Gestational Trophoblastic disease

Gestational Trophoblastic

Disease (GTD)

• Dr. Swati Singh• Department of Obs and Gyn

• UDUTH

Molar Pregnancy

It is a spectrum of trophoblastic diseases that includes:

Complete molar pregnancy

Partial molar pregnancies

Invasive mole

Choriocarcinoma

Placental site trophoblastic tumour

The last 2 may follow abortion, ectopic or normal pregnancy.

DefinitionsGestational Trophoblastic Disease (GTD)

Chorio

carcinoma

I-Pathologic Classification

II-Clinical ClassificationβhCG based: WHO, FIGO, ACOG 2004 & RCOG 2010

Benign G.T.D.

G.T. Neoplasia

Malignant G.T.D.

Partial moleComplete mole

Invasivemole

MetastaticNon metastatic

Low risk High risk

Gestational Trophoblastic Disease (GTD)

Placental site trophoblastic tumour

Persistent GTD

Classifications

-

Hydatidiform Mole

(H. MOLE)=

Vesicular Mole

Hydatidiform Moles (H.M.)Hydatidiform moles are abnormal pregnancies

characterized histologically by :

Trophoblastic proliferation (Both syncitiotrophoblast & cytotrophoblast)

Edema of the villous stroma (Hydropic) .

Based on the degree and extent of these tissue changes, hydatidiform moles are categorized as either

Complete hydatidiform mole.

Partial hydatidiform mole.

Feature Partial mole Complete mole

Karyotype

Most commonly69, XXX or - XXY

Most commonly46, XX or -,XY

Pathology

Fetus Often present Absent

Amnion, fetal RBC Usually present Absent

Villous edema Variable, focal Diffuse

Trophoblastic proliferation Focal, slight-moderate Diffuse, slight-severe

Clinical presentation

Diagnosis Missed abortion Molar gestation

Uterine size Small for dates 50% large for dates

Theca lutein cysts Rare 25-30%

Medical complications Rare 10-25%

Postmolar CTN 2.5-7.5% 6.8-20%

Features Of Partial And Complete Hydatidiform Moles

Epidemiology& Risk FactorsIncidence:USA 1/1000 South East 1/500 (Hospital) and in Nigeria 1/379.

Risk Factors:

Age: <20y (2fold) , > 40y(10 fold) & >50y (50% V.mole)

Prior Molar Pregnancy

Second molar: 1% - Third molar : 20%!

Diet:↑ in low fat Vit. A or carotene diet (complete mole)

Contraception :COC double the incidence

Previous spontaneous abortion: double the incidence

Repetitive H. moles in women with different partners

Partial moles have been linked to:Higher educational levels

Smoking

Irregular menstrual cycles

Only male infants are among the prior live births

Epidemiology & Risk Factors

Homozygous 90%

Pathogenesis of complete H. Mole

Karyotype

Pathogenesis of complete H. Mole

Heterozygous 10%

Karyotype

Pathogenesis of Partial H. Mole

Karyotype

Complete H. MoleMicroscopically Enlarged, edematous villi and abnormal trophoblastic proliferation that diffusely involve the entire villiNo fetal tissue, RBCs or amnion are produced

Macroscopically, these microscopic changes transform the chorionic villi into clusters of vesicles with variable dimensions “ like bunch of grapes" No fetal or embryonic tissue are producedUterine enlargement in excess of gestational age .Theca-lutein cyst associated in 30%

Complete hydatidiform mole: Macroscopically, these microscopic changes transform the chorionic villi into clusters of vesicles with variable dimensions the name hydatidiform mole stems from this "bunch of grapes"

Partial H. MoleMicroscopically: The enlarged, edematous villi and abnormal trophoblastic proliferation are slight and focal and did not involve the entire villi.There is a scalloping of chorionic villi Fetal or embryonic or fetal RBCs

Macroscopically: The molar pattern did not involve the entire placenta.Uterine enlargement in excess of gestational age is uncommon. Theca-lutein cysts are rare Fetal or embryonic tissue or amnion

Partial Hydatiform Mole

Vesicles

Maternal side

Partial H. mole.

The classic features are

Irregular vaginal bleeding

Hyperemesis

Excessive uterine enlargement &

Early failed pregnancy.

Breathlessness due to anaemia

Abdominal pain

Presentation

Some women will present early with passage of molar tissue

Rarer presentations include:

Hyperthyroidism

Early onset pre-eclampsia

Abdominal distension due to theca lutein cysts

Very rarely

Acute respiratory failure

Neurological symptoms such as seizures (?metastatic disease).

Clinical FindingsAnemia

Breathlessness

Pseudo- Toxemia which consist of Systolic hypertension edema and proteinuria

The Uterus is doughy in consistence

Absence of fetal part

Enlarged Cystic Ovaries

Complete Molar Pregnancy

Complete hydatidiform mole. The classic "snowstorm" appearance is created by the multiple placental vesicles.

Complete H.Mole (High-resolution) U/S Complex intrauterine mass containing many small cysts.

Complete H.Mole Associated theca-lutein cysts. U/S Power Doppler

In most patients with a partial mole,

the clinical and U/S diagnosis is

Usually missed or incomplete abortion.

This emphasizes the need for a

thorough histopathologic evaluation of

all missed or incomplete abortions

Classically: A thickened, hydropic placenta with fetal or embryonic tissue

Multiple soft markers, including:

Cystic spaces in the placenta and

Transverse to AP dimension a ratio of the gestation sac of > 1.5, is required for the reliable diagnosis of a partial molar pregnancy

Differential diagnosis

• Multiple pregnancy.

• Hydatidiform mole.

• Threatened abortion.

• Ectopic pregnancy.

Partial Molar Pregnancies

There are 2 important basic lines :

1-Evacuation of the mole

2-Regular follow-up to detect persistent

trophoblastic disease

If both basic lines are done

appropriately, mortality rates can be

reduced to zero.

Management

For Partial mole: It depends on the fetal parts

Small fetal parts :Suction curettage

Large fetal parts: Medical (oxytocics)

In partial mole the oxytocics is safe ,as the hazard to embolise and disseminate trophoblastic tissue is very low

Also, the needing for chemotherapy is 0.1- 0.5%.

Is That The Same For Partial Mole?

Post-evacuation Surveillance

Why?

To determine when pregnancy

can be allowed

To detect persistent

trophoblastic disease (i.e. GTN)

The Post-evacuation Surveillance. How?

A baseline serum β -hCG level is obtained within 48 hours after evacuation.

Levels are monitored every 1 to 2 weeks

while still elevated to detect persistent trophoblastic disease (GTN).

These levels should progressively fall to an undetectable level (<5 mu/ml).

If symptoms are persistent, more frequent β hCG estimation and U/S examination ± D&C are advised

What Is The Optimum Follow-up Period Following Normalization of β

hCG?A. For 6 months from the date of uterine

evacuation.

B. For 6 months from normalization of the β

hCG level. B

C. For 12 months from the date of uterine

evacuation. (For Nigeria)

Barrier methods until normal β hCG level.

Once βhCG level have normalized:Combined

oral contraceptive (COC ) pill may be used.

If oral COC was started before the diagnosis of

GTD ,COC can be continue as its potential to

increase risk of GTN is very low

IUCD should not be used until β hCG levels are

normal to reduce uterine perforation.

What Is Safe Contraception Following GTD?

Part II: Gestational Trophoblastic Neoplasia (GTN)

Nonmetastatic disease Locally invasive GTT develops in about

15%

Patient usually present with Irregular vaginal bleedingTheca lutein cystsUterine subinvolution or asymptomatic

enlargement Persistently elevated serum hCG level

Persistent GTTAfter hydatiaiform mole

Invasive Mole Villus formation preserved

Trophoblast cells invade myometrium and blood vessels

Myometrium invaded

Myometrium

Villus

Invasive H. Mole

Myometrial invasion

Sometimes involving the peritoneum, parametrium, or vaginal vault. Originate almost always from H. mole

Vesicles

Placental-site trophoblastic tumor

Uncommon but important variant of choriocarcinoma

Characteristic Produce small amount of hCG and

hPLRemain confined to the uterusMetastasizing late in their course

Relatively insensitive to chemotherapy

Gestational Choriocarcinoma

Aneuploidy (not multiplication of 23 )

1 in 30,000 pregnancies in western world

1 in 300 to 1000 in Nigeria

40% after molar pregnancy: Easily Diagnosed

60% non-molar pregnancy: Difficult Diagnosis

The main presentations are often non-

gynecologic including hemoptysis or pulmonary

embolism, cerebral hemorrhage, gastrointestinal

or urologic hemorrhage.

Gestational ChoriocarcinomaSheets of anaplastic cytotrophoblast and

syncytiotrophoblast cells with hemorrhage &

necrosis.

Myometrial & B. vessels invasion and early metastases

No Villus formation

Cytotrophoblast

Syncytiotrophoblast

Metastatic disease Metastatic GTT occur in about 4%

after complete mole

Symptom of metastases may result from spontaneous bleeding at metastatic foci

The common site of metastases areLung(80%)vagina(30%) pelvis(20%) liver(10%) brain(10%)

GTN Vaginal Metastasis

Cranial MRI scan: Large metastasis on the left (black arrows)

Brain MRI of a patient with a solitary brain metastasis in remission

Autopsy specimen Multiple hemorrhagic hepatic metastasis

CT Scan: Liver metastsis

Stage I Disease confined to the uterus

Stage II GTN extends outside of the uterus but is limited to the genital structures (adnexa, vagina, broad ligament)

Stage III GTN extends to the lungs, with or without known genital tract involvement

Stage IV

All other metastatic sites (brain, liver)

FIGO Anatomic Staging Of GTN

Staging : FIGO

Risk factor affecting staging hCG level > 100,000 mIU/mlDuration of disease longer than 6

months from termination of pregnancy

Stage 1-4Without risk factors a 1 risk factor bWith 2 risk factors c

FIGO SCORING 0 1 2 4

Age (years) <40 >40

Antecedent pregnancy Mole Abortion Term --

Pregnancy to treatmentInterval (months)

<4 4to <7 7to <13 ≥13

Pretreatment serum hCG (iu/l)

<1000 1000-10,000 10,000-100,000 > 100,000

Largest tumour size, including uterus (cm)

< 3 3 to<5 ≥5 --

Site of metastases Lung Spleen & Kidney

Gastro-intestinal

Liver & brain

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

Previous failed chemotherapy

-- -- Single drug ≥2 Drugs

FIGO Prognostic Scoring For GTN (2000(

Total Score Survival : ≤ 6 = Low risk (100%) ≥7 = High risk. (95%)

Non metastatic GTD Metastatic

Single agent Chemotherapy

Methotrexate or Actinomycen D

Multi-agent

Chemotherapy

Low Risk ( ≤ 6) High Risk (≥7)

What Is The Optimum Treatment For GTN?

GTN

What is the best methotrexate regimen? MTX:1mg/kg IM D:1, 3 ,5 ,7 alternating with

Folinic acid 0.1mg/kg IM D 2 , 4 , 6 , 8

followed by 6 rest days

Treatment is continued, until the hCG level

has returned to normal and then for a further

6 consecutive weeks.

As any chemotherapy treatment is reevaluated if FBC,

liver or kidney FT are affected or at drug resistance

Chemotherapy Combination chemotherapy

Triple therapy : MTX, Act-D, cyclophosphamide

EMA-CO : etoposide, MTX, Act-D, cyclophosphamide, vincristine

EMA-EP : etoposide and cisplatin on day 8

Duration of therapy Until 3 normal hCG level

After that, at least 2 additional course are administered

Follow UpStage 1-3 receive follow-up with

Weekly hCG level until normal for 3 wks

Monthly hCG level until normal for 12 months

Effective contraception during the entire interval of hormonal follow-up

Stage 4 receive follow-up with Weekly hCG level until normal for 3 wksMonthly hCG level until normal for 24

months

Stage Survival Percent %

I 424/424 100

II 27/27 100

III 130/131 99

IV 14/18 78

What Is The Survival of GTN By FIGO Stage?

Disaia &Creasman Clinical Gynecological Oncology 2007