18.05.03 Triploidy and molar pregnancy

Question 1

Give a brief overview of triploidy.

Answer 1

The term used for an additional set of chromosomes resulting in a count of 69 (3n).

Incidence of triploidy in recognised pregnancies is 1-3%

99.9% of cases spontaneously abort during the first trimester of pregnancy or are lost during the second trimester as a fetal death in utero

Estimated that 1/30,000 pregnancies at 16 weeks are triploidy, 1/250,000 at 20 weeks

Liveborn triploids have an extremely poor prognosis (survival <1 month)

An increase in maternal age is not a risk factor.

Question 2

What is type I triploidy/diandry?

Answer 2

Double paternal contribution

Question 3

What proportion of triploidy events does diandry account for? Give three clinical features associated with diandric triploidy.

Answer 3

Show cystic villi that have trophoblastic hyperplasia which is called a partial hydatidiform mole (accounts for >90% of HM).

Most common (60-80%) type of triploidy

Generally abort between the 10-20 week period, mean at 12 weeks

Before 6 weeks gestation, these cases do not appear as partial hydatidiform moles, however as the gestation increases, the placenta develops a classical partial hydatidiform mole structure.

Symmetrical IUGR with structural abnormalities, including neural tube defects

Normal head size

Oligohydramnios

High maternal hCG (80% of cases)

Increased risk of pre-eclampsia

Question 4

How can diandric triploids arise?

Answer 4

1) Majority as a result of fertilisation of a normal egg by 2 sperm (dispermy)
2) Minority as a result of fertilisation of a normal egg by a diploid sperm(caused by complete nondisjuction of entire chromosome set at spermatogenesis)

Question 5

What is type II triploidy/digyny?

Answer 5

Double maternal contribution

Question 6

Give three clinical features associated with digynic triploidy.

Answer 6

Non hydropic villi
Placenta is non molar and generally small (non-cystic)
Majority of digynic triploids abort early (mean 10 weeks), however more likely that diandric to survive to second trimester
IUGR (often asymmetrical)
Large head
Oligohydramnios
Holoprosencephaly

Question 7

How can digynic triploids arise?

Answer 7

1) Fertilisation of a diploid egg (nondisjunction of entire chromosome set at MI or MII) by a haploid sperm
2) Retention of a polar body in a fertilised egg
3) Fertilisation of an ovulated primary oocyte
4) Fusion of 2 eggs (dieggy) and fertilisation by a haploid sperm

Question 8

What is the possible cause of the different presentation of dygynic and diandric triploids?

Answer 8

Differing clinical presentation of diandric/digynyic triploidy is presumed to reflect the influence of differing imprinted states

Question 9

Give three clinical features of triploidy.

Answer 9

Face to chest fusion
Limb growth / development retardation/growth disorganisation
Macrocephaly
Midface dysplasia
Neural tube defects /open aterior trunk revealing heart and other organs
Syndactyly (usually 3/4)
Heart/renal defects
Cleft lip/palate 
Hydrocephalus

Question 10

What are the recurrence risk associated with triploidy?

Answer 10

Most cases are sporadic
Recurrence risk not increased above risk for general population
Diandric with partial mole = 1-1.5%
Dygynic - recurrent in a few famililes

Question 11

What is a hydatidiform mole?

Answer 11

Most common form of gestational trophoblastic disease

Arise from placental villus trophoblast and vary in propensity for local invasion and metastasis

Question 12

What are the pre-malignant and malignant form of gestational trophoblastic disease?

Answer 12

pre-malignant - complete and partial hydatidiform moles

malignant - invasive mole, choriocarcinoma, placental site trophoblastic tumours

Question 13

Give an overview of a complete hydatidiform mole, including incidence.

Answer 13

Diploid (46 chromosomes) androgenetic pregnancy where both sets of chromosomes are paternally derived

90% 46,XX, 10% 46,XY

Incidence of 1.3 per 1000 live births (Melamed, 2016)

75% of hydatidiform moles are complete moles

Question 14

What are the clinical features of complete hydatidiform moles?

Answer 14

1) No fetal development
2) Placenta has swollen villi with marked and widespread hypoplasia of the trophoblast
3) Extensive hydrops
4) Generally evacuated before 12 weeks gestation
5) Clinical symptoms include hypertension, oedema and vaginal bleeding

Question 15

Give an overview of a partial hydatidiform mole, including incidence.

Answer 15

Triploid (69 chromosomes) with the additional set of chromosomes being paternal in origin (diandric)

69,XXX or 69,XXY or 69XYY(Rare)

Incidence is 1.1 per 1000 live births (Melamed, 2016)

Question 16

What are the causes of complete hydatitidform moles?

Answer 16

20% - dispermic fertilisation (two sperm fertilising an empty egg; can be either XX or XY)

or

80% - monospermic fertilisation (single spermatozoan fertilises an empty egg with the male pronucleus dividing to form a diploid nucleus; can only be XX as YY zygotes lack essential genes on X chromosome necessary for development).

Question 17

Evidence for the natural occurrence of anucleate eggs has never been observed and postzygotic diploidization of triploids provides a natural explanation for 2n homozygous and heterozygous androgenetic moles and may also explain unusual cases of chimerism and mosaicism.

Answer 17

However, this theory cannot explain the 4:1 frequency of homozygous versus heterozygous androgenetic moles.

Question 18

How are partial hydatidiform defined?

Answer 18

4 histological features:

1) Two populations of villi- small normal appearing and large hydropic
2) Enlarged villi
3) Irregular villi have scalloped edges
4) Trophoblast hypoplasia

Question 19

What are the clinical features of a partial hydatidiform moles?

Answer 19

Fetal development occurs and includes stromal blood vessels, umbilical cord, amnio and chorionic plate but malformations of fetal parts are evident

Question 20

How are molar pregnancies diagnosed?

Answer 20

Molar pregnancies usually present with painless vaginal bleeding in the fourth to fifth month of pregnancy

The uterus may be larger than expected, or the ovaries may be enlarged. There may also be more vomiting than would be expected (hyperemesis). Sometimes there is an increase in blood pressure along with protein in the urine.

Blood tests will show very high levels of hCG

The diagnosis is strongly suggested by ultrasound as the mole resembles a bunch of grapes

A definitive diagnosis requires histopathological examination

Question 21

What is the recurrence risk for a complete hydatidifirm mole?

Answer 21

~1 in 100 in next pregnancy

Question 22

What is the recurrence risk following two consecutive complete hydatidifirm mole?

Answer 22

~ 1 in 5

Question 23

What is the recurrence risk for a partial hydatidifirm mole?

Answer 23

~1 in 600

Question 24

Give an overview of familial recurrent hydatidiform moles (FRHM).

Answer 24

Women have inherited predisposition to recurrent molar pregnancies, in particular complete hydatidiform moles. and are unlikely to achieve any normal, healthy pregnancies - 75% of their pregnancies will develop as a CHM.

~70 reported families and it is estimated 1 in 640 women with a CHM have FRHM

Question 25

What is the difference beween FRHM CHM and sporadic CHM?

Answer 25

CHM associated with FRHM are diploid and are genetically biparental in origin with both a maternal and paternal contribution

Complete hydatidiform moles which are androgenetic and completely paternal in origin

Biparental CHMs are histologically indistinguishable from sporadic CHMs

Question 26

Which two genes are associated with FRHM? What is their proposed function?

Answer 26

NLRP7 at 19q13.42 (OMIM: 609661)
KHDC3L at 6q13 (OMIM: 611687)

Both thought to have roles in maintaining the maternal imprint within the ovum

Question 27

What is persistent GTD?

Answer 27

GTD is not cured by initial evacuation

Neoplastic transformation of moles

10% of patients who have had a CHM require treatment with chemotherapy

Question 28

What are the proposed mechanism for persistent GTD?

Answer 28

Possible that a recessive allele is unmasked by a double paternal complement

Other possibility is that the abnormal imprinting may also have a role in the malignant potential

Question 29

What is an invasive mole and how does it present?

Answer 29

~15% risk of an invasive mole following a complete mole, 0.5% risk following a partial mole

Invasive mole usually arises from a complete mole and is characterised by invasion of the myometrium, which can lead to perforation of the uterus.

The usual presentation is with hCG elevations following a previous molar pregnancy, other clinical features can include abnormal bleeding, abdominal pain or swelling.

Question 30

What is gestational choriocarcinoma and how does it present?

Answer 30

Malignant

Highly invasive malignant tumour of the uterine wall

~3% risk of choriocarcinoma following complete mole, 0.1% risk following a partial mole

The clinical presentation of choriocarcinoma can be from the disease locally in the uterus leading to bleeding, or from distant metastases that can cause a wide variety of symptoms with the lungs, central nervous system and liver the most frequent sites of distant disease.

Increased levels of hCG and reproductive history usually provides diagnosis rather than performing a biopsy. There is a risk of haemorrhage if a biopsy is taken.

Question 31

What is Placental Site Trophoblastic Tumour (PSTT) and how does it present?

Answer 31

Placental site trophoblast tumours are the least common form of gestational trophoblast disease; < 2% of all cases.

PSTT most commonly follows a normal pregnancy but may occur after molar pregnancy

The average interval between the prior pregnancy and presentation is 3.4 years.

The clinical presentation of PSTT can range from slow growing disease limited to the uterus to more rapidly growing metastatic disease that is similar in behaviour to choriocarcinoma.

The most frequent presentations are abnormal bleeding or amenorrhea.

PSTT is diploid and arises from the non-villous trophoblast and the pathology is characterised by intermediate trophoblastic cells with vacuolated cytoplasm, the expression of PLAP rather than hCG and the absence of cytotrophoblast and villi.

Question 32

How are GTDs treated?

Answer 32

uction evacuation is recommended for complete and partial molar pregnancies.

After a molar pregnancy hCG levels should be monitored for a period of time (usually a weekly blood test).

Monitoring for up to 2 years following a complete molar pregnancy and up to 6 months following a partial molar pregnancy

To begin with the level of hCG will be in the millions however should drop off dramatically and be within the normal range within 8 weeks

Pregnancy should be avoided until after the completion of the monitoring period

Chemotherapy.

Question 33

When is chemotherapy indicated in treatment for GTD?

Answer 33

Chemotherapy recommended if:

Metastases in brain, liver, GI, lung found on XR

Histological evidence of choriocarcinoma

Rising or raised levels of hCG

The standard chemotherapy treatment is Methotrexate for low risk trophoblastic disease, generally well tolerated without much major toxicity

Most intense multi-agent chemotherapy is used for high risk trophoblastic disease