Last updated:
7/18/2025
Years published: 2019, 2025
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, Xenia Parisi, MD, Resident Physician, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, and Enrique Hernandez, MD, Abraham Roth Professor and Chair, Obstetrics, Gynecology and Reproductive Sciences; Professor, Pathology and Laboratory Medicine, Temple University, Lewis Katz School of Medicine, for the preparation of this report.
Summary
Gestational trophoblastic diseases (GTDs) are a group of rare conditions that arise from the tissue that normally develops into the placenta during pregnancy. This tissue, made up of trophoblast cells, usually helps the fertilized egg attach to the wall of the uterus and forms the placenta, which provides nutrients to the developing fetus. In GTD, however, abnormal growth occurs in this tissue, sometimes leading to tumors instead of a healthy pregnancy. These tumors may be non-cancerous (benign) or cancerous (malignant) and while many do not spread, some forms can grow aggressively and affect other parts of the body.
There are several types of GTD. These include:
Hydatidiform moles can be either complete, where there is no fetal tissue, or partial, where some abnormal fetal tissue may be present.
GTD also includes cancerous forms known as gestational trophoblastic neoplasia, which comprises invasive mole, choriocarcinoma, placental site trophoblastic tumor and epithelioid trophoblastic tumor.
Risk factors for developing GTD include being under 20 or over 35 years old and having had a previous molar pregnancy.
Common signs and symptoms include abnormal vaginal bleeding and a uterus that appears larger than expected during early pregnancy.
Diagnosis typically involves physical examinations, ultrasound imaging and blood tests to check for elevated levels of the pregnancy hormone hCG.
Treatment options vary depending on the type and extent of the disease but often include surgery, chemotherapy and sometimes radiation therapy. In addition, new treatments are being explored in clinical trials, which people may consider joining at different stages of their care. These treatments can cause side effects, and regular follow-up testing is often needed to ensure the disease has not returned. Although GTD can be serious, most cases are treatable, and many women go on to have healthy pregnancies afterward with appropriate monitoring and care.
As a group, GTD is not rare but some of the subtypes are rare.
Gestational trophoblastic diseases (GTDs), particularly hydatidiform moles and their “malignant” variants (cancerous forms), can present symptoms that closely resemble those of a normal pregnancy, which often delays diagnosis.
A molar pregnancy occurs when an egg with abnormal genetic material is fertilized by a sperm, resulting in a non-viable pregnancy. Despite the absence of a viable fetus, the abnormal tissue implants in the uterus and begins to grow, leading to symptoms commonly associated with early pregnancy. Women may have a positive pregnancy test and experience pregnancy-like sensations, even though a fetus may not be developing properly or at all. A hydatidiform mole looks like a “bunch of grapes”.
In the case of a partial hydatidiform mole, a normal egg is fertilized by two sperm, resulting in a triploid set of chromosomes. This type may include some fetal tissue along with abnormal placental growth. Signs and symptoms may include:
In a complete hydatidiform mole, an empty egg is fertilized, and all the genetic material is from the sperm. No fetus develops but abnormal tissue proliferates. Common symptoms include:
The cancerous forms of GTD such as invasive moles and choriocarcinoma, can arise if the molar tissue begins to grow into surrounding structures or spreads to other organs. These conditions may present with the following signs and symptoms:
If choriocarcinoma has metastasized the signs and symptoms may include:
Rare tumors such as placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT) may also arise, often from cells that normally help anchor the placenta. These can present subtly, but may also cause:
Because many of these symptoms overlap with normal pregnancy experiences, any unusual or severe signs, particularly vaginal bleeding, abnormal ultrasound findings, or lingering pregnancy symptoms after miscarriage, should prompt immediate medical evaluation.
In a healthy pregnancy, the process begins when the female egg and the male sperm, each carrying 23 chromosomes (a haploid genome) fuse together during fertilization. This results in the formation of a zygote, a single cell that now contains 46 chromosomes, 23 from each parent, organized into matching pairs. This zygote holds all the genetic instructions necessary to develop both the fetus and the placenta. Through a series of structured divisions, the zygote multiplies, and its cells begin to specialize. One group of these cells becomes the fetus, while another forms the placenta, the organ that connects the baby to the mother for oxygen and nutrient exchange.
The placenta develops from a type of cell called trophoblasts. These cells embed the embryo into the lining of the uterus and help establish the vital connection between mother and baby. Trophoblasts are formed by cytotrophoblasts which make up the inner layer, and syncytiotrophoblasts which form the outer layer and directly interface with the mother’s tissue and bloodstream. These cells appear around day five after fertilization during a phase called the “blastocyst stage”, a critical milestone in embryo development. At this point, the blastocyst looks like a tiny fluid-filled ball with a cluster of cells inside and the surrounding layer is beginning to form what will become the placenta.
Hydatidiform moles, a type of gestational trophoblastic disease, develop when there is an abnormal fertilization event. Instead of forming a normal zygote with one egg and one sperm contributing equal DNA, something goes wrong, often due to duplication of sperm DNA, or fertilization of an abnormal or “empty” egg. This results in a complete molar pregnancy, where no baby develops, only abnormal tissue that grows like a placenta but without a fetus.
In other cases, a normal egg is fertilized by two sperm instead of one, creating an overload of genetic material. This causes a partial molar pregnancy. While a fetus may begin to form, it carries too many chromosomes and cannot survive. The abnormal tissue still grows, often alongside the nonviable fetus.
These conditions are called hydatidiform moles, a form of gestational trophoblastic disease. They can mimic a normal pregnancy at first and may only be discovered through an ultrasound or after a miscarriage. In rare situations, the disease can even appear after what seemed like a normal pregnancy.
As a group, GTD is not rare. Molar pregnancies or hydatidiform moles occur at different rates around the world. The highest rates are seen in Southeast Asia and Japan, where about 2 in every 1,000 pregnancies are affected. In the United States, they occur in roughly 1 out of every 1,500 pregnancies and 1 out of every 600 therapeutic abortions.
Certain factors increase the risk of a molar pregnancy. These include being younger than 21 or older than 35, with the risk increasing by about 7.5 times for people over 40. A personal history of a molar pregnancy raises the chance of recurrence to around 1% which is 10 to 20 times higher than average. Having two prior molar pregnancies increases the chance to 15%–20%. Dietary factors like low intake of carotene (a form of vitamin A) and animal fats, as well as smoking, are also linked to increased risk. Additionally, a history of miscarriage can double or triple the chances of having a molar pregnancy.
When GTN develops after a molar pregnancy, it typically involves invasive growth of the tissue or, less commonly, a rare cancer called choriocarcinoma. In these cases, about 15% will have local invasion and 5% may experience spread to other parts of the body.
Choriocarcinoma is extremely rare and has different rates worldwide. In the U.S., it appears in about 1 in 20,000 to 40,000 pregnancies with half of those following full-term births, and the rest evenly split between molar pregnancies and other pregnancy-related events. The risk is higher among Asian, Native American and Black women, and is also influenced by factors like having had a complete molar pregnancy, older age, long-term use of birth control pills and having blood type A.
Though very uncommon, choriocarcinoma can also develop in men, usually between ages 20 and 30. In these cases, it affects the testicles. Fewer than 1% of testicular tumors are made up entirely of choriocarcinoma, though it is present in about 15% of mixed germ cell tumors.
Overall, both molar pregnancies and choriocarcinoma have become less frequent globally over the past three decades.
To diagnose and evaluate gestational trophoblastic disease (GTD), doctors use a combination of physical exams, blood tests, imaging tests and sometimes surgical procedures. The goals are to confirm the diagnosis, determine how far the disease has spread and plan the right treatment.
All these tests help determine if the disease is benign, invasive, or malignant, and if it has spread outside the uterus.
Hydatidiform mole
A hydatidiform mole is a type of pregnancy complication that occurs when the tissue that normally forms the placenta grows abnormally. This condition is usually diagnosed in the first three months of pregnancy. One of the most frequent symptoms is heavy vaginal bleeding which may appear dark brown, similar to prune juice. This bleeding happens when the abnormal tissue separates from the lining of the uterus. Some people may pass small sacs of tissue that resemble grape-like clusters.
Other symptoms can include:
Some people may have no symptoms, and the diagnosis is only made during routine pregnancy care. There are two main types of molar pregnancy:
Ultrasound imaging often shows a “snowstorm” or “cluster of grapes” pattern in complete moles. However, because this pattern is not always present, especially in partial moles, the final diagnosis usually depends on microscopic examination of the tissue after it’s removed from the uterus.
After treatment, β-hCG levels are monitored regularly to make sure the abnormal tissue is no longer growing. If levels stay high or begin to rise, this may suggest that the mole has become persistent or cancerous.
Invasive Mole
An invasive mole is a form of molar pregnancy where the abnormal tissue begins to grow deeper into the muscle wall of the uterus. Normally, placental tissue should stay within the inner lining of the uterus. In an invasive mole, the tissue breaks through this lining and invades the muscular layer, which is not normal. This kind of growth can resemble a condition called placenta accreta, where a healthy placenta attaches too deeply into the uterine wall.
Invasive moles are often not diagnosed unless a hysterectomy (surgical removal of the uterus) is performed, because a definitive diagnosis requires seeing under a microscope how the molar tissue has invaded the muscle wall. More often, doctors suspect an invasive mole if β-hCG levels do not return to normal after treatment, or if imaging shows a mass growing inside the uterus.
Choriocarcinoma
Choriocarcinoma is a rare but very aggressive form of cancer that can occur after any pregnancy, including miscarriage, abortion, ectopic pregnancy, or a molar pregnancy. It is made up of rapidly growing cells from the placenta that can spread (metastasize) to other parts of the body.
This cancer is usually diagnosed when β-hCG levels stay high or increase after pregnancy, and imaging studies (such as an ultrasound, CT scan, or MRI) show a suspicious mass. Common symptoms may include:
Because choriocarcinoma tumors have many blood vessels and bleed easily, they are not typically biopsied. Diagnosis relies on imaging and blood tests. Treatment often includes chemotherapy, and follow-up involves β-hCG monitoring for one year to ensure the cancer does not return.
Two other rare types of trophoblastic disease are placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT). These forms grow more slowly than choriocarcinoma and are often diagnosed after surgery or biopsy when a tissue sample is examined under a microscope.
These variants often require surgery, and sometimes additional treatment depending on how far the disease has spread.
To confirm the type of GTD, doctors send tissue samples from surgery to a pathology laboratory. Pathologists use a method called immunohistochemistry, which involves staining the tissue with colored markers to highlight specific proteins. This helps determine the exact type of GTD and guides the treatment plan. For example, strong staining for hCG usually confirms choriocarcinoma, as β-hCG is strongly present in choriocarcinoma. Markers like cytokeratin-18 and HLA-G are often present in molar tissue as they can confirm trophoblastic origin. In addition, the following markers help differentiate the rarer tumor types:
Before treatment begins, doctors also perform routine lab tests to make sure the person is healthy enough for the next steps. These typically include a quantitative hCG test, a complete blood count (CBC) to check for anemia or low platelet counts and clotting studies to assess bleeding risk. Kidney and liver function tests are run to check for any underlying issues. Electrolyte levels are reviewed to detect imbalances. If symptoms suggest overactive thyroid, such as a fast heartbeat or anxiety, thyroid tests may also be done. A urine test is used to look for protein, which can signal a pregnancy-related condition called preeclampsia involving high blood pressure. If the person is experiencing breathing problems, a chest X-ray may be performed to check for fluid in the lungs or other issues.
Lastly, knowing the affected person’s blood type and Rh factor is essential, especially since many people with molar pregnancies experience bleeding. If the person is Rh(D) negative, they will need an injection of Rho(D) immunoglobulin to prevent complications in future pregnancies. Blood types are classified into eight main categories, determined by the presence or absence of A and B antigens on red blood cells, and by the Rh factor, which is a protein on red blood cells. The Rh factor can be either positive (Rh+) or negative (Rh-). The eight main blood types are A+, A-, B+, B-, AB+, AB-, O+, and O-.
Treatment depends on the specific type and stage of the gestational trophoblastic disease (GTD), the person’s overall health and whether she desires future pregnancies.
The three main treatment approaches for GTD are:
Surgical treatment: For people diagnosed with a molar pregnancy (either partial or complete), doctors often recommend a surgical procedure called dilation and curettage, commonly known as D&C or D&E. The cervix is gently opened (dilated) and a vacuum-like device is used to remove abnormal tissue from inside the uterus. Sometimes, doctors use ultrasound guidance during surgery to ensure complete removal, particularly if the uterus is larger than normal. This method is preferred because it is effective and preserves fertility. However, it carries a small risk of uterine scarring.
Hysterectomy: A hysterectomy is a surgery where the uterus is removed completely. Doctors typically suggest this option to women who have completed their families, are older, especially above 40, since this significantly reduces the risk of developing further problems like persistent disease or cancer and who wish to reduce or avoid the need for chemotherapy afterward. Although hysterectomy greatly decreases the risk of persistent disease, it does not eliminate the risk of cancer spreading elsewhere in the body.
Chemotherapy: Chemotherapy involves drugs that stop the growth and spread of abnormal cells. Doctors select chemotherapy based on the type and stage of GTD:
Doctors use a standardized staging system called FIGO-WHO, considering factors like patient age, pregnancy history, size and spread of the tumor, and blood hCG levels. This scoring helps doctors categorize GTD as low-risk or high-risk and decide treatment
For people with low-risk GTD (stages I–III, low-risk score) usually the treatment is done with a single medication. The most common medication is methotrexate, though actinomycin D is also an option.
People with low-risk GTD often respond very well. Even if they initially do not respond, switching medications typically works successfully.
For people classified with high-risk GTD (stage II to IV, high-risk score):
Radiation therapy: Radiation therapy, which uses high-energy X-rays, is less commonly used but can be helpful, especially if GTD has spread or is causing specific symptoms. External radiation, delivered from outside the body, is the usual form used in these cases.
Before surgery, evaluation for complications such as excessive vomiting (causing electrolyte imbalance), anemia, high blood pressure in pregnancy (preeclampsia), or hyperthyroidism (overactive thyroid) is essential. These issues require immediate management before doing surgical evacuation of a molar pregnancy.
Women with Rh-negative blood type receive an injection called anti-Rh immune globulin after surgical procedures to protect future pregnancies.
After initial treatment, regular monitoring of the pregnancy hormone hCG is very important:
Pregnancy should be avoided during monitoring since pregnancy itself raises hCG levels, potentially complicating monitoring.
If hCG levels remain elevated or rise after treatment, the person has persistent GTD requiring additional therapy. Further treatment typically involves chemotherapy and sometimes another surgery.
For certain types of GTD (placental site or epithelioid trophoblastic tumors), surgery is the primary approach, and chemotherapy is usually less effective.
Women wishing to conceive again should discuss plans carefully with their doctors. After successful treatment and normalization of hCG. Future pregnancies require careful monitoring, especially early in pregnancy. An ultrasound early in pregnancy ensures normal development and placement. The placenta should be evaluated after delivery to check for any recurrence of GTD.
In rare but severe situations (such as uncontrolled bleeding, severe anemia, preeclampsia, or thyroid storm), immediate emergency care and hospitalization are required. Stabilization involves medications to control blood pressure, seizures, anemia and thyroid conditions.
Following stabilization, an obstetrics specialist or gynecologic oncologist will help guide the appropriate surgical and medical treatment.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
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Lurain JR. Gestational trophoblastic disease I: Epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole. A J Obstet Gynecol. 2010 Dec; 203(6):531-9.
INTERNET
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