Gestational Trophoblastic Disease

What is Gestational Trophoblastic Disease?

Gestational trophoblastic disease (GTD) is a group of tumors in the womb that form due to the abnormal growth of cells that normally create the placenta, which is the organ connecting the mother and baby during pregnancy. These cells, known as trophoblasts, create a hormone called human chorionic gonadotropin (hCG). GTD is divided into different types. One is hydatidiform moles (HM), which have a villi or microscopic finger-like structure, and the other ones lack this structure.

The harmful types of GTD are referred to as gestational trophoblastic neoplasia (GTN) which include invasive moles, choriocarcinoma, epithelioid trophoblastic tumors (ETT), and placental site trophoblastic tumors (PSTT). It’s important to note that these harmful tumors can develop weeks or even years after any pregnancy, but are most commonly seen after a molar pregnancy.

HM, also known as molar pregnancy, begins from the placenta and can be complete or partial. It is usually thought of as the non-harmful type of GTD. However, it’s worth noting that they have the potential to become cancerous and invasive.

Although cells grow and multiply in a well-controlled way in non-harmful GTD, this control can be lost, leading to harmful, rapidly growing, and spreading tumors. Such tumors can spread to other parts of the body and can be fatal if not promptly and effectively treated.

An invasive mole arises when unusual cells penetrate deeply into the wall of the womb and grow rapidly. This can potentially lead to complications, including abnormal bleeding from the womb.

Choriocarcinoma is a rare and aggressive type of tumor. There are two significant types of choriocarcinoma; gestational, which is connected with pregnancy and non-gestational, which is not associated with pregnancy. Both types have different biological activities and outcomes. While choriocarcinoma primarily occurs in women, it can also occur in men as part of a mixed germ cell tumor.

ETT is another rare subtype of GTN that originates from the cells that contribute to the placenta during pregnancy. This distinctive variant often emerges in women of reproductive age and can be associated with unusual vaginal bleeding or a mass in the womb.

PSTT is another rare form of GTN that originates from the site in the womb where the placenta attaches. Unlike more common tumors related to trophoblasts, PSTT tends to develop months or even years after a normal pregnancy, typically following a full-term or molar pregnancy. This tumor is characterized by slow growth and can result in irregular vaginal bleeding.

What Causes Gestational Trophoblastic Disease?

Trophoblasts are the initial cells that form after fertilization, providing nutrients to the unborn baby and begin the formation of the placenta. There are three different types of these cells – cytotrophoblasts, syncytiotrophoblasts, and intermediate trophoblasts. Problems occur when there’s too much growth of these cells, leading to a condition known as Gestational Trophoblastic Disease (GTD).

The changes in cytotrophoblasts and syncytiotrophoblasts can result in Hydatidiform moles (HMs) and choriocarcinoma, while intermediate trophoblasts can lead to Epithelioid trophoblastic tumors (ETTs) and Placental-site trophoblastic tumors (PSTTs).

HMs, also known as molar pregnancies, are non-cancerous tumors and make up about 80% of all GTD cases. They occur due to irregularities during the combination of sperm and egg. They can be complete or partial moles.

A complete molar pregnancy occurs when an egg without a nucleus (the part containing genetic material) is fertilized. Most of these moles are genetically known as 46, XX while 10% are 46, XY. The strange thing is that these moles have genes only from the father, but the mitochondrial DNA, found outside the nucleus, is from the mother. Complete moles don’t contain any fetus parts and often increase the levels of a hormone called human Chorionic Gonadotropin (hCG).

Partial molar pregnancies commonly contain both maternal and paternal DNA. They can occur as a result of one egg being fertilized by two sperms or one sperm doubling up upon fertilization. They sometimes contain identifiable fetus parts.

Invasive moles happen when these specific cells penetrate deep into the womb’s wall, but it’s uncertain what causes this to occur.

Choriocarcinoma forms from irregular cell growth, usually following a molar pregnancy. This can occur after a molar pregnancy, a regular pregnancy, or most often after a spontaneous abortion, also known as a miscarriage.

Neither the causes of ETT nor PSTT can be clearly pinpointed, due to their rare occurrence. Both types are believed to result from the abnormal cell growth related to developing the placenta during pregnancy. There’s evidence that these can also link with previous pregnancies, particularly those with molar pregnancies or gestational trophoblastic diseases.

Risk Factors and Frequency for Gestational Trophoblastic Disease

Studies have shown that the occurrence of Hydatidiform moles (HMs), a type of pregnancy complication, varies significantly worldwide. Southeast Asia and Japan see the most instances, while the United States has fewer counts. We need to manage this issue properly as 15% to 20% of patients with HMs can develop a higher risk condition requiring chemotherapy after surgery.

• The risk factors for HM include extreme ages, certain ethnic backgrounds, and a history of having HMs, which suggests a genetic cause.
• The likelihood is higher for women older than 35 and younger than 21, and significantly higher for women older than 40.
• Women with a history of HM have roughly a 1% chance of recurrence, which is 10 to 20 times higher than the general population.
• Lacking carotene (vitamin A precursor) and animal fats in diets, along with smoking, also increases the risk of HM.
• Interestingly, a history of miscarriage can double or triple the risk of getting an HM compared to women who have not experienced miscarriage.
• If a woman experiences two molar pregnancies, she has a 15% to 20% chance of having a third.

It’s difficult to provide precise numbers regarding Gestational Trophoblastic Neoplasia (GTN), a condition that can occur after pregnancy. Approximately 50% of GTN cases occur after molar pregnancy, 25% ensue miscarriage, termination, or ectopic pregnancy, and the remaining 25% may develop after either a preterm or term pregnancy.

• When GTN develops after HM, the condition is usually an invasive mole or choriocarcinoma, rarely an epithelioid trophoblastic tumor (ETT) or a placental site trophoblastic tumor (PSTT).
• After a full molar pregnancy, around 15% of patients will still have persisting local disease with tissue invasion, and 5% could develop a disease that spreads to other parts of the body.
• GTN after non-molar pregnancy happens in about 2 to 200 per 100,000 pregnancies worldwide, and it’s usually choriocarcinoma.

Choriocarcinoma is a rare type of cancer that has different occurrences worldwide. It makes up less than 0.1% of all primary ovarian cancers.

• In the US, choriocarcinoma occurs in about 1 in 20,000 to 40,000 pregnancies. Half of the cases occur after term pregnancies, a quarter after HMs, and the rest after other pregnancy events.
• In Europe, about 1 in 40,000 pregnant women and 1 in 40 women with HMs will develop choriocarcinoma.
• Choriocarcinoma risk is higher in Asian, Native American, and Black women. Other risk factors include a history of HM, older age, long-term oral contraceptive use, and blood type A.
• Choriocarcinoma can also affect men, especially between the ages of 20 and 30.

Throughout the past 30 years, choriocarcinoma and HM rates have decreased across all populations.

Signs and Symptoms of Gestational Trophoblastic Disease

A molar pregnancy, or hydatidiform mole (HM), is most commonly diagnosed during early pregnancy. Its primary symptom, experienced by about 84% of patients, is heavy vaginal bleeding, often appearing similar to dark brown or prune juice. This can be due to molar tissue separating from the uterus lining.

Some people may pass grape-like clusters or vesicles, have severe nausea and vomiting (hyperemesis) due to high hCG hormone levels, or develop early pregnancy-induced high blood pressure. Symptoms often vary depending on how far along the pregnancy is.

• In the first trimester, symptoms can include tachycardia (increased heart rate) and tremors due to heightened hCG levels.
• Late symptoms, seen around 14 to 16 weeks of pregnancy, may include signs of hyperthyroidism, pregnancy-induced hypertensions, along with proteinuria (excessive protein in urine) and/or organ dysfunction. These typically occur after 34 weeks of gestation.
• In rare cases, patients may struggle with severe respiratory distress, possibly due to a pulmonary embolization of trophoblastic tissue.

An important note: if a patient before 20 weeks of pregnancy shows signs of pre-eclampsia – a condition characterized by high blood pressure and significant amounts of protein in the urine – a complete molar pregnancy may be the cause.

Partial molar pregnancies usually present less dramatically than complete moles. Symptoms are often similar to those of miscarriage, including vaginal bleeding. Diagnosis typically occurs after surgical removal of pregnancy tissue from the uterus. Since partial moles consist of fetal tissue, the patient might have evident fetal heart tones on Doppler.

In over half the cases, during a physical exam, the uterine size may not match the expected size for the gestation date. If the mole is complete, the uterus is usually larger than expected, while in partial moles, it might be smaller.

Those suspected of having choriocarcinoma, a type of cancer that happens after a molar pregnancy, should undergo a thorough history and physical exam. This is especially vital considering any reproductive history, as miscarriages and molar pregnancies can increase the risk of choriocarcinoma.

Men can also be affected, often presenting with gynecomastia (enlarged breasts) and/or symptoms of metastatic disease, including coughing up blood. The liver, gastrointestinal tract, and brain are also commonly affected. In males with developed choriocarcinoma, the testicular anatomy is usually very small or even regressed, leaving only metastatic disease and cells.

Testing for Gestational Trophoblastic Disease

Ultrasounds are the main way to detect a gestational trophoblastic disease (GTD), like a molar pregnancy. On an ultrasound, a molar pregnancy looks a bit like a “snowstorm” or “bunch of grapes” inside the uterus. In a molar pregnancy, there’s no baby developing and no amniotic fluid (the fluid that surrounds the baby in the womb). There might also be cysts on the ovaries. In the earliest stages of pregnancy, ultrasounds typically show a complex mass that contains lots of small pockets of fluid. These pockets are what we see when we look at hydropic villi, or fluid-filled sacs, on pathology.

However, sometimes a molar pregnancy is only discovered after a presumed miscarriage, once a doctor has examined the tissue that was passed. In the case of a partial molar pregnancy, the ultrasound might show pieces of a baby or a viable baby, amniotic fluid, and an enlarged placenta (often described as having a “Swiss cheese” appearance). When this happens, the pregnancy is often thought to be a missed or incomplete miscarriage.

Ultrasound can sometimes give a false-negative or false-positive result for partial hydatiform moles (partial HMs), so doctors often have to look at tissue samples under a microscope to reach a final diagnosis. However, because doing so after every miscarriage may not be practical, your doctor may recommend checking your hCG level (a hormone produced in pregnancy) a few weeks after a miscarriage to make sure it’s back to normal.

If a molar pregnancy is diagnosed, you might have to undergo a CT scan and PET scan to figure out how far along the disease is. A chest x-ray might also be necessary if you have symptoms like difficulty breathing and increased heartbeat (called respiratory distress) or increased breathing (possibly indicating fluid buildup in the lungs).

Your doctor will likely order a number of tests before treatment begins, including blood tests to check your hCG level, to look for anemia (low red blood cell count) or thrombocytopenia (low platelet count), to check your clotting ability, to evaluate your electrolyte levels and kidney function, to assess liver function, and, if necessary, to check thyroid function. Urinalysis and certain radiological exams are also done.[49]

Your blood type is important to know because most people with complete and partial HMs have vaginal bleeding. If you’re Rh(D) negative, you’ll need a medication to prevent your body from developing antibodies that could harm your baby in future pregnancies.

In complete HMs, hCG levels are usually much higher than in a normal or ectopic pregnancy at the same stage. However, in partial moles, hCG levels might be within the normal range or even lower than expected. Nearly half of patients with complete HMs have hCG levels over 100,000 mIU/mL before treatment, which is seen in less than 10% of patients with partial HMs.

Depending on certain conditions or symptoms, doctors might have to begin chemotherapy for GTD. Some of these conditions include hCG levels not going down after treatment, heavy vaginal bleeding, bleeding in the stomach or abdominal cavity, a diagnosis of choriocarcinoma based on tissue samples, signs of metastasis (cancer spread) in the brain, liver, or gastrointestinal tract (GI tract), lung abnormalities bigger than 2 cm, still-elevated hCG levels four weeks after treatment, or hCG levels taking longer than six months to come down after treatment.

If you’ve had a molar pregnancy, and are later diagnosed with gestational trophoblastic neoplasia (GTN), a tumor formed from the tissue that grew to become the placenta, you may not have any symptoms or findings on ultrasound. So, doctors have to look at hCG levels and the size of the tumor to make a diagnosis. To check for choriocarcinoma (a type of cancer that can form after a molar pregnancy), your doctor will likely order blood tests, including coagulation studies, metabolic panels, liver function panels, and quantitative hCG tests.

Once choriocarcinoma is diagnosed, doctors have to check for metastasis (cancer spread), especially in the lungs, which is the most common site. Recommended tests include CT scans of the chest, abdomen and pelvis, and potentially CT or MRI of the brain. MRI might be necessary if your case is unusual, if the disease comes back, or if you have certain rare forms of GTD.

Treatment Options for Gestational Trophoblastic Disease

If doctors think you may have a molar pregnancy based on your ultrasound findings and hCG hormone levels, they will check for other complications. These might include electrolyte imbalances due to excessive vomiting (hyperemesis), anemia, overactive thyroid (hyperthyroidism), and high blood pressure during pregnancy (preeclampsia).

After this evaluation, decisions will be made about the best way to remove the abnormal tissue from the uterus. Medical induction is not advised due to the risk of excessive bleeding (hemorrhage). The most common method of removal is a surgical procedure, either a dilation and evacuation (D&E) or a suction curettage, for both complete and partial moles, irrespective of the size of the uterus. Ultrasound guidance may be useful for ensuring the complete removal of tissue in large uteri. If the patient’s blood type is Rh-negative, a medicine called Rho (D) immunoglobulin should be given after the procedure.

For patients who have finished having children, especially older women, a hysterectomy (removal of the uterus) can be considered. This reduces the risk of developing GTN (a growth of abnormal cells inside the uterus), which is more than 50% in women older than 40 years. It can also prevent the need for later chemotherapy, making it a reasonable choice for older patients with complete molar pregnancies.

In certain high-risk cases, prophylactic chemotherapy, alongside the surgical removal of the molar pregnancy, might help reduce the chance of GTN. But, some researchers question the validity of this method.

After the removal of the molar pregnancy, it’s vital to monitor the levels of the hCG hormone in the patient’s blood serum to check for any signs of GTN. Doctors usually advise checking levels every week until they remain undetectable for three consecutive weeks and then once a month for six months. If the levels remain stable during this period, the patient can attempt to get pregnant again.

If hCG levels don’t drop or remain high over several weeks after the molar has been removed, it is classified as GTN. The decision to diagnose GTN is also based on certain specific criteria set by the International Federation of Gynecology and Obstetrics (FIGO).

Depending on the risk profile, GTN might be managed either with a single chemotherapeutic drug, like methotrexate, or with a combination of drugs. After treatment and normalizing of hCG levels, these levels should be verified monthly for a year along with two physical exams in the same timeframe. In any future pregnancies, early ultrasound should confirm pregnancy inside the uterus due to a small but considerable risk of GTN occurrence.

Standard treatments for GTD (gestational trophoblastic disease) can include a range of options like D&E, chemotherapy, hysterectomy (partial or full), or a combination of these. The best treatment option will depend on the type and stage of the GTN.

Controversial treatments consist of prophylactic chemotherapy in place of monitoring hCG levels and conducting the second D&E on patients where the hCG level remains high post molar pregnancy evacuation. Newer treatments being studied include drugs like pembrolizumab used in drug-resistant GTN. Future randomized controlled trials will be required to assess the effectiveness of alternate treatments.

In the emergency department, clinicians’ priority is to stabilize the patient. Necessary measures are taken based on the patient’s symptoms, like respiratory distress, seizures, high blood pressure, symptoms of hyperthyroidism, and severe anemia. Appropriate consultations with the obstetrics department and the gynecological oncologist department are scheduled based on the patient’s condition and age. The older patients, typically older than 40 years, might need a hysterectomy instead of a D&E after stabilizing the patient.

What else can Gestational Trophoblastic Disease be?

When doctors are trying to identify Gestational Trophoblastic Disease (GTD), there are a number of other conditions they need to consider as these can show similar signs. These include:

• Ectopic pregnancy
• Normal pregnancy
• Cornual pregnancy
• Pregnancy in the rudimentary uterine horn
• Missed abortion
• Threatened abortion
• Incomplete abortion
• Complete abortion
• Hydropic abortion
• Blighted ovum
• hCG-secreting germ cell tumor
• Quiescent GTN
• Mosaic conception
• Placental mesenchymal dysplasia
• Other placental abnormalities
• Uterine fibroids
• Ovarian cysts
• Ovarian tumors
• Hyperemesis gravidarum (severe morning sickness)
• Hypertension (high blood pressure)
• Malignant hypertension (dangerously high blood pressure)
• Hyperthyroidism (overactive thyroid)
• Biliary obstruction (blockage in the bile ducts)
• Bladder cancer

What to expect with Gestational Trophoblastic Disease

Generally, the outlook for gestational trophoblastic disease (GTD) – a condition where abnormal cells grow inside the uterus after conception – is positive. Patients with early-stage, low-risk GTD can expect a high survival rate and successful treatment. Even for patients with late-stage, high-risk GTD disease, or those who have the disease spread to other parts of the body, the cure rates are good (80% to 90%) with a combination of chemotherapy and radiation – even without surgery.

Low-Risk GTD

Over 80% of hydatidiform moles (HMs) – a type of GTD where there’s an abnormal growth in the womb during early pregnancy – are not harmful. The risk of the disease turning aggressive in a complete molar pregnancy ranges from 15% to 20%, and in a partial molar pregnancy, it’s between 1% to 5%. Almost 95% of patients diagnosed with a HM, who then develop tumors, have a low risk of the disease persisting. Most patients benefit from single-drug chemotherapy with medications like methotrexate or dactinomycin. If the initial treatment doesn’t work, usually due to resistance, other chemotherapy drugs can be tried, achieving almost a 100% survival rate.

High-Risk GTD

Usually, patients with advanced GTD present with spread of the disease months or years after the pregnancy that caused it. Symptoms can vary depending on where the disease has spread. For instance, patients with brain spread may have headaches, seizures, or weakness on one side of the body. Those with lung spread may experience shortness of breath, coughing up blood, or chest pain. Diagnosis may not always be straightforward as irregular periods aren’t always present. Doctors recommend imaging studies like full body CT scans, MRI of the brain and pelvis, and Doppler ultrasonography. If there are no signs of brain spread, a lumbar puncture may be performed to check the ratio of cerebrospinal fluid to serum hCG (a pregnancy hormone).

Possible Complications When Diagnosed with Gestational Trophoblastic Disease

: GTD, or gestational trophoblastic disease, can lead to both surgical and medical complications. It is essential that the removal of a molar pregnancy, a form of GTD, is done as soon as the patient is in a stable medical condition. Ideally, this procedure takes place in a hospital with an intensive care unit, a blood bank, and anesthesia support, particularly if the patient’s uterus is extremely enlarged.

Medical problems related to a molar pregnancy can include excessive vomiting, hyperthyroidism, vaginal bleeding, anemia, preeclampsia, and difficulty breathing. Less common but potentially life-threatening complications can include fluid build-up in the lungs, blood clots in the lung, fluid build-up around the lungs, and embolization of the trophoblastic tissue.

In patients with high levels of hCG or suspected hyperthyroidism, undergoing surgery and anesthesia can lead to a thyroid storm, which is a severe and dangerous complication. Respiratory distress or difficulty breathing can occur during and/or after the surgical evacuation and heavy bleeding and fluid replacement could spark this. Other causes could include blood clots due to trophoblastic tissue, preeclampsia, and a thyroid storm leading to high-output heart failure. Healthcare professionals administering anesthesia need to be aware of these possible complications.

If left untreated, a choriocarcinoma (a type of GTD) can be fatal. However, with chemotherapy advancements, many patients can be cured of their disease. It’s important to bear in mind, chemotherapy does come with its own risks. Side effects often include developing secondary cancers, nausea, vomiting, hair loss, diarrhea, fevers, infections, and the need for blood transfusion.

Common Complications:

• Excessive Nausea
• Hyperthyroidism
• Vaginal bleeding
• Anemia
• Preeclampsia
• Difficulty breathing
• Fluid build-up in the lungs
• Blood clots in the lung
• Fluid build-up around the lungs
• Embolization of the trophoblastic tissue
• Thyroid storm during surgery
• Respiratory distress
• Choriocarcinoma (if untreated)
• Secondary cancers due to chemotherapy
• Nausea, vomiting, hair loss, diarrhea, fevers, infections due to chemotherapy
• Need for blood transfusion due to chemotherapy

Recovery from Gestational Trophoblastic Disease

After surgery, doctors will usually carry out weekly blood tests to check the level of hCG (a hormone produced during pregnancy) at an outpatient clinic. This is done until there’s no detectable level of hCG. It’s strongly advised that individuals who previously had a molar pregnancy (an abnormal form of pregnancy) use effective birth control. Oral contraceptives have been found to be a safe choice in such situations.

Starting a new pregnancy may disrupt weekly hCG level checks and make it hard to spot if invasive molar disease (a severe complication of molar pregnancy) occurs. Therefore, it’s crucial to adhere to the guidelines for hCG monitoring closely.

Preventing Gestational Trophoblastic Disease

Doctors and nurses play a key role in raising awareness about GTD (Gestational Trophoblastic Disease), a condition that can occur during pregnancy, and the factors that can increase the risk. Teaching patients about the value of early care during pregnancy and regular check-ups can help catch GTD early on, which leads to better patient outcomes.

For those diagnosed with GTD, it’s important that they receive clear and precise information about when they should come back for check-ups and why continuous monitoring is so crucial. Educating patients about the need for regular hCG (human chorionic gonadotropin) testing, a hormone that is checked to monitor GTD, can help ensure the early detection of recurring or persistent disease. This early detection then leads to appropriate care and improved patient outcomes.

Complications such as an invasive mole or choriocarcinoma, a rare form of cancer that occurs in a woman’s uterus (womb), can occur in about 15%-20% of patients with complete hydatidiform moles (HMs- a type of GTD) and 1%-5% with partial HMs. All patients with HMs should have regular hCG check-ups. The process for monitoring differs from one country to another, but the main steps are the same. For example, in the United Kingdom, hCG levels in blood and urine are measured every two weeks until they come back negative, then urine hCG levels are checked monthly. Patients who achieve negative hCG values within 56 days of having the uterus cleaned out (uterine evacuation) are at low risk of developing cancerous disease and are then monitored monthly for six months from the date of the cleaning.

During the hCG monitoring period, patients are advised to use reliable birth control methods. After hCG monitoring, hCG levels in blood or urine should be checked 6 and 10 weeks after each pregnancy to ensure no recurrence of previous molar disease (a type of GTD). Any woman who has delivered a baby, especially high-risk patients, should be advised to return for continued care if they have prolonged bleeding after delivery. Future prenatal care should include early ultrasound scans during pregnancy.