—  SYMPOSIUM #41  —

Gestational Trophoblastic Disease
Moderator: Dr. le-Ming Shih

Section 1 - Gestational Trophoblastic Diseases: Introduction

Ie-Ming Shih
Johns Hopkins Medical Institutions
Baltimore , Maryland


Introduction
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) [1, 2] . The anatomic locations and functional aspects of each trophoblastic subpopulation are briefly summarized below.

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 [3] . It has been postulated that through a paracrine-like mechanism, EGF-R and its ligand may provide growth stimulation for cytotrophoblast [4] . 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 [5] . 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 [6] and downregulation of Id-2 is associated with differentiation into implantation site intermediate (extravillous) trophoblast [7] . 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 [8] . 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 [9] . 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 [10] as evidenced by the virtual absence of Ki-67 labeling in syncytiotrophoblast and implantation site intermediate trophoblast. [5, 11]

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 [12] . 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 [12] . 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 early pregnancy [13, 14] . It has been suggested that the mechanisms underlying trophoblastic invasion are similar to those involved in tumor cell invasion [15, 16] 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 [17] . However, unlike malignant tumors, the invasion of implantation site intermediate trophoblast is tightly regulated, confined spatially to the implantation site and limited temporally to early pregnancy [4, 13, 14, 18, 19] . 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 [4, 18, 19, 20] . 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 [22] . It is of interest that implantation site intermediate trophoblastic cells express cyclin E but its biological significance is unknown at present [23] .

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 [24] . 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 [5, 25] . 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 [8] . Further in vitro studies are required to determine whether this interpretation is correct.

References:
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