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Figure 1.
Antibodies against placental alkaline phosphatase marked only striated and smooth muscle such as this arrector pili (original magnification ×100).

Antibodies against placental alkaline phosphatase marked only striated and smooth muscle such as this arrector pili (original magnification ×100).

Figure 2.
Anti–cytokeratin 17 immunostained portions of the hair follicle (original magnification ×200).

Anti–cytokeratin 17 immunostained portions of the hair follicle (original magnification ×200).

Figure 3.
Antibodies against cytokeratins 7 (A) and 8 (B) immunoreacted with eccrine glands (original magnification ×100).

Antibodies against cytokeratins 7 (A) and 8 (B) immunoreacted with eccrine glands (original magnification ×100).

Differential Expression of Growth Factors and Receptors in Placenta and Hemangiomas* 
Differential Expression of Growth Factors and Receptors in Placenta and Hemangiomas*
Differential Expression of Growth Factors and Receptors in Placenta and Hemangiomas*
1.
Holmdahl  K Cutaneous vascular lesions in premature and mature infants. Acta Paediatr. 1995;44370- 379Article
2.
Amir  JMetzker  AKrikler  RReisner  SH Strawberry hemangiomas in preterm infants. Pediatr Dermatol. 1986;3331- 332Article
3.
Finn  MCGlowacki  JMulliken  JB Congenital vascular lesions: clinical application of a new classification. J Pediatr Surg. 1983;18894- 900Article
4.
Kaplan  PNormandin  JJWilson  GNPlauchu  HLippman  AVekemans  M Malformations and minor anomalies in children whose mothers had prenatal diagnosis: comparison between CVS and amniocentesis. Am J Med Genet. 1990;37366- 370Article
5.
Burton  BKSchulz  CJAngle  BBurd  LI An increased incidence of haemangiomas in infants born following chorionic villous sampling. Prenat Diagn. 1995;15209- 214Article
6.
Mulliken  JBGlowacki  J Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg. 1982;69412- 422Article
7.
Mulliken  JBMulliken  JBedYoung  AEed Classification of vascular birthmarks. Vascular Birthmarks: Hemangiomas and Malformations Philadelphia, Pa WB Saunders Co1988;24- 37
8.
Folkman  J Tumor angiogenesis. Adv Cancer Res. 1974;19331- 358
9.
Folkman  J The vascularization of tumors. Sci Am. 1976;23458- 6470- 73Article
10.
Risau  WSariola  HZerwes  HG  et al.  Vasculogenesis and angiogenesis in embryonic-stem-cell–derived embryoid bodies. Development. 1988;102471- 478
11.
Folkman  JCotran  R Angiogenic factors. Science. 1987;235442- 447Article
12.
Zetter  BR Angiogenesis: state of the art. Chest. 1988;93159A- 166A
13.
Breier  GAlbrecht  USterrer  SRisau  W Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation. Development. 1992;114521- 532
14.
Pepper  MSFerrara  NOrci  LMontesano  R Potent synergism between vascular endothelial growth factors and basic fibroblast growth in the induction of angiogenesis in vitro. Biochem Biophys Res Commun. 1992;189824- 831Article
15.
Folkman  J Toward a new understanding of vascular proliferative disease in children. Pediatrics. 1984;74850- 856
16.
Azizkhan  RGAzizkhan  JCZetter  BRFolkman  J Mast cell heparin stimulates migration of capillary endothelial cells in vitro. J Exp Med. 1980;152931- 944Article
17.
Glowacki  JMulliken  JB Mast cells in hemangiomas and vascular malformations. Pediatrics. 1982;7048- 51
18.
Takahashi  KMulliken  JBKozakewich  HPWRogers  RAFolkman  JEzekowitz  RAB Cellular markers that distinguish phases of hemangioma during infancy and childhood. J Clin Invest. 1994;932357- 2364Article
19.
Beer  AESio  JO Placenta as an immunological barrier. Biol Reprod. 1982;2615- 27Article
20.
Blankenship  TNKing  BF Developmental expression of Ki-67 antigen and proliferating cell nuclear antigen in macaque placentas. Dev Dyn. 1994;201324- 333Article
21.
Kim  JGRamachandran  SZhou  HMRayner  DParthasarathy  S Implications in the maintenance of pregnancy, I: presence of immunoreactive glycodelin in human umbilical cord vein endothelial cells. Fertil Steril. 2000;73839- 842Article
22.
Pack  GTMiller  PR Hemangiomas: classification, diagnosis and treatment. Angiology. 1950;1405- 426Article
23.
Johnson  PM Immunobiology of the human placental trophoblast. Exp Clin Immunogenet. 1993;10118- 122
24.
King  ALoke  YW The influence of the maternal uterine immune response on placentation in human subjects. Proc Nutr Soc. 1999;5869- 73Article
25.
Zhou  YFisher  SJJanatpour  M  et al.  Human cytotrophoblasts adopt a vascular phenotype as they differentiate: a strategy for successful endovascular invasion? J Clin Invest. 1997;992139- 2151Article
26.
Silverberg  SGKurman  RJSobin  Led Gestational trophoblastic disease: trophoblastic development. Tumors of Uterine Corpus and Gestational Trophoblastic Disease Washington, DC American Registry of Pathology1992;219- 232AFIP Atlas of Tumor Pathology, Series III.
27.
Rachmilewitz  JGonik  BGoshen  R  et al.  Intermediate cell during cytotrophoblast differentiation in vitro. Cell Growth Differ. 1993;4395- 402
28.
Proll  JBlaschitz  AHartmann  MThalhamer  JDohr  G Cytokeratin 17 as an immunohistochemical marker for intramural cytotrophoblast in human first trimester uteroplacental arteries. Cell Tissue Res. 1997;288335- 343Article
29.
Cole  FSTaeusch  HWedBallard  RAed Immunology. Avery's Diseases of the Newborn Philadelphia, Pa WB Saunders Co1998;435- 437
30.
Covone  AEMutton  DJohnson  PMAdinolfi  M Trophoblast cells in peripheral blood from pregnant women. Lancet. 1984;2841- 843Article
31.
Tedesco  FPausa  MNardon  E  et al.  Prevalence and biological effects of anti-trophoblast and anti-endothelial cell antibodies in patients with recurrent spontaneous abortions. Am J Reprod Immunol. 1997;38205- 211Article
32.
Aractingi  SBerkane  NBertheau  P  et al.  Fetal DNA in skin of polymorphic eruptions of pregnancy. Lancet. 1998;3521898- 1901Article
33.
Arlett  CMSmith  JBJimenez  SA Identification of fetal DNA and cells in skin lesions from women with systemic sclerosis. N Engl J Med. 1998;3381186- 1191Article
34.
Krusinski  PASaurat  JH Transplacentally transferred dermatoses. Pediatr Dermatol. 1989;6166- 177Article
35.
Potter  JFSchoeneman  M Metastasis of maternal cancer to the placenta and fetus. Cancer. 1970;25380- 388Article
36.
Catlin  EA Transplacental transmission of natural-killer-cell lymphoma. N Engl J Med. 1999;34185- 91Article
37.
Quintero  RARomero  RMahoney  MJ  et al.  Embryonic demonstration of hemorrhagic lesions on the human embryo after placental trauma. Am J Obstet Gynecol. 1993;168756- 759Article
38.
Moore  KL Formation of the bilaminal embryo and formation of the trilaminar embryo. The Developing Human Philadelphia, Pa WB Saunders Co1977;33- 58
39.
Latham  SESuskin  HAPetropoulos  AHawes  CSJones  WRKalionis  B A monoclonal antibody to human placental lactogen hormone facilitates isolation of fetal cells from maternal blood in a model system. Prenat Diagn. 1996;16813- 821Article
40.
Haigh  TChen  CPJones  CJPAplin  JD Studies of mesenchymal cells from 1st trimester human placenta: expression of cytokeratin outside the trophoblast lineage. Placenta. 1999;20615- 625Article
41.
North  PEWaner  MWMizeracki  AMihm  MC Juvenile hemangiomas share a unique immunophenotype with placental microvessels: implications for pathogenesis.  Paper presented at: 13th International Workshop on Vascular Anomalies May 11, 2000 Montreal, Quebec
42.
Wara  DWAmmann  AJRudolph  AMed Immunologic disorders. Pediatrics Norwalk, Conn Appleton & Lange1987;387- 393
43.
Jaffe  RB Importance of angiogenesis in reproductive physiology. Semin Perinatol. 2000;2479- 81Article
44.
Smith  SKHe  YClark  DECharnock-Jones  DS Angiogenic growth factor expression in placenta. Semin Perinatol. 2000;2482- 86Article
45.
Smith  SCLeung  TNTo  KFBaker  PN Apoptosis is a rare event in first-trimester placental tissue. Am J Obstet Gynecol. 2000;183697- 699Article
46.
Halperin  RPeller  SRotschild  MBukovsky  ISchneider  D Placental apoptosis in normal and abnormal pregnancies. Gynecol Obstet Invest. 2000;5084- 87Article
47.
Mancini  AJSmoller  BR Proliferation and apoptosis within juvenile capillary hemangiomas. Am J Dermatopathol. 1996;18505- 514Article
48.
Razon  MJKraling  BMMulliken  JBBischoff  J Increased apoptosis coincides with onset of involution in infantile hemangioma. Microcirculation. 1998;5189- 195Article
49.
Not Available, Report of National Institute of Child Health and Human Development Workshop on Chorionic Villus Sampling and Limb and Other Defects, October 20, 1992. Am J Obstet Gynecol. 1993;1691- 6Article
50.
Ezekowitz  RABMulliken  JBFolkman  J Interferon alfa-2a therapy for life-threatening hemangiomas of infancy. N Engl J Med. 1992;3261456- 1463Article
Study
May 2001

Infantile HemangiomasSpeculation on Placental Trophoblastic Origin

Author Affiliations

From the Southern Illinois University School of Medicine, Springfield, Ill (Dr Bree); Departments of Pediatrics (Dr Siegfried) and Dermatology (Drs Siegfried and Nahass), Saint Louis University School of Medicine, St Louis, Mo; and Department of Pathology, Cardinal Glennon Children's Hospital, St Louis (Dr Sotelo-Avila). Dr Bree was a fourth-year medical student at Southern Illinois University School of Medicine at the time of the study and is currently a transitional intern at Forest Park Hospital, St Louis.

Arch Dermatol. 2001;137(5):573-577. doi:10-1001/pubs.Arch Dermatol.-ISSN-0003-987x-137-5-dst00084
Abstract

Background  The unique immunobiology of the placental trophoblast and the increased incidence of hemangiomas in infants born after chorionic villus sampling suggest that an immunologically regulated ectopic focus of trophoblasts could be the cell of origin for proliferative infantile hemangiomas.

Objective  To compare tissue from infantile hemangiomas with that of other vascular lesions for the presence of selected placental trophoblast-specific cellular markers.

Design and Patients  Twelve tissue specimens taken from infantile hemangiomas on patients aged 5 days to 2 years were retrospectively confirmed clinically and histologically. Negative controls were similarly confirmed, including 6 pyogenic granulomas and 4 vascular-lymphatic malformations. These tissues were used for immunohistochemical analysis of selected trophoblastic markers including human placental lactogen, placental alkaline phosphatase, and cytokeratins 7, 8, and 17.

Setting  Tissue submitted from patients seen at Saint Louis University Department of Dermatology and Cardinal Glennon Children's Hospital in St Louis, Mo, between January 1, 1997, and October 31, 1999.

Main Outcome Measure  Differential staining for trophoblastic markers in infantile hemangiomas compared with control tissues.

Results  The 12 infantile hemangiomas were uniformly negative for all markers tested. Control tissues were also negative for these markers. Four of the 5 histochemical markers did recognize specific nonvascular, cutaneous elements: placental alkaline phosphatase stained smooth and striated muscle, cytokeratins 7 and 8 stained eccrine glands, and cytokeratin 17 stained pilosebaceous units.

Conclusions  Our results do not support the placental trophoblast as the cell of origin for infantile hemangiomas, but we hope our observations and speculation will stimulate further study of this hypothesis.

HEMANGIOMAS are the most common tumor of infancy, with an estimated incidence of up to 12%, most often occurring in whites, females, and premature infants weighing less than 1000 g.13 Chorionic villus sampling (CVS) is an underappreciated predisposing factor. One study reported that 21% of 432 CVS-exposed infants developed hemangiomas. In one third of the cases, the lesions were multiple.4,5

The pathogenesis of this tumor has remained elusive. Insights historically have been obscured by ambiguous and inconsistent nosologic systems. Mulliken and Glowacki's6,7 breakthrough in the classification system of vascular birthmarks provided direction based on clinical and cellular features. Recent investigation has concentrated on angiogenesis as a possible pathogenic mechanism. Developmental cellular interactions with an associated imbalance of angiogenic and antiangiogenic factors have been postulated to trigger an abnormal endothelial cell proliferation.816 Other studies have focused on the role of interactions between resident mast cells and fibroblasts7,17 as well as differential expression of a variety of growth factors during hemangioma proliferation and involution.18 Some of these factors also play a role in placental physiology (Table 1).

Decades before the investigations into angiogenesis, a developmental embryonic origin of hemangiomas was postulated by several authors7,22 and deserves further examination. The placenta is a complex barrier that affords the embryo immunologically privileged growth.19,23 The cellular immune interaction between fetus and mother is a current focus of intense research interest.24 The trophoblast is a highly proliferative stem cell at the maternal-fetal junction. Invasive functions allow trophoblasts to initiate and establish maternal-fetal circulation by eroding the uterine mucosa, engulfing maternal spiral arteries, and eventually replacing arterial smooth muscle and lining the maternal-fetal intervillous space as a modified type of endothelial cell.25 Differentiated trophoblasts then mature to become the functional units of the placenta: absorbing oxygen and nutrients, producing steroid and protein hormones, and preventing fetal allograft rejection.26 The complex physiologic activity of the trophoblast is mirrored by its complex evolution into multiple cell types with expression of varying cellular and immunologic markers.23,2628

The direct contact of maternal and fetal cells at the placental interface allows admixture of not only oxygen and nutrients, but also cells. Fetal cells entering the maternal circulation have been associated with a variety of adverse sequelae. The transfer of fetal red blood cells causes Rh isoimmunization.29 Trophoblasts can be identified in maternal peripheral blood, along with antitrophoblast autoantibodies that have been implicated as a cause of recurrent spontaneous abortion.30,31 The migration of fetal cells into maternal skin have been implicated as a cause of polymorphic eruptions of pregnancy32 and are one presumed cause of the chronic graft-vs-host reaction, which manifests as systemic sclerosis in women.33 Conversely, maternal cells may enter the fetal circulation and lead to in utero graft-vs-host disease as well as metastatic malignant neoplasms.3436

The admixture of maternal and fetal cells, common to all pregnancies, is enhanced by placental trauma. Rho(D) immune globulin is routinely administered to pregnant, Rh-negative women before amniocentesis or after motor vehicle accidents to prevent isoimmunization. Inflicted placental trauma and CVS result in hemorrhagic lesions that can be seen on the embryo.37 In addition, CVS is associated with a 3-fold increase in hemangiomas, compared with amniocentesis.4,5

With these observations in mind, this study was designed to look for evidence of cellular trophoblastic markers in tissue taken from infantile hemangiomas to establish a link between these tumors and placental trophoblasts.

PATIENTS AND METHODS

Pathological specimens given the histologic diagnosis of hemangioma between January 1, 1997, and October 31, 1999, at Cardinal Glennon Children's Hospital in St Louis, Mo, were reviewed, along with clinically and histologically consistent cases of infantile hemangiomas diagnosed at St Louis University Department of Dermatology. Twelve samples were categorized as infantile hemangiomas by the histologic presence of endothelial proliferation and a consistent clinical history of postnatal disproportionate growth and eventual spontaneous resolution. The 14 negative controls included 10 pyogenic granulomas and 4 vascular-lymphatic malformations characterized by typical clinical history and consistent histologic findings. Positive controls were randomly selected normal placentas sectioned through the chorionic villi.

The tissues were all embedded in paraffin and cut at 4 µm. The sections were stained with routine immunohistochemistry techniques that used monoclonal antibodies to cytokeratin 7 (clone OVTL 12/30; Dako Corp, Carpenteria, Calif), cytokeratin 8 (low-molecular-weight keratin, clone 35βH11; Dako Corp), cytokeratin 17 (clone E3; Dako Corp), placental alkaline phosphatase (clone 8A9; Dako Corp), and polyclonal rabbit anti–human placental lactogen (lot 054; Dako Corp).

Slides were reviewed by a pediatric pathologist (C.S-A.), a dermatologist (E.S.), and a dermatopathologist (G.N.) to assess for the presence or absence of positive staining for each trophoblastic marker.

RESULTS

Tumor cells from the 12 samples of clinically and histopathologically consistent hemangiomas were uniformly negative for cytokeratins 7, 8, and 17; placental alkaline phosphatase; and human placental lactogen, as was pathological tissue from all negative controls, including 12 cases of pyogenic granulomas and 4 cases of arteriolymphatic malformations. Trophoblasts within the 2 placental samples stained for all markers. Of note, 4 monoclonal antibodies did recognize specific nonvascular, cutaneous elements: antibodies against placental alkaline phosphatase stained smooth and striated muscle (Figure 1), cytokeratin 17 stained pilosebaceous units (Figure 2), and cytokeratins 7 and 8 stained eccrine glands (Figure 3). Antibody staining for human placental lactogen was negative.

COMMENT

Our results neither supported nor excluded the concept of a trophoblastic origin for infantile hemangiomas. The complex nature of the stem cells known as trophoblasts make histochemical identification technically challenging.26,28,38 We selected commercially available immunostains relatively specific for undifferentiated trophoblasts. Human placental lactogen is known to be secreted by trophoblasts into maternal serum throughout pregnancy,39 whereas placental alkaline phosphatase is secreted during the second and third trimesters.26 Cytokeratins 7, 8, and 17 have been identified as specific markers of trophoblast subpopulations within the chorionic villi.28,40 In comparison, a recent abstract41 reported 37 juvenile hemangiomas that immunostained with monoclonal antibodies against microvascular markers uniquely coexpressed in the more well-differentiated placental microvasculature, rather than trophoblast stem cells. These markers included merosin, GLUT-1 (glucose transporter isoform 1), Lewis Y, and FcgRII (a placental endothelial antigen), which failed to react in all 25 vascular malformations.41

Our findings did not support our hypothesis, but a placental origin of hemangiomas is consistent with several well-described interactions between placenta, fetus, and mother. Our hypothesis also fits several epidemiologic and clinical features of infantile hemangiomas.

The trophoblast has many properties that could permit the development of hemangiomas. It is a stem cell with a profound and varied functional capacity. Its potential for initial invasion and subsequent implantation and proliferation26 lends itself to tumorigenesis. The eventual role of the trophoblast as a modified endothelial cell within the maternal-fetal intervillous space with adoption of a vascular phenotype25,26 makes it conceivable that this cell is under the same regulation as other placental endothelial cells and could be affected by angiogenic and antiangiogenic factors.25 The complex immunobiology of placental interactions with the presence of HLA markers and complement regulatory proteins on the trophoblastic cell surface provides evidence of this cell's unique immunologic activity, its immune-privileged status, and its strategies to provide protection.19,23,24

Clinical and epidemiologic observations also support a placental origin for infantile hemangiomas. Premature infants have a higher incidence of hemangiomas. This may be related to a relative immunologic naivete or a decrease in maternal antibody levels (including antitrophoblast antibodies), since the initial transfer of maternal IgG occurs at 20 weeks' gestation and the majority of transfer, after 32 weeks' gestation.29,42 The preponderance in female infants may be explained by a relative immunologic tolerance related to cyclic angiogenesis during menstruation, ovulation, and future pregnancies.43,44 The natural course could also be the result of immunologic responses. Postnatal proliferation is typical in these tumors and may be coincident with waning maternal IgG, including antitrophoblast antibodies (with a half-life of 25 days and nadir at 3-4 months postnatally).42 Interestingly, the approximate growth phase is 9 months, as is the growth phase of the placenta. The eventual involution of hemangiomas could represent a process related to preprogrammed placental apoptosis known to increase throughout gestation.4548

Our theory was inspired by the unexplained observation that hemangiomas are the most common anomaly associated with CVS.4,5,49 All pregnancies are at risk for cell admixture at the placental interface, even without overt trauma; however, the nature of CVS disrupts chorionic villus trophoblasts and could easily allow dissemination into the fetal circulation or amniotic fluid. Among a group of 14 CVS-exposed infants with limb disruption defects, 50% had 1 or more hemangiomas.5 Both sporadic and CVS-associated hemangiomas occur most often on the head and neck, representing 60% of fetal surface area available for implantation.4 Hemangiomas can also occur in strikingly typical patterns and locations. Ectopic implantation of placental trophoblasts could account for these characteristic distribution patterns, depending on the stage of embryonic development at implantation. Segmental or midline hemangiomas could develop after early implantation, along with the developing branchial arches of the head and neck. Late transamniotic implantation could result in focal lesions, while late hematogenous spread could result in disseminated cutaneous and visceral lesions.

Although speculative at present, the theory seems to explain many unknowns in regard to this most common and little understood tumor of infancy. Additional studies as to a placental origin of hemangiomas may provide more useful information and may eventually lead to a more specific, possibly immunologic treatment to prevent development of this neoplasm and its serious complications, including ulceration, pain, obstruction, and disfigurement.50

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Article Information

Accepted for publication January 11, 2001.

Corresponding author: Elaine Siegfried, MD, Department of Dermatology, Saint Louis University, 1402 S Grand Blvd, St Louis, MO 63104 (e-mail: siegfrec@slucare1.sluh.edu).

References
1.
Holmdahl  K Cutaneous vascular lesions in premature and mature infants. Acta Paediatr. 1995;44370- 379Article
2.
Amir  JMetzker  AKrikler  RReisner  SH Strawberry hemangiomas in preterm infants. Pediatr Dermatol. 1986;3331- 332Article
3.
Finn  MCGlowacki  JMulliken  JB Congenital vascular lesions: clinical application of a new classification. J Pediatr Surg. 1983;18894- 900Article
4.
Kaplan  PNormandin  JJWilson  GNPlauchu  HLippman  AVekemans  M Malformations and minor anomalies in children whose mothers had prenatal diagnosis: comparison between CVS and amniocentesis. Am J Med Genet. 1990;37366- 370Article
5.
Burton  BKSchulz  CJAngle  BBurd  LI An increased incidence of haemangiomas in infants born following chorionic villous sampling. Prenat Diagn. 1995;15209- 214Article
6.
Mulliken  JBGlowacki  J Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg. 1982;69412- 422Article
7.
Mulliken  JBMulliken  JBedYoung  AEed Classification of vascular birthmarks. Vascular Birthmarks: Hemangiomas and Malformations Philadelphia, Pa WB Saunders Co1988;24- 37
8.
Folkman  J Tumor angiogenesis. Adv Cancer Res. 1974;19331- 358
9.
Folkman  J The vascularization of tumors. Sci Am. 1976;23458- 6470- 73Article
10.
Risau  WSariola  HZerwes  HG  et al.  Vasculogenesis and angiogenesis in embryonic-stem-cell–derived embryoid bodies. Development. 1988;102471- 478
11.
Folkman  JCotran  R Angiogenic factors. Science. 1987;235442- 447Article
12.
Zetter  BR Angiogenesis: state of the art. Chest. 1988;93159A- 166A
13.
Breier  GAlbrecht  USterrer  SRisau  W Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation. Development. 1992;114521- 532
14.
Pepper  MSFerrara  NOrci  LMontesano  R Potent synergism between vascular endothelial growth factors and basic fibroblast growth in the induction of angiogenesis in vitro. Biochem Biophys Res Commun. 1992;189824- 831Article
15.
Folkman  J Toward a new understanding of vascular proliferative disease in children. Pediatrics. 1984;74850- 856
16.
Azizkhan  RGAzizkhan  JCZetter  BRFolkman  J Mast cell heparin stimulates migration of capillary endothelial cells in vitro. J Exp Med. 1980;152931- 944Article
17.
Glowacki  JMulliken  JB Mast cells in hemangiomas and vascular malformations. Pediatrics. 1982;7048- 51
18.
Takahashi  KMulliken  JBKozakewich  HPWRogers  RAFolkman  JEzekowitz  RAB Cellular markers that distinguish phases of hemangioma during infancy and childhood. J Clin Invest. 1994;932357- 2364Article
19.
Beer  AESio  JO Placenta as an immunological barrier. Biol Reprod. 1982;2615- 27Article
20.
Blankenship  TNKing  BF Developmental expression of Ki-67 antigen and proliferating cell nuclear antigen in macaque placentas. Dev Dyn. 1994;201324- 333Article
21.
Kim  JGRamachandran  SZhou  HMRayner  DParthasarathy  S Implications in the maintenance of pregnancy, I: presence of immunoreactive glycodelin in human umbilical cord vein endothelial cells. Fertil Steril. 2000;73839- 842Article
22.
Pack  GTMiller  PR Hemangiomas: classification, diagnosis and treatment. Angiology. 1950;1405- 426Article
23.
Johnson  PM Immunobiology of the human placental trophoblast. Exp Clin Immunogenet. 1993;10118- 122
24.
King  ALoke  YW The influence of the maternal uterine immune response on placentation in human subjects. Proc Nutr Soc. 1999;5869- 73Article
25.
Zhou  YFisher  SJJanatpour  M  et al.  Human cytotrophoblasts adopt a vascular phenotype as they differentiate: a strategy for successful endovascular invasion? J Clin Invest. 1997;992139- 2151Article
26.
Silverberg  SGKurman  RJSobin  Led Gestational trophoblastic disease: trophoblastic development. Tumors of Uterine Corpus and Gestational Trophoblastic Disease Washington, DC American Registry of Pathology1992;219- 232AFIP Atlas of Tumor Pathology, Series III.
27.
Rachmilewitz  JGonik  BGoshen  R  et al.  Intermediate cell during cytotrophoblast differentiation in vitro. Cell Growth Differ. 1993;4395- 402
28.
Proll  JBlaschitz  AHartmann  MThalhamer  JDohr  G Cytokeratin 17 as an immunohistochemical marker for intramural cytotrophoblast in human first trimester uteroplacental arteries. Cell Tissue Res. 1997;288335- 343Article
29.
Cole  FSTaeusch  HWedBallard  RAed Immunology. Avery's Diseases of the Newborn Philadelphia, Pa WB Saunders Co1998;435- 437
30.
Covone  AEMutton  DJohnson  PMAdinolfi  M Trophoblast cells in peripheral blood from pregnant women. Lancet. 1984;2841- 843Article
31.
Tedesco  FPausa  MNardon  E  et al.  Prevalence and biological effects of anti-trophoblast and anti-endothelial cell antibodies in patients with recurrent spontaneous abortions. Am J Reprod Immunol. 1997;38205- 211Article
32.
Aractingi  SBerkane  NBertheau  P  et al.  Fetal DNA in skin of polymorphic eruptions of pregnancy. Lancet. 1998;3521898- 1901Article
33.
Arlett  CMSmith  JBJimenez  SA Identification of fetal DNA and cells in skin lesions from women with systemic sclerosis. N Engl J Med. 1998;3381186- 1191Article
34.
Krusinski  PASaurat  JH Transplacentally transferred dermatoses. Pediatr Dermatol. 1989;6166- 177Article
35.
Potter  JFSchoeneman  M Metastasis of maternal cancer to the placenta and fetus. Cancer. 1970;25380- 388Article
36.
Catlin  EA Transplacental transmission of natural-killer-cell lymphoma. N Engl J Med. 1999;34185- 91Article
37.
Quintero  RARomero  RMahoney  MJ  et al.  Embryonic demonstration of hemorrhagic lesions on the human embryo after placental trauma. Am J Obstet Gynecol. 1993;168756- 759Article
38.
Moore  KL Formation of the bilaminal embryo and formation of the trilaminar embryo. The Developing Human Philadelphia, Pa WB Saunders Co1977;33- 58
39.
Latham  SESuskin  HAPetropoulos  AHawes  CSJones  WRKalionis  B A monoclonal antibody to human placental lactogen hormone facilitates isolation of fetal cells from maternal blood in a model system. Prenat Diagn. 1996;16813- 821Article
40.
Haigh  TChen  CPJones  CJPAplin  JD Studies of mesenchymal cells from 1st trimester human placenta: expression of cytokeratin outside the trophoblast lineage. Placenta. 1999;20615- 625Article
41.
North  PEWaner  MWMizeracki  AMihm  MC Juvenile hemangiomas share a unique immunophenotype with placental microvessels: implications for pathogenesis.  Paper presented at: 13th International Workshop on Vascular Anomalies May 11, 2000 Montreal, Quebec
42.
Wara  DWAmmann  AJRudolph  AMed Immunologic disorders. Pediatrics Norwalk, Conn Appleton & Lange1987;387- 393
43.
Jaffe  RB Importance of angiogenesis in reproductive physiology. Semin Perinatol. 2000;2479- 81Article
44.
Smith  SKHe  YClark  DECharnock-Jones  DS Angiogenic growth factor expression in placenta. Semin Perinatol. 2000;2482- 86Article
45.
Smith  SCLeung  TNTo  KFBaker  PN Apoptosis is a rare event in first-trimester placental tissue. Am J Obstet Gynecol. 2000;183697- 699Article
46.
Halperin  RPeller  SRotschild  MBukovsky  ISchneider  D Placental apoptosis in normal and abnormal pregnancies. Gynecol Obstet Invest. 2000;5084- 87Article
47.
Mancini  AJSmoller  BR Proliferation and apoptosis within juvenile capillary hemangiomas. Am J Dermatopathol. 1996;18505- 514Article
48.
Razon  MJKraling  BMMulliken  JBBischoff  J Increased apoptosis coincides with onset of involution in infantile hemangioma. Microcirculation. 1998;5189- 195Article
49.
Not Available, Report of National Institute of Child Health and Human Development Workshop on Chorionic Villus Sampling and Limb and Other Defects, October 20, 1992. Am J Obstet Gynecol. 1993;1691- 6Article
50.
Ezekowitz  RABMulliken  JBFolkman  J Interferon alfa-2a therapy for life-threatening hemangiomas of infancy. N Engl J Med. 1992;3261456- 1463Article
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