GESTATIONAL

TROPHOBLASTIC
DISEASES
REPRODUCTIVE HEALTH I
CLINICAL MEDICINE CLASS
DEFINITION
• Gestational trophoblastic disease (GTD) encompasses a spectrum of
proliferative abnormalities of trophoblasts associated with
pregnancy.
• These are diseases arising from the trophoblastic tissue.
• The trophoblastic tissue consist of synciotrophoblast and
cytotrophoblast
• Persistent GTD (persistently raised β-hCG) is referred as gestational
trophoblastic neoplasia (GTN).
TYPES OF GTDs
• Hydatidiform Mole
• Invasive Mole
• Choriocarcinoma
• Placental Site Tumor
HYDATIDIFORM (VESICULAR) MOLE
DEFINITION
• It is an abnormal condition of the placenta where there are partly
degenerative and partly proliferative changes in the young chorionic
villi.
• These result in the formation of clusters of small cysts of varying sizes.
• Because of its superficial resemblance to hydatid cyst, it is named as
hydatidiform mole.
• It is best regarded as a benign neoplasia of the chorion with malignant
potential.
HYDATIDIFORM MOLE
INCIDENCE
• Hydatidiform Mole is the commonest of these diseases.
• 80% of GTD
• Characterized by swelling of placental villi, proliferation of
trophoblast, absence of normal fetus
• In Taiwan the incidence is 1:125 deliveries
• USA 1:1500 deliveries
• Kenya 1:370 deliveries
• The incidence of choriocarcinoma in Kenya is 1: 847
HYDATIDIFORM MOLE
ASSOCIATED FACTORS
• More common at ages below 20yrs and above 40yrs
• Low socioeconomic status
• Low protein and low folic acid diets
• Occur in less than 5%of subsequent pregnancy
• A blood group A woman with a group O spouse has a x10 higher risk
• Blood group AB have a poor prognosis
HYDATIDIFORM MOLE
PATHOLOGY
• The uterus is distended by thin walled, translucent, grape-like vesicles of different
sizes.
• These are degenerated chorionic villi filled with fluid.
• There is no vasculature in the chorionic villi leads to early death and absorption
of the embryo.
• There is trophoblastic proliferation, with mitotic activity affecting both syncytial
and cytotrophoblastic layers.
• This causes excessive secretion of hCG, chorionic thyrotrophin and progesterone.
• On the other hand, estrogen production is low due to absence of the fetal supply of
precursors.
• High hCG causes multiple theca lutein cysts in the ovaries in about 50% of cases.
• It also results in exaggeration of the normal early pregnancy symptoms and signs.
HYDATIDIFORM MOLE
TYPES
• Complete mole
• The whole conceptus is transformed into a mass of vesicles.
• No embryo is present.
• It is the result of fertilization of anucleated ovum ( has no
chromosomes) with a sperm which will duplicate giving rise to 46
chromosomes of paternal origin only.
HYDATIDIFORM MOLE
PARTIAL MOLE
• A part of trophoblastic tissue only shows molar changes.
• There is a fetus or at least an amniotic sac.
• It is the result of fertilization of an ovum by 2 sperms so the
chromosomal number is 69 chromosomes.
HYDATIDIFORM MOLE
SYMPTOMS
• Amenorrhea usually of short period (2-3 months).
• Exaggerated symptoms of pregnancy especially vomiting.
• Vaginal bleeding which is usually dark brown and may be associated
with passage of vesicles.
• Abdominal pain: may be:-
• dull-aching due to rapid distension of the uterus
• colicky due to starting expulsion
• sudden and severe due to perforating mole
HYDATIDIFORM MOLE
GENERAL EXAMINATION
• Pre-eclampsia develops in 20% of cases, usually before 20 weeks’
gestation.
• Hyperthyroidism develops in 10% of cases manifested by enlarged
thyroid gland, tachycardia and elevated plasma thyroxin level.
• Breast signs of pregnancy.
HYDATIDIFORM MOLE
Abdominal examination
• The uterus is larger than the period of amenorrhoea in 50% of cases,
corresponds to it in 25% and smaller in 25% with inactive or dead mole.
• The uterus is doughy in consistency
• Foetal parts and heart sound cannot be detected except in partial mole.
Local examination
• Passage of vesicles (sure sign).
• Bilateral ovarian cysts (5-20 cm) in 50% of cases.
HYDATIDIFORM MOLE
INVESTIGATIONS
• Urine pregnancy test is positive in high dilution. 1/200 is highly
suggestive, 1/500 is surely diagnostic. In normal pregnancy it is
positive in dilutions up to 1/100.
• Serum b -hCG level is highly elevated ( > 100.000 mIU/m1).
• Ultrasonography reveals The characteristic intrauterine " snow
storm" appearance, no identifiable fetus, bilateral ovarian cysts may
be detected.
• X-ray shows no fetal skeleton.
HYDATIDIFORM MOLE
COMPLICATIONS
• Haemorrhage.
• Infection due to absence of the amniotic sac.
• Perforation of the uterus.
• Pregnancy induced hypertension
• Hyperthyroidism.
• Subsequent development of choriocarcinoma
HYDATIDIFORM MOLE
TREATMENT
• As soon as the diagnosis of vesicular mole is established the uterus
should be evacuated.
• The selected method depends on
• the size of the uterus
• whether partial expulsion has already occur or not
• the patient's age and fertility desire
• Cross - matched blood should be available before starting.
HYDATIDIFORM MOLE
Suction evacuation
• It is carried out under general anaesthesia, but not that which relax
the uterus as halothane as it may induce severe bleeding.
• An infusion of 20 units oxytocin in 500 m1 of 5% glucose should be
maintained throughout the procedure.
• Dilatation of the cervix is done up to a Hegar's number equal to the
period of amenorrhoea in weeks e.g. No. 10 Hegar for 10 weeks’
amenorrhoea.
• The suction canula used will be of the same size also.
HYDATIDIFORM MOLE
• A suction canula which may be metal or a disposable plastic
(preferred) is introduced into the uterine cavity.
• The canula is connected to a suction pump adjusted at negative
pressure of 300-500 mmHg according to the duration of pregnancy.
• Although some recommended a gentle sharp curettage to the uterus
after evacuation, it is preferable to wait one week for fear of uterine
perforation
HYDATIDIFORM MOLE
HYSTEROTOMY
• It may be needed for evacuation of a large mole to minimise and
facilitate control of bleeding.
HYSTERECTOMY
• It should be cosidered in women over 40 years who have completed
their family for fear of developing choriocarcinoma.
HYDATIDIFORM MOLE
MEDICAL INDUCTION
• Oxytocins and / or prostaglandins may be used to encourage expulsion of the mole
but must always be followed by surgical evacuation.
FOLLOW UP
• As choriocarcinoma may complicate the vesicular mole after its evacuation,
detection of serum ß-hCG by radioimmunoassay for 2 years is essential.
• Detection is done every;
• 2 weeks after evacuation to ensure regression of b –Hcg level
then
• every month for one year then
• every 3 months for another year
HYDATIDIFORM MOLE
• Persistent high level indicates remnants of molar tissues which
necessitate chemotherapy ( methotrexate) with or without curettage.
• Hysterectomy is indicated if women had enough children.
• Rising hCG, level after disappearance means developing of
choriocarcinoma or a new pregnancy.
• So combined contraceptive pills should be used for prevention of
pregnancy which can be misleading .
HYDATIDIFORM MOLE
• It is expected that urine pregnancy test is negative 4 weeks after
evacuation and serum b -hCG is undetectable 4 months after
evacuation.
• Early features suggesting residual molar tissue include;
• recurrent or persistent vaginal bleeding
• amenorrhoea
• failure of uterine involution, persistence of ovarian enlargement
INVASIVE MOLE(CHORIOADENOMA
DESTRUENS)
• This is a Hmole that has invaded into the myometrium
• Diagnosis is made histologically from hysterectomy spacemen
PLACENTAL SITE TROPHOBLASTIC
TUMOR (PSTT)
• It is a rare histological diagnosis.
• Syncytiotrophoblastic cells are generally absent.
• The tumor arises from the intermediate trophoblasts of the placental
bed and is composed mainly of cytotrophoblastic cells.
• Patient presents with vaginal bleeding.
• Local invasion into the myometrium and lymphatics occurs.
• PSTT is not responsive to chemotherapy.
• Hysterectomy is the preferred treatment.
GESTATIONAL TROPHOBLASTIC
NEOPLASIA/TUMOUR
• Persistent/invasive mole 20% of complete moles, 0.5% of partial
moles
• Choriocarcinoma as a result of mole, abortion, term, ectopic
pregnancies
• Placental Site Trophoblastic Tumor (PSTT – origin non-villous
trophoblast)
• Epithelioid Trophoblastic Tumor  (ETT – origin intermediate
trophoblast)
GTN
Diagnostic criteria for persistent/invasive mole/choriocarcinoma
• Rising (rise of >20% in level between any two measurements) or
plateau levels of serum β-HCG (<10% fall in hCG with 4
measurements over 3 weeks).
• Serum βHCG elevated 6 months post-evacuation.
• Histological evidence of choriocarcinoma at any site.
• Non-pulmonary metastases.
• Persistent bleeding despite repeat evacuation.
GTN
FIGO STAGING WITH MODIFIED WHO SCORING FOR GTN
• A patient’s diagnosis is allocated to a stage AND score e.g. stage II: 4 or stage IV: 9. This
should be documented in the patient’s file.
STAGING FOR GTN
Stage I Disease confined to the uterus.
Stage II GTN extends outside of the uterus, but is limited to the genital structures
(adnexae, vagina, broad ligament).
Stage III GTN extends to the lungs, with or without known genital tract involvement.
Stage IV All other metastatic sites.

SCORE: The total score for a patient is obtained by adding the individual scores for each
prognostic factor. Total score 0-6 = low risk; ≥7 = high risk.
Prognostic factors 0 1 2 4

Age (years) < 40 ≥ 40    

Previous pregnancy Mole Abortion Term  

Months since last <4 4-6 7-12 >12

pregnancy
Pretreatment βHCG (IU/L) <1,000 1,000-10,000 10,000-100,000 >100,000

Largest tumour size <3 3-5 >5  

including uterus (cm)

Site of metastases Lung Spleen/kidney GI Brain/liver

Number of metastases 0 1-4 5-8 >8

Previous failed     1 drug ≥ 2 drugs

chemotherapy
GTN
INVESTIGATIONS
• Serum βHCG levels, FHG, UECs, LFTs, HIV, blood group, GXM.
• Consider TSH, VDRL.
• Ultrasound of abdomen and pelvis
• CXR
• IF CXR or CT Chest positive do CT Brain
GTN
MANAGEMENT
Low Risk Patients
• Single agent chemotherapy
• Methotrexate or Actinomycin D.
High Risk Patients
• Multi-agent chemotherapy: EMA-CO
• EMA (Etoposide, Methotrexate & Actinomycin D)
• CO (Cyclophosphamide, Vincristine)
OR
• Surgery
GTN
Surgery
• Hysterectomy (with the option of concurrent chemotherapy) is
indicated when:
• Drug resistance to chemotherapy AND disease confined to uterus

• Emergency procedure where there is uncontrollable haemorrhage.

• Completed childbearing
• Local resection of easily accessible or chemo-resistant solitary
metastases.
GTN
LOW RISK (FIGO SCORE 0-6)  SINGLE AGENT CHEMOTHERAPY
• Actinomycin D 1.2 mg/m2 [1.5mg] IV every second week OR
• Methotrexate 50mg/m2 [75mg] IM weekly
• Continue cytotoxics until βHCG negative and administer at least 2
additional cycles after βHCG level is negative.
• If serum βHCG level “plateaus” or rises, change to multiple agent
chemotherapy.
• Chest x-ray signs may take 6 months to return to normal.
GTN
HIGH-RISK (FIGO SCORE > 7)  EMA-CO MULTIPLE AGENT CHEMOTHERAPY
It consists of 2 parts:
• EMA (Etoposide, Methotrexate & Actinomycin D) is given on days 1 and 2.
• CO (Cyclophosphamide, Vincristine) is given on day 8.
• EMA requires overnight admission, CO does not.
• Next EMA-CO cycle starts on day 15.
• Patients should have bloodwork evaluation prior to the start of each cycle.
• Repeat cycles until serum βHCG level is negative and administer 2 additional
cycles.
  CHEMO DOSE
Day 1 Etoposide 100 mg/m2 [150mg] IV infusion in

EMA
200 ml NS over 30 min

Actinomycin D 0.5 mg IV stat

Methotrexate 300 mg/m2 [450mg] in 1l NS over 12
hrs

Day 2 Etoposide 100 mg/m2 [150mg] IV infusion in

200 ml NS over 30 min

Actinomycin D 0.5 mg IV stat

Leucovorin 15 mg IM OR
15 mg PO BD for 4 doses beginning
24 hours after starting methotrexate.

Day 8 Cyclophosphamide 600 mg/m2 [900mg] IV in NS

CO

Vincristine 1 mg/m2 (max 2 mg) [1.5mg] IV stat

Day 15   Draw blood for βHCG level, FHG, UECs, LFTs.
Repeat 8 day cycle of EMA-CO
GTN
FOLLOW UP AFTER TREATMENT
• βHCG weekly until normal for 3 consecutive weeks, then monthly for
12 months.
• Ensure reliable hormonal contraception for one year.
GTN
• Managing Placental Site Trophoblastic Tumour (PSTT)/Epithelioid
Trophoblastic Tumour (ETT)
• Refer to Gynae-Oncology
• Individualize treatment
• Surgery is the cornerstone of treatment.
• Chemo and radiotherapy are occasionally indicated.
PERSISTENT GESTATIONAL
TROPHOBLASTIC DISEASE
• Persistent GTD is defined where there is persistence of trophoblastic
activity as evidenced by clinical, imaging, pathological and/or
hormonal study following initial treatment.
• This may be following treatment of hydatidiform mole, invasive mole,
choriocarcinoma or placental site trophoblastic tumor.
PERSISTENT GTD
The diagnostic features are:
• Continued vaginal bleeding.
• Persistent theca lutein cysts.
• Persistently soft and enlarged uterus.
• hCG titers either fail to become negative or remain plateau or there is
reelevation after a initial fall by 8 weeks postmolar evacuation. Local or systemic
metastases should always be excluded (X-ray chest, CT, MRI of brain and liver).
Asymptomatic patients, with a normal chest X-ray, are unlikely to have brain or
other visceral metastasis.
• Pathologically this may be due to invasive mole, choriocarcinoma or placental
site trophoblastic tumor.
POINTS TO REMEMBER
• Do not forget to look for vaginal metastases.
• DO NOT biopsy any metastases in patients with GTN.
• Histology is not required for the diagnosis of choriocarcinoma.
• Single agent prophylactic chemotherapy (+/- hysterectomy) post-
evacuation may be considered in hydatidiform mole, when loss to
follow-up is a high possibility.
• Women with GTD should use the same lab in the measurement of
βHCG in follow-up.
• Women should be advised to seek early prenatal care at the time of the
next pregnancy for ultrasound evaluation and placental pathology
evaluation at time of delivery.