Lymphatic vessel density and expressions of lymphangiogenic growth factors in salivary carcinomas

Abstract

Nodal metastasis is an important prognostic indicator in head and neck cancers, including salivary carcinomas. In these, the risk for lymph node metastasis is variable and strongly associated with the tumor histologic type. The aim of the current study was to evaluate the lymphatic vessel density (LVD) and expressions of lymphangiogenic growth factors by tumor cells in different histologic types of salivary carcinomas subdivided according to the risk for nodal metastasis. In 15 high-risk (undifferentiated, high-grade mucoepidermoid and salivary duct carcinomas) and 60 low/moderate-risk tumors (adenoid cystic, low/intermediate-grade mucoepidermoid, acinic cell, myoepithelial, epithelial-myoepithelial and polymorphic lowgrade carcinomas) the expressions of vascular endothelial growth factor-C (VEGF-C), hepatocyte growth factor (HGF) and D2-40 (for assessing LVD) were examined. No significant differences were encountered between high-and low/moderate/-risk carcinomas regarding LVD and VEGF-C or HGF expressions. Furthermore, the expression of these proteins did not correlate with LVD. Lymphatic vascular invasion was found mainly in high-risk carcinomas. Intratumoral LVD was significantly lower than peritumoral, regardless of the risk for metastasis and primary site of the lesion. The histologic types of salivary carcinomas which are associated with high-risk for nodal metastasis do not present increased LVD or VEGF-C and HGF expressions. The greater tendency for metastasis in these carcinomas seems to be related to their capacity to invade lymph vessels. Further studies on tumor cell interactions with lymphatic endothelial cells are needed to improve our understanding of the metastatic potential of salivary carcinomas. Key words: lymph vessels, salivary carcinoma, VEGF-C, HGF.Nodal metastasis is an important prognostic predictor in head and neck cancers, including salivary carcinomas. The risk for lymph node metastasis in these carcinomas is highly variable (9% -85%) [1] and strongly associated with the tumor histologic type [1][2][3][4][5]. It is a general consensus that high-grade mucoepidermoid carcinomas, salivary duct carcinomas, undifferentiated carcinomas and squamous cell carcinomas are high-risk tumors for nodal metastasis [1,[3][4][5]. In these the risk for neck metastasis has been described to be >50% [1] and, thus, elective neck dissection is considered in their management [1][2][3].Lymph vessels provide the main avenue for nodal metastasis and in head and neck squamous cell carcinoma (HNSCC) it has been shown that tumors of different anatomic regions do not vary significantly in their lymphangiogenic properties [6,7]. However, a high lymph vessel density (LVD) seems to be an indicator of the risk of lymph node metastasis in HNSCC [6][7][8][9]. Regarding salivary gland tumors, the lymphatic vessels have rarely been studied [10][11][12] and in a particular type of salivary carcinoma, i.e. in those arising in pleomorphic adenomas (CXPA) the lymphatic network was found to be composed mainly of pre-existing ...

Expression of VEGF-C/-D and lymphangiogenesis in salivary adenoid cystic carcinoma

“…However, we didn't demonstrate any correlation between either VEGF-C or VEGF-D histoscores and LVD. Similar results were published in head and neck squamous cell carcinomas [21,50] and in a group of 75 various salivary carcinomas that were tested by Mello [31]. Plausible explanation of the lacking correlation between tumoral VEGF-C and VEGF-D expressions and LVD might be found in the absence of proteolytic processing of these proteins, that is necessary for their effective binding to VEGFR-3 receptors of lymphatic endothelium [51].…”

“…The absence of tumor-associated formation of lymphatic channels in pleomorphic adenomas, was confirmed by Soares [30]. Mello [31] found no significant differences in the VEGF-C expression and LVD between salivary carcinomas with high-and low-risk of nodal involvement according to classification of Regis de Brito Santos [32]. Therefore, he concluded that these tumors applied other than VEGF-C associated molecular mechanisms for their lymphatic spread.…”

Correlation of intratumoral lymphatic microvessel density, vascular endothelial growth factor C and cell proliferation in salivary gland tumors

“…A study that evaluated the lymphatic density and expression of lymphangiogenic growth factors in high and low/moderate-risk salivary gland carcinomas showed the same absence of correlation between VEGF-C and LMV found in our results [37]. According to Mello et al, the metastatic potential of malignant tumors could be associated with their capacity to invade the lymph vessel, and not with ability for lymphatic growth [37].…”

Comparison of adenoid cystic carcinomas arising from the parotid gland vs. the submandibular gland: focus on systemic metastasis and tumor‐associated blood vessels

“…ACCs, constituting 25% of all malignant salivary gland tumors, preferentially metastasize to distant organs and rarely to lymph nodes . Such a predilection is attributable to the absence of lymphangiogenesis around the primary tumor .…”