International Journal of Gynecological Pathology

20:31–47, Lippincott Williams & Wilkins, Baltimore

© 2001 International Society of Gynecological Pathologists

The Pathology of Intermediate Trophoblastic Tumors and

Tumor-like Lesions

Ie-Ming Shih, M.D., Ph.D., and Robert J. Kurman, M.D.

Summary: An intermediate trophoblast is a distinctive trophoblastic cell population

from which four trophoblastic lesions are thought to arise: exaggerated placental site
(EPS), placental site nodule (PSN), placental site trophoblastic tumor (PSTT), and
epithelioid trophoblastic tumor (ETT). EPSs and PSTTs are related to the differentia-
tion of the intermediate trophoblast in the implantation site (implantation site inter-
mediate trophoblast), whereas PSNs and ETTs are related to the intermediate tropho-
blast of the chorion laeve (chorionic-type intermediate trophoblast). EPSs and PSNs
are nonneoplastic lesions, whereas PSTTs and ETTs are neoplasms with a potential for
local invasion and metastasis. Microscopically, intermediate trophoblastic lesions can
be confused with a variety of trophoblastic and nontrophoblastic tumors, but an ap-
preciation of the morphologic features and immunophenotype allows their diagnosis to
be relatively straightforward in most instances. Correct diagnosis is important because
each of these lesions may require different therapeutic approaches. Key Words: tro-
phoblast—intermediate trophoblast—placental site trophoblastic tumor—placental site
nodule—epithelioid trophoblastic tumor

Intermediate trophoblastic lesions include exaggerated SUBPOPULATIONS OF TROPHOBLAST

placental site (EPS), placental site nodule (PSN), placen-
tal site trophoblastic tumor (PSTT), and epithelioid tro-
phoblastic tumor (ETT). In contrast to hydatidiform
moles and choriocarcinoma, lesions of intermediate tro-
phoblast have been recognized only relatively recently,
and, therefore, their behavior has not been as well char-
acterized. This review will discuss the various subpopu-
lations of human trophoblast with emphasis on the dif-
ferentiation and morphology of intermediate trophoblast
in view of the recent findings indicating that different
types of intermediate trophoblastic lesions appear to be
derived from distinct subpopulations of intermediate tro-
phoblast. The pathologic features, clinical behavior, and
treatment of each of these lesions will be discussed with
an emphasis on differential diagnosis.
From the Division of Gynecologic Pathology, Department of Pathol-
ogy and Department of Gynecology and Obstetrics, Johns Hopkins
University School of Medicine, Baltimore, Maryland, USA
Address correspondence and reprint requests to Robert J. Kurman,
M.D., Department of Pathology, The Johns Hopkins Hospital, 600
North Wolfe Street, Baltimore, Maryland 21287–6917. Telephone:
(410) 955-0471, Fax: (410) 614-1287. E-mail: rkurman@jhmi.edu
In the human placenta, the trophoblast growing in as-
sociation 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 recognized: cytotropho-
blast, syncytiotrophoblast, and intermediate trophoblast
(Fig. 1 and Table 1). Villous trophoblast is composed, for
the most part, of cytotrophoblast and syncytiotrophoblast
with small amounts of intermediate trophoblast. The in-
termediate trophoblast on the villous surface forms tro-
phoblastic columns that anchor the placenta to the im-
plantation site. The extravillous trophoblast that infil-
trates the decidua, myometrium, and spiral arteries of the
placental site is almost exclusively composed of inter-
mediate trophoblast.
Cytotrophoblast is the trophoblastic stem cell, whereas
syncytiotrophoblast is the terminally differentiated cell
that produces most of the placental hormones and regu-
lates the diffusion of oxygen, CO2, and other nutrients
between the mother and fetus. The intermediate tropho-
blast is a distinct form of trophoblast that shares some of
the morphologic and functional features of both cytotro-

31
32 IE-MING SHIH AND ROBERT J. KURMAN

FIG. 1. A schematic representation of the trophoblastic subpopulations in the placenta and fetal membranes. Reprinted with permission from Shih
IM, Seidman JD, Kurman RJ. Placental site nodule and characterization of distinctive types of intermediate trophoblast. Hum Pathol 1999;30:687–94.

phoblast and syncytiotrophoblast. Recent morphologic
and immunohistochemical studies have demonstrated
that intermediate trophoblast is a heterogeneous cell
population that can be subcategorized by its anatomic
location (Figs. 1, 2, and Table 1) (1). Accordingly, we
have proposed that intermediate trophoblast extending
from the trophoblastic column at the anchoring villi be
designated “villous intermediate trophoblast,” that in the
implantation site (or basal plate) be designated “implan-
tation site intermediate trophoblast,” and that in the cho-
rionic laeve of the fetal membranes be designated “cho-
rionic-type intermediate trophoblast” (Fig. 1) (1). The
intermediate trophoblastic cells in the trophoblastic shell,
trophoblastic islands, and placental septa appear to be
equivalent to the implantation site intermediate tropho-
blastic cells. Chorionic-type intermediate trophoblast

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 PATHOLOGY OF INTERMEDIATE TROPHOBLASTIC TUMORS
TABLE 1. Morphologic Features of Trophoblastic Cells Throughout Gestation
Intermediate Trophoblast (IT)
Cytotrophoblast Villous IT
Nuclei Round, uniform, and Polyhedral and
small uniform
Cytoplasm Prominent cell borders; Prominent cell
scant, clear to borders; abundant,
granular cytoplasm eosinophilic to
clear cytoplasm
Growth pattern Cohesive Cohesive
is also derived from the villous intermediate trophoblast.
In contrast to the villous intermediate trophoblast that
eventually differentiates into implantation site interme-
diate trophoblast at the placental site, the villous inter-
mediate trophoblast at the opposite pole of the implan-
tation site degenerates as the decidua capsularis fuses
with amnion/chorion at 12 weeks of gestation and be-
comes chorionic-type intermediate trophoblast (1).
DIFFERENTIATION OF INTERMEDIATE
TROPHOBLAST
Cytotrophoblast appears to differentiate along two dif-
ferent pathways resulting in the development of villous
and extravillous trophoblast (2–6). In the villous path-
way, cytotrophoblast fuses directly to form syncytiotro-
phoblast on the villous surface. The differentiation of
cytotrophoblast into syncytiotrophoblast is accompanied
by complete loss of proliferative activity (7–8). The sec-
ond pathway of differentiation of cytotrophoblast takes
place at the pole of the villi that are in contact with the
placental bed. These villi, so-called “anchoring villi,”
display a morphologic spectrum of differentiation where
the cytotrophoblast merges imperceptibly into the inter-
mediate trophoblast within the trophoblastic columns
(Fig. 1), so-called “villous intermediate trophoblast.”
The proliferative activity of villous intermediate tropho-
blast gradually decreases as the cells move to the distal
tips of the villi (8). At the base of trophoblastic columns
where the intermediate trophoblast makes contact with
the endometrium, it infiltrates the decidua and myome-
trium and invades and replaces the walls of the spiral
arteries of the implantation site (basal plate) to establish
the maternal/fetal circulation. This subpopulation of in-
termediate trophoblast in the implantation site is desig-
nated “implantation site intermediate trophoblast.” Al-
though these trophoblastic cells extensively infiltrate the
placental bed, they do not demonstrate proliferative ac-
33
Implantation Site IT Chorionic-Type IT Syncytiotrophoblast
Pleomorphic, Round to polyhedral, Linearly arranged,
hyperchromatic, and regular multinucleated
large; occasionally
multinucleated
Abundant, eosinophilic Abundant eosinophilic Abundant dense
cytoplasm and clear cytoplasm cytoplasm with
multiple vacuoles and
lacunae
Infiltrating Cohesive Syncytial
tivity. Some mononucleate implantation site intermediate
trophoblastic cells fuse into multinucleated cells. In con-
trast, the intermediate trophoblast away from implanta-
tion site (i.e., the chorion frondosum) differentiates into
“chorionic-type intermediate trophoblast.” At around 20
weeks of gestation, the expanding gestational sac oblit-
erates the endometrial cavity, and the chorion frondosum
fuses with the decidua parietalis to form the chorion
laeve. As the surface area of the chorionic laeve in-
creases toward term, the chorionic-type intermediate tro-
phoblast continues to proliferate throughout gestation,
albeit at a low level.
MORPHOLOGY OF
INTERMEDIATE TROPHOBLAST
The morphologic features of intermediate trophoblast
are compared with cytotrophoblast and syncytiotropho-
blast and are summarized in Table 1.
Villous Intermediate Trophoblast
The villous intermediate trophoblast in the trophoblas-
tic columns is mononucleate and larger than cytotropho-
blast but smaller then implantation site intermediate tro-
phoblast (see below). The constituent cells are polygonal
with clear cytoplasm and highly cohesive cell-cell inter-
action.
Implantation Site Intermediate Trophoblast
Implantation site intermediate trophoblastic cells have
a variable appearance (Table 1). In the endometrium,
they are polygonal, closely resembling the decidualized
stromal cells with which they are admixed. In the myo-
metrium, they are frequently spindle shaped and re-
semble the smooth muscle cells of the myometrium.
Generally, the cytoplasm of implantation site intermedi-
ate trophoblastic cells is abundant and is eosinophilic to
amphophilic. The nuclei of implantation site intermedi-
ate trophoblastic cells are hyperchromatic with irregular
outlines. Mononucleate implantation site intermediate
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34 IE-MING SHIH AND ROBERT J. KURMAN

FIG. 2. Immunohistochemical phenotypes of subpopulations of intermediate trophoblastic cells. The majority of implantation site intermediate
trophoblastic cells are strongly positive for Mel-CAM (CD146), hPL, and oncofetal fibronectin. They are rarely positive for PlAP. In contrast, most
chorionic-type intermediate trophoblastic cells are positive for PlAP but only very occasionally for Mel-CAM (CD146), hPL, and oncofetal protein.
Villous intermediate trophoblast in the trophoblastic column demonstrates a gradient of expression in Mel-CAM, hPL, and oncofetal fibronectin
depending on the location in the column. There is a gradual increase in the expression of these proteins in villous intermediate trophoblast from the
proximal to the distal end of the column.

trophoblastic cells occasionally fuse into multinucleated
cells.
Implantation site intermediate trophoblastic cells infil-
trate the decidua, surround glands, and invade the myo-
metrium, dissecting between smooth muscle fibers with-
out 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 the implan-
tation site intermediate trophoblast. Implantation site in-
termediate trophoblastic cells are the predominant cellu-
lar population of the EPS and the PSTT (Fig. 3).
ranged in a cohesive layer in the chorion laeve. Most of
the cells are smaller than implantation site intermediate
trophoblast but larger than cytotrophoblast. As with im-
plantation site intermediate trophoblastic cells, some
chorionic-type intermediate trophoblastic cells are mul-
tinucleated. The chorionic-type intermediate trophoblast
is the cellular population found in PSNs and ETTs (Fig.
3) (1, 9).
CLINICAL AND PATHOLOGIC FEATURES OF
INTERMEDIATE TROPHOBLASTIC LESIONS

Chorionic-Type Intermediate Trophoblast. Epithelioid Trophoblastic Tumor

The chorionic-type intermediate trophoblast is com- The term “epithelioid trophoblastic tumor” was intro-
posed for the most part of relatively uniform cells with duced to describe an unusual type of trophoblastic tumor
either eosinophilic or clear (glycogen-rich) cytoplasm ar- composed of chorionic-type intermediate trophoblastic

Int J Gynecol Pathol, Vol. 20, No. 1, January 2001

 PATHOLOGY OF INTERMEDIATE TROPHOBLASTIC TUMORS 35

FIG. 3. The differentiation of an intermediate trophoblast. In the normal placenta, the cytotrophoblast undergoes two distinctive differentiation
pathways. On the villous surface, cytotrophoblast fuses directly to form a syncytiotrophoblast. In contrast, in the trophoblastic columns cytotrophoblast
differentiates into villous intermediate trophoblast, which in turn differentiates either into an implantation site intermediate trophoblast or a chorionic-
type intermediate trophoblast. Based on their morphologic and immunophenotype, intermediate trophoblastic lesions can be related to the different
subpopulations of intermediate trophoblastic cells.

cells that is distinct from PSTT and choriocarcinoma that can simulate keratin. The extensive areas of necrosis sur-
has features resembling a carcinoma (9). Patients are rounds islands of viable tumor cells, creating a “geo-
usually in their reproductive years (9) with antecedent graphic” pattern of necrosis (Fig. 8). Typically, a small
gestational events that include full-term deliveries blood vessel is located within the center of the nests of
(67%), spontaneous abortions (16%), and hydatidiform tumor. Blood vessels within the tumor are preserved with
moles (16%). The interval between the preceding gesta- occasional deposition of amorphous fibrinoid material in
tion and the diagnosis of an ETT is variable, ranging their walls. Focal calcification can sometimes be identi-
from 1 to 18 years (average 6.2). Abnormal vaginal fied within the lesions. The tumor cells (Fig. 9) resemble
bleeding is the most common presenting symptom. In
one patient, a vaginal metastasis was the presenting
manifestation of a uterine tumor (9a). Extrauterine ETTs
without an identifiable trophoblastic lesion in the uterus
have also been described (9–10) in the lungs or small
bowel. These extrauterine tumors may represent metas-
tases from a primary uterine ETT in which the primary
lesion has disappeared as has been described for chorio-
carcinoma (11–12). Like PSTTs, serum ␤-hCG levels are
nearly always elevated at the time of diagnosis, although
the levels are generally low (< 2,500 mIU/ml) compared
with those in patients with choriocarcinoma (9–10).

Gross Findings
An ETT presents as a discrete expansile nodule in the
endomyometrium or in the lower uterine segment. Some
of the tumors can be large (up to 5 cm) and protrude into
the endometrial cavity (Fig. 4). The cut surface is solid or
cystic with the solid areas typically tan to brown display-
ing varying amounts of hemorrhage and necrosis.
Microscopic Findings
ETTs are nodular and generally well circumscribed,
although foci of infiltrating tumor cells may be present in
the periphery of the tumor (9). The tumors are composed
of a relatively uniform population of mononucleate tro-
phoblastic cells typically arranged in nests, cords, and
FIG. 4. An ETT presenting as a large polypoid lesion protruding into
masses intimately associated with eosinophilic, fibrillar, the uterine cavity (Courtesy of Dr. David Brinker, Baltimore, Mary-
hyaline-like material and necrotic debris (Figs. 5–9) that land).

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36 IE-MING SHIH AND ROBERT J. KURMAN
FIG. 5. An ETT. The border of the tumor (upper part of field) is expansile. The tumor cells are embedded in an extracellular hyalinized matrix.
those in PSNs, which resemble in turn the trophoblastic
cells in the chorion laeve (chorionic-type intermediate
trophoblast) (9). These cells contain round, uniform nu-
clei and eosinophilic or clear (glycogen-rich) cytoplasm
surrounded by a well-defined cell membrane. For the
most part, the cells are larger than cytotrophoblastic cells
but smaller than the implantation site intermediate tro-
phoblastic cells. The tumor cell nuclei have finely dis-
persed chromatin and occasional prominent nucleoli. Oc-
casionally, larger cells resembling implantation site in-
termediate trophoblastic cells can be found among the
smaller tumor cells or embedded in the extracellular hya-
line matrix. The mitotic index varies from 0 to 9 mitoses
per 10 high-power fields (x40) with an average of 2
mitoses per 10 high power fields (9). Although most
ETTs have a uniform architectural pattern, focal areas
resembling PSNs, PSTTs, or choriocarcinomas can oc-
casionally be identified within the tumor. ETTs located
in the cervix sometimes grow on the surface, replacing
the surface endocervical epithelium (9).
The immunohistochemical features of ETTs are simi-
lar to those of chorionic-type intermediate trophoblast.
The typical trophoblastic markers including hPL, hCG,
and Mel-CAM (CD146) are only focally expressed (9).
Int J Gynecol Pathol, Vol. 20, No. 1, January 2001
Thus, the immunophenotype of ETTs contrasts with that
of PSTTs, which is diffusely positive for Mel-CAM and
hPL. The mean Ki-67 labeling index in ETTs is 18 ± 5%
(mean ± standard deviation) with a range from 10% to
25%. The morphologic and immunohistochemical fea-
tures of extrauterine ETTs are similar to those in the
uterus (9–10).
Differential Diagnosis
The differential diagnosis of ETT includes PSTT,
PSN, choriocarcinoma, an epithelioid smooth muscle tu-
mor, and keratinizing squamous cell carcinoma of the
cervix (9). The nodular growth pattern and expansile
border of ETTs contrasts with the PSTT, the cells of
which infiltrate the myometrium by insinuating between
muscle bundles and fibers. In addition, the cells in an
ETT are smaller than those of a PSTT and tend to grow
in nests and cords, a pattern usually not observed in the
PSTT. Blood vessels in an ETT are often surrounded by
tumor cells, but vascular invasion is not a striking fea-
ture. In contrast, vascular invasion in PSTT, like that
seen at an implantation site, results in replacement of the
smooth muscle of the walls of the vessels by tumor cells
and hyaline-like material. Finally, immunostains can be
 PATHOLOGY OF INTERMEDIATE TROPHOBLASTIC TUMORS 37

are randomly distributed as single mononucleate cells or

small clusters of cells in ETTs.
Distinguishing between an ETT and a keratinizing
squamous cell carcinoma of the cervix can be very dif-
ficult, particularly because ETTs tend to grow in the
lower uterine segment and cervix and because they re-
place and merge into the endocervical epithelium. Im-
munostains for inhibin-␣ and cytokeratins 18 are very
helpful. Almost all ETTs are positive for inhibin-␣ and
cytokeratin 18 in the majority of tumor cells, whereas
squamous cell carcinomas of the cervix are negative for
these two markers (9, 15). Furthermore, unlike ETTs, in
which the Ki-67 labeling index is relatively low (10–
25%), cervical squamous cell carcinomas almost always
have a very high Ki-67 labeling index (>50%).
Epithelioid smooth muscle tumors usually display ar-
eas composed of typical smooth muscle cells in addition

FIG. 6. An ETT. Tumor in a hysterectomy specimen shows aggregates

of atypical mononucleate trophoblastic cells forming rounded nests
simulating a carcinoma.

useful in difficult cases. Specifically, hPL and Mel-CAM

(CD146) are diffusely positive in PSTT (13–14),
whereas staining for both of these markers in ETTs is
generally focal (9).
At times, an ETT may be difficult to distinguish from
a PSN. In contrast to ETTs, PSNs are almost always a
microscopic paucicellular lesion without associated ne-
crosis. In addition, the Ki-67 index in ETTs (> 10%) is
significantly higher than in PSNs (< 10%) (Table 3).
As compared with choriocarcinoma, the cells in an
ETT form discrete nests and cords. In addition, an ETT
is not associated with marked hemorrhage as in a cho-
riocarcinoma. Immunostains for ␤-hCG can be helpful in
the differential diagnosis. ␤-hCG immunostains high-
light the dimorphic trophoblastic population of chorio-
carcinoma with ␤-hCG-negative cytotrophoblast and in- FIG. 7. An ETT. The tumor in the uterus is composed of infiltrating
cords and nests of cells surrounded by dense hyaline material. Cells
termediate trophoblast alternating with ␤-hCG-positive have single nuclei with vesicular chromatin and a moderate amount of
syncytiotrophoblast. In contrast, ␤-hCG-positive cells finely granular cytoplasm.

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38 IE-MING SHIH AND ROBERT J. KURMAN

Behavior and Treatment

The behavior of ETTs is still unclear as they have only
recently been recognized as a distinctive form of tropho-
blastic disease, and long-term follow-up is not available
(9, 9a, 10, 16–18). Based on 40 cases reported to date,
the behavior of ETTs is similar to that of PSTTs. ETTs
generally behave in a benign fashion with metastasis and
death occurring in approximately 25% and 10% of pa-
tients, respectively (9). Because the number of tumors
that have behaved in an aggressive fashion is small and
follow-up for many cases has been short, features that
predict outcome have not been identified.
Although serum hCG levels are variable and generally
low in patients with ETTs, serum hCG levels have been
used to monitor treatment (9). For those patients with
undetectable or very low serum levels of hCG, measure-
ment of urinary ␤-core fragment of hCG may be useful

FIG. 8. An ETT. Large areas of necrosis surround islands of tumor

cells that encircle small blood vessels.

to epithelioid areas. In addition, epithelioid smooth

muscle tumors are often positive for muscle markers,
including desmin and smooth muscle actin, which are not
expressed by ETTs. Conversely, as noted above, ETTs
are positive for cytokeratin 18 and inhibin-␣, which are
not detected in smooth muscle tumors (9).
The morphologic distinction between a pulmonary
ETT and a primary squamous cell carcinoma of the
lung can be extremely difficult, especially in a post-
menopausal patient (9, 10). Useful clues that support
the diagnosis of ETT include a lack of cytoplasmic
eosinophilia and intercellular bridges (which are fre-
quently observed in differentiated squamous cell carci-
noma), as well as infiltration of alveolar spaces by highly
atypical tumor cells with preservation of the alveolar FIG. 9. An ETT. The tumor is composed of a relatively uniform
septa, features not usually seen in squamous cell carci- population of chorionic-type intermediate trophoblastic cells arranged
noma (10). As in squamous cell carcinomas of the cervix, in nests and cords that are enmeshed in an eosinophilic, fibrillar, hya-
line-like material. The cells contain round, uniform nuclei and eosin-
primary squamous cell carcinoma of the lung fails to react ophilic or clear (glycogen-rich) cytoplasm. They are surrounded by a
with antibodies to inhibin-␣ and cytokeratin 18 (1, 9). well-defined cell membrane.

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 PATHOLOGY OF INTERMEDIATE TROPHOBLASTIC TUMORS 39

TABLE 2. Pathologic Features of Exaggerated Placental Site Versus Placental Site

Feature
Gross appearance
Cellular morphology
Growth pattern
Depth of invasion
Multinucleated cells
Mitoses
Associated chorionic villi
Ki-67 labeling index
Trophoblastic Tumor (PSTT)
Exaggerated Placental Site PSTT
Not evident Nodule or mass
Monomorphic; Monomorphic;
implantation site implantation site
intermediate trophoblastic intermediate trophoblastic
Usually infiltrating Usually confluent sheets
Limited to superficial 1⁄3 of myometrium Variable, can extend to the serosa
Usually abundant Occasional
Absent Variable; 0–6/10HPF
Always present Absent
0 >10%

HPF: high-power fields (400×).

(19). The available data suggest that like PSTTs, ETTs
may not be responsive to the chemotherapeutic agents
used in the treatment of other types of GTD (9). Hyster-
ectomy and lung resection have been used successfully
to treat localized disease (9, 10).
Placental Site Nodule
PSNs occur in the reproductive age group and are
typically incidental findings in uterine curettage or cer-
vical biopsy specimens and occasionally in hysterectomy
specimens (1, 20–21). In one study, 40% of PSNs were
found in the endocervix, 56% were found in the endo-
metrium, and 4% were found in the fallopian tube (1).
Many patients have a history of therapeutic abortion and
cesarean section, and a significant number have a history
of a tubal ligation (1, 22–23). The antecedent pregnancy
has been reported to have occurred as many as 108
months before the diagnosis (20, 22, 24–25). In patients
with tubal ligations, it is not clear whether the PSN is
derived from of persistent trophoblast from a pregnancy
that preceded the tubal ligation or from a new gestation
following an unsuccessful tubal ligation.
Gross Findings
PSNs range from 1 to 14 mm (average 2.1). Occasion-
ally, multiple nodules are found. When grossly visible,
PSNs appear as a yellow or tan surface nodule or plaque
in the endometrium (superficial myometrium), the lower
uterine segment, or the endocervix.
Microscopic Findings
Microscopically, PSNs are nodular with rounded,
well-circumscribed borders (Fig. 10) surrounded by a
thin rim of chronic inflammatory cells and occasionally
decidual cells. The lesions are characterized by an abun-
dant hyalinized or fibrinoid extracellular matrix that
separates trophoblastic cells resembling those found in
the chorion laeve of the fetal membranes (chorionic-type
intermediate trophoblast) (1). The trophoblastic cells are
arranged in a haphazard pattern—dispersed singly, in
small clusters and cords, or occasionally as diffuse
sheets. The cells vary in size with many having relatively
small uniform nuclei and a few having large, irregular,
and hyperchromatic nuclei (Fig. 11). Multinucleated
cells are occasionally present. The cytoplasm of the
larger trophoblastic cells is abundant and eosinophilic to

TABLE 3. Pathologic Features of Placental Site Nodule Versus Epithelioid Trophoblastic Tumor
Feature Placental Site Nodule Epithelioid Trophoblastic Tumor
Gross appearance Usually microscopic Nodular mass
Cellularity Paucicellular More cellular
Margin Well circumscribed Generally will circumscribed; foci of
infiltrating tumor cells at margins
Cell size and shape Small round and uniform More pleomorphic and atypical
Growth pattern Single cells, small nests, and cords Large nests, cords, and solid masses
Hemorrhage Absent Usually present, but limited
Necrosis Absent Extensive
Calcification Absent Usually present
Fibrinoid matrix Usually extensive Focal
Mitotic figures Absent or extremely rare Variable; 1–10/10HPF
Ki-67 labeling index <10% 10–25%

HPF: high-power fields (400×).

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40 IE-MING SHIH AND ROBERT J. KURMAN

for which we have follow-up information have had a

benign behavior.
The trophoblastic cells in the PSN exhibit an immu-
nophenotype similar to that of trophoblastic cells in the
chorion laeve but distinct from the implantation site in-
termediate trophoblast. They react with antibodies
against cytokeratin, epithelial membrane antigen, placen-
tal alkaline phosphatase, and inhibin-␣ (22, 25, 15). Most
PSNs also express the “typical” intermediate trophoblas-
tic markers, including hPL and Mel-CAM (CD146), al-
though only in a small number of cells (1). The tropho-
blastic cells in PSNs exhibit mild proliferative activity
with a Ki-67 labeling index of about 5%, similar to that
in the intermediate trophoblastic cells in the chorion
laeve (3–6%) (1). These findings contrast with the ab-
sence of Ki-67 labeling in trophoblastic cells in the nor-
mal implantation site as well as in EPS (3, 8).

FIG. 10. A PSN in a hysterectomy specimen. At low magnification,

the lesion is well circumscribed and contains eosinophilic material in
the center.

amphophilic whereas the smaller cells contain glycogen-

rich clear cytoplasm (Fig. 11). Mitotic figures are rare or
absent.
Based on their histologic and immunohistochemical
features as well as the intimate association of some ETTs
with PSNs, we have speculated that ETTs represent the
neoplastic counterpart of PSNs (1). This view is sup-
ported by our observations of PSNs that have features
intermediate between typical PSNs and ETTs that we
have provisionally designated as “atypical PSNs.” The
latter are intermediate in size between typical PSNs,
which rarely exceed 4 mm in diameter, and ETTs, which
are usually at least a few centimeters in greatest dimen-
sion. These atypical PSNs tend to have higher cellularity,
and the trophoblastic cells are arranged in more cohesive
nests and cords compared with typical PSNs (9). The
Ki-67 labeling index in atypical PSNs is higher than in FIG. 11. A PSN. The nodule is composed of hyalin material that
usual PSNs but lower than in ETTs. These findings sug- contains chorionic-type intermediate trophoblast. Most of the cells are
mononucleate with eosinophilic or clear cytoplasm. Occasionally larger
gest that atypical PSNs are an intermediate stage of de- cells are dispersed randomly in the lesion. Compare to Fig. 9 showing
velopment between a PSN and an ETT. The few lesions the similarity of the cells of PSNs and ETTs.

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 PATHOLOGY OF INTERMEDIATE TROPHOBLASTIC TUMORS 41

Differential Diagnosis nonmolar abortion; in only 5–8% of patients is there a

PSNs may be confused with PSTTs, ETTs, and inva-
sive squamous cell carcinomas of the cervix (1, 26).
Their microscopic size, circumscription, extensive hya-
linization, and paucicellularity are features that separate
them from PSTTs. In difficult cases, immunostaining is
helpful. PSNs are positive for placental alkaline phos-
phatase but only focally positive or negative for Mel-
CAM (CD146) and hPL. In contrast, PSTTs have diffuse
staining for Mel-CAM (CD146) and hPL but show only
scattered and faint staining for placental alkaline phos-
phatase. The differential diagnosis between PSNs and
cervical squamous cell carcinomas is particularly diffi-
cult in cervical biopsy specimens from patients who are
being evaluated for cervical neoplasia (1). Circumscrip-
tion of the lesion, abundant eosinophilic extracellular
hyalin, and lack of mitotic activity favor a PSN. Immu-
noreactivity for inhibin-␣, cytokeratin 18, high-
molecular-weight cytokeratin, and Ki-67 are particularly
useful in the differential diagnosis. The majority of PSNs
express inhibin-␣ and cytokeratin 18, but intraepithelial
squamous lesions and squamous cell carcinomas do not
(1). In contrast, PSNs are only focally positive or nega-
tive for high-molecular-weight cytokeratin, whereas cer-
vical squamous cell carcinomas are diffusely positive.
Additionally, the Ki-67 labeling index is low (<10%) in
PSNs in contrast to the generally high Ki-67 labeling
index in cervical carcinoma and intraepithelial squamous
lesions (>50%) (1). The immunoreactivity of ␤-hCG is
not helpful in these cases because both PSNs and cervi-
cal carcinomas can be focally reactive to ␤-hCG (27).
The differential diagnosis of a PSN with an ETT is con-
sidered in the discussion of ETTs.
clinical history of a complete mole (32–34). Sex chro-
mosome analysis suggests that the development of
PSTTs involves the paternal X chromosome (35).
Gross Findings
The gross appearance of a PSTT is variable. The tu-
mors range from a few centimeters to those that enlarge
and distort the fundus. Most PSTTs are circumscribed,
but some are poorly demarcated. PSTTs may be polyp-
oid, projecting into the uterine cavity, or may predomi-
nantly involve the myometrium (Fig. 12). The sectioned
surface is soft and tan and contains only focal areas of
hemorrhage or necrosis. The tumor frequently extends to
the uterine serosa. Perforation or extension into the broad
ligament or adnexa can occur.
Microscopic Findings
The predominant cell type in PSTTs is implantation
site intermediate trophoblast (2, 14). Most of the cellular
population is monomorphic with occasional multinucle-
ated giant cells. The cells form confluent sheets (Figs.
13–15), but at the periphery of the tumor, they invade
singly or in cords and nests, characteristically separating
individual muscle fibers and groups of fibers (Fig. 16).
The individual neoplastic cells extensively infiltrate the

Behavior and Treatment

PSNs are benign nonneoplastic lesions that are usually
removed completely by the surgical procedure that led to
their discovery. Because neither local recurrence nor pro-
gression to persistent GTD has been documented, no
specific treatment or follow-up is necessary (1, 24).

Placental Site Trophoblastic Tumor

Patients usually are in the reproductive age group and
present with either amenorrhea or abnormal bleeding.
Some patients may have uterine enlargement and fre-
quently are thought to be pregnant (28–31). When uter-
ine enlargement ceases, the diagnosis of a missed abor-
tion is usually made (30). Serum levels of ␤-hCG are
generally low. In contrast to choriocarcinoma, which is
FIG. 12. A PSTT. A well-circumscribed tumor is located in the uterine
preferentially associated with a complete mole, PSTTs corpus and protrudes into the uterine cavity (Courtesy of Dr. Andrew
occur most commonly following a normal pregnancy or Östör, Melbourne, Australia). Bar ⳱ 1 cm.

Int J Gynecol Pathol, Vol. 20, No. 1, January 2001

42 IE-MING SHIH AND ROBERT J. KURMAN

FIG. 13. A PSTT. The tumor is composed of a relatively monomorphic cell population. The wall of a blood vessel in the center of the field is
completely replaced by tumor cells with preservation of the vascular lumen.

endomyometrium and may deeply penetrate the uterine Differential Diagnosis

wall. Although some tumors appear to cause relatively
little tissue destruction, others are associated with exten-
sive necrosis, a microscopic feature that is often associ-
ated with aggressive behavior (see below).
As in the normal placental site, PSTTs are character-
ized by abundant extracellular eosinophilic fibrinoid ma-
terial. The neoplasm displays a characteristic form of
vascular invasion in which blood vessel walls are exten-
sively replaced by trophoblastic cells and fibrinoid ma-
terial, as observed in the normal placental site (Fig. 13
and 14). PSTTs are generally not associated with the
presence of chorionic villi.
Rarely a PSTT shows histologic features of both cho-
riocarcinoma and PSTT. These are termed mixed cho-
riocarcinoma-PSTTs. Similarly, a PSTT can also be as-
sociated with an ETT. Too few of these mixed cases have
been studied to determine their clinical behavior.
PSTTs are immunoreactive for cytokeratin (AE1/AE3
cocktail and cytokeratin 18), inhibin-␣ hPL, and Mel-
CAM (CD146) but rarely positive for ␤-hCG or PlAP, an
immunophenotype characteristic of implantation site in-
termediate trophoblast (Fig. 2) (3, 15).
The differential diagnosis of PSTT includes choriocar-
cinoma, ETT, EPS, PSN, and nontrophoblastic neo-
plasms such as epithelioid smooth muscle tumors, poorly
differentiated carcinomas, and melanomas. The most dif-
ficult differential diagnosis is that of an EPS (Table 2) as
both lesions are characterized by an exuberant infiltra-
tion of implantation site intermediate trophoblastic cells.
Accordingly, the immunophenotypes of both lesions are
similar. The microscopic features that support the diag-
nosis of PSTT include confluent masses of trophoblastic
cells, unequivocal mitotic figures, and absence of chori-
onic villi. In contrast, the EPS is microscopic and is
composed of intermediate trophoblastic cells separated
by masses of hyaline and usually admixed with decidua
and chorionic villi. Mitotic figures are not present. In
addition, an EPS contains more multinucleated tropho-
blastic cells than does a PSTT. The Ki-67 labeling index
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 EPS
versus a PSTT (8). The Ki-67 labeling index in a PSTT
is significantly elevated (14% ± 6.9%), but it is near 0 in

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 PATHOLOGY OF INTERMEDIATE TROPHOBLASTIC TUMORS 43

portions of trophoblastic columns should not be counted

because these normally contain proliferating trophoblas-
tic cells, and tangential sectioning of trophoblastic col-
umns could lead to a high false-positive labeling index.
In contrast to the biphasic pattern of choriocarcinoma,
PSTTs are composed of a relatively monomorphic popu-
lation of trophoblast, and the multinucleated intermediate
trophoblastic cells in PSTT should not be confused with
the syncytiotrophoblast of choriocarcinoma. In contrast
to the interlacing pattern of elongated syncytiotropho-
blast in choriocarcinoma, the multinucleated intermedi-
ate trophoblastic cells in PSTTs are usually polygonal or
round. Additionally, PSTTs are diffusely positive for
hPL but only focally positive for ␤-hCG, whereas the
reverse staining pattern is seen in choriocarcinomas. The
Ki-67 labeling index in Mel-CAM (CD146) defined in-
termediate trophoblastic cells is also helpful in the dif-
ferential diagnosis of PSTT versus choriocarcinoma (8).

FIG. 14. A PSTT. The tumor is composed of a monomorphic popu-

lation of implantation site intermediate trophoblast with pleomorphic
hyperchromatic nuclei. Fibrinoid material and intermediate trophoblast
replace the wall of a uterine blood vessel.

an exaggerated implantation site. A diagnosis of a PSTT

should be strongly considered if the Ki-67 index in im-
plantation site intermediate trophoblastic cells exceeds
5%. The Ki-67 labeling in the implantation site interme-
diate trophoblastic cells should be carefully assessed us-
ing stringent morphologic criteria because implantation
site intermediate trophoblastic cells can closely resemble
other cell types in the placental site. Many Ki-67 positive
cells in the placental site or PSTTs are natural killer cells
and activated T lymphocytes, which can be highly posi-
tive for Ki-67. A double staining technique using MIB-1
antibody to determine the Ki-67 proliferative index and
Mel-CAM (CD146) to identify implantation site inter-
mediate trophoblastic cells has been shown to be very
useful in this situation (The antibody specific for Mel-
CAM [CD146] is available on request from Dr. Shih) FIG. 15. A PSTT. The tumor cells are polygonal with abundant eo-
(8). In estimating the Ki-67 labeling index, the proximal sinophilic cytoplasm and highly atypical nuclei.

Int J Gynecol Pathol, Vol. 20, No. 1, January 2001

44 IE-MING SHIH AND ROBERT J. KURMAN
FIG. 16. A PSTT. Intermediate trophoblastic cells dissect and separate
the smooth muscle bundles. Some of the cells are multinucleated.
The Ki-67 index in intermediate trophoblastic cells of
PSTTs is 14%± 6.9% and in choriocarcinomas is 69%±
20% (p< 0.001).
The differential diagnosis from smooth muscle tumors
can be difficult, as PSTT often has a highly infiltrative
pattern within the myometrium, dissecting among the
smooth muscle fibers and simulating origin from these
cells. Helpful clues in the differential diagnosis include
the distinctive pattern of vascular invasion and the de-
position of fibrinoid material in PSTT, features not found
in smooth muscle tumors or most other malignancies.
Positive staining for hPL, inhibin-␣, and cytokeratin 18
and negative staining for smooth muscle markers con-
firm the diagnosis of PSTT (15).
Poorly differentiated carcinoma and metastatic mela-
noma can sometimes be confused with PSTT. The pat-
tern of prominent blood vessel invasion, characteristic
myometrial invasion, and extensive deposition of fibri-
noid material are the diagnostically helpful features in
this differential. Immunohistochemical stains for hPL,
Int J Gynecol Pathol, Vol. 20, No. 1, January 2001
inhibin-␣, and HMB-45 help to distinguish PSTTs from
poorly differentiated carcinomas and melanomas (15).
The differential diagnosis of a PSTT from an ETT is
considered in the section describing 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. Despite deep myometrial invasion, most
PSTTs are self limited (28, 30, 36–37), and some patients
have been cured by curettage alone. Approximately 10–
15% of PSTTs are clinically malignant (28, 38, 39), and
patients have died despite intensive multiagent chemo-
therapy. The mortality rate in patients with PSTTs is
about 15–20%, which may be an overestimate because
benign cases generally are not reported (30, 40). The
overtly malignant tumors have had widely disseminated
metastases resembling the distribution of metastatic cho-
riocarcinoma with the lungs, liver, abdominal cavity, and
brain being the most commonly involved sites.
Because PSTTs are composed of neoplastic implanta-
tion site intermediate trophoblastic cells that contain only
small amounts of ␤-hCG, serum levels of ␤-hCG are
usually low (1,000 to 2,000 mIL/ml) and much lower
than those in choriocarcinoma (33). Despite the low lev-
els of serum ␤-hCG in patients with PSTTs, it is the best
available marker to monitor the course of the disease,
although the disease may still progress even if ␤-hCG
levels are low (40). For those patients with undetectable
or very low serum levels of ␤-hCG, urinary ␤-core frag-
ment of ␤-hCG may be a better method to monitor re-
sponse to treatment (19).
It is difficult to predict with certainty the behavior of
PSTTs because it has been shown that there is no corre-
lation between clinical outcome and DNA ploidy, histo-
pathologic features, immunohistochemical features, and
S-phase fraction (41–42). Chang et al. have recently ana-
lyzed 91 cases of PSTTs and concluded that FIGO stage
is the most important prognostic factor (43). In that
study, the outcome of patients with FIGO stage I–II dis-
ease after hysterectomy was excellent, whereas those pa-
tients with FIGO stage III–IV diseases had a 30% sur-
vival rate.
The treatment of choice for patients whose disease is
confined to the uterus is hysterectomy (40). In some
patients with localized PSTT who want to preserve fer-
tility, more conservative surgical therapy may be consid-
ered (44). Curettage (45) and local excision (F. Montz,
unpublished data) may be therapeutic, but if uterine dis-
ease persists, as evidenced by persistently elevated serum
hCG levels, hysterectomy is indicated (14). For patients
with more extensive or metastatic disease, chemotherapy
 PATHOLOGY OF INTERMEDIATE TROPHOBLASTIC TUMORS 45

is indicated although the clinical outcome is variable

(28–29, 43, 46–55). With the use of imaging techniques
to define disease spread, dose-intensive chemotherapy,
and close surveillance with serologic measurement of the
␤-hCG level, most patients with PSTTs can be cured,
including those with advanced stage disease (47, 40).

Exaggerated Placental Site

The EPS is characterized by an exuberant infiltration
of the myometrium by implantation site intermediate tro-
phoblasts and represents the extreme end of a physi-
ologic process rather than a true lesion. The distinction
between a normal placental site and an EPS is somewhat
arbitrary because there are no reliable data quantifying
the amount and extent of trophoblastic infiltration at dif-
ferent stages of normal gestation (56). The EPS can oc-
cur in a normal pregnancy or an abortion from the first
trimester and is found in approximately 1.6% of sponta-
neous and elective abortions from the first trimester
based on a review of the surgical pathology files at the
Johns Hopkins Hospital.

Gross and Microscopic Findings

The EPS is grossly identical to the normal implanta-
tion site and is composed of an extensive infiltration of
the endometrium and myometrium by individual and
small cell clusters of implantation site intermediate tro-
phoblastic cells. Occasionally, aggregates of cells form
small confluent sheets (Fig. 17 and 18). Despite the mas-
sive infiltration by trophoblastic cells, the overall archi-
tecture of the placental site is not disturbed. Endometrial
glands and spiral arteries may be completely engulfed by
trophoblastic cells, but there is no necrosis. Similarly, the
smooth muscle cells of the myometrium are separated by
cords, nests, and individual trophoblastic cells that dif-
fusely infiltrate the myometrium without necrosis (Fig.
17) (2, 32). The trophoblastic cells in an EPS, which are
identical to the implantation site intermediate trophoblas-
tic cells in the normal placental site, contain abundant
eosinophilic cytoplasm with hyperchromatic and irregu-
larly shaped nuclei (Fig. 17 and 18). In many cases, there
are numerous multinucleated implantation site interme-
diate trophoblastic cells (Fig. 18). Mitotic activity is ab-
sent. The associated placentas are unremarkable.
The immunophenotypic profile of trophoblastic cells
in the EPS is identical to the implantation site interme-
diate trophoblastic cells found in the normal placental
site. These cells are diffusely positive for Mel-CAM
(CD146) and hPL and focally positive for hCG and
PlAP. The Ki-67 indices of implantation site intermedi-
ate trophoblast are near 0 despite the profuse infiltration
of implantation site intermediate trophoblast in an EPS
FIG. 17. An EPS. The lesion is characterized by an increased number
of implantation site intermediate trophoblastic cells exceeding that nor-
mally present in the implantation site.
(8). Complete hydatidiform moles are always accompa-
nied by an EPS in which the implantation site interme-
diate trophoblastic cells are often more atypical and the
Ki-67 labeling index is higher (> 5%) than those in the
EPSs that are not associated with complete moles (8). In
these cases, an EPS can be confused with a PSTT. It
should be noted that the concurrent finding of a mole and
a PSTT has never been reported nor is it likely to occur
because both lesions are distinct gestational events that
are unrelated to one another.
Differential Diagnosis
A PSTT is the most important differential diagnosis of
an EPS and is discussed in the section describing that
entity (Table 2). Occasionally, implantation site interme-
diate trophoblastic cells that infiltrate the myometrium
may resemble the atypical smooth muscle cells found in
symplastic leiomyomas. The presence of chorionic villi,
the infiltrative growth pattern of the trophoblastic cells,

Int J Gynecol Pathol, Vol. 20, No. 1, January 2001

46 IE-MING SHIH AND ROBERT J. KURMAN
FIG. 18. An EPS. Numerous mononucleate and multinucleated im-
plantation site intermediate trophoblastic cells infiltrate decidua. The
trophoblastic cells are widely spaced, lacking confluent growth. There
is no mitotic activity and no necrosis.
and positive cytokeratin and hPL stains support the di-
agnosis of an EPS.
Behavior and Treatment
An EPS is a physiologic process that resolves sponta-
neously after curettage. An EPS that is not associated
with a hydatidiform mole does not carry an increased
risk of persistent GTD. No specific treatment or follow-
up is required. If there is uncertainty as to the diagnosis,
follow-up with serum ␤-hCG levels should be per-
formed. Persistently elevated levels indicate the presence
of residual trophoblast and require further evaluation.
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