Dysgerminomas are the most common malignant germ cell tumors, accounting for about 30% to 40% of all ovarian cancers of germ cell origin. 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. 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). 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.
- Ovarian Cancer
- Epithelial Ovarian Cancer
- Nonepithelial Ovarian Cancer
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. 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. 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.
Approximately 5% of dysgerminomas are discovered in phenotypic females with abnormal gonads. 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. 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.
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.
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. 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. 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. 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.
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). 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. 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. 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.
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. 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). 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.
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). 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. The obvious advantage is the preservation of fertility. The most frequently used chemotherapeutic regimens for germ cell tumors are BEP, VBP, and VAC. 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. 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. 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. 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. 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.
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. 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.
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 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.
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. 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. 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.
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. 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.
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.
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%. The 5-year survival for patients with all stages of dysgerminoma is 85%. 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.
With current staging methods, the proportion of relapsing patients should be no more than 15% to 20%. 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.
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 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. The obvious advantage is the preservation of fertility.
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. Alternatively, radiation therapy is effective for this disease.
Revision date: July 6, 2011
Last revised: by Tatiana Kuznetsova, D.M.D.