Lancet. 2010

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www.thelancet.com Vol 376 August 28, 2010 717

Lancet 2010; 376: 71729

Published Online

July 28, 2010

DOI:10.1016/S0140-

6736(10)60280-2

Department of Cancer

Medicine (Prof M J Seckl FRCP)

and Department of

Histopathology

(N J Sebire FRCPath), Charing

Cross Gestational Trophoblastic

Disease Centre, Charing Cross

Hospital Campus of Imperial

College London, London, UK;and New England

Trophoblastic Disease Center,

Division of Gynecologic

Oncology, Department of

Obstetrics and Gynecology,

Harvard Medical School,

Brigham and Womens

Hospital, Dana-Farber Cancer

Institute, Boston, MA, USA

(R S Berkowitz MD)

Correspondence to:

Prof Michael J Seckl, Department

of Cancer Medicine, Charing Cross

Gestational Trophoblastic Disease

Centre, Charing Cross Hospital

Campus of Imperial College

London, London W6 8RF, UK

[email protected]

Gestational trophoblastic disease

Michael J Seckl, Neil J Sebire, Ross S Berkowitz

Gestational trophoblastic disease encompasses a range of pregnancy-related disorders, consisting of the premalignantdisorders of complete and partial hydatidiform mole, and the malignant disorders of invasive mole, choriocarcinoma,and the rare placental-site trophoblastic tumour. These malignant forms are termed gestational trophoblastic tumoursor neoplasia. Improvements in management and follow-up protocols mean that overall cure rates can exceed 98%with fertility retention, whereas most women would have died from malignant disease 60 years ago. This success canbe explained by the development of effective treatments, the use of human chorionic gonadotropin as a biomarker,and centralisation of care. We summarise strategies for management of gestational trophoblastic disease and addresssome of the controversies and future research directions.

IntroductionHippocrates was probably the first to describe gestational

trophoblastic disease around 400 BC in his description ofdropsy of the uterus.1 Although other observations havebeen made since, Marchand first associated hydatidiformmole with pregnancy in 1895.1 Healthy trophoblastictissue aggressively invades the endometrium and developsa rich uterine vasculature, generating an intimateconnection between the fetus and the mother known asthe placenta. Invasion is one of the distinct features ofmalignant disease, and healthy trophoblast can bedetected by PCR in the maternal circulation.2 Fortunately,malignant-like behaviour is tightly controlled in healthytrophoblast. However, in gestational trophoblastic diseasethe regulatory mechanisms fail, resulting in tumours that

are highly invasive, metastatic, and very vascular. In thisSeminar we discuss the epidemiology, origins, patho-logical changes, and clinical behaviour of the variousforms of gestational trophoblastic disease.

EpidemiologyGestational trophoblastic disease arises more frequentlyin Asia than in North America or Europe,3,4 which couldbe due to differences in prevalence, discrepanciesbetween hospital-based and population-based data, ordisparity in availability of central pathology review. In theUK, all patients are included on a national register, withcentral pathology review; and the incidence of completehydatidiform mole is around one per 1000 pregnancies

and three per 1000 for partial hydatidiform mole.5 Otherdeveloped countries report similar data.6

The incidence of molar pregnancy has decreased inSouth Korea from 44 cases per 1000 births in the 1960s to16 cases per 1000 births in the 1990s,7 possibly because ofimproved socioeconomic conditions and dietarychangesespecially since findings from studies inanimals show that diet can reset the genetic imprint.8Additionally, an increased risk of molar pregnancy isassociated with reduced consumption of dietary carotene9,10and animal fat,9 and advanced maternal age.3,1113 Ova fromolder women are more susceptible to abnormal fertilisa-tions than are those from younger women.

After a molar pregnancy, the risk of further completeand partial mole rises to 12%.11,14,15 After two molar

gestations, the risk of a third mole is 1520%,11,14,15 and therisk is not decreased by change of partner.16 Some repeat

molar pregnancies are due to familial or sporadicbiparental molar disease (figure 1).

The frequency of choriocarcinoma or placental-sitetrophoblastic tumour is less well known, since thesediseases can arise after any type of pregnancy. 17,18 Chorio-carcinoma develops in around one in 50 000 deliveries, 19and placental-site trophoblastic tumour accounts for about02% of cases of gestational trophoblastic disease in theUK.20 The risk of gestational trophoblastic neoplasia mightalso be linked to hormonal factors, since women withmenarche after 12 years of age, light menstrual flow, andprevious use of oral contraceptives are at increased risk.21,22Additionally, risk of malignant disease after hydatidiform

mole has been associated with oral contraceptive use (ifstarted when human chorionic gonadotropin [hCG]concentrations are raised) in some23 but not all24studies.

Causes and geneticsIn most cases, complete hydatidiform mole usuallyarises when an ovum without maternal chromosomes

Search strategy and selection criteria

We searched the Cochrane Library, Medline (via PubMed,

Internet Grateful Med, OVID, and Knowledgefinder), for

meta-analyses, previous systematic reviews, cohort studies

(and when appropriate comparison groups), and case-control

studies published in English between 1980 and 2010, with

the keywords trophoblastic disease, GTD, GTN,

choriocarcinoma, molar pregnancy, hydatidiform mole,

placental site trophoblastic tumor, genetics,

epidemiology, pathology, treatment, chemotherapy,

methotrexate, actinomycin D, dactinomycin, cisplatin,

paclitaxel, high-dose, management, risk factors,

hCG, imaging, ultrasound, PET, CT, MRI,

prognosis, and staging. We included results presented at

the 15th International Society for the Study of Trophoblastic

Diseases meeting in November, 2009, in Cochin, India.

Reference lists from all previous publications were scanned to

find any publications not already identified by our electronic

search strategy.

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718 www.thelancet.com Vol 376 August 28, 2010

is fertilised by one sperm that then duplicates its DNA,

resulting in a 46XX androgenetic karyotype, in which allchromosomes are paternally derived.2527 About 10% ofcomplete moles are 46XY,28 arising from fertilisation bytwo sperm (figure 1). Although nuclear DNA is entirelypaternal, mitochondrial DNA remains maternal inorigin.29 Findings from some studies30 show that patients

with recurrent disease can have biparental molar rather

than typical androgenetic disease, which might befamilial or sporadic. Genetic studies in such familiesshowed that the related genes are at chromosome19q13.313.4,31 and subsequent analysis noted NLRP7mutations in this region.32 The function of the normalprotein and the mechanism by which mutations areassociated with imprinting abnormalities andgestational trophoblastic disease are unknown.33 Datashow clustering of mutations in the leucine-rich regionof NLRP7 (figure 2), suggesting that this region iscrucial for normal function.34Some androgenetic diploidcomplete moles and possibly even triploid partialhydatidiform moles might also carry NLRP7mutations,35but confirmation from large studies is needed.

Partial hydatidiform moles are almost always triploid(figure 1), and they result from fertilisation of a seeminglyhealthy ovum by two sperm;3638 diploid partial molesprobably do not exist, with most reported cases beingmisdiagnosed complete moles.39

PathologyAll gestational trophoblastic disease is derived from theplacenta. Hydatidiform moles and choriocarcinomaarise from villous trophoblast and placental-sitetrophoblastic tumours from interstitial trophoblast.Most complete and partial hydatidiform moles havedistinctive morphological characteristics, althoughdiagnostic criteria have changed because evacuation isdone earlier in gestation (median 89 weeks in the UK).First-trimester complete moles show a characteristicabnormal budding villous structure with trophoblasthyperplasia, stromal karyorrhectic debris, and collapsedvillous blood vessels. By contrast, early partial molesshow patchy villous hydrops with scattered abnormallyshaped irregular villi, trophoblastic pseudoinclusions,and patchy trophoblast hyperplasia (figure 3).4042

Morphological distinction of non-molar miscarriagefrom partial hydatidiform mole can be diffi cult, sincevillous dysmorphism can be present but without thecharacteristic trophoblast hyperplasia that is noted inpartial mole. Ancillary techniques are needed in some

cases to differentiate non-molar miscarriage fromhydatidiform mole, including immunostaining for P57kip2,the product of CDKN1C. P57kip2 is expressed by thematernal allele and is visible on histology as nuclearstaining of cytotrophoblast and villous mesenchyme inplacenta of all gestations apart from androgenetic completemole.43,44 Additionally, ploidy analysis by in-situhybridisation or flow cytometry can distinguish diploidfrom triploid conceptions, helping to diagnose partialmole, but is unable to distinguish complete mole fromdiploid non-molar miscarriage, or molar versus non-molartriploidy, which necessitate molecular investigations.18,4547

Choriocarcinomas are malignant hCG-producingepithelial tumours with central necrosis and a characteristicbiphasic architecture recapitulating cytotrophoblast-like

T61TfsX7

E113GfsX7

Y318CfsX7

R432X

L398R C761Y

P716A

R721W

P651S

R693QR693WR693P

N913S

PYD NACHT Leucine-rich region

E570X

L6776PfsX6

P716LfsX21

Figure 2: Domain structure ofNLRP7 and identified mutations noted in 17 families with biparental repetitive

hydaditiform moles

Predicted protein domains include PYRIN (PYD), NACHT, and a leucine-rich region. The nine missense aminoacid

substitutions or mutations are shown above the protein and seven nonsense mutations are shown below theprotein. There seems to be some clustering of mutations in the leucine-rich region.

CHM

CHM

PHM

biCHM

Androgenetic diploid (monospermic)

XX

X

Androgenetic diploid (dispermic)

XY

XY

Biparental triploid

Chromosome 19q: NLRP7 (NALP7) defectSporadic or hereditaryAutosomal recessive

XXX

X

XX

X

X

X

X

Figure 1: Karyotype derivation of complete and partial hydatidiform moles

and rare biparental repetitive complete hydatidiform mole

CHM=complete hydatidiform mole. PHM=partial hydatidiform mole.

biCHM=rare biparental complete hydatidiform mole. Paternal (black) and

maternal (red) derived genes are shown.

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cells and multinucleate, pleomorphic syncytiotrophoblast-like regions; however, mononuclear cells predominate insome cases, especially after chemotherapy.48 Intraplacentalchoriocarcinoma does occur and is probably the source ofmetastatic disease after term pregnancies. Most cases ofneonatal choriocarcinoma result from metastatic spreadfrom an intraplacental choriocarcinoma.49 Placental-sitetrophoblastic tumours are the malignant equivalent of

extravillous, interstitial implantation site-like trophoblastand form uterine lesions with less haemorrhage andnecrosis, and lower hCG concentrations than doeschoriocarcinoma.48,50 Epithelioid trophoblastic tumouravariant of placental-site trophoblastic tumour with similarclinical behaviour but distinctive hyalinisationhas beenreported, but data for this disease are sparse.51

Accurate measurement of hCG is key to effectivemanagement of gestational trophoblastic disease, severalcancers, and pregnancy. Panel 1 summarises some of theissues related to hCG measurements.

Diagnostic ultrasound for molar pregnancyPatients with complete hydatidiform mole mostcommonly present with vaginal bleeding in early

pregnancy. Previously reported features such asanaemia, uterine enlargement, pre-eclampsia,hyperemesis, hyperthyroidism, and respiratory distressare now rare,60 probably because routine use ofultrasonography leads to diagnosis in the first ratherthan late-second trimester. Partial hydatidiform molesgrow more slowly and present slightly later in the firstor early second trimester than do complete moles, but

also manifest with vaginal bleeding or missed orincomplete miscarriages.61,62 Characteristic ultra-sonographic scans of complete mole show a uterinecavity filled with a heterogeneous mass (so-calledsnowstorm), without associated fetal development andwith theca lutein ovarian cysts.63,64 However, thesefeatures are not visible in the first trimester and,although some investigators6570 have suggested thatultrasound can be diagnostic of complete mole in earlypregnancy, large studies71,72 have shown that only 4060%of cases are detected as molar by sonography in routineclinical practice. Moreover, 10% of cases that are thoughtto be molar on sonography were diagnosed as non-molar hydropic abortions on histological review. 71Findings from other reports73 are similar and emphasise

BA

DC

1 mm 05 mm

01 mm 01 mm

Figure 3: Gestational trophoblastic disease

(A) Complete hydatidiform mole (magnification 20). (B) Partial hydatidiform mole (magnification 40). (C) Placental-site trophoblastic tumour (magnification 200).

(D) Choriocarcinoma (magnification 100). All forms have abnormal trophoblast proliferation, which is associated with dysmorphic chorionic villi in complete and

partial hydatidiform moles, but villi and abnormal trophoblast invasion are not noted in placental-site trophoblastic tumour or choriocarcinoma.

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that false-positive and false-negative rates are high withultrasonographyespecially for partial hydatidiformmoleand histological examination is necessary to

achieve a correct diagnosis.40,74All products of conceptionfrom non-viable pregnancies should undergo histologicalexamination irrespective of ultrasonographic findings.75

Some women who miscarry or have medicalterminations will have had unsuspected molarpregnancies. Because ultrasonography cannot reliablyconfirm molar disease and histological examination ofproducts might not be done after pregnancy termination,delayed diagnosis of gestational trophoblastic neoplasia,and hence substantial morbidity with the need for complexchemotherapy and surgery, can result.76 Histologicalexamination after every termination would beimpracticable, so checking of hCG concentrations at34 weeks after treatment to ensure a return to a valuewithin the normal range is recommended.77

Surgical evacuation

Suction curettage is the preferred method of evacuationirrespective of uterine size in patients with suspectedhydatidiform mole who want to preserve fertility.78,79Intraoperative ultrasonography can reduce the risk ofuterine perforation. Patients who are rhesus-negativeshould receive rhesus immunoglobulin at the time ofevacuation because rhesus D factor is expressed ontrophoblast. Women who are nulliparous should not begiven prostanoids to ripen the cervix since these drugscan induce uterine contractions and might increase therisk of trophoblastic embolisation to the pulmonaryvasculature.80 Hysterectomy is rarely recommended butmight be considered for women who do not want furtherchildren or have life-threatening haemorrhage.81,82

Patients should be counselled that, although hysterectomystops the risk of local invasion, it does not eliminate thepossible need for chemotherapy, and monitoring of hCGconcentrations should still be done.11

A healthy co-twin can develop alongside a completeor partial hydatidiform mole in one per20 000100 000 pregnancies (figure 4). Some investigatorshave suggested that such pregnancies should beterminated because of the low probability of successfuloutcome and the increased risk of development ofmalignant disease.83 However, evidence from a caseseries84 of 77 pregnancies suggests that about 40% ofwomen will deliver a healthy baby without a significantincrease in the risk of malignant transformation of thecomplete hydatidiform mole. Findings from a study76 of2800 singleton molar pregnancies lent support to thenotion that late evacuation of complete hydatidiformmole is not associated with an increased rate ofmalignant disease.

Registration for hCG surveillanceAll patients with hydatidiform mole should be registeredwith a specialist centre for hCG surveillance, preferablyone that is coordinated nationally. The UK establishedthe first national service for gestational trophoblasticdisease through a combined agreement of the RoyalCollege of Obstetricians and Gynaecologists and the

Department of Healths National Commissioning Group.Since 1973, all women with hydatidiform mole or otherforms of gestational trophoblastic disease have beenregistered with one of three centres for hCG monitoringand, if subsequent treatment is necessary, are treated atthe Sheffi eld Trophoblastic Disease Centre (Sheffi eld,UK) or Charing Cross Hospital Trophoblast DiseaseCentre (London, UK).

Onset of malignant change, termed persistentgestational trophoblastic disease or post-mole neoplasia,is signified by a plateaued or rising hCG concentration.Studies in the UK show that malignant change arisesafter 15% of complete and 0510% of partialhydatidiform moles.11,18,85 Rates are probably higher inother countries than the UK,86 possibly because of

Panel 1: hCG measurement in gestational trophoblastic disease and cancer

hCG comprises an subunit (shared with other members of the glycoprotein hormones,

including thyroid-stimulating hormone and luteinising hormone) and a subunit that

confers specificity. Consequently, assays designed to specifically detect hCG have to target

the subunit. In healthy pregnancy, hCG is intact and is hyperglycosylated during the first

trimester. However, in cancer, many other subtypes of -hCG can exist, including free--

hCG, -core, nicked free-, or c-terminal peptide.52,53 Therefore, hCG assays used in cancer

need to detect all forms of hCG and not only those found in healthy pregnancy. Moreover,

the different -hCG forms should be detected equally well.

Unfortunately, most commercial assays fail to or variably detect all forms of -hCG and

therefore are prone to false-negative results in patients with cancer.52,54 Additionally,

every assay is susceptible to false-positive results, usually caused by cross-reacting

heterophile antibodies. These antibodies do not pass into the urine, so if hCG is present,

a false-positive serum value can be excluded in most cases, although other approaches

to this problem might be necessary.55

However, the false-negative issue cannot be easily resolved and is potentially clinically

important, since a false-negative finding could result in delayed diagnosis or premature

withdrawal of chemotherapy, or both.52,54 No commercial assay is licensed for use in cancer

diagnosis or management at present, although many are used for this purpose.

In the UK, we use a non-commercial rabbit polyclonal antibody that detects all forms of

hCG for monitoring of patients with gestational trophoblastic disease. By comparison with

other assays, our assay seems to have a low false-negative rate and, since we routinely

measure hCG in serum and urine, false-positive results are rare. This assay is not available

worldwide and, to our knowledge, the only commercial assay that seems comparably safe

to use in gestational trophoblastic disease is the Siemens Immulite(Deerfield, IL, USA).53,54

Therefore, a new generation of cancer-specific hCG assays is urgently needed.

Findings from recent studies56,57 that used a hyperglycosylated hCG assay suggest that ahigh ratio of this variant to total hCG can detect malignant forms of gestational

trophoblastic disease. These findings correlate with some biological evidence56 suggesting

that hyperglycosylated hCG induces an invasive phenotype in trophoblast and

choriocarcinoma cells. Additionally, some preliminary studies58,59 suggest that free--hCG

is a marker for placental-site trophoblastic tumour and seminomatous germ cell tumours.

Prospective studies in large patient cohorts are needed to define the role of

hyperglycosylated hCG and free--hCG in the management of gestational cancers.

hCG=human chorionic gonadotropin.

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differences in hCG criteria and overdiagnosis of

neoplasia, scarcity of whole-population demographics, ora difference in disease biology, although this explanationis unlikely. Precise surveillance protocols vary by countrybut principles are alike. In the UK, serum and urine hCGconcentrations are measured every 2 weeks until thevalues are within the normal range, and then urine hCGconcentrations are recorded monthly. Patients withnormal hCG values within 56 days of uterine evacuationhave a reduced risk of development of malignantdisease,11,87 and are monitored for 6 months fromevacuation date. When the first hCG reading within thenormal range is noted after 56 days, monthly monitoringcontinues for 6 months.87 Some investigators suggestshortened hCG surveillance, with discontinuation after

the first value within the normal range is measured,especially for women with partial mole in whom the riskof neoplasia is reduced.88,89 Shortened surveillance couldenable women to attempt a subsequent pregnancysooner, but could result in late development of neoplasiawith increased morbidity and mortality.

Data reported at the 2009 International Society for theStudy of Trophoblastic Diseases (ISSTD) world congressfrom 22 000 women with complete and partialhydatidiform moles in the UK suggest that either formcan occasionally develop post-mole neoplasia after thehCG has returned to normal; however, the risk ofmissed gestational trophoblastic neoplasia can bereduced from one in 800 women to one in 1400 byfollowing present UK guidelines.87 Consequently, UKpractice seems good for young women, but oldernulliparous women should be made aware of the relativerisks and benefits of an early pregnancy. During hCGfollow-up, patients are encouraged to use reliablecontraception, including a combination of methods,although data are conflicting about whether oralcontraceptives increase the risk for gestationaltrophoblastic neoplasia. In the UK, practitioners avoidrecommending oral contraceptives until hCG is in thenormal range.23,24 After completion of hCG monitoring,serum or urine hCG concentrations should be checked6 weeks and 10 weeks after every pregnancy to ensure

no reactivation of previous molar disease.90,91

TreatmentIndicationsPanel 2 shows the UK indications for treatment ofgestational trophoblastic disease with chemotherapy.These recommendations are similar to those suggestedby the International Federation of Gynecology andObstetrics (FIGO)92 and include a plateaued or risinghCG (the most common reason for treatment), apersistently raised hCG at 6 months after evacuation, orhistological diagnosis of choriocarcinoma. However, ourexperience suggests that the disease is unlikely to remitspontaneously when: the hCG concentration is morethan 20 000 IU/L, 1 month after evacuation (also

associated with an increased risk of uterine perforation);or there are lung or vaginal metastases more than 2 cmin diameter (small lesions can spontaneously regress), orspread to other organs.42,92 Additionally, in the UK,

chemotherapy is started to help to stop heavy bleedingthat necessitates transfusion, even when the hCGconcentration is falling.

Staging and stratificationMost patients who develop gestational trophoblasticneoplasia after hydatidiform mole are detected early byhCG monitoring so detailed investigation is rarelyneeded. Information on which to base therapy decisionscan be obtained from clinical histories, examination,and measurement of serum hCG. Additionally, patientsshould have doppler pelvic ultrasonography to confirmabsence of pregnancy, and to measure the uterine sizeand volume, spread of disease within the pelvis, anddisease vascularity (figure 5). Disease vascularity can

Normal placenta

Complete hydatidiform mole

A B

Figure 4: Twin pregnancy of a complete hydatidiform mole and healthy co-twin

(A) Ultrasonography and (B) MRI.

Panel 2: Indications for chemotherapy for gestational

trophoblastic disease in the UK

Plateaued or rising hCG concentration after evacuation*

Heavy vaginal bleeding or evidence of gastrointestinal or

intraperitoneal haemorrhage

Histological evidence of choriocarcinoma

Evidence of metastases in brain, liver, or gastrointestinal

tract, or radiological opacities larger than 2 cm on chest

radiograph

Serum hCG concentration of 20 000 IU/L or more,

4 weeks or more after evacuation, because of the risk ofuterine perforation

Raised hCG concentration 6 months after evacuation,

even when still decreasing

hCG=human chorionic gonadotropin. *A plateaued hCG concentration is defined as

four or more equivalent values of hCG for at least 3 weeks (days 1, 7, 14, and 21), and

rising as two consecutive increases in hCG concentration of 10% or more for at least

2 weeks (days 1, 7, and 14).

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suggest patients who are at risk of treatmentresistance.93,94Pulmonary metastases are most common,so chest radiography is essential.95 Chest CT is notneeded when findings from chest radiography isnormal, since discovery of micrometastases, which canbe seen in about 40% of patients, does not affectoutcome.96,97 However, if lesions are noted on chestradiograph, brain MRI and body CT are recommendedto exclude more widespread disease affecting, forexample, the brain or liver, which would substantiallychange management.

FIGO report data for gestational trophoblastic neoplasiaby use of prognostic scoring and anatomical staging

systems (table 1). Since 2002, all physicians treating

gestational trophoblastic neoplasia should use this systemto allow comparison of data. The combined prognosticscore predicts potential for development of resistance tomonochemotherapy with methotrexate or dactinomycin.A score of 06 suggests low risk of resistance and 7 ormore indicates high risk. Such disease has almost nochance of being cured with monochemotherapy andneeds multidrug treatment. Anatomical staging does notaid therapeutic choices but helps clinicians to compareresults between centres.

Low-risk diseaseAbout 95% of patients with hydatidiform mole whodevelop neoplasia are at low risk of resistance (score 06).

In patients with stage I disease that is seemingly confinedto the uterine cavity, the use of second dilatation andcurettage to reduce the need for chemotherapy iscontroversial.98101 Results from the UK suggest thatsecondary surgery is of no value when hCG concentrationsare greater than 5000 IU/L, since more than 50% of suchpatients will need chemotherapy.101 The low effectivenessof second surgery and small risks of infection,haemorrhage, and uterine perforation should bemeasured against the almost 100% cure rate andcomparative safety of chemotherapy. Some patients withstage I neoplasia who do not want further childrenrequest hysterectomy, which can be technically diffi cultwith these highly vascular tumours and does notcompletely obviate the need for chemotherapy.

For most low-risk patients with gestational trophoblasticneoplasia, monochemotherapy with methotrexate ordactinomycin is the preferred treatment. Many regimenshave been used, showing a 5090% chance of inductionof remission in non-randomised, mostly retrospective,studies.102 The wide variability results from differences indose, frequency, route of administration, and the criteriaused to select patients for therapy.19,95 Some investigatorssuggest that intensive therapy given daily for 58 daysevery 2 weeks is better than treatments given once every2 weeks;103 others suggest that dactinomycin is morelikely to induce remission than is methotrexate.104 The

few randomised studies102 that addressed some of theseissues were underpowered and compared regimens thatare not frequently used internationally. Patients in whomfirst-line therapy failsgenerally because of resistancecan be easily salvaged with second-line or occasionallythird-line chemotherapy, so overall survival is nearly100%.105 Since survival is so high, patients should begiven the least toxic therapy first to avoid exposure tomore harmful treatments.

The regimen of methotrexate (50 mg intramuscularlyevery 48 h for four doses) with calcium folinate (folinicacid) rescue (15 mg orally 30 h after methotrexate) regimendeveloped at our UK institute is effective and is welltolerated. Courses are repeated every 2 weeks. Unlikedactinomycin, this regimen does not induce hair loss; thus

A

B

C

Prechemotherapy Postchemotherapy



Figure 5: Prechemotherapy and postchemotherapy imaging

(A) Doppler ultrasound examination of a complete hydatidiform mole with a vascular uterine mass. (B) Chest

radiograph of a patient 9 months after a term delivery with multiple pulmonary metastases. (C) Brain MRI with

three obvious haemorrhagic metastases in a patient with seizures 6 months after a term delivery.

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it has been widely used.105107 Most patients are treated athome after a short stay in hospital to monitor any bleeding.About 2% of women have mouth ulcers, sore eyes, or rarelypleuritic or peritoneal pains from serositis.105 Patients whodevelop resistance to methotrexate with folinic acid rescuecan be switched to dactinomycin when hCG concentrationsare less than or equal to 100 IU/L or multidrug chemotherapywhen concentrations are more than 100 IU/L, which willcure nearly all patients.105,106,108 The UK gestationaltrophoblastic disease service has increased the hCGconcentration at which combination chemotherapy isstarted to more than 300 IU/L, to reduce the number ofwomen being exposed to greater toxicity. Chemotherapyshould be continued until hCG is within the normal rangeand then for a further 6 weeks (figure 6), helping toeliminate any residual tumour cells and reduce the chanceof relapse.

Only 30% of patients scoring 56 can be cured with low-risk therapy.105,106,108,109 Therefore, revision of the FIGOscoring system would be helpful for early identification ofthe 70% of women in this group who develop resistance tomethotrexate with folinic acid rescue and who need moreintensive therapy. The amount of vascularisation asdetected on doppler ultrasonography could help to providethe necessary additional information.93,94 Furthermore,data108 suggest that women in this category with an hCG

concentration of more than 400 000 IU/L are unlikely to becured by methotrexate with folinic acid rescue, somultidrug treatment should be given from the outset.108

High-risk diseaseMost high-risk patients with gestational trophoblasticneoplasia present with many metastases months or yearsafter the causative pregnancy of any type. Symptoms andsigns vary with disease location. Patients with brainmetastases (figure 5) present with seizures, headaches, orhemiparesis,110 whereas those with lung metastasis ordisease in the pulmonary vasculature might have acombination of haemoptysis, shortness of breath, orpleuritic chest pain.111 Menstrual irregularity is notuniversal, so unless clinicians consider gestational

trophoblastic neoplasia in the differential of metastaticdisease and measure the serum or urine hCG the diagnosiscan be missed. If hCG concentrations are raised, thetreating physician should consult the nearest gestationaltrophoblastic disease centre about management. Imaginginvestigations should include body CT, brain MRI, andpelvic MRI and Doppler ultrasonography (figure 5). If thebrain scan is normal, a lumbar puncture to measure theratio of cerebrospinal fluid to serum hCG (normal

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vincristine (CO; table 2).116 This regimen is widely usedworldwide,115 since it seems effective with predictable andeasily managed short-term toxic effects. The Koreangestational trophoblastic disease centre noted in aretrospective comparison117 that MFA had a remissionrate of 63% (31 of 49 patients), MAC 68% (27 of 40),CHAMOCA 71% (32 of 45), and EMA-CO 91% (87 of 96).The EMA-CO regimen necessitates one overnight stayevery 2 weeks, causes reversible alopecia, and ismyelosuppressive (although support with filgrastimhelpsto maintain neutrophil count and treatment intensity, andavoids neutropenic febrile episodes).19

Cumulative 5-year survival of patients given EMA-CO isbetween 75% and 90%,116121 and was 862% (95% CI

819905) in 272 patients at our UK institute.119 Although

these results were good, long-term survival was only 27%when there were metastases in the liver, 70% with brainmetastases, and 10% with both sites of metastasis.119,122 Whythese patients have adverse outcomes is unclear, but mosthad not had previous hydatidiform mole, were notregistered for follow-up, and therefore presented withwidespread disease. Furthermore, many deaths happenedsoon after admission from haemorrhage or metabolicresults of overwhelming disease. Indeed, when deathswithin 4 weeks (before adequate chemotherapy can begiven) were excluded, survival of patients with brainmetastases was equivalent to that for other patients.110 Thiseffect may also apply to liver metastases; of 37 patients withliver metastases treated between 1977 and 2005 at our UK

institute, overall survival increased to about 50% at 5 years,but when early deaths were excluded, survival was nearly70%.123 Besides disease extent, type and duration ofantecedent pregnancy and previous chemotherapy areassociated with poor outcome.117,124

To reduce early deaths in patients with very advanceddisease, we noted that starting chemotherapy with low-dose etoposide (100 mg/m) and cisplatin (20 mg/m) for2 days, combined with dexamethasone 24 mg in 24 h ishelpful to reduce tumour oedema. Further details aboutmanagement and modifications to treatment needed forpatients with very advanced disease and diffi cult clinicalsituations such as brain metastasis and pulmonaryfailure have been reviewed elsewhere.110,125

As in low-risk disease, therapy is continued for 6 weeksof normal hCG values in patients with high-risk diseaseor 8 weeks if poor prognostic features such as liver orbrain metastases are present.19 Reimaging is then done todocument the post-treatment appearance for futurecomparison. Removal of residual masses is unnecessarysince it does not reduce risk of recurrence, which is lessthan about 3%.126128

Drug-resistant diseasePatients with gestational trophoblastic neoplasia whoprogress during or after primary chemotherapy still haveexcellent outcomes, with about 100% of low-risk and 84%

of high-risk patients being cured,128 partly because relapseis detected early by hCG monitoring so disease volume issmall. PET scanning with F-fluorodeoxyglucose can helpto identify the site of active disease to aid surgical resectionand cure.129 The half-lifefor hCG is 48 h or less after surgeryif the disease has been completely removed.130 However,when surgery is not possible or hCG concentrationsdecrease inappropriately, several salvage regimens havebeen created or adapted from the germ-cell tumoursetting.131 At our UK institute we developed a regimencombining etoposide with cisplatin (EP) alternating everyweek with EMA that omitted the second day of etoposideand dactinomycin.132 Survival is more than 80% but toxiceffects are substantial.132 Several patients with drug-resistant tumours have responded to gemcitabine133 or

Serumh

CGconcentration(IU/L)

Time (months)

Uterine evacuationof CHM

MTXFA

MTXFA

6 weeks (3 treatmentcycles) with a normalhCG concentration

100000

01 2 3 4

10

100

1000

10000

MTXFA

MTXFA MTXFA

Stop RX

Figure 6: Response to low-risk chemotherapy measured by hC G tumour marker concentrationAfter uterine evacuation of a complete hydatidiform mole, hCG remained plateaued, suggesting persistent

gestational trophoblastic disease or neoplasia, so the patient started treatment with methotrexate and folinic acid.

Time and type of intervention are shown above the line. Therapy was continued for 6 weeks after normal hCG

concentration (

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paclitaxel-based single-agent or combination therapy.134138An alternating combination of paclitaxel-cisplatin andpaclitaxel-etoposide (TP-TE) every 2 weeks (table 3) seemsfrom non-randomised studies to be much better toleratedthan is EP-EMA, and is effective in patients with relapsedor refractory neoplasia.138 On the basis of these results theISSTD has recently proposed a randomised trial of TE-TPversus EP-EMA to assess optimum therapy for patientsrelapsing after non-cisplatin-based combination therapiessuch as EMA-CO. High-dose chemotherapy withperipheral stem-cell transplantation does not cure manypatients with refractory disease,139 so selection of patientsneeds to improve.140,141

Placental-site trophoblastic tumourPlacental-site trophoblastic tumours grow more slowly,metastasise later, more commonly involve lymph-nodes,and produce less hCG than do choriocarcinomas. 142,143However, as with choriocarcinoma, this disease can

arise after any type of pregnancy, including partial mole17and most patients present with abnormal vaginalbleeding.20 The disorder should be suspected if hCGconcentrations are low for the volume of disease presenton imaging and free--hCG values are high, but thesefeatures are not diagnostic.58,59 Histological analysis isneeded to substantiate the diagnosis.

In a population-based series,20 Schmid and colleaguesexamined prognostic features for placental-site tropho-blastic tumours in 62 cases over 30 years, representing02% of UK gestational trophoblastic disease. By univariateanalysis, stage, hCG, mitotic index, and duration of morethan 4 years from preceding pregnancy were prognostic,but the FIGO score was not.142144Only time from previouspregnancy to first treatment remained predictive of

survival on multivariate analysis: all 13 patients with aninterval of 48 months or more died, and 48 of 49 with aninterval of less than 48 months survived. This effect wasnot explained by differences in disease stage or hCGconcentrations, but might suggest a biological switch intumours after this time.20

Management of placental-site trophoblastic tumourdiffers from that for choriocarcinoma. Patients withmetastatic disease need combination chemotherapy (eg,EP-EMA) until 8 weeks of normal hCG concentrations arerecorded.20 Unlike choriocarcinoma, residual masses areremoved surgically, including the uterus, which can containmicroscopic disease. The need for surgery might causediffi culties for management of stage I disease.145 The safestoption is hysterectomy with sampling of pelvic lymphnodes and ovarian conservation, unless the patient has afamily history of ovarian cancer or is postmenopausal. Inthe absence of suffi cient data for adjuvant therapy, weadvocate 8 weeks of EP-EMA or TE-TP when there are poorrisk factors such as disease presentation beyond 4 yearsfrom the antecedent pregnancy. However, youngnulliparous women generally have a strong desire topreserve fertility, especially when there seems to be a focalabnormality in the uterus. Although uterine-sparingsurgery is possible,145148 multifocal microscopic uterinedisease can happen145 and could compromise survival.Appropriate counselling is needed. Placental-site disease is

so rare that the optimum treatment will probably never beidentified, but the ISSTD has formed an internationaldatabase to pool information about cases.

Postchemotherapy sequelae and follow-upMost patients recover from even intensive chemotherapywithin weeks or months, and nearly all side-effects suchas alopecia are reversible. Fertility is an important issuefor patients with gestational disease. Fortunately,although EMA-CO advances the menopause date by 3years,149 fertility is not otherwise affected by eithermethotrexate with folinic acid rescue or EMA-COchemotherapy. Furthermore, the pregnancy rate is morethan 83% after either treatment,150 and the incidence ofcongenital malformations is not increased.150,151

Schedule

Day 1 (TP)

Dexamethasone 20 mg orally (12 h before paclitaxel)

Dexamethasone 20 mg orally (6 h before paclitaxel)

Cimetidine 30 mg in 100 mL normal saline intravenous for 30 min

Chlorphenamine 10 mg intravenous bolus

Paclitaxel 135 mg/m in 250 mL normal saline intravenous for 3 h

Mannitol 10% in 500 mL intravenous for 1 h

Cisplatin 60 mg/m in 1 L normal sal ine intravenous for 3 h

Post-hydration 1 L normal saline, 20 mmol potassium chloride, and 1 g

magnesium sulphate intravenous for 2 h

Day 15 (TE)

Dexamethasone 20 mg oral (12 h before paclitaxel)

Dexamethasone 20 mg oral (6 h before paclitaxel)

Cimetidine 30 mg in 100 mL normal saline intravenous for 30 minChlorphenamine 10 mg intravenous bolus

Paclitaxel 135 mg/m in 250 mL normal saline intravenous for 3 h

Etoposide 150 mg/m in 1 L normal saline intravenous for 1 h

TP=paclitaxel-cisplatin. TE=paclitaxel-etoposide.

Table 3: TP-TE schedule for relapsed gestational trophoblastic neoplasia

Urine Blood

Year 1

16 weeks Every week Every week

26 months Every 2 weeks Every 2 weeks

712 months Every 2 weeks

Year 2 Every 4 weeks

Year 3 Every 8 weeks

Year 4 Every 3 months

Year 5 Every 4 months

After year 5 Every 6 months

Table 4: Sampling protocol for hCG concentration in all patients after initial

chemotherapy (monotherapy or combination) and following relapse

treatment with gestational trophoblastic neoplasia in the UK

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However, patients are advised not to become pregnant

until 12 months after completion of chemotherapy toreduce the potential teratogenicity and to avoid confusionbetween a new pregnancy and relapsed disease as thecause of increasing hCG values. Between 1973 and 1997,230 women at our UK centre became pregnant during thefirst year of follow-up, despite the advice to avoid pregnancy.The risk of relapse, fetal morbidity, and maternal deathwere not increased; more than 70% continued theirpregnancies to term, but one patient relapsed withadvanced disease.152 Thus, although we advise women toavoid pregnancy for 1 year after completing chemotherapy,those who do become pregnant will probably have afavourable outcome. Any form of contraception is suitableprovided there are no other medical contraindications to

their use. When a patient does become pregnant,ultrasonography and other appropriate methods should beused to ensure that the pregnancy is healthy. Follow-uptherapy is then discontinued but hCG concentrationsshould be rechecked 6 weeks and 10 weeks after delivery toensure no recurrence or new disease. In the UK, we followup patients for life (table 4), since monitoring is easy to do(urine samples only), cheap, and we are uncertain aboutwhen stopping is safe.

Late sequelae from chemotherapy are very rare.Findings from a study153 of 15 279 patient-years offollow-up showed no significant increase in incidence ofsecond tumours after methotrexate therapy. By contrast,26 patients receiving combination chemotherapy forgestational trophoblastic neoplasia developed anothercancer when the expected rate was only 1645which isa significant difference.

ConclusionsAlthough outcomes for more than 98% of women withgestational trophoblastic neoplasia are excellent, a fewwomen die from the disease, mainly because of latepresentation and diagnosis or drug resistance.Consequently, novel therapies with improved effi cacy andreduced toxic effects need to be identified. Additionally,after diagnosis of molar pregnancy, women have to waitmany weeks or months to find out whether they need

chemotherapy. Therefore, a new prognostic test at the timeof initial molar diagnosis is needed to identify those whomight develop malignant disease. Of course, if residualcomplete hydatidiform mole acquires additional geneticchanges after evacuation, such a test might never bepossible. However, evidence comparing early versusdelayed evacuation of complete hydatidiform mole aloneand in pregnancies with a healthy twin suggest thatdelayed termination has no increased risk of malignantdisease.76,84 This finding suggests that hydatidiform molesare probably pre-programmed to behave malignantly at anearly stage of development and before uterine evacuation.

The optimum management strategy for women withrepetitive molar pregnancies to allow healthy pregnancyis unknown; even though the causative gene has been

identified for many cases, its function is unknown. The

successful UK model of centralised care for rare diseasesshould be established worldwide to improve outcomesfor gestational trophoblastic disease.

Contributors

All authors did a detailed review of published work and contributed tothe writing, review, and editing of the report. MJS had access to all thedata used to write the report and had final responsibility for submission.All authors saw and approved the final version.

Conflicts of interest

We declare that we have no conflicts of interest.

Acknowledgments

MJS and NJS thank the Department of Health, National CommissioningGroup, and the Cancer Treatment and Research Trust for their continuedsupport. MJS acknowledges support from the Imperial CollegeExperimental Cancer Medicine Centre and Biomedical Research Centregrants. RSB acknowledges the Donald P Goldstein MD TrophoblasticRegistry Endowment Fund and the Choriocarcinoma Research Fund.

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