Ovarian Dysgerminomas

INTRODUCTION

Background: The 3 major types of ovarian tumors are epithelial, sex cord, and germ cell. Epithelial cell tumors represent the majority of all ovarian neoplasms (82%). Conversely, germ cell tumors (GCTs) are rare, comprising approximately 20% of all ovarian tumors, both benign and malignant. Approximately 3-5% of ovarian GCTs are malignant. The most commonly occurring GCT is the dysgerminoma, which accounts for only 1-5% of all ovarian cancers.

Although rare, dysgerminomas are important beyond mere incidence because they affect women of reproductive age (ie, <30 y). In fact, dysgerminomas make up two thirds of all malignant ovarian neoplasms in women younger than 20 years. Moreover, once diagnosed, dysgerminomas respond highly to the prescribed treatments, rescuing patients from infertility and early mortality.

Pathophysiology: Typically, germ cells are encapsulated at birth within the primordial follicle. Should they somehow escape encapsulation, cell death usually occurs. Should the germ cells survive, rapid growth ensues because no cellular contexts exist that can provide normal contact inhibition, hence GCT formation. All dysgerminomas are considered malignant, but only one third of dysgerminomas behave aggressively. The exact etiology of dysgerminomas has not been determined.

Frequency:

• In the US: The incidence of dysgerminomas has remained unchanged over the last 30 years.

  The frequencies of the most common malignant ovarian neoplasms in women of reproductive age are as follows: epithelial (42%), dysgerminoma and other germ cell tumors [GCT] (30%), metastatic Krukenberg (14%), and sex cord stromal (Sertoli-Leydig cell tumors)[SLCT] (13%).

• Internationally: No data are available.

Mortality/Morbidity: The 5-year survival rate is 96% if the tumor is confined to the ovary and 63% if extension occurs beyond the ovaries. Pregnancy does not alter the prognosis of most ovarian malignancies, but complications such as torsion and rupture may increase the incidence of spontaneous abortion or preterm delivery.

Race: No racial predilection exists for ovarian germ tumors.

CLINICAL

History: No specific symptoms are diagnostic of dysgerminoma tumors. Many of the presenting symptoms are universal for any adnexal/ovarian mass.

• Most common presenting symptoms

• Pelvic fullness

• Pain

• Early satiety

• Urinary frequency

• Dysuria

• Vague abdominal complaints (eg, dyspepsia, digestive disturbances) are less common symptoms.

• These tumors usually present as a unilateral mass and can occur during pregnancy.

Physical: The physical examination should include a thorough abdominal and pelvic examination on a gynecology table with stirrups. The examiner also must perform a careful rectovaginal examination because some enlarged adnexal masses can be appreciated from this approach.

WORKUP

Lab Studies:
　

• Regardless of the clinical environment, obtain a urine pregnancy test. This test should be mandatory in any woman of reproductive age who presents with abdominopelvic symptoms.

• Document a guaiac test during the physical examination.

• Since dysgerminoma tumors affect women of a reproductive and sexually active age, cultures for gonorrhea and chlamydia and a wet mount are indicated at the time of speculum examination, especially if patients experience abdominopelvic pain. In this way, sexually transmissible diseases may be screened for and treated before surgery.

• The standard workup for suspected GCTs requires alpha-fetoprotein (AFP) and beta human chorionic gonadotropin (bHCG) levels, since these agents have endocrine activity. Dysgerminomas (a germ cell subtype) are an exception to this rule. The absence of an elevated AFP or bHCG does not exclude the diagnosis of dysgerminomas because they rarely produce hormones. In extremely rare cases, dysgerminomas can become infiltrated with syncytiotrophoblastic giant cells, which produce human chorionic gonadotropin. Regardless, if the differential diagnosis includes dysgerminoma, AFP and bHCG levels are highly recommended.

• Useful tumor markers for dysgerminomas

• bHCG
• AFP
• Lactate dehydrogenase (LDH)
• Cancer antigen 125 (CA125)
• These markers also can be used for postoperative follow-up care or for tracking the success of adjuvant therapy.

Imaging Studies:
　

• Imaging should never replace a careful history and physical examination in evaluating a patient with an ovarian mass. The initial approach should be an attempt to determine the nature and extent of the mass. Transvaginal ultrasound is a good preliminary imaging modality to determine if the mass is ovarian and, more importantly, if it has any malignant features (eg, thickened septations, solid and cystic components). Free abdominal fluid and bilateral masses heighten the suspicion of malignancy.

• Secondary imaging studies are used to rule out metastasis.

• Chest x-rays are performed to rule out pulmonary spread.

• Depending on the age of the patient, a preoperative mammogram is suggested to rule out primary metastasis if no study was performed 6-12 months before surgery.

• Body imaging with CT scanning and MRI can be of value in patients with GI or genitourinary signs of obstruction. In these cases, additional studies also include the following:

• Barium enema
• Upper GI series
• Colonoscopy
• Intravenous pyelography (IVP)

• Bedside ultrasonography concomitant with the physical examination, although helpful, is not indicated as a routine screening test.

Procedures:
　

• Dysgerminomas, like all ovarian cancers, can be staged only surgically. Since 5% of all Ia tumors can have occult microscopic disease on the contralateral ovary, performing a biopsy of the other ovary is recommended highly, especially if the ovary is enlarged or appears abnormal.

Histologic Findings: Grossly, dysgerminomas have a solid texture, with a tan, fleshlike appearance. Microscopically, dysgerminoma cells are round and ovoid and contain an abundance of clear cytoplasm secondary to glycogen buildup. The nuclei are irregularly shaped and contain more than 1 prominent nucleoli. These cells tend to coalesce, forming cords and sheets that are identified easily through low-power magnification. Granulocytic and lymphocytic infiltration within the intervening fibrous stroma also can be appreciated. Interestingly, cystic teratomas occasionally have small nests of dysgerminomatous tissue and vice versa.

Staging: International Federation of Gynecology and Obstetrics (FIGO) staging

• Stage I - Limited to ovaries

• Ia - Limited to 1 ovary
• Ib - Limited to both ovaries
• Ic - Ascites with malignant cells on peritoneal washings or extension beyond the capsule in either Ia or Ib

• Stage II - Pelvic extension

• IIa - Involvement of uterus or fallopian tubes
• IIb - Extension to the bladder or rectum
• IIc - Stage IIa or IIb but with positive peritoneal washings

• Stage III - Peritoneal implants outside of pelvis

• IIIa - Microscopic seeding of abdominal surfaces
• IIIb - Abdominal peritoneal implants smaller than 2 cm
• IIIc - Abdominal implants larger than 2 cm or positive lymph nodes

• Stage IV - Distant metastases

• Pleural effusions - Must confirm with positive cytology to be deemed stage IV
• Any involvement of the liver parenchyma

• During laparotomy, the contralateral ovary should be biopsied because 5% of all Ia cancers established by gross inspection will have occult microscopic disease on the opposite ovary. Some advocate leaving the opposite ovary undisturbed if it is of normal size or appearance.

TREATMENT

Medical Care: A preponderance (75-80%) of dysgerminomas present as stage I cancers and, therefore, can be treated by surgical resection alone with a unilateral salpingo-oophorectomy. This is preferred when attempting to preserve fertility; however, diligent follow-up care, with serial pelvic examinations and tumor markers (ie, hCG, AFP, LDH) is mandatory if resection is the only treatment modality.

The role of adjuvant therapy should be reserved for resectable yet advanced tumors. Chemotherapy usually is the adjuvant of choice to spare fertility and is used with recurrence after radiation therapy. Radiation therapy can be administered to patients with tumors that are stage I-III.

• Adjuvant chemotherapy

• The 4 regimens for chemotherapy are as follows: (1) vincristine, actinomycin D, and cyclophosphamide (VAC), (2) methotrexate, actinomycin D, and chlorambucil (MAC), (3) vincristine, bleomycin, and cisplatin (VBP), (4) bleomycin, etoposide, and cisplatin (BEP). Although the efficacy has been analyzed for each protocol, advanced disease or recurrent dysgerminoma is more responsive to the BEP protocol.

  　

• Bleomycin, etoposide, and cisplatin protocol
  • Bleomycin - Max 30 U IV per wk X 9; dose at 20U/m²
  • Etoposide - VP-16 100 mg/m² days 1-5 q3wk X 3; reduced 20% for granulocytic fever or previous radiotherapy
  • Cisplatin - 20 mg/m² days 1-5 q3wk X 3
• Vincristine, actinomycin D, and cyclophosphamide protocol
  • Vincristine - 1.5 mg/m²; max 2.5 mg qwk X 12
  • Actinomycin - 0.5 mg IV over 5 d q4wk
  • Cyclophosphamide - 5-7 mg/kg over 5 d q4wk
• Vincristine, bleomycin, and cisplatin protocol
  • Vinblastine - 12 mg/m² q3wk X 4 courses
  • Bleomycin - 20 U/m² (max 30 U) qwk X 7 courses, with 8th course given in wk 10
  • Cisplatin - 20 mg/m² qd X 5 q3wk for 3-4 courses

• Antiemetics

• Chlorpromazine - 25-50 mg PO/IM/PR q4h
• Lorazepam 1-2 mg PO/IV q6h
• Dexamethasone 8 mg IV prior to cisplatin and 4 mg q4h X 2

• Radiation therapy

• Radiation is used to treat periaortic and pelvic lymph node metastases. Shielding the remaining ovary in an attempt to preserve fertility is not uncommon. Oophoropexy also may be used to hold the remaining ovary mechanically away from the radiation field.
• Radiation therapy is recommended for any dysgerminomas staged Ib-III. The field of exposure extends from T11-L5, with shielding of the contralateral ovary and the femur head.
• The use of radiation in stage Ia cancers is considered precautionary. Most patients present with stage I disease and usually can be treated with simple resection (eg, unilateral salpingo-oophorectomy).
• De Palo, Freed, and Lawson developed the 3 major radiation therapy protocols. These protocols differ mainly in their treatment of the abdomen for node-positive disease and in prophylactic treatment of the mediastinum.
• Primary therapy with radiation is reserved for patients who are incapable of tolerating chemotherapy or surgical resection.

Surgical Care: Patients undergoing surgery for ovarian cancer require a mechanical and/or antibiotic bowel preparation before surgery. This contingency planning is critical in the case of unsuspected GI spread requiring bowel resection. Additionally, nutritional supplementation may be necessary, depending on the status of the patients.

• Dysgerminoma disease staged below Ia (ie, confined within the capsule of only 1 ovary) is best treated with simple unilateral salpingo-oophorectomy.

• A biopsy should be performed on the contralateral ovary at the time of surgery if the ovary is enlarged or appears abnormal. Otherwise, performing a biopsy of a normal contralateral ovary only diminishes fertility by adhesion formation postbiopsy.

• Thorough studies have questioned the prophylactic removal of both ovaries. Current recommendations advise against removal of the normal ovary because this does nothing to reduce the risk of ovarian cancer and commits patients to early menopause and infertility.

• Residual microscopic disease is extinguished readily with chemotherapy and radiation therapy, to which these cells are highly responsive. Clinical oncologists and women wishing to preserve fertility have accepted adjuvant therapy and sparing of the healthy contralateral ovary. . Recurrence after chemotherapy and radiation therapy is highly uncommon, although the literature reports 1 case.

• Bilateral disease is justification for bilateral salpingo-oophorectomy. A total abdominal hysterectomy is not mandatory, but may be performed concurrently if patients are no longer interested in bearing children.

• Full staging is completed with peritoneal washings, infracolic omentectomy, and lymph node biopsy before closure. A biopsy for unilateral disease may be performed on the ipsilateral pelvic lymph nodes. Periaortic lymph node sampling should be performed in both circumstances. Take great care to observe carefully the retroperitoneal lymph nodes because these are the most common sites of metastasis for this disease.

• According to current American College of Obstetrics and Gynecology (ACOG) recommendations, second-look laparotomies are not considered the standard of care for dysgerminomas.

Consultations:

• Preoperative evaluation by a gastroenterologist is ideal in patients who present with intestinal complaints.

• Consultation with a gynecologic oncologist is recommended when resection requires surgery beyond the straightforward bilateral salpingo-oophorectomy and hysterectomy.

• Further follow-up with oncology and/or radiation therapy is dictated by the stage and extent of disease.

Diet:

• No special diet is recommended, although total parenteral nutrition and supplementation is indicated in patients who are severely malnourished.

• The protein requirement, as with any cancer population, is increased due to increased metabolic demands for nitrogen balance.

• Patient body weight is a good indication of overall oral and protein/calorie intake.

• Anorexia due to food aversion, nausea, or generalized weakness should be treated with antiemetics and enteric or parenteral nutritional support.

Activity:

• During the immediate postoperative recovery, advise patients not to lift heavy objects to prevent strain on the abdominal wound.

• Patients may resume sexual activity if they do not have discomfort; otherwise, painful intercourse should be discouraged because this may lead to dyspareunia.

MEDICATION

The goals of pharmacotherapy are to reduce morbidity, prevent complications, and induce remission.

Drug Category: Antineoplastics -- Treatment entails chemotherapy and radiation therapy. Lesions staged higher than stage Ia require a combination of VAC, VBP, or BEP.

FOLLOW-UP

Further Inpatient Care:
　

• Follow-up care and treatment is conducted in the outpatient setting (see Further Outpatient Care).

Further Outpatient Care:
　

• Follow-up care depends on the status of metastatic disease. If no metastasis is observed at the time of laparotomy or laparoscopy, conduct observation and a physical examination every 2 months for the first 2 years, then every 6 months.

• A CT scan should be performed during months 6 and 12.

MISCELLANEOUS

Medical/Legal Pitfalls:

• Failure to observe until 16 weeks gestation before performing surgery on a pregnant patient with a presumed dysgerminoma

• Failure to remove all gonads in patients with concomitant karyotypic abnormalities due to risk of gonadoblastoma formation

• Five percent of all dysgerminomas are associated with genetic disorders of the ovaries (ie, karyotypic abnormalities - 46XY testicular feminization, gonadal dysgenesis; 45X/46XY mixed gonadal dysgenesis). Typically, these individuals have streak gonads. Under these unusual circumstances, the surgeon must remove both the dysgerminoma and the contralateral streak gonad to prevent gonadoblastoma formation. Since these individuals already are sterile, fertility preservation is not an issue.

• Individuals with a Y chromosome revealed through karyotyping require a delayed gonadectomy after puberty because secondary sexual characteristics should be allowed to develop before removal.

• Medical abnormalities associated with each respective genetic disease also must be addressed.

Special Concerns:
　

• Management in pregnancy

• Fortunately, most adnexal masses found in pregnancy resolve spontaneously within the first trimester. For this reason, a more cautious observational approach is advocated up to 16 weeks gestation. Moreover, risk of aborting a viable fetus with surgery in the first trimester approaches 30%.

• Two percent of masses presenting in pregnancy are malignant (dysgerminomas included). Most (90%) dysgerminomas found in pregnancy are unilateral.

• If surgery is indicated, the ideal intervention time is 16-18 weeks gestation. General anesthesia should be used. Placement of a higher-than-usual vertical or paramedian incision is necessary because the ovary becomes an abdominal structure after 16 weeks.

• Avoid biopsy of the contralateral ovary if the ovary appears normal.

• Also avoid lymph node sampling if the uterus proves obfuscatory.

• Frozen sections should be taken at the time of surgery. If the pathology is hyperreactioluteinalis or luteoma, nonintervention is indicated and the abdomen should be closed.

• Benign or low-grade tumors generally require unilateral salpingo-oophorectomy, whereas bilateral involvement and malignant or metastatic tumors require bilateral salpingo-oophorectomy ?total abdominal hysterectomy. If patients are at or near term, delivery of the fetus is performed, otherwise, pregnant patients with flagrant bilateral malignancies should be treated as if they are not pregnant and should receive a total abdominal hysterectomy and bilateral salpingo-oophorectomy.

• Postoperative progesterone has unproved efficacy. Use of tocolytics postoperatively has not been studied well.

• The 5-year patient survival rate for dysgerminoma removal in pregnancy is encouraging at 90%. Fetal mortality approaches 25%.

  　

• Adjuvant chemotherapy in patients who are pregnant reportedly is successful when used during the second and third trimesters with methotrexate and cisplatin. Chlorambucil has been used as early as the first trimester.