Gestational trophoblastic disease is a malignant tumorous disease of the placental trophoblasts and can be classified into partial or complete molar pregnancy. Patients with gestational trophoblastic disease are usually identified early in the disease by the detection of a markedly elevated hCG level and characteristic ultrasound findings such as focal cysts in partial moles and extensive villi edema in complete moles. Complete evacuation of the molar pregnancy is indicated as first line therapy, while chemotherapy can be reserved for patients with recurrent disease or GTN. Future normal pregnancy is expected to be not affected by previous history of gestational trophoblastic disease.

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Hydatidiform mole (3) complete type

Image: “Hydatidiform mole (3) complete type.” License: CC BY-SA 3.0


Definition of Gestational Trophoblastic Disease

Gestational trophoblastic disease (GTD) includes hydatidiform, placental site trophoblastic tumor, choriocarcinoma and gestational trophoblastic neoplasia. These are conditions that result from abnormal placental trophoblastic growth and can be thought of as a spectrum of the same disease depending on aggressiveness and invasiveness.

Epidemiology of Gestational Trophoblastic Disease

The incidence of gestational trophoblastic disease or molar pregnancy is estimated to be 1 in 1,500 live births in the United States. GTD is more common after 40 years of age, with age being the single most significant risk factor for GTD.

On the other hand, most pregnancies occur before the age of 35 years, and accordingly, the majority of the cases identified with molar pregnancy are young women in their thirties.

Previous history of a molar pregnancy puts the patient at a 10-times higher risk of developing a recurrent GTD. For unknown reasons, decreased animal fat intake has been associated with a higher risk of GTD.

History of previous spontaneous abortions and infertility also increase the risk of GTD.

Pathophysiology of Gestational Trophoblastic Disease

Similar to other forms of cancer, p53 mutations have been also identified in the histopathological examination of GTD biopsies. Other oncogenes known to be associated with GTD include c-myc, bcl-2, Rb and p21.

intermediate trophoblast

Image: “Intermediate magnification micrograph of intermediate trophoblasts, in a case of a complete hydatidiform mole. H&E stain.” by Nephron – Own work. License: CC BY-SA 3.0

Additionally, over-expression of the epidermal growth factor receptor has been described in the pathogenesis of GTD. Matrix metalloproteinases (MMPs) which module cell-to-matrix interactions are also over-expressed in GTD.

The most common form of GTD is molar pregnancy which is further subdivided into complete or partial mole. This distinction is based on gross pathology, histopathology and karyotyping.

Complete molar pregnancy occurs when an ovum that is anuclear gets fertilized by either one sperm giving the solely paternal 46XX karyotype or by two sperms giving the less common 46XY karyotype. Other features of complete moral pregnancy are described in table 1.

On the other hand, partial molar pregnancies occur when a normal ovum is fertilized by two sperms. This results in a triploid karyotype. The other features of partial molar pregnancy are described in table 1.

Characteristic Complete Molar Pregnancy Partial Molar Pregnancy
Karyotype Parenteral 46XX in 87%, Parenteral 46XY in 13% Triploid: Two sperms with one ovum
Immunohistochemistry Absent p57 and PHLDA2 Present p57 and PHLDA2
Presence of fetal tissues Absent Present but highly malformed
Human chorionic gonadotropin level Markedly elevated Usually not elevated
Villous edema Severe Mild
Risk of Gestational Trophoblastic Neoplasia 28% of the cases 4% of the cases

Table 1: A comparison between complete and partial molar pregnancy, the two most common forms of gestational trophoblastic disease.

Clinical Presentation of Gestational Trophoblastic Disease

Patients with complete molar pregnancy usually are identified by ultrasonography and a markedly elevated human chorionic gonadotropin (hCG) level and not clinical semiology. If not identified early, patients can develop early preeclampsia, a uterus that is very large according to gestational age, hyperthyroidism due to the thyroid stimulating effects of hCG, and vaginal bleeding.

Patients with partial molar pregnancy usually present with a recent history of incomplete abortion. The diagnosis is usually confirmed by histologic examination of the curettage scrapings.

Diagnostic Work-up for Gestational Trophoblastic Disease

The single, and perhaps most important test to confirm the diagnosis of GTD is the assessment of human chorionic gonadotropin levels which are usually above what is expected for the gestational age. Additionally, the level of elevation in hCG can be also predictive of the outcome in patients with GTD.

hCG correlates well with the volume of the trophoblastic tissue, and larger tumors like what is found in complete molar pregnancy are expected to have a higher hCG level.

Once hCG is confirmed to be elevated, the next diagnostic step would be to perform an ultrasonography. In fact, the majority of the cases are nowadays identified by routine ultrasonography which is then followed by hCG assessment. But traditionally, hCG levels were first checked followed by ultrasound.

Complete moles have marked chorionic villi edema and swelling which is evident on ultrasound examination. Patients with focal cystic changes in the placenta and with a fetus that is highly malformed are likely to have partial molar pregnancy.

Histopathological examination and karyotyping provide more information about the type of the GTD and can affect the management plan and prognosis of the patient. Table 1 above describes the most commonly identified features of complete versus partial molar pregnancy including histopathological and karyotyping differences.

Treatment of Gestational Trophoblastic Disease

The treatment of choice for gestational trophoblastic disease is evacuation, but before that one has to exclude anemia, preeclampsia, hyperthyroidism and renal injury. These conditions can complicate a case with gestational trophoblastic disease and can alter the decision to go for evacuation at the given moment.

When future fertility is not a concern, hysterectomy is indicated which removes the risk of local recurrence. Unfortunately, hysterectomy does not prevent metastatic disease and early diagnosis is essential to prevent metastasis.

Suction curettage is indicated when fertility preservation is desired by the patient. After suction, sharp curettage where the uterine inner cavity is scrapped is indicated to ensure complete removal of the tumor.

Gestational trophoblastic disease is associated with highly vascular tumors and once evacuation is commenced, intense bleeding can happen. Eventually, bleeding ceases after complete evacuation of the molar pregnancy.

Furthermore, intravenous oxytocin is indicated to facilitate uterine contraction which lowers the risk of uterine bleeding even more. Women who are Rh-negative should receive Rh immune globulin.

Gestational trophoblastic neoplasia (GTN) is encountered in up to 28% of the patients with complete moles after evacuation. The prediction of the risk of developing GTN is dependent on an hCG level that is above 100,000, presence of theca lutein cysts in the ovaries, and severe uterine enlargement. Accordingly, after evacuation, patients should be followed with weekly hCG assessment until hCG is normalized in three consecutive measurements.

During follow-up, oral contraceptive pills are described to prevent pregnancy which can confuse the hCG results even more. Patients who do not have an improvement, decrease in their hCG for a while are candidates for chemotherapy.

Prophylactic actinomycin-D has been used in patients with complete molar pregnancy and was found to lower the risk of GTN by approximately two thirds.

An important concern for many women is the risk of future repeat molar pregnancies and normal pregnancy. The risk of future molar pregnancy is markedly increased after a single incident of a complete or partial molar pregnancy by 10 times, 1%. Fortunately, future normal pregnancy is expected after the development of GTD.

The risk of stillbirths, ectopic pregnancy, and premature deliveries is not markedly affected by previous history of GTD. Alive births after molar pregnancy range between 68% to 75% of total pregnancies.

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