Distinction of hydatidiform moles from nonmolar specimens and their subclassification as complete hydatidiform mole (CHM) versus partial hydatidiform mole (PHM) are important for clinical practice and investigational studies to refine ascertainment of risk of persistent gestational trophoblastic disease which differs among these entities. Immunohistochemical analysis of p57 expression, a paternally imprinted maternally expressed gene on 11p15.5, and molecular genotyping are useful for improving diagnosis. CHMs are characterized by androgenetic diploidy, with the loss of p57 expression owing to lack of maternal DNA. Loss of p57 expression distinguishes CHMs from both PHMs (diandric triploidy) and nonmolar specimens (biparental diploidy) which retain expression. In the process of evaluating molar specimens in our laboratory with p57 immunohistochemistry and molecular genotyping, we identified a morphologically typical androgenetic diploid CHM with aberrant diffuse p57 expression. Molecular genotyping by short tandem repeat markers and genome-wide copy number analysis by single nucleotide polymorphism array established androgenetic diploidy with retained maternal copies of chromosomes 6 and 11, with aberrant p57 expression attributable to the latter. This case, only the second reported to date, illustrates the value of combined traditional pathologic and ancillary molecular techniques for refined diagnosis of molar specimens. Specimens with morphologic features suggestive of CHM yet retaining p57 expression should be subjected to molecular genotyping to establish a definitive diagnosis because misclassification as PHM underestimates the risk of persistent gestational trophoblastic disease. We recommend use of p57 immunohistochemistry and molecular genotyping to evaluate all products of conception specimens for which there is any consideration of a diagnosis of hydatidiform mole. Genome-wide analysis has the potential to assist in localizing imprinted genes critical for determining the morphologic and behavioral phenotypes of hydatidiform moles.
"Likewise, it appears unlikely that a major gene causing the phenotype CHM is located on the telomeric part of chromosome 2, or on chromosome 6. However, for chromosome 11 the conclusion is less clear: In two cases the phenotype CHM has been observed in moles that were diploid androgenetic except for chromosome 11, where the moles had a surplus of maternal chromosome (Fisher et al., 2004; McConnell et al., 2009). On the other hand DeScipio et al. reported the phenotype CHM in a triploid diandric mole that was disomic for paternal chromosome 11 (DeScipio et al., 2011). "
[Show abstract][Hide abstract] ABSTRACT: Hydatidiform mole is an abnormal human pregnancy, characterised by absent or abnormal embryonic differentiation, vesicular chorionic villi and trophoblastic hyperplasia. Although the mole phenotype has hereto not been correlated to mutations in the molar genome, the aetiology for hydatidiform moles clearly is genetic: Most molar genomes analysed either have had a relative excess of paternal genome sets relative to maternal genome sets, or a global error in maternally imprinted genes, giving them a "paternal pattern". However it remains yet to be specified which gene(s) in the molar genome actually causes the molar phenotype when present in a state of "paternal excess" or "maternal deficiency".
A molar pregnancy in a woman with a balanced translocation (t(2;5) was subjected to histopathological evaluation and genetic analyses of ploidy and parental origin of the genome.
Morphology: Partial hydatidiform mole. Karyotyping of metaphase chromosomes: 69,XXY,der(5)t(2;5)(q23;q33)mat. SNP array analysis mapped the breakpoints to 2q31.2 (genome position 179Mb) and 5q34 (genome position 165Mb). DNA microsatellite marker analysis showed that for the regions not involved in the translocation, the conceptus had two paternal and one maternal allele(s). Telomeric to the breakpoint on chromosome 2, the mole had two paternal and two maternal alleles and telomeric to the breakpoint on chromosome 5 the mole had paternal alleles, exclusively.
If the molar phenotype is caused by paternal excess of one gene, only, it is unlikely that this gene is located telomeric to genome position 179Mb on chromosome 2. And similarly, if the phenotype complete mole is caused by the presence of exclusively paternally imprinted alleles of one gene, this gene is not located telomeric to genome position 165Mb on chromosome 5.
"Only two cases of CHM showing bright and contiguous positive p57 KIP2 staining have been recently reported  . After exhaustive molecular genetic analysis, this false positive staining was attributed to retention of maternal chromosome 11, a phenomenon rarely seen in CHM  . Our case showed similar bright staining in a pattern similar to HA or PHM. "
[Show abstract][Hide abstract] ABSTRACT: Classification of molar gestations into complete hydatidiform mole (CHM) and partial hydatidiform mole (PHM) and their differentiation from nonmolar hydropic abortions (HA) are traditionally accomplished by morphology alone. Sometimes, the process may be inaccurate or inconclusive especially in early diagnosed cases. With the availability of p57(KIP2) immunostaining (the product of a strongly paternally imprinted and maternally expressed gene), it may be possible to classify these lesions objectively. P57(KIP2) immunostaining is absent in CHM because it lacks a maternal genome, whereas PHM and HA show positive staining. The aims of this study were to evaluate the results of routine histopathological examination and p57(KIP2) immunoreactivity in a large series of molar and nonmolar HA in Tunisia, and to compare the accuracy of p57(KIP2) immunohistochemistry with that of nuclear DNA microsatellite polymorphism in identifying CHM. The immunohistochemical expression of p57(KIP2) protein was investigated in 220 specimens of first trimester hydropic abortuses, and it was compared with the original diagnosis based on morphology, including 132 CHM, 49 PHM, and 39 HA. Concordant results were obtained in 210 cases. In 9 of 10 cases with a discordant diagnosis (negative immunostaining in 8 cases morphologically diagnosed as PHM and one case diagnosed as HA), microsatellite DNA genotyping analysis agreed with the results of p57(KIP2) staining, confirming the diagnosis of CHM in these cases. Twenty cases of CHM with negative p57(KIP2) immunostaining were also analyzed by genotyping and indicated the absence of maternal contribution and the homozygosity for a single paternal allele in concordance with the androgenetic and monospermic origin of CHM in these cases. We confirm that for distinguishing CHM from its mimics, p57(KIP2) immunohistochemistry can be used as successfully as DNA microsatellite genotyping. However, molecular techniques are still required for the evaluation of some difficult cases with discordant positive p57(KIP2) staining.
Pathology - Research and Practice 08/2011; 207(8):498-504. DOI:10.1016/j.prp.2011.06.004 · 1.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Distinction of hydatidiform moles from non-molar (NM) specimens, as well as their subclassification as complete (CHM) versus partial hydatidiform moles (PHM), is important for clinical management and accurate risk assessment for persistent gestational trophoblastic disease. Because diagnosis of hydatidiform moles based solely on morphology suffers from poor interobserver reproducibility, a variety of ancillary techniques have been developed to improve diagnosis. Immunohistochemical assessment of the paternally imprinted, maternally expressed p57 gene can identify CHMs (androgenetic diploidy) by their lack of p57 expression, but cannot distinguish PHMs (diandric monogynic triploidy) from NMs (biparental diploidy). Short tandem repeat genotyping can identify the parental source of polymorphic alleles and thus discern androgenetic diploidy, diandric triploidy, and biparental diploidy, which allows for specific diagnosis of CHMs, PHMs, and NMs, respectively. In this study, a retrospectively collected set of morphologically typical CHMs (n = 8), PHMs (n = 10), and NMs (n = 12) was subjected to an analytic validation study of both short tandem repeat genotyping and p57 immunohistochemistry. Several technical and biological problems resulted in data that were difficult to interpret. To avoid these pitfalls, we have developed an algorithm with quantitative guidelines for the interpretation of short tandem repeat genotyping data.
The Journal of molecular diagnostics: JMD 10/2009; 11(6):598-605. DOI:10.2353/jmoldx.2009.090039 · 4.85 Impact Factor
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