Correlation of pretherapy prostate cancer characteristics with seminal vesicle invasion in radical prostatectomy specimens

Int. J. Radiation

Biol.

Phys., Vol. 36, No. 3, pp. 585-591. 1996 Copyright 0 1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/96 $15.00 + .oO

PII: SO360-3016(%)00359-S

ELSEVIER

l

Oncology

Clinical Original Contribution CORRELATION

OF PRETHERAPY PROSTATE CANCER CHARACTERISTICS WITH SEMINAL VESICLE INVASION IN RADICAL PROSTATECTOMY SPECIMENS

THOMAS M. PISANSKY, M.D.,* MICHAEL L. BLUTE, M.D.,? VERA J. SUMAN, PH.D.,” DAVID G. BOSTWICK, M.D.,” JOHN D. EARLE, M.D.* AND HORST ZINCKE, M.D.+ *Division of Radiation Oncology, ‘Department of Urology, *Department of Health Sciences Research, and $Department of Laboratory Medicine and Pathology, Mayo Clinic and Mayo Foundation, Rochester, MN USA

Purpose:This studywasconductedto identify pretherapy factors associatedwith seminalvesicleinvasion(SVI) in patients with localized carcinomaof the prtitate (Cap), and to developa modelthat would allow estimation of the likelihood for SVI at the time of initial diagnosis. Methods and Materials: BetweenJanuary 1988and December1993,2959patientsunderwentradical retropubic prostatectomy,with or without pelvic lymph nodedissection,asinitial therapy for clinical StageTla-3bNO-XMO CaP. Preoperative patient and tumor-related characteristicswere evaluatedfor an associationwith SVI in univariate and multivariate logistic regressionanalyses.A model was developedand probability plots were constructed to displaythe estimatedlikelihoodfor SVI in the patient with a newdiagnosisof localizedcap. Results:Within clinical tumor stage,three groups(Tla3a, TZb-c, and T3a-b) were observedto have a distinctly different rate of SVI. Gleasonprimary gradeswerecombined(l-2,3, and 4-5) becauseof a similar observation. Univariate analysisidentified clinical tumor stage(p < O.OOOl),Gleasonprimary grade @ < O.OOOl), and serum prostate-specificantigenlevel (p < 0.0001)asfactors associatedwith the likelihoodfor SVI. Multivariate analysis confirmed the independentsignificance(p = 0.0001)of eachof thesefactors. Patient age@ = 0.16) and history of prior transurethral resectionof the prostate @ = 0.82) were not associatedwith this end point. Probability plots were constructedto display the likelihoodof SVI asa function of pretherapy clinical tumor stage,Gleason primary grade, and serumprostate-specificantigenvalue. Conclusion:In the patient with a new diagnosisof localized CaP, clinical tumor stageas determinedby digital rectal examination, diagnosticbiopsy tumor (Gleasonprimary) grade, and pretherapy serumprostate-specific antigenvalue were significantfactors for developmentof a modelthat estimatedthe likelihood of SVI. Esthuates from this type of modelmay be of value in the pretherapy diagnosticevaluation of such patients,and may aid in the administration of radiation therapy. Copyright 0 1996 Elsevier Science Inc. Grade, Prostate cancer, Neoplasmstaging, Prostatic neoplasms/pa(pathology), Prostate-specificantigen/b1 (blood), Prostatectomy,Seminalvesicles/pa(pathology), Stage.

INTRODUCTION Despite the appearance of a locally confined process, occult tumor extension into periprostatic and lymphatic tissues is a common occurrence in clinically localized carcinoma of the prostate (CaP) (19, 38). Indeed, approximately one third of patients with disease clinically confined to the prostate gland, clinical tumor Stage T 1 - 2 (l), have histologic evidence of tumor perforation of the prostatic capsule in the radical prostatectomy specimen (4, 7, 10, 24, 34), and invasion of the seminal vesicles is apparent in an additional 15% of such cases (4, 7-8, 10, 16, 23-24, 34, 36). These findings, particularly seminal vesicle invasion @VI), have considerable prognostic importance for disease outcome (4, 10,20,22, 34), and may

affect the diagnostic evaluation (5, 7) and therapeutic strategy (7-8, 16) for these patients. The role of predictive factors in CaP has received considerable attention during the last few years, and several investigators have studied the relationship between pretherapy variables and SVI (7-9, 16, 22, 24). When regarded on an individual basis, clinical tumor stage (8, 16,22,24), tumor differentiation (7-9, 16,22, 24), and serum prostate-specific antigen (PSA) value (7-9, 24) have been found to correlate with SVI. Furthermore, models that incorporate independent predictive covariates to estimate the likelihood of SVI have been developed (7, 24). However, these efforts have limitations based on sample size considerations (7), the confounding effect of preoperative androgen ablation

Reprint requests to: Dr. Thomas M. Pisansky, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Acknowledgements-The authors express their gratitude to Ms.

Sandra K. Martin for assistance in data collection, Jeffrey M. Slezak for statistical support. Accepted for publication 5 July 1996. 585

and to Mr.

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(7), and the use of estimates that may not include all known predictive covariates (7, 8, 24). With these considerations in mind, a large-scale and detailed analysis was conducted on a cohort of patients selected for and treated with radical retropubic prostatectomy (RRP) for CaP at a single medical institution. The goals of this investigation were to identify pretherapy variables that were independently associated with SVI and to provide a reliable estimation of this risk in the patient with a new diagnosis of CaP in whom there is no clinical evidence of SVI. Thereafter, a constellation of variables was sought to identify patients who may be suitable for preirradiation diagnostic assessment and to serve as a resource to assist in the design of radiation therapy (RT) treatment volumes. METHODS

AND MATERIALS

Patients Between January 1988 and December 1993,4116 consecutive patients with clinically localized (Tla-4NOXMO) (1) CaP were primarily treated with RRP at Mayo Clinic-Rochester (Minnesota). However, patients were excluded from the present analysis for the following reasons: preoperative androgen deprivation therapy or prior RT (253 patients), RRP as the initial method of histologic diagnosis (23 patients), clinical Stage T3c or T4 disease (102 patients), or some combination of these factors (58 patients). Among those potentially eligible for inclusion in the study, unknown clinical tumor stage (1 patient), unknown Gleason primary grade of the diagnostic biopsy specimen (591 patients), preoperative serum PSA not obtained (15 patients), lack of information regarding SVI (36 patients), or some combination thereof (78 patients) resulted in the exclusion of an additional 721 patients. Therefore, the study group consisted of 2959 patients. Prior to surgery, CaP was confirmed by needle biopsy of the prostate (2822 patients) or through a transurethral approach (137 patients). Clinical evaluation of disease extent typically included history, physical examination, complete blood cell count, and serum chemistry and PSA determinations. A radionuclide bone scan was obtained in 2728 patients (92%), and 739 patients (25%) underwent computed tomography (CT) of the pelvis. Evaluation of local tumor stage was determined by digital rectal examination (DRE), and staging was performed according to a minor modification of the American Joint Committee on Cancer (AJCC) Staging System (1). Thus, tumor stage was defined as: Tla, clinically inapparent primary Gleason Grade 1, 2, or 3 tumor in ~5% of resection specimen and/or 5% of resection specimen and/or 2 1 cm3 tumor volume and/or primary Gleason Grade 4 or 5; Tic, nonpalpable tumor (with or without findings on ‘Hybritech,

Inc., Tandem-R,

San Diego, CA.

Volume 36, Number 3, 1996

transrectal ultrasound) identified on needle biopsy performed due to serum PSA elevation (11); T2a, palpable tumor confined to one half of one prostatic lobe or less; T2b, palpable intraprostatic tumor that involved more than one half of one lobe; T2c, palpable tumor confined to prostate with involvement of both lobes; T3a, tumor with unilateral extracapsular extension; and T3b, tumor with bilateral extracapsular extension. Additional pretherapy characteristics of the study group are summarized in Table 1. PSA determinations Preoperative serum samples for PSA determination were collected on an ambulatory basis before prostatic manipulation. Between January 1988 and August 1992, a monoclonal radioirmnunometric assay technique ’ was performed using a duplicate 50-~1 aliquot with a 2-h incubation period. The analytic sensitivity of the assay (i.e., minimal detection level) was established at 0.1 rig/ml. Thereafter, a semiautomated fluorescent immunoassay method’ was employed. This test used a single 100~,ul aliquot with a minimal detection limit of 0.02-0.04

Table 1. Patient characteristics Patients Factor

No.

%

All patients* Clinical tumor stage Tla Tlb Tic T2a T2b T2c T3a T3b Gleason primary grade 1 2 3 4 5 Pretherapy PSA @g/ml)+ 0. I-4.0 4.1-10.0 10.1-20.0 20.1-50.0 >50 Histologic subtype Adenocarcinoma, acinar Adenocarcinoma, NOS Other

2959

100

28 74 506 594 974 491 234 58

1 3 17 20 33 17 8 2

72 894 1463 489 41

2 30 49 17 1

525 1263 674 378 119

18 43 23 13 4

1964 982 13

66 33 0.4

* Median age: 66.5 years (range 38-84). ’ Median PSA value: 8.1 rig/ml (mean 14.0; range 0.1-379). NOS: Not otherwise specified.

‘Abbott

Laboratories,

Abbott-IMx,

Abbott Park, IL.

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Table 2. Univariate analysisof pretherapyfactorspredictive of seminalvesicleinvasion Seminalvesicle invasion Factor Age at surgery(yr) 38-59 60-69 70-84 Prior TURP No Yes Clinical tumor stage Tla Tlb Tic T2a T2b T2c T3a T3b Gleasonprimary grade 1 2 3 4 5 PretherapyPSA (ngfml) 0.1-4.0 4.1-10.0 10.1-20.0 20.1-50.0 >50

No. patients

No.

%

p Value*

523 1620 816

89 283 155

17 17 19

0.17

2585 374

462 65

18 17

0.82

28 74 506 594 974 491 234 58

1 3 53 47 186 123 84 30

4 4 10 8 19 25 36 52


72 894 1463 489 41

8 75 274 151 19

11 8 19 31 46


525 1,263 674 378 119

30 131 151 142 73

6 10 22 38 61

<0.0001

* Likelihood ratio test p value from univariate logistic regressionmodeling.Age and pretherapyPSA (log,) were examinedas continuousvariables;three levels were consideredfor clinical tumor stage(Tl-2a, T2b-c, and T3a-b) and Gleasonprimary grade(l2, 3, and4-5), which were assessed usingtwo indicatorvariables.

rig/ml (13). The normal reference range for either method was based on patient age (21). Surgical approach A midline low abdominal extraperitoneal incision was made and bilateral pelvic lymph node dissection was performed (2953 patients) before RRP. Thereafter, the endopelvic fascia was incised and RRP with (1324 patients) or without (1635 patients) preservation of the neurovascular bundle(s) was accomplished in standard fashion. Pathology examination All pretherapy prostatic biopsy specimens were reviewed at Mayo Clinic-Rochester, and histologic grade was based on glandular differentiation in association with the pattern of stromal tumor growth as described by Gleason (12). Because a small-gauge needle biopsy often provided a small amount of tumor, Gleason primary grade was exclusively used in the present study owing to its degree of correlation with prostatectomy findings (2). A detailed description of preparation and reporting methods for serial-sectioned RRP specimens has been pre-

viously reported (3). In brief, the RRP specimen was promptly submitted and measured, and the external surface inked and then placed in its entirety into neutral buffered formalin for overnight fixation. The apical and bladder base portions were initially removed and the remainder of the prostate was sectioned at 3-5-mm intervals perpendicular to the longitudinal (apical-basal) axis. The seminal vesicles were sectioned in a similar manner parallel to their junction with the prostate. Histologic examination was performed to determine tumor size and location with special attention to capsular invasion, capsular perforation (tumor extension into periprostatic adipose tissue), surgical margin status, and SVI. Pelvic lymphadenectomy tissue was separately submitted and handled as frozen sections. Method of analysis The purpose of this study was to develop a model based on pretherapy factors that estimated the probability of SVI in the patient with a new diagnosis of clinically localized Cap. Assessing the performance of the final model using the same data set from which it was developed can lead to an overly optimistic view of how well the model may

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perform in predicting the status of a future patient. Therefore, a random mechanism was employed to divide the study population from each year into equal portions. The model development process used half the study population (developmental data set), and the model verification process was performed with use of the other half of the study group (verification data set). On this basis, univariate and multivariate logistic regression analysis was used to develop a model for predicting the probability of SVI in patients under consideration. Patient age, clinical tumor stage, Gleason primary grade of the diagnostic biopsy specimen, pretherapy PSA value, and history of prior transurethral prostatic resection (TURP) were examined in the developmental data set through univariate analysis for their association with the likelihood of SVI. PSA values were logarithmically converted (log, PSA) before their entry into the modeling process. Patient age and pretherapy PSA level were treated as continuous variables, and clinical tumor stage, Gleason primary grade, and history of TURP were considered as polytomous variables represented in the models by design variables. Stepwise modeling procedures were performed that led to a model that contained clinical tumor stage, Gleason primary grade, and pretherapy PSA value; there was no evidence to suggest that patient age or prior TURP was associated with the likelihood of tumor involvement of the seminal vesicles. A receiver operating characteristic (ROC) curve was constructed using the multivariate logistic model built with the developmental data set. The area under the ROC curve was approximated to be 0.80. The model was then applied to the validation data set, and the area under this ROC curve was approximated to be 0.82. The verification process suggested that the model performed well, and the model was refit to the entire study population with the results presented herein. RESULTS In our study population, 527 patients (18%) were found to have tumor invasion of the seminal vesicle(s) in the surgical specimen. As shown in Table 2, evaluation of SVI according to clinical tumor stage identified three groups (Tla-2a, T2b-c, and T3a-b) in which the rate of SVI appeared distinctly different. Thus, the eight individual clinical stages were combined into three groups for all subsequent analyses. Gleason primary Grades 1 and 2 were combined, as were Grades 4 and 5 because of similar observations. Univariate analysis identified clinical tumor stage, Gleason primary grade, and pretherapy serum PSA as factors significantly associated with the probability of SVI (Table 2). There was no evidence to suggest that either patient age or prior TURP was associated with the probability of SVI. Because covariates may be interdependent (29, multivariate analysis was performed to determine which variable(s) retained significance in the presence of the other covariates. Clinical tumor stage, Gleason

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primary grade, and pretherapy serum PSA level were found to be highly significant independent factors. The adjusted odds ratio and p values for each variable are presented in Table 3. With construction of a model for the likelihood of SVI in a patient with a new diagnosis of CaP, the model was validated with the validation data set. Using the entire data set, the model parameters were reestimated and probability plots were constructed to display the likelihood for SVI for various combinations of clinical tumor stage, Gleason primary grade, and PSA levels. These estimates are presented in Figs. 1-3, and were limited to PSA values I 130 rig/ml because of restrictions imposed by subset sample sizes. Inspection of these probability plots (Figs. l-3) indicated the importance of these three independent covariates in estimating the likelihood of SVI in the patient with a new diagnosis of clinical Stage Tla-3b Cap. DISCUSSION The public’s heightened awareness of prostate cancer and the medical community’s use of early detection methods have resulted in a striking increase in the age-adjusted incidence rate of CaP (27) and in the more common diagnosis of this disorder when clinically confined to the prostate gland (17). Despite this trend, occult tumor growth into extraprostatic tissues has been commonly observed in contemporary surgical reports (4, 7, 14) as well as in the context of prostate cancer screening trials (18, 30). In particular, the presence of prostatic tumor invasion of the seminal vesicles has been an important determinant of disease outcome in patients managed with potentially curative therapy (4, 10, 22, 37). While the mechanism(s) by which CaP gains access to the seminal vesicles has not been the subject of extensive study, it appears that SVI frequently occurs when a nontransitional zone tumor extends into the region where vas deferens and seminal vesicle converge at the prostatic base-that is, the midbase portion of the Table 3. Multivariate analysis of pretherapy factors predictive of seminal vesicle invasion Adjusted odds ratios

Factor Clinical

Stage

T2b-c*

Clinical Stage T3a-b* Gleason primary Grade 3+ Gleason primary Grade 4-5+ F’retherapy PSA (lOSO

95%

CI

p Value

2.15 4.04

1.68-2.76 2.89-5.65

O.oool O.oool

2.09

1.58-2.75

O.oool

3.01

2.20-4.11

0.0001

2.34

2.08-2.64

0.0001

Relative to risk for *clinical Stage Tl-2a, +Gleason primary Grade 1-2, or *pretherapy PSA value one unit smaller on the log. scale (2.72 units). CI = confidence interval; PSA = prostate-specific antigen.

Seminalvesicle invasion in CaP l T. M.

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lOO-

Gleason primary grade 1,2 -3

80

. w-

Gleason primary grade 1,2

01 1

Serum PSA (ng/mL) Fig. 1. Likelihood of seminal vesicle invasion for patients with clinical Stage Tla-2a prostatic carcinoma according to pretherapy PSA value and Gleason primary grade. Vertical lines represent the 95% confidence interval for PSA values of 10, 20, 40, 60, and 100 rig/ml.

prostate gland (36). Direct tumor growth from this location along the ejaculatory duct complex or through the prostatic capsule may result in involvement of the seminal vesicle(s) (22, 36). This pattern may account for the observation that the tumor volume is often greatest at the prostatic end of the seminal vesicle in the vicinity of the vas deferens (36), and that involvement of both seminal vesicles is a common finding (22). While it is reasonable to believe that the site of tumor origin, whether at the prostatic base or at the apex, would affect the likelihood for SW, this factor has not been adequately evaluated and could not be determined from this study population.

Gleason primary grade

”

I

1

&urn

50

loo

&A (ng/mL)

Fig. 2. Likelihood of seminal vesicle invasion for patients with clinical Stage T2b-c prostatic carcinoma according to pretherapy PSA value and Gleason primary grade. Vertical lines represent the 95% confidence interval for PSA values of 10, 20, 40, 60, and 100 r&ml.

I &urn

50

1.4

loo

%A (ng/mL)

Fig. 3. Likelihood of seminal vesicle invasion for patients with clinical StageT3a-bprostaticcarcinomaaccordingto pretherapy PSA value and Gleasonprimary grade.Vertical lines represent the 95% confidenceinterval for PSA valuesof 10, 20, 40, 60, and 100 rig/ml.

The present study selected a cohort of patients managed during a relatively brief and contemporaneous period at a single medical institution. For the entire group, approximately one fifth (18%) of those without clinical evidence of SVI were found to have tumor extension into the seminal vesicle(s) on histologic examination of the RRP specimen. Even among patients in whom the disease was thought to be confined to the prostate gland (clinical tumor Stages Tla-2c), 15% (Table 2) had SVI, a result comparable to other surgical reports (7, 10, 22, 34, 36). Multivariate analysis demonstrated that clinical tumor stage, as determined by DRE, Gleason primary grade of the diagnostic biopsy specimen, and pretherapy serum PSA level were independently associated with the likelihood of SVI in a highly significant manner. Inclusion of all independent covariates into the model resulted in significant modification in the estimates for the likelihood of SVI. Indeed, the importance of using all pertinent pretherapy factors was demonstrated by considering the rate of SVI observed with an individual factor (Table 2) compared with estimates that resulted from inclusion of all covariates (Figs. l-3). For example, in a patient with a clinical Stage T2b tumor, the rate of SW was 19%, yet inspection of the corresponding probability plot (Fig. 2) indicated a broad range of probabilities (l77%) that was dependent on grade and PSA level. Thus, use of all relevant pretherapy information may allow use of staging procedures in a setting where an optimal diagnostic yield may be achieved. The pretherapy assessment of extraprostatic tumor extension in the patient with clinically localized CaP has been constrained by the relatively poor accuracy of conventional imaging techniques (26, 28, 32). As a result, transrectal ultrasonography (TRUS) and CT and magnetic resonance (MR) imaging have not been considered reliable methods for evaluation of disease extent

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before therapeutic intervention. Nonetheless, the findings of TRUS in conjunction with appropriately directed biopsies of the seminal vesicles may provide a high level of accuracy in identifying SVI (31, 33, 35). Likewise, recent studies of endorectal coil MR imaging

have shown that SVI is discernible with a diagnostic accuracy that exceeds 90% when performed by an experienced examiner (5,7). While these diagnostic methods may not be indicated in all patients with clinically

localized Cap, their use on a selective basis may result in the more accurate staging of certain patient subsets. The probability plots provided here may be of value in this selection process. In addition, the information made available in this report may have importance in target volume definition

and RT treatment planning. While strict indications for elective irradiation of the seminal vesicles have not been established, elective nodal RT has been considered for patients with a risk of pelvic lymph node involvement that reaches or exceeds 15% (15,29), and a similar recommendation has been suggested in the context of SVI (8). At present, incorporation of these guidelines into therapeutic decision making appears reasonable to affect the precision of treatment delivery in an attempt

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to improve therapeutic outcome (6). Furthermore, target volume reductions that exclude the seminal vesicles in patients with a low likelihood of SVI may reduce the volume of and RT dose to nontarget normal tissues (8). In this regard, it is important to note that isolated CaP tumor deposits remote from the ejaculatory duct com-

plex have been observed in only one eighth of seminal vesicle specimens where invasion was present (22). Furthermore, the extent of SVI is generally within 1 cm of the junction of the seminal vesicles with the prostatic base (36). Therefore, inclusion of the entire seminal vesicle within the high-dose target volume may not be necessary to effectively target the site of subclinical tumor extension. Beyond its use in contemporary medical practice, the

information provided here may be of value in the development and conduct of CaP research efforts. The use of multiple predictive factors may identify a patient cohort with a high probability for SVI. This may have particular importance in the conduct of conformal RT dose escalation trials, and in identification of patients with SVI and a poor prognostic outcome (4, 10,20,22,34,37) who may be considered an appropriate group for evaluation of combined modality initiatives.

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29.

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