more common (67 vs. 12%; P Ͻ 0.001) and survival was lower (15 vs. 83% at 5 yr; 15 vs. 55% at 8 yr; P Ͻ 0.001) with those who met only UCSF criteria, compared to those who met Milan criteria. Cryptogenic cirrhosis (25 vs. 5%; P ϭ 0.015), preoperative AFP Ͼ1,000 ng/mL (20 vs. 0%; P Ͻ 0.001) and postoperative OKT3 use (40 vs. 15%; P ϭ 0.017) were more common among patients with recurrent HCC. While microvascular invasion was the strongest pathological predictor of recurrent HCC, tumor size Ն3 cm (P ϭ 0.004; odds ratio [OR] ϭ 7.42), nuclear grade (P ϭ 0.044; OR ϭ 3.25), microsatellitosis (P ϭ 0.020; OR ϭ 4.82), and giant/bizarre cells (P ϭ 0.028; OR ϭ 4.78) also predicted recurrent HCC independently from vascular invasion. The score and nomogram stratified the risk of recurrent HCC into 3 tiers: low (Ͻ5%), intermediate (40-65%), and high (Ͼ95%). In conclusion, compared to patients meeting Milan criteria, patients who meet only UCSF criteria have a worse survival and an increased rate of recurrent HCC with long-term follow-up, as well as more frequent occurrence of adverse histopathological features, such as microvascular invasion. Application of a pathological score and nomogram could help identify patients at increased risk for tumor recurrence, who may benefit from increased surveillance or adjuvant therapy. Liver Transpl 13:543-551, 2007.

Hepatic Resection for Hepatocellular Carcinoma Meeting Milan Criteria in Child-Turcotte-Pugh Class A Patients With Cirrhosis

“…However, these parameters have also been shown to be risk factors for tumor recurrence after primary OLT. [25][26][27][28] Therefore, patients who have tumors with such aggressive features would likely not benefit from OLT. Although the patients in this study are limited in number, we performed salvage OLT for six cases of recurrent HCC; none of them showed tumor recurrence to the present time (median follow up ϭ 24 months).…”

Milan criteria in liver transplantation for hepatocellular carcinoma: An evidence-based analysis of 15 years of experience

“…In this respect, the MC remain the benchmark for any other prognostic criteria proposed for expanding the use of LT in patients with cirrhosis and HCC. 24,40,80 or >1000 ng/mL 12,18,51 Up-to-7 criteria met 21,26 Tumor size >3 cm, 36 12,30,33 Total tumor volume >28 cm 3 35 or >115 cm 3 24 Total tumor diameter >8 cm 12,42 Bilobar nodules 66 Multiple nodules 52,71,76 Nodule number >3 25,26 and 13 level 2b studies 27,30,33,34,36,39,40,42,47,48,[51][52][53] have confirmed the likelihood of detecting mVI, grade 3 tumors, and microsatellites as the tumor size and number increase beyond the MC. In patients with HCCs meeting the MC, mVI is detected at a rate of 10% to 15%, poorly differentiated tumors are detected at a rate of 13% to 33%, and microsatellites are detected at a rate of 7% to 28%.…”

“…26,48 Similar rates of histological markers of tumor aggressiveness and poor prognoses have been detected in patients slightly exceeding the MC, such as patients meeting the University of California San Francisco criteria, 52,84 even though a significant proportion of patients meeting the University of California San Francisco criteria are meeting the MC as well. 24,34,47,51 We identified 10 studies 16,18,26,28,47,48,51,52,63,72 reporting frequency data for mVI and tumor grades in patients meeting or not meeting the MC, and a meta-analysis of the odds ratios was performed accordingly (Fig. 3).…”

“…39,63,77 In agreement with the proven role of AFP as a prognostic tool (rather than a diagnostic tool) for HCC, high serum levels of AFP have been correlated with a deterioration in the prognosis of patients with tumors belonging to the MC category, even though a precise cutoff is missing (Table 3). Although the strength of the evidence is impoverished by the suboptimal quality (average NOS score ¼ 6) and the limited number of studies, 12,18,20,24,35,36,[38][39][40]51,54,65,80 AFP in clinical practice represents a quite reliable and noninvasive tool for capturing potentially more aggressive HCCs within the MC. In some centers, values > 400 or >1000 ng/mL are often important determinants for delisting patients otherwise eligible for LT. 24,119,120 4.…”

Patient Transplant Survival Not Influenced by Type of Liver Graft

“…[4][5][6][7][8][9][10][11] There is general agreement that clinical tumor characteristics are not ideal for predicting HCC recurrence after liver transplantation. The future winner of the contest to accurately predict HCC recurrence has not yet established a clear lead.…”