Gestational Trophoblastic Disease
Moderator: Dr. le-Ming Shih
Section 3 -
Intermediate Trophoblastic Tumors and Tumor-like Lesions- the Clinico-pathologic Aspects
Institute of Pathology , Division of Gynecologic Pathology
University of Leipzig
As mentioned above by Dr. Shih (Part 1-Introduction), the intermediate trophoblast (IT) can be
divided into different types of intermediate (extravillous) trophoblastic cells based on their locations
in normal early placentas. Various types of IT are associated with distinct tumors and tumor-like
lesions, such as placental site nodule (PSN), exaggerated placental site (EPS), placental site
trophoblastic tumor (PSTT) and the epithelioid trophoblastic tumor (ETT; Horn & Bilek 1997). These
entities which are also recognized by the recent WHO classification (Genest et al. 2003), will be briefly
Placental Site Nodule (PSN).
The majority of PSNs are incidental findings in uterine curettages, cervical biopsies, hysterectomy
specimens or in tubal ligation specimens in patients at their reproductive ages (Huettner & Gersell
1994). More than 50% of PSNs are clinically associated with dysfunctional uterine bleeding (Baergen
1997, Shih et al. 1999). Most often, PSNs are small, microscopic lesions. When grossly visible, they
present as yellow, tan, or hemorrhagic nodules measuring up to 1 cm in diameter and located superficial
at the affected site (most often in the lower uterine segment) and might be single or multiple lesions.
On microscopy, the PSN is characterized by a well-circumscribed and lobulated border, sometimes
accompanied by chronic inflammation or decidual cells. The intermediate trophoblastic cells are arranged
in nests, cords or singly and are embedded in abundant eosinophilic extracellular matrix with a pale-pink
appearance on low power. The cells vary in size and many have relatively small uniform nuclei but others
are large with mononucleate, irregular, and hyperchromatic nuclei which might suggest a "polymorphic
lesions". But, mitoses are always absent and the Ki-67 labeling index in placental site nodules is
< 5% (Shih & Kurman 2001).
The main differential diagnoses include decidual cells, the ETT, PSTT and squamous carcinoma of the
uterine cervix (Horn & Vogel 2004). Decidual cells are negative for cytokeratin but react positive
against vimentin on immunohistochemistry. The ETT and PSTT represent clinically as tumorous lesions, are
more cellular and represent distinct vascular alterations (see below). Immunoreactivity for HLA-G,
inhibin- a and cytokeratin 18 and a low (~5%) Ki-67 labeling index also support the
diagnosis of placental site nodule but not a cervical squamous carcinoma (Singer et al. 2002). By
contrary, cervical carcinomas are always positive for p16-staining. In general, the PSN is a benign
non-neoplastic lesions. Neither local recurrence nor progression to persistent GTD has been documented.
Therefore, no specific treatment or follow-up is necessary for this lesion.
Exaggerated Placental Site (EPS).
This lesion is considered as a normal variation of a normal placental site. Formerly, it was termed
syncytial endometritis (Marchand 1895) and benign chorionic invasion. The EPS shows an exuberant number
of normal-appearing intermediate trophoblastic cells at the placental site. The intermediate cells are
smaller and less atypical than placental site trophoblastic tumor and mitoses in the trophoblastic cells
in the implantation site are absent. As in placental site trophoblastic tumor, the EPS represents
trophoblastic invasion of the underlying endometrium as well as the myometrium. In most cases, the
mononuclear intermediate trophoblastic cells are intermingled by a large number of multinucleated
trophoblastic cells of the intermediate type, as seen at normal placental implantation site. Endometrial
glands may be surrounded by the trophoblastic cells of the EPS, but are not destroyed. The occurrence of
trophoblastic cells in the lumina of spiral arteries should not be considered as an indicator for PSTT.
In almost all cases the EPS is accompanied by placental villies (Horn & Vogel 2004), which is a
hallmark in the differential diagnosis to PSTT. On immunohistochemistry, the cells of the EPS represent
an identical profile as the PSTT. The Ki-67 labeling index is near 0% (Shih & Kurman 2001). On
small biopsies or curettings, EPS can be misdiagnosed as choriocarcinoma or PSTT (Menczer et al. 1999,
Nigam & dass 2003). For differential diagnosis see below.
In general, the EPS does not have clinical significance. But, complete hydatidiform moles are
sometimes associated with exaggerated placental site. In those cases, the close follow up of the patient
with sequential HCG-measurement, as usually done in CHM, is strongly recommended.
Placental site trophoblastic tumor (PSTT). This is a relatively uncommon
lesion and was formely termed syncytioma, atypical choriocarcinoma, chorionepitheliosis and trophoblastic
pseudotumor (Marchand 1895, Kurman et al. 1976, Hassadia et al. 2005). Contrary to the choriocarcinoma,
the PSST occurs mostly after regular pregnancies or spontaneous abortions. In general, most PSTTs
represent as tumorous lesions, projecting into the uterine cavity or predominantly involving the
myometrium (sometimes up to the uterine serosa). The sectioned surface is soft, tan and, contrary to
choriocarcinoma, contains only focal areas of hemorrhage or necrosis.
PSTT is generally not associated with the presence of chorionic villi. The cells of the PSTT are
similar to cells in a normal placental site. The large and polygonal tumor cells infiltrate deep into
the myometrium and insinuate themselves between smooth muscle fibers (dissecting growth pattern). There
is no destruction of the endometrial/myometrial cells. PSTT represents an unique pattern of vascular
invasion. This pattern of vascular invasion involves intermediate trophoblastic cell replacement of the
muscular wall followed by fibrinoid material deposition in the vessel wall, which typically maintains a
central lumen. These transformed vessels appear as pink, sometimes irregular shaped rings at lower
power. Similar to implantation site intermediate trophoblastic cells (see above), PSTT is diffusely
positive for cytokeratin (AE1/AE3 cocktail and cytokeratin 18), HLA-G, hPL and Mel-CAM (CD146), but
rarely positive for beta-hCG (but, single positive cells occur in almost all PSTT) and p63. The Ki-67
labeling index is significantly elevated (> 10%) in PSTT (Shih & Kurman 2001). The detailed
immunohistochemical profiles of PSTT and their application in differential diagnosis will be discussed in
Part-4 (see below).
The differential diagnosis of PSTT includes exaggerated placental site (EPS), choriocarcinoma (CCA),
epithelioid trophoblastic tumor (ETT) and epithelioid smooth muscle tumors. The most difficult
differential is that of EPS. Features that favor a diagnosis of PSTT include the occurrence of a
tumorous lesion, the absence of chorionic villi, unequivocal mitotic figures, a relatively small amount
of multinuclear giant cells (of intermediate trophoblastic type), Ki-67 labeling index >5%. Contrary
to CCA, PSTTs lacks confluent and prominent hemorrhages, Ki-67 labeling is not exceeding about 30-50%,.
There are no syncytiotrophblast-like multinucleated giant cells with strong positive staining with HCG,
and no so called biphasic growth pattern (i.e. a close admixture of mononucleated zytotrophoblastic cells
and syncytial giant cells). PSTT are negative for vimentin, muscular and melanocytic markers (beside of
CD 146; Shih & Kurman 2001). Sometimes PSTT can be confused with squamous cell carcinoma of the
uterine cervix, especially on small biopsies (Horn et al. 1997). But, the latter one is negative with
CK18, HPL and CD 146, but positive against high molecular weight cytokeratines and p16 and shows a Ki
67-labeling index of more that 80% in the most cases. For ETT see below.
The majority of PSTT (about 85%) represent a benign behavior. But it is difficult to predict the
behavior since it has been demonstrated that no close correlation exists between clinical outcome and
molecular or morphological markers. Factors which may associated with malignancy are patients age >
35 years, last pregnancy event >2 years, highly polymorphic cells, large amount of cells with a clear
cytoplasm within the tumor large necroses, destructive growth pattern, mitotic count of >5 MF/10 HPF
(Chang et al. 1999; Feltmate et al. 2001, Baergen et al. 2006). Despite the low level of serum b -hCG in
patients with PSTT, it is still the best marker available to monitor the course of the disease (Horn et
Epithelioid trophoblastic tumor (ETT). Epithelioid trophoblastic tumor is
a rarest form of gestational trophoblastic disease and related to cells in the chorion leave (fetal
membrane; Shih & Kurman 1998). ETT might be associated with any gestational event in younger women,
but can also be diagnosed more than 10 years after the last known pregnancy or in postmenopausal women.
Macroscopically, ETT almost always presents as a discrete, expansile nodule in the endomyometrium or in
the lower uterine segment. The cut surface of the tumor is solid, often with cystic areas, and brown-tan
with areas of hemorrhage and necrosis. Sometimes calcification might occur.
Microscopically, the ETT is composed of a relatively uniform population of mononucleate trophoblastic
cells with an eosinophilic or clear cytoplasm surrounded by a well-defined cell membrane that are
intimately associated with a geographical pattern of eosinophilic, fibrilary, hyaline-like material which
may represent necrotic areas. Be aware that this dense eosinophilic material and necrotic debris can
mimic keratin and may represent irregular calcification. The ETT show an average of 2 mitoses per 10
high power fields (range 0-9 mitoses). The architectural growth patterns include demarcated nodules,
epithelioid cords and sheets. Within the tumor cell islands centrally located thin walled blood vessels
with preserved vessels wall might be seen.
The immunohistochemical features are similar to those of chorionic-type intermediate trophoblast.
Additionally, the ETT is positive for p63 and inhibin- a (Shih & Kurman 2004). The mean Ki-67
labeling index is 18% with a range from 10-25%. Beside PSTT and choriocarcinoma, the differential
diagnosis of ETT includes squamous cell carcinoma (Coulsen et al. 2000, Hui et al. 2005). On
immunostaining, the ETT reacts positive against cytokeratin 18, inhibin-alpha and HLA-G; SCC of the
cervix will be negative. Vice versa, cervical carcinomas stain positive with p16; the ETT does not. The
nodular expansile (not infiltrative !) growth pattern, the presence of geographic necrosis and
calcification favor the diagnosis of ETT versus PSTT or choriocarcinoma. Furthermore, the monomorphic
growth pattern of epithelioid trophoblastic tumor contrasts with the biphasic pattern of choriocarcinoma.
Contrary to epithelioid smooth muscle tumors, vimentin and muscle markers are negative in ETT.
The behavior of epithelioid trophoblastic tumor is still unclear at time. Although the serum hCG
level is only mildly elevated in most sequential measurement is recommended during follow up.
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