Sex Cord-Stromal Tumors of the Ovary

Clinical Features

Fibromas may occur at any age but are seen most commonly in middle-aged women, with an average age at presentation in the fifth decade. They are uncommon in women <30 years, except for patients with Gorlin syndrome (nevoid basal cell carcinoma syndrome), an autosomal-dominant disorder characterized by congenital abnormalities (e.g., developmental defects of the skeletal system) and predisposition to multiple basal cell carcinomas, ovarian fibromas (which are frequently bilateral, multinodular, and calcified), as well as other tumors. Most fibromas are incidental findings removed at the time of surgery for an unrelated condition; however, abdominal pain is the presenting symptom in approximately 40% of cases. Fibromas are rarely associated with evidence of steroid hormone production, but they have been reported to be associated with elevated levels of Cancer antigen (CA)125, which not surprisingly raises clinical suspicion for ovarian carcinoma. Fibromas >10 cm may also be associated with ascites in 10%–15% of cases or with Meigs syndrome (ascites and pleural effusion) in a small percentage of patients, both typically disappearing after removal of the tumor.

Pathologic Features

Gross Findings

Conventional fibromas are typically unilateral (90%) and may range from microscopic to >20 cm (average 6 cm). They have a smooth or lobulated surface and a homogeneous, firm, white cut section ( Fig. 15.1 ). Edema and pseudocyst formation are frequent; calcification is seen in up to 10% of tumors. Hemorrhage and necrosis are rare. Fibromas associated with Gorlin syndrome, however, are bilateral in approximately 75% and typically show multinodular growth and calcifications in almost all cases. Fibromas that are histologically cellular tend to be larger, and may have a softer, white to yellow cut surface in comparison to conventional fibromas ( Fig. 15.2 ). It is not infrequent for cellular fibromas to be associated with ovarian surface adhesions, adhesions to surrounding structures, or rupture.

Microscopic Findings

Fibromas are composed of fascicles of bland spindle cells that often display a striking storiform arrangement ( Fig. 15.3 ). The cells have scant cytoplasm and uniform oval to elongated wavy nuclei with pointy ends. The cell population is uniform and monotonous, with minimal cytologic atypia. These tumors are variably cellular depending on the amounts of edema and collagenous stroma. Hyaline bands and calcified plaques are common. Small foci of hemorrhage may be seen, but necrosis is typically absent (except with infarction).

Fibromas with increased cellularity, similar to that seen in diffuse AGCTs, are termed cellular fibromas . Tumors with this degree of cellularity are uncommon and represent approximately 10% of all ovarian fibromas. Cellular fibroma frequently has areas morphologically similar to conventional fibroma; however, in contrast to its typical counterpart, it is much less frequently associated with edema and hyaline bands. Importantly, these tumors show only minimal cytologic atypia, which is the most important diagnostic clue ( Fig. 15.4 ). Another unusual feature is the presence of an increased mitotic rate. Conventional fibromas have on average 1–2 mitoses/10 high-power fields (HPFs); mitotically active fibromas have a mean mitotic rate of 6.7/10 HPFs (ranging from 4 to 19). Importantly, 15% of these tumors have 10–19 mitoses/10 HPFs ( Fig. 15.5 ). Mitotic activity by itself is not indicative of malignancy, as it has been shown that fibromas with mitoses exceeding 3 in 10 HPFs have a similar indolent outcome to conventional tumors ( Fig. 15.5 ).

In contrast to conventional fibromas, both cellular and mitotically active cellular fibromas may show necrosis that appears sharply demarcated from the surrounding viable tumor, the latter commonly present in a perivascular location, a morphologic appearance that overlaps with tumor cell necrosis seen in malignant smooth-muscle tumors.

Other unusual findings in fibroma include sex cord-like differentiation comprising <10% of the tumor (termed “fibroma with minor sex cord elements”), intracytoplasmic hyaline droplets, bizarre nuclei and Verocay-like areas. More than one of these unusual features may be present in the same tumor.

Ancillary Studies

Differential Diagnosis

Conventional fibroma has morphologic overlap with stromal hyperplasia, massive ovarian edema, and thecoma. In contrast to fibroma, stromal hyperplasia is typically bilateral and does not present as a mass-forming lesion; it is characterized by a diffuse and cellular proliferation of ovarian stromal cells within the cortex and medulla of the ovary, which may exhibit variable nodularity and lacks collagenous stroma and hyaline plaques. Massive ovarian edema and fibroma are usually unilateral and may be histologically quite similar; however, massive ovarian edema does not displace or peripherally compress normal ovarian structures (e.g., follicles, corpora lutea, and corpora albicantia). Fibroma and thecoma may show significant morphologic overlap; indeed, a combination of fibroma and thecoma morphologies within the same tumor is a frequent event (hence use of the term “fibrothecoma”). Unlike thecomas, pure fibromas lack nodular growth and cells with abundant pale or vacuolated cytoplasm; they only express inhibin focally and are negative for CD10. Tumors with an appreciable number of lutein cells in an otherwise conventional fibroma background are best classified as thecoma. Occasionally, fibromas have striking pseudocystic degeneration and may be confused with a serous cystadenofibroma (particularly on gross examination); however, the spaces lack an epithelial lining.

Cellular fibroma and mitotically active fibroma should be distinguished from fibrosarcoma, diffuse adult-type granulosa cell tumor (AGCT), and luteinized thecoma. On gross examination, fibrosarcoma tends to be larger and softer and more commonly shows hemorrhage and necrosis. Furthermore, fibrosarcoma is rare. Morphologic criteria for the distinction between cellular fibroma and fibrosarcoma have evolved over time, and now it is recognized that cytologic atypia is the only reliable feature that distinguishes between these two entities. Fibromas have absent to at most mild nuclear atypia; conversely, moderate to severe nuclear atypia warrants the diagnosis of fibrosarcoma. As mentioned earlier, the mitotic rate can be elevated in indolent fibromas. The border of cellular and mitotically active fibromas is usually smooth; however, if extraovarian extension is present, the tumor interface with involved pelvic tissue may appear infiltrative; by itself, this finding is not diagnostic of malignancy. Like cellular fibroma, luteinized thecoma with sclerosing peritonitis (LTSP) may be densely cellular, lack cytologic atypia, and have a brisk mitotic rate. However, cellular fibromas are more homogeneously cellular; they lack luteinized cells, are typically unilateral, and are not associated with sclerosing peritonitis. Furthermore, hormonal manifestations are common in LTSP but extremely unusual in cellular fibroma. Diffuse AGCTs , which may sometimes have a striking fibromatous background, can be distinguished from cellular fibromas at higher magnification as the cells in the former often show grooved nuclei although this feature alone is not entirely specific. A reticulin stain will characteristically show a pericellular reticulin fiber distribution in fibroma, whereas AGCT has, at least focally, nests of tumor cells devoid of pericellular reticulin. Finding other areas with patterns characteristic of AGCT is also helpful.

Finally, neoplasms that rarely enter the differential diagnosis but should be considered include primary or metastatic endometrioid/endometrial stromal sarcoma (evenly spaced thin arteriolar vasculature, lack of storiform pattern, strong and diffuse CD10, negative calretinin), gastrointestinal stromal tumor (CKIT and DOG1 positivity), and Brenner tumor (solid or glandular nests of squamoid epithelial cells resembling urothelial elements).

Prognosis and Therapy

Conventional fibromas are benign tumors, and oophorectomy is adequate treatment. Cellular and mitotically active fibromas also behave in a benign fashion even when associated with ovarian adhesions or extraovarian extension. Thus, these tumors should be treated conservatively with surgery. Long-term follow-up is advised, particularly for those patients with tumor rupture or adhesions as they may recur locally.

Clinical Features

Thecomas are uncommon, representing less than 1% of all ovarian neoplasms. They typically occur in postmenopausal women, most commonly in the sixth decade, but they may occur at any age, with some presenting in women ≤30 years (more often luteinized thecomas); however, they are rare before puberty. These tumors are commonly estrogenic, and most women present with abnormal vaginal bleeding. Approximately 20% of patients will also develop concurrent endometrial carcinoma. Of note, luteinized thecomas are androgenic in approximately 10% of cases.

Pathologic Features

Gross Findings

The vast majority of thecomas are unilateral (∼95%) and can range in size from microscopic tumors to masses between 5 and 10 cm. These tumors are typically solid (but may occasionally be cystic) and have a tan-yellow, sometimes lobulated sectioned surface ( Fig. 15.6 ). On occasion, they may show areas of necrosis, hemorrhage, or calcification, the latter more common in tumors occurring in younger women.

Microscopic Findings

These tumors are composed of sheets or nodular aggregates of plump round to spindle cells with pale (lipid rich) vacuolated to eosinophilic cytoplasm with indistinct cell borders, arranged in a vaguely fascicular or storiform pattern ( Fig. 15.7A ). Their nuclei are round to oval with fine, dispersed chromatin and infrequent mitotic figures (<2/10 HPFs). This population resembles the theca interna of a developing follicle. This characteristic cell component can be seen exclusively, or variably admixed with a spindle cell component identical to ovarian fibroma, with scant cytoplasm and lack of vacuolization. The term “luteinized thecoma” has been applied when single or sharply demarcated clusters of lutein cells are present within the tumor. Like thecomatous cells, the lutein cells have abundant cytoplasm but tend to be more eosinophilic than vacuolated and their nuclei typically contain vesicular chromatin and a prominent central nucleolus. Hyaline plaques are often present and more common in between nodules ( Fig. 15.7B ); keloid-like sclerosis can occasionally occur ( Fig. 15.7C ). Stromal calcification may be seen and is sometimes prominent, particularly in tumors occurring in younger women. Minor (<10%) sex cord differentiation can be observed. Rarely, fatty metaplasia and bizarre nuclei may be seen.

Ancillary Studies

Differential Diagnosis

The principal differential diagnostic considerations include fibroma, AGCT (diffuse pattern or with extensive luteinization), and sclerosing stromal tumor.

The distinction between fibroma and thecoma is not only frequently challenging but also largely academic. The presence of a significant thecomatous (lipid-rich) component warrants a diagnosis of thecoma. The diagnosis of fibroma is reserved for those lesions purely or predominantly spindled. The term “fibrothecoma” can be applied to lesions with relatively even admixtures of thecomatous and fibromatous components, although in practice, one component usually predominates, leading to easy categorization as either fibroma or thecoma. The diffuse pattern of adult-type granulosa cell tumor (AGCT) may mimic a thecoma, particularly in cases with prominent luteinization or those with a prominent thecomatous stromal component. AGCT can be distinguished from thecoma by the presence of more typical growth patterns and characteristic nuclear grooves (although this may require careful scrutiny of nuclear morphology) but the most helpful feature is the lack of investment of individual cells by a dense fibrillar network in AGCT, as highlighted by a reticulin stain. Although thecomas are often positive for FOXL2, by immunohistochemistry, they usually lack the corresponding mutation. Thecoma may mimic a sclerosing stromal tumor as it may show a prominent nodular growth and cells with spindle and epithelioid appearance. However, sclerosing stromal tumor more commonly occurs in the first three decades of life and is less commonly associated with clinical manifestations. In addition, sclerosing stromal tumors are more vascular and contain numerous vessels with a hemangiopericytoma-like appearance. In pregnant women, thecomas may undergo extensive luteinization and may mimic pregnancy luteoma . However, the latter lacks a fibromatous or thecomatous background, and the cells contain little or no lipid. Steroid cell tumors typically have a diffuse growth of cells showing well-defined borders and containing abundant lipid vacuoles.

Prognosis and Therapy

Thecoma (including luteinized thecoma) is a benign tumor, and unilateral salpingo-oophorectomy is considered adequate treatment. Because of their hormone production and association with endometrial proliferation, endometrial sampling should be performed to exclude endometrial neoplasia.

Clinical Features

LTSP is a variant of thecoma that typically affects women in their third and fourth decades. This is an enigmatic entity in which patients present with abdominal swelling and pain, ascites and, in some cases, pleural effusion or symptoms of bowel obstruction. On pelvic examination, they are found to have unilateral or (more frequently) bilateral pelvic masses.

Pathologic Features

Gross Findings

The ovarian lesions may form bilateral large masses (up to 31 cm) or result in only slightly enlarged ovaries ( Fig. 15.8A ), replacing the entire ovary or less commonly involving the cortex. When they form a mass, the tumors typically have a prominent nodular or cerebriform surface and a solid, homogeneous, white to tan-pink and edematous cut section ( Fig. 15.8B ).

Sclerosing peritonitis, which can involve omentum, peritoneum, and intestinal serosa, appears as areas of thickening up to 2–3 mm, well demarcated from the underlying normal tissue.

Microscopic Findings

The ovarian lesion is poorly demarcated and is composed of sheets or intersecting fascicles of cells with a fibromatous to thecomatous appearance ( Fig. 15.9 ). In some cases, discrete masses are not present, but rather there is diffuse cortical spindle cell expansion mimicking stromal hyperplasia. Scattered throughout the fibrothecomatous background are distinct small nests and clusters of luteinized stromal cells (hence designation as luteinized thecoma) ( Fig. 15.10 ). These lutein cells have visible eosinophilic cytoplasm and round nuclei with inconspicuous nucleoli. The mitotic rate can be striking (up to 80 mitoses/10 HPFs), sometimes with markedly varied counts between the ovarian lesions on both sides ( Fig. 15.10 ). Significant edema may be seen with secondary cavitation (pseudocyst formation) ( Fig. 15.11 ). Residual entrapped normal ovarian elements are often present within the lesion.

The associated sclerosing peritonitis is composed of a noninfiltrative, superficial proliferation of bland-appearing fibroblasts, which are arranged in fascicular and less commonly storiform patterns with variable cellularity, collagen deposition, and inflammation ( Fig. 15.12 ). Surface fibrin and focal mesothelial hyperplasia may also be present. Extensive involvement of the omentum results in envelopment of individual lobules of adipose tissue by the fibroblastic proliferation, resulting in a dramatic accentuation of the normal lobular architecture.

Ancillary Studies

Differential Diagnosis

LTSP is part of the morphologic spectrum of luteinized thecoma (and fibrothecoma). It is different from conventional luteinized thecomas in its association with sclerosing peritonitis; at the morphologic level, the lutein cells are smaller than in conventional luteinized thecomas.

Stromal hyperthecosis falls into the differential diagnosis of LTSP because it is almost always bilateral and characterized by the presence of nests of luteinized cells within hyperplastic stroma, and, similarly to LTSP, it can also entrap normal ovarian follicles; however, it is not accompanied by ascites, prominent ovarian enlargement, or obliteration of the ovarian architecture. In addition, the stromal cells in stromal hyperthecosis are not mitotically active, which is in stark contrast to most LTSPs. Although massive ovarian edema may cause significant ovarian enlargement, occasionally may be bilateral, and contain rare foci of luteinized cells, they are typically hypocellular and associated with either diffuse marked edema or collagen deposition. Cellular fibroma can be quite edematous but is distinguished from LTSP because it is typically unilateral, and although it may be associated with ascites, it is not associated with sclerosing peritonitis. Sclerosing stromal tumor is also typically unilateral and differs morphologically from LTSP in that it is composed of a biphasic population of mitotically inactive spindle-shaped and luteinized cells arranged in a characteristic pseudolobular arrangement; in addition, the prominent hemangiopericytoma-like vascular pattern is characteristic. Even though fibrosarcoma can exhibit brisk mitotic activity, it is associated with tight fascicles of highly atypical spindle cells, features not seen in LTSP.

Prognosis and Therapy

Treatment consists of removal of the ovarian lesion(s), as well as omentectomy, lysis of adhesions, and bowel resection when necessary, to relieve symptoms of obstruction. Rare patients have benefited from hormonal treatment (gonadotropin-releasing hormone agonist) and high-dose corticosteroids. Although it appears that the ovarian lesions are benign with no evidence of recurrence or metastases, a small number of patients have died of complications related to the sclerosing peritonitis.

Clinical Features

This lesion is generally found in patients who are younger than those with either thecomas or fibromas, as 80% are < 30 years of age. Patients often present with menstrual irregularities or symptoms related to the presence of a pelvic mass. Evidence of hormone production, either estrogenic or androgenic, is documented only rarely; androgenic manifestations have been reported more frequently in pregnant patients. Ascites, Meigs syndrome, or elevated serum levels of CA125 are infrequent.

Pathologic Features

Gross Findings

Sclerosing stromal tumor is almost always unilateral and ranges from 1.5 cm to 21 cm in largest dimension. It has a well-defined border that, in some cases, has allowed enucleation of the tumor at surgery. They are white to yellow and typically solid; occasional tumors may have a large central cavity ( Fig. 15.13 ).

Microscopic Findings

Sclerosing stromal tumor is typically well circumscribed, with a sharply demarcated thin rim of normal ovarian tissue at the periphery. At low magnification, the tumor has a pseudolobular appearance, given by the alternation of cellular nodules with hypocellular edematous to markedly collagenized areas ( Fig. 15.14 ). The cellular nodular areas contain a random and heterogeneous mixture of spindled (fibromatous) cells and clusters of round luteinized cells. The lutein cells have eosinophilic to clear vacuolated cytoplasm and round nuclei with vesicular chromatin and prominent nucleoli ( Fig. 15.15 ). These cells may have a signet-ring appearance. The tumor vasculature is characteristic, composed of numerous thin-walled vessels, some of which can be dilated and branched resembling those seen in hemangiopericytoma ( Fig. 15.14 ). Cytologic atypia and mitoses are rare, with exceptions (more often in pregnant women). Furthermore, in pregnant women, the tumors may contain a larger number of more robustly luteinized cells, which may obscure the typical lobular architecture and dual cell population characteristic of this tumor.

Ancillary Studies

Differential Diagnosis

Depending upon which component is most prominent in the tumor, the entities to be considered in the differential diagnosis can vary. If the spindle cells predominate, a sclerosing stromal tumor may be confused with a fibroma or thecoma. Fibroma tends to occur in older patients (average age is approximately 50 years; <10% are under 30 years of age), and histologically, they lack the pseudolobulation, alternating cellularity, prominent vascularity, and cellular heterogeneity characteristic of sclerosing stromal tumors. Thecomas may be confused with sclerosing stromal tumor as the former may have a lobulated growth; however, thecomas are composed of a uniform population of cells with pale grey cytoplasm and lack the characteristic vascularity of sclerosing stromal tumors. Luteinized thecoma and sclerosing stromal tumor share several clinical and pathologic features. Both occur in young patients in higher frequencies than fibromas and thecomas (30% of patients with luteinized thecoma are 30 years of age or younger); both contain spindled and lutein cells and express inhibin and calretinin. However, the variegated appearance of sclerosing stromal tumor and its prominent thin-walled vessels are absent in luteinized thecoma. Sclerosing stromal tumor can mimic metastatic signet-ring cell carcinoma (Krukenberg tumor) since both lesions have variegated/alternating cellularity of hyper- and hypocellularity, and lutein cells of sclerosing stromal tumors may have a signet-ring cell resemblance. Krukenberg tumors, however, contain mucin and are positive for keratin and EMA, whereas the vacuoles in the signet-ring-like cells of the sclerosing stromal tumor contain lipid. If the lutein cells are arranged in cords, they can mimic metastatic breast carcinoma or carcinoid tumor ; however, both lack the prominent hemangiopericytoma-like vascular network seen in sclerosing stromal tumors. Negative keratin and EMA and positive inhibin and calretinin staining should distinguish sclerosing stromal tumor from these two entities. It should be kept in mind that both sclerosing stromal tumor and metastatic breast carcinoma can be ER and PR positive. Steroid cell tumor may enter into the differential diagnosis when sclerosing stromal tumors are cellular and extensively luteinized; however, the former typically lacks the characteristic admixture of spindled and luteinized cells as well as the striking vascularity. Moreover, the vast majority of sclerosing stromal tumors are not associated with hormonal manifestations. Lastly, sclerosing stromal tumors presenting during pregnancy can mimic pregnancy luteoma, as both lesions usually display prominent luteinization. Again, attention to the variegated appearance and distinct vasculature of sclerosing stromal tumor is most helpful in this differential.

Prognosis and Therapy

As these tumors are typically benign, simple oophorectomy is adequate therapy.

Clinical Features

Patients are typically premenopausal, although age range is wide. They usually present with symptoms related to a pelvic mass or it may be an incidental finding. Endocrine manifestations are rare.

Pathologic Features

Microscopic Findings

On low-power examination, this neoplasm is composed of densely cellular areas separated by variably sized hyaline bands. The tumor cells are arranged in solid sheets or cords and characteristically form empty cavities (“microcysts”) of various sizes and shapes ( Fig. 15.16 ), which is usually the dominant feature. The microcysts may coalesce and often contain lightly basophilic or clear secretions ( Fig. 15.17 ). The solid areas may vaguely resemble thecoma ( Fig. 15.18 ). Tumor cells have modest amounts of finely granular and lightly eosinophilic cytoplasm and bland round to oval nuclei containing tiny nucleoli ( Fig. 15.19 ). Intracytoplasmic vacuoles are often noted. Bizarre nuclei are not infrequent (present in ∼60% of tumors), and they usually have a patchy distribution within the tumor. Mitotic rate is typically very low, with at most 1 per 10 HPFs. Rarely, psammomatous calcifications can be seen.

Ancillary Studies

Immunohistochemistry

This tumor consistently shows diffuse and strong nuclear staining for beta-catenin ( Fig. 15.20A ). Other positive markers include vimentin, CD10, FOXL2, WT1, and cyclin D1 ( Fig. 15.20B ); most are also positive for SF1. They may show weak positivity for cytokeratin and rarely for inhibin and calretinin, whereas EMA is negative.

Differential Diagnosis

Thecoma is the most common tumor in the differential diagnosis of microcystic stromal tumor as both often occur in patients of similar age and have a vague lobulated architecture with hyaline bands. Furthermore, thecomas can also have bizarre nuclei (albeit rarely); however, they often are associated with estrogenic manifestations, and the tumor cells have more abundant cytoplasm; furthermore, thecomas lack the microcystic component and the intracytoplasmic vacuoles characteristic of microcystic stromal tumors. Thecomas are strongly positive for inhibin and calretinin and negative for nuclear beta-catenin. A steroid cell tumor may also be considered in this differential diagnosis as rarely they may contain microcysts; however, they are associated with hormonal manifestations (more often androgenic) and have a striking yellow to orange and occasionally brown cut surface. In contrast to microcystic stromal tumors, they typically show a diffuse or nested growth and may contain cells with pale, microvacuolated cytoplasm. Although both tumors stain with CD10, calretinin and inhibin positivity establish a diagnosis of steroid cell tumor. Sclerosing stromal tumors and signet-ring stromal tumors may enter into the differential diagnosis as they may have cells with intracytoplasmic vacuoles; however, both contain a second component of spindle cells and sclerosing stromal tumor also has typical luteinized cells and a staghorn vascular pattern as well as positivity for inhibin and calretinin. Nuclear beta-catenin is negative.