Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes

Abstract

Cutaneous melanoma is a common melanocytic neoplasm that can quickly metastasize to regional lymph nodes. Currently, prognosis is determined by measuring tumor thickness but more reliable markers for metastatic spread are urgently needed. We investigated whether the extent of tumor lymphangiogenesis can predict melanoma metastasis to sentinel lymph nodes. We quantified the extent of tumor lymphangiogenesis, as well as other factors, in excised primary tumors and in sentinel lymph node biopsy samples from 45 patients with primary cutaneous melanoma. The results were correlated with histological and clinical outcome. Primary melanomas from patients whose tumors had metastasized to the sentinel lymph nodes contained prominent 'hot spots' of increased lymphatic vessel density, compared to nonmetastatic tumors. 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. Highly lymphangiogenic melanomas maintained their lymphangiogenic activity after metastasis to the sentinel lymph node. The extent of tumor lymphangiogenesis is a highly sensitive (83%) and specific (89%) prognostic marker of lymph node metastasis. Assessment of lymphangiogenesis in primary melanomas may be a more effective approach than the currently used technique of measuring tumor thickness in selecting patients with early metastatic disease for aggressive therapy. Keywords: LYVE-1; lymphangiogenesis; angiogenesis; sentinel lymph node; VEGF-C and VEGF-D In 2003, it was estimated that 7700 patients in the US would die from cutaneous melanoma, 1 a melanocytic tumor with increasing worldwide incidence and mortality rates. 2 Melanoma is among the most common types of cancer in young adults, and death from melanoma occurs at a younger age than for any other common malignancy, 3 representing a substantial public health problem. The prognosis of patients with melanoma depends on the tumor stage at diagnosis, and is currently based on microstaging and clinical/radiologic evaluation for metastases. In addition to a complete surgical excision with wide margins, patients with primary melanomas 41.0 mm thick undergo intraoperative lymphatic mapping and sentinel lymph node (SLN) biopsy to identify the first deposition of microscopic metastatic cells. 4 Among several prognostic parameters, tumor thickness is currently the most sensitive parameter for predicting the metastatic risk of cutaneous melanoma. However, the prognosis for individual melanoma patients is still difficult to determine, since thin melanomas can also develop into lethal metastases. 5 More accurate prognostic indicators for melanoma metastasis are therefore urgently needed.Recently, studies in mouse tumor models have shown that some types of malignant tumors actively induce the formation of lym...

Lymphatic vessel density is associated with CD8+ T cell infiltration and immunosuppressive factors in human melanoma

“…31 Moreover, melanoma lesions have been shown to have higher intratumoral and peritumoral LVD compared to benign melanocytic lesions, likely due to pro-lymphangiogenic factors, essentially VEGF-C, secreted by tumor cells. 32-34 Detailed analysis of the distribution of LECs in primary tumors showed that LVD was already increased in the earliest stage of melanoma (melanoma in situ ) in comparison to the adjacent normal skin.…”

“…17 , 33 , 41-43 Lymphatic vessels may support migration of tumor cells, but may also modulate immune cells, as recently demonstrated in primary tumors and draining LNs in mice, 24 , 25 , 44 raising the possibility that lymphatics mediate immune suppression and poor clinical outcome in cancer patients. 19 , 31 , 42 Because corresponding human data are missing, we performed a very wide IHC analysis. Our findings reveal multiple correlations between lymphatic vessels and host immunity, suggesting immune mechanisms that act locally as well as loco-regionally in melanoma patients (Fig.…”

Stromal expression of vascular endothelial growth factor C is relevant to predict sentinel lymph node status in melanomas

“…In this latter work, immunofluorescence staining for LYVE-1 on paraffin sections was used to recognise lymphatic vessels and computer-assisted morphometric analysis to obtain vessel density and size. These findings were subsequently validated in a prospective series [12] of 45 cutaneous melanomas with SLN biopsy, using similar methods. The results showed that the lymphatic vascular area was a highly sensitive and specific prognostic marker of sentinel node metastases, even more accurately than tumour thickness.…”

“…However, research so far in malignant skin melanoma has provided contradictory findings. Whereas some authors found that lymphangiogenesis in primary melanoma was significantly increased in metastatic melanomas and that it could predict the status of the sentinel node [11][12][13], others reported that an increase in LVD was related with fewer lymph node metastases and a better prognosis [14,15].…”

Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo

“…In certain types of cancers, such as breast cancer, lymphatic metastasis occurs in the early stages of cancer development, and malignant cells can be further spread from the lymphatic system to the circulatory system (1). Recent studies demonstrate that peritumoral and intratumoral lymphatic vessels are critical structures for lymphatic metastasis (2,3). Like blood vessels, lymphatic vessels in the adult remain quiescent under normal physiological conditions.…”