Gestational Trophoblastic Disease (GTD)
Amr Nadim, MD
Professor of Obstetrics & Gynecology
Ain Shams Faculty of Medicine
[amrnadim@link.net]
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 father’s 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 doesn’t 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.

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Anemia
Abdominal swelling:

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Tedency toward severe emesis gravidarum and sometimes Hyperemesis gravidarum
Preeclampsia:

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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

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Diagnostic
Prognostic
HCG resolution law:
 Normally after emptying the mole, the β-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..


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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, grapelike 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
haven’t 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
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Largest tumor, including the original
one in the uterusScore
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Site of metastasesScore
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Lung
Spleen, kidney
Gastrointestinal tract
Brain, liver
0
1
2
4
1–4
5–8
More than 8
1
2
4
Single drug
2 or more drugs
2
4
Number of metastases found Score



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Less than 3 cm (1.2 inches) 0
3 - 5 cm
1
More than 5 cm (2 inches) 2
Prior failed chemotherapyScore


Prognostic factor
0
1
2
4
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
chemotherapy
.
.
single agent
two or more
Risk LevelScore
Low risk
High risk
1 - 7 points
8 or more points
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
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M (Distant Metastases) Stages
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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.


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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]:
complete mole has the latent risk of local
invasion or
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:
 β-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 56%.
 Repeated mole:the morbidity of invasion and metastasis increase
3~4 times.
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%

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over 40 years old
the β-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 isn’t 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 options…Stage X Stage
Class
Therapy
Molar Pregnancy
I.
Low Risk
II.
High Risk
Evacuation
Evacuation+ProphylacticChemotherapy
Low Risk
-Non metastatic
-Persistent after evacuation
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,
there is one viable fetus
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 preeclampsia.