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.
Partial hydatidiform mole — cytogenetics and morphology
A partial mole is triploid (69 chromosomes) with two paternal sets and one maternal set (diandric triploidy), almost always arising from dispermic fertilisation of a normal ovum (69,XXX / 69,XXY / less often 69,XYY). The retention of a maternal set is why fetal tissue and p57 expression are present. (Triploidy with two maternal sets — digynic — produces a non-molar growth-restricted fetus, not a partial mole; the parental origin, not merely the triploidy, defines the mole.)
Gross and microscopic features:
- Two populations of villi — some normal-sized, some hydropic — rather than the uniform swelling of a complete mole.
- Irregular, scalloped villous outlines with trophoblastic pseudo-inclusions (cross-sections of infolded surface trophoblast trapped in stroma).
- Focal, patchy and usually mild trophoblast hyperplasia (often polar, syncytiotrophoblast-predominant), with less atypia than a complete mole.
- Identifiable fetal/embryonic tissue — fetal vessels with nucleated fetal red cells, and sometimes an abnormal triploid fetus.
- p57 IHC POSITIVE (maternal genome retained), helping exclude complete mole.
Comparison table — complete vs partial mole
| Feature | Complete mole | Partial mole |
|---|---|---|
| Karyotype | Diploid, androgenetic (46,XX most; 46,XY) | Triploid, diandric (69,XXX/XXY/XYY) |
| Paternal:maternal sets | 2:0 | 2:1 |
| Fetal/embryonic tissue | Absent | Present |
| Fetal (nucleated) red cells | Absent | Present |
| Villous swelling | Diffuse, all villi | Two populations; focal |
| Cisterns | Prominent, central | Less prominent |
| Trophoblast hyperplasia | Circumferential, marked, atypical | Focal, mild |
| Villous outline | Round | Scalloped, pseudo-inclusions |
| p57^KIP2 IHC | Negative | Positive |
| Risk of post-molar GTN | ~15–20% | ~0.5–5% |
The differing GTN risk is the clinically load-bearing reason to distinguish them precisely.
Invasive mole
An invasive mole is a hydatidiform mole (usually complete) in which molar villi invade the myometrium and/or its vascular spaces, sometimes penetrating to the serosa or embolising to distant sites (lung, vagina). Histologically the defining feature is hydropic villi with trophoblast hyperplasia within the myometrium or vessels — i.e. retained villous architecture is the discriminator from choriocarcinoma, which has no villi. It is the commonest cause of persistent GTN after a complete mole and is usually diagnosed clinically/biochemically (plateauing or rising βhCG) rather than on a hysterectomy specimen, because tissue is rarely obtained.
Choriocarcinoma
Figure D3.3 — Choriocarcinoma histopathology: the biphasic cyto-/syncytiotrophoblast pattern with no chorionic villi, haemorrhage/necrosis, and early haematogenous (lung) spread.
Choriocarcinoma is a frankly malignant epithelial tumour of trophoblast. It can follow any gestational event: roughly 50% follow a complete mole, ~25% a non-molar abortion/miscarriage, ~22% a normal term pregnancy and a few an ectopic.
- Gross: soft, dark-red, haemorrhagic and necrotic mass; the viable tumour forms a rim around central haemorrhage.
- Microscopic: a biphasic, bilaminar admixture of cytotrophoblast and syncytiotrophoblast with NO chorionic villi — the absence of villi is the cardinal diagnostic feature separating it from invasive mole. There is marked cytological atypia, brisk and atypical mitoses, extensive haemorrhage and necrosis, and a striking propensity for vascular invasion (hence early haematogenous spread, classically to lung — and from there CNS, liver, kidney).
- IHC / markers: diffuse βhCG (syncytiotrophoblast), with hPL and HLA-G in intermediate elements; very high serum βhCG is characteristic. Ki-67 proliferation index is high (>90%).
Placental site trophoblastic tumour (PSTT)
PSTT arises from implantation-site intermediate trophoblast and is rare.
- Microscopic: sheets and cords of mononuclear intermediate trophoblast infiltrating between myometrial smooth-muscle fibres in a characteristically dissecting / splitting pattern; the cells replace vessel walls (vascular invasion in a "permeative" not destructive way) and there is fibrinoid deposition. Villi and the biphasic choriocarcinoma pattern are absent.
- IHC: diffuse hPL and CD146 (Mel-CAM), focal/low βhCG (hence comparatively low serum βhCG for tumour bulk — an important clinical trap), positive cytokeratin and inhibin.
- Behaviour: relatively chemoresistant compared with choriocarcinoma; mitotic count and interval from the antecedent pregnancy guide prognosis.
Epithelioid trophoblastic tumour (ETT)
ETT arises from chorionic-type intermediate trophoblast.
- Microscopic: nests and nodules of relatively uniform, epithelioid mononuclear cells with eosinophilic/clear cytoplasm, set in hyaline / eosinophilic matrix and surrounding zones of geographic necrosis, often growing in or near the cervix/lower segment and able to mimic squamous cell carcinoma of the cervix.
- IHC: p63 positive (helpful, mirrors chorionic-type origin), inhibin and cytokeratin positive, only focal βhCG and hPL; Ki-67 typically 10–25%.
- Behaviour: like PSTT, relatively chemoresistant; surgery-led management.
The exaggerated placental site and placental site nodule (non-neoplastic mimics)
Two benign, non-neoplastic trophoblastic lesions must be recognised so they are not over-treated. The exaggerated placental site is a florid but physiological intermediate-trophoblast infiltration of the implantation site (no mass, no destructive growth, low Ki-67) — the benign counterpart of PSTT. The placental site nodule is a well-circumscribed hyalinised nodule of degenerate chorionic-type intermediate trophoblast (low Ki-67, ~<10%) — the benign counterpart of ETT. Misreading either as malignant trophoblast is a classic pitfall.
Assessment
Although this is a pathology objective, the pathology is interpreted within a clinical/biochemical work-up. Molar pregnancy typically presents with first-trimester bleeding, a uterus large-for-dates, hyperemesis, and on ultrasound the "snowstorm" appearance with theca-lutein cysts; markedly elevated βhCG supports the diagnosis but the diagnosis is confirmed histologically on the products of conception. Every uterine evacuation for miscarriage or incomplete abortion should have products sent for histology precisely so that an unsuspected mole is not missed — a key NHLS/laboratory-dependent safeguard in SA practice.
Once a mole is confirmed, serial quantitative serum βhCG is the surveillance backbone. Persistent trophoblastic disease / GTN is defined biochemically (RCOG Green-top Guideline No. 38): a plateau of βhCG across four values over three weeks, a rise of ≥10% across three values over two weeks, persistence of detectable βhCG ≥6 months after evacuation, or a histological diagnosis of choriocarcinoma. For suspected GTN, staging investigations look for metastatic deposits (chest imaging for lung metastases, pelvic imaging, and brain/liver imaging where indicated). Histology of any resected tissue, with the IHC panel above (p57, βhCG, hPL, p63, inhibin, Ki-67), assigns the precise entity. Refer to gtd-diagnosis for the full diagnostic and staging algorithm and to ultrasound-malignancy-signs for imaging features.
Management
Management principles follow directly from the pathology and are detailed under gtd-diagnosis; in summary:
- Hydatidiform mole: suction (vacuum) evacuation of the uterus is the treatment of choice, with products sent for histology and post-evacuation βhCG surveillance to detect malignant transformation. Anti-D is given to Rhesus-negative women for partial moles (fetal tissue present); its role for complete moles is debated because of absent fetal red cells. Effective contraception during follow-up avoids confusing a new pregnancy with relapse.
- GTN risk stratification uses FIGO 2000 anatomical staging (I–IV) combined with the modified WHO prognostic risk score (age, antecedent pregnancy type, interval from index pregnancy, pre-treatment βhCG, largest tumour size, site and number of metastases, and prior failed chemotherapy):
- Low-risk (WHO score ≤6) → single-agent chemotherapy — methotrexate (with folinic acid rescue) or actinomycin-D.
- High-risk (WHO score ≥7) or stage IV → multi-agent chemotherapy, classically the EMA-CO regimen (etoposide, methotrexate, actinomycin-D / cyclophosphamide, vincristine).
- PSTT and ETT are relatively chemoresistant and surgery (hysterectomy) is central, with chemotherapy reserved for metastatic/high-risk disease; because these tumours secrete relatively little βhCG, the marker under-represents tumour bulk.
- Cure rates exceed 90%, including in metastatic disease, reflecting trophoblast chemosensitivity.
In the SA context, GTN is managed in oncology/gynae-oncology units with NHLS βhCG and histology support; the South African EML (Hospital Level, Adults) stocks methotrexate, folinic acid and the EMA-CO component agents. High HIV prevalence warrants attention to immune status, drug interactions and marrow tolerance of multi-agent chemotherapy, with ART (TLD — tenofovir/lamivudine/dolutegravir) continued per the SA HIV Clinicians Society guidance.
Red flags / pitfalls
- Calling choriocarcinoma when villi are present — villi mean invasive mole, not choriocarcinoma. The presence/absence of chorionic villi is the single most important discriminator.
- Missing a complete mole on a "missed/incomplete abortion" specimen — always send products of conception for histology; the p57 stain is the safeguard.
- Over-reading benign mimics — the exaggerated placental site and placental site nodule are non-neoplastic; do not treat them as PSTT/ETT (use low Ki-67 and lack of a destructive mass).
- Trusting a "normal" βhCG in PSTT/ETT — these intermediate-trophoblast tumours secrete little βhCG, so a modest marker level can badly under-stage bulky, chemoresistant disease.
- Forgetting non-molar antecedents of choriocarcinoma — it can follow a normal term delivery, abortion or ectopic, so post-partum or post-abortal persistent bleeding with a positive βhCG and no intrauterine pregnancy must raise it.
- Triploidy ≠ partial mole automatically — only diandric (two paternal sets) triploidy is a partial mole; digynic triploidy gives a non-molar growth-restricted fetus. Parental genomic origin defines the lesion.
- Inadequate surveillance / pregnancy during follow-up — a new pregnancy obscures βhCG trends; contraception and disciplined follow-up are essential.
Evidence anchors
- WHO Classification of Tumours of the Female Genital Tract, 5th edition (2020) — the authoritative histological classification used here: the three trophoblast lineages, complete vs partial mole criteria, invasive mole, choriocarcinoma, PSTT, ETT, and the benign mimics; underpins the immunohistochemical approach (p57, βhCG, hPL, p63, inhibin, Ki-67).
- RCOG Green-top Guideline No. 38 — Gestational Trophoblastic Disease (4th edition, 2020) — central registration/surveillance model, biochemical definitions of post-molar GTN, FIGO 2000 anatomical staging (I–IV) with the modified WHO prognostic score, single-agent (methotrexate ± folinic acid / actinomycin-D) for low-risk (score ≤6) versus multi-agent EMA-CO for high-risk (score ≥7)/stage IV, and the >90% cure rate. Complete = diploid androgenetic (46,XX); partial = triploid.
- FIGO — Diagnosis and management of gestational trophoblastic disease: 2021 update (Ngan HYS et al., Int J Gynecol Obstet 2021;155(Suppl 1):86–93) — current FIGO management reference; retains FIGO 2000 staging + modified WHO score, adds low-dose etoposide–cisplatin induction for ultra-high-risk (≥13) disease and immunotherapy (pembrolizumab) as salvage.
- South African EML — Hospital Level (Adults), current edition — methotrexate, folinic acid and EMA-CO component drug availability in the SA public sector; NHLS for histopathology and serial quantitative βhCG.
- South African National HIV / ART Consolidated Guidelines (2023) — first-line TLD (TDF + 3TC + DTG), continued through GTN chemotherapy in the high-HIV-prevalence SA setting, with attention to interactions and marrow tolerance.