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hydatiform mole

Wednesday 28 April 2004

molar gestation; hydatiform moles

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Definition: Hydatiform mole is a gestational trophoblastic disorder.

Accurate diagnosis and classification of hydatidiform mole (HM) are important because the risk of persistent gestational trophoblastic disease, including choriocarcinoma, is significantly higher after a pregnancy affected by a complete HM (CHM) (10%-30%) or a partial HM (PHM) (0.5%-5%) as compared with any other conception.

Genetically, most CHMs are monospermic and arise by fertilization of an anucleated egg by a haploid sperm followed by endoreduplication.

Approximately 20% of CHMs are dispermic, arising by fertilization of an anucleated egg by either 2 sperms or a single diploid sperm, the result of a failure of the second meiotic division. In either case, nearly all CHMs have a diploid karyotype that is entirely of paternal (androgenetic) origin.

An exception is the rare familial case of CHM that, although diploid, is biparental, rather than androgenetic, in origin.

In contrast, cases of PARTIAL MOLE (PHM) are triploid and usually result from fertilization of an ovum by 2 sperms, although fertilization by a single diploid sperm cannot be excluded.

The diagnosis and classification of HM have long been based on well-established histologic criteria: degree of hydrops, trophoblastic hyperplasia, fiord-like versus smooth bulbous villous outlines, myxoid VS, evidence of embryonic development.

However, the routine use of ultrasound scans in early gestation has led to evacuation of most molar pregnancies in the late first trimester (8.5-12 weeks of gestation versus 16-18 weeks of gestation in the past), before the classic morphological features of CHM (cisternae and circumferential trophoblastic proliferation) are well developed.

A variety of other genetic abnormalities such as trisomy/monosomy may be associated with abnormal villous morphology with significant morphological overlap with early molar pregnancy.

Synopsis

Placenta with grossly swollen chorionic villi (hydropic villi)
bunch of grapes aspect
varying degrees of trophoblastic proliferation
absence of embryo

Types

complete hydatiform mole

A complete mole contains no fetal tissue.
Ninety percent are 46,XX, and 10% are 46,XY. All chromosomes are of paternal origin.
An enucleate egg is fertilized by a haploid sperm (which then duplicates its chromosomes), or the egg is fertilized by 2 sperm.
In a complete mole, the chorionic villi have grapelike (hydatidiform) swelling, and trophoblastic hyperplasia is present.

A rare form of recurrent complete mole is biparental in origin and results from misexpression of imprinted genes. This type of mole occurs when maternal imprints in the ovum are lost.

Although the resulting conceptus has genes from both parents, loss of maternal imprinting gives the functional equivalent of 2 paternal genomes.
Recurrent molar pregnancies of this type are familial and appear to be inherited as an autosomal recessive trait. A candidate region of chromosome arm 19q13.4 has been identified.

partial hydatiform mole

With a partial mole, fetal tissue is often present. Fetal erythrocytes and vessels in the villi are a common finding.
The chromosomal complement is 69,XXX or 69,XXY. This results from fertilization of a haploid ovum and duplication of the paternal haploid chromosomes or from dispermy.
Tetraploidy may also be encountered. As in a complete mole, hyperplastic trophoblastic tissue and swelling of the chorionic villi occur.

Cytogenetics

complete moles homozygous, XX 46 with all the chromosomes of paternal origin.

second trimester of pregnancy with abnormal uterine bleeding
excessive uterine enlargement
high serum human chorionic gonadotropin concentration
possible complication: choriocarcinoma

diandric triploid hydatidiform mole

The p57(KIP2) protein is a potent tight-binding inhibitor of several G1 cyclin/Cdk complexes, and is a negative regulator of cell proliferation.

Molecular biology

mutations in the maternal gene NALP7 in individuals with familial and recurrent hydatidiform moles (HMs)

NALP7 is a member of the CATERPILLER protein family involved in inflammation and apoptosis. NALP7 is the first maternal effect gene identified in humans and is also responsible for recurrent spontaneous abortions, stillbirths and intrauterine growth retardation.
NALPs are cytoplasmic proteins that form a subfamily within the larger CATERPILLER protein family. Most short NALPs, such as NALP7, have an N-terminal pyrin (MEFV) (MIM.608107) domain (PYD), followed by a NACHT domain, a NACHT-associated domain (NAD), and a C-terminal leucine-rich repeat (LRR) region.
NALPs are implicated in the activation of proinflammatory caspases (CASP1) (MIM.147678) via their involvement in multiprotein complexes called inflammasomes.

Immunochemistry

p57KIP2 (CDKN1C) expression in molar pregnancy

Negative p57KIP2 (CDKN1C) immunoreactivity (paternally imprinted, maternally expressed gene) is in perfect concordance with the androgenetic origin of molar pregnancies proven by DNA polymorphism. (15971478)
p57KIP2 (CDKN1C) immunoreactivity, which can be performed in routine pathologic examinations, is a diagnostic tool to differentiate androgenetic complete moles from biparental conceptuses. (15971478)

The p57KIP2 gene is paternally imprinted and is expressed from the maternal allele, and the lack of its protein product, as detected by IHC, has been documented in CHM (because CHMs lack maternal genomic DNA). In contrast, its mimics express p57KIP2, which serves as a surrogate marker for maternal DNA.

Molecular genotyping

Distinction of hydatidiform moles (HMs) from nonmolar specimens (NMs) and subclassification of HMs as complete hydatidiform moles (CHMs) and partial hydatidiform moles (PHMs) are important for clinical practice and investigational studies.

Molecular genotyping can distinguish these entities by discerning androgenetic diploidy, diandric triploidy, and biparental diploidy to diagnose CHMs, PHMs, and NMs, respectively.

Differential diagnosis

hydropic abortion

See also

gestational trophoblastic diseases

References

Diagnostic Reproducibility of Hydatidiform Moles: Ancillary Techniques (p57 Immunohistochemistry and Molecular Genotyping) Improve Morphologic Diagnosis. Vang R, Gupta M, Wu LS, Yemelyanova AV, Kurman RJ, Murphy KM, Descipio C, Ronnett BM. Am J Surg Pathol. 2012 Mar;36(3):443-53.PMID: 22245958

Diandric Triploid Hydatidiform Mole With Loss of Maternal Chromosome 11. Descipio C, Haley L, Beierl K, Pandit AP, Murphy KM, Ronnett BM. Am J Surg Pathol. 2011 Aug 29. PMID: 21881485

Popiolek DA, Yee H, Mittal K, Chiriboga L, Prinz MK, Caragine TA, Budimlija ZM. Multiplex short tandem repeat DNA analysis confirms the accuracy of p57(KIP2) immunostaining in the diagnosis of complete hydatidiform mole. Hum Pathol. 2006 Nov;37(11):1426-34. PMID: 16949913

Murdoch S, Djuric U, Mazhar B, Seoud M, Khan R, Kuick R, Bagga R, Kircheisen R, Ao A, Ratti B, Hanash S, Rouleau GA, Slim R. Mutations in NALP7 cause recurrent hydatidiform moles and reproductive wastage in humans. Nat Genet. 2006 Feb 5; PMID: 16462743

Romaguera RL, Rodriguez MM, Bruce JH, Zuluaga T, Viciana A, Penalver MA, Mehrdad N. Molar gestations and hydropic abortions differentiated by p57 immunostaining. Fetal Pediatr Pathol. 2004 Mar-Jun;23(2-3):181-90. PMID: 15768863

Jun SY, Ro JY, Kim KR. p57kip2 is useful in the classification and differential diagnosis of complete and partial hydatidiform moles. Histopathology. 2003 Jul;43(1):17-25. PMID: 12823708