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Laparoscopic management of kidney cancer is becoming accepted as an alternative to open radical nephrectomy. Technical considerations have limited the application of laparoscopic radical nephrectomy to relatively small, clinically localized tumors. At the National Cancer Institute, we have broadened the indications to include bulky tumors. Herein, we describe the operation with attention to the technical caveats that have been gained with experience.

Purpose: Adrenal cortical sparing surgery is a relatively new approach to adrenal tumors. Laparoscopic partial nephrectomy is a technically feasible but challenging operation. We describe the use of intraoperative ultrasound to facilitate laparoscopic partial nephrectomy in a population with a hereditary predisposition to multifocal pheochromocytoma., Materials and Methods: All patients underwent a history, physical examination, serum and urine catecholamine determinations, abdominal computerized tomography-magnetic resonance imaging and metaiodobenzylguanidine scan. The adrenal gland was exposed using a standard 3 or 4 port approach. Intraoperative ultrasound was performed using a 7.5 MHz. 10 mm. transducer placed through a 12 mm. port. After imaging the whole gland and adjacent structures partial adrenalectomy was performed based on intraoperative ultrasound images using a harmonic scalpel or alternatively using a cut and sew technique that provided a 5 mm. margin. Tumors were removed intact and sent for pathological examination., Results: Since 1998, 11 patients have undergone laparoscopic partial adrenalectomy. Intraoperative ultrasound was performed in 7 patients with suspected multiple adrenal masses, including 4 and 3 who underwent unilateral and bilateral laparoscopic partial nephrectomy, respectively. Six of the 7 patients had germline defects in the von Hippel-Lindau disease gene and 1 had no identifiable alteration in the von Hippel-Lindau disease or RET gene. A solitary tumor was identified in 3 cases and multiple lesions were noted in 4. In 1 case intraoperative ultrasound localized a tumor not identified on preoperative imaging that was not readily visible via laparoscopy. Intraoperative ultrasound guided surgical dissection in all cases and identified an extra-adrenal mass in 1 patient with bilateral adrenal masses. There were no complications due to intraoperative ultrasound and no conversions to open surgery. Mean operative time was 335 minutes and mean estimated blood loss was 179 ml. Histological study demonstrated pheochromocytoma in 14 lesions and the extra-adrenal mass proved to be a splenic rest. At short-term followup no recurrences have been noted. All patients retained sufficient adrenal cortical function to avoid steroid replacement therapy., Conclusions: Laparoscopic ultrasound differentiates normal adrenal parenchyma from adrenal tumors and facilitates laparoscopic partial adrenalectomy.

Pheochromocytoma is a rare, surgically correctable cause of hypertension. Modern medical blockade has significantly improved patient survival and morbidity. The last decade has seen the identification of the genes responsible for several hereditary causes of pheochromocytoma. Evaluation of these patients has demonstrated different catecholamine profiles associated with the different syndromes. Genetic testing and new, more sensitive catecholamine tests are allowing better, earlier diagnosis of affected patients. Some patients with small tumors deemed nonfunctional by traditional methods may be safely observed until function is demonstrated. Laparoscopic surgery has supplanted the use of open surgery in the management of these tumors. Adrenocortical-sparing surgery may be performed using laparoscopy in patients with hereditary forms of pheochromocytoma.

Measurements of plasma free metanephrines, normetanephrine (NMN) and metanephrine (MN), provide a sensitive test for diagnosis of pheochromocytoma in adults but have not been evaluated in children. We therefore established reference ranges for plasma and urinary metanephrines and the catecholamines, norepinephrine (NE) and epinephrine (E), in 86 healthy children (age 5-17). A group of 158 healthy adults (age 18-72) served as a comparison group. Pediatric reference ranges were applied to examine the diagnostic utility of the various tests in 45 children evaluated for pheochromocytoma (age 8-17; 38 with von Hippel-Lindau syndrome), with tumors found on 12 occasions. Upper reference limits for E and MN were higher and those for NE and NMN lower in children than in adults. Boys had higher plasma levels of E and MN and higher urinary excretion of all four amines than girls. Plasma free metanephrines provided a diagnostic test with values for sensitivity (100%) and specificity (94%) that were equal to or higher than those of other tests. In two children screened for pheochromocytoma on multiple occasions, use of pediatric reference ranges for plasma free metanephrines indicated the tumor a year earlier than indicated using adult reference ranges. The findings indicate that plasma free metanephrines provide a sensitive tool for detection of pheochromocytoma in children. Age appropriate reference ranges should be used and gender differences should be considered.

A reusable laparoscopic instrument consisting of a flexible deployment ring and a barrel was fabricated, and an impermeable sac was sutured to the flexible ring before entrapment of the specimen and morcellation. The laparoscopic specimen entrapment device facilitated placement of large renal tumors within a sac for morcellation.

Background and Purpose: Laparoscopic radical nephrectomy (LRN) is being increasingly offered for the management of renal-cell carcinoma (RCC). Specimen removal may be performed through a small or hand-port incision or by specimen morcellation. Limited studies exist addressing the accuracy of histopathologic diagnosis in morcellated renal tumors. Because of concerns about the lack of a diagnosis secondary to the morcellation process, we performed premorcellation needle biopsies to obtain nondisrupted tissue for pathologic analysis. Herein, we compare the histopathologic diagnosis achieved via needle biopsy prior to morcellation with that of the final specimen., Patients and Methods: Following successful laparoscopic resection, specimens were entrapped in a Lapsac. Needle biopsies were performed manually through the mouth of the Lapsac, and morcellation was then done in some patients using manual and mechanical methods. The histopathologic diagnoses in the needle biopsy specimens and the morcellated material were compared., Results: Laparoscopic radical nephrectomy with specimen morcellation was performed in 15 patients. Nine patients had premorcellation needle biopsies. Eight of these biopsies had sufficient tissue for diagnosis of RCC. This finding correlated with final diagnosis from the morcellated material. Perinephric fat invasion was identified in three morcellated specimens., Conclusions: Needle biopsy prior to specimen morcellation confirmed the histologic diagnosis of the morcellated specimen. This finding suggests that such histopathology material is adequate for diagnosis and may make premorcellation needle biopsy redundant.

Pheochromocytomas are rare neuroendocrine tumors that arise from chromaffin tissue. In a small subset of patients, pheochromocytomas occur as a manifestation of von Hippel- Lindau (VHL) disease. The histology of VHL-associated pheochromocytomas has not been reported in detail. In this article, we describe histopathologic features of 14 pheochromocytomas in eight patients with VHL disease and demonstrate that VHL-associated pheochromocytomas have a distinct histologic phenotype as compared with pheochromocytomas in patients with multiple endocrine neoplasia type 2 (MEN 2). VHL tumors are characterized by a thick vascular tumor capsule; myxoid and hyalinized stroma; round, small to medium tumor cells intermixed with small vessels; predominantly amphophilic and clear cytoplasm; absence of cytoplasmic hyaline globules; and lack of nuclear atypia or mitoses. In contrast to MEN 2, there is no extratumoral adrenomedullary hyperplasia in the VHL adrenal gland. Our findings of a distinct histologic phenotype of VHL pheochromocytoma may further help in subdividing patients who clinically present with multiple, bilateral pheochromocytomas.

The management of advanced renal cell carcinoma (RCC) continues to evolve. With the advent of laparoscopic radical nephrectomy (LRN), minimally invasive approaches to kidney cancer have developed. Laparoscopic resection of locally advanced RCC yields a similar cancer-control rate with the advantage of decreased morbidity. Although cytoreductive LRN is a technically challenging procedure, it may be completed safely in selected patients. Further prospective study of the role of LRN for advanced RCC is warranted.

Background: Radiofrequency thermal ablation (RFA) is a new minimally invasive treatment for localized cancer. Minimally invasive surgical options require less resources, time, recovery, and cost, and often offer reduced morbidity and mortality, compared with more invasive methods. To be useful, image-guided, minimally invasive, local treatments will have to meet those expectations without sacrificing efficacy., Methods: Image-guided, local cancer treatment relies on the assumption that local disease control may improve survival. Recent developments in ablative techniques are being applied to patients with inoperable, small, or solitary liver tumors, recurrent metachronous hereditary renal cell carcinoma, and neoplasms in the bone, lung, breast, and adrenal gland., Results: Recent refinements in ablation technology enable large tumor volumes to be treated with image-guided needle placement, either percutaneously, laparoscopically, or with open surgery. Local disease control potentially could result in improved survival, or enhanced operability., Conclusions: Consensus indications in oncology are ill-defined, despite widespread proliferation of the technology. A brief review is presented of the current status of image-guided tumor ablation therapy. More rigorous scientific review, long-term follow-up, and randomized prospective trials are needed to help define the role of RFA in oncology.

Purpose: Laparoscopic radical nephrectomy is being performed more commonly. To our knowledge intentional resection of the diaphragm during laparoscopic radical nephrectomy for large renal tumors has not yet been described. We detail the laparoscopic management of diaphragmatic resection., Materials and Methods: From March 1996 to February 2001, 36 patients underwent cytoreductive laparoscopic radical nephrectomy at our institution in preparation for systemic immunotherapy. Charts and operative tapes were reviewed and cases were identified in which diaphragmatic resection was performed for locally invasive tumors., Results: In 3 patients a portion of the diaphragm was dissected via laparoscopy during debulking nephrectomy. All patients had renal cell carcinoma with documented metastatic disease. The diaphragm was repaired laparoscopically using intracorporeal suturing techniques in 2 of the 3 patients and a chest tube was placed in all 3. Transient systolic hypotension and hypercarbia in 1 case resolved with manual ventilation. The chest tube was removed on postoperative days 2 to 4. There were no complications and no ipsilateral pleural metastasis was identified at an average of 6 weeks (range 2 to 23) of followup., Conclusions: A portion of the diaphragm may be intentionally resected during laparoscopic radical nephrectomy. This maneuver may be successfully managed without conversion to an open procedure. In cases of a large diaphragmatic defect or the potential for coagulopathy postoperatively a chest tube should be inserted. Potential invasion of the diaphragm by large tumors should not be considered a contraindication to cytoreductive laparoscopic radical nephrectomy.

Objective: Minimally invasive approaches to the management of renal tumors are being studied intensively in urology. Herein, we describe the use of multiple organ-sparing techniques for the management of tumors in a patient with von Hippel Lindau disease (VHL)., Materials and Methods: A 42 year-old woman with VHL underwent a right partial adrenalectomy and a left renal radiofrequency ablation (RFA) of two renal tumors., Results: A 2.2 cm solitary right adrenal pheochromocytoma was resected using a transperitoneal approach. A retroperitoneal approach to the left kidney was performed and RFA of the two renal tumors completed using sonographic guidance. On the 5-month follow-up CT scan, there was no evidence of residual adrenal tumors and both renal lesions lacked contrast enhancement. No complications occurred during the post-operative recovery., Conclusions: Multiple organ-ablative laparoscopic procedures may be performed in a single sitting. Laparoscopic partial adrenalectomy is an effective technique in patients with bilateral tumors or a familial syndrome predisposing to multiple adrenal tumors. Further study of renal RFA is required to assess the long-term durability of the procedure.

Purpose: Minimally invasive surgical approaches to renal and adrenal tumors have gained increasing use. The addition of robotic assistance and mechanical devices has decreased the number of assistants required for these often long cases. We describe an articulating arm retractor holder to aid in liver and spleen retraction during laparoscopic surgery., Materials and Methods: The articulating retractor holder consists of 4 components, including a base rod, flexible extension arm, stainless steel precision clamp and table attachment. During laparoscopy the abdomen is visualized using standard approaches. The articulating retractor holder is clamped to the table via the base rod and brought into the surgical field using sterile technique. A retractor is placed intracorporeally to elevate the liver or spleen and the handle is secured in place using the precision clamp., Results: The articulating retractor holder was used in all right and approximately 50% of left laparoscopic cases. Adequate visualization was obtained in all patients. There were no device failures or retractor related complications., Conclusions: The articulating retractor holder is a useful tool to aid in laparoscopic retraction that should be added to the urologist armamentarium.

Purpose: Patients with metastatic renal cell carcinoma have a reported 5-year survival of 0% to 20%. The ability to predict which patients would benefit from nephrectomy and interleukin-2 (IL-2) therapy before any treatment is initiated would be useful for maximizing the advantage of therapy and improving the quality of life., Materials and Methods: A retrospective analysis of the x-rays and charts of patients treated at the National Institutes of Health Surgery Branch between 1985 and 1996, who presented with metastatic renal cancer beyond the locoregional area and the primary tumor in place, was performed. Preoperative computerized tomography or magnetic resonance imaging, or radiological reports if no scans were available, were used to obtain an estimate of the volume of retroperitoneal lymphadenopathy. Operative notes were used to evaluate whether all lymphadenopathy was resected or disease left in situ, or if any extrarenal resection, including venacavotomy, was performed. Mean survival rate was calculated from the time of nephrectomy to the time of death or last clinical followup. If patients received IL-2 therapy, the response to treatment was recorded. Mean survival and response rate for IL-2 were compared among patients in 3 separate analyses. Patients without preoperatively detected lymphadenopathy were compared with those with at least 1 cm.3 retroperitoneal lymphadenopathy. Also, the patients who had detectable lymphadenopathy were divided into subgroups consisting of all resected, incompletely resected, unresectable and unknown if all disease was resected. Each subgroup was compared with patients without detectable preoperative lymphadenopathy. Patients with less than were compared to those with greater than 50 cm.3 retroperitoneal lymphadenopathy. Patients undergoing extrarenal resection at nephrectomy (complex surgery) due to direct invasion of the tumor into another intra-abdominal organ were compared with those undergoing radical nephrectomy alone, regardless of lymph node status. Statistical analysis was done with the Mantel-Cox test for comparison of survival on Kaplan-Meier curves and with Fisher's exact test for response rates for IL-2., Results: A total of 154 patients with metastatic renal cell carcinoma underwent cytoreductive nephrectomy as preparation for IL-2 based regimens. There were 82 patients with metastatic renal cell carcinoma and no preoperative retroperitoneal lymphadenopathy who survived longer (median 14.7 months) than the 72 with lymphadenopathy (median 8.5, p = 0.0004). Patients with incompletely resected, unresectable or an unknown volume resected had decreased survival compared to those with no retroperitoneal lymphadenopathy. A multivariate analysis of survival was performed evaluating the known prognostic indicators, performance status and tumor burden, as represented by the number of organs involved with metastases, and the new prognostic factor, lymphadenopathy. Lymphadenopathy was more closely associated with survival than performance status, and appeared to be a new prognostic variable. Patients with and without retroperitoneal lymphadenopathy at initial presentation had similar rates for treatment with IL-2 (54% for both groups). Of the 82 patients with no lymphadenopathy 11 (13%) had long-term survival greater than 5 years. Of the 6 complete responses to IL-2, 5 occurred in this group. Only 1 other patient with incompletely resected retroperitoneal lymphadenopathy survived longer than 5 years. No significant difference in survival was seen between patients who did or did not undergo complex surgery., Conclusions: Patients who presented with metastatic renal cancer and retroperitoneal lymphadenopathy had a shorter survival than those with no detectable retroperitoneal lymphadenopathy. It is warranted to continue to perform complex extrarenal resection during nephrectomy since no significant difference in the response rate for IL-2 or mean survival compared with those of patients undergoing nephrectomy alone is currently detectable.

This study examined the mechanisms linking different biochemical and clinical phenotypes of pheochromocytoma in multiple endocrine neoplasia type 2 (MEN 2) and von Hippel-Lindau (VHL) syndrome to underlying differences in the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis, and of phenylethanolamine N-methyltransferase (PNMT), the enzyme that converts norepinephrine to epinephrine. Signs and symptoms of pheochromocytoma, plasma catecholamines and metanephrines, and tumor cell neurochemistry and expression of TH and PNMT were examined in 19 MEN 2 patients and 30 VHL patients with adrenal pheochromocytomas. MEN 2 patients were more symptomatic and had a higher incidence of hypertension (mainly paroxysmal) and higher plasma concentrations of metanephrines, but paradoxically lower total plasma concentrations of catecholamines, than VHL patients. MEN 2 patients all had elevated plasma concentrations of the epinephrine metabolite, metanephrine, whereas VHL patients showed specific increases in the norepinephrine metabolite, normetanephrine. The above differences in clinical presentation were largely explained by lower total tissue contents of catecholamines and expression of TH and negligible stores of epinephrine and expression of PNMT in pheochromocytomas from VHL than from MEN 2 patients. Thus, mutation-dependent differences in the expression of genes controlling catecholamine synthesis represent molecular mechanisms linking the underlying mutation to differences in clinical presentation of pheochromocytoma in patients with MEN 2 and the VHL syndrome.

Purpose: von Hippel-Lindau disease, hereditary papillary renal cell carcinoma, the Birt-Hogg-Dubé 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-Dubé 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 patients underwent 71 operations resulting in unilateral nephrectomy in 6, bilateral nephrectomy in 1 and partial nephrectomy in 65, with 1 to 51 tumors removed from each kidney (mean 14.7). Mean patient age was 39.5 years (range 18 to 70). Of the 65 (40%) partial nephrectomies 26 were performed with cold renal ischemia. Mean blood loss was 2.9 +/- 0.5 l (range 0.15 to 23). Postoperative complications included renal atrophy in 3 patients. Mean preoperative serum creatinine was 1.05 +/- 0.03 mg/dl (range 0.6 to 1.8), and postoperative creatinine was 1.06 +/- 0.04 mg/dl (range 0.6 to 2.0). No patient who underwent renal parenchymal sparing surgery required renal replacement therapy. Metastatic disease developed in 1 patient with a 4.5 cm renal tumor., Conclusions: Parenchymal sparing surgery with a 3 cm threshold in patients with hereditary renal cancer appears to be an effective therapeutic option to maximize renal function while minimizing the risk of metastatic disease.

Pheochromocytoma is a rare but important tumor of chromaffin cells that is frequently considered in the evaluation of hypertension, arrhythmias, or panic disorder and in the follow-up of patients with particular genetic diseases. This report provides an update about the genetics, neurochemical diagnosis, localization by imaging, and surgical management of pheochromocytoma. Specific mutations of the RET proto-oncogene cause familial predisposition to pheochromocytoma in multiple endocrine neoplasia type II, and mutations in the von Hippel-Lindau tumor suppressor gene cause familial disposition to pheochromocytoma in von Hippel-Lindau disease. Recent findings demonstrating extraordinarily high sensitivity of plasma levels of metanephrines for detecting pheochromocytoma have led to an algorithm for clinical diagnostic steps. Nuclear imaging approaches, such as(123) I-metaiodobenzylguanidine scintigraphy and 6-[(18) F]fluorodopamine positron emission tomography, enhance both diagnosis and localization of the tumor, as described in an algorithm for patients with positive biochemical test results. Since pheochromocytoma is often benign, surgical resection by laparoscopic adrenalectomy can be curative. Areas requiring further work include determining appropriate follow-up of patients with familial pheochromocytoma, elucidating the bases for phenotypic differences, improving both specificity and sensitivity of biochemical tests, optimizing cost-effectiveness of diagnostic imaging, and testing the risk for tumor recurrence after partial adrenalectomy.

Purpose: We review our 10-year experience with intraoperative ultrasound during renal parenchymal sparing surgery in patients with hereditary renal cancers., Materials and Methods: Between 1991 and 2000, 68 nephron sparing procedures were performed on 26 women and 27 men, all but 1 of whom had a hereditary predisposition to renal cancer, for example von Hippel-Lindau, hereditary papillary renal cancer. Intraoperative ultrasound was performed after the surgeon removed all visible or palpable lesions. High frequency transducers (7 MHz.) and color Doppler were used in all cases. Lesions were characterized as simple cysts, complex cysts or solid masses, and were recorded on a map., Results: A total of 935 lesions (mean 12.8 lesions per kidney) were removed in 68 nephron sparing operations performed on 53 patients. Of these lesions 870 were removed without while 65 required intraoperative ultrasound. In 17 of 68 (25%) procedures intraoperative ultrasound identified renal cancers that were not detectable by the surgeon. Mean tumor size of ultrasound detected lesions was 1.0 cm. (range 2 mm. to 4 cm.). Of the 32 cystic lesions identified by intraoperative ultrasound 5 contained renal carcinoma, and 29 of the 33 solid renal masses were renal cell carcinomas. During reoperations ultrasound enabled the surface of the kidney to be evaluated even when it was inaccessible due to scar tissue or adherent perinephric fat., Conclusions: Intraoperative ultrasound can be performed after all visible lesions have been removed and identifies additional tumors in 25% of patients with hereditary renal cancer, thus ensuring that as many tumors as possible have been removed during renal parenchymal sparing surgery.

Most adrenal tumors are found incidentally and appear as small solitary nodules on abdominal imaging. Occasionally, work-up demonstrates multifocal or bilateral adrenal tumors. Certain patients are predisposed to multiple lesions, such as those with hereditary forms of pheochromocytoma as seen in von Hippel-Lindau disease, multiple endocrine neoplasia type II, and von Recklinghausen's disease. Partial rather than total adrenalectomy should be considered for these patients in an attempt to preserve endogenous adrenocortical function. Partial adrenalectomy has also been used to resect other types of adrenal tumors, especially in patients with a solitary adrenal gland. A discussion of the indications for partial adrenalectomy and of the surgical technique follows.

von Hippel-Lindau disease (VHL) is an autosomal dominant familial syndrome that predisposes to the formation of tumors in multiple organ systems, including adrenal and extra-adrenal pheochromocytomas. However, fewer than 30% of VHL families develop pheochromocytomas. In recent years, this clinical heterogeneity has been correlated with missense mutations. The VHL patient requires vigilant, lifelong biochemical and radiographic screening for pheochromocytoma. Half of VHL pheochromocytomas present bilaterally, and there is a high incidence of recurrence after surgery. Because of the morbidity of bilateral total adrenalectomy with subsequent steroid replacement therapy, the recent therapeutic trend has been toward observation and minimally invasive adrenal-sparing procedures.

Background: Patients with von Hippel-Lindau disease (VHL) may develop pancreatic neuroendocrine tumors (PNETs), which can behave in a malignant fashion. We prospectively evaluated size criteria for resection of lesions and the role of genotype/phenotype analysis of germline VHL mutations in predicting clinical course., Methods: From December 1988 through December 1999 we screened 389 patients with VHL. The diagnosis of PNET was made by pathologic analysis of tissues or by radiographic appearance. Germline mutations were determined by quantitative Southern blotting, fluorescence in situ hybridization and complete gene sequencing., Results: Forty-four patients with PNETs have been identified; 25 have undergone surgical resection, 5 had metastatic disease, and 14 are being monitored. No patient who has undergone resection based on tumor size criteria has developed metastases. Patients with PNETs were more likely to have missense mutations (58%), and 4 of 5 patients (80%) with metastatic disease had mutations in exon 3 compared with 18 of 39 (46%) patients without metastatic disease., Conclusions: Imaging for detection and surgical resection based on size criteria have resulted in the successful management of VHL patients with PNETs. Analysis of germline mutations may help identify patients at risk for PNET and which patients may benefit from surgical intervention.

In primary hyperaldosteronism, discriminating bilateral adrenal hyperplasia (BAH) from an aldosterone-producing adenoma (APA) is important because adrenalectomy, which is usually curative in APA, is seldom effective in BAH. We analyzed the results from our most recent 7-yr series to evaluate the predictive value of preoperative noninvasive tests compared with adrenal vein sampling (AVS). Forty-eight patients with hypertensive hyperaldosteronism underwent bedside testing, computed tomography (CT) imaging, and AVS. Those in whom the results of AVS indicated APA underwent adrenalectomy. Twelve (30%) and 14 (34%) of 41 patients with APA had paradoxical falls with ambulation in plasma aldosterone concentration (PAC) and 18-hydroxycorticosterone (18-OH-B), respectively. Twenty-nine (70%) and 26 (65%) APA patients had a rise in PAC and 18-OH-B, respectively, as did all 8 BAH patients. Significant identifiers of BAH were supine PAC values less than 15 ng/dL (P: = 0.04), an increase greater than 60% (P: = 0.02) in PAC with ambulation, and supine 18-OH-B values less than 60 ng/dL (P: = 0.04). CT imaging alone was not predictive for BAH or APA. In our population, patients with a positive bedside test result (e.g. a fall in PAC and/or 18-OH-B) and a unilateral adrenal nodule on CT (10 of 41 patients) could have proceeded directly to adrenalectomy for APA. However, a positive bedside test result with a negative CT or a negative bedside test result regardless of CT findings required AVS to confirm the diagnosis and site of disease.

Suramin has been shown to have an effect on bone resorption in in vitro models. It is not clear if a similar effect is seen in patients treated with suramin. The clinical effect of suramin treatment on total serum calcium was examined in two groups of patients with hormone-refractory prostate cancer. In all, 28 patients in group 1 were examined within 2 weeks before and 2 weeks after suramin treatment and 72 patients in group 2 were examined within 2 weeks before, during, and after treatment with suramin. In addition, calcium controls spiked with suramin were run in three different commercially available assays for evaluation of the effect of suramin dose on calcium determination. Group 1 patients showed a decrease in serum calcium after treatment with suramin. The mean uncorrected serum calcium level was 2.29 +/- 0.025 mmol/l before treatment and 2.09 +/- 0.025 mmol/l after treatment (P < 0.0001, paired Wilcoxon test). The mean serum calcium value corrected for albumin was 2.33 +/- 0.02 mmol/l before treatment and 2.24 +/- 0.02 mmol/l after treatment (P = 0.0022, paired Wilcoxon test). Group 2 patients also displayed a decrease in serum calcium after treatment with suramin. The mean baseline value was 2.23 mmol/l (median 2.26 mmol/l, range 1.20-2.54 mmol/l). The mean level of serum calcium corrected for albumin as determined at the end of treatment was 2.14 mmol/l (median 2.16 mmol/l, range 0.98 2.46 mmol/l). In all, 48 patients for whom pre- and post-treatment values were available for analysis displayed a median calcium decrease of 0.09 mmol/l (P = 0.0005, Wilcoxon signed-rank test for the null hypothesis of no change). For 68 patients in group 2, data on serial serum calcium measurements during treatment were available for analysis. A projected median decrease in serum calcium of 0.06 mmol/l (range 0.43 to 0.72 mmol/l) over an 8-week interval of suramin therapy was found. Overall, 47 of the 68 slopes were negative (P = 0.0022, Wilcoxon signed-rank test). Nine patients were treated with suramin for less than 6 weeks. These patients' calcium levels were significantly higher than those of 50 patients treated for longer periods (median value 2.24 versus 2.16 mmol/l, P = 0.035, Wilcoxon rank-sum test). No correlation was found between suramin dose and calcium level using the Kodak Ektachem, Hitachi 914, or Synchron Clinical System CX3 method. In conclusion, suramin treatment was consistently associated with decreases in serum calcium in two groups of patients with hormone-refractory cancer. Suramin placed in calcium controls did not affect calcium determination using three commercially available methods.

Microcystic adenoma and cysts of the pancreas occur sporadically or as a part of von Hippel-Lindau (VHL) disease. The pathology of pancreatic cystic disease in VHL patients has not been well characterized. Furthermore, it is presently unknown whether the alteration of the VHL gene is responsible for the development of the entire spectrum of pancreatic serous cystic lesions. We performed a histopathological analysis of 21 cysts and 98 microcystic adenomas in nine VHL patients with a known germline mutation. In addition, PCR-amplified DNA from 27 pancreatic cystic lesions in three informative patients was studied for allelic deletions with polymorphic markers spanning the VHL gene locus. In all patients, pancreatic lesions were multiple: 21 benign serous cysts, 63 microscopic microcystic adenomas (size <0.4 cm), and 35 macroscopic microcystic adenomas (size >0.5 cm). The average number of lesions per patient was 2.1 benign cysts (range, 0-8), 7.7 (1-37) microscopic microcystic adenomas, and 3 (0-21) macroscopic microcystic adenomas. All lesions showed similar histology and contained prominent fibrous stroma, clear and/or amphophilic, glycogen-rich epithelial cells, endothelial and smooth muscle cells. VHL deletions were detected in all types of pancreatic cystic lesions. The presence of VHL gene allelic deletions in the spectrum of multifocal pancreatic cystic lesions provides direct molecular evidence of their neoplastic nature and integral association with VHL disease. The histopathological and molecular data establish a serous cyst-microcystic adenoma continuum in the development of pancreatic cystic neoplasia in VHL disease.

Purpose: Patients with von Hippel-Lindau disease are predisposed to multiple bilateral adrenal pheochromocytoma. In these patients partial adrenalectomy may preserve adrenocortical function and avoid the morbidity associated with medical adrenal replacement. We report our experience with such cases., Materials and Methods: Laparoscopic partial adrenalectomy was performed in patients with von Hippel-Lindau disease and pheochromocytoma when there was evidence of normal adrenocortical tissue on preoperative imaging or intraoperative examination. Suture ligature or a harmonic scalpel was used to excise the tumors, leaving a 2 to 3 mm. margin of normal tissue., Results: Two patients underwent laparoscopic partial adrenalectomy and 1 laparoscopic bilateral partial adrenalectomy with preservation of normal adrenocortical tissue. Seven pheochromocytomas were removed. Laparoscopic ultrasound was essential for localizing 2 pheochromocytomas that were not visualized by the camera. Median operative time was 324 minutes, blood loss 100 cc and parenteral narcotic requirement 22 mg. morphine equivalents. No patient required hydrocortisone replacement. There has been no pheochromocytoma recurrence during short-term followup., Conclusions: Laparoscopic partial adrenalectomy is technically feasible in patients with a hereditary form of pheochromocytoma, and may preserve adrenocortical function. Laparoscopic ultrasound was necessary to identify 2 of the 7 pheochromocytomas removed.

Photodynamic therapy is an exciting area of research for the treatment of superficial bladder cancer. Significant responses have been seen in patients resistant to standard intravesical treatments. New areas of research are focused on the development of new sensitizers and light distribution methods with less dermal and bladder toxicity.

Purpose: We describe the earliest renal lesions associated with hereditary papillary renal cancer and estimate the prevalence of microscopic papillary renal tumors., Materials and Methods: Grossly normal tissue was obtained from 12 kidneys during renal surgery in 9 patients with hereditary papillary renal cancer. Tissue was examined microscopically and findings were compared to those previously reported to be associated with von Hippel-Lindau disease and sporadic renal cell carcinoma., Results: A total of 92 microscopic papillary renal cell carcinoma lesions were identified on 46 of 88 slides (53%). No other lesions were identified. All tumors were solid and displayed the basophilic papillary histology characteristic of hereditary papillary renal cancer. Extrapolation of the data predicted the prevalence of 1,100 to 3,400 microscopic papillary tumors in a single kidney in a patient with hereditary papillary renal cancer., Conclusions: The basophilic papillary histology characteristic of clinically apparent renal tumors in patients with hereditary papillary renal cancer also characterizes the multiple microscopic lesions seen in the kidneys. These findings suggest that the earliest renal tumor in patients with an activating hereditary mutation of the met gene is papillary basophilic renal cancer. The large number of microscopic tumors in patients with hereditary papillary renal cancer was comparable to or greater than that seen in those with von Hippel-Lindau disease.

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.

Purpose: We review the literature and characterize the clinical findings of von Recklinghausen's associated pheochromocytoma., Materials and Methods: A Grateful Med search for the years 1966 to 1999 was performed on the subjects, "von Recklinghausen" and "neurofibromatosis." Articles from the Grateful Med search were then reviewed to identify older publications. Of 325 articles 118 are included in this review., Results: Pheochromocytomas have been clinically identified in 0.1 to 5.7% of patients with von Recklinghausen's disease. Mean patient age was 42 years (range 1.5 to 74) in 87 women and 61 men at presentation with pheochromocytoma. Of the 148 patients 84% had solitary adrenal tumors, 9.6% bilateral adrenal disease and 6.1% ectopic pheochromocytomas. Symptoms related to pheochromocytoma or hypertension were noted in 78% of the patients. Tumors secreted epinephrine and norepinephrine, and 87% demonstrated metaiodobenzylguanidine uptake. Of the 148 patients 6% died during pregnancy or a medical procedure, or due to hypertensive crisis without apparent provocation, 8.8% had gastrointestinal carcinoid tumors and 11.5% had metastases or local invasion from pheochromocytoma., Conclusions: Pheochromocytomas occur in a small but defined number of patients with von Recklinghausen's disease, and can be associated with significant morbidity and mortality if not detected. Screening of patients with von Recklinghausen's disease and hypertension or before provocative procedures or pregnancy seems to be indicated.

Purpose: We characterize the genetic abnormalities associated with pathological subtypes of renal tumors, which may help diagnosis or prognostication., Materials and Methods: A comprehensive literature review of genetic abnormalities associated with different renal tumor subtypes was performed., Results: Studies of sporadic and hereditary forms suggest that abnormalities in the von Hippel-Lindau and met genes are the earliest changes in conventional (clear cell) and papillary basophilic renal cancers, respectively. Renal oncocytoma and chromophobe carcinoma have common genetic abnormalities, suggesting a relationship. A similar finding has been observed between papillary adenoma and papillary basophilic renal cancer., Conclusions: These findings suggest that molecular diagnostic testing will help determine histopathological diagnosis, identify tumor types with similar genetic abnormalities suggesting a common origin and indicate potential prognostic markers for future study.

Purpose: Families with von Hippel-Lindau disease have variable risk of pheochromocytoma. Patients with von Hippel-Lindau disease and pheochromocytoma identified by screening can have no characteristic signs or symptoms. Families with von Hippel-Lindau disease were screened and followed to describe the natural history of von Hippel-Lindau pheochromocytoma, and to correlate these findings with von Hippel-Lindau germline mutation., Materials and Methods: Between 1988 and 1997, 246 individuals with von Hippel-Lindau disease were identified (von Hippel-Lindau group). Between August 1990 and June 1997, 26 consecutive patients with sporadic pheochromocytoma were evaluated (sporadic group)., Results: A total of 64 patients with von Hippel-Lindau disease had manifestations of pheochromocytoma, including 33 newly diagnosed during screening at the National Institutes of Health and 31 previously treated (93 adrenal and 13 extra-adrenal pheochromocytomas). Germline von Hippel-Lindau gene missense mutation was associated with extra-adrenal pheochromocytoma, younger age at presentation and the only patient with metastases. Of the 33 newly diagnosed patients with von Hippel-Lindau disease 4 had pheochromocytoma 2 times (37 pheochromocytomas) during followup. Of these pheochromocytomas 35% (13 of 37) were associated with no symptoms, normal blood pressure and normal catecholamine testing. Comparison of urinary catecholamines in the von Hippel-Lindau and sporadic groups demonstrated increased epinephrine, metanephrines and vanillylmandelic acid in the sporadic group. Analysis of urinary catecholamine excretion in the von Hippel-Lindau and sporadic groups together demonstrated a correlation between tumor size, and urinary metanephrines, vanillylmandelic acid, norepinephrine, epinephrine and dopamine. In 12 patients without signs or symptoms of pheochromocytoma 17 newly diagnosed pheochromocytomas were followed for a median of 34.5 months without morbidity. Median tumor doubling time was 17 months., Conclusions: Von Hippel-Lindau gene missense mutation correlated with the risk of pheochromocytoma in patients with von Hippel-Lindau disease. These findings support a von Hippel-Lindau disease clinical classification, wherein some families are at high risk for manifestations of pheochromocytoma. Von Hippel-Lindau disease pheochromocytomas identified by screening were smaller and less functional than sporadic pheochromocytomas.

Germline mutations of c-met oncogene at 7q31 have been detected in patients with hereditary papillary renal cell carcinoma. In addition, c-met mutations were shown to play a role in 13% of patients with papillary renal cell carcinoma and no family history of renal tumors. The histopathology of papillary renal cell carcinoma with c-met mutations has not been previously described. We analyzed the histopathology of 103 bilateral archival papillary renal cell carcinomas and 4 metastases in 29 patients from 6 hereditary papillary renal cell carcinoma families with germline c-met mutations and 6 papillary renal cell carcinomas with c-met mutations from 5 patients with no family history of renal tumors. Twenty-five sporadic renal tumors with prominent papillary architecture and without somatic c-met mutations were evaluated for comparison. All papillary renal cell carcinomas with c-met mutations were 75 to 100% papillary/tubulopapillary in architecture and showed chromophil basophilic, papillary renal cell carcinoma type 1 histology. Fuhrman nuclear grade 1-2 was seen in tumors from 23 patients, and nuclear grade 3 was observed focally in 8 patients. Seventeen patients had multiple papillary adenomas and microscopic papillary lesions in the surrounding renal parenchyma. Clear cells with intracytoplasmic lipid and glycogen were focally present in tumors of 94% papillary renal cell carcinoma patients. Clear cells of papillary renal cell carcinoma had small basophilic nuclei, and clear cell areas lacked a fine vascular network characteristic of conventional (clear) cell renal cell carcinoma. We conclude that papillary renal cell carcinoma patients with c-met mutations develop multiple, bilateral, papillary macroscopic and microscopic renal lesions. Renal tumors with c-met genotype show a distinctive papillary renal cell carcinoma type 1 phenotype and are genetically and histologically different from renal tumors seen in other hereditary renal syndromes and most sporadic renal tumors with papillary architecture. Although all hereditary and sporadic papillary renal cell carcinomas with c-met mutations share papillary renal cell carcinoma type 1 histology, not all type 1 sporadic papillary renal cell carcinomas harbor c-met mutations.

Purpose: We assessed morbidity, response and survival in patients with metastatic renal carcinoma treated with high dose intravenous interleukin-2 (IL-2) based immunotherapy with the primary renal tumor in place., Materials and Methods: We retrospectively analyzed the records of patients with metastatic renal carcinoma and the primary kidney tumor in situ who were treated at the surgery branch of the National Cancer Institute. Of the patients 607 were treated with IL-2 based therapy. Patient age, sex, sites of extrarenal disease, morbidity, and response and survival rates were examined., Results: From 1986 to 1996, 51 patients with the majority of disease at extrarenal sites were treated with the primary tumor in place. Treatment involved IL-2 based regimens, reflecting the evolution of immunotherapy at the National Institutes of Health. When evaluating only extrarenal sites, response was complete in 1 and partial in 2 of the 51 cases (6%). No responses were noted in the primary renal tumor. Three patients with responses at extrarenal sites underwent nephrectomy. The duration of response in these 3 cases was greater than 88, 11 and 4 months, respectively. Median survival in all 51 patients was 13 months (range 1 to 86)., Conclusions: Select patients may be treated with IL-2 based immunotherapy with the primary renal tumors in place with morbidity. A randomized study is needed to assess the role of cytoreductive nephrectomy for treating metastatic renal cell carcinoma.

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 vanillylmandelic acid., Results: The sensitivity of measurements of plasma normetanephrine and metanephrine for the detection of tumors was 97 percent, whereas the other biochemical tests had a sensitivity of only 47 to 74 percent. All patients with MEN-2 had high plasma concentrations of metanephrine, whereas the patients with von Hippel-Lindau disease had almost exclusively high plasma concentrations of only normetanephrine. One patient with von Hippel-Lindau disease had a normal plasma normetanephrine concentration; this patient had a very small adrenal tumor (<1 cm). The high sensitivity of measurements of plasma normetanephrine and metanephrine was accompanied by a high level of specificity (96 percent)., Conclusions: Measurements of plasma normetanephrine and metanephrine are useful in screening for pheochromocytomas in patients with a familial predisposition to these tumors.

Purpose: 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 largest 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 6 to 205). None of these patients had metastatic disease and none has required renal transplantation or dialysis. In 44 patients with von Hippel-Lindau disease (group 2) renal tumors larger than 3 cm. developed. Median followup from the initial radiological diagnosis of renal cancer in this group was 66.5 months (range 0 to 321). Patients in group 1 underwent parenchymal sparing surgery instead of nephrectomy more frequently than those in group 2 (46 of 48 operations or 96% versus 45 of 72 or 63%, Fisher's exact test p <0.0001). In contrast to patients in group 1, metastatic renal cancer developed in 11 of the 44 in group 2 (25%) (Fisher's exact test p <0.0001). A total of 23 patients with hereditary papillary renal cancer were also identified. Median followup in these cases was 44 months (range 0 to 237). Ten patients had tumors less than 3 cm. No patient with tumors less than 3 cm. and 2 of the 13 (15%) with larger tumors had metastases., Conclusions: Using a 3 cm. renal tumor diameter as an indication for renal surgery no patient with renal cancer and von Hippel-Lindau disease or hereditary papillary renal cancer had metastatic disease regardless of the number of tumors. Using a lesion size of 3 cm. as a threshold for performing renal parenchymal sparing surgery may help to prevent metastatic disease, unnecessary renal damage due to frequent surgery and renal dialysis or transplantation.

Objectives: Cytoreductive nephrectomy is commonly performed in patients with metastatic renal cell carcinoma before systemic interleukin-2 (IL-2) therapy. Open nephrectomy is associated with prolonged recovery during which metastatic disease can progress. The feasibility of laparoscopic cytoreductive surgery in these patients with large renal tumors was examined. The role of tumor morcellation in reducing the recovery period and allowing earlier treatment with IL-2 was investigated., Methods: Patients with metastatic renal cancer underwent either open nephrectomy (group 1, n = 19) or laparoscopic cytoreductive nephrectomy (n = 11; 6 with tumor morcellation [group 2], 5 with removal of the tumor through a small incision [group 3]). The three groups were compared to evaluate relative recovery, suitability for treatment with IL-2, and laparoscopic port site seeding., Results: A group of 19 patients underwent open nephrectomy (group 1). Eleven patients with a median tumor volume of 377 cm3 (median tumor diameter 9 cm) underwent laparoscopic cytoreductive nephrectomy. Six of these patients underwent tumor morcellation (group 2) and 5 underwent laparoscopic assisted nephrectomy (group 3). There was no difference in patient age, sex, sites of metastatic disease, ECOG status, size of renal tumor, or surgical complication rates among groups. Patients whose tumor was morcellated had reduced postoperative parenteral narcotic requirements and were discharged sooner than patients undergoing open cytoreductive nephrectomy. Time to treatment with IL-2 was shortest in the morcellation group (median time to treatment 37 days). No port site seeding was observed., Conclusions: Laparoscopic cytoreductive nephrectomy in patients with bulky renal disease is a safe procedure in selected patients. This pilot study demonstrated a significant association of laparoscopic tumor morcellation with less postoperative pain, faster time to discharge, and shorter time to treatment with IL-2. A randomized study is warranted to determine the role of laparoscopic cytoreductive nephrectomy with tumor morcellation.

Par-4 is a widely expressed leucine zipper protein that confers sensitization to apoptosis induced by exogenous insults. Because the expression of genes that promote apoptosis may be down-regulated during tumorigenesis, we sought to examine the expression of Par-4 in human tumors. We present here evidence that Par-4 protein levels were severely decreased in human renal cell carcinoma specimens relative to normal tubular cells. Replenishment of Par-4 protein levels in renal cell carcinoma cell lines conferred sensitivity to apoptosis. Because apoptosis may serve as a defense mechanism against malignant transformation or progression, decreased expression of Par-4 may contribute to the pathophysiology of renal cell carcinoma.

Pheochromocytoma is a catecholamine-producing tumor of the sympathetic nervous system. Signs and symptoms are generally related to catecholamine excess; these include hypertension, sweating, palpitatione, headaches, and anxiety attacks. Abdominal imaging and 24-h urine collection for catecholamines are usually be sufficient for diagnosis. Catecholamine blockade with phenoxybenzamine and metyrosine generally ameliorates symptoms and is necessary to prevent hypertensive crisis during surgery. Standard treatment is laparoscopic adrenalectomy, although partial adrenalectomy is gaining enthusiastic support in familial forms of pheochromocytoma. Pheochromocytomas have been estimated to be present in approximately 0.3% of patients undergoing evaluation for secondary causes of hypertension [41]. Pheochromocytomas are usually curable if diagnosed and treated properly, but they can be fatal if they are not diagnosed or are managed inappropriately. Autopsy series suggest that many pheochromocytomas are not clinically suspected and that the undiagnosed tumor can be associated with morbid consequences [42].

Purpose: In patients with von Hippel-Lindau disease multiple bilateral adrenal pheochromocytoma can develop, which has traditionally been treated with adrenalectomy. Partial adrenalectomy can preserve normal adrenal function and avoid the morbidity associated with medical adrenal replacement. We demonstrate whether adrenal function could be preserved by partial adrenalectomy in patients with von Hippel-Lindau disease., Materials and Methods: From 1995 to 1998, 13 consecutive von Hippel-Lindau disease patients with pheochromocytoma underwent 14 partial and 6 complete unilateral adrenalectomies. Function of residual normal adrenal and recurrence of adrenal pheochromocytoma were determined at followup., Results: Of the patients 2 had undergone unilateral adrenalectomy and 1 had undergone complete and partial adrenalectomy previously. Following surgery residual normal adrenal tissue consisted of 1 partial adrenal in 3 patients, bilateral partial adrenal in 5, partial and complete adrenal gland in 1, 1 complete adrenal gland in 3 and no adrenal tissue in 1. Three patients with residual adrenal tissue were placed on medical adrenal replacement until adrenocorticotropic hormone stimulation testing demonstrated adrenocortical function. In 2 patients 1 adrenal and 2 extra-adrenal new pheochromocytomas developed 11 and 152 months, respectively, after partial adrenalectomy. No morbidity related to pheochromocytoma was observed during followup., Conclusions: Partial adrenalectomy can preserve adrenal function in patients with a hereditary form of pheochromocytoma.

Purpose: We analyzed familial renal oncocytoma to provide a foundation for studies aimed at defining genes involved in the pathogenesis of renal oncocytoma., Materials and Methods: We describe 5 families with multiple members affected with renal oncocytoma. Tumors were analyzed pathologically, and affected and nonaffected members were screened clinically and genetically., Results: We identified 12 affected male and 3 affected female (ratio 4:1) individuals in the 5 families. In affected family members renal oncocytomas were often multiple and bilateral. No metastatic disease was observed. Most renal oncocytomas were detected incidentally in asymptomatic individuals or during screening of asymptomatic members of renal oncocytoma families. One identical twin pair was affected with bilateral multiple renal oncocytomas., Conclusions: Renal oncocytoma may be inherited in some families.

Although pancreatic neuroendocrine tumors (NETs) in von Hippel-Lindau (VHL) disease have been reported, their pathological features have not been characterized. In addition, it is unknown whether alterations of the VHL gene are responsible for pancreatic NET development. To evaluate NETs in VHL patients, we performed histopathological analysis of 30 pancreatic tumors in 14 patients. In addition, DNA from NETs and normal pancreatic tissue from 6 patients with documented germ-line VHL gene mutations was studied for allelic deletions of the second copy of the VHL gene by fluorescence in situ hybridization and polymerase chain reaction-based single-strand conformational polymorphism analysis. Morphologically, the tumors were characterized by solid, trabecular, and/or glandular architecture and prominent stromal collagen bands. Sixty percent of the tumors revealed at least focally clear-cell cytology. All tumors were positive for panendocrine immunohistochemistry markers (chromogranin A and/or synaptophysin); 35% of NETs demonstrated focal positivity for pancreatic polypeptide, somatostatin, insulin, and/or glucagon; and no immunostaining for pancreatic and gastrointestinal hormones was observed in 65% of tumors. Dense core neurosecretory granules were evident by electron microscopic examination, and the clear cells additionally revealed abundant intracytoplasmic lipid. All NETs that were subjected to genetic analysis showed allelic loss of the second copy of the VHL gene. We conclude that multiple, nonfunctional pancreatic NETs occur in VHL patients. Stromal collagen bands and clear-cell morphology are important histological features of VHL-associated NETs. The presence of allelic deletions of the VHL gene in pancreatic NETs provides direct molecular evidence for a role of the gene in their tumorigenesis and establishes NET as an independent tumor type of VHL disease.

Purpose: After renal parenchymal sparing surgery, residual defects may persist on imaging studies at the sites of resection. These "pseudotumors" may lead to confusion as to whether a lesion was removed or has recurred. We describe the imaging appearances and behavior of renal pseudotumors following renal parenchymal sparing surgery., Materials and Methods: From 1988 to 1997, 32 patients underwent 46 renal parenchymal sparing surgeries for removal of renal cancers, including von Hippel-Lindau disease in 27, hereditary papillary renal cancer in 2 and sporadic disease in 3. A median of 14 tumors (range 1 to 114) were removed in each operation. Thrombin soaked absorbable gelatin sponge was placed in the tumor bed after resection to aid hemostasis. We reviewed all imaging studies performed after these operations to characterize these lesions and gain further understanding into the prevalence and etiology., Results: Of the patients, 9 had a total 13 pseudotumors on initial postoperative imaging studies, including Hippel-Lindau disease in 7, hereditary papillary renal cancer in 1 and sporadic renal cancer in 1. Pseudotumors were observed after 10 of 46 operations (22%). All pseudotumors demonstrated round contours and enhancement after contrast media, simulating a tumor, yet, these lesions resolved in a mean of 13 months, leaving only small cortical scars., Conclusions: Renal pseudotumors are commonly seen after renal parenchymal sparing surgery and should not be confused with residual or recurrent disease. Enhancement is likely due to granulation tissue involving the lattice of absorbable gelatin sponge. These lesions usually resolve within a year but can take longer to do so.