Gestational Trophoblastic Disease (GTD)

Gestational trophoblastic diseases (GTD) are disorder of abnormal growth of the placenta. They are always associated with a pregnancy. A key to understanding and managing patients with GTD is serum beta human chorionic gonadotropin (BHCG), a hormone produced by the placenta. It can be detected in the blood and urine and is an extremely sensitive indicator for GTD. It is measured often during therapy and follow-up to gauge the response to treatment and to detect recurrent disease.

Types:
There are four types of gestational trophoblastic disease - hydatidiform mole (also called a molar pregnancy), invasive mole (chorioadenoma destruens), gestational choriocarcinoma, and placenta-site trophoblastic disease. Diagnosis of each specific disease requires tissue to be taken from the disease site for biopsy. The disease sites may be difficult to reach without risk, such as hemorrhage or loss of fertility.

• A hidatidiform mole results from an abnormal embryo that contains many fluid-filled cysts. There are two types of hydatidiform moles, complete and incomplete (partial). A complete mole usually has little or no fetal development and a large overgrowth of the placenta in the form of cysts (hydatids). The diagnosis of a complete hydatidiform mole is usually made during the first half of a pregnancy and is recognized by the health care provider about 50 percent of the time before the tumor cysts are expelled. A variety of clinical conditions may be confused with a molar pregnancy, but these can usually be distinguished on the basis of medical history, a physical exam and an ultrasound examination.

  In contrast, a partial mole is associated with a fetus, umbilical cord and membranes. It occurs much less frequently than a complete mole. The fetus usually dies within nine weeks after the last menstrual period although occasionally it can survive to term. Partial moles are rarely associated with multiple ovarian cysts (theca-lutein cysts), high BHCG titers and other accompaniments of a complete mole. There is also a lower incidence of malignant behavior (5 to 10 percent).

  Hydatidiform moles are sometimes associated with multiple ovarian cysts (theca-lutein cysts), high BHCG titers, and pregnancy-induced hypertension. There is also the risk that the abnormal placental tissue will persist in the uterus or elsewhere in the body. These risks are greater for women with complete moles (10 to 20 percent develop persistent disease) than for those with partial moles (5 to 10 percent).

• An invasive mole (chorioadenoma destruens) is defined as a hydatidiform mole that persists and invades the uterine wall. It develops in 10 to 20 percent of all molar pregnancies.
• Choriocarcinoma is a cancer composed of only the cells that covers the placenta (trophoblastic cells). It differs from invasive mole, which is made up of all the placental tissues. Choriocarcinoma can follow any type of pregnancy, whereas an invasive mole can only follow a hydatidiform mole. About 50 percent of all cases of gestational choriocarcinoma follow a hydatidiform mole, 25 percent follow a spontaneous abortion or tubal pregnancy and 25 percent follow a normal pregnancy. Choriocarcinoma follows a normal term pregnancy in 1 in 40,000 pregnancies. GTD after a normal pregnancy is always a choriocarcinoma, never a mole or an invasive mole.

A hydatidiform or invasive mole occurs when a single sperm fertilizes an egg without a nucleus. The chromosomes in the sperm duplicate, resulting in an abnormal embryo that has only male genetic material. A mole can also occur when two sperm fertilize a single egg. A mole develops from the abnormally fertilized egg and is characterized by a lack of a normal fetus and by many small fluid-filled cysts.

The cause of choriocarcinoma is uncertain. It can arise from a normal pregnancy, a miscarriage, a tubal pregnancy or from either type of mole.

A hydatdiform mole generally stays confined to the endometrial cavity. When it begins to invade the wall of the uterus, it is called an invasive mole.

An invasive mole can penetrate the full thickness of the uterine wall and rupture, resulting in severe internal or vaginal bleeding. Invasive moles can also spread to other organs, most commonly to the vagina and lung. This may be confusing since women with proven invasive moles who have metastases may also have choriocarcinoma. Although an invasive mole is locally more aggressive than a noninvasive mole, it is no more likely to be complicated by choriocarcinoma.

Choriocarcinoma can spread virtually anywhere in the body but most commonly spreads to the lung, the lower genital tract (cervix, vagina and vulva), the brain, the liver, kidney and the gastrointestinal tract.

Gestational trophoblastic disease occurs only in women of reproductive age. An invasive mole develops in 10 to 20 percent of all complete moles. Choriocarcinoma develops in 3 percent of complete moles but rarely in partial moles.

At significantly higher risk:
Risk for the development of a hydatidiform or invasive mole or choriocarcinoma include:

• a prior mole (30 times the risk)
• maternal age greater than 40 years (5 times) or less than 20 years (1.5 times)
• a previous spontaneous abortion (twice the risk)

At slightly lower risk:

• Eating a diet high in vitamin A and having one or more children without having a previous abortion is statistically correlated with a lower than average risk of developing a complete mole.

At risk for developing an invasive mole or choriocarcinoma:
For women with a molar pregnancy, there are several risk factors associated with the subsequent development of an invasive mole and choriocarcinoma. These include delayed hemorrhage after the mole is removed in a dilation and curettage (D&C) procedure, large ovarian (theca-lutein) cysts, acute respiratory failure at the time of the D&C, a large uterus before the D&C, a serum BHCG level greater than 40,000 mlU/mL, a history of a previous mole and maternal age over 40.

Since it is so rare, GTD is not routinely screened for. It is reasonable, however, to perform an ultrasound examination early in any subsequent pregnancy for women with prior GTD.

Common signs and symptoms:
A molar pregnancy is usually associated with bleeding in the first half of a pregnancy, an absent fetal heartbeat, pain in the lower abdomen, and occasionally with high blood pressure before 24 weeks of pregnancy, excessive nausea or vomiting, a uterus larger than normal for the gestational age (50 percent of all cases) and the expulsion of cysts.

Eighty to 90 percent of women with partial moles have abnormal uterine bleeding, a smaller than expected uterus for the gestational age of tae pregnancy or the signs and symptoms of a spontaneous abortion. The most common symptoms of choriocarcinoma are lack of a menstrual period, symptoms of pregnancy, abnormal vaginal bleeding or pelvic pain. Women with liver metastases may have bleeding within the abdomen because of a ruptured liver. Those with metastases to the lung may have a dry cough, cough up blood and have chest pain or shortness of breath. Spread to the intestinal tract may be associated with chronic blood loss and anemia or with massive hemorrhage. Brain metastases are often associated with symptoms that suggest a brain tumor or stroke.

The diagnosis is usually suspected after an ultrasound examination of the uterus, but absolute diagnosis of a mole is made by examining the cysts under a microscope. A serum BHCG level far in excess of that of a normal pregnancy would support the diagnosis of a hydatidiform mole.

An invasive mole is seldom diagnosed definitively without a hysterectomy. The diagnosis is usually suggested after a hydatidiform mole is removed and the BHCG titers remain elevated and there is no evidence of metastases. It is more properly referred to as nonmetastatic (if confined to the uterus) trophoblastic disease (NMTD).

Confirmation of choriocarcinoma by removing cells for pathological analysis is not required and may be hazardous since their tumor bleeds easily.