The overall increase in cancer risk found in our study (2.8 times) is in line with the published data of SIR for cancers related to kidney transplantation, taken from national population-based studies [7, 33].
Our results also estimate a 6-fold increase in the risk of hematological cancers, slightly underestimated compared to studies from Australia, Canada, and the USA, where an increased risk of developing lymphomas was related particularly to post-transplant lymphoproliferative disorders (PTLD) .
PTLD is one of the clinical consequences associated with EBV infection or reactivation. In fact, EBV is a ubiquitous viral pathogen, with a seroprevalence of more than 90% in adults. After primary infection, the virus persists within B lymphocytes for life with the majority of hosts demonstrating no evidence of active infection or replication. However, in kidney transplant recipients, both acute infection and reactivation of latent infection may lead to pathology, with clinical syndromes associated with non-neoplastic viral replication on one end, and EBV-mediated neoplastic transformation, including PTLD, on the other.
Transplant patients are also vulnerable to many other viral infections or the reactivation of latent infections, which can be considered one of the reasons for tumorigenesis in these subjects. Among these viruses that can cause initiation of malignancies, we can find human herpesvirus 8 (HHV-8), human papillomavirus (HPV), Merkel cell polyomavirus, hepatitis B virus (HBV), and hepatitis C virus (HCV). There is a linear correlation between the speed at which some malignant tumors develop, even after transplantation, and the initiation of immunosuppression, which could be related with uncontrolled viral replication. In support of this hypothesis, previous studies have demonstrated that recipients whose transplanted kidneys have been removed due to failure, or after reduction or cessation of immunosuppression, have lowered the risks of developing virus-induced cancers at levels observed in pre-transplant dialysis patients .
In regard to the development of KS, we found an increased risk in our population in agreement with the literature data, which report the risk of KS in solid organ transplant recipients at least 200- to 500-fold greater than in the local population [36,37,38].
The onset of KS was in all cases within 2 years after transplantation, as reported in previously published studies [38,39,40]. In four of our recipients, pre-transplant seropositivity for HHV-8 suggests rapid reactivation of latent infection favored by immunosuppressive therapy, particularly with calcineurin inhibitors.
Although screening for HHV-8 has not been routinely included in the pre-transplant guidelines and currently available serological tests are not optimal for variable sensitivity and specificity, the identification of high-risk patients would allow for careful post-transplant follow-up [41, 42].
In our study, cancer risks attributable to post-transplant immunosuppression are 99% for KS and 85% for lymphomas, while the fraction of solid tumors represents a small part of the observed cases in post-transplanted patients (38%). This result is believed to be related to impaired immune control of the oncogenic viruses (i.e., HHV-8), which can be present in the recipient prior to transplant or transmitted at the time of transplant via the donor organ.
A similar situation can be seen in patients with a compromised immune system, i.e., HIV/AIDS patients, where there is an increased risk of contracting cancers, while with post-transplanted patients, after immunosuppression withdrawal with the consequential return to dialysis regimen, we can observe a return to normal susceptibility to neoplastic risks.
This finding may represent useful information for post-transplant follow-up and the management of patient screening and monitoring. We need also to consider that the neoplastic risk is significantly increased in the first 3 years from the date of transplantation and, therefore, from the start of immunosuppressive therapy. An early diagnosis, for example, of KS, in which the mainstay of treatment is based on the minimization of the immunosuppression and treatment with an mTOR inhibitor, could be fundamental to treating cancer but also avoid graft rejection.
Another important aspect that needs to be taken into consideration is the study of pre-neoplastic lesions. Various pre-cancerous lesions were found in our analysis, but the recorded number could be underestimated. In immunosuppressed subjects, these lesions, such as pre-malignant polyps of the digestive cavity, tend to degenerate more rapidly into tumors than in the general population and must be diagnosed accurately during the follow-up before their malignant transformation .
It should be emphasized that, when comparing the neoplastic risk of the transplanted population with the one of the local population, the post-transplant path of the transplanted population should be taken into consideration.
In fact, transplant recipients are subjected to very close periodic visits by our center, considerably reducing the risk that severe complications such as tumors may not be adequately recorded, particularly in the first years of follow-up.
However, a dedicated dermatological and hematological follow-up pathway could be advisable, possibly sustained by specific guidelines. In this way, the necessary improved information of the patients concerning the post-transplant cancer risk , extremely helpful for the monitoring and compliance to follow-up, could be associated with the relief derived from the awareness solid strategy for the management of the risk.
The present study has limitations. First of all, the relatively small sample size and the retrospectively collected data do not permit a definitive conclusion about the neoplastic risk in the post-transplantation and do not allow to provide accurate estimates of the SIR for the low statistical power.
Due to the long period of years covered by this survey, the incidence rates from Italian cancer registries available at the time of the analysis were used.
Although this approach is frequently used, it should be noted that the intake of the rates is constant before and after the periods mentioned and cannot be satisfied for all the cancers analyzed. Likewise, they could not take into consideration the geographical differences in the incidence of tumors in the general Italian population due to poor coverage of extensive cancer registry areas.