Clinical manifestations and proliferative activity of various forms of uterine leiomyoma in women of reproductive age

Background. Uterine leiomyoma (UL) is one of the most common causes of reproductive dysfunction and reduced quality of life in women. The issues of early diagnosis of tumor proliferative activity, which determines the risk of recurrence, remain insufficiently studied, and existing methods are invasive and available only postoperatively. Objective. To study the pathogenetic mechanisms of UL growth in patients of fertile age and to validate diagnostic markers based on the assessment of the expression of cytotoxic receptors (NKp44, NKp46) in the population of endometrial NK cells, previously proposed in the Russian Federation Patent No. 2700003. Material and methods. The study included women of reproductive age: 82 patients with symptomatic UL (study group) and 47 somatically healthy women (control group). The material included venous blood, endometrial biopsies, and fragments of myomatous nodes. The expression of natural killer receptors (NKp44, NKp46) was assessed by multicolor flow cytometry. The level of Ki67 mRNA expression was determined by real-time RT-PCR with normalization to the GAPDH reference gene. An analysis of clinical and anamnestic data and histological examination of the endometrium were performed. To assess the diagnostic value of the NKp44+NKp46+ NK cell threshold, a ROC analysis was performed. Multivariate logistic regression analysis was performed to account for the influence of age and other factors. Results. It was confirmed that the main immunopathological changes in UL are localized in the endometrium. Risk factors for UL development were identified: surgical abortions (OR=3.904; 95% CI 1.42–10.72), chronic endometritis (OR=6.322; 95% CI 2.82–14.17), and a history of heavy menstrual bleeding (OR=12.73; 95% CI 4.17–38.88). In cases with high proliferative activity of fibroid cells (Ki67-high), a statistically significant decrease in the number of NKp44+ lymphocytes, as well as cells with co-expression of NKp44+NKp46+ in the endometrium, is observed compared to nodes with low proliferation (Ki67-low) (p=0.01 and p=0.002, respectively). The use of the previously proposed cut-off level of NKp44+NKp46+ ≤5.4% demonstrated high sensitivity (94.4%) and specificity (64.3%) for identifying patients with Ki67-high. Using a cutoff level of NKp44+NKp46+ NK cells ≤5.4% demonstrated high sensitivity (94.4%) and specificity (64.3%) for identifying patients with Ki67-high. Conclusion. The proliferative activity of a myomatous node does not always correlate with the clinical concept of «rapid growth» and does not depend on the node’s localization. The obtained data suggest that the previously proposed immunological criterion (NKp44+NKp46+ NK cells ≤5.4%) may be an effective tool for the early detection of patients with high proliferative potential of UL, which requires further confirmation in prospective studies and may contribute to the prediction of relapses and timely correction of reproductive plans.