Gestational trophoblastic disease

The key idea: whose genes are in the conceptus

• Genomic imprinting means paternal and maternal copies of some genes are not equivalent. Paternal genes drive growth of the trophoblast (placenta); maternal genes are needed for the embryo.
• A conceptus with only paternal genes (androgenetic) grows abundant trophoblast and no embryo: the complete mole.
• A conceptus with two paternal sets and one maternal set (diandric triploid) grows some embryo plus abnormal trophoblast: the partial mole.
• A triploid with two maternal sets and one paternal set (digynic) is the opposite: a small, non-cystic placenta, a severely and asymmetrically growth-restricted fetus with a relatively large head, and very low hCG on screening. It arises from a diploid egg (a retained polar body after a meiotic error) fertilised by one sperm. It is triploid but not a mole; parental origin, not chromosome count, decides.
• p57 (KIP2) is paternally imprinted, so it is expressed only from the maternal allele. Complete mole cytotrophoblast and villous stroma are p57 negative; partial moles and ordinary hydropic miscarriages are p57 positive.

Complete versus partial mole

• A 46,XX result does not exclude a mole: most complete moles are 46,XX. A 46,XY complete mole suggests dispermic origin.
• The cortical (zona) reaction normally blocks a second sperm; its failure underlies dispermy.
• Risk factors: maternal age over 40 (ageing oocytes lose their chromosomes and become "empty") and teenage pregnancy, previous mole (about 1 in 100 recurrence), Asian ethnicity. Age raises complete mole risk far more than partial.

Clinical effects of very high hCG

• Uterus larger than dates, painless first-trimester bleeding, passage of grape-like vesicles.
• Ultrasound: a snowstorm (vesicular) pattern with no fetus in a complete mole; focal cystic placental spaces with a fetus in a partial mole.
• Hyperemesis gravidarum.
• Theca lutein cysts: hCG acts like LH and luteinises theca cells, giving bilateral multiloculated ovarian cysts that regress after evacuation.
• Hyperthyroidism: hCG shares its alpha subunit with TSH, LH and FSH, and its beta subunit resembles TSH enough that very high levels stimulate the TSH receptor directly. Free T4 rises and TSH is suppressed, but there is no goitre, eye disease or TSH-receptor antibody, and it settles within weeks of evacuation. Free T4 is measured because pregnancy raises TBG and so total T4.
• Pre-eclampsia before 20 weeks strongly suggests a mole. Abundant abnormal trophoblast releases anti-angiogenic factors such as sFlt-1 and soluble endoglin, giving hypertension, proteinuria, low platelets and raised urate. Never dismiss early hypertension as "too early for pre-eclampsia".
• Hook effect: enormous hCG saturates both capture and detection antibodies of a sandwich immunoassay separately, so a urine test may be falsely negative. Repeat on a diluted sample.

Management and follow-up

• Suction evacuation is the treatment for both moles; medical evacuation is avoided for complete moles (risk of trophoblast embolisation). Rhesus-negative women with a partial mole receive anti-D.
• Tissue goes for histology, because a mole cannot be confirmed clinically.
• Serial hCG is followed until normal, then for a period set by the regional centre. Pregnancy is deferred until follow-up ends, because a new pregnancy raises hCG and hides relapse.
• When to start treatment (FIGO criteria for gestational trophoblastic neoplasia): an hCG plateau over four values across three weeks, an hCG rise over three values across two weeks, histological choriocarcinoma, or metastases. Persistently raised hCG months after evacuation is also an indication.
• Risk is scored (FIGO/WHO prognostic score). Low risk (score 0–6) uses single-agent methotrexate with folinic acid rescue, or actinomycin D; high risk (7 or more) uses combination chemotherapy (EMA-CO). Cure rates approach 100% and 90% respectively.

Gestational trophoblastic neoplasia: three lesions

• The only feature that separates choriocarcinoma from an invasive mole on tissue is the absence of chorionic villi. Lung deposits occur with both, so metastases alone do not prove choriocarcinoma.

Choriocarcinoma in detail

• Antecedent pregnancy: about 50% complete mole, 25% miscarriage or ectopic, 25% normal term pregnancy. Abnormal bleeding months after any pregnancy needs an hCG.
• Spreads by blood, not lymph: lungs most often (cannonball shadows, haemoptysis), then vagina (purple-blue nodule), brain and liver. Brain and liver deposits mean high-risk disease.
• A vaginal metastasis is extremely vascular: do not biopsy; diagnose on hCG and imaging.
• Despite aggressive spread it is highly chemosensitive.
• Gestational choriocarcinoma contains paternal DNA (alleles absent from the patient's blood but matching her partner); non-gestational (ovarian germ cell) tumour contains only the patient's DNA and has a worse prognosis. Both make hCG, so genotyping, not hCG level, separates them.

Remember Complete mole: no mother's genes, no baby, p57 negative, highest hCG. Partial mole: triploid, fetal parts, p57 positive.

Exam trap Choriocarcinoma has NO villi; villi in the myometrium mean invasive mole, even if there are lung deposits.

Exam trap A low hCG does not exclude trophoblastic tumour: PSTT secretes little hCG and stains for hPL.

How FCPS asks about this

• Karyotype of a complete mole: 46,XX, all paternal, from an empty ovum and one duplicated sperm.
• Partial mole (fetal parts, scalloped villi): 69,XXY triploid from dispermy.
• Thyrotoxicosis with a mole: hCG stimulating the TSH receptor; settles after evacuation.
• Pre-eclampsia at 15 weeks with a large uterus: molar pregnancy.
• Indication to start treatment after a mole: plateauing or rising hCG, or choriocarcinoma on histology.
• Commonest route and site of choriocarcinoma spread: haematogenous, to the lungs.
• Feature separating choriocarcinoma from invasive mole: absence of chorionic villi.