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Progress in Radioactive Isotope Scanning
Progress in Radioactive Isotope Scanning KARIN R. COREY, PH.D RICHARD S. BENUA, M.D.
Radioactive isotope scanning methods are being employed with increasing precision to determine the location and extent of cancer in various organ systems. Drs. Corey and Benua describe the technical procedures available, and the complex problems involved in the analysis of isotope distribution in various organs. Carcinoma of the thyroid can be diagnosed by the demonstration of uptake of radioiodine in any locations not normally occupied by the normal thyroid. Only a few thyroid carcinomas retain the capacity to concentrate iodide, but nevertheless, this method has been extremely useful because the uptake allows effective therapy with radioiodine. Since this discovery, an extensive search has been carried out to find suitable radioactive compounds for detection of cancer in other organs. Unfortunately, few substances exist which are metabolized mostly in a single organ, as is iodine, and almost two decades elapsed after the first thyroid carcinoma had been detected before useful radioisotope methods were found for detecting cancer for other organs. These methods are based on a variety of principles but all depend on the use of specialized equipment for the external detection and localization of the radioactivity. At present the availability of numerous radioactive compounds and good scanning equipment allows detection of primaries and metastases in many organs.
THE BASIS FOR CANCER DETECTION It is known that many tumors are highly vascular, and, therefore, any compound which distributes mainly in the vascular space will From the Department of Medical Physics and the General Medical Service, Memorial Hospital for Cancer and Allied Diseases, and the Division of Biophysics, Sloan-Kettering Institute for Cancer Research, New York, N.Y. This work has been sponsored in part by the United States Atomic Energy Commission Contract No. AT(30-1)91O. Medical Clinics of North America- Vol. 50, No. 3, May, 1966
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show an apparent concentration in tumors. This has been utilized in particular for brain tumor detection with P31-labeled albumin, Hg197_ or Hg203-labeled neohydrin and other compounds. In addition to the distribution of the isotope in the vascular space, it may penetrate into some brain tumors. Liver metastases, on the other hand, are detected with labeled compounds that are metabolized by liver tissue but not by tumor tissue. A tumor which occupies space in the liver or displaces the liver edge is then detected as an area of decreased count rate by scanning. With colloidal gold the normal liver tissue contains several hundred times the concentration of colloidal gold in the tumor tissue, but the scanner placed externally over the liver will detect gamma rays from liver tissue surrounding the lesion. The larger the lesion the smaller is the total count rate above the area. Later in this article a liver scan showing considerable metastatic disease will be described. The decrease in count rate was approximately 25 per cent over one lesion. Space-occupying lesions in many organs may be detected; for example, in the kidney by using neohydrin labeled with radioactive mercury; in the pancreas with Se 75 -labeled selenomethionine; in the spleen with Cr51 -labeled partially denatured red cells; and in the lung with Cr"l- or 1'31-labeled colloidal albumin aggregates of suitable size. Tumor and other lesions in the bone appear to cause an increase in calcium turnover in the diseased bone resulting in abnormally high deposition of radioactive calcium and strontium isotopes which can be detected by scanning. n• 7 A localized increase in such tracer uptakes of more than 20 per cent indicates a lesion. It may now be seen that the newer scanning methods depend on detection of small differences in count rates over an organ. The larger a given lesion is the easier it is to detect by scanning, as well as by other methods. However, the most useful application of scanning is for the detection of lesions that may not otherwise be observed. The equipment must, therefore, be designed to detect small lesions and small count rate differences. Equipment designed for the particular organ to be studied with collimators and crystals selected to match the depth of the organ and the energy of the emergent rays will give optimal results. With any equipment, however, one may always improve the accuracy by using long times for scanning. A patient will not remain under a scanner without motion for very long, and this limits the scanning time. To obtain higher count rates and better accuracy in a given time it is possible to increase the amount of tracer given to a patient for a test. This in turn leads to increased radiation exposure to the patient. Some of the current research work in nuclear medicine is aimed at finding tracers with such physical and biochemical characteristics as to minimize the radiation delivered into the patient's tissues, but allow high count rates. Technetium-99m with six hours half-life, for example, has been used for brain, liver and placenta scanning with excellent results.
THE MOVING SCANNER The scanner is an instrument for externally detecting and mapping the distribution of radioactivity in the body of a patient. Its basic com-
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ponent is a scintillation detector coupled with suitable electronics for registration of count rates. The detector is supported on a stand and is moved above the supine patient by motors in a prescribed pattern and at variable speeds. The most common arrangement is to have it move in one plane in a raster pattern with an adjustable spacing between the transverse paths over the patient. The distribution of radioactivity as registered by the detector is displayed on a two-dimensional map in a 1: 1 scale with the area surveyed by the detector. The detectors and the mechanical arrangements will be described first and then the various scan displays will be reviewed. The size and shape of the scintillation crystal and its surrounding shielding determines the counting efficiency and the resolution. A good resolution is needed for accurate mapping of the distribution of radioactive tracer to outline the size and shape of lesions. This is accomplished by specially designed collimators, such as the focusing collimator with holes converging towards one point. The design of the shielding, in particular of the collimators, is very important and requires detailed analysis. 3 • 9 At best the design of the detector, shield, and collimator should be made for the specific gamma energy to be used, as well as the specific tracer application to be studied. In some instances the choice of shielding material is important. At Oak Ridge gold has been used for focusing collimators, and in the High Energy Gamma-Ray Scanner here, tungsten was utilized for this purpose instead of lead. B• 9 In most scanning applications the tracer is distributed in a large organ, and often throughout the body as well. It is necessary to surround the detector with an adequate shield against gamma rays originating outside of the scanning area. During recent years improvements in detector design have led to the use of large and thick scintillation crystals, commonly 5 inches in diameter and 2 to 3 inches thick. The development of large detectors and the desire to scan large organs or the entire body has led to the construction of total body scanners of considerable size and weight, which require as much space as a good diagnostic x-ray machine. A well constructed scanner of this type, equipped with a number of collimators of different resolution and depth response, can be used for almost any type of scanning. The technique used to display a scan determines how much of the scan information can be interpreted by the clinician. Several different display techniques are presently available. To illustrate different displays, a thyroid phantom filled with an pal solution was scanned utilizing a photographic technique, a digital print-out, and a tapper. The first two scans, the photoscan (Fig. 1, A) and the digital scan were produced simultaneously. As the scanner traversed the phantom the counts detected for each O.5-cm. path were typed out on a sheet of paper, and at the same time a film was exposed to light, one flash for each individual count detected. Both the carriage of the typewriter and the light source were driven by servo motors coupled to the detector. The light source is a cathode ray tube with a square collimator producing a O.5-cm. square light spot. Another scan display produced with the typewriter is illustrated in Figure 4. For quick interpretation the scan is also recorded with a paper tape punch system. 19 The tape is read by the computer to yield a display such as is shown in Figure 1, B. The ten different levels of count rates are illustrated by the letters A to J. J is the highest value observed in this scan. In the tap scan (Fig. 1, C) a tapper prints a line each time a preset count has been reached. The tap-
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LEFT
RIGHT A
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Figure 1. Three scan displays of a thyroid phantom containing 100 !-LC. of 1131 using a focusing collimator' with 1 cm. resolution; scan speed 0.5 cm. per second; line spacing 0.5 cm. The outline of the phantom with 3 cold nodules and one hot nodule has been traced on each scan. A, Photoscan with an 0.5 cm. square light collimator. The maximum film density was 1.8. B, Computer presentation of the digital scan. The count rate for each 0.5 cm. path was recorded. The maximum rate was 439 counts per second. The letters A-J indicate 10 count rate levels 43.9 counts apart. C, Tap scan with 0.5 cm. long prints.
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per is mechanically linked to the detector. Since all the scans were taken in a 1: 1 scale with the object, the outline of the phantom could be traced directly onto the scans for the purpose of comparison. The phantom consists of two lobes in which three solid cylinders are embedded. These are areas without activity simulating cold nodules. The left lobe is approximately half the thickness of the right, except for a cylindrical volume of the same height as the right lobe. This part of the left lobe simulates a hot nodule. All three displays (Fig. 1) revealed that the left lobe had less activity than the right lobe, and one can also see the cold and hot nodules at the lower poles. At the top of the left lobe the activity was less on the right side, which indicates a thinner gland or a cold nodule. With a collimator having greater resolving power this hole could have been clearly visualized. It is interesting to note that the hot spot and cold spot in the lower ends of the lobes are best illustrated in the computer display (Fig. 1, B). If a contour was drawn around the area marked by F's at the cold spot in the lower right lobe there is close correspondence to the size of the hole. The lowest count rate observed corresponds to the two E's and is about half of the maximum in this lobe. This is the cold spot that shows up clearly as a little white hole on the photoscan. It is interesting to ask how high the activity in the hot nodule must be for detection under these scanning conditions. A calculation shows that a 25 per cent increase in pal concentration over the surrounding area would give rise to a 12 per cent increase in the actual count rate,
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which, under the conditions of this scan, would have been recorded and would be seen as a significant increase in count rate. The computer would have printed the letter G at the location of the hot spot. The small corresponding increase in density on the photographic read-out or on the tap read-out would not have been observable. When the count rates over an object vary over a great range as here, from 4 to 440 counts per second, the photoscan and the tap scan can only reveal large differences in activity, while the digital read-out records botli large and small differences. To completely represent all count rates that were significantly different (two or three standard deviations apart) one would need at least 20 different colors, or shades of gray. It is obvious that it is difficult to distinguish so many shades or colors. The best method is to record the actual count rates and then, with all the data available, select the important features of the scan for pictorial illustration by techniques such as coloring of areas with certain count rate levels or marking isocount contours. In Figure 1, B, the ten count rate levels were shown by letters, and three of these were contoured to delineate the main features of the scan. In brain scans the selection for pictorial illustration is easy. The major part of the brain has a uniform low count rate while the vascular and tumor areas have the highest count rate. In fact, brain scans have been carried out satisfactorily with tap scans with or without background erase. Until photoscans became common, background erase was utilized to improve the visualization of small count rate changes with tap scans. One may, before the scan is begun, determine the count rate outside the organ to be scanned, and set the controls so that the tapper will not print unless the count rate exceeds this preset value. Properly used, this removes the counts over areas surrounding the organ and displays the object against a white background just as in the photoscan. However, if a mistake is made and the control set too high, much of the scan is lost. From the digital scan in Figure 1, C, one may easily visualize how a cut-off at anyone of the count rate levels indicated by letters would affect the picture. For example, if the part of the scan marked with letters A to E was not recorded the resulting picture would show two small lobes with a white hole at the lower end of the right lobe. In brain scans such erase is done deliberately so that the normal brain is not visualized but only the tumors and vascular areas. This procedure is dangerous because it is altogether too easy to erase desired information. For the photoscan, the exposure for each count is also selected before the scan, to give a light gray shade on the film for the lowest count rate and a dark shade for the highest count rate. Thus the photo read-out may be adjusted to give the same range of exposures for a 20 per cent increase in count rate in one scan as for a lOO-fold increase of count rates in another situation. This flexibility has until recently made it the read-out of choice, especially for the detection of small count rate changes. With a phantom it is easy to determine the maximum and minimum count rates when the location of the areas of high and low count rates are known. In patient scans the technician must make a prescan by hand and on this basis select the settings. In many instances the areas of high and low count rates are not known until the actual scan is complete. The preselected settings are guesswork and many photoscans are wholly or partly lost due to a wrong guess in the prescan. The more experienced the technician is, and the
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better understanding of the clinical problems he has, the more educated is the guesswork. The only safe way to carry out a scan is to record all count rates, high as well as low. This eliminates completely the prescan and the guesswork and ascertains that each patient given a scan test will receive the expected profit from the test. The clinician is able to interpret the digital scan rapidly by utilizing a computer for the calculation of isocount contours, marking certain levels and making estimates of standard deviation. Several different displays emphasizing various aspects of the scan may be produced by reusing the paper tape. The idea of producing various displays of the same scans already has been described for photo or tap scan,13 utilizing densitometer techniques. This can be very helpful, and some data lost to the eye may be recovered. This does not, of course, overcome the limited range of the film or the hazards in selecting cut-offs before the scan. All the three displays in Figure 1 may be used with varying degrees of success for determination of the shape and size of organs containing radioactive isotopes and for detection of lesions within them. Additional interpretation can be made with the help of the digital scan. The count rates may be normalized for the dose injected and expressed as counts per minute (cpm) per microcurie injected. These values are then used for comparison between repeated scans on the same patient to determine the effects of treatment. Comparison of a particular digital scan with a normal range of scans by computer analysis may become available in the future. In metabolic studies, the change in the count rates with time may be determined for the whole organ. This feature will be particularly valuable for the stationary scanners.
THE STATIONARY SCANNER In contrast to the moving scanner is the so-called stationary scanner which can be of three entirely different kinds. In each version the detector views a limited area from a fixed position. In the Anger Camera, a large crystal 11 inches or more in diameter and 112 inch thick is used. 2 Various collimators with straight holes may be used. Each gamma ray will interact with the crystal in a position on a straight line from the point of origin in the body. The determination of the position at which the gamma ray interacted with the crystals has to be done electronically based on signals from 19 photomultipliers mounted behind the crystal. The Autofiuoroscope detector has a bank of 260 collimated crystals, 3/8 inch in diameter and 2 inches thick. The electronics and photomultiplier system designed for the Anger Camera was used in the original version. 4 New methods of analyzing the light output from the crystals are being developed. The numerous crystals lead to more complicated instrumentation than is necessary for the Anger Camera. A feature of this scanner is high efficiency due to the depth of the crystals. Neither the multiple crystal scanners nor the Anger Camera give a better resolution than the moving scanners. The best resolution among stationary scanners is obtainable with the image intensifier (Ter-Pogossian Camera) mentioned below. The third kind of stationary counter is based on an x-ray image intensifier instead of the conventional scanner. IS This specially built image intensifier will adequately detect gamma rays below 150 kilo-
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electron volts (kev), and display the results in a reduced scale on a screen. It can, for example, be used with iodine-125 and mercury-197, but not with iodine-131. At present none of these stationary scanners has a digital read-out, although plans for such are being made. The commercial models as well as the original design of these socalled cameras have a photographic display with Polaroid film. One of the disadvantages of the existing stationary scanners is the photographic read-out with the drawbacks of the limited range and need for preselected exposure and, in addition, a size 50 small that the direct comparison with the patient is difficult. Furthermore, it is difficult to designate anatomical landmarks such as the costal margin or the palpated liver edge on the scan record. The gamma camera is inferior to scanners with focusing collimators for visualization of small tumors deep inside the body. The great advantage of all stationary scanners is that all parts of the area of interest are measured simultaneously. At present the area is limited to at most 12 inches in diameter with the gamma camera and is even smaller with the other models. Metabolism of the labeled material frequently leads to changes in the level of radioactivity in all or part of an organ. For example, liver scans with I1:I'-l abeled rose bengal are started at a time when most of the tracer is concentrated in the liver although some additional tracer will be extracted during the scan. During the scan a considerable quantity will be excreted into the gallbladder and some tracer transferred to the intestine. Since a liver scan may take 60 minutes with a moving scanner, the result of the upper and lower parts of the scan are not strictly comparable. The stationary scanner which detects all parts of the organ simultaneously gives a more dynamically cogent display, especially if one takes several shorter exposures to illustrate the changes in tracer distribution with time. This feature is one of the major advantages of the stationary scanners. To quantitate the time dependence of the tracer distribution, the improved version of the Anger camera at Sloan-Kettering Institute will be equipped with a digital read-out from 800 or more areas of the crystal via a computer. As other short-lived isotopes become available for scanning in the future, the possibility of measuring the circulation, distribution, or transfer of tracers in various tissues becomes most exciting with positron emitters. It will become feasible to quantitate metabolic changes in several areas of an organ at different depths. There is no doubt that the stationary scanner is a most valuable addition to our armament of instrumentation, but not, as yet, as a replacement for the moving scanner.
LIVER SCANNING Metastases to liver are common in cancer and liver scanning will be discussed here in detail as an example of the application of these new techniques to the cancer patient. The disappearance of I'31-labeled rose bengal from the blood was initially investigated as a technique for studying liver disease, but has proved to offer scant advantages over methods using nonlabeled dyes. Friedell, MacIntyre, and Rejali 10,11 gave Jl'l'-labeled dyes or colloidal Au 19H to visualize the configuration of the liver. Their tap scans show the outlines of normal liver, as well as defects in the pattern caused by
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metastatic disease, cysts within the liver or masses outside compressing the liver. Scans after labeled dyes reflected the distribution of hepatic cell excretory function, whereas scans with colloidal gold reflected phagocytosis in the reticuloendothelial system. Both are suitable for outlining metastatic or primary neoplasms, which have neither of these capabilities. The radiation dose to the marrow is much less with !I:ll rose bengal than with colloidal gold-19B, however. Scans with p:ll rose bengal are begun from below to avoid emphasizing the biliary duct system and bowel pattern. Before the scan, the xiphoid process, costal margin, liver or tumor edges are designated on the skin with a fuchsin mark. Each time the scanner passes over the marks the technician presses a button which marks the digital scan with a position symbol. The interpretation of the finished scan, in particular the determination of the location of the liver and lesions, can then be made in relation to these landmarks. Any scan display that lacks such landmarks, for example that from the gamma camera, is more difficult to interpret. The placement of small radioactive sources has been used but these tend to obscure the data. The routine at Memorial Center now includes an anterior and posterior view of the liver made simultaneously. The posterior view is less helpful because of the greater distance between the liver and the detector, due to the interposition of the patient's back and the table top. In deeply placed lesions, however, the posterior scan may be very useful. A right lateral view is occasionally made, and may also localize lesions of the right lobe which are difficult to find on the anterior scan. Multiple views require the use of Au 198 colloid, since 1"lI rose bengal is turned over too rapidly. In some cases where obstruction of the bile passages needs to be excluded, however, !I:ll rose bengal may be the agent of choice. In our laboratory the digital scanning technique has been applied to liver scans.~1 Points of equal count rates are joined by lines; the isocount contours. These have been prepared manually, but now are calculated and displayed by the computer. In interpreting liver scans it is necessary first to know the normal configuration of the organ, as well as the level of counting to be expected normally from a given dose of radioactive isotope. McAfee et al. 16a discuss the normal configurations of the liver using a background erase technique. Experience with isocount contours drawn on digital data displays yields increased information about the shape of the organ. The maximum counting rate is seen at a glance, and usually occurs in the right midclavicular line just above the costal margin, except when the gallbladder is visualized. The maximum rate will depend on the collimators and isotope employed, being about 12 counts/ min./lLc. with }I'll rose bengal and 24 counts/lLc. with Au l98 colloid, with the present Memorial Center equipment. The isocount contours are normally more closely spaced along the right border of the liver, and irregular spreading along this area usually indicates disease. Patient motion, however, can cause such changes, if the motion is more than occurs with quiet respiration. Isocount contour irregularity at higher counting levels is as likely to indicate metastases as irregularities seen near the edge of the liver image. Liver size is best judged by the contour selected at a level two to three times the body background level. Some misinterpretations of photoscans of liver which have been made in the past may now be avoided by the use of digital techniques. Even though the original workers cautioned that a sufficient counting
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rate was prerequisite for the identification of cold areas in the liver, the use of background erase in certain patients with cirrhosis or severe biliary obstruction caused misinterpretations. In such patients the rate of dye or colloid clearance is markedly reduced and the maximum uptake is also less than usual. In the presence of low counting rates the photoscan appeared mottled, suggesting multiple focal lesions which in fact were due to the random nature of radioactive decay.5.20 Scans thought to show "cold" areas on such a basis occur in 15 out of 17 cirrhotics and one patient with obstructive jaundice' and have been mistaken for metastatic deposits in 1 to 2.5 per cent of such patients 8 , 12, 16a, 17 If the range of count rates over the liver was noted on the hand prescan, it would soon have been obvious that the whole liver had a depressed uptake, and then simple calculations would indicate the statistical variations to be expected. It is recommended that the technician note the maximum and minimum count rates determined by prescans to help in the interpretation of the photoscan. Routine digital scanning data will prevent such misinterpretations. Since the standard deviation of any gross number (N) of counts recorded is YN, it is possible to obtain the probability P by which a difference between two count rates might occur by statistical variation. If this probability is small, one may consider that the difference is significant and represents a biological variation. There is no sharp cut-off between significant and random differences but for ordinary purposes a P of 0.05 is often accepted. Figure 2 is a photoscan whose maximum optical density is less than 2. The light area lying between the dome of the liver and the central dark area and another light area lying medial to the central dark area can just be made out, as they could in the original using a standard x-ray film view box. The digital scan showing the isocount contours makes these metastatic deposits plain (Figs. 3, 4). Their significance, however, is best evaluated by summing the counts recorded over a 2 by 2 cm. block in each area. The box over the dark portion of the dome of the liver contains 1327 counts collected during a 30 second observation of that area. The box over the lighter area contains 997 counts. The difference is 330 ± Y1327 + 997 = 330 ± 48. This gives a P value of less than 0.0001, showing that the difference is highly significant. A similar analysis yields the same result between the light box and the dark one over the more central area. In this instance the lesion was indicated on the photoscan but only after a reference to the digital record could it be stated that there was a definite and significant depression of count rate of about 25 per cent. It should be kept in mind, however, that such analysis must always be interpreted in the light of the normal distribution of the isotope. It would be easy to show a significant difference between liver substance and adjacent nonhepatic tissue, for instance. Liver scans will successfully show metastatic disease in patients with advanced or obvious cancer. Every cold area on a scan in such a patient may not be malignant, however, as we have recently seen a patient with cancer of the colon recurrent in the right lobe in whom the left lobe showed a cold area due to a benign cyst. Cold areas may occur from abscesses, cysts, or surgical defects. Failure to see cold areas does not exclude the presence of metastases. Scans should be most useful in the management of the cancer patient when diagnostic or therapeutic
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L.B. 270 p'c 1
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Rose Bengal, Contours in C/5 sec
Figure 2. Photoscan of liver after injection of 270 /LC. 1'31 rose bengal in a patient (L.B.) with carcinoma of the colon. Focusing collimator with 1 cm. resolution; 1 cm. square light source; line spacing 1 cm.; scan speed 0.2 cm. per second. The scan reveals multiple liver metastases.
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Figure 3. Isocount contours from the digital scan made simultaneously with the photoscan in Figure 2. The contours are labeled with the gross counts per 5 seconds. The shading indicates an area counting at a rate less than 150, which is depressed and corresponds to a light area in Figure 2.
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decisions must be based on knowledge of liver metastases. In particular the decision about liver surgery may be influenced by the discovery of multiple lesions of the liver, and by their location. The digital read-out was originally designed for bone scanning and the interpretation of these scans is fast and does not require the plotting of detailed isocount contours. 15, 16 The elevated activity over an area of bone stands out quite clearlyin comparison with the normal values which are quite well established. In this technique the interpretation frequently depends on comparison with normal values, or on comparison with surrounding bone or with other normal bones. Changes in the count rate with time may also indicate abnormality. The digital readout makes it possible to detect small and new lesions and allows early treatment with radiation therapy. Liver scanning with a digital. readout leads naturally to the development of computer programs for calculating and displaying scan results. The preliminary results indicate that more lesions will be detected than by photoscanning. The importance of detecting small lesions in the liver and other organs will ultimately depend upon how effective early treatment of metastases can become. For clinical research this tool is invaluable. SUMMARY
Primary or secondary cancerous lesions in many organs may be detected by scanning, i.e., mapping the distribution of a suitable radioactive material administered to the patient. The importance of detecting small differences is stressed. Scanners and various methods of scan displays, in particular digital recording, have been discussed and illustrated. It was pointed out that with a photoscanner preselected settings are necessary which in retrospect may be found in error so that part or even the whole scan is lost. The digital scan eliminates this problem and in addition allows the detection of large and small count rate differL.B. 270 pC 1
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Figure 4. Detail from the digital scan representing a part in the upper right lobe seen in Figures 2 and 3. The contours are again shown. The sums of the counts in the boxes are shown with their standard deviations.
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ences. Digital scanning provides data for quantitative scan interpretations in addition to the customary qualitative ones. Advances in detection of liver disease with digital scanning techniques have been reviewed and attention has been given to the details of evaluation and interpretation of liver scans. ACKNOWLEDGMENTS Some of this work has been done in collaboration with Mr. David Weber and Mr. Malcolm Powell. Discussions with Mr. Peter Kenny about stationary counters have been most helpful. The authors have been stimulated and encouraged by Dr. John S. Laughlin.
REFERENCES 1. Achaval, A., Tauxe, W. N., and Gambrill, E. E.: Scintillation scanning of the liver. Mayo Clin. Proc. 40:207, 1965. 2. Anger, H. 0.: Scintillation camera. Rev. Sci. Instrum. 29:27, 1958. 3. Beck, R N.: Collimators for radioisotope scanning systems. In Medical Radioisotope Scanning, Vol. I, Vienna, IAEA, 1964. 4. Bender, M. A., and Blau, M.: Autofiuoroscopy, the use of a non-scanning device for tumor localization with radioisotopes. J. Nuclear Med. 1 :105, 1960. 5. Christie, J. H., MacIntyre, W. J., Crespo, G. C., and Koch-Weser, D.: Radioisotope scanning in hepatic cirrhosis. Radiology 81 :455, 1963. 6. Corey, K. R, Kenny, P., Greenberg, E., Pazianos, A., Pearson, O. H., and Laughlin, J. S.: U se of calcium-47 in diagnostic studies of patient with bone lesions. Am. J. Roentgenol. 85:955, 1961. 7. Corey, K. R, Kenny, P., Greenberg, E., and Laughlin, J. S.: Detection of bone metastases in scanning studies with calcium-47 and strontium-85. J. Nuclear Med. 3:454, 1962. 8. Feldman, F., Rubenfeld, S., and Collica, C.: The radioactive (I-131) rose bengal hepatoscan. Radiology 79:457, 1962. 9. Francis, J. E., Harris, C. C., and Bell, P. R.: A focussing collimator for research in scanning. J. Nuclear Med. 3:10,1962. 10. Friedell, H. L., MacIntyre, W. ]., and Rejali, A. M.: A method for the visualization of the configuration and structure of the liver. Part A. Preliminary clinical investigations. Am. J. Roentgenol. 77:455, 1957. 11. Idem: Part B. Am. J. Roentgenol. 77:471, 1957. 12. Gollin, F. F., Sims, J. F., and Cameron, J. R.: Liver scanning and liver function tests, a comparative study. J.A.M.A. 187:111, 1964. 13. Harris, C. C., Bell, P. R, Satterfield, M. M., Ross, D. A., and Jordan, J. C.: Analysis of scan records with recording densitometer- the re-scanner. In Medical Radioisotope Scanning, Vo!. I, Vienna, IAEA, 1964. 14. Kenny, P. J., Myers, M. J., Lundy, A., Ritter, F., and Laughlin, J. S.: Digital Anger camera with electronic focussing for positron emitters. Proc. Symposium on Fundamental Problems in Scanning, Chicago, May, 1965 (To be published). 15. Laughlin, J. S., Beattie, J. W., Corey, K. R, Isaacson, A., and Kenny, P.: Total body scanner for high energy gamma rays. Radiology 74:108, 1960. 16. Laughlin, J. S., Weber, D. A., Kenny, P. J., Corey, K. R., and Greenberg, E.: Total body scanning. Brit. J. Radio!. 37:287, 1964. 16a. McAfee, J. G., Ause, R. G., and Wagner, H. N., Jr.: Diagnostic value of scintillation scanning of the liver. Arch. Int. Med. 116:95, 1965. 17. Nagler, W., Bender, M. A., and Blau, M.: Radioisotope photoscanning of the liver. Gastroenterology 42:36, 1963. 18. Ter-Pogossian, M. M., Kastner, J., and Vest, T. C.: Autofiuorography of the thyroid gland by means of image amplification. Radiology 81 :984, 1963. 19. Trump, M., Lundy, A., Kenny, P., Weber, D., Corey, K., and Laughlin, J. S.: A digital data recording system using paper tape for radioisotope scanning. Presented at the Fiftieth Annual Meeting of the Radiological Society of North Arherica, November-December, 1964, Chicago, Illinois. 20. Wagner, H. N., Jr., McAfee, J. G., and Mozley, J. M.: Diagnosis of liver diseases by radioscanning. Arch. Int. Med. 107:324, 1961. 21. Weber, D. A., Kenny, P., Pochaczevsky, R, Corey, K. R, and Laughlin, J. S.: Liver scans with digital readout. J. Nuclear Med. 6:528, 1965. 444 East 68th Street New York, N. Y. 10021
Radioactive isotope scanning methods are being employed with increasing precision to determine the location and extent of cancer in various organ systems. Drs. Corey and Benua describe the technical procedures available, and the complex problems involved in the analysis of isotope distribution in various organs. Carcinoma of the thyroid can be diagnosed by the demonstration of uptake of radioiodine in any locations not normally occupied by the normal thyroid. Only a few thyroid carcinomas retain the capacity to concentrate iodide, but nevertheless, this method has been extremely useful because the uptake allows effective therapy with radioiodine. Since this discovery, an extensive search has been carried out to find suitable radioactive compounds for detection of cancer in other organs. Unfortunately, few substances exist which are metabolized mostly in a single organ, as is iodine, and almost two decades elapsed after the first thyroid carcinoma had been detected before useful radioisotope methods were found for detecting cancer for other organs. These methods are based on a variety of principles but all depend on the use of specialized equipment for the external detection and localization of the radioactivity. At present the availability of numerous radioactive compounds and good scanning equipment allows detection of primaries and metastases in many organs.
THE BASIS FOR CANCER DETECTION It is known that many tumors are highly vascular, and, therefore, any compound which distributes mainly in the vascular space will From the Department of Medical Physics and the General Medical Service, Memorial Hospital for Cancer and Allied Diseases, and the Division of Biophysics, Sloan-Kettering Institute for Cancer Research, New York, N.Y. This work has been sponsored in part by the United States Atomic Energy Commission Contract No. AT(30-1)91O. Medical Clinics of North America- Vol. 50, No. 3, May, 1966
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show an apparent concentration in tumors. This has been utilized in particular for brain tumor detection with P31-labeled albumin, Hg197_ or Hg203-labeled neohydrin and other compounds. In addition to the distribution of the isotope in the vascular space, it may penetrate into some brain tumors. Liver metastases, on the other hand, are detected with labeled compounds that are metabolized by liver tissue but not by tumor tissue. A tumor which occupies space in the liver or displaces the liver edge is then detected as an area of decreased count rate by scanning. With colloidal gold the normal liver tissue contains several hundred times the concentration of colloidal gold in the tumor tissue, but the scanner placed externally over the liver will detect gamma rays from liver tissue surrounding the lesion. The larger the lesion the smaller is the total count rate above the area. Later in this article a liver scan showing considerable metastatic disease will be described. The decrease in count rate was approximately 25 per cent over one lesion. Space-occupying lesions in many organs may be detected; for example, in the kidney by using neohydrin labeled with radioactive mercury; in the pancreas with Se 75 -labeled selenomethionine; in the spleen with Cr51 -labeled partially denatured red cells; and in the lung with Cr"l- or 1'31-labeled colloidal albumin aggregates of suitable size. Tumor and other lesions in the bone appear to cause an increase in calcium turnover in the diseased bone resulting in abnormally high deposition of radioactive calcium and strontium isotopes which can be detected by scanning. n• 7 A localized increase in such tracer uptakes of more than 20 per cent indicates a lesion. It may now be seen that the newer scanning methods depend on detection of small differences in count rates over an organ. The larger a given lesion is the easier it is to detect by scanning, as well as by other methods. However, the most useful application of scanning is for the detection of lesions that may not otherwise be observed. The equipment must, therefore, be designed to detect small lesions and small count rate differences. Equipment designed for the particular organ to be studied with collimators and crystals selected to match the depth of the organ and the energy of the emergent rays will give optimal results. With any equipment, however, one may always improve the accuracy by using long times for scanning. A patient will not remain under a scanner without motion for very long, and this limits the scanning time. To obtain higher count rates and better accuracy in a given time it is possible to increase the amount of tracer given to a patient for a test. This in turn leads to increased radiation exposure to the patient. Some of the current research work in nuclear medicine is aimed at finding tracers with such physical and biochemical characteristics as to minimize the radiation delivered into the patient's tissues, but allow high count rates. Technetium-99m with six hours half-life, for example, has been used for brain, liver and placenta scanning with excellent results.
THE MOVING SCANNER The scanner is an instrument for externally detecting and mapping the distribution of radioactivity in the body of a patient. Its basic com-
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ponent is a scintillation detector coupled with suitable electronics for registration of count rates. The detector is supported on a stand and is moved above the supine patient by motors in a prescribed pattern and at variable speeds. The most common arrangement is to have it move in one plane in a raster pattern with an adjustable spacing between the transverse paths over the patient. The distribution of radioactivity as registered by the detector is displayed on a two-dimensional map in a 1: 1 scale with the area surveyed by the detector. The detectors and the mechanical arrangements will be described first and then the various scan displays will be reviewed. The size and shape of the scintillation crystal and its surrounding shielding determines the counting efficiency and the resolution. A good resolution is needed for accurate mapping of the distribution of radioactive tracer to outline the size and shape of lesions. This is accomplished by specially designed collimators, such as the focusing collimator with holes converging towards one point. The design of the shielding, in particular of the collimators, is very important and requires detailed analysis. 3 • 9 At best the design of the detector, shield, and collimator should be made for the specific gamma energy to be used, as well as the specific tracer application to be studied. In some instances the choice of shielding material is important. At Oak Ridge gold has been used for focusing collimators, and in the High Energy Gamma-Ray Scanner here, tungsten was utilized for this purpose instead of lead. B• 9 In most scanning applications the tracer is distributed in a large organ, and often throughout the body as well. It is necessary to surround the detector with an adequate shield against gamma rays originating outside of the scanning area. During recent years improvements in detector design have led to the use of large and thick scintillation crystals, commonly 5 inches in diameter and 2 to 3 inches thick. The development of large detectors and the desire to scan large organs or the entire body has led to the construction of total body scanners of considerable size and weight, which require as much space as a good diagnostic x-ray machine. A well constructed scanner of this type, equipped with a number of collimators of different resolution and depth response, can be used for almost any type of scanning. The technique used to display a scan determines how much of the scan information can be interpreted by the clinician. Several different display techniques are presently available. To illustrate different displays, a thyroid phantom filled with an pal solution was scanned utilizing a photographic technique, a digital print-out, and a tapper. The first two scans, the photoscan (Fig. 1, A) and the digital scan were produced simultaneously. As the scanner traversed the phantom the counts detected for each O.5-cm. path were typed out on a sheet of paper, and at the same time a film was exposed to light, one flash for each individual count detected. Both the carriage of the typewriter and the light source were driven by servo motors coupled to the detector. The light source is a cathode ray tube with a square collimator producing a O.5-cm. square light spot. Another scan display produced with the typewriter is illustrated in Figure 4. For quick interpretation the scan is also recorded with a paper tape punch system. 19 The tape is read by the computer to yield a display such as is shown in Figure 1, B. The ten different levels of count rates are illustrated by the letters A to J. J is the highest value observed in this scan. In the tap scan (Fig. 1, C) a tapper prints a line each time a preset count has been reached. The tap-
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LEFT
RIGHT A
AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
Figure 1. Three scan displays of a thyroid phantom containing 100 !-LC. of 1131 using a focusing collimator' with 1 cm. resolution; scan speed 0.5 cm. per second; line spacing 0.5 cm. The outline of the phantom with 3 cold nodules and one hot nodule has been traced on each scan. A, Photoscan with an 0.5 cm. square light collimator. The maximum film density was 1.8. B, Computer presentation of the digital scan. The count rate for each 0.5 cm. path was recorded. The maximum rate was 439 counts per second. The letters A-J indicate 10 count rate levels 43.9 counts apart. C, Tap scan with 0.5 cm. long prints.
c
per is mechanically linked to the detector. Since all the scans were taken in a 1: 1 scale with the object, the outline of the phantom could be traced directly onto the scans for the purpose of comparison. The phantom consists of two lobes in which three solid cylinders are embedded. These are areas without activity simulating cold nodules. The left lobe is approximately half the thickness of the right, except for a cylindrical volume of the same height as the right lobe. This part of the left lobe simulates a hot nodule. All three displays (Fig. 1) revealed that the left lobe had less activity than the right lobe, and one can also see the cold and hot nodules at the lower poles. At the top of the left lobe the activity was less on the right side, which indicates a thinner gland or a cold nodule. With a collimator having greater resolving power this hole could have been clearly visualized. It is interesting to note that the hot spot and cold spot in the lower ends of the lobes are best illustrated in the computer display (Fig. 1, B). If a contour was drawn around the area marked by F's at the cold spot in the lower right lobe there is close correspondence to the size of the hole. The lowest count rate observed corresponds to the two E's and is about half of the maximum in this lobe. This is the cold spot that shows up clearly as a little white hole on the photoscan. It is interesting to ask how high the activity in the hot nodule must be for detection under these scanning conditions. A calculation shows that a 25 per cent increase in pal concentration over the surrounding area would give rise to a 12 per cent increase in the actual count rate,
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which, under the conditions of this scan, would have been recorded and would be seen as a significant increase in count rate. The computer would have printed the letter G at the location of the hot spot. The small corresponding increase in density on the photographic read-out or on the tap read-out would not have been observable. When the count rates over an object vary over a great range as here, from 4 to 440 counts per second, the photoscan and the tap scan can only reveal large differences in activity, while the digital read-out records botli large and small differences. To completely represent all count rates that were significantly different (two or three standard deviations apart) one would need at least 20 different colors, or shades of gray. It is obvious that it is difficult to distinguish so many shades or colors. The best method is to record the actual count rates and then, with all the data available, select the important features of the scan for pictorial illustration by techniques such as coloring of areas with certain count rate levels or marking isocount contours. In Figure 1, B, the ten count rate levels were shown by letters, and three of these were contoured to delineate the main features of the scan. In brain scans the selection for pictorial illustration is easy. The major part of the brain has a uniform low count rate while the vascular and tumor areas have the highest count rate. In fact, brain scans have been carried out satisfactorily with tap scans with or without background erase. Until photoscans became common, background erase was utilized to improve the visualization of small count rate changes with tap scans. One may, before the scan is begun, determine the count rate outside the organ to be scanned, and set the controls so that the tapper will not print unless the count rate exceeds this preset value. Properly used, this removes the counts over areas surrounding the organ and displays the object against a white background just as in the photoscan. However, if a mistake is made and the control set too high, much of the scan is lost. From the digital scan in Figure 1, C, one may easily visualize how a cut-off at anyone of the count rate levels indicated by letters would affect the picture. For example, if the part of the scan marked with letters A to E was not recorded the resulting picture would show two small lobes with a white hole at the lower end of the right lobe. In brain scans such erase is done deliberately so that the normal brain is not visualized but only the tumors and vascular areas. This procedure is dangerous because it is altogether too easy to erase desired information. For the photoscan, the exposure for each count is also selected before the scan, to give a light gray shade on the film for the lowest count rate and a dark shade for the highest count rate. Thus the photo read-out may be adjusted to give the same range of exposures for a 20 per cent increase in count rate in one scan as for a lOO-fold increase of count rates in another situation. This flexibility has until recently made it the read-out of choice, especially for the detection of small count rate changes. With a phantom it is easy to determine the maximum and minimum count rates when the location of the areas of high and low count rates are known. In patient scans the technician must make a prescan by hand and on this basis select the settings. In many instances the areas of high and low count rates are not known until the actual scan is complete. The preselected settings are guesswork and many photoscans are wholly or partly lost due to a wrong guess in the prescan. The more experienced the technician is, and the
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better understanding of the clinical problems he has, the more educated is the guesswork. The only safe way to carry out a scan is to record all count rates, high as well as low. This eliminates completely the prescan and the guesswork and ascertains that each patient given a scan test will receive the expected profit from the test. The clinician is able to interpret the digital scan rapidly by utilizing a computer for the calculation of isocount contours, marking certain levels and making estimates of standard deviation. Several different displays emphasizing various aspects of the scan may be produced by reusing the paper tape. The idea of producing various displays of the same scans already has been described for photo or tap scan,13 utilizing densitometer techniques. This can be very helpful, and some data lost to the eye may be recovered. This does not, of course, overcome the limited range of the film or the hazards in selecting cut-offs before the scan. All the three displays in Figure 1 may be used with varying degrees of success for determination of the shape and size of organs containing radioactive isotopes and for detection of lesions within them. Additional interpretation can be made with the help of the digital scan. The count rates may be normalized for the dose injected and expressed as counts per minute (cpm) per microcurie injected. These values are then used for comparison between repeated scans on the same patient to determine the effects of treatment. Comparison of a particular digital scan with a normal range of scans by computer analysis may become available in the future. In metabolic studies, the change in the count rates with time may be determined for the whole organ. This feature will be particularly valuable for the stationary scanners.
THE STATIONARY SCANNER In contrast to the moving scanner is the so-called stationary scanner which can be of three entirely different kinds. In each version the detector views a limited area from a fixed position. In the Anger Camera, a large crystal 11 inches or more in diameter and 112 inch thick is used. 2 Various collimators with straight holes may be used. Each gamma ray will interact with the crystal in a position on a straight line from the point of origin in the body. The determination of the position at which the gamma ray interacted with the crystals has to be done electronically based on signals from 19 photomultipliers mounted behind the crystal. The Autofiuoroscope detector has a bank of 260 collimated crystals, 3/8 inch in diameter and 2 inches thick. The electronics and photomultiplier system designed for the Anger Camera was used in the original version. 4 New methods of analyzing the light output from the crystals are being developed. The numerous crystals lead to more complicated instrumentation than is necessary for the Anger Camera. A feature of this scanner is high efficiency due to the depth of the crystals. Neither the multiple crystal scanners nor the Anger Camera give a better resolution than the moving scanners. The best resolution among stationary scanners is obtainable with the image intensifier (Ter-Pogossian Camera) mentioned below. The third kind of stationary counter is based on an x-ray image intensifier instead of the conventional scanner. IS This specially built image intensifier will adequately detect gamma rays below 150 kilo-
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electron volts (kev), and display the results in a reduced scale on a screen. It can, for example, be used with iodine-125 and mercury-197, but not with iodine-131. At present none of these stationary scanners has a digital read-out, although plans for such are being made. The commercial models as well as the original design of these socalled cameras have a photographic display with Polaroid film. One of the disadvantages of the existing stationary scanners is the photographic read-out with the drawbacks of the limited range and need for preselected exposure and, in addition, a size 50 small that the direct comparison with the patient is difficult. Furthermore, it is difficult to designate anatomical landmarks such as the costal margin or the palpated liver edge on the scan record. The gamma camera is inferior to scanners with focusing collimators for visualization of small tumors deep inside the body. The great advantage of all stationary scanners is that all parts of the area of interest are measured simultaneously. At present the area is limited to at most 12 inches in diameter with the gamma camera and is even smaller with the other models. Metabolism of the labeled material frequently leads to changes in the level of radioactivity in all or part of an organ. For example, liver scans with I1:I'-l abeled rose bengal are started at a time when most of the tracer is concentrated in the liver although some additional tracer will be extracted during the scan. During the scan a considerable quantity will be excreted into the gallbladder and some tracer transferred to the intestine. Since a liver scan may take 60 minutes with a moving scanner, the result of the upper and lower parts of the scan are not strictly comparable. The stationary scanner which detects all parts of the organ simultaneously gives a more dynamically cogent display, especially if one takes several shorter exposures to illustrate the changes in tracer distribution with time. This feature is one of the major advantages of the stationary scanners. To quantitate the time dependence of the tracer distribution, the improved version of the Anger camera at Sloan-Kettering Institute will be equipped with a digital read-out from 800 or more areas of the crystal via a computer. As other short-lived isotopes become available for scanning in the future, the possibility of measuring the circulation, distribution, or transfer of tracers in various tissues becomes most exciting with positron emitters. It will become feasible to quantitate metabolic changes in several areas of an organ at different depths. There is no doubt that the stationary scanner is a most valuable addition to our armament of instrumentation, but not, as yet, as a replacement for the moving scanner.
LIVER SCANNING Metastases to liver are common in cancer and liver scanning will be discussed here in detail as an example of the application of these new techniques to the cancer patient. The disappearance of I'31-labeled rose bengal from the blood was initially investigated as a technique for studying liver disease, but has proved to offer scant advantages over methods using nonlabeled dyes. Friedell, MacIntyre, and Rejali 10,11 gave Jl'l'-labeled dyes or colloidal Au 19H to visualize the configuration of the liver. Their tap scans show the outlines of normal liver, as well as defects in the pattern caused by
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metastatic disease, cysts within the liver or masses outside compressing the liver. Scans after labeled dyes reflected the distribution of hepatic cell excretory function, whereas scans with colloidal gold reflected phagocytosis in the reticuloendothelial system. Both are suitable for outlining metastatic or primary neoplasms, which have neither of these capabilities. The radiation dose to the marrow is much less with !I:ll rose bengal than with colloidal gold-19B, however. Scans with p:ll rose bengal are begun from below to avoid emphasizing the biliary duct system and bowel pattern. Before the scan, the xiphoid process, costal margin, liver or tumor edges are designated on the skin with a fuchsin mark. Each time the scanner passes over the marks the technician presses a button which marks the digital scan with a position symbol. The interpretation of the finished scan, in particular the determination of the location of the liver and lesions, can then be made in relation to these landmarks. Any scan display that lacks such landmarks, for example that from the gamma camera, is more difficult to interpret. The placement of small radioactive sources has been used but these tend to obscure the data. The routine at Memorial Center now includes an anterior and posterior view of the liver made simultaneously. The posterior view is less helpful because of the greater distance between the liver and the detector, due to the interposition of the patient's back and the table top. In deeply placed lesions, however, the posterior scan may be very useful. A right lateral view is occasionally made, and may also localize lesions of the right lobe which are difficult to find on the anterior scan. Multiple views require the use of Au 198 colloid, since 1"lI rose bengal is turned over too rapidly. In some cases where obstruction of the bile passages needs to be excluded, however, !I:ll rose bengal may be the agent of choice. In our laboratory the digital scanning technique has been applied to liver scans.~1 Points of equal count rates are joined by lines; the isocount contours. These have been prepared manually, but now are calculated and displayed by the computer. In interpreting liver scans it is necessary first to know the normal configuration of the organ, as well as the level of counting to be expected normally from a given dose of radioactive isotope. McAfee et al. 16a discuss the normal configurations of the liver using a background erase technique. Experience with isocount contours drawn on digital data displays yields increased information about the shape of the organ. The maximum counting rate is seen at a glance, and usually occurs in the right midclavicular line just above the costal margin, except when the gallbladder is visualized. The maximum rate will depend on the collimators and isotope employed, being about 12 counts/ min./lLc. with }I'll rose bengal and 24 counts/lLc. with Au l98 colloid, with the present Memorial Center equipment. The isocount contours are normally more closely spaced along the right border of the liver, and irregular spreading along this area usually indicates disease. Patient motion, however, can cause such changes, if the motion is more than occurs with quiet respiration. Isocount contour irregularity at higher counting levels is as likely to indicate metastases as irregularities seen near the edge of the liver image. Liver size is best judged by the contour selected at a level two to three times the body background level. Some misinterpretations of photoscans of liver which have been made in the past may now be avoided by the use of digital techniques. Even though the original workers cautioned that a sufficient counting
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rate was prerequisite for the identification of cold areas in the liver, the use of background erase in certain patients with cirrhosis or severe biliary obstruction caused misinterpretations. In such patients the rate of dye or colloid clearance is markedly reduced and the maximum uptake is also less than usual. In the presence of low counting rates the photoscan appeared mottled, suggesting multiple focal lesions which in fact were due to the random nature of radioactive decay.5.20 Scans thought to show "cold" areas on such a basis occur in 15 out of 17 cirrhotics and one patient with obstructive jaundice' and have been mistaken for metastatic deposits in 1 to 2.5 per cent of such patients 8 , 12, 16a, 17 If the range of count rates over the liver was noted on the hand prescan, it would soon have been obvious that the whole liver had a depressed uptake, and then simple calculations would indicate the statistical variations to be expected. It is recommended that the technician note the maximum and minimum count rates determined by prescans to help in the interpretation of the photoscan. Routine digital scanning data will prevent such misinterpretations. Since the standard deviation of any gross number (N) of counts recorded is YN, it is possible to obtain the probability P by which a difference between two count rates might occur by statistical variation. If this probability is small, one may consider that the difference is significant and represents a biological variation. There is no sharp cut-off between significant and random differences but for ordinary purposes a P of 0.05 is often accepted. Figure 2 is a photoscan whose maximum optical density is less than 2. The light area lying between the dome of the liver and the central dark area and another light area lying medial to the central dark area can just be made out, as they could in the original using a standard x-ray film view box. The digital scan showing the isocount contours makes these metastatic deposits plain (Figs. 3, 4). Their significance, however, is best evaluated by summing the counts recorded over a 2 by 2 cm. block in each area. The box over the dark portion of the dome of the liver contains 1327 counts collected during a 30 second observation of that area. The box over the lighter area contains 997 counts. The difference is 330 ± Y1327 + 997 = 330 ± 48. This gives a P value of less than 0.0001, showing that the difference is highly significant. A similar analysis yields the same result between the light box and the dark one over the more central area. In this instance the lesion was indicated on the photoscan but only after a reference to the digital record could it be stated that there was a definite and significant depression of count rate of about 25 per cent. It should be kept in mind, however, that such analysis must always be interpreted in the light of the normal distribution of the isotope. It would be easy to show a significant difference between liver substance and adjacent nonhepatic tissue, for instance. Liver scans will successfully show metastatic disease in patients with advanced or obvious cancer. Every cold area on a scan in such a patient may not be malignant, however, as we have recently seen a patient with cancer of the colon recurrent in the right lobe in whom the left lobe showed a cold area due to a benign cyst. Cold areas may occur from abscesses, cysts, or surgical defects. Failure to see cold areas does not exclude the presence of metastases. Scans should be most useful in the management of the cancer patient when diagnostic or therapeutic
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Rose Bengal, Contours in C/5 sec
Figure 2. Photoscan of liver after injection of 270 /LC. 1'31 rose bengal in a patient (L.B.) with carcinoma of the colon. Focusing collimator with 1 cm. resolution; 1 cm. square light source; line spacing 1 cm.; scan speed 0.2 cm. per second. The scan reveals multiple liver metastases.
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Figure 3. Isocount contours from the digital scan made simultaneously with the photoscan in Figure 2. The contours are labeled with the gross counts per 5 seconds. The shading indicates an area counting at a rate less than 150, which is depressed and corresponds to a light area in Figure 2.
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decisions must be based on knowledge of liver metastases. In particular the decision about liver surgery may be influenced by the discovery of multiple lesions of the liver, and by their location. The digital read-out was originally designed for bone scanning and the interpretation of these scans is fast and does not require the plotting of detailed isocount contours. 15, 16 The elevated activity over an area of bone stands out quite clearlyin comparison with the normal values which are quite well established. In this technique the interpretation frequently depends on comparison with normal values, or on comparison with surrounding bone or with other normal bones. Changes in the count rate with time may also indicate abnormality. The digital readout makes it possible to detect small and new lesions and allows early treatment with radiation therapy. Liver scanning with a digital. readout leads naturally to the development of computer programs for calculating and displaying scan results. The preliminary results indicate that more lesions will be detected than by photoscanning. The importance of detecting small lesions in the liver and other organs will ultimately depend upon how effective early treatment of metastases can become. For clinical research this tool is invaluable. SUMMARY
Primary or secondary cancerous lesions in many organs may be detected by scanning, i.e., mapping the distribution of a suitable radioactive material administered to the patient. The importance of detecting small differences is stressed. Scanners and various methods of scan displays, in particular digital recording, have been discussed and illustrated. It was pointed out that with a photoscanner preselected settings are necessary which in retrospect may be found in error so that part or even the whole scan is lost. The digital scan eliminates this problem and in addition allows the detection of large and small count rate differL.B. 270 pC 1
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Figure 4. Detail from the digital scan representing a part in the upper right lobe seen in Figures 2 and 3. The contours are again shown. The sums of the counts in the boxes are shown with their standard deviations.
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BENUA
ences. Digital scanning provides data for quantitative scan interpretations in addition to the customary qualitative ones. Advances in detection of liver disease with digital scanning techniques have been reviewed and attention has been given to the details of evaluation and interpretation of liver scans. ACKNOWLEDGMENTS Some of this work has been done in collaboration with Mr. David Weber and Mr. Malcolm Powell. Discussions with Mr. Peter Kenny about stationary counters have been most helpful. The authors have been stimulated and encouraged by Dr. John S. Laughlin.
REFERENCES 1. Achaval, A., Tauxe, W. N., and Gambrill, E. E.: Scintillation scanning of the liver. Mayo Clin. Proc. 40:207, 1965. 2. Anger, H. 0.: Scintillation camera. Rev. Sci. Instrum. 29:27, 1958. 3. Beck, R N.: Collimators for radioisotope scanning systems. In Medical Radioisotope Scanning, Vol. I, Vienna, IAEA, 1964. 4. Bender, M. A., and Blau, M.: Autofiuoroscopy, the use of a non-scanning device for tumor localization with radioisotopes. J. Nuclear Med. 1 :105, 1960. 5. Christie, J. H., MacIntyre, W. J., Crespo, G. C., and Koch-Weser, D.: Radioisotope scanning in hepatic cirrhosis. Radiology 81 :455, 1963. 6. Corey, K. R, Kenny, P., Greenberg, E., Pazianos, A., Pearson, O. H., and Laughlin, J. S.: U se of calcium-47 in diagnostic studies of patient with bone lesions. Am. J. Roentgenol. 85:955, 1961. 7. Corey, K. R, Kenny, P., Greenberg, E., and Laughlin, J. S.: Detection of bone metastases in scanning studies with calcium-47 and strontium-85. J. Nuclear Med. 3:454, 1962. 8. Feldman, F., Rubenfeld, S., and Collica, C.: The radioactive (I-131) rose bengal hepatoscan. Radiology 79:457, 1962. 9. Francis, J. E., Harris, C. C., and Bell, P. R.: A focussing collimator for research in scanning. J. Nuclear Med. 3:10,1962. 10. Friedell, H. L., MacIntyre, W. ]., and Rejali, A. M.: A method for the visualization of the configuration and structure of the liver. Part A. Preliminary clinical investigations. Am. J. Roentgenol. 77:455, 1957. 11. Idem: Part B. Am. J. Roentgenol. 77:471, 1957. 12. Gollin, F. F., Sims, J. F., and Cameron, J. R.: Liver scanning and liver function tests, a comparative study. J.A.M.A. 187:111, 1964. 13. Harris, C. C., Bell, P. R, Satterfield, M. M., Ross, D. A., and Jordan, J. C.: Analysis of scan records with recording densitometer- the re-scanner. In Medical Radioisotope Scanning, Vo!. I, Vienna, IAEA, 1964. 14. Kenny, P. J., Myers, M. J., Lundy, A., Ritter, F., and Laughlin, J. S.: Digital Anger camera with electronic focussing for positron emitters. Proc. Symposium on Fundamental Problems in Scanning, Chicago, May, 1965 (To be published). 15. Laughlin, J. S., Beattie, J. W., Corey, K. R, Isaacson, A., and Kenny, P.: Total body scanner for high energy gamma rays. Radiology 74:108, 1960. 16. Laughlin, J. S., Weber, D. A., Kenny, P. J., Corey, K. R., and Greenberg, E.: Total body scanning. Brit. J. Radio!. 37:287, 1964. 16a. McAfee, J. G., Ause, R. G., and Wagner, H. N., Jr.: Diagnostic value of scintillation scanning of the liver. Arch. Int. Med. 116:95, 1965. 17. Nagler, W., Bender, M. A., and Blau, M.: Radioisotope photoscanning of the liver. Gastroenterology 42:36, 1963. 18. Ter-Pogossian, M. M., Kastner, J., and Vest, T. C.: Autofiuorography of the thyroid gland by means of image amplification. Radiology 81 :984, 1963. 19. Trump, M., Lundy, A., Kenny, P., Weber, D., Corey, K., and Laughlin, J. S.: A digital data recording system using paper tape for radioisotope scanning. Presented at the Fiftieth Annual Meeting of the Radiological Society of North Arherica, November-December, 1964, Chicago, Illinois. 20. Wagner, H. N., Jr., McAfee, J. G., and Mozley, J. M.: Diagnosis of liver diseases by radioscanning. Arch. Int. Med. 107:324, 1961. 21. Weber, D. A., Kenny, P., Pochaczevsky, R, Corey, K. R, and Laughlin, J. S.: Liver scans with digital readout. J. Nuclear Med. 6:528, 1965. 444 East 68th Street New York, N. Y. 10021