Interstitial Lung Disease and Risk of Lung Cancer

Abstract

Importance: An association between interstitial lung disease (ILD) and lung cancer has been hypothesized but never established. To date, whether this potential association persists after controlling for genetic factors has not been addressed.

Objective: To evaluate the association between ILD and the subsequent risk of different histological subtypes of lung cancer in the general population and a sibling-controlled cohort.

Design, setting, and participants: This cohort study incorporated both population-based and sibling-controlled designs and used data from the Swedish Total Population Register and Swedish Multi-generation Register. Participants included individuals born between 1932 and 1987, with follow-up starting January 1, 1987, and continuing until December 31, 2016. Data were analyzed from February 15, 2024, to January 30, 2025.

Exposures: ILD.

Main outcomes and measures: The association between ILD and lung cancer was evaluated using multivariable hazard ratios (HRs) and 95% CIs.

Results: Among the 5 425 976 individuals involved in this study (14 624 with ILD and 5 411 352 from the general population), 2 779 108 (51.2%) were male and most (2 068 062 [38.1%]) were 20 to 40 years of age. Among patients with ILD, most (9630 [65.9%]) were older than 40 years. During a 30-year follow-up period, 40 592 cases of lung cancer were diagnosed among those without ILD (incidence rate, 26.2 per 100 000 person-years) and 227 cases among those with ILD (incidence rate, 355.4 per 100 000 person-years). After adjusting for sex, age, calendar period, educational attainment, and smoking-related diseases, individuals with ILD had a higher risk of lung cancer (HR, 2.16; 95% CI, 1.89-2.46). Sibling-controlled analyses showed a higher risk (HR, 2.91; 95% CI, 1.98-4.27). 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). Results from sibling-controlled analyses generally mirrored these findings.

Conclusions and relevance: This large prospective cohort study found that ILD was associated with increased risk of most histological subtypes of lung cancer. Therefore, the presence of ILD should be included in lung cancer risk assessment models.

Figure 1.. Flowchart of Patient Selection Process

ILD indicates interstitial lung disease. ^aIncludes all individuals born between 1932 and 2016 whose parents were also born in Sweden.

Figure 2.. Incidence and Risk by Subtypes of Lung Cancer Associated With Interstitial Lung Disease

Incidence rates (IR) per 100 000 person-years and hazard ratios (HR) with 95% CIs for various histological subtypes of lung cancer associated with interstitial lung disease (ILD) (1-year lag time). A, IRs and HRs were estimated across the general population with and without ILD. B, IRs and HRs were derived from analyses within cohorts of patients with ILD and their siblings without ILD, accounting for shared genetic and environmental factors. ^aIncludes epithelial tumor neoplasms, large cell carcinoma, undifferentiated carcinoma, bronchioloalveolar adenocarcinoma, neuroendocrine carcinoma, and adenosquamous carcinoma.