Gestational Trophoblastic Disease
Lauren Cobb
Robert L. Giuntoli II
Gestational trophoblastic disease (GTD) is a heterogeneous group of interrelated but distinct neoplasms derived from the trophoblastic cells of the placenta. Lesions range from the premalignant complete and partial hydatidiform moles to the malignant invasive mole, choriocarcinoma, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT). Most women with GTD can be cured with their fertility preserved.
EPIDEMIOLOGY OF GESTATIONAL TROPHOBLASTIC DISEASE AND TYPES OF TROPHOBLASTIC CELLS
Incidence of GTD varies widely throughout the world, with the highest rates reported in Asia, Africa, and Latin America.
In the United States, hydatidiform moles are observed in 1 in 600 therapeutic abortions and 1 in 1,000 to 1,200 pregnancies. Approximately 20% of patients require treatment for malignant sequelae after evacuation of hydatidiform mole.
Gestational choriocarcinoma, by comparison, occurs in about 1 in 20,000 to 40,000 pregnancies.
Although much less common than hydatidiform mole or choriocarcinoma, PSTT and ETT can develop after any type of pregnancy.
Risk Factors for Gestational Trophoblastic Disease
Risks for GTD include:
Extremes of reproductive age: Women older than age 40 years have a 5.2-fold increased risk, whereas women younger than age 20 years have a 1.5-fold increased risk. Persistent GTD occurs more frequently in older patients.
History of previous hydatidiform mole: The risk of a subsequent hydatidiform mole rises by 10- to 20-fold. With two previous molar pregnancies, the risk multiplies by 40-fold. Conversely, term pregnancies and live births produce a protective effect.
Obstetric history of spontaneous abortions doubles the risk of molar gestation.
Race: Asians and Latin Americans demonstrate a higher risk of being diagnosed with GTD, whereas North Americans and Europeans have lower risk.
Low socioeconomic status and dietary factors such as vitamin A deficiency and low carotene intake may be associated, as well as cigarette smoking and oral contraceptive use. However, these associations are weak and not demonstrated consistently across all studies.
Types of Cells and Hormone Secretion
Trophoblasts are specialized cells of the early blastocyst that play a role in implantation of the embryo and will eventually form the placenta.
Three types of placental trophoblastic cells have been identified: cytotrophoblast, syncytiotrophoblast, and intermediate trophoblast.
Cytotrophoblasts comprise the inner layer of the trophoblast. They are primitive trophoblastic cells that are polygonal to oval in shape. They exhibit a single nucleus and clearly defined borders. Mitotic activity is evident, as these cells behave like stem cells. Implantation of the embryo is dependent on functioning cytotrophoblasts.
Cytotrophoblasts do not produce either human chorionic gonadotropin (hCG) or human placental lactogen (hPL).
Syncytiotrophoblasts comprise the outer layer of the trophoblast. They are welldifferentiated cells that interface with the maternal circulation and produce most of the placental hormones. No mitotic activity is evident.
Syncytiotrophoblasts demonstrate hCG production at 12 days of gestation. Secretion rapidly increases and peaks by 8 to 10 weeks, with a decline thereafter. By 40 weeks, hCG is present only focally in syncytiotrophoblasts. At 12 days, hPL is also present in syncytiotrophoblasts. Production continues to rise throughout pregnancy.
Intermediate trophoblasts show infiltrative growth into decidua, myometrium, and blood vessels and in a normal pregnancy, they anchor the placenta to maternal tissue. Intermediate trophoblasts characteristically invade the wall of large vascular channels until the wall is completely replaced. Intermediate trophoblasts are the predominant cells of PSTT and exaggerated placental sites.
As early as 12 days after conception, hCG and hPL are present focally in intermediate trophoblasts. However, at 6 weeks, hCG production disappears, whereas secretion of hPL peaks at 11 to 15 weeks’ gestation.
CLASSIFICATION OF GESTATIONAL TROPHOBLASTIC DISEASE
Gestational trophoblastic neoplasms are unique among human neoplastic disorders because they are genetically related to fetal tissues. The molecular pathogenesis of these tumors is an area of active research interest.
Hydatidiform Mole
In both partial and complete hydatidiform moles, the placental villi become edematous, forming small grape-like structures. Despite the cytogenetic, pathologic, and clinical differences in these disease processes (Table 49-1), the management of patients is similar.
Ultrasound establishes the diagnosis, identifying a mixed echogenic pattern as villi and blood clots replace normal placental tissue. Medical complications occur in approximately 25% of patients, being more prominent in those with uterine enlargement >14 to 16 weeks’ gestational size.
Complete Mole
Clinical findings
Presentation is between 11 and 25 weeks’ gestation, with an average gestational age of 16 weeks.
Vaginal bleeding is the most common presenting symptom, occurring in 97% of cases.
Uterine size is often greater than expected for gestational age; however, in approximately one third of patients, the uterus is small for gestational dates. Ovarian enlargement caused by theca lutein cysts occurs in 25% to 35% of cases.
TABLE 49-1 Comparison of Complete versus Partial Hydatidiform Mole
Complete
Partial
Karyotype
Most commonly 46,XX or 46,XY
Most commonly 69,XXX or 69,XXY
Uterine size
Large for gestational age
33%
10%
Small for gestational age
33%
65%
Diagnosis by ultrasonography
Common
Rare
Theca lutein cysts
25%-35%
Rare
β-hCG (mIU/mL)
>50,000
<50,000
Malignant potential
15%-25%
<5%
Metastatic disease
<5%
<1%
Adapted from Soper JT. Gestational trophoblastic disease. Obstet Gynecol 2006;108(1):176-187.
Levels of β-hCG are generally above 50,000 mIU/mL.
Severe hyperemesis and pregnancy-induced hypertension can develop in up to 25% of women, with hyperthyroidism in 7% of cases (hCG has weak thyroidstimulating activity secondary to some homology between the beta subunits of thyroid-stimulating hormone and hCG).
Ultrasonography often, but not always, shows a classic “snowstorm” appearance.
Pathologic features
Gross findings include massively enlarged, edematous villi that give the classic grape-like appearance to the placenta and lack embryonic tissue.
Microscopic examination shows hydropic swelling in the majority of villi, accompanied by a variable degree of trophoblastic proliferation. Complete moles have widespread, diffuse immunostaining for hCG; moderately diffuse staining for hPL; and focal staining for placental alkaline phosphatase (PLAP).
Chromosomal abnormalities
Most complete moles are diploid, with a 46,XX karyotype; rare examples of triploid or tetraploid moles have been reported.
In most cases, all of the chromosomal complements are paternally derived. The XX genotype typically results from duplication of a haploid sperm pronucleus in an empty ovum. Three percent to 13% of complete moles have a 46,XY chromosome complement, presumably as a result of dispermy, in which an empty ovum is fertilized by two sperm pronuclei.
Incomplete Mole
Clinical findings
Commonly, patients present between 9 and 34 weeks’ gestation.
These tumors are consistently associated with embryonic/fetal tissue.
Patients report abnormal uterine bleeding in about 75% of cases. A clinical diagnosis of a missed or spontaneous abortion is made in 91% of women with incomplete molar pregnancy.
Uterine size is generally small for gestational dates; excessive uterine size is observed in less than 10% of patients.
Serum hCG level is in the normal or low range for gestational age.
Preeclampsia occurs with lower incidence (2.5%) and presents much later with a partial mole than with a complete mole but can be equally severe.
Pathologic features
Gross findings reveal fetal tissue in nearly all instances, although its discovery may require careful examination because early fetal death normally takes place (i.e., 8 to 9 weeks’ gestational age).
Microscopic examination finds two populations of chorionic villi: one of normal size and the other grossly hydropic. Partial moles show focal to moderate immunostaining for hCG and diffuse staining for hPL and PLAP.
Chromosomal abnormalities
Karyotype of partial moles most frequently shows triploidy (i.e., 69 chromosomes), with two paternal and one maternal chromosome complement.
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