HYDATIDIFORM MOLE—MOLAR PREGNANCY

Molar pregnancy is characterized histologically by abnormalities of the chorionic villi that consist of trophoblastic
proliferation and edema of villous stroma. USUALLY UTERINE AND RARELY ECTOPIC. The degree of tissue
changes and absence or presence of a fetus or embryonic elements is used to describe them as complete or partial.

Complete Hydatidiform Mole: Grossly, the chorionic villi appear as a mass of clear vesicles. These vary in size
from barely visible to a few centimeters and often hang in clusters from thin pedicles. Histologically, they typically
show hydropic degeneration and villous edema; absence of villous blood vessels; varying degrees of proliferation of
the trophoblastic epithelium; and absence of embryonic elements such as a fetus and amnion.

The chromosomal composition of complete moles is usually diploid and of paternal origin. About 85 percent are
46,XX with both sets of chromosomes paternal in origin.

Androgenesis, the ovum is fertilized by a haploid sperm, which duplicates its own chromosomes after meiosis. The
chromosomes of the ovum are either absent or inactivated.

Malignant Potential: Complete molar pregnancy has a higher incidence of malignant sequela compared with partial
moles. In most studies, 15 to 20 percent of complete moles had evidence of persistent trophoblastic disease.

Partial Hydatidiform Mole: Features of a partial or incomplete molar pregnancy include some element of fetal tissue
and hydatidiform changes that are focal and less advanced. There is slowly progressive swelling within the stroma of
characteristically avascular chorionic villi, whereas vascular villi that have a functioning fetal-placental circulation are
spared. The karyotype typically is triploid—69,XXX, 69,XXY, or much less commonly, 69,XYY. These are each
composed of one maternal and two paternal haploid sets of chromosomes. The risk of persistent trophoblastic
disease after a partial mole is substantially lower than that following a complete molar pregnancy. Moreover,
persistent disease seldom is choriocarcinoma. B-hCG levels correlated with increased risk for persistent disease.
Specifically, levels _ 200 mIU/mL in the Third through eighth week postevacuation were associated with at
least a 35-percent risk of persistent disease.

Twin Molar Pregnancy: A twin gestation composed of a complete diploid molar pregnancy and a normal pregnancy is
not rare. 5 percent of diploid moles were part of a twin pregnancy with a fetus. Survival of the normal coexisting fetus
is variable and depends on whether the diagnosis is made, and if so, whether problems from the molar component
such as preeclampsia or hemorrhage develop. Compared with a partial mole, women with these types of twin
Pregnancies have a substantive risk of developing subsequent gestational trophoblastic neoplasia. But this risk
does not appear greater than following a singleton complete mole

Histological Diagnosis of Hydatidiform Moles: Histological changes of complete and partial moles are
listed in Table 11-2. Attempts to relate the histological structure of individual complete moles to their
subsequent malignant potential have generally been disappointing

Cytometry: Moles evacuated early may have not yet developed the histological findings characteristic of
their type. Thus, either flow cytometry or automated image cytometry can be used to determine cellular
ploidy . Immunostaining techniques are also useful to highlight cells that are of pure paternal
derivation from those of both maternal and paternal derivation.

Theca-Lutein Cysts: In 25 to 60 percent of women with a complete mole, the ovaries contain multiple
theca-lutein cysts. These may vary from microscopic to 10 cm or more in diameter. Their surfaces are
smooth, often yellowish, and lined with lutein cells. They are thought to result from overstimulation of
lutein elements by large amounts of hCG secreted by proliferating trophoblastic cells. Persistent
gestational trophoblastic disease was more likely in women with theca-lutein cysts, especially if
bilateral. This is logical because cysts are more likely with higher serum hCG levels, which may portend
a worse prognosis. Such cysts are also seen with fetal hydrops, placental hypertrophy, and multifetal
pregnancy. Larger cysts may undergo torsion, infarction, and hemorrhage. Because they regress,
oophorectomy is not performed unless the ovary is extensively infarcted.

Epidemiology and Risk Factors

The incidence of hydatidiform mole has been relatively constant in the United States and

Europe at 1 to 2 per 1000 pregnancies. It is more prevalent in Hispanics and American Indians. Until
recently, it was held to be much more frequent in some Asian countries however, these data were from
hospital studies and thus misleading.

Age: Maternal age at either extreme of the reproductive spectrum is a risk factor for molar pregnancy.
Specifically, adolescents and women aged 36 to 40 years have a twofold risk and those over 40 years
have an almost tenfold risk

Prior Molar Pregnancy: There is a substantively increased risk for recurrent trophoblastic disease.
Frequency of recurrent moles was 1.3 percent. The risk is 1.5 percent for a complete mole and 2.7
percent for a partial mole. With two prior molar pregnancies, reported that 23 percent of women had a
third mole! Repetitive hydatidiform moles in women with different partners suggest that an oocyte defect
leads to molar development.

Other Risk Factors

Oral contraceptive use and its duration as well as previous miscarriage increase the chances for a molar
pregnancy as much as twofold. Smoking, various vitamin deficiencies, and increased paternal age.

Clinical Course

The “typical” clinical presentation of women with a molar pregnancy has changed considerably over the
past several decades because of earlier diagnosis. Most women present for pregnancy care early and
undergo sonography, thus molar pregnancies are detected before they grow to larger sizes with more
complications. In many ways, this changing presentation picture is analogous to that of ectopic
pregnancy. In general, symptoms tend to be more pronounced with complete moles compared with partial
moles.

Clinical Presentation

There is usually 1 to 2 months of amenorrhea. There may be significant nausea and vomiting. Eventually,
uterine bleeding is almost universal and may vary from spotting to profuse hemorrhage. It may begin just
before spontaneous molar abortion or more often, follow an intermittent course for weeks to months. In
more advanced moles, there may be considerable concealed uterine haemorrhage with moderate iron-
deficiency anemia. In about half of cases, uterine growth is more rapid than expected. The uterus has a
soft consistency. Large theca-lutein cysts may be difficult to distinguish from the enlarged uterus on
bimanual examination. And although the uterus is enlarged, typically no fetal heart motion is detected.
As the consequence of the thyrotropin-like effect of hCG, plasma free thyroxine levels are often elevated
and TSH levels are decreased. Despite this, clinically apparent thyrotoxicosis is unusual, but thyroid
storm has been reported. In our experiences, the serum free-T4 levels rapidly normalize after uterine
evacuation. Occasionally, earlyonset preeclampsia develops with a large mole. Because gestational
hypertension is rarely seen before 24 weeks, preeclampsia that develops before this time should raise
concerns for molar pregnancy.

Trophoblastic Deportation or Embolization: Variable amounts of trophoblast escape into the pelvic venous
system at the time of molar evacuation. In some women, this tissue subsequently invades the pulmonary
parenchyma to cause persistent trophoblastic disease or overt metastases. Acutely, the volume of tissue
may be sufficient to produce clinically apparent acute pulmonary embolism or edema. Although
deportation of massive amounts of trophoblastic tissue is probably uncommon, fatalities have been
described

Diagnosis: Some women will present early with spontaneous passage of molar tissue. In most cases,
however, there are varying durations of amenorrhea, usually followed by irregular bleeding. These
almost always prompt pregnancy testing and sonography. If left untreated, spontaneous expulsion usually
occurs around 16 weeks. The characteristic sonographic appearance of a complete mole includes a
complex, echogenic uterine mass with numerous cystic spaces and no fetus or amnionic sac.
Sonographic features of a partial mole include a thickened, hydropic placenta with fetal tissue.
Importantly, in early pregnancy, sonography will demonstrate the characteristic appearance in as few as a
third of women with a partial mole. Occasionally, molar pregnancy may be confused for a uterine
leiomyoma or multifetal pregnancy.

Management

Current mortality rates from molar pregnancies have been practically reduced to zero by prompt
diagnosis and appropriate therapy. There are two important basic tenets for management of all molar
pregnancies. The first is evacuation of the mole, and the second is regular follow-up to detect
persistent trophoblastic disease. Most clinicians obtain a preoperative chest radiograph, but unless
there is evidence of extrauterine disease, computed tomography (CT) or magnetic resonance (MR)
imaging to evaluate the liver or brain is not done routinely. Laboratory work includes a hemogram to
assess anemia, blood type and antibody screen, serum hepatic transaminase levels to assess liver
involvement, and a baseline serum -hCG levels. They concluded that hemogram and blood type with
antibody screen alone were appropriate for most patients without suspicious signs or symptoms. The
unusual circumstance of twinning with a complete mole plus a fetus and placenta is problematic,
especially if there are no apparent fetal anomalies found with sonography or karyotypic aberrations.
Neither maternal risks nor the likelihood of a healthy offspring have been precisely established if
pregnancy is continued.

Prophylactic Chemotherapy

The long-term prognosis for women with a hydatidiform mole is not improved with prophylactic
chemotherapy. Because toxicity—including death— may be significant, it is not recommended routinely.

Suction Curettage

Molar evacuation by suction curettage is usually the preferred treatment regardless of uterine size. For
large moles, adequate anesthesia and blood-banking support is imperative. With a closed cervix,
preoperative dilatation with an osmotic dilator may be helpful. The cervix is then further dilated to allow
insertion of a 10- to 12-mm suction curette. After most of the molar tissue has been removed,
oxytocin is given. After the myometrium has contracted, thorough but gentle curettage with a large
sharp curette usually is performed. We have found that intraoperative sonography helps to ensure that
the uterine cavity has been emptied.
Other Methods of Termination

In the United States, only rarely are labor induction or hysterotomy used for molar evacuation. Both will
likely increase blood loss and may increase the incidence of persistent trophoblastic disease.

Hysterectomy

If no further pregnancies are desired, hysterectomy may be preferred to suction curettage. It is a logical
procedure in women aged 40 and older, because at least a third of these women go on to develop
persistent gestational trophoblastic neoplasia. Although hysterectomy does not eliminate this possibility, it
markedly reduces its likelihood. Finally, hysterectomy is an important adjunct to treatment of
chemoresistant tumors

Postevacuation Surveillance: Consistent follow-up is imperative for women in whom a molar pregnancy
has been evacuated. The long-term goal is to ensure complete resolution of trophoblastic disease, with
chemotherapy if necessary. The following steps are recommended:

1. Prevent pregnancy for a minimum of 6 months using hormonal contraception.

2. After a baseline serum B-hCG level is obtained within 48 hours after evacuation, levels are
monitored every 1 to 2 weeks while still elevated. This is important to detect persistent trophoblastic
disease. Even small amounts of trophoblastic tissue can be detected by the assay. These levels should
progressively fall to an undetectable level.

3. Chemotherapy is not indicated as long as these serum levels continue to regress. A rise or persistent
plateau demands evaluation for persistent gestational trophoblastic disease and usually treatment. An
increase signifies trophoblastic proliferation that is most likely malignant unless the woman is again
pregnant.

4. Once the B-hCG level falls to a normal level, serum B-hCG levels are determined monthly for another 6
months. If undetectable, surveillance can then be discontinued and pregnancy allowed. Such intensive
monitoring has a high noncompliance rate. Fortunately, recent observations indicate that verifying
undetectable B-hCG levels for 6 months is likely unnecessary. A number of investigators have reported
that no woman with a partial or complete mole whose serum B-hCG levels became undetectable
subsequently developed persistent. Although not a routine part of surveillance, postevacuation
sonographic uterine examination may reveal myometrial nodules or hypervascularity, which may be
associated predictors of subsequent gestational trophoblastic neoplasia (GTN)

GESTATIONAL TROPHOBLASTIC NEOPLASIA

This group of placental tumors is characterized by their aggressive invasion into the myometrium and
propensity to metastasize. Collectively, they are also termed malignant gestational trophoblastic disease.
Histologically these tumors include invasive mole, choriocarcinoma, placental site trophoblastic tumor,
and epithelioid trophoblastic tumor. Because in most cases they are diagnosed by only persistently
elevated serum B-hCG levels, there is no tissue available for pathological study. Criteria for diagnosis of
postmolar gestational trophoblastic neoplasia:

Gestational trophoblastic neoplasia almost always develops with or follows some form of recognized
pregnancy. Most follow a hydatidiform mole, but neoplasia may follow an abortion, normal pregnancy, or
even an ectopic.

Histopathological Classification: diagnosis of neoplasia is usually made by persistently elevated serum

B-hCG levels without confirmation by pathological study. Importantly, management is not directed by
histological findings.

Invasive Mole This common manifestation of neoplasia is characterized by excessive trophoblastic

overgrowth with extensive tissue invasion by trophoblastic cells and whole villi. There is penetration deep
into the myometrium, sometimes with involvement of the peritoneum, adjacent parametrium, or vaginal
vault. Such tumors almost always arise from partial or complete moles. They are locally invasive, but
generally lack the pronounced tendency to widespread metastasis typical of choriocarcinoma.

Gestational Choriocarcinoma: This extremely malignant tumor may be considered a carcinoma of the
chorionic epithelium. It has an incidence of about 1 in 30,000 pregnancies—two thirds develop after a
normal delivery and a third follow molar gestations. It should be considered when persistent bleeding
follows any pregnancy event. The characteristic gross picture of these tumors is that of a rapidly growing
mass invading both myometrium and blood vessels, causing hemorrhage and necrosis. The tumor is dark
red or purple and ragged or friable. If it involves the endometrium, then bleeding, sloughing, and infection
of the surface usually occur early. Masses of tissue buried in the myometrium may extend outward,
appearing on the uterus as dark, irregular nodules that eventually penetrate the peritoneum. Although
cytotrophoblastic and syncytial elements are involved, one or the other may predominate. Microscopically,
columns and sheets of these trophoblastic cells penetrate the muscle and blood vessels. They sometimes
create a plexiform arrangement and at other times are completely disorganized, interspersed with clotted
blood. And, in contrast to hydatidiform or invasive mole, there is not a villous pattern. Factors involved in
malignant chorionic transformation are unknown, but its normal predisposition of invasive growth and
erosion of blood vessels is greatly augmented. Metastases often develop early and are generally blood-
borne because of the affinity of trophoblastic cells for blood vessels. The most common sites are the
lungs in more than 75 percent of cases, and the vagina in about 50 percent. The vulva, kidneys, liver,
ovaries, brain, and bowel also may contain metastases. Ovarian theca-lutein cysts are identified in
over a third of cases.

Placental Site Trophoblastic Tumor: The rare variant of trophoblastic neoplasia arises from the
placental implantation site following normal term pregnancy, spontaneous or induced abortion, or an
ectopic or molar pregnancy. Histologically, there are intermediate trophoblastic cells, many of which are
prolactin producing. For this reason, serum b-hCG levels are relatively low compared with tumor mass. A
high proportion of free B-hCG—over 30 percent—is accurate for diagnosis of this tumor . Bleeding is the
main presenting symptom. Locally invasive tumors are resistant to chemotherapy and hysterectomy is
the best treatment. Cases managed without hysterectomyhave been reported .

Epithelioid Trophoblastic Tumor: This rare trophoblastic tumor is distinct from gestational
choriocarcinoma and placental site trophoblastic tumor. The preceding pregnancy event may be remote
or, in some cases, cannot be confirmed. Epithelioid trophoblastic tumor develops from neoplastic
transformation of chorionic-type intermediate trophoblast. Microscopically, it resembles placental site
trophoblastic tumor, but the cells are smaller and display less nuclear pleomorphism. Grossly, the tumor
grows in a nodular fashion rather than the infiltrative pattern of placental site tumor. Hysterectomy is the
primary method of treatment, but approximately a fourth of these women present with metastatic disease.
There are too few reported cases to evaluate the efficacy of chemotherapy.

Clinical Course

The most common finding with gestational trophoblastic neoplasms 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
haemorrhage. Some women present with metastatic lesions to the vagina or vulva. In others, the uterine
tumor has disappeared, leaving only distant metastases. If untreated, choriocarcinoma is invariably fatal.

Diagnosis

Consideration for the possibility of gestational trophoblastic neoplasia is the most important factor in
diagnosis. Unusually persistent bleeding after pregnancy of any type should prompt measurement of
serum B-hCG levels and consideration for diagnostic curettage. Persistent or rising serum B-hCG levels
in the absence of pregnancy are indicative of trophoblastic neoplasia. After thorough pelvic assessment,
then hemogram, renal and liver function studies, and chest radiograph are obtained Solitary or multiple
pulmonary nodules are suggestive of metastasis and should prompt further imaging of the brain,
abdomen, and pelvis. The threshold for additional imaging beyond chest radiograph should be low.
Positron emission computed tomography (PET/CT) scanning may also be useful

Staging and Prognostic Scoring

Clinical staging is similar to that for ovarian cancer except that stage III allows pulmonary involvement.
Risk assessment is done using the modified World Health Organization (WHO) Prognostic Scoring
System (FIGO Oncology Committee, 2002). Scores of 0 to 4 are given for each category that includes
age; type of antecedent pregnancy and interval from it; serum B-hCG concentration; size of tumor, its site,
and the number of metastases; and previous chemotherapy. When summed, low risk neoplasia generally
includes cumulative scores of 0 to 6. Kohorn (2007) has proposed a dynamic scoring system that includes
tumor response.

Treatment

In general, oncology referral is preferable. Single-agent chemotherapy is given for nonmetastatic or low-
risk metastatic neoplasia. It was found methotrexate or actinomycin D alone equally effective compared
with a combination of the two. Methotrexate is less toxic than actinomycin D, but both are usually curative.
There is no need for hospitalization to begin initial therap. Virtually all women with nonmetastatic tumors
or low-risk gestational trophoblastic neoplasia are cured with these if treated early. Repeat
curettage may cause perforation and is avoided unless there is bleeding or a substantial amount of
retained molar tissue. On the other hand “debulking” by curettage hastens response. For women who
have completed childbearing, hysterectomy is an option. Chemotherapy subsequent to the initial dose is
guided by serial serum B-hCG levels. Of note, failure may be falsely assumed when phantom hCG
caused by heterophilic antibodies interferes with the hCG. Women are classified as high risk when the
modified WHO prognostic score is 7 or greater. In these women, combination chemotherapy—with its
increased toxicity—has produced cure rates between 67 and 85 percent. One is the EMA-CO regimen—
Etoposide, Methotrexate, Actinomycin D, Cyclophosphamide, and Oncovin (vincristine). Surgery and
radiotherapy are also frequently employed.

Subsequent Pregnancy: Surveillance is, at a minimum, 6 months for molar pregnancy, 1 year for
gestational trophoblastic neoplasia, and up to 2 years if there are metastases. Fertility is not impaired,
and pregnancy outcomes are usually normal following successful treatment. The primary concern is the
2-percent risk for developing trophoblastic disease in a subsequent pregnancy.

Risk Factors (PROMDI) Completed Incomplete (Partial)

 Paternal Age (>45 y.o.)
 Race (Southeast Asian)
 OB history (Prior molar pregnancy
5-40x risk; Hx of miscarriage or
twin pregnancy in primies;
artificial insemination)
 Maternal Age (<15y.o, >40 y.o,
and >50y.o)
 Diet (dec consumption of animal
fat and B carotene)
History
Amenorrhea
Vaginal Bleeding at 1st trimester
(+) Pregnancy Test
Abs fetal heart tones
Passage of Sago like materials
PE
- Uterine size > AOG
- Anemia 2nd ary to
haemorrhage
- (+) Thecal lutein cysts
- Hyperthyroidism
- Preeclampsia
- Respiratory distress
Diandric Diploidy
No fetal Tissues embryo dies
early in development
2.5% risk of developin
choriocarcinoma
15% risk of invasive mole
Histopathologic:
- Lack of fetal or embryonic
tissues
- Hydropic villi
- Marked atypia of
trophoblasts at the
implantation site
- Absent trophoblastic stromal
inclusions
Pelvic ultrasound
- 80% diagnosed by utz
- Prominent at 2nd trimester:
grape like/ hydropic villous
changes occurs
Diandric Triploidy
Fetal tissues typically present
No risk of choriocarcinoma
Increased risk
Histopathologic:
- Presence of fetal tissue
- Less diffuse, focal hydropic
swelling of villi
- Less pronounced trophoblastic
atypia at implantation site
- Presence of trophoblastic
scallopinc and stromal inclusions
- 70% missed by utz
- Focal cystic changes in the
placenta
- Gestational sac T:AP ratio of >1.5
- Growth retarded fetus with
multiple congenital anomalies
attached to a hydropic placenta
 OR

Note: ELEVATED B-HcG SURGIAL PATHOLOGY

- Diagnosed as early as 9
weeks AOG via UTZ
- If incomplete, may be
mistaken as incomplete or
missed abortion
Complications (HEADPHP)
Hyperemesis gravidarum
Electrolyte imbalance
Anemia
DIC
Preeclampsia
Hyperthyroidism
Pulmonary insufficiency
Medical evacuation plus
hysterectomy
- >100 000 IU/l in CHM, less
elevated in PHM
- Normally, in pregnancy, it
aprrox. increases at 100, 000
IU/L at 10 weeks AOG and
decreases thereafter.
Management:
Labs to be requested
Anemia: CBC
Pre-eclampsia: CBC, LFT, LDH,
UA, Mg, Ca,
Hyperthyroidism: THSand T4
Electrolyte imbalance:
electrolytes
Hyperemesis: BHcG levels
DIC: PT, PTT
UA and CXR to rule out other
differentials
- MANDATORY VIA SHARP
CURETTAGE
Surgical Management:
- Definitive tx is SUCTION
CURETTAGE UNDER GA
- HYSTERECTOMY definite for:
 >40 y.o. with completed
family size and consent
 Post hys: 3-5% risk of post
molar GTN
 >40y.o.: 37%
 > 50 y.o.:
Thecal Lutein cysts are best left
alone

Immunostaining if - P57kip2 maternally derived - PHLDA2 maternally

histopathologic: gene for PMH and hydropic derived gene for PMH and
abortion hydropic abortion
CHM PHM HYDROPIC ABORTION
Diploid Triploid Diploid
(-)P57kip2 (+)P57kip2 (+) P57kip2
(-) PHLDA2 (+)PHLDA2 (+) PHLDA2