Key words : De novo cancer, Renal transplantation, Skin cancer

Introduction

The preferred choice of therapy for patients with end-stage renal disease is kidney transplantation (KTx). The long-term outcomes of recipients have improved as a result of the progress in immunosup-pressive treatment modalities and surgical proce-dures over the years.¹ However, factors such as nonspecific immunosuppression, the direct onco-genic potential of immunosuppressive drugs, and virus-induced oncogenesis enhance the risk of developing malignancy in KTx recipients.^2-5

The current data define some epidemiological aspects of posttransplant malignancies. The risk of de novo carcinogenesis is greater than the risk of donor-associated neoplasia or recurrence of a preexisting malignancy.^1,3 Different incidence rates have been reported from various parts of the world, for example, 14.2% in Scandinavian populations,6 12.2% in Austrian recipients,² 9.4% in Portugal,⁷ 7.8% in Iran,⁸ 7.7% and 6.3% in Far East populations,^9,10 and 6% in Slovakia.¹¹ Skin, lip, lymphoma, and thyroid malignancies are common in European countries.^2,7,11 In contrast, urogenital and gastro-intestinal malignancies are common in the Far East.^9,10,12,13 The differences in the incidence of cancers and the most common tumor types in Turkey over time are remarkable. According to previously published studies, the incidence was between 3.7% and 4.5%, and the most common cancer was Kaposi sarcoma.^14,15 However, the latest data have shown an increased incidence to 6.8%, and the most common tumors are now skin cancers.^16-18

In recent years, some studies examining the development of de novo malignancy in solid-organ transplant patients have focused on site-specific cancer risk rather than the types of cancer. In these series, in which liver, heart, pancreas, lung, or KTx cases were assessed collectively, it was determined that the malignancy risks were raised specifically in the head and neck region.^19-23 There are few investigations that have explored the issue solely in KTx recipients.^24,25 To our knowledge, no data have been presented on this topic in Turkey.

The aim of this study was to investigate the characteristics of de novo malignancies occurring in KTx recipients followed in a tertiary hospital in Turkey and to examine those developing in the head and neck region as a subgroup.

Materials and Methods

In this retrospective and single-center study, which was started after the approval from the local ethics committee (104-11/2021), all protocols were carried out in accordance with the Declaration of Helsinki.

The data of 286 KTx recipients treated at our institution between January 2010 and July 2022 were retrospectively searched from hospital records. Exclusion criteria were pretransplant cancer diagnosis (n = 1), donor-associated neoplasia (n = 2), foreign nationality (n = 2), primary failed KTx (n = 3), and missing data (n = 47). The type and date of malignancy were noted according to the pathologists’ reports. In situ malignancies, malignancies developing after graft loss, and benign lesions were not assessed. For the 231 included patients, the time from transplant to first cancer diagnosis, allograft loss, death, end of follow-up, or end of the study (July 25, 2022) was recorded as follow-up time, whichever arose first.

In our center, chest radiography (and computed tomography if necessary), renal Doppler/abdominal ultrasonography, stool occult blood test, serum alpha-fetoprotein, and prostate-specific antigen levels (in men) are screened annually. It is also recommended that women have a gynecological examination and Papanicolaou smear test once per year and breast ultrasonography/mammography after the age of 40 years.

Statistical analyses
We used the Statistical Package for Social Sciences (SPSS, version 22.0) software for statistical analyses. In all analyses, P < .05 was considered as the statistical significance limit.

We used the t test or Mann-Whitney U test for paired group comparisons. Results were presented as mean ± standard deviation (SD) or median and interquartile ranges (IQR, 25-75 quartiles), depending on their distribution. The categorical data were analyzed with chi-square or the Fisher exact test, with results shown as frequency and percentage. Possible risk factors for de novo malignancy development (the dependent variable) were analyzed with univariate Cox proportional hazards models. Donor type (deceased or living), donor age and sex, recipient age and sex, smoking status, the primary cause of kidney disease, duration of dialysis before transplant, history of retransplant, type of induction immuno-suppressive agent, type of maintenance immuno-suppressive agents, and history of acute rejection were assessed as independent variables. Those with P < .05 in univariate analyzes were evaluated as candidates of independent predictors in multivariate analysis by adjusting for age and sex. The Kaplan-Meier method (event = death) and the log-rank test were used to analyze survival.

The risk of developing malignancy in KTx patients compared with the general population was evaluated using a standardized incidence rate (SIR) with 95% CI for periods of transplant function. The expected number of cancer cases/cancer incidence rates for the general population were obtained from Turkish data from the International Agency for Research on Cancer.²⁶ Time at risk for malignancy development was defined as the time from the first KTx to the first cancer diagnosis, graft loss, death, date of the last follow-up, or study completion.

Results

The general characteristics of 231 patients (165 males, 71.4%) are listed in Table 1. The mean age of patients at the time of KTx was 36.09 ± 11.44 years. The study comprised 2853 patient-years or a median of 11 years (range, 6-17 y) of follow-up time. Arterial hypertension and chronic glomerulonephritis were the most common primary kidney diseases. Of the donors, 62 (26.8%) were deceased donors and 169 (73.2%) were living donors. Of the living donors, 158 (93.5%) were related and 11 (6.5%) were unrelated donors (cross transplant). Of the related donors, 71 (45.0%) were first-degree relatives (mother, father, or child), 56 (35.4%) were second-degree relatives (all siblings), 5 (3.2%) were third-degree relatives (uncle, aunt and nephew), and 5 (3.2%) were fourth-degree relatives (cousins); 21 donors (13.3%) were spouses of the recipients.

During the follow-up, graft loss occurred in 34 patients (14.7%) and death occurred in 27 patients (11.7%). Nine patients (3.9%) died from infections, 6 (2.6%) died from causes directly related to cancer, 6 (2.6%) died from unexplained causes, 4 (1.7%) died from cardiovascular causes, and 2 (0.9%) died from other causes.

Recipients had a higher overall risk of cancer compared with the general population (SIR = 3.04, 95% CI, 1.82-4.26). In the analysis by sex, the risk of cancer was significantly higher in men (SIR = 2.58, 95% CI, 1.36-3.80). However, the CI of the estimated SIR for women (SIR = 3.78, 95% CI, 0.97-6.59) was quite wide, and statistical significance was not reached.

Thirty malignant tumors were detected in 24 patients (10.4%) (Table 2). Among these patients, 17 (70.8%) were male patients and 7 (29.2%) were female patients. The mean age was 41.13 ± 11.26 years at transplant, and 54.88 ± 11.44 years at diagnosis of first cancer. The median time from KTx to first cancer diagnosis was 11.5 years (range, 7-18.8 y). Four patients (16.7%) developed more than 1 tumor, with 3 tumors in 2 patients (1 patient with squamous cell carcinoma [SCC] of skin, basal cell carcinoma [BCC] of skin, and posttransplant lymphoproliferative disease [PTLD]; 1 patient with 2 different foci of BCC of skin and SCC of the skin) and 2 tumors in 2 patients (1 patient with BCC and SCC of skin and 1 patient with BCC of skin and SCC of lip).

Nonmelanoma skin cancer (NMSC) was the most common malignancy, accounting for 56.7% of all tumors. Histopathologically, 9 cases were BCC (n = 8 patients) and 8 cases were SCC (n = 8 patients). Three patients had both SCC and BCC lesions at different times. All BCC lesions were localized to the head (scalp and facial areas), and none developed metastases. One patient had 2 foci at the same time. One patient experienced a locoregional recurrence. One required a skin graft in the cheek area during curettage. All SCC lesions (6 on the head and 2 on the back of the hands) were curetted surgically. One patient developed ipsilateral retromandibular lymph node infiltration that required extensive curettage and lymph node excision. One patient had a perineural invasion in an ear-located SCC lesion.

Posttransplant lymphoproliferative diseases were the second most common tumors, representing 16.7% of all lesions (Table 2). All affected patients were seropositive for the Epstein-Barr virus and were recognized after the first year posttransplant. The first case classified as PTLD in the polymorphic category²⁷ was diagnosed with T-cell-derived lymphoma by excisional lymph node biopsy taken from the submandibular area. The switch from tacrolimus to everolimus achieved complete remission with no complications. However, systemic chemotherapy was required in the remaining 4 patients with monomorphic PTLD.²⁷ Two patients were diagnosed with diffuse B-cell lymphoma, the first by tonsil excision and the second by mass biopsy from the liver. These 2 patients died of disseminated cancer. The third patient was diagnosed with T/natural killer cell lymphoma after the excisional biopsy of the sublingual lesion and died from cancer. The fourth patient was diagnosed with high-grade B-cell lymphoma after a jejunal and partial resection of the colon; he is still undergoing follow-up treatment.

The other tumors were as follows: lung cancer (n = 2 [8.3%], small cell carcinoma and SCC of the lung), larynx cancer (n = 2 [8.3%], SCC of the larynx), lip cancer (n = 1 [4.2%], SCC of the lip), thyroid cancer (n = 1 [4.2%], papillary carcinoma), breast cancer (n = 1 [4.2%], invasive ductal carcinoma), and Kaposi sarcoma (n = 1 [4.2%]).

Twenty-two lesions (73.3%) developed in 17 patients (7.4%) that were localized to the head and neck region (Figure 1): 15 (68.2%) were cutaneous and 7 (31.8%) were noncutaneous (3 lesions of PTLD [tonsil, floor of mouth, submandibular lymph node], 2 lesions of larynx, 1 lesion of lip, 1 lesion of thyroid). Eleven (50%) were in SCC histology. The median time from KTx to head and neck cancer diagnosis was 12 years (range, 7.5-17.5 y).

Ten of 24 cancer patients (41.7%) died. The mean age at death was 54.00 ± 12.21 years. Of the patients, 6 (60%) died directly from cancer-related causes, 2 (20%) from cardiovascular causes, 1 (10%) from infection, and 1 (10%) from typical hemolytic uremic syndrome (Table 2). The follow-up period after cancer diagnosis was 19 months (range, 2.3-41.8 mo). Cancer diagnosis negatively affected patient survival after transplant (Figure 2).

The age of recipients and donors at KTx was defined as independent predictors for de novo malignancy development in univariate Cox propor-tional hazards models. The same factors were deter-mined as independent predictors also in multivariate analyzes (? = 0.089, hazard ratio = 1.093; 95% CI, 1.046-1.142; P = .001 and ? = 0.040, hazard ratio = 1.041; 95% CI, 1.002-1.081; P = .039, respectively).

Discussion

This study summarizes our institutional experience with de novo malignancies developing in KTx recipients. During the follow-up period, 10.4% of all our patients developed at least 1 malignant tumor. Nonmelanoma skin cancers were the most common malignancies. Remarkably, 73.3% of all detected tumors were in the head and neck region, and the cancer incidence for this region was calculated to be 7.4%. Patients who developed de novo malignant tumors had a higher mortality rate than patients without tumors, and the overall diagnosis of cancer was shown to adversely affect patient survival.

The incidence of de novo cancer, which ranged from 0.75% to 6.8% in previous local studies,^14-18 was reported to be 10.4% in our study. At this point, we would like to point out the relatively long follow-up period of 11 years in our study population. A longer follow-up period may be associated with a higher cumulative burden of immunosuppression and may explain, to some extent, the differences in incidence rates. Because the follow-up periods of all study populations were not disclosed, comparisons with data from other domestic studies could not be made.^14-18 However, the incidence that we calculated here is consistent with European data with similar follow-up periods.⁷ Another possible reason for the relatively high incidence rate that we calculated could be the relatively small sample size of our study. Small differences in the number of malignant cases may have led to substantial changes in the incidence calculation. However, a serious point that should not be overlooked is the possibility that the incidence of de novo cancer in our society has changed over time. It is noteworthy that previous studies reported a progressive increase in incidence rates.^14-18 This trend could be due to strict medical surveillance and cancer screening or increased cancer risk. Larger studies and national databases are needed to draw a firm conclusion on this critical issue.

An increased risk of head and neck cancer has been described in heterogeneous solid-organ transplant series, including in KTx patients.^19-23 Although this risk appears to be independent of the type of transplanted organ, data to be collected on specific groups may be useful for relevant points. To date and to our knowledge, only 2 studies have specifically examined head and neck cancers in KTx recipients.^24.25 To the best of our knowledge, this is the third study in the medical literature and the first in our country. Three-quarters of all tumors in our cohort were head and neck tumors with an incidence of 7.4%. This incidence is much higher than the rates described in the 2 previous reports.^24.25 Variations in the types of head and neck tumors evaluated in those studies, different publication dates, and/or ethnicity may also explain the differences. It may be recommended to approach with high suspicion for new skin lesions or masses that occur in thehead and neck region during follow-up of KTx recipients. Larger studies are needed on this subject.

The most common malignancy detected in our study was NMSCs, with almost equal rates of BCC and SCC. This finding was consistent with the data reported from western countries^2,7,11 and our country in the past decade.^16-18 All cutaneous malignant lesions arose in sun-exposed areas and virtually all in the head and neck region. The head and neck region can be a sensitive area for the development of skin cancer. However, this issue needs further investigation.

Actually, ultraviolet-induced pathogenesis is an important mechanism in the development of NMSC lesions.^28,29 Chronic exposure increases the risk of SCC, and intermittent-strong exposure increases the risk of BCC.²⁹ Considering the latitudes of our country, it can be thought that exposure to the sun is high. On the other hand, many studies show that NMSC lesions develop at a much higher rate in transplant patients compared with the general population living in the same geography.^1,28,29 Therefore, it can be thought that there are other factors that increase the sensitivity of transplant patients to sunlight. One of the most important of these is certainly long-term immunosuppression.^1,28 Actually, the skin can be considered an immunologic organ as it covers most of the cell types of lymphoid organs such as macrophages, T cells, dendritic cells, and Langerhans cells. Immunosuppressive agents can disturb the function of cutaneous cells, reduce the antiviral and antitumoral immune responses of the skin, and cause mutations.¹

No patients in this study died directly from skin cancer. However, a significant group of patients developed complex courses such as multiple tumors, multifocal lesions, local recurrence, regional lymph node, or perineural invasion. Depending on this significant morbidity burden, we consider that close dermatological surveillance may improve the outcomes of KTx recipients.

Posttransplant lymphoproliferative diseases were the second most common tumors encountered in this study. Three of the tumoral lesions occurred in the head and neck region and 2 in the gastrointestinal tract. The most important risk factor for PTLD has been identified as pretransplant serostatus of the recipient/donor Epstein-Barr virus. However, it should be emphasized that the virus alone is not sufficient to produce PTLD and its seropositivity does not imply continuous replication.^30,31 Consistently, in situ hybridization studies of tissue samples from our 2 cases revealed no viral replication, although all of our PTLD patients were seropositive. Complete remission was achieved in our polymorphic PTLD case. However, 3 of our monomorphic PTLD cases died from cancer related causes despite systemic chemotherapy. It should be emphasized that PTLD is a type of malignancy with a high mortality rate and that the histopathological subtype is an indicator of poor prognosis.^27,30,31

Kaposi sarcoma is an angioproliferative tumor derived from endothelial and immune cells associated with the reactivation of the human herpesvirus 8.³² It is common in immunocom-promised patients and has been defined as the most common cancer in KTx recipients in various countries, including Turkey.^9,14,33 However, in our series, only 1 patient with a typical skin lesion and lymph node involvement was detected, and the incidence was calculated as 0.43%. In fact, accumulating data over the past 2 decades have shown a gradual decline in the incidence of Kaposi sarcoma in Turkey: 3% in 1998,¹⁴ 2.4% in 2002,³³ 1.2% in 2006,¹⁵ 0.075% in 2015,¹⁶ and 0.9% in 2020.¹⁸ Actually, a similar pattern has been observed in HIV-positive patients. With the introduction of antiret-roviral therapies in the mid-1990s, stronger and sustained viral suppression has reduced the prevalence of Kaposi sarcoma, even in the patient group where it is most prevalent.³⁴ More comprehensive data from different disciplines are needed to interpret this issue.

In numerous studies, different factors such as sex, age, duration of dialysis, type/total doses of immunosuppressive agents, and retransplant have been possible risk factors for de novo malignancy in KTx recipients.^2,3,5,7 In this study, the age of donors and recipients at the time of KTx was found to be associated with tumor development. With this result, we interpret and suggest that it may be appropriate to include recipients in individualized strict follow-up programs, considering their ages.

The presented study has some limitations and some strengths. First, the number of patients is relatively small, as it is a single-center study. However, we would like to draw attention to the fact that the single-center study design provides homogenization at some critical points, such as immunosuppressive treatment regimens and malignancy screening strategies. Second, the study is open to the possibility of underreported events due to its retrospective design. However, because KTx patients are a group with high compliance with routine follow-ups, it can be thought that the probability of major bias is not high. On the other hand, the follow-up period of patients in our study was quite long. Because person-year follow-ups are given for the whole patient population (not only cancer patients), for the first time in our country, to our knowledge, the risk of malignancy in KTx patients was evaluated using standard incidence rate statistics compared with the general population. In addition, it is the first study that draws attention to head and neck lesions among the de novo lesions developed in KTx cases in our country.

As a result, KTx recipients have a higher risk of cancer than the general population. Our study has documented this well-known risk with standard incidence rates. The increasing incidence of malig-nancy in KTx patients in our country over the years is remarkable. The incidence detected in this study is also quite high. Nonmelanoma skin cancers were the most common tumors. It is presented for the first time that a significant portion of the de novo tumors develops in the head and neck region. Larger-scale studies should investigate these findings, their causes, and the consequences. The benefits of a successful transplant, of course, outweigh the risk of cancer. However, further studies evaluating changing risks and structuring patient follow-up may help improve outcomes for this critical population.

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