Hostname: page-component-78c5997874-8bhkd Total loading time: 0 Render date: 2024-11-03T02:22:54.579Z Has data issue: false hasContentIssue false

Pathogenesis of infantile haemangioma: new molecular and cellular insights

Published online by Cambridge University Press:  29 November 2007

Matthew R. Ritter
Affiliation:
The Scripps Research Institute, Department of Cell Biology, La Jolla, CA, USA.
Ross A. Butschek
Affiliation:
The Scripps Research Institute, Department of Cell Biology, La Jolla, CA, USA.
Martin Friedlander
Affiliation:
The Scripps Research Institute, Department of Cell Biology, La Jolla, CA, USA.
Sheila F. Friedlander*
Affiliation:
The Scripps Research Institute, Department of Cell Biology, La Jolla, CA, USA. Departments of Pediatrics and Medicine (Dermatology), University of California San Diego, and Department of Pediatric Dermatology, Children's Hospital San Diego, CA, USA.
*
*Corresponding author: Sheila F. Friedlander, UCSD Division of Pediatric Dermatology, Rady Children's Hospital San Diego, 8010 Frost Street, Suite 602, San Diego, CA 92123, USA. Tel: +1 858 966 6795; Fax: +1 858 576 9260; E-mail: [email protected]

Abstract

Infantile haemangioma is the most common tumour of infancy, yet the origin of these lesions remains controversial and the predictable life cycle is poorly understood. Much new information on infantile haemangiomas has emerged over the past decade, but experts continue to debate fundamental features, including cell of origin, nonrandom distribution, and mechanisms regulating the sometimes explosive growth and slow involution. The development of useful laboratory models has been difficult, in turn restricting the development of treatment options available to the clinician. Despite this, new research and creative thinking has spawned several hypotheses on the origin of these tumours and their interesting clinical behaviour, including suggestions of an intrinsic defect in local endothelial cells, a contribution of circulating endothelial progenitors or haemangioblasts, embolisation of shed placental cells and developmental field defects. While no single hypothesis seems to describe all features of infantile haemangioma, continued research seeks to integrate these ideas, create a better understanding of these important tumours and bring new treatments to the clinic.

Type
Review Article
Copyright
Copyright © Cambridge University Press 2007

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

References

1Mulliken, J.B. and Glowacki, J. (1982) Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg 69, 412-422CrossRefGoogle ScholarPubMed
2Finn, M.C., Glowacki, J. and Mulliken, J.B. (1983) Congenital vascular lesions: clinical application of a new classification. J Pediatr Surg 18, 894-900CrossRefGoogle ScholarPubMed
3Amir, J. et al. (1986) Strawberry hemangioma in preterm infants. Pediatr Dermatol 3, 331-332CrossRefGoogle ScholarPubMed
4Haggstrom, A.N. et al. (2007) Prospective study of infantile hemangiomas: demographic, prenatal, and perinatal characteristics. J Pediatr 150, 291-294CrossRefGoogle ScholarPubMed
5Haggstrom, A.N. et al. (2006) Prospective study of infantile hemangiomas: clinical characteristics predicting complications and treatment. Pediatrics 118, 882-887CrossRefGoogle Scholar
6Orlow, S.J., Isakoff, M.S. and Blei, F. (1997) Increased risk of symptomatic hemangiomas of the airway in association with cutaneous hemangiomas in a “beard” distribution. J Pediatr 131, 643-646CrossRefGoogle Scholar
7Chiller, K.G., Passaro, D. and Frieden, I.J. (2002) Hemangiomas of infancy: clinical characteristics, morphologic subtypes, and their relationship to race, ethnicity, and sex. Arch Dermatol 138, 1567-1576CrossRefGoogle Scholar
8Waner, M. et al. (2003) The nonrandom distribution of facial hemangiomas. Arch Dermatol 139, 869-875CrossRefGoogle ScholarPubMed
9Haggstrom, A.N. et al. (2006) Patterns of infantile hemangiomas: new clues to hemangioma pathogenesis and embryonic facial development. Pediatrics 117, 698-703CrossRefGoogle ScholarPubMed
10Frieden, I.J., Reese, V. and Cohen, D. (1996) PHACE syndrome. The association of posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. Arch Dermatol 132, 307-311CrossRefGoogle ScholarPubMed
11Metry, D.W. et al. (2006) A prospective study of PHACE syndrome in infantile hemangiomas: demographic features, clinical findings, and complications. Am J Med Genet A 140, 975-986CrossRefGoogle Scholar
12North, P.E. et al. (2006) Vascular tumors of infancy and childhood: beyond capillary hemangioma. Cardiovasc Pathol 15, 303-317CrossRefGoogle ScholarPubMed
13Bennett, M.L. et al. (2001) Oral corticosteroid use is effective for cutaneous hemangiomas: an evidence-based evaluation. Arch Dermatol 137, 1208-1213CrossRefGoogle ScholarPubMed
14Metz, B.J. et al. (2004) Response of ulcerated perineal hemangiomas of infancy to becaplermin gel, a recombinant human platelet-derived growth factor. Arch Dermatol 140, 867-870Google Scholar
15Martinez, M.I. et al. (2002) Infantile hemangioma: clinical resolution with 5% imiquimod cream. Arch Dermatol 138, 881-884CrossRefGoogle ScholarPubMed
16Welsh, O. et al. (2004) Treatment of infantile hemangiomas with short-term application of imiquimod 5% cream. J Am Acad Dermatol 51, 639-642CrossRefGoogle ScholarPubMed
17Hazen, P.G. et al. (2005) Proliferating hemangioma of infancy: successful treatment with topical 5% imiquimod cream. Pediatr Dermatol 22, 254-256CrossRefGoogle ScholarPubMed
18Tan, S.T. et al. (2000) Cellular and extracellular markers of hemangioma. Plast Reconstr Surg 106, 529-538CrossRefGoogle ScholarPubMed
19Kraling, B.M. et al. (1996) E-selectin is present in proliferating endothelial cells in human hemangiomas. Am J Pathol 148, 1181-1191Google ScholarPubMed
20Ritter, M.R. et al. (2002) Insulin-like growth factor 2 and potential regulators of hemangioma growth and involution identified by large-scale expression analysis. Proc Natl Acad Sci U S A 99, 7455-7460CrossRefGoogle ScholarPubMed
21Bielenberg, D.R. et al. (1999) Progressive growth of infantile cutaneous hemangiomas is directly correlated with hyperplasia and angiogenesis of adjacent epidermis and inversely correlated with expression of the endogenous angiogenesis inhibitor, IFN-beta. Int J Oncol 14, 401-408Google ScholarPubMed
22Takahashi, K. et al. (1994) Cellular markers that distinguish the phases of hemangioma during infancy and childhood. J Clin Invest 93, 2357-2364Google Scholar
23Chang, J. et al. (1999) Proliferative hemangiomas: analysis of cytokine gene expression and angiogenesis. Plast Reconstr Surg 103, 1-9Google Scholar
24Yu, Y. et al. (2001) Increased Tie2 expression, enhanced response to angiopoietin-1, and dysregulated angiopoietin-2 expression in hemangioma-derived endothelial cells. Am J Pathol 159, 2271-2280CrossRefGoogle ScholarPubMed
25Carmeliet, P. (2005) Angiogenesis in life, disease and medicine. Nature 438, 932-936CrossRefGoogle ScholarPubMed
26Drake, C.J. and Fleming, P.A. (2000) Vasculogenesis in the day 6.5 to 9.5 mouse embryo. Blood 95, 1671-1679CrossRefGoogle ScholarPubMed
27Choi, K. et al. (1998) A common precursor for hematopoietic and endothelial cells. Development 125, 725-732CrossRefGoogle ScholarPubMed
28Ferrara, N. and Kerbel, R.S. (2005) Angiogenesis as a therapeutic target. Nature 438, 967-974CrossRefGoogle ScholarPubMed
29Friedlander, S.F., Ritter, M.R. and Friedlander, M. (2005) Recent progress in our understanding of the pathogenesis of infantile hemangiomas. Lymphat Res Biol 3, 219-225CrossRefGoogle ScholarPubMed
30Bauland, C.G. et al. (2006) The pathogenesis of hemangiomas: a review. Plast Reconstr Surg 117, 29e-35eGoogle Scholar
31Blei, F. et al. (1998) Familial segregation of hemangiomas and vascular malformations as an autosomal dominant trait. Arch Dermatol 134, 718-722Google Scholar
32Walter, J.W. et al. (1999) Genetic mapping of a novel familial form of infantile hemangioma. Am J Med Genet 82, 77-83Google Scholar
33Bischoff, J. (2002) Monoclonal expansion of endothelial cells in hemangioma: an intrinsic defect with extrinsic consequences? Trends Cardiovasc Med 12, 220-224CrossRefGoogle ScholarPubMed
34Allen, R.C. et al. (1992) Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet 51, 1229-1239Google Scholar
35Boye, E. et al. (2001) Clonality and altered behavior of endothelial cells from hemangiomas. J Clin Invest 107, 745-752Google Scholar
36Walter, J.W. et al. (2002) Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma. Genes Chromosomes Cancer 33, 295-303Google Scholar
37Khan, Z.A. et al. (2006) Endothelial progenitor cells from infantile hemangioma and umbilical cord blood display unique cellular responses to endostatin. Blood 108, 915-921CrossRefGoogle ScholarPubMed
38Schmidt, A., Addicks, K. and Bloch, W. (2004) Opposite effects of endostatin on different endothelial cells. Cancer Biol Ther 3, 1162-1166; discussion 1167-1168CrossRefGoogle ScholarPubMed
39Li, Q. et al. (2003) Differential expression of CD146 in tissues and endothelial cells derived from infantile haemangioma and normal human skin. J Pathol 201, 296-302CrossRefGoogle ScholarPubMed
40Kaplan, P. et al. (1990) Malformations and minor anomalies in children whose mothers had prenatal diagnosis: comparison between CVS and amniocentesis. Am J Med Genet 37, 366-370Google Scholar
41Burton, B.K. et al. (1995) An increased incidence of haemangiomas in infants born following chorionic villus sampling (CVS). Prenat Diagn 15, 209-214CrossRefGoogle ScholarPubMed
42Powell, T.G. et al. (1987) Epidemiology of strawberry haemangioma in low birthweight infants. Br J Dermatol 116, 635-641Google Scholar
43North, P.E. et al. (2001) A unique microvascular phenotype shared by juvenile hemangiomas and human placenta. Arch Dermatol 137, 559-570Google Scholar
44North, P.E., Waner, M. and Brodsky, M.C. (2002) Are infantile hemangiomas of placental origin? Ophthalmology 109, 633-634CrossRefGoogle ScholarPubMed
45Bree, A.F. et al. (2001) Infantile hemangiomas: speculation on placental trophoblastic origin. Arch Dermatol 137, 573-577Google Scholar
46Barnes, C.M. et al. (2005) Evidence by molecular profiling for a placental origin of infantile hemangioma. Proc Natl Acad Sci U S A 102, 19097-19102CrossRefGoogle ScholarPubMed
47Asahara, T. et al. (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275, 964-967CrossRefGoogle ScholarPubMed
48Yoder, M.C. et al. (2007) Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood 109, 1801-1809CrossRefGoogle ScholarPubMed
49Kleinman, M.E. et al. (2003) Increased circulating AC133+ CD34+ endothelial progenitor cells in children with hemangioma. Lymphat Res Biol 1, 301-307Google Scholar
50Peichev, M. et al. (2000) Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood 95, 952-958Google Scholar
51Yu, Y. et al. (2004) Endothelial progenitor cells in infantile hemangioma. Blood 103, 1373-1375CrossRefGoogle ScholarPubMed
52Yu, Y. et al. (2006) Mesenchymal stem cells and adipogenesis in hemangioma involution. Stem Cells 24, 1605-1612CrossRefGoogle ScholarPubMed
53Ritter, M.R. et al. (2006) Myeloid cells in infantile hemangioma. Am J Pathol 168, 621-628Google Scholar
54Fernandez Pujol, B. et al. (2000) Endothelial-like cells derived from human CD14 positive monocytes. Differentiation 65, 287-300CrossRefGoogle ScholarPubMed
55Havemann, K., Pujol, B.F. and Adamkiewicz, J. (2003) In vitro transformation of monocytes and dendritic cells into endothelial like cells. Adv Exp Med Biol 522, 47-57Google Scholar
56Bailey, A.S. et al. (2006) Myeloid lineage progenitors give rise to vascular endothelium. Proc Natl Acad Sci U S A 103, 13156-13161Google Scholar
57Dadras, S.S. et al. (2004) Infantile hemangiomas are arrested in an early developmental vascular differentiation state. Mod Pathol 17, 1068-1079Google Scholar
58Nguyen, V.A. et al. (2006) Infantile hemangioma is a proliferation of LYVE-1-negative blood endothelial cells without lymphatic competence. Mod Pathol 19, 291-298Google Scholar
59Hamlat, A. et al. (2005) Pathophysiology of capillary haemangioma growth after birth. Med Hypotheses 64, 1093-1096Google Scholar
60Kleinman, M.E., Blei, F. and Gurtner, G.C. (2005) Circulating endothelial progenitor cells and vascular anomalies. Lymphat Res Biol 3, 234-239CrossRefGoogle ScholarPubMed
61Semenza, G.L. (1999) Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 15, 551-578CrossRefGoogle ScholarPubMed
62Cejudo-Martin, P. and Johnson, R.S. (2005) A new notch in the HIF belt: how hypoxia impacts differentiation. Dev Cell 9, 575-576Google Scholar
63Manalo, D.J. et al. (2005) Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood 105, 659-669CrossRefGoogle ScholarPubMed
64Feldser, D. et al. (1999) Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. Cancer Res 59, 3915-3918Google ScholarPubMed
65Loike, J.D. et al. (1992) Hypoxia induces glucose transporter expression in endothelial cells. Am J Physiol 263, C326-333Google Scholar
66Yu, Y. et al. (2004) Genomic imprinting of IGF2 is maintained in infantile hemangioma despite its high level of expression. Mol Med 10, 117-123CrossRefGoogle ScholarPubMed
67Burns, J.L., Jackson, D.A. and Hassan, A.B. (2001) A view through the clouds of imprinting. Faseb J 15, 1694-1703Google Scholar
68Ogawa, O. et al. (1993) Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms' tumour. Nature 362, 749-751CrossRefGoogle ScholarPubMed
69Constancia, M. et al. (2002) Placental-specific IGF-II is a major modulator of placental and fetal growth. Nature 417, 945-948CrossRefGoogle Scholar
70Ceradini, D.J. et al. (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10, 858-864CrossRefGoogle ScholarPubMed
71Ogino, S. and Redline, R.W. (2000) Villous capillary lesions of the placenta: distinctions between chorangioma, chorangiomatosis, and chorangiosis. Hum Pathol 31, 945-954CrossRefGoogle ScholarPubMed
72Reshetnikova, O.S. et al. (1996) Increased incidence of placental chorioangioma in high-altitude pregnancies: hypobaric hypoxia as a possible etiologic factor. Am J Obstet Gynecol 174, 557-561CrossRefGoogle ScholarPubMed
73Bakaris, S. et al. (2004) Case of large placental chorioangioma associated with diffuse neonatal hemangiomatosis. Pediatr Dev Pathol 7, 258-261CrossRefGoogle ScholarPubMed
74Metry, D.W. and Hebert, A.A. (2000) Benign cutaneous vascular tumors of infancy: when to worry, what to do. Arch Dermatol 136, 905-914CrossRefGoogle ScholarPubMed
75Iwata, J. et al. (1996) High frequency of apoptosis in infantile capillary haemangioma. J Pathol 179, 403-408Google Scholar
76Mancini, A.J. and Smoller, B.R. (1996) Proliferation and apoptosis within juvenile capillary hemangiomas. Am J Dermatopathol 18, 505-514Google Scholar
77Razon, M.J. et al. (1998) Increased apoptosis coincides with onset of involution in infantile hemangioma. Microcirculation 5, 189-195Google Scholar
78Halperin, R. et al. (2000) Placental apoptosis in normal and abnormal pregnancies. Gynecol Obstet Invest 50, 84-87Google Scholar
79Smith, S.C. et al. (2000) Apoptosis is a rare event in first-trimester placental tissue. Am J Obstet Gynecol 183, 697-699Google Scholar
80Ritter, M.R. et al. (2003) Identifying potential regulators of infantile hemangioma progression through large-scale expression analysis: a possible role for the immune system and indoleamine 2,3 dioxygenase (IDO) during involution. Lymphat Res Biol 1, 291-299Google Scholar
81North, P.E. et al. (2004) High expression of indoleamine 2,3 deoxygenase in infantile hemangioma: evidence for immune tolerance. Mod Pathol 17 (S1), 97A(Abstract)Google Scholar
82Mellor, A.L. et al. (2001) Prevention of T cell-driven complement activation and inflammation by tryptophan catabolism during pregnancy. Nat Immunol 2, 64-68CrossRefGoogle ScholarPubMed
83Takikawa, O. et al. (1986) Tryptophan degradation in mice initiated by indoleamine 2,3-dioxygenase. J Biol Chem 261, 3648-3653Google Scholar
84Frumento, G. et al. (2002) Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med 196, 459-468Google Scholar
85Glowacki, J. and Mulliken, J.B. (1982) Mast cells in hemangiomas and vascular malformations. Pediatrics 70, 48-51Google Scholar
86Tan, S.T. et al. (2004) Mast cells and hemangioma. Plast Reconstr Surg 113, 999-1011Google Scholar
87Hasan, Q. et al. (2000) Clusterin/apoJ expression during the development of hemangioma. Hum Pathol 31, 691-697CrossRefGoogle ScholarPubMed
88Meininger, C.J. and Zetter, B.R. (1992) Mast cells and angiogenesis. Semin Cancer Biol 3, 73-79Google Scholar
89Obeso, J., Weber, J. and Auerbach, R. (1990) A hemangioendothelioma-derived cell line: its use as a model for the study of endothelial cell biology. Lab Invest 63, 259-269Google Scholar
90Bautch, V.L. et al. (1987) Endothelial cell tumors develop in transgenic mice carrying polyoma virus middle T oncogene. Cell 51, 529-537CrossRefGoogle ScholarPubMed
91Tan, S.T. et al. (2000) A novel in vitro human model of hemangioma. Mod Pathol 13, 92-99Google Scholar
92North, P.E. et al. (2003) Ex vivo hemangiogenesis in fibrin gels: a morphological and immunohistochemical analysis. Lab Invest 83, 18A (Abstract)Google Scholar
93Frieden, I.J. et al. (2005) Infantile hemangiomas: current knowledge, future directions. Proceedings of a research workshop on infantile hemangiomas, April 7-9, 2005, Bethesda, Maryland, USA. Pediatr Dermatol 22, 383-406Google ScholarPubMed
94Peng, Q. et al. (2005) The establishment of the hemangioma model in nude mouse. J Pediatr Surg 40, 1167-1172Google Scholar
95Ezekowitz, R.A., Mulliken, J.B. and Folkman, J. (1992) Interferon alfa-2a therapy for life-threatening hemangiomas of infancy. N Engl J Med 326, 1456-1463Google Scholar
96Chang, E. et al. (1997) Successful treatment of infantile hemangiomas with interferon-alpha-2b. J Pediatr Hematol Oncol 19, 237-244Google Scholar
97Barlow, C.F. et al. (1998) Spastic diplegia as a complication of interferon Alfa-2a treatment of hemangiomas of infancy. J Pediatr 132, 527-530Google Scholar
98Greinwald, J.H. Jr. et al. (1999) An update on the treatment of hemangiomas in children with interferon alfa-2a. Arch Otolaryngol Head Neck Surg 125, 21-27Google Scholar
99Boon, L.M., MacDonald, D.M. and Mulliken, J.B. (1999) Complications of systemic corticosteroid therapy for problematic hemangioma. Plast Reconstr Surg 104, 1616-1623Google Scholar
100Huang, S.A. et al. (2000) Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. N Engl J Med 343, 185-189Google Scholar
101Pittman, K.M. et al. (2006) No evidence for maternal-fetal microchimerism in infantile hemangioma: a molecular genetic investigation. J Invest Dermatol 126, 2533-2538Google Scholar
102Regnier, S. et al. (2007) Endothelial cells in infantile haemangiomas originate from the child and not from the mother (a fluorescence in situ hybridization-based study). Br J Dermatol 157, 158-160Google Scholar
103Sasaki, G.H., Pang, C.Y. and Wittliff, J.L. (1984) Pathogenesis and treatment of infant skin strawberry hemangiomas: clinical and in vitro studies of hormonal effects. Plast Reconstr Surg 73, 359-370Google Scholar
104Lui, W. et al. (1997) Sex hormone receptors of hemangiomas in children. Chin Med J (Engl) 110, 349-351Google Scholar
105Malamitsi-Puchner, A. et al. (2000) Changes in serum levels of vascular endothelial growth factor in males and females throughout life. J Soc Gynecol Investig 7, 309-312Google Scholar
106Nguyen, V.A. et al. (2004) Infantile hemangioma is a proliferation of beta 4-negative endothelial cells adjacent to HLA-DR-positive cells with dendritic cell morphology. Hum Pathol 35, 739-744Google Scholar
107Hasan, Q. et al. (2001) Altered mitochondrial cytochrome b gene expression during the regression of hemangioma. Plast Reconstr Surg 108, 1471-1476; discussion 1477-1478CrossRefGoogle ScholarPubMed
108Hand, J.L. and Frieden, I.J. (2002) Vascular birthmarks of infancy: resolving nosologic confusion. Am J Med Genet 108, 257-264Google Scholar

Further reading, resources and contacts

The International Society for the Study of Vascular Anomalies (ISSVA.) is a worldwide organisation of medical specialists with special interest in vascular tumours and congenital vascular malformations:

Mulliken, J.B. and Young, A.E. (1988) Vascular Birthmarks: Haemangiomas and Malformations, W.B. Saunders Co., Philadelphia, PA, USAGoogle Scholar
Waner, M. and Suen, J.Y., eds (1999) Hemangiomas and Vascular Malformations of the Head and Neck, Wiley-Liss, New York, USAGoogle Scholar
Shannon, L. and Marshall, C.with Waner, M. (1997) Birthmarks: A Guide to Hemangiomas and Vascular Malformation, Women's Health Publishing, Minden, NV, USAGoogle Scholar
Mulliken, J.B. and Young, A.E. (1988) Vascular Birthmarks: Haemangiomas and Malformations, W.B. Saunders Co., Philadelphia, PA, USAGoogle Scholar
Waner, M. and Suen, J.Y., eds (1999) Hemangiomas and Vascular Malformations of the Head and Neck, Wiley-Liss, New York, USAGoogle Scholar
Shannon, L. and Marshall, C.with Waner, M. (1997) Birthmarks: A Guide to Hemangiomas and Vascular Malformation, Women's Health Publishing, Minden, NV, USAGoogle Scholar