Valor actual de los hallazgos histológicos de biopsias de próstata negativas en la predicción del riesgo futuro de cáncer de próstata clínicamente significativo / The current value of histological findings in negative prostate biopsies to predict the future risk of clinically significant prostate cancer

Introducción: Se recomienda realizar una biopsia prostática (PBx) de repetición ante una sospecha persistente de cáncer de próstata (PCa) o cuando se identifica proliferación acinar atípica (ASAP), neoplasia intraepitelial de alto grado (HGPIN) extensa (≥3 zonas de biopsia) o HGPIN con células atípicas sospechosas de adenocarcinoma (PIN-ATYP). Actualmente se recomienda realizar una resonancia magnética multiparamétrica (mpMRI) y PBx guiada por mpMRI (MRI-TBx) en una PBx de repetición. Nuestro objetivo fue analizar el valor actual para predecir el riesgo de PCa clínicamente significativo (csPCa) del hallazgo de ASAP, mHGPIN, PIN-ATYP y otros hallazgos histológicos.MétodosSe realizó un análisis retrospectivo de 377 PBx de repetición. Se realizó MRI-TBx cuando la puntuación PI-RADS fue≥3 y PBX sistemáticas de 12 cilindros guiadas por ecografía transrectal (TRUS) cuando fue≤2. ASAP, HGPIN, HGPIN multifocal (mHGPIN), PIN-ATYP y otros 8 hallazgos histológicos fueron reportados prospectivamente en las PBx negativas. El csPCa fue definido como grado ISUP≥2.ResultadosLa incidencia de ASAP, mHGPIN y PIN-ATYP fue 4,2%, 39,7% y 3,7% respectivamente, y la tasa de csPCa fue estadísticamente similar en los pacientes con estos hallazgos histológicos. Sin embargo, las tasas de csPCa con atrofia proliferativa inflamatoria (PIA) presente y ausente fueron 22,2% y 36,1%, respectivamente. La PIA fue el único hallazgo histológico que predijo un menor riesgo de csPCa, con OR de 0,54 (IC 95%: 0,308-0,945, p=0,031). La PIA fue, también, un factor predictor independiente en un modelo combinando variables clínicas y mpMRI, que obtuvo un área bajo la curva de 0,86 (95% IC: 0,83-0,90).ConclusionesLa PIA resultó ser el único hallazgo histológico predictor del riesgo de csPCa, y puede contribuir en un modelo predictivo; mHGPIN no fue predictor de riesgo de csPCa. La baja incidencia de ASAP (4,2%) y PIN-ATYP (3,7%) impidió que pudiéramos obtener conclusiones sobre estas lesiones. (AU)

Introduction: Repeat prostate biopsy (PBx) is recommended under persistent suspicion of prostate cancer (PCa) or in the face of the following findings: atypical small acinar proliferation (ASAP), extense (≥3 biopsy sites) high-grade prostatic intraepithelial neoplasia (HGPIN), or HGPIN with atypical glands, suspicious for adenocarcinoma (PIN-ATYP). Nowadays, multiparametric magnetic resonance imaging (mpMRI) and mpMRI targeted PBx (MRI-TBx) are recommended in repeat PBx. Our objective was to analyze the current value of ASAP, mHGPIN, PIN-ATYP and other histological findings to predict clinically significant PCa (csPCa) risk.MethodsRetrospective analysis of 377 repeat PBxs. MRI-TBx was performed when Prostate Imaging-Reporting and Data System (PI-RADS) score>3 and 12-core transrectal ultrasound (TRUS) systematic PBx when≤2. ASAP, HGPIN, mHGPIN, PIN-ATYP, and 8 other histological findings were prospectively reported in negative PBx. CsPCa was defined as ISUP group grade>2.ResultsIncidence of ASAP, multifocal HGPIN (mHGPIN) and PINATYP was 4.2%, 39.7% and 3.7% respectively, and csPCa rate was statistically similar among men with these histological findings. However, the rate of csPCa was 22.2% when proliferative inflammatory atrophy (PIA) was present, and 36.1% when it was not. PIA was the only histological finding which predicted lower risk of csPCa, with an OR of .54 (95% CI: .308-.945, P=.031). In addition, PIA was an independent predictor of a model combining clinical variables and mpMRI which reached area under de ROC curve of .86 (95% CI: .83-.90).ConclusionsPIA emerged as the only predictive histological finding of csPCa risk and can contribute to a predictive model. mHGPIN failed to predict csPCa risk. The low incidence of ASAP (4.2%) and PIN-ATYP (3.7%) prevented us from drawing conclusions. (AU)

The current value of histological findings in negative prostate biopsies to predict the future risk of clinically significant prostate cancer.

BACKGROUND: Repeat prostate biopsy (PBx) is recommended under persistent suspicion of prostate cancer (PCa) or in the face of the following findings: atypical small acinar proliferation (ASAP); extense (≥3 biopsy sites) high-grade prostatic intraepithelial neoplasia (HGPIN); or HGPIN with atypical glands; suspicious for adenocarcinoma (PIN-ATYP). Nowadays; multiparametric magnetic resonance imaging (mpMRI) and mpMRI targeted PBx (MRI-TBx) are recommended in repeat PBx. Our objective was to analyze the current value of ASAP; mHGPIN; PIN-ATYP and other histological findings to predict clinically significant PCa (csPCa) risk. METHODS: Retrospective analysis of 377 repeat PBxs. MRI-TBx was performed when Prostate Imaging-Reporting and Data System (PI-RADS) score >3 and 12-core transrectal ultrasound (TRUS) systematic PBx when ≤2. ASAP; HGPIN; mHGPIN; PIN-ATYP; and 8 other histological findings were prospectively reported in negative PBx. CsPCa was defined as ISUP group grade >2. RESULTS: Incidence of ASAP; multifocal HGPIN (mHGPIN) and PINATYP was 4.2%; 39.7% and 3.7% respectively; and csPCa rate was statistically similar among men with these histological findings. However; the rate of csPCa was 22.2% when proliferative inflammatory atrophy (PIA) was present; and 36.1% when it was not. PIA was the only histological finding which predicted lower risk of csPCa; with an OR of 0.54 (95%CI: 0.308-0.945; P = .031). In addition; PIA was an independent predictor of a model combining clinical variables and mpMRI which reached area under de ROC curve of 0.86 (95%CI: 0.83-0.90). CONCLUSION: PIA emerged as the only predictive histological finding of csPCa risk and can contribute to a predictive model. mHGPIN failed to predict csPCa risk. The low incidence of ASAP (4.2%) and PIN-ATYP (3.7%) prevented us from drawing conclusions.

Behavior of total and free serum testosterone as a predictor for the risk of prostate cancer and its aggressiveness.

CONTEXT: Serum testosterone is mostly bound to the sex hormone-binding globulin and albumin. A small metabolically active part is present in the form of free testosterone (FT). The relationship between serum total testosterone (TT) levels and prostate carcinogenesis is debated. Our hypothesis is that the serum FT concentration is more closely associated with the risk of prostate cancer (PC) and its aggressiveness than TT. OBJECTIVE: To analyze the scientific evidence that relates serum TT and/or FT levels with the diagnosis of PC and its aggressiveness. ACQUISITION OF EVIDENCE: A systematic review was conducted in PubMed up to January 2015 using the following mesh terms: prostate cancer, sex hormone, androgen, testosterone and free testosterone. SYNTHESIS OF THE EVIDENCE: We found 460 publications, 124 of which were reviewed to analyze the evidence. The relationship between serum TT levels and the diagnosis of PC and its aggressiveness is highly heterogeneous. The variability in the design of the studies, the quantification methods and other variables could explain this heterogeneity. In a number of studies that evaluated the estimated or measured FT, the evidence remains equally conflicting. CONCLUSIONS: Based on the current evidence, we cannot recommend the measurement of serum TT and/or TL levels for the diagnosis of PC or for assessing its aggressiveness.

Sedentarism and overweight as risk factors for the detection of prostate cancer and its aggressivenes.

OBJECTIVE: To analyze the influence of sedentary (SE) and overweight (OW) in the risk of prostate cancer detection (CP) and aggressiveness. MATERIAL AND METHOD: We performed prostate biopsy (PB) to 2,408 consecutive male, 5 ARIs untreated, because of elevated serum PSA above 4.0 ng/mL (91%) or suspicious digital rectal examination (9%). In all ultrasound guided PB, 10 cores were obtained plus 2 to 8 additionals, according to age and prostate volume. Physical activity was assessed using a survey (SE vs non-SE) and calculated body mass index (normal vs OW > 25 kg/cm(2)). The tumor aggressiveness was evaluated according to the Gleason score (high grade «HG¼: Gleason > 7) and D'Amico risk (high risk «HR¼: T > 3a or PSA > 20 or Gleason score > 7). RESULTS: We found a significant association between SE (52.5%) and OW (72.9%), P < .001. The overall PC detection rate was 35.2%. In men with SE it was 36.7% and non-SE 33.6%, P = .048. The overall rate of AG tumors was 28.3%, 29.2% in men with SE and 27.1 in non-SE, P = .261. The overall rate of AR tumors was 35%, 39.7% in men with SE and 29.4% non-SE, P < .001. CP was detected in 38.1% of men with normal BMI and 34.3% in men with OW, P = .065. HG tumor rates were 18.1% and 31.4% respectively, P < .001 and AR tumor rates were 22.6% and 39.2% respectively, P < .001. Binary logistic regression showed that SE was an independent predictor of CP, OR .791 (95% CI: .625-.989), P = .030. SE and OW were independent predictors of HG: OR .517 (95% CI: .356-.752), P = .001, and OR 1.635 (95% CI: 1070-2497), p = 0.023. SE and OW were also independent predictors of HR: OR .519 (95% CI .349-.771), P = .001, and OR 1.998 (95% CI 1.281-3.115), P = .002. CONCLUSIONS: In men who met criteria for prostate biopsy an association between sedentary and overweight exist. A sedentary lifestyle is associated with increased risk of PC detection while sedentary and overweight were associated with more aggressive tumors.

Value of percent free prostate-specific antigen for the prediction of pathological stage in men with clinically localized prostate cancer.

PURPOSE: To analyze if the percentage of free prostate-specific antigen (PSA) can provide additional information to the combination of local clinical stage, serum PSA and Gleason score in the prediction of final stage and pathological features of prostate cancer. MATERIALS AND METHODS: A group of 480 men with clinically localized prostate cancer underwent lymphadenectomy and radical prostatectomy. Total and free PSA were measured in preoperative serum. Clinical stage was T1 in 70.4% of patients and T2 in 29.6%. The biopsy Gleason score ranged between 2 and 4 in 5.6%, between 5 and 7 in 78.4%, and was higher than 7 in 16%. Total serum PSA was below 4.1 ng/mL in 4.3%, between 4.1 and 10 ng/mL in 66.4%, between 10.1 and 20 ng/mL in 22.5%, and higher than 20 in 6.7% of patients. The tumor was organ-confined in 49.8% and specimen-confined in 64.2%, and its pathological features were favorable in 35%. RESULTS: Multiple logistic regression analysis demonstrated that percent free PSA has independent predictive value for pathological stage only in the subset of patients with cT1 tumors and serum PSA between 4.1 and 10 ng/mL. In this group the probability of organ-confined cancer was 68.3% if the percent free PSA was above 15 and 56.3% if it was lower (p<0.001). The probability of specimen-confined disease was 86.6% and 71.3%, respectively (p<0.007), and the probability of favorable pathology was 59.8% and 39.6%, respectively (p<0.002). We also found higher rates of organ- and specimen-confined tumors and favorable pathology for every Gleason score when the percent free PSA was higher than 15. CONCLUSIONS: Percent free PSA seems to provide additional information to the combination of clinical stage and Gleason score for the prediction of pathological features only in patients with clinical stage T1c and serum PSA between 4.1 and 10 ng/mL.

Use of percent free prostate-specific antigen as a predictor of the pathological features of clinically localized prostate cancer.

PURPOSE: To evaluate the usefulness of percent free serum prostate-specific antigen (PSA) as a predictor of the pathological features of prostate cancer. MATERIALS AND METHODS: Total and free serum PSA were measured preoperatively in 220 consecutive patients with clinically localized prostate cancer who underwent radical prostatectomy. Organ-confined disease and favorable pathology were considered as the outcomes for this study. RESULTS: Percent free serum PSA was not able to predict these outcomes in the overall population. However, it could significantly predict favorable pathology in a subset of patients in whom digital rectal examination (DRE) was normal and total PSA ranged from 4.1 to 10 ng/ml. A 11% cutoff provided a significant distribution with an odds ratio of 2.8 (95% confidence interval 1.1-7.0), a positive predictive value of 63. 3% and a negative predictive value of 46.3%. CONCLUSIONS: According to these results, we suggest that percent free PSA may provide additional information for the staging of clinically localized prostate cancer. However, the reference population for its usefulness would be those patients with normal DRE and total PSA between 4.1 and 10 ng/ml.

Prediction of prostate volume based on total and free serum prostate-specific antigen: is it reliable?

OBJECTIVE: To analyze the utility of total/free prostate-specific antigen (PSA) and age as predictors of the prostate volume in men with symptomatic benign prostatic hyperplasia (BPH) and no evidence of prostate cancer. PATIENTS AND METHODS: Total and free serum PSA were determined in 681 patients with normal digital rectal examination and symptomatic BPH using the Hybritech method. Prostate volume was measured by transrectal ultrasound (TRUS). TRUS-guided biopsy was performed in 459 (67.4%) of the patients with a serum PSA >4.0 ng/ml. RESULTS: The relationship with prostate volume was best described in a log linear fashion by free PSA (R(2) = 0.367), total PSA (R(2) = 0.264) and age (R(2) = 0.017). Multiple linear regression demonstrates no significant influence of age. Free PSA was able to predict the individual TRUS prostate volume +/-10% in 67% of the patients and +/-20% in 91.2% and total PSA in 63 and 90. 9%, respectively. CONCLUSION: Prostate volume is strongly related with free and total PSA. Both determinations would be able to predict the TRUS prostate volume +/-20% in more than 90% of the patients.

Effect of high-grade prostatic intraepithelial neoplasia on total and percent free serum prostatic-specific antigen.

OBJECTIVE: To analyze the influence of high-grade prostatic intraepithelial neoplasia (HGPIN) on total serum prostatic-specific antigen (PSA) and percent free PSA. METHODS: Total and free serum PSA were determined in 81 consecutive patients with clinical T1c prostate cancer who underwent radical prostatectomy. HGPIN was detected in 62 specimens (76.5%). RESULTS: Median total PSA was 9.2 ng/ml when there was not HGPIN and 8.1 ng/ml when it existed, p>0.05. Median percent free PSA was 11.7 and 9.1%, respectively, p<0.03. However, a multiple linear regression analysis demonstrated there was no effect of HGPIN on total PSA nor on percent free PSA. Percent free serum PSA was significantly influenced by total PSA and the pathological tumor stage. CONCLUSION: HGPIN does not seem to contribute significantly on serum total PSA and percent free PSA.

Effect of inflammation and benign prostatic enlargement on total and percent free serum prostatic specific antigen.

OBJECTIVE: To analyze the influence of inflammation and benign prostatic enlargement on total and percent free serum prostatic specific antigen (PSA). PATIENTS AND METHODS: Total and free PSA serum levels were determined in 284 patients with no evidence of cancer in the sextant ultrasound-guided biopsy. Double antibody immunoradiometric assay Tandem and Tandem free PSA were used. Benign tissue without inflammation was found in 23.2% of the patients (group 1), while in 68.3%, it was associated with chronic prostatitis (group 2) and with acute prostatitis in 8.4% (group 3). RESULTS: Median serum PSA was 7.8 ng/ml in group 1, 6.7 ng/ml in group 2 and 6.4 ng/ml in group 3, p>0.05. Median percent free PSA was 14.1, 15.6 and 16.4%, respectively, p>0.05. Multiple linear regression analysis showed that prostatic size was the only significant contributor to serum PSA concentration. Moreover, total PSA and prostatic size contributed significantly to the percent free serum PSA. Inflammation had no significant influence on total or percent free serum PSA. CONCLUSION: Inflammation has an important prevalence in cancer-free prostatic biopsy specimens. It seems to have no significant influence on total and percent free serum PSA. However, prostatic size seems to be the major contributor.

Influence of high-grade prostatic intra-epithelial neoplasia on total and percentage free serum prostatic specific antigen.

OBJECTIVE: To analyse the influence of high-grade prostatic intra-epithelial neoplasia (HGPIN) on total and percentage free serum prostatic specific antigen (PSA). PATIENTS AND METHODS: The total and free serum PSA levels were measured (using a double-monoclonal antibody immunoassay, Tandem and Tandem free PSA, Hybritech Inc, Liège, Belgium) in 570 consecutive patients undergoing sextant ultrasound-guided prostatic biopsy because of an abnormal digital rectal examination or a serum PSA concentration of > 4.0 ng/mL. The main diagnosis was benign disease in 321 (56%) and prostate cancer in 249 (44%). HGPIN was detected in 85 (15%) of the patients; in 17 (20%) it was associated with benign tissue and in 68 (80%) with prostate cancer. RESULTS: Patients with benign disease had a median total serum PSA level of 7.2 with no HGPIN and 7.7 ng/mL when HGPIN was present (P>0.05); the corresponding values in patients with prostate cancer were 16.0 and 15.9 ng/mL (P>0.05). The median percentage free serum PSA was 15.8 in patients with HGPIN-free benign disease and 14.1 when HGPIN was present (P>0.05); the corresponding values in patients with prostate cancer were 9.7 and 11.0 (P>0.05). In a multivariate analysis, prostate cancer was the major contributor to total and percentage free serum PSA levels. CONCLUSION: The presence of HGPIN does not contribute significantly to total and percentage free serum PSA levels.

[Influence of prostatic intraepithelial neoplasia on blood levels of PSA and free PSA percentage]. / Influencia de la neoplasia intraepitelial prostática en la concentración sérica de PSA y porcentaje de PSA libre.

OBJECTIVE: To analyze the influence of prostatic intra-epithelial neoplasia (PIN) on serum total PSA levels and free PSA percentage. MATERIAL AND METHODS: Total and free PSA concentrations (IRMA Tandem and Tandem free PSA, Hybritech Inc) were determined in 349 patients with normal DRE and PSA greater than 4 ng/ml, undergoing prostatic biopsy by sextant and in 81 patients with prostate cancer in clinical stage T1c N0 M0 undergoing radical prostatectomy. In the group of patients undergoing prostatic biopsy, benign hyperplasia was diagnosed in 284 (81.6%) patients, 234 (82.4%) were PIN free, 41 (14.4%) with low grade PIN and 9 (3.2%) with high grade PIN. Cancer was diagnosed in 65 patients (18.6%), 30 of whom (46.2%) had associated high grade PIN. High grade PIN was detected in 62 (76.5%) patients in the group undergoing radical prostatectomy. RESULTS: No statistically significant differences were detected among total PSA and free PSA percentage serum concentrations relative to the detection of associated PIN, regardless of its degree, in patients undergoing prostatic biopsy. Cancer detection was the single most significant contributing variable. In patients undergoing radical prostatectomy, high degree PIN did not influence significantly. The greatest contribution in this group was the pathological stage. CONCLUSIONS: PSA serum concentration and PSA percentage are not influenced by the existence of PIN. High degree PIN is strongly associated to cancer. Accordingly, repeat biopsies are warranted in any patient presenting such lesions.

The free-to-total serum prostatic specific antigen ratio as a predictor of the pathological features of prostate cancer.

OBJECTIVES: To analyse the role of the ratio of serum free (f) to total (t) prostatic specific antigen (f/tPSA) as a predictor of the pathological features in patients with clinical stage T1c disease submitted for radical prostatectomy. PATIENTS AND METHODS: Total and fPSA were determined before surgery in 76 consecutive patients with clinical stage T1cN0M0 disease and a serum tPSA level of 4-20 ng/mL. The pathological stage was defined as organ-confined in 47 (62%), with capsular penetration in 27 (35%) and seminal vesicle infiltration in two (3%). In 18 of the specimens (24%) the surgical margins were positive. The pathology was favourable in 41 patients (55%). Total and fPSA were determined using the Tandem and Tandem-free PSA immunoassays (Hybritech Inc, Belgium) RESULTS: The mean tPSA was: 8.7 ng/mL when the tumour was organ-confined and 8.6 ng/mL when the disease was extraprostatic (P>0.05); 8.4 ng/mL when the tumour was specimen-confined and 9.3 ng/mL when positive margins or seminal vesicle involvement were detected (P>0.05); and 8.3 ng/mL when the pathology was favourable and 9.0 ng/mL when unfavourable (P>0.05). The f/tPSA was 11.8% when the tumour was organ-confined and 9.1% when it was not (P<0.03), 11.9% when the tumour was specimen-confined and 7.6% when not (P<0.002) and 12.1% when the pathology was favourable and 9.1% when unfavourable (P<0.008). A threshold of 11% f/tPSA provided an odds ratio for organ-confined disease of 2.7, for specimen-confined disease of 7.6 and for a favourable pathology of 3.9. CONCLUSION: The f/tPSA seems to provide useful information in the prediction of the pathological features of patients with clinical T1c prostate cancer and a tPSA of 4.1-20 ng/mL.

Individual variations of total and percent free serum prostatic specific antigen: could they change the indication of prostatic biopsy?

The aim of this study was to analyse the individual variations of total and percent free serum prostatic specific antigen (PSA) and to evaluate whether they could change the indication for prostatic biopsy. Prostatic needle biopsy was indicated in 63 patients with serum PSA between 4.0 and 10 ng/ml. A new determination of total and free PSA was done before the biopsy procedure. The time between the determinations ranged from 29 to 59 days. The total and free serum PSA determinations were performed by a double monoclonal antibody radioimmunoassay Tandem and Tandem free PSA. The median coefficient of variation for serum PSA was 12.9 in cancer free patients and 18.8 when cancer was detected, it was 32.6 and 42.2 respectively for percent free serum PSA. A 22.8% rate of discrepancy between the determinations was found when prostatic biopsy was indicated only by percent free PSA lower than 25. Sensitivity ranged from 93.3% to 100, and reduction of unnecessary biopsies between 15.2 and 21.8%. We conclude that individual variations in total and percent free serum PSA could have clinical implications because of the possibility that it changes the indication for a prostatic biopsy.