Comparison of performance between O-RADS, IOTA simple rules risk assessment and ADNEX model in the discrimination of ovarian Brenner tumors

To describe the clinical and sonographic features of ovarian benign Brenner tumor (BBT) and malignant Brenner tumor (MBT), and to compare performance of four diagnostic models in differentiating them. Fifteen patients with BBTs and nine patients with MBTs were retrospectively identified in our institution from January 2003 and December 2021. One ultrasound examiner categorized each mass according to ovarian-adnexal reporting and data system (O-RADS), international ovarian tumor analysis (IOTA) Simple Rules Risk (SR-Risk) assessment and assessment of different neoplasias in the adnexa (ADNEX) models with/without CA125. Receiver operating characteristic curves were generated to compare diagnostic performance. Patients with MBT had higher CA125 serum level (62.5% vs. 6.7%, P = 0.009) and larger maximum diameter of lesion (89 mm vs. 43 mm, P = 0.009) than did those with BBT. BBT tended to have higher prevalence of calcifications (100% vs. 55.6%, P = 0.012) and acoustic shadowing (93.3% vs. 33.3%, P = 0.004), and lower color scores manifesting none or minimal flow (100.0% vs. 22.2%, P < 0.001). Areas under curves of O-RADS, IOTA SR-Risk and ADNEX models with/without CA125 were 0.896, 0.913, 0.892 and 0.896, respectively. There were no significant differences between them. BBTs are often small solid tumors with sparse color Doppler signals, which contain calcifications with posterior acoustic shadowing. The most common pattern of MBT is a large multilocular-solid or solid mass with irregular tumor borders, and most were moderately or richly vascularized at color Doppler. These four models have excellent performance in distinguishing them.


Introduction
Brenner tumor (BT) is a relatively uncommon ovarian epithelial neoplasm accounting for up to 1% of all ovarian tumors, which was first identified in detail in 1907 by Fritz Brenner [1]. Nowadays there is general agreement that BT is derived from surface epithelium of the ovary through transitional cell metaplasia [2]. BT associated with other epithelial tumors in up to 25%-30% of cases, are classified as benign, borderline, and malignant categories [3]. The majority of these tumors are benign, which are mainly asymptomatic and often found incidentally in women between their fifth and sixth decades of life. It is generally believed that benign Brenner tumors (BBTs) are hypoechoic solid masses that may contain calcification [4][5][6][7].
Malignant Brenner tumor (MBT) is extremely rare, comprising < 5% of all BTs. Clinical presentation of 1 3 MBT is similar to that of other epithelial ovarian carcinomas with abdominal pain and bulk symptoms. Reliable tumor markers for MBT have not been identified. CA125 is elevated in some patients with MBT, with reports ranging from 30 to 70%. Five-year disease-specific survival of MBT patients with extra-ovarian spread was only 51.3% [8][9][10][11][12][13]. Therefore, correct preoperative differentiation between benign and malignant BTs are important for optimal patient management. However, for MBT with a low incidence, the current evidence on sonographic appearance is predominantly limited to individual case reports. To our knowledge, there is no study on the comparison of morphological features between benign vs. malignant BTs. Recently, the ESGO/ISUOG/IOTA/ESGE showed that the ultrasound-based diagnostic models were feasible and could assist clinicians to distinguish between benign and malignant ovarian tumors [14].
The purpose of the current study was to describe clinical characteristics and sonographic appearance of benign and malignant ovarian BTs, and to compare the performance of different ultrasound-based diagnostic models in differentiating them.

Materials and methods
We retrospectively identified patients with a histological diagnosis of ovarian BT, who had undergone preoperative ultrasound examination before surgical removal of the mass in our institution between January 2003 and December 2021. The clinical characteristics were retrieved retrospectively, and information on the patient's age at diagnosis, menopausal status, symptoms, the presence of coexisting other ovarian neoplasms and serum levels of tumor markers (CA125 and CA199), stage of disease were noted ( Table 1). The women providing incomplete information or without undergoing the preoperative ultrasound examination in our institution were excluded. For statistical analysis, borderline BT was classified as malignant tumor. The approval from the Institutional Ethics Board of our institution was obtained. The need for informed consent was waived for this retrospective study.
Each patient underwent a preoperative ultrasound examination, which was performed within 2 weeks prior surgery by experienced ultrasound examiners using a 5-9-MHz transvaginal and a 3.5-MHz transabdominal probe on a variety of equipment. Sonographic criteria for evaluation of the ovarian lesions is based on the quality requirements for gynecological ultrasound examinations of DEGUM level II [15].Ultrasound findings were drawn from images and reports. The masses were described using the terms and definitions of international ovarian tumor analysis (IOTA) group [16]. Moreover, the following features were recorded: tumor size, location, tumor complexity, cyst content, presence of calcification, acoustic shadowing and Doppler results. When masses were identified on both sides, the more complex or larger mass was chosen for analysis.
Of the 24 women, one patient with MBT lacking serum CA125 level was excluded. All original ultrasound images and video clips of 23 cases of ovarian BTs were collected in a central reading site where they were independently reviewed by another experienced ultrasound examiner who was familiar with basic consensus on the lexicon of the ultrasound classification systems and did not participate in the image capture. The reviewer had access to all original ultrasound images and video clips but was blinded to the patients' medical information and pathologic results. First, the reviewer analyzed the morphological features of each BT, and independently categorized the ultrasound images of each mass according to the ovarian-adnexal reporting and data system (O-RADS) published by American College of Radiology (ACR) [17], IOTA Simple Rules Risk (SR-Risk) assessment and assessment of different neoplasias in the adnexa (ADNEX) model without CA125 [18,19]. Secondly, we provided the patients' CA125 serum level at diagnosis to this reviewer, and then she analyzed the images according to IOTA ADNEX model with CA125 (Fig. 1). We calculated the risk of malignancy with IOTA SR-Risk and ADNEX model online algorithm (http:// www. iotag roup. org). The reference standard was the histopathological diagnosis of the mass after surgical removal. We investigated the diagnostic performance of the four methods, i.e. sensitivity, specificity, positive likelihood ratio (LR +) and negative likelihood ratio (LR−).
All clinical and sonographic parameters of BTs were summarized using absolute frequency (percentage) for categorical variables and median (range) for continuous variables. Categorical variables were compared using the Chi-square test or the Fisher's exact test. Receiver-operating characteristic (ROC) curve was applied to determine the optimal cutoff values with the Youden index method and calculate the areas under the curve (AUC). In order to compare the AUCs between four ultrasound classification systems, a nonparametric approach, which was proposed by Delong, was applied. All statistical analyses were carried out using IBM SPSS version 20 and MedCalc version 20.023. A two-sided value of P < 0.05 was considered statistically significant.

Comparisons of clinical and ultrasound characteristics between benign and malignant BTs
A total of 24 patients with ovarian BTs were identified. Fifteen (62.5%) cases were benign, nine (37.5%) were (1/9), 44.4% (4/9), and 44.4% (4/9) of patients with MBTs respectively, and two patients had positive lymph nodes for metastatic disease. All cases of BBTs are unilateral, only two patient had bilateral malignant lesions. Patients with MBT had higher CA125 serum level (62.5% vs. 6.7%, P = 0.009) and larger maximum diameter of lesion (89 mm vs. 43 mm, P = 0.009) than did those with BBT. Among the 13 BBTs without mucinous cystadenoma, 10 (10/13, 76.9%) lesions contained purely solid components (Fig. 2a-c), 2 ones appeared as multilocular-solid masses (Fig. 2d, e) and one exhibited the unilocular mass (Fig. 2f). In two benign cases associated with ipsilateral mucinous cystadenoma, one case appeared as a multilocular-solid mass, and cystic component was larger than solid component; the other case exhibited a mostly solid mass containing small cystic areas (Fig. 3a, b). Based on the subjective assessment by the original ultrasound examiner, the most benign masses were misdiagnosed as ovarian sex cord−stromal tumor (4/15, 26.7%), fibroma (3/15, 20.0%) or cystadenoma (2/15, 13.3%). All malignant tumors contained solid components, six (6/9, 66.7%) were described as unilocular-solid or multilocular-solid (Fig. 4a,  b), and three were described as mostly solid (> 80% of the mass) (Fig. 4c, d). The solid component and the cystic wall of all BBTs manifested no or minimal blood flow on color Doppler examination (Fig. 5a, b). The majority (77.8%, 7/9) of malignant Brenner lesions tended to have higher color scores manifesting moderate or abundant flow (Fig. 5c,  d). The color scores were significant differences between benign and malignant BTs (P < 0.001) ( Table 1). Among the malignant patients, only 1 case was misdiagnosed as ovarian cystadenoma, and the remaining 8 cases were correctly diagnosed as ovarian malignant tumor. The calcifications were located in the solid component and the septum of the tumors. BBT tended to have higher prevalence of calcifications (100% vs. 55.6%, P = 0.012) and acoustic shadowing (93.3% vs. 33.3%, P = 0.004). All (100%) benign masses on sonographic images showed internal calcifications, and acoustic shadowing was observed in 14 cases. Extensive amorphous calcification was seen in six benign cases (Fig. 2b, c), while another nine benign lesions showed diffused punctate calcification (Fig. 2a, d-f). The diffused punctate calcifications were present in four (4/9, 44.4%) malignant tumors (Fig. 4a, d), and only one extensive amorphous calcification was found. Moreover, only three malignant masses were accompanied by acoustic shadowing. Table 2 summarizes the performance of four ultrasound classification systems for the diagnosis of MBTs using the consensus data. The ROC curve analysis demonstrated that, AUCs of the O-RADS, IOTA SR-Risk and ADNEX models with/without CA125 for the discrimination between benign and malignant BTs were 0.896, 0.913, 0.892 and 0.896, respectively (Fig. 6). When comparing the AUCs of these four models, there were no significant differences between them (IOTA ADNEX without CA125 vs. ADNEX with CA125, P = 0.9341; ADNEX without CA125 vs. O-RADS, P = 1.0000; ADNEX without CA125 vs. SR-Risk, P = 0.7508; ADNEX with CA125 vs. O-RADS, P = 0.9505; ADNEX with CA125 vs. SR-Risk, P = 0.6626; and O-RADS vs. SR-Risk, P = 0.6265).

Discussion
To the best of our knowledge, this is the first study comparing the clinical characteristics and sonographic appearance between benign and malignant ovarian BTs, and validating the optimal models that offer excellent discrimination between them. The majority of patients were postmenopausal and almost all tumors are unilateral. Most patients with malignant tumors had elevated CA125 serum levels. BBTs were most often small well-defined hypoechoic solid tumors, which contain calcifications with posterior acoustic shadowing. Most BBTs were poorly vascularized and only sparse color Doppler signals were detectable. The most common pattern of MBT was a large multilocular-solid or solid mass with irregular tumor borders, and most were moderately or richly vascularized at color Doppler. These four well-established ultrasound-based diagnostic models could discriminates well between benign and malignant BTs at the optimal cutoff point.
These typical clinical and ultrasound features are crucial for distinguishing benign and malignant BTs, and they can improve our knowledge and awareness of this rare tumor. Our results are in agreement with these in the literature. Weinberger et al. [7] demonstrated that eighteen (78%) patients with BTTs were asymptomatic, and only 2 patients (8.7%) manifested raised CA125 level. The majority (82%) of the tumors were unilateral. In a recent population-based analysis, Nasioudis et al. [10] demonstrated that the majority of patients with MBT presented with unilateral tumors with a median size of 10 cm, 70.3% had elevated CA125 levels. In previous literature, MBT was extremely rare, comprising < 5% of all BTs [8][9][10][11][12][13]. However, malignancy rates were 37.5% in our series. This bias may be related to the fact that our hospital is the largest referral center for gynecologic oncology in southern region of our country. BBTs were most often small well-defined hypoechoic solid tumors. The important reason for this sonographic feature is that BTTs contain large amounts of abundant fibrous stroma, which similar to skeletal muscle. Green et al. [4] and Athey et al. [5] described the gray-scale ultrasound findings in nine and four benign Brenner tumors, respectively. BBTs were usually composed of homogeneous solid masses, rarely predominantly cystic, or occasionally multilocular-solid on ultrasound examination. Weinberger et al. [7] described 23 BBTs, of which 8 (35%) were described as solid, 8 (35%) as multilocular-solid and 7 (30%) as unilocular or multilocular. Therefore, the sonographic findings of BBTs are similar to those of subserosal pedunculated leiomyoma of the uterus and other solid ovarian masses, such as ovarian fibromas [1]. Moreover, the BBTs could be misdiagnosed as ovarian mucinous or serous cystadenoma, if it coexists with a multilocular cystic component. In our series, two cases coexisting with ipsilateral mucinous cystadenoma. One case exhibited the mixed multilocular cystic and homogeneous solid components, and cystic component was larger than solid component, which is consistent with existing literature [20]. However, the other case exhibited a mostly solid mass containing small cystic areas, and the proportion of mucinous cystadenoma was only 10%. Calcification with posterior acoustic shadowing is an important clue in diagnosis of BBTs [21]. In our series, the calcifications were located in the solid component and the septum of the tumors, which were detected in all BTTs and 55.6% of MBTs. The calcifications and posterior acoustic shadowing were more commonly seen in benign tumors than malignant ones. The important reason was that the proportion of extensive amorphous calcification was higher in benign lesions, which was accompanied by posterior heavy shadowing. Moreover, the ultrasonographic findings of MBTs were irregular multilocular-solid or solid masses and more richly vascularized on Doppler examination, which were similar to ovarian epithelial cancer. There have been multiple internal and external validations of the ultrasound-based diagnostic models [22,23]. In one external validation study using a cutoff of 10% to predict malignancy, the ADNEX model achieved a sensitivity of 98% and a specificity of 62% compared with 96.5% and 71.3% in the original study [18,22]. Chen et al. [23] focused on comparison of O-RADS and ADNEX models regarding validity in evaluating adnexal lesions. When setting a uniform cutoff 10% (> O-RADS 3) to predict malignancy, the O-RADS had higher sensitivity than the ADNEX model (96.6% vs. 91.4%), and relatively similar specificity (78.5% vs. 78.9%/79.5%). Recently, the ESGO/ISUOG/IOTA/ESGE demonstrated that the IOTA ADNEX and SR-Risk models were the best models for the characterization of ovarian masses [14], while the prediction of specific type of adnexal malignancy had lower performance. In agreement with the findings from other studies, these four well-established ultrasound-based diagnostic models had the good performance for distinguishing benign and malignant ovarian BTs in our study (AUCs ranged from 0.892 to 0.913). However, we found a relatively lower specificity at the original cutoff points in four diagnostic models, especially, O-RADS system, IOTA ADNEX without CA125 and SR-Risk. This may be related to the fact that most (73.3%) BBTs were solid masses. For example, four benign solid lesions with smooth contour and color score 2 were categorized as O-RADS 4 in our study [17]. According to our results, these models revealed some difficulties in differentiating solid ovarian tumors by using the suggested thresholds. ADNEX models with CA125 had nonsignificant slightly higher specificity than ADNEX models without CA125 at 10% cutoff (0.733 vs. 0.533), so the application value of serum CA125 level in distinguishing BBTs and MBTs needs more research data to confirm. Fortunately, when using the optimal cutoff values in these models, our gynecologists had strong confidence in identifying benign ovarian tumors with higher specificity and avoid unnecessary surgery in benign or probably benign cases, which are preoperatively diagnosed using these model.
The main strengths of our study are that it is the first study comparing the clinical characteristics and sonographic appearance between benign and malignant ovarian BTs, and validating the optimal ultrasound-based diagnostic models that offer excellent preoperative discrimination between them in the same cohort of patients. Our research was limited in two ways. First, the ultrasound information was collected retrospectively from ultrasound reports and images. Therefore, our conclusions on ultrasound features of BTs may be biased and must be interpreted with caution. Second, our data was limited to a single-institution database, the size of population was relatively small, making ROC curve and defining optimal cutoff level may be unstable, so prospective lager sample study is needed to validate the above findings.
In conclusion, our results reveal that calcification with posterior acoustic shadowing is an important clue in diagnosis of BBT. Sonographic appearance of MBT is similar to that of other epithelial ovarian carcinomas with a large and irregular multilocular-solid or solid mass, and most are moderately or richly vascularized at color Doppler. These four well-established ultrasound-based diagnostic models have excellent performance in distinguishing them.