Evaluating cancer risk profiles in lung transplant recipients.

Introduction
Lung transplantation (LTx) provides a life-saving therapy for patients with end-stage lung diseases. The primary indications for LTx are fibrotic lung diseases, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and pulmonary vascular disease (PVD). Despite significant improvements in surgical techniques and the use of immunosuppressants, complications such as chronic lung allograft dysfunction (CLAD), infections, and malignancies remain major barriers to long-term survival after LTx (1).
Previous studies have shown that solid organ transplant recipients (SOTRs) have a higher number of incidence of malignancies compared to the general non-transplant population (2-12). A 2010 report from the International Society for Heart and Lung Transplantation (ISHLT) indicated that malignancies are prevalent complications following LTx. By the 5th and 10th years post-transplant, 13% and 28% of lung transplant recipients (LTRs), respectively, had developed at least one malignancy. Malignancy-related deaths constituted 13% of all mortalities occurring between 5 and 10 years post-transplant (13). The increased incidence of cancer is associated with the immunosuppressive drugs (ISDs) used to prevent organ transplant rejection. The suppression of the immune system (IS) reduces surveillance of cancer cells, allowing them to grow and spread freely (1,14). Moreover, the progression of certain tumors is closely associated with viral infections. Additionally, older age and higher smoking rates among LTRs may be key risk factors for developing tumors post-transplant (15).
Currently, research data on the incidence of tumors following LTx in recent years are limited. A deeper understanding of the cancer risk in LTx helps elucidate the roles of the IS, infections, and other factors in tumor development. It may also identify opportunities to enhance transplant safety and provide clinicians with a basis for specific cancer screening and prevention. Therefore, we analyzed the most recent data on post-lung transplant cancer incidence from the Network/United Network for Organ Sharing (UNOS) database to investigate the incidence and dynamic evolution of malignancies in LTx. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-546/rc).

Methods

Study population and data sources
We retrieved data on 42,183 LTRs in the United States (U.S.) from the UNOS database between 1987 and 2021. To reduce confounding bias, we excluded LTRs from racial/ethnic groups outside the major categories, those with incomplete baseline information, and those lost to follow-up. Given that a history of pre-transplant malignancies may increase the risk of de novo post-transplant malignancy (PTM), we also excluded cases with such histories (16). Additionally, to avoid misclassification and early-death bias, we excluded recipients in whom a pre-existing malignancy unrecognized at the time of transplantation was diagnosed within 30 days after transplantation, as well as recipients who died within 30 days after transplantation, because such early deaths are often attributable to graft failure. After screening, we obtained a final study cohort comprising 32,480 LTRs. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Statistical analyses
We collected demographic data and baseline characteristics of LTRs, including age, gender, race, time of transplant, and type of transplant procedure. Cancer types were classified according to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program. We also recorded the time to the first diagnosis of each specific cancer post-transplant. Categorical variables were compared using the Chi-squared test or Fisher’s exact test. The start date of follow-up was defined as the date of the first LTx surgery. The exit date was defined as the earliest of the following: the date of new cancer diagnosis post-transplant, the date of death, the date of re-transplant, or the end of the follow-up period.
To determine whether the incidence of malignancies in LTRs changes over time, we calculated annual incidence rates by calendar year: the number of incident cancers diagnosed during a given year divided by the total person-years (PY) accrued in that year. Additionally, we calculated the cumulative incidence of overall cancers and the four most common cancers, stratified by gender, age, type of transplant procedure, and history of underlying lung disease.
Additionally, to measure the cancer risk in LTRs compared to the general population, we calculated the standardized incidence ratio (SIR) for all cancers and for different cancer types. The person-time in the transplant cohort was stratified by age, gender, and calendar year. The expected number of cases for all cancers and specific cancer types was calculated by multiplying the PY for each stratum by the cancer incidence rates in the U.S. general population during the observation period. We used single calendar-year strata. The cohort from 1987 to 1999 was evaluated in 5-year age intervals (0–4, 5–9, ..., 80–84, 85+ years). The cohort from 2000 to 2021 was divided into five age groups (0–14, 15–39, 40–64, 65–74, 75+ years). When studying the incidence of Kaposi’s sarcoma (KS), we used SEER data from 1973 to 1979 because, since 1980, the incidence of this disease in the general population has been closely associated with the widespread transmission of human immunodeficiency virus (HIV). The SIR was calculated as observed cases divided by expected cases, and 95% confidence intervals (CIs) were derived from the Poisson distribution. We did not analyze cancers of cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC), as well as cancers of the vulva, perineum, penis, and scrotum; and tongue and throat; sarcomas (excluding KS); and other unknown tumors, as the incidence rates for these cancers are underreported in the SEER database for the general U.S. population (17,18).
All statistical analyses were conducted using Stata/MP version 17.0 (RRID:SCR_012763).

Results
Figure 1 summarizes the study selection process and inclusion/exclusion criteria. The study cohort included 32,480 LTRs with a total follow-up time of 151,854.3 PY. Among all LTRs, 36.18% completed a 5-year follow-up, and 10.79% completed a 10-year follow-up. The cohort consisted of 57% males (n=18,430) and 43% females (n=14,050). The proportion of LTRs aged between 40 and 65 years was 61%, with a median age of 58 years and an interquartile range (IQR) of 47 to 64 years. Most LTRs were White. The predominant type of LTx was DLT (n=21,524, 66%). The most common pre-transplant underlying lung diseases included COPD, idiopathic pulmonary fibrosis (IPF), and CF (Table 1).
Table 2 describes the age of LTRs at cancer diagnosis post-transplant, the time from transplant to diagnosis, and the incidence rates. During the follow-up period after LTx, a total of 7,506 patients were diagnosed with cancer, accounting for 7,889 cancer cases, as some patients had multiple types of tumors. The incidence rate of all cancers was 24.29%. Among these cancer cases, cSCC and BCC were the most common, with 3,706 and 1,054 cases, respectively, comprising 60.34% of all cancer cases. The 3rd most common post-transplant cancer was lung cancer, with 580 cases, accounting for 7.35% of all cancers, and an incidence rate of 455.55 per 100,000 PY. The 4th and 5th most common cancers were non-Hodgkin lymphoma (NHL) and colorectal cancer. In the cohort, the median age at diagnosis of new cancers was 64 years (IQR, 58–68 years). Among the various tumors, patients with cancers of the vulva, perineum, penis, and scrotum, kidney cancer, and bladder cancer had longer times from transplant to diagnosis. In contrast, patients with KS and NHL had shorter times from transplant to diagnosis.
Figure 2 shows the trend of cancer incidence over time in LTRs post-transplant. During the 10-year follow-up after LTx, the annual incidence of overall malignancies increased annually in the first 5 years. The annual incidence was 3.147% in the 1st year, peaked at 5.439% in the 4th year, and then stabilized, reaching 5.287% in the 10th year. The annual incidence of overall cancers, excluding non-melanoma skin cancer (NMSC), remained relatively stable, with a slight increase from the 7th to the 10th year post-transplant. The annual incidence rates were 1.820% in the 1st year, 1.643% in the 5th year, and 2.276% in the 10th year. Similar to the overall trend, certain tumors also exhibited an initial increase followed by a stabilization in incidence rates. cSCC remained persistently high with an early rise and later plateau; BCC showed a similar pattern. Lung cancer increased to a mid-period peak and then declined toward year 10. Several sites (e.g., vulva/perineum/penis/scrotum, stomach, colorectal) showed modest late increases. Viral-associated tumors were most frequent early after transplant, with NHL highest in year 1 and KS elevated in the first 2 years.
The cumulative incidence of overall cancer is shown in Figures 3,4. The cumulative incidence of overall cancer increases with age. Among LTRs under 40 years old, there is no significant difference in incidence rates between sexes. However, for those aged 40 and above, male LTRs have a higher incidence rate than female recipients. The 5-year cumulative incidence of overall cancer is 21.63%, and the 10-year cumulative incidence is 40.49%. The 5-year cumulative incidence of overall cancer, excluding NMSC, is 10.24%, and the 10-year cumulative incidence is 21.00%.
Figure 5 describes the cumulative incidence stratified by race, year of transplant, and type of transplant. The figure shows that non-Hispanic Whites have a higher incidence compared to other racial groups, the incidence from 1987 to 1999 is lower, and single lung transplantation (SLT) has a higher incidence than double lung transplantation (DLT). The four tumors with the highest cumulative incidence rates are cSCC, BCC, NHL, and lung cancer (Figure 6). The 10-year cumulative incidence rates are 23.28%, 6.69%, 3.14%, and 4.22%, respectively. Figures S1-S4 show that the cumulative incidence rates of cSCC, BCC, and lung cancer follow a similar trend to the overall tumor incidence rates. However, for NHL, there is no significant difference in cumulative incidence between sexes across age groups, and it does not show an increasing trend with age.
To assess the relative cancer risk in LTRs compared to the general population, we calculated the SIR for various cancer types. As shown in Table 3, LTRs are significantly more likely to develop malignancies compared to the general U.S. population (SIR =2.83, P<0.001). Most malignancies had significantly elevated SIRs (P<0.001), including KS, stomach cancer, liver cancer, NHL, melanoma, kidney cancer, esophageal cancer, small intestine cancer, prostate cancer, laryngeal cancer, bladder cancer, colorectal cancer, and lung cancer. Among these, KS (SIR =27.39, P<0.001) had the most notably elevated SIR. The four cancers with the highest SIRs were KS, NHL, liver cancer, and lung cancer. The risk for other tumors did not significantly increase.

Discussion
Overall, this retrospective cohort study identified an increased incidence of cancer in LTRs post-transplant. NMSC comprised the largest proportion of post-LTx malignancies. The incidence rates of various tumors in LTRs exhibited slight temporal variations, with the overall cancer incidence initially rising and then stabilizing. NHL and KS were predominantly reported within the first year or two post-LTx. Compared to the general U.S. population, the SIR for PTM (excluding NMSC) was 2.83. Most malignancies demonstrated significantly elevated SIRs, with the highest observed for KS, NHL, liver cancer, and lung cancer.
NMSC is the most common malignancy among SOT. LTRs are at significantly higher risk of developing skin cancer compared to other SOTRs. In this study, NMSC had the highest post-transplant incidence, accounting for 60.34% of all tumors. As shown in Figure 2, the risk of cSCC remains elevated for a considerable time post-transplant, with annual incidence rates of 2.88% in the 5th year and 2.28% in the 10th year. Previous studies have also reported high incidences of NMSC post-transplant. For instance, a study of North American LTRs found cumulative incidence rates of any skin cancer to be 31% and 47% at 5- and 10-year post-transplant, respectively (19). Unlike in the general population, where BCC is the most common type of skin cancer, cSCC is the predominant form of NMSC among LTRs. Compared to the general population, the risk of BCC in LTRs is increased ten times, whereas the incidence of cSCC is increased 65 times (20). This significant increase is likely associated with the use of ISDs, such as calcineurin inhibitors and azathioprine, as well as susceptibility to human papillomavirus (HPV). Therefore, the high incidence of NMSC post-transplant suggests that regular dermatological monitoring should be recommended for this population.
Post-transplant lymphoproliferative disorders (PTLDs) encompass a spectrum of pathological changes and clinical manifestations ranging from benign lymphoproliferation to malignant aggressive lymphomas (21). Compared to other SOTs, LTxs involve more lymphoid tissue and require higher levels of immunosuppression, resulting in a higher incidence of PTLD among LTRs. Most large transplant registries report SIRs of approximately 10 for NHL and around 4 for Hodgkin lymphoma (HL) (22). Our findings are consistent with these results. In SOT, pre-transplant Epstein-Barr virus (EBV) seronegativity is a significant risk factor for PTLD, which explains the higher incidence of PTLD in children compared to adults (23,24). This may also account for the younger median age at diagnosis for NHL (56 years) and HL (42 years) observed in this study compared to other tumors. Additionally, NHL frequently occurs within the first year post-transplant, which can be partly explained by the high-intensity immunosuppressive therapy administered during the initial post-transplant period. This intense immunosuppression weakens the IS, increasing the risk of viral infections (such as EBV) and tumor development. Another recent large international multicenter analysis found a nonlinear relationship between age and PTLD risk, with increased risk observed in recipients transplanted between the ages of 45 and 62 years (22). This study focuses on the first 10 years post-transplant, but there are increasing reports of late-onset cases occurring more than 20 years post-transplant (25,26). Overall, younger individuals have a higher risk of PTLD in the first year post-transplant. This suggests that clinicians should focus on identifying and preventing PTLD during its peak incidence period.
The risk of lung cancer in LTRs is 455.6 per 100,000 PY, which is 4.09 times higher than that of the general population. Previous studies have found that older age, smoking history, single lung transplant, history of COPD, and history of IPF are independently associated with an increased risk of post-transplant malignancies in LTRs (27). Notably, lung cancer incidence post-LTx is higher compared to kidney, liver, and heart transplants (2). Therefore, lung cancer screening and early diagnosis post-LTx are crucial. Additionally, for recipients who receive lungs from donors with a smoking history, post-transplant low-dose chest computed tomography (CT) should be used to enable early detection of de novo lung malignancy and thereby help mitigate this risk.
Additionally, other tumors also exhibit significant incidence rates. For instance, the incidence of KS [associated with human herpesvirus-8 (HHV-8)] is 27.39 times higher than in the general population, and liver cancer (linked to hepatitis viruses) has an SIR of 5.45. The increased incidence of these tumors is related to the heightened susceptibility to viruses caused by immunosuppression. Some tumors not related to viral infections, such as melanoma, also show higher incidence rates. Treating new cancers post-transplant is challenging, as reducing immunosuppressants can trigger rejection, and immune checkpoint inhibitors (ICIs) are contraindicated in SOTRs. Therefore, early identification and treatment of tumors are crucial, based on the characteristics of post-transplant tumor development.

Conclusions
In summary, among LTRs in the U.S. from 1987 to 2021, 23.11% developed new primary lung cancer. This study aims to report the incidence and temporal evolution of tumors post-LTx to aid clinicians in the prevention and early diagnosis of post-transplant malignancies, thereby enhancing postoperative care and improving survival. Therefore, increased attention should be given to monitoring post-transplant tumors, evaluating cancer incidence, and identifying risk factors in all LTRs.

Supplementary
The article’s supplementary files as