In one line
Gestational trophoblastic disease is a spectrum of pregnancy-derived trophoblast disorders — from the premalignant complete and partial moles to the malignant gestational trophoblastic neoplasia, GTN (invasive mole, choriocarcinoma, placental-site and epithelioid trophoblastic tumour) — and that malignant arm is the rare cancer you are expected to cure: get the mole evacuated by suction (the mole itself is a histological diagnosis), register the patient for hCG surveillance, and a plateauing or rising β-hCG itself diagnoses post-molar GTN — by the FIGO criteria, without a biopsy — early enough that single- or multi-agent chemotherapy delivers survival approaching 100% for low-risk and ~90% for high-risk disease.
This chapter assumes the Intermediate groundwork on how a mole presents and is recognised — revise molar pathology and the diagnosis of GTD if those are not solid. The consultant-level material is reading the genetics, building the surveillance plan, scoring the neoplasia, and defending the chemotherapy choice from the evidence.
Epidemiology & who is at risk
Hydatidiform mole complicates roughly 1 in 1,000 pregnancies in most of the world; in high-income settings the complete mole runs at about 1–3 per 1,000 and the partial mole around 3 per 1,000. The disease is bimodal in age — risk rises at both extremes of reproductive life, with a roughly two-fold increase in teenagers and a 5–10-fold increase over the age of 45, because an empty or abnormally fertilised ovum is the substrate and gametogenesis at the edges of fertility is the driver. A previous molar pregnancy raises the risk about ten-fold, climbing further after two. Choriocarcinoma is far rarer and geographically skewed — on the order of 1 in 40,000 pregnancies in North America and Europe but several times higher in parts of South-East Asia and Japan. Dietary β-carotene and animal-fat deficiency are weak aetiological signals for the complete mole only. These numbers matter in South Africa, where a young, high-parity population spanning the reproductive extremes generates real case numbers, and where a woman with one mole must be counselled that her future-pregnancy risk is low but not zero.
Mechanism & pathophysiology
The trophoblast is the only human tissue that is genuinely foreign to the woman carrying it, and when its growth uncouples from a viable fetus the genetics define exactly what you are dealing with. The imaging, the hCG behaviour and the malignant potential all follow from that genetic origin.
The complete mole is paternal-genome-only — androgenetic diploidy. A complete hydatidiform mole (CHM) has a normal diploid chromosome count (46 chromosomes) but every chromosome is paternal in origin. The usual route is an "empty" ovum (no functional maternal nucleus) fertilised by a single sperm whose haploid set then duplicates, giving 46,XX — homozygous and entirely paternal. Less commonly two sperm fertilise the empty ovum (dispermy), giving 46,XX or 46,XY. A 46,YY conceptus is non-viable, so you do not see it. Because there is no maternal contribution and no embryo, there are no fetal parts, the villi are diffusely hydropic, and trophoblast proliferation is florid and circumferential — which is why the classic mole oversecretes hCG and why it carries the highest malignant potential of the molar pair (progression to neoplasia in roughly 15–20%).
The partial mole is triploid — two paternal sets and one maternal. A partial hydatidiform mole (PHM) has 69 chromosomes (triploid), the extra set being paternal: a normal ovum fertilised by two sperm, or by one sperm that duplicates. Because a maternal genome is present, a PHM can contain identifiable fetal or embryonic tissue (often with the stigmata of triploidy — growth restriction, syndactyly), the villous hydrops is focal rather than diffuse, and the trophoblast proliferation is more modest. Its malignant potential is correspondingly low (progression around 0.5–5%). The distinction is not academic: it changes the counselling, the anti-D decision, and the intensity of surveillance.
p57 is the immunostain that makes the genetics visible — and you must know which way it runs. p57^KIP2^ is a cyclin-dependent kinase inhibitor encoded by a gene that is paternally imprinted and maternally expressed — that is, the protein is produced only from the maternal allele. Apply that rule to the genetics above and the result is mechanical:
- Complete mole has no maternal genome, so there is nothing to express p57 → villous cytotrophoblast and stromal nuclei stain NEGATIVE.
- Partial mole has a maternal genome, so p57 is expressed → POSITIVE staining.
A negative p57 confirms a complete mole and excludes a partial mole or a hydropic non-molar abortion; a positive p57 tells you it is not a complete mole but cannot by itself separate a partial mole from a non-molar hydropic gestation (both have a maternal genome). When p57 leaves the question open, microsatellite (short tandem repeat) genotyping resolves it by quantifying the parental genetic contributions — absence of any maternal contribution = complete mole; diandric (two-paternal) triploidy = partial mole. This molecular pathway, not villous morphology alone, is the modern diagnostic standard, because early first-trimester moles increasingly lack the textbook gross appearance.
From mole to neoplasia — the malignant members of the spectrum. When trophoblast acquires invasive or metastatic behaviour, the disease is collectively gestational trophoblastic neoplasia (GTN):
- Invasive mole — molar villi that burrow into the myometrium (and occasionally embolise to lung or vagina). It is the commonest cause of persistently raised hCG after evacuation and usually needs no separate tissue diagnosis; the rising hCG is the diagnosis.
- Choriocarcinoma — a frankly malignant tumour of abnormal trophoblast with no chorionic villi, bulky, haemorrhagic and necrotic, with early haematogenous spread to lung, brain, liver, kidney and bowel. Crucially, choriocarcinoma can follow any pregnancy — a term delivery, a miscarriage or an ectopic, not just a mole — which is why an undelivered or postnatal woman with unexplained metastatic disease and a high hCG has choriocarcinoma until proven otherwise. Approximately 75% of GTN follows a molar pregnancy (FIGO 2025); the rest arises after a miscarriage, an ectopic or a term delivery, so beyond abnormal bleeding the first sign can be haemorrhage from a metastasis (liver, spleen, bowel), pulmonary symptoms, or neurological signs from a brain or spinal deposit — a serum hCG belongs in the work-up of any such unexplained presentation in a woman of reproductive age.
- Placental-site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT) — the dangerous outliers. Both arise from intermediate trophoblast (PSTT from implantation-site intermediate trophoblast, ETT from chorionic-type), grow as nodular masses in the myometrium or lower segment/cervix, and have two properties that overturn the usual rules: they secrete relatively little hCG for their bulk (so hCG is a poor monitor), and they are relatively chemoresistant. That combination makes surgery (hysterectomy) the primary treatment for PSTT/ETT, the opposite of the chemo-first logic that governs the rest of GTN. On immunohistochemistry they express hPL, MUC-4, HSD3B1, HLA-G and Mel-CAM (CD146), with only focal hCG and inhibin and a Ki-67 of about 10–30% (higher than the benign exaggerated placental-site reaction) — useful when the morphology is ambiguous. A related lesion, the atypical placental site nodule (APSN), sits between benign and malignant and coexists with, or progresses to, PSTT/ETT in about 10–15% of cases, so it earns the same wariness rather than reassurance.
Across the spectrum — paternal-only diploid CHM, diandric triploid PHM, villous-free choriocarcinoma, low-hCG chemoresistant intermediate-trophoblast tumours — the diagnosis predicts the behaviour, so management need not wait for the disease to declare itself.
Assessment
The modern presentation is sonographic, not clinical. Earlier ultrasound diagnosis has largely replaced the textbook second-trimester picture, so a consultant should expect the diagnosis to arrive before the classic syndrome:
- The hCG itself. A markedly raised β-hCG, often disproportionate to gestation, is the signature; very high levels drive the associated syndromes below. Always use an assay that detects all hCG isoforms (intact, free β, core, C-terminal, nicked and hyperglycosylated forms), because a tumour producing predominantly one variant can read falsely low or falsely negative on a narrow assay. The mirror-image trap is a false-positive ("phantom") hCG from heterophile antibodies — suspect it when a low-level hCG will not move and imaging is blank, and confirm by repeating on a different assay platform or by testing urine hCG (heterophile antibodies are not excreted) before ever treating a number you cannot corroborate. A persistently low but genuine hCG still warrants continued monitoring, because a proportion later climb into frank GTN.
- Ultrasound. The complete mole gives the "snowstorm" or vesicular/"bunch-of-grapes" appearance with no fetus and often bilateral theca-lutein cysts (ovarian cysts driven by hCG stimulation). The honest caveat is that the classic honeycomb pattern is frequently absent in the first trimester — many moles are diagnosed only on histology of products evacuated for an apparent miscarriage, which is exactly why all products of conception from a non-viable pregnancy should go for histology.
- The hCG-mediated syndromes. When hCG is very high you may see hyperemesis gravidarum, early (pre-20-week) pre-eclampsia — itself almost pathognomonic of a mole, since pre-eclampsia essentially never appears that early in a normal singleton — and hCG-mediated hyperthyroidism. The thyroid effect is worth understanding mechanistically: hCG and TSH share a common α-subunit and have structurally similar β-subunits, so at extreme concentrations hCG cross-reacts at the TSH receptor, producing a biochemical (and occasionally clinical) thyrotoxicosis that resolves once the mole is evacuated and hCG falls.
- Bleeding and vesicle passage. Irregular first- or second-trimester bleeding is the commonest symptom; passage of grape-like vesicles is now uncommon.