gestational trophoblastic tumors

2. GR

3. 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

4. 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

6. Epidemiology
 It is common in oriental countries- Philippines, China,
Indonesia, Japan, India, Central and Latin Americaand 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 occurafterany type of pregnancy 3% after
invasive mole; 16% after CM

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

8. Homozygous 85%
Pathogenesisof complete H Mole

9. Heterozygous 15%
Pathogenesisof complete H Mole

10. Pathogenesisof Partial H. Mole

11. 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 inf lammation &
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

12. 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

13. Complete Molar Pregnancy

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

15. 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

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

17. Anti-D Prophylaxis (RCOG)
NOT required in Complete Mole: becauseof poor
vascularisationof the chorionicvilli and absenceof the
D-antigen.
Required in:
-partial mole: due to presence of RBCs
-complete mole: if diagnosis is notconfirmed
histopathologically.

18. 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 heav y bleeding or curative if the
recurrent molar tissue is confined to the uterine
cavity

19. 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

20. 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 h CG 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.

21. 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 upare unavailableorunreliable.
HIGH RISK FACTORS:
. hCG level >100,000 mIU/ml
. Excessive uterineenlargement
. Theca lutiencysts 6 cm in diameter

22. 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.

23. 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
intraabdominal 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

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

25. 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 thedecidua, myometrium, & spiral arteries.
 Mainly from intermediate trophoblast derived fm cytotrophoblast

26. Metastatic Gestational Trophoblastic
Neoplasia
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

27. 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

28.  Microscopic: implanting blastocyst with central cores
of
mononuclear cytotropho surrounded by rim of
multinucleated syncytiotrophoblast & distinct absence of
chorionicvilli extensive areas of necrosis & haemorrage
&frequentevidence 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

29. 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 f luid
 PET
 Genetic studies

30. 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.

31. Metastatic disease
Sites: Symptoms:
a. Pulmonary- Chest pain, dyspnoea
80%
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.

32. 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 orwithout
known genital tract involvement
IV. All other metastatic sites

33. 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
103-104
5 cm
7-12 > 12
Pretreatment hCG
(mlU/ml)
< 103 > 104-105 > 105
Largest tumour size,
including uterus
3-4 cm
Site of metastases Spleen,
kidney
GI tract
Single
Brain, liver
Previous failed
chemotherapy
Two or more
drugs
Low risk (Score 0-6) and high risk (score> 7)

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

35. 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)

36. 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 courseof 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

37. Role of hysterectomy in non metastatic
disease i.e. Stage-I
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

38. 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.

39. 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.

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

41. 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
Day 8
Actinomycin D 500 micrograms IV push new IV
Etoposide 100 mg/m2 over 30-50 min.
Folinicacid 15 mg IV push Q 6 hrs for 8 doses
beginning 24 hrs after methotrexate bolus.
Vincristine (Oncovin) 1 mg/m2 IV
Cyclophosphamide 600 mg/m2 IV
SIDE EFFECT:- Myelosuppresion ,Mucositis , Neuropathy ,Reversible
alopecia

42. . 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.

43. 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.

44. 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 embolisationof hypogastricarteries

45. 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

46. . 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.

47. 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.

48. 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

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

50.  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

51. HCG FOLLOW UP CURVE
12000
10000
8000
6000
4000
2000
0

52.  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