Epidemiological data from 40 countries in Europe reveal the incidence of 4 million new cases of solid-organ cancer (excluding non-melanoma skin cancer; NMSC) and 1.9 million cancer-related deaths in 2020. The most common were as follows: breast in females, prostate cancer in males, colon cancer, and lung cancer in both sexes, collectively accounting for half of all cancer cases (1).

In Poland, cancer is the second leading cause of death in the general population (2–4), causing 21.8% of male deaths and 20% of female deaths in 2020 (4). They constitute a significant health problem, especially among young and middle-aged people (25–64 years old). While the incidence of malignant tumors remains stable among males, it is steadily increasing among females (3). In the female population for several years cancer has been the most common cause of death before the age of 65, accounting for 28.3% of deaths among young women and 41.6% of deaths among middle-aged women (4). Lung cancer is the predominant cancer in both sexes, accounting for one-third of all cancer-related deaths among males (3).

KTRs have a significantly higher risk of the cancer development than the general population.

This is due to the use of immunosuppressive therapy after KTX which reduces immunosurveillance against tumoral cells and promote infections with oncogenic viruses leading to an increased cancer risk.

In addition, any treatment for rejection of the transplanted organ, multidrug IS regimens or IS therapy before KTx (treatment of primary kidney disease) increases the overall “burden” of IS, which is of significant importance. KTRs are also distinguished by the fact that cysts in their own kidneys, acquired or formed in the course of ADPKD, can undergo malignant transformation over time. In addition, impaired kidney function is a significant factor increasing the risk of developing kidney cancer due to more severe oxidative stress in this population (5). As a consequence, this causes a “transfer” of cancer risk (especially of the urinary system) from the period of ESRD to the period after transplantation (Tx). All this means that kidney recipients are developing cancer at a younger age. On the other hand, standard risk factors for cancer, such as smoking, obesity, alcohol consumption, excessive exposure to ultraviolet radiation, advanced age, occupational exposure to carcinogens, or genetic predisposition, are present in the KTRs population, which, together with kidney transplant-specific factors, significantly increase the risk of cancer in this population.

Cancer is one of the three main causes of death among kidney transplant recipients (KTRs) (6–11) and thus, cancer after kidney transplantation (KTx) poses a significant challenge for clinicians.

This study aimed to retrospectively assess the occurrence of cancer within the KTRs based on data from two transplant centers.

The inclusion criteria consisted of the KTRs diagnosed with malignant neoplasia, including melanoma. The exclusion criteria included the KTRs with only NMSC and diagnosis of neoplasm after the patient’s death (in the autopsy procedure).

The group of patients with NMSC was excluded because it is a group of tumors that are characterized by a different course and different pathophysiology in comparison with solid organ tumors after Tx. In a view of the above, a separate patient database is devoted to NMSC. Only one case of a recipient in whom cancer was diagnosed in postmortem examination was excluded because it was impossible to calculate the survival time from diagnosis to death, which was of interest to us.

Moreover, this cohort excluded patients with incomplete medical documentation and patients moved to another transplant center.

All KTRs who were transplanted between 1980 and 2021 in either of the two transplant centers (TC) in Poland: the Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdansk, in Gdansk and the Departmentof Nephrology, Transplantology and Internal Medicine, Medical University of Silesia in Katowic were screened towards inclusion/exclusion criteria of our study.

Cancers with a common location and similar prognosis were analyzed together (e.g. head&neck, PTLD (regardless of immunophenotype).

KTRs with cancer diagnosis without disease recurrence 5 years after treatment were considered cured.

The cohort of 3242 KTRs screened towards the inclusion and exclusion criteria, and a total of 246 (7.6%) patients met the eligibility criteria and were included in the analysis. Among these, 140 patients (56.9%) were transplanted in the TC2. Detailed demographic and clinical characteristics of the study group are presented in Table 1 . The mean follow-up period was 35.7 months (mo) (range 0-230)/2.9y. The longest mean follow-up time was for: testis cancer (53.3 mo/4.4y), kidney cancer (48.1 mo/4y), and colon cancer (46.5 mo/3,8y). The shortest follow-up time was for: biliary tract cancer (4.5 mo/0,37y), lung cancer (9.5 mo/0,8y), and pancreas cancer (12.2 mo/1y).

Cancer, next to cardiovascular diseases (CV) and infections, is the main cause of death in patients after KTx (6–11). Data based on large databases indicate that the risk of cancer after KTx (except NMSC) is 2–3 times higher than in the general population (7, 9, 10, 12, 13). The risk is even 5–10 times higher, for cancers related to infection with oncogenic viruses such as PTLD and Kaposi’s sarcoma (7, 9).

The incidence of cancers in the general population and KTRs is distributed differently (14). In our cohort, 7.6% of KTRs developed cancers and it was similar to the other studies (7.2%, 6%, 7.6%, 6% respectively) (6, 9, 12, 15). Some literature reports have shown that males suffer from post-KTx cancer more often than females (1, 6, 9, 12, 16). Our results in the group of KTRs are in line with these observations since males constituted the majority of patients suffering from cancer.

In the general population of Poland, the most frequently diagnosed type of cancer in males remains lung cancer, prostate cancer, and colon cancer (18%, 18%, and 15% in the 2020 year, respectively) (2, 3), whereas kidney cancer is responsible for only 3.6% cancer cases (17).

Our results in KTRs revealed that the most common cancer in males was native kidney cancer (16.4%), whereas colorectal cancer was surprisingly less common (8.2%). In females, in the general population of Poland, the most frequently diagnosed cancers remain: breast cancer (25%), lung cancer (12%), and colorectal cancer (11%) in 2020 (2, 3), kidney cancer is responsible for only 2.6% cancer cases (17). In our cohort of female KTRs the most diagnosed cancer was also breast cancer (17.8%), colorectal cancer (14.5%), followed by PTLD and lung cancer (8.9%) and native kidney cancer (6.7%).

Hickman et al. observed that approximately 90% of renal cell carcinoma (RCC) is diagnosed in native kidneys in KTR (18). Our study, confirms that observation, therefore 87% of RCC were diagnosed in native kidneys, and only 13% in the transplanted kidneys. In the study by Gisco et al. (6), native kidney cancer was one of the most frequently diagnosed cancers after KTx. Moreover, Hickman et al. demonstrated even 7 times higher cases of native kidney cancer in KTRs as compared to the general population (18).

The risk of RCC development and urinary tract cancer is not only higher among patients with ESRD, but also it increases with the duration of dialysis and after KTx (19).

An association of dialysis vintage and risk of urinary tract cancers (kidney, urothelial, and bladder) after Tx has also been found by Wong et al. in the ANZDATA registry (7, 20). After KTx, the risk factors for kidney or urinary tract cancer increase due to aforementioned factors and also BKV infections (21). Additionally, in retransplants compared to primary kidney transplants in the study in United States, among all malignancies only RCC was found at a higher incidence (22). Retransplanted recipients had two-fold higher incidence of RCC than primary recipients.

The pathogenesis of RCC in CKD is not fully understood, it is suggested that is associated with renal fibrosis and tubular atrophy, chronic inflammation associated with uremia, oxidative stress, impaired immune function, the dialysis process, medications and comorbidities (7). Increased prevalence of RCC could be also explained by its association witch acquired cystic kidney disease (ACKD), which is a risk factor for RCC (18, 23). ACKD is highly prevalent in patients with CKD. In ACKD, cysts originate in dilated renal tubules, and increase in number over time, even before the need for RRT (19). After initiation of dialysis, the prevalence of cysts continues to increase, with the majority of patients having cysts after 10 years of dialysis, suggesting that the duration of CKD or dialysis is the main risk for development of renal cysts (24). RCCs can arise within complex cysts present in ACKD (25, 26). Prolonged dialysis and development of ACKD may partly explain high risk of RCC in transplant recipients and also those retransplanted.

KDIGO Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation 2020, underline these facts recommending screen with ultrasonography among kidney transplant candidates particularly those possessing following risk factors: ≥ 3 years dialysis, family history of renal cancer, ACKD or analgesic nephropathy and long term smoking. They suggest also urine cytology and cystoscopy to screen for bladder carcinoma in candidates at increased risk (high-level exposure to cyclofosfamide or heavy smoking (30 pack-years) (27).

The histopathological pattern of RCC is different in KTRs (mostly papillary, multifocal RCC) and the general population (renal clear cell carcinoma) (23, 28).

According to KDIGO, no increased rate of RCC was found among ADPKD patients (14). However, a study of removed kidneys from ADPKD showed as high as 5-8% cases of RCC. This observation raises concerns about the malignant potential in ADPKD kidneys.

In our study population, ADPKD was a cause of ESRD in 13.82% of patients. However, only one of them developed kidney cancer in a polycystic kidney.

Kidney cancer can be treated radically and the prognosis is good, in both the general and in the KTRs population (29). In our study, among patients with native kidney RCC, 82.4% are still alive. The majority of kidney cancers were detected accidentally during routine ultrasound examinations, therefore in KTRs ultrasound of the abdomen is recommended in RCC screening (30).

The peak incidence of cancer occurs 3–5 years after Tx (9, 11). In our group of recipients, most cancers occurred in the intervals 1–5 years (33.6%) and 5–10 years (34.42%) after KTx.

The risk of cancer development after KTx is influenced by pre-transplantation risk factors same as in the general population, and risk factors related to the transplantation itself such as posttransplant IS treatment. It should be mentioned, that some patients receiving KTx are already under IS treatment used in the pre-transplantation period, either due to the treatment of disease-causing ESRD or because they were already a recipient of another transplanted organ, which again increases the risk of complications of IS treatment.

In our study, 14.6% of patients receiving IS before KTx developed de novo cancers after KTx, but it was not associated with earlier development of cancer and did not contribute to poorer survival after KTx.

That’s well known, that IS drugs impair T-cell function, immune surveillance and immune control (11). TAC increases the level of TGF-B, which promotes cancer development. CsA also has a direct effect on tumor development and progression through the expression of TGF-β or IL-6 (13, 29). According to the literature, TAC increases the risk of lymphoma twice as much as CsA (13). Among older drugs, AZA increases the risk of lymphoma and NMSC (9, 13, 31).

Data from the literature suggest that less intense IS significantly reduces the risk of cancer, although increases the risk of rejection (32).

We showed that the use of induction and the IS regimen with TAC and MMF predisposed significantly to the earlier development of cancer, which is in line with the literature.

The risk of developing cancer after KTx is additionally increased in infection with oncogenic viruses promoted by IS (6–10, 12, 13, 32). For example, the HHV-8 virus increases the risk of developing Kaposi’s sarcoma 20 times (7, 10), and the human papillomavirus (HPV) increases the risk of cervical cancer 5–10 times (7), additionally, HPV is a risk factor for anus, penis, and vagina, oropharyngeal cancers (32) and may also cause genital warts in the urinary bladder with a high malignant potential in immunocompromised patients (21). In our study of cancers there were no data regarding the viral status thus, the coincidence with mentioned viral infection could not have been analyzed.

The cases of PTLD is also increased in the case of Epstein -Barr virus (EBV) infection (7, 33), while the BKV increases the risk of urinary tract cancer, hepatitis C, B virus increases the risk of liver cancer (6, 7, 12, 13, 21).

According to literature data, the EBV is the cause of approximately 60-90% cases of PTLD (9, 11, 29, 33). The use of polyclonal antibodies was associated with consistently higher risk of lymphoma (13). Due to the non-specific symptoms of PTLD, the disease is often diagnosed late (over two years after Tx) (33). The average time from diagnosis of PTLD to death is 6 months according to literature data (34). The incidence of PTLD was associated with administration of the induction therapy and the prognosis of these patients was unfavorable. In our study, PTLD was the fourth most common cancer after KTx. In both univariable and multivariable analyses, we found that induction therapy was associated with an increased risk of death in patients suffering from PTLD.

After developing cancer, the risk of death among KTRs increases (6, 16). Taborelli et al., compared KTRs with and without cancer. The 5-year survival rate among KTRs with cancer (without NMSC) was 63%, and the 5-year survival rate among KTRs without cancer was 89% (16). In another study, 46.2% of KTRs died due to cancer, and our study also showed a similar (48.8%) percentage of deaths (6). In a South Korean study, Jeong et all, showed that mortality associated with cancer after transplant was 14.9% (12). The difference may be because Jeong, unlike us, includes skin cancer, which has a very good prognosis. In our study death over 6 months from cancer diagnosis occurred in nearly half of the patients which suggests a significant advancement of cancer at the time of diagnosis. We compared patients who died in the course of cancer (regardless of the type of cancer) and those who were cured, the latter differed significantly from the former in terms of baseline nephropathy and induction treatment. In both univariable and multivariable analyses, we found that induction therapy was associated with an increased risk of death only in patients with lung cancer or PTLD. In contrast to the risk of cancer development, we did not observe significant differences in the risk of death between patients treated with TAC versus CsA or patients treated with MMF versus AZA.

In the Benoni study, patients with cancer after solid organ transplantation were compared with patients with cancer without transplantation (35). There was a 35% higher death rate among solid organ recipients. A higher mortality rate was observed among patients with lymphoma, melanoma, urothelial cancer, breast, head and neck, and colorectal cancer. There was a similar percentage of deaths between both groups among patients with prostate, lung, and kidney cancer.

According to KDIGO in recipients diagnosed with cancer before KTx, the risk of death due to cancer is three times higher than among recipients without a history of cancer (7).

In another study, Dahle et al. (36) compared KTRs with a history of cancer before transplantation (6.4%) with recipients without a history of cancer. Follow-up lasted 6.8 years, 13.7 died due to cancer recurrence, and 10.5% died due to de novo cancer. Regardless of whether the recipient suffered from cancer before or after KTx, when they suffered from cancer, they had similar overall survival (36). The greatest number of people cured were in the group of recipients who suffered from RCC, PTLD, prostate cancer, and colon cancer.

The 5.8% of KTRs in our cohort suffered from cancer before transplantation, in three cases recurrence of the disease was observed. All three recurrences were breast cancer, mean time from transplantation to recurrence was 70 mo/5.8y (range 10-118), two patients died.

Although the exact number of donor- transmitted malignancies is not known, based on the available registries and published data, the risk is approximately 0.05% (37). United Kingdom Transplant registry from 10-year period described the risk of transmission as 0.06% (these included 14–986 donors) (38). Spanish registry (39), based on a data from 1990 to 2006 year assessed the risk of transmission of malignancy to the recipients as 0.06%. Italian registry documented that the risk of transmission was 0.03% (40). Although the risk of transmission is rare but it has serious consequences (41). To ascertain the origin of the neoplasm, immunohistochemistry and molecular analysis can be employed (fluorescence in situ hybridization, microsatellite allelic analysis, and comparative genomic hybridization (41).

The presented study has some limitation: 1) the studied group of recipients is medium-sized, 2) in 3.65% of patients, who started RRT or were transferred to another center, we do not know what happened afterwards and 3) statistical analysis regarding death from any cause vs. alive is subject to the risk of systematic error (bias) because there are no people without cancer in the database. 4) Dosages and IS drug levels were not included because most of these data are limited.

The presented study shows a different distribution of cancer cases in patients after KTx as compare to the general population.

Patients after KTx require regular screening for neoplastic diseases, with particular emphasis on neoplastic diseases of the urinary system. Our findings support the need for RCC screening in all transplant candidates and recipients. This procedure should be obligatory in all candidates before including on waiting list and individualized after KTx. Recommending an annual inspection by ultrasound particularly in patients with suspicious lesions such as ACKD seems reasonable. All those possessing other pretransplant conditions mentioned in KDIGO guidelines should also be checked on individual way.