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

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

A Rare Case of Ruptured Malignant Ovarian Brenner Tumor.

BACKGROUND Ovarian cancer is the leading cause of death in women with gynecological cancers. Ovarian Brenner tumor (BT) is an extremely rare type of epithelial ovarian cancer that accounts for about 1-3% of all ovarian cancers. Herein, we report a rare case of ruptured malignant ovarian Brenner tumor. CASE REPORT A 39-year-old P0A0 woman came to the Emergency Department (ED) with abdominal pain and tenderness. Perforated appendicitis was initially suspected and an emergency laparotomy was performed by the General Surgery Department. Then, a 25×20×15 cm grayish cystic mass originating from the right adnexa was found. We consulted intraoperatively with the Gynecology Oncology Department and decided to perform complete surgical staging. Histopathological examination confirmed the diagnosis of malignant Brenner tumor (MBT). The patient was then given adjuvant chemotherapy with a paclitaxel carboplatin regimen. In this case report, we present our case along with a review of the current literature regarding the diagnosis and therapy of malignant Brenner tumor. CONCLUSIONS Ovarian MBT is an extremely rare ovarian cancer. Diagnosing MBT can be challenging as there are no clinical, laboratory, or imaging features typical for it. Surgery is the mainstay treatment in MBT cases. The role of adjuvant chemotherapy in MBT is still being debated.

Brenner Tumor of the Ovary: A 10-Year Single Institution Experience and Comprehensive Review of the Literature.

Brenner tumors (BTs) are surface-epithelial stromal cell tumors that are categorized by the World Health Organization as benign, borderline, and malignant. Due to the rarity of BTs, the published literature on these tumors is comprised primarily of case reports and small retrospective studies. We performed a pathology database review spanning the last ten years at our institution revealing nine reported benign BTs. We collected the clinical and pathological data of patients associated with those BTs, describing the clinical presentation and imaging results, and assessing the possible risk factors associated with them. The average age at diagnosis was 58 years. BTs were discovered incidentally in 7/9 cases. The tumor was multifocal and bilateral in 1/9 cases and ranged in size from 0.2 cm to 7.5 cm. Associated Walthard rests were found in 6/9 cases and transitional metaplasia of surface ovarian and/or tubal epithelium was found in 4/9 cases. One patient had an associated mucinous cystadenoma in the ipsilateral ovary. Another patient had an associated mucinous cystadenoma in the contralateral ovary. In conclusion, we found that Walthard rests and transitional metaplasia are common findings in association with BTs. Additionally, pathologists and surgeons need to be aware of the association between mucinous cystadenomas and BTs.

Borderline Brenner tumor with abnormally high serum level of carbohydrate antigen 199: a rare case report and literature review.

Ovarian Brenner tumor with abnormally increased serum carbohydrate antigen 19-9 (CA19-9) level is extremely rare. A 70-year-old woman with abnormally elevated serum CA199 (1289 U/ml) found in routine physical examination. Pelvic CT and MRI scan revealed a large mass with large patches of calcification in the right adnexal area, and the patient achieved total hysterectomy and bilateral adnexectomy. Grossly, the right ovary had a solid enlargement of about 7.0 cm × 6.0 cm × 5.0 cm with irregular nodules and smooth surface and the cut surface of the mass showed that the tumor is cystic and solid. Microscopically, the tumor showed a background of fibrous tissue hyperplasia with nested and adenoid cell clusters with uniform cell size and clear boundaries. The cells were translucent with eosinophilic cytoplasm and calcification. Immunohistochemical staining showed CK7, CA125, and P63 presented diffusely strongly positive staining, while negativity for CK20, GATA3, AR, P53, and CgA. Ki-67 showed weak positive staining, about 1%. The serum CA199 level decreased significantly on the 5th day after surgery. Postoperative pathology and immunohistochemistry confirmed borderline Brenner tumor. This is the first to report a case of borderline Brenner tumor with an abnormally high serum level of CA199 before surgery. In clinical practice, the possibility of ovarian Brenner tumor should be considered when abnormal elevation of serum CA199 level cannot be reasonably explained.

Brenner's tumour of the ovary.

Brenner's tumour of the ovary is a rare diagnosis that is usually incidental in either clinical finding or laparotomy. Pathologically, it can be classified as being an uncommon surface epithelial tumour. Originally known as a transitional cell tumour due to its histological similarity to the urothelium, Brenner is usually an unilateral and benign tumour. The site of incidence is predominantly the ovary and can very rarely occur in other locations including the testis. The following is a case of Brenner's tumour of the ovary in a postmenopausal woman after surgical treatment, the features of which will be discussed briefly.

Brenner tumors.

Brenner tumors are rare ovarian neoplasms composed of ovarian transition cells surrounded by dense fibrous tissue. Most of them are small tumors (<2 cm), detected incidentally in asymptomatic women. Its predominantly fibrous content results in relatively low signal on T2 weighted images, establishing differential diagnosis with ovarian fibroma and thecoma. Their imaging features are very similar, the differentiation is based on secondary characteristics, such as signs or symptoms of estrogen excess and the presence of a second ovarian neoplasm, which has been reported in up to 30% of patients with Brenner tumor. Although originally thought to be universally benign, there have been scattered reports in the past decades of borderline and malignant forms of Brenner tumors.

Ovarian Low-grade Basaloid Carcinoma Arising in Brenner Tumor: A New Variant of Malignant Brenner Tumor.

Brenner tumors are uncommon ovarian neoplasms, most of which are benign, although borderline and malignant variants occur. We report 2 unusual ovarian neoplasms composed of an admixture of typical benign Brenner tumor and a low-grade epithelial neoplasm which we designate as low-grade basaloid carcinoma. The latter component morphologically and immunohistochemically resembled "salivary gland-type/myoepithelial" neoplasms with variable positive staining with cytokeratins, p63, S100, and CD117. One tumor exhibited aggressive behavior with local recurrence and distant metastasis. This neoplasm exhibited focal "high-grade" transformation with diffuse mutation-type p53 staining, in contrast to the wild-type immunoreactivity in the low-grade component. As far as we are aware, such neoplasms have not previously been reported in the literature and this represents a newly described morphologic variant of malignant Brenner tumor.

MDM2 amplification in malignant Brenner tumors may play a role in progression to malignancy and aid in separation from urothelial and other ovarian carcinomas.

Malignant Brenner tumor (MBT) is diagnosed in the setting of invasive high-grade carcinoma with urothelial-like morphology and the presence of an adjacent benign Brenner tumor (BBT) or borderline Brenner tumor (BLBT). MDM2 amplification was recently detected by next-generation sequencing on a small number of MBTs, potentially significant for future targeted therapy. Experience is limited, however, and evaluation of widely available MDM2 immunohistochemistry (IHC) has not been performed to determine clinical utility. After confirming all diagnoses morphologically and immunohistochemically, we performed MDM2 IHC on 4 MBTs, 3 BLBTs, 26 BBTs, 142 high-grade serous carcinomas (HGSC), 6 ovarian endometrioid carcinomas (OEC) with urothelial-like morphology, and 49 high-grade urothelial carcinomas (HGUC). MDM2 IHC was considered positive with diffuse (>25%) nuclear reactivity; in cases of patchy staining (10-25% nuclear reactivity), MDM2 was considered equivocal. Positive staining in <10% of cells was considered negative. In cases with positive or equivocal staining, MDM2 amplification was evaluated by fluorescence in-situ hybridization (FISH). Three MBTs (75%) showed diffuse nuclear reactivity for MDM2 by IHC, a finding corroborated by amplification of MDM2 in all three cases. One MBT and 2 BLBTs showed equivocal MDM2 IHC, but all three were negative for MDM2 amplification. The final BLBT, as well as all BBTs, HGSC, OEC, and HGUC, were negative for MDM2. In conclusion, our limited cohort confirms MDM2 amplification in MBT and suggests that MDM2 IHC may have an influence in rare diagnostically challenging cases.

Brenner tumor associated with rete ovarii: a histologic and immunohistochemical analysis of six cases exploring the relationship between these entities.

The association of Brenner tumor (BT) with rete ovarii (RO) has been rarely alluded to in the literature. Both entities have debatable histogenesis. In this study of six cases of BT associated with RO, we describe the morphologic features and performed immunohistochemical staining for markers of Mullerian, Wolffian, mesothelial, and sex cord stromal derivation to explore the relationship between these entities. Histologically, all BTs were benign, microscopic, and incidental. RO was prominent and hyperplastic with gradual or abrupt transition to BT. In addition, focal areas of rete entrapped between BT nests were seen. All BTs were positive for GATA-3 and negative for PAX-8. Conversely, the RO in all cases was negative for GATA-3 and positive for PAX-8. WT-1 was positive in both entities. Sex cord stromal and mesothelial markers (other than WT-1) were negative in BT and RO. Although morphologically, BTs seem to arise from RO in these cases, they have a distinct immunophenotype. It is possible that at least some BTs arise from metaplastic changes in RO epithelium.

Borderline Brenner Tumor of the Ovary Coexisting With an Ovarian Mucinous Cystadenoma With Focal Atypical Epithelial Proliferation: A Rare Case With Review of the Literature.

Ovarian Brenner tumors, accounting for ∼5% of overall ovarian epithelial neoplasm, are often reported in association with mucinous neoplasm. Histogenetically, the two tumors are thought to arise from similar precursors. To date, fewer than 60 borderline Brenner tumors alone have been reported, and the concomitant presence of atypical proliferative components in Brenner and mucinous tumors is even rarer. Therefore, the clinicopathological characteristics and prognosis of patients with the borderline Brenner tumors alone or coexisting with mucinous neoplasm are extremely limited. Herein, we report a unique case of a 53-year-old woman with a unilateral ovarian borderline Brenner tumor associated with focal atypical mucinous epithelial proliferation and her clinical presentations. The clinicopathological features of the tumor are documented and the literature review along with the clinical molecular advances are summarized in this study.

Recurrent urothelial carcinoma-like FGFR3 genomic alterations in malignant Brenner tumors of the ovary.

Malignant Brenner tumor is a rare primary ovarian carcinoma subtype that may present diagnostic and therapeutic conundrums. Here, we characterize the genomics of 11 malignant Brenner tumors, which represented 0.1% of 14,153 clinically advanced ovarian carcinomas submitted for genomic profiling during the course of clinical care. At the time of molecular profiling, there was no evidence of a primary urothelial carcinoma of the urinary tract in any case. Cases with transitional-like morphologic features in the setting of variant ovarian serous or endometrioid carcinoma morphology were excluded from the final cohort. Malignant Brenner tumors exhibited CDKN2A/2B loss and oncogenic FGFR1/3 genomic alterations in 55% of cases, respectively; including recurrent FGFR3 S249C or FGFR3-TACC3 fusion in 45% of cases. FGFR3-mutated cases had an associated benign or borderline Brenner tumor pre-cursor components, further confirming the diagnosis and the ovarian site of origin. Malignant Brenner tumors were microsatellite stable, had low tumor mutational burden and exhibited no evidence of homologous recombination deficiency. PIK3CA mutations were enriched with FGFR3 alterations, while FGFR3 wild-type cases featured MDM2 amplification or TP53 mutations. The FGFR3 S249C short variant mutation was absent in 14,142 non-Brenner, ovarian carcinomas subtypes. In contrast to malignant Brenner tumors, FGFR1/2/3 alterations were present in ~5% of non-Brenner, ovarian serous, clear cell and endometrioid carcinoma subtypes, most often as FGFR1 amplification in serous carcinoma or FGFR2 short variant alterations in clear cell or endometrioid carcinomas, respectively. Finally, malignant Brenner tumors had overall distinct genomic signatures compared to FGFR-mutated ovarian serous, endometrioid, and clear cell carcinoma subtypes. This study provides insights into the molecular pathogenesis of malignant Brenner tumors, contrasts the extent of FGFR1/2/3 alterations in ovarian serous, clear cell and endometrioid carcinomas and emphasizes the potential value of novel and FDA-approved, anti-FGFR inhibitors, such as erdafitinib and pemigatinib, in refractory, FGFR3-mutated malignant Brenner tumors.

Benign Brenner Tumor in an Ectopic Ovary: A Case Report and Review of Literature.

Supernumerary ectopic ovaries are very rare, with fewer than 40 cases of isolated supernumerary ovaries reported in the literature since their discovery in 1864. Tumors arising in ectopic ovaries are also extremely rare, with only a handful of reports in the literature. Given the rarity of this combination of findings, we report a case of a 68-yr-old woman incidentally found to have a 4.7 cm solid retroperitoneal mass adjacent to the liver, diagnosed as a benign Brenner tumor arising in a supernumerary ectopic ovary. To our knowledge, there has been only one previously reported case of Brenner tumor arising in this unusual setting.

Malignant Brenner tumour of the ovary manifesting as distal intestinal obstruction and perforation.

A rare case of malignant Brenner tumour of ovary manifesting with intestinal perforation due to colonic infiltration is elaborated in the present report. Brenner's tumour accounts for 1%-2% of all ovarian neoplasms and malignant Brenner tumour is even rarer and only about 5% of Brenner tumours are malignant. A 62-year-old woman came to surgical emergency with 1-month history of abdominal pain, vomiting and constipation with a palpable mass in right iliac fossa. Abdominal radiograph was suggestive of colonic obstruction. Contrast-enhanced CT of the abdomen revealed cystic right ovarian mass of 10.2×8.8 cm2 with pneumoperitoneum. Exploratory laparotomy was done, which revealed mass arising from right ovary involving terminal ileum, cecum and ascending colon. Possibility of ovarian malignancy was kept. Patient underwent debulking surgery along with ileostomy and descending colon mucous fistula was created. Histology was compatible with malignant Brenner tumour of the ovary.

Amplification of MDM2 and Loss of p16 Expression: Do They Have a Role in Malignant Transformation of Ovarian Brenner Tumor?

OBJECTIVES: To review the significance of MDM2 and cyclin D1 expression and loss of p16 expression in malignant and borderline Brenner tumors (BTs) of the ovary. METHODS: We describe 2 new cases of ovarian BT, 1 malignant and 1 borderline. We studied MDM2, p16, and cyclin D1 expression by immunohistochemistry in the benign, borderline, and malignant components of these 2 cases and in 5 additional cases of benign BT. We also reviewed and summarized the literature on the clinical, immunohistochemical and molecular characteristics of borderline and malignant BTs (BdBTs and MBTs). RESULTS: Nuclear expression of MDM2 was seen only in the MBT. Loss of p16 expression was seen in both BdBT and MBT. Cyclin D1 expression was in proportion to the degree of malignancy. Amplification of MDM2, loss of CDKN2A (p16-encoding gene), and amplification of CCND1 (cyclin D1-encoding gene) were confirmed by commercial next-generation sequencing in the case of MBT. CONCLUSIONS: We are the first to report immunohistochemical expression of MDM2 in an MBT. Amplification of MDM2 and loss of p16 expression may have a role in malignant transformation of BT.

Detailed overview on rare malignant ovarian tumors.

The group of rare malignant ovarian tumors includes the group of germ cell tumors, sex cords stromal ovarian tumors, small cell carcinoma, malignant Brenner tumors, rare epithelial tumors such as mucinous carcinoma, clear cell carcinoma, or low-grade serous carcinoma, as well as ovarian carcinosarcoma. Together they comprise about 10% of all ovarian tumors. Due to their low prevalence and their heterogeneity, data and treatment recommendations are limited. Even though all ovarian tumors are staged according to the FIGO staging of epithelial ovarian tumors, treatment differs especially in germ cell tumors and sex cords stromal ovarian tumors. Non-epithelial ovarian tumors can arise from a variety of ovarian precursor cells such as germ cells, granulosa cells, theca cells, or stromal fibroblasts. As can be expected already due to their divergent precursor lesions, these malignancies are substantially different but united by their rarity. This overview article gives a comprehensive summary on the pathology and clinical presentation, as well as therapy recommendations of a selection of those rare ovarian tumors, based on the latest national guidelines and related important publications.

Extraovarian Brenner tumor in the uterus: a case report and review of literature.

BACKGROUND: Extraovarian Brenner tumors (EOBTs) are extremely rare and can be observed incidentally in both female and male patients, raising concerns regarding the origin of Brenner tumors. CASE PRESENTATION: A 53-year-old postmenopausal woman presented with a nodular lesion in the left side of the corpus uteri, which was found at a routine health check. Macroscopically, the lesion appeared as a solid nodule with a yellowish-gray cut surface, approximately 6 cm in greatest diameter. Microscopically, the lesion consisted of well-defined epithelial nests and spindled stromal cells. Parenchymal cells expressed CK7, GATA3, CK5/6, 34ßE12, and p63. A single layer of cavity-lined cells with umbrella-like shape showed apical Uroplakin III positivity. Stromal cells were positive for SMA, ER, and PR. The final diagnosis was EOBT and the patient was followed for 2 months with no recurrence. CONCLUSIONS: We report here the third case of EOBTs in the uterus. The combination of morphologic and immunohistochemical results supported the involvement of urothelial metaplasia in the development of EOBTs. The similarities between EOBTs and Walthard nests made Müllerian epithelium an attractive candidate as the cellular origin. Changes of tissue structure or sex hormones imbalance may lead to the translocation of Müllerian remnants to distant organs, explaining the pathogenesis of EOBTs.

Two types of primary mucinous ovarian tumors can be distinguished based on their origin.

The origin of primary mucinous ovarian tumors is unknown. We explore the hypothesis that they originate from either Brenner tumors or teratomas and examine differences between the tumors that arise in these settings. A total of 104 Brenner tumor-associated mucinous tumors and 58 teratoma-associated mucinous tumors were analyzed. Immunohistochemistry for 21 antigens and fluorescence in situ hybridization for ERBB2 and MYC were performed. Genome-wide copy number analysis and mutation analysis for 56 cancer-related genes was carried out on a subset of mucinous ovarian tumors and their complementary Brenner tumor or teratoma. Patients with teratoma-associated mucinous tumors were significantly younger than patients with Brenner tumor-associated mucinous tumors (43 vs. 61 years). During progression from cystadenoma to atypical proliferative mucinous (borderline) tumor to carcinoma expression of typical gastrointestinal markers was increased in both Brenner tumor-associated and teratoma-associated mucinous tumors. Brenner tumor-associated mucinous tumors showed more frequently calcifications and Walthard cell nests, rarely expressed SATB2 and showed more often co-deletion of CDKN2A and MTAP. Teratoma-associated mucinous tumors were characterized by mucinous stromal dissection, SATB2 expression and RNF43 mutations. Other frequent mutations in both Brenner tumor-associated and teratoma-associated mucinous tumors were TP53 and KRAS mutations. Based on identical mutations or copy number profiles clonal relationships were indicated in two mucinous tumors and their associated Brenner tumor. Teratomas and Brenner tumors give rise to different subtypes of mucinous ovarian tumors. Subsequent progression pathways are comparable since both Brenner tumor-associated and teratoma-associated mucinous tumors develop a gastrointestinal immunophenotype during progression and show early mutations in KRAS and TP53. Teratoma-associated mucinous tumors may more closely resemble true gastrointestinal tumors, indicated by their expression of SATB2 and the presence of RNF43 mutations.