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Nonneoplastic Ovarian Cysts & Tumors
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Follicular & Luteal Cysts
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Physiologically normal structures in the ovary such as follicles and corpora lutea may occasionally become sufficiently enlarged or cystic (Table 52-1) to present as an ovarian mass that may be difficult to distinguish from a neoplastic lesion. These include (1) follicular cysts, which are 1–5 cm in diameter and lined by flattened granulosa cells; (2) luteal cysts and hematomas formed during degeneration of the corpus luteum; and (3) theca lutein cysts, which are multiple cysts occurring in patients with trophoblastic neoplasms that secrete human chorionic gonadotropin (hCG). Theca lutein cysts resemble luteal cysts but represent hCG-induced luteinization of follicular cells lining atretic follicles rather than true corpora lutea. All of these cysts regress spontaneously.
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Luteoma of pregnancy is an extreme form of luteal hyperplasia that produces a nodular mass in the ovary in the last trimester. It may reach a large size and may be bilateral. Luteomas are commonly encountered during cesarean sections and should not be mistaken for neoplasms. Grossly, they are solid yellowish-brown masses composed microscopically of sheets of large luteinized cells with abundant eosinophilic cytoplasm. Rarely, luteomas produce androgens and cause virilization. They involute spontaneously within a few weeks after delivery.
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Polycystic Ovary Syndrome
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Polycystic ovary syndrome is characterized by (1) bilaterally enlarged ovaries; (2) multiple follicular cysts in the outer, subcapsular region; (3) absence of corpora lutea (resulting from failure of ovulation); and (4) hyperplastic ovarian stroma with thickening of the capsule (Figure 52-3).
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It is associated clinically with (1) amenorrhea, infertility, and virilism (Stein-Leventhal syndrome); (2) excess androgen secretion (usually androstenedione); (3) normal or elevated estrogen levels, which may cause endometrial hyperplasia and abnormal uterine bleeding (menorrhagia); and (4) an increased incidence of endometrial carcinoma.
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The cause of polycystic disease is probably abnormal secretion of pituitary gonadotropins; the normal luteinizing hormone (LH) surge that causes ovulation is lacking, and continuous FSH and LH stimulation leads to the development of multiple follicular cysts. Treatment with clomiphene, which stimulates ovulation, is effective; surgical wedge resection of the ovary, which was standard treatment in the past, is now rarely needed.
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The ovary is the most common site for extrauterine endometriosis (see Chapter 53: The Uterus, Vagina, & Vulva). Ovarian endometriosis is characterized by the appearance of multiple hemorrhagic cysts (chocolate cysts) characterized microscopically by a lining of endometrial epithelium and stroma.
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Neoplasms of the Ovaries
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Neoplasms of the ovary are relatively common; 75–80% are benign. Malignant ovarian neoplasms account for about 5% of all cancers in women (the fifth most common cancer in American women). Benign neoplasms occur in a younger age group (20–40 years) than malignant ones (40–60 years), but there is considerable overlap. The cause of ovarian neoplasms is unknown; risk factors are poorly defined.
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Ovarian neoplasms are classified according to their histogenesis (Figure 52-4 and Table 52-2) into neoplasms derived from the surface (celomic) epithelium, which are most common, germ cell neoplasms, stromal neoplasms, and metastases.
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Ovarian neoplasms are often found incidentally during pelvic examination, radiography, or abdominal surgery. Large neoplasms may produce a sensation of heaviness or discomfort in the lower abdomen. Pressure on the bladder may cause frequency of micturition. Malignant neoplasms often remain silent until they have metastasized.
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Hormone-secreting ovarian neoplasms present with manifestations of hormone excess. Estrogen-secreting granulosa-theca cell tumors cause endometrial hyperplasia and adenocarcinoma, leading to abnormal uterine bleeding. Androgen-secreting tumors cause virilization. Very rarely, thyroid tissue or neuroendocrine (carcinoid) elements in an ovarian teratoma lead to hyperthyroidism or carcinoid syndrome, respectively.
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Malignant ovarian neoplasms tend to spread locally in the peritoneal cavity, leading to ascites. Cytologic examination of aspirated peritoneal fluid may be diagnostic in such cases. In many of these cases, metastases in the omentum cannot be seen grossly, and random omental biopsies should be taken at the time of excision of the ovarian cancer. In other cases, omental deposits appear as extensive flat, solid masses (likened to pancakes). Lymphatic spread, to iliac and para-aortic lymph nodes, and hematogenous spread, most commonly to the lungs, occurs in the high-grade malignant neoplasms.
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Surgical removal represents the primary mode of therapy for treatment of ovarian neoplasms. With benign neoplasms and most of those of low malignant potential, surgery is curative. For malignant neoplasms, radiation therapy and chemotherapy are used in conjunction with surgery.
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Celomic (Germinal) Epithelial Neoplasms
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Neoplasms derived from the surface celomic epithelium are the most common group of ovarian neoplasms. They may differentiate into a variety of different cell types that recapitulate the differentiating potential of müllerian epithelium (Table 52-3). Within these groups, three biologic types of tumor may be recognized based on histologic criteria (Table 52-3 and Figure 52-6).
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Serous tumors are the most common ovarian neoplasms, accounting for approximately 40% of primary ovarian neoplasms and 40% of primary cancers. They occur in the age group from 15 to 50 years. Benign neoplasms tend to occur in younger women than malignant ones. Serous tumors are frequently bilateral; 25% of benign, 30% of low malignant potential (borderline), and 70% of malignant serous tumors are bilateral.
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Based on the microscopic appearance, three different biologic types are recognized (Figure 52-6).
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Benign Serous Cystadenoma
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Benign serous tumors vary in size from small cysts in the ovary (germinal inclusion cysts; serous cystomas) to large multilocular cystic neoplasms reaching a size of > 40 cm. They have a smooth external surface and a smooth or papillary internal lining (Figure 52-7) of cuboidal or flattened epithelium. Taller columnar cells—sometimes ciliated—resembling cells from the uterine tubes may be seen.
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A variant of serous cystadenoma containing, in addition, a mass of proliferating fibrous connective tissue between the cystic spaces is known as serous cystadenofibroma.
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Benign serous tumors do not infiltrate the capsule or metastasize. Surgical removal is curative.
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Serous Tumor of Low Malignant Potential
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Serous tumors of low malignant potential (also called borderline serous tumors) are distinguished from benign serous cystadenomas in having more exuberant papillary ingrowths and a complex histologic pattern. The neoplastic cells lining the papillae are taller than those lining benign neoplasms, with stratification (up to three cell layers) and mild cytologic atypia (Figures 52-6 and 52-8). Calcification in the form of round, laminated psammoma bodies is commonly present.
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Serous tumors of low malignant potential are distinguished from serous cystadenocarcinoma by the lack of infiltration of the stroma or capsule of the neoplasm. Carcinomas also have a greater degree of cell stratification and cytologic atypia (see below).
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Serous tumors of low malignant potential may metastasize to the peritoneal cavity and rarely to the lungs. They have a good prognosis (5-year survival rate of 95%) even in the presence of peritoneal metastases.
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Serous Cystadenocarcinoma
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Serous cystadenocarcinomas show irregular solid and cystic areas. The outer surface may be irregular due to infiltrating tumor (Figure 52-6). Microscopically, the cyst epithelial lining has a highly complex papillary pattern with cell stratification, marked cytologic atypia, and stromal or capsular invasion (Figure 52-6). Calcification in the form of round, laminated psammoma bodies is commonly present.
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High-grade serous cystadenocarcinoma loses its papillary appearance and becomes indistinguishable from undifferentiated carcinoma in many areas.
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Serous cystadenocarcinoma is a highly malignant neoplasm, infiltrating and metastasizing early in its course. Local spread to the peritoneum and omentum occurs early. Lymph node involvement also occurs early, with metastases in pelvic and para-aortic lymph nodes. Distant metastases occur late, with lung and liver the main sites. The 5-year survival rate is about 20%.
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Mucinous tumors account for 20% of ovarian neoplasms. They occur most often in the age group from 15 to 50 years. Most are benign. Mucinous cystadenocarcinoma accounts for 10% of ovarian cancers. Mucinous tumors are less frequently bilateral than serous tumors (20% bilaterality for tumors of low malignant potential and malignant mucinous tumors).
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Based on their histologic features, three types of mucinous tumors are recognized.
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Benign Mucinous Cystadenoma
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Mucinous cystadenoma tends to be larger than serous cystadenoma and typically is a cystic multiloculated neoplasm filled with thick mucoid fluid (Figure 52-9). The inner lining is smooth and is composed of uniform tall columnar cells with flattened basal nuclei, and the apical part of the cell is distended with mucin (Figure 52-10). The lining epithelium resembles that of the endocervix.
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Surgical removal is curative.
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Mucinous Tumor of Low Malignant Potential
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Mucinous tumors of low malignant potential (borderline mucinous tumors) are distinguished from benign tumors by the presence of complex papillary projections, cell stratification, and mild cytologic atypia of the epithelial lining; and from carcinoma by the lesser degree of stratification and cytologic atypia and the absence of stromal and capsular invasion.
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Mucinous tumors of low malignant potential grow slowly and may spread to the peritoneum, producing multiple mucoid masses with extensive adhesions (pseudomyxoma peritonei). Pseudomyxoma peritonei is usually associated with mucinous tumors that are lined with epithelium demonstrating intestinal-type features; goblet cells are seen often. Distant metastases are rare. The 5-year survival rate is approximately 90%, but the overall long-term prognosis is poor when there is extensive peritoneal disease.
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Mucinous Cystadenocarcinoma
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Mucinous cystadenocarcinoma can be recognized by the presence of solid areas and evidence of invasion. Microscopically, there is marked cytologic anaplasia and extensive infiltration. This highly malignant neoplasm infiltrates locally and metastasizes to the peritoneal cavity, lymph nodes, and distant organs in a manner similar to serous cystadenocarcinoma. Prognosis is poor.
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Endometrioid Carcinoma
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Endometrioid carcinoma accounts for 20% of malignant ovarian neoplasms. Bilaterality is present in 40% of cases. It is defined by its microscopic resemblance to endometrial carcinoma. Associated endometriosis is found in about 25% of cases. In some cases concurrent endometrial carcinoma is present, raising the question of whether the ovarian neoplasm is metastatic or a second independent primary. Origin of some endometrioid carcinomas from endometriosis has been demonstrated, but the frequency with which this occurs is probably low; in most cases, the tumor is believed to represent endometrioid differentiation of a neoplasm derived from the celomic epithelium.
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Endometrioid carcinomas grossly appear as solid and cystic masses that frequently show areas of hemorrhage and necrosis. Microscopically, the cells resemble endometrial carcinoma (Figure 52-11). Squamous metaplasia is seen in 50% of cases.
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Endometrioid carcinoma has the best prognosis among ovarian carcinomas, with a 5-year survival rate of 50%. Endometrioid tumors of low malignant potential (borderline endometrioid tumors) have been described but are rare.
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Clear cell carcinoma of the ovary was originally called mesonephric carcinoma because of a presumed origin from mesonephric rests. This hypothesis has been discredited, and this rare type of ovarian cancer is now regarded as originating from the celomic epithelium. Clear cell carcinoma accounts for 5% of malignant primary neoplasms of the ovary and is characterized histologically by large cells with clear cytoplasm arranged in solid glandular, tubular, or papillary patterns (Figure 52-12). Clear cell carcinoma has a prognosis similar to that of endometrioid carcinoma.
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Brenner tumor is uncommon, accounting for 2% of ovarian neoplasms. It occurs at all ages but is most frequently encountered as an incidental finding in older patients.
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Grossly, it is a solid, firm white neoplasm that varies from 1 to 30 cm in size. Small cysts containing mucinous material are common. Microscopically, Brenner tumors are characterized by a cellular fibroblastic stroma in which there are epithelial islands composed of uniform, cytologically benign cells that resemble transitional epithelium.
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Brenner tumors are usually benign. Rare Brenner tumors show evidence of proliferation of the transitional epithelium; these proliferating Brenner tumors are analogous to tumors of low malignant potential. Malignant Brenner tumors are very rare and resemble transitional cell carcinoma.
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Undifferentiated Carcinoma
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The term undifferentiated carcinoma is used for an epithelial neoplasm of the ovary that does not show any kind of differentiation. Such tumors are composed of solid masses of cells with necrosis, hemorrhage, and a high rate of mitotic figures. They have the poorest prognosis, with a 5-year survival rate of less than 10%.
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A variant of undifferentiated carcinoma known as small cell carcinoma of the ovary occurs in young women and is associated with hypercalcemia.
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Germ cell tumors of the ovary are similar in derivation to their counterparts in the testis, but there are some striking differences. Mature teratoma of the ovary is biologically benign at all ages—not true of teratomas of the testis—and is responsible for 80% of all germ cell tumors of the ovary. Dysgerminoma (which is histologically identical to seminoma in the testis) and yolk sac carcinoma are similar to their testicular counterparts. Immature teratoma of the ovary occurs mainly in the age group under 20 years and is a highly malignant neoplasm. Embryonal carcinoma and choriocarcinoma are extremely rare in the ovary.
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Benign Cystic Teratoma (Dermoid Cyst)
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Benign cystic teratoma is a common neoplasm of the ovary, accounting for about 15% of ovarian neoplasms. It is bilateral in 10% of cases and occurs in all age groups, most commonly over 20 years.
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Benign teratoma appears grossly as a cyst containing thick sebaceous material and hair (which is why it is sometimes called dermoid cyst). The internal lining is mostly smooth but frequently has a knob-like nodular protrusion in one area (the umbo), in which cartilage, bone, and well-formed teeth may be present (Figure 52-13A). Microscopically, skin elements dominate, including dermal appendages such as hair follicles and sebaceous glands. In most cases, however, structures of endodermal (respiratory and gastrointestinal epithelia) and mesodermal (muscle, fat, cartilage) origin are present, satisfying the definition of teratoma (Figure 52-13B). Glial elements are also commonly present. Rare ovarian teratomas are composed almost entirely of thyroid tissue (struma ovarii) or tissue resembling carcinoid tumor.
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Cystic teratomas of the ovary are benign. Very rarely, malignant transformation occurs in one of the elements of a benign teratoma, most commonly the squamous epithelium, giving rise to squamous carcinoma.
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Immature Teratoma (Malignant Teratoma)
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Immature teratoma is a rare malignant variant of teratoma that occurs mainly in patients younger than 20 years of age.
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Grossly, immature teratomas are usually solid neoplasms with minimal cystic change. Microscopically, they are composed of immature (poorly differentiated) elements derived from all three germ layers. Primitive neuroectodermal (neuroblastic) elements are especially common. Immature teratoma is graded histologically according to the amount of primitive neuroectodermal tissue it contains; tumors with large areas of neuroblast are the highest grade (grade 3) and have the worst prognosis.
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Dysgerminoma is the ovarian counterpart of seminoma of the testis. It accounts for about 2% of ovarian cancers. Dysgerminomas commonly occur in the age group from 10 to 30 years.
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Grossly, dysgerminomas are usually solid, rarely (5–10%) bilateral, and range in size from very small to enormous. They have a firm, homogeneous yellowish-white cut surface. Microscopically, nests of round germ cells are separated by fibrous trabeculae infiltrated by lymphocytes—an appearance identical to that of testicular seminoma (Figure 52-14). Necrosis and granulomatous inflammation are common.
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Although potentially malignant, small dysgerminomas confined to the ovary are usually cured by simple resection. The overall prognosis is good, with a 5-year survival rate of 80%.
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Yolk Sac Tumor (Endodermal Sinus Tumor)
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Yolk sac tumors are rare, accounting for 1% of ovarian cancers. They occur mainly in females under 20 years of age and are solid neoplasms with areas of necrosis and hemorrhage. Histologically, yolk sac tumors are composed of a lace-like arrangement of primitive cells in which are found structures resembling immature glomeruli (glomeruloid or Schiller-Duval bodies). Yolk sac tumors of the ovary are identical to their testicular counterpart. They are highly malignant neoplasms with a bad prognosis. Alpha-fetoprotein can be detected in the cytoplasm as well as in the serum. Serum α-fetoprotein assay provides a mechanism for following therapy.
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Gonadal Stromal Neoplasms
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Gonadal stromal neoplasms account for 5% of ovarian neoplasms. They are composed of variable mixtures of granulosa cells, theca cells, stromal fibroblasts, and cells resembling testicular Sertoli cells and Leydig cells.
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Granulosa-Theca Cell Tumors
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Granulosa-theca cell tumors are derived from the follicular epithelium of the primordial follicles and account for 2% of ovarian neoplasms. They may occur at any age but are most frequently seen in postmenopausal women. A variant—juvenile granulosa cell tumor—occurs in young women. About 5% are bilateral.
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Grossly, granulosa-theca cell tumors are solid yellowish fleshy masses that frequently show extensive hemorrhage and cystic change. Microscopically, they are composed of a variable mixture of granulosa and theca cells (Figure 52-15). The granulosa cells appear as small, uniform cells arranged in solid masses with a follicular or trabecular pattern; the formation of small spaces filled with eosinophilic fluid, recapitulating the normal structure of the graafian follicle (Call-Exner bodies), is characteristic. The more elongated theca cells tend to surround the granulosa cell masses.
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Granulosa-theca cell tumors typically secrete estrogens, which produce hyperplasia of the endometrium and predispose to endometrial adenocarcinoma. Abnormal uterine bleeding is the most common mode of presentation.
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The biologic behavior of these tumors cannot be predicted on the basis of their histologic features. About 25% behave in a locally aggressive manner. Distant metastases occur in about 10–15% of cases. The 5-year survival rate for patients with granulosa-theca cell tumors is 85%.
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Fibroma (Fibrothecoma)
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Ovarian fibromas are benign neoplasms that arise in the ovarian mesenchymal stroma. They account for 3% of ovarian neoplasms and occasionally (5%) are bilateral. Fibromas are most often seen in postmenopausal women.
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Grossly, fibromas form encapsulated white masses, usually less than 20 cm in diameter. Tumors that have a significant theca cell component are yellow. Microscopically, they are composed of fibroblasts and interspersed theca cells. Approximately 20% are associated with marked ascites, and a small proportion also show pleural effusions (Meigs' syndrome).
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Sertoli-Leydig Cell Tumor (Androblastoma; Arrhenoblastoma)
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Sertoli-Leydig cell tumors are rare. They occur at all ages, most commonly in the 10- to 30-year age group. Less than 5% are bilateral.
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Grossly, they are solid grayish-white neoplasms with areas of hemorrhage, necrosis, and cystic degeneration. Histologically, they are composed of large cells with abundant eosinophilic cytoplasm arranged in nests or tubules.
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Sertoli-Leydig cell tumors commonly produce androgens and cause virilization. Rarely, they secrete estrogens. They resemble the corresponding testicular tumors. Most have a benign biologic behavior; the 5-year survival rate is 90%. Malignant behavior is associated with the less well-differentiated neoplasms.
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Gonadoblastoma is a rare ovarian neoplasm composed of a mixture of stromal cells (usually Sertoli-Leydig cells) and germ cells (usually dysgerminoma). Extensive calcification is a common feature. Gonadoblastoma occurs almost exclusively in dysgenetic ovaries in patients with sex chromosome abnormalities (usually in streak ovaries of phenotypic females who have a Y chromosome in their karyotype, eg, XX/XY mosaics). The biologic behavior of gonadoblastoma depends on the amount of germ cell neoplasm that is present: The more there is, the more malignant the tumor is.
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The ovary is a common site for metastases, particularly in carcinoma of the endometrium, breast, stomach, and colon. Metastatic carcinoma causes solid enlargement of one or both ovaries, which may reach a large size. In some cases, differentiation from primary ovarian carcinoma can be difficult, particularly in undifferentiated carcinoma and metastatic colon and endometrial carcinoma, which resemble endometrioid carcinoma of the ovary.
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Krukenberg's tumor consists of bilateral involvement of the ovaries by a desmoplastic signet ring cell carcinoma of gastric origin (Figure 52-16); some authorities extend the term to denote any metastatic adenocarcinoma of the ovary.
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