Mycosis fungoides (MF) was first described over a century ago, yet the molecular events underlying MF tumorgenesis and tumor progression are largely unknown. The cause of MF is ultimately unclear, although many current hypotheses exist on its possible genetic, environmental, and immunologic etiologies.

Current hypotheses of MF include genetic and cellular signalling abnormalities such as clonal abnormalities and changes in the expression of adhesion molecules and cytokines. Genetic studies have also implicated activation of the tumor necrosis factor (TNF) antiapoptotic pathway, activation of STAT3, and inactivation or loss of tumor suppressors CDKN2A, PTEN, and p53 [1–4]. With the onset of next-generation sequencing, many T cell activating mutations have been described.

Sustained antigenic stimulation also has been shown to play a role in the development of malignant lymphomas , although the nature of antigens in the setting of MF is unknown. In 1974, Tan et al. proposed, for the first time, that chronic antigen persistence could lead to T cell proliferation and presence of reactive lymphocytes in the skin, and play an important role in the pathogenesis of MF [5]. Their proposal was based on the finding that MF patients demonstrate increased serum immunoglobulin E levels. Sustained stimulation of the immune system by antigens is thought to lead to clonal expansion and accumulation of T cells in the skin, and ultimately result in inappropriate immunological responses [6]. Many factors such as bacterial infections, viral infections, chemical exposures, prolonged sun exposure, medications, and smoking have been suggested to cause chronic antigen stimulation , and have been implicated in the pathogenesis of MF [7]. However, a large case-controlled study failed to support the role of chemical and occupational exposures [8]. Similarly, while infection with human T-lymphotropic virus type I (HTLV-1) has been reported in patients with MF, studies have failed to support its role in the pathogenesis of MF [9, 10]. In fact, it has been shown that most cutaneous T cell lymphoma (CTCL) patients are serologically HTLV-1 negative [11–13].

Alterations in the immunological milieu have also been implicated in the pathogenesis of MF. In 1976, Rowden and Lewis proposed that alterations in immunological signaling mediated by Langerhans cells (LCs) could represent an inciting event in MF [14]. Since then, immunohistochemical studies have found that the neoplastic cells of MF—so-called mycosis cells (MCs) that are uniquely characterized by irregular, “cerebriform” nuclei—have been found to frequently co-occur with LCs in the epidermis of MF skin lesions, with LCs forming close epithelial-like contacts with MCs [15]. Phenotypic characterization of the cells has revealed that SS is a malignancy derived from the central memory T cells, while MF is of skin resident effector memory T cell origin [16]. Immunologically, neoplastic T cells in tumor stage MF has been shown to derive from CD4+ T cells with a Th2 cytokine profile, and an impaired Th1 cell-mediated antitumor response has also been implicated in MF [17, 18].