Tumor-Associated Lymphatic and Venous Vessels in Medullary Thyroid Carcinomas


Objective: Medullary thyroid carcinomas (MTCs) invade local lymph node through lymphatic vessels and metastasize to distant organs hematogenously and account for a significant mortality. There are possibly increased lymphatic and venous vessels, through which the tumor spreads to lymph nodes and distant organs. Materials and Methods: By immunocytochemical staining for lymphatic and venous vessels, MTC lesions with adjacent normal thyroid and both normal and metastatic lymph nodes were studied for the peritumoral lymphatic and venous vessels, which were morphometrically compared with those of normal thyroid and lymph nodes. Sixteen cases of MTC cases with adjacent thyroid tissues and attached lymph nodes were immunocytochemically stained for lymphatic vessels using lymphatic vessel hyaluronan receptor (LYVE-1) and venous vessels for factor VIII (F-8). The immunostained sections of MTC lesions and metastatic lymph nodes were morphometrically compared for the number and sizes of the vessels with those of normal thyroid tissues and lymph nodes. Results: Significantly increased lymphatic vessels and markedly increased blood vessels were identified in many MTC cases at the peritumoral tissues and metastatic lymph nodes whereas a few lymphatic vessels and no venous vessels were identified in midst of MTCs. The irregular peritumoral lymphatic vessels resembled that of immature lymphatic vessels observed in papillary thyroid carcinomas and increased irregularly, entrapped venous vessels in peritumoral tissues resembled those observed in follicular thyroid carcinomas. Conclusion: The significantly increased lymphatic vessels and markedly increased venous vessels in the peritumoral thyroid tissue support a propensity of MTCs for providing an easy access of tumor cells to both lymphatic spread to the regional lymph nodes and venous spread to distant organs with further tumor spread through metastatic lymph nodes by moderately increased lymphatic and venous vessels.

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Tomita, T. (2015) Tumor-Associated Lymphatic and Venous Vessels in Medullary Thyroid Carcinomas. Open Journal of Pathology, 5, 50-58. doi: 10.4236/ojpathology.2015.52008.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Messina, M. and Robinson, B.G. (2007) Technology Insight: Gene Therapy and Its Potential Role in the Treatment of Medullary Thyroid Carcinoma. Nature Clinical Practice Nephrology, 3, 290-301.
[2] Rosai, J. (2004) Thyroid Gland. In: Rosai, J., Ed., Ackerman’s Surgical Pathology, 8th Edition, St. Louis, Mosby, 493-567.
[3] Marchens, A. and Dralle, H. (2013) Prognostic Impact of N Staging in 715 Medullary Thyroid Cancer Patients: Proposal for a Revised Staging System. Annals of Surgery, 257, 323-329.
[4] Alvizaki, M., Saltiki, K., Rentiziou, G., Papathoma, A., Sariak, L., et al. (2012) Medullary Thyroid Carcinoma: The Influence of Policy Changing in Clinical Characteristics and Disease Progression. European Journal of Endocrinology, 167, 799-808. http://dx.doi.org/10.1530/EJE-12-0388
[5] Balock, Z.W. and LiVolsi, V.A. (2002) Medullary Thyroid Carcinoma. In: LiVolsi, V.A. and Asa, S.L., Eds., Endocrine Pathology, Churchill Livingston, 81-83.
[6] Hall, F.T., Freeman, J.L., Asa, S.L., Jackson, D.G. and Beasley, N.J. (2003) Intratumoral Lymphatics and Lymph Node Metastases in Papillary Thyroid Carcinoma. Archives of Otolaryngology—Head and Neck Surgery, 129, 716-719.http://dx.doi.org/10.1001/archotol.129.7.716
[7] Giogadze, T.A., Baloch, Z.W., Pasha, T., Zhang, P.J. and LiVolsi, V.A. (2005) Lymphatic and Blood Vessel Density in the Follicular Lesions of Thyroid. Modern Pathology, 18, 1424-1431. http://dx.doi.org/10.1038/modpathol.3800452
[8] Lin, X., Lie, Y. and Silverman, J.F. (2010) Follicular Thyroid Carcinoma Invades Venous Rather than Lymphatic Vessels. Diagnostic Pathology, 5, 1-8. http://dx.doi.org/10.1186/1746-1596-5-8
[9] Banerji, S., Ni, J., Wang, S.W., Clasper, S., Su, J., Thommi, R., Jones, M. and Jackson, D.G. (1999) LYVE-1, a New Homologue of the CD 44 Glycoprotein, Is a Lymph-Specific Receptor for Hyaluronan. The Journal of Cell Biology, 1444, 789-801. http://dx.doi.org/10.1083/jcb.144.4.789
[10] Jackson, D.G., Prevo, R., Clasper, S. and Banerji, S. (2001) LYVE-1, Lymphatic System and Tumor Lymphangiogenesis. Trends in Immunology, 22, 317-321.
[11] Prevo, R., Banerji, S., Ferguson, J.P., Clasper, S. and Jackson, D.G. (2001) Mouse LYVE-1 Is an Endocytic Receptor for Hyaluronan in Lymphatic Endothelium. Journal of Biological Chemistry, 276, 19420-19430.http://dx.doi.org/10.1074/jbc.M011004200
[12] Jackson, D.G. (2003) The Lymphatics Revisited. New Perspectives from the Hyaluronan Receptor LYVE-1. Trends in Cardiovascular Medicine, 13, 107.
[13] Tomitat, T. (2008) Immunocytochemical Localization of Lymphatic and Venous Vessels in Colonic Polyps and Adenomas. Digestive Diseases and Sciences, 53, 1880-1885.
[14] Tomita, T. (2009) LYVE-1 Immunocytochemical Staining for Gastrointestinal Carcinoids. Pathology, 41, 248-253.http://dx.doi.org/10.1080/00313020902756253
[15] Tomita, T. (1997) Matrix Metalloproteinases and Inhibitors of Matrix Metalloproteinases in Thyroid C-Cells and Medullary Thyroid Carcinomas. Histopathology, 31, 150-156.
[16] Tomita, T. (2012) Islet Amyloid Polypeptide in Pancreatic Islets from Type 2 Diabetic Subjects. Islets, 4, 223-232.http://dx.doi.org/10.4161/isl.20477
[17] Kaio, E., Tanaka, S., Kitadai, Y., et al. (2003) Clinical Significance of Aniogenic Factor Expression at the Deepest Invasive Site of Advanced Colorectal Carcinoma. Oncoloty, 64, 61-73.
[18] Petterspn, A., Nagly, A., Brown, L.F., et al. (2000) Heterogeneity of the Angiogenic Response Induced in Different Normal Adult Tissues by Vascular Permeability Factor/Vascular Endothelial Growth Factor. Laboratory Investigation, 80, 99-115. http://dx.doi.org/10.1038/labinvest.3780013
[19] Sharinen, P., Tammela, T., Karkkanen, M.J. and Alitalo, K. (2004) Lymphatic Vasculature: Development, Molecular Regulation and Role in Tumor Metastasis and Inflammation. Trends in Immunology, 25, 387-395.http://dx.doi.org/10.1016/j.it.2004.05.003
[20] Kaneko, I., Tanaka, S., Oka, S., Kawamujra, T., et al. (2007) Lymphatic Vessels Density at the Site of Deepest Penetration of Lymph Node Metastasis in Submucosal Colorectal Carcinoma. Diseases of the Colon & Rectum, 50, 13-21.http://dx.doi.org/10.1007/s10350-006-0745-5
[21] Sipos, B., Klapper, W., Kruse, M.L., Kaltoff, H., et al. (1999) Expression of Lymphangiogenesis Factors and Evidences of Intratumoral Lymphangiogenes in Pancreatic Endocrine Tumors. American Journal of Pathology, 154, 385-394.
[22] Tomita, T. (2007) Lymphatic Vessel Endothelial Hyaluronan Receptor-1 Immunocytochemical Staining for Pancreatic Islets and Pancreatic Endocrine Tumors. Pancreas, 35, e18-e22.
[23] Kahn, H.J. and Marks, A. (2002) A Monoclonal Antibody, D2-40, for Detection of Lymphatic Invasion in Primary Tumors. Laboratory Investigation, 82, 1255-1257.
[24] Fukunaga, M. (2005) Expression of D2-40 in Lymphatic Endothelium of Normal Tissues and Vascular Tumours. Histopathology, 46, 396-402. http://dx.doi.org/10.1111/j.1365-2559.2005.02098.x
[25] Franke, F.E., Pauls, K., Rey, R., Marks, A., Bergmann, M. and Steger, K. (2004) Differentiation Markers of Sertoli Cells and Germ Cells in Fetal and Early Postnatal Human Testis. Anatomy and Embryology (Berlin), 209, 169-177.
[26] Bailey, D., Baumel, R., Law, J., Shelidan, K. and Kahn, H.J. (1986) Production of Monoclonal Antibody Specific for Seminomas and Dystgerminomas. Proceedings of the National Academy of Sciences of the United States of America, 83, 5291-5295. http://dx.doi.org/10.1073/pnas.83.14.5291
[27] Breitender-Geleff, S., Soleiman, A., Kawalski, H., et al. (1999) Angiosarcomas Express Mixed Endothelial Phenotypes of Blood and Lymphatic Capillaries: Population as a Specific Marker for Lymphatic Endothelium. American Journal of Pathology, 154, 385-394.
[28] Adachi, Y., Nakamura, H., Kitamura, Y., Taniguchi, Y., Araki, K., et al. (2007) Lymphatic Vessel Density in Pulmonary Adenocarcinoma Immunohistochemically Evaluated with Anti-Podoplanin or Anti-D2-40 Is Correlated with Lymphatic Invasion or Lymph Node Metastasis. Pathology International, 57, 171-177.http://dx.doi.org/10.1111/j.1440-1827.2007.02077.x
[29] Wigle, J.T. (1999) Prox-1 Function Is Required for the Development of the Murine Lymphatic System. Cell, 98, 769-778. http://dx.doi.org/10.1016/S0092-8674(00)81511-1

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