Detection and relevance of minimal disease in lymphomas

The detection and clinical relevance of minimal disease in non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) is reviewed. Relevant aspects of the basic biology of these diseases are introduced, including the interactions of NHL with bone marrow stromal cells and the consequences of suppressed apoptosis and induced chemoresistance which might explain why minimal lymphoma in bone marrow is a surrogate predictor of a poor clinical outcome. In contrast, NHL cells isolated from stroma, for example mobilized into blood by cytokine, may be more susceptible to apoptosis and clinically less significant. The possible role of angiogenesis in facilitating early metastasis to the bone marrow is considered. Methods of detecting minimal NHL are reviewed and differences in predictive reliability of tumor detected by culture methods versus molecular techniques which identify clonal bcl-2 or antigen receptor rearrangements are discussed. The role of detection of HD by analysis of unique rearrangements of the immunoglobulin heavy and light chain genes is discussed as is the possibility that Reed-Sternberg (RS) cells can be detected molecularly as well as grown in culture from blood and apheresis harvests of patients. It appears that patients with cells resembling RS cells in their harvest do less well following high dose therapy and transplantation and additional studies of this topic are warranted. Future developments including quantitative monitoring of disease burden by real-time automated PCR and the application of genetic profiling to identify genetic markers specific to the tumor and which, potentially can predict prognosis is suggested. Also, the problems which may arise in attempts to monitor the impact of newer therapies such as anti-lymphoma antibodies and vaccines which may preferentially deplete tumor cells from blood and marrow are considered. The past 10 years has witnessed dramatic progress in the application of techniques to monitor minimal lymphoma. This technology has helped demonstrate the success of some new therapeutic approaches e.g. antibody and vaccine therapies, and served to emphasize the failure of others, for example, stem cell selection to purge lymphoma from patient harvests. Technologically, the field is not yet mature and further evolution may be expected.