Pathology
The CCL2-CCR2 Axis in Lymph Node Metastasis From Oral Squamous Cell Carcinoma: An Immunohistochemical Study

https://doi.org/10.1016/j.joms.2016.09.052Get rights and content

Purpose

Cytokine or chemokine networks involve lymphatic and distant metastasis of various malignancies, including oral squamous cell carcinoma (OSCC). Immunohistochemical analysis was used to investigate the contribution of the axis of the CC chemokine receptor-2 (CCR2) and the CC chemokine receptor-2 ligand (CCL2) to lymphatic metastasis, particularly the relation between primary OSCC and marginal sinus histiocytosis in regional lymph nodes.

Materials and Methods

Thirteen metastasis-free cases, 15 metastatic cases at resection of primary tumor resection, and 13 postresection metastasis cases were examined. No patient was treated with radiotherapy or chemotherapy before neck dissection. Samples were fixed in formalin, embedded in paraffin, and subjected to immunohistochemical analysis using antibodies against CCL2, CCR2, podoplanin, and α-smooth muscle actin (α-SMA).

Results

Marginal sinus histiocytosis was frequently observed in metastatic cases. CCL2 was expressed in tumor-associated neutrophils (TANs) and moderately or poorly differentiated SCC was detected at primary tumor sites. TANs expressing CCL2 flowed into the marginal sinus in the lymph nodes. CCR2-positive macrophages and mesenchymal cells infiltrated the tumor stroma and were seen within the carcinoma nests. They were predominantly present in the marginal sinus of metastatic cases. In small metastatic foci, α-SMA–positive spindle cells resembling carcinoma-associated fibroblasts (CAFs) were observed adjacent to the macrophages.

Conclusion

The CCL2-CCR2 axis is associated with lymphatic metastasis. To clarify the mechanism of lymphatic metastasis from OSCC, further functional analyses of the CCL2-positive TANs, CCR2-positive macrophages, and CAF-like cells detected in this study are recommended.

Section snippets

Patients and Tissue Specimens

Forty-one cases of OSCC were obtained from the files of the Division of Oral Pathology and Bone Metabolism at the Nagasaki University Graduate School of Biomedical Sciences (Nagasaki, Japan) for histologic and immunohistochemical examination. These included 28 cases of OSCC resection with simultaneous neck dissection and 13 cases of radical neck dissection after resection of a primary tumor. Of the 28 cases of OSCC with simultaneous neck dissection, 13 exhibited no lymphatic metastasis and 15

Results

The HE-stained sections were examined to confirm the presence of sinus histiocytosis in the regional lymph nodes of patients with OSCC. The tissue sections frequently exhibited sinus histiocytosis; in particular, marginal sinus histiocytosis was detected in 93.3% of metastatic cases with concurrent resection of the primary tumor and 84.6% of postresection metastatic cases (Fig 1A). In contrast, 23.1% of metastasis-free cases exhibited sinus histiocytosis, which was markedly lower than in the

Discussion

Metastasis of tumor cells to regional lymph nodes is an important prognostic factor in determining the stage of various malignancies, including OSCC. For the establishment of lymphatic metastasis, interactions between cancer cells and various immune cells by the signaling of cytokines and chemokines are required.21, 22 These immune cells and mesenchymal cells (eg, CAFs) prepare the microenvironment to cultivate cancer stem cells and further support tumor development.16, 17, 23 A particular

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    This work was supported by the JSPS KAKENHI (grant JP25462864).

    Conflict of Interest Disclosures: None of the authors have any relevant financial relationship(s) with a commercial interest.

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