Case of the Month: Right Ovary

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2013, case 03, and is a fibrothecoma.

The histologic sections reveal a neoplastic proliferation composed of spindled to rounded cells, with ill-defined cellular borders and pale cytoplasm. They are mainly arranged in interlacing fascicles and aggregates, focally exhibiting a storiform pattern. The nuclei vary from round to spindle-shaped. Hyalinized bands and plaques are scattered throughout the tumor. Patchy areas of edema are noted. There is no evidence of significant cytologic atypia, mitotic activity, markedly increased cellularity, sex cord elements, or necrosis. Oil red-O histochemical stains performed on selected tissue sections reveal areas of cytoplasmic positivity. The microscopic findings are consistent with those of a fibrothecoma.

A spectrum of gross and microscopic features exists between fibromas and thecomas, and occasional tumors share features of both types of ovarian stromal tumors. In this context, the term fibrothecoma (thecofibromas or thecoma-fibroma) is recommended by some authors for those tumors with overlapping histological, histochemical, chromosomal, and/or immunohistochemical characteristics. However, other authors discourage the use of these terms and favor the use of more strict criteria based on histological and/or functional features to define these entities. For example, some authors recommend the use of term "fibroma" for hormonally inactive ovarian tumors of the fibroma-thecoma group, reserving the use of the term "thecoma" for hormonally active tumors.

Typical thecomas are ovarian stromal tumors mainly composed of lipid-laden cells resembling theca interna cells, associated with fibroblasts. The majority occur in postmenopausal women and they are rare before puberty. These usually endocrinologically active tumors may be associated with symptoms related to unopposed estrogen production (like abnormal uterine bleeding or endometrioid endometrial adenocarcinoma). Thecomas are unilateral in 97% of cases and typically range in size from 5.0 to 10.0 cm, but can present as very small asymptomatic tumors or as very large symptomatic tumors. Grossly, they are usually solid yellow ovarian masses with smooth or bosselated outer surfaces. The lobulated cut. surfaces can be either yellow or mainly white with only focal yellow areas and may display areas of hemorrhage, necrosis, cystic change, and/or calcification. Microscopically, thecomas are composed of sheets of round to spindle-shaped cells with ill-defined borders associated with a variable component of collagen producing fibroblasts. The cytoplasm can be pale and dense or abundant and vacuolated due to the presence of lipid. The nonatypical nuclei vary from round to spindle-shaped, although in rare tumors, degenerated “bizarre” nuclei can be identified. Some may contain a minor component of sex cord elements (granulosa cells, indifferent sex cord type cells, or sertoliform tubules). Mitotic activity is rare. Hyalinized bands and plaques are not uncommon. Reticulin stains demonstrate reticulin fibers surrounding individual thecoma cells. The differential diagnosis of typical thecomas include fibromas and (in cases with sex cord elements) granulosa cell tumors and Sertoli-stromal cell tumors.

Close to one-third of luteinized thecomas occur in patients under 30 years of age. Close to 50% of these tumors are estrogenic, and about 10% are androgenic (a higher frequency than typical thecomas). Grossly, they are similar to the typical thecomas. Microscopically, they contain luteinized cells (that can be arranged in nests, large nodules or single cells) in a fibrotic (rather than thecomatous) background. The differential diagnosis of luteinized thecomas include steroid cell tumors, stromal hyperthecosis, sclerosing stromal tumors, and pregnancy luteomas.

A rare subtype of luteinized thecomas can be associated with sclerosing peritonitis, a potentially fatal condition (the nature of which is unknown at this time). These patients are young and commonly present with abdominal swelling. These ovarian tumors are usually bilateral and range from nonpalpable small lesions to large tumors (up to 31.0 cm in diameter in one series). Upon sectioning, some of these tumors reveal variable ovarian enlargement due to cortical edema and cystic change rather than discrete tumor formation, raising the question of a hyperplastic process. Microscopic features include a dense proliferation of spindle-shaped cells mixed with luteinized cells, edema with microcyst formation and rarely nests of sex cord type cells. Although nuclear atypia is minimal, mitotic activity may be significant (up to 40 mitotic figures per 10 HPFs). The differential diagnosis of luteinized thecomas include steroid cell tumors, stromal hyperthecosis, stromal Leydig cell tumors, and (in pregnant and post-partum patients) pregnancy luteomas. The differential diagnosis of luteinized thecomas associated with sclerosing peritonitis include stromal hyperthecosis, massive ovarian edema, fibromatosis, and metastatic lobular carcinomas of the breast.

Typical fibromas account for close to 4% of all ovarian tumors and are more common in middle age women. Fibromas can occasionally be seen in association with two syndromes: Meigs syndrome and Gorlin syndrome (basal cell nevus syndrome). Meigs syndrome happens in association with 1 to 2% of ovarian fibromas and is defined as ascites and pleural effusion accompanying a fibrous ovarian tumor and disappearing after the removal of the tumor. Young patients with Gorlin syndrome have a higher than expected incidence of ovarian fibromas that tend to be bilateral, multiple, and calcified. Ascites alone is associated with 15 to 30% of ovarian fibromas >10.0 cm in diameter. Steroid production by ovarian fibromas can happen, but it is unusual. Typical fibromas are unilateral close to 90% of the time and range from nonpalpable small lesions to large tumors. Grossly they are white, with a lobulated or smooth outer surface and a solid (occasionally whorled) white or gray-white surface.

They can also exhibit edema, cystic change, and calcifications. Microscopically, they are composed of interlacing bundles of small spindle-shaped cells with ovoid nuclei occasionally arranged in a storiform pattern. Collagen deposition can take the form of bands and/or plaques. Cellular atypia and increased mitotic activity are usually absent. Occasionally lipid accumulation and/or eosinophilic hyaline globules can be observed in the cytoplasm of some cells. A minor component of sex cord elements can also be seen. The differential diagnosis of typical ovarian fibromas include thecomas, cellular fibromas, sclerosing stromal tumors, massive ovarian edema, and ovarian fibromatosis.

Fibromas are variably cellular, but in 10% of cases, the markedly increased cellularity warrants the diagnosis of cellular fibromas. These tumors tend to be larger and softer than the typical fibromas and, upon sectioning, the solid cut surfaces may reveal areas of necrosis and hemorrhage. Microscopically, the tumors are densely cellular, and the spindle-shaped cells have ill-defined cytoplasmic borders, round to oval hyperchromatic nuclei, and are arranged in patterns similar to those of typical fibromas. Nuclei can be mildly or moderately atypical and between one and three mitotic figures per 10 HPF are usually present. The term mitotically active cellular fibroma is recommended for any cellular fibroma with more than 4 mitoses per 10 HPF. In this setting, the absence of severe cellular atypia and abnormal mitotic figures should assist in the exclusion of fibrosarcoma.

The use of ancillary studies to distinguish between fibromas and thecomas is limited. Both tumors can be variably immunopositive for calretinin, alpha-inhibin, vimentin, SMA, MSA, CD34, CD56, WT-1, SF-1, ER, and PR and immunonegative for desmin and CD99. A study by Oliva et al observed mostly minimal and weak CD10 immunopositivity in 70% of the thecomas they studied, while all fibromas were immunonegative for this marker. One can assume that, at this time, immunohistochemistry may not assist in the unequivocal characterization of these tumors. Intracellular lipid can also be identified in both types of tumors, although it is more diffuse in thecomas and only focal in fibromas. Thecomas, fibrothecomas and fibromas can be aneuploid, with trisomy 12 being the most common chromosomal abnormality.

Several ovarian lesions are in the differential diagnosis of typical thecomas and fibromas as well as their variants. Here are some important features associated with these lesions that should assist in the evaluation of the fibroma-thecoma group of tumors:

• Typical steroid cell tumors have clinical and pathological features that are different from those of a typical luteinized thecoma, so differentiating between these tumors should not be a problem. However, a diagnosis of steroid cell tumor is favored when <10% of a tumor consists of a fibromatous or thecomatous component.
• Stromal hyperthecosis is an ovarian process characterized by clusters of luteinized cells scattered throughout hyperplastic ovarian stroma. Both ovaries are usually involved. When the stromal hyperplasia is prominent, the affected ovaries are enlarged, and display homogeneous yellow-white or tan cut surfaces. Androgenic or estrogenic clinical manifestations are not uncommon.
• Stromal Leydig cell tumors are histologically similar to luteinized thecomas, but the luteinized cells contain crystals of Reinke. Half of these tumors are virilizing.
• Pregnancy luteomas are characterized by single or multiple nodular hyperplastic proliferations of luteinized theca or granulosa cells that range in size from microscopic to up to 20.0 cm. Grossly, the cut surfaces are soft, yellow-brown, and well circumscribed. They can also be hemorrhagic. Histological features include large luteinized cells with eosinophilic cytoplasm and (in some cases) eosinophilic globules (similar to the ones usually seen in the corpus luteum of pregnancy). Mitotic figures, degenerative changes, and focal nuclear pleomorphism can also be observed. The stroma is not prominent. These benign proliferations tend to involute within weeks of delivery.
• Cases of massive ovarian edema are usually unilateral and are more common on the right side. The patients range in age from 6 to 37 years and clinically may present with nonspecific symptoms of a pelvic mass, including abdominal or pelvic pain. The involved ovary is usually enlarged (average 11.5 cm in diameter) and soft, and the cut surfaces are gelatinous and glistening, and commonly exude watery fluid. The adjacent fallopian tube may also be edematous. Microscopic evaluation reveals extensive stromal edema surrounding the normal ovarian components as well as vascular ectasia. The peripheral cortex is usually not edematous. Close to 40% of the cases have clusters of luteinized stromal cells and may present clinically with endocrine manifestations. This process is believed to be the result of intermittent ovarian torsion.
• Ovarian fibromatosis consists of a fibromatous proliferation that can extensively involve the ovary and is unilateral in close to 80% of cases. The patients range in age from 13 to 39 years and clinically may present with nonspecific symptoms of a pelvic mass, including abdominal or pelvic pain, or with endocrine manifestations. The involved ovary ranges in size from 8.0 to 14.0 cm and is white with smooth or lobulated outer surfaces. The cut surfaces are firm, white or gray, and may display small cysts. Microscopically, there is a proliferation of spindle-shaped stromal cells variably associated with collagen deposition that surrounds the normal ovarian components. Other findings include luteinized stromal cells, areas of edema, and (rarely) sex cord type cells. The proliferation can be diffuse or localized; for example it may be confined to the ovarian cortex in some cases.
• Sclerosing stromal tumors are rare benign and usually unilateral tumors that tend to occur in women under 30 years of age. Rarely, they can be hormonally active. Grossly, they are solid well-circumscribed white tumors that vary in size, but average 10.0 cm in greatest dimension. They have white or white yellow solid cut surfaces that may reveal edema and cyst formation. Microscopic features include lobules or pseudolobules separated by variably cellular (and mostly edematous) fibrous tissue. The lobules/pseudolobules can be variably sclerosed, are usually vascular, and contain two cell types: spindle shaped fibroblasts and round or oval lipid-laden (mostly vacuolated) cells. These vacuolated cells can occasionally display a “signet ring” appearance. Myxoid change can also be observed.

Ovarian fibromas and thecomas are usually treated by surgical excision. Rarely, fibromas may be associated with benign peritoneal implants, a finding that should not be misinterpreted as "malignant behavior." Cellular fibromas confined to the ovary can be treated by unilateral salpingo-oophorectomy. However, close follow up is necessary for cellular fibromas that are incompletely removed, or associated with adhesions or rupture, as they may locally recur.

1. Which lesion can occasionally be seen in association with Meigs syndrome and Gorlin syndrome (basal cell nevus syndrome)?
   
   1. Ovarian fibroma
   2. Ovarian sclerosing stromal tumor
   3. Ovarian steroid cell tumor
   4. Ovarian thecoma
   5. Pregnancy luteoma
2. Which lesion tends to occur in postmenopausal women and is rare before puberty?
   
   1. Massive ovarian edema
   2. Ovarian fibromatosis
   3. Ovarian sclerosing stromal tumor
   4. Ovarian thecoma
   5. Pregnancy luteoma
3. Which of the following tumors is associated with sclerosing peritonitis, a potentially fatal condition?
   
   1. Ovarian fibroma
   2. Ovarian sclerosing stromal tumor
   3. Ovarian steroid cell tumor
   4. Ovarian stromal Leydig cell tumor
   5. Ovarian luteinized thecoma

1. He H, Luthringer DJ, Hui P, Lau SK, Weiss LM, Chu PG. Expression of CD56 and WT1 in ovarian stroma and ovarian stromal tumors. Am J Surg Pathol. 2008;32(6):884-890.
2. Kurman RJ, Ellenson LH, Ronnett BM. Sex cord-stromal, steroid cell, and other ovarian tumors with endocrine, paraendocrine, and paraneoplastic manifestations. In: Blaustein's Pathology of the Female Genital Tract. 6th ed. New York, NY: Springer; 2011:805-812.
3. Micci F, Haugom L, Abeler VM, Tropé CG, Danielsen HE, Heim S. Consistent numerical chromosome aberrations in thecofibromas of the ovary. Virchows Arch. 2008;452(3):269-276.
4. Nocito AL, Sarancone S, Bacchi C, Tellez T. Ovarian thecoma: clinicopathological analysis of 50 cases. Ann Diagn Pathol. 2008;12(1):12-16.
5. Oliva E, Garcia-Miralles N, Vu Q, Young RH. CD10 expression in pure stromal and sex cord-stromal tumors of the ovary: an immunohistochemical analysis of 101 cases. Int J Gynecol Pathol. 2007;26(4):359-367.
6. Prat J. Sex-cord stromal tumors. In: Pathology of the Ovary. Philadelphia, PA: Saunders; 2004:208-217.
7. Scully, RE, Young, RH, Clement, PB. Tumors of the Ovary, Maldeveloped Gonads, Fallopian Tube, and Broad Ligament. Atlas of Tumor Pathology. Third Series, Fascicle 23.Washington, DC: Armed Forces Institute of Pathology; 1998:189-202,399-450.
8. Zhao C, Vinh TN, McManus K, Dabbs D, Barner R, Vang R. Identification of the most sensitive and robust immunohistochemical markers in different categories of ovarian sex cord-stromal tumors. Am J Surg Pathol. 2009;33(3):354-366.

2014
Nilsa C. Ramirez, MD
Surgical Pathology Committee
Nationwide Children's Hospital
Columbus, OH

1. Ovarian fibroma (a). 
2. Ovarian thecoma (d). 
3. Ovarian luteinized thecoma (e).