Aetiology & Abnormal Presentation Of Molar Pregnancy,

AETIOPATHOGENESIS & ABNORMAL PRESENTATION OF HYDATIDIFORM MOLE

06/29/09 23:46

Dr.Manoranjan Mahapatra, Asst. Prof. (O&G dept.) VSS Medical College, Burla

1

Marching in right direction ------

06/29/09 23:46

2

The critical dependent path-----

06/29/09 23:46

3

Right initiation for embryogenesis----

06/29/09 23:46

4

Other side of coin------

‘white currants in black currant juice’ Prune juice bleeding 06/29/09 23:46

5

Where is the fault ????

06/29/09 23:46

6

Salute -----------

‘Hippocrates’- 400 BC “dropsy of uterus”

Aetius - 1600 AD – hydatid mole 06/29/09 23:46

7

GESTATIONAL TROPHOBLASTIC DISEASE(GTD)

• Hydatiform mole • Invasive mole • Choriocarcinoma • Placental site trophoblastic tumor 06/29/09 23:46

8

Molar Pregnancy Background

Based on genetic and histo-pathological features. Hydatidiform mole is subdivided into • complete • partial mole • Genetic analysis by — *Chromosomal restriction fragment length polymorphisim analysis in molar &placental tissues * locus 06/29/09 23:46 specific minisatellite DNA probes

9

FEATURES OF PARTIAL AND COMPLETE MOLE Complete mole Fetal or embryonic tissue

absent

Hydatiform swelling of chorionic villi Trophoblastic hyperplasia

Karyotype

Partial mole present

extensive extensive

diploid 46XX (90%)

focal

focal

Triploid (69 XXX/XXY)

46XY (10%)

06/29/09 23:46

10 Cohn DE, Herzog TJ. Curr Opin Oncol 2000 Sep; 12(5):492-6

Complete molar pregnancy Complete hydatidiform mole forms a multivesicular mass with diffuse hydropic villi and a variable degree of trophoblastic proliferation.

• no evidence of a foetus. • This conceptus is diploid • androgenetic in origin.

06/29/09 23:46

11

HYDATIDIFORM MOLE Incidence

North America and Europe: Partial mole

1/700

Complete mole

1/1500-2000

Asian Countries: Partial mole

1/120

Complete mole

1/350-500

06/29/09 23:46

12

HYDATIDIFORM MOLE Risk factors

1. Maternal age

> 40 years < 15 years

2. Paternal age > 45 years 3. Previous hydatidiform mole

1st 2nd

1-2%

15-28%

4. Vitamin A deficiency 06/29/09 23:46

13

06/29/09 23:46

14

EXPLORATION OF CYTOGENETICS --• In the mouse, one can remove the paternal pronucleus from a fertilized oocyte, and replace this by a second maternal pronucleus, thus creating an embryo where all chromosomes have a maternal origin • These so called gynogenotes ( parthenogenesis) fail to complete normal development. No extraembryonic components are formed and the embryoblast develops into a teratoma (Surani et al., 1984, 1986). • In androgenotic embryos, containing paternal chromosomes only. fail to develop an embryoblast whereas the trophoblast proliferates excessively, resulting in a hydatidiform mole (McGrath and Solter, 1984). 06/29/09 23:46

15

Trophoblast vs embryoblast • The ratio between the maternal and paternal genomes is critical in determining the development of both the embryonic and extra-embryonic tissues, • excess of paternally derived chromosomes leading to a complete HM (no maternal genome) or partial HM (lower amount of maternal chromosomes)

06/29/09 23:46

16

complete mole --Karyotype---• 90 % - 46,XX karyotype • 10% - 46,XY karyotype • 46,YY has never been observed ( non-viable), • hydatidiform mole, all mitochondria have an exclusively maternal origin (Azuma et al., 1991 06/29/09 23:46

17

PARENTAL ORIGIN OF COMPLETE MOLE

• Source of diploid chromosome in c. mole---, - Uniparental origin - all chromosomes paternal origin - Biparental origin genomic imprinting plays a role in tumourigenesis 06/29/09 23:46

18

UNIPARENTAL (ANDROGENIC) CYTOGENETICS OF H.MOLE Arise as a consequence of • duplication of the haploid sperm following fertilisation of an ‘empty’ ovum ( diandry) (Lawler et al., 1982 ) -- ~80% • Some complete moles arise after dispermic fertilisation of an “empty’ ovum. (dispermy) (Kovacs et al., 1991 ) ~ 20% •

A third possible cause, the fertilization of an empty oocyte by a diploid sperm cell, is extremely rare (Zaragoza et al., 2000 )

06/29/09 23:46

19

-generation of an empty ovum -Endoduplication of male pronecleus -/polyspermy

“Unfortunate daughter of faulty FATHER / PARENTS” 06/29/09 23:46

20

COMPLETE MOLE Empty ovum

ENDODUPLICATION

46XX 46xx

23X

A single sperm fertilizes an empty ovum, with endoduplication of the 23X haploid set of chromosomes, giving rise to a homozygous diploid complete mole.

Complete Mole (46XX diploid) DIANDRY

Empty ovum

23X

06/29/09 23:46

46XX or 46XY 23X or Y

DISPERMY

Complete Mole (46XX or 46XY, diploid)

No 46 YY

Two sperms with two independent haploid sets of chromosomes fertilize an empty ovum, producing a dyspermic heterozygous complete mole with either 46XX or 46XY karyotype. 21 Modified from Cheung, 1995

Generation of enucleated oocytes !!! • is not clear, • but one possible error is a non-disjunction of all chromosomes during meiosis, with all chromosomes ending up in one of the polar bodie

06/29/09 23:46

22

Imprinted genetics •

The chr 11p15.5 harbours several genes with a different imprinting pattern

• • •

p57kip2, IPL H19

• •

IGF2 KCNQIOT1

•

In a hydatidiform mole, the presence of paternally derived chromosomes only leads to an abnormal expression pattern of these imprinted genes.

06/29/09 23:46

paternally imprinted or silenced

maternally imprinted.

23

Chromosome – 11p15.5

06/29/09 23:46

24

BIPARENTAL COMPLETE MOLE (imprinting switch) •

In exceptional cases ( 10 families have been reported) of histologically typical complete hydatidiform mole, a biparental origin of the chromosomes has been found (reviewed by Fisher et al., 2004b ).

•

The interpretation is that the maternal chromosomes behave as if they were of paternal origin.

•

Genomic imprinting is a reversible process, whereby the imprint is reset during gametogenesis according to the sex of the parent.

•

During oogenesis, genes silenced on the paternal chromosome must be reactivated, whereas genes active on the paternal chromosome must be silenced, and vice versa for spermatogenesis

06/29/09 23:46

25

•

At the DNA level, the signal mediating genomic imprinting is methylation of CpG residues in specific chromosomal regions

•In the normal situation, a differentially methylated region (DMR) in the KCNQIOT1 gene becomes ---methylated during oogenesis -demethylated during spermatogenesis •In the paternal HM, all imprinted genes carry an exclusively paternal imprinting or methylation pattern. •In the biparental HM, methylation but not demethylation is defective in oogenesis, leading to an abnormal methylation of maternally imprinted genes such as KCNQIOT1. 06/29/09 23:46

26

abnormal methylation of maternally imprinted genes such as KCNQIOT1.

FAULT

06/29/09 23:46

27

WAY FORWARD THOUGHTS---• Methylation depends on specific enzymes, DNA methyltransferases (Dnmt) and these are therefore excellent candidate genes for the disorder. • However, so far, no mutations have been reported in these genes (Hayward et al., 2003 ). • Meanwhile, as an alternative means to identify the molecular basis of this autosomal recessive disorder, linkage analysis has been performed in families with the disorder. • This has led to the identification of a relatively small region on chromosome 19q (Moglabey et al., 1999 ; Hodges et al., 2003 • Mutation analysis of candidate genes in this region will eventually lead to the identification of the underlying gene, and the elucidation of the pathogenesis of the disorder. 06/29/09 23:46

28

FOCAL HYDROPIC CHANGES OF PLACENTA

06/29/09 23:46

DEFECTIVE FETUS WITH HYDROPIC PLACENTA

29

Partial mole • The partial mole is caused by a triploidy, • Triploidy is one of the most common chromosomal anomalies, with an incidence of 10% in spontaneous abortions (Hassold et al., 1980 ) • The majority of triploidies are sporadic, but a few cases have been reported with recurrent triploidy

06/29/09 23:46

30

Triploid origin----•

Diandry-- Mostly following dispermic fertilisation of an ovum. (Zaragoza et al., 2000

•

Digynae-- In few failure of meiosis I or II in the oogenesis leads to Triploidy with 46 maternally derived chromosomes and 23 paternal (Zaragoza et al., 2000 ).

06/29/09 23:46

31

PARTIAL MOLE (DIANDRY)

23Y

23X

23X

23X

23X 69XXY 23Y

23X Dyspermy 23X/23Y or 23X/23X

Partial Mole (69XXY, or 69XXX, or 69XYY triploid)

Fertilization of a normal 23X haploid ovum by two sperms, producing a triploid partial mole with either 69XXY, 69XXX or 69XYY karyotype

06/29/09 23:46

32 Modified from Cheung, 1995

PARTIAL MOLE (DIGYNAE)

2 3Y/ X

23X 23X 46XX DIPLOID OVUM

06/29/09 23:46

23X

23X 69XXY

23Y/ X Partial Mole (69XXY, or 69XXX, triploid)

33 Modified from Cheung, 1995

Triploidy features-----Diandry ---double paternal chromosome – a focal molar placenta the pregnancy rarely persists beyond 20 weeks. - Digynae - double maternal chromosome – the pregnancy may persist into the third trimester. The placenta may be of normal fetus demonstrates severe asymmetrical IUGR ✂ mild ventriculomegaly, ✂ micrognathia, ✂ cardiac abnormalities, ✂ myelomeningocoele, ✂ syndactyly, ✂ ‘hitch-hiker’ toe 06/29/09 23:46 deformity.

34

Mosaic triploidy *Triploidies are almost lethal, some children carry a triploidy in only part of their cells, with the remaining cells having the normal 46 chromosomes. This is called a mosaic triploidy. *The mosaicism may originate from the incorporation of a second sperm pronucleus into one embryonic blastomere *In others, a maternal origin was detected, through the fusion of one of the (haploid) second polar bodies with an early blastomere *In one instance, the most likely explanation was chimaerism with fusion of two separate zygotes developing into a single individual *Mosaic triploidy can be viable, depending on the percentage35 of abnormal cells and their tissue distribution

06/29/09 23:46

06/29/09 23:46

36

COMPLETE HYDATIFORM MOLE CLINICAL FEATURES Vaginal bleeding (anemia)

97%

Excessive uterine size

50%

Theco-lutein ovarian cysts

50%

Preeclampsia

27%

Hyperemesis

25%

Hyperthyroidism

7%

Trophoblastic embolization

2%

(respiratory distress) NOTE – SOME ABNORMAL PRESENTATION ARE DUE TO HIGH LEVEL OF hCG 06/29/09 23:46

37

THECA LEUTIN OVARIAN CYST • • • • •

Incidence - 20- 60 % (avg – 50 %) Size - > 6cm Bilateral Moltilocular Functional ~ secrets E2 & progesteron corresponds with hCG level • Regresses spontaneously after expulsion • Very rarely undergo torsion 06/29/09 23:46

38

PREECLAMPSIA Incidence - ~ 27% of complete mole If PIH is found < 20 wks of GA suspect HM Provocating factors – 8. Very high hCG level 9. Excessive uterine size - Convulsion is very rare - Subsides dramaticaly after expulsion of mole 06/29/09 23:46

39

HYPEREMESIS • Aetiology --- high level of hCG - excessive uterine size -severe disturbance is infrequent -subsides after the expulsion of mole 06/29/09 23:46

40

HYPERTHYROIDISM alfa subunit of hCG & TSH simulate molecularly • High hCG ----- high level of free T3 & T4 Menifestations ---• • • • •

-supraventricular tachycardia Palpitation Goitre Increased sweating Heat intolarance

06/29/09 23:46

41

Thyroid storm Hyper thyroidism precipitate by – Toximia Infection Surgery Anaesthesia ventricular Tachycardia

Menifestations Delirium , convulsion Hyperthermia Fibrillation CVS collapse Treatment ---- promt tr. With - Beta blockers ,Anti thyroid medication 06/29/09 23:46

42

TROPHOBLASTIC EMBOLISATION • •

Incidence – 2% of mole Features of respiratory insufficiency --tachycardia, tachypnea, anxiety, confusion immediately after the evacuation • Reasons --6. embolisation of molar tissue to pulmonary vasculature D/D -• Cardiovascular complication of pre eclampsia • Thyroid storm • Massive fluid replacement 06/29/09 23:46

43

PARTIAL MOLE Way of encountering---1- missed abortion & incomlete abortion conceptus --- H/P & DNA analysis 2- Morphologic analysis of fetus & placenta 3- USG – -- high suspicion in early trimester --TIFA – anomaly suggesting triploidy / Placental hydropic changes 06/29/09 23:46

“Swiss cheese”

44

examination of products of conception

--All products of conception obtained after evacuation (medical or surgical) should undergo histological examination in order to exclude trophoblastic neoplasia. --Ploidy status may help in distinguishing partial from complete moles.

06/29/09 23:46

45

Diagnosis of partial mole (very early stage)

Presence of multiple soft markers 4. 5.

cystic spaces in the placenta ratio of transverse to AP dimension of the gestation sac of > 1.5

When there is diagnostic doubt about the possibility of a combined molar pregnancy with a viable fetus then ultrasound examination should be repeated before intervention.

06/29/09 23:46

46

PARTIAL MOLE FIRST TRIMESTER DIAGNOSIS

 Discrepancy between CRL and LMP  Increased fetal nuchal translucency  Increased ß HCG levels for gestational age

06/29/09 23:46

47

PARTIAL MOLE - USG – 2nd trimester More than 90% of partial moles are found in triploid fetuses. Feto-placental ultrasound findings

%

Fetal anatomic defects

92.9

Asymmetrical growth restriction

64.2

Placental molar changes

28.6

Amniotic fluid changes

47.1

Olygohydramnios

44.2

Polyhydramnios

2.9

06/29/09 23:46

Jauniaux E, Nicolaides KH: Placenta 1997, 18; 701-6

48

Variables

Ultrasound abnormalities in triploid fetuses

Malformed hands Ventriculomegaly Heart abnormalities Micrognathia Hyperechogenic bowel Renal malformations Increased nuchal thickness Spina bifida Talipes equinovarous Dandy-Walker malformation Collapsed stomach Single umbilical artery Omphalocele Holoprosencephaly Hydrops Bilateral pleural effusion Ascites Diaphragmatic hernia Kyphoscoliosis Cleft lip and palate 06/29/09 23:46

% 52.3 36.9 33.9 26.2 15.4 12.3 12.3 7.7 7.7 7.7 7.7 6.2 6.2 3.1 3.1 3.1 3.1 1.5 1.5 1.5

49 Jauniaux E, Nicolaides KH: Placenta 1997, 18; 701-6

Abnormal encountering of mole GTD and Twin Pregnancy--Incidence

1:22.000 – 1:100.000

Variants

viable fetus with partial hydatiform mole viable fetus with complete hydatiform mole

06/29/09 23:46

50

GTD and Twin Pregnancy

1. If there is one viable fetus and the other pregnancy is molar, the pregnancy could be allowed to proceed if the mother wishes, following appropriate counselling. 2- The probability of achieving a viable baby is 40% and there is a risk of complications such as pulmonary embolism and pre-eclampsia. 3- There is no increased risk of developing persistent GTN after such a twin pregnancy and outcome after chemotherapy is unaffected.

06/29/09 23:46

51

COMPLETE HYDATIFORM MOLE AND COEXISTING VIABLE FETUS

Outcome !!!

Miscarriage

50%

Stillbirth <32 wks

30%

Preterm delivery <32 wks

30%

Pre-eclampsia

> 50%

06/29/09 23:46

52

SUMMARY -----MISTAKES & PENALTY • UNFORTUNATE PENALTY TO A LADY FOR THE PARTIAL OR COMPLETE ALLOGRAFT DUE TO A SERIES OF MISTAKES OF FERTILISATION.

• PENALTY MAY BE SIMPLE TO LIFE THRETNING RESULTING IN MORBIDITY & MORTALITY

06/29/09 23:46

53

06/29/09 23:46

54