20 Gestational Trophoblastic Tumors
and Related Tumor-Like Lesions
Ie-Ming Shih . Michael T. Mazur . Robert J. Kurman
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1076
Overview of Morphology, Development,
and Biology of Trophoblast . . . . . . . . . . . . . . . . . . . . . . . . 1076
Morphology of Trophoblast . . . . . . . . . . . . . . . . . . . . . . . . 1078
Gene Expression and Immunohistochemical
Features of Trophoblastic Subpopulations . . . . . . . . . 1080
Functional Aspects of Trophoblast . . . . . . . . . . . . . . . . . 1083
Previllous Trophoblast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1083
Cytotrophoblast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1083
Syncytiotrophoblast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1083
Villous Intermediate Trophoblast . . . . . . . . . . . . . . . . . . . 1084
Implantation Site Intermediate Trophoblast . . . . . . . . 1084
Chorionic-Type Intermediate Trophoblast . . . . . . . . . . 1085
Classification of Gestational
Trophoblastic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1085
General Features of Gestational
Trophoblastic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1085
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1085
Cytogenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1086
R. J. Kurman, L. Hedrick Ellenson, B. M. Ronnett (eds.), Blaustein’s Pathology of the Female Genital Tract (6th ed.), DOI 10.1007/978-1-4419-0489-8_20,
# Springer Science+Business Media LLC 2011
Serum Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1087
Staging and Prognostic Factors . . . . . . . . . . . . . . . . . . . . . . 1088
Pathogenesis of Gestational
Trophoblastic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1089
Clinicopathological Features, Behavior,
and Treatment of Molar Placentas . . . . . . . . . . . . . . . . 1090
Complete Hydatidiform Mole . . . . . . . . . . . . . . . . . . . . . . . 1090
Partial Hydatidiform Mole . . . . . . . . . . . . . . . . . . . . . . . . . . 1095
Invasive Mole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099
Clinicopathological Features, Behavior,
and Treatment of Trophoblastic Tumors
and Tumor-like Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1101
Choriocarcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1101
Placental Site Trophoblastic Tumor . . . . . . . . . . . . . . . . . 1108
Epithelioid Trophoblastic Tumor . . . . . . . . . . . . . . . . . . . 1113
Exaggerated Placental Site (Reaction) . . . . . . . . . . . . . . . 1119
Placental Site Nodule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1121
Chorangiocarcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1125
Immunohistochemical Approach for Differential
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1126
1076 20 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
Introduction
Gestational trophoblastic disease (GTD) encompasses
a heterogeneous group of lesions with specific clinical
features, morphological characteristics, and pathogenesis.
The World Health Organization classification of GTD
includes complete and partial hydatidiform mole, invasive
mole, choriocarcinoma, placental site trophoblastic tumor
(PSTT), epithelioid trophoblastic tumor, exaggerated pla-
cental site, and placental site nodule (> Table 20.1) [145].
Some of these lesions are true neoplasms, whereas others
represent abnormally formed placentas with a predisposi-
tion for neoplastic transformation of the trophoblast. Two
benign entities, the exaggerated placental site and the
placental site nodule, are included because they are
trophoblastic lesions that must be distinguished from
other entities with malignant potential. The literature on
GTD is extensive and at times confusing because of incon-
sistencies in classification and terminology. In fact, the
necessity of a morphologic classification has been
questioned, because current management is largely med-
ical and in the case of trophoblastic disease following
a mole, treatment is often conducted in the absence of
a histological diagnosis. Thus, all trophoblastic lesions are
frequently combined under the rubric of GTD without
applying specific pathological terms. However, recent
studies demonstrate profound differences in the etiology,
morphology, and clinical behavior of various forms of the
disease. These studies underscore the importance of
a uniform histological classification to facilitate standard-
ized reporting of data and to ensure appropriate clinical
management. Nonetheless, the term GTD has clinical
. Table 20.1
World Health Organization classification of gestational
trophoblastic disease
Hydatidiform moles (abnormally formed placentas)
Complete mole
Partial mole
Invasive mole
Trophoblastic tumor-like lesions (benign lesions)
Exaggerated placental site/reaction
Placental site nodule
Trophoblastic tumors (neoplastic diseases)
Choriocarcinoma
Placental site trophoblastic tumor (PSTT)
Epithelioid trophoblastic tumor (ETT)
utility, as the principles of human chorionic gonadotropin
(hCG) monitoring in follow-up and the chemotherapy of
metastatic or persistent disease are similar for all these
entities.
This chapter discusses the clinical and pathological
features of each specific form of GTD as well as their clinical
behavior, management, and treatment. In addition, the
morphologic and immunohistochemical features of the
distinct subtypes of trophoblastic cells are reviewed since
these have important implications for diagnosis. Recent
studies have shed light on the molecular mechanisms of
trophoblastic function, especially as it relates to trophoblas-
tic disease and this material is reviewed since it enhances
our understanding of the biology of these entities.
Overview of Morphology, Development,
and Biology of Trophoblast
The abnormal trophoblastic tissue in GTD recapitulates
the trophoblast present in the early developing placenta
and the implantation site. In normal placentation, the
trophoblast growing in association with chorionic villi is
referred to as villous trophoblast, whereas the trophoblast
in all other locations is termed extravillous trophoblast.
Three distinct types of trophoblastic cells have been rec-
ognized: cytotrophoblast (CT), syncytiotrophoblast (ST),
and intermediate trophoblast (IT). Villous trophoblast is
composed, for the most part, of CT and ST with small
amounts of IT. In contrast, extravillous trophoblast that
infiltrates the decidua, myometrium, and spiral arteries of
the placental site is composed of IT.
CT (Langhans cells) is the germinative component of
trophoblast, whereas ST is the differentiated component
that interfaces with the maternal circulation and produces
most of the placental hormones. IT is a distinct form of
trophoblast that shares some of the morphologic and
functional features of CT and ST. IT has been referred to
X-cells, interstitial (cyto)trophoblast, extravillous (cyto)
trophoblast, and ‘‘cytotrophoblast.’’ The term ‘‘intermedi-
ate trophoblast’’ is preferred by pathologists since it more
clearly reflects the morphological and functional features
including hormone secretion of this unique cell popula-
tion which is ‘‘intermediate’’ between cytotrophoblast and
syncytiotrophoblast. Recent morphological and immuno-
histochemical studies have shown that intermediate tro-
phoblast is a heterogeneous cell population that can be
further categorized according to its anatomic location
(> Fig. 20.1). Accordingly, we have proposed that inter-
mediate trophoblast extending from the trophoblastic
column at the anchoring villi be designated ‘‘villous
 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
. Fig. 20.1
Schematic representation of trophoblastic subpopulations in the placenta and fetal membranes (Reprinted by permission
from reference [158])
intermediate trophoblast,’’ in the placental site (or basal
plate) ‘‘implantation site intermediate trophoblast,’’ and in
the chorion laeve of the fetal membranes ‘‘chorionic-type
intermediate trophoblast’’ (> Fig. 20.1). The intermediate
trophoblastic cells in the trophoblastic islands and placen-
tal septae appear to be equivalent to the implantation site
intermediate trophoblastic cells.
Human trophoblast is derived from the trophoectoderm,
the outermost layer of the blastocyst. Shortly after implan-
tation (day 7–8), the trophoectoderm differentiates into
a syncytiotrophoblastic mass at the implantation pole.
Small intrasyncytial vacuoles then appear in the syncytio-
trophoblastic mass and expand, becoming confluent and
forming a system of lacunae that are separated by syncytio-
trophoblastic trabeculae. On approximately day 12, the
previllous mononucleate trophoblast from the primary
chorionic plate invades the syncytiotrophoblastic trabeculae
wherein the peripheral ends of the trabeculae join together
20 1077
and form the outermost layer of the trophoblast, the tro-
phoblastic shell. After 2 weeks of gestation, the extraembry-
onic mesenchyme grows into the trabeculae, transforming
them into the primary chorionic villi. The lacunae coalesce
to form the intervillous space.
After the development of the chorionic villi, distinc-
tive trophoblastic subpopulations can be recognized
(> Fig. 20.1). The chorionic villus surface is lined by a
continuous inner layer of cytotrophoblast and an outer
layer of syncytiotrophoblast. Cytotrophoblast is the
trophoblastic stem cell on the villous surface, demon-
strating proliferative activity with a Ki-67 nuclear label-
ing index of approximately 30% in the first trimester.
Cytotrophoblast, in early gestation, differentiates
along two main pathways – villous and extravillous
[145, 154]. On the villous surface, cytotrophoblast fuses
directly to form syncytiotrophoblast. The differentiation of
cytotrophoblast into syncytiotrophoblast is accompanied
1078 20 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
by complete loss of proliferation activity [151].
As gestation progresses, the proliferative activity of
cytotrophoblast decreases with an increase in the relative
number of syncytiotrophoblast to cytotrophoblast. The
nuclei of syncytiotrophoblast gradually become apoptotic,
forming so-called syncytial knots, clusters of pyknotic
nuclei with a small amount of cytoplasm, which are even-
tually extruded into the intervillous space. The second
pathway of differentiation of cytotrophoblast occurs at
the pole of the villi that make contact with the placental
bed. These villi, the so-called anchoring villi, display
a morphologic spectrum of differentiation where
cytotrophoblast merges imperceptibly into intermediate
trophoblast within these trophoblastic columns
(> Fig. 20.1). These intermediate trophoblastic cells in the
trophoblastic columns are termed ‘‘villous intermediate
trophoblast.’’ The proliferative activity of villous interme-
diate trophoblast gradually decreases as the cells move away
from the villi [151]. At the base of trophoblastic column at
the junction with the endometrium, intermediate tropho-
blast infiltrates the decidua and myometrium and invades
and replaces the spiral arteries of the implantation site
(basal plate) to establish the maternal/fetal circulation.
This subpopulation of intermediate trophoblast in the
implantation site is designated ‘‘implantation site inter-
mediate trophoblast.’’ Although these trophoblastic cells
extensively infiltrate the placental bed, they do not
demonstrate proliferative activity. Some mononucleate
implantation site intermediate trophoblastic cells fuse
into multinucleated cells that are terminally differentiated.
In contrast to anchoring villi, floating villi are not in
contact with the placental bed. The trophoblast at the
tips of these villi appears to be analogous to implanta-
tion site intermediate trophoblast. This cell population
of trophoblast is associated with extensive deposition of
extracellular matrix protein and fibrin forming ‘‘bal-
loon-like’’ structures that have been designated ‘‘tropho-
blastic islands.’’ Like implantation site intermediate
trophoblast, the trophoblastic cells in the trophoblastic
islands are not proliferative. In contrast, the intermedi-
ate trophoblast away from implantation site (i.e., the
chorion frondosum) differentiates into ‘‘chorionic-type
intermediate trophoblast.’’ At around 20 weeks of gesta-
tion, the expanding gestational sac obliterates the endo-
metrial cavity and the chorion frondosum fuses with
the decidua parietalis to form the chorion laeve
(> Fig. 20.2). As the surface area of the chorionic laeve
increases towards term, the chorionic-type intermediate
trophoblast continues to proliferate throughout gestation,
albeit at a low level.
Morphology of Trophoblast
Previllous trophoblast. By light microscopy, the previllous
trophoblast is composed of mononucleate trophoblast
and primitive syncytiotrophoblast that invade the endo-
metrium. The dimorphic pattern of previllous trophoblast
is reminiscent of the dimorphic pattern of trophoblast
in choriocarcinoma and it has been hypothesized that
the morphologic appearance of choriocarcinoma is a reca-
pitulation of the appearance of previllous trophoblast
(> Fig. 20.3). Unlike choriocarcinoma, previllous tropho-
blastic cells are less pleomorphic and do not exhibit cellu-
lar necrosis.
Cytotrophoblast. Following the development of villi,
cytotrophoblastic cells appear as small primitive epithelial
cells, uniform, and polygonal to oval in shape (> Fig. 20.4a).
Cytotrophoblastic cells have a single nucleus, clear to
granular cytoplasm, and well-defined cell borders. Mitotic
activity is evident.
Syncytiotrophoblast. Syncytiotrophoblast is composed
of a large, multinucleate cellular mass with dense
amphophilic cytoplasm often containing multiple vacu-
oles that vary in size (> Fig. 20.4a). A distinct brush border
often lines the cell membrane. The syncytiotrophoblastic
nuclei are dark and often appear pyknotic. They do not
show mitotic activity.
Villous intermediate trophoblast. Villous intermediate
trophoblastic cells are mononucleate and larger than
cytotrophoblast with pale to clear cytoplasm and uniform
round nuclei.
Implantation site intermediate trophoblast. Implanta-
tion site intermediate trophoblastic cells have a variable
appearance, which to some extent is dependent on their
anatomic location (> Figs. 20.4b and c). For example,
implantation site intermediate trophoblastic cells in the
endometrium are polygonal or round and contain abun-
dant amphophilic cytoplasm closely resembling the
decidualized stromal cells with which they are admixed.
In contrast, implantation site intermediate trophoblastic
cells in the myometrium are frequently spindle-shaped
and resemble the smooth muscle cells of the myometrium.
Generally, the cytoplasm of implantation site intermediate
trophoblastic cells is abundant and is eosinophilic to
amphophilic. Scattered small vacuoles may be present
in the cytoplasm of implantation site intermediate tro-
phoblastic cells. The nuclei of implantation site interme-
diate trophoblastic cells have highly irregular outlines
and hyperchromatic, coarsely granular chromatin. Often
the nuclei are lobulated or show multiple deep nuclear
clefts. Nucleoli are smaller and less prominent than those
 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions 20 1079

17 weeks
3 weeks
10 weeks 12 weeks
gestational age

. Fig. 20.2
Schematic representation of the formation of the chorion laeve (yellow). At 3 weeks of gestation, the entire blastocyst is
embedded in the endometrium at the implantation site and is surrounded by the trophoblastic shell. At 10 weeks,
the definitive placenta is established at the implantation site and the chorionic villi at the opposite pole begin to
degenerate. At approximately 12 weeks, the amnion (yellow)/chorion (blue) at the opposite end of the placental site
fuses with the decidua capsularis. The intervillous space is obliterated and the chorionic villi (the small, round pale-gray
structures) degenerate. This process continues and at approximately 17 weeks of gestation the uterine cavity is largely
obliterated as the amnion and chorion laeve become apposed to the endometrium on the opposite side of the uterine
cavity. The chorion laeve, amnion, and underlying decidua constitute the fetal membranes (Reprinted by permission
from [158])

in cytotrophoblast. Cytoplasmic nuclear invaginations
may be seen. Mononucleate implantation site inter-
mediate trophoblastic cells occasionally fuse into multi-
nucleated cells.
Implantation site intermediate trophoblastic cells
infiltrate the decidua, surround glands, and invade the
myometrium, dissecting between smooth muscle fibers
without destroying them. These cells characteristically
invade spiral arteries replacing the smooth muscle of
the vessel wall but leaving the overall structure intact.
Eosinophilic fibrinoid material is often deposited around
implantation site intermediate trophoblast. The material
contains a variety of extracellular matrix proteins includ-
ing adult-type and oncofetal fibronectin, type IV collagen,
laminin, and a small amount of fibrin. Implantation site
intermediate trophoblastic cells are the predominant cel-
lular population of the exaggerated placental site and
the PSTT.
The intermediate trophoblastic cells in the trophoblas-
tic islands are mononucleate, round, and uniform in size
and contain rounded nuclei. They are embedded in
an abundant, homogeneous, and eosinophilic fibrinoid
matrix. In vitro studies suggest that the cell islands are
derived from the floating cell columns, which are not
anchored to the endometrium. As a result, abundant
extracellular matrix accumulates among the cells replacing
those in the center of the islands.
Chorionic-type intermediate trophoblast. Chorionic-
type intermediate trophoblast is composed for the most
part of relatively uniform cells with either eosinophilic
or clear (glycogen-rich) cytoplasm arranged in a cohesive
layer in the chorion laeve (> Figs. 20.1 and > 20.5). Most
of the cells are smaller than implantation site intermediate
trophoblast but larger than cytotrophoblast. Occasionally,
the cells form nests or cords that extend into the underlying
decidua. As with implantation site intermediate tropho-
blastic cells, some chorionic-type intermediate trophoblas-
tic cells are multinucleated. Chorionic-type intermediate
trophoblast is the cellular population found in placental
site nodules and epithelioid trophoblastic tumors [158].
1080 20 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
. Fig. 20.3
Primitive trophoblast. The previllous trophoblast
surrounding the blastocyst demonstrates a dimorphic
pattern composed of mononucleate trophoblastic cells and
syncytiotrophoblastic cells that resemble choriocarcinoma.
The mononucleate trophoblastic cells, in contrast to those
in choriocarcinoma, are smaller, more uniform, and not
atypical (inset). Unlike choriocarcinoma, the trophoblast
does not invade and destroy adjacent tissue
Gene Expression and
Immunohistochemical Features of
Trophoblastic Subpopulations
Trophoblast-associated gene expression as detected by
immunohistochemistry has great value in the diagnosis
of GTD as well as in the study of the biology of trophoblast
(> Table 20.2) [145, 155]. The beta-subunit of hCG,
human placental lactogen (hPL), placental alkaline phos-
phatase (PLAP), inhibin, and low-molecular-weight
cytokeratin are well-recognized markers of trophoblast.
Recently, several other genes have been identified in
human trophoblast. Antibodies against these markers,
especially those that are commercially available and recog-
nize the epitopes in formalin-fixed, paraffin-embedded tis-
sue sections, have considerable value in the study and
differential diagnosis of different types of GTD. For exam-
ple, HSD3B1 is a newly characterized trophoblastic marker
that is expressed almost exclusively in a few normal tissues
including trophoblast and sebaceous glands. The commer-
cially available antibody that reacts to HSD3B1 protein has
been shown to be very useful to distinguish a trophoblastic
from a non-trophoblastic lesion [93].
All forms of trophoblastic subpopulations and gesta-
tional trophoblastic lesions react strongly for cytokeratin
when broad-spectrum antibodies (e.g., the AE1/AE3
antibody cocktail) are used. More specifically, trophoblast
is positive for low-molecular-weight epithelium-type
cytokeratins, including cytokeratins 7, 8, 18, and 19.
In contrast, trophoblast is variably positive for cytokeratin
20 and is rarely positive for high-molecular-weight
cytokeratin that is normally expressed by stratified
squamous epithelium. Cytokeratin immunostaining is
especially useful for demonstrating the presence of
implantation site intermediate trophoblastic cells at the
placental site since these cells are always admixed with
the other cell types. The intermediate trophoblastic cells
that are positive for low-molecular-weight cytokeratin are
easily identified amid nonreactive decidual cells and
smooth muscle cells. Myometrial smooth muscle cells
can display punctate cytoplasmic cytokeratin immunore-
activity that is easily distinguished from the diffuse mem-
brane staining of IT.
Cytotrophoblast is immunoreactive for a variety of
antigens, including p63, cyclin E, leukemia inhibitory
factor receptor, epidermal growth factor receptor, P2Y6
purinergic receptor, and a number of cell adhesion mole-
cules including integrin and E-cadherin (> Table 20.2).
Unlike syncytiotrophoblast, cytotrophoblast fails to react
with antibodies against a wide variety of steroid and preg-
nancy-associated hormones. Ki-67 proliferation-related
antigen is highly expressed by cytotrophoblast (labeling
index: 25–50%) especially in the region forming the tro-
phoblastic columns (> Table 20.2). These findings con-
firm that cytotrophoblast is a stem cell with a high level of
proliferative activity and a limited functional role.
The differentiation of cytotrophoblast into syncytio-
trophoblast is accompanied by dramatic changes in gene
expression. For example, syncytiotrophoblast expresses
several pregnancy-associated hormones, including beta-
hCG, hPL, estradiol, progesterone, placental growth hor-
mone, pregnancy-specific glycoprotein, relaxins, and
inhibin. The immunodistribution of some of these hor-
mones in syncytiotrophoblast is variable, depending
on gestational age. For example, syncytiotrophoblast
contains abundant beta-hCG from at least 12 days of
gestation until approximately 8–10 weeks, after which
 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions 20 1081

. Fig. 20.4
Chorionic villus and implantation site. (a) An anchoring villus attaches to the implantation site. The villus is outlined by two
trophoblastic layers – the inner cytotrophoblast (CT) and outer syncytiotrophoblast (ST). The intermediate trophoblast (IT)
differentiates from the trophoblastic column and emanates from the distal column to the implantation site. (b) Intermediate
trophoblastic cells infiltrate into endomyometrium and assume a distinctive pattern when they invade the myometrium. (c)
Intermediate trophoblastic cells target the spiral arteries and transform them from small caliber and high resistant vascular
channels (inset) into large caliber and low resistant arteries that direct blood into the intervillous space. Intermediate
trophoblastic cells can be found in the lumen of the arteries and sometimes appear to occlude the entire lumen

Amnionic epithelium
Amnion stroma
(Chorionic epithelium)
Chorion stroma

Intermediate
trophoblast

Decidua
(parietal layer)

. Fig. 20.5
Anatomy of chorion laeve (fetal membrane). The chorion epithelium is no longer present in chorion laeve because of fusion
between the amnion and chorion. However, a cleft that represents the location where the chorionic epithelium resides
before the fusion is always present due to tissue processing artifacts. The trophoblastic cells in the chorion laeve are termed
‘‘chorionic-type intermediate trophoblastic cells’’ and are characterized by distinct morphological and
immunohistochemical features as compared to other trophoblastic subpopulations. GV: ghost villi

it diminishes. By 40 weeks it is present only focally. hPL the syncytiotrophoblast overlying the chorionic villi.
is also localized in syncytiotrophoblast at 12 days Inhibin-a exhibits the highest expression in the first
but increases steadily thereafter. From late in the sec- trimester and gradually decreases in immunointensity
ond trimester to term, hPL is diffusely distributed in through the third trimester (> Table 20.2) [152].
1082 20 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions

. Table 20.2
Expression of trophoblastic markers in different trophoblastic subpopulations

Trophoblastic types HSD3B1 HLA-G hPL β-hCG cyclin E p63 CD146∗ HNK1 Muc4 β−cat

Cytotrophoblast nuc

Syncytiotrophoblast

IT in trophoblastic varied memb

column

IT in implantation site M

IT in chorion laeve

Immunointensity: Low high

M : positive in multinucleated intermediate trophoblast (IT)

: increased expression toward the implantation site in a trophoblastic column

IT: intermediate trophoblastic cells; nuc: nuclear staining; memb: membrane staining;
varied: variable staining pattern
∗CD146 is a synonym of Mel-CAM

Syncytiotrophoblast also expresses placental alkaline phos-
phatase, leukemia inhibitory factor receptor, placental
growth hormone, epidermal growth factor receptor,
HSD3B1 (an enzyme involved in the synthesis of proges-
terone), p27kip1 (a negative regulator in cell cycle progres-
sion), c-fms oncoprotein CD10, and syncytin. Expression
of syncytin has been shown to be involved in the fusion
process of syncytiotrophoblast [102]. In contrast, several
genes are down-regulated in syncytiotrophoblast as com-
pared with cytotrophoblast. For example, syncytiotro-
phoblast fails to express E-cadherin and Ki-67 nuclear
antigen. These findings are concordant with the view
that syncytiotrophoblast is terminally differentiated and
that its major functions are hormone production and
molecular transport across the villous surface.
Among the various populations of trophoblast, the
pattern of gene expression is most complex in intermedi-
ate trophoblast and depends on the differentiation status
and anatomic location of the intermediate trophoblastic
cells, i.e., the subpopulation of intermediate trophoblast
(> Table 20.2). The villous intermediate trophoblast in
the trophoblastic columns uniquely expresses the HNK-1
carbohydrate epitope on glycosphingolipids, which is not
present in other subpopulations of trophoblastic cells [157].
The genes that are upregulated as villous intermediate
trophoblast differentiate into implantation site interme-
diate trophoblast including melanoma cell adhesion mol-
ecule (Mel-CAM or CD146; [149] inhibin-a [152],
hPL [81], and cyclin E [94] (> Table 20.2). The genes
that are downregulated during differentiation of villous
to implantation site intermediate trophoblast are Ki-67
nuclear antigen, epidermal growth factor (EGF) receptor,
and E-cadherin. In terms of hormone production, implan-
tation site intermediate trophoblast resembles syncytiotro-
phoblast. It contains abundant hPL, which appears as early
as 12 days and reaches a peak at 11–15 weeks of gestation.
Inhibin-a is also immunolocalized in the implantation site
intermediate trophoblast after 10 weeks of gestation. In
contrast, hCG is present only focally in implantation site
intermediate trophoblast, appearing as early as 12 days and
remaining until 6 weeks, after which it disappears. The so-
called multinucleated trophoblastic giant cells exhibit an
identical immunostaining pattern to the mononucleate
counterparts except the former are negative for preg-
nancy-associated major basic protein [79]. Accordingly,
these giant cells should be designated ‘‘multinucleated
intermediate trophoblastic cells’’ rather than syncytiotro-
phoblastic giant cells [149].
The implantation site intermediate trophoblastic cells
that invade the spiral arteries show the same staining
 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
pattern as those within the decidua and myometrium
except that expression of neural cell adhesion molecule
(NCAM; [15], E-cadherin, and beta-catenin are
upregulated [147]. Implantation site intermediate tropho-
blast in both the endometrium and myometrium
expresses leukemia inhibitory factor receptor [142],
which interacts with leukemia inhibitory factor expressed
by maternal decidual leukocytes. Although leukemia
inhibitory factor plays an important role in implantation
and placentation in several species, the paracrine role of
leukemia inhibitory factor in the biology of human
implantation site intermediate trophoblastic cells is not
known. Those intermediate trophoblastic cells also
express CD10, a neutral endopeptidase [64, 122].
In contrast to implantation site intermediate tropho-
blast, chorionic-type intermediate trophoblast is dif-
fusely positive for p63 but is only focally positive for
several trophoblast-associated antigens including hPL,
Mel-CAM (CD146), mucin-4, and cyclin E (> Table 20.2).
Chorionic-type intermediate trophoblastic cells exhibit
mild proliferative activity as indicated by an increased
Ki-67 labeling index (3–10%) in contrast to the absence
of Ki-67 labeling in implantation site intermediate
trophoblast.
The immunophenotype of trophoblastic cells in gesta-
tional trophoblastic lesions is similar to their normal coun-
terparts. In routine pathology practice, HSD3B1,
cytokeratin 18, hPL, p63, Ki-67, and cyclin E are particularly
useful markers in the diagnosis of trophoblastic lesions. The
practical application of immunohistochemistry in the dif-
ferential diagnosis of gestational trophoblastic lesions is
discussed under the section of immunohistochemistry
application for differential diagnosis.
Functional Aspects of Trophoblast
Trophoblast plays a crucial role in implantation and
embryonic development. The major functions of tropho-
blast are as follows. First, the villous trophoblast
(syncytiotrophoblast and cytotrophoblast) provides
a structural interface for molecular transport between
the maternal and fetal compartments. Second, implanta-
tion site intermediate trophoblast establishes the feto-
maternal circulation in the placental site (> Fig. 20.4).
Third, syncytiotrophoblast secretes several pregnancy-
associated hormones that are necessary for successful
maintenance of the placenta and fetus. Finally, syncytio-
trophoblast as well as chorionic-type intermediate
trophoblast in the fetal membranes serve as an immuno-
logical barrier that prevents allograft rejection of the
20 1083
fetus by the maternal immune system. Functional
abnormalities of trophoblast may account for several
common gestational disorders including failure
of implantation, which leads to spontaneous abortion,
preeclampsia, and intrauterine growth retardation. The
functions of specific trophoblastic subpopulations are
discussed below.
Previllous Trophoblast
The previllous syncytiotrophoblast is responsible for the
initial erosion of maternal tissues during the early stages of
implantation. Subsequently, it appears that the previllous
mononucleate trophoblastic cells are responsible for fur-
ther invasion and expansion of the implantation site
(> Fig. 20.3). At approximately 13 days of gestation, mes-
enchyme penetrates the trophoblastic mass and chorionic
villi develop thus forming the rudimentary structure of
the definitive placenta.
Cytotrophoblast
Cytotrophoblast is the trophoblastic stem cell and is
located on the villous surface. Cytotrophoblast expresses
epidermal growth factor receptor (EGF-R), which binds to
EGF secreted by the decidua. It has been postulated that by
a paracrine mechanism EGF-R and its ligand may pro-
vide persistent growth stimulation for cytotrophoblast.
Cytotrophoblast differentiates along two main pathways.
Along one pathway, cytotrophoblast continues to prolif-
erate and fuses to form the overlying syncytiotrophoblast.
This process results in expansion of the surface area of
chorionic villi in the developing placenta. In the second
pathway, cytotrophoblast differentiates into villous inter-
mediate trophoblast in the trophoblastic columns and
then into implantation site intermediate trophoblast in
the placental site or chorionic-type intermediate tropho-
blast in the chorion laeve.
Syncytiotrophoblast
Syncytiotrophoblast is composed of terminally differenti-
ated cells that synthesize and secrete a variety of pregnancy-
associated hormones that are thought to be critical in the
establishment and maintenance of pregnancy. Some of these
secretory proteins may also have a paracrine function by
regulating the local microenvironment of decidua cells,
1084 20 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
inflammatory cells, and smooth muscle cells at the placental
site. In addition to its role as an endocrine organ, the
syncytiotrophoblast is bathed in maternal blood and is
responsible for the exchange of oxygen, nutrients, and a
variety of metabolic products between the mother and fetus.
Villous Intermediate Trophoblast
Villous intermediate trophoblastic cells proliferate in the
proximal portion of trophoblastic columns and serve as
the source from which implantation site and chorionic-
type intermediate trophoblast are derived. In addition,
villous intermediate trophoblastic cells may play an
important role in maintaining the structural integrity of
the villi that anchor the placenta to the basal plate. HNK-1
carbohydrate moiety expressed on the surface of the vil-
lous intermediate trophoblast may contribute to the
intercellular cohesion in the trophoblastic columns that
counteract the mechanical sheering forces resulting from
fetal movements and the turbulence created by the pulsa-
tile blood flow in the placental bed [157].
Implantation Site Intermediate Trophoblast
The major function of implantation site intermediate
trophoblast is to establish the maternal–fetal circulation
by invading the spiral arteries in the basal plate during
early pregnancy. The mechanisms underlying tropho-
blastic invasion are similar to those involved in tumor
cell invasion. For example, proteases are responsible for
matrix degradation and tissue remodeling, a prerequisite
for trophoblastic migration and invasion. Loss of
E-cadherin expression is closely associated with the infil-
trative phenotype of implantation site intermediate tro-
phoblast [147]. Expression of growth factors and their
receptors constitutes a unique molecular mechanism reg-
ulating trophoblastic behavior and cell-to-cell com-
munication (autocrine or paracrine) including cellular
migration, proliferation, and differentiation. Expression
of cell adhesion molecules is important for trophoblastic
migration in different extracellular substrates and for
cross-talk between trophoblastic cells and their microen-
vironment. It has been shown that implantation site inter-
mediate trophoblastic cells produce hyperglycosylated
hCG, a variant of hCG. This variant appears to be an
autocrine factor, participating in the initiation and regu-
lation of trophoblastic invasion [23].
Unlike malignant tumors, the invasion of implanta-
tion site intermediate trophoblast is tightly regulated,
confined spatially to the implantation site and limited
temporally to early pregnancy. While extensively infiltrat-
ing the endometrium of the basal plate, the implantation
site intermediate trophoblast invade only the inner third
of the myometrium in the first trimester, decreasing to less
than 10% of the myometrium by term. Although the
molecular mechanism underlying the control of tropho-
blastic invasion is currently unclear, the invasive process
can be modulated by both the trophoblast and the local
microenvironment. Fusion of mononucleate implantation
site intermediate trophoblastic cells into multinucleated
cells leads to the loss of their invasive and migratory
phenotype. Although multinucleated implantation site
intermediate trophoblastic cells can be seen in trophoblas-
tic neoplasms such as PSTT, they are more frequently
encountered in the normal or exaggerated placental site, a
helpful morphological feature in distinguishing exagger-
ated placental site from PSTT.
Another feature that distinguishes non-neoplastic tro-
phoblastic cells from tumor cells is their pattern of cellular
proliferation. The differentiation of implantation site
intermediate trophoblast is accompanied by a decrease in
cellular proliferation in contrast to the uncontrolled pro-
liferation in malignant neoplasms. Indeed, implantation
site intermediate trophoblastic cells are negative for Ki-67,
a proliferation marker, and are positive for several proteins
which are involved in the arrest of cell cycle progres-
sion including p21WAF1/CIP1 [19] and p57kip-2 [21].
Accordingly, any proliferative activity (mitotic figures or
Ki-67-positive trophoblastic cells) in the implantation site
intermediate trophoblast should be considered abnormal
and a neoplastic process must be considered.
Spiral arteries at the implantation site are the targets
for invasion by implantation site intermediate tropho-
blast. The mechanisms that are responsible for the tropism
of implantation site intermediate trophoblast to the spiral
arteries, and not to other structures, are unclear; one
postulate is that the oxygen gradient may be a guiding
cue. The trophoblastic invasion into the vascular wall
is associated with abundant deposition of extracellular
matrix, which eventually replaces the entire smooth mus-
cle layer of spiral arteries, resulting in the transformation
of the arteries to large-caliber and low-resistant vascular
channels. This unique feature of vascular invasion is not
only observed in the normal placental site but also in the
PSTT. Implantation site intermediate trophoblast replaces
the lining endothelial cells and undergoes an epithelial–
endothelial transdifferentiation characterized by the
acquisition of several endothelial markers including
VCAM-1, VE-cadherin, and beta-4 integrin, [186] and
Mel-CAM (CD146) [143, 149], all of which are expressed
 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
by endothelial cells. Accordingly, the term ‘‘trophoblast
pseudo-vasculogenesis’’ has been proposed to describe
this unique differentiation pathway of implantation site
intermediate trophoblast. Some of the implantation site
intermediate trophoblastic cells that invade the spiral
arteries migrate along the vascular wall in a retrograde
fashion to reach the spiral arteries beyond the implanta-
tion site in the myometrium. The intravascular implanta-
tion site intermediate trophoblastic cells tend to form
trophoblastic aggregates that act like valves or a sieve to
control the blood flow in the trophoblast-modified spiral
arteries. The process of aggregation is associated with
the expression of NCAM and E-cadherin. These cell adhe-
sion molecules may be responsible for the enhanced
intercellular cohesion among cells in trophoblastic aggre-
gates in the spiral arteries as NCAM and E-cadherin func-
tion as homotypic cell–cell adhesion molecules. This
hypothesis has been supported by a recent study in
which the E-cadherin gene was introduced into an
E-cadherin negative implantation site intermediate tro-
phoblastic cell line, IST-1, resulting in a stationary and
cohesive phenotype of IST-1 cells in culture [147].
Chorionic-Type Intermediate Trophoblast
The functional role of chorionic-type intermediate tro-
phoblastic cells is unknown. Unlike the implantation site
intermediate trophoblast, the chorionic-type intermediate
trophoblast proliferates throughout gestation as the total
surface area of fetal membrane increases. Chorionic-
type intermediate trophoblast may contribute to the syn-
thesis of extracelluar matrix, which is required to maintain
the tensile strength of the fetal membrane. It is also pos-
sible that chorionic-type intermediate trophoblast acts
as a biological and mechanical barrier to the maternal
immune system and is important for fetal allograft sur-
vival (see below).
Classification of Gestational
Trophoblastic Disease
According to current WHO classification, GTD can be
broadly divided into molar lesions and non-molar lesions.
The molar lesions include partial and complete
hydatidiform moles and invasive moles. The non-molar
lesions include choriocarcinoma and lesions derived from
implantation site intermediate trophoblast (exaggerated
placental site and PSTT) and those from the chorionic-
type intermediate trophoblast (placental site nodule and
20 1085
epithelioid trophoblastic tumor). In the past, exaggerated
placental site and placental site nodule were classified as
‘‘unclassified GTD.’’ Both lesions are benign and have
distinct histogenesis and morphological features that jus-
tify their separate designation. The current classification
also includes epithelioid trophoblastic tumor, which is
a trophoblastic neoplasm distinct from choriocarcinoma,
and PSTT.
General Features of Gestational
Trophoblastic Disease
Epidemiology
The reported incidence of hydatidiform mole and chorio-
carcinoma varies widely throughout the world, being
greatest in Asia, Africa, and Latin America and substantially
lower in North America, Europe, and Australia. The inci-
dence rates are difficult to compare, however, because of the
limitations in the methodology of these studies. Further-
more, some studies of incidence rates have used hospital-
based rather than population-based figures, which probably
result in overreporting. There are no epidemiologic data on
incidence or geographic distribution reported for the more
recently described PSTT and epithelioid trophoblastic
tumor. Despite the various incidence rates documented,
the overall incidence of GTD has been decreasing in last
few decades, especially in those geographic areas that have
previously reported a high incidence [51, 76].
In North America and Europe, the frequency of
hydatidiform moles is approximately 100 per 100,000
pregnancies. A higher frequency was reported in some
areas of Asia and the Middle East, with an incidence rate
from 100 to 1,000 per 100,000 pregnancies [3]. Chorio-
carcinoma occurs with a frequency of 1 in 20,000 to 1 in
40,000 pregnancies in the United States and Europe [123].
Estimates for the incidence in Asia, Africa, and Latin
America generally are higher with incidence rates as high
as 1 in 500 to 1,000 pregnancies reported [123]. As with
molar disease, there are marked regional variations in
incidence rates. In Nigeria, choriocarcinoma is the third
most common malignant tumor in women at one institu-
tion, ranking behind breast and cervical carcinoma. Thus,
despite methodological problems it appears that choriocar-
cinoma occurs at a substantially higher rate in developing
countries than it does in North America and Europe. Sim-
ilar to hydatidiform moles, the overall incidence of chorio-
carcinoma in recent years has dramatically decreased as
socioeconomic conditions improve. These observations
suggest that low socioeconomic conditions or dietary
1086 20 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
factors may contribute to the development of GTD.
Recently, asbestos exposure has been reported to be associ-
ated with the development of GTD [135].
Gestational trophoblastic lesions are nearly always dis-
orders of the reproductive years. Women who are sexually
active are at risk for developing GTD, but the incidence is
substantially higher in women before 20 and after 40 years.
In rare cases, GTD can develop in a postmenopausal woman
with a long interval between the diagnosis of GTD and the
antecedent pregnancy. The absolute number of cases of
mole or choriocarcinoma in women over 40 years is smaller
because of their lower fertility. In contrast, maternal age has
no effect on the risk of partial mole. Neither paternal age nor
race seems to affect the risk of developing a hydatidiform
mole. Malignant sequelae for hydatidiform mole occur
more frequently in older patients. While hydatidiform
mole, choriocarcinoma, exaggerated placental site, and pla-
cental site nodule are nearly always confined to reproductive
age women, PSTT and epithelioid trophoblastic tumors
occur infrequently in postmenopausal women.
Several studies reveal that a history of prior spontaneous
abortions is more common in patients with hydatidiform
mole and choriocarcinoma than with a normal pregnancy.
Furthermore, women who have had one hydatidiform mole
are at increased risk of having another [123]. Conversely,
term pregnancy and live births have a protective effect,
with GTD less common in patients who are parous [123].
The protective effect appears to increase with an increased
number of live births.
Cytogenetics
Cytogenetic studies of complete and partial hydatidiform
mole show that chromosomal abnormalities play an
important role in their development [3, 175]. The karyo-
typic patterns of the two types of moles are considerably
different. Complete hydatidiform moles have a normal
DNA content and most complete moles have a karyotype
of 46,XX and develop from the fertilization of an anuclear
‘‘empty’’ ovum by a single haploid (23X) sperm, in which
the haploid genome duplicates (> Fig. 20.6) [88]. The
remaining group (4–15%) of complete moles are also
androgenetic but are formed by dispermy, i.e., fertilization
of an ovum lacking functional maternal chromosomes by
two spermatozoa. Accordingly, the complete mole, being
paternally derived, constitutes a total allograft in the
mother. The opposite pathogenesis of a complete mole
occurs in parthenogenesis, meaning that the maternal set
of chromosomes duplicates itself in oocytes, and ovarian
teratomas are believed to result from this process.
46XX
Empty egg
46XX
23X
46XX
. Fig. 20.6
Chromosomal origin of a complete hydatidiform mole.
A single sperm fertilizes an empty egg. Reduplication of
its 23X set results in a completely homozygous diploid
genome of 46XX. A similar process follows fertilization
of an empty egg by two sperms with two independent
sets of 23X or 23Y. Note that both karyotypes 46XX and
46XY can ensue
The karyotype of a partial mole is nearly always trip-
loid (69 chromosomes) (> Fig. 20.7) with a maternal
chromosome complement. Conversely, not all triploid
conceptuses demonstrate histological features of a partial
mole because the triploids are composed of different
groups with distinct pathogenesis [46]. The percentage
of partial moles among triploid conceptuses depends on
the histologic criteria for the diagnosis and on the type of
cytogenetic assays employed. When triploidy is present in
a partial mole, the chromosomal complement usually is
69,XXY or 69,XXX and rarely 69,XYY. These abnormal
conceptuses result from the fertilization of an egg with
a haploid set of chromosomes by either two sperms, each
with a set of haploid chromosomes, or by a single sperm
with a diploid genome of 46,XY [88]. This condition is
known as diandric or androgenetic (paternally derived)
triploidy in which two of the three haploid sets are of
paternal origin. Diandric triploids at early stages of devel-
opment frequently show features of an early partial mole,
but only a subgroup will go on to develop the complete
phenotype of a partial mole. A conceptus with a diploid
46XX maternal genome due to failure of the first meiotic
division and a haploid paternal set of chromosomes results
in an abnormal, triploid (69XXX or 69XXY) fetus [134].
This is referred to as a digynic (maternally derived) con-
ceptus in which two of the three haploid sets are of
maternal origin. There is no agreement as to the percent-
age of digynic triploids among all triploid placentas,
 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
69XXY
23Y
23Y
23X 69XXY
23X 23X
23X
Dispermy Diandry
69XXY
. Fig. 20.7
Chromosomal origin of the triploid, partial
hydatidiform mole. A normal egg with a 23X haploid
set is fertilized by two sperm that carry either sex
chromosome, to result in 69 chromosomes with a sex
configuration of XXY, XXX, or XYY. A similar result can be
obtained by fertilization of a sperm carrying the
unreduced paternal genome 46XY (resulting sex
complement, XXY only)
but it is believed that digynic triploids generally do not
present as a molar pregnancy. In conclusion, most well-
documented partial moles are (diandric) triploids, but not
all triploid conceptuses are associated with partial moles.
Genetic studies of choriocarcinoma have shown that
most choriocarcinomas are diploid [40], and that chorio-
carcinomas with aneuploidy may be associated with
a poorer prognosis. Several studies have demonstrated
the diandric (androgenetic) origin of choriocarcinoma
following a complete hydatidiform mole [43, 88].
The cytogenetic studies of GTD other than molar preg-
nancy and choriocarcinoma such as PSTT and epithelioid
trophoblastic tumor have not been as well studied because
of the rarity of these neoplasms. However, new techniques
such as fluorescence in situ hybridization, interphase cyto-
genetics, and polymorphism of oligonucleotide repeat
sequences (microsatellites) have been performed on fixed
tissue. Although the majority of GTD can be diagnosed by
pathologists on morphological grounds alone, the applica-
tion of these techniques may become more and more
important in diagnosis and management of GTD. For
example, microsatellite markers that differ in maternal or
paternal origins have been used to confirm a complete
mole. Both fluorescence in situ hybridization using chro-
mosome-specific markers and polymerase chain reaction
20 1087
using polymorphic markers have been employed to assist
in differentiating a hydropic abortus from a partial mole,
and a partial mole from a complete mole [13, 97].
Serum Markers
Treatment of GTD is based on determining, if possible, the
specific histological type of trophoblastic lesion, monitor-
ing serum hCG titers, and instituting chemotherapy when
appropriate. hCG has proved to be an ideal marker for
all forms of GTD and measurement of serum hCG levels is
an integral part of the management of this disease. hCG
is a glycoprotein composed of two polypeptide chains, alpha
and beta, attached to a carbohydrate moiety. The configu-
ration of hCG is similar to other gonadotropins, particularly
luteinizing hormone (LH). The a-polypeptide chain in all
these hormones is identical; it is the difference in the beta
chain that gives the hormones their unique immunologic
specificity and biologic function. Accordingly, beta-hCG is
the most specific marker for GTD. hCG is produced mainly
by syncytiotrophoblast, and it is almost invariably detectable
in the serum if trophoblastic tissue is present and when
sensitive assays are used. In addition to syncytiotrophoblast,
implantation site intermediate trophoblastic cells can also
produce a variant of hCG that is hyperglycosylated. It has
been reported that this hyperglycosylated hCG inhibits
apoptosis in intermediate trophoblastic cells while pro-
moting cell invasion and growth.
In normal pregnancy, beta-hCG peaks to 50,000–
100,000 mIU/mL at about 10 weeks gestation and decreases
to 10,000–20,000 mIU/mL by 20 weeks, remaining at that
level until term. Levels as high as 600,000 mIU/mL have
been reported in early pregnancy. In molar gestations, beta-
hCG levels at diagnosis are variable, but most show a
markedly elevated hCG titer, which is a useful diagnostic
feature. Levels greater than 2 million mIU/mL have been
reported. beta-hCG titers are generally higher in complete
than partial moles [28]. Choriocarcinoma, almost invari-
ably, produces very high level of beta-hCG and a case with
a level of 11 million mIU/mL has been reported [59]. In
contrast to the high levels in hydatidiform moles and
choriocarcinoma, beta-hCG levels are much lower in
PSTTs and epithelioid trophoblastic tumors [150]. Never-
theless, beta-hCG levels are very useful in monitoring
patients with these tumors [25].
Beta-core fragment of hCG in urine has been reported
to be an even more sensitive marker being detected in
patients whose serum hCG levels are near to or below
the limit of detection [136]. Also recently, a sensitive
radioimmunoassay (RIA) and immunoradiometric assay
1088 20 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
(IRMA) have been developed [22, 25] that can measure
serum beta-hCG to a level of 0.5 mIU/mL. The assay
can detect beta-hCG production from as few as 1,000
trophoblastic cells, thus permitting follow-up to complete
disappearance of trophoblastic tissue. Disappearance of
beta-hCG from the serum as measured by half-life shows
two components, one with a half-life of 6 h and a slower
component with a half-life of about 30 h. Since
heterophilic antibodies are known to interfere with the
measurement of serum analytes, concurrent serum, and
urine testing for hCG has been recommended to be used as
routine policy in the diagnosis and follow-up of the
patients with GTD [138]. Except for hCG, the utilization
of other trophoblastic markers including hPL, inhibin,
activin, and progesterone in the detection and follow-up
of GTD has not yet been established [141].
Staging and Prognostic Factors
Several systems including the modified International Fed-
eration of Gynecology and Obstetrics (FIGO) staging sys-
tem, the World Health Organization (WHO) prognostic
index score system, and the National Institute of Health
(NIH) classification of metastatic GTD have been devel-
oped to predict prognosis and guide treatment (reviewed
in [163]). The FIGO system uses an anatomic staging
system, which is summarized in > Table 20.3. Within
each stage, patients with no risk factors are assigned to
substage A, those with only one risk factor to substage B,
and those with two risk factors are assigned to substage C.
The NIH classification is a clinical classification and is
based on a variety of clinical features and serum hCG
levels that segregates patients into good and poor progno-
sis (> Table 20.4). The WHO scoring system divides
patients into low-, intermediate-, and high-risk groups
based on the total score of a variety of prognostic features
(> Table 20.5). Based on the WHO system, patients
. Table 20.3
International Federation of Gynecology and Obstetrics
(FIGO) staging of gestational trophoblastic disease
Stage Definition
I Confined to uterine corpus
II Metastases to pelvis and vagina
III Metastasis to lung
IV Distant metastasis
with nonmetastatic (stage I) and low-risk metastatic (stages
II and III, World Health Organization score < 7) gestational
trophoblastic neoplasm (GTN) can be treated with single-
agent chemotherapy, and the survival rate approaches
100%. In contrast, patients with high-risk metastatic GTN
(stage IV, WHO score  7) requires initial multiagent che-
motherapy with or without adjuvant radiation and surgery,
and the survival rate is 80–90% [106, 114].
In addition to the diagnosis of choriocarcinoma, poor
prognostic factors include metastatic disease at diagnosis,
cerebral or hepatic metastases, symptoms for more than 4
months, failure of prior chemotherapy, and a pretreatment
serum beta-hCG titer of more than 100,000 mIU/mL.
More recently, the critical beta-hCG level has been reduced
to 40,000 mIU/mL by some investigators. Metastatic dis-
ease limited to the lungs or vagina is not a poor prognostic
sign. In contrast, although it is difficult to assess precisely
the prognostic significance of extrapulmonary metastases,
patients with CNS metastases have an approximately 50%
remission rate compared with involvement of other vis-
ceral organs. Development of CNS metastases during the
course of treatment confers an even worse prognosis.
Patients with hepatic metastases also have a poor progno-
sis, but multiagent chemotherapy appears to increase the
survival rate. Choriocarcinoma diagnosed after a term
gestation has a worse prognosis than choriocarcinoma
diagnosed after a mole.
. Table 20.4
Clinical classification of malignant trophoblastic disease
Nonmetastatic GTD
Metastatic GTD
Good prognosis
Low hCG level (<40,000 mIU/ml serum beta-hCG)
Symptoms present for less than 4 months
No brain or liver metastasis
No prior chemotherapy
Pregnancy event is not term delivery (i.e., mole, ectopic,
or spontaneous abortion)
Poor prognosis
High pretreatment hCG level (>40,000 mIU/ml serum
beta-hCG)
Symptoms present for more than 4 months
Brain or liver metastasis
Prior chemotherapeutic failure
Antecedent term pregnancy
GTD, gestational trophoblastic disease; hCG, human chorionic
gonadotropin.
 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions 20 1089

. Table 20.5 a foster mother developed a bulky, hypertrophic placenta

World Health Organization scoring system based on similar to complete moles in humans, whereas the gynoge-
prognostic factorsa netic embryos developed only a small placenta with
a secondarily stunted embryo. Another study using the
Score
mouse embryonic fibroblasts as the cell model demonstrates
Prognostic factors 0 1 2 4 that paternal and maternal genomes confer opposite effects
Age (years) 39 >39 on proliferation, cell-cycle progression, senescence, and
Antecedent Mole Abortion Term tumor formation [54]. In comparison with biparental fibro-
pregnancy blasts, androgenetic fibroblasts whose genomic complement
Intervalb 4 4–6 7–12 >12 is exclusively from paternal origin exhibit highly prolifera-
hCG (IU/L) <103 103–104 104–105 >105
tive activity, spontaneous transformation, and formation of
tumors at low passage number, while the gynogenetic fibro-
ABO groups (female O¥ A B
blasts with exclusive maternal genomic complement show
¥ male) A¥ O AB
decreased proliferation and increased senescence. The
Largest tumor 3–5 cm >5 cm molecular mechanism underlying this observation is the
(including uterine differential expression of imprinted genes. For example,
tumor)
the maternally expressed and paternally imprinted genes
Site of metastasis Spleen, GI tract, Brain such as p57kip2 decrease cellular proliferation. In contrast,
kidney liver
the paternally expressed growth factor, Igf2, is essential for
No. of metastases 1–4 4–8 >8 the long-term proliferation of all genotypes [54]. There-
identified fore, it is likely that a similar mechanism is also involved in
Prior chemotherapy Single Two or the pathogenesis of complete and partial hydatidiform
drug more moles. In rare familial/recurrent hydatidiform moles,
drugs
which account for 2% of all molar cases, mutations have
a
The total score for a patient is obtained by adding the individual been detected in the maternal gene, NALP7, which plays
scores for each prognostic factor. Total score: 4, low risk; 5–7, middle a role in inflammation and apoptosis [108, 162].
risk; and 8, high risk.
b As previously discussed (> Table 20.1), there are at
Interval time (months) between end of antecedent pregnancy and
start of chemotherapy. least three distinctive types of GTN including the most
hCG, human chorionic gonadotropin; GI tract, gastrointestinal tract. common type, choriocarcinoma, and the less common
ones, PSTT and epithelioid trophoblastic tumor. Molecu-
lar analysis on GTN is largely based on the identification
and characterization of trophoblastic markers in various
Pathogenesis of Gestational types of GTN, and the reference of their unique gene
Trophoblastic Disease expression patterns to different trophoblastic subpopula-
tions in normal early placentas (reviewed in [145]).
The pathogenesis of GTD is largely unknown as few The main conclusion from those studies is that follow-
molecular studies have been performed [155]. This is in ing neoplastic transformation of trophoblastic stem
part due to the relative rarity of GTD and the lack of cells, presumably the cytotrophoblast, specific differentia-
appropriate experimental models. The most well-studied tion programs dictate the type of trophoblastic tumor that
gestational trophoblastic lesion is hydatidiform mole and, develops (> Fig. 20.8). These patterns of differentia-
to a lesser extent, choriocarcinoma [88]. Development of tion in GTN recapitulate the stages of early placental
a hydatidiform mole appears to be associated with an excess development. For example, choriocarcinoma is com-
of paternal haploid set of chromosomes. The higher the ratio posed of variable amounts of neoplastic cytotrophoblast,
of paternal/maternal chromosomes, the greater the molar syncytiotrophoblast, and intermediate (extravillous) tro-
change. Complete moles show a 2:0 paternal/maternal ratio, phoblast, and resembles the previllous blastocyst, which
whereas partial moles show a 2:1 ratio. This hypothesis is is composed of a similar mixture of trophoblastic
best supported by the following two studies. First, a mouse subpopulations. On the other hand, the neoplastic
model in which molecularly engineered mice that were cytotrophoblast in PSTT differentiates mainly into inter-
either androgenetic or gynogenetic (parthenogenetic) were mediate (extravillous) trophoblastic cells in an implanta-
created by microtransfer of male or female pronuclei into tion site, whereas the neoplastic cytotrophoblast in
enucleated oocytes. Androgenetic embryos transplanted to epithelioid trophoblastic tumor differentiates into
1090 20 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions

Cytotrophoblast

Syncytiotrophoblast
Normal
trophoblast

EVT (IT) at EVT (IT) at

implantation site chorion laeve
Neoplastic
transformation

Choriocarcinoma
Trophoblastic
neoplasia PSTT ETT

. Fig. 20.8
Relationship of trophoblastic neoplasms to different subpopulations of intermediate trophoblastic cells. Exaggerated
placental site and placental site trophoblastic tumor are related to the differentiation of implantation site intermediate
trophoblast, whereas placental site nodule and epithelioid trophoblastic tumor are related to chorionic-type intermediate
trophoblast. EVT: extravillous trophoblast (equivalent to intermediate trophoblast), PSTT: placental site trophoblastic
tumor, ETT: epithelioid trophoblastic tumor

chorionic-type intermediate (extravillous) trophoblastic
cells in chorion laeve. This model suggests that choriocar-
cinoma is the most primitive trophoblastic tumor,
whereas PSTT and epithelioid trophoblastic tumor are
relatively more differentiated. Furthermore, it explains
the histologic mixture of choriocarcinoma and PSTT
and/or epithelioid trophoblastic tumor in some GTNs.
Clinicopathological Features, Behavior,
and Treatment of Molar Placentas
A hydatidiform mole is an abnormal placenta character-
ized by enlarged, edematous, and vesicular chorionic villi
accompanied by villous trophoblastic hyperplasia. It is
subdivided into complete hydatidiform mole and partial
hydatidiform mole based on morphologic, cytogenetic,
and clinicopathological features. Although typical com-
plete and partial moles are easily distinguished on histo-
logic examination, the routine use of ultrasound in
pregnancy has led to the clinical diagnosis and evacuation
of moles much earlier in gestation, often in the first tri-
mester. As a result, the classical features of complete and
partial moles that in the past were based on examination
of specimens obtained in the second trimester are not as
apparent, making the histopathologic diagnosis more dif-
ficult [43]. In addition, a variety of other genetic abnor-
malities such as trisomy and monosomy may be associated
with abnormal placentas that display minor degrees of
hydropic change and trophoblastic proliferation but do
not qualify as moles. Although recent studies have pro-
posed new and expanded criteria for the diagnosis of these
early moles and abnormal placentas, the criteria are subtle
and difficult to reproduce, making the histologic diagnosis
somewhat subjective. Furthermore, with the recognition
that the genetic alterations that underlie these various
lesions are distinctly different, one can legitimately ques-
tion whether the diagnosis should be based on genetic as
well as morphologic assessment. At present there is insuf-
ficient data to provide a definitive answer. Genetic analysis
is costly, labor-intensive, and is not available in most
pathology laboratories. However as these techniques
become cheaper and more widespread it is likely that
genetic analysis will complement histopathologic evalua-
tion in the diagnosis of difficult cases [13, 97]. The ratio of
complete versus partial moles varies among studies and
most reports show that complete moles outnumber par-
tial moles [13, 28, 45, 65, 97, 121, 167]. Clinical, patho-
logic, and cytogenetic differences separate the two forms
of hydatidiform mole, yet all molar pregnancies have the
potential for persistent GTD [3], although the risk is much
higher in complete than in partial hydatidiform moles.
Complete Hydatidiform Mole
Complete hydatidiform mole is characterized by hydropic
swelling of the majority of villi, and a variable degree of
 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions 20 1091

trophoblastic proliferation and atypia. Fetal tissue usually is
not present. Most complete hydatidiform moles have a 46,
XX karyotype [43]. In a study analyzing 26 complete moles,
all of them show diandric (paternal-only) genomes and the
lesions include 24 homozygous and 2 heterozygous moles
[13]. Early complete moles may lack hydropic swelling but
trophoblastic proliferation and atypia are present.
also can be found unexpectedly in elective abortion
specimens of asymptomatic patients and may be rarely
detected in the fallopian tube and ovary. A primary mole
involving the adnexa should be discriminated from the
hydropic change that is frequent in an aborting ectopic
pregnancy and from invasive mole with extension into the
broad ligament.

Clinical Features Gross Findings

As discussed above, complete moles are being diagnosed In typical cases, massively enlarged, edematous villi give
now at an earlier gestational age than in the past the characteristic grape-like appearance to the placenta
(8.5–12 weeks versus 16–18 weeks) because of the routine
use of sonography in pregnancy. Pelvic ultrasonic exami-
nation discloses a diagnostic snowstorm pattern but
high resolution sonography typically reveals a complex
intrauterine mass with many small cysts. This pattern,
especially when associated with a markedly elevated
beta-hCG level, is clinically diagnostic of molar pregnancy.
Consequently, a complete mole now rarely presents with
the classic signs and symptoms such as excessive uterine
size, hyperemesis, theca lutein ovarian cysts, hyperthy-
roidism, or preeclampsia. The majority of patients present
with vaginal bleeding or are discovered by sonography.
While a presumptive diagnosis of an incomplete or missed
abortion is usually made, serum beta-hCG levels greater
than 100,000 mIU/mL should prompt the physician to
consider the diagnosis of molar pregnancy. In the past,
excessive uterine enlargement for the gestational age
occurred in approximately two thirds of patients. Occa-
sionally, the initial clinical manifestation is sudden pas-
sage of molar vesicles. Preeclampsia (pregnancy-induced
hypertension with edema and proteinuria) occurs in up to
one fourth of patients with complete mole. In contrast to
nonmolar gestations, in which preeclampsia occurs typi-
cally in the last trimester, in molar gestations preeclampsia
occurs in the first trimester. Thus, early onset of pre-
eclampsia, especially when coupled with excessive uterine
enlargement, suggests the presence of a molar pregnancy.
Additional clinical signs of established molar pregnancy
include hyperemesis gravidarum, hyperthyroidism, pul-
monary embolization of trophoblast, and massive ovarian
enlargement due to benign theca lutein cysts (hyperreactio
luteinalis) [43]. Usually with complete mole the beta-hCG . Fig. 20.9
titer is markedly elevated. Complete hydatidiform mole. (a) A hysterectomy specimen
Although these clinical signs and symptoms permit shows an enlarged uterus with molar tissue protruding
the diagnosis of a molar pregnancy before evacuation, into the uterine cavity. (Reprint from [146] with permission
the clinical presentation is quite variable. Up to 80% from Churchill Livingstone Elsevier.) (b) In a well-developed
of cases are first diagnosed by histological study of spon- complete mole, the hydropic villi range from a few
taneously passed or curetted tissue. Hydatidiform moles millimeters to more than 1 cm in diameter
1092 20 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
(> Fig. 20.9). However, the specimen volume of contem-
porary complete moles is significantly less than in the
past and in very early complete moles grossly hydropic
change may be absent. In advanced mole, which is now
rarely encountered, swollen villi may range from a few
millimeters to as large as 3.0 cm in diameter but usually
average about 1.5 cm. Rarely, fetal development may
occur in complete mole. After suction curettage, molar
villi may collapse and a large amount of bloody tissue
may obscure the edematous villi, especially if a mole is
extracted early in pregnancy when villous enlargement is
less striking. In this instance, there may be no gross evi-
dence of molar enlargement. Histological evaluation of the
tissue adherent to the gauze that collects suctioned uterine
contents is necessary to establish the diagnosis. Immersing
the gross tissue in saline or formalin can resuspend col-
lapsed villi.
. Fig. 20.10
Early complete hydatidiform mole. Villi have extensive
stromal edema with central cisterns (C). The periphery of the
villi expands into bulbous projections with more prominent
stromal cells. There is a large amount of proliferative
trophoblast in this field (Courtesy of Dr. B. Ronnett)
Microscopic Findings
Complete moles have two key features: trophoblastic pro-
liferation and villous edema. Many villi display central
cistern formation characterized by a prominent central
space that is entirely acellular (> Fig. 20.10). Smaller villi
usually are present but these, too, are edematous. The
villous stroma has a distinctive appearance with a pale
blue-grey appearance having widely separated spindle
cells beneath the villous surface, and edematous cen-
tral cistern. Villous stroma of a complete mole contains
numerous but inconspicuous CD34-positive blood ves-
sels. All hydatidiform moles display some degree of hap-
hazard trophoblastic proliferation on the villous surface.
This trophoblastic proliferation in complete hydatidiform
mole is circumferential around the villus (> Fig. 20.11).
Columns and streamers of cells composed of a mixture of
. Fig. 20.11
Complete hydatidiform mole. Enlarged villi with
circumferential proliferation of trophoblast
 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
. Fig. 20.12
Trophoblast in a complete mole. A mixture of
cytotrophoblast (CT), intermediate trophoblast (IT), and
syncytiotrophoblast (ST) grows from the surface of a
villus (V)
cytotrophoblast, syncytiotrophoblast, and villous inter-
mediate trophoblast project randomly from the villous
surface (> Fig. 20.12). The amount of proliferative tro-
phoblast in moles varies greatly. It may be marked, affect-
ing most villi, or it may be subtle and only focally present,
emphasizing the need for thorough sampling. Large sheets
of trophoblast including villous intermediate trophoblast
that appear to be unattached to villi also may be present.
These result from tangential sectioning, or they represent
detached fragments of the trophoblast from the implan-
tation site. Trophoblastic islands, structures seen in the
normal early placentas, are rarely present in complete
moles. The trophoblast of a complete mole always displays
cytologic atypia. At times it may be as marked as in
choriocarcinoma (> Fig. 20.12). In addition, a linear dis-
tribution of atypical intermediate trophoblast overlying
fibrin is a feature that occurs in trophoblastic lesions as
opposed to an abortus.
20 1093
. Fig. 20.13
An early complete hydatidiform mole. The villi are not
particularly hydropic and the trophoblastic hyperplasia and
atypia are not marked. The circumferential proliferation of
villous trophoblastic cells that project randomly from the
villous surface is characteristic. This case has been
molecularly confirmed as an androgenetic complete mole
(Courtesy of Dr. B. Ronnett)
As noted previously, the typical morphologic features
of a complete mole may be absent or very subtle in molar
specimens evacuated in the first trimester (> Fig. 20.13).
These complete moles are referred to as ‘‘early complete
moles’’ that do not have the typical clinical presentation or
classic sonogram appearance. The histologic features of an
early complete mole are: (1) redundant or polypoid bul-
bous terminal villi; (2) hypercellular villous stroma
with primitive stellate cells; (3) a labyrinthine network
of villous stromal canaliculi; (4) focal hyperplasia of
cytotrophoblast and syncytiotrophoblast on both villi
and the undersurface of the chorionic plate; (5) atypical
trophoblast lining the villi and in the implantation site
[72, 107]; and (6) increased villous stromal apoptosis [75].
1094 20 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
. Fig. 20.14
Exaggerated placental site. The lesion is associated with
a complete hydatidiform mole. The intermediate
trophoblastic cells extensively infiltrate the
endomyometrium. The nuclei are enlarged and show
cytologic atypia
The implantation sites associated with a complete
hydatidiform mole almost always show a morphological
feature similar to an exaggerated placental site. As with the
trophoblastic hyperplasia on the villous surface, the cells
are more abundant and atypical than what is encountered
with an abortus and for that matter an exaggerated pla-
cental site (> Fig. 20.14). The immunostaining pattern for
the markers of implantation site intermediate trophoblast
is identical between the molar implantation site and an
exaggerated placental site except the Ki-67 labeling index
in a mole is elevated as compared to no Ki-67 labeling
index in a nonmolar exaggerated placental site, suggesting
that these two types of lesions are different despite their
similar morphologic features [104, 151]. Interestingly, as
compared with the normal placentas, complete moles
exhibit a higher level of apoptosis in cytotrophoblast,
indicating a complex but delicate regulation of the cell
population in complete moles.
Differential Diagnosis (See section > Partial
Hydatidiform Mole)
The differential diagnosis of complete moles is discussed
in the section of partial moles.
Behavior and Treatment
In the past, when the complete moles were not diagnosed
early, 2 and 12% of patients experienced severe respira-
tory distress immediately after uterine evacuation of a
hydatidiform mole. This phenomenon usually is attributed
to massive deportation of trophoblast to the lungs, an
exaggeration of a physiologic process occurring in normal
pregnancy. The most serious complication after molar evac-
uation is persistent or metastatic GTD and the risk of
developing choriocarcinoma. Postmolar trophoblastic dis-
ease may represent a persistent mole in the uterine cavity or
it may be an invasive mole or a choriocarcinoma. Persistent
GTD occurs in approximately 17–20% of women who have
undergone evacuation [140] and in 3–5% of women who
have undergone hysterectomy [44]. The risk of develop-
ment of choriocarcinoma following a complete mole is
about 2–5% in the United States [26, 33] and 13% in Japan
[95]. Prediction of the behavior of complete hydatidiform
moles based on biomarkers is notoriously difficult. The
capricious nature of molar pregnancy should never be
underestimated. In the past, a number of clinical, mor-
phologic, and immunohistochemical studies have
attempted to predict the prognosis of complete moles
but no reliable features have emerged. More recently,
Cheung et al. have found that higher mRNA and protein
expression levels of Nanog, a transcription factor involved
in embryonic stem cell development, are associated with
worse clinical outcome in hydatidiform moles, i.e.,
increased risk for developing persistent GTD [148, 161].
Further studies including large case control studies or
prospective cohorts are required to confirm this finding.
It is recommended that follow-up with serial serum beta-
hCG titers using sensitive assays and radiographic imaging
remain the mainstay in managing patients with complete
hydatidiform mole.
After treatment with chemotherapy there is minimal
increase in the risk of spontaneous abortion or congenital
anomalies and many patients have successful term preg-
nancies. In general, patients with molar pregnancy can be
reassured that they can anticipate a normal future repro-
ductive outcome after appropriate treatment [11]. A chest
radiograph before treatment and 4 weeks later should
be performed to exclude metastases. Following evacuation
 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions 20 1095

of a mole, careful beta-hCG monitoring is mandatory

since it is the most reliable and sensitive method for the
early detection of persistent GTD. The titers of beta-hCG
should fall to normal between 10 and 170 days after
evacuation of a mole, and most patients will have normal
titers by 60 days postevacuation. Persistent GTD after molar
pregnancy is heralded by plateauing beta-hCG titers for 2–4
weeks, rising beta-hCG titers, persistent uterine disease
such as abnormal bleeding, or evidence of metastases. Initial
therapy for persistent disease is usually methotrexate,
dactinomycin, or a combination of the two. Multiagent
chemotherapy that includes etoposide (VP-16) is used for
the treatment of high-risk patients and for those who fail to
respond to conventional forms of chemotherapy.

Partial Hydatidiform Mole

Partial hydatidiform mole features an intimate admixture

of two populations of villi: enlarged, edematous villi and
normal-sized villi that may be fibrotic. Partial molar preg-
nancies may have a grossly identifiable embryo or fetus
with congenital anomalies.
Partial moles are usually the result of diandric trip-
loidy; however, not all triploid conceptuses are partial
moles. In a study analyzing 12 partial moles, all par-
tial moles show diandric, monogenic genomes including
11 heterozygous and one homozygous lesions [13].

Clinical Features
Patients with partial moles may have signs and symptoms
similar to those seen in complete moles, but usually this is
less likely. Uterine size is generally small for dates. Enlarge-
ment in excess of that expected for the gestational age
is uncommon. Frequently, patients with partial moles
appear to have a missed abortion, and vaginal bleeding is
the main presenting symptom. Forty-two percent of
patients with partial moles are at risk of pre-eclampsia,
which tends to occur later than in complete mole but it
can be equally severe [68]. Serum beta-hCG levels often
are in the low or normal range for gestational age. Only
a few patients with partial moles show markedly elevated
beta-hCG titers such as those seen with complete moles.
Gross Findings
The volume of tissue is generally small, less than 100 or
200 mL. The villi may be grossly evident and recognizable
. Fig. 20.15
Partial hydatidiform mole. Hydropic villi mixed with smaller,
‘‘normal-appearing’’ villi
as molar, yet are smaller than those found in a complete
mole. For early partial moles, these gross features may not
be apparent. In some cases a fetus or fetal membranes is
present. When a fetus is found, it often shows gross con-
genital anomalies.
Microscopic Findings
Partial mole shows features in some villi that are similar
to those seen in complete moles, but the molar change
is focal (> Fig. 20.15). By definition, there should be
a mixture of edematous villi and small, relatively normal-
sized villi. Central cisterns are less conspicuous than in
complete moles. Smaller villi usually show stromal fibrosis
similar to that seen in missed abortions (> Fig. 20.16).
Trophoblastic hyperplasia is less marked than in complete
1096 20 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
. Fig. 20.16
Partial hydatidiform mole. A mixture of enlarged villi and
small, normal-sized, and fibrotic villi. There is mild
haphazard trophoblastic hyperplasia and a scalloped
villous surface with trophoblastic infoldings forming
inclusions (arrow)
mole. Generally it is focal and shows little, if any, atypia,
consisting of small, haphazard tufts of trophoblast, often
syncytiotrophoblast, emanating from the surface of some
of the abnormal villi. Another feature commonly encoun-
tered in partial mole is a scalloped outline of the enlarged
villi, yielding a pattern of trophoblastic invaginations into
the villous stroma. When the invaginations do not show
continuity with the surface trophoblast, they appear as
inclusions within the stroma (> Figs. 20.15 and > 20.16).
Invaginations are not exclusive for partial moles and may,
on occasion, be found in other conditions including com-
plete mole and nonmolar hydropic abortus.
Partial moles with triploidy often are associated with
the presence of a fetus (usually abnormally formed) or its
amnion, in contrast to the absence of fetal structures in
most complete moles. Fetal demise with subsequent degen-
eration of fetal structures may make identification of fetal
tissue difficult. A subtle clue is the presence of a functioning
villous circulation containing nucleated red cells, a feature
that requires fetal development. In contrast, the embryo
associated with a complete mole usually dies before organ-
ogenesis and, therefore, fetal structures are not present in
the specimen, and fetal erythrocytes are not present within
placental vessels. One concern in the diagnosis of an appar-
ent partial mole is that the specimen represents a twin
gestation with a fetus and a complete mole. Such twin
pregnancies may occur [82], but probably are an infrequent
occurrence relative to singleton gestations of a partial
mole. In summary, a partial mole is optimally diagnosed
when the following four microscopic features are present:
(1) two populations of villi (one hydropic and one small
and fibrotic, (2) enlarged villi with central cavitation,
(3) irregular villi with geographic, scalloped borders with
trophoblast inclusions, and (4) minimal trophoblast hyper-
plasia (usually focal and involving syncytiotrophoblast)
[44, 168].
Differential Diagnosis
In a practical sense, the most important diagnostic issue
when encountering specimens with abnormal villous
morphology is recognition of complete hydatidiform
mole since this lesion has a higher risk to develop persis-
tent GTD than partial hydatidiform moles and hydropic
abortus. However, diagnosis of hydatidiform moles by
histology can be complicated by overlap of morphological
criteria for complete mole, partial mole, and a nonmolar
hydropic abortus. Nevertheless, the diagnosis of complete
versus partial moles is usually relatively straightforward,
although it can be difficult when an early complete
hydatidiform mole is encountered. The pathological fea-
tures of partial as compared to complete moles are sum-
marized in > Table 20.6. Evidence of a fetus or embryo
including villous erythrocytes strongly favors the diagno-
sis of partial mole, although the rare event of a twin
gestation with one conceptus being a complete mole
should be borne in mind.
Morphological distinction of a hydatidiform mole
from an abortus with abnormal villous morphology may
be problematic, and there is a considerable degree of
interobserver variance in making this distinction [20].
Placentas with genetic abnormalities other than triplody,
 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions 20 1097

. Table 20.6 distinguished from the trophoblastic hyperplasia of

Pathologic features and behavior of complete and partial molar pregnancy. The trophoblast proliferating from the
moles villous surface of an abortus shows polar distribution
characterized by proliferation of trophoblast at the distal
Feature Complete Partial
end of the villus that implants into the basal plate. Simi-
Karyotype 46,XX, 46,XY 69,XXY, 69,XXX larly, villi with trophoblastic islands can be regarded as
Embryo/fetus Absent Present polarized villi that are also associated with a nonmolar
Villous outline Round Scalloped abortus. This directional orientation contrasts with the
Villous Prominent Limited irregular or circumferential proliferation of molar tropho-
stromal blast. In comparing abortion specimens with a non-molar
apoptosis etiology to partial mole it was found that partial moles
Hydropic Marked; cisterns Less pronounced display at least three of the following histologic features:
swelling present and focal two discrete populations of villi, circumferential mild
All villi involved Cisterns less trophoblastic hyperplasia, trophoblastic inclusions, prom-
prominent inent scalloping of villi, or cistern formation. In contrast, a
Small fibrotic villi non-triploid abortus villi display at most two of these
can be present features of partial moles [20]. Irregular trophoblastic
Trophoblastic Circumferential; Focal and minimal
hyperplasia from the villous surface is an especially critical
proliferation Variable, may be feature for diagnosing molar pregnancy.
marked When large aggregates of atypical or proliferating tro-
Trophoblastic Often present Absent phoblast are encountered without any villi, the differential
atypia diagnosis should include choriocarcinoma or PSTT. Care
Implantation Exaggerateda Normal or
must be taken to be certain that sampling is adequate since
site occasionally villi may be sparse and fragmented. Even complete mole can
exaggerated have limited villi in the sections if much of the tissue has
P57 (kip2) Negative Diffusely positive been spontaneously aborted or if dealing with repeated
staining curettage following primary evacuation. The entire speci-
Behavior 17–20% develop <4% develop
men should be processed. Limited examination of a uterine,
pGTD pGTD vaginal, or pulmonary lesion may show only trophoblast,
a
but deeper sectioning may reveal molar villi.
Exaggerated implantation site indicates an increase in the number
Immunohistochemical stains with the p57kip2 anti-
and the extent of intermediate trophoblastic cells.
pGTD, persistent gestational trophoblastic disease. body can be helpful in the differential diagnosis of complete
hydatidiform moles. Expression of p57kip2, a paternally
imprinted gene, is either absent or low in trophoblast
in cases of complete moles in contrast to diffuse
such as trisomy, can display morphologic changes sugges- staining in partial moles and non-molar placentas
tive of partial mole and can be misinterpreted as such by (> Figs. 20.17–20.19) [17, 21]. Importantly, assessment of
morphologic diagnosis alone [20]. However, some clues p57 immunoreactivity should be performed only in villous
may be useful in assisting the differential diagnosis. Spon- trophoblast and stroma cells rather than intermediate tro-
taneous abortions often are associated with failure of phoblastic cells in the endomyometrium as the latter may
development or early demise of the embryo, the so-called reexpress p57 due to a mechanism related to ‘‘epigenetic
blighted ovum or hydropic abortus. These specimens relaxation’’ in a complete mole. The accuracy of p57
show some villous edema with hydropic swelling, features staining in the diagnosis of complete moles has been
shared with molar placentas. The hydropic abortus usually recently validated by molecular genetic studies [97, 132].
is a smaller specimen, however. The villi in a hydropic Besides the p57 expression pattern, the stromal apoptotic
abortus are enlarged only slightly and do not assume the index has been shown to be significantly higher in very
large dimensions found in complete or partial moles. early complete mole than in very early partial mole or
Cisterns can be seen in nonmolar abortions but they are normal placental tissues, which can be potentially useful
focally distributed. Hyperplasia of villous trophoblast is in differential diagnosis [75].
not evident in these cases. The proliferative trophoblast on Given the fact that complete and partial moles are
the villous surface of early pregnancy also must be characterized by distinct molecular genetic features, ploidy
1098 20 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
. Fig. 20.17
p57 immunostaining of a complete hydatidiform mole. The
villous stromal cells and cytotrophoblastic cells (dashed
arrow) do not show p57 immunoreactivity while the
intermediate trophoblastic cells (IT) (arrow) are positive
for p57
analysis has proven valuable in distinguishing a diploid
complete mole from a triploid partial mole and diploid
hydropic abortus from a triploid partial mole [175]. Flow
cytometry and digital imaging systems are frequently
employed to analyze ploidy; however, ploidy assays cannot
be used to diagnose hydatidiform moles per se or to
distinguish a diploid complete mole from a diploid
hydropic abortus. Recently, the multiplex short tandem
repeats (microsatellite markers) DNA analysis has gained
wide acceptance in genotyping products of conception
with abnormal villous morphology [89]. The assay can be
performed using commercially available kits such as those
used in practicing forensic medicine and the genomic
DNA from villi and maternal tissues can be conveniently
. Fig. 20.18
p57 immunostaining of a partial hydatidiform mole. The
villous stromal cells (dashed arrow) and cytotrophoblastic
cells (arrow) demonstrate diffuse p57 immunoreactivity
prepared from paraffin sections. Analyzing microsatellite
markers provides a useful adjunct tool in the differen-
tial diagnosis among complete mole, partial mole, and
nonmolar hydropic abortus.
In summary, it has been well known that diagnosis based
solely on morphology suffers from unsatisfied interobserver
reproducibility in distinguishing hydatidiform moles from
nonmolar specimens with hydropic villi and subclassifica-
tion of hydatidiform moles as complete hydatidiform mole,
partial hydatidiform mole, or early complete hydatidiform
mole. Moreover, chorionic villi associated with chromo-
somal abnormalities that are not triploid, such as trisomy,
may display hydropic change and abnormal villous mor-
phology that mimic a partial mole [20]. These abnormal
placentas associated with hydropic abortus are not associ-
ated with an increased risk of GTD and therefore the
 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
. Fig. 20.19
Abnormal villous morphology. The H&E shows irregularly
shaped and variably sized villi with a trophoblastic
inclusion, suggesting a partial hydatidiform mole (PHM).
Similar to a PHM, the villous stromal cells and
cytotrophoblast are diffusely positive for p57. However,
genotyping analysis demonstrated biparental
diploidy, consistent with a non-molar abortus (Courtesy
of Dr. B. Ronnett)
differential diagnosis is clinically important. A logistic
approach in differential diagnosis of specimens with
abnormal villous morphology has been proposed [97].
In that study, it is recommended that morphologically
abnormal villi should be assessed for p57 immunostaining,
which serves as a triage assay for the diagnosis of complete
hydatidiform moles. When the diagnosis by routine mor-
phology is equivocal, morphologic features together with
a negative p57 result indicate a complete hydatidiform mole
with a rare exception that the complete hydatidiform
mole retains the maternal allele of chromosome 11 in
which the p57 gene resides. Molecular genotyping is then
20 1099
applied to validate a diagnosis of complete hydatidiform
mole by demonstrating androgenetic diploidy and to
resolve p57-positive cases into diandric triploid partial
hydatidiform mole, biparental diploid nonmolar speci-
mens, and the rare complete hydatidiform mole with
aberrant p57 expression [98]. All genotyped nonmolar
specimens demonstrated biparental diploidy, while partial
hydatidiform moles demonstrated diandric triploidy.
Behavior and Treatment
Several studies have shown that partial moles are rarely
followed by persistent or metastatic GTD with risk esti-
mates ranging from 0 to 4% [9, 12, 47, 50, 82, 95, 100, 115,
140, 183]. Misinterpretation of complete moles as partial
moles is a major factor contributing to the overestimated
frequency of persistent GTD after partial mole in previous
studies. Although the risk to develop persistent GTD or
GTN is relatively low in partial mole, there are several case
reports demonstrating the association of a partial mole
and GTN. For example, invasive mole and metastatic
pulmonary lesions have been reported in association
with a partial mole [50], and choriocarcinomas have
been reported in 3 of 3,000 patients with partial moles.
In addition, an in situ or intraplacental choriocarcinoma
arising in a partial mole have also been reported [99]. The
magnitude of the risk of repeated partial moles is not
known, although repetitive partial moles do occur. There-
fore, despite the fact that development of persistent GTD
following a partial mole is uncommon, follow-up of
patients after evacuation of a partial mole is warranted.
Invasive Mole
Invasive mole is a hydatidiform mole in which hydropic
villi invade the myometrium or blood vessels or, more
rarely, are deported to extrauterine sites. Although inva-
sive mole is not a true neoplastic disease, it is often clin-
ically considered to be malignant since the lesion can
invade the myometrium and metastasize.
Clinical Features
Invasive mole is a possible sequela of a hydatidiform mole,
complete or partial. It is unusual for invasive mole to
present primarily, although invasive mole may occur
simultaneously with intracavitary molar pregnancy. Path-
ological diagnosis requires demonstration of molar villi
1100 20 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions

invading the myometrium or deported to extrauterine

sites. In histologically verified cases the lesion most often
is confined to the uterus, with distant spread occurring in
20–40% of cases. Typically this involves the lungs, but the
vagina, vulva, and broad ligament are also well recognized.
Rare examples of spread to other sites such as the
paraspinal soft tissue have been reported. The diagnosis
usually is made on a hysterectomy specimen. However,
invasive mole is rarely confirmed histologically since hys-
terectomy is rarely performed in patients with persistent
beta-hCG titers after removal of an intrauterine mole and
since metastatic lesions of GTD usually are treated suc-
cessfully with cytotoxic chemotherapy without biopsy.

Gross Findings

In the uterus, invasive mole is an erosive, hemorrhagic lesion

extending from the uterine cavity into the myometrium.
Invasion can range from superficial penetration to extension
through the wall, with perforation or involvement of the
broad ligament. Molar vesicles often are grossly apparent.

Microscopic Findings

Microscopically, the diagnostic feature is the presence of

molar villi along with trophoblast in the myometrium or
at an extrauterine site (> Fig. 20.20). Trophoblastic pro-
liferation with atypia accompanies the enlarged villi and is
as variable as in noninvasive mole, ranging from slightly
proliferative with minimal atypia to marked trophoblastic
proliferation with extreme atypia. Hydropic swelling tends
not to be as marked as in noninvasive mole. Molar villi
usually are no more than 4–5 mm in diameter. In meta-
static sites, the diagnosis is based on the presence of villi.
Careful searching may be necessary to identify villi within
a lesion seemingly composed entirely of highly prolifera-
tive trophoblast. Lesions at distant sites usually are com-
posed of molar villi confined within blood vessels without
invasion into adjacent tissue. The molar villi at the extra-
uterine sites are the result of intravascular deportation.
Differential Diagnosis
Since the pathological diagnosis of invasive moles requires
identification of molar villi and trophoblast either within
the myometrium or at an extrauterine site, there are few
lesions that enter into the differential. Recurettage of the
. Fig. 20.20
Invasive mole. A hydropic villus invades the myometrium.
Intermediate trophoblastic cell proliferation is present in
the myometrium
endometrium after diagnosis of a mole may show prolif-
erative trophoblast with villi but this does not represent an
invasive mole unless myometrial invasion is found. If
post-molar curettage yields only trophoblast, the diagno-
sis of invasive mole is not established. Two forms of
placenta accreta, specifically placenta increta or percreta,
represent normal placenta that has implanted without an
intervening decidual layer and invaded myometrium. In
contrast to invasive mole, however, the villi in accreta are
not hydropic and the trophoblast does not show the pro-
liferative activity found in a mole.
Invasive mole must be discriminated from choriocar-
cinoma. Both invasive mole and choriocarcinoma after
a hydatidiform mole are manifested by a plateau or eleva-
tion in the beta-hCG titer. Furthermore, both can give rise
to secondary lesions. Consequently, it is often not possible
clinically to distinguish between these lesions. A repeat
 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
curettage may yield more molar tissue, obvious choriocar-
cinoma, or scant fragments of trophoblast unaccompanied
by villi but lacking unequivocal features of choriocarci-
noma. In the latter instance a diagnosis of atypical tropho-
blast is appropriate, accompanied by a description and the
reasons why a diagnosis of residual mole or choriocarci-
noma was not made. When more molar tissue is found,
a diagnosis of persistent hydatidiform mole is made.
Behavior and Treatment
Invasive mole is the most common form of persistent or
metastatic GTD after hydatidiform mole, which occurs six
to ten times more frequently than choriocarcinoma. Using
modern chemotherapy, death from invasive mole is
unusual. Most patients, even with distant spread survive.
The risk of progression to choriocarcinoma is no greater
than that after complete mole.
Invasive mole is the clinical diagnosis given to many
patients with extrauterine disease or abnormally persistent
beta-hCG titers after molar pregnancy and no residual
hydatidiform mole within the uterine cavity. In such
instances, there is, however, a possibility that persistent
beta-hCG levels may be due to choriocarcinoma. In these
cases, the clinical term persistent GTD or gestational tro-
phoblastic neoplasia is used without attempting to dis-
criminate between invasive mole and choriocarcinoma.
Clinicopathological Features, Behavior,
and Treatment of Trophoblastic Tumors
and Tumor-like Lesions
Choriocarcinoma
Gestational choriocarcinoma is a highly malignant epithe-
lial tumor arising from the trophoblast of any type of
gestational event, most often a hydatidiform mole. Chorio-
carcinoma is for all practical purposes limited to reproduc-
tive-age women but rare examples in postmenopausal
women have been reported. It consists predominantly of
a biphasic proliferation of mononucleate trophoblast and
syncytiotrophoblast that morphologically recapitulates the
primitive trophoblast of the previllous stage during placen-
tal development. Chorionic villi are not a component of
this tumor with an exception of intraplacental choriocarci-
noma (see below). Molecular genetic study based on restric-
tion fragment length polymorphism analysis using a
minisatellite DNA probe suggests that the pathogenesis of
20 1101
choriocarcinoma varies, some being androgenetic and
some gynogenetic [6]. However, the case number in that
study is limited to permit from conclusions. The absence
of Y chromosome has been demonstrated in the vast
majority of choriocarcinomas, indicating that the shortfall
of Y chromosomal complements in choriocarcinomas
may simply be due to the genetic basis of their precursor
lesions, complete hydatidiform moles in which most of
cases had the genotype of XX [178].
Clinical Features
Theoretically, choriocarcinoma may arise in the trophoblast
of the primitive blastocyst during implantation, but most
cases of choriocarcinoma appear to follow a recognizable
gestational event. Indeed, ‘‘in situ’’ or intraplacental
choriocarcinoma can be found in a third-trimester pla-
centa [29, 38] with a transition from normal-appearing
cytotrophoblast to choriocarcinoma. The more abnormal
the pregnancy, the more likely that choriocarcinoma may
supervene. Hertig and Mansell found an incidence of 1 in
160,000 normal gestations, 1 in 15,386 abortions, 1 in
5,333 ectopic pregnancies, and 1 in 40 molar pregnancies
[55]. In that series, one half of the cases of choriocarci-
noma were preceded by hydatidiform mole, with 25%
following abortion, 22.5% following normal pregnancy,
and 2.5% following ectopic pregnancy [55].
The signs and symptoms of choriocarcinomas are
protean. Abnormal uterine bleeding is one of the most
frequent presentations of choriocarcinoma, but uterine
lesions may be restricted to the myometrium and remain
asymptomatic. Not all patients have a demonstrable lesion
in the uterus after an intrauterine gestation. Many examples
of metastatic choriocarcinoma without a primary uterine
tumor have been described and in those cases, it is highly
likely that the neoplasm undergoes regression in the
uterus. Although the majority of choriocarcinomas develop
shortly after the preceding gestation (> Table 20.7), long
latency (>10 years) between the gestation and diagnosis
can occur [127, 165]. Because of its rarity, the diagnosis of
a postpartum choriocarcinoma can be delayed and the
mean duration from onset of symptoms to treatment is
7 weeks [117]. Sometimes, symptoms related to metastases
are the first indication that a choriocarcinoma is present,
and the lungs are the most frequent sites for metastasis.
Thyrotoxicosis and hemorrhagic events in the central ner-
vous system, liver, and gastrointestinal or urinary tracts
also occurs in choriocarcinoma. Although rare, gesta-
tional choriocarcinoma may coexist with an intrauterine
1102 20 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions

. Table 20.7
Clinical features of gestational trophoblastic tumors

Features Choriocarcinoma PSTT ETT

Clinical presentation Persistent GTD after hydatidiform mole Missed abortion Abnormal vaginal
bleeding
Last known pregnancy Usually within months Variable, can be remote Variable, can be remote
or GTD
History of mole 50% of cases 10%–50% of cases 10%–50% of cases
Serum beta-hCG High (>10,000 IU/mL) Low (<2,000 IU/mL) Low (<2,000 IU/mL)
Clinical behavior Aggressive if untreated, curable in most Self-limited, persistent, or Self-limited, persistent, or
patients after treatment aggressive aggressive
Response to Excellent Variable Variable
chemotherapy
Primary treatment Chemotherapy Hysterectomy or local Hysterectomy or local
resection resection

. Fig. 20.21
Choriocarcinoma. Left: Choriocarcinoma in the uterus. The tumor forms a large, hemorrhagic mass that involves the
endometrium and myometrium. (Reprint from [146] with permission from Churchill Livingstone Elsevier.) Right: Liver
metastasis from choriocarcinoma. Multiple, circumscribed, and hemorrhagic masses are evident

pregnancy, either as an incidental microscopic finding or Gross Findings

a concurrent disease with the diagnosis of choriocarcinoma
during pregnancy. Gestational choriocarcinoma also may
be primary in the fallopian tube, and in this extremely rare
instance, the tumor probably is a sequela of an ectopic
pregnancy.
Uterine choriocarcinoma generally is a dark red, hemor-
rhagic mass with a shaggy, irregular surface and variable
amounts of necrosis (> Fig. 20.21). Occasionally, a lesion
may lack significant hemorrhage and appear as a fleshy,
 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
. Fig. 20.22
Choriocarcinoma. The tumor forms a circumscribed mass
within the myometrium. Hemorrhage is present in the right
lower corner
tan-gray mass with necrosis. The size of uterine lesions
varies greatly, ranging from tiny, microscopic foci to huge,
necrotic tumors. Metastases beyond the uterus appear
well circumscribed and hemorrhagic. For the rare intra-
placental choriocarcinoma, the diagnosis based on gross
specimens is very difficult as the lesion may be very small
and can mimic non-malignant conditions, such as placen-
tal infarction or even an old blood clot.
Microscopic Findings
Choriocarcinoma is characterized by masses and sheets of
trophoblastic cells that invade surrounding tissue and
permeate vascular spaces (> Figs. 20.22–20.26). Choriocar-
cinoma is generally not associated with chorionic villi
with the rare exception of choriocarcinoma arising
within a placenta. Central hemorrhage and necrosis
with viable tumor constituting only a thin peripheral rim
20 1103
. Fig. 20.23
Choriocarcinoma. Syncytiotrophoblast (ST) lining vascular
spaces and capping cytotrophoblast (CT) and intermediate
trophoblast (IT). There is an alternating arrangement of
multinucleated ST with intervening clusters of
mononucleate IT and CT
is a characteristic feature. The interface with normal tis-
sue, if preserved, is circumscribed and appears expansile
or pushing (> Fig. 20.22).
An intimate mixture of cytotrophoblast, intermediate
trophoblast, and syncytiotrophoblast forms the cellular
population of choriocarcinoma (> Fig. 20.23) [92]. The
cytotrophoblast and intermediate trophoblast tend to
grow in clusters and sheets, separated by syncytiotro-
phoblast, forming the characteristic dimorphic growth
pattern (> Fig. 20.23). These patterns of growth recapitu-
late the relationship of the trophoblast to the maternal–
placental circulation of the early implanting previllous
blastocyst. A network of syncytiotrophoblast intimately
admixed with cytotrophoblast and intermediate tropho-
blast comprises the plexiform pattern of trophoblast in
many cases. The percentage of intermediate trophoblast in
choriocarcinomas is highly variable ranging from 1 to 90%
1104 20 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
. Fig. 20.24
Choriocarcinoma with inconspicuous syncytiotrophoblast.
Occasionally, choriocarcinoma is composed predominately
of cytotrophoblast and intermediate trophoblast with
indistinct or attenuated syncytiotrophoblast (arrow)
forming monotonous and cohesive sheets. Although
syncytiotrophoblast is inconspicuous, these cells have
dense, eosinophilic cytoplasm and pyknotic nuclei. This
pattern may simulate a poorly differentiated carcinoma
of the mononucleate trophoblastic cellular population
[149], and a recent study has demonstrated that chorio-
carcinoma is composed predominantly of a mixture of
syncytiotrophoblast and intermediate trophoblast with
only a small proportion of cytotrophoblast [92]. The
intermediate trophoblastic cells in a choriocarcinoma
tend to be larger with more abundant cytoplasm
(> Fig. 20.23). They are usually located adjacent to the
cytotrophoblast, assuming a zonal pattern of differentiation
from cytotrophoblast. Occasionally, choriocarcinoma
appears predominately composed of cytotrophoblast and
intermediate trophoblast forming a monotonous and cohe-
sive sheet or mass with indistinct or attenuated syncytio-
trophoblast (> Figs. 20.24 and > 20.25). This
monomorphic variant may cause a problem in the
. Fig. 20.25
Monomorphic choriocarcinoma in the cervix. Mononucleate
trophoblast (cytotrophoblast and intermediate
trophoblast) is present and syncytiotrophoblast is indistinct
in this section. However, syncytiotrophoblast appears in
deeper sections and displays an alternating (biphasic)
pattern of syncytiotrophoblast and mononucleate
trophoblast (inset)
differential diagnosis. Careful search for syncytiotro-
phoblast, deeper sectioning of the paraffin blocks, and
immunostaining for beta-hCG may reveal syncytiotro-
phoblast in focal areas. Beta-hCG staining can be very
useful in demonstrating attenuated or indistinct
syncytiotrophoblast.
One of the unique morphological features of choriocar-
cinoma is the lack of new blood vessel formation (angio-
genesis) in the center of the tumor (> Fig. 20.26) although
blood vessels stemming from the surrounding stroma
can be detected in the periphery of a choriocarcinoma.
Instead, the tumor cells within a choriocarcinoma estab-
lish intricate pseudovascular network and blood-lakes that
are lined by trophoblastic cells rather than by endothelial
cells. Those trophoblast-lined pseudovascular channels
likely communicate with true blood vessels outside the
 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions 20 1105

. Fig. 20.26
Choriocarcinoma. (a) H&E stain shows high magnification of choriocarcinoma cells. (b) Trichrome stain demonstrates almost
undetectable connective tissue within the choriocarcinoma. (c) CD34 staining reveals no evidence of endothelium-lined
blood vessels in the tumor except in the tumor–stroma interface. The blood supply of choriocarcinoma in this specimen is
derived from trophoblastic cells creating blood-filled channels and lakes that communicate with the circulation in the soft
tissue surrounding the tumor

choriocarcinoma. The generation of microvascular-like distinguished from syncytiotrophoblast by their cyto-

channels by neoplastic cells was termed ‘‘vasculogenic
mimicry,’’ a term used to underscore their de novo gener-
ation without involvement by endothelial cells [37]. The
vasculogenic mimicry can only be seen in a sizable chorio-
carcinoma usually obtained from a hysterectomy specimen
(> Fig. 20.26) and may not be obvious in small biopsy
samples. In contrast to angiogenesis occurring in other
solid tumors, the pseudovascular channels in choriocarci-
noma are devoid of adequate stromal support, which
contributes to hemorrhage and necrosis in the center of
the tumor. Accordingly, it is not uncommon that only
a small amount of viable choriocarcinoma tissue remains
in a lesion and thus extensive sampling and sectioning
may be required to identify the typical morphological
features of choriocarcinoma.
There may be considerable cytological atypia in the
trophoblast with pleomorphic-enlarged nuclei, abnormal
mitotic figures, and bizarre cellular configurations.
Nuclear chromatin is coarsely granular, with an uneven
distribution, and nucleoli may be present (> Fig. 20.26).
Enlarged, multinucleated intermediate trophoblastic cells
with two or several nuclei also occur, and they are
plasm, which lacks the dense eosinophilia and
vacuolization and by positive CD146 (Mel-CAM)
immunostaining [149].
It is not uncommon for choriocarcinoma to display
focal differentiation of a PSTT and/or an epithelioid tro-
phoblastic tumor. The choriocarcinoma component can be
discrete or it can merge imperceptibly with areas of PSTT
or epithelioid trophoblastic tumor. To report those mixed
GTN, we recommend using a term of ‘‘choriocarcinoma
with PSTT or epithelioid trophoblastic tumor’’ to accentu-
ate the clinical importance in recognizing the choriocarci-
noma component, which requires cytotoxic chemotherapy.
Further studies are required to determine the treatment
response and clinical outcome in the mixed GTNs.
Differential Diagnosis
In general, the diagnosis of choriocarcinoma requires the
presence of the biphasic pattern of trophoblastic growth
(syncytiotrophoblast and mononucleate trophoblast) and
invasion of the tumor typically associated with necrosis
1106 20 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions

. Table 20.8
Morphological features of gestational trophoblastic tumors

Features Choriocarcinoma PSTT ETT

Cellular Dimorphic; syncytiotrophoblast alternating Monomorphic; implantation Monomorphic; chorionic-type
population with mononucleate trophoblast site intermediate trophoblastic intermediate trophoblastic
Cell size and Irregular, highly variable Large and pleiomorphic Smaller, round, and uniform
shape
Cytoplasm Variable pale to amphophilic Abundant and eosinophilic Eosinophilic or clear
Growth Circumscribed mass with central necrosis/ Confluent sheets, masses or Epithelioid nests or cords or
pattern hemorrhage infiltrating single cells solid masses
Tumor Circumscribed; pushing Infiltrating Circumscribed; expansile
border
Cellular Extensive Usually absent Extensive
necrosis
Calcification Absent Absent Usually present
Vascular Tumor thrombi From periphery to lumen Absent
invasion
Fibrinoid Absent Present Present
change
Mitosis High; 2–22/10 HPF Variable; 0–6/10 HPF Variable; 1–10/10 HPF
Associated Absent Absent Absent
chorionic villi

into the endomyometrium. The presence of detached
fragments of biphasic trophoblastic tissue alone may be
insufficient to diagnose choriocarcinoma unless very early
placentas and trophoblastic hyperplasia associated with
a complete hydatidiform mole can be excluded. Assess-
ment of endomyometrial invasion should be thoroughly
evaluated and deeper sections may be needed to demon-
strate the invasive pattern associated with choriocarci-
noma. Thus, choriocarcinoma must be distinguished
from the normal trophoblast of early gestation, from
molar pregnancies, as well as from PSTT, epithelioid tro-
phoblastic tumor, and from other forms of epithelial
malignancy. The differential diagnosis is primarily based
on morphological grounds (> Table 20.8). Occasionally,
normal trophoblast of an early gestation is found in curett-
ings without associated villi. In this circumstance, the tro-
phoblast should be present only in small quantities and
deeper sections may reveal chorionic villi. Normal tropho-
blast of an early gestation, although proliferative, does not
show atypical features including marked cellular enlarge-
ment and nuclear abnormalities found in choriocarcinoma
(> Fig. 20.27). Thus, large amounts of trophoblast show-
ing atypia should be viewed suspiciously for choriocarci-
noma. Most importantly, fragments of normal trophoblast
in curettings do not show tumor necrosis or destructive
invasion. As a general rule, choriocarcinoma should not be
diagnosed in the presence of villi. Proliferative trophoblast
in association with villi usually indicates either an abortion
or hydatidiform mole. The differential diagnosis of these
lesions is discussed under ‘‘Hydatidiform mole.’’ Rarely,
gestational choriocarcinoma arises within a normally devel-
oping placenta, with the neoplasm intimately associated
with well-formed, mature nonmolar villi [184]. If the diag-
nosis is in doubt, a chest radiograph and careful monitoring
of beta-hCG levels should help resolve the problem.
Discriminating choriocarcinoma from other carcino-
mas either within the uterus or at other sites usually is not
a problem. On occasion a biopsy may show a few syncytio-
trophoblastic cells, or the entire lesion is composed of
mononucleate trophoblastic cells, a pattern that can
mimic a poorly differentiated carcinoma (> Figs. 20.24
and > 20.25). When this differential diagnosis arises, the
clinical history may reveal a previous molar pregnancy or
another suspicious pregnancy event that can assist in the
diagnosis. Serum beta-hCG levels and immunohistochemi-
cal localization of beta-hCG, hPL, and HSD3B1 in syncytio-
trophoblast can be useful (> Fig. 20.28; > Table 20.2).
Choriocarcinoma has been described as a primary
tumor arising in a number of different sites besides the
uterus and gonads. In women of reproductive age,
however, pure choriocarcinoma that appears to be an
extrauterine primary tumor probably represents
 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
. Fig. 20.27
Normal trophoblast in an early gestation. The trophoblastic
cells in an early placenta may exhibit ‘‘biphasic’’ growth as
seen in choriocarcinoma (inset). Unlike choriocarcinoma,
the normal trophoblastic cells, although proliferative, do
not show atypical features including marked cellular
enlargement and nuclear abnormalities. Normal
trophoblast does not display tumor cell necrosis or
destructive invasion. Large amounts of trophoblast with
atypia should be viewed suspiciously for choriocarcinoma.
Moreover, the presence of chorionic villi is important to
establish the diagnosis of an early gestation. Deeper
sections can be useful in identifying villi if they are absent in
the original sections
gestational choriocarcinoma in which the index preg-
nancy is undetected. True primary choriocarcinoma at
an unusual site may be an extragonadal germ cell tumor,
or it may be derived from dedifferentiation of an ordinary
carcinoma [1]. Primary somatic tumors of the gastrointes-
tinal tract, bladder, breast, lung, or endometrium rarely
show choriocarcinomatous differentiation, and these
show transitions from ordinary carcinoma to the tropho-
blastic component. Since somatic tumors also may produce
beta-hCG without showing choriocarcinoma histology, the
20 1107
. Fig. 20.28
Syncytiotrophoblast in choriocarcinoma.
Syncytiotrophoblast surrounds nests of mononucleate
trophoblastic cells. In this case, syncytiotrophoblast is
strongly positive for beta-hCG. In choriocarcinoma
with inconspicuous syncytiotrophoblast,
immunostaining with an anti-hCG antibody can be very
useful in establishing the diagnosis by highlighting
syncytiotrophoblast
classic biphasic growth pattern should be present before
rendering the diagnosis of choriocarcinoma.
The differential diagnosis of choriocarcinoma and
PSTT and epithelioid trophoblastic tumor will be discussed
in the following specific sections and is summarized in
> Tables 20.7 and > 20.8.
Clinical Behavior and Treatment
Metastasis of choriocarcinoma most frequently occurs in
brain and liver, and the majority of therapeutic failures
have liver and/or brain metastases. High beta-hCG level is
a risk factor for predicting the occurrence of brain and
liver metastases [182]. Kidney and abdomen, including
intestinal tract, are the other common sites of spread,
1108 20 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions

but almost any organ, including the skin, may be involved. a 50% remission rate for cerebral metastases but irradia-
Lymph nodes contain tumor on occasion, often as tertiary tion to other sites generally is not useful.
metastatic lesions from other organs. Vaginal involvement
has been reported in 16–32% of patients. There have been
Placental Site Trophoblastic Tumor
a few isolated reports of metastatic choriocarcinoma
occurring in the mother and child of a term pregnancy
The PSTT is a relatively uncommon form of GTD
[39, 184]. In most cases, the infant is disease-free, however.
accounting for less than 3% of GTD cases [53, 125]. The
In untreated cases, death from choriocarcinoma most
tumor is composed of neoplastic implantation site inter-
commonly results from hemorrhage or pulmonary insuf-
mediate trophoblastic cells that resemble those infiltrating
ficiency. Fatal hemorrhage usually occurs in the central
into the endometrium and myometrium of the placental
nervous system or lungs, but intraperitoneal and gastro-
site during early pregnancy. Molecular genetic data
intestinal hemorrhages also can cause death. Exsanguina-
together with immunohistochemical findings support
tion may occur after biopsy of a vaginal metastasis.
the trophoblastic nature of PSTT [120, 160]. The neo-
Pulmonary insufficiency can be due either to a large
plasm lacks the biphasic pattern seen in choriocarcinoma,
tumor burden or to the effects of irradiation and cytotoxic
and the epithelial-like growth pattern of epithelioid
chemotherapy. An interval of less than 4 months since the
trophoblastic tumor. The PSTT was originally termed
antecedent pregnancy, a pretreatment beta-hCG level
atypical chorioepithelioma by Marchand in 1895, but
<40,000 mIU/mL, and absence of brain or liver metastases
because of its rarity, it was periodically rediscovered and
appear to be the significant predictors of a favorable out-
renamed. Terms that have been used include atypical
come in postterm choriocarcinoma [137].
choriocarcinoma, syncytioma, chorioepitheliosis, and tro-
In the past, gestational choriocarcinoma usually was
phoblastic pseudotumor [80]. PSTT has been thought to
fatal. Before cytotoxic chemotherapy was available, hys-
develop as a result of neoplastic transformation of
terectomy and, in some instances, irradiation were the
cytotrophoblastic cells and the transformed cells assume
only forms of treatment. The absolute 5-year survival for
the differentiation toward implantation site intermediate
patients treated by hysterectomy alone was 32%. Survival
trophoblast [145]. Both benign and malignant PSTTs
rates have improved dramatically since the introduction of
do not demonstrate significant karyotypic abnormalities
cytotoxic chemotherapy combined with accurate and sen-
[62, 177]. Interestingly, more than 85% of patients with
sitive assays for beta-hCG to monitor the course of the
PSTT have had a female antecedent gestation either by
disease. The chemotherapy regimens such as EMA/CO
history or genetic analysis. Furthermore, PSTTs lack
(etoposide, methotrexate, actinomycin D, cyclophospha-
Y chromosomes based on a molecular genetic analysis,
mide, and vincristine) are highly effective in eradicating
suggesting a role of the paternally derived X chromosome
choriocarcinoma cells and, thus, choriocarcinoma repre-
in the pathogenesis of PSTT [36, 61, 77, 83, 178]. Alterna-
sents one of the few cancers that are potentially curable by
tively, this shortfall of Y-chromosomal complements in
chemotherapeutic agents alone. The overall survival for
PSTTs may reinforce the notion that the majority of
choriocarcinoma at the present time approaches 100%
PSTTs are derived from previous molar gestations.
[63], although some patients develop non-operable dis-
eases with recurrent and chemoresistant choriocarcinoma.
New therapeutic regimens have been proposed to salvage Clinical Features
these unfortunate patients [145, 172].
The principles of management of choriocarcinoma are Patients usually are in the reproductive age group (19–62
similar to those for GTD after hydatidiform mole; beta- years with an average of 30 years) and can present with
hCG monitoring and chemotherapy are essential. In fol- either amenorrhea or abnormal bleeding, often accompa-
lowing the patients with beta-hCG, a measurement of nied by uterine enlargement [53, 80, 180] and frequently
urinary hCG is important due to the possible false- are thought to be pregnant. When uterine enlargement
positive serum hCG titers [138]. Hysterectomy can reduce ceases, the diagnosis of a missed abortion is made. Serum
the length of hospitalization and the amount of chemo- levels of beta-hCG are generally low (<1,000 mIU/mL).
therapy needed to induce remission. Resection of pulmo- Rarely, PSTT is associated with virilization, nephrotic
nary metastases may have therapeutic value in patients syndrome, and erythrocytosis [14, 181]. In contrast to
with persistent but limited pulmonary disease, if there is choriocarcinoma, which is preferentially associated with
no evidence of tumor at other sites and the hCG titer is a complete mole, PSTT occurs commonly following
low. Irradiation combined with chemotherapy will give a normal pregnancy but spontaneous abortions and
 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
hydatidiform moles have preceded the diagnosis of PSTT
[32, 105, 125]. Usually, the relationship to the previous
gestation is uncertain, because the PSTT can be diagnosed
long after the last known pregnancy. Patients with PSTT
can present either with amenorrhea or with abnormal
bleeding [125, 153]. Rare examples of primary tubal
and ovarian PSTT have been reported [5, 164], and
metastasis to ovary has been documented [103]. The clin-
ical features of PSTT as compared with choriocarcinoma
and epithelioid trophoblastic tumor are summarized in
> Table 20.7.
Gross Findings
Most of the tumors are well circumscribed, and they can be
polypoid, projecting into the uterine cavity or may
. Fig. 20.29
Placental site trophoblastic tumor. The tumor is composed
of a confluent mass of large, polygonal implantation site
intermediate trophoblastic cells with irregular,
hyperchromatic nuclei and dense eosinophilic to
amphophilic cytoplasm with occasional vacuoles
20 1109
predominantly involve the myometrium. The sectioned
surface is usually soft and tan, containing only focal areas
of hemorrhage or necrosis, if present. Invasion frequently
extends to the uterine serosa and, in rare instances, to the
adnexal structures including broad ligament [7].
Microscopic Findings
The predominant cell type in PSTT is the implantation site
intermediate trophoblast. The microscopic features of
PSTT are summarized in > Table 20.8. Most of the cellular
population is monomorphic in contrast to the mixture of
cell types in choriocarcinoma (> Fig. 20.29–20.33). PSTT
is composed of large, polygonal implantation site inter-
mediate trophoblastic cells with irregular, hyperchromatic
. Fig. 20.30
Placental site trophoblastic tumor. Tumor is composed of
a confluent mass of a monomorphic intermediate
trophoblast in contrast to the mixture of cytotrophoblast,
syncytiotrophoblast, and intermediate trophoblast in
choriocarcinoma. The implantation site intermediate
trophoblastic cells characteristically separate muscle
bundles as they invade the myometrium
1110 20 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
. Fig. 20.31
Placental site trophoblastic tumor. Implantation site
intermediate trophoblastic cells may assume a spindle
shape and, therefore, can be confused with
leiomyosarcoma
nuclei and dense eosinophilic to amphophilic cytoplasm
with occasional vacuoles (> Fig. 20.29). PSTT also con-
tains scattered multinucleated implantation site interme-
diate trophoblastic cells that can be mistaken for
syncytiotrophoblast. The tumor cells often aggregate into
confluent sheets; however, at the periphery of the tumor
the trophoblast cells invade singly or in cords and nests,
characteristically separating individual muscle fibers and
groups of fibers (> Fig. 20.30). Although most of the
implantation site intermediate cells are polyhedral, many
of them assume a spindle shape especially where they are
closely apposed to myometrial cells (> Fig. 20.31). Occa-
sionally, PSTT is composed almost entirely of single cells
or small nests of cells without forming sheets or masses.
The individual neoplastic cells extensively infiltrate the
endomyometrium and penetrate the uterine wall deeply.
Although some tumors appear to cause relatively little
tissue destruction, others are associated with extensive
necrosis, a microscopic feature that is often associated
with malignant behavior (see below). It is not uncommon
for a PSTT to also exhibit histological features of
. Fig. 20.32
Placental site trophoblastic tumor. Vascular invasion by
implantation site intermediate trophoblast resembles that
of the normal implantation site. The neoplastic cells
surround and invade a blood vessel, extending into the
vascular lumen. The vessel wall has been replaced by fibrin.
In some vessels, a dense eosinophilic fibrionoid deposit can
be identified in the vascular wall (inset)
choriocarcinoma and epithelioid trophoblastic tumor,
and these tumors are termed mixed choriocarcinoma
and PSTT or mixed PSTT and epithelioid trophoblastic
tumor. Too few of these mixed cases have been studied to
determine their clinical behavior.
As in the normal placental site, abundant extracellular
eosinophilic fibrinoid material is present in the tumor.
The neoplasm displays a characteristic form of vascular
invasion in which blood vessel walls are extensively
replaced by trophoblastic cells and fibrinoid material
(> Fig. 20.32), as observed in the normal placental site
(> Fig. 20.4c). These ‘‘transformed’’ blood vessels are
unique among all human solid tumors and are diagnostic
for PSTT. Decidua or an Arias-Stella reaction may be
present in the adjacent, uninvolved endometrium. Villi
are almost never identified.
PSTT is immunoreactive to the protein markers
expressed in implantation site intermediate trophoblast
 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
. Fig. 20.33
Malignant placental site trophoblastic tumor. As in a benign
PSTT, malignant PSTT grows in masses and sheets and the
cells are large with abundant eosinophilic cytoplasm.
However, the tumor cells in a malignant PSTT exhibits
a higher level of nuclear atypia
(> Table 20.2), because the tumor may likely arise from
transformation of trophoblastic stem cells, presumably
cytotrophoblast, undergoing differentiation toward the
implantation site trophoblast (> Fig. 20.6). For example,
PSTT is diffusely positive for hPL, CD146 (Mel-CAM),
HLA-G, CD10, and Mucin-4 that are expressed in normal
implantation site intermediate trophoblastic cells [84, 92,
149]. Expression of these markers can be useful in the
differential diagnosis of PSTT from other mimickers.
Differential Diagnosis
The differential diagnosis of PSTT includes exaggerated
placental site, choriocarcinoma, epithelioid trophoblastic
tumor, and epithelioid smooth muscle tumor. The most
20 1111
difficult differential diagnosis is that of an exaggerated
placental site. Both lesions are characterized by an exuber-
ant infiltration of implantation site intermediate tropho-
blastic cells. Moreover, the immunophenotype of both
lesions is similar. The histologic features that favor the
diagnosis of PSTT include confluent masses of tropho-
blastic cells, unequivocal mitotic figures, and absence of
chorionic villi (> Table 20.8). In contrast, the exaggerated
placental site is microscopic in size, lacks mitotic activity, is
composed of intermediate trophoblastic cells separated by
masses of hyaline, and usually is admixed with decidua and
chorionic villi (> Table 20.8). In addition, an exaggerated
placental site contains larger numbers of multinucleated
trophoblastic cells than PSTT. Immunostaining for Ki-67
to assess proliferation activity in the implantation site
intermediate trophoblastic cells has been shown to be
superior to the mitotic index as a diagnostic adjunct in
the differential diagnosis of an exaggerated placental site
versus a PSTT [151]. The use of immunohistochemistry in
the differential diagnosis of PSTT is discussed in the sec-
tion > Immunohistochemical Approach for Differential
Diagnosis and in > Fig. 20.53. Briefly, the Ki-67 labeling
index is significantly elevated (>10%) in PSTT but is near
zero in the normal and exaggerated implantation site.
A diagnosis of a PSTT should be strongly considered if
there are Ki-67-labeled implantation site intermediate tro-
phoblastic cells. Although the Ki-67 index in molar implan-
tation site, which is morphologically indistinguishable with
exaggerated placental site, can be 10% or higher, the diag-
nosis of a PSTT versus a complete hydatidiform mole
usually is not a problem. The Ki-67 labeling in the implan-
tation site intermediate trophoblastic cells should be care-
fully assessed using stringent morphologic criteria since
implantation site intermediate trophoblastic cells can
closely resemble other cell types in a placental site. Many
Ki-67-positive cells in the placental site or PSTT are natural
killer cells and activated T lymphocytes, which can be pos-
itive for Ki-67. A double-staining technique utilizing MIB-1
antibody to determine the Ki-67 proliferative index and
markers to identify implantation site intermediate tropho-
blastic cells such as HSD3B1, HLA-G, and Mel-CAM
(CD146) can be very useful in distinguishing an exaggerated
placental site from a PSTT [93, 144].
In contrast to the biphasic pattern of choriocarci-
noma, PSTT is composed of a relatively monomorphic
population of trophoblast. The multinucleated interme-
diate trophoblastic cells in PSTT should not be confused
with syncytiotrophoblast in choriocarcinoma. In contrast
to the interlacing pattern of elongated syncytiotrophoblast
in choriocarcinoma, the multinucleated intermediate
1112 20 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
trophoblastic cells in PSTTare usually polygonal or round.
Additionally, PSTT is diffusely (>50%) positive for hPL,
but only focally positive for beta-hCG (mostly confined
to the multinucleated intermediate trophoblastic cells).
Ki-67 labeling index in intermediate trophoblastic cells is
also helpful in the differential diagnosis of PSTT versus
choriocarcinoma [151]. The Ki-67 index in intermediate
trophoblastic cells of PSTT is significantly lower (<30%)
than choriocarcinoma (>40%).
The differential diagnosis of epithelioid smooth mus-
cle tumor can at times present a problem because of the
infiltrative pattern of PSTT within the myometrium
(> Fig. 20.31). The distinctive pattern of vascular invasion
and the deposition of fibrinoid material in PSTT are help-
ful morphological clues (> Fig. 20.32). Positive staining
for HSD3B1, cytokeratin 18, and hPL as well as the nega-
tive staining for smooth muscle markers are helpful in this
differential diagnosis [93, 144]. The use of immunohisto-
chemistry in the differential diagnosis of PSTT is discussed
in the last section (> Immunohistochemical Approach for
Differential Diagnosis) of this chapter.
Poorly differentiated carcinoma and metastatic mela-
noma can sometimes be confused with PSTT. The pattern of
prominent blood vessel invasion, characteristic myometrial
invasion, and extensive deposition of fibrinoid material
(> Figs. 20.30 and > 20.32) are key diagnostic features
of PSTT. Immunohistochemical stains for HSD3B1,
hPL, and HMB-45 help to distinguish PSTT from poorly
differentiated carcinoma and melanoma (see section
> Immunohistochemical Approach for Differential Diag-
nosis). Typically, in choriocarcinoma the serum beta-hCG
levels are high, ranging from 1,000 mIU/mL to over
1,000,000 mIU/mL, whereas in PSTT the levels are signif-
icantly lower, often less than 1,000 mIU/mL. A recent
study further demonstrates that the percentage of hCG
free beta-subunit is a reliable serum marker for PSTTs and
can be used to rule out other trophoblastic neoplasms and
non-trophoblastic tumors that produce hCG [25].
The differential diagnosis of PSTT from epithelioid
trophoblastic tumor is considered in the section describ-
ing the latter lesion.
Behavior and Treatment
PSTTs often invade through the myometrium to the
serosa, and therefore perforation at the time of curettage
may occur. These tumors may also directly invade into the
broad ligament and ovary. Despite deep myometrial inva-
sion, most cases of PSTT are self-limited [18, 53, 125] and
some patients have been cured by curettage alone.
Approximately 10–15% of PSTT are clinically malignant,
and patients have died despite intensive multiagent che-
motherapy. The mortality rate in patients with PSTT is
about 15–30%, which may be overestimated because
benign cases are generally not reported [53, 58, 125].
The outcomes of patients with FIGO stage I–II disease
after hysterectomy are excellent; while those with FIGO
stage III–IV diseases have a 30% survival [18]. A recent
large retrospective study demonstrates that the probabili-
ties of overall and recurrence-free survival 10 years after
first treatment are 70% and 73%, respectively. Patients
with stage I disease had a 10-year probability of overall
survival of 90% and the probability of overall survival at
10 years was 52% for patients with stage II disease and
49% for stage III and IV disease [139]. In one report,
metastases at presentation occur in more than 30% of
cases and recurrences develop in more than 30% of cases
[35]. The overtly malignant tumors have had widely
disseminated metastases resembling choriocarcinoma in
their distribution with lung, liver, abdominal cavity, and
brain involved. Metastases have the same histological
appearance as the primary tumor and may develop several
years after the initial diagnosis, as one fatal case recurred
5 years after hysterectomy. In general, PSTTs with multiple
metastases have poor prognosis.
Because these tumors are composed of neoplastic
implantation site intermediate trophoblastic cells that
contain only small amounts of beta-hCG, serum levels of
beta-hCG are usually in the range of 1,000 to 2,000 mIU/
mL. These levels are much lower than those in choriocarci-
noma. Despite the low level of serum beta-hCG in patients
with PSTT, it is the best available marker to monitor the
course of the disease [130]. Of note, the marker cannot be
used to diagnose PSTT versus other trophoblastic diseases
[52]. It is important to emphasize that the disease may still
progress even if beta-hCG levels are low [58]. For those
patients with undetectable or very low serum levels of
beta-hCG, urinary or serum beta-core fragment of beta-
hCG may be a better method to monitor treatment as the
percentage is much higher in PSTTs than in choriocarci-
noma and other carcinomas that produce beta-hCG [23].
It is difficult to predict with certainty the behavior of
PSTT [154]. However, some studies have found that sev-
eral clinical parameters may be associated with a poor
clinical outcome in PSTT patients and they include
FIGO stage [18, 56, 131], metastatic involvement [125],
long interval from the antecedent pregnancy [8, 53, 56,
125], age > 35, hCG > 1,000 mIU/mL, depth of invasion
[8, 131], and p53 immunoreactivity [109]. For example,
based on multivariate analysis, investigators have found
that the only significant independent predictor of overall
 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
and recurrence-free survival is time since antecedent preg-
nancy. In that report, a cutoff point of 48 months since
antecedent pregnancy could differentiate between
patients’ probability of survival (<48 months) or death
(48 months) with 93% specificity and 100% sensitivity,
and with a positive predictive value of 100% and a nega-
tive predictive value of 98% [139]. Some studies showed
that a high mitotic count was an adverse prognostic indi-
cator in PSTT patients [8, 56] but it has also been shown
that there is no correlation between clinical outcome and
DNA ploidy, histopathological features, immunohisto-
chemical features, and S-phase fraction [40, 41]. In our
experience, malignant PSTTs as compared with benign
cases generally are composed of larger masses and sheets
of cells, many with clear instead of amphophilic cyto-
plasm. They have more extensive necrosis, prominent
nuclear atypia and higher mitotic activity (> Fig. 20.33).
Our preliminary findings suggest that the Ki-67 labeling
index may be a reliable indicator of prognosis as the index
is usually higher than 50% in malignant tumors.
The treatment of choice for patients whose disease is
confined to the uterus is hysterectomy [35, 58, 131]. In
some patients with localized PSTT who desire preserva-
tion of fertility, more conservative surgical therapy may be
considered [85, 91, 118, 128]. Curettage and local excision
may be therapeutic, but if uterine disease persists, as
evidenced by persistently elevated serum beta-hCG levels,
hysterectomy is indicated. For patients with more exten-
sive or metastatic disease, chemotherapy in addition to
surgery is indicated although the clinical outcome is var-
iable [18, 30, 35, 112, 166, 171]. Combination chemother-
apy usually results in a high response rate and long-term
remission even in patients with recurrent, metastatic
PSTT, but only a few patients achieve a complete response
[10, 18, 67, 133]. In general, EMA/CO is the first line
chemotherapy regimen and EMA/EP can be used in
EMA/CO refractory cases [113]. In conclusion, with the
use of dose-intensive chemotherapy, imaging techniques
to define disease spread, surgery for localized disease, and
the close surveillance with serologic measurement of the
beta-hCG level, most patients with PSTT can be cured.
Epithelioid Trophoblastic Tumor
The term ‘‘epithelioid trophoblastic tumor’’ was introduced
to describe an unusual type of trophoblastic tumor that is
distinct from PSTT and choriocarcinoma with features
resembling a carcinoma. The tumor was originally termed
‘‘atypical choriocarcinoma’’ and was described in the lungs
of patients with antecedent choriocarcinoma following
20 1113
intensive chemotherapy [70, 96]. Similar lesions referred
to as ‘‘multiple nodules of intermediate trophoblast’’ were
subsequently reported in the uteri of patients following
evacuation of hydatidiform moles [159]. Subsequently,
similar tumors were observed in the uterus without his-
tory of antecedent GTD [150]. The relatively recent rec-
ognition of epithelioid trophoblastic tumor as
a distinctive form of trophoblastic disease is in part due
to its rarity and because many of the morphologic features
of epithelioid trophoblastic tumor are more reminiscent
of a carcinoma than of a trophoblastic tumor [150]. Epi-
thelioid trophoblastic tumor is very rare, and experience
with this tumor has been limited to approximately 59
cases reported so far [27, 49, 70, 78, 87, 90, 94, 96, 101,
109, 110, 119, 126, 150, 159, 170, 173, 174]. The tropho-
blastic nature of this tumor has been confirmed using
molecular approaches [120, 160]. Based on morphologic,
ultrastructural, and immunohistochemical studies, epi-
thelioid trophoblastic tumor appears to develop from
neoplastic transformation of cytotrophoblastic cells that
differentiate toward chorionic-type intermediate tropho-
blastic cells [96, 145, 155].
Clinical Features
Based on an analysis of published 52 cases, Palmer et al.
reported that 67% of patients present with abnormal
vaginal bleeding, 36% had evidence of antecedent molar
pregnancy, and 35% presented with metastases [124].
Mean age at diagnosis is 38 years and the mean interval
between the preceding gestation and the diagnosis of
epithelioid trophoblastic tumor is 76 months. hCG
levels are usually low (<1,000 mIU/mL) [49, 150], but
high levels of hCG can be present in some cases. Extra-
uterine epithelioid trophoblastic tumor without an iden-
tifiable trophoblastic lesion in the uterus has also been
described, [49, 86, 150], and the origin of such tumors is
not clear. It is well recognized that choriocarcinoma can
develop after a long latent period without evidence of
disease in the uterus, thus it is conceivable that extrauter-
ine epithelioid trophoblastic tumors develop in a similar
fashion. Rarely, epithelioid trophoblastic tumor can occur
in an extrauterine site including broad ligament [78], gall
bladder [90], and (para)adenxal tissue [116, 126]. Epithe-
lioid trophoblastic tumor can be seen in association with
choriocarcinoma and PSTT [150, 159]. Like PSTT,
a recent molecular genetic study on a small series of
epithelioid trophoblastic tumors demonstrates a balanced
chromosomal profile without detectable gain or loss in the
genome, suggesting that DNA copy number alterations as
1114 20 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
seen in most solid tumors are not a characteristic feature
of this tumor [176].
Gross Findings
In one study, 30% of 14 epithelioid trophoblastic tumors
were located in the uterine corpus, 50% in the lower
uterine segment or endocervix, and the remaining 20%
in extrauterine sites including the small bowel and lungs
[150]. In cases in which a hysterectomy was performed,
tumor size varied from 0.5 to 4.0 cm. All were solitary,
discrete nodules that deeply invaded the cervix or
myometrium. The cut surface was solid or cystic. Solid
areas were typically tan to brown with varying amounts
of hemorrhage and necrosis (> Fig. 20.33). Metastatic
epithelioid trophoblastic tumors show similar gross
features (> Figs. 20.34 and > 20.35).
. Fig. 20.34
Epithelioid trophoblastic tumor in the endocervical canal.
It is well circumscribed and ulcerated with hemorrhage and
necrosis (Reprinted by permission of [150])
Microscopic Findings
Epithelioid trophoblastic tumors are nodular and gener-
ally well circumscribed although focal infiltrative features
can be present at the periphery. The tumors are composed
of a relatively uniform population of mononucleate tro-
phoblastic cells typically arranged in nests and cords and
masses of cells that are intimately associated with an
eosinophilic, fibrillar, hyaline-like material, and necrotic
debris (> Figs. 20.36–20.40). This hyaline-like material,
composed of type IV collagen and fibronectin of oncofetal
and adult types, is either located within the nests or
surrounds them, coalescing to form large aggregates.
This dense eosinophilic material and necrotic debris can
simulate keratin (> Figs. 20.38–20.40). The extensive
areas of necrosis that surround islands of viable tumor
cells create a ‘‘geographic’’ pattern (> Fig. 20.36).
Typically, a small blood vessel is located within the center
of tumor nests. Blood vessels within the tumor are pre-
served with occasional deposition of amorphous fibrinoid
material in the wall. A lymphocytic infiltrate often sur-
rounds the tumor (> Fig. 20.38). In most cases, apoptotic
cells are diffusely distributed throughout the tumor.
. Fig. 20.35
Metastatic epithelioid trophoblastic tumor in the lung.
A lobectomy specimen shows a discrete nodule with
yellowish and necrotic cut surface
 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
. Fig. 20.36
Epithelioid trophoblastic tumor. Tumor in a hysterectomy
specimen contains nests of atypical mononucleate
trophoblastic cells. Large areas of genographic necrosis and
extensive calcification are characteristic features of the
tumor, which lacks the typical dimorphic pattern of
choriocarcinoma
Calcification is common in epithelioid trophoblastic
tumors but not in PSTT or choriocarcinoma, and this
morphological feature is unique among all GTDs
(> Fig. 20.36).
Chorionic-type intermediate trophoblast is the pre-
dominant cell population in the epithelioid trophoblastic
tumor [145,150]. These cells contain round, uniform
nuclei and eosinophilic or clear (glycogen-rich) cytoplasm
surrounded by a well-defined cell membrane, morpholog-
ical features characteristic of the intermediate trophoblas-
tic cells in fetal membrane (chorion laeve; > Fig. 20.5). For
the most part, the cells are larger than cytotrophoblastic
cells but smaller than the implantation site intermediate
trophoblastic cells. The tumor cell nuclei have finely dis-
persed chromatin and prominent or inconspicuous nucle-
oli. Ultrastructurally these cells are transitional between
cytotrophoblast and syncytiotrophoblast but differ from
20 1115
. Fig. 20.37
Epithelioid trophoblastic tumor. Relatively monotonous
tumor cells are present in this section surrounded by
necrosis. Occasional mitotic figures can be seen
the implantation site intermediate trophoblast [96]. Occa-
sionally, larger cells resembling implantation site interme-
diate trophoblastic cells can be found among the smaller
tumor cells or embedded in the extracellular hyaline
matrix. The mitotic index varies from 0 to 9 mitoses per
10 high power fields (40) with an average of 2 mitoses
per 10 high power fields [150]. Although most epithelioid
trophoblastic tumors display a uniform architectural
pattern, focal areas resembling placental site nodule,
PSTT, and choriocarcinoma can occasionally be identified
within the tumor. Furthermore, epithelioid trophoblastic
tumor can be associated with a concurrent germ cell
tumor such as teratoma [2], indicating epithelioid tro-
phoblastic tumor may arise, although rarely, from a
non-gestational event.
A unique feature of epithelioid trophoblastic tumor,
among all GTDs, is its ability to replace and re-epithelialize
the endocervical and/or endometrial surface epithelium
(> Fig. 20.41) [34, 150]. When this tumor involves the
1116 20 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
. Fig. 20.38
Epithelioid trophoblastic tumor. A solitary lung metastasis
after chemotherapy for typical choriocarcinoma. The tumor
cells form a cohesive sheet with scattered dense
eosinophilic debris, resembling a keratinizing squamous
cell carcinoma
lower uterine segment and endocervix, the intraepithelial
extension can mimic squamous carcinoma in situ. The
tumor cells usually stratify into two to three layers, how-
ever, and are larger than cervical squamous cells with
abundant eosinophilic cytoplasm and large
hyperchromatic, pleomorphic nuclei.
The immunohistochemical features of the epithelioid
trophoblastic tumor are similar to those of chorionic-type
intermediate trophoblast (> Table 20.2). The ‘‘classic’’
implantation site intermediate trophoblastic markers
including hPL and CD146 (Mel-CAM) are only focally
expressed. The immunophenotype of the epithelioid tro-
phoblastic tumor contrasts with the PSTT, which is
diffusely positive for CD146 (Mel-CAM) and hPL. Fur-
thermore, epithelioid trophoblastic tumor exhibits simi-
lar morphological features and gene expression profile
to the intermediate trophoblastic cells in a placental
site nodule [153, 158], suggesting that the epithelioid
. Fig. 20.39
Epithelioid trophoblastic tumor. At high magnification, the
dense eosinophilic debris is prominent within the tumor
trophoblastic tumor represents the neoplastic counterpart
of the placental site nodule. Indeed, synchronous epithe-
lioid trophoblastic tumor and placental site nodule in the
same specimens can be occasionally observed [150, 158]
and transformation of a placental site nodule into a malig-
nant epithelioid trophoblastic tumor has been recently
documented [170]. The morphological and immunohis-
tochemical features of extrauterine epithelioid tropho-
blastic tumors are similar to those in the uterus [49].
Like PSTT, epithelioid trophoblastic tumor can pre-
sent as a mixed lesion containing either a PSTT or a
choriocarcinoma (> Fig. 20.42). It has been proposed
that these mixed tumors can result from aberration in
the trophoblastic differentiation program in which the
neoplastic cytotrophoblast (stem) cells differentiate into
implantation site intermediate trophoblastic cells to form
the PSTT component, and into chorionic-type intermedi-
ate trophoblastic cells to form the epithelioid trophoblas-
tic component, or they remain relatively undifferentiated
to form the choriocarcinoma component [145].
According to this model (> Fig. 20.8), choriocarcinoma
 Gestational Trophoblastic Tumors and Related Tumor-Like Lesions
. Fig. 20.40
Epithelioid trophoblastic tumor. Dense eosinophilic
material surrounds nests of tumor cells. The tumor is
frequently accompanied by an abundant lymphocytic
infiltration
is the most primitive trophoblastic tumor, whereas PSTT
and epithelioid trophoblastic tumor are relatively more
differentiated. This hypothesis explains the existence of
trophoblastic tumors with a mixed histological pattern
including choriocarcinoma and PSTT and/or epithelioid
trophoblastic tumor. This new model also helps to explain
the findings previously reported by Mazur who originally
described epithelioid trophoblastic tumor as tumors after
intense chemotherapy of metastatic choriocarcinomas in
the lung. In these cases, it is plausible that chemothera-
peutic agents direct choriocarcinoma cells to differentiate
into an epithelioid trophoblastic tumor phenotype, which
is more refractory to chemotherapy than the original
choriocarcinoma. As a result, the epithelioid trophoblastic
tumor outgrew the choriocarcinoma after chemotherapy.
Differential Diagnosis
The differential diagnosis of epithelioid trophoblastic
tumor includes PSTT, placental site nodule, choriocarci-
noma, epithelioid smooth muscle tumor, and keratinizing
20 1117
. Fig. 20.41
Epithelioid trophoblastic tumor. An endocervical gland is
replaced by epithelium from an epithelioid trophoblastic
tumor. There is an abrupt transition between the tumor and
the endocervical epithelium (arrow) (Reprinted by
permission of [150])
squamous cell carcinoma of the cervix [150, 174].
Epithelioid trophoblastic tumors exhibit a nodular growth
pattern, and the border between the tumor and the
myometrium is expansile. In contrast, the cells of PSTT
infiltrate the myometrium by insinuating themselves
between muscle bundles and fibers. In addition, the cells
in epithelioid trophoblastic tumor are smaller than in
PSTT (> Fig. 20.43) and tend to grow in nests and cords,
a pattern usually not observed in PSTT. In epithelioid
trophoblastic tumors, there is extensive geographic
necrosis accompanied by dystrophic calcification and
the tumor cells are surrounded by fibrillar eosinophilic
material instead of the more homogeneous fibrinoid
material found in PSTT. Blood vessels in epithelioid tro-
phoblastic tumor are often surrounded by tumor cells
but vascular invasion is not a striking feature in contrast
to the vascular invasion in PSTT, where tumor cells and
hyaline material replace the vessel walls (> Fig. 20.32).
If calcification is detected, the lesion is most likely an
epithelioid trophoblastic tumor rather than a PSTT.
Finally, immunostains can be useful in difficult cases