Malignancies after renal transplantation in southern Taiwan: experience in one centre
Ying-Chin Ko, Division of Environmental Health and Occupational Medicine, National Health Research Institutes; College of Medicine, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, Kaohsiung, 807, Taiwan.
To present data on cancer distribution in renal-transplant recipients in Chinese people, as in Western studies renal-transplant recipients are reportedly at greater risk of malignancies, especially skin cancer, but there is limited information in Chinese people.
PATIENTS AND METHODS
Using the data of a cancer registry, we compared a hospital-based cohort of 283 renal-transplant recipients between 1981 and 2002 with the general population in Taiwan, to identify the incidence and risk factors of cancer.
The cumulative period of observation was 22 582.93 person-months. Twenty-five patients (8.83%) developed malignancies after renal transplantation; the standardized incidence ratio was 4.6 (95% confidence interval 2.84–6.48). Bladder and renal cancers were commonest, and the cumulative incidence rate (CIR) was 4.59%. The second most frequent type was hepatoma, where the CIR was 1.77%. The third was malignant tumour of the skin, with a CIR of 1.41%; these comprised three Kaposi’s sarcoma and one malignant lymphoma, with no incidence of squamous or basocellular skin cancer.
Compared with Western countries, the distribution pattern of cancer after kidney transplantation was different, with no squamous or basocellular skin cancers, and a very high incidence of kidney and urinary tract cancer.
(cumulative) (standardized) incidence rate (ratio)
squamous cell carcinoma
basal cell carcinoma.
Renal transplantation has now been established as the definitive treatment for end-stage chronic renal failure. Many studies show a greater incidence of cancer in patients after transplantation [1–6]. Depression of immune surveillance from the use of immunosuppressive agents was considered to cause cancer development among renal-transplant recipients (RTRs) [3–5,7]. Also, in the countries reported, cancers of the skin, especially squamous cell carcinoma (SCC) or basal cell carcinoma (BCC) were the most common malignancies [8,9]. In Japan, some studies suggested a pattern of cancer development different from that in Western countries, where gastric cancer or kidney cancer were the commonest malignancy [2,10]. Recently, Wu et al. proposed that TCC and hepatocellular carcinoma were the most common malignancies in Chinese RTRs in central Taiwan. In that study, there was no data for the standardized incidence ratio (SIR) of malignant tumours as the index of comparison with the general population. In the present study we retrospectively examined the cases in southern Taiwan to see if there were any similar findings; thus the aim was to investigate whether the cancer incidence for a specific population is higher than for the general population, and to present the data on cancer distribution in the group of Chinese RTRs.
PATIENTS AND METHODS
The study was a historical cohort design based on the clinical records from one hospital, Chang Gung Memorial Hospital-Kaohsiung, during 1981–2002; 283 RTRs (166 men and 117 women) were regularly followed and the data were collected from computerized records for transplant patients and/or from examination of individual notes. Data gathered included sex, date of transplantation, age at transplantation, type of immunosuppressant, date of diagnosis of cancer, type and site of cancer, time between transplantation and diagnosis of the first cancer, outcome of the patient, time between date of transplantation and death, and the duration of follow-up for each patient until 31 December 2002. All patients resided in Southern Taiwan, with no population movement. The RTRs had regular complete blood examination and abdominal ultrasonography. Patients with a diagnosis of cancer before or <1 month after transplantation were excluded. Only histologically confirmed tumours, which occurred after renal transplantation, were included in the analysis. The hepatitis B surface antigen, hepatitis B ‘e’ antigen and hepatitis C virus antibody were evaluated, and the patient was excluded if any result was positive. Renal function was analysed every 6 months by comparison of serum creatinine concentrations. Although graft histology was available in each case of rejection, the definition of acute rejection was the introduction of anti-rejection therapy. We used the 1995–2000 whole population of Taiwan as the control group. The cancers of the general population in Taiwan were collected and obtained from the Cancer Registry Annual Report in the Taiwan Area .
For immunosuppressive therapy, dual therapy, consisting of cyclosporin in combination with prednisolone, was used in 152 patients. Cyclosporin was given at a starting dose of 5 mg/kg/day i.v. followed by 12 mg/kg/day orally starting from 5 days after transplantation. Cyclosporin was then reduced every 2–4 weeks to a mean maintenance dose of 5 mg/kg/day. Oral prednisolone was given in one morning dose of 16 mg until the end of the third month, at a dose of 12 mg daily until the end of the sixth month, and at a maintenance dose of 8 mg daily thereafter.
Triple therapy (cyclosporin, azathioprine and prednisolone) was used in 23 patients; cyclosporin i.v. was administered at the same starting dose as in dual therapy, followed by an oral dose of 10 mg/kg/day from 5 days after transplantation. The dosage was progressively reduced by 2 mg/kg/day every 2 weeks to a maintenance regimen of 2–3 mg/kg/day. Oral prednisolone was given at the same dosage as in dual therapy, and azathioprine was given at a fixed dose of 1 mg/kg/day.
Thirteen patients received sequential therapy, i.e. the use antilymphocyte globulins or antithymus globulins as induction medicine, and afterwards cyclosporin or azathioprine might be used. The immediate treatment after transplantation was with 5 mg/kg antithymocyte globulins or monoclonal antibodies starting for 10 days.
The rest of the patients were categorized as the group of ‘others’, including two treated by azathioprine and prednisolone, three by tacrolimus and prednisolone, 11 by cyclosporin, tacrolimus and prednisolone, and two by cyclosporin, azathioprine, tacrolimus and prednisolone.
Descriptive statistics for the clinical and laboratory data are presented as the mean (sd) or mean (range); the data of the two groups, with or with no cancer, were compared by Student’s t-test for continuous data and by the chi-squared test for categorical variables. Estimates with 95% CI, not including unity, and differences with P < 0.05 were considered statistically significant.
The age- and sex-adjusted cancer incidence of RTRs was calculated by 5-year age groups using the 1995–2000 general population of Taiwan as the standard population. The ratio of observed to expected number of cancers (the SIR) was calculated for sites with observed tumour. The expected number of cancers was calculated by multiplying the person-years at risk by the appropriate sex- and age-specific incidence rates, which were obtained from the Cancer Registry Annual Report in the Taiwan Area . CIs and the statistical significance of SIRs were calculated assuming that the rate of cancer occurrence followed a Poisson distribution .
In all, 283 RTRs were followed in our clinic (cumulative period of observation 22 522.93 person-months). The mean age at renal transplantation was 39.2 (11.0) years and the mean (sd, range) follow-up was 79.6 (45.1, 1.4–208.2) months. Among them, 25 patients (8.8%) developed malignant neoplasms after renal transplantation, with an incidence density of 1.11 × 10−3/month.
Table 1 shows the characteristics of all patients with or with no cancer; for all the RTRs, being female, of low education status and older at transplantation were significant risk factors for developing malignancy (P < 0.05). Four of 45 patients who had acute rejection had malignancies, but there was no significant effect of acute rejection on the incidence of neoplasia. Of the 283 RTRs, 35 (12.4%) died; three died after the malignancy occurred, and they all received dual therapy as the immunosuppressive regimen. Of the others, one with TCC died 23 months after the diagnosis of cancer, one with nasopharyngeal cancer died 28 months after, and one with Kaposi’s sarcoma died within a week after the diagnosis of malignancy. Twelve of 152 patients who received dual therapy, six of 23 who received triple therapy, and four of 13 treated by sequential therapy had malignancies. No malignant tumour was found in patients who were treated by other methods.
Table 1. The demographic characteristics of patients with or with no cancer from 283 RTRs
|Gender (M/F)||166 (58.7)/117 (41.3)||10 (40.0)/15 (60.0)||156 (60.5)/102 (39.5)||0.047*|
|Occupation:|| || || ||0.072|
| Worker and businessman|| 77 (43.8)|| 4 (25.0)|| 73 (45.6)|| |
| Farmer|| 12 (6.8)|| 3 (18.8)|| 9 (5.6)|| |
| Others|| 87 (49.4)|| 9 (56.2)|| 78 (48.8)|| |
|Education|| || || ||0.020*|
| Primary school|| 52 (29.4)|| 9 (56.3)|| 43 (26.7)|| |
| High school and College||125 (70.6)|| 7 (43.2)|| 118 (73.3)|| |
|Residence|| || || ||0.11|
| Kaohsiung and Pintung||213 (84.2)||22 (95.7)|| 191 (83.0)|| |
| Others|| 40 (15.8)|| 1 (4.3)|| 39 (17.0)|| |
|Marriage|| || || ||0.59|
| Married||139 (71.6)||14 (77.8)||125 (71.0)|| |
| Widow or widower|| 6 (3.1)|| 1 (5.5)|| 5 (2.8)|| |
| Single|| 49 (25.3)|| 3 (16.7)|| 46 (26.2)|| |
|Acute rejection|| || || ||0.99|
| Yes|| 45 (15.9)|| 4 (16.0)|| 41 (15.9)|| |
| No||238 (84.1)||21 (84.0)||217 (84.1)|| |
|Prognosis|| || || ||0.95|
| Death|| 35 (12.4)|| 3 (12.0)|| 32 (12.4)|| |
| Live||248 (87.6)||22 (88.0)||226 (87.6)|| |
| Age, years|| 44.7 (10.8)||52.0 (11.0)|| 44.0 (10.5)||0.002*|
| Age at transplantation|| 39.2 (11.0)||46.7 (11.8)|| 38.5 (10.6)||0.002*|
| Haemodialysis time before transplantation, months|| 33.5 (26.7)||41.0 (35.6)|| 32.8 (25.7)||0.29|
Table 2 presents the cumulative incidence of malignant tumours in different sites and the pathological findings. The mean age at transplantation among patients with cancer was 46.7 years, while that of the first cancer incidence was 51.9 years. The mean latency period between transplantation and tumour diagnosis was 44.5 months. Bladder and renal cancers were commonest, and the cumulative incidence rate (CIR) was 4.59%. The second most frequent type was hepatoma, where the CIR was 1.77%. The third was malignant tumour of skin, with a CIR of 1.41%. All bladder and renal cancers were TCC, except one with SCC. Malignant tumours of skin comprised three Kaposi’s sarcoma and one malignant lymphoma, and there were no SCCs or BCCs.
Table 2. The cumulative incidence and other information of malignant tumours in different sites, and pathological findings for the patients with malignancies
|Bladder/renal|| ||13||4.59||56.1 (29.84–95.95)||48.2 (30–64)||52.2 (32–66)|| 41.1 (15.9–113.8)|
|TCC||12||4.24|| ||47.5 (30–64)||51.1 (32–66)|| 35.1 (15.9–75.6)|
|SCC|| 1||0.35|| ||56||65|| 113.8|
|Hepatoma||HCC|| 5||1.77|| 6.1 (1.96–14.23)||47 (25–58)||52.6 (36–68)|| 66.0 (22–128.1)|
|Skin|| || 4||1.41||31.4 (8.44–80.36)||41.5 (30–67)||48.7 (39–72)|| 36.2 (11.8–79.0)|
|Kaposi’s sarcoma|| 3||1.06|| ||44.6 (30–67)||50.3 (39–72)|| 35.9 (11.8–79.0)|
|Lymphoma|| 1||0.35|| ||32||44|| 37|
|Stomach||Adenocarcinoma|| 1||0.35|| ||56||59|| 32.9|
|Cervical||Carcinoma in situ|| 1||0.35|| ||28||38|| 28.4|
|Nasopharynx||Carcinoma|| 1||0.35|| ||57||65|| 43.1|
|Total|| ||25||8.83||4.6 (2.84–6.48)||46.7 (25–67)||51.9 (32–72)|| 44.5 (11.8–128.1)|
Overall, RTRs had a higher incidence risk than the general population, with a SIR of 4.6 (95% CI 2.84–6.48). The SIR of bladder and renal cancer was 56.1 (95% CI 29.84–95.95), of hepatoma was 6.1 (95% CI 1.96–14.23), and of skin tumours was 31.4 (95% CI 8.44–80.36), all significantly higher than in the general population.
In the present study, 8.83% patients developed malignant neoplasms and the SIR of all tumours was 4.6 (95% CI 2.84–6.48). These results confirm the greater incidence of cancer in RTRs than in the general population. Women and lower education status were the relevant risk factors predicting the development of cancer (Table 1). The distribution of malignant tumours in RTRs in this study was different from that in Western countries and that in the general population of Taiwan. The most common cancers in Taiwan were those of the liver, lung, colon and rectum, stomach, and oral cavity , whereas there was a higher incidence of renal and bladder cancers, hepatoma and skin tumours in RTRs. The incidence of renal and bladder cancers was obviously higher after renal transplantation (SIR 56.1).
From the results of previous studies, RTRs were at extremely high risk for TCC in Taiwan, with an incidence of 4.1% during 20 years  and high prevalence of TCC (3.1%) . In the present study, all bladder and renal cancers were TCC, except one with SCC. The conclusion of a higher risk for TCC in RTRs in Taiwan can be confirmed (CIR 4.21%). However, a high incidence (0.89%) of TCC among 1910 uraemic patients undergoing maintenance dialysis was also found in Southern Taiwan , and one study of haemodialysis patients in Northern Taiwan revealed a SIR for kidney and bladder cancer of 24.1 and 16.4, respectively , which means that the causes of renal failure might also be the risk factors for TCC.
Western RTRs have a greater risk of Kaposi’s sarcoma, with an incidence of 0.5–5.3%[17–21]. There were three patients with Kaposi’s sarcoma in the present study; two received triple therapy as their immunosuppressive method and the other dual therapy. One patient using triple therapy had visceral involvement of Kaposi’s sarcoma and he died 6.5 months after diagnosis. The lesions of the others were limited to the skin, with no systemic involvement, and they did not recur after total excision and reduction or withdrawal of immunosuppressive drugs. In addition, the only case of cutaneous lymphoma had the same result. This indicates that the lymphoproliferative disorder of RTRs is strongly associated with immunosuppressive agents, in particular cyclosporin [9,19,22].
Hepatoma is a common malignancy in Taiwan, not only in the general population but also in RTRs . The age-adjusted incidence rate (per 100 000 person-years) was 30.9 for males and 10.9 for females in Taiwan . The SIR of hepatoma of all patients was significantly high, although we had excluded all patients who had positive serology for virus C or B of hepatitis from the study. The toxicity of the immunosuppressive agent might be a possible explanation for hepatoma in RTRs .
Furthermore, many studies showed that RTRs were at greater risk of developing skin cancers, especially SCC and BCC [4,9,21,23–25], but there were no cases detected in the present study. Similar results were also found in Taiwan and Japan [2,3]. Webb et al. stated that 52% of Caucasian RTRs would have skin cancer after 20 years had elapsed, but no non-Caucasians would have the disease. Therefore the genetic background could be important in the development of SCC and BCC .
The present study had several limitations. First, as it was retrospective, the information was very restricted and the underlying problems and rejection status of RTRs that might be associated with the development of cancers could not be identified. Second, malignant tumours are rare and there are relatively few RTRs in Taiwan, so that the sample size might be insufficient. We tried to reduce the bias by conducting a cohort study and comparing it with the general population. Third, ethnic differences, viral infection and the effects of immunosuppressive agents contributing to malignant tumours need further clarification. Although the limitations mentioned might influence the interpretation of the study findings, we hope that the clinical findings and potential risk factors reported could provide valuable information for reducing the risk of malignancies in RTRs.
In conclusion, we confirm that the incidence of malignant tumours in RTRs is markedly greater than that in the general population. The type of cancer diagnosed in the present RTRs was different from that in the general population, and the distribution of cancers among RTRs in Taiwan was different from that in Western RTRs. The most common malignant tumour was renal and bladder cancer. In Taiwan, RTRs are at extremely high risk of TCC of the urinary tract, with an incidence of 4.24%. There was no increase in the incidence of skin cancer, except lymphoproliferative disorder, in RTRs in Taiwan.
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