Ovarian GermCell Tumors: Benign & Malignant
WHEC 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:
- Dysgerminoma; variant: with syncytiotrophoblast cells
- Yolk-sac tumor (endodermal sinus tumor); variants: polyvesicular vitelline tumor, hepatoid, glandular (variant: "endometroid")
- Embryonal carcinoma
- Teratoma; immature and mature; solid and cystic (dermoid cysts); with secondary tumor formation (specific type)
- Monodermal and highly specialized: Struma ovarii with thyroid tumor (specific type); Carcinoid -- insular and trabecular
- Strumal carcinoid; Mucinous carcinoid; neuroectodermal tumors; Sebaceous tumors
- Others: mixed types
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 and Extent of Primary Surgery:
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).
Proper staging procedures consist of:
- A vertical incision is usually preferred for adequate exposure, appropriate staging biopsies, and for resection of large pelvic tumors or metastatic disease in the upper abdomen.
- Peritoneal fluid collection: if ascites is present, it should be submitted for cytologic analysis. If no peritoneal fluid is noted, cytologic washings of the pelvis and bilateral paracolic gutters should be performed prior to manipulation of the intraperitoneal contents.
- Exploration of pelvic and abdominal cavities in methodical manner. If any suspicious areas are noted, they should be submitted for biopsy or excised. Primary ovarian tumor and both ovaries should be carefully assessed for size, the presence of obvious tumor involvement, capsular rupture, external excrescences, or adherence to surrounding structures. If disease seems to be limited to pelvis or confined to ovary, then random staging biopsies or biopsies of structures at risk should be performed. Any adhesions should be generously sampled.
- The paraaortic and bilateral pelvic lymph nodes should be carefully palpated. Any suspicious nodes should be excised or sampled. There is no evidence that a complete paraaortic and/or pelvic lymphadenectomy are advantageous.
- If obvious gross metastatic areas are present, it should be excised and cytoreductive surgery is helpful.
FIGO staging of ovarian germ-cell tumors:
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.
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.
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.
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).
Reproductive Function following Chemotherapy:
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.
Mature Cystic Teratoma with Recurrence:Mature cystic teratomas, most commonly referred to as dermoids, are one of several noted in the ovary and other organs. The first case of mature cystic teratomas was posthumously noted by Johannes Scultetus in 1659 in a series of cases examined at autopsy. Mature cystic teratomas are common in adolescents and other reproductive-aged women. In one series of women younger than 40 years, mature cystic teratomas represented 62% of all ovarian neoplasm (9). By definition, mature cystic teratomas contain tissue from all three germ cell layers (ectoderm, endoderm, and mesoderm). Ectodermal derivatives are commonly noted, including teeth, hair, and sebaceous material. Malignant transformation occurs in less than 2% of dermoids cysts in women of all ages, and mostly occurs in women older than 40 years. Torsion may occur in 15%, perhaps secondary to the fat content of many cysts, which may allow them to "float" in the abdomen. They may be bilateral in about 10% of cases. Although recommended in the past, bivalving the contralateral ovary for inspection is not recommended at the present time secondary to concern of adhesions and subsequent infertility. An ovarian cystectomy is almost always possible either by means of laparoscopy or laparotomy. Beginning in the mid-1990s, operative laparoscopy became the norm for cystectomy or oophorectomy for treatment of dermoids. Laparoscopy is associated with reduction in postoperative pain, blood loss, and hospital stay. However, there is a potential for increased operating room costs and delay in treatment for ovarian malignancy. Some series of laparoscopic removal report a spillage of cysts contents in 50-70% of cases. Other series have noted no difference in the rate of spillage between laparoscopy and laparotomy (10). The risk of peritonitis with intraoperative spill of sebaceous material has been raised. If this occurs either during laparoscopy or laparotomy, copious irrigation of the pelvis reduces the incidence of postoperative complications to less than 1% of cases. Aqua-dissection or use of an endobag has also been described to decrease the incidence of spill. Formation of adhesions with repeated surgeries is of concern which may be decreased by laparoscopy. Recurrences of dermoids are uncommon. The recommendation for treatment is repeat cystectomy. Exploratory laparotomy is not indicated unless there are other findings suggestive of malignancy. Because most of these patients are of reproductive age and may desire fertility, total abdominal hysterectomy or bilateral salpingo-oophorectomy is not indicated in the absence of malignancy. Observation alone and CA 125 would not be appropriate if patient is symptomatic (11).
Paraneoplastic Encephalitis associated with Benign Ovarian Teratomas:Dermoid cysts are the most common type of benign ovarian neoplasm in reproductive-aged women, accounting for 25% of ovarian neoplasms in premenopausal women (12). While the risk of paraneoplastic encephalitis resulting from dermoids is unknown, it remains an exceedingly rare condition, making serum screening for these patients neither practical nor cost-effective. As this condition becomes better defined, there remains a possible future role for such screening. Patients present with a variety of prodromal symptoms, ranging from headache and hyperthermia to a viral-like respiratory illness. This vague presentation of non-specific complaints may be dismissed or attributed to a variety of benign etiologies. Neuropsychiatric symptoms then develop, including anxiety, agitation, bizarre behavior, auditory hallucinations, delusions, and acute personality changes. The initial evaluation, including complete history and physical examination, basic laboratory analysis, lumbar puncture, brain MRI, and continuous electroencephalogram, refines the differential diagnosis. Ultimately, patients who present with suspected anti-N-methyl-D-aspartate-receptor (anti-NDMA-R) mediated encephalitis must undergo serum and CSF evaluation of anti-NMDA-R antibodies. Positive antibody assays in the setting of the described clinical presentation appear diagnostic of this condition. Current clinical evidence implicates dermoid cysts in anti-NMDA-R encephalitis. This is based on the large prevalence of dermoids found in these cases, the decrease in serum antibodies found after tumor removal, and the positive clinical response to tumor removal. Dermoids appear to have a role in this condition by expression of neural tissue which triggers an immune response resulting in over production of anti-NMDA-R antibodies. All dermoids examined in these patients contained neural tissue, and 100% (25/25) of specimens tested were positive of NMDA receptors (13). Given the recent identification of this condition and the variability of described cases, from spontaneous resolution to death has been reported. There is no identified treatment algorithm to date. The combination of tumor removal and immunotherapy (intravenous immunoglobulin, plasma exchange, corticosteroids) shows superior results in limited case series. Outcomes of this condition vary based on time to diagnosis, neurologic deterioration at diagnosis, identification, and prompt removal of the tumor. Reports document improvement ranging from immediately after initiation of treatment (intravenous immunoglobulin, plasma exchange, corticosteroids, and/or surgery) to 16 weeks after a completed course of therapy (14). While patients can, and do recover with proper treatment, it remains a dangerous condition with significant morbidity and potential mortality. Counseling of patients and families for this guarded prognosis is essential. Anti-NMDA-R-mediated encephalitis is a newly characterized disease with potential morbidity and mortality that is devastating to patients and their families. Within gynecology, increased physician awareness of its possible association with dermoid cysts is critical.
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.
- Young JL Jr, Cheng Wu X, Roffers SD et al. Ovarian cancer in children and young adults in the United States, 1992-1997. Cancer 2003;97:2694-2700
- Sekiya S, Seki K, Nagai Y. Rise of serum CA 125 in patients with pure ovarian yolk sac tumors. Int J Gynecol Obstet 1997;58:323-324
- Williams SD, Blessing JA, DiSaia PJ, et al. Second-look laparotomy in ovarian germ cell tumors: the gynecologic oncology group experience. Gynecol Oncol 1994;52:287-291.
- Brewer M, Gershenson DM, Herzong CE et al. Outcome and reproductive function after chemotherapy for ovarian dysgerminoma. J Clin Oncol 1999;17:2670-2675
- Gershenson DM, Morris M, Cangir A et al. Treatment of malignant germ cell tumors of the ovary with bleomycin, etoposide, and cisplatin. J Clin Oncol 1991;8:715-720
- Lu KH, Gershenson DM. Update on the management of ovarian germ cell tumors. J Rep Med 2005; 50:417-425
- Mitchell MF, Gershenson DM, Soeters RP et al. The long-term effects of radiation therapy on patients with ovarian dysgerminoma. Cancer 1991;67:1084-1090
- Tangir J, Zelterman D, Ma W et al. Reproductive function after conservative surgery and chemotherapy for malignant germ cell tumors of the ovary. Obstet Gynecol 2003;101:251-257
- Benoit MF, Hannigan EV, Strickland JL. Recurrent mature cystic ovarian teratoma in adolescence: atypical case of growing teratoma syndrome. Obstet Gynecol 2005;105:1264-1266
- Kaminski P, Gajewska M, Wielgos M et al. Laparoscopic management of dermoid cysts in patients of reproductive age. Neuro Endocrinol Lett 2006;27:818-821
- Templeman CL, Fallat ME, Lam AM et al. Managing mature cystic teratomas of the ovary. Obstet Gynecol Surv 2000;55:738-745
- ACOG Practice Bulletin. Management of adnexal masses. Bulletin No. 83. The American College of Obstetricians and Gynecologists. Obstet Gynecol 2007;110:201-213
- Dalmau J, Gleichman AJ, Houghes EG et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008;7:1091-1098
- Kort DH, Vallerie AM, DeMarco EF et al. Paraneoplastic Anti-N-Methyl-D-Aspartate-
Receptor encephalitis from mature cystic teratoma. Obstet Gynecol 2009;114:373-376
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