GESTATIONAL TROPHOBLASTIC DISEASE

GENERAL FEATURES
TYPES OF MOLAR PREGNANCIES
TREATMENT
THE PROBLEM OF PERSISTENT LOW LEVELS OF HCG

GENERAL FEATURES

Gestational Trophoblastic Disease is a term that includes several conditions that are the consequences of an abnormal pregnancy. The conditions are molar pregnancy, invasive mole, metastatic mole and gestational choriocarcinoma(korio carcinoma). 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 found in all other cells. 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 is, 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 (sin shishio tro fo blast) cells. The villi, or villus when describing only one, is a microscopic finger like structure containing a fetal blood vessel. It invades into the lining of the uterus. The synctio- and cytotrophoblast cells surround 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 begins to decrease as the placenta ages. At birth the placenta separates and along with the membranes and umbilical cord is 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 name for this mass of water drops is hydatidiform mole. In Latin, mole means shapeless mass and hydatid means water drop. It is referred to as a mole or 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 all well familiar with this condition and they can diagnose easily by a sonogram. There is a characteristic appearance to the uterine contents, and there are no fetal structures or heart beat. Only very rarely will there may be a coexisting fetus in which case it is thought to be a twin pregnancy; one twin normal and the other pregnancy a mole.

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 usually have 23 pairs of chromosomes, all of which are paternal in origin.
They are usually XX, both paternal in 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.

SUBTYPES OF MOLAR PREGNANCIES

What has been described above is the typical "complete" molar pregnancy. There are also "partial" molar pregnancies and a condition described as a "placental site trophoblastic tumor". Partial molar pregnancies are, in general, lesser forms of the complete mole. There are lesser degrees of trophoblastic proliferation, swollen villi and lower levels of HCG. They also have a lesser likelihood of serious sequelae. Placental site trophoblastic tumors are the rarest of all the forms of Gestational Trophoblastic Disease. It is generally benign, but can be highly malignant, metastatic and poorly responsive to chemotherapy. It requires a knowledgeable pathologist to diagnose and an experienced gynecologic oncologist to treat. These patients should be referred to a regional trophoblastic disease center for treatment.

After a 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 with 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 12 weeks. Then it is repeated every month for 3 months and then every other month until it has been normal for 6 months. During this time the woman should not become pregnant because that will also result in production of B-HCG and make things complicated.

If the B-HCG decreases but then levels off or starts to rise again, then the diagnosis is Gestational Trophoblastic Disease. This may be either persistent mole, invasive mole (mole growing into the wall of the uterus), metastatic mole, usually to the lungs, or choriocarcinoma, which is a very serious cancer. 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. The patient should be referred to a gynecologic oncologist for treatment.

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 monthly B-HCG titers. As long as they remain normal everything is normal. 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 1500 for the first mole it would be 1 in 750 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.

Poor prognostic disease indicates the need for more aggressive chemotherapy. This means a combination of drugs or the addition of surgery and or radiation to the treatment plan. The major concern is that it be treated aggressively.

GOOD PROGNOSIS POOR PROGNOSIS Last pregnancy event <4 months >4 months B-HCG level <40,000 >40,000 Prior pregnancy mole term Prior Treatment none failed Metastases none or lung brain or liver

There is also a World Health Organization Scoring System to define the good and poor prognostic groups.

WORLD HEALTH ORGANIZATION SCORING SYSTEM Prognostic factor 0 1 2 4 Age <35 >35 Prior pregnancy mole abortion term Interval <4 mo 4-6 mo 7-12 mo >12 mo Serum B-HCG <1,000 <10,000 <100,000 >100,000 ABO blood group OxA,AxO B,AB maternal x paternal Size of largest tumor 3-5 cm >5 cm Number of Metastases 1-4 4-8 >8 Prior Chemotherapy single agent multiple

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 groups require 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.

THE PROBLEM OF PERSISTENT LEVELS OF HCG

As a general rule, the presence of B-HCG or HCG indicates either pregnancy or Trophoblastic Disease. If the diagnosis is Trophoblastic Disease, and if the B-HCG level does not fall to normal with treatment, then the outcome is poor and the patient will eventually die.

HOWEVER, THERE MAY BE OTHER SOURCES OF HCG AND/OR THE TEST MAY BE WRONG.

If there are persistent levels of HCG or B-HCG inconsistent with the clinical situation, then other sources of HCG need to be evaluated. The patient should be referred to a gynecologic oncologist or to a Regional Trophoblastic Disease Center.

The pituitary gland can make low levels of HCG as well as other hormones that are similar to HCG. The pituitary can be suppressed with medicine and the B-HCG repeated. There are several commercially available tests that the laboratories can use for determining B-HCG. A specimen can be simultaneously tested with different tests. There is also a "USA hCG Reference Service", currently operated by Laurence A. Cole, M.D., at the University of New Mexico Health Sciences Center, Albuquerque, New Mexico, that can evaluate these situations.

William M. Rich, M.D.
Clinical Professor of Obstetrics and Gynecology
University of California, San Francisco
Fresno Medical Education Program
Director of Gynecologic Oncology
University Medical Center
Fresno, California