Prognostic significance of epithelial–mesenchymal transition in malignant pleural mesothelioma☆☆☆

Abstract

Epithelial-to-mesenchymal transition (EMT) is a morphologic transdifferentiation of carcinomas, conferring increased tumour invasiveness, but may also be applied to the epithelioid versus sarcomatoid histotype of malignant pleural mesothelioma (MPM). Herein, we correlated proteins of a putative MPM-EMT axis, including periostin, epidermal growth factor receptor (EGFR), integrin beta1, phosphatase and tensin homologue (PTEN), integrin-linked kinase (ILK), p21 and p27, with clinico-pathologic parameters, in particular overall survival (OS). A retrospective cohort of 352 mostly untreated patients with MPM was investigated by immunohistochemistry of a tissue microarray. Protein expression intensities were semi-quantitatively scored from 0 to 3 in their respective compartments, including peritumoural stroma as well as tumour cell plasma membrane, cytoplasm or nucleus. Data were correlated with histotype and survival outcome. A total of 32% of the tumours were diagnosed as epithelioid, 13% as sarcomatoid and 55% as biphasic histotype. High expression of membranous EGFR and integrin beta1 as well as nuclear p27 correlated with the epithelioid and high expression of cytoplasmic tumoural and stromal periostin with the sarcomatoid histotype. The median survival time of the 128 patients with complete follow-up data was 11.7 months. Univariate survival analysis revealed age, epithelioid histotype and any therapy as prognosticators for better OS. High expression of cytoplasmic PTEN or ILK as well as high expression of nuclear p21 or p27 correlated with increased, whereas high expression of cytoplasmic periostin with decreased OS (all p values <0.05). Multivariate Cox regression revealed any treatment, low cytoplasmic periostin and high cytoplasmic PTEN as independent prognosticators for better OS. Activation of periostin-triggered EMT is associated with the sarcomatoid histotype and has an impact on shorter survival of MPM patients. Finally, only the high expression of PTEN and the low expression of cytosolic periostin could be shown to be independent prognostic factors for longer OS.