Gestational Trophobalstic Disease

Gestational Trophoblastic
Disease
Prof. Athula Kaluarachchi
Faculty of Medicine
University of Colombo

11/26/2019 Reproductive Health Module AL2013

Partial Mole Complete Mole(46XX or XY
Normal Fetus with
the Placenta
Triploidy 69XXY

46xx
23x
Proliferation of
monospermic
androgenetic
complete HM
Duplication
of haploid
sperm
Maternal DNA
lost from
ovum
46xy
23x
Proliferation of
dispermic
androgenetic
complete HM
Two paternal
genetic
contributions
Maternal DNA
lost from
ovum
69xxx
23x
Proliferation of
triploid
partial HM
Maternal and two
paternal genetic
contribution
69xxy
Complete moles usually (75–80%) arise as a consequence
of duplication of a single sperm following fertilization of
an ‘empty’ ovum. Some complete moles (20–25%) can
arise after dispermic fertilization of an ‘empty’ ovum.
Partial moles are usually (90%)
triploid in origin, with two sets of
paternal haploid genes and one set of
maternal haploid genes. Partial moles
occur, in almost all cases, following
dispermic fertilization of an ovum.

Gestational Trophoblastic
Disease
 Genetics
Complete Mole
46 XX --- 85%
46 XY --- 15%
Paternal origin
Partial Mole
Triploidy 69XXY

TERMINOLOGY- Gestational
trophoblastic disease (GTD)
Benign, non-neoplastic trophoblastic
lesions
Lesions characterized by abnormal proliferation of
trophoblast of the placenta.
This category is comprised of benign, non-neoplastic
lesions,
 Placental site nodule,
 Exaggerated placental site,
 Hydatidiform mole.
Complete hydatidiform mole
Partial hydatidiform mole
Invasive mole (chorioadenoma destruens)11/26/2019 Reproductive Health Module AL2013

Gestational trophoblastic neoplasia (GTN)
Gestational neoplasms include:
 invasive mole
 epithelioid trophoblastic tumor
 choriocarcinoma
 placental site trophoblastic tumor,
 In the absence of tissue for a definitive
histopathologic diagnosis, disease diagnosed
as a result of persistent elevation of human
chorionic gonadotropin (hCG) after
evacuation of a molar pregnancy is termed11/26/2019 Reproductive Health Module AL2013

Types of GTD — There are various
histologically distinct subtypes of GTD
Benign, non-neoplastic trophoblastic lesions —
These lesions are frequently diagnosed only as an
incidental finding on an endometrial curettage or
hysterectomy specimen.
●Exaggerated placental site
●Placental site nodule
Hydatidiform mole — Hydatidiform moles result from
abnormalities in fertilization. They are essentially
benign, but carry an increased risk of persistent or
malignant gestational trophoblastic neoplasia (GTN).
 ●Complete hydatidiform mole
 ●Partial hydatidiform mole
 ●Invasive mole (chorioadenoma destruens)

Gestational Trophobalstic
Disease(GTD)
 Classification
– Hydatidiform Mole
Complete Benign
Partial
– Invasive Mole
– Gestational Choriocarcinoma GTN
Placental site trophoblastic tumour
– Epithelioid Trophoblasic Tumour

Hydatidiform Mole
 Complete Hydatidiform Mole(46XX or 46XY)
 Partial Hydatidiform Mole(69XXY)

Incidence
 The incidence of molar pregnancy in
Southeast Asia is 7 to 10 times higher
than in Europe or North America.
 In Taiwan, for example, the reported
incidence of molar pregnancy is 1 in
125, as compared with an incidence of
1 in 1500 live births in the United
States.


Incidence
Complete mole – 1: 1000 pregnancies
Partial Mole - 1: 3000 Pregnancies
Choriocarcinoma - 1: 50000 following normal
deliveries
(29% - 83% following complete mole)
Placental site Trophoblastic Tumour – Rare

Risk Factors
Age
 Increasing age is the best-established risk factor for
complete molar pregnancy, women over 40 years of
age having a 5 to 10-fold higher risk than younger
women.
 Because of the higher number of pregnancies in
younger women, however, most complete moles
occur in women under 35.
Lowest risk – Age 25 – 29 years
6 times higher – Age less than 15 yrs.
4 times higher - Age 40- 45 yrs.
400 times higher – over 50 yrs.
 Maternal age has not been associated with risk of
partial molar pregnancy.

Risk Factors
 History of previous GTD
Increases the risk
1 previous – 1:76
 Women with a prior molar gestation have a
1% risk of repeat mole, approximately 10
times the risk of molar pregnancy in the
general population.
2 previous - 1: 6.5
 Histories of prior spontaneous abortion or
infertility are risk factors for both complete
and partial molar pregnancy.

CLINICAL FEATURES
Hydatidiform Mole
 Vaginal Bleeding
 Hyperemesis Gravidarum
 Passing grape like structures
 Hyperthyroidism - Signs and symptoms of
hyperthyroidism can be present due to stimulation of
the thyroid gland by the high levels of circulating hCG
or by a thyroid stimulating substance (ie, thyrotropin)
produced by the trophoblasts. Clinical
hyperthyroidism has been reported in 3.7% of women
with a hydatidiform mole diagnosed after the
10th week of gestation

CLINICAL FEATURES
 Features of metastasis/embolization - Lung
metastases are found in 4-5% of patients with a complete
hydatidiform mole and rarely in cases of partial hydatidiform
moles.
 PARTIAL MOLE EXIBITS LESS INTENSE
FEATURES –
Uterine enlargement and preeclampsia is reported in
only 5% of patients. Theca lutein cysts, hyperemesis,
and hyperthyroidism are extremely rare.

 Examination
 Uterus more than dates
 Preeclampsia
 Theca lutein cysts: These are ovarian cysts
greater than 6 cm in diameter and
accompanying ovarian enlargement.

Partial Mole Complete Mole11/26/2019 Reproductive Health Module AL2013

Complete Hydatidiform mole

Complete Hydatidiform Mole
microscopy
Complete hydatidiform moles
have edematous placental villi,
hyperplasia of the
trophoblasts, and lack or
scarcity of fetal blood vessels.
In the partial hydatidiform mole
fetal tissue is often present, as
well as amnion and fetal
vessels with fetal red blood
cells within the mesenchyme of
the villi. Like in complete
hydatidiform moles, hydropic
(oedematous) villi and

Differences between complete mole and
partial mole

Investigations - Haematological
 Quantitative beta-hCG levels
 Complete blood cell count with platelets
 Coagulation studies
 Liver function tests
• Blood urea and serum creatinine levels
• Blood type and Rh factor
 Thyroxine level

Investigations - Radiological
Ultra sound scan

Investigations - Radiological
Chest X ray
CT/MRI – No Role in Hydatidiform mole

Management
 Stabilize the patient.
 Transfuse for anemia, and correct any coagulopathy.
 Treat hypertension.
 Watch for and be prepared to treat thyroid storm, a
rare complication.
 Administer Rh immune globulin to nonsensitized
RhD-negative women because of the possibility of a
partial mole with fetal erythrocytes that express the
RhD antigen. (RhD is not expressed in human
trophoblast cells.)

Management
Evacuation – Suction evacuation is best
oxytocins, Prostaglandins -.
 Prostaglandin or oxytocin induction is not
recommended because of the increased risk of
bleeding and malignant sequelae.

Follow- up
 How
 How often
 How long
 AVOID PREGNANCY – Need
Contraception
 (Barrier Method Recommended)

Follow up
• Serum hCG levels are obtained weekly until the
levels are within reference range for 3-4 weeks.
• Levels should consistently drop and should never
increase.
• Normal levels are usually reached within 8-12 weeks
after evacuation of the hydatidiform mole. As long as
the hCG levels are falling intervention is not needed.
• Once levels have reached the reference range for 3-4
weeks, check them monthly for 6 months. Once in 2
months for another 6 months
• If the serum hCG levels plateau or rise, the patient is
considered to have malignant disease (ie, gestational
trophoblastic neoplasia) and metastatic disease11/26/2019 Reproductive Health Module AL2013

Use of the monitoring serum hCG
following evacuation of Hydatidiform
moleMole evacuation
Days1000 50
10
100
1000
1000000
100000
10000
1 150
Start
treatment
Stop
treatment

 The risk of gestational trophoblastic neoplasia
(GTN), malignant disease, is higher for
complete than partial mole. GTN, usually
invasive mole (IM) or Choriocarcinoma,
develops in 15 to 20 percent of women with
complete mole and 1 to 5 percent of women
following partial mole.

Gestational Trophobalstic Neoplasia
 Invasive Mole
 Choriocarcinoma – Following
Complete Mole
Partial Mole
Abortion
Normal Pregnancy
 Placental site trophoblastic tumour

Gestational Trophoblastic Neoplasia(GTN)
 Hydatidiform mole (60%)
 Previous spontaneous abortion/abortion
(30%)
 Normal pregnancy or ectopic gestation (10%)
GTN most commonly follows hydatidiform mole
as a persistently elevated hCG titer. There may
also be continuing and recurring bleeding after
a mole.

Choriocarcinoma

Disease(GTD)
 Classification
– Hydatidiform Mole
Complete
Partial
– Invasive Mole
– Gestational Choriocarcinoma
– Placental site trophoblastic tumour
– Epithelioid Trophoblasic Tumour11/26/2019 Reproductive Health Module AL2013

CLINICAL FEATURES
Invasive Mole
 Persistent vaginal bleeding
 Haematuria
 Rectal bleeding
 Respiratory symptoms
 Rising HCG

CLINICAL FEATURES
 Choriocarcinoma
30% presents with symptoms due to
metastasis
Pulmonary – Parenchymal, Pleural or
embolization
Cerebral - Focal signs, Haemorrhage
Hepatic - Pain, hepatomegaly

Gestational Trophobalstic Neoplasia
 Placental Site Trophoblastic Tumour
Following
Complete Mole
Abortion
Normal Delivery
This is a rare slow growing malignant tumour
which produces little HCG

CLINICAL FEATURES
 Slow growing
 Late metastasis
 Produces HPL – Amenorrhoea
 Galactorrhoea
 hcg – usually low

Epithelioid trophoblastic tumor(Rare)
Clinical Features
 Epithelioid trophoblastic tumor (ETT) is derived from the
chorionictype intermediate trophoblast. Rarely, ETT can
coexist with choriocarcinoma or PSTT. The majority of
ETT occurs in the reproductive age group. Patients often
have symptoms resembling those in PSTT and about 70%
of patients have abnormal vaginal bleeding. The serum
hCG level is usually mildly elevated. Similar to PSTT,
ETT is not chemosensitive and it is mainly treated by
surgery.

Clinical Features
Hydatidiform Mole
Bleeding
Passing grape like
structures
Uterus more than dates
Hyperemesis
PIH
Theca lutein cysts
Hyperthyroidism
Invasive Mole
Persistent vaginal
bleeding
Haematuria
Rectal bleeding
Respiratory symptoms
Rising HCG
Choriocarcinoma
30% presents with
symptoms
due to metastasis
Pulmonary
Parenchymal,
Pleural
or embolization
Cerebral –
Focal signs,
Haemorrhage
Hepatic -
Pain, hepatomegaly
Placental site
trophoblastic tumour
Slow growing
Late metastasis
Produces HPL –
Amenorrhoea
Galactorrhoea

Management of GTN
 1. Clinical examination (watch for vaginal metastasis).
 2. Serial weekly hCG measurements on serum.
 3. Complete blood count and platelets. PT, PTT,
fibrinogen, BUN, creatinine, liver function tests.
 4. Chest X-ray.
 5. Brain, MR (or CT) scan when there is any suspicion of
cerebral metastases.
 6. Liver CT scans when indicated. A whole body CT scan
is normally performed in patients who have lung
metastases.

 7. Curettage should be performed if there is uterine
bleeding Biopsies may be obtained from accessible sites.
There is severe risk of hemorrhage at the biopsy site.
 8. MRI when indicated.
 9. T4, thyroid studies when indicated.
 10. Selective scanning using anti-hCG antibody linked to
radioactive iodine or indium may be done if there is
persistent disease resistant to chemotherapy

A score of 6 or less is low-risk disease treatable by single agent
chemotherapy. A score of 7 or greater is high-risk disease that requires
combination chemotherapy

Chemotherapy regimen
 Low risk
 High Risk

Chemotherapy regimen for low-
risk patients
 Methotrexate (MTX) -50 mg by IM injection
repeated every 48h x 4 doses
 Leucovorin(folinic acid) -15mg orally 30h after
each injection of MTX
 Courses repeated every 2 weeks, i.e. days 1,
15, 29, etc.
 Actinomycin D - Appears more effective

Chemotherapy regimen for high
risk patients - EMA/CO
Day 1 Etoposide
Actinomycin D
Methotrexate
100mg/m2 by IV infusion over 30 min
0.5 mg IV bolus
300mg/m2 by IV infusion over 12 h
Day 2 Etoposide
Actinomycin D
Folinic acid rescue
starting 24 h after
commencing the MTX
infusion
100mg/m2 by IV infusion over 30 min
0.5mg IV bolus
15mg IM or orally every 12h x 4 doses
Day 8 Vincristine
Cyclophosphamide
1mg/m2 IV bolus
600mg/m2 IV infusion over 30 min

EP/EMA if Resistant to EMA/CO
EP
Etoposide 150 mg/m2 IV
Cisplatin 75 mg/m2 IV
Etoposide 100 mg/m2 IV
Methotrexate 300 mg/m2 IV
Actinomycin D 0.5 mg IV
EMA
Day 1
Day 1
Day 2 Folinic acid 15 mg orally/IM bd x 4
24 h post MTX

Follow up of patients with gestational
trophoblastic tumours who have been
treated with chemotherapy
 Weekly for the first 6 weeks
 Then every week until 6 months
 Then fortnightly until one year
 Then monthly x 12
 Then 2 monthly x 6
 Then 6monthly for life

Three doses of chemotherapy should be given beyond
the first undetectable hcg value

Complications of GTD
a) Haemorrhage
b)Infection
c)Respiratory Complications –metastasis
Pleural effusion
Respiratory failure
d)Cerebral metastasis

Post treatment issues
 Pregnancy after treatment – wait for 12
months after completing chemotherapy
 Contraception
 Prognosis - Low risk – 100%
 High risk - 86%

Prognosis
276 patients
86% long-term survival
Poor risk factors:
Brain metastasis 80% survival
Liver metastasis 30% survival
Liver and brain 10% survival

Metastatic Disease
 Brain – Chemotherapy,Irradiation,Surgery
 Liver – Hepatic artery infusion
(Chemotherapy),Irradiation

 A 30 year old woman in her first pregnancy presents with a history of
10 weeks amenorrhea and mild vaginal bleeding. On clinical
examination the uterine size was compatible with a 16 week
pregnancy. An ultrasound scan revealed a complete hydatidiform
mole.
3.1 Describe the management of this patient until discharge from the
ward (30 marks)
3.2 Give five (5) complications of this condition (10 marks)
3.3 Outline her long term management with justification (60 marks)

Definitions
 Gestational trophoblastic disease (GTD) forms a group of
disorders spanning the conditions of complete and partial
molar pregnancies through to the malignant conditions of
invasive mole, choriocarcinoma and the very rare placental
site trophoblastic tumour (PSTT).
 If there is any evidence of persistence of GTD, most
commonly defined as a persistent elevation of beta human
chorionic gonadotrophin (βhCG), the condition is referred
to as Gestational trophoblastic neoplasia (GTN).

Neoplasia(GTN)
Persistent Gestational Trophoblastic Disease indicated
by persistent elevation of beta human chorionic
gonadotrophin(βhCG)
 Invasive Mole
 Choriocarcinoma
 Epithelioid Trophoblasic Tumour

Gestational Trophobalstic Disease

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