The Clinical Relevance of Distinguishing Between Simple and Complex Adnexal Cystic Structures by Ultrasound in the Peri- and Postmenopause

1. Introduction

The prevalence of cystic ovarian structures in the peri- and postmenopause is increased. Bimanual examination, serum tumor markers, and transvaginal ultrasound examinations can also help to detect adnexal masses. As the majority of these cystic structures show no malignant potential, it is essential to easily and effectively select the high-risk masses for appropriate care [1]. Functional and malignant cysts can be characterized by their symptoms at the same time. Therefore, more than 60% of ovarian cancers are detected at stage III. or IV.[2]. In case of ovarian malignancies CA-125 was recommended to increase the detection rate, but it can be used effectively together with transvaginal US scans [3,4,5].

Since transvaginal probes have been introduced, several scoring systems have been developed to increase the detection rate of grayscale ultrasonography [6,7,8,9,10]. Papillary projections, thick and irregular walls, and septated or large multilocular cysts proved to carry a higher risk for malignancy as they are called complex cysts [11,12,13].

As a result of international multicentre studies evidence-based scoring systems have been developed by the IOTA (International Ovarian Tumour Analysis) group [10,14,15]. The work of this collaboration group has been dominant in the ultrasound-based diagnosis of adnexal masses in the last two decades and put the diagnostic process on an evidence-based and reliable level. Since ADNEX model has been developed, a mathematical model is on hand for everyone with different experiences to distinguish between benign and malignant lesions with an efficacy reaching the level of expert's opinion, so-called ‘pattern recognition’ [16,17,18].

Risk factors affecting the formation of cystic ovarian structures, such as genetic predisposition, multiparity, and previous gynecological surgeries, were examined in several studies [19,20].

The aim of this study was to determine the efficacy of simple grayscale ultrasound markers and the additive value of CA-125 in the detection and the triage of ovarian cystic structures in the peri- and postmenopause.

2. Materials and Methods

This study was performed in the Department of Obstetrics and Gynecology at the University of Debrecen, Debrecen, Hungary. Imaging properties of peri- (PEM) and postmenopausal (POM) ovarian cysts were examined preoperatively. All patients underwent transvaginal ultrasound examinations preoperatively (ATL HDI-3000, Bothell, Washington, USA, equipped with 5,9MHz transvaginal probe and Medison Accuvix XQ, Medison Co., Ltd. Seoul, South Korea, equipped with a 5-8MHz transvaginal probe Kretztechnik AG, Zipf, Austria). Patients over the age of 40 with cystic adnexal masses were consecutively recruited. Patients without evident clinical signs of menopause reporting no climacteric symptoms were involved in the PEM group, as well as those who previously underwent hysterectomy under the age of 50 (range: 40-54yrs, average: 45.57yrs). Lack of regular periods for more than one year or hysterectomy in the history of patients over 50 years of age were selected for the POM group (range: 41-88yrs, average: 61,24yrs). Overall, 343 patients with 379 cystic structures were involved in the study. US examinations were independent of the menstrual cycle and were repeated within three months in 168 cases (44,32%). When follow-up was performed, only the preoperative US finding was chosen to participate. According to US findings, two groups were made: (1) simple cysts: unilocular, anechoic cysts without any solid structure, (2) complex cysts: cystic structures with different parameters and even containing solid parts. Imaging characteristics, and size were matched with histology and CA125 levels. The cut-off level for CA-125 was 35 kIU/L. According to the size of the cysts, two subgroups were made within each reproductive group, and 5cm was chosen for this purpose. Risk factors affecting the formation of cystic structures in the ovary were also observed in this study, such as parity, previous pelvic surgeries, and family history of ovarian cancer.

Statistical analysis was performed using SPSS 10.0. Significance was checked using Mann-Whitney, Chi-square, and Kruskal-Wallis tests.

3. Results

In the PEM group 75 simple (Ø<5cm N=32, Ø≥5cm N=43) and 122 complex cysts (Ø<5cm N=29, Ø≥5cm, N=93), while in the POM group 49 simple (Ø<5cm N=9, Ø≥5cm N=40) and 135 complex cysts (Ø<5cm N=15, Ø≥5cm N=120) were found. In the PEM group malignancy was detected only in complex cysts larger than 5cm (N=16, 17.58%). In the POM group, malignancy was present in 40 cases, three of which proved to be smaller than 5cm. The majority of the masses were functional (54.36 %) in the PEM group. In the POM group, serous cysts were the most frequent (38.04%), followed by malignant (21.74%) and mucinous cysts (13.04%). It should be noticed that in the POM group, functional cysts can also be found in 5.43% of the cases (N=10). Details are shown in Table 1.

CA 125 determination was performed in 194 cases (51.19%). In case of masses larger than 5cm the distribution of CA125 values is different between simple and complex structures (p=0.003). Postmenopausal status is responsible for this significance, as dividing the patients into PEM and POM groups (PEM: p=0.112, NS while POM: p=0.009). There is no significant difference in the CA125 values between PEM and POM groups in case of masses smaller than 5cms (p=0.51). On the other hand, a significant correlation was also detected between histological findings and abnormal biomarker values in the POM group (p‹0.05), while the same could not be seen in the PEM group (p=0.159). Naturally, higher serum biomarker levels were detected in borderline and malignant tumors (p‹0.001). Moreover, the distribution of CA125 values is different in complex morphology-associated histological results (p‹0.001) but not in the simple morphological group (p=0.171).

The occurrence of malignant or borderline lesions was significantly higher in the POM group (p=0.001) and also among the complex masses (p‹0.001). Complex morphology carries a significant risk for malignancy both in perimenopausal and postmenopausal adnexal masses (p=0.005). The same tendency cannot be noticed in lesions with simple ultrasonographic features (p=0.402). The largest diameter of the mass affects the histological findings. In the whole study population, borderline and malignant masses were significantly larger (p‹0.001). This difference is supported by perimenopausal cases (p‹0.001), while the same cannot be noticed in case of postmenopausal patients (p=0.147). Details are shown in Figure 1.

The importance of the cut-off size is supported by the fact that a significant difference (p‹0.001) is present in complex structures between different histological findings regarding the largest diameter of the tumor, which correlation is not present in case of simple cysts (p=0.109). Regardless of the cut-off size, a difference still exists between histological types of complex morphology (p‹0.001), which is present in simple morphology as well (p=0.017).

Factors affecting the formation of cystic structures in the ovary can be seen in Table 2. At least one delivery was present in 84.96% of the cases. 210 cysts caused some kind of complaint for the patient (55.41%), of which the most common was pelvic pain in 160 cases (42.22%). A positive correlation was found between the number of deliveries and symptoms: women having at least two deliveries are more likely to suffer from pelvic pain (p=0.046). A negative correlation was detected between tumor size and presence of any complaint (p=0.842) (Figure 3.). In 336 cases, laparotomy was performed (88.65%). Previous interventions affecting the pelvis were found overall in 114 cases (30.08%), majority of these were hysterectomies (N=71, 18.73%). Family history of ovarian cancer was found only in 4 cases (1.06%).

4. Discussion

Cystic structures of the ovaries can be found in 11-16% of the cases in postmenopause and more frequently in the perimenopause [21]. The risk of malignant transformation of benign cysts is still an open question [22]. It was proven in several studies that the risk of malignant transformation is directly proportional to the number of EGF receptors in the cystic fluid [23,24,25]. In our study, we did not observe this connection.

According to the fact that ovarian pathologies depend on the functional state of the ovaries, the division of the population into peri-and postmenopausal groups is necessary. Koonings et al. found 13% risk for malignant transformation in the perimenopause, which increases to 45% in the postmenopausal group [26]. This transformation is more likely to develop in larger cysts. Modesitt et al. advised 10 cm for cut off level while Osmers et al. found 3 cms of diameter for the border between low-risk and high-risk groups [27,28]. 5 cms was recommended by Auslender et al. and Reimer et al., and so it was used in this study as well [23,29]. The IOTA group advises several diagnostic algorithms for the detection of adnexal masses. In these algorithms, most ultrasound characteristics, such as tumor size, are independent of the menopausal status. On the other hand, tumor size affects the performance of subjective assessment, mathematical models (LR1 and LR2), the IOTA simple rules, and also the risk of malignancy index (RMI) in discriminating correctly between benign and malignant adnexal masses [30]. Using the IOTA simple rules to determine reproductive status is not a basic step. Subjective assessment, called as “pattern recognition” is superior to any scoring system especially if it was carried out by experienced hands [15]. On the other hand, the most developed mathematical model, the so-called ADNEX-model uses not just the largest diameter of the lesion but also the largest diameter of the presenting solid component, if there is any [16]. Based on a recent paper by Landolfo et al. the suggested method for routine management of adnexal masses is the ‘Two step strategy’ using the Benign descriptors (BD) and the ADNEX model as a second step in unclassifiable cases. According to their data 37% of the adnexal lesions can be treated as benign just using the benign descriptors, which use 10 cm as a threshold for discrimination. The unclassifiable masses were analyzed using the ADNEX model. Excellent diagnostic performance has been reported providing an AUC of 0.94 for the use of this strategy. The discrimination between benign and malignant was better calibrated in postmenopausal patients, but the diagnostic efficiency was nearly the same in both groups [31].

In our study, it was shown that perimenopausal cystic structures carry malignancy in 4.22% of the cases which correlates with the results of Ekerhovd et al (0.7%) and Osmers et al. (0.8%) [2,32]. Echogenicity, wall structure, septation, and presence of papillarization or solid part should be noticed when considering the complexity of a cyst because this is compulsory for a correct diagnostic decision. Timmerman et al. and Ueland et al. designed scoring systems based on the volume of cysts and wall structures to help these decisions [8,10]. Neither these systems nor any of the IOTA’s mathematical models were not used in this study.

In the postmenopausal group the risk of malignancy is not irrelevant which fact was supported by our result: 40 cysts found out to be malignant (10.55%) of the cases, 39 of them proved to have complex morphological findings (97.5%). Our data correlates with the results of Osmers et al. (9.6%) and Ekerhovd et al. (10%) [2,28]. According to these facts, surgical removal of these structures is necessary. According to this study, simple postmenopausal cysts can carry malignancy in only 0.26% of the cases, their regular follow-up is recommended with or without determination of CA-125. In a recent review by Ya-Na Liu et al. 1 in 10000 malignancy rate was reported in postmenopausal simple cysts which supports our finding [33].

CA-125 alone has a very low screening sensitivity for stage I. ovarian cancer (60%) and a specificity of 99% [34,35]. In combination with TVS, sensitivity increases up to 85% [36]. In this study, the detection rate was only 30.41%. It can be elevated in benign diseases such as endometriosis, PID, fibroids, and Meigs-syndrome [37,38]. Several studies support that it has to be used together with ultrasound scans to improve its diagnostic benefit and should not be used alone for the decision of the dignity of ovarian cysts, especially in perimenopause [17,39,40,41]. It has been proven that elevated CA125 values do not improve the discrimination between benign and malignant lesions, especially in experienced examiners [42]. On the other hand it is used also in the most sophisticated mathematical model, the ADNEX where it facilitates the discrimination of malignant subtypes [16].

5. Conclusions

A simple diagnostic algorithm based on simple or complex morphology of ovarian masses during ultrasonography can easily decrease the number of surgeries and high hospital costs. Categorizing cystic structures into these two groups can be a reliable alternative to mathematical models in the case of simple cysts both peri- and postmenopause.