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Chorionic Disk Extravillous Trophoblasts in Placental Diagnosis

Jerzy Stanek MD, PhD
DOI: http://dx.doi.org/10.1309/AJCPOZ73MPSPYFEZ 540-547 First published online: 1 October 2011


To study clinical and placental associations of increased amount of chorionic disk extravillous trophoblast (IAEVT), the frequency of selected clinical and placental parameters of 189 consecutive cases with IAEVT, defined as more than 5 cell islands and/or placental septa per placental section, were compared with those for all remaining 1,006 placentas examined during the same period. IAEVT was statistically significantly associated with preeclampsia, decidual arteriolopathy, placental infarction, and several chronic placental hypoxic lesions (uterine hypoxic pattern of hypoxic placental injury, microscopic chorionic pseudocysts, massive perivillous fibrin deposition, and trophoblastic multinucleated giant cells in decidua) and absence of meconium staining and umbilical cord abnormalities. The amount of chorionic disk extravillous trophoblast is increased in association with clinical conditions and placental lesions associated with chronic hypoxia of uterine origin, ie, placental malperfusion. Counting placental septa and cell islands is a valuable surrogate test of chronic placental hypoxia.

Key Words:
  • Preeclampsia
  • Extravillous trophoblasts
  • Uterine hypoxia
  • Placenta
  • Infarction
  • Microscopic chorionic pseudocysts
  • Massive perivillous fibrin deposition

The placental disk is composed of the chorionic plate, basal plate, and chorionic villi in between. Among the villous units (placentones), there are placental septa and cell islands containing the extravillous trophoblast (EVT) and matrix-type fibrinoid. During pregnancy, the EVT migrates from trophoblastic cell columns and invades the uterine wall as far as the inner third of the myometrium (interstitial trophoblast), moves into the decidual and myometrial spiral arteries, and differentiates into multinucleated trophoblastic giant cells.14 A vast amount of EVT does not invade the uterus and remains in the placenta as cell islands, placental septa, basal plate trophoblast, or placental membrane migratory EVT.2,3 Transverse sections of the tips of placental septa appear as cell islands.3 The trophoblastic component of placental septa or cell islands frequently undergoes such morphologic changes as vacuolization, cytomegaly, pseudocyst formation, hemorrhage, necrosis, and calcification Image 1.2,3,57 The function of EVT contained in placental septa and cell islands remains uncertain,2 but it is probably limited to early gestation, being an additional source of invasive EVT.4

A general opinion prevails that the aforementioned qualitative changes in cell islands and placental septa are not linked to any pathologic conditions and that the amount of the chorionic disk EVT has no diagnostic or prognostic significance, except perhaps for the total absence of cell islands or placental septa.3 However, an increased amount of immature and proliferating EVT (shown by immunohistochemical and morphometric studies) was found in the maternal floor of the placenta in patients with preeclampsia,5 and later the increase was suggested as one of the criteria for the diagnosis of inadequate maternal-fetal perfusion.8 Later, the threshold of 5 cell islands or placental septa per section of chorionic disk was proposed as the upper limit of normal for the amount of placental EVT.9 A 4-fold increased frequency of an increased amount of EVT (IAEVT) in placentas with focal and diffuse hypoxic lesions10 and a 3-fold increase in association with such chronic placental hypoxic lesions as microscopic chorionic pseudocysts7,11 and clusters of multinucleate trophoblastic giant cells in the decidua basalis were reported.12 However, apart from those reports, the clinical and placental associations of IAEVT have never been systematically studied. This retrospective analysis aimed to address the issue in a large collection of placental material.

Image 1

Morphologic variants of cell islands and placental septa. A, Cell island containing more than 50 extravillous trophoblastic cells (×10). B, Placental septum with length exceeding more than 2 times the thickness of the adjacent maternal floor extravillous trophoblastic layer (×2). C, Cell island with vacuolated trophoblast cells (×40). D, Cell island with cytomegaly (×20). E, Placental septum with microscopic chorionic pseudocysts (×10). F, Hemorrhage into a cell island (×4). G, Infarcted placental septum with leukocytic response (×10). H, Cell island with dystrophic calcification (×10) (AH, H&E).

Materials and Methods

For the study, 29 clinical (maternal and fetal) and 39 gross and microscopic placental features were statistically compared between 189 consecutive cases with IAEVT, defined as more than 5 placental septa and/or cell islands, each containing more than 50 EVT cells, per paracentral section of grossly unremarkable placental parenchyma Image 2 (study group [SG]), and 1,006 remaining placentas having fewer cell islands or placental septa (control group [CG]) from 20 or more weeks’ gestation. I examined and signed out the reports for all placentas analyzed in this study at the Department of Pathology, Sheffield Children’s NHS Trust, Sheffield, England; Department of Anatomical Pathology, Canterbury Health Laboratories, Christchurch, New Zealand; and the Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, during the years 2006 through 2009, in which time the increased numbers of placental septa or cell islands were consistently documented and included in the pathology report as IAEVT.

The placentas had been submitted for examination at the discretion of obstetricians because of the high-risk nature of a pregnancy, fetal distress, unsatisfactory condition of a neonate, operative delivery, or a grossly abnormal placenta. Placental examination was performed according to generally accepted criteria; specifically, 2 sections of placental membrane rolls and at least 2 paracentral full-thickness chorionic disk sections were routinely taken as a part of placental examination if no gross lesions were identified. The paracentral sections were random without specifically looking for the sites of entry of spiral arteries. All grossly seen lesions were additionally sampled. The samples were fixed in buffered formalin, followed by routine paraffin embedding, cutting, and staining with H&E. Definitions of clinical conditions and placental diagnoses used in this study were standard2,3,1316 or as in my previous reports.6,7,9,10,12,17 The statistical analysis included the Yates χ2 and analysis of variance, single factor, as appropriate, with the Bonferroni correction for multiple comparisons.

Image 2

Increased amount of chorionic disk intermediate trophoblasts. A, In this microscopic field from a section of grossly unremarkable placental parenchyma, 6 cell islands are seen (H&E, ×4). Confluent cell islands (B, H&E, ×4) should be distinguished from the massive perivillous fibrinoid deposition (C, H&E, ×2), which is a grossly recognizable, “lacy” lesion and microscopically presenting as anastomosing strands of matrix-type fibrinoid expanding the perivillous space and enmeshing chorionic villi.


IAEVT was most commonly seen at the end of the second and beginning of the third trimester of pregnancy. The frequency declined thereafter.

Differences in clinical and placental factors between the SG and the CG are given in Table 1. Preeclampsia and its subtypes, chronic hypertension, and maternal diabetes mellitus occurred several times more frequently in association with IAEVT. Only for eclampsia was the difference not statistically significant, but there were few cases. There were no differences in average gestational age and pregnancy-induced hypertension between the SG and the CG. Oligohydramnios, induction of labor, cesarean section, and fetal growth restriction were statistically significantly more common in the SG, but the premature rupture of membranes was significantly less common (less than half as common).

The weight of the placentas in the SG was statistically significantly less, and several acute (villous infarction) and chronic hypoxic placental patterns and lesions (uterine and postuterine chronic diffuse hypoxic patterns, microscopic chorionic pseudocysts, maternal floor multinucleate trophoblastic giant cells, massive perivillous fibrin deposition) and related lesions (decidual arteriolopathy) were likewise more common in the SG. Notably, there were no statistically significant differences between the SG and the CG in the frequency of histologic deep meconium staining and membrane laminar necrosis, hydrops-related changes, or focal lesions related to decreased or absent fetal blood flow. Various umbilical cord pathologic abnormalities, histologic acute chorioamnionitis, chronic villitis of unknown cause, and meconium macrophages in membranes were more prevalent in the CG.


Results of the present analysis are in keeping with the report on the increased amount of EVT in the maternal floor in preeclampsia.5 The authors evaluated the amount of EVT in the decidua basalis in 4 morphologic zones by morphometric and immunohistochemical (cytokeratin and proliferating cell nuclear antigen) studies. A later report by a panel of placental experts performed on 14 study and 6 control cases simplified the evaluation of the maternal floor EVT, defining its increase as the presence of tightly cohesive groups of 10 to 20 (or more) eosinophilic and/or vacuolated immature EVT arranged in sheets or clusters in the superficial basal plate near the anchoring villi.8 The panel concluded that the sensitivity of IAEVT and implantation site giant cells, unlike decidual arteriolopathy, is higher than their specificity in preeclampsia.

Based on the present analysis and my previously published reports,7,912 I believe that counting placental septa and cell islands is a practical, easy, and reproducible tool in evaluation of amount of the chorionic disk EVT. Furthermore, evaluation of the EVT in the decidua basalis/maternal floor, ie, at the separation zone between the placenta and the uterus, may not be representative of the total amount of EVT in the chorionic disk because variable amounts and proportions of the EVT and decidua are delivered with the placenta and are available for evaluation from case to case, and the remaining tissue is left behind attached to the uterus. In addition, sometimes it may be difficult to unambiguously distinguish between the decidual and trophoblastic cells in the maternal floor in H&E-stained slides, as occasionally is the case in the products of conception, and a cytokeratin18 or other trophoblastic immunostain such as CD14617 might be needed, which again is not practical for routine diagnosis. That is why I chose counting the cell islands and placental septa throughout the thickness of the grossly unremarkable chorionic disk rather than quantitatively estimating it in the decidua basalis, the approach eliminating the need for the trophoblast identification by immunohistochemical studies as the placental septa contain essentially the EVT only. Including the placental septa in addition to cell islands in the count also takes into consideration the direct extensions of the maternal floor EVT. Despite all these remarks, the previously described methods5,8 may still be suitable for research purposes.

By extending the scope of other reports,5,8 the present analysis showed that not only preeclampsia but also other maternal and fetal conditions potentially complicated by in utero hypoxia, such as chronic hypertension, maternal diabetes mellitus, and placentas from induced delivery and from cesarean section, are more commonly associated with IAEVT; for induced delivery and from cesarean section, the clinical features of in utero hypoxia are frequent indications for obstetric interventions. It is interesting but not unexpected that other clinical conditions and nonhypoxic placental lesions are less commonly seen in association with IAEVT.

IAEVT was also strongly associated with other hypoxic placental lesions and patterns, particularly with the uterine pattern of chronic hypoxic placental injury, which is a feature of inadequate uteroplacental perfusion.10 The association with the postuterine pattern of chronic hypoxic placental injury was weaker, and there was no association with the preuterine pattern and chorangiosis, ie, the chronic hypoxic patterns not caused by decreased uteroplacental perfusion10 (Table 1). This analysis again confirmed the strong association of IAEVT with microscopic chorionic pseudocysts, which is understandable as they are secondary formations in the cell islands or placental septa7 (Image 1).

It should be stressed that the differences between the SG and the CG would have probably been even more dramatic in clinical and placental features if my CG had contained placentas from normal pregnancies and not from high-risk pregnancies, frequently with complicated outcomes that could blur the differences. Only such placentas were available for retrospective comparison, however.

Association does not amount to causation. Nevertheless, an attempt to explain the observed IAEVT associations is justified. Differentiation of cytotrophoblast to syncytiotrophoblast and EVT is controlled by different agents such as transcription factors, specific genes, hormones, growth factors and cytokines, and oxygen levels.19,20 The pathologic mechanisms of the switch are uncertain. Reduced proliferation, enhanced apoptosis, or even increased fusion of EVT may be responsible for the reduction of the number of invasive trophoblasts.21 As opposed to the intramural/endovascular trophoblast, apoptosis of the interstitial trophoblast is not the ultimate means to lead to pathologically shallow invasion.22 Overexpression of activator protein-2 in preeclampsia,23 transforming growth factor β3,24 and angiotensin II25 all inhibit EVT invasion and favor the premature fusion of EVT with multinucleate trophoblastic giant cell formation.26 Preeclampsia is a condition that combines a deficiency in the second wave of trophoblastic invasion and shallow implantation27,28 and an increased amount of EVT at the maternal floor.8

Apart from the aforementioned agents, hypoxia exerts an inhibitory effect on EVT cell invasiveness,4,19,2931 but the exact mechanism by which trophoblasts sense oxygen tension is unclear. The pathways often use redox-sensitive transcription factors, of which the hypoxia-inducible factor family is the best characterized in trophoblasts.32 However, the majority of available data on the topic were obtained from in vitro experiments on first-trimester conceptions, and contrasting responses may derive from different experimental conditions.19 Supporting hypoxia as a regulatory mechanism is an observation that chronic exposure to tobacco constituents in early pregnancy changes the balance between cytotrophoblast proliferation and differentiation. Cell columns and proliferating cells are reduced (reduced invasion), while there is a corresponding increase in cell islands, the finding corresponding to the present results. The fewer trophoblasts in the uterus, the more in the placenta. This was observed as early as in the first trimester of pregnancy and was proportional to the number of cigarettes smoked per day, ie, probably to the degree of blood flow reduction and hypoxia33; however, in the current material, the IAEVT was not statistically significantly associated with maternal substance abuse, which included maternal smoking (Table 1).

Because placental hypoxia cannot be measured retrospectively in late second-trimester and third-trimester placentas, various surrogates of placental hypoxia were compared between the SG and the CG to show correlation with the potentially hypoxic clinical conditions and placental lesions. Counting placental septa and cell islands is a simple and practical way of assessment of the amount of placental EVT that may increase the sensitivity of placental examination and serve as a surrogate test of placental hypoxia, particularly uterine,34 and shallow myometrial EVT invasion not only in preeclampsia but also in other conditions at risk for in utero hypoxia.


Upon completion of this activity you will be able to:

  • discuss the differential diagnosis of the increased amount of chorionic disk extravillous trophoblasts and chorionic microcysts.

  • correlate the histologic placental lesions of uteroplacental malperfusion with complications of pregnancy.

The ASCP is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit ™ per article. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity qualifies as an American Board of Pathology Maintenance of Certification Part II Self-Assessment Module.

The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.

Questions appear on p 654. Exam is located at www.ascp.org/ajcpcme.


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