Mature cystic teratomas, also known as dermoid cysts, are the most common benign ovarian neoplasm, with a peak incidence from ages 20 to 40 years. However, they can also be seen in infancy as well as in menopausal woman. Mature cystic teratomas originate from primordial germ cells and are composed of well-differentiated derivatives of any combination of the three germ layers: ectoderm, mesoderm, and endoderm. Ectodermal elements usually predominate. Although they are in general benign, on rare occasion they may undergo malignant transformation in one of the elements, with squamous cell carcinoma being the most frequent malignant histology.

Grossly, the tumors are round or oval with a smooth, glistening, gray-white surface. The majority of tumors measure 5 to 10 cm in diameter, with 8% to 15% of cases being bilateral. The tumors are usually unilocular but occasionally multilocular and are filled with hair and a fatty material similar to sebum. A solid portion located at one pole of the cyst and projecting into the cavity is known as a Rokitansky protuberance, where all three germ cell layers are found. (Fig. 61.1). Tissues also can be found at the protuberance, such as hair, teeth, bone, glia, neural tissue, cartilage, retina, smooth muscle, fibrous and fatty tissue, gastrointestinal and bronchial mucosa, and thyroid and salivary gland
tissue. Microscopically, ovarian stroma is noted on the outside wall, with the cyst being lined by mostly squamous cell epithelium with underlying sebaceous and sweat glands (Fig. 61.2).

In the past, a diagnosis of benign cystic teratoma was usually made on an abdominal radiograph in a young woman with acute abdominal pain, because osseous differentiation or teeth could be seen in the pelvis. Transvaginal sonography, however, has become the diagnostic test of choice in most centers, although pelvic magnetic resonance imaging (MRI) can be helpful when the diagnosis is uncertain and may be especially useful when the mass is detected during pregnancy. Torsion is a frequent complication, because these tumors are relatively buoyant and mobile. Treatment usually involves ovarian cystectomy, with preservation of normal ovarian tissue and close inspection of the contralateral ovary. This often can be accomplished laparoscopically, when the dermoid cyst can be shelled out from the remaining normal ovary. Although concern for chemical peritonitis resulting from cyst rupture exists, with copious irrigation of the peritoneal cavity, this complication can be avoided.

Malignant ovarian germ cell tumors account for <5% of all ovarian cancers. Table 61.1 provides a listing of the World Health Organization classification of germ cell tumors of the ovary. Their male counterpart, testicular cancer, is approximately ten times more common than ovarian germ cell tumors, and many of the chemotherapy regimens that are used have been adapted from clinical trials in patients with the corresponding type of testicular cancer.

These interesting tumors tend to be diagnosed at an earlier stage than the common epithelial ovarian carcinomas, and they are very sensitive to chemotherapy and, in the case of dysgerminoma, to radiotherapy as well. Germ cell tumors have distinct histopathologic features and tumor markers that are useful in diagnosis and follow-up. Table 61.2 outlines the serum markers typically associated with germ cell tumors.

Thecoma is a benign tumor affecting all ages, with a predominance in the postmenopausal group; it is rare in patients younger than 35 years. It accounts for 2% of all ovarian tumors. Many women with a thecoma present with abnormal or postmenopausal uterine bleeding; some present with an endometrial adenocarcinoma as a result of unopposed estrogen production by the tumor. Thecoma is composed of lipid-laden stromal cells resembling theca cells. Rather than arising as a de novo neoplasm, it may represent changes occurring in background cortical stromal hyperplasia.

Tumor size ranges from a nonpalpable incidental finding to a large solid mass with a diameter of 15 to 20 cm. It is usually unilateral and almost never malignant. Its outer surface is smooth, and its cut surface is typically solid, lobulated, and yellow. Cystic change may be seen. Microscopic evaluation reveals masses of oval or round cells with abundant, pale, lipid-containing cytoplasm. Hyaline plaques are often noted. A luteinized thecoma sometimes occurs, usually in younger women.

Treatment for thecoma is tailored to patient age and ranges from a total abdominal hysterectomy and bilateral salpingo-oophorectomy for menopausal or postmenopausal women to a salpingo-oophorectomy or ovarian cystectomy, if possible, in patients who desire future fertility.

Like thecoma, fibroma is also a benign tumor affecting all ages, although most occur in women 40 to 60 years of age; fewer than 10% of patients are 30 years of age or younger. Fibroma is not associated with hormone production. In some cases, hydrothorax and ascites are found in association with a pelvic mass—a constellation of findings known as Meigs syndrome. In other cases, fibroma is seen in patients with a hereditary basal cell nevus syndrome, characterized by early-appearing basal cell carcinomas, keratocysts of the jaw, calcification of the dura, and mesenteric cysts.

Fibroma, like thecoma, ranges in size from a nonpalpable incidental finding to larger than 20 cm; it is usually unilateral but multinodular. Cut surface is firm and hard and has a whorled appearance. Microscopically, fibroma is composed of bundles of collagen-producing spindle cells arranged in a storiform pattern (Fig. 61.12). Hyalinization and intercellular edema are characteristic. The cytoplasm of tumor cells may contain small quantities of lipid, making distinction from thecoma difficult.

Treatment is similar to that for thecoma. In patients with Meigs syndrome, the hydrothorax and ascites usually resolve after resection of the pelvic tumor.

Approximately 44% of all juvenile granulosa cell tumors occur in the first decade of life and 97% in the first 3 decades. Isosexual pseudoprecocious puberty is commonly associated with this tumor, along with Ollier disease (enchondromatosis), Maffucci syndrome (enchondromatosis and hemangiomatosis), and abnormal karyotypes with ambiguous genitalia. Symptoms usually include abdominal pain, increasing abdominal girth, and
hemoperitoneum due to rupture. Occasionally, it may be associated with pregnancy.

The gross appearance of juvenile granulosa cell tumor is commonly a large yellow-to-gray, solid and cystic mass, similar to the adult form. A mixture of granulosa and theca cells may be present. Microscopic features that distinguish juvenile granulosa cell tumor from the adult form are hyperchromatism of the tumor cells, which generally lack grooves, and the frequent luteinization of both the granulosa and theca cells (Fig. 61.13). The follicles are usually immature (Fig. 61.14). Call-Exner bodies, which are pathognomonic of adult granulosa cell tumor, are rarely present in the juvenile form.

Treatment in young women usually consists of a unilateral salpingo-oophorectomy with a complete staging (Table 61.3), especially if preservation of reproductive function is desired and the tumor appears to be grossly confined to one ovary. Although the survival rate for stage I disease is >90%, juvenile granulosa cell tumor appears to behave more aggressively in advanced disease, with a survival rate of <50%. Isolated reports of successful treatment with various combination chemotherapies have been recorded. Due to the rarity of these tumors, a standard chemotherapeutic regimen has not emerged.

The adult form of granulosa cell tumor accounts for 1% to 2% of all ovarian tumors and 95% of all granulosa cell tumors. Although these tumors average 10 to 12 cm in diameter, a pelvic mass is not always detectable. Peak age of occurrence is 50 to 55 years, and most granulosa cell tumors produce estrogen, which in premenopausal women is manifested by menstrual irregularities such as menorrhagia,
amenorrhea due to anovulation, or metrorrhagia. In postmenopausal women, vaginal bleeding results from endometrial stimulation. Endometrial hyperplasia or carcinoma is a common occurrence, approximately twice that seen in premenopausal women. The best estimate for the frequency of associated endometrial carcinoma is 5%.

Grossly, the tumors are solid and gray-white or yellow, with cystic areas and hemorrhage. Microscopically, they are composed of granulosa cells and theca cells or fibroblasts, or both. Theca cells and fibroblasts are most likely a response of the ovarian stroma to granulosa cell proliferation, because only granulosa cells are found in metastatic sites. Granulosa cells may be round, polygonal, or spindle shaped, with scant cytoplasm and round or ovoid nuclei. Many different histologic patterns may be seen separately or together; these include the microfollicular pattern with its distinctive Call-Exner bodies (Fig. 61.15), macrofollicular, insular, trabecular, solid-tubular, and rarely hollow-tubular patterns. Less differentiated forms include the watered-silk or diffuse pattern. Rarely, a granulosa cell tumor undergoes sarcomatous transformation, producing the most aggressive form of the disease. Inhibin may be a useful immunohistochemical marker, and serum inhibin levels can be used to monitor the clinical course.

Although most granulosa cell tumors have a very low potential for malignant behavior, with 90% of tumors being stage Ia, they do have a propensity for late recurrence up to 10 to 20 years or more after initial diagnosis. In addition to full surgical staging (Table 61.3), surgery should include a total abdominal hysterectomy and bilateral salpingo-oophorectomy in postmenopausal patients. Conservative surgery is indicated in younger patients who wish to maintain fertility if the tumor is confined to one ovary. One of the largest series compared the impact of uterine-sparing surgery on survival in young women with stage I disease and found no difference in the 5-year disease-specific
survival between those women who had conservative versus standard surgical staging, 98% versus 97% respectively. Patient age and stage appear to be the most important prognostic factors. Although other prognostic factors include capsular rupture, tumor size, nuclear atypia, mitotic activity, and histologic pattern, studies of these factors have not been conclusive. It is difficult to evaluate the efficacy of chemotherapy in this group of tumors. Most retrospective series have been limited by their small sample size and short follow-up. Platinum-based therapy, including the VBP and BEP regimens, has been reported to be the most successful, with a 5-year survival of 50% for patients with advanced-stage disease. Taxane-based regimens have been proposed given the lack of durable remissions and significant toxicity of the BEP regimen. Investigators at M. D. Anderson reported a retrospective study of patients with predominantly granulosa cell tumors who received either BEP or a taxane-based regimen. While there were no statistical differences in clinical outcome, the BEP regimen was associated with higher toxicity. The authors suggest that taxane-platinum–based therapy merits consideration in future prospective trials for sexcord–stromal tumors. Radiotherapy has also been used with varying success in studies limited by small numbers. In recurrent disease, surgery followed by chemotherapy may offer the best mode of therapy.