RELATIONSHIP OF AGE TO OUTCOME AND CLINICOPATHOLOGIC FINDINGS IN MEN SUBMITTED TO RADICAL PROSTATECTOMY

Objective: It is controversial whether age is associated with higher grade and worse outcome. Some studies have not found age to be related to outcome nor younger age to be associated with better response to therapy. Materials and methods: The study population consisted of 27 patients aged 55 years or younger and 173 patients 56 years or older submitted to radical prostatectomy. The variables studied were preoperative PSA, time to PSA progression following radical prostatectomy and pathologic findings in surgical specimens: Gleason score, Gleason predominant grade, positive surgical margins, tumor extent, extraprostatic extension (pT3a), and seminal vesicle invasion (pT3b). Results: Comparing patients aged 55 years or younger and 56 years or older, there was no statistically significant difference for all variables studied: preoperative PSA (p = 0.4417), Gleason score (p = 0.3934), Gleason predominant grade (p = 0.2653), tumor extent (p = 0.1190), positive surgical margins (p = 0.8335), extraprostatic extension (p = 0.3447) and seminal vesicle invasion (p > 0.9999). During the study period, 44 patients (22%) developed PSA progression. No difference was found in the time to biochemical progression between men aged 55 years or younger and 56 years or older. Conclusions: Our findings suggest that age alone do not influence the biological aggressiveness of prostate cancer.


INTRODUCTION
It is controversial whether prostate cancer in younger men have less favorable outcome than in older men (1).For all men with prostatic carcinoma, there is a suggestion of associated higher grade, and worse outcome with increasing age (2)(3)(4).However, the data are conflicting on this issue; other studies have not found age to be related to outcome (5,6) nor have they found a younger age to be associated with a better response to surgery (7).
The purpose of our study is to show possible differences between men 55 years or younger and men older than 55 years as related to preoperative PSA, pathologic findings in the radical prostatectomy specimen and time to biochemical progression following surgery.

MATERIALS AND METHODS
The study was done on 27 patients aged 55 years or younger and on 173 patients 56 years or older submitted to retropubic prostatectomy from January 1997 to July 2004 in our Institution.The variables studied were preoperative PSA and pathologic findings in surgical specimens: Gleason score (< 7 or ≥ 7), Gleason predominant grade (< 4 or 4-5), positive surgical margins, tumor extent, extraprostatic extension (pT3a), and seminal vesicle invasion (pT3b).Time to biochemical progression following surgery was studied comparing the groups.
The surgical specimen previously fixed was weighed, measured and the entire surface inked.The bladder neck and apical margins were amputated.From each cone-shaped amputated margin, 8 fragments were processed through perpendicular sections relative to the margins.The rest of the prostate was serially cut in transverse sections at 3 to 5 mm intervals.
Blocks were embedded in paraffin, cut at 6 µm, and one section from each block was stained with hematoxylin and eosin.Presence of adenocarcinoma was diagnosed according to Mostofi & Price criteria (8).The diagnosis was based on invasion or architectural disturbance.Histological grading was performed according to the Gleason system (9).Prostatic carcinomas with final Gleason score < 7 were considered low-intermediate grade; and, with final score ≥ 7 considered high-grade (10).Tumors were also subdivided into 2 groups: with primary grade < 4 and with primary grade 4 or 5. Extraprostatic extension was diagnosed according to Bostwick & Montironi (11), whenever cancer was found in adipose tissue, and corresponded to pT3a in the 2002 TNM staging system (12).Seminal vesicle invasion was defined as an invasion of the muscular wall, as described by Epstein et al. (13), corresponding to pT3b in the 2002 TNM staging system.
Tumor extent was estimated by use of a pointcount method (14).Drawn on a sheet of paper, each quadrant of the whole mount sections contained 8 equidistant points.During the microscopic examination of the slides, the tumor area was drawn on the correspondent quadrant seen on the paper.At the end of the examination, the amount of positive points represented an estimate of the tumor extent.
Biochemical progression was defined as PSA ≥ 0.5 ng/mL.During the study period, 44 pa-tients (22%) developed a biochemical progression.The mean and median follow-up for these patients were 19.77 and 15 months, respectively (range 3 to 84 months).
The data were analyzed using the Mann-Whitney test for comparison of independent samples and Fisher's exact test for evaluating differences between proportions.Time to PSA progression was studied using the Kaplan-Meier product-limit analysis; the comparison between the groups was done using the log-rank test.The mean and median periods among 133 men without biochemical progression (censored) were 25.94 and 21 months, respectively (range 3 to 81 months); 23 patients without tests for PSA level following radical prostatectomy were excluded.P value < 0.05 was considered statistically significant.All statistical analyses were performed using Statistical 5.5 software (StatSoft, Inc., Tulsa, OK, USA).
Figure -1 shows the time to PSA progression using the Kaplan-Meier product-limit analysis.The log-rank test did not show any statistical difference between the groups (p = 0.4683).

COMMENTS
Carcinoma of the prostate is distinctly uncommon in men under 50, accounting for 1% of all patients with clinically detected prostate cancer and is exceedingly rare in children and adolescents, with only a few reported cases (1).Hereditary prostate cancer accounts for 9% of all cases of carcinoma of the prostate but 43% of cases diagnosed before age 55 (15).
The influence of age in the biological aggressiveness of prostate cancer is controversial.4) suggest that prostatic carcinoma is higher grade and has worse outcome with increasing age.However, the data are conflicting on this issue.Bauer et al. (5) and Catalona & Smith (6) have not found age to be related to outcome.Smith et al. (7) suggest that patients aged 50 years or younger have a more favorable disease-free outcome compared to older men.
The findings of our study showed that younger and older men do not have statistically significant differences as related to preoperative PSA, pathologic findings in the surgical specimen, and time to biochemical progression following radical prostatectomy.
In our study 27 (13.5%)and 173 (86.5%) were ≤ 55 year-old and > 55 year-old, respectively.This proportion is quite similar to Smith et al. (7); of a total of 477 men studied, 79 (16.56%) and 398 (83.43%) were ≤ 50 year-old and > 50 year-old, respectively.There was no statistical difference related to preoperative PSA in our study.It is noteworthy that a comparative study by Carter et al. ( 2) within age groups and within PSA groups revealed that the probability of curable cancer was more closely associated with age than preoperative serum PSA level.
There was no statistically significant difference between young and older patients considering pathologic findings in the surgical specimen: Gleason score, Gleason predominant grade, tumor extent, positive surgical margins, extraprostatic extension and seminal vesicle invasion.It is noteworthy a much higher proportion (not statistically significant) of predominant grade 4 or 5 in older patients.This may be due to the lower number of young patients in the series.In both younger and older patients, there was approximately 40% of positive surgical margins and not organ-confined tumor (pT3a and pT3b).This finding may explain the relatively short mean and median period of PSA progression (19.77 and 15 months, respectively).
proportion of 44/200 (22%) men with PSA progression following surgery in our study is similar to 23.68% of Smith et al. (7).In our series, there was no difference between the time to PSA progression in younger and older men.7) evaluated a surgically treated cohort of men 50 years or younger to determine whether disease recurred more frequently among them than those 51 to 69 years in the PSA era.Disease-free survival rates were compared using Kaplan-Meier and Cox regression techniques.The disease-free survival curves were significantly different (log-rank p = 0.010).Age remained a significant prognostic factor (Wald p = 0.033) in multivariate Cox regression analyses that controlled for race, clinical and pathological stage, and pretreatment PSA.The data suggested that patients in the PSA era who underwent radical prostatectomy and Carter et al. (2), Herold et al. (3) and Partin et al. (

Table 1 -
Clinicopathologic features of men undergoing radical prostatectomy, by age.
After multivariable Cox regression analysis using only statistically significant variables that predicted recurrence, they developed an equation that calculated the relative risk of recurrence.The model suggested that only race, preoperative prostate specific antigen, postoperative Gleason sum and pathological stage are important independent prognosticators of recurrence after radical prostatectomy for clinically localized prostate cancer.Catalona & Smith (6) used Kaplan-Meier product limit estimates to calculate 7-year cancer recurrence-free probabilities, prostate specific survival and cause survival (overall, and stratified by age, preoperative PSA, tumor grade and tumor stage.All predictors except clinical stage and age remained significant within the multivariate Cox proportional hazards models to determine clinical and pathological parameters that provided unique predictive information about cancer recurrence.Concluding, our findings suggest that age alone do not influence the biological aggressiveness of prostate cancer.