Chorangiosis: Report of Three Cases and Review of the Literature

PATHOLOGY

Teaching Case

RESEARCH AND PRACTICE © Urban & Fischer Verlag http://www.urbanfischer.de/journals/prp

Chorangiosis: Report of Three Cases and Review of the Literature Adele Caldarella, Anna Maria Buccoliero, Gian Luigi Taddei Dipartimento di Patologia Umana e Oncologia, Firenze, Italia

Summary The vascular lesions in the placenta form a heterogeneous group of possibly interrelated alterations. Gestational age distribution is different for chorangioma, chorangiosis, and chorangiomatosis; the pathogenesis is unclear, and histological features, especially those of chorangiosis and chorangiomatosis, frequently overlap. Chorangiomatosis shows intermediate features between chorangiosis and chorangioma. In this lesion, particularly when multifocal, the presence of small capillaries is similar to chorangiosis, but the gestational age is different from both chorangiosis and chorangioma. We present three cases of chorangiosis examined during one-year routine pathological analysis of placental tissue and report the histological, histochemical, and immunohistochemical features. Furthermore, we go into the difficulty of discerning the villous capillary lesions and the utility of this division, and describe the clinical effects of these lesions on fetal outcome. Key words: Chorangiosis – Chorangiomatosis – Villous capillary

Introduction Premature chorangiosis is a placental change that has not been studied extensively. It rarely occurs in normal pregnancies, but is more frequent in maternal pathological conditions such as pre-eclampsia, diabetes mellitus, drug ingestion, and urinary tract infection. Among placental conditions associated with chorangiosis, umbilical cord anomalies, abruptio placentae, and villitis have been described. Even major congenital anomalies and a low Apgar score can be associated with chorangiosis. The incidence of chorangiosis is higher in women living in high altitudes; therefore, this event seems to result Pathol. Res. Pract. 199: 847–850 (2003)

from placental hypoperfusion. Hypoxia may lead to excessive villous capillary growth and to a high proliferative activity of connective tissue. Chorangiosis has been associated with increased perinatal morbidity and mortality; therefore, it should be regarded as a placental marker of potential clinical significance for the fetal outcome.

Case Reports A total of 330 placentas were recorded in our Department from January 1, 2002, to December 31, 2002, for routine pathological examinations. Among these, in three cases, diffuse areas of chorangiosis, as well as an increase in the number of the vessels in the chorionic villi, were detected. In all patients but one, labor was at term, and healthy babies were delivered. In one woman, a stillborn fetus was delivered at 30 weeks of gestation. Age and symptoms of the women, as well as the gross and microscopic features of the placentas, are given in Table 1. Age ranged from 23 to 41 years. In two cases, signs of eclampsia or preeclampsia were discovered. Three tissue sections from placenta, one from membrane and two from umbilical cord, were taken, fixed in formalin, paraffin-embedded, and stained with hematoxylin-eosin. The sections were examined microscopically: in one case, a chorioamnionitis was detected, while in two placentas, infarctions were present. Hypoplastic villi were noted in one case, and fibrinoid necrosis was discovered in all placentas (Fig.1). Subsequently, for each case, one representative placental section was evaluated by histochemical stains for Address for correspondence: Adele Caldarella, Dipartimento di Patologia Umana e Oncologia, Università degli Studi di Firenze, Viale Morgagni 85, 50134-Firenze, Italia. Phone: +39+055-4478138, Fax: +39+055-4379868. E-mail: [email protected] 0344-0338/03/199/12-847 $15.00/0

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Fig. 1. A, B, C: Stem villi with a combination of chorangiomatosis-like vessels (A: HE 10×; B: HE 25×; C: HE 25×) D: In the same case, smaller vessels more similar to chorangiosis are detectable (D: HE 40×).

Fig. 2. A, B: Immunostaining with CD34 confirms the vascular origin of the proliferative process (A, B: CD34 25×). C: Histochemical stain for reticulin reveals a distinct basement membrane in each capillary (C: reticulin, 25×). D: Immunostaining with muscle-specific actin shows the circumferential layer of positive pericytes in terminal villi (D: actin, 40×).

Chorangiosis · 849 Table 1. Clinical Findings Maternal age

Placental weight

Gestational age

Clinical symptoms

Placental features

Case 1

23

180

30 weeks

Maternal eclampsia Stillborn 30 weeks

Placental infarction Hypoplastic villi Fibrinoid necrosis Syncytial knots

Case 2

31

730

38 weeks*

Fetal hydrops Polyhydramnios Healthy baby

Placental infarction Fibrinoid necrosis Chorioamnionitis

Case 3

41

470

36 weeks*

Maternal pre-eclampsia Healthy baby

Hypoplastic villi Fibrinoid necrosis

* Caesarean section

reticulin and by immunocytochemical studies using monoclonal antibodies specific for CD34 (Biogenex, San Ramon, California), CD68 (Dako, Glostrup, Denmark), muscle-specific actin (Dako, Glostrup, Denmark), VEGF (Santa Cruz, California), and PDGF-A and -B (Santa Cruz, California). Immunostaining with CD34 showed uniformly positive endothelial cells, disclosing more capillaries than were discernible by hematoxylin-eosin (Fig. 2). Using reticulin stain, we found that capillaries had a thin basement membrane without surrounding stromal fibrils (Fig. 2), and CD68 immunostaining revealed some positive macrophages (not shown). Staining with actin generally disclosed a continuous layer of positive pericytes surrounding the capillaries (Fig. 2). However, in one section, this feature was accompanied by actin-positive pericytes scattered around the vascular spaces of the lesion. The expressions of VEGF and PDGF in vascular lesions were similar to those noted in normal villi, with low positivity of VEGF and PDGF in the endothelial cells, and a moderate presence of PDGF in trophoblast cells.

Discussion Chorangiosis is an unclear placental alteration: its etiology is unknown, but chronic hypoperfusion or tissutal hypoxemia has been hypothesized [5]. According to this theory, the incidence of chorangiosis is higher in women living in high altitudes: hypoxia may lead to an excessive villous capillary growth and to a high proliferative activity of connective tissue, probably mediated by vascular growth factors. Chorangiosis is detected in maternal pathological conditions such as preeclampsia, diabetes mellitus, drug ingestion, and urinary tract infections, in placental alterations such as single umbilical artery, placental abruptio, amnios nodosum, villitis, and umbilical cord anomalies, or in fetal conditions like major congenital malformations or low Apgar index.

Chorangiosis is diagnosed when a 10× objective shows 10 villi, each with 10 or more vascular channels in 10 or more non-infarcted and non-ischemic zones of at least three different placental areas [1]. Normal chorionic villi contain no more than 5 vascular channels; the criteria for evaluating the severity of this process include the determination of the vessel number within each villus and the placental area throughout which the vasculature is seen [1]. Althuser [1] identified a moderate involvement (grade 1), a moderately severe change (grade 2), and a diffusely severe alteration (grade 3) of placental tissue caused by chorangiosis. Chorangiosis is different from congestion, in which vasculature is numerically normal, and from tissue ischemia with shrinkage of villi. Chorangiosis is an alteration of the terminal villus, characterized by an abnormal growth of fibrous and vascular tissues, with an increased number of capillaries in placental areas. According to some authors, this growth is due to a mild hypoxia, occurring even in high altitudes, in anemic conditions, or in female smokers. In all these events, chorangiosis has been described. However, other studies underline the high pressure in the capillaries, possibly caused by an umbilical or fetal venous obstruction. Actually, an association between chorangiosis and umbilical cord anomalies has been reported [2]. Moreover, a high number of angiogenic factors such as inflammatory cytokines in villitis and an increase in vascular growth factors in patients with diabetes have been hypothesized [6]; this hypothesis might be responsible for the recently underlined increase of chorangiosis in maternal diabetes, in Beckwith-Wiedemann syndrome, where stromal overgrowth and capillary lesions in the villi have been described [3, 4], and in villitis of unknown etiology [6]. It is likely that hypoxia is the first stimulus, or one of various stimuli, that causes growth factors produced by mesenchymal and trophoblastic cells, leading to neoangiogenesis. The implicated growth factors are angio-

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genic growth factors such as VEGF, bFGF, and PDGF. Initiation of angiogenesis depends on vascular endothelial growth factors, while continued capillary growth and development depend on platelet-derived, growth factor-dependent differentiation of pericytes, which produces angiopoietins and control-remodeling of the primary vascular plexus into a mature capillary bed [6]. Moreover, the elevated concentration of PDGF-A and PDGF-B may promote the proliferation of trophoblast. Actually, in some vascular lesions, areas of trophoblast hyperplasia have been described [6]. Occasionally, however, the vascular factors are similar to those seen in the normal villi, while an abnormal trophoblast proliferation is present [4]. In our cases, PDGF and VEGF were almost normal, and no trophoblast hyperplasia was present. Thus, one might hypothesize that the lesion has become stable and that proliferation has stopped. The differential diagnosis between chorangiosis and the other capillary villous lesions, chorangiomatosis and chorangioma, is difficult. Some histological criteria have been reported recently [6]. Chorangioma is a nodular lesion composed entirely of capillary vascular channels, with surrounding trophoblasts; it is analogous to hemangiomas occurring at other body sites. Chorangiomatosis is a more heterogeneous and less well-defined lesion, with intermediate features between chorangioma and chorangiosis. It is differentiated from chorangiosis, because capillaries, although increased, are not confined to terminal villi, but surround larger vessels in the central cores of stem villi. Moreover, while a basement membrane is detectable in each capillary in chorangiosis, bundles of reticulin fibers surround capillaries in chorangiomatosis. Some recent studies have described the presence of dense central cores of cells surrounded by dense reticulin fibers, as well as an increased amount of perivascular pericytes. These features seem to be absent in chorangiosis, where a distinct basement membrane for each capillary is detectable and the loose bundles of reticulin surrounding the capillaries are absent [6]. Our experience has shown that the distinction between chorangiomatosis and chorangiosis is very difficult. The presence of a fibrous central core in the villi is a feature of all mature intermediate villi, while a distinct basement membrane is not always detectable. The histological characteristics of chorangiosis overlap with those of chorangiomatosis. Chorangiomatosis, particularly when multifocal, frequently shows peripheral areas of smaller capillaries that are more typical of chorangiosis. Thus, this possible transition type shows stem villi with a combination of chorangioma-like vessels and smaller vessels similar to chorangiosis. As in chorangioma, the clinical outcome in chorangiomatosis is generally correlated with pre-eclampsia and multiple pregnancy, while chorangiosis is the only capillary placental lesion that has been observed in association with maternal diabetes. In our series, two of

three women were affected by preclampsia, and none of them displayed diabetes. The distribution of vascular placental lesions changes with gestational age compared with normal placentas; chorangioma and focal and segmental chorangiomatosis are overrepresented in the 32th–36th week of gestation, while multifocal chorangiomatosis is present at a gestational age less than 32 weeks. Chorangiosis generally occurs at term, but no increase has been reported to occur at any gestational age. Nevertheless, some authors have reported the absence of chorangiosis in placentas at less than 32 weeks [6]. It might be possible that the typical lesions of terminal villi, usually seen in chorangiosis, are absent in these placentas of earlier gestational age, whereas capillary alterations are evident in the immature villi. Thus, the real difference between chorangiosis and chorangiomatosis, particularly the multifocal subtype, could rest in the age of placental tissue and in the nature of the pathological villi. Chorangiosis has been correlated with increased perinatal morbidity and mortality, with an unclear pathogenetic way [5]. It has been described in 27% of neonatal deaths and in 28% of major malformations [1]. Recent studies have reported an increased frequency of chorangiosis in diabetes and IUGR, while the association between chorangiosis and pre-eclampsia or congenital malformations remains unclear [5, 6]. Fortunately, most cases diagnosed as chorangiosis are focal and represent a marker of mild hypoxia, insignificant for the fetus, while diffuse lesions generally associated with major fetal complicances are rare.

References 1. Altshuler G (1984) Chorangiosis: an important placental sign of neonatal morbidity and mortality. Arch Pathol Lab Med 108: 71–74 2. Benirschke K (1999) Recent trends in chorangiomas, especially those of multiple and recurrent chorangiomas. Pediatr Develop Pathol 2: 264–269 3. Drit R, Drut RM, Toulouse JG (1992) Hepatic hemangioendotheliomas, placental chorangiomas, and dysmorphic kidneys in Beckwith-Wiedemann syndrome. Pediatr Pathol 12: 197–203 4. Guschmann M, Schulz-Bischof K, Vogel M (2003) Incidental chorangiocarcinoma. Case report, immunohistochemistry and theories of possible histogenesis. Pathologe 24 (2): 124–127 5. Jauniax E, Nicolaides KH, Hustin J (1997) Perinatal features associated with placental mesenchymal displasia. Placenta 18: 701–706 6. La Ossa M, Cabello-Inchausti B, Robinson MJ (2001) Placental chorangiosis. Arch Pathol Lab Med 125: 1258 7. Ogino S, Redline RW (2000) Villous capillary lesions of the placenta: distinctions between chorangioma, chorangiomatosis, and chorangiosis. Hum Pathol 31: 945–954 Received: July 16, 2003 Accepted in revised version: November 26, 2003