This term primarily encompasses pathologic entities that are characterized by aggressive invasion of the endometrium and myometrium by trophoblast 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, in most cases of GTN, no tissue is available for pathologic study. Instead, GTN is diagnosed based on elevated β-hCG levels and managed clinically.
Gestational trophoblastic neoplasia typically develops with or follows some form of pregnancy. Most cases follow a hydatidiform mole. Rarely, GTN develops after a live birth, miscarriage, or termination. Occasionally, the antecedent gestation cannot be confirmed with certainty. Many of the reported nonmolar cases may actually represent disease originating from an unrecognized early mole (Sebire, 2005a).
This common manifestation of GTN is characterized by whole chorionic villi that accompany excessive trophoblastic overgrowth and invasion (Fig. 37-8). These tissues penetrate deep into the myometrium, sometimes to involve the peritoneum, adjacent parametrium, or vaginal vault. Such moles are locally invasive but generally lack the pronounced tendency to develop widespread metastases typical of choriocarcinoma. Invasive moles originate almost exclusively from a complete or a partial hydatidiform mole (Sebire, 2005a).
A. An invasive mole contains whole villi that invade locally. The arrow marks one villus invading deeply into the adjacent myometrium. (Used with permission from Dr. Ona Faye-Peterson.) B. Choriocarcinoma is a biphasic tumor characterized by intermediate trophoblast and cytotrophoblast (asterisk), intimately admixed with multinucleate syncytiotrophoblast (S). Choriocarcinoma is a vascular tumor, typically with prominent hemorrhage, as evidenced by the abundant blood in the background. (Used with permission from Dr. Kelley Carrick.)
This extremely malignant tumor contains sheets of anaplastic trophoblast and prominent hemorrhage, necrosis, and vascular invasion (see Fig. 37-8). However, formed villous structures are characteristically absent. Gestational choriocarcinoma initially invades the endometrium and myometrium but tends to develop early blood-borne systemic metastases (Fig. 37-9).
Computed-tomography (CT) scan of choriocarcinoma invading the uterus.
Most cases develop following evacuation of a molar pregnancy, but these tumors may also follow a nonmolar pregnancy. Specifically, gestational choriocarcinoma develops in approximately 1 in 30,000 nonmolar pregnancies. Two thirds of such cases follow term pregnancies, and one third develop after a spontaneous abortion or pregnancy termination. One review of 100 patients with nonmolar gestational choriocarcinoma reported that 62 presented after a live birth, 6 after a live birth preceded by a molar pregnancy, and 32 after a nonmolar abortion (Tidy, 1995). Vaginal bleeding was the most common symptom in all groups. For this reason, abnormal bleeding for more than 6 weeks following any pregnancy warrants evaluation with β-hCG testing to exclude a new pregnancy or GTN.
When choriocarcinoma is diagnosed after a live birth, the antecedent pregnancy usually proceeded normally to term. One case series collected between 1964 and 1996 showed that in 89 percent of cases, the preceding pregnancy had produced an uncomplicated live birth (Rodabaugh, 1998). Hydrops, while a notable complication in the remaining fetuses in this earlier series, was not observed in a more recent cohort compiled between 1996 and 2011 (Diver, 2013). Occasionally, unanticipated choriocarcinoma is detected in an otherwise normal-appearing placenta at delivery. More commonly, however, the diagnosis of choriocarcinoma is delayed for months due to subtle signs and symptoms. Most patients present with intermenstrual bleeding, and high β-hCG levels are detected (Lok, 2006). Less frequently, the diagnosis is made in an asymptomatic woman by an incidental positive pregnancy test (Diver, 2013). In part because of the typical delay to diagnosis, choriocarcinomas following term pregnancies are associated with high-risk features and a higher mortality rate than GTN following nonmolar abortions. Death rates range from 10 to 15 percent (Diver, 2013; Lok, 2006; Rodabaugh, 1998; Tidy, 1995).
In contrast to this gestational choriocarcinoma, primary “nongestational” choriocarcinoma is an ovarian germ cell tumor (Chap. 36). Although rare, ovarian choriocarcinoma has a histologic appearance identical to that of gestational choriocarcinoma. It is in part distinguished by the lack of a preceding pregnancy (Lee, 2009).
Placental-site Trophoblastic Tumor
This tumor consists predominantly of intermediate trophoblasts at the placental site. It is a rare GTN variant with unique disease behavior. Placental-site trophoblastic tumor (PSTT) can follow any type of pregnancy but develops most commonly following a term gestation (Papadopoulos, 2002). Typically, patients have irregular bleeding months or years after the antecedent pregnancy, and the diagnosis is not entertained until endometrial sampling has been performed (Feltmate, 2001). PSTT tends to infiltrate only within the uterus, disseminates late in its course, and produces low β-hCG levels (van Trommel, 2013). Of interest, an elevated proportion of free β-subunit can help to discriminate it from other GTN types if the endometrial biopsy is equivocal (Cole, 2008; Harvey, 2008). When this tumor does spread, the pattern mirrors that of gestational choriocarcinoma. Metastases often spread to the lungs, liver, or vagina (Baergen, 2006).
Hysterectomy is the primary treatment for nonmetastatic PSTT due to its relative insensitivity to chemotherapy. In particularly motivated patients, fertility-sparing procedures have mixed results (Feltmate, 2001; Machtinger, 2005; Papadopoulos, 2002; Taylor, 2013b).
Metastatic PSTT has a much poorer prognosis than its postmolar GTN counterparts. As a result, aggressive combination chemotherapy is indicated. EMA/EP regimens of etoposide, methotrexate, and dactinomycin (actinomycin D) that alternate with etoposide and cisplatin (Platinol) are considered the most effective (Newlands, 2000). Radiation, however, may also have a role. The overall 10-year survival is 70 percent, but patients with metastases, especially stage IV disease, have a much poorer prognosis (Hassadia, 2005; Hyman, 2013; Schmid, 2009).
Epithelioid Trophoblastic Tumor
This rare trophoblastic tumor is distinct from gestational choriocarcinoma and PSTT. The preceding pregnancy event may be remote, or in some cases, a prior gestation cannot be confirmed (Palmer, 2008). Epithelioid trophoblastic tumor develops from neoplastic transformation of chorionic-type intermediate trophoblast. Microscopically, this tumor resembles PSTT, but the cells are smaller and display less nuclear pleomorphism. Grossly, epithelioid trophoblastic tumor grows in a nodular fashion rather than the infiltrative pattern of PSTT (Shih, 1998). Hysterectomy is again the primary treatment due to presumed chemoresistance and since the diagnosis is usually confirmed in advance by endometrial biopsy. More than one third of patients will present with metastatic disease and demonstrable chemoresistance to multiagent therapy, which portends a poor prognosis (Davis, 2015; Palmer, 2008).
Most GTN cases are clinically diagnosed, using β-hCG evidence to identify persistent trophoblastic tissue (Table 37-3). Tissue is infrequently available for pathologic diagnosis, unless a diagnosis of placental-site or nongestational tumor is being considered. As a result, most centers in the United States diagnose GTN on the basis of rising β-hCG values or a persistent plateau of β-hCG values for at least 3 weeks. Unfortunately, uniformity is lacking in the definition of a persistent plateau. Additionally, the diagnostic criteria are less stringent in the United States than in Europe. This is partly because of concern that some patients may be lost to follow-up if stricter criteria are used.
TABLE 37-3FIGO Criteria for Gestational Trophoblastic Neoplasia Diagnosis ||Download (.pdf) TABLE 37-3 FIGO Criteria for Gestational Trophoblastic Neoplasia Diagnosis
|β-hCG level plateau persists in four measurements during a period of 3 weeks or longer (days 1, 7, 14, and 21) |
β-hCG level rise in 3 weekly consecutive measurements or longer, over a period of 2 weeks or more (days 1, 7, and 14)
β-hCG level remains elevated for 6 months or more
Histologic diagnosis of choriocarcinoma
When serologic criteria for GTN are met, a new intrauterine pregnancy is excluded using β-hCG levels that are correlated with sonographic findings. This is done especially if there has been a long delay in monitoring of serial β-hCG levels or noncompliance with contraception or both.
Patients with GTN undergo a thorough pretreatment assessment to determine disease extent. The initial evaluation may be limited to pelvic examination, chest radiograph, and pelvic sonography or abdominopelvic computed tomography (CT) scanning. Although approximately 40 percent of patients will have micrometastases not otherwise visible on chest radiography, chest CT is not needed because these small lesions do not affect outcome (Darby, 2009; Garner, 2004). However, pulmonary lesions identified on chest radiograph should prompt CT of the chest and magnetic resonance (MR) imaging of the brain. Fortunately, central nervous system involvement is rare in the absence of neurologic symptoms or signs (Price, 2010). Positron emission tomography (PET) may occasionally be useful to evaluate occult choriocarcinoma or relapse from previously treated GTN when conventional imaging is equivocal or fails to identify metastatic disease (Dhillon, 2006; Numnum, 2005).
Gestational trophoblastic neoplasia is anatomically staged based on a system adopted by the International Federation of Gynecology and Obstetrics (FIGO) (Table 37-4 and Fig. 37-10). Patients at low risk for therapeutic failure are distinguished from those at high risk by using the modified prognostic scoring system of the World Health Organization (WHO) (Table 37-5). About 95 percent of patients will have a WHO score of 0 to 6 and will be considered to have low-risk disease (Sita-Lumsden, 2012). The remainder will have a score of 7 or higher and be assigned to the high-risk GTN group. For the most accurate description of affected patients, the Roman numeral corresponding to FIGO stage is separated by a colon from the sum of the risk factor scores, for example, stage II:4 or stage IV:9. This description best reflects disease behavior (Ngan, 2004). Women with high-risk scores are more likely to have tumors that are resistant to single-agent chemotherapy. They are therefore treated initially with combination chemotherapy. Although patients with stage I disease infrequently have a high-risk score, those with stage IV disease invariably have a high-risk score. Women diagnosed with FIGO stage I, II, or III GTN have a survival rate approaching 100 percent (Lurain, 2010).
TABLE 37-4FIGO Anatomic Staging of GTN ||Download (.pdf) TABLE 37-4 FIGO Anatomic Staging of GTN
|Stage ||Characteristics |
|I ||Disease confined to the uterus |
|II ||GTN extends outside of the uterus but is limited to the genital structures (adnexa, vagina, broad ligament) |
|III ||GTN extends to the lungs, with or without known genital tract involvement |
|IV ||All other metastatic sites |
TABLE 37-5Modified WHO Prognostic Scoring System as Adapted by FIGO ||Download (.pdf) TABLE 37-5 Modified WHO Prognostic Scoring System as Adapted by FIGO
|Scores ||0 ||1 ||2 ||4 |
|Age (yr) ||<40 ||≥40 ||— ||— |
|Antecedent pregnancy ||Mole ||Abortion ||Term ||— |
|Interval months from index pregnancy ||<4 ||4–6 ||7–12 ||>12 |
|Pretreatment serum β-hCG (mIU/mL) ||<10 3 ||10 3–<10 4 ||10 4– <10 5 ||≥10 5 |
|Largest tumor size (including uterus) ||<3 cm ||3–4 cm ||≥5 cm ||— |
|Site of metastases ||— ||Spleen, kidney ||GI ||Liver, brain |
|Number of metastases ||— ||1–4 ||5–8 ||>8 |
|Previous failed chemotherapy drugs ||— ||— ||1 ||≥2 |
International Federation of Gynecology and Obstetrics (FIGO) staging of gestational trophoblastic neoplasia.
Invasive moles arising from complete molar gestations make up most nonmetastatic GTN cases. Approximately 12 percent of complete moles develop locally invasive disease after evacuation, compared with only 4 to 6 percent of partial moles. Epithelioid trophoblastic tumor and PSTT are other rare causes of nonmetastatic GTN. Locally invasive trophoblastic tumors may perforate the myometrium and lead to intraperitoneal bleeding (Mackenzie, 1993). Alternatively, vaginal hemorrhage can follow tumor erosion into uterine vessels, or necrotic tumor may involve the uterine wall and serve as a nidus for infection. Fortunately, the prognosis is typically excellent for all types of nonmetastatic disease despite these possible manifestations.
Choriocarcinomas originating from complete molar gestations account for most cases of metastatic GTN. Three to 4 percent of complete moles develop metastatic choriocarcinoma after evacuation. This event is rare following any other type of molar or nonmolar gestation. Choriocarcinomas have a propensity for distant spread and should be suspected in any woman of reproductive age with metastatic disease from an unknown primary (Tidy, 1995). Moreover, because of this tendency, chemotherapy is indicated whenever choriocarcinoma is diagnosed histologically.
Although many patients are largely asymptomatic, metastatic GTN is highly vascular and prone to severe hemorrhage either spontaneously or during biopsy. Heavy menstrual bleeding is a common presenting symptom. The most common sites of spread are the lungs (80 percent), vagina (30 percent), pelvis (20 percent), liver (10 percent), and brain (10 percent) (Fig. 37-11). Patients with pulmonary metastases typically have asymptomatic lesions identified on routine chest radiograph and infrequently present with cough, dyspnea, hemoptysis, pleuritic chest pain, or signs of pulmonary hypertension (Seckl, 1991). In patients with early development of respiratory failure that requires intubation, the overall outcome is poor. Hepatic or cerebral involvement is encountered almost exclusively in patients who have had an antecedent nonmolar pregnancy and a protracted delay in tumor diagnosis (Newlands, 2002; Savage, 2015b). These women may present with associated hemorrhagic events. Virtually all patients with hepatic or cerebral metastases have concurrent pulmonary or vaginal involvement or both. Great caution is used in attempting excision of any metastatic disease site due to the risk of profuse hemorrhage. Thus, this practice is almost uniformly avoided except in extenuating circumstances of life-threatening brainstem herniation or chemotherapy-resistant disease.
Common sites of gestational trophoblastic neoplasia metastasis. A. Chest radiography demonstrates widespread metastatic lesions. (Used with permission from Dr. Michael G. Connor.) B. Computed-tomography (CT) scan of metastatic disease to the lung. C. Autopsy specimen shows multiple hemorrhagic hepatic metastases. (Used with permission from Dr. Michael G. Connor.)
Most patients diagnosed with postmolar GTN have persistent tumor confined to the endometrial cavity and are treated primarily with chemotherapeutic agents. Repeat dilatation and curettage is generally avoided to prevent morbidity and mortality caused by uterine perforation, hemorrhage, infection, uterine adhesions, and anesthetic complications (American College of Obstetricians and Gynecologists, 2014). Accordingly, second evacuations are not typically performed in the United States unless patients have persistent uterine bleeding and substantial amounts of retained molar tissue. Repeat uterine curettage is a more standard part of postmolar GTN management in Europe. This practice reduces both the number of patients needing any further treatment and the number of courses in those who do require chemotherapy (Pezeshki, 2004; van Trommel, 2005). A second evacuation followed by continued surveillance, however, is a less attractive option, even for poorly compliant patients, than single-agent chemotherapy (Allen, 2003; Massad, 2000).
Hysterectomy may play several roles in GTN treatment. First, it may be performed to primarily treat PSTT, epithelioid trophoblastic tumors, or other chemotherapy-resistant disease. Second, severe uncontrollable vaginal or intraabdominal bleeding may necessitate hysterectomy as an emergency procedure (Clark, 2010). Because of these more extreme indications, most women undergoing hysterectomy have elevated pretreatment risk scores, unusual pathology, and higher mortality rates (Pisal, 2002). Finally, adjuvant hysterectomy decreases the total dose of chemotherapy needed to achieve clinical remission in low-risk GTN. Patients with disease apparently confined to the uterus who do not desire future fertility should be counseled about this option (Suzuka, 2001). However, the risk of GTN persistence after hysterectomy remains approximately 3 to 5 percent, and these patients should be monitored postoperatively (American College of Obstetricians and Gynecologists, 2014).
Residual lung metastases may persist in 10 to 20 percent of patients achieving clinical remission of GTN after chemotherapy completion. These patients do not appear to have an increased risk of relapse compared with those having normal chest radiographs or CT scans. Thus, thoracotomy is not usually necessary unless remission cannot otherwise be achieved (Powles, 2006). In general, the optimal patient to be counseled for thoracotomy will have stage III GTN, a preoperative β-hCG level <1500 mIU/mL, and a solitary lung nodule resistant to chemotherapy (Cao, 2009; Fleming, 2008).
Chemotherapy for Low-Risk GTN
Most patients with hydatidiform mole who develop GTN are at low risk of chemotherapy resistance (score 0-6) (Seckl, 2010). Single-agent methotrexate is the most common treatment, and complete response rates range from 67 to 81 percent for variations of the two most common intramuscular (IM) methotrexate regimens (Table 37-6). Although bundled as low-risk disease, the highest cure rates occur in patients with the lowest WHO scores (0-1), and rates decline proportionally as WHO scores rise (Sita-Lumsden, 2012). Thus, patients with a WHO score of 6 should at least be considered for upfront combination therapy (Taylor, 2013a). Overall, 19 to 33 percent of women develop methotrexate resistance and are switched to other agents, described subsequently.
TABLE 37-6Intramuscular Methotrexate Regimens for Treatment of Low-Risk GTN ||Download (.pdf) TABLE 37-6 Intramuscular Methotrexate Regimens for Treatment of Low-Risk GTN
|Frequency ||Dose ||Population Studied ||CR Rate (%) ||Study |
|Weekly ||30–50 mg/m 2 |
50 mg/m 2
|Nonmetastatic GTN |
| Homesley, 1988, 1990 |
|Days 1,3,5,7 ||50 mg/d |
|Low-risk GTN |
| Kang, 2010; Khan, 2003; |
With methotrexate, the Gynecologic Oncology Group (GOG) conducted a prospective cohort dose-escalation study (protocol #79) of weekly administration that established a maximum dose of 50 mg/m2 with minimal toxicity (Homesley, 1988, 1990). This regimen is continued weekly until β-hCG levels are undetectable, and then two or three additional weekly doses are given (Lybol, 2012). Alternatively, Charing Cross Hospital and University of Sheffield investigators currently use an 8-day alternating regimen of 50 mg IM methotrexate on treatment days 1, 3, 5, and 7, and oral folinic acid, 7.5 to 15 mg taken orally on days 2, 4, 6, and 8. Treatment is repeated every 2 weeks (Taylor, 2013a).
As discussed more fully in Chapter 27, methotrexate is a folic acid antagonist that inhibits DNA synthesis. Mild stomatitis is the most common side effect, but other serosal symptoms, especially pleurisy, develop in up to one quarter of patients treated with low-dose methotrexate. Pericarditis, peritonitis, and pneumonitis are infrequent (Sharma, 1999). Toxicity develops more frequently with the more intense 8-day regimens compared with weekly administration. This is despite routine folinic acid “rescue,” which is provided to protect normal mucosal and serosal cells (Chap. 27) (Gleeson, 1993).
Dactinomycin is less frequently used for the primary treatment of low-risk disease due to toxicity concerns, but it has superior efficacy as a single agent (Alazzam, 2012a; Yarandi, 2008). In a prospective GOG trial (protocol #174) of low-risk GTN, patients were randomly assigned to biweekly “pulse” 1.25-mg dose dactinomycin or to weekly methotrexate, 30 mg/m2. Among 215 eligible patients, a complete response was observed in 69 percent given dactinomycin and in 53 percent given methotrexate. However, advocates of methotrexate have speculated that the unexpectedly low efficacy of methotrexate observed in this study may be due to subtherapeutic dosing. Moreover, those randomized to dactinomycin were twice as likely to develop alopecia and were the only patients to develop grade 4 toxicity, defined in Chapter 27 (Osborne, 2008). As yet, no trials have directly compared pulse dactinomycin and the widely used 8-day methotrexate regimen. Since survival rates are so high, methotrexate is usually tried first because most clinicians consider it to be the least toxic.
Patients who do not respond to an initial single-agent chemotherapeutic regimen fail to have persistently dropping β-hCG levels. These women should have their score recalculated using the modified WHO prognostic scoring system. Most women will still be considered low-risk and may be switched to a single-agent second-line therapy. Methotrexate-resistant GTN often responds to dactinomycin (Chapman-Davis, 2012; Chen, 2004). The GOG demonstrated a 74-percent success rate in a Phase II trial (protocol #176) of pulse dactinomycin as salvage treatment in 38 patients with methotrexate-resistant GTN (Covens, 2006). Etoposide is less commonly used in this setting but is also effective (Mangili, 1996). Patients initially treated with pulse dactinomycin who develop resistant GTN may still be successfully treated with the 5-day course of dactinomycin (Kohorn, 2002). Alternatively, single-agent methotrexate or etoposide is often effective in these cases (Matsui, 2005).
Chemotherapy for High-Risk GTN
Approximately 5 percent of GTN patients present with high-risk disease and usually have numerous metastases months or years after the causative pregnancy. Such patients are likely to develop drug resistance to single-agent chemotherapy (Seckl, 2010). Etoposide, methotrexate, and dactinomycin (actinomycin D) alternating with cyclophosphamide and vincristine (Oncovin) (EMA/CO) chemotherapy is a well-tolerated and highly effective regimen for high-risk GTN. It is considered the preferred treatment for most high-risk disease. Bower and associates (1997) reported a 78-percent complete remission rate in 272 consecutive women. Similarly, other investigators have observed a 71- to 78-percent complete response rate with the EMA/CO regimen (Escobar, 2003; Lu, 2008). Response rates are comparable whether patients are treated primarily or after failure of single-agent methotrexate and/or dactinomycin.
Patients with high-risk disease have an overall survival rate of 86 to 92 percent, although approximately one quarter become refractory to or relapse from EMA/CO (Bower, 1997; Escobar, 2003; Lu, 2008; Lurain, 2010). Secondary treatment usually involves platinum-based chemotherapy combined with possible surgical excision of resistant disease (Alazzam, 2012b). Newlands and colleagues (2000) reported an 88-percent survival rate among 34 patients by replacing the cyclophosphamide and vincristine component with etoposide and cisplatin (EMA/EP). EMA/EP is an effective option in patients resistant to EMA/CO, but paclitaxel (Taxol) plus cisplatin alternating with paclitaxel plus etoposide (TP/TE) has comparable efficacy and appears less toxic (Patel, 2010; Wang, 2008). Bleomycin, etoposide, and cisplatin (BEP) is another potentially effective regimen (Lurain, 2005).
High-risk patients with a large disease burden are at risk for early death with standard EMA/CO due to tumor-lysis related hemorrhage and clinical deterioration. In these selected circumstances, “induction low-dose etoposide-cisplatin” appears to reduce the mortality risk 10-fold (Alifrangis, 2013).
Patients with cerebral metastases may present with seizures, headaches, or hemiparesis (Newlands, 2002). Occasionally, they are moribund on arrival after not recognizing the significance of their symptoms or following an extended delay in diagnosis. In such extenuating circumstances, emergency craniotomy may be indicated to stabilize the patient and is followed by critical care support throughout the active phase of treatment (Savage, 2015b). In experienced centers, virtually all GTN-related deaths occur in stage IV patients with WHO risk scores of 12 or more (Lurain, 2010).
Fortunately, the cure rate for those with brain metastases is high if neurologic deterioration does not occur within the first weeks after diagnosis. The sequence of aggressive multimodality therapy is controversial but may include chemotherapy, surgery, and radiation. Savage and coworkers (2015b) reported an 85-percent survival rate among 27 patients treated from 1991 to 2013 by EMA/CO or EMA/EP with an enhanced intravenous dose (1 g/m2) of methotrexate combined with intrathecal methotrexate until β-hCG levels were undetectable. Whole-brain radiation therapy can also be an efficacious adjunct to combination chemotherapy and surgery but can induce permanent intellectual impairment (Cagayan, 2006; Schechter, 1998).
Monitoring of patients with low-risk GTN consists of weekly β-hCG measurements until the level is undetectable for 3 consecutive weeks. This is followed by monthly titers until the level is undetectable for 12 months. Patients with high-risk disease are followed for 24 months due to the greater risk of late relapse. Patients are encouraged to use effective contraception, as outlined earlier, during the entire surveillance period.
Despite the favorable prognosis, patients and their partners carry pregnancy concerns for a protracted time (Wenzel, 1992). Sexual dysfunction is an underreported complication (Cagayan, 2008). These and other potential sequelae highlight the importance of a multidisciplinary approach to management (Ferreira, 2009).
Although patients may expect a normal reproductive outcome after achieving remission from GTD, some evidence suggests that adverse maternal outcomes and spontaneous abortion occur more frequently among those who conceive within 6 months of chemotherapy completion (Braga, 2009). Women having a pregnancy affected by a histologically confirmed complete or partial mole may be counseled that the risk of a repeat mole in a subsequent pregnancy approximates 1 percent (Garrett, 2008). Most will be of the same type of mole as the preceding pregnancy (Sebire, 2003). Women who become pregnant within 12 months postchemotherapy for GTN can be reassured of a likely favorable outcome, although the safest option is still to delay pregnancy for the full year (Williams, 2014). Pregnancy after combination EMA/CO chemotherapy for GTN also has a high probability of success and favorable outcome (Lok, 2003). All major cytotoxic treatments except methotrexate increase the risk of early menopause (Savage, 2015a).
In some cases, secondary tumors can develop as a result of cancer treatment. Etoposide-based combination chemotherapy has been associated with an increased risk of leukemia, colon cancer, melanoma, and breast cancer up to 25 years after treatment for GTN. An overall 50-percent excess risk was observed (Rustin, 1996). Etoposide is therefore reserved to treat patients who are likely to be resistant to single-agent chemotherapy and, in particular, those with high-risk metastatic disease.
Quiescent Gestational Trophoblastic Disease
Patients with persistent mild elevations (usually ≤50 mIU/mL) of true β-hCG may have a dormant premalignant condition if no tumor is identified by physical examination or imaging studies (Khanlian, 2003). In this instance, phantom β-hCG, described next, should also be conclusively excluded as a possibility. The low β-hCG titers may persist for months or years before disappearing. Chemotherapy and surgery usually have no effect. Hormonal contraception may be helpful in lowering titers to an undetectable level, but patients are closely monitored since metastatic GTN may eventually develop (Khanlian, 2003; Kohorn, 2002; Palmieri, 2007).
Occasionally, persistent mild elevations of serum β-hCG are detected that lead physicians to erroneously treat patients with cytotoxic chemotherapy or hysterectomy or both, when in reality no true β-hCG molecule or trophoblastic disease is present (Cole, 1998; Rotmensch, 2000). This “phantom” β-hCG reading results from heterophilic antibodies in the serum that interfere with the β-hCG immunoassay and cause a false-positive result.
Several steps can clarify the diagnosis. First, a urine pregnancy test can be performed. With phantom β-hCG, the heterophilic antibodies are not filtered or renally excreted. Thus, these test-altering antibodies will be absent from the urine, and urine testing will show true negative results for β-hCG. Importantly, to conclusively exclude trophoblastic disease by this method, the index serum β-hCG level must be significantly higher than the detection threshold of the urine test. Second, performing serial dilutions of the serum sample leads to a proportional decrease in the β-hCG level if β-hCG is truly present. However, phantom β-hCG measurements will be unchanged by dilution. In addition, if phantom β-hCG is suspected, some specialized laboratories may be able to block the heterophilic antibodies. Last, heterophilic antibodies will cause interference with one assay, but they may bind poorly to another assay’s antibodies. Thus, switching β-hCG assay kits to one by a different manufacturer may accurately demonstrate the absence of true β-hCG (Cole, 1998; Olsen, 2001; Rotmensch, 2000).