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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 premalignant
disorders 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 tumours
or 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 can
be explained by the development of eective treatments, the use of human chorionic gonadotropin as a biomarker,
and centralisation of care. We summarise strategies for management of gestational trophoblastic disease and address
some of the controversies and future research directions.

Hippocrates was probably the rst to describe gestational
trophoblastic disease around 400 BC in his description of
dropsy of the uterus.1 Although other observations have
been made since, Marchand rst associated hydatidiform
mole with pregnancy in 1895.1 Healthy trophoblastic
tissue aggressively invades the endometrium and develops
a rich uterine vasculature, generating an intimate
connection between the fetus and the mother known as
the placenta. Invasion is one of the distinct features of
malignant disease, and healthy trophoblast can be
detected by PCR in the maternal circulation.2 Fortunately,
malignant-like behaviour is tightly controlled in healthy
trophoblast. However, in gestational trophoblastic disease
the regulatory mechanisms fail, resulting in tumours that
are highly invasive, metastatic, and very vascular. In this
Seminar we discuss the epidemiology, origins, pathological changes, and clinical behaviour of the various
forms of gestational trophoblastic disease.

gestations, the risk of a third mole is 1520%,11,14,15 and the

risk is not decreased by change of partner.16 Some repeat
molar pregnancies are due to familial or sporadic
biparental molar disease (gure 1).
The frequency of choriocarcinoma or placental-site
trophoblastic tumour is less well known, since these
diseases can arise after any type of pregnancy.17,18 Choriocarcinoma develops in around one in 50 000 deliveries,19
and placental-site trophoblastic tumour accounts for about
02% of cases of gestational trophoblastic disease in the
UK.20 The risk of gestational trophoblastic neoplasia might
also be linked to hormonal factors, since women with
menarche after 12 years of age, light menstrual ow, and
previous use of oral contraceptives are at increased risk.21,22
Additionally, risk of malignant disease after hydatidiform
mole has been associated with oral contraceptive use (if
started when human chorionic gonadotropin [hCG]
concentrations are raised) in some23 but not all24 studies.

Lancet 2010; 376: 71729

Published Online
July 28, 2010
Department of Cancer
Medicine (Prof M J Seckl FRCP)
and Department of
(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

Causes and genetics

Gestational trophoblastic disease arises more frequently
in Asia than in North America or Europe,3,4 which could
be due to dierences in prevalence, discrepancies
between hospital-based and population-based data, or
disparity in availability of central pathology review. In the
UK, all patients are included on a national register, with
central pathology review; and the incidence of complete
hydatidiform mole is around one per 1000 pregnancies
and three per 1000 for partial hydatidiform mole.5 Other
developed countries report similar data.6
The incidence of molar pregnancy has decreased in
South Korea from 44 cases per 1000 births in the 1960s to
16 cases per 1000 births in the 1990s,7 possibly because of
improved socioeconomic conditions and dietary
changesespecially since ndings from studies in
animals show that diet can reset the genetic imprint.8
Additionally, an increased risk of molar pregnancy is
associated with reduced consumption of dietary carotene9,10
and animal fat,9 and advanced maternal age.3,1113 Ova from
older women are more susceptible to abnormal fertilisations than are those from younger women.
After a molar pregnancy, the risk of further complete
and partial mole rises to 12%.11,14,15 After two molar Vol 376 August 28, 2010

In most cases, complete hydatidiform mole usually

arises when an ovum without maternal chromosomes

Search strategy and selection criteria

We searched the Cochrane Library, Medline (via PubMed,
Internet Grateful Med, OVID, and Knowledgender), 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
nd any publications not already identied by our electronic
search strategy.



is fertilised by one sperm that then duplicates its DNA,

resulting in a 46XX androgenetic karyotype, in which all
chromosomes are paternally derived.2527 About 10% of
complete moles are 46XY,28 arising from fertilisation by
two sperm (gure 1). Although nuclear DNA is entirely
paternal, mitochondrial DNA remains maternal in
origin.29 Findings from some studies30 show that patients

Androgenetic diploid (monospermic)




Androgenetic diploid (dispermic)




with recurrent disease can have biparental molar rather

than typical androgenetic disease, which might be
familial or sporadic. Genetic studies in such families
showed that the related genes are at chromosome
19q13.313.4,31 and subsequent analysis noted NLRP7
mutations in this region.32 The function of the normal
protein and the mechanism by which mutations are
associated with imprinting abnormalities and
gestational trophoblastic disease are unknown.33 Data
show clustering of mutations in the leucine-rich region
of NLRP7 (gure 2), suggesting that this region is
crucial for normal function.34 Some androgenetic diploid
complete moles and possibly even triploid partial
hydatidiform moles might also carry NLRP7 mutations,35
but conrmation from large studies is needed.
Partial hydatidiform moles are almost always triploid
(gure 1), and they result from fertilisation of a seemingly
healthy ovum by two sperm;3638 diploid partial moles
probably do not exist, with most reported cases being
misdiagnosed complete moles.39

Biparental triploid






Chromosome 19q: NLRP7 (NALP7) defect

Sporadic or hereditary
Autosomal recessive

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.







Leucine-rich region

Figure 2: Domain structure of NLRP7 and identied 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 the
protein. There seems to be some clustering of mutations in the leucine-rich region.


All gestational trophoblastic disease is derived from the

placenta. Hydatidiform moles and choriocarcinoma
arise from villous trophoblast and placental-site
trophoblastic tumours from interstitial trophoblast.
Most complete and partial hydatidiform moles have
distinctive morphological characteristics, although
diagnostic criteria have changed because evacuation is
done earlier in gestation (median 89 weeks in the UK).
First-trimester complete moles show a characteristic
abnormal budding villous structure with trophoblast
hyperplasia, stromal karyorrhectic debris, and collapsed
villous blood vessels. By contrast, early partial moles
show patchy villous hydrops with scattered abnormally
shaped irregular villi, trophoblastic pseudoinclusions,
and patchy trophoblast hyperplasia (gure 3).4042
Morphological distinction of non-molar miscarriage
from partial hydatidiform mole can be dicult, since
villous dysmorphism can be present but without the
characteristic trophoblast hyperplasia that is noted in
partial mole. Ancillary techniques are needed in some
cases to dierentiate non-molar miscarriage from
hydatidiform mole, including immunostaining for P57kip2,
the product of CDKN1C. P57kip2 is expressed by the
maternal allele and is visible on histology as nuclear
staining of cytotrophoblast and villous mesenchyme in
placenta of all gestations apart from androgenetic complete
mole.43,44 Additionally, ploidy analysis by in-situ
hybridisation or ow cytometry can distinguish diploid
from triploid conceptions, helping to diagnose partial
mole, but is unable to distinguish complete mole from
diploid non-molar miscarriage, or molar versus non-molar
triploidy, which necessitate molecular investigations.18,4547
Choriocarcinomas are malignant hCG-producing
epithelial tumours with central necrosis and a characteristic
biphasic architecture recapitulating cytotrophoblast-like Vol 376 August 28, 2010


1 mm

05 mm

01 mm

01 mm

Figure 3: Gestational trophoblastic disease

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

cells and multinucleate, pleomorphic syncytiotrophoblastlike regions; however, mononuclear cells predominate in
some cases, especially after chemotherapy.48 Intraplacental
choriocarcinoma does occur and is probably the source of
metastatic disease after term pregnancies. Most cases of
neonatal choriocarcinoma result from metastatic spread
from an intraplacental choriocarcinoma.49 Placental-site
trophoblastic tumours are the malignant equivalent of
extravillous, interstitial implantation site-like trophoblast
and form uterine lesions with less haemorrhage and
necrosis, and lower hCG concentrations than does
choriocarcinoma.48,50 Epithelioid trophoblastic tumoura
variant of placental-site trophoblastic tumour with similar
clinical behaviour but distinctive hyalinisationhas been
reported, but data for this disease are sparse.51
Accurate measurement of hCG is key to eective
management of gestational trophoblastic disease, several
cancers, and pregnancy. Panel 1 summarises some of the
issues related to hCG measurements.

Diagnostic ultrasound for molar pregnancy

Patients with complete hydatidiform mole most
commonly present with vaginal bleeding in early Vol 376 August 28, 2010

pregnancy. Previously reported features such as

hyperemesis, hyperthyroidism, and respiratory distress
are now rare,60 probably because routine use of
ultrasonography leads to diagnosis in the rst rather
than late-second trimester. Partial hydatidiform moles
grow more slowly and present slightly later in the rst
or early second trimester than do complete moles, but
also manifest with vaginal bleeding or missed or
incomplete miscarriages.61,62 Characteristic ultrasonographic scans of complete mole show a uterine
cavity lled with a heterogeneous mass (so-called
snowstorm), without associated fetal development and
with theca lutein ovarian cysts.63,64 However, these
features are not visible in the rst trimester and,
although some investigators6570 have suggested that
ultrasound can be diagnostic of complete mole in early
pregnancy, large studies71,72 have shown that only 4060%
of cases are detected as molar by sonography in routine
clinical practice. Moreover, 10% of cases that are thought
to be molar on sonography were diagnosed as nonmolar hydropic abortions on histological review.71
Findings from other reports73 are similar and emphasise


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 specicity. Consequently, assays designed to specically detect hCG have to target
the subunit. In healthy pregnancy, hCG is intact and is hyperglycosylated during the rst
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 dierent -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 nding 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 (Deereld, IL, USA).53,54
Therefore, a new generation of cancer-specic hCG assays is urgently needed.
Findings from recent studies56,57 that used a hyperglycosylated hCG assay suggest that a
high ratio of this variant to total hCG can detect malignant forms of gestational
trophoblastic disease. These ndings 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 dene the role of
hyperglycosylated hCG and free--hCG in the management of gestational cancers.
hCG=human chorionic gonadotropin.

that false-positive and false-negative rates are high with

ultrasonographyespecially for partial hydatidiform
moleand histological examination is necessary to
achieve a correct diagnosis.40,74 All products of conception
from non-viable pregnancies should undergo histological
examination irrespective of ultrasonographic ndings.75
Some women who miscarry or have medical
terminations will have had unsuspected molar
pregnancies. Because ultrasonography cannot reliably
conrm molar disease and histological examination of
products might not be done after pregnancy termination,
delayed diagnosis of gestational trophoblastic neoplasia,
and hence substantial morbidity with the need for complex
chemotherapy and surgery, can result.76 Histological
examination after every termination would be
impracticable, so checking of hCG concentrations at
34 weeks after treatment to ensure a return to a value
within the normal range is recommended.77

Surgical evacuation
Suction curettage is the preferred method of evacuation
irrespective of uterine size in patients with suspected
hydatidiform mole who want to preserve fertility.78,79
Intraoperative ultrasonography can reduce the risk of
uterine perforation. Patients who are rhesus-negative
should receive rhesus immunoglobulin at the time of
evacuation because rhesus D factor is expressed on
trophoblast. Women who are nulliparous should not be
given prostanoids to ripen the cervix since these drugs
can induce uterine contractions and might increase the
risk of trophoblastic embolisation to the pulmonary
vasculature.80 Hysterectomy is rarely recommended but
might be considered for women who do not want further
children or have life-threatening haemorrhage.81,82
Patients should be counselled that, although hysterectomy
stops the risk of local invasion, it does not eliminate the
possible need for chemotherapy, and monitoring of hCG
concentrations should still be done.11
A healthy co-twin can develop alongside a complete
or partial hydatidiform mole in one per
20 000100 000 pregnancies (gure 4). Some investigators
have suggested that such pregnancies should be
terminated because of the low probability of successful
outcome and the increased risk of development of
malignant disease.83 However, evidence from a case
series84 of 77 pregnancies suggests that about 40% of
women will deliver a healthy baby without a signicant
increase in the risk of malignant transformation of the
complete hydatidiform mole. Findings from a study76 of
2800 singleton molar pregnancies lent support to the
notion that late evacuation of complete hydatidiform
mole is not associated with an increased rate of
malignant disease.

Registration for hCG surveillance

All patients with hydatidiform mole should be registered
with a specialist centre for hCG surveillance, preferably
one that is coordinated nationally. The UK established
the rst national service for gestational trophoblastic
disease through a combined agreement of the Royal
College of Obstetricians and Gynaecologists and the
Department of Healths National Commissioning Group.
Since 1973, all women with hydatidiform mole or other
forms of gestational trophoblastic disease have been
registered with one of three centres for hCG monitoring
and, if subsequent treatment is necessary, are treated at
the Sheeld Trophoblastic Disease Centre (Sheeld,
UK) or Charing Cross Hospital Trophoblast Disease
Centre (London, UK).
Onset of malignant change, termed persistent
gestational trophoblastic disease or post-mole neoplasia,
is signied by a plateaued or rising hCG concentration.
Studies in the UK show that malignant change arises
after 15% of complete and 0510% of partial
hydatidiform moles.11,18,85 Rates are probably higher in
other countries than the UK,86 possibly because of Vol 376 August 28, 2010


dierences in hCG criteria and overdiagnosis of

neoplasia, scarcity of whole-population demographics, or
a dierence in disease biology, although this explanation
is unlikely. Precise surveillance protocols vary by country
but principles are alike. In the UK, serum and urine hCG
concentrations are measured every 2 weeks until the
values are within the normal range, and then urine hCG
concentrations are recorded monthly. Patients with
normal hCG values within 56 days of uterine evacuation
have a reduced risk of development of malignant
disease,11,87 and are monitored for 6 months from
evacuation date. When the rst hCG reading within the
normal range is noted after 56 days, monthly monitoring
continues for 6 months.87 Some investigators suggest
shortened hCG surveillance, with discontinuation after
the rst value within the normal range is measured,
especially for women with partial mole in whom the risk
of neoplasia is reduced.88,89 Shortened surveillance could
enable women to attempt a subsequent pregnancy
sooner, but could result in late development of neoplasia
with increased morbidity and mortality.
Data reported at the 2009 International Society for the
Study of Trophoblastic Diseases (ISSTD) world congress
from 22 000 women with complete and partial
hydatidiform moles in the UK suggest that either form
can occasionally develop post-mole neoplasia after the
hCG has returned to normal; however, the risk of
missed gestational trophoblastic neoplasia can be
reduced from one in 800 women to one in 1400 by
following present UK guidelines.87 Consequently, UK
practice seems good for young women, but older
nulliparous women should be made aware of the relative
risks and benets of an early pregnancy. During hCG
follow-up, patients are encouraged to use reliable
contraception, including a combination of methods,
although data are conicting about whether oral
contraceptives increase the risk for gestational
trophoblastic neoplasia. In the UK, practitioners avoid
recommending oral contraceptives until hCG is in the
normal range.23,24 After completion of hCG monitoring,
serum or urine hCG concentrations should be checked
6 weeks and 10 weeks after every pregnancy to ensure
no reactivation of previous molar disease.90,91


Complete hydatidiform mole

Normal placenta

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
Serum hCG concentration of 20 000 IU/L or more,
4 weeks or more after evacuation, because of the risk of
uterine perforation
Raised hCG concentration 6 months after evacuation,
even when still decreasing
hCG=human chorionic gonadotropin. *A plateaued hCG concentration is dened 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).

associated with an increased risk of uterine perforation);

or there are lung or vaginal metastases more than 2 cm
in diameter (small lesions can spontaneously regress), or
spread to other organs.42,92 Additionally, in the UK,
chemotherapy is started to help to stop heavy bleeding
that necessitates transfusion, even when the hCG
concentration is falling.

Panel 2 shows the UK indications for treatment of
gestational trophoblastic disease with chemotherapy.
These recommendations are similar to those suggested
by the International Federation of Gynecology and
Obstetrics (FIGO)92 and include a plateaued or rising
hCG (the most common reason for treatment), a
persistently raised hCG at 6 months after evacuation, or
histological diagnosis of choriocarcinoma. However, our
experience suggests that the disease is unlikely to remit
spontaneously when: the hCG concentration is more
than 20 000 IU/L, 1 month after evacuation (also Vol 376 August 28, 2010

Staging and stratication

Most patients who develop gestational trophoblastic
neoplasia after hydatidiform mole are detected early by
hCG monitoring so detailed investigation is rarely
needed. Information on which to base therapy decisions
can be obtained from clinical histories, examination,
and measurement of serum hCG. Additionally, patients
should have doppler pelvic ultrasonography to conrm
absence of pregnancy, and to measure the uterine size
and volume, spread of disease within the pelvis, and
disease vascularity (gure 5). Disease vascularity can








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.

suggest patients who are at risk of treatment

resistance.93,94 Pulmonary metastases are most common,
so chest radiography is essential.95 Chest CT is not
needed when ndings from chest radiography is
normal, since discovery of micrometastases, which can
be seen in about 40% of patients, does not aect
outcome.96,97 However, if lesions are noted on chest
radiograph, brain MRI and body CT are recommended
to exclude more widespread disease aecting, for
example, the brain or liver, which would substantially
change management.
FIGO report data for gestational trophoblastic neoplasia
by use of prognostic scoring and anatomical staging

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

gestational trophoblastic neoplasia should use this system
to allow comparison of data. The combined prognostic
score predicts potential for development of resistance to
monochemotherapy with methotrexate or dactinomycin.
A score of 06 suggests low risk of resistance and 7 or
more indicates high risk. Such disease has almost no
chance of being cured with monochemotherapy and
needs multidrug treatment. Anatomical staging does not
aid therapeutic choices but helps clinicians to compare
results between centres.

Low-risk disease
About 95% of patients with hydatidiform mole who
develop neoplasia are at low risk of resistance (score 06).
In patients with stage I disease that is seemingly conned
to the uterine cavity, the use of second dilatation and
curettage to reduce the need for chemotherapy is
controversial.98101 Results from the UK suggest that
secondary surgery is of no value when hCG concentrations
are greater than 5000 IU/L, since more than 50% of such
patients will need chemotherapy.101 The low eectiveness
of second surgery and small risks of infection,
haemorrhage, and uterine perforation should be
measured against the almost 100% cure rate and
comparative safety of chemotherapy. Some patients with
stage I neoplasia who do not want further children
request hysterectomy, which can be technically dicult
with these highly vascular tumours and does not
completely obviate the need for chemotherapy.
For most low-risk patients with gestational trophoblastic
neoplasia, monochemotherapy with methotrexate or
dactinomycin is the preferred treatment. Many regimens
have been used, showing a 5090% chance of induction
of remission in non-randomised, mostly retrospective,
studies.102 The wide variability results from dierences in
dose, frequency, route of administration, and the criteria
used to select patients for therapy.19,95 Some investigators
suggest that intensive therapy given daily for 58 days
every 2 weeks is better than treatments given once every
2 weeks;103 others suggest that dactinomycin is more
likely to induce remission than is methotrexate.104 The
few randomised studies102 that addressed some of these
issues were underpowered and compared regimens that
are not frequently used internationally. Patients in whom
rst-line therapy failsgenerally because of resistance
can be easily salvaged with second-line or occasionally
third-line chemotherapy, so overall survival is nearly
100%.105 Since survival is so high, patients should be
given the least toxic therapy rst to avoid exposure to
more harmful treatments.
The regimen of methotrexate (50 mg intramuscularly
every 48 h for four doses) with calcium folinate (folinic
acid) rescue (15 mg orally 30 h after methotrexate) regimen
developed at our UK institute is eective and is well
tolerated. Courses are repeated every 2 weeks. Unlike
dactinomycin, this regimen does not induce hair loss; thus Vol 376 August 28, 2010


Age (years)



Antecedent pregnancy





Interval from antecedent pregnancy to chemotherapy (months)

hCG concentration (IU/L)
Number of metastases
Site of metastases


Spleen, kidney






Gastrointestinal tract

Largest tumour mass diameter (cm)



Previous chemotherapy


Brain, liver

Combined therapy

hCG=human chorionic gonadotropin. *Patients score is total of individual scores for the eight prognostic factors. Low risk of resistance to monochemotherapy 06, high risk
7 or more. Placental-site trophoblastic tumour should not be scored but needs to be staged. Stage I disease is conned to the uterus; stage II disease extends to the genital
tract; stage III disease is spread to lungs with or without extension to the genital tract; and stage IV occupies all other metastatic sites including liver, kidney, spleen, and brain.

Table 1: International Federation of Gynecology and Obstetrics (2000) scoring system for gestational trophoblastic neoplasia, by prognostic factor*

it has been widely used.105107 Most patients are treated at

home after a short stay in hospital to monitor any bleeding.
About 2% of women have mouth ulcers, sore eyes, or rarely
pleuritic or peritoneal pains from serositis.105 Patients who
develop resistance to methotrexate with folinic acid rescue
can be switched to dactinomycin when hCG concentrations
are less than or equal to 100 IU/L or multidrug chemotherapy
when concentrations are more than 100 IU/L, which will
cure nearly all patients.105,106,108 The UK gestational
trophoblastic disease service has increased the hCG
concentration at which combination chemotherapy is
started to more than 300 IU/L, to reduce the number of
women being exposed to greater toxicity. Chemotherapy
should be continued until hCG is within the normal range
and then for a further 6 weeks (gure 6), helping to
eliminate any residual tumour cells and reduce the chance
of relapse.
Only 30% of patients scoring 56 can be cured with lowrisk therapy.105,106,108,109 Therefore, revision of the FIGO
scoring system would be helpful for early identication of
the 70% of women in this group who develop resistance to
methotrexate with folinic acid rescue and who need more
intensive therapy. The amount of vascularisation as
detected on doppler ultrasonography could help to provide
the 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 be
cured by methotrexate with folinic acid rescue, so
multidrug treatment should be given from the outset.108

High-risk disease
Most high-risk patients with gestational trophoblastic
neoplasia present with many metastases months or years
after the causative pregnancy of any type. Symptoms and
signs vary with disease location. Patients with brain
metastases (gure 5) present with seizures, headaches, or
hemiparesis,110 whereas those with lung metastasis or
disease in the pulmonary vasculature might have a
combination of haemoptysis, shortness of breath, or
pleuritic chest pain.111 Menstrual irregularity is not
universal, so unless clinicians consider gestational Vol 376 August 28, 2010

trophoblastic neoplasia in the dierential of metastatic

disease and measure the serum or urine hCG the diagnosis
can be missed. If hCG concentrations are raised, the
treating physician should consult the nearest gestational
trophoblastic disease centre about management. Imaging
investigations should include body CT, brain MRI, and
pelvic MRI and Doppler ultrasonography (gure 5). If the
brain scan is normal, a lumbar puncture to measure the
ratio of cerebrospinal uid to serum hCG (normal <1:60)
can help to exclude occult CNS disease.110,112 Investigators
should avoid taking a biopsy sample of these highly
vascular tumours to prevent life-threatening haemorrhage.
However, when a lesion is easily accessible and bleeding
can be controlled, taking an excision biopsy sample can be
helpful. This is especially important when placental-site or
non-gestational tumours might exist, since their management diers from that of gestational choriocarcinoma.
Fortunately, placental-site trophoblastic tumour has a
distinct histological appearance and comparison of
microsatellite polymorphisms in the tumour with DNA
from the patient and her partner can establish whether
the tumour is gestational.91 The phenotypic appearance
of the tumour is not always reliable and rarely nongestational carcinomas can look morphologically very
similar to gestational choriocarcinomas and, conversely,
these carcinomas can occasionally mimic other epithelial
tumours.91,113 Chemotherapy is eective for cure of
gestational tumours, whereas the chance of survival from
a non-gestational tumour depends on the primary site.
Patients scoring 7 or more on the FIGO system (table 1)
are at high risk of developing drug resistance and are very
unlikely to be cured with monochemotherapy.
Consequently, several dierent multidrug therapies have
been developed, including methotrexate, folinic acid, and
dactinomycin (MFA); methotrexate, dactinomycin,
cyclophosphamide, doxorubicin, melphalan, hydroxycarbamide, and vincristine (CHAMOCA);114 methotrexate,
dactinomycin, and cyclophosphamide (MAC); and
etoposide, methotrexate, and dactinomycin (EMA).115 At
our UK institute, a regimen was developed consisting of
alternating EMA every week with cyclophosphamide and


100 000

Serum hCG concentration (IU/L)

10 000


Uterine evacuation
of CHM

6 weeks (3 treatment
cycles) with a normal
hCG concentration




Stop RX


Time (months)

Figure 6: Response to low-risk chemotherapy measured by hCG tumour marker concentration

After 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 (<5 IU/L) was recorded. hCG=human chorionic gonadotropin. CHM=complete hydatidiform mole.
MTXFA=methotrexate with folic acid rescue. STOP RX=stop treatment.

Day 1 (EMA)

100 mg/m by intravenous infusion for 30 min


05 mg intravenous bolus


300 mg/m by intravenous infusion for 12 h

Day 2 (EMA)*

100 mg/m by intravenous infusion for 30 min


05 mg intravenous bolus

Folinic acid rescue 15 mg intramuscular or orally every 12 h for four doses

Day 8 (CO)

1 mg/m intravenous bolus (maximum 2 mg)

Cyclophosphamide 600 mg/m intravenous infusion for 30 min

EMA=etoposide, methotrexate, and dactinomycin. CO=cyclophosphamide and
vincristine. EMA alternates with CO every week. *Reduction of the EMA by
omission of the day 2 dose of etoposide and dactinomycin is only exceptionally
needed to avoid extended intervals between courses caused by myelosuppression.
This problem is usually overcome with lgrastim and increased frequency (four
doses daily) and duration (up to 4 days) of folinic acid rescue. Rescue begun 24 h
after start of methotrexate infusion.

Table 2: EMA-CO chemotherapy regimen for patients at high risk of

monochemotherapy resistance

vincristine (CO; table 2).116 This regimen is widely used

worldwide,115 since it seems eective with predictable and
easily managed short-term toxic eects. The Korean
gestational trophoblastic disease centre noted in a
retrospective comparison117 that MFA had a remission
rate 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 stay
every 2 weeks, causes reversible alopecia, and is
myelosuppressive (although support with lgrastim helps
to maintain neutrophil count and treatment intensity, and
avoids neutropenic febrile episodes).19
Cumulative 5-year survival of patients given EMA-CO is
between 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 brain
metastases, and 10% with both sites of metastasis.119,122 Why
these patients have adverse outcomes is unclear, but most
had not had previous hydatidiform mole, were not
registered for follow-up, and therefore presented with
widespread disease. Furthermore, many deaths happened
soon after admission from haemorrhage or metabolic
results of overwhelming disease. Indeed, when deaths
within 4 weeks (before adequate chemotherapy can be
given) were excluded, survival of patients with brain
metastases was equivalent to that for other patients.110 This
eect may also apply to liver metastases; of 37 patients with
liver 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 nearly
70%.123 Besides disease extent, type and duration of
antecedent pregnancy and previous chemotherapy are
associated with poor outcome.117,124
To reduce early deaths in patients with very advanced
disease, we noted that starting chemotherapy with lowdose etoposide (100 mg/m) and cisplatin (20 mg/m) for
2 days, combined with dexamethasone 24 mg in 24 h is
helpful to reduce tumour oedema. Further details about
management and modications to treatment needed for
patients with very advanced disease and dicult clinical
situations such as brain metastasis and pulmonary
failure have been reviewed elsewhere.110,125
As in low-risk disease, therapy is continued for 6 weeks
of normal hCG values in patients with high-risk disease
or 8 weeks if poor prognostic features such as liver or
brain metastases are present.19 Reimaging is then done to
document the post-treatment appearance for future
comparison. Removal of residual masses is unnecessary
since it does not reduce risk of recurrence, which is less
than about 3%.126128

Drug-resistant disease
Patients with gestational trophoblastic neoplasia who
progress during or after primary chemotherapy still have
excellent outcomes, with about 100% of low-risk and 84%
of high-risk patients being cured,128 partly because relapse
is detected early by hCG monitoring so disease volume is
small. PET scanning with F-uorodeoxyglucose can help
to identify the site of active disease to aid surgical resection
and cure.129 The half-life for hCG is 48 h or less after surgery
if the disease has been completely removed.130 However,
when surgery is not possible or hCG concentrations
decrease inappropriately, several salvage regimens have
been created or adapted from the germ-cell tumour
setting.131 At our UK institute we developed a regimen
combining etoposide with cisplatin (EP) alternating every
week with EMA that omitted the second day of etoposide
and dactinomycin.132 Survival is more than 80% but toxic
eects are substantial.132 Several patients with drugresistant tumours have responded to gemcitabine133 or Vol 376 August 28, 2010


Day 1 (TP)



Every week

Year 1


20 mg orally (12 h before paclitaxel)

16 weeks

Every week


20 mg orally (6 h before paclitaxel)

26 months

Every 2 weeks

Every 2 weeks


30 mg in 100 mL normal saline intravenous for 30 min

712 months

Every 2 weeks


10 mg intravenous bolus

Year 2

Every 4 weeks


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

Year 3

Every 8 weeks


10% in 500 mL intravenous for 1 h

Year 4

Every 3 months


60 mg/m in 1 L normal saline intravenous for 3 h

Year 5

Every 4 months


1 L normal saline, 20 mmol potassium chloride, and 1 g

magnesium sulphate intravenous for 2 h

After year 5

Every 6 months

Day 15 (TE)

20 mg oral (12 h before paclitaxel)


20 mg oral (6 h before paclitaxel)


30 mg in 100 mL normal saline intravenous for 30 min


10 mg intravenous bolus


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


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

paclitaxel-based single-agent or combination therapy.134138

An alternating combination of paclitaxel-cisplatin and
paclitaxel-etoposide (TP-TE) every 2 weeks (table 3) seems
from non-randomised studies to be much better tolerated
than is EP-EMA, and is eective in patients with relapsed
or refractory neoplasia.138 On the basis of these results the
ISSTD has recently proposed a randomised trial of TE-TP
versus EP-EMA to assess optimum therapy for patients
relapsing after non-cisplatin-based combination therapies
such as EMA-CO. High-dose chemotherapy with
peripheral stem-cell transplantation does not cure many
patients with refractory disease,139 so selection of patients
needs to improve.140,141

Placental-site trophoblastic tumour

Placental-site trophoblastic tumours grow more slowly,
metastasise later, more commonly involve lymph-nodes,
and produce less hCG than do choriocarcinomas.142,143
However, as with choriocarcinoma, this disease can
arise after any type of pregnancy, including partial mole17
and most patients present with abnormal vaginal
bleeding.20 The disorder should be suspected if hCG
concentrations are low for the volume of disease present
on imaging and free--hCG values are high, but these
features are not diagnostic.58,59 Histological analysis is
needed to substantiate the diagnosis.
In a population-based series,20 Schmid and colleagues
examined prognostic features for placental-site trophoblastic tumours in 62 cases over 30 years, representing
02% of UK gestational trophoblastic disease. By univariate
analysis, stage, hCG, mitotic index, and duration of more
than 4 years from preceding pregnancy were prognostic,
but the FIGO score was not.142144 Only time from previous
pregnancy to rst treatment remained predictive of Vol 376 August 28, 2010

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

survival on multivariate analysis: all 13 patients with an

interval of 48 months or more died, and 48 of 49 with an
interval of less than 48 months survived. This eect was
not explained by dierences in disease stage or hCG
concentrations, but might suggest a biological switch in
tumours after this time.20
Management of placental-site trophoblastic tumour
diers from that for choriocarcinoma. Patients with
metastatic disease need combination chemotherapy (eg,
EP-EMA) until 8 weeks of normal hCG concentrations are
recorded.20 Unlike choriocarcinoma, residual masses are
removed surgically, including the uterus, which can contain
microscopic disease. The need for surgery might cause
diculties for management of stage I disease.145 The safest
option is hysterectomy with sampling of pelvic lymph
nodes and ovarian conservation, unless the patient has a
family history of ovarian cancer or is postmenopausal. In
the absence of sucient data for adjuvant therapy, we
advocate 8 weeks of EP-EMA or TE-TP when there are poor
risk factors such as disease presentation beyond 4 years
from the antecedent pregnancy. However, young
nulliparous women generally have a strong desire to
preserve fertility, especially when there seems to be a focal
abnormality in the uterus. Although uterine-sparing
surgery is possible,145148 multifocal microscopic uterine
disease can happen145 and could compromise survival.
Appropriate counselling is needed. Placental-site disease is
so rare that the optimum treatment will probably never be
identied, but the ISSTD has formed an international
database to pool information about cases.

Postchemotherapy sequelae and follow-up

Most patients recover from even intensive chemotherapy
within weeks or months, and nearly all side-eects such
as alopecia are reversible. Fertility is an important issue
for patients with gestational disease. Fortunately,
although EMA-CO advances the menopause date by 3
years,149 fertility is not otherwise aected by either
methotrexate with folinic acid rescue or EMA-CO
chemotherapy. Furthermore, the pregnancy rate is more
than 83% after either treatment,150 and the incidence of
congenital malformations is not increased.150,151


However, patients are advised not to become pregnant

until 12 months after completion of chemotherapy to
reduce the potential teratogenicity and to avoid confusion
between a new pregnancy and relapsed disease as the
cause of increasing hCG values. Between 1973 and 1997,
230 women at our UK centre became pregnant during the
rst year of follow-up, despite the advice to avoid pregnancy.
The risk of relapse, fetal morbidity, and maternal death
were not increased; more than 70% continued their
pregnancies to term, but one patient relapsed with
advanced disease.152 Thus, although we advise women to
avoid pregnancy for 1 year after completing chemotherapy,
those who do become pregnant will probably have a
favourable outcome. Any form of contraception is suitable
provided there are no other medical contraindications to
their use. When a patient does become pregnant,
ultrasonography and other appropriate methods should be
used to ensure that the pregnancy is healthy. Follow-up
therapy is then discontinued but hCG concentrations
should be rechecked 6 weeks and 10 weeks after delivery to
ensure no recurrence or new disease. In the UK, we follow
up patients for life (table 4), since monitoring is easy to do
(urine samples only), cheap, and we are uncertain about
when stopping is safe.
Late sequelae from chemotherapy are very rare.
Findings from a study153 of 15 279 patient-years of
follow-up showed no signicant increase in incidence of
second tumours after methotrexate therapy. By contrast,
26 patients receiving combination chemotherapy for
gestational trophoblastic neoplasia developed another
cancer when the expected rate was only 1645which is
a signicant dierence.

Although outcomes for more than 98% of women with
gestational trophoblastic neoplasia are excellent, a few
women die from the disease, mainly because of late
presentation and diagnosis or drug resistance.
Consequently, novel therapies with improved ecacy and
reduced toxic eects need to be identied. Additionally,
after diagnosis of molar pregnancy, women have to wait
many weeks or months to nd out whether they need
chemotherapy. Therefore, a new prognostic test at the time
of initial molar diagnosis is needed to identify those who
might develop malignant disease. Of course, if residual
complete hydatidiform mole acquires additional genetic
changes after evacuation, such a test might never be
possible. However, evidence comparing early versus
delayed evacuation of complete hydatidiform mole alone
and in pregnancies with a healthy twin suggest that
delayed termination has no increased risk of malignant
disease.76,84 This nding suggests that hydatidiform moles
are probably pre-programmed to behave malignantly at an
early stage of development and before uterine evacuation.
The optimum management strategy for women with
repetitive molar pregnancies to allow healthy pregnancy
is unknown; even though the causative gene has been

identied for many cases, its function is unknown. The

successful UK model of centralised care for rare diseases
should be established worldwide to improve outcomes
for gestational trophoblastic disease.
All authors did a detailed review of published work and contributed to
the writing, review, and editing of the report. MJS had access to all the
data used to write the report and had nal responsibility for submission.
All authors saw and approved the nal version.
Conicts of interest
We declare that we have no conicts of interest.
MJS and NJS thank the Department of Health, National Commissioning
Group, and the Cancer Treatment and Research Trust for their continued
support. MJS acknowledges support from the Imperial College
Experimental Cancer Medicine Centre and Biomedical Research Centre
grants. RSB acknowledges the Donald P Goldstein MD Trophoblastic
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