Tumor bed evaluation in non-small cell lung cancer of patients treated with different neoadjuvant strategies: morphometric analysis of stromal component.

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Diverse treatment approaches are accessible, and neoadjuvant therapy holds potential to enhance survival rates and elevate curative possibilities for patients grappling with advanced disease. In this study, the tumor bed was examined in three different cohorts of advanced NSCLC patients: 18 were subjected to immunotherapy, 9 to targeted therapy, and 9 to chemotherapy in the neoadjuvant context. Aim of the study: Different strategies are available in the neoadjuvant setting for patients with advanced or metastatic NSCLC, including chemotherapy, targeted therapy, and immunotherapy alone or in combination with chemotherapy. There are a few encouraging results coming from the use of neoadjuvant treatments in particular in the setting of immunotherapy and chemoimmunotherapy. Currently there are not granular pathological studies on the evaluation of tumor bed comparing patients treated with different neoadjuvant therapies. The study aims to identify the pathological substrates underlying the best responsiveness, hopefully providing useful information for further tailored treatments. Materials and methods: Between 2018 and 2022, a total of 36 stage IIIB to IV NSCLC patients who underwent neoadjuvant therapies were included. Main clinical and laboratory data at the time of the diagnosis were collected. The tumor bed was evaluated in line with IASLC recommendations. Further morphological lesions like lymphoid follicles, tertiary lymphoid structures, foamy macrophages, and cholesterol clefts were also reported. Additionally, computer-assisted morphometrical quantification gauged the extent of fibrosis and inflammation. Results: Tumor bed was evaluated on several sections, ranging from 1 to 17 (median 4, IQR: 3-7). Complete pathological response (CPR) and major pathological response (MPR) were diagnosed in 12/36 (33%) and 4/36 (11%) cases, respectively. Statistically significant differences were seen in viable tumor cells (p=0.007) and necrosis (p=0.042) among the three cohorts. Fibrosis and inflammation were consistently detected, with statistical variances seen in the morphometric assessment of fibrosis (p=0.028) and inflammation (p=0.010). Cholesterol clefts, interstitial foamy macrophages and giant cells were seen in 19/36 (53%) cases (p=0.008), predominantly in the immunotherapy group (14/18, 78%). Lymphoid follicles and tertiary lymphoid structures were distributed among all groups at comparable percentages. Addressing lymph nodes, a median of 6 stations were examined for each group. Metastases were described in 17/36 (47%) cases, in 11/36 (30.5%) involving N2 stations. In 11/36 (30.5%) cases, signs of treatment effects in lymph nodes were noted. Conclusions: Our findings underscore the prominence of immune checkpoint inhibitors, whether as monotherapies or in tandem with chemotherapy, as the best treatment in the neoadjuvant setting for non-oncogene addicted metastatic or locally advanced NSCLC. A plausible explanation for the best response of the immunotherapy group can be found in the different pathological lesions of the tumor bed detected in the 3 groups. In the immunotherapy cohort higher values of inflammation, mainly macrophages, and lower percentages of necrosis and fibrosis are detected compared to the chemotherapy one. Further mechanistic investigations are mandatory to gain a more comprehensive understanding of the pathways responsible for the inflammatory-driven death of the neoplastic component in patients treated with immunotherapy.