Vol. 117, April
THE JOURNAL OF UROWGY Copyright © 1977 by The Williams & Wilkins Co.
Printed in U.S.A.
BILATERAL RENAL CELL CARCINOMA IN VON RIPPEL-LINDAU SYNDROME: TREATMENT WITH STAGED BILATERAL NEPHRECTOMY AND HEMODIAL YSIS CHRIS D. FETNER,* DONALD E. BARILLA, T. SCOTT, JOHN BALLARD
AND
PAUL PETERS
From the Department of Urology and Internal Medicine, University of Texas Health Science Center, Dallas, Texas
ABSTRACT
A case of bilateral renal cell carcinoma associated with von Rippel-Lindau syndrome and treated successfully with staged bilateral nephrectomy and hemodialysis is reported. The literature is reviewed with special emphasis on early diagnosis based on family history. Hemodialysis is a logical treatment modality. This disease, unlike adult renal cell carcinoma, is multifocal and poorly treated with partial nephrectomy. The von Hippel-Lindau syndrome (Lindau's syndrome) consists of cerebellar hemangioblastomas (present in one-third of the cases) and/or retinal angiomas (present in one-half of the cases) associated with hemangiomas of the spinal cord, cysts of the pancreas, kidney, lung or epididymis, and unilateral or bilateral renal cell carcinoma. 1 • 2 A strong family history plus one of the aforementioned findings also is presumptive evidence for Lindau's syndrome. Common features include hereditary causation (autosomal dominant with 12 to 90 per cent variable penetrance), slow evolution oflesions from childhood through adolescence and a predilection for the renal lesion to undergo malignant transformation. 8 Approximately 22 per cent of the patients with cerebellar hemangioblastomas will have or develop Lindau's syndrome. 4 Pheochromocytoma also is associated with Lindau's syndrome, is often bilateral and tends to occur in certain families affiicted with this disease. 5 The renal lesion consists of a simple cyst or adenocarcinoma and has been reported to be present in 45 to 60 per cent of autopsied patients and in 25 per cent of patients diagnosed before death. &-s The renal lesions are usually late manifestations of the disease and may be observed more frequently as an increased number of patients survive the cerebellar lesion. Herein we report the first case of bilateral renal cell carcinoma associated with Lindau's syndrome and treated with bilateral radical nephrectomy and hemodialysis.
hemangioma. Treatment consisted of laminectomy and primary removal followed by postoperative irradiation. In April 1976 the patient presented to our urology service with total gross painless hematuria. Important physical find-
CASE REPORT
H. N., 44640-0293, a 34-year-old white man, was recalled from Korea in 1964 after his sister died ofrenal cell carcinoma metastatic to the lung and heart, and retinal angiomas diagnosed at autopsy. Of 5 children in the same family 2 were found to have retinal angiomas. The patient's father died of a brain tumor when he was 54 years old and his paternal grandfather died of an unexplained illness when he was 27 years old. Physical examination revealed bilateral angiomas of the retina. The patient was treated with laser photocoagulation from 1964 to 1967, eventually losing eyesight in the left eye and retaining sight in the right eye. A brain scan was normal in 1964 and 1967. A renal angiogram was performed in 1967 and also was reported as normal (Walter Reed Hospital). In May 1975 the patient suffered numbness, pruritus and dysesthesia in the right lower extremity. A myelogram at Brooke Army Hospital revealed a lesion extending from T6 to L2, which was discovered at operation to be an intramedullary Accepted for publication November 24, 1976. *Requests for reprints: Department of Urology, University of Texas Health Science Center, Southwestern Medical School, Dallas, Texas 75235. 534
Fm~ 1
ings included normal blood pressure. There was no vision in the left eye and an arrested angioma of the right eye. There were no abdominal or flank masses. A left epididymal mass that transmitted light was noted. Loss of sensation, paresthe-
535
IiE.IVIODL4.LY8IS lN Lll\iDAU 5 S SY'!'.JDR0IV1:E
FIG. 2
FIG. 3
sias and of the right lower extremity were present. Retrograde revealed bilateral renal masses and a renal a.rteriogram suggested bilateral renal cell cancer, ,,vhich was v10rse on the left side 1 and 2). Brain, liver and EMI scans were normal. A chest tomogTam and complete blood count ·were normal. Sedimentation rate was elevated to 30 mm. per hour and urinalysis showed numerous red blood cells. Serum haptoglobin was elevated to 333 µ.g. per 100 ml. (50 to 270 normal). Creatinine clearance was 75 ml. per minute. A partial nephrectomy was attempted on the right side but was unsuccessful because of multiple foci of adenocarcinoma throughout the right kidney, necessitating a radical right nephrectomy. A month later a left radical nephrectomy and placement of a Schribner shunt for hemodialysis were performed. The patient is doing well on hemodialysis with no evidence of recurrent cancer 8 months postoperatively. Gross and microscopic examination revealed extensive clear cell adenocarcinoma of both kidneys with minimal capsular invasion on the right side and renal vein involvement on the left side (fig. 3). If the patient survives 5 years on hemodialysis with no evidence of recurrent cancer he will be considered for transplantation.
DISCUSSION
Bilateral primary renal neoplasms in adults are rare, with an over-all incidence of 1.8 per cent, 9 and generally are associated with a poor prognosis. 10- 17 The most common bilateral renal neoplasm is 'iNilms tumor in the child, with a 3.6 per cent incidence. 18 In adults bilateral renal cell carcinoma is associated with Lindau's syndrome 19 and tuberous sclerosis. 20 Lindau originally considered the renal lesion as benign but Kernohan21 and others 2· 22 · 23 clearly demonstrated the malignant potential of the renal neoplasm similar to non-familial renal cell carcinoma in adults. A review of the literature with respect to renal cell carcinoma associated with Lindau's syndrome reveals the following points. 3 • 7 • 19• 21- 26 1) The majority of patients with renal cell carcinoma, as part of the Lindau's syndrome, have involvement of both kidneys. This is particularly true if the patient survives past the age of 50 years and it suggests a bilateral developmental defect. 2) The diagnosis of renal cell carcinoma is made over a wide time range, which varies from months to 14 years. This is partly owing to the heterogeneous nature of the malignancy and to the frequent failure in following suspected cases. Annual excretory uro-
536
FETNER AND ASSOCIATES
grams and angiograrr..s are appropriate in high risk patients. 3) Attempts to save a portion of 1 kidney when both are involved with cancer universally have failed because of the multifocal nature of the disease. 4) Annual screening of family members may reveal asymptomatic affected individuals. Richards and associates have performed 4 unilateral nephrectomies in affected patients, 2 of whom were asymptomatic. 26 However, the occurrence of malignant degeneration in the opposite kidney remains a distinct possibility. In summary, bilateral radical nephrectomy and hemodialysis may be a viable alternative in patients with proved bilateral lesions. REFERENCES
1. von Rippel, E.: Ueber eine sehr seltene Erkrankung der Netzhaut: Klinische Beobachtungen. Arch. f. Ophth., 59: 83, 1904. 2. Lindau, A.: Studien iiber Kleinhirncysten: Bau, Pathogenese und Beziehungen zur Angiomatosis Retinae. Acta Path. Microbiol. Scand., suppl. 1, p. 1, 1926. 3. Lauritsen, J. G.: Lindau's disease. A study of one family through six generations. Acta Chir. Scand., 139: 482, 1973. 4. Silver, M. L. and Hennigar, G. R.: Cerebellar hemangioma (hemangioblastoma); clinicopathological review of 40 cases. J. Neurosurg., 9: 484, 1952. 5. Chapman, R. C., Kemp, V. E. and Taliaferro, I.: Pheochromocytoma associated with multiple neurofibromatosis and intracranial hemangioma. Amer. J. Med., 26: 883, 1959. 6. Lindau, A.: Zur Frage der Angiomatosis retinae und ihrer Hirnkomplikationen. Acta Ophth., 4: 193, 1927. 7. Christoferson, L.A., Gustafson, M. B. and Petersen, A. G.: von Hippel-Lindau's disease. J.A.M.A., 178: 280, 1961. 8. Horton W. A., Wong, V. and Eldridge, R.: von Rippel-Lindau disease: clinical and pathological manifestations in nine families with 50 affected members. Arch. Intern. Med., 136: 76b, 1976. 9. Vermillion, C. D., Skinner, D. G. and Pfister, R. C.: Bilateral renal cell carcinoma. J. Urol., 108: 219, 1972. 10. Marshall, F. and Johnson, A. J.: Double primary urinary tumors: case report. J. Urol., 85: 724, 1961.
11. Hermann, H. B. and Lieberman, M. L.: Bilateral renal carcinoma. N. Y. State J. Med., 55: 1915, 1955. 12. Bailey, M. K. and Youngblood, V. H.: Bilateral renal hypernephroma: report of a case. J. Urol., 63: 593, 1950. 13. Hillenbrand, H. J. and Horstebrock, R.: Doppelseitige Nierenkarzinome. Z. Urol., 50: 396, 1957. 14. Borski, A. A. and Kimbrough, J. C.: Bilateral carcinoma in polycystic renal disease-an unique case. J. Urol., 71: 677, 1954. 15. Alnor, P. C.: Doppelseitige Nierentumoren, ein Beitrag zur Differentialdiagnose. Z. Urol., 45: 693, 1952. 16. Rummelhardt, S.: Gleichzeitiges Auftreten eines beidseitigen Hypernephroms. Z. Urol., 46: 658, 1953. 17. Senger, F. L., Bottone, J. J. and Murray, G.: Bilateral hypernephroma: case report. J. Urol., 57: 106, 1947. 18. Scott, L. S.: Bilateral Wilms' tumour. Brit. J. Surg., 42: 513, 1955. 19. Kaplan, C., Sayre, G. P. and Greene, L. F.: Bilateral nephrogenic carcinomas in Lindau-von Rippel disease. J. Urol., 86: 36, 1961. 20. Golji, H.: Tuberous sclerosis and renal neoplasms. J. Urol., 85: 919, 1961. 21. Kernohan, J. W., Woltman, H. W. and Adson, A. W.: Intramedullary tumors of the spinal cord: a review of fifty-one cases, with attempt at histologic classification. Arch. Neurol. & Psychiat., 25: 679, 1931. 22. Tanning, H. 0., Warren, R. F. and Barrie, H. J.: Familial haemangiomata of the cerebellum; report of 3 cases in a family of 4. J. Neurosurg., 9: 124, 1952. 23. Melman, K. L. and Rosen, S. W.: Lindau's disease. Review of the literature and study of a large kindred. Amer. J. Med., 36: 595, 1964. 24. Wright, F. W.: Bilateral renal-cell carcinomas. Radiology, 115: 543, 1975. 25. Isaac, F., Schoen, I. and Walker, P.: Unusual case of Lindau's disease; cystic disease of kidneys and pancreas with renal and cerebellar tumors. Amer. J. Roentgen., 75: 912, 1956. 26. Richards, R. D., Mebust, W. K. and Schimke, R. N.: A prospective study of von Rippel-Lindau disease. J. Urol., 110: 27, 1973.
THE JOURNAL OF UROWGY Copyright © 1977 by The Williams & Wilkins Co.
Printed in U.S.A.
BILATERAL RENAL CELL CARCINOMA IN VON RIPPEL-LINDAU SYNDROME: TREATMENT WITH STAGED BILATERAL NEPHRECTOMY AND HEMODIAL YSIS CHRIS D. FETNER,* DONALD E. BARILLA, T. SCOTT, JOHN BALLARD
AND
PAUL PETERS
From the Department of Urology and Internal Medicine, University of Texas Health Science Center, Dallas, Texas
ABSTRACT
A case of bilateral renal cell carcinoma associated with von Rippel-Lindau syndrome and treated successfully with staged bilateral nephrectomy and hemodialysis is reported. The literature is reviewed with special emphasis on early diagnosis based on family history. Hemodialysis is a logical treatment modality. This disease, unlike adult renal cell carcinoma, is multifocal and poorly treated with partial nephrectomy. The von Hippel-Lindau syndrome (Lindau's syndrome) consists of cerebellar hemangioblastomas (present in one-third of the cases) and/or retinal angiomas (present in one-half of the cases) associated with hemangiomas of the spinal cord, cysts of the pancreas, kidney, lung or epididymis, and unilateral or bilateral renal cell carcinoma. 1 • 2 A strong family history plus one of the aforementioned findings also is presumptive evidence for Lindau's syndrome. Common features include hereditary causation (autosomal dominant with 12 to 90 per cent variable penetrance), slow evolution oflesions from childhood through adolescence and a predilection for the renal lesion to undergo malignant transformation. 8 Approximately 22 per cent of the patients with cerebellar hemangioblastomas will have or develop Lindau's syndrome. 4 Pheochromocytoma also is associated with Lindau's syndrome, is often bilateral and tends to occur in certain families affiicted with this disease. 5 The renal lesion consists of a simple cyst or adenocarcinoma and has been reported to be present in 45 to 60 per cent of autopsied patients and in 25 per cent of patients diagnosed before death. &-s The renal lesions are usually late manifestations of the disease and may be observed more frequently as an increased number of patients survive the cerebellar lesion. Herein we report the first case of bilateral renal cell carcinoma associated with Lindau's syndrome and treated with bilateral radical nephrectomy and hemodialysis.
hemangioma. Treatment consisted of laminectomy and primary removal followed by postoperative irradiation. In April 1976 the patient presented to our urology service with total gross painless hematuria. Important physical find-
CASE REPORT
H. N., 44640-0293, a 34-year-old white man, was recalled from Korea in 1964 after his sister died ofrenal cell carcinoma metastatic to the lung and heart, and retinal angiomas diagnosed at autopsy. Of 5 children in the same family 2 were found to have retinal angiomas. The patient's father died of a brain tumor when he was 54 years old and his paternal grandfather died of an unexplained illness when he was 27 years old. Physical examination revealed bilateral angiomas of the retina. The patient was treated with laser photocoagulation from 1964 to 1967, eventually losing eyesight in the left eye and retaining sight in the right eye. A brain scan was normal in 1964 and 1967. A renal angiogram was performed in 1967 and also was reported as normal (Walter Reed Hospital). In May 1975 the patient suffered numbness, pruritus and dysesthesia in the right lower extremity. A myelogram at Brooke Army Hospital revealed a lesion extending from T6 to L2, which was discovered at operation to be an intramedullary Accepted for publication November 24, 1976. *Requests for reprints: Department of Urology, University of Texas Health Science Center, Southwestern Medical School, Dallas, Texas 75235. 534
Fm~ 1
ings included normal blood pressure. There was no vision in the left eye and an arrested angioma of the right eye. There were no abdominal or flank masses. A left epididymal mass that transmitted light was noted. Loss of sensation, paresthe-
535
IiE.IVIODL4.LY8IS lN Lll\iDAU 5 S SY'!'.JDR0IV1:E
FIG. 2
FIG. 3
sias and of the right lower extremity were present. Retrograde revealed bilateral renal masses and a renal a.rteriogram suggested bilateral renal cell cancer, ,,vhich was v10rse on the left side 1 and 2). Brain, liver and EMI scans were normal. A chest tomogTam and complete blood count ·were normal. Sedimentation rate was elevated to 30 mm. per hour and urinalysis showed numerous red blood cells. Serum haptoglobin was elevated to 333 µ.g. per 100 ml. (50 to 270 normal). Creatinine clearance was 75 ml. per minute. A partial nephrectomy was attempted on the right side but was unsuccessful because of multiple foci of adenocarcinoma throughout the right kidney, necessitating a radical right nephrectomy. A month later a left radical nephrectomy and placement of a Schribner shunt for hemodialysis were performed. The patient is doing well on hemodialysis with no evidence of recurrent cancer 8 months postoperatively. Gross and microscopic examination revealed extensive clear cell adenocarcinoma of both kidneys with minimal capsular invasion on the right side and renal vein involvement on the left side (fig. 3). If the patient survives 5 years on hemodialysis with no evidence of recurrent cancer he will be considered for transplantation.
DISCUSSION
Bilateral primary renal neoplasms in adults are rare, with an over-all incidence of 1.8 per cent, 9 and generally are associated with a poor prognosis. 10- 17 The most common bilateral renal neoplasm is 'iNilms tumor in the child, with a 3.6 per cent incidence. 18 In adults bilateral renal cell carcinoma is associated with Lindau's syndrome 19 and tuberous sclerosis. 20 Lindau originally considered the renal lesion as benign but Kernohan21 and others 2· 22 · 23 clearly demonstrated the malignant potential of the renal neoplasm similar to non-familial renal cell carcinoma in adults. A review of the literature with respect to renal cell carcinoma associated with Lindau's syndrome reveals the following points. 3 • 7 • 19• 21- 26 1) The majority of patients with renal cell carcinoma, as part of the Lindau's syndrome, have involvement of both kidneys. This is particularly true if the patient survives past the age of 50 years and it suggests a bilateral developmental defect. 2) The diagnosis of renal cell carcinoma is made over a wide time range, which varies from months to 14 years. This is partly owing to the heterogeneous nature of the malignancy and to the frequent failure in following suspected cases. Annual excretory uro-
536
FETNER AND ASSOCIATES
grams and angiograrr..s are appropriate in high risk patients. 3) Attempts to save a portion of 1 kidney when both are involved with cancer universally have failed because of the multifocal nature of the disease. 4) Annual screening of family members may reveal asymptomatic affected individuals. Richards and associates have performed 4 unilateral nephrectomies in affected patients, 2 of whom were asymptomatic. 26 However, the occurrence of malignant degeneration in the opposite kidney remains a distinct possibility. In summary, bilateral radical nephrectomy and hemodialysis may be a viable alternative in patients with proved bilateral lesions. REFERENCES
1. von Rippel, E.: Ueber eine sehr seltene Erkrankung der Netzhaut: Klinische Beobachtungen. Arch. f. Ophth., 59: 83, 1904. 2. Lindau, A.: Studien iiber Kleinhirncysten: Bau, Pathogenese und Beziehungen zur Angiomatosis Retinae. Acta Path. Microbiol. Scand., suppl. 1, p. 1, 1926. 3. Lauritsen, J. G.: Lindau's disease. A study of one family through six generations. Acta Chir. Scand., 139: 482, 1973. 4. Silver, M. L. and Hennigar, G. R.: Cerebellar hemangioma (hemangioblastoma); clinicopathological review of 40 cases. J. Neurosurg., 9: 484, 1952. 5. Chapman, R. C., Kemp, V. E. and Taliaferro, I.: Pheochromocytoma associated with multiple neurofibromatosis and intracranial hemangioma. Amer. J. Med., 26: 883, 1959. 6. Lindau, A.: Zur Frage der Angiomatosis retinae und ihrer Hirnkomplikationen. Acta Ophth., 4: 193, 1927. 7. Christoferson, L.A., Gustafson, M. B. and Petersen, A. G.: von Hippel-Lindau's disease. J.A.M.A., 178: 280, 1961. 8. Horton W. A., Wong, V. and Eldridge, R.: von Rippel-Lindau disease: clinical and pathological manifestations in nine families with 50 affected members. Arch. Intern. Med., 136: 76b, 1976. 9. Vermillion, C. D., Skinner, D. G. and Pfister, R. C.: Bilateral renal cell carcinoma. J. Urol., 108: 219, 1972. 10. Marshall, F. and Johnson, A. J.: Double primary urinary tumors: case report. J. Urol., 85: 724, 1961.
11. Hermann, H. B. and Lieberman, M. L.: Bilateral renal carcinoma. N. Y. State J. Med., 55: 1915, 1955. 12. Bailey, M. K. and Youngblood, V. H.: Bilateral renal hypernephroma: report of a case. J. Urol., 63: 593, 1950. 13. Hillenbrand, H. J. and Horstebrock, R.: Doppelseitige Nierenkarzinome. Z. Urol., 50: 396, 1957. 14. Borski, A. A. and Kimbrough, J. C.: Bilateral carcinoma in polycystic renal disease-an unique case. J. Urol., 71: 677, 1954. 15. Alnor, P. C.: Doppelseitige Nierentumoren, ein Beitrag zur Differentialdiagnose. Z. Urol., 45: 693, 1952. 16. Rummelhardt, S.: Gleichzeitiges Auftreten eines beidseitigen Hypernephroms. Z. Urol., 46: 658, 1953. 17. Senger, F. L., Bottone, J. J. and Murray, G.: Bilateral hypernephroma: case report. J. Urol., 57: 106, 1947. 18. Scott, L. S.: Bilateral Wilms' tumour. Brit. J. Surg., 42: 513, 1955. 19. Kaplan, C., Sayre, G. P. and Greene, L. F.: Bilateral nephrogenic carcinomas in Lindau-von Rippel disease. J. Urol., 86: 36, 1961. 20. Golji, H.: Tuberous sclerosis and renal neoplasms. J. Urol., 85: 919, 1961. 21. Kernohan, J. W., Woltman, H. W. and Adson, A. W.: Intramedullary tumors of the spinal cord: a review of fifty-one cases, with attempt at histologic classification. Arch. Neurol. & Psychiat., 25: 679, 1931. 22. Tanning, H. 0., Warren, R. F. and Barrie, H. J.: Familial haemangiomata of the cerebellum; report of 3 cases in a family of 4. J. Neurosurg., 9: 124, 1952. 23. Melman, K. L. and Rosen, S. W.: Lindau's disease. Review of the literature and study of a large kindred. Amer. J. Med., 36: 595, 1964. 24. Wright, F. W.: Bilateral renal-cell carcinomas. Radiology, 115: 543, 1975. 25. Isaac, F., Schoen, I. and Walker, P.: Unusual case of Lindau's disease; cystic disease of kidneys and pancreas with renal and cerebellar tumors. Amer. J. Roentgen., 75: 912, 1956. 26. Richards, R. D., Mebust, W. K. and Schimke, R. N.: A prospective study of von Rippel-Lindau disease. J. Urol., 110: 27, 1973.
