—  SPECIALTY CONFERENCE  —

Pediatric Pathology

Case 1 - Complete Mole with Coexisting Fetus (CMCF)

Phyllis C. Huettner
Washington University Medical Center
St. Louis, MO





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Clinical History
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 also declined.

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 - Slide 1
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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 4 - Molar villi with central cavitation
Case 1 - Figure 5 - Focal circumferential trophoblast hyperplasia
Case 1 - Figure 6 - Molar villi with trophoblast hyperplasia

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


Gross Pathology
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.

Microscopic Pathology
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.

Differential Diagnosis
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 Mole
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 [1].

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 [2]. Flow cytometry performed on fresh or formalin-fixed paraffin-embedded tissue can be used to diagnose triploidy [1]. 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 [1]. The fetus in PM typically shows symmetric growth restriction and numerous structural abnormalities including syndactyly, cerebral ventriculomegaly, cardiac defects and micrognathia [3]. The fetus in this condition usually dies in the first trimester [2]. 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
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) [2]. 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 cytometry [1].

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 [4]. 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 pathology [5].

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) [6]. There is some evidence that heterozygous moles are more likely to develop persistent gestational trophoblastic disease (pGTD) [7].

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 [8]. 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 [8]. 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 preeclampsia [8].

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 [9]. 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 [9]. 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 [10, 11, 12]. 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 [13, 14, 15]. Ploidy analysis shows that these placentas are diploid, not triploid, as would be expected in a PM [13]. The fetuses in these cases are typically normal and may survive, features that are clearly distinct from PM [13]. Interestingly, some cases of PMD are associated with Beckwith-Wiedemann syndrome [13, 16]. Occasional cases have also been associated with a twin gestation in which one twin showed PMD and the other, CM [13]. 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 this determination.

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).

Diagnosis
Complete mole with coexisting fetus (CMCF)

Discussion
CMCF is an uncommon condition, estimated to occur in about 1:20,000 to 1:100,000 pregnancies [3, 17, 18]. Most cases are eventually diagnosed on ultrasound when a normal fetus and placenta are seen next to a molar mass [3]. Yet ultrasound is correct only 21% to 68% of the time [19, 20] and the condition is often misdiagnosed, especially in the 1st trimester, as abnormal presentation, a hematoma or a placental tumor [18, 19, 20, 21]. 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) [22]. About 20% of cases will experience early onset preeclampsia [3]. Twelve to 36% of patients with CMCF will deliver preterm or experience a fetal loss (10% to 40%) [3, 21, 22, 23], but term liveborn infants were delivered in over a quarter of cases of CMCF in some studies (7% to 27%) [3, 17, 21, 22, 23]. 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 [3, 17, 21, 22, 23].

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 controversial issues [14, 17, 20, 22, 23]. 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 [17].

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 [17].

Occasionally, multiple gestations of higher order are associated with a coexisting CM [22, 24]. 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 [24]. 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 [24].

On rare occasions, a twin pregnancy consisting of a PM and a coexisting normal twin, will be observed [19, 25]. 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.

References
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