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ABSTRACT

Molar pregnancy is characterized histologically by abnormalities of the chorionic villi that consist of trophoblastic proliferation and edema of vilious stroma. Altough moles usually occupy the uterine cavity, occasionally they develop as ectopic pregnancies. The degree of tissue and absence or presence of a fetus or embryonic elements is used to describe them as a complete or partial. Hydatidiform moles are common among women under 17 or over 35. In United States, they occur in about 1 in 2000 pregnancies in the United States. For unknown reasons, moles are almost 10 times more common in Asia country.

Keywords: complete hydatidiform mole, partial hydatidiform mole, extreme marital age and hydatidiform mole

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INTRODUCTION

Gestational trophoblastic disease encompasses several disease processes that originate in the placenta. These include complete and partial moles, placental site trophoblastic tumors, choriocarcinomas, and invasive moles. Almost all women with malignant gestational trophoblastic disease can be cured with preservation of reproductive function.

This retrospective research was conducted in the Department of Obstetrics and Gynaecology of the Dr. Cipto Mangunkusumo Hospital, Jakarta, covering the period between 1977 and 1981. The incidence of hydatidiform mole was 1 in 77 pregnancies. The incidence of malignant trophoblastic disease was 1 in 185 pregnancies. Of the 406 cases of hydatidiform mole, 22.9% became malignant. Patients of 24 years of age or younger had a higher risk of getting hydatidiform mole (P less than 0.05) compared to older patients. The risk of becoming malignant increased with age and became evident after 40 years of age. Parity 1 or less was associated with a higher risk of getting hydatidiform mole (P less than 0.05), but had no influence on hydatidiform mole becoming malignant. The influence of blood group was not so clear, although there was a tendency for moles to occur more frequently in patients with blood groups A or B. By contrast, there was a tendency for the change into malignancy to occur more frequently in women with blood groups B or O. Gestational age had no influence towards the change into malignancy or metastasis. Uterine size (greater than 20 weeks gestation) correlated with the progression of hydatidiform mole into malignancy. However, subsequent metastasis was not influenced by the size of the uterus. It was found that 76.4% of malignant trophoblastic diseases originated from hydatidiform moles, 12.4% from abortions, 9.5% from normal deliveries, and 1.2% from ectopic pregnancies. Non-hydatidiform moles had a slightly greater risk for metastasis, although this was not significant. Hydatidiform mole in histologic stages II or III (Hertig- Mansell classification) had a significantly greater tendency (P less than 0.05) to become malignant than in stage I. In United States by studying elective pregnancy terminations, hydatidiform moles were determined to occur in approximately 1 in 1200 pregnancies.

The reported frequency of hydatidiform mole varies greatly. Some of this variability can be explained by differences in methodology (eg, single hospital vs population studies, identification of cases). The reported frequencies range from 1 in 100 pregnancies in Indonesia to 1 in 200 pregnancies in Mexico to 1 in 5000 pregnancies in Paraguay. The study of pathologic material from first- and second-trimester abortions established a frequency of

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complete and partial hydatidiform moles in Ireland of 1 per 1945 pregnancies and 1 per 695 pregnancies, respectively.

Maternal age at either extreme of the reproductive spectrum is a risk factor for molar pregnancy. Specifically, adolescents and women aged 36 to 40 years have twofold risk and those over 40 years have an almost tenfold risk. Hydatidiform moles are most common among women under 17 or over 35. In the United States, they occur in about 1 in 2000 pregnancies. For unknown reasons, moles are almost 10 times more common in Asian countries.

DISCUSSION

A hydatidiform mole is growth of an abnormal fertilized egg or an overgrowth of tissue from the placenta. The placenta normally feeds a fetus during pregnancy. In this condition, the tissues develop into an abnormal growth, called a mass. Most often, a hydatidiform mole is an abnormal fertilized egg that develops into a hydatidiform mole rather than a fetus (a condition called molar pregnancy).

However, a hydatidiform mole can develop from cells that remain in the uterus after a miscarriage or a full-term pregnancy. Rarely, a hydatidiform mole develops when there is a living fetus. In such cases, the fetus typically dies, and a miscarriage often occurs. About 80% of hydatidiform moles are not cancerous. About 15 to 20% invade the surrounding tissue and tend to persist. About 2 to 3% become cancerous and spread throughout the body; they are then called choriocarcinomas. Choriocarcinomas can spread quickly through the lymphatic vessels or bloodstream. Hydatidiform moles and choriocarcinomas are types of gestational trophoblastic disease. The following discussion is limited to hydatidiform moles

complete and partial hydatidiform moles in Ireland of 1 per 1945 pregnancies and 1 per 695

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(complete and partial). A partial molar pregnancy means there is an abnormal placenta and some fetal development. The partial mole has another genetic defect, a triploidy.

In a complete molar pregnancy, there is an abnormal placenta but no fetus.

Both forms are due to problems during fertilization. Potential causes may include defects in the egg, problems within the uterus, or a diet low in protein, animal fat, and vitamin A. Women under age 16 or older than 40 have a higher risk for this condition. You also are more likely to have a molar pregnancy if you have had one in the past.

A complete mole contains no fetal tissue. Ninety percent are 46,XX, and 10% are 46,XY. Complete moles can be divided into 2 types:

Androgenetic complete mole Homozygous

These account for 80% of complete moles.

Two

identical

paternal

chromosome

complements,

derived

from

duplication of the paternal haploid chromosomes. Always female; 46,YY has never been observed.

Heterozygous

These account for 20% of complete moles. May be male or female. All chromosomes are of parental origin, most likely due to dispermy. Biparental complete mole: Maternal and paternal genes are present but failure of maternal imprinting causes only the paternal genome to be expressed. The biparental complete mole is rare.

A recurrent form of biparental mole, which is

familial and appears to be

inherited as an autosomal recessive trait, has been described. Al-Hussaini

describes a series

of

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women

with

as

many as 9 consecutive molar

pregnancies. Mutations in NLRP7 at 19q13.4 have been identified as causative in recurrent molar pregnancies.

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The picture shows an origin of hydatidiform mole. The hydatidiform mole more frequently results from fertilization

The picture shows an origin of hydatidiform mole. The hydatidiform mole more frequently results from fertilization of an oocyt without active nucleus, followed by duplication of the paternal chromosomes (homozygous mole). In 20-25% of cases, two sperm cellsfertilize an oocyte without active nucleus (heterozygous mole)

Molecular investigations on DNA extracted from the villi of a hydatidiform mole can confirm the uniparental paternal origin of the chromosomes. In both instances, only paternal alleles are seen, but the two different causes described above can be distinguished. In the monospermic mole, only one single allele is detected for each locus analysed, and this is called a homozygous mole. In contrast, for loci for which the father is heterozygous, the dispermic or heterozygous mole has two different alleles. It has been suggested that heterozygous moles have a higher risk of malignancy

Features of a partial or incomplete molar pregnancy include some element of fetal tissue and hydatidiform changes that are focal and less advanced. There is slowly progressive swelling within the stroma of characteristically avascular chorionic villi, whereas vascular villi that have functioning fetal-placental circulation are spared. 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

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encountered. As in a complete mole, hyperplastic trophoblastic tissue and swelling of the chorionic villi occur.

encountered. As in a complete mole, hyperplastic trophoblastic tissue and swelling of the chorionic villi occur.

The picture shows that partial mole is caused by a diandric triploidy. The parental origin of the extra chromosomes is triploidy determines the phenotype and outcome of the fetus and placenta. A partial mole is only observed in the diandric triploidy. IUGR (intra uterine growth retardation).

The risk of persistent trophoblastic disease after a partial mole is substentially lower than that following a complete molar pregnancy. Moreover, persistent disease seldom is choriocarcinoma. Seckl and associates (2000) documented only 3 of 3000of partial moles to be complicated by choriocarcinoma. Growdon and co-workers (2006) found that higher postevacuation β-hCG levels correlated with increased risk for persistent disease. Specifically, levels ≥ 200 mIU/mL in the third trough eight week postevacuation were associated with at least a 35-percent risk of persistent disease.

Whereas triploidies are almost uniformly lethal, some children carry a triploidy in only part of their cells, with the remaining cells having the normal 46 chromosomes. This is called a mosaic triploidy. Such a mosaicism can only be explained by a postzygotic error, occurring after the first cell division. Genetic studies tracing the origin of the extra set of chromosomes have indicated a paternal origin in some, leading to the suggestion that the mosaicism may originate from the incorporation of a second sperm pronucleus into one

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embryonic blastomere . In others, a maternal origin was detected, most likely through the fusion of one of the (haploid) second polar bodies with an early blastomer. In one instance, the most likely explanation was chimaerism with fusion of two separate zygotes developing into a single individual. Mosaic triploidy can be viable, depending on the percentage of abnormal cells and their tissue distribution. Clinically, these infants have a recognizable pattern of malformations, including pre- and postnatal growth retardation, peculiar facial features, cutaneous syndactyly of fingers and toes, typically fingers 3 and 4 and toes 2 and 3 and mental retardation. Typically, body asymmetry and linear skin hyper- or hypopigmentation lesions following the Blaschko lines are seen, indicative of mosaicism. Interestingly, some children have precocious puberty, reminiscent of the maternal UPD14 phenotype, also characterized by pre- and postnatal growth retardation and precocious puberty. Diagnosis can be challenging, since in peripheral white blood cells, the starting point for classical karyotype analysis, the triploid cells have usually been selected out. Therefore, a skin biopsy with chromosome analysis on cultured fibroblasts is necessary to confirm the clinical diagnosis.

In exceptional cases (10 families have been reported) of histologically typical complete hydatidiform mole, a biparental origin of the chromosomes has been found. The interpretation is that the maternal chromosomes behave as if they were of paternal origin. Genomic imprinting is a reversible process, whereby the imprint is reset during gametogenesis according to the sex of the parent. Thus, during oogenesis, genes silenced on the paternal chromosome must be reactivated, whereas genes active on the paternal chromosome must be silenced, and vice versa for spermatogenesis. Clearly, this process can go wrong. In some instances, this results from an accidental failure of reprogramming, as observed in certain cases of Beckwith–Wiedemann syndrome, with loss of imprinting of the KCNQIOT1 gene. Likewise, failure of establishing an imprinting switch in the 15q11-13 region can cause the Prader–Willi or Angelman syndrome. Recent observations have suggested that in vitro fertilization may confer an increased risk to such imprinting defects.

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Picture A shows imprinting switch during gametogenesis. During gametogenesis the imprinting pattern of genes altered according

Picture A shows imprinting switch during gametogenesis. During gametogenesis the imprinting pattern of genes altered according to the sex of the parent. This is accompanied by changes in the methylation pattern. Picture B shows genetic differences between paternal and biparental hydatidiform moles. In the paternal hydatidiform moles all imprinted genes carry an exclusivelypaternal imprinting or methylation pattern. In the biparental mole, methylation but not demethylation is defective in oogenesis, leading to an abnormal methylation of maternally.

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Feature

Partial Mole

Complete Mole

Karyotype

Usually 69,XXX or 69,XXY

46,XX or 46,XY

Pathology

Embryo Fetus

Often present

Absent

Amnion, fetal red blood cells

Often present

Absent

Villous edema

Variable, local

Diffuse

Trophoblastic proliferation

Variable, local, slight to moderate

Variable, slight to severe

Clinical Presentation

Diagnosis

Missed abortion

Molas gestation

Uterine size

Small for dates

50% large for dates

Theca-lutein cysts

Rare

25-30%

Medical complications

Rare

Frequent

Persistent trophoblastic disease

1-5%

15-20%

Pathogenesis

In the complete mole, the hyperplasia of the placenta stands in sharp contrast to the absence of embryonic development. This suggests that for embryoblast development, the contribution of maternally inherited genes is necessary. As stated in the Introduction, the opposite is observed in the teratoma, with an exclusively maternal origin of the genomes and development of tissue characteristic of the three germ layers of the embryo, but not of the extraembryonic components. Likewise, the digynic triploidy does not develop features of a partial mole, but has a small placenta, and the fetus is growth-retarded. Thus, the ratio between the maternal and paternal genomes is critical in determining the development of both the embryonic and extra-embryonic tissues, with an excess of paternally derived chromosomes leading to a complete (no maternal genome) or partial (lower amount of maternal chromosomes) mole.

An increasing number of imprinted genes is being identified in mammals, and of these, several influence placental growth in the mouse. In humans, the prototype of an imprinting disorder featuring overgrowth is the Beckwith–Wiedemann syndrome (BWS).

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This syndrome is characterized by an intrauterine overgrowth, with visceromegaly (kidneys, liver, spleen, adrenal glands), a high birthweight, macroglossia and omphalocoele. The placenta often is enlarged. In addition, these children have an increased risk of developing paediatric tumours, typically Wilms' tumour, but also a variety of others such as hepatoblastoma, adrenal adenoma and carcinoma, fibromas of the heart, brain stem glioma, ganglioneuroma, rhabdomyosarcoma, lymphoma, pancreatoblastoma and hepatic haemangioepitheliomas. The disorder is caused by abnormalities in the chromosome 11p15 region, where a cluster of imprinted genes is located. Some of these genes are maternally imprinted (i.e. silenced on the maternal chromosome), such as the IGF2 and KCNQIOT1 (or

LIT1) genes, whereas others including the p57 kip2 , H19 and IPL genes are paternally imprinted. Among the different causes of the BWS, a frequent mechanism includes biallelic expression of the IGF2 or KCNQIOT1 genes. In 5% of cases, a mutation is found in the

maternally inherited p57 kip2 gene, which is expressed from the maternal chromosome only. In

normal placental villi, p57 kip2 is expressed from the maternal allele in both cytotrophoblast and chorion cells. As expected, in the hydatidiform mole, most villi do not express this gene,

whereas in the partial mole, p57 kip2 expression is detected, since these cells contain a maternal genome. P57 kip2 is a cyclin-dependent kinase inhibitor and functions as a negative regulator of cell proliferation. This gene therefore appeared to be a good candidate gene involved in the pathogenesis of hydatidiform moles. However, recently, a single case of

complete mole with p57 kip2 immunoreactivity has been reported, explained by the selective retention in the cells of human chromosome 11. This argues against an exclusive role of this gene, or other imprinted genes such as IGF2, H19 or IPL, on chromosome 11p in the pathogenesis of complete hydatidiform mole, as well as other genes elsewhere in the genome

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Picture shows an imprinted region on chromosomes 11p15.5. The chromosomal region 11p15.5 harbours in several genes

Picture shows an imprinted region on chromosomes 11p15.5. The chromosomal region 11p15.5 harbours in several genes with a different imprinting pattern. The p57kip2, IPL and H19 genes are paternally imprinted or silenced, whereas the IGF2 and KCNQIOT1 genes are maternally imprinted. In a hydatidiform mole, thr presence of paternally derived chromosomes only leads to an abnormal expression pattern or this imprinted genes.

Table 1. Features of Partial and Complete Hydatidiform Moles

Epidemiology

Purpose of investigation: To determine the rates of hydatidiform mole (HM) cases at extreme reproductive life in a developing country. Methods: A descriptive study was performed to assess the number of pregnancies and deliveries in Turkey, from 1932 to 2000, based on nationally or internationally published data from different university and state maternity hospitals. Results: A spectrum of prevalence rates in different hospitals were depicted. Almost all of represented data were hospital-based. Percentages of all HM cases < 19 years old and > 40 years old compared to the total number of HMs in each study were not mentioned. In addition, the number of HM compared to total number of deliveries and pregnancies in those age groups were not provided in those studies. Conclusion: There appears to be a need for further descriptive studies on a national basis, in regard to assess total number of HM cases per total pregnancies and deliveries for those age groups.

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The incidence of hydatidiform mole has been relatively constant in the United States and Europe at 1 to 2 per 1000 pregnancies. It is more prevalent in Hispanics and Americans Indians. Until recently, it was held to be much more frequent in some Asian countries however, these data were from hospital studies and thus misleading. In Korean study, Kim and collagues (2004) used current terminology and classification and reported a population based incidence of 2 per 1000 deliveries.

Clinical presentation

The typical clinical presentation of woman with a molar pregnancy has changed considerably over the past several decades because of earlier diagnosis. Most woman present for pregnancy care early and undergo sonography, thus molar pregnancies are detected before they grow to larger size with more complications. In many ways, this changing presentation this picture is analogous to that of ectopic pregnancy. In general, symptoms tend to be more pronounced

Women who have a hydatidiform mole feel as if they are pregnant. But because hydatidiform moles grow much faster than a fetus, the abdomen becomes larger much faster than it does in a normal pregnancy. Severe nausea and vomiting are common, and vaginal bleeding may occur. As parts of the mole deteriorate, small amounts of tissue, which resemble a bunch of grapes, may pass through the vaginawith complete moles compered with partial moles. Eventually, uterine bleeding is almost universal and may vary from spotting to profuse hemorrhage. It may bagin just before spontanious molar abortion or more often, follow an intermitten course for weeks to months. In more advanced moles, they may be considerable canceled uterine hemorrhage with moderate iron-deficiency anemia.

In about half of case, uterine growth is more rapid than expected. The uterus has a soft consistency. Large theca-lutein cysts may be difficult to distinguish form the enlarged uterus on bimanual examination. And although the uterus is enlarged, typically no fetal heart motion is detected.

As the consequence of the thyrotropin-like effect oh hCG, plasma free thyroxine levels are often elevated and TSH levels are decreased. Despite this, clinically apparent thyrotoxicosis is unusual, but thyroid storm has been reported. In our experiences, the serums free-T 4 levels rapidly normalize after uterine evacuation. Occasionally, early-onset preeclampsia develops with a large mole. Because gestational hypertensionis rarely seen

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before 24 weeks, preeclampsia that develops before this time should raise concerns for molar pregnancy. Interestingly, none of the 24 women with a complete mole described by Coukos and Colleagues (1999) experienced hyperemesis, clinical thyrotoxicosis, or preeclampsia. If choriocarcinoma develops, women may have other symptoms, caused by spread (metastasis) to other parts of the body.

Diagnosis

Often, doctors can diagnose a hydatidiform mole shortly after conception. The pregnancy test is positive, but no fetal movement and no fetal heartbeat are detected, and the uterus is much larger than expected.

Some women will present early with spontanious passage of molar tissue. In most case, however, there are varying durations of amenorrhea, usually followed by irregular bleeding. These almost always prompt pregnancy testing and sonography. If letf untreated, spontanious expulsion usually occurs around 16 weeks.

Ultrasonography is done to be sure that the growth is a hydatidiform mole and not a fetus or amniotic sac (which contains the fetus and fluid around it). The characteristic sonography appearance of a complete mole includes a complex, echogenic uterine mass with numerous cystic spaces and no fetus or amnionic sac. Sonographic features of a partial mole include a thickened, hydropic placenta with fetal tissue. Importantly, in early pregnancy, sonography will demonstrate the characteristic appearance in as few as a third women with a partial mole. Occasionally, molar pregnancy may be confused for a uterine leimyoma or multifetal pregnancy. Blood tests to measure the level of human chorionic gonadotropin (hCG—a hormone normally produced early in pregnancy) are done. If a hydatidiform mole is present, the level is usually very high because the mole produces a large amount of this hormone. A sample of tissue is removed or obtained when it is passed, then examined under a microscope (biopsy) to confirm the diagnosis.

Treatment

Current mortality rates for molar pregnancies have been practically reduced to zero by management of all molar pregnancies. The first is evacuation of the mole, and the second is regular follow-up to detect persistent trophoblastic disease. Most clinicians obtain a preoperative chest radiograph, but unless there is evidance of extra uterine disease, computed tomography (CT) or magnetic resonance (MR) imaging to evaluatethe liver or brain is not

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done routinely. Laboratory work includes a hemogram to assess anemia, blood type and antibody screen, serum hepatic transaminase levels to assess liver to involvement, and a baseline serum β-hCG level. That said, Knowles and Collegues analyzed the effectivenes of preevacuation testing for suspected molar pregnancy. They concluded that hemogram and blood type with antibody screen alone were appropriate for most patients without suspicious signs or symptoms.

The unsual circumstance of twinning with a complete mole plus a fetus and placenta is problematic, especially if there are no apparent fetal anomalies found with sonography or karyotypic aberrations. Neither maternal risk not the likelihood of a healthy offspring have been pricesly established if pregnancy is continued.

Prophylactic Chemotherapy

The long term prognosis for woman with a hydatidiform mole is not improved with prophylactic chemotherapy. Because toxicity, including death may be significant, it is not recommended routinely.

Suction Curettage

Molar evacuation with molar curettage is usually the preferred treatment regardless of uterine size. For large moles, adequate anasthesia and blood- banking support is imperative. With a closed cervix, preoperative dilatation with an osmotic dilator may be helpful. The cervix is then further dilated to allow insertion of a 10 to 12 mm suction curette. After most of the molar tissue has been removed, oxitocin is given. After the myometrium has contracted, thorough but gentle curettage with a large sharp curette usually is performed. We have found that intraoperative sonography helps to ensure that the uterine cavity has been emptied.

Other methods of Termination

In the United States, only rarely a labor induction or hysterectomy used for molar evacuation. Both will likely increase blood loss and may increase the incidence of persistent trophoblastic disease.

Hysterectomy

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If no further pregnancies are desired, hysterectomy may be preferred to suction curettage. It is a logical procedure to woman aged 40 and older, because at least a third of these woman go on to the develop persistent gestational trophoblastic neoplasia. Although hysterectomy does not eliminate this possibility, it markedly reduces its likelihood. Finally, hysterectomy is an important adjunct to treatment of chemoresistant tumors.

Prognosis

The cure rate for a hydatidiform mole is virtually 100% if the mole has not spread. The cure rate is 60 to 80% for choriocarcinoma that has spread widely. Most women can have children afterwards and do not have a higher risk of having complications, a miscarriage, or children with birth defects.

About 1% of women who have had a hydatidiform mole have another one. So if

women

have

had

a

hydatidiform

mole,

ultrasonography

is

done

early

in

subsequent

pregnancies.

 

CONCLUSION

Hydatidiform mole is more common at the extremes of reproductive age. Women in their early teenage or perimenopausal years are most at risk. Women older than 35 years have a 2-fold increase in risk. Women older than 40 years experience a 5- to 10-fold increase in risk compared to younger women. Parity does not affect the risk.

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REFERENCES

  • 1. Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse DJ, et al. Williams Obstetrics. Mc Graw Hill Medical. 23rd edition. 2010:257-61.

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