# Gestational Trophoblastic Disease

## Overview and Classification

### Spectrum of Disease

Gestational trophoblastic disease encompasses benign and malignant conditions arising from placental trophoblastic tissue. The benign forms are the hydatidiform moles, which include the complete hydatidiform mole and the partial hydatidiform mole. The malignant forms, collectively termed gestational trophoblastic neoplasia, include invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor.

## Complete Hydatidiform Mole

### Genetics

The complete mole is diploid and entirely paternal in origin (androgenetic). Most commonly, it results from duplication of a single sperm, producing a homozygous 46,XX karyotype. Less commonly, it arises from dispermy, producing a heterozygous 46,XY or 46,XX complement. No fetal tissue is present, and all chorionic villi show hydropic change.

### Clinical Features

The most common presentation is vaginal bleeding in the first trimester. The uterus is large for dates in approximately 50% of cases. Beta-hCG is markedly elevated, often exceeding 100,000 mIU/mL. Theca lutein cysts occur bilaterally in 15 to 25% of patients from hCG stimulation of the ovaries. Other features include hyperemesis gravidarum from high hCG, preeclampsia before 20 weeks (a rare but classic finding), and hyperthyroidism from hCG cross-reacting with the TSH receptor. Passage of grape-like vesicles per vagina is the classic but now uncommon presentation given early ultrasound diagnosis.

### Ultrasound Findings

The characteristic appearance is a "snowstorm" or "cluster of grapes" pattern, with an echogenic intrauterine mass containing multiple small cystic spaces representing hydropic villi. No fetal parts or amniotic fluid are present. Bilateral enlarged ovaries with theca lutein cysts may be visible.

### Risk of GTN

Approximately 15 to 20% of complete moles progress to gestational trophoblastic neoplasia, either invasive mole or choriocarcinoma.

## Partial Hydatidiform Mole

### Genetics

The partial mole is triploid, with two paternal and one maternal haploid set (69,XXX or 69,XXY). It results from dispermy, the fertilization of one egg by two sperm. Fetal tissue may be present but is abnormal and nonviable.

### Clinical Features

A partial mole often presents as a missed or incomplete abortion. Beta-hCG elevation is moderate, rarely exceeding 100,000 mIU/mL. The uterus may be small for dates. Theca lutein cysts and medical complications such as preeclampsia and hyperthyroidism are rare.

### Ultrasound Findings

The placenta is enlarged with cystic spaces in a "Swiss cheese" pattern. Fetal parts may be identified, often with anomalies. The ratio of cystic to normal villi varies.

### Risk of GTN

Only 1 to 5% of partial moles progress to GTN, much lower than the rate for complete moles.

| Feature | Complete Mole | Partial Mole |
|---|---|---|
| Genetics | Diploid (46,XX or 46,XY); entirely paternal | Triploid (69,XXX or 69,XXY); 2 paternal + 1 maternal |
| Fetal tissue | Absent | Present (abnormal, nonviable) |
| hCG level | Markedly elevated (often >100,000) | Moderate elevation |
| Uterus size | Large for dates (~50%) | Small or normal for dates |
| Theca lutein cysts | 15-25% | Rare |
| Ultrasound appearance | "Snowstorm" / cluster of grapes | "Swiss cheese" placenta with fetal parts |
| GTN progression risk | 15-20% | 1-5% |
| p57 immunostaining | Negative | Positive |

<image>Side-by-side comparison of complete versus partial hydatidiform mole showing genetics (diploid androgenetic vs. triploid), ultrasound appearance (snowstorm with no fetus vs. Swiss cheese placenta with fetal parts), hCG levels, uterus size, and risk of progression to GTN</image>

## Management of Hydatidiform Mole

### Suction Curettage (Uterine Evacuation)

Suction curettage is the treatment of choice for both complete and partial moles. It is preferred over medical evacuation because of the risk of incomplete evacuation and embolization with medical management. A large-bore suction cannula is used, followed by gentle sharp curettage. An oxytocin infusion is started after the cervix is dilated to promote uterine contraction and reduce bleeding. Rh immunoglobulin is administered to Rh-negative patients. Pathologic analysis confirms molar tissue, and p57 immunostaining (positive in partial moles, negative in complete moles) along with genotyping may help distinguish between the two types when histology is ambiguous.

### Hysterectomy

Hysterectomy is an alternative for patients who have completed childbearing. It eliminates the risk of invasive mole (local invasion) but does not eliminate the risk of metastatic GTN, so hCG surveillance is still required after hysterectomy.

### Medical Complications at Presentation

Preeclampsia, thyroid storm, anemia, and respiratory distress should be treated before or during evacuation. Blood products must be available for potential hemorrhage.

## hCG Surveillance After Molar Evacuation

### Protocol

Serial quantitative beta-hCG levels are measured weekly until undetectable (below 5 mIU/mL) for 3 consecutive weeks. After normalization, monthly hCG is measured for 6 months after the first normal value for both complete and partial moles (some guidelines recommend 12 months for complete moles). Reliable contraception is mandatory during surveillance because pregnancy would confound hCG monitoring. Oral contraceptive pills or barrier methods are acceptable. An IUD can be placed after hCG normalizes. Pregnancy should be avoided until surveillance is complete.

### Criteria for Diagnosing GTN (Post-Molar)

GTN is diagnosed when there is an hCG plateau with less than 10% decline over 4 consecutive weekly values, an hCG rise of 10% or more over 3 consecutive weekly values, hCG remaining elevated at 6 months after evacuation, histologic diagnosis of choriocarcinoma, or identification of metastatic disease.

<image>Graph showing expected hCG regression curve after molar evacuation with weekly measurements, alongside abnormal patterns indicating GTN: a plateau pattern where hCG levels off over 3-4 weeks, and a rising pattern where hCG increases over 2-3 consecutive measurements, with threshold lines and decision points marked</image>

## Gestational Trophoblastic Neoplasia (GTN)

### Invasive Mole

Invasive mole is a hydatidiform mole that invades the myometrium or metastasizes. It is the most common form of GTN. Diagnosis is based on rising or plateauing hCG after molar evacuation, and tissue diagnosis is rarely needed. It is highly responsive to chemotherapy.

### Choriocarcinoma

Choriocarcinoma is a highly malignant, rapidly growing tumor that can follow any gestational event: molar pregnancy (50%), term pregnancy (25%), or miscarriage and ectopic pregnancy (25%). It spreads hematogenously, with the lungs being the most common metastatic site, followed by the vagina, brain, and liver. Beta-hCG is markedly elevated. Despite its aggressiveness, it is very sensitive to chemotherapy, with cure rates exceeding 90%.

### Placental Site Trophoblastic Tumor (PSTT)

PSTT is a rare tumor arising from intermediate trophoblast. It is slow-growing and relatively chemoresistant. hCG levels are relatively low for the tumor volume. Hysterectomy is the primary treatment, with chemotherapy reserved for metastatic disease. Human placental lactogen may be elevated.

### Epithelioid Trophoblastic Tumor (ETT)

ETT is extremely rare and behaves similarly to PSTT. Treatment is hysterectomy, with chemotherapy for advanced disease.

## FIGO Staging and WHO Scoring

### FIGO Staging

Stage I disease is confined to the uterus. Stage II extends beyond the uterus but is limited to genital structures. Stage III extends to the lungs with or without genital tract involvement. Stage IV involves all other metastatic sites including brain, liver, kidney, and gastrointestinal tract.

| FIGO Stage | Extent of Disease | Treatment |
|---|---|---|
| I | Confined to uterus | Low-risk: single-agent chemo; High-risk: multi-agent |
| II | Extends to genital structures | Based on WHO score |
| III | Lung metastases ± genital tract | Based on WHO score |
| IV | Brain, liver, kidney, GI metastases | Multi-agent (EMA-CO); CNS: intrathecal MTX ± WBRT |

### WHO Prognostic Scoring System

Risk factors including age, antecedent pregnancy, interval from antecedent pregnancy, pretreatment hCG level, largest tumor size, site of metastases, number of metastases, and prior failed chemotherapy are each scored 0, 1, 2, or 4. A total score below 7 indicates low risk, while a score of 7 or greater indicates high risk. The score determines the treatment regimen.

### Metastatic Workup

The workup includes chest X-ray or CT chest for lung metastases, CT abdomen and pelvis, MRI brain if lung metastases are present or the WHO score is high risk, hCG level, and CBC, metabolic panel, liver function tests, and thyroid function tests.

## Treatment of GTN

### Low-Risk GTN (FIGO Stage I-III, WHO Score < 7)

Single-agent chemotherapy is the standard treatment. Methotrexate is the most common first-line agent, administered either as an 8-day regimen (1 mg/kg IM on days 1, 3, 5, and 7 with folinic acid rescue on alternating days) or as a weekly IM regimen of 30 to 50 mg/m2. Actinomycin D is an alternative first-line option and may be preferred when hepatic or renal dysfunction is present. Chemotherapy continues until hCG normalizes, followed by 2 to 3 consolidation cycles. The cure rate exceeds 95 to 100%. If resistance to the first-line agent develops, the alternative single agent is used, with multi-agent regimens for second-line failures.

### High-Risk GTN (FIGO Stage I-III with WHO Score >= 7, or Stage IV)

Multi-agent chemotherapy is required. EMA-CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) is the most widely used regimen, with a cure rate of 80 to 90%. EMA-EP (substituting cisplatin and etoposide) is used for EMA-CO resistant disease. Brain metastases are treated with intrathecal methotrexate and/or whole-brain radiation in addition to systemic chemotherapy. Liver metastases may benefit from hepatic artery embolization.

### PSTT and ETT

Hysterectomy is the primary treatment. Multi-agent chemotherapy with EMA-CO or EP/EMA is used for metastatic disease. These tumors are less chemosensitive than choriocarcinoma.

## Follow-Up After GTN Treatment

Monthly hCG levels are monitored for 12 months after normalization for low-risk disease and 24 months for high-risk disease. Reliable contraception is maintained during surveillance. The prognosis for future pregnancies is excellent after completing surveillance. The risk of a repeat molar pregnancy is 1 to 2%. An early ultrasound should be obtained in subsequent pregnancies to confirm normal gestation, and hCG at 6 weeks postpartum after any future pregnancy is recommended to rule out recurrence.

<image>Treatment algorithm for gestational trophoblastic neoplasia: post-molar GTN diagnosed by abnormal hCG surveillance, staged with FIGO system and scored with WHO prognostic scoring, then treated with single-agent methotrexate for low-risk (score less than 7) or multi-agent EMA-CO for high-risk (score 7 or greater), with salvage regimens for resistant disease</image>

## Clinical Pearls

Any time hCG is followed after a molar evacuation and does not decline as expected, GTN must be considered. Plateauing hCG should not be attributed to retained products without considering malignant transformation.

Complete moles are diploid and entirely paternal in origin; partial moles are triploid with fetal tissue present.

Reliable contraception is mandatory during hCG surveillance because pregnancy prevents accurate monitoring.

GTN is one of the most curable malignancies in all of oncology. Even metastatic choriocarcinoma has cure rates exceeding 90% with chemotherapy.

Preeclampsia before 20 weeks of gestation should raise suspicion for a complete molar pregnancy.

p57 immunostaining distinguishes complete moles (negative) from partial moles (positive) when histology is ambiguous.

PSTT is the exception to the rule: it is relatively chemoresistant and requires hysterectomy as the primary treatment.

After treatment of GTN, patients can have normal future pregnancies. Early ultrasound and postpartum hCG are recommended.

## References

- ACOG Practice Bulletin No. 53: Diagnosis and Treatment of Gestational Trophoblastic Disease (2004, reaffirmed 2022)
- FIGO Oncology Committee. FIGO staging for gestational trophoblastic neoplasia 2000. Int J Gynaecol Obstet. 2002;77:285-287
- Seckl MJ et al. Gestational trophoblastic disease. Lancet. 2010;376:717-729
- Berkowitz RS, Goldstein DP. Clinical practice: molar pregnancy. N Engl J Med. 2009;360:1639-1645
- Lurain JR. Gestational trophoblastic disease II: classification and management of gestational trophoblastic neoplasia. Am J Obstet Gynecol. 2011;204:11-18
- NCCN Clinical Practice Guidelines: Gestational Trophoblastic Neoplasia (Version 1.2024)