Hydatidiform Mole & Choriocarcinoma

The trophoblast is the embryonic precursor that forms the chorionic villi, the component of the placenta responsible for the exchange of oxygen and nutrients between the mother and fetus. Comprising two layers, the outer syncytiotrophoblast and inner cytotrophoblast, the trophoblast plays an essential role in pregnancy. The syncytiotrophoblast, characterized by its large, multinucleated cells, comes into direct contact with maternal blood and secretes hormones such as β-human chorionic gonadotropin (β-hCG) and human placental lactogen (HPL). The cytotrophoblast consists of mononuclear cells and forms the inner layer of the villi.

The most prevalent type of gestational trophoblastic disease is the hydatidiform mole, also known as ‘molar pregnancy.’ Risk factors for molar pregnancies include maternal age extremes (<15 or >35 years), a history of molar pregnancy, and a history of miscarriage.

Complete hydatidiform moles result in extremely high β-hCG levels, as β-hCG is primarily secreted by the syncytiotrophoblast. Complete moles are composed entirely of molar components and lack any fetal parts. The genetic material originates from an empty ovum fertilized by a normal haploid sperm, which duplicates to produce a 46XX zygote. The chorionic villi in complete moles are entirely abnormal—large, disordered, and edematous, resembling a ‘bunch of grapes.’ These abnormal villi lead to unique clinical presentations including early pregnancy vaginal bleeding, an enlarged uterus disproportionate to gestational age, and a ‘snowstorm’ pattern on ultrasound.

Complete moles can cause hyperemesis gravidarum—severe nausea and vomiting—due to the extremely high levels of β-hCG. Additionally, β-hCG shares a common alpha subunit with thyroid-stimulating hormone (TSH) and can can cause hyperthyroidism when significantly elevated. Other manifestations include bilateral theca-lutein cysts, which are multilocular ovarian cysts formed due to high β-hCG levels, as well as early-onset preeclampsia occurring before 20 weeks of gestational age, attributed to abnormal placentation.

Partial hydatidiform moles are triploid and contain fetal parts along with abnormal chorionic villi, and only slightly elevated β-hCG levels. These originate from a normal ovum fertilized by two normal sperm, resulting in a triploid zygote with chromosomes 69 XXX, XXY, or XYY. Clinically, partial moles present with a uterine size that is either normal or slightly small for gestational age and can also cause vaginal bleeding in early pregnancy. Partial moles express p57, a protein expressed by a maternal allele, which is absent in complete moles due to the lack of maternal DNA.

Complete and partial hydatidiform moles both carry the risk of malignant transformation into choriocarcinoma, though the risk is higher for complete moles. Choriocarcinoma is a gestational trophoblastic neoplasm that often presents insidiously until metastasis. Metastasis to the lungs is most common, resulting in a ‘cannonball’ metastases on CXR and hemoptysis. Choriocarcinoma should be suspected if β-hCG levels do not decrease following pregnancy termination, and can occur after any type of pregnancy—normal, preterm, terminated, ectopic, or molar—but is most commonly seen after a complete mole. Histologically, choriocarcinoma is characterized by abnormal proliferation of both cytotrophoblast and syncytiotrophoblast, but lacks chorionic villi. It manifests with rapidly rising β-hCG levels and may present with vaginal bleeding. The standard treatment for choriocarcinoma is methotrexate.