Villous Trophoblast

At the end of the first week following conception, trophectoderm of the blastocyst implants in the endometrial surface and invades the endometrial stroma. The mononuclear trophoblastic shell, composed of previllous trophoblast, has not yet formed villous structures. This is responsible for erosion of maternal tissue by production of various hormones, cytokines, a number of extracellular matrix receptors, and matrix-degrading proteases and their inhibitors.¹ The previllous trophoblast of the implanting embryonic pole differentiates into two components, the outer syncytiotrophoblast located at the maternal–fetal interface and the inner cytotrophoblast (Figure 34.1). The cytotrophoblast is an inner layer of ovoid, mononuclear cells with high proliferative activity that functions as the trophoblastic stem cell. Syncytiotrophoblast, the first differentiated trophoblast lineage, produces human chorionic gonadotropin (hCG) and proteolytic enzymes, and secretes factors that cause apoptosis of the endometrial epithelial cells and decidua. Penetration and erosion of the adjacent maternal capillaries results in the formation of lacunae within the syncytiotrophoblast,² and these structures enlarge to form the intervillous space.

Early in the third week, extraembryonic mesoderm grows into the solid primary villous trabeculae of cytotrophoblast and syncytiotrophoblast (Figure 34.2), forming secondary villi. These consist of an outer layer of syncytiotrophoblast, a middle layer of cytotrophoblast, and an inner connective tissue core. At this stage secondary chorionic villi cover the entire surface of the chorionic sac.²

Active vasculogenesis begins within the secondary villous stroma, transforming them into tertiary villi (Figure 34.3A–D). Early primitive capillaries in the villous core are formed by in situ differentiation of pluripotent mesodermal tissue into hemangioblastic stem cells that give rise to committed endothelial progenitors (angioblast) and hematopoietic stem cells. Angioblasts form angiogenic cell cords (Figure 34.3A), which develop slit-like vascular lumens during the third to fourth week (Figure 34.3B). Subsequently, distinct vascular lumens with variable numbers of immature hematopoietic cells begin to appear (Figure 34.3C). Frequent mitotic figures and occasional karyorrhexis are identified among the angiogenic cell cords and the stromal cells at this stage. After that, new blood vessels in the villous stroma are derived by sprouting, elongation, and remodeling of already existing blood vessels. Villous stroma is basophilic and myxomatous until the end of the fourth week when the ground substance gradually assumes an edematous and reticular appearance (Figure 34.3D).

As active vasculogenesis is occurring, the villi branch, trophoblast proliferates at the implanting embryonic pole, and forms a confluent shell along the external circumference of the chorionic villi (Figure 34.4). This cytotrophoblastic shell of early pregnancy mimics the trophoblastic hyperplasia of hydatidiform moles, with which it should not be confused.

Extravillous (Intermediate) Trophoblast

Extravillous trophoblast is a general term for the entire population of trophoblast residing outside the villi, including implantation site (basal plate), chorion laeve, chorionic plate (subchorionic area), and placental septum. It is commonly designated as ‘intermediate trophoblast’ by pathologists. The terms extravillous and intermediate trophoblast will be used interchangeably in this chapter.

While one group of cytotrophoblast fuses to form multinucleated syncytiotrophoblast, which encases the free villi of the placenta, another differentiates into extravillous trophoblast and develops invasive properties.³ At the basal end of anchoring villi, cytotrophoblast proliferates to form columns of ‘villous intermediate trophoblast,’ a cohesive mass of cells with high proliferative activity (Figure 34.5A). As the cells in the trophoblastic column come into contact with decidua, these cells exit the cell cycle, thereby losing their proliferative activity, detach from the cell column, and acquire migratory and invasive properties. Subsequently, the cells move into the decidua and superficial myometrium (interstitial trophoblast) (Figure 34.5B) and penetrate the decidual spiral arteries (endovascular trophoblast) (Figure 34.5C). These are collectively referred to as ‘implantation site intermediate trophoblast.’⁴

In a normal implantation site, endovascular trophoblast displaces the endothelial lining and musculoelastic tissue of spiral arteries, increasing the luminal diameter and allowing greater transport of maternal blood to the intervillous space. Proliferative and invasive ability do not coexist in one and the same cell of normal trophoblast, but rather are seen in mutually exclusive populations. This contrasts with ‘malignant’ trophoblast, where the invasive cells also proliferate.

Interstitial (intermediate) trophoblast cytology is similar to that of surrounding decidualized stromal cells (Figure 34.5A–D), but the trophoblast nuclei are slightly larger, irregular, and hyperchromatic. Trophoblastic spindle cells often have angular dark nuclei as they dissect individually or in small clusters between decidual cells (Figure 34.5D).

Chorionic villi cover the entire chorionic sac until the beginning of the eighth week but become asymmetrical as those associated with the decidua capsularis begin to degenerate. A variable thickness of trophoblastic cells persists in the chorion laeve until term, but this extravillous trophoblast is not invasive. Therefore, the fetal membrane is composed of amniotic epithelium sitting on thin connective tissue layers of amnion and chorion, maternal decidua parietalis with interposed extravillous trophoblast, and occasional ghost villi (Figure 34.6A). Microscopically, intermediate trophoblast in the chorion laeve of term placentas are composed of two populations with differing cytology and immunophenotypes (Figure 34.6A–F).^4,5 These two types of intermediate trophoblast are not strictly separated into different compartments, but rather are admixed to some extent.

Trophoblast Immunohistochemical Markers

Non-neoplastic trophoblastic lesions can be confused with a variety of trophoblastic and nontrophoblastic tumors because of their inherent cytologic atypia and pleomorphism. Immunohistochemical markers can be helpful in resolving the differential diagnosis.

All trophoblastic cells, including cytotrophoblast, syncytiotrophoblast, and intermediate trophoblast, possess epithelial antigens detected by antibodies for cytokeratin (AE1 and AE3), epithelial membrane antigen, and low molecular weight cytokeratins (CAM 5.2 and Ber-P4). Although not specific to the trophoblast, these common antibodies are useful to distinguish trophoblastic from nonepithelial tumors, such as epithelioid smooth muscle neoplasia. Some antibodies, including HSD3β1, HLA-G, and β-hCG, are used in the differential diagnosis between trophoblastic and nontrophoblastic lesions. Others, including P63, placental alkaline phosphatase, human placental lactogen, and CD146 (Mel-CAM), are useful to infer ‘chorionic-type’ or ‘implantation site’ differentiation among intermediate trophoblast. Expressions of various trophoblastic markers in subpopulations of trophoblast are summarized in Panel A of Table 34.2, and their use in resolving various differential diagnoses is shown in Panel B.

Complete Hydatidiform Mole

Early (First Trimester) Complete Hydatidiform Moles

Early moles in which trophoblastic proliferation and hydropic change is minimal (Figure 34.8) are easily confused with non-molar hydropic abortions. At this early phase, molar chorionic villi have bulbous outlines resembling blunt finger-like projections, and the villous stroma may not have appreciable hydropic change. Villous trophoblastic proliferation is minimal or is frequently proliferated in a polar fashion (Figure 34.9), resembling polar proliferation of normal anchoring villi in early developing placentas. Trophoblastic pseudoinclusions, although often present, are not diagnostic, as they also may be seen in partial moles and aneuploid gestations. It is a combination of hypercellular basophilic stroma, immature blood vessels, and abnormal villous profiles that characterizes early complete moles, as these individual features may be seen separately and to a lesser extent in normal early developing placentas.

Poorly formed immature blood vessels in the villous stroma are characteristic of early moles. Vascular structures, when present (Figure 34.10), are linear cords in basophilic stroma, similar to the angiogenic cell cords of normal placentas (Figure 34.3A). Rarely, there are cleft-like spaces within the vascular structures, but unlike normal placentas they almost never contain hematopoietic components or red blood cells. There is characteristic karyorrhexis and apoptosis of stromal cells and immature vascular structures, scattering karyorrhectic nuclear debris throughout the villous stroma (Figure 34.11). Karyorrhexis and apoptosis within the villous stroma of non-molar hydropic abortuses and normal placentas are limited to a few cells within small terminal villi.

Advanced (Second Trimester) Complete Hydatidiform Moles

The cellular and mildly edematous basophilic stroma of early moles progressively changes to form hydropic villi with central acellular cisternae, and eventually, diffusely hydropic hypocellular villi (Figure 34.12A–C). Stroma is progressively displaced from the central part of the villi by accumulated fluid. These hydropic vesicles have grossly visible ‘bunch of grapes’ appearance filling the entire uterine cavity (Figure 34.13). Circumferential proliferation of cytotrophoblast, intermediate trophoblast, and syncytiotrophoblast is prominent (Figures 34.14 and 34.15), sometimes forming large sheets of trophoblast around the edematous villi. The trophoblast of complete moles has variable degrees of cytologic atypia, which may include nuclear pleomorphism and heterochromasia, often accompanied by cytoplasmic vacuoles (Figure 34.16). The vacuoles are relatively more prominent than seen in normal trophoblast at the same gestational age. The degree of trophoblastic proliferation and hydropic change appears to be a time-dependent phenomenon that varies by gestational age, and is not related to the risk of subsequent persistent trophoblastic neoplasia.

Molar implantation sites are almost always exaggerated, in that intermediate trophoblastic cells are more atypical and the Ki-67 labeling index is higher than for a normal pregnancy.²⁴ Biparental, triploid, or tetraploid complete moles and 46,XX and 46,XY complete moles are histologically and immunohistochemically indistinguishable from the more common androgenetic diploid mole.²⁵

Partial Hydatidiform Mole

Partial hydatidiform mole is defined as a conceptus with a fetus (alive or dead) and a single placenta with focal hydatidiform change of the villi in the presence of trophoblastic hyperplasia. Although an embryo or fetus often can be demonstrated, sometimes this is not represented in the available specimen, either because of sampling error or prior passage or degeneration of fetal parts.

There is continuing uncertainty regarding the frequency and natural history of partial moles because of difficulty of histopathologic diagnosis, and variable access to ploidy and molecular genetic analysis.

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