Gestational Trophoblastic
Disease
YASHODHARA PRADEEP
Prof., OBGYN
QMH CSMMU LKO
2014
• Classification of GTT
• GTD Epidemiology, Pathogenesis, Aetiology, β hCG,
• Clinical Features of Premalignant(GTD) Complete Mole(CM);
Partial Mole
• Management of Complete Mole, or Partial Mole
• Post evacuation Follow up , Chemotherapy
• Contraception
• Clinical Features of Malignant (GTN) Invasive Mole, Placental
site tropho blastic tumor( PSTT) Chorio CA
• Investigations
• GTN ChorioCA Diagnosis, Investigation, Management
• Chemotherapy
• Follow up
Introduction
• Gestational Trophoblastic disease is a term
used to describe the heterogeneous group of
interrelated lesions that arise from abnormal
proliferation of placental trophoblast. GTD
Lesions are histologically different and can be
Benign and malignant.
WHO Classification
GTD
Premalignant Diseases
•
Complete Hydatidiform Mole ( C M )
• Partial Hyadatidiform Mole ( P M )
Malignant Diseases (Gestational Trophoblastic Neoplasia)
Nonmetastatic
• Invasive Mole
• Placental site trophoblastic tumor ( PSTT )
• Epitheloid tumour
• Metastatic
• Gestational Choriocarcinoma
Epidemiology
• It is common in oriental countries- Philippines, China, Indonesia, Japan,
India, Central and Latin America and Africa.
• Highest incidence- Philippines- 1 in 80 pregnancies
• Lowest incidence- Europe- 1 in 752 pregnancies
• India- 1 in 400 pregnancies
• Calculated Incidence of complete mole- 1 in 1945 pregnancies
partial mole- 1 in 695 pregnancies
• Age C Ms most common at the extremes of reproductive age
• The incidence of CM rises fm I:1000 to 1:76; 1:6.5 in subsequent
pregnancies
• CM is the most common antecedent to Chorio CA. But it can occur after
any type of pregnancy 3% after invasive mole; 16% after CM
Homozygous 85%
Pathogenesis of complete H Mole
Heterozygous 15%
Pathogenesis of complete H Mole
Pathogenesis of Partial H. Mole
Gestational Trophoblastic Disease
Genetic & Pathology
•
•
•
•
•
•
•
•
C M Always contains Paternal DNA alone so androgenic Macroscopically
like bunch of grapes
P M are Triploidy two paternal & one maternal sets of chromosomes
hyperplasia of chorionic villi with embryo usually dies 8-9 weeks of
gestation
P57 cycline dependent kinase inhibitor paternally imprinted gene which
is maternally expressed
P57 kip2 immunostaining is negative in CM in contrast to PMs Hydropic
abortions & normal placenta
Invasive mole can be diagnosed by USG & rising titers of hCG
Presence of chorionic villi distinguish Invasive mole from Choriocarcinoma
Chorio CA. Grossly abnormal karyotypes with diverse ploidies
PSTT are rare slow growing malignant tumor; intermediate trophoblast
from cytotrophoblast produce little hCG
Aetiological factors
• Genetic factor: Autosomal recessive Genomic Imprinting;
Abnormal Methylation
• In cases of Familial recurrent molar pregnancy; Defective
locus at 19q 13.4 at single gene NALP7 , it is member of
CATERPILLAR family involved in inflammation & Apoptosis in
genetic CM
• Three other genes H19, P57, IGF-2
• Chorio CA. heterozygosity at specific genes deletion 7p12q11.2; Amplification of 7q21-q31 region ; loss of 8p12-p21
• Breast & ovarian cancer also show the abnormalities in
heterozygosity in amplification at 7q21-q31 , & loss of 8p12p21
Human chorionic gonadotrophin
• Beta hCG is pituitary/ placental glycoprotein
• Commercially available Beta hCG test based on sandwich
assay principle & rely on two antibodies
• Rare chance of false negative or false positive results with
Rabit polyclonal antibodies RIA used in both serially diluted
urine & blood samples .
• Sensitivity of this test in serum is 1 IU/L, in urine 20 IU/L
• Beta h CG is tumor marker
• New Assay are in research Hyperglycosylated hCG (hCG-H )
specific for cases subsequently require chemotherapy (Clinical
GTDs ) Cole etal 2006a
Beta h CG as Tumor marker
• Half life is 24-36 hrs
• Marker for pregnancy ,GTD, Germ cell tumors & 15% of
epithelial ovarian malignancies
• H CG levels are also associated with tumor volume 5 IU/l
corresponds to 104-105 viable tumor size
• Beta hCG used as prognostic marker & progression of disease
or response to therapy, drug resistance at earlier stage.
• hCG is best tumor marker known
Clinical features
Complete Mole
•
•
•
•
Most common in first trimester or early Second trimester
Vaginal bleeding is the most common symptom (84-97%)
Uterus is larger than POG (28%)
Presents with the features of threatened abortion; Amenorrhea, pain &
bleeding P/V
• Associated features of Hyperemesis Gravidarum Requires Antiemetic , IV
fluids etc
• Toxaemia or PET 10-15%
• hyperthyroidism 7%
Clinical features
•
•
•
•
•
Theca leutin cysts
Beta h CG levels > 100.000
O/E
Passage of grapes like vesicle or spontaneous expulsion of entire mole
Pulmonary , cervical, Vaginal metastasis may occur disappears after
evacuation of mole
• The presence of metastasis does not necessarily imply invasive mole or
chorio CA
• Macroscopic features: Bunch of grapes due to villous swelling
• Branching contain hyperplastic cyto & syncytio trophoblast with many
vessels
Complete Molar Pregnancy
High Risk For Developing Post molar tumor
• Patients presenting with any of the following signs of
marked trophoblastic proliferations
• hCG Levels > 100,000 mIU/L
• Excessive Uterine Enlargement
• Theca leutin cyst 6cm or larger
Clinical features
PARTIALMOLE
• Findings not as characteristic as in CM
• Most commonly presents in late Ist or second trimester
• Uterus is often not enlarged more than POA
• More often presents as Missed or incomplete abortion
• Pre evacuation h CG levels are not more than 100,000IU/ L
• Macoscopic : villous swelling is less intense
• Embryo is present
• Microscopic: Trophoblastic hyperplasia, indented outlines & round
inclusions
• Presence of nucleated RBS of embryo in villous structure
• Due to Early demise of embryo less documentation of PM
Management Of Molar Pregnancy
There are 2 important basic lines:
1. Evacuation of the mole
2. Regular follow up to detect persistent Trophoblastic
disease
If both basic lines are done appropriately, mortality
rates can be reduced to zero.
Management of Molar Pregnancy
For complete mole:
Suction Curettage
Procedure:
1. Emergency tray should be ready and blood
should be handy.
2. Oxytocin infusion: begun before induction of
anaesthesia.
3.Cervical dilation
Management
4. Suction curettage: Suction canula up to a maximum of 12
mm is usually sufficient to evacuate all complete molar
pregnancies.
If the uterine size is larger than 14 weeks of gestation, one
hand should be placed on top of fundus and uterus should
be massaged to stimulate uterine contraction and reduce
the risk of perforation.
5. Sharp curettage: gentle sharp curettage is done to remove
any residual molar tissue.
Cervical preparation with prostaglandins or misoprostol
should be avoided to reduce the risk of embolisation.
Should products of conception be
examined histologically?
Histological examination is indicated in:
• Failed pregnancies (missed or molar): all medically or
surgically managed cases
• Products of conception obtained after all repeat
evacuations (post abortive or post partum).
There is no need after therapeutic termination:
provided that foetal parts are identified on USG
A urine pregnancy test should be performed 3 weeks
after medical management of failed pregnancy if
products of conception are not sent for histological
examination.
Anti-D Prophylaxis (RCOG)
NOT required in Complete Mole: because of
poor vascularisation of the chorionic villi and
absence of the D-antigen.
Required in:
-partial mole: due to presence of RBCs
-complete mole: if diagnosis is not confirmed
histopathologically.
Second uterine evacuation
• There is NO clinical indication for the routine use of
second uterine evacuation.
• It may be useful for symptom control in selected
patients with heavy bleeding or curative if the
recurrent molar tissue is confined to the uterine
cavity, particularly in those with hCG levels <1500
IU/L.(Recent Advances)
Post Evacuation Surveillance
• Done to detect persistent trophoblastic disease (GTN)
• A baseline serum βhCG is obtained within 48 hours after
evacuation
• Levels are monitored every 2 weeks until normalisation
and urine βhCG levels analysed monthly after this.
• These levels should progressively fall to an undetectable
level (<5 mu/ml).
• The average time to achieve the first normal β-hCG level
after evacuation is about 9 weeks.
• If symptoms are persistent, more frequent βhCG estimation
and USG examination ± second evacuation is advised.
Optimum follow up period following
normalization of β hCG
If βhCG has reverted to normal in
• ≤56 days (8 weeks) of the pregnancy event: follow up
is for 6 months from the date of uterine evacuation.
• >56 days of the pregnancy event: follow up is for 6
months from normalisation of hCG level.
All women should notify at the end of any future
pregnancy, whatever the outcome of the pregnancy.
β hCG levels are measured 6-8 weeks after the end of
pregnancy to exclude disease occurrence.
Contraception
• Should NOT conceive until follow up is complete.
• Use Barrier method until hCG revert to normal
(?OCPs may act as growth factor for trophoblastic
tissue).
• Once hCG has normalised, the combined oral
contraceptive pill may be used.
• IUCD should not be used until hCG levels are normal
to reduce the risk of uterine perforation.
Role of hysterectomy
• If the patient desires surgical sterilization, a
hysterectomy may be performed with the mole in
situ.
• Hysterectomy does not prevent metastasis;
therefore, patients will require follow up with
assessment of hCG levels.
• The ovaries may be preserved at the time of surgery,
even in the presence of prominent theca luiten cysts.
Role of prophylactic chemotherapy
• The long term prognosis for women with a H. Mole is
not improved with prophylactic chemotherapy.
Because toxicity- including death- may be significant, it
is not recommended routinely (ACOG 2004).
• It may be useful in the high-risk cases when follow up
are unavailable or unreliable.
HIGH RISK FACTORS:
 hCG level >100,000 mIU/ml
 Excessive uterine enlargement
 Theca lutien cysts 6 cm in diameter
Chances of malignant transformation
• Complete H.Mole
16%
• Partial H.Mole
0.5%
Gestational trophoplastic Neoplasia
Nonmetastatic
Invasive Mole:
Clinical features
• Clinical diagnosis by persistence or rising titers of Beta h CG in the weeks
after molar evacuation & USG
• Persistent bleeding p/v
• Lower abdominal pain due to invasion in myometrium, vulva, vagina or
intra abdominal metastasis
• It may spread to adjacent pervic structures bladder , rectum; hematuria,
bleeding P/ R
• Pulmonary metastasis
• Mostly due to initial diagnosis of CM is missed & not on Beta h CG follow
up
Clinical features
Placental Site Trophoblastic Tumor (PSTT):
• it is rare slow growing tumor
• Women mainly presents with menstrual irregularities & lower abdominal
pain, galactorrhea due to hyperprolactinemia increased h PL
• Little or no h CG is produced ( Free B hCG fragment )
• Rarely presents as nephrotic syndrome, hematuria or DIC
• Spread is late local Infiltration & metastasis is through lymphatic
• Microscopically: In the normal placenta it is distinct from villous
trophoblast & infiltrates the decidua, myometrium, & spiral arteries.
• Mainly from intermediate trophoblast derived fm cytotrophoblast
Metastatic Gestational Trophoblastic
Neoplasia





Second most common GTN
1 in 30,000 pregnancies
Early haematogenous spread is characterstic of
choriocarcinoma
40% after molar pregnancy: Easily Diagnosed
60% non-molar pregnancy: Difficult to Diagnose
Metastatic Gestational Trophoblastic
Neoplasia
 GTN arises when the normal regulatory mechanisms controlling
the proliferation and invasiveness of trophoblastic tissue are
lost.
 Diagnosis of the GTN is made on
 Clinical presentation
 Elevated b-HCG
 Evidence of metastasis
 Imaging
 Tissue for Histology- Seldom obtained
(Definitive Histological Diagnosis of type of GTN is not made in
most cases).
Metastatic Gestational Trophoblastic
Neoplasia
CHORIOCARCINOMA:
Clinical features
• Occurs mainly following any form of pregnancy, mainly after
CM
• Difficult to differentiate from Invasive mole as H/P is not
possible
• Clinical features of bleeding p/v , lower abdominal pain, or
in 1/3 of cases no pelvic symptoms but symptoms of distant
metastasis lungs , brain ,liver, skin, cauda equina & the heart
may present
• Highly malignant , appears as soft purple largely hemorrhagic
mass
Clinical features of chorio CA
• Microscopic: implanting blastocyst with central cores of
mononuclear cytotropho surrounded by rim of
multinucleated syncytiotrophoblast & distinct absence of
chorionic villi extensive areas of necrosis & haemorrage
&frequent evidence of tumor in the sinuses
• The hypervascularity & absence of connective tissue support
are the reason for its highly malignant behaviour
• DIAGNOSIS IS ALWAYS BY BETA h CG
investigations
•
•
•
•
•
•
•
•
•
•
Quantitative beta hCG
X Ray Chest
Pelvic Doppler USG
Abdominal doppler USG to rule out liver & renal metastasis
CT chest , abdomen
MRI brain
Beta h CG in cerebrospinal fluid
PET
FD PET
Genetic studies
Which women should be investigated for
Persistent GTD after a non molar pregnancy?
(RCOG Guideline)
• Any women who develops persistent vaginal bleeding after a
pregnancy event.
• A urine pregnancy test should be performed in all cases of
persistent or irregular vaginal bleeding after a pregnancy
event.
• Symptoms from metastatic disease, such as dyspnoea or
abnormal neurology, can occur very rarely.
FIGO REQUIREMENT FOR MAKING DIAGNOSIS
OF GTN
1. Four values or more of plateaue hCG over at
least 3 weeks: days 1, 7, 14 and 21.
2. A rise of hCG of 10% or greater for 3 values or
more over at least 2 weeks: days 1, 7, and 14.
3. Histologic diagnosis of choriocarcinoma.
4. Persistence of hCG beyond 6 months after
mole evacuation.
Myometrial invasion
Vesicles
Invasive H. Mole
Sometimes involving the peritoneum, parametrium, or
vaginal vault. Originate almost always from H. mole
Metastatic disease
Sites:
Symptoms:
a. Pulmonary- 80% Chest pain, dyspnoea
b. Vagina- 30%
Vagina bleeding , purulent
discharge and nodule.
c. Liver- 10%
Epigastric pain, jaundice, hepatic
rupture leading to intraperitoneal
haemorrhage.
d. Brain- 10%
Focal neurological deficit.
Metastatic Disease
If the pelvic examination & chest X-ray are negative,
it is very uncommon to have metastatic involvement
of other sites.
Chest X ray: widespread metastatic lesions.
GTN Vaginal Metastasis
Cranial MRI scan:
Large metastasis on the
left (black arrows)
Brain MRI of a patient
with a solitary brain
metastasis in remission
Autopsy specimen
Multiple
hemorrhagic
hepatic metastasis
CT Scan: Liver
metastsis
Management of GTN


Prognostic score is central to the
management of GTN.
A single universally accepted, anatomical
staging and prognostic scoring system for
GTN was developed by FIGO in 2000.
ANATOMIC FIGO STAGING SYSTEM FOR GTN (2000)
Stage Criteria
I.
Disease confined to the uterus
II.
Disease outside of uterus but is limited to the
genital structures
III.
Disease extends to the lungs with or without
known genital tract involvement
IV.
All other metastatic sites
FIGO prognostic score (2000)
O
1
<39
>39
Hydatidi form
mole
Abortion
Term
pregnancy
Interval from index
pregnancy, months
<4
4-6
7-12
> 12
Pretreatment hCG
(mlU/ml)
< 103
103-104
> 104-105
> 105
3-4 cm
5 cm
GI tract
Brain, liver
Single
Two or more
drugs
Age (years)
Antecedent pregnancy
Largest tumour size,
including uterus
Site of metastases
Previous failed
chemotherapy
Spleen,
kidney
2
Low risk (Score 0-6) and high risk (score> 7)
4
WORK UP OF GTN
 History & physical examination
 Serial weekly hCG measurement in serum.
 Hemogram, LFT, KFT
 Chest X-ray
 USG whole abdomen pelvis to rule out hepatic and
renal metastasis
 CT or MRI brain
 CSF analysis – in metastatic disease.
 PET
 FDG PET
 Curette to be done if there is uterine bleeding.
There is grave dangerous of hemorrhage at the
biopsy site.
GTN
FIGO scoring
Low risk (<6)
High risk (> 6)
Single-agent
chemotherapy
Combination
chemotherapy
Serial hCG levels
Resolution
Life-long hCG follow-up
Relapsed/resistant disease
Second-line chemotherapy+ surgical debulking
Low Risk GTN
FIGO score 6 or less.
 FIGO stage I, II & III.
 Drugs schedules: single agent chemotherapy
Most commonly used regimen.
Methotrexate: 1 mg/kg 1M on days 1, 3, 5, 7
Folinic acid 0.1 mg/kg 1M on days, 2, 4, 6 and 8.
Side Effects: Stomatitis, conjunctivitis, abdominal and
chest pain.
Actinomycin- D: (primary therapy in case of abnormal
liver function)

Role of hysterectomy in non metastatic
disease i.e. Stage-I



If patient does not wish to preserve fertility
hysterectomy with adjuvant single agent
chemotherapy given.
In case of stage-I PSTT.
Role of adjuvant chemotherapy.
1.
2.
3.
Decrease dissemination of viable tumor cells at surgery.
Maintain cytotoxic level of chem.
To treat any occult metastasis.
Follow up in Low risk GTN




Weekly bhCG titre until normal for 3 consecutive
weeks.
Monthly b HCG level until normal for 12 consecutive
months.
Effective contraception during the follow up (OCP)
FIGO recommends additional 2 courses of
chemotherapy after initial negative b hCG.
High Risk GTN
.







Stage I, II, III With FIGO score 7 or greater or Stage IV
.
Primary intensive combination chemotherapy and
selective use of radiation and surgery.
Regimes given :
MAC.
Modified Bagshawe (CHAMOCA)
EMA-CO
EMA-EP.
MAC-III Regime
Mtx
1 mg/kg
IM/1V
Days 1, 3, 5, 7
Folinic acid
0.1 mg/kg
IM
Days 2, 4, 6, 8
Actinomycin-D
12 g/kg
IV
Days 1-5
Cyclophosphamide
3 mg/kg
IV
Days 1-5
To be repeated every 15 days if toxicity permits.
EMA-CO Regime
Etoposide, methotrexate, actinomycin D, alternating weekly with
cyclophosphamide and oncovin.
Day 1
Actinomycin D 500 micrograms IV push
new IV. Etoposide 100 mg/m2 over 30-50 min.
Methotrexate 100 mg/m2 IV infusion over 1
hr and then
Methotrexate 200 mg/m2 IV infusion over 12 hrs
Day 2
Actinomycin D 500 micrograms IV push new IV
Etoposide 100 mg/m2 over 30-50 min.
Folinic acid 15 mg IV push Q 6 hrs for 8 doses
beginning 24 hrs after methotrexate bolus.
Day 8
Vincristine (Oncovin) 1 mg/m2 IV
Cyclophosphamide 600 mg/m2 IV
SIDE EFFECT:- Myelosuppresion ,Mucositis , Neuropathy ,Reversible
alopecia
.
EMA-EP
In patient resistant to EMA-CO
On day 8
 Etoposide- 10 mg/m2 iv.
 Cisplatin- 80 mg/m2 iv
 treatment – until 3 consecutive weekly titres
normal.
 2-4 cycles given further after initial normal b
H.C.G.

Chemotherapy Should Not Be Repeated
Unless
WBC > 3000/cu mm
Polymorph > 1500/ cu mm
Platelets > 100,000/ cu mm
BUN, SGOT, SGPT are normal
No febrile course
No oral or GIT ulceration
Follow up OF High risk GTN



Weekly bHCG until normal for 3
consecutive weeks.
Monthly bHCG for 24 consecutive
months.
Contraception in follow up period.
Management of sites of metastasis
VAGINAL &PELVIS -30%
Single agent chemotherapy –Low risk
Combination chemotherapy –High risk
If bleeding occursVaginal packing
Wide local excision
Arteriographic embolisation of hypogastric
arteries
PULMONARY-80%
Present as – Chest pain, cough, hemoptysis dyspnoea.
 X-ray features- Snowstorm
 Discrete round densities.
 Pleural effusion
 Embolic pattern
 Rx
Single agent chemotherapy-low risk.
Combination – high risk.
Thoracotomy-viable pulmonary Metastasis following
combination chemotherapy.

HEPATIC-10%
.


Worse prognosis.
Usually associated with widespread metastasis Intraperitoneal
bleeding may occur.
Rx


Chemo & concurrent radiation (2000-3000 cGy).
Hepatic resection to excise resistant foci.
Cerebral-10%




Acute focal neurological deficits.
Combination chemo + WBRT (2000-3000).
Patients with metastasis on initial evaluation respond better
than who develop Lesion during therapy.
During period of WBRT- Mtx in EMA-CO be increased to 1 g/m2
with Folinic.Acid rescue.
. AFTER THERAPY OF GTN
SURVEILLANCE DURING AND
(DISAIA Gynaecolog oncology 2007)
Monitor serum quantitative hCG levels every week during chemotherapy:
1.
Response:
>10% decline in hCG during one cycle
2.
Plateau:
±10% change in hCG during one cycle
3.
Resistance:
>10% rise in hCG during one cycle or plateau for two cycles of
chemotheraphy
- evaluate for new metastasis
- consider alternative chemotherapy
- consider extirpation of drug-resistant sites of disease
REMISSION: 3 consecutive normal weekly hCG values
1.
Maintenance chemotherapy
Surveillance of remission:
1.
hCG values every 2 weeks x 3 months
2.
hCG values every months to complete one year of follow-up
3.
hCG values every 6-12 months indefinitely; at least 3-5 years
Schedule for hCG surveillance after chemotherapy
Urine
Serum
Year 1
Weeks 1-6 after
chemotherapy
Weekly
Months 2-6
2- weekly
2-weekly
Months 7-12
2-weekly
-
Year 2
4-weekly
-
Year 3
8-weekly
-
Year 4
3monthly
-
Year 5
4monthly
_
6monthly
-
Year 6 and
above
Life-long
monitoring
Weekly
.
CONTRACEPTION
DISAIA Gynaecology oncology 2007
During follow up period
I. OCP’s
 Safe
 Started soon after evacuation of H. mole.
 Given during the entire period of follow up.
 No increased risk of postmolar GTN or rate of decline
of hCG titre with OCPs use.
II. Barrier methods
 Safe alternative to OCP’s in patients whom OCP are
contraindicated.
III. IUCD
 Contraindicated due to an increased risk of uterine
perforation .
Future Child Bearing
.DISAIA Gynaecology oncology 2007



Pregnancy outcomes in patient with history of molar
gestation are similar to patient with no such history with
respect to live birth 1st and 2nd trimester abortion, anomalies,
Stillbirth, pre-maturity and Caesarean rate.
Pregnancy outcome is similar irrespective of complete or
partial mole.
For subsequent pregnancy.
 Ist trimester TVS to confirm normal pregnancy.
 bHCG 6 wks after termination of pregnancy .
 After effective treatment for non-malignant GTN molar
pregnancy occur in 1-2% subsequent pregnancies.




Treatment of malignant GTN with Chemotherapy is
compatible with preservation of fertility and not
assess with increased risk of congenital
malformations.
Women undergoing I.U.I. after previous molar
gestations, occasionally develops repeated moles.
This is due to an oocyte defect predisposing to
abnormal fertilization.
Therapeutic alterations are:
o ICSI with pre-implementation genetic diagnosis
o Donor oocyte IVF
Co-Existence of normal pregnancy and GTN







Described in both spontaneous & IVF gestations.
Estimated incidence of twin pregnancy with 1 mole
and 1 fetus 1 per 221,000-1,00,000 or > 125 cases
reported.
Diagnosis difficult based on imaging alone.
In many cases diagnosis made only after
termination of pregnancy.
Increased risk for haemorrhage persistent GTN and
medical complications.
Pregnancy coexistent with H. mole need be
termination.
Usually preterm delivery is often required because
of complications like bleeding or preeclampsia.
Thank You