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. 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.

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. 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.

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. 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.

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. 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 nonuplatinum-based chemotherapy regimens, such as vincristine, actinomycin, and cyclophosphamide (VAC), have been somewhat successful when administered in the adjuvant situation, they have been replaced by platinum-based regimens. 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.

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. Chemotherapy is also indicated in patients who have ascites, regardless of tumor grade. The most frequently used combination chemotherapeutic regimen has been VAC. However, in a GOG study, the relapse-free survival rate in patients with incompletely resected disease was 75%. 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. 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.

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. Overall, the toxicity has been acceptable, and 91 of 93 patients with non-dysgerminomatous 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 non-dysgerminomatous 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). 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. 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. 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.

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. 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. Lesions that are mixed may have a poorer response to treatment. 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.

The most important prognostic feature of the immature teratoma is the grade of the lesion. The 5-year survivals have been reported to be 82%, 62%, and 30% for patients with grade 1, 2, and 3 lesions respectively. 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. 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%). 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.

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Provided by ArmMed Media
Revision date: July 6, 2011
Last revised: by Jorge P. Ribeiro, MD