presented by: dr. mashael shebaili assistant prof. & consultant ob/gyne department

Presented by:Dr. Mashael Shebaili

Assistant Prof. & ConsultantOb/Gyne Department

Classification of gestational Classification of gestational Trophoblastic diseaseTrophoblastic disease

WHO Classification

Malignant neoplasms of

various types of trophoblats

Malformations of the chorionic villi that are predisposed to

develop trophoblastic malignacies

Benign entities that can be confused with with these

other lesions

Choriocarcinoma

Complete

Hydatidiform moles

Placental site nodule

Exaggerated placental site

Epithilioid trophoblastic tumors

Placental site trophoblastic tumor Partial

Invasive

Hydatidiform MoleHydatidiform Mole

Definition: In latin

"hydatid" means "drop of water”"mole" means "spot”

Pathologically,Hydatidiform moles represents

placentas with abnormally developed chorionic villi (enlarged, edematous and vesicular villi with variable amounts of proliferative trophoblast)

Hydatidiform MoleHydatidiform MoleIncidence:

In the United States, • 1in 600 therapeutic abortions • 1 in 1,500 pregnancies

Internationally: • In Japan & China, 1-2 in 1,000 pregnancies • In Indonesia & India, 12 in 1,000

pregnancies

In the United Arab of Emirates,• 2 in 1000 deliveries (population-based

study; Graham IH, Fajardo AM; 1988)

In Saudi Arabia;• 1.48 in 1000 live births (hospital-based

study; Felemban AA, et al; 1969)

In the United States, •1in 600 therapeutic abortions •1 in 1,500 pregnancies

In Asian countries, •The rate is 10 times higher than in Europe and North America

In Saudi Arabia;,

•1.48 in 1000 live births (hospital-based study; Felemban AA, et al; 1969)

Table1: Factors Associated with GTD Occurrence and Corresponding Relative Risks

Odds ratio

Factors Complete Mole

Partial Mole

Maternal age (years)<20>40

Reproductive historyParity at conception

03

Spontaneous miscarriages>2

Problems with infertilityContraception

Use of oral contraceptivesICUD user

Age of 1st pregnancy <25Previous molar pregnancy

1.55.2

0.90.8

1.5–3.12.4–3.7

1.1–2.61.7–3.70.616.0

0.70.5

1.93.2

1.3

Table1:Factors Associated with GTD Occurrence and Corresponding Relative Risks

Odds ratio


Partial Mole

Family historySpontaneous abortion (yes)

Socioeconomic and lifestyleEducation (years)

>12Marital status

Never marriedSmoking

Ex-smokersCurrent smokers >15 cigarettes per day

Alcohol consumption<2 drinks

1.5

0.9–2.1

2.1

1.12.2

2.1

2.1

2.1

0.71.8

1.4

Table1: Factors Associated with GTD Occurrence and Corresponding Relative Risks

Odds ratio


Partial Mole

ABO blood typesMaternal blood

ABA

Maternal A, husband ONutrition

Vitamin A in diet above control median

2.11.71.9

0.6

1.20.9

Pathogenesis and Cytogenetics of Pathogenesis and Cytogenetics of HMHM

Genetic Constituti

on

Genetic Constituti

onDiploid

Triploid/ teraploid

Patho-genesisPatho-genesis

4%Fertilizatio

n of an empty

ovum by two

sperms“Diandric dispermy”

90%Triploid

fertilization of a

normal ovum by

two sperms

“Dispermic

triploidy”

96%Fertilizatio

n of an empty

ovum by one

sperms that

undergoes duplicatio

n“Diandric diploidy”

10%Tetraploidfertilizatio

n of a normal

ovum by three

sperms“Dispermic triploidy”

KaryotypeKaryotype46XX69XXX69YXX69YYX

46XX46XY

CompleteComplete PartialPartial

Complete Mole, Complete Mole, PathogenesisPathogenesis

Duplication 46XX

Empty ovum

23X

Diandric diploidyDiandric diploidyAndrogenesisAndrogenesis

Paternal chromosomes

only

Complete Mole, Complete Mole, PathogenesisPathogenesis

46XX

Empty ovum

23X

Dispermic diploidyDispermic diploidy

Paternal chromosomes

only

23X

23X

23X

Partial Mole, PathogenesisPartial Mole, Pathogenesis

69XXY

Normal ovum

23X

Dispermic triploidyDispermic triploidy

Paternal extra set

23Y 23X

23Y 23X23X


Alterations in Alterations in gene expression gene expression

profilesprofiles

Alterations in Alterations in gene expression gene expression

profilesprofiles

Up-regulation and down-regulation of proteins

committed to cell growth control

e.g. Up-regulation of e.g. Up-regulation of growth factor and cytokine growth factor and cytokine

mediated pathways, and mediated pathways, and antiapoptosis genesantiapoptosis genes

Trophoblastic hyperplasiaTrophoblastic hyperplasia

e.g. Down-regulation of e.g. Down-regulation of insulin growth factor insulin growth factor binding proteins and binding proteins and tumor necrosis factor tumor necrosis factor

receptorreceptor

A log plot of microarray experiment demonstrating up-regulation of STAT5B expression and downregulation of 1GFBP5 expression in mole.

Hydatidiform MoleHydatidiform MoleClinical Presentation:

Complete mole:

Vaginal bleeding

Severe anemia

Passage of

hydropic villi

Hydatidiform Mole Hydatidiform Mole

Usually, Usually, in in

associatioassociation with,n with,

Usually, Usually, in in

associatioassociation with,n with,

Excessive uterine enlargementExcessive uterine enlargement

Hyperemesis gravidarumHyperemesis gravidarum

PreeclampsiaPreeclampsia

Markedly elevated hCG 100,000 mIU/mL Markedly elevated hCG 100,000 mIU/mL

HyperthyroidismHyperthyroidism

Theca lutein cystsTheca lutein cysts

Clinical Presentation:Complete mole:


Accurate hCG Accurate hCG testingtesting

Hugh resolution Hugh resolution ultrasonographyultrasonography

The clinical presentation The clinical presentation has changedhas changed

Per-vaginal bleedingPer-vaginal bleedingAn ultrasound showing the classic findings of a “snow storm pattern”

An ultrasound showing the classic findings of a “snow storm pattern”

Table 2: The change of the clinical presentation of molar pregnancy among current patients

Study, site, sample size

Soto-Wright et al, New England (n 74)

Gemer et al,Israel (n 41)

Lindholm & Flam, Sweden (n 75)

Mean maternal Mean maternal ageage

27.7 years(range 16-51)

30.1years

--

Mean estimated Mean estimated gestational agegestational age

11.8 weeks (range 6-22)

10 weeks (range 7–14)

12.4 weeks

Mean uterine Mean uterine size size

12.4 weeks (range 7–20)

10 weeks --

Mean level of Mean level of pre-evacuation pre-evacuation hCGhCG

345 415 mIU/ml (range 828– 1680300)

275 901 IU/l (range 2011– 919 000).

--


Table 2: The change of the clinical presentation of molar pregnancy among current patients

Study, site, sample size

Soto-Wright et al, New England (n 74)

Gemer et al,Israel (n 41)

Lindholm & Flam, Sweden (n 75)

Vaginal Vaginal bleedingbleeding

84% 58% 77%

Uterine size Uterine size greater than greater than that for the that for the expected dateexpected date

28% 44% 20%

Anemia Anemia 4% 2% --

HyperemesisHyperemesis 8% 2% 19%

Preeclampsia Preeclampsia 1.3% 0% 1.3%

Hyperthyroidism Hyperthyroidism -- 0% --

AsymptomaticAsymptomatic 9% 41% 16%



Clinical Presentation: Partial mole:

•History:– Vaginal bleeding – Usually diagnosed as missed or

incomplete abortion

•Physical:– A uterus small or equal to gestational age

Hydatidiform Mole Hydatidiform Mole Diagnosis:

History Clinical examination Ultrasound examination Serum hCG levels Histopathological examination Cytogenetic and molecular

biological examination


Ultrasonography:* The diagnosis of molar pregnancy is

nearly always made by ultrasonography

Complete Complete molemole

•The classical finding is a “snow storm" pattern•Theca lutein cysts are frequent findings on ultrasound

•The classical finding is a “snow storm" pattern•Theca lutein cysts are frequent findings on ultrasound

The snow storm appearance of complete The snow storm appearance of complete hydatidiform molehydatidiform mole

Theca lutein cysts, a frequent finding on Theca lutein cysts, a frequent finding on ultrasoundultrasound


Ultrasonography:

Partial molePartial mole

Abnormal gestational sac The classic vesicular sonographic findings of a complete mole are usually not seenFocal sonographic cystic changes and/or hydropic changes in the placenta are significantly associated with the diagnosis of a partial molar pregnancy

Abnormal gestational sac The classic vesicular sonographic findings of a complete mole are usually not seenFocal sonographic cystic changes and/or hydropic changes in the placenta are significantly associated with the diagnosis of a partial molar pregnancy


Diagnosis: Ultrasonography:

•However, based on ultrasound, correct diagnosis can be suspected in only:

• 84%84% of patients with complete mole and • 30%30% of patients with partial mole (Lindholm and Flam, 1999)

•The accuracy of ultrasonogrophy is gestational age dependent

In comlete mole:• 100%100% of cases cane be diagnosed at a

gestational age of 13 eeks or more• 50%50% of cases cane be diagnosed in

earlier pregnancies(Lazarus et al, 1999)


Diagnosis: Serum hCG levels:

•Serum hCG levels of greater than 92 000 IU/l associated with absent fetal heart beat indicate a diagnosis of complete hydatidiform moles (Romero et al, 1985)

•Serum hCG level decreases quickly if the patient has an abortion, but it does not in molar pregnancy


Diagnosis: Histopathological examination:

• It should always be done as far as possible and samples should be kept for DNA analysis for a final diagnosis when histology can not differentiate molar pregnancy from abortion

Table3: Pathological features of complete and partial hydatidiform mole

Complete Mole Partial Mole

Macro-scopically

A mass of large, edematous villi that are diffusely distributed, typically described as resembling a cluster of grapes

The placental tissue is less bulkyA few enlarged villi with a focal distributionA fetus may be identified grossly that often has multiple congenital anomalies including syndactyly of the fingers & toes

The grape like vesicles in gross appearanceThe grape like vesicles in gross appearance


Complete Mole Partial Mole

Micro-scopically

Enlarged edematous villi which show a central acellular fluid-filled space referred to as a “central cistern” Abnormal trophoblastic proliferation that is circumferential in contrast to normal villi in which trophoblastic proliferation is at one end of the villusAbsence of fetal tissue

Two distinct populations of villi. One with large, edematous villi with central cisterns. The other contains small villi that show some degree of stromal fibrosisAbnormal circumferential trophoblastic proliferationIrregular, scalloped outline to some of the villi, often referred to as “fjord-like” which appear in other microscopic as islands of trophoblast in the interior of villi referred to as trophoblastic pseudoinclusions which are highly suggestive of the diagnosis Fetal tissue, RBSs

Normal villi from first trimester placenta, Normal villi from first trimester placenta, showing directional, polar growth of showing directional, polar growth of trophoblast from one end of the villi toward trophoblast from one end of the villi toward the basal plate. the basal plate.

Villus from a complete mole demonstrating Villus from a complete mole demonstrating the characteristic large, acellular centralthe characteristic large, acellular centralcisterncistern

Villus from a complete mole. There is florid, Villus from a complete mole. There is florid, circumferential hyperplasia of the trophoblast circumferential hyperplasia of the trophoblast around the periphery of the villiaround the periphery of the villi

Low power view of a partial hydatidiform mole Low power view of a partial hydatidiform mole showing the two distinct populations of villi. showing the two distinct populations of villi. Asingle large villus with multiple smaller villiAsingle large villus with multiple smaller villi

Partial mole, showing irregular, scalloped Partial mole, showing irregular, scalloped outline and trophoblastic pseudoinclusionoutline and trophoblastic pseudoinclusion


Partial Mole Complete Mole

CytogeneticsCytogenetics 69, XXX triploidy most common 2+ paternal haploid sets & 1 maternal haploid set

46, XX diploidy most commonAll chromosomes of paternalorigin

Pathology featuresPathology featuresHydropic villiTrophoblastic

proliferationFetus or fetal rbcs

Focal, variableFocal, usually slight

Usually present

Diffuse, often markedDiffuse, variable intensity

Absent

Clinical courseClinical courseClinical or ultrasound

diagnosisUterus large for

gestational datesTheca lutein cystsPre-eclampsiaHyperemesisThyrotoxicosisMalignant sequelae

Rare

Rare

RareRareRare<5%Rarely metastaticPersistent mole

>50%

25–50%

25–35%10–20%5–10%20%10–20% metastatic25–33% choriocarcinoma


Management:

Complete history and physical examinationComplete history and physical examination

InvestigationsInvestigations

Medical and surgical careMedical and surgical care

11

33

22


Management: History and physcal examination:

•Should aim to rule out the classic symptoms and signs that would lead to a diagnosis of:

– severe anemia – dehydration– preeclampsia– thyrotoxicosis

The patient should be stabilized hemodynamically


Management: Investigations:

•Laboratory: Pre-evacuation hCG Complete blood count Electrolytes, BUN, creatinine Liver function tests Thyroid function tests

• Imaging: Pelvic ultrasound Chest x-ray


Management: Medical care:

•Correction of: Anemia Dehydration Hyperthyroidism hypertension


Management: Surgical care:

Suction Suction curettage curettage (with (with

oxytocin or oxytocin or prostaglandin prostaglandin

infusion)infusion)

HysterectomyHysterectomy

•The method of choice•The method of choice

•Increased risk of medical complications

•Associated with a markedly decreased rate of malignant sequelae (3.5%) when compared with suction evacuation.

•Increased risk of medical complications

•Associated with a markedly decreased rate of malignant sequelae (3.5%) when compared with suction evacuation.


Complications associated with molar pregnacy: Those related to the increased

trophoblastic tissue volume:•Theca-lutein cysts•Pregnancy-induced hypertension,•hyperthyroidism, •Respiratory distress•Hyperemesis

Those related to its management:•Uterine perforation

Hydatidiform Mole, Hydatidiform Mole, complicationscomplications

Theca-lutein cysts: Prevalence:

• Clinically evident theca lutein cysts (usually >5–6 cm) are detected in about 25-35% of women with molar pregnancies

Association:• They usually correlate with marked elevation

of serum hCG levels above 100,000 IU/l Complications:

• Pain or pressurePain or pressure that may require percutaneous aspirations.

• Torsion, rupture, or bleedingTorsion, rupture, or bleeding are rare complications that can require oophorectomy

• Bilateral theca letein cysts increase the risk of post-molar GTD post-molar GTD

Course:Course:• The mean time for theca luteal cysts to regress

is approximately 8 weeks

Hydatidiform Mole, complicationsHydatidiform Mole, complications

Respiratory distress syndrome: Prevalence:

•Rare Pathophysiology:

•Embolization of trophoblastic tissue•Transient impairment of left ventricular

function during induction of anesthesia for suction D&C of molar pregnancy

•coexisting conditions such as anemia, hyperthyroidism, hypertension from preeclampsia

Risk factors:•Uterine size larger than 14 to 16 weeks’•High levels of hCG


Respiratory distress syndrome: Presentation:

•Tachypnia and tachycardia following evacuation

•Bilateral pulmonary infiltrates on chest x-ray

Management:•Central venous monitoring•Ventilatory support

Course:• It should resolve within 24 to 48

hours after molar evacuation


Hyperthyroidism: Prevalence:

•Clinical hyperthyroidism is seen in less than 10% of patients with molar pregnancies

•A small number of patients may have elevated thyroid function tests without clinical evidence of disease

Management:•Beta-blockers should be

administered prior to molar evacuation to prevent thyroid storm that may be induced by anesthesia and surgery.

Hydatidiform MoleHydatidiform MoleA hydatidiform mole and a co-existent

fetus: Prevalence:

• Rare (1 in 22,000–100,000)• partial moles and twin gestations with co-

existent fetuses and molar gestations Diagnosis:

• Usually, by ultrasound• Few, after examination of the placenta

following delivery Complications:

• Increased risk of medical complications• Increased risk for postmolar gestational

trophoblastic disease Management:

• No clear guidelines for management

Hydatidiform Mole Hydatidiform Mole Risk Factors for post-molar gestational

trophoblastic disease: Advanced maternal age Factors that reflect the volume of trophoblastic

tissue:Clinical factors that are associated with• high hCG levels (>100,000 mIU/mL)• uterus large for date, • bilateral theca lutein cysts, • Respiratory distress syndrome after molar

evacuation,• eclampsia, • hyperthyroidism, • Uterine subinvolution with post evacuation

hemorrhage.(With any one of these factors or a combination of

many, the risk of post-molar GTD has ranges from 25% to 100%)

Hydatidiform Mole Hydatidiform Mole Risk Factors for post-molar gestational

trophoblastic disease: The presence of “invasive trophoblast

antigen (ITA)” which has 100% sensitivity and specificity for invasive trophoblastic tumors(Cole et la, 2003)

*There is no correlation between the degree of anaplasia and the risk of post-molar GTD

Hydatidiform Mole Hydatidiform Mole Prophylactic Chemotherapy:

In one randomized clinical trial, a single course of methotrexate and folinic acid reduced the incidence of postmolar trophoblastic disease from 47.4% to 14.3% (P <.05) in patients with high-risk moles:

• hCG levels greater than 100,000 mIU/mL,• uterine size greater than gestational age, • ovarian size greater than 6 cm),

However, the incidence was not reduced in patients with low-risk moles

On the other hand, the use or prophylactic chemotherapy increases the risk of drug resistance

Because of the excellent primary cure rates among women with post-molar GTD, and mortality achieved by monitoring patients with serial hCG determinations and instituting chemotherapy only in patients with postmolar gestational trophoblastic disease outweighs the potential risk and small benefit of routine prophylactic chemotherapy.

Hydatidiform MoleHydatidiform MoleSurveillance after molar pregnancy

evacuation: Rationale:

• Prompt identification of patients who develop malignant postmolar gestational trophoblastic disease

Method:• Serial quantitative serum hCG

determinations using commercially availableassays capable of detecting β-hCG to baseline values(<5 mIU/mL)

– Frequency: within 48 hours of evacuation, weekly while elevated and then monthly when undetectable for 6 months in the case of partial moles and 12 months in the case of complete moles

• Pelvic examination:– Duration: while hCG is elevated to monitor

the involution of pelvic structures and to aid in the identification of vaginal metastasis

Hydatidiform Mole Hydatidiform Mole Surveillance after molar pregnancy evacuation:

Contraception:• Rationale:

– Pregnancy obscures the value of monitoring hCG levels during this interval and may result in a delayed diagnosis of postmolar malignant gestational trophoblastic disease

• Method:– Oral contraceptive pills Advantages:– They do not increase the incidence of postmolar

gestational trophoblastic disease – They do not alter the pattern of regression of

hCG values– In a randomizedstudy, by Berkowitz et al in 1998,

patients treated with oral contraceptives had one half as many intercurrent pregnancies as those using barrier methods, and the incidence of postmolartrophoblastic disease was lower in patients using oral

Hydatidiform Mole Hydatidiform Mole Surveillance after molar pregnancy evacuation:

What are the characteristics of false-positive hCG values, also known as “phantom hCG”?

• False positive hCG assays have been identified recently

• Cause: the presence of non-specific heterophil antibodies in the patients’ sera directed against animal antibodies present in commercial kits

• Should be suspected if hCG values plateau at relatively low levels and do not respond to therapeutic maneuvers

• Evaluation of patients with suspected false positive hCG:

• Urinary hCG• Serial dilutions of the serum

Hydatidiform Mole Hydatidiform Mole Prognosis:

Post-molar gestational trophoblastic disease:

• Risk:– Following complete mole: 20%– Following partial mole: 5%

• Type:– 70% to 90% are persistent or invasive moles– 10% to 30% are choriocarcinomas

• Diagnosis:– A rising, plateauing, or persistent elevation of

human chorionic gonadotropin after evacuation of a hydatidiform mole or an ectopic or term pregnancy


The current FIGO criteria for diagnosis of post-molar GTD

a) Four values or more of hCG documenting a plateau (±10% of hCG value) over at least 3 weeks: days 1, 7, 14, and 21.

b) A rise of hCG of 10% or greater for 3 values or longer over at least 2 weeks; days 1,7 and 14.

c) The presence of histologic choriocarcinoma.

d) Persistence of hCG 6 months after moleevacuation.

Pregnancy after Hydatidiform Pregnancy after Hydatidiform Mole:Mole:

• Risk of another molar pregnancy:– Increased by 10-fold (1–2% incidence)

• Current recommendations for management of subsequent pregnancies:

– an early ultrasound to confirm normal gestational development and dates

– A chest x-ray to screen for occult metastasis masked by the hCG rise of pregnancy

– Examination of the placenta or products of conception histologically at the time of delivery or evacuation for evidence of occult trophoblastic disease

– An hCG level should be obtained 6 weeks post evacuation or delivery to confirm normalization.

presented by: dr. mashael shebaili assistant prof. & consultant ob/gyne department

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