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Gestational Trophoblastic Disease

Gestational trophoblastic disease encompasses four types of growth disturbances of the placenta: 1) hydatidiform mole (complete and partial), 2) invasive mole, 3) choriocarcinoma, and 4) placental-site trophoblastic tumor. The term "gestational trophoblastic tumor" has been applied collectively to the latter three conditions. Despite the widespread presence of metastasis, these tumors are responsive to treatment, and reproductive function can be preserved in most women. Choriocarcinoma has been reported to arise independent of trophoblastic tissue (eg, ovary).

Hydatidiform Mole

Hydatidiform mole is a pregnancy that is associated with vesicular swelling of placental villi and, usually, the absence of an intact fetus. There is a microscopic proliferation of the trophoblast with varying degrees of hyperplasia and dysplasia. The chorionic villi are fluid filled and distended, and blood vessels are scant. Two syndromes of hydatidiform mole have been described based on

Complete hydatidiform mole undergoes early and total hydatidiform enlargement of villi in the absence of an ascertainable fetus or embryo, and the trophoblast is consistently hyperplastic with varying degrees of atypia. It usually has a 46,XX karyotype derived from fertilization by a haploid (23,X) sperm that totally replaces the maternal contribution and reaches the 46,XX status by its own duplication. The nucleus of the ovum may be either absent or inactivated after fertilization. Occasionally, a 46,XY karyotype occurs as a result of dispermic fertilization of an empty egg. Although the chromosomes of complete moles are entirely paternal, mitochondrial DNA is of maternal origin gestational trophoblastic disease, trofoblastic, molar, mole

Partial hydatidiform mole is characterized by slowly progressive hydatidiform change in the presence of functioning villous capillaries, which affects only some of the villi. The result is chorionic villi that vary in size and shape with scalloping and prominent stromal trophoblastic inclusions. Trophoblastic immaturity is

Diagnosis

The clinical presentation of complete mole has changed considerably over the past several years because diagnosis is being made earlier thanks to the availability of accurate tests for hCG and the widespread use of ultrasonography. Vaginal bleeding continues to be the most common presenting symptom, usually occurring at 6-16 weeks of gestation in 80-90% of patients. The other classic clinical signs and symptoms, such as uterine enlargement greater than expected for gestational dates (28%), hyperemesis (8%), and

Human chorionic gonadotrophin levels in complete mole are usually, but not always, elevated above levels of normal pregnancy, often exceeding 100,000 mlU/mL. A single hCG determination, however, is seldom helpful in differentiating complete mole from a normal intrauterine pregnancy, an intrauterine pregnancy complicated by multiple gestation or diseases associated with an enlarged placenta (eg, erythroblastosis fetalis, intrauterine infections), or an enlarged uterus due to uterine leiomyomas with a normal intrauterine.

Patients with partial moles usually do not present with the classic clinical features of complete moles described above. More than 90% of patients present with symptoms of incomplete or missed abortion, and the diagnosis of partial mole is usually made after histologic review of curettage specimens. The main presenting symptom is vaginal bleeding, occurring in about 75% of patients. Excessive uterine enlargement

Treatment

When the diagnosis of hydatidiform mole is established, the patient should be carefully evaluated for the presence of associated medical complications and stabilized, after which the most appropriate method of

Suction curettage is the preferred method of evacuation of a hydatidiform mole, independent of uterine size, in patients who wish to maintain their fertility. Suction evacuation should be followed by gentle sharp

Hysterectomy is an alternative to suction curettage if childbearing is complete. The adnexa may be preserved even in the presence of theca lutein cysts. Although hysterectomy reduces the risk of postmolar gestational trophoblastic tumor to approximately 3-5%, continued hCG follow-up is still required.

Follow-Up

Follow-up of patients after evacuation of a hydatidiform mole indicates that this therapy is curative in more than 80% of patients. Incomplete involution of the uterus and vaginal bleeding may be signs of persistent trophoblastic disease. A curettage may be performed if there is significant bleeding and ultrasonographic

Gestational Trophoblastic Tumors

Gestational trophoblastic tumors include invasive mole, choriocarcinoma, and placental site trophoblastic tumor. If untreated, these tumors can progress, invade, metastasize, and lead to death. The overall cure rate in the treatment of gestational trophoblastic tumors now exceeds 90%. This success is the result of the chemotherapy-sensitive nature of trophoblastic tumors; the ability to make a diagnosis and monitor therapy

Clinical Classification of Gestational Trophoblastic Tumors

I. Nonmetastatic gestational trophoblastic tumor

II. Metastatic gestational trophoblastic tumor

A. Low risk

1. hCG <100,000 IU/24-hour urine or <40,000 mlU/mL of serum

2. Symptoms present for less than 4 months

3. No brain or liver metastases

4. No prior chemotherapy

5. Pregnancy event is not term delivery (ie, mole, ectopic, spontaneous abortion)

B. High risk

1. hCG >100,000 IU/24-hour urine or >40,000 mlU/mL of serum

2. Symptoms present for more than 4 months

3. Brain or liver metastases

4. Prior chemotherapeutic failure

5. Antecedent term pregnancy

*hCG indicates human chorionic gonadotropin.

 

Staging for Gestational Trophoblastic Tumors

Stage I Disease is confined to uterus.

Stage IA Disease is confined to uterus with no risk factors.

Stage IB Disease is confined to uterus with one risk factor.

Stage IC Disease is confined to uterus with two risk factors.

Stage II Gestational trophoblastic tumor extends outside uterus but is limited to genital structures (adnexa, vagina, broad ligament).

Stage IIA Gestational trophoblastic tumor involves genital structures with no risk factors.

Stage IIB Gestational trophoblastic tumor extends outside uterus but is limited to genital structures with one risk factor.

Stage IIC Gestational trophoblastic tumor extends outside uterus but is limited to genital structures with two risk factors.

Stage III Gestational trophoblastic tumor extends to lungs with or without known genital tract involvement.

Stage IIIA Gestational trophoblastic tumor extends to lungs with or without genital tract involvement and with no risk factors.

Stage IIIB Gestational trophoblastic tumor extends to lungs with or without genital tract involvement and with one risk factor.

Stage IIIC Gestational trophoblastic tumor extends to lungs with or without genital tract involvement and with two risk factors.

Stage IV Included are all other metastatic sites.

Stage IVA Included are all other metastatic sites without risk factors.

Stage IVB Included are all other metastatic sites with one risk factor.

Stage IVC Included are all other metastatic sites with two risk factors.

*Risk factors affecting staging include the following: 1) serum human chorionic gonadotropin >100,000 mlU/mL and 2) duration of disease >6 months from termination of antecedent pregnancy. The following factors should be considered and noted in reporting: 1) prior chemotherapy has been given for known gestational trophoblastic tumor; 2) placental site tumors should be reported separately; and 3) histologic verification of disease is not required. Modified from International Federation of Gynecology and Obstetrics. Annual report on the results of treatment in gynecological cancer. 22nd edition. Stockholm: FIGO, 1994

 

Diagnosis

Gestational trophoblastic tumor is most often diagnosed by a rise or plateau in hCG levels after evacuation of a molar pregnancy. Occasionally, the diagnosis of choriocarcinoma is made on the basis of persistent elevation of hCG levels, frequently in conjunction with the demonstration of metastases, after other

Symptoms and Signs

The symptom most suggestive of trophoblastic tumor is continued uterine bleeding after evacuation of a hydatidiform mole or after any pregnancy event. Bleeding as a result of uterine perforation or metastatic lesions may result in abdominal pain, hemoptysis, melena, or evidence of increased intracranial pressure from intracerebral hemorrhage leading to headache, seizures, or hemiplegia. Patients may also present with pulmonary symptoms such as dyspnea, cough, and chest pain due to extensive lung metastases.

Signs suggestive of postmolar trophoblastic tumor are an enlarged, irregular uterus and persistent bilateral ovarian enlargement. Occasionally, a metastatic lesion is noted on examination, most commonly in the vagina. Choriocarcinoma associated with a nonmolar gestation has no characteristic physical signs but may produce symptoms as a result of metastatic disease. Gestational trophoblastic tumors should be distinguished from retained products of conception or endometritis as causes of postpartum uterine bleeding and subinvolution, primary or metastatic tumors of other organ systems, and another pregnancy occurring shortly after the first.

Classification and Staging

When a gestational trophoblastic tumor has been diagnosed, it is necessary to determine the extent of disease. If the physical examination and chest X-ray are normal, other sites of metastasis are uncommon. Measurement of hCG in the cerebrospinal fluid may be useful in detecting brain involvement. Pelvic

Therapy

Nonmetastatic Tumors

Hysterectomy is used as primary therapy in patients with presumed nonmetastatic trophoblastic tumors who no longer wish to preserve fertility or when the diagnosis is placental-site trophoblastic tumor. Adjuvant single-agent chemotherapy at the time of operation has been assumed to eradicate any occult metastases

Single-agent chemotherapy with methotrexate or dactinomycin is the treatment of choice for those patients wishing to preserve their fertility. Several different outpatient chemotherapy protocols have been used, all yielding excellent and fairly comparable remission rates. Methotrexate 0.4 mg/kg (maximum 25 mg) intravenously or intramuscularly daily for 5 days per treatment course has traditionally been the treatment of choice. Alternately, a regimen consisting of slightly higher doses of methotrexate (intramuscularly every other day) and folinic acid intramuscularly 24 hours after each dose of methotrexate has been used. This protocol has the advantage of decreased toxicity, especially stomatitis, but the disadvantages are increased cost, patient inconvenience, and an increased need for a change in chemotherapy to achieve remission.