SCINTIGRAMS COMPARED WITH AND BSP DETERMINATIONS IN THE DETECTION OF METASTATIC CARCINOMA

Satish G. Jhingran, Leon Jordan, Monroe F. Jahns, and Thomas P. Haynie The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, Houston, Texas

Liver scanning is a well-established technique in fling and color scanning devices with a 3 x 2-in. the detection of metastatic (1—5), but NaI(Tl) crystal, a 19-hole focusing collimator with from time to time reports are published which ques dot factor and scanning speed adjusted according to tion the accuracy of the scintigram compared with the maximum counting rate (Picker Magnascanner). for detecting hepatic metastases In general, only anterior views were obtained. (6) . However, liver function tests often indicate Technetium-99m liver scanning. With no prior abnormality in patients with cancer where no liver preparation, each patient received intravenously 3 metastases are present (2,7). mCi of O9mTc..sulphurcolloid. Scans were performed To assess our own experience in regard to liver 15 mm after injection using a commercially avail scintigrams and liver function tests, a retrospective able gamma camera with an 11 X ½-in.NaI(Tl) study was made comparing the diagnostic accuracy crystal, 4,000 channel straight-bore collimator, and of liver scintigrams with alkaline phosphatase (AP) oscilloscope display with Polaroid recording (Nu and bromsuiphalein (BSP) determinations in a clear-Chicago, Pho/Gamma III). Routinely, an seriesof cancer patients studied in our institution. tenor, right lateral, and posterior scans were per formed on each patient. METHODS Classification of patients. A subgrouping of the The study includes 284 patients with cancer who metastatic cases was devised on the basis of the esti were referred to the Radioisotope Laboratory of The mated extent of involvement at the time of laparot University of Texas M. D. Anderson Hospital and omy or postmortem examination of 104 patients. Tumor Institute at Houston for liver scintigrams Thus the presence of a single nodule or several nod from September 1966 through June 1968. All pri ules in the liver with less than ½of the liver in mary cancer diagnoses were proved pathologically, volved was designated as Group I, numerous nodules and the status of the liver for disease or normality involving ½—½of the liver as Group II, and ex also was substantiated by pathological examination, tensive involvement with more than 2/3 of the liver either by liver (85 cases), postmortem exami tissue replaced by tumor as Group III. nation (82 cases), laparotomy (74 cases), or lapa Interpretation of SCIntigramS. All scans were re rotomy and biopsy (43 cases) within 1 month of the viewed and assigned to a normal or abnormal cate study. Only positive evidence of metastatic disease gory. The scans were considered abnormal if they was accepted as proof of diagnosis by needle biopsy showed obvious uneven uptake or definite cold areas. because a normal needle biopsy of the liver does Abnormal scans were further reviewed to determine not rule out metastatic disease. the extent of liver involvement. Liver scintigrams were performed either with 198Au-colloidal gold and the rectilinear scanner or Liver function tests. Alkaline phosphatase (AP) with P9mTcsulfur colloid and the gamma camera. and bromsulphalein (BSP) analyses were performed The scans were about equally divided between the on each patient using standard methods (9,10) . AP two techniques. In a previous study we found no values of 2.3 Bessey-Lowry (BL) units or less significant difference in the true-positive rates be were considered normal; values above 2.3 were con tween ‘98Auand 99mTcscintigrams (8). sidered abnormal. Gold-198 liver scanning. With no prior prepara tion, each patient received intravenously 200 @Ciof Received July 1, 1970; revision accepted Dec. 11, 1970. 198Au-colloidal gold. Liver scans were begun 30 mm For reprints contact: S. 0. Jhingran, M. D. Anderson Hospital and Tumor Institute, Texas Medical Center, Hous after injection of the radionuclide using photoscan ton, Tex. 77025.

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evidence of anatomical . Figure 1 shows TABLE 1. RESULTSOF SIMULTANEOUS LIVER the correlation of metastatic disease with the results SCANS AND FUNCTION TESTSIN 284 PATIENTS of all three tests. Results of all three tests were ab correctlydiagnosedLiverscansAPPcrcent normal in 54 patients, and in this group 48 (89%) had hepatic . Results of two of three tests were abnormal in 59 patients, and 36 (61 % ) had BSP hepatic metastasis. Results of one of three tests were Overall accuracy 81 67 72 abnormal in 45 patients, and 14 (3 1% ) had hepatic No livermetastasis,79 patients 91 59 39 metastasis. Of the three tests, none gave abnormal Metastatic cancer, 146 patients 83 71 91 Nonmalignant liver disease, results in 25 patients, and six (24% ) had hepatic 59 patients 70 77 96 metastasis. Comparison of scintigrams with combined tests. In an attempt to better separate metastatic liver dis ease from normal liver, the following criteria for In BSP tests, 6% retention or less in 45 mm was classification were considered. considered normal. Criterion 1. Classify the individual as normal if two or more of the tests are normal; otherwise RESULTS classify as diseased. Comparison of tests. Of the 284 patients studied, Criterion 2. Classify the individual as abnormal 139 were diagnosed as having hepatic metastases, 53 if the scan test indicates an abnormality and if had diffuse benign disease (most commonly hepatitis one of the two other tests is also abnormal; other or cirrhosis) , six had posthepatic obstructive jaun wise classify as normal. dice, and seven had primary liver cancer. Seventy nine had no pathologic evidence of liver disease, Table 2 shows the percentages of correct diagnoses but it should be stressed that all of these patients had when diagnosis is based on scan results alone, on cancer elsewhere in the body, even though the liver was not involved. The results of the three tests were correlated with the presence of or absence of disease, and Table 1 gives the percentages of cases within each of these categories which were diagnosed cor rectly. In this series, the highest percentage of cor PERCENT WITH HEPATIC rect diagnosis was by scintiscan, with the BSP sec METASTASES ond, and the AP third. This higher percentage of accuracy for the scan was related primarily to a lesser number of false positives. The incidence of abnormality was comparable for all three tests in patients with metastatic disease. Chi-square test p ABNORMAL A113 2of3 1of3 Oof3 values (11 ) obtained from comparisons of scan results with AP results and with BSP results yielded FIG. 1. When liver scintigrams,AP, and BSPdeterminations were made simultaneously in group of patients where 57% had p < 0.01 , and p = 0.02, respectively, for the over metastatic disease and 43% did not, percent of patients with all accuracies. hepatic metastasis was correlated with number of tests which were abnormal. In metastatic liver disease, the scan, AP, and BSP gave the correct diagnosis in 83 % , 7 1% , and 81% of all metastatic cases, respectively. Statistically, there is no significant difference between these per TABLE 2. APPLICATION OF SELECTED centages since p values for scan versus BSP, and CRITERIA TO DIAGNOSIS scan versus AP are > 0. 10 and 0.09, respectively. Percentwith For cases which do not have liver disease, the scan correctdiagnosis had a significantly higher proportion of correct diag (284 patients) noses than either AP or BSP. The p values for these Scintigram alone 87 tests are < 0.01. Classify abnormal only when two or three tests abnormal 75 Combined testing. All three tests were performed Classifyabnormal only when scanand one simultaneously in 183 patients, of whom 104 (57%) or two liver functiontestsabnormal 83 had metastatic liver disease and 79 (43 % ) had no

228 JOURNAL OF NUCLEAR MEDICINE LIVER SCINTIGRAMS TO DETECT METASTATIC CARCINOMA

ALKALINE B.S.P. SCINTuRAN to be in the range from 0 to 40% . These false PHOSPHATASE

,. + 81 positive results may be attributable to subclinical ,: @37 ,. + 37 3 Y 1.17+ 1.311 I. 5.90+3.995 421 @.-2I4O.I9.84J hepatic abnormality or to disease elsewhere in the body. Abnormal AP test results have been reported II I 36@ (13,14) in benign and malignant gastrointestinal dis @ j a 301 orders in the absence of direct liver involvement. The present study revealed 8 1% accuracy in diag S 241 71 nosis of metastatic cancer in liver by BSP, which @ I8@ 1@ agrees with other studies (2,13,14,16,17,19,20) . The

a, 121 incidence of false positives from BSP in the present 5] study was 61%; other studies (2,6,13,14,17,19) 61 II I report a range from 25 % to 58%.

N I II III N I II LII The results of this evaluation show the accuracy of scanning in metastatic liver cancer to be 83%. EXTENT OF INVOLVEMENT False-positive liver scans in this series occurred in 9 % of all cases with normal liver. These values are FIG. 2. In 104 patientswith provedmetastaticdiseasegraded I, II, and Ill, and also with group of patients with no liver disease in agreement with those reported by others (1—3, (N), degree of abnormality of AP, BSP, and liver scintigram was 21,22). correlated with degree of involvement. Correlation coefficient (r) for liver scintigrams was significantly higher than for either AP For cases having metastatic liver disease, chi or BSP. square tests showed no significant difference between diagnosis by BSP retention, by AP elevation, and Criterion 1, and on Criterion 2. These alternate cri by scanning. In cancer patients without liver metas teria offer no overall improvement over diagnosis tases, the scan was definitely superior to BSP and based on scan results alone. to AP. Correlation with extent of liver metastases. Post Combination of tests. Attempts have been made mortem and/or laparotomy information on extent by others to increase the accuracy in liver metastasis of liver involvement with metastatic disease was diagnosis by combining the results of tests. Schaefer available on 104 patients with metastases. In 41 and Schiff (20) suggested that the combined BSP patients, less than ½of the liver was involved; in retention and AP were highly reliable in detecting 47, ½—½was involved; and in 16, ½or more was metastatic disease. involved. Various combinations of tests in diagnosing liver Figure 2 shows the increase in the mean values metastasis have been evaluated in this study. If any for AP and BSP as the extent of involvement by two abnormal tests are taken as evidence of metas hepatic metastasis increases, as well as the increas tasis, false positives result in 29 % of cases without ing abnormality on the scan with the increasing liver involvement. If three abnormal tests are taken degree of involvement. The correlation between the as evidence of metastasis, false positives are reduced true involvement determined by postmortem and/or to 8% , but the indication of abnormality in patients laparotomy, and the results of scan, AP, and BSP with metastasis (true positive) is only 46% . Since test results is given by each graph. The correlation neither of these combinations yielded improvement coefficients for scan, AP, and BSP are 0.8 1, 0.37, in accuracy, two additional combinations of test re and 0.37, respectively. sults were evaluated in the present study (Criterion 1 and 2, above) . None of the combinations, how DISCUSSION ever, give an improvement over diagnosis based on Increased serum AP and increased retention of scan results alone. @ BSP have long been used in the detection of neo Extent of hepatic metastasis. The results of this plasms metastasized to the liver. There are numer study, as well as those of others ( 13,14,1 7,22 ) mdi ous reports on the value of AP in diagnosing meta cate an increase in the degree of abnormality of tests static disease, the reported accuracy varying widely as extent of metastatic involvement of the liver from 20% to 94% (1,2,6,12—18).The accuracy of increases. 71 % in the present study is consistent with the re The extent of hepatic involvement indicated by sults of the majority of these reports. Abnormal AP scan results agreed with the involvement found at values were obtained in 41 % of patients with nor postmortem or laparotomy examination in 55% of mal (false positives). The incidence of false pos the cases. This is similar to the value of 60% re itives has been reported by others (2,6,12,14,15,17) ported by Mansfield et al (22). Although mean

Volume 12, Number 5 229 JHINGRAN, JORDAN, JAHNS, AND HAYNIE

values of AP and BSP increase with degree of in 6. SMITH LB, WILLIAMS RD : The relative diagnostic ac volvement, the correlation of abnormality with extent curacy of liver radioactive isotope photoscanning. Arch Surg96:693—697,1968 of involvement was inferior for liver function tests. 7. GUTMAN AB: Serum alkaline phosphatase activity in The largest number of false-negative diagnoses by diseases of the skeletal and hepatobiliary systems. Consid scan, by AP, or by BSP are in patients with early eration of the current status. Amer I Med 27: 875—901, incipient metastases. 1959 8. HAYNIE TP, JHINGRAN SG, ILTER RG, et al: Liver CONCLUSION scintigrams in patients with cancer. Cancer Bulletin 22: 33—36,1970 Because it provides anatomical information, the 9. BESSEYOA, LOWRYOH, BROCKMJ : Method for rapid liver scintigram is superior to the alkaline phospha determination of the alkaline phosphatase with five cubic tase and BSP tests in the detection of metastatic liver millimeters of serum. I Biol Chem 164: 321—329,1946 disease. The advantages of the scintigram are a lower 10. GAEBLER OH: Determination of bromsulfaphalein in percentage of false-positive results and a higher normal, turbid, hemolyzed, or icteric serums. Amer I Clin correlation with the extent of involvement than was Path 15: 452—455,1945 11. SNEDECOROW, Cocna@N WG: Statistical Methods, true for tests of liver function. 6th ed., Ames, Iowa, Iowa State University Press, 1967, p. While they are as sensitive as the scintigram in 213 detecting disease, AP and BSP retention studies pro 12. BULLARD RW: Alkaline phosphatase and metastatic duced a higher percentage of abnormality in patients liver disease. Surgery 19: 379—382,1946 with no anatomical evidence of liver disease. These 13. ARIEL IM, SHANON DB: Hepatic dysfunction in can didates for abdominal surgery, especially in patients with “false-positive―results may be related to systemic cancer. Cancer 3 : 608—623,1950 effects of cancer elsewhere in the body or to toxicity 14. MENDELSOHN ML, BODANSKY 0: The value of liver from therapeutic measures used in these patients. function tests in the diagnosis of intrahepatic metastasis in A comparison of scan results alone and in corn the nonicteric cancer patient. Cancer 5: 1—8,1952 bination with liver function tests suggested that the 15. GIBBONS TP: Hyperphosphataemia in patients with out with hepatobiliary disease. JAMA 164: 22—28, scan was as accurate in detecting hepatic involvement 1957 by metastasis as was a combination of tests. .$ 16. FINSTER CF, KLATSKIN G : Manifestations of mete The scan was the most reliable test in predicting static tumors of the liver. A study of 81 patients. Amer I the extent of liver involvement. As such, it is the Med3l: 238—248,1961 @ best of the three tests for estimating the degree of 17. YESNER R, CONN HO: Liver function tests and needle biopsy in the diagnosis of metastatic cancer of the improvement or progression of metastatic lesions liver. Ann Intern Med 59: 62—72,1963 under therapy. 18. IBER FL, GREEN R, HARVEY AM : Serum alkaline phosphatase in infiltrative diseases of liver. Biochemical REFERENCES Clinics 3: 177—180,1964 1. NAGLER W, BENDER MA, BLAU M : Radioisotope pho 19. THOMAS U, ZIMMERMAN HJ : The pattern of ab toscanning of the liver. Gasiroenterology 44: 36—43, 1963 normality of liver function tests in metastatic carcinoma. 2. GOLLIN FF, SIMS LR, CAMERON JR: Liver scanning I Lab ClinMed 39: 882—887,1952 and liver function tests. JAMA 187: 111—116,1964 20. SCHAEFER J, SCHIFF L: Liver function tests in mete 3. MCAFEE JG, Aus RG, WAGNER HN: Diagnostic value static tumors of the liver : Study of 100 cases. Gastroenter of scintillation scanning of the liver. Arch Intern Med 116: ology49:360—363,1965 95—110,1965 21. SALL S, GIR0LAM0 R, SWASDIOK: Radioisotope scm 4. BAUM S, SILVERL, VOUCHIDESD: The recognitionof tillation scanning and the diagnosis of hepatic metastasis. hepatic metastasis through radioisotope color scanning. Obstet Gynec 32: 846—850,1968 JAMA 197:675—679,1966 22. MANSFIELD CM, KRAMER S, SOUTHARDME, et al: 5. GOTTSCHALK A: Liver scanning. JAMA 200: 630— Prognosis in patients with metastatic liver disease diagnosed 633, 1967 by liver scan. Radiology 93: 77—84, 1969

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