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.

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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:

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.

Sex: These tumors mostly occur in women, although the disease also occurs in pseudohermaphrodites and patients with gonadal dysgenesis (see Medical/Legal Pitfalls). Testicular seminomas are the histologic counterparts to dysgerminomas in males.

Age: Although most ovarian cancers occur during the menopausal and perimenopausal years (ie, 50-59 y), dysgerminomas tend to frequent the pediatric population. Dysgerminomas are observed most commonly in younger women. Seventy-five percent of dysgerminomas occur in patients in their 20s and 30s, with the mean age being 22 years.

CLINICAL @

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

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.

Causes: The exact etiology for this tumor type has not been elucidated.

DIFFERENTIALS @

Ectopic Pregnancy


Other Problems to be Considered:

Gastrointestinal

Colorectal cancer
Bowel/omental adhesions
Diverticula
Fecal impaction
Low-lying cecum

Genitourinary

Pelvic abscess
Uterine fibroids
Torsed ovary
Hydrosalpinx (salpingitis isthmic nodosum)
Retroperitoneal tumor
Bladder distention
Pelvic kidney
Urachal cyst
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WORKUP @

Lab Studies:
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Imaging Studies:
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Procedures:
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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

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.

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.

Consultations:

Diet:

Activity:

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.

Drug Name
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Vincristine (Oncovin) -- Plant-derived vinca alkaloid isolated from periwinkle. Interferes with microtubule assembly, thus inhibiting cell growth in the M-phase.
Adult Dose VAC protocol: 1.5 mg/m2 IV qwk for 12 wk; not to exceed 2.5 mg
Pediatric Dose Not established
Contraindications Documented hypersensitivity; Charcot-Marie-Tooth syndrome
Interactions Acute pulmonary reaction may occur when taken concurrently with mitomycin-C; itraconazole inhibits CYP3A and may accentuate neurotoxic side effects of vincristine
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Caution in patients diagnosed with severe cardiopulmonary or hepatic impairment and patients with preexisting neuromuscular disease; dose is limited by neurotoxicity; with early use watch for predominantly peripheral nerve disorders (eg, foot drop, paresthesias, ataxia, loss of deep tendon reflexes); motor neuropathy (eg, extremity weakness, cranial nerve palsies) can be manifested in late stages of treatment
Drug Name
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Actinomycin-D (Cosmegen) -- DNA intercalator that covalently binds to guanine, forming a complex preventing RNA polymerase from transcribing DNA. Higher doses lead to inhibition of DNA synthesis.
Adult Dose VAC protocol: 0.5 mg IV given over 5 d q4wk
Pediatric Dose Not established
Contraindications Documented hypersensitivity; chicken pox or herpes zoster infection
Interactions Interacts with radiation therapy; dermatologic changes (eg, hyperpigmentation, desquamation, vesiculation) and reactivation of myelitis or enteritis in irradiated regions is not uncommon; greater myelosuppression and GI toxicity also reported with simultaneous use with radiation therapy
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Extremely myelosuppressive, predisposing patients to increased risk of bleeding and infection; monitor daily with CBC and platelet counts; do not administer to infants due to greater frequency of toxic effects
Drug Name
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Cyclophosphamide (Cytoxan, Neosar) -- Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.
Adult Dose VAC protocol: 5-7 mg/kg IV given over 5 d q4wk
Pediatric Dose Not established
Contraindications Documented hypersensitivity; severely depressed bone marrow function
Interactions Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects of cyclophosphamide; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life of cyclophosphamide while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity of cyclophosphamide; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity
Pregnancy D - Unsafe in pregnancy
Precautions Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis
Drug Name
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Etoposide (Toposar) -- Inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in the late S or early
G2 portion of the cell cycle.
Therapy should be withheld or suspended if platelet counts are <50,000 or absolute neutrophil counts are <500/mm3.
Reduce dose 20% for granulocytic fever or previous radiotherapy.
Adult Dose BEP protocol: 100 mg/m2 IV days 1-5 q3wk for 3 wk
Pediatric Dose Not established
Contraindications Documented hypersensitivity; IT administration may cause death
Interactions May prolong the effects of warfarin and increase the clearance of methotrexate; cyclosporine and etoposide have additive effects in the cytotoxicity of tumor cells
Pregnancy D - Unsafe in pregnancy
Precautions Bleeding and severe myelosuppression may occur; side effects include GI upset and alopecia; monitor for anaphylactoid reaction during and immediately after treatment
Drug Name
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Bleomycin (Blenoxane) -- A copper-chelating glycoprotein capable of inducing DNA strand scission breaks via oxidative processes. This drug is eliminated by the kidneys.
Adult Dose BEP protocol: 20 U/m2 IV qwk for 9 wk; not to exceed 30 U
VBP protocol: 20 U/m2 IV qwk for 7 courses with 8th course given in week 10; not to exceed 30 U
Pediatric Dose Not established
Contraindications Documented hypersensitivity; significant renal function impairment; compromised pulmonary function
Interactions May decrease plasma levels of digoxin and phenytoin; cisplatin may increase toxicity of bleomycin and also lead to hypomagnesemia; although rare, some patients concurrently receiving vinblastine experience a Raynaudlike syndrome
Pregnancy D - Unsafe in pregnancy
Precautions Caution in renal impairment; possibly secreted in breast milk; monitor for side effects during and after treatment; the most common side effect is mucocutaneous toxicity (50%); early warning signs of this condition include hypoesthesia and progression to hyperesthesia and paresthesias; the dose-limiting effect is determined by pulmonary toxicity (ie, interstitial pneumonitis and pulmonary fibrosis); dyspnea and rales are early warning signs (chest x-rays should be performed q1-2wk while on therapy, and antibiotics should be prescribed immediately if infectious pneumonitis is suspected)
Drug Name
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Cisplatin (Platinol) -- Inhibits DNA synthesis and, thus, cell proliferation by causing DNA cross-links and denaturation of double helix.
In general, the drug should not be administered if the leukocyte count is <4000/mm3 and platelets <100,000/mm3. Renally excreted; those with impaired renal function should postpone therapy. Not to be administered to patients with serum creatinine >1.5 mg/dL and BUN >25 mg/dL.
Administered IV in saline solution.
Adult Dose BEP protocol: 20 mg/m2 IV days 1-5 q3wk for 3 wk
VBP protocol: 20 U/m2 qd 5 times q3-4wk for 4 courses
Pediatric Dose Not established
Contraindications Documented hypersensitivity, preexisting renal insufficiency, myelosuppression, and hearing impairment
Interactions Increases toxicity of bleomycin, furosemide, and ethacrynic acid; phenytoin excretion and metabolism are hindered by cisplatin (monitor levels)
Pregnancy D - Unsafe in pregnancy
Precautions Administer adequate hydration before and 24 h after cisplatin dosing to reduce risk of nephrotoxicity; myelosuppression, ototoxicity, hypomagnesemia, nausea and vomiting, may occur
Drug Name
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Vinblastine (Velban) -- Vinca alkaloid, works by inhibiting microtubule arrangement, inhibiting cell growth in the M-phase.
Adult Dose VBP protocol: 12 mg/m2 q3wk for 4 courses
Pediatric Dose Not established
Contraindications Documented hypersensitivity and bone marrow suppression
Interactions Phenytoin plasma levels may be reduced when administered concomitantly with vinblastine; with mitomycin, erythromycin, and itraconazole, the toxicity of vinblastine may significantly increase
Pregnancy D - Unsafe in pregnancy
Precautions Caution in patients diagnosed with impaired liver function and neurotoxicity; when patient is receiving mitomycin C, monitor closely for shortness of breath and bronchospasm; tumors can be exquisitely sensitive to this medication, causing excessive purine breakdown and hyperuricemia (can be prevented with copious hydration, allopurinol, and alkalinization of the urine); caution in cachexia, ulcerative skin lesions, and elderly patients
FOLLOW-UP @

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MISCELLANEOUS @

Medical/Legal Pitfalls:

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PICTURES @

Caption: Picture 1. Dysgerminoma, microscopic image at 20X
Click to see larger picture
Picture Type: Photo
BIBLIOGRAPHY @

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