Gestational Trophoblastic

Disease (GTD)

By
Ahmed Refaat Abd ELzaher

Assistant Lecturer of Medical Oncology

South Egypt Cancer Institute
2015
 GTD Overview
• Heterogeneous group of related lesions
• Arise from abnormal proliferation of trophoblast of
the placenta
• Can follow any gestational event – abortion,
miscarriage, ectopic, normal pregnancy
• Unique because the maternal lesions arise from
fetal (not maternal) tissue
• Most GTD lesions produce (B-hCG)
• Can be cured even in the presence of widespread
metastases
 Overview
Hydatidiform Mole:
• Complete
• Partial
** Benign
Gestational Trophoblastic Neoplasia (GTN):
• Persistent/Invasive Mole
• Choriocarcinoma
• Placental-Site Trophoblastic Tumor (PSTT)
** Malignant
 Relationship of HM. IM. CH
hydatidiform therapeutic or
mole spontaneous abortion
term pregnancy
ectopic

invasion mole choriocarcinoma.

Hydatidiform mole
 Hydatidiform Mole
• North America: 0.6-1.1 per 1000 pregnancies
• Asia: 2-10 per 1000 (3x Western countries)
• Difference possibly related low dietary intake
of carotene (vitamin A deficiency) and animal
fat
• More common at reproductive extremes in
age (>35y or <20y)
 Hydatidiform Mole
Risk Factors:
• History of previous GTD
– If one previous mole, 1% chance of recurrence
(vs. 0.1% in general population)
– If 2 previous moles, risk of recurrence increases
to 16-28%
• Smoking
• Vitamin A deficiency
• Blood type:
– A or AB are at slightly higher risk than those with
type B or O
 Hydatidiform mole

1. Complete mole

23X 23X
23X
sperm empty egg
46,XX

23Y 23X 23X

23Y
sperm sperm empty egg
46,XY
 Hydatidiform mole
2. Partial mole

23X
23Y 23X 23X
23Y 23X
sperm sperm normal egg
69,XXY

23X
23X 23X 23X
23X 23X
sperm sperm Normal egg
69,XXX
 Hydatidiform Mole
Clinical Manifestations:
• Vaginal bleeding (97%) /anemia
• Enlarged uterus (size > dates)
• Pelvic pain
• Theca lutein cysts
• Hyperemesis gravidarum
• Hyperthyroidism
• Preeclampsia <20 weeks gestation
• Vaginal passage of hydropic vesicles
• Partial mole usually presented as incomplete or
missed abortion
 Diagnosis
• Complete :
U/S usually very sensitive – generalized
swelling (snow-storm )

• partial mole
U/S may detect focal cystic spaces of varying
diameter
Diagnosis on histology of curettings
 Complete vs. partial mole
Feature Complete Partial
Karyotype Diploid(usually Triploid
46,xx or rarely (69,xxx or 69,
46,xy) xxy)
Swelling of chorionic villi diffuse focal
Trophoblastic hyperplasia diffuse focal
Embryonic tissue absent Present
hCG Often > 100,000 usually<
100,000
Trophoblastic sequelae 15 - 20% <5%
Theca lutein cysts Up to 25% Rare

Medical complications Up to 25% Rare

Uterine size 50% large for dates Small for dates
 Hydatidiform Mole Treatment
• Evaluate for coexisting conditions:
- History and physical
- CBC, coagulation profile, serum chemistry
- thyroid function
- blood type and cross match
- chest radiography
- pelvic ultrasonography
• Evacuation of mole
- Suction curettage
- Hysterectomy if completed childbearing
• If Rh negative, give rhogham
Hydatidiform Mole Treatment

chemotherapy
HM don’t need usually chemotherapy
because HM is benign disease.
Follow-Up Care – Molar Pregnancy
• 80% of patients cured by evacuation
• Follow B-hCG levels every two weeks until 3 consecutive tests
negative
• Then monthly B-hCG every month for 6-12 months
• More than half of patients will have complete regression of
hCG to normal within 2 months of evacuation.
• Avoid pregnancy for at least 6 months after first normal B-hCG
(oral contraceptive pills is preferable)
• Subsequent Pregnancies:
– Send placenta for pathology
– Check B- hCG 6 weeks postpartum
 Prognosis
• Complete mole has the latent risk of local
invasion or telemetastasis
• The high-risk factors includes
– β-HCG>100000IU/L
– uterine size is > 20 weeks size.
– the luteinizing cyst is >6cm
– If >40 years old,the risk of invasion and metastasis
may be 37%, If >50 years old,the risk of invasion
and metastasis may be 56%.
– repeated mole: the morbidity of invasion and
metastasis increase 3~4 times
Gestational Trophoblastic Neoplasia
(GTN)
• Persistent/Invasive Mole
• Choriocarcinoma
• Placental-Site Trophoblastic Tumor (PSTT)
** Malignant
 Risk Factors for GTN After Mole
• Preevacuation uterine size greater than
gestationl age or larger than 20 weeks
gestation
• Theca-lutein cysts larger than 6 cm
• Age > 40 years
• Serum hCG levels > 100,000 mIU/mL
• Previous hydatidiform mole
 Invasive Mole
• Myometrial invasion by hydatidiform mole
• Formerly known as chorioadenoma destruens
• 1 in 15,000 pregnancies
• 10-17% of hydatidiform moles will progress to
invasive moles
 Persistent Mole
Definition of persistent molar disease and need for
chemotherapy (at least one of the following):
– B-hCG plateau for ≥ 4 values for ≥ 3 weeks
– B-hCG increase of ≥ 10% for ≥ 3 values for ≥ 2
weeks
– B-hCG persistence 6 months after molar
evacuation
– Histopathologic diagnosis of choriocarcinoma
– Presence of metastatic disease
 Choriocarcinoma
• Most aggressive type of GTN
• Abnormal trophoblastic hyperplasia
• Absence of chorionic villi
• Direct invasion of myometrium
• Most often develops from a complete
hydatidiform mole
• Vascular spread to distant sites:
– Lungs
– Brain
– Liver
– Pelvis and vagina
– Spleen, intestines, and kidney
 Choriocarcinoma
• May come from any type of pregnancy
- 25% follow abortion or tubal pregnancy
- 25% with term gestation
- 50% from hydatidiform moles
• 2-3% of moles progress to choriocarcinoma
• Incidence 1 in 40,000 pregnancies

– Rarely, choriocarcinomas can develop in other parts of the

body in both men and women. These are not related to
pregnancy as ovaries and testicles
• Nongestational choriocarcinoma tends to be less
responsive to chemotherapy and has a less favorable
prognosis than the gestational variant
 Placental-Site Trophoblastic Tumor
(PSTT)
• Originate from intermediate cytotrophoblast
cells
• Secrete human placental lactogen (hPL)
• B-hCG often normal
• Less vascular invasion, necrosis and
hemorrhage than choriocarcinoma
• Lymphatic spread
• Arise months to years after term pregnancy
but can occur after spontaneous abortion or
molar pregnancy
 Placental-Site Trophoblastic Tumor
(PSTT)
• Most common symptom is vaginal bleeding
• Tend to:
- Remain in uterus
- Disseminate late
- Produce low levels of B-hCG compared to
other GTN
- Be resistant to chemotherapy (treat with
surgery)
 Signs & Symptoms GTN
• Continued uterine bleeding, uterine
perforation, enlarged irregular uterus,
persistent bilateral ovarian enlargement
• From metastatic lesions: abdominal pain,
hemoptysis, melena, increased intracranial
pressure (headaches, seizures, hemiplegia),
dyspnea, cough, chest pain
 Diagnosis of GTN
• Increase or plateau in B-hCG after molar
pregnancy
• Pathologic diagnosis by D&C or biopsy of
metastatic lesions
• WARNING: biopsy of metastatic lesions can
result in massive hemorrhage
• Metastatic workup: CXR (or CT chest), CT
abdomen/pelvis +/- CT/MR of brain
 Classification & Staging of GTD
• FIGO Staging
– Describes anatomic distribution of disease
• World Health Organization (WHO) Scoring
Index
– Describes prognosis
 FIGO Staging
Stage Description
I Disease confined to the uterus

II Disease extends outside the uterus but

limited to genital structures (adnexa,
vagina, and broad ligament)
III Disease extends to the lungs with or
without genital tract involvement
IV Disease involves any other metastatic sites
The World Health Organization (WHO) scoring
system for GTD
 WHO Prognostic Score Index
Score
Characteristic 0 1 2 4
Age <40 ≥40 - -
Antecedent preg Mole Abortion Term -
Pregnancy to <4 4-6 7-12 months >12 months
treatment months months
Interval (months)
Pretreatment hCG <103 103- 104 104-105 >105
Largest tumor size < 3cm 3-4 cm ≥5cm -
(including uterus)
Site of metastases Lung Spleen, GI tract Liver, brain
kidney
Number of metastases - 1-4 5-8 >8
Previous failed - - Single drug ≥2 drugs
chemotherapy
 Therapy for GTN
• Single agent therapy for nonmetastatic
(stage I) or low-risk metastatic (stage II and
III) with score <7  survival rates ~ 100%
• Combination chemotherapy +/- radiation
and/or surgery for high-risk metastatic
disease with score ≥7
 Therapy: Nonmetastatic GTN
• Single-agent with either methotrexate or
dactinomycin
• Chemotherapy continued until hCG values normal
and then 2-3 cycles beyond
• Change to alternative single-agent for hCG plateaus
above normal or toxicities
• If significant elevation of hCG or new metastases,
switch to multiagent
• 85-90% cured with initial regimen, <5% will require
hysterectomy for cure
 Therapy: Low-risk Metastatic GTN
• Low-risk metastatic disease can be treated
with single-agent therapy with 5-day
regimens
• Cure rates ~100% but 30-50% will be develop
resistance to first agent
• If resistance to sequential single-agent
chemotherapy (5-10% of patients), switch to
multiagent chemotherapy
 Therapy: High-risk Metastatic GTN
• Stage IV
• Stage II/III with score > 7
• Disease refractory to single-agent chemotherapy

Combination Chemotherapy:
• EMACO:
– Day 1: Etoposide, Methotrexate and Dactinomycin
– Day 8: Cyclophosphamide and Vincristine
(Oncovorin)
– Repeat q2 weeks until remission
– Continue for at least 2-3 cycles beyond first normal
hCG
• MAC (Methotrexate, Dactinomycin, Cyclophosphamide)
• EMA/EP – EMA + Etoposide and Cisplatin
 Metastatic Gestational Trophoblastic Tumors

• Surgery
– It is indicated for tumor resistant to
chemotherapy and single metastases persisting
despite chemotherapy.
• RT
– RT, in combination with chemotherapy, is clearly
indicated for the primary management of patients
with brain metastases.
 PSTT Therapy
• Hysterectomy
• Chemotherapy for metastatic disease or
nonmetastatic disease with poor prognosis:
- Interval from index pregnancy > 2 years
- Deep myometrial invasion
- Tumor necrosis
- Mitotic count > 6 per 10 high-power fields
• Survival rates:
– ~100% for nonmetastatic disease
– 50-60% for metastatic disease
 Follow-up Care
• After completion of chemotherapy, follow
serial hCG every 2 weeks for three months,
then monthly for one year
• Physical examinations every 6-12 months and
imaging as indicated
 Reproductive Performance
• Most women resume normal ovarian
function
• Women who undergo chemotherapy are
advised not to conceive for one year after
completion of treatment
• No increase risk of stillbirths, abortions,
congenital anomalies, prematurity, or major
obstetric complications
 False Positive Serum hCG
• Phantom hCG syndrome/ phantom
choriocarcinoma
• 3-4% of healthy individuals have human-antimouse
antibodies that can mimic hCG immunoreactivity
• To verify:
– Urine hCG should be negative
– Should not show parallel decrease with serial dilutions
– Test at national B-hCG reference lab
 Summary
• Hydatidiform mole is a benign condition, 80%
cured with suction D&C
• Malignant GTN:
– Persistent or invasive mole
– Choriocarcinoma
– PSTT
• WHO score > 7 represents high-risk disease
• GTN very sensitive to chemotherapy
Thank You For Your Time