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Regional Lymph Node Metastases; a Singular Manifestation of the Process of Clinical Metastases in Cancer: Contemporary Animal Research and Clinical Reports Suggest Unifying Concepts

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Abstract

Research results from laboratory animals and human clinical reports provide insight into cancer cell disseminations and elaborate the complex metastatic cascade of cells into both regional lymph nodes and other distant organs. Critical appraisal of clinical trials indicates that lymph node metastases are themselves non-lethal, but indicate prognosis, confirming laboratory conclusions. Distant vital organ metastases can be resected with long term survival in highly selective situations, demonstrating metastatic specificity in oligometastatic disease.

Appreciating lymphatic system embryology, anatomy, and physiology is necessary for understanding lymph node metastases. The primary lymphatic system function was to return interstitial fluid to the circulation. Later evolutionary insertion of lymphocyte collections in lymph nodes interrupting lymph flow completed a system of analyzing external antigens to enable adaptive immunologic responses. Human cancers seldom elicit major immunological responses; they are not generally “foreign” enough. Therefore, lymphatic metastases have little meaning in evolutionary terms.

Organ specificity of both lymphatic and distant metastases occurs as metastatic cells lie dormant, but grow selectively only in liver, lung, bone, or lymph nodes. These organ specific metastatic cells have little ability to produce different organ site clinical metastases.

Thus, laboratory findings and clinical correlations emphasize that surgical lymph node removal should be de-emphasized or omitted. More physiological approaches to the highly manipulable multi-step processes of clinical metastases arising from host microenvironments will eventually prevail.

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References

  1. Irjala H, Alanen K, Grenman R, et al. Mannose receptor (MR) and common lymphatic endothelial and vascular endothelial receptor (CLEVER)-1 direct the binding of cancer cells to the lymph vessel endothelium. Cancer Res 2003; 63(15):4671–6

    PubMed  CAS  Google Scholar 

  2. Solomayer E, Diel I, Meyberg G, et al. Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastases. Br Cancer Res Treat 2000; 59:271–278

    Article  CAS  Google Scholar 

  3. Yang J, Mani S, Donaher J, et al. Twist, A Master Regulator of Morphogenesis, Plays an Essential Role in Tumor Metastasis. Cell 2004; 117:927–939

    Article  PubMed  CAS  Google Scholar 

  4. Clark E, Golub T, Lander E, Hynes R. Genomic analysis of metastasis reveals an essential role for RhoC. Nature 2000; 406:532–535

    Article  PubMed  CAS  Google Scholar 

  5. Minn A, Gupta G, Siegel P, et al. Genes that mediate breast cancer metastasis to lung. Nature 2005; 436:518–524

    Article  PubMed  CAS  Google Scholar 

  6. Kang Y, Siegel P, Shu W, et al. A multigene program mediating breast cancer metastasis to bone. Cancer Cell 2003; 3:537–549

    Article  PubMed  CAS  Google Scholar 

  7. Gervasoni JE, Jr., Taneja C, Chung MA, Cady B. Biologic and clinical significance of lymphadenectomy. Surg Clin North Am 2000; 80(6):1631–73

    Article  PubMed  Google Scholar 

  8. Halsted W. The results of radical operations for the cure of carcinoma of the breast. Ann Surg 1907; 46:1–9

    Article  PubMed  CAS  Google Scholar 

  9. Moynihan G. The surgical treatment of cancer of the sigmoid flexure and rectum. Surg Gynecol Obstet 1908; 6:463–6

    Google Scholar 

  10. Neuhaus S, Clark M, Thomas J. Dr. Herbert Lumley Snow, MD MRCS (1847–1930): The Original Champion of Elective Lymph Node Dissection in Melanoma. Annals of Surgical Oncology 2004; 11(9):875–878

    Article  Google Scholar 

  11. Taneja C, Cady B. Decreasing role of lymphatic system surgery in surgical oncology. J Surg Oncol 2005; 89(2):61–6

    Article  PubMed  Google Scholar 

  12. Kampmeier O. Evolution and Comparative Morphology of the Lymphatic System: Charles C. Thomas, 1969

  13. Cady B. Is axillary lymph node dissection necessary in routine management of breast cancer? No. Principles and Practice of Oncology 1998; 12:1–12

    Google Scholar 

  14. Miyasaka M, Tanaka T. Lymphocyte Trafficking Across High Endothelial Venules: Dogmas and Enigmas. Nature Rev 2004; 4:360–370

    Article  CAS  Google Scholar 

  15. Fisher B, Fisher E. Transmigration of Lymph Nodes by Tumor Cells. Science 1966; 152(3727):1397–1398

    Article  PubMed  CAS  Google Scholar 

  16. Huang RR, Wen DR, Guo J, et al. Selective Modulation of Paracortical Dendritic Cells and T-Lymphocytes in Breast Cancer Sentinel Lymph Nodes. Breast J 2000; 6(4):225–232

    Article  PubMed  Google Scholar 

  17. Clarke J, Cha J, Walsh M, et al. Dendritic cells as therapeutic adjuncts in surgical disease. Surgery 2005; 138(5):844–50

    Article  PubMed  Google Scholar 

  18. Tanis PJ, Nieweg OE, Valdes Olmos RA, Kroon BB. Anatomy and physiology of lymphatic drainage of the breast from the perspective of sentinel node biopsy. J Am Coll Surg 2001; 192(3):399–409

    Article  PubMed  CAS  Google Scholar 

  19. Cabanas R. An approach for the treatment of penile carcinoma. Cancer 1977; 39:456–466

    Article  PubMed  CAS  Google Scholar 

  20. Chao C, Wong SL, Tuttle TM, et al. Sentinel lymph node biopsy for breast cancer: improvement in results over time. Breast J 2004; 10(4):337–44

    Article  PubMed  Google Scholar 

  21. Cady B. Fundamentals of Contemporary Surgical Oncology: Biologic Principles and the Threshold Concept Govern Treatment and Outcomes. J Am Coll Surg 2001; 192(6):777–792

    Article  PubMed  CAS  Google Scholar 

  22. Cady B. Simplification of Breast Cancer Surgery. Annals of Surgical Oncology 2005; 12(1):6–8

    Article  PubMed  Google Scholar 

  23. Fidler I. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nature Reviews 2003; 3:1–6

    Article  CAS  Google Scholar 

  24. Tang Y, Zhang D, Fallavollita L, Brodt P. Vascular endothelial growth factor C expression and lymph node metastasis are regulated by the type I insulin-like growth factor receptor. Cancer Res 2003; 63(6):1166–71

    PubMed  CAS  Google Scholar 

  25. Fidler IJ. The organ microenvironment and cancer metastasis. Differentiation 2002; 70(9–10):498–505

    Article  PubMed  Google Scholar 

  26. LeBedis C, Chen K, Fallavollita L, et al. Peripheral lymph node stromal cells can promote growth and tumorigenicity of breast carcinoma cells through the release of IGF-I and EGF. Int J Cancer 2002; 100:2–8

    Article  PubMed  CAS  Google Scholar 

  27. Skobe M, Hawighorst T, Jackson DG, et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 2001; 7(2):192–8

    Article  PubMed  CAS  Google Scholar 

  28. Espana L, Fernandez Y, Rubio N, et al. Overexpression of Bcl-xL in human breast cancer cells enhances organ-selective lymph node metastasis. Breast Cancer Res Treat 2004; 87(1):33–44

    Article  PubMed  CAS  Google Scholar 

  29. Brodt P, Fallavollita L, Khatib AM, et al. Cooperative regulation of the invasive and metastatic phenotypes by different domains of the type I insulin-like growth factor receptor beta subunit. J Biol Chem 2001; 276(36):33608–15

    Article  PubMed  CAS  Google Scholar 

  30. Khatib AM, Fallavollita L, Wancewicz EV, et al. Inhibition of hepatic endothelial E-selectin expression by C-raf antisense oligonucleotides blocks colorectal carcinoma liver metastasis. Cancer Res 2002; 62(19):5393–8

    PubMed  CAS  Google Scholar 

  31. Onn A, Isobe T, Itasaka S, et al. Development of an orthotopic model to study the biology and therapy of primary human lung cancer in nude mice. Clin Cancer Res 2003; 9(15):5532–9

    PubMed  CAS  Google Scholar 

  32. Arap W, Kolonin M, Trepel M, et al. Steps toward mapping the human vasculature by phage display. Nat Med 2002; 8(2):121–127

    Article  PubMed  CAS  Google Scholar 

  33. Charo I, Ransohoff R. The Many Roles of Chemokines and Chemokine Receptors in Inflammation. N Engl J Med 2006; 354(6):610–621

    Article  PubMed  CAS  Google Scholar 

  34. Cady B, Jenkins RL, Steele GD, Jr., et al. Surgical margin in hepatic resection for colorectal metastasis: a critical and improvable determinant of outcome. Ann Surg 1998; 227(4):566–71

    Article  PubMed  CAS  Google Scholar 

  35. Vezeridis M, Moore R, Karakousis C. Metastatic patterns in soft-tissue sarcomas. Arch Surg 1983; 118:915

    PubMed  CAS  Google Scholar 

  36. Roayaie S, Frischer JS, Emre SH, et al. Long-term results with multimodal adjuvant therapy and liver transplantation for the treatment of hepatocellular carcinomas larger than 5 centimeters. Ann Surg 2002; 235(4):533–9

    Article  PubMed  Google Scholar 

  37. Tarin D, Price JE, Kettlewell MG, et al. Clinicopathological observations on metastasis in man studied in patients treated with peritoneovenous shunts. Br Med J (Clin Res Ed) 1984; 288(6419):749–51

    Article  CAS  Google Scholar 

  38. Cady B. Presidential address: Beyond risk groups-A new look at differentiated thyroid cancer. Surgery 1998; 124(6):947–957

    PubMed  CAS  Google Scholar 

  39. Modlin I, Lye K, Kidd M. A 5-decade Analysis of 13,715 carcinoid tumors. Cancer 2003; 97(4):934–959

    Article  PubMed  Google Scholar 

  40. Mullen J, Wang H, Yao J, et al. Carcinoid Tumors of the Duodenum. Surgery In Press 2005

  41. Samani AA, Brodt P. The Receptor for the Type I Insulin-Like Growth Factor and its Ligands Regulate Multiple Cellular Functions that Impact on Metastasis. Surg Clin North Am 2001; 10(2):289–312

    CAS  Google Scholar 

  42. Nathanson S. Insights into the Mechanisms of Lymph Node Metastasis. Cancer 2003; 98(2):413–423

    Article  PubMed  Google Scholar 

  43. Cady B. Basic principles in surgical oncology. Arch Surg 1997; 132(4):338–46

    PubMed  CAS  Google Scholar 

  44. Elias D, Liberale G, Vernerey D, et al. Hepatic and Extrahepatic Colorectal Metastases: When Resectable, Their Localization Does Not Matter, But Their Total Number Has a Prognostic Effect. Ann Surg Oncol 2005; 12(11):900–909

    Article  PubMed  Google Scholar 

  45. Chagpar A, Middleton LP, Sahin AA, et al. Clinical outcome of patients with lymph node-negative breast carcinoma who have sentinel lymph node micrometastases detected by immunohistochemistry. Cancer 2005; 103(8):1581–6

    Article  PubMed  Google Scholar 

  46. Wieder R. Insurgent micrometastases: sleeper cells and harboring the enemy. J Surg Oncol 2005; 89(4):207–10

    Article  PubMed  Google Scholar 

  47. Meng S, D. T, Frenkel EP, et al. Circulating Tumor Cells in Patients with Breast Cancer Dormancy. Clin Cancer Res 2004; 10:8152–8162

  48. Diel I, Kaufinann M, Costa S. Micrometastatic breast cancer cells in bone marrow at primary surgery: prognostic value in comparison with nodal status. J Natl Cancer Inst 1996; 8:1652–58

    Article  Google Scholar 

  49. Braun S, Pantel K, Muller P, et al. Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med 2000; 342(8):525–33

    Article  PubMed  CAS  Google Scholar 

  50. Braun S, F.D. V, B. N, et al. A Pooled Analysis of Bone Marrow Micrometastasis in Breast Cancer. N Engl J Med 2005; 353:793–802

  51. Bonavina L, Soligo D, Quirici N, et al. Bone marrow-disseminated tumor cells in patients with carcinoma of the esophagus or cardia. Surgery 2001; 129(1):15–22

    Article  PubMed  CAS  Google Scholar 

  52. O’Sullivan G, Sheehan D, Clarke A, et al. Micrometastases in esophagogastric cancer: high detection rate in resected rib segments. Gastroenterology 1999; 116(3):543–8

    Article  PubMed  CAS  Google Scholar 

  53. Kauffman HM, McBride MA, Delmonico FL. First report of the United Network for Organ Sharing Transplant Tumor Registry: donors with a history of cancer. Transplantation 2000; 70(12):1747–51

    Article  PubMed  CAS  Google Scholar 

  54. Buell JF, Trofe J, Hanaway MJ, et al. Transmission of donor cancer into cardiothoracic transplant recipients. Surgery 2001; 130(4):660–6; discussion 666–8

    Article  PubMed  CAS  Google Scholar 

  55. MacKie RM, Reid R, Junor B. Fatal melanoma transferred in a donated kidney 16 years after melanoma surgery. N Engl J Med 2003; 348(6):567–8

    Article  PubMed  Google Scholar 

  56. Page DL, Anderson TJ, Carter BA. Minimal solid tumor involvement of regional and distant sites: when is a metastasis not a metastasis? Cancer 1999; 86(12):2589–92

    Article  PubMed  CAS  Google Scholar 

  57. Naumov GN, MacDonald IC, Weinmeister PM, et al. Persistence of solitary mammary carcinoma cells in a secondary site: a possible contributor to dormancy. Cancer Res 2002; 62(7):2162–8

    PubMed  CAS  Google Scholar 

  58. Fisher B, Fisher ER. Experimental evidence in support of the dormant tumor cell. Science 1959; 130:918–9

    Article  PubMed  CAS  Google Scholar 

  59. Chambers AF, Naumov GN, Varghese HJ, et al. Critical steps in hematogenous metastasis: an overview. Surg Oncol Clin N Am 2001; 10(2):243–55, vii

    PubMed  CAS  Google Scholar 

  60. Hellman S. Karnofsky Memorial Lecture. Natural history of small breast cancers. J Clin Oncol 1994; 12(10):2229–34

    PubMed  CAS  Google Scholar 

  61. Soga W, Ohyama S, K M. A statistical evaluation of advancement in gastric cancer surgery with special reference to the significance of lymphadenectomy for cure. World J Surg 1988; 12:398

  62. Stetler-Stevenson W. (2005) Invasion and Metastases. 7th ed. Philadelphia: Lippincott Williams & Wilkins.

    Google Scholar 

  63. Zurrida S, Orecchia R, Galimberti V, et al. Axillary radiotherapy instead of axillary dissection: a randomized trial. Italian Oncological Senology Group. Ann Surg Oncol 2002; 9(2):156–60

    Article  PubMed  Google Scholar 

  64. Louis-Sylvestre C, Clough K, Asselain B, et al. Axillary treatment in conservative management of operable breast cancer: dissection or radiotherapy? Results of a randomized study with 15 years of follow-up. J Clin Oncol 2004; 22(1):97–101

    Article  PubMed  Google Scholar 

  65. Naik AM, Fey J, Gemignani M, et al. The risk of axillary relapse after sentinel lymph node biopsy for breast cancer is comparable with that of axillary lymph node dissection: a follow-up study of 4008 procedures. Ann Surg 2004; 240(3):462–8; discussion 468–71

    Article  PubMed  Google Scholar 

  66. Cady B. A Randomized Trial Comparing Axillary Dissection to No Axillary Dissection in Elderly Patients with T1N0 Breast Cancer - Results After Long-term Follow-up. Ann Surg 2005; 242(1):7–9

    Article  Google Scholar 

  67. Mendez J, Fey J, Cody H, et al. Can sentinel lymph node biopsy be omitted in patients with favorable breast cancer histology? Ann Surg Oncol 2005; 12(1):24–28

    Article  PubMed  Google Scholar 

  68. Coburn NG, Chung MA, Fulton J, Cady B. Decreased breast cancer tumor size, stage, and mortality in rhode island: an example of a well-screened population. Cancer Control 2004; 11(4):222–30

    PubMed  Google Scholar 

  69. Heimann R, Munsell M, McBride R. Mammographically detected breast cancers and the risk of axillary lymph node involvement: is it just the tumor size? Cancer J 2002; 8(3):276–81

    Article  PubMed  Google Scholar 

  70. Norden T, Thurfjell E, Hasselgren M, et al. Mammographic screening for breast cancer. What cancers do we find? Eur J Cancer 1997; 33(4):624–8

    Article  PubMed  CAS  Google Scholar 

  71. Bucchi L, Barchielli A, Ravaioli A, et al. Screen-detected vs clinical breast cancer: the advantage in the relative risk of lymph node metastases decreases with increasing tumour size. Br J Cancer 2005; 92(1):156–61

    Article  PubMed  CAS  Google Scholar 

  72. Cote RJ, Peterson HF, Chaiwun B, et al. Role of immunohistochemical detection of lymph-node metastases in management of breast cancer. International Breast Cancer Study Group. Lancet Vol. 354, 1999. pp. 896–900

    Article  PubMed  CAS  Google Scholar 

  73. Group TSOSSE. Reduction in Breast Cancer Mortality from Organised Service Screening with Mammography: Further confirmation with Extended Data and New Analytic Methods. Cancer Epidemiology, Biomarkers and Prevention In press

  74. Tabar L, Yen MF, Vitak B, et al. Mammography service screening and mortality in breast cancer patients: 20-year follow-up before and after introduction of screening. Lancet 2003; 361(9367):1405–10

    Article  PubMed  Google Scholar 

  75. Tabar L, Chen HH, Yen MF, et al. Mammographic Tumor Features Can Predict Long-term Outcomes Reliably in Women with 1-14-mm Invasive Breast Carcinoma. Cancer 2004; 101(8):1745–1759

    Article  PubMed  Google Scholar 

  76. Cabioglu N, Hunt KK, Buchholz TA, et al. Improving Local Control in Breast-Conserving Therapy - A 27-Year Single-Institution Experience. Cancer 2005; 104(1):20–29

    Article  PubMed  Google Scholar 

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Acknowledgments

The author thanks Kimberly Sanzi for her many hours of manuscript preparation and revisions.

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  1. Professor of Surgery, Brown Medical School Interim Director, Comprehensive Breast Center, Rhode Island Hospital 593 Eddy Street, APC 4 Providence, RI, 02903, United States

    Blake Cady MD

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Cady, B. Regional Lymph Node Metastases; a Singular Manifestation of the Process of Clinical Metastases in Cancer: Contemporary Animal Research and Clinical Reports Suggest Unifying Concepts. Ann Surg Oncol 14, 1790–1800 (2007). https://doi.org/10.1245/s10434-006-9234-2

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