Gestational Trophoblastic Disease
Moderator: Dr. le-Ming Shih
Section 1 -
Gestational Trophoblastic Diseases: Introduction
Johns Hopkins Medical Institutions
Baltimore , Maryland
Gestational trophoblastic disease (GTD) can be broadly classified into two groups, hydatidiform moles
which are abnormally formed placentas and intermediate (interstitial or extravillous) trophoblastic
lesions including tumors and tumor-like lesions. In contrast to hydatidiform moles, the pathogenesis of
intermediate (extravillous) trophoblastic lesions is largely unknown. In recent years, progress has been
made in elucidating the biology of human trophoblast, especially the intermediate (extravillous)
trophoblast. The identification and characterization of the genes expressed in human trophoblast has led
to a further understanding of the lineage and differentiation program of trophoblast and related this to
trophoblastic lesions. It is now clear that trophoblastic lesions recapitulate the trophoblast present
in the early developing placenta and implantation site. In pathology practice, differential diagnosis
among different types of intermediate (extravillous) trophoblastic lesions and between intermediate
trophoblastic lesions and a variety of non-trophoblastic tumors can be challenging. The distinction is
important, as the management and treatment of trophoblastic and non-trophoblastic tumors are vastly
different. For the molar lesions, diagnosis of early molar lesions can be difficult at times because of
the lack of the unique morphological features that can be seen in typical cases nowadays. However,
morphological clues are available and new technologies are being introduced to assist diagnosis and
prediction of prognosis in molar lesions. In this symposium, we will summarize the advances in
trophoblastic research in recent years with special emphasis on how we can apply these new knowledge and
technologies to the routine pathology practice in the diagnosis of GTD. In the following discussion, a
succinct summary on normal trophoblastic subpopulations is provided in order to better understand the
biology and pathology of normal trophoblastic cells and GTD. Furthermore, a modified WHO classification
is also described before the discussion of each trophoblastic lesion.
Overview of Trophoblastic Subpopulations in Normal Placenta
Based on morphologic, immunophenotypic, and functional studies, the trophoblast in villous and
extravillous locations can be divided into three distinct populations: cytotrophoblast (CT),
syncytiotrophoblast (ST), and intermediate (extravillous or interstitial) trophoblast (IT)
The anatomic locations and functional aspects of each trophoblastic subpopulation are briefly
Cytotrophoblast. Cytotrophoblast functions as a 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 through a
paracrine-like mechanism, EGF-R and its ligand may provide growth stimulation for cytotrophoblast
 . Cytotrophoblast differentiates along two main pathways. On
the villous surface, cytotrophoblast 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 in the trophoblastic column differentiates into villous intermediate trophoblast
and then into implantation site intermediate trophoblast in the placental site or chorionic-type
intermediate trophoblast in the chorion laeve  . The mechanisms underlying the
differentiation of cytotrophoblast are unclear. Recently, however, expression of syncytin has been shown
to be involved in the fusion of cytotrophoblast into syncytiotrophoblast  and downregulation
of Id-2 is associated with differentiation into implantation site intermediate (extravillous)
trophoblast  . In addition , it has been shown that cytotrophoblast expresses the ΔN
isoforms of p63 whereas chorionic-type intermediate trophoblast in the fetal membranes expresses the TA
isoforms  . Implantation site intermediate trophoblast and syncytiotrophoblast do not express
either of the p63 isoforms. As p63 isoforms have specific functions including those that relate to
regulation of apoptosis and proliferation, these findings suggest that p63 may act as a molecular switch.
Thus, turning off or turning on specific p63 isoforms may in turn control trophoblastic differentiation
and placental development. The expression of the ΔN isoform in cytotrophoblast is consistent with its
proposed function of maintaining basal or stem cells in a state where they are capable of proliferation
and differentiation, perhaps by preventing cell cycle arrest and inhibiting apoptosis  .
Thus, as cytotrophoblast differentiates into either syncytiotrophoblast or implantation site intermediate
trophoblast in the trophoblastic columns, there is a dramatic decrease in ΔNp63 expression which may
contribute to cell cycle arrest  as evidenced by the virtual absence of Ki-67 labeling in
syncytiotrophoblast and implantation site intermediate trophoblast.
Syncytiotrophoblast. Syncytiotrophoblast is composed of
terminally differentiated cells that cover the chorionic villi and synthesizes and secretes a number of
pregnancy-associated hormones including hPL, SP-1 and beta-hCG. Some of these secretory proteins may
also have a paracrine function by regulating the local microenvironment of decidual cells, 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 comprise the trophoblastic columns that anchor the chorionic villi to the basal plate
of the implantation site. They proliferate in the proximal portion of the trophoblastic columns and are
the source of implantation site and chorionic-type intermediate trophoblastic cells. In addition, they
maintain the structural integrity of the trophoblastic columns. The distinctive molecular feature that
characterizes the villous intermediate trophoblastic cells is the expression of HNK-1 carbohydrate which
is not present in any of the other trophoblastic subpopulations  . The HNK-1 moiety is
present on the cell surface and may contribute to intercellular cohesion in the trophoblastic columns
which counteracts the mechanical sheering forces resulting from fetal movement and the turbulence created
by the pulsatile blood flow in the placental bed  . Moreover, several genes including CD146
(Mel-CAM), hPL, HLA-G and cyclin E are expressed in villous intermediate trophoblastic cells increasing
from the proximal to the distal end of the trophoblastic column, and reflecting the differentiation of
implantation site intermediate trophoblast.
Implantation Site Intermediate (Interstitial or Extravillous)
Trophoblast. The major function of implantation site intermediate (extravillous) trophoblast is
to establish the maternal-fetal circulation by invading the spiral arteries in the basal plate during
. It has been suggested that the mechanisms underlying trophoblastic
invasion are similar to those involved in tumor cell invasion
as in both processes a
variety of proteases, cell adhesion molecules, growth factors and their receptors, and tumor-associated
antigens including HLA-G and CD146 are expressed in both and there is loss of E-cadherin expression
 . However, unlike malignant tumors, the invasion of implantation site intermediate
trophoblast is tightly regulated, confined spatially to the implantation site and limited temporally to
. While extensively infiltrating the endometrium of the
basal plate, the implantation site intermediate trophoblast invades only the inner third of the
myometrium in the first trimester, decreasing to less than 10% of the myometrium by term. Although the
molecular mechanisms underlying the control of trophoblastic invasion are 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. Implantation site intermediate trophoblastic cells are
not proliferative as they are negative for Ki-67, a proliferation marker, and are positive for several
proteins which are involved in the arrest of cell cycle progression including p21WAF1/CIP1
21 and p57kip-2
 . It is of interest that implantation site
intermediate trophoblastic cells express cyclin E but its biological significance is unknown at present
Chorionic-type Intermediate Trophoblast. This type of intermediate
(extravillous) trophoblast is located in the chorion laeve (fetal membrane). Unlike implantation site
intermediate trophoblastic cells, the functional role of chorionic-type intermediate trophoblastic cells
remains speculative. Chorionic-type intermediate trophoblast may contribute to the synthesis of
extracellular matrix which is required to maintain the tensile strength of the fetal membrane
 . It is also possible that chorionic-type intermediate trophoblast acts as a biological and
mechanical barrier to the maternal immune system and is important for fetal allograft survival.
Chorionic-type intermediate trophoblastic cells express HLA-G and p63 but hPL and CD146 only focally
. Chorionic-type intermediate trophoblastic cells are thought to differentiate from
cytotrophoblast but the molecular mechanisms that underlie this process are unknown. ΔNp63 is expressed
by cytotrophoblast and TAp63 is expressed by chorionic-type intermediate trophoblastic cells. It is
conceivable that an isoform switch from ΔNp63 to TAp63 may be important for the transformation of
chorionic-type intermediate trophoblast from cytotrophoblast in the fetal membranes  .
Further in vitro studies are required to determine whether this
interpretation is correct.
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