HYDATIDIFORM MOLE

Introduction

Background

Gestational trophoblastic disease encompasses several

disease processes that originate in the placenta. These
include complete and partial moles, placental site
trophoblastic tumors, choriocarcinomas, and invasive moles.

Almost all women with malignant gestational trophoblastic

disease can be cured with preservation of reproductive
function. The following discussion is limited to hydatidiform
moles (complete and partial).

Pathophysiology

A complete mole contains no fetal tissue. Ninety percent are

46,XX, and 10% are 46,XY.1,2 Complete moles can be divided
into 2 types:

• Androgenetic complete mole

o Homozygous
 These account for 80% of complete moles.
 Two identical paternal chromosome
complements, derived from duplication of the
paternal haploid chromosomes.
 Always female; 46,YY has never been
observed.
o Heterozygous
 These account for 20% of complete moles.
 May be male or female.
 All chromosomes are of parental origin, most
likely due to dispermy.
• Biparental complete mole: Maternal and paternal genes
are present but failure of maternal imprinting causes
only the paternal genome to be expressed.3
o The biparental complete mole is rare.
 o A recurrent form of biparental mole, which is
familial and appears to be inherited as an
autosomal recessive trait, has been described. Al-
Hussaini describes a series of 5 women with as
many as 9 consecutive molar pregnancies.4,5
o A candidate region of chromosome arm 19q13.4
has been identified.6,7

With a partial mole, fetal tissue is often present. Fetal

erythrocytes and vessels in the villi are a common finding.
The chromosomal complement is 69,XXX or 69,XXY.8 This
results from fertilization of a haploid ovum and duplication of
the paternal haploid chromosomes or from dispermy.
Tetraploidy may also be encountered. As in a complete mole,
hyperplastic trophoblastic tissue and swelling of the
chorionic villi occur.

Frequency

United States

By studying elective pregnancy terminations, hydatidiform

moles were determined to occur in approximately 1 in 1200
pregnancies.9

International

The reported frequency of hydatidiform mole varies greatly.

Some of this variability can be explained by differences in
methodology (eg, single hospital vs population studies,
identification of cases). The reported frequencies range from
1 in 100 pregnancies in Indonesia to 1 in 200 pregnancies in
Mexico to 1 in 5000 pregnancies in Paraguay.10 The study of
pathologic material from first- and second-trimester
abortions established a frequency of complete and partial
hydatidiform moles in Ireland of 1 per 1945 pregnancies and
1 per 695 pregnancies, respectively.11

Mortality/Morbidity
A hydatidiform mole is considered malignant if metastases
or destructive invasion of the myometrium (ie, invasive
mole) occurs, or when the serum hCG levels plateau or rise
during the period of follow-up and an intervening pregnancy
is excluded. Malignancy (see eMedicine's article Gestational
Trophoblastic Neoplasia) is diagnosed in 15-20% of patients
with a complete hydatidiform mole and 2-3% of partial
moles.12,13 Lung metastases are found in 4-5% of patients
with a complete hydatidiform mole and rarely in cases of
partial hydatidiform moles.14,15

Race

Differences in the frequency of hydatidiform moles between

ethnic groups have been reported internationally.10,16 In the
United States, comparison of frequency of hydatidiform
moles in African Americans and Caucasians have yielded
conflicting results.16 If differences exist, whether they are due
to genetic differences or environmental factors is not clear.

Sex

Hydatidiform mole is a disease of pregnancy and therefore a

disease of women.

See Medscape's Pregnancy Resource Center.

Age

Hydatidiform mole is more common at the extremes of

reproductive age. Women in their early teenage or
perimenopausal years are most at risk.17,18,19,10,16 Women
older than 35 years have a 2-fold increase in risk. Women
older than 40 years experience a 5- to 10-fold increase in
risk compared to younger women. Parity does not affect the
risk.

Clinical

History
 • Complete mole: The typical clinical presentation of
complete molar pregnancies has changed with the
advent of high-resolution ultrasonography. Most moles
are now diagnosed in the first trimester before the
onset of the classic signs and symptoms.20,21
o Vaginal bleeding: The most common classic
symptom of a complete mole is vaginal bleeding.
Molar tissue separates from the decidua, causing
bleeding. The uterus may become distended by
large amounts of blood, and dark fluid may leak
into the vagina. This symptom occurs in 50% of
cases.
o Hyperemesis: Patients may also report severe
nausea and vomiting. This is due to
extremely high levels of human chorionic
gonadotropin (hCG).
o Hyperthyroidism: Signs and symptoms of
hyperthyroidism can be present due to stimulation
of the thyroid gland by the high levels of
circulating hCG or by a thyroid stimulating
substance (ie, thyrotropin) produced by the
trophoblasts.22
• Partial mole: Patients with partial mole do not have the
same clinical features as those with complete mole.
These patients usually present with signs and
symptoms consistent with an incomplete or missed
abortion.
o Vaginal bleeding
o Absence of fetal heart tones

Physical

• Complete mole
o Size inconsistent with gestational age: A uterine
enlargement greater than expected for gestational
age is a classic sign of a complete mole.
Unexpected enlargement is caused by excessive
trophoblastic growth and retained blood. However,
patients present with size-appropriate
 enlargement or smaller-than-expected
enlargement at a similar frequency.
o Preeclampsia: Pelvic ultrasonography has resulted
in the early diagnosis of most cases of
hydatidiform mole and preeclampsia is seen in
less than 2% of cases.21
o Theca lutein cysts: These are ovarian cysts greater
than 6 cm in diameter and accompanying ovarian
enlargement. These cysts are not usually palpated
on bimanual examination but are identified by
ultrasonography. Patients may report pressure or
pelvic pain. Because of the increased ovarian size,
torsion is a risk. These cysts develop in response
to high levels of beta-hCG. They spontaneously
regress after the mole is evacuated, but it may
take up to 12 weeks for complete regression.
• Partial mole
o Uterine enlargement and preeclampsia is reported
in only 5% of patients.23
o Theca lutein cysts, hyperemesis, and
hyperthyroidism are extremely rare.
• Twinning
o Twinning with a complete mole and a fetus with a
normal placenta has been reported. Cases of
healthy infants in these circumstances have been
reported.24,8
o Women with coexistent molar and normal
gestations are at higher risk for developing
persistent disease and metastasis25 . Termination
of pregnancy is a recommended option.
o The pregnancy may be continued as long as the
maternal status is stable, without hemorrhage,
thyrotoxicosis, or severe hypertension. The patient
should be informed of the risk of severe maternal
morbidity from these complications.26
o Prenatal genetic diagnosis by chorionic villus
sampling or amniocentesis is recommended to
evaluate the karyotype of the fetus.
Causes

A diet deficient in animal fat and carotene may be a risk

factor.16,17

Hydatidiform mole

Molar pregnancy is an abnormal form of pregnancy,

characterized by the presence of a hydatidiform mole (or
hydatid mole, mola hytadidosa). Molar pregnancy
comprises two distinct entities, partial and complete moles.
Complete moles have no identifiable embryonic or fetal
tissues and arise when an empty egg with no nucleus is
fertilized by a normal sperm. In contrast, a partial mole
occurs when a normal egg is fertilized by two spermatozoa.
Hydatidiform moles may develop into choriocarcinoma, a
form of cancer.

The etymology is derived from hydatis (Greek "a drop of

water"), referring to the watery contents of the cysts, and
mole (from Latin mola = millstone/false conception).[3] The
term, however, comes from the cyst's appearance looking
very much like a hydatid cyst in an Echinococcosis.

Natural history

A hydatidiform mole is a pregnancy/conceptus in which the

placenta contains grapelike vesicles that are usually visible
with the naked eye. The vesicles arise by distention of the
chorionic villi by fluid. When inspected in the microscope,
hyperplasia of the trophoblastic tissue is noted. If left
untreated, a hydatidiform mole will almost always end as a
spontaneous abortion.

Based on morphology, hydatidiform moles can be divided

into two types: In complete moles, all the chorionic villi are
vesicular, and no sign of embryonic or fetal development is
present. In partial moles some villi are vesicular, whereas
others appear more normal, and embryonic/fetal
development may be seen but the fetus is always malformed
and is never viable.

Hydatidiform moles are a common complication of

pregnancy, occurring once in every 1000 pregnancies in the
US, with much higher rates in Asia (e.g. up to one in 100
pregnancies in Indonesia).[4]

In rare cases a hydatidiform mole co-exists in the uterus with

a normal, viable fetus. These cases are due to twinning. The
uterus contains two conceptuses: one with an abnormal
placenta and no viable fetus (the mole), and one with a
normal placenta and a viable fetus. Under careful
surveillance it is often possible for the woman to give birth to
the normal child and to be cured of the mole.[5]

The etiology of this condition is not completely understood.

Potential risk factors may include defects in the egg,
abnormalities within the uterus, or nutritional deficiencies.
Women under 20 or over 40 years of age have a higher risk.
Other risk factors include diets low in protein, folic acid, and
carotene.[6] The diploid set of sperm-only DNA means that all
chromosomes have sperm-patterned methylation
suppression of genes. This leads to overgrowth of the
syncytiotrophoblast whereas dual egg-patterned methylation
leads to a devotion of resources to the embryo, with an
underdeveloped syncytiotrophoblast. This is considered to be
the result of evolutionary competition with male genes
driving for high investment into the fetus versus female
genes driving for resource restriction to maximise the
number of children.[7]

Parental origin

In most hydatidiform moles, the parental origin of the genes

in the cellular nucleus is abnormal.

In most complete moles, all nuclear genes are inherited from

the father, only (androgenesis). In approximately 80% of
these androgenetic moles, the most probable mechanism is
that an empty egg is fertilized by a single sperm, followed by
a duplication of all chromosomes/genes (a process called
"endoreduplication"). In approximately 20% of complete
moles the most probable mechanism is that an empty egg is
fertilised by two sperms. In both cases, the moles are diploid
(i.e. there are two copies of every chromosome). In all these
cases, the mitochondrial genes are inherited from the
mother, as usual.

Most partial moles are triploid (three chromosome sets). The

most probable mechanism is that a normal haploid egg is
fertilized by two sperms. Thus the nucleus contains one
maternal set of genes and two paternal sets.

In rare cases, hydatidiform moles are tetraploid (four

chromosome sets) or have other chromosome abnormalities.

A small percentage of hydatidiform moles have biparental

diploid genomes, as in normal living persons; they have two
sets of chromosomes, one inherited from each biological
parent. Some of these moles occur in women who carry
mutations in the gene NLRP7, predisposing them towards
molar pregnancy. These rare variants of hydatidiform mole
may be complete or partial.[8][9][10]

Clinical presentation and diagnosis

Molar pregnancies usually present with painless vaginal

bleeding in the fourth to fifth month of pregnancy.[1] The
uterus may be larger than expected, or the ovaries may be
enlarged. There may also be more vomiting than would be
expected (hyperemesis). Sometimes there is an increase in
blood pressure along with protein in the urine. Blood tests
will show very high levels of human chorionic gonadotropin
(hCG).[11]

The diagnosis is strongly suggested by ultrasound

(sonogram), but definitive diagnosis requires
histopathological examination. The mole grossly resembles a
bunch of grapes ("cluster of grapes" or "honeycombed
uterus" or "snow-storm"[12]). There is increased trophoblast
proliferation and enlarging of the chorionic villi.[13]
Angiogenesis in the trophoblasts is impaired as well. [13]

Sometimes symptoms of hyperthyroidism are seen, due to

the extremely high levels of hCG, which can mimic the
normal Thyroid-stimulating hormone (TSH).[11]

Treatment

Hydatidiform moles should be treated by evacuating the

uterus by uterine suction or by surgical curettage as soon as
possible after diagnosis, in order to avoid the risks of
choriocarcinoma.[14] Patients are followed up until their serum
human chorionic gonadotrophin (hCG) level has fallen to an
undetectable level. Invasive or metastatic moles (cancer)
may require chemotherapy and often respond well to
methotrexate. The response to treatment is nearly 100%.
Patients are advised not to conceive for one year after a
molar pregnancy. The chances of having another molar
pregnancy are approximately 1%.

Management is more complicated when the mole occurs

together with one or more normal fetuses.

Carboprost medication may be used to contract the uterus.

Prognosis

More than 80% of hydatidiform moles are benign. The

outcome after treatment is usually excellent. Close follow-up
is essential. Highly effective means of contraception are
recommended to avoid pregnancy for at least 6 to 12
months.

In 10 to 15% of cases, hydatidiform moles may develop into

invasive moles. This condition is named persistent
trophoblastic disesase (PTD). The moles may intrude so far
into the uterine wall that hemorrhage or other complications
develop. It is for this reason that a post-operative full
abdominal and chest x-ray will often be requested.

In 2 to 3% of cases, hydatidiform moles may develop into

choriocarcinoma, which is a malignant, rapidly-growing, and
metastatic (spreading) form of cancer. Despite these factors
which normally indicate a poor prognosis, the rate of cure
after treatment with chemotherapy is high.

Over 90% of women with malignant, non-spreading cancer

are able to survive and retain their ability to conceive and
bear children. In those with metastatic (spreading) cancer,
remission remains at 75 to 85%, although their childbearing
ability is usually lost.

A hydatidiform mole is growth of an abnormal fertilized egg

or an overgrowth of tissue from the placenta.

• Women appear to be pregnant, but the uterus enlarges

much more rapidly than in a normal pregnancy.
• Most women have severe nausea and vomiting, vaginal
bleeding, and very high blood pressure.
• Ultrasonography, blood tests to measure human
chorionic gonadotropin (which is produced early during
pregnancy) and a biopsy are done.
• Moles are removed using dilation and curettage with
suction.
• If the disorder persists, chemotherapy is needed.

Most often, a hydatidiform mole is an abnormal fertilized egg

that develops into a hydatidiform mole rather than a fetus (a
condition called molar pregnancy). However, a hydatidiform
mole can develop from cells that remain in the uterus after a
miscarriage or a full-term pregnancy. Rarely, a hydatidiform
mole develops when there is a living fetus. In such cases, the
fetus typically dies, and a miscarriage often occurs.

Hydatidiform moles are most common among women under

17 or over 35. In the United States, they occur in about 1 in
2000 pregnancies in the United States. For unknown
reasons, moles are almost 10 times more common in Asian
countries.

About 80% of hydatidiform moles are not cancerous. About

15 to 20% invade the surrounding tissue and tend to persist.
About 2 to 3% become cancerous and spread throughout the
body; they are then called choriocarcinomas.
Choriocarcinomas can spread quickly through the lymphatic
vessels or bloodstream. Hydatidiform moles and
choriocarcinomas are types of gestational trophoblastic
disease.

Symptoms

Women who have a hydatidiform mole feel as if they are

pregnant. But because hydatidiform moles grow much faster
than a fetus, the abdomen becomes larger much faster than
it does in a normal pregnancy. Severe nausea and vomiting
are common, and vaginal bleeding may occur. As parts of
the mole deteriorate, small amounts of tissue, which
resemble a bunch of grapes, may pass through the vagina.
These symptoms indicate the need for prompt evaluation by
a doctor.

Hydatidiform moles can cause serious complications,

including infections and very high blood pressure with
increased protein in the urine (preeclampsia or eclampsia—
see Pregnancy Complications: Preeclampsia).

If choriocarcinoma develops, women may have other

symptoms, caused by spread (metastasis) to other parts of
the body.

Diagnosis

Often, doctors can diagnose a hydatidiform mole shortly

after conception. The pregnancy test is positive, but no fetal
movement and no fetal heartbeat are detected, and the
uterus is much larger than expected.
Ultrasonography is done to be sure that the growth is a
hydatidiform mole and not a fetus or amniotic sac (which
contains the fetus and fluid around it). Blood tests to
measure the level of human chorionic gonadotropin (hCG—a
hormone normally produced early in pregnancy) are done. If
a hydatidiform mole is present, the level is usually very high
because the mole produces a large amount of this hormone.
A sample of tissue is removed or obtained when it is passed,
then examined under a microscope (biopsy) to confirm the
diagnosis.

Prognosis

The cure rate for a hydatidiform mole is virtually 100% if the

mole has not spread. The cure rate is 60 to 80% for
choriocarcinoma that has spread widely. Most women can
have children afterwards and do not have a higher risk of
having complications, a miscarriage, or children with birth
defects.

About 1% of women who have had a hydatidiform mole have

another one. So if women have had a hydatidiform mole,
ultrasonography is done early in subsequent pregnancies.

Treatment

A hydatidiform mole is completely removed, usually by

dilation and curettage (D and C) with suction (see Symptoms
and Diagnosis of Gynecologic Disorders: Dilation and
Curettage). Only rarely is removal of the uterus
(hysterectomy) necessary.

A chest x-ray is done to see whether the mole has become

cancerous (that is, a choriocarcinoma) and spread to the
lungs. After surgery, the level of human chorionic
gonadotropin in the blood is measured to determine whether
the hydatidiform mole was completely removed. When
removal is complete, the level returns to normal, usually
within 10 weeks, and remains normal. If the level does not
return to normal (called persistent disease), computed
tomography (CT) of the brain, chest, abdomen, and pelvis is
done to determine whether choriocarcinoma has developed
and spread.

Hydatidiform moles do not require chemotherapy, but

persistent disease does. Usually, only one drug
( methotrexate Some Trade Names
TREXALL
or dactinomycin Some Trade Names
COSMEGEN
) is needed. Sometimes both drugs or another combination
of chemotherapy drugs is needed.

Women who have had a hydatidiform mole removed are

advised not to become pregnant for 1 year. Oral
contraceptives are frequently recommended, but other
effective contraceptive methods can be used.

SOURCES;
http://www.merck.com/mmhe/sec22/ch252/ch252h.html
http://emedicine.medscape.com/article/254657-overview
http://en.wikipedia.org/wiki/Hydatidiform_mole