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New Insights in Vascular Lesions Development and Identification with Immunohistochemical Markers

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Applied Immunohistochemistry in the Evaluation of Skin Neoplasms

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Abstract

During the last decade several advances in vascular lesions pathology have been achieved, mostly derived from discoveries in molecular genetics and biochemistry. These new discoveries have contributed to the understanding of endothelial cell proliferation and neoplastic transformation. Concurrently, new immunohistochemical markers have been developed, some of them with proved clinical utility in diagnostic histopathology. In this chapter we will review the most relevant advances in the pathogenesis of vascular lesions and we will summarize the application of new vascular markers including: endoglein, ERG, FLI-1, HIF-1 alpha, LMO-2, Lyve-1, c-Myc, Prox-1, TEMs, VEGFRs, and WT-1, among others, in the evaluation and diagnosis of vascular lesions.

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References

  1. Rao P, Lahat G, Arnold C, Gavino AC, Lahat S, Hornick JL, et al. Angiosarcoma: a tissue microarray study with diagnostic implications. Am J Dermatopathol. 2013;35(4):432–7.

    Article  PubMed  Google Scholar 

  2. Ordóñez NG. Immunohistochemical endothelial markers: a review. Adv Anat Pathol. 2012;19(5):281–95.

    Article  PubMed  CAS  Google Scholar 

  3. Millard PR, Heryet AR. An immunohistological study of factor VIII related antigen and Kaposi’s sarcoma using polyclonal and monoclonal antibodies. J Pathol. 1985;146(1):31–8.

    Article  CAS  PubMed  Google Scholar 

  4. Ordóñez NG, Batsakis JG. Comparison of Ulex europaeus I lectin and factor VIII-related antigen in vascular lesions. Arch Pathol Lab Med. 1984;108(2):129–32.

    PubMed  Google Scholar 

  5. Vanchinathan V, Mizramani N, Kantipudi R, Schwartz EJ, Sundram UN. The vascular marker CD31 also highlights histiocytes and histiocyte-like cells within cutaneous tumors. Am J Clin Pathol. 2015;143(2):177–85.

    Article  PubMed  Google Scholar 

  6. Traweek ST, Kandalaft PL, Mehta P, Battifora H. The human hematopoietic progenitor cell antigen (CD34) in vascular neoplasia. Am J Clin Pathol. 1991;96(1):25–31.

    Article  CAS  PubMed  Google Scholar 

  7. Fukunaga M. Expression of D2-40 in lymphatic endothelium of normal tissues and in vascular tumours. Histopathology. 2005;46(4):396–402.

    Article  CAS  PubMed  Google Scholar 

  8. 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(4):434–40.

    Article  PubMed  Google Scholar 

  9. Manning T, Smoller BR, Horn TD, El Darouti M, Marzouk S, Hadidi HE, et al. Evaluation of anti-thrombomodulin antibody as a tumor marker for vascular neoplasms. J Cutan Pathol. 2004;31(10):652–6.

    Article  PubMed  Google Scholar 

  10. Kleiman A, Keats EC, Chan NG, Khan ZA. Evolution of hemangioma endothelium. Exp Mol Pathol. 2012;93(2):264–72.

    Article  CAS  PubMed  Google Scholar 

  11. Pack GT, Miller TR. Hemangiomas; classification, diagnosis and treatment. Angiology. 1950;1(5):405–26.

    Article  CAS  PubMed  Google Scholar 

  12. Boye E, Yu Y, Paranya G, Mulliken JB, Olsen BR, Bischoff J. Clonality and altered behavior of endothelial cells from hemangiomas. J Clin Invest. 2001;107(6):745–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Shon W, Ida CM, Boland-Froemming JM, Rose PS, Folpe A. Cutaneous angiosarcoma arising in massive localized lymphedema of the morbidly obese: a report of five cases and review of the literature. J Cutan Pathol. 2011;38(7):560–4.

    Article  PubMed  Google Scholar 

  14. Liu L, Kakiuchi-Kiyota S, Arnold LL, Johansson SL, Wert D, Cohen SM. Pathogenesis of human hemangiosarcomas and hemangiomas. Hum Pathol. 2013;44(10):2302–11.

    Article  CAS  PubMed  Google Scholar 

  15. Holmes LB. Chorionic villus sampling and hemangiomas. J Craniofac Surg. 2009;20 Suppl 1:675–7.

    Article  PubMed  Google Scholar 

  16. Bauland CG, Smit JM, Bartelink LR, Zondervan HA, Spauwen PH. Hemangioma in the newborn: increased incidence after chorionic villus sampling. Prenat Diagn. 2010;30(10):913–7.

    Article  PubMed  Google Scholar 

  17. Wen VW, MacKenzie KL. Modeling human endothelial cell transformation in vascular neoplasias. Dis Model Mech. 2013;6(5):1066–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Blatt J, Powell CM, Burkhart CN, Stavas J, Aylsworth AS. Genetics of hemangiomas, vascular malformations, and primary lymphedema. J Pediatr Hematol Oncol. 2014;36(8):587–93.

    Article  CAS  PubMed  Google Scholar 

  19. Wong WT, Huang NF, Botham CM, Sayed N, Cooke JP. Endothelial cells derived from nuclear reprogramming. Circ Res. 2012;111(10):1363–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ritter MR, Reinisch J, Friedlander SF, Friedlander M. Myeloid cells in infantile hemangioma. Am J Pathol. 2006;168(2):621–8.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Behjati S, Tarpey PS, Sheldon H, Martincorena I, Van Loo P, Gundem G, et al. Recurrent PTPRB and PLCG1 mutations in angiosarcoma. Nat Genet. 2014;46(4):376–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Patiño-Seijas B, Lorenzo-Franco F, Rey-Sanjurjo JL, González-Cuesta M, López-Cedrún Cembranos JL. Vascular Lesions: GLUT-1 expression as a diagnostic tool to discriminate tumors from malformations. J Oral Maxillofac Surg. 2012;70(10):2333–42.

    Article  PubMed  Google Scholar 

  23. Ji Y, Chen S, Li K, Li L, Xu C, Xiang B. Signaling pathways in the development of infantile hemangioma. J Hematol Oncol. 2014;7:13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Errani C, Sung YS, Zhang L, Healey JH, Antonescu CR. Monoclonality of multifocal epithelioid hemangioendothelioma of the liver by analysis of WWTR1-CAMTA1 breakpoints. Cancer Genet. 2012;205(1–2):12–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Stiles JM, Rowntree RK, Amaya C, Diaz D, Kokta V, Mitchell DC, et al. Gene expression analysis reveals marked differences in the transcriptome of infantile hemangioma endothelial cells compared to normal dermal microvascular endothelial cells. Vasc Cell. 2013;5(1):6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Prey S, Leaute-Labreze C, Pain C, Moisan F, Vergnes P, Loot M, et al. Mast cells as possible targets of propranolol therapy: an immunohistological study of beta-adrenergic receptors in infantile haemangiomas. Histopathology. 2014;65(3):436–9.

    Article  PubMed  Google Scholar 

  27. Assaad AM, Kawut SM, Arcasoy SM, Rosenzweig EB, Wilt JS, Sonett JR, et al. Platelet-derived growth factor is increased in pulmonary capillary hemangiomatosis. Chest. 2007;131(3):850–5.

    Article  PubMed  Google Scholar 

  28. Boscolo E, Stewart CL, Greenberger S, Wu JK, Durham JT, Herman IM, et al. JAGGED1 signaling regulates hemangioma stem cell-to-pericyte/vascular smooth muscle cell differentiation. Arterioscler Thromb Vasc Biol. 2011;31(10):2181–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Koina ME, Baxter L, Adamson SJ, Arfuso F, Hu P, Madigan MC, et al. Evidence for lymphatics in the developing and adult human choroid. Invest Ophthalmol Vis Sci. 2015;56(2):1310–27.

    Article  CAS  PubMed  Google Scholar 

  30. Ji RC, Eshita Y, Xing L, Miura M. Multiple expressions of lymphatic markers and morphological evolution of newly formed lymphatics in lymphangioma and lymph node lymphangiogenesis. Microvasc Res. 2010;80(2):195–201.

    Article  CAS  PubMed  Google Scholar 

  31. Young RJ, Fernando M, Hughes D, Brown NJ, Woll PJ. Angiogenic growth factor expression in benign and malignant vascular tumours. Exp Mol Pathol. 2014;97(1):148–53.

    Article  CAS  PubMed  Google Scholar 

  32. Weihrauch M, Bader M, Lehnert G, Koch B, Wittekind C, Wrbitzky R, et al. Mutation analysis of K-ras-2 in liver angiosarcoma and adjacent nonneoplastic liver tissue from patients occupationally exposed to vinyl chloride. Environ Mol Mutagen. 2002;40(1):36–40.

    Article  CAS  PubMed  Google Scholar 

  33. Kunze K, Spieker T, Gamerdinger U, Nau K, Berger J, Dreyer T, et al. A recurrent activating PLCG1 mutation in cardiac angiosarcomas increases apoptosis resistance and invasiveness of endothelial cells. Cancer Res. 2014;74(21):6173–83.

    Article  CAS  PubMed  Google Scholar 

  34. Styring E, Seinen J, Dominguez-Valentin M, Domanski HA, Jönsson M, von Steyern FV, et al. Key roles for MYC, KIT and RET signaling in secondary angiosarcomas. Br J Cancer. 2014;111(2):407–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gramolelli S, Schulz TF. The role of Kaposi sarcoma-associated herpesvirus in the pathogenesis of Kaposi sarcoma. J Pathol. 2015;235(2):368–80.

    Article  CAS  PubMed  Google Scholar 

  36. Janmohamed SR, Madern GC, de Laat PC, Oranje AP. Educational paper: pathogenesis of infantile haemangioma, an update 2014 (part I). Eur J Pediatr. 2015;174(1):97–103.

    Article  PubMed  Google Scholar 

  37. Melis M, Cau M, Corraine S, Secci S, Addis M, Melis M. Cerebral cavernous malformations and unilateral moyamoya in a patient with a new mutation in the KRIT-1 /CCM1 gene. Cerebrovasc Dis. 2014;38(4):311–2.

    Article  PubMed  Google Scholar 

  38. Kurek KC, Luks VL, Ayturk UM, Alomari AI, Fishman SJ, Spencer SA, et al. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am J Hum Genet. 2012;90(6):1108–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, et al. A mosaic activating mutation in AKT1 associated with the proteus syndrome. N Engl J Med. 2011;365(7):611–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Miettinen M, Sarlomo-Rikala M, Wang ZF. Claudin-5 as an immunohistochemical marker for angiosarcoma and hemangioendotheliomas. Am J Surg Pathol. 2011;35(12):1848–56.

    Article  PubMed  Google Scholar 

  41. Hara H. Endoglin (CD105) and claudin-5 expression in cutaneous angiosarcoma. Am J Dermatopathol. 2012;34(7):779–82.

    Article  PubMed  Google Scholar 

  42. Yuan L, Le Bras A, Sacharidou A, Itagaki K, Zhan Y, Kondo M, et al. ETS-related gene (ERG) controls endothelial cell permeability via transcriptional regulation of the claudin 5 (CLDN5) gene. J Biol Chem. 2012;287(9):6582–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Jakab C, Halász J, Kiss A, Schaff Z, Rusvai M, Gálfi P, et al. Claudin-5 protein is a new differential marker for histopathological differential diagnosis of canine hemangiosarcoma. Histol Histopathol. 2009;24(7):801–13.

    CAS  PubMed  Google Scholar 

  44. Miettinen M, Wang ZF, Paetau A, Tan SH, Dobi A, Srivastava S, et al. ERG transcription factor as an immunohistochemical marker for vascular endothelial tumors and prostatic carcinoma. Am J Surg Pathol. 2011;35(3):432–41.

    Article  PubMed  Google Scholar 

  45. Yaskiv O, Rubin BP, He H, Falzarano S, Magi-Galluzzi C, Zhou M. ERG protein expression in human tumors detected with a rabbit monoclonal antibody. Am J Clin Pathol. 2012;138(6):803–10.

    Article  CAS  PubMed  Google Scholar 

  46. Miettinen M, Wang Z, Sarlomo-Rikala M, Abdullaev Z, Pack SD, Fetsch JF. ERG expression in epithelioid sarcoma: a diagnostic pitfall. Am J Surg Pathol. 2013;37(10):1580–5.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Sullivan HC, Edgar MA, Cohen C, Kovach CK, HooKim K, Reid MD. The utility of ERG, CD31 and CD34 in the cytological diagnosis of angiosarcoma: an analysis of 25 cases. J Clin Pathol. 2015;68(1):44–50.

    Article  PubMed  Google Scholar 

  48. Stockman DL, Hornick JL, Deavers MT, Lev DC, Lazar AJ, Wang WL. ERG and FLI1 protein expression in epithelioid sarcoma. Mod Pathol. 2014;27(4):496–501.

    Article  CAS  PubMed  Google Scholar 

  49. McKay KM, Doyle LA, Lazar AJ, Hornick JL. Expression of ERG, an Ets family transcription factor, distinguishes cutaneous angiosarcoma from histological mimics. Histopathology. 2012;61(5):989–91.

    Article  PubMed  Google Scholar 

  50. Kim S, Park HK, Jung HY, Lee SY, Min KW, Kim WY, et al. ERG immunohistochemistry as an endothelial marker for assessing lymphovascular invasion. Korean J Pathol. 2013;47(4):355–64.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Rossi S, Orvieto E, Furlanetto A, Laurino L, Ninfo V, Dei Tos AP. Utility of the immunohistochemical detection of FLI-1 expression in round cell and vascular neoplasm using a monoclonal antibody. Mod Pathol. 2004;17(5):547–52.

    Article  CAS  PubMed  Google Scholar 

  52. Landry JR, Kinston S, Knezevic K, Donaldson IJ, Green AR, Göttgens B. Fli1, Elf1, and Ets1 regulate the proximal promoter of the LMO2 gene in endothelial cells. Blood. 2005;106(8):2680–7.

    Article  CAS  PubMed  Google Scholar 

  53. 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(8):1061–6.

    Article  CAS  PubMed  Google Scholar 

  54. Cuda J, Mirzamani N, Kantipudi R, Robbins J, Welsch MJ, Sundram UN. Diagnostic utility of Fli-1 and D2-40 in distinguishing atypical fibroxanthoma from angiosarcoma. Am J Dermatopathol. 2013;35(3):316–8.

    Article  PubMed  Google Scholar 

  55. Rosado FG, Itani DM, Coffin CM, Cates JM. Utility of immunohistochemical staining with FLI1, D2-40, CD31, and CD34 in the diagnosis of acquired immunodeficiency syndrome-related and non-acquired immunodeficiency syndrome-related Kaposi sarcoma. Arch Pathol Lab Med. 2012;136(3):301–4.

    Article  PubMed  Google Scholar 

  56. Yamada Y, Pannell R, Forster A, Rabbitts TH. The LIM-domain protein Lmo2 is a key regulator of tumour angiogenesis: a new anti-angiogenesis drug target. Oncogene. 2002;21(9):1309–15.

    Article  CAS  PubMed  Google Scholar 

  57. Yamada Y, Pannell R, Forster A, Rabbitts TH. The oncogenic LIM-only transcription factor Lmo2 regulates angiogenesis but not vasculogenesis in mice. Proc Natl Acad Sci U S A. 2000;97(1):320–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Gratzinger D, Zhao S, West R, Rouse RV, Vogel H, Gil EC, et al. The transcription factor LMO2 is a robust marker of vascular endothelium and vascular neoplasms and selected other entities. Am J Clin Pathol. 2009;131(2):264–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sun ZJ, Cai Y, Chen G, Wang R, Jia J, Chen XM, Zheng LW, Zhao YF. LMO2 promotes angiogenesis probably by up-regulation of bFGF in endothelial cells: an implication of its pathophysiological role in infantile haemangioma. Histopathology. 2010;57(4):622–32.

    Google Scholar 

  60. Lossos C, Bayraktar S, Weinzierl E, Younes SF, Hosein PJ, Tibshirani RJ, et al. LMO2 and BCL6 are associated with improved survival in primary central nervous system lymphoma. Br J Haematol. 2014;165(5):640–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Tokuyama W, Mikami T, Masuzawa M, Okayasu I. Autocrine and paracrine roles of VEGF/VEGFR-2 and VEGF-C/VEGFR-3 signaling in angiosarcomas of the scalp and face. Hum Pathol. 2010;41(3):407–14.

    Article  CAS  PubMed  Google Scholar 

  62. Jin Y, Liu Y, Lin Q, Li J, Druso JE, Antonyak MA, et al. Deletion of Cdc42 enhances ADAM17-mediated vascular endothelial growth factor receptor 2 shedding and impairs vascular endothelial cell survival and vasculogenesis. Mol Cell Biol. 2013;33(21):4181–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Miettinen M, Rikala MS, Rys J, Lasota J, Wang ZF. Vascular endothelial growth factor receptor 2 as a marker for malignant vascular tumors and mesothelioma: an immunohistochemical study of 262 vascular endothelial and 1640 nonvascular tumors. Am J Surg Pathol. 2012;36(4):629–39.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Lee YJ, Karl DL, Maduekwe UN, Rothrock C, Ryeom S, D’Amore PA, et al. Differential effects of VEGFR-1 and VEGFR-2 inhibition on tumor metastases based on host organ environment. Cancer Res. 2010;70(21):8357–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Yonemori K, Tsuta K, Ando M, Hirakawa A, Hatanaka Y, Matsuno Y, et al. Contrasting prognostic implications of platelet-derived growth factor receptor-β and vascular endothelial growth factor receptor-2 in patients with angiosarcoma. Ann Surg Oncol. 2011;18(10):2841–50.

    Article  PubMed  Google Scholar 

  66. Galfione SK, Ro JY, Ayala AG, Ge Y. Diagnostic utility of WT-1 cytoplasmic stain in variety of vascular lesions. Int J Clin Exp Pathol. 2014;7(5):2536–43.

    PubMed  PubMed Central  Google Scholar 

  67. Fernandez-Flores A, Fierro S, Larralde M. Expression of WT-1 by the vascular component of acral pseudolymphomatous angiokeratoma of children. J Cutan Pathol. 2015;42(1):50–5.

    Article  PubMed  Google Scholar 

  68. Fernandez-Flores A, Saeb-Lima M. Correct evaluation and interpretation of WT-1 immunostaining in vascular lesions. J Cutan Pathol. 2014;41(9):754–5.

    Article  PubMed  Google Scholar 

  69. Garrido-Ruiz MC, Rodriguez-Pinilla SM, Pérez-Gómez B, Rodriguez-Peralto JL. WT 1 expression in nevi and melanomas: a marker of melanocytic invasion into the dermis. J Cutan Pathol. 2010;37(5):542–8.

    Article  CAS  PubMed  Google Scholar 

  70. McCluggage WG. WT-1 immunohistochemical expression in small round blue cell tumours. Histopathology. 2008;52(5):631–2.

    Article  CAS  PubMed  Google Scholar 

  71. Akishima Y, Ito K, Zhang L, Ishikawa Y, Orikasa H, Kiguchi H, et al. Immunohistochemical detection of human small lymphatic vessels under normal and pathological conditions using the LYVE-1 antibody. Virchows Arch. 2004;444(2):153–7.

    Article  CAS  PubMed  Google Scholar 

  72. Platonova N, Miquel G, Regenfuss B, Taouji S, Cursiefen C, Chevet E, et al. Evidence for the interaction of fibroblast growth factor-2 with the lymphatic endothelial cell marker LYVE-1. Blood. 2013;121(7):1229–37.

    Article  CAS  PubMed  Google Scholar 

  73. Noda Y, Amano I, Hata M, Kojima H, Sawa Y. Immunohistochemical examination on the distribution of cells expressed lymphatic endothelial marker podoplanin and LYVE-1 in the mouse tongue tissue. Acta Histochem Cytochem. 2010;43(2):61–8.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Boettcher MC, Eivazi B, Roessler M, Bette M, Cai C, Wiegand S, et al. Involvement of LYVE-1-positive endothelial cells in the formation of non-lymphatic vascular malformations. Histopathology. 2010;57(5):764–8.

    Article  PubMed  Google Scholar 

  75. Hata H, Aoyagi S, Homma E, Muramatsu R, Shimizu H. Lymphangiosarcoma with strong positivity of D2-40 and LYVE-1 presenting different clinical features from angiosarcoma. J Dermatol. 2014;41(7):656–7.

    Article  PubMed  Google Scholar 

  76. Florez-Vargas A, Vargas SO, Debelenko LV, Perez-Atayde AR, Archibald T, Kozakewich HP, et al. Comparative analysis of D2-40 and LYVE-1 immunostaining in lymphatic malformations. Lymphology. 2008;41(3):103–10.

    CAS  PubMed  Google Scholar 

  77. Heinzelbecker J, Kempf KM, Kurz K, Steidler A, Weiss C, Jackson DG, et al. Lymph vessel density in seminomatous testicular cancer assessed with the specific lymphatic endothelium cell markers D2-40 and LYVE-1: correlation with pathologic parameters and clinical outcome. Urol Oncol. 2013;31(7):1386–94.

    Article  CAS  PubMed  Google Scholar 

  78. Wilting J, Papoutsi M, Christ B, Nicolaides KH, von Kaisenberg CS, Borges J, et al. The transcription factor Prox1 is a marker for lymphatic endothelial cells in normal and diseased human tissues. FASEB J. 2002;16(10):1271–3.

    CAS  PubMed  Google Scholar 

  79. Dadras SS, Skrzypek A, Nguyen L, Shin JW, Schulz MM, Arbiser J, et al. Prox-1 promotes invasion of kaposiform hemangioendotheliomas. J Invest Dermatol. 2008;128(12):2798–806.

    Article  CAS  PubMed  Google Scholar 

  80. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Le Huu AR, Jokinen CH, Rubin BP, Mihm MC, Weiss SW, North PE, et al. Expression of prox1, lymphatic endothelial nuclear transcription factor, in Kaposiform hemangioendothelioma and tufted angioma. Am J Surg Pathol. 2010;34(11):1563–73.

    PubMed  Google Scholar 

  82. Wang L, Gao T, Wang G. Expression of Prox, 1, D2–40, and WT1 in spindle cell hemangioma. J Cutan Pathol. 2014;41(5):447–50.

    Article  PubMed  Google Scholar 

  83. Benevenuto de Andrade BA, Ramírez-Amador V, Anaya-Saavedra G, Martínez-Mata G, Fonseca FP, Graner E, et al. Expression of PROX-1 in oral Kaposi’s sarcoma spindle cells. J Oral Pathol Med. 2014;43(2):132–6.

    Article  CAS  PubMed  Google Scholar 

  84. Reis RM, Reis-Filho JS, Longatto Filho A, Tomarev S, Silva P, Lopes JM. Differential Prox-1 and CD 31 expression in mucousae, cutaneous and soft tissue vascular lesions and tumors. Pathol Res Pract. 2005;201(12):771–6.

    Article  CAS  PubMed  Google Scholar 

  85. Cimpean AM, Poenaru Sava M, Raica M, Ribatti D. Preliminary evidence of the presence of lymphatic vessels immunoreactive for D2-40 and Prox-1 in human pterygium. Oncol Rep. 2011;26(5):1111–3.

    PubMed  Google Scholar 

  86. Sultan A, Dadras SS, Bay JM, Teng NN. Prox-1, Podoplanin and HPV staining assists in identification of lymphangioma circumscriptum of the vulva and discrimination from vulvar warts. Histopathology. 2011;59(6):1274–7.

    Article  PubMed  Google Scholar 

  87. da Cunha Castro EC, Galambos C. Prox-1: a specific and sensitive marker for lymphatic endothelium in normal and diseased human tissues. Ann Thorac Surg. 2011;92(1):407.

    Article  PubMed  Google Scholar 

  88. 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(2):180–5.

    Article  CAS  PubMed  Google Scholar 

  89. Petrova TV, Bono P, Holnthoner W, Chesnes J, Pytowski B, Sihto H, et al. VEGFR-3 expression is restricted to blood and lymphatic vessels in solid tumors. Cancer Cell. 2008;13(6):554–6.

    Article  CAS  PubMed  Google Scholar 

  90. Parsons A, Sheehan DJ, Sangueza OP. Retiform hemangioendotheliomas usually do not express D2-40 and VEGFR-3. Am J Dermatopathol. 2008;30(1):31–3.

    Article  PubMed  Google Scholar 

  91. Kilvaer TK, Valkov A, Sorbye S, Smeland E, Bremnes RM, Busund LT, et al. Profiling of VEGFs and VEGFRs as prognostic factors in soft tissue sarcoma: VEGFR-3 is an independent predictor of poor prognosis. PLoS One. 2010;5(12):e15368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Itakura E, Yamamoto H, Oda Y, Furue M. Tsuneyoshi M. VEGF-C and VEGFR-3 in a series of lymphangiomas: is superficial lymphangioma a true lymphangioma? Virchows Arch. 2009;454(3):317–25.

    Article  CAS  PubMed  Google Scholar 

  93. Yusıflı Z, Kösemehmetoğlu K. CAMTA1 immunostaining is not useful in differentiating epithelioid hemangioendothelioma from its potential mimickers. Turk Patoloji Derg. 2014;30(3):159–65.

    PubMed  Google Scholar 

  94. Anderson T, Zhang L, Hameed M, Rusch V, Travis WD, Antonescu CR. Thoracic epithelioid malignant vascular tumors: a clinicopathologic study of 52 cases with emphasis on pathologic grading and molecular studies of WWTR1-CAMTA1 fusions. Am J Surg Pathol. 2015;39(1):132–9.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Boudousquie AC, Lawce HJ, Sherman R, Olson S, Magenis RE, Corless CL. Complex translocation [7;22] identified in an epithelioid hemangioendothelioma. Cancer Genet Cytogenet. 1996;92(2):116–21.

    Article  CAS  PubMed  Google Scholar 

  96. Wang JJ, Sun XC, Hu L, Liu ZF, Yu HP, Li H, et al. Endoglin (CD105) expression on microvessel endothelial cells in juvenile nasopharyngeal angiofibroma: tissue microarray analysis and association with prognostic significance. Head Neck. 2013;35(12):1719–25.

    Article  PubMed  Google Scholar 

  97. López-Novoa JM, Bernabeu C. The physiological role of endoglin in the cardiovascular system. Am J Physiol Heart Circ Physiol. 2010;299(4):H959–74.

    Article  PubMed  CAS  Google Scholar 

  98. Hou F, Dai Y, Dornhoffer JR, Suen JY, Fan CY, Saad AG, et al. Expression of endoglin (CD105) and endothelial nitric oxide synthase in head and neck arteriovenous malformations. JAMA Otolaryngol Head Neck Surg. 2013;139(3):237–43.

    Article  PubMed  Google Scholar 

  99. Mahmoud M, Allinson KR, Zhai Z, Oakenfull R, Ghandi P, Adams RH, et al. Pathogenesis of arteriovenous malformations in the absence of endoglin. Circ Res. 2010;106(8):1425–33.

    Article  CAS  PubMed  Google Scholar 

  100. Miyata Y, Mitsunari K, Asai A, Takehara K, Mochizuki Y, Sakai H. Pathological significance and prognostic role of microvessel density, evaluated using CD31, CD34, and CD105 in prostate cancer patients after radical prostatectomy with neoadjuvant therapy. Prostate. 2015;75(1):84–91.

    Article  CAS  PubMed  Google Scholar 

  101. de Oliveira DH, da Silveira EJ, de Medeiros AM, Alves PM, Queiroz LM. Study of the etiopathogenesis and differential diagnosis of oral vascular lesions by immunoexpression of GLUT-1 and HIF-1α. J Oral Pathol Med. 2014;43(1):76–80.

    Article  PubMed  CAS  Google Scholar 

  102. Shibaji T, Nagao M, Ikeda N, Kanehiro H, Hisanaga M, Ko S, et al. Prognostic significance of HIF-1 alpha overexpression in human pancreatic cancer. Anticancer Res. 2003;23(6C):4721–7.

    CAS  PubMed  Google Scholar 

  103. Medici D, Olsen BR. Rapamycin inhibits proliferation of hemangioma endothelial cells by reducing HIF-1-dependent expression of VEGF. PLoS One. 2012;7(8):e42913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Tan HH, Ge ZZ, Gao YJ, Chen HM, Fang JY, Chen HY, et al. The role of HIF-1, angiopoietin-2, Dll4 and Notch1 in bleeding gastrointestinal vascular malformations and thalidomide-associated actions: a pilot in vivo study. J Dig Dis. 2011;12(5):349–56.

    Article  CAS  PubMed  Google Scholar 

  105. Mehran R, Nilsson M, Khajavi M, Du Z, Cascone T, Wu HK, et al. Tumor endothelial markers define novel subsets of cancer-specific circulating endothelial cells associated with antitumor efficacy. Cancer Res. 2014;74(10):2731–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Facciponte JG, Ugel S, De Sanctis F, Li C, Wang L, Nair G, et al. Tumor endothelial marker 1-specific DNA vaccination targets tumor vasculature. J Clin Invest. 2014;124(4):1497–511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Bagley RG, Rouleau C, St Martin T, Boutin P, Weber W, Ruzek M, et al. Human endothelial precursor cells express tumor endothelial marker 1/endosialin/CD248. Mol Cancer Ther. 2008;7(8):2536–46.

    Article  CAS  PubMed  Google Scholar 

  108. Vallon M, Essler M. Proteolytically processed soluble tumor endothelial marker (TEM) 5 mediates endothelial cell survival during angiogenesis by linking integrin alpha(v)beta3 to glycosaminoglycans. J Biol Chem. 2006;281(45):34179–88.

    Article  CAS  PubMed  Google Scholar 

  109. Bagley RG, Rouleau C, Weber W, Mehraein K, Smale R, Curiel M, et al. Tumor endothelial marker 7 (TEM-7): a novel target for antiangiogenic therapy. Microvasc Res. 2011;82(3):253–62.

    Article  CAS  PubMed  Google Scholar 

  110. Verma K, Gu J, Werner E. Tumor endothelial marker 8 amplifies canonical Wnt signaling in blood vessels. PLoS One. 2011;6(8):e22334.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Gutwein LG, Al-Quran SZ, Fernando S, Fletcher BS, Copeland EM, Grobmyer SR. Tumor endothelial marker 8 expression in triple-negative breast cancer. Anticancer Res. 2011;31(10):3417–22.

    CAS  PubMed  Google Scholar 

  112. Ginter PS, Mosquera JM, MacDonald TY, D’Alfonso TM, Rubin MA, Shin SJ. Diagnostic utility of MYC amplification and anti-MYC immunohistochemistry in atypical vascular lesions, primary or radiation-induced mammary angiosarcomas, and primary angiosarcomas of other sites. Hum Pathol. 2014;45(4):709–16.

    Article  CAS  PubMed  Google Scholar 

  113. Manner J, Radlwimmer B, Hohenberger P, Mössinger K, Küffer S, Sauer C, et al. MYC high level gene amplification is a distinctive feature of angiosarcomas after irradiation or chronic lymphedema. Am J Pathol. 2010;176(1):34–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Shon W, Sukov WR, Jenkins SM, Folpe AL. MYC amplification and overexpression in primary cutaneous angiosarcoma: a fluorescence in-situ hybridization and immunohistochemical study. Mod Pathol. 2014;27(4):509–15.

    Article  CAS  PubMed  Google Scholar 

  115. Fernandez AP, Sun Y, Tubbs RR, Goldblum JR, Billings SD. FISH for MYC amplification and anti-MYC immunohistochemistry: useful diagnostic tools in the assessment of secondary angiosarcoma and atypical vascular proliferations. J Cutan Pathol. 2012;39(2):234–42.

    Article  PubMed  Google Scholar 

  116. Mentzel T, Schildhaus HU, Palmedo G, Büttner R, Kutzner H. Postradiation cutaneous angiosarcoma after treatment of breast carcinoma is characterized by MYC amplification in contrast to atypical vascular lesions after radiotherapy and control cases: clinicopathological, immunohistochemical and molecular analysis of 66 cases. Mod Pathol. 2012;25(1):75–85.

    Article  CAS  PubMed  Google Scholar 

  117. Ko JS, Billings SD, Lanigan CP, Buehler D, Fernandez AP, Tubbs RR. Fully automated dual-color dual-hapten silver in situ hybridization staining for MYC amplification: a diagnostic tool for discriminating secondary angiosarcoma. J Cutan Pathol. 2014;41(3):286–92.

    Article  PubMed  Google Scholar 

  118. Kuehbacher A, Urbich C, Dimmeler S. Targeting microRNA expression to regulate angiogenesis. Trends Pharmacol Sci. 2008;29(1):12–5.

    Article  CAS  PubMed  Google Scholar 

  119. Urbich C, Kuehbacher A, Dimmeler S. Role of microRNAs in vascular diseases, inflammation, and angiogenesis. Cardiovasc Res. 2008;79(4):581–8.

    Article  CAS  PubMed  Google Scholar 

  120. Bonauer A, Boon RA, Dimmeler S. Vascular microRNAs. Curr Drug Targets. 2010;11(8):943–9.

    Article  CAS  PubMed  Google Scholar 

  121. Nakashima T, Jinnin M, Etoh T, Fukushima S, Masuguchi S, Maruo K, et al. Down-regulation of mir-424 contributes to the abnormal angiogenesis via MEK1 and cyclin E1 in senile hemangioma: its implications to therapy. PLoS One. 2010;5(12):e14334.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Zhang D, Shi Z, Li M, Mi J. Hypoxia-induced miR-424 decreases tumor sensitivity to chemotherapy by inhibiting apoptosis. Cell Death Dis. 2014;5:e1301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Alimchandani M, Wang ZF, Miettinen M. CD30 expression in malignant vascular tumors and its diagnostic and clinical implications: a study of 146 cases. Appl Immunohistochem Mol Morphol. 2014;22(5):358–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Weed BR, Folpe AL. Cutaneous CD30-positive epithelioid angiosarcoma following breast-conserving therapy and irradiation: a potential diagnostic pitfall. Am J Dermatopathol. 2008;30(4):370–2.

    Article  PubMed  Google Scholar 

  125. Aggerholm-Pedersen N, Bærentzen S, Holmberg Jørgensen JP, Safwat A. A rare case of CD30(+), radiation-induced cutaneous angiosarcoma misdiagnosed as T-cell lymphoma. J Clin Oncol. 2011;29(13):e362–4.

    Article  PubMed  Google Scholar 

  126. Ebata N, Nodasaka Y, Sawa Y, Yamaoka Y, Makino S, Totsuka Y, et al. Desmoplakin as a specific marker of lymphatic vessels. Microvasc Res. 2001;61(1):40–8.

    Article  CAS  PubMed  Google Scholar 

  127. Kowalczyk AP, Navarro P, Dejana E, Bornslaeger EA, Green KJ, Kopp DS, et al. VE-cadherin and desmoplakin are assembled into dermal microvascular endothelial intercellular junctions: a pivotal role for plakoglobin in the recruitment of desmoplakin to intercellular junctions. J Cell Sci. 1998;111(Pt 20):3045–57.

    CAS  PubMed  Google Scholar 

  128. Fedele C, Berens D, Rautenfeld V, Pabst R. Desmoplakin and Plakoglobin—specific markers of lymphatic vessels in the skin? Anat Histol Embryol. 2004;33(3):168–71.

    Article  CAS  PubMed  Google Scholar 

  129. Niemelä H, Elima K, Henttinen T, Irjala H, Salmi M, Jalkanen S. Molecular identification of PAL-E, a widely used endothelial-cell marker. Blood. 2005;106(10):3405–9.

    Article  PubMed  CAS  Google Scholar 

  130. Schlingemann RO, Dingjan GM, Emeis JJ, Blok J, Warnaar SO, Ruiter DJ. Monoclonal antibody PAL-E specific for endothelium. Lab Invest. 1985;52(1):71–6.

    CAS  PubMed  Google Scholar 

  131. Keuschnigg J, Tvorogov D, Elima K, Salmi M, Alitalo K, Salminen T, et al. PV-1 is recognized by the PAL-E antibody and forms complexes with NRP-1. Blood. 2012;120(1):232–5.

    Article  CAS  PubMed  Google Scholar 

  132. Jaalouk DE, Ozawa MG, Sun J, Lahdenranta J, Schlingemann RO, Pasqualini R, et al. The original Pathologische Anatomie Leiden-Endothelium monoclonal antibody recognizes a vascular endothelial growth factor binding site within neuropilin-1. Cancer Res. 2007;67(20):9623–9.

    Article  CAS  PubMed  Google Scholar 

  133. Keuschnigg J, Henttinen T, Auvinen K, Karikoski M, Salmi M, Jalkanen S. The prototype endothelial marker PAL-E is a leukocyte trafficking molecule. Blood. 2009;114(2):478–84.

    Article  CAS  PubMed  Google Scholar 

  134. Xu B, deWaal RM, Mor-Vaknin N, Hibbard C, Markovitz DM, Kahn ML. The endothelial cell-specific antibody PAL-E identifies a secreted form of vimentin in the blood vasculature. Mol Cell Biol. 2004;24(20):9198–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Departments of Pathology and Dermatology, Medical Center Boulevard, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA

    Omar P. Sangüeza M.D.

  2. Division of Dermatopathology, Department of Pathology, Wake Forest Baptist Medical Center, 4 Medical Center Blvd, Winston-Salem, NC, 27157, USA

    Julio A. Diaz-Perez M.D.

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  1. Omar P. Sangüeza M.D.
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Correspondence to Omar P. Sangüeza M.D. .

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Editors and Affiliations

  1. Miraca Life Sciences, Dermatopathology Division, Dallas, Texas, USA

    Jose A. Plaza

  2. Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Victor G. Prieto

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Sangüeza, O.P., Diaz-Perez, J.A. (2016). New Insights in Vascular Lesions Development and Identification with Immunohistochemical Markers. In: Plaza, J., Prieto, V. (eds) Applied Immunohistochemistry in the Evaluation of Skin Neoplasms. Springer, Cham. https://doi.org/10.1007/978-3-319-30590-5_8

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