Scot.moo. J., 1975, 20: 149
BONE SCANNING: THE CURRENT POSITION Bone scanning (skeletal scintigraphy) has advanced considerably in the last 2 years for 2 main reasons. Firstly, the availability of total body imaging devices, both scanners and cameras, allow the whole skeleton to be studied in a relatively short time (20-60 minutes depending on the type of imaging equipment used). Of more importance, however, has been the introduction of 99mTc labelled phosphate compounds (Subramanian et al., 1971), of which at the time of writing, diphosphonate (ethylidene I-hydroxy 1, 1 diphosphonate) is the most valuable. Diphosphonate gives the best tumour to bone and bone to background ratios (Citrin et al., I974a). 99 mTc labelled diphosphonate fixes to apatite crystals by a process of chemisorption and it is extremely stable since there is no enzyme in man capable of degrading it. Approximately 50 per cent of an intravenously administered dose of diphosphonate becomes fixed to the skeleton, and the remainder is almost totally excreted by the kidneys. The proportion of the agent deposited throughout the skeleton is dictated primarily by the relative amount of blood flow to an area. The distribution pattern of diphosphonate and the proportion of the dose deposited in the skeleton is not greatly superior to 85Sr or 87mSr which were until recently the most commonly used bone seeking radio-nuclides. Strontium is, however, not cleared as rapidly from the blood and the bone to background ratio of radioactivity at the time of scanning is inferior to 99mTc labelled diphosphonate. In addition, Strontium is partially excreted through the gastrointestinal tract where accumulation often causes difficulty in the interpretation of scintigrams of the lumbar spine and pelvis. Although the biological properties of 18F are even more desirable than those of diphosphonate, they are more than counterbalanced by disadvantages in its physical properties. 18F is cyclotron produced and has a short half life (1.8 hours) making it expensive and available only to hospitals located near a cyclotron. Also, the energy of its emissions make it unsuitable for standard detecting devices.
The simplicity of compounding diphosphonate (and other phosphates) with 99mTc provides a radiopharmaceutical with great advantages over each of the alternative agents. 99ffiTc has a 140 Kev mono-energetic emission which is ideally suited to all of the imaging devices available, it is cheap, and in most nuclear medicine departments in constant, ready supply. The total body radiation dose from a 10 mCi. dose is approximately 0.1 rad., and the skeletal dose 0.5 rads., both of which compare favourably with the dose from a radiological skeletal survey. The low radiation dose, coupled with the non toxicity of the dose of diphosphonate (1 mg.) make this radiopharmaceutical very safe and in our combined experience of more than 1,000 studies we have not encountered any adverse reactions to it. Figure 1 (a & b) shows a normal scan, in a teenager with Hodgkin's disease, anterior and posterior projections were obtained simultaneously in 40 minutes. The main clinical value of skeletal scintgraphy is in the detection of bone metastases. For metastases to be visualised radiologically the lesion has to be 1 ctl. or greater in diameter and up to 50 per cent of the bone mineral must be lost (Edeiken, 1972). In contrast, diphosphonate (and all bone seeking radiopharmaceuticals) show greater accumulation in the metastatic region than in normal bone and for this reason the abnormal area stands out from the normal, rather than appearing as a slightly reduced area in a sea of activity, as is the case with X-rays. Figure 2 (a & b) shows grossly abnormal accumulation of 99ffiTc labelled E.H.D.P. in bone metastases in a female with breast carcinoma. It must be understood that none of the bone imaging radiopharmaceuticals are specifically taken up by tumour cells, their distribution in metastases being dictated by increased local blood flow and osteoblastic activity in bone invaded by tumour. Because of this major difference in detecting bone metastases the bone scan is more sensitive than X-ray, lesions being visualised earlier and more frequently on the scan. In a recent comparison of scans using 99ffiTc labelled diphosphonate and X-rays in 200 patients with biopsy proven evidence of primary cancer both investigations gave similar results (either both
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a b Fig. 1. (a) Normal anterior bone scan showing symmetrical distribution of radio-pharmaceutical. (b) Normal posterior scan in the same patient. 6
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Leading Articles
investigations positive or both negative) in 128 patients (64%) but whereas the X-ray showed a lesion not seen on scan in 3 patients (1.5%) the scan was abnormal in 57 patients (28.5%) where there was no radiological abnormality (Pistenma et al, 1974). The authors of that report recommend that a bone scan should be ordered in preference to radiologic metastatic survey in the work up of patients with primary malignancy. The increased sensitivity of the scan will pick up lesions not detectable by other techniques and in many patients might alter the management of the primary tumour, especially if radical surgical therapy is planned. Total skeletal scanning is also valuable in defining the extent of metastases and in planning the site for biopsy or of radiotherapy portals. The greater localisation of 99mTc labelled diphosphonate in tumour-involved bone compared with adjacent normal bone can be easily quantitated and expressed as a ratio of tumour to surrounding bone. This allows for the first time, an objective, reproducible and numerical value, which might be valuable as an index of the response of tumour to treatment (Citrin et al., 1974b). The exquisite sensitivity of diphosphonate as a bone scanning agent is unfortunately disadvantageous since the scan appears abnormal in many non malignant conditions such as trauma, with or without fracture, osteomyelitis, sickle cell crisis, adjacent infection such as sinusitis and severe arthritis. It is, therefore, important that clinical and radiological factors are carefully considered before an abnormal area in the scan is positively identified as being due to tumour. Because approximately 50 per cent of the administered dose of diphosphonate is excreted by the kidneys, these organs are usually visualised on the scan, and unsuspected lesions such as nonfunctioning kidney, hydronephrosis, horseshoe kidney or even kidney
tumour may be diagnosed. Abnormal accumulation of diphosphonate has been described in primary breast cancer (Berg et al., 1973), however further analysis indicates that this agent is not specific for this diagnosis (McDougall & Pistenma, 1974). 99mTc labelled diphosphonate is a safe, easily prepared, extremely sensitive, bone seeking radiopharmaceutical. At the current time, it provides the most accurate method of diagnosing skeletal metastases and if detecting devices become more widely available it should become a basic investigation in the evaluation of a patient with primary cancer, especially a cancer with a predilection to metastasize to bone. I. R. McDOUGALL D. L. CITRIN REFERENCES
Berg, G. R., Kalisher, L., Osmond, J. D., Pendergrass, H. P., Potsaid, M.S. (1973). 99mTc-Diphosphonate concentration in primary breast carcinoma. Radiology, 109, 393 Citrin, D. L., Bessent, R. G., Greig, W. R., Lindsay, M.K., Rogers, J. (l974a). Pharmacological studies with 99mTc labelled polyphosphate, pyrophosphate and E.H.D.P. in patients and normal subjects. British Nuclear Medicine Society, March, London Citrin, D. L., Bessent, R. G., Tuohy, J. B., Greig, W. R., Blumgart, L. H. (1974b). Quantitative bone scanning: a method for assessing response of bone metases to treatment. Lancet, 1, 1132 Edeiken, J. (1972). Radiologic approach to diagnosis of bone disease, clinical uses of radionuclides: critical comparison with other techniques. Editors: Goswitz, F. A., Andres, G. A. and Viamont, M. K. U.S.A.E.C. 27, pp 90-100. McDougall, Y. R., Pistenma, D.A. (1974). Concentration of 99mTc-diphosphonate in breast tissue. Radiology, 112, 655 Pistenma, D. A., McDougall, Y. R., Kriss, J. P. (1974). Screening for bone metastases, are only scans necessary? Journal of the American Medical Association, in press Subramanian, G., McAfee, J. G. (1971). A new complex of 99mTc for skeletal imaging. Radiology, 99, 192
151
BONE SCANNING: THE CURRENT POSITION Bone scanning (skeletal scintigraphy) has advanced considerably in the last 2 years for 2 main reasons. Firstly, the availability of total body imaging devices, both scanners and cameras, allow the whole skeleton to be studied in a relatively short time (20-60 minutes depending on the type of imaging equipment used). Of more importance, however, has been the introduction of 99mTc labelled phosphate compounds (Subramanian et al., 1971), of which at the time of writing, diphosphonate (ethylidene I-hydroxy 1, 1 diphosphonate) is the most valuable. Diphosphonate gives the best tumour to bone and bone to background ratios (Citrin et al., I974a). 99 mTc labelled diphosphonate fixes to apatite crystals by a process of chemisorption and it is extremely stable since there is no enzyme in man capable of degrading it. Approximately 50 per cent of an intravenously administered dose of diphosphonate becomes fixed to the skeleton, and the remainder is almost totally excreted by the kidneys. The proportion of the agent deposited throughout the skeleton is dictated primarily by the relative amount of blood flow to an area. The distribution pattern of diphosphonate and the proportion of the dose deposited in the skeleton is not greatly superior to 85Sr or 87mSr which were until recently the most commonly used bone seeking radio-nuclides. Strontium is, however, not cleared as rapidly from the blood and the bone to background ratio of radioactivity at the time of scanning is inferior to 99mTc labelled diphosphonate. In addition, Strontium is partially excreted through the gastrointestinal tract where accumulation often causes difficulty in the interpretation of scintigrams of the lumbar spine and pelvis. Although the biological properties of 18F are even more desirable than those of diphosphonate, they are more than counterbalanced by disadvantages in its physical properties. 18F is cyclotron produced and has a short half life (1.8 hours) making it expensive and available only to hospitals located near a cyclotron. Also, the energy of its emissions make it unsuitable for standard detecting devices.
The simplicity of compounding diphosphonate (and other phosphates) with 99mTc provides a radiopharmaceutical with great advantages over each of the alternative agents. 99ffiTc has a 140 Kev mono-energetic emission which is ideally suited to all of the imaging devices available, it is cheap, and in most nuclear medicine departments in constant, ready supply. The total body radiation dose from a 10 mCi. dose is approximately 0.1 rad., and the skeletal dose 0.5 rads., both of which compare favourably with the dose from a radiological skeletal survey. The low radiation dose, coupled with the non toxicity of the dose of diphosphonate (1 mg.) make this radiopharmaceutical very safe and in our combined experience of more than 1,000 studies we have not encountered any adverse reactions to it. Figure 1 (a & b) shows a normal scan, in a teenager with Hodgkin's disease, anterior and posterior projections were obtained simultaneously in 40 minutes. The main clinical value of skeletal scintgraphy is in the detection of bone metastases. For metastases to be visualised radiologically the lesion has to be 1 ctl. or greater in diameter and up to 50 per cent of the bone mineral must be lost (Edeiken, 1972). In contrast, diphosphonate (and all bone seeking radiopharmaceuticals) show greater accumulation in the metastatic region than in normal bone and for this reason the abnormal area stands out from the normal, rather than appearing as a slightly reduced area in a sea of activity, as is the case with X-rays. Figure 2 (a & b) shows grossly abnormal accumulation of 99ffiTc labelled E.H.D.P. in bone metastases in a female with breast carcinoma. It must be understood that none of the bone imaging radiopharmaceuticals are specifically taken up by tumour cells, their distribution in metastases being dictated by increased local blood flow and osteoblastic activity in bone invaded by tumour. Because of this major difference in detecting bone metastases the bone scan is more sensitive than X-ray, lesions being visualised earlier and more frequently on the scan. In a recent comparison of scans using 99ffiTc labelled diphosphonate and X-rays in 200 patients with biopsy proven evidence of primary cancer both investigations gave similar results (either both
..
,
•
•
•
.1
•
•
II'
.'
•
a b Fig. 1. (a) Normal anterior bone scan showing symmetrical distribution of radio-pharmaceutical. (b) Normal posterior scan in the same patient. 6
..
~"{
\
•
a Fig.
ISO
I, b
z. (a, b) Abnormal bone scan showing widespread metastases (black areas) in patient with breast cancer.
Leading Articles
investigations positive or both negative) in 128 patients (64%) but whereas the X-ray showed a lesion not seen on scan in 3 patients (1.5%) the scan was abnormal in 57 patients (28.5%) where there was no radiological abnormality (Pistenma et al, 1974). The authors of that report recommend that a bone scan should be ordered in preference to radiologic metastatic survey in the work up of patients with primary malignancy. The increased sensitivity of the scan will pick up lesions not detectable by other techniques and in many patients might alter the management of the primary tumour, especially if radical surgical therapy is planned. Total skeletal scanning is also valuable in defining the extent of metastases and in planning the site for biopsy or of radiotherapy portals. The greater localisation of 99mTc labelled diphosphonate in tumour-involved bone compared with adjacent normal bone can be easily quantitated and expressed as a ratio of tumour to surrounding bone. This allows for the first time, an objective, reproducible and numerical value, which might be valuable as an index of the response of tumour to treatment (Citrin et al., 1974b). The exquisite sensitivity of diphosphonate as a bone scanning agent is unfortunately disadvantageous since the scan appears abnormal in many non malignant conditions such as trauma, with or without fracture, osteomyelitis, sickle cell crisis, adjacent infection such as sinusitis and severe arthritis. It is, therefore, important that clinical and radiological factors are carefully considered before an abnormal area in the scan is positively identified as being due to tumour. Because approximately 50 per cent of the administered dose of diphosphonate is excreted by the kidneys, these organs are usually visualised on the scan, and unsuspected lesions such as nonfunctioning kidney, hydronephrosis, horseshoe kidney or even kidney
tumour may be diagnosed. Abnormal accumulation of diphosphonate has been described in primary breast cancer (Berg et al., 1973), however further analysis indicates that this agent is not specific for this diagnosis (McDougall & Pistenma, 1974). 99mTc labelled diphosphonate is a safe, easily prepared, extremely sensitive, bone seeking radiopharmaceutical. At the current time, it provides the most accurate method of diagnosing skeletal metastases and if detecting devices become more widely available it should become a basic investigation in the evaluation of a patient with primary cancer, especially a cancer with a predilection to metastasize to bone. I. R. McDOUGALL D. L. CITRIN REFERENCES
Berg, G. R., Kalisher, L., Osmond, J. D., Pendergrass, H. P., Potsaid, M.S. (1973). 99mTc-Diphosphonate concentration in primary breast carcinoma. Radiology, 109, 393 Citrin, D. L., Bessent, R. G., Greig, W. R., Lindsay, M.K., Rogers, J. (l974a). Pharmacological studies with 99mTc labelled polyphosphate, pyrophosphate and E.H.D.P. in patients and normal subjects. British Nuclear Medicine Society, March, London Citrin, D. L., Bessent, R. G., Tuohy, J. B., Greig, W. R., Blumgart, L. H. (1974b). Quantitative bone scanning: a method for assessing response of bone metases to treatment. Lancet, 1, 1132 Edeiken, J. (1972). Radiologic approach to diagnosis of bone disease, clinical uses of radionuclides: critical comparison with other techniques. Editors: Goswitz, F. A., Andres, G. A. and Viamont, M. K. U.S.A.E.C. 27, pp 90-100. McDougall, Y. R., Pistenma, D.A. (1974). Concentration of 99mTc-diphosphonate in breast tissue. Radiology, 112, 655 Pistenma, D. A., McDougall, Y. R., Kriss, J. P. (1974). Screening for bone metastases, are only scans necessary? Journal of the American Medical Association, in press Subramanian, G., McAfee, J. G. (1971). A new complex of 99mTc for skeletal imaging. Radiology, 99, 192
151
