Skip to main content

Advertisement

Log in

Recent advances in the detection of bone marrow micrometastases: A promising area for research or just another false hope? A review of the literature

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

The presence of early disseminated tumor cells (DTC), otherwise termed micrometastases or minimal residual disease, in the bone marrow (BM), or other secondary compartments, such as the blood and the lymph nodes, is the main reason for recurrence of patients with early stage epithelial cancers after “curative” resection of the primary tumor. There is increasing evidence, that the detection of DTC in BM aspirates may provide additional and independent prognostic information and aid in the stratification of these patients for adjuvant clinical treatment. However, the clinical relevance of micrometastases has not yet been firmly established. In addition, the molecular events and interactions that prevail in early metastatic disease and determine the formation or not of overt metastases remain poorly understood. The methods currently used for the detection of micrometastatic cells include extremely sensitive immunocytochemical and molecular assays, often in conjunction with enrichment techniques for the purification of tumor cells and additional increase of their sensitivity. Nevertheless, the specificity of these methods is mostly inadequate. After the impressive advances of molecular cytogenetics, a highly accurate and global assessment of the genetic status of tumors is now possible. Therefore, the greatest challenge of our time is the application of these novel technologies for the clarification of the key molecular events that initiate metastatic spread. This will further enable us to identify the highly specific and sensitive diagnostic and prognostic markers as well as the therapeutic targets which are so urgently needed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Chambers, A. F. (2004). Biology of the metastatic process. In American Society of Clinical Oncology (ASCO) (Ed.), ASCO 2004 educational book (pp. 696–700). USA: Lisa Graves Publisher.

    Google Scholar 

  2. Pantel, K., & Woelfle, U. (2004). Cancer micrometastasis: Detection, clinical relevance, and molecular description. In American Society of Clinical Oncology (ASCO) (Ed.), ASCO 2004 educational book (pp. 701–708). USA: Lisa Graves Publisher.

    Google Scholar 

  3. Pantel, K., Cote, R. J., & Fodstad, O. (1991). Detection and clinical importance of micrometastatic disease. Journal of the National Cancer Institute, 91, 1113–1124.

    Google Scholar 

  4. Choesmel, V., Pierga, J.-Y., Nos, C., Vincent-Salomon, A., Sigal-Zafrani, B., Thiery, J.-P., et al. (2004). Enrichment methods to detect bone marrow micrometastases in breast carcinoma patients: Clinical relevance. Breast Cancer Research, 6, R556–R570.

    PubMed  CAS  Google Scholar 

  5. Carter, C. L., Allen, C., & Henson, D. E. (1989). Relation of tumor size, lymph node status, and survival in 24,740 breast cancer cases. Cancer, 63, 181–187.

    PubMed  CAS  Google Scholar 

  6. Rosner, D., & Lane, W. W. (1993). Predicting recurrence in axillary-node negative breast cancer patients. Breast Cancer Research and Treatment, 25, 127–139.

    PubMed  CAS  Google Scholar 

  7. Feezor, R. J., Copeland, E. M., 3rd, & Hochwald, S. N. (2002). Significance of micrometastases in colorectal cancer. Annals of Surgical Oncology, 9, 944–953.

    Article  PubMed  Google Scholar 

  8. Pantel, K., & Braun, S. (2001). Molecular determinants of occult metastatic tumor cells in bone marrow. Clinical Breast Cancer, 2, 222–228.

    PubMed  CAS  Google Scholar 

  9. Seeliger, H., Spatz, H., & Jauch, K. W. (2003). Minimal residual disease in gastric cancer. Recent Results in Cancer Research, 162, 79–87.

    PubMed  Google Scholar 

  10. Zehentner, B. K. (2002). Detection of disseminated tumor cells: Strategies and diagnostic implications. Expert Review of Molecular Diagnostics, 2, 41–48.

    PubMed  Google Scholar 

  11. Zhu, L., Lam, C. K., & Chow, L. W. C. (2004). Sentinel lymph node biopsy or detection of micrometastasis in bone marrow: Which might be an alternative to axillary lymph node dissection in breast cancer patients? Asian Journal of Surgery, 27, 279–283.

    Article  PubMed  Google Scholar 

  12. Dearnaley, D. P., Sloane, J. P., Ormerod, M. G., Steele, K., Coombes, R. C., Clink, H. M., et al. (1981). Increased detection of mammary carcinoma cells in marrow smears using antisera to epithelial membrane antigen. British Journal of Cancer, 44, 85–90.

    PubMed  CAS  Google Scholar 

  13. Timar, J., Csuka, O., Orosz, Z., Jeney, A., & Kopper, L. (2002). Molecular pathology of tumor metastasis: II. Molecular staging and differential diagnosis. Pathology Oncology Research, 8, 204–219.

    PubMed  CAS  Google Scholar 

  14. Guinebretiere, J. M., & Contesso, G. (2001). “Micrometastases”: The pathologist’s point of view. Bulletin du Cancer, 88, 549–550, 555–560.

    Google Scholar 

  15. MacDonald, I. C., Groom, A. C., & Chambers, A. F. (2002). Cancer spread and micometastasis development: Quantitative approaches for in vivo models. Bioessays, 24, 885–893.

    PubMed  CAS  Google Scholar 

  16. Chambers, A. F., Naumov, G. N., Varghese, H. J., Nadkarni, K. V., MacDonald, I. C., & Groom, A. C. (2001). Critical steps in hematogenous metastasis: An overview. Surgical Oncology Clinics of North America, 10, 243–255.

    PubMed  CAS  Google Scholar 

  17. Chambers, A., F, MacDonald, I. C., Schmidt, E. E., Morris, V. L., & Groom, A. C. (1999). Pre-clinical assessment of anti-cancer therapeutic strategies using in vivo videomicroscopy. Cancer Metastasis Reviews, 17, 263–269.

    CAS  Google Scholar 

  18. Fidler, I. J. (1975). Biological behavior of malignant melanoma cells correlated to their survival in vivo. Cancer Research, 35, 218–224.

    PubMed  CAS  Google Scholar 

  19. Cameron, M. D., Schmidt, E. E., Kerkvliet, N., Nadkarni, K. V., Morris, V. L., Groom, A. C., et al. (2000). Temporal progression of metastasis in lung: Cell survival, dormancy and location dependence of metastatic inefficiency. Cancer Research, 60, 2541–2546.

    PubMed  CAS  Google Scholar 

  20. Murphy, B. O., Joshi, S., Kessinger, A., Reed, E., & Sharp, J. G. (2002). A murine model of bone marrow micrometastasis in breast cancer. Clinical & Experimental Metastasis, 19, 561–569.

    Google Scholar 

  21. Tarin, D., Price, J. E., Kettlewell, M. G., Souter, R. G., Vass, A. C., & Crossley, B. (1984). Mechanisms of human tumor metastasis studies in patients with peritoneovenous shunts. Cancer Research, 44, 3584–3592.

    PubMed  CAS  Google Scholar 

  22. Gangnus, R., Langer, S., Breit, E., Pantel, K., & Spercher, M. R. (2004). Genomic profiling of viable and proliferative micrometastatic cells from early-stage breast cancer patients. Clinical Cancer Research, 10, 3457–3464.

    PubMed  CAS  Google Scholar 

  23. Naumov, G. N., MacDonald, I. C., Weinmeister, P. M., Kerkvliet, N., Nadkarni, K. V., Wilson, S. M., et al. (2002). Persistence of solitary mammary carcinoma cells in a secondary site: A possible contributor to dormancy. Cancer Research, 62, 2162–2168.

    PubMed  CAS  Google Scholar 

  24. Demicheli, R., Abbattista, A., Miceli, R., Valagussa, P., & Bonnadonna, G. (1996). Time distribution of the recurrence risk for breast cancer patients undergoing mastectomy: Further support about the concept of tumor dormancy. Breast Cancer Research and Treatment, 41, 177–185.

    PubMed  CAS  Google Scholar 

  25. Gimbrone, M. A., Jr., Leapman, S. B., Cotran, R. S., & Folkman, J. (1972). Tumor dormancy in vivo by prevention of neovascularization. Journal of Experimental Medicine, 136, 261–276.

    PubMed  Google Scholar 

  26. Michelson, S., & Leith, J. T. (1994). Dormancy, regression and recurrence: Towards a unifying theory of growth control. Journal of Theoretical Biology, 169, 327–338.

    PubMed  CAS  Google Scholar 

  27. Stewart, T. H. (1996). Immune mechanisms and tumor dormancy. Medicina (Buenos Aires), 56, 74–82.

    CAS  Google Scholar 

  28. Yu, W., Kim, J., & Ossowski, L. (1997). Reduction in surface urokinase receptor forces malignant cells in a protracted state of dormancy. Journal of Cell Biology, 137, 767–777.

    PubMed  CAS  Google Scholar 

  29. Solakoglu, O., Maierhofer, C., Lahr, G., Breit, E., Scheunemann, P., Heumos, I., et al. (2002). Heterogeneous proliferative potential of occult metastatic cells in bone marrow of patients with solid epithelial tumors. Proceedings of the National Academy of Sciences of the United States of America, 99, 2246–2251.

    PubMed  CAS  Google Scholar 

  30. Guba, M., Cernaianu, G., Koehl, G., Geissler, E. K., Jauch, K.-W., Anthuber, W. F., et al. (2001). A primary tumor promotes dormancy of solitary tumor cells before inhibiting angiogenesis. Cancer Research, 61, 5575–5579.

    PubMed  CAS  Google Scholar 

  31. Holmgren, L., O’Reilly, M. S., & Folkman, J. (1995). Dormancy of micrometastases: Balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nature Medicine, 1, 149–153.

    PubMed  CAS  Google Scholar 

  32. O’Reilly, M. S., Holmgren, L., Shing, Y., Chen, C., Rosenthal, R. A., Moses, M., et al. (1994). Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell, 79, 315–328.

    PubMed  CAS  Google Scholar 

  33. Luzzi, K. J., MacDonald, I. C., Schmidt, E. E., Kerkvliet, N., Morris, V. L., Chambers, A. F., et al. (1998). Multistep nature of metastatic inefficiency: Dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. American Journal of Pathology, 153, 865–873.

    PubMed  CAS  Google Scholar 

  34. Murray, C. (1995). Tumor dormancy: Not so sleepy after all. Nature Medicine, 1, 117–118.

    PubMed  CAS  Google Scholar 

  35. O’Reilly, M. S., Boehm, T., Shing, Y., Fukai, N., Vasios, G., Lane, W. S., et al. (1997). Endostatin: An endogenous inhibitor of angiogenesis and tumor growth. Cell, 88, 277–285.

    PubMed  CAS  Google Scholar 

  36. O’Reilly, M. S., Pirie-Shepherd, S., Lane, W. S., & Folkman, J. (1999). Antiangiogenic activity of the cleaved conformation of the serpin antithrombin. Science, 285, 1926–1928.

    PubMed  CAS  Google Scholar 

  37. Farrar, J. D., Katz, K. H., Windsor, J., Thrush, G., Scheuermann, R. H., Uhr, J. W., et al. (1999). Cancer dormancy VII. A regulatory role for CD8+ T cells and IFN-γ in establishing and maintaining the tumor dormant state. Journal of Immunology, 162, 2842–2849.

    CAS  Google Scholar 

  38. Stevenson, F. K., George, A. J., & Glennie, M. J. (1990). Anti-idiotypic therapy of leukemias and lymphomas. Chemical Immunology, 48, 126–166.

    Article  PubMed  CAS  Google Scholar 

  39. Schirrmacher, V. (2001). T-cell immunity in the induction and maintenance of a tumor dormant state. Seminars in Cancer Biology, 11, 285–295.

    PubMed  CAS  Google Scholar 

  40. Dyke, R. J., McBride, H., George, A. J., Hamblin, T. J, & Stevenson, F. K. (1991). Idiotypic vaccination against B-cell lymphoma leads to dormant tumor. Cellular Immunology, 132, 70–83.

    PubMed  CAS  Google Scholar 

  41. Uhr, J. W., Tucker, T., May, R. D., Siu, H., & Vitetta, E. S. (1991). Cancer dormancy: Studies of the murine BCL1 lymphoma. Cancer Research, 51, 50455–50535.

    Google Scholar 

  42. Meng, S., Tripathy, D., Frenkel, E. P., Shete, S., Naftalis, E. Z., Huth, J. F., et al. (2004). Circulating tumor cells in patients with breast cancer dormancy. Clinical Cancer Research, 10, 8152–8162.

    PubMed  Google Scholar 

  43. Andratschke, M., Pauli, C., Stein, M., Chaubal, S., & Wollenberg, B. (2003). MHC-class I antigen expression on micrometastases in bone marrow of patients with head and neck squamous cell cancer. Anticancer Research, 23, 1467–1471.

    PubMed  CAS  Google Scholar 

  44. Schlimok, G., Kutter, D., Schaller, G., Geuz, T., Wiebecke, B., Backmann, R., et al. (1991). Frequent down-regulation of major histocompatibility class I antigen expression on individual micrometastatic carcinoma cells. Cancer Research, 51, 4712–4715.

    PubMed  Google Scholar 

  45. Schlimok, G., Funke, I., Bock, B., Schweiberer, B., Witte, J., & Riethmuller, G. (1990). Epithelial tumor cells in bone marrow of patients with colorectal cancer: Immunocytochemical detection, phenotypic characterization and prognostic significance. Journal of Clinical Oncology, 8, 831–837.

    PubMed  CAS  Google Scholar 

  46. Reynolds, T. (1998). Researchers slowly unveil where cancer cells hide. Journal of the National Cancer Institute, 90, 1690–1691.

    PubMed  CAS  Google Scholar 

  47. Korah, R., Boots, M., & Wieder, R. (2004). Integrin α5β1 promotes survival of growth-arrested breast cancer cells: An in vivo paradigm for breast cancer dormancy in bone marrow. Cancer Research, 64, 4514–4522.

    PubMed  CAS  Google Scholar 

  48. Ree, A. H., Tvermyr, M., Engebraaten, O., Rooman, M., Rosok, O., Hovig, E., et al. (1999). Expression of a novel factor in human breast cancer cells with metastatic potential. Cancer Research, 59, 4675–4680.

    PubMed  CAS  Google Scholar 

  49. Mansi, J. L., Berger, U., McDonnell, T., Pople, A., Rayter, Z., Gazet, J. C., et al. (1989). The fate of bone marrow micrometastases in patients with primary breast cancer. Journal of Clinical Oncology, 7, 445–449.

    PubMed  CAS  Google Scholar 

  50. Pantel, K. (2005). Symposium 34-2. Bone marrow: Homing organ for dormant micrometastatic cancer cells. Proceedings of the American Association for Cancer Research, 46, 1477–1478.

    Google Scholar 

  51. Putz, E., Witter, K., Offner, S., Stosiek, P., Zippelius, A., Johnson, J., et al. (1999). Phenotypic characteristics of cell lines derived from disseminated cancer cells in bone marrow of patients with solid epithelial tumors: Establishment of working models for human micrometastases. Cancer Research, 59, 241–248.

    PubMed  CAS  Google Scholar 

  52. Willipinski-Stapelfeldt, B., Riethdorf, S., Assmann, V., Woelfle, U., Rau, T., Sauter, G., et al. (2005). Changes in cytoskeletal proteins composition indicative of an epithelial–mesenchymal transition in human micrometastatic and primary breast carcinoma cells. Clinical Cancer Research, 11, 8006–8014.

    PubMed  CAS  Google Scholar 

  53. Fodstad, O., & Kjonniksen, I. (1994). Microenvironment revisited: Time for reappraisal of some prevailing concepts of cancer metastasis. Journal of Cellular Biochemistry, 56, 23–28.

    PubMed  CAS  Google Scholar 

  54. Fidler, I. J. (1995). Modulation of the organ microenvironment for treatment of cancer metastasis. Journal of the National Cancer Institute, 87, 1588–1592.

    PubMed  CAS  Google Scholar 

  55. Uhr, J. W., Scheuermann, R. H., Street, N. E., & Vitetta, E. S. (1997). Cancer dormancy: Opportunities for new therapeutic approaches. Nature Medicine, 3, 505–509.

    PubMed  CAS  Google Scholar 

  56. Folkman, J. (1995). Angiogenesis in cancer, vascular, rheumatoid and other diseases. Nature Medicine, 1, 27–31.

    PubMed  CAS  Google Scholar 

  57. Woelfle, U., Cloos, J., Sauter, G., Riethdorf, L., Janicke, F., van Diest, P., et al. (2003). Molecular signature associated with bone marrow micrometastasis in human breast cancer. Cancer Research, 63, 5679–5684.

    PubMed  CAS  Google Scholar 

  58. Varambally, S., Dhanasekaran, S. M., Zhou, M., Kumar-Sinha, C., Sanda, M. G., Ghosh, D., et al. (2002). The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature, 419, 624–629.

    PubMed  CAS  Google Scholar 

  59. Benoy, I. H., Salgado, R., Elst, H., Van Dam, P., Weyler, J., Van Marck, E., et al. (2005). Relative microvessel area of the primary tumor, and not lymph node status, predicts the presence of bone marrow micrometastases detected by reverse transcriptase polymerase chain reaction in patients with clinically non-metastatic breast cancer. Breast Cancer Research, 7, R210–R219.

    PubMed  CAS  Google Scholar 

  60. Z’graggen, K., Centeno, B. A., Fernandez-del Castillo, C., Jimenez, R. E., Werner, J., & Warshaw, A. L. (2001). Biological implications of tumor cells in blood and bone marrow of pancreatic cancer patients. Surgery, 129, 537–546.

    PubMed  CAS  Google Scholar 

  61. Zippelius, A., & Pantel, K. (2000). RT-PCR based detection of occult disseminated tumor cells in peripheral blood and bone marrow of patients with solid tumors. An overview. Annals of the New York Academy of Sciences, 906, 110–123.

    Article  PubMed  CAS  Google Scholar 

  62. Vona, G., Sabile, A., Louha, M., Sitruk, V., Romana, S., Schutze, K., et al. (2000). Isolation by size of epithelial tumor cells: A new method for the immunomorphological and molecular characterization of circulating tumor cells. American Journal of Pathology, 156, 57–63.

    PubMed  CAS  Google Scholar 

  63. Mehes, G., Luegmayr, A., Amros, I. M., Ladenstein, R., & Ambros, P. F. (2001). Combined automatic immunological and molecular cytogenetic analysis allows exact identification and quantification of tumor cells in the bone marrow. Clinical Cancer Research, 7, 1969–1975.

    PubMed  CAS  Google Scholar 

  64. Schmidt-Kittler, O., Ragg, T., Daskalakis, A., Granzow, M., Ahr, A., Blankenstein, T. J., et al. (2003). From latent disseminated cells to overt metastasis: Genetic analysis of systemic breast cancer progression. Proceedings of the National Academy of Sciences of the United States of America, 100, 7737–7742.

    PubMed  CAS  Google Scholar 

  65. Klein, C. A., Blakenstein, T. J., Schmidt-Kittler, O., Petronio, M., Polzer, B., Stoecklein, N. H., et al. (2002). Genetic heterogeneity of single disseminated tumor cells in minimal residual disease. Lancet, 360, 683–689.

    PubMed  CAS  Google Scholar 

  66. Albertson, D. G., Collins, C., McCormick, F., & Gray, J. W. (2003). Chromosome aberrations in solid tumors. Nature Genetics, 34, 369–376.

    PubMed  CAS  Google Scholar 

  67. Diel, I. J., Kaufmann, M., Costa, S. D., Holle, R., von Minckwitz, G., Solomayer, E. F., et al. (1996). Micrometastatic breast cancer cells in bone marrow at primary surgery: Prognostic value in comparison with nodal status. Journal of the National Cancer Institute, 88, 1652–1658.

    PubMed  CAS  Google Scholar 

  68. Molino, A., Pelosi, G., Turazza, M., Sperotto, L., Bonetti, A., Nortilli, R., et al. (1997). Bone marrow micrometastases in 109 breast cancer patients: Correlations with clinical and pathological features and prognosis. Breast Cancer Research and Treatment, 42, 23–30.

    PubMed  CAS  Google Scholar 

  69. Landys, K., Persson, S., Kovarik, J., Hultborn, R., & Holmberg, E. (1998). Prognostic value of bone marrow biopsy in operable breast cancer patients at the time of initial diagnosis: Results of a 20-year median follow-up. Breast Cancer Research and Treatment, 49, 27–33.

    PubMed  CAS  Google Scholar 

  70. Mansi, J. L., Gogas, H., Bliss, J. M., Gazet, J. C., Berger, U., & Coombes, R. C. (1999). Outcome of primary-breast-cancer patients with micrometastases: A long-term follow-up. Lancet, 354, 197–202.

    PubMed  CAS  Google Scholar 

  71. Braun, S., Pantel, K., Muller, P., Janni, W., Hepp, F., Kentenich, C. R., et al. (2000). Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II or III breast cancer. New England Journal of Medicine, 342, 525–533.

    PubMed  CAS  Google Scholar 

  72. Janni, W., Gastroph, S., Hepp, F., Kentenich, C., Rjosk, D., Schindlbeck, C., et al. (2000). Prognostic significance of an increased number of micrometastatic tumor cells in the bone marrow of patients with first recurrence of breast carcinoma. Cancer, 88, 2252–2259.

    PubMed  CAS  Google Scholar 

  73. Gerber, B., Krause, A., Muller, H., Richter, D., Reimer, T., Makovitzky, J., et al. (2001). Simultaneous immunohistochemical detection of tumor cells in lymph nodes and bone marrow aspirates in breast cancer and its correlation with other prognostic factors. Journal of Clinical Oncology, 19, 960–971.

    PubMed  CAS  Google Scholar 

  74. Gebauer, G., Fehm, T., Merkle, E., Beck, E. P., Lang, N., & Jager, W. (2001). Epithelial cells in bone marrow of breast cancer patients at time of primary surgery: Clinical outcome during long-term follow-up. Journal of Clinical Oncology, 19, 3669–3674.

    PubMed  CAS  Google Scholar 

  75. Wiedswang, G., Borgen, E., Karesen, R., Kvalheim, G., Nesland, J. M., Qvist, H., et al. (2003). Detection of isolated tumor cells in bone marrow is an independent prognostic factor in breast cancer. Journal of Clinical Oncology, 21, 3469–3478.

    PubMed  CAS  Google Scholar 

  76. Braun, S., Vogl, F. D., Naume, B., Janni, W., Osborne, M. P., Coombes, R. C., et al. (2005). A pooled analysis of bone marrow micrometastasis in breast cancer. New England Journal of Medicine, 353, 793–802.

    PubMed  CAS  Google Scholar 

  77. Lindemann, F., Schlimok, K., Dirschedl, P., Witte, J., & Riethmuller, G. (1992). Prognostic significance of micrometastatic cells in bone marrow of colorectal cancer patients. Lancet, 340, 685–689.

    PubMed  CAS  Google Scholar 

  78. Leinung, S., Wurl, P., Schonfelder, A., Weiss, C. L., Roder, I., & Schonfelder, M. (2000). Detection of cytokeratin-positive cells in bone marrow in breast cancer and colorectal carcinoma in comparison with other factors of prognosis. Journal of Hematotherapy & Stem Cell Research, 9, 905–911.

    CAS  Google Scholar 

  79. Werther, K., Normark, M., Brunner, N., & Nielsen, H. J. (2002). Cytokeratin-positive cells in preoperative blood and bone marrow aspirates of patients with colorectal cancer. Scandinavian Journal of Clinical & Laboratory Investigation, 62, 49–57.

    CAS  Google Scholar 

  80. Jauch, K. W., Heiss, M. M., Gruetzner, U., Funke, I., Pantel, K., Babic, R., et al. (1996). Prognostic significance of bone marrow micrometastases in patients with gastric cancer. Journal of Clinical Oncology, 14, 1810–1817.

    PubMed  CAS  Google Scholar 

  81. Heiss, M. M., Simon, E. H., Beyer, B. C., Gruetzner, K. U., Tarabichi, A., Babic, R., et al. (2002). Minimal residual disease in gastric cancer: Evidence of an independent prognostic relevance of urokinase receptor expression by disseminated tumor cells in the bone marrow. Journal of Clinical Oncology, 20, 2005–2016.

    PubMed  CAS  Google Scholar 

  82. de Manzoni, G., Pelosi, G., Pavanel, F., Di Leo, A., Pedrazzani, C., Durante, E., et al. (2002). The presence of bone marrow cytokeratin-immunoreactive cells does not predict outcome in gastric cancer patients. British Journal of Cancer, 86, 1047–1051.

    PubMed  Google Scholar 

  83. Inoue, H., Kajiyama, Y., & Tsurumaru, M. (2004). Clinical significance of bone marrow micrometastases in esophageal cancer. Diseases of the Esophagus, 17, 328–332.

    PubMed  CAS  Google Scholar 

  84. O’Sullivan, G. C., Sheehan, D., Clarke, A., Stuart, R., Kelly, J., Kiely, M. D., et al. (1999). Micrometastases in esophagogastric cancer: High detection rate in resected rib segments. Gastroenterologist, 116, 543–548.

    CAS  Google Scholar 

  85. Thorban, S., Rosenberg, R., Busch, R., & Roder, R. J. (2000). Epithelial cells in bone marrow of oesophageal cancer patients: A significant prognostic factor in multivariate analysis. British Journal of Cancer, 83, 35–39.

    PubMed  CAS  Google Scholar 

  86. Ryan, P., McCarthy, S., Kelly, J., Collins, J. K., Dunne, C., Grogan, L., et al. (2004). Prevalence of bone marrow micrometastases in esophagogastric cancer patients with and without neoadjuvant chemoradiotherapy. Journal of Surgical Research, 117, 121–126.

    PubMed  Google Scholar 

  87. Passlick, B. (2001). Micrometastases in non-small cell lung cancer (NSLC). Lung Cancer, 34(Suppl 3), S25–S29.

    PubMed  Google Scholar 

  88. Pantel, K., Izbicki, J., Passlick, B., Angstwurm, M., Haussinger, K., Thetter, O., et al. (1996). Frequency and prognostic significance of isolated tumor cells in bone marrow of patients with non-small-cell lung cancer without overt metastases. Lancet, 347, 649–653.

    PubMed  CAS  Google Scholar 

  89. Sugio, K., Kase, S., Sakada, T., Yamazaki, K., Yamaguchi, M., Ondo, K., et al. (2002). Micrometastasis in the bone marrow of patients with lung cancer associated with a reduced expression of E-cadherin and beta-catenin: Risk assessment by immunohistochemistry. Surgery, 131(Suppl), S226–S231.

    PubMed  Google Scholar 

  90. Braun, S., Schindlbeck, C., Hepp, F., Janni, W., Kentenich, C., Riethmuller, G., et al. (2001). Occult tumor cells in bone marrow of patients with locoregionally restricted ovarian cancer predicts early distant metastatic relapse. Journal of Clinical Oncology, 19, 368–375.

    PubMed  CAS  Google Scholar 

  91. Marth, C., Kisic, J., Kaern, J., Trope, C., & Fodstad, O. (2002). Circulating tumor cells in the peripheral blood and bone marrow of patients with ovarian carcinoma do not predict prognosis. Cancer, 94, 707–712.

    PubMed  Google Scholar 

  92. Janni, W., Hepp, F., Strobl, B., Rack, B., Rjosk, D., Kentenich, C., et al. (2003). Patterns of disease recurrence influenced by hematogenous tumor cell dissemination in patients with cervical carcinoma of the uterus. Cancer, 97, 405–411.

    PubMed  Google Scholar 

  93. Scheungraber, C., Muller, B., Kohler, C., Possover, M., Leistritz, S., Schneider, A., et al. (2002). Detection of disseminated tumor cells in patients with cervical cancer. Journal of Cancer Research and Clinical Oncology, 128, 329–335.

    PubMed  Google Scholar 

  94. Rack, B., Janni, W., Kentenich, C., Strobl, B., Klanner, E., Schindlbeck, C., et al. (2002). Incidence and prognostic significance of disseminated tumor cells in patients with cervical cancer. Acta Medica Austriaca. Supplement, 59, 36–41.

    PubMed  CAS  Google Scholar 

  95. Ellis, W. J., Pfitzenmaier, J., Colli, J., Arfman, E., Lange, P. H., & Vessella, R. L. (2003). Detection and isolation of prostate cancer cells from peripheral blood and bone marrow. Urology, 61, 277–281.

    PubMed  Google Scholar 

  96. van Heek, N. T., Tascilar, M., van Beekveld, J. L., Drillenburg, P., Offerhaus, G. J., & Gouma, D. J. (2001). Micrometastases in bone marrow of patients with suspected pancreatic and ampullary cancer. European Journal of Surgical Oncology, 27, 740–745.

    PubMed  Google Scholar 

  97. Z’graggen, K., Centeno, B. A., Fernandez-del Castillo, C., Jimenez, R. E., Werner, J., & Warshaw, A. L. (2001). Biological implications of tumor cells in blood and bone marrow of pancreatic cancer patients. Surgery, 129, 537–546.

    PubMed  CAS  Google Scholar 

  98. Trocciola, S. M., Hoda, S., Osborne, M. P., Christos, P. J., Levin, H., Martins, D., et al. (2005). Do bone marrow micrometastases correlate with sentinel lymph node metastases in breast cancer patients? Journal of the American College of Surgeons, 200, 720–725.

    PubMed  Google Scholar 

  99. Janni, W., Rack, B., Schindlbeck, C., Strobl, B., Rjosk, D., Braun, S., et al. (2005). The persistence of isolated tumor cells on bone marrow from patients with breast carcinoma predicts an increased risk for recurrence. Cancer, 103, 884–891.

    PubMed  Google Scholar 

  100. Naume, B., Wiedswang, G., Borgen, E., Kvalheim, G., Karesen, R., Qvist, H., et al. (2004). The prognostic value of isolated tumor cells in bone marrow in breast cancer patients: Evaluation of morphological categories and the number of clinically significant cells. Clinical Cancer Research, 10, 3091–3097.

    PubMed  Google Scholar 

  101. Janni, W., Rack, B., Lindemann, K., & Harbeck, N. (2005). Detection of micrometastatic disease in bone marrow. Is it ready for prime time? Oncologist, 10, 480–492.

    PubMed  Google Scholar 

  102. Borgen, E., Beiske, K., Trachsel, S., Nesland, J. M., Kvalheim, G., Herstad, T. K., et al. (1998). Immunocytochemical detection of isolated epithelial cells in bone marrow: Non-specific staining and contribution by cells directly reactive to alkaline phosphatase. Journal of Pathology, 185, 427–434.

    PubMed  CAS  Google Scholar 

  103. Braun, S., Muller, M., Hepp, F., Schlimok, G., Riethmuller, G., & Pantel, K. (1998). Re: Micrometastatic breast cancer cells in bone marrow at primary surgery: Prognostic value in comparison with nodal status. Journal of the National Cancer Institute, 90, 1099–1101.

    PubMed  CAS  Google Scholar 

  104. Pantel, K., Schlimok, G., Angstwurm, M., Wechermann, D., Schmaus, W., Gath, H., et al. (1994). Methodological analysis of immunocytochemical screening for disseminated epithelial tumor cells in bone marrow. Journal of Hematotherapy, 3, 165–173.

    PubMed  CAS  Google Scholar 

  105. Krag, D. N., Kusminsky, R., Manna, E., Ambaye, A., Weaver, D. L., Harlow, S. P., et al. (2005). The detection of isolated tumor cells in bone marrow comparing bright-field immunocytochemistry and multicolor immunofluorescence. Annals of Surgical Oncology, 12, 753–760.

    PubMed  Google Scholar 

  106. Skinner, L. J., Conlon, B. J., Russell, J. D., O’Sullivan, G. C., & O’Dwyer T. P. (2005). Detection of bone marrow micrometastases in the rib marrow of head and neck cancer patients: A prospective pilot study. European Archives of Oto-rhino-laryngology, 262, 103–106.

    PubMed  Google Scholar 

  107. Fetsch, P. A., Cowan, K. H., Weng, D. E., Freifield, A., Filie, A. C., & Abati, A. (2000). Detection of circulating tumor cells and micrometastases in stage II, III, and IV breast cancer patients utilizing cytology and immunocytochemistry. Diagnostic Cytopathology, 22, 323–328.

    PubMed  CAS  Google Scholar 

  108. Ooka, M., Tamaki, Y., Sakita, I., Fujiwara, Y., Yamamoto, H., Miyake, Y., et al. (2001). Bone marrow micrometastases detected by RT-PCR for mammaglobin can be an alternative prognostic factor of breast cancer. Breast Cancer Research and Treatment, 67, 169–175.

    PubMed  CAS  Google Scholar 

  109. Rouzier, R., Bourstyn, E., Grozier, F., Berger, A., Louvard, D., & Robins, S. (2001). Immunocytochemical detection of bone marrow micrometastases in colorectal carcinoma patients, using a monoclonal antibody to villin. Cytometry, 46, 281–289.

    PubMed  CAS  Google Scholar 

  110. Ciudad, J., San Miguel, J. F., Lopez-Berges, M. C., Vidriales, B., Valverde, B., Ocqueteau, M., et al. (1998). Prognostic value of immunophenotypic detection of minimal residual disease in acute lymphoblastic leukemia. Journal of Clinical Oncology, 16, 3774–3781.

    PubMed  CAS  Google Scholar 

  111. Jennings, C. D., & Foon, K. A. (1997). Recent advances in flow cytometry: Application to the diagnosis of hematologic malignancy. Blood, 90, 2863–2892.

    PubMed  CAS  Google Scholar 

  112. Wingren, S., Guerrieri, C., Franlund, B., & Stal, O. (1995). Loss of cytokeratins in breast cancer cells using multiparameter DNA flow cytometry is related to both cellular factors and preparation procedure. Analytical Cellular Pathology, 9, 229–233.

    PubMed  CAS  Google Scholar 

  113. Vredenburgh, J. J., Silva, O., Tyer, C., DeSombre, K., Abou-Ghalia, A., Cook, M., et al. (1996). A comparison of immunohistochemistry, two color immunofluorescence, and flow cytometry with cell sorting for the detection of micrometastatic breast cancer in the bone marrow. Journal of Hematotherapy, 5, 57–62.

    PubMed  CAS  Google Scholar 

  114. Sidransky, D. (1997). Nucleic acid-based methods for the detection of cancer. Science, 278, 1054–1059.

    PubMed  CAS  Google Scholar 

  115. Ghossein, R. A., Carusone, L., & Bhattacharya, S. (1999). Review: Polymerase chain reaction detection of micrometastases and circulating tumor cells: Application to melanoma, prostate and thyroid carcinomas. Diagnostic Molecular Pathology, 8, 165–175.

    PubMed  CAS  Google Scholar 

  116. Jung, R., Petersen, K., Kruger, W., Wolf, M., Wagener, C., Zander, A., et al. (1999). Detection of micrometastasis by cytokeratin 20 RT-PCR is limited due to stable background transcription in granulocytes. British Journal of Cancer, 81, 870–873.

    PubMed  CAS  Google Scholar 

  117. Bostick, P. J., Chatterjee, S., Chi, D. D., Huynh, K. T., Giuliano, A. E., Cote, R., et al. (1998). Limitations of specific reverse-transcriptase polymerase chain reaction markers in the detection of metastases in the lymph nodes and blood of breast cancer patients. Journal of Clinical Oncology, 2632–2640.

  118. Forus, A., Hoifodt, H. K., Overli, G. E., Myklebost, O., & Fodstad, O. (1999). Sensitive fluorescent in situ hybridization method for the characterisation of breast cancer cells in bone marrow aspirates. Molecular Pathology, 52, 68–74.

    Article  PubMed  CAS  Google Scholar 

  119. Mueller, P., Carroll, P., Bowers, E., Moore, D., 2nd, Cher, M., Presti, J., et al. (1998). Low frequency epithelial cells in bone marrow aspirates from prostate carcinoma are cytogenetically aberrant. Cancer, 83, 538–546.

    PubMed  CAS  Google Scholar 

  120. Debernardi, S., Lillington, D., & Young, B. D. (2004). Understanding cancer at the chromosome level: 40 years of progress. European Journal of Cancer, 40, 1960–1967.

    PubMed  CAS  Google Scholar 

  121. Grimwade, D., Walker, H., Oliver, F., Wheatley, K., Harrison, C., Harrison, G., et al. (1998). The importance of diagnostic cytogenetics on outcome in AML: Analysis of 1612 patients entered into the MRC AML 10 trial. The medical research council adult and children’s leukemia working parties. Blood, 92, 2322–2333.

    PubMed  CAS  Google Scholar 

  122. Polyak, K., & Riggins, G. J. (2001). Gene discovery using the serial analysis of gene expression technique: Implications for cancer research. Journal of Clinical Oncology, 19, 2948–2958.

    PubMed  CAS  Google Scholar 

  123. Velculescu, V. E., Zhang, L., Vogelstein, B., & Kinzler, K. W. (1995). Serial analysis of gene expression. Science, 270, 484–487.

    PubMed  CAS  Google Scholar 

  124. Chee, M., Yang, R., Hubbell, E., Berno, A., Huang, X. C., Stern, D., et al. (1996). Accessing genetic information with high-density DNA arrays. Science, 274, 610–614.

    PubMed  CAS  Google Scholar 

  125. Woelfle, U., Cloos, J., Sauter, G., Riethdorf, L., Janicke, F., van Diest, P., et al. (2003). Molecular signature associated with bone marrow micrometastasis in human breast cancer. Cancer Research, 63, 5679–5684.

    PubMed  CAS  Google Scholar 

  126. Kraus, J., Pantel, K., Pinkel, D., Albertson, D. G., & Speicher, M. R. (2003). High-resolution genomic profiling of occult micrometastatic tumor cells. Genes, Chromosomes & Cancer, 36, 159–166.

    CAS  Google Scholar 

  127. Weihrauch, M. R., Skibowski, E., Koslowsky, T. C., Voiss, W., Re, D., Kuhn-Regnier, F., et al. (2002). Immunomagnetic enrichment and detection of micrometastases in colorectal cancer: Correlation with established clinical parameters. Journal of Clinical Oncology, 20, 4338–4343.

    PubMed  CAS  Google Scholar 

  128. Faye, R. S., Aamdal, S., Hoifodt, H. K., Jacobsen, E., Holstad, L., Skovlund, E., et al. (2004). Immunomagnetic detection and clinical significance of micrometastatic tumor cells in malignant melanoma patients. Clinical Cancer Research, 10, 4134–4139.

    PubMed  CAS  Google Scholar 

  129. Naume, B., Borgen, E., Nesland, J. M., Beiske, K., Gilen, E., Renolen, A., et al. (1998). Increased sensitivity for detection of micrometastases in bone marrow/peripheral blood stem-cell products from breast-cancer patients by negative immunomagnetic separation. International Journal of Cancer, 78, 556–560.

    CAS  Google Scholar 

  130. Loo, W. T. Y., Fong, J. H. M., Zhui, L., Cheung, M. N. B., & Chow, L. W. C. (2005). The value of bone marrow aspirates culture for the detection of bone marrow micrometastases in breast cancer. Biomedicine & Pharmacotherapy, 59, S384–S386.

    Google Scholar 

  131. Braun, S., Kentenich, C., Janni, W., Hepp, F., de Waal, J., Willgeroth, F., et al. (2000). Lack of effect of adjuvant chemotherapy on the elimination of single dormant tumor cells in bone marrow of high-risk breast cancer patients. Journal of Clinical Oncology, 18, 80–86.

    PubMed  CAS  Google Scholar 

  132. Hohaus, S., Pforsich, M., Murea, S., Abdallah, A., Lin, Y. S., Funk, L., et al. (1997). Immunomagnetic selection of CD34+ peripheral blood stem cells for autografting in patients with breast cancer. British Journal of Haematology, 97, 881–888.

    PubMed  CAS  Google Scholar 

  133. Riethmuller, G., Holz, E., Schlimok, G., Schmiegel, W., Raab, R., Hoffken, K., et al. (1998). Monoclonal antibody therapy for resected Dukes’ C colorectal cancer: Seven-year outcome of a multicenter randomized trial. Journal of Clinical Oncology, 16, 1788–1794.

    PubMed  CAS  Google Scholar 

  134. Braun, S., Hepp, F., Kentenich, C. R., Janni, W., Pantel, K., Riethmuller, G., et al. (1999). Monoclonal antibody therapy with edrecolomab in breast cancer patients: Monitoring of elimination of disseminated cytokeratin-positive tumor cells in bone marrow. Clinical Cancer Research, 5, 3999–4004.

    PubMed  CAS  Google Scholar 

  135. Kirchner, E. M., Gerhards, R., & Voigtmann, R. (2002). Sequential immunochemotherapy and edrecolomab in the adjuvant therapy of breast cancer: Reduction of 17-1A-positive disseminated tumor cells. Annals of Oncology, 13, 1044–1048.

    PubMed  CAS  Google Scholar 

  136. Punt, C. J., Nagy, A., Douillard, J. Y., Figer, A., Skovsgaard, T., Monson, J., et al. (2002). Edrecolomab alone or in combination with fluorouracil and folinic acid in the adjuvant treatment of stage III colon cancer: A randomized study. Lancet, 360, 671–677.

    PubMed  CAS  Google Scholar 

  137. Najmi, S., Korah, R., Chandra, R., Abdellatif, M., & Wieder, R. (2005). Flavopiridol blocks integrin-mediated survival in dormant breast cancer cells. Clinical Cancer Research, 11, 2038–2046.

    PubMed  CAS  Google Scholar 

  138. Ross, J. S., Fletcher, J. A., Bloom, K. J., Linette, G. P., Stec, J., Symmans, W. F., et al. (2004). Targeted therapy in breast cancer: The HER-2/neu gene and protein. Molecular & Cellular Proteomics, 3, 379–398.

    CAS  Google Scholar 

  139. Bloom, K. J., Govil, H., Gattuso, P., Reddy, V., & Francescatti, D. (2001). Status of HER-2 in male and female breast carcinoma. American Journal of Surgery, 182, 389–392.

    PubMed  CAS  Google Scholar 

  140. Stark, A., Hulka, B. S., Joens, S., Novotny, D., Thor, A. D., Wold, L. E., et al. (2000). HER-2/neu amplification in benign breast disease and the risk of subsequent breast cancer. Journal of Clinical Oncology, 18, 267–274.

    PubMed  CAS  Google Scholar 

  141. Huston, J. S., & George, A. J. (2001). Engineered antibodies take center stage. Human Antibodies, 10, 127–142.

    PubMed  CAS  Google Scholar 

  142. Slamon, D. J., Leyland-Jones, B., Shak, S., Fuchs, H., Paton, V., Bajamonde, A., et al. (2001). Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. New England Journal of Medicine, 344, 783–792.

    PubMed  CAS  Google Scholar 

  143. Hortobagyi, G. N. (2001). Overview of treatment results with trastuzumab (Herceptin) in metastatic breast cancer. Seminars in Oncology, 28, 43–47.

    PubMed  CAS  Google Scholar 

  144. McKeage, K., & Perry, C. M. (2002). Trastuzumab: A review of its use in the treatment of metastatic breast cancer overexpressing HER2. Drugs, 62, 209–243.

    PubMed  CAS  Google Scholar 

  145. Goss, P. E., Ingle, J. N., Martino, S., Robert, N. J., Muss, H. B., Piccart, M. J., et al. (2003). A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. New England Journal of Medicine, 349, 1793–1802.

    PubMed  CAS  Google Scholar 

  146. Sachelarie, I., Grossbard, M. L., Chadha, M., Feldman, S., Ghesani, M., & Blum, R. H. (2006). Primary systemic therapy of breast cancer. Oncologist, 11, 574–589.

    PubMed  CAS  Google Scholar 

  147. Diel, I. J., Solomayer, E. F., Costa, S. D., Gollan, C., Goerner, R., Wallwiener, D., et al. (1998). Reduction in new metastases in breast cancer with adjuvant clodronate treatment. New England Journal of Medicine, 339, 357–363.

    PubMed  CAS  Google Scholar 

  148. Demicheli, R., Retsky, M. W., Swartzendruber, D. E., & Bonadonna, G. (1997). Proposal for a new model of breast cancer metastatic development. Annals of Oncology, 8, 1075–1080.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Pauline Athanassiadou.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Athanassiadou, P., Grapsa, D. Recent advances in the detection of bone marrow micrometastases: A promising area for research or just another false hope? A review of the literature. Cancer Metastasis Rev 25, 507–519 (2006). https://doi.org/10.1007/s10555-006-9030-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-006-9030-2

Keywords

Navigation