Nuclear grading, BAP1, mesothelin and PD-L1 expression in malignant pleural mesothelioma: prognostic implications

For malignant pleural mesothelioma (MPM), histopathological subtype is one of the most important prognostic factors. Several immunohistochemical stains whose expressions have possible therapeutic implications have been identified in MPM such as BAP1, mesothelin and PD-L1. The aim of our work was to evaluate the clinical significance and prognostic implications of BAP1, mesothelin and PD-L1 expression in 117 patients with a diagnosis of MPM who were diagnosed in our institution between 2002 and 2017. We also correlated this immunohistochemical profile to a recently described nuclear grading and to histopathological subtype. Mesothelin expression, BAP1 loss and PD-L1 expression were associated with histopathological subtype (p < 0.0001), BAP1 loss was more frequent in epithelioid subtype whereas PD-L1 expression was more frequent in non-epithelioid subtype. For epithelioid MPM, BAP1 expression was associated with overall survival (p = 0.034), with a longer survival when BAP1 expression is lost. Necrosis and nuclear grading are associated with overall survival (p = 0.0048 and <0.0001, respectively), with longer survival when necrosis was absent and for grade I. For non-epithelioid MPM, overall survival was not related to clinical, histopathological or immunohistochemical expression of BAP1, mesothelin or PD-L1. In multivariate analysis, grade I for nuclear grading was an independent prognostic factor associated with overall survival (p < 0.0001). In epithelioid and non-epithelioid MPM, we analysed overall survival in subgroups with combined mesothelin, BAP1 and PD-L1 expression. In epithelioid MPM, BAP1 retained/mesothelin negativity/PD-L1 > 1%, and BAP1 retained/mesothelin positivity/PD-L1 > 1% profiles, are associated with shorter overall survival. In non-epithelioid MPM, BAP1 loss/mesothelin negativity/PD-L1 > 1% is associated with shorter overall survival. Our work confirms that nuclear grading in epithelioid MPM is a strong and independent prognosis factor. Moreover, this study on several promising immunohistochemical stains whose expressions have possible therapeutic implications identifies subgroups with a poor prognosis.