Gestational Trophoblastic Disease: Symptoms, Types, Causes and Treatment

Gestational Trophoblastic Disease (GTD) is a unique and complex set of pregnancy-related disorders characterized by the abnormal growth of trophoblastic tissue, which forms part of the placenta. Though rare, these conditions can range from benign to highly malignant, and their early detection and effective treatment are crucial for excellent outcomes—especially as they mostly affect women of reproductive age. In this article, we provide a comprehensive overview of GTD, delving into its symptoms, types, causes, and treatment options, informed by recent research and clinical guidelines.

Symptoms of Gestational Trophoblastic Disease

GTD is notorious for its variable presentation. While some women may have classic symptoms, others might be entirely asymptomatic thanks to advances in early pregnancy ultrasounds. Recognizing the signs of GTD is essential for timely diagnosis and management.

Symptom	Description	Frequency/Context	Source(s)
Vaginal Bleeding	Unusual or persistent bleeding during pregnancy	Most common presenting symptom	1 2 7
Enlarged Uterus	Uterus larger than expected for gestational age	Less common with early detection	1 3
Hyperemesis Gravidarum	Severe nausea and vomiting	Previously more frequent	1 3
Theca Lutein Cysts	Ovarian cysts due to elevated hCG	Often detected on ultrasound	1 7
Early Preeclampsia	High blood pressure and proteinuria before 20 weeks	Rare, but significant	1
Hyperthyroidism	Symptoms like palpitations, weight loss	Due to hCG cross-reactivity	1
Asymptomatic	No symptoms at time of diagnosis	Increasingly common	1 2

Table 1: Key Symptoms

Classic and Modern Presentations

Historically, GTD was often diagnosed after patients developed pronounced symptoms, such as heavy vaginal bleeding, a uterus that seemed too large for the expected gestational age, or even complications like early-onset preeclampsia and hyperthyroidism. With the widespread use of first-trimester ultrasounds and hCG testing, most cases are now identified before symptoms become severe, and many patients are asymptomatic at diagnosis 1 2 3 7.

Most Common Symptom: Vaginal Bleeding

Today, vaginal bleeding remains the hallmark presenting complaint, occurring in the majority of cases. However, it is important to remember that many other pregnancy complications can also present this way, so additional testing is always required to confirm GTD 1 2.

Other Important Features

• Enlarged uterus: This was once a key diagnostic clue but is now less common due to earlier detection 1 3.
• Severe nausea/vomiting (hyperemesis gravidarum): Sometimes a result of extremely high hCG levels, but less frequently seen now 1 3.
• Theca lutein cysts: These ovarian cysts are found in some patients due to hormonal effects of elevated hCG 1 7.
• Early preeclampsia and hyperthyroidism: Rare, but when present, these are highly suggestive of GTD 1.

Asymptomatic Cases

The shift toward asymptomatic diagnosis underscores the importance of routine prenatal care and early pregnancy ultrasounds. Many women with GTD are now diagnosed before symptoms occur, improving outcomes and minimizing complications 1 2.

Types of Gestational Trophoblastic Disease

GTD is not a single condition, but a spectrum of diseases ranging from benign to highly malignant. Understanding the types is critical for guiding management and predicting prognosis.

Type	Key Features	Malignancy Risk	Source(s)
Complete Mole	No fetal tissue; diffuse trophoblastic proliferation	Premalignant	3 4 7
Partial Mole	Some fetal tissue; focal proliferation	Lower risk	3 4 7
Invasive Mole	Molar tissue invades uterine wall	Malignant (GTN)	3 4 10
Choriocarcinoma	Highly malignant, aggressive tumor	Malignant (GTN)	4 10 12
Placental Site Trophoblastic Tumor	Rare, from implantation site	Malignant (GTN)	4 10 12
Epithelioid Trophoblastic Tumor	Very rare, resembles carcinoma	Malignant (GTN)	4 10 12

Table 2: Main Types of GTD

Hydatidiform Moles

Hydatidiform moles are the most common GTD and are subdivided into:

• Complete mole: No normal fetal tissues are present. The placenta is replaced by a mass of swollen, grape-like villi. These are more likely to progress to malignancy than partial moles 3 4 7.
• Partial mole: Contains some fetal tissue alongside abnormal placental tissue. These have a lower risk of becoming malignant 3 4 7.

Gestational Trophoblastic Neoplasia (GTN)

The malignant forms of GTD are collectively termed gestational trophoblastic neoplasia and include:

• Invasive mole: Occurs when molar tissue invades the muscle wall of the uterus. This can cause local complications and, rarely, spread to other organs 4 10.
• Choriocarcinoma: A highly aggressive cancer that can arise after any type of pregnancy event (mole, miscarriage, or normal pregnancy). It is prone to spread to the lungs, liver, and brain 4 10 12.
• Placental Site Trophoblastic Tumor (PSTT) and Epithelioid Trophoblastic Tumor (ETT): These rare tumors arise from the cells at the site where the placenta attaches to the uterus. They are less sensitive to chemotherapy and require individualized treatment 4 10 12.

Spectrum and Classification

This broad spectrum—from benign partial moles to highly malignant choriocarcinoma—necessitates careful classification and staging for optimal treatment. The distinction between premalignant and malignant forms is crucial, as it guides prognosis, therapy, and follow-up 3 4 10.

Causes of Gestational Trophoblastic Disease

Understanding the origins of GTD provides insights into risk factors and prevention. GTD is rooted in abnormal fertilization and proliferation of trophoblastic cells, but genetics and other influences also play a role.

Cause	Mechanism/Description	Contributing Factors	Source(s)
Abnormal Fertilization	Defective egg or sperm leads to abnormal placenta	Most common cause	9 3
Genetic Predisposition	Mutations or chromosomal errors	Age, ethnicity, prior HM	9 3
Prior Molar Pregnancy	Increases recurrence risk	Strong risk factor	9
Unknown/Idiopathic	Cause not always identifiable	Can occur after normal pregnancy	9 12

Table 3: Key Causes and Risk Factors

Abnormal Fertilization

Most cases of GTD arise due to errors during fertilization:

• Complete moles: Typically result from fertilization of an empty egg (no maternal DNA) by a sperm that duplicates itself or, rarely, by two sperm, leading to a 46,XX or 46,XY karyotype entirely of paternal origin 9 3.
• Partial moles: Usually occur when two sperm fertilize a normal egg, resulting in a triploid conception (69 chromosomes) 9 3.

Genetic and Demographic Factors

Research suggests that certain genetic backgrounds and demographic features influence risk:

• Maternal age: Women under 20 or over 40 have a higher risk 9.
• Ethnicity: Some populations have a higher incidence, suggesting possible genetic susceptibility 9.
• History of hydatidiform mole: Previous GTD significantly increases the risk of recurrence in subsequent pregnancies 9.

Other Contributing Factors

• Prior molar pregnancy: The strongest known risk factor; women with a previous molar pregnancy are at increased risk for another 9.
• Unknown causes: In rare cases, malignant GTD (like choriocarcinoma) can arise even after a completely normal pregnancy or miscarriage, with no clear explanation 9 12.

Mechanisms of Malignant Transformation

While most moles regress after evacuation, a small percentage persist or become malignant, leading to GTN. The mechanisms behind this transformation are still being studied, with research focusing on genetic and molecular changes in trophoblastic cells 9 12.

Treatment of Gestational Trophoblastic Disease

The treatment of GTD is a success story in oncology, with cure rates exceeding 90% even for malignant forms. Management strategies depend on the type and severity of disease and often involve a combination of surgery, chemotherapy, and careful monitoring.

Treatment	Indication/Use	Cure Rate/Outcome	Source(s)
Uterine Evacuation	First-line for hydatidiform moles	High (benign forms)	3 5 7
Chemotherapy	Mainstay for malignant GTN	>90% (low-risk GTN)	4 5 10 11
Multiagent Chemotherapy	High-risk or resistant GTN	80-90% survival	10 11
Surgery	For resistant or localized disease	Adjuvant role	5 10 12
hCG Monitoring	Detects recurrence/persistence	Critical for follow-up	5 13
Radiotherapy	Rare, for brain metastases	Limited use	5 10

Table 4: Main Treatment Modalities

Initial Treatment: Uterine Evacuation

Most hydatidiform moles are managed by gentle suction curettage, which removes the abnormal placental tissue from the uterus. This is usually curative for benign moles, though close follow-up is essential to ensure complete resolution 3 5 7.

Role of Chemotherapy

When GTN develops—or if there is persistent elevation of hCG after a molar pregnancy—chemotherapy becomes the mainstay of treatment. The choice of regimen depends on risk assessment:

• Low-risk GTN: Single-agent chemotherapy (often methotrexate or actinomycin D) is highly effective, with survival rates approaching 100% 10 4 11.
• High-risk GTN: Multiagent chemotherapy (e.g., EMA-CO protocol) is used, and may be combined with surgery or radiotherapy for metastatic or resistant disease. Survival rates remain high (80-90%) but early detection is critical 10 11.

Surgery and Other Interventions

• Surgical options: May be needed for resistant disease or complications (such as heavy bleeding or localized tumor) 5 10 12.
• Hysterectomy: Considered in women who do not desire future fertility or have localized, nonresponsive disease 10 12.
• Radiotherapy: Reserved for rare cases with brain metastases 5 10.

Monitoring and Follow-Up

Close surveillance is vital to detect persistent or recurrent disease. This is done through regular measurement of serum hCG levels, which should decline to normal after successful treatment. The duration of monitoring depends on the type of GTD and its regression rate 5 13.

Supportive Care and Prognosis

• Supportive care: Managing side effects and monitoring for drug toxicity is crucial, especially during chemotherapy 11.
• Fertility preservation: Most women can conceive again after treatment, and the overall prognosis is excellent, particularly when diagnosed and treated early 3 4 13.

International Guidelines and Standardization

Efforts are ongoing to harmonize treatment protocols worldwide, as rare subtypes like PSTT and ETT require specialized management. International networks and clinical guidelines are helping to ensure best practices in diagnosis, treatment, and follow-up 13.

Conclusion

Gestational trophoblastic disease, though rare, is a fascinating and highly treatable set of disorders at the intersection of obstetrics and oncology. Advances in early detection, classification, and therapy have transformed outcomes for affected women. Key takeaways include:

• GTD encompasses a spectrum from benign moles to highly malignant tumors like choriocarcinoma 3 4 7.
• Symptoms have changed over the decades, with vaginal bleeding most common but many cases now asymptomatic due to early detection 1 2 3 7.
• Abnormal fertilization is the main cause, with genetic factors and prior molar pregnancy increasing risk 9 3.
• Treatment is highly effective, relying on uterine evacuation, chemotherapy, and hCG monitoring, with cure rates exceeding 90% for most patients 4 5 10 11.
• Long-term prognosis is excellent with appropriate care, and most women retain their fertility after treatment 3 4 13.

Gestational trophoblastic disease highlights the power of early diagnosis, multidisciplinary care, and international collaboration in improving women's health outcomes.