Clinical overview
Gestational trophoblastic disease (GTD) is a spectrum of abnormal proliferations of placental trophoblast that runs from the benign-but-premalignant hydatidiform mole (complete and partial) through to frankly malignant gestational trophoblastic neoplasia (GTN): invasive mole, choriocarcinoma, placental-site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT). What makes GTD a registrar's recurring clinical problem is that it almost always presents as something far more ordinary — a "miscarriage", a heavier-than-usual early-pregnancy bleed, persistent vomiting, or simply a uterus that feels too big for dates. The unifying diagnostic thread is the syncytiotrophoblast's production of human chorionic gonadotrophin (βhCG): the more abnormal and proliferative the trophoblast, the higher and more abnormal the hormone signal. Diagnosis therefore rests on three pillars — βhCG, pelvic ultrasound, and histopathology of evacuated products — and the diagnosis of the malignant arm (GTN) is, uniquely in oncology, frequently made biochemically and radiologically without a tissue diagnosis at all.
For the South African registrar this is not a rare-disease footnote. GTD is more common in our population than in high-income European settings, often presents late with bulky disease and marked anaemia, and is managed without the luxury of a single national trophoblast registry. The unusual but reassuring counterpoint is that GTN, even in advanced and metastatic forms, is one of the most chemo-curable solid tumours in medicine — cure rates exceed 90% — provided the diagnosis is made, the disease is correctly risk-stratified, and βhCG surveillance is rigorous. Getting the diagnosis right and getting it early is the whole game.
Core knowledge
The spectrum and its cytogenetics
Figure D2.1 — Molar pregnancy: the clinical clues (bleeding, large-for-dates uterus, hyperemesis, very high β-hCG), the ultrasound 'snowstorm', and complete vs partial mole.
The two molar pregnancies are distinguished by their genetics, which in turn predicts their behaviour and is the reason histology and ploidy matter so much.
- Complete hydatidiform mole (CHM) — diploid and entirely androgenetic (all chromosomes paternal). Most commonly an empty ovum is fertilised by a single sperm that duplicates (monospermic, 46,XX); a minority are dispermic (46,XX or 46,XY). There is no fetal tissue. All chorionic villi are abnormal, with diffuse hydropic swelling and circumferential trophoblastic hyperplasia. Risk of progression to GTN is in the order of 15–20%.
- Partial hydatidiform mole (PHM) — triploid, classically 69,XXX or 69,XXY, arising when a normal ovum is fertilised by two sperm (or one diploid sperm). There is a fetus or fetal tissue (usually non-viable, often with triploid stigmata), focal villous hydrops and focal, mild trophoblastic hyperplasia. Risk of progression to GTN is low — roughly 0.5–5%.
GTN itself comprises invasive mole (molar tissue invading myometrium, usually post-CHM), choriocarcinoma (a highly malignant, haemorrhagic, early-haematogenous-spreading tumour of cyto- and syncytiotrophoblast with no villi — can follow any pregnancy event including a normal term birth), and the intermediate-trophoblast tumours PSTT and ETT (rare, slower-growing, comparatively hCG-low for their bulk, and relatively chemoresistant — surgery-dominant). Pathological detail is developed in GTD pathology; this chapter concentrates on how each is recognised and diagnosed.
Why βhCG is the perfect tumour marker
Syncytiotrophoblast secretes hCG in proportion to its mass and proliferation. This gives clinicians a marker that is quantitative, exquisitely sensitive, and present in essentially 100% of disease (with the caveat that PSTT/ETT produce relatively little, and that human placental lactogen (hPL) is a better intermediate-trophoblast marker). A βhCG that fails to fall as expected after evacuation, plateaus, or rises is the single most important alarm in the whole field — it defines GTN. Two laboratory pitfalls must be understood:
- The "hook effect" — at extremely high hormone concentrations (as in a bulky CHM) the immunometric assay is saturated and reports a falsely low result. If clinical and ultrasound features scream mole but the βhCG looks unimpressive, ask the NHLS laboratory to re-run on serial dilutions.
- Phantom hCG / false-positive hCG — heterophile antibodies cross-react in serum assays. The discriminator is that phantom hCG is not detectable in urine (heterophiles are not renally excreted), so a negative urine hCG with a positive serum hCG points to assay interference, not disease — a vital check before committing a woman to chemotherapy.
Assessment
History and presentation
The classic CHM presentation — early-pregnancy bleeding, a uterus large for dates, expulsion of grape-like vesicles, hyperemesis, and early pre-eclampsia (before 20 weeks) — is now seen less often where early ultrasound is routine, because most moles are picked up at the first scan before they become florid. Where access to early scanning is patchy, as it still is in much of the SA public sector, the textbook late presentation remains common: a markedly enlarged uterus, severe anaemia from recurrent bleeds, theca-lutein cysts (from ovarian hyperstimulation by very high hCG), and occasionally hyperthyroidism (the alpha-subunit of hCG weakly cross-stimulates the TSH receptor) or early-onset hypertensive disease. PHM more often masquerades as an incomplete or missed miscarriage and is frequently a histological surprise on evacuated products. Choriocarcinoma can present long after any pregnancy with the consequences of metastasis — haemoptysis or a chest lesion, neurological signs from cerebral deposits, or abnormal bleeding — and must be on the differential for any reproductive-age woman with metastatic disease of unknown primary and a positive βhCG.