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Background  Few data are known regarding the molecular features and patterns of growth and presentation which characterize those lung neoplastic lesions presenting as non-solid nodules (NSN).    Methods  We retrospectively reviewed two different cohorts of NSNs detected by CT scan which, after transthoracic fine-needle aspiration (FNA) and core needle biopsy (CNB) received a final diagnosis of malignancy. All the enrolled patients were then addressed to surgical removal of lung cancer nodules or to exclusive radiotherapy. Exhaustive clinical and radiological features were available for each case.    Results  In all 62 analysed cases the diagnosis of adenocarcinoma (ADC) was reached. In cytologic samples,  EGFR  activating mutations were identified in 2 of the 28 cases (7%); no case showed  ALK/EML4  or  ROS1  translocations. In the histologic samples  EGFR  activating mutation were found in 4 out of 25 cases (16%). PD-L1 immunostains could be evaluated in 30 cytologic samples, while the remaining 7 did not reach the cellularity threshold for evaluation. TPS was < 1% in 26 cases,  > 1% < 50% in 3, and > 50% in 1. All surgical samples showed TPS < 1%. Of the 17 cases that could be evaluated on both samples, 15 were concordantly TPS 0, and 2 showed TPS > 1% < 50 on the biopsy samples. TPS was < 1% in 14 cases, > 1%/< 5% in 4 cases, > 5%/< 50% in 2 cases, > 50% in 1 case.    Conclusions  Overall PD-L1 immunostaining documented the predominance of low/negative TPS, with high concordance in FNA and corresponding surgical samples. It can be hypothesized that lung ADC with NSN pattern and predominant in situ (i.e. lepidic) components represent the first steps in tumor progression, which have not yet triggered immune response, and/or have not accumulated a significant rate of mutations and neoantigen production, or that they belong to the infiltrated-excluded category of tumors. The negative prediction of response to immunomodulating therapy underlines the importance of rapid surgical treatment of these lesions. Notably, cell block cytology seems to fail in detecting  EGFR  mutations, thus suggesting that this kind of sampling technique should be not adequate in case of DNA direct sequencing.

The growth of non-solid neoplastic lung nodules is associated with low PD L1 expression, irrespective of sampling technique