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Mcclellan M. Walther - One of the best experts on this subject based on the ideXlab platform.
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the relationship between renal tumor size and metastases in patients with Von hippel lindau Disease
The Journal of Urology, 2005Co-Authors: Branden G Duffey, Marston W Linehan, Peter L Choyke, G M Glenn, Robert L Grubb, David Venzon, Mcclellan M. WaltherAbstract:Purpose Patients with Von Hippel-Lindau Disease are at risk for multiple, bilateral, recurrent renal tumors and metastases. We previously evaluated the relationship between tumor size and metastases in families with hereditary renal cancer. We update our findings with about twice the number of patients with Von Hippel-Lindau Disease. Materials and methods Screening affected kindred or retrospective review of medical records identified 181 patients with Von Hippel-Lindau Disease and renal cell carcinoma. Patients with small tumors were followed with serial imaging until the largest tumor reached 3 cm, at which point surgery was recommended. Surgical resection was recommended to patients with tumors larger than 3 cm. Patients not undergoing screening often had large renal tumors. Results A total of 108 patients with Von Hippel-Lindau Disease and solid renal tumors on computerized tomography imaging smaller than 3 cm (group 1) were followed a mean of 58 months (range 0 to 244). Metastatic Disease did not develop in any of these patients. Renal tumors larger than 3 cm developed in 73 patients with Von Hippel-Lindau Disease (group 2). Mean followup of group 2 was 72.9 months (range 0 to 321). The proportion of procedures that were nephron sparing was higher in group 1 than in group 2 (120 of 125 [97%] compared to 85 of 125 [69%], Fisher's exact test p Conclusions No renal tumor metastases were found in patients with renal tumors less than 3 cm in diameter. We advocate a 3 cm threshold for parenchymal sparing surgery in patients with Von Hippel-Lindau Disease to decrease the risk of metastatic Disease while preserving renal function, avoiding or delaying the need for dialysis and/or renal transplant, and decreasing the number of operations which a patient may undergo. We stress the importance of early screening in the kindred of patients with Von Hippel-Lindau Disease and vigilant followup thereafter.
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parenchymal sparing surgery in patients with hereditary renal cell carcinoma 10 year experience
The Journal of Urology, 2001Co-Authors: Judi Herring, Marston W Linehan, Peter L Choyke, Erik Enquist, Allen Chernoff, Mcclellan M. WaltherAbstract:Purpose: Von Hippel-Lindau Disease, hereditary papillary renal cell carcinoma, the Birt-Hogg-Dube syndrome and familial renal oncocytoma are familial renal tumor syndromes. These hereditary disorders are noteworthy for the development of multiple bilateral renal tumors and the risk of new tumors throughout life. One management strategy is observation of solid renal tumors until reaching 3 cm., then performing parenchymal sparing surgery. We present a 5-year update on our experience.Materials and Methods: From May 1988 to October 1998, 49 patients with hereditary renal cell carcinoma, including Von Hippel-Lindau Disease in 44, hereditary papillary renal cell carcinoma in 4 and the Birt-Hogg-Dube syndrome in 1, and 1 with familial renal oncocytoma underwent exploration to attempt renal parenchymal sparing surgery. Patients were followed prospectively with periodic screening for recurrence, metastasis and loss of renal function. Median followup was 79.5 months (range 0.7 to 205).Results: A total of 50 patien...
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mosaicism in Von hippel lindau Disease lessons from kindreds with germline mutations identified in offspring with mosaic parents
American Journal of Human Genetics, 2000Co-Authors: M T Sgambati, Mcclellan M. Walther, W M Linehan, Peter L Choyke, Berton Zbar, Catherine A Stolle, G M GlennAbstract:Von Hippel-Lindau Disease (VHL [MIM 193300]) is a heritable autosomal dominant multiple-neoplastic disorder with high penetrance. It is characterized by brain and spinal-cord hemangioblastomas, retinal angiomas, clear-cell renal carcinoma, neuroendocrine tumors and cysts of the pancreas, pheochromocytomas, endolymphatic-sac tumors, and papillary cystadenomas of the epididymis and broad ligament. Although most index cases have a positive family history of VHL, some do not and may represent de novo cases. Cases without a family history of VHL may or may not have a germline mutation in their VHL tumor-suppressor gene. We present two cases of VHL mosaicism. In each of two families, standard testing methods (Southern blot analysis and direct sequencing) identified the germline mutation in the VHL gene of the offspring, but not in their clinically affected parent. Additional methods of analysis of the affected parents' blood detected the VHL-gene mutation in a portion of their peripheral blood lymphocytes. In one case, detection of the deleted allele was by FISH, and, in the second case, the 3-bp deletion was detected by conformational sensitive gel electrophoresis and DNA sequencing of cloned genomic DNA. Mosaicism in VHL is important to search for and recognize when an individual without a family history of VHL has VHL. Patients diagnosed without family histories of the Disease have been reported in as many as 23% of kindreds with VHL. Identification of individuals potentially mosaic for VHL will affect counseling of families, and these individuals should themselves be included in clinical screening programs for occult Disease.
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plasma normetanephrine and metanephrine for detecting pheochromocytoma in Von hippel lindau Disease and multiple endocrine neoplasia type 2
The New England Journal of Medicine, 1999Co-Authors: Graeme Eisenhofer, Jacques W.m. Lenders, David S. Goldstein, Mcclellan M. Walther, W M Linehan, Harry R KeiserAbstract:Background The detection of pheochromocytomas in patients at risk for these tumors, such as patients with Von Hippel–Lindau Disease or multiple endocrine neoplasia type 2 (MEN-2), is hindered by the inadequate sensitivity of commonly available biochemical tests. In this study we evaluated measurements of plasma normetanephrine and metanephrine for detecting pheochromocytomas in patients with Von Hippel–Lindau Disease or MEN-2. Methods We studied 26 patients with Von Hippel–Lindau Disease and 9 patients with MEN-2 who had histologically verified pheochromocytomas and 50 patients with Von Hippel–Lindau Disease or MEN-2 who had no radiologic evidence of pheochromocytoma. Von Hippel–Lindau Disease and MEN-2 were diagnosed on the basis of germ-line mutations of the appropriate genes. The plasma concentrations of normetanephrine and metanephrine were compared with the plasma concentrations of catecholamines (norepinephrine and epinephrine) and urinary excretion of catecholamines, metanephrines, and vanillylmand...
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renal cancer in families with hereditary renal cancer prospective analysis of a tumor size threshold for renal parenchymal sparing surgery
The Journal of Urology, 1999Co-Authors: Mcclellan M. Walther, Peter L Choyke, G M Glenn, David Venzon, Chris J Lyne, W Rayford, Marston W LinehanAbstract:AbstractPurpose: Patients with hereditary forms of renal cancer are at risk for new tumors and metastases. Renal parenchymal sparing surgery has been performed to preserve renal function and quality of life, and prevent metastases. We evaluated a 3 cm. threshold for performing renal parenchymal sparing surgery in patients with Von Hippel-Lindau Disease and hereditary papillary renal cancer.Materials and Methods: Patients with Von Hippel-Lindau Disease or hereditary papillary renal cancer and renal cancer were identified by screening affected kindred and by kindred history. Patients with small tumors were followed with serial imaging studies until the large renal tumor was 3 cm., when renal parenchymal sparing surgery was performed. Renal tumors greater than 3 cm. were resected without delay. Parenchymal sparing techniques were used when possible in each group.Results: The 3 cm. surgical threshold was evaluated in 52 patients with Von Hippel-Lindau Disease (group 1) at a median followup of 60 months (range...
Marston W Linehan - One of the best experts on this subject based on the ideXlab platform.
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association of vhl genotype with pancreatic neuroendocrine tumor phenotype in patients with Von hippel lindau Disease
JAMA Oncology, 2018Co-Authors: Amit Tirosh, Samira M Sadowski, Naris Nilubol, Marston W Linehan, Steven K Libutti, Dhaval Patel, Electron KebebewAbstract:This study evaluates the natural history of Von Hippel–Lindau Disease–associated pancreatic lesions to determine the factors associated with pancreatic neuroendocrine tumor phenotype and prognosis.
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prevalence of microscopic lesions in grossly normal Disease sporadic renal cell carcinoma and no renal Disease clinical implications renal parenchyma from patients with Von hippel lindau
2010Co-Authors: M M Walther, David Venzon, Irina A Lubensky, Berton Zbar, Marston W LinehanAbstract:Purpose: We sought to describe the earliest renal lesions in patients with Von Hippel-Lindau Disease to gain insight into the genesis of renal neoplasms in this condition. Materials and Methods: Grossly normal renal parenchyma fiom Von Hippel-Lindau Disease patients was examined microscopically and compared to findings in similar tissues obtained from patients with sporadic renal cancer and from autopsy subjects with no renal Disease. Results: Microscopic renal cystic and solid neoplasms containing only clear cell cytological features were found in patients with Von Hippel-Lindau Disease. Benign cysts with clear cell cytological features were found only in patients with Von Hippel-Lindau Disease. Benign cysts lined by cuboidal cells with eosinophilic cytoplasm, similar to renal tubular cells, were present only in patients with renal cancer. The extrapolated number of clear cell lesions in an average kidney with Von Hippel-Lindau Disease was estimated as 1,100 cysts (benign or atypical) with clear cell lining and 600 clear cell neoplasms. Conclusions: These findings support the hypothesis that abnormalities in the Von HippelLindau gene in a kidney results in the cytological cell type of clear cell renal cancer as the initial product of cellular transformation. Von Hippel-Lindau Disease is an autosomal dominant disorder characterized by the presence of retinal angiomas, central nervous system hemangioblastomas, pancreatic cysts and tumors, pheochromocytomas and renal carcinomas.1 Inheritance of the syndrome has been linked to chromosome 3pZ-4 and, recently, the Von Hippel-Lindau gene has been identified.4 Patients with renal manifestations of Von HippelLindau Disease have a spectrum of Disease ranging from benign to malignant renal lesions. Because Von Hippel-Lindau Disease patients have inherited a gene that is linked to the formation of renal tumors, they frequently have multiple tumors and are at risk for new tumors throughout their lives.5. Several cytological cell types and architectural types have been described in the renal tumors removed from patients with Von Hippel-Lindau Disease.7.S To our knowledge the microscopic forms of these lesions have not been described previously. We examined grossly normal renal tissue from patients with Von Hippel-Lindau Disease for the presence of microscopic lesions that may represent potential precursors of renal cystic lesions and carcinomas. We compared these findings to the lesions present in grossly normal renal parenchyma from patients with advanced sporadic renal cell carcinoma and from those who died with no known renal carcinoma or other renal Disease. In addition, based on these findings we projected the prevalence of microscopic renal lesions present in this subgroup of patients with renal manifestations of Von Hippel-Lindau Disease.
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neurologic manifestations of Von hippel lindau Disease
JAMA, 2008Co-Authors: John A Butman, Marston W Linehan, Russell R LonserAbstract:Von Hippel-Lindau Disease (VHL) is an autosomal-dominant neoplasia syndrome that is the result of a germline mutation of the VHL tumor suppressor gene on the short arm of chromosome 3. Patients with VHL are predisposed to develop lesions of the central nervous system and viscera. Central nervous system lesions include hemangioblastomas (the most common tumor in VHL) and endolymphatic sac tumors (ELSTs). Visceral manifestations include renal carcinomas and cysts, pancreatic neuroendocrine tumors and cysts, pheochromocytomas, and cystadenomas of the reproductive adnexal organs. Despite their benign pathology, hemangioblastomas and ELSTs are a frequent cause of morbidity and mortality in patients with VHL. Recent molecular biologic investigations into these VHL-associated central nervous system lesions provide new insight into their origin and development. Emerging data from serial imaging and clinical surveillance protocols provide insight into the natural history of these lesions. Because of the dissimilar pathobiology and clinical course between hemangioblastomas and ELSTs, the optimal management strategies for these neurologic manifestations of VHL are very different.
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concurrent robotic partial adrenalectomy and extra adrenal pheochromocytoma resection in a pediatric patient with Von hippel lindau Disease
Journal of Endourology, 2008Co-Authors: Craig G Rogers, Marston W Linehan, Adam M Blatt, George E Miles, Peter A PintoAbstract:Laparoscopic partial adrenalectomy is a surgical option for select patients with hereditary pheochromocytoma. We present a case of a pediatric patient with Von Hippel-Lindau Disease (VHL) and both an adrenal pheochromocytoma and an extra-adrenal pheochromocytoma, who underwent concurrent partial adrenalectomy and extra-adrenal pheochromocytoma resection utilizing robotic assistance. To the best of our knowledge, this is the first report of partial adrenalectomy with concurrent extra-adrenal pheochromocytoma resection.
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the relationship between renal tumor size and metastases in patients with Von hippel lindau Disease
The Journal of Urology, 2005Co-Authors: Branden G Duffey, Marston W Linehan, Peter L Choyke, G M Glenn, Robert L Grubb, David Venzon, Mcclellan M. WaltherAbstract:Purpose Patients with Von Hippel-Lindau Disease are at risk for multiple, bilateral, recurrent renal tumors and metastases. We previously evaluated the relationship between tumor size and metastases in families with hereditary renal cancer. We update our findings with about twice the number of patients with Von Hippel-Lindau Disease. Materials and methods Screening affected kindred or retrospective review of medical records identified 181 patients with Von Hippel-Lindau Disease and renal cell carcinoma. Patients with small tumors were followed with serial imaging until the largest tumor reached 3 cm, at which point surgery was recommended. Surgical resection was recommended to patients with tumors larger than 3 cm. Patients not undergoing screening often had large renal tumors. Results A total of 108 patients with Von Hippel-Lindau Disease and solid renal tumors on computerized tomography imaging smaller than 3 cm (group 1) were followed a mean of 58 months (range 0 to 244). Metastatic Disease did not develop in any of these patients. Renal tumors larger than 3 cm developed in 73 patients with Von Hippel-Lindau Disease (group 2). Mean followup of group 2 was 72.9 months (range 0 to 321). The proportion of procedures that were nephron sparing was higher in group 1 than in group 2 (120 of 125 [97%] compared to 85 of 125 [69%], Fisher's exact test p Conclusions No renal tumor metastases were found in patients with renal tumors less than 3 cm in diameter. We advocate a 3 cm threshold for parenchymal sparing surgery in patients with Von Hippel-Lindau Disease to decrease the risk of metastatic Disease while preserving renal function, avoiding or delaying the need for dialysis and/or renal transplant, and decreasing the number of operations which a patient may undergo. We stress the importance of early screening in the kindred of patients with Von Hippel-Lindau Disease and vigilant followup thereafter.
G M Glenn - One of the best experts on this subject based on the ideXlab platform.
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the relationship between renal tumor size and metastases in patients with Von hippel lindau Disease
The Journal of Urology, 2005Co-Authors: Branden G Duffey, Marston W Linehan, Peter L Choyke, G M Glenn, Robert L Grubb, David Venzon, Mcclellan M. WaltherAbstract:Purpose Patients with Von Hippel-Lindau Disease are at risk for multiple, bilateral, recurrent renal tumors and metastases. We previously evaluated the relationship between tumor size and metastases in families with hereditary renal cancer. We update our findings with about twice the number of patients with Von Hippel-Lindau Disease. Materials and methods Screening affected kindred or retrospective review of medical records identified 181 patients with Von Hippel-Lindau Disease and renal cell carcinoma. Patients with small tumors were followed with serial imaging until the largest tumor reached 3 cm, at which point surgery was recommended. Surgical resection was recommended to patients with tumors larger than 3 cm. Patients not undergoing screening often had large renal tumors. Results A total of 108 patients with Von Hippel-Lindau Disease and solid renal tumors on computerized tomography imaging smaller than 3 cm (group 1) were followed a mean of 58 months (range 0 to 244). Metastatic Disease did not develop in any of these patients. Renal tumors larger than 3 cm developed in 73 patients with Von Hippel-Lindau Disease (group 2). Mean followup of group 2 was 72.9 months (range 0 to 321). The proportion of procedures that were nephron sparing was higher in group 1 than in group 2 (120 of 125 [97%] compared to 85 of 125 [69%], Fisher's exact test p Conclusions No renal tumor metastases were found in patients with renal tumors less than 3 cm in diameter. We advocate a 3 cm threshold for parenchymal sparing surgery in patients with Von Hippel-Lindau Disease to decrease the risk of metastatic Disease while preserving renal function, avoiding or delaying the need for dialysis and/or renal transplant, and decreasing the number of operations which a patient may undergo. We stress the importance of early screening in the kindred of patients with Von Hippel-Lindau Disease and vigilant followup thereafter.
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mosaicism in Von hippel lindau Disease lessons from kindreds with germline mutations identified in offspring with mosaic parents
American Journal of Human Genetics, 2000Co-Authors: M T Sgambati, Mcclellan M. Walther, W M Linehan, Peter L Choyke, Berton Zbar, Catherine A Stolle, G M GlennAbstract:Von Hippel-Lindau Disease (VHL [MIM 193300]) is a heritable autosomal dominant multiple-neoplastic disorder with high penetrance. It is characterized by brain and spinal-cord hemangioblastomas, retinal angiomas, clear-cell renal carcinoma, neuroendocrine tumors and cysts of the pancreas, pheochromocytomas, endolymphatic-sac tumors, and papillary cystadenomas of the epididymis and broad ligament. Although most index cases have a positive family history of VHL, some do not and may represent de novo cases. Cases without a family history of VHL may or may not have a germline mutation in their VHL tumor-suppressor gene. We present two cases of VHL mosaicism. In each of two families, standard testing methods (Southern blot analysis and direct sequencing) identified the germline mutation in the VHL gene of the offspring, but not in their clinically affected parent. Additional methods of analysis of the affected parents' blood detected the VHL-gene mutation in a portion of their peripheral blood lymphocytes. In one case, detection of the deleted allele was by FISH, and, in the second case, the 3-bp deletion was detected by conformational sensitive gel electrophoresis and DNA sequencing of cloned genomic DNA. Mosaicism in VHL is important to search for and recognize when an individual without a family history of VHL has VHL. Patients diagnosed without family histories of the Disease have been reported in as many as 23% of kindreds with VHL. Identification of individuals potentially mosaic for VHL will affect counseling of families, and these individuals should themselves be included in clinical screening programs for occult Disease.
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renal cancer in families with hereditary renal cancer prospective analysis of a tumor size threshold for renal parenchymal sparing surgery
The Journal of Urology, 1999Co-Authors: Mcclellan M. Walther, Peter L Choyke, G M Glenn, David Venzon, Chris J Lyne, W Rayford, Marston W LinehanAbstract:AbstractPurpose: Patients with hereditary forms of renal cancer are at risk for new tumors and metastases. Renal parenchymal sparing surgery has been performed to preserve renal function and quality of life, and prevent metastases. We evaluated a 3 cm. threshold for performing renal parenchymal sparing surgery in patients with Von Hippel-Lindau Disease and hereditary papillary renal cancer.Materials and Methods: Patients with Von Hippel-Lindau Disease or hereditary papillary renal cancer and renal cancer were identified by screening affected kindred and by kindred history. Patients with small tumors were followed with serial imaging studies until the large renal tumor was 3 cm., when renal parenchymal sparing surgery was performed. Renal tumors greater than 3 cm. were resected without delay. Parenchymal sparing techniques were used when possible in each group.Results: The 3 cm. surgical threshold was evaluated in 52 patients with Von Hippel-Lindau Disease (group 1) at a median followup of 60 months (range...
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pancreatic neuroendocrine tumors associated with Von hippel lindau Disease diagnostic and management recommendations
Surgery, 1998Co-Authors: Steven K Libutti, Marston W Linehan, Irina A Lubensky, Mcclellan M. Walther, Peter L Choyke, G M Glenn, David L Bartlett, Hernan Vargas, Richard H AlexanderAbstract:Abstract Background: Von Hippel Lindau Disease (VHL) is an inherited syndrome characterized by tumors of the kidney, adrenal, central nervous system, and pancreas. The incidence and natural history of pancreatic neuroendocrine tumors occurring in VHL are not known. Methods: From December 1988 through November 1997, 256 patients with VHL were screened with imaging studies, and these data were reviewed from a prospective database. Results: Thirty (12%) of 256 patients had solid pancreatic lesions consistent with neuroendocrine tumors. Fourteen patients underwent resection, and 4 with metastases on imaging studies underwent biopsy only. Of the 14 patients who underwent resection, 11 remain free of Disease, 2 have experienced recurrence, and 1 has died of unrelated causes (mean follow-up, 25 months; range, 3 to 73 months). The size of the primary tumor (median, 5 cm; range, 3 to 8 cm) in patients with liver metastases was significantly larger than the size of the primary tumor (median, 2 cm; range, 1 to 5 cm) in patients without liver metastases ( P = .0013). Conclusions: Solid pancreatic lesions were detected in 12% of patients with VHL. Larger primary tumors were associated with liver metastases. Pancreatic imaging to identify neuroendocrine tumors and resection when they reach 2 to 3 cm may prevent the development of hepatic metastases. (Surgery 1998;124:1153-9.)
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improved detection of germline mutations in the Von hippel lindau Disease tumor suppressor gene
Human Mutation, 1998Co-Authors: Catherine A Stolle, Mcclellan M. Walther, Peter L Choyke, G M Glenn, Berton Zbar, Jeffrey S Humphrey, Svetlanna Pack, Kathy Hurley, Carolyn Andrey, Richard D KlausnerAbstract:Von Hippel-Lindau Disease (VHL) is an inherited neoplastic disorder characterized by the development of tumors in the eyes, brain, spinal cord, inner ear, adrenal gland, pancreas, kidney, and epididymis. The VHL tumor suppressor gene was identified in 1993. Initial studies reported the detection of germline mutations in the VHL gene in 39–75% of VHL families. We used tests that detect different types of mutations to improve the frequency of detection of germline mutations in VHL families. The methods included quantitative Southern blotting to detect deletions of the entire VHL gene, Southern blotting to detect gene rearrangements, fluorescence in situ hybridization (FISH) to confirm deletions, and complete sequencing of the gene. Here we report that we have detected germline mutations in the VHL gene in 100% (93/93) of VHL families tested. In addition, we describe 13 novel intragenic VHL germline mutations. With the methodology described in this article, it is now possible to identify germline mutations in virtually all families with VHL. Hum Mutat 12:417–423, 1998. © 1998 Wiley-Liss, Inc.
Peter L Choyke - One of the best experts on this subject based on the ideXlab platform.
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the relationship between renal tumor size and metastases in patients with Von hippel lindau Disease
The Journal of Urology, 2005Co-Authors: Branden G Duffey, Marston W Linehan, Peter L Choyke, G M Glenn, Robert L Grubb, David Venzon, Mcclellan M. WaltherAbstract:Purpose Patients with Von Hippel-Lindau Disease are at risk for multiple, bilateral, recurrent renal tumors and metastases. We previously evaluated the relationship between tumor size and metastases in families with hereditary renal cancer. We update our findings with about twice the number of patients with Von Hippel-Lindau Disease. Materials and methods Screening affected kindred or retrospective review of medical records identified 181 patients with Von Hippel-Lindau Disease and renal cell carcinoma. Patients with small tumors were followed with serial imaging until the largest tumor reached 3 cm, at which point surgery was recommended. Surgical resection was recommended to patients with tumors larger than 3 cm. Patients not undergoing screening often had large renal tumors. Results A total of 108 patients with Von Hippel-Lindau Disease and solid renal tumors on computerized tomography imaging smaller than 3 cm (group 1) were followed a mean of 58 months (range 0 to 244). Metastatic Disease did not develop in any of these patients. Renal tumors larger than 3 cm developed in 73 patients with Von Hippel-Lindau Disease (group 2). Mean followup of group 2 was 72.9 months (range 0 to 321). The proportion of procedures that were nephron sparing was higher in group 1 than in group 2 (120 of 125 [97%] compared to 85 of 125 [69%], Fisher's exact test p Conclusions No renal tumor metastases were found in patients with renal tumors less than 3 cm in diameter. We advocate a 3 cm threshold for parenchymal sparing surgery in patients with Von Hippel-Lindau Disease to decrease the risk of metastatic Disease while preserving renal function, avoiding or delaying the need for dialysis and/or renal transplant, and decreasing the number of operations which a patient may undergo. We stress the importance of early screening in the kindred of patients with Von Hippel-Lindau Disease and vigilant followup thereafter.
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parenchymal sparing surgery in patients with hereditary renal cell carcinoma 10 year experience
The Journal of Urology, 2001Co-Authors: Judi Herring, Marston W Linehan, Peter L Choyke, Erik Enquist, Allen Chernoff, Mcclellan M. WaltherAbstract:Purpose: Von Hippel-Lindau Disease, hereditary papillary renal cell carcinoma, the Birt-Hogg-Dube syndrome and familial renal oncocytoma are familial renal tumor syndromes. These hereditary disorders are noteworthy for the development of multiple bilateral renal tumors and the risk of new tumors throughout life. One management strategy is observation of solid renal tumors until reaching 3 cm., then performing parenchymal sparing surgery. We present a 5-year update on our experience.Materials and Methods: From May 1988 to October 1998, 49 patients with hereditary renal cell carcinoma, including Von Hippel-Lindau Disease in 44, hereditary papillary renal cell carcinoma in 4 and the Birt-Hogg-Dube syndrome in 1, and 1 with familial renal oncocytoma underwent exploration to attempt renal parenchymal sparing surgery. Patients were followed prospectively with periodic screening for recurrence, metastasis and loss of renal function. Median followup was 79.5 months (range 0.7 to 205).Results: A total of 50 patien...
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mosaicism in Von hippel lindau Disease lessons from kindreds with germline mutations identified in offspring with mosaic parents
American Journal of Human Genetics, 2000Co-Authors: M T Sgambati, Mcclellan M. Walther, W M Linehan, Peter L Choyke, Berton Zbar, Catherine A Stolle, G M GlennAbstract:Von Hippel-Lindau Disease (VHL [MIM 193300]) is a heritable autosomal dominant multiple-neoplastic disorder with high penetrance. It is characterized by brain and spinal-cord hemangioblastomas, retinal angiomas, clear-cell renal carcinoma, neuroendocrine tumors and cysts of the pancreas, pheochromocytomas, endolymphatic-sac tumors, and papillary cystadenomas of the epididymis and broad ligament. Although most index cases have a positive family history of VHL, some do not and may represent de novo cases. Cases without a family history of VHL may or may not have a germline mutation in their VHL tumor-suppressor gene. We present two cases of VHL mosaicism. In each of two families, standard testing methods (Southern blot analysis and direct sequencing) identified the germline mutation in the VHL gene of the offspring, but not in their clinically affected parent. Additional methods of analysis of the affected parents' blood detected the VHL-gene mutation in a portion of their peripheral blood lymphocytes. In one case, detection of the deleted allele was by FISH, and, in the second case, the 3-bp deletion was detected by conformational sensitive gel electrophoresis and DNA sequencing of cloned genomic DNA. Mosaicism in VHL is important to search for and recognize when an individual without a family history of VHL has VHL. Patients diagnosed without family histories of the Disease have been reported in as many as 23% of kindreds with VHL. Identification of individuals potentially mosaic for VHL will affect counseling of families, and these individuals should themselves be included in clinical screening programs for occult Disease.
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renal cancer in families with hereditary renal cancer prospective analysis of a tumor size threshold for renal parenchymal sparing surgery
The Journal of Urology, 1999Co-Authors: Mcclellan M. Walther, Peter L Choyke, G M Glenn, David Venzon, Chris J Lyne, W Rayford, Marston W LinehanAbstract:AbstractPurpose: Patients with hereditary forms of renal cancer are at risk for new tumors and metastases. Renal parenchymal sparing surgery has been performed to preserve renal function and quality of life, and prevent metastases. We evaluated a 3 cm. threshold for performing renal parenchymal sparing surgery in patients with Von Hippel-Lindau Disease and hereditary papillary renal cancer.Materials and Methods: Patients with Von Hippel-Lindau Disease or hereditary papillary renal cancer and renal cancer were identified by screening affected kindred and by kindred history. Patients with small tumors were followed with serial imaging studies until the large renal tumor was 3 cm., when renal parenchymal sparing surgery was performed. Renal tumors greater than 3 cm. were resected without delay. Parenchymal sparing techniques were used when possible in each group.Results: The 3 cm. surgical threshold was evaluated in 52 patients with Von Hippel-Lindau Disease (group 1) at a median followup of 60 months (range...
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pancreatic neuroendocrine tumors associated with Von hippel lindau Disease diagnostic and management recommendations
Surgery, 1998Co-Authors: Steven K Libutti, Marston W Linehan, Irina A Lubensky, Mcclellan M. Walther, Peter L Choyke, G M Glenn, David L Bartlett, Hernan Vargas, Richard H AlexanderAbstract:Abstract Background: Von Hippel Lindau Disease (VHL) is an inherited syndrome characterized by tumors of the kidney, adrenal, central nervous system, and pancreas. The incidence and natural history of pancreatic neuroendocrine tumors occurring in VHL are not known. Methods: From December 1988 through November 1997, 256 patients with VHL were screened with imaging studies, and these data were reviewed from a prospective database. Results: Thirty (12%) of 256 patients had solid pancreatic lesions consistent with neuroendocrine tumors. Fourteen patients underwent resection, and 4 with metastases on imaging studies underwent biopsy only. Of the 14 patients who underwent resection, 11 remain free of Disease, 2 have experienced recurrence, and 1 has died of unrelated causes (mean follow-up, 25 months; range, 3 to 73 months). The size of the primary tumor (median, 5 cm; range, 3 to 8 cm) in patients with liver metastases was significantly larger than the size of the primary tumor (median, 2 cm; range, 1 to 5 cm) in patients without liver metastases ( P = .0013). Conclusions: Solid pancreatic lesions were detected in 12% of patients with VHL. Larger primary tumors were associated with liver metastases. Pancreatic imaging to identify neuroendocrine tumors and resection when they reach 2 to 3 cm may prevent the development of hepatic metastases. (Surgery 1998;124:1153-9.)
Stephane Richard - One of the best experts on this subject based on the ideXlab platform.
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Von hippel lindau Disease genetics and role of genetic counseling in a multiple neoplasia syndrome
Journal of Clinical Oncology, 2016Co-Authors: Sarah M Nielsen, Eamonn R Maher, Stephane Richard, Lindsay Rhodes, Ignacio Blanco, Wendy K Chung, Charis Eng, Rachel H GilesAbstract:Von Hippel-Lindau Disease (VHL) is one of the most common inherited neoplasia syndromes and is characterized by highly vascular tumors of the eyes, brain, and spine, as well as benign and malignant tumors and/or cysts of the kidneys, adrenal medullae and sympathetic paraganglia, endolymphatic sac, epididymis, and broad ligament. Since the discovery of the VHL gene in 1993, more than 900 families with VHL have been identified and examined. Genetic testing for VHL is widely available and will detect a Disease-causing mutation in rate 95% to 100% of individuals who have a clinical diagnosis of VHL, making it the standard of care for diagnosis of VHL. Furthermore, genetic testing for VHL is indicated in some individuals with seemingly sporadic VHL-related tumor types, as ≤ 10% of pheochromocytoma or early-onset renal cell carcinoma and ≤ 40% of CNS hemangioblastoma harbor germline VHL mutations without a family history or additional features of VHL Disease. The majority of VHL mutations are private, but there...
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long term prognosis of resected pancreatic neuroendocrine tumors in Von hippel lindau Disease is favorable and not influenced by small tumors left in place
Annals of Surgery, 2015Co-Authors: Louis De Mestier, Sebastien Gaujoux, Jerome Cros, Olivia Hentic, Mariepierre Vullierme, Anne Couvelard, Guillaume Cadiot, Alain Sauvanet, Philippe Ruszniewski, Stephane RichardAbstract:BACKGROUND Management of pancreatic neuroendocrine tumors (PNETs) associated with Von Hippel-Lindau Disease (VHL) is challenging because of the malignant potential and difficulty in predicting prognosis. OBJECTIVE Compare the long-term outcome of resected VHL-PNET and sporadic PNET. METHODS Data of all patients with VHL (n = 23) operated on for nonmetastatic PNET were reviewed. Patient characteristics and recurrence-free survival rates were compared with those in patients operated on for sporadic PNET, matched for tumor size, stage, and Ki-67 index. RESULTS Patients in both groups had similar demographic characteristics, except that patients with VHL were younger (36 vs 56 years, P < 0.0001). Median tumor size was 30 mm. Median Ki-67 index was 3% and 4% in the VHL and sporadic groups (P = 0.95), respectively, and lymph node metastases were present in 43% and 30% of cases, respectively (P = 0.45). Sixteen (70%) patients with VHL had multiple PNET; lesions less than 15 mm were left in place in 11 patients. Median postoperative follow-up was 107 months (interquartile range, 57-124 months) and 71 months (interquartile range, 58-131 months) in the VHL and control groups, respectively. Median recurrence-free survival could not have been estimated in the VHL group due to the low number of events (hazard ratio, 5.6; 95% confidence interval, 1.4-22.6; P = 0.013). Five patients with VHL died (3 from VHL-related tumors including 1 from PNET), whereas only one control patient died due to unrelated causes. CONCLUSIONS The long-term outcome of resected VHL-PNET is better than that of sporadic PNET. PNET less than 15 mm left in place did not progress. A parenchyma-sparing surgical strategy seems appropriate in patients with VHL-PNET, who may develop more life-threatening tumors of other organs.
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progress in nephron sparing therapy for renal cell carcinoma and Von hippel lindau Disease
The Journal of Urology, 2011Co-Authors: Dominique Joly, A Mejean, J M Correas, Marcolivier Timsit, Virginie Verkarre, Sophie Deveaux, Paul Landais, Jeanpierre Grunfeld, Stephane RichardAbstract:Purpose Patients with Von Hippel-Lindau Disease frequently have early, multiple and recurrent renal cell carcinoma. Renal cell carcinoma treatment, which must prevent metastatic Disease and spare nephrons, has changed in the last 2 decades. We evaluated renal cell carcinoma treatments in the long term in a large series of patients with Von Hippel-Lindau Disease. Materials and Methods We retrospectively evaluated the use and results of surgery and radio frequency ablation in patients with Von Hippel-Lindau followed at our institution between 1988 and 2009. Renal anatomical survival was analyzed according to 3 periods, including 1) 1988 to 1994—the learning phase of nephron sparing surgery, 2) 1995 to 2003—routine nephron sparing surgery and 3) 2004 to 2009—the emergence of radio frequency ablation. Results A first renal cell carcinoma was treated at a mean age of 38 years (range 15 to 67) in 113 patients with Von Hippel-Lindau Disease. During a median followup of 7.2 years 251 therapeutic procedures were performed in a total of 176 kidneys. We observed a shift of first line renal cell carcinoma treatment with time, that is nephrectomy in 52% of cases in period 1, tumorectomy in 75% in period 2 and radio frequency ablation in 43% in period 3. The shift paralleled improved renal survival. While nephron sparing surgery was primarily done for lesions greater than 30 mm, radio frequency ablation was used to treat less numerous and smaller ipsilateral lesions but they required more frequent intervention. Radio frequency ablation became the most widely used second or third line procedure and allowed renal salvage in 8 patients. Conclusions Nephron sparing surgery and more recently radio frequency ablation enable earlier treatment of smaller tumors and are associated with a significant improved renal prognosis in patients with Von Hippel-Lindau Disease.
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head and neck paragangliomas in Von hippel lindau Disease and multiple endocrine neoplasia type 2
The Journal of Clinical Endocrinology and Metabolism, 2009Co-Authors: Carsten Christof Boedeker, Stephane Richard, Zoran Erlic, Udo Kontny, Anne Paule Gimenezroqueplo, Alberto Cascon, Mercedes Robledo, Jose M De Campos, Francien H Van Nederveen, Ronald R De KrijgerAbstract:Background: Head and neck paragangliomas (HNPs) occur as sporadic or familial entities, the latter mostly in association with germline mutations of the SDHB, SDHC, or SDHD (SDHx) genes. Heritable non-SDHx HNP might occur in Von Hippel-Lindau Disease (VHL, VHL gene), multiple endocrine neoplasia type 2 (MEN2, RET gene), and neurofibromatosis type 1 (NF1, NF1 gene). Reports of non-SDHx HNP presentations are scarce and guidance for genetic testing nonexistent. Patients and Methods: An international consortium registered patients with HNPs and performed mutation analyses of the SDHx, VHL, and RET genes. Those with SDHx germline mutations were excluded for purposes of this study. Personal and family histories were evaluated for paraganglial tumors, for the major tumor manifestations, and for family history of VHL, MEN2, or NF1. Results: Twelve patients were found to have hereditary non-SDHx HNPs of a total of 809 HNP and 2084 VHL registrants, 11 in the setting of germline VHL mutations and one of a RET mutation. The prevalence of hereditary HNP is five in 1000 VHL patients and nine in 1000 non-SDHx HNP patients. Comprehensive literature review revealed previous reports of HNPs in five VHL, two MEN2, and one NF1 patient. Overall, 11 here presented HNP cases, and four previously reported VHL-HNPs had lesions characteristic for VHL and/or a positive family history for VHL. Conclusions: Our observations provide evidence that molecular genetic testing for VHL or RET germline mutations in patients with HNP should be done only if personal and/or family history shows evidence for one of these syndromes.
