Clinical, morphological and molecular characterization of cancer phenotypes associated with chronic obstructive pulmonary disease (COPD): new prospective of target therapies

BACKGROUND Chronic obstructive pulmonary disease (COPD) and lung cancer are two catastrophic diseases, representing leading causes of morbidity and mortality worldwide. Although the treatment has greatly improved both diseases continue to show increasing frequency and above all an unpredictable progression. Several studies have firmly established a strict connection between COPD and lung cancer highlighting also the importance of the inflammatory response as a risk factor for both diseases. The inflammatory paradigm is undoubtedly one of the most fascinating theories to connect COPD and lung cancer and it has acquired new impetus by the recent discoveries in the COPD pathogenesis. Emerging evidence in this context has emphasized the role of adaptive immune responses, possibly with an autoimmune component due to the recognition of pulmonary selfantigens modified by cigarette smoking and to the failure of mechanisms regulating immunological tolerance. In this context, COPD-associated cancers might have specific pathogenetic and morphological features, differently from tumours arising in non-COPD patients, due to the synergic effect of cigarette smoke and chronic inflammation. AIM OF THE RESEARCH This research project focuses on the study of lung cancer in patients with COPD compared to smokers without COPD and never smoker patients in order to identify eventual distinct clinical, morphological and molecular phenotypes. MATERIALS AND METHODS From 2010 to 2012, we prospectively enrolled patients with peripheral non small lung cancer submitted to anatomical lung resection (lobectomy, bilobectomy or pneumonectomy) associated with systematic lymphadenectomy. Patients with central airway cancer, secondary lung tumours or previously submitted to inductive treatment were excluded from the study. According to respiratory functional tests and smoking history patients were then divided in 3 groups: COPD patients, smokers without COPD and never-smoker subjects with normal lung function (FEV1/FVC ratio >70%). Each patient underwent a full clinical and instrumental assessment. Morphological studies included detailed analysis of growth pattern (according to the latest revision of adenocarcinoma classification), cell proliferation (Ki67/MIB1 expression), parameters of intra-and peri-tumoral remodelling (inflammation, fibrosis and necrosis) and tumoural detection of interleukin-17 (IL-17) cytokine. Genetic analysis of EGFR and KRAS mutations was also performed in all cases. RESULTS In the study period, 66 patients who met the inclusion/exclusion criteria were initially enrolled:16 COPD, 32 smokers without COPD and 18 never smokers. As the selection criteria affected the predominant histologic profile with a clear predominance of the adenocarcinoma histotype (63% in COPD patients, 71% in smokers and 56% in neversmokers), we performed our investigations only in patients with this histology to obtain results not affected by different histotypes. Therefore the study group was composed of 43 patients (10 COPD, 23 smokers and 10 never-smokers), whose main demographic and functional parameters were comparable except for male/female ratio, reversed in never-smokers, and for lung function, reduced in COPD patients, as expected. Given the specific aim the comparison of different clinical, morphological and molecular data was mainly performed within the category of smoking patients (COPD patients and smokers without COPD), while never smokers represented control group. From a clinical point of view the most important differences concern the number of peripheral blood basophils and standard uptake value of positron emission tomography–computed tomography (SUV of PET-CT). COPD patients showed a significant higher number of basophils and lower SUV of PET-CT than smokers without COPD. Concerning the histological evaluation adenocarcinoma of COPD patients showed a more frequent lepid pattern, less evident solid aspect and lower MIB1/Ki67 index than adenocarcinoma of smokers without COPD. A significant more extensive necrosis was found in adenocarcinoma of COPD and smokers without COPD compared to never-smokers. Finally although not statistically significant a stronger IL17 tissue expression was observed in COPD cases compared to smokers without COPD. As regards molecular data the most interesting finding was a trend of less frequency of KRAS mutation in adenocarcinoma of COPD patients. CONCLUSIONS Adenocarcinoma in COPD patients presents clinical, molecular and morphological features of lower aggressiveness (higher number of basophils, low SUV of PET-CT, increased lepidic component, reduced solid pattern, lower cell proliferation and less frequent K-RAS mutation) compared to that of smokers without COPD. Alternative mechanisms of carcinogenesis may be involved in the development/progression of lung cancer in COPD patients. Given the importance of inflammation in the pathogenesis of the disease other mechanisms, such as IL-17 pathway, mainly driving inflammatory mediated carcinogenesis might be crucial. Additional knowledge of these mechanisms would be of considerable help in the fight against lung cancer especially concerning therapeutic perspectives, providing a rational basis for the development of targeted and more effective treatments