eISSN: 2299-0038
ISSN: 1643-8876
Menopause Review/Przegląd Menopauzalny
Current issue Archive Manuscripts accepted About the journal Special Issues Editorial board Abstracting and indexing Subscription Contact Instructions for authors Publication charge Ethical standards and procedures
Editorial System
Submit your Manuscript
SCImago Journal & Country Rank


2/2022
vol. 21
 
Share:
Share:
Original paper

Morphological parameters of ovarian masses and accuracy of the risk of malignancy index in diagnosing ovarian malignancy

Akmaral S. Adilgereyeva
1
,
Ibrahim A. Abdelazim
2, 3
,
Gulmira A. Zhurabekova
4
,
Tamer E. El-Ghazaly
2

  1. Department of Normal and Topographical Anatomy, West Kazakhstan Marat Ospanov Medical University, Aktobe, Kazakhstan
  2. Department of Obstetrics and Gynaecology, Ain Shams University, Cairo, Egypt
  3. Department of Obstetrics and Gynaecology, Ahmadi Hospital, Kuwait Oil Company (KOC), Kuwait
  4. Department of Fundamental Medicine, Al-Faraby Kazakh National University, Almaty, Kazakhstan
Menopause Rev 2022; 21(2): 81-91
Online publish date: 2022/05/24
Article file
Get citation
 
PlumX metrics:
 

Introduction

The symptoms of ovarian cancer are unclear, and ovarian cancer is known as the “silent killer”. In addition to the silent and slow progression of ovarian cancer, there is no universal screening method for dia-gnosis of ovarian cancer [1]. The preoperative discrimination between benign and malignant adnexal masses is important to decide further management [2].

Women with malignant tumours should be referred to a gynaecology oncologist because the quality of surgical staging/lymph node dissection is an important prognostic factor in ovarian cancer [3]. Furthermore, appropriate and timely referral to a gynaecology oncologist has been proven to increase the overall survival of women with ovarian cancer [4].

Pelvic assessment, tumour markers, and radiological investigations have been proposed for screening and early detection of ovarian tumours, but each parameter is not sensitive nor specific when considered separately. The ovarian cancer screening trial UK Collaborative Trial of Ovarian Cancer Screening recommended screening for ovarian malignancy using serum cancer antigen-125 (CA-125) with transvaginal sonography (TVS) (multimodal screening) to calculate the risk malignancy index (RMI) [5, 6]. The risk of malignancy index is calculated from the CA-125 absolute value (IU/ml), menopausal status (M), and ultrasound findings (U) [5, 6].

Recently, Dora et al. evaluated the diagnostic performance of RMI in women with adnexal masses and found RMI was simple and applicable tool in the primary evaluation of women with pelvic masses in non-specialized gynaecology centres [1]. In addition, Al-Asadi et al. found RMI was a practical and reliable tool in preoperative discrimination between benign and malignant adnexal masses [7]. Therefore, this study was designed to detect the morphological parameters of ovarian masses, and measure the accuracy of RMI in diagnosing ovarian malignancy.

Material and methods

Women ≥ 18 years old presented with adnexal masses, scheduled for surgical intervention were included in this prospective study after approval of institutes’ Ethics Committee and informed consents in accordance with the Helsinki declaration.

Sexually inactive women, those with adnexal masses with pregnancy, or with pelvic inflammatory disease (PID), women with ovarian malignancy under treatment, or pelvic masses arising from the urinary tract or gastrointestinal tract (GIT), and women who refused to participate were excluded from this study.

Participants were subjected to thorough history and examination to detect their age, parity, weight, and body mass index (BMI), followed by TVS examinations using a 7.5-MHz transvaginal probe.

After the routine preoperative investigations which were done according to the hospital protocol, and including complete blood picture, liver and kidney function, chest X-ray, and β-hCG (to exclude pregnancy). A blood sample was obtained preoperatively from each participant to measure serum CA-125, followed by TVS by an expert sonographer (blinded to the participants’ clinical data to avoid potential bias) for evaluation of the suspected ovarian masses. The suspected ovarian masses were evaluated regarding its consistency (cystic or solid), and whether the suspected masses were unilateral or bilateral, uni-locular or multi-locular, with ascites and/or extra ovarian metastasis [8, 9].

The preoperative RMI was calculated for participants using RMI-1, introduced by Jacobs et al. in 1990 [10], and using the CA-125 absolute value (mIU/ml) X Menopausal status (M) X Ultrasound score (U).

Cancer antigen-125 is a tumour marker commonly used in the screening of high-risk women for ovarian cancer. The normal serum level of CA-125 is 0–35 IU/ml [11]. Cancer antigen-125 produced in low quantities by normal ovarian epithelial cells, peritoneal lining cells, lining cells of GIT, pancreas, breast, and lung. High CA-125 is frequently associated with epithelial ovarian tumours [10]. Cancer antigen-125 is also elevated in other malignancies (breast, lung, GIT, pancreatic, endometrial, and fallopian tube cancers) and benign conditions (endometriosis, adenomyosis [1215], fibroid uterus, PID, normal, and ectopic pregnancies, peritonitis, diverticulitis, inflammatory bowel disease, tuberculosis, and liver diseases) [14, 15].

The menopausal status (M) is 1 for premenopausal women and 3 for postmenopausal women. Postmenopausal status defined as > one year of amenorrhoea or women > 50 years old after hysterectomy (confirmed by serum FSH) [10]. Women > 40–50 years who did not meet the postmenopausal criteria were included in the premenopausal group.

The ultrasound score (U) is based on ultrasound parameters, and it includes bilateral lesion, multi-loculation, solid lesion, ascites, and extra ovarian metastasis [8, 9].

U score is 0 if no ultrasound parameters are detected, 1 if one ultrasound parameter is detected, and 3 if ≥ 2 ultrasound parameters detected [16, 17].

The collected data were statistically analysed to detect the morphological parameters of the studied ovarian masses (primary outcome), and the calculated preoperative RMI was compared to postoperative histology (gold standard) to assess the accuracy of RMI in diagnosing ovarian malignancy (secondary outcome).

Sample size

The required sample size for this study was calculated using data from previous studies [1, 2, 4, 7] and G Power 3.1.9.4 for sample size calculation, setting α-error probability at 0.05, power (1β-error probability) at 0.95%, effective sample size (w) at 0.5, and t-test for statistical analysis. An effective sample size of ≥ 264 women (88 in each group) was needed to produce a statistically acceptable figure.

Statistical analysis

Numerical variables were presented as mean ±SD, while categorical variables were presented as number and percentage (%). The studied women were divided into 3 groups: a reproductive group (≥ 18–40 years), a premenopausal group (> 40–50 years), and a postmenopausal group (> 50 years), to detect the morphological parameters of ovarian masses in the 3 studied groups (especially reproductive group) and accuracy of RMI in diagnosing ovarian malignancy.

One-way ANOVA test with post-hoc Bonferroni correction was used for analysis of variance between the 3 studied groups. Student’s t and chi-square (χ2) tests were used for analysis of quantitative and qualitative data, respectively. The receiver operating characteristic (ROC) curve was used to detect the cut-off value of RMI with highest sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) in diagnosing ovarian malignancy. The correlation coefficient analysis was also used to detect the relationship between RMI and participants’ variables in the ovarian malignancy group. P < 0.05 was considered significant.

Results

In total, 264 women in 3 groups: reproductive, premenopausal, and postmenopausal (88 in each group), were included in this prospective comparative multicentre study, which was conducted over 3 years (2018–2021) to detect the morphological parameters of ovarian masses in the 3 studied groups (especially the reproductive group), as well as an assessment of the accuracy of RMI in diagnosing ovarian malignancy.

The characteristics of the 3 studied groups are shown in Table 1. There was no significant difference between the groups regarding mean age, weight, BMI, CA-125, ultrasound score, and RMI. Only the parity was significantly lower in the premenopausal group compared to the reproductive group (2.4 ±1.65 vs. 3.05 ±1.02, respectively) (p = 0.0003) (Table 1).

Table 1

Characteristics of the 3 studied groups

VariablesNMean ± SDAverageVarianceSSDFMSFp-value
Age [years]
Reproductive group8830.2 ±5.930.235.733028.5216514.2804.62.47
Premenopausal group8845.2 ±2.645.37.06
Postmenopausal group8857.5 ±4.357.618.8
Weight [kg]
Reproductive group8865.8 ±11.465.8132.43204.221602.113.42.8
Premenopausal group8873.2 ±9.573.292.03
Postmenopausal group8873.3 ±11.573.3133.7
Body mass index [kg/m2]
Reproductive group8824.8 ±3.924.815.5621.92310.920.17.5
Premenopausal group8828.02 ±3.628.0212.9
Postmenopausal group8828.2 ±4.228.1717.9
Parity
Reproductive group883.05 ±1.023.051.0631.5215.88.30.0003*
Premenopausal group882.4 ±1.652.422.8
Postmenopausal group882.24 ±1.42.241.9
CA-125 [IU/ml]
Reproductive group8825.5 ±27.925.53788.941353.4220676.711.81.27
Premenopausal group8853.9 ±60.753.993730.2
Postmenopausal group8829.9 ±27.229.89747.1
Ultrasound score
Reproductive group881.6 ±1.21.611.550.4225.224.91.2
Premenopausal group882.4 ±0.952.440.92
Postmenopausal group882.6 ±0.792.610.63
Risk malignancy index
Reproductive group8856.2 ±89.656.168125.9146713.52733564.221.23.03
Premenopausal group88152.1 ±186.8152.1135306.7
Postmenopausal group88238.7 ±44.7238.760554.5

DF – difference of freedom between groups, F – statistical test of ANOVA analysis (ANOVA coefficient), MS – mean of squares between groups, N – number (one way ANOVA test used for analysis of variance between the 3 studied groups), SD – standard deviation (significant value < 0.016 according to post-hoc test Bonferroni correction), SS – sum of squares between groups

* Significant difference

Data presented as mean ±SD

The incidence of malignant ovarian tumours was significantly higher in the premenopausal and postmenopausal groups [35.2%, (31/88)] compared to reproductive group [9.1% (8/88)], (p = 0.0008). The incidence of serous ovarian and endometriotic cysts was significantly higher in the reproductive group [38.75% (31/80) and 5% (4/80), respectively] compared to the postmenopausal group [14.0% (8/57) and 0% (0/57), respectively], (p = 0.001 and 0.03, respectively). The incidence of ovarian cystadenoma was significantly higher in the premenopausal group [31.6% (18/57)] compared to the reproductive group [13.75% (11/80)] (p = 0.04). The incidence of ovarian fibroma was significantly higher in the premenopausal and postmenopausal groups [5.3% (3/57)] compared to the reproductive group [0% (0/80)], (p = 0.01). In addition, the incidence of ovarian fibro-thecoma, and thecoma was significantly higher in the postmenopausal group [8.8% (5/57) and 3.5% (2/57), respectively] compared to the reproductive group [0% (0/80) and 0% (0/80), respectively] (p = 0.002 and p = 0.04, respectively) (Table 2).

Table 2

Histological types of the studied ovarian masses, documentation of intraoperative findings and surgical procedures

VariablesReproductive group (n = 88 women)Premenopausal group (n = 88 women)Postmenopausal group (n = 88 women)p-value
Benign tumours90.9% (80/88)64.8% (57/88)64.8% (57/88)0.05
Serous cyst38.75% (31/80)24.5% (14/57)14.0% (8/57)0.001*
Follicular cyst21.25% (17/80)8.8% (5/57)12.3% (7/57)0.05
Dermoid cyst16.25% (13/80)19.2% (11/57)21.0 % (12/57)0.05
Cystadenoma13.75% (11/80)31.6% (18/57)29.8% (17/57)0.04*
Thecal lutein cyst5% (4/80)5.3% (3/57)5.3% (3/57)0.05
Endometriotic cyst5% (4/80)3.6% (2/57)0% (0/57)0.3*
Ovarian Fibroma0% (0/80)5.3% (3/57)5.3% (3/57)0.01*
Fibro-thecoma0% (0/80)1.7% (1/57)8.8% (5/57)0.002*
Thecoma0% (0/80)0% (0/57)3.5% (2/57)0.04*
Malignant tumours9.1% (8/88)35.2% (31/88)35.2% (31/88)0.0008*
Squamous carcinoma87.5% (7/8)25.8% (8/31)35.5% (11/31)0.05
Endometrioid carcinoma12.5% (1/8)22.6% (7/31)16.1% (5/31)0.05
Cystadenocarcinoma0% (0/8)32.2% (10/31)32.3% (10/31)0.04*
Granulosa cell tumours0% (0/8)19.4% (6/31)12.9% (4/31)0.05
Malignant Brenner0% (0/8)0% (0/31)3.2% (1/31)0.05
Clear-documented intra-operative findings and surgical procedures40.9% (36/88)47.7% (42/88)88.6% (78/88)0.01*

* Significant difference

Chi-square (χ2) test used for statistical analysis. Data presented as number and percentage (%).

The incidence of ovarian cystadenocarcinoma was significantly higher in the premenopausal and postmenopausal groups [32.2% (10/31)] compared to the reproductive group [0% (0/8)], (p = 0.04) (Table 2).

The incidence of malignant and benign ovarian tumours in the reproductive group was 9.1%, and 90.9%, respectively, while it was 35.2% and 64.8%, respectively, in the premenopausal and postmenopausal groups (Table 2).

The clearly documented intra-operative findings (i.e. whether the studied masses were unilateral or bilateral, unilocular or multilocular, solid or cystic, mobile or fixed, presence of ascites, and extra ovarian metastasis), and the surgical procedures done (i.e., whether unilateral or bilateral salpingo-oophorectomy or total hysterectomy with unilateral or bilateral salpingo-oophorectomy, with or without omentectomy ± lymphadenectomy) were significantly higher in the postmenopausal group [88.6% (78/88)] compared to the reproductive and premenopausal groups [40.9% (36/88) or 47.7% (42/88), respectively] (p = 0.01 and 0.01, respectively) (Table 2).

Only the parity in the reproductive group was significantly lower in malignant ovarian tumours compared to benign tumours (1.25 ±1.4 vs. 3.2 ±0.8) (p = 0.006) (Table 3).

Table 3

Malignant vs. benign ovarian tumours in the reproductive group

VariablesMalignant tumours (n = 8)Benign tumours (n = 80)p-value (95% CI)
Age [years]36.5 ±4.429.4 ±5.40.7 (3.3, 7.1, 10.9)
Weight [kg]82.5 ±8.764.2 ±10.30.6 (10.9, 18.3, 25.6)
BMI [kg/m2]30.2 ±2.824.2 ±3.60.7 (3.7, 6, 8.3)
Parity1.25 ±1.43.2 ±0.80.006* (–3.2, –1.9, –0.75)
CA-125 [IU/ml]92.8 ±49.218.8 ±10.80.0 (32.8, 74, 115.2)
Ultrasound score3.0 ±0.01.4 ±1.11.0 (–1.5, –1,1 –0.67)
Risk of malignancy index278.6 ±147.733.9 ±34.80.0 (120.8, 244.7, 368.6)

BMI – body mass index, CA-125 – cancer antigen-125

* Significant difference

Data presented as mean ±SD. Student’s t-test used for statistical analysis.

There was no significant difference between the ma-- lignant and benign ovarian tumours in the premenopausal group regarding mean age, weight, BMI, parity, CA-125, ultrasound score, and RMI (Table 4).

Table 4

Malignant vs. benign ovarian tumours in the premenopausal group

VariablesMalignant tumours (n = 31)Benign tumours (n = 57)p-value (95% CI)
Age [years]47.4 ±1.344.2 ±2.50.9 (2.4, 3.2, 4.0)
Weight [kg]80.7 ±7.969.04 ±7.60.3 (8.2, 11.7, 15.1)
BMI [kg/m2]31.1 ±2.926.3 ±2.70.3 (3.5, 4.8, 6.1)
Parity0.68 ±0.473.37 ±1.241.0 (–3.1, –2.7, –2.3)
CA-125 [IU/ml]110.4 ± 68.323.5 ±22.10 (60.9, 86.9, 112.8)
Ultrasound score3.0 ±0.02.1 ±1.071.0 (–2.3, –2.0, –1.74)
Risk of malignancy index331.1 ±204.854.7 ±64.70.0 (198.8, 276.4, 353.9)

[i] BMI – body mass index, CA-125 – cancer antigen-125

[ii] Data presented as mean ±SD. Student’s t-test used for statistical analysis.

Body mass index in the postmenopausal group was significantly higher in malignant ovarian tumours compared to benign tumours (32.8 ±2.9 vs. 25.7 ±2.2 kg/m2, respectively), (p = 0.03) (Table 5).

Table 5

Malignant vs. benign ovarian tumours in the postmenopausal group

VariablesMalignant tumours (n = 31)Benign tumours (n = 57)p-value (95% CI)
Age [years]61.4 ±2.955.5 ±3.50.8 (4.5, 5.9, 7.2)
Weight [kg]85.8 ±7.966.5 ±6.20.05 (15.9, 19.3, 22.6)
BMI [kg/m2]32.8 ±2.925.7 ±2.20.03* (5.9, 7.1, 8.3)
Parity0.77 ±0.753.03 ±0.860.7 (–2.6, –2.3, –1.9)
CA-125 [IU/ml]87.8 ±168.814.2 ±7.10.0 (11.7, 73.6, 135)
Ultrasound score3.0 ±0.02.6 ±0.81.0 (–2.7, –2.5, –2.27)
Risk of malignancy index497.1 ±240.794.7 ±58.50.0 (312.5, 402.4, 492.3)

BMI – body mass index, CA-125 – cancer antigen-125

* Significant difference

Data presented as mean ± SD. Student’s t-test used for statistical analysis.

Regarding malignant ovarian tumours

The histological types of malignant ovarian tumours in the studied groups are listed in Figure 1. The malignant ovarian tumours (7 in the reproductive group, 31 in the premenopausal group, and 31 in the postmenopausal group) were compared to benign tumours (194) in the studied groups, with no significant difference regarding mean age, weight, BMI, parity, CA-125, ultrasound score, and RMI (Table 6).

Fig. 1

Histological types of malignant ovarian tumours in the 3 studied groups

/f/fulltexts/PM/47064/MR-21-47064-g001_min.jpg
Table 6

Malignant vs. benign ovarian tumours in the 3 studied groups

VariablesMalignant ovarian tumours (n = 70 women)Benign ovarian tumours (n = 194 women)p-value (95% CI)
Age [years]52.3 ±9.141.5 ±11.70.9 (8.1, 10.8, 13.5)
Weight [kg]83.2 ±8.466.3 ±8.70.6 (14.6, 16.9, 19.3)
BMI [kg/m2]31.8 ±3.125.3 ±3.10.4 (5.6, 6.5, 7.3)
Parity0.78 ±0.83.2 ±0.90.8 (–2.6, –2.4, –2.2)
CA-125 [IU/ml]85.5 ±57.118.8 ±14.80.0 (53, 66.7, 80.4)
Ultrasound score3.0 ±0.01.9 ±1.11.0 (–2.0, –1.85, –1.7)
Risk of malignancy index392.7 ±235.957.9 ±8.040.0 (277.8, 334.8, 391.7)
Post-operative histological examinationMalignant ovarian tumours
Squamous carcinoma 37.1% (26/70)
Cystadenocarcinoma 28.6% (20/70)
Endometrioid carcinoma 18.6% (13/70)
Granulosa-cell tumours 14.3% (10/70)
Malignant Brenner tumour 1.4% (1/70)
Benign ovarian tumours
Serous cyst: 27.3% (53/194)
Cystadenoma: 23.7% (46/194)
Dermoid cyst: 18.6% (36/194)
Follicular cyst: 14.9% (29/194)
Thecal lutein cyst: 5.2% (10/194)
Endometriotic cyst 3.1% (6/194)
Ovarian fibroma: 3.1% (6/194)
Fibro-thecoma: 3.1% (6/194)
Thecoma: 1.0% (2/194)

[i] BMI – body mass index, CA-125 – cancer antigen-125

[ii] Data presented as mean ± SD and number and percentage (%). Student’s t-test used for statistical analysis.

Risk of malignancy index

The risk of malignancy index at a cut-off value of 200 had 75% sensitivity, 98.75% specificity, 85.7% PPV, and 97.5% NPV in diagnosing ovarian malignancy in the reproductive group (Table 7). The ROC showed that RMI at a cut-off value > 231.6 had 75% sensitivity, 100% specificity, 100% PPV, and 97.3% NPV in diagnosing ovarian malignancy in the reproductive group [area under curve (AUC) 0.950, 95% CI: 0.88–0.98, p < 0.001] (Fig. 2).

Fig. 2

The receiver operating characteristic curve for risk malignancy index at a cutoff value > 231.6 in the reproductive group

RMI – risk malignancy index

/f/fulltexts/PM/47064/MR-21-47064-g002_min.jpg
Table 7

Accuracy of the risk of malignancy index at a cut-off value of 200 in diagnosing ovarian malignancy in the 3 studied groups

VariablesReproductive groupPremenopausal groupPostmenopausal group3 studied groups
Sensitivity
(TP ÷ TP + FN)×100
(6 ÷ 6 + 2) × 100 = 75%(25 ÷ 25 + 6) × 100 = 80.6%(27 ÷ 27 + 4) × 100 = 87.1%(58 ÷ 58 + 12) × 100 = 82.9%
Specificity
(TN ÷ TN + FP) × 100
(79 ÷ 79 + 1) × 100 = 98.75%(52 ÷ 52 + 5) × 100 = 91.2%(51 ÷ 51 + 6) × 100 = 89.5%(182 ÷ 182 + 12) × 100 = 93.8%
Positive
predictive value
(TP ÷ TP + FP) × 100
(6 ÷ 6 + 1) × 100 = 85.7%(25 ÷ 25 + 5) × 100 = 83.3%(27 ÷ 27 + 6) × 100 = 81.8%(58 ÷ 58 + 12) × 100 = 82.9%
Negative
predictive value
(TN ÷ TN + FN) × 100
(79 ÷ 79 + 2) × 100 = 97.5%(52 ÷ 52 + 6) × 100 = 89.7%(51 ÷ 51 + 4) × 100 = 92.7%(182 ÷ 182 + 12) × 100 = 93.8%

[i] FN – false negative, FP – false positive, TN – true negative, TP – true positive

The risk of malignancy index at a cut-off value of 200 had 80.6% sensitivity, 91.2% specificity, 83.3% PPV, and 89.7% NPV in diagnosing ovarian malignancy in the premenopausal group (Table 7). The ROC showed that RMI at a cut-off value > 247.5 had 80.65% sensitivity, 100% specificity, 100% PPV, and 97.9% NPV in diagnosing ovarian malignancy in the premenopausal group (AUC 0.96, 95% CI: 0.89–0.99, p < 0.001) (Fig. 3).

Fig. 3

The receiver operating characteristic curve for risk malignancy index at a cutoff value > 247.5 in the premenopausal group

RMI – risk malignancy index

/f/fulltexts/PM/47064/MR-21-47064-g003_min.jpg

The risk of malignancy index at a cut-off value of 200 had 87.1% sensitivity, 89.5% specificity, 81.8% PPV, and 92.7% NPV in diagnosing ovarian malignancy in the postmenopausal group (Table 7). The ROC showed that RMI at a cut-off value > 245.7 had 87.1% sensitivity, 100% specificity, 100% PPV, and 98.6% NPV in diagnosing ovarian malignancy in the postmenopausal group (AUC 0.960, 95% CI: 0.89–0.99, p < 0.001) (Fig. 4).

Fig. 4

The receiver operating characteristic curve for risk malignancy index at a cutoff value > 245.7 in the postmenopausal group

RMI – risk malignancy index

/f/fulltexts/PM/47064/MR-21-47064-g004_min.jpg

The risk of malignancy index at a cut-off value of 200 had 82.9% sensitivity, 93.8% specificity, 82.9% PPV, and 93.8% NPV in diagnosing ovarian malignancy in the 3 studied groups (Table 7). The ROC showed that RMI at a cut-off value > 247.5 had 82.9% sensitivity, 100% specificity, 100% PPV, and 98.1% NPV in diagnosing ovarian malignancy in the 3 studied groups (AUC 0.96, 95% CI: 0.92–0.97, p < 0.001) (Fig. 5).

Fig. 5

The receiver operating characteristic curve for risk malignancy index at a cutoff value > 247.5 in the 3 studied groups

RMI – risk malignancy index

/f/fulltexts/PM/47064/MR-21-47064-g005_min.jpg

The correlation between participants’ variables and the risk of malignancy index in the ovarian malignancy group

A significant positive correlation between participants’ age and RMI (r = 0.38, p = 0.001, 95% CI: 016–0.57) (Fig. 6), and between participants’ CA-125 and RMI (r = 0.55, p < 0.0001, 95% CI: 0.37–0.70) was detected (Fig. 7). There was no significant correlation between participants’ weight and RMI (r = –0.058, p = 0.6), participants’ BMI and RMI (r = 0.012, p = 0.9), participants’ parity and RMI (r = 0.117, p = 0.3), or ultrasound score and RMI (r = 0.16, p = 0.1). Only one participant in the ovarian malignancy group had an ultrasound score of 1 (multi-locular), while 69 had an ultrasound score of 3 (43 multi-locular with solid nodules and ascites, 22 multi-locular with solid nodules, and 4 multi-locular with ascites).

Fig. 6

Correlation between participants’ age and the risk of malignancy index in the ovarian malignancy group

RMI – risk malignancy index

/f/fulltexts/PM/47064/MR-21-47064-g006_min.jpg
Fig. 7

Correlation between participants’ cancer antigen-125 and the risk of malignancy index in the ovarian malignancy group

RMI – risk malignancy index

/f/fulltexts/PM/47064/MR-21-47064-g007_min.jpg

Discussion

Multimodal screening combines various diagnostic parameters to improve the accuracy of diagnosing ovarian malignancy [18]. The risk of malignancy index was introduced as RMI-1 by Jacobs et al. in 1990 as a product of the CA-125 absolute value (IU/ml), menopausal status (M), and ultrasound findings (U) [10]. The original RMI-1 was modified in 1996 by Tingulstad et al. to RMI-2 [19] and again to RMI-3 [20]. The new indices have different scoring points for the ultrasound findings and menopausal status [1920]. The preoperative discrimination between benign and malignant adnexal masses is important to decide further management [2]. Therefore, 264 women in 3 groups: reproductive, premenopausal, and postmenopausal (88 participants in each group), were included in this study to detect the morphological parameters of ovarian masses in the 3 studied groups (especially the reproductive group), and to assess the accuracy of RMI in diagnosing ovarian malignancy.

The incidence of malignant and benign ovarian tumours in the reproductive group was 9.1% (8/88) and 90.9% (80/88), respectively. Nowak et al. found that the incidence of malignant and benign ovarian tumours in reproductive age was 4.6% and 93.1%, respectively [21]. Nowak et al. also found that the reproductive age ovarian tumours were mainly benign, and only a few cases were malignant [21]. Mythily et al. found that 94.3% of ovarian tumours diagnosed at reproductive age were benign [14].

However, Nowak et al. found that 31.1% of the reproductive benign ovarian tumours were endometrioid cysts, 28.9% were teratomas, 19.3% were serous cysts, 3.7% were mucinous, and 17% were others (haemorrhagic, functional, or inflammatory) [21]. This study found that serous ovarian cysts were the commonest benign ovarian tumours in reproductive age (38.75%), followed by functional follicular cysts (21.25%), dermoid cysts (16.25%), cystadenomas (13.75%), thecal lutein (5%), and endometriotic (5%) cysts.

Dora et al. found that the most common benign ovarian tumours were mucinous cystadenoma and dermoid cysts (11.9% and 10.32%, respectively) [1]. Al-Asadi et al. reported dermoid cysts in 28.8%, functional corpus luteum in 26.2%, and simple cysts in 20% of benign ovarian tumours [7]. The difference between this study and other studies regarding the incidence of different benign ovarian tumours can be explained by the exclusion criteria and participants’ age [16, 17].

The incidence of endometriotic cysts was significantly higher in the reproductive group [5% (4/80)] compared to the postmenopausal group [0% (0/57)], (p = 0.03).

Endometriosis is a disease of adolescents and reproductive-age women, commonly occurring in the ovaries (chocolate cyst), and associated with pelvic pain and infertility [16, 17].

The parity of the reproductive group was significantly lower in the malignant ovarian tumours compared to benign tumours (p = 0.006). A retrospective study concluded that women who give birth have significantly reduced risk of all subtypes of ovarian cancer [22]. Mythily et al. found that most ovarian tumours (78.3%) in multiparous women were benign and concluded that infertility increases the risk of ovarian malignancy [14]. In addition, Tung et al. found that ovulation-supressing agents and pregnancy were inversely associated with increased risk of all histological subtypes of ovarian malignancy [23].

The incidence of malignant and benign ovarian tumours was 35.2% (31/88) and 64.8% (57/88), respectively, in the premenopausal and postmenopausal groups. The commonest benign ovarian tumour reported in the studied premenopausal and postmenopausal groups was cystadenoma (31.6% and 29.8%, respectively). Cystadenomas are common benign ovarian tumours with excellent prognosis. The serous and mucinous cystadenomas are the commonest types of ovarian cystadenomas [24, 25]. The serous ovarian cystadenoma commonly occurs at a mean age of 40–60 years [24], while the mucinous ovarian cystadenoma commonly occurs during the 3rd to 6th decades [25].

The incidence of ovarian fibroma was significantly higher in the premenopausal and postmenopausal studied groups (5.3%) compared to the reproductive group (0%) (p = 0.01). In addition, the incidence of ovarian fibrothecoma and thecoma was significantly higher in the postmenopausal group (8.8% and 3.5%, respectively) compared to the reproductive group (0% and 0%, respectively) (p = 0.002 and p = 0.04, respectively). Ovarian fibromas generally occur in perimenopausal and postmenopausal women [26]. Similarly, Dai et al. reported high incidence of ovarian fibromas and thecomas in postmenopausal women [27].

Ovarian cystadenocarcinomas were the commonest malignant ovarian tumours in the premenopausal studied group (32.2%), followed by squamous carcinomas (25.8%) and endometrioid carcinomas (22.6%). Squamous carcinomas were the commonest malignant ovarian tumours in the postmenopausal studied group (35.5%), followed by cystadenocarcinomas (32.2%) and endometrioid carcinomas (16.1%).

In this study, the incidence of cystadenocarcinomas was significantly higher in the premenopausal and postmenopausal groups (32.2%) than in the reproductive group (0%), (p = 0.04).

Al-Asadi et al. found that more than half of ovarian cancers (52.4%) were cystadenocarcinomas (mucinous and/or serous) [7]. Mythily et al. found that 60% (14/23) of their studied malignant tumours were cystadenocarcinomas (6 papillary serous, 5 serous, and 3 mucinous) [14].

Aktürk et al. reported 18 cystadenocarcinomas (10 mucinous and 8 serous) out of 20 malignant ovarian tumours (90%) [4]. Dora et al. also reported 32 cases of serous cystadenocarcinomas (25.39%) and 15 cases of mucinous cystadenocarcinomas (11.9%) out of 126 cases of suspected ovarian masses [1].

The incidence of studied malignant ovarian tumours was significantly higher in the premenopausal and postmenopausal groups (35.2%) than in the reproductive group (9.1%) (p = 0.0008). Similarly, Mythily et al. found that 66.7% of malignant ovarian tumours were diagnosed at the age of 51–60 years, and 88.8% of malignant ovarian tumours were diagnosed in postmenopausal women [14]. Jung et al. found that malignant epithelial and sex cord stromal ovarian tumours frequently occur in postmenopausal women [28].

The body mass index of studied postmenopausal group was significantly higher in malignant ovarian tumours compared to benign tumours (p = 0.03). A meta-analysis showed increased risk of ovarian cancers in postmenopausal women with a 5 kg weight gain [29]. Obesity is also associated with increased risk of endometrioid and mucinous ovarian cancers [30], and obese women with low- or high-grade serous carcinoma had poor outcome compared to non-obese controls [31]. Another meta-analysis found that regular physical activity was associated with decreased risk of ovarian cancers by 30–60% [32].

Accuracy of the risk of malignancy index

Jacobs et al. reported 85.4% sensitivity and 96.9% specificity for the RMI at a cut-off value of 200 in diagnosing ovarian malignancy [10]. Subsequently, several studies reported increased diagnostic accuracy of RMI at a cut-off value of 200 [3336].

Therefore, in this study the accuracy of RMI in diagnosing ovarian malignancy was evaluated in each studied group (reproductive, premenopausal, and postmenopausal) separately and in the 3 studied groups collectively at a cut-off value of 200, and at the best cut-off value according to ROC.

The risk of malignancy index at a cut-off value of 200 had 75% sensitivity, 98.75% specificity, 85.7% PPV, and 97.5% NPV in diagnosing ovarian malignancy in the reproductive group, while the ROC showed that RMI at a cut-off value > 231.6 had the best performance (75% sensitivity, 100% specificity, 100% PPV, and 97.3% NPV) in diagnosing ovarian malignancy in the reproductive group (p < 0.001).

The risk of malignancy index at a cut-off value of 200 had 80.6% sensitivity, 91.2% specificity, 83.3% PPV, and 89.7% NPV in diagnosing ovarian malignancy in the premenopausal group, while the ROC showed that RMI at a cut-off value > 247.5 had the best performance (80.65% sensitivity, 100% specificity, 100% PPV, and 97.9% NPV) in diagnosing ovarian malignancy in the premenopausal group (p < 0.001).

The risk of malignancy index at a cut-off value of 200 had 87.1% sensitivity, 89.5% specificity, 81.8% PPV, and 92.7% NPV in diagnosing ovarian malignancy in the postmenopausal group, while the ROC showed that RMI at a cut-off value > 245.7 had the best performance (87.1% sensitivity, 100% specificity, 100% PPV, and 98.6% NPV) in diagnosing ovarian malignancy in the postmenopausal group (p < 0.001).

The risk of malignancy index at a cut-off value of 200 had 82.9% sensitivity, 93.8% specificity, 82.9% PPV, and 93.8% NPV in diagnosing ovarian malignancy in the 3 studied groups, while the ROC showed that RMI at a cut-off value > 247.5 had the best performance (82.9% sensitivity, 100% specificity, 100% PPV, and 98.1% NPV) in diagnosing ovarian malignancy in the 3 studied groups (p < 0.001).

The difference in the RMI cut-off value in diagnosing ovarian malignancy was explained by Dora et al. and Simsek et al., and it depends on the prevalence of malignancy in the studied population [1, 37]. Similarly, Dora et al. found the best performance of RMI at cut-off value of 236 with 72.5% sensitivity, 98.2% specificity, 98.1% PPV, and 74.4% NPV [1]. Dora et al. found that the RMI at cut-off value ≥ 236 increased the probability of diagnosing ovarian malignancy from 54.8 to 98.15% [1].

Enakpene et al. also found that the RMI at a cut-off value of 250 had 88.2% sensitivity, 74.3% specificity, 71.3% PPV, and 90% NPV in diagnosing invasive ovarian lesions [38]. In addition, Yamamoto et al. reported 75% sensitivity and 91% specificity for the RMI at a cut-off value of 450 [39].

The lower cut-off values increase the RMI sensitivity at the expense of its specificity, while the higher cut-off values increase the RMI specificity at the expense of sensitivity [1]. The ideal RMI to diagnose ovarian malignancy should have a zero or close to zero false negative rate [40] with high sensitivity and specificity at the same time. Therefore, the RMI cut-off value should balance the sensitivity and specificity, and the availability of specialized oncology centres. When specialized oncology centres are not available or referral to such centres is limited because of local resources, the RMI cut-off value can be increased to achieve higher specificity [1].

The correlation analysis in this study showed significant positive correlation between participants’ age and RMI (p = 0.001) in the ovarian malignancy group. Similarly, Mythily et al. found that 66.7% of ovarian malignancies were diagnosed at the age of 51–60 years, and 88.8% of ovarian malignancy were diagnosed in postmenopausal women [14]. Jung et al. also found that malignant epithelial and sex cord stromal ovarian tumours frequently occur in postmenopausal women [28], and Dora et al. found that 81.6% of postmenopausal ovarian masses were malignant [1].

The correlation analysis also showed significant positive correlation between participants’ CA-125 and RMI (p < 0.0001) in the ovarian malignancy group. Cancer antigen-125 is widely accepted as a biomarker for estimating the risk of ovarian cancers. Aktürk et al. found that the CA-125 was significantly higher among malignant tumours compared to benign ovarian tumours [4]. Simsek et al. reported 78.6% sensitivity and 63.5% specificity for CA-125 at a cut-off value 35 IU/ml in diagnosing ovarian malignancy [37].

However, the analysis in this study showed no significant correlation between the ultrasound score and RMI in the ovarian malignancy group (p = 0.1). Only one participant in the studied ovarian malignancy group had an ultrasound score of 1, while 69 had an ultrasound score of 3.

Dora et al. found that an ultrasound score of 3 and the presence of solid nodules and/or ascites were associated with increased risk of ovarian malignancy [1]. Adilgereyeva et al. also found that the presence of ascites and/or solid nodules within the ovarian mass raises the suspicion of malignancy, especially in premenopausal or postmenopausal women [9].

This study found that the incidence of malignant and benign ovarian tumours was 9.1% and 90.9%, respectively, in the reproductive group (serous ovarian cysts were the commonest benign ovarian tumour in the reproductive group). The incidence of malignant and benign ovarian tumours was 35.2% and 64.8%, respectively, in the premenopausal and postmenopausal groups (cystadenomas were the commonest benign ovarian tumour in the premenopausal and postmenopausal groups). The incidence of malignant ovarian tumours and cystadenocarcinoma was significantly higher in the premenopausal and postmenopausal groups than in the reproductive group. The risk of malignancy index at a cut-off value of 200 had 82.9% sensitivity, 93.8% specificity, 82.9% PPV, and 93.8% NPV in diagnosing ovarian malignancy in the 3 studied groups, while the ROC showed that RMI at a cut-off value > 247.5 had the best performance (82.9% sensitivity, 100% specificity, 100% PPV, and 98.1% NPV) in dia-gnosing ovarian malignancy in the 3 studied groups. The correlation analysis showed significant positive correlation between participants’ age and RMI and between participants’ CA-125 and RMI in the ovarian malignancy group.

This study concluded that multimodal RMI is an effective tool for primary evaluation of suspected ovarian masses. The RMI at a cut-off value of 200 had 82.9% sensitivity, 93.8% specificity, 82.9% PPV, and 93.8% NPV in diagnosing ovarian malignancy in the 3 studied groups, while the ROC showed that RMI at a cut-off value > 247.5 had the best performance (82.9% sensitivity, 100% specificity, 100% PPV, and 98.1% NPV) in diagnosing ovarian malignancy in the 3 studied groups. The higher RMI cut-off values increase its specificity, and the ideal RMI cut-off values to diagnose ovarian malignancy should have high sensitivity and specificity at the same time. Therefore, the RMI cut-off value should balance the sensitivity, specificity, local resources, and availability of oncology centres.

The current study was the first prospective comparative multicentre study conducted to detect the morphological parameters of ovarian masses and the accuracy of RMI in diagnosing ovarian malignancy, including a large number of participants (264 women) in 3 groups (reproductive, premenopausal, and postmenopausal) over 3 years.

In this study, the authors were unable to compare the RMI to intra-operative findings and surgical procedures done, because the intra-operative findings and surgical procedures performed were only documented in 40.9% of the reproductive group, 47.7% of the premenopausal group, and 88.6% of the postmenopausal group.

Women who refused to participate, failure to compare the RMI to intra-operative findings and surgical procedures done, and absence of postoperative follow-up were the limitations of this study.

Conclusions

Multimodal RMI is an effective tool for primary evaluation of suspected ovarian masses. The risk of malignancy index at a cut-off value > 247.5 had the best performance (82.9% sensitivity, 100% specificity, 100% PPV, and 98.1% NPV) in diagnosing ovarian malignancy in the 3 studied groups. There was significant positive correlation between participants’ age and RMI, and between participants’ CA-125 and RMI in the studied malignant ovarian tumours. The ideal RMI cut-off values to diagnose ovarian malignancy should balance the sensitivity, specificity, local resources, and availability of oncology centres.

Acknowledgement

This prospective study was approved by the institutes’ Ethics Committee, and informed consent was obtained from all participants in accordance with the Helsinki declaration.

Disclosure

The authors report no conflict of interest.

References

1 

Dora SK, Dandapat AB, Pande B2, Hota JP. A prospective study to evaluate the risk malignancy index and its diagnostic implication in patients with suspected ovarian mass. J Ovarian Res 2017; 10: 55.

2 

Javdekar R, Maitra N. Risk of malignancy index (RMI) in evaluation of adnexal mass. J Obstet Gynaecol India 2015; 65: 117-121.

3 

Van Calster B, Timmerman D, Valentin L, et al. Triaging women with ovarian masses for surgery: observational diagnostic study to compare RCOG guidelines with an international (IOTA) group protocol. BJOG. 2012; 119: 662-671.

4 

Aktürk E, Karaka RE, Alanbay I, et al. Comparison of four malignancy risk indices in the detection of malignant ovarian masses. J Gynecol Oncol 2011; 22: 177-182.

5 

Menon U, McGuire AJ, Raikou M, et al. The cost-effectiveness of screening for ovarian cancer: results from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Br J Cancer 2017; 117: 619-627.

6 

Kearns B, Chilcott J, Whyte S, Preston L, Sadler S. Cost-effectiveness of screening for ovarian cancer amongst postmenopausal women: a model-based economic evaluation. BMC Med 2016; 14: 200.

7 

Al-Asadi JN, Al-Maliki SK, Al-Dahhhan F, Al-Naama L, Suood F. The accuracy of risk malignancy index in prediction of malignancy in women with adnexal mass in Basrah, Iraq. Niger J Clin Pract 2018; 21: 1254-1259.

8 

Doubeni CA, Doubeni AR, Myers AE. Diagnosis and management of ovarian cancer. Am Fam Physician 2016; 93: 937-944.

9 

Adilgereyeva AS, Abdelazim IA, Zhurabekova GA. Clinical and pathological features of women with adnexal masses admitted as emergency cases to the Gynaecology Department of West Kazakhstan University. Prz Menopauzalny 2019; 18: 180-183.

10 

Jacobs I, Oram D Fairbanks J Turner J Frost C Grudzinskas JG. A risk of malignancy index incorporating CA-125, ultrasound and menopausal status for the accurate preoperative diagnosis of ovarian cancer. Br J Obstet Gynaecol 1990; 97: 922-929.

11 

Demir RH, Marchand GJ. Adnexal masses suspected to be benign treated with laparoscopy. JSLS 2012; 16: 71-84.

12 

Abdelazim IA, Zhurabekova G. Reversible decreased ovarian reserve after conservative ovarian surgery for benign lesion other than endometrioma–case report. Prz Menopauzalny 2020; 19: 104-107.

13 

Abdelazim IA, AbuFaza M, Hamed MES, Bekmukhambetov Y, Zhurabekova G, Shikanova S. Severe adenomyosis with unexpectedly high CA-125: report of a rare case. Prz Menopauzalny 2020; 19: 144-146.

14 

Mythily A, Vaishnavi VS. Study of risk of malignancy index scoring system in the preoperative evaluation of patients with ovarian tumor and its correlation with histopathological examination. Paripex Indian J Res 2017; 6: 698-700.

15 

Stabile G, Zinicola G, Romano F, Laganà AS, Pozzolo CD, Ricci G. Pelvic mass, ascites, hydrothorax: a malignant or benign condition? Meigs syndrome with high levels of CA-125. Prz Menopauzalny 2021; 20: 103-107.

16 

Ameye L, Timmerman D, Valentin L, et al. Clinically oriented three-step strategy for assessment of adnexal pathology. Ultrasound Obstet Gynecol 2012; 40: 582-591.

17 

Timmerman D, Ameye L, Fischerova D, et al. Simple ultrasound rules to distinguish between benign and malignant adnexal masses before surgery: prospective validation by IOTA group. BMJ 2010; 341: c6839.

18 

Jacobs IJ, Menon U, Ryan A, et al. Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet 2016; 387: 945-956.

19 

Tingulstad S, Hagen B, Skjeldestad F, et al. Evaluation of a risk of malignancy index based on serum CA-125, ultrasound findings and menopausal status in the preoperative diagnosis of pelvic masses. BJOG Int J Obstet Gynaecol 1996; 103: 826-831.

20 

Tingulstad S, Hagen B, Skjeldestad F, Halvorsen T, Nustad K. Onsrud M. The risk-of-malignancy index to evaluate potential ovarian cancers in local hospitals. Obstet Gynecol 1999; 93: 448-452.

21 

Nowak M, Szpakowski M, Malinowski A, et al. Guzy jajników u kobiet w okresie rozrodczym [Ovarian tumors in the reproductive age group]. Ginekol Pol 2002; 73: 354-358.

22 

Gaitskell K, Green J, Pirie K, Reeves G, Beral V. Million Women Study Collaborators. Tubal ligation and ovarian cancer risk in a large cohort: substantial variation by histological type. Int J Cancer 2016; 138: 1076-1084.

23 

Tung KH, Goodman MT, Wu AH, et al. Reproductive factors and epithelial ovarian cancer risk by histologic type: a multi-ethnic case-control study. Am J Epidemiol 2003; 158: 629-638.

24 

Seidman JD, Mehrotra A. Benign ovarian serous tumors: a re-evaluation and proposed reclassification of serous “cystadenomas” and “cystadenofibromas”. Gynecol Oncol 2005; 96: 395-401.

25 

Mishra S, Yadav M, Walawakar SJ. Giant ovarian mucinous cystadenoma complicating term pregnancy. J Nepal Med Assoc (JNMA) 2018; 56: 629-632.

26 

Boujoual M, Hakimi I, Kouach J, Oukabli M, Moussaoui DR, Dehayni M. Large twisted ovarian fibroma in menopausal women: a case report. Pan Afr Med J 2015; 20: 322.

27 

Dai J, Wu H, Li J. [CT diagnosis of fibro-thecoma and fibroma of the ovary]. Zhonghua Zhong Liu Za Zhi 2000; 22: 504-506.

28 

Jung EJ, Eom HM, Byun JM, et al. Different features of the histopathological subtypes of ovarian tumors in pre-and postmenopausal women. Menopause 2017; 24: 1028-1032.

29 

Keum N, Greenwood DC, Lee DH, et al. Adult weight gain and adiposity-related cancers: a dose-response meta-analysis of prospective observational studies. J Natl Cancer Inst 2015; 107: djv088.

30 

Olsen CM, Nagle CM, Whiteman DC, et al. Ovarian Cancer Association Consortium. Obesity and risk of ovarian cancer subtypes: evidence from the Ovarian Cancer Association Consortium. Endocr Relat Cancer 2013; 20: 251-262.

31 

Nagle CM, Dixon SC, Jensen A, et al. Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium. Br J Cancer 2015; 113: 817-826.

32 

Cannioto RA, Moysich KB. Epithelial ovarian cancer and recreational physical activity: a review of the epidemiological literature and implications for exercise prescription. Gynecol Oncol 2015; 137: 559-573.

33 

Terzić M, Dotlić J, Ladjević IL, Atanacković J, Ladjević N. Evaluation of the risk malignancy index diagnostic value in patients with adnexal masses. Vojnosanit Pregl 2011; 68: 589-593.

34 

Rao JH. Risk of malignancy index in assessment of pelvic mass. Int J Biomed Res 2014; 5: 184-186.

35 

Ulusoy S, Akbayir O, Numanoglu C, Ulusoy N, Odabas E, Gulkilik A. The risk of malignancy index in discrimination of adnexal masses. Int J Gynaecol Obstet 2007; 96: 186-191.

36 

Obeidat BR, Amarin ZO, Latimer JA, Crawford RA. Risk of malignancy index in the preoperative evaluation of pelvic masses. Int J Gynaecol Obstet 2004; 85: 255-258.

37 

Simsek HS, Tokmak A, Ozgu E, et al. Role of a risk of malignancy index in clinical approaches to adnexal masses. Asian Pac J Cancer Prev 2014; 15: 7793-7797.

38 

Enakpene CA, Omigbodun AO, Goecke TW, Odukogbe AT, Beck-mann MW. Preoperative evaluation and triage of women with suspicious adnexal masses using risk of malignancy index. J Obstet Gynaecol Res 2009; 35: 131-138.

39 

Yamamoto Y, Yamada R, Oguri H, Maeda N, Fukaya T. Comparison of four malignancy risk indices in the preoperative evaluation of patients with pelvic masses. Eur J Obstet Gynecol Reprod Biol 2009; 144: 163-167.

40 

Harry VN, Narayansingh GV, Parkin DE. The risk of malignancy index for ovarian tumours in Northeast Scotland-a population-based study. Scott Med J 2009; 54: 21-23.

Copyright: © 2022 Termedia Sp. z o. o. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
 
Quick links
© 2024 Termedia Sp. z o.o.
Developed by Bentus.