GESTATIONAL TROPHOBLASTIC

DISEASE
(GTD)

Yudi Mulyana Hidayat

Dept.of Obstetrics & Gynecology Faculty of

Medicine, University of Padjadjaran
BANDUNG
DEFINITION

GTD :
A spectrum of disease, related to chorionic villi,
especially its trophoblastic cells, originated from
a gestation (pregnancy)

NON-GTD !!!!
 Various pregnancy outcome

Normal baby Abortion

 tube

uterus
ampulla

blood clot

blood clot

Ectopic pregnancy Premature baby

Anencephal baby
Hydatidiform mole  Gestational Trophoblastic Tumor
(GTT)

Gestational Trophoblasatic Diseases (GTD)

 Pathogenesis of gestational trophoblastic disease

Normal
@
Reproductive failure

Abortion

Ectopic pregnancy

Prematurity

IUFD

Congenital anomaly

CHM
Hyditidiform Mole (HM)
PHM

IM ChCa PSTT PTD

Gestasional Trophoblastic Tumor (GTT)

 Classification

1. Hydatidiform Mole (HM)

 Complete (CHM)
 Partial (PHM)

2. Gestational Trophoblastic Tumor (GTT)

 Invasive Mole
 Choriocarcinoma
 Placental Site Trophoblastic Tumor
 Persistent Trophoblastic Disease
 Complete Hydatidiform Mole
(CHM)
Macroscopic :
Entire chorionic villi change into
hydropic degeneration which
have a grapelike appearance,
without embryo

Microcopic :
Edema of the villi, absence of
vascularization with hyperplasia
of cyto & syncythio trophoblast
Etiology : Obscure
Risk Factors :
 Age : < 20 years & > 35 years
 Ethnic : mongoloid > caucasus
 Genetic : balanced translocation
 Nutrition : deficiency in protein &
 carotin, retinol
PATHOGENESIS (Androgenetic Theory )
Endoreduplication
 Empty + 23X 23X 46XX
ovum
homozygot

 Empty + 23X 46XX

ovum
+ 23X heterozygot

 Empty + 23X 46XY 46YY

ovum
+ 23Y non viable
 Partial Hydatidiform Mole (PHM)
Makroskopic : Similar to CHM, except for the presence of
foetus or part of it
Usually the foetus could not survive

Mikroskopic : Crinkling and scalloping of chorionic villi

with stromal trophoblastic inclusions, and hyperplasia of
syncythio trophoblast, mixed with normal villi
PATHOGENESIS (Triploid Theory)

 23X + 23X 69XXX

+ 23X

 23X + 23X 69XXY

+ 23Y

 23X + 23Y 69XYY 69YYY

+ 23Y non viable

Incidence :

USA : 1 : 1000 - 1500 deliveries

South Korea : 1 : 429 - 488 deliveries
Malaysia : 1 : 357 deliveries
Japan : 1 : 538 live birth
Bandung &
vicinity : 1 : 427 deliveries
West Java : 1 : 28 - 105 deliveries
Indonesia : 1 : 51 - 141 pregnancies

Incidence of PHM :<< CHM

Clinical features :

1. Main complaints
 Amenorhea
 Nausea & vomiting
 Vaginal bleeding

2. Accompaniying alteration
 Uterus >> gestational age
  hCG >> normal pregnancy
CHM 105 - > 106
Normal pregnancy < 105
 Lutein cyst., uni/bilateral

3. Complication
 HDP
 Thyrotoxicosis
 Lungs emboli (seldom)
Tentative D/
 Amenorhea
 Vaginal bleeding
 Large for date uterus
 Objective signs of
pregnancy (-)
  hCG 
 USG : Vesicular appearance

Definitive D/
 Grape like appearance
 PA
 Features of CHM & PHM
CHM PHM
Fetal/embryonic tissue Absent Present
Chorionic villi Diffuse Focal
Trophoblastic hyperplasia Diffuse Focal
Scalloping of chorionic villi Absent Present
Trophoblastic stromal inclusion Absent Present

46 XX (90 %)
Karyotype Triploid (90 %)
46 XY
Immunostaining (p57KIP2) Absent Present
Therapy

1. Objectives
 Evacuation of molar tissues
 Prevention of malignancy
 Early detection of malignancy

2. Stages
 Stabilization
 Blood transfusion
 Anti HDP
 Anti thyroid
 Evacuation
 Vaccum curretage, with/without dilatation
 Hysterectomy : (age  35 year, completed
family, difficulty to follow-up )

 Cytostatic profilaxis ( general obstetric)

 Age < 35 yrs, suspicious PA, β HCG
 Age  35 yrs : no consent for HT
 Protocol : MTX 20 mg 5 days IM
ACT D 1 flac 5 days IV
Follow up
1. Objectives : Early detection of malignancy
2. Duration : One year
3. Schedule
 First 3 months : every two weeks
 Second 3 months : every month
 Last 6 months : every two months
4. Requisite : No pregnancy within one year
Contraception : CDM / OC
End of Follow up :
12 months postevacuation : free of complaints
 hCG < 5 mIU/ml
 Normal/Abnormal regression curve of  hCG
Normal Abnormal
150 150

1000000000
1000000000
1000000
hCG mIU/mL

1000000 (1)

hCG mIU/mL
100000
100000 (2)

1000
1000
(3)
100 100 (4)
(5)
10 10

00 00
0 2 4 6 8 10 12 0 2 4 6 8 10 12
Weeks postevacuasion Weeks postevacuasion

Explanation :
- After 4 weeks < 1000 m IU/ml - After 8 weeks < 30 m IU/ml
- After 6 weeks < 100 m IU/ml - After 12 weeks < 5 m IU/ml
Prognosis

Mortality : < 1%
Malignant transformation : 15-20%
70% first 6 months
90% within 1 year
 Recurrent mole : seldom
 Reproductive performance : generally normal
 Gestational Trophoblastic Tumors
(TTG )

Definition :

Malignancies which occur after molar or non

molar pregnancy (term, abortion, ectopic)
85% preceded by HM
Insidence :

1. RSHS : 1 : 228 pregnancies

2. Bandung & vicinity : 1 : 822 deliveries
3. Malaysia : 1 : 1000 deliveries
4. Vietnam : 1 : 537 pregnancies
5. USA : 1 : 40.000 - 70.000
pregnancies
6. Swedia : 1 : 50.000 pregnancies
 EPIDEMIOLOGY

 Insidency of hidatidiform mole ( Ind > WHO)

 8-30%  GTT
: - Choriocarcinoma
- Invasive Mole
- PSTT (Plasental Site Trof. Tumor)
- PTD (Persisten Trof. Desease)

 Hidatidiform mole, to be malignant

transformation  GTT ???

 RISK FACTOR MALIGNANCY POST EVACUATION
OF HIDATIDIFORM MOLE
 DEMOGRAPHIC
 AGE> 35 y.o
 PARITY > 4

 CLINICAL
 UTERINE SIZE > 20 WEEKS
 LUTEIN CYST
 β-HCG LEVEL > 100.000 miu/ml
 PATHOLOGIC RESULT : Proliferation of trofoblastic cells
(Hidayat YM, Martaadisoebrata D 1990-1995)

 MOLECULER BIOLOGY RISK FACTOR ?? (on going research)

* Hidayat YM (Risbintekdok)  PML, Cyclin D, Her2-new-P53
* Harsono AB  MMP2 ( prediction factor of IM in HM cases)
* Winarno GNA  VEGF,Caspase3 ( HM – GTT)
Pathogenesis : obscure

Plausible theories :
 Increase oncogen
 Decrease of tumor suppresor gen
 PATHOGENESIS

Growth promoting Tumor supressor

Oncogens DNA repair
genes Genes
Siklin D, Her2-neu P53, Rb, PML dll

Mutasi amplification Mutasi inactivation

Malignant transformation
MEKANISME TRANFORMASI SEL
 PROMOSI
 Rangsangan proliferasi oleh
faktor pertumbuhan dan
hormon
 Aktifitas faktor transkripsi 
mengubah gen yang terlibat pd
proses biologi, pertumbuhan,
differensiasi
 Mempengaruhi pembelahan
sel, menghasilkan klonal yg
berubah  mutasi  terbentuk
transformed phenotipe
 CYCLIN D
M
G2 CYCLIN D :
D1
G1 D2 + cdk
D3
S
p21 PML
CEL CYCLE
p53
 PML gene
DNA Cyclin D1-gene

mRNA Cyclin D1-mRNA

protein
X
PML suppresses protein but not RNA production
of cyclin D1
Cyclin D1-gene

Cyclin D1-mRNA

PML
protein
? Cyclin D1 protein synthesis
is low because mRNA of
cyclin D1 not transport
into cytoplasm
 Analisis perubahan konsentrasi RNA

cDNA microarray

- enzim
- protein DNA/gen - 23 pasang kromosom
- 100.000 gen
RNA - 2000 gen (terekspresi
menurut waktu)
- ribuan enzim/protein
mRNA
 TO PREDICT MALIGNANCY POST
EVACUATION HYDATIDIFORM MOLE
 CLINICAL SYMTOMS
HBES from ACOSTA SISSON
H = having expelled product of conception
B = bleeding from vagina
E = enlargment of uterus
S = softness of uterus

 IMAGING (x-ray,ct-scan,MRI etc)

 LABORATORY EXAMINATION
Objective : Prevent malignancies

 Determinations of β hCG subunit levels :

- Weekly, until normal for 3 consecutive weeks
- Monthly, until normal for 6 consecutive months

150

Explanation :
(β hCG subunit levels)
hCG mIU/mL

- After 4 weeks < 1000 mIU/ml

- After 8 weeks < 20-30 mIU/ml
- After 6 weeks < 100 mIU/ml
- After 12 weeks < 5 m IU/ml
0
0 2 4 6 8 10 12

Weeks postevacuasion
 Invasive mole

 Always preceded by HM
 Short latent period (< 4 months)
 Lowgrade of malignancy, but could be fatal, due to
uterine perforation
 Prognosis : good
 Chorionic villi & trophoblastic cells among
myometrium muscles
Choriocarcinoma
 Antecedent pregnancy could be molar/non molar
Majority of cases, preceded by CHM
 X latent period > 4 months
 High grade of malignancy, metastases to various organs
 High mortality rate, due to profuse bleeding or organ
failure
 PA : abundant trophoblastic
cells with hemorrhage and
necrotic tissues
Placental Site Trophoblastic Tumor (PSTT)

 Latest variant of GTT

 Incidence : very rare
 Antecedent pregnancy non molar/molar
 -hCG
 Prognosis : poor
 PA : dominated by
intermediate trophoblastic
cells
Persistent Trophoblastic Disease

 Synonym : Clinical choriocarcinoma

 Definite D/ :
 Non PA
 Hbes
 -hCG
 Metastases
Stage

Stage I : Confined to the uterus

Stage II : Parametrium, vulva & vagina
Stage III : Lungs
Stage IV : Other organ, especially brain
Stage I
Stage II
Stage III
Stage IV
Tentative D/
After molar / non molar pregnancy
Irregular vaginal bleeding
Subinvolusion of the uterus
Red bluish mass in the vagina / vulva
Dypsnea, hemoptoe
Severe headache/neurological disorders
 -hCG
Chest x-ray : coin lession
USG (uterus) : irregular mass,
neovascularization (+)
Special characteristics of GTT

 Frequently encountered in young women with

low parity
 Has a measurable latent period
 Has a specific tumor marker : -hCG
 In early stage, it is completely curable, without
loss of reproductive function
Therapy

Objectives
 Eradication of disease
 Preservation of reproductive function

 Protocol
 Primary Th/ : chemotherapy
 Adjuvant Th/ : - surgical
- radiation
Complete remission

 Free of clinical complaint

 -hCG normal, within 3 consequtive weeks
Follow up

 Objectives
 Post Th/ surveilance
 Early detection of recidive

 Duration : 1 year
 Prognosis
Depend on stage and prognostic score

 Reproductive performance usually normal