24 Benign Tumors and Chorangiosis

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24

Benign Tumors and Chorangiosis

863

Angiomas

With rare exceptions, vascular tumors are the only benign tumors of the placenta. Tumors designated chorioangiomas, chorangiomas, ﬁbroangiomyxomas, ﬁbromas, and the many other names that have been applied in the past are essentially similar, relatively common neoplasms of the placenta. Three large reviews have been published that bring together most of the literature. DeCosta et al.

(1956) found about 250 case reports and listed all the synonyms applied previously. They also made reference to the frequency of hydramnios and associated fetal angiomas. Fox (1967), who also reviewed the often confusing nomenclature, indicated that Clarke described the ﬁrst such tumor in 1798. Since then, the review by Siddall (1924) encompassed 130 cases, that by Marchetti (1939) comprised 209 cases, and Fox traced another 127 cases.

Fox accounted for 344 published cases and gave incidence ﬁgures of 1 in 9000 to 1 in 50,000 placentas. When careful study of placentas is undertaken, the real preva- lence may be as high as 1 in 100 pregnancies, according to some authors, although in our experience this number is somewhat excessive. Wallenburg (1971) provided 13 new cases and summarized publications between 1939 and 1970. His reported incidence in consecutively col- lected placentas was 1 in 117. These authors provided an extensive literature documentation that would be redun- dant to repeat. Bashiri et al. (2002) found a signiﬁcant risk of preterm delivery in patients with chorangiomas.

Soma et al. (1991) found that the tumor existed in 0.2%

of placentas in Japanese women but was more common (2.5–7.6%) in the high-altitude population of Nepal (Soma, 2001). This is similar to the higher frequency of chorioangioma observed in placentas of women living at altitude by Reshetnikova et al. (1996). We have seen chorioangiomas associated with chronic vascular thrombi and elevated nucleated red blood cells (NRBCs) in the fetal circulation. Thus, an hypoxic stimulus is inferred to lead to excessive villous capillary proliferative stimula-

tion. Although still speculative, such angiogenesis may well be regulated by such vascular growth factors as demonstrated to occur in the placenta by Jackson et al. (1994).

A more detailed consideration of the placental villous adaptation to hypoxia can be found in the contribution by Kaufmann et al. (1993), and Kadyrov et al. (1998) provided information on how anemic women produce increased placental angiogenesis in early development.

The control of angiogenesis is complex, but it is an essen- tial aspect of placentation and regulation during anemia, preeclampsia, and other pathologic states in pregnancy.

There are numerous factors now being explored and many have significant impact on the villous vasculariza- tion. A detailed review was provided by Sherer and Abulafia (2001) that is too complex, however, for the brief consideration possible in this chapter. Guschmann (2002, 2003) and his colleagues in Berlin (Guschmann et al., 2003a) have described various angiogenesis factors in chorangiomas. It was their experience that high expression of angiopoietin-1 and -2 and their receptors was demonstrated in chorangiomas, whereas vascular endothelial growth factor (VEGF) was uniform with the normal villi, but variability existed. Further remarkable in their series was that 72% of accompanying babies were of female gender, and tumors occurred much more commonly in the first pregnancy. North et al. (2001) studied immunoreactivity for a variety of antigens in chorangiomas and juvenile angiomas. Thus, FcgammaRII, Lewis Y antigen, merosin, and glucose transporter-1 (GLUT1) were found to be highly expressed in the small placental vessels and angiomas, but not in control blood vessels or those of granulomas etc.

The typical chorioangioma is composed of fetal blood vessels that are usually supported by only scant connec- tive tissue. The tumors often bulge on the fetal surface of the placenta (Fig. 24.1). When they are embedded in the villous tissue, they are located closer to the fetal surface (Fig. 24.2). The vessels comprising this tumor may be capillary or sinusoidal (Fig. 24.3). Frequently, the stromal

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Figure 24.1. Typical chorioangioma (left), bulging on the fetal surface. Fetus and pregnancy were normal; there is slight circumvallation of the placenta at right.

Figure 24.2. Partially infarcted 1-cm chorioangioma under- neath the chorionic surface of an otherwise normal, mature placenta. It had a golden-yellow appearance and could easily have been mistaken for an infarct.

tumors often have degenerative changes, calciﬁcation, infarcts, and thromboses, which may leave hemosiderin behind (Dunn, 1959). At times, thrombosis and infarction are clinically manifest with cessation of maternal symp- tomatology, such as the frequent hydramnios that is associated with these lesions. Chazotte et al. (1990) observed such a lesion sonographically in a fetus that also had meconium peritonitis; when the chorangioma shrank there was some improvement of the hydramnios. The 5- cm chorangioma in the 620-g placenta had focal infarcts.

Hsieh and Soong (1992) challenged this report and presented a larger lesion with hydrops. It is now also possible to laser-fulgurate the vessels that supply symptom- atic chorioangiomas and thus treat the hydrops fetalis at component is abundant, and the lesion resembles a

ﬁbroma (Fig. 24.4). When Wharton’s jelly–like material participates in the formation of the tumor, the appearance is that of a myxomatous neoplasm. The latter is particularly frequent when a chorioangioma arises near the base of the umbilical cord (see Chapter 12, Figs. 12.68 and 12.69). In such cases, a mucicarmine stain reveals the presence of mucus (Dunn, 1959). Chorioangiomas are invariably covered by trophoblast; one may envisage them to be the proliferation of fetal capillaries of a villus whose surface thus expands (Figs. 24.5 and 24.6). Ogino and Redline (2000) suggest that chorangiomas derive speciﬁcally from stem villi rather than terminal villi. The

Figure 24.3. Multiple chorioangiomas in mature placenta, some of capillary type and others of more cavernous type. H&E

¥50.

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Figure 24.4. Chorioangioma with primarily ﬁbromatous appearance. It measured 2.5 cm and occurred in a 29 weeks’

gestation placenta. The cellularity of this lesion has suggested that such tumors may represent sarcomas. H&E

¥170.

Figure 24.5. Chorioangioma that was associated with fetal transplacental exsanguination. The congested capillaries of the tumor are evident. The convexity of the tumor is covered by syncytiotrophoblast. H&E

¥160.

mas. Metastases and true invasion, however, have never been seen. Cary (1914) considered his case of “sarcoma”

to be “well authenticated,” but he did not provide photo- graphs. Moreover, mother and infant did not suffer any known deleterious consequences from the 6.5 ¥ 4.0 ¥ 3.0 cm, focally calciﬁed tumor. Similar observations were made by Mesia et al. (1999), who described an atypical case that was “mitotically active.” Despite this feature and their review of the other rare cases described with similar ﬁndings, invasion or metastases did not take place. Another unusual case comes from Guschmann et al. (2003b), who described the lesion they found as “chorangiocarcinoma”

(the world’s third case), even though mother and fetus did well. The possibility of a “collision tumor” and “reactive lesion” were considered but not resolved. Expressions of angiogenic factors were not increased, but the markers for trophoblast were strongly expressed.

The tumors labeled haemangioendothelioblastomas by Williams (1921) were apparently benign. Variability of its root cause. Another modality of therapy, the injection

with alcohol, has been suggested by Nicolini et al. (1999).

These authors injected 1 mL of absolute alcohol into the veins centrally in two patients’ large tumors (5 and 6 cm) whose pregnancy was complicated by hydramnios. It was followed by immediate cessation of blood ﬂow; a second injection was necessary in both patients. Both eventually delivered normal infants; the state of the tumors at delivery, however, was not described. A case similar to this was treated by colleagues in Wisconsin (courtesy of R.

Franciosi, 2002) and eventuated with a large placental infarct.

Macroscopically, chorioangiomas may be small and multiple (Fig. 24.7); alternatively, they may constitute large masses that displace villous tissue and bulge on the fetal surface. They are ﬂeshy, dark, often congested, and invariably benign. Previous authors, impressed with mitoses and the great cellularity of some tumors, suggested that occasional chorioangiomas represent sarco-

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the histologic appearance, often within the same tumor, has confused many authors. Capillary, cavernous, endo- theliomatous, ﬁbrosing, and ﬁbromatous tumors have been included in the nomenclature suggested by Schulz- Hetzel (1978). We believe that such precision is unwarranted because the clinical outcome is almost always the same, and it depends more on the size of the mass(es) than on the composition of the tumor(s). One may regard these tumors as hemangiomas or as hamartomas. The latter designation, however, probably is unwarranted as other placental elements (e.g., trophoblast) never partici- pate in their composition. This would be expected if the designation hamartoma were to apply, a point amply discussed by Marchetti (1939). This nomenclature was also examined in some detail by Barry et al. (1951) in a discus- sion of angiomas of cord and placenta. They ruled out that the lesions represent hamartomas and supported a neoplastic etiology.

It is theoretically possible to differentiate between a neoplasm and malformation-like tumor (hamartoma)

with some precision. Linder and Gartler (1965) found that when they investigated leiomyomas of the uterus using glucose-6-phosphate dehydrogenase (G-6-PD) variants as markers in the frequently (15%) heterozygous African-American population, a single-cell origin was the rule for these neoplasms. The same was found to be true for most other tumors. Congenital tumors such as neuro- ﬁbromas, on the other hand, had multiple cell derivation.

These tumors represent a malformation or hamartoma- like type of lesion. A study of chorioangiomas using this simple technique could be decisive in differentiating hamartoma from “true” neoplasm in females with G-6- PD heterozygosity.

The relation of chorioangioma to hydramnios has been known at least since Siddall’s extensive review in 1924.

He observed that hydramnios was particularly associated with large tumors, but that the prognosis for the gravida was otherwise excellent. Marchetti (1939), who gathered 209 cases and added eight of his own, drew attention to the much commoner location of chorioangiomas near the fetal surface. He also suggested their subdivision into three types and debated whether it represented a true tumor (he thought not) or a malformation, perhaps a hamartoma. The association with hydramnios was of particular interest to McInroy and Kelsey (1954). They saw a pregnancy from whose amnionic cavity 3400 mL amnionic ﬂuid was withdrawn. The placental tumor weighed 454 g, measured 10.5 cm in greatest dimension, and had its own vascular pedicle. They suggested that the tumor represented “dead space” and was therefore responsible for ﬂuid exudation. Such a large tumor, associated with a stillborn fetus that had cardiomegaly, is shown in Figure 24.8. In an extensive consideration of this tumor, Kühnel (1933) opined that the tumor would have to cause venous obstruction before it could cause hydramnios.

Klaften (1929), who observed a patient with 6000 mL of hydramnios and a 1700-g stillbirth, found a ﬁst-sized tumor bulging on the fetal surface of the placenta. He

Figure 24.7. Chorioangiomatosis of the placenta. The nodular, pale lesions represent chorioangiomas, which comprise approximately 50% of the placenta. The lesions could easily have been mistaken for infarcts. The placenta weighed 430 g and was accompanied by a 3200-g infant with cardiomegaly, anemia (hematocrit 40%), and thrombocytopenia at birth. Chromosomes were normal.

(Courtesy of Dr. P. Bromburger, Kaiser Hospital, San Diego.)

Figure 24.6. This chorioangioma displays the feature of over- grown capillaries in an enlarged villus covered by syncytium.

H&E ¥40.

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discounted previous opinions that hydramnios was caused by the enlargement of amnionic surface from the bulging tumor mass. Rather, he believed that the tumor caused increased vascular resistance with transudation ensuing.

A different mechanism for fetal hydrops was suggested by the case described in detail by Hirata et al. (1993).

They discovered the 8.8-cm placental mass by Doppler and color ﬂow mapping sonographically, and when hydrops developed, fetal blood sampling identiﬁed a hematocrit of only 17%. The hydrops improved after intrauterine transfusion. The anemia was attributed to microangiopathic hemolytic anemia, but a Kleihauer- Betke test was not done on maternal blood. This might have shown transplacental bleeding as has been observed in other cases of placental chorangiomas. Large chorangiomas may also affect the fetal circulation directly as was probably the case in the patient with a 7-cm tumor whose premature neonate had periventricular leukomalacia (Harigaya et al., 2002).

Numerous large angiomas have been described (e.g., Lopez and Kristoffersen, 1989). These authors saw a patient with placenta previa at mid-gestation with sonographically recognized tumor. They suggested that placenta previa is one of several recognized complications with chorioangioma. The fetus was growth-restricted (899 g), and the placental tumor weighed 503 g. There are many other reports of large chorioangiomas associated with hydramnios, hydrops fetalis, and fetal death. The placenta may be edematous and large in such cases. For instance, Knoth et al. (1976) found a 1150-g placenta with multiple chorioangiomas throughout the placenta, associated with a 3250-g stillborn fetus. Other cases of fetal hydrops with large chorioangiomas were reported by Mandelbaum et al. (1969), Sweet et al. (1973), and Imakita

et al. (1988). Size alone, however, may not be the decisive factor. In Figure 24.9 we show the 900-g chorangioma (14

¥ 13 ¥ 10 cm) on a 950-g placenta in a neonate with virtu- ally no problems who survived. The umbilical cord was massively edematous (110 g) and the neonate had normal platelet counts, 14 NRBCs/100 white blood cells (WBCs) and mild hepatic enlargement and minimal edema. There had been no hydramnios, and the cesarean section done for breech presentation was the time when the neoplasm was discovered. The large artery supplying this tumor was four-ﬁfths occluded by old thrombus with calciﬁcation.

This presumably was the reason for the infarction of four ﬁfths of the tumor. The villous tissue was edematous, and there was certainly impending cardiac failure, although the cardiac size was normal. Dorman and Cardwell (1995) were the ﬁrst authors to present a description of the Ballantyne syndrome with a large chorioangioma. This syndrome (also referred to as maternal hydrops syndrome, pseudotoxemia, triple edema, mirror syndrome) occasionally exists in a variety of conditions, such as nonimmune hydrops, moles, teratoma, etc. The patient described by these authors had severe hypertension, pro- teinuria, and edema with an hydropic fetus due to a 9 ¥ 6 ¥ 8 cm chorangioma at 19 weeks gestation. After delivery, the placenta was found to have numerous infarcts in addition to the chorangioma. Ideally, such tumors will be treated in utero with laser vascular ablation in future.

The hearts of these newborns are often enlarged. The neonates may also be severely anemic, and we believe that hydrops usually develops because of fetal heart failure (Nuutinen et al., 1988). Similar observations are made when large fetal angiomas or arteriovenous ﬁstulas cause hydrops (Cohen & Sinclair, 1963; Cooper & Bolande, 1965;

Daniel & Cassady, 1968; Murray et al., 1969). Cardiomeg- Figure 24.8. Exceptionally large (400 g) chorioangioma

shelled out from its placenta. The infant was stillborn and had cardiomegaly.

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aly alone was reported with the chorangioma described by Benson and Joseph (1961). That neoplasm measured 16 ¥ 10 ¥ 6 cm and weighed 542 g. High output cardiac failure and hydramnios occurred with a 9 ¥ 8 ¥ 8 cm mass studied sonographically by Eldar-Geva et al. (1988).

Thrombocytopenia is also often observed in the newborns whose placentas have chorioangiomas. It may be associated with heart failure and disseminated intravas- cular coagulation (Greene & Iams, 1984). Froehlich and Housler (1971) and Froehlich et al. (1971) described thrombocytopenia. The latter authors found the tumors to occur more frequently in white than in African-Ameri- can mothers, more often with twins, and also more often with malformed neonates. They mentioned an association with fetal angiomas, as did Leblanc and Carrier (1979) and Bakaris et al. (2004). We have seen several neonates with hemangiomas whose placentas contained chorioangiomas, perhaps further supporting the notion that this tumor, as fetal angiomas, represents in reality some form

of congenital malformation, rather than a true neoplasm.

Many authors have posed the same question. Bakaris et al. (2004) presented a case associated with neonatal hemangiomatosis and infantile angioma of the liver. Drut et al. (1992) reported the presence of hemangioendothe- liomas and multiple chorioangiomas in the Beckwith- Wiedemann syndrome (BWS) (Fig. 24.10) and referred to a few case descriptions of similar combinations. Addi- tional consideration of the BWS will be found below and in Chapter 22. The notion of “hamartosis” was also incon- clusively discussed. Demonstration of factor VIII within the neoplastic cells suggested to Majlessi and coauthors (1983) that the origin of the large and unusually cellular tumor (327 g) they observed was endothelial. Sieracki et al. (1975), in a description of six cases, found one tumor that resembled pericytes. Accordingly, they suggested the diagnosis of pericytoma. Hydropic bovine fetuses have been associated with chorioangiomas (Corcoran &

Murphy, 1965), and Kirkbride et al. (1973) found an Figure 24.9. A 900-g subchorionic chorangioma with marked edema of the umbilical cord and thrombosis of the nourishing chorionic artery. Four ﬁfths of the tumor was infarcted, and there was villous edema and minimal neonatal cardiac failure. The infant did well.

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aborted calf with dermal, oral, and placental angiomas.

We saw a stillborn bongo (Tragelaphus eurycerus) with four huge chorangiomas (weighing up to 975 g) in which some smooth muscle ﬁbers were frequent; also, bizarre multinucleated cells were found whose origin remains obscure. Limaye and Tchabo (1989) observed maternal thrombocytopenia during the course of a pregnancy that was complicated by a 5-cm chorioangioma. They believed that the thrombocytopenia was the result of necrosis in the angioma.

Several authors have noted that chorioangiomas were associated with preeclampsia (e.g., Heggtveit et al., 1965).

Stiller and Skaﬁsh (1986) found fetomaternal hemorrhage with a placenta that had eight chorioangiomas.

Santamaria et al. (1987) saw fetal exsanguination result from such tumors. Perhaps the signiﬁcantly increased fetal circulation caused by large tumors produces fetal growth restriction (Müller & Rieckert, 1967; Mahmood, 1977; King & Lovrien, 1978). In a series of seven chorioangiomas, Philippe et al. (1969) found four underdevel- oped fetuses. Adducci (1975) reported fetal distress resultant from a large chorangioma. Aside from hydramnios, it is frequently reported that premature delivery and placenta previa are associated with chorioangiomas.

Asadourian and Taylor (1968) described the occurrence of abruptio placentae with this placental tumor. Prema- ture separation was also seen by Sulman and Sulman (1949), who additionally reported elevated maternal human chorionic gonadotropin (hCG) titers. Others have also found altered levels of pregnancy hormones with large chorioangiomas.

Giant chorioangiomas have been alluded to in several publications (e.g., 570 g in Burrows et al., 1973); the record is probably held by the 1500-g (30 ¥ 20 ¥ 5 cm) tumor described by Arodi et al. (1985). It was associated with breech presentation, placenta previa, hydramnios, preeclampsia, and abruptio placentae. The 32 weeks’ gesta-

tion fetus weighed 1000 g and died from anemia and asphyxia.

Placental chorioangiomas present other challenging pathologic features. Although placentomegaly, often with typical hydropic villi, is probably directly related to cardiac failure, anemia, and hypoproteinemia, there is no good explanation for an associated umbilical artery thrombosis as described by Sen (1970). Perhaps it is easiest to explain the anemia by the proliferative response that has been identified by Kosanke et al. (1998). These investigators showed that the hypoxia resulting from anemia increased the proliferation of trophoblast and mesenchymal cells of the human placenta. Reiner and Fries (1965) found arteriovenous fistulas in their injection study of a chorioangioma; the neonate experienced rapidly disappearing cardiomegaly. Repetitive multiple chorioangiomas were noted by Battaglia and Woolever (1968), who speculated that sequestration of plasma pro- teins into the interstices of the lesion may have accounted for the associated hypoproteinemia and edema of their case. Other cases of recurrence have been described and were reviewed by Benirschke (1999). Ludighausen and Sahiri (1983) described a woman who’s first and third gestation placentas had multiple chorangiomas. They were the presumed cause of fetal demise in both. Like- wise, Chan and Leung (1988) found recurrence of multiple chorangiomas, both eventuating in fetal demise. We have observed a case of recurrent chorangiomatosis.

The 2205-g boy was born after 39 weeks’ gestation to a 17-year-old gravida II. He had Apgar scores of 9/9 and did well. The 430-g placenta had numerous typical chorangiomatous nodules (Fig. 24.11), was markedly congested, and had numerous NRBCs in the fetal circulation.

Sonographically, “unusual notching of the umbilical vein”

had been reported. A previous pregnancy, 1 year earlier, was also complicated by multiple placental chorangiomas. Thus, in all four families summarized here the recur- Figure 24.10. Chorangiosis in placenta of infant with the

Beckwith-Wiedemann syndrome. H&E ¥400.

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rent chorangiomas were composed of multiple lesions, perhaps best deﬁned as chorangiomatosis. Whether iso- lated chorangiomas can occur repetitively is unknown.

Earn and Penner (1950) depicted a chorioangioma that was separate from the placenta; it was attached by a long vascular pedicle whose vein was diffusely calciﬁed.

The macerated fetus associated with this placenta was hydropic. Sonographic diagnosis has repeatedly been made of chorioangiomas and was well described by Dao et al. (1981), who found two large tumors (see also Hirata et al., 1993).

Because we had previously found a severely retarded fraternal twin that had a chromosomal error [46, XX t (2q-; 15q+)], with angiomatous masses in the placenta (Wurster et al., 1969) (Fig. 24.12), we later studied a single chorangioma cytogenetically; it was normal (Kim et al., 1971). Ultrastructural studies done at the same time showed normal endothelial cells and capillaries. Subse- quent electron microscopic studies of chorioangiomas were performed by Cash and Powell (1980); they revealed no major additional features. Soma et al. (1991) also studied the tumors electron microscopically and found them to be composed of angioblastic proliferation. The few other cases of chorangioma in twin gestations have been commented upon by Benirschke (1999); they are uncommon, although Wallenburg (1971) and Froehlich et al. (1971) thought otherwise. They are also more common in triplet gestations.

One publication suggested that a “missing link” might have been found between chorioangiomas and choriocar- cinomas. Jauniaux et al. (1988) described a lesion they termed “chorangiocarcinoma.” The placenta of this 35 weeks’ pregnancy contained a solitary small nodule fairly

typical of a chorioangioma. Its surface, however, was covered by apparently proliferated trophoblastic epithe- lium. The mother and child did well; there was no other chemical or cytochemical evidence of choriocarcinoma.

Electron microscopy also was no more decisive in sug- gesting that it was a combination of the two disparate tumors (see Chapter 23).

OTHER BENIGN TUMORS

Some benign tumors of the placenta have been discussed in Chapters 11, 12, and 25. There are, for instance, rare teratomas (Castaldo et al., 1972; Fox, 1978), possibly representing twins. The partial hydatidiform moles, not representing true tumors, are covered in Chapters 21 and 22. Heterotopic tissues, such as adrenal gland, have occasionally occurred in the placenta. They were never neoplastic, but they have occasionally been associated with a growth-restricted infant (Cox &

Chavrier, 1980). Fox (1978) had suggested that acceptable placental teratomas should reside on the fetal surface of the placenta.

The report by Chen et al. (1986) presented a novel type of placental tumor. It was a presumed hepatocellular adenoma. The authors observed a small-for-gestational-age (1781 g at 37 weeks) infant with a 530-g placenta that contained a 7.0 ¥ 4.2 ¥ 2.7 cm ﬁrm mass. The tumor was tan-white, sharply delimited, and composed of polyhedral cells that had the appearance of hepatocytes. There was no bile pigment, but the cells contained glycogen, and some reacted with antibodies to a-fetoprotein and a1-antitrypsin. Study by electron microscopy showed structures that strongly resembled bile canaliculi. The authors believed that the lesion was a “monodermal teratoma,” although it was not on the placental surface. The fetus and mother had an entirely benign course. Four additional hepatic adenomas were described in some detail by Khalifa et al. (1998). They were benign as well, and two had an intravillous and two a subchorionic location. Their histology and special staining characteristics were similar to those in the previous case, but hematopoiesis was a consistent ﬁnding. These authors believed that an origin from displaced yolk sac structures was the most likely. Guschmann et al. (2000) described a 2-mm nodule in the twin placenta of a mosaic Turner syndrome patient and interpreted Figure 24.11. Macroscopic appearance of placental slices in recurrent chorangiomatosis.

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it as a heterotopic adrenal lesion. The entire literature of benign, unusual placental tumors is here also competently reviewed. Doss and her colleagues (1998) reported on a hydropic neonate with hepatoblastoma of the liver whose placental vessels were crowded with meta- static hepatoblastoma cells.

Chorangiosis and Chorangiomatosis

The terminology for chorangiosis and chorangiomatosis is poorly deﬁned; indeed, Marchetti (1939) considered that this lesion was merely a diffuse ectasia of placental villous capillaries. One may possibly think of chorangiomatosis as representing multiple chorioangiomas, but chorangiosis is most certainly not a neoplastic condition.

Because of its histologic similarity to some aspects of chorioangioma, it may as well be discussed here, although it has a decidedly different pathogenesis. Meyenburg (1922) had considered this lesion as “diffuse hemangiomatosis of the placenta,” but it was Hörmann (1958) who coined the term chorioangiosis. Later authors suggested that it results from abnormal maturation of villi and hypoxia. In particular, the differentiation from the con-

gestion of diabetic mothers’ placentas has caused confu- sion in the literature. It must also be cautioned that removal of blood from capillaries renders villi relatively bloodless and thus to appear as being without vessels, whereas infusion distends the capillaries and may produce pictures like chorangiosis. Care must be taken in inter- preting the lesion properly.

Caldwell et al. (1977) considered this lesion to be a

“vascular anomaly of the placental villi with increased capillarity of their stroma.” They saw a 3100-g infant whose mother had received isoxsuprine over 5 months for vaginal bleeding and uterine contractions. The infant had thrombocytopenia and petechiae. Also present were hydramnios and a circumvallate placenta that weighed 1770 g and measured 24 ¥ 23 ¥ 6.5 cm. It was unusually thick. The villi had hugely distended vessels that were numerically increased. As is true with chorioangiomas, the depressed platelet count was probably the result of sequestration in the placental capillaries.

It was not until Altshuler (1984) considered this entity in considerable detail that some clarity resulted about the nature of chorangiosis. He diagnosed the condition Figure 24.12. Placentas of dizygotic (DZ) twins at term. The

mother had ﬁve pregnancies, was 34 years old, and suffered hydramnios at 36 weeks in this gestation. Twin A was a normal girl (2585 g); the placenta weighed 420 g. Twin B was a boy

(1642 g), with a placenta weighing 3600 g. It was interpreted as a

“mole.” Microscopically, there was primarily angiomatous change of the entire placenta, and the fetus had a translocation with duplication. (Source: Wurster et al., 1969, with permission.)

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principally by low-power lens inspection of histologic sections (stained with hematoxylin and eosin, H&E): “Cho- rangiosis was diagnosed when inspection with a ¥10 objective, showed ten villi, each with ten or more vascular channels in ten or more noninfarcted and nonischemic zones of at least three different placental areas.” He graded chorangiosis from grade 1 to 3, depending on the profusion of vessels within villi. He found an overall incidence of 5.5% among 1350 placentas and distin- guished it clearly from congestion. Because of the frequency and importance of this condition, reﬁnements of the numerical assessment have been made. Perhaps the most important observation is that by Mutema and Stanek (1998). They found that, when counting is done on slides stained with CD34 immunohistochemistry (endothelial marker), more vessels were counted in non- chorangiomatous villi (eight to 15), and thus when H&E staining only is performed, the frequency of chorangiosis may be overestimated.

Chorangiosis is not common but may have an ominous connotation (Benirschke, 1994a). Altshuler saw it associated with high frequency in stillbirths and many perinatal circumstances that suggested to him long-standing hypoxia. Thus, it is more commonly observed in the placentas of babies who develop cerebral palsy. We ﬁnd it more often with cord problems of one kind or another (Benirschke, 1994b). The increase in capillary lumen cross sections seen in this lesion comes about, we believe, through endothelial proliferation. It thus takes time to develop. Perhaps it takes as much as weeks to develop full-blown, marked chorangiosis. Its presence betrays a deleterious intrauterine environment for the fetus, and we see in its manifestation an attempt (teleologi- cally speaking) of the placenta to enlarge its diffusional

surface. It is thus not surprising to note that somewhat similar observations were made in placentas from high altitude when they were quantitatively compared with those of lower strata (Jackson et al., 1987; Reshetnikova et al., 1993, 1994, 1996; and many others). When Ali (1997) compared stereologically the villous structure of placentas from high altitude (3000 m) with those at sea level, his main ﬁnding was an increase in the number of cytotrophoblast at altitude. Birth weights, placental weights, and placental index were all lower at altitude.

The increased recruitment of cytotrophoblast was thought to result from relative hypoxia and increased syncytial turnover. Although not discussed, the microscopic picture of villi shown suggests an increase in capillaries as well.

Placental villous congestion is particularly prominent with uncontrolled diabetes and, in our experience it may mask this lesion (chorangiosis) if one is not careful (Fig.

24.13). In chorangiosis, there is an obvious numerical increase of the vessels per villus (Fig. 24.14); with congestion, the vessels are merely distended. Chorangiosis correlated significantly with perinatal deaths (39%) (e.g., Keenan & Altshuler, 1975) and congenital anomalies (27%) and was thus deemed to be an important signal for scrutiny, particularly in placentomegaly. Its final etiology, if a specific one really exists, remains to be eluci- dated. It must be cautioned, however, that not all infants whose placenta shows diffuse chorangiosis are signifi - cantly affected. Thus, the case reported by de la Ossa et al. (2001) had as the only complication severe preeclampsia that necessitated a cesarean section. Despite the chorangiosis, the infant developed normally, and no other features that might have induced chorangiosis were known.

Figure 24.13. Severe villous congestion in mature placenta of trisomy 21. This picture is difﬁcult to distinguish from that of chorangiosis. Quantitative measurements and vessel counts are necessary to make a clear distinction. H&E ¥160.

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Mesenchymal Dysplasia and the Beckwith-Wiedemann Syndrome

Chapter 22 discussed aspects of mesenchymal dysplasia because the morphology exhibited by this lesion is so often mimicked by features of partial hydatidiform moles.

These considerations will not be repeated here. It is necessary, however, to draw attention to the overlaps with BWS and chorangiomas, as they are often very similar in morphologic expression. Indeed, a clear deﬁni- tion of mesenchymal dysplasia that separates these entities is still forthcoming. The recent cases of Paradinas et al. (2001) and Matsui et al. (2003) were cited because of such overlaps. Drut et al. (1992) had described a case of BWS and chorangioma that was also associated with abnormal kidneys and liver angiomas. Thus, clearly difﬁ - culties exist for a clean separation of these three entities.

The photograph of the placenta in one of our cases with BWS (Fig. 24-10) exempliﬁes the chorangiosis in this condition. How can progress be made in this area of confu- sion? First it must be recognized that the BWS has many anomalies that are often minor and may not be recognized in the immediate neonatal period. Thus, it is uncommon that in the placental lesions here summarized, appropriate genetic studies are undertaken to rule out the syndrome. It is a syndrome whose gene appears to be located on 11p15 and has variability with respect to imprinting domains and mutations of p57(KIP2) (see

Niemitz et al., 2004). Deletions had not been recognized until their case was described; thus refined genetic scrutiny would be in order also for the chorangiomas, which, after all, also represent a form of neoplastic tendency as is the case with BWS. It just might be that some of the recurrent chorioangiomas thus find an explanation. Other recent studies of the molecular defect are those by Du et al. (2004) and Le Caignec et al. (2004), whose contribu- tions should be consulted. Mesenchymal dysplasia is often associated with “cirsoid aneurysms” of the placental surface, and the vascular abnormality may extend into stem vessels. Moreover, often one also finds some degree of chorangiosis. In addition, cases with an admixture of abnormal and dysplastic tissues should be studied chro- mosomally, as they may well be of chimeric nature. In any event, such studies, and the pursuit of angiogenic factor expression or their possible abnormalities may be of interest in the clarification of these dysplasias.

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