Fator de necrose tumoral e seus receptores no estroma de lesões ovarianas não neoplásicas e neoplasias ovarianas benignas e malignas.

Abstract

INTRODUCTION: Ovarian epithelial cancer has a high lethality among gynecological malignancies. Ovarian cancer has, in the peritumoral stroma, multiple cell types besides cancer cells, which coordinate tumor survival, growth, invasion and progression. The tumor microenvironment has molecules that can be potential targets for new cancer therapies. Patients with ovarian cancer may have high levels of TNF and Tregs expressing TNFR2, which is associated with suppressive capacity. There is increasingly evidence that TNFR2 expression in cancer microenvironment has significant implications in cancer progression, metastasis and immune evasion. Several studies have shown association of TNF-alpha and its receptors with prognosis in ovarian cancer may be targets for new treatment strategies. OBJECTIVES: The aim of the study was to evaluate the stromal immunostaining of TNF-α and its receptors in malignant ovarian neoplasms, comparing it with benign ovarian neoplasms and non-neoplastic ovarian lesions; to relate immunostaining with clinical, laboratory and pathological prognostic factors; to relate progression-free survival and overall survival in ovarian malignancy, according to TNF-α values and its receptors. MATERIALS AND METHODS: Patients treated at the Pelvic Mass Outpatient Clinic were surgically treated according to pre-established criteria. Patients with benign (n=37) or malignant (n=43) ovarian epithelial neoplasia, and non-neoplastic ovarian lesion (n=15) were included in the study. Immunohistochemical study was performed to evaluate stromal TNF-alpha, TNFR1 and TNFR2. The comparison between the groups was performed by the Chi-Square test, with a significance level lower than 0.05. The following data from the medical records were recorded in a specific database for the study: age, hormonal status, histological type, histological grade, staging (FIGO), type of carcinogenesis (type I and type II), blood count parameters and immunohistochemistry results for TNF-alpha, TNFR1 and TNFR2. For the immunohistochemical study, it was utilized streptoavidin-biotin-peroxidase technique, and TNF-alpha and its receptors was evaluated in peritumoral stroma. The values of tumor markers and blood count parameters were compared by Mann-Whitney test. For parameters that were statistically significant, the receiver operating characteristic (ROC) curve was used to obtain the area under the curve (AUC) and to determine the best cutoff values between the weak (0/1) and strong (2/3) immunostaining groups. For data with statistical significance, multivariate analysis was performed. The level of significance was less than 0.05. RESULTS: TNF-alpha stromal immunostaining was more intense (2/3) comparing benign (p<0.0001) and malignant (p<0.0001) ovarian neoplasms with non-neoplastic tumors. TNFR1 immunostaining was stronger (2/3) in the stroma of malignant neoplasms compared with benign neoplasms (p<0.0001), and stronger (2/3) when comparing benign neoplasms with non-neoplastic ovarian lesions (p=0.0002). For TNFR2, stromal immunostaining was stronger (2/3) in malignant neoplasms compared to benign neoplasms (p=0.0091), and stronger in malignant neoplasms compared to non-neoplastic lesions (p=0.0004). For TNF-alpha, analyzing the ROC curves, there was statistical significance for basophils (cut-off value > 0) and neutrophils (cut-off value ≤ 3900) between strong (2/3) and weak (0/1) immunostaining. In relation to TNFR1, a cut-off value of monocytes > 312/mm3 was found. Regarding TNFR2, the cut-off value of CA-125 was ≤ 95.16U/ml. Still in relation to TNFR2, the cut-off value for the absolute number of platelets was ≤ 298000/mm3. There was no statistical significance with the other parameters of the blood count and tumor markers evaluated. After establishing the cut-off values by the ROC curves, a multivariate analysis was performed, which showed that an absolute monocyte count > 312/mm3 is associated with strong stromal immunostaining (2/3) of TNFR1, and a platelet value ≤ 298,000/mm3 is associated with strong (2/3) stromal immunostaining of TNFR2. CONCLUSION: A stronger immunostaining for TNF-alpha e its receptors was found in ovarian cancer, suggesting that they may be targets of further studies to verify their role in carcinogenesis and the progression of ovarian neoplasms. Absolute monocyte count > 312/mm3 is associated with strong (2/3) stromal immunostaining of TNFR1, and platelet count ≤ 298,000/mm3 is associated with strong (2/3) stromal immunostaining of TNFR2.