title: Biomolecular markers and involution of hemangiomas.
abstract: OBJECTIVE
  Vascular anomalies are a diverse set of lesions with distinct clinical behaviors, whose biomolecular characteristics are largely undefined. Common hemangiomas proliferate during the first year of life, then involute at a variable pace over several years. Other vascular tumors may involute much more quickly (rapidly involuting congenital hemangiomas [RICH]), not at all (lymphatic malformation), or display malignant behavior (angiosarcoma). Key cytokines driving angiogenesis include vascular endothelial growth factor (VEGF) family members/receptors (placental growth factor [PIGF], VEGF-A, and VEGF-C) and angiopoietins. The authors hypothesized that involuting hemangiomas would display biologic markers distinctly different from noninvoluting vascular lesions.
  
  
  METHODS
  Six patient samples were analyzed: (1) RICH, (2) proliferating hemangioma, (3) involuting hemangioma, (4) tufted angioma, (5) hepatic angiosarcoma, and (6) lymphatic malformation. Detailed examination of endothelial/vascular mural cell status was performed by fluorescent double-label immunostaining using specific markers (PECAM-1, alphaSMA) in combination with markers of proliferation (anti-phospho-histone H3) or apoptosis (TUNEL). Expression of PIGF, VEGF-A, VEGF-C, and Ang-1 was localized by in situ hybridization.
  
  
  RESULTS
  Involuting/proliferating common hemangiomas demonstrated vasculature with abundant vascular mural cells (alphaSMA+); in contrast, alphaSMA(+) cells were rare in RICH vessels. Endothelial apoptosis was increased dramatically, but proliferation was unchanged during involution. VEGF-A was expressed in all lesions except lymphatic malformation, which displayed VEGF-C and Ang-1 upregulation. Strikingly, PIGF expression was increased markedly in the lesions predicted to involute/actively involuting but was virtually absent from noninvoluting tumors.
  
  
  CONCLUSIONS
  Vessel architecture and endothelial/vascular mural cell status differed between lesions, differentiating even common versus rapidly involuting hemangioma and corresponded to clinical involution. VEGF-A expression characterized endothelial-derived lesions, whereas VEGF-C marked lymphatic-derived cells. PIGF expression occurred only in vascular anomalies predicted to involute or actively involuting, a pattern potentially linked to PIGF function as a conditional antagonist of VEGF-A. Thus, distinct patterns of morphology and angiogenic factor expression characterize vascular anomalies with different clinical behaviors.
authors.affiliation: Division of Pediatric Surgery, Children's Hospital of New York-Presbyterian College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Frischer
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Huang
authors.forename: Anna
authors.initials: A
authors.lastname: Serur
authors.forename: Angela
authors.initials: A
authors.lastname: Kadenhe
authors.forename: Darrell J
authors.initials: DJ
authors.lastname: Yamashiro
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Kandel
mesh_terms: D042682:Angiopoietins / Q000096:biosynthesis; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D002675:Child, Preschool; D004730:Endothelium, Vascular / Q000166:cytology; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology; D006391:Hemangioma / Q000378:metabolism* / Q000473:pathology*; D006394:Hemangiosarcoma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007223:Infant; D007231:Infant, Newborn; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008208:Lymphatic System / Q000002:abnormalities; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000096:biosynthesis; D042442:Vascular Endothelial Growth Factors / Q000096:biosynthesis
chemical_list: D042682:Angiopoietins; D014408:Biomarkers, Tumor; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D042442:Vascular Endothelial Growth Factors; D000072483:Placenta Growth Factor