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Bone Marrow and Not Bone Is the Primary Site for Skeletal Metastasis: Critical Role of [¹⁸F]Fluorodeoxyglucose Positron Emission Tomography in This Setting

Division of Nuclear Medicine, Hospital of University of Pennsylvania, Philadelphia, PA

To the Editor:

We read with great interest the article by Liu et al¹ in which the authors compared the efficacy of [¹⁸F]fluorodeoxyglucose positron emission tomography (FDG-PET) and skeletal scintigraphy in evaluating skeletal metastasis from nasopharyngeal carcinoma at initial diagnosis. We congratulate the authors for a well-designed and timely study in the context of modern practice of oncology. We concur with their findings and wish to share our views on this very important subject. With widespread application of FDG-PET imaging in the day to day practice of medicine, it is now clear that FDG-PET detects metastasis very early on during the course of disease when it is confined to the bone marrow. In contrast, skeletal scintigraphy reflects indirect evidence for disease as a result of reactive bone formation after long standing red marrow involvement. Cancer cells are lodged in the red marrow as the initial site for skeletal metastasis. This accounts for the usual pattern of distribution of metastatic lesions where regions with high concentration of red marrow are the most common locations for the spread of cancer cells. Therefore, most commonly, the axial skeleton is the most common structure for early metastatic disease. In contrast, the extremities, which mainly contain the yellow or fatty marrow, are spared. Interestingly, in children, skeletal involvement does not infrequently include both appendicular and axial bones. The conclusion reached by these authors that FDG-PET imaging is significantly more sensitive and accurate than bone scan further corroborates the findings with similar approach in several other malignancies like lung or breast carcinomas.^2-4 These results emphasize that bone marrow is the primary site for the initial metastasis and should be the main focus for assessing skeletal disease. Hence, we believe, it is imperative that in the twenty-first century we should start emphasizing the concept of bone marrow and not the bone as the primary location for cancer spread. Although there was one rib lesion that was proven to be metastatic and detected by bone scan and missed by FDG-PET, most (more than 95%) solitary lesions in the rib are benign. We must point out that fractures that are more than 2 to 3 months old will be negative on PET and positive on bone scintigraphy⁵ which complicates treatment for most patients with cancer. Also tomographic images provided by PET allow detailed delineation of the abnormal areas while planar images with scintigraphy have very poor spatial resolution, and therefore, are insensitive for detecting early disease. In addition, response to therapy can be best assessed by disease activity in the marrow space which is the primary location for metastatic lesions. Evidence for response based on bone scintigraphy is slow because reactive new bone formation secondary to the bone marrow lesion lasts for an extended period of time after successful treatment. The description in this letter and related literature which emphasizes the superiority of FDG-PET over bone scintigraphy is primarily applicable to malignant disorders that are aggressive in nature, such as lung cancer, melanoma, and breast cancer. The osteolytic lesions (including multiple myeloma) which are commonly missed by bone scintigraphy because of the lack of osteoblastic reaction will be readily detected by FDG-PET.⁶ In contrast, osteoblastic metastasis from slow growing tumors, such as prostate⁷ and thyroid cancer, should be assessed with agents such as radiolabeled amino acids and other novel tracers⁸ for accurate assessment of the extent of the disease. Also, the role of bone scintigraphy with [¹⁸F]fluoride and PET needs to be further assessed and compared with that of FDG-PET with further well-designed studies.⁹

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The authors indicated no potential conflicts of interest.

ACKNOWLEDGMENTS

This work was supported in part by the International Union Against Cancer, Geneva, Switzerland, under the American Cancer Society International Fellowship for Beginning Investigators.

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[Abstract/Free Full Text]

2. Cheran SK, Herndon JE II, Patz EF Jr: Comparison of whole-body FDG-PET to bone scan for detection of bone metastases in patients with a new diagnosis of lung cancer. Lung Cancer 44:317-325, 2004[CrossRef][Medline]

3. Fogelman I, Cook G, Israel O, et al: Positron emission tomography and bone metastases. Semin Nucl Med 35:135-142, 2005[CrossRef][Medline]

4. Peterson JJ, Kransdorf MJ, O'Connor MI: Diagnosis of occult bone metastases: Positron emission tomography. Clin Orthop 415S:S120–S128, 2003[Medline]

5. Zhuang H, Sam JW, Chacko TK, et al: Rapid normalization of osseous FDG uptake following traumatic or surgical fractures. Eur J Nucl Med Mol Imaging 30:1096-1103, 2003[CrossRef][Medline]

6. Schirrmeister H, Bommer M, Buck AK, et al: Initial results in the assessment of multiple myeloma using 18F-FDG PET. Eur J Nucl Med Mol Imaging 29:361-366, 2002[CrossRef][Medline]

7. Shreve D, Grossman HB, Gross, et al: Metastatic prostate cancer: Initial findings of PET with 2-deoxy-2-(F-18) fluoro-d-glucose. Radiology 199:751-756, 1996[Abstract/Free Full Text]

8. Kumar R, Zhuang H, Alavi A: PET in the management of urologic malignancies. Radiol Clin North Am 42:1141-1153, 2004[CrossRef][Medline]

9. Langsteger W, Heinisch M, Fogelman I: The role of fluorodeoxyglucose, 18F-dihydroxyphenylalanine, 18F-choline, and 18F-fluoride in bone imaging with emphasis on prostate and breast. Semin Nucl Med 36:73-92, 2006[CrossRef][Medline]

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  Feng-Yuan Liu and Tzu-Chen Yen
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