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A research paper published in the Journal of Nuclear Medicine in 1967. The authors, Howard J. Cohn and Manfred H. Soiderer, investigated the relationship between brain tumor vascularity and positive brain scans. They analyzed records of patients who had brain scans at the Nuclear Medicine Unit of The University of Michigan and compared the degree of vascularity in the lesions with the clinical brain scan readings. The study found a significant correlation between tissue vascularity and positive brain scan visualization.
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The first use of a radioactive substance for detect ing brain tumors was carried out by Moore in 1948 (1 ). Fluorescein was labeled with radioiodine and detected with a hand-held G-M counter. During the past 20 years technological developments have led to the use of o9mTc and automatic scanners and cameras. But as yet, the reasons for the localization of the radioactive compound in the lesion have not been found (2—5). This paper shows that vascularity of the neoplasm is correlated with positive brain scans in the series studied and probably is a factor in the unusual per meabiity of the disrupted blood-brain barrier.
MATERIALS Records of patients who had brain scans at the Nuclear Medicine Unit of The University of Michi gan were analyzed. Tissue sections were available for review in 107 cases and these formed the basis of the study. All the tissues were accessioned at the University of Michigan Department of Pathology from 1964 to 1967 and were obtained by craniotomy following brain scanning except for one autopsy case.
METHODS Scan reading. The brain scans were done with four commercially available scanners (Picker Magna scanners III and V and Ohio-Nuclear Models 54H and 54F). The agent used was ‘°THg-chlormerodrin in a dose of 15 ,@Ci/kg (to a maximum of 1, @@Ci) or oomTc@pertechnetate in a standard dose of 10 mCi. The brain scans were put into three groups, positive, negative and equivocal, using the initially reported clinical reading. Histopathologic grading for vascularity. Routine sections cut 4—6 microns thick and stained with hematoxylin and eosin were used. Degree of vas cularity was judged according to the size and num ber of patent arterial and venous channels present in the most vascular area of the lesion without knowledge of the brain-scan readings. The degree
of vascularity was then compared to that of sur rounding tissue whenever normal brain or meninges were included in the surgical specimen. If only the lesion was available, its vascularity was compared to that of routine necropsy sections of a similar area. The following grading system was used: 1+ less vascular than normal brain 2+ vascularity similar to that of normal brain 3+ definitely more vascular than normal brain 4+ highly vascular 5+ extremely vascular All lesions were examined on two different oc casions to try to ensure consistent evaluations. The same microscope was used throughout to maintain an unvarying field size and to keep the magnifica tion constant.
Received July 5, 1968; revision accepted Feb. 28, 1969. For reprints contact: Manfred H. Soiderer, Dept. of Pathology, Univ. of Michigan Medical Center, Ann Arbor, Mich. 48104. C Present address : Nuclear Medicine Division, Mary's Help Hospital, Daly City, California 94015. RAW DATA Scan Readings (c@ 5 28 47 TOTALS
21 6
5+ 4+ 3+ 2+ 1+
VASCULARfl@V^ TiSSUE READINGS
IS 8 74 1107 TOTALS
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FIG. 1. Plotof datain 3 X 5 tableaccordingto brain-scan reading and tissue vascularity reading. Each small black dot rep resents one case. Small circles represent cases with vascular malformations, which as a group seem to be apart from main dis tribution. Inspection of raw data suggests a positive correlation. Using heavy lines, data were condensed into 2 X 2 table with four groups. Chi-square value was @3.6with p < 0.01. It may be inferred from this figure that there is significant positive corre lation between tissue vascularity and visualization on brain scan.
Volume 10, Number 8 553
Howard J. Cohn* and Manfred H. Soiderer
Wayne County General Hospital, Eloise, Michigan and University of Michigan, Ann Arbor, Michigan
COHN AND SOlDERER
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FIG.2. L.R.# 1067013.Anteriorandrightlateralpositivecularmenin@oma(X 170).Scanwasdone1 hr afterinjection brain scans and histopathological section of associated highly vas- of 10 mCi Ic with Ohio-Nuclear scanner with 5-in. crystal.
Statistical analysis. The original 3 x 5 table was condensed into a 2 X 2 table to eliminate cells with only a few members and to increase statistical valid ity. The scan reading headings used were “abnormal― and “notabnormal.― The equivocal and negative scans were placed together in the “notabnormal― group. The tissue vascularity readings used were
“abovenormal― and “normaland below.― The standard chi-square analysis was done (Fig. 1).
RESULTS Figure 1 shows the correlation of scan reading with tissue vascularity. The brain scans were from
COHN AND SOlDERER
DISCUSSION
Visualization of an abnormal region in the brain with a radioactive substance depends on many fac tors including relative intensity of uptake, size, homogeneity of uptake, sharpness of borders, depth in the brain, proximity to normal structures with high uptake, time of observation, dose and gamma ray energy of the radionuclide and the imaging de vices and aids used by the physician (2). Of these factors, little is known about the specific determinants of increased uptake in pathological brain tissue which make it possible to detect lesions in the midst of normal brain (3—5). Since 1885 when Ehrlich (6) reported that nor mal brain would exclude certain substances in the blood, the blood-brain barrier has been the subject of much investigation and speculation. It has been assumed that alteration of the normal blood-brain barrier is the reason for the differential uptake. The “barrier―is relative and the different con centrations seem to be a result of differential rates of absorption and excretion. Davson has reviewed the literature in a recent monograph (7). Although some studies have suggested varying uptake with different agents (4,8—10), the similar clinical results have led most investigators to be lieve that the penetration and retention in pathologic lesions is due to nonspecific physical diffusion through an altered blood-brain barrier rather than selective concentration (11—17). The varying uptake of vascular lesions with time has shed some light on the subject. Immediately after cerebral thrombosis the brain scan will usually be negative, become positive after 1 or 2 weeks and then frequently become negative a few weeks later. The time when the scan is positive coincides with the growth of new capillaries into the area of the infarct. These new, immature vessels could be ex pected to have an undeveloped blood-brain barrier which would be in line with current knowledge that this barrier is not well established until late in the development of the fetal brain. The time the scan reverts to normal coincides with the maturation of these vessels and development of a normal blood brain barrier.
That the number of vessels is not the only deter minant is shown by the frequently low brain-scan activity of hemangiomas which are composed of old mature vessels. Vascular tumors, however, contain relatively little tissue for uptake and are best seen when scanned shortly after injection of the agent while the blood levels are relatively high.
SUMMARY
Alteration of the normal blood-brain barrier is assumed to be responsible for visualization of intra cranial lesions on the brain scan. The specific factors are not known. To evaluate the importance of tissue vascularity as a factor, 107 brain scans with histo pathological verification were studied. The tissue vascularity was graded by an independent observer without knowledge of the brain-scan interpretation. The tissue vascularity was then compared with the clinical brain-scan readings. Chi-square analysis of these data was interpreted as indicating a correlation of the degree of vascularity of the lesions with vis ualization on brain scan. Of the five blood vessel tumors and vascular mal formations, however, two were equivocal on brain scan and three were not visualized at all. This sug gests that in addition to the degree of vascularity the maturity of the vessels and the relative meta bolic activity of the tissue are factors in visualization although the visualization of these lesions may be by a different mechanism.
ACKNOWLEDGMENT We wish to thank W. H. Beierwaltes, Director of the Nuclear Medicine Unit at The University of Michigan, for permission to use the scans and data which formed the basis of this study and to John A. Jacquez of the Depart ment of Biostatistics for reviewing the statistical analysis. This work was supported in part by USPHS Training Grant 5 TICA-5134-04.
REFERENCES
1. MooaE, G. E. : Fluorescein as an agent in the differ entiation of normal and malignant tissues. Science 106:130, 1947. 2. OVERTON, M. C., HAYNIE, T. P., ORE, W. K. AND BEENTJES, L. B. : The relationship of isotope concentration and tumor size to detectability by brain scanning with ra _diomercury. Texas Rep. Biol. Med. 24: 112, 1966.
5. JACKSON,G. L. AND CoasoN, M. L. : Radioautographic determination of cellular localization of radioactive mer cury (Hg-203) chlormerodrin. New Engi. J. Med. 277: 1,006, 1967.
TISSUE VASCULARITY IN BRAIN SCANS
7. DAVSON, H.: Physiology of the Cerebrospinal Fluid. Little, Brown and Company, Boston, 1967. 8. LONG,R. G., MCAFEE,J. G. @mWINKELMAN,J.: Evaluation of radioactive compounds for the external de tection of cerebral tumors. Cancer Re:. 23:98, 1963. 9. SOLOWAY,A. H., A@iow, S., KAUFMAN, C., VAL CftIS, J. F., WHITMAN, B. AND MESSER, J. R. : Penetration of brain and brain tumor. VI. radioactive scanning agents. _I. Nucl. Med. 8:792, 1967.
Volume 10, Number 8 557
AVAILABLENOW
Edited by John U. HIda1gO
The Proceedings of the “Symposiumon Computers and Scanning,―held at Tulane University on December 16—17,1965, are now available from the Society of Nuclear Medicine at a cost of $5 ($5.50 outside USA). The symposium, which brought together speakers experienced in both the technology of computers and the technology of scanning, covered the many uses to which computers are now being put in nuclear medicine. The Proceedings contain 19 papers totaling 216 pages. Send orders to : The Society of Nuclear Medicine, 2 11 East 43rd St., New York, New York 10017.