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Editorial: Prostate Cancer
0022-534719511531-0115$03.0010
THEJOURNAL OF UnoLocY Copyright 0 1995 by AMEnicm UROLOCICAL ASSOCIATION, IKC
Vol. 153, 115-116, January 1995 Printed in U.S.A.
EDITORIAL: PROSTATE CANCER The articles by Rogers et a1 (page 104) characterizing the erences 20 and 21 in article). This latter observation should outcome of salvage radical prostatectomy, and Hammerer serve as a major lesson from this article. Men with at least a et a1 (page 111) on the contribution to serum prostate 10-year life expectancy who have an increasing PSA level specific antigen (PSA) of each of the 3 primary glandular following external beam radiation therapy and who are zones of the prostate represent, in my opinion, major ad- judged to be candidates for salvage prostatectomy should ditions to our literature. undergo prostate needle biopsy, preferably before the PSA The extensive experience of the Baylor group in evaluating level exceeds 10.0 ng./ml. If carcinoma is detected, which and treating patients who have failed radiation therapy has should occur in approximately 80%, of such patients (referalready been characterized in several pivotal studies (refer- ences 5, 11 and 24 in article) after careful clinical staging, ences 3, 11, 15, 20,27 and 36 in article). What makes the salvage prostatectomy should be performed. The ominous present contribution unique is that within it are contained finding of a positive bladder neck in the present series, due to several salient observations stemming from thorough preop- the high likelihood of indicating seminal vesical extension, erative evaluation, careful and precise pathological analysis, probably mitigates against the value of cystoprostatectomy and long and careful followup of 40 men, 39 of whom did not in the majority of men in this setting. The observation by receive adjuvant hormonal manipulation. Two major lessons the authors of increased morbidity associated with men emerge from this treatise. One lesson is that salvage radical who have undergone pelvic lymph node dissection must be prostatectomy is associated with significant morbidity. Even considered. Due to the increasing recognition that pelvic with the tremendous experience of the authors 58% of the lymph node metastasis is unusual in properly selected men were incontinent and the median interval to achieve patients, avoiding pelvic lymph node dissection should be continence was 10 months in the remainder. Rectal injury given consideration in many men electing initial radiation occurred in 6 of the 40 men, with 2 requiring temporary therapy. Whether laparascopic pelvic lymph node dissecdiverting colostomy. Other complications included ana- tion before radiation changes the morbidity of subsequent tomical stricture, hemorrhage requiring reoperation, ure- salvage surgery remains to be defined. Salvage after priteral transection, ureterovesical junction stricture and mary ultrasound guided percutaneous seed implantation vesicoperineal fistula. One man had septic shock, 1 suf- may be associated with less morbidity due to absence of fered thrombophlebitis and 1 had wound infection. Over- surgical dissection. The increased interest in cryosurgical all, 47.5% of the men had a serious complication. Of inter- ablation of the prostate and the inevitable salvage surgical est was the observation that complications were much approaches in men who fail this modality may be anticimore common in men who underwent pelvic lymph node pated to be associated with many of the problems described dissection before radiation therapy. Of these 29 men 9 in the present series. All surgeons interested in performing (31%) had a major operative complication, including 5 of salvage prostatectomy are encouraged to study this importhe 6 rectal injuries in the series. In contrast, only 1of 11 tant contribution carefully. men (9%) in whom pelvic lymph node dissection had not Despite the salient role of PSA in the management of men been performed before radiation treatment suffered such a with prostate cancer, the pathological basis of an elevation of complication. To my knowledge this represents the first PSA remains enigmatic. Specifically, what factors allow the description of the increased risk of morbidity if surgical approximate million-fold difference between the PSA level in staging of lymph nodes is performed before radiation ther- the seminal plasma and that of systemic circulation remains apy. to be elucidated. Hammerer et a1 performed a meticulous Several technical points are described in the article, in- pathological examination of 44 prostate specimens harboring cluding the combined perineal and retropubic approach ap- either no or minimal carcinoma to study prostate zonal volplied in 12 patients. The authors believe that this may make ume and correlate prostate zonal volume with serum PSA development of the rectal plane easier. However, they noted level (Yang polyclonal assay). They clearly demonstrated that in the 11 men treated with external beam radiation that the best predictor of the serum PSA level was the volalone the surgical planes appeared relatively normal. ume of the transition zone. They found a regression coeffiDespite the significant difficulty associated with this procient of 0.934 and an estimate of 0.261 ng./ml. PSA per gm. cedure, the authors are to be congratulated on their overall success. The actuarial nonprogression 5-year survival rate benign prostatic hyperplasia (BPH), confirming their previwas 55% and when excluding PSA as an intermediate end ous calculation using weight of simple prostatectomy specipoint it was 83%, not dissimilar from many primary radical mens (reference 4 in article). The corresponding correlation prostatectomy series. The only significant predictor of patho- of PSA t o the peripheral zone and central zone volumes was logical stage and eventual outcome was the preoperative significantly less. An additional important observation in serum PSA level. The authors noted that if the PSA level was this study is the fact that, while the transition zone is highly less than 10.0 ng./ml. only 15% of the men had advanced variable between patients, the remaining glandular zones pathological stage disease. In contrast, 86% of those whose are relatively constant, confirming a prior report.' While preoperative PSA level was greater than 10.0 ng./ml. had Hammerer et a1 quantitated the volume of each zone, they unfavorable pathological findings. That PSA is the only reli- did not identify the percentage of the transition zone that is able predictor of outcome underscores the difficulty in accu- epithelial and potentially contributes to the serum PSA. It is rate evaluation of patients after radiation, clinically as well well recognized that most cases of BPH are primarily stromal. as by biopsy interpretation.' These observations would seemingly provide sound ratioOf considerable interest is the observation that, after controlling for pathological stage, patients receiving salvage nale for PSA density calculations (serum PSA divided by the following failed radiation therapy did as well as those volume of the prostate), as well as age specific PSA adjustin contemporary series of primary radical prostatectomy (ref- ment (providing different cutoffs of serum PSA level for in115 A
116
PROSTATE CANCER
creasing age defined as the 95th percentile of normal men) future research into what causes elevation of PSA in the due to the ubiquitous growth of the transition zone with systemic circulation. aging. It is interesting to note that, while PSA density calMichael K. Brawer culations have stratified men with and without prostate canDepartment of Urology cer in some reports,= PSA alone was as good as PSA density University of Washington in other ~ e r i e s . In ~.~ those studies when PSA density did Seattle, Washington seem to enhance stratification, the prostates exhibiting canREFERENCES cer were significantly smaller than in those without such 1. Brawer, M. K.,Nagle, R. B., Pitts, W., Freiha, F. and Gamble, findings, and sampling error may have explained the bias S. L.: Keratin immunoreactivity as a n aid to the diagnosis of due to the possibility that small tumors in larger glands persistent adenocarcinoma in irradiated human prostates. would be less likely to be identified at biopsy. In this regard, Cancer, 63:454, 1989. this article stands out as an exception. If one adds the mean 2. Leissner, K. H. and Tisell, L. E.: The weight of the human volume of each zone and divides it into the serum PSA level, prostate. Scand. J. Urol. Nephrol., 1 3 137,1979. 3. Benson, M. C.,Whang, I. S., Olsson, C. A,, McMahon, D. J. and the PSA density calculated for the radical prostatectomy Cooner, W. H.: The use of prostate specific antigen density to specimen (0.19) is greater than that observed from the cysenhance the predictive value of intermediate levels of serum toprostatectomy cases (0.12). Similar observations are noted prostate-specific antigen. J. Urol., part 2,147: 817,1992. if the weight of the prostate is used for the denominator in 4. Bazinet, M., Meshref, A. W., Trudel, C., Aronson, S., Peloquin, the PSA density calculation. This carefully select cohort with F., Nachabe, M., Begin, L. R. and Elhilali, M. M.: Prospective exceedingly small tumors and relatively large radical prosevaluation of prostate-specific antigen density and systematic biopsies for early detection of prostatic carcinoma. Urology, 4% tatectomy specimens (mean weight approximately 2-fold that 44, 1994. observed in most series) suggests, however, that one may not 5. Rommel, F. M., Agusta, V. E., Breslin, J. A,, Hufmagle, H. W., be able to extrapolate this group to most biopsy populations. Pohl, C. E., Sieber, P. R. and Stahl, C. A.: The use of prostate In our own experience, even with adjustment for ultrasound specific antigen and prostate specific antigen density in the volume of the transition zone, PSA alone remained as good a diagnosis of prostate cancer in a community based urology predicter of carcinoma as PSA density.6 practice. J. Urol., 151: 88, 1994. 6. Brawer, M. K.,Aramburu, E. A. G., Chen, G. L., Preston, S. D. What remains to be proved, of course, is whether the voland Ellis, W. J.: The inability of prostate specific antigen index ume of the transition zone is the major contributor to the to enhance the predictive value of prostate specific antigen in serum PSA level or whether with increasing size there is the diagnosis of prostatic carcinoma. J. Urol., 150 369, 1993. increased likelihood of pathologically abnormal areas that 7. Mettlin, C., Littrup, P. J., Kane, R. A,, Murphy, G. P., Lee, F., may allow leakage from the prostatic acini and ductule luChesley, A,, Badalament, R. and Mostofi, F. K.: Relative senmen into the systemic circulation. Indeed, the basal cell sitivity and specificity of serum PSA level compared with layer and normal basement membrane separate the high age-referenced PSA, PSA density and PSA change. Cancer, 74: 1615,1994. concentration of PSA in the lumen from the rich capillary 8. Bigler, S.A., Deering, R. E. and Brawer, M. K.: Comparison of network lying just beneath the duct acinar system in BPH microscopic vascularity in benign and malignant prostate tisand the normal prostate.'-1° We have previously shown sue. Hum. Path., 24: 220, 1993. that carcinoma, prostatic intraepithelial neoplasia and foci 9. Deering, R. E., Bigler, S. A., Brown, M. and Brawer, M. K.: of acute inflammation, lesions that are associated with Microvascularity in BPH. Prostate, in press. disruption of these barriers, were found in 34 of 35 men 10. Brawer, M. K.,Peehl, D. M., Stamey, T. A. and Bostwick, D. M.: Keratin immunoreactivity in the benign and neoplastic human undergoing simple prostatectomy for presumed BPH with prostate. Cancer Res., 45:3663,1985. a preoperative serum PSA level of greater than 4.0 ng.1 M. K.,Rennels, M. A., Nagle, R. B., Schifman, R. A. and ml." The suggestion by Hammerer et a1 that ". . . the 11. Brawer, Gaines, J.: Serum prostate-specific antigen and prostate padifferences in function might depend on reduced efficiency thology in men having- simple h e r . J. Clin. - prostatectomy. of the basal cell laver. . ." should serve as the nidus for Path.:-92: 760,1989.
THEJOURNAL OF UnoLocY Copyright 0 1995 by AMEnicm UROLOCICAL ASSOCIATION, IKC
Vol. 153, 115-116, January 1995 Printed in U.S.A.
EDITORIAL: PROSTATE CANCER The articles by Rogers et a1 (page 104) characterizing the erences 20 and 21 in article). This latter observation should outcome of salvage radical prostatectomy, and Hammerer serve as a major lesson from this article. Men with at least a et a1 (page 111) on the contribution to serum prostate 10-year life expectancy who have an increasing PSA level specific antigen (PSA) of each of the 3 primary glandular following external beam radiation therapy and who are zones of the prostate represent, in my opinion, major ad- judged to be candidates for salvage prostatectomy should ditions to our literature. undergo prostate needle biopsy, preferably before the PSA The extensive experience of the Baylor group in evaluating level exceeds 10.0 ng./ml. If carcinoma is detected, which and treating patients who have failed radiation therapy has should occur in approximately 80%, of such patients (referalready been characterized in several pivotal studies (refer- ences 5, 11 and 24 in article) after careful clinical staging, ences 3, 11, 15, 20,27 and 36 in article). What makes the salvage prostatectomy should be performed. The ominous present contribution unique is that within it are contained finding of a positive bladder neck in the present series, due to several salient observations stemming from thorough preop- the high likelihood of indicating seminal vesical extension, erative evaluation, careful and precise pathological analysis, probably mitigates against the value of cystoprostatectomy and long and careful followup of 40 men, 39 of whom did not in the majority of men in this setting. The observation by receive adjuvant hormonal manipulation. Two major lessons the authors of increased morbidity associated with men emerge from this treatise. One lesson is that salvage radical who have undergone pelvic lymph node dissection must be prostatectomy is associated with significant morbidity. Even considered. Due to the increasing recognition that pelvic with the tremendous experience of the authors 58% of the lymph node metastasis is unusual in properly selected men were incontinent and the median interval to achieve patients, avoiding pelvic lymph node dissection should be continence was 10 months in the remainder. Rectal injury given consideration in many men electing initial radiation occurred in 6 of the 40 men, with 2 requiring temporary therapy. Whether laparascopic pelvic lymph node dissecdiverting colostomy. Other complications included ana- tion before radiation changes the morbidity of subsequent tomical stricture, hemorrhage requiring reoperation, ure- salvage surgery remains to be defined. Salvage after priteral transection, ureterovesical junction stricture and mary ultrasound guided percutaneous seed implantation vesicoperineal fistula. One man had septic shock, 1 suf- may be associated with less morbidity due to absence of fered thrombophlebitis and 1 had wound infection. Over- surgical dissection. The increased interest in cryosurgical all, 47.5% of the men had a serious complication. Of inter- ablation of the prostate and the inevitable salvage surgical est was the observation that complications were much approaches in men who fail this modality may be anticimore common in men who underwent pelvic lymph node pated to be associated with many of the problems described dissection before radiation therapy. Of these 29 men 9 in the present series. All surgeons interested in performing (31%) had a major operative complication, including 5 of salvage prostatectomy are encouraged to study this importhe 6 rectal injuries in the series. In contrast, only 1of 11 tant contribution carefully. men (9%) in whom pelvic lymph node dissection had not Despite the salient role of PSA in the management of men been performed before radiation treatment suffered such a with prostate cancer, the pathological basis of an elevation of complication. To my knowledge this represents the first PSA remains enigmatic. Specifically, what factors allow the description of the increased risk of morbidity if surgical approximate million-fold difference between the PSA level in staging of lymph nodes is performed before radiation ther- the seminal plasma and that of systemic circulation remains apy. to be elucidated. Hammerer et a1 performed a meticulous Several technical points are described in the article, in- pathological examination of 44 prostate specimens harboring cluding the combined perineal and retropubic approach ap- either no or minimal carcinoma to study prostate zonal volplied in 12 patients. The authors believe that this may make ume and correlate prostate zonal volume with serum PSA development of the rectal plane easier. However, they noted level (Yang polyclonal assay). They clearly demonstrated that in the 11 men treated with external beam radiation that the best predictor of the serum PSA level was the volalone the surgical planes appeared relatively normal. ume of the transition zone. They found a regression coeffiDespite the significant difficulty associated with this procient of 0.934 and an estimate of 0.261 ng./ml. PSA per gm. cedure, the authors are to be congratulated on their overall success. The actuarial nonprogression 5-year survival rate benign prostatic hyperplasia (BPH), confirming their previwas 55% and when excluding PSA as an intermediate end ous calculation using weight of simple prostatectomy specipoint it was 83%, not dissimilar from many primary radical mens (reference 4 in article). The corresponding correlation prostatectomy series. The only significant predictor of patho- of PSA t o the peripheral zone and central zone volumes was logical stage and eventual outcome was the preoperative significantly less. An additional important observation in serum PSA level. The authors noted that if the PSA level was this study is the fact that, while the transition zone is highly less than 10.0 ng./ml. only 15% of the men had advanced variable between patients, the remaining glandular zones pathological stage disease. In contrast, 86% of those whose are relatively constant, confirming a prior report.' While preoperative PSA level was greater than 10.0 ng./ml. had Hammerer et a1 quantitated the volume of each zone, they unfavorable pathological findings. That PSA is the only reli- did not identify the percentage of the transition zone that is able predictor of outcome underscores the difficulty in accu- epithelial and potentially contributes to the serum PSA. It is rate evaluation of patients after radiation, clinically as well well recognized that most cases of BPH are primarily stromal. as by biopsy interpretation.' These observations would seemingly provide sound ratioOf considerable interest is the observation that, after controlling for pathological stage, patients receiving salvage nale for PSA density calculations (serum PSA divided by the following failed radiation therapy did as well as those volume of the prostate), as well as age specific PSA adjustin contemporary series of primary radical prostatectomy (ref- ment (providing different cutoffs of serum PSA level for in115 A
116
PROSTATE CANCER
creasing age defined as the 95th percentile of normal men) future research into what causes elevation of PSA in the due to the ubiquitous growth of the transition zone with systemic circulation. aging. It is interesting to note that, while PSA density calMichael K. Brawer culations have stratified men with and without prostate canDepartment of Urology cer in some reports,= PSA alone was as good as PSA density University of Washington in other ~ e r i e s . In ~.~ those studies when PSA density did Seattle, Washington seem to enhance stratification, the prostates exhibiting canREFERENCES cer were significantly smaller than in those without such 1. Brawer, M. K.,Nagle, R. B., Pitts, W., Freiha, F. and Gamble, findings, and sampling error may have explained the bias S. L.: Keratin immunoreactivity as a n aid to the diagnosis of due to the possibility that small tumors in larger glands persistent adenocarcinoma in irradiated human prostates. would be less likely to be identified at biopsy. In this regard, Cancer, 63:454, 1989. this article stands out as an exception. If one adds the mean 2. Leissner, K. H. and Tisell, L. E.: The weight of the human volume of each zone and divides it into the serum PSA level, prostate. Scand. J. Urol. Nephrol., 1 3 137,1979. 3. Benson, M. C.,Whang, I. S., Olsson, C. A,, McMahon, D. J. and the PSA density calculated for the radical prostatectomy Cooner, W. H.: The use of prostate specific antigen density to specimen (0.19) is greater than that observed from the cysenhance the predictive value of intermediate levels of serum toprostatectomy cases (0.12). Similar observations are noted prostate-specific antigen. J. Urol., part 2,147: 817,1992. if the weight of the prostate is used for the denominator in 4. Bazinet, M., Meshref, A. W., Trudel, C., Aronson, S., Peloquin, the PSA density calculation. This carefully select cohort with F., Nachabe, M., Begin, L. R. and Elhilali, M. M.: Prospective exceedingly small tumors and relatively large radical prosevaluation of prostate-specific antigen density and systematic biopsies for early detection of prostatic carcinoma. Urology, 4% tatectomy specimens (mean weight approximately 2-fold that 44, 1994. observed in most series) suggests, however, that one may not 5. Rommel, F. M., Agusta, V. E., Breslin, J. A,, Hufmagle, H. W., be able to extrapolate this group to most biopsy populations. Pohl, C. E., Sieber, P. R. and Stahl, C. A.: The use of prostate In our own experience, even with adjustment for ultrasound specific antigen and prostate specific antigen density in the volume of the transition zone, PSA alone remained as good a diagnosis of prostate cancer in a community based urology predicter of carcinoma as PSA density.6 practice. J. Urol., 151: 88, 1994. 6. Brawer, M. K.,Aramburu, E. A. G., Chen, G. L., Preston, S. D. What remains to be proved, of course, is whether the voland Ellis, W. J.: The inability of prostate specific antigen index ume of the transition zone is the major contributor to the to enhance the predictive value of prostate specific antigen in serum PSA level or whether with increasing size there is the diagnosis of prostatic carcinoma. J. Urol., 150 369, 1993. increased likelihood of pathologically abnormal areas that 7. Mettlin, C., Littrup, P. J., Kane, R. A,, Murphy, G. P., Lee, F., may allow leakage from the prostatic acini and ductule luChesley, A,, Badalament, R. and Mostofi, F. K.: Relative senmen into the systemic circulation. Indeed, the basal cell sitivity and specificity of serum PSA level compared with layer and normal basement membrane separate the high age-referenced PSA, PSA density and PSA change. Cancer, 74: 1615,1994. concentration of PSA in the lumen from the rich capillary 8. Bigler, S.A., Deering, R. E. and Brawer, M. K.: Comparison of network lying just beneath the duct acinar system in BPH microscopic vascularity in benign and malignant prostate tisand the normal prostate.'-1° We have previously shown sue. Hum. Path., 24: 220, 1993. that carcinoma, prostatic intraepithelial neoplasia and foci 9. Deering, R. E., Bigler, S. A., Brown, M. and Brawer, M. K.: of acute inflammation, lesions that are associated with Microvascularity in BPH. Prostate, in press. disruption of these barriers, were found in 34 of 35 men 10. Brawer, M. K.,Peehl, D. M., Stamey, T. A. and Bostwick, D. M.: Keratin immunoreactivity in the benign and neoplastic human undergoing simple prostatectomy for presumed BPH with prostate. Cancer Res., 45:3663,1985. a preoperative serum PSA level of greater than 4.0 ng.1 M. K.,Rennels, M. A., Nagle, R. B., Schifman, R. A. and ml." The suggestion by Hammerer et a1 that ". . . the 11. Brawer, Gaines, J.: Serum prostate-specific antigen and prostate padifferences in function might depend on reduced efficiency thology in men having- simple h e r . J. Clin. - prostatectomy. of the basal cell laver. . ." should serve as the nidus for Path.:-92: 760,1989.