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Bone scintigraphy — an update
Clinical Radiology (1989), 40, 231-232
Bone Scintigraphy- an Update M. V. M E R R I C K
Medical Radioisotopes Department, Western General Hospital, Edinburgh Bone scintigraphy is widely, although not universally, regraded as one of the routine procedures for staging new patients with any tumour having a high prevalence of metastases to the skeleton, especially carcinoma of the breast, prostate and lung. The lack of concensus is, however, proof that not all clinicians are convinced by the arguments which have been put forward. Additional data has partially clarified this issue and shed new light on the place of skeletal imaging. Occult skeletal metastases are revealed by scintigraphy at presentation in less than 1% of women with Stage I carcinoma of breast, 5% to 10% of those with Stage II or III and between 25% and 50% with Stage IV disease (Coleman et al., 1988). At all stages the survival of patients with bone involvement is significantly shorter than of those without. No matter how strict the criteria of interpretation, there is a residual false positive rate for scintigraphy of 1.5%, whilst less than half of those who ultimately develop overt skeletal metastases are detected by the initial staging examination (Kunkler et al., 1985). Radiography alone, without scintigraphy, has a false negative rate at least double that of scintigraphy much higher under most clinical cirumstances. In contrast, marrow aspiration at multiple sites (during the same anaesthetic as the mastectomy) identified micrometasrases in 20% of patients with To to Ta tumours (Mansi et al., 1987; Porro et al., 1988). On follow-up, one in six patients with Stage I disease eventually develops a recurrence, not necessarily in the skeleton. This increases to one in three patients with Stage II, two in three of those with Stage III, and virtually all with Stage IV. The first recurrence is in bone in approximately half of all patients who relapse. Tumour size and lymph node status are more important prognostically than the presence ofmicrometastases, only 20% of which become overt, whilst half of the patients with skeletal recurrence did not have detectable micrometastases initially. Because of the low prevalence, the number of false positives in Stage I disease equals or exceeds that of true positives. The first relapse is in bone in only one-sixth of the 17% of women who ultimately develop a recurrence. This combination of a low detection rate, large number of false positives and poor performance as a prognostic indicator does not support the suggestion that bone scintigraphy is indicated routinely for staging patients with Stage I carcinoma of the breast, although it should be performed if there are local symptoms referable to the skeleton, or unexplained abnormalities such as a raised alkaline phosphatase, In patients with Stage IV disease the decision whether to perform a mastectomy depends on how best to control the local disease and systemic treatment will, in any case, be indicated in the majority. Bone scintigraphy does not influence management and is therefore not routinely indicated in this group either. The majority of patients presenting with carcinoma of the breast fall into Stage II or Stage III. In many of the latter surgery will be necessary as the best means of controlling the local disease. Bone scintigraphy may be
requested to determine whether or not long-term chemoor endocrine therapy should be instituted. However, as the majority of relapses in these patients occur at extraskeletal sites, this may not be a valid criterion. The only clear indication for staging scintigraphy in these categories is to avoid an operation in patients with Stage II, and some of those with Stage III disease in whom surgery is not required for local control. This will be reliable only if meticulous care is taken to minimise the numbers of both false positive and false negative examinations. Scintigraphy is indicated when restaging patients with local recurrence, one third of whom have occult skeletal involvement (Kunkler and Merrick, 1986) and therefore require systemic rather than local therapy. The false negative rate can be minimised by rigorous attention to the technical quality of the examination. High count density images must be obtained at least 106 counts from the posterior projection of the thorax; there should be no patient movement or other artefacts and the photographic quality must be adequate. With some forms of display this is difficult to maintain_ Any studies not meeting these criteria which do not reveal a clear abnormality should be repeated; patient movement in particular can conceal disease. False positives can be excluded by accepting only cases in which there is definite radiological or biopsy confirmation of any scintigraphic abnormality (Merrick, 1987a). The majority of solitary and a high percentage of multiple rib lesions are benign, although most sternal lesions are metastatic (Kwai et al., 1988). If clear evidence of metastatic disease is not present on plain radiographs it is necessary to proceed to tomography; either computed or simple as appropriate. If this is still equivocal biopsy is indicated. A scintigraphic abnormality in the absence of radiographic confirmation or biopsy proof must never be accepted as evidence of skeletal metastases. The prevalence of skeletal deposits is higher at all stages of carcinoma of the prostate than at the equivalent stage in carcinoma of the breast, increasing from 10% in To to 80% in T4 tumours. Nevertheless, contrary to the common clinical impression, comparison of the prognostic significance of bone scintigraphy with that of the acid or alkaline phosphatase revealed that the prognostic importance of the acid phosphatase and of the scintigraphic findings are small compared to a raised alkaline phosphatase (Merrick et al., 1985). The latter can, however, also be the result of benign conditions, especially Paget's disease, which are comparatively common in patients of the age group in which prostatic carcinoma occurs. Thus, the only established role for bone scintigraphy in staging these patients is to distinguish the cause for an elevated alkaline phosphatase. The usual practice in the U K at present is for carcinoma of the prostate to be managed conservatively, treatment being started only when symptoms develop. A rise in the alkaline phosphatase and the development of scintigraphic abnormalities both precede the development of clinical symptoms. It is not established which of these is the more sensitive, or whether
232
CLINICAL RADIOLOGY
both are necessary: nor is it yet established whether initiating treatment when these parameters become abnormal can delay or prevent the onset of symptoms. The role of bone scintigraphy when staging carcinoma of the prostate therefore is rather less clear than is the case of carcinoma of the breast. There can be little doubt that an initial study is justified in patients who have a raised alkaline phosphatase of bone origin at presentation, in order to determine whether this is due to a benign or a malignant cause. There may, in addition, be a case for routine follow-up scintigraphy, in association with regular measurements of the alkaline phosphatase, of patients without bone metastases, but this is unproven and disputed (Corrie et al., 1988). There is no demonstrable value in obtaining routine scintigraphic follow up of patients with confirmed bone metastases. The prevalance of skeletal metastases in bladder cancer is stage for stage similar to that in carcinoma of the breast (Davey et al., 1985). Scintigraphy is not routinely indicated in Stage I disease, where the detection rate is negligible, or in more advanced cases if radical therapy is inappropriate. Provided that the same precautions are taken as in carcinoma of the breast to exclude false positives, it may be indicated in other patients who are being considered for radical treatment, either by radiotherapy or surgery. Similar considerations apply in lung cancer. Because most patients present with advanced disease, there is an impression that staging is of little use. There is evidence that stage is more important than the cell type when determining prognosis (Little et al., 1983). Overall, about 50% of patients with lung cancer have skeletal metastases at presentation. In the Edinburgh series the alkaline phosphatase was of little prognostic value whilst bone scintigraphy was the most important single prognostic investigation (Merrick and Merrick, 1986). Nevertheless, as it is evident from the clinical presentation that the majority of patients are suitable only for palliative rather than radical therapy, there is clearly no indication for routine bone scintigraphy, although this investigation is warranted prior to the initiation of radical surgery or radiotherapy. In view of the prognostic significance, bone scintigraphy should also form part of the staging procedure of any research protocol investigating therapy of this disease. Bone scintigraphy is not normally considered necessary in patients with testicular tumours. There is evidence that abnormal bone scintigraphy carries an extremely bad prognosis in seminomas, although not in teratomas or mixed tumours. In one series, all patients with skeletal
involvement died, and the only patients to die were those with skeletal deposits (Merrick, 1987b). Because of the generally good prognosis and very low prevalance of skeletal metastases, routine bone scintigraphy is not indicated in Stage I seminoma. It should be performed in patients with Stage II or further disease, and in those with recurrence. The prevalence of clinically silent bone metastases in other forms of cancer is, with one possible exception, too low to justify routine scintigraphy, although it is required to account for specific symptoms, at a low threshold of suspicion, and unexplained biochemical abnormalities such as an elevated alkaline phosphatase. The exception is the lymphomas, in which there is insufficient evidence to test a clinical impression that it is a useful staging procedure. REFERENCES Coleman, RE, Rubens, RD & Fogelman, I (1988). Reappraisal of the baseline bone scan in breast cancer. Journal of Nuclear Medicine, 29, 1045 1049. Corrie, D, Timmons, JH, Bauman, JM & Thompson, IM (1988). Efficacy of follow-up bone scans in carcinoma of the prostate. Cancer, 61, 2453-2454. Davey, P, Merrick, MV, Duncan, W & Redpath, AT (1985). Bladder cancer: the value of routine bone seintigraphy. Clinical Radiology, 36, 77-79. Kunkler, IH & Merrick, MV (1986) The value of non-staging skeletal scintigraphy in breast cancer. Clinical Radiology 37, 561-562. Kunkler, IH, Merrick, MV & Rodger, A (1985). Bone scintigraphy in breast cancer: a nine-year follow-up. Clinical Radiology 36, 279 282. Kwai, AH, Stomper, PC & Kaplan, WD (1988). Clinical significance of isolated scintigraphic sternal lesions in patients with breast cancer. Journal of Nuclear Medicine, 29, 324 328. Little, AG, DeMeester, TR & MacMahon, H (1983) The staging of lung cancer. Seminars in Oncology, 10, 56-70. Mansi, JL, Berger, U, Easton, D, McDonnell, T. Redding, WH, Gazet, JC et al. (1987). Micrometastases in bone marrow in patients with primary breast cancer: evaluation as an early predictor of bone metastases. British Medical Journal, 295, 1093 1096. Merrick, MV, Ding, CL, Chisholm, GD & Elton, RA (1985). Prognostic significance of alkaline and acid phosphatase and skeletal scintigraphy in carcinoma of the prostate. British Journal of Urology, 57, 715 720. Merrick, MV & Merriek, JM (1986). Bone scintigraphy in lung cancer; a reappraisal. British Journal of Radiology, 59, 1185 1194. Merrick, MV (1987a) Nuclear medicine techniques in oncology. In Investigational Techniques in Oncology, ed. NM Bleehan, pp. 175 190. Springer, London. Merrick, MV (1987b) Bone scintigraphy in testicular tumours. British Journal of Urology, 60, 167 169. Porro, G, Menard, S, Tagliabue, E, Orefice, S, Salvadori, B, Squiccarini, P, et al. (1988) Monoelonal antibody detection of carcinoma cells in bone marrow biopsy specimens from breast cancer patients. Cancer 61, 2407-2411.
Bone Scintigraphy- an Update M. V. M E R R I C K
Medical Radioisotopes Department, Western General Hospital, Edinburgh Bone scintigraphy is widely, although not universally, regraded as one of the routine procedures for staging new patients with any tumour having a high prevalence of metastases to the skeleton, especially carcinoma of the breast, prostate and lung. The lack of concensus is, however, proof that not all clinicians are convinced by the arguments which have been put forward. Additional data has partially clarified this issue and shed new light on the place of skeletal imaging. Occult skeletal metastases are revealed by scintigraphy at presentation in less than 1% of women with Stage I carcinoma of breast, 5% to 10% of those with Stage II or III and between 25% and 50% with Stage IV disease (Coleman et al., 1988). At all stages the survival of patients with bone involvement is significantly shorter than of those without. No matter how strict the criteria of interpretation, there is a residual false positive rate for scintigraphy of 1.5%, whilst less than half of those who ultimately develop overt skeletal metastases are detected by the initial staging examination (Kunkler et al., 1985). Radiography alone, without scintigraphy, has a false negative rate at least double that of scintigraphy much higher under most clinical cirumstances. In contrast, marrow aspiration at multiple sites (during the same anaesthetic as the mastectomy) identified micrometasrases in 20% of patients with To to Ta tumours (Mansi et al., 1987; Porro et al., 1988). On follow-up, one in six patients with Stage I disease eventually develops a recurrence, not necessarily in the skeleton. This increases to one in three patients with Stage II, two in three of those with Stage III, and virtually all with Stage IV. The first recurrence is in bone in approximately half of all patients who relapse. Tumour size and lymph node status are more important prognostically than the presence ofmicrometastases, only 20% of which become overt, whilst half of the patients with skeletal recurrence did not have detectable micrometastases initially. Because of the low prevalence, the number of false positives in Stage I disease equals or exceeds that of true positives. The first relapse is in bone in only one-sixth of the 17% of women who ultimately develop a recurrence. This combination of a low detection rate, large number of false positives and poor performance as a prognostic indicator does not support the suggestion that bone scintigraphy is indicated routinely for staging patients with Stage I carcinoma of the breast, although it should be performed if there are local symptoms referable to the skeleton, or unexplained abnormalities such as a raised alkaline phosphatase, In patients with Stage IV disease the decision whether to perform a mastectomy depends on how best to control the local disease and systemic treatment will, in any case, be indicated in the majority. Bone scintigraphy does not influence management and is therefore not routinely indicated in this group either. The majority of patients presenting with carcinoma of the breast fall into Stage II or Stage III. In many of the latter surgery will be necessary as the best means of controlling the local disease. Bone scintigraphy may be
requested to determine whether or not long-term chemoor endocrine therapy should be instituted. However, as the majority of relapses in these patients occur at extraskeletal sites, this may not be a valid criterion. The only clear indication for staging scintigraphy in these categories is to avoid an operation in patients with Stage II, and some of those with Stage III disease in whom surgery is not required for local control. This will be reliable only if meticulous care is taken to minimise the numbers of both false positive and false negative examinations. Scintigraphy is indicated when restaging patients with local recurrence, one third of whom have occult skeletal involvement (Kunkler and Merrick, 1986) and therefore require systemic rather than local therapy. The false negative rate can be minimised by rigorous attention to the technical quality of the examination. High count density images must be obtained at least 106 counts from the posterior projection of the thorax; there should be no patient movement or other artefacts and the photographic quality must be adequate. With some forms of display this is difficult to maintain_ Any studies not meeting these criteria which do not reveal a clear abnormality should be repeated; patient movement in particular can conceal disease. False positives can be excluded by accepting only cases in which there is definite radiological or biopsy confirmation of any scintigraphic abnormality (Merrick, 1987a). The majority of solitary and a high percentage of multiple rib lesions are benign, although most sternal lesions are metastatic (Kwai et al., 1988). If clear evidence of metastatic disease is not present on plain radiographs it is necessary to proceed to tomography; either computed or simple as appropriate. If this is still equivocal biopsy is indicated. A scintigraphic abnormality in the absence of radiographic confirmation or biopsy proof must never be accepted as evidence of skeletal metastases. The prevalence of skeletal deposits is higher at all stages of carcinoma of the prostate than at the equivalent stage in carcinoma of the breast, increasing from 10% in To to 80% in T4 tumours. Nevertheless, contrary to the common clinical impression, comparison of the prognostic significance of bone scintigraphy with that of the acid or alkaline phosphatase revealed that the prognostic importance of the acid phosphatase and of the scintigraphic findings are small compared to a raised alkaline phosphatase (Merrick et al., 1985). The latter can, however, also be the result of benign conditions, especially Paget's disease, which are comparatively common in patients of the age group in which prostatic carcinoma occurs. Thus, the only established role for bone scintigraphy in staging these patients is to distinguish the cause for an elevated alkaline phosphatase. The usual practice in the U K at present is for carcinoma of the prostate to be managed conservatively, treatment being started only when symptoms develop. A rise in the alkaline phosphatase and the development of scintigraphic abnormalities both precede the development of clinical symptoms. It is not established which of these is the more sensitive, or whether
232
CLINICAL RADIOLOGY
both are necessary: nor is it yet established whether initiating treatment when these parameters become abnormal can delay or prevent the onset of symptoms. The role of bone scintigraphy when staging carcinoma of the prostate therefore is rather less clear than is the case of carcinoma of the breast. There can be little doubt that an initial study is justified in patients who have a raised alkaline phosphatase of bone origin at presentation, in order to determine whether this is due to a benign or a malignant cause. There may, in addition, be a case for routine follow-up scintigraphy, in association with regular measurements of the alkaline phosphatase, of patients without bone metastases, but this is unproven and disputed (Corrie et al., 1988). There is no demonstrable value in obtaining routine scintigraphic follow up of patients with confirmed bone metastases. The prevalance of skeletal metastases in bladder cancer is stage for stage similar to that in carcinoma of the breast (Davey et al., 1985). Scintigraphy is not routinely indicated in Stage I disease, where the detection rate is negligible, or in more advanced cases if radical therapy is inappropriate. Provided that the same precautions are taken as in carcinoma of the breast to exclude false positives, it may be indicated in other patients who are being considered for radical treatment, either by radiotherapy or surgery. Similar considerations apply in lung cancer. Because most patients present with advanced disease, there is an impression that staging is of little use. There is evidence that stage is more important than the cell type when determining prognosis (Little et al., 1983). Overall, about 50% of patients with lung cancer have skeletal metastases at presentation. In the Edinburgh series the alkaline phosphatase was of little prognostic value whilst bone scintigraphy was the most important single prognostic investigation (Merrick and Merrick, 1986). Nevertheless, as it is evident from the clinical presentation that the majority of patients are suitable only for palliative rather than radical therapy, there is clearly no indication for routine bone scintigraphy, although this investigation is warranted prior to the initiation of radical surgery or radiotherapy. In view of the prognostic significance, bone scintigraphy should also form part of the staging procedure of any research protocol investigating therapy of this disease. Bone scintigraphy is not normally considered necessary in patients with testicular tumours. There is evidence that abnormal bone scintigraphy carries an extremely bad prognosis in seminomas, although not in teratomas or mixed tumours. In one series, all patients with skeletal
involvement died, and the only patients to die were those with skeletal deposits (Merrick, 1987b). Because of the generally good prognosis and very low prevalance of skeletal metastases, routine bone scintigraphy is not indicated in Stage I seminoma. It should be performed in patients with Stage II or further disease, and in those with recurrence. The prevalence of clinically silent bone metastases in other forms of cancer is, with one possible exception, too low to justify routine scintigraphy, although it is required to account for specific symptoms, at a low threshold of suspicion, and unexplained biochemical abnormalities such as an elevated alkaline phosphatase. The exception is the lymphomas, in which there is insufficient evidence to test a clinical impression that it is a useful staging procedure. REFERENCES Coleman, RE, Rubens, RD & Fogelman, I (1988). Reappraisal of the baseline bone scan in breast cancer. Journal of Nuclear Medicine, 29, 1045 1049. Corrie, D, Timmons, JH, Bauman, JM & Thompson, IM (1988). Efficacy of follow-up bone scans in carcinoma of the prostate. Cancer, 61, 2453-2454. Davey, P, Merrick, MV, Duncan, W & Redpath, AT (1985). Bladder cancer: the value of routine bone seintigraphy. Clinical Radiology, 36, 77-79. Kunkler, IH & Merrick, MV (1986) The value of non-staging skeletal scintigraphy in breast cancer. Clinical Radiology 37, 561-562. Kunkler, IH, Merrick, MV & Rodger, A (1985). Bone scintigraphy in breast cancer: a nine-year follow-up. Clinical Radiology 36, 279 282. Kwai, AH, Stomper, PC & Kaplan, WD (1988). Clinical significance of isolated scintigraphic sternal lesions in patients with breast cancer. Journal of Nuclear Medicine, 29, 324 328. Little, AG, DeMeester, TR & MacMahon, H (1983) The staging of lung cancer. Seminars in Oncology, 10, 56-70. Mansi, JL, Berger, U, Easton, D, McDonnell, T. Redding, WH, Gazet, JC et al. (1987). Micrometastases in bone marrow in patients with primary breast cancer: evaluation as an early predictor of bone metastases. British Medical Journal, 295, 1093 1096. Merrick, MV, Ding, CL, Chisholm, GD & Elton, RA (1985). Prognostic significance of alkaline and acid phosphatase and skeletal scintigraphy in carcinoma of the prostate. British Journal of Urology, 57, 715 720. Merrick, MV & Merriek, JM (1986). Bone scintigraphy in lung cancer; a reappraisal. British Journal of Radiology, 59, 1185 1194. Merrick, MV (1987a) Nuclear medicine techniques in oncology. In Investigational Techniques in Oncology, ed. NM Bleehan, pp. 175 190. Springer, London. Merrick, MV (1987b) Bone scintigraphy in testicular tumours. British Journal of Urology, 60, 167 169. Porro, G, Menard, S, Tagliabue, E, Orefice, S, Salvadori, B, Squiccarini, P, et al. (1988) Monoelonal antibody detection of carcinoma cells in bone marrow biopsy specimens from breast cancer patients. Cancer 61, 2407-2411.