Our results demonstrate that primary bronchogenic carcinoma is a prominent long-term complication of SLTx. Furthermore, our analysis has demonstrated that, although disease was often considered resectable at presentation, the clinical course was frequently recurrent, aggressive and fatal, accounting for a significant number of deaths in the SLTx population. We identified increasing age, single-lung (vs bilateral) transplant and >60-pack-year history of tobacco use as significant risks for the development of primary bronchogenic cancer after lung transplantation.
This is the first study on this topic to have used a matched cohort design to specifically compare SLTx and BLTx as risk factors for the development of primary lung malignancy; this design allows for novel analysis of lung cancer risk, controlling for native disease, smoking history, type of transplant and demographic characteristics. Our results are in contrast to those of prior studies in lung transplantation, which have uniformly found a lower frequency of de novo bronchogenic carcinoma than we did. Prior studies have reported the frequency of post-transplant bronchogenic carcinoma to range from 0% to 2.5% in SLTx recipients and to be 0% in BLTx recipients.1–5
Our higher frequency of malignancy is likely explained in part by the longer-term follow-up in our study as compared with prior studies. In our cohort we included patients surviving >90 days post-transplant and who had a mean of >5 years post-transplant follow-up. The mean interval between transplantation and diagnosis of malignancy was 52.3 months in our patients, longer than the mean follow-up reported in any previous study. The higher incidence of malignancy in our study might also reflect improved survival in recent years after lung transplantation,7
such that more patients are now living long enough to develop lung cancer as a late cause of mortality.
Our increased incidence of malignancy as compared with prior studies might also in part reflect changes in the demographics of lung transplant recipients since the time periods of past studies. In the past 15 years, the mean age of lung transplantation recipients has risen concurrent with an increase in the frequency of COPD as an indication for transplantation relative to other non–tobacco-related diagnoses.7
The mean age of our study population (55.4 years) was older than that reported in prior studies (44 to 51 years; overall mean 46.9 years); similarly, the percentage of our patients who received transplantation for COPD (75%) far exceeded the range reported in past studies (32% to 56%).1–5
As our study demonstrated that increasing age and smoking history are risk factors for the development of primary post-transplant lung cancer, it is not surprising that these demographic trends would be accompanied by an increased frequency of lung cancer in this population.
Our matched cohort study design with similar demographics and smoking histories between our SLTx and BLTx groups enabled us to evaluate the added risk of cancer conferred on patients by SLTx. Increasing age and smoking history, both established risk factors for bronchogenic cancer,10–12
were confirmed by univariate analysis to be independent risk factors in our study. We suspect strongly that all 9 malignancies arose de novo after transplant, given the negative CT findings before transplantation. Thus, our results clearly demonstrate that SLTx confers a significantly greater risk for developing lung cancer than BLTx after adjusting for age, native disease and smoking history. One limitation of the analysis is that we did not formally control for effects of rejection episodes on the development of malignancy; however, all patients received a similar immunosuppressive regimen and there did not appear to be any increased incidence of rejection among the patients with lung malignancy.
Our results are consistent with studies of other types of solid-organ transplantation, which recognized malignancy as an increasing cause of late death.6
According to a validated lung cancer risk model,10
the 10-year risk of developing lung cancer in a non-transplant recipient of our population’s mean age (55.5 years) and smoking history (49.5 pack-years) is no more than 2% with continued tobacco exposure. In our study, the frequency was 6.9% over a mean follow-up time <10 years (5.5 years in SLTx patients), implying a much higher than expected incidence of lung malignancy in the SLTx population. The increased frequency and refractoriness of cancer in this study’s population likely reflects a synergistic interaction between native lung tobacco exposure, patient age and the carcinogenic effects of long-term immunosuppression. Proposed mechanisms for this latter etiology include the inhibition of immune-mediated tumor surveillance13
and direct immune-independent carcinogenic effects of cyclosporine and other immunosuppresants.14
Our results hold important implications for the current management of SLTx recipients. The increased frequency of lung cancer in this population, despite regular radiographic surveillance, underscores the importance of aggressive investigation of suspicious radiographic or clinical findings. The high recurrence rate (60%) in our patients who underwent resection suggests that aggressive surgical management may be preferred in patients with Stage I or II disease, and consideration should be given to adjunct chemotherapy even in milder stage disease. In general, an attempt was made to reduce immunosuppression after the diagnosis of lung malignancy.
Our results contribute to ongoing debate regarding the appropriate type of transplant operation in patients with tobacco-related disease. In patients with emphysema, either single or bilateral lung transplant can be safely pursued. SLTx allows maximization of the limited donor pool by potentially allowing two recipients to benefit from a single donor. However, the benefits to society of SLTx must be weighed against the long-term outcome for each individual recipient. ISHLT registry data demonstrated improved long-term survival after BLTx compared with SLTx.7
Although the reasons for this improved long-term survival in recipients of BLTx are not entirely clear, our study has demonstrated that SLTx recipients with a history of tobacco-related lung disease are at increased risk of developing bronchogenic cancer in the years after transplantation, suggesting at least one reason for the worse overall survival of SLTx recipients as compared with BLTx recipients.
In sunmary, we have reported the development of de novo primary lung cancer in the native lung of 6.9% of recipients of single-lung transplantation in a large cohort of lung transplant recipients. In this population, native lung cancer was characterized by an aggressive and frequently fatal course. This frequency of primary lung cancer was shown to be higher than that reported in previous studies and significantly higher than in a control population of matched BLTx recipients. Thus, as improved medical and surgical management leads to improved longer-term outcomes after lung transplantation, primary lung cancer is likely to be an increasingly recognized complication in the native lung of SLTx recipients. Our results suggest that increased attention should focus on careful surveillance of the native lung in all SLTx recipients. Future studies should evaluate the frequency of lung cancer in STLx recipients over an even longer follow-up period, along with investigating additional potential risk factors and the relative effectiveness of different methods of surgical and medical management.