acog practice bulletin 53 diagnosis and treatment of trofoblastic gestacional disease

VOL. 103, NO. 6, JUNE 2004 ACOG Practice Bulletin No. 53 Diagnosis and Treatment of 1365Gestational Trophoblastic Disease

ACOGPRACTICEBULLETIN

CLINICAL MANAGEMENT GUIDELINES FOROBSTETRICIAN–GYNECOLOGISTS

NUMBER 53, JUNE 2004

This Practice Bulletin wasdeveloped by the ACOG Com-mittee on Practice Bulletins—Gynecology and the SGOEducation Committee with theassistance of John Soper, MD,Julian Schink, MD, and DavidMutch, MD. The informationis designed to aid practitionersin making decisions aboutappropriate obstetric and gyne-cologic care. These guidelinesshould not be construed asdictating an exclusive courseof treatment or procedure.Variations in practice maybe warranted based on theneeds of the individual patient,resources, and limitationsunique to the institution or typeof practice.

Diagnosis and Treatmentof GestationalTrophoblastic DiseaseGestational trophoblastic disease comprises a spectrum of interrelated condi-tions originating from the placenta. Other terms often used to refer to theseconditions include gestational trophoblastic neoplasia and gestational tro-phoblastic tumor. Histologically distinct disease entities encompassed by thisgeneral terminology include complete and partial hydatidiform moles, invasivemoles, gestational choriocarcinomas, and placental site trophoblastic tumors.Before the advent of sensitive assays for human chorionic gonadotropin (hCG)and efficacious chemotherapy, the morbidity and mortality from gestational tro-phoblastic disease were substantial. At present, with sensitive quantitativeassays for β-hCG and current approaches to chemotherapy, most women withmalignant gestational trophoblastic disease can be cured and their repro-ductive function preserved. The purpose of this document is to address currentevidence regarding the diagnosis, staging, and management of gestational tro-phoblastic disease.

BackgroundEstimates for the incidence of various forms of gestational trophoblastic diseasevary. In the United States, hydatidiform moles are observed in approximately 1in 600 therapeutic abortions and 1 in 1,500 pregnancies (1). Approximately20% of patients will develop malignant sequelae requiring administration ofchemotherapy after evacuation of hydatidiform moles (2, 3). Most patients withpostmolar gestational trophoblastic disease will have nonmetastatic molar pro-liferation or invasive moles, but gestational choriocarcinomas and metastaticdisease can develop in this setting. Gestational choriocarcinoma occurs inapproximately 1 in 20,000–40,000 pregnancies: approximately 50% after term

1366 ACOG Practice Bulletin No. 53 Diagnosis and Treatment of OBSTETRICS & GYNECOLOGYGestational Trophoblastic Disease

pregnancies, 25% after molar pregnancies, and theremainder after other gestational events (4). Althoughmuch rarer than hydatidiform moles or gestational chori-ocarcinomas, placental site trophoblastic tumors candevelop after any type of pregnancy (5, 6). To allow opti-mal management, practicing obstetrician–gynecologistsshould be able to diagnose and manage primary molarpregnancies, diagnose and stage malignant gestationaltrophoblastic disease, and assess risk in women withmalignant gestational trophoblastic disease to allowreferral for appropriate initial treatment. Experience,such as that found at regional gestational trophoblasticdisease treatment centers, improves outcomes in themanagement of malignant gestational trophoblastic dis-ease. Any woman for whom initial therapy for invasivemole has failed or who has a choriocarcinoma diagnosisshould be referred to a physician or facility with training,expertise, and experience in managing gestational tro-phoblastic disease.

Hydatidiform Mole

ClassificationPartial and complete hydatidiform moles are distinct dis-ease processes with characteristic cytogenetic, histologic,and clinical features (4). The distinct pathologic featuresand clinical presentation of these 2 entities are outlined inTable 1. Despite the cytogenetic, pathologic, and clinicaldifferences between the 2 diagnoses, the management ofpatients with complete and partial moles is similar.

The volume and amount of trophoblastic prolifera-tion in complete moles generally exceed that observed in

partial moles and are reflected in the different clinicalpresentations (see Table 1). The average initial serumhCG levels usually are higher in patients with completemoles than in patients with partial moles (7). Although anincreasing proportion of moles are diagnosed as missedabortions on the basis of an early ultrasound examinationin the absence of symptoms (8), most patients with com-plete moles have a clinical or ultrasonographic diagnosisof hydatidiform mole. Uterine enlargement beyond theexpected gestational age is observed in up to 50% ofpatients with complete moles (1). These patients maypresent with vaginal bleeding or expulsion of molar vesi-cles. Medical complications of molar pregnancy, includ-ing pregnancy-induced hypertension, hyperthyroidism,anemia, and hyperemesis gravidarum, are more frequent-ly seen among patients with complete moles (9).Approximately 15–25% of patients with complete moleswill have theca lutein cysts with ovarian enlargement ofmore than 6 cm (10). Malignant sequelae occur in lessthan 5% of patients with partial moles, compared withapproximately 20% after evacuation of complete hyda-tidiform moles (see Table 1) (4).

DiagnosisHydatidiform moles usually are diagnosed during thefirst trimester of pregnancy (8, 11). The most commonsymptom is abnormal bleeding. Other signs and symp-toms include uterine enlargement greater than expectedfor gestational age, absent fetal heart tones, cysticenlargement of the ovaries, hyperemesis gravidarum, andan abnormally high level of hCG for gestational age (4).Presence of these features in the first trimester should

Table 1. Features of Partial and Complete Hydatidiform Moles

Feature Partial Mole Complete Mole

Karyotype Most commonly 69,XXX Most commonly 46,XX or 46,XYor 69,XXY

Pathology

Fetus Often present Absent

Amnion, fetal red blood cells Usually present Absent

Villous edema Variable, focal Diffuse

Trophoblastic proliferation Focal, slight to moderate Diffuse, slight to severe

Clinical presentation

Diagnosis Missed abortion Molar gestation

Uterine size Small for gestational age 50% larger for gestational age

Theca lutein cysts Rare 15–25%

Medical complications Rare Less than 25%

Postmolar malignant sequelae <5% 6–32%

Modified from Soper JT, Lewis JL Jr, Hammond CB. Gestational trophoblastic disease. In: Hoskins WJ, Perez CA, Young RC,editors. Principals and practice of gynecologic oncology, 2nd ed. Philadelphia (PA): Lippincott-Raven; 1997. p. 1040.

alert the clinician to the possibility of a molar gestation.Pregnancy-induced hypertension in the first half of pregnancy, although uncommon, is suggestive of hyda-tidiform mole. Ultrasonography has replaced all other noninvasive means of establishing the diagnosis (4, 8).Molar tissue typically is identified as a diffuse mixedechogenic pattern replacing the placenta, produced byvilli and intrauterine blood clots, but these findings maybe subtle or lacking in cases of early complete or partialmoles (8, 11).

Management After Evacuation ofHydatidiform MoleAs long as hCG values are decreasing after molar evac-uation, there is no role for chemotherapy. However, ifhCG levels increase or plateau over several weeks,immediate evaluation and treatment for malignant post-molar gestational trophoblastic disease are indicated.Occasionally, the plateauing or increasing hCG levelsare a result of a false-positive laboratory test resultcaused by heterophilic antibodies cross-reacting with thehCG test. Such false-positive test results, also known as“phantom hCG,” are discussed later.

The diagnosis of malignant sequelae as indicated bythe need for chemotherapy include the plateau orincrease of hCG levels after evacuation of hydatidiformmoles as mentioned previously, the histologic diagnosisof choriocarcinoma or invasive mole on the basis offindings from uterine curettage, or identification of clin-ical or radiographic evidence of metastases. Repeatcurettage is not recommended because it does not ofteninduce remission or influence treatment and may resultin uterine perforation and hemorrhage (12).

A variety of hCG criteria have been used to diag-nose postmolar gestational trophoblastic disease (1–3,13, 14). Recently, the International Federation ofGynecologists and Obstetricians (FIGO) standardizedhCG criteria for the diagnosis of postmolar gestationaltrophoblastic disease (14). Based on consensus commit-tee recommendations from the Society of GynecologicOncology, the International Society for the Study ofTrophoblastic Disease, and the International Gyne-cologic Cancer Society, the following criteria were pro-posed by FIGO (14):

1. An hCG level plateau of 4 values plus or minus 10%recorded over a 3-week duration (days 1, 7, 14, and21)

2. An hCG level increase of more than 10% of 3 val-ues recorded over a 2-week duration (days 1, 7, and14)

3. Persistence of detectable hCG for more than 6 months after molar evacuation

A new intrauterine pregnancy should be ruled out on thebasis of hCG levels and ultrasonography, especiallywhen there has been a long delay in follow-up of serialhCG levels and noncompliance with contraception.

Malignant Gestational Trophoblastic Disease

Histologic ConsiderationsThe clinical presentation of malignant gestational tro-phoblastic disease is more important in determiningtreatment and outcome than the precise histologic diag-nosis (4). Postmolar gestational trophoblastic disease isonly one of many forms of malignant gestational tropho-blastic disease; it comprises noninvasive trophoblasticproliferation, invasive moles, and gestational choriocar-cinoma. Gestational choriocarcinomas are derived fromterm pregnancies in one half of cases, with equal por-tions of the remaining half from histologically normalgestations and hydatidiform moles. The rarest form ofmalignant gestational trophoblastic disease, placentalsite trophoblastic tumor, can follow any pregnancy.

The term invasive mole is used to describe diseaseconfined to the uterus and is characterized by the pres-ence of edematous chorionic villi with trophoblasticproliferation that invade directly into the myometrium.Most cases are clinically diagnosed and are not deter-mined histologically. Dilation and curettage (D&C)should be avoided to prevent morbidity and mortalitycaused by uterine perforation. Gestational choriocarci-noma is a malignancy, comprising both neoplastic syn-cytiotrophoblast and cytotrophoblast elements withoutchorionic villi (4). Gestational choriocarcinomas tendto develop early systemic metastasis (the vagina, lung,liver, and brain are the most common sites), andchemotherapy is indicated when it is diagnosed histo-logically. When indicated, chemotherapy should beinitiated in a timely manner to avoid bleeding complica-tions at metastatic sites.

Placental site trophoblastic tumors are relativelyrare (5, 6). They are characterized by absence of villiwith proliferation of intermediate trophoblast cells. Thenumber of syncytiotrophoblast cells observed isdecreased in placental site trophoblastic tumors, withrelatively lower levels of hCG secreted by these tumors.Generally, placental site trophoblastic tumors are not assensitive to chemotherapy as other forms of malignantgestational trophoblastic disease; therefore, it is impor-tant to distinguish these tumors histologically (4).Surgery assumes a critical role in the management ofplacental site trophoblastic tumors (5, 6). Fortunately,most patients have disease confined to the uterus and arecured by hysterectomy.



Clinical Diagnosis of Malignant GestationalTrophoblastic Disease

Postmolar gestational trophoblastic disease is most fre-quently diagnosed on the basis of increasing or plateau-ing hCG values. Women with malignant gestational trophoblastic disease following nonmolar pregnanciesmay have subtle signs and symptoms of disease, whichmake the diagnosis difficult (15). Abnormal bleeding formore than 6 weeks following any pregnancy should beevaluated with hCG testing to exclude a new pregnancyor gestational trophoblastic disease. Metastases of gesta-tional choriocarcinoma have been reported in virtuallyevery body site, most commonly the vagina, liver, lung,and brain; however, biopsy of these sites is rarely neces-sary and may cause excessive bleeding. Central nervoussystem metastases may produce neurologic symptoms,intracranial hemorrhage, or mass lesions. Gestationalchoriocarcinoma should be considered in any woman ofreproductive age with metastatic disease from anunknown primary site (15). A serum hCG determinationand exclusion of pregnancy are all that are required todiagnose metastatic gestational trophoblastic disease inthese circumstances.

Clinical Considerations andRecommendations

How are patients with hydatidiform molesmanaged?

With increasing frequency, the diagnosis of complete orpartial moles usually is made after performing a D&C fora suspected incomplete spontaneous abortion (8, 11). Inthese cases, patients should be monitored with serialdeterminations of quantitative hCG values. A baselinepostevacuation chest X-ray should be considered.

For patients in whom hydatidiform moles are sus-pected before evacuation, the following tests are recom-mended (4):

• Complete blood count with platelet determination

• Clotting function studies

• Renal and liver function studies

• Blood type with antibody screen

• Determination of hCG level

• Preevacuation chest X-ray

Medical complications of hydatidiform moles areobserved in approximately 25% of patients with uterineenlargement of more than 14–16 weeks’ gestational size

and are seen less frequently among patients with lesserdegrees of uterine enlargement (9). Common medicalcomplications include anemia, infection, hyperthyroid-ism, pregnancy-induced hypertension, and coagulopathy.Women with signs and symptoms of these complicationswill need more intensive evaluation (ie, thyroid-stimulat-ing hormones and coagulopathy studies). Moles shouldbe evacuated as soon as possible after stabilization of anymedical complications.

To manage potential complications of molar evacua-tion in a woman with a large uterus, consideration shouldbe given to performing the evacuation in a facility with anintensive care unit, a blood bank, and anesthesia servic-es. For most patients, the preferred method of evacuationis suction D&C (1, 9). Medical induction of labor withoxytocin or prostaglandin and hysterotomy are not rec-ommended for evacuation because they increase bloodloss and may increase the risk for malignant sequelaewhen compared with suction D&C (3, 4, 9, 16).Furthermore, patients most often require D&C to com-plete the evacuation of moles after medical induction oflabor (9). Evacuation usually is performed with thepatient under general anesthesia, but local or regionalanesthesia may be used for a cooperative patient who hasa small uterus. After serial dilation of the cervix, uterineevacuation is accomplished with the largest cannula thatcan be introduced through the cervix. In some cases,ultrasound guidance may facilitate complete evacuationof the uterus. Intravenous oxytocin is administered afterthe cervix is dilated and is continued for several hourspostoperatively. Rh-negative patients should be treatedwith anti-D immune globulin after the evacuation eventhough fetal red blood cells should not be present in acomplete mole.

Pulmonary complications are frequently observedaround the time of molar evacuation among patients withmarked uterine enlargement (9, 17, 18). Although thesyndrome of trophoblastic embolization (deportation)has been emphasized as an underlying cause of respira-tory distress syndrome following molar evacuation, thereare many other potential causes of pulmonary complica-tions in these women. Respiratory distress syndrome canbe caused by high-output congestive heart failure causedby anemia or hyperthyroidism, preeclampsia, or iatro-genic fluid overload (17, 18). Generally, these complica-tions should be treated aggressively with therapy directedby central venous or Swan-Ganz catheter monitoring andassisted ventilatory support, as required. Hyperthy-roidism and pregnancy-induced hypertension usuallyabate promptly after evacuation of the mole and may notrequire specific therapy. Theca lutein cysts are associatedwith hCG stimulation of the ovaries (10). These may take

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several months to resolve after molar evacuation butrarely need to be removed. Surgical intervention shouldbe reserved for rupture or torsion, which is rare (10).

Hysterectomy with preservation of the adnexa is analternative to suction D&C for molar evacuation inselected patients who do not wish to preserve childbear-ing. Hysterectomy reduces the risk of malignant postmo-lar sequelae when compared with evacuation by D&C.However, the risk of postmolar gestational trophoblasticdisease after hysterectomy remains approximately 3–5%,and these patients should be monitored postoperativelywith serial hCG determinations (3, 4).

How are patients monitored after evacuationof hydatidiform moles, and what are the con-siderations regarding contraception andfuture pregnancies?

After molar evacuation, it is important to monitor allpatients carefully to diagnose and treat malignant seque-lae promptly. Serial quantitative serum hCG determina-tions should be performed using commercially availableassays capable of detecting β-hCG to baseline values (<5 mIU/mL). Ideally, serum hCG levels should beobtained within 48 hours of evacuation, every 1–2 weekswhile elevated, and then at monthly intervals for an addi-tional 6 months (4). Use of reliable hormonal contra-ception is recommended while hCG values are beingmonitored. Frequent pelvic examinations are performedwhile hCG values are elevated to monitor the involutionof pelvic structures and to aid in the early identificationof vaginal metastases.

The rationale for an interval of monitoring after nor-malization of the hCG level is to identify patients whodevelop malignant postmolar gestational trophoblasticdisease. Although rare instances of long latent periodshave been reported, most episodes of malignant sequelaeafter hydatidiform moles occur within approximately 6 months of evacuation (2, 3). Although pregnancies aftermolar evacuation usually are normal gestations, preg-nancy obscures the value of monitoring hCG levels dur-ing this interval and may result in a delayed diagnosis ofpostmolar malignant gestational trophoblastic disease.

Oral contraceptives do not increase the incidence ofpostmolar gestational trophoblastic disease or alter thepattern of regression of hCG values (13, 19). In a ran-domized study, patients treated with oral contraceptiveshad one half as many intercurrent pregnancies as thoseusing barrier methods, and the incidence of postmolartrophoblastic disease was lower in patients using oralcontraceptives (20). After completion of documentedremission for 6–12 months, women who desire preg-nancy may discontinue contraception, and hCG monitor-

ing may be discontinued. Patients with prior partial orcomplete moles have a 10-fold increased risk (1–2% inci-dence) of a second hydatidiform mole in a subsequentpregnancy (20). Therefore, all future pregnancies shouldbe evaluated by early obstetric ultrasonography.

Which patients should be considered for pro-phylactic chemotherapy to reduce the risk ofpostmolar trophoblastic disease after molarevacuation?

Two randomized studies have evaluated prophylacticchemotherapy after molar evacuation. In one study, a sin-gle course of methotrexate and folinic acid reduced theincidence of postmolar trophoblastic disease from 47.4%to 14.3% (P <.05) in patients with high-risk moles (asdefined by hCG levels greater than 100,000 mIU/mL,uterine size greater than gestational age, and ovarian sizegreater than 6 cm), but the incidence was not reduced inpatients with low-risk moles (21). Patients who receivedprophylactic chemotherapy but developed postmolar tro-phoblastic disease required more chemotherapy than thosewho had not been exposed to prophylactic chemotherapy(21). In the second study, a single course of prophylacticdactinomycin was given to patients after evacuation ofhigh-risk moles (22). Postmolar trophoblastic diseaseoccurred in 50% of the control group, compared with13.8% of the treatment group. In both studies, there wereno deaths in the treatment or control groups caused by ges-tational trophoblastic disease or treatment toxicity (21,22). However, there are anecdotal cases of fatalities causedby prophylactic chemotherapy (3, 4), and prophylacticchemotherapy does not eliminate the need for postevacua-tion follow-up. In compliant patients, the low morbidityand mortality achieved by monitoring patients with serialhCG determinations and instituting chemotherapy only inpatients with postmolar gestational trophoblastic diseaseoutweighs the potential risk and small benefit of routineprophylactic chemotherapy.

What are the considerations for a patient withboth a hydatidiform mole and a co-existentfetus?

Co-existence of a fetus with molar changes of the pla-centa is relatively rare, occurring in 1 in 22,000–100,000pregnancies (23). Most of the literature covering thisentity consists of case reports, small case series, andreviews of cases reported in the literature. Both completeand partial moles with co-existent fetuses have beenreported (24). A variety of criteria have been used toevaluate these pregnancies. Many of the reports that ante-dated the histologic and cytogenetic distinction between

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complete and partial moles likely included partial molesand twin gestations with co-existent fetuses and molargestations. There may be an increased incidence of co-existing mole and fetus related to an increase in multife-tal pregnancies associated with ovulation induction, butthis may reflect reporting bias (25).

Most of these twin pregnancies are diagnosedantepartum by ultrasound findings of a complex, cysticplacental component distinct from the fetoplacental unit(23, 24); however, in a few cases, the diagnosis is not sus-pected until examination of the placenta following deliv-ery (25). Medical complications of hydatidiform molewith a co-existent fetus appear to be increased andinclude hyperthyroidism, hemorrhage, and pregnancy-induced hypertension (23, 24, 26).

Compared with singleton hydatidiform moles, twinpregnancies with a fetus and a mole carry an increasedrisk for postmolar gestational trophoblastic disease, witha higher proportion of patients having metastatic diseaseand requiring multiagent chemotherapy (23–26). Amongpatients with co-existent moles and fetuses who continuepregnancy, a subset develops early complications leadingto termination of the pregnancy before fetal viability,with a markedly increased risk of postmolar gestationaltrophoblastic disease, when compared with patientswhose pregnancies continue into the third trimester (23,24). Among 72 patients identified by a national survey ofphysicians in Japan in 1997, 24 underwent first-trimesterevacuation, with 20.8% subsequently developing post-molar gestational trophoblastic disease (26). In compar-ison, 45.2% of 31 patients who required evacuation during the second trimester and 17.6% of the 17 whogave birth in the third trimester developed postmolar ges-tational trophoblastic disease. Nine (50%) of the 18patients with proved complete hydatidiform moles inassociation with a fetus subsequently were treated forpostmolar gestational trophoblastic disease (26), but it isnot certain whether this increased risk resulted fromselection bias. Major congenital abnormalities have notbeen reported in surviving infants.

For patients with co-existing hydatidiform molesand fetuses suspected on the basis of ultrasound findings,there are no clear guidelines for management. The ultra-sound examination should be repeated to exclude retro-placental hematoma, other placental abnormalities, ordegenerating myoma and to fully evaluate the fetopla-cental unit for evidence of a partial mole or gross fetalmalformations. If the diagnosis is still suspected and con-tinuation of the pregnancy is desired, fetal karyotypeshould be obtained, a chest X-ray performed to screen formetastases, and serial serum hCG values monitored.These patients are at an increased risk for medical com-plications of pregnancy requiring evacuation, including

bleeding, preterm labor, and pregnancy-induced hyper-tension. They should be counseled about these risks andthe increased risk of postmolar trophoblastic disease afterevacuation or delivery. If the fetal karyotype is normal,major fetal malformations are excluded by ultrasoundexamination, and there is no evidence of metastatic dis-ease, it is reasonable to allow the pregnancy to continueunless pregnancy-related complications force delivery.After delivery, the placenta should be histologically eval-uated and the patient followed closely with serial hCGvalues, similar to management of a woman with a single-ton hydatidiform mole.

What are the characteristics of false-positivehCG values, also known as “phantom hCG”?

Rarely, women have persistently elevated hCG levels butare subsequently found to have a false-positive hCGassay result, sometimes after receiving chemotherapy orsurgery for presumed malignant gestational trophoblasticdisease. Most patients with false-positive hCG valueshave low-level hCG elevations (27–29), but occasionallyvalues higher than 300 mIU/mL have been recorded.False-positive hCG values result from interference withthe hCG immunometric sandwich assays, most oftencaused by nonspecific heterophilic antibodies in thepatient’s sera (27). Many of these patients have an unde-fined previous pregnancy event and do not have radi-ographic evidence of metastatic disease.

False-positive hCG values also may appear afterevacuation of a hydatidiform mole or following a clearlydefined pregnancy event, such as an ectopic pregnancy,and a urine pregnancy test may be considered to differ-entiate between the two (30). False-positive test resultsshould be suspected if hCG values plateau at relativelylow levels and do not respond to therapeutic maneuvers,such as methotrexate given for a presumed persistentmole or ectopic pregnancy. Evaluation should includeevaluation of serum hCG levels using a variety of assaytechniques at different dilutions of patient serum, com-bined with a urinary hCG level if the serum level is high-er than the threshold for the urinary assay, usually morethan 50–60 mIU/mL (27–29). False-positive hCG assaysusually will not be affected by serial dilution of patientsera and will have marked variability using differentassay techniques, with most assays reflecting unde-tectable hCG levels (27, 29). Heterophilic antibodies arenot excreted in the urine; therefore, urinary hCG valueswill not be detectable if they are the cause of serum hCGlevel elevation (27). Other techniques also are availableto inactivate or strip the patient’s serum of heterophilicantibodies. It is important to exclude the possibility offalse-positive hCG values before subjecting these

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patients to hysterectomy or chemotherapy for gestation-al trophoblastic disease.

How are patients with malignant gestationaltrophoblastic disease classified and staged?

Three systems have been used to categorize patients withmalignant gestational trophoblastic disease: 1) the WorldHealth Organization (WHO) prognostic index score,2) the Clinical Classification system developed from earlyexperience with chemotherapy for patients treated at theNational Institutes of Health (NIH), and 3) the FIGO stag-ing system, which was revised in 2000. The originalanatomic FIGO staging system did not take into accountother factors that might reflect disease outcome, such ashCG level, duration of disease, or type of antecedentpregnancy (14). The revised FIGO staging systemincludes a modification of the WHO prognostic indexscore for risk assessment (Table 2). All systems correlatewith clinical outcomes of patients treated for malignantgestational trophoblastic disease and identify patients atrisk for failure to respond to chemotherapy (4, 31–33).

The WHO prognostic index score assigned aweighted value to several individual clinical variables (4,14). The total prognostic index score used a sum of theindividual component scores to generate 3 risk cate-gories. The 2000 FIGO modification of the WHO prog-nostic index score eliminated the determination ofpatient and consort blood types because these are notuniformly available and consolidated the risk categoriesinto low-risk (total score less than 7) and high-risk (totalscore of 7 or higher) categories (14). The new FIGO riskindex also standardized the radiologic studies to be usedfor determining the number and size of metastases. In

one retrospective analysis, the new FIGO risk index cor-related with outcome better than previous modificationsof the WHO prognostic index score (32), and severalother studies have correlated outcome to WHO prognos-tic index risk categories (4, 31, 33).

The original analyses of patients treated for metasta-tic gestational trophoblastic disease at the NIH led to thecurrent Clinical Classification system that is frequentlyused in the United States (Table 3) (4). This system seg-regates patients with nonmetastatic disease from thosewith metastatic disease because virtually all patientswith nonmetastatic disease can be cured using initial sin-gle-agent chemotherapy, regardless of other risk factors(33, 34). Patients with metastatic disease are further sub-divided depending on the presence or absence of factorsthat correlate with response to initial single-agentchemotherapy (34, 35). Those who lack any of the high-risk clinical factors are likely to respond to initialsingle-agent therapy and are classified as having good-prognosis metastatic gestational trophoblastic disease.Patients who have any single high-risk clinical factor areclassified as having poor-prognosis disease. Thesepatients are not only at an increased risk of failure of sin-gle-agent chemotherapy but also have an increased riskof death if treated with single-agent therapy followed bymultiagent regimens when compared with patientsreceiving initial multiagent regimens (35).

Although the WHO prognostic index score mayprovide a more precise definition of prognosis amongpatients with high-risk disease, the Clinical Classifi-cation system is less complicated and allows easy identi-fication of patients for whom initial single-agentchemotherapy is likely to fail (33). Virtually all deathsfrom malignant gestational trophoblastic disease occur


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Table 2. Revised FIGO Scoring System

FIGO Score 0 1 2 4

Age (y) ≤39 >39 — —

Antecedent pregnancy Hydatidiform mole Abortion Term pregnancy —

Interval from index pregnancy (mo) <4 4–6 7–12 >12

Pretreatment human chorionic <1,000 1,000–10,000 >10,000–100,000 >100,000gonadotropin level (mIU/mL)

Largest tumor size including 3–4 5 — —uterus (cm)

Site of metastases Lung, vagina Spleen, kidney Gastrointestinal tract Brain, liver

Number of metastases identified 0 1–4 4–8 >8

Previous failed chemotherapy — — Single drug 2 or more drugs

The total score for a patient is obtained by adding the individual scores for each prognostic factor. Total score 0–6 = low risk; ≥7 = high risk.

Kohorn EI. The new FIGO 2000 staging and risk factor scoring system for gestational trophoblastic disease: description and clinical assessment. Int J Gynecol Cancer2001;11:73–7.

among women who fall into the poor-prognosis metastat-ic disease category, and these patients should be consid-ered to have high-risk disease (33). All patients withhigh-risk malignant gestational trophoblastic diseaseshould be referred for management in consultation withindividuals who are experienced in the treatment of thisdisease.

What are the general considerations for theevaluation and treatment of malignant gesta-tional trophoblastic disease?

Once the diagnosis of malignant gestational trophoblas-tic disease is suspected or established, immediate evalu-ation for metastases and risk factors is mandatory. Alongwith history and physical examinations, the followinglaboratory studies should be performed: complete bloodcount with platelet determinations, clotting functionstudies, renal and liver function studies, blood type andantibody screen, and determination of baseline (prether-apy) hCG level. Recommended radiographic studiesinclude chest X-ray or computerized tomography (CT)scan of the chest, pelvic ultrasonography, brain magnet-ic resonance imaging or CT scan, and abdominopelvic

CT with contrast or magnetic resonance imaging scans(14). Systemic venous metastasis of malignant gesta-tional trophoblastic disease results in pulmonary or occa-sional vaginal lesions. Systemic arterial metastasis usually occurs only after pulmonary metastases havebeen established; therefore, the minimum evaluation of apatient with postmolar gestational trophoblastic diseaseis a chest X-ray. If lung lesions are detected, furtherimaging of the abdomen and brain should be performedto identify possible liver or brain metastasis.

Because of the relative rarity of malignant gesta-tional trophoblastic disease, there are few randomizedtrials of therapy, and only one completed trial has beenreported to date (13). Most studies have been retrospec-tive analyses of single-institution experiences, but theseconfirm high activity for a variety of agents in the treat-ment of malignant gestational trophoblastic disease,including methotrexate, dactinomycin, etoposide, 5-flu-orouracil, and cisplatin (4, 36).

How is nonmetastatic gestational trophoblas-tic disease treated? In a patient with non-metastatic gestational trophoblastic disease,which is better: hysterectomy alone or incombination with chemotherapy?

Primary remission rates of patients treated with a varietyof chemotherapy regimens for nonmetastatic gestationaltrophoblastic disease are similar (4). Essentially allpatients with this condition can be cured, usually withouthysterectomy. Randomized comparisons of these regi-mens have not been completed. A prospective phase-IItrial by the Gynecologic Oncology Group reported a70–80% primary remission rate for patients with nonmetastatic gestational trophoblastic disease treatedwith weekly intramuscular methotrexate at a dose of 30–50 mg/m2 (37). There was no apparent benefit ofincreasing the dose to 50 mg/m2. It was concluded thatthe weekly methotrexate regimen was the preferredchoice of several methotrexate or dactinomycin sched-ules when efficacy, toxicity, and cost were taken intoconsideration (37, 38). Chemotherapy is continued untilhCG values have reached normal levels; an additionalcourse is administered after the first normal hCG valuehas been recorded (37, 39). Hematologic indices shouldbe monitored carefully during chemotherapy, but signif-icant hematologic toxicity is infrequent among patientstreated with weekly methotrexate (37). Patients shouldhave normal renal and liver functions before each treat-ment because methotrexate is excreted entirely by thekidney and can produce hepatic toxicity.

In patients with nonmetastatic gestational trophoblas-tic disease, early hysterectomy will shorten the duration


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Table 3. Clinical Classification System for Patients WithMalignant Gestational Trophoblastic Disease

Category Criteria

Nonmetastatic gestational No evidence of metastases; nottrophoblastic disease assigned to prognostic category

Metastatic gestational Any extrauterine metastasestrophoblastic disease

Good-prognosis metastatic No risk factors:gestational trophoblastic Short duration (<4 mo)disease Pretherapy hCG level

<40,000 mIU/mL

No brain or liver metastases

No antecedent term pregnancy

No prior chemotherapy

Poor-prognosis metastatic Any risk factor:gestational trophoblastic Long duration (≥4 mo since lastdisease pregnancy)

Pretherapy hCG level ≥40,000 mIU/mL

Brain or liver metastases

Antecedent term pregnancy

Prior chemotherapy

Abbreviation: hCG, human chorionic gonadotropin.

Soper JT, Lewis JL Jr, Hammond CB. Gestational trophoblastic disease. In: HoskinsWJ, Perez CA, Young RC, editors. Principals and practice of gynecologic oncolo-gy, 2nd ed. Philadelphia (PA): Lippincott-Raven; 1997. p. 1055.

and amount of chemotherapy required to produce remis-sion (34, 40). Therefore, each patient’s desire for futurefertility should be evaluated at the onset of treatment.Many experts prefer to perform hysterectomy during thefirst cycle of chemotherapy and continue administrationof chemotherapy for 2 cycles after a negative hCG meas-urement has been obtained. Chemotherapy after hysterec-tomy is needed until hCG values become normal.

Patients whose hCG levels reach a plateau orincrease during therapy should be switched to an alter-native single-agent regimen. If metastases appears oralternative single-agent chemotherapy fails, the patientshould be treated with multiagent regimens (4). Hyster-ectomy should be considered for the treatment of non-metastatic disease that is refractory to chemotherapy andremains confined to the uterus (34, 41).

The overall cure rate for patients with nonmetastaticdisease is nearly 100% (1, 33, 34, 37, 42). When chemo-therapy is given for an additional 1–2 cycles after the firstnormal hCG value, recurrence rates are less than 5% (39).

How is low-risk metastatic gestational tro-phoblastic disease treated?

Patients with metastatic gestational trophoblastic diseasewho lack any of the clinical high-risk factors (33–35) orhave a FIGO risk score less than 7 (14) have low-riskdisease. They can be treated successfully with initial sin-gle-agent regimens. Most often, this consists of 5-daytreatment using methotrexate or intravenous dactino-mycin recycled at 14-day intervals (33, 42, 43). Approx-imately 40% of these patients will require alternativetherapy to achieve remission (43); however, essentiallyall patients with low-risk metastatic gestational tropho-blastic disease can be cured with conventional chemo-therapy (31, 33, 34, 42). Hysterectomy in conjunctionwith chemotherapy also may decrease the amount ofchemotherapy required to achieve remission in thesepatients (34). Similar to the treatment of women withnonmetastatic gestational trophoblastic disease, 1–2cycles of chemotherapy should be given after the firstnormal hCG level. Recurrence rates are less than 5%among patients successfully treated for low-risk metasta-tic disease (39).

How is high-risk metastatic gestational tro-phoblastic disease treated?

Patients with 1 or more of the Clinical Classification sys-tem risk factors (33–35) or a FIGO risk score of 7 orhigher (14) have high-risk disease. They will requiremultiagent chemotherapy with additional surgery orradiation often incorporated into treatment (34). Survival

rates reported by trophoblastic disease centers have beenreported as high as 84% (31–34, 36, 44). In contrast topatients with nonmetastatic or low-risk metastatic gesta-tional trophoblastic disease, early hysterectomy does notappear to improve the outcome in women with high-riskmetastatic disease (34).

Aggressive treatment with multiagent chemotherapyis an important component for management of thesepatients. Triple therapy with methotrexate, dactino-mycin, and either chlorambucil or cyclophosphamidewas the standard regimen for many years in the UnitedStates (4, 35, 44). In a randomized trial, a more complexmultiagent regimen was not proved to be superior totriple therapy with methotrexate, dactinomycin, andeither chlorambucil or cyclophosphamide (44, 45). Morerecent regimens have incorporated etoposide with orwithout cisplatin into combination chemotherapy (4, 36,46–48) with high rates of success but with an increasedrisk for leukemia in survivors. A randomized comparisonof the newer combinations with triple therapy withmethotrexate, dactinomycin, and either chlorambucil orcyclophosphamide would provide helpful information.

Management of cerebral metastases is controversial.Radiation therapy has been used concurrently withchemotherapy in an attempt to limit acute hemorrhagiccomplications from these metastases. Brain irradiationcombined with systemic chemotherapy is successful incontrolling brain metastases with cure rates up to 75% inpatients with brain metastases (49). However, a similarprimary remission rate also has been reported amongpatients treated with combination regimens that incorpo-rated high-dose systemic methotrexate combined withintrathecal methotrexate infusions without brain irradia-tion (46). The best treatment for liver or other high-risksites of metastases has not been established. Even withintense chemotherapy, additional surgery may be neces-sary to control hemorrhage from metastases, removechemoresistant disease, or treat other complications tostabilize high-risk patients during therapy (34, 41).

Chemotherapy is continued until hCG values havenormalized, followed by at least 2 or 3 courses of main-tenance chemotherapy in the hope of eradicating allviable tumors. Despite the use of sensitive hCG assaysand maintenance chemotherapy, up to 13% of patientswith high-risk disease will develop recurrence afterachieving an initial remission (39).

What is the recommended surveillance fol-lowing completion of chemotherapy formalignant gestational trophoblastic disease?

After hCG remission has been achieved, patients withmalignant gestational trophoblastic disease should


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undergo serial determinations of hCG levels at 2-weekintervals for the first 3 months of remission and then at1-month intervals until monitoring has shown 1 year ofnormal hCG levels. The risk of recurrence after 1 year ofremission is less than 1% (39), but late recurrences havebeen observed rarely.

Patients should be counseled to use a reliable form ofhormonal contraception during the first year of remission.Because of the 1–2% risk for a second mole in subse-quent pregnancies (20), early ultrasound examination isrecommended for all future pregnancies. There does notappear to be an increase in the risk of congenital malfor-mations or other complications related to pregnancy (20).

Summary ofRecommendationsThe following recommendations are based ongood and consistent scientific evidence (Level A):

In women of reproductive age with abnormal bleed-ing or symptoms that could be caused by a malig-nancy, β-hCG levels should be evaluated to facilitateearly diagnosis and treatment of gestational tro-phoblastic disease.

In patients with molar pregnancy, the preferredmethod of evacuation is suction D&C. After molarevacuation, all patients should be monitored withserial hCG determinations to diagnose and treatmalignant sequelae promptly.

Oral contraceptives have been demonstrated to besafe and effective during posttreatment monitoringbased on randomized controlled trials.

Women with nonmetastatic gestational trophoblas-tic disease should be treated with single-agentchemotherapy.

For women with nonmetastatic gestational tro-phoblastic disease, weekly doses of 30–50 mg/m2 ofintramuscular methotrexate has been found to be themost cost-effective treatment when taking efficacy,toxicity, and cost into consideration.

Women with metastatic gestational trophoblasticdisease should be referred to specialists with experi-ence treating this disease.

Women with high-risk metastatic disease should betreated with multiagent chemotherapy. This includestriple therapy with methotrexate, dactinomycin, andeither chlorambucil or cyclophosphamide. Morerecent regimens further incorporate etoposide withor without cisplatin into combination chemotherapy.

The following recommendations are based on lim-ited or inconsistent scientific evidence (Level B):

False-positive test results should be suspected ifhCG values plateau at relatively low levels and donot respond to therapeutic maneuvers, such asmethotrexate given for a presumed persistent moleor ectopic pregnancy.

Serial quantitative serum hCG determinationsshould be performed using a commercially availableassay capable of detecting β-hCG to baseline values(<5 mIU/mL). Ideally, serum hCG levels should be obtained within 48 hours of evacuation, every1–2 weeks while elevated, and then at 1–2 monthintervals for an additional 6–12 months.

The following recommendations are based primar-ily on consensus and expert opinion (Level C):

Abnormal bleeding for more than 6 weeks followingany pregnancy should be evaluated with hCG testingto exclude a new pregnancy or gestational tropho-blastic disease.

In compliant patients, the low morbidity and mor-tality achieved by monitoring patients with serialhCG determinations and instituting chemotherapyonly in patients with postmolar gestational tropho-blastic disease outweighs the potential risk andsmall benefit of routine prophylactic chemotherapyafter evacuation of a molar pregnancy.

Serious complications are not uncommon in womenwith a uterus size greater than a 16-week gestation, sothey should be managed by physicians experienced inthe prevention and management of complications.

Patients for whom initial therapy for nonmetastaticor low-risk metastatic disease fails and those withhigh-risk malignant gestational trophoblastic dis-ease should be managed in consultation with indi-viduals or facilities with expertise in the complex,multimodality treatment of these patients.

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The MEDLINE database, the Cochrane Library, andACOG’s own internal resources and documents were usedto conduct a literature search to locate relevant articles pub-lished between January 1985 and February 2004. Thesearch was restricted to articles published in the Englishlanguage. Priority was given to articles reporting results oforiginal research, although review articles and commentar-ies also were consulted. Abstracts of research presented atsymposia and scientific conferences were not consideredadequate for inclusion in this document. Guidelines pub-lished by organizations or institutions such as the NationalInstitutes of Health and the American College of Obstetri-cians and Gynecologists were reviewed, and additionalstudies were located by reviewing bibliographies of identi-fied articles. When reliable research was not available,expert opinions from obstetrician–gynecologists were used.

Studies were reviewed and evaluated for quality accordingto the method outlined by the U.S. Preventive Services TaskForce:

I Evidence obtained from at least 1 properly designedrandomized controlled trial.

II-1 Evidence obtained from well-designed controlledtrials without randomization.

II-2 Evidence obtained from well-designed cohort orcase–control analytic studies, preferably from morethan 1 center or research group.

II-3 Evidence obtained from multiple time series with orwithout the intervention. Dramatic results in uncon-trolled experiments also could be regarded as thistype of evidence.

III Opinions of respected authorities, based on clinicalexperience, descriptive studies, or reports of expertcommittees.

Based on the highest level of evidence found in the data,recommendations are provided and graded according to thefollowing categories:

Level A—Recommendations are based on good and consis-tent scientific evidence.

Level B—Recommendations are based on limited or incon-sistent scientific evidence.

Level C—Recommendations are based primarily on con-sensus and expert opinion.

Copyright © June 2004 by the American College of Obstetri-cians and Gynecologists. All rights reserved. No part of thispublication may be reproduced, stored in a retrieval system, ortransmitted, in any form or by any means, electronic, mechan-ical, photocopying, recording, or otherwise, without prior writ-ten permission from the publisher.

Requests for authorization to make photocopies should bedirected to Copyright Clearance Center, 222 Rosewood Drive,Danvers, MA 01923, (978) 750-8400.

The American College of Obstetricians and Gynecologists409 12th Street, SWPO Box 96920Washington, DC 20090-6920

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Diagnosis and treatment of gestational trophoblastic disease. ACOGPractice Bulletin No. 53. American College of Obstetricians andGynecologists. Obstet Gynecol 2004;103:1365–77.


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