Clinical, molecular and immunohistochemical characterization of primary Lung Cancer developed in the context of Interstitial Lung Disease

Background: ILD is a heterogeneous group of diffuse parenchymal lung diseases, some of which are known to present an independent risk factor for lung cancer. Particularly IPF has a well-established link with LC onset. Other ILDs, such as CTD-ILD, are also associated with LC, essentially involving chronic inflammatory process. However, few data are available about these patients and molecular and histopathological features of LC associated to 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 provide a basis for upcoming specific therapeutic regimen. Aim: First, to compare the histological and molecular signature of LC in a cohort of patients with and without ILD; second, to investigate the differences between IPF-LC and other ILD-LC. Materials&methods: 28 patients with ILD-LC were enrolled and compared to 142 LC patients without ILD. Then, ILD-LC patients were divided in two subgroups based on ILD phenotype. IPF and other ILDs were compared. Demographics, clinical, serological, and functional data was gathered at LC diagnosis. PD-L1 expression and actionable mutations were analyzed as appropriate. Results were presented as percentages or medians as appropriate. Results: ILD-LC and LC patients were similar in terms of smoking history, BMI or comorbidities, but ILD-LC were mainly male (78.6%;p=0.02) and tended to be younger (66.9y;p=0.05). ILD-LC patients showed very poor functional values at spirometry, with significantly lower FVC%, TLC% and DLco (p<0.0001), lower FEV1% (p=0.07), but higher FEV1/FVC (p=0.0008). In ILD-LC group, eosinophils levels were significantly higher than in LC group (170cell/mm3;p=0.01), whereas monocyte levels only trended toward significance (750cell/mm3;p=0.051). In the ILD-LC population, the frequency of adenocarcinoma and squamous cell carcinoma were similar (35.7 and 39.3%) with a remarkable incidence of SCLC (21.4%), while in the LC group adenocarcinoma was predominant (66.2%). ILD-LC patients tended to be diagnosed at earlier stages (37% stage I-II) but did not differ regarding PD-L1 positivity or driver mutations, except for ROS1 (18.2%;p=0.004). ILD-LC patients and LC patients showed non-significant difference in survivals evaluated through Kaplan-Meier curves at 6-months and 1-year follow up (log rank:p=0.98 and 0.79). In ILD-LC cohort, 15 (54%) patients were diagnosed with IPF, 13 (46%) with other ILDs (6 were CTD-ILD). At LC diagnosis, IPF patients were mainly male (93%;p=0.04) and tended to be older (67.8y;p=0.06), and to have a heavier smoking history (47.5 p/y;p=0.06), but did not differ, compared to ILDs patients, regarding BMI, comorbidities, functional values and use of oxygen therapy. No statistically difference was found in histotype distribution, with squamous cell carcinoma as prevalent LC presentation (39%). Interestingly, in IPF patients the prevalent LC was adenocarcinoma (40%), while in ILDs patients was squamous cell carcinoma (46%). IPF patients presented lower PD-L1 positivity (27%;p=0.002) and expression (0%;p=0.008). The whole ILD-LC population presented a low burden of actionable mutations (4 (36%) out 11 adenocarcinomas), with no differences between IPF and ILDs group. IPF-LC showed non-significant lower survival evaluated trough Kaplan-Meier curves at 6-months follow up (log rank:p=0.42). Conclusions: ILD-LC patients showed similar prevalence of AC and SCC histotype, while AC was prominent in LC patients. LC tended to be diagnosed in earlier stages in ILD patients. In our case population the majority of ILD-LC patients were diagnosed with IPF. ILD-LC patients showed an unfavorable molecular presentation, with a low number of actionable mutations and furthermore a low prevalence of PD-L1 positivity and expression in IPF patients, thus leading to fewer therapeutic options. Speculations on survival need a longer evaluation time to be more exhaustive.