Ovarian reserve and mature cystic teratomas of the ovaries in patients of reproductive age

Preservation of the ovarian reserve is one of the most relevant issues of modern reproductive medicine [1]. One of the causes of diminished ovarian reserve is the presence of ovarian neoplasms (approximately in 6.6% of women of reproductive age) and their surgical treatment in medical history [1]. Over the last ten years the increasing growth in cases of this pathology reached from 6–11% to 9–25% [2]. Ovarian tumors are characterized by a wide range of morphological structures and clinical manifestations, as well as have effect on the ovarian reserve and reproductive potential in women [3]. Mature teratomas are most common ovarian tumors that develop from embryonic cells [3]. Teratoma is classified as mature, when it consists of highly differentiated tissue derived from one or more germ layers [3]. Immature teratoma contains immature epithelial (nervous or blastemal) or stromal tissue [3].  Structurally mature teratomas are divided into cystic or solid teratomas [4]. Cystic teratoma, the walls or which are lined with stratified squamous epithelium, is also known as dermoid cyst [4]. Teratoma is filled with gelatinous material including mature fragments of derivatives of the ectoderm (skin, hair), endoderm (ciliated epithelium) and mesoderm (sebaceous and sweat glands, nervous, bone and other tissues) [1, 5, 6]. Mature cystic teratomas of the ovaries account for 15 to 20% of all ovarian tumors [1, 5, 6]. The women are most affected by mature cystic teratomas of the ovaries in their second and third decades of life, under the age of 45 [1, 5, 6]. According to one of the largest studies involving 460,000 women, the annual number of cases was between 1.2 and 14.2 per 100,000 population. Mature teratomas are generally unilateral, but in 10–12% of cases can be bilateral [1]. Numerous studies have found several risk factors that are associated with mature cystic teratomas. These factors include late menarche and menstrual irregularities, alcohol abuse, teratomas in history, unrealized reproductive function, infertility, and physical activity in adolescence (associated with anovulatory cycles) [3]. Currently, different types of tests and markers, such as serum levels of estradiol, follicle-stimulating hormone, anti-Müllerian hormone (AMH), inhibin-B, and antral follicle count (AFC), are used to determine ovarian reserve [6, 7]. AMH test is considered to be the most accurate quantitative method for assessment of ovarian reserve [8]. AMH is secreted by granulosa cells of pre-antral follicles that grow to the stage of antral follicles 6–8 mm in diameter. AMH plays an important role in the growth of follicles before transitioning to hormone-dependent stage, protects the granulosa cells of growing follicles from high mitogenic effect of follicle-stimulating hormone (FSH) [8, 9]. This makes it possible to obtain thorough information on folliculogenesis and assess the number of growing follicles at the hormone-dependent stage of their growth [8, 9]. Recently, AMH level and AFC are considered to be more reliable indicators for assessment of ovarian reserve given their high sensitivity and specificity [7].

Ovarian insufficiency can develop due to chromosomal and genetic abnormalities, autoimmune pathology, the influence of environmental factors or infectious and toxic agents [7, 10]. Surgery is the leading method for treatment of benign ovarian tumors, predominantly using laparoscopic access technique and organ-sparing approach, which makes it possible to preserve patient's reproductive function [11, 12]. The use of different methods of hemostasis during organ-sparing ovarian surgery leads to irreversible neurogenic and microcirculatory damage of ovarian tissue, follicular dysfunction, and consequently, to ovarian insufficiency [13].

The objective of the study was to assess the ovarian reserve in patients of reproductive age, who had mature cystic teratomas of the ovaries before and after surgical treatment.

Materials and methods

Retrospective analysis of 267 medical histories of patients was performed, who were admitted to the Gynecological Department of the Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia with the diagnosis of ovarian teratoma from 2016 to 2022. The patients have signed informed consent to participate in the study. All patients underwent routine medical examination according to the standard algorithm: clinical and laboratory tests, determination of serum levels of CA-125 and AMH, pelvic ultrasound (using ultrasound machines GE Voluson, Philips iU), and when necessary, pelvic MRI. Evaluation of ovarian reserve (AMH level, as well as the results of ultrasound and/or MRI before and after surgical treatment) and female reproductive function was performed.   

Statistical analysis

Statistical data processing was performed using Microsoft Office Excel 2015, MedCalc v.12. The normal distribution of the variables in the samples was tested using the Kholmogorov–Smirnov test. The quantitative data in normal distribution were described using arithmetic mean (M) and standard deviation (SD) – M(SD). Relationship between the quantitative data was tested using Pearson’s correlation coefficient. Statistical significance of alterations in quantitative parameters in dynamics was determined using Student’s t-test for pairwise comparisons. The qualitative data were described using absolute and relative values (%). The differences were considered to be statistically significant at р<0.05.

Results

The mean age of patients was 35.0 (6.5) years (from 18 to 45 years). Most patients (114/267 (43%) belonged to the age group of 32–38 years, 19/267 (7%) belonged to the age group of 18–23 years, 67/267 (25%) belonged to the age group of 24–31 years, 32/267 (12%) belonged to the age group of 39–42 years, 35/267 (13%) were aged 43 years and older. Teratomas in 259/267 (97%) women were unilateral, bilateral teratomas were in 8/267 (3%) cases. The size of mature cystic teratomas varied from 1.0 cm to 17.0 cm.

The main complaints were lower abdominal pain (85%) and absence of conception (15%). The average age at menarche was 13.0 (1.02) years. The length of the menstrual cycle was 28.0 (2.5) days, and duration of menstrual periods was 5.0 (0.8) days. Heavy menstrual bleeding was detected in 111/267 (42%) women, moderate in 149/267 (56%), and scanty in 7/267 (3%) women. Painful periods were in 82/267 (31%) patients. Term births were in 117/267 (44%) women in history.

Combined pathology of the pelvic organs – endometrial hyperplastic processes, genital abnormalities, external genital endometriosis were identified in 71/267 (27%) women.

Previously, 54/267 (20%) patients have undergone surgical treatment of mature cystic teratomas of the ovaries. Among these patients, 8 women have undergone laparotomy and 46 – laparoscopy. The period of time between surgeries was 5.0 years.

According to the results of pelvic US and/or MRI, cystic teratomas of different size were detected. The average number of antral follicles was 4.0 (2.4). The values of tumor markers were within the normal range, only in 9 patients the values of CA-125 and CA-19-9 were slightly high. AMH level before surgery was on average 2.6 (2.0) ng/mL.

Correlation analysis of the sizes of cystic teratomas and AMH/AFC before surgery was performed. Correlation coefficient between AMH level and the size of cystic teratoma was r=-0.27; р<0.001. Correlation coefficient between AFC and the size of cystic teratoma was r=-0.06; р=0.347. With larger size of teratoma, the level of ANH reduced, and indicated that correlation was weak.

All patients underwent organ-sparing surgical treatment using laparoscopic access. After establishing pneumoperitoneum, the Karl Storz laparoscope and second puncture trocars were sequentially inserted into the abdominal cavity. Laparoscopy was performed using standard technique. The main stages included tumor removal, hemostasis, approximation of the ovarian edges, and extraction of the surgical material. During surgery, the ovary was fixed with a soft clamp, membrane resection was done under the neoplasm using endoscopic scissors, and the cyst was enucleated using two atraumatic forceps. Macropreparation extraction was performed in the endoscopic container. Bipolar cautery and wound irrigation was used in all cases for the purpose of identifying bleeding areas and cooling the tissues to reduce thermal damage. Intraoperatively, macro specimens were transported for histological examination at the 1st Department of Anatomic Pathology, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia (further referred to as “the Center”), using standard technique for preparation of tissue cryosection of 4–5 μm thickness and subsequent staining with hematoxylin and eosin. The intraoperative histological diagnosis of mature cystic teratoma of the ovary was made in all cases.

In most cases, the cyst contained mature ectodermal elements (mainly skin appendages (97%)) (Figure). The elements of nervous tissue were found in 32% of cases (they were predominantly the elements of mature glial tissue) (Figure). The elements of cartilage tissue were found in 25% of cases.  Among rare components of mature cystic teratoma, histological examination found the elements of the choroid plexus (4%), thyroid cells (5%) and pancreatic cells (1%).

The operating time was from 40 minutes to 2 hours and 10 minutes depending on tumor size, lesion volume and the presence of adhesions. Blood loss was 50–100 ml. Complications did not occur in the postoperative period.

After surgical treatment, patient follow-up and medical check-up was provided in the health care facility at the place of residence. In 7/267 (3%) women, recurrent teratomas were detected 12–36 months after surgery, 3 of them underwent surgical treatment in the Gynecologic Department of the Center. Left-sided lesions were in 4 patients, and right-sided lesions were in 3 patients. In all cases the content of the cyst included skin elements and appendages, in 2 cases the cysts contained the elements of mature glial tissue.

During the study 40/267 (15%) patients were planning pregnancy. Spontaneous pregnancy occurred in 29/40 (72.5%) women, and in 7/40 (17.5%) women using assisted reproductive technologies; 7 patients had cesarean delivery due to obstetric indications. Pregnancies occurred within 3–24 months after surgical treatment. Long time interval was due to patients’ private and family circumstances. Pregnancy did not occur in 4/40 (10%) women. There were no cases of termination of pregnancy or miscarriage.

The results of AMH test and ultrasound examination in patients 3 months after surgical treatment were analyzed. AMH levels (р<0,001) and AFC (р<0.001) reduced. Average level of AMH was 1.7 (1.5) ng/mL, and average AFC was 3.0 (1.8).

Discussion

Benign ovarian tumors account for 85% of all ovarian neoplasms and rank second in the structure of tumors of female reproductive organs [11, 14]. Benign tumors are detected in 19–25% of women of reproductive age [11, 14]. Over the past 10 years, the incidence of this pathology has increased from 6–11% to 9–25% [11, 14, 15]. Over the past decade, the incidence of benign ovarian tumors has increased by two times worldwide [16].  Among them, most common morphological variants are epithelial and germ cell tumors [16]. Modern diagnostics of tumors and tumor-like ovarian lesions requires a complex of diagnostic tests for early tumor detection and differential diagnosis [17]. Among germ cell tumors, most often mature cystic teratomas of the ovaries are found [18]. The main challenge in histopathological diagnosis of these neoplasms is verification of the elements of mature/immature nervous tissue, since neuroectodermal rosettes represent morphological features that make it possible to classify ovarian teratoma into the group of immature teratomas [18]. In addition, neuroectodermal area containing rosettes helps to define tumor grade and, accordingly, prognosis and indications for adjuvant therapy [18]. Moreover, an important aspect is detection of mature glial tissue, since these elements of the teratoma can spread beyond the ovary and cause damage to the peritoneum, thereby worsening the prognosis of the disease [19]. Additionally, it is important to note the need for accurate diagnosis of thyroid gland elements in terms of mature cystic teratoma, since the spread of these elements beyond the ovary, that was previously considered as a benign process (strumosis), is currently classified as metastasis, and the primary tumor (cystic teratoma) is classified as malignant tumor (carcinoma that develops from thyroid tissue) [20].

 In surgical treatment of ovarian tumors, the most relevant issues are preservation of the ovarian reserve and reproductive potential, as well as the choice of the method of surgical hemostasis [16]. Hemostasis by bipolar coagulation is the main and frequently used technique in laparoscopy [16]. Nevertheless, electrocoagulation for hemostasis should be avoided and minimized, when it is possible [16].

Our study showed relationship between the level of AMH and AFC in patients undergoing surgical treatment. Standard methods of surgical hemostasis are not always applicable in patients with low ovarian reserve. For this reason, it is necessary to continue searching for new methods that can minimize ovarian tissue damage with purpose of preservation of the ovarian reserve and subsequent realization of reproductive function.

Conclusion

In patients with ovarian teratomas, the levels of AMH and AFC are statistically low after surgery. Ovarian teratomas require timely organ-sparing surgical treatment using laparoscopic access and careful surgical hemostasis. Standard methods of surgical hemostasis are not always applicable in patients with low ovarian reserve. For this reason, it is necessary to continue searching for new methods that can minimize ovarian tissue damage with purpose of preservation of the ovarian reserve to realize reproductive function.