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Radioisotope scans in the evaluation of metastatic bronchogenic carcinoma
Radioisotope scans in the evaluation of metastatic bronchogenic carcinoma In this study, we evaluated the accuracy of radioisotope scans in detecting metastatic lesions in patients witli bronchogenic carcinoma. To be included in the study, the patient had to have undergone liver, brain, and/or bone scanning witliin 10 weeks of autopsy. Other means of evaluating these organs for metastatic involvement were used as well. The liver was checked by palpation and by determination of enzyme levels. A history, physical examination, and neurologic examination were used to establish the possibility of brain metastases. For studying bones, a history, physical examination, and conventional x-ray films were employed. Result-: of the scans and other tests were compared with findings at autopsy, and accuracy rates for each method of study were determined.
A. C. Gutierrez, M.D.,* R. G. Vincent, M.D.,** S. Bakshi, M.D.,*** and H. Takita, M.D.,**** Buffalo, N. Y.
JL n the past two decades, radioisotope scans have found widespread application in the detection of metastatic malignant lesions. 1 "' Scanning techniques were originally applied to the detection of hepatic metastases by Strirret1 in 1954. A number of works have since been published expressing varying degrees of enthusiasm for the procedure. 11 " The extremes are well represented by Hayes" and Rosenthal.' The former recommended that liver scans be employed routinely before treatment of patients with malignant disease, whereas the latter suggested that the routine use of liver scans in these patients be discouraged. The design of these studies as well as their reported accuracy rates varied considerably. Conn,in 1968; criticized five published reports, mentioning three major drawbacks: the nonrandom manner of collecting data, the lack of definition of the time interval beFrom Roswell Park Memorial Institute, Buffalo, N. Y. 14203. Received for publication Dec. 5, 1974. *Clinical Research Clinician, Thoracic Surgery. ♦♦Chief, Thoracic Surgery. ♦♦♦Associate Chief, Nuclear Medicine. ♦♦♦♦Associate Chief, Thoracic Surgery.
934
tween scanning and examining the liver, and the utilization of surgical findings as proof of absence of hepatic malignancy. Similar attempts to evaluate the accuracy of brain 1 "-' and bone scans2'1"-' in the detection of metastatic lesions have also been reported by a number of investigators. The design of these studies and their reported accuracy rates also varied. The present study is concerned with evaluating the accuracy of radioisotope scans in the detection of liver, brain, and bone metastases in patients with bronchogenic carcinoma. The criticisms of earlier reports voiced by Conn were heeded whenever possible with the materials at hand. A 3 year period was fixed, and all patients with bronchogenic carcinoma who were subjected to a liver, brain, or bone scan in our institute within this period were considered for the study, regardless of whether metastatic disease in the organ in question was suspected or unsuspected clinically. Furthermore, the maximum time interval between scanning and examination of the organ in question was rigidly set at 10 weeks. Finally, only autopsy verification was accepted as proof
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of the presence or absence of metastatic disease. Materials and methods All cases of bronchogenic carcinoma evaluated at the Roswell Park Memorial Institute in the 3 year period from January, 1971, to December, 1973, were reviewed. For the patient to be included in our study, liver, brain, and/or bone scan had to have been done within 10 weeks of autopsy. The scanning techniques used were as follows. Liver scan. In this series all of the liver scintiscans were performed exclusively with 1.5 to 2.0 mCi of 99mTc-labeled sulfur colloid on one of the following instruments; a 5 inch Picker dual-head scanner, a 5 inch Ohio Nuclear dual-head scanner, or a Nuclear-Chicago PhoGamms HP. Both of the scanners were equipped with a 5 inch focusing collimator. The Picker scanner was mounted with medium-energy Vi inch resolution collimators and the Ohio Nuclear scanner with low-energy Vi inch resolution collimators. Brain scan. Brain scans were performed either on a dual-head Picker magna scanner equipped with 5 inch focus, medium-energy collimators or on a gamma camera. Each patient received an oral dose of potassium perchlorate, and 1 hour later 15 mCi of "'"Tc-labeled sodium pertechnetate was administered intravenously. Four conventional views of the brain were obtained approximately 2I/2 hours after the administration of the radionuclide medium. Bone scan. Bone scanning was performed on the Ohio Nuclear dual-probe rectilinear scanner in the anterior and posterior projections extending from the level of the cervical spine to the middle femurs in a normal mode or in a 2:1 minification. The agents employed included the three presently available phosphate compounds labeled with !,!lmTc Sn-pyrophosphate: 99mTc Sn ethane-1-hydroxy-l-diphosphonate, 99mTc Sn polyphosphate, and 18F-sodium fluoride. The tracer doses of 99,nTc-labeled phosphate compounds and 18F-sodium fluoride were
15 and 5 mCi, respectively. The scans were obtained 3 to 4 hours after administration of the dosage. Results A total of 47 patients with bronchogenic carcinoma had liver scans within 10 weeks of autopsy during the time period of this study. Of these, 24 (52 per cent) had negative scans and negative autopsy findings, whereas 5 (10 per cent) had positive scans and positive autopsy findings. The liver scans were accurate in 29 (62 per cent) of the cases. Two (4 per cent) had positive scans and negative autopsy findings, whereas 16 (34 per cent) had negative scans and positive autopsy findings. The liver scans were inaccurate in 18 cases (38 per cent). A total of 30 patients with bronchogenic carcinoma had brain scans within 10 weeks of autopsy during the time period of this study. Of these, 19 (63 per cent) had negative scans and negative autopsy findings, whereas 7 (23 per cent) had positive scans and positive autopsy findings. The brain scans were accurate in 26 (87 per cent) of the cases. There were no patients with positive scans and negative autopsy findings. Four (13 per cent) had negative scans and positive autopsy findings. The brain scans were inaccurate in 4 cases (13 per cent). Only 9 patients with bronchogenic carcinoma had bone scans within 10 weeks of autopsy (with appropriate bone sampling) during the time period of this study. Of these, 3 (33 per cent) had negative scans and negative autopsy findings, whereas 5 (56 per cent) had positive scans and positive autopsy findings. The bone scans were accurate in 8 (89 per cent) of the cases. There were no patients with positive scans and negative autopsy findings. There was 1 case (11 per cent) of a negative scan and positive autopsy finding. The bone scans were inaccurate in 11 per cent of the cases. Other aspects of the clinical assessment of these patients were also evaluated. Levels of alkaline phosphatase, serum glutamic ox-
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aloacetic transaminase (SGOT), and lactic dehydrogenase (LDH) were studied. Of the 47 patients with liver scans, 11 (23 per cent) had normal enzyme levels and negative autopsy findings, whereas 18 (38 per cent) had one or more elevated enzymes and positive autopsy findings. The enzyme studies were accurate in 61 per cent of cases. Fifteen patients (33 per cent) had elevation of one or more enzymes and negative autopsy findings. The enzymes were inaccurate in 18 (39 per cent) of the cases. The findings on liver palpation were evaluated. Twenty-four patients (51 per cent) had nonpalpable livers and no liver metastases on autopsy; 11 (23 percent) had palpable livers and did have liver metastases on autopsy. Palpation of the liver was accurate in 74 per cent of cases. Two patients (4 per cent) had palpable livers and no hepatic metastases; whereas 10 (21 per cent) had nonpalpable livers and did have liver metastases. Palpation of the liver was inaccurate in 12 (25 per cent) of the cases. The clinical evaluation of brain metastases by history, physical examination, and neurologic examination was evaluated. Seventeen (57 per cent) had a negative clinical assessment and negative autopsy findings, whereas 10 (33 per cent) had a positive clinical assessment and positive autopsy findings. The clinical assessment by history plus physical and neurologic examination was accurate in 27 (90 per cent) of the cases. There were no patients with positive clinical assessment and negative autopsy findings; but there were 3 patients (10 per cent) with negative clinical assessment and positive autopsy findings. The clinical assessment of brain metastases by history and physical and neurologic examination was inaccurate in 3 (10 per cent) of the cases. The clinical evaluation of bone metastases by history, physical examination, and conventional x-ray films was elevated. Three (33 per cent) had negative clinical evaluations and negative autopsy findings; whereas 5 (56 per cent) had positive clinical
Thoracic and Cardiovascular Surgery
evaluation and positive autopsy findings. The clinical evaluation for osseous metastases was accurate in 8 cases (89 per cent). There were no patients with positive clinical evaluation and negative autopsy findings, but there was 1 patient (11 per cent) with a negative clinical evaluation and positive autopsy finding. The clinical evaluation for osseous metastases was inaccurate in 11 per cent of cases. Discussion Liver scans were found to have an overall accuracy rate of 62 per cent in the present study. Conn- reviewed the separate works of Nagler," Gollin,1" Czerniak,"1 McAfee,' and Baum," representing a total of 827 cases, and found an over-all accuracy rate of 65 per cent. These studies were criticized by Conn on the three items in their study designs mentioned previously. Nevertheless, a close correlation of over-all accuracy does exist between these studies and our study. When reviewing these earlier publications, one should also keep in mind that accuracy rates computed solely from true positive and false negative results are considerably different from over-all accuracy rates, which include ttrue negative and false positive rates as well. It is the over-all accuracy rate that should be used when evaluating a procedure for routine use. Evaluation of enzyme levels (SGOT, alkaline phosphatase, and LDH) provided an over-all accuracy rate of 61 per cent in this study when elevation of one, two, or all three enzymes is considered suggestive of hepatic metastases. Other investigators have also reported less than impressive accuracy rates when considering these enzymes on an individual basis. Gollin,1" for instance, reported SGOT, alkaline phosphatase, and LDH to be 58, 76, and 60 per cent accurate, respectively. Watson" studied 36 patients with proved hepatic metastases and found normal liver function tests in 52 per cent. When a combination of enzymes is used, over-all accuracy rates are improved.1' Ten patients in our study were found to have elevated levels of all three
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Positive Clinical Evaluation Accurate Clinical Evaluation
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0Accurate © Clinical © 0 Evaluation © © 0 0 0 0 0 0 © © + © © © © ©
Inaccurate Clinical Evaluation
ff) True Positive Scan
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(—A True Negative Scan 0
©
-|- False Positive Scan False Negative Scan
Fig. 1. Accuracy of clinical evaluation for liver metastases. Hepatomegaly and/or elevation of all three enzymes studied are compared to liver scan accuracy based on autopsy findings. enzymes studied (SGOT, alkaline phosthe above criteria probably will not be helpphatase, and LDH), and all proved to have ful. On the other hand, 15 patients had a hepatic metastases. The over-all accuracy positive clinical evaluation, and of these 2 rate obtained by using elevation of all three proved to be free of metastases to the liver. enzymes as an index of hepatic metastases However, in this group, there were 8 inis 75 per cent. accurate scans, all false negative, and there were 5 positive scans which were all true Hepatomegaly by palpation as an index positive. We therefore feel that patients with of the presence of hepatic metastases was 74 a positive clinical evaluation by hepatoper cent accurate, over-all, in our series. megaly and/or elevation of all three enMcAfee,1 Watson," and Fenster,1T reporting only on patients with proved hepatic zymes should be studied via liver scans. metastases, reported accurate correlation in If the scan is positive, it serves as strong clinical confirmatory evidence of hepatic 52, 57, and 89 per cent, respectively. metastases. If the scan is negative, it has Ozarda,1- working on autopsy material, relatively less clinical significance, and the found that 30 per cent of subjects with liver patient should probably have a limited surmetastases had near normal liver size. gical exploration for more accurate assessWhen hepatomegaly by palpation and/or ment of the liver. elevation of all three enzymes is considered indicative of hepatic metastases, the Use of this plan exclusive of surgical exover-all accuracy rate improves to 77 per ploration provides an 87 per cent accuracy cent (Fig. 1). According to these criteria, rate if the clinical evaluation is positive. 32 patients had a negative clinical evaluaIf the clinical evaluation is negative, the tion, and 8 proved to have hepatic metasaccuracy rate is 75 per cent. Over-all actases. However, in this group, 10 liver scans curacy with this plan used exclusive of were inaccurate, indicating that scanning surgical exploration is 79 per cent. patients with negative clinical evaluation by Therefore, it appears that routine use of
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Positive Clinical Evaluation Accurate Clinical Evaluation
© ©
Inaccurate Clinical Evaluation
© © © © © © Negative Clinical Evaluation
Accurate Clinical Evaluation
© © © ©
© 0 0 © © © e © © © © © ©
Inaccurate Clinical Evaluation
- © CE\ True Positive Scan £ ^ True Negative Scan —J- False Positive Scan
— False Negative Scan Fig. 2. Accuracy of clinical evaluation for brain metastases by history, physical examination, and neurologic examination is compared to brain scan accuracy based on autopsy findings.
liver scanning in these patients can be justified only if an over-all accuracy rate greater than 79 per cent can be achieved. The actual accuracy rate (61 per cent) by present scanning techniques is inadequate for routine use. False negative scans (34 per cent) account for the bulk of errors in evaluation by scanning. Of 16 patients with false negative scans, 13 proved to have lesions less than 2 cm. in diameter. This finding is supported by that of Castagna," who found that 7 of 12 patients with false negative results in his series had lesions less than 2 cm. in diameter. Furthermore, Ozarda12 demonstrated that the maximum diameter of liver metastases was less than 2 cm. in 31 per cent of 150 autopsy subjects with liver metastasis. Therefore, until such time as hepatic scanning techniques are refined to consistently detect lesions less than 2 cm. in diameter, routine use is not warranted. Positive scans are very useful as strong confirmatory evidence in patients with a positive clinical evaluation by hepatomegaly and/or elevation of all three enzymes studied.
The over-all accuracy rate for brain scans was 87 per cent in this study. Witcofski,18 Burrows,71 and Goodrich,1" reporting on patients with proved brain metastases, found brain scan accuracy rates of 82, 93, and 87 per cent, respectively. In the present series, there were no false positive brain scans. There were four false negative brain scans, and in all of these the lesions were 2.5 cm. or less in diameter. This result correlates with the findings of Boiler,20 who determined that lesions less than 2.7 cm. in diameter (10 c.c. in volume) cannot be consistently detected by brain scans. Nevertheless, the 87 per cent accuracy rate by brain scan alone is impressive. The clinical evaluation of brain metastases by history, physical examination, and neurologic examination also has a remarkable over-all accuracy rate of 90 per cent (Fig. 2). Goodrich,19 reporting on 118 cases of proved brain tumor, found an accuracy rate of 93 per cent. Ten patients had a positive clinical evaluation for brain metastases by history, physical examination, and neurologic examination. All proved to have brain metastases on autopsy. However, 2 of this group had
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carcinoma
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Positive Clinical Evaluation Accurate Clinical Evaluation
Inaccurate Clinical Evaluation
— © © © e Negative Clinical Evaluation Accurate Clinical Evaluation
e e e
Inaccurate Clinical Evaluation
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Q\
True Positive Scan
^ ^ True Negative Scan -f- False Positive Scan False Negative Scan
Fig. 3. Accuracy of clinical evaluation for bone metastases by history, physical examination, and conventional radiogram is compared to bone scan accuracy based on autopsy findings.
false negative brain scans. It would therefore appear that when the clinical evaluation is positive a negative brain scan does not contribute useful information. The remaining 8 patients had true positive brain scans. As a consequence, we believe that if the clinical evaluation is positive, a brain scan should be done. A positive brain scan in this setting is strong confirmatory evidence of brain metastases. Twenty patients had a negative clinical evaluation for brain metastases by history and by physical and neurologic examination. Seventeen of these had no brain metastases on autopsy. Of the 3 patients with false negative clinical evaluations, 2 had negative scans and 1 had a true positive scan. Had all patients with a negative clinical evaluation undergone brain scanning, the pickup rate would have been about 5 per cent. Two of 3 with brain metastases were missed on scanning. As with liver scans, the major source of errors with brain scans is the false negative results. This is due to the relative inaccuracy of brain scans in detecting lesions smaller than 2.5 cm. in diameter. The routine use of brain scans in these patients can be justified only if the technique can be refined to detect lesions considerably smaller than 2.5 cm. in diameter. Larger
lesions can be accurately evaluated by history, physical examination, and neurologic examination. Positive scans are useful in patients with a positive clinical evaluation and serve to appropriately strengthen the clinical evaluation. Bone scans provided an over-all accuracy rate of 89 per cent in this limited study. The clinical evaluation of osseous metastasis by history, physical examination, and conventional x-ray films had the same high degree (89 per cent) of accuracy as the bone scans (Fig. 3). These findings correlate well with those of Parsons,2" who concluded that when history, radiology, and biochemical changes all indicate bone metastases, a positive scan can be expected. Of the 5 patients with a positive clinical evaluation in our series, all proved to have bone metastases. The bone scans were positive in 4 of these cases. Of the 4 patients with a negative clinical evaluation, 3 had negative bone scans and 1 patient had a true positive scan. This series is too small to offer definite conclusions, but it appears that the routine use of bone scans in all these patients may not be warranted; a positive bone scan, on the other hand, can do much to strengthen a positive clinical and radiologic impression.
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Summary We reviewed all cases of bronchogenic carcinoma in a 3 year period at the Roswell Park Memorial Instiute that were evaluated by liver, brain, and/or bone scans within 10 weeks of autopsy. Liver, brain, and bone scans were accurate in 62, 87, and 89 per cent, of cases, respectively. Enzyme studies (alkaline phosphatase, SGOT, and LDH) showed accurate correlation in 61 per cent of cases. Elevation of one or two of the enzymes was not very helpful, but in all cases in which three enzymes were elevated, hepatic metastases were found at autopsy. Palpation of the liver provided a 74 per cent accuracy rate and should be afforded appropriate attention in the evaluation of all patients with bronchogenic carcinoma. When hepatomegaly and/or elevation of all three enzymes is considered indicative of hepatic metastases, the over-all accuracy rate improves to 77 per cent. Clinical assessment of brain metastases by history, physical examination, and neurologic examination was found to be 90 per cent accurate in this study. The correlation of bone scans with autopsy findings would theoretically require sampling of all bones. Even in patients with several areas of increased uptake, not all these areas are sampled in a routine autopsy. The number of cases that qualified for this part of the study is therefore small. In these cases, the clinical evaluation of osseous metastases by history, physical examination, and conventional x-ray films had the same high degree (89 per cent) of accuracy as the bone scans. A plan is suggested for evaluating patients for hepatic metastases by considering hepatomegaly and/or evaluation of all three enzymes (SGOT, alkaline phosphatase, and LDH) to be suggestive of hepatic metastases. If clinically positive, liver scans should be obtained. Positive scans are adequate evidence of hepatic metastases in these patients. An exploratory laparotomy is suggested for those with positive clinical evaluation and negative scans.
Thoracic and Cardiovascular Surgery
Similarly, brain scans are suggested when supportive evidence for a positive clinical evaluation by history, physical examination, and neurologic examination is needed. Supportive evidence is provided by a positive scan; a negative scan is of relatively less clinical importance. The evaluation for bone metastases by history, physical examination, and conventional bone radiograms had a high accuracy rate. Scans are suggested when supportive data are needed in patients with a positive clinical evaluation. In such patients, a positive scan is of significance. We wish to point out that our reported false negative rate may be higher than the actual value because of the time lapse (maximum 10 weeks, average 5 weeks) between the scans and the autopsies. It is entirely possible that metastatic lesions could have developed in this time interval. Also, of the two false positive liver scans reported, only one is unexplained, the other was due to an intrahepatic hematoma which the scan accurately assessed as a space-occupying lesion. We gratefully acknowledge the efforts of Mrs. Tona Flak in the preparation of this manuscript. REFERENCES 1 Stirret, L. A., Yuhl, E. T., and Cassen, B.: Clinical Application of Hepatic Radioactivity Surveys, Am. J. Gastroenterol. 21: 310, 1954. 2 Conn, H. O., and Elkington, S. G.: Is Hepatic Scanning Overrated? Gastroenterology 54: 135, 1968. 3 Rosenthal, S., and Kaufman, S.: The Liver Scan in Metastatic Disease, Arch. Surg. 106: 656, 1973. 4 McAffee, J. G., Ause, R. G., and Wagner, H. N., Jr.: Diagnostic Value of Scintillation Scanning of the Liver, Arch. Intern. Med. 116: 95, 1965. 5 Johnson, P. M., and Sweeney, W. A.: The False-Positive Hepatic Scan, J. Nucl. Med. 8: 451, 1967. 6 Hayes, T. P., Davis, L. W., and Raventos, A.: Brain and Liver Scans in the Evaluation of Lung Cancer Patients, Cancer 27: 362, 1971. 7 Jhingran, S. G., Jordan, L., Jahns, M. F., and Haynie, T. P.: Liver Scintiscans Compared With Alkaline Phosphatase and BSP Determination in the Detection of Metastatic Carcinoma, J. Nucl. Med. 12: 227, 1971.
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8 Ludbrook, J., Slavotinek, A. H., and Ronai, P. M.: Observer Error in Reporting on Liver Scans for Space Occupying Lesions, Gastroenterology 62: 1013, 1972. 9 Watson, A., and Torrance, H. B.: Liver Scanning in Surgical Practice, Br. J. Surg. 57: 405, 1970. 10 Gollin, F. F., Sims, J. L., and Cameron, J. R.: Liver Scannning and Liver Function Tests, J. A. M. A. 187: 111, 1964. 11 Nagler, W., Bender, M. A., and Blau, M.: Isotope Photoscanning of the Liver, Gastroenterology 44: 36, 1963. 12 Ozarda, A., and Pickren, J.: The Topographic Distribution of Liver Metastases: Its Relation to Surgical and Isotope Diagnosis, J. Nucl. Med. 3: 149, 1962. 13 Castagna, J., Benfield, J. R., Yamada, H., and Johnson, D. E.: The Reliability of Liver Scans and Function Tests in Detecting Metastases, Surg. Gynec. Obstet. 134: 463, 1972. 14 Baum, S., Silver, L., and Vouchides, D.: The Recognition of Hepatic Metastases Through Radioisotope Color Scanning, J. A. M. A. 197: 1966. 15 Freeman, L. M., Meng, C. H., Johnson, P. M., Bernstein, R. G., and Bosniak, M. A.: False Positive Liver Scans Caused by Disease Processes in Adjacent Organs and Structures, Br. J. Radiol. 42: 651, 1969. 16 Lin, S., Mansfield, C. M., Kramer, S., and Southard, M. E.: Liver Scanning in Patients With Suspected or Proven Cancer, Am. J. Roentgenol. Radium Ther. Nucl. Med. 108: 98, 1970. 17 Fenster, L. F., and Klatskin, G.: Manifestations of Metastatic Tumors of the Liver, Am. J. Med. 3 1 : 238, 1961. 18 Witcofski, R. L., Maynard, C. D., and Roper, R. J.: A Comparative Analysis of the Accuracy of the Technetium-99m Pertechnetate Brain Scan: Followup of 1,000 Patients, J. Nucl. Med. 8: 187, 1967.
19 Goodrich, J. K., and Tutor, F. T.: The Isotope Encephalogram in Brain Tumor Diagnosis, J. Nucl. Med. 6: 541, 1965. 20 Boiler, F., Patten, D. H., and Howes, D.: Correlation of Brain Scan Results With Neuropathological Findings, Lancet 1: 1143, 1973. 21 Burrows, E. H.: False Negative Results in Brain Scanning, Br. J. Med. 1: 473, 1972. 22 Shaw, R. A., Dusault, L. A., and Wilner, H. J.: False Negative Brain Scans Excluding Those Found in Cerebral Infarction, Radiology 99: 369, 1971. 23 Holman, B. L.: The Brain Scan, Postgrad. Med. 54: 143, 1973. 24 Legge, D. A., Newlon Tauxe, W., Pugh, D. G., and Utz, D. C : Radioisotope Scanning of Metastatic Lesions of Bone, Mayo Clin. Proc. 45: 755, 1970. 25 Merrick, M. V.: Detection of Skeletal Metastases: A Comparison of Three Radioisotopic Techniques Using 1 S F and Radiology, Br. J. Radiol. 46: 968, 1973. 26 Galaski, C. S. B., and Doyle, F. H.: The Detection of Skeletal Metastases From Mammary Cancer. A Regional Comparison Between Radiology and Scintigraphy, Clin. Radiol. 23: 295, 1972. 27 Charkes, N. D., Sklaroff, D. M., and Young, I.: A Critical Analysis of Strontium Bone Scanning for Detection of Metastatic Cancer, Am. J. Roentgenol. Radium Ther. Nucl. Med. 96: 647, 1966. 28 DeNardo, G. L., Horner, R. W., Leach, P. J., and Bowes, D. J.: Radioisotope Skeletal Survey, J. A. M. A. 200: 111, 1967. 29 Parsons, V., Williams, M., Hill, D., Frost, P., and Lapham, A.: Strontium-85 Scanning of Suspected Bone Disease, Br. Med. J. 1: 19, 1969. 30 Czerniak, P.: Scanning Study of 700 Livers: Evaluation of Existing Diagnostic Procedures, Medical Radioisotope Scanning, Vienna, International Atomic Energy Agency 2: 401, 1964.
A. C. Gutierrez, M.D.,* R. G. Vincent, M.D.,** S. Bakshi, M.D.,*** and H. Takita, M.D.,**** Buffalo, N. Y.
JL n the past two decades, radioisotope scans have found widespread application in the detection of metastatic malignant lesions. 1 "' Scanning techniques were originally applied to the detection of hepatic metastases by Strirret1 in 1954. A number of works have since been published expressing varying degrees of enthusiasm for the procedure. 11 " The extremes are well represented by Hayes" and Rosenthal.' The former recommended that liver scans be employed routinely before treatment of patients with malignant disease, whereas the latter suggested that the routine use of liver scans in these patients be discouraged. The design of these studies as well as their reported accuracy rates varied considerably. Conn,in 1968; criticized five published reports, mentioning three major drawbacks: the nonrandom manner of collecting data, the lack of definition of the time interval beFrom Roswell Park Memorial Institute, Buffalo, N. Y. 14203. Received for publication Dec. 5, 1974. *Clinical Research Clinician, Thoracic Surgery. ♦♦Chief, Thoracic Surgery. ♦♦♦Associate Chief, Nuclear Medicine. ♦♦♦♦Associate Chief, Thoracic Surgery.
934
tween scanning and examining the liver, and the utilization of surgical findings as proof of absence of hepatic malignancy. Similar attempts to evaluate the accuracy of brain 1 "-' and bone scans2'1"-' in the detection of metastatic lesions have also been reported by a number of investigators. The design of these studies and their reported accuracy rates also varied. The present study is concerned with evaluating the accuracy of radioisotope scans in the detection of liver, brain, and bone metastases in patients with bronchogenic carcinoma. The criticisms of earlier reports voiced by Conn were heeded whenever possible with the materials at hand. A 3 year period was fixed, and all patients with bronchogenic carcinoma who were subjected to a liver, brain, or bone scan in our institute within this period were considered for the study, regardless of whether metastatic disease in the organ in question was suspected or unsuspected clinically. Furthermore, the maximum time interval between scanning and examination of the organ in question was rigidly set at 10 weeks. Finally, only autopsy verification was accepted as proof
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of the presence or absence of metastatic disease. Materials and methods All cases of bronchogenic carcinoma evaluated at the Roswell Park Memorial Institute in the 3 year period from January, 1971, to December, 1973, were reviewed. For the patient to be included in our study, liver, brain, and/or bone scan had to have been done within 10 weeks of autopsy. The scanning techniques used were as follows. Liver scan. In this series all of the liver scintiscans were performed exclusively with 1.5 to 2.0 mCi of 99mTc-labeled sulfur colloid on one of the following instruments; a 5 inch Picker dual-head scanner, a 5 inch Ohio Nuclear dual-head scanner, or a Nuclear-Chicago PhoGamms HP. Both of the scanners were equipped with a 5 inch focusing collimator. The Picker scanner was mounted with medium-energy Vi inch resolution collimators and the Ohio Nuclear scanner with low-energy Vi inch resolution collimators. Brain scan. Brain scans were performed either on a dual-head Picker magna scanner equipped with 5 inch focus, medium-energy collimators or on a gamma camera. Each patient received an oral dose of potassium perchlorate, and 1 hour later 15 mCi of "'"Tc-labeled sodium pertechnetate was administered intravenously. Four conventional views of the brain were obtained approximately 2I/2 hours after the administration of the radionuclide medium. Bone scan. Bone scanning was performed on the Ohio Nuclear dual-probe rectilinear scanner in the anterior and posterior projections extending from the level of the cervical spine to the middle femurs in a normal mode or in a 2:1 minification. The agents employed included the three presently available phosphate compounds labeled with !,!lmTc Sn-pyrophosphate: 99mTc Sn ethane-1-hydroxy-l-diphosphonate, 99mTc Sn polyphosphate, and 18F-sodium fluoride. The tracer doses of 99,nTc-labeled phosphate compounds and 18F-sodium fluoride were
15 and 5 mCi, respectively. The scans were obtained 3 to 4 hours after administration of the dosage. Results A total of 47 patients with bronchogenic carcinoma had liver scans within 10 weeks of autopsy during the time period of this study. Of these, 24 (52 per cent) had negative scans and negative autopsy findings, whereas 5 (10 per cent) had positive scans and positive autopsy findings. The liver scans were accurate in 29 (62 per cent) of the cases. Two (4 per cent) had positive scans and negative autopsy findings, whereas 16 (34 per cent) had negative scans and positive autopsy findings. The liver scans were inaccurate in 18 cases (38 per cent). A total of 30 patients with bronchogenic carcinoma had brain scans within 10 weeks of autopsy during the time period of this study. Of these, 19 (63 per cent) had negative scans and negative autopsy findings, whereas 7 (23 per cent) had positive scans and positive autopsy findings. The brain scans were accurate in 26 (87 per cent) of the cases. There were no patients with positive scans and negative autopsy findings. Four (13 per cent) had negative scans and positive autopsy findings. The brain scans were inaccurate in 4 cases (13 per cent). Only 9 patients with bronchogenic carcinoma had bone scans within 10 weeks of autopsy (with appropriate bone sampling) during the time period of this study. Of these, 3 (33 per cent) had negative scans and negative autopsy findings, whereas 5 (56 per cent) had positive scans and positive autopsy findings. The bone scans were accurate in 8 (89 per cent) of the cases. There were no patients with positive scans and negative autopsy findings. There was 1 case (11 per cent) of a negative scan and positive autopsy finding. The bone scans were inaccurate in 11 per cent of the cases. Other aspects of the clinical assessment of these patients were also evaluated. Levels of alkaline phosphatase, serum glutamic ox-
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aloacetic transaminase (SGOT), and lactic dehydrogenase (LDH) were studied. Of the 47 patients with liver scans, 11 (23 per cent) had normal enzyme levels and negative autopsy findings, whereas 18 (38 per cent) had one or more elevated enzymes and positive autopsy findings. The enzyme studies were accurate in 61 per cent of cases. Fifteen patients (33 per cent) had elevation of one or more enzymes and negative autopsy findings. The enzymes were inaccurate in 18 (39 per cent) of the cases. The findings on liver palpation were evaluated. Twenty-four patients (51 per cent) had nonpalpable livers and no liver metastases on autopsy; 11 (23 percent) had palpable livers and did have liver metastases on autopsy. Palpation of the liver was accurate in 74 per cent of cases. Two patients (4 per cent) had palpable livers and no hepatic metastases; whereas 10 (21 per cent) had nonpalpable livers and did have liver metastases. Palpation of the liver was inaccurate in 12 (25 per cent) of the cases. The clinical evaluation of brain metastases by history, physical examination, and neurologic examination was evaluated. Seventeen (57 per cent) had a negative clinical assessment and negative autopsy findings, whereas 10 (33 per cent) had a positive clinical assessment and positive autopsy findings. The clinical assessment by history plus physical and neurologic examination was accurate in 27 (90 per cent) of the cases. There were no patients with positive clinical assessment and negative autopsy findings; but there were 3 patients (10 per cent) with negative clinical assessment and positive autopsy findings. The clinical assessment of brain metastases by history and physical and neurologic examination was inaccurate in 3 (10 per cent) of the cases. The clinical evaluation of bone metastases by history, physical examination, and conventional x-ray films was elevated. Three (33 per cent) had negative clinical evaluations and negative autopsy findings; whereas 5 (56 per cent) had positive clinical
Thoracic and Cardiovascular Surgery
evaluation and positive autopsy findings. The clinical evaluation for osseous metastases was accurate in 8 cases (89 per cent). There were no patients with positive clinical evaluation and negative autopsy findings, but there was 1 patient (11 per cent) with a negative clinical evaluation and positive autopsy finding. The clinical evaluation for osseous metastases was inaccurate in 11 per cent of cases. Discussion Liver scans were found to have an overall accuracy rate of 62 per cent in the present study. Conn- reviewed the separate works of Nagler," Gollin,1" Czerniak,"1 McAfee,' and Baum," representing a total of 827 cases, and found an over-all accuracy rate of 65 per cent. These studies were criticized by Conn on the three items in their study designs mentioned previously. Nevertheless, a close correlation of over-all accuracy does exist between these studies and our study. When reviewing these earlier publications, one should also keep in mind that accuracy rates computed solely from true positive and false negative results are considerably different from over-all accuracy rates, which include ttrue negative and false positive rates as well. It is the over-all accuracy rate that should be used when evaluating a procedure for routine use. Evaluation of enzyme levels (SGOT, alkaline phosphatase, and LDH) provided an over-all accuracy rate of 61 per cent in this study when elevation of one, two, or all three enzymes is considered suggestive of hepatic metastases. Other investigators have also reported less than impressive accuracy rates when considering these enzymes on an individual basis. Gollin,1" for instance, reported SGOT, alkaline phosphatase, and LDH to be 58, 76, and 60 per cent accurate, respectively. Watson" studied 36 patients with proved hepatic metastases and found normal liver function tests in 52 per cent. When a combination of enzymes is used, over-all accuracy rates are improved.1' Ten patients in our study were found to have elevated levels of all three
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Fig. 1. Accuracy of clinical evaluation for liver metastases. Hepatomegaly and/or elevation of all three enzymes studied are compared to liver scan accuracy based on autopsy findings. enzymes studied (SGOT, alkaline phosthe above criteria probably will not be helpphatase, and LDH), and all proved to have ful. On the other hand, 15 patients had a hepatic metastases. The over-all accuracy positive clinical evaluation, and of these 2 rate obtained by using elevation of all three proved to be free of metastases to the liver. enzymes as an index of hepatic metastases However, in this group, there were 8 inis 75 per cent. accurate scans, all false negative, and there were 5 positive scans which were all true Hepatomegaly by palpation as an index positive. We therefore feel that patients with of the presence of hepatic metastases was 74 a positive clinical evaluation by hepatoper cent accurate, over-all, in our series. megaly and/or elevation of all three enMcAfee,1 Watson," and Fenster,1T reporting only on patients with proved hepatic zymes should be studied via liver scans. metastases, reported accurate correlation in If the scan is positive, it serves as strong clinical confirmatory evidence of hepatic 52, 57, and 89 per cent, respectively. metastases. If the scan is negative, it has Ozarda,1- working on autopsy material, relatively less clinical significance, and the found that 30 per cent of subjects with liver patient should probably have a limited surmetastases had near normal liver size. gical exploration for more accurate assessWhen hepatomegaly by palpation and/or ment of the liver. elevation of all three enzymes is considered indicative of hepatic metastases, the Use of this plan exclusive of surgical exover-all accuracy rate improves to 77 per ploration provides an 87 per cent accuracy cent (Fig. 1). According to these criteria, rate if the clinical evaluation is positive. 32 patients had a negative clinical evaluaIf the clinical evaluation is negative, the tion, and 8 proved to have hepatic metasaccuracy rate is 75 per cent. Over-all actases. However, in this group, 10 liver scans curacy with this plan used exclusive of were inaccurate, indicating that scanning surgical exploration is 79 per cent. patients with negative clinical evaluation by Therefore, it appears that routine use of
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Accurate Clinical Evaluation
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— False Negative Scan Fig. 2. Accuracy of clinical evaluation for brain metastases by history, physical examination, and neurologic examination is compared to brain scan accuracy based on autopsy findings.
liver scanning in these patients can be justified only if an over-all accuracy rate greater than 79 per cent can be achieved. The actual accuracy rate (61 per cent) by present scanning techniques is inadequate for routine use. False negative scans (34 per cent) account for the bulk of errors in evaluation by scanning. Of 16 patients with false negative scans, 13 proved to have lesions less than 2 cm. in diameter. This finding is supported by that of Castagna," who found that 7 of 12 patients with false negative results in his series had lesions less than 2 cm. in diameter. Furthermore, Ozarda12 demonstrated that the maximum diameter of liver metastases was less than 2 cm. in 31 per cent of 150 autopsy subjects with liver metastasis. Therefore, until such time as hepatic scanning techniques are refined to consistently detect lesions less than 2 cm. in diameter, routine use is not warranted. Positive scans are very useful as strong confirmatory evidence in patients with a positive clinical evaluation by hepatomegaly and/or elevation of all three enzymes studied.
The over-all accuracy rate for brain scans was 87 per cent in this study. Witcofski,18 Burrows,71 and Goodrich,1" reporting on patients with proved brain metastases, found brain scan accuracy rates of 82, 93, and 87 per cent, respectively. In the present series, there were no false positive brain scans. There were four false negative brain scans, and in all of these the lesions were 2.5 cm. or less in diameter. This result correlates with the findings of Boiler,20 who determined that lesions less than 2.7 cm. in diameter (10 c.c. in volume) cannot be consistently detected by brain scans. Nevertheless, the 87 per cent accuracy rate by brain scan alone is impressive. The clinical evaluation of brain metastases by history, physical examination, and neurologic examination also has a remarkable over-all accuracy rate of 90 per cent (Fig. 2). Goodrich,19 reporting on 118 cases of proved brain tumor, found an accuracy rate of 93 per cent. Ten patients had a positive clinical evaluation for brain metastases by history, physical examination, and neurologic examination. All proved to have brain metastases on autopsy. However, 2 of this group had
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Fig. 3. Accuracy of clinical evaluation for bone metastases by history, physical examination, and conventional radiogram is compared to bone scan accuracy based on autopsy findings.
false negative brain scans. It would therefore appear that when the clinical evaluation is positive a negative brain scan does not contribute useful information. The remaining 8 patients had true positive brain scans. As a consequence, we believe that if the clinical evaluation is positive, a brain scan should be done. A positive brain scan in this setting is strong confirmatory evidence of brain metastases. Twenty patients had a negative clinical evaluation for brain metastases by history and by physical and neurologic examination. Seventeen of these had no brain metastases on autopsy. Of the 3 patients with false negative clinical evaluations, 2 had negative scans and 1 had a true positive scan. Had all patients with a negative clinical evaluation undergone brain scanning, the pickup rate would have been about 5 per cent. Two of 3 with brain metastases were missed on scanning. As with liver scans, the major source of errors with brain scans is the false negative results. This is due to the relative inaccuracy of brain scans in detecting lesions smaller than 2.5 cm. in diameter. The routine use of brain scans in these patients can be justified only if the technique can be refined to detect lesions considerably smaller than 2.5 cm. in diameter. Larger
lesions can be accurately evaluated by history, physical examination, and neurologic examination. Positive scans are useful in patients with a positive clinical evaluation and serve to appropriately strengthen the clinical evaluation. Bone scans provided an over-all accuracy rate of 89 per cent in this limited study. The clinical evaluation of osseous metastasis by history, physical examination, and conventional x-ray films had the same high degree (89 per cent) of accuracy as the bone scans (Fig. 3). These findings correlate well with those of Parsons,2" who concluded that when history, radiology, and biochemical changes all indicate bone metastases, a positive scan can be expected. Of the 5 patients with a positive clinical evaluation in our series, all proved to have bone metastases. The bone scans were positive in 4 of these cases. Of the 4 patients with a negative clinical evaluation, 3 had negative bone scans and 1 patient had a true positive scan. This series is too small to offer definite conclusions, but it appears that the routine use of bone scans in all these patients may not be warranted; a positive bone scan, on the other hand, can do much to strengthen a positive clinical and radiologic impression.
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Summary We reviewed all cases of bronchogenic carcinoma in a 3 year period at the Roswell Park Memorial Instiute that were evaluated by liver, brain, and/or bone scans within 10 weeks of autopsy. Liver, brain, and bone scans were accurate in 62, 87, and 89 per cent, of cases, respectively. Enzyme studies (alkaline phosphatase, SGOT, and LDH) showed accurate correlation in 61 per cent of cases. Elevation of one or two of the enzymes was not very helpful, but in all cases in which three enzymes were elevated, hepatic metastases were found at autopsy. Palpation of the liver provided a 74 per cent accuracy rate and should be afforded appropriate attention in the evaluation of all patients with bronchogenic carcinoma. When hepatomegaly and/or elevation of all three enzymes is considered indicative of hepatic metastases, the over-all accuracy rate improves to 77 per cent. Clinical assessment of brain metastases by history, physical examination, and neurologic examination was found to be 90 per cent accurate in this study. The correlation of bone scans with autopsy findings would theoretically require sampling of all bones. Even in patients with several areas of increased uptake, not all these areas are sampled in a routine autopsy. The number of cases that qualified for this part of the study is therefore small. In these cases, the clinical evaluation of osseous metastases by history, physical examination, and conventional x-ray films had the same high degree (89 per cent) of accuracy as the bone scans. A plan is suggested for evaluating patients for hepatic metastases by considering hepatomegaly and/or evaluation of all three enzymes (SGOT, alkaline phosphatase, and LDH) to be suggestive of hepatic metastases. If clinically positive, liver scans should be obtained. Positive scans are adequate evidence of hepatic metastases in these patients. An exploratory laparotomy is suggested for those with positive clinical evaluation and negative scans.
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Similarly, brain scans are suggested when supportive evidence for a positive clinical evaluation by history, physical examination, and neurologic examination is needed. Supportive evidence is provided by a positive scan; a negative scan is of relatively less clinical importance. The evaluation for bone metastases by history, physical examination, and conventional bone radiograms had a high accuracy rate. Scans are suggested when supportive data are needed in patients with a positive clinical evaluation. In such patients, a positive scan is of significance. We wish to point out that our reported false negative rate may be higher than the actual value because of the time lapse (maximum 10 weeks, average 5 weeks) between the scans and the autopsies. It is entirely possible that metastatic lesions could have developed in this time interval. Also, of the two false positive liver scans reported, only one is unexplained, the other was due to an intrahepatic hematoma which the scan accurately assessed as a space-occupying lesion. We gratefully acknowledge the efforts of Mrs. Tona Flak in the preparation of this manuscript. REFERENCES 1 Stirret, L. A., Yuhl, E. T., and Cassen, B.: Clinical Application of Hepatic Radioactivity Surveys, Am. J. Gastroenterol. 21: 310, 1954. 2 Conn, H. O., and Elkington, S. G.: Is Hepatic Scanning Overrated? Gastroenterology 54: 135, 1968. 3 Rosenthal, S., and Kaufman, S.: The Liver Scan in Metastatic Disease, Arch. Surg. 106: 656, 1973. 4 McAffee, J. G., Ause, R. G., and Wagner, H. N., Jr.: Diagnostic Value of Scintillation Scanning of the Liver, Arch. Intern. Med. 116: 95, 1965. 5 Johnson, P. M., and Sweeney, W. A.: The False-Positive Hepatic Scan, J. Nucl. Med. 8: 451, 1967. 6 Hayes, T. P., Davis, L. W., and Raventos, A.: Brain and Liver Scans in the Evaluation of Lung Cancer Patients, Cancer 27: 362, 1971. 7 Jhingran, S. G., Jordan, L., Jahns, M. F., and Haynie, T. P.: Liver Scintiscans Compared With Alkaline Phosphatase and BSP Determination in the Detection of Metastatic Carcinoma, J. Nucl. Med. 12: 227, 1971.
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8 Ludbrook, J., Slavotinek, A. H., and Ronai, P. M.: Observer Error in Reporting on Liver Scans for Space Occupying Lesions, Gastroenterology 62: 1013, 1972. 9 Watson, A., and Torrance, H. B.: Liver Scanning in Surgical Practice, Br. J. Surg. 57: 405, 1970. 10 Gollin, F. F., Sims, J. L., and Cameron, J. R.: Liver Scannning and Liver Function Tests, J. A. M. A. 187: 111, 1964. 11 Nagler, W., Bender, M. A., and Blau, M.: Isotope Photoscanning of the Liver, Gastroenterology 44: 36, 1963. 12 Ozarda, A., and Pickren, J.: The Topographic Distribution of Liver Metastases: Its Relation to Surgical and Isotope Diagnosis, J. Nucl. Med. 3: 149, 1962. 13 Castagna, J., Benfield, J. R., Yamada, H., and Johnson, D. E.: The Reliability of Liver Scans and Function Tests in Detecting Metastases, Surg. Gynec. Obstet. 134: 463, 1972. 14 Baum, S., Silver, L., and Vouchides, D.: The Recognition of Hepatic Metastases Through Radioisotope Color Scanning, J. A. M. A. 197: 1966. 15 Freeman, L. M., Meng, C. H., Johnson, P. M., Bernstein, R. G., and Bosniak, M. A.: False Positive Liver Scans Caused by Disease Processes in Adjacent Organs and Structures, Br. J. Radiol. 42: 651, 1969. 16 Lin, S., Mansfield, C. M., Kramer, S., and Southard, M. E.: Liver Scanning in Patients With Suspected or Proven Cancer, Am. J. Roentgenol. Radium Ther. Nucl. Med. 108: 98, 1970. 17 Fenster, L. F., and Klatskin, G.: Manifestations of Metastatic Tumors of the Liver, Am. J. Med. 3 1 : 238, 1961. 18 Witcofski, R. L., Maynard, C. D., and Roper, R. J.: A Comparative Analysis of the Accuracy of the Technetium-99m Pertechnetate Brain Scan: Followup of 1,000 Patients, J. Nucl. Med. 8: 187, 1967.
19 Goodrich, J. K., and Tutor, F. T.: The Isotope Encephalogram in Brain Tumor Diagnosis, J. Nucl. Med. 6: 541, 1965. 20 Boiler, F., Patten, D. H., and Howes, D.: Correlation of Brain Scan Results With Neuropathological Findings, Lancet 1: 1143, 1973. 21 Burrows, E. H.: False Negative Results in Brain Scanning, Br. J. Med. 1: 473, 1972. 22 Shaw, R. A., Dusault, L. A., and Wilner, H. J.: False Negative Brain Scans Excluding Those Found in Cerebral Infarction, Radiology 99: 369, 1971. 23 Holman, B. L.: The Brain Scan, Postgrad. Med. 54: 143, 1973. 24 Legge, D. A., Newlon Tauxe, W., Pugh, D. G., and Utz, D. C : Radioisotope Scanning of Metastatic Lesions of Bone, Mayo Clin. Proc. 45: 755, 1970. 25 Merrick, M. V.: Detection of Skeletal Metastases: A Comparison of Three Radioisotopic Techniques Using 1 S F and Radiology, Br. J. Radiol. 46: 968, 1973. 26 Galaski, C. S. B., and Doyle, F. H.: The Detection of Skeletal Metastases From Mammary Cancer. A Regional Comparison Between Radiology and Scintigraphy, Clin. Radiol. 23: 295, 1972. 27 Charkes, N. D., Sklaroff, D. M., and Young, I.: A Critical Analysis of Strontium Bone Scanning for Detection of Metastatic Cancer, Am. J. Roentgenol. Radium Ther. Nucl. Med. 96: 647, 1966. 28 DeNardo, G. L., Horner, R. W., Leach, P. J., and Bowes, D. J.: Radioisotope Skeletal Survey, J. A. M. A. 200: 111, 1967. 29 Parsons, V., Williams, M., Hill, D., Frost, P., and Lapham, A.: Strontium-85 Scanning of Suspected Bone Disease, Br. Med. J. 1: 19, 1969. 30 Czerniak, P.: Scanning Study of 700 Livers: Evaluation of Existing Diagnostic Procedures, Medical Radioisotope Scanning, Vienna, International Atomic Energy Agency 2: 401, 1964.