gestational trophoblastic diseases

1. GESTATIONAL
TROPHOBLASTIC
DISEASES
ATANAZIO CHIFUINRO
MGUNDA
MBBS 5
College of medicine
malawi(Mw)

2. OUTLINE
Definition
embryology
Epidemiology
Classification
Risk factors
Clinical features
Diagnosis
Staging and management
Prognosis and follow-up
Complications

3. DEFINITION
Spectrum of abnormal proliferation of trophoblasts,
ranging from benign to malignant
The trophoblast layer develops into the placenta.
Early in normal development, the cells of the trophoblast
form tiny, finger-like projections known as villi.

4. EMBRYOLOGY
 30hours:fertilization
• Zygote mitotically divides into 2 cells-blastomere
3days: morula formation
• 12-16 blastomeres
4days: blastocyst formation within morula
blastocyst:
• Inner cell mass called embryoblast
• Outer cell mass called trophoblast
Day 6:Implantation
• Blastocyst attaches to endometrial lining,
trophoblasts invade

5. TROPHOBLAST.
By eighth day post fertilization the trophoblast differentiates
into:
1. Syncytiotrophoblast
• outer layer
• Invades endometrial blood vessels
• 2nd week end
• early utero-placental circulation that surrounds conceptus
• the primitive primary secretory component within the placenta
2. Cytotrophoblasts
• inner layer
• 2-3week surrounded by syncytioblast
• forms papillary projections called villi
• Villi functional units of placenta
• transport of oxygen and nutrients
• Cytotrophoblasts are the germinal cells

6. EPIDEMIOLOGY
Incidence of GTDs
1 to 2 per 1,000 deliveries
(South Africa, United States and Europe, Turkey)
higher incidence rates in Asia
40 per 1000
Although recent studies have found 2 per 1000
Reason: population-based vs hospital-based data
collection

7. RISK FACTORS FOR GTDS
Maternal Age
 Teenagers
 7.5 fold higher in > 40years
 Premature and post mature ova
 higher rates of abnormal fertilization
 Older Paternal age implicated
Race
 Hispanics and Native Americans living in USA
 Influence from environment or other factors

8. RISK FACTORS
Obstetric history
 In previous molar pregnancy, 10-fold risk
 Complete moles 20%
 Partial mole 2.9-9.9%
 Double risk in previous spontaneous abortion
Blood group
 Blood group B associated with recurrent molar
 No evidence against rhesus negative group
Smoking
combination oral contraceptive
Vitamin A deficiency

9. WORLD HEALTH ORGANISATION
(WHO) CLASSIFICATION OF
TROPHOBLASTIC DISEASE
Benign
 Hydatidiform mole
 Complete
 Partial
Malignant gestational trophoblastic neoplasia
 Invasive hydatidiform mole
 Choriocarcinoma
 Placental site trophoblastic tumour
 Trophoblastic tumour, miscellaneous
 Exaggerated placental site
 Placental site nodule or plaque
Unclassified trophoblastic lesions

10. BENIGN
Hyatidiform mole(vesicular)
The most common form of GTD
It is made up of villi that are enlarged, edematous and
vesicular
The swollen villi grow in clusters that look like bunches
of grapes
Partial and complete differ in morphology, clinico-
pathology and cytogenic features

11. COMPLETE HYATIDIFORM MOLE
Mole without fetus or embryo
Most often develops when either 1 or 2 sperm
cells fertilize an egg cell that contains no
nucleus or DNA
All the genetic material are paternal.
Therefore, there is no fetal tissue.
Usually diploid, with a 46,XX karyotype, and all
molar chromosomes are paternal in origin.
About 10% have a 46,XY karyotype, which arises
from fertilization by two spermatozoa.

12. COMPLETE MOLE,
PATHOGENESIS
Duplication 46XX
Empty ovum
23X
Diandric diploidy
Androgenesis
Paternal
chromosomes only

13. COMPLETE MOLE,
PATHOGENESIS
46XX
Empty ovum
23X
Dispermic diploidy
Paternal
chromosomes only
23X 23X
23X

14. FEATURES
Edematous chorionic villi in clusters “grape like”
Different sizes
Average size of 1.5cm in diameter
Microscopic features
some enlarged villi show fluid filled space
“Central cistern pattern”
High hCG production

15. COMPLETE MOLAR PREGNANCY

17. PARTIAL HYDATIDIFORM
MOLE
Develops when 2 sperm fertilize a normal egg.
Dispermy, fertilization of an intact ovum by two
spermatozoa 69XXX, 69XXY
Fetus growth restricted and has multiple congenital
malformations often mixed in with the trophoblastic
tissue.
Often associated with severe hypertension
Few enlarged villi and fewer masses of grape like villi.

18. PARTIAL MOLE,
PATHOGENESIS
69XXY
Normal ovum
23X
Dispermic triploidy
Paternal extra set
23Y 23X
23Y 23X
23X

19. PARTIAL HYDATIDIFORM MOLE

20. DIFFERENCES BETWEEN COMPLETE
AND PARTIAL

21. DIAGNOSIS
Symptoms
Amenorrhea
 usually of short period (2-3 months).
Vaginal bleeding
 due separation of vesicles from uterine wall
 Prune juice discharge may occur.
 The blood may be concealed causing enlargement & tenderness of the uterus
 Passage of vesicles is diagnostic.
pre-eclampsia symptoms
 headache, and edema

22. DIAGNOSIS
Symptoms cont,
Abdominal pain
dull-aching- Colicky or Sudden
Hyperemesis gravidarum
 Persistent & excessive nausea & vomiting
 Due to abnormally hCG levels

23. DIAGNOSIS
Signs
Pallor
Pre-eclampsia (20-30% of cases)
 usually before 20 weeks’ gestation
 Eclamptic Convulsions are rare.
Hyperthyroidism(3-10% of cases)
 Persistent tachycardia
 tremors.
 hCG is a glycoprotein similar to TSH with weak thyroid stimulating hormone
Breast signs of pregnancy
 Breast tenderness
 large areolae

24. DIAGNOSIS CONT
Signs
 Per-abdomen
Uterine enlargement more than gestational age(50%)
Absent fetal parts
 The uterus has a doughy feel
Absent FH
 Very rarely a mole & fetus will co-exist
 Partial moles can have a fetal heart
Bilateral ovarian cysts in 50% of cases-theca lutein cyst
Vaginal examination
Passage of vesicles (sure sign).

25. INVESTIGATIONS
Blood related
Quantitative serum ᵦhCG
 Serum b -hCG level is highly elevated ( > 100.000 mIU/m1)
FBC, Blood group & x-match
U&Es & LFTs & TFTs
Imaging
Chest radiograph -metastasis
 cannon ball
 pleural effusion and consolidation
Ultrasound
 snow storm appearance
 no identifiable fetus
Doppler color flow of uterus
CT-scan and MRI-metastasis
Histopathology(if curettage done)

26. INVESTIGATIONS
Blood related
Quantitative serum ᵦhCG
 Serum b -hCG level is highly elevated ( > 100.000 mIU/m1)
FBC, Blood group & x-match
U&Es & LFTs & TFTs
Imaging
Chest radiograph -metastasis
 cannon ball
 pleural effusion and consolidation
Ultrasound
 snow storm appearance
 no identifiable fetus
Doppler color flow of uterus-rule out invasive mole
CT-scan and MRI-metastasis
Histopathology(if curettage done)

27. PARTIAL MOLE: COMPLEX MASS WITH MANY
CYSTIC AREAS (B/T ARROWHEADS) AND AN
EMBRYO (ARROW) IN A PATIENT WITH A Β-HCG
OF 280,000 MIU/ML

28. COMPLETE MOLE
Complete mole:
“snowstorm” appearance
with multiple cystic areas,
no fetal tissue present
Corresponding T1
weighted MRI (MRI can be
helpful in determining
extent of trophoblastic

30. TREATMENT
Mainstay is resuscitation and surgery
Resuscitation
Correction of fluid loss
Blood transfusion for anaemia
Correction of coagulopathy
Carbimazole/ propanol for hyperthyroidism
Surgery
Suction and curettage for a non- invasive mole
No D&C in known invasive mole due to risk of life threatening
Haemorrhage
Hysterectomy
 Patients with Hyatidiform moles who do not want children any more
 Uncontrolled bleeding after evacuation

31. SUCTION, DILATATION AND
CURETTAGEOxytocin infused in IV fluids after the start of
evacuation
continued for several hours to enhance
uterine contractility
Prostaglandins reserved if oxytocin ineffective
Products of conception taken for histological
examination

32. COMPLICATIONS OF
HYDATIDIFORM MOLE.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
 Infection
 Haemorrhage
choriocarcinoma in about 5% of cases
invasive mole in about 10% of cases.
Recurrent mole may occur(1-2%).

33. 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.
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.

34. THECA LUTEIN CYSTS
They are hormone dependent.
Disappear spontaneously after evacuation of the mole.
So, they are not removed surgically unless complication
occur as torsion or rupture

35. ACCORDING TO MALAWIAN
GUIDELINES(2015)
If asymptomatic, then schedule D&E under anesthesia
with oxytocin infusion
misoprostol ready due to high risk of Haemorrhage.
If actively aborting, send patient to theatre immediately
& do D&E, with oxytocin and misoprostol ready.
Give Antibiotics (Doxycycline 100 mg BD x 3 days or
Metronidazole 400 mg BD x 5 days) for prophylaxis
If at high risk for choriocarcinoma, consult medical
oncology

36. THAT’S A MONKEY, NOTHING
TO DO WITH GTDS, DON’T
THINK TOO MUCH

37. CLASSIFICATION OF GESTATIONAL
TROPHOBLASTIC DISEASE
WHO Classification
Malignant
neoplasms of
various types of
trophoblast
Malformations of
the chorionic villi
that are
predisposed to
develop
trophoblastic
malignancies
Choriocarcinoma
Complete
Hydatidiform moles
Epithilioid
trophoblastic tumors
Placental site
trophoblastic tumor
Partial
Invasive

38. MALIGNANT-GTDS AKA GTN
1. Invasive mole (chorioadenoma destruens)
A Hyatidiform mole that has grown into
the muscle layer of the uterus.
Invasive moles can either be complete or
partial
Complete moles become invasive much
more often than partial moles.
Invasive moles develop in a little less
than 1 out of 5 women who have had a
complete mole removed.

39. MALIGNANT GTDS
2. Choriocarcinoma
Invades myometrium and local vasculature to
disseminate haematogenously to the lung (57-80%),
vagina (30%), pelvis (20%), brain (17%), and liver (10%)
Half of all choriocarcinomas start off as molar
pregnancies.
About one-quarter develop in women who have a
miscarriage , intentional abortion, or tubal pregnancy .
Another quarter (25%) develop after normal pregnancy
and delivery.

40. CHORIOCARCINOMA
Symptoms & signs
Bleeding
Infection
Abdominal swelling
Vaginal mass
Lung symptoms
Symptoms from other
metastases

41. MALIGNANT GTDS
3. Placental-site trophoblastic tumor
very rare form of GTD
develops where the placenta attaches to the lining of the uterus.
This tumor most often develops after a normal pregnancy or abortion,
It may also develop after a complete or partial mole is removed.
They do not spread to other sites in the body. But these tumors have a
tendency to invade the myometrium
They are treated with surgery, not sensitive to drugs.

42. MALIGNANT GTDS
4. Epithelioid trophoblastic tumor (ETT)
extremely rare type of GTD
can be hard to diagnose.
It can be found growing in the cervix, to be confused with cervical
cancer.
ETT does not respond very well to chemotherapy the main treatment is
surgery.
It might have already metastasized when it is diagnosed which carries a
poorer prognosis.

43. DIAGNOSIS OF GTN
If following are met after initial evacuation
Plateau of hCG lasting for four
measurements over a period of 3 weeks
 E.g. days 1,7,14,21
Rise in Hcg for 3 weekly consecutive
measurements
Hcg remains elevated for 6months or
more
Histological diagnosis of
choriocarcinoma

44. EARLY FEATURES SUGGESTING
PERSISTENT GTD OR POST MOLAR
SYNDROME
1. Recurrent Or Persistent Vaginal Bleeding
2. Subinvoluation
3. Amenorrhea
4. Persistence of ovarian enlargement.
5. No malignancy in endometrial biopsy

45. INVESTIGATIONS
Blood related
Quantitative serum ᵦhCG
 Serum b -hCG level is highly elevated ( > 100.000 mIU/m1)
FBC, Blood group & x-match
U&Es & LFTs & TFTs
Imaging
Chest radiograph -metastasis
 cannon ball
 pleural effusion and consolidation
Ultrasound
 snow storm appearance
 no identifiable fetus
Doppler color flow of uterus
CT-scan and MRI-metastasis
Histopathology(if curettage done)

46. DOPPLER SCANS
choriocarcinoma Invasive mole “snow storm”

47. CANNON BALL APPEARANCE
ON X-RAY

48. PROGNOSTIC SCORING SYSTEM
 To predict the likelihood of drug resistance
 To assist in selecting appropriate chemotherapy
 Low risk GTD (WHO score 4 or less)
 Intermediate risk GTD (WHO score 5–7)
 High risk GTD (WHO score 8 or more)

49. Modified WHO Prognostic Scoring System
0 1 2 4
Age <40 ≥40 – –
Antecedent
pregnancy
mole abortion term –
Interval months from
index pregnancy
<4 4–6 7–12 >12
Pretreatment serum
hCG (IU/L)
<103 103–104 104–105 >105
Largest tumor size
(including uterus)
<3 3–4 cm ≥5 cm –
Site of metastases lung spleen, kidney gastrointestinal liver, brain
Number of
metastases
– 1–4 5–8 >8
Previous failed
chemotherapy
– – single drug ≥2 drugs

50. SIGNIFICANCE OF WHO
SCORING
WHO score 4 or less
Commence treatment as soon as possible.
A low risk of GTD can be managed with single-agent
chemotherapy using methotrexate with folinic acid.
Other drugs include etoposide.
If single-agent chemotherapy is used and is not working,
a more aggressive treatment is warranted to prevent the
emergence of drug resistance.

51. SIGNIFICANCE OF WHO
SCORING
Intermediate risk GTD (WHO score 5–7)
Commence on regimen that includes combination
chemotherapy
 methotrexate and actinomycin D.
If a complete response is not achieved on this regimen
the patient should be commenced on etoposide,
methotrexate and actinomycin D, alternating with
cyclophosphamide and vincristine (EMA-CO).

52. SIGNIFICANCE OF WHO
SCORING
High risk GTD (WHO score 8 or more)
These patients require significant chemotherapy because
they include those with brain metastases, liver and
gastrointestinal tract metastases and they are at
significant risk from massive bleeding.
A combination of chemotherapy, either EMA-CO or
methotrexate and folinic acid chemotherapy is indicated.

53. FIGO STAGING OF GTN
 Stage I:
 Patients have persistently elevated hCG levels and tumor confined to the uterine
corpus.
 Stage II:
 Patients have metastases to the vagina and pelvis or both.
 Stage III:
 Patients have pulmonary metastases with or without uterine, vaginal, or pelvic
involvement.
 The diagnosis is based on a rising hCG level in the presence of pulmonary
lesions on chest radiograph.
 Stage IV:
 Patients have advanced disease and involvement of the brain, liver, kidneys, or
gastrointestinal tract.
 These patients are in the highest risk category, because they are most likely to
be resistant to chemotherapy.
 The histologic pattern of choriocarcinoma is usually present, and disease
commonly follows a nonmolar pregnancy.

55. TREATMENT
It is important to begin treatment as soon as possible
after GTN has been detected. The main methods of
treatment are:
Chemotherapy
Surgery
Radiation therapy (which is used less often)

56. CHEMOTHERAPY FOR GTD.
Chemotherapy uses anti-cancer drugs , useful for metastasized
GTD.
GTD cancers can almost always be cured by chemo no matter how
advanced it is.
The drugs that can be used to treat GTD include:
· Methotrexate (with or without leucovorin)
· Actinomycin-D (dactinomycin),Cyclophosphamide (Cytoxan®)
· Chlorambucil, Vincristine (Oncovin®)
· Etoposide (VP-16)
· Cisplatin
· Ifosfamide (Ifex®)
· Bleomycin
· Fluorouracil (5-FU

57. CHEMOTHERAPY
Depends on the FIGO scoring
In terms of score < than 6 (low risk)
Single agent chemotherapy
Methotrexate followed by folinic acid rescue
2>cycles after hCG negative
Cure rate of 100%
Score of >7(High risk)
Combination of therapeutic drugs e.g. etoposide, methotrexate, actinomycin-D,
cyclophosphamide, ncovin (EMACO)
3>cycles after hCG negative
Cure rate of 70%
Chemotherapy administered IV
hCG measured after each cycle

58. SIDE EFFECTS OF
CHEMOTHERAPY
depends on the type, dose and duration of drugs given
Common side effects of chemotherapy drugs include:
· Hair loss
· Mouth sores
· Loss of appetite
· Nausea and vomiting
· Low blood counts

59. ROLE OF SURGERY
Secondary role
Chemotherapy is effective in vast majority
Indications
Hysterectomy
 disease confined to uterus
 Placental site trophoblastic tumours
 epithelioid trophoblastic tumors.
Resection of Isolated chemotherapy-resistant nodules
e.g. thoracotomy, craniotomy
Laparotomy for bowel or urinary tract obstruction
Oophorectomy for torsion of ovarian cyst

60. RADIOTHERAPY
For extensive metastases
Brain and liver metastases
In combination with chemotherapy

61. ACCORDING TO MW
GUIDELINES(2015)
Management of choriocarcinoma
• Chemotherapy is first then Refer to medical oncology
• If older and multiparous woman,
 placental site choriocarcinoma
 uterine perforation
 failed chemotherapy
 refer to medical oncology and perform hysterectomy.
Pre-op chemo- for 5 days prevents dissemination
Post-op chemo treats residual and disseminated tissue

62. FOLLOW-UP
Pregnancy is allowed if the test remains negative for one
year.
Persistent high level or Rising hCG level after
disappearance means developing of Choriocarcinoma or
a new pregnancy.
Serum B-hCG is undetectable 4 months after evacuation
Early ultrasound in next pregnancy to rule out GTDs

63. CONTRACEPTION AFTER
GTDS
The combined pill is started when the beta-HCG
becomes negative.
oestrogen stimulates the growth of trophoblast
Till this happens, the condom can be used.
The intrauterine device is not used because it may lead
to irregular uterine bleeding which confuses the follow
up

64. ACCORDING TO MW
GUIDELINES(2015)Follow up of molar pregnancy
Follow up for 2 years
Monthly follow up until urine pregnancy test is negative
Send urine for serial pregnancy tests (should disappear by
6 wks post D&E)
Then follow up every 3 months in 1st year and every 6
months in 2ndyear
Conduct speculum exam of vagina and suburethral area
for metastases
Conduct bimanual pelvic exam
If pregnancy test remains positive at 3 months
Order US to monitor ovarian cyst and residual/invasive
mole
CXR for metastasis
Prescribe family planning, i.e. implants, depo-provera
injections, COC condoms

65. END
“AMAT VICTORIA CURUM”
VICTORY LOVES PREPARATION

66. REFERENCES
Williams Obstetrics, 22nd edition.
TF Kruger, MH botha; Clinical Gynaecology
FIGO 2012; gestational trophoblastic disease
http://www.cancer.org/cancer/gestationaltrophoblasticd
isease/detailedguide/gestational-trophoblastic-disease
http://www.rcog.org.uk/news/new-green-top-
guideline-management-gestational-trophoblastic-
disease
Obstetrics by Ten teachers, 16th edition.
Breech and Novack’s gynaecology fourteenth edition