Tumor-Like Lesions of the Ovary

Solitary follicle cysts (FCs) are most common in nonpregnant women of reproductive age, particularly around the menarche and menopause and are likely due to abnormal pituitary gonadotropin secretion, such as an FSH-secreting pituitary adenoma (Kawaguchi et al.). Postmenopausal FCs are uncommon but rarely may cause postmenopausal bleeding.

FCs may present as a palpable mass or menstrual irregularities (due to estrogen production). Rupture can rarely lead to an acute abdomen with hemoperitoneum and even exsanguination. Most FCs, however, are asymptomatic.

Although rare in children, FCs may cause isosexual pseudoprecocity that regresses after removal or puncture of the cyst; occasionally regression is spontaneous. These cysts are likely autonomous as gonadotropin levels are not elevated.

FCs in children may be a component of the McCune–Albright syndrome; there may be one or several, occasionally bilateral, cysts. Rarely there is ovulation with a possibility of pregnancy. Unlike isolated FCs, McCune–Albright-related FCs may recur after removal with return of the precocity.

FCs develop rarely in utero (due to maternal hormonal stimulation) and may be apparent then or during the neonatal period; they may undergo torsion, hemorrhage, or rupture. They almost always regress within a few months after birth if managed conservatively.

FCs are a rare complication in patients with pituitary adenomas and in such cases are typically bilateral and often large. They can grossly mimic the appearance of pregnancy-related FCs (hyperreactio luteinalis; see corresponding heading below).

FCs can also be encountered in cases of autoimmune oophoritis (see separate heading).

Solitary FCs are almost always <8 cm in size (typically ~4 cm) except during pregnancy or the puerperium or when pituitary adenoma-associated, and usually have a smooth surface, thin walls, and contain watery fluid or occasionally blood.

FCs are typically lined by one to several layers of uniform, usually luteinized, granulosa cells with a variably prominent outer layer of luteinized theca cells. The lining granulosa cells may be denuded to varying degrees.

Occasionally a FC (or cystic follicle) can collapse or is fragmented during prosection or tissue processing erroneously suggesting a multicystic lesion that can be misconstrued as a cystic granulosa cell tumor. Awareness of this artifact and the focal presence of the typical cells lining a FC that contrast with those lining a GCT will aid in the diagnosis.

When the lining of a FC is denuded, distinction from a simple cyst is aided by the presence of a peripheral layer of theca cells. Similar findings distinguish an FC from a serous cyst, a diagnostic error occasionally made.

Cystic atretic follicles are often multiple and smaller than FCs. Their lining of granulosa cells may be sloughed or if present lack the eosinophilic cytoplasm of the granulosa cells lining most FCs.

Rarely a FC may suggest an endometriotic cyst with a denuded lining but the persistence of a theca layer in a FC and endometriotic stroma subtending the lining of an endometriotic cyst aid diagnosis.

Unilocular GCTs, like FCs, are lined by granulosa cells and have theca cells in their walls, but are almost always much larger than FCs, have a more disorderly admixture of the two cell types, and often have mural aggregates of granulosa cells.

The neoplastic granulosa cells of a unilocular adult-type GCT are generally not luteinized like those of a FC and have nuclear features resembling those of typical GCTs.

Distinction from a unilocular juvenile GCT may be more problematic because its cells also often have abundant eosinophilic cytoplasm, but usual follicle formation in the lining or wall of the cyst is diagnostic of a GCT.

Polycystic ovarian syndrome (PCOS) typically occurs in young women who present with irregular bleeding (due to chronic anovulation), hirsutism, and/or infertility. Associated manifestations may include obesity and diabetes.

The etiology is unknown, but there is abnormal gonadotropin release (low FSH, high LH), hyperandrogenemia, an elevated serum estrone level, and in some cases, hyperinsulinemia.

The endometrium in women with PCOS varies from inactive to hyperplastic to rarely carcinomatous (almost always a low-grade endometrioid carcinoma).

Bilateral ovarian wedge resection is no longer used to treat this disorder, and thus ovarian tissue from these patients is rarely encountered by the pathologist.

Both ovaries are typically enlarged and rounded with multiple small follicle cysts beneath a thickened white superficial cortex; occasionally the ovaries are of normal size.

Sectioning reveals multiple cortical cysts of approximately equal size and a medulla consisting of homogeneous stroma with absent or sparse corpora lutea or corpora albicantia.

The cysts are lined by a thin layer of nonluteinized granulosa cells and usually a thick layer of luteinized theca interna cells, which may also be prominent around atretic follicles (‘follicular hyperthecosis’).

Occasional luteinized stromal cells are usually present, indicating a component of stromal hyperthecosis (see below). The outer cortex is typically hypocellular and fibrotic.

PCOS-like ovaries may be seen in normal prepubertal and peripubertal children, in adolescent females with primary hypothyroidism, in ovaries from female-to-male transgender patients treated with testosterone, and occasionally in adult women with unimpaired fertility.

In postmenopausal women there are generally no overt clinical manifestations although estrogenic findings on pathologic examination (endometrial polyp, endometrial hyperplasia, endometrioid carcinoma) are common (Zhang et al.) and rare cases of virilization in this age group have been reported (Guerrero et al.).

In premenopausal women, there may be PCOS-like clinical manifestations, but more often there is a gradual or, less commonly, an abrupt onset of virilization (with elevated serum testosterone). The patients are often obese, hypertensive, and have decreased glucose tolerance. Some cases are familial.

Insulin resistance, sometimes accompanied by diabetes, acanthosis nigricans, and hyperandrogenism (HAIR-AN syndrome) occur in a small subset of women with stromal hyperthecosis or PCOS.

Both ovaries (rarely only one) may be enlarged to 8 cm, with variable replacement by solid white to yellow tissue, sometimes simulating bilateral neoplasms. However, in most cases there is no or minimal ovarian enlargement.

Microscopically, lipid-poor luteinized cells with eosinophilic cytoplasm or, less often, foamy (lipid-rich) cytoplasm are scattered singly, in small nests, or nodules (nodular hyperthecosis), typically in a background of stromal hyperplasia but occasionally the latter is absent. The luteinized cells stain for inhibin and calretinin.

In premenopausal women, sclerocystic changes (a white opaque external surface and multiple superficial follicle cysts) similar to those of PCOS may also be present.

Rare findings may include a synchronous ovarian neoplasm, most often a small steroid cell tumor (stromal luteoma), uni- or bilateral hilus cell hyperplasia, or a hilus cell tumor.

Patients with the HAIR-AN syndrome almost always have stromal hyperthecosis with multiple follicle cysts, sometimes accompanied by superficial cortical sclerosis and stromal edema and fibrosis.

A small steroid cell tumor (stromal luteoma). An arbitrary size criterion (>1 cm) separates this lesion from nodular hyperthecosis.

Although traditionally considered a common incidental microscopic finding in the ovaries of perimenopausal or postmenopausal women, careful examination of the ovaries in such cases usually reveals rare luteinized cells, and thus stromal hyperthecosis. In the absence of luteinized cells, inhibin+ stromal cells may be found, suggesting lutein cell precursors.

Occasionally there are androgenic or estrogenic manifestations as well as obesity, hypertension, and disorders of glucose metabolism, although these findings are much less frequent and are milder than in stromal hyperthecosis.

The ovaries may be normal in size or slightly enlarged by ill-defined, white or pale yellow, occasionally confluent, nodules within the stroma of the medulla, cortex, or both.

Microscopically, the medulla, and to a lesser extent, the cortex, are expanded by a nodular or diffuse densely cellular proliferation of small stromal cells with scanty, nonluteinized cytoplasm.

Ovarian fibroma ( Chapter 16 ).

Low-grade endometrioid stromal sarcoma ( Chapter 17 ). Features favoring or diagnostic of this tumor include marked ovarian enlargement, oval rather than spindle-shaped cells, mitotic figures, an arteriolar network, and reactivity for CD10.

Patients with this rare disorder have ranged from 6 to 33 (mean, 21) years of age, most presenting with abdominal pain, which may be acute, and abdominal swelling. Other findings may include abnormal menstrual bleeding, evidence of androgen excess, or both.

Laparotomy reveals ovarian enlargement, which is bilateral in 10–30% of cases, and partial or complete torsion of the ovarian pedicle in half the cases, implicating torsion in the pathogenesis. A synchronous large ipsilateral broad ligament leiomyoma that may have impinged on lymphatic or venous drainage was found in one case.

The ovaries range up to 35 cm (mean, 11.5 cm) in diameter with an opaque, white, outer surface through which small cysts may be seen. Abundant watery fluid typically exudes from the sectioned surfaces, which appear edematous or gelatinous.

Microscopically, edematous hypocellular stroma surrounds rather than displaces follicles and their derivatives. The peripheral cortex is typically composed of dense, nonedematous, collagenous tissue. Uncommon findings include fibromatous foci and luteinized stromal cells.

If the diagnosis is suspected clinically or intraoperatively, a wedge biopsy from one ovary with frozen-section confirmation of the diagnosis can allow for conservative treatment.

Edematous fibroma and Krukenberg tumor. These considerations may be a realistic problem at the time of frozen section but are unlikely to be a problem when an entirely resected mass is available. Distinction from a Krukenberg tumor depends on the absence of signet-ring cells in the edematous tissue.

Rare cases of obstruction of ovarian lymphatics by metastatic carcinoma can result in an appearance mimicking typical massive edema.

This disorder, which is not related to the soft tissue lesion, is even rarer than massive edema. It has occurred in patients 13–39 (mean, 25) years of age, who usually present with menstrual irregularities or amenorrhea, and rarely, virilization.

At operation the process is bilateral in 20% of cases; occasionally the involved ovaries have twisted on their pedicles.

The enlarged ovaries range up to 14 cm in size and have smooth or lobulated external surfaces. The sectioned surfaces are typically firm and white or grey; small cysts may be visible.

Proliferating spindle cells and abundant collagen surround follicular derivatives. The fibromatous proliferation is usually diffuse.

Luteinized stromal cells, foci of stromal edema, and focal nests of sex cord-type cells are occasionally present.

Fibroma. These tumors are usually more cellular and lack the extensive entrapment of follicular derivatives characteristic of fibromatosis. The distinction between the two lesions in a superficial biopsy may not be possible but the rarity of fibromatosis should be borne in mind.

Brenner tumor vs fibromatosis with sex cord-like foci. The cells in sex cord-like foci are easily distinguishable from those of a Brenner tumor in their number, shape, and nuclear features.

Fibromatosis, soft-tissue type (see Chapter 17 ).

The patients are typically in their third or fourth decades; 80% are multiparous. The lesion is usually an incidental finding during cesarean section or postpartum tubal ligation; rarely a pelvic mass is palpable or obstructs the birth canal.

In 25% of cases, hirsutism or virilization appears during the latter half of pregnancy; 70% of female infants born to masculinized mothers are also virilized. Plasma androgens, including testosterone, are elevated in virilized patients and occasionally in nonvirilized patients and their infants.

The lesion regresses postpartum and serum androgen levels normalize within several weeks.

Pregnancy luteomas range from microscopic to >20 cm in size (median diameter of 6.6 cm in one study), with solid, fleshy, circumscribed, red to brown, and often focally hemorrhagic cut surfaces. The lesions are multiple and bilateral in at least one-half and one-third of cases, respectively.

Microscopically, well-circumscribed nodules, which may contain spaces filled with pale fluid or colloid-like material, consist of large cells with abundant eosinophilic cytoplasm that may contain rare cytoplasmic hyaline globules.

The cells have central, sometimes slightly pleomorphic and hyperchromatic nuclei, prominent nucleoli, and mitoses (up to 7 mf/10 hpf) that may be abnormal. The lesional cells are inhibin+ and calretinin+. Scanty stroma and reticulin fibrils surround groups of cells. Focal ballooning degeneration of the cytoplasm and intracellular colloid droplets may also be seen.

Within days to weeks postpartum, the luteomas degenerate with eventual conversion to brown puckered scars. Microscopic examination reveals shrunken nests of degenerating lipid-filled luteoma cells with pyknotic nuclei, lymphocytes, and fibrosis.

Metastatic tumor (when intraoperative inspection reveals multiple and/or bilateral nodules). Metastatic cancer can usually be excluded by frozen-section examination.

A lipid-poor steroid cell tumor ( Chapter 16 ). An ovarian mass composed entirely of lipid-poor steroid type cells in the third trimester should be considered a pregnancy luteoma unless there is strong evidence to the contrary. Follicle-like spaces and cells with more abundant cytoplasm further support pregnancy luteoma.

Juvenile granulosa cell tumor (see Chapter 16 ).

Hyperreactio luteinalis (HL) is usually associated with conditions accompanied by elevated hCG levels, such as hydatidiform mole, choriocarcinoma, fetal hydrops, and multiple gestations. The frequency of HL in women with GTD ranges from 10% (by clinical examination) to 40% (by ultrasonography). Half of the cases unassociated with GTD are associated with a normal singleton pregnancy.

The usual presentation is an asymptomatic pelvic mass during any trimester, at cesarean section, or rarely, during the puerperium. Complications that may cause abdominal pain include intracystic hemorrhage, torsion, rupture, and potentially fatal hemoperitoneum.

In cases of HL secondary to GTD, ovarian enlargement may be detected at the time of the diagnostic D&C or during the postoperative follow-up period.

Virilization of the patient but not the female infant occurs in 15% of cases unassociated with GTD. Elevated plasma testosterone levels occur in these patients as well as in nonvirilized patients with GTD.

Puerperal regression typically occurs, but may not be complete until 6 months postpartum. Rarely, spontaneous regression occurs during pregnancy. In GTD-associated cases, regression typically occurs 2–12 weeks after uterine evacuation, but occasionally the cysts persist for long periods.

The ovarian hyperstimulation syndrome (OHS) is an iatrogenic form of HL.

• OHS occurs after ovulation in women undergoing ovulation induction (with FSH and hCG or clomiphene) and is more severe in patients who conceive.

• Severe cases of OHS may result in massive ovarian enlargement, ascites, hydrothorax, and elevation of serum estrogens, progesterone, and testosterone. Hemoconcentration may lead to oliguria and life-threatening thromboembolic phenomena.

Operative intervention in cases of HL and the OHS is needed only to remove infarcted tissue, control hemorrhage, or diminish androgen production in virilized patients.

Multiple, almost always bilateral, thin-walled cysts enlarge the ovaries, sometimes massively; the cysts are filled with clear or hemorrhagic fluid.

Microscopic examination reveals multiple follicle cysts of varying size in which the theca interna cells and to a lesser degree the granulosa cells are enlarged and luteinized. Edema of the theca interna and the interfollicular stroma is common; the latter almost always contain luteinized cells.

The changes in OHS are identical with the additional finding of one or more corpora lutea.

HL may be mistaken at laparotomy for a cystic ovarian tumor, occasionally leading to an unwarranted bilateral oophorectomy. Rarely, a coexistent pregnancy luteoma increases the suspicion of a neoplastic process. Frozen-section examination of the cyst wall should facilitate the diagnosis but the clinical background is paramount in suggesting the correct diagnosis.

Multiple luteinized follicle cysts grossly and microscopically similar to the process seen in pregnancy may be encountered in patients with a pituitary adenoma. The clinical setting makes the distinction.

Unilocular cystic GCTs, adult or juvenile type ( Chapter 16 ). These tumors are grossly indistinguishable from the luteinized cyst but have different microscopic features analogous to those considered in the differential diagnosis of a typical FC vs a GCT (see Follicle Cyst ).