Abstract

Chorioangiomas are benign angiomas arising from chorionic tissue and they are the most common non-trophoblastic tumors of the placenta, as they are observed in 1% of all placentas examined. Most chorioangiomas are small and asymptomatic, often undetected during a prenatal ultrasound, and their clinical significance is still unknown. Large chorioangiomas, measuring more than 4-5 cm in diameter, can usually be detected prenatally by gray-scale or color Doppler sonography, and may be associated with maternal or fetal complications, such as preeclampsia, maternal mirror syndrome, preterm delivery, nonimmune fetal hydrops, fetal growth restriction and fetal demise. We herein describe the clinical-pathological features of a monocentric series of 30 placental chorioangiomas and discuss their clinical-pathological features and possible molecular mechanisms underlying their development.

Introduction

The human placenta is a disc-shaped, hemochorial organ and is the largest organ of fetal origin 1,2. It regulates the exchanges between maternal and fetal circulations, by allowing the transport of nutrients and oxygen from the mother to the fetus and the removal of waste products from the fetal blood 3,4. It releases hormones that affect pregnancy, maternal metabolism, fetal growth and parturition 2,4. The placenta also acts as a selective barrier, protecting the fetus against xenobiotic molecules and infections. Therefore, proper placental development and function are essential to maintain pregnancy and preserve fetal health and growth. Abnormalities of the placental structure and function can cause fetal growth restriction, spontaneous preterm birth, and intrauterine fetal demise 5,6.

The histopathological examination of the placenta provides crucial information about the nature and cause of some pathological conditions affecting both the fetus and the mother. Placental lesions include a group of fetal-stromal vascular lesions, and a subgroup has been identified within it, defined as villus capillary lesions 5,7, which appear to be caused by excessive angiogenesis 5,8. The villus capillary lesions include chorangiosis, chorangiomatosis, chorioangioma (CA) and multiple CA syndrome 5,9,10. A chorioangioma (CA) is a placental hemangioma and benign vascular tumor 11. It arises from chorionic tissue and is the most common benign non-trophoblastic tumors of the placenta, occurring in 1% of all placentas examined 12. It is observed with a higher incidence in cases of maternal hypertension, diabetes, twin pregnancies and female fetal sex 13.

In most cases, a chorioangioma is small, less than 4 cm in diameter, and asymptomatic. It is generally not considered clinically significant, although its relevance remains unknown 14. A CA measuring more than 4-5 cm in diameter is rare, affecting approximately 1 in 10,000 pregnancies 15, and can be associated with maternal and fetal complications 16-19. Early prenatal diagnosis, close surveillance and appropriate intervention may prevent the severe complications caused by large chorioangiomas 12.

The mechanisms underlying the development of a CA are poorly understood; some studies suggest that the environment for life at higher-altitudes and genetic factors could be involved in the pathogenesis of CA 20,21.

In this study, we describe a series of 30 large and small placental CA with related pregnancy complications, and we discuss their pathological features and the possible molecular mechanisms underlying their development.

Materials and methods

PLACENTAL SAMPLE COLLECTION AND IMMUNOHISTOCHEMICAL ANALYSIS

Thirty cases of histologically confirmed placental solitary CAs diagnosed from 2011 to 2021 were retrospectively selected from the archive of the Section of Pathology, Department of Health Sciences, University of Florence, Italy, after excluding cases of major fetal malformations and twin pregnancies. The indications for referral of placentas for pathological examination were those defined by the SIAPEC/SIGO-AOGOI recommendations 22.

Most CAs examined (27 out of 30) were small and measured less than 1 cm in diameter. Three cases were greater in size and measured between 5.5 and 12 cm in diameter. These three CAs had been detected during prenatal ultrasounds at the Ultrasound Unit of the Department of Obstetrics and Gynecology of Careggi Hospital, where the patients received sonographic follow-up over the course of their pregnancy. The medical records and clinical data of the pregnancy for each case were also reviewed, and the incidence of pregnancy complications was retrospectively evaluated.

Hematoxylin and eosin-stained slides were reviewed, and representative formalin-fixed and paraffin-embedded (FFPE) tissues were selected for additional immunohistochemical analyses. FFPE sections 4 μm in thickness were immunostained with anti-CD34 antibody (Ventana; Roche Tissue Diagnostics, Indianapolis, USA), on a Ventana automated slide stainer.

Results

PREGNANCY CHARACTERISTICS AND OUTCOMES

Clinical information, pregnancy complications and neonatal outcomes of the 30 cases are reported in Table I. The mean maternal age was 36.30 ± 4.75 years, and the mean gestational age at delivery was 36.1 weeks ± 3.40. Overall, we observed a 13.3% incidence of hypertensive pregnancy disorders, a 33% incidence of fetal growth restriction (FGR), and a 10% incidence of preterm premature rupture of the membranes (pPROM). All the cases were live births, but in one case the child died of sepsis at 8 months of age. This was a case of extremely preterm birth due to maternal preeclampsia, and the child developed sepsis in the postnatal period, which was the cause of death. 11/30 neonates (37%) were admitted to the neonatal intensive care unit (Tab. I).

The presence of a large CA did not affect pregnancy outcome in two of the cases, because both mothers and fetuses did not present any specific complication - in particular, no signs of fetal anemia, cardiac failure, hydrops, or intrauterine growth restriction were detected. In one of our cases, fetal anemia was suspected antenatally, and confirmed after birth.

ULTRASOUND CHARACTERISTICS OF THE LARGE CHORIOANGIOMA

Figure 1 shows the sonographic images of case #30, in which the diagnosis of a large CA was made during an antenatal ultrasound. The diagnosis was first suspected at the 20-weeks anatomy scan, which showed a vascularized hypoechoic mass measuring 56x39x36 mm underneath the chorionic plate, near the placental insertion of the umbilical cord. An ultrasound follow-up was performed every two weeks until 27+6 weeks of gestation (Fig. 1B), and the size of the mass remained stable over time. Afterwards, a scan was conducted once a week to detect possible signs of fetal anemia. The size of the mass remained unchanged (Fig. 1C), but signs of fetal anemia were observed at 34+5 weeks of gestation, when the MCA-PSV was 79.01 cm/sec (1.57 MoM, Fig. 1D). Based on the suspicion of fetal anemia and given the gestational age, delivery by C-section was indicated. The diagnosis of anemia was confirmed in the newborn.

HISTOPATHOLOGICAL AND IMMUNOHISTOCHEMICAL ANALYSIS

Tissues were sampled, macroscopically evaluated, and examined by conventional histopathology following the Amsterdam Placental Workshop Consensus Statement 23. Placental weight, funicle insertion and membrane color were recorded. (Tab. II).

Then, for each placenta we submitted a minimum of 4 blocks: one block included a roll of the extraplacental membranes and 2 cross sections of the umbilical cord, the other blocks contained a full-thickness section of normal-appearing placenta parenchyma. If gross lesions were identified, they were described and sampled for histological evaluation.

In the three cases where the chorioangioma was identified macroscopically, it was described and measured, and subsequently, samples were taken for its histological evaluation.

Macroscopically, the three large CAs were described as solid, well circumscribed masses. Histopathological examination showed the presence of placental chorioangioma in all cases. Both small and large chorioangiomas appeared as well-circumscribed vascular proliferations arising in and protruding from large stem villi (Fig. 2). In addition, the following histopathological parameters were evaluated and recorded (Tab. III): funisitis (absent/present), chorioamnionitis (absent/present), infarcts (absent/present), hemorrhage (absent/present), and chorangiosis (absent/present).

All the CAs were identified as solitary lesions. The tumors were composed of numerous predominantly small capillary sized vascular channels decorated by endothelial cells embedded within connective tissue. Endothelial cells did not show signs of cytological atypia or mitotic activity. There was no necrosis. The adjacent villi were normal or slightly enlarged and covered by a trophoblast layer.

Discussion

Placental CA is a benign tumor derived from non-trophoblast cells in the placenta with predominantly vascular involvement 11. The estimated incidence of CA is about 1% in microscopically examined placentas 24.

Most CAs are less than 0.5 cm at their point of greatest dimension and are incidental findings during microscopic evaluation. In contrast, larger lesions can be identified by gross examination of the placenta as single, well-circumscribed, solid, nodular lesions, most often found just below the chorionic plate or at the placental margin 12-25. The color varies from red-brown to tan-white depending on the ratio of the vascular and stromal components.

During the prenatal period, sonography can be used to diagnose a large CA. In most cases, it appears as a hypoechoic mass bulging on the fetal surface of the placenta, underneath the chorionic plate near the umbilical cord insertion. Some studies have described only arterial blood flow within the mass, others have found only venous waveforms, while a few studies have demonstrated both arterial and venous waveforms 26. A large CA may have clinical implications, as it can be associated with maternal or fetal complications including fetal growth restriction, polyhydramnios, fetal hydrops, preeclampsia, maternal mirror syndrome, preterm delivery and fetal demise 16-19,27-29. No data in the literature has correlated the presence of a CA with the occurrence of pPROM. These pathological conditions are associated with poor pregnancy outcomes.

Because of the lack of a control group in our case series, we could not evaluate if the presence of a subcentimetric CA is associated with adverse maternal, fetal and neonatal outcomes related to placental dysfunction. We chose to not include normal placentas as controls because the placentas sent to the Pathology Service, including those used in this study, come from pregnancies that had pathological conditions, during the course of the pregnancy or at the time of birth, requiring placental histological analysis (such as intrauterine growth restriction, preeclampsia, suspicion of intraamniotic infection). Therefore, comparing outcomes of our selected cases with those of placentas from normal pregnancies would have led to a selection bias. Although we have reported the outcomes of pregnancy for the cases studied, the main aim of the study was to describe the diagnosis and histological characteristics of placental chorioangiomas.

Chorangiosis, multifocal chorangiomatosis, and CA are three histological entities characterized by excessive vascularity in the placental villi, and the diagnosis of CA must be differentiated from these other villus capillary lesions, as they share overlapping similarities with CA, and similar clinical implications 30. The exact causes of these villus capillary lesions are poorly understood but they probably involve abnormal angiogenesis 31-33.

Chorangiosis is characterised by an increase in the number of capillary cross sections per villus and is defined as 10 or more villi containing 10 or more capillary cross sections in different regions of the placenta 34. Chorangiosis is the most common of these three lesions 30,35. Histopathologically, capillaries in villus chorangiosis are lined by a single layer of endothelium, a continuous basement membrane and lack surrounding pericytes. This lesion can involve the entire placenta but most commonly has a patchy distribution. Immunohistochemistry does not play a central role in the diagnosis as CD31 and CD34 may overestimate the density of the capillaries 30,35. Generally, CD31 and CD34 are also not required for the diagnosis of CA, but they can be helpful in highlighting endothelial cells 11.

Multifocal chorangiomatosis is characterized by small anastomosing capillaries affecting immature intermediate and small stem villi. Unlike chorangiosis, capillaries in this lesion lack a continuous basement membrane 36.

CA also need to be differentiated from multiple chorioangioma syndrome, a rare phenomenon characterized by the presence of multiple vascular tumors, from small and early lesions to well-developed chorioangiomas 37.

This syndrome has similar adverse maternal and fetal outcomes as the ones described in large chorioangiomas 38.

Furthermore, CA needs to be distinguished from choriocarcinoma, a trophoblastic malignant lesion. This is a very rare tumor characterized by abnormal trophoblastic proliferation associated with a hypervascular chorangiosis, nuclear atypia, large areas of necrosis and high mitotic activity 39,40. A high proliferative rate (> 90%) detected by Ki-67/MIB-1 is generally observed.

Histopathologically, CA and chorangiomatosis are distinguished from chorangiosis by the presence of capillary-vascular spaces, that are surrounded by a continuous layer of muscle specific actin (MSA)-positive pericytes and by a high stromal collagenization and cellularity, which increase the spacing of the capillary vascular channels 11,30.

Endothelial cells are positively stained for both CD31 and CD34 in CA, chorangiosis and chorangiomatosis, while macrophages are rarely found 11.

The villi with chorangiosis show structural features similar to the normal terminal villi, including uniformly CD31/34-positive endothelium and a thin, well-circumscribed basement membrane. The lack of Ki-67 positive cells suggests that capillaries in chorangiosis are not in a phase of active endothelial proliferation. The number of smooth muscle actin-positive pericytes is slightly higher compared to the normal villi but does not form the continuous perivascular layer observed in cases of CA and chorangiomatosis 11.

The molecular mechanisms underlying the development of a CA are still poorly understood. Indeed, few data are available on genetic analysis and on protein expression of CAs 8,11,21,41. Changes in gene expression levels between recurrent multiple chorioangioma and normal placenta using angiogenesis tissue array were evaluated by Gallot et al. The authors demonstrated that the transforming growth factor receptor 3 (TGFR3), epidermal growth factor receptor (EGFR), Integrin-V (ITG5), tyrosine kinase VEGF receptor 2 (FLK1) and the tissue inhibitor of metalloproteinase 2 (TIMP2) are lower, whereas the angiotensin 2 (ANGPT2) and osteopontin (SPP1) are higher in recurrent multiple chorioangioma compared to the normal placenta 8. Sirtotikna et al. 21, investigated the deletions and duplications in the CA genome using an array comparative genomic hybridization method. Their analyses did not reveal any rare or novel structural change involving gain or loss of genetic material in the CA samples compared with either standard control DNA or unaffected placenta DNA.

Conclusion

During the prenatal period, ultrasound can be used to diagnose a large CA, which may have clinical implications as it may be associated with adverse maternal or fetal outcomes. On the other hand, a subcentimeter CA might not be evident in ultrasound scans, but only be detected through placental histologic examination. It is unknown if a small CA can cause adverse maternal, fetal, or neonatal outcomes, and further study including larger cohorts and control groups should investigate the association with placental-related complications.

The genetic basis and the protein expression of CAs is an open field of investigation and, for this reason, further molecular studies are desirable. In particular, future research should aim to better characterize the molecular mechanisms underlying the CA. The analysis of our case series involved both the clinician and the pathologist. Multidisciplinarity is an essential aspect of studies on the placenta, as it allows the evaluation of the morpho-phenotypic profile in relation to clinical outcomes.

CONFLICT OF INTEREST STATEMENT

The authors declare that there is no conflict of interest.

FUNDING

The research reported in this publication was supported by Fondazione CRF Firenze Grant number B15F21003630007.

AUTHORS’ CONTRIBUTION

Conceptualization: EN, FC; Data acquisition: AS, IA, EN, EO; Writing: EN, AS, IA; Funding acquisition: DM; Supervision: FC, VS, MDT, DM; Review: FC, VS, MDT, DM.

ETHICAL CONSIDERATION

The present study complied with the Ethical Principles for Medical Research Involving Human Subjects according to the World Medical Association Declaration of Helsinki; all samples were anonymized before histology and immunohistochemistry; no futher ethical approval was necessary to perform the retrospective study.

History

Received: April 1, 2024

Accepted: August 31, 2024

Figures and tables

Figure 1. Sonographic features of a large chorioangioma. (A) 25+3 weeks: color Doppler flow imaging demonstrates large vascular channels within the tumor; (B) Size of the mass at 27+ 6 weeks; (C) Size of the mass at 34+5 weeks. (D) Pulsed-wave Doppler of the middle cerebral artery demonstrating increased peak systolic velocity.

Figure 2. Histopathology of small placental chorioangioma. (A, B, C and E) Representative H&E images of well-demarcated solitary tumor mass within placental parenchyma. The tumor is composed of a capillary vascular proliferation decorated by cytologically bland endothelial cells. (D, F). Immunohistochemical stain of anti-CD34 in small placental chorioangioma shows strong positivity in endothelial cells. (A-B) magnification x3, inset x7; (C, D) magnification 0.5;(E, F) magnification x2.

Case Maternal age (years) Gestational weeks at delivery Baby weight/Sex Indications for referral of placenta Pregnancy complications Neonatal complications
1 27 39+5 2900 g/F FGR FRG -
2 41 37+1 2400 g/F Small for gestational age newborn - Small for gestational age
3 40 38+3 2500 g/M Small for gestational age newborn Intrahepatic cholestasis of pregnancy Small for gestational age
4 31 39+4 3340 g/M Suspected intraamniotic infection Maternal intrapartum fever, purulent cervical drainage Admission to NICU
5 32 33+1 1440 g/M Small for gestational age newborn Gestational hypertension, FGR, iatrogenic preterm delivery Low birth weight due to preterm birth Admission to NICU Small for gestational age newborn
6 37 37+5 2350 g/M Small for gestational age newborn Preeclampsia Preeclampsia, FGR Admission to NICU Low birth-weight Small for gestational age
7 33 30+0 715 g /F Small for gestational age newborn Very preterm birth Gestational diabetes, FGR, iatrogenic preterm delivery Admission to NICU Small for gestational age Low birth-weight due to preterm birth. Lost at follow-up due to transfer to a different hospital
8 43 37+2 2510 g/F Preeclampsia Preeclampsia None
9 42 32+3 2230 g/M pPROM, pPROM, preterm delivery Admission to NICU Low birth-weight due to preterm birth
10 38 40+2 3350 g/F Suspected intraamniotic infection Gestational diabetes Maternal intrapartum fever, fetal tachycardia Admission to NICU
11 36 32+6 1720 g/M pPROM, Small for gestationa age newborn pPROM, preterm delivery Admission to NICU Small for gestational age Low birth-weight due to preterm birth
12 34 26+5 750 g/M pPROM, Small for gestational age newborn Very preterm birth pPROM, FGR, iatrogenic preterm delivery Admission to NICU Small for gestational age newborn Low birth-weight due to preterm birth
13 37 37+1 2910 g/F Suspected intraamniotc infection Maternal intrapartum fever, fetal tachycardia Admission to NICU Neonatal jaundice
14 37 39+1 2410 g/M Small fo gestationa age newborn Oligohydramnios Low birth-weight Small for gestational age
15 28 36+6 2010 g/F Small for gestational age newborn FGR, iatrogenic preterm delivery Admission to NICU Low birth-weight Small for gestational age
16 35 37+0 2150 g/M Small for gestational age newborn - Admission to NICU Low birth-weight Small for gestational age; neonatal jaundice
17 26 38+3 2310 g/F Small for gestational age newborn Gestational diabetes, FGR Low birth-weight Small for gestational age
18 43 39+1 3710 g/M Suspected intraamniotic infection Maternal intrapartum fever, purulent cervical drainage Neonatal jaundice
19 41 38+5 2720 g/F Cord pH ≤ 7.05 - Admission to NICU Cord pH ≤ 7.05 Neonatal jaundice
20 35 40+4 2860 g/F Small for gestational age newborn Symptomatic COVID infection during delivery Small for gestational age
21 43 37+0 2600 g/F Cord arterial pH ≤ 7.05 Placenta previa Placenta accreta spectrum Admission to NICU Cord arterial pH ≤ 7.05 Neonatal jaundice, neonatal weight loss
22 40 27+6 900 g/F Small for gestation age newborn Extremely preterm birth Intrahepatic cholestasis of pregnancy; iatrogenic preterm delivery Admission to NICU Small for gestational age Low birth-weight due to preterm birth Respiratory distress Anemia Bronchodysplasia
23 37 37+4 2180 g/F Small for gestational age newborn FGR Low birth-weight Small for gestational age
24 38 40+3 2852 g/F Small for gestational age newborn Cord arterial pH ≤ 7.05 Gestational diabetes Admission to NICU Small for gestational age
25 31 27+1 580 g/F Small for gestational age newborn Extremely preterm birth Preeclampsia Gestational diabetes, preeclampsia, iatrogenic preterm delivery Admission to NICU Admission to NICU Low birth-weight due to preterm birth Small for gestational age Premature birth complications and postnatal death at 8 months of age due to sepsis
26 36 37+3 1930 g/F Small for gestational age newborn FGR, oligohydramnios Low birth-weight Small for gestational age
27 34 39+5 2220 g/M Small for gestational age newborn PROM; FGR Low birth-weight Small for gestational age
28* 41 34+1 2140 g/F Prenatal diagnosis of large chorioangioma Intrahepatic cholestasis of pregnancy, iatrogenic preterm delivery Low birth-weight due to preterm birth
29* 33 38+6 3560 g/F Prenatal diagnosis of large chorioangioma Prenatal diagnosis of large chorioangioma None
30* 40 34+6 2360 g/F Prenatal diagnosis of large chorioangioma Iatrogenic preterm delivery Admission to NICU Low birth-weight due to preterm birth Neonatal anemia
F: female; M: male; FGR: fetal growth restriction; (p)PROM: (preterm) premature rupture of the membranes; * These cases had a prenatal diagnosis of large chorioangioma.
Table I. Clinical information, pregnancy complications and neonatal outcome of placental chorioangioma (n = 30).
Number of cases (%)
Weight 9 (33.3%)
≤ 350 g 18 (66.7%)
> 350 g
Funicle insertion
Eccentric 18 (66.6%)
Marginal 7 (26.0%)
Velamentous 2 (7.4%)
Membrane color
Shiny transparent 21 (75.0%)
Opaque 4 (14.3%)
Yellowish 3 (10.7%)
Table II. Macroscopic placental examination.
Number of cases (%)
Funisitis
- Absent 28 (93.3%)
- Present 2 (6.7%)
Chorioamnionitis
- Absent 25 (83.3%)
- Present 5 (16.7%)
Infarcts
- Absent 20 (66.7%)
- Present 10 (33.3%)
Hemorrhages
- Absent 27 (90%)
- Present 3 (10%)
Chorangiosis
- Absent 25 (83.3%)
- Present 5 (16.7%)
Table III. Microscopic placental examination.

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Authors

Eleonora Nardi - Department of Health Sciences, Section of Pathology, University of Florence, Florence, Italy; *These authors equally contributed to this work

Angela Silvano - Department of Health Sciences, Division of Obstetrics and Gynecology, Careggi Hospital, University of Florence, Florence Italy; *These authors equally contributed to this work

Francesca Castiglione - Department of Health Sciences, Section of Pathology, University of Florence, Florence, Italy

Erika Olivo - Department of Health Sciences, Section of Pathology, University of Florence, Florence, Italy

Isabella Abati - Department of Health Sciences, Division of Obstetrics and Gynecology, Careggi Hospital, University of Florence, Florence, Italy

Daniela Massi - Department of Health Sciences, Section of Pathology, University of Florence, Florence, Italy

Viola Seravalli - Department of Health Sciences, Division of Obstetrics and Gynecology, Careggi Hospital, University of Florence, Florence Italy; *These authors equally contributed to this work

Mariarosaria Di Tommaso - Department of Health Sciences, Division of Obstetrics and Gynecology, Careggi Hospital, University of Florence, Florence Italy; *These authors equally contributed to this work

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Copyright (c) 2024 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology

How to Cite
Nardi, E., Silvano, A., Castiglione, F., Olivo, E., Abati, I., Massi, D., Seravalli, V., & Di Tommaso, M. (2024). A case series of chorioangiomas in placentas with clinical indication for histological examination. Pathologica - Journal of the Italian Society of Anatomic Pathology and Diagnostic Cytopathology, 116(4), 258–266. https://doi.org/10.32074/1591-951X-1003
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