Gestational Trophoblastic Disease: An Overview

The following information is from Drs. Donald P. Goldstein, M.D., and Ross S. Berkowitz, M.D., at the New England Trophoblastic Disease Center at Dana Farber/Brigham and Women’s Cancer Center in Boston, Massachusetts. Dr. Goldstein is often referred to by women in molar pregnancy support groups as a source of advice and information, and he has provided this information for use on this Web site so that everyone can share it. Please remember that any opinions or data you receive online or from anyone not DIRECTLY involved in your care will be for information only and should not be taken as medical advice. Any medical decisions you make should be discussed with your own personal doctor.

Dr. Goldstein has long been a friend to women with molar pregnancy, and the work his team does helps us all. If you’d like to make a donation to Brigham and Women’s Hospital’s choriocarcinoma research, click here.

Gestational trophoblastic disease (GTD) is a rare group of interrelated tumors that develop following conception that lead to abnormal development of the placenta.  More than 80% of GTD cases are non-cancerous.  All forms of GTD can be treated, and in the great majority of cases the treatment results in a cure.   Most women who have had a single incidence of GTD can go on to have normal pregnancies.

There are three main types of GTD:

1. Hydatidiform Mole

A hydatidiform mole (also called a “molar pregnancy”) is a form of GTD that arises when  fertilization of an egg cell results in an abnormal pregnancy. There are two types of molar pregnancies, complete and partial.  A complete molar pregnancy develops when the fertilized egg cell lacks maternal genes. The pregnancy that results contains no fetal tissue and resembles grape-like cysts that fill the uterine cavity.   A partial molar pregnancy occurs when more than one sperm fertilizes a normal egg resulting in a pregnancy where both the fetus and placenta are abnormal.  The term partial is used because the placenta contains both normal tissue and grape-like cysts similar to that seen in complete moles.  80% of molar pregnancies are benign in that they cause no further trouble after they are removed from the uterus.  However, in approximately 20% of complete molar pregnancy and 1-4% of partial moles the molar tissue either spreads locally within the muscular wall of the uterus (called invasive mole) or spreads more widely to other parts of the body, most commonly the lungs (called metastases), which requires treatment.   Hydatidiform moles occur in only one of every 1,000-1,200 pregnancies in the United States.

2. Choriocarcinoma

Choriocarcinoma is a highly malignant form of GTD that spreads rapidly throughout the body and requires vigorous treatment.  It may have begun as a molar pregnancy or from tissue that remains in the uterus following a miscarriage or childbirth.  Choriocarcinoma is even less common, arising in only one of every 20,000-40,000 pregnancies.

3. Placental-Site Trophoblastic Tumor

Placental-site GTD is a very rare form of the disease that arises in the uterus at the site where the placenta was attached.  These tumors penetrate the muscle layer of the uterus and usually do not spread to other parts of the body.

Risk Factors

Although doctors cannot always explain why a women develops GTD, there are a number of factors that may increase a women’s risk of developing the disease:

  • Age Since GTD develops from pregnancy this disease only occurs in women in the childbearing age group.  The risk of developing GTD increases with age, particularly after age 40.
  • Prior GTD  Women who have had a previous molar pregnancy or choriocarcinoma are at increased risk of another. For example, a second molar pregnancy occurs ten times more frequently than the first mole.
  • Diet Women whose diets are low in beta carotene or vitamin A appear to have a higher risk of developing complete molar pregnancy.
  • Use of Oral Contraceptives Long-term use of contraceptives appear to increase the risk of partial molar pregnancy.
  • Irregular periods Women who have irregular periods appear to have an increased risk of partial molar pregnancy.
  • Fertility problems Women who have had spontaneous abortions appear to have an increased risk of complete and partial molar pregnancy.

Symptoms

The most common symptoms of hydatidiform mole are feeling pregnant and vaginal bleeding, which can be either bright red or watery brown discharge. Other symptoms are:

  • Abdominal bloating
  • Nausea and vomiting which is generally more severe than in normal pregnancy
  • Fatigue, shortness of breath and lack of energy due to anemia, if there has been a great deal of blood loss
  • Signs of an overactive thyroid gland including rapid heartbeat, warm skin, and mild shaking seen rarely in patients with complete mole.
  • High blood pressure due to pre-eclampsia (also called toxemia of pregnancy) which can develop if the molar pregnancy continues beyond twelve weeks

 Women who develop choriocarcinoma may be symptom-free or experience symptoms based on which organ(s) are involved:

  • Uterus: Vaginal bleeding, discharge
  • Lung: Coughing up blood, shortness of breath, chest pain
  • Liver: Abdominal pain
  • Brain: Headache, trouble with vision, weakness or loss of function, convulsion
  • Kidney: Blood in urine
  • Bowel: Blood in stool

Diagnosis

The diagnosis of hydatidiform mole is most commonly made by an ultrasound, a test which uses sound waves to show the contents of the uterus.  The ultrasound picture of a complete hydatidiform mole will show the uterus filled with cysts. There is no evidence of a fetus.

The early diagnosis of a partial hydatidiform mole will look like a miscarriage or show an abnormal fetus with an abnormal placenta depending upon the number of weeks pregnant.  In most cases of partial mole the diagnosis is made by the pathologist. A blood test will also be done to look for a hormone called human chorionic gonadotropin (known as hCG or beta-hCG) which is also present in normal pregnancy. This hormone is an important test which will be used to determine whether the molar pregnancy will become malignant, to determine if treatment is working, and to find out if the GTD has returned.

The diagnosis of choriocarcinoma is usually made when the patient develops abnormal vaginal bleeding or other symptoms, or on rare occasions when a pregnancy test is found to be elevated and there is no pregnancy.

Treatment

After the diagnosis of complete or partial hydatidiform mole is made or suspected, the uterine contents are removed by suctioning (called Dilation and Evacuation, D&E)   Hysterectomy may be advisable in older patients who have completed childbearing to reduce the risk of malignancy. After the uterus is emptied, testing for human chorionic gonadotropin should be performed weekly tests until a negative (<5) value is reached. Once a negative value is reached, follow with two additional consecutive weekly beta hCG tests. If all three weekly test are negative, follow with three consecutive monthly beta hCG tests. If all hCG tests remain negative, follow-up is complete and pregnancy may be attempted, if appropriate. If the beta hCG level plateaus over three consecutive weeks, or re-elevates over two consecutive weeks, evaluation for persistent gestational trophoblastic neoplasia is mandatory. Birth control pills or other forms of hormonal contraceptives are safe and effective. IUDs should not be inserted until the hCG is undetectable.

A rise in the hormone level indicates that the molar pregnancy is malignant GTD (also called gestational trophoblastic neoplasia, GTN). More tests will be done to find out if the cancer has spread from the uterus to other parts of the body (called staging). Even if GTD has spread to other parts of the body it is still highly curable. The stages of malignant GTD are:

Stage I. The cancer has not spread from the uterus

Stage II. The cancer has spread from the uterus to other structures in the pelvis

Stage III. The cancer has spread to the lungs

Stage IV. The cancer has spread to other organs

The treatment of malignant GTD depends on the stage and number of risk factors which determine the type of drugs that will most likely cure the disease.  The factors that are characteristic of women who are likely to be cured by one or more single chemotherapy drugs (called low-risk malignant GTD) are:

  1. The last pregnancy was less than 4 months ago
  2. The level of hCG in the blood is low
  3. The cancer has not spread to the liver, brain and/or other distant organs
  4.  The patient has not received chemotherapy treatments earlier

The risk factors of women who develop malignant GTD who are NOT likely to be cured by one or more single chemotherapy drugs and who require treatments containing multiple agents to effect cure (called high-risk malignant GTD) are.:

  1. The last pregnancy was more than 4 months ago
  2. The level of hCG in the blood is high
  3. The cancer has spread to the liver, brain and/or other distant organs
  4. The patient received chemotherapy earlier and the cancer did not go away
  5. The tumor began after completion of a normal pregnancy

Three kinds of treatment are used for malignant GTD: surgery (removing the cancer), chemotherapy (using drugs to kill the cancer), and radiation therapy (uses high energy x-rays to kill cancer cells and shrink tumors). The most common operation used for malignant GTD is hysterectomy, an operation to take out the uterus. Surgery may also be used to remove cancer involving the lungs and other organs which have not gone away with drug therapy.

Chemotherapy is the main treatment for malignant GTD and is generally highly effective. Chemotherapy uses drugs to kill cancer cells.  It may be taken by pill, or by a needle in vein or muscle.  It is called systemic treatment because the drugs enter the bloodstream, travel through the body, and can kill cancer cells outside the uterus.  Chemotherapy may be given before or after surgery or alone.  Patients can preserve fertility and still be cured with chemotherapy even in the presence of widespread disease.

Radiation may infrequently be used in certain cases to treat cancer that has spread to other parts of the body, particularly the brain. Radiation may come from a machine outside the body (external-beam radiation therapy) or from putting materials that produce radiation (radioisotopes) through thin plastic tubes into the area where the cancer cells are found (internal radiation).

Placental site trophoblastic tumors, unlike choriocarcinoma, are not very sensitive to chemotherapy. Since in most cases the tumor is localized to the uterus, hysterectomy is generally curative.  When the disease spreads outside the uterus, high dose chemotherapy is used with some success.

Once You Have Been Treated, Then What?

Hormone follow-up by measuring the level of human chorionic gonadotropin (hCG) in blood  continues until the hormone level is normal for three weeks, then should continue monthly for 12 months (24 months or patients with Stage IV disease).  During that time the patient should avoid pregnancy.  Women who conceive within 12 months of completing chemotherapy have an increased risk of miscarriage, particularly if they have received multiple chemotherapeutic agents.  If pregnancy occurs before follow-up is complete, tumor relapse may be difficult to detect and diagnosis of relapse may be delayed.

The chemotherapy used for the treatment of malignant GTD is generally well tolerated without long-term side effects with two exceptions: 1) the use of multi-agent chemotherapy is associated with an earlier menopause,  and 2) women with high-risk GTN who require multi-agent chemotherapy which includes a drug called etoposide and survive for more than 25 years should be advised that they may be at increased risk of developing secondary tumors,  particularly acute myeloid leukemia, colon cancer, melanoma, and breast cancer.

Recurrent Disease

GTN is a highly curable disease.  Women with hydatidiform mole have an excellent prognosis and women with malignant GTD (called GTN) usually have a very good prognosis.  Choriocarcinoma, for example, is an uncommon, yet almost always curable cancer.  Although choriocarcinoma is a highly malignant tumor and life-threatening disease, it is very sensitive to chemotherapy. 85-90% of women with low-risk malignant GTD are cured by the initial chemotherapy and the remaining are cured by the use of stronger combinations of drugs, or  surgery. Similarly, 85-90% of women who develop high-risk malignant GTD are cured by chemotherapy used together with the selective use of surgery and radiation.  Approximately 10-15% of women with high-risk malignant GTD will develop drug resistance after prolonged chemotherapy.  This group is made up of patients with stage IV disease that involves distant organs such as the brain, liver and bowel. Specially designed chemotherapy treatments using drugs that have been shown to be effective against other cancers are being employed to salvage many of these women.

Becoming Pregnant Again

After completing hormone follow-up for hydatidiform mole women may try for pregnancy whenever they wish. The risk of another molar pregnancy is low. More than 98% of women who become pregnant following a molar pregnancy will not have a further hydatidiform mole or be at increased risk for complications. Since patients with hydatidiform mole are at increased risk of another molar pregnancy it is advisable for them to undergo ultrasound examinations at 10 weeks of gestation to determine if the pregnancy is progressing normally.

Most women who require treatment for malignant GTD can become pregnant again and can have normal pregnancy outcomes.  After chemotherapy is completed women should postpone pregnancy for 12 months (24 months for women with stage IV disease) while they are being followed with hormone testing to make sure the tumor does not recur.  There does not appear to be an increase rate of congenital malformation irrespective of the chemotherapy used. Following GTD the expectation of normal future pregnancy is about comparable to the general population.

Summary  

Gestational trophoblastic disease, although highly curable, is an emotionally traumatic event in a women’s life, not only because of the pregnancy loss, but also because of the fear of cancer.  Treatment of malignant GTD can impact significantly on her self-image, relationship with her spouse/significant other, family and friends.  It is important for women to make use of all available psychological and social services and spiritual support to help them through this difficult time.

In response to the many E-mails and phone calls he has received from women with molar pregnancy, Dr. Goldstein has created additional pamphlets regarding the hCG diagnosis of molar pregnancy and the wait times for trying to conceive again after diagnosis. This information is based on Dr. Goldstein’s most current research and experience but again should NOT override your own doctor’s advice. He or she is familiar with you personally and your illness. If you have questions based on this information, SPEAK TO YOUR DOCTOR ABOUT IT before making any decisions about your care.

The Management of Molar Pregnancy

The diagnosis of malignancy is made by following the blood level of human chorionic gonadotropin (called hCG) after the uterus is emptied by suction evacuation or hysterectomy if childbearing is complete.. The risk of developing a malignancy after a complete mole is approximately 20% and after a partial mole is approximately 3%. After molar evacuation hCG tests should be performed weekly until negative (<5) for three consecutive weeks, then monthly for three consecutive months, after which it is safe to try for pregnancy. Recent research has shown that pregnancy may be safely undertaken after three months of normal (<5) hCG tests.

If the blood hCG level plateaus (fails to drop) or rises after removal of the molar tissue it means that the molar pregnancy has become malignant, and treatment with chemotherapy should be started promptly. Malignancy that develops following a molar pregnancy is highly curable with chemotherapy.

The risk of a repeat mole increases from 1:1000 to 1:100 pregnancies. If a patient has two molar pregnancies, the risk increases to 1:5 pregnancies. It has recently been determined that repeat molar pregnancies may be due to a genetic problem.

A normal ultrasound at 10 weeks of a subsequent pregnancy means that that the pregnancy is non-molar and can be managed normally.

Molar Pregnancy Follow-Up

  • WEEKLY B-hCG tests until negative (<5) value reached.
  • Once a negative value is reached, follow with 2 additional consecutive WEEKLY beta hCG tests.
  • If all three weekly test are negative, follow with 3 consecutive MONTHLY beta hCG tests.
  • If all hCG tests remain negative, follow-up is complete and pregnancy may be attempted, if appropriate.
  • If the beta hCG level plateaus over 3 consecutive weeks, or re-elevates over 2 consecutive weeks, evaluation for persistent gestational trophoblastic neoplasia is mandatory.
  • Birth control pills or other forms of hormonal contraceptives are safe and effective. IUDs should not be inserted until the hCG is undetectable.

References

Berkowitz RS, Goldstein DP. Molar pregnancy. N Engl J Med 2009;360:1639.
Feltmate C, et al. Human chorionic gonadotropin follow-up in patients with molar pregnancy: a time for re-evaluation. Obstet Gynecol 2003;101:732.
Growdon WB, et al. Post evacuation hCG levels and risk of gestational trophoblastic neoplasia among women with partial molar pregnancies. J Reprod Med 2006;51:871.
Wolfberg A, et al. Low risk of relapse after achieving undetectable hCG levels in women with complete molar pregnancy. Obstet Gynecol 2004;104:551.
Wolfberg A, et al. Low risk of relapse after achieving undetectable hCG levels in women with partial molar pregnancy. Obstet Gynecol 2006;108:393.

The descriptions and advice given here have been provided by Drs. Donald P. Goldstein, M.D., and Ross S. Berkowitz, M.D., at the New England Trophoblastic Disease Center at Dana Farber/Brigham and Women’s Cancer Center in Boston, Massachusetts. This information is freely available from the doctors upon request and has been published here with the knowledge and approval of Dr. Goldstein. Jennifer Wood Gilbreath takes no credit for this information, has no medical training, and has no affiliation with Drs. Goldstein and Berkowitz or the institutions in which they work. This material is intended for educational purposes only and is not intended to replace the advice of physicians directly involved in your care. None of the persons listed here accept any legal responsibility for the use or misuse of this information.