Gestational Trophoblastic Disease

Gestational trophoblastic disease (GTD) is a spectrum of pregnancy-related disorders arising from abnormal proliferation of placental (trophoblastic) tissue, ranging from the benign hydatidiform mole to frankly malignant choriocarcinoma. It is a NEET PG favourite because it links cytogenetics, characteristic ultrasound signs, a tumour marker (beta-hCG) that is both diagnostic and prognostic, and one of the few solid tumours curable by chemotherapy even when metastatic.

Classification

GTD is broadly split into molar pregnancy (premalignant) and gestational trophoblastic neoplasia / GTN (malignant, persistent disease).

Category	Entity	Nature
Molar (hydatidiform mole)	Complete mole	Premalignant (15–20% → GTN)
	Partial mole	Premalignant (1–5% → GTN)
GTN (malignant)	Invasive mole (chorioadenoma destruens)	Locally invasive
	Choriocarcinoma	Highly malignant, haematogenous spread
	Placental site trophoblastic tumour (PSTT)	Rare, chemoresistant
	Epithelioid trophoblastic tumour (ETT)	Rarest, mimics carcinoma

High-yield: "Molar pregnancy" is premalignant; "GTN" is the malignant umbrella that includes invasive mole, choriocarcinoma, PSTT and ETT. GTN can follow a molar pregnancy, abortion, ectopic or even a normal term delivery (most chorios after term pregnancy).

Hydatidiform mole — complete vs partial

This comparison is the single most tested table in the topic.

Feature	Complete mole	Partial mole
Karyotype	46,XX (90%) or 46,XY — diploid, entirely paternal	Triploid 69,XXY / 69,XXX
Mechanism	Empty ovum fertilised by 1 sperm that duplicates (or 2 sperm)	Normal ovum + 2 sperm (dispermy)
Embryo/fetus	Absent	Present (often anomalous, dies early)
Villous oedema	Diffuse, all villi	Focal
Trophoblast proliferation	Diffuse, circumferential	Focal, mild
Scalloping of villi / stromal inclusions	Absent	Present
Fetal RBCs in villi	Absent	Present (nucleated RBCs)
beta-hCG	Very high (often >100,000)	Mildly raised
Snowstorm on USG	Classic	Less obvious; may show cystic placenta + fetus
Risk of GTN	15–20%	1–5%
p57^KIP2 immunostain	Negative (no maternal DNA)	Positive

High-yield: Complete mole = diploid, all paternal (androgenetic), no fetus, p57 negative, snowstorm appearance. Partial mole = triploid 69,XXY, fetus present, p57 positive.

Mnemonic — Complete mole "C" = Completely paternal, no Child (no fetus), Cancer risk higher.

Etiology & risk factors

• Extremes of maternal age — teenage and especially >40 years (older oocytes prone to abnormal fertilisation).
• Previous molar pregnancy (recurrence risk ~1%, rising to 15–20% after two moles).
• Dietary deficiency of carotene / vitamin A and animal fat.
• Blood group A woman with group O partner (classic association, esp. choriocarcinoma).
• Geographic: higher incidence in South-East Asia than the West.

High-yield: The two clear-cut epidemiological risk factors are extremes of maternal age and a prior molar pregnancy.

Pathophysiology

The molar villi secrete enormous amounts of beta-hCG. Because the alpha subunit of hCG is shared with TSH, LH and FSH, very high hCG causes:

• Theca lutein cysts (bilateral, multi-cystic ovarian enlargement from FSH/LH-like stimulation).
• Hyperemesis gravidarum (hCG stimulates the chemoreceptor trigger zone).
• Early-onset pre-eclampsia (<20 weeks) — pre-eclampsia before 20 weeks is molar pregnancy until proven otherwise.
• Hyperthyroidism / thyroid storm (hCG cross-reacts with the TSH receptor).

Clinical features

Classic complete-mole presentation:

• Vaginal bleeding in the first trimester (commonest symptom) — may pass grape-like vesicles.
• Uterus larger than dates (in ~50%).
• Absent fetal heart sounds, no palpable fetal parts.
• Exaggerated pregnancy symptoms: hyperemesis, early pre-eclampsia, thyrotoxic features.
• Theca lutein cysts palpable as adnexal masses.

Partial moles often masquerade as a missed or incomplete abortion, and the diagnosis is made on histology of the products of conception.

High-yield: Earlier presentation now (routine first-trimester USG) means the "classic" picture (huge uterus, hyperthyroidism) is increasingly uncommon. Bleeding remains the dominant symptom.

Diagnosis & investigation of choice

Diagnostic flow: Suspicious symptoms → quantitative serum beta-hCG (markedly elevated, often >100,000 mIU/mL) → transvaginal ultrasound (investigation of choice) showing the "snowstorm" / "bunch of grapes" appearance with multiple cystic spaces and no fetus → suction evacuation → histopathology + p57 immunostain = definitive diagnosis.

• USG (investigation of choice): classic snowstorm/honeycomb pattern; theca lutein cysts; absent fetus in complete mole.
• Serum beta-hCG: disproportionately high for gestational age; serves as baseline for follow-up.
• Histopathology is the gold standard; p57 distinguishes complete (negative) from partial (positive) moles.
• Chest X-ray — baseline to detect lung metastases (commonest site of GTN spread).

Management of molar pregnancy

Stepwise approach:

1. Stabilise — correct anaemia, treat pre-eclampsia/thyroid storm; group and cross-match.
2. Suction evacuation (D&E) is the treatment of choice irrespective of uterine size; oxytocin started after cervix dilated/uterus begins to empty.
3. Anti-D immunoglobulin to Rh-negative women (partial moles, and all moles by current practice).
4. Hysterectomy is an option in women >40 who have completed childbearing (does not remove the need for hCG follow-up).
5. beta-hCG surveillance (see below).
6. Effective contraception during follow-up — combined oral contraceptive pills are safe and preferred; avoid IUCD (perforation risk while uterus involutes) and avoid pregnancy during monitoring.

High-yield: Suction evacuation is the treatment of choice for molar pregnancy at any uterine size. Theca lutein cysts regress spontaneously after evacuation — do not operate on them.

beta-hCG follow-up protocol

This is a perennial exam question — know the intervals.

Step	Schedule
After evacuation	Serum beta-hCG weekly until 3 consecutive normal (undetectable) values
Then	Monthly for 6 months
Contraception	Throughout follow-up; pregnancy deferred until surveillance complete

High-yield: Weekly hCG until 3 consecutive negatives, then monthly for 6 months. Older texts quoted 1 year of monthly monitoring; current FIGO/RCOG practice has shortened low-risk follow-up to ~6 months after normalisation.

Diagnosis of post-molar GTN (FIGO criteria) — any ONE of:

1. Plateau of hCG (±10%) across 4 values over 3 weeks (days 1, 7, 14, 21).
2. Rise in hCG ≥10% across 3 values over 2 weeks (days 1, 7, 14).
3. Persistence of detectable hCG for ≥6 months after evacuation.
4. Histological diagnosis of choriocarcinoma.

Gestational trophoblastic neoplasia (GTN)

Invasive mole (chorioadenoma destruens)

Molar villi invade the myometrium and may perforate or cause vessel erosion (haemorrhage). Most common form of post-molar GTN; rarely metastasises; responds well to chemotherapy.

Choriocarcinoma

Pure epithelial malignancy of cytotrophoblast and syncytiotrophoblast with no chorionic villi (a key histology point distinguishing it from invasive mole). Early haematogenous spread — lungs are the commonest metastatic site ("cannonball" lesions), then vagina, brain, liver. ~50% follow a molar pregnancy, 25% an abortion, 25% a normal term pregnancy.

High-yield: Choriocarcinoma histology = sheets of trophoblast without villi, with haemorrhage and necrosis; metastasises early to lung. Vaginal metastases are purple, vascular nodules — never biopsy them (torrential bleeding).

PSTT and ETT

Arise from intermediate trophoblast; secrete relatively low hCG but high human placental lactogen (hPL). They are relatively chemoresistant, so hysterectomy is the primary treatment.

FIGO staging & WHO prognostic score

FIGO stage	Extent
I	Confined to uterus
II	Extends to genital structures (adnexa, vagina)
III	Lung metastases
IV	Other distant metastases (brain, liver, GI)

The modified WHO prognostic score (age, antecedent pregnancy type, interval, pretreatment hCG, tumour size, site/number of metastases, prior failed chemotherapy) classifies GTN into:

• Low risk: score ≤6 → single-agent chemotherapy.
• High risk: score ≥7 → multi-agent chemotherapy.

Chemotherapy — drug of choice

Risk group	Regimen	First-line drug
Low-risk GTN (WHO ≤6)	Single agent	Methotrexate (with folinic acid rescue) or Actinomycin-D (dactinomycin)
High-risk GTN (WHO ≥7)	Multi-agent	EMA-CO (Etoposide, Methotrexate, Actinomycin-D, Cyclophosphamide, Vincristine/Oncovin)
PSTT / ETT	Surgery primary	Hysterectomy ± EP-EMA for metastatic

High-yield: Single-agent methotrexate = drug of choice for low-risk GTN. EMA-CO = regimen of choice for high-risk GTN. Chemotherapy is continued until hCG normalises and then for 2–3 consolidation cycles. GTN is one of the most chemosensitive solid tumours — cure rates approach 100% (low-risk) and >80% (high-risk).

Brain metastases may require additional intrathecal methotrexate and/or whole-brain radiotherapy.

Complications

• Haemorrhage (during/after evacuation; uterine perforation by invasive mole).
• Trophoblastic pulmonary embolisation during evacuation of a large mole → acute respiratory distress.
• Thyroid storm during anaesthesia/evacuation (treat with beta-blockers).
• Progression to GTN / choriocarcinoma.
• Metastatic bleeding — intracerebral or intraperitoneal haemorrhage from vascular metastases.
• Chemotherapy-related: myelosuppression, mucositis (methotrexate), secondary malignancy (etoposide → AML, leukaemia).

Key differentials

Condition	Distinguishing point
Threatened/missed abortion	hCG appropriate for dates; USG shows gestational sac/fetus, no snowstorm
Multiple (twin) pregnancy	High hCG + large uterus, but USG shows multiple viable fetuses
Fibroid/ovarian mass with pregnancy	Large uterus but normal hCG trend, fetus present
Hyperemesis from other cause	Normal hCG trend, normal USG
Coexistent twin (normal fetus + complete mole)	Rare; USG shows a normal fetus alongside molar tissue

Recently asked / exam angle

• Chromosomal composition of complete mole (46,XX, all paternal) vs partial mole (triploid 69,XXY) — repeatedly asked.
• p57 immunostain — negative in complete, positive in partial mole (newer molecular-pathology MCQ).
• Snowstorm appearance on USG and absence of fetus → diagnosis.
• beta-hCG follow-up intervals (weekly to 3 negatives, then monthly × 6 months) and FIGO criteria for diagnosing post-molar GTN (plateau/rise definitions).
• Drug of choice: methotrexate for low-risk, EMA-CO for high-risk GTN.
• Commonest site of metastasis = lung; never biopsy vaginal metastasis.
• PSTT secretes hPL, is chemoresistant, treated by hysterectomy.
• Pre-eclampsia before 20 weeks = think molar pregnancy.
• Image-based: gross "bunch of grapes" vesicles; histology of choriocarcinoma (no villi, biphasic trophoblast, haemorrhage).

Rapid revision

1. Complete mole = diploid 46,XX, entirely paternal, no fetus, p57 negative, GTN risk 15–20%.
2. Partial mole = triploid 69,XXY, fetus present, p57 positive, GTN risk 1–5%.
3. Snowstorm/honeycomb USG + markedly raised beta-hCG = molar pregnancy; USG is the investigation of choice.
4. Suction evacuation is the treatment of choice at any uterine size; give anti-D if Rh-negative.
5. Theca lutein cysts regress spontaneously — leave them alone.
6. Follow-up: weekly hCG until 3 negatives, then monthly × 6 months; use COCPs, avoid pregnancy.
7. Pre-eclampsia <20 weeks or hyperthyroidism in pregnancy → suspect a mole.
8. Post-molar GTN diagnosed by hCG plateau (4 values/3 wk), rise (≥10%, 3 values/2 wk), persistence ≥6 months, or choriocarcinoma histology.
9. Choriocarcinoma = no villi, early haematogenous spread; lung is the commonest metastatic site; never biopsy vaginal nodules.
10. Methotrexate (with folinic acid rescue) = drug of choice for low-risk GTN (WHO ≤6); EMA-CO for high-risk (WHO ≥7).
11. PSTT/ETT = intermediate trophoblast, secrete hPL, chemoresistant → hysterectomy.
12. GTN is highly chemosensitive — overall cure rates approach 100% in low-risk disease.