Vol. 114, December
THE JOURNAL OF UROLOG Y
Copyright© 1975 by The Williams & Wilkins Co.
Print ed in U.S.A.
EPIDEMIOLOGY AND TREATMENT OF RENAL PELVIC AND URETERAL TUMORS SAVA D. PETKOVIC From the Urological Clinic of th e M edical Faculty, Univ ersity of Belgrade, Yugoslavia
ABSTRACT
Throughout the world the number of cases of renal pelvic and ureteral tumors has increased considerably during the last 2 decades. In Yugoslavia this increase has been exceptionally high since about 1953 or 1954. Many of our patients with these tumors come from regions where the population is affected by endemic nephropathy, the frequency of tumors in these regions being about 100 times higher than it is in other parts of Yugoslavia. In many cases these patients have renal failure and, therefore, conservative procedures are undertaken. Herein are reported the causes and results of therapy in 972 cases of renal pelvic and ureteral tumors collected in Yugoslavia. Particular attention has been paid to conservative operations (37 cases of renal pelvic and 64 cases of ureteral tumors), including their indications and possibilities. That many patients with renal pelvic and ureteral tumors have favorable conditions for a conservative procedure is confirmed by the comparatively good followup. However, in other cases a conservative operation is unreasonable and nephroureterectomy is mandatory. Tumors in the renal pelvis and ureter are noted more frequently now than they were in the past. ,.. In 1933 Swift-Joly found only 337 cases of renal pelvic tumors in the world literature• and in 1943 Scott found only 182 cases of ureteral tumors. 6 However, during the last decade some investigators have reported as many as 50 to 100 personal cases. 1 • 10 In Yugoslavia the frequency of-cases involving renal pelvic and ureteral tumors also has increased. This increase was first noticed around 1953 or 1954 and it has been limited to certain regions of the country where endemic nephropathy has been noted. 3 Collaboration with our colleagues has enabled us to collect almost all cases observed in Yugoslavia-a total of 972 cases, or 609 renal pelvic tumors (266 of which were from our clinic) and 363 ureteral tumors (150 of which were from our clinic). The difference that we have found in the morbidity rate is great, with populations of small villages with endemic nephropathy affected approximately 100 or even 200 times more often than populations in towns. The incidence of these tumors also is impressive. We have found some families with 2 or even 3 members affected by renal pelvic or ureteral tumors, all suffering endemic nephropathy . Although there is a high frequency of renal pelvic and ureteral tumors in regions of endemic nephropathy, there is a relatively normal frequency of bladder cancer in these regions. We cannot Accepted for publication January 17, 1975. Read at annual meeting of American Urological Association, St. Louis, Missouri, May 19- 23, 1974. 858
explain this discrepancy. On the contrary, it is easy to explain the localization of industrial bladder cancer when the bladder is affected in about 95 per cent of the cases but the renal pelvis or ureter is affected in only 4 to 6 per cent. The bladder is a reservoir for urine and an active carcinogenic agent can sustain its carcinogenicity for a longer period in the bladder than in the renal pelvis or ureter. Our explanation for the absence of bladder cancer in our series of cases is that the active carcinogenic agent is rapidly absorbed by renal pelvic and ureteral mucosa during passage. GEOGRAPHICAL DISTRIBUTION OF PATIENTS
The geographical distribution in Yugoslavia of patients with renal pelvic and ureteral tumors was studied to elucidate some etiologic factors. Many of the 972 patients came from small villages close to the rivers of Sava, Drina, Maiava, Kolubara and Morava (fig. 1). We also studied the geographical distribution of patients with bladder cancer, since we saw more patients with that disease than most centers. Between 1950 and 1972 we saw 1,625 patients with bladder cancer but the distribution of these patients is quite different from that of patients with renal pelvic or ureteral tumors. The highest concentration of patients with bladder cancer is in large urban areas (fig. 2). ENDEMIC NEPHROPATHY
Endemic nephropathy has been described previously by Danilovic in Yugoslavia, 11 Puchlev in Bulgaria, 12 and Bruckner and associates in Romania. 13 It has been recognized as a unique
'
859
RENAL PELVIC AND URETERAL T UMORS
13.Xll.1913
FIG. 1. Geographic distribution of patients with renal pelvic and ureteral tumors
F1G. 2. Geographical distribution of patients with bladder tumors.
•
I
entity among chronic interstitial nephropat hies in recent books by Hamburger and Royer" and by Strauss and Welt . 15 It is a special t ype of nephropathy that develops slowly (approximately 20 years) and it does not have an acute phase. T here a re few symptoms, including occasiona l albuminuria and scant urinary sediment with rare red and white cells. The patient is not hypertensive but has a pale yellow face, characterizing renal failure. Renal failure develops in the latter phases of the disease and is accompanied by a high urinary out put. Death occurs in a few years . More of our t umor patients have died of renal fa ilure than of metastases. This nephropathy is strictly limited t o some terrains and some houses. It is a familial but not a heredit ary disease, t hat is although it affects m any members of a family living in t he same house it is not dete rmined genetically. Some members of a family who leave t heir home early in life are not affected, while some members who marry into the family and are living in the family home are affected . The cause of endemic nephropathy is obscure, 3 although it has been not ed recently t hat the drinking water of ma ny households conta ins high concent rations of radon and minerals, as high as 4 to 5 cm . per I. 16 E ndemic nephropathy seems to be a degenerat ive interstitial disease. In its latter phases small cell infiltrations are noted and, at that ti me, it closely resembles pyelonephritis (fig. 3). The association of t his degenerative disease of t he pa renchym atous organ (kidney) and t he carcinomatous disease of t he excretory conducting system is a rare
860
PETKOVIC
FIG. 3. Microscopic section from kidney of patient with renal pelvic tumor reveals interstitial nephropathy with some nests of polymorphonuclear and lymphatic cells.
example in our pathology. In recent collaboration with Dammin from Boston a diffuse effect of carcinogenic agents was strongly suspected by findings of mucous dysplasia, cancer in situ or even microscopic papillomas or cancer outside the tumor in grossly normal mucosa (fig. 4).
It seems that we have a similar case with analgesic nephropathy. Angervall and associates found a high frequency of renal pelvic and ureteral tumors among abusers of analgesics in Sweden. 17 Of 104 patients with analgesic nephropathy there were 9 cases of tumors. Patients were predominantly male subjects who abused the use of analgesics more often because of their employment in a factory of analgesics. In Australia Taylor found the frequency of renal pelvic and ureteral tumors among male patients with radiological and histological signs of analgesic nephropathy 150 times higher than that in other patients. 18 Female patients were affected with nephropathy 5.5 times more than what exactly corresponds to the relation of sex among abusers.
or biopsied during a conversative operation has been interstitial nephropathy. It is noteworthy that renal failure has been found with a comparatively high frequency in patients from regions not affected by endemic nephropathy. This fact suggests that some toxic agents probably also provoke this type of cancer in large populations. It is also noteworthy that renal failure occurs in later years in patients from regions not affected by endemic nephropathy. Since we have discovered recently new regions of endemic nephropathy it is possible that we now have some distribution of causative agents outside these regions. We have not found renal failure to be an accompanying syndrome in patients with renal parenchymal or bladder tumors. Immediately prior to death patients with renal failure and tumor have a large urinary output and a high level of blood urea nitrogen. In some of these patients output has been between 2 and 4 1. per day for the few days before death (fig. 5). At the same time there has been no obstruction or infection despite the histological picture of focal pyelonephritis in the advanced stages of this nephropathy.
RENAL FAILURE
DESCRIPTION OF RENAL PELVIC AND URETERAL TUMORS
We studied the incidence of renal failure in patients with renal pelvic and ureteral tumors in relation to the geographic distribution of patients (table 1). Clinical or laboratory signs of renal failure were noted in 50 per cent of our patients and this percentage would have been higher if we had followed our patients for a longer period. Since many of our current patients with renal failure did not have this sign when we first saw them it is likely that a large percentage of patients included in the current group without renal failure will manifest it later. As previously stated, more of our patients have died of renal failure than of the tumor or metastases. The proved pathological etiology of renal failure in many of our patients subjected to nephrectomy
Generally these tumors behave as classical tumors, although they are of low grade malignancy and relatively slow evolution (figs. 6 and 7). The relatively low anatomic malignancy of these tumors is evident because many 1) are either of benign histological structure (papillomas) or papillary carcinomas without a tendency to infiltrate into deep layers, 2) have a more pronounced proliferative tendency than the tendency of infiltration, 3) have no special tendency to relapse, 4) do not express multiplicity and 5) have low percentage of high grade malignancy. Therefore, when we read reports from other investigators on renal pelvic and ureteral tumors we must be aware of a distinct difference in malignancy. Our early statistics revealed more
DISCUSSION
RENAL PELVIC AND URETERAL TUMORS
861
I
FIG. 4. A, microscopic section from renal pelvic tumor. Biopsy of normal-appearing mucosa outside tumor shows clear papillary proliferations. B, microscopic section from ureteral tumor. Biopsy outside tumor shows hyperplasia and dysplasia. (Courtesy of Dr. Dammin, Boston, Massachusetts.) TABLE
1. Renal failure in patients according to geographic distribution Total No. Pts.
Pts. With Renal Failure No. (%)
Renal pe lvie tumors Ureteral tumors Totals
Pts. From Endemic Regions No.
(%)
Pts. From Other Regions No.
(%)
266
127 (48)
150 416
77 (51) 39 of 61 (64) 38 of 89 (43) 204 (50) 111 of 187 (63) 93 of 229 (40)
72 of 126 (60) 55 of 140 (39)
tumors with a large base, infiltrative growth and with poor prognosis. The multiplicity is not excessive and can be considered classical. In our first series 32 per cent of the cases had multiple tumors. Albarran and Imbert found the multiplicity of tumors in 33 per cent of their cases, 19 Dufour in 30 per cent, 9 Deming in 40 per cent 20 and Thackray in 70 per cent. 21 The multiplicity of tumors is the result of a long evolution. Therefore, if we observe our patients for longer periods we will have a higher percentage. Kimball and Ferris noted that of their 74 cases with multiple tumors 24 had them at the time of diagnosis. 22 Generally, the multiplicity is not more pronounced in our series than in others.
Bilateral tumors were noted in 42 of 416 renal pelvic and ureteral tumors in our series (10 per cent), which is a rather high proportion compared to old original statistics. Bilateral tumors were found in 4.2 per cent of the cases reviewed by Deming, 23 in 1 per cent of the pelvic cases and 1.6 per cent of the ureteral cases reviewed by Scott•• and in 0.9 per cent of the ureteral cases reviewed by Abeshouse. 25 TREATMENT OF RENAL PELVIC AND URETERAL TUMORS
Conservative or radical therapy? Whenever possible we have used conservative operations because 1) the high incidence of renal failure has changed our tendency to be radical, 2) our incidence of bilateral tumors in 10 per cent of the cases was a strong indication to preserve at least 1 kidney and 3) some patients had a tumor in a solitary kidney, having already been subjected to nephrectomy of the contralateral kidney. Ferris and Daut were the first to report on the conservative approach in cases of renal pelvic tumor, 26 while Vest was the first to report on this approach in cases of ureteral tumor. 27 The reasons extensive radical procedures are not recommended are 1) a bladder relapse can occur even after an
862
PETKOVIC
extensive nephroureterectomy and large resection of the bladder, 2) total cystectomy is not indicated when bladder papillomas or proliferative tumors are small or of moderate size, 3) with a conservative operation it is easier to prevent tumor implantation into surrounding tissue-at the end of the operation we carefully wash the renal pelvis, ureter and bladder to be certain that all particles of tumor are removed completely, 4) some late relapses are not caused by implantation of the original tumor but are entirely new tumors and 5) the tendency to have a relapse is not as strong as we originally believed. By the end of 1973 we had treated 266 patients with renal pelvic and 150 patients with ureteral
--.. .........
tumors but our results of therapy are based on patients treated through 1970 (table 2). Despite renal failure only 24 of 333 patients (7 per cent) were not subjected to an operation. Nephrectomy for renal pelvic tumors. The best radical operation is a total nephroureterectomy but final results with simple nephrectomies were satisfactory. Operations had been done on 188 patients by the end of 1970 (table 3). If we include in our statistics only patients who were subjected to nephrectomy by 1968 (5-year period) we would have 165 under control, 60 of whom (36 per cent) survived 5 years. The difference in results between nephroureterectomy and simple nephrectomy is significant (17 per cent). Of the 57 patients who
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//'~
'
1
march 17 18
19 20 ZI Z2 23 1" 25 26 2'I 28 29 30 31 MARCH
Blagajwic Nedo/jlto
Op TU. PYELI ot URE! bil.
- - - BUJOD UREA
------ DIURESIS ............... SPEC. WEIGHT
Fm. 5. Blood urea level, urinary output and specific weight of patient with bilateral renal pelvic tumors and endemic nephropathy a few days before death.
Fm. 6. Conservative operation was done for renal pelvic tumor on left side in February 1966. A and B, slight stenosis noted on right side beneath ureteropelvic junction in November 1971. There is visible defect under ureteropelvic junction (slow evolution 1). Conservative operation was done on that side. C, IVP 1 year after operation on right side and 6 years after operation on left side.
863
RENAL PELVIC AND URETERAL TUMORS
iI
Fm. 7. A, IVP on right side of patient in August 1968 revealed small defect in upper calix of duplicated kidney. Operation was refused. B, pyelography on right side in August 1973 revealed great defect. Papillary carcinoma with slow evolution was found at operation. TABLE
2. Therapy through 1970 for patients with renal pelvic and ureteral t.umors Renal Pelvic Tumors
Ureteral Tumors
24 (+2) 188 7 219
48 (+1) 49 17 114
Conservative operations Nephrectomy Not treated Totals
survived more than 5 years we would have 43 patients subjected to nephrectomy, 30 of whom have a known destiny. Fifteen of these 30 patients (50 per cent) survived more than 5 years. Postoperative deaths occurred in 4 of the 26 total nephroureterectomies (15 per cent). There was no mortality in 23 simple nephrectomies. Conservative operations for renal pelvic tumor. Conservative procedures have been done in 37 of the 266 cases of renal pelvic tumors seen by the end of 1973 (14 per cent), or in 26 of the 219 cases seen by the end of 1970 (12 per cent). Followup of the latter 26 patients is presented in table 5. Of the 16 patients who were operated on more than 5 years ago we have 12 (74 per cent), plus 1 with secondary nephrectomy, who survived more than 5 years. Only 2 recurrences have been noted and these occurred in patients who survived 10 years or more with uremia and a solitary kidney. Another important factor is the high percentage of uremia that we have noted. There was no postoperative mortality in the 26 patients operated on for renal pelvic tumors. Conservative operations for ureteral tumors. Conservative procedures have been done in 49 of 114 patients with ureteral tumors seen by the end of 1970 (43 per cent), or 64 of the 150 cases seen by the end of 1973 (42 per cent). Table 6 lists the conservative procedures used in these cases. Of the 32 patients followed for a 5-year period 21 are alive (66 per cent). A few patients survived more than 10 years (4 of 8 died 5 years postoperatively). The postoperative mortality rate was 2 per cent (1 of 49). Results were poor in cases in which the complete circumference of the ureter was resected and ureterorrhaphy since tumors in these cases TABLE
4. Follow up of 49 patients operated on for ureteral tumors before January 197J(nephrectomy) Yrs. Dead
Yrs. Alive I UnTotals known \5 5 Yrs. Dead
Total nephroureterectomy Simple nephrectomy Totals
23
7
6
1
1
20
3
61
53 76
11 18
12 18
9 10
4
5
22 42
16 19
127 188
underwent total nephroureterectomy 26 (48 per cent) survived more than 5 years. Of the 108 patients who underwent simple nephrectomy 34 (31 per cent) survived more than 5 years. Postoperative death occurred in 2 of the 58 total nephroureterectomies (3.5 per cent) and 2 of the 110 simple nephrectomies (1.8 per cent). Nephrectomy for ureteral tumors. Of the 49 patients who underwent nephrectomy for ureteral tumors before the end of 1970, 44 have been controlled (table 4). If we include in our statistics only patients operated on before 1968 and who
Yrs. Alive
--
3. Followup of 188 patients operated on for renal pelvic tumors before January 1971 (nephrectomy)
TABLE
5 5
Total nephroureterectomy Simple nephrectomy Totals
TABLE
Unknown Totals
4
4
5
5
1
5
2
26
5 9
2 6
1 6
7 12
1 2
4 9
3 5
23 49
5. Followup of 26 patients operated on for renal pelvic tumors before January 1971 (conservative operations) Uremia
Survival of patients who have died: 1-3yrs. 5-10 yrs. More than 10 yrs. Survival of patients still living: 3-5 yrs. 5-10 yrs. More than 10 yrs.
2 2
Recurrence Excellent Totals
3
3
4*
2 1
* Secondary nephrectomy.
3 2 3
1 (1)* (1)
3 5
10 7
864
PETKOVIC
were large and required a more extensive resection (fig. 8).
Treatment of bilateral tumors. We operated upon 31 of the 35 patients with bilateral tumors who were seen by the end of 1970-7 bilateral conservative procedures, 10 unilateral conservative TABLE
6. Followup of 49 patients operated on for ureteral tumors before January 1971 (conservative operations) Yrs. Dead
Yrs. Alive Totals
Transvesical Ureterotomy plus ablation Resection ureterorrhaphy Resection plus ureterovesical anastomosis Totals
5
5
-
2 3 4 8
5 3 5
4 14 13 18
17
13
49
4 2 2
-
1
-
1 2 2 3
8
3
8
2
Fm. 8. IVP in 1970 revealed defect on right side in renal pelvis. Conservative operation was done. Stricture in left ureter believed to be caused by cancer. Operation on left side in 1972 revealed inflammatory stenosis. TABLE
7. Causes of death Conservative Operations
Totals
Renal pelvic tumors Uremia Relapse Transvesical Metastases Others Unknown
8
23
6 6 2 15
8 22 3 25
7 1 (+2)
38 1 14 28 5
40
Ureteral tumors Uremia Metastases Others Unknown
2 5 7
4
13
1 5
3 2
17 2 9 14
procedures and nephrectomy on the opposite side, and 12 unilateral nephrectomies. The remaining patients were not subjected to operations or underwent palliative procedures only and all are dead. Of the 31 patients operated upon 18 (60 per cent) survived more than 5 years. All patients who did not survive died of uremia. Only 3 patients had a relapse before death. Causes of death. The causes of death in 126 cases of renal pelvic tumors and 42 cases of ureteral tumors are noted in table 7. Uremia caused death in 23 of 78 patients subjected to nephrectomy for renal pelvic tumor, and in 4 of 12 patients subjected to nephrectomy for ureteral tumors and 13 of 16 patients subjected to conservative procedures for ureteral tumors. REFERENCES
1. Petkovic, S., Tomic, M. and Mutavdzic, M.: Quelques considerations sur l'etiologie et la clinique du cancer du bassinet. J. Urol. Nephrol., 72: 429, 1966. 2. Petkovic, S., Mutavdzic, M., Petronic, V. and Markovic, V.: Geographical distribution of cancer of the urothelium in Yugoslavia. A suspicion of a special carcinogenic agent. Urologia, 35: 1, 1968. 3. Petkovic, S. D.: A plea for conservative operation for ureteral tumors. J. Urol., 107: 220, 1972. 4. Petkovic, S. D.: Conservation of the kidney in operations for tumours of the renal pelvis and calyces: a report of 26 cases. Brit. J. Urol., 44: 1, 1972. 5. Swift-Joly, J.: Rapport au Congres de la Societe Internationale d'Urologie, London, England, p. 211, 1933. 6. Scott, W. W.: A review of primary carcinoma of the ureter. Presenting two cases. J. Urol., 50: 45, 1943. 7. Beck, A. D., Heslin, J.E., Milner, W. A. and Garlick, W. B.: Primary tumors of the ureter: diagnosis and management. J. Urol., 102: 683, 1969. 8. McIntyre, D., Pyrah, L. N. and Raper, F. P.: Primary ureteric neoplasmas: with a report of forty cases. Brit. J. Urol., 37: 160, 1965. 9. Dufour, B.: Remarques sur 56 cas de tumeurs pyelocalicielles, These, Paris, France, 1967. 10. Bloom, N. A., Vidone, R. A. and Lytton, B.: Primary carcinoma of the ureter: a report of 102 new cases. J. Urol., 103: 590, 1970. 11. Danilovic, V.: Chronic nephritis due to ingestion of lead-contaminated flour. Brit. Med. J., 1: 27, 1958. 12. Puchlev, A.: Endemic nephropathy in Bulgaria. In: The Balkan Nephropathy. Edited by G. E. W. Wolstenholme and J. Knight. Ciba Foundation Study Group No. 30. Boston: Little, Brown and Co., 1967. 13. Bruckner, I., Stoica, G. and Serban, M.: Studies on urinary proteins in endemic nephropathy. In: The Balkan Nephropathy. Ciba Foundation Study Group No. 30. Boston: Little, Brown and Co., 1967. 14. Hamburger, J. and Royer, P.: Nephrologie. Paris: Flammarion, p. 1078, 1966. 15. Strauss, M. B. and Welt, L. G.: Diseases of the Kidney. Boston: Little, Brown and Co., pp. 678-679 and 1265-1266, 1971. 16. Perie, J.: Personal communication. 17. Angervall, L., Bengtsson, U., Zetterlund, C. G. and Zsigmond, M.: Renal pelvic carcinoma in a Swed-
RENAL PELVIC AND URETERAL TUMORS
18. 19. 20.
21.
22.
ish district with abuse of a phenacetin-containing drug. Brit. J. Urol., 41: 401, 1969. Taylor, S. J.: Analgesics and carcinoma of the kidney. Brit. J. Urol., 44: 126, 1972. Albarran. J. and Imbert, L.: Les Tumeurs du Rein. Paris: Masson et Cie, 1903. Deming, C. L.: Tumors of the kidney. In: Urology, 3rd ed. Edited by M. F. Campbell and ,J. H. Harrison. Philadelphia: W. B. Saunders 1970. Thackray, A. C.: Tumours of the renal and ureter. In: Modern Trends in Urology. Edited by E. Riches. London: Butterworth Inc., second series, p. 82, 1960. Kimball, F. N. and Ferris, H. W.: Papillomatous tumor of the renal pelvis associated with similar tumors of the ureter and bladder. Review of
23. 24.
25.
26.
27.
865
literature and report of two cases. J. Urol., 31: 257, 1934. Deming, C. L.: Renal neoplasms: an enigma and a challenge. ,J. Urol., 69: 1, 1953. Scott, W.W.: Tumors of the ureter. In: Urology, 3rd ed. Edited by M. F. Campbell and J. H. Harrison. Philadelphia: W. B. Saunders Co., 1970. Abeshouse, B. S.: Primary benign and malignant tumors of the ureter; review ofliterature and report of one benign and 12 malignant tumors. Amer. J. Surg., 91: 237, 1956. Ferris, D. 0. and Daut, R. V.: Epithelioma of the pelvis of a solitary kidney treated by electrocoag-ulation. J. Urol., 59: 577, 1948. Vest, S. A.: Conservative surgery in certain benign tumors of the ureter. J. Urol., 53: 97, 1945.
THE JOURNAL OF UROLOG Y
Copyright© 1975 by The Williams & Wilkins Co.
Print ed in U.S.A.
EPIDEMIOLOGY AND TREATMENT OF RENAL PELVIC AND URETERAL TUMORS SAVA D. PETKOVIC From the Urological Clinic of th e M edical Faculty, Univ ersity of Belgrade, Yugoslavia
ABSTRACT
Throughout the world the number of cases of renal pelvic and ureteral tumors has increased considerably during the last 2 decades. In Yugoslavia this increase has been exceptionally high since about 1953 or 1954. Many of our patients with these tumors come from regions where the population is affected by endemic nephropathy, the frequency of tumors in these regions being about 100 times higher than it is in other parts of Yugoslavia. In many cases these patients have renal failure and, therefore, conservative procedures are undertaken. Herein are reported the causes and results of therapy in 972 cases of renal pelvic and ureteral tumors collected in Yugoslavia. Particular attention has been paid to conservative operations (37 cases of renal pelvic and 64 cases of ureteral tumors), including their indications and possibilities. That many patients with renal pelvic and ureteral tumors have favorable conditions for a conservative procedure is confirmed by the comparatively good followup. However, in other cases a conservative operation is unreasonable and nephroureterectomy is mandatory. Tumors in the renal pelvis and ureter are noted more frequently now than they were in the past. ,.. In 1933 Swift-Joly found only 337 cases of renal pelvic tumors in the world literature• and in 1943 Scott found only 182 cases of ureteral tumors. 6 However, during the last decade some investigators have reported as many as 50 to 100 personal cases. 1 • 10 In Yugoslavia the frequency of-cases involving renal pelvic and ureteral tumors also has increased. This increase was first noticed around 1953 or 1954 and it has been limited to certain regions of the country where endemic nephropathy has been noted. 3 Collaboration with our colleagues has enabled us to collect almost all cases observed in Yugoslavia-a total of 972 cases, or 609 renal pelvic tumors (266 of which were from our clinic) and 363 ureteral tumors (150 of which were from our clinic). The difference that we have found in the morbidity rate is great, with populations of small villages with endemic nephropathy affected approximately 100 or even 200 times more often than populations in towns. The incidence of these tumors also is impressive. We have found some families with 2 or even 3 members affected by renal pelvic or ureteral tumors, all suffering endemic nephropathy . Although there is a high frequency of renal pelvic and ureteral tumors in regions of endemic nephropathy, there is a relatively normal frequency of bladder cancer in these regions. We cannot Accepted for publication January 17, 1975. Read at annual meeting of American Urological Association, St. Louis, Missouri, May 19- 23, 1974. 858
explain this discrepancy. On the contrary, it is easy to explain the localization of industrial bladder cancer when the bladder is affected in about 95 per cent of the cases but the renal pelvis or ureter is affected in only 4 to 6 per cent. The bladder is a reservoir for urine and an active carcinogenic agent can sustain its carcinogenicity for a longer period in the bladder than in the renal pelvis or ureter. Our explanation for the absence of bladder cancer in our series of cases is that the active carcinogenic agent is rapidly absorbed by renal pelvic and ureteral mucosa during passage. GEOGRAPHICAL DISTRIBUTION OF PATIENTS
The geographical distribution in Yugoslavia of patients with renal pelvic and ureteral tumors was studied to elucidate some etiologic factors. Many of the 972 patients came from small villages close to the rivers of Sava, Drina, Maiava, Kolubara and Morava (fig. 1). We also studied the geographical distribution of patients with bladder cancer, since we saw more patients with that disease than most centers. Between 1950 and 1972 we saw 1,625 patients with bladder cancer but the distribution of these patients is quite different from that of patients with renal pelvic or ureteral tumors. The highest concentration of patients with bladder cancer is in large urban areas (fig. 2). ENDEMIC NEPHROPATHY
Endemic nephropathy has been described previously by Danilovic in Yugoslavia, 11 Puchlev in Bulgaria, 12 and Bruckner and associates in Romania. 13 It has been recognized as a unique
'
859
RENAL PELVIC AND URETERAL T UMORS
13.Xll.1913
FIG. 1. Geographic distribution of patients with renal pelvic and ureteral tumors
F1G. 2. Geographical distribution of patients with bladder tumors.
•
I
entity among chronic interstitial nephropat hies in recent books by Hamburger and Royer" and by Strauss and Welt . 15 It is a special t ype of nephropathy that develops slowly (approximately 20 years) and it does not have an acute phase. T here a re few symptoms, including occasiona l albuminuria and scant urinary sediment with rare red and white cells. The patient is not hypertensive but has a pale yellow face, characterizing renal failure. Renal failure develops in the latter phases of the disease and is accompanied by a high urinary out put. Death occurs in a few years . More of our t umor patients have died of renal fa ilure than of metastases. This nephropathy is strictly limited t o some terrains and some houses. It is a familial but not a heredit ary disease, t hat is although it affects m any members of a family living in t he same house it is not dete rmined genetically. Some members of a family who leave t heir home early in life are not affected, while some members who marry into the family and are living in the family home are affected . The cause of endemic nephropathy is obscure, 3 although it has been not ed recently t hat the drinking water of ma ny households conta ins high concent rations of radon and minerals, as high as 4 to 5 cm . per I. 16 E ndemic nephropathy seems to be a degenerat ive interstitial disease. In its latter phases small cell infiltrations are noted and, at that ti me, it closely resembles pyelonephritis (fig. 3). The association of t his degenerative disease of t he pa renchym atous organ (kidney) and t he carcinomatous disease of t he excretory conducting system is a rare
860
PETKOVIC
FIG. 3. Microscopic section from kidney of patient with renal pelvic tumor reveals interstitial nephropathy with some nests of polymorphonuclear and lymphatic cells.
example in our pathology. In recent collaboration with Dammin from Boston a diffuse effect of carcinogenic agents was strongly suspected by findings of mucous dysplasia, cancer in situ or even microscopic papillomas or cancer outside the tumor in grossly normal mucosa (fig. 4).
It seems that we have a similar case with analgesic nephropathy. Angervall and associates found a high frequency of renal pelvic and ureteral tumors among abusers of analgesics in Sweden. 17 Of 104 patients with analgesic nephropathy there were 9 cases of tumors. Patients were predominantly male subjects who abused the use of analgesics more often because of their employment in a factory of analgesics. In Australia Taylor found the frequency of renal pelvic and ureteral tumors among male patients with radiological and histological signs of analgesic nephropathy 150 times higher than that in other patients. 18 Female patients were affected with nephropathy 5.5 times more than what exactly corresponds to the relation of sex among abusers.
or biopsied during a conversative operation has been interstitial nephropathy. It is noteworthy that renal failure has been found with a comparatively high frequency in patients from regions not affected by endemic nephropathy. This fact suggests that some toxic agents probably also provoke this type of cancer in large populations. It is also noteworthy that renal failure occurs in later years in patients from regions not affected by endemic nephropathy. Since we have discovered recently new regions of endemic nephropathy it is possible that we now have some distribution of causative agents outside these regions. We have not found renal failure to be an accompanying syndrome in patients with renal parenchymal or bladder tumors. Immediately prior to death patients with renal failure and tumor have a large urinary output and a high level of blood urea nitrogen. In some of these patients output has been between 2 and 4 1. per day for the few days before death (fig. 5). At the same time there has been no obstruction or infection despite the histological picture of focal pyelonephritis in the advanced stages of this nephropathy.
RENAL FAILURE
DESCRIPTION OF RENAL PELVIC AND URETERAL TUMORS
We studied the incidence of renal failure in patients with renal pelvic and ureteral tumors in relation to the geographic distribution of patients (table 1). Clinical or laboratory signs of renal failure were noted in 50 per cent of our patients and this percentage would have been higher if we had followed our patients for a longer period. Since many of our current patients with renal failure did not have this sign when we first saw them it is likely that a large percentage of patients included in the current group without renal failure will manifest it later. As previously stated, more of our patients have died of renal failure than of the tumor or metastases. The proved pathological etiology of renal failure in many of our patients subjected to nephrectomy
Generally these tumors behave as classical tumors, although they are of low grade malignancy and relatively slow evolution (figs. 6 and 7). The relatively low anatomic malignancy of these tumors is evident because many 1) are either of benign histological structure (papillomas) or papillary carcinomas without a tendency to infiltrate into deep layers, 2) have a more pronounced proliferative tendency than the tendency of infiltration, 3) have no special tendency to relapse, 4) do not express multiplicity and 5) have low percentage of high grade malignancy. Therefore, when we read reports from other investigators on renal pelvic and ureteral tumors we must be aware of a distinct difference in malignancy. Our early statistics revealed more
DISCUSSION
RENAL PELVIC AND URETERAL TUMORS
861
I
FIG. 4. A, microscopic section from renal pelvic tumor. Biopsy of normal-appearing mucosa outside tumor shows clear papillary proliferations. B, microscopic section from ureteral tumor. Biopsy outside tumor shows hyperplasia and dysplasia. (Courtesy of Dr. Dammin, Boston, Massachusetts.) TABLE
1. Renal failure in patients according to geographic distribution Total No. Pts.
Pts. With Renal Failure No. (%)
Renal pe lvie tumors Ureteral tumors Totals
Pts. From Endemic Regions No.
(%)
Pts. From Other Regions No.
(%)
266
127 (48)
150 416
77 (51) 39 of 61 (64) 38 of 89 (43) 204 (50) 111 of 187 (63) 93 of 229 (40)
72 of 126 (60) 55 of 140 (39)
tumors with a large base, infiltrative growth and with poor prognosis. The multiplicity is not excessive and can be considered classical. In our first series 32 per cent of the cases had multiple tumors. Albarran and Imbert found the multiplicity of tumors in 33 per cent of their cases, 19 Dufour in 30 per cent, 9 Deming in 40 per cent 20 and Thackray in 70 per cent. 21 The multiplicity of tumors is the result of a long evolution. Therefore, if we observe our patients for longer periods we will have a higher percentage. Kimball and Ferris noted that of their 74 cases with multiple tumors 24 had them at the time of diagnosis. 22 Generally, the multiplicity is not more pronounced in our series than in others.
Bilateral tumors were noted in 42 of 416 renal pelvic and ureteral tumors in our series (10 per cent), which is a rather high proportion compared to old original statistics. Bilateral tumors were found in 4.2 per cent of the cases reviewed by Deming, 23 in 1 per cent of the pelvic cases and 1.6 per cent of the ureteral cases reviewed by Scott•• and in 0.9 per cent of the ureteral cases reviewed by Abeshouse. 25 TREATMENT OF RENAL PELVIC AND URETERAL TUMORS
Conservative or radical therapy? Whenever possible we have used conservative operations because 1) the high incidence of renal failure has changed our tendency to be radical, 2) our incidence of bilateral tumors in 10 per cent of the cases was a strong indication to preserve at least 1 kidney and 3) some patients had a tumor in a solitary kidney, having already been subjected to nephrectomy of the contralateral kidney. Ferris and Daut were the first to report on the conservative approach in cases of renal pelvic tumor, 26 while Vest was the first to report on this approach in cases of ureteral tumor. 27 The reasons extensive radical procedures are not recommended are 1) a bladder relapse can occur even after an
862
PETKOVIC
extensive nephroureterectomy and large resection of the bladder, 2) total cystectomy is not indicated when bladder papillomas or proliferative tumors are small or of moderate size, 3) with a conservative operation it is easier to prevent tumor implantation into surrounding tissue-at the end of the operation we carefully wash the renal pelvis, ureter and bladder to be certain that all particles of tumor are removed completely, 4) some late relapses are not caused by implantation of the original tumor but are entirely new tumors and 5) the tendency to have a relapse is not as strong as we originally believed. By the end of 1973 we had treated 266 patients with renal pelvic and 150 patients with ureteral
--.. .........
tumors but our results of therapy are based on patients treated through 1970 (table 2). Despite renal failure only 24 of 333 patients (7 per cent) were not subjected to an operation. Nephrectomy for renal pelvic tumors. The best radical operation is a total nephroureterectomy but final results with simple nephrectomies were satisfactory. Operations had been done on 188 patients by the end of 1970 (table 3). If we include in our statistics only patients who were subjected to nephrectomy by 1968 (5-year period) we would have 165 under control, 60 of whom (36 per cent) survived 5 years. The difference in results between nephroureterectomy and simple nephrectomy is significant (17 per cent). Of the 57 patients who
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Fm. 5. Blood urea level, urinary output and specific weight of patient with bilateral renal pelvic tumors and endemic nephropathy a few days before death.
Fm. 6. Conservative operation was done for renal pelvic tumor on left side in February 1966. A and B, slight stenosis noted on right side beneath ureteropelvic junction in November 1971. There is visible defect under ureteropelvic junction (slow evolution 1). Conservative operation was done on that side. C, IVP 1 year after operation on right side and 6 years after operation on left side.
863
RENAL PELVIC AND URETERAL TUMORS
iI
Fm. 7. A, IVP on right side of patient in August 1968 revealed small defect in upper calix of duplicated kidney. Operation was refused. B, pyelography on right side in August 1973 revealed great defect. Papillary carcinoma with slow evolution was found at operation. TABLE
2. Therapy through 1970 for patients with renal pelvic and ureteral t.umors Renal Pelvic Tumors
Ureteral Tumors
24 (+2) 188 7 219
48 (+1) 49 17 114
Conservative operations Nephrectomy Not treated Totals
survived more than 5 years we would have 43 patients subjected to nephrectomy, 30 of whom have a known destiny. Fifteen of these 30 patients (50 per cent) survived more than 5 years. Postoperative deaths occurred in 4 of the 26 total nephroureterectomies (15 per cent). There was no mortality in 23 simple nephrectomies. Conservative operations for renal pelvic tumor. Conservative procedures have been done in 37 of the 266 cases of renal pelvic tumors seen by the end of 1973 (14 per cent), or in 26 of the 219 cases seen by the end of 1970 (12 per cent). Followup of the latter 26 patients is presented in table 5. Of the 16 patients who were operated on more than 5 years ago we have 12 (74 per cent), plus 1 with secondary nephrectomy, who survived more than 5 years. Only 2 recurrences have been noted and these occurred in patients who survived 10 years or more with uremia and a solitary kidney. Another important factor is the high percentage of uremia that we have noted. There was no postoperative mortality in the 26 patients operated on for renal pelvic tumors. Conservative operations for ureteral tumors. Conservative procedures have been done in 49 of 114 patients with ureteral tumors seen by the end of 1970 (43 per cent), or 64 of the 150 cases seen by the end of 1973 (42 per cent). Table 6 lists the conservative procedures used in these cases. Of the 32 patients followed for a 5-year period 21 are alive (66 per cent). A few patients survived more than 10 years (4 of 8 died 5 years postoperatively). The postoperative mortality rate was 2 per cent (1 of 49). Results were poor in cases in which the complete circumference of the ureter was resected and ureterorrhaphy since tumors in these cases TABLE
4. Follow up of 49 patients operated on for ureteral tumors before January 197J(nephrectomy) Yrs. Dead
Yrs. Alive I UnTotals known \5 5 Yrs. Dead
Total nephroureterectomy Simple nephrectomy Totals
23
7
6
1
1
20
3
61
53 76
11 18
12 18
9 10
4
5
22 42
16 19
127 188
underwent total nephroureterectomy 26 (48 per cent) survived more than 5 years. Of the 108 patients who underwent simple nephrectomy 34 (31 per cent) survived more than 5 years. Postoperative death occurred in 2 of the 58 total nephroureterectomies (3.5 per cent) and 2 of the 110 simple nephrectomies (1.8 per cent). Nephrectomy for ureteral tumors. Of the 49 patients who underwent nephrectomy for ureteral tumors before the end of 1970, 44 have been controlled (table 4). If we include in our statistics only patients operated on before 1968 and who
Yrs. Alive
--
3. Followup of 188 patients operated on for renal pelvic tumors before January 1971 (nephrectomy)
TABLE
5 5
Total nephroureterectomy Simple nephrectomy Totals
TABLE
Unknown Totals
4
4
5
5
1
5
2
26
5 9
2 6
1 6
7 12
1 2
4 9
3 5
23 49
5. Followup of 26 patients operated on for renal pelvic tumors before January 1971 (conservative operations) Uremia
Survival of patients who have died: 1-3yrs. 5-10 yrs. More than 10 yrs. Survival of patients still living: 3-5 yrs. 5-10 yrs. More than 10 yrs.
2 2
Recurrence Excellent Totals
3
3
4*
2 1
* Secondary nephrectomy.
3 2 3
1 (1)* (1)
3 5
10 7
864
PETKOVIC
were large and required a more extensive resection (fig. 8).
Treatment of bilateral tumors. We operated upon 31 of the 35 patients with bilateral tumors who were seen by the end of 1970-7 bilateral conservative procedures, 10 unilateral conservative TABLE
6. Followup of 49 patients operated on for ureteral tumors before January 1971 (conservative operations) Yrs. Dead
Yrs. Alive Totals
Transvesical Ureterotomy plus ablation Resection ureterorrhaphy Resection plus ureterovesical anastomosis Totals
5
5
-
2 3 4 8
5 3 5
4 14 13 18
17
13
49
4 2 2
-
1
-
1 2 2 3
8
3
8
2
Fm. 8. IVP in 1970 revealed defect on right side in renal pelvis. Conservative operation was done. Stricture in left ureter believed to be caused by cancer. Operation on left side in 1972 revealed inflammatory stenosis. TABLE
7. Causes of death Conservative Operations
Totals
Renal pelvic tumors Uremia Relapse Transvesical Metastases Others Unknown
8
23
6 6 2 15
8 22 3 25
7 1 (+2)
38 1 14 28 5
40
Ureteral tumors Uremia Metastases Others Unknown
2 5 7
4
13
1 5
3 2
17 2 9 14
procedures and nephrectomy on the opposite side, and 12 unilateral nephrectomies. The remaining patients were not subjected to operations or underwent palliative procedures only and all are dead. Of the 31 patients operated upon 18 (60 per cent) survived more than 5 years. All patients who did not survive died of uremia. Only 3 patients had a relapse before death. Causes of death. The causes of death in 126 cases of renal pelvic tumors and 42 cases of ureteral tumors are noted in table 7. Uremia caused death in 23 of 78 patients subjected to nephrectomy for renal pelvic tumor, and in 4 of 12 patients subjected to nephrectomy for ureteral tumors and 13 of 16 patients subjected to conservative procedures for ureteral tumors. REFERENCES
1. Petkovic, S., Tomic, M. and Mutavdzic, M.: Quelques considerations sur l'etiologie et la clinique du cancer du bassinet. J. Urol. Nephrol., 72: 429, 1966. 2. Petkovic, S., Mutavdzic, M., Petronic, V. and Markovic, V.: Geographical distribution of cancer of the urothelium in Yugoslavia. A suspicion of a special carcinogenic agent. Urologia, 35: 1, 1968. 3. Petkovic, S. D.: A plea for conservative operation for ureteral tumors. J. Urol., 107: 220, 1972. 4. Petkovic, S. D.: Conservation of the kidney in operations for tumours of the renal pelvis and calyces: a report of 26 cases. Brit. J. Urol., 44: 1, 1972. 5. Swift-Joly, J.: Rapport au Congres de la Societe Internationale d'Urologie, London, England, p. 211, 1933. 6. Scott, W. W.: A review of primary carcinoma of the ureter. Presenting two cases. J. Urol., 50: 45, 1943. 7. Beck, A. D., Heslin, J.E., Milner, W. A. and Garlick, W. B.: Primary tumors of the ureter: diagnosis and management. J. Urol., 102: 683, 1969. 8. McIntyre, D., Pyrah, L. N. and Raper, F. P.: Primary ureteric neoplasmas: with a report of forty cases. Brit. J. Urol., 37: 160, 1965. 9. Dufour, B.: Remarques sur 56 cas de tumeurs pyelocalicielles, These, Paris, France, 1967. 10. Bloom, N. A., Vidone, R. A. and Lytton, B.: Primary carcinoma of the ureter: a report of 102 new cases. J. Urol., 103: 590, 1970. 11. Danilovic, V.: Chronic nephritis due to ingestion of lead-contaminated flour. Brit. Med. J., 1: 27, 1958. 12. Puchlev, A.: Endemic nephropathy in Bulgaria. In: The Balkan Nephropathy. Edited by G. E. W. Wolstenholme and J. Knight. Ciba Foundation Study Group No. 30. Boston: Little, Brown and Co., 1967. 13. Bruckner, I., Stoica, G. and Serban, M.: Studies on urinary proteins in endemic nephropathy. In: The Balkan Nephropathy. Ciba Foundation Study Group No. 30. Boston: Little, Brown and Co., 1967. 14. Hamburger, J. and Royer, P.: Nephrologie. Paris: Flammarion, p. 1078, 1966. 15. Strauss, M. B. and Welt, L. G.: Diseases of the Kidney. Boston: Little, Brown and Co., pp. 678-679 and 1265-1266, 1971. 16. Perie, J.: Personal communication. 17. Angervall, L., Bengtsson, U., Zetterlund, C. G. and Zsigmond, M.: Renal pelvic carcinoma in a Swed-
RENAL PELVIC AND URETERAL TUMORS
18. 19. 20.
21.
22.
ish district with abuse of a phenacetin-containing drug. Brit. J. Urol., 41: 401, 1969. Taylor, S. J.: Analgesics and carcinoma of the kidney. Brit. J. Urol., 44: 126, 1972. Albarran. J. and Imbert, L.: Les Tumeurs du Rein. Paris: Masson et Cie, 1903. Deming, C. L.: Tumors of the kidney. In: Urology, 3rd ed. Edited by M. F. Campbell and ,J. H. Harrison. Philadelphia: W. B. Saunders 1970. Thackray, A. C.: Tumours of the renal and ureter. In: Modern Trends in Urology. Edited by E. Riches. London: Butterworth Inc., second series, p. 82, 1960. Kimball, F. N. and Ferris, H. W.: Papillomatous tumor of the renal pelvis associated with similar tumors of the ureter and bladder. Review of
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literature and report of two cases. J. Urol., 31: 257, 1934. Deming, C. L.: Renal neoplasms: an enigma and a challenge. ,J. Urol., 69: 1, 1953. Scott, W.W.: Tumors of the ureter. In: Urology, 3rd ed. Edited by M. F. Campbell and J. H. Harrison. Philadelphia: W. B. Saunders Co., 1970. Abeshouse, B. S.: Primary benign and malignant tumors of the ureter; review ofliterature and report of one benign and 12 malignant tumors. Amer. J. Surg., 91: 237, 1956. Ferris, D. 0. and Daut, R. V.: Epithelioma of the pelvis of a solitary kidney treated by electrocoag-ulation. J. Urol., 59: 577, 1948. Vest, S. A.: Conservative surgery in certain benign tumors of the ureter. J. Urol., 53: 97, 1945.
