Henry Ford Hospital Medical Journal

Volume 30 Number 2 Article 5

6-1982

Acid Phosphatase: Clinical Utility of the First Tumor Marker

Christopher J. DiPaolo

Jan Rival

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Recommended Citation DiPaolo, Christopher J. and Rival, Jan (1982) "Acid Phosphatase: Clinical Utility of the First Tumor Marker," Henry Ford Hospital Medical Journal : Vol. 30 : No. 2 , 70-76. Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol30/iss2/5

This Article is brought to you for free and open access by Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Henry Ford Hospital Medical Journal by an authorized editor of Henry Ford Health System Scholarly Commons. Henry Ford Hosp Med J Vol 30, No 2,1982

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Acid Phosphatase: Clinical Utility of the First Tumor Markert

Christopher J. DiPaolo, MD* and Jan Rival, MD'

Acid phosphatase was the first tumor marker to be mea­ after prostate massage. Recent studies demonstrate that sured in blood. Although it is used as a marker of pros­ levels are not significantly increased after routine rectal tatic carcinoma, serum levels are also elevated in many examination. Although of limited use as a screening test, diseases of prostate, bone, and hematologic tissue. the assay may be useful in staging, prognostication dur­ While serum acid phosphatase concentration is elevated ing hormonal therapy, and in making clinical decisions. in patients with prostatic carcinoma or infarction, it may Rectal examination remains the best screening test for also be increased merely with benign hypertrophy and carcinoma of the prostate.

CZarcinoma ofthe prostate is the second most common Physical examination disclosed pallor and tenderness of causeof cancer death among American men, with42,000 the sternum and left ribs. The prostate was enlarged and new cases and 17,000 deaths per year (1,2). It has been the right lobe was indurated. There was mild distal sen­ estimated that 30% of new cases are potentially curable sory neuropathy. (3,4). Digital examination of the prostate has been the standard screening test, but it has been reported that as Hemoglobin was 9.5 g/dl and the leukocyte count was many as80% of patients have advanced disease on initial 8400/cu mm with 36% polymorphonuclear forms, 10% presentation (5). Thus, prostatic carcinoma, although bands, 30% lymphocytes, 16% monocytes, 1% eosino­ often detected early as a nodule in the gland, continues phils, 4% atypical lymphocytes, 1% metamyelocytes, 1% to be a difficult problem for the primary care physician. myelocytes, and 1% promyelocytes. The platelet count Civen the difficulties of anatomic tumor detection, was 70,000/mm3. Urinalysis disclosed 1+ protein and 2+ attention has turned to the use of tumor markers in this glucose reactions,2 red blood cells, and4 leukocytes per condition, and the measurement of serum acid phos­ high powered field. Electrolyte concentrations were phatase (SAP) has been widely used. Although assay normal, fasting blood glucose was 300 mg/dl, calcium methodology has advanced in recent years, several was 9.2 mg/dl with an albumin of 4.0 g/dl, and phos­ problems remain in using SAP as a marker both for phate was 4.0 mg/dl. The alkaline phosphatase was 185 screening and corroboration of diagnosis. This is well u/l (normal: 35-115), serum aspartate aminotransferase illustrated by the following case report. (SCOT) waslO u/L (normal: 9-33), and lactic dehydroge­ nase was 1106 u/L (normal: 106-290). The acid phospha­ Case Report tase assayed by thymolphthalein monophosphate sub­ strate was 21.8 u/L (normal: 0-0.7). A 70-year-old white man presented with fatigue, a 40- pound weight loss, bone pain, and polyuria of 6-12 Although chest and left rib roentgenograms were nor- months' duration. His past medical history included dia­ betes mellitus type II controlled with diet and chlorpro­ pamide 500 mg daily, coal miner's pneumoconiosis, and Submitted for publication: December 7.1981 hypothyroidism, for which he was receiving desiccated Accepted for publication: December 28.1981 thyroid. In 1974, he had undergone cholecystectomy, tihis paper received the Annual In-Training Manuscript Award presented by the Henry Ford Hospital Medical Journal vagotomy, and pyloroplasty for cholelithiasis and a •Departmenl of Internal Medicine. First Medical Division, Henry Ford Hospital duodenal ulcer. Address reprint requests to Dr. DiPaolo. Department of Internal Medicine, Henry Ford Hospital. 2799 W Grand Blvd. Detroit. Ml 48202

70 Clinical Use of Acid Phosphatase

mal, a '^mTC methylene diphosphonate bone scan re­ primarily a secretory product. In the reticuloendothelial vealed increased activity in the left lower ribs, a ^smTC system, acid phosphatase is a lysosomal enzyme that sulfur colloid liver/spleen scan demonstrated non­ accounts for the activity in the liver and spleen. Other visualization of the left lobe of the liver and a defect on cells containing significant quantities include osteo­ the medial aspect of the spleen. Based on clinical diag­ clasts, granulocytes, and platelets (8). nosis of carcinoma ofthe prostate with bone metastases, transurethral resection of the prostate was performed. Polyacrylamide gel electrophoresis has demonstrated The tissue diagnosis was benign prostatic hypertrophy. the heterogenicity of the acid phosphatases from var­ Subsequent bone marrow biopsy revealed malignant ious tissues (Table 1). By means of isoenzyme analysis, it histiocytosis. can be demonstrated that in prostatic carcinoma metas­ tatic to bone the elevated SAP is due to prostatic acid Discussion phosphatase, while in other bone disease, including metastases from nonprostatic carcinoma, the SAP origi­ Acid phosphatase activity (EC 3.1.3.2) refers to the ability nates from osteoclasts. Sensitive techniques demon­ ofa group of enzymes to hydrolyze phosphate esters in strate low SAP activity in normal persons. Plasma con­ an acid environment. In 1924, the activity was first discov­ tains fraction 5, while serum contains fractions 3 and 5. ered in erythrocytes, and in 1935, intermittent surges of Therefore, osteoclasts and platelets rather than prostate acid phosphatase activity originating from the prostate cells account for normal SAP activity. This cumbersome was demonstrated in the urine of men. From 1936 to technique is not readily available for clinical use. 1942, Gutman (6) studied serum acid phosphatase in human disease and found high levels in patients with Clinical enzymatic assays employ a phosphate ester sub­ prostatic carcinoma, particularly those with bone metas­ strate which when hydrolyzed by phosphatase in the tases. I n this way, the measurement of serum acid phos­ patient's serum yields a colorimetrically measurable phatase as the first tumor marker was established. In product. Substrates used include phenylphosphate (King 1941, Huggins (7) published his classic paper demonstrat- Armstrong units), B-glycerol phosphate (Bodansky units), ingthatthe prostatic epithelium is under hormonal con­ nitrophenyl phosphate, and more recently, thymol­ trol and that in patients with prostatic cancer, castration phthalein phosphate (international units). The last is the and estrogen administration lower SAP, while andro­ most popular substrate used at present and probably the gens raise the level. These observations form the basis most specific for prostatic acid phosphatase isoenzymes for modern hormonal therapy. (9).

While much is known about the activity of these Since the development of antibodies to prostatic acid enzymes in vitro, their in vivo function is unknown, phosphatase in 1972, several immunoassays have been because all in vitro studies have used artificial substrates developed. These include competitive binding radioim- in a hostile acid environment. Acid phosphatase is pres­ unoassay (RIA),enzymoimmunoassays, and immunohis- ent in all tissues and body fluids. Gram for gram, the tologic methods (10). normal prostate contains a thousand times more of the The instability of SAP by enzyme assay has been a major enzyme than any other tissue. In the prostate, the drawback to its clinical use. When separated from the enzyme is found in the epithelium and lumenwhereitis clot at room temperature, activity is attenuated in one to

TABLE I

Polyacrylamide Gel Electrophoresis

Isoenzyme slowest fastest

1 Tissue Gaucher's tissue prostate, platelets, prostate, osteoclasts, origin cells bound leukocytes other other histiocytes tissues tissues

modified from Yam (8)

71 DiPaolo and Rival

two hours but is well preserved when buffered to a pH of TABLE II 6.2 to 6.4. Because SAP concentration is altered not only Diseases Demonstrating Elevated SAP Activity by enzyme inactivation but also by the contribution of platelet enzyme, the ideal specimen is a fresh plasma Tissue % with elevated Maximum sample buffered to a pH of 6.4 (8). Radioimmunoassay is SAP elevation not affected by enzyme instability. X upper limil of normal Acid phosphatase in nonprostatic disease

Table II lists the major diseases that are accompanied by Prostate elevations in SAP. In bone disease other than metastatic Malignant prostatic carcinoma, acid phosphatase is of electropho- Localized 0-25 2 retic group 5 and reflects osteoclastic activity. Alkaline Soft tissue extension 10-60 6 phosphatase reflects osteoblastic activity. Both enzymes Bone Metastases 80 300 may be complementary for the early detection of bone Nonprostatic carcinoma • 2 metastases in breast cancer patients (11). Miscellaneous invading prostate conditions for which scanty data exist include multiple Benign I myeloma, osteoporosis, osteogenesis imperfecta, and Infaraion (12,13) 30-80 thyroid and renal osteopathy (12). Hypertrophy (11) 4-5 Bone The frequency of SAP elevation in Gaucher's disease depends upon the substrate used; it approaches 100% Malignant with phenylphosphate but only 20% with glycerol phos­ Primary bone tumor 10 phate. Increased SAP has not been reported inTay-Sachs Metastases 19 or Letterer-Siwe disease. Benign Paget's disease 21 The elevations in SAP induced by platelet lysis during Hyperparathyroidism 33 clotting are usually small (approximately 0.15 lU/ml), Reticulendothelial System unless thrombocytosis is present (13). Thrombocytosis does account for the elevated SAP in thrombocythemia, Malignant polycythemia vera, and chronic granulocytic leukemia. Malignant histiocytosis 20-90 Increased concentrations found in patients with mye­ Benign loid metaplasia and acute lymphoblastic leukemia, the Gaucher's disease 100 lymphoproliferative disorders fail to produce elevations Familial sea-blue 50-100 histiocyte syndrome in SAP (14). Platelet lysis may produce mild elevations in Nieman Picks thromboembolic disorders. There are anecdotal reports of SAP elevations in liver disease and in the multiple Hematologic endocrine neoplasia syndrome (15). A familial defi­ Leukocytes ciency of lysosomal acid phosphatase has been reported Myeloproliferative 56 8 that presents as failure to thrive in infancy (16). Lymphproliferative 10 Platelets Acid phosphatase in prostatic disease Idiopathic thrombocytopenic 90-100 purpura While SAP activity in nonprostatic disease is fascinating from a biological viewpoint and essential to understand when levels in an individual patient are to be inter­ modified from White (14) preted, the ultimate use of the assay is as a marker of prostatic carcinoma; indeed, assay methods have been directed toward this end. There remain, however, sev­ eral areas of confusion. obstruction, they studied the effect of prostatic massage In 1949, after Hock and Tessler (17) had observed discre­ on the SAP of 20 patients with prostatic disorders. pancies in the SAP of a patient who had undergone Although a rise in SAP occured in 17 patients, only four prostatic massage and catheterization for urinary achieved levels compatible with a diagnosis of prostate

72 Clinical Use of Acid Phosphatase

carcinoma. However, the authors recommended that SAP in patients with stage B, C, and D carcinoma did not the determination of SAP be delayed 24 hours after correlate with five-year survival during stilbertrol treat­ prostatic massage. While this effect of massage has been ment. The report has been corroborated but has not corroborated by some (18,19) and appears to be accepted been correlated with histological grade, primarily by many urologists (20), some recent authors (21) have because of technical difficulties (32). However, 14% of failed to find SAP elevations. These early studies patients with stage D disease reported by Griffiths (11) employed assay methods now known to have poor had normal SAP, and 90% were classified histologically as reproducibility, especially at low normal levels (22). anaplastic. Furthermore, during anti-adrogenic therapy, Nevertheless, the concept that routine rectal examina­ patients who exhibit a rise in SAP have a poor prognosis, tion with palpation of the normal prostate may cause while those in whom SAP falls have an improved prog­ elevations in SAP is widespread (23). Although many nosis (31,32). In those who relapse after hormonal ther­ recent studies refute this belief (20-25), it persists tena­ apy, a fall in SAP may correlate with survival, a 50% ciously as an aphorism taught to medical students. reduction in tumor mass, and relief of pain after chemo­ therapy (30). Some early authors concluded that a rise in SAP after rectal examination indicated prostatic carcinoma (26,27), but recent studies have also failed to corroborate this Acid phosphatase as a screening test * concept (20,24). One source of difficulty in establishing a Until 1977, it was believed that elevated SAP by enzyme relationship between SAP levels and prostatic carcinoma assay signified the presence of extracapsular, hence is the wide random fluctuations which occur normally incurable, disease. That year, in a pilot study employing (20,28). In addition, after transurethral resection of the radioimmunoassay, Foti (33) concluded that over one- prostate performed on patients either with benign half of all intracapsular disease could be detected. hypertrophy or with carcinoma, SAP elevations of 150- Therefore, SAP by radioimmunoassay was recommended fold normal occur in the former, while no elevation is as a screening procedure for intracapsular disease, even observed in those with malignancy. The difference that undetectable by rectal examination, which was could be due to more limited resection of the carcino­ referred to as the "male PAP test" (34). matous gland, but this variable has been acceptably con­ trolled. Very likely, the normally differentiated benign Despite the difficulties ofthe reported studies, there are gland contains more phosphatase than does malignant several points of agreement. Nevertheless, Foti's optim­ tissue (29). istic report on the sensitivity for the diagnosis of intra­ capsular disease has not been confirmed. Although the It has been fairly well documented that infarction of the sensitivity of RIA is better than that of enzyme assays, it prostate can cause SAP to rise four to seven times nor­ cannot signal the presence of intracapsular disease. mal. For example, 8.3% of patients with benign prostate Moreover, the specificity of RIA is only marginally better hypertrophy were found to have elevated SAP; in all than that of the enzyme assay. cases, infarction was documented histologically (30). Silber (31) reported elevated SAP in 30% of those with The predictive value of SAP can be calculated using data infarction. Many such patients present with acute outlet for the incidence of prostate cancer, with the sensitivity obstruction from the edema of infarction after a long and the specificity of RIA. The prevalence of the disease history of prostatisin. It is likely that the hypertrophied in the U.S. adult white male population was 35 per gland outgrows its blood supply and releases acid phos­ 100,000 in 1964. Radioimmunoassay sensitivity of 70% phatase after infarction. and specificity of 94%, determined by Foti (33) for all stages, can be used. Thus, the predictive value ofthis test Correlation with disease activity will be 0.41% for the male population; that is, one of The studies of Huggins (7) in 1941 established the ratio­ every 244 subjects with elevated SAP will have prostatic nale for hormonal therapy of prostatic carcinoma and carcinoma. Even if the specificity of the test reached proposed a use for SAP as a marker of disease activity. 100%, the cost of detecting one case of prostate carci­ However, only 75-85% of patients with an advanced noma by screening blood tests would be $36,000. Clearly, stage of the disease have elevated SAP. The possible the test has little utility for screening an unselected pop­ explanations for this variation, such as lack of secretion ulation. If used to screen only men 50 to 85 years of age, with differentiation, low rates of secretion, or some bar­ i.e., those at highest risk, the predictive value remains rier to secretion enzyme, are all unproved. Moreover, SAP levels fluctuate randomly by 44-97%, making inter­ •See the Appendix fora discussion of the sensitivity and specificity of SAP by RIA pretation very difficult (28). Ishibe (31) observed that the and by enzyme assay.

73 DiPaolo and Rival

only 7%. To obtain a predictive value of 50%, as accurate Appendix as the flip of a coin, even in this high risk population, a sensitivity of 98% and a specificity of 99.5% would be The utility of a test for screening purposes is a function of its required (35). Statistical considerations alone demon­ predictive value, which is dependent upon its sensitivity and strate the futility of SAP screening tests. specificity as well as the prevalence of the disease in the popu­ lation to be screened (38). On the other hand, ifthe disease prevalence is increased Table III defines the relevant statistics. In the evaluation of a by further selection, the predictive value of SAP assay is diagnostic test, the initial step is to determine how often the improved considerably. The probability of malignancy test is abnormal in a population with well-defined disease; the in a given prostatic nodule is 50%. In this population, the sensitivity and specificity so determined are useful in compar­ predictive value ofa positive test is 93% and ofa negative ing tests to each other. In practice, however, the question is test is 84%. This information is particularly useful in eval­ not whether the person with disease has an abnormal test but uating a patient with a nodule when needle biopsy whether the person with the abnormal test has disease. In a demonstrates benign hypertrophy. If SAP is above nor­ population with a low prevalence of disease, the positive pre­ mal, the probability of carcinoma is 93%, and the patient dictive value depends more on prevalence and specificity than on sensitivity. should have a second biopsy. If the SAP is normal, the probability of benign disease is 84%, and multiple biop­ The major studies of the sensitivity and specificity of SAP both sies are not indicated (36). by RIA and by enzyme assay in the diagnosis of prostatic carcinoma are chiefly impressive in the wide divergence of the Guinan (37) compared prospectively ten screening tests data. Several recent reviewers have discussed immune metho­ for prostatic carcinoma. The population consisted of 300 dology (10,40,41,42,35), While most employ double antibody men between the ages of 50 and 90 who were examined radioimmunoassay, Chu (43) used counterimmunoelectro­ for symptoms of urinary obstruction. Final determined phoresis, an assay known to be less sensitive (10). To improve prevalence of carcinoma was 0.23%. Staging was not specificity, most assays use human prostatic fluid as a sou ree of reported. On the basis of rectal examination, 85% of antigen. Chu (43) used malignant prostatictissueasa sourceof patients were classified correctly. SAP by enzyme assay antigen, although there is no evidence foran acid phosphatase classified 84% correctly, while SAP by RIA was only 70% specific for malignancy. The concept of a unique prostate- accurate. The reasons for the poor sensitivity and speci­ specific acid phosphatase is unproven, for low levels of SAP by ficity of RIA in this study are unclear. Rectal examination TABLE III in this study was performed by a urologist, and patients Calculation of the Predictive Value were selected because they had symptoms of disease. of a Single Laboratory Test The qualifications of the examiner may explain the superior accuracy of the rectal exam, but the stateof the patients would be expected to enhance the efficiency of Se probability that a person with the disease has a postive test all tests. While the problem of asymptomatic patients is TP not addressed in this study, the rectal examination is TP + FN clearly the simplest, least costly, most reliable screening test available. Sp probability thata person without the disease hasa negative test Lindholm (38) questions the very concept of detecting TN intracapsular disease. He argues that such a small tumor TN + FP focus should not be expected to raise SAP above thresh­ PVpos probability that a person with a positive test old when the neoplasm produces less enzyme on a has the disease gram-for-gram basis than the normal or hypertrophic TP gland. Moreover, specificity of the test is not perfect; the TP-i- FP secreted enzyme is diluted in five liters of blood and (Se) (P) then measured in a nonphysiologic environment. While (Se)(P) + (1-Sp)(1-P) SAP may be of some utility in staging, prognosticating du ring therapy, and clinical decision making, it is irrele­ Se sensitivity vant to diagnosis. Sp specificity PVpos positive predictive value P prevalence of the disease in the population TP true positive FP false positive TN true negative FN false negative

74 Clinical Use of Acid Phosphatase

RIA are detectable in women and prostatectomized men (34). macro-infarction. Foti (33) failed to comment on infarction in However, the difficulty may be technical, as Lindholm (38) his group with hypertrophy. Thus, the incidence of elevated found no cross-reactivity with acid phosphatase derived from SAP in uncomplicated benign hypertrophy is uncertain but platelets, erythrocytes, Gaucher's disease, and nonprostatic probably very low. carcinoma. In addition to the use of differing control populations, failure Sensitivity and specificity are interdependent and their calcu­ to include staging criteria contributes to the varying reliability lation is based on data including the presumed upper limit of reported for SAP assay as a diagnostic test for prostate carci­ normal. Published studies are frequently not comparable noma. Understaging, which is common when clinically staged becausetheselected"normal" populations differ. Foti(33) set patients are subsequently pathologically staged, will increase the upper limit of normal above that of the entire normal the apparent sensitivity for early disease (41). Of Lind holm's 98 control group. Griffiths (34) chose as a threshold value the patients (38), 43 were staged pathologically. While he found mean plus two standard deviations based on a normal male sensitivities of 22% and 29% in stages A and B, respectively, control group. Persons with histologically confirmed benign none of the seven pathologically staged patients in his group hypertrophy comprised the control group of Bruce (44), whose had a positive test, and none of those with a positive test were upper limit was in the 97.5 percentile. Because Lindholm (38) pathologically staged. Bruce (44) staged the group with intra- established the upper limit on the basis of a specificity of 94% prostatic disease by bimanual exam. While Foti in his original and 97.5%, his sensitivities can be compared to those of others. paper made no comment on staging details, he later confirmed He, too, used a group with benign hypertrophy as a control that he staged laparotomy for stage B disease (45). but, interestingly,excludedthose with clinically suspected and histologically proved infarction. Griffiths (34) excluded no one Aside from simple lack of specificity, the only other proposed from his group with benign hypertrophy and found that, of 19 etiology of false positivity is hyperlipoidemia, which Griffiths with elevated SAP, 17 had histologic evidence of micro- or (34) found in two of his normal control group. While SAP was markedly elevated by RIA, the enzyme assay was normal. References

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