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

• Published in: Virchows Archiv : an international journal of pathology 2011-08, Vol.459 (2), p.183-191
• Main Authors: Bösmüller, Hans, Haitchi-Petnehazy, Sophie, Webersinke, Gerald, Marschon, Renate, Roithmeier, Franz, Stummvoll, Wolfgang, Fehm, Tanja, Klier-Richter, Margit, Bonzheim, Irina, Staebler, Annette, Fend, Falko
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Agents - therapeutic use; Biological and medical sciences; CD3 antigen; Chemotherapy; Cystadenocarcinoma, Serous - drug therapy; Cystadenocarcinoma, Serous - genetics; Cystadenocarcinoma, Serous - immunology; DNA-Binding Proteins - genetics; Drug Resistance, Neoplasm - genetics; Drug Resistance, Neoplasm - immunology; Endonucleases - genetics; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Humans; Immunohistochemistry; Investigative techniques, diagnostic techniques (general aspects); Lymphocytes; Lymphocytes, Tumor-Infiltrating - immunology; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Original Article; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - immunology; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Platinum; Platinum Compounds - therapeutic use; Polymorphism, Single Nucleotide; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - analysis; Subpopulations; Tumors
• ISSN: 0945-6317; 1432-2307
• DOI: 10.1007/s00428-011-1110-1

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.