Keywords
placental mesenchymal dysplasia - sFlt-1 - preeclampsia - intrauterine growth restriction
Placental mesenchymal dysplasia (PMD) is a rare anomaly characterized by an enlarged
placenta with abnormal cystic villi similar to that seen in a hydatidiform mole.[1] PMD should be considered when an apparently normal fetus with a cystic lesion of
the placenta is observed by ultrasonography. However, differentiation from a complete
mole with a co-twin is sometimes difficult.[2] In spite of similar morphology to a hydatidiform mole, genetic and histological
features are different and the fetal karyotype is usually normal. Unlike molar pregnancies,
which are characterized by an absent or malformed fetus, pregnancy with PMD often
extends to the third trimester without significant maternal morbidity.[3] Therefore, termination of the pregnancy is usually inappropriate when PMD is suspected.
We, however, encountered a case of PMD in which a decision was made to terminate the
pregnancy for the protection of the maternal health because of the development of
severe preeclampsia (PE) in the second trimester of pregnancy. The case presented
unique clinical features, including a marked elevation of serum soluble fms-like tyrosine
kinase-1 (sFlt-1). To our knowledge, this is the first report demonstrating the histological
findings of placental sFlt-1 overexpression in such a condition. It provides a novel
insight supporting the use of this biomarker to predict the extremely early development
of severe PE in PMD.
Case Report
Clinical Course
A 39-year-old nulliparous woman (1G0P) was referred at 19 weeks of gestation because
of a fetal morphological abnormality. On ultrasonography, the placenta was markedly
thickened ([Fig. 1A]) and multiple cystic structures without internal blood flow were observed ([Fig. 1B]). The fetus was severely growth restricted (−2.8 SD) with an omphalocele. PMD was
suspected, with a differential diagnosis of a hydatidiform mole with a coexisting
fetus.
Fig. 1 Ultrasonographic findings of the placenta. (A) Markedly thickened placenta with multiple cystic structures. (B) No blood flow was observed in the cystic lesion. Macroscopic findings of the placenta.
(C, D) Cystic structures similar to molar pregnancy observed in places on the maternal
side of the placenta.
At 21 weeks and 2 days of gestation, the patient developed severe hypertension (180/95 mm
Hg). Urine and blood examinations confirmed marked proteinuria (urinary protein/creatinine = 9.2),
high uric acid (0.47 mmol/L), and an abnormally elevated sFlt level (47,000 pg/L,
sFlt/placental growth factor ratio = 200). Based on a diagnosis of severe extremely
early-onset PE, termination of pregnancy was chosen to protect maternal health.
Stillbirth was induced by cervical dilatation using Laminaria followed by the intravaginal
administration of prostaglandin E1, and the pregnancy was terminated at 21 weeks and
6 days of gestation. No external anomalies except for omphalocele were observed. Placental
weight was 450 g, the insertion site of the umbilical cord was marginal, and no vascular
dilatation was observed on the fetal side of the placenta. Cystic structures similar
to a molar pregnancy were observed in places on the maternal side of the placenta
([Fig. 1C, D]). Villous chromosome examination revealed a normal karyotype (46XX), consistent
with the diagnosis of PMD. Maternal hypertension persisted for 2 weeks after delivery
and oral administration of nifedipine was required during that period.
Pathological Finding
Microscopic findings of the placenta revealed focal enlarged stem villi with cistern
and edematous loose myxoid stroma, surrounded by apparently normal villi with maturation
consistent with the patient's gestational age ([Fig. 2A, B]). Trophoblastic hyperplasia or inclusions, suggestive of molar pregnancy, were absent
([Fig. 2C, D]). Histological findings of decidual vessels revealed vasculopathy characterized
by fibrinoid necrosis and infiltration of foamy macrophages in the vascular wall,
either of which is characteristic of gestational hypertension and fetal growth restriction
([Fig. 3]).
Fig. 2 Microscopic findings of the placenta. (A, B) Enlarged stem villi with cistern (asterisk) or edematous loose myxoid stroma (arrowheads) were focally present, surrounded by normal-appearing villi with gestational age-appropriate
maturation. (C, D) Absence of trophoblastic hyperplasia or inclusions, suggestive of molar pregnancy
(arrows) Original magnification A: ×12.5, B–D: ×40. A–D: Hematoxylin & eosin stain.
Fig. 3 Histological findings of decidual vessels. (A–D) Vasculopathy characterized by fibrinoid necrosis and infiltration of foamy macrophages
(arrows) in the vascular wall Original magnification A, B: ×100, A, B: Hematoxylin & eosin
stain.
In the chorionic vessel lumen, the formation of fresh thrombus was present and marked
luminal stenosis with organizing intimal sclerosis was noted in some of the chorionic
vessels ([Fig. 4A, B]).
Fig. 4 (A) Formation of fresh thrombus in a chorionic vessel lumen (arrows). (B) Marked luminal stenosis with organizing intimal sclerosis in some of the chorionic
vessels (asterisk) Original magnification A, B: ×100, C, D: ×200.
Because of the abnormally high value of serum sFlt-1 we investigated its expression
in the placenta. Immunohistochemical staining of trophoblasts of PMD showed a high
expression of sFlt-1 localized in the syncytiotrophoblast of the enlarged villi in
PMD ([Fig. 5A]). However, its expression was weak in a control case terminated at 20 weeks of gestational
age due to uterine rupture ([Fig. 5B]).
Fig. 5 Immunohistochemical staining of sFlt in trophoblasts of PMD (A, B) and control (C, D). Higher expression of sFlt was identified in the syncytiotrophoblast of enlarged
villi in PMD (arrows), whereas its expression was weak in the control case, wherein the pregnancy was
terminated at 20 weeks gestation due to uterine rupture. sFlt, soluble fms-like tyrosine-kinase-1;
PMD, placental mesenchymal dysplasia.
Discussion
PMD is a unique placental anomaly first recognized by Takayama et al in 1986[4] and later defined by Moscoso et al in 1991.[1] Thereafter, a number of case reports have been published and the clinical features
have been clarified. Characteristic findings are of a large placenta with multicystic
anechoic lesions observed by ultrasonography and macroscopically recognized widely
distributed edematous large villi, either of which is similar to that in a hydatidiform
mole.[1] Further, PMD is sometimes accompanied by a dilated vascular aneurysm on the fetal
surface of the placenta, which was not observed in the present case.[5] The histological finding is characterized by abnormally enlarged cystic stem villi
in the absence of trophoblastic proliferation, which is the most obvious feature distinguishing
it from hydatidiform mole, along with fetal karyotype.[6] It is known that Beckwith-Wiedemann syndrome (BWS) is observed in about 20% of the
cases; however, the difference in clinical characteristics from those with or without
BWS has not been clarified.[3] Because morphological information from the small fetus terminated in the midtrimester
was inadequate and no diagnostic genetic testing for BWS was performed, it is unclear
whether the present case had BWS.
In recent years, intrauterine growth restriction, late pregnancy loss, PE, and placental
abruption have come to be regarded as a series of placenta-mediated pregnancy complications
which develop in relation to placental hypoplasia and/or dysfunction.[7] In a systematic review of PMD published in 2006, about 5% of the cases were complicated
by PE.[3] There are no reports in the literature of the detailed clinical course of patients
with PMD complicated by PE, except for one case that in which the patient developed
severe PE similar to the patient in the present case.[8] Therefore, the clinical picture of this condition has not yet been elucidated.
Recently, the etiology of PE has been described as a vascular endothelial disorder
originating from placental hypoplasia. The sFlt-1 produced from trophoblasts under
hypoxic conditions is known to be a central mediator in the pathogenesis.[9] Since serum sFlt-1 values rise prior to the onset of PE, in recent years it has
been used as a predictive marker.[10] In addition to the pathological findings of vascular endothelial dysfunction characteristic
of the placenta in PE cases, the present case showed an overexpression of sFlt-1 localized
in the trophoblast of enlarged villi. To our knowledge, this is the first report suggesting
that the etiology of PE that develops in PMD cases is associated with the abnormal
enhanced expression of sFlt-1 in the syncytiotrophoblast of enlarged villi. When PMD
is suspected, the clinician should keep in mind the possibility of development of
extremely early severe PE and that monitoring the serum sFlt-1 value may be useful
in this regard.
Conclusion
In the case of placental findings similar to those of hydatidiform mole with a coexistent
fetus, it is inappropriate to make an immediate decision to terminate the pregnancy,
and it is important to evaluate it carefully and consider the possibility of PMD.
More frequent antenatal assessments should take place if the pregnancy is to be continued,
not only because of fetal growth restriction or late pregnancy loss, but also because
of the potential for very early onset of severe PE. The monitoring of serum sFlt-1
level is suggested to be beneficial for perinatal management in this condition.
