- Email: [email protected]
Urine Cytology Findings in Analgesic Nephropathy
0022-5347/78/1 ~'.95-:)145$02. 00/0 T::-rn J·0u111•JAI.. GF URoL.JGY Copyright © HY/8 by The '01illian1s
\IVHki:is Cv.
URIN.E CYTOLOGY FINDINGS IN ANALGESIC NEPHROPATHY B. JACKSON,* J. A. KIRKLAND, J. R. LAWRENCE, A. S. NARAYAN, H. E. BROWN
AND
L. R. MILLS
From the Renal Unit, The Queen Elizabeth Hospital, Woodville and the Department of Pathology, the University of Adelaide, Adelaide, South Australia
ABSTRACT
Urine cytology screening for neoplasm led to the detection of 3 urothelial carcinomas and l severe urothelial dysplasia in 98 patients with analgesic-induced papillary necrosis. A further 18 patients had changes suggesting that they were at risk of incurring malignancy in the near future. Routine urine cytology is recommended in all cases of analgesic nephropathy. Carcinoma of the urinary tract has been associated with analgesic nephropathy. Initially, Scandinavian studies revealed renal pelvic and ureteral tumors. 1 • 2 Recently, analgesic nephropathy has been linked to renal pelvic, ureteral and bladder cancers.:i-s The value of urine cytology in the diagnosis and followup of bladder tumors is well established. H 3 Recently, urine cytology has been accepted as useful in the diagnosis of upper urothelial malignancies. 14-18 After the discovery of several urothelial malignancies associated with analgesic neph:ropathy at The Queen Elizabeth Hospital, urine ·cytology was introduced as a regular screen for cancer. This report summarizes our findings to date. MATERIAL AND METHODS
Freshly voided urine was processed by filtration through a millipore filter, and the cellular elements were stained (Papanicolaou, hematoxylin, orange-green 6 and Ehrlich's acid 50) and examined microscopically for changes (fig. 1). The changes were graded as A) normal - no changes seen, B) cells with enlarged nuclei, early vacuolated cytoplasm and occasional multinucleation, C) cells suspicious of malignancybizarre nuclear shape, vacuolated cytoplasm with nuclear enlargement and irregularity of chromatic structure or D) cells indistinguishable from malignancy - bizarre nuclear shape, reduced cytoplasm, nuclear variation and chromatic condensation. Nucleoli are prominent. The diagnosis of analgesic nephropathy was sustained only if there was a definite history of analgesic abuse (more than 3 powders or tablets per day for a minimum of 5 years, that is 2 kg. aspirin or phenacetin) and papillary necrosis was demonstrated a radiological technique (excretory urography -IVP- or retrograde pyelography) or was identified histologically. When performed, renal biopsy showed chronic interstitial nephritis and a concentration defect was present on antidiuretic hormone testing. RESULTS
We used the aforementioned criteria to study 98 patients suffering from analgesic nephropathy. Urine cytology was examined on 411 occasions (mean of 4.2 per patient), with an average cytology followup of 17 months. Patients were grouped according to the most severe changes seen (see table). There were 76 patients (78 per cent) with urinary cytology abnormalities and 22 patients (22.4 per cent) had changes suggestive of malignant change. These 22 patients have been Accepted for publication July 1, 1977. *Current address: Department of Medicine, Division of Nephrology, Medical College of Virginia, Box 197, MCV Station, Richmond, Virginia 23298. 145
investigated further by an IVP, cystoscopy, retrograde pyelography, collection ofureteral urine for cytology, examination of biopsies and nephrectomy. Of the 22 patients adequate investigations were done in 19. Carcinoma of the bladder was encountered in 2 cases and confined histologically. A presumed carcinoma of the renal pelvis was encountered in a third case (lateralizing cytology, and a space-occupying lesion that is growing progressively on IVP but anesthetic is impossible for medical reasons). In a fourth case renal artery stenosis progressed to thrombosis, with development of hypertension. Ureteronephrectomy was performed. Imprints of the entire renal pelvis and ureter yielded type D cells. Histological section showed advanced dysplastic changes. Because of abnormalities of urine cytology random bladder biopsies had been taken 12 months earlier. These also showed dysplastic changes that were less marked than in the nephrectomy specimen. No carcinoma was encountered in any case when type A or B cells only were found. There was no correlation between quantity of analgesic consumed and degree of abnormality. There was a significant trend for the more severe cytological changes to occur in more severe renal failure (class A versus class C and D, 0.01 > p > 0.001). However, all cell varieties were encountered at all degrees ofrenal failure (fig. 2). There was an increasing percentage of male patients with an increasing degree of change (class A was 4. 7 per cent male, class B 17 per cent male, class C 42 per cent male and class D 40 per cent male). There was no significant age difference between cytology classes. The analgesic abused most commonly was "Bex" (containing aspirin, phenacetin and caffeine, more recently with paracetamol replacing phenacetin), which was used exclusively in 45 per cent of the patients and in combination with other preparations in a further 39 per cent, that is 84 per cent of cases. Other analgesics abused included Vincents, Ascotin, Veganin and soluble aspirin. There was no correlation among the analgesic brand abused, degree of renal failure nor degree of cytology abnormality. As assessed by history and urine assay approximately half of the patients had abstained from analgesics during the survey. In a few cases cytological changes tended to improve slowly during 1 to 2 years with abstinence from analgesics. There was no pattern of improvement in patients still consuming analgesics who, generally, tended to have more severe changes. However, there were several patients in whom analgesic abuse had ceased up to 8 years previously in whom class C and D cells were found. DISCUSSION
Analgesic abusers with renal papillary necrosis are at risk of incurring urothelial malignancy.
146
JACKSON AND ASSOCIATES
Fm. 1. I, class B cells with nuclear enlargement and early vacuolated cytoplasm. II, class C cells with bizarre nuclear shape, nuclear enlargement, irregularity of chromatic structure and cytoplasmic vacuolation. III, class D cells with bizarre nuclear shape, chromatin condensation and reduced cytoplasm. Reduced from xl,000.
Cytology Class
No. Pts.
A D
22 54 17 5
Total
98
B C
Leistenschneider and Ehmann, in a retrospective study, revealed a significant increase of renal pelvic tumors in analgesic abusers 19 and, in a prospective study, Bengtsson and associates reported 9 tumors of the renal pelvis and 2 bladder tumors that had developed in 104 patients during a period of 3 to 5 years. 2 Subsequently, some of their patients have been followed for up to 12 months before the tumor suspected on the basis of urine cytology could be demonstrated by radiology. 20 The mean period from commencement of analgesic abuse to development of tumor is 22.5 years (range 15 to 30 years). 3 Our patients with class C or D changes had a mean of 15 years since commencement of analgesics. Of these patients 3 had tumors. The remaining cases are presumably at risk of having malignancies in the near future. Cytological changes similar to those of class C and D changes have been described in primary carcinoma in situ of the renal pelvis and ureter. 21 Lewis and associates state that although falsely negative
cytology may be obtained for low grade, low stage lesions the presence of positive cytology in the face of a negative cystoscopy warrants further investigation by random biopsy and lavage of the collecting systems. 18 Although this was done in 1 of our patients dysplasia only was found. Allegra and associates followed 8 patients with falsely positive urine cytology results for 5 years and demonstrated ultimately positive lesions by biopsy in 6 of them. 22 In a review of the literature of falsely positive results Lewis and associates documented 62 cases in which positive cytology preceded the cystoscopic diagnosis of malignancy by 1112 to 46 months. 18 The interpretation of falsely positive results in our study remains to be clarified. Based on the aforementioned reported findings, we are closely surveying all cases of suspicious cytology with regular cystoscopy and ureteral collections for cytology. In several cases cellular abnormalities have been found in urine from both ureters, implying a generalized dysplasia of the urothelium. Multifocal neoplasm commonly occurs in analgesic nephropathy, which supports the concept of exposure of the urothelium to a cytotoxin. The exact nature of this cytotoxin is unclear. The data to date would point to phenacetin or one of its metabolites as being responsible. 23 To diminish the risk of tumor development when analgesics
147
CHI..
1
D
100
200
300
400
300
600
700
800 JJAA@I/L
900
1000
HOO
1200
D1AlYSl5
o• if.tAN§PLANT
Fm. 2. Cytolog'".)1 class versus degree of renal impairment. More severe cytology changes (C and D) occurred in association with more severe renal failure (A versus C and D, 0.01 > p > 0.001) but all classes of change were seen with all degrees of renal function.
must be used long-term it would seem reasonable to avoid phenacetin and its derivatives, and change the analgesic compound at intervals. We recommend that urine cytology be used as a regular screen in all cases of analgesic nephropathy and in patients on long-term analgesic therapy.
tumors. Acta Cytol., 14: 145, 1970. 11. Johnson, W/. D.: Cytopathological correlations in tumors of the urinary bladder. Cancer, 17: 867, 1964. 12. Papanicolaou, G. N. and Marshall, V. F.: Urine sediment 13.
REFERENCES 1. Hultengren, N., Lagergren, G. and Ljungqvist, A.: Carcinoma
2.
3. 4. 5.
6. 7. 8. 9. 10.
of the renal pelvis in renal papillary necrosis. Acta Chir. Scand., 30: 314, 1965. Bengtsson, U., Angervall, L., Ekman H. and Lehmann, L.: Transitional cell tumors on the renal pelvis in analgesic abusers. Scand. J. UroL Nephro!., 2: 145, 1968. Johansson, S., Angervall, L., Bengtsson, U. and Wahlqvist, L.: Uroepithelial tumors of the renal pelvis associated with abuse of phenacetin-containing analgesics. Cancer, 33: 743, 1974. Begley, M., Chadwick, J. M. and Jepson, R. P.: A possible case of analgesic abuse associated with transitional-cell carcinoma of the bladder. Med. J. Aust., 2: 1133, 1970. Adam, W. R., Dawborn, J. K., Price, C. G., Riddell, J. and Story, H.: Anaplastic transitional cell carcinoma of the renal pelvis in association with analgesic abuse. Med. J. Aust., 1: 1108, 1970. Mannion, R. A. and Susmano, D.: Phenacetin abuse causing bladder tumor. J. Urol., 106: 692, 1971. Liu, T., Smith, G. V•T. and Rankin, J. T.: Renal pelvic tumor associated with analgesic abuse. Canad. Med" Ass. J", 107: 768, 1972. Taylor, J. S.: Carcinoma of the urinary tract and analgesic abuse. Med. J. Aust., 1: 407, 1972. Eriksson, 0. and Skjaeggestad, 0.: Cytological diagnosis of transitional cell tumors of the urinary bladder using millipore filter technique. Acta Path. Microbial. Scand., 8: 222, 1973. Esposti, P. L., Modberg, G. and Zajicek, J.: The cytological diagnosis of transitional cell tumors of the urinary bladder and its histologic basis. A study of 576 cases of urinary tract disorders including 170 untreated and 182 irradiated bladder
14.
15.
16. 17.
18.
19. 20. 21. 22. 23.
smears as a diagnostic procedure in cancers of the urinary tract. Science, 101: 519, 1945. Sarnacki, C. T., McCormack, L. J., Kiser, W. S., Hazard, J.B., McLaughlin, T. C. and Belovich, D. M.: Urinary cytology and the clinical diagnosis of urinary tract malignancy: a clinicopathological study of 1,400 patients. J. Urol., Hl6: 761, 1971. Harrison, J. H., Botsford, J. W. and Tucker, M. R.: The use of the urinary sediment in the diagnosis and management of the neoplasm of the kidney and bladder. Surg., Gynec. & Obst., 92: 129, 1951. Naib, Z. M.: Exfoliative cytology of renal pelvic lesions. Cancer, 14: 1085, 1961. Cullen, T. H., Popham, R. R. and Voss, H. J.: Urine cytology and primary carcinoma of the renal pelvis and ureter. Aust. New Zeal. J. Surg., 41: 230, 1972. Eriksson, 0. and Johansson, S.: Uroepithelial neoplasms of the upper urinary tract. A correlation between cytologic and histologic findings in 43 patients with uroepithelial neoplasms of renal pelvis or ureter. Acta Cytol., 20: 20, 1976. Lewis, R. W., Jackson, A. C., Jr., Murphy, W. M., LeBlanc, G. A. and JVJ:eehan, W. L.: Cytology in the diagnosis and followup of transitional cell carcinoma of the urothelium: a review with a case series. cT. Urol., 116: 43, 1976. Leistenschneider, W. and Ehmann, R.: Nierenbeckenkarzinom nach Phenazetinabusus. Schweiz. Med. Wochenschr., 103: 433, 1973. Bengtsson, U.: Personal communication. Murphy, W. M., Von Buedingen, R. P. and Poley, R. W.: Primary carcinoma in situ of renal pelvis and ureter. Cancer, 34: 1126, 1974. Allegra, S. R., Broderick, P. A. and Corvese, N. L.: Cytologic and histogenic observations in well differentiated transitional cell carcinoma of bladder. J. Urol., 107: 777, 1972. Rathert, P., Melchior, H. and Lutzeyer, W.: Phenacetin: a carcinogen for the urinary tract? J. Urol., 113: 653, 1975.
\IVHki:is Cv.
URIN.E CYTOLOGY FINDINGS IN ANALGESIC NEPHROPATHY B. JACKSON,* J. A. KIRKLAND, J. R. LAWRENCE, A. S. NARAYAN, H. E. BROWN
AND
L. R. MILLS
From the Renal Unit, The Queen Elizabeth Hospital, Woodville and the Department of Pathology, the University of Adelaide, Adelaide, South Australia
ABSTRACT
Urine cytology screening for neoplasm led to the detection of 3 urothelial carcinomas and l severe urothelial dysplasia in 98 patients with analgesic-induced papillary necrosis. A further 18 patients had changes suggesting that they were at risk of incurring malignancy in the near future. Routine urine cytology is recommended in all cases of analgesic nephropathy. Carcinoma of the urinary tract has been associated with analgesic nephropathy. Initially, Scandinavian studies revealed renal pelvic and ureteral tumors. 1 • 2 Recently, analgesic nephropathy has been linked to renal pelvic, ureteral and bladder cancers.:i-s The value of urine cytology in the diagnosis and followup of bladder tumors is well established. H 3 Recently, urine cytology has been accepted as useful in the diagnosis of upper urothelial malignancies. 14-18 After the discovery of several urothelial malignancies associated with analgesic neph:ropathy at The Queen Elizabeth Hospital, urine ·cytology was introduced as a regular screen for cancer. This report summarizes our findings to date. MATERIAL AND METHODS
Freshly voided urine was processed by filtration through a millipore filter, and the cellular elements were stained (Papanicolaou, hematoxylin, orange-green 6 and Ehrlich's acid 50) and examined microscopically for changes (fig. 1). The changes were graded as A) normal - no changes seen, B) cells with enlarged nuclei, early vacuolated cytoplasm and occasional multinucleation, C) cells suspicious of malignancybizarre nuclear shape, vacuolated cytoplasm with nuclear enlargement and irregularity of chromatic structure or D) cells indistinguishable from malignancy - bizarre nuclear shape, reduced cytoplasm, nuclear variation and chromatic condensation. Nucleoli are prominent. The diagnosis of analgesic nephropathy was sustained only if there was a definite history of analgesic abuse (more than 3 powders or tablets per day for a minimum of 5 years, that is 2 kg. aspirin or phenacetin) and papillary necrosis was demonstrated a radiological technique (excretory urography -IVP- or retrograde pyelography) or was identified histologically. When performed, renal biopsy showed chronic interstitial nephritis and a concentration defect was present on antidiuretic hormone testing. RESULTS
We used the aforementioned criteria to study 98 patients suffering from analgesic nephropathy. Urine cytology was examined on 411 occasions (mean of 4.2 per patient), with an average cytology followup of 17 months. Patients were grouped according to the most severe changes seen (see table). There were 76 patients (78 per cent) with urinary cytology abnormalities and 22 patients (22.4 per cent) had changes suggestive of malignant change. These 22 patients have been Accepted for publication July 1, 1977. *Current address: Department of Medicine, Division of Nephrology, Medical College of Virginia, Box 197, MCV Station, Richmond, Virginia 23298. 145
investigated further by an IVP, cystoscopy, retrograde pyelography, collection ofureteral urine for cytology, examination of biopsies and nephrectomy. Of the 22 patients adequate investigations were done in 19. Carcinoma of the bladder was encountered in 2 cases and confined histologically. A presumed carcinoma of the renal pelvis was encountered in a third case (lateralizing cytology, and a space-occupying lesion that is growing progressively on IVP but anesthetic is impossible for medical reasons). In a fourth case renal artery stenosis progressed to thrombosis, with development of hypertension. Ureteronephrectomy was performed. Imprints of the entire renal pelvis and ureter yielded type D cells. Histological section showed advanced dysplastic changes. Because of abnormalities of urine cytology random bladder biopsies had been taken 12 months earlier. These also showed dysplastic changes that were less marked than in the nephrectomy specimen. No carcinoma was encountered in any case when type A or B cells only were found. There was no correlation between quantity of analgesic consumed and degree of abnormality. There was a significant trend for the more severe cytological changes to occur in more severe renal failure (class A versus class C and D, 0.01 > p > 0.001). However, all cell varieties were encountered at all degrees ofrenal failure (fig. 2). There was an increasing percentage of male patients with an increasing degree of change (class A was 4. 7 per cent male, class B 17 per cent male, class C 42 per cent male and class D 40 per cent male). There was no significant age difference between cytology classes. The analgesic abused most commonly was "Bex" (containing aspirin, phenacetin and caffeine, more recently with paracetamol replacing phenacetin), which was used exclusively in 45 per cent of the patients and in combination with other preparations in a further 39 per cent, that is 84 per cent of cases. Other analgesics abused included Vincents, Ascotin, Veganin and soluble aspirin. There was no correlation among the analgesic brand abused, degree of renal failure nor degree of cytology abnormality. As assessed by history and urine assay approximately half of the patients had abstained from analgesics during the survey. In a few cases cytological changes tended to improve slowly during 1 to 2 years with abstinence from analgesics. There was no pattern of improvement in patients still consuming analgesics who, generally, tended to have more severe changes. However, there were several patients in whom analgesic abuse had ceased up to 8 years previously in whom class C and D cells were found. DISCUSSION
Analgesic abusers with renal papillary necrosis are at risk of incurring urothelial malignancy.
146
JACKSON AND ASSOCIATES
Fm. 1. I, class B cells with nuclear enlargement and early vacuolated cytoplasm. II, class C cells with bizarre nuclear shape, nuclear enlargement, irregularity of chromatic structure and cytoplasmic vacuolation. III, class D cells with bizarre nuclear shape, chromatin condensation and reduced cytoplasm. Reduced from xl,000.
Cytology Class
No. Pts.
A D
22 54 17 5
Total
98
B C
Leistenschneider and Ehmann, in a retrospective study, revealed a significant increase of renal pelvic tumors in analgesic abusers 19 and, in a prospective study, Bengtsson and associates reported 9 tumors of the renal pelvis and 2 bladder tumors that had developed in 104 patients during a period of 3 to 5 years. 2 Subsequently, some of their patients have been followed for up to 12 months before the tumor suspected on the basis of urine cytology could be demonstrated by radiology. 20 The mean period from commencement of analgesic abuse to development of tumor is 22.5 years (range 15 to 30 years). 3 Our patients with class C or D changes had a mean of 15 years since commencement of analgesics. Of these patients 3 had tumors. The remaining cases are presumably at risk of having malignancies in the near future. Cytological changes similar to those of class C and D changes have been described in primary carcinoma in situ of the renal pelvis and ureter. 21 Lewis and associates state that although falsely negative
cytology may be obtained for low grade, low stage lesions the presence of positive cytology in the face of a negative cystoscopy warrants further investigation by random biopsy and lavage of the collecting systems. 18 Although this was done in 1 of our patients dysplasia only was found. Allegra and associates followed 8 patients with falsely positive urine cytology results for 5 years and demonstrated ultimately positive lesions by biopsy in 6 of them. 22 In a review of the literature of falsely positive results Lewis and associates documented 62 cases in which positive cytology preceded the cystoscopic diagnosis of malignancy by 1112 to 46 months. 18 The interpretation of falsely positive results in our study remains to be clarified. Based on the aforementioned reported findings, we are closely surveying all cases of suspicious cytology with regular cystoscopy and ureteral collections for cytology. In several cases cellular abnormalities have been found in urine from both ureters, implying a generalized dysplasia of the urothelium. Multifocal neoplasm commonly occurs in analgesic nephropathy, which supports the concept of exposure of the urothelium to a cytotoxin. The exact nature of this cytotoxin is unclear. The data to date would point to phenacetin or one of its metabolites as being responsible. 23 To diminish the risk of tumor development when analgesics
147
CHI..
1
D
100
200
300
400
300
600
700
800 JJAA@I/L
900
1000
HOO
1200
D1AlYSl5
o• if.tAN§PLANT
Fm. 2. Cytolog'".)1 class versus degree of renal impairment. More severe cytology changes (C and D) occurred in association with more severe renal failure (A versus C and D, 0.01 > p > 0.001) but all classes of change were seen with all degrees of renal function.
must be used long-term it would seem reasonable to avoid phenacetin and its derivatives, and change the analgesic compound at intervals. We recommend that urine cytology be used as a regular screen in all cases of analgesic nephropathy and in patients on long-term analgesic therapy.
tumors. Acta Cytol., 14: 145, 1970. 11. Johnson, W/. D.: Cytopathological correlations in tumors of the urinary bladder. Cancer, 17: 867, 1964. 12. Papanicolaou, G. N. and Marshall, V. F.: Urine sediment 13.
REFERENCES 1. Hultengren, N., Lagergren, G. and Ljungqvist, A.: Carcinoma
2.
3. 4. 5.
6. 7. 8. 9. 10.
of the renal pelvis in renal papillary necrosis. Acta Chir. Scand., 30: 314, 1965. Bengtsson, U., Angervall, L., Ekman H. and Lehmann, L.: Transitional cell tumors on the renal pelvis in analgesic abusers. Scand. J. UroL Nephro!., 2: 145, 1968. Johansson, S., Angervall, L., Bengtsson, U. and Wahlqvist, L.: Uroepithelial tumors of the renal pelvis associated with abuse of phenacetin-containing analgesics. Cancer, 33: 743, 1974. Begley, M., Chadwick, J. M. and Jepson, R. P.: A possible case of analgesic abuse associated with transitional-cell carcinoma of the bladder. Med. J. Aust., 2: 1133, 1970. Adam, W. R., Dawborn, J. K., Price, C. G., Riddell, J. and Story, H.: Anaplastic transitional cell carcinoma of the renal pelvis in association with analgesic abuse. Med. J. Aust., 1: 1108, 1970. Mannion, R. A. and Susmano, D.: Phenacetin abuse causing bladder tumor. J. Urol., 106: 692, 1971. Liu, T., Smith, G. V•T. and Rankin, J. T.: Renal pelvic tumor associated with analgesic abuse. Canad. Med" Ass. J", 107: 768, 1972. Taylor, J. S.: Carcinoma of the urinary tract and analgesic abuse. Med. J. Aust., 1: 407, 1972. Eriksson, 0. and Skjaeggestad, 0.: Cytological diagnosis of transitional cell tumors of the urinary bladder using millipore filter technique. Acta Path. Microbial. Scand., 8: 222, 1973. Esposti, P. L., Modberg, G. and Zajicek, J.: The cytological diagnosis of transitional cell tumors of the urinary bladder and its histologic basis. A study of 576 cases of urinary tract disorders including 170 untreated and 182 irradiated bladder
14.
15.
16. 17.
18.
19. 20. 21. 22. 23.
smears as a diagnostic procedure in cancers of the urinary tract. Science, 101: 519, 1945. Sarnacki, C. T., McCormack, L. J., Kiser, W. S., Hazard, J.B., McLaughlin, T. C. and Belovich, D. M.: Urinary cytology and the clinical diagnosis of urinary tract malignancy: a clinicopathological study of 1,400 patients. J. Urol., Hl6: 761, 1971. Harrison, J. H., Botsford, J. W. and Tucker, M. R.: The use of the urinary sediment in the diagnosis and management of the neoplasm of the kidney and bladder. Surg., Gynec. & Obst., 92: 129, 1951. Naib, Z. M.: Exfoliative cytology of renal pelvic lesions. Cancer, 14: 1085, 1961. Cullen, T. H., Popham, R. R. and Voss, H. J.: Urine cytology and primary carcinoma of the renal pelvis and ureter. Aust. New Zeal. J. Surg., 41: 230, 1972. Eriksson, 0. and Johansson, S.: Uroepithelial neoplasms of the upper urinary tract. A correlation between cytologic and histologic findings in 43 patients with uroepithelial neoplasms of renal pelvis or ureter. Acta Cytol., 20: 20, 1976. Lewis, R. W., Jackson, A. C., Jr., Murphy, W. M., LeBlanc, G. A. and JVJ:eehan, W. L.: Cytology in the diagnosis and followup of transitional cell carcinoma of the urothelium: a review with a case series. cT. Urol., 116: 43, 1976. Leistenschneider, W. and Ehmann, R.: Nierenbeckenkarzinom nach Phenazetinabusus. Schweiz. Med. Wochenschr., 103: 433, 1973. Bengtsson, U.: Personal communication. Murphy, W. M., Von Buedingen, R. P. and Poley, R. W.: Primary carcinoma in situ of renal pelvis and ureter. Cancer, 34: 1126, 1974. Allegra, S. R., Broderick, P. A. and Corvese, N. L.: Cytologic and histogenic observations in well differentiated transitional cell carcinoma of bladder. J. Urol., 107: 777, 1972. Rathert, P., Melchior, H. and Lutzeyer, W.: Phenacetin: a carcinogen for the urinary tract? J. Urol., 113: 653, 1975.