Both NSCLC and MPM are composed of different histotypes. These histotypes are clinically relevant, since both mutational profiles and response to chemotherapeutic drugs are different. Next to histotype markers, predictors such as EGFR are increasingly required in clinical pathology, also on cell blocks from pleural effusions. Such effusions can arise from both lung adenocarcinoma and MPM, thus are a valid resource for new biomarkers. We identified the epithelial-mesenchymal transition N-glycoprotein periostin in effusions from lung AC by shotgun mass spectrometry. EMT is an important transdifferentiation concept, whereby polarized epithelial cells detach from their solid lattice and become migratory and invasive via acquisition of a fibroblastoid phenotype. The EMT programme is regulated by a complex signalling network, leading to an upregulation of mesenchymal proteins like vimentin, associated with loss of E-cadherin. The EMT protein periostin was correlated with clinico-pathological parameters of tumour progression, the squamous cell histotype of NSCLC and the sarcomatoid of MPM, respectively. Importantly, EMT is related to the cancer stem cell phenotype, conferring increased drug resistance. Both NSCLC and MPM tumour cells are embedded in a prominent desmoplastic stroma. A microenvironment therapy could comprise a combination of inhibitors directed against tumour cell surface receptors, neo-vessels, extracellular matrix fibres and immune cells. Derivatives of the human monoclonal scFv antibodies L19 and F16, specific to the splice isoforms of fibronectin (with extracellular domain B) and tenascin-C (Al domain) are clinically effective, thus intracavitary chemotherapy with pleural infusion is a phase 1/2 study rationale for advanced lung AC or MPM.