Prognostic Parameters OtherThan Gleason Score for the Daily Evaluation of Prostate Cancer in Needle Biopsy

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1 European Urology European Urology 48 (2005) Prostate Cancer Prognostic Parameters OtherThan Gleason Score for the Daily Evaluation of Prostate Cancer in Needle Biopsy F. Algaba a,b, *, Y. Arce a, A. Oliver c, C. Barandica d,1, J.M a Santaularia a, R. Montañés c a Pathology Section, Fundació Puigvert, Calle Cartagena , Barcelona, Spain b Department of Morphology, Faculty of Medicine, Autonomic University, Barcelona, Spain c Central Laboratory Service, Fundació Puigvert, Barcelona, Spain d Fellowship in the Pathology Section of Fundació Puigvert Accepted 28 June 2005 Available online 18 July 2005 Abstract Objective: To evaluate in prostate needle biopsies the usefulness and the efficacy of not time-consuming morphologic parameters in order to predict whether prostate cancer is organ-confined or it is not, that could contribute additional information to pre-surgical serum PSA and Gleason score, both of them parameters already accepted as clinically significant. Methods: Three hundred and two consecutive patients were evaluated, of whom a diagnostic needle biopsy and the radical prostatectomy specimen with no pre-surgical hormone therapy were available. Bilateral or unilateral extension, number of positive cores, percentage of positive cores, intraprostatic perineural invasion (IPNI) and the presence of high-grade prostatic intraepithelial neoplasia (HGPIN) in any of the biopsy cores were evaluated in the needle biopsy. Results: The median of cores is 6. The IPNI, the presence of bilateral tumour, and the percentage of positive cores, higher than 37.5% (ROC curve), show significant crude OR (4.0, 2.8, 6.9 respectively). The regression model discloses that only the percentage of positive cores shows a significant OR (5.8) adjusting for bilaterality, IPNI, HGPIN and age. Conclusions: The percentage of cores with cancer and the bilateral involvement are another two parameters predictive of cancer with extraprostatic extension. (p < in both). IPNI has statistical significance too (p < 0.002), but it is related to the tumour volume expressed through the two mentioned parameters. # 2005 Elsevier B.V. All rights reserved. Keywords: Prostate cancer; Perineural invasion; Volume prostate cancer; Needle prostate biopsy 1. Introduction Even though the primary objective of a prostate needle biopsy is to diagnose the presence of carcinoma, once this has been identified the pathologist is always requested to assess its aggressiveness, which often is equivalent to requesting him/her to determine whether it will be an organ-confined neoplasia (pt2) or not * Corresponding author. Tel ; Fax: address: falgaba@fundacio-puigvert.es (F. Algaba). 1 Present address: Clínica Colsanitas, Bogotá, Colombia. (pt3) in case a radical prostatectomy needs to be made. There are different tested protocols in literature that constitute guidelines regarding which prognostic parameters should be included in the pathology report, in addition to the Gleason score (Gs) [1,2]. However, in the course of a recent survey among urologists as to which of these parameters are used to make therapeutic decisions, different outlooks have been disclosed [3]. These differences may be a reflection of not enough interpersonal reproducibility, and consequently of various intergroup yields, and for this reason the pathologist s efforts in search of time-consuming factors are /$ see front matter # 2005 Elsevier B.V. All rights reserved. doi: /j.eururo

2 F. Algaba et al. / European Urology 48 (2005) not taken into account because the urologist usually pays more attention to the serum PSA and to the Gs than to other findings. The purpose of this paper is to assess the usefulness and the level of efficacy of morphologic, basic and not time-consuming parameters to predict whether a tumour is organ-confined or not, that could addinformationtotheserumpsaandtothebiopsy Gs. 2. Materials and methods Three hundred and two consecutive patients were studied, of whom a diagnostic needle biopsy and a radical prostatectomy specimen, without pre-surgical hormone treatment, were available; these patients are selected according to the Gs of the biopsy and the serum PSA, following our protocol [4]. The age of the patient at the time of diagnosis, the total serum PSA, the PSA s free fraction (FPSA) and the PSA s ratio (RPSA) prior to the needle biopsy, with which the diagnosis of prostate adenocarcinoma was established, were recorded in all cases. PSA and FPSA determinations were performed by means of an immunometric assay with an Immulite analyser (DPC, Dipesa). The needle biopsy and the prostatectomy specimen parameters measured were those recorded in the pathological report, performed by three uropathologists (only one pathologists for every report) in the course of their daily evaluations. Only those cases in which intraprostatic perineural invasion (IPNI) had been detected were re-evaluated by the three pathologists in order to quantify and qualify their characteristics. A median of 6 cores [4 14] random biopsies were made per patient; in 42 (13.9%) cases there were more than 10 cores (with a maximum 14) because the transition zone biopsy was included, all of them with an 18-gauge needle. They were fixed in Bouin s fluid between sponges to keep them stretch. Twelve levels of each of the cores were made. The parameters evaluated in the needle biopsy were (Table 1): Gs, taking into account the primary and secondary pattern. In the needle biopsies with more than two patterns, the worst pattern is reflected in the Gs, even if it is not the predominant or the secondary pattern [5]. The IPNI detected in the usual sections stained with haematoxylin-eosin, (no immunohistochemical markers for nerve recognition were used) and in those cases in which they were found to be invaded, the invasion was specified to be in one site or both, unifocal (one nerve) or multifocal (more than one nerve) and whether it affected only a part or the whole of the perimeter of the nerve. Unilateral or bilateral involvement was evaluated as a parameter of carcinoma extension, as well as the number and the percentage of positive cores over the whole number obtained. This system was chosen as the fastest and most reproducible method, thus avoiding the problem of how to quantify cases with scattered and isolated carcinoma foci in a same core, and also because there are studies that have shown a correlation between the percentage of fragments with cancer and the volume affected by neoplasia [6]. The presence of High Grade Prostatic Intraepithelial Neoplasia (HGPIN) at the cores was also verified, concomitant or not concomitant to the adenocarcinoma foci. The prostatectomy specimens were fixed in buffered formaldehyde, and entirely included in whole mounting sections, after inking of the surgical margins. The relationship of the carcinoma with the inked margin was determined, and a margin was considered positive only if the neoplasia contacted the Indian ink. The carcinoma was considered extraprostatic only if the surrounding fat tissue and/or the extraprostatic seminal vesicles muscle had been invaded. Carcinoma involvement of the margin without fat tissue, with no evidence of extension into the above-mentioned structures, was considered an intraprostatic tumour Statistical analysis Differences between percentages (qualitative variables) were analysed by means of contingency tables and the chi-square test. Differences between quantitative variables were evaluated with the Student-Fisher s test or with the Mann-Withney s nonparametric tests. Calculation of the positive core percentage cut-off in the biopsy was made by means of a Receiver Operating Characteristic (ROC) curve. Crude odds-ratio (OR) were calculated and adjusted by means of a conditioned logistic regression model. p 0.05 is considered significant. SPSS v 12.0 and MedCalc softwares were used. Table 1 Needle biopsy parameters Parameter Gleason score Intraprostatic Perineural Invasion (IPNI) (by H&E) Tumour Volume High grade Prostatic Intraepithelial Neoplasia (HGPIN) Criteria Primary pattern + Secondary pattern (The worst pattern is always reflected) One site/both sites One nerve (unifocal)/more that one nerve (multifocal) Partial perimeter involvement/whole perimeter One site/both sites Number of positive cores Percent of positive cores Presence/absence 3. Results The patients mean age is years (range 44 to 73 years). All of them have an acinar prostate adenocarcinoma. Two hundred and forty-two patients (80.1%) have an intraprostatic tumour (pt2). Sixty patients (19.9%) have an extraprostatic carcinoma; forty patients (13.2%) have pt3a, and 20 (6.7%) have invasion of the extraprostatic seminal vesicle (pt3b). There are no significant differences in age between these two groups. The total number of cores is similar in both groups of patients, with a median in the case of intraprostatic cancer, and in the

3 568 F. Algaba et al. / European Urology 48 (2005) Table 2 Serum PSA previous to diagnosis according pt category of radical prostatectomy specimen pt Category N Mean Std. Deviation p PSA pt pt FPSA pt pt RPSA pt pt extraprostatic involvement (a median of 6 in each of the groups). The surgical margins are positive in 137 cases (45.4%). Table 2 shows the serum PSA (total, free and ratio) values. No significant differences are detected concerning total and FPSA levels. Patients with extraprostatic tumour show significantly lower values of the FPSA/ total PSA ratio (p = 0.011). The median of the Gleason score of the biopsies is 6, both among patients with intraprostatic disease and in the not-organ-confined ones, with no significant differences. IPNI is found in 24 (7.9%) patients. Eleven patients (18.3% - IC 95%: ) with both IPNI and extraprostatic extension was detected. The different IPNI characteristics are similar between the organconfined cases and those that are not (Table 3). There is a significantly higher percentage (48.3%; IC 95%: ; p < ) of patients with bilateral involvement and extraprostatic cancer. The average cores with carcinoma among the organconfined tumour cases is 2.2 (median 2), and they amount to 32% (median 25%) of the extracted cores, whereas among the patients with extraprostatic cancer the average positive cores is 3.7 (median 3) and they amount to 52% (median 50%) of the biopsy cores. These differences are statistically significant (p < ). The cut-off point obtained with the ROC curve is 37.5% (Fig. 1). The area under the curve Table 3 Intraprostatic perineural invasion (IPNI) features according pt category of the radical prostatectomy specimen pt2 (intra) (n = 13) pt3 (extra) (n = 11) Bilateral 2/13 (15.3%) 5/11 (45.4%) 0.24 Multiple nerves 10/13 (76.9%) 8/11 (72.7%) 0.81 Circumferential involvement 7/13 (53.8%) 5/11 (45.4%) 1.00 p Fig. 1. ROC curve of percentage of positive cores. is 0.73 ( ). Sensitivity is 71.7%, specificity is 73.2%, positive predictive value is 39.8%, and negative predictive value is 91.2%. There are no differences between groups regarding HGPIN incidence in the needle biopsy, as it is shown in 95 patients (39%) with intraprostatic carcinoma, and in 23 extraprostatic patients (38%). No association of the evaluated parameters with surgical margin involvement is shown, with the exception of the Gleason score. In 61.8% of the patients with negative margins the Gs is <7, 29.7% are Gs 7, and 8.5% have a Gs > 7, whereas among the cases with a positive margin carcinoma the Gs s are 43.8%, 39.4% and 16.8% respectively (p = 0.004). Table 4 shows the extraprostatic tumour risks (crude and adjusted OR) associated with the different predictive variables. IPNI, as well as the presence of bilateral tumour and the percentage of positive cores, higher than 37.5% (ROC curve), show some significant crude OR (4.0, 2.8, and 6.9 respectively). The presence of a bilateral tumour behaves as a confusion variable of the association observed between the presence of an extraprostatic tumour and the IPNI and percentage of positive cores (37.5%). The regression model reveals that only the percentage of positive cores shows a significant OR (5.8) adjusting for laterality, IPNI, HGPIN and age. The Gs of this series is not related to the presence of extraprostatic invasion, since it was used to make the decision of performing prostatectomy.

4 F. Algaba et al. / European Urology 48 (2005) Table 4 Biopsy findings according the pt category of the radical prostatectomy specimen pt2 (intra) (n = 242) pt3 (extra) (n = 60) p Crude OR Adjusted OR Biopsy Gleason <7 129 (53.3%) 33 (55.0%) 7 84 (34.7%) 19 (31.7%) >7 29 (12.0%) 8 (13.3%) HGPIN 95 (39.3%) 23 (38.3%) IPNI 13 (5.4%) 11 (18.3%) ( ) 1.8 ( ) Bilateral 60 (24.8%) 29 (48.3%) < ( ) 1.2 ( ) Positive Cores < (1 to 3) 3 (2 to 5) % + cores < Patients > 37.5% of + cores 65 (26.9%) 43 (71.7%) < ( ) 5.8 ( ) + cores < 30% 131 (54.1%) 14 (23.3%) + cores 30 50% 83 (34.3%) 25 (41.7%) 2.8 ( ) 2.6 ( ) + cores > 50% 28 (11.6%) 21 (35%) < ( ) 5.1 ( ) 4. Discussion The present study is similar in its characteristics to other papers in the literature, both regarding the age range and the pathological T category [7 10]. The core median is 6, as in other series similar to this one [6,8,9], and so our findings may be compared to them. No significant differences are observed between the groups concerning PSA and FPSA, but they are indeed observed in the case of RPSA; in any case the RPSA value is below the 0.15 cut-off value, which is considered by our laboratory and using our methodology, discriminatory between benign and malignant prostate processes. The value of the Gleason score in our patients is quite limited, since all of them have been selected for prostatectomy according to the recent update of the clinical parameters (digital rectal examination), analytical parameters (serum PSA) and Gleason score at the biopsy [4,11], and so our findings do not oppose theliteraturedata[7,8,10], because the Gs was used before radical prostatectomy as a local staging predictor parameter. We have found a relationship between Gs and involvement of the surgical margins of prostatectomy. IPNI has always been a parameter considered to be associated with prostate cancer extension, possibly because in 85% of cases the extraprostatic invasion goes through neurovascular bundles [12], which makes us assume that it arrives by means of dissection of the intraprostatic perineural spaces for tissue planes of least resistance [13]. This assumption is supported by the verification of a greater post-radiation therapy biochemical recurrence in patients with IPNI, probably due to a higher incidence of cases with non-organconfined cancer [14]. Our IPNI incidence is 7.9%, and that of the literature oscillates between 7% [15] and 35% [16] with an average of 19.4% [7,15 25] these differences can be explained for several reasons: biopsy selection criteria, different type of series (some with re-evaluation of the needle biopsies), but the intention of this paper is to show only the real daily usefulness of the parameters. In this paper the IPNI presence in a biopsy means a 3.95-fold higher risk of extraprostatic carcinoma and it is statistically significant (sensitivity 18.3%, specificity 94.6%, positive predictive value 22.5% and negative predictive value 93.1%); these figures are similar to most of the univariant statistical studies [16,18,19,21,25,26]. In some series, the extension (IPNI multifocality), as well as the focal or circumferential affectation of the nerve trunk strengthen the specificity prognostic significance of IPNI [17,23], but such finding has not been reproduced in our cases. Tumour volume is a widely accepted prognostic factor [27], and the amount of tumour in a prostate needle biopsy is an important pathologic parameter for extension prediction, but there is lack of consensus in the literature as to the best method of reporting the extent of tumour involvement, and many of those methods are time-consuming. Our findings have shown that some volume measures such as bilateral cancer, the number of positive cores and the percentage of these regarding the total cores obtained, correlate to extension in a statistically significant manner (p < ) (Table 4), as shown by several published series [6,8,28] in which a correlation can be found with the clinical outcome post radical prostatectomy [6,9] and the response to radiotherapy [14,29].

5 570 F. Algaba et al. / European Urology 48 (2005) The presence of HGPIN has shown no meaning whatsoever, which confirms the no correspondence between HGPIN presence and the tumour stage or volume [30]. Even though some paper has stated the relationship between the percentage of positive cores and the presence of positive margins [7], we have found no relationship between the parameters studied and the tumour involvement of the prostatectomy margins with the exception of the Gleason score (p = 0.004), as already stated by the literature [31]. When calculating the risk of extraprostatic extension associated to the studied variables, the percentage of positive cores contributes most of the mentioned variability and makes the predictive meaning of the rest of parameters disappear; when adjusting the OR according to bilateralism this one modifies, even though it continues to be statistically significant both regarding unilateral and bilateral. For this reason. although IPNI has been associated with a higher risk of residual disease in non-sparing radical prostatectomy [32] lymph node metastasis incidence [33], and has been related to aggressive molecular expression [34,35], we believe that its presence is an indirect marker of the tumour volume as already suggested by some authors [6,9,18,20]; and so we find that from 37.5% of positive cores, the risk of extraprostatic invasion amounts to 5.8-fold in patients previously selected as possible prostatectomy candidates according to their serum PSA and their Gs. 5. Conclusion In core biopsy, the predictive parameter of cancer with extraprostatic extension (additionally to the Gleason score) is tumour volume that can be easily evaluated through the percentage of positive cores (with 37.5% of positive cores, the risk of extraprostatic invasion amounts to 5.8-fold) (p < ), and bilateral involvement (p < ). IPNI and RPSA have statistical significance as well, but they are closely related to tumour volume, which confirms the prognostic value of the local extension of tumour volume, as already stated in the literature [36], and can be explained by the existing evidence of a greater involvement of the prostate base (near the bladder neck and the seminal vesicles), in the larger tumours [37]. References [1] Epstein JI. The diagnosis and reporting of adenocarcinoma of the prostate in core needle biopsy specimens. Cancer 1996;78: [2] Boccon-Gibod L, van der Kwast ThH, Montironi R, Boccon-Gibod L. Handling and pathology reporting of prostate biopsies. Eur Urol 2004;46: [3] Rubin MA, Bismar TA, Curtis S, Montie JE. Prostate needle biopsy reporting. How are the surgical members of the society of urologic oncology using pathology reports to guide treatment of prostate cancer patients? 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