Williams Manual of Pregnancy Complications, 23 ed.

CHAPTER 44. Gestational Trophoblastic Disease

Gestational trophoblastic disease can be divided into hydatidiform mole and post-molar gestational trophoblastic neoplasia (Table 44-1). The latter is termed malignant gestational trophoblastic disease by the American College of Obstetricians and Gynecologists (Diagnosis and treatment of gestational trophoblastic disease. Obstet Gynecol 103: 1365, 2004). Effective classification and treatment schemas based principally on clinical findings and serum β-human chorionic gonadotropin (β-hCG) levels have been developed. When management algorithms are followed, most gestational tumors are eminently curable.

TABLE 44-1. Classification of Gestational Trophoblastic Disease



A hydatidiform mole develops in approximately 1 in 1000 pregnancies. Molar pregnancy is characterized histologically by varying degrees of trophoblastic proliferation and edema of villous stroma. Moles are usually in the uterine cavity; however, they may occasionally develop as ectopic pregnancies. The absence or presence of a fetus or embryonic elements has been used to classify them as complete and partial moles (Table 44-2).

TABLE 44-2. Features of Partial and Complete Hydatidiform Moles


Complete Hydatidiform Mole

Histologically, complete moles are typically characterized by hydropic degeneration and villous edema, absence of villous blood vessels, varying degrees of proliferation of the trophoblastic epithelium, and absence of embryonic elements such as a fetus and amnion. Grossly, the chorionic villi appear as a mass of clear vesicles that vary in size from barely visible to a few centimeters in diameter.

The chromosomal composition of complete hydatidiform moles is most often 46,XX, with both sets of chromosomes paternal in origin. This phenomenon is referred to as androgenesis. The risk of gestational trophoblastic neoplasia developing from a complete mole is approximately 20 percent.

Partial Hydatidiform Mole

Hydatidiform changes are focal and less advanced, and fetal tissues are typically seen in partial moles. As noted in Table 44-2, the karyotype typically is triploid—69,XXX, 69,XXY, or 69,XYY—with one maternal and two paternal haploid complements. The fetus of a partial mole typically has stigmata of trip-loidy, which includes multiple congenital malformations and growth restriction, and it is nonviable. The risk of choriocarcinoma arising from a partial mole is very low.

Twin Molar Pregnancy

A twin gestation composed of a diploid molar pregnancy and a normal pregnancy is not rare. Survival of the coexisting fetus is variable and depends on whether problems from the molar component such as preeclampsia or hemorrhage develop. The risk of developing subsequent gestational trophoblastic neoplasia appears to be greater than that of a partial mole but less than following a singleton complete mole.

Theca-lutein Cysts

In many cases of hydatidiform mole, the ovaries contain multiple theca-lutein cysts that are thought to result from overstimulation of lutein elements by large amounts of hCG. These cysts may vary from microscopic size to 10 cm or more in diameter, and the surfaces of the cysts are smooth and yellow. Some of these, especially very large cysts, may undergo torsion, infarction, and hemorrhage. Because the cysts regress after delivery, oophorectomy should not be performed unless the ovary is extensively infarcted.

Clinical Features of Molar Pregnancies

Risk factors associated with molar pregnancy are extremes of age, prior molar pregnancy, OCP use, prior miscarriage, smoking, various vitamin deficiencies, and increased paternal age. The clinical presentation of most molar pregnancies has changed over the past several decades because transvaginal ultrasound and quantitative serum hCG have led to earlier diagnosis. Uterine bleeding is almost universal and may vary from spotting to profuse hemorrhage. In about half of cases, uterine size clearly exceeds that expected. Typically no fetal heart action is detected.

Of special importance is the association of preeclampsia with molar pregnancies that persist into the second trimester. Indeed, because preeclampsia is rarely seen before 24 weeks, preeclampsia that develops before this time should suggest hydatidiform mole. Significant nausea and vomiting may occur. Due to the thyrotropin-like effect of hCG, plasma thyroxine levels in women with molar pregnancy are often elevated, but clinically apparent hyperthyroidism is unusual.

Diagnostic Features

Some women will present early with spontaneous passage of molar tissue before the mole is aborted spontaneously or removed by operation. The greatest diagnostic accuracy is obtained from the characteristic ultrasonic appearance of hydatidiform mole (Figure 44-1). The clinical and diagnostic features of a complete hydatidiform mole are summarized in Table 44-3.

TABLE 44-3. Clinical and Diagnostic Features of Hydatidiform Molar Pregnancy



FIGURE 44-1 Sagittal sonogram image of a 20-week-sized uterus with a complete hydatidiform mole (black arrows) and associated ovarian theca-lutein cysts (white arrows). (Reproduced, with permission, from Cunningham FG, Leveno KJ, Bloom SL, et al (eds). Williams Obstetrics. 23rd ed. New York, NY: McGraw-Hill; 2010.)


There are two important basic tenets for management of all molar pregnancies. The first is evacuation of the mole, and the second is regular follow-up to detect persistent trophoblastic disease. Most clinicians obtain a preoperative chest radiograph, but unless there is evidence of extrauterine disease, computed tomography or magnetic resonance imaging to evaluate the liver or brain is not done routinely.

Termination of Molar Pregnancy

Molar evacuation by suction curettage is usually the preferred treatment regardless of uterine size. For large moles, adequate anesthesia and blood-banking support is imperative. With a closed cervix, preoperative dilatation with an osmotic dilator may be helpful. The cervix is then further dilated to allow insertion of a 10- to 12-mm suction curette. After most of the molar tissue has been removed, oxytocin is given. After the myometrium has contracted, thorough but gentle curettage with a large sharp curette usually is performed. Intraoperative sonography helps ensure that the uterine cavity has been emptied.

If age and parity are such that no further pregnancies are desired, then hysterectomy may be preferred to suction curettage. Hysterectomy is a logical procedure in women aged 40 or over, because of the increased frequency with which malignant trophoblastic disease ensues in this age group.

Postevacuation Surveillance

A general method of follow-up is listed in Table 44-4. The prime objective is prompt detection of any change suggestive of malignancy. Management centers on serial measurement of serum hCG values to detect persistent trophoblastic disease. Even small amounts of trophoblastic tissue can be detected by the assay. These levels should progressively fall to an undetectable level as shown in Figure 44-2. An increase signifies trophoblastic proliferation that is most likely malignant unless the woman is again pregnant.

TABLE 44-4. Principles for Follow-up of Hydatidiform Molar Pregnancy



FIGURE 44-2 Schematic illustration of composite medians of β-subunit chorionic gonadotropin regression curves in women with a partial or complete hydatidiform mole. (Composite constructed using median data reported by Golfier F, Raudrant D, Frappart L, et al: First epidemiologic data from the French Trophoblastic Disease Reference Center. Am J Obstet Gynecol 196:172.e1, 2007; Schlaerth JB, Morrow CP, Kletzky OA, et al: Prognostic characteristics of serum human chorionic gonadotropin titer regression following molar pregnancy. Obstet Gynecol 58:478, 1981; Wolfberg AJ, Feltmate C, Goldstein DP, et al: Low risk of relapse after achieving undetectable hCG levels in women with complete molar pregnancy. Obstet Gynecol 104:551, 2004; Wolfberg AJ, Berkowitz RS, Goldstein DP, et al: Postevacuation hCG levels and risk of gestational trophoblastic neoplasia in women with complete molar pregnancy. Obstet Gynecol 106:548, 2005; Wolfberg AJ, Growdon WB, Feltmate CM, et al: Low risk of relapse after achieving undetectable hCG levels in women with partial molar pregnancy. Obstet Gynecol 108:393, 2006.)


Mortality from moles has been reduced to near zero because of prompt diagnosis. Variable amounts of trophoblast with or without villous stroma may escape from the uterus into the venous outflow at evacuation. The volume may be such as to produce signs and symptoms of acute pulmonary embolism and even death. Such fatalities are rare, and massive trophoblastic embolization with molar evacuation is infrequent.

Even though trophoblast usually embolizes to the lungs in volumes too small to produce overt blockade of the pulmonary vasculature, these can subsequently invade the pulmonary parenchyma to establish metastases that are evident radiographically. The lesions may consist of trophoblast alone (metastatic choriocarcinoma) or trophoblast with villous stroma (metastatic hydatidiform mole).


Also known as malignant gestational trophoblastic disease, this term refers to invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. The criteria for the diagnosis of postmolar gestational trophoblastic neoplasia are shown in Table 44-5.

TABLE 44-5. Criteria for Diagnosis of Gestational Trophoblastic Neoplasia or Postmolar Gestational Trophoblastic Disease



Gestational trophoblastic neoplasia almost always develops with or follows some sort of recognized pregnancy. Most follow a hydatidiform mole, but neoplasia may follow an abortion, normal pregnancy, or even an ectopic pregnancy. In most cases of gestational trophoblastic neoplasia, the diagnosis is made by persistent serum hCG (see preceding discussion).


In this extremely malignant form of trophoblastic tumor, the predisposition of normal trophoblast to invasive growth and erosion of blood vessels is greatly increased. The characteristic gross appearance is of a rapidly growing mass invading both myometrium and blood vessels, causing hemorrhage and necrosis. The tumor is dark red or purple and friable. Microscopically, trophoblasts penetrate the muscle and blood vessels in a plexiform or disorganized arrangement. An important diagnostic feature of choriocarcinoma, in contrast to hydatidiform mole or invasive mole, is absence of a villous pattern.

Metastases often develop early and are generally blood borne because of the affinity of trophoblast for blood vessels. The most common sites of metastasis are the lungs (over 75 percent) and the vagina (about 50 percent). Ovarian thecalutein cysts are identified in over a third of cases.

Invasive Mole

The distinguishing features of invasive mole are excessive trophoblastic overgrowth and extensive penetration by the trophoblastic elements, including whole villi, into the depths of the myometrium. Such moles are locally invasive, but generally lack the pronounced tendency to widespread metastasis characteristic of choriocarcinoma.

Placental Site Trophoblastic Tumor

Very rarely, a trophoblastic tumor arises from the placental implantation site following either a normal term pregnancy or abortion. Bleeding is the main presenting symptom.

Epithelioid Trophoblastic Tumor

This rare tumor develops from neoplastic transformation of chorionic-type intermediate trophoblast. The preceding pregnancy event may be remote or may not even be confirmed. Grossly, the tumor grows in a nodular fashion.

Clinical Features

Malignant gestational trophoblastic disease may follow hydatidiform mole, abortion, ectopic pregnancy, or normal pregnancy. The most common sign is irregular bleeding. The bleeding may be continuous or intermittent, with sudden and sometimes massive hemorrhage. Some women present with metastatic lesions to vagina and vulva. In others, the uterine tumor has disappeared, leaving only distant metastasis. If untreated, choriocarcinoma is invariably fatal.

Diagnostic Features

Unusually persistent bleeding after pregnancy of any type should prompt measurement of serum β-hCG levels and consideration for diagnostic curettage. Persistent or rising gonadotropin levels in the absence of pregnancy are indicative of trophoblastic neoplasia. Solitary or multiple nodules present on a chest x-ray are suggestive of metastasis and should prompt further imaging of the brain, lungs, liver, and pelvis via computed tomography or magnetic resonance imaging.


Single-agent chemotherapy is given for nonmetastatic or low-risk metastatic disease. Methotrexate and actinomycin D have been widely used with considerable success. Patients are classified as high risk based on age, type of antecedent pregnancy and interval from it, serum hCG concentration, size of tumor, site, number of metastases, and whether chemotherapy was previously given. Hysterectomy may offer the best therapeutic outcome for placental site and epithelioid trophoblastic tumors.


Women with nonmetastatic tumors or low-risk gestational trophoblastic neoplasia are cured virtually 100 percent of the time. Women with high-risk metastatic disease have appreciable mortality that depends on which factors were considered “high risk.” Remission rates have been reported to vary from about 45 to 65 percent. The three factors primarily responsible for this increased mortality are (1) extensive choriocarcinoma at initial diagnosis, (2) lack of appropriately aggressive initial treatment, and (3) failure of currently used chemotherapy.

Pregnancy After Trophoblastic Disease

Fertility is not impaired following trophoblastic disease, even if standard chemotherapy protocols are given for gestational trophoblastic neoplasia and outcomes are usually normal.

For further reading in Williams Obstetrics, 23rd ed.,

see Chapter 11, “Gestational Trophoblastic Disease.”