•
•
Nuclear Medicine
Gallium-67 Scintigraphy in Multisystem Malignant Melanoma 1 Frank I. Jackson, C.R.C.P.(C), T. Alexander McPherson, M.D., and Brian C. Lentle, M.D. In a prospective study of the value of gallium-67 scintigraphy in cases of multisystem malignant melanoma, 69 scans were obtained for 36 patients. No abnormality was found in 18 scans; in only 3 was there other evidence of disease. Of 54 sites of disease demonstrated by scintigraphy, 40 were correlated with other investigations: biopsy (5), surgery (7), autopsy (7), radiographic (13), or clinical (8). Metastatic melanoma was found in 37 (69 %) of the sites; no such disease was found in 3 (5.7 %). The life expectancy of patients with an abnormal scan was shorter than that of patients with a normal scan. Gallium studies reliably indicated the extent of multisystem melanoma, and are of value in clinical management. INDEX TERMS:
Melanoma
Radiology 122:163-167, January, 1977
•
• ALLlUM-67
CITRATE
(67Ga-citrate)
has
been
Table I:
extensively investigated as a radionuclide for tumor G imaging (1-7); Milder et al. (8) reported favorably upon its
Stage
I
accuracy in the detection of multisystem malignant melanoma. We attempted to confirm its usefulness in this regard.
II III
METHODS IV
As part of a phase II protocol for the treatment of Stages III and IV (TABLE I) melanoma (9), 36 consecutive patients referred to the Cross Cancer Institute were investigated by 67Ga-citrate scintigraphy at the time of referral and at subsequent intervals. A total of 69 scintlqraphs were evaluated. Liver and spleen scintigraphs with technetium-99m sulfur-colloid (99mTc-SC) were also obtained immediately preceeding the injection of 67Ga-citrate. Chest radiography with tomography of the whole lung was also performed at 3 monthly intervals. The details of our 67Ga-citrate scintigraphy technique have been previously described (10). Briefly, an Ohio Nuclear dual 12.5-cm probe rectilinear scanner is used in the minification mode. Neither contrast enhancement nor background erase is used, and scintigraphs are made to an information density of 100 counts/ern- over the liver, using the 184-keV photopeak of 67Ga. The radiation dosimetry is acceptable, as the skeleton, the critical organ, receives a dose of 1.32 rads (11). Because of colonic concentration of the radiotracer, bowel cleansing is used. The dose used is 3.0 mCi in adults. Scintigraphs are obtained 48 hours and, on occasion, 72 hours after injection. All 67Ga-citrate scintigraphs were interpreted with prior knowledge of the observers (F .I.J. or B.C.L.) restricted to the diagnosis of malignant melanoma. The findings were recorded and subsequently correlated with other evidence
Staging of Malignant Melanoma
Superficial melanoma No metastases-primary melanoma only A Intact primary melanoma B Primary melanoma locally excised C Multiple primary melanomas Local recurrence or metastases All melanotic lesions withi n 3 cm of primary site (satellosis) Regional metastases (>3 cm from primary site) A Intradermal (in transit metastases) B Regional lymph nodes AB Intradermal and regional nodes Distant hematogenous metastases A Cutaneous B VisceralC Lymph nodes A-C Combinations of the above
of disease, e.g., biopsy (5 patients), major surgery (7), autopsy (7), radiographic examination (13) and/or clinical examination (8).
MALIGNANT MELANOMA :
1.0
CENSORED SURVIVAL RATES COMPARING POSITIVE TO NEGATIVE SCAN. ~ -ve SCAN
o..,....,....,.....,_,...........,.....,......._~.,....,.. ........,......, o
4
8 12 16 MONTHS SURVIVAL
20
24
Fig. 1. A graph of censored survival rates indicates the poor survival of patients with abnormal scintigraphs compared to that of patients having normal scans (14).
1 From the Departments of Nuclear Medicine and Medicine, Dr. W. W. Cross Cancer Inst., Edmonton, Albta., Can. Accepted for publication in June, 1976. ss
163
FRANK J. JACKSON AND OTHERS
164
The patients, of whom 23 were men and 13 women, all had had pathologically proved malignant melanoma from months to years prior to this study; their age range was 25 to 78 years.
Table II:
January 1977
Negative Gallium-67 Scintigraphs
Negative gallium-67 scintigraphs No evidence of clinical disease Evidence of clinical disease*
16 patients 13 patients 3 patients
(100%) (81 %) (19%)
*Skin: two patients; axilla: one patient.
RESULTS
Of the 69 scintigraphs obtained, 18 were considered normal, and this interpretation correlated with investigative and/or clinical findings in 15; of the remaining 3 patients, 2 had cutaneous, and 1 had axillary lymph node, metastases (TABLE II). • Of 54 sites of disease demonstrated by scintigraphy, 37 (69 % ) were histologically found to be melanoma deposits. Only 3 (5.7%) of the sites were found by histological ex-
Fig. 2. Anterior projection gallium-67 citrate scintiscan of a 58-year-old woman. Diffuse uptake of radiotracer throughout the abdomen was shown at autopsy to correspond with massive deposits of tumor on the peritoneum and omentum.
amination to be apparently unrelated to such disease foci. In 15 sites of focal uptake of the radiotracer, no correlation was obtained, as biopsy or other investigations were not performed (TABLE III). That many of these sites would have been shown to contain melanoma, if investigated, is suggested by the fact that of the patients studied, those with a normal scintigraph lived an average of 10.8 months. Those with an abnormal scan at any time, however, lived an average of only 7.3 months, a significant difference (p < 0.05) (Fig. 1). The difference was analyzed by a test of censored survival (12). Of the patients with abnormal scans, 5 had a diffuse increase in uptake of the tracer in the lungs. In 1 patient, this abnormality persisted after two examinations done three months apart, and one month later was less evident. Over this same period, a single pulmonary lesion, demonstrated radiologically, was observed to regress with treatment (Fig. 4). In a second patient with a diffuse abnormal degree of pulmonary uptake, the chest radiograph, initially normal, demonstrated multiple nodules two months later. These were considered, but not proved, to be metastatic. In the light of this and our experience (13) with a patient with histologically proved interstitial pulmonary metastatic breast cancer which correlated with an abnormal 67Ga-citrate scintigraph, but with no radiographic abnormality, it appears possible that these 2 patients with abnormal scintigraphs and normal chest radiographs may have had diffuse pulmonary melanoma. Of the three false-positive sites of accumulation of radiogallium, one occurred in the pelvis and one in the lung which remained unexplained at autopsy. The third occurred in a patient in whom a hematoma developed after an inguinal node dissection; the scintigraph remained positive at this site for 5 months. At autopsy, carried out one month after the last scintigraph, no tumor was found by histological examination. Other surgical sites have been found not to be abnormal in excess of 20 days postoperatively. In one patient, unilateral abnormal uptake of 67Ga within breast tissue was found .at autopsy to correlate with a site of metastic melanoma. In view of a report of augmented relative uptake of radiocolloid in the spleen in patients with malignant melanoma (14), the liver-spleen scans obtained in this group of patients were reviewed. In only one was the normal ratio of uptake reversed, and in this patient the cause was almost certainly diffuse metastatic involvement of the liver, as three months later such metastatic disease was apparent on a repeat scan, with the lesions having presumably increased to a size permitting their resolution. Shortly thereafter the patient died with clinical and radiological evidence of disseminated disease.
Vol. '22
GA-67 SCINTIGRAPHY IN MALIGNANT MELANOMA
DISCUSSION
With the increasing interest in innovative approaches, both chemotherapeutic and immunotherapeutic, to the management of late stage melanoma, a technique of acceptable accuracy for determining tumor extent and response is important. In such a context, our findings confirm the results reported by Milder et al. (8) concerning the accuracy of the technique. Their "false-positive" incidence of 2 % compares with the 5.7% reported here. On the basis of both sets of data, a positive scintigraph must be considered highly suggestive of metastatic spread if, in an appropriate clinical setting, the limitations of 67Ga-citrate scintiscanning are considered. The most important Iimi-
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tation is the nonspecificity of localization of the radiotracer, which is known to accumulate in sites of focal inflammation (2, 15). Roth et al. (16) have found liver, bone, and brain scans, and whole body "tumor" scans (using bleomycin chelated with "'Indium) to be of no value in patients with disease we classify as Stages I, II and III. The relevance of this finding to our study is in doubt without a controlled comparison, as, for patients with several types of malignant disease, but chiefly lymphoma, 67Ga-citrate has proved superior to "'In-bleomycin (17). Moreover. our experience with "'In-bleomycin is in keeping with the evidence (18) that the indium label on this tracer dissociates in vivo from the bleomycin, so that this agent is one which cannot be
Fig. 3. Anterior and posterior projection gallium-67 citrate scintiscans of a 72-year-old man. Focal areas of uptake are demonstrated in both lungs and in the right adrenal gland (arrow). At autopsy 19 days later it was shown that these sites represented metastases of malignant melanoma.
166
FRANK
Table III:
I. JACKSON AND OTHERS
Correlation of Positive Gallium-67 Scintiscans
Positive Sites Brain Liver Bone Lung Lymph nodes Skin Peritoneal Cavity Adrenal Breast Mediastinum Face Subcutaneous Tissues Pelvis
Proved Positive
False Positive
o o o
2 3
o
1 1
12 11 1 3 1 1 1 1 1
o o o o o o o
o
37 Total positive Positive sites, pathologically proved Positive sites, false positive
53 37 3
Not Proved
o 1
o 4
4 1
o
o o 1 o
1
1 1
3
13
(100%) (70%) (5.7%)
January 1977
regarded as having been reliably characterized. The value of 67 Ga-citrate in the evaluation of patients with Stages I and " melanoma remains to be investigated. A negative 67 08_citrate scintiscan is a reliable indicator of the absence of otherwise detectable disease. This has only been untrue, in effect, in one patient with axillary node metastases; the detection geometry of a focussed-collimator rectilinear scanner is designed to provide deep "tomographic" sections, and is inappropriate for the identification of the two sites of cutaneous metastases which have been included in the three sites of false-negative findings we found. Gallium-57 citrate scintiscans are mainly of application in determining the presence of metastases within the thorax and abdomen, where other techniques are less accurate or more invasive. For 2 patients on oral BeG therapy, however, it is tempting to speculate that the treatment may have caused
Fig. 4. Anterior projection gallium-67 citrate scintiscans of a 65-year-old woman. The scintiscan on the left was obtained on admission, the middle scan 3 months later, and that on the right one month after the second scan. The improvement was mirrored in chest radiographs, which, at the same time, showed a metastatic nodule diminishing in size.
Vol. 122
GA-67 SCINTIGRAPHY IN MALIGNANT MELANOMA
an abnormal uptake of radiogallium. In one there has been increasing abnormal uptake of the tracer in the left upper abdomen while the patient remains well. This has progressed over the treatment time of one year, and is unexplained by barium examinations and colonoscopy. In the second patient, abnormal pulmonary uptake of 67Ga_ citrate was observed only while the patient was taking BCG. These findings are tabulated with those patients for whom no correlation was available, although it may be found that immunotherapy modifies the distribution of this radiotracer, further complicating the interpretation of the scintigraphs. ACKNOWLEDGMENTS: We wish to acknowledge the help of Dr. M. Grace. Director of Research and Development, for the statistical analysis; Mrs. Mary Laschowski, for typing the manuscript; Ms. M. Chen, for assistance in analysis of the data; and Mr. Karl Liesner, for preparing the illustrations.
Department of Nuclear Medicine Dr. W. W. Cross Cancer Institute 11560 University Ave. Edmonton, Alberta, Can. T6G 1Z2
REFERENCES 1. Johnston G, Benua RS, Teates CD, et al: 67Gacitrate imaging in untreated Hodgkin's disease: preliminary report of cooperative group. J Nucl Med 15:399-403, Jun 1974 2. Milder MS: Malignant melanoma. [In]: Johnston GS, Jones eds: Atlas of Gallium-67 Scintigraphy: A New Method of Radionuclide Medical Diagnosis. New York, Plenum, 1974, ch 10, pp 149-160 3. Greenlaw RH, Weinstein MB, Brill AB, et al: 67Ga-citrate
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imaging in untreated malignant lymphoma: preliminary report of cooperative group. J Nucl Med 15:404-407, Jun 1974 4. DeLand FH, Sauerbrunn BJL. Boyd C, et al: 67Ga-citrate imaging in untreated primary lung cancer: preliminary report of cooperative group. J Nucl Med 15: 408-411, Jun 1974 5. Edwards ci, Hayes RL: Tumor scanning with 6 7Ga citrate. J Nucl Med 10:103-105, Feb 1969 6. Berelowitz M, Blake KCH: 67Gallium in the detection and localization of tumors. S Afr Med J 45:1351-1359, 1971 7. Langhammer H, Glaubitt G, Grebe SF, et al: 67Ga for tumor scanning. J Nucl Med 13:25-30, Jan 1972 8. Milder MS, Frankel RS, Bulkley GB, et al: Gallium-67 scintigraphy in malignant melanoma. Cancer 32:1350-1356, Dec 1973 9. Luce JK, McBride CM, Frei E III: Melanoma. [in]: Holland JL, Frei E 111, eds: . Cancer Medicine. Philadelphia, Lea & Febiger, 1973, ch XXIX, pp 1.832-1,843 10. Jackson FI, Dierich HC, Lentle BC: Gallium-67 citrate scintiscanning in testicular neoplasia. J Canad Assoc Radiol 27:84-88, 1976 11. MIRD/Dose Estimate Report No.2. J Nucl Med 14:755-756, Oct 1973 12. Burdette WJ, Gahan EA: Planning and Analysis of Clinical Studies. Springfield, III, Thomas, 1970, pp 41-46 13. Band PR, Lentle BC, Amy R, et al: Radiologically occult pulmonary Iymphangitic carcinomatosis from breast carcinoma. Ann Intern Med (In press) 14. Goldman AB, Braunstein P, Song C: Augmented splenic uptake of radiocolloid in patients with malignant melanoma. Lancet 1:460, 1974 15. Lavender JP, Lowe J, Barker JR, et al: Gallium-67 citrate scanning in neoplastic and inflammatory lesions. Br J Radiol 44: 361-366, May 1971 16. Roth JA, Eilber FR, Bennett LR, et al: Radionuclide photoscanning: usefulness in preoperative evaluation of melanoma patients. Arch Surg 110:1,211,1975 17. Patterson AHG, Taylor DM, McCready VR: A clinical comparison of the tumour-imaging radiopharmaceuticals 67Gallium citrate and 111lndium-labelled bleomycin. Br J Radiol 48:832-842, 1975 18. Hoffer PB, Gottschalk A: Tumor scanning agents. Semin Nucl Med 4:305-316, 1974
