CLINICAL, MORPHOLOGICAL, AND EPIDEMIOLOGICAL CHARACTERISTICS OF ENDOMETRIAL HYPERPLASTIC PROCESSES IN SUMY REGION.

endometrial hyperplasia cases was registered in women aged 66+, while atypical hyperplasia cases – in women under 30 years of age. Glandular polyps of the endometrium were most often diagnosed at the age of 31–44; the lowest number of these was found in women over 66 years. Most glandular-fibrous endometrial polyps were observed in women aged 45– 55 years, while women under 30 presented with the fewest cases. Fibrous endometrial polyps were most common in older age groups – 66+; the lowest number of such endometrial polyps was found in women under 30 years. We attributed the decreased incidence of endometrial hyperplastic processes in 2020 to the quarantine measures introduced, which, as a consequence, led to the decreased number of diagnosed cases, since they are often asymptomatic.


Introduction/Вступ
Endometrial hyperplasia (EH) is a pathological condition characterized by hyperplastic changes in the glandular and stromal structures of the endometrium in the uterine cavity [1]. This is a histological diagnosis often made by morphologists and clinical gynecologists.
Clinicians and pathologists pay special attention to endometrial hyperplastic processes (EHP) due to the increasing incidence of this pathology (more than 200,000 new cases registered in developed countries per year) and the high risk of malignant transformation in untreated patients [2].
According to foreign authors, EHP developing in peri-and postmenopausal women leads to malignant transformation in 80% of cases. The frequency and timing of malignant transformation depend on the type of EHP [3]. Although there is no screening tool available for endometrial cancer, EHPs are recognized as prognostic markers for it, and thus, timely detection of EHP will help prevent the development of malignant processes [4]. Despite the high frequency of endometrial hyperplastic processes in the premenopausal period (up to 60-76%), there is an increasing trend of young women diagnosed with this disease. Due to anovulation secondary to chronic hyperestrogenemia, EHP became one of the causes of infertility in women of reproductive age [5]. The prevalence of endometrial polyps (EP) in women is about 7.8%. But in women over 30, it reaches 9.2%. In most cases, the polyps are benign. Estimation of endometrial cancer risks secondary to polyps varies depending on age groups and amounts to 1.1-4.9%. In older age groups, the risk of malignancy is higher [6]. The malignant potential of polyps is understudied [7].
There is no statistics available on the incidence of endometrial hyperplasia in Ukraine [8].
In 2000, a group of gynecologists suggested a classification of endometrial intraepithelial neoplasia (EIN) based on computerized morphometric analysis. Morphological D-score is calculated as stromal volume over total tissue volume. The total tissue volume includes the epithelium, stromal volume, and gland lumen. The endometrial tissue is considered benign if D > 1 and EIN if D < 1 [10].
The diagnostic criteria for EH are based on the assessment of the balance of glandular and stromal endometrial components, as well as the presence or otherwise of atypical epithelial cells. EHPs are characterized by endometrial glands proliferation, which leads to an increase in the gland to stroma ratio > 50%, in contrast to normal proliferative endometrium (gland to stroma ratio < 50%) [11].
Given the urgency of this problem, the goal of our study was to evaluate the prevalence of endometrial hyperplastic processes in Sumy region in 2011-2020 and to perform an analysis of the data.

Materials and methods
Data were collected and analyzed at MI of Sumy Regional Council "Sumy Regional Pathoanatomical Bureau" and at Department of Pathology of Medical Institute of Sumy State University in 2011-2020. The treated cases of endometrial hyperplastic process were analyzed using the data provided by Municipal Non-Profit Enterprise of Sumy Regional Council "Sumy Regional Clinical Oncological Dispensary", Municipal Non-Profit Enterprise of Sumy Municipal Council "Blessed Virgin Mary Clinical Maternity Hospital", and Municipal Non-Profit Enterprise of Sumy Regional Council "Regional Clinical Perinatal Center" in 2011-2020. Histological specimens were studied using morphological methods. Methods of statistical analysis were used to process the obtained results. Results and discussion An analysis of case histories and medical records showed that in 60% of cases, EHPs were accompanied by menstrual disorders, such as dysmenorrhea, oligomenorrhea, menorrhagia, and metrorrhagia. In 40% of cases, endometrial hyperplastic processes were asymptomatic. Analysis of histological material revealed that glandular hyperplasia of the endometrium is characterized by glands of various shapes and sizes (small to large and cystic). The latter were lined with high prismatic epithelial cells with multiple rows of nuclei and clearly defined apical sides of cells. The nuclei were oval and rich in chromatin. The cytoplasm was basophilic, usually with no secretion, although sometimes there was some mucus in the lumen of the glands. Stromal cells were slightly enlarged and had acidophilic cytoplasm. In glandular and stromal cells, mitotic figures were often observed, which indicated active proliferation of glandular and stromal elements [12].
According to the results of the analysis, it was found that the largest number of EHP cases in Sumy region over the past 10 years was registered in 2016 (2020 cases of which 1679 EH cases (83.1%) and 341 EP cases (16.9%)), and the lowest number of EHP casesin 2020 (1317 cases of which 899 EH cases (68.3%) and 418 EP cases (31.7%)) (Fig. 1). The latter might be due to the COVID-19 pandemic and related quarantine measures which led to a reduction in the number of diagnosed EHP cases. According to the study results, the most of nonatypical EH cases were registered in 2016 (1656 cases -98.6% of the total number of diagnosed EH cases in 2016), while the minimum number was reported in 2020 (861 cases -95.8% of the total number of diagnosed EH in 2020). Atypical EH cases were most prevalent in 2017 (75 cases -5.8% of the total diagnosed EH cases in 2017), while the fewest atypical EH cases were reported in 2011 (5 cases -0.35% of the total diagnosed EH cases in 2011) (Fig. 2).
Analysis of the frequency of diagnosed EH during 2011-2020 showed an age-dependent correlation. Thus, the largest number of simple non-atypical EH was observed in women aged 45-55 years (a total of 6965 cases over 10 years in women of this age group, i.e. 52.7% of the total diagnosed non-atypical EH cases in 2011-2020). The minimal number of simple non-atypical EH was registered in women aged 66+ (a total of 181 cases over 10 years in women of this age group, i.e. 1.4% of the total diagnosed non-atypical EH cases in 2011-2020) (Fig. 3).

Figure 3 -Age structure of simple non-atypical EH in Sumy region in 2011-2020
The most of atypical EH cases were also observed in women aged 45-55 (a total of 132 cases over 10 years in women of this age group, i.e. 47.1% of the total diagnosed atypical EH cases in 2011-2020). The minimal number of atypical EH was reported in women under 30 (a total of only 7 atypical EH cases over 10 years in women of this age group, i.e. 2.5% of the total diagnosed atypical EH cases in 2011-2020) (Fig. 4).

Figure 4 -Age structure of atypical EH in Sumy region in 2011-2020
Analysis of clinical data of the patients diagnosed with EHP showed that in 40% of women, EHPs manifested with menopause and metrorrhagia, in 15%with oligomenorrhea, in 5% of caseswith dysmenorrhea; 40% of EHPs were asymptomatic. In 30% of cases, endometrial hyperplastic processes were relapsing. casesuterine leiomyoma, in 40% of casesendometriosis, in 25% of casescervical erosion, in 15% of casesmastopathy; in 10% of caseschronic adnexitis, in 5% of casesovarian cysts. 85% of women had pregnancies and deliveries. 15% of women had a history of infertility. Concomitant extragenital pathologies were: in 35% of casesobesity and hypertension, in 20% of casesgastrointestinal diseases, in 15% of casespathologies of the nervous system, in 10% of casesdiabetes mellitus, in 5% of casesrespiratory and urinary tract diseases.
A study of the histological material related to endometrial polyps showed that the polyps were localized elevations of endometrial glands and stroma protruding from the endometrium (focal endometrial hyperplasia) [13]. Most polyps were benign, although malignant transformation was observed in 0 to 13% of cases. We noted that polyp malignant potential was determined by the patient's age and menopausal status. These data were consistent with the literature data [14]. According to the histological structure, we distinguished glandular, glandular-fibrous, and fibrous polyps of the endometrium. Glandular polyps were usually formed from the basal layer and contained stroma and glands. Glandular-fibrous EP consisted of connective tissue stroma and a limited number of glands. Fibrous polyps derived from connective tissue and were often collagenized, with a few or no glands. We noted that the hyperplasia of the endometrium and the surrounding stroma formed broad-based polypoid vegetations, which later developed a stalk. We found that EP could be single or multiple (in 26% of cases). We noted that with a long-term and favorable course, glandular polyps sometimes reversed by replacing glandular elements with fibrous tissue. According to some authors [15], this was usually accompanied by a decrease in the primary focus size.
According to the study results, the most EP cases were registered in 2019 (597 cases -38.3% of the total number of diagnosed EP cases in 2019), while the minimum number of EP cases was reported in 2012 (92 cases -6.5% of the total number of diagnosed EP in 2012). According to the analysis of EP histological structure, the most of glandular EP cases were registered in 2018 (475 cases -81.2% of the total diagnosed EP cases in 2018), while the minimum number of glandular EP cases was reported in 2012 (73 cases -79.3% of the total diagnosed EP cases in 2012). Glandular-fibrous EPs were most prevalent in 2019 (180 cases -30.1% of the total diagnosed EP cases in 2019), while the fewest glandular-fibrous EP cases were reported in 2011 (4 cases -3.8% of the total diagnosed EP cases in 2011). Fibrous EPs were most prevalent in 2019 (13 cases -2.2% of the total diagnosed EP cases in 2019), while there were no fibrous EP cases diagnosed in 2011 and 2016 (Fig. 5).

Figure 5 -Number of different histological EP types in Sumy region in 2011-2020
Analysis of EP-related age structure revealed a correlation with age. Thus, glandular polyps of the endometrium were most often diagnosed at the age of 31-44 (a total of 907 cases over 10 years in women of this age group, i.e. 40.9% of the total diagnosed glandular EP cases in 2011-2020); the lowest number of glandular EP cases was observed in women over 66 years (a total of 113 cases over 10 years in women of this age group, i.e. 5.1% of the total diagnosed glandular EP cases in 2011-2020).
Glandular-fibrous polyps of the endometrium were most often diagnosed at the age of 45-55 (a total of 237 cases over 10 years in women of this age group, i.e. 37.1% of the total diagnosed glandular-fibrous EP cases in 2011-2020); the lowest number of such EP cases was observed in women under 30 years (a total of 31 cases over 10 years in women of this age group, i.e. 4.9% of the total diagnosed glandular-fibrous EP cases in 2011-2020). Fibrous polyps of the endometrium were most often registered in older patients -66+ years (a total of 23 cases over 10 years in women of this age group, i.e. 45.1% of the total diagnosed fibrous EP cases in 2011-2020); the fewest fibrous EP cases were observed in women under 30 years (a total of only 2 cases over 10 years in women of this age group, i.e. 3.9% of the total diagnosed fibrous EP cases in 2011-2020). According to the results of the analysis, the largest number of EH cases treated at Municipal Non-Profit Enterprise of Sumy Regional Council was registered in 2018 (72 cases), and the largest number of endometrial polypsin 2020 (32 cases). EH and EP cases treated at Municipal Non-Profit Enterprise of Sumy Municipal Council "Blessed Virgin Mary Clinical Maternity Hospital" were most prevalent in 2019 (98 and 63 cases, respectively). The most EP cases treated at Municipal Non-Profit Enterprise of Sumy Regional Council "Regional Clinical Perinatal Center" were reported in 2019 (161 cases).
Data analysis showed that there was an increasing trend in the incidence of endometrial hyperplastic processes in Sumy. We attributed the decreased incidence of endometrial hyperplastic processes in 2020 to the quarantine measures introduced with relation to the COVID-19 pandemic, which, as a consequence, led to the decreased number of diagnosed cases, since they often have asymptomatic course. In older age groups, local EHP with a fibrous component predominated.

Conclusions/Висновки
Statistical data analysis showed an increasing trend in the incidence of EHP in Sumy region in 2011-2020. We attributed the decreased incidence of EHP in 2020 to the quarantine measures, since EHP often has an asymptomatic course and patients do not seek medical attention. Therefore, mandatory outpatient follow-up of such patients should be introduced. The maximum EHP incidence was observed in 2016. There is a correlation between EHP incidence and age, which requires appropriate attention from family physicians and gynecologists.

Prospects for future research/Перспективи подальших досліджень
Study of the morphological and immunohistochemical features of different types of endometrial hyperplastic processes and investigation of the role of genetic polymorphisms in the development of endometrial hyperplastic processes.