Gestational trophoblastic disease Novak 2003 Hydatidiform Mole

Report
GESTATIONAL
TROPHOBLASTIC
DISEASE
Novak 2003
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Hydatidiform Mole
Persistent Gestational
Trophoblastic Tumor
Chemotherapy
HYDATIDIFORM MOLE
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Epidemiology
Complete versus partial mole
Clinical picture
Natural history
Diagnosis
Treatment
Follow up
INTRODUCTION
GTD is among the rare tumors that can be cured
even if metastasized
Types:
 Complete mole
 Partial mole
 Placental site mole
 Choriocarcinoma
Persistent GTT:
Most commonly follow molar pregnancy
May also follow: abortion, ectopic or term pregnancy
EPIDEMIOLOGY
% varies in different sites:
Japan =
2 : 1000 pregnancies
USA = 0.6 – 1.1 : 1000 pregnancies
In pathological studies:
Complete mole 1 : 945
Partial mole
1 : 695
Risk factors in complete mole:
1 – nutritional:
↓ carotene
↓ vit A
2 – Age:
> 35 years = X 2
> 40 years = X 7.5
Risk factors in partial mole:
1 - OCCP
2 - H/O irregular menstruation
COMPLETE VERSUS PARTIAL MOLE
Complete mole
Pathology:
 No fetal or embryonic tissue
 Villi show:
Diffuse hydropic swelling
Diffuse trophoblastic hyperplasia
Chromosome:
90% 46XX
10% 46XY
Chromosomes are entirely paternal
Mitochondria DNA is maternal in origin
1 - Absent or inactivated ovum nucleus
+ 1 haploid sperm
 endoredublication
 homozygous mole
2– Absent or inactivated ovum nucleus
+ 2 haploid sperms
 heterozygous mole
Partial mole
Villi vary in size and show:
 Focal hydropic swelling
 Focal trophoblastic hyperplasia
 Focal cavitation
 Stromal trophoblastic inclusion
 Scalloping
Fetal or embryonic tissues
Chromosomes:
Absent or inactivated ovum nucleus
+ 3 haploid sperms  triploid in 90%
= 69XXX, 69XXY, 69XYY
The fetus shows triploidy stigmata:
 GR
 Multiple congenital anomalies as:
Syndactyly - Hydrocephalus
Complete
Fetus
absent
Karyotype
46XX(90%)
46XY
Hydropic swelling diffuse
Trophoblastic
diffuse
hyperpleasia
Scalloping
no
Stromal inclusions no
Partial
present
69XXX
(90%)
focal
focal
present
present
CLINICAL PICTURE
Complete
past
now
Vaginal bleeding
97%
84%
Anemia
50%
5%
Excessive uterine size 50%
28%
Preeclampsia
50%
1.5%
Hyperemesis
27%
8%
Hyperthyroidism
7%
0%
Trophoblastic embolism 2%
0%
Theca lutein cysts
50%
HCG > 100,000mIU/mL
Partial
74%
4%
6%
Excessive uterine size:
= ↑ trophoblastic tissue
 ↑ hCG
 ↑ preeclampsia
 ↑ hyperthyroidism
 ↑ hyperemesis gravidarum
 ↑ trophoblastic embolization
 ↑ theca lutein cyst size
Preeclampsia:
Early preeclampsia = hydatidiform mole
Hyperthyroidism:
Due to ↑ free T3, T4
C/P:
 tachycardia
 warm skin
 tremor
Thyroid storms:
Give β–blockers before anesthesia
to avoid thyroid storms
C/P:
↑ pulse, ↑ temp, ↑ COP
+ delirium + convulsions
may  HF
Trophoblastic embolization:
C/P:
 dyspnea
 cough
 tachypnea
 ↑P
 chest pain
 asymptomatic
Chest examination  diffuse rales
Chest X ray  bilateral infiltrates
Causes of respiratory distress:
 Trophoblastion embolization
 Complications of:
• preeclampsia
• thyroid storm
• excessive fluid intake
Theca lutein ovarian cysts
 Due to ovarian overstimulation by ↑ hCG
 May not be felt with oversized uterus
 May  pressure symptoms  treated
by decompression by laparoscopic or
U/S guided aspiration
 If ruptured or torsion occur acute pain
 laparoscope
NATURAL HISTORY
Complete mole
 Invasive
= 15%
 Metastatic =
4%
Risk factors:
 hCG > 100,000 mIU/mL
 Excessive uterine size
 Theca lutein cysts = 6 cm
Low risk = 60%
 3.4%
0.6% metastatic
High risk = 40%
 31%
9%
Age:
> 40 years =
> 50 years =
persistent mole
persistent mole
metastatic
37%
56%
DIAGNOSIS
Complete mole
U/S  vesicular pattern
Partial mole
U/S  focal cystic spaces in placenta
+ ↑ transverse diameter of GS
Both together  90% +ve predictive
value
TREATMENT
I – Hystrectomy
+ aspiration of CL cyst
+ follow up as usual
2 - Suction evacuation
Preferred ttt for hydatidiform mole
Give oxytocine before anesthesia
Use 12 canula
If > 14 weeks support the fundus
+ do fundal massage
Dilatation  ↑ bleeding
Suction evacuation  ↓ bleeding
If RH –ve  give Anti RH Ig
3 - Prophylactic chemotherapy
↓ invasive mole to 4% after 1st course
↓ “””””””””””””””””” 0% after 2nd course
Controversial : Why to expose all
patients to chemotherapy while only
20% will need it?
Useful if follow up is:
Unreliable
Unavailable
Study:
Prophylactic chemotherapy in
high risk patients ↓ persistent
mole from 47% to 14%
FOLLOW UP
1 - HCG
Average time needed to return to
normal values = 9 weeks
Measure hCG/week
 3 consecutive normal results
/month  6 consecutive normal R
2 - Contraception:
OCCP or barrier methods
IUD is C/I  perforation
PERSISTENT GESTATIONAL
TROPHOBLASTIC
TUMOR
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Nonmetastatic disease
Placental-site TT
Metastatic D
Staging
Prognostic scoring systems
Diagnostic evaluation
Management
NONMETASTATIC DISEASE
Invasive mole = 15% after evacuation
C/P:
 Irregular vaginal bleeding
 Uterine subinvolution
 Theca lutein cysts
 ↑hCG
 Perforation of myometrium  internal Hg
 Perforation of uterine vessels  vaginal Hg
 Infection  acute pain
purulent discharge
Histology:
 After molar pregnancy
 hydatidiform mole or
choriocarcinoma
 After nonmolar pregnancy
 choriocarcinoma
= sheets of anaplastic
cytotrophoblast and
syncytiotrophoblast
+ no villi
PLACENTAL-SITE TT
Uncommon
Variant of choriocarcinoma
Consists of intermediate trophoblast
Produce small amounts of hCG & hPL
Tends to be confined to the uterus
Metastasize late
Resistant to chemotherapy
METASTATIC DISEASE
= 4% after molar pregnancy
More often after nonmolar pregnancy
Usually associated with choriocarcinoma
Highly vascular  spontaneous bleeding
Early vascular spreading
Sites:
Pulmonary
80%
Hepatic 10%
Vaginal
30% Brain
10%
Pelvic
20%
1 – Pulmonary metastases:
Symptoms:
dyspnea
cough
hemoptysis
chest pain
asymptomatic
May be acute of chronic
Chest X ray:
 Snowstorm pattern
 Discrete rounded densities
 Pleural effusion
 Pulmonary artery embolism
May be misdiagnosed as 1ry pulmonary
disease and only recognized as GTD
after thoracotomy
Pulmonary embolism may 
pulmonary HTN
Early RF + intubation = bad prognosis
2 – Vaginal metastasis
highly vascular
biopsy may  excessive bleeding
Symptoms:
Vaginal bleeding
Purulent discharge
Site: fornices/suburethral
3 – Hepatic metastasis
Usually in advanced cases
Symptoms:
Epigastric or upper RT ¼ pain due to
stretching subcapsular hematoma
Rupture  internal Hg
4 – Brain metastasis
Usually in advanced cases
Spontaneous bleeding  acute focal
neurological defects
STAGING
Stage I confined to uterus
Stage II confined to genital structures
Stage III pulmonary metastasis
Stage IV other metastasis
At any stage:
A = no risk factors
B = 1 risk factor
C = 2 risk factors
PROGNOSTIC SCORING SYSTEMS
0
1
2
4
Age
≤39
>39
Pregnancy mole
abortion term
Duration
<4m
4-6
7-12
>12
hCG
<1000 <10000 <100000 >
Largest size <3cm 3-5
>5
Site of met 0 kidney/spleen GIT/liver brain
Number
<3
1-3
4-8
>8
ABO group 0
A/O
B/AB
Chemotherapy
1
≥2
DIAGNOSTIC EVALUATION
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H/O
Examination
hCG
Liver function tests
Kidney function tests
Thyroid function tests
WBCs
Platelet count
IMAGING
Chest
 X-ray -- CT
Abd & pelvis  U/S -- CT
Brain
 MRI -- CT
If no pulmonary or vaginal metastasis
 metastasis are rare
Chest CT  for micrometastasis
Liver CT  for abnormal LFTs
Brain CT  for asymptomatic lesions
If brain CT is normalmeasure CSF hCG
If serum hCG/CSF hCG = < 60% then
there is brain metastasis
Pelvic U/S for:
 Extent of uterine lesion
 Localization of resistant lesions
 Identifying patients who will benefit
from hystrectomy
MANAGEMENT
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Stage I
Stage II & III
Stage IV
STAGE I
If the patient does not wish to
preserve fertility
 Hystrectomy + Chemotherapy to:
 ↓ dissemination of GTD
 Treat dissemination of GTD
 Treat occult metastasis
 ↓ bleeding
 ↓ sepsis
If the patient wish to preserve fertility:
Low risk  Single agent
High risk  Combined chemotherapy
Resistant  Local uterine resection
after localization of
resistant sites by U/S,
MRI, or arteriography
Placental site GTD:
- Only curative ttt for nonmetastatic
cases is hystrectomy
- Resistant to chemotherapy  few
metastatic cases reported complete
remission after chemotherapy
STAGE II & III
Pulmonary metastasis
Low risk  single agent  82% CR
High risk  combined chemotherapy
Resistant  thoracotomy after
localization of and
exclusion of other
resistant sites
Vaginal metastasis
Low risk  single agent  84% CR
High risk  combined chemotherapy
Resistant  wide local excision
Vaginal bleeding:
 Packing of the vagina
 Wide local excision
 Embolization of hypogastric arteries
Hystrectomy
- In metastatic disease 
- to control Hg
- to control sepsis
- In extensive uterine disease 
- to ↓ GTT burden
- to ↓ chemotherapy
courses
Follow up of stage I, II, III:
hCG/week
 3 consecutive normal results
hCG/month
 12 consecutive normal results
+ effective contraception
STAGE IV
Should be referred to specialized centers
May be unresponsive or rapidly progress
All should receive intensive combined
chemotherapy ± irradiation / surgery
Hepatic metastasis:
Resistant cases  intrahepatic infusion
of chemotherapy
Hemorrhage
 local excision or
arterial embolization
Brain metastasis:
All cases receive:
 Whole brain irradiation by 3000
cGy in 10 fractions
 Combined chemotherapy +
intrathecal MTX  86% CR
Resistant  local excision
Hemorrhage craniotomy50%CR
No residual neurologic deficits
CHEMOTHERAPY
SINGLE AGENT CHEMOTHERAPY
Used in nonmetastatic and low risk mm
MTX&Act-D are used/other week X5days
1964: MTX-FA  well tolerated
 ↓ toxicity
MTX-FA  the preferred ttt for GTD
MTX-FA  88% CR
81% by single course
90% CR in stage I
68% CR in stage II
Complications:
 Thrombocytopenia
1.6%
 Agranulocytopenia
6%
 Hepatotoxicity
14%
Resistant cases:
 Choriocarcinoma
 Metastasis
 Initial hCG > 50,000 mIU/mL
Technique:
 Measure hCG after each course
 Draw a curve
 Stop MTX if the curve is progressively ↓
 Do not give MTX at any predetermined
or fixed interval
 Give another course if:
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
hCG is ↑ or plateaus for > 3 weeks
hCG ↓ < 1 log at day 18 post ttt
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If the response to the 1st course is
adequate  give the same dose
If the response to the 1st course is
inadequate  ↑ the dose to 1.5 mg/Kg
body weight/day X 4 days
Adequate response = ↓ hCG by 1 log
If the response to the 2nd & 3rd courses
is inadequate  give ACT-D
If the response to ACT-D is inadequate
 give combined chemotherapy
COMBINED CHEMOTHERAPY
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Triple therapy ( MTX + ACT-D +
cyclophosphamide ) is inadequate in
ttt of high risk cases  50% CR only
Etoposide  95% CR in nonmetastatic
and low risk metastatic cases
1984: triple therapy + Etoposide
+ Vincristine ( EMA-CO ) 

83% CR in high risk patients

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EMA-CO is well tolerated and is the
preferred 1ry ttt for patients with
metastasis and high risk score
 76% CR when used as 1ry ttt
 86% CR in brain metastasis
If resistant to EMA-CO
 give EMA-EP (cisplatin) on day 8
 76% CR in resistant patients
Duration of Therapy:
 Give combined chemotherapy 
3 consecutive normal results
 Add at least 2 additional courses
to ↓ risk of relapse
SUBSEQUENT PREGNANCIES
Complete/Partial mole Persistent GTT
Term
70%
70%
PTL
7%
6%
Ectopic
1%
1%
SB
½%
11/2%
Recurrence
11/2%
1%
1st T abortion
16%
15%
2nd T abortion
1.6%
1.5%
Congenital anom
4%
2.5%
CS
16%
19%
Recurrence rate:
1 mole = 1%
2 mole = 20%
In the next pregnancy:
 Do U/S < 14 weeks
 Measure hCG 6 weeks after
termination/labour
 Send placenta or product of
conception to pathology

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