Nonneoplastic Lesions of the Ovary

Clinical Features

Solitary follicular cysts are usually an incidental finding; when persistent, they may cause symptoms secondary to a pelvic mass and are typically excised to exclude malignancy. Acute abdominal pain secondary to torsion, with or without hemoperitoneum, may occur, particularly in neonates, although most follicular cysts that occur during the neonatal period regress within the first 6 months. Occasionally, follicular cysts may be associated with manifestations of excess estrogen production (isosexual pseudoprecocity in children or irregular menses related to disordered proliferative endometrium and/or endometrial hyperplasia in women of reproductive age). Postpubertal women with cystic fibrosis may have a predisposition to developing solitary follicular cysts.

Multiple follicular cysts are part of the spectrum of abnormalities seen in polycystic ovary syndrome (PCOS), a common disorder characterized by hyperandrogenism of ovarian origin resulting in virilization, infertility, obesity, and insulin resistance (Stein–Leventhal syndrome). Only up to 10% of women with polycystic ovaries have clinical manifestations. A family history is common, but the genetic factors in this disease are poorly understood. The most common etiology is insulin resistance of peripheral tissue and/or an abnormality of the hypothalamic–pituitary–ovarian axis. The findings of multiple ovarian cysts associated with cortical sclerosis, although part of the spectrum of PCOS, is not specific and can be seen in other causes of chronic anovulation; therefore, clinical and biochemical assessment is required for this diagnosis. Solitary or multiple follicular cysts may also occur in association with McCune–Albright syndrome (polyostotic fibrous dysplasia, cutaneous melanin pigmentation, and endocrine organ hyperactivity) and in prepubertal patients with hypothyroidism.

Cystic corpora lutea are a frequent finding in residual ovarian tissue in the setting of ovarian remnant syndrome. They may manifest as menstrual irregularities and rarely hematoperitoneum.

Radiologic Features

Transvaginal ultrasound shows simple thin-walled cysts; however, if there is intracystic hemorrhage, the appearance is that of a complex adnexal mass and may suggest a neoplasm. Small cysts can be followed with ultrasound; their disappearance over a period of weeks allows a presumptive benign diagnosis. The ultrasound appearance of multiple cysts in the ovarian cortex, associated with PCOS, is characteristic but, as noted previously, not specific.

Pathologic Features

Gross Findings

Solitary follicular cysts ( Fig. 13.2 ) have smooth surfaces, are thin walled, and are, by definition, >3 cm in diameter (but usually <10 cm). Cysts in neonates can be larger (average 8 cm). Cysts <3 cm are referred to as “cystic follicles” and are considered to be within the range of normal follicular development. Cyst contents are typically serous or serosanguinous. A corpus luteum cyst, also, by definition, >3 cm in diameter, more commonly contains intracystic hemorrhage and exhibits an undulating yellow rim of variable thickness ( Fig. 13.3A,B ). As follicular and luteal cysts are often received fragmented at the time of gross examination, exact measurement is not possible and designation as a cyst should rely on clinical/radiologic impression. Ovaries in PCOS typically show bilateral enlargement with numerous cortical cysts, most measuring <3 cm, and a band of white firm tissue that replaces the superficial cortex overlying the cysts ( Fig. 13.4 ).

Microscopic Findings

Follicular cysts, whether solitary or multiple, are lined by an inner layer of granulosa cells and surrounded by an outer layer of theca interna cells ( Fig. 13.5 ). Both are composed of round cells in a stratified or layered configuration. Granulosa cells have round nuclei with very scant clear cytoplasm, whereas theca cells have more abundant eosinophilic cytoplasm and less hyperchromatic nuclei. Both granulosa and theca interna layers can display variable degrees of luteinization. Sometimes, the distinction between the two cell layers may be difficult and a reticulin may be of help as theca cells are typically surrounded by individual reticulum fibers whereas granulosa cells lack reticulin. If torsion occurs, the cyst, as well as the surrounding ovary, may infarct and the cyst contents have a grumous appearance ( Fig. 13.6A ). If infarction occurs, careful scrutiny of the cyst should be performed in order to exclude malignancy, and extensive sampling is indicated. Ovarian parenchyma near the cyst may show ghost cells including primary follicles ( Fig. 13.6B ).

Corpora lutea cysts have undulating contours and show prominent luteinization of granulosa and, to a lesser extent, theca interna cells ( Fig. 13.7 ). In ovaries removed from patients with PCOS, there is prominent sclerosis of the superficial cortex, visible as a pale rim of heavily collagenized stroma underlying the surface epithelium, associated with multiple relatively uniformly sized and evenly spaced follicular cysts ( Fig. 13.8 ). Usually, the theca interna is thicker than in a normal follicle and the theca cells often appear luteinized. The granulosa cell layer may be of variable thickness, but it is typically not luteinized. Evidence of prior ovulation (e.g., corpora albicantia or lutea) is sparse. It is also common to find increased numbers of hilar cells.

Ancillary Studies

Differential Diagnosis

The chief differential diagnosis is with epithelial cysts , particularly when the lining is partially denuded. The most helpful features in establishing the diagnosis of a follicular cyst are the findings of surrounding theca cells, the stratification of round nuclei devoid of significant cytoplasm, and the lack of cilia. Cystic struma ovarii may also mimic a follicular cyst but will typically show small follicles, which may contain eosinophilic colloid within the wall. Immunohistochemistry can be used in difficult cases as epithelial cells are positive for epithelial membrane antigen and negative for inhibin; cystic struma is positive for TTF1 and thyroglobulin. Solitary follicular cysts must also be distinguished from unilocular cystic granulosa cell tumors , which are typically larger and have a thicker granulosa cell lining (average 10 cells thick), which sometimes displays papillary or microfollicular patterns (the former with fibrous cores, the latter with Call-Exner bodies). An important pitfall to keep in mind is that cystic granulosa cell tumors can have luteinized theca cells at the periphery, although most often the wall of the cyst is composed of fibrous tissue. Sampling of the adjacent parenchyma is important, as it may reveal more typical areas of granulosa cell tumor. In difficult cases, the presence of a FOXL2 mutation will be confirmatory of adult-type granulosa cell tumor.

The main differential diagnostic consideration for a corpus luteum cyst is with a steroid cell tumor as the periphery of the former can have a nested architecture and cells with abundant pale eosinophilic cytoplasm. However, the low-power undulating contours, as well as the central cystic component often filled with recent or clotted blood, will help in establishing the diagnosis of a corpus luteum cyst. In addition, patients with steroid cell tumors often present with hormonal manifestations (typically androgenic). The lining of endometriotic cysts is often denuded and may be replaced by abundant foamy cells with ample eosinophilic cytoplasm, thus mimicking the appearance of a corpus luteum cyst ( Fig. 13.9A,B ). The presence of recent or old hemorrhage should prompt careful scrutiny for endometrial-type epithelium and stroma.

Although the histologic findings of PCOS are classic, diagnosis should not be based on histopathologic findings alone as similar findings can be seen in other diseases that may be associated with chronic anovulation including autoimmune oophoritis, multiple follicular cysts secondary to hypothyroidism, and adrenal disorders including congenital adrenal hyperplasia; therefore, clinical-pathologic correlation is essential.

Prognosis and Therapy

Solitary follicular and corpora lutea cysts will usually resolve spontaneously. Management of PCOS depends on the severity of the clinical manifestations and whether pregnancy is desired. Depending on the symptoms and the fertility goals, patients undergo hormonal therapy (oral contraceptives or progestins), ovulation induction, weight loss, and medical treatment of insulin resistance and hirsutism.

Clinical Features

Stromal hyperplasia and hyperthecosis are most common in patients in their sixth to seventh decade; in this age group, stromal hyperplasia is seen in up to one-third of women. Many patients are asymptomatic. Symptoms, which are more common in hyperthecosis, include:

• 1.

  Androgen manifestations, characteristically virilization and acne.

• 2.

  Estrogenic manifestations, including abnormal uterine bleeding due to disordered proliferative endometrium, endometrial hyperplasia, or even well-differentiated endometrioid adenocarcinoma.

• 3.

  Other symptoms such as obesity, hypertension, and hyperinsulinemia. A small percentage of patients have HAIR-AN syndrome, which consists of hyperandrogenism (HA), insulin resistance (IR), and acanthosis nigricans (AN).

Pathologic Features

Gross Findings

Stromal hyperplasia and stromal hyperthecosis typically involve both ovaries, which may be normal sized or enlarged (up to 7.0 cm). They display a diffuse or nodular, firm cut surface that is white to yellow (stromal hyperplasia) or yellow to brown (stromal hyperthecosis) ( Fig. 13.10 ).

Microscopic Findings

Stromal hyperplasia is characterized by a nodular and/or diffuse, cortical and medullary (latter more frequent) proliferation of mitotically inactive stromal cells with ovoid nuclei and indistinct nucleoli ( Fig. 13.11 ). In stromal hyperthecosis, nodular aggregates (up to 0.5 cm; Fig. 13.12A ), nests, or isolated luteinized cells are present in a background of stromal hyperplasia ( Fig. 13.12B ). The luteinized cells have abundant eosinophilic or vacuolated cytoplasm and central, round nuclei with small nucleoli. Hilar cell hyperplasia may be seen with stromal hyperplasia or stromal hyperthecosis. In addition, in patients with HAIR-AN syndrome, the ovaries show multiple follicle cysts associated with cortical sclerosis, akin to that seen in PCOS.

Ancillary Studies

Differential Diagnosis

Stromal hyperthecosis should be distinguished from other processes characterized by lipid-laden cells such as thecoma and steroid cell tumors, including stromal luteoma. In the past, stromal luteoma was defined as a tumor composed of lutein cells <2 cm in size that typically arose in a background of stromal hyperthecosis. Currently, stromal luteoma does not represent a distinct entity since it was incorporated into the steroid cell tumor category. In contrast to stromal hyperthecosis, thecoma and steroid cell tumor form a distinct mass or nodule on macroscopic examination and are typically unilateral.

Prognosis and Therapy

Patients with hyperandrogenic manifestations may respond to gonadotropin-releasing hormone (GnRH) agonists or oral contraceptives. Bilateral oophorectomy results in complete resolution of the androgenic symptoms, but the insulin resistance in HAIR-AN syndrome usually persists.

Clinical Features

Hilar cell hyperplasia is often an incidental finding in ovaries removed for an unrelated gynecologic disorder. It typically occurs in postmenopausal women in association with stromal hyperplasia or stromal hyperthecosis as well as in pregnant women. Mild hyperplasia is very common and usually subclinical. More significant forms of hilar cell hyperplasia are associated with virilization and most frequently occur in younger women, occasionally during pregnancy.

Pathologic Features

Microscopic Findings

Hilar cell hyperplasia is located in the interface between ovarian parenchyma and the supporting vascular and connective tissues (the ovarian “hilum”). It is typically seen as nodular aggregates, nests, clusters or, less commonly, diffuse sheets of polygonal cells ( Fig. 13.13A ). The cells have abundant eosinophilic cytoplasm and rounded, hyperchromatic nuclei, usually monomorphic but occasionally displaying nuclear pleomorphism. Intracytoplasmic elongated, eosinophilic Reinke crystals, when present, are pathognomonic ( Fig. 13.13B ). Mitotic figures may be present. Oftentimes, the cells are in close association with peripheral nerve bundles.

Ancillary Studies

Differential Diagnosis

The high-power features of hilar cell hyperplasia closely overlap with those seen in a hilar (Leydig) cell tumor ; however, the latter forms a mass, it may have fibrinoid necrosis of blood vessels, often shows aggregation of nuclei alternating with nuclear free areas, and is usually associated with endocrine manifestations. Hilar cell hyperplasia involving the ovarian cortex can be indistinguishable from stromal hyperthecosis , unless Reinke crystals are identified.