SIGNIFICANCECutaneous T-cell lymphomas are a heterogeneous group of extranodal non-Hodgkin's lymphomas that are characterized by a cutaneous infiltration of malignant monoclonal T lymphocytes. Tumor cells in cutaneous T-cell lymphoma express limited numbers of chemokine receptors on their cell surface. We analyzed the expression patterns of CXCR3, CCR3, CCR4 and CCR10 in skin samples from patients with cutaneous T-cell lymphoma. In addition, we investigated the relationship between chemokine receptor expression and survival prognosis. Differential patterns of CXCR3, CCR3, CCR4 and CCR10 expression were useful for the diagnosis of cutaneous T cell lymphoma. Moreover, expression of CCR3 or CCR4 suggested a poor prognosis in cutaneous T-cell lymphoma.Tumor cells in cutaneous T-cell lymphoma express limited numbers of chemokine receptors. We investigated the expression patterns of CXCR3, CCR3, CCR4 and CCR10 in mycosis fungoides, Sézary syndrome, lymphomatoid papulosis and anaplastic large cell lymphoma in 121 skin biopsy samples. CXCR3 was expressed in 86% of mycosis fungoides cases but in no anaplastic large cell lymphoma cases. CCR3 was expressed in 73% of cases of CD30 + lymphoproliferative disorders such as lymphomatoid papulosis and anaplastic large cell lymphoma. Mycosis fungoides/Sézary syndrome patients with high CCR3 or CCR4 expression had a poorer survival prognosis than mycosis fungoides/Sézary syndrome patients whose tumor cells did not express these receptors. CCR10 was expressed in 50% of mycosis fungoides/Sézary syndrome cases and in 13% of cases with CD30 + lymphoproliferative disorders. These results suggest that differential patterns of CXCR3, CCR3, CCR4 and CCR10 expression are useful for the diagnosis of cutaneous T-cell lymphoma. Moreover, expression of CCR3 or CCR4 suggests a poor prognosis in mycosis fungoides/Sézary syndrome.

In many malignancies, dysregulation of the Notch pathways, composed of 4 Notch receptors (Notch1–4) and 5 Notch ligands (Jagged1–2, Delta-like ligand-1, 3–4), is associated with their development. In mycosis fungoides, interaction between Notch1 and Jagged1 is known to activate the Notch pathways and promote the proliferation of tumour cells. However, the involvement of other Notch ligands has not been reported. This study investigated the roles of Delta-like ligand 4 in mycosis fungoides. Delta-like ligand 4 mRNA levels in lesional skin of patients with mycosis fungoides were significantly elevated compared with those of normal controls, and correlated with disease-specific mortality. Immunohistochemical staining demonstrated prominent expression of Delta-like ligand 4 on vascular endothelial cells and tumour cells in mycosis fungoides lesional skin. In addition, Delta-like ligand 4 augmented the proliferation of cutaneous T-cell lymphoma cell lines. These results suggest that enhanced Delta-like ligand 4 expression may contribute directly to the progression of mycosis fungoides through proliferating tumour cells.

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