Pathology

III. Neoplasms

Objectives

After completing this section you will know:

• the main groups of ovarian neoplasms
• which group is most common
• which group accounts for the most deaths
• which group presents with hormonal activity and which produces tumor markers
• which group has analogous testicular tumors

The ovary presents a wide range of major tumors, which reflect the various histologic elements found in the organ. The many variants of these tumors make the ovary the organ with the widest variety of tumors in the human body. The tumors can be broadly categorized into three groups. Tumors derived from:

• Surface epithelium, termed common epithelial tumors are the most common
• Ovarian stroma, many are hormonally active
• Germ cells, homologous, but not always, to testicular germ cell tumors.

Some of the tumors come to light because they are hormonally active. The vast majority, however, produce relatively mild symptoms until they have reached a large size. Since they are difficult to detect early in their development when still curable, malignant ovarian tumors have usually spread beyond the ovary by the time of diagnosis leading to a disproportionate number of mortality from these tumors.

Patients most frequently present with abdominal pain and distension, urinary and gastrointestinal symptoms due to compression or invasion by tumor, and vaginal bleeding. Benign tumors are often entirely asymptomatic and detected as incidental findings at the time of surgery for other reasons.

Sections:

1. Epithelial Tumors
2. Germ Cell Tumors
3. Sex Cord - Stromal Tumors
4. Miscellaneous Ovarian Tumors

1. Epithelial Tumors

Objectives

After completing this section you will:

• know the common subtypes and which are most often bilateral
• match the various subtypes with epithelium in other parts of the female genital tract
• understand the concept of borderline tumors and how to distinguish them from carcinomas
• be able to describe clinical features including relevant associations
• be able to suggest possible clinical outcomes and response to treatment

Epidemiology

This group, which includes both completely benign and highly malignant neoplasms, accounts for 60 to 80% of ovarian tumors and more than 90% of cancers. Benign tumors occur mostly in young women between 20 and 45 years while malignant tumors are more common in women some 20 years older.

Classification

The tumors arise from the ovarian surface epithelium and the neoplastic cells resemble epithelial cells from other parts of the female genital tract. The group is subdivided into five subgroups:

• Serous tumors, composed of columnar to cuboidal epithelial cells that mimic fallopian tube epithelial cells
• Mucinous tumors, which resemble endocervical mucinous glands
• Endometrioid tumors, which contain glands identical to those of uterine endometrial adenocarcinoma
• Clear cell tumors,
• Brenner tumors, which in contrast to the others, resemble transitional epithelium of the urinary tract.

Mixture of epithelia frequently occurs in the same tumor. Grossly, the tumors range in size from small to massive tumors, which may fill the pelvic and abdominal cavities. They may be cystic, cystic and solid or entirely solid. The amount of solid tumor tissue present roughly corresponds with the risk of malignancy.

Concept of borderline tumors

This is a very important concept. The terminology "borderline ovarian tumors" (also designated "tumors of low malignant potential") refers to a group of epithelial tumors that share an excellent prognosis inspite of their malignant cytologic features. The tumors tend to remain confined to the ovary and a surgical cure is always possible. When the tumors have even spread to the peritoneal cavity 5-year survival is 80 to 90%. Borderline tumors occur predominantly in premenopausal women. In women less than 40 years two-thirds of all non-benign ovarian tumors are borderline, whereas in patients over 40 years, only 10% of non-benign lesions are borderline.

Although borderline tumors show a greater degree of proliferative activity and cellular atypia than benign tumors, they generally show less atypia than their overtly carcinomatous counterparts. They are differentiated from carcinomas by the absence of ovarian stromal invasion in them and its presence in carcinomas.

The validity of the concept has been questioned by some because of the generally non-malignant nature of these tumors.

• Serous tumors

Serous ovarian neoplasms are the most common group of epithelial tumors. The tumors are subdivided into benign (60%), borderline (15%) and malignant (25%). Serous tumors are often bilateral. The more malignant the lesion, the more likely it is to be bilateral. Only about 20 to 30% of benign tumors are bilateral while 30 to 40% of borderline and 65 to 75% of carcinomas are bilateral. The tumors are often cystic and filled with a clear serous fluid. The fluid may be mucoid in quality, and the distinction from mucinous tumors is not made on the gross qualities of the fluid but on the histologic features.

Benign serous tumors, called serous cystadenomas, are frequently large, entirely cystic and thin-walled, and commonly unilocular but may be multiloculated. They are lined by smooth epithelial surface and contain thin, clear yellow fluid.

Unilocular serous cystadenoma.

Histologically, a single, uniform layer of cuboidal or columnar epithelium resembling fallopian tube epithelium lines the tumors. Papillae, when present, comprise fibrovascular core covered by a similar single layer epithelium.

Serous cystadenoma. Note single layer of lining epithelium with no cellular stratification or papillary tufting.

Borderline serous tumors may be cystic with thin wall and smooth surface, but often have multiple papillary excresences, which range from grape-like clusters to abundant papillary structures, protruding into the lumen in places.

Borderline papillary serous tumor showing grape-like papillary protrusions.

Histologic features include complex papillary projections lined by epithelial cells showing stratification, nuclear pleomorphism and hyperchromasia and mitoses. By definition, there is no stromal invasion.

Borderline papillary serous tumor.Note absence of stromal invasion.

High power view of papillary tuft in borderline serous tumor.Note cellular pleomorphism.

Malignant serous tumors (serous cystadenocarcinoma) is the commonest malignant ovarian tumor, forming about a third of all cancers of the ovary. The tumors are cystic but exuberant excrescences, which produce solid areas in places, often with necrosis and hemorrhage, usually line the entire surface. Ovarian surface involvement may be present.These tumors usually present with ascietes due to abdominal metastases.

Bilateral serous cystadenocarcinoma Note metastases to omentum (top).

Histologically, the tumors range from well to poorly-differentiated. The well- differentiated tumors are papillary with features similar to those of borderline tumors but there is ovarian stromal invasion. In the poorly differentiated tumors, there is a predominance of invasive sheets of solid malignant cells with inconspicuous papillary pattern. Concentric calcified bodies, psammoma bodies, are often present.

Serous cystadenocarcinoma showing malignant glands invading stroma.

• Mucinous tumors

Mucinous tumors form about 25% of all ovarian neoplasms. Their nomenclature and subdivision parallel those of serous tumors. 80 to 85% are benign, 5 to 10% borderline and 10% are malignant. The tumors are less often bilateral with about 5% of benign, 10% borderline and 20% of carcinomas being bilateral. Benign tumors present in patients between 20 and 50 years while malignant ones occur in those over 40 years old. Mucinous tumors are among the largest tumors recorded. They are typically cystic and multilocular and filled with thick sticky, viscous, less often, thin and watery fluid. As with serous tumors, the gross quality of the cyst fluid cannot be reliably used to identify the tumors.

The benign tumors are called mucinous cystadenoma. The tumors have thin walls lacking solid areas.

Histologically, a single layer of tall columnar mucinous epithelial cells with basally placed nuclei and containing apical mucin, lines the cystic spaces. No ciliated cells are present. In some cases, the epithelium lining the cysts resembles that of colonic mucosa with goblet cells among cells not secreting mucus, Paneth and neuroendocrine (argentaffin) cells. The cyst wall may be composed of collagenous tissue or ovarian stroma.

Mucinous cystadenoma with basally placed nuclei and apical mucin. Four locules are present in this section. Note resemblance to endocervical type epithelium.

Borderline mucinous tumors have gross appearances similar to benign tumors but the lining of the cyst locules exhibit focal papillary excrescences and thickening of the wall. Necrosis and hemorrhage are not seen in borderline tumors.

Histologically, the tumors show greater degree of proliferative activity than benign tumors with increased glandular complexity. The lining epithelium is thrown into small papillae with cellular stratification and atypia in the form of nuclear hyperchromasia, increased nuclear cytoplasmic ration and enlarged nucleoli.

Borderline mucinous tumor showing papillary configuration of lining epithelium.

High power view. Note nuclear stratification.

Malignant mucinous tumors form about 10% of all ovarian cancers. The tumors are usually very large partly cystic, partly solid tumors up to about 30 cm in greatest dimension, but may be very massive. The external surface may show areas where the tumor has broached the cortical surface. On cut section, necrosis and hemorrhage are frequently seen in the solid areas, whereas these features are not found in borderline tumors.

Mucinous cystadenocarcinoma. Note bulging, glistening cysts filled with mucin.

Histologically, there is a gradation of differentiation from well through moderately- to poorly-differentiated. Well-differentiated tumors show glands lined by tall columnar cells containing intracytoplasmic mucin, hyperchromatic nuclei, marked cellular stratification and showing mitotic activity. Tumors with moderate to poor differentiation show progressive reduction in gland formation with solid sheets of tumor cells and increasing nuclear atypia, often with many atypical mitotic figures.

Metastatic mucinous cystadenocarcinoma in a lymph node.

Mucinous cystadenocarcinoma showing intestinal type epithelium with argentaffin cells. Note presence of goblet cells.

Pseudomyxoma peritonei

Pseudomyxoma peritonei refers to the presence of large amounts of mucinous material in the peritoneal cavity. This may be due to wide dissemination of a primary ovarian or appendiceal mucinous neoplasm or metaplastic change of the peritoneal lining cells to mucinous cells. The most commonly associated ovarian neoplasm is the intestinal variant of borderline mucinous tumor. Also usually present is a low-grade mucinous adenocarcinoma of the appendix, which shows histologic appearances similar to the ovarian tumor. In such cases it is usually impossible to determine if the ovarian and appendiceal tumors are independent or the ovarian tumors (bilateral in a third to two-thirds of cases) are metastases from the appendix.

Histologically, large pools of mucin associated with cytologically benign or only mildly atypical mucinous epithelium of intestinal type are present in dense fibrous stroma.

There is no effective treatment for this condition, which may lead to considerable morbidity and mortality from fibrous intestinal adhesions and obstruction.

• Endometrioid tumors

The designation endometrioid means "endometrium-like" which emphasizes the histologic similarity of such ovarian tumors to their counterparts in the endometrium. Endometrioid tumors form 5% of all ovarian tumors. Unlike the serous and mucinous tumors, the benign and borderline forms of endometrioid tumors are less well-defined and so most of the neoplasms are malignant.

It is doubtful whether pure benign endometrioid tumors exist. The only well-defined benign endometrioid tumors of the ovary are cystadenofibromata (see mixed epithelial-mesenchymal tumors below).

Borderline endometrioid tumors are rare.

Endometrioid carcinomas form 20% of all ovarian cancers. They are bilateral in 30 to 40% of cases. The tumors have both cystic and solid areas or, occasionally, may be entirely solid. Papillary fronds and projections protrude into the lumen. The cyst fluid may be clear, mucoid or dark and bloody. The solid areas commonly contain foci of necrosis and hemorrhage.

Cystic endometrioid carcinoma. Note dark, clotted bloody content.

Microscopically, endometrioid carcinoma contains glandular spaces lined by epithelium resembling that of uterine endometrial adenocarcinoma. Papillae projecting into cysts may be present.

Well-differentiated endometrioid adenocarcinoma. Glands show irregular budding but have smooth contours.

Endometrioid adenocarcinoma. High power view showing well-formed glands with nuclear stratification.

Occasionally, islands of well-differentiated squamous epithelium (resembling endometrial adenoacanthoma) are present.

Endometrioid adenoacanthoma. Note solid sheet of squamous epithelium (morule).

A synchronous endometrial adenocarcinoma is present with 15 to 30% of ovarian endometrioid carcinoma. The endometrial tumor is a second primary rather than metastatic. The presence of histologically identical tumors in both the ovary and uterus in such a large number of patients is indicative of a "field effect". About 15% of ovarian endometrioid carcinoma coexist with endometriosis but are not considered to have arisen from these non-neoplastic lesions. Foci of other types of surface epithelial tumors may be found.

Question: In what other sites of the female genital tract is a "field effect" or widespread stimulus for neoplasia seen and with what tumor(s) is this associated?

• Clear cell tumors

Benign and borderline clear cell tumors of the ovary are very rare and poorly characterized. Virtually, all clear cell tumors encountered are malignant. Malignant clear cell tumors constitute 5 to10% of all ovarian cancers and up to 40% are bilateral. The tumors are seen most commonly in women in the fifth to eighth decade, with the mean age in the mid-fifties.

Clear cell carcinomas cannot be distinguished from the other surface epithelial tumors by their gross appearances. The tumors are partially cystic but may be entirely solid. Necrosis and hemorrhage may be seen in the solid areas.

Clear cell carcinoma. Tumor nodules protruding into cyst lumen.

Another example of clear cell carcinoma.

Microscopically, clear cell carcinoma of the ovary consists of tumor cells with clear well-defined borders and abundant pale or clear cytoplasm containing a small, often eccentric nucleus, lining tubules or cysts or forming solid sheets. In addition, hobnail cells having prominent nuclei, which bulge from the luminal surface of the cells, may be present lining tubules and cysts.

Clear cell carcinoma. Solid sheet of clear cells.

Clear cell carcinoma showing a tubulopapillary pattern with prominent hobnail cells.

• Brenner tumors

As with other surface epithelial ovarian tumors, the Brenner tumor exists in benign, borderline and malignant forms. The latter two are rare and Brenner tumors encountered are almost invariably benign. The tumor is relatively uncommon forming 1-2% of all ovarian tumors. It is almost always unilateral and usually occurs in women in their fifties.

Benign Brenner tumors vary in size with about half being microscopic incidental findings. Most of the larger tumors are between 2 to 3 cm, solid, well circumscribed and may be calcified. Cut surface is gray, white or yellow.

Brenner tumor, well circumscribed, yellow lobulated tumor.

The histologic appearance of benign Brenner tumor is quite distinctive. There are variable numbers of nests of transitional epithelial cells with coffee bean-shaped nuclei scattered in a dense fibrous stroma. Cell nests often become cystic containing eosinophilic debris or mucin.

Brenner tumor showing nests of transitional epithelium in cellular fibrous stroma.

Brenner tumor. Nest containing microcysts, one filled with eosinophilic debris.

Brenner tumor. High power view showing the "coffee-bean" appearance of the nuclei.

Brenner tumor. High power view showing Reinke's crystalloids.

[Epithelial Tumors][Germ Cell Tumors][Sex Cord - Stromal Tumors][Miscellaneous Ovarian Tumors]

2. Germ Cell Tumors

Objectives

After completing this section you will:

• understand how germ cell tumors originate
• know the commonest type
• be able to describe clinical features including relevant associations
• know which tumor produces which marker
• predict possible clinical outcomes and response to treatment

Epidemiology

Germ cell tumors (GCTs) of the ovary account for 15-20% of all ovarian neoplasms and 95% of these are benign cystic teratomas (dermoid cysts). The remainder tends to be malignant. Unlike the malignant epithelial tumors, which usually occur during the sixth decade, this group of malignant tumors tends to occur mainly in children and young adults and are rare after the menopause.

As a group, the tumors are characterized by rapid growth, predilection for lymphatic and hematogenous spread, predominantly unilateral development, frequent mixtures of germ cell types and association with good prognosis. Many produce biologic (tumor) markers, which may be monitored to assess response to treatment.

Cytogenetic analysis of GCTs has identified isochromosome of the short arm of chromosome 12 [i(12p)] as a specific cytogenetic abnormality seen in over 80% of GCTs, both primary and secondary lesions. This means that the cause(s) and process(s) involved in this genetic alteration may be important in the neoplastic transformation of germ cells. The presence of more than 3 copies of 12p may predict resistance to chemotherapy and augurs a higher likelihood of treatment failure.

Classification

Germ cell tumors are believed to arise from germ cells that in the female follow different lines of differentiation, giving rise to tumors, which with minor variations are analogous to testicular germ cell tumors.

• Dysgerminoma

The dysgerminoma represents the ovarian counterpart of the testicular seminoma. These two tumors are histologically identical and the term germinoma has been proposed for both. Although dysgerminoma is relatively uncommon, accounting for about 2% of all ovarian malignancies, it is the most common malignant germ cell tumor comprising half of all such tumors. The tumor affects primarily younger females with the majority in the second and third decades. It is the most frequently encountered ovarian malignancy in pregnancy. It usually occurs in normally developed females but is the most frequent ovarian malignant tumor found in dysgenetic females, testicular feminization, hermaphrodites and ambiguous genitalia.

Most are unilateral but 10% of gross lesions are bilateral while occult lesions are seen in the other ovary in about 20% of tumors confined to the ovary (stage I). Dysgerminomas tend to be large, solid and bosselated with a smooth surface. The cut surface is soft, fleshy and bulging with a homogeneous pink-tan color.

Dysgerminoma. Note lobulation and uniform tan color with foci of hemorrhage.

Microscopically, the tumors show sheets of monotonous rounded cells with central nuclei containing 1 to 2 prominent nucleoli, surrounded by fibrous stroma infiltrated with mature lymphocytes. Occasional giant cells which stain positively with hCG may be seen. There may be enough of these giant cells to produce clinically detectable hCG levels.

Dysgerminoma showing sheets of monotonous rounded cells with pale cytoplasm and central nuclei. Lymphocytes infiltrate the stroma.

Tumors confined to the ovary have an excellent prognosis, with 5-year survival approaching 100%. Dysgerminomas, like their testicular counterparts, are highly radiosensitive. As with testicular seminomas, an anaplastic form of ovarian dysgerminoma has been described that tends to present at a more advanced stage.

• Teratomas

A teratoma is a germ cell tumor that shows differentiation toward embryonic tissues. They are usually composed of tissues from any, but usually all three germ (embryonic) layers and which are foreign to the ovary. The tumors are subdivided into mature, immature and monodermal. Unlike in the testis, the vast majority of ovarian germ cell tumors are benign mature cystic teratomas.

Question: What are the three germ layers?

Mature teratomas are benign and may be solid or cystic. Solid mature teratomas are uncommon and always unilateral. Mature cystic teratomas form about a fourth of all ovarian tumors and about a third of all benign ovarian tumors. The tumors are found mainly in young women between 20 and 30 years old and are usually unilateral with about 10% being bilateral. They are also called dermoid cysts because 90% of the cysts are lined by mature epidermal tissue with underlying pilosebaceous structures. They are typically filled with sebaceous material and hair. About a third contain well-formed teeth in the wall. Other tissues commonly seen include cartilage, bone, and respiratory epithelium. There is often at one pole of the cyst an irregular nodule of solid tissue (Rokitansky’s nodule or protuberance or mammary body) which usually contains bone, cartilage or fat.

Mature cystic teratoma containing hair and inspissated sebaceous material (lower right corner)

Mature cystic teratoma. Note well-formed tooth (upper right corner)

Mature cystic teratoma showing keratinized squamous epithelium, and respiratory epithelium.

Mature cystic teratoma

Mature teratomas remain confined to the ovary. Very rarely (1%), one of the components, usually the squamous, undergoes malignant transformation in females older than 40 years. Even when this occurs, the prognosis remains good, the tumor invading locally with lymph node and distant organ spread being uncommon. Metastases, if they occur, resemble the adult type malignancy.

Question: How do mature ovarian teratomas arise?

 

Question: What is the likely genotype of an ovarian cystic teratoma and why?

Immature teratomas are composed totally or partially of immature or fetal tissues. They are found mainly in young pre-pubertal adolescents and young women less than 20 years in whom they form about 20% of all malignant tumors. They form about 20% of all malignant germ cell tumors.

The tumors are bulky with smooth external surfaces and usually unilateral (less than 5% are bilateral). Cut surface shows a solid or partly solid tumor with areas of necrosis and hemorrhage.

Immature teratoma with areas of necrosis and hemorrhage.

Microscopically, there is a disorganized collection of tissues from the three germ layers with at least part showing immature, embryonic appearance. Neuroepithelium (brain tissue) is the most common immature element.

Immature teratoma containing primitive neuroepithelium with multiple neural tubes.

Immature teratoma. High power view showing neural epithelium and neural tube.

Rupture of an immature is associated with the development of peritoneal tumor implants. These implants are usually neural and may mature, producing a condition known as gliomatosis peritonei. The latter is benign, but if the implants remain immature, the patient is at high risk of dying from the disease.

Gliomatosis peritonei. Mature brain tissue (lower half) in omental fat.

 

• Monodermal teratomas are teratomas that show unidirectional development to produce one tissue type. They are rare, the most common are struma ovarii and carcinoid. The tumors are always unilateral but a contralateral teratoma may be present.

Struma ovarii is composed entirely of mature thyroid tissue. There may be hyperfunction of the thyroid tissue to cause hyperthyroidism.

Struma ovarii showing mature thyroid follicles containing colloid.

Ovarian carcinoid presumably results from monodirectional differentiation toward argentaffin type cells. The tumor may be functional, producing 5-hydroxytrptamine (serotonin) and cause the carcinoid syndrome. Most remain confined to the ovary even if carcinoid syndrome develops. Primary ovarian carcinoids are uncommonly malignant (<2%) and metastases are rare.

• Endodermal sinus tumor (Yolk sac carcinoma)

Endodermal sinus tumor is a highly malignant and clinically aggressive neoplasm seen most frequently in young females particularly in the first three decades. It is rare after 40 years and is perhaps, the most rapidly growing neoplasm that occurs at any site. It forms approximately 20% of malignant germ cell tumors. The testicular counterpart is uncommon in its pure form, and is usually seen only in infants.

Typically, the endodermal sinus tumor is large, predominantly solid and shows extensive necrosis and hemorrhage. Many have already spread beyond the ovary at time of surgery with bulky, friable tumor filling the pelvic cavity. Patients commonly present with abdominal pain resembling acute abdomen.

The tumor displays multiple histologic patterns. The name is derived from a peculiar pattern, the Schiller-Duval body that resembles the endodermal sinus or yolk sac of rat embryos and seen in over half of the tumors. The Schiller-Duval body is a glomerulus-like structure with central blood vessel surrounded by embryonal cells lying within a space also lined by embryonal cells. Conspicuous intra and extra cellular hyaline globules of alpha-fetoprotein are seen. The AFP is secreted and appears in the blood as a biologic marker for the tumors used both for diagnosis and monitoring response to therapy.

Endodermal sinus tumor showing a Schiller-Duval body.

Endodermal sinus tumor. Pink globules of alpha-fetoprotein are present both intra- and extra-cellularly.

Despite their clinically aggressive nature, 5-year survivals for stage I tumors approach 80% with newer forms of chemotherapy.

• Choriocarcinoma

The vast majority of choriocarcinomas occurring in women arises within the uterus. Choriocarcinoma arises much less commonly in the ovary from ovarian germ cells, unrelated to pregnancy and which differentiates into extra-embryonic (trophoblastic) tissue.

Ovarian choriocarcinoma is unilateral, solid and hemorrhagic. Clinically, the tumor behaves like the testicular form and has undergone wide hematogenous spread by the time of diagnosis. It frequently occurs in association with other germ cell tumors.

Histologically, it is composed of malignant cytotrophoblasts and intermediate trophoblasts surrounded by syncytiotrophoblasts. Immunohistochemical staining shows production, or at least storage of hCG in syncytiotrophoblasts, but not in cytotrophoblasts.

Choriocarcinoma showing syncytiotrophoblasts (lower right corner) and cytotrophoblasts (upper left corner).

The serum marker for choriocarcinoma is beta subunit of hCG, which may be used in diagnosis and to monitor response to treatment or tumor recurrence.

Unlike gestational choriocarcinoma, the ovarian tumor is resistant to methotrexate, used in treating the former. There is often a marked response to newer forms of chemotherapy.

[Epithelial Tumors][Germ Cell Tumors][Sex Cord - Stromal Tumors][Miscellaneous Ovarian Tumors]

3. Sex Cord - Stromal Tumors

Objectives

After completing this section you will:

• understand the origins of these tumors
• know which are feminizing, virilizing or both
• describe clinical features and relevant associations
• predict possible clinical outcomes/behavior and response to treatment

These are tumors that are derived from the gonadal (sex) cords and stroma and account for about 3% of all ovarian tumors.

Classification

In the indifferent gonad in human embryos, the celomic epithelium of the genital (gonadal) ridge proliferates and penetrates the primitive mesenchyme. In the male, the epithelium forms medullary cords, which later develop into the Sertoli cells. In the female, the medullary cords degenerate while cortical cords develop from the surface celomic epithelium and surround the primitive germ cells. These epithelial cells subsequently develop into granulosa cells. The primitive mesenchyme of the genital ridge develops to form the Leydig cells in the male and the special ovarian stroma in the female. Thus tumors in this group may consist of ovarian stromal cells, theca cells, granulosa cells, Sertoli cells and Leydig cells either singly or in various combination. These tumors account for the substantial majority of the hormonally active neoplasms of the ovary. The cells from which they are derived normally secrete estrogens (theca and granulosa cells) or androgens (Leydig cells) and consequently the neoplasms are either feminizing or virilizing. Most of the tumors have analogous testicular counterparts.

• Granulosa-theca cell tumor

These are tumors composed almost entirely of granulosa cells or with varying proportions of theca cells. Tumors with a prominent theca cell component are almost always hormonally active, and about 75% of pure granulosa cell tumors are functional, making granulosa-theca cell tumors the most common estrogenic ovarian neoplasm.

The tumors exist in an adult and juvenile forms. The adult form occurs mainly in postmenopausal women while the juvenile type occurs in the first two decades. In both types, the tumor is virtually always unilateral. Functioning tumors in prepubertal girls may cause precocious sexual development. In adults, they are associated with endometrial hyperplasia and carcinoma.

The tumors vary in size from small incidental findings to very large, focally cystic to entirely solid masses. Cut surface shows yellow and white areas with focal hemorrhages, which may be massive.

Microscopically, these tumors have very diverse appearances. The most well-known pattern consists of monotonous islands of granulosa cells with "coffee-bean" nuclei and containing small punched out spaces lined by granulosa cells giving a follicle-like appearance called Carl-Exner bodies

Granulosa cell tumor. Sheets of granulosa cells containing spaces lined by the cells to give a follicle-like appearance (Carl-Exner bodies).

The granulosa cell tumors are usually confined to the ovary when clinically detected (90%) and have a small but definite risk of malignancy. Histologic evaluation is of little value in predicting biologic behavior of a particular tumor and so all the tumors are potentially malignant. Malignancy, however, is low grade and such tumors pursue an indolent course in which local recurrences may appear 10 to 20 years after removal of original tumor.

• Thecoma

Pure theca cell tumors also occur. They are functional tumors producing estrogen and occur in postmenopausal women. The tumors are unilateral and cause menstrual irregularities and breast enlargement. Endometrial hyperplasia or carcinoma may develop.

Thecomas vary in size from small, impalpable tumors to large, rubbery, solid tumors, usually 5 to 10 cm in diameter and vary in color from yellow to orange depending on the amount of lipid content.

Thecoma. Solid tumor with variegated yellow - orange appearance.

Histologically, the tumor is composed of round to oval cells with pale cytoplasm containing lipid.

Thecoma composed of sheets of pale cells.

Thecoma stained for fat. Note the numerous lipid-laden cells (stained red).

Thecomas are virtually never malignant.

• Fibroma

Fibromas are the commonest ovarian stromal tumors. Pure forms are nonfunctioning but others containing theca cells and called fibrothecomas may be estrogenic. The tumors usually occur in middle-aged, perimenopausal women as unilateral, fibrous solid growths, with a hard, gray to white, whorled cut surface. They are frequently extensively calcified and difficult to cut. Bilateral cases are associated the basal cell nevus syndrome. Fibrothecomas show shades of yellow to orange coloration depending on amount of lipid present.

Bilateral fibromas.

Histologically, fibromas are composed of well-differentiated fibroblasts in a collagenous stroma.

Fibroma

The tumors are virtually benign. Very rarely fibrosarcomas (malignant counterpart) develop in the ovary.

Meig’s syndrome. About 40% of fibromas greater than 6 cm are associated with ascites. Occasionally hydrothorax, usually only on the right, may be present. The combination of a benign ovarian tumor with ascites and hydrothorax is known as Meig’s syndrome. The underlying ovarian tumor is usually, but not invariably, a fibroma. The importance of this syndrome lies in its proper recognition, as frequently the findings of ascites and pleural effusion are interpreted as evidence of peritoneal or pleural metastases from a malignant lesion. The mechanism of Meig’s syndrome is unknown, but may relate to altered lymphatic permeability.

• Sertoli-Leydig cell tumors

These are among the rarest of ovarian tumors forming less than 1% of ovarian neoplasms. The name is derived from the presence in the tumors of cells resembling the Sertoli and Leydig cells of the testis. They occur predominantly in young women with mean age in the mid-twenties. Commonly androgenic, many are nonfunctioning and a few are feminizing. Functioning tumors may cause defeminization of women manifested as breast atrophy, amenorrhea, and loss of hair and hip fat. This may progress to virilization with hirsutism, male distribution of hair, hypertrophy of clitoris and deepening of the voice. The tumors are invariably unilateral and vary in size from microscopic to very large, forming yellow to tan lobulated masses. Areas of hemorrhage and necrosis are present in some tumors.

Microscopically, well-differentiated tumors contain tubules composed of Sertoli cells surrounded by a stroma filled with Leydig cells, mimicking the architecture of the testis. Homogeneous, eosinophilic, rod-shaped structures called Reinke’s crystals may be seen in some of the Leydig cells. Poorly differentiated tumors show a variety of histologic appearances.

Well-differentiated Sertoli-Leydig cell tumor with tubules lined by Sertoli cells and sheet of Leydig cells (upper right corner).

Leydig cells showing Reinke’s crystals.

Recurrences or metastases are rare with well-differentiated tumors but poorly differentiated tumors may recur and metastasize.

[Epithelial Tumors][Germ Cell Tumors][Sex Cord - Stromal Tumors][Miscellaneous Ovarian Tumors]

4. Miscellaneous Ovarian Tumors

Objectives

After completing this section you will know:

• The various mixed epithelial-mesenchymal tumors, their components and clinical behavior
• the commonest primary site of metastasis to the ovary
• what Krukenberg tumor is and the common primary sites from which it may arise

Mixed epithelial-mesenchymal tumors

Tumors containing a mixture of both epithelial and stromal elements. They are subdivided according to the benign or malignant nature of the epithelial and mesenchymal components as follows:

• Adenofibroma – in which both components are benign. The epithelial component may be serous, mucinous, endometrioid, or clear cell.
• Adenosarcoma – composed of benign epithelium and malignant stroma. The tumors are prone to recurrence but metastases are infrequent and consist only of the stromal component.
• Malignant mixed tumors (carcinosarcoma) – containing malignant epithelium and stroma. Like the uterine counterparts, the mesenchymal component may differentiate toward tissue ‘homologous’ to the female genital tract or to ‘heterologous’ tissue foreign to the female genital tract. The tumors are highly malignant and show extraovarian spread at time of diagnosis. Long-term survival is almost nonexistent.

Metastases

The ovary may be the site of metastatic tumor. About 3% of malignant tumors in the ovary are metastatic. The most common primary site is the breast followed by the large intestine, stomach, and other genital tract organs.

Most metastastases from the breast are microscopic. Metastases from the colon produce large ovaries, which may mimic primary ovarian tumor.

Krukenberg tumor is applied to the uniform enlargement of the ovaries (usually bilaterally) due to diffuse infiltration of the ovarian stroma by metastatic signet-ring cell carcinoma. The commonest primary site is the stomach followed by the colon.