GESTATIONAL TROPHOBLASTIC

DISEASE
Definition;
Gestational trophoblastic disease (GTD);
spectrum of interrelated but histologically distinct
tumors originating from the placenta.
 All forms are characterized by distinct tumor
marker
 Beta-HCG
 Pathogenesis is unique b/c it is maternal tumor
arising from gestational rather than maternal tissue.
Intrduction cont’d

Histologic types
1.Hydatidiform mole
▪ Can be partial or complete
2.Invasive mole
3.Choriocarcinoma GTN
4.Placental site trophoblastic tumor(PSTT)
 The latter three are malignant b/c of risk of
local invasion and metastasis
Hydatidiform mole

 Hydatidiform moles are abnormal

pregnancies characterized histologically by
aberrant changes within the placenta.
 Chromosomal abnormalities play an integral
role in hydatidiform mole development.
RISK FACTORS

 Two main risks are

 Extreme maternal age
▪ Most well established risk
▪ Significant in age more than 35 yrs and slight increase in
age less than 20 yrs old
▪ Paternal age is not a risk
 History of previous GTD
▪ Recurrence =1% after any type of one GTD(10 times
increases risk
▪ but 0.1% incidence for the general population
▪ 16-28% of recurrence after two molar pregnancies
5
 Other risks
 Current smoking(more than 15 per day)
 Maternal blood type AB,A or B
 History of infertility, nulliparity
 Use of OCP
▪ But,ocp do not increase the risk of developing post molar
GTD
COMPLETE MOLAR PREGNANCY
 have a diploid karyotype.
 The chromosomes are entirely of paternal origin, and
thus, the diploid set is described as diandric.
 The ovum fails to contribute chromosomes.
 Specifically, complete moles are formed by androgenesis,
in which the ovum is fertilized by a haploid sperm that
then duplicates its own chromosomes after meiosis.
 85 to 90 percent of these moles are 46,XX, but dispermic
fertilization of a single ovum, that is, simultaneous
fertilization by two sperm, can produce a 46,XY
karyotype .
Complete mole cont’d
 Microscopically, complete moles display enlarged,
edematous villi and abnormal trophoblastic proliferation.
 These changes diffusely involve the entire placenta
 Macroscopically, these changes transform the chorionic
villi into clusters of vesicles with variable dimensions
 The name hydatidiform mole literally stems from this
“bunch of grapes” appearance.
 In these pregnancies, no fetal tissue or amnion is
produced.
 As a result, this mass of placental tissue completely fills
the endometrial cavity
Clinical presentation
 Previously- late presentation
 Anemia
 Excessive uterine size
 Hyperemesis gravidarum
 Preeclampsia
 Theca lutein cysts-
▪ A form of ovarian hyperstimulation 2o to high level of HCG
▪ Often multiloculated and bilateral
▪ Resolve few wks to months after treatment of GTD
 Thyrotoxicosis due to excessive HCG stimulation of thyroid gland
because TSH and HCG have similar ‘alpha’ subunit
 Vaginal passage of hydropic vesicles
 Currently- early pregnancy followup is common
 Vaginal bleeeding
Partial mole

 differ from complete hydatidiform moles clinically, genetically, and

histologically.
 The degree and extent of trophoblastic proliferation and villous
edema are decreased compared with those of complete moles.
 most partial moles contain fetal tissue and amnion, in addition to
placental tissues.
 patients with partial moles typically present with signs and
symptoms of an incomplete or missed abortion.
 Other dramatic features of complete mole are absent with partial
mole.
 Preevacuation β-hCG levels are typically much lower than those for
complete moles and often do not exceed 100,000 mIU/mL.
 For this reason, partial moles are often not identifed until after a
histologic review of a curettage specimen.
Partial mole
Comparison of complete versus partial hydatidiform
moles
Evaluation of molar pregnancy

 Evaluation include
 Serum B-HCG
 40% of complete moles are associated with
HCG level more than 100,000 miu/ml
 Normal non pregnant level=less than 5 miu/ml
 Peak normal pregnancy level=less than 100,00
miu/ml
Ultrasound feature of complete mole

 Central heterogeneous mass with many discrete

anechoic spaces
▪ Are diffuse hydatidiform swelling of the hydropic
chorionic villi
▪ Small cystic areas are hydropic villi
 Classically described as “snow storm appearance”
which is created by the multiple placental vesicles.
 Theca lutein cysts
Ultrasound feature of partial mole

 A fetus is present
▪ May be viable but often growth restricted
 AF present but may be reduced
 Focal anechoic spaces and /or increase
echogenecity of chorionic villi (swiss cheese
pattern)
 Increase transverse diameter of gestational sac
 Theca lutein cysts are abscent
 Misdiagnosed as missed or incomplete
abortion in 15-60% of cases
Treatment of molar pregnancy
Suction curettage
 Preferred method for those who need to preserve fertility
 As aspiration of molar tissues ensues, intravenous dilute
oxytocin is given.
 Rh immune globulin is given to nonsensitized Rh D-
negative women.
 Rh immune globulin, however, may be withheld if the
diagnosis of complete mole is certain.
Hysterectomy
 If the patient has completed her fertility
 eliminates the risk of local invasion, but does not prevent
metastasis.
prophylactic chemotherapy
 The issue of prophylactic chemotherapy is controversial
due to the drug toxicity.
 It decreases the risk of persistence, but it also increases
the risk of chemotherapy resistant disease if persistence
occurs.
 Single dose of methotrexate or actinomycine D
 considered in patients with a complete mole and
 compliance with hCG follow-up may be difficult and
 who have any of the following high-risk features
▪ hCG level over 100,000
▪ Presence of large theca lutein cysts >6 cm in diameter
▪ Significant uterine enlargment
Post molar survillence

 Gestational trophoblastic neoplasia develops

after evacuation in 15 percent of patients with
complete moles.
 Of those women who develop GTN, three
quarters have locally invasive molar disease and
the remaining one quarter develop metastases.
 In contrast, GTN develops in only 4 to 6 percent
of patients with partial moles following
evacuation.
 Postmolar surveillance with serial quantitative
serum β-hCG levels is the standard.
 Titers are monitored following uterine
evacuation
 Every 1 to 2 weeks until undetectable.
 After undetectable monthly for six months
Prevention of pregnancy

 When pregnancies occur during the monitoring period, the resulting

normal β-hCG production can hinder detection of postmolar progression
to GTN.
 To prevent difficulties with interpretation, women are encouraged to use
effective contraception until achieving a β-hCG titer < 5 mIU/mL or below
the individual assay’s threshold.
 Contraception
 COC- preferred contraceptive option because it has regular pattern of
bleeding and is effective methode of contraceptive
 Injectable medroxyprogesterone acetate is particularly useful when
poor compliance is anticipated.
 Intrauterine devices are not inserted until the β-hCG level is
undetectable because the risk of uterine perforation if an invasive mole
is present.
GESTATIONAL TROPHOBLASTIC NEOPLASIA

 A subset of gestational trophoblastic disease that

develops malignant sequelae
 Histologic categories include
 invasive mole
 gestational choriocarcinoma,
 placental-site trophoblastic
 epithelioid trophoblastic tumor.
 Although these histologic types have been characterized, in most
cases of GTN, no tissue is available for pathologic study.
 Instead, GTN is diagnosed based on elevated β-hCG levels and
managed clinically.(persistent GTD)
 Gestational trophoblastic neoplasia typically develops with or follows
some form of pregnancy; usually molar pregnancies, but it could also
occur following abortion or normal delivery.
Peculiar characteristics of GTN

 Unlike most other malignancies have reliable

tumor marker
 Have excellent prognosis even with
widespread disease
 Unlike carcinomas which methasthesize via
lymphatic route choriocarcinoma
methasthesizes hematogenouslly
 Are tumors arising from non self tissue
Serum beta-HCG following uterine
evacuation

26
Nonmetastatic Disease

 Locally invasive trophoblastic tumors may

perforate the myometrium and lead to
intraperitoneal bleeding
 Vaginal hemorrhage may also occure
following erosion of tumor in to the uterine
vessels
 Prognosis is typically excellent
INVASIVE MOLE

Is a hydatidiform mole characterized by the presence

of enlarged hydropic villi with proliferation of
trophoblast.
 The abnormal villi penetrate deeply into the myometrium.
 Clinically, invasive moles are often considered gestational
trophoblastic neoplasia.
 invasion could be difficult to diagnose microscopically
because the samples obtained by curettage may not
contain the intact myometrium required for this
assessment.
 Thus, it is diagnosed histologically only if a hysterectomy
has been performed.
cont’d

 75 percent of cases of stable or serially rising

serum beta-hCG concentrations after a molar
pregnancy represent invasive moles.
 25 percent are choriocarcinomas (placental site
trophoblastic tumor is rare)
 In contrast, persistent elevation of serum beta-
hCG following any nonmolar pregnancy, eg,
miscarriage, ectopic, or preterm/term
pregnancy, is always due to choriocarcinoma or
placental site trophoblastic tumor (rare)
PSTT
 Rare malignant neoplasms originating from
intermediate cytotrophoblast cells.
 present microscopically as trophoblastic infiltration
that is confined to the endometrium and
myometrium of the placental implantation site.
 On histological examination, there are no chorionic
villi
 associated with relatively low level of HCG due to
absence of syncitiotropholast.
 Increase in human placental lactogen (hPL) and
placental alkaline phosphatase (PAP).
Metastatic Disease

CHORIOCARCINOMA
 A highly malignant epithelial tumor.
 It can arise from any type of trophoblastic tissue The
most common sites of metastases are lung(80%),
brain(10%), liver(10%), pelvis(20%), vagina(30%),
spleen, intestine, and kidney.
 Histologically
 appears as sheets of anaplastic cytotrophoblasts and
syncytiotrophoblasts without chorionic villi.
 Extensive necrosis, hemorrhage, and vascular invasion are
common.
Metastatic Disease

 Choriocarcinomas originating from complete

molar gestations account for most cases of
metastatic GTN.
 Choriocarcinomas have a propensity for distant
spread and should be suspected in any woman of
reproductive age with metastatic disease from an
unknown Primary
 Because of this tendency chemotherapy is
indicated whenever choriocarcinoma is
diagnosed histologically
Staging
anatomic staging system
 The most common sites of spread are
 the lungs (80 percent),
 vagina (30 percent),
 pelvis (20 percent),
 liver (10 percent), and
 brain (10 percent)
 Patients with pulmonary metastases typically have
asymptomatic lesions identifed on routine chest
radiograph and infrequently present with cough,
dyspnea, hemoptysis, pleuritic chest pain, or signs of
pulmonary hypertension
 cerebral involvement is encountered almost exclusively in
patients who have had an antecedent nonmolar pregnancy
and a protracted delay in tumor diagnosis.
 These women may present with associated hemorrhagic
events.
 Virtually all patients with hepatic or cerebral metastases
have concurrent pulmonary or vaginal involvement or both.
 Great caution is used in attempting excision of any metastatic
disease site due to the risk of profuse hemorrhage.
 Thus, this practice is almost uniformly avoided except in
extenuating circumstances of life-threatening brainstem
herniation or chemotherapy-resistant disease.
investigations
 Patients with GTN undergo a thorough pretreatment
assessment to determine disease extent.
 The initial evaluation
 pelvic examination,
 chest radiograph,
 Pelvic sonography or
 abdominopelvic computed tomography (CT )
 However, pulmonary lesions identified on chest radiograph
should prompt CT of the chest and magnetic resonance
(MR) imaging o the brain.
 central nervous system involvement is rare in the absence
of neurologic symptoms or signs.
WHO prognostic scoring for GTN
Treatment of GTN

 Chemotherapy- is the main stay of

management
 Could be single agent or multiagent based on
the stage and WHO prognostic score which
classifies them as high risk or low risk disease.
 FIGO stage 1 and FIGO stage 2 and 3 with
WHO sore <7 considered as low risk.
 FIGO stage 4 and FIGO stage 2 and 3 with
WHO sore =>7 considered as high risk.
Chemothrapy for low risk GTN

 Single agent chemothreapy is preferred

 Methotrexate
 First line drug
 Folic acid antagonist, given with folinic acid to
minimiza sideeffects
 After negative HCG 2-3 cycles should be given for
consolidation
 Dactinomycine
Chemothrapy for low risk GTN
Chemothrapy for low risk GTN
 Serum B-HCG is assesed and rescored and restaged
after each cycle of chemothreapy
 if the patient develops high risk score in the course
of single agent chemotherapy she will be switched to
multiagent chemotherapy.
 If the patient has increasing B-HCG while on single
agent chemotheapy but do not fulfill criteria for high
risk GTN can be swithched from one single agent to
another.
Chemotherapy for high risk GTN

 Approximately 5 percent of GTN patients

present with highrisk disease.
 usually have numerous metastases months or
years after the causative pregnancy.
 Such patients are likely to develop drug
resistance to single-agent chemotherapy
 They should be started with multiagent
chemotherapy
Multiagent chemotherapy options

 EMACO regimen- preferred regimen

 Etoposide
 Methotrexate
 actinomycineD
 Cyclophosphamide
 Vincristine/oncoverine
 EMA/EP- vincristine replaced by cisplatin- for
patients with failed EMACO regimen
 MAC- less favored
Treatment of GTN

 Surgery
 Repeat evacuation- if there is significant amount of
residual tissue
 Hysterectomy- may be primarily performed for PSTT,
ETT or other chemotherapy resistant disease
▪ Also can be performed for uncontrolled hemorrhage
▪ Pateints with GTN who do not require future fertility should be
counciled for hysterectomy
 For some Residual lung methasthesis- thoracotomy
 Radiotherapy- may be used for hemostatit purpose
sometimes
 Patients with cerebral metastases may
present with seizures, headaches, or
hemiparesis
Follow up after treatment of GTN

1. Weekly measurement of serum HcG till

normal for 3 consecutive weeks
2. Monthly till 12 normal consecutive results for
stage 1-3 and 2yrs for stage 4
3. Effective contraception
4. CXR
Pregnancy after previous GTD

 High chance of recurrence

 Early evaluation to confirm normal gestation
 Placental examination
 Pathology of products of conception if
abortion occurs
 Measurement of serum B- HCG at 6weeks
post partum
False negative and false positive serum B-HCG

• False negative results

▪ "hook effect“ with extremly very high amount of HCG, serum
measurement may be negative due to over saturation of the HCG assay
▪ Diluting the sample
▪ Urine HCG
 False positive HCG
 Phantom B-HCG
 Occasionally, persistent mild elevations of serum β-hCG areDetected but
those are not true β-hCG
 This “phantom” β-hCG reading results from heterophilic antibodies in the
serum that interfere with the β-hCG immunoassay and cause a false-
positive result
 Can be differentiated from true HCG by urine testing because patients
with phantom B-HCG will have –ve urine HCG result.
references

 Williams gynecology 3rd edition

 UTD 21.2
 Berek and Novaks Gynecology 14th edition