Histopathology and Pathogenesis of Vascular Tumors and Malformations

  • Sara Szabo
  • Paula E. NorthEmail author
Part of the Molecular and Translational Medicine book series (MOLEMED)


Accurate histopathological description combined with knowledgeable clinical and radiological evaluation is an absolute requisite for both study and meaningful diagnosis of vascular anomalies, both neoplastic and malformative. Unfortunately, traditional over-generic use of the hemangioma has caused inappropriate lumping of entities that we now know are both biologically as well as clinically dissimilar. This chapter provides an overview of the current clinical, histological, and immunophenotypical features that distinguish the major types of vascular tumors and malformations presenting in infancy and childhood, and summarizes the diagnostic histopathological criteria and nomenclature currently applied to these lesions in most major vascular anomalies centers around the world. The classification presented is congruent with the latest (2014) guidelines of the International Society for the Study of Vascular Anomalies. A general discussion of pathogenesis is also included for most entities, providing correlation between clinical, epidemiological, histo-immunophenotypic, and, for many, genetic features.


Hemangioma Infantile hemangioma Congenital nonprogressive hemangioma NICH RICH Hepatic hemangioma Spindle cell hemangioma Hobnail hemangioma Epithelioid hemangioma Spindle cell hemangioma Kaposiform hemangioendothelioma Tufted angioma Multifocal lymphagioendothelioma with thrombocytopenia (MLT) Papillary intralymphatic angioendothelioma Retiform hemangioendothelioma Composite hemangioendothelioma Epithelioid hemangioendothelioma Angiosarcoma Capillary/venulocapillary malformation Port-wine stain Venous malformation Verrucous venulocapillary malformation Glomuvenous malformation Arteriovenous malformation Capillary malformation–arteriovenous malformation (CM-AVM) PTEN hamartoma tumor syndrome Parkes–Weber syndrome Hereditary hemorrhagic telangiectasia (HHT) Lymphatic malformation Generalized lymphatic anomaly Gorham–Stout disease Klippel–Trenaunay syndrome CLOVES syndrome 


  1. 1.
    Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg. 1982;69:412–22.PubMedCrossRefGoogle Scholar
  2. 2.
    Wassef M, Blei F, Adams D, Alomari A, Baselga E, Berenstein A, Burrows P, Frieden IJ, Garzon MC, Lopez-Gutierrez J-C, Lord DJE, Mitchel S, Powell J, Prendiville J, Vikkula M. Vascular anomalies classification: recommendations from the international society for the study of vascular anomalies. Pediatrics, originally published online 8 June 2015; doi:  10.1542/peds.2014-3673
  3. 3.
    Bowers RE, Graham EA, Thominson KM. The natural history of the strawberry nevus. Arch Dermatol. 1960;82:667–70.CrossRefGoogle Scholar
  4. 4.
    Powell TG, West CR, Pharoah PO, Cooke RW. Epidemiology of strawberry haemangioma in low birthweight infants. Brit J Dermatol. 1987;116:635–41.CrossRefGoogle Scholar
  5. 5.
    Waner M, Suen JY. The natural history of hemangiomas. In: Waner M, Suen JY, editors. Hemangiomas and vascular malformations of the head and neck. New York: Wiley; 1999. p. 13–45.Google Scholar
  6. 6.
    Mulliken JB, Fishman SJ, Burrows PE. Vascular anomalies. Curr Probl Surg. 2000;37:519–84.CrossRefGoogle Scholar
  7. 7.
    Huang SA, Tu HM, Harney JW, Venihaki M, Butte AJ, Kozakewich HP, Fishman SJ, Larsen PR. Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. N Engl J Med. 2000;343(3):185–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Waner M, North PE, Scherer K, Frieden I, Mihm M. The non-random distribution of facial hemangiomas. Arch Dermatol. 2003;139:869–75.PubMedCrossRefGoogle Scholar
  9. 9.
    Metry DW, Haggstrom AN, Drolet BA, et al. A prospective study of PHACE syndrome in infantile hemangiomas: demographic features, clinical findings, and complications. Am J Med Genet Part A. 2006;140A:975–86.CrossRefGoogle Scholar
  10. 10.
    Drolet BA, Dohil M, Golomb MR, et al. Early stroke and cerebral vasculopathy in children with facial hemangiomas and PHACE association. Pediatrics. 2006;117(3):959–64.PubMedCrossRefGoogle Scholar
  11. 11.
    Iacobas I, Burrows PE, Frieden IJ, Liang MG, Mulliken JB, Mancini AJ, Kramer D, Paller AS, Silverman R, Wagner AM, Metry DW. LUMBAR: association between cutaneous infantile hemangiomas of the lower body and regional congenital anomalies. J Pediatr. 2010;157(5):795–801.e1-7. doi: 10.1016/j.jpeds.2010.05.027. Epub 2010 Jul 2.
  12. 12.
    Leaute-Babreze C, Dumas de la Roque E, Hubiche T, et al. Propranolol for severe hemangiomas of infancy. NEJM. 2008;358(24):2649–51.CrossRefGoogle Scholar
  13. 13.
    Drolet BA, Frommelt PC, Chamlin SL, Haggstrom A, Bauman NM, Chiu YE, Chun RH, Garzon MC, Holland KE, Liberman L, MacLellan-Tobert S, Mancini AJ, Metry D, Puttgen KB, Seefeldt M, Sidbury R, Ward KM, Blei F, Baselga E, Cassidy L, Darrow DH, Joachim S, Kwon EK, Martin K, Perkins J, Siegel DH, Boucek RJ, Frieden IJ. Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Pediatrics. 2013;131(1):128–40. doi: 10.1542/peds.2012-1691. Epub 2012 Dec 24.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Mawn LA. Infantile hemangioma: treatment with surgery or steroids. Am Orthopt J. 2013;63:6–13.PubMedCrossRefGoogle Scholar
  15. 15.
    North PE, Waner M, Buckmiller L, James CA, Mihm MC. Vascular tumors of infancy and childhood: beyond capillary hemangioma. Cardiovasc Pathol. 2006;15:303–17.PubMedCrossRefGoogle Scholar
  16. 16.
    North PE. Vascular tumors and malformations of infancy and childhood. Pathol Case Rev. 2008;13(6):213–35.CrossRefGoogle Scholar
  17. 17.
    North PE, Waner M, Mizeracki A, et al. Jr. GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas. Hum Pathol. 2000;31:11–22.PubMedCrossRefGoogle Scholar
  18. 18.
    North PE, Waner M, Mizeracki A, et al. A unique microvascular phenotype shared by juvenile hemangiomas and human placenta. Arch Dermatol. 2001;137:559–70.PubMedCrossRefGoogle Scholar
  19. 19.
    Ritter MR, Dorrell MI, Edmonds J, Friedlander SF, Friedlander M. Insulin-like growth factor 2 and potential regulators of hemangioma growth and involution identified by large-scale expression analysis. Proc Natl Acad Sci. 2002;99:7455–60.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Blei F, Walter J, Orlow SJ, et al. Familial segregation of hemangiomas and vascular malformations as an autosomal dominant trait. Arch Dermatol. 1998;134:718–22.PubMedCrossRefGoogle Scholar
  21. 21.
    Walter JW, Blei F, Anderson JL, et al. Genetic mapping of a novel familial form of infantile hemangioma. Am J Med Genet. 1999;82:77–83.PubMedCrossRefGoogle Scholar
  22. 22.
    Cheung DS, Warman ML, Mulliken JB. Hemangioma in twins. Ann Plast Surg. 1997;38:269–74.PubMedCrossRefGoogle Scholar
  23. 23.
    Barnes C, Huang S, Kaipainen A, et al. Evidence by molecular profiling for a placental origin of infantile hemangioma. PNAS. 2005;102:19097–102.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Ritter MR, Butschek RA, Friedlander M, et al. Pathogenesis of infantile hemangioma: new molecular and cellular insights. Exp Rev Mol Med. 2007;9:1–19.CrossRefGoogle Scholar
  25. 25.
    North PE, Waner M, Brodsky MC. Are infantile hemangiomas of placental origin? Ophthalmology. 2002;109:633–4.PubMedCrossRefGoogle Scholar
  26. 26.
    Kleinman ME, Tepper OM, Capla JM, et al. Increased circulating AC133+ CD34+ endothelial progenitor cells in children with hemangioma. Lymphat Res Biol. 2003;1(4):301–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Yu Y, Flint AF, Mulliken JB, Wu JK, Bischoff J. Endothelial progenitor cells in infantile hemangioma. Blood. 2004;103(4):1373–5.PubMedCrossRefGoogle Scholar
  28. 28.
    Khan ZA, Boscolo E, Picard A, et al. Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice. J Clin Invest. 2008;118(7):2592–9.PubMedCentralPubMedGoogle Scholar
  29. 29.
    Dadras SS, North PE, Bertoncini J, Mihm MC, Detmar M. Infantile hemangiomas are arrested in an early developmental vascular differentiation state. Mod Pathol. 2004;17(9):1068–79.PubMedCrossRefGoogle Scholar
  30. 30.
    Jinnin M, Medici D, Park L, Limaye N, et al. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nat Med. 2008;14(11):1236–46.Google Scholar
  31. 31.
    Munabi NC, Tan QK, Garzon MC, Behr GG, Shawber CJ, Wu JK. Growth hormone induces recurrence of infantile hemangiomas after apparent involution: evidence of growth hormone receptors in infantile hemangioma. Pediatr Dermatol. 2015;1–5.Google Scholar
  32. 32.
    North PE, Waner M, James CJ, et al. Congenital nonprogressive hemangioma: a distinct clinicopathological entity unlike infantile hemangioma. Arch Dermatol. 2001;137:1607–20.PubMedCrossRefGoogle Scholar
  33. 33.
    Enjolras O, Mulliken JB, Boon LM, et al. Noninvoluting congenital hemangioma: a rare cutaneous vascular anomaly. Plast Reconstr Surg. 2001;107:1647–54.PubMedCrossRefGoogle Scholar
  34. 34.
    Berenguer B, Mulliken JB, Enjolras O, et al. Rapidly involuting congenital hemangioma: clinical and histopathologic features. Pediatr Dev Pathol. 2003;6:495–510.PubMedCrossRefGoogle Scholar
  35. 35.
    Nasseri E, Piram M, McCuaig CC, Kokta V, Dubois J, Powell J. Partially involuting congenital hemangiomas: a report of 8 cases and review of the literature. J Am Acad Dermatol. 2014;70(1):75–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Gorincour G, Kokta V, Rypens F, Garel L, Powell J, Dubois J. Imaging characteristics of two subtypes of congenital hemangiomas: rapidly involuting congenital hemangiomas and non-involuting congenital hemangiomas. Pediatr Radiol. 2005;35(12):1178–85.PubMedCrossRefGoogle Scholar
  37. 37.
    DeAos I, James CA, North PE. Hepatic “hemangioma”: not a singular entity. Abstracts, 15th international congress on vascular anomalies, Wellington, NZ, 23 Feb 2004, p. 12.Google Scholar
  38. 38.
    Paltiel HJ, Burrows PE, Kozakewich HPW, et al. Solitary infantile hemangioma: a distinct clinicopathological entity. Abstracts, 15th international congress on vascular anomalies, Wellington, NZ, 23 Feb 2004, p. 12.Google Scholar
  39. 39.
    Christison-Lagay ER, Burrows PE, Alomari A, et al. Hepatic hemangiomas: subtype classification and development of a clinical practice algorithm and registry. J Pediatr Surg. 2007;42:62.PubMedCrossRefGoogle Scholar
  40. 40.
    Hsi Dickie B, Fishman SJ, Azizkhan RG. Hepatic vascular tumors. Semin Pediatr Surg. 2014;23(4):168–72.PubMedCrossRefGoogle Scholar
  41. 41.
    Huang SA, Tu HM, Harney JW, Venihaki M, Butte AJ, Kozakewich HP, Fishman SJ, Larsen PR. Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. NEJM. 2000;343(3):185–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Al Dhaybi R, Lam C, Hatami A, Powell J, McCuaig C, Kokta V. Targetoid hemosiderotic hemangiomas (hobnail hemangiomas) are vascular lymphatic malformations: a study of 12 pediatric cases. J Am Acad Dermatol. 2012;66:116–20.PubMedCrossRefGoogle Scholar
  43. 43.
    Mentzel T, Partanen TA, Kutzner H. Hobnail hemangioma (‘targetoid hemosiderotic hemangioma’): clinicopathologic and immunohistochemical analysis of 62 cases. J Cutan Pathol. 1999;26:279–86.PubMedCrossRefGoogle Scholar
  44. 44.
    Franke FE, Steger K, Marks A, Kutzner H, Mentzel TJ. Hobnail hemangiomas (targetoid hemosiderotic hemangiomas) are true lymphangiomas. J Cutan Pathol. 2004;31(5):362–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Olsen TG, Helwig EB. Angiolymphoid hyperplasia with eosinophilia. A clinicopathologic study of 116 patients. J Am Acad Dermatol. 1985;12:781–96.PubMedCrossRefGoogle Scholar
  46. 46.
    Nielsen GP, Srivastava A, Kattapuram S, et al. Epithelioid hemangioma of bone revisited. A study of 50 cases. Am J Surg Pathol. 2009;33:270.PubMedCrossRefGoogle Scholar
  47. 47.
    Fetsch JE, Weiss S. Observations concerning the pathogenesis of epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia). Mod Pathol. 1991;4:449.PubMedGoogle Scholar
  48. 48.
    Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. WHO classification of soft tissue tumours. In: WHO classification of tumours of soft tissue and bone, 4th edn. Lyon: IARC Press; 2013. p. 11.Google Scholar
  49. 49.
    Antonescu C. Malignant vascular tumors – an update. Mod Pathol. 2014;27:S30–8.PubMedCrossRefGoogle Scholar
  50. 50.
    Weiss SW, Enzinger FM. Spindle cell hemangioendothelioma. A low-grade angiosarcoma resembling a cavernous hemangioma and Kaposi’s sarcoma. Am J Surg Pathol. 1986;10:521–30.PubMedCrossRefGoogle Scholar
  51. 51.
    Perkins P, Weiss SW. Spindle cell hemangioendothelioma. An analysis of 78 cases with reassessment of its pathogenesis and biologic behavior. Am J Surg Pathol. 1996;20:1196–204.PubMedCrossRefGoogle Scholar
  52. 52.
    Fletcher CD. Vascular tumors: an update with emphasis on the diagnosis of angiosarcoma and borderline vascular neoplasms. Monogr Pathol. 1996;38(Chapter 6):181–206.PubMedGoogle Scholar
  53. 53.
    Fletcher CD, Beham A, Schmid C. Spindle cell haemangioendothelioma: a clinicopathological and immunohistochemical study indicative of a non-neoplastic lesion. Histopathology. 1991;18:291–301.PubMedCrossRefGoogle Scholar
  54. 54.
    Imayama S, Murakamai Y, Hashimoto H, Hori Y. Spindle cell hemangioendothelioma exhibits the ultrastructural features of reactive vascular proliferation rather than of angiosarcoma. Am J Clin Pathol. 1992;97:279–87.PubMedGoogle Scholar
  55. 55.
    Fukunaga M, Ushigome S, Nikaido T, et al. Spindle cell hemangioendothelioma: an immunohistochemical and flow cytometric study of six cases. Pathol Int. 1995;45:589–95.PubMedCrossRefGoogle Scholar
  56. 56.
    Amyere M, Dompmartin A, Wouters V, Enjolras O, Kaitila I, Docquier P-L, Godfraind C, Mulliken JB, Boon LM, Vikkula M. Common somatic alterations identified in Maffucci syndrome by molecular karyotyping. Mol Syndromol. 2014;5:259–67.PubMedCentralPubMedGoogle Scholar
  57. 57.
    Pansuriya TC, van Eijk R, d’Adamo P, van Ruler MA, Kuijjer ML, Oosting J, Cleton-Jansen AM, van Oosterwijk JG, Verbeke SL, Meijer D, van Wezel T, Nord KH, Sangiorgi L, Toker B, Liegl-Atzwanger B, San-Julian M, Sciot R, Limaye N, Kindblom LG, Daugaard S, Godfraind C, Boon LM, Vikkula M, Kurek KC, Szuhai K, French PJ, Bovée JV. Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet. 2011;43(12):1256–61.PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Schaap FG, Frech PJ, Bovée JV. Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 in tumors. Adv Anat Pathol. 2013;20:32–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Enjolras O, Wassef M, Mazoyer E, Frieden IJ, Rieu PN, Drouet L, Taieb A, Stalder JF, Escande JP. Infants with Kasabach–Merritt syndrome do not have “true” hemangiomas. J Pediatr. 1997;130:631–40.PubMedCrossRefGoogle Scholar
  60. 60.
    Zukerberg LR, Nickoloff BJ, Weiss SW. Kaposiform hemangioendothelioma of infancy and childhood. An aggressive neoplasm associated with Kasabach-Merritt syndrome and lymphangiomatosis. Am J Surg Pathol. 1993;17:321–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Niedt GW, Greco MA, Wieczorek R, et al. Hemangioma with Kaposi’s sarcoma-like features: report of two cases. Pediatr Pathol. 1989;9:567–75.PubMedCrossRefGoogle Scholar
  62. 62.
    Lyons LL, North PE, Mac-Moune Lai F, et al. Kaposiform hemangioendothelioma: a study of 33 cases emphasizing its pathologic, immunophenotypic, and biologic uniqueness from juvenile hemangioma. Am J Surg Pathol. 2004;28(5):559–68.PubMedCrossRefGoogle Scholar
  63. 63.
    Enjolras O, Mulliken JB, Wassef M, et al. Residual lesions after Kasabach-Merritt phenomenon in 41 patients. J Am Acad Dermatol. 2000;42:225–35.PubMedCrossRefGoogle Scholar
  64. 64.
    Le Huu AR, Jokinen CH, Ruben BP, Mihm M, Weiss SW, North PE, Dadras SS. Expression of Prox1, lymphatic endothelial nuclear transcription factor, in kaposiform hemangioendothelioma and tufted hemangioma. Am J Surg Pathol. 2010;34(11):1563–73.Google Scholar
  65. 65.
    North PE, Kahn T, Cordisco MR, et al. Multifocal lymphangioendotheliomatosis with thrombocytopenia: a newly recognized clinicopathological entity. Arch Dermatol. 2004;140:599–606.PubMedCrossRefGoogle Scholar
  66. 66.
    Prasad V, Fishman SJ, Mulliken JB, et al. Cutaneovisceral angiomatosis with thrombocytopenia. Pediatr Dev Pathol. 2005;8:407–19.PubMedCrossRefGoogle Scholar
  67. 67.
    Maronn M, Catrine K, North PE, et al. Expanding the phenotype of multifocal lymphangioendotheliomatosis with thrombocytopenia. Pediatr Blood Cancer. 2009;52(4):531–4.PubMedCrossRefGoogle Scholar
  68. 68.
    Fanburg-Smith JC, Michal M, Partanen TA, et al. Papillary intralymphatic angioendothelioma (PILA): a report of twelve cases of a distinctive vascular tumor with phenotypic features of lymphatic vessels. Am J Surg Pathol. 1999;23:1004–10.PubMedCrossRefGoogle Scholar
  69. 69.
    Fanburg-Smith JC. Papillary intralymphatic angioendothelioma. In: Fletcher CDM, Bridge JA, Hogendoorn PW, Mertens F, editors. WHO classification of tumors of soft tissue and bone. Lyon: IARC Press; 2013. Chap. 8, p. 148.Google Scholar
  70. 70.
    Goldblum JR, Folpe AL, Weiss SW. Hobnail (Dabska-retiform) hemangioendothelioma. In: Enzinger and Weiss’s soft tissue tumors, 6th edn. Philadelphia: Elsevier Saunders; 2014. p. 693–8.Google Scholar
  71. 71.
    Sangüeza OP, Requena L. Malignant neoplasms. In: Pathology of vascular skin lesions. Totowa: Humana Press; 2003. Chap. 9, p. 217–74.Google Scholar
  72. 72.
    Requena L, Kutzner H. Hemangioendothelioma. Semin Diagn Pathol. 2013;30:29–44.PubMedCrossRefGoogle Scholar
  73. 73.
    Parsons A, Sheehan DJ, Sangueza OP. Retiform hemangioendotheliomas usually do not express D2-40 and VEGFR-3. Am J Dermatopathol. 2008;30:31–3.PubMedCrossRefGoogle Scholar
  74. 74.
    Calonje E, Fletcher CD, Wilson-Jones E, Rosai J. Retiform hemangioendothelioma. A distinctive form of low-grade angiosarcoma delineated in a series of 15 cases. Am J Surg Pathol. 1994;18:115–25.PubMedCrossRefGoogle Scholar
  75. 75.
    Weiss SW, Goldblum JR. Enzinger and Weiss’s soft tissue tumors, 4th edn. St. Louis: Mosby; 2001.Google Scholar
  76. 76.
    Schommer M, Herbst RA, Brodersen JP, et al. Retiform hemangioendothelioma: another tumor associated with human herpesvirus 8? J Am Acad Dermatol. 2000;42:290–2.PubMedCrossRefGoogle Scholar
  77. 77.
    Reis-Filho JS, Paiva ME, Lopes JM. Congenital composite hemangioendothelioma: case report and reappraisal of the hemangioendothelioma spectrum. J Cutan Pathol. 2002;29(4):226–31.PubMedCrossRefGoogle Scholar
  78. 78.
    Requena L, Luis Díaz J, Manzarbeitia F, Carrillo R, Fernández-Herrera J, Kutzner H. Cutaneous composite hemangioendothelioma with satellitosis and lymph node metastases. J Cutan Pathol. 2008;35(2):225–30.PubMedGoogle Scholar
  79. 79.
    Nayler SJ, Rubin BP, Calonje E, Chan JK, Fletcher CD. Composite hemangioendothelioma: a complex, low-grade vascular lesion mimicking angiosarcoma. Am J Surg Pathol. 2000;24(3):352–61.PubMedCrossRefGoogle Scholar
  80. 80.
    Aydingöz IE, Demirkesen C, Serdar ZA, Mansur AT, Yaşar S, Aslan C. Composite haemangioendothelioma with lymph-node metastasis: an unusual presentation at an uncommon site. Clin Exp Dermatol. 2009;34(8):e802–6.PubMedCrossRefGoogle Scholar
  81. 81.
    McNab PM, Quigley BC, Glass LF, Jukic DM. Composite hemangioendothelioma and its classification as a low-grade malignancy. Am J Dermatopathol. 2013;35(4):517–22.PubMedCrossRefGoogle Scholar
  82. 82.
    Fukunaga M, Suzuki K, Saegusa N, Folpe AL. Composite hemangioendothelioma: report of 5 cases including one with associated Maffucci syndrome. Am J Surg Pathol. 2007;31(10):1567–72. PMID: 17895759.PubMedCrossRefGoogle Scholar
  83. 83.
    Lau K, Massad M, Pollak C, Rubin C, Yeh J, Wang J, Edelman G, Yeh J, Prasad S, Weinberg G. Clinical patterns and outcome in epithelioid hemangioendothelioma with or without pulmonary involvement: insights from an internet registry in the study of a rare cancer. Chest. 2011;140(5):1312–8. PMID: 21546438.PubMedCrossRefGoogle Scholar
  84. 84.
    Vignon-Pennamen MD, Varroud-Vial C, Janssen F, Degott C, Verola O, Cottenot F. Cutaneous metastases of hepatic epithelioid hemangioendothelioma. Ann Dermatol Venereol. 1989;116(11):864–6. French. PMID: 2619191.PubMedGoogle Scholar
  85. 85.
    Mentzel T, Beham A, Calonje E, et al. Epithelioid hemangioendothelioma of skin and soft tissues: clinicopathologic and immunohistochemical study of 30 cases. Am J Surg Pathol. 1997;21:363–74.PubMedCrossRefGoogle Scholar
  86. 86.
    Miettinen M, Wang ZF. Prox1 transcription factor as a marker for vascular tumors-evaluation of 314 vascular endothelial and 1086 nonvascular tumors. Am J Surg Pathol. 2012;36(3):351–9.PubMedCentralPubMedCrossRefGoogle Scholar
  87. 87.
    Naqvi J, Ordonez NG, Luna MA, Williams MD, Weber RS, El-Naggar AK. Epithelioid hemangioendothelioma of the head and neck: role of podoplanin in the differential diagnosis. Head Neck Pathol. 2008;2(1):25–30.PubMedCentralPubMedCrossRefGoogle Scholar
  88. 88.
    Vasquez M, Ordóñez NG, English GW, Mackay B. Epithelioid hemangioendothelioma of soft tissue: report of a case with ultrastructural observations. Ultrastruct Pathol. 1998;22(1):73–8.PubMedCrossRefGoogle Scholar
  89. 89.
    Quante M, Patel NK, Hill S, et al. Epithelioid hemangioendothelioma presenting in the skin: a clinicopathologic study of eight cases. Am J Dermatopathol. 1998;20:541–6.PubMedCrossRefGoogle Scholar
  90. 90.
    Tanas MR, Sboner A, Oliveira AM, Erickson-Johnson MR, Hespelt J, Hanwright PJ, Flanagan J, Luo Y, Fenwick K, Natrajan R, Mitsopoulos C, Zvelebil M, Hoch BL, Weiss SW, Debiec-Rychter M, Sciot R, West RB, Lazar AJ, Ashworth A, Reis-Filho JS, Lord CJ, Gerstein MB, Rubin MA, Rubin BP. Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma. Sci Transl Med. 2011;3(98):98.CrossRefGoogle Scholar
  91. 91.
    Errani C, Zhang L, Sung YS, Hajdu M, Singer S, Maki RG, Healey JH, Antonescu CR. A novel WWTR1-CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites. Genes Chromosomes Cancer. 2011;50(8):644–53. PMID: 21584898.PubMedCentralPubMedCrossRefGoogle Scholar
  92. 92.
    Mitelman F, Johansson B, Mertens F. The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer. 2007;7(4):233–45. PMID: 17361217.PubMedCrossRefGoogle Scholar
  93. 93.
    Chan SW, Lim CJ, Chen L, et al. The Hippo pathway in biological control and cancer development. J Cell Physiol. 2011;226:928–39.PubMedCrossRefGoogle Scholar
  94. 94.
    Attiyeh EF, London WB, Mosse YP, et al. Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med. 2005;353:2243–53.PubMedCrossRefGoogle Scholar
  95. 95.
    Barbashina V, Salazar P, Holland EC, et al. Allelic losses at 1p36 and 19q13 in gliomas: correlation with histologic classification, definition of a 150-kb minimal deleted region on 1p36, and evaluation of CAMTA1 as a candidate tumor suppressor gene. Clin Cancer Res. 2005;11:1119–28.PubMedGoogle Scholar
  96. 96.
    Antonescu CR, Le Loarer F, Mosquera JM, Sboner A, Zhang L, Chen CL, Chen HW, Pathan N, Krausz T, Dickson BC, Weinreb I, Rubin MA, Hameed M, Fletcher CD. Novel YAP1-TFE3 fusion defines a distinct subset of epithelioid hemangioendothelioma. Genes Chromosomes Cancer. 2013;52:775–84.PubMedCentralPubMedCrossRefGoogle Scholar
  97. 97.
    Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA, Gayyed MF, Anders RA, Maitra A, Pan D. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell. 2007;130(6):1120–33.PubMedCentralPubMedCrossRefGoogle Scholar
  98. 98.
    Ladanyi M, Lui MY, Antonescu CR, Krause-Boehm A, Meindl A, Argani P, Healey JH, Ueda T, Yoshikawa H, Meloni-Ehrig A, Sorensen PH, Mertens F, Mandahl N, van den Berghe H, Sciot R, Dal Cin P, Bridge J. The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Oncogene. 2001;20:48–57.PubMedCrossRefGoogle Scholar
  99. 99.
    Flucke U, Vogels RJ, de Saint Aubain Somerhausen N, Creytens DH, Riedl RG, van Gorp JM, Milne AN, Huysentruyt CJ, Verdijk MA, van Asseldonk MM, Suurmeijer AJ, Bras J, Palmedo G, Groenen PJ, Mentzel T. Epithelioid hemangioendothelioma: clinicopathologic, immunhistochemical, and molecular genetic analysis of 39 cases. Diagn Pathol. 2014;9:131. PMID: 24986479.PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Ferrari A, Casanova M, Bisogno G, Cecchetto G, Meazza C, Gandola L, Garaventa A, Mattke A, Treuner J, Carli M. Malignant vascular tumors in children and adolescents: a report from the Italian and German Soft Tissue Sarcoma Cooperative Group. Med Pediatr Oncol. 2002;39:109–14. PMID: 12116058.PubMedCrossRefGoogle Scholar
  101. 101.
    Deyrup AT, Miettinen M, North PE, Khoury JD, Tighiouart M, Spunt SL, Parham D, Weiss SW, Shehata BM. Angiosarcomas arising in the viscera and soft tissue of children and young adults: a clinicopathologic study of 15 cases. Am J Surg Pathol. 2009;33:264–9. PMID: 18987547.PubMedCrossRefGoogle Scholar
  102. 102.
    Holden CA, Spittle MF, Jones EW. Angiosarcoma of the face and scalp, prognosis and treatment. Cancer. 1987;59:1046–57.PubMedCrossRefGoogle Scholar
  103. 103.
    Brenn T, Fletcher CD. Radiation-associated cutaneous atypical vascular lesions and angiosarcoma: clinicopathologic analysis of 42 cases. Am J Surg Pathol. 2005;29:983–96.PubMedGoogle Scholar
  104. 104.
    Deyrup AT, Miettinen M, North PE, Khoury JD, Tighiouart M, Spunt SL, Parham DM, Shehata BM, Weiss SW. Pediatric cutaneous angiosarcomas: a clinicopathologic study of 10 cases. Am J Surg Pathol. 2011;35:70–5.PubMedCrossRefGoogle Scholar
  105. 105.
    Deyrup AT, McKenney JK, Tighiouart M, Folpe AL, Weiss SW. Sporadic cutaneous angiosarcomas: a proposal for risk stratification based on 69 cases. Am J Surg Pathol. 2008;32:72–7.PubMedCrossRefGoogle Scholar
  106. 106.
    Folpe AL, Chand EM, Goldblum JR, Weiss SW. Expression of Fli-1, a nuclear transcription factor, distinguishes vascular neoplasms from potential mimics. Am J Surg Pathol. 2001;25:1061–6. PMID: 11474291.PubMedCrossRefGoogle Scholar
  107. 107.
    DeYoung BR, Swanson PE, Argenyi ZB, Ritter JH, Fitzgibbon JF, Stahl DJ, Hoover W, Wick MR. CD31 immunoreactivity in mesenchymal neoplasms of the skin and subcutis: report of 145 cases and review of putative immunohistologic markers of endothelial differentiation. J Cutan Pathol. 1995;22:215–22.PubMedCrossRefGoogle Scholar
  108. 108.
    Miettinen M, Lindenmayer AE, Chaubal A. Endothelial cell markers CD31, CD34, and BNH9 antibody to H- and Y-antigens – evaluation of their specificity and sensitivity in the diagnosis of vascular tumors and comparison with von Willebrand factor. Mod Pathol. 1994;7(1):82–90. PMID: 7512718.PubMedGoogle Scholar
  109. 109.
    Breiteneder-Geleff S, Soleiman A, Kowalski H, Horvat R, Amann G, Kriehuber E, Diem K, Weninger W, Tschachler E, Alitalo K, Kerjaschki D. Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am J Pathol. 1999;154:385–94. PMID: 10027397.PubMedCentralPubMedCrossRefGoogle Scholar
  110. 110.
    Kahn HJ, Bailey D, Marks A. Monoclonal antibody D2-40, a new marker of lymphatic endothelium, reacts with Kaposi’s sarcoma and a subset of angiosarcomas. Mod Pathol. 2002;15:434–40.PubMedCrossRefGoogle Scholar
  111. 111.
    Antonescu CR, Yoshida A, Guo T, Chang NE, Zhang L, Agaram NP, Qin LX, Brennan MF, Singer S, Maki RG. KDR activating mutations in human angiosarcomas are sensitive to specific kinase inhibitors. Cancer Res. 2009;69:7175–9. PMID: 19723655.PubMedCentralPubMedCrossRefGoogle Scholar
  112. 112.
    Manner J, Radlwimmer B, Hohenberger P, Mössinger K, Küffer S, Sauer C, Belharazem D, Zettl A, Coindre JM, Hallermann C, Hartmann JT, Katenkamp D, Katenkamp K, Schöffski P, Sciot R, Wozniak A, Lichter P, Marx A, Ströbel P. MYC high level gene amplification is a distinctive feature of angiosarcomas after irradiation or chronic lymphedema. Am J Pathol. 2010;176:34–9.PubMedCentralPubMedCrossRefGoogle Scholar
  113. 113.
    Guo T, Zhang L, Chang NE, Singer S, Maki RG, Antonescu CR. Consistent MYC and FLT4 gene amplification in radiation-induced angiosarcoma but not in other radiation-associated atypical vascular lesions. Genes Chromosomes Cancer. 2011;50:25–33. PMID: 20949568.PubMedCentralPubMedCrossRefGoogle Scholar
  114. 114.
    Italiano A, Thomas R, Breen M, Zhang L, Crago AM, Singer S, Khanin R, Maki RG, Mihailovic A, Hafner M, Tuschl T, Antonescu CR. The miR-17-92 cluster and its target THBS1 are differentially expressed in angiosarcomas dependent on MYC amplification. Genes Chromosomes Cancer. 2012;51:569–78. PMID:22383169.PubMedCentralPubMedCrossRefGoogle Scholar
  115. 115.
    Popper H, Thomas L, Telles NC, et al. Development of hepatic angiosarcoma in man induced by vinyl chloride, thorotrast, and arsenic. Am J Pathol. 1978;92:349.PubMedCentralPubMedGoogle Scholar
  116. 116.
    Jennings TA, Peterson L, Axiotis CA, et al. Angiosarcoma associated with foreign body material. A report of three cases. Cancer. 1988;62:2436–44.PubMedCrossRefGoogle Scholar
  117. 117.
    Bessis D, Sotto A, Roubert P, et al. Endothelin-secreting angiosarcoma occurring at the site of an arteriovenous fistula for haemodialysis in a renal transplant recipient. Br J Dermatol. 1998;138:361–3.PubMedCrossRefGoogle Scholar
  118. 118.
    Leake J, Sheehan MP, Rampling D, et al. Angiosarcoma complicating xeroderma pigmentosum. Histopathology. 1992;21:179–81.PubMedCrossRefGoogle Scholar
  119. 119.
    Ulbright TM, Clark SA, Einhorn LH. Angiosarcoma associated with germ cell tumors. Hum Pathol. 1985;16:268.PubMedCrossRefGoogle Scholar
  120. 120.
    Tso CY, Sommer A, Hamoudi AB. Aicardi syndrome, metastatic angiosarcoma of the leg, and scalp lipoma. Am J Med Genet. 1993;45:594.CrossRefGoogle Scholar
  121. 121.
    Cafiero F, Gipponi M, Peressini A, et al. Radiation-associated angiosarcoma: diagnostic and therapeutic implications: two case reports and review of the literature. Cancer. 1196;77:249.Google Scholar
  122. 122.
    McLaughlin ER, Brown LF, Weiss SW, et al. VEGF receptors are expressed in a pediatric angiosarcoma in a patient with Aicardi’s syndrome. J Invest Dermatol. 2000;114:1209.PubMedCrossRefGoogle Scholar
  123. 123.
    Cancellieri A, Eusebi V, Mambelli V, et al. Well-differentiated angiosarcoma of the skin following radiotherapy. Report of two cases. Pathol Res Pract. 1991;187:301–6.PubMedCrossRefGoogle Scholar
  124. 124.
    Caldwell JB, Ryan MT, Benson PM, et al. Cutaneous angiosarcoma arising in the radiation site of a congenital hemangioma. J Am Acad Dermatol. 1995;33:865–70.PubMedCrossRefGoogle Scholar
  125. 125.
    Lezama-del Valle P, Gerald WL, Tsai J, et al. Malignant vascular tumors in young patients. Cancer. 1998;83:1634–9.PubMedCrossRefGoogle Scholar
  126. 126.
    Rossi S, Fletcher CD. Angiosarcoma arising in hemangioma/vascular malformation: report of four cases and review of the literature. Am J Sur Pathol. 2002;26:1319.CrossRefGoogle Scholar
  127. 127.
    Nord KM, Kandel J, Lefkowitch JH, Lobritto SJ, Morel KD, North PE, Garzon MC. Multiple cutaneous infantile hemangiomas associated with hepatic angiosarcoma: case report and review of the literature. Pediatrics. 2006;118:e907–13. PMID: 16880251.PubMedCrossRefGoogle Scholar
  128. 128.
    Stewart FW, Treves N. Lymphangiosarcoma in postmastectomy lymphedema. Cancer. 1948;1:64–81.PubMedCrossRefGoogle Scholar
  129. 129.
    Folpe AL, Veikkola T, Valtola R, Weiss SW. Vascular endothelial growth factor receptor-3 (VEGFR-3): a marker of vascular tumors with presumed lymphatic differentiation, including Kaposi’s sarcoma, kaposiform and Dabska-type hemangioendotheliomas, and a subset of angiosarcomas. Mod Pathol. 2000;13:180–5.PubMedCrossRefGoogle Scholar
  130. 130.
    Shirley MD, Tang H, Gallione CJ, Baugher JD, Frelin LP, Cohen B, North PE, Marchuk DA, Comi AM, Pevsner J. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med. 2013;368:1971–9.PubMedCentralPubMedCrossRefGoogle Scholar
  131. 131.
    Sudarsanam A, Ardern-Holmes SL. Sturge-Weber syndrome: from the past to the present. Eur J Paediatr Neurol. 2014;18:257–66.PubMedCrossRefGoogle Scholar
  132. 132.
    Eerola I, Boon LM, Mulliken JB, Burrows PE, Dompmartin A, Watanabe S, Vanwijck R, Vikkula M. Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet. 2003;73:1240–9. PMID: 14639529.PubMedCentralPubMedCrossRefGoogle Scholar
  133. 133.
    Piccione M, Fragapane T, Antona V, Giachino D, Cupido F, Corsello G. PTEN hamartoma tumor syndromes in childhood: description of two cases and a proposal for follow-up protocol. Am J Med Genet A. 2013;161A(11):2902–8.PubMedCrossRefGoogle Scholar
  134. 134.
    Luks VL, Kamitaki N, Vivero MP, Uller W, Rab R, Bovée JV, Rialon KL, Guevara CJ, Alomari AI, Greene AK, Fishman SJ, Kozakewich HP, Maclellan RA, Mulliken JB, Rahbar R, Spencer SA, Trenor 3rd CC, Upton J, Zurakowski D, Perkins JA, Kirsh A, Bennett JT, Dobyns WB, Kurek KC, Warman ML, McCarroll SA, Murillo R. Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. J Pediatr. 2015;166(4):1048–54. PMID: 25681199.PubMedCrossRefGoogle Scholar
  135. 135.
    Lee MS, Liang MG, Mulliken JB. Diffuse capillary malformation with overgrowth: a clinical subtype of vascular anomalies with hypertrophy. J Am Acad Dermatol. 2013;69(4):589–94. PMID: 23906555.PubMedCrossRefGoogle Scholar
  136. 136.
    Couto JA, Huang L, Vivero MP, Kamitaki N, Maclellan RA, Mulliken JB, Bischoff J, Warman ML, Greene AK. Abstract 72: endothelial cells from capillary malformations are enriched for somatic GNAQ mutations and aberrantly express PDGFRβ. Plastic Reconstr Surg. 2015;135:56.CrossRefGoogle Scholar
  137. 137.
    Comi AM. Update on Sturge-Weber syndrome: diagnosis, treatment, quantitative measures, and controversies. Lymphat Res Biol. 2007;5:257–64.PubMedCrossRefGoogle Scholar
  138. 138.
    Piram M, Lorette G, Sirinelli D, Herbreteau D, Giraudeau B, Maruani A. Sturge-Weber syndrome in patients with facial port-wine stain. Pediatr Dermatol. 2012;29:32–7.PubMedCrossRefGoogle Scholar
  139. 139.
    Ch’ng S, Tan ST. Facial port-wine stains – clinical stratification and risks of neuro-ocular involvement. J Plast Reconstr Aesthet Surg. 2008;61:889–93.PubMedCrossRefGoogle Scholar
  140. 140.
    North PE, Sanchez-Carpintero I, Mizeracki A, Waner M, Mihm MC. The distinctive histology of lip enlargement in port-wine stains: a clinicopathological study. Lab Invest. 2003;83(1):96A.Google Scholar
  141. 141.
    Sanchez-Carpintero I, Mihm MC, Waner M, Mizeracki A, North PE. Epithelial and mesenchymal hamartomatous changes in mature port-wine stains: morphological evidence for a multiple germ layer field defect. J Am Acad Dermatol. 2004;50(4):606–12.CrossRefGoogle Scholar
  142. 142.
    Finley JL, Clark RA, Colvin RB, et al. Immunofluorescent staining with antibodies to factor VIII, fibronectin, and collagenous basement membrane protein in normal human skin and port wine stains. Arch Dermatol. 1982;118:971–5.PubMedCrossRefGoogle Scholar
  143. 143.
    Barsky SH, Rosen S, Geer DE, Noe JM. The nature and evolution of port wine stains: a computer-assisted study. J Invest Dermatol. 1980;74:154–7.PubMedCrossRefGoogle Scholar
  144. 144.
    Smoller BR, Rosen S. Port-wine stains. A disease of altered neural modulation of blood vessels? Arch Dermatol. 1986;122:177–9.PubMedCrossRefGoogle Scholar
  145. 145.
    Rydh M, Malm M, Jernbeck J, et al. Ectatic blood vessels in port-wine stains lack innervation: possible role in pathogenesis. Plast Reconstr Surg. 1991;87:419–22.PubMedCrossRefGoogle Scholar
  146. 146.
    Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCune–Albright syndrome. N Engl J Med. 1991;325:1688–95. PubMed: 1944469.PubMedCrossRefGoogle Scholar
  147. 147.
    Van Raamsdonk CD, Bezrookove V, Green G, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009;457:599–602. PubMed: 19078957.PubMedCentralPubMedCrossRefGoogle Scholar
  148. 148.
    Calvert JT, Riney TJ, Kontos CD, et al. Allelic and locus heterogeneity in inherited venous malformations. Hum Mol Genet. 1999;8:1279–89.PubMedCrossRefGoogle Scholar
  149. 149.
    Vikkula M, Boon LM, Carraway KL, 3rd, et al. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. [see comments]. Cell. 1996;87:1181–90.Google Scholar
  150. 150.
    Limaye N, Wouters V, Uebelhoer M, Tuominen M, Wirkkala R, et al. Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations. Nat Genet. 2009;41:118–24.PubMedCentralPubMedCrossRefGoogle Scholar
  151. 151.
    Wouters V, et al. Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects. Eur J Hum Genet. 2010;18:414–20.PubMedCentralPubMedCrossRefGoogle Scholar
  152. 152.
    Soblet J, Limaye N, Uebelhoer M, Boon LM, Vikkula M. Variable somatic TIE2 mutations in half of sporadic venous malformations. Mol Syndromol. 2013;4:179–83.PubMedCentralPubMedGoogle Scholar
  153. 153.
    Uebelhoer M, et al. Venous malformation-causative TIE2 mutations mediate an AKT-dependent decrease in PDGFB. Hum Mol Genet. 2013;22:3438–48.PubMedCentralPubMedCrossRefGoogle Scholar
  154. 154.
    Bean WB. Anomylous vascular spiders and related lesions of the skin. Springfield: Charles C. Thomas; 1958.Google Scholar
  155. 155.
    Nguyen H-L, Boon LM, Vikkula M. Genetics of vascular malformations. Semin Pediatr Surg. 2014;23:221–6.PubMedCrossRefGoogle Scholar
  156. 156.
    Imperial R, Helwig EB. Verrucous hemangioma. A clinicopathologic study of 21 cases. Arch Dermatol. 1967;96(3):247–53. PMID: 6038751.PubMedCrossRefGoogle Scholar
  157. 157.
    Mankani MH, Dufresne CR. Verrucous malformations: their presentation and management. Ann Plast Surg. 2000;45:31–6.PubMedCrossRefGoogle Scholar
  158. 158.
    Mulliken JB. Capillary malformations, hyperkeratotic stains, and miscellaneous vascular blots. In: Mulliken & Young’s vascular anomalies: hemangiomas and malformations, 2nd edn. Oxford: Oxford University Press; 2013, p. 538.Google Scholar
  159. 159.
    Couto JA, Vivero MP, Kozakewich HP, Taghinia AH, Mulliken JB, Warman ML, Greene AK. A somatic MAP3K3 mutation is associated with verrucous venous malformation. Am J Hum Genet. 2015;96:480–6. PMID: 25728774.PubMedCentralPubMedCrossRefGoogle Scholar
  160. 160.
    Tennant LB, Mulliken JB, Perez-Atayde AR, Kozakewich HP. Verrucous hemangioma revisited. Pediatr Dermatol. 2006;23:208–15.PubMedCrossRefGoogle Scholar
  161. 161.
    Wang L, Gao T, Wang G. Verrucous hemangioma: a clinicopathological and immunohistochemical analysis of 74 cases. J Cutan Pathol. 2014;41:823–30.PubMedCrossRefGoogle Scholar
  162. 162.
    Laing EL, Brasch HD, Steel R, Jia J, Itinteang T, Tan ST, Day DJ. Verrucous hemangioma expresses primitive markers. J Cutan Pathol. 2013;40:391–6.PubMedCrossRefGoogle Scholar
  163. 163.
    Mounayer C, Wassef M, Enjolras O, et al. Facial ‘glomangiomas’: large facial venous malformations with glomus cells. J Am Acad Dermatol. 2001;45:239–45.PubMedCrossRefGoogle Scholar
  164. 164.
    Gould EW, Manivel JC, Albores-Saavedra J, et al. Locally infiltrative glomus tumors and glomangiosarcomas. A clinical, ultrastructural, and immunohistochemical study. Cancer. 1990;65:310–8.PubMedCrossRefGoogle Scholar
  165. 165.
    Yang JS, Ko JW, Suh KS, et al. Congenital multiple plaque-like glomangiomyoma. Am J Dermatopathol. 1999;21:454–7.PubMedCrossRefGoogle Scholar
  166. 166.
    Rycroft RJ, Menter MA, Sharvill DE, et al. Hereditary multiple glomus tumours. Report of four families and a review of literature. Trans St Johns Hosp Dermatol Soc. 1975;61:70–81.PubMedGoogle Scholar
  167. 167.
    Wood WS, Dimmick JE. Multiple infiltrating glomus tumors in children. Cancer. 1977;40:1680–5.PubMedCrossRefGoogle Scholar
  168. 168.
    Boon LM, Mulliken JB, Enjolras O, et al. Glomulovenous malformation (glomangioma) and venous malformation: distinct clinicopathologic and genetic entities. Arch Dermatol. 2004;140:971–6.PubMedCrossRefGoogle Scholar
  169. 169.
    Irrthum A, Brouillard P, Enjolras O, et al. Linkage disequilibrium narrows locus for venous malformation with glomus cells (VMGLOM) to a single 1.48 Mbp YAC. Eur J Hum Genet. 2001;9:34–8.PubMedCrossRefGoogle Scholar
  170. 170.
    Brouillard P, Olsen BR, Vikkula M. High-resolution physical and transcript map of the locus for venous malformations with glomus cells (VMGLOM) on chromosome 1p21-p22. Genomics. 2000;67:96–101.PubMedCrossRefGoogle Scholar
  171. 171.
    Brouillard P, Boon LM, Vikkula M. Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations (“glomangiomas”). Am J Hum Genet. 2002;70:866–74.PubMedCentralPubMedCrossRefGoogle Scholar
  172. 172.
    Brouillard P, Boon LM, Revencu N, Berg J, Dompmartin A, Dubois J, Garzon M, Holden S, Kangesu L, Labrèze C, Lynch SA, McKeown C, Meskauskas R, Quere I, Syed S, Vabres P, Wassef M, Mulliken JB, Vikkula M, GVM Study Group. Genotypes and phenotypes of 162 families with a glomulin mutation. Mol Syndromol. 2013;4:157–64.PubMedCentralPubMedGoogle Scholar
  173. 173.
    Amyere M, Aerts V, Brouillard P, McIntyre BA, Duhoux FP, Wassef M, Enjolras O, Mulliken JB, Devuyst O, Antoine-Poirel H, Boon LM, Vikkula M. Somatic uniparental isodisomy explains multifocality of glomuvenous malformations. Am J Hum Genet. 2013;92:188–96.PubMedCentralPubMedCrossRefGoogle Scholar
  174. 174.
    Grisendi S, Chambraud B, Gout I, Comoglio PM, Crepaldi T. Ligand-regulated binding of FAP68 to the hepatocyte growth factor receptor. J Biol Chem. 2001;276:46632–8.PubMedCrossRefGoogle Scholar
  175. 175.
    Chambraud B, Radanyi C, Camonis JH, Shazand K, Rajkowski K, Baulieu E. FAP48, a new protein that forms specific complexes with both immunophilins FKBP59 and FKBP12: prevention by the immunosuppressant drugs FK506 and rapamycin. J Biol Chem. 1996;271:32923–9.PubMedCrossRefGoogle Scholar
  176. 176.
    Tron AE, Arai T, Duda DM, Kuwabara H, Olszewski JL, Fujiwara Y, Bahamon BN, Signoretti S, Schulman BA, DeCaprio JA. The glomuvenous malformation protein glomulin binds Rbx1 and regulates cullin RING ligase-mediated turnover of Fbw7. Mol Cell. 2012;46:67–78.PubMedCentralPubMedCrossRefGoogle Scholar
  177. 177.
    McIntyre BA, Brouillard P, Aerts V, Gutierrez-Roelens I, Vikkula M. Glomulin is predominantly expressed in vascular smooth muscle cells in the embryonic and adult mouse. Gene Expr Patterns. 2004;4:351–8.PubMedCrossRefGoogle Scholar
  178. 178.
    Enjolras O, Logeart I, Gelbert F, et al. Arteriovenous malformations: a study of 200 cases. Ann Dermatol Venereol (Fr). 1999;127:17–22.Google Scholar
  179. 179.
    Bluefarb SM, Adams LA. Arteriovenous malformation with angiodermatitis. Stasis dermatitis simulating Kaposi’s disease. Arch Dermatol. 1967;96:176–81. PMID: 6039154.PubMedCrossRefGoogle Scholar
  180. 180.
    Guttmacher AE, Marchuk DA, White RI. Hereditary hemorrhagic telangiectasia. N Engl J Med. 1995;333:918–24.PubMedCrossRefGoogle Scholar
  181. 181.
    Abdalla SA, Letarte M. Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. J Med Genet. 2006;43:97–110.PubMedCentralPubMedCrossRefGoogle Scholar
  182. 182.
    Revencu N, Boon LM, Mendola A, et al. RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation. Hum Mutat. 2013;34:1632–41.PubMedCrossRefGoogle Scholar
  183. 183.
    Kim C, Ko CJ, Baker KE, Antaya RJ. Histopathologic and ultrasound characteristics of cutaneous capillary malformations in a patient with capillary malformation-arteriovenous malformation syndrome. Pediatr Dermatol. 2015;32:128–31.PubMedCrossRefGoogle Scholar
  184. 184.
    Kozakewich HPW, Mulliken JB. Histopathology of vascular malformations. In: Mulliken & Young’s vascular anomalies: hemangiomas and malformations, 2nd edn. Oxford: Oxford University Press; 2013. p. 500–1.Google Scholar
  185. 185.
    Kozakewich HPW, Mulliken JB. Histopathology of vascular malformations. In: Mulliken & Young’s vascular anomalies: hemangiomas and malformations, 2nd edn. Oxford: Oxford University Press; 2013. p. 488.Google Scholar
  186. 186.
    Hershkovitz D, Bercovich D, Sprecher E, Lapidot M. RASA1 mutations may cause hereditary capillary malformations without arteriovenous malformations. Br J Dermatol. 2008;158:1035–40.PubMedCrossRefGoogle Scholar
  187. 187.
    Thiex R, Mulliken JB, Revencu N, Boon LM, Burrows PE, Cordisco M, Dwight Y, Smith ER, Vikkula M, Orbach DB. A novel association between RASA1 mutations and spinal arteriovenous anomalies. Am J Neuroradiol. 2010;31:775–9.PubMedCrossRefGoogle Scholar
  188. 188.
    Wooderchak-Donahue W, Stevenson DA, McDonald J, Grimmer JF, Gedge F, Bayrak-Toydemir P. RASA1 analysis: clinical and molecular findings in a series of consecutive cases. Eur J Med Genet. 2012;55:91–5.PubMedCrossRefGoogle Scholar
  189. 189.
    Henkemeyer M, Rossi DJ, Holmyard DP, Puri MC, Mbamalu G, Harpal K, Shih TS, Jacks T, Pawson T. Vascular system defects and neuronal apoptosis in mice lacking ras GTPase-activating protein. Nature. 1995;377:695–701.PubMedCrossRefGoogle Scholar
  190. 190.
    Friedman E, Gejman PV, Martin GA, McCormick F. Nonsense mutations in the C-terminal SH2 region of the GTPase activating protein (GAP) gene in human tumours. Nat Genet. 1993;5:242–7.PubMedCrossRefGoogle Scholar
  191. 191.
    Burrows PE, Gonzalez-Garay ML, Rasmussen JC, Aldrich MB, Guilliod R, Maus EA, Fife CE, Kwon S, Lapinski PE, King PD, Sevick-Muraca EM. Lymphatic abnormalities are associated with RASA1 gene mutations in mouse and man. Proc Natl Acad Sci U S A. 2013;110:8621–6.PubMedCentralPubMedCrossRefGoogle Scholar
  192. 192.
    Lubeck BA, Lapinski PE, Bauler TJ, Oliver JA, Hughes ED, Saunders TL, King PD. Blood vascular abnormalities in Rasa1(R780Q) knockin mice: implications for the pathogenesis of capillary malformation-arteriovenous malformation. Am J Pathol. 2014;184:3163–9.PubMedCentralPubMedCrossRefGoogle Scholar
  193. 193.
    Lapinski PE, Kwon S, Lubeck BA, Wilkinson JE, Srinivasan RS, Sevick-Muraca E, King PD. RASA1 maintains the lymphatic vasculature in a quiescent functional state in mice. J Clin Invest. 2012;122:733–47.PubMedCentralPubMedCrossRefGoogle Scholar
  194. 194.
    Kawasaki J, Aegerter S, Fevurly RD, Mammoto A, Mammoto T, Sahin M, Mably JD, Fishman SJ, Chan J. RASA1 functions in EPHB4 signaling pathway to suppress endothelial mTORC1 activity. J Clin Invest. 2014;124:2774–84.PubMedCentralPubMedCrossRefGoogle Scholar
  195. 195.
    McAllister KA, Grogg KM, Johnson DW, et al. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet. 1994;8:345–51.PubMedCrossRefGoogle Scholar
  196. 196.
    Johnson DW, Berg JN, Baldwin MA, et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet. 1996;13:189–95.PubMedCrossRefGoogle Scholar
  197. 197.
    Gallione CJ, Repetto GM, Legius E, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 32. (SMAD4). Lancet. 2004;363(9412):852–9.PubMedCrossRefGoogle Scholar
  198. 198.
    Tillet E, Bailly S. Emerging roles of BMP9 and BMP10 in hereditary hemorrhagic telangiectasia. Front Genet. 2015;8;5:456.Google Scholar
  199. 199.
    Wooderchak-Donahue WL, McDonald J, O’Fallon B, Upton PD, Li W, Roman BL, Young S, Plant P, Fülöp GT, Langa C, Morrell NW, Botella LM, Bernabeu C, Stevenson DA, Runo JR, Bayrak-Toydemir P. BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia. Am J Hum Genet. 2013;5; 93:530–7.CrossRefGoogle Scholar
  200. 200.
    Sansal I, Sellers WR. The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol. 2004;22:2954–63.PubMedCrossRefGoogle Scholar
  201. 201.
    Brewis C, Pracy JP, Albert DM. Treatment of lymphangiomas of the head and neck in children by intralesional injection of OK-432 (Picibanil). Clin Otolaryngol. 2000;25:130–5.PubMedCrossRefGoogle Scholar
  202. 202.
    Molitch HI, Unger EC, White EL, et al. Percutaneous sclerotherapy of lymphangiomas. Radiology. 1995;194:343–7. Lancet. 2004;363:852–9.CrossRefGoogle Scholar
  203. 203.
    Easterly NB. Cutaneous hemangiomas, vascular stains and malformations, and associated syndromes [Review]. Probl Dermatol. 1995;7:67–108.Google Scholar
  204. 204.
    Chitayat D, Kalousek DK, Bamforth JS, et al. Lymphatic abnormalities in fetuses with posterior cervical cystic hydroma. Am J Med Genet. 1989;33:352–6.PubMedCrossRefGoogle Scholar
  205. 205.
    Kurek KC, Luks VL, Ayturk UM, Alomari AI, Fishman SJ, Spenser SA, et al. Somatic activating mutations in PIK3CA cause CLOVES syndrome. Am J Hum Genet. 2012;90:1108–15.PubMedCentralPubMedCrossRefGoogle Scholar
  206. 206.
    Lee JH, Huynh M, Silhavy JL, Kim S, Dixon-Salazar T, Heiberg A, et al. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat Genet. 2012;44:941–5.PubMedCentralPubMedCrossRefGoogle Scholar
  207. 207.
    Maclellan RA, Luks VL, Vivero MP, Mulliken JB, Zurakowski D, Padwa BL, et al. PIK3CA activating mutations in facial infiltrating lipomatosis. Plast Reconstr Surg. 2014;133:12e–9.PubMedCrossRefGoogle Scholar
  208. 208.
    Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304:554.PubMedCrossRefGoogle Scholar
  209. 209.
    Kinross KM, Montgomery KG, Kleinschmidt M, Waring P, Ivetac I, Tikoo A, et al. An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice. J Clin Invest. 2012;122:553–7.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory MedicineChildren’s Hospital of WisconsinMilwaukeeUSA
  2. 2.Department of Pathology, Division of Pediatric PathologyMedical College of WisconsinMilwaukeeUSA

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