Berek and Novak's Gynecology 15th Ed.

37 Ovarian, Fallopian Tube, and Peritoneal Cancer

Jonathan S. Berek

Teri A. Longacre

Michael Friedlander

• The peak incidence of invasive epithelial ovarian cancer is at about 60 years of age. About 30% of ovarian neoplasms in postmenopausal women are malignant, whereas only about 7% of ovarian epithelial tumors in premenopausal patients are frankly malignant. The average age of patients with borderline tumors is approximately 46 years.

• Ovarian cancer is associated with low parity and infertility. Because parity is inversely related to the risk of ovarian cancer, having at least one child is protective for the disease, with a risk reduction of 0.3 to 0.4.

• Oral contraceptive use reduces the risk of epithelial ovarian cancer. Women who use oral contraceptives for 5 or more years reduce their relative risk to 0.5 (i.e., there is a 50% reduction in the likelihood of development of ovarian cancer).

• Given the false-positive results for both CA125 and transvaginal ultrasonography, particularly in premenopausal women, and the absence of evidence from randomized trials that these tests reduce the mortality of ovarian cancer, these tests should not be used routinely to screen women at risk for ovarian cancer.

• Most epithelial ovarian cancers are sporadic, but at least 5% to 10% result from inherited susceptibility and are hereditary. Hereditary ovarian cancers, particularly those caused by BRCA1mutations, occur in women approximately 10 years younger than those with nonhereditary tumors.

• Most hereditary ovarian cancers result from germline mutations in the BRCA1 and BRCA2 genes. The mutations are inherited in an autosomal dominant fashion, and therefore a full pedigree analysis (i.e., both maternal and paternal sides of the family history for both breast and ovarian cancer) must be carefully evaluated in all patients with epithelial ovarian cancer, and those with fallopian tube cancer and peritoneal cancer. The value of prophylactic salpingo-oophorectomy in these patients is well documented and is the most effective way to reduce risk of these cancers.

• The importance of thorough surgical staging cannot be overemphasized, because subsequent treatment and prognosis will be determined by the stage of disease. Patients with advanced-stage disease should undergo debulking or cytoreductive surgery to remove as much of the tumor and its metastases as possible, if the patient is medically fit for major surgery. The performance of a debulking operation as early as possible in the course of the patient’s treatment is considered the standard of care for most patients. Most patients have a primary debulking surgery, while a smaller proportion of patients not suitable for initial surgery receive two to three cycles of primary chemotherapy followed by interval debulking surgery.

• Combination chemotherapy with carboplatin and paclitaxel is recommended for patients with high-risk, low-stage disease. For advanced-stage epithelial ovarian cancer, the choice of intravenous versus intraperitoneal platinum and taxane chemotherapy should be individualized.

• In the first two decades of life, almost 70% of ovarian tumors are of germ cell origin, and one-third of these are malignant. In contrast to the relatively slow-growing epithelial ovarian tumors, germ cell malignancies grow rapidly.

• The most common types of malignant germ cell tumors are dysgerminomas, immature teratomas, and endodermal sinus tumors. Preservation of fertility should be standard in most patients. The most effective chemotherapy is bleomycin, etoposide, and cisplatin (BEP).

• Stromal tumors include granulosa cell tumors, which are low-grade malignancies. In premenopausal women, they can be treated conservatively. Adjuvant chemotherapy is of unproven value.

• Metastatic tumors to the ovaries are most frequently from the breast and gastrointestinal tract.

• Fallopian tube carcinomas and peritoneal cancers are treated the same as ovarian cancer, with staging and cytoreductive surgery followed by platinum and taxane chemotherapy.

Of all the gynecologic cancers, ovarian malignancies represent the greatest clinical challenge because they have a high mortality. Epithelial cancers are the most common ovarian malignancy, and over two-thirds of patients have advanced disease at diagnosis. Ovarian cancer represents a major surgical challenge, and optimal therapy includes surgical debulking followed by platinum-based combination chemotherapy. It has the highest fatality-to-case ratio of all the gynecologic malignancies. There are nearly 22,000 new cases annually in the United States, and 15,460 women can be expected to succumb to their illness (1). Ovarian cancer is the seventh most common cancer in women in the United States, accounting for 3% of all malignancies and 6% of deaths from cancer in women and almost one-third of invasive malignancies of the female genital organs. Ovarian cancer is the fifth most common cause of death from malignancy in women. A woman’s risk at birth of having ovarian cancer at some point in her lifetime is 1% to 1.5% and that of dying from ovarian cancer is almost 0.5% (2).

Epithelial Ovarian Cancer

Approximately 90% of ovarian cancers are derived from the coelomic epithelium or mesothelium (2). The cells are a product of the primitive mesoderm, which can undergo metaplasia. A classification of the histologic types of epithelial tumors of the ovary is presented in Table 37.1. Neoplastic transformation can occur when the cells are genetically predisposed to oncogenesis or exposed to an oncogenic agent or both (3).

Table 37.1 Epithelial Ovarian Tumors


Histologic Type

Cellular Type

I. Serous


 A. Benign


 B. Borderline


 C. Malignant


II. Mucinous

Intestinal, Endocervical

 A. Benign


 B. Borderline


 C. Malignant


III. Endometrioid


 A. Benign


 B. Borderline


 C. Malignant


IV. Clear-cell


 A. Benign


 B. Borderline


 C. Malignant


V. Brenner


 A. Benign


 B. Borderline (proliferating)


 C. Malignant


VI. Mixed epithelial


 A. Benign


 B. Borderline


 C. Malignant


VII. Undifferentiated

May be anaplastic

VIII. Unclassified


From Seroy SF, Scully RE, Sobin LH. International histological classification of tumours no. 9. Histological typing of ovarian tumors. Geneva, Switzerland: World Health Organization, 1973, with permission.


Invasive Cancer

Seventy-five percent to 80% of epithelial cancers are of the serous histologic type. Less common types are endometrioid (10%), clear cell (5%), mucinous (5%), transitional (Brenner), and undifferentiated carcinomas, with each of the last two types representing less than 1% of epithelial lesions (2). Each of the major tumor types is named on the basis of a histologic pattern that resembles epithelium in the lower genital tract (3). For example, serous tumors have an appearance similar to that of the glandular epithelial lining of the fallopian tube, endometrioid tumors resemble proliferative endometrium, and clear cell tumors resemble secretory or gestational endometrium. Mucinous tumors may contain cells that resemble endocervical glands, but more commonly these cells resemble the gastrointestinal epithelium. Transitional (Brenner) tumors are so named because of a resemblance to the epithelium in Walthard rests and bladder urothelium.

Although it was believed that epithelial ovarian cancers arise from either the surface epithelium of the ovary or from inclusion cysts within the ovary, there is growing evidence to suggest that many, if not most, high-grade serous carcinomas of the ovary arise from the fimbrial end of the fallopian tube rather than from the ovary (4,5). It is suggested that serous epithelial ovarian cancers be separated into two distinct groups—type I and type II serous tumors—as they differ considerably in the cell of origin, molecular pathogenesis, and their biological behavior (6). Type I tumors include serous borderline tumors and low-grade serous carcinoma; they are genetically stable and are characterized by mutations in KRAS and BRAF. Type II serous tumors are rapidly growing, highly aggressive neoplasms that lack well-defined precursor lesions; most are advanced stage at, or soon after, their inception and many appear to arise in the fimbrial end of the fallopian tube (7). The type II tumors are genetically unstable and harbor p53 mutations.

Borderline Tumors

An important group of tumors to distinguish is the tumor of low malignant potential, also called the borderline tumor. Borderline tumors are lesions that tend to remain confined to the ovary for long periods, occur predominantly in premenopausal women, and are associated with a very good prognosis (2,3,812). They are encountered most frequently in women between the ages of 30 and 50 years, whereas invasive carcinomas occur more often in women between the ages of 50 and 70 years (2).

Although uncommon, implants may occur with serous borderline tumors. Such implants are divided into noninvasive and invasive forms. The latter group has a higher likelihood of developing into progressive, proliferative disease in the peritoneal cavity, which can lead to intestinal obstruction and death (2,6).

Classification of Epithelial Ovarian Tumors

Serous Tumors

Serous tumors are so classified because they resemble tubal secretory cells. Psammoma bodies are frequently found in these neoplasms, and they are made up of concentric rings of calcification. Several hypotheses pertaining to the origin and development of psammoma bodies are proposed, including apoptosis of tumor cells and osteoinductive cytokines produced by macrophages (6). In the wall of the mesothelial invaginations, papillary ingrowths are common, representing the early stages of development of a papillary serous cystadenoma. There are many variations in the proliferation of these mesothelial inclusions. Several foci may be lined with flattened inactive epithelium; in adjacent cavities, papillary excrescences are present, often resulting from local irritants (2).

Borderline Serous Tumors

Approximately 10% of all ovarian serous tumors fall into the category of a tumor of low malignant potential or borderline tumor (Fig. 37.1), and 50% occur before the age of 40 years. The criteria for the diagnosis of serous borderline tumors are as follows (11):

1. Epithelial hyperplasia in the form of pseudostratification, tufting, cribriform, and micropapillary architecture

2. Mild nuclear atypia and mild increased mitotic activity

3. Detached cell clusters

4. Absence of destructive stromal invasion (i.e., without tissue destruction)

Serous borderline tumors that are composed of an exuberant micropapillary architecture are designated as serous borderline tumors with micropapillary features (Fig. 37.2); these tumors are more frequently bilateral, exophytic, and high-stage than the usual serous borderline tumor.

Figure 37.1 Serous borderline tumor of the ovary. Complex papillary fronds with hierarchical branching are lined with pseudostratified columnar cells. The epithelium and the stroma are clearly separated by a basement membrane, indicating no stromal invasion.

Figure 37.2 Serous borderline tumor with micropapillary features. The papillae have a non-hierarchical branching pattern and are lined by a monomorphous population of cells.

It should be emphasized that up to 40% of serous borderline tumors are associated with spread beyond the ovary, but high-stage disease does not necessarily warrant a diagnosis of carcinoma. The diagnosis of a serous borderline tumor versus serous carcinoma is based on the histologic features of the primary tumor (11). Up to 10% of women with ovarian serous borderline tumors and extraovarian implants may have invasive implants, and these can behave more aggressively (13). The 5-year overall survival for women with invasive implants is about 50% if stringent criteria are applied (10,1315). Most implants are noninvasive (10,16). In the noninvasive implants, papillary proliferations of atypical cells involve the peritoneal surface and form smooth invaginations (10). In contrast, the invasive implants resemble well-differentiated serous carcinoma and are characterized by atypical cells forming irregular glands with sharp borders. Implants are usually confined to the abdominal cavity and may be seen in the pelvis, omentum, and adjacent tissues, including lymph nodes, but spread outside the abdominal cavity is rare. Death can occur as the result of intestinal obstruction (1619).

Borderline serous tumors may harbor foci of stromal microinvasion (18). Most patients are young and International Federation of Gynecology and Obstetrics (FIGO) stage I. Stromal microinvasion is increased about ninefold in pregnant women with serous borderline tumors.

The presence of stromal microinvasion is associated with lymphovascular space invasion in the primary ovarian tumor (and likely represents a form of true stromal invasion), but it is not associated with an aggressive clinical course, and patients with this finding should be managed in the same way as patients without stromal microinvasion.

Serous Carcinomas

In malignant serous tumors, stromal invasion is present (2). The grade of tumor is important and needs to be documented. In low-grade serous adenocarcinomas, papillary and glandular structures predominate (Fig. 37.3); high-grade neoplasms are characterized by solid sheets of cells, nuclear pleomorphism, and high mitotic activity (Fig. 37.4). Laminated, calcified psammoma bodies are found in 80% of serous carcinomas. Serous psammocarcinoma is a rare variant of serous carcinoma characterized by massive psammoma body formation and low-grade cytological features. At least 75% of the epithelial nests are associated with psammoma body formation. Patients with serous psammocarcinoma have a protracted clinical course and a relatively favorable prognosis; their clinical course more closely resembles that of high-stage, progressive serous borderline tumor than serous carcinoma.

Figure 37.3 Low-grade serous adenocarcinoma of the ovary. Clusters and papillae of malignant cells are in direct contact with fibrous stroma indicative of stromal invasion.

Mucinous Tumors

These cystic ovarian tumors have loculi lined with mucin-secreting epithelium. The lining epithelial cells contain intracytoplasmic mucin and resemble those of endocervix, gastric pylorus, or intestine. They represent about 8% to 10% of epithelial ovarian tumors. They may reach enormous size, filling the entire abdominal cavity (2).

Borderline Mucinous Tumors

The mucinous tumor of low malignant potential is often difficult to diagnose. Although it is common to find a rather uniform pattern from section to section in the serous borderline tumor, this is not true in the mucinous tumors. Well-differentiated mucinous epithelium may be seen immediately adjacent to a poorly differentiated focus. It is important to take multiple sections from many areas in the mucinous tumor to identify the most malignant alteration (2).

Mucinous Carcinomas

Bilateral tumors occur in 8% to 10% of cases. The mucinous lesions are confined to the ovary in 95% to 98% of cases (Fig. 37.5). Because most ovarian mucinous carcinomas contain intestinal-type cells, they cannot be distinguished from metastatic carcinoma of the gastrointestinal tract on the basis of histology alone (2,6). Primary ovarian neoplasms rarely metastasize to the mucosa of the bowel, although they commonly involve the serosa, whereas gastrointestinal lesions frequently involve the ovary by direct extension or lymphatic spread (2).

Figure 37.4 High-grade serous adenocarcinoma. Papillae lined by sheets of cytologically malignant cells invade stroma, often with associated necrosis.

Figure 37.5 Mucinous adenocarcinoma of the ovary. Irregular glandular spaces are lined with a layer of tall columnar cells with abundant mucinous cytoplasm, resembling intestinal epithelium at the left. At the right, there is destructive invasion into the ovarian stroma.

Pseudomyxoma Peritonei

Pseudomyxoma peritonei is a clinical term used to describe the finding of abundant mucoid or gelatinous material in the pelvis and abdominal cavity surrounded by fibrous tissue. It is most commonly secondary to a well-differentiated appendiceal mucinous neoplasm or other gastrointestinal primary; rarely, mucinous tumors arising in an ovarian mature teratoma are associated with pseudomyxoma peritonei.

Endometrioid Tumors

Endometrioid lesions constitute 6% to 8% of epithelial tumors. Endometrioid neoplasia includes all the benign demonstrations of endometriosis. In 1925, Sampson suggested that certain cases of adenocarcinoma of the ovary probably arose in areas of endometriosis (19). The adenocarcinomas are similar to those seen in the uterine corpus. The malignant potential of endometriosis is very low, although a transition from benign to malignant epithelium may be demonstrated.

Borderline Endometrioid Tumors

The endometrioid tumor of low malignant potential has a wide morphologic spectrum. Tumors may resemble an endometrial polyp or complex endometrial hyperplasia with glandular crowding. When there are back-to-back, architecturally complex glands with no intervening stroma, the tumor is classified as a well-differentiated endometrioid carcinoma. Some borderline endometrioid tumors have a prominent fibromatous component. In such cases, the term adenofibroma is used to describe them (2).

Endometrioid Carcinomas

Endometrioid tumors are characterized by a markedly complex glandular pattern with all the potential variations of epithelia found in the uterus (Fig. 37.6).

Figure 37.6 Endometrioid cancer. Round to tubular glands lined by stratified columnar cells with confluent growth pattern.

Multifocal Disease

The endometrioid tumors afford the greatest opportunity to evaluate multifocal disease. Endometrioid carcinoma of the ovary is associated in 15% to 20% of the cases with carcinoma of the endometrium. Identification of multifocal disease is important because patients with disease metastatic from the uterus to the ovaries have a 30% to 40% 5-year survival, whereas those with synchronous multifocal disease have a 75% to 80% 5-year survival (20). When the histologic appearance of endometrial and ovarian tumors is different, the two tumors most likely represent two separate primary lesions. When they appear similar, the endometrial tumor can be considered a separate primary tumor if it is well differentiated and only superficially invasive.

Clear Cell Carcinomas

Several basic histologic patterns are present in the clear cell adenocarcinoma (i.e., tubulocystic, papillary, reticular, and solid). The tumors are made up of clear and hobnail cells that project their nuclei into the apical cytoplasm. The clear cells have abundant clear or vacuolated cytoplasm, hyperchromatic irregular nuclei, and nucleoli of various sizes (Fig. 37.7). Focal areas of endometriosis are common and mixed clear cell and endometrioid carcinoma may occur (20). The clear cell carcinoma seen in the ovary is histologically identical to that seen in the uterus or vagina of the young patient who has been exposed to diethylstilbestrol (DES) in utero. Nuclei of clear cell carcinoma range from grade 1 to grade 3, but pure grade 1 tumors are extremely rare. Almost invariably high-grade (grade 3) nuclei are identified. Hence, clear cell carcinoma is not graded.

Figure 37.7 Clear cell carcinoma of the ovary. Note the solid variant of clear cell carcinoma with sheets of cells that have clear cytoplasm (“hobnail” cells).

Transitional (Brenner) Tumors

Borderline Brenner Tumors

In the past, proliferative Brenner tumors were subclassified as proliferating tumors (those tumors that resemble low-grade papillary urothelial carcinoma of the urinary bladder) and borderline tumors (those tumors that resemble high-grade papillary urothelial carcinoma), but both groups of tumors are now classified as borderline Brenner tumors (21). Complete surgical removal usually results in cure.

Malignant Brenner Tumors

These rare tumors are defined as benign or borderline Brenner tumors coexisting with invasive transitional cell carcinoma.

Transitional Cell Carcinoma

The designation transitional cell carcinoma refers to a primary ovarian carcinoma resembling transitional cell carcinoma of the urinary bladder without a recognizable Brenner tumor. It is reported that those ovarian carcinomas that contain more than 50% of transitional cell carcinoma are more sensitive to chemotherapy and have a more favorable prognosis than other poorly differentiated ovarian carcinomas of comparable stage (22,23). Transitional cell tumors differ from malignant Brenner tumors in that they are more frequently diagnosed in an advanced stage and are associated with a poorer survival rate (24).

Peritoneal Carcinomas

Peritoneal tumors are histologically indistinguishable from ovarian serous tumors. In the case of borderline serous peritoneal tumors and serous peritoneal carcinomas, the ovaries are normal or minimally involved, and the tumors affect predominantly the uterosacral ligaments, pelvic peritoneum, or omentum. The overall prognosis for borderline serous peritoneal tumors is excellent and comparable to that of ovarian borderline serous tumors (2527). In the review of 38 cases of peritoneal borderline serous tumors from the literature, 32 women had no persistent disease, 4 were well after resection of recurrence, 1 developed an invasive serous carcinoma, and 1 died from the effects of the tumor (25).

Carcinoma that appears predominantly as peritoneal carcinomatosis without appreciable ovarian or fallopian tube enlargement is called peritoneal carcinoma or müllerian carcinoma when tumors spread from the breast, gastrointestinal tract, and other organs of nonmüllerian origin are excluded. Most are peritoneal serous carcinomas, which have the appearance of a moderately to poorly differentiated serous ovarian carcinoma. Peritoneal endometrioid carcinoma is less common.

Peritoneal carcinoma should be considered clinically the same as ovarian and fallopian tube cancers. In patients for whom exploratory surgery is performed, there may be microscopic or small macroscopic cancer on the surface of the ovary and extensive disease in the upper abdomen, particularly in the omentum (28).


Peritoneal malignant mesotheliomas may be epithelial, sarcomatous, or biphasic (2,29). Deciduoid peritoneal mesothelioma is an unusual variant that resembles exuberant, ectopic decidual reaction of the peritoneum. Asbestos exposure is not correlated with peritoneal mesotheliomas in women. These lesions typically appear as multiple intraperitoneal masses, often coating the entire peritoneum and can develop after hysterectomy and bilateral salpingo-oophorectomy for benign disease. Malignant mesotheliomas should be distinguished from benign multicystic peritoneal mesothelioma (multilocular peritoneal inclusion cyst), and ovarian tumor implants and primary peritoneal müllerian neoplasms.

Clinical Features

More than 80% of epithelial ovarian cancers are found in postmenopausal women (Fig. 37.8). The peak incidence of invasive epithelial ovarian cancer is at 56 to 60 years of age (2,3,30). The age-specific incidence of ovarian epithelial cancer rises precipitously from 20 to 80 years of age and subsequently declines (30). These cancers are relatively uncommon in women younger than age 45. Fewer than 1% of epithelial ovarian cancers occur before the age of 21 years, two-thirds of ovarian malignancies in such patients being germ cell tumors (2,30,31). About 30% of ovarian neoplasms in postmenopausal women are malignant, whereas only about 7% of ovarian epithelial tumors in premenopausal patients are frankly malignant (2,3).

Figure 37.8 Ovarian cancer incidence: distribution by age. (From Nagy K. The side effects of managed care on the drug industry. J Natl Cancer Inst 1995;87:1280, with permission.)

The average age of patients with borderline tumors is approximately 46 years (2,3,9). Eighty percent to 90% of ovarian cancers, including borderline forms, occur after the age of 40 years, whereas 30% to 40% of malignancies occur after the age of 65 years. The chance that a primary epithelial tumor will be of borderline or invasive malignancy in a patient younger than 40 years is approximately 1 in 10, but after that age it rises to 1 in 3 (2,3). Less than 1% of epithelial ovarian cancers occur before the age of 20 years, with two-thirds of ovarian malignancies in such patients being germ cell tumors (31).


Ovarian cancer is associated with low parity and infertility (32). Although there are a variety of epidemiologic variables correlated with ovarian cancer, such as talc use, galactose consumption, and tubal ligation (see Chapter 4), none is so strongly correlated as prior reproductive history and duration of the reproductive career (32,33). Early menarche and late menopause increase the risk of ovarian cancer (33). These factors and the relationship of parity and infertility to the risk of ovarian cancer led to the hypothesis that suppression of ovulation may be an important factor. Theoretically, the surface epithelium undergoes repetitive disruption and repair. It is thought that this process might lead to a higher probability of spontaneous mutations that can unmask germline mutations or otherwise lead to the oncogenic phenotype (see Chapter 6).


Because parity is inversely related to the risk of ovarian cancer, having at least one child is protective for the disease, with a risk reduction of 0.3 to 0.4. Oral contraceptive use reduces the risk of epithelial ovarian cancer(32). Women who use oral contraceptives for 5 or more years reduce their relative risk to 0.5 (i.e., there is a 50% reduction in the likelihood of development of ovarian cancer). Women who had two children and used oral contraceptives for 5 or more years have a relative risk of ovarian cancer as low as 0.3, or a 70% reduction (34). The oral contraceptive pill is the only documented method of chemoprevention for ovarian cancer, and it should be recommended to women for this purpose. When counseling patients regarding birth control options, this important benefit of oral contraceptive use should be emphasized. This is important for women with a strong family history of ovarian cancer.

The performance of a prophylactic salpingo-oophorectomy significantly reduces, but does not totally eliminate, the risk of nonuterine pelvic cancers; because the entire peritoneum is at risk, peritoneal carcinomas can occur in 2% to 3% of women even after prophylactic bilateral salpingo-oophorectomy (25,28).

A thorough discussion of the risks and benefits of oophorectomy should be undertaken in premenopausal women who are undergoing a hysterectomy for benign disease, who do not carry germline mutations, and do not have a family history that suggests that they are at higher than average risk for ovarian cancer (35). The ovaries may provide protection from cardiovascular disease and osteoporosis, and long-term mortality may not be decreased by the performance of prophylactic oophorectomy in women at population risk of ovarian cancer (36).


The value of tumor markers and ultrasonography to screen for epithelial ovarian cancer is not established by prospective studies. Screening results with transabdominal ultrasonography are encouraging in postmenopausal women, but specificity is limited (3739). Advances in transvaginal ultrasonography showed a very high (>95%) sensitivity for the detection of early-stage ovarian cancer, although this test alone might require performance of as many as 10 to 15 laparotomy procedures for each case of ovarian cancer detected (37,38). Routine annual pelvic examinations have disappointing results in the early detection of ovarian cancer (40). Transvaginal color flow Doppler to assess the vascularity of the ovarian vessels is a useful adjunct to ultrasonography, but it is not useful in screening (41,42).

CA125 is useful for monitoring epithelial ovarian cancer patients during their chemotherapy, but the role of CA125 is still being defined in a screening setting (4349). Regarding the sensitivity of the test, elevated CA125 levels are seen in 50% of patients with stage I disease (43,48). Data suggest that the specificity of CA125 is improved when the test is combined with transvaginal ultrasonography or when the CA125 levels are followed over time (49,50). These data encouraged the development of prospective screening studies in Sweden and the United Kingdom (45,47). In these studies, patients with elevated CA125 levels (>30 U/mL) underwent abdominal ultrasonography, and 14 ovarian cancers were discovered among 27,000 women screened. About four laparotomies were performed for each case of cancer detected (47).

A randomized trial of nearly 22,000 women aged 45 years or older was performed in the United Kingdom (50). The patients were assigned to either a control group of routine pelvic examination (n = 0,977) or to a screening group (n = 10,958). The screening consisted of three annual screens that involved measurement of serum CA125 levels, pelvic ultrasonography if the CA125 was 30 U/mL or higher, and referral for gynecologic examination if the ovarian volume was 8.8 mL or greater on the ultrasonography. Of the 468 women in the screened group with an elevated CA125, 29 were referred for surgery, 6 cancers were discovered, and 23 had false-positive screening results, yielding a positive predictive value of 20.7%. During a 7-year follow-up period, cancer developed in 10 additional women in the screened group, as it did in 20 women in the control group. Although the median survival of women in whom cancer developed in the screened group was 72.9 months, compared with 41.8 months in the control group (p = .0112), the number of deaths did not differ significantly between the control and screened groups (18/10,977 vs. 9/10,958; relative risk 2.0 [0.78 to 5.13]). These data show that a multimodal approach to ovarian cancer screening is feasible, but a larger trial is necessary to determine whether this approach affects mortality. Such a three-arm randomized trial is ongoing in the United Kingdom, and the anticipated accrual is approximately 50,000 women per study arm and 100,000 women in the control arm. Based on the risk of ovarian cancer (ROC) algorithm for CA125 levels, patients in the third group will be referred for transvaginal ultrasonography and/or surgery (51). Women will be screened for 3 years and studied for 7 years. The aims of this trial are to determine the feasibility of screening for ovarian cancer and whether ovarian cancers can be diagnosed at an earlier stage and the impact of early detection on survival.

Another approach is the use of proteomic patterns to identify ovarian cancer using surface-enhanced laser desorption ionization time-of-flight (SELDI-TOF) technology (52). In a study using this technology, the sensitivity for predicting ovarian cancer was 100%, with a specificity of 95% and a positive predictive value of 94%. The assay correctly identified all 18 women with stage I tumors. This technology is in the early phases of development and validation, and its efficacy has yet to be demonstrated in large population-based studies (53).

Given the false-positive and false-negative results for both CA125 and transvaginal ultrasonography and the absence of good data to show that screening detects ovarian cancers at an earlier stage, these tests are not recommended and should not be used routinely to screen women with a population risk or high risk for ovarian cancer (5456). In the future, new markers or technologies may improve the specificity of ovarian cancer screening, but proof of this will require a large, prospective study (47,48). Screening in women who have a familial risk may have a better yield, but to date there is no evidence to demonstrate a benefit of screening even in high-risk women, and this is being actively investigated (55,57). The findings of two prospective studies of annual transvaginal ultrasound and CA125 screening in 888 BRCA1and BRCA2 mutation carriers in the Netherlands and 279 mutation carriers in the United Kingdom are not encouraging and suggest a very limited benefit of screening in high-risk women (55,56). Despite annual gynecologic screening Hermsen et al. reported that a high proportion of ovarian cancers in BRCA1-2 carriers were interval cancers and the large majority of all cancers diagnosed were at advanced stages; similar results were reported by Woodward et al. (55,56).

Genetic Risk for Epithelial Ovarian Cancer

The lifetime risk of ovarian carcinoma for women in the United States is about 1.4% (13). The risk of ovarian cancer is higher than that in the general population in women with certain family histories (5160). Most epithelial ovarian cancer is sporadic, with familial or hereditary causes accounting for 5% to 10% of invasive epithelial ovarian cancer (59).

Hereditary Ovarian Cancer


Most hereditary ovarian cancer is associated with mutations in the BRCA1 gene, located on chromosome 17 (5869). A small proportion of inherited disease is associated with germline mutations in another gene, BRCA2, located on chromosome 13 (60). Discovered through linkage analyses, these two high-penetrance genes are associated with the genetic predisposition to both ovarian and breast cancers. There are almost certainly other low- to moderate-penetrance genes that predispose to ovarian and breast cancer, and this is an area of intense research interest (1).

It was thought that there were two distinct syndromes associated with a genetic risk, site-specific hereditary ovarian cancer and hereditary breast-ovarian cancer syndrome. It is now believed that these groups represent a continuum of mutations with different degrees of penetrance within a given family (62,70). There is a higher-than-expected risk of ovarian and endometrial cancer in Lynch syndrome, known as the hereditary nonpolyposis colorectal cancer syndrome (HNPCC syndrome) (71).

The mutations are inherited in an autosomal dominant fashion, and therefore a full pedigree analysis (i.e., both maternal and paternal sides of the family) must be carefully evaluated (62). There are numerous distinct mutations that were identified on each of these genes, and the mutations have different degrees of penetrance that may account for the preponderance of either breast cancer, ovarian cancer, or both, in any given family. Based on analysis of women who have a mutation in the BRCA1 gene and are from high-risk families, the lifetime risk of ovarian cancer may be as high as 28% to 44%, and the risk was calculated to be as high as 27% for those women with a BRCA2 mutation (59,60,6669). The risk of breast cancer in women with a BRCA1 or BRCA2 mutation may be as high as 56% to 87%.

Hereditary ovarian cancers occur in women approximately 10 years younger than those with nonhereditary tumors (i.e., closer to age 50 compared to age 60 for those with sporadic cancer) (59). A woman with a first- or second-degree relative who had premenopausal ovarian cancer may have a higher probability of carrying an affected gene. Breast and ovarian cancer may exist in a family in which there is a combination of epithelial ovarian and breast cancers, affecting a mixture of first- and second-degree relatives. Women with this syndrome tend to have these tumors at a young age, and the breast cancers may be bilateral. If two first-degree relatives are affected, this pedigree is consistent with an autosomal dominant mode of inheritance (50,58). Most BRCA1 ovarian cancers are high-grade serous carcinomas (Fig. 37.9).

Figure 37.9 BRCA1-associated ovarian carcinoma is typically a high-grade serous adenocarcinoma with numerous mitotic figures and marked nuclear pleomorphism. A brisk lymphocytic infiltrate with tumor infiltrating lymphocytes is not uncommon in these tumors.

Founder Effect

There is a higher carrier rate of BRCA1 and BRCA2 mutations in women of Ashkenazi Jewish descent, in Icelandic women, and in many other ethnic groups (64,65,6769). There are three specific founder mutations carried by the Ashkenazi population, 185delAG and 5382insC on BRCA1, and 6174delT on BRCA2. Individuals of Ashkenazi Jewish descent have a 1 in 40, or 2.5%, chance of having a mutation in BRCA1 or BRCA2, and thus there is a greater risk in this population. The increased risk is a result of the founder effect, in which a higher rate of specific mutations occurs in an ethnic group from a defined geographic area. These founder mutations generated considerable interest, because they facilitate studies of prevalence and penetrance and can be used to quantify the degree of homogeneity within a population.

Pedigree Analysis

The risk of carrying a germline mutation that predisposes to ovarian cancer depends on the number of first- or second-degree relatives (or both) with a history of epithelial ovarian carcinoma or breast cancer (or both) and on the number of malignancies that occurs at an earlier age. The degree of risk is difficult to determine precisely unless a full pedigree analysis is performed.

1. In families with two first-degree relatives (i.e., mother, sister, or daughter) with documented premenopausal epithelial ovarian cancer, the risk that a female first-degree relative has an affected gene could be as high as 35% to 40% (60).

2. In families with a single first-degree relative and a single second-degree relative (i.e., grandmother, aunt, first cousin, or granddaughter) with epithelial ovarian cancer, the risk that a woman has an affected gene may be increased. The risk may be two- to 10-fold higher than in those without a familial history of the disease (60).

3. In families with a single postmenopausal first-degree relative with epithelial ovarian carcinoma, a woman may not have an increased risk of having an affected gene because the case is most likely to be sporadic. If the ovarian cancer occurs in a premenopausal relative, this could be significant, and a full pedigree analysis should be undertaken.

4. Women with a primary history of breast cancer have twice the expected incidence of subsequent ovarian cancer (59).

Lynch Syndrome or Hereditary Nonpolyposis Colon Cancer

Lynch syndrome (HNPCC), which includes multiple adenocarcinomas, involves a combination of colon cancer and endometrial or ovarian cancer and other malignancies of the gastrointestinal and genitourinary systems (71). The mutations that are associated with this syndrome are MSH2MLH1PMS1, and PMS2. The risk that a woman who is a member of one of these families will develop epithelial ovarian cancer depends on the frequency of this disease in first- and second-degree relatives, although these women appear to have at least three times the relative risk of the general population. A full pedigree analysis of such families should be performed by a geneticist to more accurately determine the risk.

Management of Women at High Risk for Ovarian Cancer

The management of a woman with a strong family history of epithelial ovarian cancer must be individualized and depends on her age, her reproductive plans, and the extent of risk. In all of these syndromes, women at risk benefit from a thorough pedigree analysis. A geneticist should evaluate the family pedigree for at least three generations. Decisions about management are best made after careful study and, whenever possible, verification of the histologic diagnosis of the family members' ovarian cancer.

The value of testing for BRCA1 and BRCA2 is established, and there are guidelines for testing (62,70,72). The importance of genetic counseling cannot be overemphasized because the decision is complex. The American Society of Clinical Oncology offered guidelines that emphasize careful evaluation by geneticists, careful maintenance of medical records, and an understanding in a genetic screening clinic of how to effectively counsel and manage these patients. Concerns remain over the use of the information, the impact on insurability, the interpretation of the results, and how the information will be used within a specific family (e.g., to counsel children).

Although there are some conflicting data, the behavior of breast cancers arising in women with germline mutations in BRCA1 or BRCA2 is comparable to the behavior of sporadic tumors (61,73). Women with breast cancer who carry these mutations are at a greatly increased risk of ovarian cancer and a second breast cancer: the lifetime risk of ovarian cancer is 54% for women who have a BRCA1mutation and 23% for those with a BRCA2mutation, and for the two groups together, there is an 82% lifetime risk of breast cancer (73).

Despite recommendation by the National Institutes of Health Consensus Conference on Ovarian Cancer, the value of screening with transvaginal ultrasonography, CA125 levels, or other procedures is not established in women at high risk (74). Bourne and coworkers showed that, using this approach, tumors can be detected approximately 10 times more often than in the general population, and they recommend screening in high-risk women, but other groups have not confirmed these findings, and bilateral salpingo-oophorectomy remains the most effective way to reduce risk (57,75).

Data derived from a multicenter consortium of genetic screening centers indicate that the use of the oral contraceptive pill is associated with a lower risk for development of ovarian cancer in women who have a mutation in either BRCA1 or BRCA2 (76). The risk reduction is significant: in women who take oral contraceptives for 5 or more years, the relative risk of ovarian cancer is 0.4, or a 60% reduction in the incidence of the disease.

Prophylactic Salpingo-oophorectomy in High-Risk Women

The value of prophylactic salpingo-oophorectomy in these patients is documented (7783). Women at high risk for ovarian cancer who undergo prophylactic salpingo-oophorectomy have a risk of harboring occult neoplasia: in one series of 98 such operations, 3 (3.1%) patients had a low-stage ovarian malignancy (80). The protection against ovarian cancer is excellent: the performance of a prophylactic salpingo-oophorectomy reduced the risk of BRCA-related gynecologic cancer by 96% (80). In a series of 42 such operations, 4 patients (9.5%) had a malignancy, 1 of which was noted at surgery and 3 that were microscopic; all were smaller than 5 mm (78). Although the risk of ovarian cancer is significantly diminished, there remains the small risk of peritoneal carcinoma, a tumor for which women who have mutations in BRCA1 and BRCA2 may have a higher predisposition. In these series, the subsequent development of peritoneal carcinoma was 0.8% and 1%, respectively (78,79). The risk of developing subsequent breast cancer was reduced by 50% to 80%.

The role of hysterectomy is more controversial. Most studies show no increase in the rate of uterine and cervical tumors, but there are rare reports of an increase of papillary serous tumors of the endometrium (83). Women on tamoxifen are at higher risk for benign endometrial lesions (e.g., polyps) and endometrial cancer. It is reasonable to consider the performance of a prophylactic hysterectomy in conjunction with salpingo-oophorectomy, but this decision should be individualized.

The survival of women who have a BRCA1 or BRCA2 mutation and develop ovarian cancer is longer than that for those who do not have a mutation. In one study, the median survival for mutation carriers was 53.4 months compared with 37.8 months for those with sporadic ovarian cancer from the same institution (84).


Current recommendations for management of women at high risk for ovarian cancer are summarized as follows (72,82):

1. Women who appear to be at high risk for ovarian or breast cancer should undergo genetic counseling and, if the risk appears to be substantial (i.e., a calculated risk of at least 10% in having a mutation in BRCA1 or BRCA2), may be offered genetic testing for BRCA1 and BRCA2.

2. Women who wish to preserve their reproductive capacity can undergo screening by transvaginal ultrasonography every 6 months, although the efficacy of this approach is not established.

3. Oral contraceptives should be recommended to young women before they embark on an attempt to have a family.

4. Women who do not wish to maintain their fertility or who have completed their families should be recommended to undergo prophylactic bilateral salpingo-oophorectomy after the age of 35, but by age 40 years. The risk of ovarian cancers under the age of 40 is very low but the decision regarding the age of surgery should be based on the age of onset of ovarian cancers in the family. Most BRCA2-related ovarian cancers tend to occur after the age of 50, whereas BRCA1-related cancers occur at an earlier age. The risk should be clearly documented, preferably established by BRCA1 and BRCA2 testing, before salpingo-oophorectomy is performed. These women should be counseled that this operation does not offer absolute protection, because peritoneal carcinomas can occur after bilateral salpingo-oophorectomy (25,28,83).

5. In women who have a strong family history of breast or ovarian cancer, annual breast screening should be performed beginning at age 30 years using a combination of magnetic resonance imaging (MRI), mammograms, and ultrasound. Ideally, these women should be followed in clinics that manage women at high risk for cancer.

6. Women with a documented HNPCC syndrome should be treated as mentioned above, and they should undergo periodic colonoscopy, endometrial biopsy, or prophylactic hysterectomy after the completion of childbearing (71).


The majority of women with epithelial ovarian cancer have vague and nonspecific symptoms (3,8587). In early-stage disease, if the patient is premenopausal, she may experience irregular menses. If a pelvic mass is compressing the bladder or rectum, she may report urinary frequency or constipation (8587). Occasionally, she may perceive lower abdominal distention, pressure, or pain, such as dyspareunia. Acute symptoms, such as pain secondary to rupture or torsion, are unusual.

In advanced-stage disease, patients have symptoms related to the presence of ascites, omental metastases, or bowel metastases. The symptoms include abdominal distention, bloating, constipation, nausea, anorexia, or early satiety. Premenopausal women may report irregular or heavy menses, whereas vaginal bleeding may occur in postmenopausal women (86).

Traditionally, ovarian cancer was considered a “silent killer” that did not produce symptoms until far advanced. Some patients with ovarian cancers confined to the ovary are asymptomatic, but the majority will have nonspecific symptoms that do not necessarily suggest an origin in the ovary (86,8890). In one survey of 1,725 with ovarian cancer, 95% recalled symptoms before diagnosis, including 89% with stage I and II disease and 97% with stages III and IV disease (86). Some 70% had abdominal or gastrointestinal symptoms, 58% pain, 34% urinary symptoms, and 26% pelvic discomfort. At least some of these symptoms could have reflected pressure on the pelvic viscera from the enlarging ovary. Goff et al. developed an ovarian cancer symptom index and reported that symptoms associated with ovarian cancer, when present for less than 1 year and occurring longer than 12 days a month, were pelvic/abdominal pain, urinary frequency/urgency, increased abdominal size or bloating, and difficulty eating or feeing full (88). The index had a sensitivity of 56.7% for early ovarian cancer and 79.5% for advanced stage disease. A population-based study from Australia found that there did not appear to be a significant difference in the duration of symptoms or the nature of symptoms in patients with early as opposed to advanced stage ovarian cancer, reinforcing the concept that they are biologically different entities and arguing against the widely held misconception that early stage ovarian cancers are at an early stage because they were diagnosed earlier than patients with more advanced stage cancers (89).


The most important sign of epithelial ovarian cancer is the presence of a pelvic mass on physical examination. A solid, irregular, fixed pelvic mass is highly suggestive of an ovarian malignancy. If an upper abdominal mass or ascites is present, the diagnosis of ovarian cancer is almost certain. Because the patient usually reports abdominal symptoms, she may not have a pelvic examination, and a tumor may be missed.

In patients who are at least 1 year past menopause, the ovaries should be atrophic and not palpable. It was proposed that any palpable pelvic mass in these patients should be considered potentially malignant, a situation that was referred to as the postmenopausal palpable ovary syndrome (91). This concept was challenged, because subsequent authors reported that only about 3% of palpable masses measuring less than 5 cm in postmenopausal women are malignant (57).


Ovarian epithelial cancers must be differentiated from benign neoplasms and functional cysts of the ovaries. A variety of benign conditions of the reproductive tract, such as pelvic inflammatory disease, endometriosis, and pedunculated uterine leiomyomas, can simulate ovarian cancer. Nongynecologic causes of a pelvic tumor, such as an inflammatory (e.g., diverticular) disease or neoplastic colonic mass, must be excluded (3). A pelvic kidney can simulate ovarian cancer.

Serum CA125 levels are useful in distinguishing malignant from benign pelvic masses (92). For a postmenopausal patient with an adnexal mass and a very high serum CA125 level (>200 U/mL), there is a 96% positive predictive value for malignancy. For premenopausal patients, the specificity of the test is low because the CA125 level tends to be elevated in common benign conditions.

For the premenopausal patient, a period of observation is reasonable provided the adnexal mass does not have characteristics that suggest malignancy (i.e., it is mobile, mostly cystic, unilateral, and of regular contour).An interval of no more than 2 months is allowed, during which hormonal suppression with an oral contraceptive may be used. If the lesion is not neoplastic, it should regress, as measured by pelvic examination and pelvic ultrasonography. If the mass does not regress or if it increases in size, it must be presumed to be neoplastic and must be removed surgically.

The size of the lesion is important. If a cystic mass is greater than 8 cm in diameter, the probability is high that the lesion is neoplastic, unless the patient is taking clomiphene citrate or other agents to induce ovulation (3740). Premenopausal patients whose lesions are clinically suspicious (i.e., large, predominantly solid, relatively fixed, or irregularly shaped) should undergo laparotomy, as should postmenopausal patients with complex adnexal masses of any size.

Ultrasonographic signs of malignancy include an adnexal pelvic mass with areas of complexity, such as irregular borders, multiple echogenic patterns within the mass, and dense multiple irregular septae. Bilateral tumors are more likely to be malignant, although the individual characteristics of the lesions are of greater significance. Transvaginal ultrasonography may have a somewhat better resolution than transabdominal ultrasonography for adnexal neoplasms (9396). Doppler color flow imaging may enhance the specificity of ultrasonography for demonstrating findings consistent with malignancy (9799).

In postmenopausal women with unilocular cysts measuring 8 to 10 cm or less and normal serial CA125 levels, expectant management is acceptable, and this approach may decrease the number of surgical interventions (100102).

The diagnosis of an ovarian cancer requires an exploratory laparotomy. The preoperative evaluation of the patient with an adnexal mass is outlined in Figure 14.19 (see Chapter 14).

Before the planned exploration, the patient should undergo routine hematologic and biochemical assessments. A preoperative evaluation in a patient undergoing laparotomy should include a radiograph of the chest. Abdominal and pelvic computed tomography (CT) or MRI are of limited value for a patient with a definite pelvic mass (103105). A CT or MRI should be performed for patients with ascites and no pelvic mass to look for liver or pancreatic tumors. The findings only rarely preclude laparotomy (103). The value of PET scanning is still being evaluated (105107). If the hepatic enzyme values are normal, the likelihood of liver disease is low. Liver-spleen scans, bone scans, and brain scans are unnecessary unless symptoms or signs suggest metastases to these sites.

The preoperative evaluation should exclude other primary cancers metastatic to the ovary. A barium enema or colonoscopy is indicated in selected patients with symptoms and signs suspicious for colon cancer. This study should be performed for any patient who has evidence of occult blood in the stool or of intestinal obstruction. An upper gastrointestinal radiographic series or gastroscopy is indicated if there are upper gastrointestinal symptoms such as nausea, vomiting, or hematemesis (3,108). Bilateral mammography is indicated if there is any breast mass, because breast cancer metastatic to the ovaries can simulate primary ovarian cancer.

A Papanicolaou (Pap) test should be performed, although its value for the detection of ovarian cancer is very limited. Patients who have irregular menses or postmenopausal vaginal bleeding should have endometrial biopsy and endocervical curettage to exclude the presence of uterine or endocervical cancer metastatic to the ovary.

Differential Diagnosis

Ovarian epithelial cancers must be differentiated from benign neoplasms and functional cysts of the ovaries (100102). A variety of benign conditions of the reproductive tract, such as pelvic inflammatory disease, endometriosis, and pedunculated uterine leiomyomata, can simulate ovarian cancer. Nongynecologic causes of a pelvic tumor, such as an inflammatory or neoplastic colonic mass, must be excluded. A pelvic kidney can simulate ovarian cancer.

Patterns of Spread

Ovarian epithelial cancers spread primarily by exfoliation of cells into the peritoneal cavity, by lymphatic dissemination, and by hematogenous spread.


The most common and earliest mode of dissemination of ovarian epithelial cancer is by exfoliation of cells that implant along the surfaces of the peritoneal cavity. The cells tend to follow the circulatory path of the peritoneal fluid. The fluid moves with the forces of respiration from the pelvis, up the paracolic gutters, especially on the right, along the intestinal mesenteries, to the right hemidiaphragm. Metastases are typically seen on the posterior cul-de-sac, paracolic gutters, right hemidiaphragm, liver capsule, the peritoneal surfaces of the intestines and their mesenteries, and the omentum. The disease seldom invades the intestinal lumen but progressively agglutinates loops of bowel, leading to a functional intestinal obstruction. This condition is known as carcinomatous ileus (3).


Lymphatic dissemination to the pelvic and para-aortic lymph nodes is common, particularly in advanced-stage disease (109111). Spread through the lymphatic channels of the diaphragm and through the retroperitoneal lymph nodes can lead to dissemination above the diaphragm, especially to the supraclavicular lymph nodes (109). Burghardt et al. reported that 78% of patients with stage III disease have metastases to the pelvic lymph nodes (111). In another series, the rate of para-aortic lymph nodes positive for metastasis was 18% in stage I, 20% in stage II, 42% in stage III, and 67% in stage IV (109).


Hematogenous dissemination at the time of diagnosis is uncommon. Spread to vital organ parenchyma, such as the lungs and liver, occurs in only about 2% to 3% of patients. Most patients with disease above the diaphragm when diagnosed have a right pleural effusion (3). Systemic metastases appear more frequently in patients who survived for some years. Dauplat et al. reported that distant metastasis consistent with stage IV disease ultimately occurred in 38% of the patients whose disease was originally intraperitoneal (112).

Prognostic Factors

The outcome of treatment can be evaluated in the context of prognostic factors, which can be grouped into pathologic, biologic, and clinical factors (113).

Pathologic Factors

The morphology and histologic pattern, including the architecture and grade of the lesion, are important prognostic variables (3). Histologic type was not believed to have prognostic significance, but several papers contained suggestions that clear cell carcinomas are associated with a prognosis worse than that of other histologic types (113,114).

Histologic grade, as determined either by the pattern of differentiation or by the extent of cellular anaplasia and the proportion of undifferentiated cells, seems to be of prognostic significance (115118). Studies of the reproducibility of grading ovarian cancers show a high degree of intraobserver and interobserver variation (119,120). Because there is significant heterogeneity of tumors and observational bias, the value of histologic grade as an independent prognostic factor is not established. Baak et al. have presented a standard grading system based on morphometric analysis, and the system seems to correlate with prognosis, especially in its ability to distinguish low-grade or borderline patterns from other tumors (121).

Clinical Factors

In addition to stage, the extent of residual disease after primary surgery, the volume of ascites, patient age, and performance status are all independent prognostic variables (122131). Among patients with stage I disease, Dembo et al. showed, in a multivariate analysis, that tumor grade and dense adherence to the pelvic peritoneum had a significant adverse impact on prognosis, whereas intraoperative tumor spillage or rupture did not (128). Sjövall et al. confirmed that ovarian cancers that undergo intraoperative rupture or spillage do not worsen prognosis, whereas tumors that are ruptured preoperatively do have a poorer prognosis (129). A multivariate analysis of these and several other studies was performed by Vergote et al., who found that for early-stage disease, poor prognostic variables were tumor grade, capsular penetration, surface excrescences, and malignant ascites, but not iatrogenic rupture (131).

Initial Surgery for Ovarian Cancer


Ovarian epithelial malignancies are staged according to the FIGO system listed in Table 37.2 (30). The FIGO staging is based on findings at surgical exploration. A preoperative evaluation should exclude the presence of extraperitoneal metastases.

Table 37.2 FIGO Staging for Primary Carcinoma of the Ovary


Stage I

Growth limited to the ovaries.


Growth limited to one ovary; no ascites containing malignant cells.


No tumor on the external surface; capsule intact.


Growth limited to both ovaries; no ascites containing malignant cells.


No tumor on the external surfaces; capsules intact.


Tumor either stage IA or IB but with tumor on the surface of one or both ovaries; or with capsule ruptured; or with ascites present containing malignant cells or with positive peritoneal washings.

Stage II

Growth involving one or both ovaries with pelvic extension.


Extension and/or metastases to the uterus and/or fallopian tubes.


Extension to other pelvic tissues.


Tumor either stage IIA or IIB but with tumor on the surface of one or both ovaries; or with capsule(s) ruptured; or with ascites present containing malignant cells or with positive peritoneal washings.

Stage III

Tumor involving one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes. Superficial liver metastasis equals stage III. Tumor is limited to the true pelvis, but with histologically proven malignant extension to small bowel or omentum.


Tumor grossly limited to the true pelvis with negative nodes but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces.


Tumor of one or both ovaries with histologically confirmed implants of abdominal peritoneal surfaces, none exceeding 2 cm in diameter. Nodes negative.


Abdominal implants >2 cm in diameter or positive retroperitoneal or inguinal nodes or both.

Stage IV

Growth involving one or both ovaries with distant metastasis. If pleural effusion is present, there must be positive cytologic test results to allot a case to stage IV. Parenchymal liver metastasis equals stage IV.

These categories are based on findings at clinical examination or surgical exploration or both. The histologic characteristics are to beconsidered in the staging, as are results of cytologic testing as far as effusions are concerned. It is desirable that a biopsy be performed onsuspicious areas outside the pelvis.

FIGO, International Federation of Obstetrics and Gynecology.

aTo evaluate the impact on prognosis of the different criteria for allotting cases to stage IC or IIC, it would be of value to know if rupture of thecapsule was (i) spontaneous or (ii) caused by the surgeon and if the source of malignant cells detected was (i) peritoneal washings or (ii) ascites.

Reproduced from Berek JS, Hacker NFBerek & Hacker’s Gynecologic Oncology. 5th ed. Lippincott Williams & Wilkins. 2010:455, adaptedfrom FIGO Annual Report, Vol 26, Int J Gynecol Obstet 2006;105:3–4.

The importance of thorough surgical staging cannot be overemphasized, because subsequent treatment will be determined by the stage of disease. For patients in whom exploratory laparotomy does not reveal any macroscopic evidence of disease on inspection and palpation of the entire intra-abdominal space, a careful search for microscopic spread must be undertaken. In earlier series in which patients did not undergo careful surgical staging, the overall 5-year survival for patients with apparent stage I epithelial ovarian cancer was only about 60% (132). Since then, survival rates of 90% to 100% are reported for patients who were properly staged and were found to have stage IA or IB disease (133,134).

Technique for Surgical Staging

In patients whose preoperative evaluation suggests a probable malignancy, a midline or paramedian abdominal incision is recommended to allow adequate access to the upper abdomen (3,132). When a malignancy is unexpectedly discovered in a patient who has a lower transverse incision, the rectus muscles can be either divided or detached from the symphysis pubis to allow better access to the upper abdomen. If this is not sufficient, the incision can be extended on one side to create a “J” incision (3).

The ovarian tumor should be removed intact, if possible, and a frozen histologic section should be obtained. If ovarian malignancy is present and the tumor is apparently confined to the ovaries or the pelvis, thorough surgical staging should be performed. Staging involves the following steps (3,132):

1. Any free fluid, especially in the pelvic cul-de-sac, should be submitted for cytologic evaluation.

2. If no free fluid is present, peritoneal washings should be performed by instilling and recovering 50 to 100 mL of saline from the pelvic cul-de-sac, each paracolic gutter, and beneath each hemidiaphragm. Obtaining the specimens from under the diaphragms can be facilitated with the use of a rubber catheter attached to the end of a bulb syringe.

3. A systematic exploration of all the intra-abdominal surfaces and viscera is performed, proceeding in a clockwise fashion from the cecum cephalad along the paracolic gutter and the ascending colon to the right kidney, the liver and gallbladder, the right hemidiaphragm, the entrance to the lesser sac at the para-aortic area, across the transverse colon to the left hemidiaphragm, down the left gutter and the descending colon to the rectosigmoid colon. The small intestine and its mesentery from the Treitz ligament to the cecum should be inspected.

4. Any suspicious areas or adhesions on the peritoneal surfaces should be biopsied. If there is no evidence of disease, multiple intraperitoneal biopsies should be performed. Tissue from the peritoneum of the pelvic cul-de-sac, both paracolic gutters, the peritoneum over the bladder, and the intestinal mesenteries should be taken for biopsy.

5. The diaphragm should be sampled, either by biopsy or by scraping with a tongue depressor, and a sample obtained for cytologic assessment. Biopsies of any irregularities on the surface of the diaphragm can be facilitated by use of the laparoscope and the associated biopsy instrument.

6. The omentum should be resected from the transverse colon, a procedure called an infracolic omentectomy. The procedure is initiated on the underside of the greater omentum, where the peritoneum is incised just a few millimeters away from the transverse colon. The branches of the gastroepiploic vessels are clamped, ligated, and divided, along with all the small branching vessels that feed the infracolic omentum. If the gastrocolic ligament is palpably normal, it does not need to be resected.

7. The retroperitoneal spaces should be explored to evaluate the pelvic and para-aortic lymph nodes. The retroperitoneal dissection is performed by incision of the peritoneum over the psoas muscles. This may be performed on the ipsilateral side only for unilateral tumors. Any enlarged lymph nodes should be resected and submitted for frozen section. If no metastases are present, a formal pelvic lymphadenectomy should be performed. The para-aortic area should be explored.


Metastases in apparent stage I and II epithelial ovarian cancer occur in as many as 3 in 10 patients whose tumors appear to be confined to the pelvis but who have occult metastatic disease in the upper abdomen or the retroperitoneal lymph nodes (110,133140). In a literature review, occult metastases in such patients were found in biopsies of the diaphragm in 7.3%, biopsies of the omentum in 8.6%, the pelvic lymph nodes in 5.9%, the aortic lymph nodes in 18.1%, and in 26.4% of peritoneal washings (132).

The importance of careful initial surgical staging is emphasized by the findings of a cooperative national study in which 100 patients with apparent stage I and II disease were referred for subsequent therapy and underwent additional surgical staging (133). In this series, 28% of the patients initially believed to have stage I disease were upstaged and 43% of those believed to have stage II disease had more advanced lesions. A total of 31% of the patients were upstaged as a result of additional surgery, and 77% were reclassified as having actual stage III disease. Histologic grade was a significant predictor of occult metastasis. Sixteen percent of the patients with grade 1 lesions were upstaged, compared with 34% with grade 2 disease and 46% with grade 3 disease.

Borderline Tumors

The principal treatment of borderline (low malignant potential) ovarian tumors is surgical resection of the primary tumor. There is no evidence that either subsequent chemotherapy or radiation therapy improves survival. When a frozen section determines that the histology is borderline, premenopausal patients who desire preservation of ovarian function may undergo a conservative operation, a unilateral oophorectomy (3,141). In a study of patients who underwent unilateral ovarian cystectomy only for apparent stage I borderline serous tumors, Lim-Tan et al. found that this conservative operation was safe, with only 8% of the patients developing recurrences 2 to 18 years later, all with curable disease confined to the ovaries (141). Recurrence was associated with positive margins of the removed ovarian cyst. Thus, hormonal function and fertility can be maintained (3,141). For patients who had an oophorectomy or cystectomy and a borderline tumor is documented later in the permanent pathology, no additional immediate surgery is necessary.

Stage I

After a comprehensive staging laparotomy, only a minority of women will have local disease (FIGO stage I). There are over 20,000 women diagnosed yearly with epithelial ovarian cancer in the United States, and nearly 4,000 of these have disease confined to the ovaries (1,142). The prognosis for these patients depends on the clinical–pathologic features, as outlined below. Because of this emphasis on the importance of surgical staging, the rate of lymph node sampling increased in the United States, with a study showing that for women with stages I and II disease, the percentage having lymph nodes sampled increased from 38% to 59% from 1991 to 1996 (143).

The primary surgical treatment for stage I epithelial ovarian cancer is surgical, and patients should undergo total abdominal hysterectomy, bilateral salpingo-oophorectomy, and surgical staging(132,133). In certain circumstances, a unilateral salpingo-oophorectomy may be performed. Based on the findings at surgery and the pathologic evaluation, patients with stage I ovarian cancer can be grouped into low-risk and high-risk categories (Table 37.3).

Table 37.3 Prognostic Variables in Early-Stage Epithelial Ovarian Cancer


Low Risk

High Risk

Low grade

High grade

Intact capsule

Tumor growth through capsule

No surface excrescences

Surface excrescences

No ascites


Negative peritoneal cytologic findings

Malignant cells in fluid

Unruptured or intraoperative rupture

Preoperative rupture

No dense adherence

Dense adherence

Diploid tumor

Aneuploid tumor

Modified from Berek JS, Hacker NFBerek & Hacker’s Gynecologic Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:458,with permission.

Stage I Low Risk

Fertility Preservation in Early-Stage Ovarian Cancer

For patients who underwent a thorough staging laparotomy and who have no evidence of spread beyond the ovary, abdominal hysterectomy and bilateral salpingo-oophorectomy are appropriate therapy. The uterus and the contralateral ovary can be preserved in women with stage IA, grade 1 to 2 disease who desire to preserve fertility. The conditions of the women should be monitored carefully with routine periodic pelvic examinations and determinations of serum CA125 levels. Generally, the other ovary and the uterus are removed at the completion of childbearing.

Guthrie et al. studied the outcome of 656 patients with early-stage epithelial ovarian cancer (140). No untreated patients who had stage IA, grade 1 cancer died of their disease; thus, adjuvant radiation and chemotherapy are unnecessary. Furthermore, the Gynecologic Oncology Group (GOG) carried out a prospective, randomized trial of observation versus melphalan for patients with stage IA and IB, grade 1 or 2 disease (114). Five-year survival for each group was 94% and 96%, respectively, confirming that no further treatment is needed for such patients.

Stage I High Risk

Patients who have more poorly differentiated disease or who have malignant cells, either in ascites fluid or in peritoneal washings, must undergo complete surgical staging (3). The surgery should include the performance of a hysterectomy and bilateral salpingo-oophorectomy in addition to the staging laparotomy. Although the optimal supportive therapy for these patients is not known, most patients are treated with chemotherapy, as outlined below.

Advanced-Stage Ovarian Cancer

The surgical management of all patients with advanced-stage disease is approached in a similar manner, with modifications made in response to the overall status and general health of the patient and the extent of residual disease present at the time treatment is initiated. A treatment scheme is outlined in Figure 37.10Most patients subsequently receive combination chemotherapy for an empiric number of cycles.

Cytoreductive Surgery for Advanced-Stage Disease

If the patient is medically stable, she should undergo cytoreductive surgery to remove as much of the tumor and its metastases as possible (144171). The operation to remove the primary tumor and the associated metastatic disease is referred to as debulking or cytoreductive surgery. The operation typically includes the performance of a total abdominal hysterectomy and bilateral salpingo-oophorectomy, along with a complete omentectomy and resection of any metastatic lesions from the peritoneal surfaces or from the intestines. The pelvic tumor often directly involves the rectosigmoid colon, the terminal ileum, and the cecum (Fig. 37.11). In a minority of patients, most or all of the disease is confined to the pelvic viscera and the omentum, so that removal of these organs will result in extirpation of all gross tumor, a situation that is associated with a reasonable chance of prolonged progression-free survival.

Figure 37.10 Treatment scheme for patients with advanced-stage ovarian cancer. *In selected cases of Stage IIIc/IV disease, neoadjuvant chemotherapy may be given, and then an interval cytoreductive surgery is performed after 3 cycles. +Chemotherapy depends on whether platinum-sensitive or platinum-resistant. (Modified from Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:460, with permission.)

Figure 37.11 Extensive ovarian carcinoma involving the bladder, rectosigmoid, and ileocecal area. (Redrawn from Heintz APM, Berek JS. Cytoreductive surgery for ovarian carcinoma. In: Piver MS, ed. Ovarian malignancies. Edinburgh, UK: Churchill Livingstone, 1987:134, with permission.)

The removal of bulky tumor masses may reduce the volume of ascites present. Often, ascites will disappear after removal of the primary tumor and a large omental “cake.” Removal of the omental cake may alleviate the nausea and early satiety that many patients experience. Removal of intestinal metastases may restore adequate intestinal function and improve the overall nutritional status of the patient, thereby facilitating the patient’s ability to tolerate subsequent chemotherapy.

A large, bulky tumor may contain areas that are poorly vascularized, and these areas will be exposed to suboptimal concentrations of chemotherapeutic agents. Similarly, these areas are poorly oxygenated, so that radiation therapy, which requires adequate oxygenation to achieve maximal cell kill, will be less effective. Surgical removal of these bulky tumors may eliminate areas that could be relatively resistant to radiation and chemotherapeutic treatment.

Larger tumor masses tend to be composed of a higher proportion of cells that are either nondividing or in the “resting” phase (i.e., G0 cells, which are essentially resistant to the therapy). A low growth fraction is characteristic of bulky tumor masses, and cytoreductive surgery can result in smaller residual masses with a relatively higher growth fraction.

Goals of Cytoreductive Surgery

The principal goal of cytoreductive surgery is removal of all of the primary cancer and, if possible, all metastatic disease. If resection of all metastases is not feasible, the goal is to reduce the tumor burden by resection of all individual tumors to an optimal status. Griffiths initially proposed that all metastatic nodules should be reduced to less than 1.5 cm in maximal diameter and showed that survival was significantly longer in patients for whom this was achieved (144).

Hacker and Berek demonstrated that patients whose largest residual lesions were less than 5 mm had a superior survival rate, which was substantiated by Van Lindert et al. (145148). The median survival of patients in this category was 40 months, compared with 18 months for patients whose lesions were less than 1.5 cm and 6 months for patients with nodules greater than 1.5 cm. Patients whose disease is completely resected to no macroscopic (microscopic only) residual disease have the best overall survival (149) (Fig. 37.12). Approximately 30% to 40% of patients in this category will be free of disease at 5 years.

Figure 37.12 Survival of patients with stage IIIC epithelial ovarian cancer based on the maximal size of residual tumor after exploratory laparotomy and tumor resection. (From Heintz APM, Odicino F, Maisonneuve P, et al. Carcinoma of the ovary. Twenty-sixth annual report of the results of treatment of gynaecological cancer. Int J Gynecol Oncol 2006;95(suppl 1):S161–S192, with permission.)

The resectability of the metastatic tumor is usually determined by the location of the disease. Optimal cytoreduction is difficult to achieve in the presence of extensive disease on the diaphragm, in the parenchyma of the liver, along the base of the small bowel mesentery, in the lesser omentum, or in the porta hepatis.

The ability of cytoreductive surgery to influence survival is limited by the extent of metastases before cytoreduction, presumably because of the presence of phenotypically resistant clones of cells in large metastatic masses. A patient whose metastatic tumor is very large (i.e., >10 cm before cytoreductive surgery) has a shorter survival than those with smaller areas of disease (147,149). Extensive carcinomatosis, the presence of ascites, and poor tumor grade, even with lesions that measure less than 5 mm, may shorten the survival (150153).


The supine position on the operating table may be sufficient for surgical exploration of most patients. For patients with extensive pelvic disease and for whom a low resection of the colon may be necessary, the low lithotomy position should be used. Debulking operations should be performed through a vertical incision to gain adequate access to the upper abdomen and to the pelvis.

After the peritoneal cavity is opened, ascites fluid, if present, should be evacuated. In some centers, fluid is submitted for in vitro research studies, such as molecular analyses. In cases of massive ascites, careful attention must be given to hemodynamic monitoring, especially for patients with borderline cardiovascular function.

The peritoneal cavity and retroperitoneum are thoroughly inspected and palpated to assess the extent of the primary tumor and the metastatic disease. All abdominal viscera must be palpated to exclude the possibility that the ovarian disease is metastatic, particularly from the stomach, colon, or pancreas. If optimal status is not considered achievable, extensive bowel and urologic resections are not indicated, except to overcome a bowel obstruction. Removal of the primary tumor and omental cake is usually both feasible and desirable.

Figure 37.13 The resection of the pelvic tumor may include removal of the uterus, tubes, and ovaries, as well as portions of the lower intestinal tract. The arrows represent the plane of resection. (From Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:465, with permission.)

Pelvic Tumor Resection

The essential principle of pelvic tumor removal is the retroperitoneal approach. To accomplish this, the retroperitoneum is entered laterally, along the surface of the psoas muscles, which avoids the iliac vessels and the ureters. If the uterus is present, the procedure is initiated by bilateral division of the round ligaments. The peritoneal incision is extended cephalad, lateral to the ovarian vessels within the infundibulopelvic ligament, and caudally toward the bladder. With careful dissection, the retroperitoneal space is explored, and the ureter and pelvic vessels are identified. The pararectal and paravesicular spaces are identified and developed, as described in Chapter 36.

The peritoneum overlying the bladder is dissected to connect the peritoneal incisions anteriorly. The vesicouterine plane is identified, and with careful sharp dissection the bladder is mobilized from the anterior surface of the cervix. The ovarian vessels are isolated, doubly ligated, and divided.

Hysterectomy is then performed. The ureters must be carefully displayed to avoid injury. During this procedure, the uterine vessels can be identified. Ligation of the uterine vessels and the remainder of the tissues within the cardinal ligaments completes the hysterectomy and resection of the contiguous tumor.

Figure 37.14 Separation of the omentum from stomach and transverse colon. Arrow, the direction of the initial surgical approach. (From Heintz APM, Berek JS. Cytoreductive surgery for ovarian carcinoma. In: Piver MS, ed. Ovarian malignancies. Edinburgh, UK: Churchill Livingstone, 1987:134, with permission.)

Because epithelial ovarian cancers tend not to invade the lumina of the colon or bladder, it is usually feasible to resect pelvic tumors without having to resect portions of the lower colon or the urinary tract (154,155). Resection of a small portion of the bladder may be required and, if so, a cystotomy should be performed to assist in resection of the disease (155).

Intestinal Resection

Resection of focal areas of disease involving the small or large intestine should be performed if that would permit the removal of all or most of the abdominal metastases and leave the patient with optimal disease at the end of the cytoreduction. Apart from the rectosigmoid colon, the most frequent sites of intestinal metastasis are the terminal ileum, the cecum, and the transverse colon. Resection of one or more of these segments of bowel may be necessary (154,156).

If the disease surrounds the rectosigmoid colon and its mesentery, that portion of the colon may have to be removed in order to clear the pelvic disease (Fig. 37.13) (154). When the pararectal space is identified in such patients, the proximal site of colonic involvement is identified, the colon and its mesentery are divided, and the rectosigmoid is removed along with the uterus en bloc. A reanastomosis of the colon is performed.


Advanced epithelial ovarian cancer often completely replaces the omentum, forming an “omental cake.” This disease may be adherent to the parietal peritoneum of the anterior abdominal wall, making entry into the abdominal cavity difficult. After freeing the omentum from any adhesions to parietal peritoneum, adherent loops of small intestine are freed by sharp dissection. The omentum is lifted and pulled gently in the cranial direction, exposing the attachment of the infracolic omentum to the transverse colon. The peritoneum is incised to open the appropriate plane, which is developed by sharp dissection along the serosa of the transverse colon. Small vessels are ligated with hemoclips. The omentum is separated from the greater curvature of the stomach by ligation of the right and left gastroepiploic arteries and ligation of the short gastric arteries (Fig. 37.14).

The disease in the gastrocolic ligament can extend to the hilus of the spleen and splenic flexure of the colon on the left and to the capsule of the liver and the hepatic flexure of the colon on the right.Usually, the disease does not invade the parenchyma of the liver or spleen, and a plane can be found between the tumor and these organs. It will occasionally be necessary to perform splenectomy to remove all the omental disease (157).

Resection of Other Metastases

Other large masses of tumor located on the parietal peritoneum should be removed, particularly if they are isolated masses and their removal will permit optimal cytoreduction. Resection of extensive disease from the surfaces of the diaphragm is neither practical nor feasible, although solitary metastases may be resected, the diaphragm sutured, and a chest tube placed for a few days (157,158). The use of the Cavitron Ultrasonic Surgical Aspirator (CUSA) and the argon beam coagulator may facilitate resection of small tumor nodules, especially those on flat surfaces (159,160).

Feasibility and Outcome

There was no randomized prospective study performed to define the value of primary cytoreductive surgery, but all retrospective studies indicate that the diameter of the largest residual tumor nodule before the initiation of chemotherapy is significantly related to progression-free survival in patients with advanced ovarian cancer (163). Quality of life may be significantly enhanced by removal of bulky tumor masses from the pelvis and upper abdomen (166).

An analysis of the retrospective data indicates that, when performed by gynecologic oncologists, successful operations are feasible in 70% to 90% of patients (152,153). Major morbidity is approximately 5% and operative mortality is 1% (156,161,162). Intestinal resection in these patients does not appear to increase the overall morbidity caused by the operation (156).

In a meta-analysis of 81 studies of women who underwent cytoreductive surgery for advanced ovarian cancer, Bristow et al. documented that the extent of debulking correlated with incremental benefits in survival (i.e., the greater the percentage of tumor reduction, the longer the survival). Each 10% increase in cytoreduction equaled a 5.5% increase in median survival (163). Women whose cytoreduction was greater than 75% of their tumor burden had a median survival of 33.9 months compared with 22.7 months for women whose tumors were cytoreduced less than 75% (p < 0.001). The performance of a pelvic and para-aortic lymphadenectomy in patients with stage III disease does not prolong survival, based on the results of a large prospective, randomized trial (164).

A prospective randomized study of “interval” cytoreductive surgery was carried out by the European Organisation for the Research and Treatment of Cancer (EORTC). Interval surgery was performed after three cycles of platinum-combination chemotherapy in patients whose primary attempt at cytoreduction was suboptimal. The initial surgery for most of these patients was not an aggressive attempt to debulk their tumors. Patients in the surgical arm of the study demonstrated a survival benefit when compared with those who did not undergo interval debulking (165). The risk of mortality was reduced by more than 40% in the group that was randomized to the debulking arm of the study. Based on these data, the performance of a debulking operation as early as possible in the course of the patient’s treatment should be considered the standard of care (166).

A prospective phase III study of interval cytoreductive surgery was conducted by the GOG; the patients entered on the trial had a maximal attempt at tumor resection at their initial surgery (167). The randomized findings showed no difference between the patients who had an additional attempt at debulking after three cycles of chemotherapy compared with those who did not. The median survival of the 216 women who underwent interval cytoreduction was 32 months compared with 33 months for the 209 women who did not undergo surgical cytoreduction.

There is evidence that the survival of women with advanced ovarian cancer is improved when the surgeon is specifically trained to perform cytoreductive surgery and when there is centralization of care (168171). Whenever feasible, patients with advanced ovarian malignancy should be referred to a subspecialty unit for primary surgery, and every effort should be made to attain as complete a cytoreduction as possible.


Stage I Epithelial Ovarian Cancer

Early Stage, Low Risk

Guthrie et al. studied the outcome of 656 patients with early-stage epithelial ovarian cancer (140). Patients who had stage IA, grade 1 cancer and did not receive radiation or chemotherapy did not die of their disease; indicating that adjuvant therapy is unnecessary. The GOG carried out a prospective, randomized trial of observation versus melphalan for patients with stage IA and IB, grades 1 and 2 disease (114). Five-year survival for each group was 94% and 96%, respectively, confirming that adjuvant treatment did not improve survival. Therefore, no adjuvant chemotherapy is recommended for these patients.

Early Stage, High Risk

In patients whose disease is high risk (e.g., more poorly differentiated or in whom there are malignant cells either in ascites fluid or in peritoneal washings), additional therapy is indicated. Most investigators recommend chemotherapy for these patients (172185). Chemotherapy for patients with early-stage high-risk epithelial ovarian cancer can be either single agent or multiagent. Some researchers question the wisdom of overly aggressive chemotherapy in women with early-stage disease, suggesting that the evidence for a durable impact on survival is marginal (174,175,181). The risk of leukemia with alkylating agents and platinum make the administration of adjuvant therapy hazardous unless there is a significant benefit (186,187).

Because cisplatincarboplatincyclophosphamide, and paclitaxel (Taxol) are active single agents against epithelial ovarian cancer, these drugs are administered in various combinations. There are some series in which cisplatin or cyclophosphamide (PC) or both have been used to treat patients with stage I disease (176181). In a GOG trial of three cycles of cisplatin and cyclophosphamide versus intraperitoneal chromic phosphate (32P) in patients with stage IB and IC disease, the progression-free survival of women receiving the platinum-based chemotherapy was 31% higher than those receiving the radiocolloid (178). Similar results were reported by a multicenter trial performed in Italy by the Gruppo Italiano Collaborativo Oncologica Ginecologica (GICOG) for progression-free survival, although there was no overall survival advantage (179).

Two large parallel randomized phase III clinical trials were conducted on women with early-stage disease: the International Collaborative Ovarian Neoplasm Trial 1 (ICON1) and the Adjuvant Chemotherapy Trial in Ovarian Neoplasia (ACTION) (188,189).

In the ICON1 trial, 477 patients from 84 centers in Europe were entered. Patients of all stages were eligible for the trial if, in the opinion of the investigator, it was unclear whether adjuvant therapy would be of benefit. Most patients were considered to have stage I and IIA disease, but optimal surgical staging was not required, and it is likely that a significant number of these women had stage III disease. Adjuvant platinum-based chemotherapy was given to 241 patients, and no adjuvant chemotherapy was given to 236 patients. The 5-year survival was 73% in the group who received adjuvant chemotherapy compared with 62% in the control group (hazard ratio [HR] = 0.65, p = 0.01) (189).

In the ACTION trial, 440 patients from 40 European centers were randomized; 224 patients received adjuvant platinum-based chemotherapy, and 224 patients did not (188). Patients with As I and IIa, grades 2 and 3 were eligible. Only about one-third of the total group was optimally staged (151 patients). In the observation arm, optimal staging was associated with a better survival (HR = 2.31, p = 0.03), and in the suboptimally staged patients, adjuvant chemotherapy was associated with an improvement in survival (HR = 1.78, p = 0.009). In optimally staged patients, no benefit of adjuvant chemotherapy was seen. In the ACTION trial, the benefit from adjuvant chemotherapy was limited to the patients with suboptimal staging, suggesting that patients benefit only if they had a likelihood of occult microscopic dissemination.

When the data from the two trials were combined and analyzed, a total of 465 patients were randomized to receive platinum-based adjuvant chemotherapy and 460 to observation until disease progression (190). After a median follow-up of more than 4 years, the overall survival was 82% in the chemotherapy arm and 74% in the observation arm (HR = 0.67, p = 0.001). Recurrence-free survival was better in the chemotherapy arm: 76% versus 65% (HR = 0.64, p = 0.001). The results of this analysis must be interpreted with caution, because most of the patients did not undergo thorough surgical staging, but the findings suggest that platinum-based chemotherapy should be given to patients who were not optimally staged.

Carboplatin is widely used instead of cisplatin, as it is equivalent in efficacy and much better tolerated with significantly fewer side effects (191). A randomized phase III trial of three versus six cycles of adjuvant carboplatin and paclitaxel in 457 patients with early stage epithelial ovarian carcinoma was conducted by the GOG (192). An unexpectedly large number of patients (126 patients, 29%) had incomplete or inadequately documented surgical staging in this study. The recurrence rate for six cycles was 24% lower (HR = 0.76; confidence interval [CI], 0.5–1.13; p = 0.18) versus three cycles, but this was not statistically significant. The estimates of probability of recurrence at 5 years were 20.1% for six cycles and 25.4% for three cycles. The authors concluded that three cycles of adjuvant carboplatin and paclitaxel was a reasonable option for women with high-risk early stage ovarian cancer. The current GOG trial includes patients with high-risk stage I and stage II disease, and offers three cycles of carboplatin and paclitaxel followed by a randomization to either observation versus 26 weeks of weekly low-dose (40 mg/m2paclitaxel.High-risk stage I is defined as stage IA or IB, grade 3, stage IC, or clear cell carcinomas.

The recommendations for therapy follow:

• Patients with high-grade, high-risk stage I epithelial ovarian cancer should be given adjuvant chemotherapy. The type depends on the patient’s overall health and medical comorbidities

• Treatment with carboplatin and paclitaxel chemotherapy for three to six cycles is used in these patients, whereas single agent carboplatin may be preferable for older women and patients with other medical comorbidities.

Advanced-Stage Epithelial Ovarian Cancer

Systemic multiagent chemotherapy is the standard treatment for metastatic epithelial ovarian cancer (193217). After the introduction of cisplatin in the latter half of the 1970s, platinum-based combination chemotherapy became the most frequently used treatment regimen in the United States. Paclitaxel became available in the 1980s, and this drug was incorporated into the combination chemotherapy in the 1990s (192196). Comparative trials of paclitaxelcisplatin, and carboplatin are summarized below.

In a meta-analysis performed on studies of patients with advanced-stage disease, those patients given cisplatin-containing combination chemotherapy were compared with those treated with regimens that did not include cisplatin(197). Survival differences between the groups were seen from 2 to 5 years, with the cisplatin group having a slight survival advantage, but this difference disappeared by 8 years.

A major advance in the treatment of advanced-stage disease was the incorporation of paclitaxel into the chemotherapeutic regimens in the late 1990s. A series of randomized, prospective clinical trials with paclitaxel-containing arms defined carboplatin and paclitaxel as the standard treatment protocol in advanced epithelial ovarian cancer, although there are data to support intraperitoneal chemotherapy in selected patients (194,195,201,202).

Reporting the GOG data (Protocol 111), McGuire et al. showed that the combination of cisplatin (75 mg/m2) and paclitaxel (135 mg/m2) was superior to cisplatin (75 mg/m2) and cyclophosphamide (600 mg/m2), each given for six cycles (194). In suboptimally resected patients, the paclitaxel-containing arm produced a 36% reduction in mortality. These data were verified in a trial conducted jointly by the EORTC, the Nordic Ovarian Cancer Study Group (NOCOVA), and the National Cancer Institute of Canada (NCIC), in which patients with both optimal and suboptimal disease were treated (195). In this study, the paclitaxel-containing arm produced a significant improvement in both progression-free interval and overall survival in both optimal and suboptimal groups. Based on these two studies, paclitaxel is included in the primary treatment of all women with advanced-stage epithelial ovarian cancer, unless there are contraindications to paclitaxel, such as preexisting peripheral neuropathy.

A three-arm comparison of paclitaxel (T) versus cisplatin (P) versus PT in suboptimal stage III and IV patients (Protocol 132) showed equivalency in the three groups, but crossover from one drug to the other was permitted (196). The study showed that the combination regimen was better tolerated than the sequential administration of the agents in suboptimally resected patients.

The second-generation platinum analogue, carboplatin, was developed to have less toxicity than its parent compound, cisplatin. In early trials, carboplatin had lower overall toxicity (204). Fewer gastrointestinal side effects, especially nausea and vomiting, were observed than with cisplatin, and there was less nephrotoxicity, neurotoxicity, and ototoxicity. Carboplatin is associated with a higher degree of myelosuppression (206).

The dose of carboplatin is calculated by using the area under the curve (AUC) and the glomerular filtration rate (GFR) according to the Calvert formula (207). The target AUC is 5 to 6 for previously untreated patients with ovarian cancer.

Carboplatin and Paclitaxel

Two randomized, prospective clinical studies compared the combination of paclitaxel and carboplatin to paclitaxel and cisplatin (201,202). In both studies, the efficacy and survivals were similar, but the toxicity was more acceptable with the carboplatin-containing regimen. In the first trial, GOG Protocol 158, the randomization was carboplatin AUC = 7.5 and paclitaxel 175 mg/m2 over 3 hours versus cisplatin 75 mg/m2 and paclitaxel 135 mg/m2 over 24 hours (Fig. 37.15). The disease progression-free survival of the carboplatin-containing arm was 22 months versus 21.7 months for the control arm (201). The gastrointestinal and neurotoxicity of the carboplatin arm were appreciably lower than that of the cisplatin arm. A similar result was obtained in a large randomized trial in Germany, in which the dose of carboplatin was AUC = 6 and paclitaxel was 185 mg/m2 over 3 hours compared with the same dose of paclitaxel and cisplatin 75 mg/m2 (202). Based on these data, the preferred regimen in patients with advanced-stage disease is the paclitaxel plus carboplatin combination (203).

Figure 37.15 Survival of patients with stage III epithelial ovarian cancer treated with carboplatin and paclitaxel versus cisplatin and paclitaxel: a Gynecologic Oncology Group study. A: Survival by treatment. B: Survival by treatment group (micro vs. macro). (From Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol 2003;21:3194–3200, with permission; Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology.4th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:475, with permission.)

The ICON3 trial was a study of 2,074 women with all stages of ovarian cancer, including 20% who had stage I or II disease (208). Carboplatin plus paclitaxel was compared with two non-paclitaxelregimens, carboplatin(70%), or cyclophosphamideAdriamycin, and cisplatin (CAP) (30%). The regimens were chosen before randomization and based on the clinical preference of the treating physician. One-third of patients who received carboplatin or CAP subsequently received second-line paclitaxel, and this additional chemotherapy was often given before clinical progression. With a median follow-up of 51 months, the carboplatin plus paclitaxel and the control groups had a similar progression-free survival (0.93) and overall survival (0.98). The median survival for the paclitaxel plus carboplatin and control groups was 36.1 and 35.4 months, respectively. The median duration of progression-free survival was 17.3 and 16.1 months, respectively. The researchers concluded that single agent carboplatin and CAP were as effective as paclitaxel and carboplatin for first-line chemotherapy. Because carboplatin as a single agent had a lower toxicity than the other regimens and the median survival (33 months) was similar in the prior trial (ICON2) that compared carboplatin and CAP as first-line treatment, the researchers suggested that carboplatin alone was the preferred therapy (209). The design of the study limited the interpretation of the results and was criticized, because patients with FIGO stages I to IV disease were included, the extent of primary surgery was variable, and the majority (85%) of patients who relapsed after single-agent carboplatin or CAP received paclitaxel. The results of this study did not change the practice in the United Kingdom where the study was predominantly carried out.

Carboplatin and Docetaxel

Docetaxel has a different toxicity profile from paclitaxel. The SCOT-ROC (Scottish Gynaecological Cancer Trials Group) study randomly assigned 1,077 women with stages Ic to IV epithelial ovarian cancer to carboplatin with either paclitaxel or docetaxel (210). The efficacy of docetaxel appeared to be similar to paclitaxel: The median progression-free survival was 15.1 months versus 15.4 months, and the docetaxel group had fewer neurologic effects, arthralgias, myalgias, and extremity weakness than the paclitaxel group. The docetaxel plus carboplatin regimen was associated with significantly more myelosuppression and its consequences (i.e., serious infections and prolonged grade 3 to 4 neutropenia). Additional study is necessary to determine whether docetaxel should supplant paclitaxel in the primary treatment of epithelial ovarian cancer.

Five-Arm Trial

An Intergroup, international trial—GOG 182/Southwest Oncology Group (SWOG) 182/ICON5—compared the standard combination of carboplatin and paclitaxel with these drugs in combination with gemcitabinetopotecan, or liposomal doxorubicin in sequential doublets or triplets (211). The study showed that the addition of any these three drugs to the standard chemotherapy with carboplatin and paclitaxel did not improve progression-free survival or overall survival.

Intraperitoneal Chemotherapy

A randomized, prospective GOG study (Protocol 104) of intraperitoneal cisplatin versus intravenous cisplatin (100 mg/m2), each given with 750 mg/m2 cyclophosphamide, was performed jointly by the SWOG and the GOG in patients with minimal residual disease (212). The intraperitoneal cisplatin arm had a somewhat longer overall median survival than the intravenous arm, 49 versus 41 months(p = 0.03). In the patients with minimal residual disease (<0.5 cm maximal residual), paradoxically, there was no difference between the two treatments, 51 versus 46 months (p = 0.08).

In a follow-up GOG study (Protocol 114), the dose-intense arm was initiated by giving a moderately high dose of carboplatin (dose AUC = 9) for two induction cycles, followed by intraperitoneal cisplatin100 mg/m2 and intravenous paclitaxel 135 mg/m2 over 24 hours, versus intravenous cisplatin 75 mg/m2 and intravenous paclitaxel 135 mg/m2 (213). The dose-intense arm results were slightly better—the disease progression-free median survival was 27.6 months compared with 22.5 months for the control arm (p = 0.02). There was no difference in overall survival (52.9 months versus 47.6 months, p = 0.056). Based on this study, it was unclear whether dose intensification with intraperitoneal cisplatin has a sustained long-term impact on the survival of these patients.

A third randomized prospective GOG study (Protocol 172) compared intraperitoneal cisplatin and paclitaxel versus intravenous cisplatin and paclitaxel (214). The combination of cisplatin 75 mg/m2 and paclitaxel 135 mg/m2 given intravenously every 3 weeks was compared with paclitaxel 135 mg/m2 intravenous day 1, followed by cisplatin 100 mg/m2 intraperitoneal day 2, and paclitaxel 60 mg/m2 intraperitoneal day 8 every 3 weeks, each given for six cycles. Although 83% of the patients randomized to intravenous chemotherapy completed all six cycles of therapy, only 42% of those treated with intraperitoneal chemotherapy completed the six cycles, principally because of catheter-related complications. For patients in either group who could not complete the therapy because of cisplatin-related toxicity, the chemotherapy was switched to intravenous carboplatin. Comparing the intravenous and intraperitoneal arms, the median duration of progression-free survival was 18.3 and 23.8 months, respectively (p = 0.05). The median duration of overall survival in the intravenous-therapy and intraperitoneal-therapy groups was 49.7 and 65.6 months, respectively (p = 0.03) (214). Quality of life was significantly worse in the intraperitoneal-therapy group before cycle four and 3 to 6 weeks after treatment but not 1 year after treatment. A summary of the intraperitoneal catheter-related issues in this trial was presented (215).

Based on these randomized trials, the intraperitoneal route of administration for cisplatin and paclitaxel chemotherapy in the primary treatment of optimally resected stage III ovarian cancer is an acceptable therapeutic alternative to intravenous chemotherapy with carboplatin and paclitaxel (216). There are no reports of randomized direct comparisons of this intraperitoneal regimen to intravenous carboplatin and paclitaxelor to intraperitoneal carboplatin and paclitaxel. Intraperitoneal therapy can be used in patients with optimally resected tumors who have a good performance status and are in overall good health. Because intraperitoneal chemotherapy is more cumbersome and has a higher morbidity than intravenous therapy, the use of this technique of drug delivery should be individualized after thorough discussion with the patient.

Dose-Dense Intravenous Chemotherapy

The Japanese GOG randomized 637 patients with ovarian cancer to receive carboplatin AUC 6 and paclitaxel 180 mg/m2 every 3 weeks or the same dose of carboplatin and 80 mg/m2 paclitaxel every week for at least six cycles (217). The median progression-free survival was 28 months in the dose-dense arm and 17 months in the control group, and they reported relatively little difference in toxicity between the two arms and that grade 3 to 4 neurotoxicity in particular was very low. In the 417 patients who had stage III disease, about half had less than 1 cm maximum residual disease, similar to the patients in GOG 172. There is no subgroup analysis to determine whether these optimally debulked patients fared better with dose-dense paclitaxel, but the hazard ratio for recurrence was 0.69 for stage III as a group. These findings are very encouraging but need to be validated in another study. There is good evidence that weekly paclitaxel is more effective than paclitaxel every 3 weeks in breast cancer and the Japanese GOG study suggests that the same may apply to ovarian cancer. This important question is being studied in GOG and other studies comparing intravenous dose-dense treatment with intraperitoneal chemotherapy.

Neoadjuvant Chemotherapy

Some authors suggested that selected patients with suboptimal stage III and stage IV disease and those with large volume ascites and pleural effusions should have chemotherapy prior to debulking surgery. A series performed by Schwartz et al. suggested that these patients treated with neoadjuvant or cytoreductive chemotherapy had survival that was comparable to those patients treated in the same institution with debulking surgery followed by conventional chemotherapy (218). It is accepted that two or three cycles of chemotherapy before cytoreductive surgery may be helpful in patients with massive ascites and large pleural effusions. The chemotherapy may “dry up” the effusions, improve the patient’s performance status, and decrease postoperative morbidity, particularly chest morbidity (219,220).

The EORTC completed a large randomized trial in 718 patients with advanced ovarian cancer comparing initial surgery followed by six cycles of carboplatin and paclitaxel with three cycles of neoadjuvant chemotherapy followed by surgical debulking and another three cycles of chemotherapy. The study found that the progression-free survival was identical in both arms (12 months) and similarly the overall survival (30 months) was the same in both arms (221). The morbidity of surgery was significantly less in patients receiving neoadjuvant chemotherapy, suggesting that in selected patients with very advanced (stages IIIC and IV) ovarian cancer two to three cycles of neoadjuvant chemotherapy prior to surgical debulking is a reasonable option.

Chemotherapy and Bevacizumab

Inhibition of angiogenesis with drugs such as bevacizumab demonstrated activity and benefit in women with recurrent ovarian cancer. There is evidence in other tumor types such as breast cancer and colon cancer that the addition of bevacizumab to chemotherapy increases response rates, progression-free survival, and survival in some studies (222224). Two large randomized trials (GOG 218 and ICON7) investigating the impact of the addition of bevacizumabto standard carboplatin and paclitaxel in patients with advanced ovarian cancer were completed (225,226). GOG 218 is a phase III three-arm randomized double-blind placebo-controlled trial. Patients in arm one received six cycles of carboplatin and paclitaxel and placebo starting with the second cycle and continuing for 16 additional cycles after the completion of chemotherapy. Patients in arm two received six cycles of chemotherapy with bevacizumabstarting with cycle two and administered with chemotherapy followed by 16 cycles of placebo, and in arm three patients received bevacizumab starting with cycle two of chemotherapy and then received 16 additional cycles after the completion of chemotherapy. This study was designed to investigate the benefit of bevacizumab in combination with chemotherapy and as a maintenance therapy. The bevacizumab was administered at a does of 15 mg/kg, starting with the second cycle of chemotherapy, to decrease the risk of gastrointestinal perforation, which is a rare complication of this agent in the setting of its use in colorectal cancer. The results of GOG 218 reported a modest improvement of 3.8 months in progression-free survival in patients randomized to receive bevacizumab in combination with carboplatin and paclitaxel every 3 weeks and then as a maintenance therapy every 3 weeks for an additional 16 cycles for a total of 15 months' treatment (225). The toxicity of bevacizumab was acceptable and the risk of bowel perforation very low (below 2%). The study did not find any improvement in overall survival, but follow-up is required. The ICON7 study is similar to the GOG study, although it is a two-arm study of carboplatin and paclitaxel plus or minus bevacizumab 7.5 mg/kg administered every 3 weeks with chemotherapy for six cycles and then as maintenance therapy for 12 additional cycles. The ICON7 results were presented and reported a statistically significant, yet modest, 1.7-month improvement in median progression-free survival in the experimental arm (226). The results of these studies support a role of bevacizumab in combination with chemotherapy in patients with advanced ovarian cancer. However, the cost of bevacizumab is very high and the improvement in progressive-free survival is short.

Chemotherapeutic Recommendation in Advanced Epithelial Ovarian Cancer

For the treatment of advanced-stage epithelial ovarian cancer, the following is recommended (Table 37.4):

Table 37.4 Combination Chemotherapy for Advanced Epithelial Ovarian Cancer: Recommended Regimens

• Combination chemotherapy or intravenous carboplatin and paclitaxel or intraperitoneal cisplatin and paclitaxel (using the GOG 172 protocol) are the treatments of choice for patients with advanced disease. The advantages and disadvantages of the intravenous versus intraperitoneal routes of administration of these drugs should be discussed with the patient.

• The recommended doses and schedule for intravenous chemotherapy are: carboplatin (starting dose AUC = 5–6), and paclitaxel (175 mg/m2), every 3 weeks for six to eight cycles, or the dose-dense regimen of carboplatin AUC 6 every 3 weeks for six cycles and weekly paclitaxel 80 mg/m2 (217).

• The recommended doses and schedule for intraperitoneal chemotherapy are paclitaxel 135 mg/m2 intravenous on day 1, followed by cisplatin 75 to 100 mg/m2 intraperitoneal on day 2, followed by paclitaxel 60 mg/m2 intraperitoneal on day 8, every 3 weeks for six cycles, as tolerated. (Many centers modified the dose of cisplatin to 75 mg/m2 rather than 100 mg/m2 to reduce toxicity. Others substitute carboplatin (AUC 6) for cisplatin in the regimen.) The impact on outcome of these pragmatic modifications is unknown.

• Bevacizumab 7.5--15 mg/kg can be added to any of these intravenous or intraperitoneal chemotherapy regimens.

• In patients who cannot tolerate combination chemotherapy, single-agent, intravenously administered carboplatin (AUC 5–6) can be given.

• In patients who have a hypersensitivity to paclitaxel or carboplatin, an alternative active drug can be substituted (e.g., docetaxel, nanoparticle paclitaxel, cisplatin). In the case of carboplatin hypersensitivity, desensitization could be attempted.

The treatment of all patients with advanced-stage disease is approached in a similar manner, with modifications based on the overall status and general health of the patient and the extent of residual disease present at the time treatment is initiated.

Maintenance of Complete Clinical Response to First-Line Chemotherapy

Because as many as 80% of women with advanced-stage disease who completely respond to their first-line chemotherapy will ultimately relapse, several trials were conducted that administer a drug to these patients immediately following their primary treatment in an effort to decrease the relapse rate.


In a study conducted by the GOG and SWOG, 277 women with advanced ovarian cancer who had a complete clinical remission to first-line chemotherapy were randomized to receive 3 or 12 cycles of additional single-agent paclitaxel (175 or 135 mg/m2 every 28 days) (227). Patients were excluded if they developed grade 2 or 3 neurotoxicity during their initial chemotherapy. Because of cumulative toxicity, the mean number of actual cycles of paclitaxel received by the group assigned to receive 12 cycles was 9. The treatment-related grade 2 to 3 neuropathy was more common with longer treatment, 24% versus 14% of patients, respectively. The study closed after a median follow-up of only 8.5 months, and an interim analysis showed a significant 7-month prolongation in median progression-free survival (28 versus 21 months) with 9 versus 3 months of consolidation paclitaxel.There was no difference in median overall survival and this study has not changed practice. The rate of disease progression increased significantly after maintenance therapy was discontinued, which suggested that long-term survival was not likely to be improved. It is improbable that a survival benefit will appear with longer follow-up, because patients assigned to three cycles were given the option of receiving an additional nine courses of paclitaxelafter the study was discontinued (228). Another placebo-controlled, randomized trial using two formulations of paclitaxel is being conducted by the GOG.


Four additional treatment courses of topotecan were administered to patients following six cycles of carboplatin and paclitaxel in two randomized trials, one conducted in Italy and the other in Germany (229,230). In the larger trial conducted in Germany, 1,059 evaluable patients were randomly assigned to six cycles of paclitaxel (175 mg/m2 over 3 hours) and carboplatin (AUC 5) with (537 patients) or without (522 patients) four additional cycles of topotecan(1.25 mg/m2 intravenous days 1 to 5 every 3 weeks) (230). In the Italian trial, 273 women were randomly assigned to receive four additional cycles (137 patients) of topotecan at a dose of 1 mg/m2 on days 1 to 5 every 3 weeks or no further chemotherapy (136 patients) (229). Preliminary reports suggest no significant differences in either progression-free or overall survival in patients who received four to six cycles of consolidation topotecan.


In a randomized clinical trial of intraperitoneal cisplatin for consolidation versus observation, there was no difference in survival between the treatment arms (231).

Biologic Therapies

As noted above, the use of the monoclonal antibody (MonAb) bevacizumab with first-line carboplatin and paclitaxel chemotherapy followed by maintenance bevacizumab for a year was associated with a modest improvement in progression-free survival, (225,226). Patients and their physicians may consider maintenance therapy with bevacizumab as delivered in GOG 218 and ICON7. There are a number of ongoing trials addressing the role of oral angiogenesis inhibitors as maintenance therapy after completion of first-line therapy in women with advanced ovarian cancer.

Studies MonAbs directed toward CA125 (OvaRex) and toward the HMFG (human milk fat globulin) tumor–associated antigens were conducted (232234). In a randomized, placebo-controlled trial of intravenous oregovomab (anti-CA125 MonAb) as maintenance therapy, Berek et al. reported that oregovomab did not demonstrate a survival advantage as a maintenance therapy (233). A randomized trial of an intraperitoneally administered yttrium-labeled antimucin (HMFG) MonAb versus placebo was not associated with an improved overall survival after a negative second-look laparoscopy (234).

Treatment Assessment

Many patients who undergo optimal cytoreductive surgery and subsequent chemotherapy for epithelial ovarian cancer have no evidence of disease at the completion of treatment. Tumor markers and radiologic assessments are too insensitive to exclude the presence of subclinical disease. Historically, a second-look surgery was performed to evaluate these patients, but was abandoned, as there is no evidence of a meaningful benefit to patients (132,235244).

Tumor Markers

The level of CA125, a surface glycoprotein associated with müllerian epithelial tissues, is elevated in about 80% of patients with epithelial ovarian cancers, particularly those with nonmucinous tumors (245247). The levels frequently become undetectable after the initial surgical resection and one or two cycles of chemotherapy. Carcinoembryonic antigen (CEA) levels are often elevated in patients with ovarian cancer, and the test is too nonspecific and insensitive to be used in the management of these patients, apart from patients with a mucinous cancer of the ovary (48).

Levels of CA125 were correlated with findings at second-look operations. Elevated levels are useful in predicting the presence of disease, but negative levels are an insensitive determinant of the absence of disease. In a prospective study, the predictive value of a positive test was 100%; if the level of CA125 was elevated (>35 U/mL), disease was always detectable in patients at the second-look procedure (245). The predictive value of a negative test was only 56%; if the level was less than 35 U/mL, disease was present in 44% of the patients at the time of the second-look surgery. A literature review suggests that an elevated CA125 level predicts persistent disease at second-look surgery in 97% of the casesbut the CA125 level is not sensitive enough to exclude subclinical disease in many patients (246).

Serum CA125 levels can be used during chemotherapy to follow those patients whose levels were positive at the initiation of therapy (245). The change in level correlates with response. Those patients with persistently elevated levels after three cycles of treatment probably have persistent disease. When levels rise after treatment, almost invariably treatment has failed, and continuation of the current regimen is futile. A retrospective study determined that a doubling of the CA125 level from its nadir in those patients with a persistently elevated level accurately predicts disease progression (247).

Radiologic Assessment

Radiologic tests assess response in patients with measurable lesions at the start of therapy. In patients who have no or minimal residual disease following cytoreductive surgery, the value of these tests is limited, but they may be useful in follow-up, especially to document the site of recurrence. Ascites can be readily detected, but quite large omental metastases can be missed on CT scan in patients with recurrent disease (248). If liver enzyme levels are abnormal, the liver can be evaluated with a CT scan or ultrasonography. A positive CT scan and fine-needle aspiration (FNA) cytology indicating tumor persistence could document persistent or recurrent disease, but the false-negative rate of a CT scan is about 45% (249). Positron-emission tomography (PET) alone, or with CT imaging, may help detect relapse, although the relative value of adding PET is not established. There appears to be a higher false-positive rate with PET compared with CT (106,107). MRI can be used as an alternative to CT in patients with allergies to the contrast medium (105).

Second-Line Therapy

Secondary Cytoreductive Surgery

Secondary cytoreduction may be defined as an attempt at cytoreductive surgery at some stage following completion of first-line chemotherapy (250253). Patients with progressive disease on chemotherapy are not suitable candidates for secondary cytoreduction, but patients with recurrent disease are occasionally candidates for surgical excision of their disease. Tumor resection under these circumstances should be restricted to those who have a disease-free interval of at least 12, but preferably 24, months or those in whom it is expected that all macroscopic disease can be resected, regardless of the disease-free interval (250258). Complete resection is possible when there are only one or two isolated recurrences in patients without diffuse carcinomatosis (258).

Chemotherapy for Persistent-Recurrent Ovarian Cancer

The majority of women who relapse will be offered more chemotherapy with the likelihood of benefit related to the initial response and the duration of response. The goals of treatment include improving control of disease-related symptoms, maintaining or improving quality of life, delaying time to progression, and possibly prolonging survival, particularly in women with platinum-sensitive recurrences. Many active chemotherapy agents (platinumpaclitaxel, topotecan, liposomal doxorubicin, docetaxel, gemcitabine, and etoposide) and targeted agents (bevacizumab) are available, and the choice of treatment is based on many factors including likelihood of benefit, potential toxicity, and patient convenience.

Women who relapse later than 6 months after primary chemotherapy are classified as platinum-sensitive and usually receive further platinum-based chemotherapy with response rates ranging from 27% to 65% and a median survival of 12 to 24 months (259263). Patients who relapse within 6 months of completing first-line chemotherapy are classified as platinum-resistant and have a median survival of 6 to 9 months and a 10% to 30% likelihood of responding to chemotherapy. Patients who progress while on treatment are classified as having platinum-refractory disease.Objective response rates to chemotherapy in patients with platinum-refractory ovarian cancer are low—less than 20% (264).

The potential adverse effects associated with chemotherapy in trials in women with recurrent ovarian cancer are well documented and should not be underestimated. The three most commonly used drugs are paclitaxel, topotecan, and liposomal doxorubicin (265291). The reported adverse effects associated with paclitaxel were alopecia in 62% to 100%, neurotoxicity (any grade) in 5% to 42% of patients, and severe leukopenia in 4% to 24% of patients. Topotecan is associated with significantly greater myelosuppression than liposomal doxorubicin or paclitaxel and is observed in 49% to 76% of patients. Liposomal doxorubicin is associated with palmer-planter erythrodysesthesia (PPE) of any grade in over 50% of patients and is severe in 23%. Severe stomatitis is reported in up to 10% of patients (265268).

Platinum-Sensitive Disease

The use of combination platinum plus paclitaxel chemotherapy versus a single-agent platinum was tested in two multinational randomized phase III trials and a randomized phase II study (292,293). In a report of the ICON4 and AGO-OVAR-2.2 (AGO Studiengruppe Ovarialkarzinom) trials, 802 women with platinum-sensitive ovarian cancer, who relapsed after being treatment free for at least 6 to 12 months were randomized to platinum-based chemotherapy (72% carboplatin or cisplatin alone; 17% CAP; 4% carboplatin plus cisplatin; and 3% cisplatin plus doxorubicin) or paclitaxel plus platinum-based chemotherapy (80% paclitaxel plus carboplatin; 10% paclitaxelplus cisplatin; 5% paclitaxel plus both carboplatin and cisplatin; and 4% paclitaxel alone) (292). The AGO-OVAR-2.2 trial did not accrue its planned number of patients. In both trials, a significant proportion of the patients did not receive paclitaxel as part of their initial chemotherapeutic regimen. Combining the trials for analysis, there was a significant survival advantage for the paclitaxel-containing therapy (HR = 0.82) with a median follow-up of 42 months. The absolute 2-year survival advantage was 7% (57% versus 50%), and there was a 5-month improvement in median survival (29 versus 24 months). Progression-free survival was better with the paclitaxelregimen (HR = 0.76); there was a 10% difference in 1-year progression-free survival (50% versus 40%) and a 3-month prolongation in median progression-free survival (13 versus 10 months). The toxicities were comparable, except for a significantly higher incidence of neurologic toxicity and alopecia in the paclitaxel group, while myelosuppression was significantly greater with the non-paclitaxel-containing regimens. These data support the slight advantage of a second-line regimen containing both paclitaxel and a platinum agent compared with platinum-based therapy alone in patients who have not received paclitaxel in their primary chemotherapeutic regimen.

There were two randomized trials comparing carboplatin alone to carboplatin and gemcitabine or liposomal doxorubicin (294,295). There was a higher response rate with the combination therapy and a longer progression-free survival, but the studies were not powered to look at overall survival. In the Gynecologic Oncology Intergroup (GCIG) study comparing carboplatin and gemcitabine with carboplatinalone, the response rate was 47.2% for the combination and 30.9% for carboplatin, with the progression-free survival being 8.6 months and 5.8 months, respectively (294). A large GCIG study (CALYPSO) compared carboplatin and liposomal doxorubicin (CD) with carboplatin and paclitaxel (CP) in 976 patients (296). The progression-free survival for the CD arm was statistically superior to CP arm with a median progression-free survival of 11.3 months versus 9.4 months, respectively. Overall survival data are not yet available. The CD arm was better tolerated with less severe toxicities, and this combination is now widely used (296).

Platinum-Resistant and Refractory Disease

Patients with platinum-refractory and resistant ovarian cancer are treated with chemotherapy and may have a number of lines of therapy depending on response and performance status. In platinum-refractory patients (i.e., those progressing on treatment), response rates to second-line chemotherapy are less than 10% and the median survival is short, around 3 to 5 months (260264). The management of women who are platinum-resistant (i.e., progressing within 6 months of completion of chemotherapy) is difficult and “non-cross-resistant agents” are selected, but there does not appear to be one best treatment. Single-agent therapy is typically used because combination regimens are associated with more toxicity without any apparent additional benefit. High response rates of 48% to 64% were reported with dose-dense weekly carboplatin (AUC4) plus paclitaxel (90 mg/m2), and this deserves more study (297). There are a variety of potentially active drugs: paclitaxeldocetaxeltopotecanliposomal doxorubicingemcitabineoral etoposidetamoxifen, and bevacizumab are the most frequently used. Other agents include vinorelbine and newer drugs such as trabectedin.

The results of a study comparing topotecan with liposomal doxorubicin demonstrate the low response rates and poor prognosis among women with platinum-resistant ovarian cancer (265). There were two randomized trials comparing liposomal doxorubicin with either topotecan or paclitaxel. In a study of 237 women who relapsed after receiving one platinum-containing regimen, 117 of whom (49.4%) had platinum-refractory disease, liposomal doxorubicin 50 mg/m2 over 1 hour every 4 weeks was compared with topotecan 1.5 mg/m2/day for 5 days every 3 weeks (265). The two treatments had a similar overall response rate (20% versus 17%), time to progression (22 versus 20 weeks), and median overall survival (66 versus 56 weeks). The myelotoxicity was significantly lower in the liposomal doxorubicin-treated patients than with those receiving topotecan. In a second study comparing liposomal doxorubicin with single-agent paclitaxel in 214 platinum-treated patients who had not received prior taxanes, the overall response rates for liposomal doxorubicin and paclitaxel were 18% versus 22%, respectively, and median survival durations were 46 and 56 weeks, respectively, and these were not significantly different (266). In practice, most patients are treated with a starting dose of 40 mg/m2 of liposomal doxorubicin every 4 weeks, because of the toxicity associated with the higher dose and the need to dose reduce when 50 mg/m2 is used. In a subset analysis of platinum-resistant patients, the median time to progression ranged from 9.1 to 13.6 weeks for topotecan and liposomal doxorubicin, respectively. The median survival (p = 0.455) was 35.6 weeks for pegylated liposomal doxorubicin and 41.3 weeks for topotecan. Objective response rates were recorded in 6.5% of patients who received topotecan and in 12.3% of those who received pegylated liposomal doxorubicin (p = 0.118). It is not known whether the treatment improved symptoms control or quality of life because this was not specifically addressed.

In another randomized trial in 195 patients with platinum-resistant ovarian cancer, patients were randomized to receive either liposomal doxorubicin (PLD) or gemcitabine (298). In the gemcitabine and PLD groups, median progression-free survival was 3.6 versus 3.1 months; median overall survival was 12.7 versus 13.5 months; overall response rate was 6.1% versus 8.3%; and in the subset of patients with measurable disease, overall response rate was 9.2% versus 11.7%, respectively. None of the efficacy end points showed a statistically significant difference between treatment groups. The PLD group experienced significantly more hand-foot syndrome and mucositis; the gemcitabine group experienced significantly more constipation, nausea or vomiting, fatigue, and neutropenia.

Some researchers attempted to treat patients with non-platinum drugs to prolong the platinum-free interval, hoping that would allow the tumor to become platinum-sensitive during the interval use of non-cross-resistant agents. The rationale for this approach is the belief that the platinum-free interval is equivalent to the treatment-free interval, and before the availability of other active drugs, these two terms were synonymous. There are no data to support the hypothesis that the interposition of another drug can produce an increased platinum sensitivity as a result of a longer interval since the last platinum treatment.


Single-agent paclitaxel shows objective responses in 20% to 30% in phase II trials of women with platinum-resistant ovarian cancer (269274). The main toxicities are fatigue and peripheral neuropathy. Weekly paclitaxel is active, and the toxicity, especially myelosuppression, is less than with the every 3-week regimens. In a study of 53 women with platinum-resistant ovarian cancer, weekly paclitaxel (80 mg/m2 over 1 hour) had an objective response of 25% in patients with measurable disease, and 27% of patients without measurable disease had a 75% decline in serum CA125 levels (269).

Docetaxel has some activity in these patients (299301). The GOG studied 60 women with platinum-resistant ovarian or primary peritoneal cancer (301). Although there was a 22% objective response rate, the median response duration was only 2.5 months, and therapy was complicated by severe neutropenia in three-quarters of the patients.


Topotecan is an active second-line treatment for patients with platinum-sensitive and platinum-resistant disease (277291). In a study of 139 women receiving topotecan 1.5 mg/m2 daily for 5 days, response rates were 19% and 13% in patients with platinum-sensitive and platinum-resistant disease, respectively (287). The predominant toxicity of topotecan is hematologic, especially neutropenia. With the 5-day dosing schedule, approximately 70% to 80% of patients have severe neutropenia, and 25% have febrile neutropenia with or without infection. In some studies, regimens of 5 days produce better response rates than regimens of shorter duration, but in others, reducing the dose to 1.0 mg/m2 per day for 3 days is associated with similar response rates but lower toxicity (280,290). In a study of 31 patients, one-half of whom were platinum refractory, topotecan 2 mg/m2 per day for 3 days every 21 days had a 32% response rate (285). Continuous infusion topotecan (0.4 mg/m2 per day for 14 to 21 days) had a 27% to 35% objective response rate in platinum-refractory patients (284). Weekly topotecan administered at a dose of 4 mg/m2 per week for 3 weeks with a week off every month produced a response rate similar to the 5-day regimen with considerably less toxicity, and this is the preferred dose schedule in the recurrent setting (290).

Oral topotecan, not available in the United States, results in similar response rates with less hematologic toxicity (286). The intravenous and oral formulations of topotecan were compared in a randomized trial of 266 women as a third-line regimen after an initial platinum-based regimen (291). Compared with intravenous topotecan (1.5 mg/m2 daily for 5 days every 3 weeks), oral topotecan (2.3 mg/m2 per day for 5 days every 3 weeks) produced a similar response rate (13% versus 20%), less severe myelosuppression, and only a slightly shorter median survival (51 versus 58 weeks).

Liposomal Doxorubicin

Liposomal doxorubicin (Doxil in the United States and Caelyx in Europe), as noted above, has activity in platinum- and taxane-refractory disease (265268,295). One of the most important side effects of liposomal doxorubicin is the hand-foot syndrome, also known as palmar-plantar erythrodysesthesia or acral erythema, which occurs in 20% of patients who receive 50 mg/m2 every 4 weeks (266). Most oncologists administer 40 mg/m2 and escalate only if there are no side effects. Liposomal doxorubicin has a low rate of alopecia. In a study of 89 patients with platinum-refractory disease, including 82 paclitaxel-resistant patients, liposomal doxorubicin (50 mg/m2 every 3 weeks) produced a response in 17% (1 complete and 14 partial responses) (268). In another study, an objective response of 26% was reported, although there were no responses in women who progressed during first-line therapy (265).


Gemcitabine is associated with response rates of 20% to 50%, with 15% to 30% in patients who are platinum-resistant (302306). The principal toxicities are myelosuppression and gastrointestinal. The drug is used in doublet combinations with cisplatin or carboplatin with acceptable responses and toxicities, and in the triplet combination with carboplatin and paclitaxel (304).

Oral Etoposide

The most common toxicities with oral etoposide are myelosuppression and gastrointestinal: grade 4 neutropenia is observed in about one-fourth of patients, and 10% to 15% have severe nausea and vomiting (307,308). A study of oral etoposide given for a prolonged treatment (50 mg/m2 daily for 21 days every 4 weeks) had a 27% response rate in 41 women with platinum-resistant disease, 3 of whom had durable complete responses (308). In 25 patients with platinum and taxane-resistant disease, 8 objective responses (32%) were reported.

Hormonal Therapy

Tamoxifen is associated with CA125 response rates of 15% to 20% in small studies of patients with recurrent ovarian cancer (309315). Aromatase inhibitors (e.g., letrozoleanastrozole, and exemestane), which have activity in metastatic breast cancer, are being studied in relapsed ovarian cancer (316). One of the principal advantages of this class of agents is its very low toxicity (317).

Targeted Therapies

Knowledge of molecular pathways within normal and malignant cells is leading to the development of cancer treatment agents with specific molecular targets. There is great potential in targeting angiogenesis, in particular vascular endothelial growth factor (VEGF), which plays a major role in the biology of epithelial ovarian cancer (318). There are three main approaches to target angiogenesis: the first is to target VEGF itself, the second to target the VEGF receptor, and the third is to inhibit tyrosine kinase activation and downstream signaling with small molecules that work at the intracellular level.

Bevacizumab is the first targeted agent to show significant single agent activity in ovarian cancer. It is a humanized monoclonal antibody that targets angiogenesis by binding to VEGF-A, thereby blocking the interaction of VEGF with its receptor. There are a number of phase II studies reported using bevacizumab in patients with platinum-sensitive and platinum-resistant ovarian cancer with response rates ranging from 16% to 22% in both platinum-sensitive and -refractory patients (319). Up to 40% of patients had stabilization of disease for at least 6 months. A study of low-dose metronomic chemotherapy with 50 mg of cyclophosphamide daily and bevacizumab 10 mg/kg intravenously every 2 weeks showed significant activity in a study of 70 patients with recurrent ovarian cancer (320). The primary end point was progression-free survival at 6 months. The probability of being alive and progression free at 6 months was 56%. A partial response was achieved in 17 patients (24%). Median time to progression and survival were 7.2 and 16.9 months, respectively. This comes with toxicity. The side effects of bevacizumab are well recognized and include hypertension, fatigue, proteinuria, gastrointestinal perforation or fistula, and uncommonly, vascular thrombosis and central nervous system ischemia, pulmonary hypertension, and bleeding and wound healing complications. The most common side effects are hypertension that is grade 3 in 7% of patients and is usually treatable. The most concerning side effect is bowel perforation and the study by Cannistra et al. was stopped after recruiting 44 patients because of an 11% incidence of perforation of the bowel (321).

It was suggested that the bowel perforation complication could be avoided by carefully screening patients. Simpkins et al. limited bevacizumab treatment to patients without clinical symptoms of bowel obstruction or evidence of rectosigmoid involvement on pelvic examination or bowel involvement on CT scan (322). Their study included 25 patients with platinum-resistant ovarian cancer who were heavily pretreated, and they observed a response rate of 28% and no bowel perforations or any other grade 3 or 4 toxicities were reported. This highlights the importance of patient selection and suggests that increased experience with these agents will result in less toxicity.

VEGF Trap functions as a soluble decoy receptor soaking up ligand before it can interact with its receptor and is being evaluated in phase II trials in patients with recurrent ovarian cancer. There are other oral agents that target angiogenesis through tyrosine kinase inhibition that are in clinical trial (323).

Radiation Therapy

Whole-abdominal radiation therapy given as a treatment for recurrent or persistent disease is associated with a high morbidity and is not used. The principal problem associated with this approach is the development of acute and chronic intestinal morbidity. As many as 30% of patients treated with this approach develop intestinal obstruction, which necessitated exploratory surgery with potential morbidity (324).

Intestinal Obstruction

Patients with epithelial ovarian cancer often develop intestinal obstruction, either at the time of initial diagnosis or in association with recurrent disease (325340). Obstruction may be related to a mechanical blockage or to carcinomatous ileus.

The intestinal blockage can be corrected in most patients whose obstruction appears at initial diagnosis. The decision to perform an exploratory procedure to ease intestinal obstruction in patients with recurrent disease is more difficult. For patients whose life expectancy is very short (e.g., less than 2 months), surgical relief of the obstruction is not indicated (325330). In those patients with a longer projected lifespan, features predicting a reasonable likelihood of correcting the obstruction include young age, good nutritional status, and the absence of rapidly accumulating ascites (326).

For most patients with recurrent ovarian cancer and intestinal obstruction, initial management should include proper radiographic documentation of the obstruction, hydration, correction of any electrolyte disturbances, parenteral alimentation, and intestinal intubation. For some patients, the obstruction may be alleviated by this conservative approach. A preoperative upper gastrointestinal radiographic series and a barium enema will define possible sites of obstruction.

If exploratory surgery is deemed appropriate, the type of operation to be performed will depend on the site and the number of obstructions. Multiple sites of obstruction are not uncommon in patients with recurrent epithelial ovarian cancer. More than one-half of the patients have small bowel obstruction, one-third have colonic obstruction, and one-sixth have both (327331). If the obstruction is principally contained in one area of the bowel (e.g., the terminal ileum), this area can be either resected or bypassed, depending on what is easier to accomplish safely. Intestinal bypass is less morbid than resection, and in patients with progressive cancer, the survival time after these two operations is the same (332337).

If multiple obstructions are present, resection of several segments of intestine is usually not indicated, and intestinal bypass and/or colostomy should be performed. A gastrostomy may be useful in this circumstance, and this can usually be placed percutaneously (336,339).

Surgery for bowel obstruction in patients with ovarian cancer carries an operative mortality of about 10% and a major complications rate of about 30% (325337). The need for multiple reanastomoses and prior radiation therapy increase the morbidity, which consists primarily of sepsis and enterocutaneous fistulae. The median survival ranges from 3 to 12 months, although about 20% of such patients survive longer than 12 months (337340).


The prognosis for patients with epithelial ovarian cancer is related to several clinical variables. Survival analyses based on prognostic variables are presented (1,3,30,123127). Including patients at all stages, patients younger than 50 years of age have a 5-year survival rate of about 40%, compared with about 15% for patients older than 50 years.

The 5-year survival rate for carefully and properly staged patients with stage I disease is as high as 94%, for stage II is 73%, for stage III or IV 28% (1). The 5-year survival rate for stage IIIA is 41%, for stage IIIB about 25%, for stage IIIC 23%, and for stage IV disease 11% (Fig. 37.16). An analysis of the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database reveals a trend toward improved survival for ovarian cancer in the United States. In this cohort, the survival for stage I was 93%, for stage II 70%, for stage III 37%, and for stage IV 25% (341).

Figure 37.16 Survival of patients with epithelial ovarian cancer by substage. (From Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:491, adapted with permission from Heintz APM, Odicino F, Maisonneuve P, et al.Carcinoma of the ovary. In Twenty-sixth annual report of the results of treatment of gynaecological cancer. Int J Gynecol Oncol 2006;95(suppl 1):S161–S192.

Survival of patients with borderline tumors is excellent, with stage I lesions having a 98% 15-year survival (30). When all stages of borderline tumors are included, the 5-year survival rate is about 86% to 90%.

Patients with stage III disease with microscopic residual disease at the start of treatment have a 5-year survival rate of about 40% to 75%, compared with about 30% to 40% for those with optimal disease and only 5% for those with suboptimal disease (126,127,149). Patients whose Karnofsky index (KI) is low (<70) have a significantly shorter survival than those with a KI greater than 70 (30).

Nonepithelial Ovarian Cancers

Compared with epithelial ovarian cancers, other malignant tumors of the ovary are uncommon. Nonepithelial malignancies of the ovary account for about 10% of all ovarian cancers (2,3,342). Nonepithelial ovarian cancers include malignancies of germ cell origin, sex cord–stromal cell origin, metastatic carcinomas to the ovary, and a variety of extremely rare ovarian cancers (e.g., sarcomas). Although there are similarities in the presentation, evaluation, and management of these patients, the tumors have unique qualities that require a special approach (2,342345).

Germ Cell Malignancies

Germ cell tumors are derived from the primordial germ cells of the ovary. Their incidence is about one-tenth the incidence of malignant germ cell tumors of the testis, so most of the advances in the management of these tumors are extrapolations from experience with the corresponding testicular tumors. Although malignant germ cell tumors can arise in extragonadal sites such as the mediastinum and the retroperitoneum, most germ cell tumors arise in the gonad from undifferentiated germ cells. The variation in the site of these cancers is explained by the embryonic migration of the germ cells from the caudal part of the yolk sac to the dorsal mesentery before their incorporation into the sex cords of the developing gonads (2,3,342).


A histologic classification of ovarian germ cell tumors is presented in Table 37.5 (3,342). Both α-fetoprotein (AFP) and human chorionic gonadotropin (hCG) are secreted by some germ cell malignancies; therefore, the presence of circulating hormones can be clinically useful in the diagnosis of a pelvic mass and in monitoring the course of a patient after surgery. Placental alkaline phosphatase (PLAP) and lactate dehydrogenase (LDH) are produced by up to 95% of dysgerminomas, and serial measurements of LDH may be useful for monitoring the disease. When the histologic and immunohistologic identification of these substances in tumors is correlated, a classification of germ cell tumors emerges (Fig. 37.17) (346).

Table 37.5 Histologic Typing of Ovarian Germ Cell Tumors


1.Primitive germ cell tumors

3.Monodermal teratoma and somatic-type

 A. Dysgerminoma

 tumors associated with dermoid cysts

 B. Yolk sac tumor

 A. Thyroid tumor

 C. Embryonal carcinoma

 1. Struma ovarii

 D. Polyembryoma

  a. Benign

 E. Non-gestational choriocarcinoma

  b. Malignant

 F. Mixed germ cell tumor

 B. Carcinoid

 2.Biphasic or triphasic teratoma

 C. Neuroectodermal tumor

 A. Immature teratoma

 D. Carcinoma

 B. Mature teratoma

 E. Melanocytic

 1. Solid

 F. Sarcoma

 2. Cystic

 G. Sebaceous tumor

  a. Dermoid cyst

 H. Pituitary-type tumor

  b. Fetiform teratoma (homunculus)

 I. Others

Adapted from Tavassoll FA, Devllee P, eds. World Health Organization classification of tumours. Pathology and genetics of tumors of the breast and female organs. Lyon: IARC Press, 2003.

Figure 37.17 Relationship between types of pure malignant tumors. Germ cell tumors and their secreted marker substances. (From Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010:511, with permission.

In this scheme, embryonal carcinoma (a cancer composed of undifferentiated cells) synthesizes both hCG and AFP, and this lesion is the progenitor of several other germ cell tumors (346348). More differentiated germ cell tumors, such as the endodermal sinus tumor, which secretes AFP, and the choriocarcinoma, which secretes hCG, are derived from the extraembryonic tissues; the immature teratomas derived from the embryonic cells have lost the ability to secrete these substances. Pure germinomas do not secrete these markers.


Although 20% to 25% of all benign and malignant ovarian neoplasms are of germ cell origin, only about 3% of these tumors are malignant (2,3). Germ cell malignancies account for fewer than 5% of all ovarian cancers in Western countries. Germ cell malignancies represent up to 15% of ovarian cancers in Asian and African American societies, where epithelial ovarian cancers are much less common.

In the first two decades of life, almost 70% of ovarian tumors are of germ cell origin, and one-third of these are malignant (2,3,342). Germ cell cancers are seen in the third decade, but thereafter they become quite rare.

Clinical Features


In contrast to the slower-growing epithelial ovarian tumors, germ cell malignancies grow rapidly and are characterized by subacute pelvic pain related to capsular distention, hemorrhage, or necrosis. The rapidly enlarging pelvic mass may produce pressure symptoms on the bladder or rectum, and menstrual irregularities may occur in menarcheal patients. Some young patients misinterpret the early symptoms of a neoplasm as those of pregnancy, which can lead to a delay in the diagnosis. Acute symptoms associated with torsion or rupture of the adnexa can develop. These symptoms may be confused with acute appendicitis. In more advanced cases, ascites may develop, and the patient can have abdominal distention (336).


For a patient with a palpable adnexal mass, the evaluation can proceed as outlined. Some patients with germ cell tumors will be premenarcheal and may require examination under anesthesia. If the lesions are principally solid or a combination of solid and cystic, as might be noted on an ultrasonographic evaluation, a neoplasm is probable and a malignancy is possible (see Fig. 14.8 and Chapter 14). During the remainder of the physical examination, effort should be directed to searching for signs of ascites, pleural effusion, and organomegaly.


Adnexal masses measuring 2 cm or larger in premenarcheal girls or 8 cm or larger in other premenopausal patients will usually require surgical exploration. For young patients, blood tests should include serum hCG and AFP and LDH. A CT scan of the chest is important because germ cell tumors can metastasize to the lungs or mediastinum. A karyotype should be obtained preoperatively for all premenarcheal girls, particularly those with dysgerminomas, because of the propensity of these tumors to arise in dysgenetic gonads (343,349). A preoperative CT scan or MRI may document the presence and extent of retroperitoneal lymphadenopathy or liver metastases; however, because these patients require surgical exploration, preoperative imaging is not usually required. If postmenarcheal patients have predominantly cystic lesions up to 8 cm in diameter, they may be observed or given oral contraceptives for two menstrual cycles (350).


Dysgerminoma is the most common malignant germ cell tumor, accounting for about 30% to 40% of all ovarian cancers of germ cell origin (2,3,346). The tumors represent only 1% to 3% of all ovarian cancers, but they represent as many as 5% to 10% of ovarian cancers in patients younger than 20 years. Seventy-five percent of dysgerminomas occur between the ages of 10 and 30 years, 5% occur before the age of 10 years, and they rarely occur after 50 years of age (2,3,336). Because these malignancies occur in young women, 20% to 30% of ovarian malignancies associated with pregnancy are dysgerminomas.

Germinomas are found in both sexes and may arise in gonadal or extragonadal sites. The latter include the midline structures from the pineal gland to the mediastinum and the retroperitoneum. Histologically, they represent abnormal proliferations of the basic germ cell. In the ovary, the germ cells are encapsulated at birth (the primordial follicle), and the unencapsulated or free cells die. If either of the latter processes fails, it is possible that the germ cell could free itself of its normal control and multiply indiscriminately.

The size of dysgerminomas varies widely, but they are usually 5 to 15 cm in diameter (2,3). The capsule is slightly bosselated, and the consistency of the cut surface is fleshy and pale tan to gray-brown in color (Fig. 37.18).

Figure 37.18 Dysgerminoma of the ovary. Note that the lesion is principally solid with some cystic areas and necrosis.

The histologic characteristics of the dysgerminoma are very distinctive. The large round, ovoid, or polygonal cells have abundant, clear, very-pale–staining cytoplasm, large and irregular nuclei, and prominent nucleoli(Fig. 37.19). Mitotic figures are seen in varying numbers, although they are usually numerous. Another characteristic feature is the arrangement of the elements in lobules and nests separated by fibrous septa, which are often extensively infiltrated with lymphocytes, plasma cells, and granulomas with epithelioid cells and multinucleated giant cells. When necrosis is extensive, the lesion may be confused with tuberculosis. Dysgerminomas may contain syncytiotrophoblastic giant cells and may be associated with precocious puberty or virilization. The presence of these cells does not seem to alter the behavior of the tumor (2,3). The presence of calcifications should prompt a search for a possible underlying gonadoblastoma.

Figure 37.19 Dysgerminoma of ovary. Primitive germ cells are divided into clusters and lobules by fibrous septa rich in lymphocytes.

Because the dysgerminoma is a germ cell tumor and parthenogenesis (stimulation of the basic germ cell to atypical division) is the accepted genesis for the more immature teratomas, it is logical that these two tumors may coexist. Choriocarcinoma, endodermal sinus tumor, and other extraembryonal lesions may be associated with the dysgerminoma.

Approximately 5% of dysgerminomas are discovered in phenotypic women with abnormal gonads (2,349,351). This malignancy can be associated with patients who have pure gonadal dysgenesis (46,XY, bilateral streak gonads), mixed gonadal dysgenesis (45,X/46,XY, unilateral streak gonad, contralateral testis), and the androgen insensitivity syndrome (46,XY, testicular feminization). For premenarcheal patients with a pelvic mass, the karyotype should be determined (see Chapter 29).

For most patients with gonadal dysgenesis, dysgerminomas arise in gonadoblastomas, which are benign ovarian tumors that are composed of germ cells and sex cord stroma. If gonadoblastomas are left in situ in patients with gonadal dysgenesis, more than 50% will develop into ovarian malignancies (351).

About 65% of dysgerminomas are stage I (i.e., confined to one or both ovaries) at diagnosis (2,3,352–356). About 85% to 90% of stage I tumors are confined to one ovary; 10% to 15% are bilateral. Dysgerminoma is the only germ cell malignancy that has this significant rate of bilaterality. Other germ cell tumors are rarely bilateral.

For patients whose contralateral ovary is preserved, disease can develop in 5% to 10% of the retained gonads over the next 2 years (2). This figure includes those not given additional therapy and patients with gonadal dysgenesis.

In the 25% of patients who are diagnosed initially with metastatic disease, the tumor commonly spreads via the lymphatic system. It can spread hematogenously or by direct extension through the capsule of the ovary with exfoliation and dissemination of cells throughout the peritoneal surfaces. Metastases to the contralateral ovary may be present when there is no other evidence of spread. An uncommon site of metastatic disease is bone; when metastasis to this site occurs, the lesions are principally in the lower vertebrae. Metastases to the lungs, liver, and brain are often in patients with longstanding or recurrent disease. Metastasis to the mediastinum and supraclavicular lymph nodes is usually a late manifestation of disease (352,353).


The treatment of patients with early dysgerminoma is primarily surgical, including resection of the primary lesion and proper surgical staging. Chemotherapy is administered to patients with metastatic disease. Because the disease principally affects girls and young women, special consideration must be given to the preservation of fertility and use of chemotherapy whenever possible.An algorithm for the management of ovarian dysgerminoma is presented in Figure 37.20.

Figure 37.20 Management of dysgerminoma of the ovary. BEP = bleomycin, etoposide, and cisplatin; CT = computed tomogram. (From Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:515, with permission.


The minimal surgical operation for ovarian dysgerminoma is a unilateral oophorectomy (354). If there is a desire to preserve fertility, as there almost always is, the contralateral ovary, fallopian tube, and uterus should be left in situ, even in the presence of metastatic disease, because of the sensitivity of the tumor to chemotherapy. If fertility need not be preserved, it may be appropriate to perform a total abdominal hysterectomy and bilateral salpingo-oophorectomy for patients with advanced disease (356). For patients whose karyotype analysis reveals a Y chromosome, both ovaries should be removed, although the uterus may be left in situ for possible future embryo transfer (351). Whereas cytoreductive surgery is of unproved value, bulky disease that can be readily resected (e.g., an omental cake) should be removed during the initial operation.

In patients in whom the neoplasm appears on inspection to be confined to the ovary, a careful staging operation should be undertaken to determine the presence of any occult metastatic disease. All peritoneal surfaces should be inspected and palpated, and any suspicious lesions should be sampled for biopsy. Unilateral pelvic lymphadenectomy and careful palpation and biopsy of enlarged para-aortic nodes are particularly important parts of the staging. These tumors often metastasize to the para-aortic nodes around the renal vessels. Dysgerminoma is the only germ cell tumor that tends to be bilateral, excisional biopsy of any suspicious masses is desirable (354356). If a small contralateral tumor is found, it may be possible to resect it and preserve some normal ovary.

Many patients with a dysgerminoma will have a tumor that is apparently confined to one ovary and will be referred after unilateral salpingo-oophorectomy without surgical staging. The options for such patients are (i) repeat laparotomy for surgical staging, (ii) regular pelvic and abdominal CT scans, or (iii) adjuvant chemotherapy. Because these are rapidly growing tumors, the preference is to perform regular surveillance. Tumor markers (LDH, AFP, and β-hCG) should be monitored in case occult mixed germ cell elements are present.

Radiation Therapy

Dysgerminomas are very sensitive to radiation therapy, and doses of 2,500 to 3,500 cGy may be curative, even for gross metastatic disease. Loss of fertility is a problem with radiation therapy, and radiation is rarely used as first-line treatment ().


There is very good evidence to demonstrate the effectiveness of platinum-based chemotherapy, which is regarded as the treatment of choice (356367). The obvious advantage is the preservation of fertility (368).

The most frequently used chemotherapeutic regimen for germ cell tumors is BEP (bleomycin, etoposide, and cisplatin), EP or EC (etoposide and carboplatin) (356373) (Table 37.6).

Table 37.6 Combination Chemotherapy for Germ Cell Tumors of the Ovary


Regimen and Drugs

Dose and Schedulea




15 units/m2/week × 5; then on day 1 of course 4


100 mg/m2/day × 5 days every 3 weeks


20 mg/m2/day × 5 days, or 100 mg/m2/day × 1 day


every 3 weeks




0.15 mg/kg days 1 and 2 every 3 weeks


15 units/m2/week × 5; then on day 1 of course 4


100 mg/m2 on day 1 every 3 weeks




1–1.5 mg/m2 on day 1 every 4 weeks

 Actinomycin D

0.5 mg/day × 5 days every 4 weeks


150 mg/m2/day × 5 days every 4 weeks

aAll doses given intravenously.

The GOG studied three cycles of the EC regimen, consisting of etoposide (120 mg/m2 intravenously on days 1, 2, and 3 every 4 weeks) and carboplatin (400 mg/m2 intravenously on day 1 every 4 weeks) for patients with completely resected ovarian dysgerminoma, stage IB, IC, II, or III (364). The results showed a sustained disease-free remission rate of 100%.

For patients with advanced, incompletely resected germ cell tumors, the GOG studied cisplatin-based chemotherapy in two consecutive protocols (357,358). In the first study, patients received four cycles of vinblastine (12 mg/m2every 3 weeks), bleomycin (20 units/m2 intravenously every week for 12 weeks), and cisplatin (20 mg/m2 per day intravenously for 5 days every 3 weeks). Patients with persistent or progressive disease at second-look laparotomy were treated with six cycles of VAC (vincristineactinomycin D, and cyclophosphamide). In the second trial, patients received three cycles of BEP initially, followed by consolidation with VAC, which was later discontinued in patients with dysgerminomas (358). The VAC consolidation after BEP is no longer used. A total of 20 evaluable patients with stages III and IV dysgerminoma were treated in these two protocols, and 19 were alive and free of disease after 6 to 68 months (median = 26 months). Fourteen of these patients had a second-look laparotomy, and all findings were negative. Another study at M. D. Anderson Cancer Center used BEP in 14 patients with residual disease, and all patients were free of disease during long-term follow-up (361). These results demonstrate that patients with advanced-stage, incompletely resected dysgerminoma have an excellent prognosis when treated with cisplatin-based combination chemotherapy. The standard regimen is three to four cycles of BEP, depending on assigned risk based on the data from testicular cancers (372,373).

Recurrent Disease

About 75% of recurrences occur within the first year after initial treatment, the most common sites being the peritoneal cavity and the retroperitoneal lymph nodes (2,335,336). These patients should be treated with chemotherapy, although radiation may be appropriate in selected patients. Patients with recurrent disease who had no therapy other than surgery should be treated with chemotherapy. If prior chemotherapy with BEP was given, there are a number of second-line options including TIP (paclitaxeliphosphamidecisplatin) or VIP (vinblastineiphosphamidecisplatin) (Table 35.7), and consideration should be given to the use of high-dose chemotherapy in selected patients. Patients with recurrent disease should be managed in specialized centers. Radiation therapy is effective for this disease, with the major disadvantage being loss of fertility if pelvic and abdominal irradiation is required.

Table 37.7 POMB-ACE Chemotherapy for Germ Cell Tumors of the Ovary




 Day 1

Vincristine 1 mg/m2 IV; methotrexate 300 mg/m2 as a 12-hr infusion

 Day 2

Bleomycin 15 mg as a 24-hr infusion: folinic acid rescue started at 24 hr after the start of methotrexate in a dose of 15 mg every 12 hr for 4 doses

 Day 3

Bleomycin infusion 15 mg by 24-hr infusion

 Day 4

Cisplatin 120 mg/m2 as a 12-hr infusion, given with hydration and 3 g magnesium sulfate supplementation



 Days 1–5

Etoposide (VP16–213) 100 mg/m2, days 1–5

 Days 3, 4, 5

Actinomycin D 0.5 mg IV, days 3, 4, and 5

 Day 5

Cyclophosphamide 500 mg/m2 IV, day 5



 Day 1

Vincristine 1 mg/m2 IV; methotrexate 300 mg/m2 as a 12-hr infusion

 Day 2

Bleomycin 15 mg by 24-hr infusion; folinic acid rescue started at 24 hrs after start of methotrexate in a dose of 15 mg every 12 hr for 4 doses

 Day 3

Bleomycin 15 mg by 24-hr infusion

IV, intravenous.

The sequence of treatment schedules is two courses of POMB followed by ACE. POMB is then alternated with ACE until patients are in biochemical remission as measured by human chorionic gonadotropin (hCG) and α-fetoprotein (AFP), placental alkaline phosphatase (PLAP), and lactate dehydrogenase (LDH). The usual number of courses of POMB is three to five. Following biochemical remission, patients alternate ACE with OMB until remission has been maintained for approximately 12 weeks. The interval between courses of treatment is kept to the minimum (usually 9 to 11 days). If delays are caused by myelosuppression after courses of ACE, the first 2 days of etoposide are omitted from subsequent courses of ACE.

From Newlands ES, Southall PJ, Paradinas FJ, et al. Management of ovarian germ cell tumours. In: Williams CJ, Kaikorian JG, Green MR, et al., eds. Textbook of uncommon cancer. New York: John Wiley and Sons, 1988:47, with permission.


Because dysgerminomas tend to occur in young patients, they may coexist with pregnancy. When a stage IA cancer is found, the tumor can be removed intact and the pregnancy continued. For patients with more advanced disease, continuation of the pregnancy depends on the gestational age of the fetus. Chemotherapy can be given in the second and third trimesters in the same dosages as given for the nonpregnant patient without apparent detriment to the fetus (368).


For patients whose initial disease is stage Ia (i.e., a unilateral encapsulated dysgerminoma), unilateral oophorectomy alone results in a 5-year disease-free survival rate of greater than 95% (355). The features associated with a higher tendency to recur, include lesions larger than 10 to 15 cm in diameter, age younger than 20 years, and a microscopic pattern that includes numerous mitoses, anaplasia, and a medullary pattern (2,346).

Surgery for advanced disease followed by pelvic and abdominal radiation resulted in a 5-year survival rate of 63% to 83%, for this same group of patients cure rates of 85% to 90% are reported with the use of VBP (vinblastinebleomycincisplatin), BEP, or EC combination chemotherapy and radiation is infrequently indicated (356376).

Immature Teratomas

Immature teratomas contain elements that resemble tissues derived from the embryo. Immature teratomatous elements may occur in combination with other germ cell tumors as mixed germ cell tumors. The pure immature teratoma accounts for fewer than 1% of all ovarian cancers, but it is the second most common germ cell malignancy and accounts for 10% to 20% of all ovarian malignancies seen in women younger than 20 years (2). About 50% of pure immature teratomas of the ovary occur in women between the ages of 10 and 20 years, and they rarely occur in postmenopausal women.

Pathology and Grading

Of fundamental importance in the understanding of the teratoma is recognition of the maturation of the various elements. If maturation continues along normal lines, the mature or adult teratoma results, and the prognosis is excellent. Conversely, abnormal maturation of these elements can result in an immature teratoma that has metastatic potential. Teratomas containing immature elements, although relatively rare, were recognized more often as pathologists became more alert to their presence (Fig. 37.21). Among the tumors with embryonal elements, those containing neural tissues demonstrate the ability to mature.

Figure 37.21 Ovarian teratoma. This tumor contains both mature and immature neural elements with a neural tube-like structure near its center.

Semiquantification of immature neuroepithelium correlates with survival in ovarian immature teratoma and is the basis for grading of these tumors (377379). Those with less than one low power field (X 4) of immature neuroepithelium on the slide with the greatest amount of such tissue (grade 1) have a survival of at least 95%, whereas greater amounts of immature neuroepithelium (grades 2 and 3) appear to have a lower overall survival (approximately 85%) (379). This may not apply to immature teratomas of the ovary in children because they have a good outcome with surgery alone, regardless of the degree of immaturity (380,381). The significant inter- and intraobserver difficulty with a three-tier system led some authorities to recommend the two-tier grading system in use, with immature teratomas categorized as either low grade or high grade (377). Immature ovarian teratomas may be associated with gliomatosis peritonei, a favorable prognostic finding if composed of completely mature tissues; reports using molecular methods indicate these glial implants are not tumor derived but represent teratoma-induced metaplasia of pluripotent müllerian stem cells in the peritoneum (382,383).

Somatic malignant change in benign cystic teratomas was recorded as occurring in 0.5% to 2% of cases, usually in patients older than 40 years of age (377). The most common malignancy developing in the initially benign teratoma is squamous cell carcinoma. Other neoplasms were reported (e.g., adenocarcinomas, melanomas, which may arise from the skin or retinal anlage, and sarcomas, including leiomyosarcomas and mixed mesodermal tumors) (2). Carcinomas may arise from any of the epithelial elements.


The preoperative evaluation and differential diagnosis of immature teratomas are the same as for other germ cell tumors. Some of these lesions will contain calcifications similar to those of mature teratomas, which can be detected by a radiograph of the abdomen or by ultrasonography. Rarely they are associated with the production of steroid hormones and can be accompanied by sexual pseudoprecocity (342). Tumor markers are negative unless a mixed germ cell tumor is present.



In a premenopausal patient whose lesion appears to be confined to a single ovary, unilateral oophorectomy and surgical staging should be performed. For a postmenopausal patient, a total abdominal hysterectomy and bilateral salpingo-oophorectomy may be performed. Contralateral involvement is rare, and routine resection or wedge biopsy of the contralateral ovary is unnecessary (3,378,379). Any lesions on the peritoneal surfaces should be sampled and submitted for histologic evaluation. The most frequent site of dissemination is the peritoneum and, much less commonly, the retroperitoneal lymph nodes. Blood-borne metastases to organ parenchyma, such as the lungs, liver, or brain, are uncommon. When present, they are usually seen in patients with late or recurrent disease and most often in tumors that are poorly differentiated (i.e., grade 3).

It is unclear whether debulking of metastatic implants enhances the response to combination chemotherapy (384390). Unlike epithelial lesions, immature teratomas are chemosensitive. Because cure depends on the prompt delivery of chemotherapy, any surgical resection that is potentially morbid and could delay chemotherapy should be resisted.


Patients with IA, grade 1 tumors have an excellent prognosis, and no adjuvant therapy is required. For patients whose tumors are stage IA, grade 2 or 3, adjuvant chemotherapy should be used(359361,374,375378). Chemotherapy is indicated for patients who have ascites, regardless of tumor grade. The standard approach is BEP. The most frequently used combination chemotherapeutic regimen was VAC, but this regimen is no longer used (359,360,391397).

The GOG is prospectively studying three courses of BEP therapy for patients with completely resected stages I, II, and III ovarian germ cell tumors (359,360,397). Overall, the toxicity is acceptable, and 91 of 93 patients whose nondysgerminomatous tumors were treated are clinically free of disease. The BEP regimen, which is standard of care for testicular cancer, is also the most appropriate chemotherapy regimen for nondysgerminomatous germ cells tumors of the ovary. As these tumors can progress rapidly, treatment should be initiated as soon as possible after surgery, preferably within 7 to 10 days (398).

The switch from VBP to BEP was prompted by the experience in patients with testicular cancer, in which the replacement of vinblastine with etoposide was associated with a better therapeutic index (i.e., equivalent efficacy and lower morbidity), especially less neurologic and gastrointestinal toxicity. The use of bleomycin seems to be important for this group of patients. In a randomized study of three cycles of etoposide plus cisplatinwith or without bleomycin (EP versus BEP) in 166 patients with germ cell tumors of the testes, the BEP regimen had a relapse-free survival rate of 84% compared with 69% for the EP regimen (p = 0.03) (372). Cisplatin may be slightly better than carboplatin in the setting of metastatic germ cell tumors. One hundred ninety-two patients with germ cell tumors of the testes were entered into a study of four cycles of etoposide plus cisplatin (EP) versus four cycles of etoposide plus carboplatin (EC). There were three relapses with the EP regimen versus seven with the EC regimen, although the overall survival of the two groups is identical thus far (373). In view of these results, BEP is the preferred treatment regimen for patients with gross residual disease and has replaced the VAC regimen for patients with completely resected disease.

It is unclear whether adjuvant chemotherapy is indicated or required for all patients with resected immature teratomas. Several reports support the successful management of these patients with surgery alone and close surveillance (390,399). In the largest series, an Intergroup study from the Pediatric Oncology Group and the Children’s Cancer Group, 73 children with immature teratoma (44 of ovarian origin) underwent surgery followed by surveillance. With a median follow-up of 35 months, the overall 3-year event-free survival rates for all patients and those with ovarian teratomas were 93% and 100%, respectively. Thirteen of the 44 girls with an immature ovarian teratoma had microscopic foci of yolk sac tumor in the teratoma; one developed recurrent disease and was successfully treated with cisplatin-based chemotherapy. Of note, 82% of the tumors were grade 1 or 2; however, 92% of those with foci of yolk sac tumor were grade 2 or 3.

Second-Look Laparotomy

The need for a second-look operation was questioned (375,376). It seems not to be justified in patients who received chemotherapy in an adjuvant setting, because chemotherapy in these patients is effective. Second-look laparotomy in patients with macroscopic residual disease at the start of chemotherapy may be of value in selected patients, as some patients may have residual mature teratoma and are at risk of growing teratoma syndrome, a rare complication of immature teratomas (400,401). Cancers can arise at a later date in residual mature teratoma. It is important to resect any residual mass and exclude persistent disease because further chemotherapy may be indicated. The principles of surgery are based on the much larger experience of surgery in males with residual masses following chemotherapy for germ cell tumors with a component of immature teratoma (402). Mathew et al. reported their experience of laparotomy in assessing the nature of postchemotherapy residue in ovarian germ cell tumors. Sixty-eight patients completed combination chemotherapy with cisplatin regimes, and 35 had radiological residual masses. Twenty-nine of these 35 patients underwent laparotomy and 3 patients had viable tumor, 7 immature teratomas, 3 mature teratoma, and 16 only necrosis or fibrosis. None of the patients with dysgerminoma, embryonal carcinoma, absence of teratoma element in the primary tumor, and radiological residual mass of less than 5 cm had viable tumor, whereas all patients with tumors containing the teratoma component initially had residual tumor, strengthening the case for surgery in patients with immature teratoma and any residual mass (403,404).


The most important prognostic feature of the immature teratoma is the grade of the lesion (2,370). The stage of disease and the extent of tumor at the initiation of treatment have an impact on the curability of the lesion. Overall, the 5-year survival rate for patients with all stages of pure immature teratomas is 70% to 80%, and it is 90% to 95% for patients with surgically staged, stage I lesions (374,377,386).

Endodermal Sinus Tumors

Endodermal sinus tumors (EST) are referred to as yolk sac carcinomas because they are derived from the primitive yolk sac (23). These lesions are the third most frequent malignant germ cell tumors of the ovary. ESTs occur in patients with a median age of 16 to 18 years (2,3,405). About one-third of the patients are premenarcheal at the time of diagnosis. Abdominal or pelvic pain is the most frequent initial symptom, occurring in about 75% of patients, whereas an asymptomatic pelvic mass is documented in 10% of patients (343).


The gross appearance of an EST is soft grayish-brown. Cystic areas caused by degeneration or necrosis are present in these rapidly growing lesions. The capsule is intact in most cases.

The EST is unilateral in 100% of cases; thus, biopsy of the opposite ovary is contraindicated. The association of such lesions with gonadal dysgenesis must be appreciated, and chromosomal analysis should be performed preoperatively in premenarcheal patients (3).

Microscopically, the characteristic feature is the endodermal sinus, or Schiller-Duval body (Fig. 37.22). The cystic space is lined with a layer of flattened or irregular endothelium into which projects a glomerulus-like tuft with a central vascular core. These structures vary throughout the tumor, and the reticular, myxoid elements simulate undifferentiated mesoblast. The lining of the papillary infolding and the cavity is irregular, with an occasional cell containing clear, glassy cytoplasm, simulating the hobnail appearance of the epithelium in clear cell tumors. The association of EST with dysgerminoma must be emphasized if diagnosis and therapy are to be optimal (2,3).

Figure 37.22 Endodermal sinus tumor of the ovary. Note the classic Schiller-Duval body with its central vessel and mantle of endoderm.

Most EST lesions secrete AFP and, rarely, they may elaborate detectable alpha-1 antitrypsin (AAT). AFP can be demonstrated in the tumor by means of the immunoperoxidase technique. There is a good correlation between the extent of disease and the level of AFP, although discordance is observed. The serum level of these markers, particularly AFP, is useful in monitoring the patient’s response to treatment (405409).



The treatment of the EST consists of surgical exploration, unilateral salpingo-oophorectomy, and a frozen section for diagnosis. The addition of a hysterectomy and contralateral salpingo-oophorectomy does not alter outcome (407). Any gross metastases should be removed, if possible, but thorough surgical staging is not indicated because all patients need chemotherapy. At surgery, the tumors tend to be solid and large, ranging in size from 7 to 28 cm (median, 15 cm) in the GOG series (397). Bilaterality does not occur, and the other ovary is involved with metastatic disease only when there are other metastases in the peritoneal cavity. Most patients have early-stage disease: 71%, stage I; 6%, stage II; and 23%, stage III (409).


All patients with ESTs are treated with either adjuvant or therapeutic chemotherapy. Before the routine use of combination chemotherapy for this disease, the 2-year survival rate was only about 25%. After the introduction of the VAC regimen, this rate improved to 60% to 70%, indicating the chemosensitivity of most of these tumors (392,393). With conservative surgery and adjuvant chemotherapy, fertility can be preserved as with other germ cell tumors.

Cisplatin-containing combination chemotherapy with three to four cycles of BEP should be used as primary chemotherapy for EST. The GOG protocols used three to four treatment cycles given every 3 weeks (397,410).

Rare Germ Cell Tumors of the Ovary

Embryonal Carcinoma

Embryonal carcinoma of the ovary is an extremely rare tumor that is distinguished from a choriocarcinoma of the ovary by the absence of syncytiotrophoblastic and cytotrophoblastic cells. The patients are very young; ages ranged between 4 and 28 years (median, 14 years) in two series (411). Older patients were reported (412). Embryonal carcinomas may secrete estrogen, with the patient exhibiting symptoms and signs of precocious pseudopuberty or irregular bleeding (2). The clinical picture is otherwise similar to that of the EST. The primary lesions tend to be large, and about two-thirds are confined to one ovary at the time of diagnosis. These lesions frequently secrete AFP and hCG, which are useful for following the response to subsequent therapy (408). The treatment of embryonal carcinomas is the same as for the EST (i.e., a unilateral oophorectomy followed by combination chemotherapy with BEP) (360,397).

Choriocarcinoma of the Ovary

Pure nongestational choriocarcinoma of the ovary is an extremely rare tumor. Histologically, it has the same appearance as gestational choriocarcinoma metastatic to the ovaries (413). Most patients with this cancer are younger than 20 years. The presence of hCG can be useful in monitoring the patient’s response to treatment. In the presence of high hCG levels, isosexual precocity occurs in about 50% of patients whose lesions appear before menarche(413,414).

There are only a few limited reports on the use of chemotherapy for nongestational choriocarcinomas, but complete responses were reported with the MAC (methotrexateactinomycin D, and cyclophosphamide) regimen used in a manner described for gestational trophoblastic disease (379) (see Chapter 39). Alternatively, the BEP regimen can be used. The prognosis of ovarian choriocarcinomas is poor, with most patients having metastases to organ parenchyma at the time of diagnosis.


Polyembryoma of the ovary is another extremely rare tumor, which is composed of embryoid bodies. This tumor replicates the structures of early embryonic differentiation (i.e., the three somatic layers: endoderm, mesoderm, and ectoderm) (2,346). The lesion tends to occur in very young, premenarcheal girls with signs of pseudopuberty and elevated AFP and hCG levels. Anecdotally, the VAC chemotherapeutic regimen is reported to be effective (346,415).

Mixed Germ Cell Tumors

Mixed germ cell malignancies of the ovary contain two or more elements of the lesions described above. In one series, the most common component of a mixed malignancy was dysgerminoma, which occurred in 80%, followed by EST in 70%, immature teratoma in 53%, choriocarcinoma in 20%, and embryonal carcinoma in 16% (415). The most frequent combination was a dysgerminoma and an EST. The mixed lesions may secrete either AFP, hCG, or both or neither of these markers, depending on the components.

These lesions should be managed with combination chemotherapy, preferably BEP. The serum marker, if positive initially, may become negative during chemotherapy, but this finding may reflect regression of only a particular component of the mixed lesion. Therefore, for these patients, a second-look laparotomy may be indicated to determine the precise response to therapy if macroscopic disease was present at initiation of chemotherapy.

The most important prognostic features are the size of the primary tumor and the relative size of its most malignant component (416). For stage IA lesions smaller than 10 cm, survival is 100%. Tumors composed of less than one-third EST, choriocarcinoma, or grade 3, immature teratoma have an excellent prognosis, but it is less favorable when these components constitute most of the mixed lesions.

Late Effects of Treatment of Malignant Germ Cell Tumors of the Ovary

Although there are substantial data regarding late effects of cisplatin-based therapy in men with testicular cancer, sparse information is available for women with ovarian germ cell tumors. Among the adverse events from chemotherapy reported in men are renal and gonadal dysfunction, neurotoxicity, cardiovascular toxicity, and secondary malignancies.

Gonadal Function

An important cause of infertility in patients with ovarian germ cell tumors is unnecessary bilateral salpingo-oophorectomy and hysterectomy. Although temporary ovarian dysfunction or failure is common with platinum-based chemotherapy, most women will resume normal ovarian function, and childbearing is usually preserved (349,355). In one representative series of 47 patients treated with combination chemotherapy for germ cell malignancies, 91.5% resumed normal menstrual function, and there were 14 healthy live births and no birth defects (370). Factors such as older age at initiation of chemotherapy, greater cumulative drug dose, and longer duration of therapy all have an adverse effect on future gonadal function.

Secondary Malignancies

An important cause of late morbidity and mortality in patients receiving chemotherapy for germ cell tumors is the development of secondary tumors. Etoposide in particular was implicated in the development of treatment-related leukemias (417,418).

The chance of developing treatment-related leukemia following etoposide is dose related. The incidence of leukemia is approximately 0.4% to 0.5% (representing a 30-fold increased likelihood) in patients receiving a cumulative etoposide dose of less than 2,000 mg/m2, compared with as much as 5% (representing a 336-fold increased likelihood) in those receiving more than 2,000 mg/m2 (417). In a typical three- or four-cycle course of BEP, patients receive a cumulative etoposide dose of 1,500 or 2,000 mg/m2, respectively.

Despite the risk of secondary leukemia, risk-benefit analyses concluded that etoposide-containing chemotherapy regimens are beneficial in advanced germ cell tumors; one case of treatment-induced leukemia would be expected for every 20 additionally cured patients who receive BEP as compared with platinum, vincristine, bleomycin (PVB). The risk–benefit balance for low-risk disease, or for high-dose etoposidein the salvage setting, is less clear (418).

Sex Cord–Stromal Tumors

Sex cord–stromal tumors of the ovary account for about 5% to 8% of all ovarian malignancies (2,3,342,343,419425). This group of ovarian neoplasms is derived from the sex cords and the ovarian stroma or mesenchyme. The tumors usually are composed of various combinations of elements, including the “female” cells (i.e., granulosa and theca cells) and “male” cells (i.e., Sertoli and Leydig cells), and morphologically indifferent cells. A classification of this group of tumors is presented in Table 37.8.

Table 37.8 Sex Cord–Stromal and Steroid Cell Tumors

1.Granulosa-stromal cell tumors

 A. Granulosa cell tumor

 B. Tumors in thecoma-fibroma group

  1. Thecoma

  2. Fibroma

  3. Unclassified

  2.Androblastomas; Sertoli-Leydig cell tumors

 A. Well-differentiated

  1. Sertoli cell tumor

  2. Sertoli-Leydig cell tumor

  3. Leydig cell tumor; hilus cell tumor

 B. Moderately differentiated

 C. Poorly differentiated (sarcomatoid)

 D. With heterologous elements


4.Sex cord tumor with annular tubules

5.Sex cord-stromal tumors, unclassified

6.Steroid cell tumors

 A. Stromal luteoma

 B. Leydig cell tumor

 C. Steroid cell tumor, not otherwise classified

Granulosa-Stromal Cell Tumors

Granulosa-stromal cell tumors include granulosa cell tumors, thecomas, and fibromas. The granulosa cell tumor is a low-grade malignancy; rarely, thecomas and fibromas have morphologic features of malignancy and may be referred to as fibrosarcomas.

Figure 37.23 Granulosa cell tumor of the ovary. Note the classic Call-Exner bodies with a minimal stromal component in this tumor of folliculoid pattern. (Arrow points to an example.)

Granulosa cell tumors, which secrete estrogen, are seen in women of all ages. They are found in prepubertal girls in 5% of cases; the remainder are found in women throughout their reproductive and postmenopausal years (422). Granulosa cell tumors are bilateral in only 2% of patients.


Granulosa cell tumors range from a few millimeters to 20 cm or more in diameter. The tumors are rarely bilateral and have a smooth, lobulated surface. The solid portions of the tumor are granular, frequently trabeculated, and yellow or gray-yellow in color. After clear cell carcinoma, the granulosa-theca cell tumor is probably the most inaccurately diagnosed tumor of the female gonad. Of 477 ovarian tumors from the Emil Novak Ovarian Tumor Registry diagnosed initially as granulosa-theca cell tumors, almost 15% were reclassified after histologic review. Lesions misdiagnosed as granulosa cell tumors included primary or metastatic carcinomas, teratoid tumors, and poorly differentiated mesothelial tumors (419).

The classic adult granulosa cell is round or ovoid with scant cytoplasm. The nucleus contains compact, finely granular chromatin and is either euchromatic or hypochromatic (3). “Coffee bean” grooved nuclei are characteristic; mitotic figures may be present, but numerous mitotic figures should prompt consideration for poorly differentiated or undifferentiated carcinoma. In the most common variety, the adult granulosa cells show a tendency to arrange themselves in small clusters or rosettes around a central cavity, so there is a resemblance to primordial follicles (i.e., Call-Exner bodies) (Fig. 37.23). The stroma is similar to the theca and may be luteinized. In children and adolescents, the granular cell tumors are often cystic, contain luteinized cells, and can be associated with precocious puberty. Juvenile granulosa cell tumors, so named because of their tendency to occur in younger patients, feature rounder, more hyperchromatic nuclei and may contain numerous mitotic figures. The presence of large, irregular follicle spaces is an additional distinguishing feature of the juvenile granulosa cell tumor. The adult granulosa cell tumor tends to occur in older women and the juvenile tumor in children and young women, but the diagnosis is not based on age of presentation, but on histology. Adult granulosa cell tumors, but not juvenile granulose cell tumors, harbor a somatic mutation in the FOXL2 gene (426).


Granulosa cell tumors, which secrete estrogen, are seen in women of all ages. They are found in prepubertal girls in 5% of cases (typically the juvenile form); the remainder are distributed throughout the reproductive and postmenopausal years (422– 425). They are bilateral in only 2% of patients.

Of the rare prepubertal lesions, 75% are associated with sexual pseudoprecocity because of the estrogen secretion (422). Most reproductive-age patients have menstrual irregularities or secondary amenorrhea, and, frequently, cystic hyperplasia of the endometrium. Abnormal uterine bleeding is often the initial symptom for postmenopausal women. The estrogen secretion in these patients can be sufficient to stimulate the development of endometrial cancer. Low-grade endometrial cancer occurs in association with granulosa cell tumors in at least 5% of cases, and 25% to 50% are associated with endometrial hyperplasia (2,413,419422,426).

The other symptoms and signs of granulosa cell tumors are nonspecific and the same as most ovarian malignancies. Ascites is present in about 10% of cases, and, rarely, a pleural effusion is present (419422). Granulosa tumors tend to be hemorrhagic; occasionally, they rupture and produce a hemoperitoneum.

Adult granulosa cell tumors are usually stage I at diagnosis, but may recur 5 to 30 years after initial diagnosis (421). Most juvenile granulosa cell tumors are clinically benign; only about 10% recur and when they do so, it is generally within 5 years of the initial diagnosis. The tumors may spread hematogenously, and metastases can develop in the lungs, liver, and brain years after initial diagnosis. When adult granulosa cell tumors do recur, they can progress rapidly. Malignant thecomas are extremely rare, and their signs and symptoms, management, and outcome are similar to those of the granulosa cell tumors (419). Inhibin is secreted by some granulosa cell tumors and is a useful marker for the disease (427431). An elevated serum inhibin level in a premenopausal woman presenting with amenorrhea and infertility is suggestive of a granulosa cell tumor (432).


The treatment of granulosa cell tumors depends on the age of the patient and the extent of disease. For most patients, surgery alone is sufficient primary therapy; radiation and chemotherapy are reserved for the treatment of recurrent or metastatic disease (422429,433436).


Because granulosa cell tumors are bilateral in only about 2% of patients, a unilateral salpingo-oophorectomy is appropriate therapy for stage IA tumors in children or in women of reproductive age (420). At the time of laparotomy, if a granulosa cell tumor is identified by frozen section, a staging operation is performed, including an assessment of the contralateral ovary. If the opposite ovary appears enlarged, it should be sampled for biopsy. For perimenopausal and postmenopausal women for whom ovarian preservation is not important, a hysterectomy and bilateral salpingo-oophorectomy should be performed. For premenopausal patients in whom the uterus is left in situ, an endometrial biopsy should be performed because of the possibility of a coexistent adenocarcinoma of the endometrium (422).

Radiation Therapy

There is no evidence to support the use of adjuvant radiation therapy for granulosa cell tumors, although pelvic irradiation may help to palliate isolated pelvic recurrences (422,434).


There is no evidence that adjuvant chemotherapy will prevent recurrence of disease (436439). Metastatic lesions and recurrences were treated with a variety of antineoplastic drugs. Although the data are inconclusive, BEP or carboplatin and paclitaxel are used in selected patients with stage III or IV tumors or recurrent disease (433). In a GOG study, 37% (14 of 30) patients treated with BEP had a negative second-look laparotomy, and these patients had a median time to progression of 24.4 months (440). Granulosa cell tumors are potentially hormonally responsive, with about 30% of granulosa tumors expressing estrogen receptors and almost 100% expressing progesterone receptors. Hormonal agents such as progestins or luteinizing hormone-releasing hormone agonists are used to treat these patients because they are often elderly (441445). There are case reports of durable response to aromatase inhibitors in patients with metastatic granulosa cell tumors who received multiple prior treatment (443). Small clinical series and case reports indicated that luteinizing hormone-releasing hormone agonists had a 50% response rate in 13 patients, while 4 of 5 patients in the literature responded to a progestational agent. Two case series reported durable responses in a total of six patients receiving aromatase inhibitors among those who progressed on or were intolerant of chemotherapy (442445).


Adult granulosa cell tumors have a prolonged natural history and a tendency toward late relapse, reflecting their low-grade biology. Ten-year survival rates of about 90% are reported, with 20-year survival rates dropping to 75% (420422,432,433). Most histologic types have the same prognosis, but patients with the more poorly differentiated diffuse or sarcomatoid type tend to do worse (419).

The DNA ploidy of the tumors is correlated with survival. Holland et al. reported DNA aneuploidy in 13 of 37 patients (35%) with primary adult granulosa cell tumors (437). The presence of residual disease is the most important predictor of progression-free survival, but DNA ploidy is an independent prognostic factor. Patients with residual-negative DNA diploid tumors had a 10-year progression-free survival of 96%.

Juvenile granulosa cell tumors of the ovary are rare and constitute less than 5% of ovarian tumors in childhood and adolescence (446). About 90% are diagnosed in stage I, and they have a favorable prognosis. The juvenile subtype behaves less aggressively than the adult type. Only about 10% of juvenile granulosa cell tumors are malignant and late relapse is unusual. Advanced-stage tumors are successfully treated with platinum-based combination chemotherapy (e.g., BEP) (433,440).

Sertoli-Leydig Tumors

Sertoli-Leydig tumors occur most frequently in the third and fourth decades of life; 75% of these tumors are seen in women younger than 40 years. These neoplasms are extremely rare and account for less than 0.2% of ovarian cancers (2,447,448). Sertoli-Leydig cell tumors are most frequently low-grade malignancies; a poorly differentiated variety may behave more aggressively (Fig. 37.24) (447449).

Figure 37.24 Sertoli-Leydig cell tumor of the ovary. Note the aggregates of eosinophilic Leydig cells in the stroma adjacent to Sertoli cell tubules.

The tumors typically produce androgens, and clinical virilization is noted in 70% to 85% of patients (449). Signs of virilization include oligomenorrhea followed by amenorrhea, breast atrophy, acne, hirsutism, clitoromegaly, deepening of the voice, and a receding hairline. Measurement of plasma androgens may reveal elevated testosterone and androstenedione, with normal or slightly elevated dehydroepiandrosterone sulphate (2,450). Rarely, the Sertoli-Leydig tumor is associated with manifestations of estrogenization (i.e., isosexual precocity, irregular or postmenopausal bleeding).


Because these low-grade lesions are only rarely bilateral (<1%), the usual treatment is unilateral salpingo-oophorectomy and evaluation of the contralateral ovary for patients who are in their reproductive years (3,422). For older patients, hysterectomy and bilateral salpingo-oophorectomy are appropriate (447,448).

There are insufficient data to document the utility of radiation or chemotherapy for patients with persistent disease, but some responses in patients with measurable disease were reported with pelvic irradiation and the VAC chemotherapy regimen (3,451455).


The 5-year survival rate is 70% to 90%, and recurrences thereafter are uncommon (3,450–455). Most fatalities occur in the presence of poorly differentiated tumors.

Uncommon Ovarian Cancers

There are several varieties of malignant ovarian tumors that together constitute only 0.1% of ovarian malignancies (2). Two of these lesions are the lipoid (or lipid) cell tumors and the primary ovarian sarcomas.

Lipoid Cell Tumors

Lipoid cell tumors are believed to arise in adrenal cortical rests that reside in the vicinity of the ovary. More than 100 cases were reported, and bilateral disease was noted in only a few (2). Most are associated with virilization and, occasionally, with obesity, hypertension, and glucose intolerance, reflecting corticosteroid secretion. Rare cases of estrogen secretion and isosexual precocity were reported.

Most of these tumors have benign or low-grade behavior, but about 20%, most of which are initially larger than 8 cm in diameter, are associated with metastatic lesions. Metastases are usually in the peritoneal cavity but can occur at distant sites. The primary treatment is surgical extirpation of the primary lesion. There are no data regarding the effectiveness of radiation or chemotherapy for this disease.


Malignant mixed mesodermal tumors (MMMT) of the ovary or carcinosarcomas are uncommon. Clinical, morphologic and molecular data suggest that MMMTs are monoclonal and are metaplastic carcinomas in which the mesenchymal part reflects dedifferentiation. Most tumors are heterologous, and 80% occur in postmenopausal women. The signs and symptoms are similar to those of most ovarian malignancies. These tumors are biologically aggressive, and most patients have evidence of metastases at presentation. They are treated either with carboplatin and paclitaxel or iphosphamide and cisplatin, but in general have a poor prognosis.

Small Cell Carcinoma, Hypercalcemic Type

This rare tumor occurs at an average age of 24 years (range 2 to 46 years) (456). The tumors are typically unilateral. Approximately two-thirds of the tumors are accompanied by paraendocrine hypercalcemia. This tumor accounts for one-half of all of the cases of hypercalcemia associated with ovarian tumors. About 50% of the tumors have spread beyond the ovaries when they are diagnosed (456). Immunohistochemical stains are helpful to differentiate this tumor from a lymphoma, leukemia, or sarcoma.

The management of these malignancies consists of surgery followed by platinum-based chemotherapy or radiation therapy or both. In addition to the primary treatment of the disease, control of the hypercalcemia may require aggressive hydration, loop diuretics, and the use of bisphosphonates or calcitonin. The prognosis tends to be poor, with most patients dying within 2 years of diagnosis in spite of treatment.

Figure 37.25 Metastatic carcinoma in the ovary. Note the linear, single cell pattern found in this metastatic breast carcinoma.

Metastatic Tumors

About 5% to 6% of ovarian tumors are metastatic from other organs, most frequently from the female genital tract, the breast, or the gastrointestinal tract (457473). The metastases may occur from direct extension of another pelvic neoplasm, by hematogenous or lymphatic spread, or by transcoelomic dissemination, with surface implantation of tumors that spread in the peritoneal cavity.


Nonovarian cancers of the genital tract can spread by direct extension or metastasize to the ovaries. Tubal carcinoma involves the ovaries secondarily in 13% of cases, usually by direct extension (2,3). Under some circumstances, it is difficult to know whether the tumor originated in the tube or in the ovary when both are involved. Cervical cancer spreads to the ovary only in rare cases (<1%), and most of these are of an advanced clinical stage or are adenocarcinomas. Adenocarcinoma of the endometrium can spread and implant directly onto the surface of the ovaries in about 5% of cases, but two synchronous primary tumors probably occur with greater frequency (472). In these cases, an endometrioid carcinoma of the ovary is usually associated with the adenocarcinoma of the endometrium.


The frequency of metastatic breast carcinoma to the ovaries varies according to the method of determination, but the phenomenon is common (Fig. 37.25). In autopsy data of women who died of metastatic breast cancer, the ovaries were involved in 24% of cases, and 80% of the involvement was bilateral (457462). Similarly, when ovaries are removed to palliate advanced breast cancer, about 20% to 30% of the cases reveal ovarian involvement, 60% of those bilaterally. The involvement of ovaries in early-stage breast cancer seems to be considerably lower, but precise figures are not available. In almost all cases, either ovarian involvement is occult or a pelvic mass is discovered after other metastatic disease becomes apparent.

Krukenberg Tumor

The Krukenberg tumor, which can account for 30% to 40% of metastatic cancers to the ovaries, arises in the ovarian stroma and has characteristic mucin-filled, signet-ring cells (463465) (Fig. 37.26). The primary tumor is frequently located in the stomach and less commonly in the colon, appendix (so-called goblet cell carcinoid), breast, or biliary tract. Rarely, the cervix or the bladder may be the primary site. Krukenberg tumors can account for about 2% of ovarian cancers at some institutions, and they are usually bilateral. The lesions are usually not discovered until the primary disease is advanced, and, therefore, most patients die of their disease within 1 year. In some cases, a primary tumor is never found.

Figure 37.26 Krukenberg tumor of the ovary metastatic from a gastric carcinoma. Malignant cells have discrete vacuoles that push nuclei eccentrically, giving a signet-ring appearance. Mucicarmine stain demonstrates the cytoplasmic vacuoles to be mucin.

Other Gastrointestinal Tumors

In other cases of metastasis from the gastrointestinal tract to the ovary, the tumor does not have the classic histologic appearance of a Krukenberg tumor; most of these are from the colon and, less commonly, the pancreato-biliary tract, appendix, and small intestine (Fig. 37.27). As many as 1% to 2% of women with intestinal carcinomas will develop metastases to the ovaries during the course of their disease (459). Before exploration for an adnexal tumor in a woman older than 40 years, a barium enema is indicated to exclude a primary gastrointestinal carcinoma with metastases to the ovaries, particularly if there are any gastrointestinal symptoms. Metastatic colon cancer can mimic a mucinous cystadenocarcinoma of the ovary histologically, and the histological distinction between the two can be difficult (458,459,466470). Lesions that arise in the appendix may be associated with ovarian metastasis and confused with primary ovarian malignancies, especially when associated with pseudomyxoma peritonei (466,470). It is reasonable to consider the performance of prophylactic bilateral salpingo-oophorectomy at the time of surgery for women with colon cancer (471).

Figure 37.27 Metastatic colorectal carcinoma in the ovary often has areas of necrotic debris (so-called dirty necrosis) adjacent to partial gland structures showing a cribriform pattern.


Rare cases of malignant melanoma metastatic to the ovaries were reported (473). In these circumstances, the melanomas are usually widely disseminated. Removal would be warranted for palliation of abdominal or pelvic pain, bleeding, or torsion. Malignant melanoma can arise, rarely, in a mature cystic teratoma (474).

Carcinoid Tumors

Metastatic carcinoid tumors represent fewer than 2% of metastatic lesions to the ovaries (475). Only about 2% of patients with primary carcinoids have evidence of ovarian metastasis, and only 40% of them have the carcinoid syndrome at the discovery of the metastatic carcinoid. In perimenopausal and postmenopausal women explored for an intestinal carcinoid, it is reasonable to remove the ovaries to prevent subsequent ovarian metastasis. The discovery of an ovarian carcinoid should prompt a careful search for a primary intestinal lesion (476).

Lymphoma and Leukemia

Lymphomas and leukemia can involve the ovary. When they do, the involvement is usually bilateral (477479). About 5% of patients with Hodgkin’s lymphoma will have lymphomatous involvement of the ovaries, but this involvement occurs typically with advanced-stage disease. With Burkitt’s lymphoma, ovarian involvement is very common. Other types of lymphoma involve the ovaries less frequently, and leukemic infiltration of the ovaries is uncommon (479). Sometimes the ovaries can be the only apparent sites of involvement of the abdominal or pelvic viscera with a lymphoma; if this circumstance is found, a careful surgical exploration may be necessary. Intraoperatively, a hematologist-oncologist should be consulted to determine the need for these procedures if frozen section of a solid ovarian mass reveals a lymphoma. Most lymphomas no longer require extensive surgical staging; biopsy of enlarged lymph nodes should be performed. In some cases of Hodgkin’s lymphoma, a more extensive evaluation may be necessary. Treatment involves that of the lymphoma or leukemia. Removal of a large ovarian mass may improve patient comfort and facilitate a response to subsequent radiation or chemotherapy.

Fallopian Tube Cancer

Historically, carcinoma of the fallopian tube accounted for 0.3% of all cancers of the female genital tract (2,3,480486). Data suggest primary fallopian tube carcinoma may be more common. In histologic features and behavior, fallopian tube carcinoma is similar to ovarian cancer; thus, the evaluation and treatment are essentially the same (Fig 37.28). The fallopian tubes frequently are involved secondarily from other primary sites, most often the ovaries, endometrium, gastrointestinal tract, or breast. They may be involved in primary peritoneal carcinomatosis. Almost all cancers are of epithelial origin, frequently of serous histology. Rarely, sarcomas are reported.

Figure 37.28 Carcinoma of the fallopian tube. This is a high-grade serous carcinoma that has invaded the lamina propria of the tubal mucosa. Most primary fallopian tube carcinomas arise in the distal (fimbria) portion of the fallopian tube.

As noted above, there is growing evidence to suggest that many high-grade serous carcinomas of the ovary may prove to arise from the fimbrial end of the fallopian tube (5,7). The true incidence of fallopian tube cancer may be historically underestimated because of the convention of assigning many of these as ovarian cancer when the site of origin is unclear. Despite the uncertainty concerning site of origin, all evidence suggests that our evaluation and treatment of these high-grade serous carcinomas should be the same. In recognition of this, many pathologists resorted to diagnosing these tumors as (nonuterine) high-grade serous carcinomas without definite assignment to primary site.

Clinical Features

Tubal cancers are seen most frequently in the fifth and sixth decades, with a mean age of 55 to 60 years (480). Women who have germline mutations in BRCA1 and BRCA2 are at substantially higher risk for developing fallopian tube carcinoma; therefore, prophylactic surgery in these women should include a complete removal of both tubes along with the ovaries (78,487).

Symptoms and Signs

The classic triad of symptoms and signs associated with fallopian tube cancer is (i) a prominent watery vaginal discharge (i.e., hydrops tubae profluens), (ii) pelvic pain, and (iii) a pelvic mass. This triad is noted in fewer than 15% of patients, and may be less common based on the histopathologic origins of fallopian tube cancers (3).

Vaginal discharge or bleeding is the most common symptom reported by patients with tubal carcinoma and is documented in more than 50% of patients (3,481). Lower abdominal or pelvic pressure and pain are noted in many patients. The symptoms may be rather vague and nonspecific. For perimenopausal and postmenopausal women with unusual, unexplained, or persistent vaginal discharge, in the absence of bleeding, the clinician should be concerned about the possibility of occult tubal cancer. Fallopian tube cancer may be found incidentally in asymptomatic women at the time of abdominal hysterectomy and bilateral salpingo-oophorectomy.

On examination, a pelvic mass is present in about 60% of patients, and ascites may be present if advanced disease exists. For patients with tubal carcinoma, the results of dilation and curettage will be negative, although abnormal or adenocarcinomatous cells may be seen in cytologic specimens obtained from the cervix in 10% of patients (483).

Spread Pattern

Tubal cancers spread in the same manner as epithelial ovarian malignancies, principally by the transcoelomic exfoliation of cells that implant throughout the peritoneal cavity. In about 80% of the patients with advanced disease, metastases are confined to the peritoneal cavity at the time of diagnosis (482).

The fallopian tubes are richly permeated with lymphatic channels, as are the ovaries, and spread to the para-aortic and pelvic lymph nodes is common. Metastases to the para-aortic lymph nodes are documented in at least 33% of the patients with all stages of disease (486).


Fallopian tube cancer is staged according to FIGO (480,485). The staging is based on the surgical findings at laparotomy (Table 37.9). According to this system, about 20% to 25% of patients have stage I disease, 20% to 25% have stage II disease, 40% to 50% have stage III disease, and 5% to 10% have stage IV disease (480). A somewhat lower incidence of advanced disease is seen in these patients than in patients with epithelial ovarian carcinomas, presumably because of the earlier occurrence of symptoms, particularly vaginal bleeding or unusual vaginal discharge. Findings on transvaginal ultrasonography and CT scan may be suspicious for tubal carcinomas (488).

Table 37.9 FIGO Staging for Carcinoma of the Fallopian Tube


Stage 0

Carcinoma in situ (limited to tubal mucosa).

Stage I

Growth is limited to the fallopian tubes.


Growth is limited to one tube with extension into the submucosac and/or muscularis but not penetrating the serosal surface; no ascites.


Growth is limited to both tubes with extension into the submucosac and/or muscularis but not penetrating the serosal surface; no ascites.


Tumor either stage IA or IB but with tumor extension through or onto the tubal serosa; or with ascites present containing malignant cells or with positive peritoneal washings.

Stage II

Growth involving one or both fallopian tubes with pelvic extension.


Extension and/or metastasis to the uterus and/or ovaries.


Extension to other pelvic tissues.


Tumor either stage IIA or IIB but with tumor extension through or onto the tubal serosa; or with ascites present containing malignant cells or with positive peritoneal washings.

Stage III

Tumor involves one or both fallopian tubes with peritoneal implants outside of the pelvis and/or positive retroperitoneal or inguinal nodes. Superficial liver metastases equals stage III. Tumor appears limited to the true pelvis but with histologically proven malignant extension to the small bowel or omentum.


Tumor is grossly limited to the true pelvis with negative nodes but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces.


Tumor involving one or both tubes with histologically confirmed implants of abdominal peritoneal surfaces, none exceeding 2 cm in diameter. Lymph nodes are negative.


Abdominal implants greater than 2 cm in diameter and/or positive retroperitoneal or inguinal nodes.

Stage IV

Growth involving one or both fallopian tubes with distant metastases. If pleural effusion is present, there must be positive cytology to be stage IV. Parenchymal liver metastases equals stage IV.

FIGO, International Federation of Gynecology and Obstetrics.

From Berek JS, Hacker NF. Berek and Hacker’s Gynecologic Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:494;adapted from FIGO Annual Report. Vol 26, Int J Gynecol Obstet2006;105:3–4.


The treatment of this disease is the same as that of epithelial ovarian cancer (480,483,489–495). Exploratory laparotomy is necessary to remove the primary tumor, to stage the disease, and to resect metastases. After surgery, the chemotherapy is the same as with epithelial ovarian cancer (i.e., carboplatin and paclitaxel).


Patients with tubal carcinoma should undergo total abdominal hysterectomy and bilateral salpingo-oophorectomy (3). If there is no evidence of gross tumor spread, a staging operation is performed. The retroperitoneal lymph nodes should be adequately evaluated, and peritoneal cytologic studies and biopsies should be performed, along with an infracolic omentectomy.

In patients with metastatic disease, an effort should be made to remove as much tumor bulk as possible. The role of cytoreductive surgery in this disease is unclear, but extrapolation from the experience with epithelial ovarian cancer indicates that significant benefit might be expected, particularly if all macroscopic disease can be resected (490).


As with epithelial ovarian cancer, the most active agents are platinum and the taxanes (489,490). The recommended treatment for fallopian tube cancer is the same as that for epithelial ovarian cancer (i.e., platinum and taxane-based chemotherapy). A variety of other chemotherapeutic agents that are effective against recurrent ovarian cancer appear to be active in recurrent or persistent fallopian tube carcinomas. These agents include docetaxeletoposidetopotecangemcitabine, and liposomally encapsulated doxorubicin (491495). As data on well-staged lesions are scarce, it is unclear whether patients with disease confined to the fallopian tube (i.e., a stage IA, grade 1 or 2 carcinoma) benefit from additional therapy.


The overall 5-year survival for patients with epithelial tubal carcinomas is about 40%. This number is higher than for patients with ovarian cancer and reflects the somewhat higher proportion of patients diagnosed with early-stage disease. These data may reflect the fact that some advanced stage tubal cancers were classified as ovarian cancers. The reported 5-year survival rate for patients with stage I disease is only about 65%. The 5-year survival rate for patients with stage II disease is 50% to 60%, but it is only 10% to 20% for patients with stages III and IV disease (480,485).

Tubal Sarcomas

Tubal sarcomas, particularly malignant mixed mesodermal tumors, are described, but rare. They occur mainly in the sixth decade and typically are advanced at the time of diagnosis. If all gross disease can be resected, platinum-based combination chemotherapy should be tried. Survival is poor, and most patients die of their disease within 2 years (2,450).


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