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Biochemical Procedures As Aids in Diagnosis of Different Forms of Cancer

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Biochemical Procedures As Aids in Diagnosis of Different Forms of Cancer A n n a l s o f C l i n i c a l An d L a b o r a t o r y S c i e n c e , Vol. 4, No. 2 Copyright © 1974, Institute for Clinical Science Biochemical Procedures as Aids in Diagnosis of Different Forms of Cancer MORTON K. SCHWARTZ, Ph.D. Memorial Sloan-Kettering Cancer Center, New York, NY 10021 ABSTRACT The application of biochemical analyses as aids in the diagnosis of cancer is discussed with emphasis on the fact that biochemical testing is more useful in following the regression and progression of disease than in early initial diagnosis. The uses of biochemical analyses of metabolic degradation products, lipids, hormones and their receptors, enzymes, including isoenzymes, and trace metals are included. Introduction indicated in table I these include neuro­ Diagnostic procedures in cancer must be blastoma, pheochromocytoma, carcinoid, designed to achieve several purposes. They hepatocellular carcinoma, multiple mye­ must define the disease, describe its extent loma, osteogenic sarcoma and other osteo­ and be useful in following its progression blastic bone tumors. In these diseases, the or regression. For more than 75 years, in­ assay of the listed components is essential vestigators have searched for biochemical for confirmation of the diagnosis and in defects in cancer cells that could be ex­ following the response to therapy. ploited in diagnosis. Despite these long and continuing studies, few biochemical proce­ Serum Enzymes dures have been developed for early diag­ Historically, the biochemical procedure nosis of specific forms of cancer. The most used for the longest time as a diagnostic useful application of biochemical assays aid in cancer is acid phosphatase. This has been in following the regression and serum enzyme has been used for 35 years progression of disease and in establishing in the evaluation of carcinoma of the pros­ the presence of métastasés.35’36 tate. The enzyme activity is elevated in From the standpoint of general use, the only 24 percent of patients with non­ most important tests would be those useful metastatic prostate carcinoma and in 81 in cancers with the highest population inci­ percent of patients with skeletal metas- dence. In the United States these are can­ tases.39 Efforts have been made to increase cer of the colon and rectum, female breast, the sensitivity of the acid phosphatase as­ lung, bronchus and uterus. However, most say in prostatic disease by utilizing specific well defined biochemical procedures are tartrate inhibition of prostatic acid phos­ those related to rarer forms of cancer. As phatase and assay of the “prostatic” frac- 95 9 6 SCHWARTZ TA BLE I B i o c h e m i c a l A s s a y s U s e f u l i n I n i t i a l D i a g n o s i s a n d F o l l o w -U p o f R a r e C a n c e r s Disease Biochemical Constituent Neuroblas toma Catecholamines, vanillyl- mandelic acid, metanephrine, cystathionine, dopamine 3-hydrolase, dopamine, homovanillic acid Pheo chromo cy toma Catecholamines, metanephrine, vanillylmandelic acid Carcinoid 5-Hydroxyindoleacetic acid Trophoblastic neoplasms Chorionic gonadotrophin (choriocarcinoma, testicular tumors) Multiple myeloma Bence-Jones protein, immuno­ globulin Hepatocellular et-Fetoprotein carcinoma Osteogenic sarcoma Alkaline phosphatase tion.13 In one study, elevations of tartrate- serum from a patient with prostatic carci­ sensitive acid phosphatase were found in noma (total serum acid phosphatase of 290 14 of 34 patients with prostatic carcinoma, units) or of a homogenate of prostatic tis­ 2 of 90 patients with benign prostatic sue demonstrated additional isoenzymes in hypertrophy, 15 of 76 patients with other the post albumin area. This technique re­ forms of cancer, and 23 patients without quires further evaluation as a diagnostic cancer.16 It has been our experience that aid in cancer of the prostate.31 Assays of the prostatic acid phosphatase as deter­ bone marrow serum acid phosphatase have mined by tartrate inhibition is not useful as been proposed as a technique for detecting a clinical laboratory tool.8 early metastasis to bone in adenocarcinoma Disc electrophoresis on polyacrylamide of the prostate and in staging of the dis­ gel has indicated there are three to five ease.30 acid phosphatase isoenzymes in the serum Many other serum enzymes have been of healthy adults.31 Electrophoresis of the suggested as useful parameters in the di­ BIOCHEMICAL DIAGNOSIS 9 7 agnosis of cancer.36 Serum amylase is ele­ pared with placental alkaline phospha­ vated in a small percentage of patients with tase.12’40 In two studies of 913 patients with cancer of the pancreas,38 and alkaline phos­ a variety of cancers, the Regan isoenzyme phatase is elevated in primary tumors of was observed in the serum in 66 instances bone.39 Alkaline phosphatase is more useful or 7.2 percent.22’41 The highest incidence in evaluating metastatic disease to bone was in patients with cancer of the ovary and liver. The enzyme is elevated predom­ and lung. With a sensitive immunochemical inantly in osteoblastic bone lesions. In assay, Regan isoenzyme has been detected breast carcinoma, most cases of bony me- in serum of 89 of 91 normal adults and 106 tastases are osteolytic, and alkaline phos­ of 112 serums from patients with malignant phatase levels are usually in the normal disease.45 In the cancer patients, only 11 range or slightly elevated. In prostatic car­ showed elevated activities to an extent of cinoma, most of the metastatic lesions are 3 to 300 times the average normal value. An osteoblastic, and the serum alkaline phos­ alkaline phosphatase variant different from phatase is elevated to levels 4 to 10 times the Regan isoenzyme has been observed in the upper limit of normal.39 serum of patients with hepatoma. In one During successful treatment, there may study, 6 of 21 patients with hepatoma ex­ be an elevation in the serum alkaline phos­ hibited the alkaline phosphatase variant.28 phatase presumably related to the repair of All of these patients had «-fetoprotein in bone. These elevations have been referred their serum. It was concluded that the alka­ to as the “paradoxical rise” in serum alka­ line phosphatase variant was not useful in line phosphatase.39 In liver disease, eleva­ hepatoma. tions of alkaline phosphatase may be ob­ An important demand made of the clin­ served in patients with extrahepatic ob­ ical biochemistry laboratory is to aid the struction of the biliary tract and in patients clinician in establishing whether or not an with intrahepatic metastases. In infiltrative elevated serum alkaline phosphatase is due disease of the liver such as leukemia, retic­ to liver or bone metastases or to a combi­ ulum cell sarcoma and Hodgkin’s disease, nation of both. Numerous attempts have alkaline phosphatase activity is markedly been made to use electrophoresis to sepa­ elevated, the activity being directly related rate liver from bone alkaline phosphatase. to the extent of liver involvement.36 However, in our experience, there is too Recently, there has been great interest in much overlap in the electrophoretic migra­ the isoenzymes of serum alkaline phospha­ tion of these isoenzymes to permit their tase and the so-called “Regan isoenzyme” routine clinical use. We have successfully has been used in studies of patients with used serum 5'-nucleotidase for this pur­ cancer. In 1968, Fishman and his associates pose.39 5'-Nucleotidase is a substrate spe­ identified an alkaline phosphatase in the cific phosphatase present in liver tissue but serum and tissue of a patient with carci­ not in bone. When it is elevated in the noma of the lung.10 This enzyme was serum, it is indicative of liver involvement. named the Regan isoenzyme after the pa­ Two other enzymes, y-glutamyl trans­ tient in whom it was found.11 Investigations peptidase and leucine aminopeptidase have have indicated that the isoenzyme is iden­ also been used as specific indicators of liver tical to the heat stable, L-phenylalanine disease. In a comparison of these enzymes sensitive alkaline phosphatase of the hu­ in a series of 96 patients in whom the man placenta, that it demonstrates iden­ clinician suspected liver involvement, the tical electrophoretic mobility to that from three enzyme activities were observed placenta before and after neuramidase within normal limits in 26 individuals and treatment and reacts with antiserum pre­ all elevated in 39 others. In seven patients, 9 8 SCHWARTZ TA BLE II E l e v a t i o n s o f “ U b i q u i t o u s E n z y m e s ” i n S e r u m o f P a t i e n t s w i t h C a r c i n o m a M e t a s t a t i c t o L i v e r 42 No. of No. with Percent Enzyme Patients Elevations Elevated Phosphohexose isomerase 72 60 84 Aldolase 100 75 75 Lactate dehydrogenase 1 5 6 108 69 Malate dehydrogenase 70 43 62 Isocitrate dehydrogenase 65 34 53 Aspartate aminotransferase 188 94 50 Glutathione reductase 68 32 47 Alanine aminotransferase 179 60 33 y-glutamyl transpeptidase was the only course of disease in patients with liver elevation; in two patients, this enzyme was metastases. Of all these enzymes, serum normal when the others were elevated. In phosphohexose isomerase appears to be each of two other cases, either 5'-nucleo- elevated in the greatest number of patients tidase or leucine aminopeptidase was ele­ (table II).42 vated when the other activities were within normal limits.
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