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Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003.

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Holland-Frei Cancer Medicine. 6th edition.

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Nonepithelial Ovarian Cancer

, MD and , MD.

Nonepithelial cancers of the ovary are uncommon. They include malignancies of germ cell origin, sex cord-stromal cell origin, metastatic carcinomas to the ovary, and a variety of extremely rare ovarian cancers, such as sarcomas and lipoid cell tumors (Figure 118-7). Nonepithelial malignancies account for about 10% of all ovarian cancers. 379 Although there are many similarities in the presentation, evaluation, and management of these patients, there are also many unique qualities of these tumors that require a special approach. This is particularly true because many more nonepithelial lesions are germ cell in origin, and they are usually found in young patients. 131, 197, 380, 381

Figure 118-7. Relationship between examples of pure malignant germ cell tumors and their secreted substances.

Figure 118-7

Relationship between examples of pure malignant germ cell tumors and their secreted substances. AFP = α-fetoprotein; hCG = human chorionic gonadotropin. Reprinted with permission from Berek JS, Hacker NF. Nonepithelial ovarian cancer. In: Berek (more...)

Germ Cell Malignancies

Germ cell tumors are derived from the primordial germ cells of the ovary. Whereas malignant germ cell tumors 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 sites 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, prior to their incorporation into the sex cords of the developing gonads. 382

Classification

A histologic classification of ovarian germ cell tumors is presented in Table 118-9. 382 α-fetoprotein (AFP) and human chorionic gonadotropin (hCG) are both secreted by some germ cell malignancies and, 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. α-1-antitrypsin (AAT) can be detected rarely in association with germ cell tumors. By correlating the histologic and immunohistologic identification of these substances in tumors, a classification of germ cell tumors can be made. In this classification, embryonal carcinoma, which is composed of undifferentiated cells, synthesizes both hCG and AFP, and this tumor is the progenitor of several other germ cell malignancies. More differentiated germ cell tumors, such as the endodermal sinus tumor, which secretes AFP, and the choriocarcinoma, which secretes hCG, are derived from the extraembryonic tissues, whereas the immature teratomas are derived from the embryonic cells that have lost the ability to secrete these substances. 383 Pure germinomas do not secrete these markers.

Table 118-9. Histologic Typing of Ovarian Germ Cell Tumors.

Table 118-9

Histologic Typing of Ovarian Germ Cell Tumors.

Epidemiology

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

In the first 2 decades of life, almost 70% of ovarian tumors are of germ cell origin, and one third of these are malignant. 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 become quite rare.

Clinical Features

The most common symptom in young patients with a germ cell tumor of the ovary is a pelvic fullness, urinary frequency, or dysuria. Rectal pressure, menstrual irregularities in postmenarchal patients, and lower abdominal pain or pressure may be present. Some young patients may misinterpret the early symptoms of a neoplasm as those of pregnancy, and this can lead to a further delay in the diagnosis of the cancer. Acute symptoms associated with the 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 extensive abdominal distension. 132

In patients with a palpable adnexal mass, the evaluation should proceed expeditiously. 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, a neoplasm is probable and a malignancy is possible. The rest of the physical examination should search for signs of ascites, pleural effusion, and organomegaly. 132

Diagnosis

When an adnexal mass is 2 cm or larger in a premenarchal female, or 8 cm or larger in other premenopausal females, surgical exploration is frequently required. In young patients, blood tests should include serum hCG and AFP levels, a complete blood count, and liver function tests. A chest radiograph should be performed because germ cell tumors can metastasize to the lung or mediastinum. A karyotype should be obtained preoperatively on all premenarchal females, because of the propensity for these tumors to arise in dysgenetic gonads. 294 A preoperative CT scan may document the presence and extent of retroperitoneal lymphadenopathy or liver metastases, but because these patients require surgical exploration, a more extensive and time-consuming preoperative evaluation is unnecessary. If postmenarchal patients have predominantly cystic lesions up to 8 cm in diameter, they may undergo a trial of hormonal suppression for two menstrual cycles.

Dysgerminomas

Dysgerminomas are the most common malignant germ cell tumors, accounting for about 30% to 40% of all ovarian cancers of germ cell origin. 394 The tumor represents only 1% to 3% of all ovarian cancers, but 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% under the age of 10 years, and rarely over the age of 50 years. 2, 388 Because these malignancies occur in young women, 20% to 30% of ovarian malignancies associated with pregnancy are dysgerminomas.

Much has been, and continues to be learned about the management of dysgerminoma by analogy with its male counterpart, testicular seminoma (Figure 118-8). 385 The dominant route of spread in both is nodal, via the gonadal lymphatics to the renal hilar and para-aortic nodes. Both are exquisitely radiosensitive and curable with modest doses of radiotherapy, 2,500 to 3,500 cGy, even when bulk disease up to 5 cm is being treated. For this reason, excellent long-term survival rates are obtained when surgical removal, using oophorectomy or hysterectomy/bilateral salpingo-oophorectomy, is followed by radiotherapy to para-aortic and pelvic nodes. 386, 387

Figure 118-8. Dysgerminoma.

Figure 118-8

Dysgerminoma. (Four-color version of figure on CD-ROM)

About 75% of dysgerminomas are stage I at diagnosis, that is, confined to one or both ovaries. About 85% to 90% of stage I tumors are confined to one ovary; 10% to 15% are bilateral. In fact, dysgerminoma is the only germ cell malignancy that has this significant rate of bilaterality, other germ cell tumors rarely being bilateral.

Dysgerminomas affect younger women (85% are under 29 years of age) and are present in two thirds of cases as stage IA. Dysgenetic gonads tend to develop dysgerminoma. 388, 389 Therapeutic concepts have changed dramatically over the past few years, largely because of (1) the recognition of dysgerminomas' chemosensitivity, allowing cure without ovarian ablation by surgery or radiotherapy in many cases; (2) the advent of improved techniques of imaging the retroperitoneum, with lymphography, and CT and MRI scanning that allow detection of disease under 3 to 5 cm in diameter when it is eminently curable; (3) tumor markers, AFP and the beta subunit of human chorionic gonadotrophin (β-hCG), which distinguish pure dysgerminoma from the mixed germ-cell tumors; and (4) the emerging emphasis in treatment on preservation of childbearing capacity, presumably without compromising cure.

Many aspects of management are controversial, such as the need for complete surgical staging; the extent of the primary operative procedure in unilateral, bilateral, and metastatic disease; the role of postoperative observation in stage IA; the choice between radiotherapy and chemotherapy; the decision as to which chemotherapy drugs should be used; and the need for a second-look operation. The subject was recently reviewed in greater depth than is possible here.

In the 25% of patients who present with metastatic disease, the tumor most commonly spreads via the lymphatics. 2 It also can spread hematogenously, or by direct extension through the capsule of the ovary, with exfoliation and dissemination of cells over the peritoneal surfaces. Metastases to the contralateral ovary occur and may be present when there is no other evidence of spread. An uncommon site of metastatic disease is bone, and when it does occur here, the lesions are seen principally in the lower vertebrae. Metastases to the lungs, liver, and brain are seen most often in patients whose disease is longstanding or recurrent. Metastatic disease to the mediastinum and supraclavicular lymph nodes is usually a late manifestation of disease.

Dysgenetic Gonads

Approximately 5% of dysgerminomas are discovered in phenotypic females with abnormal gonads. 2, 390 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), or the androgen insensitivity syndrome (46XY, testicular feminization). Therefore, premenarchal patients with a pelvic mass should have their karyotype determined. In most patients with gonadal dysgenesis, dysgerminomas arise in gonadoblastomas, which are benign ovarian tumors that are composed of germ cells and sex cord stroma. If gonadoblastomas are left in place in patients with gonadal dysgenesis, more than 50% will develop into ovarian malignancies. 389 Also, dysgerminomas that contain significant numbers of syncytiotrophoblastic cells can be hormonally active, producing isosexual precocious pseudopuberty in premenarchal females and menstrual irregularities in older women. 379, 388

Surgery

The treatment of patients with dysgerminoma is primarily surgical, including the resection of the primary lesion and proper surgical staging. If necessary, radiation or chemotherapy is administered to selected patients. Because the disease principally affects young females, special consideration must be given to the preservation of fertility whenever possible. 2, 387

Ideally, the initial operation should include exploration of the abdominal contents, with careful palpation of the retroperitoneal node-bearing areas, sampling of enlarged nodes, and cytologic examination of peritoneal washings. If these steps were omitted in what was apparently stage I disease, the need for reexploration for restaging purposes is questionable, simply because noninvasive imaging techniques are capable of detecting disease of less than 5 cm, which is highly curable, unlike the cystadenocarcinomas. For the same reason, biopsy of nonpalpable lymph nodes is probably unnecessary. A benefit of cytoreductive surgery has not been shown in this disease.

The minimum operation for ovarian dysgerminoma is a unilateral oophorectomy or salpingo-oophorectomy. 391 If there is a desire to preserve fertility, the contralateral ovary, fallopian tube, and uterus should be conserved. This is probably true even in the presence of metastatic disease, because of the sensitivity of the tumor to chemotherapy. 384 In patients whose fertility need not be preserved, it is appropriate to perform a total abdominal hysterectomy and bilateral salpingo-oophorectomy. In patients whose karyotype analysis reveals a Y chromosome, both ovaries should be removed, although the uterus might be conserved for possible future embryo transfer. 387 Dysgerminoma is the only germ cell tumor that tends to be bilateral, and not all of the bilateral lesions have obvious ovarian enlargement. Therefore, bisection of the contralateral ovary and excisional biopsy of any suspicious lesion are desirable. 388

Postoperative workup should include the serum markers AFP and β-hCG, a chest radiograph, and an abdominopelvic CT or MRI scan. In premenarchal females with an ovarian mass, preoperative karyotyping should be performed, as detection of a Y chromosome is an indication for bilateral oophorectomy, as discussed below. Even with a histologic diagnosis of pure dysgerminoma, the presence of an elevated AFP value or a markedly elevated β-hCG level (over approximately 100 IU/L), indicates the presence of nondysgerminomatous elements, and is reason enough to base treatment on these more aggressive elements. As with seminoma, lower β-hCG levels are sometimes found in the pure form of the disease, produced by syncytial-like giant interstitial cells. Lymphography can be useful, both in detecting nodal involvement and in localizing the nodal chains for radiation treatment.

Management of Stage IA

The extent of the initial extirpative surgery can be quite conservative. Long-term survival results in concurrent series reported for a policy of unilateral adnexectomy with subsequent treatment withheld until relapse (91% in 145 cases) are not inferior to results of hysterectomy, bilateral adnexectomy, and routine postoperative radiotherapy (85% in 53 cases). 390, 392 This is so because, in these older series, two thirds of relapses were salvaged by reexcision or radiotherapy. Better results would be expected today, because marker studies would show that some of the patients included did not have pure dysgerminoma from the outset; because relapse would be detected earlier by modern imaging techniques, when tumor bulk was lower; and because chemotherapy and megavoltage radiotherapy would be expected to salvage nearly all first relapses. However, a conservative approach requires frequent patient monitoring: clinical and tumor marker checks every 2 months, and CT scans every 3 months in the first 2 to 3 years. In patients whose contralateral ovary has been preserved, disease can develop in 5% to 15% of the retained gonads over the next 2 years. 390 This figure includes those not treated with additional therapy, as well as patients with gonadal dysgenesis.

The reasons for a conservative initial approach are (1) to avoid ablative surgery and radiotherapy in the majority of cases (probably 80% to 85% of properly evaluated stage IA patients are cured by oophorectomy), and (2) to preserve fertility. Because the morbidity of low-dose radiotherapy is small, and the dollar cost of close surveillance of conservatively managed patients is appreciable, the strongest justification for conservatism is the desire to preserve fertility. This requires a highly compliant patient and a knowledgeable, attentive physician.

Management of Relapsed Stage I

The choice of salvage therapy depends on the site and size of the relapse when it is detected, and the desire to maintain fertility. In general, treatment of relapse need not imply loss of fertility if chemotherapy or pelvis-sparing radiotherapy is used.

There is argument as to whether a tumor size over 10 cm at diagnosis is a contraindication to conservative therapy, since a higher relapse rate is associated with larger tumors. 393, 394 The literature does not resolve this issue, but in the opinion of the authors and others a large tumor size per se does not preclude a conservative approach. 394–396,

Stages IB, II, III, IV, and Recurrences

About 6% of patients present with bilateral ovarian involvement, and a similar number of stage IA patients experience recurrence in the opposite ovary. In general, bilateral oophorectomy is advised for stage IB, possibly with uterus conservation for future embryo transfer. The choice of postoperative therapy in stage IB-III is as described above for disease that recurs after primary management of stage IA. When radiation is used, the portals should include the pelvic nodes on the affected side(s) and the renal hilar and paraaortic nodes up to the diaphragm. Because a small fraction (10% to 20%) of abdominal spread is transperitoneal, abdominopelvic radiotherapy can also be used as in the epithelial tumors. 394 Prophylactic mediastinal/supraclavicular irradiation is not advised, since its value is questionable, and it may compromise subsequent chemotherapy because of marrow ablation.

The most frequently used chemotherapeutic regimens for germ cell tumors are BEP (bleomycin, etoposide, and cisplatin), VBP (vinblastine, bleomycin, and cisplatin), and VAC (vincristine, actinomycin, and cytoxan) (Table 118-10). -346, 397 Encouraging results (long-term disease-free status over 90% in previously untreated patients, and in about 70% of recurrent cases) have been reported in a number of series using cisplatin, vinblastine, bleomycin (PVB), VAC, or variants. 398–401, 435 .

Table 118-10. Combination Chemotherapy for Germ Cell Tumors of the Ovary.

Table 118-10

Combination Chemotherapy for Germ Cell Tumors of the Ovary.

Unlike the nondysgermanomatous ovarian germ-cell tumors, whose chemoresponsiveness is not as great as for the nonseminomatous testicular tumors, dysgerminoma may be even more chemosensitive than the testicular tumors. For example, one report cites a sustained complete response in 7 of 10 patients with residual disease treated with a doxorubicin/cyclophosphamide (AC) combination (two of the three relapses were salvaged with PVB). 402 The same report describes an additional eight patients treated with PVB; all eight are alive without disease, although one patient who relapsed in the brain was salvaged by radiotherapy. Of some note is that four patients had residual ovarian or uterine disease; all are disease-free, and one, treated with AC, has subsequently borne a child.

There have been numerous reports of successful control of metastatic dysgerminomas with systemic chemotherapy, and this should now be regarded as the treatment of choice. 403–408- 127 The obvious advantage is the preservation of fertility. 408 The most frequently used chemotherapeutic regimens for germ cell tumors are BEP, VBP, and VAC. 396, 400, 128 The Gynecologic Oncology Group (GOG) studied 3 cycles of (EC) etoposide (120 mg/M2 intravenously on days 1, 2, and 3 every 4 weeks) carboplatin (400 mg/M2 intravenously on day 1 every 4 weeks) for patients with completely resected ovarian dysgerminoma, stages Ib, Ic, II, or III. 402 The results showed a sustained disease-free remission rate of 100%.

For patients with advanced, incompletely resected germ cell tumors, the GOG studied cisplatin-based chemotherapy on two consecutive protocols. 403 In the first study, patients received 4 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 6 cycles of VAC. In the second trial, patients received 3 cycles of BEP initially, followed by consolidation with VAC, which was later discontinued in patients with dysgerminomas. 403 The VAC consolidation after BEP in patients with tumors other than dysgerminoma is still being investigated, but VAC does not appear to improve the outcome of the BEP regimen. A total of 20 evaluable patients with stage 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. Another study at M.D. Anderson Hospital used BEP in 14 patients with residual disease, and all patients were free of disease with long-term follow-up. 402 These results suggest that patients with advanced-stage, incompletely resected dysgerminoma have an excellent prognosis when treated with cisplatin-based combination chemotherapy. The best regimen is 4 cycles of BEP, based on the data from testes cancers. 410–412 .

There appears to be no need to perform a second-look laparotomy in patients with dysgerminoma whose macroscopic disease has all been resected at the primary operation. 2, 4, 412, 415, 129, 130 In patients with macroscopic residual disease at the start of chemotherapy, we prefer to perform a second-look operation because second-line therapy is available and the earlier persistent disease is identified, the better the prognosis should be.

Recurrent Disease

About 75% of recurrences occur within the first year after initial treatment the most common sites being the peritoneal cavity and the retroperitoneal lymph nodes. 2, 4, 131, 132 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 prior chemotherapy with BEP has been given, POMB-ACE may be used (Table 118-11), and consideration should be given to the use of high-dose chemotherapy (eg, with carboplatin and etoposide) and autologous bone marrow transplantation. Alternatively, radiation therapy is effective for this disease, with the major disadvantage being loss of fertility if pelvic and abdominal radiation is required.

Table 118-11. POMB/ACE Chemotherapy for Germ Cell Tumors of the Ovary.

Table 118-11

POMB/ACE Chemotherapy for Germ Cell Tumors of the Ovary.

These results suggest that patients with advanced-stage, incompletely resected dysgerminoma have an excellent prognosis when treated with cisplatin-based combination chemotherapy. The optimal regimen is unknown, but three to four cycles of BEP seem sufficient.

Our recommendations, like the regimens themselves, are based on the literature regarding testicular cancer. In brief, the testicular cancer experience has shown that PVB is more effective than VAC, and that the substitution of etoposide for vinblastine in PVB (ie, BEP) improves the therapeutic ratio by reducing toxicity and improving response rates. 415 It has been demonstrated that dysgerminomas are very sensitive to platinum-based chemotherapy. Williams and colleagues reported treatment of patients with advanced dysgerminomas using platinum-based chemotherapy. 414 At an overall follow-up of 9 to 96 months (median 26 months), 17 of 18 patients with advanced dysgerminoma were disease-free. These excellent results in patients with advanced disease have implications for the treatment of patients with early-stage dysgerminoma.

Second-Look Laparotomy

There appears to be no need to perform a second-look laparotomy in patients with dysgerminoma whose macroscopic disease was all resected at the primary operation. 394, 423, 133 In patients with macroscopic residual disease at the start of chemotherapy, we prefer to perform a second-look operation because second-line therapy is available and the earlier persistent disease is identified, the better the prognosis should be. 394

Coexistent with Pregnancy

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, but chemotherapy can be given in the second half of pregnancy in the same dosages as given for the nonpregnant patient. 395

Prognosis

In patients whose initial disease is stage IA (ie, a unilateral encapsulated dysgerminoma), the conservative approach outlined above results in 5-year disease-free survivals of greater than 95%. 390, 401 , The 5-year survival for patients with all stages of dysgerminoma is 85%. 410, 411, 414, 415, 134 The features that have been associated with a higher tendency to recur include lesions larger than 10 to 15 cm in diameter, age younger than 20 years, and microscopic characteristics that include numerous mitoses, anaplasia, and a medullary pattern. 136, 222

With current staging methods, the proportion of relapsing patients should be no more than 15% to 20%. 426 The theoretic cure rate of this group is 98%. Although in the past, surgery for advanced disease followed by pelvic and abdominal radiation produced a 5-year survival of 63% to 83%, cure rates of 85% to 90% for this same group of patients are being seen now with combination chemotherapy. ,427, 429

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. 425 The options for such patients are repeat laparotomy for surgical staging, regular pelvic and abdominal surveillance with CT scans, and adjuvant chemotherapy. As these are rapidly growing tumors, our preference is to perform regular CT surveillance. Tumor markers (AFP and hCG-b) should also be monitored in case occult mixed germ cell elements are present.

There have been numerous reports of the successful control of metastatic dysgerminomas with systemic chemotherapy, and this should now be regarded as the treatment of choice. 408–411 The obvious advantage is the preservation of fertility.

Recurrent Disease

About 75% of recurrences occur within the first year after initial treatment, the most common sites being the peritoneal cavity and the retroperitoneal lymph nodes. These patients should be treated with either radiation or chemotherapy, depending on their primary treatment. Patients with recurrent disease who have no therapy other than surgery should be treated with chemotherapy. If prior chemotherapy with BEP has been given, POMB-ACE may be used (Table 118-12), and consideration should be given to the use of high-dose chemotherapy (eg, with carboplatin and etoposide) and autologous bone marrow transplantation. 400 Alternatively, radiation therapy is effective for this disease.

Table 118-12. Sex Cord-Stromal Tumors.

Table 118-12

Sex Cord-Stromal Tumors.

Immature Teratomas

Immature teratomas contain elements resembling 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 less 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 females under 20 years of age and 30% of the deaths from ovarian cancer in this age group. 2, 416 About 50% of pure immature teratomas of the ovary occur between the ages of 10 and 20 years, and they rarely are seen in postmenopausal women. Immature teratomas are classified according to a grading system (grades 1 to 3) that is based on the degree of differentiation and the quantity of immature tissue. 417, 418

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 these can be detected by a radiograph of the abdomen or by ultrasonography. Rarely, they are associated with the production of steroid hormones and can present with sexual pseudoprecosity. 430 Patients may present with abnormal bleeding, but most frequently the symptoms and signs are nonspecific, usually those of a pelvic mass with or without pelvic pressure or pain. The lesions may be growing rapidly, and thus the symptoms and signs often have a subacute onset. Tumor markers are negative unless a mixed germ cell tumor is present.

Surgery

As with the dysgerminoma in a young patient whose lesion appears confined to a single ovary, a unilateral oophorectomy or salpingo-oophorectomy and surgical staging should be performed. In older patients who do not desire preservation of fertility, a total abdominal hysterectomy and bilateral salpingo-oophorectomy should be carried out. Contralateral involvement is rare, and in patients whose contralateral ovary reveals no evidence of gross involvement, routine resection or wedge biopsy is unnecessary. 419 Any lesions on the peritoneal surfaces should be sampled carefully and submitted for histologic evaluation. The most frequent site of dissemination is the peritoneum and, much less commonly, the retroperitoneal lymph nodes. Blood-borne metastases to organ parenchyma, such as the lungs, liver, or brain, are uncommon. When present, they are usually seen in patients with late or recurrent disease, and most often in tumors that are poorly differentiated.

Chemotherapy

The results of therapy for patients with germ cell tumors other than dysgerminomas (eg, immature teratomas and endodermal sinus tumors of the ovary) have improved with cisplatin-based chemotherapy. The primary prognostic factor in patients with immature teratoma is the tumor grade. In patients whose tumors are stage IA, grades 2 and 3, chemotherapy should be used. 420, 421 There is no evidence that chemotherapy will improve the outcome of patients with stage IA, grade 1 lesions. In patients who have ascites and ruptured tumors, chemotherapy is indicated, regardless of tumor grade. While patients with stage I, grade 1 immature teratoma rarely suffer a relapse, most patients with grades 2 and 3 tumors will not be cured by surgery alone. Similarly, most patients with endodermal sinus tumors will not be cured by surgery alone, as discussed below. Adjuvant chemotherapy is recommended for all patients other than those with stage I, grade 1 immature teratomas. Although nonûplatinum-based chemotherapy regimens, such as vincristine, actinomycin, and cyclophosphamide (VAC) 423 , have been somewhat successful when administered in the adjuvant situation, they have been replaced by platinum-based regimens. 423, 424 Standard therapy in this situation is now the BEP regimen. In the most recent GOG trial, 50 of 52 stage I, stage II, and stage III patients with completely resected tumor remain disease-free after three courses of BEP. 421

Patients with stage IA, grade 1 tumors have an excellent prognosis, and no adjvuant therapy is required. In patients whose tumors are stage IA, grade 2 or 3, adjuvant chemotherapy should be used. 422 Chemotherapy is also indicated in patients who have ascites, regardless of tumor grade. The most frequently used combination chemotherapeutic regimen has been VAC. 135 However, in a GOG study, the relapse-free survival rate in patients with incompletely resected disease was 75%. 430 The newer approach 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. 438, 439, 442 No direct comparison of these regimens with VAC has been reported, but the BEP combination can save some patients who have persistent or recurrent disease after VAC." 421, 412, 430

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. 430 Overall, the toxicity has been acceptable, and 91 of 93 patients with nondysgerminomatous tumors treated are clinically free of disease. Thus the BEP regimen, which is used more extensively for testicular cancer, appears to be superior to the VAC regimen in the treatment of completely resected nondysgerminomatous germ cell tumors of the ovary. Because some patients can progress rapidly, 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 (ie, 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 versus BEP) in 166 patients with germ cell tumors of the testes, the BEP regimen had a relapse-free survival rate of 84% compared with 69% for the EP regimen (p = .03). 421 In addition, cisplatin may be slightly better than carboplatin in the setting of metastatic germ cell tumors. One hundred ninety-two patients with germ cell tumors of the testes were entered into a study of 4 cycles of etoposide plus cisplatin (EP) versus 4 cycles of etoposide plus carboplatin (EC). There have been three relapses with the EP regimen versus seven with the EC regimen, although the overall survival of the two groups is identical thus far. 422 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.

Immature teratomas with malignant squamous elements appear to have a poorer prognosis than those tumors without these elements. 418 The treatment in these patients is also the BEP regimen.

Radiation Therapy

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 does chemotherapy alone. Radiation should be reserved for patients with localized persistent disease after chemotherapy. 418

Second-Look Procedure

The need for a second look has been questioned, and it may not be necessary in most patients who have received chemotherapy, particularly those who were treated in an adjuvant setting (ie, stage IA, grades 2 and 3 disease) because chemotherapy in these patients is so effective. 422 Although the role of a second-look procedure remains unclear, it might be used in those who are at high risk for failure, that is, those with incompletely resected metastatic disease prior to the initiation of chemotherapy. 136 Lesions that are mixed may have a poorer response to treatment 136 . If a second-look procedure is performed, a careful sampling of any peritoneal lesions should be included and the retroperitoneal lymph nodes should be evaluated carefully. If only mature elements are found at the second look, chemotherapy should be discontinued. If persistent immature elements are documented, alternative chemotherapy should be used. An enlarged contralateral ovary may contain a benign cyst or a mature cystic teratoma, which may be managed with an ovarian cystectomy. 430

Prognosis

The most important prognostic feature of the immature teratoma is the grade of the lesion. 2, 418 The 5-year survivals have been reported to be 82%, 62%, and 30% for patients with grade 1, 2, and 3 lesions respectively. 418 Occasionally, these tumors are associated with mature or low-grade glial elements that have become implanted throughout the peritoneum, and such patients typically have a favorable long-term survival. 417 In addition, the stage of disease and the extent of tumor at the initiation of treatment also affect the curability of the lesion. Patients whose tumors have been incompletely resected prior to treatment have a significantly lower 5-year survival than do those patients whose lesions have been completely resected (94% versus 50%). 388 In young women with conserved contralateral ovaries and a uterus, normal reproductive function and pregnancy have been reported in a significant fraction of successfully treated patients. 408 Overall, the 5-year survival of patients with all stages of pure immature teratomas is 70% to 80%, whereas it is 90% to 95% for patients with surgical stage I lesions 2

Endodermal Sinus Tumors

Endodermal sinus tumors (EST) have also been referred to as yolk sac carcinomas, because they are derived from the primitive yolk sac. 2, 400 These lesions are the third most frequent malignant germ cell tumor of the ovary. Endodermal sinus tumors occur at a median age of 18 years, and about one third of the patients are premenarchal at the time of presentation. Like the other nondysgerminomatous ovarian malignancies, abdominal or pelvic pain is the most frequent presenting symptom, occurring in about 75% of patients. An asymptomatic pelvic mass is documented in about 10% of patients. 2, 433, 436

Most EST lesions secrete AFP and rarely they may produce detectable AAT. There is a good correlation with the extent of disease and the AFP level, although discordance has been observed. The serum level of AFP is particularly useful in monitoring the patient during and after treatment. 437

Surgery

The treatment of EST includes a surgical exploration, a unilateral oophorectomy, and a frozen section for diagnosis. Any gross metastases should be removed if possible, but a thorough surgical staging is not necessary because all patients need chemotherapy. The tumors tend to be solid and large, ranging in size from 7 to 28 cm (median is 15 cm). 2, 433, 436 The EST is thought never to be bilateral, and the other ovary will have metastasis only when there are other metastases in the peritoneal cavity. 437 Most patients have early-stage disease: 71% have stage I, 6% have stage II, and 23% have stage III. 432 The performance of a hysterectomy and contralateral salpingo-oophorectomy does not alter outcome. 432, 436, 437

Chemotherapy

Endodermal sinus tumors are treated in all patients, regardless of stage, with either adjuvant or therapeutic chemotherapy. Prior to the routine use of combination chemotherapy for this disease, the 2-year survival was only about 25%. After the introduction of the VAC regimen, this rate improved to 60% to 70%, indicating the chemosensitivity of the majority of these tumors. 441 Furthermore, with conservative surgery and adjuvant chemotherapy, fertility can be preserved as with other germ cell tumors.

As with other nondysgerminomatous germ-cell tumors, a cisplatin-containing combination chemotherapy regimen, either BEP or VBP, is most effective in the treatment of EST, particularly in the treatment of measurable or incompletely resected tumors. ,437, 441 In the GOG series, only about 20% of patients with residual metastatic disease responded completely to the VAC regimen, whereas about 60% of those treated with VBP had a complete response. 435 In addition, this regimen may salvage some failures of V therapy. As with patients with immature teratomas, BEP probably is the best current primary chemotherapy for this disease. The optimal number of treatment cycles has not been established. The GOG protocols have used nine treatment cycles of VBP given every 4 weeks. 458 but four to six cycles may be equally effective. 442

Second-Look Procedure

It is unclear whether a second look has any value in patients with EST, and it may be reasonable to omit the operation in those with pure lesions that are of low stage and in those whose AFP values return to normal and remain normal for the rest of their treatment. 441 In patients with advanced-stage disease or in those with measurable or incompletely resected lesions whose AFP levels do not return to normal, persistent disease can be assumed and alternative chemotherapy offered.

Embryonal Carcinoma

Embryonal carcinoma of the ovary is an extremely rare tumor. It can be distinguished from a choriocarcinoma by the absence of syncytiotrophoblastic and cytotrophoblastic cells. Embryonal carcinomas may be hormonally active, with some patients developing precocious pseudopuberty or irregular bleeding. The presentation is similar to that of the EST. The patient's ages ranged between 4 and 28 years (median was 14 years) in one series. 444 The primary lesions tend to be larger than 15 cm in diameter, and about two thirds are confined to one ovary at the time of presentation. As with the pure EST, these lesions often secrete AFP and hCG, and these markers are useful for following the response to subsequent therapy. The treatment of embryonal carcinomas is the same as for the EST, that is, the performance of a unilateral oophorectomy or salpingo-oophorectomy followed by combination chemotherapy with BEP. 431, 432, 434

Choriocarcinoma of the Ovary

Pure nongestational choriocarcinoma of the ovary is an extremely rare tumor. 445 Histologically, it has the same appearance as gestational choriocarcinoma metastatic to the ovaries. 2 The majority of patients with this cancer are younger than 20 years. Isosexual precocity has been documented in about 50% of patients whose lesions arise prior to menarche. The presence of hCG can be useful in monitoring the patient during and after treatment. Because of its rarity, there are only a few series of reports in which chemotherapy was used for these nongestational choriocarcinomas, but there have been complete responses reported to the MAC regimen (methotrexate, actinomycin D, and cyclophosphamide). 446 However, as the BEP or EP is active in gestational choriocarcinoma, these regimens are also a reasonable approach for the nongestational lesions. 429 The prognosis for ovarian choriocarcinoma has been poor, with the majority of patients having metastatic disease to organ parenchyma at the time of initial diagnosis. 2, 447

Mixed Germ-Cell Tumors

Mixed germ-cell malignancies of the ovary contain two or more elements of the lesions described above. In one series, the most common component of a mixed malignancy was dysgerminoma, which occurred in 80%, followed by EST in 70%, immature teratoma in 53%, choriocarcinoma in 20%, and embryonal carcinoma in 16%. ,440 The most frequent combination was a dysgerminoma and an EST. The mixed lesion may secrete either AFP or hCG, or both or neither, depending on the components. 443

Because most of these lesions contain poorly differentiated elements, mixed germ-cell malignancies should be treated with combination chemotherapy, probably BEP or VBP. 459 The serum marker, if positive initially, may become negative during chemotherapy, but this may reflect the regression of only a particular component of the mixed lesion. Therefore, in patients with advanced-stage mixed germ-cell malignancies, a second-look laparotomy may be useful to determine the response to therapy, unless the tumor was confined initially to the ovary.

The most important prognostic features are the size of the primary tumor and the relative amount of its most malignant component. 443 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 make up the majority of the mixed lesions.

Sex Cord-Stromal Tumors

Sex cord stromal tumors of the ovary account for about 5% to 8% of all ovarian malignancies. 2, 459 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 (granulosa and theca cells) and “male” cells (Sertoli and Leydig cells), as well as morphologically indifferent cells. A classification of this group of tumors is presented (Table 118-12).

Granulosa-Stromal Cell Tumors

This group of tumors includes granulosa cell tumors, thecomas, and fibromas. The granulosa cell tumor is a low-grade malignancy, and rarely thecomas and fibromas become malignant and are called fibrosarcomas. 2

Granulosa cell tumors, which are estrogen secreting, are seen in women of all ages (Figure 118-9). They are found in prepubertal females in 5% of cases, and the rest throughout the reproductive and postmenopausal years. 448 They are bilateral in 2% of patients. In the rare prepubertal lesion, three fourths are associated with sexual pseudoprecocity because of the estrogen secretion. 449 In the reproductive age group, most patients present with menstrual irregularities or secondary amenorrhea, and cystic hyperplasia of the endometrium may accompany these lesions. 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 about 5% of cases; 25% are associated with endometrial hyperplasia. 2, 449, 450 The other symptoms and signs of granulosa cell tumors are nonspecific and are the same as for most ovarian malignancies. Ascites is present in about 10% of cases, and, rarely, a pleural effusion is present. 450, 451 Granulosa tumors tend to be hemorrhagic, and occasionally rupture and produce a hemoperitoneum. 466 Inhibin is secreted by granulosa cell tumors and is a useful marker for the disease. 451–453

Figure 118-9. Granulosa cell tumor.

Figure 118-9

Granulosa cell tumor. (Four-color version of figure on CD-ROM)

Granulosa cell tumors are usually stage I at diagnosis, but they may recur 5 to 30 years after initial diagnosis. 450 The tumors also may spread hematogenously, and patients can develop metastases years after initial diagnosis in the lungs, liver, and brain. When they do recur, they can progress rapidly. Malignant thecomas are extremely rare, and their presentation, management, and outcome are similar to those of the granulosa cell tumors. 454, 455

Surgery

The treatment of a granulosa cell tumor depends on the age of the patient and the extent of disease. For most patients, surgery alone is sufficient primary therapy. The performance of a unilateral oophorectomy or salpingo-oophorectomy is appropriate therapy for stage IA tumors in children or in women of reproductive age. 463 If a granulosa cell tumor is identified by frozen section at laparotomy, 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 not removed, a dilation and curettage of the uterus should be carried out because of a possible coexistent adenocarcinoma of the endometrium. 464

Treatment

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. 454 Furthermore, it is unclear that adjuvant chemotherapy will prevent recurrence of disease. However, metastatic lesions and recurrences have been treated with a variety of different antineoplastic drugs. There is no consistently effective regimen in these patients, although complete responses have been reported anecdotally in patients treated with a single alkylating agent, cyclophosphamide or melphalan, as well as those treated with combinations, VAC (vincristine, Adriamycin, cyclophosphamide) and PAC (cisplatin, Adriamycin, cyclophosphamide). 456 The AcFuCy regimen (actinomycin D, 5-fluorouracil, and cyclophosphamide) has been used by the GOG and has been associated with approximately a 20% response rate. 388 The use of hormonal agents, such as progestins or antiestrogens, has been suggested, but there are no data available. 465

Prognosis

Granulosa cell tumors have a prolonged natural history and a tendency for late relapse, reflecting their low grade. As such, 10-year survivals of about 90% have been reported, with 20-year survivals of 75%. 454, 455 Most histologic types have the same prognosis, but the more poorly differentiated diffuse or sarcomatoid type tends to do worse. 457

The DNA ploidy of the tumors has been correlated with survival. Holland and colleagues reported DNA aneuploidy in 13 of 37 patients (35%) with primary granulosa cell tumors. 474 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%.

Sertoli-Leydig Cell Tumors. This group of tumors occurs most frequently in the third and fourth decades, with 75% of the lesions seen in women younger than 40 years. They are rare, representing less than 0.2% of ovarian cancers. 2, 459 Sertoli-Leydig cell tumors are usually low-grade malignancies, although a poorly differentiated variety may behave more aggressively.

The tumors typically produce androgens, and clinical virilization is noted in 70% to 85% of patients. 400 Signs of virilization include oligomenorrhea, amenorrhea, breast atrophy, acne, hirsutism, clitoromegaly, a deepening voice, and a receding hairline. Measurement of plasma androgens may reveal an elevated testosterone and androstenedione, with normal or slightly elevated dehydroepiandrosterone sulfate. 2 Rarely, the Sertoli-Leydig tumor can be associated with manifestations of estrogenization, such as, isosexual precocity or irregular or postmenopausal bleeding.

Because these low-grade lesions are only rarely bilateral (under 1%), the usual treatment for patients in their reproductive years is a unilateral oophorectomy or salpingo-oophorectomy and evaluation of the contralateral ovary. 460 In older patients for whom fertility is not an issue, the performance of a hysterectomy and bilateral salpingo-oophorectomy is appropriate. There are insufficient data to document the value of radiation or chemotherapy in patients with persistent disease, but some responses in those with measurable disease have been reported with pelvic radiation and the VAC chemotherapy regimen. 460 The 5-year survival is 70% to 90%, and recurrences thereafter are uncommon. Poorly differentiated lesions account for the majority of fatalities.

Uncommon Ovarian Tumors

There are several types of rare malignant ovarian tumors that together compose about 0.1% of ovarian malignancies 2 . These lesions include small cell carcinomas, lipoid cell tumors and primary ovarian sarcomas.

Small-Cell Carcinomas

This rare tumor occurs at an average of 24 years (range 2 to 46 years). 461 The tumors are all bilateral. Approximately two-thirds of the tumors are accompanied by paraendocrine hypercalcemia. This tumor accounts for one-half of all of the cases of hypercalcemia associated with ovarian tumors. About 50% of the tumors have spread beyond the ovaries when they are diagnosed. 461

The management of these maliganacies consists surgery followed by platinum-based chemotherapy and 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 phosphates. The prognosis tends to be poor with most patients dying within two years of diagnosis in spite of treatment.

Lipoid Cell Tumor

The lipoid cell tumor is thought to arise in adrenal cortical rests that reside near the ovary. Over 100 cases have been reported, and bilaterality in only a few. 2 Most are associated with virilization, and occasionally with obesity, hypertension, and glucose intolerance, reflecting glucocorticoid secretion. Rare cases of hyperestrogenism and isosexual precocity occur.

The majority of lipoid cell tumors have a benign or low-grade behavior, but about 20%, most of which are initially larger than 8 cm in diameter, develop metastatic lesions. Metastases are usually within the peritoneal cavity, and rarely to distant sites. 461 The primary treatment is the surgical extirpation of the primary lesion, and there are no reports of effective radiation or chemotherapy.

Sarcomas

Malignant mixed mesodermal sarcomas of the ovary are rare, and only about 100 cases have been reported. 462, 463 Most are heterologous, and 80% occur in postmenopausal women. The presentation is similar to that of most ovarian malignancies, although these tumors are biologically aggressive, and the majority of patients have metastases to organ parenchyma, such as the liver and lung, and to the retroperitoneal lymph nodes.

Adriamycin, with or without cyclophosphamide, has produced an occasional partial response, and cisplatin is currently undergoing clinical trials. 139 Ifosfamide with mesna has been reported to be useful in metastatic sarcomas of the female genital tract, and this combination might be appropriate for the treatment of ovarian sarcomas. Long-term survivors are uncommon, although some stage I patients have survived for 5 years.

Metastatic Tumors

About 5 to 6% of ovarian tumors are metastatic from other organs, most frequently from the female genital tract, the breast, or the gastrointestinal tract. 464, 465 The metastasis may occur from direct extension of another pelvic neoplasm, by hematogenous spread, by lymphatic spread, or by transcoelomic spread, that is, by surface implantation of the peritoneal cavity.

Gynecologic

Nonovarian cancers of the genital tract can spread by direct extension or metastasize to the ovaries. Tubal carcinomas involve the ovaries secondarily in 13% of cases usually by direct extension. 467, 468 Under some circumstances, it is difficult to ascertain 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 (less than 1%), and most of these are of advanced clinical stage or of adenocarcinoma histotype. 468 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 primaries probably occur with greater frequency. In these cases, there is usually an endometrioid carcinoma of the ovary associated with the adenocarcinoma of the endometrium. Malignant melanoma rarely can metastasize to the ovaries 469 .

Non-Gynecologic

The reported frequency of metastatic breast carcinoma to the ovaries varies, but the phenomenon is common. 470 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. 471, 472 Similarly, when ovaries are removed to palliate advanced breast cancer, about 20% to 30% of cases reveal ovarian involvement, 60% bilaterally.487, 137 The involvement of ovaries in early-stage breast cancer appears to be considerably lower, but precise figures are not available. In almost all cases, ovarian involvement either is occult or a pelvic mass is discovered after other metastatic disease becomes apparent.

Krukenberg

The Krukenberg tumor accounts for 30% to 40% of metastatic cancers to the ovaries and for 1% to 2% of all malignant ovarian tumors reported at some institutions. 466 It involves the ovarian stroma and has characteristic mucin-filled, signet ring cells. 2 The primary tumor is most often from the stomach, but less commonly from the colon, breast, or biliary tract, and rarely, from the cervix or bladder. 473 Most are bilateral. The lesions may not be discovered until the primary disease is advanced, and most patients die of their disease within a year. In some cases, a primary tumor is not found.

In other cases of metastasis from the gastrointestinal tract to the ovary, the tumor does not have the classic histologic appearance of Krukenberg tumor, and most of these are from the colon and, less commonly, the small intestine. As many as 1% to 2% of women with intestinal carcinomas will develop metastases to the ovaries during the course of their disease. 473 Prior to exploration for an adnexal tumor in a woman older than 40 years, a barium enema is indicated to exclude a primary gastrointestinal carcinoma with metastases to the ovaries. Metastatic colon cancer can mimic a mucinous cystadenocarcinoma of the ovary. 2, 473

Carcinoid

Metastatic carcinoid tumors are rare, representing less than 2% of metastatic lesions to the ovaries. 474, 475 Conversely, only about 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. Therefore, in perimenopausal and postmenopausal women with an intestinal carcinoid, it is reasonable to remove the ovaries to prevent subsequent metastasis. The discovery of an ovarian carcinoid should prompt a careful search for a primary intestinal lesion. 138

Lymphoma and Leukemia

Lymphoma and leukemia can involve the ovary, and when they do, the involvement is usually bilateral.476,477 Less than 5% of patients with Hodgkin's disease develop lymphomatous involvement of the ovaries, and then typically only with advanced-stage disease. With Burkitt lymphoma, ovarian involvement is very common. Other types of non-Hodgkin lymphoma involve the ovaries more frequently than Hodgkin's disease but 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 non-Hodgkin's lymphoma, and if this circumstance is found, a careful surgical staging is necessary. If a frozen section of a solid ovarian mass reveals a lymphoma, the patient needs a careful operative evaluation, including a palpation of the entire intra-abdominal contents. Treatment for the lymphoma or leukemia involves the use of chemotherapy and/or radiotherapy appropriate for the specific type of primary lesion. Consideration should be given to removal of significantly enlarged ovarian disease to palliate symptoms and possibly to facilitate a response to treatment.

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Copyright © 2003, BC Decker Inc.
Bookshelf ID: NBK13342

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