Liver Transplantation for NASH-Related Hepatocellular... : Transplantation (original) (raw)
Hepatocellular carcinoma (HCC) in the context of nonalcoholic steatohepatitis (NASH) is becoming the fastest growing indication for liver transplant (LT) for HCC in the United States.1 Traditionally, HCC has been associated with liver diseases that lead to chronic inflammatory changes of the liver, and hence contribute to carcinogenesis including cirrhosis from hepatitis C, hepatitis B, and alcohol-induced injury. In the recent past, there has been much interest in the newly growing body of evidence that supports the association between HCC and nonalcoholic fatty liver disease (NAFLD), and its respective spectrum of pathology.1-11
NAFLD is the most common cause of liver disease worldwide.12 It is estimated to affect approximately 30% of the general population in developed countries, however the prevalence ranges from 75% to 92% in patients with morbid obesity.13-17 NAFLD comprises a spectrum of histopathology including steatosis to steatohepatitis (NASH) with or without cirrhosis, with the potential of HCC development.18 Of those with NAFLD, it is estimated that 15% to 20% have NASH.19 It is in the setting of NASH cirrhosis that HCC develops, with an estimated incidence of 2.6% per year.10 Although the incidence of HCC in patients with NASH cirrhosis is lower than those with viral hepatitis, the increasing prevalence of NASH in the general population is likely a major contributor to the reason HCC is becoming the fastest growing cause of cancer death in the United States.20 Therefore, there is a need to better understand the best oncologic management of HCC in the context of this liver disease.10,21
LT is the most effective treatment for selected HCC as it eliminates the primary tumor(s), as well as the field effect of the underlying disease process.22 LT for HCC from all causes has demonstrated excellent 1- and 5-year survival rates of 85% and 70%, respectively.23 Less well understood is the success of LT specifically in the context of NASH-related HCC. Given that the pathophysiology for the development of cancer in this context may be different, the results after LT may be different too.24-30 To the best of our knowledge, there have been few studies to describe the outcomes of LT for patients with HCC in the specific context of NASH cirrhosis and the number of patients that received a LT in those series has been few.
The goal of this study was to characterize the specific population of patients with NASH-related HCC who underwent LT and to ascertain if the “oncological” outcomes are different than in patients with end stage liver disease from other etiologies.
MATERIALS AND METHODS
Patient Characteristics
This was a dual-center retrospective cohort design study. Patients who received a LT for a primary diagnosis of HCC between January 1, 2004, and December 31, 2014, from 2 major transplant centers in North America (University of Toronto [U of T] and University of California San Francisco [UCSF]) were reviewed. Patients with incidental tumors at the explant were excluded. Prospective data was collected at each respective center upon Research Ethics Board approval. This information contributed to retrospective databases, which were collected at each respective center, and then collated for analysis purposes for this study.
Demographic data included age and sex. Clinicopathologic data included underlying liver disease diagnosis, date of radiographic diagnosis of HCC, and tumor features (number and size) at time of diagnosis. Transplant-related data included date of listing, tumor features at time of listing, number and modality of bridging therapies received awaiting transplant, date of transplant, type of graft transplanted, and serum alpha-fetoprotein (AFP) (ng/mL) at the time of transplant. Histopathologic data of the explant included number and size of viable tumors, tumor grade, and microvascular and macrovascular invasion. Only tumors that had viable cells were included in the analysis for tumor number and size. This means that tumors with no viable cells at time of explant were not included in final tumor counts.31 Posttransplantation data included recurrence, date of recurrence, site of recurrence, and treatment of recurrence. Status was recorded at last point of contact with patient deceased or living.
Patients were stratified by etiology of underlying liver disease into 2 groups: NASH versus non-NASH groups. NASH was defined according to histological features where biopsies were available; from explant pathology; or from a clinical diagnosis where in the presence of metabolic risk factors, the absence of alcohol intake and cryptogenic cirrhosis—a diagnosis of NASH was assumed.10 The diagnosis of HCC was made based upon American Association for the Study of Liver Diseases/European Association of the Study for the Liver Criteria with radiographic confirmation from computerized tomography (CT) scan or magnetic resonance imaging (MRI).32 Surveillance ultrasound was not considered a diagnostic modality, thus date of diagnosis was based on time of confirmatory imaging with CT scan or MRI. Outcome measures included long term overall survival and disease-free survival.
Data Analyses and Statistics
Data are given as counts and percentages for categorical data; means and standard deviation were used when continuous data was normally distributed, and medians and interquartile ranges if they were not. Parametric, nonparametric statistical tests and survival analysis with Kaplan-Meier Curves were used. Mann-Whitney U test of comparison of independent samples’ medians was used on non-normally distributed continuous data. Pearson chi-square test was used for categorical data. Fisher’s exact test was used when cell sizes were less than 5. Significance level was set at α = 0.05. Finally, both univariate and multivariate Cox proportional regression models were performed to identify significant risk factors for recurrence among all patients. Univariate Cox Regression analysis was performed, and variables with P values less than 0.25 were included in the multivariate analysis. All assumptions for the final model were checked and met including the absence of multicollinearity and proportionality of hazards. As an exploratory analysis we then identified risk factors for tumor recurrence based on disease severity as stratified by within or beyond Milan criteria at explant pathology. For the Cox regression, categorical variables were dichotomized into subsets: NASH status versus not, hepatitis C virus (HCV) status versus not, microvascular and/or macrovascular invasion versus not (“vascular invasion”), poorly differentiated versus not, and serum AFP greater than versus less than 400 ng/mL. A serum AFP level of 400 ng/mL was chosen as the cutoff as this level is acknowledged in current literature to be a level of clinical significance in patients with HCC and eligibility for transplant.33 Study period was also included in the Cox regression to address possible era effect. This variable was dichotomized between the first and last half of the study period: 2004 to 2009 versus 2010 to 2014. HCV status was included in the Cox regression because it was felt that this etiology of HCC could confound the regression results as it has been shown in the literature that this population typically has worse transplant outcomes.34 All analyses were performed using SPSS 23.0 (IBM Corporation, Armonk, NY). The median follow-up from the time of transplant was 56.1 (29.2-82.2) months.
RESULTS
Between January 2004 and December 2014, 929 patients were transplanted for HCC. Of these, 60 (6.5%) of 929 had HCC with NASH as the underlying disease and 869/929 (93.5%) had other etiologies of liver disease (Table 1). At UCSF, 32 (7.3%) of 440 had HCC with NASH, comparable to the 28 (5.7%) of 489 at U of T. The proportion of LT performed for NASH-related HCC significantly increased over time (2004-2009 4% vs 2010-2014 9.2%; P = 0.001) (Figure 1).
Preoperative characteristics of patients
Number of LTs for NASH-related HCC from year 2004 to 2014.
Center differences for patient preoperative characteristics are demonstrated in Table S1, SDC (https://links.lww.com/TP/B512). Statistically significant differences existed between U of T and UCSF with respect to age, sex, etiology of liver disease, tumor number, median time on the waitlist, use of bridging therapy, use of transarterial chemoembolization (TACE), tumors within/beyond Milan criteria, and type of graft used.
In terms of demographics, significant differences were found in regards to age and sex between the NASH group and the non-NASH group (Table 1). The NASH group median age was significantly older than the non-NASH group (63.1 years vs 58.8 years; P < 0.001). Furthermore, the NASH group included significantly more females than the non-NASH group (38.3% vs 18.5%; P < 0.001).
There were no significant differences between NASH and non-NASH groups for pretransplant tumor characteristics including number and size of tumors at time of diagnosis (Table 1). The proportion of patients receiving bridging therapies was similar (86.7% NASH vs 82.1% non-NASH; P = 0.373). However, more NASH patients received TACE than the non-NASH group (63.3% vs 48.7%; P = 0.028). There was no difference between groups for time on the waiting list for transplant (7.8 months NASH group vs 7.4 months non-NASH group; P = 0.682).
The explant pathology characteristics were similar between NASH and non-NASH groups (Table 2). The median number of viable tumors at time of explant was not different between groups. The median tumor size of the largest lesion at the explant was also not different between groups (2.3 cm NASH vs 2.0 cm non-NASH, P = 0.096). In each group, approximately 31% of the tumors were beyond Milan criteria. There was no statistically significant difference in the rate of microvascular (26.7% NASH vs 17.1% non-NASH, P = 0.06) or macrovascular (1.7% NASH vs 4% non-NASH, P = 0.36) invasion between groups. There were no differences in the tumor grade between groups. At time of explant, nonviable tumors were present in 18.3% and 22.6% of the NASH and non-NASH groups respectively, and thus grade could not be determined in these patients.
Explant pathology characteristics and outcomes for patients transplanted for HCC
Tumor Recurrence After Liver Transplantation
The proportion of patients with tumor recurrence was 13.3% in the NASH group versus 14% in the non-NASH group (P = 0.879). There was no difference in the number of recurrences, nor the frequency of recurrence location between groups, although both groups showed a greater proportion of extrahepatic recurrences (87.5% NASH group vs 50.8% non-NASH group, P = 0.12). Both groups' cases of recurrences had similar rates of surgical treatments (37.5% NASH group vs 29.1% non-NASH group), nonsurgical treatments (50% NASH group vs 52.1% non-NASH group), or best palliative care (12.5% NASH group vs 18.8% non-NASH group, P = 0.84).
Overall Survival After Liver Transplantation
Overall survival and disease-free survival between the NASH and non-NASH groups were not significantly different (Figure 2 and Figure 3). The actuarial 1-, 3-, and 5-year survival was 98%, 96%, and 80% in the NASH group versus 95%, 84%, and 78% in the non-NASH group (P = 0.1). Within the NASH group, 7 patients died during follow-up. In 4 of these cases, the cause of death was late recurrence (approximately 4 years after LT).
Overall survival between NASH and non-NASH groups.
Disease-free survival between NASH and non-NASH groups.
Survival analysis was then performed based on Milan criteria, stratifying the groups by within or beyond Milan criteria on explant pathology. There were 290 patients that were beyond Milan criteria; 19 in the NASH group and 271 in the non-NASH group. In the beyond Milan strata, the tumor recurrence was 10.5% in the NASH group versus 29.2% in the non-NASH group (P = 0.079). Within these patients there was no significant difference in terms of overall survival or disease-free survival. The 1-, 3-, and 5-year actuarial survival was 95%, 89%, and 89% in the NASH group versus 94%, 75%, and 66% in the non-NASH (P = 0.08; Figure 4). The 1-, 3-, and 5-year disease-free survival was 89% at all time intervals for the NASH group versus 87%, 71%, and 68% in the non-NASH group, P = 0.113. When only tumors within Milan criteria were considered, HCC recurrence was 14.6% in NASH and 7.2% in non-NASH, P = 0.08. There were no significant differences in the HCC recurrence rate in the NASH group between the within and beyond Milan HCC patients (14.6% vs 10.5%, P = 0.5). Conversely, the recurrence rate was 7.2% in the within Milan non-NASH group compared with 29.2% in the beyond Milan non-NASH group (P < 0.001). There were no statistically significant differences between HCC tumor factors (tumor size, tumor number, differentiation, vascular invasion, AFP) between NASH and non-NASH groups, specifically at the beyond Milan stratum (Table S2, SDC, https://links.lww.com/TP/B512). Although not statistically significant, the proportion of patients with microvascular invasion in the NASH group was 57.9% versus 36.6% in the non-NASH group (P = 0.07).
Overall survival between NASH and non-NASH groups for beyond Milan criteria only.
Predictors of Outcome
Among all patients transplanted for HCC, the univariate analysis revealed study period, pretransplant Milan status, Milan status at explant, microvascular and/or macrovascular invasion, serum AFP at the time of transplant, and tumor differentiation as significant predictors for recurrence (Table 3). These factors were then used in the multivariate Cox regression for all patients. The multivariate analysis demonstrated Milan status at explant and vascular invasion as significant predictors for recurrence (Table 3).
Univariate and multivariate Cox Regression analyses of disease-free survival for all patients that were transplanted for HCC
This analysis was then repeated with stratification by Milan status: within and beyond Milan Criteria (Table 4). For the cohort of patients within Milan criteria, the significant predictors of recurrence for the univariate Cox regression were vascular invasion, tumor differentiation, AFP at time of transplant, and NASH status. The multivariate Cox regression with these variables resulted in vascular invasion as the only significant factor to predict disease-free survival (hazard ratio [HR] 4.6; 95% confidence interval [CI], 2.5-8.7; P < 0.001). For the beyond Milan criteria cohort, the univariate Cox regression revealed vascular invasion, AFP at time of transplant, NASH status, and study period as statistically significant predictors. For the multivariate model, vascular invasion appeared as a risk factor (HR, 4.3; 95% CI, 2.7-6.9; P < 0.001) for recurrence, whereas NASH status was protective in patients with beyond Milan tumors (HR, 0.2; 95% CI, 0.05-0.9; P = 0.029).
Univariate and multivariate Cox Regression analyses of disease-free survival for patients stratified for within and beyond Milan Criteria at explant that were transplanted for HCC
DISCUSSION
This is one of the largest cohort studies comparing the outcomes of patients with NASH and non–NASH-related HCC after LT with a comprehensive median follow up period. We have demonstrated that the overall outcomes of LT in these populations are similar. Interestingly, we found that patients with beyond Milan tumors may do better after LT if they have NASH cirrhosis as compared with other indications, but this deserves further study and at this point this finding is only hypothesis generating and should not be implemented into clinical decision-making.
NASH-related HCC is the fastest-growing indication for LT in the United States.1 This trend is also true for the current study which had a significantly higher number of LT for NASH-related HCC in the last 5 years of the study period, compared with the first 5 years. The preoperative tumor characteristics were similar in the 2 groups in this study with the exception of TACE therapy, which was more frequently used in NASH recipients. Even though there were no statistical differences in the size of the tumor pretransplant between groups, it can be inferred that clinically, tumors were too large (median, >3 cm) in the NASH group to undergo radiofrequency ablation. Explant findings were also similar, suggesting that both groups had similar stage disease and response to bridging therapies.
There were center differences observed between the 2 study sites. Age, sex, and etiology of liver disease and tumor number were statistically significant, but unlikely to be clinically relevant. UCSF had significantly greater rates of bridging therapy and lower rates of living donor grafts, and this likely correlates to the longer time on the waitlist. TACE was more often used at UCSF, but was generally used more than radiofrequency ablation in the entire cohort. A priori, the decision to focus the analysis on the entire cohort was made, despite these center differences given that an impact of these differences on the primary outcome was thought to be unlikely. Even though there were some statistical differences between centers, we believe that this multicenter, international study reflects varied real-world practice patterns and thus our findings are likely more valid and generalizable than if data from only a single center had been used.
Previous studies have also shown that NASH patients with HCC have good outcomes with LT. Reddy et al34 analyzed a cohort of 52 patients with NASH-related HCC with respect to outcomes of curative intent treatments including ablation, resection, and LT. Of these patients, only 20 were transplanted for NASH-related HCC. In their study they found better overall survival for patients with NASH cirrhosis compared to patients with HCV infection or alcohol induced cirrhosis after curative treatments but no information on the outcomes after LT specifically, was available from this comparison. A second, more recent study by Weinmann et al35 analyzed treatment and survival of 1119 patients with HCC, 45 of which were NASH-related. In their study, they reported no difference in overall survival among all curative treatments for patients with NASH and non–NASH-related HCC.35 Only 2 NASH-related HCC cases underwent LT for treatment, and therefore no conclusions on the results of LT for NASH-related cirrhosis can be drawn.35 In the current series, up to 60 patients were transplanted with NASH-related HCC between both centers. Most recently, Lewin and colleagues36 used data from a national database to characterize the association between underlying etiology of liver disease at time of transplant listing with tumor features of HCC on explant. In this study, 271 patients with NASH-related HCC were analyzed. It was demonstrated that NASH-related HCC was associated with lower likelihood of high risk tumor features on explant. The main limitation of that study was that it was performed using a national database36 and thus was not able to capture the granularity allowed for with the present multicenter study such as type of local-regional treatments received or accurate characterization of HCC recurrence (given that recurrence is likely under-reported in the United Network for Organ Sharing database). Additionally, explant pathology was only available in United Network for Organ Sharing since April 2012, whereas the present study dated back to 2004 allowing for characterization of temporal trends in LT for NASH-related HCC over a much longer follow-up period.
An exploratory analysis was performed to identify prognostic factors and assess if NASH status could impact recurrence after transplant in beyond Milan tumors. Our multivariate analysis showed an 80% decrease in the hazard of recurrence in those patients with more advanced tumors (beyond Milan criteria) in the NASH group compared to the non-NASH group when adjusting to other covariates of interest and well described risk factors for tumor recurrence. Importantly, the study period was taken into consideration to explore a possible era effect to explain this finding, especially as it was demonstrated that over the course of the study period more transplants were completed for NASH-related HCC. The study period was not a significant predictor of disease-free survival in the multivariate model among all patients transplanted, nor at the beyond or within Milan subgroup analysis. Even though we considered that HCV treatment could modify the results of our model, direct-acting antivirals and their relationship to HCV clearance was not included as this treatment modality was only approved for use in 2014 in Ontario (University of Toronto), and only 3 patients from the UCSF cohort were found to have been treated in this cohort. Therefore we did not feel it was a clinically relevant factor for this study population. This will however be an important factor to consider in future cohorts, in this post–direct-acting antivirals era. On the other hand, HCV status was included as a factor in the regression model, as it has been demonstrated that patients with HCV tend to have worse outcomes after transplant, and thus we wanted to ensure this did not confound our results.34 As demonstrated, HCV status was not a significant predictor of tumor recurrence in any of the regression models. Therefore, we can infer that our findings are not simply a reflection of HCV patients having worse outcomes than NASH patients, and rather in our model NASH status itself is an independently significant predictor of tumor recurrence.
Our results suggest that the diagnosis of NASH may confer a more favorable oncologic prognosis for patients with advanced HCC. This is supported by the results of the Cox regression model at the beyond Milan level, but also demonstrated by the trend that proportionally more NASH-related HCC tumors had microvascular invasion compared to the non-NASH group, yet maintained low rates of tumor recurrence. This suggests NASH-related HCC tumors may have an intrinsic nature to be less aggressive. We are cautious in this interpretation of our results recognizing the limitations of the small sample size (n = 19), and the inherent deficiencies of a retrospective cohort design. We emphasize the hypothesis generating nature of this finding, and do not recommend that these results impact clinical decision making nor practice patterns. We look forward to other research directed towards better elucidating this relationship with more rigorous study designs. However, the notion of NASH-related HCC tumors being inherently less aggressive than other etiologies of liver disease leading to HCC has been echoed in other studies.7,11,36-40 For example, Mittal et al11 found a trend that NASH-related HCC tumors tended to be less associated with elevated AFP levels, suggesting less aggressive tumor biology. Similarly, Hashimoto and Tokushige40 found that NASH-related HCC tumors tended to have higher levels of des-γ-carboxy prothrombin and lower levels of AFP compared to HCC related to HCV. Moreover, the fact that HCC develops in noncirrhotic NAFLD suggests that there may be unique pathophysiology driving oncogenesis in NASH patients.2,25 The sequence of molecular events leading to hepatocarcinogenesis in the context of NASH is unique, with insulin resistance, oxidative stress, inflammation and fibrosis-stimulating cytokines. The hypoglycemic agent metformin is often used in frequently comorbid diabetes, and has been reported as a chemopreventive agent in HCC, potentially inhibiting HCC recurrence in the NASH patient population; further support for a unique pathogenesis.
This study has several limitations. One of the major limitations is the retrospective design which 1) precluded inclusion of granular data on changes in body mass index over time and the evolution of other metabolically-relevant co-morbidities. and 2) did not allow us to control for unknown confounding factors that may have affected the estimates and statistically significant covariates in our multivariate model. Nevertheless, our study represents the largest comparison of transplanted patients with NASH-related HCC with other HCC-related etiologies of liver disease over a long term follow-up period.
In conclusion, we found similar outcomes of patients with NASH-related HCC compared with non-NASH patients after LT. In a multivariate analysis controlling for known HCC risk factors, the diagnosis of NASH was associated with better disease-free survival specifically in patients with advanced HCC. We have generated a hypothesis that HCC developing in the context of NASH may have different pathogenesis and prognosis but this merits further investigation to better understand this relationship.
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