Perineural invasion on prostate needle biopsy: an independent predictor of final pathologic stage

ADULT UROLOGY

PERINEURAL INVASION ON PROSTATE NEEDLE BIOPSY: AN INDEPENDENT PREDICTOR OF FINAL PATHOLOGIC STAGE ALEXANDRE

TAILLE, AARON KATZ, EMILIA BAGIELLA, CARL A. OLSSON, KATHLEEN M. O’TOOLE, AND MARK A. RUBIN

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ABSTRACT Objectives. To examine the significance of perineural invasion (PNI) in predicting pathologic findings in patients treated by radical prostatectomy, because a recent study concluded that PNI on needle biopsy has no independent predictive value. Methods. Between 1993 and 1998, radical prostatectomy was performed in 319 consecutive patients. Prostate needle biopsies were reviewed in all cases. We compared PNI with other preoperative parameters, including digital rectal examination, PSA, and biopsy Gleason score, for the ability to predict tumor stage. Clinical records and pathologic findings were reviewed for all cases. Tumor stage was defined as either pT2 (organ confined) or pT3 (extraprostatic extension and/or seminal vesicle invasion). Results. The median age was 61.4 years (range 40 to 75.6). Seventy-two percent of the 95 men with nonpalpable disease and 67% of the 224 men with palpable disease had organ-confined prostate cancer on final pathologic staging. Of 205 men with a Gleason score on biopsy of 6 or less, 159 (78%) had organconfined disease compared with 59 (52%) of 114 with a Gleason score of 7 to 9 (P ⬍0.001, chi-square test). PNI was identified in 77 (24%) of 319 patients, with 83% specificity and 40% sensitivity for Stage pT3 disease (odds ratio 3.49). Of men with pT3 disease on final pathologic staging, 18%, 27%, and 56% had preoperative PSA levels of 0 to 4, more than 4 to 10, and greater than 10 ng/mL, respectively (P ⬍0.001, Mantel-Haenszel chi-square test). On multivariate analysis, PNI (P ⫽ 0.0031), PSA (P ⫽ 0.0004), and Gleason score (P ⫽ 0.0003) independently predicted stage (pT3 disease). Conclusions. PNI is an important preoperative predictor of pathologic stage and should be reported when adenocarcinoma is diagnosed on prostate needle biopsies. UROLOGY 54: 1039–1043, 1999. © 1999, Elsevier Science Inc.

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he preoperative under-staging of most men with prostate cancer is of great concern. Nearly 60% of newly diagnosed cases of prostate cancer are predicted to be organ-confined on the basis of digital rectal examination (DRE), serum prostate-specific antigen (PSA) levels, and histologic grading (Gleason score on biopsy). Yet, no more than 60% of these patients are ultimately

This study was supported by the Association de Recherche sur les Tumeurs de Prostate, Laboratoire Pierre Fabre, France and the Programme Lavoisier, Ministe`re des Affaires Etrange`res, France. From the Departments of Urology, Biostatistics, and Pathology, Columbia University College of Physicians and Surgeons, New York, New York Reprint requests: Mark A. Rubin, M.D., Department of Pathology, University of Michigan, 1500 East Medical Center Drive, Room 2G332/Box 0054, Ann Arbor, MI 48109-0054 Submitted: May 19, 1999, accepted (with revisions): June 30, 1999 © 1999, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED

found to have organ-confined disease at pathologic analysis of the radical prostatectomy specimen.1 Thus, more than one third of men with clinically localized prostate cancer have extraprostatic disease at the time of surgery and may not be curable by surgery alone.2 Perineural invasion (PNI) is a well-known feature of prostatic adenocarcinoma.3– 6 Villers et al.7 found that extraprostatic extension (EPE) was localized selectively to the area where nerves penetrate the prostate capsule, suggesting that PNI may facilitate extraprostatic spread. PNI in the diagnostic needle biopsy has been advocated as a marker of extraprostatic extension.8 In 1994, the College of American Pathologists recommended the inclusion of this histologic finding for all prostate needle biopsy reports with adenocarcinoma. Recently, however, Egan and Bostwick9 reported that PNI 0090-4295/99/$20.00 PII S0090-4295(99)00350-7 1039

had no independent predictive value for the presence of EPE, seminal vesicle (SV) invasion, or pathologic stage. We reviewed PNI on needle biopsies from 319 consecutive patients with prostate cancer from our institution who were treated by radical prostatectomy as a monotherapy (ie, no prior hormonal or radiation treatment) to determinate the utility of this preoperative parameter as a predictor of pathologic findings.

TABLE I. Patient demographics for 319 consecutive radical retropubic prostatectomy specimens Age (yr) Serum PSA (ng/mL) Gleason score on biopsy Follow-up (mo)

Average

Range

61.4 8.02 6.15 25.4

40–75.6 0.5–35 4–9 0.2–62.1

KEY: PSA ⫽ prostate-specific antigen.

MATERIAL AND METHODS PATIENT SELECTION From January 1993 to March 1998, 319 patients with clinically localized prostate cancer (T1c-T2c) who were scheduled for radical prostatectomy were entered into this study, which was approved by our institutional review board. One surgeon (C.A.O.) performed all DREs and radical prostatectomies.

PATHOLOGIC ANALYSIS Prostate Needle Biopsies. Needle core biopsies were examined by the study pathologists (M.A.R. and/or K.M.O.). The presence or absence of PNI was reported in all cases. The Gleason score, even if only a single focus of tumor was identified, was also reported. Radical Prostatectomy Samples. Each of the 319 radical prostatectomy specimens was weighed, inked, and fixed in 10% neutral buffered formalin. After fixation, a thin piece of tissue was shaved from the proximal and distal surgical margins (base and apex) and transected into multiple sections. The remaining prostate gland was inspected for any area of grossly recognizable tumor. In most cases, gross tumor was not evident, and four to five representative sections (with inked peripheral margins) were submitted from the right and left sides sequentially from the apex to base. The SVs were submitted at the junction where they enter the prostate gland. EPE was diagnosed if tumor was seen in the periprostatic soft tissue or penetrating through a fibromuscular capsule and coming out the other side. SV invasion was diagnosed if tumor was seen within the muscular wall of the SVs; tumor seen in the soft tissue surrounding the SVs was considered EPE. A positive surgical margin was denoted by the presence of carcinoma abutting on India ink. The surgical margin status was not used to determine the final pathologic stage. Tumors were then categorized as either Stage pT2 (organ confined) or pT3 (EPE and/or SV invasion). All pelvic lymph nodes were evaluated for the presence of metastatic disease. All cases were assigned a Gleason score.

STATISTICAL ANALYSIS Statistical Analysis System, version 6.11 software (SAS Institute, Cary, NC) was used for the analysis, and all tests were performed at the 0.05 significance level. The sensitivity and specificity of PNI were compared with the surgical pathologic findings. We summarized all data using mean and standard deviations for the continuous variables and frequency tables for the categorical variables. We performed univariate analysis by using chi-square tests. We used a logistic regression analysis to carry out the multivariate analysis.

RESULTS PATIENT POPULATION Radical prostatectomy specimens from 319 consecutive men were included in this study. Patient characteristics are given in Table I. Most of these 1040

patients had clinically localized disease by DRE (224 [70.2%] of 319) and one third of them had a normal DRE (95 [29.8%] of 319). The mean serum PSA was 8.02 ng/mL. Sixty-one patients (19%) had a serum PSA greater than 10 ng/mL. The needle biopsies ranged from 1 to 12 cores, with a mean Gleason score of 6. Most (184 of 319) of the needle biopsies had a Gleason score of 5 or 6. Pathologic analysis of the 319 radical prostatectomy specimens revealed 218 with Stage pT2 (68.4%) and 101 with pT3 (31.6%). Seventy-two percent of the 95 men with nonpalpable disease and 67% of the 224 men with palpable disease had organ-confined prostate disease. Of 205 men with a Gleason score of 6 or less on biopsy, 159 (78%) had organ-confined disease compared with 59 (52%) of 114 with a Gleason score of 7 to 9 (P ⬍0.001, chi-square test). Of the men with pT3 disease, 18%, 27%, and 56% had preoperative PSA levels of 0 to 4, more than 4 to 10, and greater than 10 ng/mL, respectively (P ⬍0.001, Mantel-Haenszel chi-square test). Two patients had node-positive disease as determined on final pathologic evaluation; the lymph node frozen sections were negative in all cases. PNI AS PREDICTOR OF PATHOLOGIC STAGE BY UNIVARIATE ANALYSIS PNI was strongly associated with higher pathologic stage. PNI was identified in 77 (24%) of 319 patients, with 83% specificity and 40% sensitivity for Stage pT3 disease (odds ratio 3.49). Forty (52%) of 77 patients with PNI on biopsy had pT3 disease versus 61 (25%) of 242 patients without PNI on biopsy (P ⫽ 0.01, chi-square test). Patients with PNI on biopsy had a 3.5 times greater chance of having pT3 disease compared with patients without PNI on biopsy. The analysis of the remaining individual tests’ ability to predict tumor stage is presented in Table II. For serum PSA, various cutoff limits were explored; Table II used a PSA of 10 ng/mL or greater as a “positive” test result. Although specificity was good for the examined categories, sensitivity was low. To predict Stage pT3 disease, the greatest odds UROLOGY 54 (6), 1999

TABLE II. Comparison of PNI and other preoperative parameters to predict pathologic stage

Stage (pT3)* Sensitivity (%) Specificity (%) Odds ratio P value† SV invasion Sensitivity (%) Specificity (%) Odds ratio P value† Positive SM Sensitivity (%) Specificity (%) Odds ratio P value†

Gleason Score >7

PNI ⴙ Gleason Score >7

PNI ⴙ PSA >10 ng/mL

PNI

DRE

PSA >10 ng/mL

40 83 3.49 ⬍0.001

51 31 0.48 0.44

34 88 3.59 ⬍0.001

54 73 3.22 ⬍0.001

28 94 5.59 ⬍0.001

14 97 5.69 ⬍0.001

63 80 6.88 ⬍0.001

90 30 1.27 0.55

27 82 1.62 0.26

43 65 1.42 0.36

20 87 1.7 0.27

13 94 2.62 0.09

32 78 1.7 0.074

75 31 1.35 0.33

29 84 2.13 0.015

49 68 1.98 0.013

24 89 2.55 0.006

10 95 2.1 0.12

KEY: PNI ⫽ perineural invasion; DRE ⫽ digital rectal examination; PSA ⫽ prostate-specific antigen; SV ⫽ seminal vesicle; SM ⫽ surgical margin (as defined in text); EPE ⫽ extraprostatic extension. * pT3 ⫽ EPE and/or SV invasion. † Univariate analysis (chi-square test).

ratio (5.69) was seen for men with a PSA greater than 10 ng/mL and PNI found on needle biopsy. MULTIVARIATE ANALYSIS TO EVALUATE THE BEST PREDICTIVE FACTORS Multivariate analysis was performed to identify the best predictors of pathologic findings. The results are presented in Table III. Serum PSA was a strong predictor of stage compared with other preoperative parameters (DRE, Gleason score on biopsy of 7 or greater, and PNI). However, Gleason score and PNI independently predicted stage. For SV invasion, PSA and Gleason score were the best predictors. COMMENT The nerve branches to the prostate and SVs travel together in the neurovascular bundle, which lies laterally to the prostate in the plane of the rectal surface.10 As the nerve courses distally, it sends branches into the prostate along its posterolateral aspect and then terminates in the corpora cavernosa distal to the prostatic apex. Early studies of PNI presumed that it represented perineural lymphatic invasion,11 but more recent work12 has shown that there are no lymphatics within the perineurium and that tumor growth within the perineural space reflects extension of cancer along tissue planes of least resistance. It is not easy to explain why PNI should independently predict final pathologic results given that most radical prostatectomy specimens demonstrate some PNI. However, one explanation might be that finding PNI on the preoperative needle biopsy may be a UROLOGY 54 (6), 1999

TABLE III. Multivariate analysis comparing PNI with other preoperative parameters to predict tumor stage, SV invasion, and positive SM Parameters Stage (pT3)* Gleason biopsy ⱖ7 Serum PSA† DRE PNI SV invasion Gleason biopsy ⱖ7 Serum PSA† DRE PNI Positive SM Gleason biopsy ⱖ7 Serum PSA† DRE PNI

Odds Ratio (95% CI)

P Value

2.12 1.11 1.03 2.41

(1.37–3.28) (1.05–1.17) (0.56–1.87) (1.34–4.33)

0.0003 0.0004 0.9274 0.0031

2.34 1.08 0.37 1.88

(1.18–4.63) (1.01–1.16) (0.14–0.99) (0.67–5.24)

0.014 0.033 0.048 0.2278

1.40 1.05 1.37 1.32

(0.90–2.19) (0.99–1.10) (0.71–2.65) (0.70–2.48)

0.1419 0.0565 0.3395 0.3896

KEY: CI ⫽ confidence interval; other abbreviations as in Table II. * pT3 ⫽ EPE and/or SV invasion. † PSA considered as continuous parameter; thus, the risk increases 0.11 (for stage) for each point of serum PSA.

surrogate marker of tumor volume. This would partially explain why in the study by Egan and Bostwick9 in which they measured the tumor burden in the needle biopsies, PNI was no longer an independent predictor. Because the biopsies at our institution were not systematically measured in the same fashion, this parameter was not available for all cases. Villers et al.7 proposed that the inability of most 1041

prostate cancers to penetrate the prostate capsule without the aid of perineural spaces is a morphologic reflection of the low metastatic potential. Areas showing direct capsule penetration were common only on larger tumors, which are known to have a high frequency of more poorly differentiated (grade 4 to 5) areas and a high risk of metastasis.13 Yang et al.14 studied proliferative and apoptotic activities of perineural and nonperineural prostate cancer cells. The apoptotic index in prostate cancer without PNI was significantly lower than in prostate cancer with PNI. Their results suggest that PNI by prostate carcinoma cells may not be a volume effect of growing carcinoma; the neural components may favor the growth of carcinoma by inhibiting apoptosis, presumably through a paracrine mechanism, and thereby facilitate the spread of carcinoma cells along nerves. At present, preoperative staging is based on DRE, serum PSA, prostate needle biopsies, and radiologic examinations. DRE frequently understages the extent of tumor, and magnetic resonance imaging and ultrasound add little to the accuracy of preoperative staging. The preoperative interpretation of serum PSA is confounded by the volume of benign prostatic hyperplasia and the degree of tumor differentiation.2 Therefore, serum PSA levels are not sufficiently reliable to predict final pathologic stage on an individual basis in patients with localized prostate cancer. Preoperative Gleason score determined from needle biopsy specimens is strongly associated with the final pathologic stage for patients at either extreme of the system (ie, scores of 2 to 4 and 8 to 10).15 However, more than 75% of men have a Gleason score between 5 and 7, scores at which the prediction of pathologic stage is not as good. Improvements of existing preoperative techniques are needed. Preoperative staging of prostate cancer remains a great concern for urologists. The ability of PNI to predict tumor stage has been examined by several studies to date. Bastacky et al.8 found the positive predictive value of detecting EPE when PNI is present to be 93%. The absence of PNI was not as predictive, with only 49% of patients without PNI having organ-confined disease. Egan and Bostwick9 reported a 51% sensitivity (versus 27% for Bastacky et al.8 and 41% in our study) and a 70% specificity (versus 96% for Bastacky et al.8 and 83% in our study). Ravery et al.16 reported 72.7% of patients with PNI on biopsy who had EPE versus 45.9% of patients without PNI (P ⬍0.05). Ukimura et al.17 found that 60.8% of their patients with PNI had EPE versus 20.5% of patients without PNI (P ⫽ 0.031). In the present study, the positive predictive value was 52%. This lower value may be because the specimens were partially submitted. For example, in the study by 1042

Bastacky et al.,8 the prostatectomy specimens were entirely embedded. This difference may account for the lower predictive ability of PNI. The patient populations may also explain some of the differences in the predictive ability of PNI. In our series of 319 patients, only 2 men had nodepositive disease determined on final pathologic examination (frozen sections were negative in all cases). This percentage (0.6%) is low compared with the 6.6% (23 of 349 patients) from the Mayo Clinic study.9 Bastacky et al.8 reported that only 32% of their patients had organ-confined disease (n ⫽ 320); it was 64% in the study by Egan and Bostwick9 and 68% in our series. These differences may represent a trend toward more precise clinical preoperative staging, as seen in the lower percentage of men with node-positive prostate cancer and a larger percentage of organ-confined tumors. However, the higher percentage of patients with organ-confined disease in the present study may also be due to the partial submission of the prostatectomy specimens. Yet, despite the possibility of understaging, PNI was still found to be an independent predictor of tumor stage and SV invasion. A recent study from our group found that when examining only preoperative factors, PNI independently predicted PSA recurrence after radical prostatectomy.18 PNI correlated statistically with PSA recurrence. Kaplan-Meier analysis revealed disease-free survival rates of 24% versus 64% when PNI was and was not present, respectively, in the prostate biopsy (P ⫽ 0.0003, log rank 12.92). Multivariate analysis demonstrated PNI (P ⫽ 0.012) and PSA (P ⫽ 0.005) were independent preoperative predictive factors of PSA recurrence. The usefulness of PNI to predict pelvic lymph metastases in men with Stage T1 or T2 adenocarcinoma of the prostate was examined by Stone et al.19 In their study of 212 men with localized prostate cancer who underwent radical prostatectomy, preoperative factors were analyzed for their ability to predict lymph node positivity. The logistic regression model found that a positive SV biopsy (P ⫽ 0.0006), presence of PNI (P ⫽ 0.04), and PSA greater than 20 ng/mL (P ⫽ 0.044) were all independent predictors of positive pelvic lymph nodes. Another clinically significant question is whether the presence of PNI on needle biopsy would be helpful in predicting which men would have neurovascular bundle involvement. This hypothesis was examined by Holmes et al.20 They examined 80 radical prostatectomy specimens from men with PNI found on needle biopsy to determine whether tumor involved the neurovascular bundle. Interestingly, the neurovascular bundle was involved by tumor in only 14 (17.5%) of 80 cases. Therefore, they concluded that the morbidity of resecting one or both neurovasUROLOGY 54 (6), 1999

cular bundles must be weighed against the benefit of reducing the incidence of positive margins. In conclusion, we found that the presence of PNI in preoperative needle biopsy is a strong independent predictor of final pathologic stage for patients with prostate cancer treated by radical prostatectomy. On the basis of these findings, we would suggest that the presence or absence of PNI should continue to be reported when adenocarcinoma is diagnosed on needle biopsy. REFERENCES 1. Carter HB, and Coffey DS: Prostate cancer: the magnitude of the problem in the United States, in Coffey DS, Resnick MI, Dorr FA, et al (Eds): A Multidisciplinary Analysis of Controversies in the Management of Prostate Cancer. New York, Plenum Press, 1998, pp 1–7. 2. Partin AW, Yoo J, Carter B, et al: The use of prostatic specific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostatic cancer. J Urol 150: 110 –114, 1993. 3. Byar DP, and Mostofi FK: Carcinoma of the prostate: prognostic evaluation of certain pathologic features in 208 radical prostatectomies. Examined by step section technique. Cancer 30: 5–13, 1972. 4. Epstein JI: Diagnostic criteria of limited adenocarcinoma of the prostate on needle biopsy. Hum Pathol 26: 223– 229, 1995. 5. Kahler JE: Carcinoma of the prostate gland: pathologic study. J Urol 41: 224 –228, 1939. 6. McNeal JE, and Yemoto CEM: Spread of adenocarcinoma within prostatic ducts and acini: morphologic and clinical correlations. Am J Surg Pathol 20: 807– 814, 1996. 7. Villers A, McNeal JE, Redwine EA, et al: The role of perineural space invasion in the local spread of prostatic adenocarcinoma. J Urol 142: 763–768, 1989. 8. Bastacky SI, Walsh PC, and Epstein JI: Relationship between perineural tumor invasion on needle biopsy and radical prostatectomy capsular penetration in clinical stage B adenocarcinoma of the prostate. Am J Surg Pathol 17: 336 –341, 1993. 9. Egan AJM, and Bostwick DG: Prediction of extrapros-

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