ATLAS OF GALLIUM-67 SCINTIGRAPHY A New Method of Radionuclide Medical Diagnosis ATLAS OF GALLIUM-67 SCINTIGRAPHY A New Method of Radionuclide Medical Diagnosis Gerald S. Johnston and A. Eric Jones Department of Nuclear Medicine Qinical Center Department of Health, Education, and Welfare National Institutes of Health Bethesda, Maryland PLENUM PRESS • NEW YORK-LONDON Library of Congress Cataloging in Publication Data Johnston, Gerald S 1930- Atlas of gallium-67 scintigraphy. Bibliography: p. 1. Radioisotope scanning-Atlases. 2. Gallium-Isotopes. I. Jones, Alfred Eric, 1935- joint author. II. Title [DNLM: 1. Gallium-Diagnostic use-Atlases. 2. Neoplasms-Radiography-Atiases. 3. Radioisotope scanning-Atlases. WNl7 J72a 1973] RC78.7.R4J63 616.07'575 73-18375 ISBN-13: 978-1-4613-4498-8 e-ISBN-13: 978-1-4613-4496-4 DOT: 10.1007/978-1-4613-4496-4 Plenum Press is a Division of Plenum Publishing Corporation 227 West 17th Street, New York, N.Y. 10011 United Kingdom edition published by Plenum Press, London A Division of Plenum Publishing Company, Ltd. Davis House (4th Floor), 8 Scrubs Lane, Harlesden, London, NW10 6SE, England All rights reserved No part of this publication may be reproduced in any form without written permission from the publisher CONTRIBUTORS National Institutes of Health, Bethesda, Maryland James C. Arseneau, M. D. Medicine Branch, National Cancer Institute Robert S. Frankel, M. D. Department of Nuclear Medicine, Clinical Center Louis G. Gelrud, M. D. Section on Diseases of the Liver, Metabolic Diseases Branch, National Institute of Arthritis, Metabolism and Digestive Diseases Gerald S. Johnston, M. D. Department of Nuclear Medicine, Clinical Center Alfred E. Jones, M. D. Department of Nuclear Medicine, Clinical Center Robert J. Kramer, M. D. Department of Nuclear Medicine, Clinical Center Michael S. Milder, M. D. Department of Nuclear Medicine, Clinical Center Steven D. Richman, M. D. Department of Nuclear Medicine, Clinical Center v PREFACE In 1970, under the sponsorship of Oak Ridge Associated Univer sities (ORAU), a group of clinical investigators formed the Cooper ative Group to Study Localization of Radiopharmaceuticals. The first radiopharmaceutical selected for study was 67-Gallium (67-Ga) administered as the citrate. The object of the study was to de termine the usefulness of 67-Ga in the diagnosis and treatment of patients with various malignancies. Funding for the project was granted by the U. S. Atomic Energy Commission and the National Cancer Institute, National Institutes of Health (NIH). The Nuclear Medicine Department of the Clinical Center, NIH, agreed to assist ORAU with aspects of this study, particularly with 67-Ga scin tigraphy of patients with lymphoma and Hodgkin's disease. Pre liminary reports from the ORAU study are in press. Since April 1971, 67-Ga scintigraphy has gained increasing use in the study of cancer patients at the Clinical Center, NIH, where well over 1000 such patients have been examined by this method. This monograph was written to present selected examples from this group of a variety of malignancies seen in this 28-month period. No attempt has been made to correlate this overall experience statistically. Rather, this presentation is to help familiarize the practitioner of Nuclear Medicine with the wide range of usefulness for 67-Ga scintigraphy while making him aware of the variation in scan appearance and watchful of the many pitfalls of 67-Ga scan interpretation. Permission to use these patient studies and x-rays was generously granted by Dr. Paul P. Carbone, Associate Director, Medical Oncology, Division of Cancer Treatment, National Cancer Institute; Dr. John L. Doppman, Chief, Department of Radiology, Clinical Center; Dr. Alfred S. Ketcham, Clinical Director and Chief, Surgery Branch, National Cancer Institute; Dr. Ralph E. Johnson, Chief, Radiation Branch, National Cancer Institute; and Dr. John M. Van Buren, Chief, Surgical Neurology Branch, National Institute of Neurological Diseases and Stroke. All scintigraphs were obtained with the expert technical help of Camille L. Boyce, Jeanne K. Honicker, Bonnie A. Mefferd, Eleanor J. Myers and Sybil J. Swann. The manuscript was typed by Luella Bentz, Paula McPherson, and Cathy S. Yarrison. CONTENTS Chapter 1 History and Method of 67Gallium Citrate Scan 1 Chemical and Physical Characteristics 3 Imaging Technique 3 Chapter 2 Metabolism 7 Chapter 3 Scintigraphic Interpretation 11 Chapter 4 Bone Tumors 31 Chapter 5 Lung Tumors 51 Chapter 6 Tumors of Head and Neck 59 Chapter 7 Tumors of the Reticuloendothelial and Hematopoietic Systems 73 Malignant Lymphomas 73 Leukemia 75 Chapter 8 Gastrointestinal and Pelvic Tumors 119 Chapter 9 Breast Carcinoma 135 Chapter 10 Malignant Melanoma 149 Chapter 11 Brain Tumors 161 Chapter 12 Inflammation 181 Chapter 13 Clinical Applications 199 References 213 Index 219 ix CHAPI'ER 1 History and Method of Scan Gerald S. Johnston, M. D. Department of Nuclear Medicine, Clinical Center National Institutes of Health, Bethesda, Maryland In the late 1940's, radionuclides from the Oak Ridge reactor were made available for medical use. Up to that time, most nuclear medical experience had been with the application of phosphorus-32 (32-P) to hematologic diseases and iodine-131 (131-I) to thyroid problems. Both of these radionuclides were found to have valuable therapeutic applications in addition to their diagnostic uses. Therapeutic "successes" with 32-P and 131-1 helped encourage the hope that radionuclides would have important uses in cancer treatment. Among the radioactive agents studied to determine therapeutic usefulness were radioisotopes of gallium. These were examined for efficacy in the treatment of malignancies involving bone (1-5), and for usefulness in diagnosing bone involvement with tumor (3,4), and the presence of soft tumor (3). Toxic in high dosage, gallium-72 (72-Ga) did concentrate in bone tumors. When 72-Ga was shown to be ineffective in the treatment of bone tumors, gallium-67 (67-Ga) was produced in a carrier-free state with the thought of increasing the amount of radioactivity that bone would concentrate by eliminating the carrier gallium which had produced toxic symptoms with 72-Ga (6). Surprisingly, the cyclotron produced, carrier-free 67-Ga had a different distribution in experimental animals than the high carrier reactor produced 67-Ga. 67-Ga did not accumulate in bones to any great extent, and so the therapeutic concentrations of this radionuclide could not be achieved in bony lesions. The addition of cold gallium to the 67-Ga in amounts equivalent to that found with 72-Ga resulted in similar 72-Ga and 67-Ga characteristics, but the cold gallium returned the problem of toxicity. Two patterns of gallium 2 CHAPTER 1 concentration were thus established, that with carrier-free 67-Ga and that with cold gallium carrier in amounts above 0.25 mg/kg body weight mixed with 67-Ga. This latter gives the same pattern observed with carrier containing 72-Ga (6). Similar observations were made for 68-Ga (7). However, the studies previously done with high carrier 72-Ga were not repeated with carrier-free 67-Ga or 68-Ga at the time these latter two isotopes became available. Increased experience with radionuclides in medicine soon indicated that the many hoped-for therapeutic applications were not at hand. Instead, the possibilities of diagnostic uses for radionuclides were emerging one after another. The hope then arose that a tumor-localizing agent would be found to help with the diagnosis and staging of cancer. Gallium isotopes faded into the background temporarily as having no readily apparent use in nuclear medicine. With technological advances in the field, bone imaging emerged as a valuable diagnostic method in the 1960's. Strontium-85 was found to localize readily in areas of osteoblastic activity present in primary and metastatic bone lesions (8). However, the long half-life and energetic photon of 85-Sr were not satisfactory, and the search continued for a better bone imaging agent. Fluorine-18 met the need for a shorter lived bone seeking nuclide (9), but it was difficult to deliver so short lived a nuclide and the photon energy was still too high to provide high resolution images. Gallium, a known bone-seeker, was being investigated by Hayes and Edwards for its efficacy as a bone imaging agent when the soft tumor localizing tendency was observed for carrier-free 67-Ga citrate (10). Since that first observation, 67-Ga citrate has been admini stered to thousands of cancer patients as a diagnostic aid. Between April 1971 and August 1973, 1022 patient whole body scintiscan studies were performed by the Nuclear Medicine Depart ment, Clinical Center, National Institutes of Health, on patients with malignancies (Table 1-1). Selected examples from among these patients are presented in this monograph. A wide variation in tumor localization of 67-Ga has been observed with the general agreement that some tumors consistently concentrate 67-Ga better than others. The size of the tumor, its localization with respect to the body surface and to normal bodily sites of 67-Ga concentration, and the treatment status of the patient have all seemed to be important considerations in interpreting 67-Ga scintigraphic images. These variations in 67-Ga concentration from tumor site to tumor site have resulted in a relatively high rate of false negative studies. The high potential for false negative findings has placed emphasis on positive sites of 67-Ga concentration in these studies. A positive 67-Ga scintigram requires definitive evaluation: a negative scintigram does not rule out the necessity for further HISTORY AND METHOD OF SCAN 3 study. Chemical and Physical Characteristics Gallium, like aluminum, is an amphoteric element, behaving as a metal in acid and as a nonmetal in alkaline media. It has a blue-gray metallic appearance and may be encountered as liquid or a solid because of a low melting point (29.8°c). Gallium, with atomic number 31 and mass numbers 69 and 71 (stable) exists in three valence states (+1, +2 and +3) (11). The trivalent citrate compound is used for imaging in nuclear medicine. Attempts at using other compounds than citrate have encountered problems, mainly with solubility (12). Gallium Citrate Isotopes of gallium have mass numbers from 64 through 74. Of these, 67-Ga is the isotope with the best physical characteristics for scintigraphy at this point in technological development, and is the one used to perform the studies presented here. Carrier-free 67-Ga is produced in the cyclotron by bombarding a zinc target with protons. 67-Ga undergoes electron capture decay with a half life of 78 hours. Gamma emissions occur between 0.88 and 0.093 MeV with principal photopeaks of 0.093, 0.188, 0.296 and 0.388 MeV. Imaging Technique The tendency for 67-Ga to label many types of malignancy and the metastases of those malignancies has provided a place for this radionuclide in screening patients with cancer to determine the extent of the primary tumor and to determine the presence and location of metastatic lesions. An additional role may be estab lished for 67-Ga in screening patients to help diagnose the presence or absence of primary malignancy. Since the possibilities are limitless for sites of cancer involvement, the whole body scan has become the study of choice when 67-Ga is used as the scanning agent. Selected adjunctive gamma scintillation camera views can be helpful in delineating a borderline abnormality and in studying tumors involving the head and neck, including brain. The gamma scintillation camera technique is described in Chapter 11. 4 CHAPTER 1 Whole body scanning with 67-Ga citrate requires 50 ~Ci/kg of body weight to be given intravenously. After an interval of 48 to 96 hours, the patient returns for whole body scanning. A laxative is given at 12 and at 36 hours before the scan to encourage excretion of stool containing the radionuclide. The patient is made comfortable in the supine position and scanned from head to toe using 5:1 minification without background erase or enhancement. A variety of pulse height window settings are possible. The scans illustrated herein were made with a window from 130 to 330. Generally, the liver count rate is used to determine the intensity. Scanning time varies between l~ and 2 hours for a person 5' 10" tall. Areas of interest are sometimes rescanned with the patient in the lateral position to determine localization of a site in the antero-posterior plane. The nuclear medical evaluation of patients known to have cancer has frequently required the use of several imaging procedures. The following tests were often ordered for the same patient; liver scintigraphy, brain scintigraphy, whole body skeletal scan and 67-Ga whole body scan. It is advisable to perform the studies in the above mentioned order since it involves the least delay. An initial patient evaluation with 67-Ga will result in interference with other studies and cause a delay (in further scintigraphic studies) for at least one week.