Adenocarcinoma and squamous cell carcinoma, which comprise the vast majority of non-small cell lung cancers, are both associated with different pre-invasive disease states. This talk will review the current histological definition of these disease states, describe our current understanding of the clonal relationship between pre-invasive and invasive disease states in these tumour types and include novel data which informs how pre-invasive and invasive disease relate, within individual patients.
 

The presentation will include the current role of the pathologist in the diagnosis and management of interstitial lung diseases (ILD), the development of genetic testing in familial ILD, and the recognition of various patterns in connective tissue diseases- associated ILD.

A better understanding of the tumour microenvironment (TME) in lung cancer is needed to improve patient treatment and outcomes. Highly multiplexed antibody-based profiling methods such as imaging mass cytometry (IMC) are greatly advancing our understanding of tissue organisation and the immune response. We applied IMC to create a spatial immune atlas of non-small cell lung cancer (NSCLC), and linked resulting TME features to paired histology, sequencing and outcome data. 198 samples were obtained from 81 patients enrolled in TRACERx, a prospectively recruited study of patients with early-stage resectable NSCLC. We identified four TME classes defined by the intra-tumour and stromal densities of myeloid and lymphoid immune cells. Immune hot adenocarcinomas harboured communities of macrophages and T cells that were associated with the burden of expressed clonal neoantigens and intrinsic immune escape. In squamous cell carcinomas, spatial communities of plasma and B cells were enriched in immune excluded TMEs and increased with clonal neoantigen burden. In both histologies, fibroblasts may act as a barrier to immune infiltration in immune low tumours. A fourth TME class was defined by high tumour-associated neutrophils (TAN), low lymphocytic infiltration and a greater distance to vasculature. An H&E-derived TAN score expanded the IMC cohort to an additional 332 patients. TAN high tumours were associated with PIK3CA mutations and haboured recently expanded cancer subclones, an evolutionary feature associated with metastasis and poor outcome. In a multivariable model, TAN-high tumours were associated with shorter disease-free survival independent of stage. These findings were validated in TCGA H&Es using PathExplore, a deep-learning model for cell type and tissue classification. This study has begun to unravel how the spatial organisation of the TME is linked to underlying clinically-relevant genomic features and identifies specific immune contexts linked to tumour progression and poor outcome that may represent therapeutic targets in early-stage lung cancer.