Complete Mole with Coexisting Fetus (CMCF)
Phyllis C. Huettner
Washington University Medical Center
St. Louis, MO
The patient was a 30 year old G4P0120 white woman who was referred to the Fetal Maternal
Medicine Clinic at 13 weeks gestation for an abnormal ultrasound. Past obstetrical history included
delivery of a preterm infant at 21 weeks in 2003 and spontaneous abortions at 8 and 10 weeks in 2004 and
2005, respectively. This pregnancy was conceived on Clomid. She experienced spotting in the first
trimester. An ultrasound at 8 weeks showed a 6x6x4 cm hematoma adjacent to the placenta. Weekly
ultrasound showed persistence of the mass or clot, size unchanged. At 12 weeks, multiple small cysts
developed within the mass. Serum hCG levels were elevated at about three times normal for gestational
age. The patient had a history of chronic hypertension that was well controlled on Aldomet and
Labetalol. No hyperemesis was reported. Thyroid studies were normal.
Ultrasound at our institution at 13 weeks showed a normal fetus. A large amount of cystic
tissue filled the fundus. The ovaries were enlarged and cystic. Because of the abnormal ultrasound
findings, the patient was offered termination which was declined. Karyotyping was recommended but was
At 19 weeks gestation cervical shortening was noted. Given the past history of delivery
at 21 weeks, a cerclage was placed. At 24 weeks, intrauterine growth restriction (< 10th
percentile) was noted. Umbilical artery Doppler showed intermittently absent diastolic flow and a
notched umbilical artery indicating increased placental resistance. The placental mass was essentially
unchanged. The patient was hospitalized and placed on bed rest. At 25 weeks the patient requested
karyotyping which was normal 46 XX. Over the next few weeks, the amniotic fluid index progressively
decreased. At 28 weeks gestation the baby stopped growing. A Cesarean section was performed. The
infant was a normal 530 gram female with Apgar scores of 4 at one minute and 9 at five minutes.
Case 1 - Figure 1 - Gross photograph of the fused twin placenta with normal parenchyma on the left and molar tissue on the right
Case 1 - Figure 2 - Close up of the pale, molar tissue with large, fluid-filled molar villi
Case 1 - Figure 3 - Extensively necrotic, fluid-filled molar villi
Case 1 - Figure 7 - Higher power of trophoblast hyperplasia with extensive necrosis
Case 1 - Figure 8 - Non-molar villi with accelerated villous maturation for gestational age
Case 1 - Figure 9 - Accelerated villous maturation with small, long villi and increased syncytiotrophoblastic knots
The placental disc weighed 105 grams and measured 8 x 7 x 2 cm. A shiny blue-gray fetal
plate had surrounding fetal membranes and a centrally inserted umbilical cord with normal branching
vasculature. The underlying parenchyma was brown and spongy without focal abnormalities. Attached to a
portion of the fetal membranes was a 5 x 3 cm area of pale vesicular tissue with individual vesicles
measuring up to 7 mm. Detached fragments of vesicular tissue were also present.
The pale, hydropic tissue was largely necrotic but, where viable, showed markedly enlarged
villi with central cavitation and, in focal areas, exuberant, circumferential trophoblast hyperplasia.
Some of the villi had irregular outlines and occasional trophoblast inclusions were identified. The
villi underlying normal fetal plate showed accelerated maturation for 28 weeks gestation characterized by
small, narrow chorionic villi with few, very small caliber capillary vessels and increased syncytial
knots. The fetal membranes and umbilical cord were normal.
There are several diagnostic possibilities when confronted with a fetus and enlarged,
possibly molar villi in the placenta. Standard morphology, immunohistochemistry, cytogenetics and more
advanced molecular techniques can help sort out these possibilities. This is an important exercise since
the treatment, follow up, and prognosis vary considerably among the diagnostic possibilities.
Partial hydatidiform mole (PM) may show enlarged, hydropic villi and may have a coexistent
fetus. The diagnosis of PM is most confidently made on morphologic grounds when these four features are
present: 1). two populations of villi, one small and normal and the other enlarged, irregular and/or
dilated 2). at least some villi greater than or equal to 3 mm with central cavitation 3). circumferential
trophoblast hyperplasia that is usually minimal and focal, composed of buds of syncytiotrophoblast and
4). irregular, scalloped villous outlines with some trophoblast inclusions .
PMs are triploid, usually 69XXY or 69 XXX. The extra set of chromosomes are of paternal origin and
are the result of fertilization of the haploid egg by one haploid sperm that doubles, or by two sperm,
resulting in an excess of paternal genetic material which is responsible for abnormal regulation of
trophoblast growth . Flow cytometry performed on fresh or formalin-fixed paraffin-embedded tissue can
be used to diagnose triploidy . Other techniques may also prove useful (see below). Patients with PM
typically present as a missed abortion with normal or even low hCG levels and ultrasound may not show the
changes of molar pregnancy . The fetus in PM typically shows symmetric growth restriction and
numerous structural abnormalities including syndactyly, cerebral ventriculomegaly, cardiac defects and
The fetus in this condition usually dies in the first trimester . The normal
features of the infant in our case argue against PM. In addition, in PM the molar villi are intermixed
with normal villi not regionally segregated as they are in this case.
Complete mole (CM) is another diagnostic possibility. In CM even more of the villi are
enlarged, and more dramatically so, than in PM. Generally, the villous outlines are not as scalloped and
irregular as in PM. Another very helpful feature is the exuberant, often highly atypical trophoblast
hyperplasia seen in CM.
CMs are diploid but both sets of chromosomes are of paternal origin and are usually (80%)
the result of fertilization of an empty egg by a haploid sperm that duplicates (homozygous CM) or less
often (20%), by fertilization of an empty egg by two different haploid sperm (heterozygous CM) .
Since they are diploid, CMs can be distinguished from PMs, which are triploid, by flow cytometry. This
technique does not distinguish a CM from a hydropic abortus, which would also be diploid, by flow
Immunohistochemistry with an antibody to p57KIP2 can also be very useful in
differentiating CM from PM, and can aid in the distinction of CM from hydropic abortus.
P57KIP2 protein is a tumor suppressor and cell cycle inhibitor that is strongly paternally
imprinted, meaning that due to differential DNA methylation, its gene is expressed predominantly from the
maternal allele. Because CMs have only paternal DNA, expression of p57KIP2 will be absent or
markedly decreased. Partial moles and hydropic abortuses have one copy of maternal DNA and therefore
show expression of this protein by nuclear staining of cytotrophoblast and villous mesenchymal cells
. There is excellent correlation between the results of p57KIP2 staining and more
complex molecular analysis (see below) in detecting CMs, even among cases that are equivocal on routine
Other molecular studies (see below) can also make the distinction between PM and CM, as
well as between hydropic abortus and CM. In addition, these studies can determine whether a CM is or
homozygous (one sperm with duplication) or heterozygous (two different sperm) . There is some
evidence that heterozygous moles are more likely to develop persistent gestational trophoblastic disease
Classically, CMs have a characteristic ultrasound appearance and clinical presentation.
The fluid-filled, dilated villi give a "snowstorm" pattern on ultrasound. Classically, the hCG is
markedly elevated and patients present with vaginal bleeding, uterine size greater than dates, ovarian
theca-lutein cysts and sometimes hyperemesis gravidarum and preeclampsia . More recently, studies
have shown that with routine ultrasound early in the first trimester and accurate hCG assays, most
abnormal pregnancies, including molar pregnancies, are diagnosed much earlier in gestation . Today,
CMs typically present as a missed abortion with some vaginal bleeding. The hCG may be normal, only
slightly elevated or even low. The ultrasound may not be abnormal. It is much less common now for
patients with CM to present with classic symptoms such as size greater than dates, hyperemesis and
Like the clinical presentation, the morphologic features of CMs that are evacuated early
in gestation are also going to be more subtle than those evacuated later in gestation, but it is
important to remember that these early CMs are associated with the same adverse outcomes, including pGTD
and choriocarcinoma, as CMs diagnosed later in gestation . Therefore, it is very important for
pathologists to be able to recognize the subtle morphologic features of these early CMs. In early CMs
the villi are generally small with little cavitation but they do have very distinctive shapes with
"claw-like" or "cauliflower-like" villous outlines. The villous stroma has a distinctive blue,
mesenchymal appearance with anatomizing stromal channels or canaliculi. Karyorrhexis is prominent, a
very helpful feature as it is uncommon in hydropic abortus and PMs. At least focally, the trophoblast is
hyperplastic, and atypical trophoblast is frequently observed in the implantation site . It is
important to emphasize that fetal tissue, particularly amnion, yolk sac and nucleated red blood cells may
be seen in CM early in gestation
It would be extremely unusual, however, for a fully formed
fetus to occur in a CM in the absence of a twin pregnancy with one normal twin and one molar twin.
Placental Mesenchymal Dysplasia
Placental mesenchymal dysplasia (PMD) is another diagnostic possibility for hydropic villi
and a normal fetus. This condition is often confused with molar disease, particularly PM. The
characteristic features are 1). placentomegaly 2). variably-sized villi including some that are markedly
hydropic with cavitation and irregular contours 3). lack of trophoblast hyperplasia or inclusions 4).
chorangiomas 5). chorangiosis and 6). enlarged, tortuous stem villous vessels with mural hypertrophy
and thrombi, some enveloped by a peculiar loose, edematous, mesenchymal stroma
shows that these placentas are diploid, not triploid, as would be expected in a PM . The fetuses in
these cases are typically normal and may survive, features that are clearly distinct from PM .
Interestingly, some cases of PMD are associated with Beckwith-Wiedemann syndrome
cases have also been associated with a twin gestation in which one twin showed PMD and the other, CM
. In our case, trophoblast hyperplasia was present, the hydropic villi were not confined to the stem
villi and the other features of placental mesenchymal dysplasia were not present.
Twin Gestation with Molar Pregnancy and Coexisting Normal Fetus
The final entity in the differential diagnosis is a twin gestation in which one twin is
molar, either complete or partial, and the other is a normal coexisting fetus. This is a very rare
occurrence. Complete mole with a normal coexisting fetus (CMCF) is much more common than partial mole
with a coexisting normal fetus. CMCF would explain the features in our case – a large placenta with two
distinct areas, one normal and the other with molar features, and the presence of a normal fetus. Due to
the extensive necrosis of the presumed molar areas, it was difficult to make a determination of whether
our case represented a partial mole or a complete mole. Molecular studies were quite helpful in making
DNA from the normal placenta, the putative molar placenta and the mother (decidua) was
isolated by microdissecting tissue off glass slides. Polymorphic microsatellite alleles (also known as
short tandem repeats or STRs) were characterized using the ABI AmpFISTR* Profiler Plus TM multiplex PCR
assay. The genetic markers included 10 STRs distributed on nine different human autosomes plus the X and
Y chromosomes. The DNA fragments were separated by electrophoresis and ABI Gene Mapper software was used
to determine the fragment sizes. The pattern of DNA short tandem repeats was analyzed from all three
populations. Analysis of DNA fragments of the normal villi showed that some DNA was inherited from the
mother and that some could not have been inherited from the mother (i.e. was paternal in origin).
Analysis of the putative molar villi showed that they contained only genetic material that could not be
derived from maternal tissue. In addition, only one allele size was noted at each locus in the putative
molar tissue, consistent with DNA derived from only one parent (the father); this finding indicates that
the tissue is a complete mole not a partial mole. These findings are diagnostic of a twin pregnancy in
which one twin was normal and one twin was a CM of homologous type (duplication of a single sperm).
Complete mole with coexisting fetus (CMCF)
CMCF is an uncommon condition, estimated to occur in about 1:20,000 to 1:100,000
Most cases are eventually diagnosed on ultrasound when a normal fetus and
placenta are seen next to a molar mass .
Yet ultrasound is correct only 21% to 68% of the time
and the condition is often misdiagnosed, especially in the 1st trimester, as abnormal
presentation, a hematoma or a placental tumor
Compared to singleton CMs, CMCF is more likely to
present later in gestation (13 weeks vs. 22.2 weeks), to have increased uterine size (14 week size vs.
28.3 week size), and to have high hCG levels (839,563 vs. 232,135) . About 20% of cases will
experience early onset preeclampsia . Twelve to 36% of patients with CMCF will deliver preterm or
experience a fetal loss (10% to 40%)
but term liveborn infants were delivered in over a
quarter of cases of CMCF in some studies (7% to 27%)
These outcomes may not reflect the
true natural history of CMCF, however, since a high percentage of patients elect to terminate the
pregnancy once the diagnosis is made
The most serious complication of CMCF is the development of persistent gestational
trophoblastic disease (pGTD). In some studies as many as 68% of patients developed this complication,
but whether the rates of pGTD or the rate of pGTD with metastatic disease are significantly increased in
patients with CMCF compared to singleton CM, or CMCF that deliver viable vs. previable infants remain
Those cases that are associated with delivery of a viable
infant are usually diagnosed later, have less vaginal bleeding and lower hCG levels leading some to
speculate that the molar component in these cases may be less aggressive or largely degenerated .
Management of these unusual pregnancies can be aided by a karyotype. If the fetus is
triploid, this represents a PM and the fetus is unlikely to survive to term; termination can be
considered. If the karyotype is normal diploid, this likely represents a CMCF. Since about a quarter of
these women will deliver a term, liveborn infant, they can be followed expectantly, especially if hCG
levels are falling, with the awareness that there is a risk for the development of preeclampsia, severe
vaginal bleeding and preterm delivery .
Occasionally, multiple gestations of higher order are associated with a coexisting CM
Ten cases of triplet pregnancies consisting of twins with a coexisting CM have been reported in the
literature. Most miscarried before 25 weeks but occasionally infants with longterm survival are born
. Although the data are more limited, it appears that there is less likelihood of a successful
outcome with CM and coexisting twin pregnancy than CMCF .
On rare occasions, a twin pregnancy consisting of a PM and a coexisting normal twin, will
In addition to finding morphologic features of PM, the normal fetus and its
placenta should be diploid, while the molar placenta and any fetus that might be associated with it
should be triploid. Flow cytometry, immunohistochemistry for p57KIP2 , and molecular STR
analysis can be used to confirm the diagnosis.
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