High IL-6 levels in ascitic fluid correlate with reactive thrombocytosis in patients with epithelial ovarian cancer
Non-haematopoietic malignancies are commonly associated with thrombocytosis. The aetiology of tumour-associated thrombocytosis is still unclear but may be related to tumour-derived thrombopoietin-like factors. Epithelial ovarian tumour cells have been shown to release IL-6 in vitro and high IL-6 levels have been identified in ascites of patients with ovarian cancer. Since IL-6 is a potent stimulator of megakaryocytopoiesis we examined IL-6 production at the tumour site and its relationship to serum IL-6 levels and circulating platelet counts in patients with ovarian cancer. Forty patients undergoing exploratory laparotomy for epithelial ovarian cancer [stage I+II: 6 (15%); stage III: 25 (62.5%); stage IV: 9 (22.5%)] and 24 women with benign ovarian conditions were evaluated. Sera were available from 39 cases with ovarian cancer and from 19 cases with benign ovarian tumours. Ascites was obtained from 35 patients with ovarian cancer. IL-6 activity in serum and ascitic fluid was determined by the standard B9 proliferation assay (detection level: 1 pg/ml). IL-6 bioactivity was detectable in 22 (56%) sera from patients with ovarian cancer, but in only five (26%) of the serum samples obtained from benign cases (P < 0.001). Serum IL-6 levels in patients with ovarian cancer were significantly higher (median 3 pg/ml; range < 1 to 1221 pg/ml) than in patients with benign ovarian conditions (median 0 pg/ml; range < 1 to 4 pg/ml) (P < 0.001). However, much higher concentrations of IL-6 were measured in malignant ascites specimens (median 22,100 pg/ml; range < 1 to 182,600 pg/ml). IL-6 bioactivity in serum and ascites samples was completely inhibited by a neutralizing goat anti-human IL-6 antiserum. Thrombocytosis (platelet counts > 400 x 10(9)/l) occurred in 25 (62.5%) of the 40 patients with ovarian cancer, but in only two (8%) of the 24 cases with benign ovarian tumours. In eight (20%) cases with malignant disease platelet counts ranged between 600 x 10(9)/l and 1060 x 10(9)/l. IL-6 bioactivity in ascitic fluid correlated significantly with circulating platelet counts (r = 0.5916; P < 0.001). Maximum IL-6 bioactivity in ascites and highest platelet counts occurred in patients with undifferentiated ovarian adenocarcinoma or advanced disease. In conclusion, these observations strongly suggest a role for IL-6 in the development of tumour-associated thrombocytosis.