presented by: dr. mashael shebaili assistant prof. & consultant ob/gyne department
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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
Factors Complete Mole
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
Factors Complete Mole
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
Hydatidiform MoleHydatidiform Mole
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:
Hydatidiform Mole Hydatidiform 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).
--
Hydatidiform Mole Hydatidiform Mole
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%
Hydatidiform Mole Hydatidiform Mole
Hydatidiform Mole Hydatidiform Mole
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
Hydatidiform Mole Hydatidiform Mole Diagnosis:
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
Hydatidiform Mole Hydatidiform Mole Diagnosis:
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
Hydatidiform MoleHydatidiform Mole
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)
Hydatidiform Mole Hydatidiform Mole
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
Hydatidiform Mole Hydatidiform Mole
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
Table3: Pathological features of complete and partial hydatidiform mole
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
Table3: Pathological features of complete and partial hydatidiform mole
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
Hydatidiform MoleHydatidiform Mole
Management:
Complete history and physical examinationComplete history and physical examination
InvestigationsInvestigations
Medical and surgical careMedical and surgical care
11
33
22
Hydatidiform Mole Hydatidiform Mole
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
Hydatidiform Mole Hydatidiform Mole
Management: Investigations:
•Laboratory: Pre-evacuation hCG Complete blood count Electrolytes, BUN, creatinine Liver function tests Thyroid function tests
• Imaging: Pelvic ultrasound Chest x-ray
Hydatidiform Mole Hydatidiform Mole
Management: Medical care:
•Correction of: Anemia Dehydration Hyperthyroidism hypertension
Hydatidiform Mole Hydatidiform Mole
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.
Hydatidiform MoleHydatidiform Mole
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
Hydatidiform Mole, complicationsHydatidiform Mole, complications
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
Hydatidiform Mole, complicationsHydatidiform Mole, complications
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
Hydatidiform Mole Hydatidiform Mole
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.