Lymphatic Dissemination

  • Alexandre Nakao Odashiro


Lymphatics compose the second vascular system found in higher vertebrates in addition to the blood vasculature. It has several vital functions including the regulation of tissue pressure, immune surveillance and the absorption of dietary fat in the intestine Cueni and Detmar (Lymphat Res Biol 6:109–122, 2008).


Permeability Migration Tyrosine Integrin Psoriasis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Achen MG, Stacker SA (2006) Tumor lymphangiogenesis and metastatic spread-new players begin to emerge. Int J Cancer 119:1755–1760PubMedCrossRefGoogle Scholar
  2. Achen MG, Stacker SA (2008) Molecular control of lymphatic metastasis. Ann N Y Acad Sci 1131:225–234PubMedCrossRefGoogle Scholar
  3. Amioka T et al (2002) Vascular endothelial growth factor-C expression predicts lymph node metastasis of human gastric carcinomas invading the submucosa. Eur J Cancer 38:1413–1419PubMedCrossRefGoogle Scholar
  4. Aurello P et al (2009) Vascular endothelial growth factor C and microvessel density in gastric carcinoma: Correlation with clinicopathological factors. Our experience and review of the literature. Oncol Res 17:405–411PubMedCrossRefGoogle Scholar
  5. Azzali G (2006) On the transendothelial passage of tumor cell from extravasal matrix into the lumen of absorbing lymphatic vessel. Microvasc Res 72:74–85PubMedCrossRefGoogle Scholar
  6. Balch CM et al (2001) Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 19:3635–3648PubMedGoogle Scholar
  7. Bolenz C et al (2009) The role of lymphangiogenesis in lymphatic tumour spread of urological cancers. BJU Int 104:592–597PubMedCrossRefGoogle Scholar
  8. Britto AV et al (2009) Immunostaining with D2–40 improves evaluation of lymphovascular invasion, but may not predict sentinel lymph node status in early breast cancer. BMC Cancer 9:109PubMedCrossRefGoogle Scholar
  9. Clasper S et al (2008) A novel gene expression profile in lymphatics associated with tumor growth and nodal metastasis. Cancer Res 68:7293–7303PubMedCrossRefGoogle Scholar
  10. Compton C, Fenoglio-Preiser CM, Pettigrew N, Fielding LP (2000) American Joint Committee on Cancer Prognostic Factors Consensus Conference: Colorectal Working Group. Cancer 88:1739–1757PubMedCrossRefGoogle Scholar
  11. Cueni LN, Detmar M (2008) The lymphatic system in health and disease. Lymphat Res Biol 6:109–122PubMedCrossRefGoogle Scholar
  12. Dadras SS et al (2003) Tumor lymphangiogenesis: A novel prognostic indicator for cutaneous melanoma metastasis and survival. Am J Pathol 162:1951–1960PubMedCrossRefGoogle Scholar
  13. de Boer M, van Dijck JA, Bult P, Borm GF, Tjan-Heijnen VC (2010) Breast cancer prognosis and occult lymph node metastases, isolated tumor cells, and micrometastases. J Natl Cancer Inst 102:410–425PubMedCrossRefGoogle Scholar
  14. De Giorgi V et al (2007) Outcome of patients with melanoma and histologically negative sentinel lymph nodes: one institution’s experience. Oncology 73:401–406PubMedCrossRefGoogle Scholar
  15. Dietrich T et al (2010) Cutting edge: Lymphatic vessels, not blood vessels, primarily mediate immune rejections after transplantation. J Immunol 184:535–539PubMedCrossRefGoogle Scholar
  16. Donnem T et al (2009a) VEGF-A and VEGFR-3 correlate with nodal status in operable non-small cell lung cancer: inverse correlation between expression in tumor and stromal cells. Lung Cancer 63:277–283CrossRefGoogle Scholar
  17. Donnem T, Al-Shibli K, Al-Saad S, Busund LT, Bremnes RM (2009b) Prognostic impact of fibroblast growth factor 2 in non-small cell lung cancer: Coexpression with VEGFR-3 and PDGF-B predicts poor survival. J Thorac Oncol 4:578–585CrossRefGoogle Scholar
  18. Donnem T, Al-Saad S, Al-Shibli K, Busund LT, Bremnes RM (2010) Co-expression of PDGF-B and VEGFR-3 strongly correlates with lymph node metastasis and poor survival in non-small-cell lung cancer. Ann Oncol 21:223–231PubMedCrossRefGoogle Scholar
  19. Franchi A et al (2006) Inducible nitric oxide synthase activity correlates with lymphangiogenesis and vascular endothelial growth factor-C expression in head and neck squamous cell carcinoma. J Pathol 208:439–445PubMedCrossRefGoogle Scholar
  20. Franchi A, Gallo O, Massi D, Baroni G, Santucci M (2004) Tumor lymphangiogenesis in head and neck squamous cell carcinoma: a morphometric study with clinical correlations. Cancer 101:973–978PubMedCrossRefGoogle Scholar
  21. Garmy-Susini B et al (2010) Integrin {alpha}4{beta}1 Signaling Is Required for Lymphangiogenesis and Tumor Metastasis. Cancer ResGoogle Scholar
  22. Govindarajan A, Ghazarian DM, McCready DR, Leong WL (2007) Histological features of melanoma sentinel lymph node metastases associated with status of the completion lymphadenectomy and rate of subsequent relapse. Ann Surg Oncol 14:906–912PubMedCrossRefGoogle Scholar
  23. Gu Y, Qi X, Guo S (2008) Lymphangiogenesis induced by VEGF-C and VEGF-D promotes metastasis and a poor outcome in breast carcinoma: A retrospective study of 61 cases. Clin Exp Metastasis 25:717–725PubMedCrossRefGoogle Scholar
  24. Harris JR, Lippman ME, Veronesi U, Willett W (1992) Breast cancer (3). N Engl J Med 327:473–480PubMedCrossRefGoogle Scholar
  25. Heindl LM et al (2009) Intraocular lymphangiogenesis in malignant melanomas of the ciliary body with extraocular extension. Invest Ophthalmol Vis Sci 50:1988–1995PubMedCrossRefGoogle Scholar
  26. Heindl LM et al (2010) Intraocular tumor-associated lymphangiogenesis a novel prognostic factor for ciliary body melanomas with extraocular extension? Ophthalmology 117:334–342PubMedCrossRefGoogle Scholar
  27. Henno A et al (2009) Altered expression of angiogenesis and lymphangiogenesis markers in the uninvolved skin of plaque-type psoriasis. Br J Dermatol 160:581–590PubMedCrossRefGoogle Scholar
  28. Hirakawa S et al (2005) VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J Exp Med 201:1089–1099PubMedCrossRefGoogle Scholar
  29. Hirakawa S et al (2009) Nodal lymphangiogenesis and metastasis: Role of tumor-induced lymphatic vessel activation in extramammary Paget’s disease. Am J Pathol 175:2235–2248PubMedCrossRefGoogle Scholar
  30. Hong YK et al (2002) Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate. Dev Dyn 225:351–357PubMedCrossRefGoogle Scholar
  31. Iwase H, Yamamoto Y, Kawasoe T, Ibusuki M (2009) Advantage of sentinel lymph node biopsy before neoadjuvant chemotherapy in breast cancer treatment. Surg Today 39:374–380PubMedCrossRefGoogle Scholar
  32. Kerjaschki D et al (2004) Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. J Am Soc Nephrol 15:603–612PubMedCrossRefGoogle Scholar
  33. Kitadai Y et al (2005) Quantitative analysis of lymphangiogenic markers for predicting metastasis of human gastric carcinoma to lymph nodes. Int J Cancer 115:388–392PubMedCrossRefGoogle Scholar
  34. Kitadai Y (2010) Angiogenesis and lymphangiogenesis of gastric cancer. J Oncol 2010:468725PubMedCrossRefGoogle Scholar
  35. Koyama H et al (2008) Significance of tumor-associated stroma in promotion of intratumoral lymphangiogenesis: pivotal role of a hyaluronan-rich tumor microenvironment. Am J Pathol 172:179–193PubMedCrossRefGoogle Scholar
  36. Kyzas PA, Geleff S, Batistatou A, Agnantis NJ, Stefanou D (2005) Evidence for lymphangiogenesis and its prognostic implications in head and neck squamous cell carcinoma. J Pathol 206:170–177PubMedCrossRefGoogle Scholar
  37. Lahdenranta J et al (2009) Endothelial nitric oxide synthase mediates lymphangiogenesis and lymphatic metastasis. Cancer Res 69:2801–2808PubMedCrossRefGoogle Scholar
  38. Laurent TC, Fraser JR (1992) Hyaluronan. FASEB J 6:2397–2404PubMedGoogle Scholar
  39. Lee K et al (2010) Increased intratumoral lymphatic vessel density correlates with lymph node metastasis in early gastric carcinoma. Ann Surg Oncol 17:73–80PubMedCrossRefGoogle Scholar
  40. Leong SP et al (2006) Clinical patterns of metastasis. Cancer Metastasis Rev 25:221–232PubMedCrossRefGoogle Scholar
  41. Mandriota SJ et al (2001) Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J 20:672–682PubMedCrossRefGoogle Scholar
  42. Massi D et al (2009) Inducible nitric oxide synthase expression in melanoma: implications in lymphangiogenesis. Mod Pathol 22:21–30PubMedCrossRefGoogle Scholar
  43. Matsumoto K et al (2007) Lymphatic microvessel density is an independent prognostic factor in colorectal cancer. Dis Colon Rectum 50:308–314PubMedCrossRefGoogle Scholar
  44. Maula SM et al (2003) Intratumoral lymphatics are essential for the metastatic spread and prognosis in squamous cell carcinomas of the head and neck region. Cancer Res 63:1920–1926PubMedGoogle Scholar
  45. Moroi Y (2009) Significance of sentinel lymph node biopsy in malignant melanoma: Overview of international data. Int J Clin Oncol 14:485–489PubMedCrossRefGoogle Scholar
  46. Munoz-Guerra MF, Marazuela EG, Martin-Villar E, Quintanilla M, Gamallo C (2004) Prognostic significance of intratumoral lymphangiogenesis in squamous cell carcinoma of the oral cavity. Cancer 100:553–560PubMedCrossRefGoogle Scholar
  47. Murali R et al (2009) Interobserver reproducibility of histologic parameters of melanoma deposits in sentinel lymph nodes: implications for management of patients with melanoma. Cancer 115:5026–5037PubMedCrossRefGoogle Scholar
  48. Ohhashi T, Mizuno R, Ikomi F, Kawai Y (2005) Current topics of physiology and pharmacology in the lymphatic system. Pharmacol Ther 105:165–188PubMedCrossRefGoogle Scholar
  49. Padera TP et al (2002) Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296:1883–1886PubMedCrossRefGoogle Scholar
  50. Pasquali S et al (2010) Early (sentinel lymph node biopsy-guided) versus delayed lymphadenectomy in melanoma patients with lymph node metastases: Personal experience and literature meta-analysis. Cancer 116:1201–1209PubMedCrossRefGoogle Scholar
  51. Pedica F, Ligorio C, Tonelli P, Bartolini S, Baccarini P (2008) Lymphangiogenesis in Crohn’s disease: an immunohistochemical study using monoclonal antibody D2–Virchows Arch 452:57–63CrossRefGoogle Scholar
  52. Pepper MS (2001) Lymphangiogenesis and tumor metastasis: Myth or reality? Clin Cancer Res 7:462-468PubMedGoogle Scholar
  53. Prevo R, Banerji S, Ferguson DJ, Clasper S, Jackson DG (2001) Mouse LYVE-1 is an endocytic receptor for hyaluronan in lymphatic endothelium. J Biol Chem 276:19420–19430PubMedCrossRefGoogle Scholar
  54. Ran S, Volk L, Hall K, Flister MJ (2009) Lymphangiogenesis and lymphatic metastasis in breast cancer. PathophysiologyGoogle Scholar
  55. Renyi-Vamos F et al (2005) Lymphangiogenesis correlates with lymph node metastasis, prognosis, and angiogenic phenotype in human non-small cell lung cancer. Clin Cancer Res 11:7344–7353PubMedCrossRefGoogle Scholar
  56. Rescigno J, Zampell JC, Axelrod D (2009) Patterns of axillary surgical care for breast cancer in the era of sentinel lymph node biopsy. Ann Surg Oncol 16:687–696PubMedCrossRefGoogle Scholar
  57. Rinderknecht M, Detmar M (2008) Tumor lymphangiogenesis and melanoma metastasis. J Cell Physiol 216:347–354PubMedCrossRefGoogle Scholar
  58. Salem A (2009) Sentinel lymph node biopsy in breast cancer: A comprehensive literature review. J Surg Educ 66:267–275PubMedCrossRefGoogle Scholar
  59. Scavelli C, Vacca A, Di Pietro G, Dammacco F, Ribatti D (2004) Crosstalk between angiogenesis and lymphangiogenesis in tumor progression. Leukemia 18:1054–1058PubMedCrossRefGoogle Scholar
  60. Schoppmann SF et al (2004) Prognostic value of lymphangiogenesis and lymphovascular invasion in invasive breast cancer. Ann Surg 240:306–312PubMedCrossRefGoogle Scholar
  61. Sedivy R, Beck-Mannagetta J, Haverkampf C, Battistutti W, Honigschnabl S (2003) Expression of vascular endothelial growth factor-C correlates with the lymphatic microvessel density and the nodal status in oral squamous cell cancer. J Oral Pathol Med 32:455–460PubMedCrossRefGoogle Scholar
  62. Shayan R, Achen MG, Stacker SA (2006) Lymphatic vessels in cancer metastasis: bridging the gaps. Carcinogenesis 27:1729–1738PubMedCrossRefGoogle Scholar
  63. Sleeman J, Schmid A, Thiele W (2009) Tumor lymphatics. Semin Cancer Biol 19:285–297PubMedCrossRefGoogle Scholar
  64. Sleeman JP, Thiele W (2009) Tumor metastasis and the lymphatic vasculature. Int J Cancer 125:2747–2756PubMedCrossRefGoogle Scholar
  65. Starz H, Balda BR, Kramer KU, Buchels H, Wang H (2001) A micromorphometry-based concept for routine classification of sentinel lymph node metastases and its clinical relevance for patients with melanoma. Cancer 91:2110–2121PubMedCrossRefGoogle Scholar
  66. Swartz MA, Skobe M (2001) Lymphatic function, lymphangiogenesis, and cancer metastasis. Microsc Res Tech 55:92–99PubMedCrossRefGoogle Scholar
  67. Tammela T, Alitalo K (2010) Lymphangiogenesis: Molecular mechanisms and future promise. Cell 140:460–476PubMedCrossRefGoogle Scholar
  68. Uhara H, Takata M, Saida T (2009) Sentinel lymph node biopsy in Japan. Int J Clin Oncol 14:490–496PubMedCrossRefGoogle Scholar
  69. Valencak J et al (2004) Selective immunohistochemical staining shows significant prognostic influence of lymphatic and blood vessels in patients with malignant melanoma. Eur J Cancer 40:358–364PubMedCrossRefGoogle Scholar
  70. van Akkooi AC, Spatz A, Eggermont AM, Mihm M, Cook MG (2009) Expert opinion in melanoma: the sentinel node; EORTC Melanoma Group recommendations on practical methodology of the measurement of the microanatomic location of metastases and metastatic tumour burden. Eur J Cancer 45:2736–2742PubMedCrossRefGoogle Scholar
  71. Van Trappen PO et al (2003) Expression of vascular endothelial growth factor (VEGF)-C and VEGF-D, and their receptor VEGFR-3, during different stages of cervical carcinogenesis. J Pathol 201:544–554PubMedCrossRefGoogle Scholar
  72. Wang TB, Huang YH, Lan P, Song XM, Wang JP (2005) [Correlation of lymphangiogenesis to progression of colorectal cancer]. Ai Zheng 24:1276–1279PubMedGoogle Scholar
  73. Witte D, Thomas A, Ali N, Carlson N, Younes M (2002) Expression of the vascular endothelial growth factor receptor-3 (VEGFR-3) and its ligand VEGF-C in human colorectal adenocarcinoma. Anticancer Res 22:1463–1466PubMedGoogle Scholar
  74. Witte MH et al (2006) Structure function relationships in the lymphatic system and implications for cancer biology. Cancer Metastasis Rev 25:159–184PubMedCrossRefGoogle Scholar
  75. Yarbro JW, Page DL, Fielding LP, Partridge EE, Murphy GP (1999) American Joint Committee on Cancer prognostic factors consensus conference. Cancer 86:2436–2446PubMedCrossRefGoogle Scholar
  76. Zeng Y, Opeskin K, Horvath LG, Sutherland RL, Williams ED (2005) Lymphatic vessel density and lymph node metastasis in prostate cancer. Prostate 65:222–230PubMedCrossRefGoogle Scholar
  77. Zhan P et al (2009) Prognostic value of vascular endothelial growth factor expression in patients with lung cancer: a systematic review with meta-analysis. J Thorac Oncol 4:1094–1103PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Alexandre Nakao Odashiro
    • 1
  1. 1.Département de Pathologie & Cytologie du Centre HospitalierAffilié universitaire de Québec (CHA) Hôpital l’Enfant-JésusQuébecCanada

Personalised recommendations