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Acquired Upper Ureteral Stricture in a Phenacetin Abuser
0022-534 7/80/1246-0892$02.00/0 Vol. 124, December
THE JOURNAL OF UROLOGY
Copyright© 1980 by The Williams & Wilkins Co.
Printed in U.S.A.
Clinicopathologi cal Conference ACQUIRED UPPER URETERAL STRICTURE IN A PHENACETIN ABUSER STUART BERGMAN,* JOHN FORREST,t WILLIAM BETSILL*
AND
JAY GILLENWATER§
From the Departments of Urology and Pathology, University of Virginia School of Medicine, Charlottesville, Virginia
the causes of an acquired upper ureteral or ureteropelvic junction obstruction, since she had had a normal IVP 2 years before this hospitalization. The 2 general causes of ureteral obstruction are intrinsic or extrinsic. Acquired intrinsic problems can be caused by transitional cell tumors. With negative brush biopsy and cytology this cause is unlikely. The other possibility is an acquired ureteral stricture from an inflammatory response to either primary or secondary obstructive episodes secondary to the passage of sloughed papillae caused by the long-term phenaccetin abuse. This possibility would be unlikely since the right kidney showed no signs of papillary necrosis and the patient had no clinical history of such. Of course, calculi could cause the same picture. The other possible cause of ureteral obstruction is extrinsic compression. This can be from 1) retroperitoneal fibrosis, 2) a previous operation in and around the kidney, 3) retroperitoneal neoplasm, 4) radiation fibrosis, 5) ascending lymphangitis, 6) granulomatous disease (tuberculosis and sarcoidosis), 7) chronic urinary tract infections, 8) perinephric abscess and 9) perinephric hematomas. Of these possibilities retroperitoneal fibrosis and malignancy are the most likely causes. Retroperitoneal fibrosis has been reported in association with phenacetin abuse. 1 Although retroperitoneal fibrosis usually is bilateral and involves the mid ureter and great vessels it may be spotty and located anywhere from the pelvis to involve just the biliary tree or even to extend into the mediastinum. The possibility of an intestinal neoplasm has been eliminated by a normal barium enema and upper gastrointestinal series. Pancreatic and hepatic primary or secondary malignancies were excluded by a normal CT scan. Unfortunately, however, a CT scan did not reveal any mass or plaque in the region of the left ureteropelvic junction to aid in the differential diagnosis. The possibility of other causes of acquired ureteral obstruction can be eliminated easily by careful history, physical examination and basic laboratory tests. This leaves us with a diagnosis of an acquired benign upper ureteral stricture. With renal failure all attempts should be made to restore and preserve renal function. The hypertension could be caused by the unilateral hydronephrosis. Studies by Vaughan and associates showed that chronic hydronephrosis was associated with and usually did not cause the hypertension. 2
CASE PRESENTATIONII
Dr. John Forrest. The patient is a 66-year-old white woman who had been hospitalized in 1964 for evaluation of renal insufficiency. She had a long history of phenacetin abuse at that time. Serum creatinine was 6.9 mg. per cent. Renal function improved when use of phenacetin was stopped and stabilized at 1.3 mg. per cent. An excretory urogram (IVP) in November 1978 was normal. Serum creatinine then was 2.1 mg. per cent. During an outpatient visit in June 1979 the woman was noted to be hypertensive and the creatinine had increased. She was hospitalized for further evaluation. In addition to analgesic abuse history included adult onset diabetes mellitus, anemia and hyperthyroidism. When the patient was hospitalized blood pressure was 160/95, pulse 84 and respiration 34 per minute, and she was afebrile. Funduscopic examination showed A-V nicking and arteriolar narrowing. The thyroid was enlarged. Examination of the chest revealed scattered basilar rales. Abdominal and pelvic examinations were unremarkable except for mild left costovertebral angle tenderness. The remainder of the physical examination was unremarkable. A chest x-ray showed an elevated right hemidiaphragm that had not changed for many years. No acute pathological condition was seen. The hematocrit was 28 per cent and the white blood count was 8,200. Differential revealed 52 per cent polymorphonuclear leukocytes, 28 per cent lymphocytes, 11 per cent mononucleocytes and 9 per cent eosinophils. Clotting studies and platelet count were normal. Sedimentation rate was elevated at 107 mm. per hour. Sodium was 143, potassium 5.8, chloride 107 and carbon dioxide 16 mEq./1. Serum creatinine was 5.3 mg. per cent and blood urea nitrogen was 70 mg. per cent. Creatinine clearance was 9 cc per minute. Liver function studies were all within normal limits. Because of progressive renal insufficiency renal ultrasound examination was done, revealing a hydronephrotic left kidney. Retrograde pyelograms showed a normal right renal collecting system but an irregular stenotic area of the upper ureter near the ureteropelvic junction with pyelocaliectasis of the left kidney (fig. 1). Brush biopsy and cytology of the left kidney were negative for malignancy. Purified protein derivative was negative. An upper gastrointestinal series and barium enema were normal. Computerized tomography (CT) of the abdomen confirmed a hydronephrotic left kidney, with no evidence of a retroperitoneal tumor or mass. The liver, pancreas and other abdominal organs appeared normal. DIFFERENTIAL DIAGNOSIS
Dr. Stuart Bergman. This patient with chronic renal failure from phenacetin abuse presents the problem of differentiating
* Chief Resident, Department of Urology. Current address: Tulane Medical Center, 1430 Tulane Ave., New Orleans, Louisiana 70112. t Senior Resident, Department of Urology. :j: Associate Professor, Department of Pathology. § Professor and Chairman, Department of Urology. II Case presented at Urologic Rounds, 1979.
DISCUSSION OF SURGERY
Doctor Bergman. Because of the chronic phenacetin nephritis we thought that it was worth trying to salvage the kidney in an attempt to improve the chronic renal insufficiency. Therefore, exploration was undertaken with the aim of relieving obstruction to the left kidney, either with a Davis intubated ureterostomy or pyeloplasty. The kidney was approached through a left flank incision. A fibrotic scar was found encasing the upper ureter and renal pelvis, and extending laterally to involve the lower pole of the kidney and medially to the ureter and renal pelvis. The aorta was not involved. Some periureteral and lower pole renal tissue was sent for frozen section histologic 892
ACQUIRED UPPER URETERAL STRICTURE IN PHENACETIN ABUSER
893
The ultrastructural evaluation by a transmission electron microscope confirmed the epithelial nature of the lesion. 3 Spindle cells containing few cytoplasmic organelles, prominent desmosomal attachments and focal attenuated brush border formation (microvilli) were noted. Interspersed cells (corresponding to the clear cells previously mentioned) manifested cytoplasmic accumulations of lipid droplets and glycogen granules. Collagen was present in the intercellular ground substance. The differential diagnosis includes various other renal sarcomas, including Wilms tumor. Among 2,100 renal cell carcinomas Farrow and associates identified 1.8 per cent tumors with the sarcomatoid pattern. 4 The fibrosarcomatous pattern was most common (24 of 37 cases). Other tumors resembled rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcoma, chondrosarcoma and poorly differentiated sarcomas of unspecified type. The most helpful feature in differentiating renal cell carcinoma from various other sarcomas is the finding of light microscopic evidence of identifiable renal cell carcinoma (clear cell or granular cell pattern) interspersed among the sarcomatoid cells. This case supports the contention of Farrow and associates that a careful microscopic evaluation will identify carcinoma in each case. Of 37 cases of sarcomatoid renal cell carcinoma they identified the clear cell variety in 36 and the granular cell variety in 1. In addition, the ultrastructural features support the diagnosis of carcinoma over sarcoma. DISCUSSION OF PROGNOSIS AND FURTHER THERAPY
FIG. 1. Occlusive retrograde pyelogram of left kidney shows stenotic proximal ureter and hydronephrotic kidney.
Dr. Jay Gillenwater. These tumors have been called carcinosarcoma, which implies 2 distinct cell lines: 1) ectoderm or endoderm for the carcinoma and 2) mesoderm for the sarcoma. This can come either from simultaneous anaplastic degeneration of stromal and tubular cells or from metaplastic transformation of the adenocarcinoma cells. This tumor indicates that neither is the case but that the sarcomatous cells are, in fact, adenocarcinoma cells with brush borders reminiscent of the renal tubular cells.
analysis. This analysis revealed a malignant tumor, possibly a retroperitoneal sarcoma. Since it appeared that the tumor was confined to the renal hilus left nephrectomy was done. Convalescence was unremarkable. Renal function and blood pressure were unchanged from the preoperative values. DISCUSSION OF PATHOLOGY
Dr. William Betsill. The 65 gm. kidney manifested a markedly hemorrhagic and roughened external surface. Much of the lower pole was replaced by an infiltrative tan-white tumor, approximately 3.5 X 2.5 x 2.0 cm. No evidence of capsular penetration by the underlying tumor was noted upon superficial examination. The cut surface demonstrated a markedly dilated caliceal system with parenchymal atrophy (fig. 2). The tumor, well demarcated in some areas, merged imperceptibly into adjacent renal parenchyma elsewhere. No obvious gross vascular invasion was noted. Tumor nodules were present within periureteral and perirenal adipose tissue. The tumor manifested a spindle cell pattern (fig. 3, A). Fairly uniform spindle cells permeated the renal parenchyma, creating areas with varying degrees of cellularity. Mitotic activity was maximal in hypercellular areas (up to 13 mitoses per 10 high power fields). The tumor elicited a fibrous response with large areas ofhyalinized collagen-like tissue interspersed throughout. Microscopic capsular and small caliber vessel penetration was identified. Focally, the spindle cells were arranged in whorls and fascicles but much of the spindle cell arrangement appeared quite disorganized. Rare foci of interspersed large vacuolated cells were noted, identifying the lesion as renal cell carcinoma (fig. 3, B). These foci merged subtly into the spindle cell areas. No granular tumor cells were noted. Dilated epithelial lined cyst-like structures were present throughout the tissue and were formed secondary to distal tubular obstruction by the infiltrating tumor.
FIG. 2. Gross appearance of left kidney with tumor in lower pole
CLINICOPATHOLOGICAL CONFERENCE
894
Fm. 3. A, photomicrograph shows spindle cell pattern. H & E, reduced from Xl50. B, higher magnification shows large clear cells. H & E, reduced from X600.
Prognosis of sarcomatoid renal adenocarcinoma is poor. In 1 report 80 per cent of the patients were dead in 30 months, with a median survival of 6 months. 4 There are rare reports of chemotherapy with multiple drugs for this tumor. 5 Because of the poor renal function multiple drug chemotherapy is contraindicated. Radiation therapy is not effective in controlling hypernephroma. Finney showed no increased survival nor increased local control in a prospective clinical trial of patients treated with an operation plus radiation compared to patients treated with an operation alone. 6 FINAL DIAGNOSIS
2.
3. 4.
5.
Sarcomatoid renal adenocarcinoma. REFERENCE
1. Lewis, C. T., Molland, E. A., Marshall, V. F., Tresidder, G. C. and
6.
Blandy, J. P.: Analgesic abuse, ureteric obstruction, and retroperitoneal fibrosis. Brit. Med. J., 2: 76, 1975. Vaughan, E. D., Jr., Buhler, F. R. and Laragh, J. H.: Normal renin secretion in hypertensive patients with primarily unilateral chronic hydronephrosis. J. Urol., 112: 153, 1974. Tannenbaum, M.: Ultrastructural pathology of human renal cell tumors. Path. Ann., 6: 249, 1971. Farrow, G. M., Harrison, E. G. and Utz, D. C.: Sarcomas and sarcomatoid and mixed malignant tumors of the kidney in adults. 3. Cancer, 22: 556, 1968. Krutchik, A. N., Sullivan, C., Sinkovics, J. G. and Ayala, A.: Chemoimmunotherapy of sarcomatoid renal cell carcinoma. Med. Ped. Oncol., 5: 9, 1978. Finney, R.: An evaluation of postoperative radiotherapy in hypernephroma treatment-a clinical trial. Cancer, 32: 1332, 1973.
THE JOURNAL OF UROLOGY
Copyright© 1980 by The Williams & Wilkins Co.
Printed in U.S.A.
Clinicopathologi cal Conference ACQUIRED UPPER URETERAL STRICTURE IN A PHENACETIN ABUSER STUART BERGMAN,* JOHN FORREST,t WILLIAM BETSILL*
AND
JAY GILLENWATER§
From the Departments of Urology and Pathology, University of Virginia School of Medicine, Charlottesville, Virginia
the causes of an acquired upper ureteral or ureteropelvic junction obstruction, since she had had a normal IVP 2 years before this hospitalization. The 2 general causes of ureteral obstruction are intrinsic or extrinsic. Acquired intrinsic problems can be caused by transitional cell tumors. With negative brush biopsy and cytology this cause is unlikely. The other possibility is an acquired ureteral stricture from an inflammatory response to either primary or secondary obstructive episodes secondary to the passage of sloughed papillae caused by the long-term phenaccetin abuse. This possibility would be unlikely since the right kidney showed no signs of papillary necrosis and the patient had no clinical history of such. Of course, calculi could cause the same picture. The other possible cause of ureteral obstruction is extrinsic compression. This can be from 1) retroperitoneal fibrosis, 2) a previous operation in and around the kidney, 3) retroperitoneal neoplasm, 4) radiation fibrosis, 5) ascending lymphangitis, 6) granulomatous disease (tuberculosis and sarcoidosis), 7) chronic urinary tract infections, 8) perinephric abscess and 9) perinephric hematomas. Of these possibilities retroperitoneal fibrosis and malignancy are the most likely causes. Retroperitoneal fibrosis has been reported in association with phenacetin abuse. 1 Although retroperitoneal fibrosis usually is bilateral and involves the mid ureter and great vessels it may be spotty and located anywhere from the pelvis to involve just the biliary tree or even to extend into the mediastinum. The possibility of an intestinal neoplasm has been eliminated by a normal barium enema and upper gastrointestinal series. Pancreatic and hepatic primary or secondary malignancies were excluded by a normal CT scan. Unfortunately, however, a CT scan did not reveal any mass or plaque in the region of the left ureteropelvic junction to aid in the differential diagnosis. The possibility of other causes of acquired ureteral obstruction can be eliminated easily by careful history, physical examination and basic laboratory tests. This leaves us with a diagnosis of an acquired benign upper ureteral stricture. With renal failure all attempts should be made to restore and preserve renal function. The hypertension could be caused by the unilateral hydronephrosis. Studies by Vaughan and associates showed that chronic hydronephrosis was associated with and usually did not cause the hypertension. 2
CASE PRESENTATIONII
Dr. John Forrest. The patient is a 66-year-old white woman who had been hospitalized in 1964 for evaluation of renal insufficiency. She had a long history of phenacetin abuse at that time. Serum creatinine was 6.9 mg. per cent. Renal function improved when use of phenacetin was stopped and stabilized at 1.3 mg. per cent. An excretory urogram (IVP) in November 1978 was normal. Serum creatinine then was 2.1 mg. per cent. During an outpatient visit in June 1979 the woman was noted to be hypertensive and the creatinine had increased. She was hospitalized for further evaluation. In addition to analgesic abuse history included adult onset diabetes mellitus, anemia and hyperthyroidism. When the patient was hospitalized blood pressure was 160/95, pulse 84 and respiration 34 per minute, and she was afebrile. Funduscopic examination showed A-V nicking and arteriolar narrowing. The thyroid was enlarged. Examination of the chest revealed scattered basilar rales. Abdominal and pelvic examinations were unremarkable except for mild left costovertebral angle tenderness. The remainder of the physical examination was unremarkable. A chest x-ray showed an elevated right hemidiaphragm that had not changed for many years. No acute pathological condition was seen. The hematocrit was 28 per cent and the white blood count was 8,200. Differential revealed 52 per cent polymorphonuclear leukocytes, 28 per cent lymphocytes, 11 per cent mononucleocytes and 9 per cent eosinophils. Clotting studies and platelet count were normal. Sedimentation rate was elevated at 107 mm. per hour. Sodium was 143, potassium 5.8, chloride 107 and carbon dioxide 16 mEq./1. Serum creatinine was 5.3 mg. per cent and blood urea nitrogen was 70 mg. per cent. Creatinine clearance was 9 cc per minute. Liver function studies were all within normal limits. Because of progressive renal insufficiency renal ultrasound examination was done, revealing a hydronephrotic left kidney. Retrograde pyelograms showed a normal right renal collecting system but an irregular stenotic area of the upper ureter near the ureteropelvic junction with pyelocaliectasis of the left kidney (fig. 1). Brush biopsy and cytology of the left kidney were negative for malignancy. Purified protein derivative was negative. An upper gastrointestinal series and barium enema were normal. Computerized tomography (CT) of the abdomen confirmed a hydronephrotic left kidney, with no evidence of a retroperitoneal tumor or mass. The liver, pancreas and other abdominal organs appeared normal. DIFFERENTIAL DIAGNOSIS
Dr. Stuart Bergman. This patient with chronic renal failure from phenacetin abuse presents the problem of differentiating
* Chief Resident, Department of Urology. Current address: Tulane Medical Center, 1430 Tulane Ave., New Orleans, Louisiana 70112. t Senior Resident, Department of Urology. :j: Associate Professor, Department of Pathology. § Professor and Chairman, Department of Urology. II Case presented at Urologic Rounds, 1979.
DISCUSSION OF SURGERY
Doctor Bergman. Because of the chronic phenacetin nephritis we thought that it was worth trying to salvage the kidney in an attempt to improve the chronic renal insufficiency. Therefore, exploration was undertaken with the aim of relieving obstruction to the left kidney, either with a Davis intubated ureterostomy or pyeloplasty. The kidney was approached through a left flank incision. A fibrotic scar was found encasing the upper ureter and renal pelvis, and extending laterally to involve the lower pole of the kidney and medially to the ureter and renal pelvis. The aorta was not involved. Some periureteral and lower pole renal tissue was sent for frozen section histologic 892
ACQUIRED UPPER URETERAL STRICTURE IN PHENACETIN ABUSER
893
The ultrastructural evaluation by a transmission electron microscope confirmed the epithelial nature of the lesion. 3 Spindle cells containing few cytoplasmic organelles, prominent desmosomal attachments and focal attenuated brush border formation (microvilli) were noted. Interspersed cells (corresponding to the clear cells previously mentioned) manifested cytoplasmic accumulations of lipid droplets and glycogen granules. Collagen was present in the intercellular ground substance. The differential diagnosis includes various other renal sarcomas, including Wilms tumor. Among 2,100 renal cell carcinomas Farrow and associates identified 1.8 per cent tumors with the sarcomatoid pattern. 4 The fibrosarcomatous pattern was most common (24 of 37 cases). Other tumors resembled rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcoma, chondrosarcoma and poorly differentiated sarcomas of unspecified type. The most helpful feature in differentiating renal cell carcinoma from various other sarcomas is the finding of light microscopic evidence of identifiable renal cell carcinoma (clear cell or granular cell pattern) interspersed among the sarcomatoid cells. This case supports the contention of Farrow and associates that a careful microscopic evaluation will identify carcinoma in each case. Of 37 cases of sarcomatoid renal cell carcinoma they identified the clear cell variety in 36 and the granular cell variety in 1. In addition, the ultrastructural features support the diagnosis of carcinoma over sarcoma. DISCUSSION OF PROGNOSIS AND FURTHER THERAPY
FIG. 1. Occlusive retrograde pyelogram of left kidney shows stenotic proximal ureter and hydronephrotic kidney.
Dr. Jay Gillenwater. These tumors have been called carcinosarcoma, which implies 2 distinct cell lines: 1) ectoderm or endoderm for the carcinoma and 2) mesoderm for the sarcoma. This can come either from simultaneous anaplastic degeneration of stromal and tubular cells or from metaplastic transformation of the adenocarcinoma cells. This tumor indicates that neither is the case but that the sarcomatous cells are, in fact, adenocarcinoma cells with brush borders reminiscent of the renal tubular cells.
analysis. This analysis revealed a malignant tumor, possibly a retroperitoneal sarcoma. Since it appeared that the tumor was confined to the renal hilus left nephrectomy was done. Convalescence was unremarkable. Renal function and blood pressure were unchanged from the preoperative values. DISCUSSION OF PATHOLOGY
Dr. William Betsill. The 65 gm. kidney manifested a markedly hemorrhagic and roughened external surface. Much of the lower pole was replaced by an infiltrative tan-white tumor, approximately 3.5 X 2.5 x 2.0 cm. No evidence of capsular penetration by the underlying tumor was noted upon superficial examination. The cut surface demonstrated a markedly dilated caliceal system with parenchymal atrophy (fig. 2). The tumor, well demarcated in some areas, merged imperceptibly into adjacent renal parenchyma elsewhere. No obvious gross vascular invasion was noted. Tumor nodules were present within periureteral and perirenal adipose tissue. The tumor manifested a spindle cell pattern (fig. 3, A). Fairly uniform spindle cells permeated the renal parenchyma, creating areas with varying degrees of cellularity. Mitotic activity was maximal in hypercellular areas (up to 13 mitoses per 10 high power fields). The tumor elicited a fibrous response with large areas ofhyalinized collagen-like tissue interspersed throughout. Microscopic capsular and small caliber vessel penetration was identified. Focally, the spindle cells were arranged in whorls and fascicles but much of the spindle cell arrangement appeared quite disorganized. Rare foci of interspersed large vacuolated cells were noted, identifying the lesion as renal cell carcinoma (fig. 3, B). These foci merged subtly into the spindle cell areas. No granular tumor cells were noted. Dilated epithelial lined cyst-like structures were present throughout the tissue and were formed secondary to distal tubular obstruction by the infiltrating tumor.
FIG. 2. Gross appearance of left kidney with tumor in lower pole
CLINICOPATHOLOGICAL CONFERENCE
894
Fm. 3. A, photomicrograph shows spindle cell pattern. H & E, reduced from Xl50. B, higher magnification shows large clear cells. H & E, reduced from X600.
Prognosis of sarcomatoid renal adenocarcinoma is poor. In 1 report 80 per cent of the patients were dead in 30 months, with a median survival of 6 months. 4 There are rare reports of chemotherapy with multiple drugs for this tumor. 5 Because of the poor renal function multiple drug chemotherapy is contraindicated. Radiation therapy is not effective in controlling hypernephroma. Finney showed no increased survival nor increased local control in a prospective clinical trial of patients treated with an operation plus radiation compared to patients treated with an operation alone. 6 FINAL DIAGNOSIS
2.
3. 4.
5.
Sarcomatoid renal adenocarcinoma. REFERENCE
1. Lewis, C. T., Molland, E. A., Marshall, V. F., Tresidder, G. C. and
6.
Blandy, J. P.: Analgesic abuse, ureteric obstruction, and retroperitoneal fibrosis. Brit. Med. J., 2: 76, 1975. Vaughan, E. D., Jr., Buhler, F. R. and Laragh, J. H.: Normal renin secretion in hypertensive patients with primarily unilateral chronic hydronephrosis. J. Urol., 112: 153, 1974. Tannenbaum, M.: Ultrastructural pathology of human renal cell tumors. Path. Ann., 6: 249, 1971. Farrow, G. M., Harrison, E. G. and Utz, D. C.: Sarcomas and sarcomatoid and mixed malignant tumors of the kidney in adults. 3. Cancer, 22: 556, 1968. Krutchik, A. N., Sullivan, C., Sinkovics, J. G. and Ayala, A.: Chemoimmunotherapy of sarcomatoid renal cell carcinoma. Med. Ped. Oncol., 5: 9, 1978. Finney, R.: An evaluation of postoperative radiotherapy in hypernephroma treatment-a clinical trial. Cancer, 32: 1332, 1973.