Von Hippel-Lindau disease and pheochromocytoma.
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Adrenal Gland Neoplasms↗
Biomedical subjects
M M Walther
Publications and source records attributed to M M Walther.
Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis.
OBJECTIVE: To describe the incidence of, clinical manifestations of, and risk factors for cyclophosphamide-induced urinary bladder toxicity in patients treated for nonmalignant disease. DESIGN: Retrospective analysis of patients followed at the National Institutes of Allergy and Infectious Diseases from 1967 to 1993. SETTING: The Warren G. Magnuson Clinical Center of the National Institutes of Health (NIH). PATIENTS: 145 patients who received cyclophosphamide for the treatment of Wegener granulomatosis and were followed for 0.5 to 27 years (median, 8.5 years), for a total of 1333 patient-years. MEASUREMENTS: Clinical characteristics, cystoscopic findings, results of cytologic examination of urine, surgical pathology, and total dose and duration of cyclophosphamide therapy were recorded and analyzed using a computer-based information retrieval system. RESULTS: Nonglomerular hematuria occurred in 73 of 145 patients treated with cyclophosphamide (50%). Sixty of the 73 patients with nonglomerular hematuria (82%) had cystoscopy at the NIH. Forty-two of the 60 patients (70%) who had cystoscopy had macroscopic changes consistent with cyclophosphamide-induced bladder injury. Seven patients (5%) developed transitional-cell carcinoma of the urinary bladder. In 6 of these 7 patients, the total cumulative cyclophosphamide dose exceeded 100 g, and the cumulative duration of cyclophosphamide therapy exceeded 2.7 years. Before they were given a diagnosis of bladder cancer, all 7 patients had had one or more episodes of microscopic or gross nonglomerular hematuria. In contrast, none of the 72 patients who had never had nonglomerular hematuria developed bladder cancer. Cox proportional hazards regression analysis showed that only microscopic nonglomerular hematuria was a significant risk factor for the development of bladder cancer (P < 0.01). CONCLUSION: Long-term oral cyclophosphamide therapy is associated with substantial urotoxicity, including the development of transitional-cell carcinoma of the urinary bladder. In this cohort of patients, the estimated incidence of bladder cancer after the first exposure to cyclophosphamide was 5% at 10 years and 16% at 15 years. Nonglomerular hematuria was a frequent manifestation of cyclophosphamide-induced cystitis, and it identified a subgroup of patients at high risk for the development of bladder cancer.
Aged↗
Enucleation procedures in patients with multiple hereditary renal tumors.
Parenchymal sparing surgery is frequently appropriate in patients with familial renal tumors detected through the screening of affected kindreds. An enucleation technique for the rapid removal and hemostasis of multiple small renal tumors in patients with hereditary renal cancers is described herein. This technique facilitates the removal of multiple small superficial renal tumors, usually without hypothermia.
Follow-Up Studies↗
Characterization of the renal pathology of a familial form of renal cell carcinoma associated with von Hippel-Lindau disease: clinical and molecular genetic implications.
We examined 12 patients with von Hippel-Lindau disease and renal cell carcinoma to characterize the pathological findings after renal surgery (total 161 lesions). Tissue from 15 partial nephrectomies and 1 radical nephrectomy was obtained for examination. Pathological evaluation identified 116 cystic lesions, 25 of which (21%) were malignant, and 45 solid lesions, 41 of which (91%) were renal cell carcinoma. Each kidney had a mean of 7.8 cystic and 3.0 solid lesions. Of 66 malignant lesions 35 (53%) were comprised of cells with only clear cell cytological features and 30 (45.5%) contained predominantly clear cells with scattered granular cells. One malignant lesion (1.5%) contained sarcomatoid renal cell carcinoma with clear and granular cells. Microscopic invasion of the pseudocapsule was common (13 of 25 clinically cystic tumors [52%] and 31 of 41 clinically solid lesions [76%]) but no tumor extended through the pseudocapsule. All lesions without a pseudocapsule were well circumscribed. Our study establishes the clear cell cytological features as the primary finding observed in patients with von Hippel-Lindau disease. Many cystic lesions contained renal cancer, demonstrating the need for removal of all cystic lesions when this can be safely performed. The well circumscribed nature of the tumors lends them to parenchymal sparing procedures.
Adult↗
von Hippel-Lindau disease: genetic, clinical, and imaging features.
von Hippel-Lindau (VHL) disease is an autosomal dominant disorder that causes retinal hemangioblastomas, hemangioblastomas of the central nervous system, endolymphatic sac tumors, renal cell carcinomas, pancreatic cysts and tumors, pheochromocytomas, and epididymal cystadenomas, among other less common manifestations. Although this entity has been recognized for almost 70 years, recent developments in the genetics and imaging of VHL disease have greatly improved understanding of the disease and its natural history. This review describes the major events that led to the discovery of the gene for VHL and will familiarize the reader with recent developments in the magnetic resonance Imaging, computed tomographic, and ultrasound findings of this entity. Despite advances in the genetic understanding of this disease, imaging techniques will continue to play a major role in the diagnosis, management, and treatment of VHL.
Adenoma, Islet Cell↗
Prevalence of microscopic lesions in grossly normal renal parenchyma from patients with von Hippel-Lindau disease, sporadic renal cell carcinoma and no renal disease: clinical implications.
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 from 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 Hippel-Lindau gene in a kidney results in the cytological cell type of clear cell renal cancer as the initial product of cellular transformation.
Adolescent↗
Loss of heterozygosity occurs centromeric to RB without associated abnormalities in the retinoblastoma gene in tumors from patients with metastatic renal cell carcinoma.
Tumor suppressor genes have been found to have loss of function in a number of malignancies. This loss of function is believed to contribute to malignant transformation or metastatic spread. In the present study, expression of the retinoblastoma (RB) tumor suppressor gene was examined in cell lines and tumor tissue obtained from primary renal and metastatic sites in patients with metastatic renal cell carcinoma. Three of fifteen (20%) of informative renal carcinoma cell lines had loss of heterozygosity (LOH) in the RB gene (intron 20) detected by polymerase chain reaction analysis. Using restriction fragment length polymorphism (RFLP) analysis, 7 of 22 (32%) informative cell lines had LOH centromeric to the RB gene at the D13S1 locus. No LOH (0 of 7) was seen telomeric to the RB gene at the D13S2 locus. None of the 28 cell lines examined had decreased RB mRNA expression compared with short-term cultures of proximal renal tubular cells. Western blotting demonstrated phosphorylated and unphosphorylated forms of RB protein of expected molecular weight in all 41 cell lines (33 primary and 8 metastatic) examined. Twenty-nine primary cell lines and 6 metastatic cell lines all demonstrated normal immunohistochemical staining. Loss of RB immunohistochemical staining in paraffin-embedded tissue was detected in none of the primary tumors (0 of 30) or metastatic tumors (0 of 12). The absence of abnormalities of RB expression detected in these renal cell carcinomas suggests that abnormalities of the RB gene are not central to malignant transformation or progression in this tumor type; however, another tumor suppressor gene centromeric to the RB locus may be important in renal cell carcinogenesis.
Base Sequence↗
Expression of nm23 in cell lines derived from patients with metastatic renal cell carcinoma.
Reduced expression of nm23 has been associated with increased metastases and decreased survival in a variety of malignancies. In the present study, the expression of nm23 was examined by Northern and Western blot analyses in a series of cell lines derived from patients with metastatic renal cell carcinoma. Two of twelve (17%) informative cell lines derived from 9 patients had loss of heterozygosity at Nm23-H1. Twenty-two renal cancer cell lines derived from primary tumors, 5 cell lines derived from metastatic tumors and 4 short-term cultures of normal proximal renal tubular cells all expressed Nm23 mRNA in varying amounts. On average, the level of expression of Nm23 mRNA in short-term cultures of benign proximal renal tubular cells was found to be similar to the level seen in renal cancer cell lines. Twenty-eight cell lines derived from renal primary tumors and 8 cell lines derived from metastatic tumors expressed both the Nm23-H1 and Nm23-H2 proteins. High or low relative expression of nm23 at the mRNA or protein level did not correlate with survival. The absence of any anomalous pattern of expression of the nm23 genes and the lack of correlation of expression with survival suggests that nm23 does not play a central role in the progression of this tumor type.
Blotting, Northern↗
Renal cell carcinoma. Molecular genetics and clinical implications.
The combined efforts of a number of investigators have led to the identification of the VHL gene, which appears to function as a tumor suppressor gene and is implicated in both sporadic and familial forms of RCC. These findings should increase our understanding of the molecular biology of this malignancy; however, there is much work to be done. Identification of the mechanism of inactivation of the VHL gene, as well as the structure and function of the VHL gene product, ultimately may provide clinicians with greater understanding of this malignancy as well as with methods for earlier diagnosis. The role of other tumor suppressor genes, such as p53, is incompletely understood. It is hoped that the techniques that have been applied to the study of RCC also will result in advances in our knowledge of other urologic malignancies.
Aged↗
Hereditary papillary renal cell carcinoma: clinical studies in 10 families.
We recently described a 3-generation family with members affected with papillary renal cell carcinoma, an uncommon histological type of renal cell carcinoma. Possibly family 150 is an isolated occurrence, a reflection of some as yet unknown environmental factor. Alternatively, family 150 may represent a distinct class of inherited cancer. To distinguish between these 2 possibilities we sought additional families with papillary renal cell carcinoma and we identified 9 with members affected with papillary renal cell carcinoma. There were 29 affected male and 12 affected female subjects (ratio 2.41:1), including affected members of family 150. Papillary renal cell carcinomas were often detected incidentally in asymptomatic individuals or during screening of asymptomatic members of renal cell carcinoma families. The penetrance, the proportion of obligate gene carriers that showed clinical evidence of the disease, was reduced. The median survival of affected individuals was 52 years. The results support the concept that the predisposition to develop papillary renal cell carcinomas may be inherited and that hereditary papillary renal cell carcinoma constitutes a distinct class of inherited cancer.
Adolescent↗
Parenchymal sparing surgery in patients with hereditary renal cell carcinoma.
The von Hippel-Lindau syndrome is the most well known cause of familial renal cancer. Because affected individuals with renal lesions can have complex, multisystem manifestations of von Hippel-Lindau disease, our renal management strategy has included parenchymal sparing surgery whenever possible. From May 1988 to January 1993, 20 patients with hereditary renal cell carcinoma (19 with von Hippel-Lindau disease and 1 with hereditary papillary renal cancer) underwent renal exploration with the intent of performing parenchymal sparing surgery. A total of 7 nephrectomies and 27 parenchymal sparing procedures was performed. Additional procedures performed included 2 bilateral adrenalectomies for pheochromocytomas, 1 resection of a renal vein thrombus and 1 resection of a pancreatic islet cell tumor. Renal atrophy occurred in 3 of 27 kidneys (11%) treated by parenchymal sparing surgery. In 8 kidneys of 7 patients new solid lesions developed and in 14 kidneys of 12 patients no new solid lesions developed during a mean followup of 26 months (range 6 to 60 months). The use of parenchymal sparing surgery in patients with familial forms of kidney cancer is based on a desire to maintain renal function as long as possible while reducing the risk of metastases. The potential advantages and disadvantages of more ablative surgical treatment requiring subsequent dialysis or transplantation in patients with existing or potential central nervous system, eye, pancreas and/or adrenal tumors must be weighed against the possibility of renal cancer metastases or recurrence when deciding on the use of parenchymal sparing surgery.
Adult↗
The use of molecular genetic analysis in the diagnosis of renal cell carcinoma.
The most common genetic aberration seen in nonpapillary renal cell carcinoma is believed to be the loss or inactivation of allelic material on the short arm of chromosome 3 (3p). Two patients underwent nephrectomy at our institution, each initially receiving a histologic diagnosis of renal cell carcinoma. Molecular analysis of these tissues revealed no genetic deletion on 3p, prompting further histologic and immunohistochemical evaluation of the original specimens. These additional studies confirmed alternate histologies other than renal cell carcinoma in each case. These data suggest that the loss of genetic material on the short arm of chromosome 3 may be specific for nonpapillary renal cell carcinoma. Molecular analysis may prove to be a useful adjunct in establishing the diagnosis in renal neoplasms with equivocal histologies.
Adult↗
Evaluation of color Doppler intraoperative ultrasound in parenchymal sparing renal surgery.
A renal parenchymal sparing surgical approach may be recommended in select patients with von Hippel-Lindau disease and renal cancer or in those with sporadic renal cancer and limited normal renal function. We performed 27 partial nephrectomies or enucleations in 17 patients with the use of intraoperative ultrasound to examine a subset of all renal lesions identified on preoperative examination. Of 24 lesions deep in the renal parenchyma that were examined, localized or identified with intraoperative ultrasound 18 were characterized as cystic and 6 as solid. The deep cystic lesions were characterized with ultrasound as benign simple cysts. Intraoperative ultrasound was used to locate and mark the line of incision over 2 impalpable solid renal cell carcinomas. Four solid renal cell tumors extended deep into the renal parenchyma where color Doppler intraoperative ultrasound helped to define the plane of dissection adjacent to vital vascular structures. Renal hypothermia was not used in 3 renal operations based on intraoperative ultrasound findings.
Adult↗
Suramin inhibits proliferation and DNA synthesis in transitional carcinoma cell lines.
Suramin is polysulfonated naphthylurea which has a broad range of antitumor activity. The mechanism of action of suramin is not completely understood, although it is known to inhibit enzymes in all cellular compartments, inhibit steroidogenesis and interfere with ligand-receptor binding. Suramin's large molecular size and negative charge should make it poorly absorbed through the bladder mucosa, a desired characteristic for an intravesical chemotherapeutic agent. We examined the ability of suramin to inhibit thymidine uptake and decrease cellular proliferation in 4 transitional cell carcinoma cell lines grown in vitro to determine if suramin might be a new candidate drug of treatment for patients with superficial bladder cancer. Suramin inhibited cellular proliferation of all cell lines tested (MBT2, T24, RT4 and TCCSUP) in a dose-dependent fashion. Fifty per cent inhibition of cellular proliferation compared with controls was seen with suramin concentrations of 250 to 400 micrograms/ml. by, at most, 5 to 9 days of exposure. The cell line RT4 was the cell line most sensitive to the growth inhibitory effect of suramin, with 50% growth inhibition compared with controls achieved after 3 days' exposure to a suramin concentration of 100 micrograms/ml. Suramin inhibited DNA synthesis in a dose-dependent fashion, as measured by thymidine uptake, in 3 of the 4 cell lines tested (MBT2, T24, and RT4). Suramin inhibited thymidine uptake by TCCSUP in a dose-dependent fashion, but did not achieve statistical significance.
Animals↗
Hereditary papillary renal cell carcinoma.
We describe a 3 generation family with members affected with papillary renal cell carcinoma, an uncommon histological type of renal cell carcinoma. Multiple tumors of varying size were present in both kidneys of affected family members. The disorder was not linked to polymorphic markers on chromosome 3p and there was no loss of heterozygosity at loci on 3p in renal tumors. The results suggest the presence of a renal cell carcinoma gene not located on 3p that predisposes to renal cell carcinoma with a distinct histological appearance. The inherited disorder in this family appears to be different from recognized hereditary cancer syndromes.
Adolescent↗
Effect of suramin on the mitogenic response of the human prostate carcinoma cell line PC-3.
BACKGROUND: Suramin is an anthelmintic drug that recently has been shown to have clinical efficacy in the treatment of patients with some advanced malignancies, including prostate carcinoma. The current study was done to assess the effect of suramin at clinically relevant doses on the growth in culture of a human prostatic carcinoma cell line, PC-3. METHODS: The antiproliferative effect of varying doses of suramin on PC-3 was assessed. Northern blot analysis was done to assess the potential changes in genetic expression at different times after the initiation of treatment. RESULTS: Suramin inhibited the proliferation of PC-3 in a dose-related manner (concentration range, 30-300 microM). Compared with fetal calf serum 2%, when the cells were grown in fetal calf serum 10%, higher concentrations of suramin were required to inhibit tritiated thymidine incorporation. When grown in RPMI without supplement, the PC-3 cell number remained the same. When 100 microM suramin was included, the cell number decreased. By contrast, when RPMI was supplemented with insulin, transferrin, and selenium (ITS), PC-3 grew well. The inhibition of the proliferation of PC-3 cells by suramin was decreased when ITS were added to the cells grown under serum-free conditions. CONCLUSIONS: These results were consistent with the hypothesis that in vitro inhibition of the growth of PC-3 cells by suramin may be caused, at least in part, by the growth factor antagonism of the drug. In fetal calf serum 2%, the suramin inhibition was reversible after 3 days. If the treatment was extended to 6 days, however, the PC-3 cells were unable to recover. Cell-cycle analysis revealed that, after 6 days of treatment, there was a decrease in the number of cells in G1 that corresponded with an increased number of cells in G2/M. This suggested that critical antineoplastic events were occurring during this time. Molecular analysis did not detect any altered expression of actin, transforming growth factors alpha or beta, or histone compared with untreated control samples.
Blotting, Northern↗
Cytoreductive surgery prior to interleukin-2-based therapy in patients with metastatic renal cell carcinoma.
From May 1985 to December 1990, 93 patients with the clinical diagnosis of metastatic renal cell carcinoma and their primary tumor in place were evaluated for cytoreductive surgery as preparation for systemic therapy with regimens based on interleukin-2. These patients had typical sites of metastatic disease and manifestations of paraneoplastic syndromes. Patients underwent removal of the primary tumor, as well as debulking when this could be performed safely. Thirty-two percent of patients (30/93) had a second surgical resection in addition to their nephrectomy, frequently because of the large size of the primary tumor and its invasion of adjacent structures. Thirteen percent of patients (12/93) experienced postoperative complications. There were no perioperative mortalities. Forty percent of patients (37/93) who underwent nephrectomy could not be treated with immunotherapy, usually because of progression of disease. A preoperative ECOG status greater than or equal to 2 was the only significant risk factor associated with failure to undergo immunotherapy (P = 0.043). The response rate to immunotherapy in the 56 patients receiving interleukin-2 was 27 percent (4 CR, 11 PR).
Adolescent↗
Intraoperative ultrasound in the evaluation of tumor involvement of the inferior vena cava.
The successful excision of genitourinary malignancies extending to the inferior vena cava relies heavily on accurate preoperative imaging. For the majority of these patients magnetic resonance imaging, inferior venacavography, abdominal ultrasound or abdominal computerized tomography will reliably predict the extent of inferior vena caval involvement by tumor. However, occasionally the results of these studies will conflict or be called into question intraoperatively. We report on 8 patients considered to be at risk for inferior vena caval involvement by tumor and for whom intraoperative ultrasound was obtained to clarify the presence or extent of thrombus. Five patients had renal cell carcinoma and 3 had adrenal carcinoma. In all patients concern as to the extent or presence of tumor was based on either inconclusive preoperative studies or unexpected intraoperative findings. In each case intraoperative ultrasound clearly visualized the inferior vena cava and established the presence or extent of tumor invasion. In 4 patients venacavotomy was avoided as a consequence of these findings. Intraoperative ultrasound is a useful tool that can accurately assess the inferior vena cava for possible tumor invasion, especially when the presence or extent of tumor involvement is not definitively established preoperatively.
Adolescent↗