Histiocytic necrotizing lymphadenitis (Kikuchi's disease): in situ end-labeling, immunohistochemical, and serologic evidence supporting cytotoxic lymphocyte-mediated apoptotic cell death.

Histiocytic necrotizing lymphadenitis (Kikuchi's disease) is a benign, self-limited disorder that is sometimes confused with malignant lymphoma. Kikuchi's disease is characterized by collections of histiocytes and lymphocytes surrounding areas of necrosis containing fragments of karyorrhectic nuclear debris. Polymorphonuclear leukocytes are generally absent. The mechanism of cell death involved has not been extensively studied, and a definitive etiology has not been identified. Recent articles proposed that the mechanism of cell death is more characteristic of coagulative necrosis than apoptosis, but, to our knowledge, this has not been studied with the use of currently available assays of apoptosis. To study the mechanism of cell death in Kikuchi's disease, we employed an in situ end-labeling technique on formalin-fixed, paraffin-embedded sections of lymph nodes with Kikuchi's disease. These studies demonstrated that the lymphocytes and histiocytes within and surrounding the areas of necrosis showed nuclear DNA fragmentation, a feature characteristic of early apoptosis. Immunohistochemical studies revealed an increase in CD8(+)-T lymphocytes and lymphocytes containing TIA-1, a cytotoxic granule-associated protein, within foci of cellular debris, with a relative paucity of CD56+ cells. Moreover, TIA-1-positive granules were present within the cytoplasm of many apoptotic bodies. In one of the patients for whom acute phase serum was available, evaluation by enzyme-linked immunosorbent assay demonstrated that the serum concentrations of the T-cell activating cytokines interleukin-2 and interleukin-6 were increased; no such increase was noted in eight patients with other lymphoproliferative disorders. In contrast, the serum concentrations of the immunosuppressive molecules interleukin-10, soluble interleukin-2 receptor, and soluble tumor necrosis factor receptor were expressed at normal levels in the patient with Kikuchi's disease. These findings suggested that the predominate mechanism of cellular destruction in Kikuchi's disease was apoptosis mediated by cytolytic lymphocytes. These data supported the prevailing hypothesis of a viral or autoimmune pathogenesis in Kikuchi's disease.