Brenner tumors

Abstract

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.

Introduction

Brenner tumors (BTs) are rare ovarian neoplasms, representing 2–3% of ovarian tumors.¹

They are the most common subtype of ovarian urothelial-type tumors and usually occur in older patients. The majority of BT arise in adults in the fifth to seventh decade of life, although they may occur in patients aged under 30 years or over 80 years.^2,3

Based on the classification of female genital tumors by the World Health Organization (WHO), BT can be benign, borderline or malignant, based on proliferation and invasiveness.³

Benign Brenner tumors (BBT), which represent about 95% of cases, are often incidental findings in asymptomatic females, as they usually present as small neoplasms.

Borderline and malignant tumors correspond to 5 and 1% of patients with BT, respectively, and tend to be symptomatic more frequently, due to their bigger dimensions.⁴

The most common clinical presentation of borderline or malignant BT is the presence of an abdominal mass, abdominal pain and post-menopausal bleeding. Other symptoms, such as nausea, vomiting, back pain, bowel obstruction, tumor-induced anorexia and weight loss have been seldomly described.⁵ Abdominal symptoms can be explained by mass effect on the adjacent tissues in neoplasm with bigger dimensions. Borderline and malignant BT are usually not functional. However, the presence of post-menopausal bleeding may indicate hormone-secreting elements.⁶

BT are frequently identified incidentally following resection of other tumors, since as many as 30% present as combined neoplasms.^1,7

This article outlines the spectrum of imaging features of BT on different imaging techniques, emphasizing the main differential diagnoses, as well as their pathological characteristics.

Radiological findings

Ultrasound

First-line imaging method for evaluation of ovarian tumors. Demonstrates a small, solid tumor, with variable echogenicity and minimal blood flow on Color Doppler examination (Figure 1). It can also present as a multilocular cystic mass with solid component when there is association with other ovarian neoplasms (Figure 2). Most masses have calcifications.⁸

Figure 1.

Solid Brenner tumor of the right ovary. Transvaginal ultrasound images show solid, hypoechoic ovarian tumor, with multiple milimetric calcifications (arrow), representing a benign Brenner tumor.

Figure 2.

Benign mixed Brenner tumor and mucinous cystadenoma of the right ovary. (a) Transvaginal ultrasound images show mixed cystic and solid components, with calcifications in the solid portion (arrow); (b) Macroscopic evaluation revealed an ovary partially replaced by a solid and cystic tumor.

Computed tomography

Not the ideal imaging technique for the characterization of ovarian masses. Most ovarian neoplasms are detected as incidental findings on CT. BT presents as a dense, solid or as multilocular cystic mass with heterogeneous enhancement. CT is the best method for demonstrating calcifications (Figure 3).¹

Figure 3.

Benign mixed Brenner tumor and mucinous cystadenoma of the left ovary. (a) CT axial image shows mixed cystic (arrow head) and solid neoplasm, with milimetric calcifications (arrow), in which the solid part represents the Brenner tumor component; (b) CT coronal image better depicts the calcifications present in the solid component (arrow).

Magnetic resonance (MR)

Gold-standard for the characterization of ovarian tumors. Due to their fibrous content, BT exhibit low signal intensity on T₂ weighted images (WI) and patchy enhancement on gadolinium-enhanced T₁WI with fat saturation (FAT SAT) (Figure 4).

Figure 4.

Solid Brenner tumor of the left ovary. (a) Axial T₂WI shows a solid, hypointense left ovarian tumor (arrow); (b) Sagittal T₂WI depicts a solid, hypointense tumor (arrow); (c) Tumor exhibits heterogeneous enhancement on T₁WI FATSAT after contrast images (arrow); (d) The neoplasm presents a Type 2 curve, typical of benign tumors; (e) Patient underwent left oophorectomy. The ovary is almost entirely replaced by a pale yellow tumor, firm in consistency, with 30 mm in the long axis. FATSAT, fat saturation; WI, weighted image.

If associated with other tumors, BT can be identified in mostly cystic lesions, like mucinous cystadenomas, in which case imaging demonstrates a lesion with both cystic (high signal intensity on T₂WI) and solid (low signal intensity on T₂WI) components, the latter representing the Brenner component.^1,9

Benign vs malignant

The vast majority of BT are benign. Borderline and malignant BT are more frequent in the post-menopausal period.⁴

Differentiating benign from malignant forms is relevant for prognosis, but remains challenging, since their radiological appearance is similar. This diagnosis is ultimately histopathological.

Benign BT exhibit homogenous low signal intensity in T₂WI, reflecting their abundant fibrous content, which represents the hallmark of Brenner component. On gadolinium-enhanced T₁WI with FAT SAT they show patchy enhancement (Figure 4). They can also present as a multilocular cystic mass, mainly when seen in association with other ovarian neoplasms neoplasms. The most commonly associated neoplasm is mucinous adenoma¹ (Figure 3).

There are few reports of the imaging features of borderline (Figure 5) and malignant (Figure 6) BT. They typically arise from benign forms and tend to present as larger neoplasms. Its most described aspect is of a large cystic mass with a mural papillary projection into its lumen. The papillary projection shows relatively low signal intensity on T₂WI, but higher than signal intensity for muscle, and rapid and persistent enhancement in dynamic contrast-enhanced T₁WI with FAT SAT.¹⁰ There is an overlap in the appearance of borderline and malignant BTs and other malignant ovarian neoplasms. The distinction is based on histopathology.

Figure 5.

Borderline Brenner tumor of the right ovary. (a) Axial T₂WI shows a solid, hypointense right ovarian tumor (arrow). (b,c) The neoplasm does not exhibit restriction to diffusion. Histopathological analysis revealed a Borderline Brenner tumor. WI, weighted image.

Figure 6.

Malignant Brenner tumor of the left ovary. (a) Axial T₂WI shows a solid, hypointense, heterogeneous, left ovarian tumor (arrow). (b) Coronal T₂WI depicts a markedly hypointense central area, surrounded by a less hypointense component. (c) Tumor exhibits heterogeneous enhancement on T₁WI FATSAT post-contrast images (arrow). Histopathological analysis revealed a Malignant Brenner tumor. FATSAT, fat saturation; WI, weighted image.

Although imaging does not allow confident differentiation between benign and borderline/malignant forms, it is thought that there may be a difference in the signal intensity of the solid component in T₂WI, which may be related to less intervening fibrous stroma in the latter, leading to higher intensity on T₂WI.^10–12

The main imaging features of benign and borderline/malignant BT as well as its main differential diagnosis are summarized on Table 1.

Table 1.

Main imaging features of Brenner tumors, as well as its differential diagnosis

Imaging features on MRI
Benign Brenner tumor	Borderline/Malignant Brenner tumor	Fibroma or thecoma	Pedunculated leiomyoma	Cystadenofibroma
Imaging features are overlapping and the final diagnosis is based on histopathology.		Well-delineated neoplasms with low signal intensity on T2 WI Calcifications are uncommon Thecomas may secret estrogens, leading to endometrial thickening Association with ascites or pleural effusion - Meigs syndrome	Adjacent to the uterus, in continuity with it by means of a stalk Homogeneous hypointensity on T2WI and isointensity on T1WI compared with myometrium May exhibit calcifications	Differential diagnosis of the cystic form of Brenner tumors. Multilocular cystic mass, with a solid component with hypointensity on T2WI, sometimes containing small cystic locules Multilocular cystic mass with diffuse or partial thickening of the cyst wall, with hypointensity on T2WI
Small (<2 cm) Solid, well-circumscribed masses Homogenous low signal intensity in T2WI Patchy enhancement Calcifications may be present Association with other ovarian neoplasm: most commonly mucinous cystadenoma.	Usually larger (medium size of 12 cm) Cystic nature and papillary luminal projections, with relatively low signal intensity on T2WI (higher than muscle) and rapid and persistent enhancement in dynamic contrast-enhanced T1WI with FAT SAT Completely solid tumors are less frequent Calcifications may be present

FATSAT, fat saturation; WI, weighted image.

Pathogenesis and histological characteristics

The pathogenesis of BT is not completely understood. BT show transitional-type differentiation, typically seen in bladder and ureters. They are believed to originate in sites of transitional cell metaplasia within the paratubal tissue, also known as Walthard cell nests. These are more likely present in females with BT or other ovarian neoplasm than in controls.¹³

The rare cases of BT associated with teratoma are thought to originate from germ cells.

Benign Brenner tumors

Most neoplasms are small (<2 cm) and only rarely exceed 10 cm in diameter. They are solid, well-circumscribed masses, with a firm rubbery consistency. The cut surface is grayish-white or yellow and may be calcified (Figure 4). Small cysts are common and, less frequently, the tumor can be predominantly cystic (Figure 2).^3,4

Association with other tumors, most commonly cystadenoma, is frequent.^1,7

These tumors are typically composed of a dense fibromatous stroma with small, oval to irregular nests of bland transitional/urothelial epithelium, which often show microcystic spaces containing eosinophilic or mucinous material (Figure 7). This lumina may be lined by transitional, mucinous, ciliated or cuboidal cells.^3,4

Figure 7.

Brenner tumor (a) low power view of a dense ovarian tumor with dispersed nest of epithelial cells. (b) Small nests of bland urothelial type of epithelium with focal lumina (arrow); (c) dense fibromatous stroma with bland tumor nest; (d) nuclear grooving in some cells ”coffee beans” (arrows).

Focal or extensive calcification is frequent and the stroma can be hyalinized.

Myc amplification has been reported as a mutation associated with these tumors. They usually express GATA3, CK7, p63, S100P, AR, uroplakin, and thrombomodulin.

BBT typically exhibit low mitotic activity and there should not be significant epithelial atypia.³

Borderline Brenner tumor

Typically large tumors (medium size of 12 cm) with cystic nature and papillary luminal projections. Solid areas often reflect a benign Brenner component. Less frequently, may present as completely solid tumors.

They correspond to tumors of transitional/urothelial epithelium, displaying papillary architecture, with no stromal invasion.³

The disease-specific mutations are not known, but alterations in CDKN2A, resulting in loss of p16, have been reported.

Immunohistochemistry is usually positive for p63 and GATA3.³

Cytologically, tumors resemble low-grade papillary urothelial neoplasms of the urothelial tract. In most cases, the cells are uniform and show elongated nuclei with fine chromatin and visible nucleoli; occasionally, moderate to severe atypia is seen, as well as mucinous or squamous metaplasia.

Although there is increased mitotic activity and/or cytological atypia in these lesions, there should be no evidence of stromal invasion.^3,6

Malignant Brenner tumor

Although known to arise from benign and borderline BTs, key molecular alterations and the exact pathway to their development have not been elucidated.

They correspond to an ovarian carcinoma resembling an invasive urothelial carcinoma, associated with benign or borderline BBT component. They are defined by the presence of stromal invasion, represented by infiltrative nests with a desmoplastic stromal response.^3,6

Its macroscopic appearance is similar to BBTs, presenting as large, cystic masses with luminal papillary projections.³

Immunohistochemistry is usually positive for p63 and GATA3.³

They are composed of irregularly shaped masses of atypical transitional/urothelial-type cells, which may have focal squamous differentiation. Cystic areas within the tumor are lined by multilayered epithelium, resembling invasive urothelial carcinoma with hyperchromatic pleomorphic nuclei, variably prominent nucleoli, dense eosinophilic cytoplasm, and prominent mitotic activity. Mucinous glandular elements and mucinous adenocarcinoma may coexist within the Brenner components.^3,6

The absence of a benign or a borderline Brenner component should raise the possibility of high grade serous or endometrioid carcinoma with transitional cell-like differentiation.³

Differential diagnosis

Ovarian fibroma or thecoma

The main differential diagnosis to consider in cases of solid BT is ovarian fibroma or thecoma, which are included in the category of sex-cord stromal tumors of the ovary. They present as well-delineated, fibrous neoplasms with low signal intensity on T₂WI, no diffusion restriction, and poor blood supply. Calcifications are uncommon.^1,7

Thecomas may secret estrogens, leading to endometrial thickening.^1,14

There is a common association between stromal tumors of the ovary and ascites or pleural effusion, denominated Meigs syndrome (Figure 8).¹⁵

Figure 8.

Meigs Syndrome – Ovarian fibroma and ascites. (a) Axial T₂WI shows an ovarian neoplasm that is hypointense (arrow), as well as mild ascites (arrow head); (b) The tumor exhibits hypointensity on T₁WI (c) and (d) The ovarian tumor shows no diffusion restriction.

Pedunculated leiomyoma

May mimic an ovarian neoplasm, since the mass is adjacent to the uterus, in continuity with it by means of a stalk. It is characterized by homogeneous hypointensity on T₂WI and isointensity on T₁WI compared with the myometrium (Figure 9). CT scans show a relatively hypodense mass, that may exhibit calcifications (Figure 10).^15,16

Figure 9.

Pedunculated leiomyoma. (a) Axial T₂WI shows a solid, hypointense tumor (arrow); (b) Sagittal T₂WI depicts that the tumor (arrow) is connected to the uterus by a stalk (arrow head). WI, weighted image.

Figure 10.

Pedunculated leiomyoma. (a) CT axial image shows an hypodense, solid right ovarian neoplasm, with calcifications (arrow); (b) The tumor is connected to the uterus by means of a stalk (arrow head).

The presence of the “bridging vessel” sign, which refers to the appearance of vessels coursing from the uterus into an adjoining pelvic mass, suggests that the tumor originates from the uterus.¹⁶

Cystadenofibroma

Regarding the cystic form of BTs, the differential diagnosis is mainly cystadenofibroma, an uncommon subtype of surface epithelial tumor of the ovary that contains fibrous stroma.¹⁵

The most frequent form is the benign variant, that presents as a multilocular cystic mass, with a solid component with hypointensity on T₂WI, sometimes containing small cystic locules. It may also correspond to multilocular cystic mass with diffuse or partial thickening of the cyst wall (Figure 11).¹⁷

Figure 11.

Cystadenofibroma of the left ovary. (a) Sagittal T₂WI shows a cystic, multilocular, neoplasm (arrow), with an area of mixed low signal intensity with small cystic locules (arrow head). (b) Axial T₂WI better depicts the solid area of mixed low signal intensity. (c, d) The tumor shows no diffusion restriction on b1000 images. WI, weighted image.

Conclusion

BTs are rare ovarian neoplasms whose imaging features are non-specific. The great majority of BTs are benign, but their borderline and malignant forms should also be considered.

Ovarian fibroma and thecoma, pedunculated leiomyoma and cystadenofibroma represent the main differential diagnosis.

Due to the overlap of imaging characteristics, the diagnosis is ultimately based on histopathology.