Multi-Cystic Placental Lesions.
In this case, twin A is a complete hydatidiform mole and the placenta of twin B demonstrates placental mesenchymal dysplasia (PMD).
Multi-cystic placental lesions present a challenging diagnostic dilemma. The differential diagnosis includes hydatidiform mole (complete and partial), massive subchorionic thrombo-hematomas, multiple chorangiomas, and multiple subchorionic cysts. Particularly when prenatal ultrasound describes a cystic appearance, PMD is also an important consideration to inform management and therapy.
Since PMD may most closely mimic molar pregnancy based on ultrasound findings, this discussion will focus on ways to distinguish between the two. Molar pregnancy is associated with either a nonviable fetus (partial mole) or absent embryonic development (complete mole) and confers increased risk of gestational trophoblastic disease. PMD is a rare, benign vascular lesion which may be associated with a viable fetus, and accurate diagnosis can avoid pregnancy termination. Suspected PMD requires close monitoring during pregnancy due to significant maternal/fetal risks. Intrauterine growth restriction or intrauterine fetal demise each approach 50% in PMD, and additional fetal associations include visceral hamartomas, visceral cutaneous hemangiomas, and neonatal diabetes mellitus. There is also increased maternal risk of preeclampsia.
On gross examination of the placenta, PMD is characterized by placentomegaly, aneurysmally dilated and possibly thrombosed chorionic plate fetal vessels, and scattered parenchymal cysts, as seen in placenta B. Histologically, stem villi are cystically dilated with increased stromal fibrosis and variably myxoid stroma. Fetal vessels in stem villi are often abnormally large with thick, muscular walls. Features of fetal vascular malperfusion often accompany PMD, and thrombosed stem villous vessels and avascular villi were present in placenta B of this case.
Several histologic features differentiate PMD from complete or partial mole. In both PMD and partial moles, the villous population is dimorphic: hydropic stem and intermediate villi are admixed with normal-appearing terminal villi (as in placenta B). However, in partial moles, villous cytotrophoblast demonstrate abnormally increased proliferation with a scalloped pattern; these features are absent in PMD, which demonstrates normal villous cytotrophoblast proliferation. In contrast, complete moles typically show a uniform population of diffusely hydropic villi (as in twin A), and villous cytotrophoblast demonstrate circumferential proliferation and frequently atypia. Finally, identifying nucleated red blood cells implies the presence of a fetus and would therefore be present in PMD and partial moles, but these are generally absent (or rare) in complete moles.
Immunohistochemistry with p57 antibody can also help distinguish PMD from molar lesions: p57 encodes a cyclin-dependent kinase inhibitor and is maternally expressed/paternally silenced, so positive expression in villous cytotrophoblast and villous stroma indicates maternal DNA contribution. In partial moles, maternal DNA contribution results in normal p57 staining pattern (positive in extravillous trophoblast, villous cytotrophoblast, and villous stromal cells). However, due to completely paternally-derived DNA in complete moles, both villous cytotrophoblast and villous stroma are negative; however, atypical extravillous trophoblast clusters may stain. In PMD, p57 staining is variable: expression is often retained in stromal cells of normal-appearing villi and absent in stromal cells of hydropic villi, reflecting biparental/androgenetic mosaicism (see below).
PMD is a rare vascular anomaly, and less than 100 cases have been documented since it was first described in the early 1990s (estimated incidence 0.02%). Although the etiology is not fully understood, most examples described in the literature resulted from either biparental/androgenetic mosaicism, where a subpopulation of placental cells contain only paternal DNA, or gene alterations/abnormal imprinting on chromosome 11p15.5. The former mechanism may contribute to the observed 4:1 predominance of female fetuses, while the latter mechanism might explain its association with Beckwith-Wiedemann syndrome, which occurs in 25% of PMD cases. Recently, PMD cases have also been described in association with alterations on chromosome 13, including trisomy 13. Consequently, the fetus in PMD is most often diploid karotype, and microarray analysis may be required to identify specific genetic abnormalities. In contrast, partial hydatidiform moles are most often diandric triploid resulting from two sperm fertilizing a normal egg, while complete hydatidiform moles are most often androgenetic diploid resulting from one sperm fertilizing an empty egg followed by chromosome duplication.
Clinically, PMD may resemble either partial or complete mole. Ultrasound findings demonstrating a fetus alongside a thick, multi-cystic placenta most classically mimic partial molar pregnancy, which can be ruled out by karyotype, as described above. These findings could also indicate a dizygotic twin pregnancy with one complete mole and one viable fetus (complete mole with a co-twin), as in this case. Since the fetus/placenta are diploid in both scenarios, karyotype performed on amniocentesis samples will not distinguish between PMD and complete mole with a co-twin, and establishing the diagnosis in utero remains challenging. While abnormally high maternal blood beta hCG levels point toward complete mole with a co-twin, elevated hCG levels have been reported in over one third of PMD cases. A recent retrospective study showed that prenatal magnetic resonance imaging can distinguish between these, but additional studies are needed to assess both accuracy and safety of this modality during pregnancy.
In summary, PMD is a rare placental vascular lesion with complex genetic origins that should be included in the differential of multi-cystic placental lesions, but is associated with a fetus. Due to serious implications for maternal and fetal outcomes, it is critical to distinguish this entity in particular from partial and complete moles.
Contributed by Lauren Brilli Skvarca, MD, PhD, Stefan Kostadinov, MD