Clinicopathological prognostic parameters in patients with tubo-ovarian carcinoma effusions.

OBJECTIVE: To analyse the predictive and prognostic role of clinicopathological parameters in patients with tubo-ovarian carcinoma and malignant effusion. METHODS: A retrospective series of 700 malignant peritoneal (n = 610) and pleural (n = 90) effusions from 558 patients was revised for histotype based on the 2014 World Health Organization criteria. The role of clinicopathological parameters in determining outcome was assessed. RESULTS: The majority of specimens (597 effusions from 473 patients) were high-grade serous carcinomas (HGSC), followed by low-grade serous carcinoma (LGSC; 48 effusions, 37 patients), clear cell carcinoma (CCC; 23 effusions, 19 patients) and carcinosarcoma (CS; 16 effusions, 16 patients). Patients with CCC and CS had the shortest, those with HGSC intermediate, and those with LGSC longest overall and progression-free survival (both P < 0.001). For patients with HGSC, older age (P = 0.002), more advanced FIGO stage (IV vs III; P < 0.001), delayed/no surgery (P < 0.001), larger residual disease volume (RD; P < 0.001), non-complete response to chemotherapy at diagnosis (P < 0.001), and primary platinum resistance (P < 0.001) were associated with shorter overall survival. In Cox multivariate analysis, FIGO stage (P = 0.002) and primary platinum resistance (P < 0.001) were independent prognosticators. Significant association was additionally found for parameters analysed for progression-free survival in HGSC (previous chemotherapy: P = 0.029; age: P = 0.046; FIGO stage, upfront therapy, RD: P < 0.001), of which previous chemotherapy, upfront therapy, and RD were independent prognosticators (all P < 0.001). CONCLUSIONS: The vast majority of malignant effusions in patients with tubo-ovarian carcinoma are derived from serous carcinoma or related tumours, such as CS. Histology is a powerful prognostic factor in this patient group, as are established clinical parameters.

Heat shock protein 90 is a putative therapeutic target in patients with recurrent advanced-stage ovarian carcinoma with serous effusions.

Heat shock protein 90 (HSP90) has anti-apoptotic properties exerted through its cytoprotective function of chaperone activity and increased expression in response to stress. The present study analyzed the clinical role of HSP90 in effusions from patients with advanced-stage ovarian carcinoma. HSP90 protein expression was investigated in 265 effusions using immunohistochemistry. Results were analyzed for association with clinicopathologic parameters, including chemotherapy response and survival. The correlation between HSP90 and a panel of previously-studied antiapoptotic proteins was additionally investigated. HSP90 was expressed in the cytoplasm and nucleus of tumor cells in 97% and 18% of specimens, respectively. Nuclear HSP90 expression was significantly higher in post-chemotherapy compared to pre-chemotherapy effusions (P = .005), significantly related to previous treatment with both platinol (P = .024) and paclitaxel (P = .007). Cytoplasmic HSP90 expression was significantly higher in effusions from patients with complete compared to incomplete/no response after second-line chemotherapy (P = .016). No association was found between HSP90 expression and other clinicopathologic parameters or survival. Cytoplasmic HSP90 expression was significantly associated with that of Bcl-2 in pre-chemotherapy effusions (P = .04), and marginally associated with cytoplasmic Survivin expression in post-chemotherapy effusions (P = .05). HSP90 is upregulated along tumor progression from primary diagnosis to recurrent effusion. HSP90 does not provide prognostic data in patients with advanced ovarian carcinoma effusions. However, HSP90 may be of predictive value as to who will benefit from treatment with HSP90 inhibitors to potentiate the effectiveness of platinol and paclitaxel in patients with recurrent advanced ovarian carcinoma effusions. We propose HSP90 as a potential therapeutic target in this patient group.

Evaluation of cell surface expression of phosphatidylserine in ovarian carcinoma effusions using the annexin-V/7-AAD assay: clinical relevance and comparison with other apoptosis parameters.

Phosphatidylserine cell surface exposure during apoptosis can be detected by its binding to the protein annexin-V. We investigated annexin-V expression in 76 ovarian carcinoma effusions using flow cytometry. Results were analyzed for association with clinicopathologic parameters and survival. Annexin-V expression was additionally compared with the previously studied apoptotic markers cleaved caspase-3, cleaved caspase-8, and deoxyuridine triphosphate (dUTP) incorporation into DNA fragments. Annexin-V was expressed in all specimens and was more frequently detected compared with cleaved caspases and dUTP incorporation (P < .001). Annexin-V expression was higher in grade 3 vs grades 1 and 2 tumors (P = .014). A higher percentage of annexin-V-expressing cells in postchemotherapy specimens was associated with poor overall (P = .005) and progression-free (P = .013) survival. We present the first evidence of annexin-V expression in ovarian carcinoma effusions. The higher annexin-V expression compared with other apoptosis parameters and its association with high-grade disease and poor survival in postchemotherapy patients suggest a role in cell survival rather than apoptosis in effusions.

Expression and clinical role of antiapoptotic proteins of the bag, heat shock, and Bcl-2 families in effusions, primary tumors, and solid metastases in ovarian carcinoma.

Cancer progression is associated with reduced apoptosis and increased proliferation. We hypothesized that upregulation of the Bag family of survival cochaperones and its molecular partners of the Bcl-2 and heat shock protein (HSP) families would correlate with disease progression and survival in ovarian cancer. Bag-1, Bag-4, HSP27, HSP70, Bcl-2, and Bcl-X(L) expression was immunohistochemically analyzed in effusions (188) and patient-matched solid tumors (43 primary carcinomas, 81 solid metastases). Results were analyzed for anatomic site-related differences, and association with clinicopathologic parameters and survival. Bag-1, Bag-4, and HSP70 were detected in the tumor cell nuclei and cytoplasm, whereas HSP27, Bcl-2, and Bcl-X(L) had exclusively cytoplasmic localization. Antiapoptotic protein expression in effusions differed significantly from primary tumors and metastases. Cytoplasmic Bag-1 (P=0.002), nuclear and cytoplasmic HSP70 (P<0.001), and Bcl-2 (P=0.001) expression was higher in primary carcinomas and solid metastases compared with effusions, whereas Bcl-X(L) (P=0.01), nuclear Bag-1 (P<0.001), nuclear Bag-4 (P=0.01), and cytoplasmic Bag-4 (P=0.002) were upregulated in effusions. Bcl-X(L) expression was associated with poor response to chemotherapy at diagnosis (P=0.02) and HSP27 expression was associated with high-grade tumors (P=0.01). Increased cytoplasmic HSP70 staining in effusions correlated with poor overall survival for the entire cohort (P=0.01). In primary carcinomas, higher Bcl-2 expression correlated with worse overall (P=0.04) and progression-free (P=0.02) survival. Antiapoptotic proteins are differentially expressed in effusions compared with solid tumors, whereas primary carcinomas and solid metastases have comparable expression patterns. HSP70 expression in effusions may be a prognostic marker of poor survival, with a similar role for Bcl-2 in primary carcinomas.

NK- and B-cell infiltration correlates with worse outcome in metastatic ovarian carcinoma.

We studied the clinical role of leukocyte infiltration and chemokine receptor expression in ovarian carcinoma effusions. Expression of leukocyte markers (CD3, CD4, CD8, CD4/CD8 ratio, CD16, CD19, and CD14) and chemokine receptors (CXCR1, CXCR4, CCR2, CCR5, and CCR7) was studied in 73 effusions by using flow cytometry. CXCR4, CCR5, and CCR7 were expressed abundantly on leukocytes, but all receptors were expressed rarely on cancer cells. The presence of natural killer cells (P = .042) and International Federation of Gynecology and Obstetrics (FIGO) stage IV disease (P = .024) predicted worse overall survival (OS). A higher percentage of CD19+ cells (P = .015) and stage IV disease (P = .008) predicted poor survival for patients with postchemotherapy effusions. Only FIGO stage retained significance as a predictor of OS (P = .035) in multivariate analysis. Chemokine receptors are expressed widely on leukocytes but rarely on carcinoma cells in ovarian carcinoma effusions, arguing against an autocrine chemokine pathway in this malignancy. Immune response parameters in ovarian cancer effusions are weak predictors of outcome.