LECTURE 19: Gestational Trophoblastic Disease

Dr. Alvarina | April 29, 2021

- Pregnancy occurring at extremes of maternal age

OUTLINE: (<16 and 45 years) revealing a “J-curve”
I. INTRODUCTION ₪ (<15 & >40 y/o)
II. HYDATIDIFORM MOLE - ↑ risk after age 35
• Risk Factor
- a five- to tenfold fold increase in after age 40
• Histopathology
• Clinical Manifestations » Common in Southeast Asia because of the low
• Diagnosis socioeconomic status of women
• Treatment
• Surveillance • Reproductive History
III. GESTATIONAL TROPHOBLASTIC NEOPLASIA - History of HM, ↑ risk in future pregnancies by 5- to
• Characteristics 40-fold
• Classification and Staging - Subsequent pregnancies have an approximate 1%
• Diagnosis risk, increasing to 25% when the number of previous
• Treatment
HM is two or more
IV. REFERENCES
V. APPENDIX - risk is not affected by changing partners
- recurrent molar pregnancies are also at increased
Important Audio Record Book Power point risk for the malignant sequelae of GTN
 » ß ₪ • Diet
- ↑ risk of Complete HM with decreasing
ß DEFINITIONS consumption of animal fat and beta-carotene
• a heterogeneous spectrum of diseases of abnormal (precursor to vitamin A)
trophoblastic proliferation ranging from benign to • Genetics
malignant, with varying predilections toward local - A rare autosomal recessive disorder known as
invasion and distant metastasis
familial recurrent HM has been identified on
• most curable of all gynecologic malignancies, gestational chromosome 19q
trophoblastic disease (GTD) - mutation of NLRP7 gene
• GTD is classified (WHO) according to:
- Histopathologic HISTOPATHOLOGY AND CYTOGENETIC FEATURES
- Cytogenetic • Normally, during early embryonic differentiation
- clinical features trophoblasts are derived from the outer blastocyst layer,
• Histologic categories of GTD: with three distinct trophoblasts recognized:
- Cytotrophoblasts
- Syncytiotrophoblasts
- intermediate trophoblasts
» these cells release B-hCG and hPL
• In HM, chromosomal abnormalities differentiate the
disease:
Complete HM Partial HM
• Derived from • Derived from
paternal maternal & paternal
• >90% 46, XX • Triploid genotype/
genotype or 46 XY dispermy: 69, XXX or
» Most common of the GTN is the Choriocarcinoma • Mechanism: 69, XXY
fertilization of an • Mechanism: haploid
empty ovum ovum fertilized by 2
ß HYDATIDIFORM MOLE haploid
RISK FACTOR spermatozoa.
• Age
- Teenagers have a 1.5- to twofold increased risk of
GTD

Uy| Urbiztondo
Page 1 of 7
 LECTURE 19: Gestational Trophoblastic Disease
Dr. Alvarina | April 29, 2021

5. Absence of the molar implantation

trophoblastic or site
stromal inclusion 5. Presence of
trophoblastic
scalloping and stromal
inclusion

CLINICAL FEATURES
• average gestational age of diagnosis of CHM today is 9.6
weeks
• Following a delayed menses, CHM typically presents in
the first trimester as vaginal bleeding, with or without
the passage of molar vesicles
• a large-for-date uterus
• absence of fetal movement
• anemia secondary to occult hemorrhage
• gestational hypertension before 20 weeks’ gestation
• presence of theca lutein cysts (β-hCG is homologous to
LH)
• hyperemesis
• hyperthyroidism (β-hCG is homologous to TRH)
• respiratory distress from trophoblastic emboli to the
lungs
• When uterine enlargement is more than 14 to 16 weeks,
25% complications related to the high levels of β-hCG
• Conditions confused pathologically with PHM:
- Beckwith-Wiedemann syndrome
- placental angiomatous malformation
- twin gestation with complete mole
- an existing fetus
- early complete mole
- hydropic complete mole

₪ Complete HM
Gross:
• Non-viable fertilized
egg
• Swollen chorionic villi
(grow in clusters)
• Grape like mass (“sago”
in Phil)
Histopath:
1. Lack of fetal tissues
2. Hydrophic villi
3. Diffuse trophoblastiv
hyperplasia
4. Marked atypia of
trophioblast at the
implantation site
Partial HM
Gross:
• Smaller volume of
hydrophic villi and the
possible presence of
fetus and fetal tissues
Histopath:
1. Presence of fetal
embryonic tissues
2. Less diffuse, focal
hydrophic swelling of
villi
3. Focal trophoblastic
hyperplasia
4. Less pronounced
trophoblastic atypic at

Uy| Urbiztondo
Page 2 of 7
 LECTURE 19: Gestational Trophoblastic Disease
Dr. Alvarina | April 29, 2021
DIAGNOSIS
1. Ultrasound (US)
• standard imaging modality for the diagnosis of a
mole
• CHMs are easier to diagnose by US than PHM
• CHM appearance on US: an echogenic endometrial
mass accompanying an enlarged uterus, the so-
called “snowstorm appearance” or “honeycomb
uterus” or cystic spaces inside the uterus.
• Features suggestive of CHM on US:
o absence of fetal or embryonic tissue
o absence of amniotic fluid
o enlarged placenta with multiple cysts
o ovarian theca lutein cysts.
• Features suggestive of PHM on US:
o presence of fetal or embryonic tissue
o presence of amniotic fluid
o abnormal placenta with multiple cysts or
increased echogenicity of chorionic villi
o increased transverse diameter of
gestational sac
o absence of theca lutein cysts
2. Human Chorionic Gonadotropin (hCG)
₪ Hormone produced by the placenta after
implantation
• Outside of pregnancy, an elevated β-hCG level
signifies the following:
(1) GTN
(2) nongestational tumors secreting hCG
(3) false positives
(4) menopause (secondary to LH elevation and cross
reactivity of assays)
• unexpected elevation of β-hCG level during
pregnancy may suggest the diagnosis of CHM above
100,000 IU/L.
Uy| Urbiztondo
TREATMENT (see algorithm on last page)
₪ Termination of pregnancy
1. Suction Dilation and Curettage
• Preferred method of uterine evacuation of HM
under general anesthetic
o cervix is serially dilated
o a large suction curette is advanced just past
the endocervix into the endometrial canal
o After activating the suction device, a
solution of crystalloid and oxytocin (20 U/L)
is infused to increase uterine tone; this is
continued postoperatively to reduce
bleeding
o A gentle sharp curettage may be performed
to complete the procedure.
o Care must be taken during D&C to avoid
perforation of the enlarged soft uterus in
HM
2. Hysterectomy
• hysterectomy with preservation of the adnexa is a
treatment option
• For women older than 40 years with HM,
hysterectomy is reasonable as the risk of developing
GTN is 53% in women older than 40 and 60% in
women older than 50
• Following hysterectomy, the risk of postmolar GTN is
3% to 5%, emphasizing the need for continued β-
hCG monitoring
3. Prophylactic Chemotherapy
• Following surgical evacuation, post molar GTN,
usually in the form of a locally invasive mole, occurs
in 15% to 20% of CHM cases and only rarely
• If post-evacuation follow-up is anticipated to be
compromised, patients with high risk CHM may be
considered for treatment with prophylactic
chemotherapy
• METHOTREXATE- DOC administered IM or oral
• Actinomycin D, alternative in the presence of
hypersensitivity to methotrexate or liver toxicity.
₪ Criteria for Prophylactic Chemotherapy:
a. Advanced maternal age ≥35 years
b. Gravidity of ≥4
c. Uterine size larger than gestation by ≥6 weeks
d. Serum β-hCG titer ≥100,000 mIU/ml
e. Theca lutein cyst(s) ≥6cm
Page 3 of 7
 LECTURE 19: Gestational Trophoblastic Disease
Dr. Alvarina | April 29, 2021
f. Presence of any medical complication
associated with increased trophoblastic
proliferation: preeclampsia, thyrotoxicosis,
pulmonary insufficiency and disseminated
intravascular coagulopathy
g. Repeat molar pregnancy
h. Poor patient compliance to follow up
Surveillance Following Hydatidiform Mole Evacuation
Following evacuation of a HM, surveillance with serial β-
hCG serum measurements are required to ensure a timely
diagnosis of postmolar malignant GTN
1. Within 48 hours of evacuation, a baseline β-hCG
level should be obtained and repeated weekly until
the level returns to normal (<5 mIU/mL).
2. Most cases of postmolar GTN will occur within 6
months of evacuation, so monthly β-hCG monitoring
is recommended following normalization for an
additional 6 to 12 months.
3. During this period of surveillance, use of reliable
contraception is strongly recommended to ensure
that a rise in β-hCG level represents postmolar GTN
and not a new pregnancy.
₪ Repeat 1 week after evacuation, then every 2 weeks
until normal for 3 consecutive determination, monthly
for 6 months and every 2 months for the next 6 months.
Phantom β-Human Chorionic Gonadotropin
• Persistent low levels of β-hCG must be evaluated to
rule out false-positive assay results or phantom Hcg
• a rare finding that is secondary to heterophilic
antibodies or proteolytic enzymes that mimic hCG.
Quiescent Gestational Trophoblastic Disease
• Following a hydatidiform mole, choriocarcinoma, or
spontaneous abortion, the persistence of low levels
(range, 1 to 212 IU/L) of β-hCG for 3 months or
longer with no obvious increase or decrease in the β-
hCG level trend along with the absence of clinical or
radiologic evidence of GTN
• This process is more common following a CHM but
may occur after PHM, invasive mole, or
choriocarcinoma and has been identified in patients
treated with single-agent or multiagent
chemotherapy.
Uy| Urbiztondo
GESTATIONAL TROPHOBLASTIC NEOPLASIA
» Is a complication, Malignant version of Gestational
Trophoblastic Disease. Occurs with patients diagnosed with
previous molar pregnancies
Characteristics
Histopathology and Cytogenic Features:
• Invasive moles are Hydatidiform Moles characterized by:
o Syncytiotrophoblast cytotrophoblast hyperplasia
with presence of villi - Most are diploid, EXCEPT for
anaplastic tumors
o Gestational choriocarcinoma – dominant histology in
metastatic Gestational Neoplasia - Appears as sheets of
cytotrophoblast and syncytiotrophoblast cells with NO
chorionic villi
- Cells invade adjacent tissues with a
propensity for vascular infiltration
- Cytogenetically anaplastic
o Primary gonadal (nongestational) choriocarcinoma –
can develop without pregnancy - Have similar histologic
appearance
- Significantly inferior outcomes than
Gestational choriocarcinoma
o Placental site Trophoblastic Tumor (PSTT) – rarest
form of Gestational Trophoblastic Neoplasm
- Comprised almost entirely of intermediate
trophoblasts
- Lacks syncytiotrophoblast and
cytotrophoblast.
- Infiltrative pattern with nests or sheets of
cells invading between myometrial cells and
fibers.
- Immunohistochemical staining is positive
50-100% for Human placental Lactogen/
Human chorionic somatomammotropin
CLINICAL FEATURES
• Symptoms associated with invasive mole include:
o Irregular vaginal bleeding
o Uterine subinvolution
o Theca lutein cysts
• Most are identified in patients undergoing surveillance
following evacuation of Hydatidiform moles on the basis of β-
hCG as outlined by FIGO
•surgical evacuation of Hydatidiform moles = exponential
decrease of β-hCG values
Page 4 of 7
 LECTURE 19: Gestational Trophoblastic Disease
Dr. Alvarina | April 29, 2021

• A WHO score of 6 or lower = lower risk.

• A score of 7 or greater is considered high risk.
Generally, stage relates to risk scoring
• Stage I = low risk
• Stage IV = high risk
Prognostic factors:
• Age
• Antecedent pregnancy
• Interval months from index pregnancy
» Biochemical Diagnosis is the basis for GTN • Pretreatment serum β-hCG levels
• Largest tumor in cm
• Site of metastases
CLASSIFICATION AND STAGING • Number of metastases
• Previous failed chemotherapy

DIAGNOSIS

• Complete physical examination accompanied by

qualitative β-hCG, CBC and renal, liver and thyroid
function testing
• Ultrasound – rule out concurrent intrauterine
pregnancy and better visualization than CT scan
• Doppler Ultrasound – show hypervascularization and
areas of necrosis
- Chest Xray to tule out lung metastases
- CT of thorax may demonstrate small
volume metastases
• MRI – for CNS, vaginal or parametrial lesions
Locally invasive Gestational Trophoblastic Neoplasia
• Patients Negative for chest Xray and CT scan and are
• Myometrial invasion may involve local capillaries and veins
asymptomatic = further investigation is not required
• Persistent vaginal bleeding – most commonly reported
• High-risk sites of metastasis are rarely seen without
symptom
evidence of pulmonary metastases
• Uterine perforation with intraperitoneal hemorrhage
• Infection secondary to tumor necrosis – most tumors will
regress spontaneously
TREATMENT
Malignant Gestational Trophoblastic Neoplasia
Low Risk Gestational Trophoblastic Neoplasia
• Most results from choriocarcinoma
• Management is based on clinical presentation than
Placental site Trophoblastic Tumor – associated with
histologic diagnosis except for Placental site
metastases at the time of initial diagnosis in 10% of cases.
Trophoblastic Tumor (PSTT)
• Metastases result from hematogenous dissemination to
• 8-day Methotrexate alternating with folinic acid rescue
almost any possible site
– most common first line agent regiment for low risk
• Tend to be hemorrhagic and Necrotic
» Methotrexate or EMA-CO - most significant
• Local metastases include:
therapeutic agent
o Vagina
• Distant metastases include:
o Lung – usually first organ involved
o Brain – most common
o Liver
o GI tract
o Kidney
• Symptoms of GTN includes:
o Hemoptysis
o Headache
• Biopsy is contraindicated because of potential risk of High Risk Gestational Trophoblastic Neoplasia
uncontrollable hemorrhage since lesions are highly • uncommon in the developed world
vascularized

Uy| Urbiztondo
Page 5 of 7
 LECTURE 19: Gestational Trophoblastic Disease
Dr. Alvarina | April 29, 2021

• Multiagent combination chemotherapy reflects the

increased risk of treatment failure with single agents
Invasive Mole • Most common trophoblastic
neoplasm arising from partial
or complete mole
Choriocarcinoma • Most common type to follow a
term pregnancy or a
miscarriage
• Metastases often develops early
are generally blood borne
ETT (Epithelioid • Rare tumor develops from
Trophoblastic chorionic type intermediate
Tumor) trophoblast
• Primary treatment is
hysterectomy because this
tumor is relatively resistant to
chemotherapy
PSTT (Placental • Uncommon tumor arises from
Site implantation site intermediate
HIGH RISK SITES OF METASTASES
Trophoblastic trophoblast
Tumor) • Associated serum B-hCG levels
Central Nervous System Metastases – poor prognosis
that may be only modestly
- Whole-brain radiotherapy to achieve hemostasis and
elevated
tumor shrinkage in conjunction with chemotherapy
• Hysterectomy is preferred
- Chemotherapy – preferred option
because they are usually
resistant to chemotherapy
Pulmonary Metastases – Respiratory failure is a concern in
patients with:
QUESTION:
o Chest pain
The patient was diagnosed with a previous partial mole and
o Cyanosis
during B-HCG monitoring after 2 months the B-HCG is still
o Anemia
elevated, then you did a transvaginal ultrasound then you
o More than 50% lung field opacification
saw a endometrial mass with 50% involvement of the
- Operative treatment is recommended for recurrent drug
myometrium
resistant cases in patients with: o adequate performance
status to tolerate surgery
Answer: The Diagnosis is GTN Stage 2
o no evidence of active tumor elsewhere
Explanation: Stage 2 because it is confined to the pelvic
o pulmonary metastases limited to one lung
organs

Liver Metastases – increased risk of hemorrhage with

chemotherapy initiation
- other treatment modalities include: o radiation therapy
o embolization
END OF TRANSCRIPTION
o surgical resection
REFERENCES
Vaginal Metastases – high risk for hemorrhage ● Comprehensive Gynecology 7th edition
- embolization or surgery to control acute bleeding ● Dr. Alvarina’s ppt
● CPG for Dx and Mgt of GTD

Uy| Urbiztondo
Page 6 of 7
 LECTURE 19: Gestational Trophoblastic Disease
Dr. Alvarina | April 29, 2021

Uy| Urbiztondo
Page 7 of 7