Gestational trophoblastic disease (GTD) includes a spectrum of conditions from benign hydatidiform moles to malignant choriocarcinoma. GTD is classified pathologically and clinically, ranging from benign to malignant trophoblastic disease. Hydatidiform moles are generally benign but have potential to develop into invasive moles or choriocarcinoma. Choriocarcinoma is an aggressive form of GTD that can be life-threatening if not treated properly. Treatment depends on the type and severity of GTD, and may include surgery, single or multi-agent chemotherapy, and radiotherapy, with the goal of curing patients through early diagnosis and appropriate treatment.

1. Gestational Trophoblastic
Disease (GTD)
By Shiferaw Negash/MD
AAUMF, Obs-Gyn

2. Types of GTD
Benign
• Hydatidiform mole/molar pregnancy
(complete or incomplete)
malignant
• Invasive mole
• Choriocarcinoma (chorioepithelioma)
• Placental site trophoblastic tumor

3.  The term Gestational Trophoblastic
Tumors has been applied the latter
three conditions
 Arise from the trophoblastic elements
 Retain the invasive tendencies of the
normal placenta or metastasis
 Keep secretion of the human chorionic
gonadotropin (hCG)
Types of GTD

4. PATHOLOGIC
CLASSIFICATION
CLINICAL
CLASSIFICATION
Hydatidiform mole
*complete
*incomplete
Benign gestational
trophoblastic disease
Invasive mole
Malignant
trophoblastic disease
Nonmetastatic
Placental site
trophoblastic
tumor
Metastatic
Choriocarcinoma High risk Low risk
Pathologic and clinical classifications
for gestational trophoblastic disease

5. Hydatidiform Mole
(molar pregnancy)

6. Definition and Etiology
 Hydatidiform mole is a pregnancy
characterized by vesicular swelling of
placental villi and usually the absence of
an intact fetus.
 The etiology of Hydatidiform mole
remains unclear, but it appears to be due
to abnormal gametogenesis and
fertilization

7.  In a ‘complete mole’ the mass of
tissue is completely made up of
abnormal cells
 There is no fetus and nothing can
be found at the time of the first
scan.
Definition and Etiology

8.  In a ‘partial mole’, the mass may
contain both these abnormal cells and
often a fetus that has severe defects.
 In this case the fetus will be
consumed ( destroyed) by the
growing abnormal mass very quickly.
(shrink)
Definition and Etiology

9. Incidence
• 1 out of 1500-2000 pregnancies in the
U.S. and Europe
• 1 out of 500-600 (another report 1%)
pregnancies in some Asian countries.
• Complete > incomplete

10.  Repeat Hydatidiform moles occur 0.5-2.6%
of patients, and these patients have a
subsequent greater risk of developing
invasive mole or Choriocarcinoma
 There is an increased risk of molar
pregnancy for women over the age 40
Incidence

11.  Approximately 10-17% of Hydatidiform
moles will result in invasive mole
 Approximately 2-3% of Hydatidiform
moles progress to Choriocarcinoma ( most
of them are curable)
Incidence
Not definitely benign disease , has a tight
relationship with GTT

12. Clinical risk factors for molar pregnancy
Age (extremes of reproductive years)
<15
>40
Reproductive history
Prior Hydatidiform mole
Prior spontaneous abortion
Diet
Vitamin A deficiency
Birthplace
Outside North America( occasionally has this disease)

13. Cytogenetics
Complete molar pregnancy
 Chromosomes are paternal , diploid
 46,XX in 90% cases
 46,XY in a small part
Partial molar pregnancy
 Chromosomes are paternal and maternal, triploid.
 69,XXY 80%
 69,XXX or 69,XYY 10-20%
Wrong life message , so can not develop normally

14. Comparative Pathologic Features of
Complete and Partial Hydatidiform Mole
Feature Complete Mole Partial Mole
Karyotype Usually diploid 46XX Usually triploidy 69XXY most
common.
Villi All villi hydropiC; no
normal adjacent villi
Normal adjacent villi may be
present
vessels present they contain no
fetal blood cells
blood cells
Fetal tissue None present Usually present
Trophoblast Hyperplasia usually
present to variable
degrees
Hyperplasia mild and focal

15. Complete Hydatidiform mole demonstrating
enlarged villi of various size

16. Hydatidiform mole: specimen from suction
curettage

17. A large amount of villi in the uterus.

18. The microscopic appearance of Hydatidiform mole:
•Hyperplasia of trophobasitc cells
•Hydropic swelling of all villi
•Vessels are usually absent

19. A sonographic findings of a molar pregnancy. The
characteristic “snowstorm” pattern is evident.

20. Transvaginal sonogram demonstrating the “ snow storm” appearance.

21. Color Doppler facilitates visualization of the enlarged spiral
Arteries close proximity to the “ snow storm” appearance

22. Color Doppler image of a Hydatidiform mole and surrounding
vessels. The uterine artery is easily identified from its anatomical
location.

24. Doppler waveform analysis demonstrates low vascular resistance(RI=0.29) in
the spiral arteries, much lower than that obtained in normal early pregnancy

26. Partial Hydatidiform mole

27. Microscopic image of partial molar pregnancy.

28. Here is a partial mole in a case of triploidy. Note
the scattered grape-like masses with intervening
normal-appearing placental tissue.

29. Large bilateral theca lutein cysts resembling ovarian germ cell
tumors. With resolution of the human chorionic gonadotropin(HCG)
stimulation, they return to normal-appearing ovaries.

30. Signs and Symptoms of Complete
Hydatidiform Mole
• Vaginal bleeding
• Passage of vesicles, exaggerated Sx of
pregnancy
• Hyperemesis gravidarum
• Size inconsistent with gestational age(with
no fetal heart beating and fetal movement)
• Preeclampsia, Thyrotoxicosis
• Theca lutein ovarian cysts

31. Signs and Symptoms of Partial
Hydatidiform Mole
• Vaginal bleeding
• Absence of fetal heart tones
• Uterine enlargement and preeclampsia is
reported in only 3% of patients.
• Theca lutein cysts, hyperemesis is rare.

32. Diagnosis of Hydatidiform mole
•History and physical diagnosis
• Quantitative beta-HCG( elaborates
unique tumor marker for diagnosis &
follow-up)
• Ultrasound is the criterion standard for
identifying both complete and partial
molar pregnancies. The classic image
is of a “snowstorm” pattern

33.  The most common symptom of a mole is vaginal
bleeding during the first trimester
 however very often no signs of a problem appear
and the mole can only be diagnosed by use of
ultrasound scanning.
 Occasionally, a uterus that is too large for the
stage of the pregnancy can be an indication.
 NOTE: Vaginal bleeding does not always indicate
a problem!
Diagnosis(Hx & P/E)

34. Differential diagnosis
• Abortion
• Multiple pregnancy
• Polyhydramnios
• Pelvic tumors

35. Investigation
 CBC,
 BG& RH,
 U/A,
 Serum beta hCG,
 TFT, workup for PE,
 serum electrolyte,
 PT, aPTT,
 OFT, HIV test
 Imaging:-
– U/S(ABD/VAG), Doppler U/S, CXR(if indicated)

36. Treatment
 General:
- ABC(shock,CHF)
- HTN, Thyrotoxicosis
- Blood transfusion, Anemia
- Anti-D(Rh alloimmunization)
- Infection

37. Treatment
•
Specific:
 Suction(MVA,EVA), dilation and curettage:
– to remove benign Hydatidiform moles
When the diagnosis of Hydatidiform mole is established,
the molar pregnancy should be evacuated.
 An oxytocic agent should be infused IV after the start
of evacuation and continued for several hours.

38.  Hysterectomy : -used rarely,
– If future pregnancy is no longer desired.
– Age>40years
Treatment

39. • Chemotherapy with a single-agent
drug
 Prophylactic chemotherapy at the
time of or immediately following molar
evacuation may be considered for the
high-risk patients.
Recommendation- Default follow-up
Treatment

40. High-risk for postmolar
trophoblastic tumor
1. Pre-evacuation uterine size larger than expected for
gestational duration
2. Bilateral ovarian enlargement (> 9 cm theca lutein cysts)
3. Age greater than 40 years
4. Very high hCG levels(>100,000 m IU/ml)
5. Medical complications of molar pregnancy such as
toxemia, hyperthyroidism and trophoblastic
embolization (villi come out of placenta )
6. Recurrent Hydatidiform mole

41.  >80% of Patients with Hydatidiform mole are
cured by treatment of evacuation alone.
 The follow-up after evacuation is key necessary
 uterine involution, ovarian cyst regression and
cessation of bleeding
Follow-up

42.  Quantitative serum hCG levels should be
obtained every 1-2 weeks until negative for
three consecutive determinations,
 Followed every 1 month for 6 months and
every 2 months for 1 year.
 Contraception using OCP should be practiced
during this follow-up period
Follow-up

43. Invasive mole

44. Definition
 This term is applied to a molar pregnancy
in which molar villi grow into the
– myometrium or its blood vessels, and
– may extend into the broad ligament and
– metastasize to the lungs, vagina or vulva.

45. Invasive mole: the tissue invades into the myometrial layer.
No obvious borderline, with obvious bleeding.

46. Invasive Hydatidiform mole infiltrating the myometrium

47. A case of invasive mole: inside the uterine cavity the typical
“snow storm” appearance can be detected, The location of
blood flow suggest an invasive mole.

48. The same patient owing to the myometrial invasion.
Reduced vascular resistance is detected in the uterine artery.

49. Transvaginal color Doppler scan of a patient with invasive mole Following
uterine curettage, Persistent color signals within the myometeriun

50. Doppler image of invasive mole

51. Power Doppler easily detects a vascular echogenic
nodule within the myometrium, suggesting
invasive mole

52. Doppler image of invasive mole. Doppler waveform
analysis depicts low vascular resistance (RI= 0.35)

53. Common Sites for Metastatic
Gestational Trophoblastic Tumors
Site Per cent
Lung 60-95(80)
Vagina 40-50(30)
Vulva/cervix 10-15(10)
Brain 5-15(10)
Liver 5-15(10)
Kidney 0-5
Spleen 0-5
Gastrointestinal 0-5

54. Choriocarcinoma

55. Definition
 A malignant form of GTD which can develop
from a Hydatidiform mole or from placental
trophoblastic cells following normal pregnancy ,
an abortion or an ectopic pregnancy.
 Is a life threatening condition
 Is an extreme of the disease known as GTN

56.  Characterized by abnormal trophoblastic
hyperplasia and anaplasia , absence of
chorionic villi
Definition

57. Gross specimen of Choriocarcinoma

58. Microscopic image of Choriocarcinoma
absence of chorionic villi

59. Microscopic image of Choriocarcinoma

60. Doppler image of Choriocarcinoma

61. Doppler image of Choriocarcinoma

62. Symptoms and signs
• Bleeding
• Infection
• Abdominal swelling
• Vaginal mass
• Lung symptoms
• Symptoms from other metastases

63. Mod WHO Prognostic Scoring System
Score
Prognostic factor 0 1 2 4
Age(years) ≤39 >39 — —
Pregnancy history
Hydatidiform
mole
Abortion,
ectopic
Term
pregnancy
—
Interval (months) of
treatment
<4 4-6 7-12 >12
Initial hCG(mIU/ml) <103 103-104 104-105 >105
Largest tumor(cm) <3 3-5 >5 —
Sites of metastasis Lung
Spleen,
kidney
GI tract, liver Brain
No. of metastasis — 1-4 4-8 8
Previous (treatment) — — Single drug 2 or more
<7 low risk, 7 high risk for death

64. FIGO Staging System for Gestational
Trophoblastic Tumors
Stage Description
Ⅰ Limited to uterine corpus
Ⅱ
Extends to the adnexal, outside the uterus, but
limited to the genital structures
Ⅲ Extends to the lungs with or without genital tract
Ⅳ All other metastatic sites

65.  Sub-stages assigned for each stage as follows:
A: No risk factors present
B: One risk factor
C: Both risk factors
 Risk factors used to assign sub-stages:
1. Pretherapy serum hCG > 100,000 mlU/ml
2. Duration of disease >6 months
FIGO Staging System for Gestational
Trophoblastic Tumors

67. IIb
IIa

68. IIIa<3cm or locate in half lung
IIIb disease beyond IIIa

70. Diagnosis and evaluation
 Choriocarcinoma is diagnosed by rising
hCG following evacuation of a molar
pregnancy or any pregnancy
event(Biochemical), Histological.
 Once the diagnosis established the
further examinations should be done
to determine the extent of disease ( X-
ray, CT, MRI)

71. Treatment
 Non-metastatic GTD
 Low-Risk Metastatic GTD
 High-Risk Metastatic GTD
 Virtually all patients are potentially
curable with chemotherapy, especially
if correctly diagnosed and appropriate
drugs are commenced early in the
course of the disease

72. Treatment
 Principles:
- Chemotherapy
- Surgery(resistant & persistent
metastasis)- Liver, Brain, Lung, other
- Radiotherapy
- Hypogastric artery embolization

73. Treatment of Nonmetastatic GTD
 Hysterectomy is advisable as initial treatment in
patients with non-metastatic GTD who no longer
wish to preserve fertility
 This choice can reduce the number of course
and shorter duration of chemotherapy.
 Adjusted single-agent chemotherapy at the time
of operation is indicated to eradicate any occult
metastases and reduce tumor dissemination.

74.  Single-agent chemotherapy is the
treatment of choice for patients wishing to
preserve their fertility.
 Methotrexate(MTX) or Actinomycin-D
 Treatment is continued until three
consecutive normal hCG levels have been
obtained and two courses have been given
after the first normal hCG level.
Treatment of Nonmetastatic GTD
To prevent relapse or metastasis

75.  Single-agent chemotherapy with MTX or Actinomycin-
D is the treatment for patients in this category
 If resistance to sequential single-agent chemotherapy
develops, combination chemotherapy would be taken
 Approximately 10-15% of patients treated with single-
agent chemotherapy will require combination
chemotherapy with or without surgery to achieve
remission
Treatment of Low-Risk
Metastatic GTD

76. Dosage for Methotrexate
& Actinomycin-D
 Methotrexate:
1- 0.4mg/Kg IM/wk/5days, repeat
Q2wks(10% failure rate).
2- 1mg/Kg/IM on days(1,3,5,7),
alternate with folinic acid 0.1mg/Kg IM
on days(2,4,6,8), after 24hrs of MTX
3- 50mg/M2 IM weekly(30% failure)

77. Dosage for Methotrexate
& Actinomycin-D
 Actinomycin-D:
1- 12mcg/Kg IV/day/5days repeat Q2
weeks(8% failure)
2- 1.25mg/M2 IV Q2weeks(20% failure)
3- MTX 250mg iv over 12hrs(EMA-CO
regimen) – 30% failure

78.  Multiagent chemotherapy with or without
adjuvant radiotherapy or surgery should be
the initial treatment for patients with high-
risk metastatic GTD
 EMA-CO regimen formula is good choice for
high-risk metastatic GTD
 MAC(MTX,Actinomycin-D,
Cytoxan/chlorambucil)-alternative to EMA-
CO(risk of leukemia)
Treatment of High-Risk
Metastatic GTD

79. Treatment of High-Risk
Metastatic GTD
 Resistant to EMA-CO: EMA-EP, EMA-PA
 Resistant to EMA-EP: Taxol with cisplatin
alternating with Taxol-etoposide or Taxol-
5FU or ICE or BEP
 Adjusted surgeries such as removing foci of
chemotherapy-resistant disease, controlling
hemorrhage may be the one of treatment
regimen
 Brain metastasis: Increase MTX dose in
EMA-CO to1gm/M2, alkalinize urine by iv
bicarbonate

80. Treatment of High-Risk
Metastatic GTD
 Radiotherapy: Brain & Liver metastasis
Can be given with chemotherapy.
1- Brain:- 300 rads/day/5days/week
X2weeks- 3000 rads total
2- Liver:- 200 rads/day/5days/week X
2weeks- 2000 rads total
•
Pelvic artery embolization- intractable
hemorrhage

81. EMA-CO Chemotherapy for poor
Prognostic Disease
Etoposide(VP-16) 100mg/M2 IV daily×2 days
(over 30-45 minutes)
Methotrexate 100mg/M2
IV loading dose,
then 200mg/M2
over 12 hours day 1
Actinomycin D 0.5mg IV daily×2 days
Folinic acid
15mg IM or p.o. q 12 hours×4 starting 24
hours after starting Methotrexate
Cyclophosphamide 600mg/M2 IV on day8
Oncovin (vincristine) 1mg/M2 IV on day8
(Repeat every 15 days as toxicity permits)

82. Prognosis
 Cure rates should approach 100% in
nonmetastatic and low-risk metastatic
GTD
 Intensive multimodality therapy has
resulted in cure rates of 80-90% in
patients with high-risk metastatic GTD

83. Follow-up After Successful
Treatment
 Quantitative serum hCG levels should be
obtained monthly for 6 months, every two
months for remainder of the first year, every 3
months during the second year
 Contraception should be maintained for at least
1 year after the completion of chemotherapy.
Condom is the choice.
 Pregnancy: patient must wait 1 year after
completion of chemotherapy

84. Placenta Site Trophoblastic
Tumor (PSTT)

85.  Placenta Site Trophoblastic Tumor is an
extremely rare tumor that arises from the
placental implantation site
 Tumor cells infiltrate the myometrium and
grow between smooth-muscle cells
Definition

87.  Serum hCG levels are relatively low
compared to those seen with
Choriocarcinoma.
 Several reports have noted a benign
behavior of this disease. They are relatively
chemotherapy-resistant, and deaths from
metastasis have occurred.
 Surgery has been the mainstay of treatment
Diagnosis and treatment