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.

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.

Clonality analysis of combined Brenner and mucinous tumours of the ovary reveals their monoclonal origin.

The derivation of ovarian intestinal-type mucinous tumours is not well established. Some are derived from teratomas but the origin of the majority is not clear. It has been recently proposed that the non-germ cell group may be derived from Brenner tumours, as the association of a mucinous tumour with a Brenner tumour is frequently observed. In order to explore the histogenesis of these neoplasms, we undertook a clonality analysis of the two components of ten combined Brenner and mucinous tumours using a human androgen receptor gene (HUMARA) assay. All eight informative cases of ten showed a concordant X-chromosome inactivation pattern between the two tumour components, indicative of a shared clonal origin (p = 0.0039). Microsatellite genotyping in five of the combined tumours displayed an identical heterozygous pattern with paired Fallopian tube tissue, indicative of a somatic cell origin. In addition, paired box protein 8, a highly sensitive Müllerian epithelial marker, was not detected by immunohistochemistry in either tumour component in any of the ten tumours, suggesting that this subset of mucinous tumours does not originate from Müllerian-derived epithelium. In conclusion, this study demonstrates that in combined mucinous and Brenner tumours, there is a shared clonal relationship between the two different tumour components and suggests that some pure mucinous tumours may develop from a Brenner tumour in which the Brenner tumour component becomes compressed and obliterated by an expanding mucinous neoplasm.

Transitional cell carcinoma of the ovary is related to high-grade serous carcinoma and is distinct from malignant brenner tumor.

Transitional cell tumors of the ovary include benign, borderline (atypically proliferating), and malignant Brenner tumors (BT), as well as transitional cell carcinoma (TCC). Some TCCs could conceivably be examples of malignant BT where the benign component has been overgrown. Our objectives were: (A) compare the immunophenotypes of BT and TCC and (B) examine a large cohort of ovarian carcinomas for cases with the immunophenotype of BT and transitional features but lacking a benign BT component. Seven BTs (3 benign, 3 borderline/atypically proliferating, 1 malignant) and 7 TCCs were stained for WT1, ER, p53, and p16(INK4a). The BTs were negative for WT1, p53 overexpression, ER (except for weak positivity in 1), and negative or weakly positive for p16(INK4a). In contrast, the TCCs stained as follows: 4/6 positive for WT1, 5/7 positive for ER, 2/7 strongly positive for p16(INK4a), and 6/7 showed abnormal p53, an immunophenotype resembling that of high-grade serous carcinoma. A database of 500 cases of ovarian carcinoma was searched and 116 showed an immunoprofile characteristic of BT: WT1 negative, ER negative, p16(INK4a) or weak positive, p53 negative (77 clear cell carcinoma, 14 endometrioid carcinoma, 12 mucinous carcinoma, 8 high-grade serous carcinoma). None of these tumors showed transitional features on review, indicating that if examples of malignant BT where there has been overgrowth of benign BT components exist, they are rare. Our results suggest that BT and TCC are unrelated, and should not be combined for classification purposes.

Ovarian cystic tumor composed of Brenner tumor and struma ovarii.

Ovarian tumor composed only of Brenner tumor and struma ovarii is very rare; only 6 cases have been reported in the English literature, to the best of the author's knowledge. A 66-year-old woman underwent right oophorectomy because of torsion of right ovarian cyst. Macroscopically, the ovarian cyst was hemorrhagic and red. Cystic content was hemorrhagic fluid. Microscopically, the cyst walls were composed only of Brenner tumor (50% in area) and struma ovarii (50% in area). Hemorrhage and ischemic changes were seen. Other elements were not recognized. No malignant transformation was noted. These two elements were separately present, and no mergers between them were recognized. Immunohistochemically, the Brenner tumor element was positive for cytokeratins (AE1/3 and CAM5.2) and Ki67 (labeling=3%), but negative for thyroglobulin, TTF-1, p53, CA125, and vimentin. The struma ovarii element was positive for cytokeratins (AE1/3 and CAM5.2), thyroglobulin, TTF-1 and Ki67 (labeling=5%), but negative for p53, CA125 and vimentin. The findings suggests that there were cases of ovarian cyst composed only of Brenner tumor and struma ovarii, that such a case may be monodermal mature cystic teratoma or the Brenner tumor element was derived from surface epithelium in the preexisting struma ovarii, and that such a tumor manifest as cystic torsion.

Transitional cell tumors of the ovary: a comparative clinicopathologic, immunohistochemical, and molecular genetic analysis of Brenner tumors and transitional cell carcinomas.

Transitional cell tumors of the ovary include 2 distinct clinicopathologic categories: Brenner tumors and transitional cell carcinomas (TCCs). Their molecular genetic alterations have not been fully investigated. We have performed a clinicopathologic, immunohistochemical, and molecular genetic analysis of 19 transitional cell tumors including 13 Brenner tumors (5 benign, 7 borderline, and 1 malignant) and 6 TCCs. Immunoreactivity for epidermal growth factor receptor (EGFR), Ras, Cyclin D1, p16, Rb, and p53, as well as fluorescence in situ hybridization analysis for EGFR were assessed in all cases. Screening for mutations in K-Ras, B-Raf, CTNNB1, PIK3CA, and p53 genes was also performed. The mean patient age was 58 years (range, 32 to 85 y). Abdominal enlargement and pain were the usual complaints. Treatment was known in 14 patients: 10 had hysterectomy with bilateral salpingo-oophorectomy, which was accompanied by omentectomy in 7; and 4 had only unilateral or bilateral salpingo-oophorectomy, 1 with omentectomy. Four patients had brachytherapy. Six borderline Brenner tumors were stage IA and 1 stage IIA. The malignant Brenner tumor was stage IA. One TCC was stage IA, one IC, 2 IIIC and the stage was unknown in 2 cases. Follow-up information was available only in 5 of the nonbenign cases. Two patients who had borderline Brenner tumors were alive and well at 3 and 10.9 years. The patient who had a malignant Brenner tumor died of pulmonary thromboembolism shortly postoperatively, and 2 patients with TCCs died of tumor 1.8 and 13 years, postoperatively. Brenner tumors and TCCs differed mainly in the expression of EGFR, p16, and p53. Benign Brenner tumors showed a low immunoexpression for all markers. Borderline Brenner tumors failed to immunoreact for p16, Rb, and p53; and showed weak immunostaining for Cyclin D1, moderate for Ras, and strong for EGFR. The malignant Brenner tumor was also negative for p16, Rb, and p53, and strongly positive for Cyclin D1, Ras, and EGFR. In contrast, TCCs had p53 mutations with p53 and p16 protein overexpression and showed a negative immunoreaction for EGFR, Cyclin D1, and Ras. Our results suggest that Brenner tumors and TCCs follow different tumorigenic pathways, whereas borderline and malignant Brenner tumors are low-grade neoplasms with activation of the PI3K/AKT pathway through EGFR, TCCs are high-grade tumors that have p53 mutations and p16 and p53 protein overexpression.

Expression of claudins 1, 4, 5, and 7 in ovarian tumors of diverse types.

In this study, 60 different types of ovarian lesions, mainly consisting of ovarian neoplasms, were studied for the expression of claudins 1, 4, 5, and 7. Strong expression of claudins 1, 4, and 7 was seen in benign and malignant epithelial ovarian tumors. Expression of claudin 5, reported to be mainly present in endothelial cells, was seen in ovarian epithelial tumors, but with a significantly lower frequency than claudins 1, 4, and 7. On the contrary, sex-cord stromal tumors and cysts, such as fibromas/thecomas, Sertoli-Leydig cell tumors, granulosa cell tumors, and follicular and luteinized cysts were mainly negative for claudins 1, 4, 5, and 7. Interestingly, adenomatoid tumors did not express claudin 5, which is in agreement with their non-endothelial nature. They were also negative for claudin 4, but expressed claudins 1 and 7, but to a lesser degree than epithelial lesions. In immature teratomas, the epithelial component was usually positive whereas other components were negative for these claudins. Dysgerminomas did not express any of the claudins studied. The results show that claudins 1, 4, and 7 are mainly expressed in ovarian epithelial tumors and can thus be used to indicate epithelial differentiation in them. Eventhough considered an endothelial marker, claudin 5 was also present in a subset of epithelial lesions. However, this claudin can be used to differentiate adenomatoid tumors from vascular lesions. No significant difference was seen between epithelial benign and malignant lesions, except for claudin 5, which seemed stronger in malignant epithelial tumors.

A case of virilizing brenner tumor in a postmenopausal woman with stromal androgenic activity.

Although there are several reports of Brenner tumor showing estrogen activities, it is an extremely rare cause of androgen excess leading to virilism, and the source or mechanism of its androgen production is also unknown at present. A 74-year-old woman presented with lower abdominal pain and increased facial hair growth of 6-month duration. Bilateral ovarian tumors were detected, and her serum testosterone (1.7 ng/mL) and estradiol (75 pg/mL) levels were elevated. Bilateral salpingo-oophorectomy was performed. The ovarian tumors were diagnosed as benign Brenner tumor associated with fibrothecoma-like and luteinized stromal cells. Postoperatively, the serum testosterone and estradiol levels decreased. Immunohistochemically, fibrothecoma-like stromal cells were positive for cytochrome P-450 aromatase, which catalyzes the conversion from androgen to estrogen, and negative for c-Jun protein, which has recently reported to attenuate estrogen biosynthesis by directly down-regulating transcription of the aromatase gene. On the other hand, luteinized stromal cells were negative for cytochrome P-450 aromatase and positive for c-Jun protein. It is suggested that androgen is produced mainly in the luteinized stromal cells, because androgen is not converted to estrogen caused by suppression of aromatase biosynthesis by c-Jun.

Increasing expression of extracellular matrix metalloprotease inducer in ovary tumors: tissue microarray analysis of immunostaining score with clinicopathological parameters.

Ovary cancer invasion is responsible for both local tissue destruction and distant metastasis. Invasion is largely mediated by matrix metalloproteases that are thought to be induced by tumor cell-derived extracellular matrix metalloprotease inducer (EMMPRIN) in surrounding fibroblasts. We hypothesized that EMMPRIN isoverexpressed in ovary tumors. Immunohistochemical analysis of EMMPRIN was performed in tissue microarrays of ovary neoplasms including 84 cases of serous adenocarcinoma, 23 cases of mucinous adenocarcinoma, 10 cases of endometrioid adenocarcinoma, 12 cases of yolk sac tumor, 12 cases of clear cell carcinoma, 8 cases of dysgerminoma, 8 cases of granulosa cell tumor, 6 cases of transitional cell carcinoma, and 6 cases of Brenner tumor. All malignant ovary tumors showed significant immunohistochemical expression of EMMPRIN. The EMMPRIN scores in malignant ovary tumors were significantly higher than their nontumor counterparts (313+/-28 for serous adenocarcinoma; 308+/-25 for mucinous adenocarcinoma; 187+/-19 for endometrioid adenocarcinoma; 265+/-23 for yolk sac tumors; 87+/-13 for clear cellcarcinoma; 126+/-15 for dysgerminoma; 243+/-26 for granulosa cell tumor; 87+/-16 for transitional cell carcinoma). The EMMPRIN score was significantly higher in serous adenocarcinomas than in serous adenomas and serous borderline tumors and was correlated with nodal stage. Our findings show for the first time that EMMPRIN is overexpressed in all malignant ovary tumors.

Brenner tumors but not transitional cell carcinomas of the ovary show urothelial differentiation: immunohistochemical staining of urothelial markers, including cytokeratins and uroplakins.

To determine whether Brenner tumors and transitional cell carcinomas (TCCs) of the ovary are urothelial in type, the immunoprofiles of 14 Brenner tumors, including three malignant examples, and eight ovarian TCCs were compared with those of Walthard nests, urothelium, 12 urinary bladder TCCs and 17 ovarian adenocarcinomas (serous, endometrioid, mucinous, and undifferentiated type). The immunohistochemical stains used included those for cytokeratins CKs 5/6, CK7, CK8, CK13, and CK20, vimentin, CA125, and the specific urothelial differentiation marker uroplakin III. CK7 and CK8 were broadly expressed in most tumors of ovary and bladder examined, while vimentin was focally present in some ovarian TCCs and adenocarcinomas. As in normal and neoplastic bladder urothelium, urothelial markers, including uroplakin III, CK13, and CK20, were detected in the epithelial nests of Brenner tumors. Brenner tumor cells also expressed uroplakins Ia and II. CA125 was observed focally in some Brenner tumors. In contrast, TCCs of the ovary and Walthard nests lacked uroplakins and were essentially negative for CK20 and CK13 but quite strongly expressed CA125. This immunophenotype closely resembled that found in ovarian adenocarcinomas. Thus, it appears that the only true urothelial-type ovarian neoplasm is the Brenner tumor, whereas ovarian TCC most likely represents a poorly differentiated adenocarcinoma with a morphologic transitional cell pattern. These results may explain the controversies as expressed in the recent literature concerning TCC of the ovary and establish its place among the ovarian adenocarcinomas of müllerian type.

Brenner tumor of the ovary: a comparative immunohistochemical and ultrastructural study with transitional cell carcinoma of the bladder.

Because of a fancied light microscopic resemblance to transitional epithelium (urothelium), Brenner tumor (BT) of the ovary is commonly described as a transitional cell neoplasm. An inability to detect a great deal of similarity between the two at the ultrastructural level prompted this electron microscopic study comparing 3 benign Brenner tumors with normal urothelium and 6 transitional cell carcinomas (TCC) of varying histologic grade from the urinary bladder. To complement the ultrastructural observations, the immunophenotype of 8 benign BTs was evaluated together with that of 12 TCCs of the bladder using antibodies to thrombomodulin (TM), cytokeratin 20, cytokeratin 7, and carcinoembryonic antigen (CEA), all of which have been shown to react with TCCs of urothelial origin. At the ultrastructural level, there was only limited evidence of a morphologic likeness between the epithelial cells of BTs and those of the benign or neoplastic urothelium. The immunophenotype of the two tumors also differed significantly in that there was no reactivity for TM or cytokeratin 20 in the BTs, while these markers were expressed in the TCCs. Both BTs and TCCs were positive for cytokeratin 7 and may express CEA.

Differential diagnosis, prognostic factors, and clinical treatment of proliferative Brenner tumor of the ovary.

Brenner tumors are rare ovarian tumors displaying benign, borderline or proliferative, and malignant variants. The case of a 63-year-old woman with a proliferative Brenner tumor is presented and the histomorphological differential diagnosis of this tumor entity is compared to that of its benign and malignant counterparts. Light microscopy, immunohistochemistry, and electron microscopy were performed to allow discrimination from the other subtypes. Despite a considerable overlap of pathological features the differential diagnosis of proliferative Brenner tumor could be established. Electron microscopy allowed assessment of characteristic infoldings of the nuclear membrane that proved to be a valuable ultrastructural criterion. Considering that the vast majority of Brenner tumors are benign, precise identification of the small proportion of malignant tumors allows the extent of surgical therapy to be adapted.

Uroplakin III is a highly specific and moderately sensitive immunohistochemical marker for primary and metastatic urothelial carcinomas.

Uroplakins are specific differentiation products of terminally differentiated superficial urothelial cells. We tested the value of a new commercially available monoclonal antibody against uroplakin III (clone AU 1) as a paraffin-reactive immunohistochemical marker for primary and metastatic urothelial carcinomas. The study cases included 67 urothelial carcinomas of the urinary tract (35 primary tumors, 32 metastases) and 318 nonurothelial carcinomas, as well as 5 benign Brenner tumors and 2 transitional cell carcinomas of the ovaries. Uroplakin III was detected in 21 (60%) of the primary urothelial carcinomas and 17 (53%) of the metastases, resulting in an overall sensitivity of 0.57. The studied Brenner tumors also were immunoreactive for uroplakin III. All other studied carcinomas were consistently uroplakin III-negative (specificity 1.00). We found the new monoclonal antibody AU 1 against uroplakin III to be a highly specific paraffin-reactive immunohistochemical marker for urothelial tumors with a moderate sensitivity for the identification of primary and metastatic urothelial carcinomas.

Well-differentiated mucinous carcinoma of the ovary and a coexisting Brenner tumor both exhibit amplification of 12q14-21 by comparative genomic hybridization.

Although the coexistence of mucinous ovarian neoplasms and Brenner tumors is well established, the histogenesis and developmental relationship between the two remain unknown. We used comparative genomic hybridization to analyze two such tumors occurring simultaneously, one in each ovary, in a patient. Amplification of 12q14-21 sequences was found in both tumors; in addition, both tumors also had other, different changes, four identified in the Brenner tumor and six in the mucinous carcinoma. The occurrence of the same genetic alteration in both tumors in this woman suggests that the mucinous carcinoma and Brenner tumor may be clonally related, i.e., one arose from the other by means of metastatic spreading of transformed cells from one ovary to the other. An alternative explanation is that some unknown, putative tumorigenic agent induced similar and synchronous pathogenetic changes in the epithelium of both ovaries. The phenotypic differences between the tumors are presumably attributable to the other unique genetic abnormalities identified in both tumor types.

Immunohistochemical detection of p185 product, p21 product, and proliferating cell nuclear antigen (PCNA) in formalin-fixed, paraffin-embedded tissues from ovarian carcinomas. Preliminary data.

Immunohistochemical techniques for the detection of oncogene products and the assessment of cell kinetics can represent promising investigational tools in clinical oncology. In the present paper the immunohistochemical expression of p185, p21 and proliferating cell nuclear antigen (PCNA) was retrospectively assessed in formalin-fixed, paraffin-embedded tissue samples taken from 28 primary ovarian carcinomas at first surgery. Positive immunostaining for p185 was found in 0% of 6 Stage I and 23% of 22 Stage III-IV tumors. Positive immunostaining for p21 was observed in 0% of early and 41% of advanced carcinomas; this immunohistochemical finding correlated significantly with histologic grade (G3 vs G1-2 = 47% vs 9%, p = 0.042). Elevated PCNA immunoreactivity was detected in 33% of Stage I and 50% of Stage III-IV tumors. Among the 20 patients with advanced carcinoma who underwent cisplatin or carboplatin based chemotherapy followed by second-look laparotomy, the pathologic complete response (pCR) rate was 36% for patients with low PCNA expression and 0% for those with elevated PCNA expression. A tendency towards a higher pCR rate was also found for patients with negative immunostaining for p185 or for p21. The prognostic value of the immunohistochemical detection of p185, p21, and PCNA in ovarian carcinoma deserves to be further investigated.

[Benign and malignant Brenner tumor of the ovary: a clinicopathological and immunohistochemical study].

The clinicopathological and immunohistochemical features of 7 cases of benign and malignant Brenner tumor of the ovary, including 5 benign and 2 malignant tumors are described. Microscopically, all of the benign cases were composed of both epithelial nest and fibrous stroma. Two cases of the malignant Brenner tumor showed that the histologic features resembled the structure of non-keratinized squamous carcinoma or transitional cell carcinoma. Immunohistochemistry showed that tumor cells of the epithelial nest were keratin and EMA positive in 7 cases; CEA-positive in 5 cases; and negative in 2 cases of benign Brenner tumor. The results indicated that Brenner tumor is an epithelial neoplasm in nature. The diagnostic criteria and histogenetic origin are discussed.