Benign Ovarian Neoplasms: Clinical Guidelines

List of Abbreviations

Terms and Definitions

Benign ovarian neoplasms are cystic or solid ovarian masses without pathological elements and blood flow, having a minimal potential for malignant transformation [1].

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Benign ovarian neoplasms are cystic or solid ovarian masses without pathological elements and blood flow, having a minimal potential for malignant transformation [1].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The etiology and pathogenesis of benign ovarian neoplasms remain incompletely understood to date. All structures of the ovary (surface epithelium, granulosa cells, theca tissue, Leydig cells, embryonic structures, connective tissue, etc.) are potential histogenetic sources of ovarian tumors. Therefore, ovarian tumors are subdivided into: epithelial, mesenchymal, mixed epithelial-mesenchymal, sex cord-stromal, germ cell, and mixed germ cell and sex cord-stromal tumors [2].

There are two main theories regarding the pathogenesis of epithelial ovarian masses: their development from inclusion cysts due to metaplasia of the ovarian surface epithelium, and their formation from inclusion cysts whose lining epithelium is formed as a result of the implantation of tubal epithelium onto the ovarian surface followed by invagination [3], [4], [5], [6], [7].

In the origin of non-epithelial tumors (stromal-cell and germ cell), which are more common in young women and children, adverse factors during embryogenesis are considered to play the primary role, resulting in mutations in various genes responsible for normal cell development [8], [9], [10].

Atrophy of the ovaries and Fallopian tubes is a pathological process characterized by a reduction in size, loss of structural integrity, and functional activity of these organs. Unlike age-related physiological involution, acquired atrophy is caused by exogenous and endogenous damaging factors, including chronic inflammation, surgical interventions, chemo- and radiotherapy, as well as autoimmune processes.

Cystic developmental anomalies of the ovary arise as a result of embryonic development disorders or hormonal dysregulation. They can manifest across various age groups, from newborns to adult women, and range from functional cysts to complex tumor masses.

Prolapse and hernia of the ovary and Fallopian tube is a rare condition in which the ovary and/or tube are displaced beyond their anatomical location (into the inguinal canal, postoperative hernias, etc.). It occurs most frequently in girls and adolescents, and less commonly in women of reproductive or elderly age.

1.3 Epidemiology of the Disease or Condition

The incidence of benign ovarian tumors is 13.3% among all gynecological pathologies. Cystadenomas account for 80% of all ovarian neoplasms. Sex cord-stromal tumors are detected in 14.9%, among which granulosa cell tumors account for 28.2%, and thecomas and fibromas account for 6.4% [10], [11].

Benign ovarian tumors (BOTs) occur in women of any age. The majority of patients with BOTs (69.1%) belong to the age group between 31 and 60 years.

The incidence of ovarian tumors in pregnant women is 0.5–3.4%. During ultrasound screening in the 1st trimester of pregnancy, corpus luteum cysts are most commonly detected, which spontaneously regress within 2–4 months [12].

Inguinal hernias in women account for 3–6% of the total number, and 15% to 30% contain the ovary and tube in girls [13].

Risk factors for the development of BOTs include: genetic predisposition; chronic inflammatory pelvic diseases; early or late menarche; late onset of menopause; smoking; obesity, diabetes mellitus; PCOS; ovarian hyperstimulation [14], [15].

1.4 Features of Coding the Disease or Condition

D27 – Benign neoplasm of ovary

N83.0 – Follicular cyst of ovary

N83.1 – Corpus luteum cyst

N83.2 – Other and unspecified ovarian cysts

N83.3 – Acquired atrophy of ovary and Fallopian tube

N83.4 – Prolapse and hernia of ovary and Fallopian tube

N83.5 – Torsion of ovary, ovarian pedicle and Fallopian tube

N83.6 – Hematosalpinx

N83.7 – Hematoma of broad ligament

N83.8 – Other noninflammatory disorders of ovary, Fallopian tube and broad ligament

N83.9 – Noninflammatory disorder of ovary, Fallopian tube and broad ligament, unspecified

Q50.1 – Cystic developmental anomaly of ovary.

Q50.5 – Embryonic cyst of broad ligament

1.5 Classification of the disease or condition

1.5.1 WHO Classification (2020):

Currently, the most relevant and substantiated histological classification of ovarian tumors is the one adopted by the WHO in 2020, taking into account modern concepts of the pathogenesis of ovarian tumors, as well as their molecular-genetic and biological features [2]. See Appendix B.

In accordance with the WHO classification (2020), the main nosological groups are formed by categories[2]: epithelial, stromal, mesenchymal tumors, sex cord-stromal tumors, germ cell tumors, mixed, tumor-like conditions, secondary (metastatic) tumors.

Depending on morphological signs of cellular atypia and the presence of invasion, ovarian tumors are subdivided into: benign tumor, uncertain malignant potential or borderline tumor, carcinoma in situ, malignant invasive tumor [2].

1.6 Clinical presentation of the disease or condition

In the vast majority of cases, ovarian tumors are asymptomatic [12].

Clinical symptoms appear upon:

✓ the occurrence of complications (tumor torsion, rupture, hemorrhage, suppuration of the ovarian mass) – "acute abdomen" symptoms;

✓ the development of ascites, hydrothorax in combination with the presence of an ovarian neoplasm (for Meigs' syndrome);

✓ hormonal activity of the tumor (symptoms of androgen or estrogen hyperproduction in sex cord-stromal tumors; symptoms of hyperthyroidism in dysgerminomas) [12].

Signs of androgen-producing tumors:

✓ defeminization – development of virilization – disappearance of female secondary sex characteristics, oligo-/amenorrhea,

✓ masculinization (virilization) – appearance of male secondary sex characteristics (hirsutism, male-pattern redistribution of adipose tissue, deepening of the voice) [16], [17], [18], [19].

Signs of estrogen-producing tumors:

✓ precocious puberty;

✓ menstrual irregularities of the AUB type in reproductive age;

✓ development of hormone-induced endometrial hyperplasia,

✓ absence of signs of age-related atrophy of the external and internal genitalia in postmenopause [16], [17].

Patients with asymptomatic BOTs should be informed about the signs and symptoms of ovarian torsion [20]. A number of retrospective studies have shown that at least 80% of ovarian torsions occur with ovarian masses 5 cm or more in diameter [21], [22], [23], [24].

The most common histological subtypes of ovarian masses in ovarian torsion are corpus luteum cysts, mature teratomas, and serous cystadenomas [21], [23], [25].

Acquired atrophy of the ovaries and Fallopian tubes leads to menstrual irregularities and infertility.

In some cases, tubo-ovarian masses are formed, involving the Fallopian tubes (in the form of hydrosalpinx or hematosalpinx); the main symptom of these masses is pain.

Pronounced pain is also observed in hematoma of the broad ligament of the uterus.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis is established based on patient complaints and medical history, physical examination, and instrumental diagnostic methods (pelvic ultrasound, pelvic MRI, diagnostic laparoscopy).

2.1 Complaints and Anamnesis

See the "Clinical Presentation" section.

2.2 Physical Examination

Comments: Gynecological examination is not always informative.

Bimanual and rectovaginal examination allows determining the size of the tumor, mobility, surface, consistency of the tumor masses, tenderness, unilateral or bilateral nature of the lesion, mutual arrangement of the pelvic organs, examining the pouch of Douglas, the anterior wall of the rectum, parametria, etc. However, in patients with a BMI greater than 30 kg/m², its use is limited [16].

2.3 Laboratory Diagnostics

No specific laboratory diagnostics for BOTs have been developed.

Comment: most biochemical markers for ovarian cancer are non-specific, so their use for primary diagnosis of ovarian neoplasms is limited. Cancer antigen 125 (CA125) and human epididymis secretory protein 4 (HE4) are the most studied markers for ovarian cancer. A CA 125 level >35 IU/ml or higher is detected in 78-100% of patients with ovarian cancer (mainly in the serous form) [31], [32]. At the same time, CA125 can be elevated during pregnancy, endometriosis, and any inflammatory process [30], [33]. As an additional marker, the best results were obtained for HE4, which is more sensitive and specific than CA 125 for the diagnosis of ovarian cancer (73% vs. 43.3% and 95% vs. 76.4%, respectively). However, it is elevated in endometriosis and can be false-positive in benign tumors [32], [33]. Tumor markers specific for germ cell ovarian tumors include: human chorionic gonadotropin (hCG), alpha-fetoprotein (AFP), lactate dehydrogenase (LDH)—a specific marker for pure dysgerminoma (elevated in almost 100% of cases) [27], [28], [30]. In women under 40 years of age with adnexal masses, rare forms of ovarian cancer must be considered, and further measurements of tumor markers should be performed, including human chorionic gonadotropin, lactate dehydrogenase, and alpha-fetoprotein levels [29].

In bilateral ovarian masses, for differential diagnosis and to rule out metastatic ovarian lesions, additional serum tumor marker tests are used, such as carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9), and cancer antigen 15-3 (CA15-3). CEA levels are elevated in colorectal cancer, CA 15-3 in breast cancer, and less frequently in colorectal, lung, ovarian, cervical, and endometrial cancer. CA 19-9 is a tumor marker for lesions of the pancreas, liver, bile ducts, sigmoid colon, and rectum [29], [34], [35].

2.4 Instrumental Diagnostics

Comment: Ultrasound should be used at the primary stage of evaluation in all age groups of patients [20], [36], [37].

Reduced ovarian size and the absence of antral follicles are characteristic of acquired atrophy of the ovaries and fallopian tubes.

Ultrasound diagnostics is indispensable in diagnosing hematosalpinx due to detailed visualization of the degree of fallopian tube lumen dilation, wall thickness, and the homogeneity or layering of the contents within the lumen.

Ultrasound diagnostics allows the detection of a hematoma between the leaves of the broad ligament.

The primary diagnostic method for a cystic developmental anomaly of the ovary is ultrasound examination, which allows for the evaluation of the size, structure, and nature of the cyst.

A high-frequency scanner detects the structure of the ovary and fallopian tube within the hernia sac, and Doppler ultrasound detects the presence or absence of blood flow in case of torsion, which is diagnostically significant for prolapse and herniation of the ovary and fallopian tube.

Comment: Based on randomized trials, the International Ovarian Tumor Analysis (IOTA) group has developed ultrasound criteria for benign and malignant ovarian tumors ("B-rules" and "M-rules", respectively), with sensitivity and specificity reaching 95% and 91%, respectively [38], [40], [41] (See Appendix A3.1). One of the modern promising systems for assessing the ultrasound characteristics of ovarian tumors is the standardized O-RADS (Ovarian-Adnexal Reporting and Data System) scale published in 2018 by the American College of Radiology, aimed at improving interdisciplinary collaboration among specialists (functional diagnosticians, gynecologists, and oncologists) and increasing diagnostic accuracy [42], [43]. (See Appendix A3.1).

Comments: MRI is not recommended as a primary diagnostic examination for the detection of ovarian tumors [20], [36], [37]. Pelvic MRI is used as an additional imaging method in cases of "indeterminate" ovarian masses on ultrasound (sensitivity and specificity of the method are 96.6% and 94.0%, respectively) [20], [44].

Comment: Contrast-enhanced MRI improves the differential diagnosis of benign and malignant ovarian tumors to a greater extent than color Doppler ultrasound, unenhanced MRI, and CT. Contrast-enhanced MRI is indicated to clarify the anatomical relationships of the structures evaluated, the tumor growth pattern, to detect signs of ascites, and for patients in whom pelvic ultrasound is uninformative [20], [44].

Comment: RMI calculation should be used as part of the comprehensive assessment of ovarian masses prior to surgical treatment. The sensitivity and specificity of this method reach 70–78% and 87–90%, respectively [29], [45], whereas the sensitivity and specificity of measuring CA 125 levels alone in peri- and postmenopausal patients do not exceed 78%. Normally, the RMI does not exceed 200. An increase above 200 is a predictor of ovarian cancer development. (See Appendix A3.1). It has been established that the ultrasound criteria developed by IOTA are more accurate than the RMI [45].

Comment: patients with ovarian masses should be referred to an oncologist if there is a high risk of ovarian cancer based on family history [20], [36]; a high risk of ovarian cancer according to the IOTA or RMI prognostic models [38], [42]; fixed pelvic tumor masses or bilateral firm or nodular tumor masses in postmenopausal patients; ascites; or suspicion of regional or distant metastases [20].

Comment: aspiration biopsy of tumor contents has low informative value, its sensitivity for the differential diagnosis of benign and malignant ovarian tumors does not exceed 25%, and the risk of tumor dissemination is high; it is strictly not recommended in the presence of ultrasound signs of malignancy in order to preserve ablastics [20].

Comment: the use of a laparoscopic approach allows for determining tumor mobility, assessing the internal structure of the mass, taking a biopsy to determine the morphological structure of the disease and the extent of the process, and visualizing small ovarian tumors that do not cause gross volumetric transformation. During diagnostic laparoscopy, a biopsy may be taken only from a solid tumor with immediate intraoperative morphological examination and cytological examination of peritoneal fluid [12].

Comments: a definitive conclusion regarding the nature of the process (benign/malignant) and the prognosis of the disease can only be made after receiving the results of a detailed morphological examination of the resected gross specimen [20].

2.5 Other Procedures

Absent

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Medical treatment

Comment: the prescription of COCs (according to ATC: Progestogens and estrogens, fixed combinations) does not accelerate the regression of functional ovarian cysts. Expectant management in patients with functional ovarian cysts without medical treatment achieves recovery rates similar to those with the use of COCs (according to ATC: Progestogens and estrogens, fixed combinations) [20], [29], [46]. Prophylactic use of COCs (according to ATC: Progestogens and estrogens, fixed combinations) is justified in patients with a history of recurrent hemorrhagic cysts, cyst rupture, and ovarian apoplexy [20], [29], [47].

3.2 Surgical Treatment

Comments: Laparoscopic approach is preferred over laparotomy. Laparoscopy is associated with a shorter hospital stay, faster recovery, less pain, and less bleeding compared to laparotomy [48].

Comment: The goals of surgical intervention in reproductive-age patients with benign ovarian masses are: 1) complete removal of the neoplasm; 2) preservation of reproductive function [20].

In order to preserve ovarian reserve, patients of reproductive age with benign ovarian masses should undergo ovarian resection by enucleating the cyst capsule, minimizing trauma to the cortical layer and maximally preserving healthy ovarian tissue. In cases of uterine adnexal torsion in reproductive-age patients with benign ovarian masses, detorsion is permissible if signs of tissue viability are preserved. Ovarian apoplexy accompanied by bleeding requires coagulation of the rupture site with enucleation of the cyst wall.

It is important during surgery for benign ovarian masses to adhere to the principles of ablastics, removing the capsule of the cystic formation within an endobag in an ablastic manner [48].

For large ovarian masses, hemostasis of the bed after enucleation should be performed using bipolar coagulation or a defocused laser beam, and structural integrity should be restored by suturing the ovary including the base using absorbable suture material, which promotes proper reparative regeneration, preserves ovarian reserve, and prevents adhesions.

Surgical treatment of hematosalpinx in reproductive-age patients should aim to preserve the fallopian tube, although in some cases its removal is required.

Surgical treatment of a broad ligament hematoma depends on the size, clinical presentation, and cause of the condition.

Comment: Prior to surgical treatment, the surgical approach and extent of surgery must be agreed upon with the patient. The extent of surgical treatment depends on concomitant pathology [20]. If adjacent organs are involved, the surgical team must include profile specialists (urologist, general surgeon, oncologist, etc.) [20].

3.3 Other Treatment

Treatment of reproductive-age patients with acquired atrophy of the ovaries and fallopian tubes aims to correct menstrual cycle disorders, and in the presence of complaints of infertility – early reproductive assistance.

The treatment tactics for patients with cystic developmental anomalies of the ovary depend on the patient's age, and the size and nature of the cyst. Functional cysts in newborns and children often do not require intervention and are subject to dynamic monitoring.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

5. Prevention and Dispensary Observation

Comment: To detect neoplasms and abnormalities of the internal reproductive organs, a bimanual pelvic examination and comprehensive pelvic ultrasound (transvaginal and transabdominal) are performed.

No special diet therapy, dietary supplements, vitamins, or mineral supplements are prescribed as a method of treating the disease in patients with benign ovarian tumors [20], [49].

Comments: regardless of the women's age, asymptomatic, simple, unilateral, unilocular ovarian cysts less than 5 cm in diameter have a low risk of malignancy (risk of malignancy <1%) [50], [51], [52]. Large prospective studies have shown that most simple cystic formations undergo spontaneous regression within a short time, regardless of the patient's age. Corpus luteum cysts or functional ovarian cysts (hemorrhagic cysts) less than 5 cm in diameter regress spontaneously within 2–3 months [53], [54]. Surgical intervention is not performed in patients with newly diagnosed asymptomatic simple or unilocular cystic ovarian masses up to 5 cm in diameter. With normal serum CA 125 levels, the management is conservative, with a follow-up examination in 2–3 months.

True tumors and tumors suspicious of malignancy require surgical treatment. Hemorrhagic ovarian cysts (corpus luteum cysts and functional cysts) should not occur in childhood (before puberty) and in postmenopausal women. If they are diagnosed in these patients, they require additional evaluation and surgical treatment [36], [37].

6. Organization of Medical Care

Comment: emergency care can be provided in level 1 and level 2 hospitals. Medical care in level 3 hospitals is provided in the presence of severe concomitant somatic pathology in patients with ovarian masses, large tumors, combination with pronounced adhesions involving adjacent organs, tumors of undetermined origin, conditions requiring high-tech care, or preservation of reproductive system function

Comments: Before laparoscopy, the following issues should be discussed with the patient [38]:

- What laparoscopy involves;

- Benefits and risks;

- Potential impact on ovarian reserve and fertility;

- Potential extent of surgical treatment if malignant pathology is detected.

Indications for emergency hospitalization to a medical organization [38]:

2) cyst rupture or torsion of the cyst pedicle;

3) Pain syndrome in the presence of pelvic masses;

4) Symptoms of acute abdomen.

Given the need to provide specialized, including high-tech, medical care to patients with benign ovarian masses, hospitalization in a level 3 medical organization is recommended.

If adjacent organs are involved, consultation with relevant specialists is required.

7. Additional Information

7.1 Treatment and management tactics for patients with benign adnexal masses of the uterus during pregnancy

The incidence of benign ovarian masses during pregnancy is 2% [55]. Most of these masses are discovered during the first trimester of pregnancy and are functional cysts that spontaneously regress in the second trimester of pregnancy. About 80–95% of ovarian cysts smaller than 6 cm in diameter spontaneously regress in pregnant women [55].

The management of female patients with pelvic masses detected in the first trimester is determined by clinical, anamnestic, and sonographic data. Most frequently, these cystic ovarian masses in the first trimester present as corpus luteum cysts, which regress spontaneously. In the absence of positive dynamics, an ovarian tumor is diagnosed, which in most cases is a mature teratoma or serous cystadenoma [55]. Ovarian tumors persisting throughout pregnancy are most commonly functional cysts with a very low malignancy rate or mature cystic teratomas with a malignant transformation rate ranging from 2% to 6% [55].

Comment: Depending on the gestational age, in some cases it is advisable to perform abdominal ultrasound due to the displacement of the tumor beyond the lesser pelvis by the gravid uterus. If necessary and indicated, based on a multidisciplinary team decision, non-contrast CT and MRI may be used [71,72]. Performing MRI (second-line examination, following ultrasound) in pregnant women with unclassified ovarian masses for definitive diagnosis and differential diagnosis between benign and malignant neoplasms [56].

• Measurement of CA 125 level is not recommended, as its levels may be elevated throughout pregnancy [20], [55].

GGR CLOC 5Grade of Recommendation C (Level of Evidence – 5).

Comment: Surgery in pregnant women should be performed by an experienced physician in a level III facility. Fetal heart rate monitoring is necessary in the perioperative period [58], [57]. Surgical intervention during pregnancy may complicate its subsequent course. However, pregnancy outcomes after elective surgical treatment for benign ovarian tumors are better than those performed on an emergency basis due to the development of complications [57].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Leyla V. Adamyan – Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Deputy Director of the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health, Honored Scientist of Russia, Head of the Department of Obstetrics, Gynecology and Reproductive Medicine at the Russian University of Medicine, Chief Freelance Gynecologist of the Russian Ministry of Health, member of the Society for Reproductive Medicine and Surgery, Russian Association of Gynecologic Endoscopists, Russian Association for Endometriosis, Russian Society of Obstetricians and Gynecologists.

Alexandra V. Asaturova – Doctor of Medical Sciences, Head of the 1st Pathological Anatomy Department at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health.

Natalya V. Artymuk – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics and Gynecology named after Professor G.A. Ushakova at Kemerovo State Medical University of the Russian Ministry of Health, Chief freelance specialist in obstetrics and gynecology of the Russian Ministry of Health in the Siberian Federal District, member of the Russian Society of Obstetricians and Gynecologists.

Tatyana E. Belokrinitskaya – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics and Gynecology, Faculty of Continuing Professional Education, Chita State Medical Academy of the Russian Ministry of Health, Honored Doctor of the Russian Federation, Chief Freelance Specialist in Obstetrics and Gynecology of the Russian Ministry of Health in the Far Eastern Federal District (Chita), member of the Russian Society of Obstetricians and Gynecologists, President of the Trans-Baikal Society of Obstetricians and Gynecologists.

Vitaly F. Bezhenar – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics, Gynecology and Neonatology at the First Pavlov State Medical University of St. Petersburg of the Ministry of Health of Russia, Chief Freelance Specialist in Obstetrics and Gynecology for the Health Committee of St. Petersburg, member of the Society for Reproductive Medicine and Surgery, Russian Association of Gynecologic Endoscopists, Russian Society of Obstetricians and Gynecologists.

Yulia E. Dobrohotova – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics and Gynecology at the Faculty of Medicine of the Pirogov Russian National Research Medical University of the Ministry of Health of Russia, Honored Physician of the RF, Honored Scientist of the RF, Laureate of the Government Prize of the RF, member of the Society for Reproductive Medicine and Surgery, Russian Association of Gynecologic Endoscopists, Russian Society of Obstetricians and Gynecologists.

Stanislav I. Kiselev – Doctor of Medical Sciences, Professor of the Department of Reproductive Medicine and Surgery at the A.I. Yevdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health, laureate of the Government Prize of the Russian Federation in Science and Technology, member of the Russian Association of Gynecologic Endoscopists, Russian Society of Obstetricians and Gynecologists.

Anna I. Malyshkina – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics and Gynecology, Medical Genetics at the Ivanovo State Medical Academy of the Russian Ministry of Health, Chief Freelance Specialist in Obstetrics and Gynecology of the Russian Ministry of Health in the Central Federal District, member of the Society for Reproductive Medicine and Surgery, Russian Society of Obstetricians and Gynecologists.

Irina A. Salnikova – Candidate of Medical Sciences, Researcher at the 2nd Gynecological Department of the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health.

Narine M. Tonoyan – Candidate of Medical Sciences, Obstetrician-Gynecologist at the Department of Operative Gynecology of the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Ministry of Health of the Russian Federation.

Elena V. Uvarova – Corresponding Member of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Honored Scientist of the Russian Federation, Head of the 2nd Gynecological Department at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health, Professor at the Department of Obstetrics, Gynecology and Reproductology of the Institute of Professional Education at the I.M. Sechenov First Moscow State Medical University (Sechenov University) of the Ministry of Health of the Russian Federation, Chief Freelance Pediatric and Adolescent Gynecologist of the Russian Ministry of Health, President of the Association of Pediatric and Adolescent Gynecologists of Russia, member of the Russian Society of Obstetricians and Gynecologists.

Filippov Oleg Semenovich – D.Sc. in Medicine, Professor, Honored Doctor of the Russian Federation, Chief freelance Obstetrician-Gynecologist of the Federal Medical-Biological Agency (FMBA) of Russia, Deputy Director of the Federal Scientific and Clinical Center of Children and Adolescents of FMBA of Russia, Professor at the Department of Obstetrics, Gynecology and Reproductive Medicine, Russian University of Medicine.

Maria I. Yarmolinskaya – Professor of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Head of the Department of Gynecology and Reproductive Endocrinology at the D.O. Ott Research Institute of Obstetrics and Gynecology, Professor at the Department of Obstetrics and Gynecology at the I.I. Mechnikov North-Western State Medical University of the Russian Ministry of Health, member of the Russian Society of Obstetricians and Gynecologists.

Conflict of interest:

All members of the working group declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Obstetricians-gynecologists,

2. Endocrinologists,

3. Surgeons,

4. Urologists,

5. Oncologists,

6. Family medicine physicians,

7. Students, residents, PhD candidates, and faculty of medical universities.

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for evaluating the levels of evidence (LE) for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for evaluating the levels of recommendation certainty (LRC) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural healing factors (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines were developed taking into account the following regulatory legal documents:

1. Order of the Ministry of Health of the Russian Federation No. 1130n dated October 20, 2020 "On approval of the Procedure for the provision of medical care in the profile of 'obstetrics and gynecology'".

2. Order of the Ministry of Health of the Russian Federation No. 803n dated July 31, 2020, "On the procedure for the use of assisted reproductive technologies, contraindications and restrictions on their use."

3. Clinical guidelines for the diagnosis and treatment of patients with ovarian, fallopian tube, or primary peritoneal cancer. Association of Oncologists of Russia, 2014.

4. Obstetrics. National Guidelines. Moscow: GEOTAR-Media, 2015. - 1080 p.

5. Savelieva G. M. et al. Gynecology: National Guidelines. Short edition / ed. by G.M. Savelieva, G.T. Sukhikh, V.N. Serov, V.E. Radzinsky, I.B. Manukhin. – 2nd ed., rev. and supp. – Moscow : GEOTAR-Media, 2020. – 1056 p. – DOI: 10.33029/9704-5739-9-GIN-2020-1-056.

6. Clinical Gynecologic Oncology: in 3 vols. / ed. by F.J. DiSaia, W.T. Creasman; transl. from English ed. by E.G. Novikova. - Moscow: Prakticheskaya Meditsina, 2012. - Vol.3. - p.: ill.

7. Guideline No. 404: Initial Investigation and Management of Benign Ovarian Masses. Wolfman W, Thurston J, Yeung G, Glanc P.J Obstet Gynaecol Can. 2020 Aug;42(8):1040-1050.e1. doi: 10.1016/j.jogc.2020.01.014.PMID: 32736855

8. Guideline No. 403: Initial Investigation and Management of Adnexal Masses. Salvador S, Scott S, Glanc P, Eiriksson L, Jang JH, Sebastianelli A, Dean E.J Obstet Gynaecol Can. 2020 Aug;42(8):1021-1029.e3. doi: 10.1016/j.jogc.2019.08.044.PMID: 32736853

9. The Management of Ovarian Cysts in Postmenopausal Women. RCOG Green-top Guideline No. 34, July 2016.

10. O-RADS US Risk Stratification and Management System: A Consensus Guideline from the ACR Ovarian-Adnexal Reporting and Data System Committee. Andreotti RF, Timmerman D, Strachowski LM, Froyman W, Benacerraf BR, Bennett GL, Bourne T, Brown DL, Coleman BG, Frates MC, Goldstein SR, Hamper UM, Horrow MM, Hernanz-Schulman M, Reinhold C, Rose SL, Whitcomb BP, Wolfman WL, Glanc P.Radiology. 2020 Jan;294(1):168-185. doi: 10.1148/radiol.2019191150. Epub 2019 Nov 5.PMID: 3168792

11. Grimes D.A., Jones L.B., Lopez L.M., Schulz K.F. Oral contraceptives for function ovarian cysts // Cochrane Database Syst. Rev. 2014/ Vol. 4/ CD006134.

12. V.I. Kulakov, L.V. Adamyan. Endoscopy in Gynecology: A Guide for Physicians. – Moscow: Meditsina, 2000. – 384 p.: ill.

13. Serov V. N., Sukhikh G. T. Clinical Guidelines. Obstetrics and Gynecology // M: GEOTAR-Media. – 4th ed. – 2017. Moscow: Problemy Reproduktsii.

Appendix A3.1 Histological classification of ovarian tumors (WHO, 2020).

Simple Rules ultrasound classification of benign and malignant tumors (IOTA Group)

O-RADS US Risk Stratification and Management System: A Consensus Guideline from the ACR Ovarian-Adnexal Reporting and Data System Committee.

Andreotti RF, Timmerman D, Strachowski LM, Froyman W, Benacerraf BR, Bennett GL, Bourne T, Brown DL, Coleman BG, Frates MC, Goldstein SR, Hamper UM, Horrow MM, Hernanz-Schulman M, Reinhold C, Rose SL, Whitcomb BP, Wolfman WL, Glanc P.Radiology. 2020 Jan;294(1):168-185. doi: 10.1148/radiol.2019191150. Epub 2019 Nov 5.PMID: 31687921

O-RADS Ovarian-Adnexal Reporting and Data System

Risk of Malignancy Index for pelvic masses (RMI by Jacobs et al., 1990)

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

• Benign ovarian tumors occur at any age and are characterized by an asymptomatic course, which makes the annual gynecological examination and annual pelvic ultrasound particularly valuable.

• Effective screening for early ovarian cancer is currently unavailable.

• Lower abdominal and back pain, abdominal enlargement, fatigue, and weight loss are late symptoms of ovarian cancer.

• In 99.0% of cases, ovarian tumors do not cause menstrual irregularities.

• The occurrence of complications – adnexal torsion, perforation of the ovarian mass wall, ovarian apoplexy ("acute abdomen") – is an indication for emergency admission to a gynecological inpatient unit.

• More than 50% of cystic adnexal masses in menstruating women are functional, i.e., capable of spontaneous regression. Confirmation of the functional nature of an ovarian cystic mass is performed via repeat ultrasound 4–6 weeks after the initial scan.

• In postmenopausal women, the detection of an ovarian cystic mass is a tumor (benign or malignant) in the vast majority of cases. A definitive conclusion regarding the nature of the process can only be made after tumor removal, i.e., surgical treatment.

• When visiting a gynecologist, it is essential to provide detailed information about ALL relatives who suffered from malignant tumors of any localization on both the maternal and paternal sides, specifically noting breast, ovarian, endometrial, colorectal, and gastric cancers.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not applicable.