Fetal Medicine

Gestational Trophoblastic Disease

Jeannet E. Canda, RN,MAED
NDDU
College of Nursing
Fetal Medicine
Gestational Trophoblastic Disease (GTD)
is a relatively rare event with a calculated incidence of 1/714 live
births.

There is evidence of ethnic variation in the incidence of GTD in the
UK, with women from Asia having a higher incidence compared with
non-Asian women (1/387 versus 1/752 live births).

This may under-represent the true incidence of the disease
because of problems with reporting, particularly with regard to
partial moles.


Fetal Medicine
Hydatiform mole
Invasive mole
Choriocarcinoma
Placental site trophoblastic tumor
Partial
Complete
GESTATIONAL TROPHOBLASTIC DISEASE

Fetal Medicine
Epidemiology

The incidence of molar pregnancy varies in different parts of the
world.

Women of Asian origin: 1 in 550 to 1 in 600.
Women of European origin: 1 in 1200 live births




Fetal Medicine

Age is probably the most important factor in the incidence of
developing complete hydatidiform mole.

Where the incidence for women aged 25 to 29 is standardized
as 1, the risk is

6 X in women who become pregnant under 15 years

411 X in patients who become pregnant over the age of 50

Epidemiology

Fetal Medicine
North America and Europe:
Partial mole 1/700
Complete mole 1/1500-2000

Asian Countries:
Partial mole 1/120
Complete mole 1/350-500

HYDATIDIFORM MOLE
Incidence
Fetal Medicine
1. Maternal age > 40 years
< 15 years

2. Paternal age > 45 years

3. Previous hydatidiform mole 1
st
1-2%
2
nd
15-28%

4. Vitamin A deficiency

HYDATIDIFORM MOLE
Risk factors
Fetal Medicine
Background

Hydatidiform mole is subdivided into complete and partial mole
based on genetic and histo-pathological features.

Complete moles are
diploid
andro-genetic in origin
no evidence of fetal tissue.

Arise as a consequence of
1. duplication of the haploid sperm following fertilisation of an empty
ovum ( diandry)
2. Some complete moles arise after dispermic fertilisation of an
empty ovum. (dispermy)



Molar Pregnancy
Complete Mole
Fetal Medicine
Empty
ovum
Empty
ovum
46XX
46XX
or 46XY
23X or Y 23X
23X
Complete Mole
(46XX diploid)
Complete Mole (46XX
or 46XY, diploid)
A single sperm fertilizes an
empty ovum, with duplication
of the 23X haploid set of
chromosomes, giving rise to a
homozygous diploid complete
mole.
Two sperms with two
independent haploid sets of
chromosomes fertilize an
empty ovum, producing a
dyspermic complete mole with
either 46XX or 46XY
karyotype.
COMPLETE MOLE
Modified from Cheung, 1995
Fetal Medicine
Complete molar pregnancy
Complete hydatidiform mole forms a multivesicular mass with
diffuse hydropic villi and a variable degree of trophoblastic
proliferation.

There is usually no evidence of a foetus. This conceptus is diploid
and androgenetic in origin.


The incidence of a GT Tumour is approximately 1000X more likely
following a complete hydatidiform mole than after a full-term
pregnancy.
One possible explanation is that genomic imprinting plays a
role in tumourigenesis since the complete mole is androgenetic in
origin.
Fetal Medicine
Fetal Medicine
Fetal Medicine
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Triploid in origin with usually two sets of paternal haploid genes and
one set of maternal haploid genes.

They occur, in almost all cases, following dispermic
fertilisation of an ovum. There is usually evidence of a fetus
or fetal red blood cells.
In some cases failure of meiosis I or II in the ovum leads to
Triploidy with 46 maternally derived chromosomes and 23
paternal

Partial Molar Pregnancy

Fetal Medicine
23X
23X
Dyspermy
23X/23Y or
23X/23X
23Y
Partial Mole (69XXY,
or 69XXX, or 69XYY
triploid)
PARTIAL MOLE
23X
23X
23Y
69XXY
Fertilization of a normal 23X haploid ovum by two sperms, producing a
triploid partial mole with either 69XXY, 69XXX or 69XYY karyotype
Modified from Cheung, 1995
Fetal Medicine
Fetal or embryonic tissue absent present
Hydatiform swelling of chorionic villi extensive focal
Trophoblastic hyperplasia extensive focal
Scalloping of chorionic villi absent present
Trophoblastic stromal inclusions absent present
Karyotype 46XX (90%); Triploid (69 XXY)
46XY (10%)
Complete mole Partial mole
Cohn DE, Herzog TJ. Curr Opin Oncol 2000 Sep; 12(5):492-6
FEATURES OF PARTIAL AND COMPLETE MOLE

Fetal Medicine
Fetal Medicine

Persistent GTD
The term persistent "gestational trophoblastic disease" is widely
used to describe the situation where a woman has had a
hydatidiform mole and still has persistently raised human chorionic
gonadotrophin (hCG) estimations

Since in the majority of cases the disease either remits
spontaneously or can be successfully treated without further
pathological sampling, it is difficult to say exactly in what
proportion of patients their hydatiform mole modulates to
choriocarcinoma.
This event probably happens in 3% to 5% of patients who have had
a complete hydatidiform mole
Fetal Medicine
Gestational Trophoblastic Disease


Persistent GTD may develop
1. After a molar pregnancy,
2. After a non-molar pregnancy
3. After a live birth (~ 1/50 000)



Fetal Medicine
Gestational Trophoblastic Tumours
Overview

GTT are unique in cancer biology in that they follow
1. either a normal or abnormal pregnancy,
2. the tumours contain paternal genes and are therefore an
allograft in the maternal host.
Fetal Medicine
Invasive Hydatidiform Mole
Invasive hydatidiform mole (complete or partial) is common since
molar trophoblast invades the myometrium in most cases.

Pathologically invasive hydatidiform mole can be diagnosed only
when sufficient myometrium is made available to the pathologist
either on curettings or by hysterectomy
Fetal Medicine
Invasive Hydatidiform Mole

An invasive mole retains hydropic villi, which penetrate the
uterine wall.
Can cause uterine rupture and can be life threatening.
Hydropic villi may embolize to distant organs, but this tumor
does not have metastatic potential.
Cure is possible by hysterectomy or chemotherapy.
Fetal Medicine
Choriocarcinoma
It is an unusual tumour in that it stimulates virtually no stromal
reaction and is therefore essentially a mixture of haemorrhage and
necrosis with tumour cells scattered within the mass.

Tumour cells can be scanty and present problems of pathological
interpretation if the possibility of choriocarcinoma has not been
raised.

The pathology of choriocarcinoma is reflected in its clinical
behaviour with widespread intravascular dissemination to lungs,
brain and other sites.
Fetal Medicine
Choriocarcinoma

Is a very aggressive malignant tumor and arises either from
gestational chorionic epithelium or less frequently, from
totipotential cells within gonads or elsewhere.

Incidence is 1/ 30,000 pregnancies in US.

More common in Asian and African countries.
Fetal Medicine
Choriocarcinoma


Most cases are discovered by the appearance of a bloody, brownish
discharge, accompanied by a rising titer of HCG, particularly the
beta subunit.

Usually appear as very hemorrhagic, necrotic masses within the
uterus.


Widespread dissemination via blood, lung (50%), vagina (30-40%),
brain, liver and kidney.
Fetal Medicine
Placental site trophoblastic tumours
Placental site trophoblastic tumours are now recognised as a
separate entity.

1. rare and
2. are composed mainly of cytotrophoblastic cells
3. tend to be locally invasive
4. less widely metastatic than choriocarcinoma

The optimal management of patients with placental site
trophoblastic tumours is unclear.
This is because
(i) the tumours are rare and
(ii) their biological behaviour does appear to be variable.
Fetal Medicine

Where the disease is localised to the uterus, hysterectomy is the
treatment of choice.

A small number of patients treated with intensive chemotherapy
initially have achieved complete remission but the chemosensitivity
of placental site trophoblastic tumours appears to be quite variable

Placental site trophoblastic tumours
Fetal Medicine
Clinical presentation

The most common presentation of a patient with a GTD is
1. vaginal bleeding towards the end of the first trimester of
pregnancy.
2. nausea and vomiting and
3. uterus larger for dates than for a normal pregnancy.


Since the quantity of hCG produced by a normal pregnancy can vary
over quite a wide range, the initial hCG estimation is not helpful in
differentiating between a pregnancy and a hydatidiform mole.
Fetal Medicine
COMPLETE HYDATIFORM MOLE
CLINICAL FEATURES
Vaginal bleeding (anemia) 97%
Excessive uterine size 50%
Theco-lutein ovarian cysts 50%
Preeclampsia 27%
Hyperemesis 25%
Hyperthyroidism 7%
Trophoblastic embolization 2%
(respiratory distress)
Fetal Medicine
The increasing performance of ultrasound examination,
either routinely in the first trimester or for management of
early pregnancy complications, allows evacuation of most
pregnancies affected by hydatiform mole prior to
development of the classic sonographic and pathological
features.
ULTRASOUND FINDINGS

Fetal Medicine
Multiple hypoechoic areas extensive focal
Increased echogenicity extensive focal
Enlarged uterine volume present absent
Theca-lutein cysts present absent
> gestational sac - present
< Uterine artery PI present -
Complete mole Partial mole
ULTRASOUND FINDINGS

Fetal Medicine
Diagnosis of Gestational Trophoblastic Disease

Increasing use of ultrasound in early pregnancy has led to the
earlier diagnosis of molar pregnancy.

The majority of histologically proven complete moles however are
associated with an ultrasound diagnosis of delayed miscarriage or
anembryonic pregnancy

The ultrasound features of a complete mole are reliable but the
ultrasound diagnosis of a partial molar pregnancy is more complex.
RCOG, February 2004

Fetal Medicine
Management of GTD
Suction curettage is the method of choice of evacuation for
complete molar pregnancies.

Because of the lack of fetal parts a suction catheter, up to a
maximum of 12 mm, is usually sufficient to evacuate all complete
molar pregnancies

Medical termination of complete molar pregnancies, including
cervical preparation prior to suction evacuation, should be avoided
where possible because of the potential to embolise and
disseminate trophoblastic tissue through the venous system


Fetal Medicine
In partial molar pregnancies where the size of the fetal parts
deters the use of suction curettage, medical termination can be
used.

These women may be at an increased risk of requiring treatment
for persistent trophoblastic neoplasia, although the proportion of
women with partial molar pregnancies needing chemotherapy is low
(0.5%)

Management of GTD
Fetal Medicine
Gestational Tropholastic Neoplasia-
Requirement for diagnosis
1. 4 or more values of hCG plateau over ay least 3 weeks
2. A rise of hCG of 10% or greater for > 3 values over at least 2
weeks
3. Presence of Choriocarcinoma
4. Persistence of hCG 6 months after mole evacuation
Fetal Medicine
Women scoring >7 (high risk) receive combination chemotherapy.



IV Etoposide, Methotrexate, Actinomycin D for 2 days
followed by Cyclophosphamide and Vincristine (Oncovin) (EMA-CO)
one week later.
The course is then repeated after six days.
Charing Cross Hospital, London

Treatment of persistent GTD
Fetal Medicine
Future pregnancy

Women should be advised not to conceive until their hCG levels
have been normal for six months.

Women who undergo chemotherapy are advised not to conceive for
one year after completion of treatment

Risk of a further molar pregnancy is low (~ 2%)
>98% of women who become pregnant following a molar pregnancy
will not have a further mole or be at increased risk of obstetric
complications.
If a further molar pregnancy does occur, in 6880% of cases it will
be of the same histological type


Fetal Medicine
Follow-up and Fertility after Chemotherapy
Approximately 90% of patients who want to become pregnant
following chemotherapy have succeeded and there is no evidence of
increase in foetal abnormalities.

Occasionally a G.T.T. can occur or recur after a subsequent normal
pregnancy
This emphasises the importance of reconfirming that hCG levels
return to normal after any subsequent pregnancy in a woman who
has had a trophoblastic disease event
Fetal Medicine

Contraception and hormone replacement
therapy

The COC-pill, if taken while hCG levels are raised, may increase the
need for treatment.

However, it can be used safely after the hCG levels have returned
to normal.
Other forms of hormonal contraception do not appear to be linked
to an increased need for treatment.

The small potential risk of using emergency hormonal
contraception, in women with raised hCG levels, is outweighed by
the potential risk of pregnancy to the woman.

Hormone replacement therapy may be used safely once hCG levels
have returned to normal.

Fetal Medicine
Survival

The overall survival in the Charing Cross series, with a maximum
follow-up of 15 years is ~ 94%
Fetal Medicine
The successful outcome in patients with GTT depends on several
factors:-
(i) Need for a national registration scheme of patients at risk of
developing a GTT
(ii) The ability to monitor the disease and its response to
treatment with serial hCG estimations.
(iii) The intrinsic biological property of GTT in being inherently
very sensitive to a range of chemotherapeutic agents.
Survival

Fetal Medicine



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