Micrometastatic bone marrow involvement: detection and prognostic significance

The present review focuses on the methodology and clinical significance of new diagnostic approaches to identify individual cancer cells present in bo ne marrow, both as a frequent site of metastasis formation and an indicator organ for hematogenous tumor cell dissemination. The steadily increasing n umber of studies on this issue is characterized by considerable methodologi cal variations of important variables, such as the size of the study popula tion, and the reliability of monoclonal antibodies used for tumor cell dete ction. Emerging data indicate that this disturbing heterogeneity might be o vercome by the use of reliable and specific anti-cytokeratin antibodies (fo r example, A45-B/B3) as, for the time, standard markers for the detection o f micrometastatic tumor cells in bone marrow. Prospective clinical studies have shown that immunoassays based on anti-CK antibodies identify patients' subgroups with a poor clinical prognosis with regard to early metastasis m anifestation and reduced overall survival in various epithelial tumor entit ies, including breast, colon, rectum, stomach, esophagous, prostate, renal, bladder, and nonsmall cell lung cancer. The immunocytochemical assays may be therefore used to improve tumor staging with potential consequences for adjuvant therapy, because disseminated cells appeared to be dormant, non-cy cling (for example Ki-67 antigen-negative) cells, suggesting a resistence t o cell-cycle dependent therapy, such as chemotherapy. Therefore, cell-cycle independent antibody-based immunotherapy might be an interesting option to complement chemotherapy. Another promising clinical application is monitor ing the response of micrometastatic cells to adjuvant therapies, which, at present, can only be assessed retrospectively after an extended period of c linical followup. The outlined current strategies for detection and charact erization of cancer micrometastasis might help to design and control new th erapeutic strategies for secondary prevention of metastatic relapse in pati ents with operable primary carcinomas.