Chapter 22Chapter 22

Gestational Trophoblastic DisGestational Trophoblastic Diseaseease

WomenWomen’’s Hospital, School of Medicine Zhejiang Unives Hospital, School of Medicine Zhejiang Universityrsity

Xiaodong ChengXiaodong Cheng

Gestational trophoblastic diGestational trophoblastic diseasesease

AA group of diseases group of diseases originated from placental trophoblastic cellsoriginated from placental trophoblastic cells

Gestational trophoblasitc disease (GTD)Gestational trophoblasitc disease (GTD) Hydatidiform mole (complete and partial) Hydatidiform mole (complete and partial) Invasive moleInvasive mole Choriocarcinoma Choriocarcinoma Placental-site trophoblastic tumor (PSTT)Placental-site trophoblastic tumor (PSTT)

Gestational trophoblastic neoplasia (GTN)Gestational trophoblastic neoplasia (GTN)

Non-gestational trophoblastic tumorNon-gestational trophoblastic tumor Uncommon, derived from germ cells in ovarian or Uncommon, derived from germ cells in ovarian or

testiculartesticular  

histologically clinically

Development and Development and differentiation of gestational differentiation of gestational

trophoblastic cellstrophoblastic cells gestational trophoblastic cellsgestational trophoblastic cells evolved from evolved from extrextr

a-embryonic cellsa-embryonic cells At the time of implantation At the time of implantation cytotrophoblast cytotrophoblast outermost layer of the outermost layer of the

blastocyst blastocyst 7-8 days after implantation 7-8 days after implantation syncytiotrophoblast syncytiotrophoblast implantation site implantation site Before villi formation Before villi formation previllous trophoblastprevillous trophoblast 2 weeks after pregnancy, primary villi 2 weeks after pregnancy, primary villi

formation formation Villous surface Villous surface villous trophoblastvillous trophoblast Other parts Other parts extravillous trophoblastextravillous trophoblast

Development and Differentiation Development and Differentiation of gestational trophoblastic cellsof gestational trophoblastic cells

CytotrophoblastCytotrophoblast trophoblast stem cells trophoblast stem cells

proliferability and differentiabilityproliferability and differentiability SyncytiotrophoblastSyncytiotrophoblast differentiated mature cellsdifferentiated mature cells synthesize pregnancy-related hormones synthesize pregnancy-related hormones

material exchange between the fetus and material exchange between the fetus and the motherthe mother

Two differentiated forms of Two differentiated forms of CytotrophoblCytotrophoblastast

villous surface area Syncytiotrophoblastvillous surface area Syncytiotrophoblast

extravillous Intermediate trophoblastextravillous Intermediate trophoblast

Hydatidiform moleHydatidiform mole

Hydatidiform mole Hydatidiform mole

Complete molesComplete moles Hydropic degeneration of all villiHydropic degeneration of all villi Villous edema, trophoblastic hyperplasia, fetal-Villous edema, trophoblastic hyperplasia, fetal-

derived derived

blood vessels disappear in stromablood vessels disappear in stroma Partial molesPartial moles

combine embryo or fetuscombine embryo or fetus Villous edemaVillous edema partially, t partially, trophoblastic rophoblastic

proliferation proliferation

lighterly, fetal-derived blood vessels lighterly, fetal-derived blood vessels presentpresent stromastroma

Complete moles Partial moles

Hydatidiform moleHydatidiform moleRelated FactorsRelated Factors Complete molesComplete moles

Area common in Latin America, AsiaArea common in Latin America, Asia uncommon in uncommon in North America and EuropeNorth America and Europe Race dRace differences of ifferences of the same race in the same race in different different

regionsregions Nutrition and EconomyNutrition and Economy lack of Vit Alack of Vit A Age Age < 20 or >35 years< 20 or >35 years The fertilization of an empty eggThe fertilization of an empty egg the fertilization of an empty egg by a haploid sperthe fertilization of an empty egg by a haploid sper

mm Diploid genome 90% of the time (usually 46,XX)Diploid genome 90% of the time (usually 46,XX) Genomic imprinting disorderGenomic imprinting disorder

Hydatidiform moleHydatidiform mole Partial molesPartial moles high-risk factors are still unknownhigh-risk factors are still unknown "Haploid egg" fertilization"Haploid egg" fertilization usually usually two sperm fertilize a normal eggtwo sperm fertilize a normal egg a triploid karyotype (69 chromosomes ), with the a triploid karyotype (69 chromosomes ), with the

extra haploid set of chromosomes derived from fextra haploid set of chromosomes derived from fatherather

CompleteComplete PartialPartial

Karyotype Karyotype 46, XX(90%) 46, XX(90%) 46, XY(10%)46, XY(10%)

TriploidTriploid

(69XXY, 69XXX)(69XXY, 69XXX)

Embryo Embryo AbsentAbsent PresentPresent

Villi Villi Hydropic Hydropic Few hydropic Few hydropic

TrophoblastsTrophoblasts Diffuse hyperplasia Diffuse hyperplasia Mild focal Mild focal hyperplasia hyperplasia

Villus outlineVillus outline regularregular irregularirregular

Blood vesselBlood vessel absenceabsence presencepresence

Comparison of complete and partiComparison of complete and partial hydatidiform molesal hydatidiform moles

Hydatidiform moleHydatidiform moleClinical PresentationClinical Presentation Complete molesComplete moles Abnormal vaginal bleeding during early pregnancy( 8-1Abnormal vaginal bleeding during early pregnancy( 8-1

2week)2week) most common symptom most common symptom Uterine enlargement exceeding normal pregnant uterus Uterine enlargement exceeding normal pregnant uterus Others Others Abdominal painAbdominal pain Pregnancy-induced hypertensionPregnancy-induced hypertension Theca lutein ovarian cystTheca lutein ovarian cyst Hyperthyroidism (CHM)Hyperthyroidism (CHM) Partial molesPartial moles Mild symptoms, Confused with abortion easilyMild symptoms, Confused with abortion easily

Hydatidiform moleHydatidiform molehCG regression pattern after hydatidiformhCG regression pattern after hydatidiform Mean time of the hCG regressed to normalMean time of the hCG regressed to normal — — 9 weeks no more than 14 weeks 9 weeks no more than 14 weeks Abnormal hCG regression pattern after hydatidiform Abnormal hCG regression pattern after hydatidiform signifies the presence of GTNsignifies the presence of GTN Complete moleComplete mole 15%15% l local invasion and 4% distant metastasis ocal invasion and 4% distant metastasis High –risk :High –risk :

①①HCG>100,000U/LHCG>100,000U/L② ② Enlargement of UterineEnlargement of Uterine③ ③ Theca lutein ovarian cyst >6cmTheca lutein ovarian cyst >6cm

Partial molePartial mole 4%l4%local invasion and almost no distant ocal invasion and almost no distant

metastasis metastasis High –risk :unclearHigh –risk :unclear

Hydatidiform moleHydatidiform mole DiagnosisDiagnosis Abnormal bleeding after amenorrheaAbnormal bleeding after amenorrhea Inappropriately enlarged uterusInappropriately enlarged uterus Absence of fetal heart sounds Absence of fetal heart sounds not palpate fetus between 16-20not palpate fetus between 16-20thth week week Vaginal discharge hydatidiform-like Vaginal discharge hydatidiform-like

tissuetissue

Hydatidiform mole should be consideredHydatidiform mole should be considered

Hydatidiform moleHydatidiform mole DiagnosisDiagnosis Ultrasound Ultrasound Complete moles produce a characteristic vesicular sonogComplete moles produce a characteristic vesicular sonog

raphic pattern, usually referred to as a “snowstorm” praphic pattern, usually referred to as a “snowstorm” patternattern

HCGHCG Elevated above expected for gestational ageElevated above expected for gestational age Dynamic observation for 8-10 weeks, continued to riseDynamic observation for 8-10 weeks, continued to rise HCG-related moleculesHCG-related molecules Hyperglycosylated HCGHyperglycosylated HCG free β-HCG subunitfree β-HCG subunit

DNA karyotype DNA karyotype Complete moles — usually diploid Complete moles — usually diploid Partial moles — usually triploidPartial moles — usually triploid

a “snowstorm” pattern

Hydatidiform moleHydatidiform mole TreatmentTreatmentSuction curettageSuction curettage Molar pregnancy should be terminated as Molar pregnancy should be terminated as

soon as possible when diagnosis has been soon as possible when diagnosis has been confirmedconfirmed

Suction curettage is a first choice, Suction curettage is a first choice, must must be fully done in operating roombe fully done in operating room

tissue from curettage should tissue from curettage should be submitted to pathologybe submitted to pathology

Hydatidiform moleHydatidiform moleTreatmentTreatment Theca lutein cysts of the ovaryTheca lutein cysts of the ovary do not need special treatmentdo not need special treatment Prophylactic chemotherapy: Prophylactic chemotherapy: A controversial topic A controversial topic only be offered to patients with high-risk factor only be offered to patients with high-risk factor

or or impossible follow-upimpossible follow-up HysterectomyHysterectomy Only remove local invasion, but not distant metOnly remove local invasion, but not distant met

astasisastasis Only for old women without childbearing desireOnly for old women without childbearing desire

Hydatidiform moleHydatidiform moleFollow-upFollow-up necessary for diagnosis of early GTNnecessary for diagnosis of early GTN Methods:Methods: HCGHCG Symptom: Abnormal uterine bleedingSymptom: Abnormal uterine bleeding Pelvic examination Pelvic examination Ultrasound, chest X-ray and CTUltrasound, chest X-ray and CT Contraception: Contraception: Condom and oral contraceptives,Condom and oral contraceptives, not IUD not IUD Duration for contraceptiom Duration for contraceptiom —— 1 year 1 year

Gestational TroGestational Tro

phoblastic Neopphoblastic Neop

lasialasia

General ConsiderationGeneral Consideration Antecedent gestation Antecedent gestation 60% hydatidiform mole 60% hydatidiform mole 30% follow abortion 30% follow abortion 10% term pregnancy or ectopic pregna10% term pregnancy or ectopic pregna

ncyncy from molefrom mole — — invasive mole invasive mole or choriocarcinoma or choriocarcinoma

from from Non-mole Non-mole

—— choriocarcinomachoriocarcinoma

Gestational Trophoblastic NGestational Trophoblastic Neoplasiaeoplasia

PathogenesisPathogenesis Invasive moleInvasive mole Invasive mole is a hydatidiform mole that invades Invasive mole is a hydatidiform mole that invades

the myometrium and may produce distant metastthe myometrium and may produce distant metastases. ases.

Microscopic finding are the same as in hydatidifoMicroscopic finding are the same as in hydatidiform molerm mole

ChoriocarcinomaChoriocarcinoma GlossGloss ：： invades the myometrium , penetrate the invades the myometrium , penetrate the

serosaserosa and may produce distant metastasesand may produce distant metastases MicroscopyMicroscopy ：： no villi, but instead sheets or foci ono villi, but instead sheets or foci o

f trophoblasts on a background of hemorrhage anf trophoblasts on a background of hemorrhage and necrosisd necrosis

Invasive moleInvasive mole

Invasive moleInvasive mole

Invasive moleInvasive mole

ChoriocarcinomaChoriocarcinoma

ChoriocarcinomaChoriocarcinoma

ChoriocarcinomaChoriocarcinoma

invades the myometrium

Lung metastases

Brain metastases

cervical metastases

Gestational Trophoblastic NGestational Trophoblastic Neoplasiaeoplasia

Clinical ManifestationClinical ManifestationNonmetastatic GTNNonmetastatic GTN the antecedent gestational event is usually the antecedent gestational event is usually

HMHM Abnormal vaginal bleeding after mole Abnormal vaginal bleeding after mole Others:Others: Enlarged uterus Enlarged uterus Theca lutein cysts of the ovaryTheca lutein cysts of the ovary Abdominal pain Abdominal pain Fake pregnancy symptomsFake pregnancy symptoms

Gestational Trophoblastic NeoGestational Trophoblastic Neoplasiaplasia

Metastatic GTNMetastatic GTNUsually chroriocarcinomaUsually chroriocarcinoma Primary symptoms Primary symptoms Metastatic symptoms Metastatic symptoms

Lung metastases are frequently common Lung metastases are frequently common vaginal metastases are the second commonvaginal metastases are the second common liver and brain metastases usually death caliver and brain metastases usually death ca

use use other metastastic sites other metastastic sites spleen, kidney, bladder, gastrointestinal syspleen, kidney, bladder, gastrointestinal sy

stem, and bone stem, and bone

Simultateously occur or not

Gestational Trophoblastic NeoGestational Trophoblastic Neoplasiaplasia

DiagnosisDiagnosis Symptoms and signs:Symptoms and signs:◆◆ Abnormal vaginal bleeding Abnormal vaginal bleeding after post-evacuation, abortion, term after post-evacuation, abortion, term

pregnancy or ectopic pregnancy, pregnancy or ectopic pregnancy, ◆ ◆ Metastatic symptoms Metastatic symptoms GTT should be consideredGTT should be considered

Gestational Trophoblastic NeoplasGestational Trophoblastic Neoplasiaia

HCG assayHCG assay Most important and sometimes only diagnostic evidence Most important and sometimes only diagnostic evidence Diagnostic criteria for post- HM GTN (FIGO2000)Diagnostic criteria for post- HM GTN (FIGO2000) hCG plateau for >4 values hCG plateau for >4 values （（ ±10±10 ％）， ％）， over 3 weeksover 3 weeks hCG increase of ≥10% over 2 weekshCG increase of ≥10% over 2 weeks hCG persistence after evacuation of mole for 6 monthshCG persistence after evacuation of mole for 6 months

Diagnostic criteria for non post-HM GTNDiagnostic criteria for non post-HM GTNHCG elevated at 4w after abortion, term or ectopic pregHCG elevated at 4w after abortion, term or ectopic preg

nancynancyRe-rising HCG titer after reaching normal levelsRe-rising HCG titer after reaching normal levels

Gestational Trophoblastic NeoplasGestational Trophoblastic Neoplasiaia

Chest X-rayChest X-ray lung metastases lung metastases CTCT small lung metastases and brain metastases small lung metastases and brain metastases MRIMRI Liver and brain metastases Liver and brain metastases UltrasoundUltrasound primary lesions of uterus and pevical metastasprimary lesions of uterus and pevical metastas

es es Imaging supports diagnosis, but not Imaging supports diagnosis, but not

necessarynecessary

Gestational Trophoblastic NeoplasGestational Trophoblastic Neoplasiaia

Histological diagnosisHistological diagnosis villus shape can be found in primary or villus shape can be found in primary or

metastatical lesionsmetastatical lesions Presence of villus shape Invasive molPresence of villus shape Invasive mol

e e Absence of villus shape ChoriocarcinAbsence of villus shape Choriocarcin

omaoma Histology is not necessary Histology is not necessary for diagnosis of GTNfor diagnosis of GTN

Anatomy staging of GTN (FIGO, 2000)Anatomy staging of GTN (FIGO, 2000) StageIStageI Localized to the uterusLocalized to the uterus

StageIIStageII Lesion diffused, but Localized to the genitalia (aLesion diffused, but Localized to the genitalia (accessory,vagina,broad ligament)ccessory,vagina,broad ligament)

StageIIIStageIII Lung metastasis, with or without genitalia Lung metastasis, with or without genitalia changechange

StageⅣStageⅣ Other metastasisOther metastasis

Gestational Trophoblastic NeoplasiaGestational Trophoblastic Neoplasia

Stage I

Stage II

Stage III

Stage IV

Prognostic scoring system for GTT Prognostic scoring system for GTT

(FIGO,2000)(FIGO,2000) scorescore 00 11 22 44

Age(y)Age(y) ＜＜ 4040 ≥≥4040 -- --

Antecedent Antecedent molemole abortionabortion termterm --

Interval (mo) Interval (mo) ＜＜ 44 44 ～～ 66 77 ～～ 1212 ≥≥1313

Pretreatment b-hCG (mIU/Pretreatment b-hCG (mIU/ml) ml)

＜＜ 1010 ３３ 1010 ３３～～ 1010 ４４ ＞ ＞ 1010 ４４～～ 1010５５

＞ ＞ 1010 ５５

Largest tumor (cm) Largest tumor (cm) －－ 33 ～～ 4 cm 4 cm ≥≥5cm5cm --

Site of metastases Site of metastases LungLung Spleen, KidneySpleen, Kidney GastrointestiGastrointestinal nal

Liver, brainLiver, brain

Number of metastases Number of metastases －－ 11 ～～ 44 55 ～～ 88 ＞＞ 88

Prior chemotherapy failed Prior chemotherapy failed －－ －－ single single ＞＞ 22

* Total score≤6 low risk, ≥7 high risk

Gestational Trophoblastic NeoplasGestational Trophoblastic Neoplasiaia

TreatmentTreatment Chemotherapy combining surgery, radiotherapy Chemotherapy combining surgery, radiotherapy

and other treatmentand other treatment Base on the assessment and stage, therapy stratifiBase on the assessment and stage, therapy stratifi

ed ed Chemotherapy : Chemotherapy : Single-agent chemotherapy is applied in low-risk Single-agent chemotherapy is applied in low-risk

gestational trophoblastic disease (MTX, Act-D, 5-gestational trophoblastic disease (MTX, Act-D, 5-Fu)Fu)

High-risk patients commonly use combined cheHigh-risk patients commonly use combined chemotherapy (EMA-CO)motherapy (EMA-CO)

Single agent chemotherapySingle agent chemotherapy

DAY Therapy Interval DAY Therapy Interval

1-5 MTX 0.4mg/kg im qd 14d1-5 MTX 0.4mg/kg im qd 14d 11、、 33、、 55、、 7 MTX1mg/kg im 14d 7 MTX1mg/kg im 14d 22、、 44、、 66、、 8 FA 0.1mg/kg im or po 8 FA 0.1mg/kg im or po 1-5 Act-D10-12ug/kg ivgtt qd 14d 1-5 Act-D10-12ug/kg ivgtt qd 14d

1-8 5-Fu 28-30mg/kg ivgtt qd 121-8 5-Fu 28-30mg/kg ivgtt qd 12 －－ 14d14d

Combined chemotherapyCombined chemotherapy

Drugs Drugs Dose ,pathway,periodsDose ,pathway,periods Interval Interval

5-Fu+KSM5-Fu+KSM 3weeks3weeks

5-Fu5-Fu 26-28mg/kg·d26-28mg/kg·d ，， ivgtt for 8daysivgtt for 8days

KSMKSM 66g/kg·dg/kg·d ， ， ivgtt for 8daysivgtt for 8days

Combined chemotherapyCombined chemotherapy

EMA-COEMA-CO Interval Interval 2weeks2weeks

the first part EMAthe first part EMA

11stst day VP16 100mg/m day VP16 100mg/m2 2 ivgttivgtt

Act-D 0.5mg ivgttAct-D 0.5mg ivgtt

MTX 100 mg/mMTX 100 mg/m2 2 ivgttivgtt

MTX 200mg/mMTX 200mg/m22 ivgtt for 12hours ivgtt for 12hours

22ndnd day VP16 100mg/m day VP16 100mg/m22 ，， ivgttivgtt

Act-D 0.5mg ivgttAct-D 0.5mg ivgtt

CF15mgCF15mg ，， imim

（（ after 24hours from the use of MTXafter 24hours from the use of MTX ， ， once every 12hoursonce every 12hours ，， twictwicee ））33rdrd CF15mg CF15mg ，， imim ，， once every 12hoursonce every 12hours ，， twicetwice 。。44thth to 7 to 7thth rest rest （（ no drugno drug ）） the second part COthe second part CO

88thth day VCR1.0mg/m day VCR1.0mg/m22 ， ， ivgttivgtt

CTX600mg/mCTX600mg/m22 ， ， ivgttivgtt

PSTTPSTT

A special type, more rarely in clinicA special type, more rarely in clinic Most of them have a good prognosisMost of them have a good prognosis Form Form the intermediate trophoblast the intermediate trophoblast

cellscells Clinical manifestationsClinical manifestations More common occur at reproductive period womMore common occur at reproductive period wom

en en More common occur following term or ectopic prMore common occur following term or ectopic pr

egnancyegnancy Abnormal bleeding after amenorrheaAbnormal bleeding after amenorrhea

PSTTPSTT

DiagnosisDiagnosis HCG was negativeHCG was negative

HPL mildly elevatedHPL mildly elevated  Confirmed by histologyConfirmed by histology

TreatmentTreatment

Surgery is the preferred treatment Surgery is the preferred treatment

Chemotherapy is adjuvant therapyChemotherapy is adjuvant therapy

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