Gestational trophoblastic disease is a spectrum of proliferative disorders arising from placental trophoblastic tissue, ranging from benign hydatidiform moles to malignant conditions such as choriocarcinoma.

Gestational Trophoblastic Disease (GTD)

Epidemiology

Risk Factor	Mechanism / Explanation
Extremes of maternal age (< 20, > 35–40 years)	Defective oocytes → abnormal fertilisation → molar pregnancy ^[1]^[2]
Previous molar pregnancy	Risk of recurrence ~1–2% after one mole; ~15–20% after two moles ^[1]^[2]
Previous history of miscarriage	Suggests underlying oocyte or fertilisation defects
Ethnicity (Asian)	Higher incidence in Hong Kong, Southeast Asia, Japan ^[1]^[2]
Dietary factors	Low intake of carotene (vitamin A precursor) and animal fats; folate deficiency
Blood group	Some evidence of A × O pairing conferring higher risk of choriocarcinoma
Oral contraceptive use (prolonged)	Weak association, debated
ABO blood group discordance	Associated with choriocarcinoma risk post-mole ^[1]

Exam High Yield

When asked about risk factors for GTD, always mention: (1) extremes of reproductive age, (2) previous molar pregnancy, (3) Asian ethnicity. These three are the most consistently tested.

Anatomy and Function: The Trophoblast

To understand GTD, you must understand the trophoblast — the cell lineage from which these tumours arise.

After fertilisation, the zygote develops into a blastocyst by day 5–6. The blastocyst has two cell populations:

Inner cell mass (embryoblast) → becomes the embryo/fetus
Outer cell layer (trophoblast) → becomes the placenta

The trophoblast differentiates into three main subtypes:

Trophoblast Subtype	Location & Function	GTN Counterpart
Cytotrophoblast	Stem cells of the trophoblast; mononuclear; proliferative layer sitting on basement membrane	Hydatidiform mole, invasive mole
Syncytiotrophoblast	Multinucleated outer layer formed by fusion of cytotrophoblasts; in direct contact with maternal blood; produces hCG; mediates nutrient/gas exchange	Choriocarcinoma
Intermediate (extravillous) trophoblast	Invades the uterine wall and remodels spiral arteries to establish uteroplacental circulation	PSTT, ETT

Aetiology and Pathophysiology

A. Hydatidiform Mole — The Premalignant Lesion

A hydatidiform mole results from abnormal fertilisation leading to excessive trophoblastic proliferation with hydropic degeneration of chorionic villi. There are two distinct entities:

Feature	Complete Mole	Partial Mole
Karyotype	46,XX (or 46,XY) — diploid, all paternal	69,XXX/XXY/XYY — triploid
Fertilisation	Empty ovum + 1 sperm (duplicates) or 2 sperm	Normal ovum + 2 sperm
Fetal tissue	Absent	Present (usually abnormal, non-viable)
Villous oedema	Diffuse — all villi hydropic	Focal — mixed normal and hydropic villi
Trophoblastic hyperplasia	Diffuse, circumferential	Focal, mild
hCG level	Very high (often > 100,000 mIU/mL)	Less elevated
Uterine size	Large for dates (50%)	Small or normal for dates
Theca lutein cysts	Common (due to very high hCG stimulating ovaries)	Rare
Risk of GTN	15–20%	< 5%
p57KIP2	Negative	Positive
"Snowstorm" on USS	Classic	Less dramatic, may mimic incomplete miscarriage

Common Exam Mistake

Students frequently confuse the genetics. Remember: Complete mole = completely paternal (no maternal DNA). Partial mole = part maternal, part paternal (triploid). The word "partial" refers to the partial presence of embryonic tissue AND the partial nature of the hydropic change.

B. Gestational Trophoblastic Neoplasia (GTN) — The Malignant Spectrum

GTN refers to the malignant conditions that can arise from trophoblastic tissue. They can follow:

Hydatidiform mole (most common antecedent — ~50% of GTN follows a molar pregnancy) ^[1]^[2]
Miscarriage or ectopic pregnancy (~25%)
Normal term pregnancy (~25%) — particularly for choriocarcinoma and PSTT ^[1]

Classification

Stage	Description
I	Disease confined to the uterus
II	GTN extends outside uterus but limited to genital structures (vagina, adnexa, broad ligament)
III	GTN extends to lungs ± genital tract involvement
IV	All other metastatic sites (brain, liver, kidney, GI tract)

Used to classify GTN as low-risk vs high-risk to guide chemotherapy regimen:

Prognostic Factor	Score 0	Score 1	Score 2	Score 4
Age (years)	< 40	≥ 40	—	—
Antecedent pregnancy	Mole	Abortion	Term	—
Interval from index pregnancy (months)	< 4	4–6	7–12	> 12
Pretreatment hCG (IU/L)	< 10³	10³–10⁴	10⁴–10⁵	> 10⁵
Largest tumour size (cm, incl. uterus)	< 3	3–4	≥ 5	—
Site of metastases	Lung	Spleen, kidney	GI tract	Brain, liver
Number of metastases	0	1–4	5–8	> 8
Previous failed chemotherapy	—	—	Single drug	≥ 2 drugs

Total score ≤ 6 = Low risk → single-agent chemotherapy (methotrexate or actinomycin D)
Total score ≥ 7 = High risk → multi-agent chemotherapy (EMA-CO regimen)

Exam High Yield

The FIGO staging is anatomical (where the disease is). The WHO scoring system is prognostic (how aggressive the disease is). Both are used together: e.g., "Stage III, score 5 = Stage III low-risk GTN." Know that score ≤ 6 = low risk (single agent) and score ≥ 7 = high risk (combination EMA-CO).

Clinical Features

A. Symptoms (with pathophysiological basis)

Symptom	Pathophysiological Basis
Vaginal bleeding (most common presenting symptom, ~80–90%)	Separation of hydropic villi from decidua → disruption of maternal blood vessels → bleeding into uterine cavity. The "prune juice" or dark brown colour is due to retained blood undergoing oxidation ^[1]^[2]
Passage of grape-like vesicles per vagina (pathognomonic but uncommon now due to early USS diagnosis)	Hydropic villi detach and are expelled through the cervix — the classic "grape-like" or "snowstorm" material ^[1]
Hyperemesis gravidarum (excessive nausea/vomiting)	Markedly elevated hCG stimulates the vomiting centre (via serotonin and possibly direct chemoreceptor trigger zone stimulation). hCG is much higher in complete moles → hyperemesis more common ^[1]^[2]
Uterus larger than expected for gestational age (in ~50% of complete moles)	Excessive trophoblastic proliferation + accumulated blood and hydropic villi within the uterine cavity ^[1]
Symptoms of thyrotoxicosis: tremor, tachycardia, heat intolerance, anxiety, weight loss	Very high hCG cross-reacts with TSH receptor (structural homology of β-subunits) → stimulates thyroid hormone production → clinical thyrotoxicosis. Occurs in ~5–10% of complete moles ^[1]^[3]
Symptoms of pre-eclampsia before 20 weeks	Pre-eclampsia classically occurs after 20 weeks in normal pregnancy. Pre-eclampsia in the first trimester/early second trimester is highly suspicious for molar pregnancy because the exuberant abnormal trophoblast releases excessive anti-angiogenic factors (sFlt-1) and other vasoactive substances → endothelial dysfunction → hypertension + proteinuria ^[1]^[4]
Respiratory distress (rare but life-threatening)	(1) Trophoblastic embolisation to pulmonary vasculature during or after molar evacuation; (2) Fluid overload from aggressive IV hydration; (3) Thyroid storm causing high-output cardiac failure; (4) Pre-eclampsia with pulmonary oedema ^[1]
Pelvic pressure or pain	Rapid uterine enlargement stretching the uterine wall and peritoneum
Absent fetal movements / no fetal heart activity (in complete mole)	No fetus in complete mole; in partial mole, the fetus is usually non-viable

Important Clinical Pearl

The classic "textbook" presentation of complete molar pregnancy (markedly elevated hCG, uterus large for dates, theca lutein cysts, hyperemesis, pre-eclampsia before 20 weeks, thyrotoxicosis) is now UNCOMMON in developed settings like Hong Kong because most molar pregnancies are diagnosed in the first trimester by routine early ultrasound before these features have time to develop ^[1]^[2]. Most patients now present simply with first-trimester vaginal bleeding and are diagnosed on ultrasound + hCG.

Symptom	Pathophysiological Basis
Persistent or irregular vaginal bleeding after any pregnancy event	Malignant trophoblast invading myometrium → erosion of blood vessels → abnormal uterine bleeding. This is the most common presentation ^[1]
Subinvolution of the uterus (uterus fails to return to normal size after pregnancy)	Persistent trophoblastic tissue within the myometrium prevents normal involution
Haemoptysis or dyspnoea (pulmonary metastases — most common site of metastasis)	Choriocarcinoma spreads haematogenously (like its normal counterpart — trophoblast that invades blood vessels). Lung metastases → haemoptysis from erosion into airways; dyspnoea from multiple lesions ^[1]
Neurological symptoms (headache, seizures, focal deficits)	Brain metastases — choriocarcinoma has a predilection for CNS. Haemorrhagic metastases → acute neurological deterioration
Hepatic symptoms (right upper quadrant pain, hepatomegaly)	Liver metastases — haemorrhagic lesions can cause subcapsular haemorrhage or intraperitoneal bleeding
Abdominal pain	Uterine perforation by invasive mole/choriocarcinoma; haemoperitoneum

Clinical Red Flag

Any woman of reproductive age presenting with unexplained haemoptysis, seizures, or bizarre neurological symptoms should have a pregnancy test (serum β-hCG) performed. Choriocarcinoma can present with metastatic disease (especially lung or brain) even when the primary uterine tumour is small or undetectable. Missing this diagnosis can be fatal — and the disease is highly curable if treated.

Sign	Pathophysiological Basis
Uterus larger than dates (in ~50% of complete moles)	Excessive trophoblastic proliferation + accumulated blood and hydropic villi within the uterine cavity
Uterus smaller than dates (in some partial moles)	Partial moles often present earlier and with less trophoblastic proliferation
Absent fetal heart sounds (complete mole) / Fetal heart present but abnormal fetus (partial mole)	No fetus in complete mole; triploid fetus in partial mole is usually growth-restricted with anomalies
Bilateral theca lutein cysts (ovarian enlargement)	Very high hCG overstimulates ovarian follicles → multiple luteinised cysts (can be very large, up to 10–20 cm). More common in complete moles. Usually regress spontaneously as hCG falls post-evacuation. Can cause ovarian torsion ^[1]
Hypertension + proteinuria before 20 weeks (pre-eclampsia)	Abnormal trophoblast releases excessive anti-angiogenic factors → endothelial dysfunction. Pre-eclampsia before 20 weeks is almost pathognomonic of molar pregnancy ^[1]^[4]
Signs of thyrotoxicosis: tachycardia, tremor, lid lag, warm moist skin, hyperreflexia	hCG cross-reacting with TSH receptor → excess thyroid hormone production ^[3]
Anaemia (pallor, tachycardia)	Chronic or acute vaginal bleeding from the molar pregnancy
Vaginal/vulval metastatic lesions (dark red/purple vascular nodules)	Choriocarcinoma metastases to vagina — appear as highly vascular, haemorrhagic nodules. DO NOT BIOPSY — risk of torrential haemorrhage ^[1]
Hepatomegaly	Liver metastases in advanced GTN
Chest signs (crackles, decreased breath sounds)	Pulmonary metastases or trophoblastic pulmonary embolism

The classical triad of complete molar pregnancy is: (1) vaginal bleeding in early pregnancy, (2) uterus large for gestational age, and (3) markedly elevated hCG ^[1]^[2]. However, with early ultrasound diagnosis, the full triad is now seen less commonly.

Pathophysiology — Integrated Summary

Higher incidence: As an Asian population, Hong Kong has a higher incidence of hydatidiform mole (~1 in 500–600 pregnancies) compared to Western populations (~1 in 1000–1500) ^[1]^[2]
Referral centres: GTN is managed at specialised trophoblastic disease centres — in Hong Kong, Queen Mary Hospital is a major referral centre
hCG monitoring: Post-evacuation hCG surveillance is well-established in Hong Kong obstetric practice, with standardised follow-up protocols
Gestational thyrotoxicosis: Given the higher prevalence of molar pregnancy in Asian populations, and the known susceptibility of Asian patients to thyrotoxic periodic paralysis (TPP), clinicians should be vigilant for thyrotoxic complications in molar pregnancy ^[3]
Hydatidiform mole is listed as a predisposing factor for pre-eclampsia in Hong Kong obstetric teaching ^[4]

High Yield Summary

Definition: GTD is a spectrum of trophoblastic tumours ranging from benign (hydatidiform mole) to malignant (GTN: invasive mole, choriocarcinoma, PSTT, ETT).

Epidemiology: Higher in Asia/HK (~1:500–600). Bimodal age risk (< 20, > 35–40). Previous mole is a strong risk factor.

Complete vs Partial Mole:

Complete: 46,XX (all paternal), no fetus, diffuse hydropic villi, very high hCG, 15–20% GTN risk
Partial: 69,XXY (triploid), fetal tissue present, focal changes, lower hCG, < 5% GTN risk

Clinical Features: Vaginal bleeding (most common), uterus large-for-dates, theca lutein cysts, hyperemesis, thyrotoxicosis (hCG cross-reacts with TSH-R), pre-eclampsia before 20 weeks.

Pre-eclampsia before 20 weeks = think molar pregnancy.

Choriocarcinoma: Highly malignant, haematogenous spread (lung > brain > liver), very high hCG, NO villi histologically, but exquisitely chemosensitive.

hCG is the universal marker for diagnosis, monitoring, and surveillance.

Any reproductive-age woman with unexplained haemoptysis/neurological symptoms → check β-hCG.

Active Recall - Gestational Trophoblastic Disease (Part 1)

Differential Diagnosis of Gestational Trophoblastic Disease

This is the bread-and-butter scenario: a woman in early pregnancy presents with vaginal bleeding ± pelvic pain ± a positive pregnancy test. The DDx here is essentially the "complications of early pregnancy" list.

Differential	Key Distinguishing Features	Why It Can Mimic GTD
Threatened miscarriage	Viable IUP on USS, closed cervix, vaginal bleeding settles. hCG rises normally	Both present with PV bleeding in early pregnancy. Molar pregnancy can mimic threatened miscarriage ^[1]^[2]
Incomplete miscarriage	Products of conception partially expelled; open cervical os; retained echogenic tissue on USS but NOT the classic "snowstorm" pattern. hCG falling	PV bleeding + tissue passage. Partial mole can look very similar to incomplete miscarriage on USS — the "grape-like vesicles" may be subtle or absent early on
Missed miscarriage (silent / delayed miscarriage)	Non-viable IUP (no cardiac activity) with retained gestational sac. hCG plateauing or falling. No "snowstorm"	A partial mole in particular can be difficult to distinguish from a missed miscarriage with hydropic degeneration of the placenta. The key is histological examination of evacuated products
Anembryonic pregnancy (blighted ovum)	Gestational sac present but no embryo/yolk sac by expected dates. hCG often subnormal	An early complete mole before the classic "snowstorm" develops can look like an empty sac on early USS
Ectopic pregnancy	No IUP on USS despite positive hCG. hCG rising suboptimally (< 66% rise in 48 h). Adnexal mass or free fluid ± pain. hCG usually < 100,000	Both cause PV bleeding with positive hCG and no visible IUP. However, ectopic pregnancy hCG levels are typically far lower than molar pregnancy. The key distinguishing feature is adnexal mass (ectopic) vs intrauterine "snowstorm" (mole). Beware: theca lutein cysts from molar pregnancy can be mistaken for ectopic pregnancy
Cervical pathology (cervical polyp, cervical ectropion, cervical carcinoma)	Bleeding originates from cervix on speculum exam; hCG level appropriate for dates if incidentally pregnant	Coincidental cervical bleeding in a pregnant woman. Always perform speculum exam

Critical Exam Point

Partial molar pregnancy is the most commonly MISSED diagnosis because it closely mimics an incomplete or missed miscarriage on ultrasound. The hydropic villi may be subtle, and the fetus (if present) may be mistaken for a normal but failing pregnancy. Histological examination of ALL products of conception after surgical evacuation for miscarriage is essential — this is how many partial moles are diagnosed retrospectively ^[1]^[2].

When the serum β-hCG is disproportionately high for the gestational age, you need to consider why. This is a crucial clinical reasoning step because markedly elevated hCG is the hallmark of complete molar pregnancy.

Condition	Typical hCG Range	Why hCG Is Elevated
Complete hydatidiform mole	Often > 100,000 mIU/mL, can exceed 1,000,000	Massive trophoblastic proliferation → massive syncytiotrophoblast mass → enormous hCG secretion
Multiple pregnancy (twins/triplets)	Higher than singleton but usually < 200,000	Two or more placentae producing hCG; proportional increase. Twin pregnancy is a risk factor for very high hCG and gestational thyrotoxicosis ^[3]
Choriocarcinoma	Can be extremely high (> 100,000)	Malignant syncytiotrophoblast producing hCG autonomously
Non-gestational germ cell tumour (ovarian or testicular)	Variable; in testicular NSGCT, hCG 80–85% positive ^[5]	Germ cell tumours (especially choriocarcinoma component) can produce hCG. Testicular tumour markers include LDH, AFP, and hCG ^[5]
Normal early pregnancy	Doubles every 48 h; peaks at 10–12 weeks (~100,000)	Physiological peak of hCG at 10–12 weeks ^[3]
Hyperemesis gravidarum	Usually correlates with high-normal or mildly elevated hCG	hCG stimulates vomiting centre. Very high hCG (twin pregnancy, hyperemesis gravidarum, molar pregnancy) causes gestational thyrotoxicosis ^[3]

High Yield Principle

The rule of thumb: hCG > 100,000 mIU/mL in early pregnancy with no viable fetus = complete molar pregnancy until proven otherwise. However, always correlate with ultrasound findings and clinical picture.

When the uterine size exceeds the expected size for gestational age, the DDx includes:

Condition	Mechanism
Complete molar pregnancy	Excessive trophoblastic tissue + blood accumulation within uterine cavity
Multiple pregnancy	Two or more fetuses → increased uterine volume
Polyhydramnios	Excess amniotic fluid (e.g., fetal swallowing disorders, diabetes)
Uterine fibroids (leiomyoma)	Pre-existing fibroids enlarge during pregnancy due to oestrogen stimulation
Inaccurate dating	Pregnancy further advanced than estimated
Macrosomia	Large fetus (e.g., gestational diabetes) — usually a later pregnancy finding

This is a classic exam scenario. Pre-eclampsia normally presents after 20 weeks of gestation. Early-onset pre-eclampsia (before 20 weeks) is highly suggestive of molar pregnancy ^[1]^[4].

Condition	Distinguishing Features
Hydatidiform mole	Vaginal bleeding, markedly elevated hCG, "snowstorm" on USS, no viable fetus (complete mole). Hydatidiform mole is listed as a predisposing factor/obstetric condition associated with pre-eclampsia ^[4]
Pre-existing chronic hypertension	Hypertension present before pregnancy or before 20 weeks but without proteinuria initially, and without the other features of molar pregnancy. Often has prior history of hypertension
Chronic renal disease	Pre-existing proteinuria + hypertension. Renal function tests abnormal. History of renal disease. Pre-existing renal disease is a predisposing factor for pre-eclampsia ^[4]
Antiphospholipid syndrome (APS)	Can cause early pre-eclampsia. History of recurrent miscarriage, thrombosis. Anti-cardiolipin / lupus anticoagulant positive. APS is a predisposing factor for pre-eclampsia ^[4]

After any pregnancy event (delivery, miscarriage, molar evacuation), hCG should fall to undetectable. If hCG plateaus or rises, the DDx is:

Condition	Distinguishing Features
Gestational trophoblastic neoplasia (GTN) — invasive mole, choriocarcinoma	Persistence of elevated hCG after primary treatment of GTD. Diagnosis does not require histological confirmation ^[1]^[2]. Rising/plateauing hCG, ± abnormal uterine USS, ± metastatic lesions
New pregnancy	The most common "false alarm." A new intrauterine pregnancy will cause hCG to rise. Always perform USS to exclude new pregnancy before diagnosing GTN
Retained products of conception	Incomplete evacuation of molar or non-molar pregnancy. hCG may remain mildly elevated. USS shows retained intrauterine tissue
Phantom hCG (heterophilic antibody interference)	False-positive hCG due to heterophilic antibodies (e.g., human anti-mouse antibodies) interfering with the immunoassay. Suspected when hCG is low-positive and does not rise or fall appropriately. Confirmed by testing with a different assay platform or by urine hCG (heterophilic antibodies are not excreted in urine, so urine hCG will be negative)
Pituitary hCG production	Postmenopausal women can have mildly elevated hCG (up to ~10–14 mIU/mL) from pituitary gonadotrophs. Not relevant in reproductive-age women unless post-bilateral oophorectomy
Non-gestational hCG-secreting tumour	Ovarian germ cell tumour, testicular tumour (if male — obviously not post-pregnancy), or other rare tumours. hCG is raised in molar pregnancy and GCT ^[5]^[6]

To diagnose GTD, requires a tissue pathological diagnosis. To diagnose GTN, requires a prior diagnosis of GTD that was treated, but the hCG remains persistently high — tissue diagnosis is thus not required ^[2].

Key Distinction: GTD vs GTN Diagnosis

This is an important conceptual point from the lecture slides. GTD (molar pregnancy) is a histological diagnosis — you need tissue. GTN is a clinical/biochemical diagnosis — you diagnose it based on persistently elevated or rising hCG after treatment of a known GTD, without necessarily needing another tissue sample. This is because biopsy of suspected GTN (e.g., vaginal metastasis of choriocarcinoma) is dangerous due to haemorrhage risk ^[1]^[2].

F. Differential Diagnosis of Metastatic GTN (Presenting with Distant Symptoms)

This is the scenario where choriocarcinoma has spread and the patient presents with symptoms from metastatic sites, often without a known preceding molar pregnancy.

Differential	Distinguishing Features
Choriocarcinoma (pulmonary metastases)	Reproductive-age woman, history of recent pregnancy/miscarriage/mole, markedly elevated hCG, multiple bilateral "cannonball" lesions on CXR
Pulmonary embolism	Acute dyspnoea, pleuritic chest pain, risk factors (immobilisation, DVT). D-dimer elevated. CT pulmonary angiography diagnostic
Lung carcinoma (primary)	Usually older patient, smoking history. Single mass or hilar lesion. hCG negative
Pulmonary tuberculosis	Common in Hong Kong. Cough, night sweats, weight loss, apical infiltrates. Sputum AFB
Pneumonia	Fever, productive cough, consolidation on CXR. Responds to antibiotics
Pulmonary metastases from other primary	History of known primary malignancy (breast, colon, etc.). hCG negative

Differential	Distinguishing Features
Choriocarcinoma (brain metastases)	Reproductive-age woman, may have haemorrhagic lesions on CT/MRI. Elevated hCG. History of pregnancy
Eclampsia	Occurs in setting of pre-eclampsia (hypertension, proteinuria, oedema). Seizures. Usually third trimester or postpartum
Cerebral venous sinus thrombosis	Headache, seizures, focal deficits. Associated with pregnancy/postpartum hypercoagulable state. MRV diagnostic
Primary brain tumour / other metastatic disease	Imaging characteristics differ; hCG negative
Stroke (ischaemic or haemorrhagic)	Risk factors for stroke. hCG negative

Never-Miss Rule

Any woman of reproductive age with unexplained haemoptysis, seizures, or neurological symptoms MUST have a serum β-hCG checked. Choriocarcinoma is curable even when metastatic — missing the diagnosis is a catastrophic but entirely preventable error. The hCG test costs almost nothing and takes minutes.

Hyperemesis gravidarum can be life threatening and it is important to exclude other specific diagnoses ^[1]^[2].

Condition	Key Features
Molar pregnancy with gestational thyrotoxicosis	Very high hCG cross-reacts with TSH-R → thyrotoxicosis. "Snowstorm" on USS. hCG > > 100,000. Anti-thyroid drugs are NOT indicated — resolves when mole is evacuated ^[3]
Gestational thyrotoxicosis (non-molar)	Physiological hCG peak at 10–12 weeks can cause mild thyrotoxicosis, especially in multiple pregnancy or hyperemesis gravidarum. Biochemically indistinguishable from other aetiologies (e.g. Graves'), distinguished by: past history of thyroid disease, any thyrotoxic symptoms pre-conception, any goitre, autoAb profile. Closely monitor fT4: expect to decline after 1st trimester ^[3]
Graves' disease	Pre-existing goitre, ophthalmopathy, positive TRAb. Symptoms present before conception. Does NOT resolve with falling hCG
Other causes of hyperemesis	Gastroenteritis, pancreatitis, hepatitis, urinary tract infection, raised intracranial pressure, Addison's disease. Diagnose by appropriate investigations

When USS shows bilateral large ovarian cysts in pregnancy, consider:

Condition	Key Features
Theca lutein cysts from molar pregnancy	Bilateral, multiloculated, associated with very high hCG. Regress spontaneously after molar evacuation
Ovarian hyperstimulation syndrome (OHSS)	History of assisted reproduction (ovulation induction). Bilateral enlarged ovaries with multiple cysts. Ascites, pleural effusion
Bilateral ovarian cystadenoma / cystadenocarcinoma	Unilateral more common than bilateral; solid components on USS; CA-125 may be raised
Bilateral dermoid cysts (mature cystic teratoma)	Characteristic USS features (fat, calcification, "tip of the iceberg" sign). Usually incidental finding
PCOS	Multiple small follicles (< 10 mm) — very different from the large cysts of theca lutein

Presenting Scenario	Primary DDx to Consider
First-trimester PV bleeding	Threatened/incomplete/missed miscarriage, ectopic pregnancy, hydatidiform mole
Markedly elevated hCG with no viable fetus	Complete molar pregnancy, multiple pregnancy
Pre-eclampsia before 20 weeks	Molar pregnancy, chronic HTN, renal disease, APS
Persistent/rising hCG post-pregnancy	GTN, new pregnancy, retained products, phantom hCG
Haemoptysis in reproductive-age woman	Choriocarcinoma (lung mets), PE, TB, pneumonia
Seizures/neurological symptoms post-pregnancy	Choriocarcinoma (brain mets), eclampsia, CVST, stroke
Hyperemesis + thyrotoxicosis	Molar pregnancy, gestational thyrotoxicosis, Graves' disease
Bilateral large ovarian cysts in pregnancy	Theca lutein cysts (molar pregnancy), OHSS

High Yield Summary

GTD is a great mimicker — it masquerades as threatened miscarriage (PV bleeding), hyperemesis gravidarum (severe vomiting), pre-eclampsia (hypertension before 20 weeks), and even metastatic cancer (haemoptysis, seizures).

Key DDx principles:

Molar pregnancy is an important DDx of threatened miscarriage — always consider it when there is PV bleeding + positive hCG + abnormal USS.
Partial mole mimics missed/incomplete miscarriage — histological examination of all evacuated products is essential.
Pre-eclampsia before 20 weeks = think molar pregnancy.
Any reproductive-age woman with unexplained haemoptysis or seizures → check β-hCG.
Persistently elevated hCG after any pregnancy event = GTN until proven otherwise (after excluding new pregnancy).
GTD requires tissue diagnosis; GTN does not — it is diagnosed by persistent hCG elevation after treated GTD.
Gestational thyrotoxicosis from molar pregnancy does NOT require antithyroid drugs — treat the mole.

Active Recall - GTD Differential Diagnosis

References

^[1] Lecture slides: GC 223. Complications of Early Pregnancy.pdf ^[2] Lecture slides: Block C - Complications of Early Pregnancy (CFB WCS in 2023_24).pdf ^[3] Senior notes: Maksim Medicine Notes.pdf (p95 — Gestational thyrotoxicosis / hCG–TSH homology) ^[4] Lecture slides: GC 224. Hypertension and Pregnancy.pdf (p15 — predisposing factors for pre-eclampsia including hydatidiform mole) ^[5] Senior notes: Maksim Surgery Notes.pdf (p326 — testicular tumour markers including hCG) ^[6] Senior notes: Maksim Medicine Notes.pdf (p337 — tumour markers table including hCG)

Diagnosis of Gestational Trophoblastic Disease

Diagnostic Criteria

There are no formal "diagnostic criteria" per se — it is a clinico-pathological diagnosis based on:

Component	Details
Clinical suspicion	First-trimester vaginal bleeding, positive pregnancy test, ± exaggerated pregnancy symptoms, ± uterus large for dates
Ultrasound findings	"Snowstorm" appearance; theca lutein cysts of ovary ^[1]. Complex, echogenic, intrauterine mass containing many small cystic spaces — "clusters of grapes" ^[1]
Serum β-hCG	Markedly elevated (often > 100,000 mIU/mL in complete moles; less elevated in partial moles)
Definitive diagnosis	Histopathological examination of evacuated products of conception — this is the gold standard ^[1]^[2]

The FIGO 2000 criteria (updated and endorsed by RCOG Green-top Guideline No. 38, June 2020 ^[1]) define post-molar GTN when any one of the following is met after evacuation of a hydatidiform mole:

Criterion	Explanation
hCG plateau (4 values ± 10% over ≥ 3 weeks — days 1, 7, 14, 21)	hCG is no longer falling. This indicates persistent viable trophoblastic tissue that is not being spontaneously cleared by the immune system
hCG rise (≥ 10% rise across 3 values over ≥ 2 weeks — days 1, 7, 14)	hCG is actively increasing. This indicates proliferating malignant trophoblast
hCG remains elevated > 6 months after molar evacuation	Even if slowly falling, persistent hCG this long after evacuation suggests GTN
Histological diagnosis of choriocarcinoma	If tissue is obtained (e.g., from hysterectomy or metastatic biopsy) showing choriocarcinoma

Why These Criteria Make Sense

After evacuating a hydatidiform mole, the residual normal trophoblastic tissue should be cleared by the maternal immune system, and hCG should fall exponentially to undetectable. The half-life of hCG is approximately 24–36 hours. If hCG does not fall as expected (plateau), or worse, rises — it means there is autonomous, proliferating trophoblastic tissue that is behaving as a malignancy. You do not need a tissue biopsy to make this diagnosis — the biochemical behaviour IS the diagnosis.

Investigation Modalities — Detailed Breakdown

Why this test? hCG is produced by all trophoblastic tissue. It is the single most important investigation in GTD — used for diagnosis, monitoring, and surveillance.

Aspect	Details
When to order	At initial presentation (suspected molar pregnancy); serially post-evacuation
Expected findings in complete mole	Markedly elevated, often > 100,000 mIU/mL (can exceed 1,000,000). This is because of the massive syncytiotrophoblast mass producing hCG autonomously
Expected findings in partial mole	Lower elevation, often in the range expected for gestational age or mildly above
Post-evacuation monitoring	hCG should be measured weekly until normalised, then at intervals per protocol (see below). The half-life of hCG is ~24–36 hours; expect a log-linear decline
Interpretation of post-evacuation trend	Falling → good (spontaneous resolution). Plateau (± 10% over 3 weeks) or rise (≥ 10% over 2 weeks) → GTN — persistence of GTD after primary treatment (persistent elevated hCG) ^[1]^[2]
Pitfalls	(1) Phantom hCG from heterophilic antibodies — confirm with urine hCG or different assay. (2) New pregnancy — always USS before diagnosing GTN. (3) Pituitary hCG in perimenopause — low levels only

hCG is the first investigation listed in the management of hydatidiform mole ^[1].

Clinical Pearl: hCG Monitoring Schedule Post-Evacuation

RCOG Green-top Guideline No. 38 (2020) ^[1] recommends:

Complete mole: Weekly serum hCG until normalised. Then monthly for 6 months after normalisation.
Partial mole: Weekly serum hCG until normalised. If normalised within 56 days of evacuation, no further follow-up needed. If not normalised by 56 days, continue monthly monitoring for 6 months.
Contraception during the entire monitoring period (to avoid confounding hCG interpretation with a new pregnancy). Hormonal contraception is safe (combined OCP or progesterone-only) once hCG is normal.

Why this test? It is the primary imaging modality for detecting and characterising intrauterine pathology in early pregnancy. It is non-invasive, readily available, and avoids ionising radiation.

Finding	Complete Mole	Partial Mole	Interpretation
"Snowstorm" appearance	Classic finding — diffuse echogenic intrauterine mass with innumerable small anechoic spaces (representing the hydropic villi)	Not typical; may show a mixed-echogenicity placenta with scattered cystic spaces	The "snowstorm" results from the ultrasound beam reflecting off the many interfaces between hydropic villi and blood/fluid in the uterine cavity ^[1]
"Clusters of grapes"	Complex, echogenic, intrauterine mass containing many small cystic spaces ^[1]	Focal areas of cystic change within the placenta, mixed with normal-appearing villi	The "grapes" are the individual hydropic villi, each swollen with fluid to form a cyst-like structure
Fetal structures	Absent (no fetus, no amniotic sac, no fetal heart)	Present (a fetus may be visible, though often growth-restricted with anomalies; may show fetal cardiac activity)	Presence or absence of fetal tissue is the key ultrasound distinction between complete and partial mole
Theca lutein cysts	Common — bilateral, multiloculated, large (can be > 6 cm)	Rare	Result from ovarian hyperstimulation by very high hCG. Ultrasound shows bilateral multicystic ovarian enlargement ^[1]
Myometrial invasion	Not typically visible in uncomplicated mole	Not typical	If myometrial invasion is suspected (irregular myometrial echogenicity, increased vascularity), consider invasive mole → further imaging

Diagnosis of hydatidiform mole: ultrasound examination — "snowstorm" appearance; theca lutein cysts of ovary. Complex, echogenic, intrauterine mass containing many small cystic spaces — "clusters of grapes" ^[1].

Important Caveat

In the first trimester (especially < 10 weeks), the classic "snowstorm" appearance may NOT yet be present — the hydropic villi are still too small. Early complete moles can appear as a non-specific echogenic intrauterine mass or even mimic an anembryonic pregnancy (empty gestational sac). Most molar pregnancies in modern practice are diagnosed earlier (due to routine early USS), so the classic second-trimester "snowstorm" is increasingly rare. Partial moles are even harder to detect on USS — many are diagnosed only on histology after evacuation for presumed miscarriage.

Why this test? This is the gold standard for diagnosing hydatidiform mole. Ultrasound and hCG are suggestive, but histology is definitive.

Feature	Complete Mole	Partial Mole	Non-Molar Hydropic Abortus
Villous oedema	Diffuse — all villi swollen with central cisterns	Focal — two populations (normal + hydropic)	May have mild focal oedema but no cisterns
Trophoblastic hyperplasia	Diffuse, circumferential, marked	Focal, mild	Absent or minimal
Villous outline	Round, smooth	Scalloped, irregular ("fjord-like") with trophoblastic inclusions	Round, regular
Fetal blood vessels	Absent	May be present (with nucleated fetal RBCs)	Present
Fetal tissue	Absent	May be present (usually anomalous)	Present (if not completely expelled)
p57KIP2 immunostaining	Negative (paternally imprinted, maternally expressed gene — absent because no maternal genome)	Positive (maternal genome present)	Positive
Ploidy analysis (flow cytometry / FISH / genotyping)	Diploid (46,XX or 46,XY — all paternal)	Triploid (69,XXX/XXY/XYY)	Diploid or aneuploid

p57KIP2 deserves special mention:

It is encoded by the CDKN1C gene on chromosome 11p15.5
It is maternally expressed (paternally imprinted — i.e., the paternal copy is silenced)
In a complete mole (all paternal DNA, no maternal DNA) → p57 is not expressed → immunohistochemistry is negative
In a partial mole or non-molar pregnancy (maternal DNA present) → p57 is expressed → immunohistochemistry is positive
This makes p57 an extremely useful ancillary test to distinguish complete mole from partial mole and from non-molar hydropic abortus

When Histology Is Ambiguous

Sometimes histological distinction between partial mole and non-molar hydropic miscarriage is difficult. In these cases:

p57KIP2 immunostaining helps distinguish complete mole (negative) from partial mole/non-molar (positive)
Genotyping (e.g., short tandem repeat analysis) can confirm androgenetic diploidy (complete mole) vs triploidy (partial mole) vs biparental diploidy (non-molar)
Flow cytometry can assess ploidy (diploid vs triploid) These ancillary tests are increasingly used in modern practice to ensure accurate diagnosis, because the risk of GTN and surveillance requirements differ significantly between complete and partial moles.

Management of hydatidiform mole: hCG, CBP, type and screen ^[1].

Investigation	Rationale
Serum β-hCG	Baseline level for monitoring post-evacuation; confirms diagnosis; correlates with risk of complications ^[1]
Complete blood picture (CBP)	Assess for anaemia (from chronic/acute PV bleeding); baseline haemoglobin before surgical evacuation ^[1]
Blood group and antibody screen ("type and screen")	Preparation for potential transfusion (evacuation can cause significant haemorrhage); determine Rh status for anti-D prophylaxis ^[1]
Thyroid function tests (TFT)	"If the patient has thyroid symptoms" ^[1]. Very high hCG can cross-react with TSH receptor causing thyrotoxicosis. Check TSH, fT4. Important for anaesthetic safety (thyroid storm risk)
Chest X-ray (CXR)	"If the patient has chest symptoms" ^[1]. Screen for pulmonary metastases (trophoblastic embolisation or choriocarcinoma). Also baseline for post-evacuation comparison
Renal function tests, electrolytes	Baseline; assess for dehydration (if hyperemesis); pre-eclampsia workup
Liver function tests	Baseline; pre-eclampsia workup (HELLP syndrome); screen for liver metastases
Coagulation profile	Risk of DIC with molar pregnancy, especially if delayed evacuation
Urinalysis	Proteinuria screen (pre-eclampsia)

Key Point on CXR and TFT

The lecture slides emphasise a symptom-directed approach: CXR if the patient has chest symptoms; TFT if the patient has thyroid symptoms ^[1]. In practice, many centres perform CXR routinely for complete moles (given the 15–20% risk of GTN) and TFT when hCG is very high (> 100,000). The RCOG guideline recommends CXR for all patients with GTN (not just molar pregnancy) and for staging purposes.

If hCG surveillance post-evacuation shows plateau or rise (meeting FIGO criteria for GTN), staging investigations are performed:

Investigation	Purpose	Key Findings
CXR	Screen for pulmonary metastases (most common site)	"Cannonball" lesions (well-defined round opacities) — multiple bilateral nodules. Also can show pulmonary infiltrates or pleural effusion. CXR has ~40% sensitivity for small mets
CT thorax	More sensitive than CXR for pulmonary metastases	Multiple bilateral pulmonary nodules, lymphangitic spread. Detects small metastases missed by CXR. Some centres use CT for staging all GTN
Pelvic Doppler USS	Assess uterine invasion, vascularity, residual disease	Invasive mole: echogenic mass within myometrium with increased vascularity on Doppler (low-resistance, high-velocity arterial flow). May show areas of myometrial invasion
MRI pelvis	Better soft tissue resolution than USS for myometrial invasion	Defines depth of myometrial invasion; characterises uterine mass; useful for PSTT/ETT (which may not respond to chemotherapy and may need surgery)
CT/MRI brain	Screen for cerebral metastases (choriocarcinoma has predilection for brain)	Haemorrhagic enhancing lesions. Mandatory if hCG > 100,000 or lung metastases present (brain mets occur in ~10% of Stage IV GTN)
CT abdomen	Screen for hepatic and other abdominal metastases	Liver metastases (usually haemorrhagic), lymphadenopathy, renal/splenic involvement
Lumbar puncture (CSF:serum hCG ratio)	Detect occult CNS disease	CSF:serum hCG ratio > 1:60 suggests CNS involvement (normally hCG does not cross the blood-brain barrier significantly). Used when brain imaging is equivocal

Special Diagnostic Scenarios

Investigation	Complete Mole	Partial Mole	GTN (Invasive Mole / Choriocarcinoma)
Serum β-hCG	Very high ( > 100,000)	Mildly-moderately elevated	Elevated / rising / plateau post-evacuation
TVUS	Snowstorm, no fetus, ± theca lutein cysts	Focal cystic placenta, ± abnormal fetus	Myometrial mass with increased vascularity
Histopathology	Diffuse hydropic villi, diffuse trophoblastic hyperplasia, no fetal tissue, no fetal vessels	Focal hydropic villi, focal hyperplasia, ± fetal tissue/vessels, scalloped villi	Invasive mole: villi invading myometrium. Choriocarcinoma: sheets of malignant trophoblast, NO villi, haemorrhage/necrosis
p57KIP2	Negative	Positive	Variable (depends on tumour type)
CXR	Usually normal (unless trophoblastic embolism)	Usually normal	Cannonball lesions (lung mets)
CT/MRI brain	Not indicated	Not indicated	Haemorrhagic brain metastases if Stage IV

High Yield Summary

Diagnosis of GTD (Molar Pregnancy):

Clinical suspicion (PV bleeding + very high hCG + abnormal USS) → suction evacuation → histopathology confirms diagnosis.
USS: "snowstorm" appearance, complex echogenic intrauterine mass containing many small cystic spaces ("clusters of grapes"), ± theca lutein cysts ^[1].
Pre-evacuation workup: hCG, CBP, type and screen. CXR and TFT if symptomatic ^[1].
Histopathology is the gold standard — always send evacuated products.
p57KIP2 immunostaining: negative in complete mole (no maternal DNA), positive in partial mole.

Diagnosis of GTN:

Does not require histological confirmation ^[1]^[2] — diagnosed by persistent/rising hCG post-evacuation.
FIGO criteria: hCG plateau (4 values over 3 weeks) OR hCG rise (3 values over 2 weeks) OR hCG elevated > 6 months OR histological choriocarcinoma.
Staging: FIGO I–IV (anatomical) + WHO risk score (≤ 6 low risk, ≥ 7 high risk).

Don't forget:

Anti-D prophylaxis for Rh-negative women ^[1].
Histological examination of ALL products of conception — catches unsuspected partial moles.
Exclude new pregnancy before diagnosing GTN (USS!).

Active Recall - GTD Diagnosis

References

Management of Gestational Trophoblastic Disease

Before any surgical intervention, assess and manage acute complications:

Complication	Management	Rationale
Haemorrhage	IV access (2 large-bore cannulae), crossmatch blood, fluid resuscitation, urgent evacuation	Molar pregnancy can bleed heavily — hydropic villi separate from decidua disrupting maternal vessels
Pre-eclampsia	IV magnesium sulfate (seizure prophylaxis), antihypertensives (labetalol, hydralazine, nifedipine), urgent evacuation	Pre-eclampsia in early pregnancy from molar pregnancy resolves after evacuation; MgSO₄ prevents eclamptic seizures
Thyrotoxicosis / thyroid storm	Beta-blockers (propranolol), cooling, definitive treatment is evacuation of mole. Anti-thyroid drugs are NOT indicated ^[3]	hCG-mediated thyrotoxicosis resolves once hCG falls. Propranolol controls adrenergic symptoms. Important for anaesthetic safety — inform anaesthetist
Respiratory distress	Oxygen, CXR, supportive care, consider trophoblastic embolism vs pulmonary oedema vs thyroid storm	May occur during or shortly after evacuation from trophoblastic deportation to lungs
Hyperemesis	IV fluids, antiemetics (ondansetron), electrolyte correction, thiamine supplementation	Severe vomiting from high hCG can cause dehydration, Wernicke's encephalopathy if thiamine-depleted

Step 2: Suction Evacuation — The Primary Treatment

Management of hydatidiform mole: suction evacuation ^[1].

Aspect	Details
Method	Suction evacuation (suction curettage) — this is the treatment of choice for ALL molar pregnancies regardless of uterine size ^[1]
Why suction?	Suction is gentler on the myometrium than sharp curettage, reducing the risk of uterine perforation (remember: the trophoblast is already invasive). It is also more efficient at removing the large volume of molar tissue
Cervical preparation	Cervical priming with misoprostol or osmotic dilators may be used. However, medical evacuation (misoprostol alone / mifepristone + misoprostol) is NOT recommended for complete moles — it is less effective at complete evacuation, may increase risk of GTN, and does not provide adequate tissue for histology
Oxytocic agents	Use of oxytocic infusion prior to completion of removal is NOT recommended ^[1]
Anti-D	+/- Anti-D prophylaxis — administer if mother is Rh(D)-negative ^[1]
Anaesthesia	General anaesthesia preferred (allows uterine relaxation, better surgical conditions)
Intraoperative USS guidance	Recommended to confirm complete evacuation and reduce risk of perforation

Why No Oxytocics Before Completion of Evacuation?

Use of oxytocic infusion prior to completion of removal is not recommended ^[1]. The reasoning: oxytocin causes the uterus to contract, which theoretically could force molar tissue into the open uterine venous sinuses → trophoblastic embolisation to the lungs. This can cause acute respiratory distress or even fatal pulmonary embolism. Once the uterus is empty, oxytocin can be given to promote uterine involution and reduce bleeding. This is an important exam point.

Step 4: Post-Evacuation hCG Surveillance

This is the cornerstone of GTD management. The entire follow-up protocol revolves around serial hCG measurements.

Mole Type	Frequency	Duration	Notes
Complete mole	Weekly serum hCG until normalised (undetectable or < 5 mIU/mL on 3 consecutive occasions) → then monthly for 6 months	Total: until 6 months of normal hCG values	Higher risk of GTN (15–20%) necessitates longer surveillance
Partial mole	Weekly serum hCG until normalised	If normalised within 56 days (8 weeks) of evacuation → no further follow-up needed. If NOT normalised by 56 days → continue monthly for 6 months	Lower risk of GTN (< 5%). If hCG normalises quickly, the risk is very low and prolonged surveillance is unnecessary

Pattern	Interpretation	Action
Exponential decline	Normal spontaneous resolution — the immune system is clearing residual trophoblast	Continue surveillance per protocol
Slow decline	May be normal if still trending down, but warrants close monitoring	Continue weekly hCG; do not yet diagnose GTN
Plateau (4 values ± 10% over ≥ 3 weeks)	GTN — persistent viable trophoblastic tissue	Diagnose GTN → staging + risk scoring → chemotherapy
Rise (≥ 10% over 3 values across ≥ 2 weeks)	GTN — proliferating malignant trophoblast	Diagnose GTN → staging + risk scoring → chemotherapy
Elevated > 6 months	GTN by definition	Diagnose GTN → staging + risk scoring → chemotherapy

Contraception is essential during the entire hCG monitoring period.

Why? A new pregnancy would elevate hCG, making it impossible to distinguish between GTN and a normal new pregnancy. This could either:

Delay diagnosis of GTN (falsely reassured that hCG rise is from pregnancy)
Lead to unnecessary treatment (misinterpret pregnancy hCG as GTN)

Contraceptive Method	Recommendation
Barrier methods (condoms)	Safe at any time. Less reliable for prevention but acceptable
Combined oral contraceptive pill (COCP)	Safe once hCG has normalised. Historically there was concern that oestrogen might stimulate residual trophoblast, but multiple studies show no increased risk of GTN with COCP use
Progesterone-only methods	Safe once hCG has normalised
Intrauterine device (IUD)	Avoid until hCG has normalised — risk of uterine perforation (post-evacuation uterus is soft, potentially invaded by trophoblast) and confounding bleeding
When to conceive?	Advised to wait until surveillance is complete (i.e., hCG has been normal for the required monitoring period — 6 months for complete moles). After that, there is no increased risk of adverse pregnancy outcome

Step 6: Management of GTN — Chemotherapy

When hCG surveillance indicates GTN, treatment is guided by FIGO staging + WHO risk score.

Single or multi-agent chemotherapy if GTN ^[1].

First-line: Single-agent chemotherapy

Regimen	Protocol	Mechanism	Notes
Methotrexate (MTX) + folinic acid (leucovorin) rescue	MTX 1 mg/kg IM on days 1, 3, 5, 7 alternating with folinic acid 0.1 mg/kg on days 2, 4, 6, 8 (8-day regimen). Repeated every 2 weeks	MTX is a folate antagonist — it inhibits dihydrofolate reductase (DHFR), blocking thymidylate synthesis → impairs DNA synthesis in rapidly dividing trophoblastic cells. "Metho-trexate" → "methyl" + Greek "trexa" (to destroy). Folinic acid (leucovorin) provides a "rescue" source of reduced folate to normal tissues, reducing toxicity	Preferred first-line agent in most centres. Well-tolerated. ~70–90% primary remission rate for low-risk GTN
Actinomycin D (dactinomycin)	1.25 mg/m² IV every 2 weeks (pulsed) or 5-day regimen 0.5 mg IV daily x5 every 2 weeks	Intercalates into DNA → inhibits RNA transcription → blocks protein synthesis. Particularly effective in rapidly dividing cells	Used as first-line alternative if MTX contraindicated (e.g., renal impairment, liver disease) or as second-line if MTX-resistant

Monitoring during single-agent chemotherapy:

Serum hCG measured before each cycle
Continue treatment until hCG normalises, then give 2–3 consolidation cycles beyond normalisation (to eliminate any residual microscopic disease)
If hCG plateaus or rises on one agent → switch to the other single agent
If resistant to both single agents → escalate to multi-agent regimen (EMA-CO)

Side effects of methotrexate:

Mucositis (stomatitis, oral ulcers) — most common dose-limiting toxicity
Myelosuppression (neutropenia, thrombocytopenia)
Hepatotoxicity
Nausea/vomiting
Rarely: pneumonitis, nephrotoxicity
Folinic acid rescue mitigates many of these effects

Why Consolidation Cycles?

Even after hCG becomes undetectable, there may be residual microscopic viable trophoblastic cells below the detection threshold of the hCG assay. Giving 2–3 additional cycles of chemotherapy after normalisation ensures these cells are eradicated, reducing relapse risk. Think of it as "mopping up" after the main battle.

First-line: Multi-agent chemotherapy — EMA-CO

Component	Day	Drug	Mechanism
EMA	Day 1	Etoposide + Methotrexate + Actinomycin D	Etoposide: topoisomerase II inhibitor → DNA strand breaks. MTX: DHFR inhibitor. ActD: DNA intercalator
	Day 2	Etoposide + folinic acid rescue
CO	Day 8	Cyclophosphamide + Vincristine (Oncovin)	Cyclophosphamide: alkylating agent → DNA crosslinking. Vincristine: vinca alkaloid → microtubule inhibitor → blocks mitosis
			Cycle repeats every 2 weeks (alternating EMA and CO)

Remission rate: ~85–95% for high-risk GTN
Continue until hCG normalises + 3 consolidation cycles
Monitor with weekly hCG, CBC before each cycle, LFT/RFT periodically

Why EMA-CO and not just single-agent? High-risk GTN has a larger tumour burden, more aggressive biology, and/or metastatic disease. A single drug cannot achieve adequate cell kill. Multiple drugs with different mechanisms of action:

Attack cells at different phases of the cell cycle
Reduce the probability of drug resistance (Goldie-Coldman hypothesis)
Achieve synergistic cell kill

Surgery is adjunctive to chemotherapy in most cases, not the primary treatment (because chemotherapy is so effective). However, surgery has specific roles:

Surgical Procedure	Indication	Rationale
Hysterectomy	(1) PSTT / ETT — primary treatment because these are less chemosensitive ^[1]. (2) Older women who have completed family with localised uterine disease. (3) Life-threatening uterine haemorrhage unresponsive to conservative measures. (4) Chemoresistant localised disease	PSTT arises from intermediate trophoblast (produces hPL, not much hCG) and responds poorly to standard chemotherapy. Hysterectomy achieves cure in localised disease
Thoracotomy / pulmonary metastasectomy	Isolated chemoresistant pulmonary nodule(s) after maximal chemotherapy	If a single residual pulmonary lesion remains after chemotherapy and hCG is normalising/normalised, surgical resection can be curative
Craniotomy	Acute intracranial haemorrhage from brain metastasis; chemoresistant brain metastasis	Emergency decompression for haemorrhagic brain mets. Also consider stereotactic radiosurgery
Hepatic resection	Isolated chemoresistant hepatic metastasis (rare)	Selected cases only
Uterine artery embolisation	Intractable uterine haemorrhage	Interventional radiology procedure to control bleeding when evacuation and uterotonics fail

Step 8: Special Considerations

Question	Answer
When can I conceive?	After completion of hCG surveillance (6 months of normal hCG for complete moles). No increased risk to future pregnancies thereafter
Does chemotherapy affect fertility?	Single-agent MTX has minimal impact on long-term fertility. EMA-CO may cause temporary amenorrhoea but fertility typically recovers. Premature menopause risk is low
Risk in future pregnancies	Risk of recurrent molar pregnancy: ~1–2% after one mole; ~15–20% after two moles. Recommend early USS in subsequent pregnancies + post-delivery hCG check to confirm normalisation
Monitoring after future delivery	Send placenta for histology; check hCG at 6 weeks post-delivery to confirm return to normal

Phase	Complete Mole	Partial Mole	GTN (Low Risk)	GTN (High Risk)	PSTT/ETT
Primary Tx	Suction evacuation	Suction evacuation	Single-agent chemo (MTX or ActD)	Multi-agent chemo (EMA-CO)	Hysterectomy
hCG monitoring	Weekly → monthly x6	Weekly → discharge at 56d if normal	Before each cycle + post-Tx surveillance	Before each cycle + post-Tx surveillance	Serial hCG + hPL
Consolidation	N/A	N/A	2–3 cycles after hCG normalisation	3 cycles after hCG normalisation	N/A
Contraception	Until surveillance complete	Until surveillance complete	During + 12 months after chemo	During + 12 months after chemo	Permanent (hysterectomy)
Prognosis	80–85% spontaneous resolution; 15–20% → GTN	> 95% spontaneous resolution; < 5% → GTN	> 98% cure rate	~85–95% cure rate	~90% if localised; worse if metastatic

High Yield Summary

Primary treatment of molar pregnancy:

Suction evacuation ^[1] — treatment of choice for ALL molar pregnancies.
Do NOT use oxytocic infusion before completion of evacuation (risk of trophoblastic embolisation) ^[1].
Anti-D prophylaxis for Rh-negative women ^[1].
Pre-op workup: hCG, CBP, type and screen; CXR and TFT if symptomatic ^[1].
Send ALL products for histopathology.

Post-evacuation hCG surveillance:

Complete mole: weekly until normal → monthly × 6 months.
Partial mole: weekly until normal; if normal within 56 days → discharge; otherwise monthly × 6 months.
Contraception throughout surveillance.

GTN treatment:

Single or multi-agent chemotherapy if GTN ^[1].
Low risk (score ≤ 6): single-agent MTX or actinomycin D. Switch agents if resistant. Escalate to EMA-CO if both fail.
High risk (score ≥ 7): EMA-CO first-line.
PSTT/ETT: hysterectomy (less chemosensitive).
Consolidation cycles after hCG normalisation.
GTN is one of the most curable malignancies — even metastatic disease has > 85% cure rate.

Do NOT forget:

Anti-thyroid drugs are NOT indicated for gestational thyrotoxicosis from molar pregnancy — use beta-blockers; resolves after evacuation ^[3].
Theca lutein cysts resolve spontaneously — watch for torsion.
Register with specialist GTD centre for centralised surveillance.

Active Recall - GTD Management

References

Complications of Gestational Trophoblastic Disease

A. Complications of the Molar Pregnancy Itself

Aspect	Details
Mechanism	Hydropic villi separate from the decidua, tearing open the maternal spiral arteries and venous sinuses → vaginal bleeding, which can be massive. The abnormal trophoblast fails to undergo normal controlled invasion → friable tissue prone to bleeding
Clinical features	Recurrent or heavy vaginal bleeding; anaemia (microcytic from chronic blood loss or normocytic from acute haemorrhage); haemodynamic instability in severe cases
Management	IV resuscitation, crossmatch and transfusion, urgent suction evacuation. Post-evacuation: oxytocin infusion (only after uterus is empty), uterine massage, ± uterine artery embolisation if intractable
Why important	Haemorrhage is the most common acute complication and the most common presenting symptom of molar pregnancy

This is the most important complication of hydatidiform mole and the entire reason for post-evacuation hCG surveillance.

Aspect	Details
Mechanism	Residual trophoblastic tissue after evacuation may persist and undergo malignant transformation. In complete moles, the entirely paternal genome with unopposed growth-promoting imprinted genes creates a milieu primed for malignancy. The abnormal trophoblast acquires the ability to invade the myometrium (invasive mole) or dedifferentiate completely (choriocarcinoma)
Risk	Complete mole: 15–20% risk of GTN. Partial mole: < 5% risk ^[1]
Detection	Serial hCG monitoring post-evacuation. Plateau or rise in hCG = GTN
Spectrum	Invasive mole (most common form of GTN), choriocarcinoma, and rarely PSTT/ETT
Why important	GTN can be life-threatening if undetected (haematogenous spread to lungs, brain, liver) but is highly curable with chemotherapy if caught early through hCG surveillance

Why Complete Moles Have Higher Risk of GTN

The entirely paternal genome in complete moles means:

Unopposed paternal growth-promoting genes (e.g., IGF2) drive trophoblastic proliferation
Absence of maternal tumour-suppressor imprinted genes (e.g., p57KIP2, H19) removes growth restraint
More extensive trophoblastic hyperplasia = larger "pool" of abnormal cells with malignant potential
Higher hCG levels correlate with larger tumour burden and more aggressive biological behaviour

In partial moles, the presence of maternal genes provides some growth restraint, and the trophoblastic hyperplasia is focal and mild → lower malignant potential.

Aspect	Details
Mechanism	Beta-subunit of hCG shares homology with beta-subunit of TSH → physiological rise of hCG stimulates TSH-R ^[3]. In molar pregnancy, hCG levels far exceed normal pregnancy → clinically significant thyrotoxicosis. Occurs in ~5–10% of complete moles
Clinical features	Tachycardia, tremor, heat intolerance, anxiety, weight loss, lid lag, warm moist skin. In severe cases: thyroid storm (high fever, delirium, cardiovascular collapse) — particularly dangerous during anaesthesia for evacuation
Management	Anti-thyroid drugs are NOT indicated ^[3]. Beta-blockers (propranolol) for symptom control. Thyrotoxicosis resolves when hCG falls after evacuation. Inform anaesthetist pre-operatively
Complications of thyrotoxicosis	Arrhythmia (atrial fibrillation), heart failure, thyroid storm. In Asian patients, theoretically could trigger thyrotoxic periodic paralysis (TPP) — though this is exceedingly rare in the context of molar pregnancy ^[3]

Aspect	Details
Mechanism	Abnormal trophoblast produces excessive anti-angiogenic factors (sFlt-1, soluble endoglin) → endothelial dysfunction → hypertension + proteinuria. In molar pregnancy, this occurs before 20 weeks (unlike typical pre-eclampsia which occurs after 20 weeks) because the grossly abnormal trophoblast generates these factors early
Clinical features	Hypertension ( > 140/90 mmHg), proteinuria, oedema. May progress to eclampsia (seizures), HELLP syndrome (haemolysis, elevated liver enzymes, low platelets)
Management	Antihypertensives, MgSO₄ for seizure prophylaxis, urgent evacuation of mole (definitive treatment — removes the source of anti-angiogenic factors). Pre-eclampsia resolves after evacuation
Exam point	Early onset pre-eclampsia is listed as a presenting feature of hydatidiform mole ^[1]. Hydatidiform mole is a predisposing factor for pre-eclampsia ^[4]

Aspect	Details
Mechanism	Very high hCG overstimulates ovarian follicles via LH/hCG receptor → multiple follicles undergo luteinisation → bilateral, multiloculated ovarian cysts (can exceed 10–20 cm diameter). More common with complete moles (higher hCG)
Complications	Ovarian torsion: the enlarged heavy ovary twists on its vascular pedicle → acute ischaemia → severe acute pelvic pain, nausea/vomiting, adnexal tenderness. Rupture: cyst rupture → haemoperitoneum → acute abdomen. Compression: very large cysts may compress adjacent structures (ureter, bowel)
Management	Usually conservative — cysts regress spontaneously as hCG falls post-evacuation (may take weeks to months). If torsion: urgent surgical detorsion ± cystectomy (preserve ovarian tissue for fertility). If rupture: laparoscopy/laparotomy for haemostasis
Key point	Do NOT remove the ovaries during evacuation even if they are massively enlarged — they will return to normal. Unnecessary oophorectomy destroys fertility

Aspect	Details
Mechanism	During or shortly after evacuation, fragments of trophoblastic tissue can embolise through the uterine venous sinuses → inferior vena cava → pulmonary vasculature → acute pulmonary embolism/respiratory distress. This is distinct from true metastatic disease — it is "deportation" of benign trophoblastic tissue, not haematogenous spread of malignant cells
Risk factors	Uterine size > 16 weeks, very high hCG ( > 100,000), use of oxytocin before completion of evacuation (uterine contractions force tissue into venous sinuses). This is why use of oxytocic infusion prior to completion of removal is not recommended ^[1]
Clinical features	Acute dyspnoea, tachypnoea, hypoxia, chest pain, tachycardia during or immediately after evacuation. CXR may show diffuse bilateral infiltrates ("trophoblastic storm")
Management	Supportive: oxygen, mechanical ventilation if severe, haemodynamic support. Usually self-limiting as the deported trophoblastic tissue is cleared by the immune system. Distinguish from actual pulmonary metastases (GTN) by clinical context and hCG trajectory

Aspect	Details
Mechanism	The large amount of abnormal trophoblastic tissue releases thromboplastin and tissue factor → activates the coagulation cascade → widespread microvascular thrombosis → consumption of clotting factors and platelets → paradoxical bleeding. More common with large moles, delayed evacuation, or concomitant haemorrhage/sepsis
Clinical features	Oozing from puncture sites, petechiae, prolonged bleeding from evacuation site, laboratory evidence (prolonged PT/APTT, low fibrinogen, elevated D-dimer, low platelets, schistocytes on blood film)
Management	Treat the underlying cause (evacuate the mole), replace consumed factors (FFP, cryoprecipitate, platelets), supportive care

Aspect	Details
Mechanism	Very high hCG stimulates the chemoreceptor trigger zone and vomiting centre (likely via serotonin pathways). The extremely high hCG in complete moles causes more severe nausea/vomiting than normal pregnancy
Complications	Dehydration, electrolyte imbalance (hypokalaemia, hyponatraemia), metabolic alkalosis (from loss of HCl in vomitus), malnutrition, Wernicke's encephalopathy (thiamine deficiency from prolonged vomiting), Mallory-Weiss tear (from forceful retching)
Management	IV fluids, electrolyte replacement, antiemetics (ondansetron, cyclizine), thiamine supplementation (give thiamine BEFORE dextrose to prevent Wernicke's encephalopathy), definitive treatment is evacuation of the mole
Exam point	Hyperemesis gravidarum can be life threatening and it is important to exclude other specific diagnoses ^[1]^[2]

B. Complications of Treatment

Complication	Mechanism	Management
Uterine perforation	The myometrium of a molar pregnancy uterus is often softened and thinned by trophoblastic invasion. The suction curette can perforate through the wall, especially at the fundus. Risk increased with large uterine size	Immediate recognition (sudden loss of resistance, excessive bleeding, fat/omentum at curette tip). Laparoscopy/laparotomy for repair. Conservative if small perforation without intra-abdominal haemorrhage
Incomplete evacuation	Molar tissue may be tenaciously adherent to the myometrium, especially in invasive moles. Some tissue may be missed, particularly in large moles	USS-guided evacuation to confirm completeness. Second evacuation may be considered but with caution (discuss with GTD centre). Do not confuse retained tissue with GTN — distinguish by hCG trajectory
Cervical laceration	Forced dilatation of an underprepared cervix	Cervical priming (misoprostol), careful technique. Suture repair if lacerated
Haemorrhage	Post-operative bleeding from the evacuation site, especially if large mole or coagulopathy	Oxytocin (after evacuation is complete), uterine massage, balloon tamponade, uterine artery embolisation if refractory
Infection (endometritis)	Post-procedural uterine infection from ascending organisms	Prophylactic antibiotics in some protocols; treat with broad-spectrum antibiotics if infection develops
Asherman's syndrome	Intrauterine adhesions from aggressive or repeated curettage → may impair future fertility	Minimise by using suction rather than sharp curettage; avoid excessive instrumentation. Treat with hysteroscopic adhesiolysis if occurs
Trophoblastic embolisation	As described above	Supportive care

Complication	Mechanism	Notes
Myelosuppression (neutropenia, anaemia, thrombocytopenia)	Chemotherapy targets rapidly dividing cells → bone marrow progenitor cells are also affected	Monitor CBC before each cycle. Dose-reduce or delay cycle if counts too low. G-CSF if severe neutropenia. Transfuse if needed
Mucositis / stomatitis	Methotrexate inhibits folate-dependent DNA synthesis → rapidly dividing oral mucosal epithelium is damaged	Folinic acid rescue reduces severity. Oral hygiene, mouthwashes, analgesia
Nausea and vomiting	Direct emetogenic effect of chemotherapy agents (especially cisplatin, cyclophosphamide in EMA-CO) on chemoreceptor trigger zone	Antiemetics: ondansetron, dexamethasone, aprepitant
Hepatotoxicity	Methotrexate causes direct hepatocellular damage; polyglutamated MTX accumulates in hepatocytes	Monitor LFT. Avoid alcohol. Dose-adjust if significant transaminase elevation
Nephrotoxicity	Methotrexate crystallises in renal tubules (especially in acidic urine); cisplatin causes direct tubular damage	Adequate hydration, urinary alkalinisation for high-dose MTX. Monitor RFT
Pulmonary toxicity	MTX pneumonitis (hypersensitivity); bleomycin lung fibrosis (if used in salvage regimens like BEP)	CXR monitoring. Stop offending agent if pneumonitis develops
Alopecia	Chemotherapy damages hair follicle cells (rapidly dividing)	Usually reversible after completion of chemotherapy
Peripheral neuropathy	Vincristine (in EMA-CO) disrupts microtubule function in peripheral nerves → axonal damage	Dose-limiting. Paraesthesiae in hands/feet, loss of deep tendon reflexes. May need dose reduction
Infertility	Alkylating agents (cyclophosphamide) can cause premature ovarian failure by destroying oocytes	Single-agent MTX has minimal impact on long-term fertility. EMA-CO: temporary amenorrhoea common; most women resume ovulation. Premature menopause is uncommon but possible, especially with prolonged multi-agent therapy
Secondary malignancy	Alkylating agents and etoposide carry a small long-term risk of secondary leukaemia (especially AML)	Risk is low but real; justify chemotherapy by the high cure rate of GTN

C. Complications of GTN (Malignant Transformation)

Choriocarcinoma is characterised by early haematogenous spread because trophoblastic cells are inherently designed to invade blood vessels (this is how normal placentation establishes uteroplacental circulation). The tumour essentially "hijacks" this normal invasive programme.

Metastatic Site	Frequency	Clinical Features	Mechanism
Lungs	~80% (most common)	Haemoptysis, dyspnoea, cough, chest pain. CXR: multiple bilateral "cannonball" lesions or diffuse infiltrates. Very rarely haemoptysis or seizures (metastasis) ^[1]	Trophoblastic cells enter uterine veins → IVC → pulmonary vasculature. Lung is the first capillary bed encountered
Vagina	~30%	Dark red/purple vascular nodules on vaginal walls. DO NOT BIOPSY — risk of torrential haemorrhage	Retrograde venous embolisation via uterine and vaginal venous plexuses
Brain	~10%	Headache, seizures, focal neurological deficits, altered consciousness. Often presents as haemorrhagic stroke because choriocarcinoma metastases are characteristically haemorrhagic. Very rarely seizures (metastasis) ^[1]	Haematogenous spread through systemic arterial circulation. Brain mets are haemorrhagic because trophoblastic tissue erodes vessel walls
Liver	~10%	Right upper quadrant pain, hepatomegaly. Risk of subcapsular haemorrhage → haemoperitoneum	Haematogenous spread
Kidney, spleen, GI tract	< 5% each	Variable presentations	Haematogenous spread

Why Are Choriocarcinoma Metastases So Haemorrhagic?

Normal syncytiotrophoblast function involves eroding into maternal blood vessels to establish the intervillous space for nutrient exchange. Choriocarcinoma retains this property — malignant trophoblast erodes into blood vessel walls at metastatic sites, creating haemorrhagic, necrotic masses. This is why brain metastases present as haemorrhagic stroke, and why biopsy of vaginal metastases is so dangerous.

Aspect	Details
Mechanism	Invasive mole or choriocarcinoma invades through the full thickness of the myometrium → perforation → haemoperitoneum
Clinical features	Acute abdominal pain, signs of peritonism, haemodynamic instability
Management	Emergency laparotomy/laparoscopy. May require hysterectomy if perforation is large and uncontrollable. Chemotherapy for the underlying GTN

D. Long-Term Sequelae

Aspect	Details
Risk	~1–2% after one molar pregnancy; ~15–20% after two consecutive molar pregnancies
Mechanism	Likely reflects an underlying predisposition to abnormal fertilisation events (defective oocytes, genetic factors). Biallelic mutations in NLRP7 or KHDC3L have been identified in women with recurrent hydatidiform moles — these cause familial recurrent hydatidiform mole (autosomal recessive), where all pregnancies are complete moles regardless of partner
Management	Early ultrasound in subsequent pregnancies to exclude molar pregnancy. Check hCG at 6–8 weeks post-delivery in all future pregnancies to confirm normalisation. Genetic counselling if recurrent

Issue	Details
Fertility after evacuation alone	Not significantly affected. Most women conceive normally after completion of hCG surveillance
Fertility after single-agent chemotherapy	Not significantly affected. MTX causes temporary anovulation but fertility returns
Fertility after multi-agent chemotherapy	Some risk of temporary amenorrhoea. Premature menopause rare but possible. Counsel about fertility preservation (oocyte/embryo cryopreservation) before starting treatment if prolonged multi-agent chemotherapy anticipated
Pregnancy outcomes after GTD	Reassuringly, studies show no increased risk of congenital anomalies, miscarriage, or preterm birth in pregnancies after GTD treatment (provided adequate washout period — typically advised to wait 6–12 months after chemotherapy)
Monitoring in subsequent pregnancies	Early USS to confirm normal IUP and exclude recurrent mole. Post-delivery hCG check at 6 weeks

Aspect	Details
Nature of distress	Loss of a desired pregnancy, anxiety about cancer diagnosis, prolonged hCG surveillance causing persistent anxiety, fear of recurrence, delay in future conception due to surveillance/treatment, grief and bereavement
Risk factors for poor psychological outcome	Pre-existing mental health disorders, lack of social support, longer duration of surveillance/treatment, need for chemotherapy, recurrent molar pregnancy
Management	Counselling, psychological support, patient support groups, clear communication about prognosis (emphasise the excellent cure rates). Consider referral to clinical psychology/psychiatry if significant anxiety or depression

Timeline	Complications
At presentation (pre-evacuation)	Haemorrhage, hyperemesis, thyrotoxicosis, pre-eclampsia, theca lutein cyst torsion/rupture, DIC, respiratory distress
During/immediately after evacuation	Uterine perforation, haemorrhage, trophoblastic embolisation, cervical laceration, anaesthetic complications (thyroid storm)
Post-evacuation (surveillance period)	Malignant transformation → GTN (15–20% for complete mole, < 5% for partial mole) ^[1]
During chemotherapy	Myelosuppression, mucositis, hepatotoxicity, nephrotoxicity, alopecia, nausea/vomiting, neuropathy
If GTN with metastases	Pulmonary: haemoptysis, respiratory failure. Brain: haemorrhagic stroke, seizures. Liver: haemoperitoneum. Vaginal: haemorrhage. Uterine perforation
Long-term	Recurrent molar pregnancy (~1–2%), reproductive consequences, psychological impact, secondary malignancy (rare)

High Yield Summary

Most important complications to remember:

Malignant transformation (GTN) — 15–20% for complete mole, < 5% for partial mole ^[1]. Detected by hCG surveillance. This is the entire rationale for post-evacuation monitoring.
Haemorrhage — most common acute complication. Can occur at presentation, during evacuation, or from metastatic sites (especially vaginal — DO NOT BIOPSY).
Trophoblastic embolisation — fragments embolise to lungs during evacuation. This is why oxytocin must NOT be given before completion of evacuation ^[1].
Thyrotoxicosis — from hCG cross-reacting with TSH-R. Anti-thyroid drugs are NOT indicated ^[3]. Resolves after evacuation.
Pre-eclampsia before 20 weeks — hallmark of molar pregnancy. Resolves after evacuation.
Metastatic complications of choriocarcinoma — haemoptysis or seizures (metastasis) ^[1]. Lung and brain metastases are characteristically haemorrhagic because trophoblast inherently erodes blood vessels.
Chemotherapy side effects — myelosuppression, mucositis, hepatotoxicity. Single-agent MTX is well-tolerated; EMA-CO has more toxicity.
Recurrence — ~1–2% after one mole. Early USS in future pregnancies.

Active Recall - GTD Complications

References

High Yield Summary

Definition: GTD is a spectrum of trophoblastic tumours ranging from benign (hydatidiform mole) to malignant (GTN: invasive mole, choriocarcinoma, PSTT, ETT).

Epidemiology: Higher in Asia/HK (~1:500–600). Bimodal age risk (< 20, > 35–40). Previous mole is a strong risk factor.

Complete vs Partial Mole:

Complete: 46,XX (all paternal), no fetus, diffuse hydropic villi, very high hCG, 15–20% GTN risk
Partial: 69,XXY (triploid), fetal tissue present, focal changes, lower hCG, < 5% GTN risk

Clinical Features: Vaginal bleeding (most common), uterus large-for-dates, theca lutein cysts, hyperemesis, thyrotoxicosis (hCG cross-reacts with TSH-R), pre-eclampsia before 20 weeks.

Pre-eclampsia before 20 weeks = think molar pregnancy.

Choriocarcinoma: Highly malignant, haematogenous spread (lung > brain > liver), very high hCG, NO villi histologically, but exquisitely chemosensitive.

hCG is the universal marker for diagnosis, monitoring, and surveillance.

Any reproductive-age woman with unexplained haemoptysis/neurological symptoms → check β-hCG.

High Yield Summary

Key DDx principles:

Molar pregnancy is an important DDx of threatened miscarriage — always consider it when there is PV bleeding + positive hCG + abnormal USS.
Partial mole mimics missed/incomplete miscarriage — histological examination of all evacuated products is essential.
Pre-eclampsia before 20 weeks = think molar pregnancy.
Any reproductive-age woman with unexplained haemoptysis or seizures → check β-hCG.
Persistently elevated hCG after any pregnancy event = GTN until proven otherwise (after excluding new pregnancy).
GTD requires tissue diagnosis; GTN does not — it is diagnosed by persistent hCG elevation after treated GTD.
Gestational thyrotoxicosis from molar pregnancy does NOT require antithyroid drugs — treat the mole.

High Yield Summary

Diagnosis of GTD (Molar Pregnancy):

Clinical suspicion (PV bleeding + very high hCG + abnormal USS) → suction evacuation → histopathology confirms diagnosis.
USS: "snowstorm" appearance, complex echogenic intrauterine mass containing many small cystic spaces ("clusters of grapes"), ± theca lutein cysts.
Pre-evacuation workup: hCG, CBP, type and screen. CXR and TFT if symptomatic.
Histopathology is the gold standard — always send evacuated products.
p57KIP2 immunostaining: negative in complete mole (no maternal DNA), positive in partial mole.

Diagnosis of GTN:

Does not require histological confirmation — diagnosed by persistent/rising hCG post-evacuation.
FIGO criteria: hCG plateau (4 values over 3 weeks) OR hCG rise (3 values over 2 weeks) OR hCG elevated > 6 months OR histological choriocarcinoma.
Staging: FIGO I–IV (anatomical) + WHO risk score (≤ 6 low risk, ≥ 7 high risk).

Don't forget:

Anti-D prophylaxis for Rh-negative women.
Histological examination of ALL products of conception — catches unsuspected partial moles.
Exclude new pregnancy before diagnosing GTN (USS!).

High Yield Summary

Primary treatment of molar pregnancy:

Suction evacuation — treatment of choice for ALL molar pregnancies.
Do NOT use oxytocic infusion before completion of evacuation (risk of trophoblastic embolisation).
Anti-D prophylaxis for Rh-negative women.
Pre-op workup: hCG, CBP, type and screen; CXR and TFT if symptomatic.
Send ALL products for histopathology.

Post-evacuation hCG surveillance:

Complete mole: weekly until normal → monthly × 6 months.
Partial mole: weekly until normal; if normal within 56 days → discharge; otherwise monthly × 6 months.
Contraception throughout surveillance.

GTN treatment:

Single or multi-agent chemotherapy if GTN.
Low risk (score ≤ 6): single-agent MTX or actinomycin D. Switch agents if resistant. Escalate to EMA-CO if both fail.
High risk (score ≥ 7): EMA-CO first-line.
PSTT/ETT: hysterectomy (less chemosensitive).
Consolidation cycles after hCG normalisation.
GTN is one of the most curable malignancies — even metastatic disease has > 85% cure rate.

Do NOT forget:

Anti-thyroid drugs are NOT indicated for gestational thyrotoxicosis from molar pregnancy — use beta-blockers; resolves after evacuation.
Theca lutein cysts resolve spontaneously — watch for torsion.
Register with specialist GTD centre for centralised surveillance.

High Yield Summary

Most important complications to remember:

Malignant transformation (GTN) — 15–20% for complete mole, < 5% for partial mole. Detected by hCG surveillance. This is the entire rationale for post-evacuation monitoring.
Haemorrhage — most common acute complication. Can occur at presentation, during evacuation, or from metastatic sites (especially vaginal — DO NOT BIOPSY).
Trophoblastic embolisation — fragments embolise to lungs during evacuation. This is why oxytocin must NOT be given before completion of evacuation.
Thyrotoxicosis — from hCG cross-reacting with TSH-R. Anti-thyroid drugs are NOT indicated. Resolves after evacuation.
Pre-eclampsia before 20 weeks — hallmark of molar pregnancy. Resolves after evacuation.
Metastatic complications of choriocarcinoma — haemoptysis or seizures (metastasis). Lung and brain metastases are characteristically haemorrhagic because trophoblast inherently erodes blood vessels.
Chemotherapy side effects — myelosuppression, mucositis, hepatotoxicity. Single-agent MTX is well-tolerated; EMA-CO has more toxicity.
Recurrence — ~1–2% after one mole. Early USS in future pregnancies.

Gestational Trophoblastic Disease

Definition

Epidemiology

Global Incidence

Demographics

Risk Factors

Anatomy and Function: The Trophoblast

Normal Trophoblast Biology

Why This Matters for GTD

hCG — The Master Marker

Aetiology and Pathophysiology

A. Hydatidiform Mole — The Premalignant Lesion

1. Complete Hydatidiform Mole (CHM)

2. Partial Hydatidiform Mole (PHM)

Summary Table: Complete vs Partial Mole

B. Gestational Trophoblastic Neoplasia (GTN) — The Malignant Spectrum

1. Invasive Mole (Chorioadenoma destruens)

2. Choriocarcinoma

3. Placental Site Trophoblastic Tumour (PSTT)

4. Epithelioid Trophoblastic Tumour (ETT)

Classification

FIGO Classification of GTD (2021, updated from 2000)

Clinicopathological Classification (Practical Approach)

FIGO Staging of GTN (for malignant disease)

WHO Prognostic Scoring System (Modified WHO/FIGO)

Clinical Features

A. Symptoms (with pathophysiological basis)

Hydatidiform Mole (the most common presentation of GTD)

Gestational Trophoblastic Neoplasia (Choriocarcinoma, Invasive Mole, PSTT)

B. Signs (with pathophysiological basis)

Pathophysiology — Integrated Summary

Why Does Pre-eclampsia Occur Early in Molar Pregnancy?

Why Are Theca Lutein Cysts Formed?

Special Considerations for Hong Kong

Active Recall - Gestational Trophoblastic Disease (Part 1)

References

Framing the Problem

A. Differential Diagnosis of First-Trimester Vaginal Bleeding (The Most Common Presentation)

B. Differential Diagnosis of Markedly Elevated hCG

C. Differential Diagnosis of Uterus Large for Dates

D. Differential Diagnosis of Pre-eclampsia Before 20 Weeks

E. Differential Diagnosis of Persistent Elevated hCG Post-Pregnancy (Suspecting GTN)

F. Differential Diagnosis of Metastatic GTN (Presenting with Distant Symptoms)

Pulmonary Metastases (Haemoptysis / Dyspnoea / CXR Abnormalities)

Neurological Symptoms (Headache / Seizures / Focal Deficits)

G. Differential Diagnosis of Hyperemesis with Thyrotoxicosis in Early Pregnancy

H. Differential Diagnosis of Theca Lutein Cysts / Bilateral Ovarian Enlargement

Summary: Approach to DDx by Clinical Scenario

Active Recall - GTD Differential Diagnosis

Overarching Diagnostic Principles

Diagnostic Criteria

A. Diagnosis of Hydatidiform Mole

B. FIGO Criteria for Diagnosis of GTN (Post-Molar GTN)

C. Diagnosis of GTN After Non-Molar Pregnancy

Diagnostic Algorithm

Investigation Modalities — Detailed Breakdown

1. Serum β-hCG (Quantitative)

2. Transvaginal Ultrasound (TVUS)

3. Histopathology of Evacuated Products

4. Pre-Evacuation Bloods

5. Investigations for Staging GTN (When GTN Is Diagnosed)

6. Anti-D Prophylaxis

Integrated Diagnostic Approach — Summary Algorithm

Special Diagnostic Scenarios

Diagnosing Partial Mole — The Diagnostic Challenge

Diagnosing GTN After Non-Molar Pregnancy

Distinguishing Gestational from Non-Gestational Choriocarcinoma

Key Findings — Summary Table

Active Recall - GTD Diagnosis

Overarching Management Principles

Master Management Algorithm

Step 1: Initial Stabilisation

Step 2: Suction Evacuation — The Primary Treatment

Procedure Details

What About Second Evacuation?

Hysterectomy as Primary Treatment

Step 3: Histopathological Examination

Step 4: Post-Evacuation hCG Surveillance

Surveillance Protocol (Based on RCOG Green-top Guideline No. 38, 2020 [1])

What Constitutes "Normal" hCG?