Significance of the craniocaudal distribution of cancer in radical prostatectomy specimens

Authors


Thomas M Wheeler MD, Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Room T-203, Houston, Texas 77030, USA. E-mail: twheeler@bcm.edu

Abstract

Objectives:  To examine the differences in the distribution of prostate cancer (PCa) in the craniocaudal dimension and their potential significance.

Methods:  We studied 1253 patients with clinically localized PCa treated with radical prostatectomy (RP) from 1983 to 2000. We analyzed the clinicopathological features according to the craniocaudal distribution (apex, mid, base) of the largest cancer focus.

Results:  Of these patients, 456 (36%) had the largest cancer focus in the apex, 728 (58%) in the mid, and 69 (6%) in the base. The cancers in the apex were less invasive than those in the mid or base, as evidenced by the lower frequency of extracapsular extension (27% vs 43%, 52%, respectively) and/or seminal vesicle involvement (5% vs 13%, 20%, respectively). The frequency of the largest cancer focus in the apex has increased significantly over time, from 26% before 1995 to 46% after 1995 (P < 0.001). Serum prostate specific antigen non-progression rate at 10 years for patients with a cancer at the apex was 83%, which was better than 76% and 77% of patients with a cancer at the mid or base (P = 0.029, P = 0.14, respectively).

Conclusion:  The cancers dominant at the apex are increasing over time and represent half of the patients treated by RP in recent years. These cancers tend to be less aggressive compared to those in the mid or base of the prostate. This knowledge may be useful in understanding the biology of and maximizing the detection of PCa

Introduction

With the advent of widespread screening with serum prostate specific antigen (PSA) almost two decades ago, new cases of prostate cancer (PCa) have been detected at earlier stages. A number of subsequent studies have used the detailed pathological stage data derived from the radical prostatectomy (RP) specimen to predict patient outcome.1–4 Although in our previous study, total tumor volume in RP specimens had not changed from 1983 to 1995, after 1995 tumors in the RP specimens were smaller than in the previous 12 years with a median of less than 1.0 cm3 and were observed more frequently in the apex of the prostate (distal third).5 Consistent with this observation, it follows that most early, and therefore small, cancers arise in the apex of the prostate. Traditionally, the distribution of PCa was assessed according to a zonal distribution such as peripheral, transition, or central zones, which were extensively investigated by McNeal et al.6–8 In contrast to those studies that focused on the distribution of a cancer on a transverse view of the prostate, to our knowledge, there are few studies addressing the distribution of cancer in the craniocaudal aspect.9,10

Knowledge of a craniocaudal distribution of cancer may provide additional clinically useful information, such as an improvement of cancer detection using needle biopsy or in determining the type and/or extent of the treatment regimen for the cancer.

Therefore, the present study was undertaken in which the largest cancer focus was classified according to the craniocaudal regions (apex, mid and base) in a large RP series and correlated with other established pathological features and patient outcome. PCa, of particularly early stage and/or smaller volume, has increased since the introduction of widespread PSA screening was introduced. Our hypothesis is that assessment of spatial distribution of PCa may lead to improvement in detection, selection of specific treatment type and patient outcome.

Materials and methods

Patient population

From 1983 to 2000, 1253 patients with clinical stage T1-3 PCa, who had not received any previous radiotherapy or hormonal therapy, underwent bilateral pelvic lymphadenectomy and radical retropubic prostatectomy by either of two surgeons (P.T.S. and K.M.S.). Mean patient age was 62 years (median 63, range 37–81).

Clinical stage

Clinical stage was assigned using the 2002 American Joint Committee on Cancer and tumor-node-metastasis (AJCC-TNM) staging system.11 Serum levels of PSA were measured with the Tandem-R assay (Hybritech, Inc., San Diego, CA, USA).

Pathological evaluation

The surgical margins were marked with permanent ink, and the RP specimens were fixed en bloc in 10% neutral buffered formalin. Following fixation of 1–3 days, the apical and bladder neck margins were removed as a 2 mm section at 90 degrees from the long axis of the urethra and then each was cut radially like a pie and the pieces embedded on edge in the respective blocks. The remainder of the prostate and the lower third of the seminal vesicles were sectioned transversely at 4–5 mm intervals and processed by the whole-mount (WM) technique. The location and extent of cancer was identified by one pathologist (T.M.W) and precisely mapped in each section. Total tumor volume of each cancer on each WM RP section was determined by a planimetric method with software using an image analysis system (OPTIMAS, Media Cybernetics, Inc., Silver Spring, MD, USA).12 The location of the largest cancer focus was assigned to its predominant craniocaudal location (apex, mid and base) and assigned a zonal distribution (peripheral or transition zone). For purposes of this study, no attempt was made to determine central zone origin, and therefore these would be included with those of the peripheral zone. The determination of apex, mid and base was determined from the WM RP sections (without seminal vesicle sections) as follows: if there were more than five WM sections – apex as distal two sections, base as proximal two sections, and the remaining sections were defined as mid; if there were five WM sections – apex as distal two sections, base as proximal two sections and mid as the remaining section; if there were four WM sections – apex as distal two sections, base as proximal one section and mid as the remaining one section.

Follow up

Patients were followed postoperatively with digital rectal examination and serum PSA levels every 3 months for 1 year, every 6 months for 4 years and then annually. Progression of disease was defined as PSA 0.4 ng/mL or greater on two or more occasions at least a month apart. Follow up ranged from 1 to 201 months (mean 53).

Methods of analysis

The χ2 test was used to assess whether the frequency of various pathological features correlated significantly with each craniocaudal distribution. The χ2 test for trends was used to determine whether there was a significant difference in craniocaudal distribution over the time. The progression-free rate was determined by the Kaplan-Meier method and difference in progression-free rates was assessed with the log-rank test. Cox proportional hazards regression model was used for multivariate analysis to test the association of pathological features, including the craniocaudal distribution, extracapsular extension, seminal vesicle involvement, lymph node metastasis and Gleason score. The analysis was carried out with statistics software package (STATA Version 8.2, College Town, TX, USA).

Results

Among the 1253 patients, 456 (36%) had the largest cancer focus in the apex of the prostate, 728 (58%) in the mid and 69 (6%) in the base. Also, 994 (80%) had the largest cancer focus in the peripheral zone and 256 (20%) in the transition zone.

Serum PSA level was available for 444 patients in the apex category, 691 in the mid category and 63 in the base category. Mean serum PSA level of patients with the largest cancer focus in the apex was significantly lower than the mid category (P = 0.001). Prostate gland volume measured by transrectal ultrasound was available for 431 patients in the apex category, 687 in the mid category and 64 in the base category. The median of prostate gland volume for patients with the largest cancer in the apex was 37 cc compared to 34 cc and 33 cc of patients with those in the mid or base categories (P = 0.58 and P = 0.97, respectively) (Table 1). The clinical stage of those in the apex category tended to be T1c (38%), although not significantly more often than the 33% T1c of the mid category (P = 0.077).

Table 1.  Comparison of clinical and pathological parameters of prostate cancer according to craniocaudal distribution
VariablesCraniocaudal distributionP-value
ApexMidBase
  1. PSA, prostate specific antigen.

Patients, n (%)456 (36)728 (58)69 (6) 
Mean clinical variables ± SD
 Age62.0 ± 7.061.8 ± 6.962.4 ± 7.0Apex vs Mid, 0.60
Apex vs Base, 0.79
Mid vs Base, 0.63
 PSA, ng/mL, (range)8.1 ± 7.6 (0.2–84)10.1 ± 11.0 (0.6–100)10.8 ± 13.6 (0.5–97.5)Apex vs Mid, 0.001
Apex vs Base, 0.15
Mid vs Base, 1.00
Clinical stage, n (%)   Apex vs Mid, <0.001
 T1a-b23 (5)49 (7)7 (10)Apex vs Base, 0.01
 T1c172 (38)238 (33)23 (33)Mid vs Base, 0.099
 T2a107 (24)116 (16)15 (22) 
 T2b83 (19)197 (27)16 (23) 
 T2c48 (11)77 (11)2 (3) 
 T3a13 (3)47 (6)6 (9) 
 T3b1 (0.2)0 (0)0 (0) 
Median prostate volume, cc, (range)37 (11.1–208.9)34 (8.7–188)33 (15.3–176.8)Apex vs Mid, 0.58
Apex vs Base, 0.97
Mid vs Base, 0.82
Prostatectomy Gleason score, n (%)   Apex vs Mid, 0.059
 6 or Less238 (52)339 (47)32 (46)Apex vs Base, 0.37
 7 or Greater218 (48)389 (53)37 (54)Mid vs Base, 0.98
Pathological stage, n (%)   Apex vs Mid, <0.001
 Organ confined325 (71)405 (56)33 (48)Apex vs Base, <0.001
 Extracapsular extention100 (22)210 (29)21 (30)Mid vs Base, 0.41
 Seminal vesicle involvement16 (4)68 (9)10 (15) 
 Lymph node metastasis15 (3)45 (6)5 (7) 
Surgical margin, n (%)   Apex vs Mid, 0.1
 Positive66 (14)84 (12)4 (6)Apex vs Base, 0.048
 Negative390 (86)643 (88)65 (94)Mid vs Base, 0.16
Median tumor volume, cc, (range)1.16 (0.002–11.2)2.11 (0.01–26.27)1.3 (0.031–18.2)Apex vs Mid, 0.0001
Apex vs Base, 0.16
Mid vs Base, 0.033

Patients classified to the apex category had a significantly lower frequency of extracapsular extension (27%) compared to those in the mid (43%; P < 0.005) or base categories (52%; P < 0.005). Seminal vesicle involvement was also less likely in the apex category (5%) compared to those in the mid (13%; P < 0.005) or base categories (20%; P < 0.005). The frequency of poorly differentiated cancer (defined as Gleason score ≥ 7) was not different among any of the three categories. Those of the apex category were more likely to have origin in the transition zone (26%) compared to the mid (18%) and base (13%) (P < 0.001, P = 0.016, respectively). However, this significance disappeared when only patients with clinical stage T1c were assessed. The median of total tumor volume for patients in the apex category was 1.16 cc, which was significantly smaller than the 2.11 cc of the mid (P < 0.001), but was similar to the 1.3 cc of the base categories (P = 0.16).

Prostate specific antigen non-progression rate at 10 years for patients with the largest cancer in the apex was 83%, which was significantly better than the 76% non-progression rate of the mid category (P = 0.029), but the 77% non-progression rate for patients in the base category was not significant (P = 0.14) (Fig. 1). PSA non-progression rates according to the location and Gleason score are shown in Figure 2. Of interest, even for the same Gleason score, PSA non-progression rates were different by the different location category. Patients with Gleason score ≤ 6 cancer in the apex or mid had a better non-progression rate than those with Gleason score ≤ 6 cancer in the base. Moreover, PSA non-progression rate according to zonal and craniocaudal distribution was compared, there was a trend that transition zone PCa had a better non-progression rate than peripheral zone PCa in the apex and mid ( Fig. 3). However, the category of craniocaudal distribution of cancer was not significant (P = 0.79) in a multivariate analysis when other established parameters such as Gleason score (P < 0.001), extracapsular extension (P < 0.001), seminal vesicle involvement (P < 0.001) and positive lymph nodes (P < 0.001) were controlled.

Figure 1.

Prostate specific antigen (PSA) non-progression rate by craniocaudal distribution.

Figure 2.

Actuarial probability of freedom from prostate specific antigen (PSA) progression for poorly (Gleason score ≥ 7) or moderately to well (Gleason score ≤ 6) differentiated cancer in each craniocaudal distribution.

Figure 3.

Actuarial probability of freedom from prostate specific antigen (PSA) progression for each combination of zonal and craniocaudal distribution.

The proportion of patients with the largest cancer focus in the apex compared to the other two categories has significantly increased over time, from 26% before 1995 to 46% after 1995 (P < 0.001) (Table 2). This change has happened as the mean age, serum PSA level and total tumor volume of patients with PCa treated by RP have decreased and the frequency of T1c patients has significantly increased over this time period.

Table 2.  Trend of prostate cancer in craniocaudal distribution before 1995 and after 1995
VariablesCraniocaudal distributionBefore 1995After 1995TotalP-value
  1. PSA, prostate specific antigen.

No. patients 5936601253 
Clinical features (Mean [Median]± SD)
 Age 62.9 (63.6) ± 6.461.0 (61.2) ± 7.261.9 (62.6) ± 6.9< 0.001
 PSA (ng/mL) 10.8 (6.7) ± 12.18.2 (7.4) ± 7.89.4 (6.7) ± 10.1< 0.003
 Prostate volume (cc) 37.5 (32.0) ± 18.643.3 (37.2) ± 22.840.6 (35.0) ± 21.2< 0.001
Pathological features (Mean [Median]± SD)
 Confined cancer, n (%) 297 (50)466 (71)763 (61)< 0.001
 Total tumor volume (cc) 3.27 (2.14) ± 3.911.96 (1.29) ± 2.352.60 (1.60) ± 3.27< 0.001
All tumor, n (%)Apex154 (26)302 (46)456 (36)< 0.001
Mid402 (68)326 (49)728 (58)< 0.001
Base37 (6)32 (5)69 (6)0.28
T1c tumor, n (%)Apex35 (26)137 (46)172 (40)< 0.001
Mid93 (69)145 (48)238 (55)< 0.001
Base6 (5)17 (6)23 (5)0.82
Clinically indolent cancer, n (%)Apex28 (39)62 (54)90 (48)0.055
Mid38 (54)48 (42)86 (46)0.12
Base5 (7)5 (4)10 (5)0.43

Discussion

The proportion of early stage PCa has been increasing since the widespread use of serum PSA screening and the introduction of transrectal ultrasound guided biopsy.13,14 We previously reported that total tumor volume in RP specimens did not change from 1983 to 1995.5 Similarly, Stamey et al. reported that there was no change in tumor volume and percent of clinically insignificant cancer between 1988 and 1996.7 However, in our patient series after 1995, it was determined that many of the smaller cancers that were found were being detected in the apex of the prostate.15 In fact, the frequency of the largest cancer in the apex after 1995 was 46%, which was significantly higher than 26% before 1995 in present series.

In this study, we chose the largest cancer focus because this focus drives the prognosis in the individual patient.16,17 However, some investigators have examined the three-dimensional distribution of all tumor foci of PCa within RP specimens.9,10,18–21 Chen et al. analyzed the spatial distribution of cancer foci using a three-dimensional prostate model.21 Smaller volume cancers tended to be concentrated in the apical half of the prostate in the peripheral zone. Moreover, they reported that as total cancer volume increase, the basal portions of the prostate become involved. Takashima et al. also analyzed T1c cancers in Japanese men by using a similar method. They described that 82.3% of all tumors were located in the apex and tumors were significantly denser in the apex to mid-prostate.9 Mazal et al. compared RP specimens between patients with negative initial biopsy and patients with positive initial biopsy.19 As a result, RP specimens with negative initial biopsies showed more frequently cancer foci in the apical and dorsal prostate and the cancer foci were also smaller in size in the RP specimen than those patients with positive initial biopsies. Although we did not assess the features of PCa in biopsy specimens in the present study, our and other studies suggest that many early cancers are located in the apex of the prostate gland.

Incidental PCa in cystoprostatectomy specimens may also represent characteristics of early stage PCa. Troncoso et al. reported 41% of patients with incidental prostate cancers in cystoprostatectomy specimens had tumor in the apex.22 Kabalin et al. also investigated prostates obtained from cystoprostatectomy specimens. Of 66 patients with no history of or clinical evidence of PCa, 38% had PCa with a mean of 0.11 cc, and these were located exclusively in the apex.23 However, when they found peripheral zone cancers greater than 4 cc in volume, they appeared to be directed toward the base.24 Thus, one hypothesis is that most incidentally found prostate cancers, especially peripheral zone cancers, arise in the apex and spread toward the base. These findings, like the results of clinically detected cancers in the present study, indicate that clinically favorable (including indolent) cancers are located preferentially in the apex. Thus, it follows that a positive biopsy core limited to the apex may be more likely a clinically indolent cancer than a positive core limited to the mid or base alone.

Reflecting the pathological outcomes such as the low frequencies of extracapsular extension or seminal vesicle involvement, the patients with the largest cancer focus in the apex had a better PSA non-progression rate than the patients with those in the mid or base (Fig. 1). However, in comparing poorly differentiated cancer (Gleason score ≥ 7) to those of well- to moderately-differentiated cancer (Gleason score ≤ 6), poorly differentiated cancers in the apex demonstrated a worse prognosis than well- to moderately-differentiated cancer in the apex. Furthermore, poorly-differentiated PCa in the apex had a worse prognosis than well- to moderately-differentiated PCa patients with the predominant focus in the mid or base (Fig. 2). Also, there was a trend that transition zone PCa did better than peripheral zone PCa in the apex and mid (there were no predominant transition zone PCas at the base) (Fig. 3). This may be the result of the penetration of inferior pedicle of the neurovascular bundle posterolaterally at the apex.6,25 Transition zone tumors have more favorable pathological features and tend to be less invasive than peripheral zone tumors.26,27 The overall better PSA non-progression rate of the apex category patients in the present series may be accounted for by predominance of transition cancer (Fig. 1).

The clinical implications that early favorable PCa arise in the apex are those of detection and treatment strategies. There may be less clinical importance to a well- or moderately-detected cancer only on an apical biopsy compared to a similar grade tumor detected only in the mid or base biopsy. Also, if PCa preferentially begins in the apex, this may have significant implications for the emerging field of focal therapy for PCa, where at the apex, the tumor focus would be closer to the potentially vulnerable external sphincter and prostatic urethra.

Conclusion

The largest PCa focus located predominantly in the apex has increased significantly over time and may represent the earlier detection of PCa in recent years. This fact has implications for the determination of whether treatment should be considered (likelihood of indolent PCa), and if so, what type (focal vs definitive). Although the cancers in the apex tend to be less aggressive compared to those in the mid or base of the prostate, this does not hold for poorly differentiated cancer in the apex compared to the mid or base. This knowledge may be useful in understanding the biology of PCa and should be investigated by others.

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