CHAPTER 20: Gestational Trophoblastic Disease

Gestational trophoblastic disease (GTD) is the term used to encompass a group of tumors typified by abnormal trophoblast proliferation. Trophoblast produces human chorionic gonadotropin (hCG), thus the measurement of this peptide hormone in serum is essential for GTD diagnosis, management, and surveillance. GTD histologically is divided into hydatidiform moles, which are characterized by the presence of villi, and into nonmolar trophoblastic malignant neoplasms, which lack villi.

Hydatidiform moles are excessively edematous immature placentas (Benirschke, 2012). These include the benign complete hydatidiform mole and partial hydatidiform mole and the malignant invasive mole. Invasive mole is deemed malignant due to its marked penetration into and destruction of the myometrium and its ability to metastasize.

Nonmolar trophoblastic neoplasms include choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. These three are differentiated by the type of trophoblast they contain.

The malignant forms of gestational trophoblastic disease are termed gestational trophoblastic neoplasia (GTN). These include invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. Other terms applied to GTN are malignant gestational trophoblastic disease and persistent gestational trophoblastic disease. These malignancies develop weeks or years following any type of pregnancy, but frequently follow a hydatidiform mole.

Each of the GTN malignancy types is histologically distinct and varies in its propensity to invade and metastasize. However, histological confirmation is typically not available. Instead, measurement of serum hCG levels combined with clinical findings— rather than a histological specimen—is used to diagnose and treat this malignancy. Accordingly, GTN is often identified and effectively treated as a group.

In the past, these metastatic tumors had a prohibitively high mortality rate. However, with chemotherapy, most tumors currently are highly curable. Early-stage GTN is typically cured with single-agent chemotherapy, whereas later-stage disease usually responds to combination chemotherapy (Ngan, 2015).

The classic histological findings of molar pregnancy include trophoblast proliferation and villi with stromal edema (Fig. 20-1). The degree of histological changes, karyotypic differences, and the absence or presence of embryonic elements are used to classify them as either complete or partial moles. These two also vary in their associated risks for developing medical comorbidities and postevacuation GTN. Of the two, GTN more frequently follows complete hydatidiform mole.

A complete mole has abnormal chorionic villi that grossly appear as a mass of clear vesicles. These vary in size and often hang in clusters from thin pedicles. In contrast, a partial molar pregnancy has focal and less advanced hydatidiform changes and contains some fetal tissue. Both forms of moles usually fill the uterine cavity, but they rarely may be tubal or other forms of ectopic pregnancy (Hassadia, 2012; Sebire, 2005).

Epidemiology and Risk Factors

An ethnic predisposition is seen with hydatidiform mole, which has increased prevalence in Asians, Hispanics, and American Indians (Drake, 2006; Lee, 2011; Smith, 2006). The incidence in the United States and Europe has been relatively constant at 1 to 2 per 1000 deliveries (Eysbouts, 2016; Lee, 2011).

The strongest risk factors are age and a prior hydatidiform mole. Women at both extremes of reproductive age are most vulnerable. Specifically, adolescents and women aged 36 to 40 years have a twofold risk, but those older than 40 have an almost tenfold risk (Altman, 2008; Sebire, 2002a). With a prior complete mole, the risk of another mole is 0.9 percent, and with a previous partial mole, the rate is 0.3 percent. After two prior complete moles, approximately 20 percent of women have a third mole (Eagles, 2015).

Pathogenesis

Molar pregnancies typically arise from chromosomally abnormal fertilizations Figure 20-2. Complete moles most often have a diploid chromosomal composition (Table 20-1). These usually are 46,XX and result from androgenesis, meaning both sets of chromosomes are paternal in origin. The chromosomes of the ovum are either absent or inactivated. The ovum is fertilized by a haploid sperm, which then duplicates its own chromosomes after meiosis. Less commonly, the chromosomal pattern may be 46,XY or 46,XX and due to fertilization by two sperm, that is, dispermic fertilization or dispermy (Lawler, 1991; Lipata, 2010).

Partial moles usually have a triploid karyotype—69,XXX, 69,XXY—or much less commonly, 69,XYY. These are each composed of two paternal haploid sets of chromosomes contributed by dispermy and one maternal haploid set (see Fig. 20-2B). Less frequently, a similar haploid egg may be fertilized by an unreduced diploid 46,XY sperm. These triploid zygotes result in some embryonic development, however, it ultimately is a lethal fetal condition (Joergensen, 2014; Lakovschek, 2011). Fetuses that reach advanced ages have severe growth restriction, multiple congenital anomalies, or both.

Twin Pregnancy

Rarely, in some twin pregnancies, one chromosomally normal fetus is paired with a complete diploid molar pregnancy. Importantly, these cases must be distinguished from a single partial molar pregnancy with its associated abnormal fetus. Amniocentesis and fetal karyotyping aid confirmation.

Several unique pregnancy problems complicate such twin pregnancies. And, many women may choose to terminate the gestation, if diagnosed early. In those with continuing pregnancy, survival of the normal fetus varies and depends on associated comorbidity from the molar component. The most worrisome are preeclampsia or hemorrhage, which frequently necessitate preterm delivery. Wee and Jauniaux (2005) reviewed outcomes in 174 women, of whom 82 chose termination. Of the remaining 92 pregnancies, 42 percent either miscarried or had a perinatal death; approximately 60 percent delivered preterm; and only 40 percent delivered at term.

Another concern for those continuing their pregnancy is the risk for developing subsequent GTN. However, most data indicate no significant difference between women who continue or terminate their pregnancy (Massardier, 2009; Sebire, 2002b). Postdelivery surveillance is conducted as for any molar pregnancy (Gestational Trophoblastic Neoplasia).

Clinical Findings

The presentation of women with a molar pregnancy has changed remarkably over the past several decades because prenatal care is sought much earlier and because sonography is virtually universal. Typically, 1 to 2 months of amenorrhea precede the diagnosis. For example, in 194 women with a complete mole, evacuation was completed at a median gestational age of 9 weeks and at 12 weeks for 172 patients with a partial mole (Sun, 2015b). As a result, most molar pregnancies are detected before complications ensue (Kerkmeijer, 2009; Mangili, 2008).

As gestation advances, symptoms tend to be more pronounced with complete compared with partial moles (Niemann, 2007). Untreated molar pregnancies will almost always cause uterine bleeding that varies from spotting to profuse hemorrhage. Bleeding may presage spontaneous molar abortion, but more often, it follows an intermittent course for weeks to months. In more advanced moles with considerable concealed uterine hemorrhage, moderate iron-deficiency anemia develops. Nausea and vomiting may be significant. Of physical findings, many women have uterine growth that is more rapid than expected, and the enlarged uterus is comparatively softer. Fetal heart motion is absent with complete moles. The ovaries can be fuller and cystic from multiple theca-lutein cysts (Fig. 20-3). These are more common with a complete mole and likely result from ovarian overstimulation by excessive hCG levels. Because theca-lutein cysts regress following pregnancy evacuation, expectant management is preferred. Occasionally a larger cyst may undergo torsion, infarction, and hemorrhage. However, oophorectomy is not performed unless extensive infarction persists after untwisting.

The thyrotropin-like effects of hCG frequently cause serum free thyroxine (fT₄) levels to be elevated and thyroid-stimulating hormone (TSH) levels to be decreased. Despite this, clinically apparent thyrotoxicosis is unusual and in our experience can be mimicked by bleeding and sepsis from infected products. Moreover, the serum free T₄ levels rapidly normalize after uterine evacuation. Despite this, cases of presumed “thyroid storm” have been reported (Kofinas, 2015).

Severe preeclampsia and eclampsia are relatively common with advanced molar pregnancies. However, these are seldom seen today because of early diagnosis and evacuation. An exception is the case of a normal fetus coexisting with a complete mole, described earlier. In continuing twin gestations, severe preeclampsia frequently mandates preterm delivery.

Diagnosis

Serum β-HCG Measurements

Most women initially have irregular bleeding that almost always prompts pregnancy testing and sonography. Some women will present with spontaneous passage of molar tissue.

With a complete molar pregnancy, serum β-hCG levels are commonly elevated above those expected for gestational age. With more advanced moles, values in the millions are not unusual. Importantly, these high values can lead to erroneous false-negative urine pregnancy test results. Termed a “hook effect,” excessive β-hCG hormone levels oversaturate the assay’s targeting antibody and create a falsely low reading (Cormano, 2016). In these cases, serum β-hCG determinations with or without sample dilution will clarify the conundrum. With a partial mole, β-hCG levels may also be significantly elevated, but more commonly concentrations fall into ranges expected for gestational age.

Sonography

Although this is the mainstay of trophoblastic disease diagnosis, not all cases are confirmed initially. Sonographically, a complete mole appears as an echogenic uterine mass with numerous anechoic cystic spaces but without a fetus or amnionic sac. The appearance is often described as a “snowstorm” (Fig. 20-4). A partial mole has features that include a thickened, multicystic placenta along with a fetus or at least fetal tissue. However, in early pregnancy, these sonographic characteristics are seen in fewer than half of hydatidiform moles. In the largest series of more than 1000 patients with molar pregnancy, the reported sensitivity and specificity of sonography were 44 and 74 percent, respectively (Fowler, 2006). The most common mimics are incomplete or missed abortion. Occasionally, molar pregnancy may be confused for a multifetal pregnancy or a uterine leiomyoma with cystic degeneration.

Pathology

Surveillance for subsequent neoplasia following molar pregnancy is crucial. Thus, moles must be distinguished from other types of pregnancy failure that have hydropic placental degeneration, which can mimic molar villous changes. Some distinguishing histological characteristics are shown in Table 20-1.

In pregnancies before 10 weeks, classic molar changes may not be apparent because villi may not be enlarged and molar stroma may not yet be edematous and avascular. Histopathologic evaluation can be enhanced by immunohistochemical staining for p57 expression and by molecular genotyping (Banet, 2014). p57^KIP2 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 p57^KIP2 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 p57^KIP2 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 alleles. Thereby, it can distinguish among a diploid diandric genome (complete mole), a triploid diandric-monogynic genome (partial mole), or biparental diploidy (nonmolar abortus).

Management

Maternal deaths from molar pregnancies are rare because of early diagnosis, timely evacuation, and vigilant postevacuation surveillance for GTN. Preoperative evaluation attempts to identify known potential complications such as preeclampsia, hyperthyroidism, anemia, electrolyte depletions from hyperemesis, and metastatic disease (Table 20-2) (Lurain, 2010). Most recommend chest radiography, whereas computed tomography (CT) and magnetic resonance (MR) imaging are not routinely done unless a chest radiograph shows lung lesions or unless other extrauterine disease is suspected.

Molar Pregnancy Termination

Regardless of uterine size, molar evacuation by suction curettage is usually the preferred treatment. Preoperative cervical dilatation with an osmotic dilator is recommended if the cervix is minimally dilated. Intraoperative bleeding can be greater with molar pregnancy than with a comparably sized uterus containing nonmolar products. Thus with large moles, adequate anesthesia, sufficient intravenous access, and blood-banking support is imperative. The cervix is mechanically dilated to preferably allow insertion of a larger suction curette. Depending on uterine size, a 10- to 14-mm diameter is typical. As evacuation is begun, oxytocin is infused to limit bleeding. Intraoperative sonography is often recommended to help ensure complete uterine cavity emptying. When the myometrium has contracted, a thorough but gentle curettage with a sharp large-loop Sims curette is performed. If bleeding continues despite uterine evacuation and oxytocin infusion, other uterotonic agents are given (see Table 20-2). In rare cases, pelvic arterial embolization or hysterectomy may be necessary (Tse, 2007). Profuse hemorrhage and surgical methods that may be useful for its management are discussed in Chapter 41 (General Considerations).

Some volume of trophoblast is deported into the pelvic venous system during molar evacuation (Hankins, 1987). With large moles, the amount of tissue may be sufficient to produce clinically apparent respiratory insufficiency, pulmonary edema, or even embolism. In our earlier experiences with substantial moles, these and their chest radiographic manifestations clear rapidly without specific treatment. However, fatalities have been described (Delmis, 2000). Because of deportation, there is concern that trophoblastic tissue will thrive within the lung parenchyma to cause persistent disease or even overt malignancy. Fortunately, no evidence suggests that this is a major problem.

Following curettage, anti-D immunoglobulin (Rhogam) is given to Rh D-negative women because fetal tissues with a partial mole may include red cells with D-antigen (Chap. 15, Prevention of Anti-D Alloimmunization). Those with suspected complete mole are similarly treated because a definitive diagnosis of complete versus partial mole may not be confirmed until histological evaluation of the evacuated products.

Following evacuation, the long-term prognosis for women with a hydatidiform mole is not improved with prophylactic chemotherapy. Moreover, chemotherapy toxicity—including death—may be significant, and thus it is not recommended routinely (Gueye, 2014; Wang, 2017).

Methods other than suction curettage can be considered for select cases. Hysterectomy with ovarian preservation may be preferable for women with complete moles who have finished childbearing. Of women aged 40 to 49 years, 30 to 50 percent will subsequently develop GTN, and hysterectomy markedly reduces this likelihood (Bandy, 1984; Elias, 2010, 2012). Theca-lutein cysts seen at the time of hysterectomy do not require removal, and they spontaneously regress following molar termination. Labor induction or hysterotomy is seldom used for molar evacuation in the United States. Both will likely increase blood loss and theoretically may increase the incidence of persistent trophoblastic disease (American College of Obstetricians and Gynecologists, 2016; Tidy, 2000).

Postevacuation Surveillance

Close biochemical surveillance for persistent gestational neoplasia follows each hydatidiform mole evacuation. This monitoring is by serial measurement of serum β-hCG to detect persistent or renewed trophoblastic proliferation. As a glycoprotein, hCG shows structural heterogeneity and exists in different isoforms. Thus for surveillance, an hCG assay that can detect all forms of hCG should be used (Harvey, 2010; Ngan, 2015). These are different from those used for routine pregnancy testing (de Medeiros, 2009). The initial β-hCG level is obtained within 48 hours after evacuation. This serves as the baseline, which is compared with β-hCG quantification done thereafter every 1 to 2 weeks until levels progressively decline to become undetectable.

The median time for such resolution is 7 weeks for partial moles and 9 weeks for complete moles. Once β-hCG is undetectable, this is confirmed with monthly determinations for another 6 months (Lurain, 2010; Sebire, 2007). Concurrently, reliable contraception is imperative to avoid confusion caused by rising β-hCG levels from a new pregnancy. Most recommend combination hormonal contraception, injectable depot medroxyprogesterone acetate, or progestin implant (Dantas, 2017). The latter two are particularly useful if poor patient compliance is anticipated. Intrauterine devices are not used until β-hCG levels are undetectable because of the risk of uterine perforation if there is an invasive mole. Although not recommended, if a woman conceives during surveillance, live-birth rates and risk for congenital anomalies appear to mirror the general population (Tuncer, 1999a,b). After these 6 months, monitoring is discontinued and pregnancy allowed.

Importantly, during β-hCG level surveillance, either increasing or persistently plateaued levels mandate evaluation for trophoblastic neoplasia. If the woman has not become pregnant, then these levels signify increasing trophoblastic proliferation that is most likely malignant. Several factors predispose a patient to trophoblastic neoplasia following molar evacuation. Most important, complete moles have a 15 to 20 percent incidence of malignant sequelae, compared with 1 to 5 percent following partial moles. Surprisingly, with much earlier recognition and evacuation of molar pregnancies, the risk for neoplasia has not been lowered (Schorge, 2000; Sun, 2015a). Other risk factors are older maternal age, β-hCG levels >100,000 mIU/mL, uterine size that is large for gestational age, theca-lutein cysts >6 cm, and slow decline in β-hCG levels (Berkowitz, 2009; Kang, 2012; Wolfberg, 2005).

This group includes invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. These tumors almost always develop with or after some form of recognized pregnancy. Half follow hydatidiform mole, a fourth follow miscarriage or tubal pregnancy, and another fourth develop after a preterm or term pregnancy (Goldstein, 2012). Although these four tumor types are histologically distinct, they are usually diagnosed solely by persistently elevated serum β-hCG levels because tissue is infrequently available for study. Criteria to diagnose postmolar GTN are shown in Table 20-3.

Clinical Findings

These placental tumors are characterized clinically by their aggressive invasion into the myometrium and propensity to metastasize. The most common finding with GTN is irregular bleeding associated with uterine subinvolution. The bleeding may be continuous or intermittent, with sudden and sometimes massive hemorrhage. Myometrial perforation from trophoblastic growth may cause intraperitoneal hemorrhage. In some women, lower genital tract metastases are evident, whereas in others only distant metastases are found with no trace of uterine tumor.

Diagnosis, Staging, and Prognostic Scoring

Consideration for the possibility of GTN is the most important factor in its recognition. Unusually persistent bleeding after any type of pregnancy should prompt measurement of serum β-hCG levels and consideration for diagnostic curettage if levels are elevated. Uterine size is assessed along with careful examination for lower genital tract metastases, which usually appear as bluish vascular masses (Cagayan, 2010). Tissue diagnosis is unnecessary, thus biopsy is not required and may cause significant bleeding.

Once the diagnosis is verified, in addition to a baseline serum β-hCG level and hemogram, a search for local disease and metastases includes tests of liver and renal function, transvaginal sonography, chest CT scan or radiograph, and brain and abdominopelvic CT scan or MR imaging. Less commonly, positron-emission tomographic (PET) scanning and cerebrospinal fluid β-hCG level determination are used to identify metastases (Lurain, 2011).

GTN is staged clinically using the system of the International Federation of Gynecology and Obstetrics (FIGO) (2009). This includes a modification of the World Health Organization (WHO) (1983) prognostic index score, with which scores of 0 to 4 are given for each of the categories shown in Table 20-4. Women with WHO scores of 0 to 6 are considered to have low-risk disease, whereas those with a score ≥7 are considered in the high-risk group.

Histological Classification

Again, it is stressed that the diagnosis of trophoblastic neoplasias is usually made by persistently elevated serum β-hCG levels without confirmation by tissue study. Clinical staging is assigned without regard to histological findings, even if available. Still, there are distinct histological types, described next.

Invasive Mole

These are the most common trophoblastic neoplasms that follow hydatidiform moles, and almost all invasive moles arise from partial or complete moles. Previously known as chorioadenoma destruens, invasive mole is characterized by extensive tissue invasion by trophoblast and whole villi. There is penetration deep into the myometrium, sometimes with involvement of the peritoneum, adjacent parametrium, or vaginal vault. Although locally aggressive, invasive moles are less prone to metastasize.

Gestational Choriocarcinoma

This is the most common type of trophoblastic neoplasm to follow a term pregnancy or a miscarriage, and only a third of cases follow a molar gestation (Soper, 2006). Choriocarcinoma is composed of cells reminiscent of early cytotrophoblast and syncytiotrophoblast, however, it contains no villi. This rapidly growing tumor invades both myometrium and blood vessels to create hemorrhage and necrosis. Myometrial tumor may spread outward and become visible on the uterine surface as dark, irregular nodules. Metastases often develop early and are generally blood-borne (Fig. 20-5). The most common sites are the lungs and vagina, but tumor may travel to the vulva, kidneys, liver, brain, ovaries, and bowel. Bleeding can complicated these metastases (Fatema, 2016; Wei, 2016; Zhang, 2017). Choriocarcinomas are commonly accompanied by ovarian theca-lutein cysts.

Placental Site Trophoblastic Tumor

This rare tumor arises from intermediate trophoblasts at the placental site. These tumors have associated serum β-hCG levels that may be only modestly elevated. However, they produce variant forms of hCG, and identification of a high proportion of free β-hCG is considered diagnostic. Treatment of placental site trophoblastic tumor by hysterectomy is preferred because these locally invasive tumors are usually resistant to chemotherapy (Baergen, 2006). For higher-risk stage I and for later stages, adjuvant multidrug chemotherapy is also given (Schmid, 2009).

Epithelioid Trophoblastic Tumor

This rare tumor develops from chorionic-type intermediate trophoblast. The uterus is the main site of involvement, and bleeding and low hCG levels are typical findings (Scott, 2012). Primary treatment is hysterectomy because this tumor is relatively resistant to chemotherapy. Metastatic disease is common, and combination chemotherapy is employed (Davis, 2015).

Treatment

Women with GTN are best managed by oncologists, and some evidence supports treatment in centers specializing in GTN (Kohorn, 2014). The prognosis is excellent with rare exceptions, and patients are routinely cured even in the presence of widespread disease. Chemotherapy alone is usually the primary treatment. Although controversial, some also consider a second uterine evacuation to be an adjuvant therapeutic option in some GTN cases to avoid or minimize chemotherapy (Pezeshki, 2004; van Trommel, 2005). In other cases, suction curettage may infrequently be needed to resolve bleeding or remove a substantial amount of retained molar tissue. In specific cases, hysterectomy may be primary or adjuvant treatment (Clark, 2010).

Single-agent chemotherapy protocols are usually sufficient for nonmetastatic or low-risk metastatic neoplasia (Lawrie, 2016). In their review of 108 women with low-risk disease, Abrão and colleagues (2008) reported that monotherapy protocols with either methotrexate or actinomycin D were equally effective compared with a regimen containing both. In general, methotrexate is less toxic than actinomycin D (Chan, 2006; Seckl, 2010). Regimens are repeated until serum β-hCG levels are undetectable.

Combination chemotherapy is given for high-risk disease, and reported cure rates approximate 90 percent (Lurain, 2010). Several regimens have been used with success. One is EMA-CO, which includes etoposide, methotrexate, actinomycin D, cyclophosphamide, and Oncovin (vincristine). In selected cases, adjuvant surgical and radiotherapy may also be employed (Hanna, 2010). Frequent causes of death include hemorrhage from metastatic sites, respiratory failure, sepsis, and multiorgan failure due to widespread chemoresistant disease (Lybol, 2012; Neubauer, 2015).

With either low- or high-risk disease, once serum β-hCG levels are undetectable, serosurveillance is continued for 1 year. During this time, effective contraception is crucial to avoid any teratogenic effects of chemotherapy to the fetus and to mitigate confusion from rising β-hCG levels caused by superimposed pregnancy (Seckl, 2010; Williams, 2014). For those who conceive despite this within the surveillance year following treatment, pregnancy may continue since most will have a favorable outcome (Tse, 2012; Woolas, 1998). Importantly, this group is advised of the low but important risk of delayed diagnosis if tumor recurs during the pregnancy (Blagden, 2002; Tuncer, 1999b).

A small number of women during surveillance, despite no evidence of metastases, will be found to have very low β-hCG levels that plateau. This phenomenon is called quiescent hCG and presumably is caused by dormant trophoblast. Close observation without therapy is recommended, but 20 percent will eventually have recurrent active and progressive trophoblastic neoplasia (Ngu, 2014).

Women with prior hydatidiform mole generally do not have impaired fertility, and their pregnancy outcomes are usually normal (Joneborg, 2014; Matsui, 2011; Sebire, 2003). One concern is the 2-percent risk for developing trophoblastic disease in a subsequent pregnancy, which was described earlier. Sonographic evaluation is recommended in early pregnancy, and subsequently if indicated.

Women who have successfully completed GTN chemotherapy are advised to delay pregnancy for 12 months. Fertility and pregnancy outcomes are typically normal, and congenital anomaly rates are not increased (Berkowitz, 2000; Tse, 2012). One exception is an unexplained higher stillbirth rate of 1.5 percent compared with a background rate of 0.8 percent (Vargas, 2014).

After hydatidiform mole or GTN treatment, in subsequent pregnancy, the placenta or products of conception are sent for pathological evaluation at delivery. A serum β-hCG level is measured 6 weeks postpartum (Lurain, 2010).