Diagnosis and Subclassification of Hydatidiform Moles Using p57 Immunohistochemistry and Molecular Genotyping: Validation and Prospective Analysis in Routine and Consultation Practice Settings With Development of an Algorithmic Approach

Department of Pathology, The Johns Hopkins University School of Medicine and Hospital, Baltimore, MD 21231, USA.
The American journal of surgical pathology (Impact Factor: 5.15). 02/2009; 33(6):805-17. DOI: 10.1097/PAS.0b013e318191f309
Source: PubMed


Distinction of hydatidiform moles (HM) from nonmolar specimens and subclassification of HMs as complete hydatidiform mole (CHM), partial hydatidiform mole (PHM), or early CHM (eCHM) are important for clinical practice and investigational studies but diagnosis based solely on morphology suffers from poor interobserver reproducibility. Recent studies have demonstrated the use of p57 immunostaining and molecular genotyping for improving diagnosis of HMs. After performing a validation study of both techniques on 24 archival products of conception specimens (7 CHMs, 8 PHMs, 9 nonmolar), we prospectively analyzed 42 cases, largely obtained from a gynecologic pathology consultation practice, for which there was any consideration of a diagnosis of HM. After satisfactory experience with prospective cases, a modified approach was adopted, with p57 immunostaining used in conjunction with morphology to triage cases for molecular genotyping. Final diagnoses for the prospective cases based on combined morphology and ancillary testing were 24 CHMs (including 7 eCHMs), 7 PHMs, and 11 nonmolar specimens. P57 immunostaining, performed on all 66 cases, was negative in all CHMs, with the exception of 1 case of molecularly confirmed CHM with diffuse p57 expression, and positive in all PHMs and nonmolar specimens, with the exception of 3 cases of molecularly confirmed PHMs with an equivocal extent of p57 expression. Molecular genotyping of 51 cases (24 validation, 27 prospective) yielded data consistent with p57 results in the 47 cases with unequivocal p57 expression patterns and was used to establish the diagnoses for the 4 cases with aberrant or equivocal p57 results. All 17 genotyped CHMs demonstrated androgenetic diploidy, including the CHM with retained p57 expression; this case also demonstrated trisomy of chromosome 11 (retained maternal allele), accounting for the aberrant p57 expression. The remaining 14 CHMs were diagnosed by morphology and negative p57 results alone. All 15 PHMs demonstrated diandric triploidy. All genotyped nonmolar specimens demonstrated biparental diploidy. This study validates p57 immunostaining as a prospectively applicable triage assay for the diagnosis of CHMs based on morphology and a negative p57 result. Molecular genotyping is validated as a method to confirm a diagnosis of CHM by demonstrating androgenetic diploidy and to resolve p57-positive cases into diandric triploid PHMs, biparental diploid nonmolar specimens, and the rare CHM with aberrant p57 expression.

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    • "Evidences indicated that some complementary methods to the pathologic interpretation such as genetic studies and immunohistochemistery could help us in this regard.[89] "
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    ABSTRACT: Considering the limitations of current pathologic methods in distinguishing two subtypes of hydatidiform mole and non-molar pregnancy, the utility of immunohistochemical markers in this regards and the importance of differentiating of mentioned pathologic patterns, in this study the expression of P63 in patients with complete hydatidiform mole (CHM), partial hydatidiform mole (PHM) and non-molar pregnancy was determined. In this study, formalin-fixed and paraffin-embedded tissues of 61 patients with definitive pathologic diagnosis of CHM, PHM and non-molar pregnancy retrieved. Diagnoses were based on the study of hematoxylin and eosin stained slides. Sections from all samples were stained for P63 marker using immunohistochemistry method. The nuclear immune reactivity of P63 marker in the three pathologic groups was determined by two pathologists. P63 immune-staining was used to evaluate 20, 26 and 15 non-molar pregnancy, CHM and PHM cases, respectively. Mean ± SD of P63 nuclear immune-staining in molar pregnancy (CHM and PHM) and non-molar pregnancy were 32.4 ± 17.4 and 18.9 ± 17.2, respectively (P = 0.006). The means were significantly different between non-molar pregnancy and PHM (P < 0.000), CHM and PHM (P = 0.02) and non-molar pregnancy and CHM (P = 0.04). Considering the findings of the current study, though the nuclear immunoreactivity of P63 was higher in molar than non-molar pregnancy and in PHM than CHM, but using this marker alone is not suitable as a diagnostic test due to its low sensitivity and specificity. It could be used as adjuvant test in conflict cases. It is recommended to evaluate the role of other immunohistochemical markers like Ki-67 in this regard.
    Journal of research in medical sciences 06/2013; 18(6):462-6. · 0.65 Impact Factor
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    • "Endocrine-Related Cancer (2012) 19 827–840 Maggiori & Peres 2007, Hoffner et al. 2008, LeGallo et al. 2008, McConnell et al. 2009, Kipp et al. 2010 "
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    ABSTRACT: Sialic acid immunoglobulin-like lectin (Siglec)-6 is a transmembrane receptor that binds leptin. Leptin is an obesity associated peptide hormone overexpressed in gestational trophoblastic disease (GTD). GTD encompasses several placental abnormalities that range from benign to malignant. Among GTD, molar placentas are characterized by excess proliferation, whereas gestational trophoblastic neoplasias (GTN) have characteristically aggressive invasion. We hypothesized that in GTD, Siglec-6 expression would increase with disease severity and that Siglec-6 and leptin would promote proliferation, inhibit apoptosis and/or promote invasion. Siglec-6 expression patterns were evaluated with particular attention to the diagnostic utility of Siglec-6 in GTD [controls: normal placentas (n=32), hydropic abortus placentas (n=7), non-GTD reproductive tract cancers (n=2). GTD: partial moles (n=11), complete moles (n=24), GTN (n=6)]. In normal placentas, Siglec-6 expression dramatically decreased after eight weeks gestation. Complete molar placentas had significantly higher Siglec-6 expression than controls, but expression was not significantly different from partial moles. In GTN, Siglec-6 expression was low. These data suggest that Siglec-6 may have diagnostic utility for distinguishing complete moles from normal and hydropic abortus placentas. Functional studies in choriocarcinoma derived BeWO cells demonstrated a complex interplay between Siglec-6 expression and leptin exposure. In cells lacking Siglec-6, leptin treatment promoted invasion, likely through interaction with LepR leptin receptor, without affecting proliferation or apoptosis. Siglec-6 expression promoted proliferation in a leptin-dependent manner, but protected cells from apoptosis and promoted invasion in a leptin-independent manner. We propose that Siglec-6 and leptin play a role in the aberrant properties characteristic of GTD, namely excess proliferation and invasion.
    Endocrine Related Cancer 10/2012; 19(6). DOI:10.1530/ERC-11-0379 · 4.81 Impact Factor
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    • "The genetic analysis of embryonic and molar tissue confirmed the androgenic origin of molar tissue and the biparental origin of the embryo, leading to a final diagnosis of a normal twin coexisting with CHM. Furthermore, the microsatellite genotyping analysis is useful to confirm the androgenetic origin of CHM [2] [16] [17] [19] [22] [27] [31] [32]. "
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    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
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