Long-term cancer risk associated with lung nodules observed on low-dose screening CT scans
Introduction
Non-calcified nodules (NCNs) associated with false positive low-dose CT (LDCT) screens for lung cancer have been attributed to various causes, including infectious and inflammatory processes [1,2]. There is also evidence that some NCNs may represent lung cancer precursors. This evidence comes from case series of surgically resected NCNs, where some lesions have been shown to represent atypical adenomatous hyperplasia, a lung adenocarcinoma precursor [3,4]. Further indirect support for this hypothesis comes from a study of participants in the National Lung Screening Trial (NLST) who had NCNs found on LDCT screening [5]. Participants with baseline NCNs had significantly higher lung cancer incidence in the period 5–7 years post-screening controlling for standard lung cancer risk factors. Additionally, the excess risk was location-specific, as the location of the lung cancer was correlated with the location of the baseline NCN [5].
In this paper, we extend the above analysis of NLST LDCT arm participants in several ways. First, we extend the follow-up time for baseline nodules to up to 12 years. Second, we also assess long-term risk associated with new (non-pre-existing) nodules reported on post-baseline screens. Finally, we examine lung cancer histology in relation to NCN status and time period.
Section snippets
NLST design
The design of NLST has been reported previously [6,7]. Briefly, men and women aged 55−74 years with at least 30 pack-years of cigarette smoking and who were either current smokers or had quit within the past 15 years were enrolled at 33 medical institutions across the U.S. between 2002 and 2004. Exclusion criteria included previous lung cancer diagnosis, a CT scan in the prior 18 months, unexplained weight loss in the year before enrollment, or hemoptysis. Participants were randomized into a
Baseline analysis
A total of 26,309 participants received the baseline LDCT screen (Fig. 1). For this baseline cohort, 59 % were men, 50 % current smokers and 27 % age 65 or over. Median (25th/75th) follow-up for cancer incidence was 11.3 (9.3/11.7) years.
Of the 26,309 participants, 7090 (26.9 %) had a NCN at baseline (Table 1). For the lobe-level analysis, among all 131,545 (i.e., 5*26,309) lobes, 9448 (7.2 %) had a baseline NCN. Among lobes with NCNs, 75.8 % had at least 1 solid NCN, 20.5 % had at least one
Discussion
We have shown here that NCNs identified on LDCT screening were predictive of lung cancer risk up to ten or more years following the screen. Further, the risk was spatially correlated with nodule location, with the rate-ratio higher for the lobe-level than person-level analysis. The excess risk persisted when controlling for other lung cancer risk factors, suggesting that the NCNs themselves, at least a subset, may be lung cancer precursors. If this is the case, this sheds light on the natural
CRediT authorship contribution statement
Paul Pinsky: Conceptualization, Methodology, Formal analysis, Investigation, Resources, Writing - original draft, Writing - review & editing. David S. Gierada: Conceptualization, Investigation, Resources, Writing - review & editing.
Declaration of Competing Interest
The authors have no competing interests to declare.
Acknowledgments
This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors. The authors report no conflicts.
Cancer incidence data have been provided by the following state cancer registries: Alabama, Arizona, California, Colorado, District of Columbia, Georgia, Hawaii, Idaho, Indiana, Iowa, Kentucky, Louisiana, Maryland, Massachusetts, Michigan, Minnesota, Missouri, Nevada, North Carolina, Ohio, Pennsylvania, Rhode Island, Texas, Utah, Virginia
References (16)
- et al.
Can lung cancer screening by computed tomography be effective in areas with endemic histoplasmosis?
J. Thorac. Cardiovasc. Surg.
(2011) - et al.
Benign features of infection-related tumor-like lesions of the lung: a retrospective imaging review study
J. Med. Imaging Radiat. Oncol.
(2017) - et al.
Persistent pulmonary nodular ground-glass opacity at thin-section CT: histopathologic comparisons
Radiology
(2007) - et al.
A clinicopathological study of resected pulmonary nodules with focal pure ground-glass opacity
Eur. J. Cardiothorac. Surg.
(2006) - et al.
Short- and long-term lung cancer risk associated with noncalcified nodules observed on low-dose CT
Cancer Prev. Res. Phila. (Phila)
(2014) - et al.
The National Lung Screening Trial: overview and study design
Radiology
(2011) Reduced lung-cancer mortality with low-dose computed tomographic screening
N. Engl. J. Med.
(2011)Lung cancer incidence and mortality with extended follow-up in the National Lung Screening Trial
J. Thorac. Oncol.
(2019)
Cited by (16)
Low-Dose Computed Tomography Screening in Relatives With a Family History of Lung Cancer
2023, Journal of Thoracic OncologyPotential Impact of Criteria Modifications on Race and Sex Disparities in Eligibility for Lung Cancer Screening
2023, Journal of Thoracic OncologyCitation Excerpt :Annually, lung nodules are incidentally detected in thousands of individuals who had radiologic imaging for reasons other than a concern for lung cancer, a few of which ultimately prove to have lung cancer.17,18 Although the risk characteristics of such persons vary significantly from participants in LDCT programs, guideline-concordant management of incidentally detected lung nodules provides an alternative pathway to early lung cancer detection.8,15,19–21 Systematic evaluation of this population provides a “natural experiment” to gain insight into the lung cancer risk characteristics of individuals across the spectrum of alternative LDCT eligibility criteria.
Management of Lung Cancer Screening Results Based on Individual Prediction of Current and Future Lung Cancer Risks
2022, Journal of Thoracic OncologyCitation Excerpt :For individuals who do not have a negative screen result but instead have an abnormal LDCT result that does not lead to a lung cancer diagnosis (a “return-to-screening” abnormal LDCT result), it is unclear whether biennial screening could be acceptable. Abnormal LDCT results, which are usually abnormal because of a nodule with longest diameter of 4 mm or greater, are common1,14 and increase future lung cancer risk.15 Many individuals with abnormal results are recommended a surveillance CT, and the vast majority have “return-to-screening” abnormal LDCT results because they do not lead to immediate cancer diagnosis.1,16,17
RASSF1A: A promising target for the diagnosis and treatment of cancer
2020, Clinica Chimica ActaCitation Excerpt :Currently, low-dose Computed Tomography (CT) is routinely used to diagnose lung cancer in high-risk people. However, it has a high false-positive rate (96%) for the diagnosis of early lung cancer [22,23]. Therefore, it is imperative to identify patients with lung cancer at earlier stages by a reliable marker.
Acute pneumothorax due to immunotherapy administration in non-small cell lung cancer
2020, Respiratory Medicine Case ReportsCitation Excerpt :It is still diagnosed at advanced stage since there are no early disease symptoms. Currently we are trying to identify high risk patients and develop and algorithm of diagnosis and pulmonary nodule follow up [2,3]. We have novel diagnostic equipment with radial-endobronchial ultrasound (R-EBUS), convex probe endobronchial ultrasound (CP-EBUS), electromagnetic navigation, Veran SPiNDrive system, transthoracic needle biopsy with under CONE BEAM CT, archimedes bronchoscopic trans-parenchymal nodule biopsy, bronchoscopic transparenchymal nodule access, thin-ebus [4–7].