College of American Pathologists
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2009 — November Case of the Month

Updated October 28, 2009


CAP Foundation November 2009 Online Case of the Month

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A 48-year-old G1P1 woman presented with uterine bleeding and pelvic pain. On pelvic examination uterine nodules were noted. The patient underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy. A 250.0 gm uterus with attached l fallopian tubes and ovaries was received. The myometrium contained numerous leiomyomata and the left ovary had a protruding 2.0 cm well circumscribed, white, firm nodule.

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2006, Case 29 and is a Brenner tumor.

Criteria for Diagnosis and Comments: Ovarian tumors with transitional or urothelial-like epithelium are uncommon, accounting for only 1%-2% of all ovarian tumors and representing approximately 4% to 5% of benign ovarian tumors within the surface epithelial - stromal category. The Brenner tumor is the most common type of transitional cell tumor of the ovary, accounting for just over 90% within this category.

Brenner tumors are usually diagnosed in women between the ages of 40 to 60. The tumors are typically small with over 50% being less than 2 cm in diameter (only about 10% of Brenner tumors are greater than 10 cm in diameter). Most Brenner tumors are incidental findings with approximately 25% being found in association with another type of tumor, most commonly a mucinous cystadenoma. Occasionally Brenner tumors have been documented as hormone secreting and, if so, are more commonly associated with estrogenic rather than androgenic manifestations. The vast majority of Brenner tumors are well circumscribed and unilateral (the rate of bilateral occurrence is 5 to 7% in large study series). Gross examination typically reveals a well circumscribed, firm to rubbery mass that may occasionally have a bosselated surface. The cut surface is usually white to light yellow and may be gritty due to calcification. Variably sized cystic areas are occasionally noted within the tumor.

Histologically, the Brenner tumor of the ovary is a biphasic tumor composed largely of a fibrous stromal component surrounding smaller islands of urothelial-like epithelium, qualifying as an adenofibroma. The urothelial-like epithelium, which typically grows in trabeculae or solid nests, is composed of bland cells that have pale eosinophilic cytoplasm and oval nuclei with a central longitudinal groove (often described as a "coffee bean" nuclear appearance). Within the solid nests of this urothelial-like epithelium, cystic cavities may be present and lined by a variety of mullerian type epithelium such as endocervical mucous cells, pseudostratified ciliated-serous, indifferent glandular cells or squamous epithelium. The stroma may be quite cellular with thecomatous features (lipid-rich cytoplasm) or, more commonly, resembling the appearance of an ovarian fibroma with dense whirling collagen bundles. Areas of hyalinization and spiculated calcification may also occur. Immunohistochemical findings are not particularly useful for diagnostic purposes. Argyrophilic cells which stain for chromogranin A, neuron specific enolase and serotonin have been described in about one third of cases. Immunohistochemical staining patterns of the benign Brenner tumor show urothelial differentiation. Uroplakin III stain is reported to be positive, as are the classical urothelial markers cytokeratin 20, and thrombomodulin.

The characteristic appearance of the Brenner tumor rarely poses a diagnostic challenge. Some of the neoplasms that it may be confused with include:
1) endometrioid adenofibroma;
2) adult granulosa cell tumor, insular pattern;
3) mucinous cystic tumors,
4) carcinoid tumor and rarely
5) metastatic carcinoma.
The presence of mucinous and transitional or urothelial-like epithelium, the latter with its characteristic nuclear grooves distinguish the Brenner tumor from endometrioid adenofibroma, which is characterized by glands lined with stratified epithelium that may contain squamous morules. The grooved, but slightly cleaved, oval nucleus of the cells, positive inhibin staining and other typical histologic features of granulosa cell tumor architecture aid in correctly identifying this tumor. Occasionally Brenner tumors may possess a cystic lumen with eosinophilic secretion that may mimic vaguely a Call-Exner body but such structures are rare. Mucinous tumors are problematic when the Brenner tumor contains prominent cysts. Mucinous tumors however lack the urothelial-like epithelium readily identified within the solid component of the epithelial islands. Insular carcinoid tumors may be associated with fibromatous stroma and mimic a Brenner tumor; however, the characteristic nuclear features of a carcinoid tumor with its coarse, stippled chromatin help in its recognition. Positive immunoperoxidase staining for chromogranin may be useful in difficult cases. Metastatic carcinoma may have a passing resemblance to the nests of cells in Brenner tumor, but metastases would show significant cytologic atypia and mitotic activity.

Supplementary Questions For each of the following, select the most likely diagnosis from the diagnostic set (an answer may be used once, more than once, or not at all).

Question Diagnostic Set
Which entity is characterized by bland, stratified, typically non-mucin containing glands in a fibromatous stroma that may be associated with squamous morules? A. Brenner tumor
B. Endometrioid adenofibroma
C. Granulosa cell tumor
D. Mucinous cystadenoma
E. Metastatic carcinoma
Which entity may have solid nests of epithelial cells that stain positively for uroplakin III, cystic cavities containing eosinophilic secretions and a fibromatous stroma? A. Brenner tumor
B. Endometrioid adenofibroma
C. Granulosa cell tumor
D. Mucinous cystadenoma
E. Metastatic carcinoma
Which entity is frequently found in association with a Brenner tumor? A. Brenner tumor
B. Endometrioid adenofibroma
C. Granulosa cell tumor
D. Mucinous cystadenoma
E. Metastatic carcinoma


  1. Fox H, Wells M. Haines and Taylor Obstetrical and Gynaecological Pathology. 5th ed. London, England: Churchill Livingstone; 2003:716-717,727-728,732-733.
  2. Kaku T, Ogawa S, Kawano Y, et al: Histologic classification of ovarian cancer. Med Electron Microsc. 2003;36:9-17.
  3. Logani S, Oliva E, Amin M, et al. Immunoprofile of ovarian tumors with putative transitional cell (urothelial) differentiation using novel urothelial markers-histogenesis and diagnostic implications. Am J Surg Pathol. 2003;27:1434-1441.
  4. Reidel I, Czernobilsky B, Lifschitz-Mercer B, et al. Brenner tumors but not transitional cell carcinomas of the ovary show urothelial differentiation: immunohistochemical staining of urothelial markers, including cytokeratins and uroplakins. Virchows Arch. 2001;438:181-191.
  5. Steinberg SS, Antonioli DA, Carter D, et al. Diagnostic Surgical Pathology. 3rd ed. Philadelphia, Pa: Lippincott Williams and Wilkins; 1999:2339.

Mary S. Richardson, MD, DDS
Surgical Pathology Committee
Medical University of South Carolina
Charleston, SC