Gestational trophoblastic disease (Hydatidiform mole)

A hydatidiform mole (Latin hydatis, "drop of water" + mola, "mass") is an abnormal pregnancy in which the chorionic villi swell into grape-like cysts, producing a cystic placenta in place of (or alongside) a viable fetus. Gestational trophoblastic disease (GTD) is the spectrum from these benign molar pregnancies to malignant trophoblastic neoplasia:

A separate AR Mendelian disease: biallelic maternal variants in oocyte-restricted "maternal-effect" genes disrupt the female germline so that all the patient's pregnancies (regardless of partner) develop into complete moles, which are now biparental rather than androgenetic.

Counseling for familial recurrent HM:

• AR, recurrence ~25% per pregnancy in carrier couples; the additional issue is that the affected woman's all pregnancies tend to be molar, regardless of partner genotype, because of the maternal-effect mechanism
• Egg/oocyte donation is the reproductive option that allows a successful pregnancy; donor oocytes lack the defective maternal-effect proteins
• Testing NLRP7/KHDC3L in any woman with two or more consecutive molar pregnancies is recommended

Clinical presentation:

• Vaginal bleeding (most common; passage of "grape-like" vesicles is pathognomonic)
• Uterine size larger than dates (complete moles especially)
• Severe hyperemesis gravidarum (hCG mimics TSH at supraphysiologic levels → can also produce biochemical hyperthyroidism)
• Early-onset preeclampsia (<20 weeks gestation; outside the typical preeclampsia window, this is a major red flag for molar pregnancy)
• Theca lutein ovarian cysts (large bilateral; from hCG hyperstimulation)
• Markedly elevated β-hCG, especially in complete moles
• Respiratory distress from trophoblastic embolization (rare, after evacuation)

Imaging:

• Complete mole: classic "snowstorm" or "bunch of grapes" intrauterine pattern; no fetus; bilateral theca lutein cysts
• Partial mole: enlarged placenta with cystic spaces; fetus may be present (often with triploid features); growth restriction

• Quantitative β-hCG (markedly elevated in complete moles) plus pelvic ultrasound ("snowstorm" pattern, theca lutein cysts)
• Histopathology of evacuated tissue is definitive; p57 immunohistochemistry distinguishes complete (p57-negative, no maternal genome) from partial moles (p57-positive)
• Ploidy/genotyping resolves ambiguous cases (complete = diploid androgenetic; partial = triploid)
• Baseline chest imaging if persistent GTN is suspected (lungs are the most common metastatic site)

Evacuation:

• Suction dilation and curettage with sharp curettage
• Send tissue for pathology (with p57 IHC) and ploidy
• Anti-D immunoglobulin if Rh-negative
• Hysterectomy is an option for women not desiring future fertility (reduces but does not eliminate persistent GTN risk)

Post-molar surveillance, the critical step:

• Serial weekly β-hCG until undetectable for 3 consecutive weeks
• Then monthly β-hCG for 6 months (some protocols 12 months)
• Reliable contraception during the entire surveillance period (a new pregnancy raises hCG and obscures detection of persistent GTN)
• Plateau or rise in β-hCG → diagnose persistent GTN → chemotherapy (single-agent methotrexate for low-risk; EMA-CO for high-risk per FIGO scoring)

Future pregnancies:

• Recurrence risk after a single sporadic mole: ~1-2% (vs. background ~0.1%)
• Recurrence after two moles: ~15-20%; test NLRP7/KHDC3L
• First-trimester ultrasound recommended in subsequent pregnancies
• Place placenta after delivery for pathology