Interstitial lung diseases with concomitant lung cancer: a data mining approach revealing a complex condition with gender- and immune-associated specific implications

Abstract

Background: Interstitial lung diseases (ILDs) comprise a family of heterogeneous entities, primarily characterised by chronic scarring of the lung parenchyma. Among ILDs, idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonitis, associated with progressive functional decline leading to respiratory failure, a high symptom burden, and mortality. Notably, the incidence of lung cancer (LC) in patients already affected by ILDs-mainly IPF-is significantly higher than in the general population. Moreover, these cases are often neglected and deprived of active oncologic treatments.

Methods: We here aim to identify variables predictive of outcome (mortality) in a multicentre retrospective cohort of ILD associated with lung cancer, collected from 2018 to the end of 2023. Overall, 73 cases were identified, and exhaustive clinicopathologic data were available for 55 patients. Among them, 42 had IPF. The entire dataset was then analysed by using the JMP partition algorithm (JMP-Statistical Discoveries, from SAS), which can choose the optimum splits from many possible trees, making it a powerful modelling and data discovery tool.

Results: The average age at lung cancer diagnosis was 71.4 years, whereas the average age at IPF diagnosis was 69.5 years. The average Charlson Comorbidity Index was 4.6. Female patients constituted 28.3% (15) of the evaluated cases. The most frequent tumour histotype was adenocarcinoma (45.2%), and in more than 60% of the cases (67.9%), cancer was diagnosed at an early stage (TNM I-II-IIIA). A significant gender difference emerges regarding the overall patient survival, and quite unexpectedly, surgical approach to IPF-associated LC and the detection of serum autoantibodies are among the strongest outcome predictors.

Conclusions: The analysis performed is descriptive and successfully identifies key features of this specific and rare cancer population. IPF-associated LC emerges as a unique malignant disease defined by specific gender and histopathologic clinical and molecular parameters, which might benefit from active treatments.

Keywords: gender; idiopathic pulmonary fibrosis; interstitial lung diseases; lung cancer; predictors.

Figure 1

Study design. Overall, 73 cases were identified during the study interval (2018–2023); 18 of them were excluded due to a lack of exhaustive data and the absence of confirmed lung origin of the tumour. CTD, connective tissue disease-associated ILD; undet, undetermined fibrotic disease; RB-ILD, respiratory bronchiolitis interstitial lung disease; PM, pleural mesothelioma. One patient satisfied criteria for progressive pulmonary fibrosis (PPF) according to current guidelines. Serum autoantibodies detected in CTD patients included antinuclear antibodies (ANA) (all patients, 100%) and antibodies against topoisomerase 1 (Scl-70) (two patients, 33%). The patient with “undeterminate UIP” was treated with nintedanib due to a progressive fibrosing course. Patients with CTD-ILD received appropriate immunosuppressive treatment: methotrexate (50% of cases), mycophenolate (9%), and azathioprine (18%).

Figure 2

(A) Kaplan–Meier survival curves for IPF patients with LC based on their gender. Survival by first-line therapy against cancer: probability density curve (B) with logarithmic fit–nonparametric overlay (C).

Figure 3

(A) Concomitant pulmonary comorbidity (COPD) and probability of survival shown as density curves with logarithmic fit–nonparametric overlay. (B) Detection of autoantibodies and probability of survival presented as density curves with logarithmic fit–nonparametric overlay.

Figure 4

Molecular asset. (A) Distribution of PDL-1 level, survival, and CMI based on gender differences. (B) Distribution of autoantibody detection and PDL-1 levels based on smoking habits. Analysis of EGFR status vs. total amount of PDL-1 (C) and autoantibody detection (D). (E) Partition analysis for EGFR status vs. gender and smoking, confirming that the wild-type receptor is more frequently associated with male sex and smoking habits. M, male; F, female; CMI, Charlson Comorbidity Index; E, past smoker; C, current smoker; N, never smoker; M, mutated; W, wild type.