Department of Gynecology and Obstetrics, University Hospitals of Geneva, Boulevard de la Cluse 30, 1211 Geneva 14, Switzerland
1 To whom correspondence should be addressed. e-mail: patrick.petignat{at}hcuge.ch
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Abstract |
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Key words: complete hydatidiform mole/gestational trophoblastic disease/partial hydatidiform mole/triploidy
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Introduction |
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Although ultrasonography and -hCG level may be useful diagnostic tools in the identification of hydatidiform mole (HM), the final diagnosis is often confirmed only upon histological review. Nevertheless, several studies have shown that even experienced pathologists may have difficulties in distinguishing this disorder and some atypical cases are not easy to classify definitively on the basis of morphologic criteria alone. For example, it has been found that the concordance rate between pathologists for the diagnosis of molar pregnancies (CHM or PHM) ranges from 5575% (Javey et al., 1979
; Driscoll, 1987
; Messerli et al., 1987
). PHM may be particularly difficult to identify because it has features in common with both normal placenta and CHM. Paradinas and co-workers analysed retrospectively 400 cases of HM initially classified as PHM. PHM was confirmed in 50% of cases, CHM in 29%, and in 21% the diagnosis of HM was excluded (Paradinas, 1998
). These misclassifications can be attributed to the absence of strict morphological criteria to differentiate the HM and because some characteristics have significant overlap. A useful complement to the pathological interpretation is to assay the ploidy of molar tissue with DNA cytometry analysis or fluorescence in-situ hybridization (FISH), but it may also be associated with a significant rate of misclassification, particularly if no fresh tissue is available and if abundant tissue of maternal origin is present (Bell et al., 1999
). Moreover, ploidy analysis cannot be used to distinguish a diploid mole from spontaneous abortion which can also exhibit hydropic changes and trophoblast hyperplasia mimicking HM.
Genetic analysis may eliminate this dilemma and the aim of this study is to review the genetic basis of HM and to discuss its relevance in the routine management of the disorder.
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Complete hydatidiform mole (CHM) |
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Contribution of genetic studies and perspectives
CHM may be either monospermic if it arises from the doubling of a haploid sperm (homozygous moles), or dispermic if it arises from two haploid sperm (heterozygous moles) (Figure 3) (Ohama et al., 1981). Homozygous and heterozygous CHM are two genetically distinct entities which can only be distinguished on the basis of genetic analysis. Studies have suggested that heterozygous mole may have a more malignant potential than its homozygous counterpart. Wake et al. found that three of five patients with heterozygous moles had required treatment for post-molar trophoblastic tumour, compared with only one out of 21 patients with homozygous moles (Wake et al., 1984
). However, these results have not been confirmed by other investigators who found no significant different risk between both groups (Lawler et al., 1982a
; Kajii et al., 1984
; Lawler and Fisher 1987
; Lawler et al., 1991
; Mutter et al., 1993
). However, it should be mentioned that the number of published cases is small and additional studies are required to determine conclusively whether the heterozygous form is potentially more aggressive. If one form has really a higher malignant potential, it will be important to distinguish between both forms so that the relative risk can be assessed.
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Partial hydatidiform mole (PHM) |
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Origin and genetic constitution of PHM
Partial moles are generally triploid gestations in which the extra chromosomal load is of paternal or maternal origin; the karyotype is 69,XXY, 69,XXX, or rarely 69,XYY (Jacobs et al., 1982; McFadden and Kalousek, 1991
; McFadden et al., 1993
). Triploid PHM may either arise through fertilization of a haploid oocyte by one spermatozoon which doubles its chromosomes after fertilization, or two sperm (one maternal and two paternal contributions), or through the fertilization of a diploid oocyte by one spermatozoon (two maternal and one paternal contribution) (Figure 4) (Lawler et al., 1982b
; Jacobs et al., 1982
). A diploid oocyte originates from failure of meiosis I or II. Another mechanism at the origin of diploid oocyte involves the fusion of two ova (dieggy) (Zaragoza et al., 2000
)
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Contribution of genetic studies and perspectives
Studies of the genetic origins of triploid PHM have demonstrated that fetal and placental phenotypes of triploid pregnancies correlate with parental origin and permit the definition of two types (Jacobs et al. 1982; McFadden and Kalousek 1991
; McFadden et al. 1993
; Zaragoza et al., 2000
).
Type I triploid fetus or paternally-derived or diandric triploidy
The fetus is of normal size for gestational age and the placenta is abnormally large and cystic (Figure 4). In most cases, the fetus dies a few weeks after conception and, to our knowledge, no fetus of paternal origin has survived until term.
Type II triploid fetus or maternally-derived or digynic triploidy
The fetus is growth-retarded and the placenta is abnormally small without cystic formation (Figure 4). Some cases of triploid fetuses of maternal origin have been previously described as born alive with a survival of a few months (Fryns et al., 1977).
Currently, it is unclear if type I (diandric) and type II (digynic) triploidies have different malignant potential and if the distinction will have a direct impact on the management and counselling of patients. However, it appears that PHM type I is more aggressive than type II. Seckl et al. (2000) studied 3000 patients with PHM, three of whom developed a choriocarcinoma; genetic analysis showed that all three were PHM type I.
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Unusual cases |
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CHM with biparental contribution
Several investigators have reported cases of CHM with genetic markers consistent with a normal conception. The constitution has both a paternal and maternal contribution to the genome, but are pathologically identical as classical androgenetic CHM (Jacobs et al., 1980; Davis et al., 1984
; Kovacs et al., 1991
; Fisher et al., 1997
; Moglabey et al., 1999
; Fisher et al., 2000
). Such cases suggest that there may be more than two subgroups of CHM and other mechanisms could be involved that cause molar placental changes. Recently Fisher and colleagues have studied an HM of biparental origin (by comparing microsatellites polymorphism) and found no evidence of chromosomal uniparental disomy, suggesting that HM in these cases may results from uniparental disomy of only a small region of the paternal genome (Fisher et al., 2000
). Cases with biparental origin could be a valuable tool in identifying the imprinted gene involved in molar development.
HM with unusual ploidy
Although the majority of PHM are triploid, uncommon DNA content such as haploid, diploid, tetraploid and mosaicism PHM have been reported (Vejerslev et al., 1987; Lage et al., 1992
). Cases of triploid, tetraploid and mosaicism CHM have been reported also. These unusual ploidies associated with both partial and CHM render their differentiation and classification exceptionally difficult. However, the most important factor appears to be the ratio of paternal and maternal chromosomes and not the ploidy of the tissue (Vejerslev et al., 1987
). For example, tetraploidy without maternal genome has the pathologic features of CHM and if maternal genome is present, the histopathology resembles a PHM. The implications of this rare condition in terms of malignancy are still unknown, but it seems that the degree of molar change correlates with both the proportion of paternal contribution and the risk of PTT.
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Discussion |
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Alternative approaches have been developed to provide more objective diagnostic criteria to distinguish different forms of trophoblastic disease. An adjunct to histological diagnosis may be to determine the cell ploidy by means of flow cytometry or fluorescent in-situ hybridization (FISH). The combination of morphology and DNA content may be a useful aid in the differential diagnosis of molar pregnancy and improve the pathologists concordance (Conran et al., 1993). However, cytometry or FISH results will not aid distinction of CHM from non-molar gestation given that there is a significant overlap in the histologic and ploidy characteristics between these two entities (Bell et al., 1999
). Recently, an immuno-histopathological staining technique using p57kip2 expression analysis has been reported as a good diagnostic adjunct complementary to histology and ploidy analysis to distinguish CHM from other types of conceptuses. This method could be easier to perform and interpret than genetic analysis in a pathology setting; however additional studies are required to determine the specificity and sensitivity of the technique (Zaragoza et al. 2000
).
In the past, the laborious cytogenetic preparation of cell cultures and the potential misinterpretation on analysis of size and staining variants have precluded routine genetic studies. Currently, new molecular biology tools have made feasible the analysis of both molar and parental DNA on a routine basis. Such examinations may be performed, for example, by PCR amplification of several microsatellites markers of DNA and by comparing the sequences in the molar tissue and in genitors. In Figure 3, the analysis of the alleles (electrophoretic band) of each DNA indicates that the genetic content of the mole is of monospermic origin. This analysis is however semi-quantitative and does not inform about the ploidy of the molar tissue. This information can be determined by (FISH) using chromosome-specific DNA probes (Figure 5). Both methods are rapid and less costly than cell culture, can be assessed on either fresh tissues or paraffin-embedded specimens, thus providing accurate information on the genetic constitution of the conceptus. By combining histopathology, FISH and DNA analysis of the microsatellites, it is possible to distinguish CHM from PHM, or banal hydropic abortion from an HM.
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Acknowledgements |
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