The reality of de novo malignancy: Sadly, not fake news

De novo malignancy (DNM) in liver transplantation recipients (LTRs) is a leading cause of longterm mortality. DNM can be at least partly attributed to infection with oncogenic viruses and to the loss of immunogenic surveillance in the setting of immunosuppression. In this issue of Liver Transplantation, Rademacher et al. report their experience in 1616 adult LTRs who were prospectively followed for up to 3 decades (median follow-up approximately 14 years). In a predominantly Caucasian population, 16.5% of recipients developed DNMs, which included solid organ tumors (59%) followed by skin tumors (26%) then hematologic malignancy (15%). The 10-year probability of developing a DNM was 12.9%, somewhat lower than what had been reported previously (up to 20%22%). Although more than half of the DNMs in this study were solid organ tumors, the skin cancer rate was well below previously published rates, impacting the overall DNM rate. The exclusion of high-grade colon dysplasia in this study also affects comparison of incidence rates. Variability in reported DNM incidence in different studies may reflect varying environmental exposures, specific immunosuppressive regimen, or diverse genetic predisposition. Additionally, retrospective data undoubtedly fail to capture 100% of cancers. Thus, reported incidence rates should be regarded as the lower end of the spectrum. In the current study, the authors confirm that the risk for any DNM was higher in patients with advanced age, as in other studies. A surprising observation was an apparent lower risk in patients with primary sclerosing cholangitis (PSC). While the authors astutely highlight that the low rate of smoking in this PSC cohort could contribute to lower DNM risk, this difference could also be explained by fewer patients with PSC and possibly different prevalence of inflammatory bowel disease (IBD) or colectomies that were not evaluated in the current study. Changing indications for LT will also affect cancer incidence rates. Patients with chronic hepatitis C virus (HCV) were at higher risk for posttransplant lymphoproliferative disorder but at lower risk for solid organ malignancies. The current era of DAAs and HCV eradication will likely see this risk diminish, but increased anticipated longterm survival may see increased rates of other malignancies. Because the HCV-infected recipients underwent transplantation prior to 2006, one can assume they were viremic, and recurrence of HCV can be implicated in the lymphoma risk. Rademacher et al. affirm the observation previously noted by Tjon et al. that cyclosporine-based immunosuppression increased the risk for DNM, particularly for solid organ tumors. The data presented are confusing, however, as a univariate analysis of a subset of patients receiving prolonged tacrolimusor cyclosporine-based regimen support this link, but once corrected for other risk factors (in the Supporting Table) the opposite is true. Additionally, when comparing calcineurin inhibitor (CNI) effects over 28 years of follow-up, care must be taken to account for era effect and dosing. Higher CNI dosing is related to increased risk, as shown by Carenco et al., whereas high tacrolimus trough levels (> 8 ng/mL during the first year and > 7 ng/mL during the 3 years after transplant) were associated with de novo solid organ tumors. Aguiar et al. recently reported that LT recipients who were switched from a CNI-based regimen to mycophenolate mofetil monotherapy had a lower risk for developing DNM. Higher level immunosuppression and CNI-based immunosuppression are clearly implicated in an increased risk of DNM. Consistent findings from this and similar studies are that malignancies such as lung cancer, oropharyngeal cancers, gastrointestinal cancers (in other studies with Abbreviations: CNI, calcineurin inhibitor; DNM, de novo malignancy; HCV, hepatitis C virus; LTR, liver transplantation recipient; PSC, primary sclerosing cholangitis.