1. GESTATIONAL TROPHOBLASTIC Assistant Prof. & Consultant
DISEASE
Presented by:
Dr. Mashael Shebaili
Assistant Prof. & Consultant
Ob/Gyne Department

2. Classification of gestational Trophoblastic disease
WHO Classification
Malignant neoplasms of various types of trophoblats
Malformations of the chorionic villi that are predisposed to develop trophoblastic malignacies
Benign entities that can be confused with with these other lesions
Choriocarcinoma
Hydatidiform moles
Exaggerated placental site
Placental site trophoblastic tumor
Placental site nodule
Complete
Partial
Epithilioid trophoblastic tumors
Invasive

3. Hydatidiform Mole Definition: In latin Pathologically,
"hydatid" means "drop of water”
"mole" means "spot”
Pathologically,
Hydatidiform moles represents placentas with abnormally developed chorionic villi (enlarged, edematous and vesicular villi with variable amounts of proliferative trophoblast)

5. Hydatidiform Mole Incidence: In the United States, Internationally:
1in 600 therapeutic abortions
1 in 1,500 pregnancies
Internationally:
In Japan & China, 1-2 in 1,000 pregnancies
In Indonesia & India, 12 in 1,000 pregnancies
In the United Arab of Emirates,
2 in 1000 deliveries (population-based study; Graham IH, Fajardo AM; 1988)
In Saudi Arabia;
1.48 in 1000 live births (hospital-based study; Felemban AA, et al; 1969)

6. In the United States,
1in 600 therapeutic abortions
1 in 1,500 pregnancies
In Asian countries,
The rate is 10 times higher than in Europe and North America
In Saudi Arabia;,
1.48 in 1000 live births (hospital-based study; Felemban AA, et al; 1969)

7. Table1: Factors Associated with GTD Occurrence and Corresponding Relative Risks
Odds ratio
Factors
Complete Mole
Partial Mole
Maternal age (years)
<20
>40
Reproductive history
Parity at conception 3
Spontaneous miscarriages
>2
Problems with infertility
Contraception
Use of oral contraceptives
ICUD user
Age of 1st pregnancy <25
Previous molar pregnancy
1.5
5.2
0.9
0.8
1.5–3.1
2.4–3.7
1.1–2.6
1.7–3.7
0.6
16.0
0.7
0.5
1.9
3.2
1.3

8. Table1:Factors Associated with GTD Occurrence and Corresponding Relative Risks
Odds ratio
Factors
Complete Mole
Partial Mole
Family history
Spontaneous abortion (yes)
Socioeconomic and lifestyle
Education (years)
>12
Marital status
Never married
Smoking
Ex-smokers
Current smokers > cigarettes per day
Alcohol consumption
<2 drinks
1.5
0.9–2.1
2.1
1.1
2.2
0.7
1.8
1.4

9. Table1: Factors Associated with GTD Occurrence and Corresponding Relative Risks
Odds ratio
Factors
Complete Mole
Partial Mole
ABO blood types
Maternal blood AB A
Maternal A, husband O
Nutrition
Vitamin A in diet above control median
2.1
1.7
1.9
0.6
1.2
0.9

10. Pathogenesis and Cytogenetics of HM
Complete
Partial
Genetic Constitution
Diploid
Triploid/ teraploid
96%
Fertilization of an empty ovum by one sperms that undergoes duplication
“Diandric diploidy” 4%
Fertilization of an empty ovum by two sperms
“Diandric dispermy”
90%
Triploid
fertilization of a normal ovum by two sperms
“Dispermic triploidy”
10%
Tetraploid
fertilization of a normal ovum by three sperms
“Dispermic triploidy”
Patho-genesis
Karyotype
46XX
46XX
46XY
69XXX
69YXX
69YYX

11. Complete Mole, Pathogenesis
Paternal chromosomes only
Empty ovum
Duplication
46XX
23X
Diandric diploidy
Androgenesis

12. Complete Mole, Pathogenesis
Paternal chromosomes only
Empty ovum
46XX
23X
23X
23X
23X
Dispermic diploidy

13. Partial Mole, Pathogenesis
Paternal extra set
Normal ovum
69XXY
23X
23Y
23X
23Y
23X
23X
Dispermic triploidy

14. Alterations in gene expression profiles Trophoblastic hyperplasia
Hydatidiform Mole
Alterations in gene expression profiles
Up-regulation and down-regulation of proteins committed to cell growth control
e.g. Up-regulation of growth factor and cytokine mediated pathways, and antiapoptosis genes
e.g. Down-regulation of insulin growth factor binding proteins and tumor necrosis factor receptor
Trophoblastic hyperplasia

15. A log plot of microarray experiment demonstrating up-regulation of STAT5B expression and downregulation of 1GFBP5 expression in mole.

16. Passage of hydropic villi
Hydatidiform Mole
Clinical Presentation:
Complete mole:
Vaginal bleeding
Severe anemia
Passage of hydropic villi

17. Usually, in association with,
Hydatidiform Mole
Clinical Presentation:
Complete mole:
Excessive uterine enlargement
Theca lutein cysts
Usually, in association with,
Hyperthyroidism
Hyperemesis gravidarum
Preeclampsia
Markedly elevated hCG 100,000 mIU/mL

18. Hydatidiform Mole Hugh resolution ultrasonography Accurate hCG testing
The clinical presentation has changed
Per-vaginal bleeding
An ultrasound showing the classic findings of a “snow storm pattern”

19. Hydatidiform Mole
Table 2: The change of the clinical presentation of molar pregnancy among current patients
Study, site, sample size
Soto-Wright et al, New England (n 74)
Gemer et al,
Israel (n 41)
Lindholm & Flam, Sweden (n 75)
Mean maternal age
27.7 years
(range 16-51)
30.1
years --
Mean estimated gestational age
11.8 weeks
(range 6-22)
10 weeks
(range 7–14)
12.4 weeks
Mean uterine size
(range 7–20)
Mean level of pre-evacuation hCG
mIU/ml (range 828– )
IU/l (range 2011– ).

20. Hydatidiform Mole
Table 2: The change of the clinical presentation of molar pregnancy among current patients
Study, site, sample size
Soto-Wright et al, New England (n 74)
Gemer et al,
Israel (n 41)
Lindholm & Flam, Sweden (n 75)
Vaginal bleeding
84%
58%
77%
Uterine size greater than that for the expected date
28%
44%
20%
Anemia 4% 2% --
Hyperemesis 8%
19%
Preeclampsia
1.3% 0%
Hyperthyroidism
Asymptomatic 9%
41%
16%

21. Hydatidiform Mole Clinical Presentation: Partial mole: History:
Vaginal bleeding
Usually diagnosed as missed or incomplete abortion
Physical:
A uterus small or equal to gestational age

22. Hydatidiform Mole Diagnosis: History Clinical examination
Ultrasound examination
Serum hCG levels
Histopathological examination
Cytogenetic and molecular biological examination

23. Hydatidiform Mole Diagnosis: Ultrasonography: Complete mole
* The diagnosis of molar pregnancy is nearly always made by ultrasonography
The classical finding is a “snow storm" pattern
Theca lutein cysts are frequent findings on ultrasound
Complete mole

24. The snow storm appearance of complete hydatidiform mole

25. Theca lutein cysts, a frequent finding on ultrasound

26. Hydatidiform Mole Diagnosis: Partial mole Ultrasonography:
Abnormal gestational sac
The classic vesicular sonographic findings of a complete mole are usually not seen
Focal sonographic cystic changes and/or hydropic changes in the placenta are significantly associated with the diagnosis of a partial molar pregnancy
Partial mole

27. Hydatidiform Mole Diagnosis:
Ultrasonography:
However, based on ultrasound, correct diagnosis can be suspected in only:
84% of patients with complete mole and
30% of patients with partial mole
(Lindholm and Flam, 1999)
The accuracy of ultrasonogrophy is gestational age dependent
In comlete mole:
100% of cases cane be diagnosed at a gestational age of 13 eeks or more
50% of cases cane be diagnosed in earlier pregnancies
(Lazarus et al, 1999)

28. Hydatidiform Mole Diagnosis: Serum hCG levels:
Serum hCG levels of greater than IU/l associated with absent fetal heart beat indicate a diagnosis of complete hydatidiform moles (Romero et al, 1985)
Serum hCG level decreases quickly if the patient has an abortion, but it does not in molar pregnancy

29. Hydatidiform Mole Diagnosis: Histopathological examination:
It should always be done as far as possible and samples should be kept for DNA analysis for a final diagnosis when histology can not differentiate molar pregnancy from abortion

30. Table3: Pathological features of complete and partial hydatidiform mole
Complete Mole
Partial Mole
Macro-scopically
A mass of large, edematous villi that are diffusely distributed, typically described as resembling a cluster of grapes
The placental tissue is less bulky
A few enlarged villi with a focal distribution
A fetus may be identified grossly that often has multiple congenital anomalies including syndactyly of the fingers & toes

31. The grape like vesicles in gross appearance

32. Table3: Pathological features of complete and partial hydatidiform mole
Complete Mole
Partial Mole
Micro-scopically
Enlarged edematous villi which show a central acellular fluid-filled space referred to as a “central cistern”
Abnormal trophoblastic proliferation that is circumferential in contrast to normal villi in which trophoblastic proliferation is at one end of the villus
Absence of fetal tissue
Two distinct populations of villi. One with large, edematous villi with central cisterns. The other contains small villi that show some degree of stromal fibrosis
Abnormal circumferential trophoblastic proliferation
Irregular, scalloped outline to some of the villi, often referred to as “fjord-like” which appear in other microscopic as islands of trophoblast in the interior of villi referred to as trophoblastic pseudoinclusions which are highly suggestive of the diagnosis
Fetal tissue, RBSs

33. Normal villi from first trimester placenta, showing directional, polar growth of trophoblast from one end of the villi toward the basal plate.

34. Villus from a complete mole demonstrating the characteristic large, acellular central
cistern

35. Villus from a complete mole
Villus from a complete mole. There is florid, circumferential hyperplasia of the trophoblast around the periphery of the villi

36. Low power view of a partial hydatidiform mole showing the two distinct populations of villi. Asingle large villus with multiple smaller villi

37. Partial mole, showing irregular, scalloped outline and trophoblastic pseudoinclusion

38. Partial Mole Complete Mole
Table3: Pathological features of complete and partial hydatidiform mole
Partial Mole
Complete Mole
Cytogenetics
69, XXX triploidy most common
2+ paternal haploid sets & 1 maternal haploid set
46, XX diploidy most common
All chromosomes of paternal
origin
Pathology features
Hydropic villi
Trophoblastic
proliferation
Fetus or fetal rbcs
Focal, variable
Focal, usually slight
Usually present
Diffuse, often marked
Diffuse, variable intensity
Absent
Clinical course
Clinical or ultrasound
diagnosis
Uterus large for
gestational dates
Theca lutein cysts
Pre-eclampsia
Hyperemesis
Thyrotoxicosis
Malignant sequelae
Rare
<5%
Rarely metastatic
Persistent mole
>50%
25–50%
25–35%
10–20%
5–10%
20%
10–20% metastatic
25–33% choriocarcinoma

39. Hydatidiform Mole Management:1
Complete history and physical examination 2
Investigations
Medical and surgical care 3

40. Hydatidiform Mole Management: History and physcal examination:
Should aim to rule out the classic symptoms and signs that would lead to a diagnosis of:
severe anemia
dehydration
preeclampsia
thyrotoxicosis
The patient should be stabilized hemodynamically 

41. Hydatidiform Mole Management: Investigations: Laboratory: Imaging:
Pre-evacuation hCG
Complete blood count
Electrolytes, BUN, creatinine
Liver function tests
Thyroid function tests
Imaging:
Pelvic ultrasound
Chest x-ray

42. Hydatidiform Mole Management: Medical care: Correction of: Anemia
Dehydration
Hyperthyroidism
hypertension

43. Suction curettage (with oxytocin or prostaglandin infusion)
Hydatidiform Mole
Management:
Surgical care:
Suction curettage (with oxytocin or prostaglandin infusion)
The method of choice
Hysterectomy
Increased risk of medical complications
Associated with a markedly decreased rate of malignant sequelae (3.5%) when compared with suction evacuation.

44. Hydatidiform Mole Complications associated with molar pregnacy:
Those related to the increased trophoblastic tissue volume:
Theca-lutein cysts
Pregnancy-induced hypertension,
hyperthyroidism,
Respiratory distress
Hyperemesis
Those related to its management:
Uterine perforation

45. Hydatidiform Mole, complications
Theca-lutein cysts:
Prevalence:
Clinically evident theca lutein cysts (usually >5–6 cm) are detected in about 25-35% of women with molar pregnancies
Association:
They usually correlate with marked elevation of serum hCG levels above 100,000 IU/l
Complications:
Pain or pressure that may require percutaneous aspirations.
Torsion, rupture, or bleeding are rare complications that can require oophorectomy
Bilateral theca letein cysts increase the risk of post-molar GTD
Course:
The mean time for theca luteal cysts to regress is approximately 8 weeks

46. Hydatidiform Mole, complications
Respiratory distress syndrome:
Prevalence:
Rare
Pathophysiology:
Embolization of trophoblastic tissue
Transient impairment of left ventricular function during induction of anesthesia for suction D&C of molar pregnancy
coexisting conditions such as anemia, hyperthyroidism, hypertension from preeclampsia
Risk factors:
Uterine size larger than 14 to 16 weeks’
High levels of hCG

47. Hydatidiform Mole, complications
Respiratory distress syndrome:
Presentation:
Tachypnia and tachycardia following evacuation
Bilateral pulmonary infiltrates on chest x-ray
Management:
Central venous monitoring
Ventilatory support
Course:
It should resolve within 24 to 48 hours after molar evacuation

48. Hydatidiform Mole, complications
Hyperthyroidism:
Prevalence:
Clinical hyperthyroidism is seen in less than 10% of patients with molar pregnancies
A small number of patients may have elevated thyroid function tests without clinical evidence of disease
Management:
Beta-blockers should be administered prior to molar evacuation to prevent thyroid storm that may be induced by anesthesia and surgery.

49. Hydatidiform Mole A hydatidiform mole and a co-existent fetus:
Prevalence:
Rare (1 in 22,000–100,000)
partial moles and twin gestations with co-existent fetuses and molar gestations
Diagnosis:
Usually, by ultrasound
Few, after examination of the placenta following delivery
Complications:
Increased risk of medical complications
Increased risk for postmolar gestational trophoblastic disease
Management:
No clear guidelines for management

50. Hydatidiform Mole
Risk Factors for post-molar gestational trophoblastic disease:
Advanced maternal age
Factors that reflect the volume of trophoblastic tissue:Clinical factors that are associated with
high hCG levels (>100,000 mIU/mL)
uterus large for date,
bilateral theca lutein cysts,
Respiratory distress syndrome after molar evacuation,
eclampsia,
hyperthyroidism,
Uterine subinvolution with post evacuation hemorrhage.
(With any one of these factors or a combination of many, the risk of post-molar GTD has ranges from 25% to 100%)

51. Hydatidiform Mole
Risk Factors for post-molar gestational trophoblastic disease:
The presence of “invasive trophoblast antigen (ITA)” which has 100% sensitivity and specificity for invasive trophoblastic tumors
(Cole et la, 2003)
*There is no correlation between the degree of anaplasia and the risk of post-molar GTD

52. Hydatidiform Mole Prophylactic Chemotherapy:
In one randomized clinical trial, a single course of methotrexate and folinic acid reduced the incidence of postmolar trophoblastic disease from 47.4% to 14.3% (P <.05) in patients with high-risk moles:
hCG levels greater than 100,000 mIU/mL,
uterine size greater than gestational age,
ovarian size greater than 6 cm),
However, the incidence was not reduced in patients with low-risk moles
On the other hand, the use or prophylactic chemotherapy increases the risk of drug resistance
Because of the excellent primary cure rates among women with post-molar GTD, and mortality achieved by monitoring patients with serial hCG determinations and instituting chemotherapy only in patients with postmolar gestational trophoblastic disease outweighs the potential risk and small benefit of routine prophylactic chemotherapy.

53. Hydatidiform Mole Surveillance after molar pregnancy evacuation:
Rationale:
Prompt identification of patients who develop malignant postmolar gestational trophoblastic disease
Method:
Serial quantitative serum hCG determinations using commercially availableassays capable of detecting β-hCG to baseline values(<5 mIU/mL)
Frequency: within 48 hours of evacuation, weekly while elevated and then monthly when undetectable for 6 months in the case of partial moles and 12 months in the case of complete moles
Pelvic examination:
Duration: while hCG is elevated to monitor the involution of pelvic structures and to aid in the identification of vaginal metastasis

54. Hydatidiform Mole Surveillance after molar pregnancy evacuation:
Contraception:
Rationale:
Pregnancy obscures the value of monitoring hCG levels during this interval and may result in a delayed diagnosis of postmolar malignant gestational trophoblastic disease
Method:
Oral contraceptive pills
Advantages:
They do not increase the incidence of postmolar gestational trophoblastic disease
They do not alter the pattern of regression of hCG values
In a randomizedstudy, by Berkowitz et al in 1998, patients treated with oral contraceptives had one half as many intercurrent pregnancies as those using barrier methods, and the incidence of postmolartrophoblastic disease was lower in patients using oral

55. Hydatidiform Mole Surveillance after molar pregnancy evacuation:
What are the characteristics of false-positive hCG values, also known as “phantom hCG”?
False positive hCG assays have been identified recently
Cause: the presence of non-specific heterophil antibodies in the patients’ sera directed against animal antibodies present in commercial kits
Should be suspected if hCG values plateau at relatively low levels and do not respond to therapeutic maneuvers
Evaluation of patients with suspected false positive hCG:
Urinary hCG
Serial dilutions of the serum

56. Hydatidiform Mole Prognosis:
Post-molar gestational trophoblastic disease:
Risk:
Following complete mole: 20%
Following partial mole: 5%
Type:
70% to 90% are persistent or invasive moles
10% to 30% are choriocarcinomas
Diagnosis:
A rising, plateauing, or persistent elevation of human chorionic gonadotropin after evacuation of a hydatidiform mole or an ectopic or term pregnancy

57. The current FIGO criteria for diagnosis of post-molar GTD
Hydatidiform Mole
The current FIGO criteria for diagnosis of post-molar GTD
a) Four values or more of hCG documenting a plateau (±10% of hCG value) over at least 3 weeks: days 1, 7, 14, and 21.
b) A rise of hCG of 10% or greater for 3 values or longer over at least 2 weeks; days 1,7 and 14.
c) The presence of histologic choriocarcinoma.
d) Persistence of hCG 6 months after mole
evacuation.

58. Pregnancy after Hydatidiform Mole:
Risk of another molar pregnancy:
Increased by 10-fold (1–2% incidence)
Current recommendations for management of subsequent pregnancies:
an early ultrasound to confirm normal gestational development and dates
A chest x-ray to screen for occult metastasis masked by the hCG rise of pregnancy
Examination of the placenta or products of conception histologically at the time of delivery or evacuation for evidence of occult trophoblastic disease
An hCG level should be obtained 6 weeks post evacuation or delivery to confirm normalization.