Malignant Brenner Tumor of the Ovary: A Systematic Review of the Literature

Simple Summary Malignant Brenner tumors are rare ovarian neoplasms. Our aim is to provide insights concerning this rare entity. We reviewed 115 cases reported in the English literature until 15 September 2023, and analyzed the available demographic, clinical, and pathologic data. We also described the treatment modalities. A comparison of the available data showed that patients treated with lymph node dissection had a better disease-related survival rate. Disease recurrence was associated with tumor stage with marginal statistical significance and was more frequent in patients with ascites and those with abnormal CA-125 levels. Larger series with treatment details and long term follow-up data are needed to define the optimal management for this uncommon entity. Abstract Background: Malignant Brenner tumors are rare ovarian tumors, accounting for less than 1% of malignant ovarian neoplasms. The aim of this manuscript is to systematically review the current literature concerning malignant Brenner tumors. Methods: We searched three medical databases (PubMed, Scopus, and Web of Science) for relevant articles published until 15 September 2023. Results: After applying inclusion and exclusion criteria, 48 manuscripts describing 115 cases were included in this study from the English literature. Conclusions: We analyzed the demographic, clinical, pathological, and oncological characteristics of 115 patients with malignant Brenner tumors. The statistical analysis showed that recurrence was marginally statistically significantly related to tumor stage and was more common in patients with ascites and in women with abnormal CA-125 levels; patients that were treated with lymphadenectomy had better disease-specific survival.


Introduction
Brenner tumors are an uncommon subtype of epithelial neoplasms, accounting for less than 5% of ovarian tumors [1].They are usually unilateral and have a propensity for postmenopausal women; they are commonly asymptomatic and incidental due to their small size, but patients sometimes experience symptoms such as pain or a palpable mass [2].

Introduction
Brenner tumors are an uncommon subtype of epithelial neoplasms, accounting for less than 5% of ovarian tumors [1].They are usually unilateral and have a propensity for postmenopausal women; they are commonly asymptomatic and incidental due to their small size, but patients sometimes experience symptoms such as pain or a palpable mass [2].
The origin of these tumors is unknown.A number of them may derive from fallopian tube epithelium or Walthard nests [3], while when rarely associated with teratomas, they may originate from germ cells [1].MacNoughton-Jones first described Brenner tumors in 1898, whereas in 1907, Fritz Brenner published the article "Das oophoroma folliculare" [4], considering them a variant of the granulosa cell tumor [5].This neoplasm was first called a Brenner tumor by Meyer in 1932 [6].Von Numers was the first to describe a malignant Brenner tumor (MBT) in 1945 [7].
Brenner tumors are classified into benign, borderline, and malignant variants, with benign being the most common.Borderline variants are infrequent (less than 5% of all cases), and MBTs are extremely rare, with less than 150 cases reported in the English literature.Histologically, MBTs are composed of atypical transitional/urothelial-type cells that occasionally display focal squamous differentiation.By definition, they show stromal invasion, usually with a desmoplastic stromal response, and are associated with a benign and/or borderline element [8].
This study aims to review MBTs' clinical, pathological, diagnostic, molecular, and treatment features, focusing on differential diagnosis.
We applied the following criteria: • Eligibility/inclusion criteria: (1) Study design: We only included original studies and case reports describing cases of MBT.(2) Population: Studies involving adult patients diagnosed with MBT that provided adequate surgical and/or oncological information were included.(3) Intervention or exposure : We included studies that examined any treatment or intervention for MBT, including surgery, chemotherapy, radiation therapy, or targeted therapies.(4) Outcome: We included studies that reported on the presence or absence of disease relapse as an outcome measure.(5) Language: The included studies were written in the English language.

•
Exclusion criteria: (1) Review articles and editorials: We excluded narrative or systematic reviews, meta-analyses, opinion pieces, and other articles that did not present original research findings.Three authors (I.B., D.D., and K.S.) worked independently to remove duplicate papers.They also reviewed the titles and abstracts of all the search results (n = 1007).Any disagreement was resolved by consensus.After applying eligibility and exclusion criteria, 48 manuscripts describing 115 cases of MBT were included in this review (Table 1 and Supplementary Table S1).

Statistical Analysis
Statistical analysis was performed via the SAS for Windows 9.4 software platform (SAS Institute Inc., Cary, NC, USA).Descriptive values were expressed as the mean ± standard deviation (SD) and, when no normality was confirmed (via the Shapiro-Wilk test), as median value, 1st (Q1) and 3rd (Q3) quartile values, respectively.For categorical data we reported the appearance frequency and the relevant percentages.
Comparisons between groups for the qualitative parameters were made using the chi-square test.For the numerical data (such as a woman's age), normality was not possible to ensure, therefore, non-parametric tests were applied, specifically the Kruskal-Wallis test.
Furthermore, we estimated survival time using the Kaplan-Meier method; we considered that the follow-up time reported in the studies was equal to the survival time for those women that died from the disease, while in all other cases, the follow-up time was considered as the time point for censored cases.Additional tests for factors that could affect survival time were performed using the log-rank method.
The significance level (α) was set to 0.05 for all statistical tests; thus, a statistically significant difference between compared groups was when p < 0.05 and all tests were two sided.

Molecular Findings
Two cases were tested for BRCA1/2 mutations [41,49].A BRCA-2 pathogenic mutation was present in the case reported by Toboni et al. [41].No other information was provided.

Results of Inferential Statistical Analysis
The available data allowed for the performance of inferential statistics and the extraction of possible relations.A possible role of the tumor side (left or right) and the development of ascites was not possible to confirm (p = 0.1165).We furthermore studied all collected data for their role in recurrence, with the results being summarized in Table 3. Age, tumor size, tumor location (left or right), and the administration of adjuvant therapy did not have any statistically significant impact on subsequent recurrence.CA-125 was higher in women with recurrence (median: 91.7 Q1-Q3: 43-273.4,vs. median: 27 Q1:Q3: 13-184.2,p = 0.1164).When considering CA-125 levels as normal/abnormal (using 35 U/mL as a cut-off the value), the percentage of women who had normal CA-125 levels and still recurred was only 29.63%, while it was 70.37% for women without recurrence.The correlation of CA125 to disease recurrence was marginally significant (p = 0.0522) without enough statistical power to make a definitive statement about it.Moreover, it was observed that in women with recurrence, ascites was more common (38.1% vs. 22.5%, p = 0.1033).Clearly, stage was a decisive factor for recurrence (see Table 3), since 24.4% of the women with stage I had a recurrence, while the percentage was more than 60% for disease at stage II-IV (p = 0.0018).
The tumor side (left, right, or bilateral) had no role in patient survival time (log-rank p = 0.9378; Figure 3 highlights relevant survival curves and the number of women at risk).In contrast, an abnormal CA-125 level was linked to lower survival (Figure 3, p = 0.0476), with a mean survival of 29 months (Q1-Q3: 20-64 months) and 47 months (Q1-Q3: 24-96 months) for abnormal and normal CA-125 status, respectively.Similarly, women with tumors at stage I experienced better survival than women at stages higher In contrast, an abnormal CA-125 level was linked to lower survival (Figure 3, p = 0.0476), with a mean survival of 29 months (Q1-Q3: 20-64 months) and 47 months (Q1-Q3: 24-96 months) for abnormal and normal CA-125 status, respectively.Similarly, women with tumors at stage I experienced better survival than women at stages higher than I (Figure 3, p = 0.0057); specifically, the median survival was 53 months (Q1-Q3: 24-94 months) for stage I cases and 39 months (Q1-Q3: 20-78 months) for tumors at stage higher than I, respectively.Furthermore, ascites was not an important factor for lower survival (p = 0.8735).Finally, patients with lymph node dissection (LND), had better survival than patients without LND (p = 0.0131); specifically, the median survival for the 34 women in whom LND was performed was 117 months, and for the women without LND, it was 69 months.

Discussion
Ovarian cancer is the fifth most common cause of cancer-related death from gynecological carcinomas [54,55].Due to their rarity, MBTs comprise only a small fraction of these tumors.To our knowledge, this study is the first to review the literature systematically.In 1988, Austin and Morris first recognized that a subgroup of MBTs lacking a benign Brenner component represented, in fact, high-grade ovarian serous carcinomas with a transitional architectural pattern [56].To ensure that we did not include such cases, we included, for cases reported before 1988, only invasive tumors associated with a benign and/or borderline Brenner component.
In our study, the mean age of patients presenting with MBT is 59 years.In comparison, a previous study reported the mean age of patients to be 65 years [57].For other histotypes, the age of presentation ranges from 55 years for mucinous and endometrioid carcinoma, 56 years for clear-cell carcinoma, and 65 years for serous carcinoma [1].MBTs tend to present at a lower stage compared to serous carcinoma [1].The symptoms of MBT are similar to those of other epithelial ovarian carcinomas.The most common symptoms reported were abdominal pain, adnexal, abdominal or pelvic mass, abdominal distention, and vaginal bleeding.According to the literature, ascites is present in <10% of MBT cases.Our study reveals a much higher (28.9%) percentage.MBTs have no specific ultrasound or MRI findings [58,59].
The inferential statistical analysis performed in our study showed that disease stage I is associated with a statistically significant lower percentage of disease recurrence compared to stages II-IV.Also, disease recurrence is more commonly related to the presence of ascites and elevated CA-125 levels.Furthermore, the analysis showed a relation between higher CA-125 levels and a stage higher than I with decreased survival.In contrast to the study by Nasioudis et al., our analysis showed that patients treated with LND had a better survival rate [57].
The first step in correctly managing every malignancy is a precise diagnosis.The differential diagnosis of MBT includes high-grade ovarian serous carcinoma with a transitional architectural pattern, primary squamous cell carcinoma (SqCC), SqCC arising in a mature cystic teratoma, endometrioid borderline tumor, endometrioid carcinoma, metastatic SqCC, and metastatic urothelial carcinoma.
High-grade ovarian serous carcinoma with a transitional architectural pattern shows areas of conventional high-grade serous carcinoma with high-grade nuclear atypia, prominent nucleoli, and significant pleomorphism.It lacks a benign Brenner component, and, immunohistochemically, it is positive for WT-1 and estrogen receptors [60].
Primary ovarian SqCC usually shows keratinization and high-grade nuclear features, lacking a benign Brenner component; it may arise from a mature teratoma [61,62].Endometrioid borderline tumors and endometrioid carcinoma show at least partially endometrioid-type glands and are immunohistochemically positive for ER; they are frequently related to endometriosis.
In the differential diagnosis of metastatic tumors (either SqCC or urothelial carcinoma), knowledge of the previous clinical history is of great importance.Furthermore, metastatic tumors tend to be bilateral, displaying a multinodular growth pattern and lacking a benign Brenner component.
For instance, metastatic SqCC also does not show a papillary architecture.The summary of essential clinical, histologic, and immunohistochemical features for the distinction of the entities mentioned above is shown in Tables 4 and 5. Concerning the molecular findings in MBTs, the most common are inactivating mutations in the CDKN2A and CDKN2B loci encoding the cyclin-dependent kinase inhibitors p16INK4a and p15INK4b, respectively, followed by activating mutations in FGFR3 and PIK3CA [63].Notably, the p53 signaling was frequently disrupted in MBTs.The amplification of murine double minute 2 (MDM2)-encoding an E3 ubiquitin ligase that counteracts p53 suppressor activity-was a frequent event [63].Only a few cases harbored TP53 truncating and missense mutations, which were shown in a mutually exclusive pattern with MDM2 amplification [64].Interestingly, MDM2 amplification or TP53 mutations were mainly present in FGFR3 wild-type cases [63].Wang et al., reported amplification of MDM2 and CCND1 (encoding Cyclin D1), and loss of CDKN2A and CDKN2B in one case of MBT [48].Also, MBTs lack TERT promoter mutations, commonly found in urothelial carcinoma [65,66].Genomic alterations in genes involved in the homologous recombination deficiency (HRD) pathway were rare; Lin et al., revealed homozygous inactivating mutations only in BAP1 in rare cases [63].A pathogenic BRCA2 mutation was found in the case presented by Toboni et al. [41].Overall, it seems that MBT has unique molecular features among gynecological malignancies.In addition, previous data revealed that the FGFR3 and MDM2/P53 pathways, along with CDKN2A/B loss, play a key role in the pathogenesis of MBT.However, as MBT is rare, additional studies are required to shed light on the molecular events driving this entity.A summary of the molecular alterations is presented in Supplementary Table S5.
Surgery is the basis of MBT treatment.The majority of patients in our review were treated with HBSO, with or without omentectomy, appendectomy, and lymph node dissection.
The role of adjuvant chemotherapy has yet to be defined.In early stage disease, the benefit of chemotherapy is not clear.For instance, Gezginc et al., reported that patients of stages IA and IB could be followed up, and Han et al., spared patients of stage IA disease from chemotherapy [45].It is reasonable, therefore, to discuss with the patient the pros and cons and potentially offer adjuvant chemotherapy to those with stage IC and higher disease due to increased recurrence risk.
Importantly, antiangiogenic factors increase the progression free survival of patients with locally advanced and metastatic, high-grade epithelial ovarian cancer; however, patients with MBT were not included in these clinical trials [68,69].Lang et al., reported clinical benefit with the addition of Bevacizumab in a patient with recurrent MBT [42].
Due to the rarity of the disease, patients with recurrent or metastatic disease should be encouraged to undergo a genetic next-generation sequencing analysis of the tumor.This may shed light on the pathogenesis of this malignancy and allow for a treatment approach tailored to the patient.
Data on the role of radiotherapy are lacking in the literature.Only a few cases are reported, receiving radiotherapy as part of their adjuvant treatment [21,51] and in the case of recurrence [27,42,45,51].The use of radiotherapy cannot be advocated, particularly in early stage disease; it is reasonable, however, to consider targeted radiotherapy for symptom control.
Besides, the low incidence of this disease does not permit clinicians to carry out randomized clinical trials.Treatment protocols are therefore based on a case-by-case experience.It is therefore highly recommended that these cases be discussed in multidisciplinary team boards and published to accumulate clinical evidence.

Conclusions
In the present manuscript, we have collected data presenting a systematic review of MBTs', presenting their demographic, clinical, pathological, molecular, and treatment characteristics, with a special focus on the differential diagnosis.To our knowledge, this is the first study to systematically review the characteristics of these tumors.More multicentric studies reporting in detail treatment modalities and long-term follow-up are needed to define the optimal management for this rare entity.

Figure 1 .
Figure 1.PRISMA 2020 flowchart showing the search strategy, excluded studies, and finally included reports.

Figure 1 .
Figure 1.PRISMA 2020 flowchart showing the search strategy, excluded studies, and finally included reports.Our retrospective observational study search was conducted through the PICO process: • Population: Women with a diagnosis of MBT; • Intervention: Surgical treatment of the primary ovarian tumor; • Comparison: None; • Outcome: Patient treatment, follow-up.

( 2 ) 3 ) 4 )
Insufficient information: Cases with insufficient or too much aggregated data were excluded.(Uncertain diagnosis: Cases with an uncertain/doubtful diagnosis were excluded.(Histologic criteria: Cases lacking a benign or borderline Brenner component were excluded.(5) Language: Manuscripts in languages other than English were excluded.

Figure 2 .
Figure 2. Kaplan-Meier curves for patient survival.The horizontal axis shows the follow-up period in months and the number of patients at risk for various time points, vertical lines correspond to censored cases (previously unpublished original photo).

Figure 2 .
Figure 2. Kaplan-Meier curves for patient survival.The horizontal axis shows the follow-up period in months and the number of patients at risk for various time points, vertical lines correspond to censored cases (previously unpublished original photo).

Table 1 .
Clinic-pathologic and treatment features of the cases of malignant Brenner tumors.

Table 3 .
Comparison of results between women with recurrence and no recurrence.

Table 3 .
Comparison of results between women with recurrence and no recurrence.

Table 4 .
Clinical and histologic features of malignant Brenner tumors and their differential diagnoses.

Table 5 .
Immunohistochemical features of malignant Brenner tumors and their differential diagnoses.