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 !. "n #nited $tates, they occur in about 1 in %&&& pregnancies in the #nited $tates. 'or un(nown reasons, moles are almost 1& times more common in Asia country. Keywords: complete hydatidiform mole, partial hydatidiform mole, e)treme marital age and hydatidiform mole

INTRODUCTION *estational 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 +epartment of ,bstetrics and *ynaecology of the +r. -ipto Mangun(usumo Hospital, .a(arta, covering the period between 1/77 and 1/01. The incidence of hydatidiform mole was 1 in 77 pregnancies. The incidence of malignant trophoblastic disease was 1 in 10! pregnancies. ,f the 1&2 cases of hydatidiform mole, %%./3 became malignant. 4atients of %1 years of age or younger had a higher ris( of getting hydatidiform mole 54 less than &.&!6 compared to older patients. The ris( of becoming malignant increased with age and became evident after 1& years of age. 4arity 1 or less was associated with a higher ris( of getting hydatidiform mole 54 less than &.&!6, 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 fre7uently in patients with blood groups A or 8. 8y contrast, there was a tendency for the change into malignancy to occur more fre7uently in women with blood groups 8 or ,. *estational age had no influence towards the change into malignancy or metastasis. #terine size 5greater than %& wee(s gestation6 correlated with the progression of hydatidiform mole into malignancy. However, subse7uent metastasis was not influenced by the size of the uterus. "t was found that 72.13 of malignant trophoblastic diseases originated from hydatidiform moles, 1%.13 from abortions, /.!3 from normal deliveries, and 1.%3 from ectopic pregnancies. 9on:hydatidiform moles had a slightly greater ris( for metastasis, although this was not significant. Hydatidiform mole in histologic stages "" or """ 5Hertig: Mansell classification6 had a significantly greater tendency 54 less than &.&!6 to become malignant than in stage ". "n #nited $tates by studying elective pregnancy terminations, hydatidiform moles were determined to occur in appro)imately 1 in 1%&& pregnancies. The reported fre7uency of hydatidiform mole varies greatly. $ome of this variability can be e)plained by differences in methodology 5eg, single hospital vs population studies, identification of cases6. The reported fre7uencies range from 1 in 1&& pregnancies in "ndonesia to 1 in %&& pregnancies in Me)ico to 1 in !&&& pregnancies in 4araguay. The study of pathologic material from first: and second:trimester abortions established a fre7uency of
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complete and partial hydatidiform moles in "reland of 1 per 1/1! pregnancies and 1 per 2/! pregnancies, respectively. Maternal age at either e)treme of the reproductive spectrum is a ris( factor for molar pregnancy. $pecifically, adolescents and women aged 2 to 1& years have twofold ris( and those over 1& years have an almost tenfold ris(. Hydatidiform moles are most common among women under 17 or over !. "n the #nited $tates, they occur in about 1 in %&&& pregnancies. 'or un(nown reasons, moles are almost 1& 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. "n 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 5a condition called molar pregnancy6. However, a hydatidiform mole can develop from cells that remain in the uterus after a miscarriage or a full:term pregnancy. ;arely, a hydatidiform mole develops when there is a living fetus. "n such cases, the fetus typically dies, and a miscarriage often occurs. About 0&3 of hydatidiform moles are not cancerous. About 1! to %&3 invade the surrounding tissue and tend to persist. About % to 3 become cancerous and spread throughout the body< they are then called choriocarcinomas. -horiocarcinomas can spread 7uic(ly through the lymphatic vessels or bloodstream. Hydatidiform moles and choriocarcinomas are types of gestational trophoblastic disease. The following discussion is limited to hydatidiform moles

5complete and partial6. A partial molar pregnancy means there is an abnormal placenta and some fetal development. The partial mole has another genetic defect, a triploidy. "n a complete molar pregnancy, there is an abnormal placenta but no fetus. 8oth forms are due to problems during fertilization. 4otential causes may include defects in the egg, problems within the uterus, or a diet low in protein, animal fat, and vitamin A. =omen under age 12 or older than 1& have a higher ris( for this condition. >ou also are more li(ely to have a molar pregnancy if you have had one in the past. A complete mole contains no fetal tissue. 9inety percent are 12,??, and 1&3 are 12,?>. -omplete moles can be divided into % types@ Androgenetic complete mole Homozygous These account for 0&3 of complete moles. Two identical paternal chromosome complements, derived from duplication of the paternal haploid chromosomes. Always female< 12,>> has never been observed. Heterozygous These account for %&3 of complete moles. May be male or female. All chromosomes are of parental origin, most li(ely due to dispermy. 8iparental complete mole@ Maternal and paternal genes are present but failure of maternal imprinting causes only the paternal genome to be e)pressed. 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 ! women with as many as / consecutive molar pregnancies. Mutations in NLRP7 at 1/71 .1 have been identified as causative in recurrent molar pregnancies.

The picture shows an origin of hydatidiform mole. The hydatidiform mole more fre7uently results from fertilization of an oocyt without active nucleus, followed by duplication of the paternal chromosomes 5homozygous mole6. "n %&:%!3 of cases, two sperm cellsfertilize an oocyte without active nucleus 5heterozygous mole6 Molecular investigations on +9A e)tracted from the villi of a hydatidiform mole can confirm the uniparental paternal origin of the chromosomes. "n both instances, only paternal alleles are seen, but the two different causes described above can be distinguished. "n the monospermic mole, only one single allele is detected for each locus analysed, and this is called a homozygous mole. "n contrast, for loci for which the father is heterozygous, the dispermic or heterozygous mole has two different alleles. "t has been suggested that heterozygous moles have a higher ris( of malignancy 'eatures 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 2/,??? or 2/,??>. 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.

The picture shows that partial mole is caused by a diandric triploidy. The parental origin of the e)tra chromosomes is triploidy determines the phenotype and outcome of the fetus and placenta. A partial mole is only observed in the diandric triploidy. "#*; 5intra uterine growth retardation6. The ris( of persistent trophoblastic disease after a partial mole is substentially lower than that following a complete molar pregnancy. Moreover, persistent disease seldom is choriocarcinoma. $ec(l and associates 5%&&&6 documented only of &&&of partial moles to be complicated by choriocarcinoma. *rowdon and co:wor(ers 5%&&26 found that higher postevacuation A:h-* levels correlated with increased ris( for persistent disease. $pecifically, levels B %&& m"#CmD in the third trough eight wee( postevacuation were associated with at least a !:percent ris( of persistent disease. =hereas triploidies are almost uniformly lethal, some children carry a triploidy in only part of their cells, with the remaining cells having the normal 12 chromosomes. This is called a mosaic triploidy. $uch a mosaicism can only be e)plained by a postzygotic error, occurring after the first cell division. *enetic studies tracing the origin of the e)tra 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 . "n others, a maternal origin was detected, most li(ely through the fusion of one of the 5haploid6 second polar bodies with an early blastomer. "n one instance, the most li(ely e)planation 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. -linically, 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 and 1 and toes % and and mental retardation. Typically, body asymmetry and linear s(in hyper: or hypopigmentation lesions following the 8lasch(o lines are seen, indicative of mosaicism. "nterestingly, some children have precocious puberty, reminiscent of the maternal #4+11 phenotype, also characterized by pre: and postnatal growth retardation and precocious puberty. +iagnosis can be challenging, since in peripheral white blood cells, the starting point for classical (aryotype analysis, the triploid cells have usually been selected out. Therefore, a s(in biopsy with chromosome analysis on cultured fibroblasts is necessary to confirm the clinical diagnosis. "n e)ceptional cases 51& families have been reported6 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. *enomic imprinting is a reversible process, whereby the imprint is reset during gametogenesis according to the se) 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. -learly, this process can go wrong. "n some instances, this results from an accidental failure of reprogramming, as observed in certain cases of 8ec(withE=iedemann syndrome, with loss of imprinting of the KCNQIOT1 gene. Di(ewise, failure of establishing an imprinting switch in the 1!711:1 region can cause the 4raderE=illi or Angelman syndrome. ;ecent observations have suggested that in vitro fertilization may confer an increased ris( to such imprinting defects.

4icture A shows imprinting switch during gametogenesis. +uring gametogenesis the imprinting pattern of genes altered according to the se) of the parent. This is accompanied by changes in the methylation pattern. 4icture 8 shows genetic differences between paternal and biparental hydatidiform moles. "n the paternal hydatidiform moles all imprinted genes carry an e)clusivelypaternal imprinting or methylation pattern. "n the biparental mole, methylation but not demethylation is defective in oogenesis, leading to an abnormal methylation of maternally.

'eature Karyotype Pathology Fmbryo 'etus Amnion, fetal red blood cells Gillous edema Trophoblastic proliferation Clinical Presentation +iagnosis #terine size Theca:lutein cysts Medical complications 4ersistent trophoblastic disease

4artial Mole #sually 2/,??? or 2/,??>

-omplete Mole 12,?? or 12,?>

,ften present ,ften present Gariable, local Gariable, local, slight to moderate

Absent Absent +iffuse Gariable, slight to severe

Missed abortion $mall for dates ;are ;are 1:!3

Molas gestation !&3 large for dates %!: &3 're7uent 1!:%&3

Pathogenesis "n 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 "ntroduction, the opposite is observed in the teratoma, with an e)clusively maternal origin of the genomes and development of tissue characteristic of the three germ layers of the embryo, but not of the e)traembryonic components. Di(ewise, 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 e)tra:embryonic tissues, with an e)cess of paternally derived chromosomes leading to a complete 5no maternal genome6 or partial 5lower amount of maternal chromosomes6 mole. An increasing number of imprinted genes is being identified in mammals, and of these, several influence placental growth in the mouse. "n humans, the prototype of an imprinting disorder featuring overgrowth is the 8ec(withE=iedemann syndrome 58=$6.

This syndrome is characterized by an intrauterine overgrowth, with visceromegaly 5(idneys, liver, spleen, adrenal glands6, a high birthweight, macroglossia and omphalocoele. The placenta often is enlarged. "n addition, these children have an increased ris( of developing paediatric tumours, typically =ilmsH 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 11p1! region, where a cluster of imprinted genes is located. $ome of these genes are maternally imprinted 5i.e. silenced on the maternal chromosome6, such as the IGF2 and KCNQIOT1 5or LIT16 genes, whereas others including the p57kip2, H19 and IPL genes are paternally imprinted. Among the different causes of the 8=$, a fre7uent mechanism includes biallelic e)pression of the IGF2 or KCNQIOT1 genes. "n !3 of cases, a mutation is found in the maternally inherited p57kip2 gene, which is e)pressed from the maternal chromosome only. "n normal placental villi, p57kip2 is e)pressed from the maternal allele in both cytotrophoblast and chorion cells. As e)pected, in the hydatidiform mole, most villi do not e)press this gene, whereas in the partial mole, p57kip2 e)pression is detected, since these cells contain a maternal genome. P57kip2 is a cyclin:dependent (inase 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 p57kip2 immunoreactivity has been reported, e)plained by the selective retention in the cells of human chromosome 11. This argues against an e)clusive 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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4icture shows an imprinted region on chromosomes 11p1!.!. The chromosomal region 11p1!.! harbours in several genes with a different imprinting pattern. The p!7(ip%, "4D and H1/ genes are paternally imprinted or silenced, whereas the "*'% and I-9J",T1 genes are maternally imprinted. "n a hydatidiform mole, thr presence of paternally derived chromosomes only leads to an abnormal e)pression pattern or this imprinted genes.
Table 1. 'eatures of 4artial and -omplete Hydatidiform Moles

pide!iology 4urpose of investigation@ To determine the rates of hydatidiform mole 5HM6 cases at e)treme reproductive life in a developing country. Methods@ A descriptive study was performed to assess the number of pregnancies and deliveries in Tur(ey, from 1/ % to %&&&, based on nationally or internationally published data from different university and state maternity hospitals. ;esults@ A spectrum of prevalence rates in different hospitals were depicted. Almost all of represented data were hospital:based. 4ercentages of all HM cases K 1/ years old and L 1& years old compared to the total number of HMs in each study were not mentioned. "n addition, the number of HM compared to total number of deliveries and pregnancies in those age groups were not provided in those studies. -onclusion@ 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 #nited $tates and Furope at 1 to % per 1&&& pregnancies. "t is more prevalent in Hispanics and Americans "ndians. #ntil recently, it was held to be much more fre7uent in some Asian countries however, these data were from hospital studies and thus misleading. "n Iorean study, Iim and collagues 5%&&16 used current terminology and classification and reported a population based incidence of % per 1&&& 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. "n many ways, this changing presentation this picture is analogous to that of ectopic pregnancy. "n general, symptoms tend to be more pronounced =omen who have a hydatidiform mole feel as if they are pregnant. 8ut because hydatidiform moles grow much faster than a fetus, the abdomen becomes larger much faster than it does in a normal pregnancy. $evere nausea and vomiting are common, and vaginal bleeding may occur. As parts of the mole deteriorate, small amounts of tissue, which resemble a bunch of grapes, may pass through the vaginawith complete moles compered with partial moles. Fventually, uterine bleeding is almost universal and may vary from spotting to profuse hemorrhage. "t may bagin Must before spontanious molar abortion or more often, follow an intermitten course for wee(s to months. "n more advanced moles, they may be considerable canceled uterine hemorrhage with moderate iron:deficiency anemia. "n about half of case, uterine growth is more rapid than e)pected. The uterus has a soft consistency. Darge theca:lutein cysts may be difficult to distinguish form the enlarged uterus on bimanual e)amination. And although the uterus is enlarged, typically no fetal heart motion is detected. As the conse7uence of the thyrotropin:li(e effect oh h-*, plasma free thyro)ine levels are often elevated and T$H levels are decreased. +espite this, clinically apparent thyroto)icosis is unusual, but thyroid storm has been reported. "n our e)periences, the serums free:T1 levels rapidly normalize after uterine evacuation. ,ccasionally, early:onset preeclampsia develops with a large mole. 8ecause gestational hypertensionis rarely seen
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before %1 wee(s, preeclampsia that develops before this time should raise concerns for molar pregnancy. "nterestingly, none of the %1 women with a complete mole described by -ou(os and -olleagues 51///6 e)perienced hyperemesis, clinical thyroto)icosis, or preeclampsia. "f choriocarcinoma develops, women may have other symptoms, caused by spread 5metastasis6 to other parts of the body. Diagnosis ,ften, 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 e)pected. $ome women will present early with spontanious passage of molar tissue. "n most case, however, there are varying durations of amenorrhea, usually followed by irregular bleeding. These almost always prompt pregnancy testing and sonography. "f letf untreated, spontanious e)pulsion usually occurs around 12 wee(s. #ltrasonography is done to be sure that the growth is a hydatidiform mole and not a fetus or amniotic sac 5which contains the fetus and fluid around it6. The characteristic sonography appearance of a complete mole includes a comple), echogenic uterine mass with numerous cystic spaces and no fetus or amnionic sac. $onographic features of a partial mole include a thic(ened, hydropic placenta with fetal tissue. "mportantly, in early pregnancy, sonography will demonstrate the characteristic appearance in as few as a third women with a partial mole. ,ccasionally, molar pregnancy may be confused for a uterine leimyoma or multifetal pregnancy. 8lood tests to measure the level of human chorionic gonadotropin 5h-*Na hormone normally produced early in pregnancy6 are done. "f 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 e)amined under a microscope 5biopsy6 to confirm the diagnosis. Treat!ent -urrent 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 e)tra uterine disease, computed tomography 5-T6 or magnetic resonance 5M;6 imaging to evaluatethe liver or brain is not
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done routinely. Daboratory wor( includes a hemogram to assess anemia, blood type and antibody screen, serum hepatic transaminase levels to assess liver to involvement, and a baseline serum A:h-* level. That said, Inowles and -ollegues 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 (aryotypic aberrations. 9either maternal ris( not the li(elihood of a healthy offspring have been pricesly established if pregnancy is continued. 4rophylactic -hemotherapy The long term prognosis for woman with a hydatidiform mole is not improved with prophylactic chemotherapy. 8ecause to)icity, including death may be significant, it is not recommended routinely. $uction -urettage Molar evacuation with molar curettage is usually the preferred treatment regardless of uterine size. 'or large moles, ade7uate anasthesia and blood: ban(ing support is imperative. =ith a closed cervi), preoperative dilatation with an osmotic dilator may be helpful. The cervi) is then further dilated to allow insertion of a 1& to 1% mm suction curette. After most of the molar tissue has been removed, o)itocin is given. After the myometrium has contracted, thorough but gentle curettage with a large sharp curette usually is performed. =e have found that intraoperative sonography helps to ensure that the uterine cavity has been emptied. ,ther methods of Termination "n the #nited $tates, only rarely a labor induction or hysterectomy used for molar evacuation. 8oth will li(ely increase blood loss and may increase the incidence of persistent trophoblastic disease. Hysterectomy
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"f no further pregnancies are desired, hysterectomy may be preferred to suction curettage. "t is a logical procedure to woman aged 1& 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 mar(edly reduces its li(elihood. 'inally, hysterectomy is an important adMunct to treatment of chemoresistant tumors. Prognosis The cure rate for a hydatidiform mole is virtually 1&&3 if the mole has not spread. The cure rate is 2& to 0&3 for choriocarcinoma that has spread widely. Most women can have children afterwards and do not have a higher ris( of having complications, a miscarriage, or children with birth defects. About 13 of women who have had a hydatidiform mole have another one. $o if women have had a hydatidiform mole, ultrasonography is done early in subse7uent pregnancies.

CONC"USION Hydatidiform mole is more common at the e)tremes of reproductive age. =omen in their early teenage or perimenopausal years are most at ris(. =omen older than ! years have a %:fold increase in ris(. =omen older than 1& years e)perience a !: to 1&:fold increase in ris( compared to younger women. 4arity does not affect the ris(.

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R # R NC S 1. -unningham '*, Deveno I., 8loom $D, Hauth .-, ;ouse +., et al. =illiams ,bstetrics. Mc *raw Hill Medical. % rd edition. %&1&@%!7:21. %. Moore DF, Hernandez F. Hydatidiform Mole. Fmedicine from =ebM+, %&1&. Available at@ http@CCemedicine.medscape.comCarticleC%!12!7:overview Accesed .anuary 1&,%&11 . Aziz M', Iampono 9, Moegni FM, $Mamsuddin $, 8arnas 8, et al. Fpidemiology of gestational trophoblastic neoplasm at the +r. -ipto Mangun(usumo Hospital, .a(arta, "ndonesia, 1/01. Available at@ http@CCwww.ncbi.nlm.nih.govCpubmedC2&/ 12& Accesed .anuary /,%&11 1. *ershenson +M, ;amirez 4T. Hydatidiform Mole@ -ancers of the 'emale ;eproductive $ystem. The Merc( manuals online medical library, %&&0. Available at@ http@CCwww.merc(manuals.comChomeCsec%%Cch%!%Cch%!%h.html Accesed .anuary /, %&11 !. +efiniton of Hydatidiform Mole. Medicine9et.com, %&&%. Available at@ http@CCwww.medterms.comCscriptCmainCart.aspOarticle(eyP 0%1 Accesed .anuary 1&, %&11 2. +evriendt I. Hydatidiform mole and triploidy@ the role of genomic imprinting in placental development. ,)ford .ournals, %&&!. Available at@ http@CChumupd.o)fordMournals.orgCcontentC11C%C1 7.full Accesed .anuary 11, %&11 7. Gorvic( D. Hydatidiform Mole. The 9ew >or( Times Health *uide, %&&0. Available at@ http@CChealth.nytimes.comChealthCguidesCdiseaseChydatidiform: moleCoverview.html Accesed .anuary 1&, %&11 0. ,zalp $$, >alcin ,T, Tanir HM. Hydatidiform Mole at e)treme ages of reproductive life in a developing country from 1/ % to %&&&. Furopean Mournal of gynacecological oncology, %&&%. Available at@ http@CCwww.biomedsearch.comCnihCHydatidiform:mole: at:e)treme:agesC1%%11712.html Accesed .anuary 1&, %&11

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