Pediatric and Developmental Pathology 18, 410–415, 2015 DOI: 10.2350/14-11-1570-CR.1 ª 2015 Society for Pediatric Pathology

Chorangioendothelioma of the Placenta: A Myth or Reality? SUNIL JAIMAN,1* EVITA FERNANDEZ,2

AND

SIRISHA RAO GUNDABATTULA3

1 Department of Anatomic and Perinatal Pathology and Cytology, Fernandez Hospital Unit 3, Plot 769, Road No. 44, Jubilee Hills, Hyderabad – 500033, India 2 Department of Obstetrics, Fernandez Hospital Unit 3, Plot 769, Road No. 44, Jubilee Hills, Hyderabad – 500033, India 3 Department of Gynaecology, Fernandez Hospital Unit 3, Plot 769, Road No. 44, Jubilee Hills, Hyderabad – 500033, India

Received November 7, 2014; accepted April 22, 2015; published online April 23, 2015.

ABSTRACT Chorangiomas of the placenta are often discovered incidentally and, although they are not common (1 in 9000 to 1 in 50 000 placentas), these tumors may be found in 0.5% to 1% of carefully examined placentas. The vast majority are of no clinical importance and complications are seen only in association with tumors measuring more than 4 cm in diameter. In contrast, hemangioendotheliomas are vascular tumors with varying grades of malignant potential and hardly ever involve the placenta. Here we describe a large placental chorangioma causing fetal hydrops and demonstrating distinctive intravascular luminal endothelial proliferation and tufting. To the best of our knowledge, this is probably only the second case of a placental hemangioendothelioma reported in the literature. Key words: chorangioendothelioma, chorangioma, hemangioendothelioma, hydrops fetalis, placental tumor, vascular lesion

INTRODUCTION Chorangioma is a hemangioma of the placenta and is usually discovered serendipitously. The incidence of chorangiomas is reported to be 1 in 9000 to 1 in 50 000 placentas [1], and they usually present as solitary nodules on the fetal surface of the placenta. The clinical significance is related to the size of the tumor; those larger than 4 cm may be associated with maternal complications such as polyhydramnios, diabetes, and hypertension, as well as fetal complications such as hydrops [2–4]. Hemangioendotheliomas, on the other hand, rarely involve the placenta and demonstrate a propensity to present in the lungs, liver, and musculoskeletal system [5]. They are vascular neoplasms that show a borderline *Corresponding author, e-mail: [email protected], [email protected]

biological behavior intermediate between entirely benign hemangiomas and highly malignant angiosarcomas. A chorangioma with concomitant intravascular endothelial proliferation is a seldom described lesion, with only 1 case report of multifocal hemangioendotheliomas of the fetus and placenta [6] retrievable on PubMed search. The authors describe a lesion confined to the placenta without fetal involvement and attempt to denominate this as “chorangioendothelioma.”

CASE REPORT A 28-year-old sixth gravida with 5 pregnancy losses (3 miscarriages and 2 ectopic pregnancies) was diagnosed with diabetes mellitus at 10 weeks of gestation and treated with insulin in addition to aspirin, heparin, estradiol, and progesterone supplements. There was no consanguinity, karyotype was normal, and her blood group was B positive. The pregnancy was complicated by premature rupture of membranes at 14 weeks and managed conservatively. Ultrasonography at 21 weeks demonstrated mild pericardial effusion and a 47- 3 37-mm placental chorangioma. A follow-up scan 2 weeks later revealed fetal hydrops, cardiomegaly, moderate pericardial effusion, significant diastolic dysfunction, and dilated umbilical vein. The patient underwent termination of the pregnancy at 24 weeks of gestation and delivered a 727.1 g (94th percentile) stillborn female fetus, which was submitted for postmortem examination along with the placenta. The autopsy was conducted using a combination of Virchow’s and Rokitansky’s techniques (in situ dissection of individual organs). The baby was cyanosed and hydropic. There were no hemangiomas of the skin or soft tissues; nor was there any evidence of thrombocytopenia or intravascular coagulation to suggest Kasabach-Merritt syndrome. The heart weighed 8.5 g (99th percentile) versus the mean of 4.1 g for gestational age, confirming cardiomegaly. The cardiac findings were a consequence of the arteriovenous shunt, which caused a strain on the circulation, and there were no histologic features of cardiomyopathy. The lungs weighed 7.3 g (6th percentile), in comparison to the

Figure 1. A. Fetal surface of placenta. B. Maternal surface of placenta. C. Cut section of chorangioma.

gestational average of 14.4 g, and the lung weight/body weight ratio was 0.010 (a ratio ,0.015 is indicative of pulmonary hypoplasia before 28 weeks of gestation). Other notable features included a high arched palate; ascites; hepatosplenomegaly; distended umbilical vein, inferior vena cava, and renal veins; and pericardial effusion (4.5 mL). The placenta (17.5 3 13.5 3 3.0 cm; 576.9 g fixed and trimmed; 10th and 90th weight percentiles for

gestational age are 145 and 233 g, respectively) had normal fetal (Fig. 1A) and maternal (Fig. 1B) surfaces and demonstrated a large chorangioma (8 cm in diameter, 142.2 g) at the margin of the disk. The cut surface of the tumor (Fig. 1C) was fleshy and tan-brown with interspersed dilated vascular channels. Three sections from the cord, 2 sections from the membranes, 7 sections from the placental parenchyma (a standard practice at the

Figure 2. Microscopic images of placenta stained with hematoxylin and eosin. A,B. Immature intermediate villi with increased vascularity (3100). C–H. Chorangioma with intravascular proliferation and tufting conspicuous in magnification 3200 and 3400 (C: 320; D,E: 340; F: 3100; G: 3200; H: 3400). I. Mitotic figure indicated by the arrow (3400). A color version of this figure is available online.

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Figure 3. Immunohistochemistry of chorangioma. A,B. CD 34 positivity (3100 and 3200). C,D. CD 31 positivity (3200 and 3400). E. Low Ki-67 proliferation index. F. GLUT1 positivity. A color version of this figure is available online.

institute), and, in view of the unusually large chorangioma, an additional 10 sections from the tumor were submitted. Paraffin-embedded 4-mm tissue sections stained with hematoxylin and eosin were examined microscopically. The placenta displayed a predominance of mature intermediate villi, stromal edema, and conspicuous Hofbauer cells. Interspersed were vast expanses of

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immature intermediate villi with increased capillaries that appeared abnormal for the gestational age and involved more than 5 contiguous villous cross sections, simulating chorangiomatosis (Fig. 2A,B). There was no evidence of extramedullary hematopoiesis in the chorionic villi. Chorangioma sections demonstrated a striking presence of intravascular luminal tufting of endothelial cells

Table 1.

Vascular tumors and malformations [7–11]

Characteristic

Vascular tumor

Vascular malformation

Definition

Overgrowth of normal vessels, which show increased endothelial proliferation (expansion by hyperplasia)

Common types

Infantile hemangioma, congenital hemangioma, tufted angioma, kaposiform hemangioendothelioma

Clinical course

Infantile hemangiomas appear 2 to 3 weeks after birth, grow rapidly over the next 6 months, and then involute by 9 to 10 years of age Congenital hemangiomas are present and fully developed at birth; some involute rapidly during the first year of life, whereas others are noninvoluting

Proposed theories of pathogenesis

N

Cluster of deformed vessels caused by an error in vascular development (expansion by hypertrophy) Divided into subtypes based on the constituent vessels: capillary, venous, arterial, lymphatic, and combined forms Usually present from birth, grow proportionately with the child, never regress, and persist throughout life Capillary and lymphatic: usually evident at birth or within the first year of life Venous: appear any time between birth and early adulthood Arterial and arteriovenous: often appear at puberty or during pregnancy N Dysmorphogenesis caused by sporadic mutations N Significant role for angiogenesis N Familial hereditary component N Defective autonomic innervation or neuroreceptor deficit N Abnormal, often combined, capillary, arterial, venous, and lymphatic vascular elements N Normal ultrastructural characteristics N Arteries and arterioles are an integral part; nerve bundles consistently present No GLUT1 immunoreactivity

N N

Histology

GLUT1

Originate from endothelial progenitor cells (CD133+) that proliferate under hypoxic conditions Perturbation of angiogenic factors Estrogen signaling may play a role

N

Endothelial hyperplasia in proliferative phase; fibrosis and fat deposition in involution phase N Ultrastructural increase in fibronectin, perlecan, and laminin in the extracellular matrix N Arteries and arterioles are not part of the lesion; nerve bundles absent Specific for juvenile hemangioma

(Fig. 2C–H). The mitotic activity was 4–5/10 high-power fields (Fig. 2I) with occasional atypical cells. Immunohistochemistry for the markers CD31, CD34, Ki-67 (Dako Corp, Carpinteria, CA, USA), and GLUT1 (PathnSitu, Livermore, CA, USA) was performed in accordance with the recommendations of the manufacturers. The endothelial cells showed CD34 (Fig. 3A,B) and CD31 positivity (Fig. 3C,D), a low Ki-67 proliferation index (Fig. 3E), and GLUT1 positivity (Fig. 3F).

DISCUSSION Vascular anomalies are congenital lesions of abnormal vascular development. They are classified into vascular tumors and vascular malformations. Vascular tumors represent neoplastic proliferations of normal blood vessels that are apparent at birth or within the first few weeks of life; many of these involute with time. Conversely, vascular malformations are clusters of abnormal vessels that are usually present at birth but may also manifest later in life and do not regress with time. Histologically, the former demonstrate endothelial hyperplasia, whereas the latter are congregations of abnormal (often combined) capillary, arterial, venous, and lymphatic vascular elements (Table 1) [7–11]. It remains unresolved whether chorangiomas are hemangiomas or hamartomas. The occurrence of hemangiomas with unusual frequency in

pregnancies at high altitude, in relatively poorly perfused marginal and subchorial locations within the placenta, and in women with preeclampsia suggests that they may be part of a spectrum of hypoxia-induced vascular proliferation [12,13]. A contrasting view that the placental hemangioma could be a true neoplasm is supported by the occasional presence of mitotic figures and frequent evidence of disproportionate growth between the angioma and the rest of the placenta [4]. Finally, the recurrence of chorangiomas in subsequent pregnancies and the coexistence of placental chorangioma with hemangiomas in other fetal organs allude to a possible genetic predisposition in their pathogenesis [12]. In our case, the presence of mitotic figures, endothelial proliferation within the chorangioma, and GLUT1 positivity favor a neoplastic origin of this lesion. The vast majority of placental hemangiomas are of no clinical importance; complications are only found in association with tumors measuring more than 4 cm in diameter [2]. Polyhydramnios may complicate 16% to 33% of cases. The overall perinatal mortality is only minimally increased and occurs in those rare cases in which a large tumor, multiple tumors, or diffuse hemangiomatosis is present in the placenta. Fetal demise has been attributed to hypoxia caused by the shunting of fetal blood through the physiological dead space of the tumor, thus allowing it to bypass the functioning placental

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Table 2.

Villous capillary lesions of the placenta [13]

Characteristic

Chorangioma

Chorangiomatosis

Chorangiosis

Definition

Benign neoplastic proliferation of capillaries and stroma forming an expansile nodular lesion

Diffuse increase in the number of villous capillaries

Placental histology

N

Lesion characterized by increase in villous capillaries that permeates normal stem villi; nonexpansile, nonnodular N Histologic characteristics overlap with chorangioma involving normal stem villi N Continuous perivascular layer of muscle-specific actin-positive pericytes and loose bundles of perivascular reticulin fibres that merge with the surrounding stroma N Central core of vimentin-positive cells surrounded by dense reticulin fibers in some villi

N

N

Capillary vascular channels, intervening stromal cells and surrounding trophoblast Continuous perivascular layer of muscle-specific actin-positive pericytes and loose bundles of perivascular reticulin fibers that merge with the surrounding stroma Nonspecific mild to moderate trophoblast hyperplasia in 50% of cases

Location

Most commonly subchorionic and marginal (poorly perfused areas); seen most commonly as bulging protuberances on the fetal surface of the intact placenta

Prevalence

0.5%, common at 32 to 36 weeks

Proposed pathogenesis

N

Other placental pathology

Prenatal complications

Originates in the relatively hypoxic subtrophoblastic reticular connective tissue of stem villi N Reports of recurrence of multiple chorangiomas raises the possibility of a genetic factor Absent

Preeclampsia, multiple gestation, premature delivery at 32–36 weeks, polyhydramnios, hydrops fetalis, disseminated intravascular coagulation

N

Focal: single area of 1 to 5 villous cross sections N Segmental:.5 contiguous villous cross sections N Diffuse multifocal: multiple independent areas of the placenta N 0.5%, common at 32 to 36 weeks N Diffuse multifocal (0.2%) common at ,32 weeks N Localized type originates in the reticular connective tissue of stem villi N Diffuse multifocal type may be the result of a primary abnormality affecting normal villous stromalvascular development Delayed villous maturation, placentomegaly, multiple foci of avascular villi in the diffuse multifocal form N Preeclampsia, multiple gestation, premature delivery at 32–36 weeks N Diffuse multifocal variant associated with prematurity ,32 weeks, congenital malformations, fetal growth restriction

tissue and be returned to the fetus in an oxygen-depleted state, resulting in high-output cardiac failure. The newborn infant is subject to further complications, usually of a transitory nature, such as cardiomegaly, anemia, and thrombocytopenia [4]. Chorangioma must be differentiated from other villous capillary lesions, namely, chorangiomatosis and chorangiosis. Whereas chorangioma is a benign placental vascular tumor with endothelial proliferation forming an expansile nodular lesion, chorangiomatosis is a nonexpansile, nonnodular lesion consisting of increased villous capillaries permeating normal stem villi and chorangiosis is characterized by a diffuse increase in the number of terminal villous capillaries (Table 2).

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10 villi, each with 10 vascular channels in 10 noninfarcted and nonischemic zones of at least 3 different placental areas (Altshuler criteria) N Vessels lack a continuous perivascular pericytic cell layer and have wellcircumscribed, thin basement membranes without surrounding stromal fibrils Confined to terminal villi with sparing of stem villi N

5.5% to 7%, common at term

Aberrant terminal villous growth pattern is possibly triggered by excessive growth factors, low-level hypoxia, increased capillary pressure or excess cytokines Delayed villous maturation, placentomegaly, villitis of unknown etiology Maternal diabetes, stillbirths

In contrast to benign hemangiomas, hemangioendotheliomas demonstrate borderline biological behavior. Most hemangioendotheliomas are low-grade vascular neoplasms with a tendency to recur locally and exhibit a low metastatic potential. Their histologic variants include epithelioid hemangioendothelioma, kaposiform hemangioendothelioma, papillary intralymphatic angioendothelioma, pseudomyogenic hemangioendothelioma, retiform hemangioendothelioma, and composite hemangioendothelioma [14]. The tumor encountered by us was a large welldelineated chorangioma with intraluminal endothelial proliferation reminiscent of Dabska tumor (papillary intralymphatic angioendothelioma), albeit with low mitotic

activity. The only other reported case of a placental hemangioendothelioma dates back to 1997, when Marton and coworkers [6] described multifocal hemangioendotheliomas of the fetus (liver, adrenal gland) and placenta consistent with infantile hemangioendothelioma type 2. They proposed that, although multifocal development was the most obvious explanation for the disease, placenta was the most likely primary site [6]. Atypical cellular chorangioma, reported by Majlessi and colleagues [15], demonstrated histologic features suggestive of sarcoma and stained positive for factor VIII antigen, but it lacked evidence of invasion and biologic aggressiveness. Their case did not exhibit any features to suggest hemangioendothelioma [15]. Our case differed significantly from both aforementioned lesions in that it was solitary and confined to the placenta and did not demonstrate histologic features mimicking a sarcoma. Despite the fact that our case demonstrated a mitotic activity of 4–5/10 high-power fields (and low Ki-67 index), it is not known whether this tumor had the potential to metastasize and manifest as a multifocal hemangioendothelioma had the pregnancy continued. Finally, the perplexing association of diabetes with our lesion stands in stark contrast to the earlier observations, which demonstrated a complete absence of diabetes in patients with chorangioma [12,13]. Although 1 case report does not form a paradigm, we conclude that chorangioendothelioma may not be a myth after all. ACKNOWLEDGMENTS The authors are deeply indebted to the staff of the Department of Anatomic and Perinatal Pathology and Cytology and to Mr V. Srinivas for their help in the preparation of this manuscript.

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Chorangioendothelioma of the Placenta: A Myth or Reality?

Chorangiomas of the placenta are often discovered incidentally and, although they are not common (1 in 9000 to 1 in 50 000 placentas), these tumors ma...
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