PATHOLOGIC OBSTETRICS

Topic: Gestational Trophoblastic Disease

Lecturer: Dr. Reaport (JCR)

DEFINITION Lecture Discussion: Complete Mole

Gestational Trophoblastic Disease (GTD) (Figure A) - A haploid sperm will fertilize an empty egg. The haploid sperm
 A group of tumors typified by abnormal trophoblast proliferation (23,X) will duplicate on its own to produce 46,XX  now a diploid karyotype.
Trophoblast So purely, the chromosome that you will develop here from the fertilized
 Produces the peptide hormone human chorionic gonadotropin (hCG) product will be of paternal in origin  hence we call this type of fertilization,
“androgenesis.”
 Measurement of hCG in serum is essential for GTD diagnosis,
management, and surveillance Sometimes you could have a product of 46,XY. It is being developed from
your dispermic fertilization wherein 2 haploid sperm both coming from the
Hydatidiform Mole father will be combining itself to form 46,XY because the Y chromosome only
 Characterized by the presence of villi excessively edematous immature be coming from your male factor
placentas
Note that the ovum is empty  so the mother has no contribution on its
 3 Types: development
1) Benign complete hydatidiform mole
2) Partial hydatidiform mole  Partial moles usually have a triploid karyotype- 69,XXX, 69,XXY-or
3) Malignant invasive mole much less commonly, 69,XYY.
Nonmolar Trophoblastic Malignant Neoplasms  Each composed of 2 paternal haploid sets of chromosomes contributed
 Lack villi by dispermy and 1 maternal haploid set
 Include choriocarcinoma, placental site trophoblastic tumor, and  Less frequently, haploid egg may be fertilized by an unreduced diploid
epithelioid trophoblastic tumor 46,XY sperm
 Triploid zygotes result in some embryonic development, but ultimately
Gestational Trophoblastic Neoplasia
is a lethal fetal condition
 Malignant forms of gestational trophoblastic disease
 Fetuses that reach advanced ages have severe growth restriction,
 Include invasive mole, choriocarcinoma, placental site trophoblastic
multiple congenital anomalies, or both.
tumor, and epithelioid trophoblastic tumor.
 Also known as malignant gestational trophoblastic disease and
persistent gestational trophoblastic disease
 Early-stage GTN is cured with single-agent chemotherapy and later
stage with combination chemotherapy

HYDATIDIFORM MOLE
 Classic histological findings of molar pregnancy include trophoblast
proliferation and villi with stromal edema
 Complete mole has abnormal chorionic villi that grossly appear as a
mass of clear vesicles
 Partial molar pregnancy has focal and less advanced hydatidiform
changes and contains some fetal tissue
Epidemiology and Risk Factors:
 Increased prevalence in Asians, Hispanics, and American Indians
 Strongest risk factors are age and a prior hydatidiform mole:
o With prior complete mole  risk of another mole is 0.9%
o With a previous partial mole  rate is 0.3%
o After 2 prior complete moles  risk of 3rd mole is 20%
 Women at both extremes of reproductive age are most vulnerable
(adolescents & 36-40 yo: twofold risk) , (>40 yo: tenfold risk)
Lecture Discussion: Partial Mole
Compared to the complete mole where the ovum has no contribution, here
the mother’s ovum is active (has a maternal contribution). So 2 sets of
haploid sperm fertilizes the ovum  produce 3 sets of chromosomes (2 sets
from father, 1 set from mother)  a triploid karyotype. The zygote that you
will produce from this fertilization will usually present as misabortion later
on as pregnancy advances because it will contain a lot of congenital
anomalies, lethal fetal conditions and it could be very small (hence it will not
reach term pregnancy)
Features of Partial and Complete Hydatidiform Moles

Pathogenesis:
 Molar pregnancies typically arise from chromosomally abnormal
fertilizations
 Complete moles: have a diploid chromosome (46,XX) and result from
androgenesis
 Chromosomes of the ovum are either absent or inactivated
 Ovum is fertilized by a haploid sperm  duplicates its own
chromosomes after meiosis
 Chromosomal pattern may be 46,XY or 46,XX due to fertilization by two
sperm (dispermic fertilization or Dispermy)  less common

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 PATHOLOGIC OBSTETRICS
Topic: Gestational Trophoblastic Disease
Lecturer: Dr. Reaport (JCR)
Lecture Discussion: Differentiating Partial and Complete Mole
Risk for Malignancy/Neoplasia  higher in complete mole (15-20%)
Serum hCG levels  higher in complete mole (>100,000 mIU/mL)
 It can stimulate your ovary to produce multiple theca-lutein cysts
 Can also produce symptoms like nausea, vomiting and some
electrolyte imbalances  medical complications much more
common here
Large for dates uterus  in complete mole
 This means that when you compute for the AOG, the discrepancy is
very significant. For example, supposedly the AOG is 4 months only
(so that is half way the umbilicus and the symphysis pubis) but when
you get the fundic height, it is almost 5 or 6 months size uterus 
there is a discrepancy of about 2-3 weeks or more
Presence of fetal elements  seen in partial mole
 You don’t see any fetal elements in your complete mole, that’s why
diagnosing complete by UTZ is very easy. When you reach the age
of pregnancy wherein your embryo should be visible, yet you do not
see one  you’ll highly consider complete mole
In both partial and complete mole, histologically, it will show villous edema,
trophoblastic proliferation, and trophoblastic atypia BUT it is more diffuse
and marked in complete mole
Special staining (p57KIP2) is seen in partial mole
 It is always negative in complete mole because p57KIP2 is maternally
expressed. Remember that in the pathogenesis of complete mole,
the haploid sperm fertilizes an empty ovum (no maternal
chromosomes)
Twin Pregnancy
 Rarely, one chromosomally normal fetus is paired with a complete
diploid molar pregnancy
 Must be distinguished from a single partial molar pregnancy with its
associated abnormal fetus
 Amniocentesis and fetal karyotyping aid confirmation
 Survival of the normal fetus varies and depends on associated
comorbidity from the molar component
 Preeclampsia or haemorrhage are most worrisome which frequently
necessitate preterm delivery
The more advance the pregnancy, the more likely that the complete
mole will have a tendency to bleed  we watch out for this
 Risk for developing subsequent GTN (20% risk), for those who continue
their pregnancy
 Post-delivery surveillance is conducted as for any molar pregnancy
Lecture Discussion: Twin Pregnancy
Sometimes your molar could be presenting with a normal pregnancy in the
form of twin pregnancy  so 1 complete molar and 1 normal pregnancy. You
really need to differentiate that you are dealing with a twin pregnancy (1 is
normal, other is complete molar) because management differs if it is found
that the other one is a partial molar pregnancy (meaning the other one was
not a normal pregnancy)
 Twin pregnancy (with normal pregnancy)  monitor the living fetus
until it reaches the age of viability
 You can differentiate it via karyotyping and amniocentesis
Clinical Findings
 Typically, 1 to 2 months of amenorrhea precede the diagnosis.
 Symptoms tend to be more pronounced with complete compared with
partial moles as gestation advances
 Untreated molar pregnancies will almost always cause uterine bleeding
(spotting to profuse hemorrhage)
 Moderate iron-deficiency anemia develops in more advanced moles
with considerable concealed uterine hemorrhage
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 Nausea and vomiting may be significant
 Uterine growth that is more rapid than expected, and is comparatively
softer. Fetal heart motion is absent with complete moles
 Ovaries can be fuller and cystic from multiple theca-lutein cysts
(common with complete mole) and likely result from ovarian
overstimulation by excessive hCG levels
o Expectant management is preferred because they regress
following pregnancy evacuation
o Larger cyst may undergo torsion, infarction, and hemorrhage,
but oophorectomy is not performed unless extensive
infarction persists after untwisting
 Serum free thyroxine (fT4) levels elevated and thyroid-stimulating
hormone (TSH) levels decreased due to thyrotropin-like effects of hCG,
but clinically apparent thyrotoxicosis is unusual
 Severe preeclampsia and eclampsia are relatively common with
advanced molar pregnancies, but seldom seen today because of early
diagnosis and evacuation
 In continuing twin gestations, severe preeclampsia frequently
mandates preterm delivery
Diagnosis
Serum β-hCG
 Values in the millions are not unusual with more advanced moles, and
can lead to erroneous false-negative urine pregnancy test results
 "Hook effect," excessive β-hCG hormone levels oversaturate the
assay's targeting antibody and create a falsely low reading
This happens when a patient uses a normal pregnancy test kit 
registers the pregnancy as negative but when they undergo serum
β-hCG quantification, you would see that the values are already in
hundred thousand or millions. This is a possibility due to
oversaturation of the receptor of the test kit
 β-hCG levels may also be significantly elevated, but more commonly
concentrations fall into ranges expected for gestational age with a
partial mole.
Sonography
 Mainstay of trophoblastic disease diagnosis, not all cases are confirmed
initially
 Complete mole: echogenic uterine mass with numerous anechoic cystic
spaces but without a fetus or amnionic sac  "snowstorm"
 Partial mole: has features that include a thickened, multicystic placenta
along with a fetus or at least fetal tissue; in early pregnancy, these
sonographic characteristics are seen in fewer than half of hydatidiform
moles
 Sensitivity 44% & Specificity 74%
 Most common mimics: incomplete or missed abortion, confused for a
multifetal pregnancy or a uterine leiomyoma with cystic degeneration
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 PATHOLOGIC OBSTETRICS
Topic: Gestational Trophoblastic Disease
Lecturer: Dr. Reaport (JCR)
Pathology
 Classic molar changes may not be apparent because villi may not be
enlarged and molar stroma may not yet be edematous and avascular In
pregnancies before 10 weeks
 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. Strongly expressed in normal placentas, in
spontaneous pregnancy losses with hydropic degeneration, and in
partial hydatidiform moles
 Complete moles contain only paternal genes. p57KIP2 protein is absent
and tissues do not pick up stain.
 Molecular genotyping determines the parental source of alleles. It can
distinguish among a diploid diandric genome (complete mole), 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 like preeclampsia, hyperthyroidism, anemia, electrolyte
depletions from hyperemesis, and metastatic disease
 Most recommend chest radiography
 CT and MRI are not routinely done unless a chest radiograph shows lung
lesions or unless other extrauterine disease is suspected
Some Considerations for Management of Hydatidiform Mole
Lecture Discussion: Some Considerations for Management of H. mole
Preoperative:
 You could have bleeding problems so you request for baseline CBC
levels. If initially the patient is presenting with anemia, make sure that
you transfuse your patient before doing a surgical procedure
 We also get the baseline serum β-hCG, electrolytes and thyroid
function
 Check the kidney function (creatinine) and liver function (hepatic
aminotransferase)  because in some cases wherein we need to give
prophylactic chemotherapy, the drug is metabolized to those 2 organs
(make sure that it is functioning well before giving it)
 Chest radiography is mandatory
 Hydroscopic dilators  the cervix need to be soft enough to
accommodate the 14 mm cannula (because if it is not soft enough 
laceration = bleeding)
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Intraoperative:
 2 large-bore IV catheters are needed before doing the procedure
(1 for blood transfusion, 1 for medications)
 Anesthesia is also given (can be either regional or general
anesthesia)
 Use also uterotonics to allow the uterus to contract (most
commonly used is oxytocin)  if oxytocin is not effective, use
methylergonovine, carboprost, or misoprostol
Contracted uterus = lesser bleeding
 Sonography machine  used while performing suction with
dilatation & curettage
Suction is needed, not just only D&C, because we want the
trophoblastic product to be evacuated immediately (to prevent
more bleeding which is why we want to perform the procedure
faster)
Postevacuation:
 Anti-D immune globulin  given if Rh D-negative
Done to prevent the desensitization of the mother to the next
succeeding pregnancy since molar pregnancy is still a pregnancy
(considered an abortion)
 Submit specimen for pathologic examination  to confirm
diagnosis
 Initiate contraception  later on you will be monitoring the serum
β-hCG levels serially UNTIL it goes back to normal (6 months)
So within 6 months the patient should not get pregnant which is
why contraception is needed. We do not want her to get
pregnant because β-hCG will increase and monitoring of it will
be confounded
Molar Pregnancy Termination
 Molar evacuation by suction curettage is usually the preferred
treatment regardless of uterine size
 Preoperative cervical dilatation with an osmotic dilator is
recommended if the cervix is minimally dilated.
 Intraoperative bleeding can be greater with molar pregnancy
 With large moles, adequate anesthesia, sufficient intravenous access,
and blood-banking support is imperative
 Use of larger suction curette and oxytocin is infused to limit bleeding
 Intraoperative sonography is often recommended to help ensure
complete uterine cavity emptying
 A thorough but gentle curettage with a sharp largeloop
 Sims curette is performed when myometrium has contracted
Lecture Discussion: Suction Curettage
Suction curettage will be inserted into the uterus
getting all the trophoblasts that it can suck in. After
doing this, the uterus is now partially evacuated. You
now start with uterotonics (Oxytocin)  once it is
contracted do now dilatation & curettage in order to
remove the remaining trophoblasts at the corneal
area of uterus. After which, specimen is submitted
for pathologic examination. Large-bore IV catheters
are required for blood transfusion and medication
 Pelvic arterial embolization or hysterectomy may be necessary in rare
cases
 With large moles, the amount of tissue may be sufficient to produce
clinically apparent respiratory insufficiency, pulmonary edema, or even
embolism
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 PATHOLOGIC OBSTETRICS
Topic: Gestational Trophoblastic Disease
Lecturer: Dr. Reaport (JCR)
Molar Pregnancy Termination continued…..
 Anti-D immunoglobulin is given to Rh D-negative women because fetal
tissues with a partial mole may include red cells with D-antigen
following curettage
 Long-term prognosis for women with a hydatidiform mole is not
improved with prophylactic chemotherapy. Chemotherapy toxicity
(including death) may be significant, hence is not recommended
routinely
 Hysterectomy with ovarian preservation may be preferable for women
with complete moles who have finished childbearing.
o Women 40-49 yo have 30-50% risk of subsequently GTN
 Theca-lutein cysts do not require removal, and they spontaneously
regress following molar termination
 Labor induction or hysterotomy will likely increase blood loss and
theoretically may increase the incidence of persistent trophoblastic
disease (ACOG, 2016)
Post-evacuation Surveillance
 Monitoring is by serial measurement of serum β-hCG to detect
persistent or renewed trophoblastic proliferation
 Initial β-hCG level is obtained within 48 hours after evacuation
 β-hCG quantification done thereafter every 1 to 2 weeks until levels
progressively decline to become undetectable
o Normal: <5 mIU/mL
 Median time for such resolution is:
o 7 weeks for partial moles
o 9 weeks for complete moles
So we expect that in 2 months’ time, the serum β-hCG
should be normal
 Once β-hCG is undetectable, this is confirmed with monthly
determinations for another 6 months
 A reliable contraception is imperative to avoid confusion caused by
rising β-hCG levels from a new pregnancy
Reliable contraception means use of medications. Other means like
withdrawal or use of calendar and the likes are not really reliable
 Most recommend:
o Combination hormonal contraception
o Injectable depot medroxyprogesterone acetate
o 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.
 Increasing or persistently plateaued levels mandate evaluation for
trophoblastic neoplasia
 Factors predispose a patient to trophoblastic neoplasia following molar
evacuation:
o Complete moles  15-20% incidence of malignant sequelae
(partial moles 1-5%)
o Older maternal age
o β-hCG levels > 100,000 mIU/mL
o Uterine size large for gestational age
o Theca-lutein cysts >6 cm
o Slow decline in β-hCG levels
So these are the patients we consider as high risk for developing
neoplasia. They are the ones whom we can give
chemoprophylaxis. We use methotrexate (vs. Actinomycin)
because it is less toxic
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GESTATIONAL TROPHOBLASTIC NEOPLASIA (GTN)
 Why do we monitor the serum β-hCG? Because if it is not ↓ to normal
or it is ↑ despite monitoring, we already consider the patient as having
GTN
 Includes invasive mole, choriocarcinoma, placental site trophoblastic
tumor, and epithelioid trophoblastic tumor
 Almost always develop with or after some form of recognized
pregnancy
 Half (50%) follow hydatidiform mole, a fourth (25%) follow miscarriage
or tubal pregnancy, and another fourth (25%) develop after a preterm
or term pregnancy
 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
Criteria for Diagnosis of Gestational Trophoblastic Neoplasia
1. Plateau of serum β-hCG (±10%) for 4 measurements during a period of
3 weeks or longer – days 1, 7, 14, 21
2. Rise of serum β-hCG level >10% during 3 weekly consecutive
measurements or longer, during a period of 2 weeks or more – days 1,
7, 14
3. Serum β-hCG level remains detectable for 6 months or more
4. Histological criteria for choriocarcinoma
Clinical Findings
 Characterized clinically by their aggressive invasion into the
myometrium and propensity to metastasize.
 Most common finding is irregular bleeding associated with uterine
subinvolution. Bleeding may be continuous or intermittent, with
sudden and sometimes massive hemorrhage.
 Myometrial perforation from trophoblastic growth may cause
intraperitoneal hemorrhage.
 Lower genital tract metastases are evident in some, whereas in others
only distant metastases are found with no trace of uterine tumor.
Diagnosis, Staging, Prognostic Scoring
 Unusually persistent bleeding after 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 (bluish vascular masses). Biopsy is not required and
may cause significant bleeding.
 Baseline serum β-hCG level and hemogram, search for local disease and
metastases includes tests of:
o Liver and renal function
o TVS
o Chest CT scan or radiograph
o Brain and abdominopelvic CT scan or MRI.
o Less commonly, PET scan and CSF β-hCG level determination
are used to identify metastases
 GTN is staged clinically using the system of the FIGO 2009:
o Low risk: scores of 0 to 6
o High risk: >7
 PATHOLOGIC OBSTETRICS
Topic: Gestational Trophoblastic Disease
Lecturer: Dr. Reaport (JCR)
Lecture Discussion: FIGO Staging and Diagnostic Scoring System for GTN
A patient scoring >7 and is Stage IV  consider giving multiple drug therapy
If patient scoring <7 and Early stage  single drug therapy
Example, patient with serum β-hCG of >100,000 = score of 4
metastasis in the lungs and liver = score of 4
8  high risk
Histologic Classification
A. Invasive Mole
 Most common trophoblastic neoplasms that follow hydatidiform
moles, and almost all invasive moles arise from partial or complete
moles.
 Previously known as chorioadenoma destruens, characterized by
extensive tissue invasion by trophoblast and whole villi and there is
penetration deep into the myometrium, sometimes with involvement
of the peritoneum, adjacent parametrium, or vaginal vault.
 Locally aggressive, but are less prone to metastasize
B. Gestational Choriocarcinoma
 Most common type of trophoblastic neoplasm to follow a term
pregnancy or a miscarriage, and only a third of cases follow a molar
gestation
 Composed of cells reminiscent of early cytotrophoblast and
syncytiotrophoblast, and contains no villi
 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 often develop early and are generally blood-borne. Most
common sites: lungs and vagina, but tumor may travel to the vulva,
kidneys, liver, brain, ovaries, and bowel.
 Commonly accompanied by ovarian theca-lutein cysts
C. Placental Site Trophoblastic Tumor
 Rare tumor arises from intermediate trophoblasts at the placental site.
 Associated with serum β-hCG levels that may be only modestly
elevated. They produce variant forms of hCG, and identification of a
high proportion of free β-hCG is considered diagnostic.
 Treatment by hysterectomy is preferred because these locally invasive
tumors are usually resistant to chemotherapy. For higher-risk stage I
and for later stages, adjuvant multidrug chemotherapy is also given.
But if you are dealing with a patient that is very young (1st pregnancy
is PSTT)  of course you try 1st chemotherapeutic drugs because
they will still desire to get pregnant later on. So although
hysterectomy is the preferred treatment for PSTT, our treatment
still depends of the future fertility plan of the patient
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D. Epithelioid Trophoblastic Tumor
 Rare tumor develops from chorionic-type intermediate trophoblast
 Uterus is the main site of involvement, and bleeding and low hCG levels
are typical findings
 Primary treatment is hysterectomy because they are relatively resistant
to chemotherapy.
 Metastatic disease is common, and combination chemotherapy is
employed
Treatment
 Best managed by oncologists
 Prognosis is excellent with rare exceptions
 Chemotherapy alone is usually the primary treatment.
 Some also consider a second uterine evacuation to be an adjuvant
therapeutic option in some GTN cases to avoid or minimize
chemotherapy.
o Suction curettage may infrequently be needed to resolve
bleeding or remove a substantial amount of retained molar
tissue.
 Hysterectomy may be primary or adjuvant treatment
This may be offered if the patient is already old and she does not
want to get pregnant anymore  helps lessen the dose of
chemotherapy given
 Single-agent chemotherapy protocols are usually sufficient for
nonmetastatic or low-risk metastatic neoplasia. Methotrexate is less
toxic than actinomycin D.
 Combination chemotherapy is given for high-risk disease, reported
cure rates approx. 90%
o EMA-CO: which includes Etoposide, Methotrexate,
Actinomycin D, Cyclophosphamide & Oncovin (vincristine)
 Frequent causes of death include hemorrhage from metastatic sites,
respiratory failure, sepsis, and multiorgan failure due to widespread
chemoresistant disease
 Once serum β-hCG levels are undetectable, serosurveillance is
continued for 1 year.
o Effective contraception is crucial to avoid any teratogenic
effects of chemotherapy to the fetus and to mitigate confusion
from rising β-hCG levels caused by superimposed pregnancy.
 Quiescent hCG is a phenomenon where there is very low β-hCG levels
that plateau and presumably is caused by dormant trophoblast.
o Close observation without therapy is recommended, but 20%
will eventually have recurrent active and progressive
trophoblastic neoplasia
Subsequent Pregnancy
 Women with prior hydatidiform mole generally do not have impaired
fertility, and their pregnancy outcomes are usually normal
 2% risk for developing trophoblastic disease in a subsequent pregnancy
 Sonographic evaluation is recommended in early pregnancy
 Women who have successfully completed GTN chemotherapy are
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% compared with a background rate of 0.8%
 After hydatidiform mole or GTN treatment, in subsequent pregnancy:
o The placenta or products of conception are sent for
pathological evaluation at delivery
o A serum β-hCG level is measured 6 weeks postpartum
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