Relationship of mast cell density with lymphangiogenesis and prognostic parameters in breast carcinoma

Abstract

In many cancers, mast cell density (MCD) in the tumor microenvironment is associated with tumor progression and, to a greater extent, angiogenesis. Our study was designed to investigate the correlation between MCD, tumor lymphangiogenesis, and several well-established prognostic parameters in breast cancer. One hundred and four cases of invasive breast carcinoma diagnosed in our clinic between 2007 and 2011 were included. Mast cells and lymphatic vessels were stained with toluidine blue and D2-40, respectively, and their densities were calculated in various areas of tumors and lymph nodes. The variables of MCD and lymphatic vessel density (LVD) were compared using prognostic parameters as well as with each other. As tumor size and volume increased, MCD increased comparably in metastatic lymph nodes; intratumoral and peritumoral LVD also increased. Lymphovascular invasion, lymphatic invasion, perineural invasion, and estrogen receptor positivity were positively related to intratumoral MCD. The relationship between peritumoral MCD and nontumoral breast tissue MCD was statistically significant. Stage was correlated with MCD in metastatic lymph nodes. Metastatic lymph node MCD and intratumoral MCD were also significantly related. Stage, lymphatic invasion, perineural invasion, lymphovascular invasion, and metastatic lymph node MCD were all correlated with intratumoral and/or peritumoral LVD. As nuclear grade increased, intratumoral LVD became higher. In breast carcinoma, MCD, depending on its location, was related to several prognostic parameters. Notably, mast cells may have at least some effect on lymphangiogenesis, which appears to be a predictor of tumor progression.

Mast Cell, the Neglected Member of the Tumor Microenvironment: Role in Breast Cancer

“…Formation of lymphatic vessels or lymphangiogenesis is also a reliable predictor of lymph node metastasis [ 96 , 97 ]. A recent study by Keser et al found that mast cells were present in all invasive primary tumors and in the metastatic lymph nodes [ 98 ]. In previous studies, mast cells were generally observed in the stroma adjacent to the neoplastic cells and near vascular structures [ 87 , 88 , 99 ].…”

“…Still, mast cell count was better correlated with metastatic lymph nodes than with reactive lymph nodes, which could indicate a specific mast cell role in metastasis of breast cancer cells. Although the study by Keser et al did not find a correlation between mast cell density and disease-free/overall survival, the authors reported a significant link between lymphatic vessel density (LVD) and other poor prognostic parameters, such as tumor diameter, tumor volume, tumor nuclear grade, perineural invasion, metastatic lymph node count, and tumor stage [ 98 ]. Interestingly, LVD also correlated with a shorter period of disease-free survival.…”

“…Concerning the tumor location of mast cells, one study found that intratumoral mast cells were better associated with lymphatic and perineural invasion, and this was an adverse prognostic parameter [ 98 ]. Contrary to della Rovere et al's study, indicating a potential positive role for peritumoral mast cells, other studies have found that these cells secrete proteases that facilitate vascular invasion and accelerate metastatic spread [ 92 , 95 , 98 ]. Thus, peritumoral mast cells seem to contribute to breast cancer progression.…”

Lymphatic changes in cancer and drug delivery to the lymphatics in solid tumors

“…VEGF-C [18] IL-6 [19] Ring finger protein 180 [20] ID-1 [21] Sonic hedgehog [22] iNOS [23] Melanoma VEGF-C [24,25] FAS [24] Microphthalmia-associated transcription factor [25] c-Jun N-terminal kinase and p38/mitogen-activated protein kinase [25] Integrin α4β1 [26,27] FLT4 [28] High fat diet -CCL18, CCL21/CCR7 axis [ [34] Ezrin [34] COX-2 [35,38] Prostaglandin E2 and E receptor [35] NCoR and TRβ1 [36] TAMs [39,40] IL-24 [41] ELK3 [37] S1P [42] SEMA7a [43] DcR3 [44] Sulf2 [45] Mast cell density [46]…”

“…Other immune cells that may be related to lymphangiogenesis are mast cells. Mast cell density within the tumor microenvironment is a sign of tumor progression [46]. With increasing tumor size and volume, there is a positive correlation in mast cell density in lymph nodes with metastases.…”