INTERPRETATION OF THE 67Gd PHOTOSCAN

Steven M. Larson, Michael S. Milder, and Gerald S. Johnston National Institutes of Health, Bethesda, Maryland

Gallium-67 citrate is used to locate sites of of these investigators was not achieved, several im tumor involvement throughout the body. In or portant observations were made. The distribution of der to make proper use of this new agent, a carrier-free "7Ga was predominantly found within knowledge of the normal ' t.u distribution and the , spleen, kidney, and bone in rats. The addi physiological variations is necessary. For this tion of stable caused a progressive increase report, over 400 whole-body rectilinear scans in relative concentration within the skeleton and a using 35 fid/kg "~Ga citrate were reviewed. At relative decrease in soft tissue concentration. As a 48 hr, normal 6~Ga activity is concentrated in result of this early work, ^Ga with a carrier was the axial skeleton, liver, spleen, and around the later evaluated as a bone scanning agent, and it was large joints. Foci of uptake are often seen in while scanning the bones of a patient with Hodgkin's the salivary, lacrimal, and mammary glands. disease that the tumor-specific properties of 67Ga- Activity is also found in the region of the naso citrate were discovered (2). . Under certain physiological condi The distribution of 07Ga in humans has subse tions, intense localisation may occur within the quently been studied (77-73). When carrier-free breast, bowel, and long bones. These variations 07Ga-citrate is injected intravenously, the majority may mimic malignant tumors. Lymph nodes of the isotope is bound to plasma protein, especially involved by malignant disease present a dis . tinctive pattern that aids in their identification. During the first day after injection, the kidney ex cretes about 12% of the administered dose and con tains the highest concentration of the nuclide. After Tumor visualization using H7Gaphotoscanning was this the fecal route of excretion becomes predomi first reported by Edwards and Hayes in 1969 (7,2). nant. During the usual scanning period, between 48 Since that time, several investigators have confirmed and 72 hr, the highest concentrations are seen in the the tumor-specific properties of fi7Ga for a number bones, liver, and spleen. About one-third of the iso of epithelial and lymphoreticular (3—8). tope is excreted over the first week, and the remain To date we have scanned over 400 patients with ing two-thirds is distributed within the liver (6%)*, "7Ga-citrate. The purpose of this communication is spleen (1%), kidney (2%), skeleton (including to emphasize the special features of our experience marrow) (24%), and other soft tissues (34%). that are important to proper interpretation of the Other organs with relatively high concentration in "~Ga photoscan. We will discuss: (A) the normal clude the adrenals, bowel, and . scan pattern of S7Ga distribution; (B) problems of interpretation caused by physiologic concentration METHODS of radiogallium; and (c) the anatomic distribution Patient population. Table 1 shows the diagnostic and scan appearance of the lymph nodes often in categories and the number of patients scanned dur volved in neoplastic disorders. ing the past 19 months at the National Institutes of A review of the physiology of K7Ga uptake is a necessary prerequisite to proper interpretation. The initial studies of B7Gadistribution were performed by Received July 10, 1972; revision accepted Nov. 1, 1972. For reprints contact: Michael S. Milder, Dept. of Nuclear Bruner, Hayes, and Perkinson (9) as part of an Medicine. Clinical Center, Room 1B-44A, National Insti tutes of Health, Bethesda, Md. 20014. attempt to use gallium isotopes for specific therapy * All percentages in this section refer to percentage of of bone tumors (70). Although the primary purpose the administered dose of 07Ga.

208 JOURNAL OF Health. All of the patients scanned in this series had documented neoplastic disease or a high suspicion for a malignant disorder. A wide variety of tumor types were represented. Malignant and leukemia patients predominated, reflecting the cur rent clinical research emphasis of the National Can cer Institute. A complete statistical evaluation of the scanning results from this series will be presented in another publication as part of the report of the Cooperative Group to Study Localization of Radio- pharmaceuticals sponsored by Oak Ridge Associated Universities and the National Institute. The present communication is intended to review the population of Table 1 with respect to the techni al and physiologic factors important to proper int

TABLE 1. <"Ga WHOLE-BODY SCANS (APR. 1971-SEPT. 1972)

Diagnosis Scans

92 Hodgkin's disease 73 Leukemia 60 Lung 38 Head and neck cancers 40 Melanomas 33 Breast cancers 11 Soft tissue sarcomas 21 Uterine cancers 18 Primary bone cancers 21 Pancreatic cancers 6 Central nervous system tumors 22 Ovarian cancers 6 Hepatomas 3 Miscellaneous neoplasms 25 Unknown malignancies 19 FIG. 2. Anterior Ga scan of 15-year-old female with acute 488 myelogenous leukemia. Myeloblastomas are shown in nasopharynx (arrow) and left breast.

Volume 14, Number 4 209 LARSON, MILDER, AND JOHNSTON

within the bony thorax, spine, and scapulae. These structures may occasionally cause interpretation problems. On the anterior view, concentration of 67Ga in the sternum may be so prominent as to mimic tumor uptake. The triangular shape of the manubrium with the apex pointed downward (Fig. 4) and the superior orientation are of some benefit in differentiating the sternum from enlarged hilar or peritracheal lymph nodes. These structures can be separated by a lateral view of the chest. On the posterior view, the lower ends of the scapu lae often show a prominent concentration near the lateral chest wall (Fig. 1). This must be differen tiated from rib lesions or tumors in axillary or lateral thoracic nodes. Again, lateral views may be of help. Occasionally, uptake occurs in the breasts, which is particularly prominent when the breasts are under the physiologic stimulus of the menarche, cyclic estrogenic and progestational agents, or (14). Figure 3 is a photoscan of a woman with Hodg- kin's disease who was scanned 3 weeks postpartum. The patient was not nursing her infant, but she was

R

FIG. 3. Anterior "'Go scan of 25-year-old woman performed at 6 weeks postpartum. Intense ' 'Ga uptake in both breasts was confirmed by finding of high activity in breast milk. nuclide normally distributed throughout the soft tissues of the scalp, the osseous structure and mar row cavity of the skull, and the soft tissues of the neck. The most active concentration is normally seen in the region of the nose on the anterior pro jection and the marrow containing spaces of the occiput on the posterior projection. The lacrimal glands concentrate 67Ga to a variable extent and may be strikingly prominent on the anterior projec tion (Fig. 1). In addition, the salivary glands can also be observed. Pathologic concentration near the nasal antrum may be masked by the normal uptake in this region. Figure 2 is a whole-body scan of a patient with acute myeloblastic leukemia whose biopsy revealed myelo- blastoma in the region of the posterior nasopharynx and tonsils (arrow). Initially, this scan was inter preted as normal in this region, and it was only after treatment had ablated uptake that an abnormality was appreciated. In retrospect, this region concen »1 trates the isotope more extensively than usual in cases of physiologic uptake in the region of the mouth (see FIG. 4. Anterior '"Go scan ¡n33-year-old man showing marked localization of activity in colon obscuring abdominal detail. In Fig. 1). addition, manubrium is prominent and must be distinguished from Thorax. In the thorax, B7Gais normally distributed mediasti nal disease.

210 JOURNAL OF NUCLEAR MEDICINE INTERPRETATION OF THE 67Ga PHOTOSCAN

involvement of the liver. Figure 5 shows the 99roTc- sulfur colloid liver scan with a large filling defect because of hepatoma in the right lobe. The 67Ga scan of the liver appears to be entirely normal with homogeneous distribution of the radiogallium throughout its substance. In the right neck, how ever, there is a previously undiagnosed metastatic node (arrow) in the deep cervical lymph node chain, which is the only abnormality on the gallium photo- scan. The hepatoma actively concentrates B7Ga in the liver and the neck, but the hepatic primary could not be diagnosed because the normal liver tissue also accumulates activity as seen in Fig. 1. Suzuki and others have reported that tumor uptake of 67Ga was indistinguishable from normal liver uptake in 8 out of 19 cases of hepatic with satisfactory scans (75). The kidneys have the greatest activity in the body during the first day after a gallium injection; by the time of scanning, concentration has fallen greatly (73). Hayes had shown excellent visualization of the FIG. 5. ' '"Te sulfur colloid liver scan on left shows large mass kidneys in a rat scanned at 1 hr with 88Ga (76). lesion in patient with hepatoma. Anterior Go scan on right shows uniform uptake in liver and tumor. In neck also takes However, the kidneys normally do not appear on the up gallium (arrow). 47—72-hrhuman scan. We have observed definite renal activity in malig able to manually express a small amount of milk nant involvement of the kidneys as well as acute from both breasts. Concentration of 67Ga was meas ured at 90 and 120 hr after injection and found to be approximately 70 nCi/ml, indicating that 67Ga in appreciable amounts was being excreted in the milk. The breast is also a common site of myeloblas- tomas, which may mimic physiologic uptake. The uptake of gallium in the left breast of the patient in Fig. 2 was a result of myeloblastoma. Involvement of this degree should not be confused with physiologic uptake in the stimulated breast, which is usually symmetrical even when less prominent. Abdomen. Gallium-67 is normally concentrated within the liver and spleen, but other intra-abdominal structures are normally not seen (Fig. 1). On the posterior view the spine and sacrum are prominent. The most common problem of photoscan inter pretation in the abdomen is the presence of 67Ga within the bowel. Figure 4 shows the abdomen of a patient in whom accumulation of 87Ga was so dense that no interpretation was possible in the region of the abdomen. The entire outline of the colon can be seen including cecum, ascending, transverse, and descending portions. If the cleansing of the bowel has been inadequate, interpretation of any abnor mality in the abdomen should be made with great care. The physiologic concentration of gallium in the FIG. 6. Posterior '^Go scon of 54-year-old mole with Hodgkin's disease involving both kidneys as well as bones, liver, and wide liver may interfere with the diagnosis of malignant spread lymph nodes.

Volume 14, Number 4 211 LARSON, MILDER, AND JOHNSTON

involvement (arrows) was noted after the 67Ga scan showed uptake in these regions. This must be dif ferentiated from activity in the site of 67Ga injection.

LYMPH NODE CORRELATION An understanding of the regional distribution and scan appearance of lymph node groups is of signifi cant importance to 87Ga whole-body scanning in lymphoma and leukemia. Figure 9 is an anterior photoscan of a patient with lymphosarcoma and widespread involvement of many lymph node chains. Particularly well shown in this patient is the left infraclavicular chain which is contiguous medially with the left peritracheal and supraclavicular lymph node groups. Laterally, the infraclavicular group A ** blends into the axillary lymph nodes. Although in this case the peritracheal and para-aortic lymph node chains are distorted by considerable enlargement, it is still possible to see the characteristic left and right orientation of these lymph node groups. In the ab domen, the right para-aortic lymph node chain sends a branch across the midline to form the left common ; R iliac lymph node chain. Involvement of the external iliac, femoral, and inguinal lymph nodes is also seen FIG. 7. Normal and abnormal ' 'Go uptake in epiphyses of in this patient. Care must be taken to insure adequate long bones is shown by these scans. On right is scan of 12-year- old patient with Ewing's sarcoma and physiologic uptake in bones due to rapid growth. On left is scan of 53-year-old patient with leukemia showing similar localization.

pyelonephritis and nephrolithiasis. Figure 6 shows the 48-hr scan of a patient with proven Hodgkin's disease involving the kidneys. Intense localization occurs in both kidneys. Extremities. The concentration of 87Gais normally greatest in the epiphyseal region of the long bones, appearing in the shoulders, elbows, and knees. This may be particularly prominent in children with rapidly growing bones as shown by the scan on the right in Fig. 7 of a 12-year-old girl with Ewing's sarcoma of the right ilium. Occasionally such normal concentration may be confused with the increased concentration around the knees and distal extremi ties seen in the patieint with leukemia. Figure 7, on the left, shows a 53-year-old man with chronic myelogenous leukemia in blast crisis. The increase in radionuclide is not confined to the epiphyses but occupies the entire distal femur and proximal tibia. The reason for this concentration in such patients , is not known, but it does appear to correspond to the most active site of the functioning marrow in such patients (77). A pattern of specific concentration of radionuclide is seen in malignant involvement of the epitrochlear FIG. 8. Posterior "TGa scan of 27-year-old woman with Hodg nodes. Figure 8 shows a 53-year-old obese woman kin's disease involving epitrochlear nodes. There is also normal with lymphosarcoma whose bilateral epitrochlear uptake in tips of both scapulae.

212 JOURNAL OF NUCLEAR MEDICINE INTERPRETATION OF THE B7Ga PHOTOSCAN

fers from other bone scans in showing more soft tissue background and less distal long bones. In contrast to 1SF, the bladder is not seen as a route cervical of excretion, but various other secretory organs— iupraclavicular Infraclavicular such as the lacrimal, salivary, and mammary glands —may be seen.

Paratrachea Familiarity with the scan projection of the various Axillary lymph node groups, as described here, is also impor Bronchia Hilar tant. The lymph nodes are normally not visualized on 87Ga scans; their appearance is an indication of Celiac disease. In this series lymph node visualization did ra-aortic (lumbar) not occur with benign reactive hyperplasia. Uptake in lymph node areas was from a tumor in most cases Common iliac and suppurative infection in a few. It is often impossible to differentiate neoplastic External Iliac from inflammatory lesions on the scan alone. This requires correlation with the patient's history and Inguinal Femoral other diagnostic studies. We have not observed gal lium uptake in benign tumors. When there is uncertainty about a focus of ac tivity, lateral views will frequently help separate the normal structures from lymph node groups. Other sources of data are also required. These include the patient's history, particularly the age, hormonal status, localizing symptoms, and bowel movements before scan. Physical examination may confirm pal pable nodes or masses seen. Correlation with radio graphs is also of help. However, it should be remem FIG. 9. Commonly visualized lymph node groups are shown on bered that the may provide the first anterior GJ scan of woman with widespread lymphosarcoma. evidence of a malignant lesion before it is detected by physical examination or . A sus bowel cleansing when interpreting pelvic nodes. The epitrochlear node group, not seen on this patient, is pected lesion that cannot be shown to be a normal variant should be an indication for further study to shown in Fig. 8. include plain x-rays, , and other radio- In a number of cases we have observed gallium isotopie procedures. localization in mediastinal and epigastric lymph nodes before radiographie evidence of disease. These REFERENCES findings were subsequently supported by histologie /. EDWARDSCL, HAYES RL: Scanning malignant neo or radiographie findings or response to therapy. plasms with gallium 67. JAMA 212: 1182-1190, 1970 2. EDWARDSCL. HAYESRL: Tumor scanning with "Ga- DISCUSSION citrate. i NucíMed 10: 103-105, 1969 Brief reports of the "normal" appearance of the 3. VAIDYA SG, CHAUDHRIMA. MORRISON R, et al: Lo calisation of gallium-67 in malignant neoplasms. Lancet 2: gallium scan have appeared in the literature (18,19). 911-914, 1970 However, as described in this report, there are many 4. WINCHELL HS, SANCHEZ PD, WATANABE CK, et al: variations on the normal pattern. These may appear Visualization of tumors in humans using "7Ga-citrate and in the absence of disease under the influence of vari the Anger whole-body scanner, scintillation camera, and tomographic scanner. J NucíMed 11: 459-466, 1970 ous physiologic phenomena such as lactation and 5. LANGHAMMERH, GLAUBITT G, GREBE SF, et al: 67Ga puberty. Neoplastic and inflammatory lesions may for tumor scanning. J NucíMed 13: 25-30, 1972 cause gallium uptake that closely resembles these 6. HIGASI T, NAKAYAMA Y, MURATA A, et al: Clinical normal patterns. evaluation of "Ga-citrate scanning. J NucíMed 13: 196-201, A thorough knowledge of all the usual and variant 1972 localizations of gallium is necessary for the most re 7. LARSON SM, GRAFF KS, TRETNER IH, et al: Positive liable interpretation. In normal patients, 87Ga-citrate gallium-67 photoscan in myeloblastoma. JAMA 222: 321- acts as a bone scanning agent similar to 1KFand 8SSr 323, 1972 S. PINSKY SM, HOFFER PB, TURNER DA, et al: Place with localization in the axial skeleton and the epiph- of ^Ga in the staging of Hodgkin's disease. J NucíMed 12: yses of the long bones. The normal r>TGascan dif 385, 1971

Volume 14, Number 4 213 LARSON, MILDER, AND JOHNSTON

9. BRUNERHD. HAYESRL, PERKINSONJD: Preliminary 14. LARSON SM, SCHALL GL: Gallium-67 concentration data on gallium"7. 61: 602-612, 1953 in human breast milk. JAMA 218: 257, 1971 10. BRUCER M, ANDREWS G A, BRUNER HD: A study 15. SUZUKI T, HONJO I, HAMAMOTO K, et al: Positive of gallium^. Radiology 61: 534-543, 1953 scintiphotography of cancer of the liver with Gae7-citrate. //. HARTMANRE, HAYES RL: The binding of gallium Amer J Roentgen 113: 92-103, 1971 and indium by blood serum proteins. In 1967 Research 16. HAYES RL, CARLTON JE, BYRD BL: Bone scanning Report, Medical Division. Oak Ridge Associated Univer with galHum-68: a carrier effect. J NucíMed 6: 605-609, sities, ORAU-106, Oak Ridge, 1967 1965 12. EDWARDSCL, HAYES RL, NELSON B, et al: Radio 17. LARSON SM, NELP WB: The radiocolloid bone mar active gallium uptake in tumors. In 1969 Research Report, row scan in malignant disease. J Surg Oncol 3: 685-697, Medical Division, Oak Ridge Associated Universities, 1971. ORAU-110, Oak Ridge, 1969 18. SMALL RC, BENNETT LR: Normal 67Ga scan. J Nucí 13. NELSON B. HAYES RL, EDWARDSCL, et al: Distribu Med 12: 394, 1971 tion of gallium in human tissues after intravenous admin 19. EDWARDSCL, HAYES RL, NELSON B: The "normal" istration. J NucíMed 13: 92-100, 1972 "TGa scan. J NucíMed 13: 428, 1972

Accepted Articles To Appear in Upcoming Issues

""I Triolein Absorption Test (Letter to the Editor). Accepted 10/30/72. Quality Control of Kits (Letter to the Editor). A. H. Smith and C. J. Hayter Accepted 12/7/72. Computer-Aided Statistical Analysis of the Scintillation Camera M. W. Billinghurst Irnl-Hippuran Renogram. Accepted 11/8/72. Author's Reply to Letter to the Editor. Accepted 12/7/72. A. Halko, G. Burke, A. Sorkin. and J. Enenstein H. J. Dworkin Brain Scan in Schilder's Disease (Case Report). Accepted 11/8/72. New Radiopharmaceutical for Combined Lung-Liver Scan—Prelimi S. D. Weisbaum and E. S. Garnett nary Experiment in Animals (Concise Communication). Accepted 1:"I Triolein Absorption Test (Letter to the Editor). Accepted 11/9/72. 12/7/72. Aaron P. Sanders Tapan K. Chaudhuri, Tuhin K. Chaudhuri, and James H. Christie Radionuclide in the Diagnosis of Cerebrovascular Dis Localization of Technetium"""1 in the Choroid Plexus of the Fourth ease. Accepted 11/9/72. Ventricle (Case Report). Accepted 12/7/72. Satish G. Jhingran and Philip C. Johnson Raymundo T. Go and John J. Ptacek Reduction in Scan Time with Minifìcation(Letter to the Editor). Distribution of "C-Isoxazole in Adrenals, Ovaries, and Breast Car Accepted 11/19/72. cinoma. Accepted 12/14/72. D. C. Barker Ung Y. Ryo, and William H. Beierwaltes Uptake of *7mSr By Liver Metastasis from Carcinoma of Colon (Case Focal latrogenic Increased Radiocolloid Uptake on Liver Scan (Case Report). Accepted 11/29/72. Report). Accepted 12/14/72. Raymundo T. Go, Tapan K. Chaudhuri. Tuhin K. Chaudhuri, and Herbert D. Heibig James H. Christie i»mjcPertechnetate Transport in Man: Absorption After Subcutane Kit for Carrier Free Sodium '«I-Iiodide VIII. Accepted 11/29/72. ous and Oral Administration Secretion into Saliva and Gastric Juice. Richard M. Lambrecht. Elinor Norton, and Alfred P. Wolf Accepted 12/29/72. Compromise in K"'SrBone Scanning (Reply to Letter to the Editor). Marguerite T. Hays Accepted 11/29/72. Radiopotassium-38 for In Vivo Studies of Dynamic Processes (Pre P. Braunstein. J. G. Hernberg. and R. Chandra liminary Note). Accepted 12/29/72. Evaluation of Serum Thyroxine by Radioimmunoassay. Accepted William G. Myers 11/29/72. Caval-Portal Shunting as a cause of a Focal Increase in Radiocolloid C. Beckers. C. Cornette and M. Thalasso Uptake in Normal (Concise Communication). Accepted Two alternate Techniques of Labeling Iron-free Albumin Microspheres 12/29/72. with »i»Tcand '""In (Concise Communication). Accepted 11/30/72. Donald L. Holmquest and John A. Burdine P. Raban, V. Gregora, J. Sindelar. J. Alvarez-Cervera Radionuclide Demonstration of Spinal Durai Leaks (Case Report). Evaluation of Myocardial Perfusion After Intracoronary Injection of Accepted 12/29/72. Radiopotassium. Accepted 11/30/72. Arie L. Liebeskind. David A. Herz, Alan D. Rosenthal, and B. Leonard Holman. Per Eldh, Douglass F. Adams, Mon H. Han, Leonard M. Freeman J. Kenneth Poggernburg. and S. James Adelstein Sdntigraphic Study of Pulmonary Blood Flow Distribution in Cystic Whole-Body Immobilizer (Letter to the Editor). Accepted 11/30/72. Fibrosis. Accepted 12/29/72. A. Piepsz. P. Decostre, D. Baran James H. Larose, Winston O. Johnson, and Robert A. Harbort Normalized Resin Uptake of Displaced '-'I-T, Using Denatured More Efficient Technique for Total Body Skeletal Imaging Using Rec tilinear Scanner (Letter to the Editor). Accepted 11/30/72. Serum. Accepted 12/29/72. Marvin L. Mitchell Jacqueline L. Houston. Frank P. Castronovo, Jr. and Majic S. Use of a Probe Tvpe Colorimeter for the Continuous Monitoring of Potsaid pH In Association with the ""mBa-EDTA Infusion System. Accepted Scintiphotographic Diagnosis of Abruplio Placentae (Case Report). 1/11/73. Accepted 11/30/72. Frank P. Castronovo Morton L. Moss and Leonard M. Freeman Excess Extrahepatic Uptake of Radiocolloid Associated with Liver Extraosseous Osteogenic Sarcoma of the Small Bowel Demonstrated Abscesses (Case Report). Accepted 1/18/73. by "F Scanning (Case Report). Accepted 11/30/72. Gary F. Gates, John L. Gwinn. Fred A. Lee. and Vaughn <_. Parvez H. Shirazi, Garimella V. Rayudu. and Ernest W. Fordham Measurement of Serum Thyroxine by the TetraluteR Procedure : The Payne, Jr. Effect of 131Iand MmTc Administration. Accepted 11/30/72. Aspergillomatous Abscesses of the Brain and Thryoid (Case Report). Accepted 1/18/73. Manfred Blum, Ramesh Chandra, and William D. Drucker Robert Lisbona, Yves Lacourciere. and Leonard Rosenthall Subdurai Hematoma—What is the role of brain scanning in its Clinical Evaluation of Radioimmunoassay of Digoxin (Concise Com Diagnosis. Accepted 11/30/72. munication). Accepted 1/18/73. David L. Gilday, Geoffrey Coates, and David Goldenberg H. M. Park. I-Wen Chen, G. T. Manitasas, Andy Lowey, and Rapid Sequential Scintiphotography in the Radionuclide Detection of Eugene L. Saenger Subdural Hematomas. Accepted 11/30/72. Liver Scintiphotography as an Index of Liver Abnormality. Accepted G. Bruce Hopkins and Kai A. B. Kristensen 1/18/73. Radionuclide (Concise Communication). Accepted 12' Jack F. Mangum and Malcolm R. Powell 7/72. Measurement of Regional Area Gas Exchange (RAGE) by Perfusion George B. McDonald. Glen W. Hamilton. Robert W. Barnes. and Clearance of 1:e!Xenon from the Lung. Accepted 1/18/73. Thomas G. Rudd. D. E. Strandness. and Wil B. Nelp Scott R. Inkley and William J. Maclntyre Simple Way to Widen the Spectrometer Window in the Ohio-Nuclear Intravenous Perchlorate in Brain Scanning (Preliminary Note). Ac Scanner for «*GaScanning (Letter to the Editor). Accepted 12/7/72. cepted 1/29/73. En-lin Yen I. H. Buttfield, J. C. Wrench. N. Adiseshan. and J. Arnold

214 JOURNAL OF NUCLEAR MEDICINE