Points to Remember in Ovarian Eponyms Pearls: Dr. Fritz Malignant Brenner Tumor

Dear Editor,

Malignant Brenner tumor (MBT) of the ovary is a rare and uncommon ovarian neoplasm that consists of both epithelial and stromal cells.[1] While benign Brenner tumors are quite common, accounting for 1%–2% of all ovarian tumors, their malignant counterpart is extremely rare, accounting for <2% of ovarian epithelial malignancies.[1,2] This tumor was first described by Dr. Firtz Brenner in 1907 article named “Oophoroma Folliculare.” Robert Meyer popularized this tumor, citing its relationship with pseudo-mucinous cysts, lack of endocrine function, and possible derivation from “Walthard’s cell” resting.[1] The Brenner tumor is the only ovarian tumor without a pathological designation other than eponymic.[1,2]

MBTs are often derived from benign Brenner tumors but have malignant characteristics such as invasion, atypia, and metastases.[3] The pathophysiology of MBT remains unknown, and the tumor’s clinical behavior is frequently unpredictable. These tumors are most typically identified in postmenopausal women, but they can also affect younger women.[2,3]

This case study features a 34-year-old female patient who was admitted to the general surgery outpatient department with complaints of dull aching pain in the lower abdomen radiating toward the lower back for 5 months. Following a contrast-enhanced magnetic resonance imaging pelvis, a multiloculated solid cystic lesion in bilateral adnexa encircling the uterus was identified, measuring 11.9 cm × 11.2 cm × 11.3 cm and 5.2 cm × 4.6 cm × 4.1 cm in left and right adnexa, respectively. On investigation, CA-125 level was 800 U/mL (normal range (NR) 0–35 U/mL), carcinoembryonic antigen 0.50 ng/mL (NR 0–2.5 ng/mL for nonsmokers and 0–5 ng/mL for smokers), CA 19.9 was 13.69 U/mL (NR 0–37 U/mL). Hence, she underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy (BSO) with infracolic omentectomy, glissonectomy, peritonectomy, and pelvic lymph node dissection. Histopathological examination and immunohistochemistry showed the features of malignant Brenner’s tumor [Figure 1] with pathological stage of pT3a N0 M1b and the International Federation of Gynecology and Obstetrics Stage IV. The patient was having metastatic deposits on the right and left fallopian tube, pelvic peritoneum, the liver, small and large bowel, the pouch of Douglas, Gerota’s fascia, falciform ligament, and the omentum. The peritoneal wash sent for cytopathological examination was negative for malignancy. A total of 42 lymph nodes were dissected, and all were free of tumor. The rest postoperative period was uneventful, and the patient was discharged in the stable and ambulatory condition with the follow-up advice. At present, the patient is doing well and on regular follow-up and advised six cycles of chemotherapy with paclitaxel-carboplatin/paclitaxel-cisplatin.

Figure 1.

(a) Gross photomicrograph shows larger (>10 cm) grayish white fleshy, polypoid left ovarian mass, (b) Hematoxylin and eosin (H and E) stained section shows that a tumor is composed of irregularly nests and sheets of cytologically atypical transitional/urothelial-type cells, resembles invasive urothelial carcinoma (H and E; ×40), (c) Higher magnification shows hyperchromatic pleomorphic nuclei, variably prominent nucleoli, dense eosinophilic cytoplasm, and prominent mitotic activity (H and E, ×400), (d) Tumor cells diffusely immunopositive for pan cytokeratin (×100), (e) Tumor cells displaying focal estrogen receptor positivity (×100), (f) Tumor cells focally positive for vimentin (×200), (g) Tumor cells immunonegative for Wilms’ tumor gene 1 (WT-1; ×100)

The clinical presentation of MBT is often nonspecific, with symptoms such as abdominal distension, pelvic pain, or abdominal bulk. Consequently, the diagnosis is frequently established at an advanced stage when surgical intervention is necessary.[2,3] On imaging studies, MBTs are often indistinguishable from surface epithelial ovarian tumors, complicating preoperative assessment.[4] Histopathological testing reveals characteristic transitional epithelium and a thick, stringy stroma, exhibiting features of mild atypia, mitotic activity, and stromal invasion.[3,4] For malignant Brenner tumors, surgical resection remains the primary treatment; chemotherapy may be considered if the tumor has progressed or recurred. However, due to the rarity of MBT, little is known about the optimal treatment approach and long-term prognosis. Prognoses for patients with malignant Brenner tumors vary based on histological grade, treatment response, and disease stage at diagnosis[5,6] [Table 1].

Table 1.

Difference between benign, borderline, and malignant Brenner tumor[6]

Criteria	Benign Brenner tumor	Borderline Brenner tumor	MBT
Essential histopathology	Nests of bland transitional/urothelial epithelium embedded in a thick fibromatous stroma	Transitional/urothelial epithelial tumor that has papillary architecture but no stromal invasion	Resembles invasive urothelial carcinoma and is often accompanied with benign or borderline Brenner tumor
Clinical feature	<30 years or >80 years Usually unilateral; however, they might be bilateral on occasion	>50 years old Unilateral and limited to the ovary	>50 years old Typically, unilateral (more than 80% of the time) but can also be bilateral
Pathogenesis	Walthard nests MYC amplification	CDKN2A KRAS and PIK3CA	PIK3CA mutations and MDM2 amplification
Gross findings	Typically, tiny (<2 cm) and seldom larger than 10 cm	Often large (median size: 12 cm) and cystic	Median size of 10 cm They may be solid or cystic, with mural nodules
Prognosis	No recurrence or disease advancement	Often benign; local recurrence is uncommon	Stage I tumours have a disease-specific 5-year survival rate of 94.5% However, 51.3% in patients with extraovarian dissemination (stages II, III, IV)

MYC: Myelocytomatosis oncogene, CDKN2A: Cyclin-dependent kinase inhibitor 2A, KRAS: Kirsten rat sarcoma viral oncogene homolog, PIK3CA: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, MDM2: Mouse double minute 2, MBT: Malignant Brenner tumor

As per the largest systematic review done by Koufopoulos et al.,[1] complete surgical resection (hysterectomy + BSO + omentectomy + lymph node dissection) is advised in stages I to III, as surgical management continues to be the mainstay of MBT treatment. Stage IIIb/IV patients were primarily considered for neoadjuvant chemotherapy (paclitaxel-carboplatin/paclitaxel-cisplatin/melphalan) along with radiotherapy. Adjuvant chemotherapy should be recommended if there is the proof of lymph node involvement, metastasis, or peritoneal spread.[1,3] The management of MBT lacks a standardized approach, although due to the small number of cases. Like other ovarian carcinomas, platinum-based chemotherapy is typically used in cases with advanced disease or recurrence. There is not enough evidence to support radiation therapy as a standard component of treatment for MBT, and its role in the treatment is debatable.[3,4] When the tumor is limited to the ovary, the prognosis is usually better, and the outcome is more favorable. The prognosis is typically worse for patients with recurrent tumors, poor differentiation, or advanced disease. The variation in clinical results, as with many uncommon ovarian cancers, emphasizes the significance of customized treatment regimens and careful monitoring.[2,5]

The prognosis for MBT patients depends on several variables, such as the disease’s stage at diagnosis, the extent of malignancy, and the patient’s reaction to treatment. Stage I MBT usually has a good prognosis with complete surgical resection, but advanced-stage tumors with peritoneal spread or high-grade features have a worse prognosis. As per the current available literature, the disease-specific 5-year survival rate for patients with stage I tumors is 94.5%, whereas the disease-specific 5-year survival rate for patients with extraovarian dissemination (stages II, III, and IV) is 51.3%.[2,4] However, due to the rarity of MBT and the lack of extensive research, it is difficult to determine the definitive prognostic factors or survival statistics.[1,4]

Given the paucity of clinical experience with MBT, more investigation is required to clarify the molecular and genetic foundations of this uncommon tumor and to improve treatment strategies for afflicted individuals. An overview of the clinical, pathological, and therapeutic aspects of malignant Brenner tumors is given in this introduction, with a focus on the need for improved diagnostic tools and greater awareness in the management of this rare ovarian cancer.

Ethics statement

This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki and its amendments. The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Author contributions

Conceptualization, AK, RT, and RHP; Conceptualization, RHP; Validation, AK and RT; Formal analysis, writing original draft preparation, AK, RT and RHP; Writing-review and editing, AK, RT and RHP; Supervision, RHP. All authors have read and agreed to the final version of the manuscript.

Data availability statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.