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Title: Gestational Trophoblastic Disease Ermos Nicolaou Fetal


1
Gestational Trophoblastic Disease
  • Ermos Nicolaou
  • Fetal Medicine Centre
  • Chris Hani Baragwanath Hospital
  • University of the Witwatersrand

2
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.
3
GESTATIONAL TROPHOBLASTIC DISEASE
  • Hydatiform mole
  • Invasive mole
  • Choriocarcinoma
  • Placental site trophoblastic tumor

Partial Complete
4
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

5
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

6
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
7
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
8
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)

9
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
10
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.

11
F
Father
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17
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

18
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
19
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.

20
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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23
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

24
Gestational Trophoblastic Disease
  • Persistent GTD may develop
  • After a molar pregnancy,
  • After a non-molar pregnancy
  • After a live birth ( 1/50 000)

25
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.

26
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

27
  • 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.

28
  • 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
29
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
30
Study Conclusion
  • Invasion is not only a question of reproductive
    immunology but also a question of tumor immunology

31
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

32
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.

33
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.

34
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.

35
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.

36
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.

37
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

38
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.

39
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)
40
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.
41
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 -
42
COMPLETE MOLE
snow storm
43
PARTIAL MOLE
Swiss cheese
44
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

45
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.
46
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

47
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
48
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
49
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
50
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.

51
DIFFERENTIAL DIAGNOSIS
Fetus absent
Fetus present
  • partial mole
  • hydatiform mole viable fetus
  • mesenchymal dysplasia

complete mole
52
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
53
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
54
PARTIAL MOLE FIRST TRIMESTER DIAGNOSIS
  • Discrepancy between CRL and LMP
  • Increased fetal nuchal translucency
  • Increased ß HCG levels for gestational age

55
GTD and Twin Pregnancy
56
GTD and Twin Pregnancy
Incidence 122.000 1100.000 Variants viable
fetus with partial hydatiform mole viable fetus
with complete hydatiform mole
57
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.

58
COMPLETE HYDATIFORM MOLE AND COEXISTING VIABLE
FETUS
Prognosis
Miscarriage 50 Stillbirth lt32 wks 30
Preterm delivery lt32 wks 30 Pre-eclampsia gt
50
59
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

60
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)

61
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.

62
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)

63
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

64
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

65
FIGO Staging
  • STAGE
  • Confined to the uterus
  • Outside of uterus, limited to genital structures
  • Extends to lungs - genital tract involvement
  • All other metastatic sites

66
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FIGO score
Low Score lt6 High Score gt 7
68
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.

69
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

70
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

71
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

72
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.

73
Survival
  • The overall survival in the Charing Cross series,
    with a maximum
  • follow-up of 15 years is 94

74
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.

75
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