De novo neoplasms are among the leading causes of late mortality in liver transplant recipients (LTRs) [1,2]. Within this group of diseases, lung cancer (LC) is one of the most frequent non-cutaneous tumors [3,4]. LTRs have a risk of LC that is twice as high as that of the general population [5–7], and their prognosis is worse due to competing mortality risks [8].

The risk of LC is higher after liver transplantation than after kidney transplantation [5]. Although immunosuppression plays a significant role in the development of de novo neoplasms [9], no studies have demonstrated that LTRs have a higher incidence of LC than non-immunosuppressed individuals when other risk factors are equal.

The main risk factor for LC in both, general population and LTRs, is smoking [10]. Smoking cessation is associated with a reduced risk of LC in both groups [6,11]. Other risk factors include female sex [12] and pulmonary centrilobular emphysema [13].

Although earlier studies did not show that chest X-ray screening reduced LC mortality [14–16], since the 1990s, low-dose computed tomography (LDCT) has demonstrated a reduction in LC mortality [17–19]. Given the higher incidence of LC in LTRs, screening in this population is particularly important. A recent study by our group showed that LDCT screening enables early diagnosis in a high percentage of LTRs [20].

The present study aims to analyse whether LTRs have a higher incidence of LC than a high-risk matched control group enrolled in a LC screening program. We compared screening results in LTRs with a matched cohort of non-immunosuppressed patients and analysed tumour characteristics and post-diagnosis outcomes in both groups.

This study compares two cohorts participating in an LC screening program: LTRs and non-immunosuppressed controls. Both cohorts were comparable in key LC risk factors: age, sex [12], cumulative smoking history [23,24], current smoking status [11], and emphysema.

A key finding is the higher LC incidence in LTRs compared to non-transplanted patients. Previous studies have shown increased LC incidence in LTRs [5–7], but did not account for differences in tobacco exposure. Given that alcohol-related liver disease is a major indication for liver transplantation and is associated with tobacco use [25], the higher LC incidence may reflect a greater proportion of smokers among LTRs. Our control group consisted of smokers with comparable tobacco histories. Thus, our findings reinforce the increased risk of LC in LTR, making them a vulnerable population, especially if they have a heavy smoking history or centrilobular emphysema.

Another important result is that LDCT screening enabled early diagnosis in a comparable or even higher proportion of LTRs than controls. This aligns with findings by Sigel et al. [8], who reported earlier LC stages at diagnosis in solid organ transplant recipients. This may be due to more intensive medical follow-up in transplant patients. Previous studies, such as Jiménez et al. [10], found that most LTRs were diagnosed at advanced stages and were associated to poor short term survival rates. In our series, early diagnosis led to better survival outcomes in LTRs than in other series and comparable to non-transplanted patients. However, survival curves showed reduced survival in LTRs after three years, likely due to higher comorbidity burden, despite similar cancer-specific survival [8].

Finally, histological differences were observed: LTRs had more squamous cell carcinomas, consistent with Sigel's findings [8]. Recent studies show increasing adenocarcinoma incidence [26], as seen in the NLST and NELSON trials [27,28]. These tumour types have distinct genomic profiles [29], influencing treatment response. Immunosuppression, particularly calcineurin inhibitors, may affect oncogene activation differently. In the same way, the proportion of histological subtypes of skin cancer is different in LTR and in general population. Basal cell carcinoma is the predominant skin cancer in general population (70% of them), while squamous cell carcinomas are more frequent than basal cell carcinomas in LTR [30]. Recently, a mutational signature has been found in tumours from patients on chronic immunosuppressive therapy (solid organ or allogeneic stem cell transplant recipients). This signature was not found in tumour from non-transplanted patients [31]. Specific mutational signatures, such as this, may explain in part these differences in the histological subtypes of malignancies between transplanted and non-transplanted patients.

Our study also identified cumulative tobacco exposure above 35 pack-years and centrilobular emphysema as significant LC risks factors. These high-risk patients may benefit from closer monitoring and stricter immunosuppression management [9]. In fact, the criteria for entering the LC screening program in our center (age above 40 years and cumulative smoking above 10 pack-years) [21] are less strict than the recommendations suggested by other groups such as the United States Preventive Services Task Force, that focus LC screening in patients between 55 and 80 years with a cumulative smoking history above 20 pack-years [32]. The use of the current stricter criteria may serve to do the LDCT screening more cost-effective. Despite our inclusion criteria, that were less strict than current recommendations, the cumulative incidence of LC in the control group was comparable or even higher than in other studies [17,33]. This reinforces the idea of the high risk of LC in LTR.

The main limitation of this study is its retrospective design, that may introduce information bias and carries the risk of missing variables that could be of relevance. Another limitation is the relatively small cohort size, which limits statistical significance. Nevertheless, this is the largest series evaluating LDCT screening in LTRs and the first to compare LTRs with matched controls. As with any single center study, the conclusions of this paper cannot be extrapolated to other centers in other geographical areas. Although carried out in a single centre, the study followed the screening protocol of the International Early Lung Cancer Action Project guidelines. Thus, their findings could be easily generalizable. Another important issue is the role of the cumulative exposure to immunosuppression [9], and its duration on the risk of LC. Unfortunately, due to the retrospective design and the limited sample size, this aspect could not be further explored.

In conclusion, LTRs have a higher risk of LC than the general population. LDCT screening enables early diagnosis in most cases and yields survival outcomes comparable to non-transplanted patients. Future multicenter studies are needed to confirm these findings. These studies should be prospective and include both transplanted and non-immunosuppressed patients. They could also be useful for individualizing LC screening programs according to risk factors and for further investigation of the potential role of different immunosuppressive therapies on the risk of LC.

Study conception: MCL, GB, JJZ, JP de-T, LS, JIH.

Data collection: MCL, PRPL, MI, AE, MS, FR.

Data analysis and interpretation: MCL, PRPL, GB, JIH.

Drafting of the manuscript: MCL, GB, JIH.

Critical review of the manuscript: All the authors.

Final approval of the manuscript: All the authors.

The authors have used Copilot for helping in the translation of the manuscript to English language and Notebook LM for the generation of the visual abstract.

This research did not receive any specific grant from funding agencies in the public, commercial, or non-profit sectors.

The authors declare not to have any conflicts of interest that may be considered to influence directly or indirectly the content of the manuscript.