Lymphoproliferative lung diseases are a heterogeneous group of disorders characterized by primary or secondary involvement of the lung. Primary pulmonary lymphomas are the most common type, representing 0.5–1% of all primary malignancies of the lung. The radiological presentation is often heterogeneous and non-specific: consolidations, masses, and nodules are the most common findings, followed by ground-glass opacities and interstitial involvement, more common in secondary lung lymphomas. These findings usually show a prevalent perilymphatic spread along bronchovascular bundles, without a prevalence in the upper or lower lung lobes. An ancillary sign, such as a “halo sign”, “reverse halo sign”, air bronchogram, or CT angiogram sign, may be present and can help rule out a differential diagnosis. Since a wide spectrum of pulmonary parenchymal diseases may mimic lymphoma, a correct clinical evaluation and a multidisciplinary approach are mandatory. In this sense, despite High-Resolution Computer Tomography (HRCT) representing the gold standard, a tissue sample is needed for a certain and definitive diagnosis. Cryobiopsy is a relatively new technique that permits the obtaining of a larger amount of tissue without significant artifacts, and is less invasive and more precise than surgical biopsy.

The expression level of Programmed Death-Ligand 1 (PD-L1) determined by the immunohistochemical method is currently approved to test the potential efficacy of immune-checkpoint inhibitors and to candidate patients with Non-Small Cell Lung Cancer (NSCLC) for treatment with immunotherapeutic drugs. As part of the CORELAB (New prediCtivebiOmaRkers of activity and Efficacy of immune checkpoint inhibitors in advanced non-small cell Lung cArcinoma) project, aimed at identifying new predictive and prognostic biomarkers in NSCLC patients receiving immunotherapeutic drugs, we investigated the role of circulating tumor DNA (ctDNA) molecular characterization as an additional predictive biomarker. We analyzed plasma ctDNA by targeted Next Generation Sequencing in a subset of 50 patients at different time points. ctDNA content was inversely correlated with the clinical outcome both at a baseline and after 2 months of treatment. OS was significantly higher in patients with ≥50% ctDNA reduction. TP53 and KRAS were the most frequently mutated genes, and patients with KRAS and/or TP53 mutations showed worse outcomes than patients without detectable variants or with mutations in other genes. Fewer common variants were found in BRAF, EGFR, MAP2K1, MET, NRAS, and PIK3CA genes. Our data demonstrated that molecular characterization of ctDNA and also its quantitative evaluation could serve as a dynamic, real-time prognostic, and predictive biomarker, enabling regular molecular monitoring of therapy efficacy in support of other medical examinations.