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Tumor Biology in Cutaneous Malignant Lymphomas

resent a heterogeneous group of nonHodgkin lymphomas (NHL), which show a considerable variation in clinical presentation, histology, immunophenotype, and prognosis. At the present time, CL can be best classified by means of the EORTC classification for primary cutaneous lymphomas (Table) (1). Following the group of primary gastrointestinal lymphomas, they form the secondmost common group of extranodal NHL. The annual incidence is estimated between 0.5 and 1 per 100,000. Despite their heterogeneity, CL can be defined as clonal proliferation of skin-infiltrating B/T lymphocytes primarily presenting in the cutaneous compartment (at least 6 months). By applying PCR based techniques, clonal T cells can be detected in about 75% of clinically and histologically diagnosed CL (2). As determined by fragment analysis, a shift from a predominance of polyand oligoclonal cases to monoclonality can be observed during the progression of Large Plaque Parapsoriasis to tumor stage Mycosis fungoides (MF). This suggests a step-wise genesis of CL from polyclonal via oligoclonal towards a monoclonal proliferation of lymphocytes, which might be caused by chronic stimulation. Although environmental and infectious agents are speculated to play major roles in chronic lymphocyte stimulation, until recently neither an environmental (3) nor an infectious agent could be demonstrated to have induced the lymphoma in the majority of CL cases. However, identification of a CL inducing virus remains possible, since viral infections cause lymphomas in a strongly site-dependent manner as shown in the case of Epstein-Barr virus and cytotoxic nasal lymphomas (4). Further support comes from the association of CL with a number of specific human leukocyte antigens such as HLA Aw31, Aw32, B8, Bw35, and DR5 (5). Moreover, chronic stimulation induces genetic aberrations which might represent a further step in CL pathogenesis. Although an identical alteration, presenting in the majority of CL, is absent, CL cells, unlike normal lymphocytes, possess a considerable ability to develop multiple numeric and structural aberrations (6, 7). On account of this ability, CL cells have been given the term genotraumatic cells (8). The genetic instability might be associated with alterations in telomerase activity which, usually weak, is increased even at early stages of cutaneous T cell lymphomas (CTCL) and in Parapsoriasis en Plaques (9). Although genotraumatic cells are not per se malignant, their genetic instability may cause transformation into malignant cells by achieving distinct genetic defects. The role of oncogenes within these genetic defects remains obscure, since p53 is not affected at a significant frequency of CL, and, in a larger cohort of CTCL, all 21 cases were negative for the bcl-2 protein (10). Likewise, neither the majority of CL cases nor a distinct CL entity showed expression of p16, p21, p62, or PCNA (11). Once established, changes in extraand intracellular signaling and metabolism pathways as well as alterations in the local and systemic cytokine pattern and the immune response against the neoplastic cells are also involved in persistence and progression of the malignancy. In this process, cytokines are considered to be of major importance because they might be responsible for the stimulation of malignant cell proliferation, The Journal of Dermatology Vol. 28: 606–609, 2001