The Pathogenesis of Mycosis Fungoides

Abstract

utaneous t-cell lymphoma represents a complex array of dis -orders with various manifestations, clinical courses, and therapeutic consider-ations. Mycosis fungoides — in which the skin is variably affected by flat patch-es, thin plaques, or tumors — is the most common form of cutaneous T-cell lymphoma; consequently, more is understood about it from a basic immunologic and molecular perspective than is understood about the other variants. The related Sézary syndrome is a more aggressive form of cutaneous T-cell lymphoma in which the skin is diffusely af-fected and there is measurable involvement within the peripheral blood. In addition to mycosis fungoides and the Sézary syndrome, several other disease entities have been grouped under the heading of cutaneous T-cell lymphoma, each of which has distinct clinical manifestations and natural histories but all of which are characterized by expan-sions of malignant T cells within the skin. In this review, we focus on recent discoveries in the field of T-cell biology as they relate to the pathogenesis of mycosis fungoides and the Sézary syndrome. Advances in cellular and molecular biology have revealed many details about lym-phocytes, including the incredible diversity of their T-cell antigen receptors, the efficien-cy with which they navigate the endoreticular system, and their capacity for recruitment to specific tissues. 1 The integration of these activities may result in the beneficial elim-ination of foreign microbial agents and the inhibition of tumor development and growth, or it may lead to the untoward effects seen in inflammatory and autoimmune diseases. The complexity of mycosis fungoides may best be appreciated as a cancer of T cells that continue in many respects to function as T cells under normal physiologic conditions, but the behavior of which is dominated by their propensity to home to the skin, be ac-tivated and persist in an activated state, and achieve clonal dominance, thereby accumu-lating in the skin, lymph nodes, and peripheral blood. Knowledge of the unifying char-acteristics relating to disease behavior influences the evaluation and therapy of patients with mycosis fungoides, and an understanding of the pathogenesis and treatment of my-cosis fungoides offers insights into fundamental mechanisms of T-cell signaling, ap-optosis, and immunosurveillance. Mycosis fungoides is a relatively rare, extranodal, non-Hodgkin's lymphoma with a stable incidence of approximately 0.36 per 100,000 person-years. 2,3 Infectious agents, occupational exposures, and genetic mutations have been evaluated as etiologic factors in relation to mycosis fungoides, but evidence of causation has not been readily forth-coming. 4 Whereas viruses have been identified as etiologic agents in at least two cutane-ous lymphomas (human T-cell lymphotropic virus–associated adult T-cell lymphoma– leukemia and Epstein–Barr virus–associated nasal natural-killer–T-cell lymphoma), no such relation has been confirmed for mycosis fungoides. Nevertheless, according to a recent intriguing report, 97 percent of patients with late-stage mycosis fungoides or the Sézary syndrome are seropositive for cytomegalovirus, in contrast to healthy bone mar-row donors, whose seropositivity rate is 57 percent. 5 In addition, it is important to note that a variety of T-cell lymphomas may involve the skin during their clinical evolution, c