According to a large longitudinal study recently published in the Journal of the American Medical Association, interstitial lung disease (ILD) more than doubled the risk of lung cancer. A sibling-controlled analysis showed nearly a tripling of lung cancer risk for individuals with ILD.1
“This is something that we had noticed in our own screening data,” said Claudia Henschke, PhD, MD, Professor of Radiology and Director of the Early Lung Cancer and Cardiac Action Program at the Icahn School of Medicine at Mount Sinai. “In our screening population, we often see early ILD, and in some cases, it progresses. And when patients with ILD [got] a lung tumor, they were more aggressive.
“This is the first study that I know of with a large cohort and that looked at siblings for genetic effects. I absolutely think ILD should be considered a risk factor in our lung cancer risk models.”
The study, Interstitial Lung Disease and Risk of Lung Cancer, followed 5.4 million individuals in the Swedish Total Population Register born between 1932 and 1987. All were followed from January 1,1987, until the first diagnosis of lung cancer, emigration from Sweden, death, or December 31, 2016, whichever occurred first.1
“Increased lung cancer risk with ILD is something we’ve had at least some data on for quite a long time,” said Bradford C. Bemiss, MD, Associate Professor of Pulmonary and Critical Care Medicine at Northwestern University Feinberg School of Medicine. “What has been harder to parse out is how much of that risk is due to smoking in general—it is very common that patients with ILD have a history of smoking—and how much may be related to genetics or other familiar factors, or environment. This study offers a clear answer to that question: Yes, patients with ILD have an increased risk of developing lung cancer.”
About half of the individuals in the study (51.2%) were male and 38.1% were 20 to 40 years of age. ILD was more common in men (58.1%) and in individuals older than 40 years old (65.9%). Of the 14,624 individuals who had ILD at baseline or were diagnosed during the study period, 9,157 had at least one full sibling without ILD.1
Individuals without ILD had 40,592 cases of lung cancer diagnosed during 30 years of follow up, an incidence rate (IR) of 26.2 per 100,000 person years. Among individuals with ILD, there were 227 cases of lung cancer—an IR of 355.4 per 100,000 person years. According to the study, elevated risks were observed for adenocarcinoma (HR, 1.60; 95% CI, 1.28-2.01), squamous cell carcinoma (HR, 2.56; 95% CI, 1.99-3.29), small cell carcinoma (HR, 3.29; 95% CI, 2.32-4.68), and other histological types (HR, 2.32; 95% CI, 1.78-3.01).
After adjusting for sex, age, calendar period, educational level, and smoking-related diseases, ILD had a hazard ratio (HR) of 2.16 (95% CI, 1.89–2.46)—a twofold increase. In the sibling cohort, ILD had an HR of 2.91 (95% CI, 1.98-4.27). Among individuals without smoking-related diseases, a proxy for smoking exposure, ILD carried an HR of 3.68 (95% CI, 3.07-4.41). Researchers concluded that smoking-related confounding did not account for the observed association between ILD and lung cancer risk.1
However, the statistical analysis does not completely rule out smoking effects in this cohort; smoking, lung cancer, and ILD may have other similar risks. Experts acknowledged the lack of information regarding ILD subtypes was a limitation. Additionally, information on the lung cancer lesions is also needed. For example, if a lesion developed in the area of ILD, fibrotic transformation may be linked with cancer cells development.
In addition to potential implications for lung cancer screening guidelines, this data may change how clinicians monitor their patients with ILD. For example, Dr. Bemiss said some clinicians order high-resolution follow-up CT scans every two to three years to track disease progression.
“Do I now get more frequent high-resolution scans?” he asked. “Probably not, because of radiation exposure. But I’m paying a lot more attention to what might be small lung nodules masquerading as confluences of scar tissue. This study increases the need to follow guidelines for lung nodule follow-up and not ignore some of those smaller, maybe less significant nodules we see.”
Dr. Henschke recommended low-dose CT scan lung cancer screening for individuals with ILD.
“For people with ILD, clinicians should suggest lung cancer screening because there is higher risk, and the tumors are typically more aggressive,” she said. “Low-dose CT scan is what is needed for effective lung cancer screening, even for individuals with ILD. You can do a tremendous amount of good by finding tumors early.”
The study’s authors said future research should focus on identifying the underlying mechanisms linking ILD with various histological subtypes of lung cancer.
References
1. Xu H, Yin L, Bian W, Kang M, Adami HO, Ye W. Interstitial lung disease and risk of lung cancer. JAMA Netw Open. 2025;8(7):e2519630. Published 2025 Jul 1. doi:10.1001/jamanetworkopen.2025.19630
