Incidence of Primary and Second Cancers in Renal Transplant Recipients: A Multicenter Cohort Study

Authors


Gianpaolo Tessari, gianpaolo.tessari@ospedaleuniverona.it

Abstract

Limited data exist about cancer prognosis and the development of second cancers in renal transplant recipients. In a retrospective cohort study on 3537 patients incidence rates of the first and, if any, of a second cancer, and standardized incidence ratios [SIR (95% CI)] were computed. Two hundred and sixty-three (7.5%) patients developed a NMSC, and 253 (7.2%) another type of cancer after a median follow-up of 6.5 and 9.0 years, respectively. A statistically significant excess risk, if compared to an age- and sex-matched reference general population, was observed for Kaposi sarcoma and NMSC, followed by non-Hodgkin lymphoma and carcinoma of cervix uteri; a small number of unusual cancers such as tumors of the salivary glands, small intestine and thyroid also were detected at a level worthy of additional scrutiny. Ten-year survival rate of all noncutaneous cancers was 71.3%, with lower rates for lung carcinoma and non-Hodgkin lymphoma (0% and 41.7%, respectively). Patients with NMSC had an increased risk of developing a second NMSC [SIR 8.3 (7.0–10.0)], and patients with a primary noncutaneous cancer had increased risk of developing a second noncutaneous cancer [SIR 1.8 (1.2–2.8)], if compared to the whole cohort. Our study underscore that the high risk of primary and second cancer in renal transplant recipients, including unusual cancers.

Abbreviations
NMSC

nonmelanoma skin cancer

Introduction

Renal transplant recipients are at increased risk of developing nonmelanoma skin cancer (NMSC) and other types of cancer. An elevated excess risk is reported for Kaposi's sarcoma and NMSC, followed by lymphoproliferative disorders, and carcinoma of cervix uteri. For other solid-organ cancers, such as colorectal, lung and kidney cancers and multiple myeloma the risk is moderately increased. Incidence rates of breast and prostate cancers in the transplant population are similar to those observed in the general population, and in a recent multicenter study the risk seem to be even reduced (2008, 2011, 2011). For less frequent cancers (e.g. thyroid, small intestine, salivary glands) conflicting data are reported (2010, 2009, 2012). Despite the increased incidence of cancer, conflicting reports exist on cancer prognosis in transplant recipients compared to nonimmunosuppressed patients, and whether in these patients survival is long enough to allow the development of second primary cancers. Some studies reported a 10-year survival rate of transplanted patients after the diagnosis of cancer of 22–56%, with a median survival time of 2.1 years (range 0–25 years) depending of cancer type and staging, and a proportion of patients dying of cancer of 30–100% (2011, 2010, 2003). Miao et al. reported that in solid organ transplant recipients all cancers present in an advanced stage at the time of the diagnosis, and have higher mortality rates compared with the general population (2009). Kiberd et al. showed that only 5.3% of death in renal transplant patients was due to cancer, and that overall mortality rates were not substantially different compared to the general population (2009). The development of subsequent noncutaneous cancers in immunocompetent patients surviving to a primary childhood and adult onset noncutaneous cancer has been recently reviewed (2010, 2008). The pathogenesis is multifactorial, and include high dose radiotherapy, mutagenic activity of some chemotherapeutic agents, persistence of unhealthy habits as smoking or drinking, genetic predisposition and various other risk factors (2010, 2008). A recent systematic review revealed strong evidence that history of NMSC is associated to a 10–50% increased risk of noncutaneous cancers when compared to patients with no history of NMSC, even after adjusting for potential confounders as age, ethnicity, smoking and other risk factors (2010). Despite the high incidence of cancer in solid organ transplant recipients due to immunosuppression, insufficient data exist about the risk of second cancers, as in the majority of studies the main outcome is the diagnosis of the first cancer (2011, 2011, 2010, 2003). Some studies have demonstrated that solid organ transplant recipients with a primary NMSC may develop a subsequent NMSC within 3 years (14–16), but only two studies have reported the occurrence of second noncutaneous cancers, but with conflicting results (2003, 2006).

The aim of the present study was to estimate the incidence of primary noncutaneous malignancies and primary NMSC and of subsequent noncutaneous cancers and NMSC in a multicenter cohort of transplanted patients. The incidence of primary cancers was computed and it was compared to the incidence of cancers in an age- and sex-matched reference population living in the same geographic area. Survival rates of the whole cohort, and of renal transplant recipients with cancer, and causes of death were also analyzed.

Patients and Methods

Patients

This was a retrospective cohort study including a series of 3537 consecutive kidney transplant recipients transplanted after 1980 at four Italian transplantation centers in Northern Italy (Verona, in the Veneto Region; Bergamo, Brescia and Milano Niguarda, in the Lombardy region). Patients were regularly followed up every 4 months after transplantation at the outpatient nephrologic clinic and those with cutaneous lesions were also seen by a consultant dermatologist. At the end of any medical examination the physician updated an electronic database. In addition, every effort was made to collect information on any dermatologic diagnoses made outside the study centers. Detailed clinical records were available for all participants. Induction therapy was usually performed with antiinterleukin two receptor monoclonal antibody (Simulect; Novartis AG, Basel, Switzerland) or antithymocyte immunoglobulins (BioMerieux Italia s.p.a., Bagno a Ripoli, Italy or Genzyme Corp., Cambridge, MA, USA). Long-term maintenance immunosuppressive therapy, either alone or in various combinations, included azathioprine (1.0–2.5 mg/kg/day), cyclosporine (3–9 mg/kg/day), methylprednisolone (5–10 mg/day), tacrolimus (0.15–0.30 mg/kg/day), mycophenolate mofetil (2 g/day), and with increasing frequency sirolimus (2–5 mg/day) and everolimus (1.5 mg/day). Acute rejection was usually treated with pulsed i.v. methylprednisolone (0.5–1.0 g/day for 3 consecutive days). Corticosteroid-resistant acute rejection was treated with plasmapheresis, muromonab (anti-CD3 monoclonal antibody), or antithymocyte immunoglobulins (2007).

Collection of data

Data recorded for all the patients were date of birth, sex, date of transplantation, type of immunosuppressive therapy at the last visit, and the dates of cancer, death or of the last follow-up, causes of death or loss to follow-up. The main outcomes were the diagnosis of noncutaneous cancer and the diagnosis of NMSC. Only patients with histology proven cutaneous basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (SCC) were considered to have a NMSC. The second cancer was defined as a cancer occurred in a patient who had already diagnosed a malignancy after transplantation, but was located in a different site and was histologically defined as nonmetastatic cancer (2008, 2010). To be considered a second NMSC it should not be contiguous to a scar, which could represent a previously treated NMSC site, and it had to occur at least 3 months after treatment of the first NMSC (14–16).

Statistical analysis

Kaplan–Meier survival analysis was used to estimate the cumulative incidences of cancer after transplantation. Concerning the first cancer, the number of person-years was computed between the date of transplantation (used as the opening date) and the date of cancer diagnosis (considered to be the end point), or the end of follow-up (June 30, 2011). When evaluating the second cancer, the number of person-years was computed between the date of the diagnosis of the first cancer and the date of the diagnosis of the second cancer (considered to be the end point), or the end of follow-up (June 30, 2011). The incidence of the first cancer in the study population was compared with the incidence in the general population by calculating standardized incidence ratios (SIR) with 95% confidence interval and was matched for age, sex and time period in which the malignancy had occurred. Ninety-five percent CIs for the SIR were derived using an exact method that assumes the observed counts follow a Poisson distribution (1994). Expected values were computed extracting incidence rates of cancer for the Veneto and Lombardy regions of Italy, from the Italian Association of Cancer Registries (AIRTUM- http://www.registri-tumori.it) and from the Registro Tumori della Regione Veneto (http://www.registrotumoriveneto.it). No substantial differences existed between the two registries, and for this reason data from the AIRTUM were used. In the subgroup of patients with a primary cancer, the incidence of the second cancer was compared with the incidence in the whole cohort by calculating standardized incidence ratios (SIR) with 95% confidence interval and was matched for age, sex and time period in which the malignancy had occurred. Expected values were computed using incidence rates of the primary cancer in the present cohort. Kaplan–Meier survival curves were used for estimate survival of the patients after the diagnosis of cancer. Mortality due to cancer was compared with mortality in an age- and sex-matched reference population by calculating standardized mortality ratio (SMR). Expected values were computed using mortality rates for Italy from the International Agency on Research on Cancer (IARC) at http://www.iarc.fr (last accessed July 27, 2012).

Statistical analyses were performed using a statistical software package (Stata, version 10; Stata- Corp LP, College Station, TX, USA) (1994). Informed consent for the scientific use of the data was provided by all the participants, and the study was approved by the local ethical committee.

Results

Baseline characteristics of the cohort

There were 3537 patients, 2309 men and 1228 women; median age at transplantation was 45.0 years (range 18.0–68.0), and the median mean follow-up time since transplantation was 6.9 years (range 1.0–28.0). The total posttransplantation person-years were 29000. Seven hundred and three patients (19.9%) had been transplanted in the years 1980–1989, 1314 (37.1%) in the years 1990–2000, and 1520 (43.0%) between 2001 and 2011. Immunosuppressive regimens at the last follow-up were calcineurin inhibitor (cyclosporine or tacrolimus) plus prednisolone in 898 (25.4%) patients, antimetabolites (azathioprine or mycophenolate) plus prednisolone in 529 (15.0%) patients, antimetabolites plus calcineurin inhibitor plus prednisolone in 1877 (53.1%) patients, and m-TOR inhibitors (Sirolimus or everolimus) plus prednisolone in 232 (6.6%) patients. Censored observations are as follows: 724 (20.5%) patients developed chronic graft rejection, 569 (16.1%) patients died during the follow-up, and only 120 (3.4%) patients were lost to follow-up.

Characteristics of primary cancers

Two hundred and sixty three patients out 3537 (7.5%) developed a NMSC after a median follow-up of 6.5 years (range 0.3–24.2) and 253/3537 (7.2%) another type of cancer after a median follow-up of 9.0 years (range 1.1–27.0). Ten-year incidence rate of the first cancer was 7.5% (95% CI 6.5–8.9) for noncutaneous cancer, and 8.8% (95% CI 7.7–10.9) for NMSC, respectively (Figure 1). Characteristics of the patients with posttransplant malignancies, and cumulative incidences of all the cancers separated by type of cancer calculated with the Kaplan–Meier method are presented in Table 1. Standardized incidence ratios of primary cancers are shown in Table 2. A statistically significant excess risk, if compared to an age- and sex-matched reference population, was observed for Kaposi sarcoma and NMSC, followed by non-Hodgkin lymphoma and cervix uteri, and unusual cancers such as salivary glands, small intestine and thyroid cancers.

Figure 1.

Cumulative incidence of NMSC and noncutaneous cancers in the study cohort.

Table 1. Characteristics of the patients with malignancies occurring after kidney transplantation
     Cumulative incidence (%) after different time periods after the transplantation (Kaplan–Meier)4
Type of cancer1No.2Sex M/FMedian age at the diagnosis (range)Median follow-up (years) since transplantation to the diagnosis of cancer (range)1 year3 years5 years10 years15 years
  • 1

    All malignancies were carcinomas unless otherwise indicated.

  • 2

    Some patients had more than one type of malignancy.

  • 3

    All breast cancers were in females.

  • 4

    Cumulative incidence was calculated with the Kaplan–Meier curves.

Nonmelanoma skin cancer263201/6258.1 (31.5–73.5)6.5 (0.1–24.2)0.31.63.38.815.2 
 Basal cell carcinoma114 84/3055.5 (34.5–71.3)6.4 (0.1–21.7)0.20.61.43.96.8
 Squamous cell carcinoma149117/3259.3 (44.4–73.7)6.4 (0.6–24.2)0.10.91.94.98.4
Melanoma of the skin6  3/3 60.2 (38.4–62.7)7.3 (1.9–14.4)0.00.10.10.10.4
All but skin2253177/7656.4 (22.7–76.8)9.0 (1.1–27.0)0.31.12.37.513.8 
 Breast326  0/2655.1 (38.1–76.8)5.6 (0.1–25.6)0.20.30.92.63.2
 Bladder13 11/2 56.7 (47.3–68.2)4.7 (0.4–23.2)0.00.10.30.40.7
 Colon15 12/3 51.1 (41.6–75.3)9.5 (1.5–23.3)0.00.10.10.61.0
 Larynx4  4/0 57.2 (31.3–62.6)7.1 (5.4–18.9)0.00.00.00.20.2
 Hodgkin's lymphoma1152.0 (n.a.)      
 Kaposi sarcoma24 22/2 57.9 (28.8–66.6)0.8 (0.1–3.0)0.40.60.80.80.8
 Kidney (native)35 30/5 53.4 (28.9–66.1)6.4 (1.0–18.5)0.10.30.51.31.7
 Leukemias3  3/0 72.9 (54.5–73.1)8.1 (6.7–13.5)0.00.00.00.10.3
 Liver6  5/1 60.2 (52.7–70.4)19.7 (1.1–30.9)0.00.10.10.10.2
 Lung18 17/1 58.5 (45.7–68.6)8.0 (0.1–23.9)0.00.20.20.81.0
 Myeloma3  3/0 54.7 (52.0–64.4)3.5 (0.4–5.1)0.00.00.10.10.1
 Non-Hodgkin lymphoma47 32/1554.6 (22.7–73.1)6.1 (0.1–13.5)0.30.50.82.23.0
 Pancreas3  1/2 50.7 (49.0–52.0)4.8 (2.1–16.4)0.00.00.10.10.1
 Prostate19 19/0 62.4 (47.0–72.2)5.9 (0.1–27.7)0.10.30.31.01.2
 Small intestine4  2/2 60.2 (48.8–75.2)7.2 (0.1–13.8)0.00.00.10.10.4
 Stomach6  4/2 59.3 (55.9–68.6)4.7 (0.1–19.1)0.00.00.10.20.3
 Rectum4  2/2 58.0 (44.0–63.5)14.7 (2.9–22.6)0.00.00.00.00.2
 Salivary glands3  3/0 50.7 (48.3–55.2.)11.8 (11.4–27.8)0.00.00.00.00.2
 Thyroid8  4/4 43.7 (27.1–63.2)4.3 (0.1–13.2)0.00.10.10.40.6
 Uterus (body)3  0/3 44.9 (44.5–62.1)1.2 (0.8–1.2)0.10.20.20.20.2
 Uterus (cervix)8  0/8 51.7 (39.9–66.7)9.4 (2.1–17.1)0.00.10.10.61.5
Table 2. Standardized incidence ratios for different types of cancer developed after kidney transplantation
 Total patientsMalesFemales
Type of cancer1Obs.Exp.SIR95% CIObs.Exp.SIR95% CIObs.Exp.SIR95% CI
  • 1

    All malignancies were carcinomas unless otherwise indicated.

  • 2

    Many patients had more than one type of malignancy.

  • 3

    All the breast cancers were in females.

  • Obs = Observed; Exp = Expected.

Nonmelanoma skin cancer2638.929.326.0–33.12017.028.725.0–33.0622.623.918.7–30.7
 Basal cell carcinoma11423.24.94.1–5.98416.94.94.0–6.1307.34.12.8–5.9
 Squamous cell carcinoma1493.443.637.2–51.33123.137.431.2–44.8320.742.930.3–60.67
Melanoma of the skin65.91.00.4–3.033.50.80.3–2.632.01.40.5–4.5
All but skin253160.61.51.3–1.8176113.21.51.3–1.87552.41.41.1–1.8
 Breast3        2620.31.20.8–1.8
 Bladder138.71.40.8–2.5119.71.10.6–2.021.11.80.4–7.2
 Colon1512.51.20.7–1.9129.31.20.7–2.333.90.70.2–2.3
 Larynx44.80.80.3- 2.243.11.30.5–3.400.20.0n.a.
 Hodgkin's lymphoma10.91.00.1–7.110.91.00.1–7.110.91.00.1–7.1
 Kaposi sarcoma240.384.956.9–126.7220.363.942.1–97.120.0123.530.9–493.9
 Kidney (native)354.97.05.0–9.8304.66.44.5–9.351.14.72.0–11.3
 Leukemias33.10.90.3–2.932.41.20.4–3.800.90n.a.
 Liver64.81.20.5–2.755.10.90.4–2.310.71.20.2–8.9
 Lung1816.11.10.1–1.71714.71.10.7–1.812.30.40.6–3.0
 Myeloma31.71.70.5–5.331.71.70.5–5.3    
 Non-Hodgkin lymphoma475.97.96.0–10.5324.57.15.0–10.0151.88.14.9–13.5
 Pancreas35.20.50.2–1.813.30.30.0–2.121.01.90.5–7.5
 Prostate3    1914.31.30.8–2.1    
 Small intestine40.66.12.3- 16.220.44.71.2–19.020.116.34.2–66.9
 Stomach65.51.10.5–2.443.61.10.4–2.921.01.90.5–7.8
 Rectum45.40.70.3–2.024.50.40.1–1.821.41.40.3–5.7
 Salivary glands30.38.52.7–26.330.213.14.2–40.700.10n.a
 Thyroid82.13.81.9–7.741.42.91.1–7.842.21.80.7–4.7
 Uterus (body)3        32.81.10.3–3.3
 Uterus (cervix)3        80.98.94.4–17.7

Characteristics of second cancers

Among 263 patients with a first NMSC, 120 (45.6%) patients developed a subsequent NMSC after a median follow-up of 1.4 years (range 0.3–10.2) since the diagnosis of the first NMSC, and 17 (6.5%) patients had a subsequent noncutaneous cancer, detected after a median follow-up time of 2.4 years (range 0.5–11.0) since the diagnosis of the first NMSC. Of the 17 noncutaneous cancers, 4 were lung cancers, 3 were cancer of the native kidney, 3 were non-Hodgkin lymphoma, 2 were bladder cancers, and one of each of the following: leukemia, myeloma, cancer of cervix uteri, salivary glands and liver. Of the 17 patients, 10 died of cancer, 6 were alive with functioning graft and 1 returned to dialysis. The 263 patients with a first NMSC had an increased risk of developing a subsequent NMSC if compared to the whole cohort [SIR 8.3 (95% CI 7.0–10.0)], but the risk of developing a subsequent noncutaneous cancer did not increase [SIR 0.9 (95% CI 0.5–1.5)]. Among the 253 patients with a primary noncutaneous cancer, 21 (8.3%) patients had a second noncutaneous cancer (Table 3), after a median follow-up time since the first of 2.3 years (range 0.2–8.5), and 15 (5.7%) had a subsequent NMSC (7 SCC, 8 BCC) after a median follow-up of 2.2 years, range (0.4–7.9) since the first. Of the 21 patients with a second noncutaneous cancer, 10 died of the second cancer, 7 were alive with functioning graft and 4 returned to dialysis. Of the 15 patients with a subsequent NMSC, 10 were alive with functioning graft and 5 returned to dialysis. The 253 patients with a primary noncutaneous cancer had increased risk of being diagnosed with a second noncutaneous cancer, if compared to the whole cohort (SIR 1.8; 95% CI 1.2–2.8), but their risk of developing a NMSC as second cancer was reduced (SIR 0.5; 95% CI 0.3–0.8).

Table 3. Second noncutaneous cancers occurring after the diagnosis of a primary noncutaneous cancer
No.Sex /age at the diagnosis (years)Type of the firstcancerTime since transplantation to the diagnosis of the first cancer (years)Type of the second primary cancerTime since the first cancer to the diagnosis of the second cancer (years)Follow-up
1M/ 51Bladder23Liver carcinoma6Died of the second cancer
2M/ 42Kidney9Thyroid4Alive with functioning graft
3M/ 50Kaposi sarcoma4Kidney1Alive with functioning graft
4F/ 62Kidney1Bladder2Alive with functioning graft
5F/ 57Thyroid1Non-Hodgkin lymphoma7Died of the second cancer
6M/ 60Bladder2Kidney3Alive, returned to dialysis
7M/65Non-Hodgkin lymphoma3Kaposi sarcoma0.5Alive, returned to dialysis
8M/49Kidney4Liver carcinoma1Died of the second cancer
9F/45Uterus (Body)1Lung1Died of the second cancer
10F/59Breast8Non-Hodgkin lymphoma5Died of the second cancer
11M/54Kaposi sarcoma3Colon9Died of the second cancer
12F/41Breast6Breast1Alive with functioning graft
13M/73Chronic myeloid leukemia8Small intestine2Died of the second cancer
14F/46Breast16Uterus (Cervix)3Alive, returned to dialysis
15F/55Breast2Uterus (Cervix)1Alive with functioning graft
16F/51Breast5Non-Hodgkin lymphoma5Alive with functioning graft
17M/60Kaposi sarcoma1Prostate5Alive with functioning graft
18M/42Colon18Kidney0.7Alive, returned to dialysis
19F/64Breast14Rectum0.9Died of the second cancer
20M/60Bladder15Liver carcinoma2Died of the second cancer
21M/68Kidney8Leukemia5Died of the second cancer

Survival rates and causes of death

Of the 569 patients who died during the follow-up, only 109 died of cancer, 265 died of cardiovascular diseases, 113 died of infections and 82 died of other causes. In the Kaplan–Meier analysis, the 10-year survival rate of the whole cohort of 3537 was 87% (95% CI 85.2–87.7) with a median survival time of 9.2 years (range 0.3–28.3). Kaplan–Meier 10-year survival rate of all noncutaneous cancers was 71.3% (95% CI 64.8–76.8), and median survival time was 7.8 years (range 0.3–31.1). The lowest 10-year survival rates were observed for lung carcinoma (0%), non-Hodgkin lymphoma (41.7%) and colon cancer (47.6%) (Table 4). SMR of patients with all cancers was 1.5 (95% CI 1.0–1.8) with no differences between sexes; in patients at the age of 50 or younger, SMR was 4.3 (95% CI 3.0–6.1), and in patients older than 50 was 1.2 (95% CI 0.7–1.3). An excess mortality rate was observed in patients with non-Hodgkin lymphoma and carcinoma of the native kidney (Table 4).

Table 4. Survival rates of the transplanted patients after the diagnosis of the most frequently occurring malignancies
      Survival rates at different time periods after the malignancies (Kaplan–Meier)
Type of cancerPatients with cancer (No.)Total deceased (No.)Causes of death (Cancer/other causes)Median follow-up (years) from cancer diagnosis to death (range)SMR**(95% CI)1 year3 years5 years10 years
  • *

    Of the 38 patients, 3 died of metastatic SCC, 11 patients died of noncutaneous cancers occurred after the diagnosis of NMSC, and 24 patients died of cardiovascular diseases.

  • **

    Expected values were computed using mortality rates for Italy from the International Agency on Research on Cancer (IARC) at http://www.iarc.fr (last accessed July 27, 2012). Mortality rates for Kaposi sarcoma and NMSC were not available.

Nonmelanoma skin cancer*2633814/244.0 (0.3–13.6) 99.294.486.976.4
 Basal cell carcinoma114158/74.2 (1.0–8.0) 10096.187.079.0
 Squamous cell carcinoma14923 6/173.5 (0.3–13.6) 98.692.487.173.4
Melanoma of the skin622/0      
All but skin2539685/117.8 (0.3–31.1)1.5 (1.0–1.8)97.291.685.971.3
 Breast2654/11.9 (1.3–4.6)0.7 (0.3–1.7)10086.472.972.9
 Bladder1343/11.5 (0.5–9.6)2.5 (0.9–6.8)92.376.176.157.1
 Colon1566/00.3 (0.1–6.4)0.9 (0.4–2.0)71.463.463.447.6
 Larynx411/0      
 Hodgkin's lymphoma100/0      
 Kaposi Sarcoma2464/22.4 (0.1–14.9) 87.587.581.673.5
 Kidney (native)351413/1 0.5 (0.1–13.2)9.6 (5.7–16.3)78.372.368.860.7
 Leukemias322/0      
 Liver633/0      
 Lung181212/0 0.5 (0.1–6.4)1.3 (0.7–2.4)47.032.932.90.0
 Myeloma300/0      
 Non-Hodgkin lymphoma472620/6 0.2 (0.1–6.6)14.1 (9.8–20.1)63.649.245.941.7
 Pancreas333/0      
 Prostate1933/09.6 (1.8–11.0)1.3 (0.4–4.1)100.094.794.747.3
 Small intestine411/0      
 Stomach633/0      
 Rectum422/0      
 Salivary glands322/0      
 Thyroid811/0      
 Uterus (body)311/0      
 Uterus (cervix)811/0      

Discussion

NMSC is the most common cancer occurring after organ transplantation, after a median time of 5–8 years, and about half of transplanted patients with a primary NMSC develop a second NMSC (2010, 2010, 2006). The burden of morbidity related to NMSC may be severe. The localization of cancer on the head and face may require complex surgical procedures, and the recurrence rate after surgery is increased in comparison to immunocompetent people (2011). Death due to metastatic dissemination of SCC is rare, as observed in our cohort (Table 4), and the impact of NMSC on overall transplant related mortality and graft survival is uncertain (2011, 2011). Incidence rates of noncutaneous cancer in the present study were comparable to those reported in other studies, ranging from 13% at 10 years to 30% after 20 years (2008, 2011, 2011). An excess risk of cancer, compared to an age- and sex-matched reference population, was observed for Kaposi sarcoma and NMSC, followed by non-Hodgkin lymphoma, and cancer of cervix uteri and of thyroid. These cancers, with the exception of thyroid cancer, are also detected in patients with AIDS, thus supporting the role of reduced immune surveillance in pathogenesis (2011, 2011, 2007, 2009, 2009). The increased risk of thyroid cancer in transplanted patients has recently been described in a meta-analysis (2010). The number of cancers of the small intestine and of the salivary glands was limited but significantly higher than expected in an age- and sex-matched reference population. Given our inability to assess the role of enhanced clinical surveillance inherent in transplant follow-up on the detection of these rare tumors, caution should be exercised in overinterpreting the risk of these tumors in the transplant population. Further studies are needed to determine whether these tumors are actually influenced by transplant-associated therapies. No excess risk for other common epithelial cancers including breast, colon and prostate cancers as well as melanoma was observed, suggesting the heterogeneous role of immune surveillance against tumors. An excess risk for lung, bladder, stomach and pancreas cancer in kidney transplanted patients has been reported in various studies (2011, 2011), but not in the present study, possibly due to the smaller cohort of patients. Patients in the waiting list for kidney transplantation must be therefore extensively screened for cancer including salivary glands, small intestine and thyroid glands (2010, 2009, 2012, 2010). In our cohort overall mortality rates due to cancer were similar to the general population, with an excess risk only in patients at the age of 50 years or younger, in agreement with Kiberd et al. (2009). In this study patients younger than 50 years had higher cancer-related SMR, whereas those who were older and diabetic had a reduced cancer-related SMR, due to competing risk of cardiovascular mortality (2009). A possible bias is represented by the low number of patients and by the lack of information about cancer staging, but transplanted patients undergo a strict medical screening and follow-up, and cancers are usually detected at an early stage, and may have thus a better prognosis (2008, 2009). Our data confirm the severe prognosis of posttransplant lymphomas (2010). The detection of an excess mortality due to carcinoma of the native kidney in our cohort is in contrast with the reports of a favourable prognosis of this cancer in transplanted patients, if compared to nontransplanted patients (2012, 2010). The reduced number of patients in our cohort, and the different study design of the studies cited, may possibly explain these discrepancies, that need to be further investigated.

Limited data exist about the occurrence of second cancers in solid organ transplant recipients (2003, 2006). The occurrence of a second NMSC in nearly 40% of transplanted patients with a first NMSC is well established (14–16), and it has been confirmed in the present study.

The number of second noncutaneous cancers in patients with a first noncutaneous cancer is small, but higher than expected in the whole cohort of transplanted patients, and this is a main novelty of our study. Due to the limited number of second noncutaneous cancers, we could not determine which type of noncutaneous cancer could predict the risk of a second cancer and possible risk factors. Our findings are in agreement with the review by Ng et al (2010, 2008) and with the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute (USA), reporting a second cancer in about 8% of cancer patients (irrespective of the type of the first cancer) and an observed/expected ratio of at least 1.27, for patients diagnosed of cancer at the age of 50–60, that is the median age at the diagnosis of our cohort (2006). Our study failed to demonstrate an excess risk of second noncutaneous cancers in patients with a previous NMSC. This is possibly due differences in the biology and immunology of NMSC and noncutaneous cancers and to the small size of our cohort. Our study reports an increased risk of primary and second cancers in renal transplant recipients when compared to nonimmunosuppressed patients. The type of the second cancer is determined by the type of the primary, with patients with primary NMSC being at risk of subsequent NMSC, and patients with noncutaneous cancers being at risk of noncutaneous cancers, emphasizing again the role of factors specific to each cancer type. Interestingly enough, cancer mortality seems not to be increased, if compared to the reference population. Further studies on larger cohorts should better investigate the phenomenon of second neoplasms, therapeutic strategies, and modulation of immunosuppressive therapy.

Acknowledgments

We gratefully acknowledge D.ssa Paola Zambon, from the Registro Tumori Della Regione Veneto, and Dott. Emanuele Crocetti and Dott. Stefano Ferretti from the AIRTUM, for having provided incidence rates of cancer in the nonimmunosuppressed population.

Disclosure

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

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