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Renal Cell Carcinoma in a Solitary Kidney: Late Nephrectomy after 35 Years and Analysis of Tumor Deoxyribonucleic Acid Content
0022-534 7/88/1392-0350$02.00/0 Vol. 139, February Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright © 1988 by The Williams & Wilkins Co.
RENAL CELL CARCINOMA IN A SOLITARY KIDNEY: LATE NEPHRECTOMY AFTER 35 YEARS AND ANALYSIS OF TUMOR DEOXYRIBONUCLEIC ACID CONTENT BORJE LJUNGBERG, MILOS DUCHEK, SVEN-OLA HIETALA, GORAN ROOS AND ROGER STENLING From the Departments of Urology and Andrology, Diagnostic Radiology and Pathology, University of Umea, Umea, Sweden
ABSTRACT
We report a case of renal cell carcinoma in a solitary kidney, which was palpable for 35 years and verified histopathologically 31 years before nephrectomy. Deoxyribonucleic acid analysis of paraffin embedded and new surgical samples showed a similar aneuploid deoxyribonucleic acid content with an index of 1.3. The unusually long survival of this patient is discussed. (J. Ural., 139: 350-352, 1988) Renal cell carcinoma is a lethal disease and the 5-year survival rate is about 2 per cent for untreated patients' compared to about 60 per cent for those treated by radical nephrectomy. 2 • 3 Partial nephrectomy has been the most successful therapy for patients with renal cell carcinoma in a solitary kidney, with a median survival time of about 5 years.4-6 Only 2 untreated patients who have survived for more than 10 years have been described in the literature. 1• 7 In these patients nephrectomy was performed 8 and 9 years after diagnosis, respectively. Analysis of the tumor deoxyribonucleic acid (DNA) content has been shown to provide reliable prognostic information on renal cell carcinoma.8 • 9 We report a case of renal cell carcinoma in a solitary kidney for 35 years before nephrectomy and without evidence of metastases. DNA analysis was performed on paraffin embedded, archival and fresh samples from this tumor. CASE REPORT
A 71-year-old woman noticed in 1951 a palpable mass in the right upper quadrant of the abdomen. A year later the mass had grown but the patient was not admitted to the hospital until 1955. According to hospital records, excretory urography (IVP) revealed a huge renal mass. Angiography showed a hypovascular renal tumor on the right side and renal agenesis on the left side. At exploration the tumor involved almost the entire right kidney. Partial resection was deemed impossible and 2 biopsies were taken for histopathological examination. The predominant symptoms suffered by the patient during the next 31 years were intermittent hematuria and ureteral colic. Repeated episodes of ureteral obstruction by blood clots were managed by ureteral catheterization, transureteral extraction of blood clots and local infusion of streptokinase. The serum creatinine remained normal or slightly elevated until 1980, when it began to increase continuously. Glomerular filtration rate decreased from 146 ml. per minute (creatinine clearance) in 1962 to 22 ml. per minute (chromium-ethylenediaminetetraacetic acid clearance) in 1983. Owing to permanent anuria hemodialysis became necessary in July 1986 and in August perifascial nephrectomy was performed. The inferior vena cava was resected because of invastion by a tumor thrombus that reached the level of the lower hepatic veins. After nephrectomy the patient continued on chronic hemodialysis and at 7-month followup she was healthy with no evidence of tumor recurrence.
RADIOLOGICAL EVALUATION
The radiograms from 1955 were not available. On the IVP from 1960 the tumor measured 14 x 15 cm. Selective renal angiography in 1986 revealed a moderately hypervascular lesion. The size of the tumor was unchanged compared to the 1960 IVP (fig. 1), although calcifications in the tumor had increased considerably during this period. In 1986 the patient was examined preoperatively by pulmonary x-ray, computerized tomography, ultrasonography, inferior venacavography, skeletal scintigraphy and angiography of the liver and kidney. There were no signs of distant metastases. HISTOPATHOLOGICAL EXAMINATION
The 2 paraffin embedded biopsies from 1955 were reviewed and, according to Skinner and associates, 3 the tumor was classified as grade 2 (fig. 2, A). In 1986 the tumor involved almost the entire nephrectomized kidney and it measured about 15 X 12 x 10 cm. A sample from the remaining renal cortex and 8 tumor tissue samples were taken for morphological examination and DNA analysis as described previously. 10 Four additional tumor samples were fixed in formalin and embedded in paraffin. The tumor contained many necrotic and fibrotic areas, and it was classified as grade 2/3 (fig. 2, B ). There was invasion into the vena cava but no tumor growth through the renal capsule. Microscopically, the tumor was sharply demarcated from the surrounding tissues. DNA ANALYSIS
Flow cytometry of fresh and paraffin embedded tissues was performed as described previously using propidium-iodide staining and a FACS analyzer flow cytometer*. 11 The paraffin embedded surgical biopsies from 1955 showed aneuploidy with a DNA index estimated at 1.4 (fig. 3, a and b ). Analysis of the tumor samples from 1986 revealed a similar aneuploid population with a DNA index of 1.3 in the 4 paraffin embedded (fig. 3, c and d) and in the 8 fresh tumor samples (fig. 3, e and/). Furthermore, in 1 of the 8 fresh tumor samples a second peak with a DNA index of 2.5 was noted (fig. 3, /). In another sample a possible cell population with a DNA index of 1. 7 was found (not shown). Assignment of cells to different cell cycle phases was performed using the consort-30 ands-fit softwares,* which allowed for proper analysis of 3 paraffin embedded samples from 1986. The obtained s-phase fractions were 4, 7 and 8 per cent, respectively. * Becton-Dickinson, Sunnyvale, California.
Accepted for publication July 17, 1987. 350
RENAL CELL CARCINOMA IN SOLITARY KIDNEY
351
FIG. 1. A, IVP from 1960. B, selective renal angiogram from 1986
FIG. 2. Light micrographs of renal cell carcinoma. A, biopsy sample from 1955. B, representative part of removed tumor in 1986. Reduced from X220.
DISCUSSION
To our knowledge our patient represents the longest reported survivor of those with untreated renal cell carcinoma. 1· 7 Although she had a solitary kidney, partial nephrectomy by bench surgery5 might have been possible at the time of diagnosis. However, such treatment would have been doubtful since at that time the tumor was large. In 1986 partial nephrectomy was proved to be impossible, as judged by examination of the nephrectomized kidney. The long survival of our patient is interesting. Although vena caval invasion was noted there was no tumor growth through the renal capsule. It should be emphasized that invasion of the vena cava alone does not alter the prognosis compared to tumors confined to the kidney (stage 1). 2 • 3 It has been shown previously that if renal cell carcinoma arises in a solitary kidney the average survival is superior to asynchronous bilateral tumors.5·6 During the 26 years of radiological followup no obvious increase in tumor size was noted, which must be a reflection of a balance among cell proliferation, cell arrest and cell death. The specific factors modulating such a balance remain unknown but it has been reported in renal cell carcinoma that cell loss and large nonproliferating compartments can contribute to a delay in tumor progression. 10 The tumor in our case was characterized by large necrotic areas and during the years increasing amounts of calcifications. Speculatively, tumor necrosis factors, interferons, tumor angiogenic factors and different growth factors might act directly and indirectly in a scenario leading to a stable disease state. 12 The mechanism for the apparently stable disease in our patient might be similar to the
mechanism of spontaneous regression most commonly reported in renal cell carcinoma. 13 It has been shown that the tumor DNA content can provide reliable prognostic information for patients with renal cell carcinoma. 8 • 9 • 14 The tumor in our case was aneuploid with a DNA index of 1.3. Tumors with an aneuploid DNA content near the diploid region might possibly have a better prognosis than aneuploid tumors with larger DNA indexes. In a previous study using static cytometry, a method with lower resolution than flow cytometry, 11 some of the patients surviving for more than 10 years had tumor DNA indexes of about 1.25 and the tumors were denominated as a diploid/near diploid DNA content in that study. 8 However, it must be stressed that the tumor DNA content in individual patients might provide less prognostic information than other factors of importance for tumor progression. We have reported previously a frequent intratumoral heterogeneity of the DNA content in renal cell carcinoma. 15 In the tumor in our case the DNA indexes were about the same in 1955 and 1986 but 2 of the 12 new samples each contained an additional aneuploid clone. Analysis of more samples in 1986 might explain the finding of these additional aneuploid peaks. The tumor was rather genetically stable as judged by the DNA content. It has been found that genetic instability of tumors often is associated with a highly malignant character. 16 Thus, the relatively homogeneous DNA content might be a parameter of importance for the benign clinical course of our patient. REFERENCES 1. Riches, E.: The natural history of renal tumors. In: Tumors of the Kidney and Ureter. Baltimore: The Williams & Wilkins Co., pp. 124-134, 1964. 2. Angervall, L. and W ahlqvist, L.: Follow-up and prognosis of renal cell carcinoma in a series operated by perifascial nephrectomy combined with adrenalectomy and retroperitoneal lymphadenectomy. Eur. Urol., 4: 13, 1978. 3. Skinner, D. G., Colvin, R. B., Vermillion, C. D., Pfister, R. C. and Leadbetter, W. F.: Diagnosis and management of renal cell carcinoma. A clinical and pathologic study of 309 cases. Cancer, 28: 1165, 1971. 4. Smith, R. B., deKernion, J.B., Ehrlich, R. M., Skinner, D. G. and Kaufman, J. J.: Bilateral renal cell carcinoma and renal cell carcinoma in the solitary kidney. J. Urol., 132: 450, 1984. 5. Wickham, J.E. A.: Conservative renal surgery for adenocarcinoma: the place of bench surgery. Brit. J. Urol., 47: 25, 1975. 6. Malek, R. S., Utz, D. C. and Culp, 0. S.: Hypernephroma in the solitary kidney: experience with 20 cases and review of the literature. J. Urol., 116: 553, 1976. 7. Carlson, H. E. and Ockerblad, N. F.: A case of unoperated hypernephroma of 10 years' duration. Amer. J. Roentgen., 45: 221, . 1941. 8. Ljungberg, B., Forsslund, G., Stenling, R. and Zetterberg, A.: Prog-
352
LJUNGBERG AND ASSOCIATES
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0
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0
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DNA CONTENT (index) FIG. 3. Flow cytometry DNA histograms. a and b, paraffin embedded tumor samples from 1955. c and d, paraffin embedded samples from 1986. e and f, fresh tumor samples. In addition to ploidy level at 1.3 another peak at 2.5 is demonstrated in part /.
9. 10. 11. 12.
nostic significance of the DNA content in renal cell carcinoma. J. Urol., 135: 422, 1986. Otto, U., Baisch, H., Huland, H. and Kliippel, G.: Tumor cell deoxyribonucleic acid content and prognosis in human renal cell carcinoma. J. Urol., 132: 237, 1984. Rabes, H. M., Carl, P., Meister, P. and Rattenhuber, U.: Analysis of proliferative compartments in human tumors: I. Renal adenocarcinoma. Cancer, 44: 799, 1979. Roos, G., Stenling, R. and Ljungberg, B.: DNA content in renal cell carcinoma-a comparison between flow and static cytometric methods. Scand. J. Urol. Nephrol., 20: 295, 1986. Droller, M. J.: Immunotherapy and genitourinary neoplasia: an
overview. World J. Urol., 3: 200, 1986. 13. Katz, S. E. and Schapira, H. E.: Spontaneous regression of genitourinary cancer-an update. J. Urol., 128: 1, 1982. 14. Rainwater, L. M., Hosaka, Y., Farrow, G. M. and Lieber, M. M.: Well differentiated clear cell renal carcinoma: significance of nuclear deoxyribonucleic acid patterns studied by flow cytometry. J. Urol., 137: 15, 1987. 15. Ljungberg, B., Stenling, R. and Roos, G.: DNA content in renal cell carcinoma with reference to tumor heterogeneity. Cancer, 56: 503, 1985. 16. Nicolson, G. L.: Generation ofphenotypic diversity and progression in metastatic tumor cells. Cancer Met. Rev., 3: 25, 1984.
THE JOURNAL OF UROLOGY
Copyright © 1988 by The Williams & Wilkins Co.
RENAL CELL CARCINOMA IN A SOLITARY KIDNEY: LATE NEPHRECTOMY AFTER 35 YEARS AND ANALYSIS OF TUMOR DEOXYRIBONUCLEIC ACID CONTENT BORJE LJUNGBERG, MILOS DUCHEK, SVEN-OLA HIETALA, GORAN ROOS AND ROGER STENLING From the Departments of Urology and Andrology, Diagnostic Radiology and Pathology, University of Umea, Umea, Sweden
ABSTRACT
We report a case of renal cell carcinoma in a solitary kidney, which was palpable for 35 years and verified histopathologically 31 years before nephrectomy. Deoxyribonucleic acid analysis of paraffin embedded and new surgical samples showed a similar aneuploid deoxyribonucleic acid content with an index of 1.3. The unusually long survival of this patient is discussed. (J. Ural., 139: 350-352, 1988) Renal cell carcinoma is a lethal disease and the 5-year survival rate is about 2 per cent for untreated patients' compared to about 60 per cent for those treated by radical nephrectomy. 2 • 3 Partial nephrectomy has been the most successful therapy for patients with renal cell carcinoma in a solitary kidney, with a median survival time of about 5 years.4-6 Only 2 untreated patients who have survived for more than 10 years have been described in the literature. 1• 7 In these patients nephrectomy was performed 8 and 9 years after diagnosis, respectively. Analysis of the tumor deoxyribonucleic acid (DNA) content has been shown to provide reliable prognostic information on renal cell carcinoma.8 • 9 We report a case of renal cell carcinoma in a solitary kidney for 35 years before nephrectomy and without evidence of metastases. DNA analysis was performed on paraffin embedded, archival and fresh samples from this tumor. CASE REPORT
A 71-year-old woman noticed in 1951 a palpable mass in the right upper quadrant of the abdomen. A year later the mass had grown but the patient was not admitted to the hospital until 1955. According to hospital records, excretory urography (IVP) revealed a huge renal mass. Angiography showed a hypovascular renal tumor on the right side and renal agenesis on the left side. At exploration the tumor involved almost the entire right kidney. Partial resection was deemed impossible and 2 biopsies were taken for histopathological examination. The predominant symptoms suffered by the patient during the next 31 years were intermittent hematuria and ureteral colic. Repeated episodes of ureteral obstruction by blood clots were managed by ureteral catheterization, transureteral extraction of blood clots and local infusion of streptokinase. The serum creatinine remained normal or slightly elevated until 1980, when it began to increase continuously. Glomerular filtration rate decreased from 146 ml. per minute (creatinine clearance) in 1962 to 22 ml. per minute (chromium-ethylenediaminetetraacetic acid clearance) in 1983. Owing to permanent anuria hemodialysis became necessary in July 1986 and in August perifascial nephrectomy was performed. The inferior vena cava was resected because of invastion by a tumor thrombus that reached the level of the lower hepatic veins. After nephrectomy the patient continued on chronic hemodialysis and at 7-month followup she was healthy with no evidence of tumor recurrence.
RADIOLOGICAL EVALUATION
The radiograms from 1955 were not available. On the IVP from 1960 the tumor measured 14 x 15 cm. Selective renal angiography in 1986 revealed a moderately hypervascular lesion. The size of the tumor was unchanged compared to the 1960 IVP (fig. 1), although calcifications in the tumor had increased considerably during this period. In 1986 the patient was examined preoperatively by pulmonary x-ray, computerized tomography, ultrasonography, inferior venacavography, skeletal scintigraphy and angiography of the liver and kidney. There were no signs of distant metastases. HISTOPATHOLOGICAL EXAMINATION
The 2 paraffin embedded biopsies from 1955 were reviewed and, according to Skinner and associates, 3 the tumor was classified as grade 2 (fig. 2, A). In 1986 the tumor involved almost the entire nephrectomized kidney and it measured about 15 X 12 x 10 cm. A sample from the remaining renal cortex and 8 tumor tissue samples were taken for morphological examination and DNA analysis as described previously. 10 Four additional tumor samples were fixed in formalin and embedded in paraffin. The tumor contained many necrotic and fibrotic areas, and it was classified as grade 2/3 (fig. 2, B ). There was invasion into the vena cava but no tumor growth through the renal capsule. Microscopically, the tumor was sharply demarcated from the surrounding tissues. DNA ANALYSIS
Flow cytometry of fresh and paraffin embedded tissues was performed as described previously using propidium-iodide staining and a FACS analyzer flow cytometer*. 11 The paraffin embedded surgical biopsies from 1955 showed aneuploidy with a DNA index estimated at 1.4 (fig. 3, a and b ). Analysis of the tumor samples from 1986 revealed a similar aneuploid population with a DNA index of 1.3 in the 4 paraffin embedded (fig. 3, c and d) and in the 8 fresh tumor samples (fig. 3, e and/). Furthermore, in 1 of the 8 fresh tumor samples a second peak with a DNA index of 2.5 was noted (fig. 3, /). In another sample a possible cell population with a DNA index of 1. 7 was found (not shown). Assignment of cells to different cell cycle phases was performed using the consort-30 ands-fit softwares,* which allowed for proper analysis of 3 paraffin embedded samples from 1986. The obtained s-phase fractions were 4, 7 and 8 per cent, respectively. * Becton-Dickinson, Sunnyvale, California.
Accepted for publication July 17, 1987. 350
RENAL CELL CARCINOMA IN SOLITARY KIDNEY
351
FIG. 1. A, IVP from 1960. B, selective renal angiogram from 1986
FIG. 2. Light micrographs of renal cell carcinoma. A, biopsy sample from 1955. B, representative part of removed tumor in 1986. Reduced from X220.
DISCUSSION
To our knowledge our patient represents the longest reported survivor of those with untreated renal cell carcinoma. 1· 7 Although she had a solitary kidney, partial nephrectomy by bench surgery5 might have been possible at the time of diagnosis. However, such treatment would have been doubtful since at that time the tumor was large. In 1986 partial nephrectomy was proved to be impossible, as judged by examination of the nephrectomized kidney. The long survival of our patient is interesting. Although vena caval invasion was noted there was no tumor growth through the renal capsule. It should be emphasized that invasion of the vena cava alone does not alter the prognosis compared to tumors confined to the kidney (stage 1). 2 • 3 It has been shown previously that if renal cell carcinoma arises in a solitary kidney the average survival is superior to asynchronous bilateral tumors.5·6 During the 26 years of radiological followup no obvious increase in tumor size was noted, which must be a reflection of a balance among cell proliferation, cell arrest and cell death. The specific factors modulating such a balance remain unknown but it has been reported in renal cell carcinoma that cell loss and large nonproliferating compartments can contribute to a delay in tumor progression. 10 The tumor in our case was characterized by large necrotic areas and during the years increasing amounts of calcifications. Speculatively, tumor necrosis factors, interferons, tumor angiogenic factors and different growth factors might act directly and indirectly in a scenario leading to a stable disease state. 12 The mechanism for the apparently stable disease in our patient might be similar to the
mechanism of spontaneous regression most commonly reported in renal cell carcinoma. 13 It has been shown that the tumor DNA content can provide reliable prognostic information for patients with renal cell carcinoma. 8 • 9 • 14 The tumor in our case was aneuploid with a DNA index of 1.3. Tumors with an aneuploid DNA content near the diploid region might possibly have a better prognosis than aneuploid tumors with larger DNA indexes. In a previous study using static cytometry, a method with lower resolution than flow cytometry, 11 some of the patients surviving for more than 10 years had tumor DNA indexes of about 1.25 and the tumors were denominated as a diploid/near diploid DNA content in that study. 8 However, it must be stressed that the tumor DNA content in individual patients might provide less prognostic information than other factors of importance for tumor progression. We have reported previously a frequent intratumoral heterogeneity of the DNA content in renal cell carcinoma. 15 In the tumor in our case the DNA indexes were about the same in 1955 and 1986 but 2 of the 12 new samples each contained an additional aneuploid clone. Analysis of more samples in 1986 might explain the finding of these additional aneuploid peaks. The tumor was rather genetically stable as judged by the DNA content. It has been found that genetic instability of tumors often is associated with a highly malignant character. 16 Thus, the relatively homogeneous DNA content might be a parameter of importance for the benign clinical course of our patient. REFERENCES 1. Riches, E.: The natural history of renal tumors. In: Tumors of the Kidney and Ureter. Baltimore: The Williams & Wilkins Co., pp. 124-134, 1964. 2. Angervall, L. and W ahlqvist, L.: Follow-up and prognosis of renal cell carcinoma in a series operated by perifascial nephrectomy combined with adrenalectomy and retroperitoneal lymphadenectomy. Eur. Urol., 4: 13, 1978. 3. Skinner, D. G., Colvin, R. B., Vermillion, C. D., Pfister, R. C. and Leadbetter, W. F.: Diagnosis and management of renal cell carcinoma. A clinical and pathologic study of 309 cases. Cancer, 28: 1165, 1971. 4. Smith, R. B., deKernion, J.B., Ehrlich, R. M., Skinner, D. G. and Kaufman, J. J.: Bilateral renal cell carcinoma and renal cell carcinoma in the solitary kidney. J. Urol., 132: 450, 1984. 5. Wickham, J.E. A.: Conservative renal surgery for adenocarcinoma: the place of bench surgery. Brit. J. Urol., 47: 25, 1975. 6. Malek, R. S., Utz, D. C. and Culp, 0. S.: Hypernephroma in the solitary kidney: experience with 20 cases and review of the literature. J. Urol., 116: 553, 1976. 7. Carlson, H. E. and Ockerblad, N. F.: A case of unoperated hypernephroma of 10 years' duration. Amer. J. Roentgen., 45: 221, . 1941. 8. Ljungberg, B., Forsslund, G., Stenling, R. and Zetterberg, A.: Prog-
352
LJUNGBERG AND ASSOCIATES
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_J _J
d
LU (.)
0
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DNA CONTENT (index) FIG. 3. Flow cytometry DNA histograms. a and b, paraffin embedded tumor samples from 1955. c and d, paraffin embedded samples from 1986. e and f, fresh tumor samples. In addition to ploidy level at 1.3 another peak at 2.5 is demonstrated in part /.
9. 10. 11. 12.
nostic significance of the DNA content in renal cell carcinoma. J. Urol., 135: 422, 1986. Otto, U., Baisch, H., Huland, H. and Kliippel, G.: Tumor cell deoxyribonucleic acid content and prognosis in human renal cell carcinoma. J. Urol., 132: 237, 1984. Rabes, H. M., Carl, P., Meister, P. and Rattenhuber, U.: Analysis of proliferative compartments in human tumors: I. Renal adenocarcinoma. Cancer, 44: 799, 1979. Roos, G., Stenling, R. and Ljungberg, B.: DNA content in renal cell carcinoma-a comparison between flow and static cytometric methods. Scand. J. Urol. Nephrol., 20: 295, 1986. Droller, M. J.: Immunotherapy and genitourinary neoplasia: an
overview. World J. Urol., 3: 200, 1986. 13. Katz, S. E. and Schapira, H. E.: Spontaneous regression of genitourinary cancer-an update. J. Urol., 128: 1, 1982. 14. Rainwater, L. M., Hosaka, Y., Farrow, G. M. and Lieber, M. M.: Well differentiated clear cell renal carcinoma: significance of nuclear deoxyribonucleic acid patterns studied by flow cytometry. J. Urol., 137: 15, 1987. 15. Ljungberg, B., Stenling, R. and Roos, G.: DNA content in renal cell carcinoma with reference to tumor heterogeneity. Cancer, 56: 503, 1985. 16. Nicolson, G. L.: Generation ofphenotypic diversity and progression in metastatic tumor cells. Cancer Met. Rev., 3: 25, 1984.