Gestational trophoblastic disease (GTD) refers to a spectrum of interrelated but histologically distinct tumors originating from the placenta (Table 10-1). These diseases are characterized by a reliable tumor marker, the β-subunit of human chorionic gonadotropin (β-hCG), and have varying tendencies toward local invasion and metastasis.
Gestational trophoblastic neoplasia (GTN) refers to a subset of GTD that develops malignant sequelae. These tumors require formal staging and typically respond very favorably to chemotherapy. GTN develops most commonly after a molar pregnancy, yet it may follow any gestation—including a normal term delivery. The prognosis is excellent with rare exceptions, and patients are routinely cured even in the presence of widespread disease. Moreover, fertility can be preserved in virtually all cases. The likelihood of a successful subsequent pregnancy outcome is equally bright (Vargas, 2014; Williams, 2014; Wong, 2014). Accordingly, although gestational trophoblastic disease is uncommon, it is so intimately related to pregnancy that clinicians practicing obstetrics should be familiar with its presentation, diagnosis, and management.
The incidence of gestational trophoblastic disease has remained fairly constant at approximately 1 to 2 per 1000 deliveries in North America and Europe (Drake, 2006; Loukovaara, 2005; Lybol, 2011). A similar frequency has been observed in South Africa and Turkey (Cakmak, 2014; Moodley, 2003). Although historically higher incidence rates have been reported in parts of Asia, this may have largely reflected discrepancies between population-based and hospital-based data collection (Kim, 2004). Improved socioeconomic conditions and dietary changes may also be partly responsible. That said, Hispanics and Native Americans living in the United States reportedly do have an increased incidence, as do certain population groups living in Southeast Asia (Drake, 2006; Smith, 2003; Tham, 2003). In at least one study, GTN was found to be more aggressive in Asian women (Maesta, 2015).
Of other risk factors, the upper and lower extremes of maternal age have classically been associated with a higher risk of developing GTD (Altman, 2008; Loukovaara, 2005). This association is much greater for complete moles, whereas the risk of partial molar pregnancy varies relatively little with age. Moreover, compared with the risk of those with maternal age of 15 years or younger, the degree of risk is much greater for women 45 years (1 percent) or older (17 percent at age 50) (Savage, 2010; Sebire, 2002a). One explanation may relate to ova from older women having higher rates of abnormal fertilization. Similarly, older paternal age has also been associated with elevated risk (La Vecchia, 1984; Parazzini, 1986).
Prior unsuccessful pregnancies also increase the risk of GTD. For example, previous spontaneous abortion at least doubles the risk of molar pregnancy (Parazzini, 1991). More significant, a personal history of GTD increases the risk of developing a molar gestation in a subsequent pregnancy by at least 10-fold. The frequency in a subsequent conception is approximately 1 percent, and most cases mirror the same type of mole (Garrett, 2008; Sebire, 2003). Furthermore, following two episodes of molar pregnancy, 23 percent of later conceptions result in another molar gestation (Berkowitz, 1998). For this reason, women with a prior history of GTD should undergo early first-trimester sonographic examination in subsequent pregnancies. Familial hydatidiform moles, however, are rare (Fallahian, 2003).
Oral contraceptive pill use is weakly associated with an increased risk of GTD in some case-control studies. Although use may roughly double the risk, which is dependent on the duration, the overall impact is slight and could be explained by confounding factors other than causality (Palmer, 1999; Parazzini, 2002). Moreover, women who used oral contraceptive pills during the cycle in which they became pregnant had a higher risk in some but not all studies (Costa, 2006; Palmer, 1999).
Certain other epidemiologic characteristics also appear to differ markedly between complete and partial moles. For example, vitamin A deficiency and low dietary intake of carotene are associated with an increased risk of only complete moles (Berkowitz, 1985, 1995; Parazzini, 1988). Partial moles have been linked to higher educational levels, smoking, irregular menstrual cycles, and obstetric histories in which only male infants are among the prior live births (Berkowitz, 1995; Parazzini, 1986).
Hydatidiform moles are categorized as either complete hydatidiform moles or partial hydatidiform moles (Table 10-2). These are abnormal pregnancies characterized histologically by aberrant changes within the placenta. Classically, the chorionic villi in these placentas show trophoblastic proliferation and edema of the villous stroma. This proliferation leads to the abnormally high β-hCG levels frequently found. Chromosomal abnormalities play an integral role in development of these tumors and also in differentiating between partial and complete types (Lage, 1992).
| Feature | Complete Mole | Partial Mole |
|---|---|---|
| Karyotype | 46,XX or 46,XY | 69,XXX or 69,XXY |
| Pathology | ||
| Fetus/embryo | Absent | Present |
| Villous edema | Diffuse | Focal |
| Trophoblastic proliferation | Can be marked | Focal and minimal |
| p57Kip2 immunostaining | Negative | Positive |
| Clinical presentation | ||
| Typical diagnosis | Molar gestation | Missed abortion |
| Postmolar malignant sequelae | 15% | 4–6% |
Classically, complete molar pregnancies are distinguished from partial moles by stark differences in their karyotype, histologic appearance, and clinical presentation. First, complete moles typically have a diploid karyotype, and 85 to 90 percent of cases are 46,XX (Fig. 10-1). The chromosomes, however, in these pregnancies are entirely of paternal origin. In a process termed androgenesis, the ovum is fertilized by a haploid sperm, which then duplicates its own chromosomes after meiosis (Fan, 2002; Kajii, 1977). The diploid set is described as diandric. Less commonly, dispermic fertilization of a single ovum can produce a 46,XY karyotype (Lawler, 1987).
FIGURE 10-1
A. A 46,XX complete mole may be formed if a 23,X-bearing haploid sperm penetrates a 23,X-containing haploid egg whose genes have become “inactive.” Paternal chromosomes then duplicate to create a 46,XX diploid chromosomal complement solely of paternal origin. Alternatively, this same type of inactivated egg can be fertilized independently by two sperm, either 23,X- or 23,Y-bearing, to create a 46,XX or 46,XY chromosomal complement, again of paternal origin only. B. Partial moles may be formed if two sperm, either 23,X- or 23,Y-bearing, both fertilize a 23,X-containing haploid egg, whose genes have not been inactivated. The resulting fertilized egg is triploid. Alternatively, a similar haploid egg may be fertilized by an unreduced diploid 46,XY sperm. (Reproduced with permission from Schorge JO: Gestational trophoblastic disease. In Hoffman BL, Schorge JO, Bradshaw KD, et al: Williams Gynecology, 3rd ed. New York, McGraw-Hill Education, 2016.)
Microscopically, complete moles display enlarged, edematous villi and abnormal trophoblastic proliferation that diffusely involve the entire placenta (Fig. 10-2). Grossly, these changes transform the chorionic villi into clusters of vesicles with variable dimensions (Fig. 10-3). No fetal tissue or amnion is produced. As a result, this mass of placental tissue completely fills the endometrial cavity.
FIGURE 10-2
Complete moles are characterized by diffuse placental villous edema, which produces villous enlargement and cistern formation in some villi (black asterisks). This striking villous edema is the etiology of the vesicle-like villous morphology noted grossly in complete moles (see Fig. 10-3). Complete moles also typically show trophoblastic proliferation (yellow asterisk), which may be focal or widespread. This leads to the excessive levels of beta human chorionic gonadotropin (β-hCG) often seen with molar pregnancy. (Used with permission from Dr. Erika Fong.)
FIGURE 10-3
Complete hydatidiform mole with grapelike fluid-filled clusters formed by swollen chorionic villi. (Used with permission from Dr. Sasha Andrews. Reproduced with permission from Schorge JO: Gestational trophoblastic disease. In Hoffman BL, Schorge JO, Bradshaw KD, et al: Williams Gynecology, 3rd ed. New York, McGraw-Hill Education, 2016.)
The classic presentation of a complete mole has changed over the past few decades. Previously, common signs were heavy vaginal bleeding, significant anemia, and uterine sizes well in excess of that predicted for their gestational age. Hyperemesis gravidarum and preeclampsia developed in approximately one quarter of women (Montz, 1988; Soto-Wright, 1995). Theca-lutein cysts arise from prolonged exposure to luteinizing hormone (LH) or β-hCG and range in size from 3 to 20 cm (Fig. 10-4). When theca-lutein cysts are present, and especially if bilateral, the risk of postmolar GTN is increased.
Today, many of these signs and symptoms are no longer seen (Mangili, 2008). As a result of β-hCG testing and sonography, the mean gestational age at evacuation of a complete mole currently is earlier and approximates 9 weeks. This compares with 12 weeks in the 1990s, and 16 to 17 weeks in the 1960s and 1970s (Drake, 2006; Soto-Wright, 1995; Sun, 2015). A large proportion of patients are asymptomatic at diagnosis (Joneborg, 2014). For the remainder, vaginal bleeding remains the most common presenting symptom, and β-hCG levels are often much higher than expected. One quarter of women have uterine size noticeably greater than dates, but the incidence of anemia is less than 10 percent. Hyperemesis gravidarum, preeclampsia, and symptomatic theca-lutein cysts are rarely observed (Lazarus, 1999; Mosher, 1998; Soto-Wright, 1995). Currently, these sequelae typically develop chiefly in patients without early prenatal care who present with a more advanced gestational age and markedly elevated serum β-hCG levels. Plasma thyroxine levels are often increased in women with complete moles, but clinical hyperthyroidism is infrequent. In these circumstances, serum free thyroxine levels are elevated as a consequence of the thyrotropin-like effect of β-hCG (Hershman, 2004).
These moles vary from complete hydatidiform moles by having a triploid karyotype, coexisting fetus, and less-pronounced clinical features. Partial moles have a triploid karyotype (69,XXX, 69,XXY, or less commonly 69,XYY) that is composed of one maternal and two paternal haploid sets of chromosomes (see Fig. 10-1) (Lawler, 1991). The coexisting fetus present with a partial mole is nonviable and typically has multiple malformations with abnormal growth (Jauniaux, 1999). The degree and extent of trophoblastic proliferation and villous edema is decreased compared with that of complete moles. Moreover, most partial moles contain fetal tissue and amnion, in addition to placental tissues.
Patients with partial moles typically present with signs and symptoms of an incomplete or missed abortion unless sonographic features suggesting placental abnormalities are detected beforehand. Many women will have vaginal bleeding, but because trophoblastic proliferation is slight and only focal, uterine enlargement in excess of gestational age is uncommon. Similarly, preeclampsia, theca-lutein cysts, hyperthyroidism, or other dramatic clinical features are rare (Stefos, 2002). Preevacuation β-hCG levels are typically much lower than those for complete moles and often do not exceed 100,000 mIU/mL. For this reason, partial moles are often not identified, or even suspected, until after a histologic review of a curettage specimen.
An important characteristic of complete molar pregnancy, less so for partial moles, is its tendency to produce β-hCG well in excess of that expected for the gestational age (Sasaki, 2003). Robust proliferation of trophoblasts in complete moles results in dramatically elevated β-hCG levels. When combined with transvaginal sonography, serum β-hCG measurement is so suggestive of the diagnosis that most complete moles are now diagnosed before 10 weeks’ gestation and prior to patient symptoms (Sun, 2015).
Although β-hCG levels are helpful, the diagnosis of complete molar pregnancy is more frequently confirmed sonographically because of the easily identifiable diffuse, swollen, and enlarged chorionic villi. Typically, complete moles show a complex intrauterine mass composed of multiple small echogenic spaces. Fetal tissues and amnionic sac are absent (Fig. 10-5) (Benson, 2000). In contrast, sonographic features of a partial molar pregnancy tend to be much more subtle, showing a thickened, hydropic placenta with concomitant fetus (Zhou, 2005).
Despite the utility of these tools, there are diagnostic limitations. Lazarus and colleagues (1999) reported that β-hCG levels in early molar pregnancies may not always be elevated in the first trimester. These same investigators also found that sonography could lead to a false-negative diagnosis if performed at very early gestational ages and before the chorionic villi have attained their characteristic vesicular pattern. Specifically, only 20 to 30 percent of patients may have sonographic evidence to indicate a partial mole (Johns, 2005; Lindholm, 1999; Sebire, 2001). Consequently, the preoperative diagnosis in very early gestations can be difficult and may not be entirely clear until after a comprehensive histologic review of the abortal specimen. In unclear cases with a live fetus and a desired pregnancy, fetal karyotyping to identify a triploid fetal chromosomal pattern can clarify the diagnosis and management.
In early pregnancy, it may also be histologically difficult to distinguish among complete moles, partial moles, and hydropic abortuses (Fukunaga, 2005; Mosher, 1998). Hydropic abortuses are pregnancies that were formed by the traditional union of one haploid egg and one haploid sperm but have failed. Their placentas display hydropic degeneration, in which villi are edematous and swollen, and thus mimic some villous features of hydatidiform moles. Most moles are readily identifiable histologically, but when histology is not definitive, ancillary testing may be required.
Histopathologic evaluation can be enhanced by immunohistochemical staining for p57 expression and by molecular genotyping. p57KIP2 is a nuclear protein whose gene is paternally imprinted and maternally expressed. This means that the gene product is produced only in tissues containing a maternal allele. Because complete moles contain only paternal genes, the p57KIP2 protein is absent in complete moles, and tissues do not pick up this stain (Merchant, 2005). In contrast, this nuclear protein is strongly expressed in normal placentas, in spontaneous pregnancy losses with hydropic degeneration, and in partial hydatidiform moles (Castrillon, 2001). Accordingly, immunostaining for p57KIP2 is an effective means to isolate complete mole from the diagnostic list.
For distinction of a partial mole from a nonmolar hydropic abortus, both of which express p57, molecular genotyping can be used. Molecular genotyping determines the parental source of polymorphic alleles. Thereby, it can distinguish among a diploid-diandric genome (complete mole), a triploid diandric-monogynic genome (partial mole), or biparental diploidy (nonmolar abortus).
Suction curettage is the preferred method of evacuation regardless of uterine size or type of molar pregnancy in patients who wish to remain fertile (American College of Obstetricians and Gynecologists, 2016; Tidy, 2000). Preoperative evaluation attempts to identify known potential complications such as preeclampsia, hyperthyroidism, anemia, and electrolyte depletion from hyperemesis (Lurain, 2010). Because molar tissue can infrequently be deported to the lung parenchyma, most recommend a preoperative chest radiograph. Gravidas should not be given prostanoids to ripen the cervix, since these drugs can induce uterine contractions and might increase the risk of trophoblastic embolization to the pulmonary vasculature (Seckl, 2010).
Because of the tremendous vascularity of these placentas, blood products should be available prior to the evacuation of larger moles, and adequate infusion lines established. At the beginning of the evacuation, the cervix is dilated to admit a 10- to 12-mm plastic suction curette. The technique mirrors that for other failed pregnancies, which is illustrated in Chapter 9 (p. 136). As aspiration of molar tissues ensues, intravenous oxytocin is given to help minimize bleeding. At our institution, 20 units of synthetic oxytocin are mixed with 1 L of crystalloid and infused at rates to achieve uterine contraction. In some cases, intraoperative sonography may be indicated to help reduce the risk of uterine perforation and assist in confirming complete evacuation. After suction evacuation, a thorough, gentle curettage is performed. If bleeding continues despite uterine evacuation and oxytocin infusion, other uterotonic agents, such as those described in Chapter 29 (p. 470), are given. In rare cases, pelvic arterial embolization or hysterectomy may be necessary (Tse, 2007).
It is invariable that some degree of trophoblastic deportation into the pelvic venous system takes place during molar evacuation (Hankins, 1987). With large molar pregnancies, the volume of tissue may be sufficient to produce clinically apparent respiratory insufficiency, pulmonary edema, or even embolism. In our earlier experiences with very large moles, these and their chest radiograph manifestations clear rapidly without specific treatment and do not cause persistent disease. However, fatalities have been described (Delmis, 2000).
Methods other than suction curettage may be considered for select cases. Hysterectomy with ovarian preservation may be preferable for women who have completed childbearing. Of women aged 40 and older, approximately a third will subsequently develop GTN, and hysterectomy markedly reduces this likelihood (Hanna, 2010). Theca-lutein ovarian cysts, if present, do not require intervention since they will regress after molar evacuation. In extreme cases, these may be aspirated, but oophorectomy is not performed except when torsion leads to extensive ovarian infarction (Mungan, 1996).
Following curettage, because of the possibility of partial mole and its attendant fetal tissue, Rh immune globulin should be given to nonsensitized Rh D-negative women. Rh immune globulin, however, may be withheld if the diagnosis of complete mole is absolute (Fung Kee, 2003).
With hydatidiform moles, no pathologic or clinical features at presentation consistently predict which patients will ultimately develop subsequent GTN. Because of the trophoblastic proliferation that characterizes these neoplasms, serial serum β-hCG levels following evacuation can be used to effectively monitor patients for GTN development. Therefore, postmolar surveillance with serial quantitative serum β-hCG levels is standard. Titers are monitored following uterine evacuation at least every 1 to 2 weeks until they become undetectable.
After achieving undetectable β-hCG levels, monthly levels are drawn during 6 months of surveillance (Sebire, 2007). However, poor compliance with prolonged monitoring has been reported—especially among indigent women and certain ethnic groups in the United States (Allen, 2003; Massad, 2000). A single blood sample demonstrating an undetectable level of β-hCG following molar evacuation is sufficient to exclude the possibility of progression to GTN in more than 99 percent of patients (Braga, 2016). Thus, after appropriate counseling, some women may elect to be discharged from routine surveillance once an undetectable value is achieved (Lavie, 2005; Wolfberg, 2004). One of the benefits of this strategy is that shortened surveillance could enable women to attempt a subsequent pregnancy sooner. However, GTN may still rarely develop after a β-hCG level has normalized, and this should be communicated to the patient (Kerkmeijer, 2007; Sebire, 2007).
Conception during the monitoring period elevates serum β-hCG levels and can hinder detection of postmolar progression to GTN (Allen, 2003). But other than complicating the monitoring schedule, these pregnancies fortunately are otherwise uneventful (Tuncer, 1999). To prevent difficulties with interpretation, women are encouraged to use effective contraception until achieving a β-hCG titer less than 5 mIU/mL or below the threshold of the individual assay. Oral contraceptive pills or injectable medroxyprogesterone acetate are preferred to less-effective barrier contraception (Braga, 2015; Costa, 2006; Massad, 2000). In contrast, intrauterine devices are not inserted until the β-hCG level is undetectable because of the risk of uterine perforation if an invasive mole is present.
The purpose of administering chemotherapy at the time of molar evacuation is mainly to prevent GTN development in high-risk patients who are unlikely to be compliant or for whom β-hCG surveillance is not available. In clinical practice, the correct classification of high-risk complete moles, however, is extremely difficult, as there is no universally accepted combination of risk factors that accurately predict GTN development. Regardless of how a high-risk complete mole is defined, few women will ultimately be assigned to this group. Due to the risks of increased drug resistance, delayed treatment of GTN, and toxic side effects with fatalities reported, this practice cannot currently be recommended (American College of Obstetricians and Gynecologists, 2016; Fu, 2012). As a result, prophylactic chemotherapy is generally only used in those countries with limited resources to reliably monitor patients after evacuation (Uberti, 2009).
The true incidence of ectopic gestational trophoblastic disease approximates 1.5 per 1 million births (Gillespie, 2004). More than 90 percent of suspected cases will actually reflect an overdiagnosis of florid extravillous trophoblastic proliferation in the fallopian tube (Burton, 2001; Sebire, 2005b). As with any ectopic pregnancy, initial management usually involves surgical removal of the conceptus and histopathologic evaluation.
Rarely, a twin pregnancy consists of a hydatidiform mole and a coexisting normal fetus. The estimated incidence is 1 per 20,000 to 100,000 pregnancies (Fig. 10-6). In those with continuing pregnancy, survival of the normal fetus is variable and dependent on complications that commonly develop from the molar component. The most worrisome is preeclampsia or hemorrhage, which frequently necessitate preterm delivery.
FIGURE 10-6
Placentas from a twin pregnancy composed of one normal twin and one complete mole. The complete mole (left) shows the characteristic vesicular structure. The placenta of the normal cotwin (right) appears grossly normal. Inset: A transverse section through the border between these two is shown. (Used with permission from Drs. April Bleich and Brian Levenson. Reproduced with permission from Schorge JO: Gestational trophoblastic disease. In Hoffman BL, Schorge JO, Bradshaw KD, et al: Williams Gynecology, 3rd ed. New York, McGraw-Hill Education, 2016.)
Sebire and associates (2002b) described the outcome of 77 twin pregnancies, each composed of a complete mole and a healthy cotwin. Of this group, 24 women chose to have an elective termination, and 53 continued their pregnancies. Twenty-three gestations spontaneously aborted at less than 24 weeks, two were terminated due to severe preeclampsia, and 28 pregnancies lasted at least 24 weeks—resulting in 20 live births. The authors demonstrated that coexisting complete moles and healthy cotwin pregnancies have a high risk of spontaneous abortion, but approximately 40 percent result in live births. The risk of progression to GTN was 16 percent in first-trimester terminations and not significantly higher (21 percent) in women who continued their pregnancies. Because the risk of malignancy is unchanged with advancement of gestational age, pregnancy continuation may be allowed, provided that severe maternal complications are controlled and fetal growth is normal. Fetal karyotyping to confirm a normal fetal chromosomal pattern is also recommended (Marcorelles, 2005; Matsui, 2000).
This term primarily encompasses pathologic entities that are characterized by aggressive invasion of the endometrium and myometrium by trophoblastic cells. Histologic categories include common tumors such as the invasive mole and gestational choriocarcinoma, as well as the rare placental-site trophoblastic tumor and epithelioid trophoblastic tumor. Although these histologic types have been characterized and described, in most cases of GTN, no tissue is available for pathologic study. Most cases of GTN are diagnosed based on elevated β-hCG levels and managed clinically.
GTN typically develops with or follows some form of pregnancy, but occasionally the antecedent gestation cannot be confirmed with certainty. Rarely, GTN develops after a live birth, miscarriage, or termination. The overwhelming majority of cases follow a hydatidiform mole. GTN develops after evacuation in 15 to 20 percent of complete moles (Golfier, 2007; Wolfberg, 2004). Despite the trend toward diagnosis at earlier gestational ages, this incidence has not decreased (Sun, 2015). Of those women who develop GTN, three quarters have locally invasive molar disease, and the remaining one quarter develops metastases. In contrast, GTN develops in only 4 to 6 percent of partial moles following evacuation (Feltmate, 2006; Lavie, 2005). Most are locally invasive, and metastatic choriocarcinoma is rare (Cheung, 2004; Seckl, 2000).
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