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Journal of Clinical Oncology, Vol 25, No 10 (April 1), 2007: pp. 1297-1299 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.4877
In ReplyDepartment of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan We appreciate the interest of Dr Basu and Professor Alavi in our research which demonstrated [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) to be more sensitive than skeletal scintigraphy for detecting bone metastasis in endemic nasopharyngeal carcinoma at initial staging.1 They have shared interesting views on the important subject of bone metastasis and stressed the central role of bone marrow rather than bone. We agree with some of their points but want to elaborate related concepts with more details. Bone consists of cortical, trabecular, and marrow components, and different imaging modalities have different strength and weakness in evaluating bone metastasis.2 We concur on the viewpoint that distant bone metastasis starts in the bone marrow. This has been corroborated by the research of disseminated tumor cells (DTCs), in addition to clinical and imaging observations. DTCs in the marrow have been shown to be present in a significant proportion of patients with early-stage malignancies.3 A pooled analysis of more than 4,700 patients with stage I, II, or III breast cancer confirmed the presence of DTCs in the bone marrow at the time of primary diagnosis to be an independent predictor of a poor outcome.4 Recent studies suggested that DTCs in bone marrow originate from circulating tumor stem cells, which may adhere onto the endothelial cells that line the blood vessels within the bone marrow and then extravasate into the bone marrow space. The expression of CD44, a cell surface receptor for hyaluronic acid (HA), and the retention of HA coating on the cancer cell surface are well-implicated in this process.5 An animal study showed virtually aborted formation of osteosarcoma metastasis in mice with disruption of the CD44 gene.6 Interestingly, the breast cancer stem cells have been identified with a CD44+/CD24–/low phenotype and the large portion of early DTCs in the bone marrow are also of this phenotype.7,8 Cancer stem cells have the strong ability to self-renew and proliferate at distant sites, potentially initiating and forming metastasis. Before tumor invasion into the bone matrix becomes obvious, there probably have been plenty of metabolically active tumor cells occupying in the bone marrow. This accounts for the superior sensitivities of FDG-PET and magnetic resonance imaging in detecting early bone metastasis as compared with skeletal scintigraphy and computed tomography in aggressive malignancies. However, further questions arise. First, how do we define bone metastasis? According to the sixth edition of the TNM classification, 9 a tumor deposit is defined as being between 0.2 cm and 0.2 mm in its greatest dimension. Thus, tumor deposits in either bone marrow or bone matrix with the greatest dimension larger than 0.2 mm will be classified as M1 and may be designated as M1(mi) if there is no micrometastasis larger than 0.2 cm.9 For patients without overt evidence of bone metastasis on imaging studies, bone marrow aspiration will be required to aid in such a differentiation. This is still not justified as a clinical routine because of its more invasive nature, significant possibility of sampling errors, and uncertain impact on treatment selection. With rapid technical advances and growing availability, noninvasive PET and magnetic resonance imaging may assume important roles in the detection of early bone metastasis. Second, is there differential response to systemic therapy between metastases mainly confined in the bone marrow and those with significant bone matrix involvement? Becker et al10 analyzed the bone marrow status in 112 breast cancer patients with nodal stage of N0 or N1 who had received two times of bone marrow aspiration. The positivity rates of DTCs were 83% at the time of primary surgery and 24% at a mean interval of 12 months after the initiation of adjuvant systemic treatment. This implies that systemic treatment is effective in reducing tumor cells in the bone marrow. It has also been proven in large-scaled studies that systemic treatment can translate into survival benefit by eradicating occult metastases. In contrast, overt bone metastasis is typically considered as incurable, although a minority of patients may achieve long-term remission and survival. When cancer cells secret proteolytic emzymes at the endostial surface or within the bone matrix, the degradation of bone matrix can be initiated. Hill et al11 have suggested that HA-induced CD44 signaling in breast cancer cells may activate the transcription of proteolytic emzymes, including MMP-9 and cathepsin K. The release of tumor growth factor-beta and other growth factors from the bone matrix in turn can stimulate the growth and colonization of breast cancer cells. Tumor growth factor-beta can also increase the production and release of growth factors such as parathyroid hormone-related protein from breast cancer cells. Parathyroid hormone-related protein plays a critical role in stimulating the increase and activation of osteoclasts, which in turn degrade more bone matrix. A viscious cycle of osteolysis-predominant metastasis is thus formed. Do tumor cells in this setting have the same response to systemic treatment as those confined in the bone marrow? Further studies are needed to answer this question. Nevertheless, metabolic imaging by PET has the potential to become a clinically useful modality in monitoring response of bone metastases to treatment, irrespective of the extent to which the bone matrix has been involved. Cook et al12 have demonstrated that osteoblastic lesions in breast cancer patients have lower metabolic activity than osteolytic lesions. It is possible that osteoblastic lesions in breast cancer are in a more stable or regressive state. Stafford et al13 showed the changes in standardized uptake value of the index bone lesion on serial FDG-PET have strong correlation with clinical response and tumor marker level in breast cancer patients during therapy. Morris et al14 performed an analysis of 157 osseous lesions in 17 patients with progressive metastatic prostate cancer. Thirty of 31 osseous lesions evident on bone scan only were stable, while eight osseous lesions evident on FDG-PET only proved to be progressing. It was suggested that FDG-PET can discriminate active from quiescent osseous lesions. Further research is well warranted. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. ACKNOWLEDGMENTS Supported by grants (CMRPG32042) from the Chang Gung Memorial Hospital and Chang Gung University. REFERENCES
1. Liu FY, Chang JT, Wang HM, et al: [18F]fluorodeoxyglucose positron emission tomography is more sensitive than skeletal scintigraphy for detecting bone metastasis in endemic nasopharyngeal carcinoma at initial staging. J Clin Oncol 24:599-604, 2006 2. Hamaoka T, Madewell JE, Podoloff DA, et al: Bone imaging in metastatic breast cancer. J Clin Oncol 22:2942-2953, 2004 3. Braun S, Naume B: Circulating and disseminated tumor cells. J Clin Oncol 23:1623-1626, 2005 4. Braun S, Vogl FD, Naume B, et al: A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353:793-802, 2005 5. Draffin JE, McFarlane S, Hill A, et al: CD44 potentiates the adherence of metastatic prostate and breast cancer cells to bone marrow endothelial cells. Cancer Res 64:5702-5711, 2004 6. Weber GF, Bronson RT, Ilagan J, et al: Absence of the CD44 gene prevents sarcoma metastasis. Cancer Res 62:2281-2286, 2002 7. Al-Hajj M, Wicha MS, Benito-Hernandez A, et al: Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100:3983-3988, 2003 8. Balic M, Lin H, Young L, et al: Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res 12:5615-5621, 2006 9. Hermanek P, Hutter RV, Sobin LH, et al: International Union Against Cancer: Classification of isolated tumor cells and micrometastasis. Cancer 86:2668-2673, 1999[CrossRef][Medline] 10. Becker S, Becker-Pergola G, Wallwiener D, et al: Detection of cytokeratin-positive cells in the bone marrow of breast cancer patients undergoing adjuvant therapy. Breast Cancer Res Treat 97:91-96, 2006[CrossRef][Medline] 11. Hill A, McFarlane S, Johnston PG, et al: The emerging role of CD44 in regulating skeletal micrometastasis. Cancer Lett 237:1-9, 2006[CrossRef][Medline] 12. Cook GJ, Houston S, Rubens R, et al: Detection of bone metastases in breast cancer by 18FDG PET: Differing metabolic activity in osteoblastic and osteolytic lesions. J Clin Oncol 16:3375-3379, 1998[Abstract] 13. Stafford SE, Gralow JR, Schubert EK, et al: Use of serial FDG PET to measure the response of bone-dominant breast cancer to therapy. Acad Radiol 9:913-921, 2002[CrossRef][Medline] 14. Morris MJ, Akhurst T, Osman I, et al: Fluorinated deoxyglucose positron emission tomography imaging in progressive metastatic prostate cancer. Urology 59:913-918, 2002[CrossRef][Medline]
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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