Utilization and outcomes of lung transplant from donors with cancer: a UNOS study

Introduction

Lung transplantation is the only option for selected patients with end-stage lung disease. However, approximately 15% of transplant candidates die on the waitlist each year due to a shortage of adequate donors (1). Expanding the size of the donor pool by transplanting organs from extended criteria donors has resulted in increasing the number of transplants without increasing the risk of mortality relative to standard donors (2). Donors with cancer diagnosis are another potential under-utilized source of lung allografts.

The primary concern when utilizing allografts from donors with cancer is the possibility of donor to recipient cancer transmission. In the setting of systemic immunosuppression following transplantation, micro-metastases in the transplanted organ could theoretically evade the host immunosurveillance and clearance and progress to invasive malignancies known as donor-transmitted cancer (DTC). We would like to clarify the difference between DTC and donor-derived cancer (DDC) that were often used in literatures. DDC by definition, refers to cancer genetically derived from donor cells, this includes DTC as well as de novo malignancy arising from any donor-origin cells residing in the transplanted organ. In the case of lungs there are pneumocytes, epithelial, endothelial and lung resident immune cells. If an extrapulmonary malignancy develops in the recipient shares the same pathological features as donor’s diagnosed malignancy, it would be highly suspicious for a DTC. On the other hand, if a primary lung cancer developed in the transplanted lung, it would likely be an undetected donor lung cancer at the time of donation or a de novo primary cancer after transplant. These are both DDC but should not be considered as DTCs and or as a risk for utilizing donors with a cancer diagnosis. The American Society of Transplant Surgeons (ASTS) published recommendations to guide transplant centers with donor cancer transmission risk stratification in the early 2000s (3,4). These guidelines were formulated from several pilot studies published in the 1990s to early 2000s (5,6), which reported a 23–46% rate of DTC from donors with solid organ malignancies. This substantial risk of transmission set the tone for the later published expert consensus which discouraged the use of organs from donors with diagnosed malignancies with limited few exceptions (7,8).

However, the evidence supporting these guidelines came from a few case reports and several large samples studies based on The Israel Penn International Transplant Tumor Registry (IPTTR), a voluntary registry which focused on collecting data from patients with transplant-related tumors from across the world. The intrinsic reporting bias limited its ability to reflect the true prevalence of DTC, let alone to provide evidence for clinical guidelines. Meanwhile, other publications based on national mandatory registries or non-selective institutional data have found a much lower rate of DTC (<0.03%) when using donors with primary brain cancers (9-15). In addition, a separate study of recipients of organs from donors with extracranial cancers (16,17), including the first United Network for Organ Sharing (UNOS) study on donors with cancer published in 2000 (18), found no cases of DTC after 2 years follow-up.

A recently published prospective study that followed 778 transplant recipients from 2000 to 2016 who received organs from donors with diagnosis of primary brain cancer, observed 83 cases with post-transplant malignancy. None of the malignancies matched the histology of the donor cancer type, which suggested the malignancies was not DTC. Furthermore, after matching on variables that could affect post-transplant survival, specific to the organ that was transplanted, the survival between the recipients of donor organs with cancer and matched controls was equivalent (19). A limitation of these findings was that the malignancy type was limited to brain tumors, so the results do not generalize to other cancers. However, these results suggest that the current recommendations regarding the use of donors with cancer are conservative, and further studies are necessary.

In the present study, we utilized the UNOS database to compare the outcomes of lung transplant recipients from donors with intracranial or extracranial cancer at procurement to the recipients of standard donors without cancer during the period of 2006 to 2023). We hypothesized that recipients of donors with cancer have similar survival and risks of cancer transmission when compared to those of donors without cancer. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-861/rc).

Methods

Database

Data were obtained from UNOS in the form of a deidentified Standard Transplant Analysis and Research (STAR) file, based on Organ Procurement and Transplantation Network data as of September 30, 2023. The STAR file includes selected data on all deceased organ donors and transplant recipients in the United States across all solid organ transplants. Donor records were linked to transplant recipients using the unique donor identification code. Data on cancer location (intracranial vs. extracranial) were provided in a supplementary file from UNOS and also linked via the donor identification code. Follow-up data were obtained from the transplant recipients follow-up file which contains an annual visit report. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of the University of Pittsburgh (STUDY20050181). Informed consent was not required as the data are publicly available from the UNOS.

Population

Deceased donors with cancer were identified from the deceased donor file. Inclusion criteria included adult lung transplant recipients (≥18 years of age) who received lungs procured during the Lung Allocation Score (LAS) era (May 4, 2005 to March 9, 2023) or the Continuous Distribution era (March 9, 2023 to September 30, 2023). Exclusion criteria were cases of skin cancer, which were categorized separately and considered neither extracranial nor intracranial; multiorgan transplants; and recipients with a history of prior transplant.

Exposure

The “Deceased Donor Registration Worksheet” of UNOS listed two cancer relevant variables: “History of cancer” and “Cancer at the time of procurement”. We used the latter in our study, which excluded remote cancers that are considered cured.

Outcomes

The primary outcome of this study was overall survival (OS) of lung transplant recipients from time of transplant. The secondary outcomes are cancer-related outcomes including the incidence of any post-transplant malignancy, donor-related malignancy, recurrence of pre-transplant malignancy of recipients and de novo malignancy after transplant. All the above stated outcomes were collected in the UNOS database and reported by the institution where the recipients underwent follow-up visits. Note that “donor-related malignancy” was reported as a survey question by clinicians where definitive proof of donor relation to the cancer (e.g., genetic testing, pathology) was not required or collected by UNOS.

Statistical analysis

The analysis used statistical matching to match recipients of lungs from donors with cancer to recipients of standard lungs. Donor variables for matching included age, sex, type (donation after circulatory death vs. brain death), Epstein-Barr virus (EBV), and cytomegalovirus (CMV) serostatus, terminal creatinine, smoking history, presence of heavy alcohol use, and history of hypertension. Recipient variables for matching included age, sex, and diagnostic indication for transplant. Variables were selected based on clinical experience, links to cancer risk, and prior literature (19). Matching was performed using a genetic matching algorithm with a four-to-one control to case ratio. Matching success was verified by confirming that standardized mean differences on all matching variables were <0.10.

Univariable comparisons were conducted to assess differences in donor and recipient characteristics between groups defined by donor cancer status (no cancer, intracranial cancer, and extracranial cancer). Continuous variables were analyzed using Wilcoxon rank sum tests and categorical variables were analyzed using Pearson’s Chi-squared or Fisher’s exact tests, as appropriate. Results are reported as median [interquartile range (IQR)] for continuous variables and count (percentage) for categorical variables. Where overall differences were significant in comparisons involving more than two levels, post hoc pairwise comparisons were performed using Dunn’s test for continuous variables, and adjusted standardized residuals were examined for categorical variables.

Survival was analyzed using the Kaplan-Meier method, with differences between groups evaluated using the log-rank test. Follow-up time was defined from the date of transplant to the date of death or last known follow-up. Survival curves were generated using the survminer and survival packages in R. Multivariable Cox proportional hazards regressions were performed with donor and recipient variables that were significantly different between groups in univariable comparison entered as nuisance covariates. The proportional hazards assumption was tested by testing for an association between the Schoenfeld residuals with time. Hazard ratios (HRs) are presented as HR [95% confidence interval (CI)].

All statistical tests were two-sided, with a significance threshold of P<0.05. Analyses were conducted in R (version 4.5.1), using the gtsummary, survival, survminer, and dunn.test packages (20).

Results

From April 2006 to September 2023 there were 935 donors registered in the UNOS database that had cancer diagnosis at procurement (Figure 1). Extracranial malignancies were 67% (n=631) and 33% were intracranial (n=304). Of the 935 deceased donors with cancer at procurement, 66.5% (n=622) had at least one organ transplanted. Organs were more likely to be transplanted if the donor had intracranial vs. extracranial cancer (Table 1). Among donors with extracranial cancer there was no association between the location of the extracranial tumor and the likelihood of the lungs from these donors being transplanted (Table S1).

Figure 1 Flow chart of patient selection.

Of the 151 pairs of lungs recovered from donors with cancer at procurement 125 (83%) were transplanted. Of the 125 transplants, 123 were single or double lung transplants. Four cases were missing data on matching variables [hypertension history (n=2), smoking history (n=1), and EBV status (n=1)] yielding a final cohort of 119 donors who had lungs transplanted. The 119 cases were successfully matched to 476 control cases. After matching, there remained an expected association between donor cause of death and treatment group with the donors with cancer group having higher rates of death from CNS tumor than the control group (Table 2; 49% vs. 0.9%, P<0.001). There was an association between donor race and group with the cancer group having lower than expected rates of Hispanic donors (6.7% vs. 14%, P=0.03). Additionally, donors with cancer had slightly higher pH [7.44 (IQR, 7.40–7.48) vs. 7.42 (IQR, 7.38–7.46), P<0.001], and tended to have slightly lower rates of donors with at least one extended criterion (67% vs. 79%, P=0.008) than donors without cancer.

Recipients of lung allografts from donors with cancer were overall similar to recipients of allografts from standard donors (Table 3). Recipients of lung allografts from donors with cancer did tend to have lower wedge pressure [8.0 (IQR, 6.0–12.0) vs. 10.0 (IQR, 6.0–14.0) mmHg, P=0.02] than recipients of allografts from standard donors.

Long-term clinical follow-up data provided by the annual recipient visit report were available for 113 (95.0%) recipients of allografts from donors with cancer, and 439 (92.2%) recipients of allografts from standard donors. Recipients without follow-up data were either within one year of transplant or deceased before the 1-year follow-up. Post-transplant malignancy rates were similar between recipients of allografts from donors with cancer and recipients from standard donors (Table 4; 27% vs. 23%, P=0.40), and donor-related malignancies were similar and very low (0.9% vs. 0.2%, P=0.37). The single case of donor-related malignancy (or DDC) that occurred in a recipient was from a donor with intracranial cancer (Table S2). There was also no difference in rates of recurrence of pre-transplant malignancy (0.9% vs. 1.4%, P>0.99), or de novo malignancies (25% vs. 21%, P=0.37) between recipients of donors with intracranial vs. extracranial cancer.

Survival data were available for the complete study population. The median follow-up time was 3.0 years. During follow-up, 65 (54.6%) deaths occurred in recipients of allografts from donors with cancer, and 239 (50.2%) deaths occurred in recipients of standard donor lungs. There was no association between donor type and cause of death in recipients (Table S3; P=0.14). There was no significant difference in survival time between the two groups [Figure 2; donors with cancer: 6.6 (IQR, 5.3–9.7) years vs. donors without cancer: 6.4 (IQR, 5.6–7.1) years; χ²(1) =0.86; P=0.35]. The difference between groups remained nonsignificant when nuisance covariates (donor race, donor cause of death, donor pH, 1+ extended criteria, recipient pulmonary wedge pressure) were added to the model [cancer HR: 1.10 (95% CI: 0.63–1.32); P=0.61; nuisance covariate data not significant and not shown].

Figure 2 Kaplan-Meier survival analysis of lung transplant recipients with allografts from donors with cancer vs. without cancer at procurement.

When the location of donor cancer (intracranial vs. extracranial) was separated, there was also no difference in survival time between groups {Figure S1; intracranial cancer 6.5 (IQR, 5.2–9.9) years, extracranial cancer 6.6 [5.0–infinity (Inf)] years, donors without-cancer 6.4 (IQR, 5.6–7.1) years; χ²(2) =1.05; P=0.59}. The difference between groups remained nonsignificant when nuisance covariates were added to the model [extracranial cancer HR: 1.04 (95% CI: 0.62–1.48), intracranial cancer HR: 1.23 (95% CI: 0.43–1.53), P=0.85 and 0.52, respectively; nuisance covariate data not significant and not shown].

As a sensitivity analysis, we excluded 15 recipients (13% of the cancer group) with a history of malignancy and repeated propensity score matching in the reduced cohort. Outcome comparisons remained consistent with the primary analysis; p-values for group differences remained non-significant (Table S4).

Discussion

Lung transplants from donors with cancer at procurement are rarely performed. The major concern when utilizing a donor with cancer arises from the transmission of donor cancer (known as DTC), regardless of histological types. However, confirmation of a DTC requires genetic testing to identify its donor origin or at least pathology to show an identical histological feature as the known donor cancer. In UNOS or the majority of the other registries, DDC or donor-related malignancy, instead of DTC was reported to reflect cancers developed on recipients that are related to the donors (10). And the judgement of relation was based on pathology and/or tumor locations by clinician.

Previous studies that have examined outcomes of organ transplants from donors with cancers often did not include lung transplants (17,21-23). Typically, the focus has been on stratifying the risks of DDC based on the histologic features of the primary tumor and applying such criteria globally to solid organ transplantation. Systematic reviews have been reported on tumor transmission after kidney transplantation (21,24). However, different organs harbor distinct levels of risks for developing metastasis or transmitting donor cancers. One published case series reported discrepancies in donor cancers transmission among different organs recovered from the same donors (23). Data on lung transplantation is necessary to appropriately evaluate the risks of cancer transmission, outcomes, and the safety of selective use of these donors. In the present study we used a nationwide database to examine the risk of DDC in the context of lung transplantation. Although true DTC risk is not comparable, DDC as a larger entity that contains DTC and allograft lung cancers, still provides a valuable assessment of cancer transmission. Nevertheless, we found that the risk for DDC was similar between donors with and without cancer at time of procurement.

Central nervous system (CNS) tumors were the first type of tumor considered for organ donation as they are thought to possess a lower risk for transmission than extracranial cancers. Low grade tumors, such as meningioma, are widely accepted for organ donation while utilization of donors with high grade CNS tumors remains controversial (11,13,15). Studies on the risk of cancer transmission to extracranial organs from high grade CNS tumors had found the risk not to be significantly different from low grade CNS tumors, despite only a 78% utilization of donors with grade 3 and 60% with grade 4 primary brain tumors (19). The present study found a comparable low risk of DDC in lung transplant recipients from donors with CNS tumors. Unfortunately, given the limitation of UNOS database, we were unable to further examine the safety of using donors with high grade tumors without high-risk factors (25,26) at time of donation.

Additionally, we observed that lungs from donors with intracranial cancer at procurement were three times more likely to be used than donors with extracranial cancer. This finding reflects the general concern of undetected lung metastases from non-CNS malignancy. Similarly, although without significant impact on primary outcomes, lung transplants of donors with cancer presented with more optimal baseline characteristics (less 1+ extended criteria donors, lower wedge pressures in recipients) suggesting a potential selection bias by the transplant team. Our subgroup analysis between intra- and extracranial cancer donors did not demonstrate a difference in survival and cancer risks. There was only one case of DDC reported in the extracranial group. In the cohort we studied, risk of DDC via lung transplant remains low in donors with extracranial cancer at procurement and the OS was comparable to standard donors. However, we were unable to draw any definitive conclusion on the safety of using cancer donors since there is a lack of granularity in the UNOS database in regards to histology gradings, cancer staging, time of diagnosis and cancer therapies at the time of donation.

Our data also found no differences in all categories of post-transplant cancer between recipients of donors with and without cancer. Notably, the donor-related malignancy (or DDC) rate of 0.07% in the non-cancer group in our study, is a much higher rate than reported rate among all organ transplants (0.017%) (27) but consistent with rates in general lung transplant recipients cohort reported in the United Kingdom Registry (23). Since there was no established diagnosis of cancer in the corresponding donors in the controlled lung transplant recipient cohort, these were primary lung cancers developed on lung allografts, rather than DTC from donors. It is possible that immunosuppression needs in lung transplant recipients and the relatively higher incidence rate in primary lung cancer explains the higher rates than other organs. We should be cautious that although primary allograft cancers were documented as DDC/donor-related malignancy, it should not be considered a risk associated with the use of donors with extra-pulmonary malignancy.

There are multiple limitations in the current study. First of all, the sample size of recipients of lungs from donors with cancer was small—likely an effect of the hesitation of transplant programs to utilize this resource. This limited sample size conferred reduced statistical power in the survival analyses and reduced our ability to explore heterogeneity within the cancer group. Additionally, the large overall sample size when comparing to non-cancer donors may have overpowered the univariable comparisons to detect differences that were due to chance but not clinically meaningful. Second, we were unable to perform analyses of cancer-free survival time of the recipients due to lack of data in UNOS on when the cancer was diagnosed. Additionally, although the rate of donor-related cancer was not higher in recipients of lungs from donors with cancer, we cannot fully eliminate the possibility that the reported de novo malignancies were actually donor origin metastasis without genetic testing. Most importantly, the UNOS registry does not include characteristics of donor cancer such as grading, staging, treatment and clinical progression, which precludes more sophisticated analyses thus limits our ability to conclude on the risk and safety of utilizing cancer donors. A low-grade, early-stage malignancy would have less risk of micro-metastasizing to the lungs, evading from recipients’ immunosurveillance and developing a DTC. Thus, the risk of DTC ideally should be studied based on stratification of the donor cancers. We want to emphasize the necessity of including these donor data in future studies to further validate this phenomenon. Studies on multiorgan donors with cancer will also be important to compare this phenomenon on other solid organ transplants.

Conclusions

The data in the present study suggests that lung transplants from selected donors with cancer at procurement might not necessarily cause direct cancer transmission or affect post-transplant survival on the recipients. However, the lack of data granularity of donor cancers and the small sample size might limit the validity of the presented results and should be acknowledged. We report this preliminary observation to advocate for cancer-related data collection by national and institutional registries to facilitate thorough investigations in safety of utilizing donors with cancer in lung transplantation.

Acknowledgments

We thank the Department of Health and Human Services of the United States for supporting the UNOS database.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-861/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-861/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-861/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of the University of Pittsburgh (STUDY20050181). Informed consent was not required as the data are publicly available from the UNOS.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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