Gestational trophoblastic disease (GTD) includes invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. These develop after molar or non-molar pregnancies. Treatment depends on disease stage and risk score. Low-risk GTD is treated with single-agent chemotherapy like methotrexate or actinomycin D. High-risk GTD receives multi-agent chemotherapy like EMA/CO. Residual masses may require additional treatment. Relapsed or resistant GTD can be treated with salvage chemotherapy, surgery, or high-dose chemotherapy with stem cell transplant. Side effects depend on chemotherapy drugs used.

1. GESTATIONAL TROPHOBLASTIC
DISEASE PART - 2
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2. GESTATIONAL TROPHOBLASTIC
NEOPLASIA
 Accounts < 1% of female reproductive system cancers
 Develops after a molar pregnancy , a live birth or an
abortion/ectopic pregnancy
 Includes :
1. INVASIVE MOLE
2. CHORIOCARCINOMA
3. PLACENTAL SITE TROPHOBLASTIC TUMOUR
4. EPITHELOID TROPHOBLASTIC TUMOUR
2

3. EPIDEMIOLOGY FOR CHORIOCARCINOMA
 Incidence after live birth – 1 in 50,000 pregnancies
COUNTRY INCIDENCE
EUROPE / NORTH AMERICA 1 in 40,000 pregnancies
1 in 40 hydatiform moles
SOUTHEAST ASIA 9.2 / 40,000 pregnancies
JAPAN 3.2 / 40,000 pregnancies
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4. INVASIVE MOLE (CHORIOADENOMA DESTRUENS)
 Always develop from hydatiform mole and not normal pregnancy
 Arise from myometrial invasion ( direct tissue or venous channels)
 Complete mole – 15% 15 % metastasize to lung and vagina
Partial mole – 3 to 4%
 Rest ,
- perforate myometrium :intraperitoneal bleed
- erode uterine vessels : vaginal hemorrhage
- necrotic tumour involve uterine wall :
nidus for bacterial infection
 Microscopic : presence of hydropic villi with trophoblasts extending to
myometrium
 Diagnosed clinically and treated with chemotherapy
4

5. GESTATIONAL NON GESTATIONAL
• Gross : dark or red blackish mass with
hemorrhage
•Seen in both genders
• Microscopic :
- abnormal trophoblastic hyperplasia
- absence of chorionic villi
- hemorrhage and necrosis invading
myometrium
• Develop in ovaries , testicles, chest and
abdomen
• Vascular invasion resulting in spread to
distant sites
• Choriocarcinoma mixed with other types of
cancer forming mixed germ cell tumor
• Lung (80%) , vagina( 30%), pelvis (20%) ,
liver (10%), brain (10%) and others
( spleen , kidney , GIT)
• Less responsive to chemotherapy and less
favorable prognosis
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6. 6

7. PLACENTAL SITE TROPHOBLASTIC TUMOUR
 Extremely rare , slow growing , rarely metastasize
 Mostly follow non molar pregnancy but
seen with hydatiform mole and abortion
 Arise from placental implantation site
 Predominantly of mononuclear intermediate
trophoblasts without chorionic villi infiltrating
myometrial fibres
 Confined to uterus with propensity for lymphatic and late lung, brain
metastasis
 Low levels of hCG compared to tumor burden
 Immunohistochemical staining reveals diffuse presence of cytokeratin and
HPL whereas hcg is only focal
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8. EPITHELOID TROPHOBLASTIC TUMOUR
 Rare variant of GTD
 Behaves like PSTT
 Most often occurs after term pregnancy
but can take several years to occur
 Used to be called as atypical choriocarcinoma
 Can be found growing in cervix , confused with cervical cancer
 Develops from neoplastic transformation of chorionic type
intermediate trophoblasts
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9. CLINICAL FEATURES
 POST MOLAR GTN ( invasive mole or choriocarcinoma)
SYMPTOMS SIGNS
• Irregular vaginal bleeding • Enlarged irregular uterus
• Infection causing vaginal
discharge, pelvic cramps
and fever
• Persistent B/L ovarian
enlargement
• Rarely, intra abdominal
bleeding with severe pain
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10.  METASTASIZE
 Diagnosis of choriocarcinoma should be considered in any
women of reproductive age group presenting with these acute
events
AREA INVOLVED SYMPTOMS
• Pulmonary • Chest pain, cough , hemoptysis, dyspnea
• Vaginal lesions • Fornices or suburetheral region
extremely vascular
• Liver • Epigastric pain or right upper quadrant pain,
Jaundice, hemoptysis
• Brain • Headache,seizures, hemiplegia
10

11. 11

12.  Non molar GTN
- Choriocarcinoma has no characteristic symptoms or sign
( either related to uterus or metastatic sites)
 PSTT & ETT : irregular uterine bleeding
: symmetric uterine enlargement
: symptoms related to metastatic sites
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13. INDICATION OF CHEMOTHERAPY IN GTD
1. Plateaued or rising hCG after evacuation
- Plateau Four or more values over a period of 3 weeks or longer
( 1,7,14, 21 )
- Rise (>10%) during three weekly consecutive measurements or longer during
a period of 2 weeks or more (1,7,14)
2. Elevated hcg 6 months after evacuation even if still falling
3. Histological evidence of choriocarcinoma
4. Evidence of metastasis in brain , liver or GIT , or radiological opacities
>2 cm on chest Xray
5. Pulmonary, vulval or vaginal metastases unless hcg falling
6. Heavy vaginal bleeding or evidence of GI or intraperitoneal
hemorrhage
7. Serum hcg >20,000 IU/L more than 4 weeks after evacuation
( risk of uterine perforation)
13

14. DIAGNOSIS
 History
 Pelvic examination
 Serum ßhcg level
 Pelvic doppler ultrasound
 Chest X-ray
OTHERS
 CT , MRI
 Blood investigations : CBC, LFT, RFT, PS, TFT
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15. 1) History
- Age
- Symptoms
- Duration
- Antecedent pregnancy ( molar or non molar)
- Interval from antecedent pregnancy
- Prior treatment ( evacuation or chemotherapy with single or
multiple agent)
2) Examination
- Pallor
- R/S ( RR or rales on auscultation)
- CNS ( level of consciousness)
- P/A ( uterine enlargement, organomegaly , tenderness, guarding )
- P/S ( bleeding , vaginal/ suburetheral nodules)
- Bimanual ( uterine size and theca lutein cyst)
15

16. 3 ) Pelvic Doppler USG
- volume of uterus measured
- theca lutein cyst and uterine involvement
- molar tissue has low resistance circulation( AV shunting)
- low pulsatile index of uterine artery ( poor prognosis and
predictor of chemotherapy response)
16

17. 4 ) ß hcg
 exists in 2 forms
- ß hcg regular : normal pregnancy
- hcg – H : produced by invasive cytotrophoblast
ß hcg hcg - H
Production Syncytiotrophoblast Invasive cytotrophoblast
Present - Full normal pregnancy
- All forms of GTD
- Implantation phase of normal
pregnancy
- In GTN
Method of action Endocrine Autocrine
Role Maintain progesterone
production
Promotes growth and invasion
of trophoblasts
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18. 5) CHEST XRAY
- Snowstorm appearance
- Discrete rounded densities
- Pleural effusion
- Embolic pattern caused by
pulmonary occlusion
 Negative pelvic examination
and chest Xray – metastasis of
other site uncommon
 If chest X-ray positive :
- CT chest – to find out micrometastasis ( 40%)
- MRI brain – early cerebral lesion , MRI pelvis
- CT abdomen
- Check CSF hcg level, CSF / serum > 1:60 – cerebral metastasis
18

19. PATHOLOGIC DIAGNOSIS
1. Curettage
 Repeat curettage avoided
- To prevent risk of hemorrhage, perforation or infection
- Increase risk of need of chemotherapy ( hcg > 5000 IU/L)
- Unless excessive uterine bleeding and intracavitary , should be
avoided
2. Biopsy of metastatic lesion
( dangerous for vaginal lesion – profuse bleeding)
3. Examination of hysterectomy specimen and placenta
19

20. FIGO ANATOMIC STAGING SYSTEM FOR GTN
 Stage 1 : patients have persistently elevated hcg level and tumor
confined to the uterine corpus
 Stage 2 : patients have metastasis to genital tract
( adnexa, vagina , broad ligament)
 Stage 3 : patients have pulmonary metastases with or without
uterine, vaginal, or pelvic involvement
 Stage 4 : patients have advanced disease and involvement of the
brain , liver , kidneys or GIT 20

21. PROGNOSTIC SCORING AND STAGING
 Prognostic score is central to management of GTN
 Predicts likelihood of developing resistance to single agent
chemotherapy
 Two categories : low risk (0-6)
: high risk (≥7)
 Predicts likelihood of cure
- Low risk: 100%
- High risk : 95%
 Adverse Prognostic factors in high risk group:
- Longer duration from antecedent pregnancy
- Presence of liver metastases
- Combined liver and brain metastasis ( 10% survival)
21

22. 0 1 2 4
 Age (yrs) ≤39 >39
 Antecedent pregnancy Hydatiform
mole
Abortion Term
 Interval b/w end of
antecedent pregnancy
and start of
chemotherapy
( months)
<4 4-6 7-12 >12
 Pretreatment hcg
(IU/L)
<10³ 10³ - 104 104 - 105 >105
 ABO groups O or A B or AB
 Largest tumor,
including uterine (cm)
<3 3-5 >5
 Site of metastases spleen ,
kidney
GIT Brain , Liver
 Number of metastases 1-3 4-8 >8
 Prior chemotherapy 1 drug ≥2 drugs
Low risk:<7 and High risk : >7
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23. TREATMENT
 MEDICAL
 SURGICAL
 RADIATION
23

24. LOW RISK DISEASE
 Includes : stage 1
: stage 2 and 3 , score <7
 single agent chemotherapy with Methotrexate or Actinomycin D
 Fertility desired : single agent chemotherapy resistant ( 20%)
sequential single agent
local uterine resection combination resistant (10%)
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25.  If fertility not desired
- Hysterectomy + adjuvant single agent chemotherapy
- Adjuvant chemo : 1) to prevent dissemination of tumor cells
2) maintain cytotoxic level in case of dissemination
3) treat occult metastases @ the time of surgery
 Chemotherapy continued until hcg normal and at least further 6 weeks
RESISTANCE IN STAGE 1 RESISTANCE IN STAGE 2 -3
• Presence of metastases • Age >35 years
• Clinicopathologic diagnosis of
choriocarcinoma
• FIGO score > 7
• Pretreatment hcg > 50,000 IU/L • Pretreatment hcg > 100,000 IU/l
• Non molar antecedent
pregnancy
• Large vaginal metastases
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26. CHEMOTHERAPY REGIMENS FOR LOW RISK
 Methotrexate and folinic acid – cycle repeated every 14 days
 Remission rate – 70 to 90%
METHOTREXATE FOLINIC ACID
• 1mg/kg IM d 1,3,5,7 • 0.1 mg/kg IM d 2,4,6,8
• 50 mg IM every 48 hrs for total 4
doses
• 15 mg orally 30 hr after each injection
of methotrexate
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27. HIGH RISK DISEASE
 Includes : stage 4
: stage 2-3 , score ≥7
 Initial treatment with multiagent chemotherapy with or without adjuvant
surgery or radiation therapy
 Chemotherapy continued for at least 6 weeks after the first normal hcg
YEAR REGIMEN
•1970s • MAC ( MTX , Act- D, cyclophosphamide) regimen
• early 1980s • CHAMOCA ( Cyclophosphamide , Hydroxyurea , Act-D ,
MTX-FA , Vincristine , doxorubicin) regimen
•1980s • EMA-CO( Etoposide, high dose MTX-FA , Act-D,
Cyclophosphamide , Vincristine) regimen
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28. CHEMOTHERAPY REGIMEN FOR HIGH RISK
DAY DRUG DOSING
1 Etoposide
Actinomycin D
MTX
100mg/m² IV over 30 min
0.5mg IVP
100mg/m² IVP , then
200mg/m² in 500 ml over
12h
2 Etoposide
Actinomycin D
FA
100mg/m² IV over 30 min
0.5mg IVP
15 mg IM or PO every
12 h for 4 doses starting
24 h after MTX
8 Cyclophosphamide
vincristine
600mg/m² IV
1 mg/m² IVP
EVERY 2 WEEKS
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29. RESIDUAL POST TREATMENT MASSES
 After chemotherapy , patients are reimaged
 Pelvic USG and any abnormal investigation at diagnosis
 In USG, presence of uterine vascular malformations are normal and no
intervention needed unless active bleeding
 UAE prevents need of hysterectomy
 Residual brain lesion needs irradiation:
- Whole brain irradiation ( 3000 cGy in 200 cGy fractions) , or
- Surgical excision with stereotactic irradiation with simultaneous
systemic chemotherapy ( EMA –CO with MTX 1mg/m² and FA every 12
hr for 3 days starting 32 hrs after MTX infusion )
- Alternative to brain irradiation, intrathecal MTX with high dose IV MTX
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30.  Residual masses at other sites - not resected and follow up
by standard hcg surveillance
 Liver metastasis – if resistant to combination chemo
: hepatic arterial infusion of chemo
: hepatic resection
: hepatic arterial embolisation
 Complete serological response necessary for cure but
complete radiological response is not
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31. RESISTANT AND RELAPSED HIGH RISK DISEASE
 Relapsed – rising hcg after complete serological response
to EMA/CO ( at least 6 weeks of normal hcg
post chemo)
 Resistant/ refractory – rising or plateau hcg while on
EMA /CO
 FDG – PET ( fluorodeoxyglucose) can be used to find sites of
disease
 Treatment – surgical resection with chemotherapy or
salvage chemotherapy alone 31

32.  Most effective 2nd line regimen
– EMA/EP ( EMA and etoposide plus cisplatin – omits 2nd day dose of
etoposide and ACT-D)
 Less toxic , alternative
– fortnightly regimen of paclitaxel + cisplatin
alternating with paclitaxel + etoposide
 Other drugs – vinblastine, bleomycin, ifosfamide, 5-FU
 High dose chemotherapy with peripheral stem cell transplantation
 New chemotherapy drugs – molecular targeted therapies 32

33. 33

34. SIDE EFFECTS
COMMON SPECIFIC
•Hair loss •Methotrexate : diarrhea, sore throat, stomatitis,
conjunctivitis, abdominal and chest pain , liver damage
-Hair loss and blood effects not seen
•Mouth sores •Actinomycin – D : severe nausea and vomiting, hair loss,
blood effects
•Loss of appetite •Etoposide : leukemia, breast cancer, colon cancer
•Nausea and vomiting •Cyclophosphamide and ifosfamide : nausea and hair
loss, bladder irritation
•Low blood counts •Bleomycin : lung problems
•Advancing age of
menopause :
1 year – single agent
3 yrs – multi agent
•Vincristine and cisplatin : neuropathy
•hearing loss and kidney damage ( persists)
34

35. PSTTS AND ETTS
 Chemoresistant with lymphatic spread
 Standard treatment – hysterectomy with lymph node clearance and
ovarian preservation
 In metastasis, EMA/EP with or without surgical resection
 Most imp prognostic factor : interval from causative pregnancy
- > 4 yrs post pregnancy( high mortality)
- < 4 yrs post pregnancy ( high survival)
 5 reported cases of fertility sparing surgery
- One : successful pregnancy
- Two: long term remission but no term pregnancy
- Two : need for hysterectomy for relapse
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36. FOLLOW UP AFTER CHEMOTHERAPY
 Relapse risk : 3% with maximum in 1st year
 Measure serum hCG weekly after course of chemotherapy
3 consecutive week normal value
low risk high risk
monthly for an year monthly for 2 years
- Physical exam every 3-6 months for first year and then 6
monthly further 37

37. MANAGEMENT OF GTN
Hydatiform mole
Evacuation
serial hcg
level Resolution
6 months follow up
GTN
Figo
scoring
Low risk High risk
Single agent
chemotherapy
Combination
chemotherapy
Serial hcg
level
Resolution
Life long hcg follow up
Relapsed / resistant disease
Second line chemo with or without surgical bulking
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38. CONTRACEPTION AND FUTURE PREGNANCY
 Contraception should be maintained during treatment and for 1 year
after completion of chemotherapy, preferably oral contraceptives
 Helps in uninterrupted hcg follow up
 Permit elimination of mature ova that may have been damaged by
exposure to cytotoxic drugs
 Most women resume ovarian function after chemotherapy
 Had successful pregnancies without increase congenital anomalies but
high risk of abortions and still birth
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39. THANK YOU
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