Primary cutaneous T cell lymphomas (CTCL), comprise a group of distinct disease entities with Mycosis Fungoides (MF) and Sezary Syndrome (SS) being the most common types, followed by primary cutaneous CD30+ T cell lymphoproliferative disorder. The recent WHO classification for hematologic neoplasms (4th edition 2008), includes three new variants of primary CTCL: primary cutaneous gamma delta T cell lymphoma, and the provisional entities of primary cutaneous CD4+ small/medium T cell lymphoma and primary cutaneous aggressive epidermotropic CD8+ cytotoxic T cell lymphoma. Staging and classification of these diseases are performed according to the revised WHO/EORTC system which provides accurate diagnostic details concerning the tumor burden, the lymph node infiltration and the visceral involvement incorporating at the same time advances for understanding the pathogenesis of these diseases and variables for the uniform application into clinical trials.
The etiology of MF and SS remains largely unknown. It has been proposed that viral infections such as the human T-cell lymphotropic virus type 1 (HTLV-1) and other chronic antigenic stimulation can trigger a cataract of events that lead to the escape from immune surveillance and the clinical evidence of lymphoma. Based on older studies, half of the patients with early stage and almost all with advanced stage disease have reduced T-cell receptor diversity compared with healthy controls with a normal T cell repertoire in the blood.
The skin homing mechanism of malignant T cells is not yet clear. The MF and SS cells bear a CLA+ phenotype and express various chemokine receptors such as CCR4 and CCR10. It has been shown that these chemokines and their ligands play an important role in the recruitment of malignant T cells in the skin. Newer data added the information that the homeostatic chemokine CXCL13 is upregulated in SS and by the synergistic action of CCL19 and CCL21, it enhances chemotaxis of tumor cells to the skin. CTCL has a favorable prognosis in the early stages but patients with tumors or disseminated disease or SS do not respond to chemotherapy and progress rapidly. This phenomenon is due partly to a defective apoptosis including Fas/Fas Ligand expression which is reduced as disease progresses. Mutations of the gene encoding for CD95 receptor or non functional receptor have also been described. A number of cytogenetic studies have demonstrated chromosomal aberrations, primarily of 1, 6, 8, 9, 10, 11 and 17 chromosomes, that correlate with disease burden and resistance to therapy. Experimental studies have shown that the malignant T cells can acquire a T regulatory cell phenotype after the exposure to dendritic cells, secrete interleukin 10 and transforming growth factor β and induce further cell proliferation and survival. The nuclear factor-kappaB which is involved in proliferation, cytokine production and cell survival, was found constitutively activated in CTCL cell lines and in the blood of SS patients.
By using microarray studies, a MF signature was detected which includes deregulation of TNF signaling and at the same time, a TNF survival pathway activation by a feedback stimulation of the TNF receptors.
Existing data and ongoing research hopefully will elucidate the pathogenesis of these disease entities and will provide new therapeutic options for the restitution of immune balance.