Expression Changes in Programmed Death Ligand 1 from Precancerous Lesions to Invasive Adenocarcinoma in Subcentimeter Pulmonary Nodules: A Large Study of 2022 Cases in China.

PURPOSE: This large-scale, multicenter, retrospective observational study aimed to evaluate the clinicopathological and molecular profiles associated with programmed death-ligand 1 (PD-L1) expression in precancerous lesions and invasive adenocarcinoma in subcentimeter pulmonary nodules. PATIENTS AND METHODS: Patients with histologically confirmed atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (ADC) were included. PD-L1 expression was evaluated at each center using a PD-L1 immunohistochemistry 22C3 pharmDx kit (Agilent, Santa Clara, CA, USA). The tumor proportion score (TPS) cutoff values were set at ≥ 1% and ≥ 50%. RESULTS: A total of 2022 nodules from 1844 patients were analyzed. Of these, 9 (0.45%) nodules had PD-L1 TPS ≥ 50%, 187 (9.25%) had PD-L1 TPS 1-49%, and 1826 (90.30%) had PD-L1 TPS < 1%. A total of 378 (18.69%), 1016 (50.25%), and 628 (31.06%) nodules were diagnosed as AAH/AIS, MIA, and ADC, respectively, by pathology. A total of 1377 (68.10%), 591 (25.67%), and 54 (2.67%) nodules were diagnosed as pure ground-glass opacity (GGO), mixed GGO, and solid nodules, respectively, by computed tomography. There was a significant difference between PD-L1 expression and anaplastic lymphoma kinase (ALK) mutation status (P < 0.001). PD-L1 expression levels were significantly different from those determined using the International Association for the Study of Lung Cancer (IASLC) grading system (P < 0.001). CONCLUSIONS: PD-L1 expression was significantly associated with radiological and pathological invasiveness and driver mutation status in subcentimeter pulmonary nodules. The significance of PD-L1 expression in the evolution of early-stage lung adenocarcinoma requires further investigation.

Radiomics-based Support Vector Machine Distinguishes Molecular Events Driving Progression of Lung Adenocarcinoma.

INTRODUCTION: An increasing number of early-stage lung adenocarcinoma (LUAD) are detected as lung nodules. The radiological features related to LUAD progression remain further investigation. Exploration is required to bridge the gap between radiomics features and molecular characteristics of lung nodules. METHODS: Consensus clustering was applied to the radiomics features of 1,212 patients to establish stable clustering. Clusters were illustrated using clinicopathological and next-generation sequencing (NGS). A classifier was constructed to further investigate the molecular characteristic in patients with paired CT and RNA-seq data. RESULTS: Patients were clustered into 4 clusters. Cluster 1 was associated with a low consolidation-to-tumor ratio (CTR), pre-invasion, grade I disease and good prognosis. Clusters 2 and 3 showed increasing malignancy with higher CTR, higher pathological grade and poor prognosis. Cluster 2 possessed more spread through air spaces (STAS) and cluster 3 showed higher proportion of pleural invasion. Cluster 4 had similar clinicopathological features with cluster 1 except higher proportion of grade II disease. RNA-seq indicated that cluster 1 represented nodules with indolent growth and good differentiation, whereas cluster 4 showed progression in cell development but still had low proliferative activity. Nodules with high proliferation were classified into clusters 2 and 3. Additionally, the radiomics classifier distinguished cluster 2 as nodules harboring an activated immune environment, while cluster 3 represented nodules with a suppressive immune environment. Furthermore, gene signatures associated with the prognosis of early-stage LUAD were validated in external datasets. CONCLUSION: Radiomics features can manifest molecular events driving progression of lung adenocarcinoma. Our study provides a molecular insight into radiomics features and assists in the diagnosis and treatment of early stage LUAD.

A Novel Radiopathological Grading System to Tailor Recurrence Risk for Pathologic Stage IA Lung Adenocarcinoma.

To validate the efficiency of pathologic grading system in pathologic stage IA lung adenocarcinoma (LUAD), and explore whether integrating preoperative radiological features would enhance the performance of recurrence discrimination. We retrospectively collected 510 patients with resected stage IA LUAD between January 2012 and December 2019 from Guangdong Provincial People's Hospital (GDPH). Pathologic grade classification of each case was based on the International Association for the Study of Lung Cancer (IASLC) pathologic staging system. Kaplan-Meier curves was used to assess the power of recurrence stratification. Concordance index (C-Index) and receiver operating characteristic curves (ROC) were used for evaluating the clinical utility of different grading systems for recurrence discrimination. Patients of lower IASLC grade showed improved recurrence-free survival (RFS) (P < 0.0001) where numerically difference was found between grade II and grade III (P = 0.119). By integrating the IASLC grading system and radiological feature, we found the RFS rate decreased as the novel radiopathological (RP) grading system increased (P < 0.0001). The difference of RFS curves between any 2 groups as per the RP grading system was statisticallysignificant (RP grade I vs RP grade II, p = 0.007; RP grade I vs RP grade III, P < 0.0001; RP grade II vs RP grade III, P = 0.0003). Compared with the IASLC grading system, the RP grading system remarkably improved recurrence survival discrimination (C-index: 0.822; area under the curve, 0.845). Integrating imaging features into pathologic grading system enhanced the efficiency of recurrence discrimination for resected stage IA LUAD and might help conduct subsequent management.

Spatial downregulation of CD74 signatures may drive invasive component development in part-solid lung adenocarcinoma.

Pulmonary nodules with part-solid imaging features manifest during the progression from preinvasive to invasive lung adenocarcinoma. To define the spatial composition and evolutionary trajectories of early-stage lung adenocarcinoma, we combined spatial transcriptomics (ST) and pathological annotations from 20 part-solid nodules (PSNs), four of which were matched with single-cell RNA sequencing. Two malignant cell populations (MC1 and MC2) were identified, and a linear evolutionary relationship was observed. Compared to MC2, the pre-existing malignant MC1 exhibited a lower metastatic signature, corresponding to the preinvasive component (lepidic) on pathology and the ground glass component on PSN imaging. Higher immune infiltration was observed among MC1 regions in ST profiles, and further analysis revealed that macrophages may be involved in this process through the CD74 axis. This work provides deeper insights into the evolutionary process and spatial immune cell composition behind PSNs and highlights the mechanisms of immune escape behind this adenocarcinoma trajectory.

Lack of incremental value of three-dimensional measurement in assessing invasiveness for lung cancer.

OBJECTIVES: The aim of this study was to evaluate the performance of consolidation-to-tumour ratio (CTR) and the radiomic models in two- and three-dimensional modalities for assessing radiological invasiveness in early-stage lung adenocarcinoma. METHODS: A retrospective analysis was conducted on patients with early-stage lung adenocarcinoma from Guangdong Provincial People's Hospital and Shenzhen People's Hospital. Manual delineation of pulmonary nodules along the boundary was performed on cross-sectional images to extract radiomic features. Clinicopathological characteristics and radiomic signatures were identified in both cohorts. CTR and radiomic score for every patient were calculated. The performance of CTR and radiomic models were tested and validated in the respective cohorts. RESULTS: A total of 818 patients from Guangdong Provincial People's Hospital were included in the primary cohort, while 474 patients from Shenzhen People's Hospital constituted an independent validation cohort. Both CTR and radiomic score were identified as independent factors for predicting pathological invasiveness. CTR in two- and three-dimensional modalities exhibited comparable results with areas under the receiver operating characteristic curves and were demonstrated in the validation cohort (area under the curve: 0.807 vs 0.826, P = 0.059) Furthermore, both CTR in two- and three-dimensional modalities was able to stratify patients with significant relapse-free survival (P < 0.000 vs P < 0.000) and overall survival (P = 0.003 vs P = 0.001). The radiomic models in two- and three-dimensional modalities demonstrated favourable discrimination and calibration in independent cohorts (P = 0.189). CONCLUSIONS: Three-dimensional measurement provides no additional clinical benefit compared to two-dimensional.

Intratumoral genetic and immune microenvironmental heterogeneity in T4N0M0 (diameter ≥ 7 cm) non-small cell lung cancers.

BACKGROUND: Starting with low metastatic capability, T4N0M0 (diameter ≥ 7 cm) non-small cell lung cancers (NSCLCs) constitute a unique tumor subset, as with a large tumor size but no regional or distant metastases. We systematically investigated intratumoral heterogeneity, clonal structure, chromosomal instability (CIN), and immune microenvironment in T4N0M0 (≥7 cm) NSCLCs. METHODS: Whole-exome sequencing, RNA sequencing, and multiplex immunohistochemistry (mIHC) staining were conducted to analyze 24 spatially segregated tumor samples from eight patients who were pathologically diagnosed with T4N0M0 (diameter ≥ 7 cm) NSCLCs. The adjacent normal tissues and peripheral blood served as controls. RESULTS: In total, 35.2% of mutations and 91.1% of somatic copy number alterations were classified as subclonal events, which exhibited widespread genetic intratumoral heterogeneity. In contrast, a low degree of CIN was observed. None of the patients had genome doubling. The burden of loss of heterozygosity, aneuploidy, and the genome instability index of these tumors were significantly lower than those in the TRACERx cohort. Expression profiles revealed significantly upregulated expression of cell division-related signals and the G2/M checkpoint pathway. In addition, a similar expression pattern of the immune microenvironment was observed in different regions of the tumor, which was confirmed by mIHC profiles. CONCLUSIONS: Our study indicates the presence of intratumoral genetic heterogeneity and immune microenvironmental heterogeneity features in T4N0M0 NSCLCs, and the low degree of CIN may be related to the low metastatic capability.