Lung cancer and interstitial lung diseases: immunological and molecular presentation

Background: Interstitial lung disease (ILD) is a heterogeneous group of diffuse parenchymal lung diseases. Fibrotic ILD are known independent risk factor for lung cancer (LC) and shares predisposing factors. Particularly idiopathic pulmonary fibrosis (IPF), the archetype for ILD, occurring predominantly in male smokers  60 years old, has a well-established link with LC development. However, few data are available about these patients and molecular and histopathological features of LC associated with ILD are yet to be fully understood, especially in the light of the new therapeutic opportunities. Identifying a specific phenotype of ILD-LC should be the key to providing a basis for an upcoming specific therapeutic regimen. Aim of the study: This study aimed to evaluate the histological, immunological, and mutational presentation of LC in ILD patients. To this aim, we evaluated LC in a retrospectively enrolled cohort and compared IPF and non-IPF-ILD patients. To better evaluate PD-L1 positivity and expression and the prevalence of driver mutations, ILD-LC patients were compared to a cohort of non-smoker with LC patients and a cohort of chronic obstructive pulmonary disease (COPD) with LC patients. We also aimed to evaluate different treatment strategies among the populations. Material and methods: Patients with ILD-LC were enrolled between 2019 and 2024. ILD-LC patients were divided into two subgroups based on diagnosis. IPF and non-IPF-ILDs were compared. Demographics, clinical, haematological, and functional data were gathered at LC diagnosis. PD-L1 expression and actionable mutations were analysed as appropriate only in NSCLC. PD-L1 and driver mutations were compared with non-smoker and chronic obstructive pulmonary disease (COPD) patients with LC enrolled between 2019 and 2023. Survival analysis was performed to evaluate the impact of ILD, histotype, PD-L1, mutations and treatment strategies. Results: 43 patients with ILD-LC were enrolled. Of them, 17 were diagnosed with IPF, while 26 with Non-IPF-ILD. IPF and Non-IPF-ILD patients were similar regarding clinical, functional and blood count data. LC histotype was similar between IPF and Non-IPF-ILD populations. However, IPF patients presented a higher prevalence of adenocarcinoma (ADC) (41%) while Non-IPF-ILD had a higher prevalence of squamous cell carcinoma (SCC) (50%). The two populations were similar in their overall survival. To better evaluate the role of PD-L1 and mutations the 33 ILD patients presenting NSCLC were compared to 22 non-smoker and 29 COPD patients with LC. ILD patients did not present any difference regarding PD-L1 expression when evaluated as a whole. When divided IPF patients presented a statistically significant lower PD-L1 positivity (31 vs 90 vs 59 vs 76%, p=0.002) and expression (0 vs 47.5 vs 4 vs 15%, p=0.02) compared to non-IPF-ILDs, non-smokers and COPD patients. ILD patients presented a lower prevalence of driver mutations, with IPF showing the lowest compared to the other populations (14 vs 43 vs 82 vs 58%, p=0.01). The populations did not differ regarding the treatment approach. COPD patients showed the worst survival, with non-smokers presenting the best. Surgery showed the best overall survival even among the ILD population. The presence of mutations or PD-L1 positivity did not modify the survival. Conclusions: ILD-LC needs utmost attention for early detection. In IPF patients the condition is further complicated by the low prevalence of PD-L1 positivity and driver mutations. Even in ILD patients, with the right clinical characteristics, surgery has the best survival. Further studies prospective studies are needed to better understand the prognostic role of PD-L1 and driver mutations in ILD patients.