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Follow-up:
Follow up with the neonatologist revealed that the newborn was markedly anemic, coagulopathic, and had severe respiratory insufficiency. Flow cytometric evaluation for the presence of fetal hemoglobin in the mother's blood revealed levels indicative of a massive fetomaternal hemorrhage of 40.5 mL. The infant died at approximately 8 h of age despite aggressive medical efforts including transfusions, fluid and pressor support, and oscillatory ventilator therapy. A complete postmortem examination was performed that revealed anasarca (12-14 mL pleural effusions, 4 mL of pericardial effusion, and 30 mL of blood tinged ascites with nearly 380 g increase over birth weight); congestive biventricular cardiac dilatation; marked increase in extramedullary erythropoiesis in the liver (with dyserythropoeisis); abnormally increased levels of extramedullary erthropoiesis in the spleen and visceral interstitia; and right frontoparietal leukomalacia. The infant was structurally normal, and no hepatic or pulmonic lesions (i.e., mesenchymal hamartomas) were found. Results of postmortem microbiologic blood and lung cultures were negative.
Differential Diagnosis:
Clinical diagnoses: partial hydatidiform mole, dichorionic twins with a normal fetus and complete mole, multiple choriangiomas, multiple Breus' mole (subchorionic thrombohematomas); Beckwith-Wiedemann Syndrome (BWS)

Pathologic differential: Partial mole, BWS, chorangiomatosis, chorangiosis, mesenchymal dysplasia, hydrops secondary to chronic fetal-maternal hemorrhage.

Final Diagnosis
Gross and histomorphologic features of placental mesenchymal dysplasia (PMD). (See Discussion)

Case Discussion
This case demonstrates the gross and histomorphologic features of placental mesenchymal dysplasia (PMD), and enables discussion of the applications of immunoperoxidase stains to detect p57^kip2 expression and molecular genetic methodologies employed to verify the anatomic diagnosis of this entity. As will be discussed, positive results with these ancillary tests are considered confirmatory, if not diagnostic, of PMD. However, there are challenging cases for which characteristic structural gross and histomorphology of PMD are present, but for which these tests yield inconclusive or negative results. The actual index case, upon which this unknown was originally based, was one such example. The classification of such atypical cases is problematic. In order to provide a broad representation of the "classic findings" of PMD, I have drawn upon the images contributed by several esteemed colleagues. Thus, I am indebted to my colleagues for their generous provision of case materials.

PMD is a rare placental anomaly (0.02% estimated incidence) [1] of incompletely understood etiopathogenesis. It has also been referred to as "pseudo-partial" or "partly-partial" mole. [2, 3, 4, 5] Roughly 90 cases have been described, [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36] since the initial reports of this entity published in the early 1990's. [6, 7, 8, 9] Because of its rarity, its true incidence is unknown, but it shows a strong female preponderance of 3.6-4:1. [5, 19] PMD is characterized by placentomegaly, cirsoid vessels of the chorionic plate and stem villi, and parenchymal grape-like villous vesicles, similar to those seen in molar gestations. The fetus, however, is structurally normal. Clinically, antenatal ultrasonography reveals an enlarged and thickened placenta with hyperechoic (cystic) areas that are concentrated within the zone underlying the fetal surface. These ultrasonographic features are detectable at the beginning of the second trimester (13 weeks of gestation), [31] but detection of cyst formation has been seen as early as 8 weeks. [1] The chorionic vascular dilatations and cysts progressively enlarge and become more numerous and/or complex as gestation proceeds. [1, 10] The pathologic correlates of these ultrasonographic changes are evident when mid-gestational placentas with PMD are compared to those of mid-third trimester PMD placentas. Grossly, chorionic and subchorionic, ropey, tangled, aneursymal vessels and microscopic "clusterings" of affected villi are more evident in placentas with this entity, from more advanced gestations. These findings are suggestive evidence that the vascular malformations undergo progressive dysplasia/hyperplasia that results in redundancy, ectasia, and vascular luminal pressure changes and/or hypoxia. These complications, especially hypoxia, likely contribute to the co-existent development of sites of chorangiosis, chorangioma formation, and chorangiomatosis seen in some cases of PMD. [19, 22]

Ultrasonographic differential diagnosis:
The clinical ultrasonographic differential diagnosis of PMD includes partial hydatidiform mole; dichorionic twinning resulting in a normal fetus and complete mole; multiple choriangiomas; Beckwith-Wiedemann Syndrome (BWS); and, in this discussant's experience, multiple subchorionic thrombohematomas. Elevations in maternal serum alpha-fetoprotein (AFP) levels are common and progressive, if not characteristic, [1] and probably due to leakage/increased transfer of AFP across malformed vessels, [8, 18] and/or hydropic stroma (i.e., Fig.5, 9). Heazell and colleagues [31] also found that PMD was associated with abnormal development of lymphatic structures in the villi. However, in contrast to molar pregnancies, maternal serum ßhCG levels are normal to slightly increased, [2] likely reflecting the histologic absence of trophoblastic proliferation in PMD. Other common gestational complications include hypertensive disorders of pregnancy and polyhydramnios. [5]

Pathological differential diagnosis:
1. Partial hydaditiform mole, especially since partial moles can occasionally exhibit dilated vessels. However, PMD does not show trophoblastic proliferation or pseudoinclusions, and its numerous and thick-walled vascular outlines are peripherally concentrated beneath the trophoblast. In addition, partial moles are triploid, whereas PMD is diploid.
2. Complete hydatidiform mole is also diploid, but the presence of stromal vessels and the lack of trophoblastic proliferation distinguish PMD from complete mole.
3. Chorangiomas [5, 37, 38] are hamartomatous masses that typically arise from stem villi close to the fetal surface, are peripheral in location, frequently bulge from the fetal surface, and, upon close inspection, prominent "feeder vessels" that supply the mass may be seen. However, in contrast to PMD, chorangiomas exhibit a grossly detectable, well-circumscribed, spheroid configuration of tissue rather than aneurysmally dilated, convoluted vessels. Microscopically, a chorangioma consists of a bulbous mass of numerous small capillaries embedded in scant connective tissue that is covered by trophoblast; it appearance is compatible with a centrally expanded, hemangiomatous stem villus. While cellular and myxoid variants exist and degenerative changes (thrombosis, infarction, hemorrhage, and calcification) are common, chorangiomas do not demonstrate the spectrum or location of dysplastic vessels seen in PMD.
4. Chorangiosis, unlike PMD, is a capillary lesion of terminal, and not stem villi, [5, 37, 39].
5. Diffuse, multifocal chorangiomatosis, the type of chorangiomatosis (versus localized focal and segmental forms) more likely to be confused with PMD, does not affect umbilical cord or chorionic plate vessels, or produce cirsoid, cavernous vessels in the plate, and ectatic vessels in primary stem villi. Multifocal chorangiomatosis is a villous capillary lesion that affects immature more distal branch stem or immature intermediate villi, and the vessels in chorangiomatosis are small, numerous, typically do not have thickened walls, are surrounded by exhibit alpha-smooth muscle actin positive pericytes, and are distributed in a dense reticulin fiber rich stroma. [37, 40] However, as noted above, because hypoxic stimulus may lead to the development of chorangiosis, chorangioma, and/or chorangiomatosis, these other villous capillary lesions may co-exist in some cases of PMD. This somewhat challenging reality means that it is important to recognize or exclude the primary presence of PMD.
6. Fetoplacental hydrops, secondary to chronic fetal-maternal hemorrhage, shows generalized villous edema, with orthochromic normoblastemia (excessive numbers of nucleated fetal erythrocytes (NRBCs) with small, perfectly round, dense, "ink dot" nuclei in a rim of brightly eosinophilic cytoplasm) or frank erythroblastosis (circulating, more immature fetal NRBC precursors with a larger nucleocytoplasmic ratio, and more basophilic cytoplasm.) Immature intermediate and distal villi are affected, while the mature stem and intermediate villi are relatively spared, due to their collagenous stroma. Cistern formations and the thick walled, numerous and ectatic anomalous vessels of PMD are absent. FMH also can be detected clinically, by analysis of maternal blood by Kleihauer-Betke or flow cytometric methologies, In my experience careful examination may also reveal numerous NRBCs in the maternal space whose fetal origin can be confirmed by immunohistochemical stains for fetal hemoglobin However, as was seen in the index case, FMH may complicate some cases of PMD. [33]

Etiology:
The etiology of PMD is incompletely understood, but there is mounting evidence that it is due to placental villous androgenetic/biparental mosaicism and resulting allelic imbalance of imprinted genes (parent-of-origin dependent expression of developmentally important genes) in the chorionic mesoderm of the membranes and villous stroma, and in rare cases, the amnion. PMD generally displays overgrowth of all components of the mesenchyme, but with a predominance of vascular overgrowth (proliferation, redundancy, and ectasia.) In the cases studied, the allelic imbalance has essentially been limited to the chorionic mesoderm, and not identified in the trophoblast. However, Kaiser-Rogers, et al. [16] studied term placentas and could not exclude the possibility that androgenetic cells might have contributed to early undifferentiated cytotophoblastic differentiation but, due to limited ability to differentiate and persist to term, were undetectable.

As noted above, PMD is characterized by a diploid DNA content, but sophisticated molecular genetic techniques [tissue digestion, PCR amplification and quantification of single nucleotide polymorphisms (SNPNs) or polymorphic short tandem repeats (STRs), comparative genomic hybridization (CGH), polymorphic deletion probe (PDP) fluorescence in situ hybridization (FISH) probes, and various array analyses] [3, 4, 15, 16, 21, 24, 41, 42, 43, 44] have revealed that villous stromal cells are derived from paternal DNA (i.e., pangenomic paternal uniparental disomy or androgenetic disomy.) They have also shown that PMD epithelial trophoblasts are derived from diploid cells bearing one maternal and one paternal chromosome complement (biparental diploidy.) Evidence of this segregation has been demonstrated by use of immunoperoxidase stains for the paternally imprinted (methylated and silenced) gene p57^KIP2 on 11p15, which encodes a cyclin-dependent kinase inhibitor and which is expressed from the maternal genome. [45] (Fig 10.) The typical case of PMD shows foci with positive linear staining of the villous surface trophoblast (presence of the product of the maternally derived active allele) but absence of nuclear staining in the stroma, indicating androgenetic allelic imbalance in villi with the morphology of PMD, but not in the normal appearing villi. However, it is important to emphasize that the molecular and immunohistochemical changes in the stroma are mosaic, and sampling is a potential issue. Immunohistochemical staining for p57, while an indirect assessment of androgenetic/biparental mosaicism, has not, thus far, exhibited a patchy staining pattern of the trophoblast in immature placentas, diagnosed as PMD.

The mechanisms by which this rare anomalous condition of PMD and androgenetic/biparental mosaicism arise have been investigated, [3, 4, 14, 20, 23, 25, 42, 43] and, to date, evidence indicates that it results from two possible pathways. In one, fertilization is normal, but the subsequent mitoses are abnormal, and, in the second, a single ovum is fertilized by two haploid sperm. [16, 21]

In the first proposed mechanism, normal fertilization between an ovum and a sperm occurs, but, instead of the normal process of pronuclear fusion of the paternally and maternally derived genome occurring with generation of a normal diploid zygote, the paternally derived pronuclear genome, but not the maternally derived pronucleus, undergoes a mitotic division. The daughter cells resulting from this event would,therefore, be different: one would contain a normal diploid complement, and one, only the paternally derived haploid genome. The abnormal paternal haploid complement would undergo endoreplication, and achieve a diploid complement, but one that is completely androgenetic and isodisomic. [16] In the second scenario, a single ovum is fertilized by two sperm (dispermy) and a tri-pronuclear zygote is formed (i.e., diandric triploidy). In this case, daughter cells would contain one normal maternally derived (M) haploid genome and one of the paternally derived (P) genomic haploid complements (P1 or P2). The result combinations could include a mixed and potentially unevenly apportioned populations of MP1 and MP2 cells and androgenetic disomic P1P2 or homozygotic P1P1 or P2P2 cell lines. MP1/P1P2 and MP1/P2P2 mosaic placentas have been identified by Robinson, et al. [21]

The above models are consistent with the high female preponderance in cases of PMD; 46,YY cell lines would be generated, but they would not be viable. To date, and for reasons that are unclear, it appears that, in cases of PMD, there is preferential allocation of the normal diploid cells to the trophoblastic epithelium, and the abnormal androgenetic cells to the extraembryonic destined to form the placental chorion. [16] These studies also offer an explanation for the excessive stromal growth in PMD; insulin-like growth factor-2 whose gene is maternally imprinted, is over-expressed in the androgenetic cells.

PMD and BWS:
As a correlative note, about one-fourth to one-third of cases of PMD have been associated with fetuses exhibiting composite or select features of BWS [16] (macrosomia, omphalocele, macroglossia, renal anomalies). [2, 6, 10, 12]. The genetic locus for BWS is on 11p15.5 [46] and the mosaic loss of 11p15.5 gene imprinting has lead to PMD, [24] in some instances, since it includes the locus for IGF-2 (maternally imprinted) and p57 (paternally imprinted.) PMD has also been reported in cases of confined placental mosaicism for trisomy 13 [28] and this observation further suggests that PMD represents an allelic imbalance of imprinting, possibly involving genetic loci on chromosome 13.

PMD is also associated with the presence of infant mesenchymal hamartomas of the liver, [5, 11, 23, 26, 32, 35] hamartomas of the lung, [32] and hemangiomas of liver and/or skin. [21, 47] Recent studies have indicated PMD-associated [23, 26, 35] and sporadic, [47] hepatic mesenchymal hamartomas both exhibit androgenetic/biparental mosaicism. These observations further confirm those made by Robinson, et al. [21] that androgenetic/biparental mosaicism is not limited to the extraembryonic mesenchyme. While, theoretically, the short umbilical stalk of early embryogenesis might provide a migratory access for the extraembryonic cells, investigators favor that the fetal liver itself may have two embryo-derived cell populations of androgenetic/biparental mosaicism. [21, 26, 47]

While BWS is common with PMD, and placentomegaly characteristic, PMD is, also strongly associated with f etal intrauterine growth restriction (IUGR); IUGR complicates 50% of gestations with PMD, not associated with BWS. This seeming paradox again appears to reflect androgenetic/biparental mosaicism that is confined to the placenta, or of such limited distribution in the fetus that infants are remain structurally unaffected and free of hamartomatous growths. The work by Robinson, et al [21] indicates that there are many possibilities for the make-up of the abnormal cell lines, and those with androgenetic isodisomy (P1P1 or P2P2) may have worse outcomes than those with androgenetic heterodisomy (P1P2) or some other imbalance of imprinting that is more limited to a single chromosome (i.e., Chr 11 or Trisomy 13.) [28] (It remains to be seen if Chr 7, Chr 15, or other chromosomes with imprinted loci might result in a rare instances of PMD.) The development of IUGR versus macrosomia may also reflect the percentage and distribution of the abnormal villi with androgenetic/biparental stromal mosaicism, since higher levels would presumably result in greater reduction in villous functional exchange and nutritional capacities due to the primary abnormalities of the villous vasculature and stroma, and/or the sequelae of FTV and hypoxia. Excessive cord coiling and cord length have also been seen with PMD. [5] Not surprisingly, intrauterine fetal demise (IUFD) is another common complication with PMD (43%, in cases without BWS) and its increased risks of perinatal mortality may be due to fetomaternal hemorrhage and/or fetal/neonatal coagulopathy [33] as were seen in this case.

Summary
In summary, PMD is a rare, incompletely understood, placental vascular lesion producing placentomegaly that is associated with BWS, IUGR, feto/neonatal visceral hamartomas and visceral cutaneous hemangiomas, and high risks of perinatal morbidity and mortality. Demonstration of androgenetic/biparental mosaicism is held by some to be the requirement for the diagnosis of PMD. Immunostaining with p57 offers a means of confirmation, but in the absence of a discrete staining pattern, molecular genetic studies (quantitative STR, etc.) offer more sensitive methods to detect the presence of allelic imbalance. However, those cases with typical gross and microscopic features but negative results with these additional studies may represent "atypical PMD." Elucidation of the etiology of the "pseudo-molar" morphology of PMD requires further investigation. Future investigations may disclose that these atypical cases have surprising genetic aberrations, such as a uniformly biparental cell make up, but with global imprinting defects in a subset of cells. [21] Indeed, an early case of clinically suspected and gross and microscopic PMD, reported by Makrydimas, et al. [44] had androgenetic biparental mosaicism, but trophoblastic hyperplasia, and the diagnosis of PMD was deemed unsubstantiated. However, since rare cases of complete mole have shown a biparental origin [48, 49] or presence of select maternal chromosomes, [50] and some partial mole have shown loss of select maternal chromosome, [51] PMD may prove to have heterogeneous etiologies, with androgenetic/biparental mosaicism being the most common. Of note, persistent gestational trophoblastic disease has been found with placental and fetal androgenetic/biparental mosaicism. [20] Thus, investigation of PMD provides numerous insights into the role of androgenetic biparental mosaicism in fetoplacental maldevelopment, isolated visceral maldevelopment, and adverse pregnancy outcomes.

The original case, upon which this presentation was based, appears to represent an "atypical" example of PMD. It had clear gross and morphologic features of PMD, per consultation with several pathologists (L.M. Ernst, M.D.; A. Hereema-McKenney, M.D.; R.N. Baergen MD; and R.P, Kapur M.D., Ph.D.), but neither p57 nor molecular genetic analysis with quantitative STR revealed androgenetic/biparental mosaicism. Future studies, of this and other cases like it, may disclose another genetic abnormality(s) or result in a revision of the current concepts concerning PMD.

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