- Email: [email protected]
Advances in Management of Prostatic Disease
ADVANCES IN MANAGEMENT OF PROSTATIC DISEASE CORNELIUS
W.
VERMEULEN,
M.D.*
In general, surveys of results following prostatic operations have shown a gratifying fall in mortality rates in the last few decades. A recent study of mortality following all prostatic operations for benign hypertrophy performed in Bellevue HospitaP during the years from 1920 to 1946 shows a fall from approximately 40 per cent in the early years to 4.6 per cent in 1946. This decrease in mortality rate is in large part a reflection of improvements in surgery generally, with increased understanding of the physiology of the aged, more adequate treatment of shock, chemotherapy, and other factors. Specific urologic advances have also contributed to the improved picture. Some of the more recent changes and improvements in this field will be reviewed in this paper. ANATOMIC AND PHYSIOLOGIC CONSIDERATIONS
"Lobes" of the Prostate.-Any discussion of prostatism necessarily involves mention of the "lobes" of the prostate. We speak of lateral, median, anterior and posterior lobes, yet from the standpoint of normal human anatomy, both gross and microscopic, there seems to be little justification for dividing the prostate into lobes at all. Nevertheless, the behavior of the human prostate in disease justifies some sort of division. It is recognized that the condition of benign prostatic hyperplasia arises in the prostatic tissue situated nearest to and surrounding the urethra in the anterior portion of the prostate. Hyperplastic nodules appear in this location and grow to large lobular masses. In growth they displace and compress the more peripheral prostatic tissue which thus forms a sort of capsule about them. The compressed prostatic tissue about the adenomatous lobes is the "surgical capsule" within which the operation of prostatectomy-more correctly enucleation of nodules-is ordinarily done for benign prostatic obstruction. Carcinoma of the prostate, on the other hand, is known to arise characteristically in the posterior areas of the prostate nearer the rectum and relatively distant from the urethra. In the normal prostate of man, Huggins2 has now described an interesting differentiation between the anterior periurethral and the posterior prostate. He has indicated, by experiment, that the response of these two portions of the prostate to estrogens differs even in the normal gland. After estrogen administration a fairly clear-cut division between the From the Department of Surgery, University of Illinois College of Medicine, Chicago. * Clinical Associate Professor of Urology, University of Illinois College of Medicine; Attending Physician in Urology, Chicago Memorial Hospital and Illinois Research and Educational Hospital, Chicago. 1505
1506
CORNELIUS W. VERMEULEN
anterior three-fourths and the posterior one-fourth of the prostate can be demonstrated histologically. This and other observations lead Huggins to postulate that the human prostate, in common with that of many other species, is not a homogeneous organ but is in fact a double gland consisting of a larger anterior and a smaller posterior prostate. Phosphatase.-Despite an awakened interest in the physiology of the prostate gland in recent years, understanding of its functions is very imperfect. At the present timethe only known function in humans is that of contributing an enzyme to the semen that results in its liquefaction. Other enzymes also are known to occur in normal prostatic fluid. One of these-a phosphatase-has assumed importance in recent years in connection with carcinoma arising in the prostate. The normal prostatic epithelium elaborates this enzyme and contributes it to the prostatic fluid in enormous quantities. The prostatic phosphatase is of a peculiar variety. The phosphatase produced in other parts of the body functions as a catalyst to split organic phosphates in a medium that must be alkaline, whereas prostatic phosphatase works in an acid medium and thus is called "acid phosphatase." It has been found that not only does normal prostatic epithelium produce this substance, but often carcinoma cells derived from prostatic epithelium continue to elaborate acid phosphatase, even when they have metastasized. In this case, the elaborated phosphatase diffuses into the blood since it has no excretory channel and appropriate test will detect the acid phosphatase in the serum. 3 Further consideration will be given to phosphatase in discussion of cancer of the prostate. PREOPERATIVE MANAGEMENT OF URINARY RETENTION
Since the purpose of this report is to highlight newer concepts, it is not intended to review completely the long-accepted principles of the care of prostatic obstruction. Decompression of the Bladder.-The old dictum that a distended bladder must be decompressed gradually over an extended period of time has been generally abandoned. The basis upon which this idea rests has been shown to be false. Sudden decompression is no more likely to lead to hemorrhage or uremia than gradual decompression. These complications are due to infection and not to mechanical factors. In both animals and man, observations over many years have shown that if there is any difference between sudden and gradual bladder decompression it is in favor of rapid emptying. 4 Minimum Instrumentation.-Emphasis now is being placed upon minimum preoperative instrumentation and manipulation in the case of the chronically distended bladder. It is realized that often a previously sterile urinary system is infected by needless preoperative catheterization, repeated cystoscopy or other instrumentation, so that when operation finally is performed the patient approaches it with a very complete diagnosis but completely infected as well. The routine preoperative
ADVANCES IN MANAGEMENT OF PROSTATIC DISEASE
1507
intravenous urogram is becoming increasingly popular, not only for dis~ covering the frequent presence of hydronephrosis, or vesical calculi, but also to gain information regarding the type and amount of prostatic hypertrophy. The cystoscope, however, is not easily discarded. Diagnosis and determination of the best method of treatment are often inadequate without it. The plan of D. K. Rose and others 5 in the preoperative man~ agement of urinary retention seems particularly logical. N 0 catheteriza~ tion or instrumentation of any kind is done until immediately before surgery. The patient is cystoscoped in the operating room, the best type of operation decided upon, and surgery performed forthwith. An extreme example of minimum preoperative instrumentation is the procedure of Wilson Hey in England. On the theory that "postoperative uremia is due to infection and is encouraged by any method of slow decompression, open drainage, or instrumentation," Hey performs what he calls "aseptic prostatectomy." Diagnosis is made without the use of preoperative urethral instrumentation of any kind. Suprapubic enucleation of the adenoma is followed by retrograde introduction of a catheter into the urethra from the bladder end downward so as to minimize infecting the bladder and prostatic bed from the contaminated distal urethra. Others in England 6 seem to be impressed by Hey's idea and enthusiastically follow his method in treating patients with acute urinary retention by such emergency operation. It would seem that the practice Hey condemns, preoperative infection by instrumentation, is offset by too much uncertainty in diagnosis. SOME RECENT CONTRIBUTIONS TO THE TECHNIC OF OPERATIONS UPON THE PROSTATE
Transurethral Resection.~It is now conceded that, to ayoid persistent postoperative infection or recurrence of obstruction, a transurethral resection should remove all adenomatous tissue. To remove a small core of periurethral tissue is no longer considered adequate. The expert strives to resect all tissue down to the prostatic capsule itself. It must be admitted that many operators fail to accomplish this end. The unsatisfactory results ensuing have made some urologists abandon resection in favor of open surgery for all but the small obstructing prostates. Recent analyses show, however, that transurethral resection is still the most popular method of operation for prostatic disease. 7 Postresection Hemolysis.~More complete and thorough resections of the prostate have resulted in a new difficulty. Intravascular hemolysis has been shown to accompany a large proportion of transurethral resections. Experiments by Creevy8 suggest that this hitherto unsuspected complication results from irrigating fluid entering the general circulation. The irrigant enters the blood by way of veins opened during the resec~ tion, especially when the prostatic capsule is approached where large venous sinuses exist. Since the irrigating medium under which a resection is done must not be an electrical conductor, sterile distilled or tap water commonly has been used. If enough of such a hypotonic fluid enters the
1508
CORNELIUS W. VERMEULEN
blood, hemolysis of red cells inevitably follows. Creevy has demonstrated that considerable amounts of irrigant may in fact appear in the blood. Using 5 per cent glucose solution as the irrigating medium in resections, he has shown elevations of blood sugar as high as 1000 mg. per 100 cc. directly after operation. With isotonic glucose, hemolysis of course does not occur. When water is used, the amount of hemolysis found has been quite variable. In a recent report from the Mayo Clinic,9 6 percent of resected patients showed postoperative plasma hemoglobin levels of more than 500 mg. per 100 cc., while 70 per cent were found with levels below 100 mg. per 100 cc. Development of intravascular hemolysis in resection is of more than academic interest. The fatal effects of massive hemolysis are well illustrated in blackwater fever, in extensive burns and following transfusion of incompatible blood. In these conditions, hemoglobinemia and hemoglobinuria are shortly followed by oliguria, anuria and uremia. Consequently postresection hemolysis has been offered as an explanation of the cases of postresection uremia occasionally seen. There are certain objections to this explanation. Blood levels of plasma hemoglobin have as yet not been reported approaching those required experimentally to produce renal impairment. In clinical patients where hemolysis has been accompanied by uremia, other factors have regularly been present which explain the uremia as well or better than hemolysis. Nevertheless hemolysis does occur. Undesirable reactions therefrom are to be expected-if not uremia, at least gastrointestinal symptoms. To prevent hemolysis, isotonic solutions of nonelectrolytes are now being used as irrigants in transurethral resections. Creevy uses 4 or 5 per cent glucose solution. Technical difficulties with glucose have prompted Nesbit to use an isotonic solution of glycine. Suprapubic Prostatectomy.-Current urologic literature demonstrates that the one-time discredited suprapubic prostatectomy is still a respectable operation possessed of distinct advantages. Of all prostatic operations it remains the simplest and much the easiest to master. If for no other reason, its popularity will doubtless continue. One-stage Operation.-Suprapubic prostatectomy is now commonly done as a one-stage procedure. Suprapubic cystostomy preliminary to actual removal of the prostate is no longer considered necessary in most cases. The result has been a shortening of the period of hospitalization and an easier enucleation of the prostate without increase in mortality.7 One-stage suprapubic prostatectomy with primary closure of the bladder has been reported. Mter enucleation, the bladder incision is closed tight with drainage provided by an indwelling urethral catheter only. In general, urologists are making every effort to have the patient voiding spontaneously through the urethra as soon as possible. Hemosiatics.-Mter the introduction of Oxycel gauze and Gelfoam, urologists were quick to seize upon these substances to minimize immediate postoperative bleeding. They have been used extensively in suprapuhic prostatectomy. No complication arises from packing the
ADVANCES IN MANAGEMENT OF PROSTATIC DISEASE
1509
prostatic capsule with such material after enucleation. Proper application results in excellent hemostasis. Perineal Prostatectomy.-Judging from available statistics, prostatectomy by the perineal route is not popular. The peculiar disadvantagesloss of sexual potency, rectal injury with fistula and postoperative urinary incontinence-have prevented common acceptance. On the other hand, in one respect the perineal approach is without parallel. Up to the present time this route offers the only way to remove a carcinoma by radical prostatectomy. Semiradical Prostatectomy for Carcinoma Prevention.-Perineal prostatectomy as commonly done for benign conditions results in enucleation of the adenomatous lobes leaving the compressed prostatic tissue behind, just as in other methods of prostatectomy. It is precisely the tissue left behind in which carcinoma so frequently arises. By enlarging the usual perineal operation somewhat it is possible to do a "subtotal prostatectomy" and remove this surgical capsule as well as the hyperplastic nodules. Thus small unsuspected carcinomas already present would be removed and future occurrence of cancer prevented. Considering the extreme frequency of carcinoma of the prostate, the advantage of such a semiradical prostatectomy for benign hypertrophy cannot be dismissed lightly. Such an operation has been advocated by Marshall. 10 Retropubic Prostatectomy.-Terrence Millinl l of London has added a fourth operative approach to the prostate-a suprapubic, extravesical, retropubic prostatectomy. The essential difference between this operation and the old suprapubic prostatectomy lies in the point at which the urinary system is entered to attack the adenomatous gland. Whereas in the conventional suprapubic operation the urinary system is entered above the obstruction by incision of the bladder, in Millin's retropubic prostatectomy entrance is accomplished directly at the location of the obstruction by incising the anterior prostatic capsule. This allows greater visibility at the site of operation and better control of hemorrhage, as well as other operative refinements. Though Millin's first operation was done in 1945, already thousands have been performed in Europe and America.12, 13, 14, 15, 16 Retropubic prostatectomy is done through an incision just above the pubis. Dissection is carried down in the space of Retzius, between the bladder and under surface of the pubis. Here the prostate is exposed on its anterior aspect. Unfortunately a large plexus of veins is located directly over the prostate in this location. Some of these vessels must be divided to reach the prostatic capsule and considerable care is necessary to prevent occasional alarming hemorrhage. With the anterior capsule of the prostate exposed a transverse incision is made through both the true capsule and the surgical capsule beneath it. The cleavage line between adenoma and surgical capsule is easily identified and the hyperplastic tissue can be enucleated without difficulty. It is now possible to inspect the prostatic cavity. Bleeding vessels within it can be ligated or fulgurated. The vesical neck is exposed and a wedge-shaped segment of the
1510
CORNELIUS 'Y. VERMEULEN
posterior lip excised to prevent postoperative retention or stricture. Since this is all done through an incision in the prostatic capsule, the bladder remains undisturbed. Vesical calculi, if present, can usually be extracted without difficulty through the vesical neck. To complete the operation an urethral catheter is inserted and the incision in the prostatic capsule closed with a continuous catgut suture. The abdominal wall is repaired about a small drain leading to the space of Retzius. In three to eight days the urethral catheter is removed. Suprapubic drainage of urine ordinarily does not occur at any time. Postoperative urethral incontinence is not seen because the urethral sphincter is below the field of operation and not injured. For the same reason, the sexual function after operation is good. Almost everyone who has reported any considerable number of cases operated upon by Millin's technic has been pleased with the logic of the operation, the smooth postoperative course and the late functional result. However, this operation cannot be considered an easy one, operative bleeding may be troublesome and exposure sometimes difficult. The possibilities of this approach for radical prostatectomy in cases of carcinoma of the prostate are being explored. It appears that by this approach removal of the prostate with its true capsule, the seminal vesicles and, if necessary, the vesical neck is feasible. Anastomosis of the bladder to the distal urethra is then accomplished to restore the continuity of the urinary tract. Several reports of small series of such operations have appeared. Indeed Souttar17 in England gives a modified technic for complete removal of the prostate by the retropubic route which he uses routinely even in the absence of cancer. CARCINOMA OF THE PROSTATE
Unfortunately early diagnosis in carcinoma of the prostate remains uncommon because symptoms are usually late in appearing. If seen early, however, a definite diagnosis of cancer often cannot be made by rectal palpation of the prostate. Although cancer ordinarily appears in that portion of the prostate near the rectum, it may first appear elsewhere in regions not accessible to palpation. In cases where a suspicious lesion has been felt but diagnosis remained in doubt, biopsy has ordinarily been done through a perineal incision. Simpler but less exact methods of biopsy have been advocated, using a needle or special trocar to remove a core of suspected tissue for histologic study. The newest and simplest procedure to obtain cytologic confirmation in doubtful cases is the examination of either urine or prostatic fluid for carcinoma cells by the Papanicolaou technic. 18 Herbert and Lubin,19 using smears of prostatic fluid obtained by massage, have shown how accurate this test can be. When the smears gave positive results, carcinoma was shown regularly to be present. An occasional negative result in the presence of carcinoma was ascribed to scanty secretions of poor quality. ,Perhaps by the large scale use of such methods the percentage of early diagnoses, where radical operation is still possible, can be increased from the present miserable 5 per cent.
ADVANCES IN MANAGEMENT OF PROSTATIC DISEASE
1511
As already mentioned, in cases of cancer of the prostate where the disease has not spread beyond the capsule, radical prostatectomy is indicated. 20 In this operation the prostate, prostatic capsule and seminal vesicles are removed. In the small number of patients suitable for this operation, cure of the disease can be expected in approximately half of the patients. Endocrine Therapy.-Without doubt one of the most stimulating advances of recent years in the therapy of prostatic disease has been the discovery that prostatic carcinoma can be suppressed temporarily by castration or estrogens. It has long been known that the normal prostate will fail to develop if deprived of male sex hormone. It was shown by Huggins21 , 22 that carcinoma cells derived from prostatic epithelium similarly can be suppressed by deprivation of androgen. Orchiectomy.-In cases of carcinoma of the prostate with metastasis dramatic relief of pain often appears within twenty-four hours following castration because of shrinking of the carcinoma cells and suppresion of growth. Serial biopsies of accessible metastases have shown that castration produces extremely interesting regressive changes in the tumor. Similar effects have been noted in the primary tumor in the prostate itself. Occasionally bone metastases undergo profound changes that can be detected on the x-ray, with initial increase in sclerosis and gradual fading out of the lesion. As mentioned previously, prostatic epithelium normally produces acid phosphatase. Often carcinomatous tissue, even metastatic, continues to produce this substance which can be detected in the blood. Following castration the production of acid phosphatase falls off sharply as the metastasis becomes inhibited. Serial phosphatase determinations therefore give objective evidence of the effect of castration upon the tumor besides serving as an aid in making the diagnosis initially. In diagnosis of carcinoma, the level of acid phosphatase in the blood has distinct limitations. When it is elevated the diagnosis of prostatic cancer is almost certain. On the other hand, a normal level does not exclude carcinoma. In the absence of metastases normal levels are found. In many instances, even with extensive metastases, the blood acid phosphatase may not be increased. Perhaps such carcinomas have become more anaplastic and lost the adult function of producing this enzyme. Changes also occur in the alkaline phosphatase of the blood in metastatic cancer of the prostate. These changes are not specific for prostatic carcinoma but are due to the response on the part of the bone to the metastases within it with the marked osteoplastic reaction so commonly seen. Following castration a favorable response is indicated by a fall in the acid phosphatase because of decreased activity of the carcinoma cells. At the same time the alkaline phosphatase often rises higher than previously. These changes in the blood phosphatase generally parallel the clinical response of the patient with decrease or complete elimination of metastatic pain. Estrogen Administration.-Shortly after the discovery that orchiectomy resulted in suppression of prostatic carcinoma, it was found that
1512
CoRNELIUS W. VERMI
administration of estrogens without castration produced a similar effect. At the present time diethylstilbestrol therapy has largely replaced castration in the clinical case. Dosage has varied widely and is dependent upon clinical response and toleration of the drug. Good responses may be obtained with doses of a few milligrams a day, while in other cases enormous doses have been administered. Initially it was hoped that endocrine suppression of carcinoma might be permanent. It was soon found that the initial gratifying relief from pain, the phosphatase response, et cetera, were only temporary. After a period of a few months to years, despite continuous treatment, symptoms return and the carcinoma runs its course uninhibited by continued estrogenic treatment. Nonetheless, sufficient evidence is available to show that endocrine therapy does significantly prolong the survival period in patients with metastatic carcinoma of the prostate. On the other hand, it must be mentioned that in a considerable proportion of cases orchiectomy or estrogen therapy produces little or no effect, even initially. Very recent reports have appeared suggesting that estrogenic treatment is not without some danger. Carcinoma developing in the male breast following long-continued stilbestrol therapy has been reported. The incidence of this complication must be very low considering the many thousands of patients that have been treated with estrogens for prostatic carcinoma. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.
Draper, J. W.: Surgery 23:515, 1948. Huggins, C. and Webster, W. 0.: J. Urol. 59:258, 1948. Huggins, C.: Physiol. Rev. 25:281,1945. Creevy, C. D.: J. Urol. 39:403, 1938. Rose, D. K.: J. Urol. 53:470,1945. Walters, G. A. Bagot: Brit. M. J. 1:638, 1948. Shivers, C. H. DeT. and Groom, C. E.: J. Urol. 59:893, 1948. Creevy, C. D.: J. Urol. 58:125, 1947. Biorn, C. L. and Greene, L. F.: Surg., Gynec. & Obst. 88:389,1949. Marshall, Victor F.: J. Urol. 52:250,1944. Millin, Terrence: Retropubic Urinary Surgery. Baltimore, Williams & Wilkins Co., 1947. Millin, Terrence: J. Urol. 59:267,1948. Lowsley, O. S. and Gentile, A.: J. Urol. 59:281,1948. Grant, O. and Lich, R.: Ann. Surg. 127:1010, 1948. Moore, T. D.: J. Urol. 61:46,1949. Bacon, S. K.: J. Urol. 61:75, 1949. Souttar, H. S.: Brit. M. J. 1:917, 1947. Papanicolaou, G. N.: J.A.M.A., 131:372, 1946. Herbert, P. A. and Lubin, E. N.: J. Urol. 57:542, 1947. Hinman, F.: J.A.M.A., 135:136, 1947. Huggins, C. and Hodges, C. V.: Cancer Research 1 :293,1941. Huggins, C., Stevens, R. E., and Hodges, C. V.: Arch. Surg. 43:209, 1941.
W.
VERMEULEN,
M.D.*
In general, surveys of results following prostatic operations have shown a gratifying fall in mortality rates in the last few decades. A recent study of mortality following all prostatic operations for benign hypertrophy performed in Bellevue HospitaP during the years from 1920 to 1946 shows a fall from approximately 40 per cent in the early years to 4.6 per cent in 1946. This decrease in mortality rate is in large part a reflection of improvements in surgery generally, with increased understanding of the physiology of the aged, more adequate treatment of shock, chemotherapy, and other factors. Specific urologic advances have also contributed to the improved picture. Some of the more recent changes and improvements in this field will be reviewed in this paper. ANATOMIC AND PHYSIOLOGIC CONSIDERATIONS
"Lobes" of the Prostate.-Any discussion of prostatism necessarily involves mention of the "lobes" of the prostate. We speak of lateral, median, anterior and posterior lobes, yet from the standpoint of normal human anatomy, both gross and microscopic, there seems to be little justification for dividing the prostate into lobes at all. Nevertheless, the behavior of the human prostate in disease justifies some sort of division. It is recognized that the condition of benign prostatic hyperplasia arises in the prostatic tissue situated nearest to and surrounding the urethra in the anterior portion of the prostate. Hyperplastic nodules appear in this location and grow to large lobular masses. In growth they displace and compress the more peripheral prostatic tissue which thus forms a sort of capsule about them. The compressed prostatic tissue about the adenomatous lobes is the "surgical capsule" within which the operation of prostatectomy-more correctly enucleation of nodules-is ordinarily done for benign prostatic obstruction. Carcinoma of the prostate, on the other hand, is known to arise characteristically in the posterior areas of the prostate nearer the rectum and relatively distant from the urethra. In the normal prostate of man, Huggins2 has now described an interesting differentiation between the anterior periurethral and the posterior prostate. He has indicated, by experiment, that the response of these two portions of the prostate to estrogens differs even in the normal gland. After estrogen administration a fairly clear-cut division between the From the Department of Surgery, University of Illinois College of Medicine, Chicago. * Clinical Associate Professor of Urology, University of Illinois College of Medicine; Attending Physician in Urology, Chicago Memorial Hospital and Illinois Research and Educational Hospital, Chicago. 1505
1506
CORNELIUS W. VERMEULEN
anterior three-fourths and the posterior one-fourth of the prostate can be demonstrated histologically. This and other observations lead Huggins to postulate that the human prostate, in common with that of many other species, is not a homogeneous organ but is in fact a double gland consisting of a larger anterior and a smaller posterior prostate. Phosphatase.-Despite an awakened interest in the physiology of the prostate gland in recent years, understanding of its functions is very imperfect. At the present timethe only known function in humans is that of contributing an enzyme to the semen that results in its liquefaction. Other enzymes also are known to occur in normal prostatic fluid. One of these-a phosphatase-has assumed importance in recent years in connection with carcinoma arising in the prostate. The normal prostatic epithelium elaborates this enzyme and contributes it to the prostatic fluid in enormous quantities. The prostatic phosphatase is of a peculiar variety. The phosphatase produced in other parts of the body functions as a catalyst to split organic phosphates in a medium that must be alkaline, whereas prostatic phosphatase works in an acid medium and thus is called "acid phosphatase." It has been found that not only does normal prostatic epithelium produce this substance, but often carcinoma cells derived from prostatic epithelium continue to elaborate acid phosphatase, even when they have metastasized. In this case, the elaborated phosphatase diffuses into the blood since it has no excretory channel and appropriate test will detect the acid phosphatase in the serum. 3 Further consideration will be given to phosphatase in discussion of cancer of the prostate. PREOPERATIVE MANAGEMENT OF URINARY RETENTION
Since the purpose of this report is to highlight newer concepts, it is not intended to review completely the long-accepted principles of the care of prostatic obstruction. Decompression of the Bladder.-The old dictum that a distended bladder must be decompressed gradually over an extended period of time has been generally abandoned. The basis upon which this idea rests has been shown to be false. Sudden decompression is no more likely to lead to hemorrhage or uremia than gradual decompression. These complications are due to infection and not to mechanical factors. In both animals and man, observations over many years have shown that if there is any difference between sudden and gradual bladder decompression it is in favor of rapid emptying. 4 Minimum Instrumentation.-Emphasis now is being placed upon minimum preoperative instrumentation and manipulation in the case of the chronically distended bladder. It is realized that often a previously sterile urinary system is infected by needless preoperative catheterization, repeated cystoscopy or other instrumentation, so that when operation finally is performed the patient approaches it with a very complete diagnosis but completely infected as well. The routine preoperative
ADVANCES IN MANAGEMENT OF PROSTATIC DISEASE
1507
intravenous urogram is becoming increasingly popular, not only for dis~ covering the frequent presence of hydronephrosis, or vesical calculi, but also to gain information regarding the type and amount of prostatic hypertrophy. The cystoscope, however, is not easily discarded. Diagnosis and determination of the best method of treatment are often inadequate without it. The plan of D. K. Rose and others 5 in the preoperative man~ agement of urinary retention seems particularly logical. N 0 catheteriza~ tion or instrumentation of any kind is done until immediately before surgery. The patient is cystoscoped in the operating room, the best type of operation decided upon, and surgery performed forthwith. An extreme example of minimum preoperative instrumentation is the procedure of Wilson Hey in England. On the theory that "postoperative uremia is due to infection and is encouraged by any method of slow decompression, open drainage, or instrumentation," Hey performs what he calls "aseptic prostatectomy." Diagnosis is made without the use of preoperative urethral instrumentation of any kind. Suprapubic enucleation of the adenoma is followed by retrograde introduction of a catheter into the urethra from the bladder end downward so as to minimize infecting the bladder and prostatic bed from the contaminated distal urethra. Others in England 6 seem to be impressed by Hey's idea and enthusiastically follow his method in treating patients with acute urinary retention by such emergency operation. It would seem that the practice Hey condemns, preoperative infection by instrumentation, is offset by too much uncertainty in diagnosis. SOME RECENT CONTRIBUTIONS TO THE TECHNIC OF OPERATIONS UPON THE PROSTATE
Transurethral Resection.~It is now conceded that, to ayoid persistent postoperative infection or recurrence of obstruction, a transurethral resection should remove all adenomatous tissue. To remove a small core of periurethral tissue is no longer considered adequate. The expert strives to resect all tissue down to the prostatic capsule itself. It must be admitted that many operators fail to accomplish this end. The unsatisfactory results ensuing have made some urologists abandon resection in favor of open surgery for all but the small obstructing prostates. Recent analyses show, however, that transurethral resection is still the most popular method of operation for prostatic disease. 7 Postresection Hemolysis.~More complete and thorough resections of the prostate have resulted in a new difficulty. Intravascular hemolysis has been shown to accompany a large proportion of transurethral resections. Experiments by Creevy8 suggest that this hitherto unsuspected complication results from irrigating fluid entering the general circulation. The irrigant enters the blood by way of veins opened during the resec~ tion, especially when the prostatic capsule is approached where large venous sinuses exist. Since the irrigating medium under which a resection is done must not be an electrical conductor, sterile distilled or tap water commonly has been used. If enough of such a hypotonic fluid enters the
1508
CORNELIUS W. VERMEULEN
blood, hemolysis of red cells inevitably follows. Creevy has demonstrated that considerable amounts of irrigant may in fact appear in the blood. Using 5 per cent glucose solution as the irrigating medium in resections, he has shown elevations of blood sugar as high as 1000 mg. per 100 cc. directly after operation. With isotonic glucose, hemolysis of course does not occur. When water is used, the amount of hemolysis found has been quite variable. In a recent report from the Mayo Clinic,9 6 percent of resected patients showed postoperative plasma hemoglobin levels of more than 500 mg. per 100 cc., while 70 per cent were found with levels below 100 mg. per 100 cc. Development of intravascular hemolysis in resection is of more than academic interest. The fatal effects of massive hemolysis are well illustrated in blackwater fever, in extensive burns and following transfusion of incompatible blood. In these conditions, hemoglobinemia and hemoglobinuria are shortly followed by oliguria, anuria and uremia. Consequently postresection hemolysis has been offered as an explanation of the cases of postresection uremia occasionally seen. There are certain objections to this explanation. Blood levels of plasma hemoglobin have as yet not been reported approaching those required experimentally to produce renal impairment. In clinical patients where hemolysis has been accompanied by uremia, other factors have regularly been present which explain the uremia as well or better than hemolysis. Nevertheless hemolysis does occur. Undesirable reactions therefrom are to be expected-if not uremia, at least gastrointestinal symptoms. To prevent hemolysis, isotonic solutions of nonelectrolytes are now being used as irrigants in transurethral resections. Creevy uses 4 or 5 per cent glucose solution. Technical difficulties with glucose have prompted Nesbit to use an isotonic solution of glycine. Suprapubic Prostatectomy.-Current urologic literature demonstrates that the one-time discredited suprapubic prostatectomy is still a respectable operation possessed of distinct advantages. Of all prostatic operations it remains the simplest and much the easiest to master. If for no other reason, its popularity will doubtless continue. One-stage Operation.-Suprapubic prostatectomy is now commonly done as a one-stage procedure. Suprapubic cystostomy preliminary to actual removal of the prostate is no longer considered necessary in most cases. The result has been a shortening of the period of hospitalization and an easier enucleation of the prostate without increase in mortality.7 One-stage suprapubic prostatectomy with primary closure of the bladder has been reported. Mter enucleation, the bladder incision is closed tight with drainage provided by an indwelling urethral catheter only. In general, urologists are making every effort to have the patient voiding spontaneously through the urethra as soon as possible. Hemosiatics.-Mter the introduction of Oxycel gauze and Gelfoam, urologists were quick to seize upon these substances to minimize immediate postoperative bleeding. They have been used extensively in suprapuhic prostatectomy. No complication arises from packing the
ADVANCES IN MANAGEMENT OF PROSTATIC DISEASE
1509
prostatic capsule with such material after enucleation. Proper application results in excellent hemostasis. Perineal Prostatectomy.-Judging from available statistics, prostatectomy by the perineal route is not popular. The peculiar disadvantagesloss of sexual potency, rectal injury with fistula and postoperative urinary incontinence-have prevented common acceptance. On the other hand, in one respect the perineal approach is without parallel. Up to the present time this route offers the only way to remove a carcinoma by radical prostatectomy. Semiradical Prostatectomy for Carcinoma Prevention.-Perineal prostatectomy as commonly done for benign conditions results in enucleation of the adenomatous lobes leaving the compressed prostatic tissue behind, just as in other methods of prostatectomy. It is precisely the tissue left behind in which carcinoma so frequently arises. By enlarging the usual perineal operation somewhat it is possible to do a "subtotal prostatectomy" and remove this surgical capsule as well as the hyperplastic nodules. Thus small unsuspected carcinomas already present would be removed and future occurrence of cancer prevented. Considering the extreme frequency of carcinoma of the prostate, the advantage of such a semiradical prostatectomy for benign hypertrophy cannot be dismissed lightly. Such an operation has been advocated by Marshall. 10 Retropubic Prostatectomy.-Terrence Millinl l of London has added a fourth operative approach to the prostate-a suprapubic, extravesical, retropubic prostatectomy. The essential difference between this operation and the old suprapubic prostatectomy lies in the point at which the urinary system is entered to attack the adenomatous gland. Whereas in the conventional suprapubic operation the urinary system is entered above the obstruction by incision of the bladder, in Millin's retropubic prostatectomy entrance is accomplished directly at the location of the obstruction by incising the anterior prostatic capsule. This allows greater visibility at the site of operation and better control of hemorrhage, as well as other operative refinements. Though Millin's first operation was done in 1945, already thousands have been performed in Europe and America.12, 13, 14, 15, 16 Retropubic prostatectomy is done through an incision just above the pubis. Dissection is carried down in the space of Retzius, between the bladder and under surface of the pubis. Here the prostate is exposed on its anterior aspect. Unfortunately a large plexus of veins is located directly over the prostate in this location. Some of these vessels must be divided to reach the prostatic capsule and considerable care is necessary to prevent occasional alarming hemorrhage. With the anterior capsule of the prostate exposed a transverse incision is made through both the true capsule and the surgical capsule beneath it. The cleavage line between adenoma and surgical capsule is easily identified and the hyperplastic tissue can be enucleated without difficulty. It is now possible to inspect the prostatic cavity. Bleeding vessels within it can be ligated or fulgurated. The vesical neck is exposed and a wedge-shaped segment of the
1510
CORNELIUS 'Y. VERMEULEN
posterior lip excised to prevent postoperative retention or stricture. Since this is all done through an incision in the prostatic capsule, the bladder remains undisturbed. Vesical calculi, if present, can usually be extracted without difficulty through the vesical neck. To complete the operation an urethral catheter is inserted and the incision in the prostatic capsule closed with a continuous catgut suture. The abdominal wall is repaired about a small drain leading to the space of Retzius. In three to eight days the urethral catheter is removed. Suprapubic drainage of urine ordinarily does not occur at any time. Postoperative urethral incontinence is not seen because the urethral sphincter is below the field of operation and not injured. For the same reason, the sexual function after operation is good. Almost everyone who has reported any considerable number of cases operated upon by Millin's technic has been pleased with the logic of the operation, the smooth postoperative course and the late functional result. However, this operation cannot be considered an easy one, operative bleeding may be troublesome and exposure sometimes difficult. The possibilities of this approach for radical prostatectomy in cases of carcinoma of the prostate are being explored. It appears that by this approach removal of the prostate with its true capsule, the seminal vesicles and, if necessary, the vesical neck is feasible. Anastomosis of the bladder to the distal urethra is then accomplished to restore the continuity of the urinary tract. Several reports of small series of such operations have appeared. Indeed Souttar17 in England gives a modified technic for complete removal of the prostate by the retropubic route which he uses routinely even in the absence of cancer. CARCINOMA OF THE PROSTATE
Unfortunately early diagnosis in carcinoma of the prostate remains uncommon because symptoms are usually late in appearing. If seen early, however, a definite diagnosis of cancer often cannot be made by rectal palpation of the prostate. Although cancer ordinarily appears in that portion of the prostate near the rectum, it may first appear elsewhere in regions not accessible to palpation. In cases where a suspicious lesion has been felt but diagnosis remained in doubt, biopsy has ordinarily been done through a perineal incision. Simpler but less exact methods of biopsy have been advocated, using a needle or special trocar to remove a core of suspected tissue for histologic study. The newest and simplest procedure to obtain cytologic confirmation in doubtful cases is the examination of either urine or prostatic fluid for carcinoma cells by the Papanicolaou technic. 18 Herbert and Lubin,19 using smears of prostatic fluid obtained by massage, have shown how accurate this test can be. When the smears gave positive results, carcinoma was shown regularly to be present. An occasional negative result in the presence of carcinoma was ascribed to scanty secretions of poor quality. ,Perhaps by the large scale use of such methods the percentage of early diagnoses, where radical operation is still possible, can be increased from the present miserable 5 per cent.
ADVANCES IN MANAGEMENT OF PROSTATIC DISEASE
1511
As already mentioned, in cases of cancer of the prostate where the disease has not spread beyond the capsule, radical prostatectomy is indicated. 20 In this operation the prostate, prostatic capsule and seminal vesicles are removed. In the small number of patients suitable for this operation, cure of the disease can be expected in approximately half of the patients. Endocrine Therapy.-Without doubt one of the most stimulating advances of recent years in the therapy of prostatic disease has been the discovery that prostatic carcinoma can be suppressed temporarily by castration or estrogens. It has long been known that the normal prostate will fail to develop if deprived of male sex hormone. It was shown by Huggins21 , 22 that carcinoma cells derived from prostatic epithelium similarly can be suppressed by deprivation of androgen. Orchiectomy.-In cases of carcinoma of the prostate with metastasis dramatic relief of pain often appears within twenty-four hours following castration because of shrinking of the carcinoma cells and suppresion of growth. Serial biopsies of accessible metastases have shown that castration produces extremely interesting regressive changes in the tumor. Similar effects have been noted in the primary tumor in the prostate itself. Occasionally bone metastases undergo profound changes that can be detected on the x-ray, with initial increase in sclerosis and gradual fading out of the lesion. As mentioned previously, prostatic epithelium normally produces acid phosphatase. Often carcinomatous tissue, even metastatic, continues to produce this substance which can be detected in the blood. Following castration the production of acid phosphatase falls off sharply as the metastasis becomes inhibited. Serial phosphatase determinations therefore give objective evidence of the effect of castration upon the tumor besides serving as an aid in making the diagnosis initially. In diagnosis of carcinoma, the level of acid phosphatase in the blood has distinct limitations. When it is elevated the diagnosis of prostatic cancer is almost certain. On the other hand, a normal level does not exclude carcinoma. In the absence of metastases normal levels are found. In many instances, even with extensive metastases, the blood acid phosphatase may not be increased. Perhaps such carcinomas have become more anaplastic and lost the adult function of producing this enzyme. Changes also occur in the alkaline phosphatase of the blood in metastatic cancer of the prostate. These changes are not specific for prostatic carcinoma but are due to the response on the part of the bone to the metastases within it with the marked osteoplastic reaction so commonly seen. Following castration a favorable response is indicated by a fall in the acid phosphatase because of decreased activity of the carcinoma cells. At the same time the alkaline phosphatase often rises higher than previously. These changes in the blood phosphatase generally parallel the clinical response of the patient with decrease or complete elimination of metastatic pain. Estrogen Administration.-Shortly after the discovery that orchiectomy resulted in suppression of prostatic carcinoma, it was found that
1512
CoRNELIUS W. VERMI
administration of estrogens without castration produced a similar effect. At the present time diethylstilbestrol therapy has largely replaced castration in the clinical case. Dosage has varied widely and is dependent upon clinical response and toleration of the drug. Good responses may be obtained with doses of a few milligrams a day, while in other cases enormous doses have been administered. Initially it was hoped that endocrine suppression of carcinoma might be permanent. It was soon found that the initial gratifying relief from pain, the phosphatase response, et cetera, were only temporary. After a period of a few months to years, despite continuous treatment, symptoms return and the carcinoma runs its course uninhibited by continued estrogenic treatment. Nonetheless, sufficient evidence is available to show that endocrine therapy does significantly prolong the survival period in patients with metastatic carcinoma of the prostate. On the other hand, it must be mentioned that in a considerable proportion of cases orchiectomy or estrogen therapy produces little or no effect, even initially. Very recent reports have appeared suggesting that estrogenic treatment is not without some danger. Carcinoma developing in the male breast following long-continued stilbestrol therapy has been reported. The incidence of this complication must be very low considering the many thousands of patients that have been treated with estrogens for prostatic carcinoma. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.
Draper, J. W.: Surgery 23:515, 1948. Huggins, C. and Webster, W. 0.: J. Urol. 59:258, 1948. Huggins, C.: Physiol. Rev. 25:281,1945. Creevy, C. D.: J. Urol. 39:403, 1938. Rose, D. K.: J. Urol. 53:470,1945. Walters, G. A. Bagot: Brit. M. J. 1:638, 1948. Shivers, C. H. DeT. and Groom, C. E.: J. Urol. 59:893, 1948. Creevy, C. D.: J. Urol. 58:125, 1947. Biorn, C. L. and Greene, L. F.: Surg., Gynec. & Obst. 88:389,1949. Marshall, Victor F.: J. Urol. 52:250,1944. Millin, Terrence: Retropubic Urinary Surgery. Baltimore, Williams & Wilkins Co., 1947. Millin, Terrence: J. Urol. 59:267,1948. Lowsley, O. S. and Gentile, A.: J. Urol. 59:281,1948. Grant, O. and Lich, R.: Ann. Surg. 127:1010, 1948. Moore, T. D.: J. Urol. 61:46,1949. Bacon, S. K.: J. Urol. 61:75, 1949. Souttar, H. S.: Brit. M. J. 1:917, 1947. Papanicolaou, G. N.: J.A.M.A., 131:372, 1946. Herbert, P. A. and Lubin, E. N.: J. Urol. 57:542, 1947. Hinman, F.: J.A.M.A., 135:136, 1947. Huggins, C. and Hodges, C. V.: Cancer Research 1 :293,1941. Huggins, C., Stevens, R. E., and Hodges, C. V.: Arch. Surg. 43:209, 1941.