Gestational Trophoblastic Neoplasia

Gestational trophoblastic neoplasia (GTN) is persistent malignant disease arising from abnormal trophoblast after a pregnancy event. It comprises invasive mole, choriocarcinoma, placental site trophoblastic tumour and epithelioid trophoblastic tumour. It follows a complete hydatidiform mole in about 15 to 20% and a partial mole in 1 to 5%, and rarely follows a miscarriage, ectopic pregnancy or term delivery (choriocarcinoma after term birth is about 1 in 160,000 pregnancies).

Incidence of GTN is about 1 in 50,000 pregnancies in Europe and North America, higher in Asia and Africa. Risk factors: maternal age above 40 or below 20, previous mole, and a complete mole with markedly raised hCG.

GTN produces human chorionic gonadotrophin (hCG), a reliable tumour marker, and spreads rapidly by blood (lung 80%, vagina 30%, brain 10%, liver 10%).

Cure rates exceed 95% with chemotherapy, even with metastases.

• Persistent or irregular vaginal bleeding after a molar evacuation, miscarriage or delivery
• Uterine subinvolution, enlarged uterus, theca lutein cysts, persistently raised hCG
• Haemorrhage from uterine or metastatic sites (intraperitoneal, vaginal, cerebral)
• Metastatic symptoms: cough, haemoptysis, dyspnoea (lung); headache, seizures, focal deficits (brain); abdominal pain (liver)
• Hyperthyroidism from hCG cross reactivity at very high levels; pre-eclampsia before 20 weeks in the antecedent mole
• Any woman of reproductive age with unexplained metastatic disease needs a serum hCG

After molar evacuation, GTN is diagnosed on hCG criteria without histology:

• hCG plateau (four values within 10% of each other over 3 weeks: days 1, 7, 14 and 21)
• hCG rise of more than 10% over 2 weeks (three values: days 1, 7 and 14)
• hCG still detectable 6 months after evacuation
• Histological evidence of choriocarcinoma

Workup: pelvic ultrasound with Doppler (vascular myometrial mass), chest radiograph or CT chest, MRI brain and CT or MRI abdomen and pelvis for lung metastases or high risk disease, full blood count, liver and renal function, thyroid function, blood group, baseline hCG, and exclusion of a new pregnancy.

Staging is anatomical: stage I confined to the uterus; stage II extending to adnexa or vagina; stage III lung metastases; stage IV other distant metastases. A prognostic risk score combines age, antecedent pregnancy, interval from the index pregnancy, pretreatment hCG, largest tumour size, site and number of metastases, and prior chemotherapy. A score of 6 or less is low risk; 7 or more is high risk.

• Low risk (score 0 to 6): single agent methotrexate 50 mg IM (or 1 mg/kg) on days 1, 3, 5 and 7 alternating with folinic acid 15 mg orally 24 hours after each methotrexate dose, repeated every 2 weeks; or methotrexate 0.4 mg/kg IV (maximum 25 mg) daily for 5 days every 2 weeks; or actinomycin D 1.25 mg/m2 IV every 2 weeks (preferred if hepatic or renal impairment, or after methotrexate resistance). Give 2 to 3 consolidation courses after hCG normalises. Cure is 98 to 100%
• Methotrexate resistance (hCG plateau or rise): switch to actinomycin D; if still resistant, move to multiagent therapy. Selected localised disease can be treated by hysterectomy once the family is complete
• High risk (score 7 or more): EMA-CO every 2 weeks. Day 1: etoposide 100 mg/m2 IV, actinomycin D 0.5 mg IV bolus, methotrexate 300 mg/m2 IV over 12 hours. Day 2: etoposide 100 mg/m2, actinomycin D 0.5 mg, and folinic acid 15 mg every 12 hours for 4 doses starting 24 hours after methotrexate began. Day 8: cyclophosphamide 600 mg/m2 and vincristine 1 mg/m2. Continue for 2 to 3 courses beyond normal hCG. Cure is 90 to 95%. Resistant disease: etoposide cisplatin alternating with EMA, paclitaxel cisplatin alternating with paclitaxel etoposide, or checkpoint inhibitors (pembrolizumab, avelumab) in refractory disease
• Brain metastases: whole brain radiotherapy 30 Gy, or a higher methotrexate dose (1 g/m2) with intrathecal methotrexate 12.5 mg during EMA-CO; surgery for bleeding
• Haemorrhage: transfusion, embolisation, hysterectomy
• Follow up: weekly hCG until normal for 3 consecutive weeks, then monthly for 12 months (low risk) or 24 months (high risk). Reliable contraception throughout (oral contraceptive pill is acceptable; avoid an IUD until hCG is normal). Later pregnancies are generally safe, with early ultrasound and an hCG 6 weeks after any pregnancy