Gestational trophoblastic disease I: epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole John R. Lurain, MD G estational trophoblastic disease (GTD) is a spectrum of cellular proliferations arising from the placental villous trophoblast encompassing 4 main clinicopathologic forms: hydatidi- form mole (complete and partial), inva- sive mole, choriocarcinoma, and placen- tal site trophoblastic tumor (PSTT) (Table). The term “gestational tropho- blastic neoplasia” (GTN) has been ap- plied collectively to the latter 3 condi- tions, which can progress, invade, metastasize, and lead to death if left untreated. GTD was historically associated with significant morbidity and mortality. Hydatidiform moles were often accom- panied by serious bleeding and other medical complications prior to the development of early detection and ef- fective uterine evacuation means in the 1970s. The outcomes for GTN were like- wise poor before the introduction of che- motherapy into their management 50 years ago. The mortality rate for invasive mole approached 15%, most often be- cause of hemorrhage, sepsis, embolic phenomena, or complications from sur- gery. Choriocarcinoma had a mortality rate of almost 100% when metastases were present and approximately 60% even when hysterectomy was done for apparent nonmetastatic disease. Gesta- tional trophoblastic neoplasms are now some of the most curable of all solid tu- mors, with cure rates 90% even in the presence of widespread metastatic disease. 1-3 Epidemiology The incidence and etiologic factors con- tributing to the development of GTD have been difficult to characterize. The problems in accumulating reliable epi- demiologic data can be attributed to a number of factors, such as inconsisten- cies in case definitions, inability to ade- quately characterize the population at risk, no centralized databases, lack of well-chosen control groups against which to compare possible risk factors, and rarity of the diseases. 4 Epidemiologic studies have reported wide regional variations in the incidence of hydatidiform mole. 5 Estimates from studies conducted in North America, Australia, New Zealand, and Europe have shown the incidence of hydatidi- form mole to range from 0.57–1.1 per 1000 pregnancies, whereas studies in Southeast Asia and Japan have suggested an incidence as high as 2.0 per 1000 preg- nancies. 6 Investigations into possible ethnic and racial differences leading to an increased incidence of hydatidiform mole among American Indians, Eski- mos, Hispanics, and African Americans as well as various Asian populations have not been able to attribute them to genetic traits, cultural factors, or simply differ- ences in reporting. 7-9 Data with respect to choriocarcinoma incidence rates are even more limited. Collection of data on the incidence of choriocarcinoma has been more difficult not only for reasons similar to those en- countered with hydatidiform moles, but also because of the rarity of choriocarci- noma and the difficulty in clinically dis- tinguishing postmolar choriocarcinoma from invasive mole. In Europe and North America, choriocarcinoma affects approximately 1 in 40,000 pregnancies and 1 in 40 hydatidiform moles, whereas in Southeast Asia and Japan choriocarci- noma rates are higher at 9.2 and 3.3 per 40,000 pregnancies, respectively. The in- cidence rates of both hydatidiform mole and choriocarcinoma have declined over the past 30 years in all populations. 10,11 Several potential etiologic risk factors have been evaluated for the development of complete hydatidiform mole. 12 The 2 established risk factors that have emerged are extremes of maternal age and prior molar pregnancy. Advanced or very young maternal age has consis- tently correlated with higher rates of complete hydatidiform mole. Compared From the John I. Brewer Trophoblastic Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL. Received April 13, 2010; revised June 16, 2010; accepted June 30, 2010. Reprints: John R. Lurain, MD, John I. Brewer Trophoblastic Disease Center, Northwestern University Feinberg School of Medicine, 250 E. Superior St., Suite 05-2168, Chicago, IL 60611. [email protected]. 0002-9378/free © 2010 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2010.06.073 For Editors’ Commentary, see Table of Contents Gestational trophoblastic disease includes hydatidiform mole (complete and partial) and gestational trophoblastic neoplasia (invasive mole, choriocarcinoma, placental site tropho- blastic tumor, and epithelioid trophoblastic tumor). The epidemiology, pathology, clinical presentation, and diagnosis of each of these trophoblastic disease variants are discussed. Particular emphasis is given to management of hydatidiform mole, including evacuation, twin mole/normal fetus pregnancy, prophylactic chemotherapy, and follow-up. Key words: chemotherapy, choriocarcinoma, gestational trophoblastic disease, gestational trophoblastic neoplasia, hydatidiform mole www.AJOG.org Reviews DECEMBER 2010 American Journal of Obstetrics & Gynecology 531
Gestational trophoblastic disease I: epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole
Dec 19, 2022
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
G c d J
G p v m f s t ( b p t m u
s H p m d f 1 w m y m c p g r
F D F
0 © d
www.AJOG.org Reviews
ohn R. Lurain, MD
w e a t s m p d
E T t h p d n c q r w w a
w o s A h f 1 S a n
a m m a n t e
i C c n c a n t f N a a i n 4 c a t
h o 2 e a o t
estational trophoblastic disease (GTD) is a spectrum of cellular
roliferations arising from the placental illous trophoblast encompassing 4 ain 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 left ntreated. GTD was historically associated with
ignificant morbidity and mortality. ydatidiform moles were often accom-
anied by serious bleeding and other edical complications prior to the
evelopment of early detection and ef- ective uterine evacuation means in the 970s. The outcomes for GTN were like- ise poor before the introduction of che- otherapy into their management 50
ears ago. The mortality rate for invasive ole approached 15%, most often be-
ause of hemorrhage, sepsis, embolic henomena, or complications from sur- ery. Choriocarcinoma had a mortality ate of almost 100% when metastases
rom the John I. Brewer Trophoblastic isease Center, Northwestern University einberg School of Medicine, Chicago, IL.
eceived April 13, 2010; revised June 16, 010; accepted June 30, 2010.
eprints: John R. Lurain, MD, John I. Brewer rophoblastic Disease Center, Northwestern niversity Feinberg School of Medicine, 250 E. uperior St., Suite 05-2168, Chicago, IL 0611. [email protected].
002-9378/free 2010 Mosby, Inc. All rights reserved.
oi: 10.1016/j.ajog.2010.06.073
e see Table of Contents
ere present and approximately 60% ven when hysterectomy was done for pparent nonmetastatic disease. Gesta- ional trophoblastic neoplasms are now ome of the most curable of all solid tu-
ors, with cure rates 90% even in the resence of widespread metastatic isease.1-3
pidemiology he incidence and etiologic factors con-
ributing to the development of GTD ave been difficult to characterize. The roblems in accumulating reliable epi- emiologic data can be attributed to a umber of factors, such as inconsisten- ies in case definitions, inability to ade- uately characterize the population at isk, no centralized databases, lack of ell-chosen control groups against hich to compare possible risk factors,
nd rarity of the diseases.4
Epidemiologic studies have reported ide regional variations in the incidence f hydatidiform mole.5 Estimates from tudies conducted in North America, ustralia, New Zealand, and Europe ave shown the incidence of hydatidi-
orm mole to range from 0.57–1.1 per 000 pregnancies, whereas studies in outheast Asia and Japan have suggested n incidence as high as 2.0 per 1000 preg- ancies.6 Investigations into possible
Gestational trophoblastic disease includes gestational trophoblastic neoplasia (invasive blastic tumor, and epithelioid trophoblastic presentation, and diagnosis of each of these Particular emphasis is given to manageme twin mole/normal fetus pregnancy, prophyl
Key words: chemotherapy, choriocarcinom gestational trophoblastic neoplasia, hydatid
thnic and racial differences leading to c
DECEMBER 2010 Am
n increased incidence of hydatidiform ole among American Indians, Eski- os, Hispanics, and African Americans
s well as various Asian populations have ot been able to attribute them to genetic
raits, cultural factors, or simply differ- nces in reporting.7-9
Data with respect to choriocarcinoma ncidence rates are even more limited. ollection of data on the incidence of
horiocarcinoma has been more difficult ot only for reasons similar to those en- ountered with hydatidiform moles, but lso because of the rarity of choriocarci- oma and the difficulty in clinically dis-
inguishing postmolar choriocarcinoma rom invasive mole. In Europe and orth America, choriocarcinoma affects
pproximately 1 in 40,000 pregnancies nd 1 in 40 hydatidiform moles, whereas n Southeast Asia and Japan choriocarci- oma rates are higher at 9.2 and 3.3 per 0,000 pregnancies, respectively. The in- idence rates of both hydatidiform mole nd choriocarcinoma have declined over he past 30 years in all populations.10,11
Several potential etiologic risk factors ave been evaluated for the development f complete hydatidiform mole.12 The
established risk factors that have merged are extremes of maternal age nd prior molar pregnancy. Advanced r very young maternal age has consis- ently correlated with higher rates of
atidiform mole (complete and partial) and le, choriocarcinoma, placental site tropho- or). The epidemiology, pathology, clinical phoblastic disease variants are discussed. f hydatidiform mole, including evacuation, ic chemotherapy, and follow-up.
gestational trophoblastic disease, m mole
hyd mo tum tro
i l
c e C t t r a r n c n b w u
P M p f t b d i p
g f c i e r b g m c c a p p
H H m d ( p c a d d a h
ynec
5
o women aged 21-35 years, the risk of omplete mole is 1.9 times higher for omen both 35 years and 21 years as ell 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 after mole is about 1%, or about 10-20 times
he risk for the general population.15,16
amilial clusters of biparental complete ydatidiform moles associated with ovel missense NLRP7 gene mutations n chromosome 19q have also been
dentified.17 Another reported obstetric isk factor for both complete and partial oles 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 of iscarriage.12 Although many possible
nvironmental etiologies for complete ole have been studied, the only consis-
ent association has been an inverse rela- ionship between -carotene and animal at dietary intake and the incidence of
olar pregnancy.18,19 Ovulation induc- ion for fertility may also be associated
TABLE Clinicopathologic features of gesta
Gestational trophoblastic disease Pathol
...................................................................................................................
...................................................................................................................
...................................................................................................................
...................................................................................................................
...................................................................................................................
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 mole han after another pregnancy event. The isk is also increased in women of Asian nd American Indian descent as well as Af- ican Americans. Similar to molar preg- ancies, the median age of women with horiocarcinoma is higher than that for ormal pregnancies.11 There also seems to e an increased risk of choriocarcinoma in omen with long-term oral contraceptive se and blood group A.5,20
athology olar pregnancies and gestational tro-
hoblastic neoplasms all take their origin rom the placental trophoblast. Normal rophoblast 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
15-20% t hCG often Medical c
.........................................................................................................................
9, XXY; 69, XYY; 69 XXX) fetus/embryo lling of villi oblastic hyperplasia
5% trop hCG usua Rare med
.........................................................................................................................
15% met Most ofte
.........................................................................................................................
ls infiltrate myometrium with mphatic invasion te cells/absent villi rrhage and necrosis
ls stain positive for hPL
Extremely hCG level Relatively Mainly su
.........................................................................................................................
ol 2010.
DECEMBER 2010
onadotropin (hCG). Cytotrophoblast unctions to supply the syncytium with ells in addition to forming outpouch- ngs that become the chorionic villi cov- ring the chorionic sac. The villous cho- ion adjacent to the endometrium and asalis layer of the endometrium to- ether form the functional placenta for aternal-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 they roliferate.21,22
ydatidiform mole ydatidiform mole refers to an abnor- al pregnancy characterized by varying
egrees of trophoblastic proliferation both cytotrophoblast and syncytiotro- hoblast) and vesicular swelling of pla- ental villi associated with an absent or n abnormal fetus/embryo. Two syn- romes of hydatidiform mole have been escribed based on both morphologic nd cytogenetic criteria.23,24 Complete ydatidiform moles undergo early and
ures
..................................................................................................................
..................................................................................................................
..................................................................................................................
..................................................................................................................
......... .........
niform hydatid enlargement of villi in
t e h a ( p d h e a 1 X o b r 1 f t w s m t c a m 6 o s d c s fi
I I a d t u t m t m r s a m d
C C c h c s
C h L
www.AJOG.org Reviews
he absence of an ascertainable fetus or mbryo, the trophoblast is consistently yperplastic with varying degrees of typia, and villous capillaries are absent Figure 1). Approximately 90% of com- lete moles are 46, XX, originating from uplication of the chromosomes of a aploid sperm after fertilization of an gg in which the maternal chromosomes re either inactive or absent. The other 0% of complete moles are 46, XY, or 46, X, as a result of fertilization of an empty vum by 2 sperm (dispermy). Tropho- lastic neoplasia (invasive mole or cho- iocarcinoma) follows complete mole in 5-20% of cases.23-27 Partial hydatidi- orm moles demonstrate identifiable fe- al or embryonic tissue, chorionic villi ith 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 mild typia only (Figure 2). Most partial oles have a triploid karyotype (usually
9, XXY), resulting from the fertilization f an apparently normal ovum by 2 perm. Less than 5% of partial moles will evelop 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 mole nvasive mole is a benign tumor that rises from myometrial invasion of a hy- atidiform mole via direct extension hrough tissue or venous channels (Fig- re 3). Approximately 10-17% of hyda-
idiform moles will result in invasive ole, and about 15% of these will metas-
asize to the lungs or vagina. Invasive ole 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
haracterized by abnormal trophoblastic yperplasia and anaplasia, absence of horionic villi, hemorrhage, and necro-
is (Figure 4), with direct invasion into
FIGURE 1 Complete hydatidiform mole
omplete hydatidiform mole with hydropic villi, absence of villous blood vessels, proliferation of yperplastic cytotrophoblast, and syncytiotrophoblast. urain. Gestational trophoblastic disease I. Am J Obstet Gynecol 2010.
FIGURE 2 Partial 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 trophoblastic yperplasia. urain. Gestational trophoblastic disease I. Am J Obstet Gynecol 2010.
DECEMBER 2010 American Journal of Obstetrics & Gynecology 533
t r c v s p p c n p 5 t m
P P a s m w s b l h i t v a h
r l n
E E i c h d o b t
C C C m u t c u p p h m c a
e o c m a
P P s t h a m s t a s p p v l o
G G i e P r a t g l b s b w C m s l o p v a r d t o t p r m c
I t L
5
he myometrium and vascular invasion esulting in spread to distant sites, most ommonly to the lungs, brain, liver, pel- is and vagina, kidney, intestines, and pleen. Choriocarcinoma has been re- orted to occur in association with any regnancy event. Approximately 25% of ases follow abortion or tubal preg- ancy, 25% are associated with term or reterm gestation, and the remaining 0% arise from hydatidiform moles, al- hough only 2-3% of hydatidiform
oles progress to choriocarcinoma.32
lacental site trophoblastic tumor STT is an extremely rare disease that rises from the placental implantation ite and consists predominantly of
ononuclear intermediate trophoblasts ithout chorionic villi infiltrating in
heets or cords between myometrial fi- ers (Figure 5). PSTT is associated with
ess vascular invasion, necrosis, and emorrhage than choriocarcinoma, and
t has a propensity for lymphatic metas- asis. Immunohistochemical staining re- eals the diffuse presence of cytokeratin nd human placental lactogen, whereas
FIGURE 3 Invasive mole
nvasive mole with direct extension of molar tissu rophoblast, 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 follow onmolar gestations.33
pithelioid trophoblastic tumor pithelioid trophoblastic tumor (ETT)
s a rare variant of PSTT that simulates arcinoma. Based on morphologic and istochemical features, it appears to evelop from neoplastic transformation f chorionic-type intermediate tropho- lasts. Most ETTs present many years af- er a full-term delivery.34,35
linical presentation omplete hydatidiform mole omplete 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 classic linical signs and symptoms, such as terine enlargement greater than ex- ected for gestational dates (28%), hy- eremesis (8%), and pregnancy-induced ypertension in the first or second tri- ester (1%), occur less frequently in re-
ent years because of earlier diagnosis as result of widespread use of ultrasonog-
ncluding hydropic villi and covering hyperplastic
010.
DECEMBER 2010
ral theca lutein cyst enlargement of the varies occurs in approximately 15% of ases, hCG levels are often 100,000 IU/mL, and fetal heart tones are
bsent.36-39
artial mole artial mole does not have the same pre- enting features as complete mole. More han 90% of patients with partial moles ave symptoms of incomplete or missed bortion, and the diagnosis is usually ade after histologic review of curettage
pecimens. The main presenting symp- om is vaginal bleeding, which occurs in pproximately 75% of patients. Exces- ive uterine enlargement, hyperemesis, regnancy-induced hypertension, hy- erthyroidism, and theca lutein cysts de- elop infrequently. Preevacuation hCG evels are 100,000 mIU/mL in 10% f patients with partial moles.40-42
estational trophoblastic neoplasia TN 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 presents s irregular bleeding following evacua- ion of a hydatidiform mole. Signs sug- estive of postmolar GTN are an en- arged, irregular uterus and persistent ilateral ovarian enlargement. Occa- ionally, a metastatic vaginal lesion may e noted on evacuation, disruption of hich 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 uterus r at metastatic sites. In patients with ostpartum uterine bleeding and subin- olution, GTN should be considered long with other possible causes, such as etained products of conception or en- omyometritis, primary or metastatic umors of other organ systems, or an- ther pregnancy occurring shortly after he first. Bleeding as a result of uterine erforation or metastatic lesions may esult in abdominal pain, hemoptysis, elena, or evidence of increased intra-
ranial pressure from intracerebral hem-
e, i
col 2
rrhage leading to headaches, seizures,
o p c s a b n t i s e
D U U t t o s c s s c w f a t s c g
H h p g e u b o c s g t S l t n u u e a n a f p c
C a L
P c L
www.AJOG.org Reviews
r hemiplegia. Patients may also exhibit ulmonary symptoms, such as dyspnea, ough, and chest pain, caused by exten- ive lung metastases.32 PSTTs and ETTs lmost always cause irregular uterine leeding often distant from a preceding onmolar gestation, and rarely viriliza-
ion or nephrotic syndrome. The uterus s usually symmetrically enlarged, and erum hCG levels are only slightly levated.33-35
iagnosis ltrasonography ltrasonography plays a critical role in
he diagnosis of both complete and par- ial mole, and it has virtually replaced all ther means of preoperative diagno- is.38,43-45 Because the chorionic villi of omplete moles exhibit diffuse hydropic welling, 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 may lso facilitate the early diagnosis of a par- ial mole by demonstrating focal cystic paces within the placenta and an in- rease in the transverse diameter of the estational sac.45
uman chorionic gonadotropin CG is a disease-specific tumor marker roduced by hydatidiform moles and estational trophoblastic neoplasms. It is asily measured quantitatively in both rine and blood, and hCG levels have een shown to correlate with the burden f disease. It is a placental glycoprotein omposed of 2 dissimilar subunits: an ubunit resembling that of the pituitary lycoprotein hormones and a subunit hat is unique to placental production. everal forms of hCG exist, including at east 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 heterogenous nd degraded than those in normal preg- ancy, therefore, an assay that will detect ll main forms of hCG and its multiple ragments should be used to follow up atients with GTD. Most institutions
urrently use rapid, automated radiola-
FIGURE 4 Choriocarcinoma
FIGURE 5 Placental site trophoblastic tumor
lacental site trophoblastic tumor with sheets of mononuclear intermediate trophoblast cells without horionic villi infiltrating between myometrial fibers. urain. Gestational trophoblastic disease I. Am J Obstet Gynecol 2010.
DECEMBER 2010 American Journal of Obstetrics & Gynecology 535
b a h
a l A c l h h f m p t t c t t n m n l p
i i e
r fi q c p c h
h a t r r 8 h g t t c p T h m t d f s
n s q s d u l c h e m a c
d i i ( l o w h m h w t p q a a h t T d f r s b o s t w p t i c
P P p c c p d c
P e L
eled monoclonal antibody sandwich ssays that measure different mixtures of CG-related molecules.46-48
Hydatidiform moles are commonly ssociated with markedly elevated hCG evels above those of normal pregnancy. pproximately 50% of patients with omplete mole have preevacuation hCG evels 100,000 mIU/mL.49,50 A single CG determination, however, is seldom elpful in differentiating complete mole
rom a normal intrauterine pregnancy, a ultiple gestation, or a pregnancy com-
licated by diseases such as erythroblas- osis fetalis or intrauterine infections hat are associated with an enlarged pla- enta, because hCG levels are highest in he late first trimester of pregnancy at a ime when a diagnosis of molar preg- ancy is usually being considered. Partial oles, on the other hand, are most often
ot distinguished by such elevated hCG evels, 100,000 mIU/mL in 10% of atients.40,42
A clinical diagnosis of postmolar GTN s most often made by the finding of ris- ng or plateauing hCG levels following
FIGURE 6 Pelvic ultrasound of…
G p v m f s t ( b p t m u
s H p m d f 1 w m y m c p g r
F D F
0 © d
www.AJOG.org Reviews
ohn R. Lurain, MD
w e a t s m p d
E T t h p d n c q r w w a
w o s A h f 1 S a n
a m m a n t e
i C c n c a n t f N a a i n 4 c a t
h o 2 e a o t
estational trophoblastic disease (GTD) is a spectrum of cellular
roliferations arising from the placental illous trophoblast encompassing 4 ain 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 left ntreated. GTD was historically associated with
ignificant morbidity and mortality. ydatidiform moles were often accom-
anied by serious bleeding and other edical complications prior to the
evelopment of early detection and ef- ective uterine evacuation means in the 970s. The outcomes for GTN were like- ise poor before the introduction of che- otherapy into their management 50
ears ago. The mortality rate for invasive ole approached 15%, most often be-
ause of hemorrhage, sepsis, embolic henomena, or complications from sur- ery. Choriocarcinoma had a mortality ate of almost 100% when metastases
rom the John I. Brewer Trophoblastic isease Center, Northwestern University einberg School of Medicine, Chicago, IL.
eceived April 13, 2010; revised June 16, 010; accepted June 30, 2010.
eprints: John R. Lurain, MD, John I. Brewer rophoblastic Disease Center, Northwestern niversity Feinberg School of Medicine, 250 E. uperior St., Suite 05-2168, Chicago, IL 0611. [email protected].
002-9378/free 2010 Mosby, Inc. All rights reserved.
oi: 10.1016/j.ajog.2010.06.073
e see Table of Contents
ere present and approximately 60% ven when hysterectomy was done for pparent nonmetastatic disease. Gesta- ional trophoblastic neoplasms are now ome of the most curable of all solid tu-
ors, with cure rates 90% even in the resence of widespread metastatic isease.1-3
pidemiology he incidence and etiologic factors con-
ributing to the development of GTD ave been difficult to characterize. The roblems in accumulating reliable epi- emiologic data can be attributed to a umber of factors, such as inconsisten- ies in case definitions, inability to ade- uately characterize the population at isk, no centralized databases, lack of ell-chosen control groups against hich to compare possible risk factors,
nd rarity of the diseases.4
Epidemiologic studies have reported ide regional variations in the incidence f hydatidiform mole.5 Estimates from tudies conducted in North America, ustralia, New Zealand, and Europe ave shown the incidence of hydatidi-
orm mole to range from 0.57–1.1 per 000 pregnancies, whereas studies in outheast Asia and Japan have suggested n incidence as high as 2.0 per 1000 preg- ancies.6 Investigations into possible
Gestational trophoblastic disease includes gestational trophoblastic neoplasia (invasive blastic tumor, and epithelioid trophoblastic presentation, and diagnosis of each of these Particular emphasis is given to manageme twin mole/normal fetus pregnancy, prophyl
Key words: chemotherapy, choriocarcinom gestational trophoblastic neoplasia, hydatid
thnic and racial differences leading to c
DECEMBER 2010 Am
n increased incidence of hydatidiform ole among American Indians, Eski- os, Hispanics, and African Americans
s well as various Asian populations have ot been able to attribute them to genetic
raits, cultural factors, or simply differ- nces in reporting.7-9
Data with respect to choriocarcinoma ncidence rates are even more limited. ollection of data on the incidence of
horiocarcinoma has been more difficult ot only for reasons similar to those en- ountered with hydatidiform moles, but lso because of the rarity of choriocarci- oma and the difficulty in clinically dis-
inguishing postmolar choriocarcinoma rom invasive mole. In Europe and orth America, choriocarcinoma affects
pproximately 1 in 40,000 pregnancies nd 1 in 40 hydatidiform moles, whereas n Southeast Asia and Japan choriocarci- oma rates are higher at 9.2 and 3.3 per 0,000 pregnancies, respectively. The in- idence rates of both hydatidiform mole nd choriocarcinoma have declined over he past 30 years in all populations.10,11
Several potential etiologic risk factors ave been evaluated for the development f complete hydatidiform mole.12 The
established risk factors that have merged are extremes of maternal age nd prior molar pregnancy. Advanced r very young maternal age has consis- ently correlated with higher rates of
atidiform mole (complete and partial) and le, choriocarcinoma, placental site tropho- or). The epidemiology, pathology, clinical phoblastic disease variants are discussed. f hydatidiform mole, including evacuation, ic chemotherapy, and follow-up.
gestational trophoblastic disease, m mole
hyd mo tum tro
i l
c e C t t r a r n c n b w u
P M p f t b d i p
g f c i e r b g m c c a p p
H H m d ( p c a d d a h
ynec
5
o women aged 21-35 years, the risk of omplete mole is 1.9 times higher for omen both 35 years and 21 years as ell 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 after mole is about 1%, or about 10-20 times
he risk for the general population.15,16
amilial clusters of biparental complete ydatidiform moles associated with ovel missense NLRP7 gene mutations n chromosome 19q have also been
dentified.17 Another reported obstetric isk factor for both complete and partial oles 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 of iscarriage.12 Although many possible
nvironmental etiologies for complete ole have been studied, the only consis-
ent association has been an inverse rela- ionship between -carotene and animal at dietary intake and the incidence of
olar pregnancy.18,19 Ovulation induc- ion for fertility may also be associated
TABLE Clinicopathologic features of gesta
Gestational trophoblastic disease Pathol
...................................................................................................................
...................................................................................................................
...................................................................................................................
...................................................................................................................
...................................................................................................................
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 mole han after another pregnancy event. The isk is also increased in women of Asian nd American Indian descent as well as Af- ican Americans. Similar to molar preg- ancies, the median age of women with horiocarcinoma is higher than that for ormal pregnancies.11 There also seems to e an increased risk of choriocarcinoma in omen with long-term oral contraceptive se and blood group A.5,20
athology olar pregnancies and gestational tro-
hoblastic neoplasms all take their origin rom the placental trophoblast. Normal rophoblast 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
15-20% t hCG often Medical c
.........................................................................................................................
9, XXY; 69, XYY; 69 XXX) fetus/embryo lling of villi oblastic hyperplasia
5% trop hCG usua Rare med
.........................................................................................................................
15% met Most ofte
.........................................................................................................................
ls infiltrate myometrium with mphatic invasion te cells/absent villi rrhage and necrosis
ls stain positive for hPL
Extremely hCG level Relatively Mainly su
.........................................................................................................................
ol 2010.
DECEMBER 2010
onadotropin (hCG). Cytotrophoblast unctions to supply the syncytium with ells in addition to forming outpouch- ngs that become the chorionic villi cov- ring the chorionic sac. The villous cho- ion adjacent to the endometrium and asalis layer of the endometrium to- ether form the functional placenta for aternal-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 they roliferate.21,22
ydatidiform mole ydatidiform mole refers to an abnor- al pregnancy characterized by varying
egrees of trophoblastic proliferation both cytotrophoblast and syncytiotro- hoblast) and vesicular swelling of pla- ental villi associated with an absent or n abnormal fetus/embryo. Two syn- romes of hydatidiform mole have been escribed based on both morphologic nd cytogenetic criteria.23,24 Complete ydatidiform moles undergo early and
ures
..................................................................................................................
..................................................................................................................
..................................................................................................................
..................................................................................................................
......... .........
niform hydatid enlargement of villi in
t e h a ( p d h e a 1 X o b r 1 f t w s m t c a m 6 o s d c s fi
I I a d t u t m t m r s a m d
C C c h c s
C h L
www.AJOG.org Reviews
he absence of an ascertainable fetus or mbryo, the trophoblast is consistently yperplastic with varying degrees of typia, and villous capillaries are absent Figure 1). Approximately 90% of com- lete moles are 46, XX, originating from uplication of the chromosomes of a aploid sperm after fertilization of an gg in which the maternal chromosomes re either inactive or absent. The other 0% of complete moles are 46, XY, or 46, X, as a result of fertilization of an empty vum by 2 sperm (dispermy). Tropho- lastic neoplasia (invasive mole or cho- iocarcinoma) follows complete mole in 5-20% of cases.23-27 Partial hydatidi- orm moles demonstrate identifiable fe- al or embryonic tissue, chorionic villi ith 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 mild typia only (Figure 2). Most partial oles have a triploid karyotype (usually
9, XXY), resulting from the fertilization f an apparently normal ovum by 2 perm. Less than 5% of partial moles will evelop 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 mole nvasive mole is a benign tumor that rises from myometrial invasion of a hy- atidiform mole via direct extension hrough tissue or venous channels (Fig- re 3). Approximately 10-17% of hyda-
idiform moles will result in invasive ole, and about 15% of these will metas-
asize to the lungs or vagina. Invasive ole 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
haracterized by abnormal trophoblastic yperplasia and anaplasia, absence of horionic villi, hemorrhage, and necro-
is (Figure 4), with direct invasion into
FIGURE 1 Complete hydatidiform mole
omplete hydatidiform mole with hydropic villi, absence of villous blood vessels, proliferation of yperplastic cytotrophoblast, and syncytiotrophoblast. urain. Gestational trophoblastic disease I. Am J Obstet Gynecol 2010.
FIGURE 2 Partial 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 trophoblastic yperplasia. urain. Gestational trophoblastic disease I. Am J Obstet Gynecol 2010.
DECEMBER 2010 American Journal of Obstetrics & Gynecology 533
t r c v s p p c n p 5 t m
P P a s m w s b l h i t v a h
r l n
E E i c h d o b t
C C C m u t c u p p h m c a
e o c m a
P P s t h a m s t a s p p v l o
G G i e P r a t g l b s b w C m s l o p v a r d t o t p r m c
I t L
5
he myometrium and vascular invasion esulting in spread to distant sites, most ommonly to the lungs, brain, liver, pel- is and vagina, kidney, intestines, and pleen. Choriocarcinoma has been re- orted to occur in association with any regnancy event. Approximately 25% of ases follow abortion or tubal preg- ancy, 25% are associated with term or reterm gestation, and the remaining 0% arise from hydatidiform moles, al- hough only 2-3% of hydatidiform
oles progress to choriocarcinoma.32
lacental site trophoblastic tumor STT is an extremely rare disease that rises from the placental implantation ite and consists predominantly of
ononuclear intermediate trophoblasts ithout chorionic villi infiltrating in
heets or cords between myometrial fi- ers (Figure 5). PSTT is associated with
ess vascular invasion, necrosis, and emorrhage than choriocarcinoma, and
t has a propensity for lymphatic metas- asis. Immunohistochemical staining re- eals the diffuse presence of cytokeratin nd human placental lactogen, whereas
FIGURE 3 Invasive mole
nvasive mole with direct extension of molar tissu rophoblast, 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 follow onmolar gestations.33
pithelioid trophoblastic tumor pithelioid trophoblastic tumor (ETT)
s a rare variant of PSTT that simulates arcinoma. Based on morphologic and istochemical features, it appears to evelop from neoplastic transformation f chorionic-type intermediate tropho- lasts. Most ETTs present many years af- er a full-term delivery.34,35
linical presentation omplete hydatidiform mole omplete 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 classic linical signs and symptoms, such as terine enlargement greater than ex- ected for gestational dates (28%), hy- eremesis (8%), and pregnancy-induced ypertension in the first or second tri- ester (1%), occur less frequently in re-
ent years because of earlier diagnosis as result of widespread use of ultrasonog-
ncluding hydropic villi and covering hyperplastic
010.
DECEMBER 2010
ral theca lutein cyst enlargement of the varies occurs in approximately 15% of ases, hCG levels are often 100,000 IU/mL, and fetal heart tones are
bsent.36-39
artial mole artial mole does not have the same pre- enting features as complete mole. More han 90% of patients with partial moles ave symptoms of incomplete or missed bortion, and the diagnosis is usually ade after histologic review of curettage
pecimens. The main presenting symp- om is vaginal bleeding, which occurs in pproximately 75% of patients. Exces- ive uterine enlargement, hyperemesis, regnancy-induced hypertension, hy- erthyroidism, and theca lutein cysts de- elop infrequently. Preevacuation hCG evels are 100,000 mIU/mL in 10% f patients with partial moles.40-42
estational trophoblastic neoplasia TN 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 presents s irregular bleeding following evacua- ion of a hydatidiform mole. Signs sug- estive of postmolar GTN are an en- arged, irregular uterus and persistent ilateral ovarian enlargement. Occa- ionally, a metastatic vaginal lesion may e noted on evacuation, disruption of hich 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 uterus r at metastatic sites. In patients with ostpartum uterine bleeding and subin- olution, GTN should be considered long with other possible causes, such as etained products of conception or en- omyometritis, primary or metastatic umors of other organ systems, or an- ther pregnancy occurring shortly after he first. Bleeding as a result of uterine erforation or metastatic lesions may esult in abdominal pain, hemoptysis, elena, or evidence of increased intra-
ranial pressure from intracerebral hem-
e, i
col 2
rrhage leading to headaches, seizures,
o p c s a b n t i s e
D U U t t o s c s s c w f a t s c g
H h p g e u b o c s g t S l t n u u e a n a f p c
C a L
P c L
www.AJOG.org Reviews
r hemiplegia. Patients may also exhibit ulmonary symptoms, such as dyspnea, ough, and chest pain, caused by exten- ive lung metastases.32 PSTTs and ETTs lmost always cause irregular uterine leeding often distant from a preceding onmolar gestation, and rarely viriliza-
ion or nephrotic syndrome. The uterus s usually symmetrically enlarged, and erum hCG levels are only slightly levated.33-35
iagnosis ltrasonography ltrasonography plays a critical role in
he diagnosis of both complete and par- ial mole, and it has virtually replaced all ther means of preoperative diagno- is.38,43-45 Because the chorionic villi of omplete moles exhibit diffuse hydropic welling, 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 may lso facilitate the early diagnosis of a par- ial mole by demonstrating focal cystic paces within the placenta and an in- rease in the transverse diameter of the estational sac.45
uman chorionic gonadotropin CG is a disease-specific tumor marker roduced by hydatidiform moles and estational trophoblastic neoplasms. It is asily measured quantitatively in both rine and blood, and hCG levels have een shown to correlate with the burden f disease. It is a placental glycoprotein omposed of 2 dissimilar subunits: an ubunit resembling that of the pituitary lycoprotein hormones and a subunit hat is unique to placental production. everal forms of hCG exist, including at east 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 heterogenous nd degraded than those in normal preg- ancy, therefore, an assay that will detect ll main forms of hCG and its multiple ragments should be used to follow up atients with GTD. Most institutions
urrently use rapid, automated radiola-
FIGURE 4 Choriocarcinoma
FIGURE 5 Placental site trophoblastic tumor
lacental site trophoblastic tumor with sheets of mononuclear intermediate trophoblast cells without horionic villi infiltrating between myometrial fibers. urain. Gestational trophoblastic disease I. Am J Obstet Gynecol 2010.
DECEMBER 2010 American Journal of Obstetrics & Gynecology 535
b a h
a l A c l h h f m p t t c t t n m n l p
i i e
r fi q c p c h
h a t r r 8 h g t t c p T h m t d f s
n s q s d u l c h e m a c
d i i ( l o w h m h w t p q a a h t T d f r s b o s t w p t i c
P P p c c p d c
P e L
eled monoclonal antibody sandwich ssays that measure different mixtures of CG-related molecules.46-48
Hydatidiform moles are commonly ssociated with markedly elevated hCG evels above those of normal pregnancy. pproximately 50% of patients with omplete mole have preevacuation hCG evels 100,000 mIU/mL.49,50 A single CG determination, however, is seldom elpful in differentiating complete mole
rom a normal intrauterine pregnancy, a ultiple gestation, or a pregnancy com-
licated by diseases such as erythroblas- osis fetalis or intrauterine infections hat are associated with an enlarged pla- enta, because hCG levels are highest in he late first trimester of pregnancy at a ime when a diagnosis of molar preg- ancy is usually being considered. Partial oles, on the other hand, are most often
ot distinguished by such elevated hCG evels, 100,000 mIU/mL in 10% of atients.40,42
A clinical diagnosis of postmolar GTN s most often made by the finding of ris- ng or plateauing hCG levels following
FIGURE 6 Pelvic ultrasound of…
Related Documents
