Gestational

Gestational
Trophoblastic
Trophoblastic Disease
Disease

(GTD)
(GTD)
By
Dr Amir Z.
 Gestational
Trophoblastic Disease
• Is the general term for a spectrum
of proliferative abnormalities
originating from the trophoblast of
the placenta.

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 GTD
Clinical Classification
• Hydatidiform mole (molar
pregnancy)
– Complete, or classic
– Incomplete, or partial
• Gestational trophoblastic neoplasia
– Nonmetastatic
– Metastatic
• Low risk (good prognosis)
• High risk (poor prognosis)

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 GTD
Hydatidiform mole
• Characterized by abnormal
proliferation of the placental
trophoblastic cells.
• Abnormal cells distend the uterus
and secrete the polypeptide
hormone hCG.
• complete (classic) or partial
(incomplete).

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 GTD
Gestational trophoblastic tumor
(GTT)
• Malignant form of GTD, which
arises from the trophoblastic
elements of the developing
blastocyst, retains the invasive
tendencies of the normal placenta
and remains able to secrete hCG.
• Can be either metastatic or
nonmetastatic

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 Incidence
Benign GTD
• Occurs in 1 of 1500 pregnancies in the
United States and in as many as 1 of
125 pregnancies in parts of eastern
Asia.
• Risk factors:
– age < 20 or > 40
– Genetic factors
– Low socioeconomic status
– Protein,folic acid & carotene deficiency
– Previous molar pregnancy

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 Incidence
Malignant GTD
• Develops in 20 % of complete moles
• Identified in 1 of 20,000 pregnancies in
the United States and can occur after
any type of pregnancy.
• May follow
– Molar pregnancy (50%)
– Normal pregnancy (25%)
– Spontaneous abortion or ectopic pregnancy
(25%)

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 Hydatidiform Mole
• Complete mole
• Partial mole

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 Complete mole
• The whole conceptus is transformed
into a mass of vesicles.
• No embryo is present.
• It is the result of fertilization of
anucleated ovum (has no
chromosomes) with a sperm which
will duplicate giving rise to 46
chromosomes of paternal origin
only.

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 Partial mole
• A part of trophoblastic tissue only
shows molar changes.
• There is a fetus or at least an
amniotic sac.
• It is the result of fertilization of an
ovum by 2 sperms so the
chromosomal number is 69
chromosomes.

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DIFFERNTIATION BETWEEN
COMPLETE & PARTIAL MOLE
Feature Complete Partial
Embryonic or Absent Present
Fetal tissue
Swelling of Diffuse Focal
villi
Trophoblastic Diffuse Focal
hyperplasia
Karyotype 46 XX(96%) or 69XXY or
46 XY(4%) 69 XYY
Risk of 20% 4%

persistence 13
 Hydatidiform Mole
Characteristics (microscopic features )
Complete mole
a. Marked edema & enlargement of villi.
b. Disappearance of the villous blood
vessels
c. Proliferation of the trophoblastic lining of
the villi
d. Absence of fetus, cord & amniotic
membrane.
e. Normal karyotype (usually XX, rarely XY)

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 Hydatidiform Mole
Characteristics (microscopic
features )
Incomplete mole
a. Marked swelling of the villi with
atrophic trophpblastic cells.
b. Presence of normal villi.
c. Presence of fetus, cord and
amniotic membrane.
d. Abnormal karyotype, usually
triploidy or trisomy.

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 Hydatidiform Mole
Clinical features
• Vaginal bleeding
• Passage of grape like vesicles
• The uterus is often larger than
expected in terms of LMP
• Nausea & vomiting ( 1/3 of pts)
• Preeclampsia (27% of cases)
• Clinical hyperthyroidism (7%)

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 Hydatidiform Mole
Clinical features
• Abdominal pain : may be
– Dull-aching due to rapid distension of
the uterus
– Colicky due to starting expulsion
– Sudden & severe due to perforating
mole.
– 20 to theca luthein cysts (15%)

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 Hydatidiform Mole
Diagnosis
• Passage of vesicular tissue
• A quantitative hCG titer of > 100,000
mlU/ml with enlarged uterus & bleeding is
suggestive of a mole.
• Amniography (honey comb appearance).
• A flat plate of the abdomen after 15 wks
fails to show a fetal skeleton.
• U/S : multiple echoes without normal GS
or fetus (typical snow storm appearance).

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 Hydatidiform Mole
1) Diagnostic studies
• Laboratory tests: CBC,
quantitative hCG, coagulation
studies, type and screen, baseline
RFT,LFT and thyroid function tests.
• Imaging studies include chest
radiograph to evaluate for lung
metastases and ultrasound

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 Complications
• Hemorrhage
• Infection due to absence of
amniotic sac
• Perforation of the uterus
• PIH
• Hyperthyroidism
• Subsequent development of
choriocarcinoma

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 Management
2) Suction curettage in conjunction
with iv Oxytocin.
3) Hysterectomy is a treatment
option for patients who do not
desire future fertility.

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• The risk of developing GTT after
evacuation is
– 20% for a complete mole and
– 4% for a partial mole.
• High-risk factors associated with
persistent disease include :
– pretreatment hCG > 100,000 mIU/mL
– theca lutein cysts > 6 cm
– age older than 40 years
– previous molar pregnancy.

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 Follow-up
• After evacuation, the expected
average time to complete
elimination of hCG is 9 to 11
weeks.
• This period depends on :
– The initial level of hCG,
– The amount of viable trophoblastic
tissue remaining after evacuation
– The half-life of hCG.

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 Follow-up
Determinations of hCG
• at 48 hours post evacuation, then
• weekly until the results are negative
for 3 consecutive weeks, then
• every month for 6 months, and then
• yearly.
An increase or plateau in hCG indicates
the development of GTT and
necessitates the initiation of
chemotherapy.

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• It is expected that urine
pregnancy test is negative 4
weeks after evacuation & serum ß-
hCG is undetectable 4 months
after evacuation.
• Early features suggesting molar
tissue include:
– Recurrent or persitant vaginal
bleeding
– Amenorrhea
– Failure of uterine involution
– Persistence of ovarian enlargement.
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 Follow-up
Physical examination, including a
pelvic examination, at regular intervals
until remission to ensure adequate
involution of pelvic organs.
Birth control (recommended for 1 year).
Oral contraceptives or
medroxyprogesterone (Depo-Provera)
injections are recommended.
Pregnancy can be attempted after 1 year
from the diagnosis.
Prophylactic Chemotherapy is rarely
recommended

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 Future fertility
• Normal pregnancy is the most likely
result of future gestations.
• Risk of :
– a second molar pregnancy is 1% ; risk of
– a third molar pregnancy is 15-28% .
– The risk following three molar pregnancies
is nearly 100%.

• Subsequent molar pregnancies may be

complete or partial, regardless of the
type of initial molar pregnancy.

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 Gestational Trophoblastic
Tumor (GTT)
• The occurrence of GTT after a molar
pregnancy may have the histologic
appearance of a mole or
choriocarcinoma.
• After a normal pregnancy, abortion,
or ectopic pregnancy, GTT always
has the appearance of
choriocarcinoma, or occasionally the
aggressive placental site
trophoblastic tumor variant of
choriocarcinoma.
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 Classification of GTN
Nonmetastatic: disease confined to the
uterus
Metastatic: disease spread outside the uterus
• Good prognosis (low risk)
– Short duration: disease present <4 months
– Pretreatment hCG titer: <40,000 mIU/mL
– No previous chemotherapy
• Poor prognosis (high risk)
– Long duration: disease present >4 months
– Pretreatment hCG titer: >40,000 mIU/mL
– Brain or liver metastases
– Failure of previous chemotherapy
– Disease after term pregnancy

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 Nonmetastatic GTT
• (persistent or invasive mole) is
molar tissue that:
– invades the uterine wall
– produces persistent hCG elevation,
– and potentially causes bleeding.
• It is confined to the uterus and is
the most common form of GTT.

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 Metastatic disease
• Lung (80%)
• Vagina (30%)
• Liver (10%)
• Brain (10%).

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 Metastatic disease
Patients have various symptoms, such
as :
• Vaginal bleeding (vaginal
metastasis)
• Hemoptysis (pulmonary metastases)
• Neurologic symptoms (brain
metastases).
The disease is often associated with
hemorrhage because of the
propensity of trophoblastic tissue to
invade vessels.

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 Metastatic disease
• Metastases are very friable, and
biopsy to confirm diagnosis is not
recommended.
• In the setting of the appropriate
clinical history and an elevated
hCG, lesions visualized on
radiographic studies are treated.

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 Diagnosis

• After evacuation of a molar pregnancy,

GTT is diagnosed when
– there is a documented increase in hCG, the
value of hCG reaches a plateau for 3 weeks,
or
– metastatic disease is identified.
• Weeks or years after an abortion or
ectopic pregnancy, elevated hCG may
indicate GTT or another pregnancy.

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 Management
Workup of patients with GTT should
include the following:
• Complete history and physical examination
• Pretreatment hCG titer, hematologic
survey, serum chemistries, and liver
function studies
• Pelvic ultrasound
• Computed tomography (CT) scan of the
abdomen and pelvis
• Chest radiograph or chest CT
• CT or magnetic resonance imaging of the
brain in high-risk patients
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 Management
Nonmetastatic GTT
• almost 100% curable
• Single-agent chemotherapy
cures more than 90% of patients.
• Hysterectomy may be offered to
decrease the number of
treatments required for the
patient who does not desire future
fertility.

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 Management of NMGTT
• Methotrexate is the most commonly used
treatment agent.
– inhibits purine synthesis by blocking the
dihydrofolate reductase enzyme required to
process folic acid. This results in arrested
synthesis of DNA, RNA, and proteins..
– Side effects :
• Nausea
• Ulcerations of the mouth and GIT
mucosa
• Myelosuppression,Hepatotoxicity,
Nephrotoxicity, Alopecia and Pneumonitis

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 Management of NMGTT
• Leucovorin (folinic acid) is
administered 24 hours after each
methotrexate dose to rescue
normal cells from methotrexate
toxicity.
• Folic acid should be avoided during
methotrexate treatment as it
interferes with the action of the
methotrexate

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 Management of NMGTT
Actinomycin D
• is an antibiotic that intercalates
DNA strands.
• It is also an effective single-agent
treatment for nonmetastatic GTT.
• Failure-agent treatment is rare.
Most patients are still curable by
switching to another agent or
switching to a multidrug regimen.

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 Follow up (NMGTT)
• hCG titers should be followed carefully:
weekly until normal for 3 months, then
monthly until normal for 6 months.
• Contraception, preferably with oral
contraceptives or
medroxyprogesterone (Depo-Provera),
should be used for 6 to 12 months.

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 Management of MGTT

• Good-prognosis metastatic GTT

• Poor-prognosis metastatic GTT

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 patients
• Patients are treated as for NMGTD,
including methotrexate or
dactinomycin.
• Hysterectomy in conjunction with
chemotherapy may decrease the
amount of chemotherapy required.
• Patients are followed as for NMGTD.
• 40% of patients may experience failure
of therapy (i.e., new metastatic lesions
appear, or titers do not decrease
progressively), and this is an indication
for more aggressive therapy

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 Therapy for High-Risk
patients
• An aggressive combination
chemotherapy with adjuvant
radiotherapy or surgical therapy is critical
for gaining disease remission.
• Patients are usually treated in major
oncology centers or trophoblastic disease
centers with intensive and continual
monitoring, long-term additional
maintenance therapy, and prompt
intervention with radiotherapy or surgery

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 Therapy for High-Risk patients

• Multiagent chemotherapy such

as EMA-CO (etopo-side,
methotrexate, actinomycin D,
cyclophosphamide, and vincristine
[Oncovin]) and a multiple modality
approach (i.e., chemotherapy,
surgery, and radiation).

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 Therapy for High-Risk
patients

• High-risk patients should be treated in

centers that have a special interest and
expertise in this disease, especially
when life-threatening toxicity from
therapy is a factor.
• The survival rate is approximately
80%.
• Hysterectomy usually does not improve
the outcome.

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 Follow-up
• Three additional courses of
chemotherapy after a negative
hCG titer.
• Monitoring of hCG levels (similar
to that for nonmetastatic GTT).
• Contraception for at least 1 year
after negative levels of hCG.

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 Recurrence rates

• NMGTT: 1%
• Good-prognosis MGTT: 5%
• Poor-prognosis MGTT: up to 20%

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 Future fertility

• Fertility after chemotherapy for

GTT is usually retained since the
chemotherapy agents used do not
deplete the oocytes in the ovary.
• Women who choose to become
pregnant should be monitored
carefully.

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 Future fertility
• A normal intrauterine pregnancy
should be documented in the first
trimester.
• The placenta should be
histologically evaluated after
delivery, and
• hCG titers should be followed to
zero postpartum.

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 Placental Site Trophoblastic
Tumor
(PSTT)
• Rarest form of trophoblastic
neoplasia.
• Is a lesion of intermediate
trophoblasts, occurring as sheets
of trophoblastic cells invading into
the myometrium.
• Does not have the biphasic
pattern of cyto- and
syncytiotrophoblasts seen with
choriocarcinomas.
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 PSTT

• The tumor, in addition to invading

the myometrium, characteristically
invades vascular structures,
replacing the endothelial cell lining
seen with normal placental
implantation.
• Chorionic villi are rarely seen.

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 Diagnosis
Clinical Profile
• Patients are usually parous and
present with either amenorrhea or
abnormal vaginal bleeding and
uterine enlargement.
• Sensitive pregnancy tests are required
to detect the small amounts of hCG
produced by the tumor.
• Serum human placental lactogen
levels may be elevated.
• Patients are thought to be pregnant but,
when no further uterine enlargement
occurs, they are initially thought to have
experienced a missed abortion.
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 Pathology
• Myometrial invasion is prominent,
and
• uterine perforation with
intraperitoneal hemorrhage may
occur.
• Despite deep myometrial invasion,
the tumor in most cases is limited
and confined to the uterus,
resulting in a more benign course.

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 Pathology
• In other cases, however, malignant
behavior with widely disseminated
metastases to the lung, liver, and
central nervous system may occur.
• Metastatic PSTT is generally
unresponsive to chemotherapy.
• Immunohistochemical studies show
diffuse staining with human placental
lactogen, and serum levels may be
helpful in monitoring these lesions.

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 Treatment
• With deep myometrial invasion,
curettage is ineffective in
removing the lesion entirely but
may remove enough tissue to
establish the diagnosis.
• At the time of the currettage, care
must be exercised to prevent
uterine perforation.

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 Treatment
• Hysterectomy is the treatment of
choice when the disease persists.
• PSTT is generally unresponsive to
multi-agent chemotherapy, but
occasional cases have shown
response.
• Mortality rate with malignant
lesions is 15% to 20%.

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