Management of Gestational Trophoblastic

Neoplasia

A Presentation by OPS Unit

Presenter: Dr A.P. Soibi-Harry
 Outline
• Overview

• Case Report

• Clinical Presentation

• Metastatic Sites

• Diagnosis

• Staging and Risk Assessment

• Treatment

• Follow Up

• Conclusion

• References
 Gestational Trophoblastic
Neoplasia

Gestational Invasive Mole/

Trophoblastic Tumour Chorioadenoma
destruens

Placental Site Epithelioid

Choriocarcinoma Trophoblastic Trophoblastic
Tumour Tumour
 Overview
• GTN are malignant lesions that arise from placental villous and extra-
villous trophoblast.

• They are characterized by a distinct Tumour marker (β-hCG) and have varying
tendencies towards local invasion and distant metastasis

• It occurs in 1:40,000 pregnancies and is more common in Asia than in Europe

or North America, 1 in 205-375 pregnancies in Nigeria.

• Approximately 50% of cases of GTN arise from molar pregnancy, 25% from
miscarriages or ectopic pregnancy, and 25% from term or preterm pregnancy.
 Case Scenario
• A 42yr old G6P5 woman referred to the OB-GYN A/E at 11 weeks' gestation for
suspected molar pregnancy.

• At presentation, the patient complained of a 3/7 history of headache, right-

sided abdominal pain, epistaxis, vaginal bleeding, nausea and vomiting. She
was anxious and diaphoretic, her BP was (148/98), PR 105bpm and RR 28cpm,
chest was clear.

• Abd exam: Enlarged, MWR, No organomegaly, Uterus 20wks size

• VE: V/V smeared with altered blood.

• Investigations:

• Blood PT- Pos

• FBC: Hct: 34%, PLT- 250000mm3

• Serum β-HCG- >500,000mIU/L

• Urinalysis for protein: (neg)

• LFT: ALT 116 (4–36) Iu/L, AST 80 (8–33) Iu/L

• TFT: TSH- 0.07 (0.34–5.6) u[Iu]/mL, T4- 25 (6.0–12.0) ug/L, T3- 291 (87–188) ng/mL, free T4-
4.09 (0.82–1.77) ng/dL, and free T3- 9.7 (2.0–4.4) pg/mL

• EUCR: Normal

• Chest X-ray: Normal

Pelvic USS
 Clinical Presentation
• Amenorrhea • Jaundice

• Pre-evacuation uterine size larger than gestational age
• Bilateral adnexal mass (theca lutein cysts)
• Abnormal uterine bleeding
• Abdominal pain
• Endocrine dx- hyperthyroidism, hyperemesis
• Sub-urethral nodule
• CNS metastases- increased intracranial pressure
leading to headaches, dizziness, seizures, or
hemiplegia.
• Pulmonary metastases- dyspnea, cough, hemoptysis
or chest pain

• Pre-eclampsia • Virilization- male pattern hair growth, deepening of

the voice, or clitoromegaly
 Metastatic sites
• The risk of metastases depends on the histologic type and the duration of disease.

• Pulmonary - 80 %

• Vagina- 30%

• Central nervous system (CNS) metastases – 10%

• Liver - 10%

• Other sites- kidney, gastrointestinal tract and spleen

 Diagnosis- Clinical
• GTN is a clinical diagnosis made based on elevation of serum B-hCG, after a non
molar pregnancy and other aetiologies of an elevated hCG have been excluded.
Unlike other solid tumours, tissue diagnosis is not required prior to treatment.

• Key elements of the diagnostic evaluation are

• To confirm an elevated human chorionic gonadotropin (hCG)

• To evaluate for complications arising from hCG stimulation effects

• To evaluate for metastatic disease

• Uterine curettage or other biopsies have a limited role in the diagnosis of GTN.
 B-hCG Levels as Predictor of Tumour Type
Histologic Sub-type of Tumour B-hCG levels

Invasive Mole 100 to over 100,000 mIu/ml

Choriocarcinoma 100 to over 100,000 mIu/ml

Placental Site Trophoblastic Tumour Undetectable- <1000

Epithelioid Trophoblastic Tumour Undetectable- <1000

 Pelvic USS Findings
Histologic Sub-type of Tumour
Invasive Mole
Choriocarcinoma
Placental Site Trophoblastic Tumour
Epithelioid Trophoblastic Tumour
USS Features
Poorly defined masses in the uterus with anechoic areas.
Color Doppler of the anechoic areas reveals high vascular flow and invasion into the
myometrium may be visualized.
Mass enlarging the uterus, with a heterogeneous appearance that correlates with
areas of necrosis and hemorrhage. The tumor is usually markedly hypervascular on
color Doppler and may extend into the parametrium.
Hyperechoic intrauterine mass, usually with less hemorrhage than observed with
choriocarcinoma. Both cystic and solid lesions can be present, with or without a
central component. The mass usually invades the myometrial wall.
Early Dx- irregular anechoic lacunae within the myometrium, filled with low-resistance,
turbulent blood flow on Doppler.
Late Dx- well-circumscribed echogenic lesion in the uterine fundus, often with no
detectable blood flow on Doppler imaging. Most reported cases of ETT show solitary
nodules with sharp margins on ultrasound.
Invasive Mole
Placental Site Trophoblastic Tumour
Choriocarcinoma
Epithelioid Trophoblastic Tumour
 Other Imagings
• Chest X-ray patterns :
• Discrete rounded densities
• An alveolar or "snowstorm" pattern
• Pleural effusion
• Embolic pattern caused by pulmonary arterial occlusion

• CT of the abdomen and pelvis

• Whole-body 18-fluorodeoxyglucose positron emission tomography (18-FDG-PET) scan

• MRI or CT scan of the brain

• Uterine curettage — Uterine curettage has a limited role in the evaluation of GTN
 FIGO Diagnostic Criteria of GTN
• Following a molar pregnancy
• Weekly hCG levels plateau (remain within ±10% of the previous result) over a three-week
period

• hCG level increases > 10% across three values recorded over a two-week duration

• Persistence of detectable serum hCG for more than six months after molar evacuation

• Following a non molar pregnancy

• Elevated hCG, after excluding other causes (normal or abnormal pregnancy, ovarian mass etc.)

• Examination findings or imaging suggesting metastatic disease

• Histologic result of Endometrial biopsy

 STAGING AND RISK ASSESSMENT
• GTN is staged using a combination of the International Federation of
Gynecology and Obstetrics (FIGO) staging system and the World Health
Organization (WHO) Prognostic Scoring System.

• The final stage is the anatomic stage with the actual prognostic score number
shown together (separated by a colon).

• An example of this is II:5.

 Treatment of GTN

Low High
Risk Dx Risk Dx
Stage I GTN Stage IV GTN

Stage II or III Stages II or III

GTN with WHO GTN with WHO
risk score <7 risk score >6
 Low Risk DX- Drugs and Dosage
Methotrexate Actinomycin D Etoposide Fluorouracil
MTX-FA eight-day “Pulsed"dosing 100 mg/m2, IV, daily for 30 mg/kg daily for 10 days
regimen 1.25 mg/m2 biweekly five days every 10 days every 28 days
MTX five-day regimen IV push 10 to 12ug/kg dly
for five days every other
week
Weekly MTX

Weekly MTX
 Methotrexate Regimens
Methotrexate Dosing

MTX five-day regimen IM or IV MTX, 0.3 to 0.5 mg/kg, for five consecutive days
every two weeks

MTX-FA eight-day regimen IM or IV MTX 1 mg/kg on days 1, 3, 5, and 7.

Oral FA 15mg is administered 24 hours after each dose of
MTX
Weekly MTX IM MTX 30 to 50 mg/m2 (long remission time)

High-dose MTX MTX, 100 mg/m2 IV push, then 12-hour continuous infusion
at 200 mg/m2
Oral FA 15 mg stat 24 hours after the start of the initial MTX
dose then every 12 hours for six doses.
 General Considerations for High Risk Dx
• Multi-agent regimen chemotherapy, is the main treatment modality

• However, primary treatment may be a combination of surgery and chemotherapy

• Radiation therapy (RT) may be indicated

• Treatment may result in ovarian insufficiency

• Oral contraceptives should be administered to suppress the pituitary glands'

production of luteinizing hormone in order to protect the ovaries from the toxicity
and also suppress the pituitary production of (hCG).
 High Risk DX- Drugs Comparison (Deng et al, 2013)

Regimen Constituents Remission Rate Mortality Rate

MA MTX + ActD + FA 63% 37%

CHAMOCA MTX + ActD+ Cyclophosphamide 76% 22%

+ Doxorubicin + Melphalan +Hydroxyurea +
Vincristine

MAC MTX + ActD, + Chlorambucil 68% 33%

EMA-CO Etoposide + MTX+ Leucovorin 91% 9%

+ Cyclophosphamide +
Vincristine
 EMA-CO Regimen
Time Treatment
2
Etoposide 100 mg/m by IV infusion in 200 mL of normal saline over 30 minutes

Dactinomycin 0.5 mg IV push

Day 1 2
Methotrexate 100 mg/m IV bolus followed by
2
Methotrexate 200 mg/m by IV infusion over 12 hours
2
Etoposide 100 mg/m by IV infusion in 200 mL of normal saline over 30 minutes

Dactinomycin 0.5 mg IV push

Day 2
Leucovorin 15 mg IM or orally every 12 hours for four doses beginning 24 hours after
starting methotrexate
2
Cyclophosphamide 600 mg/m IV in normal saline
Day 8 2
Vincristine 1 mg/m IV push
 EMA-EP Regimen
Time Treatment

2
Etoposide 100 mg/m by IV infusion in 200 mL of normal saline over 30 minutes

Dactinomycin 0.5 mg IV push

Day 1
2
Methotrexate 100 mg/m IV bolus followed by
2
Methotrexate 200 mg/m by IV infusion over 12 hours

Leucovorin 15 mg IM or orally every 12 hours for four doses beginning 24 hours after
Day 2
starting methotrexate

2
Cisplatin 75mg/m IV in normal saline
Day 8
2
Etoposide 100 mg/m by IV infusion in 200 mL of normal saline over 30 minutes
 Special Considerations
• Surgery — 50% of patients with high-risk, metastatic GTN will require adjuvant surgery to achieve
cure. Hysterectomy, pulmonary resection, thoracotomy, uterine wedge resection, small bowel
resection, and selective uterine artery embolization, craniotomy etc.

• Patients with brain metastases — modified EMA-CO using MTX (1000 mg/m2 over 24 hours). In
addition, these patients should receive dexamethasone to decrease cerebral edema.

• Consolidation therapy — After complete remission is attained, consolidation therapy should be

administered to prevent relapse. This consists of three courses of the last effective regimen.
 Placental Site/Epithelioid Trophoblastic
Tumour
• PSTT arises from the intermediate trophoblast, usually following a term pregnancy (1–3 years).
Secretes low amount of HCG but high human placental lactogen (HPL) and as such it is not
chemosensitive.

• Immunohistochemistry for ETT- P63 is positive and can be particularly useful to differentiate

• Surgery is the main modality of management as tumours are poorly sensitive to chemotherapy

• Multi-agent regimens are usually administered--EMA-CO and EMA-EP

• Treatment may be monitored with human placental lactogen (HPL) for PSTT

• Patients with metastatic disease have a relatively poor prognosis and a high fatality rate.
 Follow Up
• All women with GTN should be monitored with serial measurements of hCG at the
start of treatment and then at weekly intervals during therapy.

• Posttreatment surveillance — After remission is achieved, hCG should be measured

monthly until monitoring has shown one year of normal hCG levels
• Contraception
• Estrogen-progestin contraceptives are preferred because of their low failure rate and relatively
low incidence of irregular bleeding

• Barrier methods may be used, but have less contraceptive efficacy

• Avoid intrauterine devices because there is a risk of uterine perforation

 Follow Up II
• Resistant disease
• hCG level remains elevated despite chemotherapy

• Recurrent disease
• hCG level re-elevates after becoming undetectable for three consecutive weeks

• Despite the success of combination chemotherapy, patients treated for high-risk gestational trophoblastic
neoplasia (GTN) have an 8 to 10% percent risk of recurrence, dependent on stage and risk score.

• FERTILITY AND PREGNANCY

• Most women will have normal pregnancies

• No increased risk of congenital anomalies

• Surveillance – early uss confirmation, send placenta for histology and monitor hCG at PNC
 Conclusion
• GTN is a rare but curable disease entity, however it is a great
masquerader and therefore requires a high index of suspicion in order
to clinch the diagnosis.
 References
• Kohorn EI. The new FIGO 2000 staging and risk factor scoring system for gestational trophoblastic
disease: description and critical assessment. Int J Gynecol Cancer 2001; 11:73.
• Kohorn EI. Negotiating a staging and risk factor scoring system for gestational trophoblastic
neoplasia. A progress report. J Reprod Med 2002; 47:445.
• Ngan HY, Bender H, Benedet JL, et al. Gestational trophoblastic neoplasia, FIGO 2000 staging and
classification. Int J Gynaecol Obstet 2003; 83 Suppl 1:175.
• Chapman-Davis E, Hoekstra AV, Rademaker AW, et al. Treatment of nonmetastatic and metastatic
low-risk gestational trophoblastic neoplasia: factors associated with resistance to single-agent
methotrexate chemotherapy. Gynecol Oncol 2012; 125:572.
• Kim SJ, Bae SN, Kim JH, et al. Effects of multiagent chemotherapy and independent risk factors in
the treatment of high-risk GTT--25 years experiences of KRI-TRD. Int J Gynaecol Obstet 1998; 60
Suppl 1:S85.
• Deng L, Zhang J, Wu T, Lawrie TA. Combination chemotherapy for primary treatment of high-risk
gestational trophoblastic tumour. Cochrane Database Syst Rev 2013; :CD005196.
• Kolawole AO, Nwajagu JK, Oguntayo AO, Zayyan MS, Adewuyi S. Gestational trophoblastic disease
in Abuth Zaria, Nigeria: A 5-year review. Trop J Obstet Gynaecol 2016;33:209-15.