Gestational Trophoblastic Disease

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Gestational Trophoblastic Disease

• Ermos Nicolaou
• Fetal Medicine Centre
• Chris Hani Baragwanath Hospital
• University of the Witwatersrand

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Gestational Trophoblastic Disease (GTD) is a
relatively rare event with a calculated incidence
of 1/714 live births. There is evidence of
ethnic variation in the incidence of GTD in the
UK, with women from Asia having a higher
incidence compared with non-Asian women (1/387
versus 1/752 live births). This may
under-represent the true incidence of the disease
because of problems with reporting, particularly
with regard to partial moles.
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GESTATIONAL TROPHOBLASTIC DISEASE

• Hydatiform mole
• Invasive mole
• Choriocarcinoma
• Placental site trophoblastic tumor

Partial Complete
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Epidemiology

• The incidence of molar pregnancy varies in
  different parts of the
• world.
• Women of Asian origin 1 in 550 to 1 in
  600.
• Women of European origin 1 in 1200 live births

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Epidemiology

• Age is probably the most important factor in the
  incidence of
• developing complete hydatidiform mole.
• Where the incidence for women aged 25 to 29 is
  standardized
• as 1, the risk is
• 6 X in women who become pregnant under 15 years
• 411 X in patients who become pregnant over the
  age of 50

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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
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HYDATIDIFORM MOLE Risk factors
1. Maternal age gt 40 years lt 15
years 2. Paternal age gt 45 years 3. Previous
hydatidiform mole 1st 1-2 2nd 15-28 4.
Vitamin A deficiency
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Molar Pregnancy Complete Mole

• Background
• Hydatidiform mole is subdivided into complete and
  partial mole
• based on genetic and histo-pathological features.
  
• Complete moles are
• diploid
• andro-genetic in origin
• no evidence of fetal tissue.
• Arise as a consequence of
• duplication of the haploid sperm following
  fertilisation of an empty ovum ( diandry)
• Some complete moles arise after dispermic
  fertilisation of an
• empty ovum. (dispermy)

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COMPLETE MOLE
A single sperm fertilizes an empty ovum, with
duplication of the 23X haploid set of
chromosomes, giving rise to a homozygous diploid
complete mole.
Empty ovum
46XX
23X
Complete Mole (46XX diploid)
Two sperms with two independent haploid sets of
chromosomes fertilize an empty ovum, producing a
dyspermic complete mole with either 46XX or 46XY
karyotype.
Empty ovum
46XX or 46XY
23X or Y
23X
Complete Mole (46XX or 46XY, diploid)
Modified from Cheung, 1995
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Complete molar pregnancy

• Complete hydatidiform mole forms a multivesicular
  mass with
• diffuse hydropic villi and a variable degree of
  trophoblastic
• proliferation.
• There is usually no evidence of a foetus. This
  conceptus is diploid
• and androgenetic in origin.
• The incidence of a GT Tumour is approximately
  1000X more likely
• following a complete hydatidiform mole than after
  a full-term
• pregnancy.
• One possible explanation is that genomic
  imprinting plays a
• role in tumourigenesis since the complete mole is
  androgenetic in
• origin.

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F
Father
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Partial Molar Pregnancy

• Triploid in origin with usually two sets of
  paternal haploid genes and
• one set of maternal haploid genes.
• They occur, in almost all cases, following
  dispermic fertilisation of an ovum. There is
  usually evidence of a fetus or fetal red blood
  cells.
• In some cases failure of meiosis I or II in the
  ovum leads to Triploidy with 46 maternally
  derived chromosomes and 23 paternal

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PARTIAL MOLE
23Y
23X
23X
23X
23X
69XXY
23Y
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
Modified from Cheung, 1995
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Triploidy
When extra set of chromosomes is paternally
derived, is associated with a molar placenta and
the pregnancy rarely persists beyond 20 weeks.
When there is a double maternal chromosome
contribution, the pregnancy may persist into the
third trimester. The placenta may be of normal
consistency and the fetus demonstrates severe
asymmetrical growth retardation

• mild ventriculomegaly,
• micrognathia,
• cardiac abnormalities,
• myelomeningocoele,
• syndactyly,
• hitch-hiker toe deformity.

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FEATURES OF PARTIAL AND COMPLETE MOLE
Complete mole
Partial mole
Fetal or embryonic tissue absent present Hydati
form swelling of chorionic villi extensive
focal Trophoblastic hyperplasia extensi
ve focal Scalloping of chorionic
villi absent present Trophoblastic stromal
inclusions absent present Karyotype 46XX
(90) Triploid (69 XXY) 46XY (10)
Cohn DE, Herzog TJ. Curr Opin Oncol 2000 Sep
12(5)492-6
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Persistent GTD

• The term persistent "gestational trophoblastic
  disease" is widely
• used to describe the situation where a woman has
  had a
• hydatidiform mole and still has persistently
  raised human chorionic
• gonadotrophin (hCG) estimations
• Since in the majority of cases the disease either
  remits
• spontaneously or can be successfully treated
  without further
• pathological sampling, it is difficult to say
  exactly in what
• proportion of patients their hydatiform mole
  modulates to
• choriocarcinoma.
• This event probably happens in 3 to 5 of
  patients who have had
• a complete hydatidiform mole

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Gestational Trophoblastic Disease

• Persistent GTD may develop
• After a molar pregnancy,
• After a non-molar pregnancy
• After a live birth ( 1/50 000)

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Gestational Trophoblastic Tumours

• Overview
• GTT are unique in cancer biology in that they
  follow
• either a normal or abnormal pregnancy,
• the tumours contain paternal genes and are
  therefore an
• allograft in the maternal host.

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Distribution of Immunocompetent Cells in
Decidua of Controlled and Uncontrolled(Choriocarci
noma/Hydatidiform mole)Trophoblast InvasionS.
Knoeller, E. Lim, L. Aleta, et alAJRI 2003 50
4147

• A significantly increased number of T lymphocytes
  positive for
• CD8, CD3 are observed in Chorio-Carcinoma and
  Hydatiform Mole
• compared with samples from Normal Pregnancies (P
  lt 0.001).
• T cells are known to be prominent only during
  early pregnancy and
• are rapidly down regulated in normal human
  pregnancies.
• It seems to be likely that T cells are important
  for implantation to occur with respect to
  controlling natural killer (NK) cell activity

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• Lymphocytes positive for natural killer (NK) cell
  marker CD56 are
• significantly decreased in CC and HM versus NP (P
  lt 0.001).
• In normal decidua the number of CD56 NK cells is
  very prominent
• and increases with gestational age.
• Natural killer cells discriminate self from
  non-self in a manner
• distinct from T cells.
• NK cells exhibit cytotoxicity against
  missing-self by killing all cells
• but so-called self cells.

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• Trophoblast cells appear to evade the attack by
  the NK cells via
• interactions with killer inhibitory receptor
  molecules on CD56ve
• Lymphocytes

Choriocarcinoma
Hydatidiform Mole Normal
Pregnancy
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AC depicts staining against cytokeratin-positive
cells,which identify trophoblast / tumor cells,
marked by brown staining. DF shows
representative examples of the distribution and
density of CD8 cells, which are present as
clusters in CC (D) and HM (E).
Choriocarcinoma
Hydatidiform Mole Normal
Pregnancy
S. Knoeller, E. Lim, L. Aleta, et alAJRI 2003
50 4147
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Study Conclusion

• Invasion is not only a question of reproductive
  immunology but also a question of tumor immunology

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Invasive Hydatidiform Mole

• Invasive hydatidiform mole (complete or partial)
  is common since
• molar trophoblast invades the myometrium in most
  cases.
• Pathologically invasive hydatidiform mole can be
  diagnosed only
• when sufficient myometrium is made available to
  the pathologist
• either on curettings or by hysterectomy

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Invasive Hydatidiform Mole

• An invasive mole retains hydropic villi, which
  penetrate the uterine wall.
• Can cause uterine rupture and can be life
  threatening.
• Hydropic villi may embolize to distant organs,
  but this tumor does not have metastatic
  potential.
• Cure is possible by hysterectomy or chemotherapy.

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Choriocarcinoma

• It is an unusual tumour in that it stimulates
  virtually no stromal
• reaction and is therefore essentially a mixture
  of haemorrhage and
• necrosis with tumour cells scattered within the
  mass.
• Tumour cells can be scanty and present problems
  of pathological
• interpretation if the possibility of
  choriocarcinoma has not been
• raised.
• The pathology of choriocarcinoma is reflected in
  its clinical
• behaviour with widespread intravascular
  dissemination to lungs,
• brain and other sites.

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Choriocarcinoma

• Is a very aggressive malignant tumor and arises
  either from
• gestational chorionic epithelium or less
  frequently, from
• totipotential cells within gonads or elsewhere.
• Incidence is 1/ 30,000 pregnancies in US.
• More common in Asian and African countries.

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Choriocarcinoma

• Most cases are discovered by the appearance of a
  bloody, brownish
• discharge, accompanied by a rising titer of HCG,
  particularly the
• beta subunit.
• Usually appear as very hemorrhagic, necrotic
  masses within the
• uterus.
• Widespread dissemination via blood, lung (50),
  vagina (30-40),
• brain, liver and kidney.

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Placental site trophoblastic tumours

• Placental site trophoblastic tumours are now
  recognised as a
• separate entity.
• rare and
• are composed mainly of cytotrophoblastic cells
• tend to be locally invasive
• less widely metastatic than choriocarcinoma
• The optimal management of patients with placental
  site
• trophoblastic tumours is unclear.
• This is because
• the tumours are rare and
• their biological behaviour does appear to be
  variable.

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Placental site trophoblastic tumours

• Where the disease is localised to the uterus,
  hysterectomy is the
• treatment of choice.
• A small number of patients treated with intensive
  chemotherapy
• initially have achieved complete remission but
  the chemosensitivity
• of placental site trophoblastic tumours appears
  to be quite variable

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Clinical presentation

• The most common presentation of a patient with a
  GTD is
• vaginal bleeding towards the end of the first
  trimester of pregnancy.
• nausea and vomiting and
• uterus larger for dates than for a normal
  pregnancy.
• Since the quantity of hCG produced by a normal
  pregnancy can vary
• over quite a wide range, the initial hCG
  estimation is not helpful in
• differentiating between a pregnancy and a
  hydatidiform mole.

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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)
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ULTRASOUND FINDINGS
The increasing performance of ultrasound
examination, either routinely in the first
trimester or for management of early pregnancy
complications, allows evacuation of most
pregnancies affected by hydatiform mole prior to
development of the classic sonographic and
pathological features.
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ULTRASOUND FINDINGS
Complete mole
Partial mole
Multiple hypoechoic areas extensive focal Increas
ed echogenicity extensive focal Enlarged
uterine volume present absent Theca-lutein
cysts present absent gt Ø gestational sac
- present lt Uterine artery PI present -
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COMPLETE MOLE
snow storm
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PARTIAL MOLE
Swiss cheese
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Diagnosis of Gestational Trophoblastic Disease

• Increasing use of ultrasound in early pregnancy
  has led to the
• earlier diagnosis of molar pregnancy.
• The majority of histologically proven complete
  moles however are
• associated with an ultrasound diagnosis of
  delayed miscarriage or
• anembryonic pregnancy
• The ultrasound features of a complete mole are
  reliable but the
• ultrasound diagnosis of a partial molar pregnancy
  is more complex.
• RCOG, February 2004

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Sebire NJ et al. Ultrasound Obstet Gynecol 2001
Dec 18 (6) 662
The diagnostic implications of routine
ultrasound examination in histologically
confirmed early molar pregnancies
OBJECTIVE to determine the sonographic findings
of routine ultrasound examinations in patients
with a proven histological diagnosis of complete
or partial hydatiform mole.
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Sebire NJ et al. Ultrasound Obstet Gynecol 2001
Dec 18 (6) 662

• retrospective review ( 6-month period)
• 194 cases referred to the National Trophoblastic
  Disease Surveillance Centre (Charing Cross
  Hospital) with suspected molar pregnancies
• review of ultrasound findings
• final histological diagnosis

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Sebire NJ et al. Ultrasound Obstet Gynecol 2001
Dec 18 (6) 662
131 (67) missed misc./anembryonic pregn.
194
63 (33) hydatiform mole
53 (84) hydatiform mole
64 compl mole
37 (58) mole
155
91 partial mole
16 (17) mole
Ultrasonographic diagnosis
Histological diagnosis
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CONCLUSION of study

• The majority of cases of molar pregnancy present
  sonographically as missed abortion/anembryonic
  pregnancy (importance of histological
  examination).
• A false-positive result on U.S. is relatively
  unlikely.
• It is highly likely that centres with specific
  expertise can identify some cases more accurately.

Sebire NJ et al. Ultrasound Obstet Gynecol 2001
Dec 18 (6) 662
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DIAGNOSTIC ACCURACY OF ULTRASONOGRAPHY IN
COMPLETE MOLAR PREGNANCY
Sebire et al. (2000) 58 Lazarus et al.
(1999) 57 Benson et al. (2000) 79
Lindholm et al. (1999) 80
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Diagnosis of Gestational Trophoblastic Disease

• Presence of multiple soft markers including,
• cystic spaces in the placenta and
• a ratio of transverse to AP dimension of the
  gestation sac
• of gt 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.

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DIFFERENTIAL DIAGNOSIS
Fetus absent
Fetus present

• partial mole
• hydatiform mole viable fetus
• mesenchymal dysplasia

complete mole
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PARTIAL MOLE
More than 90 of partial moles are found in
triploid fetuses.
Feto-placental ultrasound findings n
Fetal anatomic defects 65 92.9 1 10 14.3 2 23 32.9
gt2 32 45.7 Asymmetrical growth
restriction 45 64.2 Placental molar
changes 20 28.6 Amniotic fluid changes 33 47.1 Oly
gohydramnios 31 44.2 Polyhydramnios 2 2.9
Jauniaux E, Nicolaides KH Placenta 1997, 18
701-6
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Ultrasound abnormalities in triploid fetuses
Variables n 65
Malformed hands 34 52.3 Ventriculomegaly 24 36.9
Heart abnormalities 22 33.9 Micrognathia 17 26.2 H
yperechogenic bowel 10 15.4 Renal
malformations 8 12.3 Increased nuchal
thickness 8 12.3 Spina bifida 5 7.7 Talipes
equinovarous 5 7.7 Dandy-Walker
malformation 5 7.7 Collapsed stomach 5 7.7 Single
umbilical artery 4 6.2 Omphalocele 4 6.2 Holoprose
ncephaly 2 3.1 Hydrops 2 3.1 Bilateral pleural
effusion 2 3.1 Ascites 2 3.1 Diaphragmatic
hernia 1 1.5 Kyphoscoliosis 1 1.5 Cleft lip and
palate 1 1.5
Jauniaux E, Nicolaides KH Placenta 1997, 18
701-6
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PARTIAL MOLE FIRST TRIMESTER DIAGNOSIS

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

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GTD and Twin Pregnancy
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GTD and Twin Pregnancy
Incidence 122.000 1100.000 Variants viable
fetus with partial hydatiform mole viable fetus
with complete hydatiform mole
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GTD and Twin Pregnancy

• 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.
• The probability of achieving a viable baby is 40
  and there is a risk
• of complications such as pulmonary embolism and
  pre-eclampsia.
• There is no increased risk of developing
  persistent GTN after such
• a twin pregnancy and outcome after chemotherapy
  is unaffected.

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COMPLETE HYDATIFORM MOLE AND COEXISTING VIABLE
FETUS
Prognosis
Miscarriage 50 Stillbirth lt32 wks 30
Preterm delivery lt32 wks 30 Pre-eclampsia gt
50
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Management of GTD

• Suction curettage is the method of choice of
  evacuation for
• complete molar pregnancies.
• Because of the lack of fetal parts a suction
  catheter, up to a
• maximum of 12 mm, is usually sufficient to
  evacuate all complete
• molar pregnancies
• Medical termination of complete molar
  pregnancies, including
• cervical preparation prior to suction evacuation,
  should be avoided
• where possible because of the potential to
  embolise and
• disseminate trophoblastic tissue through the
  venous system

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Management of GTD

• In partial molar pregnancies where the size of
  the fetal parts
• deters the use of suction curettage, medical
  termination can be
• used.
• These women may be at an increased risk of
  requiring treatment
• for persistent trophoblastic neoplasia, although
  the proportion of
• women with partial molar pregnancies needing
  chemotherapy is low
• (0.5)

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Histological 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.

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Persistent GTD after a non-molar pregnancy

• Persistent GTD can occur after non-molar
  pregnancies.
• Presenting symptoms
• Vaginal bleeding is common
• Symptoms from metastatic disease, such as
  dyspnoea or abnormal
• neurology
• The prognosis for women with GTD after non-molar
  pregnancies
• may be worse
• -21 mortality after a live birth,
• - 6 after a non-molar miscarriage
• Reason ? due to the delay in diagnosis (0.558.0
  months)

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Gestational Tropholastic Neoplasia- Requirement
for diagnosis

• 4 or more values of hCG plateau over ay least 3
  weeks
• A rise of hCG of 10 or greater for gt 3 values
  over at least 2 weeks
• Presence of Choriocarcinoma
• Persistence of hCG 6 months after mole evacuation

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Treatment of persistent GTD

• Women with persistent GTD should be treated at a
  specialist
• centre with appropriate chemotherapy.
• Need for chemotherapy following a complete mole
  is 15
• following a
  partial mole 0.5
• Disease risk is scored according to the FIGO
  staging for GTN

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FIGO Staging

• STAGE
• Confined to the uterus
• Outside of uterus, limited to genital structures
• Extends to lungs - genital tract involvement
• All other metastatic sites

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FIGO score
Low Score lt6 High Score gt 7
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Treatment of persistent GTD

• Women scoring lt6 (low risk)
• Methotrexate imi on alternate days, each course
  consisting of
• four injections
• followed by six rest days
• Women who develop resistance to Methotrexate are
  treated with a
• combination of intravenous Actinomycin D and
  Etoposide.

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Treatment of persistent GTD

• Women scoring gt7 (high risk) receive combination
  chemotherapy.
• IV Etoposide, Methotrexate, Actinomycin D for 2
  days
• followed by Cyclophosphamide and Vincristine
  (Oncovin) (EMA-CO)
• one week later.
• The course is then repeated after six days.
• Charing Cross Hospital, London

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Future pregnancy

• Women should be advised not to conceive until
  their hCG levels
• have been normal for six months.
• Women who undergo chemotherapy are advised not to
  conceive for
• one year after completion of treatment
• Risk of a further molar pregnancy is low ( 2)
• gt98 of women who become pregnant following a
  molar pregnancy
• will not have a further mole or be at increased
  risk of obstetric
• complications.
• If a further molar pregnancy does occur, in
  6880 of cases it will
• be of the same histological type

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Follow-up and Fertility after Chemotherapy

• Approximately 90 of patients who want to become
  pregnant
• following chemotherapy have succeeded and there
  is no evidence of
• increase in foetal abnormalities.
• Occasionally a G.T.T. can occur or recur after a
  subsequent normal
• pregnancy
• This emphasises the importance of reconfirming
  that hCG levels
• return to normal after any subsequent pregnancy
  in a woman who
• has had a trophoblastic disease event

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Contraception and hormone replacement therapy

• The COC-pill, if taken while hCG levels are
  raised, may increase the
• need for treatment.
• However, it can be used safely after the hCG
  levels have returned
• to normal.
• Other forms of hormonal contraception do not
  appear to be linked
• to an increased need for treatment.
• The small potential risk of using emergency
  hormonal
• contraception, in women with raised hCG levels,
  is outweighed by
• the potential risk of pregnancy to the woman.
• Hormone replacement therapy may be used safely
  once hCG levels
• have returned to normal.

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Survival

• The overall survival in the Charing Cross series,
  with a maximum
• follow-up of 15 years is 94

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Survival

• The successful outcome in patients with GTT
  depends on several factors-
• (i) Need for a national registration scheme of
  patients at risk of developing a GTT (ii) The
  ability to monitor the disease and its response
  to treatment with serial hCG estimations.(iii)
  The intrinsic biological property of GTT in being
  inherently very sensitive to a range of
  chemotherapeutic agents.

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• Thank you