Gestational Trophoblastic Gestational Trophoblastic Disease (GTD)Disease (GTD)

Types of GTDTypes of GTD

BenignBenign• Hydatidiform mole/molar pregnancy Hydatidiform mole/molar pregnancy

(complete or incomplete)(complete or incomplete)

malignantmalignant• Invasive mole Invasive mole • Choriocarcinoma Choriocarcinoma

(chorioepithelioma)(chorioepithelioma)• Placental site trophoblastic tumorPlacental site trophoblastic tumor

The term The term Gestational Trophoblastic Gestational Trophoblastic Tumors Tumors has been applied the latter has been applied the latter three conditionsthree conditions

Arise from the trophoblastic Arise from the trophoblastic elementselements

Retain the invasive tendencies of Retain the invasive tendencies of the normal placenta or metastasisthe normal placenta or metastasis

Keep secretion of the human Keep secretion of the human chorionic gonadotropin (hCG)chorionic gonadotropin (hCG)

Types of GTDTypes of GTD

PATHOLOGIC PATHOLOGIC CLASSIFICATIONCLASSIFICATION

CLINICAL CLINICAL CLASSIFICATIONCLASSIFICATION

Hydatidiform Hydatidiform molemole

*complete*complete

*incomplete*incomplete

Benign gestational Benign gestational trophoblastic diseasetrophoblastic disease

Invasive moleInvasive moleMalignant Malignant

trophoblastic diseasetrophoblastic diseaseNonmetastatic Nonmetastatic

Placental site Placental site trophoblastic trophoblastic tumortumor

Metastatic Metastatic

ChoriocarcinomChoriocarcinoma a High risk High risk Low riskLow risk

Pathologic and clinical classifications for gestational

trophoblastic disease

Hydatidiform MoleHydatidiform Mole (molar pregnancy) (molar pregnancy)

Definition and Etiology Definition and Etiology Hydatidiform mole is a pregnancy Hydatidiform mole is a pregnancy

characterized by vesicular swelling characterized by vesicular swelling of placental villi and usually the of placental villi and usually the absence of an intact fetus.absence of an intact fetus.

The etiology of hydatidiform mole The etiology of hydatidiform mole remains unclear, but it appears to remains unclear, but it appears to be due to abnormal gametogenesis be due to abnormal gametogenesis and fertilization and fertilization

In a ‘In a ‘complete molecomplete mole’ the mass of ’ the mass of tissue is completely made up of tissue is completely made up of abnormal cells abnormal cells

There is no fetus and nothing can There is no fetus and nothing can be found at the time of the first be found at the time of the first scan. scan.

Definition and Etiology Definition and Etiology

In a ‘In a ‘partial molepartial mole’, the mass may ’, the mass may contain both these abnormal cells contain both these abnormal cells and often a fetus that has severe and often a fetus that has severe defects. defects.

In this case the fetus will be In this case the fetus will be consumed ( destroyed) by the consumed ( destroyed) by the growing abnormal mass very growing abnormal mass very quickly.quickly. (shrink)(shrink)

Definition and Etiology Definition and Etiology

Incidence Incidence

• 1 out of 1500-2000 pregnancies 1 out of 1500-2000 pregnancies in the U.S. and Europein the U.S. and Europe

• 1 out of 500-600 (another report 1 out of 500-600 (another report 1%) pregnancies in some Asian 1%) pregnancies in some Asian countries. countries.

• Complete > incompleteComplete > incomplete

Repeat hydatidiform moles occure Repeat hydatidiform moles occure in 0.5-2.6% of patients, and these in 0.5-2.6% of patients, and these patiens have a subsequent patiens have a subsequent greater risk of developing greater risk of developing invasive mole or choriocarcinomainvasive mole or choriocarcinoma

There is an increased risk of There is an increased risk of molar pregnancy for women over molar pregnancy for women over the age 40the age 40

Incidence Incidence

Approximately 10-17% of Approximately 10-17% of hydatidiform moles will result in hydatidiform moles will result in invasive moleinvasive mole

Approximately 2-3% of Approximately 2-3% of hydatidiform moles progress to hydatidiform moles progress to choriocarcinoma ( most of them choriocarcinoma ( most of them are curable) are curable)

Incidence Incidence

Not definitely benign disease , Not definitely benign disease , has a tight relationship with GTThas a tight relationship with GTT

Clinical risk factors for molar Clinical risk factors for molar pregnancypregnancy

Age (extremes of reproductive years)Age (extremes of reproductive years)

<15<15

>40>40

Reproductive historyReproductive history

prior hydatidiform moleprior hydatidiform mole

prior spontaneous abortionprior spontaneous abortion

DietDiet

Vitamin A deficiencyVitamin A deficiency

Birthplace Birthplace

Outside North America( occasionally has Outside North America( occasionally has this disease) this disease)

CytogeneticsCytogenetics

Complete molar pregnancyComplete molar pregnancy Chromosomes are paternal , diploidChromosomes are paternal , diploid

46,XX in 90% cases46,XX in 90% cases 46,XY in a small part46,XY in a small part

Partial molar pregnancyPartial molar pregnancy Chromosomes are paternal and maternal, Chromosomes are paternal and maternal, triploid. triploid.

69,XXY 80%69,XXY 80% 69,XXX or 69,XYY 10-20%69,XXX or 69,XYY 10-20%

Wrong life message , so can not develop normally

Comparative Pathologic Features of Comparative Pathologic Features of Complete and Partial Hydatidiform Complete and Partial Hydatidiform

MoleMoleFeatureFeature Complete MoleComplete Mole Partial MolePartial Mole

KaryotypeKaryotype Usually diploid 46XXUsually diploid 46XX Usually triploidy 69XXX most Usually triploidy 69XXX most common. common.

VilliVilli All villi hydropin; no All villi hydropin; no normal adjacent villinormal adjacent villi

Normal adjacent villi may be Normal adjacent villi may be present present

vesselsvessels present they contain present they contain no fetal blood cellsno fetal blood cells

blood cellsblood cells

Fetal tissueFetal tissue None presentNone present Usually presentUsually present

TrophoblastTrophoblast Hyperplasia usually Hyperplasia usually present to variable present to variable degreesdegrees

Hyperplasia mild and focalHyperplasia mild and focal

Complete hydatidiform mole demonstrating enlarged villi of various

size

Hydatidiform mole: specimen from suction curettage

A large amount of villi in the uterus.

The microscopic appearance of hydatidiform mole:

•Hyperplasia of trophobasitc cells

•Hydropic swelling of all villi

•Vessles are usually absent

A sonographic findings of a molar pregnancy. The characteristic “snowstorm” pattern is evident.

Transvaginal sonogram demonstrating the “ snow storm” appearance.

Color Dopplor facilitates visualization of the enlarged spiral arteriesclose proximity to the “ snow storm” appearance

Color Doppler image of a hydatidiform mole and surrounding vessels. The uterine artery is easily identified from its anatomical location.

Dopplor waveform analysis demonstrates low vascular resistance(RI=0.29) in the spiral arteries, much lower than that obtained in normal early pregnancy

Partial hydartidiform mole

Microscopic image of partial molar pregnancy.

Here is a partial mole in a case of triploidy. Note the scattered grape-like masses with intervening normal-appearing placental tissue.

Large bilateral theca lutein cysts resembling ovarian germ cell tumors. With resolution of the human chorionic gonadotropin(HCG) stimulation, they return to normal-appearing ovaries.

Signs and Symptoms of Signs and Symptoms of Complete Hydatidiform MoleComplete Hydatidiform Mole

• Vaginal bleedingVaginal bleeding• Hyperemesis ( severe vomit)Hyperemesis ( severe vomit)• Size inconsistent with gestational Size inconsistent with gestational

age( with no fetal heart beating age( with no fetal heart beating and fetal movement)and fetal movement)

• PreeclampsiaPreeclampsia• Theca lutein ovarian cystsTheca lutein ovarian cysts

Signs and Symptoms of Partial Signs and Symptoms of Partial Hydatidiform MoleHydatidiform Mole

• Vaginal bleedingVaginal bleeding• Absence of fetal heart tonesAbsence of fetal heart tones• Uterine enlargement and Uterine enlargement and

preeclampsia is reported in only preeclampsia is reported in only 3% of patients.3% of patients.

• Theca lutein cysts, hyperemesis Theca lutein cysts, hyperemesis is rare.is rare.

Diagnosis of hydatidiform Diagnosis of hydatidiform molemoleQuantitative beta-HCGQuantitative beta-HCG

Ultrasound is the criterion standard Ultrasound is the criterion standard for identifying both complete and for identifying both complete and partial molar pregnancies. The partial molar pregnancies. The classic image is of a “snowstorm” classic image is of a “snowstorm” patternpattern

The most common symptom of a mole is The most common symptom of a mole is vaginal bleeding during the first trimester vaginal bleeding during the first trimester

however very often no signs of a problem however very often no signs of a problem appear and the mole can only be diagnosed by appear and the mole can only be diagnosed by use of ultrasound scanning. (rutting check)use of ultrasound scanning. (rutting check)

Occasionally, a uterus that is too large for the Occasionally, a uterus that is too large for the stage of the pregnancy can be an indication. stage of the pregnancy can be an indication.

NOTE: Vaginal bleeding does not always NOTE: Vaginal bleeding does not always indicate a problem!indicate a problem!

DiagnosisDiagnosis

Differential diagnosis Differential diagnosis

•AbortionAbortion•Multiple pregnancy Multiple pregnancy •PolyhydramniosPolyhydramnios

Treatment Treatment

Suction dilation and curettageSuction dilation and curettage :to :to remove benign hydatidiform molesremove benign hydatidiform moles

When the diagnosis of hydatidiform When the diagnosis of hydatidiform mole is established, the molar mole is established, the molar pregnancy should be evacuated. pregnancy should be evacuated.

An oxytocic agent should be infused An oxytocic agent should be infused intravenously after the start of intravenously after the start of evacuation and continued for several evacuation and continued for several hours to enhance uterine contractilityhours to enhance uterine contractility

• Removal of the uterus Removal of the uterus (hysterectomy)(hysterectomy) : used rarely to treat : used rarely to treat hydatidiform moles if future pregnancy hydatidiform moles if future pregnancy is no longer desired. is no longer desired.

Treatment Treatment

Chemotherapy with a Chemotherapy with a single-agent drugsingle-agent drug

Prophylactic (for Prophylactic (for prevention) chemotherapy prevention) chemotherapy at the time of or at the time of or immediately following molar immediately following molar evacuation may be evacuation may be considered for the high-risk considered for the high-risk patients( to prevent spread patients( to prevent spread of disease )of disease )

Treatment Treatment

High-risk postmolar High-risk postmolar trophoblastic tumortrophoblastic tumor

1.1. Pre-evacuation uterine size larger than Pre-evacuation uterine size larger than expected for gestational durationexpected for gestational duration

2.2. Bilateral ovarian enlargement (> 9 cm theca Bilateral ovarian enlargement (> 9 cm theca lutein cysts) lutein cysts)

3.3. Age greater than 40 yearsAge greater than 40 years4.4. Very high hCG levels(>100,000 m IU/ml)Very high hCG levels(>100,000 m IU/ml)5.5. Medical complications of molar pregnancy such Medical complications of molar pregnancy such

as toxemia, hyperthyrodism and trophoblastic as toxemia, hyperthyrodism and trophoblastic embolization (villi come out of placenta )embolization (villi come out of placenta )

6.6. repeat hydatidiform mole repeat hydatidiform mole

Patients with hudatidiform mole Patients with hudatidiform mole are curative over 80% by are curative over 80% by treatment of evacuation. treatment of evacuation.

The follow-up after evacuation is The follow-up after evacuation is key necessary key necessary

uterine involution, ovarian cyst uterine involution, ovarian cyst regression and cessation of regression and cessation of bleedingbleeding

Follow-upFollow-up

Quantitative serum hCG levels Quantitative serum hCG levels should be obtained every 1-2 should be obtained every 1-2 weeks until negative for three weeks until negative for three consecutive determinations, consecutive determinations,

Followed by every 3 months for 1 Followed by every 3 months for 1 years. years.

Contraception should be Contraception should be practiced during this follow-up practiced during this follow-up periodperiod

Follow-upFollow-up

Invasive moleInvasive mole

Definition Definition

This term is applied to a molar This term is applied to a molar pregnancy in which molar villi pregnancy in which molar villi grow into the myometrium or its grow into the myometrium or its blood vessels, and may extend blood vessels, and may extend into the broad ligament and into the broad ligament and metastasize to the lungs, the metastasize to the lungs, the vagina or the vulva. vagina or the vulva.

Invasive mole: the tissue invades into the myometrial layer. No obvious borderline, with obvious bleeding.

Invasive hydatidiform mole infiltrating the myometrium

A case of invasive mole: inside the uterine cavity the typical A case of invasive mole: inside the uterine cavity the typical ““snow storm” appearance can be detected, The location ofsnow storm” appearance can be detected, The location of

blood flow suggest an invasive mole.blood flow suggest an invasive mole.

The same patient owing to the myometrial invasion. The same patient owing to the myometrial invasion.

Reduced vascular resistance is detected in the uterine artery.Reduced vascular resistance is detected in the uterine artery.

Transvaginal color Doppler scan of a patient with invasive mole Following uterine curettage, Persistent color signals within the myometeriun

Doppler image of invasive mole

Power Doppler easily detects a vascular echogenic nodule within the myometrium,

suggesting invasive mole

Doppler image of invasive mole. Doppler waveform

analysis depicts low vascular resistance (RI= 0.35)

Common Sites for Metastatic Common Sites for Metastatic Gestational Trophoblastic TumorsGestational Trophoblastic Tumors

Site Site Per centPer cent

Lung Lung 60-9560-95

Vagina Vagina 40-5040-50

Vulva/cervixVulva/cervix 10-1510-15

Brain Brain 5-155-15

Liver Liver 5-155-15

Kidney Kidney 0-50-5

Spleen Spleen 0-50-5

Gastrointestinal Gastrointestinal 0-50-5

Choriocarcinoma Choriocarcinoma

Definition Definition

A malignant form of GTD A malignant form of GTD which can develop from a which can develop from a hydatidiform mole or from hydatidiform mole or from placental trophoblast cells placental trophoblast cells associated with a healthy associated with a healthy fetus ,an abortion or an ectopic fetus ,an abortion or an ectopic pregnancy.pregnancy.

Characterized by abnormal Characterized by abnormal trophoblastic hyperplasia and trophoblastic hyperplasia and anaplasia , absence of chorionic anaplasia , absence of chorionic villivilli

Definition Definition

Gross specimen of choriocarcinoma

Microscopic image of choriocarcinoma

absence of chorionic villiabsence of chorionic villi

Microscopic image of choriocarcinoma

Doppler image of choriocarcinoma

Doppler image of choriocarcinoma

Symptoms and signs Symptoms and signs

• BleedingBleeding• InfectionInfection• Abdominal swellingAbdominal swelling• Vaginal massVaginal mass• Lung symptomsLung symptoms• Symptoms from other metastasesSymptoms from other metastases

WHO Prognostic Scoring SystemWHO Prognostic Scoring System

ScoreScore Prognostic factorPrognostic factor 00 11 22 44

Age(years)Age(years) ≤≤3939 >39>39 —— ——

Pregnancy historyPregnancy history HydatidiforHydatidiform molem mole

Abortion,Abortion,

ectopicectopicTerm Term pregnancypregnancy ——

Interval (months) of Interval (months) of treatment treatment <4<4 4-64-6 7-127-12 >12>12

Initial hCG(mIU/ml)Initial hCG(mIU/ml) <10<1033 101033-10-1044 101044-10-1055 >10>1055

Largest tumor(cm)Largest tumor(cm) <3<3 3-53-5 >5>5 ——

Sites of metastasisSites of metastasis Lung Lung Spleen,Spleen,

kidneykidneyGI tract, GI tract, liverliver BrainBrain

No. of metastasisNo. of metastasis —— 1-41-4 4-84-8 88

Previous Previous (treatment)(treatment) —— —— Single drugSingle drug 2 or 2 or

moremore0-4 low risk, 5-7 intermediate risk, >8 high risk for death

FIGO Staging System for Gestational FIGO Staging System for Gestational Trophoblastic TumorsTrophoblastic Tumors

StageStage Description Description

ⅠⅠ Limited to uterine corpusLimited to uterine corpus

ⅡⅡExtends to the adnexae, outside the Extends to the adnexae, outside the uterus, but limited to the genital uterus, but limited to the genital structuresstructures

ⅢⅢExtends to the lungs with or without Extends to the lungs with or without genital tractgenital tract

ⅣⅣ All other metastatic sitesAll other metastatic sites

Substages assigned for each stage as follows:Substages assigned for each stage as follows: A: No risk factors presentA: No risk factors present B: One risk factorB: One risk factor C: Both risk factorsC: Both risk factors Risk factors used to assign substages:Risk factors used to assign substages: 1. Pretherapy serum hCG > 100,000 1. Pretherapy serum hCG > 100,000

mlU/mlmlU/ml 2. Duration of disease >6 months2. Duration of disease >6 months

FIGO Staging System for Gestational FIGO Staging System for Gestational Trophoblastic TumorsTrophoblastic Tumors

IIb

IIa

IIIa<3cm or locate in half lungIIIb disease beyond IIIa

Diagnosis and Diagnosis and evaluationevaluation Gestational trophoblastic tumor is Gestational trophoblastic tumor is

diagnosed by rising hCG following diagnosed by rising hCG following evacuation of a molar pregnancy evacuation of a molar pregnancy or any pregnancy eventor any pregnancy event

Once the diagnosis established Once the diagnosis established the further examinations should the further examinations should be done to determine the extent be done to determine the extent of disease ( X-ray, CT, MRI)of disease ( X-ray, CT, MRI)

Treatment Treatment

Nonmetastatic GTDNonmetastatic GTD Low-Risk Metastatic GTDLow-Risk Metastatic GTD High-Risk Metastatic GTDHigh-Risk Metastatic GTD

Treatment of Nonmetastatic Treatment of Nonmetastatic GTDGTD

Hysterectomy is advisable as initial Hysterectomy is advisable as initial treatment in patients with nonmetastatic treatment in patients with nonmetastatic GTD who no longer wish to preserve fertility GTD who no longer wish to preserve fertility

This choice can reduce the number of course This choice can reduce the number of course and shorter duration of chemotherapy.and shorter duration of chemotherapy.

Adjusted single-agent chemotherapy at the Adjusted single-agent chemotherapy at the time of operation is indicated to eradicate time of operation is indicated to eradicate any occult metastases and reduce tumor any occult metastases and reduce tumor dissemination.dissemination.

Single-agent chemotherapy is the Single-agent chemotherapy is the treatment of choice for patients wishing to treatment of choice for patients wishing to preserve their fertility.preserve their fertility.

Methotrexate(MTX) and Actinomycin-D are Methotrexate(MTX) and Actinomycin-D are generally chemotherapy agentsgenerally chemotherapy agents

Treatment is continued until three Treatment is continued until three consecutive normal hCG levels have been consecutive normal hCG levels have been obtained and two courses have been given obtained and two courses have been given after the first normal hCG level. after the first normal hCG level.

Treatment of Nonmetastatic Treatment of Nonmetastatic GTDGTD

To prevent relapse or metastasisTo prevent relapse or metastasis

Single-agent chemotherapy with MTX or actinomycin-Single-agent chemotherapy with MTX or actinomycin-D is the treatment for patients in this categoryD is the treatment for patients in this category

If resistance to sequential single-agent chemotherapy If resistance to sequential single-agent chemotherapy develops, combination chemotherapy would be taken develops, combination chemotherapy would be taken

Approximately 10-15% of patients treated with single-Approximately 10-15% of patients treated with single-agent chemotherapy will require combination agent chemotherapy will require combination chemotherapy with or without surgery to achieve chemotherapy with or without surgery to achieve remissionremission

Treatment of Low-Risk Treatment of Low-Risk Metastatic GTDMetastatic GTD

Multiagent chemotherapy with or Multiagent chemotherapy with or without adjuvant radiotherapy or surgery without adjuvant radiotherapy or surgery should be the initial treatment for should be the initial treatment for patients with high-rist metastatic GTDpatients with high-rist metastatic GTD

EMA-CO regimen formula is good choice EMA-CO regimen formula is good choice for high-rist metastatic GTDfor high-rist metastatic GTD

Adjusted surgeries such as removing foci Adjusted surgeries such as removing foci of chemotherapy-resistant disease, of chemotherapy-resistant disease, controlling hemorrhage may be the one controlling hemorrhage may be the one ofof treatment treatment regimenregimen

Treatment of High-Risk Treatment of High-Risk Metastatic GTDMetastatic GTD

EMA-CO Chemotherapy for poor EMA-CO Chemotherapy for poor Prognostic DiseasePrognostic Disease

Etoposide(VP-16)Etoposide(VP-16) 100mg/M100mg/M22

IV daily×2 days IV daily×2 days (over 30-45 (over 30-45 minutes)minutes)

MethotrexateMethotrexate 100mg/M100mg/M22

IV losding dose, IV losding dose, then 200mg/M2 then 200mg/M2 over 12 hours day over 12 hours day 11

Actinomycin DActinomycin D 0.5mg0.5mg IV daily×2 daysIV daily×2 days

Folinic acidFolinic acid15mg IM or p.o. q 12 hours×4 15mg IM or p.o. q 12 hours×4 starting 24 hours after starting starting 24 hours after starting methotrexatemethotrexate

CyclophosphamidCyclophosphamide e 600mg/M600mg/M22 IV on day8IV on day8

Oncovin Oncovin (vincristine)(vincristine) 1mg/M1mg/M22 IV on day8IV on day8

(Repeat every 15 days as toxicity permits) (Repeat every 15 days as toxicity permits)

PrognosisPrognosis

Cure rates should approach 100% Cure rates should approach 100% in nonmetastatic and low-risk in nonmetastatic and low-risk metastatic GTDmetastatic GTD

Intensive multimodality therapy Intensive multimodality therapy has resulted in cure rates of 80-has resulted in cure rates of 80-90% in patients with high-risk 90% in patients with high-risk metastatic GTDmetastatic GTD

Follow-up After Follow-up After Successful TreatmentSuccessful Treatment

Quantitative serum hCG levels should Quantitative serum hCG levels should be obtained monthly for 6 months, be obtained monthly for 6 months, every two months for remainder of the every two months for remainder of the first year, every 3 months during the first year, every 3 months during the second yearsecond year

Contraception should be maintained for Contraception should be maintained for at least 1 year after the completion of at least 1 year after the completion of chemotherapy. Condom is the choice.chemotherapy. Condom is the choice.

Placenta Site Placenta Site Trophoblastic Trophoblastic Tumor (PSTT)Tumor (PSTT)

Placenta Site Trophoblastic Tumor is Placenta Site Trophoblastic Tumor is an extremely rare tumor that arised an extremely rare tumor that arised from the placental implantation sitefrom the placental implantation site

Tumor cells infiltrate the myometrium Tumor cells infiltrate the myometrium and grow between smooth-muscle and grow between smooth-muscle cellscells

Definition Definition

Surum hCG levels are relatively low Surum hCG levels are relatively low compared to those seen with compared to those seen with choriocarcinoma. choriocarcinoma.

Several reports have noted a benign Several reports have noted a benign behavior of this disease. They are behavior of this disease. They are relatively chemotherapy-resistant, and relatively chemotherapy-resistant, and deaths from metastasis have occurred. deaths from metastasis have occurred.

Surgery has been the mainstay of Surgery has been the mainstay of treatmenttreatment

Dignosis and treatment Dignosis and treatment