TUMOUR-INFILTRATING LYMPHOCYTES AND BAP-1, VEGFR-2 AND IGF-1R EXPRESSION IN MALIGNANT PLEURAL MESOTHELIOMA

Objectives: Malignant pleural mesothelioma (MPM) is a rare disease strongly related to asbestos exposure. MPM is frequently associated with a prominent inflammatory reaction. In this study, we investigated whether there was any relationship between survival and the presence of tumor infiltrating lymphocytes (TILs). The expression of BAP-1 (BRCA1-Associated Protein 1), VEGFR-2 (vascular endothelial growth factor receptor 2) and IGF-1R (Insulin-Like Growth Factor 1 Receptor) in tissue samples was also assessed. Methods: Forty-four cases of MPM were identified. All the biopsies used were obtained at the time of diagnosis. There were 24 males; mean age was 69 years. Twenty-six patients were smokers and 26 had a certain history of asbestos exposure. All histological slides were revised for the study; there were 28 epithelioid subtypes, 8 biphasic subtypes and 8 sarcomatoid subtypes. The presence of TILs was scored as absent, weak, moderate and strong according to a quantitative assessment on hematoxylin and eosin slides. The expression of BAP-1, VEGFR-2 and IGF-1R was analyzed by immunohistochemistry. The impact of asbestos exposure, tobacco consumption and histological subtypes on survival were also assessed. The survival analysis was analyzed by Kaplan Meier curve. Results: TILs were present in 89% of cases (weak 18%, moderate 36%, strong 34%) and were found to be a favorable prognostic factor (p=0.05). Median survival in TILs and non-TILs patients was 21 months and 4 months, respectively (Figure 1). Epithelioid MPM was characterized by an increased expression of VEGFR-2, both in tumor cells (p=0.04) and TILs (p=0.05) and more frequent inactivation of BAP1 (75%, p=0.05) than biphasic and sarcomatoid subtypes. IGF-1R was overexpressed in 57% of the tumors (14 epitheliods and 11 sarcomatoids) and in 23% of TILs (7 epitheliods and 3 sarcomatoids). The expression of VEGFR-2, BAP1 and IGF-1R was not significantly related with survival. Tobacco (p=0.93) and asbestos (p=0.62) exposures were also not significantly correlated with survival. Histology had no effect on survival (p=0.23) although epithelioid MPM fared better than sarcomatoid and biphasic tumors with a median survival of six months. Conclusion: The presence of TILs favorably affects survival of MPM. Epithelioid MPM is characterized by longer survival, higher BAP1 loss and increased VEGFR-2 expression. Histological markers may improve the prognostic assessment of MPM and provide mechanistic clues for new therapeutic strategies.