Diagnosis and management of gestational trophoblastic diseases

1. 1
GESTATIONAL
TROPHOBLASTIC
DISEASES
BY
DR. AYODELE, NOSRULLAH S
FMC, BIRNIN KEBI

2. OUTLINE
 INTRODUCTION
 EPIDEMIOLOGY
 PREDISPOSING FACTORS
 CLASSIFICATION
 AETIOPATHOGENESIS
 HISTOPATHOLOGY
 CLINICAL PRESENTATION
 DIAGNOSTIC CRITERIA
 MANAGEMENT
 CONCLUSION
 REFERENCES
2

3. INTRODUCTION
 Gestational trophoblastic diseases (GTD)
constitute a spectrum of tumours and tumour-
like conditions characterized by abnormal
proliferation of pregnancy associated
trophoblastic tissue of varying propensities for
invasion and spread 1
 These diseases are characterized by a reliable
tumour marker - β-subunit of human chorionic
gonadotropin (β-hCG)
3

4. INTRODUCTION
 Gestational trophoblastic neoplasia (GTN) refers
to the subset of gestational trophoblastic disease
that develops malignant sequelae. 2
 These are evident by persistent elevation of beta
human chorionic gonadotrophin (βhCG) 3
4

5. INTRODUCTION
 WHO classified GTD into the following 4
1. Molar pregnancies (Hydatidiform mole)
 Complete hydatidiform mole
 Partial mole
 Invasive mole
2. Non-neoplastic lesions
 Exaggerated placenta site
 Placenta site nodule and plaque
5

6. INTRODUCTION
3. Gestational trophoblastic neoplasms (GTN)
 Gestational choriocarcinoma
 Placenta site trophoblastic tumour (PSTT)
 Epithelioid trophoblastic tumour (ETT)
4. Abnormal (nonmolar) villous lesions
6

7. EPIDEMIOLOGY
 Variation in the incidence of GTD occurs globally
 Prevalence is higher in Asia compared to
Europe 5. E.g
 Japan = 2 per 1000 deliveries
 Europe = 0.6 - 1.1 per 1000 deliveries
 West Africa = 0.81 - 4.9 per 1000 deliveries
 Nigerian studies
 Port Harcourt = 2.3 per 1000 deliveries 5
 ABUTH, Zaria = 7.2 per 1000 deliveries 6
7

8. EPIDEMIOLOGY
 Choriocarcinoma
 1 in 30,000 pregnancies in western world
 1 in 300 to 1000 in Nigeria
8

9. PREDISPOSING FACTORS
 Age: <20y (2fold) , > 40y(10 fold) & >50y (17%
V.mole)
 Prior spontaneous miscarriage: doubles risk
 Prior Molar Pregnancy- 1 episode (1%), 2
episodes (23%)
 Diet: Vit. A deficiency, low carotene intake
(complete mole)
 Contraception : COCP double the risk
 Repetitive H. moles in women with different
partners
9

10. PREDISPOSING FACTORS
 Partial moles have been linked to:
 Higher educational levels
 Smoking
 Irregular menstrual cycles
 Only male infants among the prior live births
10

11. HYDATIDIFORM MOLE
11

12. AETIOPATHOGENESIS
 Hydatidiform moles are abnormal pregnancies
characterized histologically by aberrant changes
within the placenta
 The chorionic villi in these placenta show
varying degrees of trophoblastic proliferation
and oedema of the villous stroma
 They are categorized into complete and partial
hydatidiform moles
12

13. AETIOPATHOGENESIS
 COMPLETE HYDATIDIFORM MOLE
13

14. AETIOPATHOGENESIS
 COMPLETE HYDATIDIFORM MOLE
14

15. AETIOPATHOGENESIS
 PARTIAL HYDATIDIFORM MOLE
15

16. HISTOPATHOLOGY OF
COMPLETE MOLES
 Complete hydatidiform mole are abnormal
pregnancies characterized
 Macroscopically by:
 Clusters of vesicles with variable dimensions like
“bunch of grapes“
 No foetal or embryonic tissue are produced
 This mass of placental tissue completely fills the
endometrial cavity
16

17. HISTOPATHOLOGY OF
COMPLETE MOLES
 Uterine enlargement in excess of gestational age
 Theca-lutein cyst associated in 30%
 Microscopically by
 Enlarged, oedematous villi
 Abnormal trophoblastic proliferation that diffusely
involve the entire villi
 No foetal tissue, RBCs or amnion are produced
17

18. HISTOPATHOLOGY OF
COMPLETE MOLES
18Grape-like fluid-filled clusters of chorionic villi as seen
in complete mole

19. Normal term placenta showing smaller, non-edematous villi and
absence of trophoblastic proliferation
HISTOPATHOLOGY OF
COMPLETE MOLES

20. HISTOPATHOLOGY OF
COMPLETE MOLES
20
Complete moles characterized by diffuse placental villous oedema, which produces villous
enlargement and cistern formation in some villi
Villous
enlargement
Trophoblastic
proliferation

21. HISTOPATHOLGY OF PARTIAL
MOLE
 Macroscopically:
 The molar pattern does not involve the entire
placenta.
 Uterine enlargement in excess of gestational age is
uncommon.
 Theca-lutein cysts are rare
 Foetal or embryonic tissue or amnion are present
 Chorionic sac wall, amnion, umbilical cord and
embryonic/foetal tissue are common
21

22. HISTOPATHOLGY OF PARTIAL
MOLE
 Microscopically partial moles are characterized
by:
 Two populations of villi, one hydropic and one
"normal“
 Minimal syncytiotrophoblast hyperplasia.
 Enlarged cavitated villi.
 Other villi with scalloped borders, often containing
trophoblastic inclusions.
 Stromal blood vessels often contain nucleated foetal
red blood cells
22

23. HISTOPATHOLGY OF PARTIAL
MOLE
23
Macroscopic appearance of partial mole

24. HISTOPATHOLGY OF PARTIAL
MOLE
24
Micrograph of partial mole

25. HISTOPATHOLGY OF PARTIAL
MOLE
 Features of complete versus partial moles
25
Feature Complete Mole Partial Mole
Karyotype 46,XX 46XY Triploid
(69XXX,XXY,XYY)
Villous edema All villi Some villi
Trophoblast proliferation Diffuse, circumferential Focal, slight
Atypia Often present Absent
Serum B hCG Elevated Less elevated
HCG in tissue ++++ +
Fetus/embryo/RBC Absent Present
Typical diagnosis Molar gestation Missed abortion
Post molar malignant
sequelae
15% 4-6%

26. CLINICAL PRESENTATION OF
MOLAR PREGNANCY
 The classic features are:
 Irregular vaginal bleeding
 Anaemia
 Hyperemesis
 Excessive uterine enlargement
 Early failed pregnancy.
 Breathlessness (due to anaemia)
 Abdominal pain
26

27. CLINICAL PRESENTATION OF
MOLAR PREGNANCY
 Rarer presentations include:
 Hyperthyroidism
 Early onset pre-eclampsia
 Abdominal distension due to theca lutein cysts
 Very rarely
 Acute respiratory failure
 Neurological symptoms such as seizures (?metastatic
disease).
27

28. INVASIVE HYDATIDIFORM MOLE
(Chorioadenoma destruens)
 This is a common manifestation of GTN
 It is characterized by whole chorionic villi that
accompany excessive trophoblastic overgrowth and
invasion.
 These tissues penetrate deep into the myometrium,
sometimes to involve the peritoneum, adjacent
parametrium, or vaginal vault.
 The moles are locally invasive, but not metastatic
 Originate almost exclusively from complete or
partial molar gestations 28

29. HISTOPATHOLOGY OF
INVASIVE MOLE

30. GESTATIONAL
TROPHOBLASTIC NEOPLASIA
(GTN)
30

31. GESTATIONAL
CHORIOCARCINOMA
 A malignant, trophoblastic tumour consisting of a
trimorphic proliferation of intermediate
trophoblastic cells, syncytiotrophoblast and
cytotrophoblast, in the absence of chorionic villi.4
 It may occur subsequent to
 a molar pregnancy (50% of instances),
 an abortion (25%),
 a normal gestation (22.5%)
 An ectopic pregnancy (2.5%)
 May occur de novo (germ cell tumour) 31

32. GESTATIONAL
CHORIOCARCINOMA
 Macroscopically
 The choriocarcinoma is classically a soft, fleshy,
yellow-white tumour with a marked tendency to
form large pale areas of ischemic necrosis, foci
of cystic softening, and extensive hemorrhage
32

33. GESTATIONAL
CHORIOCARCINOMA
 Microscopically
 Diffusely infiltrative or solid masses of cohesive sheets
of trimorphic malignant trophoblast consisting of
intermediate trophoblast and cytotrophoblast, rimmed
with syncytiotrophoblast
 Presence of haemorrhage and necrosis
 Presence of lymphovascular invasion
 Cytological atypia (generally striking)
 Numerous mitotic figures
 No intrinsic stromal and vascular elements (makes it a
unique malignant solid tumour) 33

34. HISTOPATHOLOGY OF
CHORIOCARCINOMA
34
Gestational choriocarcinoma. Sagittal section demonstrates a bulky, destructive, haemorrhagic and
necrotic mass involving the uterine corpus with extension into the cervical canal

35. HISTOPATHOLOGY OF
CHORIOCARCINOMA
35
Cytotropho
blast
Syncytiotro
phoblast
Intermediate
trophoblast

36. CLINICAL PRESENTATION OF
CHORIOCARCINOMA
 Vaginal bleeding and/or extra-uterine
haemorrhage
 Non gynaecological symptoms
 Lungs – pleuritic chest pain, cough, hemoptysis,
pulmonary hypertension
 GIT - haemorrhage, hepatomegaly, hepatic rupture
 Urologic – hematuria
 CNS – headache, LOC, neurological deficit
36

37. PLACENTAL SITE TROPHOBLASTIC
TUMOUR (PSTT)
 A trophoblastic tumour consisting of neoplastic
implantation site-type intermediate trophoblast
 It comprise less than 2% of gestational
trophoblastic neoplasms
 May be preceded by a normal pregnancy (1/2),
spontaneous abortion (1/6), or hydatidiform mole
(1/5)
 It tends to infiltrate only within the uterus,
disseminate late in their course and may follow
metastatic course like choriocarcinoma 37

38. HISTOPATHOLOGY OF PSTT
 Macroscopically
 PSTT generally involves the endomyometrium as
nodular, solid masses of 1–10 cm in size.
 Deep myometrial invasion is seen in 50% of the
cases.
 The cut surface of the tumour is usually solid and
fleshy with a white-tan to light yellow colour.
 Focal haemorrhage and necrosis are present in nearly
half of the cases
38

39. HISTOPATHOLOGY OF PSTT
 Microscopically, the tumour cells are
 medium to large sized
 mononuclear, multinucleated or convoluted nuclei with
hyperchromasia
 mild to marked nuclear atypia,
 prominent nucleoli,
 eosinophilic to clear cytoplasm,
 scattered mitoses
 occasional intranuclear inclusions
39

40. 40
HISTOPATHOLOGY OF PSTT
PSTT – coronal section
showing neoplasm
diffusely infiltrating the
uterine wall, atypia and
numerous mitotic
figures

41. HISTOPATHOLOGY OF PSTT
Tumour cells have abundant eosinophilic cytoplasm and marked
cytological atypia with frequent large convoluted nuclei.

42. EPITHELIOID TROPHOBLASTIC
TUMOUR (ETT)
 A trophoblastic tumour consisting of neoplastic
chorionic-type intermediate trophoblast
 Usually occurs in women ranging in age from
15–48 years (mean of 36.1 years)
 Vaginal bleeding or menometrorrhagia are the
most common symptoms
 Antecedent gestations include term pregnancy
in 67%, spontaneous abortion in 16% and
hydatidiform mole in 16% of cases
42

43. HISTOPATHOLOGY OF ETT
 Macroscopically
 Discrete nodules or cystic haemorrhagic masses
deeply invading surrounding structures
 Commonly in the cervix or lower uterine segment
 The cut surface of the tumour is white-tan to brown,
with varying amounts of haemorrhage and necrosis
 Ulceration and fistula formation are not uncommon
43

44. HISTOPATHOLOGY OF ETT
 Microscopically
 nodular growth of medium-sized tumour cells
arranged in nests or cords to large masses
 moderate amount of finely granular, eosinophilic to
clear cytoplasm
 distinct cell membranes
 round nuclei with distinct small nucleoli.
 moderate nuclear atypia
 mitotic count ranges from 0–9 per 10 HPF
 extensive necrosis
44

45. HISTOPATHOLOGY OF ETT
45
The tumour is characterized by geographic necrosis
Area of
necrosis

46. HISTOPATHOLOGY OF ETT
46Nest of tumour cells with a relatively uniform population of mononucleate
intermediate trophoblastic cells surrounded by necrotic debris.

47. NON-NEOPLASTIC LESIONS
47

48. EXAGGERATED PLACENTA
SITE
 It represents part of the spectrum of normal
implantation-site change
 It is associated with normal gestation or
hydatidiform mole and has no specific clinical
symptoms
 It does not alter the overall endomyometrial
anatomy
48

49. EXAGGERATED PLACENTA
SITE
 The lesion consists of an exuberant infiltration of
mononucleate implantation site intermediate
trophoblast, accompanied by multinucleate giant
cells.
49Numerous multinucleated intermediate trophoblastic
cells are present

50. PLACENTA SITE NODULE AND
PLAQUE
 A benign, well circumscribed nodule or plaque
with abundant hyalinized stroma containing
chorionic-type intermediate trophoblast
 Generally an incidental finding in endometrial or
endocervical curettings
 Sometimes detected in a woman being
evaluated for abnormal cervical cytology
 The lesion is nodular, ranging in size from 4–10
mm
50

51. PLACENTA SITE NODULE AND
PLAQUE
 The clinical significance of these lesions is not
known as they have not been studied in detail
51
Well-circumscribed nodule with hyalinized centre surrounded by
chorionic-type intermediate trophoblastic cells.

52. ABNORMAL (NONMOLAR)
VILLOUS LESIONS
 Various non-molar, villous lesions with
histological features simulating a partial
hydatidiform mole
 Clinically presents as missed or incomplete
abortion
 Entities include
 hydropic abortions,
 chromosomal trisomy syndromes,
 digynic triploid conceptions,
 placental mesenchymal dysplasia/ Beckwith-
Wiedemann syndrome
52

53. ABNORMAL (NONMOLAR)
VILLOUS LESIONS
 Macroscopically: They vary from normal gross
findings to discernible vesicle formation
 Microscopically:
 Chorionic villi often display some degree of irregularity
in size and shape
 focal, mild, trophoblastic hyperplasia (syncytio)
53

54. DIAGNOSTIC CRITERIA
 Clinical history e.g.
 amenorrhoea,
 vaginal bleeding,
 passage of vesicles,
 hyperemesis
 Examination
 uterus large for date, doughy feel
 Others
54

55. DIAGNOSTIC CRITERIA
Investigations
 β hCG measurement
 excess of that expected for the gestational age
 criteria for the diagnosis of GTN
 Ultrasonography (vaginal or abdominal)
 diffuse swelling and enlargement of the chorionic villi
 snow-storm appearance
 absent / present fetal tissue
55

56. DIAGNOSTIC CRITERIA
 Histopathology –as discussed above
 Ploidy determination (cytometry) – determination of
complete set of chromosomes
 Immunostaining - p57KIP2 (a nuclear protein) is
absent in complete moles
56

57. OTHER INVESTIGATIONS
 Chest x-ray – as baseline, Canon ball
appearance in choriocarcinoma
 FBC
 LFT
 TFT
 E/U/Cr
 Clotting profile – exclude coagulopathy
 Blood group, rhesus factor, cross matching
57

59. DIAGNOSTIC FEATURES OF GESTATIONAL TROPHOBLASTIC
TUMOURS

60. STAGING OF GTN
 GTN is anatomically staged according to FIGO
adopted system
 WHO modified prognostic scoring system is
used to further classify patients on risks of drug
failure
 Those with WHO scores of 0 to 6 are considered
to have low-risk disease, score of 7 or higher are
assigned to the high-risk GTN group
60

61. STAGING OF GTN
 Roman numeral corresponding to FIGO stage is
separated by a colon from the sum of all the
actual risk factor scores, for example, stage II:4
or stage IV:9
 The addition of risk scoring to anatomic staging
has been shown to best reflect disease
behaviour 2
61

62. FIGO STAGING OF GTN
Stage Characteristics
I Disease confined to the uterus
II GTN extends outside the uterus but is
limited to the genital structures
(adnexa, vagina, broad ligament)
III GTN extends to the lungs, with or without
known genital tract involvement
IV All other metastasis
62
FIGO – International Federation of Gynaecology and Obstetrics

63. The common site
of metastases
are
Lung(80%)
vagina(30%)
pelvis(20%)
liver(10%)
brain(10%)

64. MODIFIED WHO PROGNOSTIC SCORING
SYSTEM (as adapted by FIGO)
64
Scores 0 1 2 4
Age (yr) <40 ≥40 - -
Antecedent pregnancy Mole Abortion Term -
Interval months from index
pregnancy
<4 4-6 7-12 >12
Pretreatment serum (B-hCG
(mIU/ml))
<103 103-<104 104-<105 ≥105
Largest tumour size (including
uterus)
<3cm 3-4cm ≥5cm -
Site of metastasis - Spleen,
Kidney
GI Liver,
brain
Number of metastasis - 1-4 5-8 >8
Previous failed chemotherapy
drugs
- - 1 ≥2
Low risk = score of 0-6 High risk = score of ≥7

65. MANAGEMENT OF MOLAR
PREGNANCY
 There are 2 important basic lines
 Evacuation of the mole (suction curettage)
 Regular follow-up to detect persistent trophoblastic
disease
 If both basic lines are done appropriately,
mortality rates can be reduced to zero.
 Hysterectomy may be recommended if
 patient wishes for surgical sterilization
 patient is approaching menopause
65

66. MANAGEMENT OF MOLAR
PREGNANCY
 there is excessive bleeding
 some cases of invasive mole or PSTT
 For partial mole, evacuation method depends on
size of foetal part
 Small foetal part - suction curettage
 Large foetal part – medical (oxytocic) – safe, risk of
embolism is very low, reduces need for chemotherapy
to 0.1-0.5%
66

67. SURGICAL EVACUATION
 Prerequisites
 Patient should be well evaluated and treated for
associated medical problems before surgery,
 Blood should be made available (esp for large moles)
 IV live should be established
 Procedure to be done in the theatre under GA
67

68. SURGICAL EVACUATION
 Cervix is dilated to admit a 10- to 12-mm plastic
suction curette
 Suction commenced
 I.V oxytocin infusion is started .
 Gentle curettage is done after evacuation
 The curette is gently rotated to ovoid perforation
of the soft uterus
 Anti D Ig is given to Rh negative women (not
necessary in complete mole)
68

69. POST EVACUATION
SURVEILLANCE
 After the uterus has been evacuated :
 About 85% of cases ,the trophoblastic tissue die out
completely.
 About 15% of cases the trophoblastic tissue does not
die out completely and may persist or recur as
invasive mole or choriocarcinoma.
 This makes follow up important for early
recognition of persistent trophoblastic disease.
 Also to know when pregnancy can be allowed
69

70. POST EVACUATION
SURVEILLANCE
 Postmolar surveillance is done with serial
quantitative serum β-hCG levels
 A baseline serum β -hCG level is obtained within
48 hours after evacuation.
 Levels are monitored every 1 to 2 weeks until
they become undetectable (<5mIU/ml)
 β –hCG is subsequently monitored monthly
70

71. OPTIMUM FOLLOW-UP AFTER
DIAGNOSIS OF GTD
 6 months from the date of uterine evacuation
 If hCG has reverted to normal within 56 days of the
pregnancy event 3
 6 months from normalisation of the hCG level
 If hCG has not reverted to normal within 56 days of
the pregnancy event 3
71

72. OPTIMUM FOLLOW-UP
AFTER DIAGNOSIS OF GTD
 Effective contraception should be used during
the process of follow up
 Condom used till hCG normalizes 3
 COCP may be used afterwards 3
 Avoid IUCD until hCG normalizes 3
72

73. INDICATION FOR CHEMOTHERAPY
 Serum hCG >20000 i.u/L , at any time after
evacuation of mole
 Raised hCG at 4 to 6 weeks after evacuation of
mole
 Evidence of metastases, hepatic, brain and
pulmonary
 Persistent uterine hemorrhage after evacuation
of mole with raised hCG levels.
73

74. MANAGEMENT OF GTN
74

80. CONCLUSION
Gestational trophoblastic diseases are a group of
tumours and tumour-like disorders of pregnancy
which when appropriately and diagnosed early
may lead to hundred percent cure rates even in
the metastatic variants. Therefore, healthcare
professionals should be well acquainted with their
diagnosis and proper management in order to
prevent undue maternal morbidity and mortality.
80

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2016 Apr 22.
3. Royal College of Obstetricians and Gynaecologists. Management
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4. Robert J, Kurman ML, Simon Herrington C, Young RH. WHO
classification of tumours of female reproductive organs. Lyon,
France: WHO. 2014:69-73.
5. Nyengidiki TK, Bassey G, Inimgba NM, Orazulike NC, Amadi C. A
five-year review of gestational trophoblastic diseases in Port
Harcourt, Nigeria. Port Harcourt Medical Journal. 2016;10(1):18-24.81

82. REFERENCES
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82

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