20.05.03 Triploidy and molar pregnancies

Question 1

What is triploidy?

Answer 1

• Additional set of chromosomes resulting in a count of 69 (3n)
• Found in 1-3% of pregnancies
• Most abort during first trimester, very few recorded to have survived to birth
• Clinical features = face to chest fusion, limb growth retardation, macrocephaly, midface dysplasia, neual tube defects, cleft lip, heart/renal defects
• Most cases are sporadic, no increased recurrence risk

Question 2

What is diandry?

(Type 1 triploidy)

Answer 2

• Triploidy caused by double PATERNAL contribution (60-80% of cases)
• Have cystic villi that have trophoblastic hyperplasia which is called a partial hydatidiform mole
• Usually arise from:
  1) Fertilisation of a normal egg by 2 sperm (dispermy) - most cases
  2) Fertilisation of a normal egg by a diploid sperm (caused by complete nondisjuction of entire chromosome set at spermatogenesis)
• Mean abortion at 12 weeks
• Get symmetrical IUGR, normal head size, large placenta and oligohydramnios
• 80% of women also get high maternal hCG levels

Question 3

What is digyny?

(Type 2 triploidy)

Answer 3

• Double MATERNAL contribution
• Non hydropic villi and placenta is non molar and generally small
• Can arise from:
  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
• Mean abortion at 10 weeks
• • Get asymmetrical IUGR, large head, small placenta and oligohydramnios

Question 4

What is a Hydatidiform Mole?

Answer 4

• Most common form of gestational trophoblastic disease (GTD)
• WHO classification divides GTD into:
  1) Pre-malignant forms
• Complete hydatidiform mole
• Partial hydatidiform mole

2) Malignant forms

• Invasive mole
• Choriocarcinoma (trophoblastic cancer)
• Placental site trophoblastic tumours
• Arise from placental villous trophoblast and vary in propensity for local invasion and metastasis.
• Most cases of malignant GTD (95%) can be successfully treated and cured if diagnosed early and adequate follow-up care is provided.
• 10% of patients with a CHM require chemotherapy for malignant GTD
• All GTD tumours produce human chorionic gonadotrophin (hCG) and this is used as a unique biochemical marker to aid in early detection, diagnosis and follow-up.

Question 5

What is a complete mole and how does it arise?

Answer 5

• Diploid conception - two PAT contributions
• 80-90% of cases are 46,XX - Empty anucleated egg (no nucleus or MAT chromosomes due to error at MII) is fertilized by a single sperm, then get duplication of the PAT haploid chromosome
• 10-20% of cases are 46,XX or 46,XY - Dispermic fertilization of an anucleated egg
• Only MAT genetic material is present in the MIT of the egg
• excess PAT material causes trophoblast hyperplasia and no formation of fetus
• Placenta has swollen villi (looks like grapes) and causes maternal hyertension, oedema and vaginal bleeding
• Mat blood often has very high hCG levels
• 15-20% risk of malignant trophoblastic disease

Question 6

What is a partial mole and how does it arise?

Answer 6

• Triploid, usually with the additional set of chromosomes being paternal in origin (diandric)
• 69,XXX or 69,XXY or 69,XYY (Rare) which arise by:
  1) Dispermic fertilizaition of a normal egg
  2) Duplication of chromosomes in a single sperm after fertilization of a normal egg
• Clinical features =
• Two populations of villi- small normal appearing and large hydropic
• Enlarged villi
• Irregular villi have scalloped edges
• Trophoblast hypoplasia

- Fetal development occurs and includes stromal blood vessels, umbilical cord, amnio and chorionic plate, but malformations of fetal parts are evident. Ovaries and uterus may be larger than expected.

• Diagnosed by painless bleeding at 4-5 months, and USS shows mole as grape-like structure
• Low risk of malignancy (<5%)

Question 7

Recurrence risk of molar pregnancies

Answer 7

1) Risk in a subsequent pregnancy following a complete mole is ~1 in 100.
2) Risk following two consecutive complete moles is ~1 in 5.
3) Small increase in risk of second mole following partial mole ~1 in 600).
4) Recurrence can be either of the same (complete or partial) or of the other type

Question 8

Familial recurrent hydatidiform moles (FRHM)

Answer 8

• Maternal-effect AR condition
• Very rare; ~70 families to date
• Inherited predisposition to recurrent molar pregnancies, in particular complete moles
• 75% of pregnancies develop as a complete mole
• Very unlikely to achieve any normal healthy pregnancies
• CHM associated with FRHM are diploid and are genetically biparental in origin with both a maternal and paternal contribution
• This differs to sporadic complete hydatidiform moles which are androgenetic and completely paternal in origin
• HOM and compound HET mutations in two genes; NLRP7 at 19q13.42 (OMIM: 609661) and KHDC3L at 6q13 (OMIM: 611687)
• Both thought to have roles in maintaining the maternal imprint within the ovum

Question 9

Malignant GTD - What is an invasive mole?

Answer 9

• 15% after a CHM
• 0.5% risk after a PHM
• Caused by invasion of the myometrium, which can lead to perforation of the uterus
• Diagnosed by high hCG levels after a previous molar pregnancy (plus possible abnormal bleeding, abdominal pain, swelling)

Question 10

Malignant GTD - What is Gestational choriocarcinoma?

Answer 10

• 3% risk after CHM
• 0.1% risk after PHM
• Causes bleeding in the uterus ( and distant metastases that can cause a wide variety of symptoms with the lungs, CNS and liver the most frequent sites of distant disease)
• Diagnosed by high level sof hCG and reproductive history (NOT biopsy as this can cause haemorrhaging)

Question 11

Malignant GTD - What is Placental site trophoblastic tumour (PSTT)?

Answer 11

• Least common form of gestational trophoblast disease (< 2%)
• Commonly follows a normal pregnancy (up to 5 years) but may occur after molar pregnancy
• Can range from slow growing disease limited to the uterus to more rapidly growing metastatic disease that is similar in behaviour to choriocarcinoma
• Frequent presentations are abnormal bleeding or amenorrhea

Question 12

Treatment of GTDs

Answer 12

• Suction evacuation for CHM and PHM
• 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 CHM and up to 6 months following a PHM
• 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 recommended if:

1) Metastases in brain, liver, GI, lung found on XR
2) Histological evidence of choriocarcinoma
3) 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.