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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: e.jauniaux@ucl.ac.uk

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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The Obstetr ic ian

Gynaecalogis t

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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