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Correlation of Brain Tumor Vascularity & Positive Brain Scans: Cohn & Soiderer Study, Exercises of Nuclear medicine

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 1,050
@@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+
TiSSUE
VASCULARfl@V
READINGS
IS 8 74 1107
TOTALS
. OnsCos. @)ç@.I5.S4p@OOI
0 AIIQICIVIOSS VOSCIIIOfNolfon.otions
FIG.1. Plotofdatain 3 X 5 tableaccordingtobrain-scan
reading and tissuevascularity 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
TISSUE VASCULARITY IN POSITIVE
AND NEGATIVE BRAIN SCANS
Howard J. Cohn* and Manfred H. Soiderer
Wayne County General Hospital, Eloise, Michigan and University of Michigan, Ann Arbor, Michigan
pf3
pf4
pf5

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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

. OnsCos. @)ç@.I5.S4 p@OOI 0 AIIQICIVIOSS VOSCIIIOfNolfon.otions

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

TISSUE VASCULARITY IN POSITIVE

AND NEGATIVE BRAIN SCANS

Howard J. Cohn* and Manfred H. Soiderer

Wayne County General Hospital, Eloise, Michigan and University of Michigan, Ann Arbor, Michigan

COHN AND SOlDERER

_,@ :@eIj1;_*

I

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

554 JOURNAL OF NUCLEAR MEDICINE

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.

  1. TATOR,C. H., MORLEY,T. P. ANDOLSZEWSKI,J.:_ A study of the factors responsible for the accumulation of radioactive iodinated human serum albumin (RIHSA) by intracranial tumours and other lesions. I. Neurosurg. 22:60,
  2. MArrHEWS, C. M. E. ANDMoLn'@o, 0. : A study of the relative value of radioactive substances used for brain tumor localization and of the mechanism of tumor: brain concentration uptake in transplantable fibrosarcoma, brain and other organs in the rat. Brit. I. Exp. Patho!. 44:260,

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.

  1. EHRLICH, P. : Eine Farbenanalytische Studie, Berlin,

556 JOURNAL OF NUCLEAR MEDICINE

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.

  1. GOrrSCHALK,A., MCCORMACK,K. R., Ai@s, J. E._ AND ANGER, H. 0.: A comparison of results of brain scan sung using Ga-68 EDTA and the positron scintillation camera, with Hg-203 neohydrin and the conventional fo cused collimator scanner. Radiology 84:502, 1965. 11. MEALY, J., JR., DEHNER, J. R. @siwREESE,I. C.: Clinical comparison of two agents used in brain scanning, radioiodinated serum albumin vs chiormerodrin Hg-203. _I. Am. Med. Assoc. 189:260, 1964.
  2. QuiNN, J. L., III, Cnuc, I. Auw HAUSER, W. N.:_ Analysis of 96 abnormal brain scans using technetium 99-m (pertechnetate form). I. Am. Med. Assoc. 194:157, 1965. 13. OVERTON,M. C., ifi, SNODORASS,S. R. ANDHAYNIE, T. P.: Brain scans in neoplastic intracranial lesions: scan ning with chlormerodrin Hg-203 and chiormerodrin Hg _197. 1. Am. Med. Assoc. 192:747, 1965.
  3. RHOTON,A. L., JR.,EICHLING,J. @inTn@-PoGoSsiAN,_ M. M. : Comparative study of mercury 197 chlormerodrin and mercury 203 chlormerodrin for brain scanning. I. Nuci. Med. 7:50, 1966. 15. MCAFEE, J. G., FUEGER, C. F., Smar@, H. S., WAG NER, H. N., JR. AND MIGATA, T. : Tc-99m pertechnetate for brain scanning. I. Nuc!. Med. 5 :81 1, 1964. 16. WITCOFSKI,R. L., MAmA@m,C. D. AND ROPER, T. J.: A comparative analysis of the accuracy of the tech netium-99m pertechnetate brain scan: follow-up of 1000 patients. I. Nuci. Med. 8 :187, 1967. 17. B@u@&y,L. : The Blood-Brain Barrier, With Special Regard to the use of Radioactive Isotopes, C. C. Thomas, Springfield, Illinois, 1956, p. 129. 18. WAGNER,H. N., JR.: Principles of Nuclear Mcdi cine, W. B. Saunders, Philadelphia, 1968, p. 662.

Volume 10, Number 8 557

AVAILABLENOW

PROCEEDINGS OF THE SYMPOSIUM ON

COMPUTERS AND SCANNING

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.