Clinical overview
Gestational trophoblastic disease (GTD) is a spectrum of placental disorders united by abnormal proliferation of trophoblast. It runs from the benign-but-premalignant hydatidiform moles (complete and partial) through to the frankly malignant gestational trophoblastic neoplasias (GTN): invasive mole, choriocarcinoma, placental site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT). The unifying feature is that the tumour arises from the conceptus, not the host, which makes GTD biologically unique — it is effectively an allograft-derived neoplasm, secretes human chorionic gonadotrophin (βhCG) as a near-perfect tumour marker, and is among the most chemosensitive solid tumours known, with cure rates exceeding 90% even in metastatic disease.
For the FCOG(SA) candidate this objective is fundamentally a pathology objective: you must be able to describe the gross, microscopic, immunohistochemical and cytogenetic features that distinguish each entity, because the diagnosis is histological and the management (single-agent versus multi-agent chemotherapy, surveillance intensity) flows directly from correct classification. In the South African context GTD matters disproportionately: incidence of molar pregnancy is higher in many African and Asian populations than in high-income Western settings, presentation is frequently late, and the high background HIV prevalence raises practical questions about immune surveillance and chemotherapy tolerance. Accurate pathology — supported by NHLS histopathology and βhCG monitoring — is the foundation of a curable disease that is otherwise lethal if missed. See GTD diagnosis for the clinical work-up and staging, and Pregnancy and neoplasia for the broader picture of malignancy complicating pregnancy.
Core knowledge
Classification and the trophoblast lineages
Figure D3.1 — The GTN spectrum by trophoblast lineage: invasive mole, choriocarcinoma, PSTT and ETT — villi, β-hCG behaviour, spread and chemosensitivity.
The WHO Classification of Tumours of the Female Genital Tract, 5th edition (2020) frames GTD around the three trophoblast cell types of the normal placenta, because each tumour recapitulates a particular lineage:
- Cytotrophoblast — the proliferative stem cell of the trophoblast.
- Syncytiotrophoblast — the terminally differentiated, multinucleated cell that secretes βhCG; large eosinophilic to amphophilic cytoplasm, no mitoses.
- Intermediate trophoblast — divided into implantation-site intermediate trophoblast (infiltrates the placental bed and remodels spiral arteries; expresses human placental lactogen, hPL) and chorionic-type intermediate trophoblast (of the chorion laeve; the cell of origin of ETT).
Mapping tumour to lineage is the key revision tool: choriocarcinoma recapitulates the villous (cyto- + syncytio-) trophoblast biphasic pattern; PSTT recapitulates implantation-site intermediate trophoblast; ETT recapitulates chorionic-type intermediate trophoblast; the moles are abnormal villous tissue.
Complete hydatidiform mole — gross and cytogenetics
Figure D3.2 — Complete vs partial hydatidiform mole: cytogenetics (46,XX diploid androgenetic vs triploid diandric), villous morphology, p57 immunostaining, and post-molar GTN risk.
A complete mole is classically a bulky mass of grossly swollen "grape-like" or "bunch-of-grapes" vesicles, with no identifiable fetal or embryonic tissue, no amnion and no fetal red cells. The uterus is often large-for-dates.
Cytogenetically the complete mole is diploid and entirely androgenetic — the entire nuclear genome is paternal, while mitochondrial DNA remains maternal. The commonest mechanism (~80%) is monospermic fertilisation of an empty ovum (one lacking maternal chromosomes) by a single sperm that then duplicates its haploid set, giving 46,XX (a 46,YY conceptus is non-viable). A minority (~20%) are dispermic (two sperm fertilising an empty ovum), yielding 46,XX or 46,XY. The absence of any maternal contribution explains the absence of an embryo and the gross hydropic change.
Complete mole — microscopic features
- Diffuse, marked villous hydrops — large, oedematous villi affecting essentially the whole villous population.
- Central cistern formation — acellular fluid-filled cavities within enlarged villi.
- Circumferential ("global") trophoblast hyperplasia surrounding villi (rather than the polar hyperplasia of a partial mole), involving both cytotrophoblast and syncytiotrophoblast with cytological atypia.
- Absent or scanty villous (fetal) capillaries; no nucleated fetal red cells.
- Trophoblastic atypia in the implantation site.
A crucial diagnostic adjunct is p57^KIP2 (CDKN1C) immunohistochemistry: p57 is a paternally-imprinted, maternally-expressed gene, so in the purely androgenetic complete mole villous cytotrophoblast and stromal nuclei are p57-NEGATIVE (with retained internal positive controls in maternal decidua and intervillous trophoblast). This single stain reliably separates complete mole (negative) from partial mole and non-molar hydropic abortus (both positive, because they retain maternal DNA). Ploidy analysis (flow cytometry / FISH) supplements this where morphology is equivocal.