Prostatic Acid Phosphatase: Clinical Utility in D etection, Assessment, and Monitoring Carcinoma of the Prostate*

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1 ANNALS O F CLINICAL AND LABORATORY SC IEN C E, Vol. 14, No. 4 Copyright 1984, Institute for Clinical Science, Inc. Prostatic Acid Phosphatase: Clinical Utility in D etection, Assessment, and Monitoring Carcinoma of the Prostate* ALEX A. PAPPAS, M.D. an d RICHARD H. GADSDEN, S r., Ph.D. Departm ent o f Laboratory Medicine, Medical University o f South Carolina, Charleston, SC ABSTRACT Prostatic carcinoma is a significant cause of male cancer death. The majority of cases present as incurable disease. The measurement of acid phosphatase has served to confirm clinically suspected disease and staging. The immunochemical methods have increased clinical sensitivity and specificity in detecting curable occult or confined disease, but not significantly so as to warrant mass screening. Prostatic acid phosphatase remains a test for confirming clinical staging of prostatic carcinoma and a response factor to therapy at present. Introduction Prostatic carcinoma is the third most common malignancy in males. It is the second most common cause of cancer death in males over the age of 55. In 1983 there will be an estimated 73,000 new cases and 23,000 prostatic cancer deaths.35 Prostatic carcinom a is frequently called the pathologist s carcinoma in that it is often found as an occult malignancy at autopsy or in the course of a routine transurethral prostatectom y (TURP). This incidence of occult carcinoma is in direct proportion to the age of the patient at this demise and to the thoroughness for which the malignancy is searched at autopsy. The autopsy incidence increases from approximately 10 percent at age 50 * Address requests for reprints to Richard H. Gadsden, Sr., Ph.D. to approximately 40 percent at age 80 or at a rate of one percent per year.2,22,33 The actual clinical incidence is much less; it is 0.2 percent at age 50, increasing to 0.8 percent at age Thus, it appears there might be two different types of prostatic carcinoma: one of very low m alignant potential which may never manifest itself clinically and one which early on fulfills the biologic and clinical criteria of malignancy.39 Discussion Prostatic carcinoma is most often an adenocarcinoma arising in the acinus of the gland, usually being multifocal or extensive in most cases. The carcinom a tends to be in the periphery of the gland in contrast to benign prostatic hyperplasia (BPH) which tends to localize to the periurethral center of the gland.3,7, /84/ $01.20 Institute for Clinical Science, Inc.

2 8 6 PAPPAS AND GADSDEN Prostatic carcinom a is a malignancy which is hormonally dependent upon the action of androgens, primarily dihydrotestosterone, but the hormones are not considered to play a

2 2 8 6 PAPPAS AND GADSDEN Prostatic carcinom a is a malignancy which is hormonally dependent upon the action of androgens, primarily dihydrotestosterone, but the hormones are not considered to play a primary role in the pathogenesis of the malignancy.13 Benign prostatic hyperplasia, although hormonally dependent, does not predispose towards malignancy.22 Various clinical staging classifications are presently used which may or may not be comparable (table I). The American Urological Society (AUS) has defined four clinical stages which have been subsequently subdivided. Stage A is occult malignancy and stage B is localized within the prostatic capsule. Both stage A and stage B malignancies are potentially curable.24 Unfortunately, intracapsular malignancy presents clinically in less than 20 to 25 percent of cases. Most prostatic carcinomas present as locally invasive Stage C or as metastic stage D disease. The overall survival is inversely correlated with the extent of the disease (table II). The clinical symptoms of advanced disease, stages C and D, may be urinary obstruction, bone pain, and/or a hard nodular prostate on rectal examination. These findings are present in over 50 percent of cases. The five to 10 year survival has been correlated with T ABLE I Comparison of the Various Clinical Staging Classifications for Prostatic Carcinoma W h itm o r e 39 V a c u r g * 37 Al/Sf29 A J C l /U I C C t2 ^ B 1 B2 T 1N0M 0 T2No M q C l t 3 n 0 m0 c 2 D1 D2 t 4n0m0 t -4» -3 m0 t 1-4 n 1-3 m1 Veterans A d m in is tr a tio n C o o p e r a tiv e G roup. fa m eric a n U r o l o g i c a l S y stem. ^A m erican J o i n t C o m m is s io n /I n te r n a tio n a l U nion A g a in s t C a n c e r. T = tu m o r; N - n o d e s ; M = m e t a s t a s i s the clinical stages. The best survival is with intracapsular disease and the worst obviously with metastatic disease. In initial staging, lymphatic metastases may have occurred and may not be recognized clinically. This would then reclassify initial intracapsular stage A or B or extracapsular C to a metastatic stage D category. The frequency of lymphatic metastases and initial staging appears to correlate even b e tte r w ith the overall survival (table III). The clinical stage of prostatic carcinom a dictates the therapy.30 Beginning with the original reports by the Gutmans,19 serum acid phosphatase (ACP), in fact, the first described tumor marker, has been a valuable adjunct in the diagnosis and management of prostatic carcinoma.15 It became readily apparent with clinical experience that ACP determinations are neither entirely sensitive in detecting early prostatic carcinoma nor specific for prostatic carcinoma.8,21,41 There has been an evolution in the various methods for the analysis of ACP in regards to analytical specificity and sensitivity of the prostatic fraction of ACP culminating with the present immunoassays. The acid phosphatases are a group of phosphohydrolases which hydrolyze phosphoric monoesters in an acidic medium. In prostatic epithelium, the major role of ACP is not known. In prostatic fluid, these ACPs are concerned with metabolic activity of spermatozoa by catalyzing the transfer of phosphates. In the normal prostatic epithelium, there is an orderly process of secretory product synthesis. In BPH and with carcinoma, there is a decrease in the amount of PAP secreted p er cell but an increase in overall PAP production because of the overall increase in cellular mass.34 Various isoenzym es of serum acid phosphatase have been identified. These isoenzymes have been conveniently classified as to being tartrate sensitive (the

CARCINOMA OF THE PROSTATE 2 8 7 TABLE I I Staging of Prostatic Carcinoma Clinical Incidence/Prevalence/Survival6 '20'38 Clinical Estimated Adjusted Clinical Incidence Prevalence Survival* Stage

3 CARCINOMA OF THE PROSTATE TABLE I I Staging of Prostatic Carcinoma Clinical Incidence/Prevalence/Survival6 '20'38 Clinical Estimated Adjusted Clinical Incidence Prevalence Survival* Stage Physical Findings Percent Percent Percent a i Negative rectal focal tumor *2 Negative rectal diffuse tumor B1 Nodule <1.5 cm or <1 lobe (diffuse) b2 Nodule >1.5 cm or >1 lobe (diffuse) C1 No involvement of seminal vescicles <70g C2 Involvement of seminal vescicles >70g»! Pelvic lymph node involvement or urethral obstruction d 2 Distant lymph node or bone involvement *Five to ten years. prostatic fraction, PAP) or tartrate resistant (the non-prostatic fraction). The tartrate sensitive fraction, which is supposedly specific for the prostatic fraction of total acid phosphatase, is also found in leukocytes, platelets, and other tissues. Normally the prostatic fraction constitutes only 10 to 25 percent of the total serum acid phosphatase found in males, while the platelet fraction constitutes the majority of the remaining fraction.26,41 Elevations of PAP in patients with prostatic carcinoma are due to an actual increase in tum or mass, loss of ductal connections, tissue necrosis, and neovascularization with subsequent leakage of the enzyme into the circulation. Regional lymphatic spread and distant metastases may establish independent sites of enzyme secreting tumor. Parenthetically, nonelevations of PAP may be explained TABLE III Clinical Stage of Prostatic Carcinoma-Incidence of Lymph Node Metastasis and Survival &'29'38 Clinical Stage Frequency of Lymph Node Metastasis Percent Survival Percent 5 95 A1 a B b ci/c D1/D by poorly differentiated m alignancies which have little activity, nondetection by the analytical method used, potential inactivation of the enzyme, tumor barrier, or concomitant hormonal, radiation or chemotherapy ,33,40 With the potential of increased sensitivity and specificity using radioimmunoassay (RIA), the probability of detecting (screening) intracapsular prostatic carcinoma became a potential reality.12 However, this initial enthusiasm has waned considerably.10 In comparing the clinical sensitivity (positive test (p)/presence of disease (d)) of PAP in detecting non-invasive prostatic carcinoma, there is a wide range of sensitivities ranging from 12 to 33 percent in occult stage A disease and eight to 79 percent in intracapsular stage B disease (table IV). There appears to be a general increase in sensitivity as the extent (stage) of disease increases. Stages C and D disease, however, are quite often evident clinically by either rectal exam or by a suspicious history. Measurements of PAP in stages C and D disease are usually only confirmatory of the disease and are usually indicative of the probable extent of the disease. The overall sensitivity of PAP determination by radioimmunoassay for all stages is approximately 50 percent. The various nonisotopic immunoassays appear to have comparable clinical sensitiv

4 288 PAPPAS AND GADSDEN TABLE IV Clinical Sensitivity in Detecting Prostatic Carcinoma by Clinical Stage Percentage Positive (%)-Positive Test/Presence of Disease (P/D) Quinones^2 Mahan28 B r u c e 5 Griffiths G r i f f i t h s F o t i 12 Cumulative Clinical Sensitivity Stage %- (P/D) %- (P/D) %-(P/D) %-(P/D) % (P/D) %- (P/D) % (P/D) A ( 1 / 4 ) ( 2 /1 6 ) ( 4 /3 2 ) ( 7 /5 8 ) ( 4 /2 5 ) ( 8 /2 4 ) 1 6 -( 2 6 /1 5 9 ) B 8 - ( 1 / 1 2 ) ( 9 /1 6 ) ( 1 1 /3 8 ) ( 1 3 /4 1 ) ( 1 0 /2 5 ) ( 2 6 /3 3 ) 4 2 -( 7 0 /1 6 5 ) C ( 6 /1 3 ) ( 6 /2 0 ) ( 3 / 1 4 ) ( 1 7 /3 6 ) ( 1 1 /2 5 ) ( 2 2 /3 1 ) 4 7 -( 6 5 /1 3 9 ) D 5 2 -( 1 4 /2 7 ) ( 2 0 /3 2 ) ( 3 6 /4 1 ) ( 6 2 /7 2 ) 7 6 -( 1 9 /2 5 ) ( 2 3 /2 5 ) 7 8 -(1 7 4 /2 2 2 ) 4 9 -(3 3 5 /6 8 5 ) ities in detecting prostatic carcinoma at the various stages of the disease (table V). However, the enzyme immunoassay (EIA) method described by Davies and Griffiths11 (table V) shows lack of sensitivity at clinical stages C and D. The immunoassay portion of the assay is designed to isolate PAP from the serum milieu with measurement being of PAP activity. As previously pointed out, PAP activity m easurem ents lack the sensitivity as currently demonstrated by the immunoassay (mass measurements). It is now evident that the use of PAP in screening the asymptomatic patient is not warranted because of the relatively low sensitivity in detecting stage A, or even stage B disease, when coupled with the relatively low prevalence of prostatic carcinoma. Even the screening of higher risk groups older men and negroes does not increase the predictive value of a positive test.13 It has been suggested that baseline levels may be drawn on an individual patient and subsequently followed periodically. Although the decision level may not be reached, any upward change from the baseline value may be significant for the individual patient.17 In BPH, elevations of PAP are observed in the various immunoassays: RIA, 10 percent; enzyme linked immunosorbent assay (ELISA), 30 percent; and EIA, six percent. Possible etiologies for the observed PAP elevations in this benign process are: prostatic manipulation, cytolysis of acinar cells, cellular hyperplasia with a concomitant overall increase in enzyme secretion or indeed an occult malignancy which has not been clinically detected (table VI). It is interesting that elevations of PAP TABLE V Clinical Sensitivity Nonisotipic PAP Immunoassays in Detecting Prostatic Carcinoma by Clinical Stage Percent Positive (%)-Positive Test/Presence of Disease (P/D) Griffiths Cooper^ Davies 11 Lee Griffiths18 Cumulative Clinical ELISA (1982) ELISA (1981) EIA (1982) FIA (1980) FIA (1982) Sensitivity Stage %~(P/D) %-(P/D) %- (P/D) %- (P/D) %- (P/D) %-(P/D) A ( 5 / 2 5 ) ( 1 1 / 3 2 ) * ( 7 / 3 1 ) * ( 1 1 /1 5 ) ( 6 / 2 5 ) ( 4 1 / ) B ( 1 1 / 2 5 ) ( 2 4 / 4 3 ) ( 1 1 / 2 5 ) ( 4 6 / 9 3 ) C ( 1 3 / 2 5 ) ( 2 0 / 3 5 ) ( 1 0 / 2 3 ) ( 3 1 / 3 8 ) ( 1 3 / 2 5 ) ( 8 7 / ) D ( 2 1 / 2 5 ) ( 4 7 /5 1 ) ( 2 6 / 5 8 ) ( 3 2 /3 7 ) ( 2 1 / 2 5 ) ( /1 9 6 ) ( /5 6 3 ) ELISA - E nzym e L in k e d I m m u n o s o rb e n t A s s a y. EIA = Enzyme Immuno A ssa y. F IA = F lu o ro im m u n o a s s a y. * C om b ined s t a g e s A & B.

5 CARCINOMA OF THE PROSTATE TABLE VI Prostatic Acid Phosphatase (PAP)-Elevations in Benign Prostatic Hypertrophy (BPH) Percent Elevations-(Number Positive Tests/Total Number Patients) (P/D) %- (P/D) %-(P/D) Quinones32 G r i f f i t h s * 6 Griffiths17 6-(2/36) 9-(2/22) 9-(19/213) 20-(17/84) 9-(6/68) Cooper3 40-(22/56) Davies1 20-(17/84) 6-(4/68) Cumulative 10-(46/423) 31-(39/140) 12-(89/731) Elevation by all immunochemical methods in BPH 6-(4/68) RIA = Radioimmunoassay. ELISA = Enzyme Linked Immunosorbent Assay. EIA = Enzyme Immunoassay. occur in eight percent (33/406) of nonprostatic m alignancies. Overall, these malignancies are of a potentially secretory type: neuroendocrine, carcinoids, oat cell carcinom as, or hem atopoietic malignancies. It is possible that these tumors elaborate one of several substances that are quite immunologically similar to PAP (table VII). Prostatic acid phosphatase is one of several defined response criteria in monitoring patients with prostatic carcinoma. TABLE VII Serum PAP E le v a tio n i n N o n -P ro s ta tic M alig n an cies P e rc e n t E le v a tio n s -(N o. E le v a tio n s /T o ta l No. T ested ) F o t i 12 11% (9/83) Unknown (5) Pulm onary (4) Q uinones32 4% (2/51) Lynphoma (2) G r i f f i t h s 16 9% (10/109) Oat C e ll Carcinom a (4) C arcinoid (2) R enal C e ll Carcinom a (1) A denocarcinom a - Lung (1) A denocarcinom a -. B r e a s t (1) A denocarcinom a - P a n c reas (1) D avies11 8% (3/36) O at C e ll Carcinom a (1) Lymphoma (1) M u ltip le Myeloma (1) Cum ulative 9% (24/279) ELISA - EIA C ooper9 40% (3/80) B ladder Carcinoma (3) D avies11 8% (3/36) O at C e ll Carcinom a (1) Lymphoma (1) Pulm onary Carcinom a (1) Cum ulative 5% (6/116) 8% (30/395) - E le v a tio n by a l l immunochemical methods i n n o n p ro s ta tic m alig n an cy. RIA = R adioim m unoassay. ELISA = Enzyme L inked Im m unosorbent A ssay. EIA = Enzyme Immunoassay. Generally, normalization of a previously elevated value correlates well with response to therapy.25 However, it is important to observe several sequential levels of PAP before determining the response to therapy, i.e., there may be a random or even diurnal fluctuation in isolated determ inations.4 Patients who have a normalization of PAP generally tend to survive longer than patients who continue to have elevations even after rather intensive therapy.31 Summary The newer immunochemical methods are more analytically sensitive and specific. The sensitivity in detecting clinically occult and curable disease has increased, but not significantly enough to warrant using PAP as a screening procedure. The rectal exam remains still the most effective screening procedure. The increased analytical sensitivity has resulted in observed elevations of PAP in the presence of clinically evident BPH. An elevated PAP with a negative rectal exam and prostatic biopsy places the physician in a dilemma as to resolving whether or not occult malignancy indeed exists. This question of false positive PAP is yet to be resolved clinically. The presence of PAP elevation is non-pros

2 9 0 PAPPAS AND GADSDEN tatic malignancies is of interest and generally indicates a secretory type of malignancy which is elaborating a protein similar in antigenic qualities as PAP.

6 2 9 0 PAPPAS AND GADSDEN tatic malignancies is of interest and generally indicates a secretory type of malignancy which is elaborating a protein similar in antigenic qualities as PAP. Prostatic acid phosphatase remains a response factor in monitoring the progression or regression of clinical disease and confirmation of initial clinical disease. References 1. American Joint Committee for Cancer Staging and End Results Reporting. (Committee: O. H. Beahrs, D. T. Carr and P. Rubin). Manual for Staging Cancer Chicago, Whiting Press, 1978, pp B a r o n, E. and A ngrist, A.: Incidence of occult adenocarcinoma of the prostate after 50 years of age. Arch. Path. 32: , B l e n n e r h a s s e t, J. B. and V i c k e r y, A. L.: Carcinoma of the prostate gland. Cancer 19: , B r e c k m a n,w. D., L a s t i n g e r,l. B., and S e d o r, F.: Unpredictable fluctuations in serum acid phosphatase activity in prostatic cancer. J. Am. Med. Assoc. 245: , B r u c e, A. W., M a h a n, D. E., S u l l i v a n, L. D., and G o l d e n b e r g, L.: The significance of prostatic acid phosphatase in adenocarcinoma of the prostate. J. Urol. 725: , C a t a l o n a, W. J. and Sc o t t, W. W.: Carcinoma of the prostate: A review. J. Urol. JJ9:l-8, C o f f e y, D. S. and Is a a c s,j. T.: Control of prostate growth. Urology (Suppl.) 17:17-24, C o o k, W. B., F i s h m a n, W. H., and C l a r k, B. G.: Serum acid phosphatase of prostatic origin in the diagnosis of prostatic cancer: clinical evaluation of 2408 tests by the Fishman-Lerner Method. J. Urol. 88: , C o o p e r, E. H., G l a s h a n, R., R o b i n s o n, M. R. G., M o r g a n, D. B., and T r a u t n e r, K.: The evaluation of a new enzyme immunoassay for the measurement of prostatic acid phosphatase. Clin. Chim. Acta 113:27-34, C o o p e r, J. F. : The radioimmunochemical measurement of prostatic acid phosphatase: current state of the art. Urol. Clin. N. Am. 7: , D avies,s. N. and G riffiths,j. C.: Prostate specific acid phosphatase: further studies with immunological techniques. Clin. Chim. Acta 122:29-38, F oti,a. G., C o o p e r,j. F., H e r s c h m a n, H., and M a l v a e z,r. R.: Detection of prostatic cancer by solid-phase radioimmunoassay of serum prostatic acid phosphatase. New Eng. J. Med. 297: , F ra nk s, L. M.: Etiology, epidemiology, and pathology of prostatic cancer. Cancer 32: , G ittes, R.: Acid phosphatase reappraised, New Engl. J. Med. 297: , G i t t e s, R. F.,and C h u, T. M.: Detection and diagnosis of prostate cancer, Seminars in Oncology. 3: , G r i f f i t h s, J. C.: Prostate-specific acid phosphatase: re-evaluation of radioimmunoassay in diagnosing prostatic disease. Clin. Chem. 26: , G r i f f i t h s, J., R i p p e, D. F., and P a n f i l i, P. R.: Comparison of enzyme-linked immunosorbent assay and radioimmunoassay for prostate-specific acid phosphatase in prostatic disease. Clin. Chem. 28: , G r i f f i t h s, J. : Clinical applications of fluoroimmunoassay: An evaluation in the diagnosis of early prostate adenocarcinoma. XI International Congress of Clinical Chemistry. Kaiser, E., Gabi, F., Muller, M. M., and Bayer, M., eds. New York, Walter de Gruytel & Co., 1982, pp G u t m a n, A. B. and G u t m a n, E. B.: An acid phosphatase occurring in the serum of patients with metastasizing carcinoma of the prostate gland. J. Clin. Invest. 17: , H a n a s h, K. A., U t z, D. C., C o o k, E. N., T a y l o r, W. F., and T it u s, J. L.: Carcinoma of the prostate: a 15-year followup. J. U r o l. 107: , H e r b e r t, F. K.: The estimation of prostatic phosphatase in serum and its use in the diagnosis of prostatic carcinoma. Q. J. Med. 15: , H u t c h i n s o n, G. B.: Epidemiology of prostatic cancer. Semin. Oncology, 3: , International Union Against Cancer (UICC): Classification of Malignant Tumors, 3rd ed. Geneva, 1978, pp J e w e t t, H. J.: The present status of radical prostatectomy for stages A & B prostatic cancer. Urol. Clin. N. Am. 2: , J o h n s o n, D. E. S., S c o t t, W. W., G i b b o n s, R. P., P r o u t, G. R., S c h m i d t, J. D., and M u r p h y, G. P.: Clinical significance of serum acid phosphatase levels in advanced prostatic carcinoma. Urology 8: , Lam, L. W., Li, C. Y., Yam, L. T., Smith R. S., and H a c k e r, B.: Comparison of prostatic and nonprostatic acid phosphatase in prostatic acid phosphatase measurement: Its role in detection and management of prostatic cancer. Ann. N.Y. Acad. Sei. 390:1-15, L e e, C. L., C h u, T. M., W a y s m a n, C. Z., S l a c k, H. H., and M u r p h y, G. P.: Value of a new fluorescent immunoassay for human prostatic acid phosphatase in prostatic cancer. Urology i5: , M a h a n, D. E. and D o c t o r, B. P.: A radioimmune assay for human prostatic acid phosphatase levels in prostatic disease. Clin. Biochem. 12:10-17, M u r p h y, G. P., G a e t a, J. F., P i c k e n s, J., and W a j s m a n, Z.: Current status of classification and staging of prostate cancer. Cancer 45: , M u r p h y, G. P. : Prostatic cancer: continuing process. C A 3i:96 110, 1981.

7 3 1. P a u l s o n, D. F., B e r r y, W. R., C o x, E. B., W a l k e r, A., and L a s z l o, J.: Treatment of metastatic endocrine-unresponsive carcinoma of the prostate gland with multiagent chemotherapy: indicators of response to therapy. J. Natl. Can. Inst. 63: , Q u i n o n e s, G. R., R o h n e r, T. J., D r a c o, J. R., and D e m e r s, L. M.: Will prostatic acid phosphatase determination by radioimmunoassay increase the diagnosis of early prostatic cancer? J. Urol, 225: , S c o t t, R., Jr., M u t c h n i k, D. L., L a s k o w s k i, T. Z., and S c h m a l h o r s t, W. R.: Carcinoma of the prostate in elderly men: incidence, growth characteristics and clinical significance. J. Urol. 101: , S o d e m a n, T. M. and B a t s a k is, J. G.: Acid Phosphatase. Urologic Pathology: The Prostate. Myron Tannenbaum, M., ed. Philadelphia, Lea & Febiger, 1977, pp S i l v e r b e r g E. and L u b e r a, J. A.: A review of CARCINOMA OF THE PROSTATE American Cancer Society estimates of cancer cases and deaths. CA 33:2-25, Urz, D. C. and F a r r o w, G. M.: Pathological differentiation and prognosis of prostatic carcinoma. J. Am. Med. Assoc. 209: , The Veterans Administration Co-operative Urological Research Group: Carcinoma of the prostate: A continuing co-operative study. J. Urol. 92: , The Veterans Administration Co-operative Urological Research Group: Treatment and survival of patients with cancer of the prostate. Surg. Gynec. Obstet. 224:1011:1017, W h i t m o r e, W. F., Jr.: Hormone therapy in prostatic cancer. Am. J. Med. 22: , W o o d w a r d, H. Q.: The clinical significance of serum acid phosphatase. Am. J. Med. 27: , Y a m, L. T.: Clinical significance of the human acid phosphatase a review. Am. J. Med. 56: , 1974.

Definition Prostate cancer

Prostate cancer 61 Definition Prostate cancer is a malignant neoplasm that arises from the prostate gland and the most common form of cancer in men. localized prostate cancer is curable by surgery or radiation