Evaluating tumor angiogenesis, lymphangiogenesis helpful

November 1, 2006

Noordwijk, Netherlands - Though malignant melanoma is the most serious form of skin cancer, with a little more than 100,000 new cases diagnosed each year, this potentially deadly cancer can be curable if diagnosed early and limited to the skin.

Yet, once the cancer metastasizes to the regional lymph nodes, treatment is usually difficult and protracted, and the prognosis of the unfortunate patient can be bleak. Melanoma researchers have therefore been concentrating their efforts on learning more about angiogenesis, lymphangiogenesis and the nature of metastasis in order to better understand which types of melanomas have a tendency to metastasize. Such metastases directly affect treatment choices and regimens as well as prognosis, according to Michael Detmar, M.D., professor of pharmacogenomics at the Institute of Pharmaceutical Sciences, Zurich, Switzerland, and associate professor of dermatology at Harvard Medical School.

Modes of metastases

Spread can occur by local invasion into the surrounding tissue, by systemic metastasis via tumor-associated blood vessels to distant organs, or by lymphatic metastasis via tumor-associated lymphatic vessels to draining sentinel lymph nodes, then to distal lymph nodes and from there to distant organs. The extent of lymph node involvement will dictate the prognosis as well as therapeutic decisions.

"The induction of angiogenesis is a critical point in the development of melanoma," Dr. Detmar says. "The elevated expression of several angiogenic factors, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF) and interleukin-8, has been detected in primary cutaneous melanomas, and the importance of these mediators in promoting melanoma angiogenesis and metastasis has been confirmed in tumor xenotransplant models. These findings have important implications for the prognosis and treatment of human melanoma."

Vascular growth factors key

Currently, tumor thickness is the main factor considered when determining prognosis, but a considerable number of patients with thin melanomas also go on to develop metastatic disease.

Therefore, according to Dr. Detmar, more reliable markers for metastatic spread are urgently needed. Dr. Detmar set out to investigate whether the extent of tumor lymphangiogenesis can predict melanoma metastasis to sentinel lymph nodes.

Dr. Detmar and his team of researchers conducted a study consisting of 45 patients with primary cutaneous melanoma, where the extent of tumor lymphangiogenesis in the excised primary tumors and the presence of metastases in the sentinel lymph node biopsy samples were examined.

Results showed that prominent "hot spots" of increased lymphatic vessel density were seen in the primary melanomas of patients whose tumors had metastasized to the sentinel lymph nodes, as compared to nonmetastatic tumors.

Dr. Detmar postulates that metastatic melanomas can therefore be characterized by increased lymphangiogenesis, as compared to non-metastatic tumors, and that the degree of tumor lymphangiogenesis can serve as a novel predictor of lymph node metastasis and overall patient survival, independent of tumor thickness.

"Multivariate risk analysis revealed that the lymphatic vascular area of primary melanomas, an index of tumor lymphangiogenesis, was the most sensitive prognostic marker for sentinel lymph node metastasis, and was even able to more accurately predict which tumors were metastatic to sentinel lymph nodes than the currently used method of measuring tumor thickness," Dr. Detmar tells Dermatology Times.

Dr. Detmar notes, "It is tempting to speculate that the lymphangiogenic factors, in addition to increasing the mass of tumor-associated lymphatic vessels, might activate the lymphatic endothelium to express increased amounts of chemokines or adhesion molecules and receptors, which are involved in tumor cell-LEC interactions, thereby actively contributing to cancer dissemination."

He explains that the extent of tumor lymphangiogenesis is a highly sensitive (83 percent) and specific (89 percent) prognostic marker of lymph node metastasis.

Therefore, Dr. Detmar suggests that this seemingly more effective approach (as compared to just measuring tumor thickness) could be used in selecting patients with early metastatic disease for aggressive therapy. He stresses that the quantitation of tumor lymphangiogenesis may, in the future, help patients and their physicians to better evaluate the disease prognosis and the therapeutic choices to be made.