Gestational Trophoblastic

Disease
 INTRODUCTION
Gestational trophoblastic disease (GTD) is the term used to encompass a group of tumors
typified by abnormal trophoblast proliferation. Trophoblast produces human chorionic
gonadotropin (hCG), thus the measurement of this peptide hormone in serum is essential for
GTD diagnosis, management, and surveillance.
GTD histologically is divided into hydatidiform moles, which are characterized by the
presence of villi, and into nonmolar trophoblastic malignant neoplasms, which lack villi.
Hydatidiform moles are excessively edematous immature placentas
These include the benign complete hydatidiform mole and partial
hydatidiform mole and the malignant invasive mole
.Nonmolar trophoblastic neoplasms include choriocarcinoma, placental
site trophoblastic tumor, and epithelioid trophoblastic tumor. These
three are di erentiated by the type of trophoblast they contain.
The malignant forms of gestational trophoblastic disease are termed
gestational trophoblastic neoplasia (GTN). These include invasive
mole, choriocarcinoma, placental site trophoblastic tumor, and
epithelioid trophoblastic tumorHowever, histological confirmation is
typically not available. Instead, measurement of serum hCG levels
combined with clinical finding.
 HYDATIDIFORM MOLE
The classic histological findings of molar pregnancy include
trophoblast proliferation and villi with stromal edema (Fig. 20-1).
The degree of histological changes, karyotypic di erences, and the
absence or presence of embryonic elements are used to classify them
as either complete or partial moles.
Complete hydatidiform mole. A. Gross specimen with characteristic
vesicles of variable size.
A complete mole has abnormal chorionic villi that grossly appear as a mass of clear vesicles.
These vary in size and o en hang in clusters from thin pedicles. In contrast, a partial molar
pregnancy has focal and less advanced hydatidiform changes and contains some fetal tissue.
Both forms of moles usually fill the uterine cavity, but they rarely may be tubal or other forms
of ectopic pregnancy
 Epidemiology and Risk Factors
An ethnic predisposition is seen with hydatidiform mole, which has increased prevalence in
Asians, Hispanics, and American Indians
. The incidence in the United States and Europe has been relatively constant at 1 to 2 per 1000
deliveries.
The strongest risk factors are age and a prior hydatidiform mole. Women at both extremes of
reproductive age are most vulnerable. Specifically, adolescents and women aged 36 to 40
years have a twofold risk, but those older than 40 have an almost tenfold risk
. With a prior complete mole, the risk of another mole is 0.9 percent, and with a previous
partial mole, the rate is 0.3 percent. two prior complete moles, approximately 20 percent of
women have a third mole.
 Pathogenesis
Complete moles most o en have a diploid chromosomal composition (
These usually are 46,XX and result from androgenesis, meaning both sets of chromosomes are
paternal in origin. The chromosomes of the ovum are either absent or inactivated. The ovum
is fertilized by a haploid sperm, which then duplicates its own chromosomes a meiosis. Less
commonly, the chromosomal pattern may be 46,XY or 46,XX and due to fertilization by two
sperm, that is, dispermic fertilization or dispermy
Typical pathogenesis of complete and partial moles. A. A 46,XX complete mole may be
formed if a 23,X-bearing haploid sperm penetrates a 23,X-containing haploid egg whose genes
have been “inactivated.” Paternal chromosomes then duplicate to create a 46,XX diploid
complement solely of paternal origin. B. A partial mole may be formed if two sperm—either
23,X- or 23,Y-bearing—both fertilize (dispermy) a 23,X-containing haploid egg whose genes
have not been inactivated. The resulting fertilized egg is triploid with two chromosome sets
being donated by the father. This paternal contribution is termed diandry..
Twin Pregnancy
Rarely, in some twin pregnancies, one chromosomally normal fetus is paired with a complete diploid
molar pregnancy. Importantly, these cases must be distinguished from a single partial molar pregnancy
with its associated abnormal fetus. Amniocentesis and fetal karyotyping aid confirmation.

Several unique pregnancy problems complicate such twin pregnancies. And, many women may choose to
terminate the gestation, if diagnosed early. In those with continuing pregnancy, survival of the normal
fetus varies and depends on associated comorbidity from the molar component. The most worrisome are
preeclampsia or hemorrhage, which frequently necessitate preterm delivery.

Another concern for those continuing their pregnancy is the risk for developing subsequent GTN.
However, most data indicate no significant di erence between women who continue or terminate their
pregnancy
 Clinical Findings
The presentation of women with a molar pregnancy has changed
remarkably over the past several decades because prenatal care is
sought much earlier and because sonography is virtually universal.
Typically, 1 to 2 months of amenorrhea precede the diagnosis.
 Untreated molar pregnancies will almost always cause uterine
bleeding that varies from spotting to profuse hemorrhage.
Bleeding may presage spontaneous molar abortion, but more o en, it
follows an intermittent course for weeks to months. In more advanced
moles with considerable concealed uterine hemorrhage, moderate iron-
deficiency anemia develops.
Nausea and vomiting may be significant. These are more common
with a complete mole and likely result from ovarian overstimulation by
excessive hCG levels.
theca-lutein cysts regress following pregnancy evacuation, expectant
management is preferred.
The thyrotropin-like e ects of hCG frequently cause serum free
thyroxine (fT4) levels to be elevated and thyroid-stimulating hormone
(TSH) levels to be decreased. Despite this, clinically apparent
thyrotoxicosis is unusual and in our experience can be mimicked by
bleeding and sepsis from infected products.
Severe preeclampsia and eclampsia are relatively common with
advanced molar pregnancies.
 Diagnosis
Serum β-HCG Measurements
With a complete molar pregnancy, serum β-hCG levels are commonly
elevated above those expected for gestational age.

With more advanced moles, values in the millions are not unusual.
Importantly, these high values can lead to erroneous false-negative
urine pregnancy test results. Termed a “hook effect,” excessive β-hCG
hormone levels oversaturate the assay’s targeting antibody and create a
falsely low reading
Sonography
. complete mole appears as an echogenic uterine mass with numerous anechoic
cystic spaces but without a fetus or amnionic sac. The appearance is o en described
as a “snowstorm”

A partial mole has features that include a thickened, multicystic placenta along with
a fetus or at least fetal tissue. However, in early pregnancy, these sonographic
characteristics are seen in fewer than half of hydatidiform moles.

Sonograms of hydatidiform moles. A. Sagittal view of a uterus with a complete

hydatidiform mole. The characteristic “snowstorm” appearance is due to an
echogenic uterine mass, marked by calipers, that has numerous anechoic cystic
spaces..
Pathology In pregnancies before 10 weeks, classic molar changes may not be apparent because villi
may not be enlarged and molar stroma may not yet be edematous and avascular.
Histopathologic evaluation can be enhanced by immunohistochemical staining for p57
expression and by molecular genotyping
p57KIP2 is a nuclear protein whose gene is paternally imprinted and maternally expressed.
This means that the gene product is produced only in tissues containing a maternal allele.
Because complete moles contain only paternal genes, the p57KIP2 protein is absent in
complete moles, and tissues do not pick up this stain
In contrast, this nuclear protein is strongly expressed in normal placentas, in spontaneous
pregnancy losses with hydropic degeneration, and in partial hydatidiform moles
Accordingly, immunostaining for p57KIP2 is a negative means to isolate complete mole
from the diagnostic list.
For distinction of a partial mole from a nonmolar hydropic abortus, both of which express
p57, molecular genotyping can be used. Molecular genotyping determines the parental
source of alleles. Thereby, it can distinguish among a diploid diandric genome (complete
mole), a triploid diandric-monogynic genome (partial mole), or biparental diploidy
(nonmolar abortus).
 Management

Maternal deaths from molar pregnancies are rare because of early

diagnosis, timely evacuation, and vigilant postevacuation surveillance
for GTN. Preoperative evaluation attempts to identify known potential
complications such as preeclampsia, hyperthyroidism, anemia,
electrolyte depletions from hyperemesis, and metastatic disease.
Most recommend chest radiography, whereas computed tomography
(CT) and magnetic resonance (MR) imaging are not routinely done
unless a chest radiograph shows lung lesion.
 Molar Pregnancy Termination
Regardless of uterine size, molar evacuation by suction curettage is usually the preferred
treatment
. Preoperative cervical dilatation with an osmotic dilator is recommended if the cervix is
minimally dilated.
Intraoperative bleeding can be greater with molar pregnancy than with a comparably sized
uterus containing nonmolar products.
The cervix is mechanically dilated to preferably allow insertion of a larger suction curette.
Depending on uterine size, a 10- to 14-mm diameter is typical. As evacuation is begun,
oxytocin is infused to limit bleeding. Intraoperative sonography is o en recommended to
help ensure complete uterine cavity emptying. When the myometrium has contracted, a
thorough but gentle curettage with a sharp large-loop Sims curette is performed.
If bleeding continues despite uterine evacuation and oxytocin infusion,
other uterotonic agents are given
Some volume of trophoblast is deported into the pelvic venous system
during molar evacuation With large moles, the amount of tissue may be
suficient to produce clinically apparent respiratory insufficiency,
pulmonary edema, or even embolism.
In our earlier experiences with substantial moles, these and their chest
radiographic manifestations clear rapidly without specific treatment.
Because of deportation, there is concern that trophoblastic tissue will
thrive within the lung parenchyma to cause persistent disease or even
overt malignancy. Fortunately, no evidence suggests that this is a
major problem.
Following curettage, anti-D immunoglobulin (Rhogam) is given to Rh
D-negative women because fetal tissues with a partial mole may
include red cells with D- antigen
Following evacuation, the long-term prognosis for women with a
hydatidiform mole is not improved with prophylactic chemotherapy it
is not recommended routinely .
. Hysterectomy with ovarian preservation may be preferable for
women with complete moles who have finished childbearing. Of
women aged 40 to 49 years, 30 to 50 percent will subsequently
develop GTN, and hysterectomy markedly reduces this likelihood
Theca-lutein cysts seen at the time of hysterectomy do not require
removal.
 Postevacuation Surveillance
Close biochemical surveillance for persistent gestational neoplasia
follows each hydatidiform mole evacuation. This monitoring is by
serial measurement of serum β-hCG to detect persistent or renewed
trophoblastic proliferation. As a glycoprotein, hCG shows structural
heterogeneity and exists in di erent isoforms.
Thus for surveillance, an hCG assay that can detect all forms of hCG
should be used These are diferent from those used for routine
pregnancy testing The initial β-hCG level is obtained within 48 hours
after evacuation. This serves as the baseline, which is compared with
β- hCG quantification done therea er every 1 to 2 weeks until levels
progressively decline to become undetectable.
The median time for such resolution is 7 weeks for partial moles and 9 weeks for complete
moles. Once β-hCG is undetectable, this is confirmed with monthly determinations for
another 6 months
Concurrently, reliable contraception is imperative to avoid confusion caused by rising β-hCG
levels from a new pregnancy. Most recommend combination hormonal contraception,
injectable depot medroxyprogesterone acetate, or progestin implant
. Intrauterine devices are not used until β-hCG levels are undetectable because of the risk
of uterine perforation if there is an invasive mole. Although not recommended, if a woman
conceives during surveillance, live- birth rates and risk for congenital anomalies appear to
mirror the general population After these 6 months, monitoring is discontinued and
pregnancy allowed.
Importantly, during β-hCG level surveillance, either increasing or persistently
plateaued levels mandate evaluation for trophoblastic neoplasia. Other risk
factors are older maternal age, β-hCG levels >100,000 mIU/mL, uterine size
that is large for gestational age, theca-lutein cysts >6 cm, and slow decline in
β-hCG levels.
 GESTATIONAL TROPHOBLASTIC
NEOPLASIA
invasive mole, choriocarcinoma, placental site trophoblastic tumor, and
epithelioid trophoblastic tumor.
These tumors almost always develop with or after some form of recognized
pregnancy. Half follow hydatidiform mole, a fourth follow miscarriage or
tubal pregnancy, and another fourth develop after a preterm or term
pregnancy
Although these four tumor types are histologically distinct, they are usually
diagnosed solely by persistently elevated serum β-hCG levels because tissue
is infrequently available for study
 Clinical Findings
These placental tumors are characterized clinically by their aggressive invasion into the
myometrium and propensity to metastasize. The most common finding with GTN is irregular
bleeding associated with uterine subinvolution. The bleeding may be continuous or
intermittent, with sudden and sometimes massive hemorrhage. Myometrial perforation from
trophoblastic growth may cause intraperitoneal hemorrhage. In some women, lower genital
tract metastases are evident, whereas in others only distant metastases are found with no trace
of uterine tumor.
 Diagnosis, Staging, and Prognostic
Scoring
Consideration for the possibility of GTN is the most important factor in its recognition.
Unusually persistent bleeding a er any type of pregnancy should prompt measurement of
serum β-hCG levels and consideration for diagnostic curettage if levels are elevated. Uterine
size is assessed along with careful examination for lower genital tract metastases, which
usually appear as bluish vascular masses (Cagayan, 2010). Tissue diagnosis is unnecessary,
thus biopsy is not required and may cause significant bleeding.
Once the diagnosis is verified, in addition to a baseline serum β-hCG level and hemogram, a
search for local disease and metastases includes tests of liver and
renal function, transvaginal sonography, chest CT scan or radiograph, and brain and
abdominopelvic CT scan or MR imaging. Less commonly, positron-emission
tomographic (PET) scanning and cerebrospinal fluid β-hCG level determination are used to
identify metastases
 Invasive Mole

These are the most common trophoblastic neoplasms that follow

hydatidiform moles, and almost all invasive moles arise from partial or
complete moles.
Previously known as chorioadenoma destruens, invasive mole is
characterized by extensive tissue invasion by trophoblast and whole
villi. There is penetration deep into the myometrium, sometimes with
involvement of the peritoneum, adjacent parametrium, or vaginal
vault. Although locally aggressive, invasive moles are less prone to
metastasize.
 Gestational Choriocarcinoma
This is the most common type of trophoblastic neoplasm to follow a term pregnancy or a
miscarriage, and only a third of cases follow a molar gestation (Soper, 2006). Choriocarcinoma
is composed of cells reminiscent of early cytotrophoblast and syncytiotrophoblast, however, it
contains no villi. This rapidly growing tumor invades both myometrium and blood vessels to
create hemorrhage and necrosis. Myometrial tumor may spread outward and become visible on
the uterine surface as dark, irregular nodules. Metastases o en develop early and are generally
blood-borne (Fig. 20-5).
The most common sites are the lungs and vagina, but tumor may travel to the vulva, kidneys,
liver, brain, ovaries, and bowel. Bleeding can complicated these metastases (Fatema, 2016;
Wei, 2016; Zhang, 2017). Choriocarcinomas are commonly accompanied by ovarian theca-
lutein cysts.
Metastatic choriocarcinoma. A. Chest radiograph demonstrates widespread metastatic lesions.
B. Autopsy specimen with multiple hemorrhagic hepatic metastases.
This rare tumor arises from intermediate trophoblasts at the placental site. These tumors have
associated serum β-hCG levels that may be only modestly elevated. However, they produce
variant forms of hCG, and identification of a high proportion of free β-hCG is considered
diagnostic. Treatment of placental site trophoblastic tumor by hysterectomy is preferred
because these locally invasive tumors are usually resistant to chemotherapy (Baergen, 2006).
For higher-risk stage I and for later stages, adjuvant multidrug chemotherapy is also given
 Epithelioid Trophoblastic Tumor

This rare tumor develops from chorionic-type intermediate trophoblast.

The uterus is the main site of involvement, and bleeding and low hCG
levels are typical findings
Primary treatment is hysterectomy because this tumor is relatively
resistant to chemotherapy. Metastatic disease is common, and
combination chemotherapy is employed
 Treatment
Women with GTN are best managed by oncologists, and some evidence supports treatment in
centers specializing in GTN
The prognosis is excellent with rare exceptions, and patients are routinely cured even in the
presence of widespread disease. Chemotherapy alone is usually the primary treatment.
Although controversial, some also consider a second uterine evacuation to be an adjuvant
therapeutic option in some GTN cases to avoid or minimize chemotherapy.
In other cases, suction curettage may infrequently be needed to resolve bleeding or remove a
substantial amount of retained molar tissue. In specific cases, hysterectomy may be primary or
adjuvant treatment
Single-agent chemotherapy protocols are usually sufficient for
nonmetastatic or low-risk metastatic neoplasia
Combination chemotherapy is given for high-risk disease, and reported
cure rates approximate 90 percent
Frequent causes of death include hemorrhage from metastatic sites,
respiratory failure, sepsis, and multiorgan failure due to widespread
chemoresistant disease
With either low- or high-risk disease, once serum β-hCG levels are
undetectable, serosurveillance is continued for 1 year. During this time,
e ective contraception is crucial to avoid any teratogenic e ects of
chemotherapy to the fetus and to mitigate confusion from rising β-hCG
levels caused by superimposed pregnancy
A small number of women during surveillance, despite no evidence of
metastases, will be found to have very low β-hCG levels that plateau.
This phenomenon is called quiescent hCG and presumably is caused
by dormant trophoblast. Close observation without therapy is
recommended, but 20 percent will eventually have recurrent active
and progressive trophoblastic neoplasia
SUBSEQUENTWomen
PREGNANCY
with prior hydatidiform mole generally do not have impaired fertility,
and their pregnancy outcomes are usually normal
One concern is the 2-percent risk for developing trophoblastic disease in a
subsequent pregnancy, which was described earlier.
Sonographic evaluation is recommended in early pregnancy, Women
successfully completed GTN chemotherapy advised to delay pregnancy for
12 months.
Fertility and pregnancy outcomes are typically normal, and congenital
anomaly rates are not increased One exception is an unexplained higher
stillbirth rate of 1.5 percent compared with a background rate of 0.8 percent
A er hydatidiform mole or GTN treatment, in subsequent pregnancy, the
placenta or products of conception are sent for pathological evaluation at
delivery. A serum β-hCG level is measured 6 weeks postpartum
thank you