Gestational Trophoblastic Disease

(GTD)

Amr Nadim, MD
Professor of Obstetrics & Gynecology
Ain Shams Faculty of Medicine
[[email protected]]

Definition:
Gestational Trophoblastic Disease/
Tumors(GTD/ GTTs)is a group of disease
originating from trophoblastic
cells,including
Hydatidiform mole,
Invasive mole,
Choriocarcinoma and a
Less commonly encountered : Placental
site Trophoblastic Tumor
These are cancers and cancer like conditions of
placental elements

Hhydatidiform mole means that the placenta

trophoblastic cells proliferate abnormally:

There is stromal edema ,

With formation of vesicules looking like grape on its
appearance.
Two types exist:
Complete Hydatiform Mole
Partial Hydatiform Mole

Complete Vs Partial
Hydatiform Mole
Complete hydatidiform mole

A sperm has fertilized an

empty egg (contains no
nucleus or DNA).
All the genetic material comes
from the fathers sperm.
Therefore, there is no fetal
tissue.
Up to 20% of patients with
complete moles will need
additional surgery or
chemotherapy after their initial
surgery.
A small percentage of complete
moles may develop into
choriocarcinoma, a malignant
form of GTD.

Partial hydatidiform

mole

Two sperm fertilize a

normal egg.
These contain some
fetal tissue mixed in
with the trophoblastic
tissue.
No viable fetus is being
formed.
Only a small percentage
of patients with partial
moles need further
treatment after initial
surgery.
ComPartial moles rarely
develop into malignant
GTD.

Invasive Mole
An invasive mole (formerly known as

chorioadenoma destruens) is a hydatidiform

mole that penetrates the muscular wall of the
uterus (myometrium).
These develop in about 20% of women who have
had a complete mole removed by curettage.
The risk of developing these in women with
complete moles is increased if:

There is a long time (more than 4 months) between

the time periods had stopped and treatment.
The uterus has become very large.
The woman is older than 40 years.
The woman has had GTD in the past.

Invasive Mole
Invasive moles can be complete or partial,
Complete moles invade much more often than

partial nodes.
These moles sometimes disappear on their own,
but most require treatment with chemotherapy.
In about 15% of cases, the tumor spreads
through the bloodstream (metastasizes) to other
sites, usually the lungs.
Pathology:

Grossly: different size of vesicles in myometrium,there may be

or may not be primary focus in uterine cavity.
Microscopically: villous structure and trophoblastic cells
proliferation
and differentiation

Choriocarcinoma
Choriocarcinoma is a malignant form of GTD.
Most often develops from a complete hydatidiform

mole,
But

it can occur after a normal pregnancy

or after an early fetal demise.
Rarely, choriocarcinomas can develop in other parts of
the body in both men and women. These are not
related to pregnancy: ovaries, testicles, chest, or
abdomen [mixed germ cell tumor]
Nongestational choriocarcinoma tends to be less
responsive to chemotherapy and has a less favorable
prognosis than the gestational variant.

Choriocarcinoma is more likely to spread to organs

away from the uterus.

Pathology
Grossly

most choriocarcinoma occurs in uterus,

the tumor diameter 2-10cm,its color is redin cut section,
cancer embolus is often found in parauterine veins,ovarian
luteinizing cyst may be formed

Microscopic examination:the most obvious difference between

choriocarcinoma and common cancer is that

the choriocarcinoma does not have tumor intrinsic connective

stromal cells nor intrinsic blood vessels.
Under microscope the hyperplastic cytotrophoblastic cells and
syntrophoblastic cells invade the myometrium and blood vessels
accompanied by the bleeding and necrosis,so the cancer cells can
not be found in the center of normal tissues

We should NOT rely only on histopathology for the diagnosis of

Choriocarcinoma

Placental-site Trophoblastic
Tumor
Placental-site trophoblastic tumor (PSTT) is a rare

form of GTD that develops where the placenta

attaches to the uterus.
This tumor most often develops after a normal
pregnancy or abortion.
Most placental-site tumors do not spread to other
sites in the body. Sometimes, though, these tumors
penetrate the muscle layer of the uterus.

Although most forms of GTD are very sensitive to

chemotherapy drugs, placental-site tumors are not
and, therefore, they must be completely removed by
surgery.

Why..?
Complete Mole
A sperm cell fertilizes an egg that
contains no nucleus.
After fertilization, the
chromosomes from the sperm
duplicate themselves, so there are
2 copies of identical chromosomes
that both come from the sperm.
Sometimes an abnormal egg
without any chromosomes may
be fertilized by 2 sperm cells.
Again, there are 2 copies of the
father's chromosomes and
none from the mother, and a
complete mole forms.
This situation prevents normal
development, and no fetus is
formed. Instead, a complete
hydatidiform mole develops.

Partial moles
2 sperm cells manage to
penetrate a normal egg at the
same time.
Now the fertilized egg
contains 3 sets of
chromosomes (69) instead
of the usual 2 sets (46).
An embryo with 3
chromosome copies cannot
develop into a fully
developed infant. This
situation leads to an
abnormal (malformed)
fetus along with some
normal placental tissue and
a partial hydatidiform mole.

Choriocarcinomas can develop when bits of tissue are left behind in

the uterus after spontaneous (miscarriage) or intended abortion or

after delivery of a baby following an otherwise normal pregnancy.
Most develop from persistent hydatidiform moles.

Risk Factors
Age:
The risk of complete molar pregnancy is highest in women
over age 40 and younger than 20.
Age is less a factor for partial moles.
all women of childbearing age are at risk for the disease.
Pregnancy number: Nulliparous women are at more

risk.
Having a molar pregnancy before:

Once a woman has had a hydatidiform mole, there is about

a 1 in 60 chance that she will have another one.
It is important to remember that 98% of subsequent
pregnancies will be normal.

Blood type:
Women with blood type A or AB are at slightly higher risk
than those with type B or O.

Risk Factors
Birth control pills:
Women who take birth control pills are about 50%
more likely to get GTD when they do become
pregnant.

This risk is lower for shorter use of birth control pills

and higher for longer use.
But the risk is still so low that it doesnt outweigh the
benefit of using the pills.

Lifestyle:
smoking and drinking alcohol can increase the risk
of GTD.
Number of sexual partners: Having more than

10 sexual partners increases the risk of GTD.

Socioeconomic status: Lower socioeconomic
status has been associated with an increased
risk.

Clinical manifestation
[Hydatiform Mole]

Vaginal bleeding:

97% with complete hydatidiform moles

less often with incomplete (partial) moles.
Bleeding typically starts during the first trimester, often between the 6th and the 16th
week of pregnancy.

Anemia
Abdominal swelling:

Tedency toward severe emesis gravidarum and sometimes Hyperemesis gravidarum

Preeclampsia:

A uterus larger than the period of amenorrhea is seen with complete hydatiform mole.

Vomiting:

Women with GTD often pass blood clots or watery brown discharge from the vagina
(Prune juice)
Sometimes, pieces of the moles resembling a bunch of grapes become dislodged from
the uterus and are discharged through the vagina.
Women with partial moles are mostly diagnosed after a partial or missed miscarriage.
The molar pregnancy is found when the D & C is done to remove the products of
conception.

Preeclampsia develop during the first or second trimester of a complete molar

pregnancy.
It affects about 25% of women with complete moles but only about 4% of women with
partial moles.

Hyperthyroidism:

Hyperthyroidism (overactivity of the thyroid gland) occurs in about 7% of women with

complete hydatidiform moles. Symptoms of hyperthyroidism include rapid heartbeat,
warm skin, and mild tremors (shaking).

Clinical manifestation
[Invasive Mole and
Choriocarcinoma]
There is a history of:

A complete mole and less commonly after a partial mole.

The tumors can also develop after a normal pregnancy, ectopic
pregnancy or miscarriage.

Bleeding:

The most common symptom is vaginal bleeding.

Rarely, the tumor penetrates the uterine wall with development of
internal hge

Infection:

Infection producing a discharge from the vagina, crampy pain in the

pelvic region, and fever.

Abdominal swelling:

Enlarged uterus
Theca-lutein cysts

Vaginal mass/Ulcer.
Lung symptoms after metastasis.
Symptoms of distant spread:

Brain
GIT

Clinical manifestation
[Placental Site Tumor]
Bleeding:
Vaginal Bleeding.
If the disease penetrates the uterine
wall, there will be bleeding into the
abdominal cavity along with severe
abdominal pain.
Persistent abdominal swelling

Investigations
Blood Tests

Beta subunit hCG

Diagnostic
Prognostic
HCG resolution law:

Normally after emptying the mole, the -HCG regression curve is steadly
decreased,and reach normal level within 9~14 weeks
Persistent mole: if the HCG is still positive 3 months after the mole is
completely emptied,called persistent mole
Liver and kidney function tests
Blood cell counts can detect anemia and leucopenia.

Imaging Studies

Ultrasonography (ultrasound): Ultrasound can identify most cases of GTD..

In a normal pregnancy, ultrasound imaging would show a picture of the developing fetus
In a molar pregnancy, however, the ultrasound shows that there is no fetus. (The rare
exception, occurring in less than 1% of cases, would be a "twin" pregnancy in which one
of the twins is a normal fetus and the other is a hydatidiform mole.) Instead, the
ultrasound detects the large, grape-like swollen villi that are typical of GTD.
Ultrasound is used to help diagnose a mole and find out if it is invading local tissues.
More imaging tests will be done if after the mole has been removed and the blood levels
of HCG havent disappeared

The Snow storm appearance

Investigations
Chest x-ray
Computed tomography (CT)
Magnetic resonance imaging (MRI)
Positron emission tomography

(PET)

Gestational Trophoblastic
Disease Classification
Systems
AgeScore

40 or younger
0
Older than 40
1
Prior PregnancyScore
Hydatidiform mole
0
Abortion
1
Birth (term)
2
Time from end of pregnancy
Score
Less than 4 months
0
4 - 6 months
1
7 - 12 months
2
More than 12 months
4
HCG levels (mIU/mL) in
bloodScore
Less than 1,000
0
1,000 - 9,999
1
10,000 - 100,000
2
More than 100,000
4

Largest tumor, including the original

one in the uterusScore

Site of metastasesScore

Lung
Spleen, kidney
Gastrointestinal tract
Brain, liver

0
1
2
4

Number of metastases found Score

Less than 3 cm (1.2 inches) 0

3 - 5 cm
1
More than 5 cm (2 inches) 2

14
58
More than 8

1
2
4

Prior failed chemotherapyScore

Single drug
2 or more drugs

2
4

Prognostic
factor

Age

<39

>=39

Prior pregnancy

mole

abortion

term

Interval

<4 mo

4-6 mo

7-12 mo

>12 mo

B-HCG

<1,000

<10,000

<100,000

>100,000

ABO blood
group

OxA or AxO

B or AB

Size of largest
tumor

3-5cm

>5cm

Site of
metastases

spleen,kidney

GI,liver

brain

Number of
metastases

1-4

4-8

>8

Prior
chemotherap
y

single agent

two or more

Risk LevelScore
Low risk
High risk

points

1 - 7 points
8 or more

Anatomic Stage Of
Trophoblastic Cell Tumor
I : tumor is located in uterus
II:
tumor spread to adnexa,vagina,broad

ligament
III: tumor spread to lung,there is or not
tumor in
reproductive system
IV : metastasis to other organs

T (Tumor) Stages

M (Distant Metastases) Stages

Stage IIA: Low risk

Stage IIB: High risk

Stage III: Any T, M1a: The cancer has spread to the lungs; it may or may
not also involve genital structures such as the vagina or vulva.

Stage IA: Low risk (If your prognostic score shows you are low risk, your
stage is Stage 1A.)
Stage IB: High risk (If your prognostic score shows you are high risk,
your stage is Stage 1B.)

Stage II: T2, M0: The cancer has spread outside the uterus but is limited
to the genital structures (vagina or pelvis or both).

M0: No distant spread

M1a: Lung metastases
M1b: Other distant metastases

Stage I: T1, M0: The tumor has not spread outside the uterus.

T0: The original tumor can no longer be found.

T1: The tumor is only in the uterus.
T2: The tumor has spread to local tissues around the uterus (ovary, tubes, and/or
vagina).

Stage IIIA: Low risk

Stage IIIB: High risk

Stage IV: Any T, M1b: The cancer has spread distantly to other organs
(such as the brain, liver, kidneys, and/or gastrointestinal tract).

Stage IVA: High risk

Stage IVB: Low risk

[Prognosis]:
invasion or

complete mole has the latent risk of local

telemetastasis, research proved that after emptying

the mole , the rate of uterine invasion or telemetastasis is 15% and

4% respectively.
If the patient has the following high-risk factors,the risk of local
invasion or telemetastasis may increase 10 times.
The high-risk factors includes:
-HCG>100000IU/L;

Uterine size is obviously larger than that with the same

gestational time.
Theca lutein cyst is >6cm.
If age >40 years old,the risk of invasion and metastasis may be
37%,
If >50 years old,the risk of invasion and metastasis may be

Management
Emptying uterine cavity: once the

diagnosis is confirmed the uterine cavity

should be emptied as soon as possible
uterine aspiration and curettage
application of oxytocin during operation
indication of the second curettage
Hysterectomy

over 40 years old with high-risk factors

uterine size is over 14 gestational weeks

 Preventive chemotherapy: the malignant

change rate is 14.5%

over 40 years old
the -HCG is over 100kIU/L before emptying
mole
the HCG regresion curve is not progressively
declined
uterus is obviously larger than the size of
the amenorrhea
luteinizing cyst is >6cm
there is still over hyperplasia of
trophoblastic cells in the second curettage
no follow up conditions

follow up
Regular follow up can find persistent or metastatic trophoblastic
cells tumor
HCG measurement:
after emptying the mole ,the HCG should be measured
once a week until it is to the normal level
follow up:

once a week in the first 3 monthes,

then once / 2 weeks in the next 3 monthes and
once a month for half a year,
once half a year in the second year,
and totally follow up for 2 year

Overall, one should look for :HCG, abnormal vaginal bleeding,

cough, hemoptysis, metastatic symptoms, gynecologic

examination, pelvic ultrasound and chest x-ray.
The hydatidiform mole patients should take contraception for
2 years after treatment,condom is the best but COCs are an
equal good option

Chemotherapy

As a general rule,

women who have metastatic disease and are classified as low risk are given a single
chemotherapy drug.
Women with one or more risk factors usually receive combinations of drugs, often at
higher doses. The drugs given may include methotrexate (often combined with
leucovorin), actinomycin-D, cyclophosphamide (Cytoxan), vincristine, etoposide, and
cisplatin.

Chemotherapy with methotrexate alone will be used in most women with good-risk
disease. The methotrexate is injected into a vein or a muscle every day for 5 days.
After a 9-day "rest period," the treatment is repeated. These cycles continue until
remission occurs.

Folinic acid or leucovorin reduces the side effects of methotrexate.

In this course of treatment (regimen), methotrexate is given on days 1, 3, 5, and 7, and

leucovorin is given on days 2, 4, 6, and 8. Each cycle has 8 days of drug treatment,
followed by a 7-day rest period.
The cycles are repeated until blood levels of HCG remain normal for a few weeks. This
method may reduce the risk of side effects. However, it involves more treatment days, so
it may be less convenient, and the persistence rate is higher than methotrexate given on
a daily basis.

The major side effects of methotrexate are diarrhea and sores in the mouth.

Actinomycin-D (sometimes called dactinomycin) is the first choice of chemotherapy

for GTD in patients who also have liver or kidney disease because methotrexate is
toxic to the liver and kidneys and this drug is not.

It is usually given in a vein (intravenously or through an IV) every day for 5 days,
followed by 7 days without treatment.
These cycles are repeated until HCG levels have stayed in the normal range for several
weeks.
Actinomycin-D can cause fairly severe nausea and vomiting.

Chemotherapy
Women with higher-risk disease will receive

combinations of drugs such as methotrexate and

actinomycin together, along with a third drug such a
cyclophosphamide.

Cyclophosphamide can cause some nausea and hair

loss. It can also cause bladder irritation.
Another drug, etoposide, may also be added to the
regimen or used instead of cyclophosphamide.
Etoposide treatment has been occasionally associated
with the development of leukemia several years later.
Other drugs that are used are vincristine and cisplatin.
These drugs can be neurotoxic. Patients will experience
tingling and numbness, particularly in the hands and
feet. Cisplatin can also cause hearing loss and kidney
damage.

Depending on the drugs used, other possible side

effects include skin changes, fever, and problems

with the heart, nervous system, ears, or kidneys.

Hysterectomy
?

Radiation
Usually radiation isnt used for treatment

of GTD unless it has spread and is not

responding to chemotherapy.

Then radiation may be used to treat sites

where the cancer may be causing pain or
other problems. It will also be used when
GTD has spread to the brain.

Treatment with radiation begins with the

first dose of combination chemotherapy.

The type of radiation therapy used in
treating GTD is called external beam
therapy.

Treatment optionsStage X
Class
Stage
Therapy
Molar Pregnancy
I.
Low Risk
II.
High Risk
Low Risk
-Non metastatic
-Persistent after
evacuation

Evacuation
Evacuation+ProphylacticChemotherapy
Single Agent Chemotherapy
TAH+ Chemotherapy

High Risk
-Non Metastatic
-Myometrial residual

Single Agent Chemotherapy

TAH+ Chemotherapy

Low Risk Metastatic

TAH for he, sepsis or large bulky tumor+

Single agent Chemotherapy

High Risk Metastatic

-Triple Chemotherapy
- Whole brain Radiotherapy, Hepatic
radiotherapy, etc

Additional lines of
treatment

Could it be early
diagnosed?

Could it be prevented?

Twins,
when there is one viable
fetus and the other
.pregnancy is molar
The pregnancy should be

allowed to proceed if the

mother wishes, following
appropriate counselling.

Twins,
when there is one viable fetus
and the other pregnancy is
molar
The probability of achieving
a viable baby is 40% and
there is a risk of
complications such as
pulmonary embolism and
pre-eclampsia.