Gestational trophoblastic disease

Doc. dr. sci. Edin Međedović

Gestational trophoblastic disease
(GTD) comprises a heterogeneous
group of related lesions arising
from abnormal proliferation of
trophoblast of the placenta. In
GTD, the lesion arises from fetal,
not maternal, tissue.
The non-molar or malignant forms
of GTD are called gestational
trophoblastic neoplasia (GTN).
Epidemiology and risk factors
Approximately 1 in every 1,000 pregnancies is diagnosed as a molar pregnancy.
Twenty percent of these patients will develop malignant transformation requiring
chemotherapy after the evacuation of the mole.
Various factors are associated with molar pregnancy, including:
• Maternal age - molar pregnancy is more likely in women older than age 35 or
younger than age 20.
• Previous molar pregnancy – repeated molar pregnancy happens, on average, in
1 out of every 100 women.
Types of GTD
• Benign‚ non-neoplastic trophoblastic lesions — These lesions are frequently diagnosed only as
an incidental finding on an endometrial curettage or hysterectomy specimen.
• Exaggerated placental site
• Placental site nodule

• Hydatidiform mole — Hydatidiform moles result from abnormalities in fertilization. They are

essentially benign, but carry an increased risk of persistent or malignant gestational trophoblastic
neoplasia (GTN).
• Complete hydatidiform mole
• Partial hydatidiform mole
• Invasive mole (chorioadenoma destruens)
Types of GTD
• Gestational trophoblastic neoplasia — a group of tumors with the potential for
local invasion and metastases, curable in 85-100% of cases, even in the presence
of advanced disease.
• Choriocarcinoma
• Placental site trophoblastic tumor
• Epithelioid trophoblastic tumor

In addition, the recent World Health Organization (WHO) classification adds an

additional category of "abnormal (nonmolar) villous lesions," which are considered
to have histologic features simulating a partial hydatidiform mole
Benign, non-neoplastic trophoblastic lesions 

Exaggerated placental site 

The exaggerated placental site (EPS) is characterized
by an extensive infiltration of the endometrium and
myometrium by implantation site intermediate
(extravillous) trophoblastic cells that occur in clusters
or as single cells. There is no destruction of the
normal endometrial glands and stroma, and it occurs
in the presence of a current pregnancy (ie, chorionic
villi). It likely represents an excessive physiologic
process rather than a true lesion.
The EPS can occur in a normal pregnancy or after a
first trimester abortion. The associated placenta is
usually normal. However, EPS occurs with increased
frequency in molar pregnancies and thus can give a
clue to diagnosis of these lesions.  Numerous multinucleate intermediate
trophoblasts infiltrating the myometrium (10x).
Benign, non-neoplastic trophoblastic lesions 

Placental site nodule 

Placental site nodules (PSN) are predominantly located in
the endometrium and endocervix of reproductive-age
women. The intermediate trophoblastic cells of PSNs are
likely derived from the migratory intermediate (extravillous)
trophoblasts of the placenta.
In approximately one-half of cases, PSNs are discovered as
an incidental finding in curettage or hysterectomy
specimens. They can occasionally arise in extrauterine sites
like the fallopian tube, presumably developing after an
ectopic pregnancy.
When grossly identifiable, they are characterized by a
yellow or tan surface and range from 1 to 14 mm (average
2.1 mm) in size. They are occasionally found as multiple
nodules or plaques. Hysteroscopic resection of the endometrial
lesion (white arrow) with a monopolar loop.
Hydatidiform mole
The hydatidiform mole is the most common form of GTD,
representing 80% of cases. Hydatidiform moles are
essentially very edematous immature placentas. The
classic description of gestational trophoblastic tissue is a
„bunch of grapes“.
Moles may be complete, partial, or invasive. Complete
and partial hydatidiform moles are differentiated by their
karyotype, gross morphology, histologic appearance, and
clinical features; invasive moles act in an aggressive
manner and are often treated similarly to
choriocarcinomas.
The development of gestational trophoblastic neoplasia
(GTN) is significantly increased after a complete mole, but
only slightly increased after a partial mole.
 Hydatidiform mole
A complete mole most commonly has a 46,XX
karyotype, with all chromosomes of paternal origin.
This results from fertilization of an "empty" egg (ie,
absent or inactivated maternal chromosomes) by a
haploid sperm that then duplicates (46,YY moles do
not occur because this karyotype is lethal); a complete
mole resulting from a spermatogonium (diploid)
has also been described.
A small number (3-13%) of complete moles have a
46,XY chromosome complement; this is thought to
occur when an empty ovum is fertilized by two
sperm. A few complete moles have a 46,XX
karyotype but develop from fertilization of an
empty ovum by two sperm.
Because the nucleus is entirely paternal in origin, a
complete mole is actually a paternal allograft in the
mother.
Hydatidiform mole
Partial moles are pathologically and
karyotypically distinct from complete
moles. They are usually (approximately
90%) triploid (69,XXX, 69,XXY, rarely
69,XYY) due to the fertilization of an ovum
(one set of haploid maternal
chromosomes) by two sperm (two sets of
haploid paternal chromosomes).
The fetal or embryonic tissue that is
present with a partial mole will most
commonly have a triploid karyotype.
 Hydatidiform mole

Histology 
Hydatidiform moles are characterized by a marked
proliferation of villous trophoblast associated with
hydropic swelling of the chorionic villi.
A major difference between complete and partial molar
pregnancy is that complete moles typically do not contain
any fetal/embryonic tissue whereas partial moles contain
fetal tissue admixed with hydropic villi.
A twin pregnancy may be
complicated by GTD, with a
combination of a normal
conceptus and a mole
(complete or partial) or two
moles.
 Invasive mole 
An invasive mole is a hydatidiform mole
characterized by the presence of enlarged hydropic
villi invading into the myometrium, into vascular
spaces, or into extrauterine sites. The abnormal villi
penetrate deeply into the myometrium.
Both invasive moles and choriocarcinoma may show
invasion of the uterine vasculature and the
production of secondary metastatic lesions,
particularly involving the vagina and lungs. Invasive
moles do not often resolve spontaneously.
Invasion can be difficult to diagnose by curettage, as
myometrium is often not present. Thus, it is usually
only diagnosed histologically if a hysterectomy has
been performed.
Gestational
trophoblastic neoplasia

The group of true gestational trophoblastic neoplasia

(GTN) includes choriocarcinoma, placental site
trophoblastic tumor (PSTT), and epithelioid
trophoblastic tumor (ETT).
Each of these neoplasms can follow a normal
pregnancy or a molar pregnancy. Choriocarcinoma
follows a mole in 50% of cases, while PSTT and ETT
follow a mole in only 8% of cases.
Invasive mole that does not resolve spontaneously is
also GTN.
In the absence of tissue for a definitive histopathologic
diagnosis, persistent elevation of hCG after evacuation
of a molar pregnancy is considered GTN.
Gestational
trophoblastic neoplasia

After the evacuation of a molar pregnancy,

trophoblastic tissue persists in approximately 20% of
patients overall, but in a greater proportion of high-
risk patients (older age, longer interval from previous
pregnancy, and higher beta-hCG levels).
Surveillance is essential after the evacuation of a
molar pregnancy to exclude the presence of persistent
disease. The diagnosis is usually based upon the
finding of stable or serially rising serum beta-hCG
concentrations rather than by examination of tissue.
GTN may occur many years after the pregnancy and
may even occur during menopause. 
Gestational
trophoblastic neoplasia
Histologically, 75% of cases of stable or serially rising serum hCG
concentrations after a molar pregnancy represent invasive moles,
and 25% are choriocarcinomas. Often there is no histopathologic
confirmation and patients are treated empirically.
The risk of choriocarcinoma is increased after a complete mole and
has only rarely been reported after a partial mole. Therefore, a rise
in serum hCG after a molar pregnancy signals the presence of
persistent or recurrent GTD, which may be a recurrent mole,
invasive mole, or choriocarcinoma.
In contrast, persistent elevation of serum hCG following any
nonmolar pregnancy (eg, miscarriage, ectopic, or preterm/term
pregnancy) may be due to development of choriocarcinoma or PSTT
(placental site trophoblastic tumor), rather than invasive mole.
Choriocarcinoma 
Choriocarcinoma is a highly malignant epithelial tumor. It
can arise from any type of trophoblastic tissue (molar
pregnancy, abortion, ectopic, preterm/term intrauterine
pregnancy) but occurs only rarely, if ever, after a partial
mole.
Choriocarcinoma following a normal gestation is often
comprised of biparental chromosomes identical to the fetus.
Postmolar choriocarcinoma is often comprised exclusively of
paternal DNA or androgenetic; most choriocarcinomas that
follow molar pregnancies are aneuploid.
Some choriocarcinomas appear to arise within a term
placenta, referred to as an intraplacental choriocarcinoma.
These are most often biparental in origin and do not
necessarily arise after a molar pregnancy.
 Choriocarcinoma 
Most lesions begin in the uterus, although ectopic pregnancies
provide extrauterine sites of origin. When choriocarcinoma
metastasizes, the most common sites are lung, brain, liver, pelvis,
vagina, spleen, intestine, and kidney.
Sometimes, when curettage is performed for an early pregnancy
loss, gestational endometrium and implantation site without villi
may be found. Histopathologic diagnosis of choriocarcinoma in the
setting of an early pregnancy is often problematic. Although the
presumptive diagnosis is a missed abortion, choriocarcinoma may
have to be excluded by following quantitative serum hCG
concentrations and performing a chest radiograph.

 X-ray and contrast-enhanced computed

tomography (CT) scan of the chest
documenting diffuse metastatic cancer. (A)
Chest X-ray with multiple lesions in the
lungs. (B) Chest CT scan showing bilateral
pulmonary nodules.
Placental site trophoblastic tumors
PSTT (placental site trophoblastic tumor), is a rare,
potentially malignant neoplasm originating from
extravillous (intermediate) trophoblast cells. They can
occur months to years after a pregnancy. PSTTs most
commonly develop after a term gestation, but also occur
after a molar pregnancy in approximately 8% of cases; a
PSTT can develop after any type of pregnancy. The
majority of PSTTs, approximately 70%, act in a benign
manner, while the remaining 30% can develop metastasis
and even result in death.
Gross examination of the uterus. An ill-defined and localized friable tumor measuring 3 cm in
diameter invading the uterine corpus myometrium. A cystic portion with a thin wall is observed.
The uterine serosa is undisturbed.
Epithelioid trophoblastic tumor
ETT is a rare form of trophoblastic disease. ETT
primarily occurs in reproductive-age women up to 18
years following a prior gestation. The majority of ETT
occur after a full-term pregnancy, but approximately
one-third arise following a spontaneous abortion or
hydatidiform mole. Serum hCG levels are elevated, but
usually do not exceed 2500 mIU/mL.
Gross inspection of ETT shows a solid to cystic, fleshy,
and well-defined mass in the uterine wall, lower
uterine segment, or endocervix. ETTs are clinically,
pathologically, and prognostically similar to PSTTs.
Approximately one-third of patients present with
metastatic disease. A minority of ETTs act in a
malignant manner and treatment is usually
problematic in those cases.
Diagnosis of molar pregnancy
A molar pregnancy may seem like a normal pregnancy at first, but most molar
pregnancies cause specific signs and symptoms, including:
• Dark brown to bright red vaginal bleeding (usually begins between weeks 6 and
12 of pregnancy)
• Severe nausea and vomiting
• Sometimes vaginal passage of grapelike cysts
• Pelvic pressure or pain
Other signs that can indicate a molar pregnancy are: rapid uterine growth, high
blood pressure, preeclampisa, ovarian cysts, anemina, hyperthyroidism.
Diagnosis of molar pregnancy
Hydatidiform moles, choriocarcinomas, and the majority of PSTTs and ETTs are
identified by a marker, the beta subunit of human chorionic gonadotropin or by the
marker for human placental lactogen. Moles have characteristic chromosomal
abnormalities.
Clinical Presentation
• Partial: uterus small for gestational age, low presenting hCG level, rare medical
complications.
• Complete: uterus 50% larger for gestational age, high presenting hCG level,
medical complications occur approximately 25% of the time and include
hypertension, hyperthyroidism, anemia, hyperemesis gravidarum.
Ultrasonography findings
An ultrasound of a complete molar pregnancy — which can be detected as early as eight or
nine weeks of pregnancy — may show:
• No embryo or fetus
• No amniotic fluid
• A thick cystic placenta nearly filling the uterus
• Ovarian cysts

An ultrasound of a partial molar pregnancy may show:

• A fetus that's unexpectedly small for gestational age
• Low amniotic fluid
• Placenta that appears abnormal
 Ultrasonography findings

Transverse sonographic view of a uterus with the Partial hydatidiform mole with focal vesicular
classic „snowstorm“ appearence of complete changes and nonviable fetus
hydatiform mole.
 Ultrasonography findings

Twin pregnancy consisting of a Normal placenta anterior and

The fetus and molar placenta
complete mole and a normal fetus hydatiform mole posterior
 Ultrasonography findings

Uterus with intramyometrial mass - invasive mole Multiple theca-lutein cysts within one ovary of a woman
with a complete molar pregnancy. Bilateral, multiple
simple cysts are characteristic findings.
Evaluation
Ultrasound is the gold standard in non-invasive techniques. The most commonly
described appearance of a molar pregnancy on ultrasound is the "snowstorm" or
"bunches of grapes" pattern of the uterus.
However, the majority of first-trimester complete moles have a sonographic
appearance of a complex, echogenic intrauterine mass which contains multiple
small cystic spaces. These spaces correspond to the hydropic villi on gross
pathology.
Despite the utility of ultrasound in making this diagnosis, in patient's who are
presumed to have a spontaneous abortion, a molar pregnancy is detected only
after pathology evaluation of a uterine curettage sample. This most often occurs
in those with a partial mole.
Management of molar pregnancy
A molar pregnancy can't continue as a normal viable pregnancy. To prevent
complications, the abnormal placental tissue must be removed. Surgical uterine
evacuation (dilation and evacuation, suction curettage) is the mainstay of
management for complete or partial moles. A hysterectomy is an option for patients
who have completed childbearing.
All patients with hydatiform mole should be monitored with serial serum hCG testing
values after evacuation to evaluate for post-molar gestational trophoblastic
neoplasia(GTN).  Guidelines from the American College of Obstetricians and
Gynecologists advise the following protocol:
Every week until non-detectable for 3 weeks, then
Every month for 6 months: If the hCG remains undetectable for six months,
then the patient may resume trying to become pregnant.
Management of molar pregnancy
If hCG levels rise or remain elevated over several weeks after evacuation of molar
pregnancy, the patient is classified as having GTN. The diagnosis of post-molar GTN is
based upon the International Federation of Gynecology and Obstetrics (FIGO) criteria:
• hCG levels plateau (remain within +/-10% of the previous result) across four
measurements over a 3-week period.
• hCG level increases more than 10% across three values over a 2-week duration
• persistence of detectable serum hCG for more than 6 months after molar
evacuation.
GTN) occurs in about 15% to 20% of complete molar pregnancies, and up to 5% of
partial molar pregnancies. Persistent GTN can nearly always be successfully treated,
most often with chemotherapy.
Management of molar pregnancy
Risk factors for developing GTN:
• Complete mole with signs of trophoblastic proliferation (uterine size greater than
gestational age, serum human chorionic gonadotropin [hCG] levels more than 100,000
mIU/mL)
• Ovarian theca lutein cysts greater than 6 cm in diameter
• Age greater than 35 to 40 years.

Rarely, a cancerous form of GTN - choriocarcinoma develops and spreads to other organs.
Choriocarcinoma is usually successfully treated with multiple cancer drugs. Some
institutions offer prophylactic chemotherapy for high-risk women with complete moles.
Evidence shows that this may decrease the incidence of gestational trophoblastic neoplasia.
All patients with GTD should have a chest x-ray to evaluate for pulmonary metastasis.