Ovarian Cancer – Germ Cell and Stromal Cancers
1. What every clinician should know Are you sure your patient has the disease? What should you expect to find?
Germ cell and sex cord-stromal tumors are rare gynecologic malignancies, comprising less than 15% of ovarian cancers combined. In general, these types of tumors affect young women and present in early stage disease, which governs the treatment rationale. Each group is composed of a variety of histologic subtypes, but despite this variation, they are treated using the same general clinical and surgical principles.
The most common types of germ cell tumors are dysgerminomas, endodermal sinus tumors (otherwise known as yolk-sac tumors), and immature teratomas. Other types, including nongestational choriocarcinoma, embryonal carcinoma, and polyembryomas are extremely rare and are typically seen as a component of mixed germ cell tumors when they do occur. The most common types of sex cord-stromal tumors include granulosa cell and Sertoli-Leydig tumors.
Granulosa cell tumors, which account for approximately 70% of sex cord-stromal tumors, mostly affect women who are peri- or post-menopausal. Juvenile granulosa cell tumors typically affect younger women, but only account for a fraction of the total number of granulosa cell tumors. Sertoli-Leydig tumors, like germ cell tumors, also are noted more frequently in younger women. Other quite rare malignant histologic sex cord-stromal tumor subtypes include gynandroblastoma, sex cord tumor with annular tubules, and steroid cell tumors not otherwise specified.
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Various tumor markers have been validated in germ cell and sex cord-stromal tumors. Lactate dehydrogenase (LDH) is commonly elevated in patients with dygerminomas; if syncytiotrophoblasts are present within a dysgerminoma, b-hCG may also be elevated. Endodermal sinus tumors and immature teratomas can secrete alpha fetoprotein. A combination of these markers may be elevated in mixed germ cell tumors, depending on the composition of the tumor. Inhibin B and anti-Müllerian hormone are usually elevated in patients with granulosa cell tumors, and testosterone is elevated in approximately 40% of patients with Sertoli-Leydig tumors.
Given that the majority of women who are affected by germ cell tumors are less than 30 years of age at the time of diagnosis, future fertility is generally a significant consideration when planning treatment. Conservative surgery has been shown to preserve reproductive potential without increasing cancer-related mortality. Removal of just the affected ovary in the young ovarian germ cell cancer patient desiring future fertility, along with appropriate staging with omentectomy, selected peritoneal biopsies, and lymphadenectomy, is an important component of the management of germ cell tumors. In contrast, sex cord-stromal tumors rarely metastasize to the lymph nodes, even in advanced stage disease. Therefore, lymphadenectomy can be safely omitted. The endometrium should be evaluated in women with a granulosa cell tumor due to the high incidence of concomitant endometrial pathology. Debulking of advanced stage disease improves outcome for women with either germ cell or sex cord-stromal tumors.
Adjuvant therapy consisting of bleomycin, etoposide, and cisplatin (BEP) is very effective for the management of selective early stage and all advanced stage germ cell tumors of the ovary. Various adjuvant therapies have been utilized to treat advanced stage or recurrent granulosa cell and other select stromal tumors. These therapies most commonly include BEP and paclitaxel and carboplatin.
2. Diagnosis and differential diagnosis
The two most frequent presenting symptoms in women with germ cell or sex cord-stromal tumors are abdominal pain and palpable mass, as these types of tumors are generally large and grow rapidly. Patients can also present with stigmata of hormonal excess. Patients with embryonal carcinoma, nongestational choriocarcinoma, granulosa cell tumor, and Sertoli-Leydig tumor may have precocious puberty, primary or secondary amenorrhea, irregular vaginal bleeding, postmenopausal bleeding, and hirsutism, depending on patient age and tumor type.
In addition to an ovarian neoplasm, the differential diagnosis for a young female patient who presents with severe abdominal pain needs to include miscarriage, ectopic pregnancy, ruptured ovarian cyst, ovarian torsion, pelvic inflammatory disease, and tubo-ovarian abscess. An abdominal exam should assess for peritonitis and location of pain. A pelvic exam should be performed to rule out a pelvic mass, and an ultrasound should be obtained. A transvaginal ultrasound will yield the most information, but, depending on a patient’s age and prior sexual history, an abdominal ultrasound may be more appropriate. In general, sonographic findings typical of a germ cell or stromal cell tumor include a large solid irregular mass with varying degrees of vascularity, necrosis, and calcification. A large amount of ascites in the pelvis is abnormal and strong consideration should be given to a neoplastic process. Endometrial thickening is often noted in patients with granulosa cell tumors.
Appropriate tumor markers will also help narrow the differential. A urine pregnancy test or serum b-hCG should be first obtained to help rule out complications related to pregnancy (i.e., miscarriage, ectopic pregnancy, or hemorrhagic ovarian cyst); however, an elevated b-hCG does not rule out an ovarian neoplasm. Dysgerminomas with a syncytiotrophoblastic component and mixed germ cell tumors can secrete b-hCG. Rare types of germ cell tumors, such as embryonal carcinoma, nongestational choriocarcinoma, and polyembryoma can also be associated with an elevated b-hCG.
Other tumor markers should be considered, but may not be readily available to assist in the immediate management of a patient. For example, lactate dehydrogenase is characteristically elevated in patients with dysgerminomas, although specific normal ranges are laboratory-dependent. Sex cord-stromal tumors, being hormonally active, can have elevated estrogen or testosterone levels, especially if there is evidence of precocious puberty or virilization, respectively. If a patient with a Sertoli-Leydig tumor presents with virilization, testosterone can be used as a tumor marker, but only 40% of patients have signs of androgen excess.
While elevated in 70% of patients with granulosa cell tumors, estrogen is fairly non-specific. Inhibin is a peptide hormone secreted by granulosa cells that varies inversely with FSH. Inhibin B was shown to be a sensitive and specific marker for granulosa cell tumors and is now used widely in the treatment phase to follow disease burden. Similarly, anti-Müllerian hormone (AMH, also known as Müllerian-inhibiting substance) is a glycoprotein secreted by granulosa cells surrounding developing follicles. It varies in concentration throughout the menstrual cycle and becomes undetectable after menopause. In a comparative study, it was found that inhibin and AMH have similar prognostic value and therefore can be used to monitor patients with granulosa cell tumors.
Due to the often-rapid enlargement of sex cord-stromal and germ cell tumors, ovarian torsion and rupture of tumor capsule leading to hemoperitoneum are not uncommon presentations. Both conditions are surgical emergencies that require immediate support and intervention. If a mass is noted on imaging and the patient has other symptoms suspicious of one of these ovarian tumor types, tumor markers should be drawn prior to surgery and an appropriate subspecialist should be consulted for possible assistance with surgical staging, if feasible.
Certain germ cell and sex cord-stromal tumors are associated with chromosomal disorders. Up to 10% of patients with dysgerminomas are diagnosed with concomitant gonadoblastomas, which are associated with gonadal dysgenesis syndromes, such as Turner’s syndrome (karyotype 45, XO), Klinefelter’s syndrome (karyotype 47, XXY), and Swyer’s syndrome (karyotype 46, XY with complete gonadal dysgenesis). If stigmata of gonadal dysgenesis such as primary amenorrhea, blind vaginal pouch, or ambiguous genitalia are present in patients with dysgerminomas, karyotype should be performed to rule out gonadal dysgenetic syndromes and consideration should be given to prophylactic oophorectomy to prevent further development of malignancy.
Sex cord tumor with annual tubules, a histology that is considered to be an amalgam of both Sertoli and granulosa cell tumors, has up to a 33% association with Peutz-Jeghers syndrome (PJS). PJS is an autosomal dominant syndrome that is associated with an increased risk of breast, gynecologic, and GI malignancies in affected women. Diagnosis of PJS is clinical, and only 50%-60% of affected individuals are positive for known mutations. Women who are diagnosed with PJS should undergo regular cancer screening starting at an early age. A detailed personal and family history should be obtained from any patient with annular tubules diagnosed with sex cord tumor to exclude the possibility of PJS.
3. Management
A. What therapies should you initiate immediately, i.e., emergently?
As discussed earlier, a germ cell tumor should be high on the differential for any woman of reproductive age who presents with abdominal pain and pelvic mass. An acute abdomen in an unstable patient is a surgical emergency and the patient should undergo expeditious surgical exploration. If a large ruptured pelvic mass is noted, it should be removed and sent for frozen section. Fertility-sparing therapy should be the mainstay of treatment in either the unstable or stable young patient with a pelvic mass suggestive of a germ cell tumor. Most germ cell tumors are confined to a single ovary; dysgerminomas may affect both ovaries in less than 10% of patients.
Thus, unilateral salpingoophorectomy does not compromise survival. Biopsy of a contralateral normal-appearing ovary is not necessary or recommended due to low yield and possible compromise of future fertility. Staging with lymphadenectomy, omentectomy, and selective peritoneal biopsies in most patients with a suspected germ cell tumor is also important. Almost 30% of patients with dysgerminomas will have positive lymph nodes, and a significant 5-year survival advantage for women who undergo a full staging procedure has been shown. All efforts should be made to achieve optimal cytoreduction, defined as residual tumor implants < 1 cm, in patients with obvious advanced stage disease as this has been shown to strongly correlate with survival.
Pathologic examination is generally required for definitive diagnosis of germ cell tumors, and even then expertise in these malignancies is needed to distinguish between types. However, there are pathognomonic features of the most common types of germ cell tumors. Epithelioid cells arranged in sheets or small clusters with lymphocyte infiltration are characteristic of a dysgerminoma. Schiller-Duval bodies, comprised of a central capillary surrounded by connective tissue and peripheral columnar cells located in cavities lined by endodermal sinus tumor cells, are pathognomonic for EST but are not always present. Immature teratomas are distinguished from their mature counterparts by amount of immature neural tissue that is present on a low power field of microscopic examination; the greater the amount, the higher the grade.
Call-Exner bodies are small eosinophilic bodies between tumor cells that are often found in adult granulosa cell tumors, but not in juvenile granulosa cell tumors. Likewise, “coffee-bean” nuclei, which are nuclei that have longitudinal grooves that are characteristically seen in adult GCT, are also used to distinguish the two variants of granulosa cell tumor. Sertoli-Leydig tumors that are primarily composed of tubular structures are considered well-differentiated and are generally benign; tumors that recapitulate the embryonic testis or have heterologous elements such as intestinal-type epithelium and cartilage are considered to be moderately- to poorly-differentiated and are associated with a poorer prognosis
B. What should the initial definitive therapy for the cancer be?
Germ cell tumors are exquisitely chemosensitive, therefore even patients with advanced-stage disease, if optimally debulked, have an excellent five-year prognosis. Well-staged patients with a stage Ia dysgerminoma or a stage Ia grade 1 immature teratoma will not require adjuvant chemotherapy. In general, all other germ cell tumor patients will require adjuvant chemotherapy, although there has been a trend (especially in the pediatric population) towards intense surveillance of stage I tumors of all germ cell types and deferral of chemotherapy until recurrence.
Chemotherapy regimens utilized for germ cell tumors of the ovary have largely been derived from those used successfully in germ cell tumors of the testes. The Gynecologic Oncology Group conducted two prospective phase II trials evaluating BEP in patients with all stages of germ cell tumors treated. The specific regimen included bleomycin 30 units IV days 1, 8 and 15 of each cycle; etoposide 100mg/m2 IV daily days 1-5 of each cycle; and cisplatin 20mg/m2 IV daily days 1-5 of each cycle for 3-4 cycles depending on the stage of disease and the amount of residual tumor. These studies established the significant efficacy of this combination, with an overall 97.8% durable response rate.
Specific complications from BEP should be carefully monitored for. Approximately 25% of patients on this regimen develop febrile neutropenia, but any treatment delay can influence outcome. Therefore, patients should be supported with colony-stimulating factors and broad-spectrum antibiotics as needed. Cisplatin is a well-known nephrotoxin, therefore patients must have adequate renal function and be well-hydrated during infusion. Peripheral neuropathy remains a significant side-effect, but no effective treatment has been found. Bleomycin, an antibiotic cytopathic agent, is associated with bleomycin-induced pneumonitis that can progress to life-threatening pulmonary fibrosis. This is generally dose-related and is rarely seen if the cumulative bleomycin dose is less than 300 mg.
Pulmonary function tests are used to monitor for signs of bleomycin toxicity, but the most sensitive predictor of clinically significant lung injury is development of fine rales bilaterally at the lung bases that do not clear with cough on lung exam. Etoposide is a topoisomerase II inhibitor that can cause secondary malignancies. In patients who receive more than 2000 mg/m 2, the risk of a secondary hematologic malignancy approaches 5%. While these risks exist, most patients suffer no significant long-term consequences, and the long-term survival benefits in patients with germ cell tumors far outweigh the risks.
Surveillance is critical to detect recurrences. Most patients with germ cell tumors relapse within 24 months of initial diagnosis, therefore frequent monitoring can identify recurrent disease early and salvage therapy can be instituted rapidly. The surveillance strategy includes physical exams, appropriate tumor markers, and imaging as needed for up to ten years at lengthening intervals.
Because recurrence is so rare in patients with even advanced stage germ cell tumors, little data exists regarding the appropriate regimen for a patient who has relapsed. The data that do exist has been extrapolated from the treatment of analogous, more common testicular tumors. Regimens that are acceptable according to the NCCN include paclitaxel/ifosfamide/cisplatin (TIP), vincristine/adriamycin/cisplatin (VAC), vinblastine/ifosfamide/cisplatin (VeIP), vincristine/ifosfamide/cisplatin (VIP), cisplatin/etoposide, docetaxel/carboplatin, paclitaxel/carboplatin, paclitaxel/gemcitabine, paclitaxel/ifosfamide, and single agent taxane. High-dose chemotherapy with stem cell rescue may also be an option.
Patients diagnosed with a sex cord-stromal tumor generally present with early stage disease. Adjuvant chemotherapy for these patients is not indicated. The hallmark of adult granulosa cell tumors is that of indolence with late abdominal-pelvic recurrences. Sertoli-Leydig tumors, if well-differentiated, rarely recur. Median time to recurrent disease is approximately six years in patients with adult granulosa cell tumors, but there are case reports documenting recurrent disease 30 to 40 years after initial diagnosis. Therefore, regular surveillance with appropriate tumor markers and imaging is a lifelong necessity. Surveillance schedules for Sertoli-Leydig tumors have not been established given the rarity of the disease and the even rarer event of a recurrence. Secondary surgical debulking is often utilized in the setting of recurrent granulosa cell and Sertoli-Leydig cell tumors.
In contrast to germ cell tumors, sex cord-stromal tumors are relatively chemo-insensitive. BEP has been demonstrated to have some activity in patients with metastatic or recurrent granulosa cell cancer. Given the limitations in activity and potential toxicity associated with BEP, there has been interest in other agents. Paclitaxel and carboplatin have been used in case series in patients in both the adjuvant and recurrent setting. The overall response rate was just over 50%. Although BEP and paclitaxel/carboplatin appear to have essentially equal efficacy, many physicians will consider using the latter regimen given its more favorable toxicity profile.
Alternate therapies for patients with a granulosa cell tumor have also been investigated. These tumors are hormonally active, therefore use of agents such as anastrazole (an aromatase inhibitor), GnRH agonists, megace, and tamoxifen has been detailed with various successes in case reports and in a small series of women with recurrent granulosa cell tumor. Up to 70% of patients have been reported to have at least a partial response to these agents. Recently, interest in bevacizumab, a monoclonal antibody to VEGF, has risen given its activity in epithelial ovarian cancers. A case series of eight heavily pretreated patients who were given bevacizumab showed a response rate of 38%.
4. Prognosis and outcome
A. What would you tell a patient and their family about the prognosis?
Germ cell tumors have become almost curable diseases since the advent of combination chemotherapy. Overall, the five-year survival for patients with a localized germ cell tumor is 98.4%, and that for regional or distant disease is 89.6%. Women with early-stage sex cord-stromal tumors also have a similar excellent five-year survival rate of 95%. However, women with advanced stage disease have only a 59% five-year survival rate. This likely is due to the difference in chemosensitivity of the two groups of tumors, as discussed above.
Retention of fertility is an important concept in many patients diagnosed with germ cell and sex cord-stromal tumors. As mentioned previously, fertility-sparing surgery has become standard surgical treatment, without compromise of survival rates. Numerous case series have documented successful pregnancies after conservative surgery and chemotherapy without concomitant increase in fetal defects or pregnancy-related complications.
In summary, germ cell and sex cord-stromal tumors are rare ovarian malignancies that primarily affect young women. Appropriate surgical management is key to identifying the stage of disease and debulking metastatic disease, parameters which significantly affect prognosis. Fortunately, most patients affected by one of these tumors are diagnosed with early stage disease.
Adjuvant treatment for patients with a germ cell tumor, when indicated, is reasonably tolerated and highly effective. For those patients with advanced or recurrent sex cord-stromal tumors, secondary debulking and appropriate use of adjuvant chemotherapy may significantly prolong overall survival. Involvement of a specialist in the management of patients with a suspected or diagnosed germ cell or sex cord-stromal tumor is strongly advised.
5. What is the evidence for specific management and treatment recommendations?
Williams, SD, Birch, R, Einhorn, LH, Irwin, L, Greco, FA, Loehrer, PJ. “Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide”. N Engl J Med. vol. 316. 1987. pp. 1435-40. (Superiority of BEP over other chemotherapeutic regimens in advanced-stage germ cell tumors.
Williams, S, Blessing, JA, Liao, SY, Ball, H, Hanjani, P. “Adjuvant therapy of ovarian germ cell tumors with cisplatin, etoposide, and bleomycin: a trial of the Gynecologic Oncology Group”. J Clin Oncol. vol. 12. 1994. pp. 701-6. (Rationale for adjuvant chemotherapy in germ cell tumors.)
Kumar, S, Shah, JP, Bryant, CS. “The prevalence and prognostic impact of lymph node metastasis in malignant germ cell tumors of the ovary”. Gynecol Oncol. vol. 110. 2008. pp. 125-32. (Importance of correct staging in germ cell tumors.)
Patterson, DM, Murugaesu, N, Holden, L, Seckl, MJ, Rustin, GJ. “A review of the close surveillance policy for stage I female germ cell tumors of the ovary and other sites”. Int J Gynecol Cancer. vol. 18. 2008. pp. 43-50. (Surveillance strategy for early stage germ cell tumors.)
Lai, CH, Chang, TC, Hsueh, S. “Outcome and prognostic factors in ovarian germ cell malignancies”. Gynecol Oncol. vol. 96. 2005. pp. 784-91. (Survival rates for patients with germ cell tumors after institution of combination chemotherapy.)
Zanetta, G, Bonazzi, C, Cantu, M. “Survival and reproductive function after treatment of malignant germ cell ovarian tumors”. J Clin Oncol. vol. 19. 2001. pp. 1015-20. (Reproductive outcomes after BEP chemotherapy.)
Zhang, M, Cheung, MK, Shin, JY. “Prognostic factors responsible for survival in sex cord-stromal tumors of the ovary–an analysis of 376 women”. Gynecol Oncol. vol. 104. 2007. pp. 396-400. (Important prognostic factors in women with sex cord-stromal tumors.)
Brown, J, Sood, AK, Deavers, MT, Milojevic, L, Gershenson, DM. “Patterns of metastasis in sex cord-stromal tumors of the ovary: Can routine staging lymphadenectomy be omitted”. Gynecol Oncol. vol. 113. 2009. pp. 86-90. (Rationale for omitting lymphadenectomy in patients with sex cord-stromal tumors.)
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