Berek and Hacker's Gynecologic Oncology, 5th Edition


Germ Cell and Other Nonepithelial Ovarian Cancers

Jonathan S. Berek

Michael Friedlander

Neville F. Hacker


Compared with epithelial ovarian cancers, other malignant tumors of the female genital adnexal structures are uncommon. 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, lipoid cell tumors).

Nonepithelial malignancies of the ovary account for approximately 10% of all ovarian cancers (1,2). Although there are many similarities in the presentation, evaluation, and management of these patients, these tumors also have unique qualities that require a special approach (1,2,3,4,5).

Germ Cell Malignancies

Germ cell tumors are derived from the primordial germ cells of the ovary. Their incidence is only about one-tenth the incidence of malignant germ cell tumors of the testis.Although they can arise in extragonadal sites such as the mediastinum and the retroperitoneum, the majority of germ cell tumors arise in the gonad from the 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 (1,2).

Germ cell tumors are a model of a curable cancer. The management of patients with ovarian germ cell tumors has largely been extrapolated from the experience of treating the more common testicular germ cell tumors. There have been many randomized trials for testicular germ cell tumors, which have provided a strong evidence base for treatment decision making (6,7). The outcome of patients with testicular germ cell tumors is better in experienced centers, and it is reasonable to suggest the same will be true for the less common ovarian counterparts. The cure rate is high, and currently efforts are being made to reduce toxicity without compromising survival. There are still a small number of patients who die from the disease, and studies are in progress to try to improve the outcome for this high-risk poor-prognostic subset (6,7).

In one of the largest reported series, which included 113 patients with advanced ovarian germ cell tumors treated with cisplatin-based chemotherapy, Murugaesu et al. (8) reported that stage and elevated tumor markers were independent poor prognostic indicators. These findings are important because they identify similar prognostic factors for ovarian germ cell tumors as has been described previously for testicular germ cell tumors. This is in accordance with the clinical observation that testicular and ovarian germ cell tumors behave similarly. This is relevant for the management of patients with ovarian germ cell tumors because it could help to identify patients who may require more intensive therapeutic strategies (8).


Table 12.1 Histologic Typing of Ovarian Germ Cell Tumors

I. Primitive Germ Cell Tumors

III. Monodermal Teratoma and Somatic-Type Tumors Associated with Dermoid Cysts



Thyroid tumor

Yolk sac tumor



Struma ovarii

Embryonal carcinoma










Nongestational choriocarcinoma



Mixed germ cell tumor


Neuroectodermal tumor

II. Biphasic or Triphasic Teratoma



Immature teratoma



Mature teratoma






Sebaceous tumor




Pituitary-type tumor



Dermoid cyst





Fetiform teratoma (homunculus)





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


A histologic classification of ovarian germ cell tumors is presented in Table 12.1 (1). 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 as many as 95% of dysgerminomas, and serial monitoring of serum LDH titers may be useful for monitoring the disease. PLAP is more useful as an immunohistochemical marker than as a serum marker. When the histologic and immunohistologic identification of these substances in tumors is correlated, a classification of germ cell tumors emerges (Fig. 12.1) (9).

In this scheme, embryonal carcinoma, which is a cancer composed of undifferentiated cells, synthesizes both hCG and AFP, and this lesion is the progenitor of several other germ cell tumors (4,9). More differentiated germ cell tumors—such as the endodermal sinus tumor, which secretes AFP, and 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. Elevated hCG levels are seen in 3% of dysgerminomas (1).


Although 20% to 25% of all benign and malignant ovarian neoplasms are of germ cell origin, only some 3% of these tumors are malignant (1). Germ cell malignancies account for fewer than 5% of all ovarian cancers in Western countries. Germ cell malignancies represent as much as 15% of ovarian cancers in Asian and black 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 (1,2). Germ cell tumors account for two-thirds of the ovarian malignancies in this age group. Germ cell cancers also are seen in the third decade, but thereafter they become quite rare.



Figure 12.1 Relationship between examples of pure malignant germ cell tumors and their secreted marker substances.

Clinical Features


In contrast to the relatively slow-growing epithelial ovarian tumors, germ cell malignancies grow rapidly and often 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 also may occur in menarchal patients. Some young patients may misinterpret the early symptoms of a neoplasm as those of pregnancy, and this 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 present with abdominal distention (3).


In patients with a palpable adnexal mass, the evaluation can proceed as outlined in Chapter 11. Some patients with germ cell tumors will be premenarchal 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, then a neoplasm is probable and a malignancy is possible (Fig. 12.2). The remainder of the physical examination should search for signs of ascites, pleural effusion, and organomegaly.


Adnexal masses measuring 2 cm or more in premenarchal girls or complex masses 8 cm or more in premenopausal patients will usually require surgical exploration (Fig. 12.3). In young patients, blood tests should include serum hCG, AFP, and CA125 titers, a complete blood count, and liver function tests. A radiograph of the chest is important because germ cell tumors can metastasize to the lungs or mediastinum. A karyotype should ideally be obtained preoperatively on all premenarchal girls because of the propensity of these tumors to arise in dysgenetic gonads, but this may not be practical (3,10). A preoperative computed tomographic (CT) scan or magnetic resonance imaging (MRI) may document the presence and extent of retroperitoneal lymphadenopathy or liver metastases, but unless there is very extensive metastatic disease, is unlikely to influence the decision to operate on the patient initially. If postmenarchal patients have predominantly cystic lesions up to 8 cm in diameter, they may undergo observation or a trial of hormonal suppression for two cycles (11).



Figure 12.2 Dysgerminoma of the ovary. Note that the lesion is principally solid with some cystic areas and necrosis. From Berek JS, Natarajan S. Ovarian and fallopian tube cancer. In: Berek JS, ed. Berek & Novak's Gynecology, 14th ed. Philadelphia: Lippincott Williams & Wilkins, 2007.


The dysgerminoma is the most common malignant germ cell tumor, accounting for approximately 30% to 40% of all ovarian cancers of germ cell origin (2,9). 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 of age. Seventy-five percent of dysgerminomas occur between the ages of 10 and 30 years, 5% occur before the age of 10 years, and rarely after age 50 (1,4). Because these malignancies occur in young women, 20% to 30% of ovarian malignancies associated with pregnancy are dysgerminomas.

Approximately 5% of dysgerminomas are discovered in phenotypic females with abnormal gonads (1,10). This malignancy can be associated with patients who have pure gonadal dysgenesis (46XY, bilateral streak gonads), mixed gonadal dysgenesis (45X/46XY, unilateral streak gonad, contralateral testis), and the androgen insensitivity syndrome (46XY, testicular feminization). Therefore, in premenarchal patients with a pelvic mass, the karyotype should be determined (Fig 12.4).

In most patients with gonadal dysgenesis, dysgerminomas arise in a gonadoblastoma, which is a benign ovarian tumor 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 (12).



Figure 12.3 Evaluation of a pelvic mass in young female patients.

Approximately 65% of dysgerminomas are stage I (i.e., confined to one or both ovaries) at diagnosis (1,3,5,13,14,15,16). Approximately 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 being rarely bilateral.

In patients whose contralateral ovary has been preserved, disease can develop in 5% to 10% of the retained gonads over the next 2 years (1). This figure includes those not given additional therapy, as well as patients with gonadal dysgenesis.

In the 25% of patients who present with metastatic disease, the tumor most commonly spreads via the lymphatics, particularly to the higher paraaortic nodes. It can also 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, and when metastasis to this site occurs, the lesions are seen principally in the lower vertebrae. Metastases to the lungs, liver, and brain are seen most often in patients with long-standing or recurrent disease. Metastasis to the mediastinum and supraclavicular lymph nodes is usually a late manifestation of disease (13,14).



Figure 12.4 A 16-year-old girl with 46XY gonadal dysgenesis, showing lack of secondary sexual features, who developed dysgerminoma.


The treatment of patients with early dysgerminoma is primarily surgical, including resection of the primary lesion and proper surgical staging. Chemotherapy or radiation or both is administered to patients with metastatic disease. Because the disease principally affects young women, special consideration must be given to the preservation of fertility whenever possible. An algorithm for the management of ovarian dysgerminoma is presented in Fig. 12.5.


The minimum operation for ovarian dysgerminoma is unilateral oophorectomy (15,17). If there is a desire to preserve fertility, as is usually the case, then 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, then it may be appropriate to perform a total abdominal hysterectomy and bilateral salpingo-oophorectomy in patients with advanced disease (5), although this will be appropriate in only a small minority of patients. In patients whose karyotype contains a Y chromosome, both ovaries should be removed, although the uterus may be left in situ for possible future embryo transfer. Whereas cytoreductive surgery is of unproven value, bulky disease that can be readily resected (e.g., an omental cake) should be removed at 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 biopsied. Unilateral pelvic lymphadenectomy and at least careful palpation and excisional biopsy of enlarged paraaortic nodes are particularly important parts of the staging. These tumors often metastasize to the paraaortic nodes around the renal vessels. Dysgerminoma is the only germ cell tumor that tends to be bilateral, and not all of the bilateral lesions have obvious ovarian enlargement. Therefore careful inspection and palpation of the contralateral ovary and excisional biopsy of any suspicious lesion are desirable (5,15,16,17). If a small contralateral tumor is found, then it may be possible to resect it and preserve some normal ovary.



Figure 12.5 Management of dysgerminoma of the ovary. BEP = bleomycin, etoposide, and cisplatin; CT = computed tomogram.

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, our preference is to perform regular surveillance in patients with stage I tumors. Tumor markers (LDH, AFP, and β-hCG) should also be monitored in case occult mixed germ cell elements are present (Fig. 12.1).


Dysgerminomas are very sensitive to radiation therapy, and doses of 2,500 to 3,500 centiGray may be curative, even for gross metastatic disease. Loss of fertility is a problem with radiation therapy, so radiation should rarely be used as first-line treatment (5,16).


There have been numerous reports of successful control of metastatic dysgerminomas with systemic chemotherapy, and this should be regarded as the treatment of choice(17,18,19,20,21,22,23,24,25,26,27). The obvious advantage is the preservation of fertility in most patients with chemotherapy (17,28,29,30,31,32).

The most frequently used chemotherapeutic regimen for germ cell tumors is BEP (bleomycin, etoposide, and cisplatin), although less-intensive regimens have been used in selected patients with dysgerminomas. In the past, VBP (vinblastine, bleomycin, and cisplatin), and VAC (vincristine, actinomycin, and cyclophosphamide) were commonly used but are now rarely prescribed (17,18,19,20,21,22) (Table 12.2).

The Gynecologic Oncology Group (GOG) studied three cycles of EC: etoposide (120 mg/m2 intravenously on days 1, 2, and 3 every 4 weeks) and carboplatin (400 mg/m2intravenously on day 1 every 4 weeks) in 39 patients with completely resected ovarian dysgerminoma, stages IB, IC, II, or III (25). The results were excellent, and GOG reported a sustained disease-free remission rate of 100%.

For patients with advanced, incompletely resected germ cell tumors, the GOG studied cisplatin-based chemotherapy on two consecutive protocols (18,19). In the first study, patients received four cycles of vinblastine (12 mg/m2 every 3 weeks), bleomycin (20 units/m2 intravenously every week for 12 weeks), and cisplatin (20 mg/m2/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. In the second trial, patients received three cycles of BEP initially, followed by consolidation with VAC, which was later discontinued in patients with dysgerminomas (19). VAC does not appear to improve the outcome of the BEP regimen and is no longer used.

A total of 20 evaluable patients with stages III and IV dysgerminoma were treated in these two protocols, and 19 are 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. A study at M. D. Anderson Hospital (22) used BEP in 14 patients with residual disease, and all patients were free of disease with long-term follow-up. In another series of 26 patients with pure ovarian dysgerminoma who received BEP chemotherapy, 54% of whom had stage IIIC or IV disease, 25 (96%) remained continuously disease free following three to six cycles of therapy (27).

These results suggest that patients with advanced-stage, incompletely resected dysgerminoma have an excellent prognosis when treated with cisplatin-based combination chemotherapy (26,27,28,29,30,31). The best regimen is three to four cycles of BEP based on the data from testis cancers (32,33) depending on the extent of disease and the presence or absence of visceral metastases. These are uncommon tumors, and most of the principles of management are extrapolated from seminomas, their counterparts in males. If bleomycin is contraindicated or omitted because of lung toxicity, then consideration should be given to four cycles of cisplatin and etoposide.

Table 12.2 Combination Chemotherapy for Germ Cell Tumors of the Ovary

Regimen and Drugs

Dose and Schedulea




30,000 IU weekly for a total of 12 weeks


100 mg/m2/day × 5 days every 3 weeks


20 mg/m2/day × 5 days every 3 weeks

Loehrer PJ, Johnson D, Elson P, Einhorn LH, Trump D. Importance of bleomycin in favorable-prognosis disseminated germ cell tumors: an Eastern Cooperative Oncology Group trial. J Clin Oncol 1995;13: 470-476.


There is no need to perform a second-look laparotomy in patients with dysgerminomas (34,35,36). The role of surgery to resect residual masses following chemotherapy for dysgerminomas is not clear, and the vast majority of these patients will only have necrotic tissue and nonviable tumor. In general, these patients should be closely monitored with scans and tumor markers. A positron emission tomography (PET) scan should be considered in patients who have bulky residual masses more than 4 weeks after chemotherapy. A positive PET scan is a reliable predictor of residual seminoma in males with residual lesions >3cm (37), and the same may apply to females with dysgerminomas. If the PET is positive or if there is a suggestion of progressive disease on scans, then ideally there should be histological evaluation and confirmation of residual disease before embarking on salvage therapy.

Recurrent Disease

Approximately 75% of recurrences occur within the first year after initial treatment (1,2,3,4), the most common sites being the peritoneal cavity and the retroperitoneal lymph nodes. These patients should be treated with either radiation or chemotherapy, depending on their primary treatment. Patients with recurrent disease who have had no therapy other than surgery should be treated with chemotherapy. If previous chemotherapy with BEP has been given, then an alternative regimen such as TIP (paclitaxel, ifosfamide, andcisplatin) is a reasonable option based on the experience in testicular tumors (38).

These treatment decisions should be made in a multidisciplinary setting with the input of physicians experienced in the treatment of patients with germ cell tumors (Table 12.3).

Table 12.3 POMB-ACE Chemotherapy for Germ Cell Tumors of the Ovary



Day 1

Vincristine 1 mg/m2 intravenously; methotrexate 300 mg/m2 as a 12-h infusion

Day 2

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

Day 3

Bleomycin infusion 15 mg by 24-h infusion

Day 4

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



Days 1-5

Etoposide (VP-16-213) 100 mg/m2, days 1 to 5

Day 3, 4, 5

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

Day 5

Cyclophosphamide 500 mg/m2 intravenously, day 5



Day 1

Vincristine 1 mg/m2 intravenously; methotrexate 300 mg/m2 as a 12-h infusion

Day 2

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

Day 3

Bleomycin 15 mg by 24-h infusion

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 and α-fetoprotein, and placental alkaline phosphatase and lactate dehydrogenase. The usual number of courses of POMB is three to five. After 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, then the first two days of etoposide are omitted from subsequent courses of ACE.

Reproduced from Newlands ES, Southall PJ, Paradinas FJ, Holden L. Management of ovarian germ cell tumors. In: Williams CJ, Krikorian JG, Green MR, Ragavan D, eds. Textbook of uncommon cancer. New York: John Wiley & Sons, 1988:37-53, with permission.


Consideration should be given to the use of high-dose chemotherapy with peripheral stem cell support. A number of high dose regimens have been used in phase 2 studies, and the choice depends on the previous chemotherapy, the time to recurrence, and the residual toxicity from the previous therapy. Alternatively, radiation therapy may be given, but this has the major disadvantage of causing loss of fertility if pelvic and abdominal radiation is required. It will also compromise the ability to deliver further chemotherapy if unsuccessful.


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. In patients with more advanced disease, continuation of the pregnancy will depend on gestational age. 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 (28).


In 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% (5,16). The features that have been associated with a higher tendency to recurrence 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 (1,9).

Kumar et al. abstracted data on malignant ovarian germ cell tumors from the Surveillance, Epidemiology, and End Results (SEER) program from 1988 through 2004 (39). There were a total of 1,296 patients with dysgerminomas, immature teratomas, or mixed germ cell tumors, 613 (47.3%) of whom had lymphadenectomies. Lymph node metastases were present in 28% of dysgermanomas, 8% of immature teratomas, and 16% of mixed germ cell tumors (p <0.05). The 5-year survival for patients with negative nodes was 95.7% compared to 82.8% for patients with positive nodes (p <0.001). Multivariate analysis revealed the presence of lymph node involvement to be an independent predictor of poor survival.

Although surgery for advanced disease followed by pelvic and abdominal radiation resulted in the past in a 5-year survival rate of 63% to 83%, cure rates of 90% to 100% for this same group of patients are now being reported with the use of BEP or EC combination chemotherapy (18,19,20,21,22,23,24,25,26,27,28,29,30,31).

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. This lesion represents 10% to 20% of all ovarian malignancies seen in women younger than 20 years of age and 30% of the deaths from ovarian cancer in this age group (1). Approximately 50% of pure immature teratomas of the ovary occur between the ages of 10 and 20 years, and they rarely occur in postmenopausal women.

Semiquantification of the amount of neuroepithelium correlates with survival in ovarian immature teratomas and is the basis for the grading of these tumors (40,41,42). Those with less than one lower-power field (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%) (42). This may not apply, however, to immature teratomas of the ovary in children because they appear to have a very good outcome with surgery alone, regardless of the degree of immaturity (43,44).

Some authorities have recommended a two-tier grading system and have recommended that immature teratomas be categorized as either low grade or high grade because of the significant inter- and intraobserver difficulty with a three-grade system (42). This is our current practice.

Immature ovarian teratomas are associated with gliomatosis peritonei, a favorable prognostic finding if composed of completely mature tissues. Recent reports using molecular methods have determined that these glial “implants” are not tumor derived but represent teratomainduced metaplasia of pluripotential müllerian stem cells in the peritoneum (45,46).

Malignant transformation of a mature teratoma is a rare event. Squamous cell carcinoma is the most frequent subtype of malignancy in this setting, but adenocarcinomas, primary melanomas, and carcinoids also occur (see below) (24). The risk is reported to be between 0.5% and 2% of teratomas, usually in postmenopausal patients.



The preoperative evaluation and differential diagnosis are the same as for patients with other germ cell tumors. Some of these lesions will contain calcifications similar to mature teratomas, and this 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 (4). Tumor markers are negative unless a mixed germ cell tumor is present.



In a premenopausal patient whose lesion appears confined to a single ovary, unilateral oophorectomy and surgical staging should be performed. In postmenopausal patients, 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 (2). 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 high grade (4).

It is unclear whether debulking of metastatic implants enhances the response to combination chemotherapy (47,48). Cure ultimately depends on the ability to deliver chemotherapy promptly. Any surgical resection that may be potentially morbid and therefore delay chemotherapy should be resisted, although surgical resection of any residual disease should be considered at the completion of chemotherapy.


Patients with stage IA, grade 1 tumors have an excellent prognosis, and no adjuvant therapy is required. In patients whose tumors are stage IA, grades 2 or 3, high grade, adjuvant chemotherapy has commonly been given although this has been questioned and excellent results have been also reported with close surveillance and only treating patients who have a recurrence (see below) (20,21,22,35,49,50,51,52,53,54,55,56,57,58,59,60,61).

The most frequently used combination chemotherapeutic regimen in the past has been VAC (55,56,57), but a GOG study reported a relapse-free survival rate in patients with incompletely resected disease of only 75% (57).

The approach over the last 20 years has been to incorporate cisplatin into the primary treatment of these tumors, and most of the experience has been with the VBP and BEP regimens.

The GOG has been prospectively studying three courses of BEP therapy in patients with completely resected stage I, II, and III ovarian germ cell tumors (24). Overall, the toxicity was acceptable, and 91 of 93 patients (97.8%) with nondysgerminomatous tumors were clinically free of disease. In nonrandomized studies, the BEP regimen is superior to the VAC regimen in the treatment of completely resected nondysgerminomatous germ cell tumors of the ovary. Some patients can progress rapidly postoperatively, and, in general, treatment should be initiated as soon as possible after surgery, preferably within 7 to 10 days.

The switch from VBP to BEP has been prompted by the experience in patients with testicular cancer, where the replacement of vinblastine with etoposide has been associated with a better therapeutic index (i.e., equivalent efficacy and lower morbidity), especially less neurologic and gastrointestinal toxicity. Furthermore, the use of bleomycin appears to be important in this group of patients. In a randomized study of three cycles of etoposide plus cisplatin with or without bleomycin (EP vs. 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) (33).

Cisplatin is superior to carboplatin in metastatic germ cell tumors of the testis. One hundred ninety-two patients with good prognosis germ cell tumors of the testes were entered into a study of four cycles of etoposide plus cisplatin (EP) versus 4 cycles of etoposide plus carboplatin (EC). There were three relapses with the EP regimen versus seven with the EC regimen (34). A German group randomized patients to (i) a BEP regimen of three cycles at standard doses given days 1-5 versus (ii) a CEB regimen of carboplatin (target AUC of 5 mg/dl × min) on day 1), etoposide 120 mg/m2 on days 1 to 3, and bleomycin 30 mg on days 1, 8, and 15 (62). Four cycles of CEB were given, with the omission of bleomycin in the fourth cycle so that the cumulative doses of etoposide and bleomycin in the two treatment arms were comparable. Fifty-four patients were entered on the trial; 29 were treated with PEB and 25 with CEB chemotherapy. More patients treated with CEB relapsed after therapy (32% versus 13%). Four patients (16%) treated with CEB died of disease progression in contrast to one patient (3%) after BEP therapy. The trial was terminated early after an interim analysis. The inferiority of carboplatin was confirmed in a larger randomized trial reported by Horwich et al. (63). 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.


Radiation therapy is generally not used in the primary treatment of patients with immature teratomas. Furthermore, there is no evidence that the combination of chemotherapy and radiation has a higher rate of disease control than chemotherapy alone. Radiation should be reserved for patients with localized persistent disease after chemotherapy (5,35).

Second-Look Laparotomy

The need for a second-look operation for ovarian germ cell tumors has been questioned (36,37). It is not justified in patients who have received chemotherapy in an adjuvant setting (i.e., stage IA, grades 2 and 3) because these patients have an excellent prognosis. However, we continue to prefer second-look laparotomy in patients with residual disease at the completion of chemotherapy because these patients may have residual mature teratoma and are at risk of growing teratoma syndrome, a rare complication of immature teratomas (64,65). Furthermore, cancers can arise at a later date in residual mature teratoma, and 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 (66). Mathew et al. (67) reported their experience of laparotomy in assessing the nature of postchemotherapy residual masses in ovarian germ cell tumors. Sixty-eight patients completed combination chemotherapy with cisplatin regimens, of whom 35 had radiological residual masses. Twenty-nine of these 35 patients underwent laparotomy, and three patients (10.3%) had viable tumor, seven (24%) immature teratoma, three (10.3%) mature teratoma, and 16 (55.2%) necrosis or fibrosis only. None of the patients with a dysgerminoma or embryonal carcinoma and radiological residual mass of <5 cm had viable tumor present, whereas all patients with primary tumors containing a component of teratoma had residual tumor, strengthening the case for surgery in patients with immature teratoma and any residual mass (67). An enlarged contralateral ovary may contain a benign cyst or a mature cystic terotoma, and ovarian cystectomy should be performed (2,4).


The most important prognostic feature of the immature teratoma is the grade of the lesion (1,40). In addition, the stage of disease and the extent of tumor at the initiation of treatment also have an impact on curability. Patients whose tumors have been incompletely resected before treatment have a significantly lower probability of 5-year survival than those whose lesions have been completely resected (i.e., 94% vs. 50%) (4). 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 surgical stage I lesions (35,40,49).

The degree or grade of immaturity generally predicts the metastatic potential and curability. The 5-year survival rates have been reported to be 82%, 62%, and 30% for patients with grades 1, 2, and 3, respectively (40). However, many of these patients were treated in an era before optimal chemotherapy was available, and these figures do not match current experience and more recently published data. For example, Lai et al. reported on the long-term outcome of 84 patients with ovarian germ cell tumors, including 29 immature teratomas, and the 5-year survival was 97.4% (68).

Occasionally, these tumors are associated with mature or low-grade glial elements that have implanted throughout the peritoneum. Such patients have a favorable long-term survival (4). However, mature glial elements can grow and mimic malignant disease and may need to be resected to relieve pressure on surrounding structures.


Endodermal Sinus Tumor

Endodermal sinus tumors (ESTs) have also been referred to as yolk sac carcinomas because they are derived from the primitive yolk sac (1). These lesions are the third most frequent malignant germ cell tumor of the ovary.

ESTs have a median age of 18 years (1,2,3,69,70). Approximately one-third of the patients are premenarchal at the time of initial presentation. Abdominal or pelvic pain is the most frequent presenting symptom, occurring in some 75% of patients, whereas an asymptomatic pelvic mass is documented in 10% of patients (3).

Most EST lesions secrete AFP and rarely may elaborate detectable alpha-1-antitrypsin (AAT). There is a good correlation between the extent of disease and the level of AFP, although discordance also has been observed. The serum level of these markers, particularly AFP, is useful in monitoring the patient's response to treatment (69,70,71,72,73,74,75).



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 and is not indicated (4,72). Furthermore, with conservative surgery and adjuvant chemotherapy, fertility can be preserved as with other germ cell tumors (17). Any gross metastases should be resected 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. Bilaterality is not seen in these lesions, 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 (76).


All patients with endodermal sinus tumors are treated with either adjuvant or therapeutic chemotherapy. Before the routine use of combination chemotherapy for this disease, the 2-year survival rate was approximately 25%. After the introduction of the VAC regimen, this rate improved to 60% to 70%, indicating the chemosensitivity of the majority of these tumors (56,57). Currently, all patients are treated with cisplatin-based regimens such as BEP, which is considered the standard of care. The chance of cure now approaches 100% for early stage patients and at least 75% for more advanced-stage patients.

The optimal number of treatment cycles has not been established in ovarian germ cell tumors, but it is reasonable to extrapolate from the much larger experience in testicular germ cell tumors where three cycles of BEP is considered optimal for good prognosis, low-risk patients and four cycles for patients with intermediate to high-risk tumors (7). In patients for whom bleomycin is omitted or discontinued because of toxicity, four cycles of cisplatin and etoposide are recommended. An alternative approach is to use VIP (etoposide, ifosfamide, and cisplatin) in patients with more advanced disease in whom bleomycin is contraindicated. Four cycles of VIP are equivalent to four cycles of BEP, but it is more myelotoxic and generally requires growth-factor support (6,7).

A number of years ago, the group from the Charing Cross Hospital in London developed the POMB-ACE* regimen for high-risk germ cell tumors of any histologic type (75) (Table 12.3). Their results appear to be superior to BEP in patients with poor prognostic features. This protocol introduces seven drugs into the initial management, which is intended to minimize the chances of developing drug resistance. This is particularly relevant for patients with massive metastatic disease. We have tended to use the POMB-ACE regimen as primary therapy for such cases, as well as for patients with liver or brain metastases.

The POMB schedule is only moderately myelosuppressive, so the intervals between each course can be kept to a maximum of 14 days (usually 9 to 11 days), thereby minimizing the time for tumor regrowth between courses. When bleomycin is given by a 48-hour infusion, pulmonary toxicity is reduced. With a maximum of 9 years of follow-up, the Charing Cross group has seen no long-term side effects in patients treated with POMB-ACE. Children have developed normally, menstruation has been physiologic, and several women have completed normal pregnancies. It is still not clear if POMB-ACE is superior to BEP, but it is unlikely that this will ever be addressed in a randomized trial.

Second-Look Laparotomy

The value of a second-look operation is not established in patients with EST. It is reasonable to omit surgery in patients whose AFP values return to normal and remain normal for the balance of their treatment (73,74). There have been reported cases in which the AFP titer has returned to normal in spite of persistent measurable disease; some of these cases have been mixed germ cell tumors (74).

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, their ages ranging between 4 and 28 years (median = 14 years) in two series (76). Older patients have been reported (77). Embryonal carcinomas may secrete estrogens, with the patient exhibiting symptoms and signs of precocious pseudopuberty or irregular bleeding (1). The presentation is otherwise similar to that of the endodermal sinus tumor. The primary lesions tend to be large, and approximately two-thirds are confined to one ovary at the time of presentation. These lesions frequently secrete AFP and hCG, which are useful for following the response to subsequent therapy (73).

The treatment of embryonal carcinomas is the same as for the EST (i.e., a unilateral oophorectomy followed by combination chemotherapy with BEP) (21,61,78).

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 (79). The majority of 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 has been seen, occurring in approximately 50% of patients whose tumors appear before menarche (80).

There are only a few limited reports on the use of chemotherapy for these nongestational choriocarcinomas, but complete responses have been reported to the MAC regimen (methotrexate, actinomycin D, and cyclophosphamide) used in a manner described for gestational trophoblastic disease (79) (see Chapter 15). These tumors are so rare that no good data are available, but the options also include the BEP or POMB-ACE regimens. The prognosis for ovarian choriocarcinomas has been poor, with the majority of patients having metastases to organ parenchyma at the time of initial 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) (1,9). The lesion tends to occur in very young, premenarchal girls with signs of pseudopuberty, and AFP and hCG levels are elevated. Women with polyembryomas that are surgically staged and confined to one ovary may be followed with serial tumor markers and diagnostic-imaging techniques to avoid cytotoxic chemotherapy. In patients who require chemotherapy, the BEP regimen is appropriate (56).

Mixed Germ Cell Tumors

Mixed germ cell malignancies of the ovary contain two or more elements of the lesions described above. In one series (78), 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%. The most frequent combination was a dysgerminoma and an EST. The mixed lesions may secrete either AFP or hCG—or both or neither—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 may reflect regression of only a particular component of the mixed lesion. Therefore, in these patients a second-look laparotomy may be indicated if there is residual disease following chemotherapy, particularly if there was an immature teratomatous component in the original tumor.

The most important prognostic features are the size of the primary tumor and the relative amount of its most malignant component (78). In stage IA lesions smaller than 10 cm, survival is 100%. Tumors composed of less than one-third EST, choriocarcinoma, or grade 3 immature teratoma also have an excellent prognosis, but it is less favorable when these components compose the majority of the mixed lesions.

Surveillance for Stage I Ovarian Germ Cell Tumors

Surveillance is a common approach to the management of young men with apparent stage I testicular germ cell tumors. There is a large body of evidence to support this approach, as well as guidelines on what constitutes appropriate surveillance (6,7). Although as many as 20% to 30% of patients will relapse, almost all will be cured with salvage chemotherapy with BEP, and the potential adverse effects of chemotherapy can be avoided in most patients.

Although this is a very common approach to management of young men with stage I testicular germ cell tumors, it has not been widely adopted in females with ovarian germ cell tumors. However, some data are now available to support surveillance in selected patients who have been surgically staged. Cushing et al. reported a study of 44 pediatric patients with completely resected ovarian immature teratomas who were followed carefully for recurrence of disease with appropriate diagnostic imaging and serum tumor markers (81). Thirty-one patients (70.5%) had pure ovarian immature teratomas with a tumor grade of 1 (n = 17), 2 (n = 12), or 3 (n = 2). Thirteen patients (29.5%) had an ovarian immature teratoma plus microscopic foci of yolk sac tumor. The 4-year event-free and overall survival for the ovarian immature teratoma group and for the ovarian immature teratoma plus yolk sac tumor group was 97.7% (95% confidence interval, 84.9% to 99.7%) and 100%, respectively. The only yolk sac tumor relapse occurred in a child with ovarian immature teratoma and yolk sac tumor who was then treated and salvaged with chemotherapy (81).

The Charing Cross Group reported a study of 24 patients with stage IA ovarian germ cell tumors who were also enrolled in a surveillance program. The group consisted of nine patients (37.5%) with dysgerminoma, nine (37.5%) with pure immature teratoma, and six (25%) with endodermal sinus tumors (with or without immature teratoma). Treatment consisted of surgical resection without adjuvant chemotherapy, followed by a surveillance program of clinical, serologic, and radiologic review. A second-look operation was performed, and all but one patient were alive and in remission after a median follow-up of 6.8 years. The 5-year overall survival was 95%, and the 5-year disease-free survival was 68%. Eight patients required chemotherapy for recurrent disease or second primary ovarian germ cell tumor. This included three patients with grade II immature teratoma, three patients with dysgerminoma, and two patients with dysgerminoma who developed a contralateral dysgerminoma 4.5 and 5.2 years after their first tumor. All but one, who died of a pulmonary embolus, were successfully salvaged with chemotherapy (82).

More recently, the same group updated its experience and reported on the safety of the ongoing surveillance program of all stage IA female germ cell tumors (83). Thirty-seven patients (median age 26, range 14-48 years) with stage I disease were referred to Mount Vernon and Charing Cross Hospitals between 1981 and 2003. Patients underwent surgery and staging followed by intense surveillance, which included regular tumor markers and imaging. The median period of follow-up was 6 years. Relapse rates for stage IA nondysgerminomatous tumors and dysgerminomas were 8 of 22 (36%) and 2 of 9 (22%), respectively. In addition, one patient with mature teratoma and glial implants also relapsed. Ten of these 11 patients (91%) were successfully cured with platinum-based chemotherapy. Only one patient died from chemoresistant disease. All relapses occurred within 13 months of initial surgery. The overall disease-specific survival of malignant ovarian germ cell tumors was 94%.

More than 50% of patients who underwent fertility-sparing surgery went on to have successful pregnancies. They concluded that surveillance of all stage IA ovarian germ cell tumors is very safe, and that the outcome is comparable with testicular tumors. They questioned the need for potentially toxic adjuvant chemotherapy in patients with nondysgerminomas who have greater than 90% chance of being salvaged with chemotherapy if they relapse.


This strategy is appealing and is supported by a larger pediatric literature, but there is much less experience in adults. It deserves further study, but this will require international collaboration. If a surveillance program is to be instigated, it is essential that the protocols used by the Charing Cross group are closely adhered to and that patients understand that the data for adults are limited.

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, much less information is available for women with ovarian germ cell tumors. The toxicity of BEP chemotherapy has been well documented and includes significant pulmonary toxicity in 5% of patients, with fatal lung toxicity in 1%; acute myeloid leukemia or myelodysplastic syndrome in 0.2% to 1% of patients; neuropathy in 20% to 30%; Raynaud's phenomenon in 20%; tinnitus in 24%; and high-tone hearing loss in as many as 70% of patients. In addition, late effects occur on gonadal function, there is an increased risk of hypertension and cardiovascular disease, and some degree of renal impairmentoccurs in 30% of patients (84,85). These side effects underscore the importance of limiting the number of cycles of chemotherapy and also highlight the need for these patients to be referred to clinicians with experience in managing germ cell tumors.

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(10,16,17,28,29,30,31,32). In one representative series of 47 patients treated with combination chemotherapy for germ cell malignancies, 91.5% of patients resumed normal menstrual function, and there were 14 healthy live births and no birth defects (17). Factors such as older age at initiation of chemotherapy, greater cumulative drug dose, and longer duration of therapy all have adverse effects on future gonadal function (29).

A large study of reproductive and sexual function after platinum-based chemotherapy in ovarian germ cell tumor survivors was recently reported by the GOG, and 132 survivors were included in the study. Interestingly, and quite revealing, was the fact that only 71 (53.8%) had fertility-sparing surgery; of these, 87.3% were still having regular menstrual periods. Twenty-four survivors had 37 offspring after cancer treatment (86).

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 has been implicated in the development of treatment-related leukemias.

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 (87) compared with as much as 5% (representing a 336-fold increased likelihood) in those receiving more than 2,000 mg/m2 (88). 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 have 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 PVB (cisplatin, vinblastine, and bleomycin). The risk-benefit balance for low-risk disease or for high-dose etoposide in the salvage setting is less clear (88).

Sex-Cord-Stromal Tumors

Sex-cord-stromal tumors of the ovary account for approximately 5% to 8% of all ovarian malignancies (1,2,3,4,89,90,91,92,93). 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), as well as morphologically indifferent cells. A classification of this group of tumors is presented in Table 12.4.


Table 12.4 Sex-Cord-Stromal Tumors


Granulosa-stromal cell tumors



Granulosa cell tumor



Tumors in thecoma-fibroma group



(1) Thecoma



(2) Fibroma



(3) Unclassified


Androblastomas; Sertoli-Leydig cell tumors



Well differentiated



(1) Sertoli cell tumor



(2) Sertoli-Leydig cell tumor



(3) Leydig cell tumor; hilus cell tumor



Moderately differentiated



Poorly differentiated (sarcomatoid)



With heterologous elements





Modified and reprinted from Young RE, Scully RE. Ovarian sex cord-stromal tumors: recent progress. Int J Gynecol Pathol 1980;1:153, with permission.

Granulosa-Stromal-Cell Tumors

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

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 distributed throughout the reproductive and postmenopausal years (92,93,94,95). They are bilateral in only 2% of patients.

Of the rare prepubertal lesions, 75% are associated with sexual pseudoprecocity because of the estrogen secretion (93). In the reproductive age group, most patients have menstrual irregularities or secondary amenorrhea, and cystic hyperplasia of the endometrium is frequently present. In postmenopausal women, abnormal uterine bleeding is frequently the presenting symptom. Indeed, the estrogen secretion in these patients can be sufficient to stimulate the development of endometrial cancer. Endometrial cancer occurs in association with granulosa cell tumors in at least 5% of cases, and 25% to 50% are associated with endometrial hyperplasia (1,92,93,94). Rarely, granulosa cell tumors may produce androgens and cause virilization.

The other symptoms and signs of granulosa cell tumors are nonspecific and the same as most ovarian malignancies. Ascites is present in approximately 10% of cases, and rarely a pleural effusion is present (92,93). Granulosa tumors tend to be hemorrhagic; occasionally they rupture and produce a hemoperitoneum.

Granulosa cell tumors are usually stage I at diagnosis but may recur 5 to 30 years after initial diagnosis (91). The tumors may also spread hematogenously, and metastases can develop in the lungs, liver, and brain years after initial diagnosis. When they do recur, they can progress quite rapidly. Malignant thecomas are extremely rare, and their presentation, management, and outcome are similar to those of the granulosa cell tumors (95).


Inhibin is secreted by granulosa cell tumors and is a useful marker for the disease (96,97,98,99). Inhibin is an ovarian product that decreases to nondetectable levels after menopause. However, certain ovarian cancers (mucinous epithelial ovarian carcinomas and granulosa cell tumors) produce inhibin, which may predate clinical disease (100,101,102). An elevated serum inhibin level in a premenopausal woman presenting with amenorrhea and infertility is suggestive of a granulosa cell tumor.

Müllerian inhibitory substance (MIS), which is produced by granulosa cells, is emerging as a potential marker for these tumors (99). An elevated MIS level appears to have high specificity, but the test is not clinically available except for research purposes. An elevated estradiol level is not a sensitive marker of this disease (101).

The histological diagnosis can be facilitated by staining for markers of ovarian granulosa cell tumors (e.g., inhibin, CD99, and MIS) (96,97). Antibodies against inhibin appear to be the most useful, but they are not specific. In one report, positive staining for inhibin was present in 94% of granulosa cell tumors and in 10% to 20% of ovarian endometrioid tumors and metastatic carcinomas to the ovary (99). The latter demonstrated significantly weaker staining.


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, with radiation and chemotherapy reserved for the treatment of recurrent or metastatic disease (92,93,94,95).


Because granulosa cell tumors are bilateral in only some 2% of patients, a unilateral salpingo-oophorectomy is appropriate therapy for stage IA tumors in children or in women of reproductive age (90). At the time of laparotomy, if a granulosa cell tumor is identified by frozen section, then a staging operation is performed, including an assessment of the contralateral ovary. If the opposite ovary appears enlarged, it should be biopsied. In perimenopausal and postmenopausal women for whom ovarian preservation is not important, a hysterectomy and bilateral salpingo-oophorectomy should be performed. In premenopausal patients in whom the uterus is left in situ, a dilatation and curettage of the uterus should be performed because of the possibility of a coexistent adenocarcinoma of the endometrium (92).


There is no evidence to support the use of adjuvant radiation therapy for granulosa cell tumors, although pelvic radiation may help to palliate isolated pelvic recurrences (92). Radiation can induce clinical responses and occasional long-term remission in patients with persistent or recurrent granulosa cell tumors, particularly if the disease is surgically cytoreduced (102,103,104). In one review of 34 patients treated at one center for more than 40 years, 14 were treated with measurable disease (103). Three (21%) were alive without progression 10 to 21 years following treatment.


There is no evidence that adjuvant chemotherapy in patients with stage I disease will prevent recurrence.

Metastatic lesions and recurrences have been treated with a variety of different antineoplastic drugs. There has been no consistently effective regimen in these patients, although complete responses have been reported anecdotally in patients treated with the single agents cyclophosphamide and melphalan, as well as the combinations VAC, PAC (cisplatin, doxorubicin, cyclophosphamide), PVB, BEP (4,105,106,107,108,109,110,111,112,113,114,115,116,117), and, more recently, carboplatin and paclitaxel (102).

The rarity of these tumors has made it impossible to conduct well-designed randomized studies assessing the value of therapy for patients with stages II to IV disease. In retrospective series, postoperative chemotherapy has been associated with a prolonged progression-free interval in women with stage III or IV disease (107), but an overall survival benefit has not been shown (108). Despite the absence of data supporting a survival benefit, some experts recommend postoperative chemotherapy for women with completely resected stage II to IV disease because of the high risk of disease progression and the potential for long-term survival after platinum-based chemotherapy (102,109,110,111,112). Among the acceptable options are BEP, EP, PAC, and carboplatin and paclitaxel (102).

For patients with suboptimally cytoreduced disease, combinations of BEP have produced overall response rates of 58% to 83% (109,114). In one study, 14 of 38 patients (37%) with advanced disease undergoing second-look laparotomy following four courses of BEP had negative findings (109). With a median follow-up of 3 years, 11 of 16 patients (69%) with primary advanced disease and 21of 41 patients (51%) with recurrent disease were progression free. This regimen was associated with severe toxicity and two bleomycin-related deaths. Carboplatin and etoposide (115), PVB (92,116), and PAC (105,117) are other chemotherapeutic regimens with reported relatively high response rates.

There is a need to develop less-toxic and equally active regimens for this older group of patients. Paclitaxel is an active agent, and the combination of platinum with a taxane has been reported to have a response rate of 60%, which makes it a more viable alternative (118,119).

Recurrent Disease

The median time to relapse is approximately 4 to 6 years after initial diagnosis (91,112,113). There is no standard approach to the management of relapsed disease. A common site of recurrence is the pelvis, although the upper abdomen may be involved as well. Further surgery can be effective if the tumor is localized, but diffuse intraabdominal disease is difficult to treat. Chemotherapy or radiation may be useful in selected patients.

Approximately 30% of these tumors have estrogen receptors and 100% have progesterone receptors (120,121). The use of hormonal agents such as progestins or luteinizing hormone-releasing hormone (LHRH) agonists has been suggested as an option, but very limited data are available (101). Small clinical series and case reports have indicated that LHRH agonists had a 50% response rate in 13 patients (121,122,123), whereas four of five patients were reported to respond to a progestational agent (124). Freeman recently reported two patients with recurrent adult granulosa cell tumors who had received multiple treatment modalities, including chemotherapy, and had previously progressed on leuprolide. Both patients were treated with anastrozole. Inhibin B levels normalized, as did clinical findings. Both were maintained on treatment for 14 and 18 months, respectively (125). The numbers are too small to draw any conclusions, and it is likely that there has been significant publication bias, with more reports of responses to treatment.


The prognosis of granulosa cell tumor of the ovary depends on the surgical stage of disease at the time of diagnosis (91,93,102). Most granulosa cell tumors have an indolent growth pattern and are confined to one ovary; the cure rate for stage I disease is 75% to 92% (93,112). However, late recurrences are not uncommon (90,91,93). In one report of 37 women with stage I disease, survival rates at 5, 10, and 20 years were 94%, 82%, and 62%, respectively. The survival rates for stages II to IV at 5 and 10 years were 55% and 34%, respectively (102).

In adult tumors, cellular atypia, mitotic rate, and the absence of Call-Exner bodies are the only significant pathologic predictors of early recurrence (111). Neither an abnormal tumor karyotype nor p53 overexpression appear to be prognostic (126). The DNA ploidy of the tumors has been correlated with survival. Holland and colleagues (106) reported DNA aneuploidy in 13 of 37 patients (35%) with primary granulosa cell tumors. The presence of residual disease was found to be the most important predictor of progression-free survival, but DNA ploidy was an independent prognostic factor. Patients with no residual disease and DNA diploid tumors had a 10-year progression-free survival of 96%.

Juvenile Granulosa Cell Tumors

Juvenile granulosa cell tumors of the ovary are rare and make up less than 5% of ovarian tumors in childhood and adolescence (115). Approximately 90% are diagnosed in stage I and have a favorable prognosis. The juvenile subtype behaves less aggressively than the adult type. Advanced-stage tumors have been successfully treated with platinum-based combination chemotherapy (e.g., BEP) (102).

Sertoli-Leydig Tumors

Sertoli-Leydig tumors occur most frequently in the third and fourth decades, with 75% of the lesions seen in women younger than 40 years. These lesions account for less than 0.2% of ovarian cancers (1). Sertoli-Leydig cell tumors are most frequently low-grade malignancies, although occasionally a poorly differentiated variety may behave more aggressively.

The tumors typically produce androgens, and clinical virilization is noted in 70% to 85% of patients (127,128). Signs of virilization include oligomenorrhea followed by amenorrhea, breast atrophy, acne, hirsutism, clitoromegaly, a deepening voice, and a receding hairline (Fig. 12.6). Measurement of plasma androgens may reveal elevated testosterone and androstenedione, with normal or slightly elevated dehydroepiandrosterone sulfate (1). Rarely, the Sertoli-Leydig tumor can be associated with manifestations of estrogenization (i.e., isosexual precocity, irregular or postmenopausal bleeding) (128).



Figure 12.6 A young woman with a Sertoli-Leydig cell tumor demonstrating temporal baldness.


Because these low-grade lesions are bilateral in less than 1% of cases, the usual treatment is unilateral salpingo-oophorectomy and evaluation of the contralateral ovary in patients who are in their reproductive years (128). In older patients, hysterectomy and bilateral salpingo-oophorectomy are appropriate.

There are limited data regarding the utility of chemotherapy in patients with persistent disease, but responses in patients with measurable disease have been reported with cisplatinin combination with doxorubicin or ifosfamide or both (128) as well as the regimens mentioned above for granulosa cell tumors. Because of their rarity, most series have included them with granulosa cell tumors (110). Pelvic radiation can also be used for recurrent pelvic tumor but with limited responses.


The 5-year survival rate is 70% to 90%, and recurrences thereafter are uncommon (1,2,128). Poorly differentiated lesions compose the majority of fatalities.

Uncommon Ovarian Cancers

There are several varieties of malignant ovarian tumors, which together constitute only 0.1% of ovarian malignancies. These lesions include lipoid (or lipid) cell tumors, primary ovarian sarcomas, and small cell ovarian carcinomas.

Lipoid Cell Tumors

Lipoid cell tumors are thought to arise in adrenal cortical rests that reside in the vicinity of the ovary. More than 100 cases have been reported, and bilaterality has been noted in only a few (1). Most are associated with virilization and occasionally with obesity, hypertension, and glucose intolerance, reflecting glucocorticoid secretion. Rare cases of estrogen secretion and isosexual precocity have been reported.

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


Malignant mixed mesodermal sarcomas of the ovary are extremely rare (129,130,131,132,133,134,135). Most lesions are heterologous, and 80% occur in postmenopausal women. The presentation is similar to that of most ovarian malignancies. These lesions are biologically aggressive, and the majority of patients have evidence of metastases.

Such patients should be treated by cytoreductive surgery and postoperative platinum-containing combination chemotherapy (134,135). Silasi et al. recently reported their experience with 22 patients from Yale, all but two of whom presented with advanced-stage disease (136). The median survival for the entire cohort was 38 months. The median survival was 46 months for 18 optimally debulked (<1 cm) patients and 27 months for four suboptimally debulked (>1 cm) patients. Six patients were treated with optimal cytoreduction and adjuvant cisplatin and ifosfamide; they had a median progression-free interval of 13 months and median survival of 51 months. The combination of carboplatinand paclitaxel was administered to four patients following optimal cytoreduction; their median progression-free interval was 6 months, and median survival was 38 months. The difference in survival between the cisplatin and ifosfamide group and the carboplatin and paclitaxel group was not statistically significant (p = 0.48). First-line cisplatin andifosfamide or carboplatin and paclitaxel can achieve survival rates comparable to those observed in epithelial ovarian cancer.

Leiser et al. reported the Memorial Sloan-Kettering experience with platinum and paclitaxel in 30 patients with carcinosarcomas of the ovary, and they also found it was very active (137). Twelve patients (40%) had a complete response, seven (23%) a partial response, two (7%) stable disease, and nine (30%) progression of disease. The median time to progression for responders was 12 months; with a median follow-up of 23 months, the median overall survival was 43 months for survivors. The 3- and 5-year survival rates were 53% and 30%, respectively.

Small Cell Carcinomas

This rare tumor occurs at an average age of 24 years (range 2 to 46 years) (138). The tumors are all bilateral. Approximately two-thirds of the tumors are accompanied by paraneoplastic hypercalcemia. This tumor accounts for one-half of all of the cases of hypercalcemia associated with ovarian tumors. Approximately 50% of the tumors have spread beyond the ovaries at the time of diagnosis (1,2).

Management consists of surgery followed by platinum-based chemotherapy or radiation therapy. In addition to the primary treatment of the disease, control of the hypercalcemia may require aggressive hydration, loop diuretics, and the use of bisphosphonates. There have been a number of recent reports on the treatment of patients with small cell carcinoma of the ovary. In a collaborative Gynecologic Cancer Intergroup study, data were collected for 17 patients treated in Australia, Canada, and Europe (139). The median follow-up was 13 months for all patients and 35.5 months for surviving patients. Ten patients had FIGO stage I tumors, six stage III tumors, and one stage unknown. All underwent surgical resection. Adjuvant platinum-based chemotherapy was given to all patients. Seven received adjuvant pelvic, whole-abdominal or extended-field radiation. The median survival for stage I tumors was not reached, whereas it was 6 months for stage III tumors. For the ten patients with stage I tumors, six received adjuvant radiotherapy, with five alive and disease-free; four received no adjuvant radiotherapy, with one alive and disease-free; and three have relapsed, with one alive and disease-free after resection. Of the seven patients with stage III or unknown stage tumors, all but one have died. Recurrences were most frequent in the pelvis and the abdomen. Patients receiving salvage treatment with chemotherapy and radiotherapy did poorly.

Although the optimal approach to management is not known, in view of these findings we advocate a multimodality treatment approach including surgical resection of gross disease, chemotherapy with carboplatin and paclitaxel or cisplatin and ifosfamide, and the addition of radiotherapy either sequentially or concurrently. Others have advocated high-dose chemotherapy with stem cell support and have reported a number of long-term survivors (140).

Metastatic Tumors

Approximately 5% to 6% of ovarian tumors are metastatic from other organs, most frequently from the female genital tract, the breast, or the gastrointestinal tract(141,142,143,144,145,146,147,148,149,150,151,152,153,154,155). The metastases may occur from direct extension of another pelvic neoplasm, by hematogenous spread, by lymphatic spread, or from 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 (1), usually by direct extension. Under some circumstances, it is difficult to know whether the tumor originates 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. Although adenocarcinoma of the endometrium can spread and implant directly onto the surface of the ovaries in as many as 5% of cases, two synchronous primary tumors probably occur with greater frequency. In these cases, an endometrioid carcinoma of the ovary is usually associated with the adenocarcinoma of the endometrium (156).


The frequency of metastatic breast carcinoma to the ovaries varies according to the method of determination, but the phenomenon is common. In autopsy data of women who die of metastatic breast cancer, the ovaries are involved in 24% of cases, and 80% of the involvement is bilateral (141,142,143,144,145,146,147). Similarly, when ovaries are removed to palliate advanced breast cancer, approximately 20% to 30% of the cases reveal ovarian involvement, 60% bilaterally. The involvement of ovaries in early stage breast cancer appears 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(148,149). The primary tumor is most frequently the stomach (Fig. 12.7) but less commonly the colon, breast, or biliary tract. Rarely, the cervix or the bladder may be the primary site. Krukenberg tumors can account for approximately 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 a year. In some cases, a primary tumor is never found.

Other Gastrointestinal

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 small intestine. One percent to 2% of women with intestinal carcinomas will develop metastases to the ovaries during the course of their disease(143,150,151). Before exploration for an adnexal tumor in a woman more than 40 years of age, a colonoscopy or gastroscopy is indicated to exclude a primary gastrointestinal carcinoma with metastases to the ovaries, 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 (150,151,152,153,154). Lesions that arise in the appendix may be associated with ovarian metastasis and have frequently been confused with primary ovarian malignancies, especially when associated with pseudomyxoma peritonei (150,154) (see Chapters 5 and 11). Therefore, it is reasonable to consider the performance of prophylactic bilateral salpingo-oophorectomy at the time of surgery for women with colon cancer (155).



Figure 12.7 Bilateral Krukenberg tumors from a primary stomach cancer.


Rare cases of malignant melanoma metastatic to the ovaries have been reported (157). These must be distinguished from the rare case of a melanoma arising in an ovarian teratoma (158). In these circumstances, the melanomas are usually widely disseminated. Removal would be warranted for palliation of abdominal or pelvic pain, bleeding, or torsion.


Metastatic carcinoid tumors are rare, representing fewer than 2% of metastatic lesions to the ovaries (159). Conversely, only some 2% of primary carcinoids have evidence of ovarian metastasis, and only 40% of these patients have the carcinoid syndrome at the time of discovery of the metastatic carcinoid (160). However, in perimenopausal and postmenopausal women explored for an intestinal carcinoid, it is reasonable to remove the ovaries to prevent subsequent ovarian metastasis. Furthermore, the discovery of an ovarian carcinoid should prompt a careful search for a primary intestinal lesion.

Lymphoma and Leukemia

Lymphomas and leukemia can involve the ovary. When they do, the involvement is usually bilateral (161,162,163). Approximately 5% of patients with Hodgkin's disease will have lymphomatous involvement of the ovaries, but this occurs typically with advanced-stage disease. With Burkitt's lymphoma, ovarian involvement is very common. Other types of lymphoma involve the ovaries much less frequently, and leukemic infiltration of the ovaries is uncommon.

Sometimes the ovaries can be the only apparent site of involvement of the abdominal or pelvic viscera with a lymphoma; if this circumstance is found, a careful surgical exploration may be necessary. An intraoperative consultation with a hematologist-oncologist should be obtained to determine the need for such procedures if frozen section of a solid ovarian mass reveals a lymphoma. In general, most lymphomas no longer require extensive surgical staging, although enlarged lymph nodes should generally be biopsied. In some cases of Hodgkin's disease, a more extensive evaluation may be necessary. Treatment involves that of the lymphoma or leukemia in general. Removal of a large ovarian mass may improve patient comfort and facilitate a response to subsequent radiation or chemotherapy (163).



  1. Scully RE, Young RH, Clement RB. Tumors of the ovary, maldeveloped gonads, fallopian tube, and broad ligament. In: Atlas of tumor pathology: 3rd series, Fascicle 23. Washington, DC: Armed Forces Institute of Pathology, 1998:169-498.
  2. Chen LM, Berek JS. Ovarian and fallopian tubes. In: Haskell CM, ed. Cancer treatment, 5th ed. Philadelphia: WB Saunders, 2000:900-932.
  3. Imai A, Furui T, Tamaya T. Gynecologic tumors and symptoms in childhood and adolescence: 10-years' experience. Int J Gynaecol Obstet 1994;45:227-234.
  4. Gershenson DM. Management of early ovarian cancer: germ cell and sex-cord stromal tumors. Gynecol Oncol 1994;55:S62-S72.
  5. Gershenson DM. Update on malignant ovarian germ cell tumors. Cancer 1993;71:1581-1590.
  6. Krege S, Beyer J, Souchon R, Albers P, Albrecht W, Algaba F, et al. European Consensus Conference on Diagnosis and Treatment of Germ Cell Cancer: A Report of the Second Meeting of the European Germ Cell Cancer Consensus group (EGCCCG): Part I. Eur Urol 2008 Mar;53:478-496.
  7. Krege S, Beyer J, Souchon R, Albers P, Albrecht W, Algaba F, et al. European Consensus Conference on Diagnosis and Treatment of Germ Cell Cancer: A Report of the Second Meeting of the European Germ Cell Cancer Consensus Group (EGCCCG): Part II. Eur Urol 2008 Mar;53:497-513.
  8. Murugaesu N, Schmid P, Dancey G, Agarwal R, Holden L, McNeish I, et al. Malignant ovarian germ cell tumors: identification of novel prognostic markers and long-term outcome after multimodality treatment. J Clin Oncol 2006 Oct 20;24:4862-4866.
  9. Kurman RJ, Scardino PT, Waldmann TA, Javadpour N, Norris HJ. Malignant germ cell tumors of the ovary and testis: an immunohistologic study of 69 cases. Ann Clin Lab Sci1979;9:462-466.
  10. Obata NH, Nakashima N, Kawai M, Nikkawa F, Mamba S, Tomoda Y. Gonadoblastoma with dysgerminoma in one ovary and gonadoblastoma with dysgerminoma and yolk sac tumor in the contralateral ovary in a girl with 46XX karyotype. Gynecol Oncol 1995;58:124-128.
  11. Spanos WJ. Preoperative hormonal therapy of cystic adnexal masses. Am J Obstet Gynecol 1973;116:551-556.
  12. Bremer GL, Land JA, Tiebosch A, Van Der Putten HW. Five different histologic subtypes of germ cell malignancies in an XY female. Gynecol Oncol 1993;50:247-248.
  13. Mayordomo JI, Paz-Ares L, Rivera F, López-Brea M, López Martain E, Mendiola C, et al. Ovarian and extragonadal malignant germ-cell tumors in females: a single-institution experience with 43 patients. Ann Oncol 1994;5:225-231.
  14. Piura B, Dgani R, Zalel Y, Nemet D, Yanai-Inbar I, Cohen Y, Glezerman M. Malignant germ cell tumors of the ovary: a study of 20 cases. J Surg Oncol 1995;59:155-161.
  15. Gordon A, Lipton D, Woodruff JD. Dysgerminoma: a review of 158 cases from the Emil Novak Ovarian Tumor Registry. Obstet Gynecol 1981;58:497-504.
  16. Thomas GM, Dembo AJ, Hacker NF, DePetrillo AD. Current therapy for dysgerminoma of the ovary. Obstet Gynecol 1987;70: 268-275.
  17. Low JJ, Perrin LC, Crandon AJ, Hacker NF. Conservative surgery to preserve ovarian function in patients with malignant ovarian germ cell tumors: a review of 74 cases. Cancer2000;89:391-398.
  18. Williams SD, Birch R, Einhorn LH, Irwin L, Greco FA, Loehrer PJ. Treatment of disseminated germ cell tumors with cisplatin, bleomycin and either vinblastine or etoposide. N Engl J Med 1987; 316:1435-1440.
  19. Williams SD, Blessing JA, Hatch K, Homesley HD. Chemotherapy of advanced ovarian dysgerminoma: trials of the Gynecologic Oncology Group. J Clin Oncol 1991;9:1950-1955.
  20. Williams SD, Blessing JA, Moore DH, Homesley HD, Adcock L. Cisplatin, vinblastine, and bleomycin in advanced and recurrent ovarian germ-cell tumors. Ann Intern Med1989;111:22-27.
  21. Williams SD, Blessing JA, Liao S, Ball HJ 3rd, Hanjani P. Adjuvant therapy of ovarian germ cell tumors with cisplatin, etoposide, and bleomycin: a trial of the Gynecologic Oncology Group. J Clin Oncol 1994;12:701-706.
  22. Gershenson DM, Morris M, Cangir A, Kavanagh JJ, Stringer CA, Edwards CL, et al. Treatment of malignant germ cell tumors of the ovary with bleomycin, etoposide, and cisplatin. J Clin Oncol 1990;8:715-720.
  23. Bekaii-Saab T, Einhorn LH, Williams SD. Late relapse of ovarian dysgerminoma: case report and literature review. Gynecol Oncol 1999;72:111-112.
  24. Kurtz JE, Jaeck D, Maloisel F, Jung GM, Chenard MP, Dufour P. Combined modality treatment for malignant transformation of a benign ovarian teratoma. Gynecol Oncol1999;73:319-321.
  25. Williams SD. Ovarian germ cell tumors: an update. Semin Oncol 1998;25:407.
  26. Pawinski A, Favalli G, Ploch E, Sahmoud T, van Oosterom AT, Pecorelli S. PVB chemotherapy in patients with recurrent or advanced dysgerminoma: a phase II study of the EORTC Gynaecological Cancer Cooperative Group. Clin Oncol (R Coll Radiol) 1998;10:301-305.
  27. Brewer M, Gershenson DM, Herzog CE, Mitchell MF, Silva EC, Wharton JT. Outcome and reproductive function after chemotherapy for ovarian dysgerminoma. J Clin Oncol1999;17:2670-2675.
  28. Gershenson DM. Menstrual and reproductive function after treatment with combination chemotherapy for malignant ovarian germ cell tumors. J Clin Oncol 1988;6:270-275.
  29. Kanazawa K, Suzuki T, Sakumoto K. Treatment of malignant ovarian germ cell tumors with preservation of fertility: reproductive performance after persistent remission. Am J Clin Oncol 2000;23: 244-248.
  30. El-Lamie IK, Shehata NA, Abou-Loz SK, El-Lamie KI. Conservative surgical management of malignant ovarian germ cell tumors: the experience of the Gynecologic Oncology Unit at Ain Shams University. Eur J Gynaecol Oncol 2000;21:605-609.
  31. Tangir J, Zelterman D, Ma W, Schwartz PE. Reproductive function after conservative surgery and chemotherapy for malignant germ cell tumors of the ovary. Obstet Gynecol2003;101:251-257.
  32. Loehrer PJ, Johnson D, Elson P, Einhorn LH, Trump D. Importance of bleomycin in favorable-prognosis disseminated germ cell tumors: an Eastern Cooperative Oncology Group trial. J Clin Oncol 1995;13:470-476.
  33. Bajorin DF, Sarosdy MF, Pfister GD, Mazumdar M, Motzer RJ, Scher HI. Randomized trial of etoposide and cisplatin versus etoposide and carboplatin in patients with good-risk germ cell tumors: a multi-institutional study. J Clin Oncol 1993;11:598-606.
  34. Schwartz PE, Chambers SK, Chambers JT, Kohorn E, McIntosh S. Ovarian germ cell malignancies: the Yale University experience. Gynecol Oncol 1992;45:26-31.
  35. Williams SD, Blessing JA, DiSaia PJ, Major FJ, Ball HG 3rd, Liao SY. Second-look laparotomy in ovarian germ cell tumors. Gynecol Oncol 1994;52:287-291.
  36. Culine S, Lhomme C, Michel G, Leclere J, Duvillard P, Droz JP. Is there a role for second-look laparotomy in the management of malignant germ cell tumors of the ovary? Experience at Institute Gustave Roussy. J Surg Oncol 1996;62:40-45.
  37. De Santis M, Bokemeyer C, Becherer A, Stoiber F, Oechsle K, Kletter K, et al. Predictive impact of 2-18fluoro-2-deoxy-D-glucose positron emission tomography for residual postchemotherapy masses in patients with bulky seminoma. J Clin Oncol. 2001;1:19: 3740-3744.
  38. Motzer RJ, Sheinfeld J, Mazumdar M, Bains M, Mariani T, Bacik J, et al. Paclitaxel, ifosfamide, and cisplatin second-line therapy for patients with relapsed testicular germ cell cancer. J Clin Oncol 2000;18:2413-8.
  39. Kumar S, Shah JP, Bryant CS, Imudia AN, Cote ML, Ali-fehmi R et al. The prevalence and prognostic impact of lymph node metastases in malignant germ cell tumors of the ovary.Gynecol Oncol 2008;110:125-132.
  40. O'Conner DM, Norris HJ. The influence of grade on the outcome of stage I ovarian immature (malignant) teratomas and the reproducibility of grading. Int J Gynecol Pathol1994;13:283-289.
  41. Norris HJ, Zirkin HJ, Benson WL. Immature (malignant) teratoma of the ovary: a clinical and pathologic study of 58 cases. Cancer 1976;37:2359-2372.


  1. Ulbright, TM. Germ cell tumors of the gonads: a selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues. A review. Mod Pathol 2005;18 Suppl 2:S61-S79.
  2. Heifetz SA, Cushing B, Giller R, Shuster JJ, Stolar CJ, Vinocur CD, et al. Immature teratomas in children: pathologic considerations: a report from the combined Pediatric Oncology Group/Children's Cancer Group. Am J Surg Pathol 1998;22:1115-1124.
  3. Marina NM, Cushing B, Giller R, Cohen L, Lauer SJ, Ablin A, et al. Complete surgical excision is effective treatment for children with immature teratomas with or without malignant elements: A Pediatric Oncology Group/Children's Cancer Group Intergroup Study. J Clin Oncol 1999; 17:2137-2143.
  4. Ferguson AW, Katabuchi H, Ronnett BM, Cho KR. Glial implants in gliomatosis peritonei arise from normal tissue, not from the associated teratoma. Am J Pathol 2001 Jul;159:51-55.
  5. Best DH, Butz GM, Moller K, Coleman WB, Thomas DB. Molecular analysis of an immature ovarian teratoma with gliomatosis peritonei and recurrence suggests genetic independence of multiple tumors. Int J Oncol 2004;25:17-25.
  6. Dimopoulos MA, Papadopoulou M, Andreopoulou E, Papadimitriou C, Pavlidis N, Aravantinos G, et al. Favorable outcome of ovarian germ cell malignancies treated with cisplatinor carboplatin-based chemotherapy: a Hellenic Cooperative Oncology Group study. Gynecol Oncol 1998;70:70-74.
  7. Bafna UD, Umadevi K, Kumaran C, Nagarathna DS, Shashikala P, Tanseem R. Germ cell tumors of the ovary: is there a role for aggressive cytoreductive surgery for nondysgerminomatous tumors? Int J Gynecol Cancer 2001;11:300-304.
  8. De Palo G, Zambetli M, Pilotti S, Rottoli L, Spatti G, Fontanelli R, et al. Non-dysgerminomatous tumors of the ovary treated with cisplatin, vinblastine, and bleomycin: long-term results. Gynecol Oncol 1992;47:239-246.
  9. Culine S, Kattan J, Lhomme C, Duvillard P, Michel G, Castaigne D, et al. A phase II study of high-dose cisplatin, vinblastine, bleomycin, and etoposide (PVeBV regimen) in malignant nondysgerminomatous germ-cell tumors of the ovary. Gynecol Oncol 1994;54:47-53.
  10. Mann JR, Raafat F, Robinson K, Imeson J, Gornell P, Sokal M, et al. The United Kingdom Children's Cancer Study Group's second germ cell tumor study: carboplatin, etoposide,and bleomycin are effective treatment for children with malignant extracranial germ cell tumors, with acceptable toxicity. J Clin Oncol 2000;18: 3809-3818.
  11. Segelov E, Campbell J, Ng M, Tattersall M, Rome R, Free K, et al. Cisplatin-based chemotherapy for ovarian germ cell malignancies: the Australian experience. J Clin Oncol1994;12:378-384.
  12. Marina NM, Cushing B, Giller R, Cohen L, Lauer SJ, Ablin A, et al. Complete surgical excision is effective treatment for children with immature teratomas with or without malignant elements: a Pediatric Oncology Group/Children's Cancer Group Intergroup Study. J Clin Oncol 1999;17:2137-2143.
  13. Bonazzi C, Peccatori F, Colombo N, Lucchini V, Cantu MG, Mangioni C. Pure ovarian immature teratoma, a unique and curable disease: 10 years' experience of 32 prospectively treated patients. Obstet Gynecol 1994;84:598-604.
  14. Cangir A, Smith J, van Eys J. Improved prognosis in children with ovarian cancers following modified VAC (vincristine sulfate, dactinomycin, and cyclophosphamide) chemotherapy. Cancer 1978;42: 1234-1238.
  15. Chapman DC, Grover R, Schwartz PE. Conservative management of an ovarian polyembryoma. Obstet Gynecol 1994;83:879-882.
  16. Slayton RE, Park RC, Silverberg SC, Shingleton H, Creasman WT, Blessing JA. Vincristine, dactinomycin, and cyclophosphamide in the treatment of malignant germ cell tumors of the ovary: a Gynecologic Oncology Group study (a final report). Cancer 1985;56:243-248.
  17. Creasman WJ, Soper JT. Assessment of the contemporary management of germ cell malignancies of the ovary. Am J Obstet Gynecol 1985;153:828-834.
  18. Taylor MH, DePetrillo AD, Turner AR. Vinblastine, bleomycin, and cisplatin in malignant germ cell tumors of the ovary. Cancer 1985;56:1341-1349.
  19. Culine S, Lhomme C, Kattan J, Michel G, Duvillard P, Droz JP. Cisplatin-based chemotherapy in the management of germ cell tumors of the ovary: the Institute Gustave Roussy experience. Gynecol Oncol 1997;64:160-165.
  20. Williams SD, Wong LC, Ngan HYS. Management of ovarian germ cell tumors. In: Gershenson DM, McGuire WP, eds. Ovarian cancer. New York: Churchill-Livingstone, 1998:399-415.
  21. Bokemeyer C, Köhrmann O, Tischler J, Weissbach L, Räth U, Haupt A, et al. Schmoll HJA randomized trial of cisplatin, etoposide, and bleomycin (PEB) versus carboplatin, etoposide, and bleomycin (CEB) for patients with “good-risk” metastatic non-seminomatous germ cell tumors. Ann Oncol 1996;7:1015-1021.
  22. Horwich A, Sleijfer DT, Fosså SD, Kaye SB, Oliver RT, Cullen MH, et al. Randomized trial of bleomycin, etoposide, and cisplatin compared with bleomycin, etoposide, andcarboplatin in good-prognosis metastatic nonseminomatous germ cell cancer: a Multiinstitutional Medical Research Council/European Organization for Research and Treatment of Cancer Trial. J Clin Oncol 1997;15:1844-1852.
  23. Hariprasad R, Kumar L, Janga D, Kumar S, Vijayaraghavan M. Growing teratoma syndrome of ovary. Int J Clin Oncol 2008;13:83-87.
  24. Tangjitgamol S, Manusirivithaya S, Leelahakorn S, Thawaramara T, Suekwatana P, Sheanakul C. The growing teratoma syndrome: a case report and a review of the literature. Int J Gynecol Cancer 2006;16 Suppl 1:384-390.
  25. Carver BS, Shayegan B, Serio A, Motzer RJ, Bosl GJ, Sheinfeld J. Long-term clinical outcome after postchemotherapy retroperitoneal lymph node dissection in men with residual teratoma. J Clin Oncol 2007;25:1033-1037.
  26. Mathew GK, Singh SS, Swaminathan RG, Tenali SG. Laparotomy for post chemotherapy residue in ovarian germ cell tumors. J Postgrad Med 2006;52:262-265.
  27. Lai CH, Chang TC, Hsueh S, Wu TI, Chao A, Chou HH, et al. Outcome and prognostic factors in ovarian germ cell malignancies. Gynecol Oncol 2005 Mar;96:784-791.
  28. Talerman A. Germ cell tumors of the ovary. Curr Opin Obstet Gynecol 1997;9:44-47.
  29. Kleiman GM, Young RH, Scully RE. Primary neuroectodermal tumors of the ovary: a report of 25 cases. Am J Surg Pathol 1993; 17:764-778.
  30. Sasaki H, Furusata M, Teshima S, Kiyokawa T, Tada A, Aizawa S, et al. Prognostic significance of histopathological subtypes in stage I pure yolk sac tumour of the ovary. Br J Cancer 1994;69:529-536.
  31. Fujita M, Inoue M, Tanizawa O, Miagawa J, Yamada T, Tani T. Retrospective review of 41 patients with endodermal sinus tumor of the ovary. Int J Gynecol Cancer 1993;3:329-335.
  32. Kawai M, Kano T, Kikkawa F, Morikawa Y, Oguchi H, Nakashima N, et al. Seven tumor markers in benign and malignant germ cell tumors of the ovary. Gynecol Oncol 1992;45:248-253.
  33. Abu-Rustum NR, Aghajanian C. Management of malignant germ cell tumors of the ovary. Semin Oncol 1998;25:235-242.
  34. Newlands ES, Southall PJ, Paradinas FJ, Holden L. Management of ovarian germ cell tumours. In: Williams CJ, Krikorian JG, Green MR, Ragavan D, eds. Textbook of uncommon cancer. New York: John Wiley & Sons, 1988:37-53.
  35. Ueda G, Abe Y, Yoshida M, Fujiwara T. Embryonal carcinoma of the ovary: a six-year survival. Gynecol Oncol 1990;31:287-292.
  36. Kammerer-Doak D, Baurick K, Black W, Barbo DM, Smith HO. Endodermal sinus tumor and embryonal carcinoma of the ovary in a 53-year-old woman. Gynecol Oncol 1996;63:133-137.
  37. Tay SK, Tan LK. Experience of a 2-day BEP regimen in postsurgical adjuvant chemotherapy of ovarian germ cell tumors. Int J Gynecol Cancer 2000;10:13-18.
  38. Simosek T, Trak B, Thnoc M, Karaveli S, Uner M, Seonmez C. Primary pure choriocarcinoma of the ovary in reproductive ages: a case report. Eur J Gynaecol Oncol 1998;19:284-286.
  39. Oliva E, Andrada E, Pezzica E, Prat J. Ovarian carcinomas with choriocarcinomatous differentiation. Cancer 1993;72:2441-2446.
  40. Cushing B, Giller R, Ablin A, Cohen L, Cullen J, Hawkins E, et al. Surgical resection alone is effective treatment for ovarian immature teratoma in children and adolescents: a report of the Pediatric Oncology Group and the Children's Cancer Group. Am J Obstet Gynecol 1999;181:353-358.


  1. Dark GG, Bower M, Newlands ES, Paradinas F, Rustin G. Surveillance policy for stage I ovarian germ cell tumors. J Clin Oncol 1997;15:620-624.
  2. Patterson DM, Murugaesu N, Holden L, Seckl MJ, Rustin GJ. A review of the close surveillance policy for stage I female germ cell tumors of the ovary and other sites. Int J Gynecol Cancer 2008;18:43-50.
  3. Efstathiou E, Logothetis CJ. Review of late complications of treatment and late relapse in testicular cancer. J Natl Compr Canc Netw 2006;4:1059-1070.
  4. Chaudhary UB, Haldas JR. Long-term complications of chemotherapy for germ cell tumours. Drugs 2003;63:1565-1577.
  5. Gershenson DM, Miller AM, Champion VL, Monahan PO, Zhao Q, Cella D, et al., for the Gynecologic Oncology Group. Reproductive and sexual function after platinum-based chemotherapy in long-term ovarian germ cell tumor survivors: a Gynecologic Oncology Group Study. J Clin Oncol 2007;25:2792-2797.
  6. Schneider DT, Hilgenfeld E, Schwabe D, Behnisch W, Zoubek A, Wessalowski R, et al. Acute myelogenous leukemia after treatment for malignant germ cell tumors in children. J Clin Oncol 1999;17:3226-3233.
  7. Kollmannsberger C, Beyer J, Droz JP, Harstrick A, Hartmann JT, Biron P, et al. Secondary leukemia following high cumulative doses of etoposide in patients treated for advanced germ cell tumors. J Clin Oncol 1998;16:3386-3391.
  8. Young RE, Scully RE. Ovarian sex cord-stromal tumors: problems in differential diagnosis. Ann Pathol 1988;23:237-296.
  9. Miller BE, Barron BA, Wan JY, Delmore JE, Silva EG, Gershenson DM. Prognostic factors in adult granulosa cell tumor of the ovary. Cancer 1997;79:1951-1955.
  10. Malmström H, Högberg T, Risberg B, Simonsen E. Granulosa cell tumors of the ovary: prognostic factors and outcome. Gynecol Oncol 1994;52:50-55.
  11. Segal R, DePetrillo AD, Thomas G. Clinical review of adult granulosa cell tumors of the ovary. Gynecol Oncol 1995;56:338-344.
  12. Cronje HS, Niemand I, Barn, RH, Woodruff JD. Review of the granulosa-theca cell tumors from the Emil Novak ovarian tumor registry. Am J Obstet Gynecol 1999;180:323-328.
  13. Aboud E. A review of granulosa cell tumours and thecomas of the ovary. Arch Gynecol Obstet 1997;259:161-165.
  14. Young R, Clement PB, Scully RE. The ovary. In: Sternberg SS, ed. Diagnostic surgical pathology. New York: Raven Press, 1989:1687.
  15. Lappohn RE, Burger HG, Bouma J, Bangah M, Krans M, de Bruijn HW. Inhibin as a marker for granulosa-cell tumors. N Engl J Med 1989;321:790-793.
  16. Hildebrandt RH, Rouse RV, Longacre TA. Value of inhibin in the identification of granulosa cell tumors of the ovary. Hum Pathol 1997;28:1387-1395.
  17. Richi M, Howard LN, Bratthauae GL, Tavassoli FA. Use of monoclonoal antibody against human inhibin as a marker for sex-cord-stromal tumors of the ovary. Am J Surg Pathol1997:21:583-589.
  18. Matias-Guiu X, Pons C, Prat J. Müllerian inhibiting substance, alpha-inhibin, and CD99 expression in sex cord-stromal tumors and endometrioid ovarian carcinomas resembling sex cord-stromal tumors. Hum Pathol 1998;29:840-845.
  19. McCluggage WG. Recent advances in immunohistochemistry in the diagnosis of ovarian neoplasms. J Clin Pathol 2000;53:327-334.
  20. Rey RA, Lhomme C, Marcillac I, Lahlou N, Duvillard P, Josso N, et al. Antimüllerian hormone as a serum marker of granulosa cell tumors of the ovary: comparative study with serum alpha-inhibin and estradiol. Am J Obstet Gynecol 1996;174:958-965.
  21. Schumer ST, Cannistra SA. Granulosa cell tumor of the ovary. J Clin Oncol 2003;21:1180-1189.
  22. Wolf JK, Mullen J, Eifel PJ, Burke TW, Levenback C, Gershenson DM. Radiation treatment of advanced or recurrent granulosa cell tumor of the ovary. Gynecol Oncol1999;73:35-41.
  23. Savage P, Constenla D, Fisher C, Shepherd JH, Barton DP, Blake P, et al. Granulosa cell tumours of the ovary: demographics, survival and the management of advanced disease.Clin Oncol (R Coll Radiol) 1998;10:242-245.
  24. Gershenson DM, Copeland IA, Kavanagh JJ, Stringer CA, Saul PB, Wharton JT. Treatment of metastatic stromal tumors of the ovary with cisplatin, doxorubicin, andcyclophosphamide. Obstet Gynecol 1987;5:765-769.
  25. Holland DR, Le Riche J, Swenerton KD, Elit L, Spinelli J. Flow cytometric assessment of DNA ploidy is a useful prognostic factor for patients with granulosa cell ovarian tumors.Int J Gynecol Cancer 1991;1:227-232.
  26. Uygun K, Aydiner A, Saip P, Kocak Z, Basaran M, Dincer M, et al. Clinical parameters and treatment results in recurrent granulosa cell tumor of the ovary. Gynecol Oncol2003;88:400-403.
  27. Al-Badawi IA, Brasher PM, Ghatage P, Nation JG, Schepansky A, Stuart GC. Postoperative chemotherapy in advanced ovarian granulosa cell tumors. Int J Gynecol Cancer2002;12:119-123.
  28. Homesley HD, Bundy BN, Hurteau JA, Roth LM. Bleomycin, etoposide, and cisplatin combination therapy of ovarian granulosa cell tumors and other stromal malignancies: a Gynecologic Oncology Group study. Gynecol Oncol 1999;72:131-137.
  29. Colombo N, Sessa C, Landoni F, Sartori E, Pecorelli S, Mangioni C. Cisplatin, vinblastine, and bleomycin combination chemotherapy in metastatic granulosa cell tumor of the ovary. Obstet Gynecol 1986;67:265-268.
  30. Zambetti M, Escobedo A, Pilotti S, De Palo G. Cis-platinum/vinblastine/bleomycin combination chemotherapy in advanced or recurrent granulosa cell tumors of the ovary.Gynecol Oncol 1990; 36:317-320.
  31. Lauszus FF, Petersen,AC, Greisen J, Jakobsen A. Granulosa cell tumor of the ovary: a population-based study of 37 women with stage I disease. Gynecol Oncol 2001;81:456-460.
  32. Miller BE, Barron BA, Wan JY, Delmore JE, Silva EG, Gershenson DM. Prognostic factors in adult granulosa cell tumor of the ovary. Cancer 1997;79:1951-1955.
  33. Gershenson DM, Morris M, Burke TW, Levenback C, Matthews CM, Wharton JT. Treatment of poor-prognosis sex cord-stromal tumors of the ovary with the combination ofbleomycin, etoposide, and cisplatin. Obstet Gynecol 1996;87:527-531.
  34. Powell JL, Otis CN. Management of advanced juvenile granulosa cell tumor of the ovary. Gynecol Oncol 1997;64:282-284.
  35. Pecorelli S, Wagenaar HC, Vergote IB, Curran D, Beex LV, Wiltshaw E, et al. Cisplatin (P), vinblastine (V), and bleomycin (B) combination chemotherapy in recurrent or advanced granulosa(-theca) cell tumours of the ovary. An EORTC Gynaecological Cancer Cooperative Group study. Eur J Cancer 1999;35:1331-1337.
  36. Muntz HG, Goff BA, Fuller AF Jr. Recurrent ovarian granulosa cell tumor: role of combination chemotherapy with report of a long-term response to a cyclophosphamide, doxorubicin, and cisplatin regimen. Eur J Gynaecol Oncol 1990;11:263-268.
  37. Tresukosol D, Kudelka AP, Edwards CL, Charnsangavej C, Narboni N, Kavanagh JJ. Recurrent ovarian granulosa cell tumor: a case report of a dramatic response to Taxol. Int J Gynecol Cancer 1995;5:156-159.
  38. Brown J, Shvartsman HS, Deavers MT, Ramondetta LM, Burke TW, Munsell MF, et al. The activity of taxanes compared with bleomycin, etoposide, and cisplatin in the treatment of sex cord-stromal ovarian tumors. Gynecol Oncol 2005;97:489-496.
  39. Hardy RD, Bell JG, Nicely CJ, Reid GC. Hormonal treatment of a recurrent granulosa cell tumor of the ovary: case report and review of the literature. Gynecol Oncol2005;96:865-869.
  40. Emons G, Schally AV. The use of luteinizing hormone releasing hormone agonists and antagonists in gynaecological cancers. Hum Reprod 1994;9:1364-1379.
  41. Martikainen H, Penttinen J, Huhtaniemi I, Kauppila A. Gonadotropin-releasing hormone agonist analog therapy effective in ovarian granulosa cell malignancy. Gynecol Oncol1989;35:406.
  42. Fishman A, Kudelka. AP, Tresukosol D, Edwards CL, Freedman RS, Kaplan AL, et al. Leuprolide acetate for treating refractory or persistent ovarian granulosa cell tumor. J Reprod Med 1996;41:393-396.
  43. Briasoulis E, Karavasilis V, Pavlidis N. Megestrol activity in recurrent adult type granulosa cell tumour of the ovary. Ann Oncol 1997;8:811-812.
  44. Freeman SA, Modesitt SC. Anastrozole therapy in recurrent ovarian adult granulosa cell tumors: a report of 2 cases. Gynecol Oncol 2006 Nov;103:755-758.
  45. Ala-Fossi SL, Maenpaa J, Aine R, Koivisto P, Koivisto AM, Punnonen R. Prognostic significance of p53 expression in ovarian granulosa cell tumors. Gynecol Oncol 1997;66:475-479.


  1. Roth LM, Anderson MC, Govan AD, Langley FA, Gowing NF, Woodcock AS. Sertoli-Leydig cell tumors: a clinicopathologic study of 34 cases. Cancer 1981;48:187-197.
  2. Tomlinson MW, Treadwell MC, Deppe G. Platinum based chemotherapy to treat recurrent Sertoli-Leydig cell ovarian carcinoma during pregnancy. Eur J Gynaecol Oncol1997;18:44-46.
  3. Le T, Krepart GV, Lotocki RJ, Heywood MS. Malignant mixed mesodermal ovarian tumor treatment and prognosis: a 20-year experience. Gynecol Oncol 1997;65:237-240.
  4. Piura B, Rabinovich A, Yanai-Inbar I, Cohen Y, Glezerman M. Primary sarcoma of the ovary: report of five cases and review of the literature. Eur J Gynaecol Oncol 1998;19:257-261.
  5. Topuz E, Eralp Y, Aydiner A, Saip P, Tas F, Yavuz E, et al. The role of chemotherapy in malignant mixed müllerian tumors of the female genital tract. Eur J Gynaecol Oncol2001;22:469-472.
  6. van Rijswijk RE, Tognon G, Burger CW, Baak JP, Kenemans P, Vermorken JB. The effect of chemotherapy on the different components of advanced carcinosarcomas (malignant mixed mesodermal tumors) of the female genital tract. Int J Gynecol Cancer 1994;4: 52-60.
  7. Berek JS, Hacker NF. Sarcomas of the female genital tract. In: Eilber FR, Morton DL, Sondak VK, Economou JS, eds. The soft tissue sarcomas. Orlando, FL: Grune & Stratton, 1987:229-238.
  8. Barakat RR, Rubin SC, Wong G, Saigo PE, Markman M, Hoskins WJ. Mixed mesodermal tumor of the ovary: analysis of prognostic factors in 31 cases. Obstet Gynecol 1992;80:660-664.
  9. Fowler JM, Nathan L, Nieberg RK, Berek JS. Mixed mesodermal sarcoma of the ovary in a young patient. Eur J Obstet Gynecol Reproduc Biol 1996;65:249-253.
  10. Silasi DA, Illuzzi JL, Kelly MG, Rutherford TJ, Mor G, Azodi M, et al. Carcinosarcoma of the ovary. Int J Gynecol Cancer 2008;18:22-29.
  11. Leiser AL, Chi DS, Ishill NM, Tew WP. Carcinosarcoma of the ovary treated with platinum and taxane: the Memorial Sloan-Kettering Cancer Center experience. Gynecol Oncol2007;105:657-661.
  12. Young RH, Oliva E, Scully RE. Small cell sarcoma of the ovary, hypercalcemic type: a clinicopathological analysis of 150 cases. Am J Surg Pathol 1994;18:1102-1116.
  13. Harrison ML, Hoskins P, du Bois A, Quinn M, Rustin GJ, Ledermann JA, et al. Small cell of the ovary, hypercalcemic type—analysis of combined experience and recommendation for management. A GCIG study. Gynecol Oncol 2006;100:233-238.
  14. Pautier P, Ribrag V, Duvillard P, Rey A, Elghissassi I, Sillet-Bach I, et al. Results of a prospective dose-intensive regimen in 27 patients with small cell carcinoma of the ovary of the hypercalcemic type. Ann Oncol 2007;18:1985-1989.
  15. Petru E, Pickel H, Heydarfadai M, Lahousen M, Haas J, Schaider H, et al. Non-genital cancers metastatic to the ovary. Gynecol Oncol 1992;44:83-86.
  16. Demopoulos RI, Touger L, Dubin N. Secondary ovarian carcinoma: a clinical and pathological evaluation. Int J Gynecol Pathol 1987;6:166-175.
  17. Young RH, Scully RE. Metastatic tumors in the ovary: a problemoriented approach and review of the recent literature. Semin Diagn Pathol 1991;8:250-276.
  18. Moore RG, Chung M, Granai CO, Gajewski W, Steinhoff MM. Incidence of metastasis to the ovaries from nongenital tract tumors. Gynecol Oncol 2004;93:87-91.
  19. Ayhan A, Tuncer ZS, Bukulmez O. Malignant tumors metastatic to the ovaries. J Surg Oncol 1995;60:268-276.
  20. Curtin JP, Barakat RR, Hoskins WJ. Ovarian disease in women with breast cancer. Obstet Gynecol 1994;84:449-452.
  21. Yada-Hashimoto N, Yamamoto T, Kamiura S, Seino H, Ohira H, Sawai K, et al. Metastatic ovarian tumors: a review of 64 cases. Gynecol Oncol 2003;89:314-317.
  22. Kim HK, Heo DS, Bang YJ, Kim NK. Prognostic factors of Krukenberg's tumor. Gynecol Oncol 2001;82:105-109.
  23. Yakushiji M, Tazaki T, Nishimura H, Kato T. Krukenberg tumors of the ovary: a clinicopathologic analysis of 112 cases. Acta Obstet Gynaecol Jpn 1987;39:479-485.
  24. Misdraji J, Yantiss RK, Graeme-Cook FM, Balis UJ, Young RH. Appendiceal mucinous neoplasms: a clinicopathologic analysis of 107 cases. Am J Surg Pathol 2003;27:1089-1103.
  25. Chou YY, Jeng YM, Kao HL, Chen T, Mao TL, Lin MC. Differentiation of ovarian mucinous carci-noma and metastatic colorectal adenocarcinoma by immunostaining with beta-catenin. Histopathology 2003 ;43:151-156.
  26. Seidman JD, Kurman RJ, Ronnett BM. Primary and metastatic mucinous adenocarcinomas in the ovaries: incidence in routine practice with a new approach to improve intraoperative diagnosis. Am J Surg Pathol 2003;27:985-993.
  27. Lee KR, Young RH. The distinction between primary and metastatic mucinous carcinomas of the ovary: gross and histologic findings in 50 cases. Am J Surg Pathol 2003;27:281-292.
  28. McBroom JW, Parker MF, Krivak TC, Rose GS, Crothers B. Primary appendiceal malignancy mimicking advanced stage ovarian carcinoma: a case series. Gynecol Oncol2000;78:388-390.
  29. Schofield A, Pitt J, Biring G, Dawson PM. Oophorectomy in primary colorectal cancer. Ann R Coll Surg Engl 2001;83:81-84.
  30. Ayhan A, Guvenal T, Coskun F, Basaran M, Salman MC. Survival and prognostic factors in patients with synchronous ovarian and endometrial cancers and endometrial cancers metastatic to the ovaries. Eur J Gynaecol Oncol 2003;24:171-174.
  31. Young RH, Scully RE. Malignant melanoma metastatic to the ovary: a clinicopathologic analysis of 20 cases. Am J Surg Pathol 1991;15:849-860.
  32. Davis GL. Malignant melanoma arising in mature ovarian cystic teratoma (dermoid cyst): report of two cases and literature analysis. Int J Gynecol Pathol 1996;15:356-362.
  33. Motoyama T, Katayama Y, Watanabe H, Okazaki E, Shibuya H. Functioning ovarian carcinoids induce severe constipation. Cancer 1991;70:513-518.
  34. Robbins ML, Sunshine TJ. Metastatic carcinoid diagnosed at laparoscopic excision of pelvic endometriosis. J Am Assoc Gynecol Laparosc 2000;7:251-253.
  35. Fox H, Langley FA, Govan AD, Hill AS, Bennett MH. Malignant lymphoma presenting as an ovarian tumour: a clinicopathological analysis of 34 cases. BJOG 1988;95:386-390.
  36. Monterroso V, Jaffe ES, Merino MJ, Medeiros LJ. Malignant lymphomas involving the ovary: a clinicopathologic analysis of 39 cases. Am J Surg Pathol 1993;17:154-170.
  37. Azizoglu C, Altinok G, Uner A, Sokmensuer C, Kucukali T, Ayhan A. Ovarian lymphomas: a clinicopathological analysis of 10 cases. Arch Gynecol Obstet 2001;265:91-93.