Over the past 20 years, there has been a notable increase in thoracic organ transplantation, with double lung transplantation (DLT) surpassing single lung transplantation nearly two-fold since 2005 [1–4]. Immunosuppressive therapy has substantially improved post-transplant outcomes by mitigating acute and chronic rejection episodes [5–7]. The standard immunosuppressive regimen for lung transplantation consists of calcineurin inhibitors, antimetabolites, and corticosteroids [8, 9]. This regimen has effectively reduced allograft tissue rejection and graft failure, enhancing transplant recipients’ survival outcomes [10, 11].

The immunosuppressive regimen attenuates the signaling between antigen-presenting cells and T-cells, inhibits T-cell activation and proliferation, reduces antibody production by B cells, and suppresses antibody-mediated complement system activation [12–14]. However, this immunosuppressive microenvironment may inadvertently promote tumor development and progression, facilitating immune evasion by cancer cells [15, 16]. Consequently, while immunosuppressive therapy has successfully suppressed allograft rejection, malignancies associated with immunosuppression are increasingly acknowledged as a significant post-transplant complication [17, 18].

Although the relationship between post-transplant malignancy (PTM) and immunosuppressive therapy has been suggested, PTM remains a leading cause of mortality in thoracic transplantation patients [19–21]. Transplant recipients face a lifelong risk of PTM, necessitating diligent screening for de novo PTM. A thorough examination of PTM, accounting for transplant recipient characteristics and time since transplantation, is crucial for informing PTM management strategies.

In this study, we investigated the annual incidence, cumulative risk, and survival outcomes of PTM in patients who underwent DLT for non-cancerous diseases. We utilized data from the Organ Procurement and Transplantation Network (OPTN) to better understand PTM characteristics following DLT.

Data: Data pertaining to thoracic transplantation was procured from the United Network for Organ Sharing (UNOS)—a non-profit organization committed to its mission of overseeing the nation’s transplant system under the purview of the federal government ¹ . The data, which were de-identified, anonymized, and accompanied by coding files in STATA format, were sourced from the thoracic transplant registry of the OPTN as of 7 October 2022. Only DLT recipients were included while single or multi-organ transplants were excluded given the potential for confounding bias. Among the 29,335 documented DLT cases conducted between 1993 and June 2022, a total of 23,935 recipients who had eligible data were ultimately assessed for de novo PTMs following DLT, upon reviewing data suitability. Recipients who had undergone DLT for malignancy were excluded from the study, which received approval from Northwestern University’s Institutional Review Board Committee in Chicago, IL, United States (IRB#: STU00207117). The collected data encompassed recipient age at the time of transplantation, sex, smoking history, prior indication for DLT, presence, and date of de novo PTM, PTM type, date and cause of death. The recipient cohorts were divided into two groups: those without de novo PTM (n = 18,306) and those with de novo PTM (n = 5,629). The incidence, annual and cumulative risks of each PTM subtype were scrutinized, and survival outcomes were contrasted.

Analysis: Clinical factors and survival outcomes were evaluated at 5 and 10 years post-DLT for all recipients. Incidence, as well as annual and cumulative risks of PTM, were computed according to PTM type. Furthermore, the variation in annual risk proportion was compared as the follow-up period extended. With a follow-up period of at least 18 years, the cumulative risk was ascertained for the four most prevalent PTM causes: squamous cell skin cancer (SCC), basal cell skin cancer (BCC), lymphoma, and lung cancer. Recipients with PTM were further categorized based on the number of PTMs they developed, and the overall survival (OS) was analyzed for statistical differences based on the number of PTMs.

Statistics: Quantitative variables were compared using the t-test, and categorical variables were analyzed using the χ² test. The survival outcomes were analyzed with the Kaplan–Meier survival method. For multivariate analysis, the Cox regression analysis was performed, considering age, sex, and cigarette use at the time of DLT as the variables. For the landmark analysis, we chose 3, 5, 7, 10, 15, and 20 years after transplantation as landmark time points. Only patients alive at this point were included in this analysis and performed an analysis with recipients with or without PTM before time points. All statistical analyses were performed using the SPSS software (version 29.0 SPSS, IBM, Chicago, IL, United States), and a p-value of <0.05 was used to determine statistical significance.

Our study’s major findings include: 1) around one-fourth of the recipients who underwent DLT for non-cancerous diseases experienced PTM, with 27 different PTMs occurring during the follow-up period; 2) annual and cumulative risks of each PTM varied based on elapsed time post-DLT, with the highest PTM incidence in the second year after transplantation; 3) PTM incidence differed among age groups, particularly post-transplant lung cancer, which had the highest incidence in the 70–79 age group; 4) one in five recipients with PTM after DLT was diagnosed with multiple PTMs (up to four different types), with the most common tumor types differing based on the order of occurrence; 5) OS after DLT was better in recipients with PTM than those without PTM at the 3-year, and 5-year landmark time points and in recipients diagnosed with multiple PTMs rather than a single PTM.

Organ transplantation has increased, and survival outcomes have improved due to advancements in immunosuppressive therapy [22, 23]. However, de novo malignancy development post-transplantation, mainly related to immunosuppressive therapy [17, 24]. In the context of lung transplantation, although the immunosuppressive protocols are similar for both single and bilateral transplantations, our study exclusively focused on DLT. This approach was adopted to mitigate potential confounding factors such as the presence of latent lung cancer in the native lung or underlying conditions like pulmonary fibrosis that could elevate the risk of lung cancer [25, 26].

Major PTM incidences after DLT was highest in the second-year post-transplantation. However, lymphoma was most frequent at the first year than second year. Lymphoma, a post-transplant lymphoproliferative disease, typically occurs within 4–6 months after hematopoietic stem cell transplantation and mainly after the first year of solid organ transplantation [27–29]. Notably, lymphoma post-solid organ transplantation occurs 11.8-fold more frequently than in the non-transplant population (p < 0.001), and the age-stratified relative risk is higher in children under 10 years old and adults over 60 years. This PTM is often life-threatening, with a higher risk in heart, lung, intestinal, and multi-organ transplants [30–32]. The occurrence of post-transplant lymphoma is strongly associated with immunosuppressants, such as FK506, OKT3, and ATG [33, 34].

After DLT for non-cancerous diseases, approximately 24% of all recipients were diagnosed with PTMs in their lifetimes, with one-fifth of them being diagnosed multiple times. There were four types of post-transplant skin cancer, including SCC, BCC, melanoma, and cutaneous Kaposi sarcoma. While BCC is more prevalent than SCC in the general population at a 4:1 ratio, where SCC occurs more frequently in transplant patients with an incidence rate 65- to 250-fold higher [35]. Particularly, SCC in organ transplant recipients shows a worse prognosis with nine times higher cancer-specific mortality than in the general population [36–38]. In our study, post-transplant SCC was 3-fold higher than BCC after DLT, and the OS of recipients with BCC was better than that of those with SCC which was similar to the trend observed in the general population [39].

SCC was the most common type of PTM in most age groups, and lymphoma was the most prevalent only in the 19–29 age group. Colorectal cancer ranked as the 5th most common PTM after DLT and mainly occurred within 1 year after DLT in recipients in their 50s. After DLT, the risk of developing lymphoma and lung cancer was highest within the first year, while bladder cancer was most likely to occur 8 years after DLT. Other types of PTM occurred mainly in the second year after transplantation, with the incidence gradually decreasing over time. Interestingly, lung cancer was the 4th most common PTM after DLT, despite recipients having received bilateral allogenic lung transplantation. The incidence rates of lung cancer after DLT were only 2%–3% in most age groups, and its incidence was the highest at 8% in the 70–79 age group. While the incidence of lung cancer in the general population gradually increases with age, the recipients who received DLT showed lower occurrence rates until their 60s, which then rapidly increased in their 70s [40, 41].

Although immunosuppressive therapy after solid organ transplantation is necessary to prevent complications after transplantation [6, 42, 43]. However, long-term immunosuppression may promote cancer progression, whether it is a pre-existing or new lesion and the risk of PTM is increased approximately 3- to 4-fold compared with the general population [44–46]. A conventional protocol for maintenance immunosuppressive therapy for lung transplantation is the “triple regimen,” which includes a calcineurin inhibitor (cyclosporine or tacrolimus), antiproliferative agents (azathioprine, mycophenolate, sirolimus, and everolimus), and corticosteroids. Tacrolimus has a pro-oncogenic effect by producing transforming growth factor β1 [47], and azathioprine is known to increase the risk of skin cancers after organ transplantation, especially SCC [48, 49]. Cyclosporine use is also associated with lymphoma and skin cancer [50]. And the use of Voriconazole increases the risk for cutaneous SCC among solid organ transplant recipients [51, 52]. However, the association between mycophenolate mofetil and increased cancer incidence after transplantation is unclear. Moreover, sirolimus is known to have both an anticancer effect (by targeting mTOR) and an immunosuppressive effect [53]. To summarize, different PTMs occur depending on the regimen of immunosuppressive agents [21, 28, 54–56]. However, information on PTM remains insufficient, and there are no guidelines for modified immunosuppressive therapy that can minimize the occurrence of PTMs.

In this study, we found that recipients with PTM had significantly better survival outcomes than those without PTM. However, since an earlier study had reported significantly lower 1-year and 3-year survival rates for patients with PTM [57], we conducted a landmark survival analysis to shed more light on this discrepancy. We assumed this was because of the immortal time bias, which means that longer recipients have a higher chance of being diagnosed with PTM. To compensate for this error, which refers to a bias that can occur in observational studies when the time between a defined event (e.g., transplantation) and the start of follow-up (e.g., diagnosis of PTM) is not considered [58], we performed landmark analysis with 3, 5, 7, 10, 15, and 20 years as the landmark time points. Recipients with PTM had better short-term survival (3–5 years) but worse long-term survival (10 years and beyond). Immunosuppressive therapy may contribute to PTM while preventing graft rejection. Graft failure was a major cause of death in recipients without PTM. Factors like age and comorbidities may have a greater impact on long-term survival. Beyond 15–20 years, there was no statistical difference in survival, possibly due to other factors and decreased statistical power.

The major limitation of this study is that not all patients had the same length of follow-up period and actual incidence of PTM could not be calculated for individuals who did not reach the 1-year follow-up after transplantation. And although at least 10 years of follow-up results were investigated for most PTMs, only 9, 6, and 4 years of follow-up results were available for leukemia, Kaposi sarcoma, and brain tumor, respectively. Another limitation of this study is that we did not completely correct for the higher chance of developing cancer over time, even though we performed a landmark analysis. However, this study provided general information on PTMs in recipients who received DLT for non-cancerous diseases, offering a comprehensive landscape in this field.

In conclusion, the types and characteristics of PTMs in recipients who received DLT for non-cancerous diseases were highly diverse, and the incidence varied according to age and duration after transplantation. Additionally, the survival outcomes showed significant differences depending on the existence or types of PTM. Nevertheless, we were able to identify the specific times at which each type of PTM frequently occurred. By gaining a more comprehensive understanding of the characteristics of PTMs in recipients who have undergone DLT, it may become possible to predict with greater accuracy the specific types of PTM that are most likely to occur over time and to facilitate their early detection. Such insights can potentially revolutionize our approach to monitoring and managing PTMs in DLT recipients, ultimately leading to improved clinical outcomes and a better quality of life for those who have undergone this procedure.