Chronic Inflammatory Lesions of the Placenta and Preterm Birth

Educational Gaps

1. Chronic inflammatory lesions of the placenta are not as well recognized or understood as acute inflammatory response to ascending infection.

2. Some chronic inflammatory lesions of the placenta have known associations with preterm birth, growth restriction, and recurrence.

Objectives

After reading this article, readers should be able to:

1. Understand the basic mechanisms for immune tolerance in pregnancy.

2. Recognize the difference between acute and chronic inflammatory lesions.

3. Recognize the various chronic inflammatory lesions of the placenta.

4. Understand the clinical significance of chronic villitis.

Chronic versus Acute Inflammation in the Placenta

Chronic inflammatory lesions have been less well characterized and studied than the more common acute inflammatory response to ascending infection in pregnancy. The latter is well characterized clinically and pathologically as maternal and fetal neutrophilic infiltrates. Pathologically we recognize gradations of these maternal and fetal acute inflammatory responses. The maternal acute inflammatory response can range in severity from acute deciduitis to acute chorionitis/subchorionitis to acute chorioamnionitis to acute severe/necrotizing chorioamnionitis. (8) Similarly, the fetal acute inflammatory response can range in severity from inflammation of just 1 umbilical vessel (acute umbilical phlebitis or arteritis) to extension of inflammation into Wharton jelly (acute funisitis). (8) These increases in histologic severity usually correlate with the time of onset of the ascending infection during pregnancy, with the fetal response almost always beginning after some degree of maternal response. (9)

In contrast, the chronic inflammatory response is less well understood both clinically and pathologically. Chronic inflammatory infiltrates are usually described as focal or multifocal, but there is no clear correlation between severity of inflammation and etiology or clinical outcome. The clinical associations with chronic villitis (CV), chronic deciduitis (CD), or chronic chorioamnionitis (CC) are less well defined than in the acute inflammatory responses, but include intrauterine growth restriction, intrauterine fetal demise (IUFD), and recurrence of these lesions in a subsequent pregnancy (Table). Chronic inflammatory infiltrates can include lymphocytes, plasma cells, and histiocytes that are often found incidentally on microscopic pathologic examination (Fig 1). Eosinophils appear occasionally in the placenta, primarily as part of the fetal inflammatory infiltrate in both eosinophilic/T-cell chorionic vasculitis (ETCV) and acute chorionic vasculitis. (10)(11)

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Figure 1.

Chronic inflammatory cells occupy various compartments of the placenta. Although lymphocytes are normal inhabitants of the decidua (1), they are usually increased and accompanied by plasma cells in chronic deciduitis (2). Intravillous lymphocytes and histiocytes with or without plasma cells are seen in basal chorionic villi (3) and chronic villitis (4). Collections of histiocytes and some lymphocytes are in the intervillous space in chronic intervillositis (5). Lymphocytes infiltrate the chorioamnion in chronic chorioamnionitis (6). In eosinophilic/T-cell chorionic vasculitis, a mixed lymphocytic and eosinophilic infiltrate migrates from a chorionic vessel toward the intervillous space (7). (Reprinted with adaptations from Katzman PJ. Chronic inflammatory lesions of the placenta. Semin Perinatol. 2015;39:20–26, Copyright 2015, with permission from Elsevier.)

Definitions, Associations, and Significance of Chronic Inflammatory Lesions

One of the difficulties in characterizing chronic inflammatory lesions in the placenta is the large array of placental sites at which chronic inflammatory cells can be found (Fig 1). Although occasionally a large focus of CV may be seen on gross examination, (12) these inflammatory lesions are primarily identified on microscopic examination of sampled placental tissue. Therefore, it is often pathologists trained in placental pathology who will most likely reproducibly identify these lesions. Although histology is usually sufficient for diagnosing most chronic inflammatory lesions, histochemical stains and immunohistochemical stains are useful for identifying some inflammatory cells, such as T lymphocytes and histiocytes, or for identifying microorganisms that may be the cause of the inflammation.

The Normal Chorionic Villous Tree

The placenta is a branching organ that grows in tandem with the fetus. Embryologically, both the placenta and fetus arise from the fertilized oocyte, with fetal and placental growth diverging at the time of implantation. As the placenta develops, the chorionic villous tree becomes more complex. Large primary villi with thick-walled muscular arteries and abundant stroma branch into secondary and tertiary villi that have increasing numbers of small vessels with lesser amounts of supporting stroma (Fig 2A). Stromal histiocytes (Hofbauer cells) are native to the villi but other chronic inflammatory cells, including lymphocytes and plasma cells, are not normally present in the villi. Second-trimester tertiary villi, which are generally larger than their counterparts in the third trimester, often have a prominent stromal cellularity that can be confused with a lymphocytic infiltrate, but the homogenous and diffuse pattern of this stromal cellularity is not characteristic of CV (see next section). Although the villi are bathed in maternal blood that circulates throughout the intervillous space, all villi are enveloped in syncytiotrophoblast, the specialized cell that controls transport of nutrients and wastes between fetal and maternal circulations; as described before, the syncytiotrophoblast plays a role in maintaining the fetal-maternal immunologic barrier.

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Figure 2.

A. Compared with normal third-trimester chorionic villi, cytomegaloviral chronic villitis. B. A lymphoplasmacytic infiltrate with agglutination of adjacent villi and some sclerotic villi (asterisk). Chronic villitis of unknown etiology appears similar but usually without a plasma cell infiltrate. C. Chronic villitis can occur along the basal plate (maternal floor) adjacent to chronic deciduitis (plasma cells, white arrows) and basal villi can be inflamed and sclerotic (asterisks). D. A predominantly histiocytic infiltrate (with fewer lymphocytes) is present in the intervillous space in chronic intervillositis (original magnification A, B, C, ×200; D, ×400).

Chronic Villitis

Chronic villitis is an infiltration of lymphocytes, histiocytes, and in some cases, plasma cells, into chorionic villi, frequently resulting in villous agglutination (sticking together) (Fig 2B). This agglutination appears histologically in many cases to involve a disruption, at least focally, in the syncytiotrophoblastic layer on involved villi. CV is usually multifocal and can have a prominent basal component in which villi along the maternal floor are involved. CD (described later) is often present alongside basal CV( Fig 2C). CV can be a manifestation of infection involving 1 of several organisms as described by the TORCH acronym (toxoplasmosis, other agents, cytomegalovirus, and herpes simplex virus; screening for rubella is usually not performed because of widespread immunity). Cytomegaloviral infection specifically elicits a chronic inflammatory reaction that often includes plasma cells. When no organism is identified after special stains are used on formalin-fixed, paraffin-embedded tissue sections, the lesion can be diagnosed as “chronic villitis of unknown etiology” (CVUE).

Chronic Villitis of Unknown Etiology

Chronic villitis of unknown etiology is a multifocal chronic villitis in which no infectious etiology is identified. My colleagues and I previously hypothesized that if CVUE is an alloimmune process with disruption of the maternal-fetal barrier, an aberrant upregulation of MHC class II molecules may occur on the surface of the semiallogenic trophoblast cell in the placenta, allowing maternal lymphocytes to enter chorionic villi. MHC class II molecule expression was identified in the increased numbers of histiocytes at CV sites but only focally on syncytiotrophoblast. Although there was no clear upregulation of MHC class II molecules, we determined that Tregs are present in the cellular infiltrate of CV. CVUE is recognized primarily in the third trimester and is a recurrent lesion in some patients. Perinatal loss can be up to 37% in nonrecurrent cases of CVUE and as high as 60% in recurrent CVUE. (13)

An interesting histologic finding in CVUE is the presence of villous sclerosis in affected villi probably because of the inflammatory reaction in the villi that injures the fetal vessels. In widespread CVUE, the presence of this process, called “obliterative fetal vasculopathy,” is a likely mechanism for IUFD. Villous sclerosis is also seen in fetal thrombotic vasculopathy (FTV), in which either umbilical cord obstruction or an inherited thrombophilia causes vascular thrombosis in fetal vessels. Downstream vessels suffer from the absence of upstream blood flow, leading to small-vessel degeneration and villous sclerosis. FTV can also be associated with IUFD and preterm birth. CVUE and FTV can occur concurrently, but it is important to separate these 2 entities histologically to guide clinicians with postnatal counseling. Thrombi in larger chorionic villi that are not involved by CVUE can be helpful to make this distinction. Histologic examination of the placenta allows an important clinical distinction to be made in cases of IUFD without signs of CVUE or FTV. The presence of diffuse villous sclerosis is consistent with IUFD, whereas the presence of patchy villous sclerosis is more consistent with FTV. However, in severe maceration (degeneration) of fetal tissue consistent with prolonged retention after IUFD, the extensive villous sclerosis in the placenta may obscure the presence of both FTV and CVUE.

Chronic Deciduitis

Chronic deciduitis is an infiltrate of plasma cells admixed with lymphocytes in the decidua. It is often a patchy lesion that is paired with basal CV (Fig 2C). In some cases, the plasma cells spill into the basal chorionic villi. CD has been attributed to both infection and an alloimmune response and has been seen in preterm labor as well as both clinical and histologic acute chorioamnionitis.

Chronic Intervillositis

Chronic intervillositis (CI), also called “massive chronic intervillositis” and “chronic histiocytic intervillositis,” is an infiltrate of histiocytes in the intervillous space, often with wisps of fibrinous material, with or without a lymphocytic component and usually not in a background of CV (Fig 2D). A recent study identified immunophenotypic similarities in CI and CV infiltrates. (14) This lesion could be the result of infection or, as suggested more recently by the identification of Tregs in lesional infiltrates, an alloimmune response. (15) The recognized infectious etiologies of CI include malaria and cytomegalovirus (also known as “human herpesvirus 5”). (16)(17) When no infectious agent is identified, the lesion is called “chronic intervillositis of unknown etiology”.

Chronic Chorioamnionitis

Chronic chorioamnionitis is a lymphocytic infiltrate in the chorion on the fetal surface and in the free membranes (Fig 3A). It often occurs concurrently with CV and CD. Some cases of CC, especially those not associated with CV or CD, may have an infectious etiology. In some cases of CC, a cellular proliferation at the base of the chorion accompanies the lymphocytic infiltrate (Fig 3B). The significance of this basal chorionic cellular infiltrate, recently described as chorionic stromal hyperplasia, (12)(18) is not clear but it must be differentiated from CC using special stains for T cells.

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Figure 3.

A. Chronic chorioamnionitis is a collection of lymphocytes, almost exclusively T cells, in the chorion. B. A linear collection of stromal cells at the base of the chorion can mimic chronic chorioamnionitis (between white arrows). C. A focal infiltrate of variable cellularity is occasionally seen in chorionic vessels in eosinophilic/T-cell chorionic vasculitis (ETCV). D. In ETCV, a mixture of eosinophils (red granules in cells) and lymphocytes is present (original magnification A, B, ×200; C, ×100; D, ×400).

Eosinophilic/T-cell Chorionic Vasculitis

Eosinophilic/T-cell chorionic vasculitis is a focal collection of fetal lymphocytes (T cells) and eosinophils marginating out of a chorionic vessel toward the intervillous space. (10) We found that Tregs are part of the cellular infiltrate of ETCV and occur concurrently with CV in a significant number of ETCV cases. (11) The number of eosinophils can vary from few to many. The infiltrate can be present at the edge of the vessel or on the side facing the amnion, so it must be differentiated from an acute chorionic vasculitis. Because the lymphocytic infiltrate in CV is of maternal origin and the infiltrate in ETCV is of fetal origin, it is not clear whether CV and ETCV are related lesions, even though CV is seen concurrently with ETCV in about one third of cases. (11) Even more prevalent (42%) is the presence of an organizing thrombus in the vessels affected by ETCV. (11) It is not clear whether the thrombus forms as a result of the inflammation in the vessel or whether the inflammation is reacting to the formation of the thrombus. Thrombi are also not uncommon in chorionic vessels; acute chorionic vasculitis is a part of the fetal acute inflammatory reaction in ascending infections.