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Molecular Diagnosis of Hydatidiform Moles is Ready for Primetime | OMICS International
ISSN: 2161-0681
Journal of Clinical & Experimental Pathology

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Molecular Diagnosis of Hydatidiform Moles is Ready for Primetime

Pei Hui*

Associate Professor, Department of Pathology, Yale University, USA

*Corresponding Author:
Pei Hui
Department of Pathology, P.O Box 208023
310 Cedar Street BML 250, New Haven
CT 06520-8023, USA
Tel: 203-785-6498
Fax: 203-785-7146

Received Date:September 11, 2011;Accepted Date:December 30, 2011;Published Date:January 07, 2012

Citation:Hui P (2012) Molecular Diagnosis of Hydatidiform Moles is Ready for Primetime. J Clinic Experiment Pathol 2:e105. doi: 10.4172/2161-0681.1000e105

Copyright:© 2012 Hui P. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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In recent months, two specialty pathology journals chose article images of molecular diagnosis of hydatidiform mole as their front covers: the March issue of International Journal of Gynecological Pathology [1] and the July issue of Journal of Molecular Diagnostics released [2]. Such emerging interests in the molecular diagnosis of hydatidiform moles may be explained by one simple reason that is our frequent inability to accurately diagnose these common conditions by traditional histology and conventional ancillary studies.

Hydatidiform moles are generally subclassified into complete and partial moles. While histological diagnosis of well-developed complete mole is generally reliable, increasingly evacuated at a much earlier stage nowadays, an early complete mole is often mistaken as a hydropic abortus or a normal pregnancy by both clinicians and pathologists [3]. Partial moles are even more problematic with both under and over diagnosis in about 50% of the cases in the current practice [4]. Yet, it is clinically important to distinguish a hydatidiform mole from a non-molar hydropic abortus, primarily because of the associated risk of development of postmolar gestational trophoblastic neoplasia [3-6]. Accurate subclassification of hydatidiform moles is also important as a complete mole has a much higher risk of progression to gestational trophoblastic neoplasia (18 to 29%) [5] than a partial mole (1.0 to 5.6%) [5,6]. On the other hand, over-diagnosis of molar pregnancy is not without clinical consequence, as all such patients should enter the trophoblastic disease surveillance program that can be particularly burdensome and costly [5]. Thus, reliable diagnostic approaches of molar pregnancy with improved sensitivity and specificity are highly desirable.

It has been firmly established that the pathogenesis of hydatidiform moles requires specific abnormal genetic compositions present in conception. Molecular investigations in the 1970’s established the genetic bases for the development of hydatidiform moles [7]. In contrast to a normal diploid gestation of monogynic and monoandric parental complement (46, XX or XY), essentially all complete hydatidiform moles have a diandric, paternal-only genome, with either 46, XX diploid karyotype arising from the fertilization of an enucleated egg by one spermatozoon followed by duplication (monospermic or homozygous, 80%), or 46, XX or XY karyotype arising from the fertilization of an enucleated egg by two spermatozoa simultaneously (dispermic or heterozygous, 20%) [8]. A rare exception is the existence of biparental (monogynic and monoandric genome) complete mole, which is frequently recurrent with strong familiar tendency and associated with mutations of NAPL7 [9].

The genetic profile of partial hydatidiform moles is triploid with a diandric, monogynic genome arising from the fertilization of a haploid egg by either two spermatozoa (dispermic or heterozygous, 90%) or one spermatozoon with duplication (monospermic or homozygous, 10%) [8]. The resulting conception is triploid with diandric and monogynic genome, 69, XXX or XXY karyotype. It is important to note that one-third of the triploid early missed abortions are digynic and monoandric, but are not partial hydatidiform moles [4]. Therefore, at the genetic level, determination of the parental source of the haploid sets is crucial for the separation of a partial mole from a nonmolar triploid gestation.

Various genetic and molecular approaches were explored in the past to improve the diagnostic accuracy of hydatidiform moles. Flow cytometry is the most common method for ploidy analysis to separate a partial mole from a complete mole or a diploid non-molar hydropic abortus by demonstration of triploidy. Conventional karyotyping is the most accurate chromosomal enumeration method that may be used to confirm the presence of triploidy in a partial mole or diploidy in a complete mole. Interphase FISH can be used for the determination of the number of haploid chromosome sets. However, all these methods cannot distinguish a diploid complete mole from a much more common nonmolar hydropic abortus, and are unable to separate a true diandricmonogynic partial mole from a digynic-monoandric non-molar gestation. Cytogenetic studies based on analysis of pericentromeric chromosome heteromorphisms can be used to identify the parental source of chromosomes and may specifically diagnose and subtype hydatidiform moles [7,10]. However, similar to the conventional karyotyping, it requires fresh chorionic villous samples and in vitro cell culture. Polymorphic deletion probe (PDP) fluorescence insitu hybridization based on copy number variants that are highly polymorphic and has been recently applied for the diagnosis of molar gestations using paraffin embedded tissue specimens [2]. Using such PDP probes, however, the diagnostic sensitivity was quite limited: 40% of complete moles and 46.2% for partial moles [2], likely due to small number of polymorphic PDP probes available.

DNA genotyping provides the best measurement of genetic variation between members of a species and therefore, can be used to identify parental source of genomic haploid set(s) in a hydatidiform mole. Different molecular methods have been explored, including DNA restriction fragment length polymorphism; enzyme polymorphism and single nucleotide polymorphism [11]. Recently the short tandem repeat (STR) polymorphism analysis has emerged as the most sensitive and specific genotyping method for the diagnosis of hydatidiform moles [12] and its diagnostic power and clinical applicability have been confirmed by several studies [8,11,12]. A potential pitfall for the genotypic diagnosis of hydatidiform mole is the presence of a small subset of complete moles of biparental origin, which are histologically indistinguishable from the diandric uniparental complete moles and DNA genotyping is not helpful [9].

Although hydatidiform moles are evacuated at a much earlier gestational age in modern medicine, their associated risks for postmolar gestational trophoblastic neoplasia have not changed [5]. In the absence of typical clinical and imaging features, the role of a pathologist has become even more crucial. Pathologists need to have a high index of suspicion for early complete hydatidiform moles, which are easily misinterpreted as hydropic abortions or even normal pregnancies. When in doubt, ancillary studies such as p57 immunohistochemistry and STR genotyping should be used to rule out a molar gestation. Although inconclusive, recent clinical data support the notion that heterozygous (dispermic) complete moles are more aggressive than the homozygous (monospermic) ones [13]. Therefore a precise genotyping of every complete mole may be desirable. Genotyping diagnosis is highly recommended when a partial mole is suspected, as even with careful histological examination and ploidy analysis, pathologists can only reproducibly recognize up to 50% of true partial moles [4]. The money saved by avoiding imprecise DNA ploidy analysis and over-treating nonmolar patients should easily offset the cost of STR genotyping. With rapidly increasing acquirement of molecular diagnostic capabilities at most medical centers, DNA genotyping should become an integral component of the routine diagnostic workup of both complete and partial hydatidiform moles.


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