In this study of 223,660 recipients of a solid organ transplant, the incidence of de novo
HCC was notably increased among recipients of a liver but not of a non-liver transplant when compared with the general population. The absence of an overall elevated risk among non-liver transplant recipients is consistent with results from studies of kidney transplant recipients in Canada (4
) and solid organ transplant recipients in Sweden (84% of whom were kidney recipients) (14
). It contrasts with a recent Australian study that reported a three-fold elevated risk of liver cancer following kidney transplantation (2
). These prior studies were much smaller than the present study (i.e., 5,931–11,155 vs. 178,367 non-liver recipients). Also unlike the present study, which relied upon transplant center reports of HCC, the prior studies utilized linked data from cancer registries (2
). Therefore, the apparent differences in HCC risk across these four studies could be due to imprecision in risk estimates due to the rarity of HCC, differences in cancer ascertainment, or differences in the prevalence of HCC risk factors. To our knowledge no large study reporting incidence of de novo
HCC in liver recipients exists with which to compare our findings.
Differentiation between de novo
and recurrent HCC among liver recipients is essential to measure incidence and assess risk factors. Among liver recipients, part of the elevated HCC incidence within the first years after transplantation may represent recurrence of occult tumors not detected during pre-transplantation screening or on examination of the explanted organ. Recurrent HCC has typically been described to arise within several years of transplantation (median time to HCC recurrence 11–21 months) (16
). This early recurrence is also consistent with the doubling time of HCC (80–200 days) (18
). Although delayed recurrence of HCC has been reported (19
), the occurrence of HCC later after transplant is most consistent with the development of de novo
tumors. Given the rarity of other cancers in donors, we believe that unsuspected transmission of other cancer types, with subsequent seeding of the liver, did not contribute substantially to our results.
Although overall HCC incidence was not elevated among non-liver recipients, we identified several risk factors associated with increased HCC risk in this population. As seen in the general population, HCV infection, HBV infection, and diabetes mellitus were all strongly associated with development of HCC. In addition, the hazard ratios that we estimated were similar to relative risks reported for the general U.S. population, i.e., 1.3–17 fold for HCV antibody positivity (20
), 5–15 fold for HBsAg positivity (22
), and 2.5 for diabetes mellitus (7
). Among people with AIDS (another immunosuppressed population), HCV infection is estimated to increase HCC risk 2.4-fold (10
). Two other risk factors associated with HCC in the general population, age and male sex, were associated with HCC incidence in univariate analyses but were no longer significant in a multivariate regression model because of their relationships with HCV status, HBsAg status, and diabetes mellitus.
Among liver transplant recipients, HCC risk was associated with HCV infection, diabetes mellitus, male sex, and older age at transplant. We did not find an association between HBsAg positivity and HCC in multivariate modeling overall, although HCC cases arising late after transplant were more likely to be HBsAg positive (). Our finding of a lower risk related to HBV infection than previously reported in other populations may reflect the slow progression of HBV-mediated HCC (23
), and with long-term follow-up greater than 10 years, it is possible that a greater impact of HBV will be observed. Another potential reason for not finding an independent increased risk conferred by HBV in the liver transplant population is the intensive prophylactic therapy used among patients with chronic HBV. Since 1999, standard practice has been to administer hepatitis B immune globulin and a prolonged course of lamivudine to HBsAg positive transplant recipients (6
). The association between HCV infection and HCC risk was also noticeably weaker among liver recipients than in the general population, perhaps because of the potential for HCV to increase risk for graft failure or death from other causes. These competing risks arise from rapid re-infection of the liver graft by HCV following transplantation and progressive liver disease (6
Several negative observations should be addressed. First, the lack of association of HCC risk with rejection during the first year post-transplant or level of HLA mismatch (which correlates with more frequent rejection episodes) argues against a major effect of pulse doses of immunosuppression on HCC risk. In addition, HCC risk for non-liver recipients did not appear to increase over time from organ transplant (data not shown), which is consistent with a lack of a cumulative effect of immunosuppression. Similarly, HCC risk was not associated with use of specific immunosuppressive agents (data not shown). However, we had no information on medication dosage, we had few subjects on some medications that might modify cancer risk, including sirolimus, (25
) and we did not have data on medication changes over time.
Strengths of our study include its large size, representation of both non-liver and liver transplant recipients, and availability of data on several important HCC risk factors. Our study also has several limitations. First, we did not have complete follow-up on subjects. Individuals transplanted before 1999 contributed only to later follow-up, while those transplanted after 1999 contributed to earlier follow-up. If there have been substantial changes in HCC risk factors over time, this difference in follow-up could have introduced bias. Therefore, we were unable to reliably examine changes in HCC incidence according to time since transplantation. An additional limitation is that, while many subjects contributed follow-up time for various intervals in the first 10 years post-transplant, there was little follow-up beyond this period, so we could not fully evaluate late HCC risk. Second, we may have missed some cases of HCC. We evaluated follow-up time starting with 1999, but even with improvements in follow-up, we may still lack a complete record of HCC cases. Furthermore, under-ascertainment may have been higher for kidney recipients and could have increased over time since transplant, because such transplant recipients may have transferred their care back to community providers. If under-ascertainment occurred, the incidence for the non-liver recipients may have been underestimated and the SIR for the non-liver group incorrectly low. An additional limitation is that we were missing data on important characteristics for some recipients. For example, information regarding HCV status was unavailable for 25% of the subjects. Furthermore, approximately 20% of individuals with HCV antibodies do not have active infection as a result of earlier clearance (26
). We did not have complete data on plasma HCV RNA levels, which would have allowed us to distinguish between chronic and resolved infection, and including individuals with resolved HCV infection may have slightly attenuated the association between HCV and HCC. In addition, we anticipate some misclassification among liver allograft recipients who had occult HCC at the time of transplant and developed recurrent rather than de novo
HCC. Finally, HCC is rare, limiting the study’s power to fully explore factors potentially associated with HCC.
In conclusion, we identified an increased risk of HCC among liver transplant recipients, as well as several strong risk factors for HCC in both liver and non-liver recipients. This information may be useful for management of patients post-transplant. Our findings support the value in suppressing chronic viral hepatitis infections among solid organ recipients, both liver and non-liver. Furthermore, our results suggest a positive impact related to suppression of chronic HBV infection and add further reason to accelerate efforts to develop therapy to suppress HCV replication and protect liver allografts from HCV infection when transplanted to an HCV positive recipient. Continued long-term follow-up will be important to further assess the impact of viral hepatitis infection and to explore the long-term impact of immunosuppression on development of HCC.