Original Article

Virchows Archiv

, Volume 459, Issue 2, pp 183-191

Intratumoral lymphocyte density in serous ovarian carcinoma is superior to ERCC1 expression for predicting response to platinum-based therapy

  • Hans BösmüllerAffiliated withDepartment of Pathology, Krankenhaus Barmherzige Schwestern LinzDepartment of Pathology, University of Tübingen Email author 
  • , Sophie Haitchi-PetnehazyAffiliated withDepartment of Pathology, Krankenhaus Barmherzige Schwestern Linz
  • , Gerald WebersinkeAffiliated withLaboratory of Molecular Biology, Krankenhaus Barmherzige Schwestern Linz
  • , Renate MarschonAffiliated withLaboratory of Molecular Biology, Krankenhaus Barmherzige Schwestern Linz
  • , Franz RoithmeierAffiliated withDepartment of Gynecology, Krankenhaus Barmherzige Schwestern Linz
  • , Wolfgang StummvollAffiliated withDepartment of Gynecology, Krankenhaus Barmherzige Schwestern Linz
  • , Tanja FehmAffiliated withDepartment of Gynecology, University of Tübingen
  • , Margit Klier-RichterAffiliated withDepartment of Pathology, University of Tübingen
  • , Irina BonzheimAffiliated withDepartment of Pathology, University of Tübingen
    • , Annette StaeblerAffiliated withDepartment of Pathology, University of Tübingen
    • , Falko FendAffiliated withDepartment of Pathology, University of Tübingen

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Abstract

Intratumoral immune cells and ERCC1 expression are likely to play a role in the response of ovarian carcinoma to chemotherapy, but their impact on therapy outcome is still unclear. Therefore, 41 cases of optimally resected high grade serous ovarian carcinomas were examined retrospectively for stromal and intraepithelial lymphocyte populations and ERCC1 status in relation to response to platinum-based therapy. Based on RECIST criteria, 27 patients were classified as responsive and 14 as therapy resistant, respectively. Using immunohistochemistry for CD3, CD8, CD4, TIA1, MUM1 and FOX P3 on representative tumor sections, we quantitatively evaluated the intratumoral density of lymphocyte subpopulations. In addition, ERCC1 protein and mRNA expression were determined by immunohistochemistry using the Steffensen score and quantitative RT-PCR, respectively. Furthermore, ERCC1 SNP’s C8092A and codon 118 were analysed. Response to chemotherapy was significantly associated with higher numbers of stromal CD3+ (mean 21.33 lymphocytes/HPF versus 8.21 lymphocytes/HPF, p = 0.002) and CD8+ lymphocytes (mean 9.22 lymphocytes/HPF versus 4.57 lymphocytes/HPF, p = 0.013). Counts of intraepithelial CD3+ and CD8+ lymphocytes, stromal and intraepithelial FOXP3+ and TIA1+ cells, CD4+ lymphocytes, and MUM1+ plasma cells did not reach statistical significance. Neither ERCC1 protein expression (p = 0.232) nor SNPs codon 118 and C8092A of the ERCC1 gene (p = 0.269 and p = 0.543) showed an association with therapy response. The same was true for ERCC1 mRNA levels (p = 0.896), probably due to intratumoral lymphocyte contamination. In conclusion, the density of CD3+ and CD8+ T-cells in tumor stroma proved to be a significant predictor for response to platinum-based therapy, whereas examination of ERCC1 failed to identify therapy-responsive patients.

Keywords

Serous ovarian adenocarcinoma ERCC1 immunohistochemistry ERCC1 mRNA expression ERCC1 SNP Intraepithelial lymphocytes Stromal lymphocytes