Lymphovascular space invasion and Ki67 as predictors of lymph node metastasis in primary low grade serous ovarian cancer.

OBJECTIVE: Low grade serous ovarian cancers characterize a unique clinical pattern and likely less frequent incidence of lymphatic metastasis. The expression level of Ki67 is associated with differences in prognosis and therapy outcome. However, its expression in combination with lymphovascular space invasion has not been evaluated in the prediction of lymphatic metastasis. METHODS: Patients with low grade serous ovarian cancer were identified in an institutional database. Patients with primary low grade serous ovarian cancer diagnosed and/or treated at our center between September 2000 and December 2018 were identified. Receiver operator characteristics curve analysis was performed to find the cut-off values of per cent Ki67 to discriminate patients with lymph node metastasis. The association between the presence of lymphovascular space invasion and lymph node involvement was analyzed. RESULTS: A total of 109 patients with primary low grade serous ovarian cancer were identified in our institution's database. Of these, 72 (66.1%) patients underwent primary surgery with pelvic and para-aortic lymph node dissection. Complete data for Ki67 expression and lymphovascular space invasion were obtained for 61 (84.7%) of these patients. Among them, 37 (60.7%) patients had lymph node metastasis. The presence of lymphovascular space invasion was associated with an increased risk of lymph node metastases (odds ratio (OR)=12.78, 95% confidence interval (CI) 3.15 to 51.81; p<0.001). In multivariate analysis including age >65 years, peritoneal carcinomatosis, and ascites>500 mL, lymphovascular space invasion remained a significant risk factor for lymphatic metastases (OR=35.11, 95% CI 2.38 to 517.69; p=0.010). Ki67 ≥6% was associated with a higher risk of lymphovascular space invasion (OR=3.67, 95% CI 1.26 to 10.64; p=0.017). No significant correlation between Ki67 expression level and nodal metastases was found (OR=2.19, 95% CI 0.76 to 6.26; p=0.14). Neither presence of lymphovascular space invasion or nodal metastases was associated with a statistically poorer prognosis. CONCLUSIONS: We showed an association between lymphovascular space invasion, Ki67 expression, and risk of lymph node metastasis in primary low grade ovarian cancer. Further prospective trials evaluating lymphovascular space invasion and Ki-67 as predictors of lymph node metastasis are needed.

Recurrent Treatment in Ovarian Cancer Patients: What Are the Best Regimens and the Order They Should Be Given?

OPINION STATEMENT: The choice of the right treatment regimen for recurrent ovarian cancer (rOC) remains a case-by-case decision. It is based on multiple factors that involve patient characteristics and biological factors at the same time. The prioritization of factors is still subject to changes with a trend towards a more personalized medicine. Therefore, participation and engagement in clinical studies constitutes a substantial need for the future development of the treatment algorithm of rOC.

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.

Vascular endothelial growth factor receptor 2 (VEGFR2) correlates with long-term survival in patients with advanced high-grade serous ovarian cancer (HGSOC): a study from the Tumor Bank Ovarian Cancer (TOC) Consortium.

OBJECTIVE: The impact of angiogenesis on long-term survival of high-grade serous ovarian cancer (HGSOC) patients remains unclear. This study investigated whether angiogenic markers correlated with 5-year progression-free survival (PFS) in a large cohort of matched advanced HGSOC tissue samples. METHODS: Tumor samples from 124 primary HGSOC patients were retrospectively collected within the Tumor Bank Ovarian Cancer ( http://www.toc-network.de ). All patients were in advanced stages (FIGO stage III-IV). No patient had received anti-angiogenesis therapy. The cohort contains 62 long-term survivors and 62 controls matched by age and post-surgical tumor residuals. Long-term survivors were defined as patients with no relapse within 5 years after the end of first-line chemotherapy. Controls were patients who suffered from first relapse within 6-36 months after primary treatment. Samples were assessed for immunohistochemical expression of vascular endothelial growth factor (VEGF) A and VEGF receptor 2 (VEGFR2). Expression profiles of VEGFA and VEGFR2 were compared between the two groups. RESULTS: Significant correlation between VEGFA and VEGFR2 expression was observed (p < 0.0001, Spearman coefficient 0.347). A high expression of VEGFR2 (VEGFR2high) was found more frequently in long-term survivors (77.4%, 48/62) than in controls (51.6%, 30/62, p = 0.001), independent of FIGO stage and VEGFA expression in multivariate analysis (p = 0.005). Also, VEGFR2high was found the most frequently in women with PFS ≥ 10 years (p = 0.001) among all 124 patients. However, no significant association was detected between VEGFA expression and 5-year PFS (p = 0.075). CONCLUSIONS: VEGFR2 overexpression significantly correlated with long-term PFS in HGSOC patients, independent of age, FIGO stage, tumor residual and VEGFA expression.