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 (chorioepithelioma)Choriocarcinoma (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 elementsArise from the trophoblastic elements Retain the invasive tendencies of the Retain the invasive tendencies of the

normal placenta or metastasisnormal placenta or metastasis Keep secretion of the human chorionic Keep secretion of the human chorionic

gonadotropin (hCG)gonadotropin (hCG)

Types of GTDTypes of GTD

Low riskHigh risk Choriocarcinoma

Metastatic Placental site trophoblastic tumor

Nonmetastatic Malignant trophoblastic disease

Invasive mole

Benign gestational trophoblastic disease

Hydatidiform mole *complete *incomplete

CLINICAL CLASSIFICATION

PATHOLOGIC CLASSIFICATION

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

The etiology of hydatidiform mole The etiology of hydatidiform mole remains unclear, but it appears to be due remains unclear, but it appears to be due to abnormal gametogenesis and to abnormal gametogenesis and fertilization 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 in the 1 out of 1500-2000 pregnancies in the U.S. and EuropeU.S. and Europe

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

• Complete > incompleteComplete > incomplete

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

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

Incidence Incidence

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

Approximately 2-3% of hydatidiform Approximately 2-3% of hydatidiform moles progress to choriocarcinoma moles progress to choriocarcinoma ( most of them are curable) ( most of them 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 pregnancyClinical risk factors for molar pregnancy

Outside North America( occasionally has this disease)

Birthplace Vitamin A deficiency Diet prior spontaneous abortion prior hydatidiform mole Reproductive history >40 <15

Age (extremes of reproductive years)

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, triploid. Chromosomes are paternal and maternal, 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 MoleComplete and Partial Hydatidiform Mole

Hyperplasia mild and focalHyperplasia usually present to variable degrees

Trophoblast

Usually presentNone presentFetal tissue

blood cellspresent they contain no fetal blood cells

vessels

Normal adjacent villi may be present

All villi hydropin; no normal adjacent villi

Villi

Usually triploidy 69XXX most common.

Usually diploid 46XXKaryotype

Partial MoleComplete MoleFeature

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 Complete Signs and Symptoms of Complete Hydatidiform MoleHydatidiform Mole

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

age( with no fetal heart beating and age( with no fetal heart beating and fetal movement)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 3% preeclampsia is reported in only 3% of patients.of patients.

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

Diagnosis of hydatidiform moleDiagnosis of hydatidiform mole

Quantitative beta-HCGQuantitative beta-HCG

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

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 remove :to remove benign hydatidiform molesbenign hydatidiform moles

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

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

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

Treatment Treatment

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

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

Treatment Treatment

High-risk postmolar High-risk postmolar trophoblastic tumortrophoblastic tumor

1.1. Pre-evacuation uterine size larger than expected Pre-evacuation uterine size larger than expected for gestational durationfor 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 as Medical complications of molar pregnancy such as

toxemia, hyperthyrodism and trophoblastic 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 are Patients with hudatidiform mole are curative over 80% by treatment of curative over 80% by treatment of evacuation. evacuation.

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

uterine involution, ovarian cyst uterine involution, ovarian cyst regression and cessation of bleedingregression and cessation of bleeding

Follow-upFollow-up

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

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

Contraception should be practiced Contraception should be practiced during this follow-up periodduring this follow-up period

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

0-5Gastrointestinal 0-5Spleen 0-5Kidney 5-15Liver 5-15Brain 10-15Vulva/cervix40-50Vagina 60-95Lung

Per centSite

Choriocarcinoma Choriocarcinoma

Definition Definition

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

Characterized by abnormal Characterized by abnormal trophoblastic hyperplasia and trophoblastic hyperplasia and anaplasia , absence of chorionic villianaplasia , absence of chorionic villi

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

2 or moreSingle drug——Previous (treatment)

84-81-4—No. of metastasis

BrainGI tract, liverSpleen, kidney

Lung Sites of metastasis

—>53-5<3Largest tumor(cm)

>105104-105103-104<103Initial hCG(mIU/ml)

>127-124-6<4Interval (months) of treatment

—Term pregnancy

Abortion,ectopic

Hydatidiform molePregnancy history

——>39≤39Age(years)

4210Prognostic factor

Score

0-4 low risk, 5-7 intermediate risk, >8 high risk for death

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

All other metastatic sitesⅣ

Extends to the lungs with or without genital tractⅢ

Extends to the adnexae, outside the uterus, but limited to the genital structuresⅡ

Limited to uterine corpusⅠ

Description Stage

Substages assigned for each stage as Substages assigned for each stage as follows: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 mlU/1. Pretherapy serum hCG > 100,000 mlU/

mlml 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 evaluationDiagnosis and evaluation

Gestational trophoblastic tumor is Gestational trophoblastic tumor is diagnosed by rising hCG following diagnosed by rising hCG following evacuation of a molar pregnancy or evacuation of a molar pregnancy or any pregnancy eventany pregnancy event

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

Hysterectomy is advisable as initial treatment in Hysterectomy is advisable as initial treatment in patients with nonmetastatic GTD who no longer patients with nonmetastatic GTD who no longer wish to preserve fertility 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 time Adjusted single-agent chemotherapy at the time of operation is indicated to eradicate any occult of operation is indicated to eradicate any occult metastases and reduce tumor dissemination.metastases and reduce tumor dissemination.

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

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

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

Treatment of Nonmetastatic GTDTreatment of Nonmetastatic GTD

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

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

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

(Repeat every 15 days as toxicity permits)

IV on day81mg/M2Oncovin (vincristine)

IV on day8600mg/M2Cyclophosphamide

15mg IM or p.o. q 12 hours×4 starting 24 hours after starting methotrexateFolinic acid

IV daily×2 days0.5mgActinomycin D

IV losding dose, then 200mg/M2 over 12 hours day 1

100mg/M2Methotrexate

IV daily×2 days (over 30-45 minutes)

100mg/M2Etoposide(VP-16)

PrognosisPrognosis

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

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

Follow-up After Successful Follow-up After Successful TreatmentTreatment

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

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

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

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

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

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 relatively behavior of this disease. They are relatively chemotherapy-resistant, and deaths from chemotherapy-resistant, and deaths from metastasis have occurred. metastasis have occurred.

Surgery has been the mainstay of treatmentSurgery has been the mainstay of treatment

Dignosis and treatment Dignosis and treatment