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Multiple Tumors of the Urinary Tract
THE JOURNAL OF UROLOGY
Vol. 64, No. 2, August 1950 Printed in U.S.A.
MULTIPLE TUMORS OF THE URINARY TRACT EUGENE C. ST. MARTIN, HAROLD A. O'BRIEN
AND
JOSEPH D. MITCHELL
The association of multiple tumors in various parts of the urinary tract is one of the most interesting conditions in the study of urological neoplasms. These tumors are similar, grossly and microscopically, are "transitional cell" in type, usually papillary in form, and may develop in any combination of the renal pelvis, ureter, bladder, and urethra. Likewise, the successful diagnosis of this condition may require one's keenest diagnostic ability. In the past year, the importance of investigation of the entire urinary tract, subsequent to the discovery of a papillary tumor, has been re-emphasized to us. This necessitates good pyelo-ureterograms, with thorough inspection of the lower tract, for disposition of the one tumor and failure to detect the other or others, make faulty urology. Experience teaches slowly, and at the cost of mistakes. If one might profit by our experiences, then the presentation of this paper will have been -worth while. MATERIAL
Interest in this study has been stimulated by the relative frequency of multiple tumors seen in the period from January through September 1949. Four out of nine renal tumors have been papillary carcinoma of the renal pelvis. This is a greater incidence than the usual quoted 5-10 per cent. Hematuria was the presenting finding in all cases. Included is 1 case where the nephrectomy was done before the patient was referred to us. In 2 cases, the ureter was involved; in 1, the bladder. One patient, a 79 year old white man, did not come to surgery because of extremely poor general condition produced by an incompatible blood transfusion given in preparation for surgery. Two of thirteen bladder tumors were associated with tumors in the upper urinary tract. Another was an invasion through the trigone from carcinoma of the prostate; this was a villous tumor with no involvement of the mucosa of the prostatic urethra. One of the bladder tumors was associated with tumors of the anterior urethra. The latter preceded the bladder tumor. Two of the patients with bladder tumors were in the group with papillomatosis of the bladder, and were not included in this study. One of these has been treated for recurrent papillomas over a period of 10 years. Four out of 25 patients had multiple tumors of the urinary tract. The various tumors seen from January through September 1949, exclusive of carcinoma of the prostate and testicle, are listed as follows (table 1): The interesting features in four of these cases will be presented. Read at annual meeting, South Central Section, American Urological Association, Colorado Springs, Colo., October 19, 1949. 426
427
MULTIPLE TUMORS OF THE URINARY TRACT CASE REPORTS
Case 1. G. J. M., 61 year old white man, was referred to us on January 3, 1949 because of recurrent, total, painless hematuria. The left kidney had been removed 4 months previously, for papillary carcinoma of the renal pelvis. He remained well for 3 months, but during the last month he had progressive hematuria. Cystoscopy disclosed two papillary tumors high up on the posterior wall, one quite large, the other small. There was active bleeding from the large tumor The ureteral orifices and the ridges beyond appeared normal. However, it was believed that the tumors were likely related to the original papillary carcinoma TABLE
1
Kidney Clear cell carcinoma ... With isolated bone metastasis. Papillary cystadenocarcinoma. Papillary carcinoma of renal pelvis .... Involved ureter. Involved bladder ...
1
Ureter Papillary tumor. In vol vecl bladder ..
l
Bladder. Tumors in ureter or renal pelvis. Invasion from carcinoma of prostate. Urethra. Tumor in bladder. Total.
4 2 4
2 1
13 2
1 2
1
25
3
7
of the renal pelvis, because of their high position on the posterior wall. A catheter would not go beyond 3 cm. on the left, and an attempted ureterogram with the head dmvn was unsuccessful. The right pyelo-utererogram was normal. The patient's general condition was good. Although the hematuria had been profuse, hemoglobin was 13.8 gm., and he had 4,460,000 red blood cells. The blood urea was 48, and the chest x-ray was normal. Two days later, the patient was operated upon. A midline suprapubic incision was selected so that the abdomen could be explored and the ureter removed through the same incision. No extension of the bladder tumor to the peritoneum was found. Then the ureteral stump was approached transperitoneally. It had been severed just above the iliac vessels, was normal in size, but felt full. The ureter was dissected free to near the bladder, and the peritoneal incisions were closed. The bladder was opened extraperitoneally, and the segment of the bladder
428
E. C. ST. MARTIN, H. A. O'BRIEN AND J. D. MITCHELL
with the tumors was resected. The incision was extended to the intramural portion of the left ureter, and a cuff of bladder and the stump of the ureter were removed. The bladder ,vas closed with continuous chromic sutures. A suprapubic tube was left for drainage.
FIG. 1
FIG. 2
The specimens revealed the two tumors from the bladder (fig. 1) and eight papillary tumors in the ureteral stump (fig. 2). There were t,vo small tumors near the ureterovesical junction, but it was difficult to explain the inability to get a catheter beyond this point. The sections were returned with the report "papillary transitional cell carcinoma, grade 2, of the bladder and ureter." The sections were identical histologically, with the exception of infiltration of the submucosa of the bladder by tumor.
MULTIPLE TUMORS OF THE URINARY TRACT
429
The immediate postoperative course was uneventful. However, the patient developed a fatal pulmonary embolus on the thirteenth postoperative day. Ambulation was begun the second day. Attempts to secure this man's original urograms have been unsuccessful. The nephrectomy was done by a general surgeon. Failure to detect the associated bladder and ureteral tumors was more likely than the subsequent development of these tumors. The lack of good pyelo-ureterograms and careful cystoscopy was apparent. In addition, the importance of adequate treatment of papillary carcinoma in the renal pelvis was demonstrated. The ureter, as well as the kidney, must be removed in its entirety, and best with a cuff of bladder.
FIG. 3
Case 2. J.B. C., a 78 year old white woman, was admitted to Baylor Hospital in May 1948, for investigation of hematuria. Approximately 7 weeks before, following a fall, she experienced painless, total hematuria for the first time. This continued for 2 or 3 weeks, then subsided, to recur later at intervals. She also noticed during this time severe backache in the upper lumbar area. This also had subsided at the time of admission. The patient's general condition was good for her stated age. The right kidney could be palpated. A ptosis belt had been prescribed 8 years previously. The hemoglobin was 14.2 gm., with 4,380,000 red cells, and blood urea was 20. The urine was loaded with red blood cells. A small right hydronephrosis with rotation and a questionable filling defect in the left pyelogram were seen in excretory urograms (fig. 3, A). Cystoscopy revealed a normal bladder, but a dark efflux from the left ureter. Many red cells
430
E. C. ST. MARTIN,, H. A. O'BRIEN AND J. D. MITCHELL
were found in the urine from the left kidney. The urine from the right kidney was completely normal. Retrograde pyelograms revealed the rotation of the right kidney and a large filling defect in the left (fig. 3, B). There was also seen, at this time, a compression fracture of the body of the first lumbar vertebra. (fig. Ll, A). After a few days, the hematuria stopped, and the left pyelogram was repeated. There was no change, and the tentative diagnosis was papillary carcinoma of the renal pelvis. However, the opinion of the roentgenologist was that this patient had metastasis in the first lumbar vertebra, with pathological fracture. Because of this, operation was considered inadvisable. Deep x-ray therapy was given, following which she was discharged. The hematuria had cleared up. She returned to Baylor Hospital 8 months later for further evaluation. Despite intermittent hematuria, the patient had done quite ·well, and her general con-
Fm. 4
dition appeared even better than on her initial admission. At this time, the urine contained only a few pus cells and the blood urea was 31. The hemoglobin was 12.6 gm., with 4,000,000 red cells. The pyelograms were repeated. Little change from the previous films was noticed. However, the collapsed first lumbar vertebra showed healing (fig. 4, B), so the opinion of the radiologist was now reversed. He believed that this must have been a traumatic fracture with subsequent healing. Because of this, and in the absence of other metastases, nephrectomy was advised. Through a lumbar incision, the left kidney was easily removed ,vith as much of the ureter as possible. Because of the patient's age, it was felt inadvisable to do the entire ureterectomy at the same time. Three weeks later, through a midline incision, the remaining left ureter was removed extraperitoneally. After the ureter was freed dmvn to the bladder, it was tented and a purse string suture was taken around the base. The ureter was then excised, along with a cuff of bladder, and the stump was inverted in the manner of doing an appendectomy. The wall of the bladder being thin, this
MULTIPLE TUMORS OF THE URINARY TRACT
431
method was found very satisfactory, as the entire intramural ureter and a cuff of bladder were removed. The kidney specimen revealed multiple papillary growths in the upper half of a bifid pelvis. Sections of this tumor revealed "papillary transitional cell carcinoma of the renal pelvis, grade 2," with no evidence of invasion of the renal parenchyma. The ureter was free of any associated tumors, and the sections showed "chronic ureteritis" with occasional focal accummulations of inflammatory cells in the submucosa, chiefly lymphocytic in type. A similar microscopic picture has been described by Bothe. In his study of 6 surgical specimens of carcinoma of the renal pelvis, Bothe made sections of the distant pelvis and ureter where the surface appeared normal, congested, indurated, or ulcerated. The areas appearing nonpathological were either normal microscopically or showed subsurface hyperemia or round cell infiltration. Where the surface appeared congested or edematous, the sections showed moderate to extensive round cell infiltration with thickening of the transitional cell layer due to proliferation of the basal layer. Sections through granular and elevated areas showed marked thickening of the epithelial layer with digital penetration and surface papillary formation. In the indurated, ulcerated areas, extensive infiltration of irregular large epithelial cells with dense stroma and round cell infiltration was seen in the sections. Bothe made the hypothesis that these studies indicate, first, that the areas of inflamation illustrate early reaction, while the areas of proliferating basal cells are more advanced lesions which eventually become papillary and neoplastic. He assumed that the intramural changes which start in the basal layer regions are due to irritants or carcinogenic agents which have been excreted by the kidneys or transmitted by the blood or lymph. Similar findings by Gay in the bladder of aniline dye workers and the early inflamatory reaction to the subcutaneous injections of 20-methylcholanthrene formed the basis for Bothe's hypothesis. The diagnosis of a pathological fracture, rather than a traumatic one, was wrong. Fortunately, the tumor grew slowly so that apparently the interval of 8 months made no difference in the prognosis. The value of getting more detail from a retrograde pyelo-ureterogram than from an excretory urogram has been shown (fig. 3). The excretory urogram will often fail to reveal multiple tumors in the upper urinary tract. The patient returned 2 months later, with a complaint of pain between the scapulae, following another fall. Roentgen examination revealed another compression fracture, this time the seventh thoracic vertebra. It was believed that this was definitely a traumatic fracture due to senile osteoporosis in the patient. Her general condition remained good, and she was discharged with a light brace for support. Six weeks ago, she was in excellent health and very active (reported by her niece). Although there were no other papillary tumors associated with the tumor of the pelvis in this case, it was selected because of the coincidental fracture, and because it illustrated the intermittent hematuria and slow growth of papillary carcinoma of the renal pelvis.
432
E. C. ST. MARTIN, H. A. O'BRIEN AND J. D. MITCHELL
Case 3. S. D., a 50 year old white woman, was referred to us in April 1948. For the past 3 years, she had experienced several episodes of dysuria, frequency, urgency, and she now felt another was approaching. In the past, there had been spontaneous remission of her symptoms. Two years before, a hysterectomy was done for fibroids. A few days postoperatively, she developed pain in her right loin, and the kidney was found to be obstructed. During the following year, the right ureter was periodically dilated. Despite this, there was complete loss of function, and a right nephrectomy was done a year later. The urine contained a rare pus cell. A urethral stricture and marked papillary urethritis were found to explain her lower urinary tract symptoms, and, in addition, a small papillary tumor was found between the right ureteral orifice and the bladder neck. This was considered an incidental finding. However, her local doctor was called, and he assured us that the removed kidney had been simply an old hydronephrosis. This doctor had performed the hysterectomy, but had referred her to another surgeon to handle the renal obstruction. The tumor was resected, and the posterior urethra thoroughly fulgurated. Sections of the tumor were returned with the report "papilloma of the bladder." Excretory urograms revealed a normal left side. The patient returned home with instructions to have cystoscopy repeated every 3 months, to guard against a recurrence of the tumor. Ten months later, at routine cystoscopy, a small tumor was found on the posterior bladder wall by her local doctor, and was fulgurated. Two months later, she returned to us for another examination. The patient looked well, and she appeared to be in good health. The urine contained a few pus cells. The bladder was carefully inspected and a scar still remained on the posterior wall from the recent fulguration. However, a small tumor frond was seen on the medial margin of the right ureteral orifice. The right ureteral ridge was also elevated, and a tongue of tumor tissue jetted through the orifice intermittently. A right ureterogram was made 2 days later (fig. 5) and a large filling defect was seen in the remaining right ureter. The diagnosis was apparent: a tumor of the right ureter. A left retrograde pyelo-ureterogram was normal. Two days later, through a midline incision, the remaining portion of the right ureter was removed extraperitoneally. The ureter was found to be enlarged in a fusiform manner; there was no pelvic node involvement. A ureteral catheter had been inserted preoperatively to facilitate identification of the ureter. The ureter was severed flush with the bladder, because of excessive bleeding. The specimen (fig. 6) showed a large papillary tumor that extended down to the intramural portion of the ureter. The sections showed "transitional cell carcinoma of the ureter, grade l." There was definite invasion of the muscularis by the tumor. Fourteen days postoperatively, the intramural portion of the ureter was fulgurated cystoscopically, and the small tumor seen on the medial margin of the orifice was completely destroyed. The postoperative course of the patient was complicated by the development
Fm. 5
B
Fm. 6 433
434
E. C. ST. ,MARTIN, H. A. O'BRIEN AND J. D. MITCHELL
of a pelvic abscess. This prolonged the hospital stay, but the patient was soon discharged, well healed and in good condition. In a recent letter, the patient reported she was doing fine and continued to be free of the sore spot in her lower right quadrant. The prognosis of this case, of course, is still uncertain. Undoubtedly she had the ureteral tumor at the time of the hysterectomy. She volunteered the information, after the ureterectomy, that she had had a sore spot in the lower right quadrant almost continuously since 1946, prior to the hysterectomy, and now, for the first time, she was completely free of it. In fact, the hysterectomy was supposed to relieve this right lower quadrant pain. Additional information has since been obtained from the surgeon who did the nephrectomy. He was called to see this patient on the eighth postoperative day for severe pain in the lower right quadrant. There had been excessive bleeding ineurred on the right side in doing the hysterectomy, and there was the natural concern about a ureteral injury. On cystoscopy no indigo carmine appeared from the right side within 20 minutes. He pushed a ureteral catheter through an obstruction in the lower ureter. Because of the x-ray film shortage at that time pyelograms were not made. The catheter was left indwelling for a few days, then removed, with an uneventful convalescence. Later excretory urograms were made. These showed a moderate right hydronephrosis, but no unusual ureteral dilatation. With subsequent loss of function, the kidney was removed. The mistakes on our part were failure to dig into the minute details of the history and failure to make a ureterogram of the right ureteral stump, when the first bladder tumor was seen. Both were lessons to learn well. Visualization of ureteral stumps in the work-up of isolated bladder tumors has not been stressed in the literature. Therefore, the importance of complete and impartial examination of the urinary tract in the face of a papillary tumor, was again emphasized to us. Case 4- L. D. P., a 75 year old white man, was first seen in August 1946, with a suprapubic cystotomy of 3 months' duration. His general condition had previously precluded a prostatectomy, but now warranted it. He was resected at this time. Nine months later, he returned with many venereal warts along the corona and at the external meatus. Podophyllin was successfully used, except for the development of a balanoposthitis. A circumcision was performed. The ''warts" recurred a year later. They now had the appearance of papillomas and extended from the external meatus along the anterior urethra. No tumors were seen in the bladder. By means of a 24 F resectoscope, they were removed. The sections showed "chronic inflammation and papillary epithelial hyperplasia." A stricture of the anterior urethra resulted, and the urethra was periodically dilated. Seven months later, the papillomas recurred in the anterior urethra, and were again resected. No tumors were seen in the bladder. The sections were returned "urethral papillomas." This was in December 1948.
MUL'rIPLE TUMORS OF THE URINARY TRACT
435
During the past year, periodic dilatation of the urethra has been necessary to keep the stricture open. Recently, the papilloma recurred in the external meatus. It was "meaty" and injected. Because of the persistent pyuria, the entire urinary tract was surveyed and recurrent tumors were found in the distal and bulbous urethra. In addition, a papillary tumor of the bladder was found at the end of the right ureteral ridge. Numerous small cysts, with fine vascular markings, -were also seen. The upper urinary tract was negative, with normal urine and pyelograms. The bladder tumor and the urethral tumors were resected and the bases fulgurated. The sections were returned "epidermoid carcinoma of the bladder, squamous cell type, grade I," and "epidermoid carcinoma of the urethra, squamous cell type, grade I." The pyuria has improved steadily. Cysto-urethroscopy, 3 weeks ago, was negative for any recurrence. The transition from benignity to malignancy in these urethral tumors has been interesting. Perhaps radiation was indicated because of the many recurrences, but local resection and fulguration should have controlled the benign tumors. The possible development of additional tumors will be interesting to watch, as it seems this patient's urothelium is affected by some carcinogenic agent. DISCUSSION
This neoplastic disease of multiplicity found in the urinary tract is indeed complex. The successful diagnosis of this condition can be made easy if careful cystoscopy is done and good pyelo-ureterograms are obtained. This disease will often be seen in the bladder. All vesical tumors warrant a complete study, particularly the papillary tumors. In 25 per cent of cases of multiple tumors, the bladder will be involved. Small tumor fronds in the ureteral orifices or elevation of the ureteral ridges beyond can be easily missed if casual cystoscopy is done. The ureteral orifice, obstructed by a bladder tumor, should always be highly suggestive of a tumor above. The diagnosis of papillary tumors of the upper urinary tract is usually made from the persistent filling defect in the pyelogram or ureterogram. N onopaque calculi or blood clots sometimes enter into the differential diagnosis. Trattner has developed the renoscope for direct vision of the renal pelvis. This procedure seems to be too cumbersome to be practical. The Papanicolaou stain of the urinary sediment, when positive, adds to the available diagnostic evidence. It alone should not be the conclusive evidence. Finally, surgical exploration warrants no criticism in the doubtful case. Although the pathogenesis of this condition is still controversial, that of multiple independent tumors versus a primary tumor with secondary transplantation, the surgical management is well established from a practical standpoint. The benign papilloma should be handled as radically as the papillary carcinoma, whether in the renal pelvis or the ureter. The occasional exception may arise as in the case of Ferris and Daut. They excised a papillary epithelioma of
436
E. C. ST. MARTIN, H. A. O'BRIEN AND J. D. MITCHELL
the renal pelvis in a solitary kidney. That patient is living and well, three years postoperatively. In a recent article, O'Conor emphasizes the importance of 2-dequate surgical management. The results of excision of a benign ureteral papilloma, V{ith re-anastomosis of ureter, as reported by Vest and by McClelland 2-re spectacular. The management of papillary tumors of the pelvis and the ureter should be nephrectomy plus total ureterectomy, including a cuff of bladder. Too often has there been recurrence in the remaining ureteral stump. Of the 74 cases of tumors of the renal pelvis associated with similar tumors of the ureter and bladder, collected by Kimball and Ferris, 48 developed new tumors in the ureter or bladder after the original pelvic tumors had been observed or treated. In the 48 cases, the ureteral orifices and adjacent bladder were involved in 48 per cent, the ureter and distant bladder in 36 per cent, the bladder alone in 14 per cent. There was a total known recurrence of 64 per cent. In 24 cases, with involvement of the pelvis and ureter and/or bladder at the original observation and treated by nephrectomy and complete ureterectomy, there were no recurrences. These figures were conclusive, and there should be no doubt in anyone's mind as to the value of total ureterectomy. The procedure may be done in one or two stages, depending on the condition of the patient. Management of the intramural ureter depends on the mobility of the bladder, thickness of the bladder wall, or involvement of the bladder. Colston cuts the ureter flush with the bladder and fulgurates the mucosa of the intramural ureter. Kirwin has modified this by lifting up on the ureter, purse stringingthe base, removing a cuff of bladder with the ureter, fulgurating and inverting the edges. This works ·well where the bladder wall is thin. If the bladder is involved and the tumor has a narrow pedicle, simple looping and fulgurating is adequate. In the broad base pedicle, segmental resection of the bladder is necessary, with the incision extended to include the intramural ureter and a cuff of bladder. Where there are small tumor fronds, then cystoscopic fulguration is satisfactory. Cystoscopy at increasing intervals should follow nephro-ureterectomy, even in bladders not involved at the original surgery. The subsequent development of a tumor in the bladder is not beyond the realm of possibility. CONCLUSION
In a short period, 9 months, a relatively large number of multiple tumors of the urinary tract have been seen. The diagnosis of this condition was made after the discovery of papillary tumors in one part of the urinary tract, in 3 out of 4 cases. The importance of complete and impartial investigation of the entire urinary tract has been emphasized, after the discovery of a papillary tumor of the bladder. Visualization by x-ray of the ureteral stump has not been previously emphasized where nephrectomy was supposedly done for some nonneoplastic condition. The treatment of papillary carcinoma of the pelvis and ureter continues to be nephrectomy and complete ureterectomy. Subsequent cystoscopy is also indicated to guard against any recurrence in the bladder.
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Papillomatosis of the bladder was not discussed, as it is believed that this presented a different clinical condition. Medical Arts Bldg., Shreveport, La., (E. C. St. M.) Medical Arts Bldg., Dallas, Texas (H. A. O'B. and J. D. lJ!I.) REFERENCES BAILEY, lVI. K., FoIL, C. A. AND HARLIN, H. C.: Papillary carcinoma of ureter and bladder arising after nephrectomy for tumor of kidney pelvis. J. Urol., 62: 44-47, 1949. BO'l'HE, A. E.: Carcinoma of the renal pelvis and ureter. J. Urol., 49: 69-76, 1943. COLSTON, J. A. C.: Complete nephro-ureterectomy; a new method employing the principle of electro-coagulation to the intramural portion of the ureter. J. Urol., 33: 110-130, 1935. CROSS, W. W.: Extensive papillo-carcinoma of the kidney pelvis and ureter. Urol. and Cutan. Rev., 43: 321-323, 1949. DAVIDSON, 0. W.: Squamous cell carcinoma of the renal pelvis. J. Urol., 47: 348-352, 1942. DAVIS, E.: Chemical carcinogenesis, drugs, dyes, remedies and cosmetics with particular reference to bladder tumors. J. Urol., 49: 45-64, 1943. DEMING, C. L.: Papillomatosis of bladder and entire urethra. J. Urol., 52: 309-318, HJ44. FAGERSTROM, D. P.: Ureterectomy: Its indications as an adjunct to nephrectomy. J. Urol., 41: 137-150, 1939. FAGERSTROM, D. P.: Proliferative tumors of the ureter and renal pelvis with further observation on the significance of "epithelial cell nests." J. Urol., 59: 333-357, 1948. FERGUSON, R. S.: Etiology of bladder carcinomas. J. Urol., 31: 122-126, 1934. FERRIS, D. 0. AND DAuT, R. V.: Epithelioma of the pelvis of a solitary kidney treated by electrocoagulation. J. Urol., 59: 577-579, 1948. FERRIS, D. 0.: Personal communication. GAY, D. M.: Pathology of aniline tumors of the bladder. J. Urol., 31: 137-148, 1934. GEI-IRMANN, G. II.: The carcinogenetic agent: Chemistry and industrial aspects. J. Urol., 31: 126-137, 1934. IIAMM, F. C. AND LAVELLE, L. L.: Tumors of the ureter. J. Urol., 61: 493-505, 1949. HuNT, V. C.: Papillary epithelioma of the renal pelvis. J. Urol., 18: 225-246, 1927. KAMINSKY, A. F.: Associated kidney and bladder tumors. J. Urol., 61: 997-1002, 1949. KIMBALL, F. N. AND FERRIS, II. W.: Papillomatous tumor of the renal pelvis associated with similar tumors of the ureter and bladder. J. Urol., 31: 257-304, 1935. KIRWIN, T. J.: Papillary carcinoma of the renal pelvis. Surg., Gynec. & Obst., 72: 759-76,5, 1941. KIRWIN, T. J.: Papillomatosis of bladder, new conceptions of etiology and treatment. J. U rol., 49: 1-13, 1943. LAZARUS, J. A. AND lVIARKS, lVI. S.: Primary carcinoma of ureter with special reference to hydronephrosis. J. Urol., 54: 140-157, 1945. MALLORY Case No. 26091, N. E. Med. J., 222: 354---356, 1940. MALLORY Case No. 32422, J\i. E. Med. J., 235: 599-602, 1946. MALLORY Case No. 33212, N. E. Med. J., 236: 809-811, 1947. McCLELLAND, J. C.: Primary carcinoma of ureter, treated by excision and anastomosis of the cut ends. J. Urol., 52: 522-525, 1944. McMAHON, S.: Tumors of the ureter. J. U rol., 51: 616-622, 1944. MELEl\, D.R.: Tumors of the renal pelvis. J. Urol., 51: 386-394, 1944. MELicow, M. M.: Classification of renal neoplasms. J. Urol., 51: 333-385, 1944. O'BRIEN, II. A.: Primary carcinoma of the ureter. J. Urol., 37: 49-53, 1937. O'CoNOR, V. J.: The treatment and prognosis of papillary tumors of the renal pelvis and ureter. J. Urol., 61: 488-492, 1949. PATTON, J. F.: Total ureterectomy: A new technique of extravesical removal of the intramural ureter. J. U rol., 47: 353-360, 1942. REAGAN, J. R.: Papillary carcinoma of the ureter. J. Urol., 50: 304-306, 1943. RosE, D. K.: Influence of anilin dyes on urinary tract tumors. J. Urol., 51: 81-84, 1944. SCHULTE, T. L. AND PRIESTLEY, J. T.: Association of renal and vesical neoplasms. Proc. Staff Meet., Mayo Clin., 16: 381-384, 1941. SCOTT, W.W.: A review of primary carcinoma of the ureter. J. Urol., 50: 45-63, 1943. THOMAS, G. J. AND REGNIER, E. A.: Tumors of the kidney pelvis and ureter. J. Urol., 11: 205-238, 1924. TRATTNER, II. R.: Instrumental visualization of renal pelvis. J. Urol., 60: 817-834, 1948. VES'l', S. A.: Conservative surgery in certain benign tumors of the ureter. J. Urol., 53: 97121, 1945. WASHBURN, V. D.: The treatment of anilin tumors of the urinary bladder. J. Urol. 31: 155-162, 1934.
Vol. 64, No. 2, August 1950 Printed in U.S.A.
MULTIPLE TUMORS OF THE URINARY TRACT EUGENE C. ST. MARTIN, HAROLD A. O'BRIEN
AND
JOSEPH D. MITCHELL
The association of multiple tumors in various parts of the urinary tract is one of the most interesting conditions in the study of urological neoplasms. These tumors are similar, grossly and microscopically, are "transitional cell" in type, usually papillary in form, and may develop in any combination of the renal pelvis, ureter, bladder, and urethra. Likewise, the successful diagnosis of this condition may require one's keenest diagnostic ability. In the past year, the importance of investigation of the entire urinary tract, subsequent to the discovery of a papillary tumor, has been re-emphasized to us. This necessitates good pyelo-ureterograms, with thorough inspection of the lower tract, for disposition of the one tumor and failure to detect the other or others, make faulty urology. Experience teaches slowly, and at the cost of mistakes. If one might profit by our experiences, then the presentation of this paper will have been -worth while. MATERIAL
Interest in this study has been stimulated by the relative frequency of multiple tumors seen in the period from January through September 1949. Four out of nine renal tumors have been papillary carcinoma of the renal pelvis. This is a greater incidence than the usual quoted 5-10 per cent. Hematuria was the presenting finding in all cases. Included is 1 case where the nephrectomy was done before the patient was referred to us. In 2 cases, the ureter was involved; in 1, the bladder. One patient, a 79 year old white man, did not come to surgery because of extremely poor general condition produced by an incompatible blood transfusion given in preparation for surgery. Two of thirteen bladder tumors were associated with tumors in the upper urinary tract. Another was an invasion through the trigone from carcinoma of the prostate; this was a villous tumor with no involvement of the mucosa of the prostatic urethra. One of the bladder tumors was associated with tumors of the anterior urethra. The latter preceded the bladder tumor. Two of the patients with bladder tumors were in the group with papillomatosis of the bladder, and were not included in this study. One of these has been treated for recurrent papillomas over a period of 10 years. Four out of 25 patients had multiple tumors of the urinary tract. The various tumors seen from January through September 1949, exclusive of carcinoma of the prostate and testicle, are listed as follows (table 1): The interesting features in four of these cases will be presented. Read at annual meeting, South Central Section, American Urological Association, Colorado Springs, Colo., October 19, 1949. 426
427
MULTIPLE TUMORS OF THE URINARY TRACT CASE REPORTS
Case 1. G. J. M., 61 year old white man, was referred to us on January 3, 1949 because of recurrent, total, painless hematuria. The left kidney had been removed 4 months previously, for papillary carcinoma of the renal pelvis. He remained well for 3 months, but during the last month he had progressive hematuria. Cystoscopy disclosed two papillary tumors high up on the posterior wall, one quite large, the other small. There was active bleeding from the large tumor The ureteral orifices and the ridges beyond appeared normal. However, it was believed that the tumors were likely related to the original papillary carcinoma TABLE
1
Kidney Clear cell carcinoma ... With isolated bone metastasis. Papillary cystadenocarcinoma. Papillary carcinoma of renal pelvis .... Involved ureter. Involved bladder ...
1
Ureter Papillary tumor. In vol vecl bladder ..
l
Bladder. Tumors in ureter or renal pelvis. Invasion from carcinoma of prostate. Urethra. Tumor in bladder. Total.
4 2 4
2 1
13 2
1 2
1
25
3
7
of the renal pelvis, because of their high position on the posterior wall. A catheter would not go beyond 3 cm. on the left, and an attempted ureterogram with the head dmvn was unsuccessful. The right pyelo-utererogram was normal. The patient's general condition was good. Although the hematuria had been profuse, hemoglobin was 13.8 gm., and he had 4,460,000 red blood cells. The blood urea was 48, and the chest x-ray was normal. Two days later, the patient was operated upon. A midline suprapubic incision was selected so that the abdomen could be explored and the ureter removed through the same incision. No extension of the bladder tumor to the peritoneum was found. Then the ureteral stump was approached transperitoneally. It had been severed just above the iliac vessels, was normal in size, but felt full. The ureter was dissected free to near the bladder, and the peritoneal incisions were closed. The bladder was opened extraperitoneally, and the segment of the bladder
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with the tumors was resected. The incision was extended to the intramural portion of the left ureter, and a cuff of bladder and the stump of the ureter were removed. The bladder ,vas closed with continuous chromic sutures. A suprapubic tube was left for drainage.
FIG. 1
FIG. 2
The specimens revealed the two tumors from the bladder (fig. 1) and eight papillary tumors in the ureteral stump (fig. 2). There were t,vo small tumors near the ureterovesical junction, but it was difficult to explain the inability to get a catheter beyond this point. The sections were returned with the report "papillary transitional cell carcinoma, grade 2, of the bladder and ureter." The sections were identical histologically, with the exception of infiltration of the submucosa of the bladder by tumor.
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The immediate postoperative course was uneventful. However, the patient developed a fatal pulmonary embolus on the thirteenth postoperative day. Ambulation was begun the second day. Attempts to secure this man's original urograms have been unsuccessful. The nephrectomy was done by a general surgeon. Failure to detect the associated bladder and ureteral tumors was more likely than the subsequent development of these tumors. The lack of good pyelo-ureterograms and careful cystoscopy was apparent. In addition, the importance of adequate treatment of papillary carcinoma in the renal pelvis was demonstrated. The ureter, as well as the kidney, must be removed in its entirety, and best with a cuff of bladder.
FIG. 3
Case 2. J.B. C., a 78 year old white woman, was admitted to Baylor Hospital in May 1948, for investigation of hematuria. Approximately 7 weeks before, following a fall, she experienced painless, total hematuria for the first time. This continued for 2 or 3 weeks, then subsided, to recur later at intervals. She also noticed during this time severe backache in the upper lumbar area. This also had subsided at the time of admission. The patient's general condition was good for her stated age. The right kidney could be palpated. A ptosis belt had been prescribed 8 years previously. The hemoglobin was 14.2 gm., with 4,380,000 red cells, and blood urea was 20. The urine was loaded with red blood cells. A small right hydronephrosis with rotation and a questionable filling defect in the left pyelogram were seen in excretory urograms (fig. 3, A). Cystoscopy revealed a normal bladder, but a dark efflux from the left ureter. Many red cells
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E. C. ST. MARTIN,, H. A. O'BRIEN AND J. D. MITCHELL
were found in the urine from the left kidney. The urine from the right kidney was completely normal. Retrograde pyelograms revealed the rotation of the right kidney and a large filling defect in the left (fig. 3, B). There was also seen, at this time, a compression fracture of the body of the first lumbar vertebra. (fig. Ll, A). After a few days, the hematuria stopped, and the left pyelogram was repeated. There was no change, and the tentative diagnosis was papillary carcinoma of the renal pelvis. However, the opinion of the roentgenologist was that this patient had metastasis in the first lumbar vertebra, with pathological fracture. Because of this, operation was considered inadvisable. Deep x-ray therapy was given, following which she was discharged. The hematuria had cleared up. She returned to Baylor Hospital 8 months later for further evaluation. Despite intermittent hematuria, the patient had done quite ·well, and her general con-
Fm. 4
dition appeared even better than on her initial admission. At this time, the urine contained only a few pus cells and the blood urea was 31. The hemoglobin was 12.6 gm., with 4,000,000 red cells. The pyelograms were repeated. Little change from the previous films was noticed. However, the collapsed first lumbar vertebra showed healing (fig. 4, B), so the opinion of the radiologist was now reversed. He believed that this must have been a traumatic fracture with subsequent healing. Because of this, and in the absence of other metastases, nephrectomy was advised. Through a lumbar incision, the left kidney was easily removed ,vith as much of the ureter as possible. Because of the patient's age, it was felt inadvisable to do the entire ureterectomy at the same time. Three weeks later, through a midline incision, the remaining left ureter was removed extraperitoneally. After the ureter was freed dmvn to the bladder, it was tented and a purse string suture was taken around the base. The ureter was then excised, along with a cuff of bladder, and the stump was inverted in the manner of doing an appendectomy. The wall of the bladder being thin, this
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method was found very satisfactory, as the entire intramural ureter and a cuff of bladder were removed. The kidney specimen revealed multiple papillary growths in the upper half of a bifid pelvis. Sections of this tumor revealed "papillary transitional cell carcinoma of the renal pelvis, grade 2," with no evidence of invasion of the renal parenchyma. The ureter was free of any associated tumors, and the sections showed "chronic ureteritis" with occasional focal accummulations of inflammatory cells in the submucosa, chiefly lymphocytic in type. A similar microscopic picture has been described by Bothe. In his study of 6 surgical specimens of carcinoma of the renal pelvis, Bothe made sections of the distant pelvis and ureter where the surface appeared normal, congested, indurated, or ulcerated. The areas appearing nonpathological were either normal microscopically or showed subsurface hyperemia or round cell infiltration. Where the surface appeared congested or edematous, the sections showed moderate to extensive round cell infiltration with thickening of the transitional cell layer due to proliferation of the basal layer. Sections through granular and elevated areas showed marked thickening of the epithelial layer with digital penetration and surface papillary formation. In the indurated, ulcerated areas, extensive infiltration of irregular large epithelial cells with dense stroma and round cell infiltration was seen in the sections. Bothe made the hypothesis that these studies indicate, first, that the areas of inflamation illustrate early reaction, while the areas of proliferating basal cells are more advanced lesions which eventually become papillary and neoplastic. He assumed that the intramural changes which start in the basal layer regions are due to irritants or carcinogenic agents which have been excreted by the kidneys or transmitted by the blood or lymph. Similar findings by Gay in the bladder of aniline dye workers and the early inflamatory reaction to the subcutaneous injections of 20-methylcholanthrene formed the basis for Bothe's hypothesis. The diagnosis of a pathological fracture, rather than a traumatic one, was wrong. Fortunately, the tumor grew slowly so that apparently the interval of 8 months made no difference in the prognosis. The value of getting more detail from a retrograde pyelo-ureterogram than from an excretory urogram has been shown (fig. 3). The excretory urogram will often fail to reveal multiple tumors in the upper urinary tract. The patient returned 2 months later, with a complaint of pain between the scapulae, following another fall. Roentgen examination revealed another compression fracture, this time the seventh thoracic vertebra. It was believed that this was definitely a traumatic fracture due to senile osteoporosis in the patient. Her general condition remained good, and she was discharged with a light brace for support. Six weeks ago, she was in excellent health and very active (reported by her niece). Although there were no other papillary tumors associated with the tumor of the pelvis in this case, it was selected because of the coincidental fracture, and because it illustrated the intermittent hematuria and slow growth of papillary carcinoma of the renal pelvis.
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Case 3. S. D., a 50 year old white woman, was referred to us in April 1948. For the past 3 years, she had experienced several episodes of dysuria, frequency, urgency, and she now felt another was approaching. In the past, there had been spontaneous remission of her symptoms. Two years before, a hysterectomy was done for fibroids. A few days postoperatively, she developed pain in her right loin, and the kidney was found to be obstructed. During the following year, the right ureter was periodically dilated. Despite this, there was complete loss of function, and a right nephrectomy was done a year later. The urine contained a rare pus cell. A urethral stricture and marked papillary urethritis were found to explain her lower urinary tract symptoms, and, in addition, a small papillary tumor was found between the right ureteral orifice and the bladder neck. This was considered an incidental finding. However, her local doctor was called, and he assured us that the removed kidney had been simply an old hydronephrosis. This doctor had performed the hysterectomy, but had referred her to another surgeon to handle the renal obstruction. The tumor was resected, and the posterior urethra thoroughly fulgurated. Sections of the tumor were returned with the report "papilloma of the bladder." Excretory urograms revealed a normal left side. The patient returned home with instructions to have cystoscopy repeated every 3 months, to guard against a recurrence of the tumor. Ten months later, at routine cystoscopy, a small tumor was found on the posterior bladder wall by her local doctor, and was fulgurated. Two months later, she returned to us for another examination. The patient looked well, and she appeared to be in good health. The urine contained a few pus cells. The bladder was carefully inspected and a scar still remained on the posterior wall from the recent fulguration. However, a small tumor frond was seen on the medial margin of the right ureteral orifice. The right ureteral ridge was also elevated, and a tongue of tumor tissue jetted through the orifice intermittently. A right ureterogram was made 2 days later (fig. 5) and a large filling defect was seen in the remaining right ureter. The diagnosis was apparent: a tumor of the right ureter. A left retrograde pyelo-ureterogram was normal. Two days later, through a midline incision, the remaining portion of the right ureter was removed extraperitoneally. The ureter was found to be enlarged in a fusiform manner; there was no pelvic node involvement. A ureteral catheter had been inserted preoperatively to facilitate identification of the ureter. The ureter was severed flush with the bladder, because of excessive bleeding. The specimen (fig. 6) showed a large papillary tumor that extended down to the intramural portion of the ureter. The sections showed "transitional cell carcinoma of the ureter, grade l." There was definite invasion of the muscularis by the tumor. Fourteen days postoperatively, the intramural portion of the ureter was fulgurated cystoscopically, and the small tumor seen on the medial margin of the orifice was completely destroyed. The postoperative course of the patient was complicated by the development
Fm. 5
B
Fm. 6 433
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E. C. ST. ,MARTIN, H. A. O'BRIEN AND J. D. MITCHELL
of a pelvic abscess. This prolonged the hospital stay, but the patient was soon discharged, well healed and in good condition. In a recent letter, the patient reported she was doing fine and continued to be free of the sore spot in her lower right quadrant. The prognosis of this case, of course, is still uncertain. Undoubtedly she had the ureteral tumor at the time of the hysterectomy. She volunteered the information, after the ureterectomy, that she had had a sore spot in the lower right quadrant almost continuously since 1946, prior to the hysterectomy, and now, for the first time, she was completely free of it. In fact, the hysterectomy was supposed to relieve this right lower quadrant pain. Additional information has since been obtained from the surgeon who did the nephrectomy. He was called to see this patient on the eighth postoperative day for severe pain in the lower right quadrant. There had been excessive bleeding ineurred on the right side in doing the hysterectomy, and there was the natural concern about a ureteral injury. On cystoscopy no indigo carmine appeared from the right side within 20 minutes. He pushed a ureteral catheter through an obstruction in the lower ureter. Because of the x-ray film shortage at that time pyelograms were not made. The catheter was left indwelling for a few days, then removed, with an uneventful convalescence. Later excretory urograms were made. These showed a moderate right hydronephrosis, but no unusual ureteral dilatation. With subsequent loss of function, the kidney was removed. The mistakes on our part were failure to dig into the minute details of the history and failure to make a ureterogram of the right ureteral stump, when the first bladder tumor was seen. Both were lessons to learn well. Visualization of ureteral stumps in the work-up of isolated bladder tumors has not been stressed in the literature. Therefore, the importance of complete and impartial examination of the urinary tract in the face of a papillary tumor, was again emphasized to us. Case 4- L. D. P., a 75 year old white man, was first seen in August 1946, with a suprapubic cystotomy of 3 months' duration. His general condition had previously precluded a prostatectomy, but now warranted it. He was resected at this time. Nine months later, he returned with many venereal warts along the corona and at the external meatus. Podophyllin was successfully used, except for the development of a balanoposthitis. A circumcision was performed. The ''warts" recurred a year later. They now had the appearance of papillomas and extended from the external meatus along the anterior urethra. No tumors were seen in the bladder. By means of a 24 F resectoscope, they were removed. The sections showed "chronic inflammation and papillary epithelial hyperplasia." A stricture of the anterior urethra resulted, and the urethra was periodically dilated. Seven months later, the papillomas recurred in the anterior urethra, and were again resected. No tumors were seen in the bladder. The sections were returned "urethral papillomas." This was in December 1948.
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During the past year, periodic dilatation of the urethra has been necessary to keep the stricture open. Recently, the papilloma recurred in the external meatus. It was "meaty" and injected. Because of the persistent pyuria, the entire urinary tract was surveyed and recurrent tumors were found in the distal and bulbous urethra. In addition, a papillary tumor of the bladder was found at the end of the right ureteral ridge. Numerous small cysts, with fine vascular markings, -were also seen. The upper urinary tract was negative, with normal urine and pyelograms. The bladder tumor and the urethral tumors were resected and the bases fulgurated. The sections were returned "epidermoid carcinoma of the bladder, squamous cell type, grade I," and "epidermoid carcinoma of the urethra, squamous cell type, grade I." The pyuria has improved steadily. Cysto-urethroscopy, 3 weeks ago, was negative for any recurrence. The transition from benignity to malignancy in these urethral tumors has been interesting. Perhaps radiation was indicated because of the many recurrences, but local resection and fulguration should have controlled the benign tumors. The possible development of additional tumors will be interesting to watch, as it seems this patient's urothelium is affected by some carcinogenic agent. DISCUSSION
This neoplastic disease of multiplicity found in the urinary tract is indeed complex. The successful diagnosis of this condition can be made easy if careful cystoscopy is done and good pyelo-ureterograms are obtained. This disease will often be seen in the bladder. All vesical tumors warrant a complete study, particularly the papillary tumors. In 25 per cent of cases of multiple tumors, the bladder will be involved. Small tumor fronds in the ureteral orifices or elevation of the ureteral ridges beyond can be easily missed if casual cystoscopy is done. The ureteral orifice, obstructed by a bladder tumor, should always be highly suggestive of a tumor above. The diagnosis of papillary tumors of the upper urinary tract is usually made from the persistent filling defect in the pyelogram or ureterogram. N onopaque calculi or blood clots sometimes enter into the differential diagnosis. Trattner has developed the renoscope for direct vision of the renal pelvis. This procedure seems to be too cumbersome to be practical. The Papanicolaou stain of the urinary sediment, when positive, adds to the available diagnostic evidence. It alone should not be the conclusive evidence. Finally, surgical exploration warrants no criticism in the doubtful case. Although the pathogenesis of this condition is still controversial, that of multiple independent tumors versus a primary tumor with secondary transplantation, the surgical management is well established from a practical standpoint. The benign papilloma should be handled as radically as the papillary carcinoma, whether in the renal pelvis or the ureter. The occasional exception may arise as in the case of Ferris and Daut. They excised a papillary epithelioma of
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the renal pelvis in a solitary kidney. That patient is living and well, three years postoperatively. In a recent article, O'Conor emphasizes the importance of 2-dequate surgical management. The results of excision of a benign ureteral papilloma, V{ith re-anastomosis of ureter, as reported by Vest and by McClelland 2-re spectacular. The management of papillary tumors of the pelvis and the ureter should be nephrectomy plus total ureterectomy, including a cuff of bladder. Too often has there been recurrence in the remaining ureteral stump. Of the 74 cases of tumors of the renal pelvis associated with similar tumors of the ureter and bladder, collected by Kimball and Ferris, 48 developed new tumors in the ureter or bladder after the original pelvic tumors had been observed or treated. In the 48 cases, the ureteral orifices and adjacent bladder were involved in 48 per cent, the ureter and distant bladder in 36 per cent, the bladder alone in 14 per cent. There was a total known recurrence of 64 per cent. In 24 cases, with involvement of the pelvis and ureter and/or bladder at the original observation and treated by nephrectomy and complete ureterectomy, there were no recurrences. These figures were conclusive, and there should be no doubt in anyone's mind as to the value of total ureterectomy. The procedure may be done in one or two stages, depending on the condition of the patient. Management of the intramural ureter depends on the mobility of the bladder, thickness of the bladder wall, or involvement of the bladder. Colston cuts the ureter flush with the bladder and fulgurates the mucosa of the intramural ureter. Kirwin has modified this by lifting up on the ureter, purse stringingthe base, removing a cuff of bladder with the ureter, fulgurating and inverting the edges. This works ·well where the bladder wall is thin. If the bladder is involved and the tumor has a narrow pedicle, simple looping and fulgurating is adequate. In the broad base pedicle, segmental resection of the bladder is necessary, with the incision extended to include the intramural ureter and a cuff of bladder. Where there are small tumor fronds, then cystoscopic fulguration is satisfactory. Cystoscopy at increasing intervals should follow nephro-ureterectomy, even in bladders not involved at the original surgery. The subsequent development of a tumor in the bladder is not beyond the realm of possibility. CONCLUSION
In a short period, 9 months, a relatively large number of multiple tumors of the urinary tract have been seen. The diagnosis of this condition was made after the discovery of papillary tumors in one part of the urinary tract, in 3 out of 4 cases. The importance of complete and impartial investigation of the entire urinary tract has been emphasized, after the discovery of a papillary tumor of the bladder. Visualization by x-ray of the ureteral stump has not been previously emphasized where nephrectomy was supposedly done for some nonneoplastic condition. The treatment of papillary carcinoma of the pelvis and ureter continues to be nephrectomy and complete ureterectomy. Subsequent cystoscopy is also indicated to guard against any recurrence in the bladder.
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Papillomatosis of the bladder was not discussed, as it is believed that this presented a different clinical condition. Medical Arts Bldg., Shreveport, La., (E. C. St. M.) Medical Arts Bldg., Dallas, Texas (H. A. O'B. and J. D. lJ!I.) REFERENCES BAILEY, lVI. K., FoIL, C. A. AND HARLIN, H. C.: Papillary carcinoma of ureter and bladder arising after nephrectomy for tumor of kidney pelvis. J. Urol., 62: 44-47, 1949. BO'l'HE, A. E.: Carcinoma of the renal pelvis and ureter. J. Urol., 49: 69-76, 1943. COLSTON, J. A. C.: Complete nephro-ureterectomy; a new method employing the principle of electro-coagulation to the intramural portion of the ureter. J. Urol., 33: 110-130, 1935. CROSS, W. W.: Extensive papillo-carcinoma of the kidney pelvis and ureter. Urol. and Cutan. Rev., 43: 321-323, 1949. DAVIDSON, 0. W.: Squamous cell carcinoma of the renal pelvis. J. Urol., 47: 348-352, 1942. DAVIS, E.: Chemical carcinogenesis, drugs, dyes, remedies and cosmetics with particular reference to bladder tumors. J. Urol., 49: 45-64, 1943. DEMING, C. L.: Papillomatosis of bladder and entire urethra. J. Urol., 52: 309-318, HJ44. FAGERSTROM, D. P.: Ureterectomy: Its indications as an adjunct to nephrectomy. J. Urol., 41: 137-150, 1939. FAGERSTROM, D. P.: Proliferative tumors of the ureter and renal pelvis with further observation on the significance of "epithelial cell nests." J. Urol., 59: 333-357, 1948. FERGUSON, R. S.: Etiology of bladder carcinomas. J. Urol., 31: 122-126, 1934. FERRIS, D. 0. AND DAuT, R. V.: Epithelioma of the pelvis of a solitary kidney treated by electrocoagulation. J. Urol., 59: 577-579, 1948. FERRIS, D. 0.: Personal communication. GAY, D. M.: Pathology of aniline tumors of the bladder. J. Urol., 31: 137-148, 1934. GEI-IRMANN, G. II.: The carcinogenetic agent: Chemistry and industrial aspects. J. Urol., 31: 126-137, 1934. IIAMM, F. C. AND LAVELLE, L. L.: Tumors of the ureter. J. Urol., 61: 493-505, 1949. HuNT, V. C.: Papillary epithelioma of the renal pelvis. J. Urol., 18: 225-246, 1927. KAMINSKY, A. F.: Associated kidney and bladder tumors. J. Urol., 61: 997-1002, 1949. KIMBALL, F. N. AND FERRIS, II. W.: Papillomatous tumor of the renal pelvis associated with similar tumors of the ureter and bladder. J. Urol., 31: 257-304, 1935. KIRWIN, T. J.: Papillary carcinoma of the renal pelvis. Surg., Gynec. & Obst., 72: 759-76,5, 1941. KIRWIN, T. J.: Papillomatosis of bladder, new conceptions of etiology and treatment. J. U rol., 49: 1-13, 1943. LAZARUS, J. A. AND lVIARKS, lVI. S.: Primary carcinoma of ureter with special reference to hydronephrosis. J. Urol., 54: 140-157, 1945. MALLORY Case No. 26091, N. E. Med. J., 222: 354---356, 1940. MALLORY Case No. 32422, J\i. E. Med. J., 235: 599-602, 1946. MALLORY Case No. 33212, N. E. Med. J., 236: 809-811, 1947. McCLELLAND, J. C.: Primary carcinoma of ureter, treated by excision and anastomosis of the cut ends. J. Urol., 52: 522-525, 1944. McMAHON, S.: Tumors of the ureter. J. U rol., 51: 616-622, 1944. MELEl\, D.R.: Tumors of the renal pelvis. J. Urol., 51: 386-394, 1944. MELicow, M. M.: Classification of renal neoplasms. J. Urol., 51: 333-385, 1944. O'BRIEN, II. A.: Primary carcinoma of the ureter. J. Urol., 37: 49-53, 1937. O'CoNOR, V. J.: The treatment and prognosis of papillary tumors of the renal pelvis and ureter. J. Urol., 61: 488-492, 1949. PATTON, J. F.: Total ureterectomy: A new technique of extravesical removal of the intramural ureter. J. U rol., 47: 353-360, 1942. REAGAN, J. R.: Papillary carcinoma of the ureter. J. Urol., 50: 304-306, 1943. RosE, D. K.: Influence of anilin dyes on urinary tract tumors. J. Urol., 51: 81-84, 1944. SCHULTE, T. L. AND PRIESTLEY, J. T.: Association of renal and vesical neoplasms. Proc. Staff Meet., Mayo Clin., 16: 381-384, 1941. SCOTT, W.W.: A review of primary carcinoma of the ureter. J. Urol., 50: 45-63, 1943. THOMAS, G. J. AND REGNIER, E. A.: Tumors of the kidney pelvis and ureter. J. Urol., 11: 205-238, 1924. TRATTNER, II. R.: Instrumental visualization of renal pelvis. J. Urol., 60: 817-834, 1948. VES'l', S. A.: Conservative surgery in certain benign tumors of the ureter. J. Urol., 53: 97121, 1945. WASHBURN, V. D.: The treatment of anilin tumors of the urinary bladder. J. Urol. 31: 155-162, 1934.