Gestational trophoblastic disease (GTD) – Long journey of gyn&obs

An uncommon complication of pregnancy.
A group of inter-related diseases
- Pre-malignant disorders
  - partial (PHM)
  - complete hydatidiform mole (CHM)
- Malignant diseases à collectively named gestational trophoblastic neoplasia (GTN).
  - invasive mole,
  - choriocarcinoma
  - placental site trophoblastic tumour/epithelioid trophoblastic tumour (PSTT/ETT).
Persistent GTD most commonly follows a molar pregnancy, it can be seen after any type of gestation, including term pregnancy, abortion and ectopic pregnancy.
Tumours produce hCG à important in the diagnosis, management and follow-up à An ‘ideal’ tumour marker.

Incidence

From UK registry

PHM – 3 per 1000 pregnancies
CHM – 1–3 per 1000 pregnancies
Choriocarcinoma and PSTT is less clear.
PSTT – 2 per 1000

Risk factors:

Ethnicity – twice as high in some asian countries and in native Americans.
Extreme of Maternal age –
‘J curve’,
< 15 years à moderately increased risk,
> 50 years à a substantially increased risk.
Past hx –
Following one mole, – 1–2 % risk
1. After two molar pregnancies -15–20 %risk. (not decreased by changing partner).
1. family clusters implicating an underlying genetic disorders.
Nutritional factors – low dietary intake of carotene and animal fat à increased incidence of CHM.

PATHOLOGY

All forms of GTD arise from components of the placenta,

villous trophoblast – hydatidiform moles and choriocarcinoma
interstitial trophoblast – PSTT.

Complete hydatidiform moles –

usually diploid
androgenic in origin,
the most common type being 46XX
monospermic CHM– duplication of haploid genome of a single sperm – 80%.
Dispermic CHM – dispermic fertilization – 20%
the maternal chromosomes are lost before or after fertilization.
Diploid parental CHM –
- familial recurrent hydatidiform mole (FRHM) à an autosomal recessive disease
- a biparental karyotype
- Mutations in two genes, NLRP7 and, more rarely, KHDC3L, in the ovum.

Partial hydatidiform moles –

most often from dispermic fertilisation of normal ova.
generally triploid, -90%
Tetrapoloid or mosaic conception – 10%
Fetal tissue or fetal RBC present.
If fetus present has the features of triploidy, including growth retardation and multiple congenital malformations, and is never viable.

Complete mole misclassified as partial mole or nonmolar abortion due to subtle morphological abnormalities especially when associated with chromosomal abnormalities.

Abortions due to trisomy, monosomy, maternally derived triploidy and translocations often develop some degree of hydropic change which can cause diagnostic confusion with molar pregnancies.

DIFFERENTIATE PHM, CHM, NON-MOLAR HYDROPIC ABORTIONS.

Ploidy analysis by in-situ hybridisation or flow cytometry (triploid in PHM) or molecular genotyping can help to distinguish PHM from CHM and non-molar hydropic abortions.
p57KIP2, an imprinted marker expressed only by the maternal genome, CHM can be excluded with immunostaining of p57KIP2 but positive in non-molar pregnancies or PHM. .

invasive mole

complete or, less commonly, a partial mole invades deeply into the myometrium.
no pathological or molecular features predict which patients will develop persistent GTD
All patients with an evacuated molar pregnancy will need surveillance with hCG.

Gestational choriocarcinoma

originate from a previous hydatidiform mole or from a normal conception.
histopathological diagnosis –
A dimorphic population of both cytotrophoblast and syncytiotrophoblast without the presence of formed chorionic villi, & evidence of myometrial invasion.
Because of the availability of a sensitive tumour marker, the majority of patients are treated without the benefit of a histological diagnosis.
Metastasises widely to the lungs, pelvic organs and brain.

PSTT & the newly recognised variant ETT

develop after any type of pregnancy
originate from intermediate trophoblastic tissue.
produce less hCG,
grow more slowly, infiltrating and pushing apart the myometrial cells
metastasise later with a slightly increased propensity for involving the lymphatics.
After the placenta is lost from the uterus, small nodules of placental tissue can remain in the myometrium. These usually resorb over time but in some, they persist as placental site nodules (PSNs) à may develop atypical features (atypical placental site nodules: APSNs) that include increased mitoses and can progress to PSTT/ETT.

CLINICAL FEATURES

CHM or PHM

PHM are usually less severe than CHM
Majority diagnosed prior to 16 weeks . Now it is improved to 12weeks.
PHM frequently diagnosed on histological review of curetting from clinically miscarriage.
Most patient present with early pregnancy failure. – vaginal bleeding in T1
Rarely presented with:
- Excessive uterine size,
- anaemia,
- hyperemesis,
- hyperthyroidism
- preeclampsia,
- Abdominal distension due to theca lutein cysts,
- metastatic disease – acute respiratory disease or neurological symptoms such as seizure.

INVASIVE MOLE

regress spontaneously
can produce heavy bleeding, lower abdominal pain or intraperitoneal haemorrhage.
increased uterine size, theca lutein cysts and preeclampsia in small %.
bladder or rectum is infiltrated à haematuria or rectal bleeding.
may embolise to the lungs à do not usually exhibit the progression of true malignancy.
frequently diagnosed on histological review of curetting
appeared clinically to be a miscarriage.

DIAGNOSTIC INVESTIGATIONS

CHM & PHM

US in T1 à no clear evidence of a normal pregnancy so prompt early evacuation.
US in T2 à
- The classic ‘snowstorm’ sonographic pattern of CHM
- theca lutein ovarian cysts is rarely seen due to earlier presentation with bleeding.
US diagnosis of a PHM
- more complex.
- multiple soft markers , including both cystic spaces in the placenta and a ratio of transverse to anterioposterior dimension of the gestational sac of greater than 1.5.
histological analysis is essential in making the correct diagnosis.
hCG in PHM are only infrequently above the range for a normal pregnancy.

invasive moles,

increased areas of echogenicity are seen within the myometrium.
it produces a unique specific marker in the form of hCG à correlates precisely with the amount of disease present.

Beta hCG

A large placental glycoprotein composed of two peptide subunits
produced naturally during pregnancy.
alpha subunit is similar to those of other pituitary glycoprotein hormones,
beta subunit is specific to hCG alone.
Higher than normal levels of hCG (particularly when >200,000 IU/L) are suggestive of molar pregnancy , ( hCG levels > 2 multiples of the median may help.)

EVACUATION OF MOLAR PREGNANCY

US guided Suction curettage is the method of choice
CHM à lack of fetal parts à A suction catheter of up to 12 mm is usually sufficient. Medical mx should be avoided.—– an increased risk for requiring treatment for persistent trophoblastic disease,
PHM à size of fetal parts deters the use of suction curettage, medical termination can be used.
Sharp curettage not generally recommended
uterine perforation
risk of Asherman’s syndrome (uterine synechiae).

Ultrasound can help to guide the procedure and ensure complete uterine evacuation.

Following suction curettage of a PHM, should have anti-RhD prophylaxis.

Poor vascularization of chorionic villi and absence of antiD Ag in CHM à anti RhD is not required.
Anti D can be delayed until the confirmation of histology with in the acceptable time frame.

Medical termination should be avoided where possible.

possibility of forcing trophoblastic tissue into the venous spaces of the placental bed and disseminating disease to the lungs.
Data from the management of molar pregnancies with mifepristone are incomplete
evacuation of complete mole with mifepristone may be best avoided, as it increases the sensitivity of the uterus to prostaglandins.

Cervical preparation immediately prior to evacuation is safe.

No evidence that ripening of the cervix prior to uterine evacuation was linked to a higher risk for needing chemotherapy.
Prolonged cervical preparation, particularly with prostaglandins, should be avoided à to reduce the risk of embolization of trophoblastic cells.

Ergometrine commenced once evacuation is complete.

produces sustained rather than rhythmic contractions.
Ergometrine is preferred to syntocinon due to its persistent uterotonic effect.

oxytocic infusions

Excessive vaginal bleeding can be associated with molar pregnancy
a senior surgeon directly supervising surgical evacuation is advised.
Oxytocic infusion prior to completion of the evacuation is not recommended.
- theoretical concern of the potential to embolise and disseminate trophoblastic tissue through the venous system.
If significant haemorrhage
- prior to evacuation, surgical evacuation should be expedited and the need for oxytocin infusion weighed up against the risk of tumour embolisation.
- prostaglandin analogues should be reserved for cases for which oxytocic therapy is ineffective.

histological assessment of material obtained from incomplete miscarriages is mandates.

all products of conception obtained after evacuation , all repeat evacuations performed for persisting symptoms should be histologically examined.
no need to routinely send products of conception for histological examination following therapeutic termination of pregnancy, provided that fetal parts have been identified on prior ultrasound examination.
U.hCG should be done after 3weeks of evacuation if the products are not sent for histopathology.

strict follow-up is essential, to detect persistent disease à require chemotherapy

Persisting gynaecological symptoms after an evacuation for molar pregnancy

Consultation with the relevant trophoblastic screening centre
no clinical indication for the routine use of second uterine evacuation
evaluation of the patient with hCG estimation and ultrasound examination
second evacuation in selected cases when the hCG is < 5000 units/litre.

Persistent GTN after a non-molar pregnancy

Persistent vaginal bleeding after a pregnancy is at risk of having GTN à urine pregnancy test should be performed
Symptoms from metastatic disease, such as dyspnoea or abnormal neurology, can occur very rarely
The prognosis for women with GTN after non-molar pregnancies may be worse, à delay in diagnosis or advanced disease, such as liver or CNS disease, at presentation.

Follow up

All women diagnosed with GTD should be provided with written information about the condition and the need for referral for follow-up to a trophoblastic screening centre should be explained.

complete hydatidiform mole
partial hydatidiform mole
twin pregnancy with complete or partial hydatidiform mole
limited macroscopic or microscopic molar change suggesting possible partial or early complete molar change
choriocarcinoma
placental-site trophoblastic tumour
atypical placental site nodules: designated by nuclear atypia of trophoblast, areas of necrosis, calcification and increased proliferation within a placental site nodule.

Registration of women with GTD represents a minimum standard of care.

Follow up individualised.

If hCG has reverted to normal within 56 days à follow up will be for 6 months from the date of uterine evacuation.

If hCG has not reverted to normal within 56 days à follow-up will be for 6 months from normalisation of the hCG level.

All women at the end of any future pregnancy, whatever the outcome of the pregnancy à hCG levels are measured 6-8 weeks after the end of the pregnancy to exclude disease recurrence.

Persistent trophoblastic disease (gestational trophoblastic neoplasia)

indicated by a persistently elevated hCG or continuing clinical symptoms, particularly vaginal bleeding.
Excessive uterine size, markedly elevated hCG levels and prominent theca lutein cysts may predict persistent trophoblastic disease.
after 15% of CHM and 0.5–1%of PHM.
development of postpartum GTN 1/50000 births.
hCG follow up for six months after evacuation was safe and effectiveà requiring chemotherapy for persistent disease are recognised early.

The role of repeat curettage for patients with stage I disease in reducing the need for chemotherapy remains controversial.

considered in patients where the hCG is still <5,000 IU/L and the abnormalities on ultrasound are confined to the uterine cavity.
In all other cases chemotherapy is the treatment of choice.–> cure rates of almost 100% are obtained with chemotherapy and the risks involved with suction curettage.

CHOICE OF CHEMOTHERAPY

by assessing the patient’s prognostic risk.
from the history, examination and investigations à assigned to a risk group,
selection of the least toxic, most effective treatment for that individual

The most important prognostic variables include

the duration of the disease (risk of drug resistance of GTN varies inversely with time),
the serum hCG concentration (correlation with viable tumour volume)
presence of liver and/or brain metastases.

Patients will need

Doppler pelvic ultrasound ,
CXR à pulmonary metastases are most common
CT of the chest and MRI of the brain if CXR abnormal (pulmonary micrometastases do not influence the outcome)

FIGO score of 0–6 à disease at low risk of becoming resistant to single-agent chemotherapy à methotrexate with folinic acid or actinomycin D
FIGO score > 7 à high risk of drug resistance and should therefore be treated with combination-agent chemotherapy. à EMA (etoposide, methotrexate, actinomycin D) alternated weekly with CO (cyclophosphamide and vincristine).
Treatment is continued until the hCG level has returned to normal and then for a further 6 consecutive weeks.
The cure rate score ≤ 6 is almost 100%;
the rate for women with a score ≥ 7 is 95%
both the low- and high-risk treatments have no significant effect on subsequent fertility.
The risk of a further molar pregnancy is low (1/80)
> 98% of women who become pregnant following a molar pregnancy will not have a further molar pregnancy nor are they at increased risk of obstetric complications.
If a further molar pregnancy à 68–80% of the same histological type.

GTD à advised not to conceive until their follow-up is complete.

Women who undergo chemotherapy à advised not to conceive for 1 year after completion of treatment.

POSTPARTUM CHORIOCARCINOMA

present with abnormal vaginal bleeding following delivery
presenting with metastatic disease à diagnosis may be delayed à should have her hCG level à If this is elevated à biopsy to confirm the diagnosis may promote life-threatening haemorrhage and may not be necessary à prompt recognition and early transfer to the specialist national centres is likely to maximize chances of cure with chemotherapy.

SURGERY

hysterectomy for stage I disease

eliminates the complications of local invasion,
not prevent metastatic disease à monitoring of hCG concentrations should be done. à assess need for chemotherapy
As GTD is highly chemosensitive, the need for surgical intervention is small.
Hysterectomy
- To minimise the risk of trophoblastic emboli,
  - the vessels draining the uterus should be ligated at an early stage
  - uterine tissues should be handled as gently as possible.
- Conservative uterine surgery(local excision of a bleeding invasive trophoblastic tumour is performed) à preserving fertility in young women à may then be cured medically

vaginal bleeding after completion of successful chemotherapy – rare

due to a post-molar arteriovenous malformation.
Selective embolisation or ligation may preserve fertility,
sometimes hysterectomy is necessary.

Thoracotomy –

indications – multiagent chemotherapy, a solitary lung lesion confined to one lung and no other sites of active disease
achieve remission in over two thirds of patients.

Stereotactic radiosurgery

treatment of accessible deposits before starting chemotherapy because of the risk of precipitating haemorrhage.

PSTT/ETT

a slow growth rate
can present many years after term delivery, non-molar miscarriage or complete mole.
metastasise, particularly to the lung
presentation is with local disease
- vaginal bleeding
- amenorrhoea.
for localised disease – Surgery alone is the treatment of choice ;
metastatic PSTT — combination chemotherapy is needed
In contrast to choriocarcinoma, once the hCG has normalised residual masses are removed surgically, including the uterus as this can potentially harbour microscopic disease.

Long term outcome of chemotherapy:

The age at menopause for women who receive single-agent chemotherapy is advanced by 1 year and by 3 years if they receive multi-agent chemotherapy.

multi-agent chemotherapy which includes etoposide should be advised that they may be at increased risk of developing secondary cancers.

less than 6 months à no increased risk of secondary cancers.

safe contraception following a diagnosis of GTD

use barrier method until hCG levels revert to normal.
Once hCG level have normalised, the combined oral contraceptive pill may be used
no evidence as to whether single-agent progestogens have any effect on GTN.
If oral contraception has been started before the diagnosis of GTD à advised to remain on oral contraception à advised that there is a potential but low increased risk of developing GTN.
Intrauterine contraceptive devices should not be used until hCG levels are normal to reduce the risk of uterine perforation.
Hormone replacement therapy may be used safely once hCG levels have returned to normal.

Twin molar pregnancy

Twin pregnancies comprising a normal fetus and a hydatidiform mole are estimated to occur in between 1:20,000 and 1:100,000 pregnancies.
If diagnostic doubtà regional fetal medicine unit and the relevant trophoblastic screening centre.
the woman should be counselled about the increased risk of perinatal morbidity and outcome for GTN in one viable fetus if the other pregnancy is molar.
- A successful pregnancy outcome occurs in around 40% of cases, with no obvious increase in the risk of malignant change.
- risk of early fetal loss (40%)
- premature delivery (36%).
- The incidence of pre-eclampsia is variable 20% reported.
Prenatal invasive testing for fetal karyotype should be considered
- in cases unclear if the pregnancy is a complete mole with a coexisting normal twin or a partial mole.
- in cases of abnormal placenta, such as suspected mesenchymal hyperplasia of the placenta.