A Rare Case of Bilateral Malignant Brenner Tumors of the Ovaries Associated with Peritoneal Effusion

Background: Malignant ovarian Brenner tumors are extremely rare worldwide, accounting for only 1% of malignant ovarian tumors. Their clinical symptoms and pathology are complex and erratic,and the images are mostly non-specific. This poses difficulties in preoperative diagnosis and distinguishing them from other cystic solid ovarian tumors.Here this study has reported on a case of bilateral malignant ovarian Brenner tumor with peritoneal effusion. Case presentation: A 54-year-old woman presented with intermittent vaginal bleeding for more than two months and abdominal pain for one month. Two hard mass of five centimeters with poor movement could be touched at each side of the ovarian areas. The CT findings indicated the presence of two large cystic and solid masses in both adnexal regions.The operation had watched the size of the masses in the bilateral ovarian was both 6cmx6cmx5cm and their surface ulceration showed rotten fleshy tissue. After the operation,combined with morphological and immunohistochemical features,the ovarian specimens were consistent with bilateral ovarian malignant Brenner tumors. Conclusions: Although the incidence of bilateral malignant OBT is extremely low and this disease is extremely rare clinically, the gynecologists should be more informed of its diagnosis and treatment.

A 54-year-old woman presented with intermittent vaginal bleeding for more than two months and abdominal pain for one month. She came to the hospital on June 17 th , 2017. The patient had an appendectomy 26 years ago and went through natural menopause three years ago.On performing the admission examination, the following observations were made: there were no enlarged superficial lymph nodes in the whole body but a hard mass with unclear size could be touched in the upper abdomen. The upper abdomen had positive tenderness accompanied by obvious percussion pain in the liver area. The gynecological examination was then performed and the following were observed: the vagina was smooth with a large amount of bloody fluid and its dome was not thickened. A hyperplastic tumor with a three-centimeter diameter resembling cauliflower was found in the cervical canal and active bleeding was observed. The uterine body had positive tenderness with poor movement and the ligaments were not thickened at both sides of the uterus. Two hard mass of five centimeters with poor movement could be touched at each side of the ovarian areas.
Next,the trimanual gynecologic examination was carried and it was observed that the sacral ligaments and the main ligaments were not thickened; there was no abnormal mass in the rectouterine fossa; the rectal mucosa was smooth, and the finger covers were not stained with blood. The tumor markers of CA125, CEA, and AFP were 213 KU/L, CEA 3.60 KU/L, and 1.31μg/L, respectively. The CT findings indicated the presence of two large cystic and solid masses in both adnexal regions, and that the solid components were enhanced unevenly. The cervix was irregular in shape and showed uneven and obvious enhancement. The endometrium was inhomogeneously thickened. Multiple small nodules were observed behind the peritoneum and a small amount of fluid density was observed in the pelvic cavity (Picture 1). During the operation, about 500ml of bloody ascites was found and 200ml was taken for cytological examination. The omentum majus was thickened to form an 8 cm x 8cm hard cake(Picture 3).The surface of the pelvic peritoneum, colonic groove, right colon bowel, and bladder were all covered with gray brittle nodules and the gastric surface was covered with grain size nodules. The surfaces of the liver and the transverse septum were smooth. The uterus was of two-months pregnancy size and there were several peanut-sized nodules in the isthmus. There was no swollen lymph node in the pelvic cavity and beside the abdominal aorta. The bilateral ovarian was enlarged to 6cm x 6cm x 5cm size with surface ulceration showing rotten fleshy tissue.
The bilateral fallopian tubes were thickened and the umbrella section of the right fallopian tube presented rotten fleshy tissue. The bilateral adnexa adhered closely to the lateral pelvic wall and intestinal canal(Picture 4). From the above findings, stage Ⅲ of ovarian cancer was diagnosed during operation, and therefore tumor cytoreductive surgery was performed. The cancer nodules on the surface of the intestine and the peritoneum were removed, followed by removal of the omentum majus. Because the pelvic cavity was hyperemic with extensive adhesions, the lymph node dissection was not performed.

Microscopy
Combined with morphological and immunohistochemical features,the ovarian specimens were consistent with malignant bilateral ovarian Brenner tumors.The invasion of carcinoma was spread into the whole layer with multiple focal necroses.
The invasion into the bilateral fallopian tubes and mesangial membranes with

Immunohistochemical phenotype
The tumor cells were mostly positive for CK5/6, CK34βE12, P63 and CK20, as well as CA125、Pgp and P53. The proliferation index of PR and ER was about 95% and 80%, respectively. The positive rate of ki-67 was approximately 80%.

The Treatment Process
After the operation, the final diagnoses were Stage III C of bilateral ovarian malignant

Ovarian Brenner tumor (OBT) was first reported by MacNaughton-Jones in 1898 and
named by Fritz Brenner in 1907 [1] .It accounts for 2%-5% of all ovarian tumors, 95% of which are benign with no obvious symptoms [2] .The incidence of malignant OBT(MBT) is less than 1% and is commonly found in unilateral ovaries. The incidence of 12% was reported for bilateral ovaries and is more common in patients aged fifty to sixty. About half of these patients are found accidentally with no obvious symptoms and mostly in their middle or late stages. Most patients seek medical help with abdominal mass or digestive system symptoms as the first complaint [3][4][5] .
MBT is very rare with few local and global literature reports. Most of the documented literature are case reports which lack epidemiological and prognostic clinical data. The first two cases of malignant OBT were reported by Claés von Numers in 1945 [2] .Some malignant cases had irregular vaginal bleeding,signifying the importance of routine gynecological examination for adult women [6] . In some cases, the level of estrogen was increased, and the metastatic foci presented the corresponding symptoms [7] . It was reported that four out of nine cases of MBT, presented with pleural effusion, and among the four cases, two were accompanied by ascites [4] . Furthermore, it was considered that the presence of pleural effusion and ascites could be used as the reference indices for distinguishing benign and malignant OBT.
Therefore, special attention should be paid to the examination of the reproductive organs, such as the ovaries and the fallopian tubes to exclude the lesions when the elderly women have unexplained pleural effusion and ascites. A case of a 63-year-old woman with malignant OBT who was initially diagnosed with cervical cancer stage IA by preoperative loop electrosurgical excision had already been reported. In that case,preoperative abdominal ultrasound also found bilateral adnexal masses with a size of 50-60 mm. The masses were removed during the operation and sent to the rapid pathology which indicated that they were malignant Brenner tumor of the ovaries [7] .

Tumor Markers
Currently, there are no specific tumor markers for malignant OBT. In 13 cases of malignant OBT, the preoperative serum CA125 of six patients (46.2%) were higher than in normal people, and was significantly increased in two cases but decreased dramatically to normal levels after the chemotherapy. At present, it is believed that serum CA125 is still the preferred reference index for judging benign and malignant ovarian epithelial tumors including MBT. It is also used to predict the treatment effects and prognosis under certain conditions [8][9][10][11] .

Pathological Origins
There are different opinions on the origin of MBT in the ovary. Some believe that it is derived from the germinal epithelium on the surface of the ovary. Others think that it is originated from the Walthard cells, the ovarian net, teratoma, or the ovarian stroma.
Walthard cell nest is formed by metaplastic transitional epithelium and trapped in the tissues adjacent to the fallopian tubes, where most Brenner tumors are located. From the perspective of embryology, most scholars believe that the ovarian MBT is derived from the surface epithelium, which is generated by the the epithelium [12][13] .
In 2003, WHO [5] classified OBT as ovarian surface epithelial-stromal tumor and Brenner cell nests can be seen in the tumor, which differentiates OBT from transitional cell carcinoma [7] . According to the immunohistochemical markers, OBTs present the characteristics of urethral epithelial differentiation, has similar immunophenotype to that of normal urethral epithelium and urethral epithelial tumor, such as CK7 and 13, and has positive expression of Gata3 and S100P [8] .

Pathological Features
The extreme rarity of the malignant Brenner tumors can be explained by the following proofs [4,[12][13] . adjacent to the endometriosis cyst were considered endometrioid tumor [14][15] .
Roma et al [9] conducted a molecular analysis on 32 cases of Brenner tumors and found that 43% (13/32) had subserous Walthard cell nests in the serosa of fallopian tubes. Kondi-Pafiti et al [14] studied 30 cases of ovarian Brenner tumors immunohistochemically and found that all cases expressed CK7,but did not express CK20,while WT-1 was focally positive in five cases. A casereported that p63 was positive in benign and borderline ovarian Brenner tumors, whereas p16 and p53 were negative in both types of tumors [13] .Malignant Brenner tumors need to be differentiated from metastatic transitional cell carcinoma, which is diagnosed based on the history of a tumor in the urinary system and the immunohistochemical markers.
Both urinary transitional cell carcinomas and ovarian malignant Brenner tumors are usually CK7 positive,but only the former is CK20 positive [15] .

Treatment and Prognosis
Surgery is still the most effective treatment, and similar to the epithelial ovarian cancer, it is advisable to perform the comprehensive staging surgery for the MBT as much as possible. The staging can be done with pelvic and abdominal lymph node dissection; however, studies have shown that it has no improvement on the survival rate , and retroperitoneal lymph node dissection is not emphasized. Malignant patients should undergo complete hysterectomy with double adnexa as well as pelvic and abdominal lymph node dissection [11][12] .
The six courses of chemotherapy with paclitaxel plus platinum might be the main chemotherapeutic approach after surgery as the curative effect could be better.
Systemic chemotherapy is required after surgery and was found to be effective for patients with local recurrence. Patients with malignant OBT confined to the ovary might have a good prognosis with a 5-year survival rate. When distant metastasis such as abdominal metastasis occurs, the opportunity of operation is lost and therefore, conservative treatment with a five-year survival rate of 51.3% would be the main treatment [13][14] .
The operative principle of malignant Brenner tumor is consistent with that of epithelial ovarian cancers, but lymphadenectomy could be of no benefit to the prognosis. The prognosis of those with extraovarian dissemination is extremely poor.
The treatment regimen of malignant OBT remains unclear due to its rarity and lack of clinical application of the corresponding scale but generally, it is similar to that of ovarian epithelial malignant tumors. The standard regimen is paclitaxel plus platinum and although most malignant OBT are sensitive to chemotherapy, the recurrence rate is still high [15][16] .In another investigation, nine out of ten cases of malignant OBT treated with the chemotherapy of paclitaxel plus platinum were completely relieved, but the recurrence rate was as high as 52% [6] .
In our case introduced above, the patient presented with extremely atypical symptoms with cervical lesions and ascites, which were once considered as "cervical tumor" before surgery. Furthermore, the patient was in poor condition with abdominal metastasis occurring before it was discovered. And due to the late stage and lack of the related experiences, the doctors had no other better option and did not make wise decisions, thus chemotherapy and radiotherapy were not so effective and so standard.This resulted in an extremely poor prognosis which is a sad lesson needs every medical practitioners to be warned.

5.Conclusion
In conclusion, although the incidence of bilateral malignant OBT is extremely low and this disease is extremely rare clinically, the gynecologists should be more informed of its diagnosis and treatment. Besides, the medical practitioners should advise the patients to have a regular physical examination, which might help in early diagnosis and treatment hence, prolonging the survival period.

Ethics approval and consent to participate
This study was approved by the program of Human Ethics Committee of the Health Administration of Henan Province(LHGJ20191494). A written informed consent was obtained from all the patients at the time of admission, with which the blood, tissue and other sample were authorized to scientific purpose.

Consent for publication
Written informed consent was obtained from the patient for the publication of this case report and any accompanying images. A copy of the written consent is available.

Availability of data and materials
The authors declare that all data and materials of the article are available to all readers of our article.