a summary on gestational trophoblastic disease

1. Dr.S.NIVEDHITHA
MSOG IIIrd yr
GRH,MDU

2. Introduction
 Gestational Trophoblastic diseases- heterogeneous
group of interrelated lesions that arise from abnormal
proliferation of placental trophoblast.
 GTN-subset of malignancies that have varying
propensities for local invasion & mets
 GTN-rare human tumors, cured even in the presence
of widespread dissemination

3. WHO Classification
GTD
Premalignant Diseases
 Complete Hydatidiform Mole ( C M )
• Partial Hyadatidiform Mole ( P M )
Malignant Diseases (Gestational Trophoblastic Neoplasia)
Nonmetastatic
• Invasive Mole
• Placental site trophoblastic tumor ( PSTT )
• Epitheloid tumour
• Metastatic
• Gestational Choriocarcinoma

5. Epidemiology
 It is common in oriental countries- Philippines, China,
Indonesia, Japan, India, Central and Latin America and Africa.
 India- 1 in 400 pregnancies
 Calculated Incidence of complete mole- 1 in 1945 pregnancies
partial mole- 1 in 695 pregnancies
 Age -CMs most common at the extremes of reproductive age
 The incidence of CM rises fm I:1000 to 1:76; 1:6.5 in subsequent
pregnancies
 CM is the most common antecedent to
Chorio CA. But it can occur after any type of pregnancy 3% after
invasive mole; 16% after CM

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. Homozygous 85%
Pathogenesis of complete H Mole

8. Pathogenesis of complete H Mole
Heterozygous 15%

9. Pathogenesis of Partial H. Mole

10. GENETICS
 P57 cycline dependent kinase inhibitor paternally
imprinted gene which is maternally expressed
 P57 kip2 immunostaining is negative in CM in contrast
to PMs Hydropic abortions & normal placenta
 Abnormal Methylation
 In cases of Familial recurrent molar pregnancy; Defective
locus at 19q 13.4 at single gene NALP7 , it is member of
CATERPILLAR family involved in inflammation &
Apoptosis in genetic CM
 Three other genes H19, P57, IGF-2
 Chorio CA-specific genes deletion 7p12-q11.2;
Amplification of 7q21-q31 region ; loss of 8p12-p21

11. CLINICAL FEATURES
Complete Mole
 Vaginal bleeding
 Uterus is larger than POG
 Hyperemesis Gravidarum
 PET 10-15%
 hyperthyroidism 7%
 Theca leutin cysts
 Beta h CG levels >>
 Passage of grapes like vesicle

12. Complete Molar Pregnancy

13. High Risk For Developing Post molar tumor
 hCG Levels > 100,000 mIU/L
 Excessive Uterine Enlargement
 Theca leutin cyst 6cm or larger

14. Clinical features
PARTIALMOLE
 Uterus is often not enlarged more than POG
 More often presents as Missed or incomplete
abortion
 Pre evacuation h CG levels are not more than
100,000IU/ L
 Macroscopic : villous swelling is less intense
 Embryo is present

15. Management of Molar Pregnancy
Suction Curettage
Cervical preparation with prostaglandins or
misoprostol should be avoided to reduce the risk
of embolisation.

16. Anti-D Prophylaxis (RCOG)
NOT required in Complete Mole: because of poor
vascularisation of the chorionic villi and absence of the
D-antigen.
Required in:
-partial mole: due to presence of RBCs
-complete mole: if diagnosis is not confirmed
histopathologically.

17. Second uterine evacuation
 There is NO clinical indication for the routine use
of second uterine evacuation.
 It may be useful for symptom control in selected
patients with heavy bleeding or curative if the
recurrent molar tissue is confined to the uterine
cavity

18. FOLLOW UP
HCG:
 weekly determination
of B-HCG until these levels
are normal for 3 consecutive
weeks,folld by monthly values
until normal for 6 consecutive
months
 Average time for first normal
HCG post evacuation is 9 weeks,
 non detectable HCG levels-risk of GTN is 0

19. Contraception
 Should NOT conceive until follow up is complete.
 Use Barrier method until hCG revert to normal
(?OCPs may act as growth factor for trophoblastic
tissue).
 Once hCG has normalised, the combined oral
contraceptive pill may be used.
 IUCD should not be used until hCG levels are
normal to reduce the risk of uterine perforation.

20. Role of prophylactic chemotherapy
 The long term prognosis for women with a H. Mole is
not improved with prophylactic chemotherapy.
Because toxicity- including death- may be significant,
it is not recommended routinely (ACOG 2004).
 It may be useful in the high-risk cases when
follow up are unavailable or unreliable.
HIGH RISK FACTORS:
 hCG level >100,000 mIU/ml
 Excessive uterine enlargement
 Theca lutien cysts 6 cm in diameter

21. Role of hysterectomy
 If the patient desires surgical sterilization, a
hysterectomy may be performed with the mole in
situ.
 Hysterectomy does not prevent metastasis;
therefore, patients will require follow up with
assessment of hCG levels.
 The ovaries may be preserved at the time of
surgery, even in the presence of prominent theca
luiten cysts.

22. Gestational trophoplastic Neoplasia
Nonmetastatic
Invasive Mole:
Clinical features
 Clinical diagnosis by persistence or rising titers of Beta h CG in the weeks
after molar evacuation & USG
 Persistent bleeding p/v
 Lower abdominal pain due to invasion in myometrium, vulva, vagina or
intra abdominal metastasis
 It may spread to adjacent pervic structures bladder , rectum; hematuria,
bleeding P/ R
 Pulmonary metastasis
 Mostly due to initial diagnosis of CM is missed & not on Beta h CG follow
up

23. Invasive H. Mole
Myometrial invasion
Sometimes involving the peritoneum, parametrium, or
vaginal vault. Originate almost always from H. mole
Vesicles

24. Clinical features
Placental Site Trophoblastic Tumor (PSTT):
 rare slow growing tumor
 menstrual irregularities & lower abdominal pain, galactorrhea due to
hyperprolactinemia increased h PL
 Little or no h CG is produced ( Free B hCG fragment )
 Rarely presents as nephrotic syndrome, hematuria or DIC
 Spread is late local Infiltration & metastasis is through lymphatic
 Microscopically: In the normal placenta it is distinct from villous
trophoblast & infiltrates the decidua, myometrium, & spiral arteries.
 Mainly from intermediate trophoblast derived fm cytotrophoblast

25.  GTN arises when the normal regulatory mechanisms controlling
the proliferation and invasiveness of trophoblastic tissue are
lost.
 Diagnosis of the GTN is made on
 Clinical presentation
 Elevated b-HCG
 Evidence of metastasis
 Imaging
 Tissue for Histology
Metastatic Gestational Trophoblastic
Neoplasia

26. Metastatic Gestational Trophoblastic Neoplasia
CHORIOCARCINOMA:
Clinical features
 Occurs mainly following any form of pregnancy, mainly
after CM
 Clinical features of bleeding p/v , lower abdominal pain,
or in 1/3 of cases no pelvic symptoms but symptoms of
distant metastasis lungs , brain ,liver, skin, cauda equina &
the heart may present
 Highly malignant , appears as soft purple largely
hemorrhagic mass

27.  Microscopic: implanting blastocyst with central cores of
mononuclear cytotropho surrounded by rim of
multinucleated syncytiotrophoblast & distinct absence of
chorionic villi extensive areas of necrosis & haemorrage
&frequent evidence of tumor in the sinuses
 The hypervascularity & absence of connective tissue
support are the reason for its highly malignant
behaviour
 DIAGNOSIS IS BY BETA h CG

28. investigations
 Quantitative beta hCG
 X Ray Chest
 Pelvic Doppler USG
 Abdominal doppler USG to rule out liver & renal metastasis
 CT chest , abdomen
 MRI brain
 Beta h CG in cerebrospinal fluid
 PET
 Genetic studies

29. FIGO REQUIREMENT FOR MAKING DIAGNOSIS
OF GTN
1. Four values or more of plateaue hCG over at
least 3 weeks: days 1, 7, 14 and 21.
2. A rise of hCG of 10% or greater for 3 values or
more over at least 2 weeks: days 1, 7, and 14.
3. Histologic diagnosis of choriocarcinoma.
4. Persistence of hCG beyond 6 months after
mole evacuation.

30. Metastatic disease
Sites: Symptoms:
a. Pulmonary-
80%
Chest pain, dyspnoea
b. Vagina- 30% Vagina bleeding , purulent
discharge and nodule.
c. Liver- 10% Epigastric pain, jaundice,
hepatic rupture leading to
intraperitoneal haemorrhage.
d. Brain- 10% Focal neurological deficit.

31. ANATOMIC FIGO STAGING SYSTEM FOR GTN (2000)
Stage Criteria
I. Disease confined to the uterus
II. Disease outside of uterus but is limited to
the genital structures
III. Disease extends to the lungs with or without
known genital tract involvement
IV. All other metastatic sites

32. FIGO prognostic score (2000)
O 1 2 4
Age (years) <39 >39
Antecedent
pregnancy
Hydatidi form
mole
Abortion Term
pregnancy
Interval from index
pregnancy, months
< 4 4-6 7-12 > 12
Pretreatment hCG
(mlU/ml)
< 103 103-104 > 104-105 > 105
Largest tumour size,
including uterus
3-4 cm 5 cm
Site of metastases Spleen,
kidney
GI tract Brain, liver
Previous failed
chemotherapy
Single Two or more
drugs
Low risk (Score 0-6) and high risk (score> 7)

33. GTN
FIGO scoring
Low risk (<6) High risk (> 6)
Single-agent
chemotherapy
Combination
chemotherapy
Serial hCG levels
Resolution
Life-long hCG follow-up
Relapsed/resistant disease
Second-line chemotherapy+ surgical debulking

34. Low Risk GTN
 FIGO score 6 or less.
 Drugs schedules: single agent chemotherapy
Most commonly used regimen.
Methotrexate: 1 mg/kg 1M on days 1, 3, 5, 7
Folinic acid 0.1 mg/kg 1M on days, 2, 4, 6 and 8.
Side Effects: Stomatitis, conjunctivitis, abdominal and
chest pain.
Actinomycin- D: (primary therapy in case of abnormal
liver function)

35. After the first treatment
 Further chemotherapy is withheld as long as the
HCG level is falling progressively
 Additional single agent chemotherapy is not
administered at any predetermined or fixed
interval
II course of CT if:
 If HCG level plateaus for more than 3 consecutive
weeks or begins to rise again
 If HCG level does not decline by 1 log within 18
days of completion of first treatment
 If response to first treatment was inadequate,dose of
MTX is increased from 1mg/kg/day to 1.5 mg/kg/day
for each of the 4 treatment days

36.  If patient does not wish to preserve fertility
hysterectomy with adjuvant single agent
chemotherapy given.
 In case of stage-I PSTT.
 Role of adjuvant chemotherapy.
1. Decrease dissemination of viable tumor cells at
surgery.
2. Maintain cytotoxic level of chem.
3. To treat any occult metastasis
Role of hysterectomy in non metastatic
disease i.e. Stage-I

37. Follow up in Low risk GTN
 Weekly bhCG titre until normal for 3 consecutive
weeks.
 Monthly b HCG level until normal for 12 consecutive
months.
 Effective contraception during the follow up
 FIGO recommends additional 2 courses of
chemotherapy after initial negative b hCG.

38. High Risk GTN
 Stage I, II, III With FIGO score 7 or greater or Stage IV
 Primary intensive combination chemotherapy
 Regimes given :
 MAC.
 Modified Bagshawe (CHAMOCA)
 EMA-CO
 EMA-EP.

39. MAC-III Regime
Mtx 1 mg/kg IM/1V Days 1, 3, 5, 7
Folinic acid 0.1 mg/kg IM Days 2, 4, 6, 8
Actinomycin-D 12 g/kg IV Days 1-5
Cyclophosphamide 3 mg/kg IV Days 1-5
To be repeated every 15 days if toxicity permits.

40. EMA-CO Regime
Etoposide, methotrexate, actinomycin D, alternating weekly with
cyclophosphamide and oncovin.
Day 1 Actinomycin D 500 micrograms IV push
IV. Etoposide 100 mg/m2 over 30-50 min.
Methotrexate 100 mg/m2 IV infusion over 1
hr and then
Methotrexate 200 mg/m2 IV infusion over 12 hrs
Day 2 Actinomycin D 500 micrograms IV push new IV
Etoposide 100 mg/m2 over 30-50 min.
Folinic acid 15 mg IV push Q 6 hrs for 8 doses
beginning 24 hrs after methotrexate bolus.
Day 8 Vincristine (Oncovin) 1 mg/m2 IV
Cyclophosphamide 600 mg/m2 IV
SIDE EFFECT:- Myelosuppresion ,Mucositis , Neuropathy ,Reversible
alopecia

41. EMA-EP
 In patient resistant to EMA-CO
On day 8
 Etoposide- 10 mg/m2 iv.
 Cisplatin- 80 mg/m2 iv
 treatment – until 3 consecutive weekly titres
normal.
 2-4 cycles given further after initial normal b
H.C.G.
.

42. Follow up OF High risk GTN
 Weekly bHCG until normal for 3
consecutive weeks.
 Monthly bHCG for 24 consecutive
months.
 Contraception in follow up period.

43. Management of sites of metastasis
VAGINAL &PELVIS -30%
Single agent chemotherapy –Low risk
Combination chemotherapy –High risk
If bleeding occurs-
Vaginal packing
Wide local excision
Arteriographic embolisation of hypogastric arteries

44. PULMONARY-80%
 Present as – Chest pain, cough, hemoptysis dyspnoea.
 X-ray features- Snowstorm
 Discrete round densities.
 Pleural effusion
 Embolic pattern
 Rx
Single agent chemotherapy-low risk.
Combination – high risk.
Thoracotomy-viable pulmonary
Metastasis following comb chemo

45. HEPATIC-10%
 Worse prognosis.
 Usually associated with widespread metastasis Intraperitoneal
bleeding may occur.
Rx
 Chemo & concurrent radiation (2000-3000 cGy).
 Hepatic resection to excise resistant foci.
Cerebral-10%
 Acute focal neurological deficits.
 Combination chemo + WBRT (2000-3000).
 Patients with metastasis on initial evaluation respond better
than who develop Lesion during therapy.
 During period of WBRT- Mtx in EMA-CO be increased to 1 g/m2
with Folinic.Acid rescue.
.

46.  For subsequent pregnancy.
 Ist trimester TVS to confirm normal pregnancy.
 bHCG 6 wks after termination of pregnancy .
 After effective treatment for non-malignant GTN molar
pregnancy occur in 1-2% subsequent pregnancies.

47. CASES REGISTERED IN GTD
CLINIC,GRH
 Total no of cases-15
 Case 1:
Mrs.Kavitha,28 yr old P2L2A2/MTP with TAT done in
FPAI(8.4.15)/C/O bleeding pv/RPOC with secondary
infection/?invasive partial mole(hcg-1247)-GRH admission-
SE 0n 4.5.15-(hcg-141 on 8.5)
 Pt was on weekly b-hcg follow up until 3 normal
values,monthly follow up until 6 normal values,
 17.02.16-1.02
 16.03.16-120.6
 Started on methotrexate

48. 0
200
400
600
800
1000
1200
1400
HCG FOLLOW UP CURVE

49.  Case 2:latha 19 yr unmarried/molar pregnancy/SE @
GRH on 12.08.15 for molar/presented with bleeding pv
I mth later with severe anemia/re evacuation done for
retained tissues
 In the post molar evacuation surveillance,weekly b-
hcg rising trend-started on single agent CT
 EMACO started

50. HCG FOLLOW UP CURVE
0
2000
4000
6000
8000
10000
12000
19-09-15
26-09-15
03-10-15
10-10-15
17-10-15
24-10-15
31-10-15
07-11-15
14-11-15
21-11-15
28-11-15
05-12-15
12-12-15
19-12-15
26-12-15
02-01-16

51.  Case 3:
 Mrs,nambuselvi,42 yr old primi/ms 22 yrs/13 wks
GA/partial molar pregnancy/SE done
 Pre evacuation B-HCG-1,14,560
 Chest x ray-S/O tiny nodular opacity in left midzone
 Pt transferred to med onco in view of invasive mole
 Single agent CT-MTX