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REVIEW
The Obstetrician
&
Gynaecologist
2003;5:130-5
Keywords
gestational
trophoblastic disease
(GTD),
human chorionic
gonadotropin (hCG),
hydatidiform mole,
trophoblastic
tumour
Author details
Eric Jauniaux MD PhD MRCOG.
Professor in Obstetrics and
Gynaecology Academic
Departments
of
Obstetrics and
Gynaecology Royal Free and
University College London Medical
School University College London
86-96 Chenies Mews London
WClE
6HX
UK.
ernail: [email protected]
130
Trophoblastic diseases and
pregnancy
Eric Jauniaux
Gestational trophoblastic disease (GTD) s a term commonly applied to
a
spectrum of interrelated disorders originating from the placental
trophoblast. These include complete, partial and invasive moles,
placental site trophoblastic tumours and choriocarcinomas. Modern
genetic and molecular biology techniques enable rapid and accurate
diagnosis and have contributed to
a
better understanding of the
pathophysiology of GTD.
As a
result most women can be treated
before they develop severe complications. This review addresses the
perinatal diagnosis of
GTD
and focuses on the roles of ultrasound and
Doppler examination in prenatal diagnosis and the importance of
histopathology in the postnatal diagnosis of GTD.
Introduction
Gestational trophoblastic diseases result from
abnormal proliferation of the trophoblast. They
include
a
wide spectrum of disorders, ranging
from molar pregnancy
at
the benign end to
neoplastic placental site trophoblastic tumours.'
Estimates of the incidence of the different forms
of GTD throughout the world vary, mainly
because few countries have registries and, rather
than being population based, incidence figures
are often based on hospital cases. Furthermore,
the vast majority of complete and partial moles
miscarry during the first trimester of pregnancy.
The incidence of molar pregnancies has been
estimated to be
as
high
as
one per
41
miscarriages.'With the advent of
a
sensitive assay
for human chorionic gonadotropin (hCG) for
monitoring trophoblastic tumours and new
approaches to chemotherapy, most women
diagnosed with a GTD are efficiently followed
up and can be treated before the development of
severe complications.
Pat
hophysiolog
y
of gestat ona
troDhoblastic disease
Although there is a well established clinical
association between molar changes of the villi
and trophoblastic hyperplasia, hydropic villous
changes can be found in conditions that are not
related to GTD. Hydropic (hydatidiform)
transformation of the villous mesenchyme, by
either
a
lack, maldevelopment or regression of
the villous vasculature, prevents the drainage of
fluid supplied by the trophoblast. Mild to
moderate generalised villous oedema can follow
the demise
of
an embryo or early gestational age
fetus. However, gross waterlogging and villous
cistern formation are only found in complete
hydatidiform moles (CHM) and partial hydati-
diform moles (PHM). The process of
hydatidiform transformation in CHM is rapid,
but not instantaneous, and
a
small proportion of
the villi retain
a
prehydatidiform, still solid, core
complete with remnants of villous capillaries.'
Since the embryo only partially forms or dies
early in development, well before the establish-
ment of an embryo-placental circulation, the
vestigial villous vessels contain no embryonic
erythrocytes and usually disappear by the sixth
week following conception. In delayed
miscarriage, independent of chromosomal
abnormality, the progressive disappearance of the
villous vasculature after embryonic death (before
seven to eight weeks menstrual age) leads to
villous hydrops. However, this does not
necessarily lead to
a
PHM.
Biochemical analysis of the molar fluid suggests
that it is derived from maternal plasma by
diffusion and/or synthesis by the trophoblast and
that it is unchanged by fetal rnetaboli~m.~he
high levels of sodium, potassium and chloride
found in molar fluid are most probably
secondary to the absence of villous drainage, as
the trophoblast continues to transfer water and
electrolytes for
a
few weeks following embry-
onic demise. However, a-fetoprotein, which is
synthesised by the secondary yolk sac and the
fetal liver but not by the villous trophoblast, is
found in all molar fluid samples. Analysis of
concanavalin A affinity molecular variants of a-
fetoprotein in molar vesicle fluid indicates that
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originates from the yolk sac.3This suggests that
in CHM the conceptus develops
at
least up to
the blastocyst stage and, even if the embryo does
not form, cellular differentiation in the primary
and secondary yolk sac is sufficient to start the
synthesis of a-fetoprotein molecules.
The investigation of reconstituted mouse eggs
suggests that the maternal contribution to the
zygote is essential for normal growth and
development of the embryo; whereas the
paternal contribution is crucial in the develop-
ment of extra-embryonic tissues, n particular the
placenta and its tr~phoblas t.~
Complete hydatidiform moles are diploid with
chromosomes totally derived from the paternal
genome, probably resulting from the fertilisation
of an ‘empty oocyte’. The oocyte, devoid of the
maternal
X
chromosome, is instead fertilised by
a
single spermatozoon whose chromosomes
double without cell cytokinesis.’These moles are
characterised by generalised trophoblastic
hyperplasia and rapidly developing villous
oedema with central cistern formation, giving
the macroscopic appearance of
a
‘bunch of
grapes’.’ The fluid, at first uniformly distributed
in the core of the villi, collects in several loculi to
coalesce into
a
central cistern.
Partial hydatidiform moles are almost always
triploid, having inherited two sets of
chromosomes from the father (diandric) and one
from the mother.‘.’ Early cytogenetic studies
have suggested that the majority of triploidies
are of paternal-diandric origin, resulting from
the fertilisation of a haploid ovum either by
two
single sperm or a single diploid sperm.6Less than
one-third of triploidies encountered in the first
trimester are of digynic origin, resulting from
a
double maternal haploid contribution when the
ovum fails to undergo the first or second meiotic
division before fertilisation.’ A single paternal
haploid set imparted to the ovum gives
a
total of
69 chromosomes.A study of 91 cases of triploid
miscarriages has confirmed that the majority of
cases are diandric in origin; but that only a
proportion of these paternally derived triplodies
develop a partial molar phenotype.8This suggests
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The Obstetrician
&
Gynaecologist
2003;5:130-5
that the mere presence of two paternal genomes
is not sufficient for molar development.
Diagnosis
of
gestational
trophoblastic disease during
pregnancy
Angiography was first used in both the diagnosis
of molar pregnancy
in
utero and the follow up of
women at risk of persistent trophoblastic disease.
In women with persistent trophoblastic disease,
or with chemotherapy-resistant disease, angio-
graphy has been of value in the diagnostic work-
up of myometrial invasion and surgical
management. Because of associated costs,
maternal discomfort and morbidity it was
progressively replaced by ultrasound imaging in
the 1960s. Ultrasonography has now also
replaced all other methods in early screening and
in establishing the differential diagnosis of molar
pregnancies
in
utero.
Singleton complete hydatidiform
moles
Classically, patients with singleton C HM present
with vaginal bleeding, abnormally high levels
of
maternal serum P-hCG and uterine enlarge-
ment that
is
greater than expected for the
gestational age (Table 1).Medical complications
include pregnancy-induced hypertension, hyper-
thyroidism, hyperemesis, anaemia and the
development of ovarian theca lutein cysts.
Ovarian hyperstimulation and enlargement of
both ovaries may subsequently lead to ovarian
torsion or rupture of theca lutein cysts. Earlier
diagnosis has led to a reduction in the incidence
of these
complication^.^
Molar changes can now
be detected from the second month of
pregnancy by ultrasound, which typically reveals
a
uterine cavity filled with multiple sonolucent
Table 1 . Clinical features and maternal complications
( ) of
complete and triploid partial
hydatidiform moles.” (modified from Jaunauix”)
Features Complete hydatidiform mol e Triploid partial hydatidiforrn mole
KaVotyPe
Maternal serum P-hCG
Vaginal bleeding
Bilateral multicystic ovaries
Hyperemesis gravidarum
Pre-eclampsia
Hyperthyroidism
Uterine enlargement
Anaemia
Postmolar GTD
46 XX
(90%)
1G200 MOM
84-97%
15-25%
8-26%
12-27%
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2003;5:130-5
areas of varying size and shape ('snow storm'
appearance) without associated embryonic or
f e t a l s t r u c t ~ r e . ~ ~ ' ~arge sonolucent areas
resulting from stasis of maternal blood in
between the molar villi are often found. Theca
lutein cysts, secondary to the high serum P-hCG
levels, may be diagnosed in up to 50% of second-
trimester cases of CHM, but their prevalence in
early pregnancy is much lower. Elevated serum
P-hCG levels combined with these specific
sonographic features are highly indicative of the
presence of
a
hydatidiform mole, even before the
final histopathological diagnosis is confirmed.
Within this context the role of Doppler, which
almost always demonstrates high velocities and
low resistance to flow in the uterine arterial
circulation, s limited and will only be of clinical
interest in the diagnosis of an invasive mole.
Complete hydatidiform moles in
multiple pregnancies
A CHM may coexist with
a
normal fetus and
placenta in cases of molar transformation of one
ovum in
a
dizygotic twin pr eg na n~ y. ~' ~~ '~
Mothers with this condition are at a higher risk
of persistent trophoblastic tumour, requiring
multiple cycles of chemotherapy, than patients
with
a
classic molar pregnancy, 5040% versus
10-1 5 respectively, (Table 2).VaginaI bleeding
from the second month of pregnancy is the most
common presenting symptom and is found in
90% of cases.The mother must be informed that
if she wishes to continue with the pregnancy she
will be at
a
high risk of developing the severe
medical complications associated with
a
CHM.
Pregnancy induced hypertension is observed in
50-60% of cases of continuing pregnancy. These
complications are often related to high maternal
serum P-hCG levels. In women deciding to
continue with the pregnancy serum P-hCG
levels can be used to monitor the growth of the
molar mass until fetal viability is reached.
Table 2 . Outcome
of
multiple pregnancies combining a complete
hydatidiform mole and normal fetus and placenta*'
Variables
I
I1
I11
n=22) n=18) n=7)
Mean gestational age at diagnosis (weeks) 21 N / A 14
Complications of ongoing pregnancies
Vaginal bleedmg 21 N / A 6
Termination of pregnancy 12 8 1
Pregnancy-induced hypertension 6
5
2
Theca lute in cyst
6 N / A 2
Outcome
Term delivery
Preterm delivery
Intrauterine death
2
2
2
5 1 3
3 2 1
I = USA and the world, ' I1 =Japan, I = U K (author's database).
Pregnancy Induced H ypertension occurred in 13 out
of21
(62%)ongoing pregnancies)
Diagnosis of
a
CHM with a coexisting fetus is
usually made at
a
later gestational age (around
15-20 weeks) than with
a
singleton CHM. s
CHMs produce a characteristic vesicular
sonographic pattern, their association with a
normal gestational sac can be accurately
determined at the end of the first
trimester.' ^
Partial hydatidiform moles
Partial hydatidiform moles refer to the
combination of a fetus with localised placental
molar degenerations.l6 Histologically PHM are
characterised by focal swelling of the villous
tissue, focal trophoblastic hyperplasia and
embryonic or fetal tissue.The abnormal villi are
scattered within macroscopically normal
placental tissue, which tends to retain its shape.
In around 90% of cases PHM are triploid, the
remaining 10% includes tetraploidies and rare
cases of placental diploid or triploid mosaics.'6
O n ultrasound, PHM present
as
an enlarged
placenta (thickness >4cm at 18-22 weeks)
containing multicystic avascular sonolucent
~paces.'~~''s triploidy is
a
highly lethal
chromosomal abnormality most embryos
affected by this defect die within
a
few weeks of
conception. Diandric PHM triploidies are
associated with a higher miscarriage rate than
digynic triploidies; probably because the excess
of paternal contribution to the zygote has
a
deleterious effect on placental implantation and
development. This can explain why
PHM are
only observed in about one-third
of
all
triploidies diagnosed after 11 weeks of
gestation.I6 Furthermore, in PHM the hydati-
diform transformation is slower and before 12-
weeks gestation some partial moles may present
as an enlarged placenta without obvious
macroscopic vesicular changes.Vaginal bleeding
in the first or second trimester is the most
common maternal symptom reported in both
types of triploidies (Table 1).The phenotypic
expression of both diandric and digynic
triploidies includes growth restriction and
disturbance of organogenesis, it becomes
obvious in fetuses surviving into the second
trimester. From 16 weeks of gestation almost all
triploid fetuses have a least
one
measurement
below the normal range and more than 70%
present with severe growth restriction.l6 It must
be highlighted that more than 80% of fetuses
with triploid PHM present with symmetrical
growth restriction, which is important from a
differential diagnosis point of view. Structural
fetal defects are observed antenatally in about
93%
of all cases. Th e most common are
abnormalities of the hands, bilateral cerebral
ventriculomegaly, heart anomalies and
micrognathia.
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Aneuploidies, and in particular trisomy 13 and
21 (but also mesenchymal dysplasia of the
placenta in Beckwith-Wiedemann syndrome),
can present with vesicular transformation of
some villous trunks. However, they are without
trophoblastic abnormalities and so cannot be
classified as 'true' PHM. The combined use of
ultrasound features, maternal serum proteins and
fetal cytogenetic findings enable early differential
diagnosis in utero and perinatal management of
those molar pregnancies that often present with
an anatomically normal fetus.l*
Persistent trophoblastic disease
Following uterine evacuation, 18-29% of
patients with a CHM and 1-11% of patients
with
a
PHM will develop
a
persistent tropho-
blastic disease.',16 While the incidence of
maternal complications has been reduced by
early diagnosis, the incidence of persistent
trophoblastic disease has remained unchanged
since the introduction of routine ultrasound
examination during pregnancy.'* This suggests
there is
a
similar risk of post-molar tumour after
a first-trimester spontaneous molar miscarriage
than after the therapeutic abortion of a second-
trimester molar pregnancy. Serial hCG levels are
the standard method used for diagnosing and
monitoring therapeutic response of persistent
trophoblastic disease. Before the development of
transvaginal sonography, transabdominal sono-
graphy was used for the assessment of
trophoblastic uterine involvement in patients
with non-metastastic GTD. Transabdominal
sonography is only capable of detecting massive
uterine involvement.All studies have shown that
transvaginal sonography is
a
more accurate
method for the assessment of the depth of
myometrial invasion than transabdominal
sonography. The use of colour Doppler
imaging, with its added capability of displaying
bloodflow data, has improved the accuracy of
transvaginal sonography. Newly formed vessels
with frequent arteriovenous anastomosis, which
produce a characteristic ultrasound pattern,
surround nodules of residual GTD. The most
frequent feature is hypoechoic areas (blood
lacunae) surrounded by irregular echogenic areas
(trophoblastic nodules) and numerous
intramyometrial signals (vascular shunts). In these
cases Doppler investigation of the uterine
vasculature and of small intratumoural vessels has
consistently shown
a
low resistance to flow and
high peak systolic velocities.
Invasive hydatidiforin moles
An invasive mole is defined
as
the penetration of
molar villi from
a
complete or partial hydatidi-
form mole into the myometrium or the uterine
vasculature.' Rarely, the molar tissue may
penetrate the whole thickness of the myo-
metrium (percreta) leading to uterine
perforation and/or local pelvic extension. In
contrast to a choriocarcinoma, an invasive mole
contains villus structures with a variable degree
of trophoblastic proliferation and produces
a
lower level of hCG. An invasive mole usually
becomes clinically apparent after the evacuation
of a molar pregnancy, the patient usually
presenting with heavy vaginal bleeding. The
tumour appears sonographically as a focal area of
increased echogenicity within the myometrium.
These nodules usually appear several weeks after
evacuation of a mole but may occur con-
currently with
a
mole. The sonographic features
of the nodules are similar to the lesions found in
cases of placental-site trophoblastic tumours.
Placental site trophoblastic
tumours
Placental site trophoblastic tumours are the rarest
form of GTD. This particular variant of
malignant trophoblastic tumour is composed of
intermediate trophoblastic cells from the
extravillous trophoblast of the placental bed.' In
more than 90% of the cases placental site
trophoblastic tumours develop after a normal
pregnancy. Rare cases have been reported
following a diploid or triploid mole and in
postmenopausal women. Common presenting
symptoms include amenorrhoea of up to one
year or irregular vaginal bleeding of varying
duration.' Placental site trophoblastic tumours
invade the myometrium by separating muscle
bundles and fibres. Around 15-20% of them
behave in
a
malignant fashion with metastases to
the lungs, liver, abdominal cavity and brain. The
principal protein produced by the intermediate
trophoblast is human placental lactogen.'
Relatively low hCG levels and high human
placental lactogen levels should be found in the
serum of patients with placental site
trophoblastic tumours. Maternal biology can be
an important parameter in the differential
dagnosis since on ultrasound these tumours
appear as small heterogeneous echogenic areas
with fluid filled cysts, representing haemor-
rhagic areas, similar in appearance to an invasive
mole or persistent GTD.
Choriocarcinomas
Choriocarcinomas are highly malignant
tumours that arise from the trophoblastic
epithelium; they metastasise readily to the lungs,
liver and brain.9 Many women with a
choriocarcinoma will present with dyspnoea,
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REVIEW neurological symptoms and abdominal pain.
These symptoms usually appear
a
few weeks or
months following pregnancy, but can sometimes
appear up to 10-15 years after the last
pregnancy's9 Around 50% of choriocarcinomas
follow a molar pregnancy, 30% occur after a
miscarriage and 20% after an apparently normal
pregnancy.' Seckl
et
al . demonstrated that
choriocarcinomas can also occur after
a
triploid
PHM.I9 There have been a few well docu-
mented examples of choriocarcinoma arising
from villous tissue in an otherwise normally
developed placenta; suggesting that most
choriocarcinomas that follow an apparently
normal pregnancy are in reality metastases from
a
small intraplacental choriocarcinoma.' The
primary tumour is usually small in size, ranging
from 2.5-8 mm, and an extensive search of the
entire placenta is often required to find the
lesion. In most cases of intraplacental
choriocarcinoma the mother presents with
multiple metastases during the course of
pregnancy, but the infant is usually free of
disease. In s ttr choriocarcinomas can also arise in
association with
a
chorioangioma.
The Obstetrician
Gynaecologist
2003;5:130-5
Histopathological diagnosis
Most triploid placentas, between 7-12 weeks of
gestation, have no noticeable macroscopic
features of molar change, suggesting that molar
transformation becomes more pronounced as
pregnancy advances.*' In early pregnancy, molar
changes are often identified by histopathological
examination only; suggesting that most triploidy
will escape clinical detection in cases of first-
trimester miscarriage. The histological diagnosis
of hydatidiform moles depends on the presence
of trophoblastic hyperplasia.' In the vast majority
of PHM the trophoblastic hyperplasia is often
focal, involving the syncytiotrophoblast alone.'6.20
Th e hydatidiform changes are also focal,
resulting in an irregular patchwork of seemingly
normal and affected areas. Unusually conspic-
uous
trophoblastic anomalies and insufficient
placental sampling may cause errors. Most
authors found that the atypical pattern of
trophoblastic hyperplasia is the important
diagnostic histological feature of
a
partial
mole.Z.lb,ZO However, most histopathologists have
difficulties in differentiating pseudomolar
pregnancies presenting with hydropic villous
changes from PHM. We found that the positive
predictive value and sensitivity of histology for
the detection of triploidy in first-trimester
miscarriages was high. Discordant results were
mainly found for specimens with histological
alterations due to prolonged placental post-
mortem retention where the trophoblastic
hyperplasia was not apparent. Delayed fixation
can also alter the results of microscopic
examination.To minimise the rate of histological
examination failure, it has been our policy to
request the whole specimen from the referring
physician and to process the samples
immediately upon arrival at the laboratory.
Pathological examination, in some cases, may
also be complicated by the fact that the molar
placental tissue may come from
a
resorbed twin.
Within this context, many diploid PHM
previously reported in the literature were
probably complete hydatidiform moles with
a
coexisting fetus and placenta.16 Ploidy
determination by flow cytometry allows further
classification of molar gestations, even if villous
tissue has been embedded in paraffin. This
procedure is easier, faster and cheaper than cell
culture and can provide useful information that
may serve
as
an adjunct to equivocal histological
diagnosis. New techniques such
as
fluorescent in
situ
hybridisation can also be readily used in
determining the ploidy of placental tissues from
partial moles, but are more expensive than flow
cytometry. Furthermore, the latter technique
enables the investigation of large cell
populations and is able to discover molar
mosaicism.
Recommendations and follow
up
It is important to record the occurrence of
gestational trophoblastic diseases. The RCOG
along with the Departments of Health for
England, Scotland and Wales recommend that
women with either a CH M, PHM, twin
pregnancy with CHM or PHM, or macroscopic
or microscopic molar change that requires
follow up should be registered. Information on
registering patients is available through the
Hydatidiform Mole Choriocarcinoma UK
Information and Support Service webi~te.'~
Although the risk of having
a
further molar
pregnancy is low, the RCOG recommends that
women considering future pregnancy should be
advised to avoid conceiving until their hCG
levels have been normal for six months. Women
should also avoid taking the oral contraceptive
pill or hormone replacement therapy until their
serum hCG levels are considered normal.
Modern methods of diagnosis and treatment
have led to improved outcomes for women diag-
nosed with trophoblastic diseases. But because of
the diagnostic and management difficulties for
women, in the second trimester of pregnancy,
with ultrasonic features that are suggestive of
molar transformation, it is important to refer
them to
a
specialised fetal medicine unit.
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