Elsevier

Lung Cancer

Volume 139, January 2020, Pages 179-184
Lung Cancer

Long-term cancer risk associated with lung nodules observed on low-dose screening CT scans

https://doi.org/10.1016/j.lungcan.2019.11.017Get rights and content

Highlights

  • The presence of nodules on low-dose CT screening was associated with increased risk of lung cancer up to 12 years later.

  • Lung cancers diagnosed even more than 4 years after nodule detection tended to occur in the same lung lobe as the nodule.

  • Long-term lung cancer risk differed based on the size and attenuation of nodules.

Abstract

Objective

Non-calcified nodules (NCNs) associated with false positive low-dose CT (LDCT) lung cancer screens have been attributed to various causes. Some, however, may represent lung cancer precursors. An association of NCNs with long-term lung cancer risk would provide indirect evidence of some NCNs being cancer precursors.

Methods

LDCT arm participants in the National Lung Screening Trial (NLST) received LDCT screens at baseline and years 1-2. The relationship between NCNs found on LDCT screens and subsequent lung cancer diagnosis over different time periods was examined at the person and lobe level. For the latter, a lobe had a cancer outcome only if the cancer was located in the lobe. Separate analyses were performed on baseline and post-baseline LDCT findings; for the latter, those with baseline NCNs were excluded and only new (non-pre-existing) NCNs examined. Raw and adjusted rate-ratios (RRs) were computed for presence of NCNs and subsequent lung cancer risk; adjusted RRs controlled for demographic and smoking factors.

Results

26,309 participants received the baseline LDCT screen. Over median 11.3 years follow-up, 1675 lung cancers were diagnosed. Adjusted RRs for time periods 0–4, 4–8 and 8−12 years following the baseline screen were 5.1 (95 % CI:4.4–5.9), 1.5 (95 % CI:1.3–1.9) and 1.5 (95 % CI:1.2-1.8) at the person-level and 14.7 (95 % CI:12.6–17.2), 2.6 (95 % CI: 2.0–3.4) and 2.2 (95 % CI:1.6–2.9) at the lobe-level. 18,585 participants were included in the post-baseline analysis. Adjusted RRs for periods 0–4, 4–8 and 8−11 years were 5.6 (95 % CI: 4.5–7.0), 1.9 (95 % CI: 1.3–2.7) and 1.6 (95 % CI: 0.9–2.9) at the person-level and 19.6 (95 % CI:14.9–25.3), 2.5 (95 % CI:1.3–4.7) and 3.3 (95 % CI:1.4–7.6) at the lobe-level. Raw RRs were similar.

Conclusion

NCNs are associated with excess long-term lung cancer risk, suggesting that some may be lung cancer precursors.

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)

  • S.L. Starnes et al.

    Can lung cancer screening by computed tomography be effective in areas with endemic histoplasmosis?

    J. Thorac. Cardiovasc. Surg.

    (2011)
  • C. Huang et al.

    Benign features of infection-related tumor-like lesions of the lung: a retrospective imaging review study

    J. Med. Imaging Radiat. Oncol.

    (2017)
  • H.Y. Kim et al.

    Persistent pulmonary nodular ground-glass opacity at thin-section CT: histopathologic comparisons

    Radiology

    (2007)
  • T. Ohtsuka et al.

    A clinicopathological study of resected pulmonary nodules with focal pure ground-glass opacity

    Eur. J. Cardiothorac. Surg.

    (2006)
  • P.F. Pinsky et al.

    Short- and long-term lung cancer risk associated with noncalcified nodules observed on low-dose CT

    Cancer Prev. Res. Phila. (Phila)

    (2014)
  • D.R. Aberle et al.

    The National Lung Screening Trial: overview and study design

    Radiology

    (2011)
  • The National Lung Screening Trial Research Team

    Reduced lung-cancer mortality with low-dose computed tomographic screening

    N. Engl. J. Med.

    (2011)
  • National Lung Screening Trial Research Team

    Lung cancer incidence and mortality with extended follow-up in the National Lung Screening Trial

    J. Thorac. Oncol.

    (2019)
There are more references available in the full text version of this article.

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