Gestational Trophoblastic Disease
What is GTD?
Gestational trophoblastic disease (GTD) is a group of rare tumours that involve abnormal growth of cells inside a woman’s uterus (womb). GTD does not develop from cells of the uterus like cervical cancer or endometrial (uterine lining) cancer do. Instead, these tumours start in the cells that would normally develop into the placenta during pregnancy. (The term “gestational” refers to pregnancy).
Any of a group of abnormalities that develops from trophoblastic cells (cells that help an embryo attach to the uterus and help form the placenta) after fertilization of an egg by a sperm is named gestational trophoblastic disease.
Most GTDs are benign (non cancerous) and they don’t invade deeply into body tissues or spread to other parts of the body. But some are cancerous. Because not all of these tumours are cancerous, this group of tumours may be referred to as gestational trophoblastic disease, gestational trophoblastic tumours, or gestational trophoblastic neoplasia.
All forms of GTD can be treated. And in most cases the treatment produces a complete cure. To treat this cancer, removal of the womb (hysterectomy) typically is not necessary. Many women go on to have children after treatment.
There are several types of GTD. The different kinds of GTD depend on how they look like under the microscope (histopathology).
The following are the types of GTD:
Hydatidiform Mole (Complete or Partial)
Complete and partial hydatidiform moles are non cancerous, localized tumours that develop as a result of an aberrant fertilization event that leads to a proliferative process. They comprise 90% of GTD cases.
The following three types of GTD are considered malignant (cancerous) because of their potential for local and distant dissemination (spreading):
Persistent/Invasive Gestational Trophoblastic Neoplasia (GTN)
In a normal pregnancy the trophoblast (cells that help an embryo attach to the uterus and help form the placenta) invades into and through the lining of the womb. This is necessary to make the placenta and hold it in the womb. Sometimes the trophoblast of a molar pregnancy invades much more deeply into the womb than it should. Rarely it can spread outside.
A cancerous, fast-growing tumour that develops from trophoblastic cells (cells that help an embryo attach to the uterus and help form the placenta). Almost all choriocarcinomas form in the uterus after fertilization of an egg by a sperm. Choriocarcinomas spread through the blood to other organs, especially the lungs.
Placental Site Trophoblastic Tumours
A very rare type of gestational trophoblastic tumour that starts in the uterus where the placenta was attached.
The following are risk factors for GTD:
- Extremes of maternal age: The most well established risk factor for GTD is maternal age. Compared to the risk of GTD in the general population of reproductive-age women, the risk is higher in those older than age 35 and slightly increased in those under age 20. Paternal age does not appear to influence the risk of GTD.
- History of previous GTD: Women with a history of one molar pregnancy (partial, complete, or persistent GTD) have an approximately 1% percent chance of recurrence in subsequent pregnancies (compared to a 0.1% incidence in the general population). The chance of developing GTD is much higher after two molar pregnancies (16 to 28%).
- Smoking cigarettes.
- Maternal blood type AB, A, or B.
- History of infertility.
- Use of oral contraceptives (the pill).
Some of the above risk factors have not been demonstrated consistently though.
Diagnosis and Staging
It’s important to let your general practitioner and/or obstetrician know about any abnormal symptoms you are having during pregnancy. Your doctor may suspect that GTD is present based on a typical pattern of signs and symptoms. Many of these may also be caused by conditions other than GTD. Still, if you have any of these, it’s important to see your doctor as soon as possible so the problem can be found and treated, if needed.
This is the process of finding out how far a cancer has spread. This information helps me to choose the type of treatment that offers the best possible results.
Molar pregnancies (complete and partial moles) are usually completely removed during a D&C (Dilatation & curettage), or, rarely, hysterectomy. They don’t need to be surgically “staged”. Staging is more useful for persistent GTDs, including invasive moles and choriocarcinomas.
Gestational Trophoblastic Disease (GTD) Classification
The stage of most cancers depends on how large they are and whether they have spread to lymph nodes or distant sites. This is part of staging for GTD as well. But because treatment is usually effective regardless of the extent of the disease, other factors such as a woman’s age, length of time from the pregnancy, and HCG level are more useful in predicting outcomes (prognosis). These factors are taken into account in a scoring system, which will help to guide your treatment.
The International Federation of Gynaecology and Obstetrics (FIGO) has developed a staging system based on the extent of the GTD as follows:
Stage I: The tumour is still within the uterus.
Stage II: The tumour has grown outside of the uterus to involve other genital structures (like the vagina or ovaries). It has not spread outside the pelvis.
Stage III: The tumour has spread to the lungs; it may or may not also involve genital structures such as the vagina or vulva.
Stage IV: The tumour has spread to distant organs such as the brain, liver, kidneys, and/or gastrointestinal tract.
Signs and Symptoms
Complete Hydatidiform Moles (Molar Pregnancies)
Most of these signs and symptoms (except for bleeding), are seen less commonly now than in the past because they tend to occur late in the course of the disease. Most women with GTD are now diagnosed early because of the use of blood tests and ultrasound early in pregnancy.
Almost all women with complete hydatidiform moles have irregular vaginal bleeding during pregnancy. It occurs a little less often with partial moles. Bleeding typically starts during the first trimester (13 weeks) of pregnancy. Women with GTD often pass blood clots or watery brown discharge from the vagina. Sometimes, pieces of the mole resembling a cluster of grapes become dislodged from the uterus and are discharged through the vagina. This bleeding often leads the doctor to order an ultrasound (imaging test), which leads to the diagnosis of a molar pregnancy.
In cases of serious or prolonged bleeding, a woman’s body is not able to replace red blood cells as fast as they are lost. This can lead to anaemia (low red blood cell counts). Symptoms can include fatigue and shortness of breath, especially with physical activity.
The uterus and abdomen can get bigger faster in a complete molar pregnancy than they do in a normal pregnancy. Abnormal uterine enlargement occurs in about 1 out 4 women with complete moles but rarely in women with partial moles.
Human chorionic gonadotropin (HCG), a hormone made by the tumour, may cause fluid-filled cysts to form in the ovaries. These cysts can be large enough to cause abdominal swelling. They only occur with very high levels of HCG. Even though they can become quite large, they usually go away on their own about 8 weeks after the molar pregnancy is removed. Sometimes they can twist on their blood supply (called torsion). This can cause severe pain and needs to be treated with surgery (to remove the cyst) or a procedure to drain the fluid inside the cyst.
Many women have nausea and vomiting during the course of a typical pregnancy. With GTD, however, the vomiting may be more frequent and severe than normal.
Pre-eclampsia (toxaemia of pregnancy) can occur as a complication of a normal pregnancy (usually in the third trimester). When it occurs earlier in pregnancy (like during the first or early second trimester), it can be a sign of a complete molar pregnancy. Pre-eclampsia may cause problems such as high blood pressure, headache, exaggerated reflexes, swelling in the hands or feet, and too much protein leaking into the urine. It affects a small number of women with complete moles but is rare in women with partial moles.
Hyperthyroidism (overactive thyroid gland) occurs in some women with complete hydatidiform moles. It occurs only in women with very high HCGblood levels. Symptoms of hyperthyroidism can include rapid heartbeat, warm skin, sweating, problems tolerating heat, and mild tremors (shaking). This occurs in less than 10% of women with complete molar pregnancy.
Partial hydatiform moles
The signs and symptoms of partial hydatidiform moles are similar to those of complete moles, but often are less severe. Some symptoms, such as frequent vomiting or an overactive thyroid gland, rarely, if ever, occur with partial moles.
Partial moles are often diagnosed after what is thought to be a miscarriage. The molar pregnancy is found when the uterus is scraped during a suction dilation and curettage (D&C) and the products of conception are looked at under a microscope.
Invasive moles and choriocarcinoma
These more invasive forms of GTD sometimes develop after a complete mole has been removed. They occur less commonly after a partial mole. Choriocarcinoma can also develop after a normal pregnancy, ectopic pregnancy (where the foetus grows outside of the uterus, such as inside a fallopian tube), or miscarriage. Symptoms can include:
The most common symptom is vaginal bleeding. Rarely, the tumour grows through the uterine wall, which can cause bleeding into the abdominal cavity along with severe abdominal pain.
In larger tumours, some of the tumour cells may die, creating an area where bacteria can grow. Infection may develop, which can cause vaginal discharge, crampy pelvic pain, and fever.
Like hydatidiform moles, more invasive forms of GTD can expand the uterus, causing abdominal swelling. Human chorionic gonadotropin (HCG), a hormone made by the tumour, may cause fluid-filled cysts (called theca lutein cysts) to form in the ovaries, which can be large and may also contribute to abdominal swelling.
The lung is a common site for distant spread of GTD. Spread to the lungs may cause coughing up of blood, a dry cough, chest pain, or trouble breathing.
These tumours can sometimes spread to the vagina, which can cause vaginal bleeding or a pus-like discharge. The doctor may also notice a cancerous growth on the vagina during a pelvic exam.
Other Symptoms of Distant Spread
Symptoms depend on where the spread occurs. If GTD has spread to the brain, symptoms can include headache, vomiting, dizziness, seizures, or paralysis on one side of the body. Spread to the liver can cause abdominal pain and a yellowing of the skin or eyes (jaundice).
Placental Site Trophoblastic Tumours (PSTTs)
PSTTs rarely spread to distant sites. More often, they grow into the wall of the uterus.
As with other forms of GTD, the most common symptom of PSTT is vaginal bleeding. If the tumour grows all the way through the wall of the uterus, it can cause bleeding into the abdominal cavity with severe abdominal pain.
As they grow within the wall of the uterus, PSTTs may cause the uterus to enlarge.
Laboratory tests: blood and urine tests
Human Chorionic Gonadotropin (HCG)
Trophoblastic cells of both normal placentas and GTD make a hormone called HCG, which is vital in supporting a pregnancy. HCG is released into the blood, and some of it is excreted in the urine. The sub-unit commonly measured in the blood and urine tests is called beta-HCG (βHCG). A complete mole usually releases more HCG than a normal placenta, so finding higher than expected HCG levels in the blood can be a sign that a complete mole is present.
Ultrasound can identify most cases of GTD that are in the uterus, and will likely be the first test you will have if there a suspicion of GTD. It is a test used to examine the vagina, uterus, fallopian tubes, and bladder. Most ultrasounds are done with the transducer placed on the skin after is first lubricated with gel. For better views an ultrasound transducer (probe) is inserted into the vagina and used to bounce high-energy sound waves (ultrasound) off internal tissues or organs and make echoes. The echoes form a picture of body tissues.
A chest x-ray may be done in cases of persistent GTD to see if there is any spread to the lungs, which is very unlikely unless the disease is far advanced. I have been using more frequently CT scan of the chest due its higher detection rate of disease.
An x-ray machine linked to a computer takes a series of detailed pictures of your organs. A tumour in the liver, lungs, or elsewhere in the body can show up on the CT scan. You may receive contrast material by injection in your arm or hand, by mouth, or by enema. The contrast material makes abnormal areas easier to see.
A powerful magnet linked to a computer is used to make detailed pictures of your pelvis and abdomen. I can view these pictures on a monitor and can print them on film. An MRI gives excellent details of nearby cancer spread. Sometimes contrast material makes abnormal areas show up more clearly on the picture.
PET (Positron Emission Tomography) Scan
You receive an injection of a small amount of radioactive sugar. A machine makes computerized pictures of the sugar being used by cells in your body. Cancer cells use sugar faster than normal cells, and areas with cancer look brighter on the pictures. Still, PET scan is rarely used for GTD.
Some machines are able to perform both a PET and CT scan at the same time (PET CT scan). This allows the radiologist to compare areas of higher radioactivity on the PET with the appearance of that area on the CT.
After GTD is diagnosed and staged I will discuss treatment options in a multidisciplinary meeting and a recommendation of one or more treatments will be made. No matter what type or stage of GTD a woman has, treatment is available. Your treatment choice depends on many factors. The location and the extent of the disease are very important. Other important factors include the type of GTD present, the level of human chorionic gonadotropin (HCG), duration of the disease, sites of spread if any, and the extent of prior treatment. In selecting a treatment plan, I will also consider your age, general state of health, and personal preferences.
It is important to begin treatment as soon as possible after GTD has been detected. The main methods of treatment are surgery, chemotherapy, and less frequently radiation therapy. Sometimes the best approach uses a combination of 2 or more of these methods.
Completing treatment can be both stressful and exciting. You may be relieved to finish treatment, but find it hard not to worry about cancer coming back (this is named recurrence). This is a common concern in people who have had cancer. It is a very real concern for some women with GTD. The risk of GTD returning is very small for molar pregnancies and low-risk GTD, but may be as high as 10% to 15% in women with high-risk GTD. For this reason, follow-up is very important.
The exact steps in the follow-up program depend on the type of GTD you had and the treatment you received.
In all cases, the most basic test involves measuring levels of HCG in the blood. Rising HCG levels may indicate that the disease is growing again in the uterus (if hysterectomy was not done) or that it has spread to another location and is growing there.
Depending on your situation, you may need to have certain tests or procedures such as chest x-rays or other imaging tests, from time to time.
If cancer does recur, it will most likely be detected with blood HCG tests before it causes any symptoms. If GTD does come back, in most cases it can be treated successfully.
Dr Marcelo Nascimento
MD MSc FRANZCOG CGO
I am a clinical specialist in the treatment of gynaecological pre-cancers, cancersand complex non-cancer gynaecological conditions. I am dedicated to improving the quality of life for women with gynaecological conditions providing the highest quality of diagnosis, treatment and recovery pathways in a caring and supporting environment. I work with fertility-preserving surgery whenever possible which allows women more options for treatment without compromising oncologic outcomes.