Gestational trophoblastic tumors

Definition

A gestational trophoblastic tumor (GTT) is a rare cancer that develops in tissues formed when a sperm fertilizes an egg but does not create a fetus.

Description

Also known as gestational trophoblastic neoplasms (GTN), these highly curable malignancies originate inside the uterus, in cells (trophoblasts) that make up one layer of the placenta. The most common types of GTT are hydatidiform mole (molar pregnancy) and choriocarcinoma. Placental-site trophoblastic tumor is an extremely rare type of GTT. It originates at the place where the placenta was attached to the wall of the uterus.

Hydatidiform mole

A hydatidiform mole forms when sperm and egg cells unite but do not create a fetus. Cells that form the placenta continue to grow until they look like drops of rain or clusters of grapes. Also known as molar pregnancy, a hydatidiform mole does not spread beyond the uterus.

Choriocarcinoma

Characterized by rapid growth and heavy bleeding, this aggressive, invasive tumor is considered a medical emergency and requires immediate medical attention. Although choriocarcinoma usually originates in a hydatidiform mole, it can also develop in tissue that remains in the uterus following a normal delivery, an abortion, or an ectopic pregnancy.

A malignancy of the trophoblastic cells that form the lining of the uterus (epithelium), choriocarcinoma can spread (metastasize) to any part of the body. Metastasis begins at an early stage of the disease and usually involves the lungs, vagina, pelvis, brain, and/or liver. Symptoms of lung metastasis include severe shortness of breath (respiratory insufficiency) and coughing up blood. Irregular, abnormal bleeding can indicate that choriocarcinoma has invaded the vagina. The central nervous system (CNS) is rarely affected unless the disease has spread to one or both lungs; a patient whose brain does become involved may experience headaches, seizures, and stroke-like symptoms. More rarely, choriocarcinoma may spread to the kidneys, spleen, and/or gastrointestinal tract.

Demographics

GTTs occur only in women of childbearing age. These tumors are most common:

• before the age of 16
• after the age of 40
• in women who have had them before
• among women who are poor

Accounting for only 1% of all gynecologic malignancies, GTTs are five times more common in Africa and Asia than in Europe and North America. In the United States, hydatidiform mole occurs in only one of every 1, 500 to 2, 000 pregnancies.

Causes and symptoms

The cause of GTTs is unknown. A woman's chance of developing a second GTT, while still very low, is about twice as great as her risk of developing a first one.

Symptoms of hydatidiform mole

The most common symptoms of hydatidiform mole are vaginal bleeding and severe morning sickness during the first trimester of pregnancy. Other symptoms that suggest a hydatidiform mole include:

• a uterus larger than expected at a particular stage of pregnancy
• a uterus enlarged on only one side
• a fetus not visible on a sonogram
• absence of fetal heart sounds
• passage of clots with the color and consistency of prune juice or of finger-like structures containing fetal blood cells (villi)
• toxemia
• ovarian cysts
• hyperthyroidism

Recurrent bleeding often causes iron deficiency anemia in women who have had a hydatidiform mole. Although molar pregnancy is almost always diagnosed during the first trimester, it is often difficult to distinguish this condition from the early stages of a normal pregnancy. A woman should see her doctor if she experiences abnormal bleeding or cannot feel her baby move when she should.

Symptoms of choriocarcinoma

This GTT occurs in 4% of women whose hydatidi-form mole was surgically removed or treated with radiation therapy . Following term pregnancies or abortion, the incidence of choriocarcinoma is 1 in 40, 000.

A doctor should always consider choriocarcinoma when vaginal bleeding persists after a woman has given birth. Other abnormalities commonly associated with choriocarcinoma are unusual and unexplained neurological symptoms in women of childbearing age and lesions that can be seen on a chest x ray but do not cause shortness of breath or other symptoms.

Diagnosis

The process of diagnosing GTT usually begins with an internal pelvic examination that allows the doctor to detect lumps or abnormalities in the size or shape of the uterus. Imaging studies such as computed tomography (CT) scans, magnetic resonance imaging (MRI), and ultrasound may be used to locate tumors. Blood and urine tests measure levels of beta human chorionic gonadotropin (HCG). This hormone is normally produced during pregnancy but is abnormally elevated in the blood and urine of a woman with GTT. HCG is a sensitive marker of the presence of GTT before, during, and after treatment.

After diagnosing GTT, the doctor will perform a regular blood test (every week), pelvic exam (every other week), and chest x ray (every four to six weeks) until the level of HCG in the patient's blood has returned to normal. Once the patient's HCG levels have normalized, medical monitoring includes blood tests with decreasing frequency for the next three years.

Treatment team

GTT is typically treated by a treatment team of gynecologists, gynecologic oncologists, and medical oncologists. A patient who has a poor prognosis should be treated at a specialized trophoblastic disease center by a doctor experienced in caring for high-risk GTT patients.

Clinical staging, treatments, and prognosis

A common system used in U.S. cancer centers to describe the extent (stage) of GTT classifies patients into different prognostic groups. These groups include:

• Nonmetastatic disease: Cancer cells have not invaded tissues outside of the uterus. Cancer found in the muscle of the uterus is called invasive mole or choriocarcinoma destruens.
• Metastatic disease, good prognosis: Cancer cells have invaded tissues outside of the uterus but have not spread to the liver or brain; levels of HCG in the blood are low and the last pregnancy was less than four months ago. No chemotherapy treatment has been initiated.
• Metastatic disease, poor prognosis: Cancer cells have invaded tissues outside of the uterus, including the liver or brain; levels of HCG in the blood are high and/or the last pregnancy was more than four months ago. Chemotherapy treatment has been given but was not successful.

Treatment options

Because GTT cells respond well to chemotherapy drugs and HCG blood tests are a reliable means of determining whether cancer cells are still present and if therapy should continue, this disease is one of the most curable cancers of the female reproductive system.

Doctors usually treat GTT with surgery to remove the tumor, followed by chemotherapy taken in pill form or administered intravenously to kill any cancer cells still present after surgery. Radiation therapy is sometimes used to treat GTT that has spread to other parts of the body. Radiation used to treat GTT may be provided by:

• machine (external-beam radiation)
• radiation-producing pellets (radioisotopes) inserted into the area of the body where cancer cells have been found

Choice of treatment is determined by the following factors:

• patient's age and general health
• tumor type
• stage of disease
• areas of the body to which GTT has spread
• HCG levels in the patient's blood
• how much time elapsed between conception and start of treatment
• prior pregnancy-related problems
• extent of treatment for prior pregnancy-related problems
• whether the patient wants to become pregnant in the future

HYDATIDIFORM MOLE.

Hydatidiform mole is 100% curable with surgery. If the patient wants to become pregnant in the future, the doctor performs dilatation and curettage (D&C) with suction evacuation. This procedure involves:

• stretching the opening of the uterus (cervix)
• using a small vacuum-like device to remove material from inside the uterus
• gently scraping the walls of the uterus to remove any remaining material.

If the patient does not wish to become pregnant in the future, the doctor removes her uterus (hysterectomy).

Following either of these operations, the doctor carefully monitors the level of HCG in the patient's blood. Chemotherapy is initiated when:

• HCG levels continue to rise for a period of two weeks or remain constant for a period of three weeks
• HCG levels become elevated after having fallen to normal value
• analysis of tissue removed during surgery indicates the presence of invasive disease (choriocarcinoma)
• heavy, unexplained bleeding occurs after material has been evacuated from the uterus

PLACENTAL-SITE GTT.

Hysterectomy is usually performed to remove cancer cells that have developed where the placenta was attached to the wall of the uterus. Although placental-site GTTs do not generally spread to other parts of the body, they do not respond well to chemotherapy and can be fatal.

NONMETASTATIC DISEASE.

The most common form of GTT, nonmetastatic disease does not spread beyond the uterus, where its cells develop from tissue remaining after treatment for hydatidiform mole, normal delivery, or abortion. Treatment for nonmetastatic disease consists of single-agent chemotherapy. Hysterectomy is sometimes performed if the patient does not want to become pregnant in the future.

METASTATIC DISEASE, GOOD PROGNOSIS.

This type of GTT originates as nonmetastatic disease but spreads from the uterus to other parts of the body. The likelihood of cure (prognosis) is considered good if:

• less than four months has elapsed since the patient's previous pregnancy
• HCG blood levels are low
• cancer cells have not spread to the liver or brain
• the patient has not previously received chemotherapy

Doctors may treat metastatic disease with good prognosis with chemotherapy alone, hysterectomy followed by chemotherapy, or chemotherapy followed by hysterectomy. These patients must be carefully monitored. Almost all of these cases can be cured, but between 40% and 50% will develop resistance to the first chemotherapy drug used in treatment.

METASTATIC DISEASE, POOR PROGNOSIS.

The prognosis for metastatic disease is considered poor if:

• more than four months has elapsed since the patient's previous pregnancy
• HCG blood levels are high
• cancer cells have spread to the liver or brain
• previous chemotherapy treatments did not eradicate the patient's disease

Treatment for this type of GTT must be started immediately and should be performed in a specialized medical center or by a doctor experienced in treating this disease. Treatment usually consists of combination chemotherapy but may include surgery and radiation to parts of the body that cancer cells have invaded.

Metastatic GTT is can also be described as low-risk, medium-risk, or high-risk. This classification enables doctors to identify patients who should be treated with the strongest, most effective combination of chemotherapy drugs. Factors used to determine a woman's risk include:

• age
• prior pregnancy experience
• how much time elapsed between conception and start of treatment
• HGC levels in her blood
• the size of her largest tumor
• where and to how many locations the cancer has spread
• whether she has previously been treated with chemotherapy

RECURRENT DISEASE.

GTT that recurs after a woman has been treated may reappear in the uterus or in another part of her body. One study indicates that GTT recurs in:

• 2.5% of patients treated for nonmetastatic disease
• 3.7% of patients treated for metastatic disease, good prognosis
• 13% of patients treated for metastatic disease, poor prognosis

All these recurrences happened within 36 months of the disappearance of symptoms of the initial disease (remission), while 85% occurred within 18 months of remission.

A woman who develops one or more new GTTs after having been treated with chemotherapy is considered to be a high-risk patient and is categorized as having a poor prognosis. She should subsequently be treated with aggressive chemotherapy. If surgery is not successful in eradicating the cancer, treatment with single-agent chemotherapy is usually indicated unless one or more risk factors indicate that she should receive multiple-drug therapy. When recurrent disease spreads to the central nervous system, whole brain radiation and systemic chemotherapy are given at the same time. About half (50% to 60%) of patients receiving this treatment experience sustained remission. Combination chemotherapy may also be used to treat a woman whose recurrent GTT has spread to the brain.

The prognosis is poor for a woman whose recurrent GTT has spread to her liver; in this case radiation does not improve survival and may make chemotherapy less effective. The prognosis is even poorer if both the liver and brain are affected. "Salvage" surgery is sometimes used to treat patients whose disease has not responded to any other available form of treatment.

Disease outcomes

Although very rare in North America, GTT is an important disease because of its life-threatening potential and high curability rates with early, specialized treatment. The probability of cure is high even when the disease has spread far from the uterus. About 70% of patients with high-risk disease go into remission, while the cure rates for properly managed molar pregnancy and vigorously treated nonmetastatic GTT are nearly 100%. About 80% of patients with widely metastasized disease are cured when treated with prompt, aggressive chemotherapy sometimes combined with surgery and radiation.

Combination chemotherapy achieves results in nearly three out of four patients (74%) who have not responded to other forms of treatment, and more than three out of four high-risk patients (76%) who have not previously been treated with chemotherapy. More than half of patients (57%) whose earlier treatment did not eradicate the disease also achieve good results with combination chemotherapy. The survival rate for patients treated with combination chemotherapy is 84%.

Clinical trials

Researchers throughout the United States are currently investigating the following concerns:

• How effective are certain chemotherapy drugs in treating GTT that has not responded to other therapies or that has recurred after treatment?
• At what dosages do specific chemotherapy drugs become toxic?
• How does the frequency of chemotherapy treatments affect a patient's prognosis?
• What is the relationship between the start of chemotherapy and an immediate drop in a patient's HCG levels?

Prevention

The cause of GTT is not known, but the risk is higher than normal for a woman who belongs to blood group A and whose partner belongs to blood group O.

Special concerns

Medical oncologists emphasize the importance of the following treatment factors:

• Chemotherapy should be started as early in the course of the disease as possible.
• Chemotherapy should be administered every 14 to 21 days until HCG blood levels drop to normal.
• High-risk patients should be treated with combination chemotherapy regardless of the stage of their disease.
• Monthly blood tests should be continued for one year after HCG levels drop to normal.
• A woman who has been treated for GTT should wait at least a year before becoming pregnant and see her doctor as soon as she becomes or thinks she might be pregnant.

Resources

BOOKS

DeVita, Vincent T. Jr., et al, eds. Cancer: Principles & Practice of Oncology, 5th ed. Philadelphia: Lippinott-Raven, 1997, pp. 1499-1501.

Kirkwood, John M., et al, eds. Current Cancer Therapeutics, 3rd ed. Philadelphia:Current Medicine, Inc., 1998, pp. 252-254.

ORGANIZATIONS

American College of Obstetricians and Gynecologists. 40912th St. SW, PO Box 96920, Washington, DC 20090-6920. (202) 863-2518. <http://www.acog.org>.

National Cancer Institute. 31 Center Dr., MSC 2580, Bethesda, MD 20892-2580. (800) 4-CANCER. <http://cancernet.nci.nih.gov>.

OTHER

"Gestational Trophoblastic Disease." American Cancer Society. 27 March 2000. 5 July 2001. <http://www3.cancer.org/cancerinfo/load_cont.asp?st=ds&ct=49>.

"Gestational Trophoblastic Disease." OBGYN.net Publications. 2001. 3 July 2001. <http://www.obgyn.net/women/articles/rich/gest.htm>.

"Gestational Trophoblastic Tumor." National Cancer Institute. May 2001. 3 July 2001. <http://cancernet.nci.nih.gov/cancer_Types/Gestational_Trophoblastic_Tumor.shtml>.

Maureen Haggerty

KEY TERMS

Ectopic pregnancy

—An abnormal pregnancy in which the fertilized egg becomes implanted outside the uterus.

Ovarian cyst

—A fluid-filled or semi-solid sac that may be painful or malignant.

Placenta

—The organ that develops in the uterus during pregnancy and connects the mother's blood supply with the baby.

Remission

—Disappearance or lessening of symptoms.

Salvage surgery

—An operation used to treat a patient who has not responded to any other therapy.

Systemic

—Affecting the whole body.

Toxemia

—An abnormal pregnancy-related condition characterized by high blood pressure, swelling and fluid retention, and proteins in the urine.

QUESTIONS TO ASK THE DOCTOR

• What should I do if I am not sure my pregnancy is proceeding normally?
• Why is it important for me to see my doctor as soon as I realize something might be wrong?
• Will GTT affect my ability to have other children?
• Why must I wait so long before becoming pregnant?