Incidence of Non-Hodgkin Lymphomas and the Ten Most Commonly Diagnosed Cancers After Heart Transplantation

Malignancy is the leading cause of morbidity and mortality in heart transplant recipients (1). Several large population-based studies have reported increased risks of cancer in patients after heart transplantation (2, 3). However, the distribution of cancer types appeared to be different between Western and non-Western populations (4–6). Therefore, the aim of this nationwide population-based study was to investigate the incidences and risks of non-Hodgkin lymphomas and the 10 most commonly diagnosed cancers in Taiwanese heart transplant patients. This study was a secondary analysis of the National Health Insurance Research Database (NHIRD) maintained by the National Health Research Institute, Taiwan. The study protocol was approved by the institutional review board of the study hospital. The NHIRD contains comprehensive administrative and claim data from the National Health Insurance program, which is a mandatory single-payer social health insurance system implemented in March 1995. We identified heart transplant recipients using the International Classification of Diseases, Ninth Revision, Clinical Modification code V42.1 and 996.83 in the catastrophic illness file of the NHIRD between January 1, 2001, and December 31, 2011. In Taiwan, solid organ transplantation and cancers are classified as catastrophic illnesses. Related medical copayment is waived for holders of the certificates during the validity period. The catastrophic illness registry is highly accurate because application of a catastrophic illness certificate for cancer is reviewed by at least two specialists based on cytological reports, pathologic reports, and other evidence supportive of malignancy. All heart transplant recipients were followed up from the date of transplantation to the date of a first-time diagnosis of cancer or their most recent ambulatory care visit before December 31, 2011, using the records in the 2000 Longitudinal Health Insurance Database. Non-Hodgkin lymphomas and the 10 most commonly diagnosed cancers in Taiwan were identified using their respective International Classification of Diseases, Ninth Revision, Clinical Modification codes. Patients diagnosed with cancer before or within 30 days after heart transplantation were excluded from the analysis to allow for a lag time between transplantation and the occurrence of clinically detectable cancers. Risks of cancer associated with heart transplantation were compared with those of the general Taiwan population using standardized incidence ratios (SIRs). The SIR was calculated as the number of observed cancer cases among heart transplant recipients divided by expected number of cancer cases. Expected number of cancer cases was calculated by multiplying the number of person-year at risk by the national age-specific, sex-specific, and calendar year-specific incidence rates available from the Taiwan National Cancer Registry (https://cris.hpa.gov.tw/). Because the 2011 incidence rates were not yet available for use at the time of writing, the rates of 2010 was substituted for 2011. Person-years of observation were calculated starting after the first 30 days after heart transplantation to the date of a first-time cancer diagnosis for patients who developed cancer or the date of the most recent ambulatory care visit before December 31, 2011, for patients without cancer. In other words, for those without cancer, their follow-up time is censored on the date of their last ambulatory care visit. Calculations of the observed events were conducted using IBM SPSS Statistics software package, version 21.0 (IBM Corp., Armonk, NY), and calculations of SIRs were performed using PANCOMP, version 1.41 (7). The 95% confidence intervals (CI) and corresponding P values were calculated for SIRs assuming a Poisson distribution for the observed number of events using the mid-P exact test. P less than 0.05 was considered statistically significant. The study cohort consisted of 1,001 heart transplant patients with 76.2% men and a mean age of 47.3 years at transplant. About half of the transplantations were performed among patients between the ages of 40 and 59 years. The mean length of follow-up was 4.4 years with 4,398 person-years of follow-up. Half of the transplantations were performed between 2001 and 2005. Table 1 shows the SIR for non-Hodgkin lymphomas and the 10 most commonly diagnosed cancers in Taiwan. Non-Hodgkin lymphomas (SIR, 1.8; 95% CI, 4.8–24.6), particularly in men (SIR, 11.7; 95% CI, 4.3–25.8) showed significantly higher SIR. In addition, our study also revealed an elevated, albeit not statistically significant, risks of trachea, bronchus, and lung cancer (SIR, 2.1; 95% CI, 0.9–4.4) and prostate cancer (SIR, 2.9; 95% CI, 0.9–7.0). These findings are similar to those from a cohort of 1,703 heart transplant recipients identified from the Canadian Organ Replacement Registry database regarding the increased risks of non-Hodgkin lymphomas and lung cancer (2). The lack of elevated risks of oral cancer and skin non-melanoma cancer observed in our study is consistent with two other studies of heart transplantation in Taiwan (4, 5). Increased incidence of prostate cancer was previously reported in a French study of 702 heart transplant recipients (8). Nevertheless, a cohort study using linked data from the United States Scientific Registry of Transplant Recipients (1987–2008) and cancer registries showed no excess risk of prostate cancer after solid organ transplantation (9).TABLE 1: Standardized incidence ratios for non-Hodgkin lymphomas and 10 most commonly diagnosed cancers in Taiwan among 1,001 heart transplant recipientsWe noted a few limitations in our study. First, because only 10 years of the NHIRD data files were available for use in this study, the mean follow-up time after heart transplantation was 4.4 years. Second, data on patients’ clinical characteristics, such as indications for transplantation, use of induction prophylaxis, maintenance immunosuppressive therapies, and Epstein-Barr virus serology were not available in the NHIRD database. Third, because of the limitations of our data set, we were unable to identify whether any of our patients might have received organ transplants abroad. Nevertheless, patients awaiting heart transplantation are typically too ill to travel abroad for the procedure. In conclusion, our study demonstrated that Taiwanese heart transplant recipients could have an increased risk for non-Hodgkin lymphomas and trachea, bronchus, and lung cancer. Increased vigilance is warranted for these cancer types after transplantation to ensure early detection and treatment. Wen-Yao Yin, MD 1,2 Malcolm Koo, PhD3,4 Ming-Che Lee, MD2,5 Ming-Chi Lu, MD, PhD2,6 1 Division of General Surgery Dalin Tzu Chi Hospital Buddhist Tzu Chi Medical Foundation Chiayi, Taiwan 2 School of Medicine Tzu Chi University Hualien, Taiwan 3 Department of Medical Research Dalin Tzu Chi Hospital Buddhist Tzu Chi Medical Foundation Chiayi, Taiwan 4 Dalla Lana School of Public Health University of Toronto Ontario, Canada 5 Department of General Surgery Hualien Tzu Chi Medical Center Hualien, Taiwan 6 Division of Allergy Immunology and Rheumatology Dalin Tzu Chi Hospital Buddhist Tzu Chi Medical Foundation Chiayi, Taiwan

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