Ovarian GermCell Tumors: Benign & MalignantWHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC). Germ cell tumors represent a relatively small proportion (~20%) of all ovarian tumors, but are becoming increasingly important in the clinical practice of obstetrics and gynecology. Malignant germ cell tumors of the ovary account for <5% of ovarian cancers in the United States. Most of these neoplasms occur in young women, and extirpation of the disease involves decisions concerning childbearing and probabilities of recurrence. The median age of women diagnosed with a malignant germ cell tumor is 16-20 years, and the range is 6-46 years. Ovarian germ cell tumors are the most common ovarian malignancy in women under the age of 20. After age 20, epithelial ovarian cancer rates exceed germ cell tumor rates (1). These are found in the second and third decades of life and are frequently diagnosed by finding a palpable abdominal mass, often associated with pain. Recent development in chemotherapy has dramatically changed the prognosis for many patients who develop the more aggressive types of germ cell tumors. The purpose of this document is to understand the presentation of disease, surgical management, adjuvant chemotherapy and chemotherapy in advanced stage and recurrent disease. Reproductive function following the treatment of ovarian germ cell tumors is also reviewed. Intraoperative decision making is crucial in preserving reproductive function in girls and young women with malignant ovarian germ cell tumors. The development of effective combination chemotherapy for girls and young women with malignant ovarian germ cell tumors has been one of the true success stories in medicine. This group of ovarian neoplasms consists of several histologically different tumor types and embraces all the neoplasms considered to be ultimately derived from the primitive germ cells of the embryonic gonad. These neoplasms can be divided into three major categories: benign tumors -- almost all of which are accounted for by dermoid cysts; malignant tumors -- arising from constituents of dermoid cysts; and primitive malignant germ-cell tumors -- recapitulate normal embryonic and extra-embryonic cells and structures. The World Health Organization (WHO) classification of germ-cell tumors of the ovary is: Malignant germ-cell tumors of the ovary occur mainly in girls and young women, age between 6 to 40 years with a median age of 16 to 20 years depending upon histologic type. Abdominal pain associated with a palpable pelvic-abdominal mass is present in approximately 85% of patients; acute abdominal pain usually caused by rupture, hemorrhage, or torsion of these tumors. Endodermal sinus tumor or mixed germ-cell tumors are frequently misdiagnosed as acute appendicitis because of their presentation of acute abdomen. Less common signs and symptoms include abdominal distension (35%, and vaginal bleeding 10%). Marked increase in AFP indicates the presence of a germ-cell tumor with yolk-sac component. By and large, patients with ovarian tumors diagnosed during pregnancy can be treated successfully without compromising the health of the fetus. Many germ-cell tumors possess the unique property of producing biologic markers that can be detected in serum. The development of specific and sensitive radioimmunoassay techniques to measure hCG and AFP led to dramatic improvement in monitoring of patients with these tumors. Endodermal sinus tumor and choriocarcinomas are prototypes for AFP and respectively for hCG production. Embryonal carcinoma can secrete both hCG and AFP, but most commonly produces hCG. Mixed tumors may produce either, both, or none of the markers depending on the type and quality of elements present. Dysgerminoma is commonly devoid of hormonal production, although a small percentage of tumors produce low levels of hCG. The levels of AFP or high levels of hCG (>100 U/mL) denotes the presence of tumor elements other than dysgerminoma. Therapy should be adjusted accordingly. A third tumor marker is lactic dehydrogenase (LDH) and is frequently elevated in patients with ovarian germ-cell tumors, particularly in dysgerminoma. It is less specific than hCG or AFP, which limits its usefulness. The level of CA 125 is also elevated in some patients with ovarian germ-cell tumors, but this is also non-specific (2). Surgical staging is essential for determining the extent of disease, for providing prognostic information, and for guiding post-operative management. Staging of ovarian-germ-cell tumors follows the same principles applicable to epithelial ovarian tumors, as described by the International Federation of Gynecologists and Obstetricians (FIGO). FIGO staging of ovarian germ-cell tumors: Stage I Tumor limited to ovaries. IA: Tumor limited to one ovary, no ascites, intact capsule; IB: Tumor limited to both ovaries, no ascites, intact capsule; IC: Tumor either stage IA or IB, but with ascites present containing malignant cells or with ovarian capsule involvement or rupture or with positive peritoneal washings. Stage II Tumor involving one or both ovaries with extension to the pelvis. IIA: Extension to uterus or tubes; IIB: Involvement of both ovaries with pelvic extension. IIC: Tumor either stage IIA or IIB, but with ascites present containing malignant cells or with positive peritoneal washings. Stage III Tumor involving one or both ovaries with tumor implants outside the pelvis or with positive retroperitoneal or inguinal lymph nodes. Superficial liver metastases qualify as stage III. IIIA: Tumor limited to the pelvis with negative nodes but with microscopic seeding of the abdominal peritoneal surface. IIIB: Negative nodes, tumor implants in the abdominal cavity <2cm. IIIC: Positive nodes or tumor implants in the abdominal cavity >2cm. Stage IV Distant metastases present The GOG experience with second-look laparotomy in ovarian germ-cell tumors review of 117 patients enrolled prospectively on one of three GOG protocols using brief cisplatin-based chemotherapy after initial surgical staging and cytoreduction underwent second-look surgical procedures (3). The consensus is the value of second-look surgery in patients with incompletely resected germ-cell tumors not containing teratoma is arguably minimal. However, in the subgroup of patients with incompletely resected tumors containing teratomatous elements (total of 24 patients) second-look surgery had an impact on subsequent management. Advances in imaging technology, including the advent of PET scanning, may further obviate the need for surgical re-exploration. Whereas, PET scanning is sensitive for detecting active (malignant) tumor, its usefulness in evaluating residual mature teratoma is more limited. Whether adjuvant chemotherapy is recommended or not depends on the histologic type of germ cell tumor. For well-staged stage I patients with dysgerminoma and low grade immature teratoma, careful observation and follow-up are sufficient. Long-term survival in patients with stage I dysgerminoma who receive no adjuvant therapy is >90%. Patients with low grade, stage I immature teratoma who receive no adjuvant therapy have similar low rates of recurrence (4). A high percentage of patients with early-stage, completely resected endodermal sinus tumors and embryonal carcinomas relapsed and died. Therefore, patients with completely resected stage I endodermal sinus tumor and embryonal carcinoma, or mixed tumors containing these elements require adjuvant chemotherapy. In addition, patients with stage I non-gestational ovarian choriocarcinomas and stage I high grade immature teratoma should also receive adjuvant therapy. 3 or 4 cycles of bleomycin, etoposide and cisplatin (BEP) given every 21 days is recommended. Discussions of side effects of chemotherapy are important. All women who undergo BEP treatment will develop alopecia while on therapy. Cisplatin induced neurotoxicity and nephrotoxicity, bleomycin-induced pulmonary fibrosis and etoposide-related acute leukemia are rare. The risk of developing etoposide-related acute leukemia has been reported to be approximately 2% (5). In contrast to those with epithelial ovarian cancer, women with advanced-stage germ cell tumors can often be cured. After cytoreduction surgery, patients with metastatic germ cell tumors of all histologies currently receive combination chemotherapy with BEP. For patients with incompletely resected advanced-stage tumor, the prognosis is still good with cure rates of 60-80%. 4-6 courses of BEP given every 21 days should be planned and physicians can follow tumor markers if elevated. Full doses of medication and strict adherence to the schedule are important. Management of Residual or Recurrent Disease: In 90% of germ cell tumors patients who experience a recurrence, it develops in the first 2 years after initial therapy. Patients who have completed therapy are generally seen every 3 months for the first 2 years. Patients who had elevated serum tumor markers may have serum tumor marker studies performed monthly for the first 2 years. Patients with germ cell tumors who initially were treated with surgery alone (stage I dysgerminoma and stage I low grade immature teratoma) can be treated with BEP chemotherapy for recurrence. Patients with no residual disease who received adjuvant chemotherapy and undergoes a recurrence months after completion of treatment can be retreated with a platinum-based regimen. Patients who previously received combination chemotherapy and have persistent or recurrent disease present more challenging management issues. Prognosis is usually better for patients who are platinum sensitive, i.e., showed a response to platinum and progressed later than 6 weeks off treatment. Patients who are frankly platinum resistant will have a poorer prognosis, and treatment options are limited. High-dose chemotherapy with carboplatin and etoposide and stem cell support have been shown in some studies to have 30-50% response rates and 20-34% sustained response rates in testicular germ cell tumors. All of these patients should also be considered for clinical trials. The role of secondary cytoreductive surgery in the management of persistent or recurrent malignant ovarian germ cell tumors is unclear (6). Despite the remarkable radiosensitivity of dysgerminoma, radiotherapy is rarely performed nowadays since chemotherapy is equally or more effective; less toxic and permits preservation of gonadal function. Furthermore, considering the recent developments in the field of chemotherapy, it is accepted that primary chemotherapy is equally or more effective than irradiation of extensive normal tissue volumes, and is subsequently less likely to compromise salvage therapy when patients relapse after primary therapy. Given that most patients will be cured of their ovarian tumors, and that most patients are of relatively young age at diagnosis, some consideration should also be given to the delayed carcinogenic effects of intermediate-dose radiation in young women. Although this issue has not been specifically addressed in women with ovarian germ cell tumors, it is logical to extrapolate from the experience of younger women who are frequently successfully treated with radiation for cancer of the uterine cervix, and in whom the risk of second malignancies (both within and remote from the primary radiation fields) may be elevated two or three decades following successful initial treatment (7). For girls and young women who are successfully treated, questions regarding their ability to conceive and carry a pregnancy in the future become important. Several recent articles confirm that the majority of these young women treated with fertility-sparing surgery with or without chemotherapy are able to conceive and bear children. None of these studies reported an increase in birth defects or miscarriage in women treated with chemotherapy (8). Therefore, young women of reproductive age who are diagnosed with an ovarian germ cell tumor, even advanced disease can expect not only a cure but also preservation of reproductive function. Surgery continues to have a pivotal role in the management of all patients with ovarian germ-cell tumors. Initial careful surgical staging is important for selection of appropriate subsequent therapy. Intraoperative decision making is crucial in preserving reproductive function in girls and young women with malignant ovarian germ-cell tumors. While such tumors are rare, gynecologists should be familiar with the natural history and current management. The judicious use of surgery followed by chemotherapy will cure the majority of patients with ovarian germ-cell tumors at the expense of minimal and predictable immediate and late toxicities. Preserving fertility and decreasing long-term side effects studies in this field will continue to improve efficacy. The evolutionary development and refinement of combination chemotherapy have resulted in the cure of a high percentage of patients with chemosensitive tumors, such as lymphomas, testicular cancer, gestational trophoblastic disease, and malignant ovarian germ-cell tumors. |