Bo, M.

Capello, S.

Casetta, G.

Fabris, F.

Marinello, R.

Ventura, M.

English

Bo, Mario

Institutional Research Information System University of Turin

Relationship between Prostatic Specific Antigen (PSA) and volume ofthe prostate in the Benign Prostatic Hyperplasia in the elderlyMario Bo a,1, Manuel Ventura a, Renata Marinello a, Simona Capello b,Giovanni Casetta c, Fabrizio Fabris a,*a Department of Medical and Surgical Science, Section of Gerontology, University of Turin, Turin, Italyb Department of Radiology, University of Turin, Turin, Italyc Department of Urology, University of Turin, Turin, ItalyAccepted 22 April 2003Contents1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2082. Subjects and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2083. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2084. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211Critical Reviews in Oncology/Hematology 47 (2003) 207/211www.elsevier.com/locate/critrevoncAbstractIncrease of the Prostatic Specific Antigen (PSA) is a non-invasive, sensitive and specific markers for prostatic diseases, includingprostatic cancer. However, age-related Benign Prostatic Hyperplasia (BPH), as well as prostatitis, may at the same time alter PSAvalues. The aim of this study was to evaluate the relationship between ageing and PSA, and whether age-specific upper normal limitsof PSA should be considered for elderly patients. We evaluated 569 consecutive subjects aged 60 years or more (mean age 74.2 years)who were free from malignant prostatic disease, without clinical evidence of prostatic phlogosis and who were not receiving PSAlevels affecting drugs. All patients underwent Digital Rectal Examination (DRE) and Trans-Rectal Ultrasonography (TRU), withdetermination of the three prostatic diameters, the Maximum Adenoma Diameter (MAD) and calculation of the prostatic volume(PV) by the ellipsoid formula. PSA was determined in all patients before DRE and TRU, and the PSA free ratio was determined inthose with total PSA values /4 ng/ml. The PSA density was calculated according to the formula PSA/PV. One hundred andseventy-nine subjects (31.6%) were found to have PSA values /4 ng/ml: among them, 26 (14.5%) had values exceeding 10 ng/ml.Age was slightly correlated with PV (PB/0.05), but not with PSA values. On the contrary, PSA values were strongly related with PVand MAD (PB/0.01 both). Mean PSA-free ratio was 16.39/6.0% and most of patients had values in the so-called ‘grey zone’ ofdiscrimination between benignity and malignity.* Corresponding author. Present address: Department of Medical and Surgical Disciplines, Geriatric Section, University of Torino, CorsoDogliotti 14, Turin 100126, Italy. Tel.: /11-663-7140/11-633-6734; fax: /11-696-1045.E-mail address: fabrizio.fabris@unito.it (F. Fabris).1 Present address: Institute of Gerontology, University of Turin, Corso Bramante 88, 10126, Torino, Italy. Tel.:/33-011-6337140; fax:/33-011-6961045.1040-8428/03/$ - see front matter # 2003 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/S1040-8428(03)00094-5M. Bo et al. / Critical Reviews in Oncology/Hematology 47 (2003) 207/211208Elevated PSA levels are common in older subjects without evidence of prostatic malignancy; PSA values are poorly affected byage itself and strongly correlated with increasing PV. These results suggest the possibility to consider as indicative of benignity PSAvalues between 4 and 10 ng/ml, when these values are associated with relevant increase of PV and with PSA-free ratio greater than10%.# 2003 Elsevier Ireland Ltd. All rights reserved.Keywords: Prostatic Specific Antigen (PSA); Benign Prostatic Hyperplasia (BPH); Elderly; Prostatic volume1. IntroductionMost of prostatic diseases occur in advanced age. TheProstatic Specific Antigen (PSA), sinthetyzed only byprostatic gland cells, is currently regarded as a sensitiveand specific markers for prostatic diseases, includingBenign Prostatic Hypertrophia (BPH), prostatitis andcancer. Although very sensitive, it is not at all specificfor a special prostatic disease. Currently total PSAvalues /4 ng/ml are considered pathologic, and whenexceeding 10 ng/ml are strongly suggestive of malig-nancy. However, ageing is associated with physiologicalhypertrophic modifications of the prostate and BPH isextremely common among older subjects [1,2]. It iswidely demonstrated that BPH may be associated withslight increases in PSA values [3,4]. Oesterling [5] founda positive correlation between PSA and prostaticvolume (PV), whereas Dalkin et al. [6] and Crawford[7] proposed age-specific PSA ranges.There remain important areas of uncertainty aboutthe relationship between ageing, BPH and ‘normal’ PSAvalues. The aim of this study was to evaluate primarilythe relationship between ageing, increasing PV and PSAvalues, and, secondary, whether these relationshipsmight justify the adoption of age-specific PSA values.2. Subjects and methodsIn the period between March 1999 and May 2000, 569consecutive patients were enrolled among those ad-mitted to the Geriatric Acute Ward and to the UrologyDepartment of Molinette, a university-teaching hospitalin Turin, according to the following inclusion criteria:age /60 and 5/90 years, Digital Rectal Examination(DRE) negative for suspected malignancy, absence ofprostatic malignancy on the basis of postoperativehistological specimens and/or negative bioptic responsein patients with PSA values exceeding 4 ng/ml, absenceof clinical and histological evidences of prostatic phlo-gosis [8] and absence of current or previous medicaltreatment with drugs which could affect PSA values (5-areductase inhibitors, GnRH agonists, antiandrogens,progestative agents and a-channel blockers) [9,10].In all patients serum total PSA was determined usingimmunoenzymatic assay (Immulite 2000); in patientswhose total PSA values were greater than 4 ng/ml, thePSA free ratio was also determined. Blood sample forPSA determination were obtained before DRE andTrans-Rectal Ultrasonography (TRU) to avoid falsepositive results due to the compression of the gland.DRE was performed in all patients by qualified urolo-gist, aimed to exclude objective evidence suggestive ofmalignancy or phlogosis, and to evaluate volume andconsistence of the prostate. TRU was performed byradiologist qualified in this investigation using a 5 MHzprobe and the following measures were determined:anteroposterior (A ), transversal (B ) and longitudinal(C ) diameters of the whole prostate and the MaximumAdenoma Diameter (MAD). The PV was calculatedaccording to the ellipsoid formula [11]: PV/4/3p/A /2/B /2/C /2. The TRU examination was completed byobtaining multiple bioptic specimens to rule out thepresence of malignancy in those patients who weresuspected for cancer in reason of high PSA values and/or abnormal DRE.The PSA density (PSAD) was calculated by dividingthe total PSA value for the volume of the prostate(PSAD/PSA/PV).Statistical analysis was performed by Student t-test,ANOVA and evaluation of the Pearson’s index of linearcorrelation ‘r ’, for continuous variables, using SPSS/PC/ packaging.3. ResultsFive hundred and sixty-nine subjects (mean age74.29/6.8 years, range 60/90 years) participated at thestudy. The following mean values (9/ standard devia-tion) were observed: PSA 3.719/3.07 ng/ml; PV 55.59/29.9 ml (upper normal limit: 15 ml [12]; MAD 3.69/1.2cm; and PSAD 0.0679/0.055 ng/ml.Three hundred and ninety subjects (68.4%) had totalPSA values within the upper normal limit (5/4 ng/ml),while 179 patients (31.6%) had PSA values exceedingthis limit. Among these latter subjects, 153 (85.5%) hadPSA values /4 and 5/10 ng/ml and 26 (14.5%) hadtotal PSA values /10 ng/ml.Only 16 subjects (2.8%) had PV within the uppernormal limit (15 ml); moderate and severe increases ofthe PV were observed, respectively in 449 (80%) and in104 (17.2%) patients.Age was found to be weakly but significantly corre-lated with increasing PV (PB/0.05), but not with totalPSA values, whereas PSA values were strongly corre-lated either with PV and with MAD (PB/0.01 both)(Fig. 1). Table 1 shows mean PV and MAD valuesaccording to PSA ranges commonly used in clinicalsettings (5/4, /4 and 5/10, /10 ng/ml): either PV andMAD values increased significantly (PB/0.0001 both)according to the increasing values of PSA considered.The mean PSA free ratio in the 179 subjects with totalPSA /4 ng/ml was 16.39/6.0%; most of these subjectshad PSA free ratio values between the 25th and the 75thpercentile, (respectively 12.3 and 20.2%). No significantcorrelations were observed between PSA free values andother variables investigated (PV, age, PSA and MAD)with the exception of a slight inverse correlation withPSAD.4. DiscussionIn this study we observed that roughly a third ofsubjects over 60 years had PSA values exceeding theupper normal limit. Despite the high prevalence of thisalteration, results of the present study indicate that thisfinding should not be considered ageing-related butrather age-associated disease related. In fact, accord-ingly with previous studies [3,4,13], we found strongFig. 1. Pearson’s correlation between the variables (PSA, age, PV, maximum diameter of adenoma).Table 1Values (media9/standard deviation) of PV and maximum diameter of adenoma in relation with PSA expressed for groupsPSA5/4 ng/ml (n/390) 4/ PSA5/10 ng/ml (n/153) PSA /10 ng/ml (n/26) F PVolume (ml) 45.949/23.35 72.109/30.44 101.729/4.81 53.38 B/0.0001Diameter of adenoma (cm) 3.299/1.08 4.199/0.97 4.819/1.50 28.03 B/0.0001M. Bo et al. / Critical Reviews in Oncology/Hematology 47 (2003) 207/211 209correlations of PSA values with PV and MAD values,but not with age itself [14,15]. Moreover, the absence ofa correlation between age and PSAD (which is avolume-corrected PSA) strongly reinforces this conclu-sion. Therefore, as suggested in previous papers[3,4,13,16], it is likely the increased amount of secretingtissue, as it occurs in BPH, is the main responsible forthese slight to moderate increases in PSA values.Although the increase of PSA values may be consideredslight to moderate (5/10 ng/ml) in most of patients, asmall group of subjects (4.5%) may have more severeincreases (/10 ng/ml). The PSA free ratio is of limitedutility in these patients: in fact in most subjects withPSA values exceeding the upper normal limit; the PSAfree ratio values were within the so-called grey zone.These data indicate that in older subjects values of PSAexceeding the upper normal limit are commonly ob-served in absence of malignant disease, thereby increas-ing the likelihood of false positive results. In our view,these results provide further arguments against ‘abuse’of PSA as diagnostic or screening tool in elderlysubjects. Whether routine screening of all men is cost-effective remains controversial, especially for men age 75and older [17]. If early detection of prostatic cancerimproves health outcomes, the population most likely tobenefit from screening will be men 50/70 years of agewho were at higher risk. Older men and men with othersignificant medical problems who have limited life-expectancy are unlikely to benefit from screening [18].Some limitations of this study should be discussed.The cross sectional design of this study and the absenceof prospective observation do not allow to verify thetrue absence of malignancy. In fact, even the negativityof multiple bioptic specimens does not rule out,particularly in severe BPH, the possibility of a carci-noma in situ. The adoption of a hospital-derived samplemight have facilitated the selection of subjects with moresevere diseases. Finally, the absence of a comparisonwith a group of consecutive patients with prostatecancer does not seem to limit the validity of the resultsobserved.With these limits, this study showed that slight tomoderate increases of PSA values are common in oldersubjects without evidence of malignancy and that theyare mainly accounted for by a greater PV. On thesebasis, the adoption of age-specific range for PSA valuesis not recommended. This possibility of false positiveresults further reduces the indications to use PSA as adiagnostic screening tool in elderly subjects.ReviewersDomenico Cucinotta , M.D., Chairman, Departmentof Internal Medicine and Aging, S. Orsola MalpighiUniversity Hospital, Via Albertoni 15, I-40138 Bologna,Italy.Prof. Hans-Ju¨rg Leisinger , Service d’Urologie, CHUV(Centre Hospitalier Universitaire Vaudois), Rue duBugnon, CH-1011 Lausanne, Switzerland.Prof. Dr. D. Hauri , Direktor Urologische Klinik,Universita¨tsspital Zu¨rich, Frauenklinikstrasse 10, CH-8091, Zu¨rich, Switzerland.References[1] Thomas Rhodes, Cynthia J Girman, Steven J Jacobsen, RosebudO Roberts, Harry A Guess, Michael M Lieber. Longitudinalprostate growth rates during 5 years in randomly selectedcommunity men 40 to 79 years old. J Urol 1999;161:1174/9.[2] Jakobsen H, Torp-Pedersen S, Juul Niels. Ultrasonic evaluationof age-related human prostatic growth and development of benignprostatic hyperplasia. Scand J Urol Nephrol 1988;Suppl. 107:26.[3] Roherborn CG, Boyle P, Gould L, Waldstreicher J. Serumprostate-specific antigen as predictor of prostate volume in menwith benign prostatic hyperplasia. Urology 1998;53:581/9.[4] Hammerer PG, McNeal JE, Stamey TA. Correlation betweenserum prostate specific antigen levels and the volume of theindividual glandular zones of the human prostate. J Urol1995;153:111/4.[5] Oesterling JE. Prostate-specific antigen: a critical assessment ofthe most useful tumor marker for adenocarcinoma of theprostate. J Urol 1991;145:907/23.[6] Dalkin B, Ahmann F, Southwick P, Bottaccini M. Derivation ofnormal prostate specific antigen (PSA) level by age. J Urol1993;149:413A.[7] Crawford E. Report on the 1993 prostate cancer awareness week.J Urol 1993;71:445/50.[8] Neal D, jr., Clejan S, Sarma D, et al. Prostate specific antigen andprostatitis: effect of prostatitis on serum PSA in the human andnon human primate. Prostate 1992;20:105/11.[9] Gormley GJ, Stoner E, Bruskewitz RC, et al. The effect offinasteride in men with benign prostatic hyperplasia. New Eng JMed 1992;327:1185/91.[10] Salerno R, Moneti G, Forti G, et al. Simultaneous determinationof testosterone, dihydrotestosterone and 5a-androstan-3a-17b-diol by isotopic dilution mass spectrometry in plasma andprostatic tissue of patientes affected by benign prostatic hyper-plasia effects of a 3-month treatment with a GnRH analog. JAndrol 1998:234/9.[11] Aarnink RG, Giesen RJ, de la Rosette J, Huynen AL, DebruyneF, Wijkstra H. Planimetric volumetry of the prostate: howaccurate is it? Physiol Meas 1995;16:141/50.[12] Bensadoun H. Hypertrophie be´nigne de la prostate: diagnostic,examens comple´mentaires, choix the´rapeutique. Presse Med1997;26:1875/80.[13] Rietbergen JBW, Kranse R, Hoedemaeker RF, Kruger AEB,Bangma CH, Schro¨der K, Schro¨der FH. Comparison of prostate-specific antigen corrected for total prostate volume and transitionzone volume in a population-based screening study. Urology1998;52:237/46.[14] Bosch JLHR, Hop VJW, Bangma CH, Kirkels WJ, Schro¨der FH.Prostate specific antigen in a community-based sample of menwithout prostate cancer: correlations with prostate volume, age,body mass index, and symptoms of prostatism. Prostate1995;27:241/9.M. Bo et al. / Critical Reviews in Oncology/Hematology 47 (2003) 207/211210[15] Kirillos MM. Prostate-specific antigen and age. Is there acorrelation? And why does it seem to vary? Eur Urol1996;30:296/301.[16] Fong CJ, Sherwood ER, Braun EJ, Berg LA, Lee C, KozlowskiJM. Regulation of prostatic carcinoma cell proliferation andsecretory activity by extracellular matrix and stromal secretions.Prostate 1992;21:121.[17] Gambert SR. Prostate cancer. When to offer screening in theprimary care setting. Geriatrics 2001;56:22/31.[18] Harris RP, Lohr KN. Screening for prostate cancer: an update ofthe evidence for the U.S. preventive services task force. Ann IntMed 2002;137:917/29.BiographiesMario Bo was born 1959 in Turin (Italy). MedicalDoctor (1984), Graduate in Geriatrics and GeriatricSurgery and in Cardiology. University researcher in theUniversity of Turin, Institute of Gerontology.Fabrizio Fabris is full Professor of Gerontology andGeriatrics in the Faculty of Medicine, University ofTorino, since 1980. He leads the Post-Graduate Schoolof Geriatrics of the University of Torino and theGeriatric Department of the Faculty of Medicine,University of Torino.He is a member of the Italian Atherosclerosis StudyGroup and Director of the Center of Torino. He was amember of the National Commission for Drug Evalua-tion of the Italian Ministry of Health from 1993 to 1996.He promoted the creation of the University Post-graduating Course of Psychogeriatrics. Main researchfields: Atherosclerosis and ageing; Geriatric therapy;Public Health Organization (services for the elderly). Hehas devoted himself to the problems of gerontology andgeriatrics for over 30 years, with particular regard to thematters connected with the life quality of the elderly. Hehas proposed intervention models aimed at preservingtheir physical, psychological and social autonomy andmaintaining them in the family as long as possible. Hewas one of the first to realize the day hospital for theelderly and has proposed an original model of homecare.He is currently involved in the development of adepartment for high risk disabling pathologies.M. Bo et al. / Critical Reviews in Oncology/Hematology 47 (2003) 207/211 211

Relationship between Prostatic Specific Antigen (PSA) and volume of the prostate in the Benign Prostatic Hyperplasia in the elderly.

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Relationship between Prostatic Specific Antigen (PSA) and volume of the prostate in the Benign Prostatic Hyperplasia in the elderly.

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