What is Gestational Trophoblastic Neoplasia?
Gestational trophoblastic disease (GTD) was first mentioned by the famous Greek physician Hippocrates around 400 BC. However, it was only in 1895 that Felix Marchand found a link between pregnancy and this condition. Normally, a healthy trophoblastic tissue (part of the embryo that helps form the placenta) attaches to the lining of the womb, creating the placenta which acts like a lifeline between the mother and baby during pregnancy. But if this tissue becomes harmful or cancerous, it can invade the womb.
Usually, the body controls this process well in a healthy trophoblast (the tissue that forms the placenta), but with GTD, things can get out of hand, leading to growths that can spread into the blood vessels and other parts of the body. Gestational trophoblastic neoplasia (GTN) is a term for the harmful types of GTD, which include: choriocarcinoma, invasive mole, epithelioid trophoblastic tumor (ETT), and placental site trophoblastic tumor (PSTT). All these conditions can spread throughout the body and can be deadly if not diagnosed and treated quickly and effectively.
What Causes Gestational Trophoblastic Neoplasia?
Trophoblasts, the very first cells that form from a fertilized egg, play a crucial role in feeding the growing embryo and eventually make up part of the placenta, which is the organ that develops during pregnancy to provide nutrients and oxygen to the baby. Trophoblasts are actually what lead to molar pregnancies and a condition known as Gestational Trophoblastic Neoplasia (GTN). There are different kinds of trophoblasts: cytotrophoblasts, syncytiotrophoblasts, and intermediate trophoblasts.
Specifically, cytotrophoblasts and syncytiotrophoblasts are responsible for creating two conditions, hydatidiform moles, which is an abnormal growth of placental tissue, and choriocarcinomas, a rare and fast-growing form of cancer that occurs in a woman’s uterus (womb). Other conditions, known as Placental-Site Trophoblastic Tumors (PSTTs) and Epithelioid Trophoblastic Tumors (ETTs), come from intermediate trophoblasts.
Risk Factors and Frequency for Gestational Trophoblastic Neoplasia
Gestational trophoblastic neoplasia (GTN) is quite challenging to track accurately because pregnancy numbers and trophoblastic disease data can vary a lot. GTN is closely linked with different types of pregnancies and their outcomes. About half of GTN cases occur after a molar pregnancy. On the other hand, 25% might develop this condition following a miscarriage, abortion, or an ectopic pregnancy. The remaining 25% might experience GTN after giving birth, either prematurely or at full term.
If GTN occurs after a molar pregnancy, it often shows up as an invasive mole or choriocarcinoma, which is a malignant tumor of the placenta. It’s infrequent to see placental-site trophoblastic tumor (PSTT) or epithelioid trophoblastic tumor (ETT) in these situations. After fully molar pregnancies, around 15% of patients will have persistent disease with invasion, and about 5% might develop metastatic disease. GTN following nonmolar pregnancy can range from 2 to 200 cases per 100,000 pregnancies, typically manifesting as choriocarcinoma. The incidence of GTN following a pregnancy loss is around 1 in 15,000 cases, while after a full-term pregnancy, it happens in about 1 in 150,000 cases.
The risk of having a repeat mole following a molar pregnancy is between 1% and 2%. If there have been two previous molar gestations, the risk of having a third mole increases to 15% to 20%. The rates of choriocarcinomas, PSTTs, and ETTs are uncertain, as these conditions can occur after a pregnancy.
Signs and Symptoms of Gestational Trophoblastic Neoplasia
A Hydatidiform mole (HM) is a condition that usually gets diagnosed early because of routine ultrasound tests and beta-hCG testing. Some signs and symptoms of complete HMs include vaginal bleeding around week 6 to 16 of pregnancy, an unusually large uterine size, and severe morning sickness. However, some patients have no symptoms at all.
In contrast, partial HMs usually aren’t diagnosed until after surgical evacuation of the uterus. This diagnosis requires a histological examination of specimens removed during a procedure after an incomplete or missed abortion. Just like with complete HMs, most patients with partial HMs experience vaginal bleeding, but they tend to show these symptoms later than those with complete HMs. Complete HMs are linked with significantly higher hCG levels, with about half of the patients having hCG levels greater than 100,000 mIU/mL. Such high levels are found in less than 10% of patients with partial HM.
- Vaginal bleeding usually around week 6 to 16
- Unusually large uterus size
- Severe morning sickness
- In some cases, there may be no symptoms at all
- For partial HMs, vaginal bleeding is also a symptom but usually surfaces later
- Complete HM is often associated with very high hCG levels
Testing for Gestational Trophoblastic Neoplasia
If your doctor suspects you may have gestational trophoblastic neoplasia (GTN), a type of tumor that grows in the uterus, they’ll likely use an ultrasound as the first step in diagnosing you. This scan might show that your uterus is filled with a mixed mass that is often referred to as the “snowstorm” sign. It might also show that there’s no developing fetus and that there are cysts on your ovaries.
Unfortunately, these signs might not be detectable in the first three months of pregnancy. Also, ultrasounds can sometimes give either false-negative results (meaning you have the condition, but the ultrasound doesn’t show it) or false-positive results (meaning you don’t have the condition, but the ultrasound suggests you do). This is especially true with partial hydatidiform moles, a specific type of GTN.
Because of this, it’s usually necessary to also do a histological examination (a lab test that looks at cells under a microscope) to determine a final diagnosis. It might not be practical to do this test after every termination of pregnancy, so a test of your hCG level (a hormone that’s high when you’re pregnant) 3 to 4 weeks after the termination can be done to make sure it returns to a negative reading, indicating no pregnancy.
Sometimes patients with postmolar GTN (a type of GTN that occurs after a molar pregnancy – when a non-viable fertilized egg implants in the uterus) won’t have any symptoms, or their ultrasounds won’t show any specific signs. In these cases, a diagnosis is reached by looking at the relationship between the level of hCG hormone in the blood and the size of the tumor.
Finally, magnetic resonance imaging (MRI), another type of imaging scan, is not usually necessary in the normal evaluation of GTN, unless the situation is unusual – such as recurrence of GTN or certain specific forms of GTN – then an MRI scan might be recommended.
Treatment Options for Gestational Trophoblastic Neoplasia
There are a variety of treatment options for Gestational Trophoblastic Neoplasia (GTN), a condition that causes tumors in a woman’s uterus during pregnancy. These methods depend on the exact type of GTN you have and how far it has advanced.
Common treatments include dilation and curettage (D&C), where the uterus is scraped to remove abnormal tissue, chemotherapy, which involves using medication to kill cancer cells, and hysterectomy, a surgical procedure to remove the uterus. Let’s take a look at these in more detail:
D&C is often used in the case of molar pregnancy (a type of GTN that begins with an abnormal fertilized egg), especially when the patient desires to maintain their fertility. After D&C, it is crucial to frequently check the patient to make sure the disease doesn’t return.
Chemotherapy is another treatment option. It may involve one or more types of medication, including drugs like methotrexate, etoposide, actinomycin D, cyclophosphamide, cisplatin, and vincristine.
A hysterectomy is usually considered for patients who don’t respond to other treatment methods, if the GTN is severe, or if the patient doesn’t wish to have children in the future.
Placental-Site Trophoblastic Tumor (PSTT) and Epithelioid Trophoblastic Tumor (ETT) are specific types of GTN that haven’t spread outside the uterus are often initially treated with hysterectomy and salpingectomy (removal of a fallopian tube). If these diseases have spread to other parts of the body, removal of the uterus, fallopian tube, and affected tissue may be followed by platinum-based chemotherapy.
There are also some controversial treatment options.
One such option is prophylactic chemotherapy, which is administered as a preventive measure, rather than as a response to existing cancer. This approach has been suggested to reduce the need for more intense chemotherapy regimens and enhance the chance of total recovery. However, a recent review suggests avoiding this practice.
In some cases, a second D&C might be performed if initial treatment didn’t bring the levels of the pregnancy hormone hCG down to reassuring levels. But, this is typically avoided if there’s a high risk of uterine perforation (puncture of the uterus) or hemorrhage (heavy bleeding).
Only a small percentage of women with GTN do not respond to standard treatments, and the disease remains. In such cases, a drug called Pembrolizumab has been studied and found to be a promising new treatment approach. However, alternative treatment plans may have additional side effects, and further research is needed to evaluate their effectiveness.
What else can Gestational Trophoblastic Neoplasia be?
When trying to diagnose gestational trophoblastic neoplasia (GTN), doctors must consider whether the cancer has spread, and if so, to which organs. They will also consider other conditions that might explain the symptoms, such as:
- Incomplete abortion
- Ectopic pregnancy
- Cornual pregnancy
- Pregnancy in the rudimentary uterine horn
- Tumors in the germ cells that produce hCG, a pregnancy hormone
- Biliary obstruction, a blockage in the tubes that carry bile from the liver to the gallbladder and small intestine
- Bladder cancer
What to expect with Gestational Trophoblastic Neoplasia
About 95% of patients who are diagnosed with a tumor in the womb (a condition known as HM) are generally at a low risk for the tumor to persist or stay. For most of these patients, the preferred treatment is a type of cancer drug commonly known as methotrexate or dactinomycin. If these medications don’t work as expected, usually because of resistance, other chemotherapy drugs can be tried, making recovery almost certain.
Patients with a high risk of hydatiform mole (a rapidly growing and potentially dangerous form of pregnancy tissue) often show signs of the disease months or even years after the pregnancy that caused it. Signs and symptoms can vary depending on the location of the disease. For instance, patients with brain metastases (spread of cancer to the brain) may experience headaches, seizures or muscle weakness on one side of the body (hemiparesis). Whereas, patients with lung metastasis (cancer spread to the lung) may suffer from shortness of breath, coughing up blood (hemoptysis), or a sharp chest pain.
As regular menstruation isn’t always affected, diagnosis can sometimes be missed. That’s why medical imaging studies such as CT scans of the whole body, MRI of the brain and pelvis (lower body), and Doppler ultrasound, which uses sound waves to monitor blood flow, are recommended. If nothing unusual appears on the brain scan, a lumbar puncture (spinal tap) should be done to check the amount of pregnancy hormone (hCG) in the fluid from the spine.
Possible Complications When Diagnosed with Gestational Trophoblastic Neoplasia
Common issues linked to a molar pregnancy often include severe vomiting, an overactive thyroid, bleeding from the vagina, low red blood cells, high blood pressure during pregnancy, and breathing difficulties. Complications involving the lung are less common but can be potentially fatal. They could include water in the lungs, a blockage in a lung’s artery, excess fluid around the lungs, and the movement of abnormal cells from the placenta into the lungs.
Here are the common complications:
- Severe vomiting (hyperemesis)
- Overactive thyroid (hyperthyroidism)
- Bleeding from the vagina (vaginal hemorrhage)
- Low red blood cells (anemia)
- High blood pressure during pregnancy (preeclampsia)
- Breathing difficulties (respiratory distress)
- Water in the lungs (pulmonary edema, less common)
- Blockage in a lung’s artery (pulmonary embolism, less common)
- Excess fluid around the lungs (pleural effusion, less common)
- Movement of abnormal cells from the placenta into the lungs (trophoblastic embolization, less common)
Preventing Gestational Trophoblastic Neoplasia
People diagnosed with HMs (Hydatidiform moles, a type of benign tumor that forms in the womb) need to have regular checks of their hCG (human chorionic gonadotropin), a hormone that usually increases during pregnancy. Although different countries have different methods of carrying out these checks, the basic practice is the same.
In the United Kingdom, blood and urine tests are taken every two weeks to measure hCG levels until they drop down to normal levels. Once this happens, urine is tested for hCG every month. Patients whose hCG levels return to normal within 56 days after the mole has been surgically removed from the womb are less likely to develop malignant (cancerous) disease. These patients then continue to have their hCG levels checked monthly for six months after the date of surgery.
During this period, patients are advised to implement birth control methods reliably. This is to avoid another pregnancy while the previous mole disease is still being monitored. It is recommended to combine different contraceptive methods for the most reliable results. After this continuous monitoring of hCG levels, it is important that hCG concentrations in blood or urine are tested again at 6 and 10 weeks after any subsequent pregnancy, to ensure the mole disease has not returned.
After the removal of a molar pregnancy, it is crucial to maintain close monitoring to detect any complications (referred to as trophoblastic sequelae), including an invasive mole or choriocarcinoma. This is especially critical because there is a 15% to 20% chance of these complications occurring for patients who had complete HMs, and 1% to 5% for patients who had partial HMs.
