Morphology and tumour-infiltrating lymphocytes in high-stage, high-grade serous ovarian carcinoma correlated with long-term survival.

AIMS: Advanced-stage ovarian high-grade serous carcinoma (HGSC) is a poor-prognosis cancer; however, a small and poorly characterised subset of patients shows long-term survival. We aimed to establish a cohort of HGSC long-term survivors for histopathological and molecular analysis. METHODS AND RESULTS: Paraffin blocks from 151 patients with primary FIGO III/IV HGSC and progression-free survival (PFS) >5 years were collected within the Tumorbank Ovarian Cancer (TOC) Network; 77 HGSC with a PFS <3 years were used as a control group. A standardised analysis of histological type and morphological features was performed. Ki67 index, tumour-infiltrating lymphocytes (TILs) and major histocompatibility complex expression (MHC1/2) were determined by immunohistochemistry. A total of 117 of 151 tumours (77.5%) in the long-term survivor group fulfilled the World Health Organisation (WHO) criteria of HGSC after review, and of these, 83 patients (70.9%) fulfilled all clinical criteria for inclusion into our cohort. Tumours of long-term survivors had significantly higher CD3+ and CD8+ TILs and were more frequently positive for MHC2 than controls (P = 0.004, P = 0.025, P = 0.048). However, there were also long-term survivors (up to 20%) with low TILs or low MHC expression. TILs and MHC had no impact on survival in long-term survivors. Morphological and Ki67 analysis revealed no differences between long-term survivors and controls. CONCLUSIONS: HGSC from long-term survivors have higher-level T cell infiltration and antigen-presentation capacity; however, this is not a prerequisite for an excellent prognosis. Histopathological criteria are not capable to identify these patients. Further extensive clinical and molecular characterisation of this enigmatic subgroup is ongoing to understand the reasons of long-term survival in HGSC.

Dynamics of the Intratumoral Immune Response during Progression of High-Grade Serous Ovarian Cancer.

PURPOSE: Tumor-infiltrating lymphocytes (TILs) have an established impact on the prognosis of high-grade serous ovarian carcinoma (HGSOC), however, their role in recurrent ovarian cancer is largely unknown. We therefore systematically investigated TIL densities and MHC class I and II (MHC1, 2) expression in the progression of HGSOC. EXPERIMENTAL DESIGN: CD3+, CD4+, CD8+ TILs and MHC1, 2 expression were evaluated by immunohistochemistry on tissue microarrays in 113 paired primary and recurrent HGSOC. TILs were quantified by image analysis. All patients had been included to the EU-funded OCTIPS FP7 project. RESULTS: CD3+, CD4+, CD8+ TILs and MHC1 and MHC2 expression showed significant correlations between primary and recurrent tumor levels (Spearman rho 0.427, 0.533, 0.361, 0.456, 0.526 respectively; P<.0001 each). Paired testing revealed higher CD4+ densities and MHC1 expression in recurrent tumors (Wilcoxon P=.034 and P=.018). There was also a shift towards higher CD3+ TILs levels in recurrent carcinomas when analyzing platinum-sensitive tumors only (Wilcoxon P=.026) and in pairs with recurrent tumor tissue from first relapse only (Wilcoxon P=.031). High MHC2 expression was the only parameter to be significantly linked to prolonged progression-free survival after first relapse (PFS2, log-rank P=.012). CONCLUSIONS: This is the first study that analyzed the development of TILs density and MHC expression in paired primary and recurrent HGSOC. The level of the antitumoral immune response in recurrent tumors was clearly dependent on the one in the primary tumor. Our data contribute to the understanding of temporal heterogeneity of HGSOC immune microenvironment and have implications for selection of samples for biomarker testing in the setting of immune-targeting therapeutics.