Biology and management of histologic transformation of indolent lymphoma.

The evolution of indolent lymphomas to aggressive histologies, known as histologic transformation (HT), is a frequent occurrence for all subtypes of low grade B cell lymphoproliferative disorders. The risk of developing HT is approximately 3% per year for patients with indolent lymphoma. Clinically these present with a rapid change in the behavior of the disease, with evidence of a highly proliferative malignancy with a propensity to involve extranodal sites. The prognosis of patients following transformation is generally poor, with median survival of about 12 months. Recent studies suggest that the development of HT is very complex with the acquisition of multiple cytogenetic abnormalities in the low-grade lymphoma cells prior to HT. To date, there are no biologic or genetic parameters predictive of the development of HT. A myriad of genetic lesions have been identified in HT, and provide insight into its pathogenesis. These include genes regulating proliferation (C-MYC and C-MYC-regulated genes); control of the cell cycle (CDKN2a and CDKN2B); and programmed cell death (TP53, C-MYC, and BCL2). Gene expression profiling has been applied to the study of HT and has increased our understanding of the transformation process. There has been limited progress in the treatment of patients with HT. Conventional chemotherapy is generally of limited benefit, although a subset of patients are long-term survivors following high-dose therapy and autologous stem cell transplantation. The use of radioimmunotherapy and new agents targeting specific lesions or aberrant pathways may impact on the management of these aggressive diseases.