estational trophoblastic disease I: epidemiology, pathology,linical presentation and diagnosis of gestational trophoblasticisease, and management of hydatidiform mole
ohn R. Lurain, MD
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estational trophoblastic disease(GTD) is a spectrum of cellular
roliferations arising from the placentalillous trophoblast encompassing 4ain clinicopathologic forms: hydatidi-
orm mole (complete and partial), inva-ive mole, choriocarcinoma, and placen-al site trophoblastic tumor (PSTT)Table). The term “gestational tropho-lastic neoplasia” (GTN) has been ap-lied collectively to the latter 3 condi-ions, which can progress, invade,
etastasize, and lead to death if leftntreated.GTD was historically associated with
ignificant morbidity and mortality.ydatidiform moles were often accom-
anied by serious bleeding and otheredical complications prior to the
evelopment of early detection and ef-ective uterine evacuation means in the970s. The outcomes for GTN were like-ise poor before the introduction of che-otherapy into their management 50
ears ago. The mortality rate for invasiveole approached 15%, most often be-
ause of hemorrhage, sepsis, embolichenomena, or complications from sur-ery. Choriocarcinoma had a mortalityate of almost 100% when metastases
rom the John I. Brewer Trophoblasticisease Center, Northwestern Universityeinberg School of Medicine, Chicago, IL.
eceived April 13, 2010; revised June 16,010; accepted June 30, 2010.
eprints: John R. Lurain, MD, John I. Brewerrophoblastic Disease Center, Northwesternniversity Feinberg School of Medicine, 250 E.uperior St., Suite 05-2168, Chicago, IL0611. [email protected].
002-9378/free2010 Mosby, Inc. All rights reserved.
oi: 10.1016/j.ajog.2010.06.073
For Editors’ Commentary,
esee Table of Contents
ere present and approximately 60%ven when hysterectomy was done forpparent nonmetastatic disease. Gesta-ional trophoblastic neoplasms are nowome of the most curable of all solid tu-
ors, with cure rates �90% even in theresence of widespread metastaticisease.1-3
pidemiologyhe incidence and etiologic factors con-
ributing to the development of GTDave been difficult to characterize. Theroblems in accumulating reliable epi-emiologic data can be attributed to aumber of factors, such as inconsisten-ies in case definitions, inability to ade-uately characterize the population atisk, no centralized databases, lack ofell-chosen control groups againsthich to compare possible risk factors,
nd rarity of the diseases.4
Epidemiologic studies have reportedide regional variations in the incidencef hydatidiform mole.5 Estimates fromtudies conducted in North America,ustralia, New Zealand, and Europeave shown the incidence of hydatidi-
orm mole to range from 0.57–1.1 per000 pregnancies, whereas studies inoutheast Asia and Japan have suggestedn incidence as high as 2.0 per 1000 preg-ancies.6 Investigations into possible
Gestational trophoblastic disease includesgestational trophoblastic neoplasia (invasiveblastic tumor, and epithelioid trophoblasticpresentation, and diagnosis of each of theseParticular emphasis is given to managemetwin mole/normal fetus pregnancy, prophyl
n increased incidence of hydatidiformole among American Indians, Eski-os, Hispanics, and African Americans
s well as various Asian populations haveot been able to attribute them to genetic
raits, cultural factors, or simply differ-nces in reporting.7-9
Data with respect to choriocarcinomancidence rates are even more limited.ollection of data on the incidence of
horiocarcinoma has been more difficultot only for reasons similar to those en-ountered with hydatidiform moles, butlso because of the rarity of choriocarci-oma and the difficulty in clinically dis-
inguishing postmolar choriocarcinomarom invasive mole. In Europe andorth America, choriocarcinoma affects
pproximately 1 in 40,000 pregnanciesnd 1 in 40 hydatidiform moles, whereasn Southeast Asia and Japan choriocarci-oma rates are higher at 9.2 and 3.3 per0,000 pregnancies, respectively. The in-idence rates of both hydatidiform molend choriocarcinoma have declined overhe past 30 years in all populations.10,11
Several potential etiologic risk factorsave been evaluated for the developmentf complete hydatidiform mole.12 The
established risk factors that havemerged are extremes of maternal agend prior molar pregnancy. Advancedr very young maternal age has consis-ently correlated with higher rates of
atidiform mole (complete and partial) andle, choriocarcinoma, placental site tropho-or). The epidemiology, pathology, clinicalphoblastic disease variants are discussed.f hydatidiform mole, including evacuation,ic chemotherapy, and follow-up.
o women aged 21-35 years, the risk ofomplete mole is 1.9 times higher foromen both �35 years and �21 years asell as 7.5 times higher for women �40
ears.13,14 Prior hydatidiform mole pre-isposes to another molar pregnancy.he risk of repeat molar pregnancy aftermole is about 1%, or about 10-20 times
he risk for the general population.15,16
amilial clusters of biparental completeydatidiform moles associated withovel missense NLRP7 gene mutationsn chromosome 19q have also been
dentified.17 Another reported obstetricisk factor for both complete and partialoles is a history of spontaneous abor-
ion, giving women a 2- to 3-fold in-reased risk of a molar pregnancy com-ared to women without a history ofiscarriage.12 Although many possible
nvironmental etiologies for completeole have been studied, the only consis-
ent association has been an inverse rela-ionship between �-carotene and animalat dietary intake and the incidence of
olar pregnancy.18,19 Ovulation induc-ion for fertility may also be associated
hCG, human chorionic gonadotropin; hPL, human placental la
Lurain. Gestational trophoblastic disease I. Am J Obstet G
ith an increase in pregnancies consist- t
32 American Journal of Obstetrics & Gynecology
ng of a normal fetus or fetuses and a mo-ar gestation.
Risk factors for choriocarcinoma in-lude prior complete hydatidiform mole,thnicity, and advanced maternal age.horiocarcinoma is approximately 1000
imes more likely after a complete molehan after another pregnancy event. Theisk is also increased in women of Asiannd American Indian descent as well as Af-ican Americans. Similar to molar preg-ancies, the median age of women withhoriocarcinoma is higher than that forormal pregnancies.11 There also seems toe an increased risk of choriocarcinoma inomen with long-term oral contraceptivese and blood group A.5,20
athologyolar pregnancies and gestational tro-
hoblastic neoplasms all take their originrom the placental trophoblast. Normalrophoblast is composed of cytotropho-last, syncytiotrophoblast, and interme-iate trophoblast. Syncytiotrophoblast
nvades the endometrial stroma with im-lantation of the blastocyst and is the cell
nal trophoblastic disease
c features Clinical f
inly); 46,XYus/embryoelling of villiphoblastic hyperplasia
onadotropin (hCG). Cytotrophoblastunctions to supply the syncytium withells in addition to forming outpouch-ngs that become the chorionic villi cov-ring the chorionic sac. The villous cho-ion adjacent to the endometrium andasalis layer of the endometrium to-ether form the functional placenta foraternal-fetal nutrient and waste ex-
hange. Intermediate trophoblast is lo-ated in the villi, the implantation site,nd the chorionic sac. All 3 types of tro-hoblast may result in GTD when theyroliferate.21,22
ydatidiform moleydatidiform mole refers to an abnor-al pregnancy characterized by varying
egrees of trophoblastic proliferationboth cytotrophoblast and syncytiotro-hoblast) and vesicular swelling of pla-ental villi associated with an absent orn abnormal fetus/embryo. Two syn-romes of hydatidiform mole have beenescribed based on both morphologicnd cytogenetic criteria.23,24 Completeydatidiform moles undergo early and
he absence of an ascertainable fetus ormbryo, the trophoblast is consistentlyyperplastic with varying degrees oftypia, and villous capillaries are absentFigure 1). Approximately 90% of com-lete moles are 46, XX, originating fromuplication of the chromosomes of aaploid sperm after fertilization of angg in which the maternal chromosomesre either inactive or absent. The other0% of complete moles are 46, XY, or 46,X, as a result of fertilization of an emptyvum by 2 sperm (dispermy). Tropho-lastic neoplasia (invasive mole or cho-iocarcinoma) follows complete mole in5-20% of cases.23-27 Partial hydatidi-orm moles demonstrate identifiable fe-al or embryonic tissue, chorionic villiith focal edema that vary in size and
hape, scalloping and prominent stro-al trophoblastic inclusions, and a func-
ioning villous circulation, as well as fo-al trophoblastic hyperplasia with mildtypia only (Figure 2). Most partialoles have a triploid karyotype (usually
9, XXY), resulting from the fertilizationf an apparently normal ovum by 2perm. Less than 5% of partial moles willevelop postmolar GTN; metastases oc-ur rarely and a histopathologic diagno-is of choriocarcinoma has not been con-rmed after a partial mole.23,24,27-30
nvasive molenvasive mole is a benign tumor thatrises from myometrial invasion of a hy-atidiform mole via direct extensionhrough tissue or venous channels (Fig-re 3). Approximately 10-17% of hyda-
idiform moles will result in invasiveole, and about 15% of these will metas-
asize to the lungs or vagina. Invasiveole is most often diagnosed clinically
ather than pathologically based on per-istent hCG elevation after molar evacu-tion and is frequently treated with che-otherapy without a histopathologic
iagnosis.31
horiocarcinomahoriocarcinoma is a malignant disease
haracterized by abnormal trophoblasticyperplasia and anaplasia, absence ofhorionic villi, hemorrhage, and necro-
is (Figure 4), with direct invasion into
FIGURE 1Complete hydatidiform mole
omplete hydatidiform mole with hydropic villi, absence of villous blood vessels, proliferation ofyperplastic cytotrophoblast, and syncytiotrophoblast.urain. Gestational trophoblastic disease I. Am J Obstet Gynecol 2010.
FIGURE 2Partial hydatidiform mole
artial hydatidiform mole with chorionic villi of varying size and shape with focal edema and scallop-ng, stromal trophoblastic inclusions, and functioning villous circulation, as well as focal trophoblasticyperplasia.urain. Gestational trophoblastic disease I. Am J Obstet Gynecol 2010.
DECEMBER 2010 American Journal of Obstetrics & Gynecology 533
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he myometrium and vascular invasionesulting in spread to distant sites, mostommonly to the lungs, brain, liver, pel-is and vagina, kidney, intestines, andpleen. Choriocarcinoma has been re-orted to occur in association with anyregnancy event. Approximately 25% ofases follow abortion or tubal preg-ancy, 25% are associated with term orreterm gestation, and the remaining0% arise from hydatidiform moles, al-hough only 2-3% of hydatidiform
oles progress to choriocarcinoma.32
lacental site trophoblastic tumorSTT is an extremely rare disease thatrises from the placental implantationite and consists predominantly of
ononuclear intermediate trophoblastsithout chorionic villi infiltrating in
heets or cords between myometrial fi-ers (Figure 5). PSTT is associated with
ess vascular invasion, necrosis, andemorrhage than choriocarcinoma, and
t has a propensity for lymphatic metas-asis. Immunohistochemical staining re-eals the diffuse presence of cytokeratinnd human placental lactogen, whereas
FIGURE 3Invasive mole
nvasive mole with direct extension of molar tissurophoblast, into the myometrium.urain. Gestational trophoblastic disease I. Am J Obstet Gyne
CG is only focal. Cytogenic studies have r
34 American Journal of Obstetrics & Gynecology
evealed that PSTTs are more often dip-oid than aneuploid. Most PSTTs followonmolar gestations.33
s a rare variant of PSTT that simulatesarcinoma. Based on morphologic andistochemical features, it appears toevelop from neoplastic transformationf chorionic-type intermediate tropho-lasts. Most ETTs present many years af-er a full-term delivery.34,35
linical presentationomplete hydatidiform moleomplete hydatidiform mole most com-only presents with vaginal bleeding,
sually occurring at 6-16 weeks of gesta-ion in 80-90% of cases. The other classiclinical signs and symptoms, such asterine enlargement greater than ex-ected for gestational dates (28%), hy-eremesis (8%), and pregnancy-inducedypertension in the first or second tri-ester (1%), occur less frequently in re-
ent years because of earlier diagnosis asresult of widespread use of ultrasonog-
ncluding hydropic villi and covering hyperplastic
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aphy and accurate tests for hCG. Bilat- o
DECEMBER 2010
ral theca lutein cyst enlargement of thevaries occurs in approximately 15% ofases, hCG levels are often �100,000IU/mL, and fetal heart tones are
bsent.36-39
artial moleartial mole does not have the same pre-enting features as complete mole. Morehan 90% of patients with partial molesave symptoms of incomplete or missedbortion, and the diagnosis is usuallyade after histologic review of curettage
pecimens. The main presenting symp-om is vaginal bleeding, which occurs inpproximately 75% of patients. Exces-ive uterine enlargement, hyperemesis,regnancy-induced hypertension, hy-erthyroidism, and theca lutein cysts de-elop infrequently. Preevacuation hCGevels are �100,000 mIU/mL in �10%f patients with partial moles.40-42
estational trophoblastic neoplasiaTN has a varied presentation depend-
ng on the antecedent pregnancy event,xtent of disease, and histopathology.ostmolar GTN (invasive mole or cho-iocarcinoma) most commonly presentss irregular bleeding following evacua-ion of a hydatidiform mole. Signs sug-estive of postmolar GTN are an en-arged, irregular uterus and persistentilateral ovarian enlargement. Occa-ionally, a metastatic vaginal lesion maye noted on evacuation, disruption ofhich may cause uncontrolled bleeding.horiocarcinoma associated with non-olar gestation has no characteristic
ymptoms or signs, which are mostly re-ated to invasion of tumor in the uterusr at metastatic sites. In patients withostpartum uterine bleeding and subin-olution, GTN should be consideredlong with other possible causes, such asetained products of conception or en-omyometritis, primary or metastaticumors of other organ systems, or an-ther pregnancy occurring shortly afterhe first. Bleeding as a result of uterineerforation or metastatic lesions mayesult in abdominal pain, hemoptysis,elena, or evidence of increased intra-
ranial pressure from intracerebral hem-
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r hemiplegia. Patients may also exhibitulmonary symptoms, such as dyspnea,ough, and chest pain, caused by exten-ive lung metastases.32 PSTTs and ETTslmost always cause irregular uterineleeding often distant from a precedingonmolar gestation, and rarely viriliza-
ion or nephrotic syndrome. The uteruss usually symmetrically enlarged, anderum hCG levels are only slightlylevated.33-35
iagnosisltrasonographyltrasonography plays a critical role in
he diagnosis of both complete and par-ial mole, and it has virtually replaced allther means of preoperative diagno-is.38,43-45 Because the chorionic villi ofomplete moles exhibit diffuse hydropicwelling, a characteristic vesicular ultra-onographic pattern can be observed,onsisting of multiples echoes (holes)ithin the placental mass and usually no
etus (Figure 6). Ultrasonography maylso facilitate the early diagnosis of a par-ial mole by demonstrating focal cysticpaces within the placenta and an in-rease in the transverse diameter of theestational sac.45
uman chorionic gonadotropinCG is a disease-specific tumor markerroduced by hydatidiform moles andestational trophoblastic neoplasms. It isasily measured quantitatively in bothrine and blood, and hCG levels haveeen shown to correlate with the burdenf disease. It is a placental glycoproteinomposed of 2 dissimilar subunits: an �ubunit resembling that of the pituitarylycoprotein hormones and a � subunithat is unique to placental production.everal forms of hCG exist, including ateast 6 major variants that can be de-ected in serum: hyperglycosylated,icked, absent C-terminal of the � sub-nit, free � subunit, nicked free � sub-nit, and free � subunit. The hCG mol-cules in GTD are more heterogenousnd degraded than those in normal preg-ancy, therefore, an assay that will detectll main forms of hCG and its multipleragments should be used to follow upatients with GTD. Most institutions
urrently use rapid, automated radiola-
FIGURE 4Choriocarcinoma
horiocarcinoma composed of abnormal cytotrophoblast and syncytiotrophoblast with hyperplasiand anaplasia, absence of chorionic villi, hemorrhage, and necrosis.urain. Gestational trophoblastic disease I. Am J Obstet Gynecol 2010.
FIGURE 5Placental site trophoblastic tumor
lacental site trophoblastic tumor with sheets of mononuclear intermediate trophoblast cells withouthorionic villi infiltrating between myometrial fibers.urain. Gestational trophoblastic disease I. Am J Obstet Gynecol 2010.
DECEMBER 2010 American Journal of Obstetrics & Gynecology 535
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eled monoclonal antibody sandwichssays that measure different mixtures ofCG-related molecules.46-48
Hydatidiform moles are commonlyssociated with markedly elevated hCGevels above those of normal pregnancy.pproximately 50% of patients withomplete mole have preevacuation hCGevels �100,000 mIU/mL.49,50 A singleCG determination, however, is seldomelpful in differentiating complete mole
rom a normal intrauterine pregnancy, aultiple gestation, or a pregnancy com-
licated by diseases such as erythroblas-osis fetalis or intrauterine infectionshat are associated with an enlarged pla-enta, because hCG levels are highest inhe late first trimester of pregnancy at aime when a diagnosis of molar preg-ancy is usually being considered. Partialoles, on the other hand, are most often
ot distinguished by such elevated hCGevels, �100,000 mIU/mL in �10% ofatients.40,42
A clinical diagnosis of postmolar GTNs most often made by the finding of ris-ng or plateauing hCG levels following
FIGURE 6Pelvic ultrasound of a complete hy
elvic ultrasound of complete hydatidiform mochoes, holes within placental mass, and no fetuurain. Gestational trophoblastic disease I. Am J Obstet Gyne
vacuation of a hydatidiform mole. Cho- m
36 American Journal of Obstetrics & Gynecology
iocarcinoma is usually diagnosed by thending of an elevated hCG level, fre-uently in conjunction with the dis-overy of metastases, following otherregnancy events. PSTT and ETT areommonly associated with slightly raisedCG levels.Although accurate measurements of
CG levels are invaluable in diagnosingnd later monitoring GTD, some labora-ory assays may yield false-positive hCGesults.51 These so-called phantom hCGesults, with levels reported as high as00 mIU/mL, have led to treatment ofealthy patients with unnecessary sur-ery and chemotherapy.52 The causes ofhese false-positive test results are pro-eolytic enzymes that produce nonspe-ific protein interference and hetero-hile (human antimouse) antibodies.hese antibodies are found in 3-4% ofealthy people and can mimic hCG im-unoreactivity by linking and capturing
racer mouse IgG. There are 3 ways toetermine whether hCG assays are
alsely positive when there is a clinicaluspicion of phantom hCG: (1) deter-
idiform mole
ith characteristic vesicular pattern of multiple
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ine a urine hCG level, which should be h
DECEMBER 2010
egative because the interfering sub-tances are not excreted in urine; (2) re-uest serial dilution of the serum, whichhould not show a parallel decrease withilution; and (3) send the serum andrine of the patient to an hCG reference
aboratory. Additionally, there is someross-reactivity of hCG with luteinizingormone (LH), which may lead to falselylevated low levels of hCG. Measure-ent of LH to identify this possibility
nd suppression of LH with oral contra-eptive pills will prevent this problem.53
“Quiescent gestational trophoblasticisease” is a term applied to a presumed
nactive form of GTN that is character-zed by persistent, unchanging low levels�200 mIU/mL) of “real” hCG for ateast 3 months associated with a historyf GTD or spontaneous abortion, butithout clinically detectable disease. TheCG levels do not change with che-otherapy or surgery. Subanalysis of
CG reveals no hyperglycosylated hCG,hich is associated with cytotrophoblas-
ic invasion. Follow-up of patients withresumed quiescent GTD reveals subse-uent development of active GTN inbout one-quarter, which is heralded byn increase in both hyperglycosylatedCG and total hCG.54,55 According tohe International Society for the Study ofrophoblastic Disease 2001 recommen-ations for managing this condition,
alse-positive hCG resulting from hete-ophile antibodies or LH interferencehould be excluded, the patient shoulde thoroughly investigated for evidencef disease, immediate chemotherapy orurgery should be avoided, and the pa-ient should be monitored long termith periodic hCG testing while avoidingregnancy. Treatment should be under-aken only when there is a sustained risen hCG or the appearance of overt clini-al disease.53
athologic diagnosisathologic diagnosis of complete andartial moles is made by examination ofurettage specimens. Immunohistologi-al staining for p57 (a paternally im-rinted, maternally expressed gene) canifferentiate absent immunostainingomplete moles from positively staining
dat
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nd flow cytometry can distinguish dip-oid complete from triploid partial
oles.56,57 Additionally, pathologic di-gnosis of invasive mole, choriocarci-oma, PSTT, and ETT can sometimes beade by curettage, biopsy of metastatic
esions, or examination of hysterectomypecimens or placentas. Biopsy of a vag-nal lesion suggestive of a gestational tro-hoblastic tumor is dangerous becausef the massive bleeding that may occur.58
ydatidiform molereatmentnce the diagnosis of molar pregnancy is
uspected by history, physical examina-ion, hCG levels, and ultrasound find-ngs, the patient should be evaluated forhe presence of medical complicationsanemia, preeclampsia, hyperthyroid-sm) by way of vital signs and laboratoryests, such as complete blood cell counts,asic chemistry, hepatic and thyroidanels, urinalysis, and chest x-ray. Thereoperative evaluation should also in-lude blood type and crossmatch, serumCG level, and electrocardiogram if ap-ropriate. After the diagnosis is con-rmed and the patient is determined toe hemodynamically stable, the most ap-ropriate method of molar evacuationhould be decided upon.59,60
Suction evacuation and curettage ishe preferred method of evacuation of aydatidiform mole, independent ofterine size, for patients who wish toaintain their fertility.61,62 After anes-
hesia is achieved, the cervix is dilated tollow a 12- to 14-mm suction cannula toass into the lower uterine segment. Theannula is then rotated as the intrauter-ne contents are removed. It is recom-
ended that an intravenous oxytocin in-usion be started at the onset of suctionurettage and continued for severalours postoperatively to enhance uter-
ne contractability. Suction evacuationhould be followed by gentle sharp curet-age. Because the risk of bleeding in-reases with uterine size, at least 2 U oflood should be immediately availablehen the uterus is �16-weeks’ gesta-
ional size. Attention to blood and crys-alloid replacement decreases pulmo-ary complications. It is clear that with
udicious use of appropriate equipment, t
ccess to blood products, careful intra-perative monitoring, and early antici-ation of complications patient outcome
mproves. Patients who are Rh negativehould receive Rh immune globulin athe time of evacuation, as Rh D factor isxpressed on trophoblastic cells.59,60
Hysterectomy is an alternative to suc-ion curettage if childbearing has beenompleted. The adnexa may be left intactven in the presence of theca lutein cysts.n addition to evacuating the molarregnancy, hysterectomy provides per-anent sterilization and eliminates the
isk of local myometrial invasion as aause of persistent disease. Because of theotential for metastatic disease even af-er hysterectomy, the risk of postmolarTN still remains at 3-5%, thereby re-uiring continued hCG follow-up.61
Medical induction of labor and hys-erotomy are not recommended for
olar evacuation. These methods in-rease maternal morbidity, such aslood loss, incomplete evacuation re-uiring dilation and curettage, and theequirement for cesarean delivery inubsequent pregnancies. They also in-rease trophoblastic disseminationnd the development of postmolarTN requiring chemotherapy.62
A twin pregnancy consisting of a com-lete mole and a coexisting normal fetus
s estimated to occur once in every2,000-100,000 pregnancies. It must beistinguished from a partial mole (trip-
oid pregnancy with fetus). The diagno-is can usually be established by ultra-ound, but cytogenetics may be used toifferentiate between chromosomallyormal, potentially viable fetuses and
riploid nonviable fetuses. Patients withtwin normal fetus/complete mole preg-ancy should be cautioned that they maye at increased risk for hemorrhage andedical complications as well as devel-
pment of persistent GTN. Suctionvacuation and curettage in the operat-ng room is recommended for desiredregnancy termination, bleeding, oromplications, however, up to 40% ofhese pregnancies will result in normaliable fetuses if allowed to continue.63-66
Prophylactic administration of eitherethotrexate or actinomycin D chemo-
herapy at the time of or immediately af- t
DECEMBER 2010 Am
er evacuation of a hydatidiform mole isssociated with a reduction in incidencef postmolar GTN from approximately5-20% down to 3-8%. The use of pro-hylactic chemotherapy should be lim-
ted, however, to special situations inhich the risk of postmolar GTN isuch greater than normal or where ad-
quate hCG follow-up is not possible, asssentially all patients who are followedp with serial hCG testing after molarvacuation and found to have persistentTN can be cured with appropriate
hemotherapy.67-69
ollow-up after molar evacuationollow-up after evacuation of a hydatid-
form mole is essential to detect tro-hoblastic sequelae (invasive mole orhoriocarcinoma), which develop in ap-roximately 15-20% with completeole and 1-5% with partial mole.59,70-74
linical findings of prompt uterine invo-ution, ovarian cyst regression, and ces-ation of bleeding are all reassuring signs,owever, definitive follow-up requireserial serum quantitative hCG measure-
ents every 1-2 weeks until 3 consecu-ive tests show normal levels, after whichCG levels should be determined at-month intervals for 6 months after thepontaneous return to normal. Morehan half of patients will have completeegression of hCG to normal within 2onths of evacuation. Contraception is
ecommended for 6 months after therst normal hCG result, to distinguish aising hCG because of persistent or re-urrent disease from a rising hCG asso-iated with a subsequent pregnancy. These of oral contraceptive pills is prefera-le because they have the advantage ofuppressing endogenous LH, which maynterfere with the measurement of hCGt low levels and studies have shown thathey do not increase the risk of postmo-ar trophoblastic neoplasia.75-77 Patho-ogic examination of the placenta andther products of conception as well asetermination of a 6-week postpartumCG level is recommended with all fu-ure pregnancies.
The likelihood of persistent disease de-eloping after evacuation of a completeole increases with evidence of marked
vacuation hCG level �100,000 mIU/L, excessive uterine growth (�20-eek size), and theca lutein cysts �6 cm
n diameter. Patients with �1 of theseigns have approximately a 40% inci-ence of postmolar GTN compared to% for those without any of these signs.atients with an age �40 years, a repeatolar pregnancy, an aneuploid mole,
nd medical complications of molarregnancy, such as toxemia, hyperthy-oidism, and trophoblastic emboliza-ion, are also at increased risk for post-
olar GTN.59 f
EFERENCES. Hancock BW, Seckl MJ, Berkowitz RS, ColeA, eds. Gestational trophoblastic disease, 3rdd. London, UK: International Society for thetudy of Trophoblastic Diseases; 2009.. Soper JT. Gestational trophoblastic disease.bstet Gynecol 2006;108:176-87.. Berkowitz RS, Goldstein DP. Current man-gement of gestational trophoblastic disease.ynecol Oncol 2009;112:654-62.. Bracken MB. Incidence and etiology of hyda-idiform mole: an epidemiological review. Br Jbstet Gyncol 1987;94:1123-35.. Palmer JR. Advances in the epidemiology ofestational trophoblastic disease. J Reproded 1994;39:155-62.. Atrash HK, Hogue CJR, Grimes DA. Epide-iology of hydatidiform mole during early ges-
ation. Am J Obstet Gynecol 1986;154:906-9.. Bagshawe KD, Dent J, Webb J. Hydatidiformole in England and Wales 1973-1983. Lancet986;2:673-7.. Takeuchi S. Incidence of gestational tropho-lastic disease by regional registration in Japan.um Reprod 1987;2:729-34.. Smith HO. Gestational trophoblastic disease:pidemiology and trends. Clin Obstet Gynecol003;46:541-56.0. Brinton LA, Bracken MB, Connelly RR.horiocarcinoma incidence in the Unitedtates. Am J Epidemiol 1986;123:1094-100.1. Smith HO, Qualls CR, Prairie BA, et al.rends in gestational choriocarcinoma: a 27-ear perspective. Obstet Gynecol 2003;102:78-87.2. Parazzini F, Mangili G, LaVecchia C, et al.isk factors for gestational trophoblastic dis-ase: a separate analysis of complete and par-ial hydatidiform moles. Obstet Gynecol 1991;8:1039-45.3. Parazzini F, LaVecchia C, Pampallona S.arental age and risk of complete and partialydatidiform mole. Br J Obstet Gynecol 1986;3:582-5.4. Sebire NJ, Foskett M, Fisher RA, et al. Riskf partial and complete molar pregnancy in re-
ation to maternal age. Br J Obstet Gynecol
002;109:99-102. m
38 American Journal of Obstetrics & Gynecology
5. Sand PK, Lurain JR, Brewer JL. Repeatestational trophoblastic disease. Obstet Gy-ecol 1984;63:140-4.6. Berkowitz RS, Im SS, Bernstein MR, Gold-tein DP. Gestational trophoblastic disease:ubsequent pregnancy outcome, including re-eat molar pregnancy. J Reprod Med 1998;3:81-6.7. Wang CM, Dixon PH, Decordova S, et al.
dentification of 13 novel NLRP7 mutations in 20amilies with recurrent hydatidiform mole; mis-ense mutations cluster in the leucine-rich re-ion. J Med Genet 2009;46:569-75.8. Berkowitz RS, Cramer DW, Bernstein MR,t al. Risk factors for complete molar pregnancyrom a case-control study. Am J Obstet Gy-ecol 1985;152:1016-20.9. Parazzini F, LaVecchia C, Mangili G, et al.ietary factors and risk of trophoblastic dis-ase. Am J Obstet Gynecol 1988;158:93-9.0. Palmer JR, Driscoll SG, Rosenberg L, et al.ral contraceptive use and the risk of gesta-
ional trophoblastic tumors. J Natl Cancer Inst999;91:635-40.1. Moore KL, Persaud TVN. The developinguman–clinically oriented embryology. Phila-elphia (PA): WB Saunders; 1993.2. Bentley RC. Pathology of gestational tro-hoblastic disease. Clin Obstet Gynecol 2003;6:513-22.3. Szulman AE, Surti U. The syndromes of hy-atidiform mole, I: cytogenetic and morpho-
ogic correlations. Am J Obstet Gynecol 1978;31:665-71.4. Szulman AE, Surti U. The syndromes of hy-atidiform mole, II: morphologic evolution of theomplete and partial mole. Am J Obstet Gy-ecol 1978;132:20-7.5. Berkowitz RS, Goldstein DP, Bernstein MR.volving concepts of molar pregnancy. J Re-rod Med 1991;36:40-4.6. Mosher R, Goldstein DP, Berkowitz R, et al.omplete hydatidiform mole: comparison oflinicopathologic features, current and past. Jeprod Med 1998;43:21-7.7. Lage JM, Mark SD, Roberts DJ, et al. A flowytometric study of 137 fresh hydropic placen-as: correlation between types of hydatidiformoles and nuclear DNA ploidy. Obstet Gynecol992;79:403-10.8. Paradinas FJ, Browne P, Fisher RA, et al. Alinical, histopathological and flow of cytometrictudy of 149 complete moles, 146 partial molesnd 107 non-molar hydropic abortions. Histo-athology 1996;28:101-10.9. Sebire NJ, Fisher RA, Rees HC. His-opathologic diagnosis of partial and completeydatidiform mole in the first trimester of preg-ancy. Pediatr Dev Pathol 2003;6:69-77.0. Sebire NJ, Makrydimas G, Agnantis NJ, etl. Updated diagnostic criteria for partial andomplete hydatidiform moles in early preg-ancy. Anticancer Res 2003;23:1723-8.1. Lurain JR, Brewer JI. Invasive mole. Seminncol 1982;9:174-80.2. Lurain JR. Gestational trophoblastic tu-
ors. Semin Surg Oncol 1990;6:347-53. p
DECEMBER 2010
3. Baergen RN, Rutgers JL, Young RH, et al.lacental site trophoblastic tumor: a study of 55ases and review of the literature emphasizingactors of prognostic significance. Gynecol On-ol 2006;100:511-20.4. Shih IM, Kurman RJ. Epithelioid trophoblas-ic tumor: a neoplasm distinct from choriocarci-oma and placental site trophoblastic tumorimulating carcinoma. Am J Surg Pathol 1998;2:1393-403.5. Allison KH, Love JE, Garcia RL. Epithelioidrophoblastic tumor: review of a rare neoplasmf the chorionic-type intermediate trophoblast.rch Pathol Lab Med 2006;130:1875-7.6. Curry SL, Hammond CB, Tyrey L, et al. Hy-atidiform mole: diagnosis, management, and
ong-term follow-up of 347 patients. Obstet Gy-ecol 1975;45:1-8.7. Kohorn EI. Molar pregnancy: presentationnd diagnosis. Clin Obstet Gynecol 1984;27:81-9.8. Soto-Wright V, Bernstein MR, GoldsteinP, et al. The changing clinical presentation ofomplete molar pregnancy. Obstet Gynecol995;86:775-9.9. Hou JL, Wan XR, Xiang Y, et al. Changes inlinical features in hydatidiform mole: analysisn 113 cases. J Reprod Med 2008;53:629-33.0. Czernobilsky B, Barash A, Lancet M. Partialoles: a clinicopathologic study of 25 cases.bstet Gynecol 1982;59:75-7.1. Szulman AE, Surti U. The clinicopathologicrofile of the partial hydatidiform mole. Obstetynecol 1982;59:597-602.2. Berkowitz RS, Goldstein DP, Bernstein MR.atural history of partial molar pregnancy. Ob-tet Gynecol 1985;66:677-81.3. Santos-Ramos R, Forney JP, Schwarz BE.onographic findings and clinical correlations inolar pregnancy. Obstet Gynecol 1980;56:86-92.4. Benson CB, Genest DR, Bernstein MR, etl. Sonographic appearance of first trimesteromplete hydatidiform moles. Ultrasound Ob-tet Gynecol 2000;16:188-91.5. Fine C, Bundy AL, Berkowitz RS, et al.onographic diagnosis of partial hydatidiformole. Obstet Gynecol 1989;73:414-8.6. Cole LA. hCG, its free subunits and its me-abolites: roles in pregnancy and trophoblasticisease. J Reprod Med 1998;43:3-10.7. Berkowitz RS, Ozturk M, Goldstein D, et al.uman chorionic gonadotropin and free sub-nits’ serum levels in patients with partial andomplete hydatidiform moles. Obstet Gynecol989;74:212-6.8. Ozturk M, Berkowitz R, Goldstein D, et al.ifferential production of human chorionic go-adotropin and free subunits in gestational tro-hoblastic disease. Am J Obstet Gynecol988;158:193-8.9. Menczer J, Modan M, Serr DM. Prospective
ollow-up of patients with hydatidiform mole.bstet Gynecol 1980;55:346-9.0. Genest DR, Laborde O, Berkowitz RS, et al.clinicopathologic study of 153 cases of com-
lete hydatidiform mole (1980-1990): histologic
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www.AJOG.org Reviews
rade lacks prognostic significance. Obstetynecol 1991;78:402-9.1. Palmieri C, Dhillon T, Fisher RA, et al. Man-gement and outcome of healthy women with aersistently elevated �-hCG. Gynecol Oncol007;106:35-43.2. Rotmensch S, Cole LA. False diagnosis andeedless therapy of presumed malignant dis-ase in women with false-positive human cho-ionic gonadotropin concentrations. Lancet000;355:712-5.3. Hancock BW. hCG measurement in gesta-ional trophoblastic neoplasia: a critical ap-raisal. J Reprod Med 2006;51:859-60.4. Cole LA, Butler SA, Khanlian SA, et al. Ges-ational trophoblastic diseases, 2: hyperglyco-ylated hCG as a tumor marker of active neo-lasia. Gynecol Oncol 2006;102:151-9.5. Khanlian SA, Cole LA. Management of ges-ational trophoblastic disease and other casesith low serum levels of human chorionic go-adotropin. J Reprod Med 2006;51:812-8.6. Castrillon DH, Sun D, Weremowicz S, et al.iscrimination of complete hydatidiform mole
rom its mimics by immunohistochemistry of theaternally imprinted gene product p57K1P2.m J Surg Pathol 2001;25:1225-30.7. Thaker HM, Berlin A, Tycko B, et al. Immu-ohistochemistry for the imprinted gene prod-ct IPL/PHLDA2 for facilitating the differentialiagnosis of complete hydatidiform mole. J Re-rod Med 2004;49:630-6.8. Berry E, Hagopian GS, Lurain JR. Vaginaletastases in gestational trophoblastic neopla-
ia. J Reprod Med 2008;53:487-92.9. Berkowitz RS, Goldstein DS. Clinical prac-ice: molar pregnancy. N Engl J Med 2009;
60:1639-45. J
0. Hancock BW, Tidy JA. Current manage-ent of molar pregnancy. J Reprod Med002;47:347-54.1. Soper JT. Surgical therapy for gestationalrophoblastic disease. J Reprod Med 1994;9:168-74.2. Tidy JA, Gillespie AM, Bright N, et al. Ges-ational trophoblastic disease: a study of modef evacuation and subsequent need for treat-ent with chemotherapy. Gynecol Oncol000;78:309-12.3. Stellar MA, Genest DR, Bernstein MF, et al.linical features of multiple conception with par-
ial or complete molar pregnancy and coexistingetus. J Reprod Med 1994;39:147-54.4. Fishman DA, Padilla LA, Keh P, et al. Man-gement of twin pregnancies consisting of aomplete hydatidiform mole and normal fetus.bstet Gynecol 1998;91:546-50.5. Matsui H, Sekiya S, Hando T, et al. Hyda-idiform mole coexistent with a twin live fetus: aational collaborative study in Japan. Hum Re-rod 2000;15:608-11.6. Sebire NJ, Foskett M, Paradinas FJ, et al.utcome of twin pregnancies with completeydatidiform mole and healthy co-twin. Lancet002;359:2165-6.7. Kashimura Y, Kashmira M, Sugimori H, etl. Prophylactic chemotherapy for hydatidiformole: 5-15 years follow-up. Cancer 1986;58:24-9.8. Kim DS, Moon H, Kim KT, et al. Effects ofrophylactic chemotherapy for persistent tro-hoblastic disease in patients with completeydatidiform mole. Obstet Gynecol 1986;67:90-4.9. Limpongsanurak S. Prophylactic actinomy-in D for high-risk complete hydatidiform mole.
Reprod Med 2001;46:110-6.
DECEMBER 2010 Am
0. Lurain JR, Brewer JI, Torok E, Halpern B.atural history of hydatidiform mole after pri-ary evacuation. Am J Obstet Gynecol 1983;45:591-5.1. Feltmate CM, Batorfi J, Fulop V, et al. Hu-an chorionic gonadotropin follow-up in pa-
ients with molar pregnancy: a time for reevalu-tion. Obstet Gynecol 2003;101:732-6.2. Hancock BW, Nazir K, Everard JE. Persis-ent gestational trophoblastic neoplasia afterartial hydatidiform mole: incidence and out-ome. J Reprod Med 2006;51:764-6.3. Feltmate CM, Growdon WB, Wolfberg AJ,t al. Clinical characteristics of persistent ges-ational trophoblastic neoplasia after partial hy-atidiform molar pregnancy. J Reprod Med006;51:902-6.4. Goto S, Yamada A, Ishizuka T, Tomodo Y.evelopment of postmolar trophoblastic dis-ase after partial molar pregnancy. Gynecol On-ol 1993;48:165-70.5. Berkowitz RS, Goldstein DP, Marean AR, etl. Oral contraceptives and postmolar gesta-ional trophoblastic disease. Obstet Gynecol981;58:474-7.6. Curry SL, Schlaerth JB, Kohorn EI, et al.ormonal contraception and trophoblastic se-uelae after hydatidiform mole (a gynecologicncology group study). Am J Obstet Gynecol989;160:805-11.7. Deicas RE, Miller DS, Rademaker AW, et al.he role of contraception in the development ofostmolar gestational trophoblastic tumor. Ob-tet Gynecol 1991;78:221-6.
