br Materials and methods br Results br Discussion A synoptic
Materials and methods
Discussion A synoptic review of these cases will be given. In Case 1 the process presented in a photodistributed fashion in a 79-year-old woman; while the infiltrate was atypical, it was non-effacing with polyclonal molecular studies. The disease eventually resolved spontaneously and the patient passed away years later of unrelated causes. In Cases 2, 3, and 4 diagnostic features of a T cell lymphoma were uncovered whereby in Case 2, the neoplastic process represented a CD30 negative large cell T cell lymphoma while in the other two cases the processes were predominated by small monomorphic T cells. In Case 3 where the infiltrate was dominated by large neoplastic T cells, the patient's clinical course was subsequently aggressive as manifested by widespread metastatic disease to the liver, spleen, and lymph nodes. In contrast, the patients with the small lymphocytic form of lymphoma are alive with one patient (Case 2) in remission following local radiation and Case 4 with widespread cutaneous disease that initially responded to chemotherapy but has since recurred without any evidence of extracutaneous disease. The aggressive course of the CD30 negative large cell T cell lymphoma case is similar to the aggressive clinical course seen in the other forms of primary cutaneous CD30 negative peripheral T cell lymphoma, manifesting a large transformed morphology [8,9]. Case 4 was particularly interesting because of its resemblance clinically and light microscopically to MF. However, the onset was quite sudden with a rapid course to tumor progression while cytologically the GGsTop were atypical but not cerebriform. The uniqueness of all of the cases is the nature of the CD4 positive T cells that defined the dominant infiltrate. Although cytotoxic protein expression was seen in all cases, positive staining for CD56, CD16 or CD57 characteristic of NK-T cell lymphoma was not seen. Cytotoxicity is either attributable to granule exocytosis or reflective of the interaction of FAS and FAS ligand. Perforin induces pores into a cell resulting in osmotic lysis. TIA (GMP-17) is a granule protein that is mostly restricted to NK cells, neutrophils and CD8 positive T lymphocytes. TIA is expressed by such cells regardless of their activation status. Perforin and granzyme are inducible when the cells are in a state of activation and this would correlate with the induction of cytolytic activity . Not surprisingly in the case where an aggressive clinical course developed, the cytotoxic cells expressed both granzyme and TIA. There are really no reports to date on cutaneous lymphomas that are derived from CD4 positive cytotoxic T cells that are CD30 negative other than cases of tumor stage MF and a subset of cases that fall under the rubric of small cell variant of ALCL . Lymphomagenesis is a multistep process that likely has as its inception an overzealous clonal response in a benign counterpart. In this regard, the classification of lymphoma is one that may be reflective of the ontogeny of the benign counterpart. The natural age-related deterioration of the lymphocyte compartment is heralded by the accumulation of mature T cells that express CD4 that have lost their expression of CD28, falling under the designation of a CD4 positive/CD28 null T cell. CD28 is a homodimeric stimulatory cell surface receptor of the Ig superfamily. It is expressed on virtually all T cells in rodents. In humans it is largely limited in expression to CD4 positive T cells and only half of CD8 positive T cells. CD80 and CD86 are the natural ligands for CD28. If they are upregulated by an exogenous trigger, the end result would be T cell proliferation. CD28 induces a co-stimulatory signal in T cells recognizing cognate antigen major histocompatibility complexes in their T cell receptor . It should be emphasized that CD28 exerts a critical influence on T cell survival. It is a booster to T cell proliferation. The interaction between CD28 and CD80 leads to the intracellular accumulation of the antiapoptotic protein BCL-XL rendering T cells resistant to intrinsic and extrinsic death signals . The premature accumulation of an immunosenescent T cell that no longer expresses the critical CD28 molecule has been described in patients with various autoimmune conditions including lupus erythematosus, rheumatoid arthritis and multiple sclerosis as well as patients who have underlying cardiovascular disease [13,14]. These T cells secrete inflammatory mediators and cytolytic molecules and hence, not surprisingly, one of the cardinal hallmarks of this T cell population is the expression of cytotoxic proteins such as granzyme and TIA. The chronic proinflammatory environment, repeated immune stimulation in autoimmune disease, certain viral infections and repetitive inflammatory events that occur with age can result in aging of the immune system either in the context of chronological normal aging or accelerated aging in the setting of autoimmune and viral disease. When there is an acceleration of aging of the immune system, it falls under the designation of premature immunosenescence [6,7]. At least in the setting of cardiovascular diseases, this immunosenescent T cell population can migrate to the sites of atherosclerotic change, destabilizing the atherosclerotic plaque, leading to cardiac events. Paradoxically, lymphocytes that express cytotoxic proteins do not specifically undergo apoptosis due to various mechanisms including intracytoplasmic inhibitors of serine proteases namely serpins and a cell surface protective molecule that prevents the disruption of the cytoplasmic membrane by perforins .