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Home , Bone scintigraphy, Skeletal survey

Use of Scanning and Skeletal in the Diagnosis of Bone

JAY C. MALL, M .D . AND PAUL B. HOFFER, M .D .

Department of , University of California Medical Center. San Francisco, California

The radionuclide bone scan is becoming in­ half-life of 65 days severely limited the administered creasingly useful for evaluating a wide variety of bone dose, which was usually 100 microcuries. The pres­ and disorders. However, the commonest ap­ ence of bowel activity in the first few days follow­ plication is still the detection of skeletal metastases in ing injection necessitated cleansing enemas and/or the patient with known or suspected neoplastic dis­ long delays between isotope administration and scan. ease. The role of this examination relative to other Its 514 kev photon was also much higher than ideal well established methods of evaluating these patients, for nuclear imaging instrumentation. Nevertheless, especially the radiographic , is not 85 Sr was a clinically useful bone scanning agent. clear to all physicians. We hope in this communica­ Strontium-87m has a considerably shorter phys­ tion to define the role of the radionuclide bone scan ical half-life (2.8 hours) and lower photon energy (388 and to place in perspective the integral relationship kev) making it a physically more desirable agent. between the "scan" and the "survey," the two Unfortunately, the high body-background during the radiologic modalities whi_ch today are the principal first 12 hours following injection results in less than methods of evaluating the skeletal system for optimal clinical images (2) and, therefore, this agent metastatic disease. has not been widely used for bone imaging. . Historically, numerous Fluorine-18. Fluorine-18 is a hydroxyl analogue agents have been used for bone scanning, but only a which is incorporated into bone by an ion-exchange small number have been applicable for general process forming a fluorapatite crystal (I, 5). Bone has clinical use. The first of these were the strontium a very high affinity for fluorine with most of the isotopes, strontium-85 and strontium-87m. Subse­ radionuclide extracted from the blood on the initial quently, fl uorine-18 and, most recently, the transit (2, 5). The renal extraction efficiency is also technetium-99m-labeled phosphate compounds have high and, therefore, plasma clearance of 18F is the been used. most rapid of any of the clinically useful bone scan­ Strontium. Strontium is an analogue of calcium ning radionuclides (6,7). Excellent bone-to-back­ and, as such, is incorporated into the ground . ratios can be obtained with 18F at . l to 2 crystal by an ion-exchange process with calcium (I). hours following intravenous injection (3, 6). The half­ Unfortunately, the plasma clearance of strontium is life is very short ( 1.8 hours) which is advantageous slow due to partial binding with plasma proteins (2, from the standpoint of patient dose. However, the 3). Excretion occurs by both urinary tract and bowel short half-life of 18 F is also a problem because it is (4) . cyclotron-produced (8) and, therefore, its use is Strontium-85 nitrate was one of the first agents limited to those locations in close proximity to a used for imaging of bone lesions. Its long physical cyclotron. The 511 kev annihilation radiation from 18 F makes imaging with the difficult. Presented by Dr. Hoffer at ihe Postgraduate C ourse in The best images are obtained with a rectilinear scan­ Nuclear , February 27, 1975, Williamsburg, Virginia. ner or special camera (5, 9). Transportation

108 MCV Q UARTERLY 11(3): 108-115, 1975 MALL AND HOFFER: BONE SCANNING AND SKELETAL RADIOGRAPHY 109

problems and cost, both related to the short half-life in bone crystal by surface chemisorption rather than of 18F, have inhibited its clinical use. ionic exchange (10,11). The terminal phosphate Technetium-99m-labeled compounds. This group groups of the 99mTc-labeled compound react with the of compounds contains the phosphate polymers, " phosphate gaps" which are present in the imperfect pyrophosphate and polyphosphate, and their organic bone crystals. (The 99mTc acts only as a label unlike analogues, the diphosphonates. These agents localize 18 F and the Sr isotopes). Plasma clearance varies

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Fig I- Decreased uptake in Ilium (arrow) in patient with Fig 2-Diffuse in crease in skeletal activity denoted by " a bsence" metastatic bone lesion. Such "photopenic" lesions occur as a result of renal acti vity. In additi on to diffuse metastasis, the absent of lack of hyperemic respo nse to tumor due to debilita tio n, fa ilure kidney sign may also be seen in severe renal disease, hyper­ o f tumo r to provoke response, or radia ti on to region of lesio n. parathyroidism a nd hypermetabo lic sta tes. 110 MALL AND HOFFER: BONE SCANNING AND SKELETAL RADIOGRAPHY

that achieved with 18F at l to 2 hours (6, 7). Other ad­ TABLE I Bone Scans vs. Skeletal Survey vantages of this group of agents are the short half-life for the Detection of Metastatic Lesions to Bone of 99mTc (6 hours) which permits the safe administra­ tion of millicurie doses and near optimal gamma Radionuclide energy (140 kev) and high photon flux which make No. of +scan -scan Source pts. -x-ray +x-ray possible rapid performance of the procedure and good spatial resolution with the gamma camera, the Sr DeNardo (1966) 84 38% 4% most widely used nuclear imaging device. The ready DeNardo et al. (1972) availability and easy preparation from commercial Briggs (1967) 83 20% 1% Bessler ( 1968) 104 15% 1% kits with a long shelf-life also make them ideal for Harmer et al. (1969) 47 41% 6% general clinical use. The 99mTc-labeled compounds Legge et al. (1970) 186 13% 2% are the current agents of choice for bone scanning. G nekow et al. ( 1972) 353 8% 2% The availability of these excellent and convenient 18 Fl Harmer et al. ( 1969) 112 31% 3% agents has fostered the recent widespread clinical Blau et al. ( 1972) 239 15% 4.5% popularity of bone scanning. Hopkins et al. (1972) 104 20% 4% Merrick ( 1973) 119 13% 0 "Scans Signs" of Tumor. Considerable lab­ 99mTc Desaul'1iers (1973) 100 9% 1% oratory data has accumulated over the past years Pendergrass (1973) 259 20% 2% indicating that the two principal factors involved in Citrin et al. (1974) 70 10% 0 the uptake of bone-seeking radionuclides into the Barrett and Smith ( 1974) 90 71 % (of 2% bone are I) bone blood flow and 2) metabolic activity lesions) of the bone ( I 0, 12, 13 ). Recent evidence has in­ dicated that for 18F and the 99mTc-labeled phosphate among the principal agents comprising this group compounds, bone blood fl.ow is the most important with the diphosphonates being cleared most rapidly, factor ( I 0). pyrophosphate cleared somewhat less rapidly, and The detection of metastatic tumor in bone is polyphosphates being cleared least rapidly (7). The based on the premise that the destructive and bone-to-background ratios achieved with the reparative events that occur in the bone as a result of diphosphonates at 3 hours is almost comparable to a metastatic deposit cause a localized increase in blood fl.ow and bone turnover. This in turn results in localized increased uptake of the bone scanning agent TABLE 2 which is imaged as a "hot spot" on the bone scan. Bone Scan vs. Skeletal Survey For Specific Tumor Types This "hot spot" can usually be easily recognized by an alteration in the bilateral symmetry or, as with + scan - scan the axial skeleton, an alteration of the homogeneous Source # ofpts. - x-ray + x-ray uptake in the spine. A second "scan sign" of tumor Breast involvement is a localized area of decreased uptake of Sklaroff and Charkes ( 1968) 64 16% 0 the bone scanning agent (Fig 1). This has been re­ Galasko (1969) 100 29% 0 Galasko (1971) ferred to as a "photon deficient" or "photopenic" ab­ Marty and Hoffman (1972) 164 26% normality and occurs in cases where there is replace­ Lung ment of a portion of bone by tumor with little or no Sauerbrum et al (1972) 82 30% 0 reparative response on the part of the host because of Shirazi et al ( 1973) 206 7% 1% the nature of the tumor or the debilitated state of the patient (14 ). (Similar findings noted by R. S. Hatt­ Morgan and Mills(l968) 66 42% 0 ner, MD, unpublished data.) This is a distinctly less Williams et al (1968) 70 2 1% 0 common sign of skeletal involvement than a localized Royetal(l971) 30 53% 0 Shearer et al (1974) 61 12% 1% area of increased uptake. A third "scan sign" of met­ Bisson et al (1974) 81 27% 1% astatic involvement of the skeleton is diffuse but uni­ Lymphoma form increased uptake which does not alter the bi­ Weber et al (1968) 19 74% 0 lateral symmetry and may only be recognized by the H arbert and Ashburn (1968) 51 12% 4% decrease in renal activity (Fig 2) (15). Normally, the Moran et al ( 1973) 80 5% 0 kidneys in adult patients can be clearly identified at MALL AND HOFFER: BONE SCANNING AND SKELETAL RADIOGRAPHY 111

3 to 4 hours following administration of the 99mTc compounds. The absence of renal activity is a rare but important manifestation of metastatic skeletal in­ volvement which occurs when so much of the radio­ nuclide is deposited in bone that virtually none is available to be localized in the kidney. In some re­ ported series, this "scan sign" was unrecognized and such cases were termed false-negative ( 16, 17). Comparison of Bone Scan to Bone Survey. Many clinical studies have been performed comparing the relative sensitivity of the radionuclide bone scan and the radiographic skeletal survey for the detection of skeletal metastases. In earlier reports, 85Sr and 87mSr were the isotopes used for radionuclide bone scan­ ning, but in more recent reports 18F and 99mTc-labeled phosphate compounds have been employed. These studies are summarized in Table 1 (5, 18-28). All of these studies-indicate that the radionuclide bone scan is more sensitive than the radiographic skeletal sur­ vey for detecting skeletal metastases. Some reports indicate that the results with 99mTc-labeled phosphate compounds are even better than with 18 F or the Sr agents (26-31 ). For certain common , a particularly large experience has accrued over the years to compare the two techniques of bone scan­ ning and skeletal survey on a tumor-oriented basis. These comparisons are summarized in Table 2 (32- 45) and as noted by E. M. Moran, MD (oral communication, June, 1973). Although it is quite clear that the radionuclide bone scan is more sensitive than the radiographic skeletal survey for detecting skeletal metastases, it is important to remember that the examination is non­ specific in nature. Focal areas of increased ' radionuclide uptake in bone are invariably due to some skeletal abnormality; however, it must be noted that the scan can be "positive" in numerous condi­ tions other than (Fig 3A and 38) (46, 47). Table 3 is a list of non-neoplastic conditions which cause focal increase in radionudide uptake in bone. The radiograph, on the other hand, while not as sen­ Fig 3A - Abnormal bone scan revealing increased radionuclide sitive, is quite specific and may exhibit characteristic uptake in the left clavicle and p roximal right tibia. patterns which allow for a more accurate etiologic diagnosis. For these reasons, a radiograph is always necessary to assess the significance of a scan abnor­ myeloma; 2) some patients with tumor of anaplastic mality. cell type; 3) some severely debilitated patients with False-negative radionuclide bone scans occur in­ poor host response; 4) patients with diffuse disease frequently, in approximately 0.4% of patients in most uniformly involving the whole skeleton; 5) patients of the recent studies as noted in Tables I and 2. These with pelvic lesions obscured by a high level of activity have been seen to occur in certain specific situa­ in the bladder; 6) lesions that have been irradiated. tions ( 17,48-50). They are: 1) Some patients with As to the incidence of false-positive bone scans, in 112 MALL AND HOFFER: BONE SCANNING AND SKELETAL RADIOGRAPHY

Fig 38-Radiograph of clavicle reveals coarsened trabecular pattern and sclerosis typical of Paget's disease. those clinical studies in which lesions detected by The Unified Radiologic Approach. Because of the scan but not by x-ray were .evaluated by follow-up x­ already high and ever increasing cost of medical care, rays, biopsy, or autopsy, no actual false-positives we need to reassess the manner in which bone scans have occurred (20,24,39 ,49 ). and radiographs are utilized so that the patient may benefit from minimum waste and duplication of TABLE 3 effort. To this end, we have developed a unified Non-Neoplastic Causes of Posi1ive Bone Scan radiologic approach to the detection of skeletal Traumatic metastases (51 ). An appropriate examination is Fracture "tailored" individually for each patient according to Slipped epiphysis the scheme outlined in Figure 4 which is based on an Metabolic extensive review of the literature as noted above. Paget's Because of the extensive experience in patients Renal osteodystrophy with primary neoplasms of breast, lung, and prostate, Hypertrophic pulmonary osteoarthropathy Gout and also lymphoma, it is reasonable to perform the Rickets bone scan as the primary study in these patients. It Inflammatory has even been suggested that the bone scan com­ Arthritis (any type) pletely replace the skeletal survey in the evaluation of Osteomyelitis all patients for skeletal metastases (52). This may Tendinitis shortly come to pass; however, reported experience Miscellaneous with primary neoplasms other than those mentioned Aseptic necrosis is not yet great enough. Therefore, we believe that in Osteitis pubis those patients it is still necessary to perform both Hyperostosis frontalis interna complete examinations. It is much more efficient, Post-thoracotomy nevertheless, to perform the scan as the initial study, MALL AND HOFFER: BONE SCANNING AND SKELETAL RADIOGRAPHY I 13

Skeletal Survey

Skeletal Survey & Add itiona l Xroys CONSULTATION REQUEST Review by Radiologist Inte rpretation

Pelvis Xroy

Xrays

Fig 4-Scheme for radiologic examination of patients with suspected pone metastasis.

even in the latter group. This is because the or inappropriate studies were requested in almost radionuclide bone scan, as generally performed, is an half the patients examined (51 ). evaluation of the entire skeleton whereas the radiographic skeletal survey, as generally performed, Conclusions. covers only the axial skeleton. Thus, any sites outside I. Technetium-99m-labeled phosphate com­ the axial skeleton which may be positive on the scan pounds are currently the agents of choice for radio­ can be radiographed at the time the skeletal survey i~ nuclide bone scanning. obtained, thereby eliminating wasted time and effort. 2. Metastatic involvement of bone is most fre­ This approach is feasible only if false-negative, and to quently identified by a localized area of increased up­ a lesser extent, false-positive bone scans occur infre­ take. Uncommon signs of skeletal metastasis are a quently.False-negative scans occur infrequently and localized area of decreased uptake and generalized usually in specific circumstances as described above. symmetrically increased upta.ke with reduced renal To further minimize this possibility, however, we excretion. have incorporated into our approach a radiograph of 3. Radionuclide bone scanning is much more the even if the scan is normal. As explained sensitive than the radiographic skeletal survey for the above, false-positive bone scans are, for practical detection of skeletal metastases. purposes, almost nonexistent. 4. Since the findings on the bone scan are non­ The efficacy and practicability of the unified ap­ specific, all abnormal areas should be radiographed proach was determined in a trial period during which to determine the nature of the abnormality. it was applied to all patients referred to the radiology 5. The incorporation of the radionuclide bone department for either radionuclide bone scan or scan and the radiographic skeletal survey into a single radiographic skeletal survey for the detection of unified examination for the detection of skeletal skeletal metastases. A comparison of the individually metastases, formulated and coordinated by the "tailored" examination actually performed with the radiologist, is desirable, practicable, and efficacious. examination (or examinations) requested by the clinical service revealed malutilization of these Table I and Table 2 reprinted with permission from radiologic modalities; that is, superfluous, inadequate Radiology, Vol. 117, No. I. 114 MALL AND HOFFER: BONE SCANNING AND SKELETAL RADIOGRAPHY

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