1. Gestational Trophoblastic
Disease(GTD)
Dr D. T. Dambo
N.D.U.T.H.

2. INTRODUCTION
• Gestational Trophoblastic Disease is a term
commonly applied to a spectrum of inter-related
diseases originating from the placental trophoblast.
• It is a spectrum of a disease entity that worsens in
prognosis with its progression from one entity to the
other.
• It is one of the rare human tumours that
cure is achievable even in the presence of
widespread dissemination.

3. INTRODUCTION
• Gestational Trophoblastic Disease are classified into`
-Hydatiform mole (Complete or Partial)
-Invasive mole
-Placental site trophoblastic tumour(PSTT)
-Choriocarcinoma
• They arise from fetal tissue within the maternal host and
are composed of both syncytiotrophoblastic and
cytotrophoblastic cells except PSTT, which is derived from
intermediate trophoblastic cells.

4. INTRODUCTION
• These conditions represent a neoplastic spectrum
with moles at the benign end, and choriocarcinoma
at the malignant extreme, and invasive mole being
equivalent to a neoplasm of borderline malignancy.

5. Incidence & Epidemiology
The incidence of GTD is higher in Asia and Latin America
than in western countries.
- South Asia – 3.2 to 9.9 per 1000 pregnancies.
- In Europe/North America – 0.6 to 1.1 per 1000
pregnancies.
- Mexico – 4.6 per 1000 pregnancies.
- Japan – 2 per 1000 pregnancies.
- Philippines – 5.0 per 1000 deliveries.
- Nigeria – 2.6 per 1000 deliveries(highest in Yorubas).
- NDUTH -- 3 cases in 2010.
6.2 per 1000 deliveries

6. Risk Factors
• Racial –more common in Orients, blacks > Caucasians
• ABO group: Women with blood type A or AB are at
slightly higher risk than those with type B or O.
• Age: < 20 and >40yrs
• Consanguineous marriages
• Previous molar pregnancy (2% after one, 25% after
two)
• Previous spontaneous abortion (2-3x after one
abortion > nil)
• Multiparity
• Low social class
• Diet – low protein, folic acid and vitamin A

7. Pathophysiology
• Complete hydatidiform mole –
• an abnormal conceptus, without an embryo.
• Characterised by generalized swelling of the placental
villi, with diffuse trophoblastic hyperplasia.
• comprised of both cytotrophoblast and syncytial
elements.
• It is avascular
• A classic mole resemble a bunch of grapes.
• Serum and tissue HCG levels are markedly raised.
• May either resolve or may progress to invasive mole or
choriocarcinoma(15-20%).

8. Pathophysiology
Partial hydatidiform mole – an abnormal
conceptus with an embryo or fetus that tend to die
early.
• The placenta has focal villous swelling and focal
trophoblastic hyperplasia with cistern formation.
• The chorionic villi have characteristically marked
scalloping and prominent stromal trophoblastic
inclusions.
• Less often progress to choriocarcinoma

9. Pathophysiology
• Invasive mole – this is a tumour invading the
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myometrium .
Commonly results from complete hydatidiform mole.
Usually does not progress to choriocarcinoma.
If untreated it invades the uterine wall and , resulting
in perforation and haemorrhage.
May resolve spontaneously

10. Pathophysiology
Placental site trophoblastic tumour –
• a tumour arising from the trophoblastic tissue of the
placental bed.
• Composed mainly of cytotrophoblastic cells and
produces low levels of hCG relative to its mass.
• Produces abundant human placental lactogen(HPL).
• Though locally invasive, many are self limiting and
subject to cure by hysterectomy or surgical excision.
• This condition is much more resistant to standard
chemotherapy than other forms of GTB.

11. Pathophysiology
• Gestational choriocarcinoma – it is a
carcinoma arising from trophoblastic epithelium that
shows both syncytiotrophoblastic and
cytotrophoblastic elements.
• Preceding conception could result in a live birth, stillbirth, abortion at any stage, ectopic pregnancy or
hydatidiform mole.
• Antecedent pregnancy –
-50% - complete mole
- 25% - abortion
- 22% - normal pregnancy
- 3% - ectopic pregnancy

12. Genetics
• Complete mole results when a haploid sperm (23x)
fertilizes an empty ova (nucleus is lost or inactivated)
and duplicate itself to form a 46xx complement –
paternal chromosomes.
• A small percentage of complete mole results from
dispermy – 2 haploid sperm (23x) fertilizing an empty
egg.
• The karyotype of complete mole is usually
46xx(homozygous) and only in minority is it
46xy(heterozygous).

13. Genetics
• A complete mole with 46yy chromosome
complement is never seen – b/c at least one xchromosome is essential for cell survival.

14. genetics
Partial hydatidiform mole results from triploidy
(69xxx or 69xxy or 69xyy) with one maternal(23x)
and 2 paternal(23x,23y) chromosome sets.
– About 90-93% of partial mole have been reported to
be triploid.
– some may have tetraploid karyotype.

15. Clinical Features
Complete Mole
1.Vaginal bleeding – most common 97%
2. Dislodged pieces of tumour that pass from
vagina, resembling a bunch of grapes(vessicles).
3.Pre-eclampsia/PIH - 27% of patients with
complete moles. May occur as early as 16Wks
4. Hyperemesis gravidarum – 8%
5. Changes in uterine size – 28%.
a)Uterus larger than dates in 50% of cases’
b)Uterus corresponds with dates in 25%
c)Uterus smaller than dates in 25%

16. .

17. Clinical Features
6. Lack of fetal movement.
7.Hyperthyroidism – 7%
8. Features of trophoblastic embolisation –
Respiratory distress
9. Theca Lutein ovarian cysts. Abdominal
pain due ovarian accidents. Disappear in 4
months following evacuation.
10. DIC

18. Clinical Features
Partial Moles
-Do not exhibit most of these dramatic features.
-Generally they have signs and symptoms of
incomplete or missed abortion

19. Clinical Features
• INVASIVE MOLE
Irregular vaginal bleeding
- Theca lutein cysts
- Uterine subinvolution
- Persistently elevated serum hCG levels
- Intra peritoneal bleeding (perforation through
myometrial wall)
- Abnormal Vaginal discharge/acute pelvic pain
when there is associated sepsis
−

20. Clinical Features
• CHORIOCARCINOMA
Has a tendency toward early vascular invasion with wide spread
dissemination.
Most common sites are -
lungs
Vagina
Pelvis
Liver
Brain
-80%
-30%
- 20%
- 10%
- 10%
. Symptoms Relating to metastasis are due to spontaneous
bleeding at metastatic site.
Lungs
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Chest pain
Cough, haemoptysis, dyspnoea

21. Clinical Features
• Vagina
Suburethral nodule, fleshy mass
Hepatic
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Irregular vaginal bleeding
Abnormal Vaginal discharge
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CNS-
Epigastric or Right upper quadrant
pain
May cause hepatic rupture/intra
peritoneal bleeding when the lesion is
Haemorrhagic.
Focal Neurologic deficit following
spontaneous haemorrhage in the brain.

22. Features of Complete and Partial mole
.

23. STAGING
• The official International Federation of Gynecology and
Obstetrics(FIGO) staging of gestational trophoblastic
neoplasia is as follows:
• Stage I – Confined to the uterus
• Stage II – Limited to the genital structures (ovary, tube,
vagina, broad ligament)
• Stage III – Lung metastases with or without known
genital tract involvement.
• Stage IV – Other metastases
Substage
• A – No risk factor
• B – One risk factor
• C – Two risk factors

24. •
RISK FACTORS AFFECTING STAGING
INCLUDE:
1. hCG > 100,000 IU / 24-hour urine
2. The detection of disease > 6 months from
termination of the antecedent pregnancy to
diagnosis.

25. Prognostic scoring systems
The American National institute of health
(N.I.H ) system
Modified WHO Prognostic Scoring System as
Adapted by FIGO. Based on Bagshawe`s
analysis of the prognostic factors.

26. Revised FIGO Scoring System
.

27. • The total score for a patient is obtained by adding the
individual scores for each prognostic factor.
Total score
•
-A score of 6 or less – low risk disease treatable by
single agent chemotherapy
•
-A score of 7 or greater – high risk disease that
requires combination chemotherapy.
•
- Minimum score = 0, maximum sore = 25
•
-Medium risk categorization no more in use

28. •
THE AMERICAN NATIONAL INSTITUTE OF HEALTH
(NIH)
Clinical criteria
- Non metastatic
- Metastatic (GTN)- disease outside the uterus
a) Good prognosis
b) Poor prognosis

29. THE AMERICAN NATIONAL INSTITUTE OF HEALTH (NIH)
contd
1. Good- Prognosis metastatic disease (i.e.,absence of
high risk factor)
a. Short duration(<4 months).
b. Serum B-hCG < 40,000mIU/ml (PRETREATMENT)
c. No metastasis to brain or liver
d. No prior unsuccessful chemotherapy
e. No malignant GTN following term pregnancy

30. 2. Poor-prognosis metastatic disease (i.e.,any
single high risk factor)
a. Long duration (>4 months).
b. Serum B-hCG >40,000mIU/ml
c. Metastasis to brain or liver
d. Prior unsuccessful chemotherapy
e. Gestational trophoblastic neoplasia following
term pregnancy.

31. SURVIVAL RATE
-Based on data from the new England
Trophoblastic disease center:
-The overall survival rate for stages I,II & III ( OR
NON-METASTATIC AND LOW RISK
METASTATIC) is virtually 100%.
-Stage IV ( OR HIGH RISK METASTATIC) dx
Survival rate - 70-73%

32. Differentials
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Abortion
Ectopic pregnancy
Pre-eclampsia
Hyperthyroidism
Cervical cancer

33. INVESTIGATIONS
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FBC, + differential
Bld culture,
ABO Bld grp
Urine - Urinalysis &m/c/s,
HVS m/c/s,
Retroviral screening
HBsAg screening
E/U/Cr
BhCG [csf:bld ratio=1/60]. Normal serum level <2IU/L.
TFT
LFT
CXR
USS(Theca lutein cyst)
CT scan (bm)
MRI (sm)
Histology (RPC)

34. TREATMENT
Patients should be managed in a specialist unit.
• SURGICAL
• MEDICAL
• RADIOTHERAPY
• Choice of Tx modality is to a great extent dependent
on
-the spectrum of the disease,
- the stage,
-the prognostic indices.

35. SURGICAL:
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Suction evacuation.
Main surgical procedure esp. in H. mole.
In the theatre start with IV fluids, usually with
crystalloids
Select the most appropriate cannula to use, usually the
largest.
Oxytocin used when moderate amount has been
evacuated and is maintained for 24hrs post evacuation
Pulmonary trophoblastic embolization may occur
especially if the oxytocin drip is started before the
suction evacuation begins.
This is to help the uterus to contract

36. SURGICAL:
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Suction evacuation contd.
After suction is completed, a gentle sharp
curettage is done to remove any molar
tissue that may be left behind.
All specimens taken should be sent for
histology.
Post operative ultrasound is done to verify
the emptiness of the uterus.
If uterus is not empty repeat the curettage
in 2 weeks or when bleeding occurs.

37. SURGICAL:
• Medical induction with
PG, Oxytocin, Hypertonic solutions
(saline,urea,glucose,) are no longer
acceptable methods for evacuation of a
molar pregnancy.
• Hysterectomy
• Craniotomy(borehole), Thoracotomy, Angio
graphic embolization, Hepatic resection

38. The risk of hydatidiform mole progressing to
choriocarcinoma increases
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Pre-evacuation hCG level >100,000IU/l
Uterine size greater than gestational age
Large (>6cm) theca lutein cyst
Maternal age >40yrs
Use of oral contraceptive pill before hCG level
falls to undetectable level
• Medical induction

39. Follow-up for hydatidiform mole
• Choriocarcinoma occurs in 3% of cases of
complete hydatidiform mole, the risk is low
with partial mole.
• Follow-up is necessary to detect those who
require chemotherapy for invasive mole or
choriocarcinoma.
• The serum hCG is assayed weekly until it
becomes undetectable (< 2IU/l) 3 normal
values, then monthly in the 1st year after
evacuation and every 3 months in the 2nd year
after evacuation.

40. • The hCG measurement should continue for at least 6
months after it has become undetectable.
• The hCG must have been undetectable for 6months
before starting another pregnancy.
• After all subsequent pregnancy monitor hCG – due to
risk of hydatidiform mole and choriocarcinoma.
• Post chemotherapy – hCG follow-up is for life.

41. Criteria for chemotherapy after
hydatidiform mole
• High hCG level more than 4 weeks after evacuation.
Serum level > 20,000IU/l or urine level > 30,000IU/l
• Progressively rising hCG levels at anytime after
evacuation.
• Beta-hCG levels rising for 2 successive weeks.
• Beta-hCG constant(plateau) for 3 successive weeks.
• Beta-hCG levels elevated at 15 weeks
postevacuation.
• Rising Beta-hCG titer after reaching normal levels.

42. Criteria for chemotherapy after
hydatidiform mole contd
• Raised hCG levels 6 months after evacuation
(even if falling).
• Persistent uterine bleeding and positive hCG
levels
• Histological diagnosis of choriocarcinoma
• Evidence of CNS, renal, hepatic, GIT or
pulmonary metastasis > 2cm in diameter or >3
in number.

43. MEDICAL-CHEMOTHERAPY
Single agent therapy:
Methotrexate or actinomycin D
• MTX 30-60mg/m2 once a wk. For non-metastatic only.
• MTX 0.4mg/kg/day IV or IM x5/7, repeat every 14/7.
• MTX 1 mg/kg IM on days 1,3,5,and 7 and
folinic acid 0.1mg/kg IM on days 2,4,6,and 8,
repeat every 15-18 days.
• Actinomycin – D 12µg/kg/day IV for 5 days
• Actinomycin – D 1.25mg/m2 IV every 2 weeks
• This drug may be especially useful in patients with liver
problems, because it is less toxic to the liver than
methotrexate is.
This regimen is for low risk groups

44. Combination therapy for high risk group
MAC
Methotrexate 15mg IM
Actinomycin D 0.5mg IV
Cyclophosphamide 3.0mg/kg body weight. PO or
Chlorambucil 6-10mg PO
All daily for 5 days and repeat after 2 or 3 weeks.

45. EMA/CO
Day 1: Etoposide
Actinomycin D
MTX
Day 2: Etoposide
Actinomycin D
Folinic acid
100mg/m2 IV (in 200ml of N/S over 30 minutes)
0.5mg IV bolus
100mg/m2 IV bolus
200mg/m2 IV (infused over 12hrs)
`100mg/m2 IV (in 200ml of N/S over 30minutes)
0.5mg IV bolus
15mg IM or orally every 12hrs for
4 doses beginning 24hrs after start of
MTX.
Day 8: Cyclophosphamide 600mg/m2 IV in saline
Oncovin( Vincristine)
1mg/m2 IV bolus.

46. EMA/CE
Day 1: Etoposide
Actinomycin D
MTX
100mg/m2 IV (in 200ml of N/S over 30 minutes)
0.5mg IV bolus
100mg/m2 IV bolus
1000mg/m2 IV (infused over 12hrs)
Day 2: Ectoposide
Actinomycin D
Folinic acid
100mg/m2 IV (in 200ml of N/S over 30 minutes)
0.5mg IV bolus
30mg IM or orally every 12hrs for
6 doses beginning 32hrs after start of
MTX.
Day 8: Cisplatin
Etoposide
60mg/m2 IV with prehydration
100mg/m2 IV (in 200ml of N/S over 30 minutes)
PVB : Cisplatin, Vinblastine, Bleomycin
Cisplatin
Vinblastine
Bleomycin

47. The side effects of chemotherapy
• Common side effects of chemotherapy drugs
include:
• · Alopecia
• · Mucositis
• · Loss of appetite
• · Nausea and vomiting
• · Myelosupression
• Most of these side effects are short-term and tend to
go away after treatment is finished.

48. • Along with the effects listed above, some side effects
are specific to certain chemotherapy agents:
• Methotrexate can cause
stomatitis, hepatitis, nephrotoxicity, dermatatis and
hepatocellular damage.
• Actinomycin-D can cause diarrhea & cardiomyopathy
• Bleomycin can cause pulmonary fibrosis.
• Cyclophosphamide can cause
nephrotoxicity, ototoxicity, haemorrhagic
cystitis, decrease sperm production, cessation of
menstruation, infertility and secondary cancers.

49. • Etoposide and vincristine can cause
constipation, paralytic
ileus, neurotoxicity, peripheral neuropathy
and bladder atony.
• Cisplatin can cause ototoxicity, nephrotoxicity
and neurotoxicity..

50. Brain metastasis
• Increase the methotrexate dose in EMA-CO protocol
to 1g/m2, the urine should be alkalinized with iv
bicarbonate
• Depending on tumour size there might be need for
irradiation of whole brain or excisional surgery.
• The irradiation is to prevent catastrophic
haemorrhage rather than controlling the
trophoblastic disease.
• Irradiation may also be needed for liver metastasis.

51. • Radiotherapy: used concomitantly with
combined chemotherapy in patients with liver
or brain metastasis.
• Cerebral metastasis Rx over 2 wks with 300
rads daily, 5 days a week, to a total organ dose
of 3000 rads.
• Whole liver irradiation Rx over 10 days with
200 rads daily, 5 days a week, to a total organ
dose of 2000 rads
• Pelvic artery embolization is used in cases of
intractable haemorrhage.

52. FERTILITY
• Regular menses starts btw 2-6mths following
chemotherapy.
• Average age of menopause is reduced by 1yr
with Methotrexate & 3yrs with EMACO
• Patient should avoid pregnancy for
1yr(following chemotherapy) to reduce risk of
teratogenicity from chemotherapeutic agents
& confusion from rising HCG levels.
• 83% of patients have been able to achieve a
live birth following chemotherapy

53. ROLE OF SURGERY
The development of effective chemotherapeutic
agents has relegated surgery to a secondary
role in the management of trophoblastic
tumour.
Surgery has been limited to the treatment of :- resistant cases to chemotherapy,
- uncontrollable haemorrhage from the uterus
- Tumour perforation of the uterus
- Infected uterine tumour not responding to
antibiotics, thus delaying chemotherapy..

54. Role of surgery in mgt of trophoblastic
diseases contd
• Suction-Evacuation
• Uterine perforation managed by local
resection of tumour and uterine repair.
• Hysterectomy may be required for persistent
heavy bleeding – but usually responds to
chemotherapy
• Surgical removal of drug-resistant disease in
resectable site. (lungs or brain)).

55. FOLLOW-UP
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BhCG Titre wkly until 3 consecutive normal titres
Monthly for 12 months
3 monthly for 1 additional year
6 monthly indefinitely
Contraception for at least 1yr after
remission(OCP, Condom)
• Gynaecologic examination started 1 week post
evacuation – assess Ut size, adnexal masses, check
for metastases on the vulva, vagina, urethra, and
cervix. If no complication repeat exam 4 wkly
throughout period of surveillance.

56. FOLLOW-UP CONTD
• Laboratory investigation follow-up =
FBC+DIFF, E&U+C, LFT, etc
• CXR repeated every 4wks for those that had
pulmonary metastasis prior to evacuation, until
remission, thereafter every 3 months for period of
surveillance.
• Switch to alternate drug in an event of BhCG titre
rises 10x or more, plateaus at elevated
levels, histological identification of ca cells, persistent
uterine bleeding
• CMT continues for 2 courses after –ve BhCG titre.

57. COMPLICATIONS:
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Anaesthetic complications
Uterine perforation
Injury to adjacent structures
Haemorrhage
Sepsis
Infertility
Convulsion
Coma
Death

58. PROGNOSIS:
• Excellent.
• Over 90% of patients have been able to
preserve reproductive functions.

59. HYPERGLYCOSYLATED HCG
• Hyperglycosylated hCG (hCG-H) is a glycosylation variant
of the hormone hCG.
• it is a very different molecule to the hormone hCG.
• hCG-H is produced by cytotrophoblast cells while regular
hCG is made in syncytiotrophoblast cell.
• it is an autocrine acting directly on the cells which
produce it, while regular hCG is an endocrine acting on
maternal corpus luteal cells.
• hCG-H has minimal biological activity in promoting
progesterone production compared to regular hCG.
• hCG-H functions unlike regular hCG as an invasion
promoter, whether invasion as in choriocarcinoma and
testicular germ cell malignancies, or as in implantation of
pregnancy.

60. hCG-H CONTD
• hCG-H is an essential component for successful human
implantation to prevent early pregnancy loss and
spontaneous abortion.
• hCG-H is critical for promoting the midtrimester
hemochorial implantation, and for preventing
pre-eclampsia.
• measurements of hCG-H have advantages over
measurements of regular hCG or total hCG, in detecting
pregnancy, pregnancy outcome (failing or term
pregnancy), predicting pre-eclampsia in pregnancy, or as
a tumor marker for gestational trophoblastic diseases.
• PMID: 17346790 [PubMed - indexed for MEDLINE]

61. SUMMARY
• GTD forms a spectrum of illness, from borderline
malignancy of HM to Choriocarcinoma, which were
fatal in the past.
• However in the last 55yrs a lot has been learnt about
the biology, pathology and natural history of GTD.
• Furthermore, accurate diagnostic and monitoring
methods have been developed, together with
effective treatment regimens.

62. SUMMARY CONTD
• As a result GTD is one of the modern day success
stories in oncology

63. THANK YOU

64. INTRODUCTION

65. INTRODUCTION

66. HYPERGLYCOSYLATED HCG
• Hyperglycosylated hCG (hCG-H) is a glycosylation variant of
the hormone hCG.
• it is a very different molecule to the hormone hCG.
• hCG-H is produced by cytotrophoblast cells while regular hCG
is made in syncytiotrophoblast cell.
• it is an autocrine acting directly on the cells which produce it,
while regular hCG is an endocrine acting on maternal corpus
luteal cells.
• hCG-H has minimal biological activity in promoting
progesterone production compared to regular hCG.
• hCG-H functions unlike regular hCG as an invasion promoter,
whether invasion as in choriocarcinoma and testicular germ
cell malignancies, or as in implantation of pregnancy. These
functions seemingly occur through action on cytotrophoblast
cell TGFbeta receptors.

67. SUMMARY CONTD
• Hyperglycosylated hCG is a biological variant of
BhCG still under research and is believed to enhance
the management of GTD because it has been found
to be more sensitive than BhCG in detecting
quiescent variant of GTD as against the invasive
variety.
• As a result GTD is one of the modern day success
stories in oncology