Gestational Trophoblastic Disease

By William M. Rich MD


This is a term that includes several conditions that are associated with the results of a pregnancy. The conditions are molar pregnancy, invasive mole, metastatic mole and gestational choriocarcinoma. These are cancers and cancer like conditions of placental elements. The concept is so far beyond most people's experience, that unless they have been to medical school they will never have heard of it. It is not uncommon.

The easiest way to explain this disease is to start at the beginning. In the beginning, a single egg produced by the mother is fertilized by a single sperm from the father. The egg and the sperm are unique because each has only one chromosome from each of the 23 pairs of chromosomes. At fertilization the complete complement of 23 pairs is thus restored. The fertilized egg divides and forms two daughter cells. Before division occurs it must duplicate its chromosomes so that each daughter cell has a complete complement of 23 pairs. This type of cell division is called mitosis. These two daughter cells divide by mitosis and so there are now four identical cells each with the normal 23 pairs of chromosomes. Further cell division results in 8, then 16, then 32, then 64 identical cells. Then things start to become complicated.

Certain cells begin to differentiate and become different from the other cells. Some of the cells will eventually form the extra-embryonic tissues. That means the placenta, the membranes (bag of water), and the umbilical cord. The fetus is eventually formed by the remaining cells. The placenta is composed of three elements. The villi, the cytotrophoblast cells and the synctiotrophoblast cells. The villi, or villus when describing only one, is a microscopic finger like structure containing a fetal blood vessel that invades into the lining of the uterus. The synctio- and cytotrophoblast cells create the villi and help the villi to erode into the maternal blood vessels in the wall of the uterus.

There are millions of villi in a placenta. Oxygen and nutrients that are supplied to the fetus from the mother's blood must traverse the villus to be picked up by the fetal blood vessel in the villus. There is one fetal blood capillary per villus. The fetal blood is separate from the maternal blood. The villi and the cyto- and synctiotrophoblasts have to invade the lining of the uterus to reach the maternal blood vessels. As the pregnancy progresses the number of villi initially increases then begin to decrease as the placenta ages. At birth the placenta separates and along with the membranes and umbilical cord are discarded. They have done their job. This is the normal way the placenta functions. The invasion into the lining of the uterus is similar to the invasion of a cancer, but in pregnancy this is normal.

Sometimes something goes wrong very early in pregnancy. The fetus does not develop but the placental elements continue to grow. There is swelling of the villi and overgrowth of the cyto-and synctiotrophoblast cells. The villi can become so swollen that they are visible and look like drops of water. The scientific (Latin) name for this mass of water drops is hydatidiform mole, and it is referred to as a molar pregnancy. The trophoblastic cells make the pregnancy hormone, Human Chorionic Gonadotropin, HCG, which is the basis for all pregnancy tests. There is an overproduction of HCG as well as exaggerated symptoms of pregnancy.

Eventually, the patient will spontaneously miscarry and pass the mole. If the molar pregnancy is detected before that happens then an abortion has to be done to evacuate the uterus. Obstetricians are well familiar with this condition and can diagnose it by a sonogram. There is a characteristic appearance to the uterine contents, and there are no fetal structures or heart beat. Very rarely there may be a coexisting fetus. Why molar pregnancies occur is unknown, but there are some remarkable features about them:

They have the ability to invade into the wall of the uterus.
They can metastasize to other organs.
They can develop into choriocarcinoma which is a virulent cancer.
They have 23 pairs of chromosomes, all of which are paternal in origin.
They are XX, and both of the X chromosomes are also of paternal origin.
The incidence in Asia is about 1 in 120 pregnancies.
The incidence in Northern Europe is 1 in 2000 pregnancies.
In the USA the incidence is about 1 in 1500 pregnancies.
Metastatic disease sometimes undergoes spontaneous regression.

After the molar pregnancy is evacuated there must be rigorous surveillance for any sequelae. The consequences of a mole can be persistent mole, invasive mole, metastatic mole or choriocarcinoma. The follow up is done by a weekly blood test for HCG. Actually, it is for a specific sub-unit of the HCG molecule called B-HCG ( Beta HCG). The B-HCG may be in the millions and has to fall to less than 2. Usually the blood test is normal within 8 weeks. Then it is repeated every month for 6 months and then every other month for 6 months. During this time the woman should not become pregnant again because that will also increase the B-HCG, and make things complicated.

If the B-HCG decreases but then levels off and starts to rise again, then the diagnosis is Gestational Trophoblastic Disease. This may be either invasive mole (mole growing into the wall of the uterus), metastatic mole, usually to the lungs, or choriocarcinoma. At this point the patient is reexamined, a chest x-ray obtained and perhaps a scan of the liver. But for sure the patient needs chemotherapy. This is one case where chemotherapy is given on the basis of a blood test without a tissue diagnosis. If there is B-HCG, and the patient is not pregnant, she must be treated. Sometimes molar tissue will regress spontaneously. Treatment is usually easy. A single chemotherapeutic agent is given and repeated every two weeks until one course of treatment is given after the titer is normal (titer is the level of B-HCG in the blood). Then the patient is followed for a year with B-HCG titers. As long as they remain normal everything is normal,. There is no source of B-HCG other than the trophoblasic cells. After the year is up the patient can become pregnant again. The risk for another molar pregnancy is about doubled. But that is still a small number. If it were 1 in 500 for the first mole it would be 1 in 250 for the next pregnancy.

Molar pregnancies and their management is the easy part. The problem is when they are ignored, not followed adequately, or inadequately treated because then major problems occur. If a previous pregnancy ended in a miscarriage and there was no pathologic specimen it may have been an unknown molar pregnancy. If the last pregnancy was a normal term pregnancy and delivery, then nobody would be expecting choriocarcinoma to develop. But it can and it is usually not diagnosed promptly. It can be anywhere in the body and is a very aggressive cancer. It metastasizes widely and early. It is very invasive and destroys the tissue. It bleeds profusely. If it is in the brain then signs of a stroke or seizure may occur; if in the lung then the patient may cough up blood; if in the uterus then irregular bleeding. A simple pregnancy test that is positive will indicate the diagnosis.

Gestational trophoblastic disease is characterized as either metastatic or nonmetastatic. If nonmetastatic then treatment is by single agent chemotherapy or sometimes by hysterectomy. If metastatic, then it is divided into good prognosis and poor prognosis disease.

ParameterGood PrognosisPoor Prognosis
Last pregnancy eventless than 4 monthsmore than 4 months
B-HCG levelless than 40,000more than 40,000
Prior pregnancymoleterm
Treatmentno prior treatmentfailed prior chemo

There is also a World Health Organization Scoring System.

Prognostic factor0124
Age<39>=39..
Prior pregnancymoleabortionterm.
Interval<4 mo4-6 mo7-12 mo>12 mo
B-HCG<1,000<10,000<100,000>100,000
ABO blood group.OxA or AxOB or AB.
Size of largest tumor.3-5cm>5cm.
Site of metastases.spleen,kidneyGI,liverbrain
Number of metastases.1-44-8>8
Prior chemotherapy..single agenttwo or more

Total score: 0-4 low risk, 5-7 intermediate risk, >8 high risk for death.

The scoring systems indicate the need for multi-agent chemotherapy. The high risk groups and the poor prognosis group requires aggressive multi-drug regimens. Resistant areas that can be irradiated are irradiated. Involved organs or parts of organs that can be removed are removed surgically, because if the B-HCG titer does not go down to normal and stay there, the patient is going to die.

These patients should be treated at a center experienced in treating this disease. They will need extensive therapy and support. The treatment is vigorous and at times ruthless. This is a cancer that can be cured, even though widely metastatic.

The prognosis depends on the extent of disease and the aggressiveness of treatment. If a molar pregnancy is managed properly, the cure rate is about 100%. If non metastatic trophoblastic disease is vigorously treated the cure rate is also about 100%. Widely metastatic disease if recognized promptly and treated aggressively with multi-agent chemotherapy, surgery and radiation if necessary, is curable in about 80% of the cases.

William M. Rich, MD
Clinical Professor of Obstetrics and Gynecology
University of California San Francisco
Director of Gynecologic Oncology
Valley Medical Center
Fresno, Ca.

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Last updated 2 July 1996


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