Multifocality is not associated with worse survival in sporadic pancreatic neuroendocrine tumors.

BACKGROUND AND OBJECTIVES: Pancreatic neuroendocrine tumors (pNETs) in patients with hereditary cancer syndromes are typically multifocal. In contrast, sporadic pNETs are usually unifocal and the incidence of multifocal sporadic pNETs is unknown. The primary aim of this study was to investigate the incidence of multifocality in sporadic pNETs and any associated effect on recurrence risk and survival. METHODS: Patients who underwent resection of pNETs at Mayo Clinic from 2000 to 2019 were identified and clinical data were obtained from medical records. Syndromic disease was defined as pNETs arising in the setting of a hereditary cancer syndrome. Statistical comparisons were made using χ2 , Fisher's exact, and Kruskal-Wallis tests and survival was assessed using the Kaplan-Meier method. RESULTS: Six hundred and sixty-one patients with sporadic pNETs and fifty-nine with syndromic pNETs were identified. Multifocal disease was present in 4.8% of sporadic patients and 84.7% of syndromic patients (p < .001). Within patients with sporadic pNETs, clinicopathologic features and recurrence-free and overall survival were similar between patients with unifocal and multifocal disease. CONCLUSIONS: Multifocal sporadic pNETs are rare and multifocality is not associated with worse survival or increased recurrence risk. Patients with multifocal sporadic pNETs can likely be safely managed with a combination of resection and observation as indicated for each tumor.

Survival and causes of death in patients with von Hippel-Lindau disease.

BACKGROUND: Historically, the survival of patients with von Hippel-Lindau disease (vHL) has been poorer than that of the general population. We aimed to determine whether the survival of VHL mutation carriers and their risk of vHL-related death has changed over time and how it has been affected by sex, genotype and surveillance attendance. METHODS: In a retrospective cohort study, we included all known Danish vHL families with a VHL mutation. We assessed the survival and causes of death for 143 VHL mutation carriers using Cox regression models and compared vHL survival with that of 137 siblings without vHL. vHL life expectancy was compared with the general population using a relative survival model. RESULTS: The estimated mean life expectancies for male and female patients born in 2000 were 67 and 60 years, respectively. Survival is influenced by the sex and genotype of the patient. Female patients have a significantly higher risk of vHL-related death than male patients (HR=2.25, 95% CI 1.20 to 4.20, p=0.011). Overall, 79% (53 of 67) of deaths were vHL-related, but the risk of vHL-related death has decreased over time, as has the frequency of renal cell carcinoma (RCC)-related death. Surveillance is especially beneficial for truncating mutation carriers, who have the greatest RCC and central nervous system (CNS) hemangioblastoma risk. CONCLUSIONS: vHL survival has improved over time and has become closer to that of siblings without vHL and the general population. Even though the risk of vHL-related death has decreased significantly, the main cause of death is still CNS hemangioblastomas and hence improved treatment options are essential.

Sunitinib for the treatment of benign and malignant neoplasms from von Hippel-Lindau disease: A single-arm, prospective phase II clinical study from the PREDIR group.

Von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary cancer syndrome that predisposes affected individuals to the development of multiple benign and malignant tumors. One of the main manifestations of VHL is renal cell carcinoma (RCC). RCC is increasingly being treated with targeted therapies, which offer an alternative treatment option for patients with VHL disease. This study investigated the effectiveness of sunitinib in VHL patients with advanced tumors or tumors unsuitable for surgery.This multicenter, phase II, open-label study from the PREDIR VHL network, treated patients with genetically-confirmed advanced VHL disease with oral sunitinib (50 mg/day for 28 days then a 2-week rest period) until progression. Lesions were performed using magnetic resonance imaging (MRI) and computed tomographic (CT) scan. The primary endpoint was objective response rate; secondary endpoints included tolerability and overall survival.All five patients showed stable disease as best response at 6 months. Two patients showed impressive transitory clinical improvement during early cycles. No patient died during sunitinib treatment. Reasons for discontinuing sunitinib therapy were disease progression (n=1), unacceptable toxicity (n=3) and lack of clinical improvement after 7 cycles (10.5 months) with unacceptable toxicity (n=1).In conclusion, sunitinib was of limited benefit in patients with advanced VHL disease, but had better efficacy against metastatic RCC than other VHL-related lesions. Treatment-related toxicity is an important limiting factor in this frail patient population. New agents with different mechanisms of action are required to treat this disease.

Long-term Prognosis of Resected Pancreatic Neuroendocrine Tumors in von Hippel-Lindau Disease Is Favorable and Not Influenced by Small Tumors Left in Place.

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.

Telomere shortening is associated with genetic anticipation in Chinese Von Hippel-Lindau disease families.

Von Hippel-Lindau (VHL) disease is a rare autosomal dominant cancer syndrome. A phenomenon known as genetic anticipation has been documented in some hereditary cancer syndromes, where it was proved to relate to telomere shortening. Because studies of this phenomenon in VHL disease have been relatively scarce, we investigated anticipation in 18 Chinese VHL disease families. We recruited 34 parent-child patient pairs (57 patients) from 18 families with VHL disease. Onset age was defined as the age when any symptom or sign of VHL disease first appeared. Anticipation of onset age was analyzed by paired t test and the other two special tests (HV and RY2). Relative telomere length of peripheral leukocytes was measured in 29 patients and 325 healthy controls. Onset age was younger in child than in parent in 31 of the 34 parent-child pairs. Patients in the first generation had older onset age with longer age-adjusted relative telomere length, and those in the next generation had younger onset age with shorter age-adjusted relative telomere length (P < 0.001) in the 10 parent-child pairs from eight families with VHL disease. In addition, relative telomere length was shorter in the 29 patients with VHL disease than in the normal controls (P = 0.003). The anticipation may relate to the shortening of telomere length in patients with VHL in successive generations. These findings indicate that anticipation is present in families with VHL disease and may be helpful for genetic counseling for families with VHL disease families and for further understanding the pathogenesis of VHL disease.

Renal tumor size is an independent prognostic factor for overall survival in von Hippel-Lindau disease.

OBJECTIVES: To evaluate the effect of renal cell carcinoma (RCC) on survival in von Hippel-Lindau (VHL) disease and to assess the relationship between tumor size and survival. MATERIALS AND METHODS: In this retrospective cohort study, the medical records of 72 patients who presented with VHL disease between 1994 and 2012 were reviewed. Clinical VHL-related characteristics were analyzed, and the prognostic value of renal tumor size for overall survival was assessed by using Cox regression models. RESULTS: Of the 72 VHL patients, 42 (58.3 %) and 30 (41.7 %) were male and female, respectively. The mean age was 37.9 years, and the median follow-up period was 61.5 months. In terms of VHL-related manifestations, 40 (55.6 %) had RCC, 46 (63.8 %) had hemangioblastoma in the cerebellum, 10 (13.9 %) had hemangioblastoma in the spinal cord, 34 (47.2 %) had a pancreatic mass, 18 (25.0 %) had pheochromocytoma, and 14 (19.4 %) had retinal capillary hemangioma. RCC was a major cause of mortality: Of the 11 patients who died, nine (12.5 %) died due to RCC progression. The 5-year overall survival rate was 85.6 % for all patients, 96.9 % for patients without RCC, 83.6 % for patients with RCC < 3 cm, and 75.8 % for patients with RCC ≥ 3 cm. Multivariable analysis showed that RCC ≥ 3 cm was an independent predictor of overall survival (HR 9.87, 95 % CI 1.17-83.00, p = 0.035) along with age (HR 1.05, 95 % CI 1.01-1.10, p = 0.027). CONCLUSIONS: Renal tumor size was an independent prognostic factor for overall survival in VHL disease. This observation will be helpful for planning RCC treatment in VHL disease.

Epidemiological study of a von Hippel-Lindau family in northwest China.

von Hippel-Lindau (VHL) disease is a rare, inherited neoplastic disease characterized by hemangioblastomas (HBL) of the central nervous system (CNS), retinal angiomas, renal cell carcinomas (RCC), pancreatic endocrine tumors (PETs), pheochromocytomas, paragangliomas, and visceral cysts. We encountered a large VHL family in northwest China and conducted a systematic screening of the family members based on their epidemiological and clinical characteristics. A self-designed questionnaire was used to collect the general sociodemographic and health information of the family members. For the preliminary family screening, physical examination and abdomen B ultrasonography were performed. The suspected patients were subjected to cranial computerized tomography and fundus examination. The clinical data of the patients with confirmed VHL disease were collected from hospital records. A total of 63 lineal descendants in six generations were observed in the family (generations O, A, B, C, D, E), including 9 dead suspected cases (6 males, 3 females) and 10 living cases (2 males, 8 females). Among the 10 living cases, 4, 2, 1, 3, 4, 8, and 2 manifested HBLs of the CNS, PETs, RCC, pancreatic cysts, renal cysts, pheochromocytomas (4 hemi and 4 bilateral), and paragangliomas, respectively. Data showed that the morbidity of VHL disease in generation C was lower than that in generation B, but the age of onset was younger. This study is the first to report VHL disease in northwest China and VHL-associated PET cases in Chinese. Therefore, follow-up checkups of the family should be focused on younger generations. Proper family screening protocols should be followed for the treatment of patients with VHL disease.

Pregnancy-related hemangioblastoma progression and complications in von Hippel-Lindau disease.

OBJECTIVE: We studied the reciprocal effect of pregnancy and von Hippel-Lindau (VHL) disease by analyzing the influence of pregnancy on VHL disease-related lesions and VHL disease on pregnancy outcome. METHODS: Medical charts and imaging reports from the VHL disease expertise centers in the Netherlands were used to retrospectively assess lesion progression score before and after pregnancy and to obtain data on pregnancy outcome and VHL disease-related lesions. The Friedman test was used for analysis (p ≤ 0.05). Twenty-nine patients were studied (48 pregnancies, 49 newborns). RESULTS: The progression score of cerebellar hemangioblastomas significantly changed between the single MRI scan before and the 2 scans after pregnancy (p = 0.049) (n = 12). Fetal mortality rate was 2% (n = 1) caused by maternal pheochromocytoma. Maternal VHL disease-related complications occurred in 17% (n = 8) of all pregnancies. In 4 patients, a life-threatening situation emerged: hydrocephalus due to cerebellar hemangioblastoma (n = 2) and pheochromocytoma (n = 2). CONCLUSIONS: Pregnancy in patients with VHL disease induces cerebellar hemangioblastoma progression and causes a high VHL disease-related pregnancy complication rate. We recommend intensified surveillance of patients with VHL disease, especially of cerebellar hemangioblastomas during preconception care and pregnancy.

Active surveillance of renal masses in von Hippel-Lindau disease: growth rates and clinical outcome over a median follow-up period of 56 months.

To evaluate the natural outcome of a surveillance strategy for enhancing renal masses associated with von Hippel-Lindau disease (VHL). From January 1988 to June 2011, a watchful waiting strategy was carried out in 16 cases with 42 enhancing renal masses. Clinical data were reviewed to determine tumor growth rate, subsequent interventions, and outcome of follow-up. During a median follow-up of 83 months (range, 55-279), 18 surgical interventions were performed in 13 cases; local recurrence of tumor occurred in 4 cases; 4 patients died (two of metastasis disease, one of CNS Hemangioblastomas with hemorrhage, and one of an unrelated disease) and 12 survived. The median follow-up duration for 42 renal masses was 56 months (range, 19-116 months). The mean tumor growth rate observed was 0.529 cm/year (range, 0.036-1.870 cm/year). The mean growth rate of the tumors larger than 3 cm was 0.573 cm/year, which was not significantly different from that of those smaller tumors (growth rate 0.507 cm/year, P = 0.5905). There was no significant correlation between initial tumor size and growth rate in our cohort with a correlation coefficient of 0.149(P = 0.3480). At the last follow-up, 38 (90.5%) tumors were larger than 3 cm and no metastasis disease developed among tumors ≤4 cm. Progression to metastatic disease was detected in 2 patients. The majority of the enhancing renal masses with VHL disease may still be indolent and do not metastasize during a long period of follow-up even in tumors larger than 3 cm. Metastatic potential during active surveillance appears to be low in VHL patients with Renal tumors ≤4 cm.

Long-term outcomes, branch-specific expressivity, and disease-related mortality in von Hippel-Lindau type 2A.

Although a large kindred with familial pheochromocytoma (Pheo) and paraganglioma (PGL) was discovered in 1962 and later found to represent von Hippel-Lindau (VHL) type 2A (mutation Y112H), the phenotype lacks current characterization. Branch-specific expressivity was suspected based on oral family history. Family pedigree analysis, prospective interviews, and extensive record review were used to extend the pedigree, determine phenotype, examine branch-specific expression, and analyze mortality rates over 5 decades. In its 3 known affected branches the kindred now comprises 107 people with or at-risk for VHL, of whom 49 have been diagnosed and 35/49 (71%) are clinically affected. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. The mean ages for VHL and Pheo/PGL diagnosis were younger in successive generations. Branch II-4 predominately expressed RA, while branch II-5 predominantly expressed Pheo/PGL. Disease-specific mortality occurred early and was less frequent in successive generations. This analysis of Y112H VHL confirms a high cumulative risk for pheochromocytoma/paraganglioma. Over time, both age at diagnosis and disease-specific mortality have decreased. The observed branch-specific expressivity prompts further study of genetic and environmental disease modifiers in this large family.

Prospective evaluation of radiosurgery for hemangioblastomas in von Hippel-Lindau disease.

To determine the effectiveness of stereotactic radiosurgery (SRS) treatment to central nervous system (CNS) hemangioblastomas in von Hippel-Lindau disease (VHL), we analyzed long-term results in VHL patients treated with SRS. Patients were enrolled in a prospective VHL natural history study, undergoing SRS treatment of CNS hemangioblastomas. Treatment regimens, serial clinical evaluations, and longitudinal imaging data were analyzed. Twenty VHL patients (10 males and 10 females) underwent SRS treatment of 44 CNS hemangioblastomas (39 cerebellar and 5 brainstem). Mean (+/-SD) age at treatment was 37.5 +/- 12.0 years (range: 13-67). Mean follow-up was 8.5 +/- 3.2 years (range: 3.0-17.6 years). All patients were alive at last follow-up. Mean treated tumor volume was 0.5 +/- 0.7 cm(3) (range: 0.01-3.6 cm(3)). Mean prescription dose was 18.9 Gy (range: 12-24 Gy) at the tumor margin. Local control rate at 2, 5, 10, and 15 years after SRS treatment was 91%, 83%, 61%, and 51%, respectively. Univariate analysis did not identify variables associated (P > .05) with worse tumor control at last follow-up. Thirty-three percent of SRS-treated small (<1.0 cm diameter), asymptomatic tumors progressed over a long-term follow-up. There were no long-term adverse radiation effects. Although SRS treatment of hemangioblastomas in VHL has a low risk for adverse radiation effects, it is associated with diminishing control over a long-term follow-up. These results indicate that SRS should not be used to prophylactically treat asymptomatic tumors and should be reserved for the treatment of tumors that are not surgically resectable.

Endocrine pancreatic tumors in von Hippel-Lindau disease: clinical, histological, and genetic features.

OBJECTIVES: Endocrine pancreatic tumors (EPTs) in von Hippel-Lindau (VHL) disease pose difficult management problems. We aimed to assess (1) the accuracy of somatostatin receptor scintigraphy, (2) histological features with focus on malignancy and genotype-phenotype correlations, and (3) prognosis of VHL-EPT. METHODS: Thirty-five patients with EPT-VHL (20 women; median age, 37 years) from 29 families were studied. Histological diagnosis was available in 29 patients. Endocrine pancreatic tumor patients were treated surgically (n = 22), medically (n = 8), or followed (n = 5). Somatostatin receptor scintigraphy was performed in 27 patients. Germinal alterations of the VHL gene were determined. RESULTS: Tumors were malignant in 58% of patients. Somatostatin receptor scintigraphy was positive in 60% of cases, and weak expression of the somatostatin receptor type 2A was found in 47% of tumors. In operated patients, there was no mortality or tumor relapse (median follow-up, 5 [1-10] years). Mortality rate due to EPT was 6%. Germinal mutations were mainly located in exons 3 and 1, and a specific mutation (P86S) was identified. CONCLUSIONS: Most EPTs in VHL patients are somatostatin receptor scintigraphy-positive and malignant, without correlation with the VHL genotype. Surgical resection is often required, but prognosis of these EPTs seems to be fairly good.

Clinical, genetic and radiographic analysis of 108 patients with von Hippel-Lindau disease (VHL) manifested by pancreatic neuroendocrine neoplasms (PNETs).

BACKGROUND: von Hippel-Lindau (vHL) disease is an autosomal dominant syndrome associated with neoplasms in multiple organs, which includes the pancreas. Here, we report the greatest single center experience in patients with vHL pancreatic endocrine neoplasm (PNETs). METHODS: Between December 1998 and November 2006, 633 patients with vHL were evaluated and those with PNETs were enrolled on a prospective protocol. RESULTS: Overall, 108 vHL patients had PNETs (17%). Nine patients had metastatic disease (8.3%) from their PNET. Patients with lesions greater than 3 cm (n = 25) were more likely to develop metastases than patients with lesions less than 3 cm (n = 83) (P < .005). Thirty-nine patients underwent resection. Germline sequencing showed that 78% of patients with metastases (7/9) had exon 3 mutations compared with 46% of patients without metastases (32/98; P < .01). Tumor doubling time was calculated for the largest PNET. The group with metastases had an average tumor doubling time of 337 days (range, 180-463 days) compared with 2630 days (range, 103-9614 days) for those without metastases (P < .0001). CONCLUSIONS: By implementing a system of selective operative resection based on defined criteria, vHL patients with PNETs can be managed safely. For patients with small primary lesions (<3 cm), without a mutation of exon 3 and slow tumor doubling time (>500 days), a nonoperative approach may be appropriate for these nonfunctional neoplasms.

Clinical characteristics of pancreatic neuroendocrine tumors in Japanese patients with von Hippel-Lindau disease.

OBJECTIVE: The aim of this study was to elucidate the clinical characteristics of pancreatic neuroendocrine tumors (NET) in Japanese patients with von Hippel-Lindau (VHL) disease. METHODS: We sent a questionnaire to all members of the Japan Pancreas Society in 2002 asking for the number of patients with VHL and complications of NET and/or cystic lesion in the pancreas. Furthermore, we sent a second questionnaire to obtain detailed information about the clinical characteristics of pancreatic NET. RESULTS: A total of 58 patients with VHL were reported. Among these, 34 (59%) patients had pancreatic lesions, including 10 with pancreatic NET, 23 with a cystic lesion, and one with both. The mean age at identification of pancreatic NET was 34.6 years (range, 22-64 years). The mean diameter of the tumors was 4.3 cm (range, 1-12.5 cm). Distant metastases were found in 2 (20%) cases. During the follow-up period (3.3 years; range, 0-8 years), 7 patients are alive, and 2 patients died of hemangioblastomas. CONCLUSIONS: Pancreatic NET in the VHL disease showed a relatively lower incidence of metastasis compared with sporadic non-functioning pancreatic NET, yielding a favorable prognosis. Because they present no hormonal syndrome, periodic screening examinations are warranted to identify pancreatic NET at an early stage.

The long-term results of gamma knife radiosurgery for hemangioblastomas of the brain.

OBJECT: The authors assessed the long-term result of gamma knife surgery (GKS) for hemangioblastomas of the brain (HABs) and show histopathological findings after GKS. METHODS: Thirty-five patients, 28 men and seven women, with a mean age of 36 years underwent GKS. Eighteen patients presented with multiple tumors and 17 with a solitary tumor. Twenty-one patients had von Hippel-Lindau (VHL) disease. The mean tumor diameter was 13 mm (range 5-55 mm). The mean follow up after GKS was 66 months (range 24-114 months). The mean prescription dose was 17.2 Gy (range 12-24 Gy) at the tumor margin. For tumors close to or within the brainstem a prescription dose of 12 to 13 Gy was used. At the most recent follow up, 29 patients were alive, six were dead, and satisfactory tumor control had been achieved in 29. A stable or improved neurological status was obtained in 21 patients. Eight patients underwent open surgery because of tumor-associated cyst enlargement or the development of new tumors after GKS. Seven patients developed new tumors and five of them required a second GKS. The 1-year tumor control rate was 94%; 2 years, 85%; 3 years, 82%; 4 years, 79%; and 5 years, 71%. Histopathology showed that no tumor cells were found and there was degeneration and necrosis in a tumor nodule 48 months after GKS with a prescription dose of 18 Gy. CONCLUSIONS: Gamma knife surgery was a useful choice for small- or medium-sized, solid HAB in the long term, especially when the tumor margin dose was 18 Gy. Although GKS can treat multiple tumors in a single session, for HABs associated with VHL disease, GKS faces the dual problems of tumor recurrence or development of a new tumor.

[von Hippel-Lindau syndrome: molecular diagnosis of two Lebanese families and analysis of the genotype-phenotype correlation]. / La maladie de von Hippel-Lindau: Etude moléculaire de deux families libanaises et analyse de la corrélation génotype-phénotype.

The von Hippel-Lindau syndrome (VHL) is a dominantly transmitted hereditary disorder associating multisystemic tumors affecting mainly the central nervous system, the kidneys, the pancreas, as well as pheochromocytomas. Mutations of the tumor suppressor gene VHL on chromosome 3 are responsible for the disease. This article reports for the first time the study of two Lebanese VHL affected families, presenting particularly hemangioblastomas of the central nervous system. Two different mutations of the VHL gene, S65W and F76S, respectively identified in the two families, confirmed the clinical diagnosis of the patients. Molecular diagnosis was then performed for at risk members of these families. This article reveals the importance of molecular diagnosis for suspected patients and of presymptomatic diagnosis for at risk members, especially that a close follow-up of carriers allows an early detection of tumors and prevents the metastasis stage, the most common cause of death of these patients.

Nephron sparing surgery for renal cell carcinoma and von Hippel-Lindau's disease: a single center experience.

PURPOSE: We reviewed the efficacy and safety of nephron sparing surgery for renal cell carcinoma in patients with von Hippel-Lindau disease. MATERIALS AND METHODS: Data were collated for all 56 patients with a mean age of 37.2 +/- 11.3 years (range 14 to 62) with von Hippel-Lindau disease who underwent radical nephrectomy or nephron sparing surgery at our department for 1 or more 25 to 60 mm renal cell carcinomas between 1988 and 2001. RESULTS: Overall 30 nephrectomies (33%) and 62 enucleations (67%) were performed for 62 bilateral and 30 unilateral tumors. For nephron sparing surgery estimated intraoperative blood loss was 175 +/- 231.7 cc (range 50 to 1,300), 97% of surgeries had vascular pedicle clamping for 32 +/- 10.4 minutes (range 10 to 50) and there were 4 immediate complications (1 perinephric abscess, 2 urinary fistulas and 1 acute renal failure requiring temporary dialysis). Renal atrophy was noted in 7.3% of cases. Tumor diameter was 31.2 +/- 10.7 mm (range 15 to 60) and recurrence diameter was 22 +/- 7.8 mm (range 4 to 45). Hospital stay was 7.6 +/- 2.4 days (range 5 to 21). Preoperative and postoperative creatinine was 1.0 +/- 0.2 (range 0.6 to 1.7) and 1.2 +/- 0.9 mg/dl (range 0.7 to 6.5), respectively. Median followup was 55.9 months. There were 17 local recurrences (27.4%) and no metastases at recurrence. The overall survival rate was 100% at 5 years and 67% at 10 years. CONCLUSIONS: Nephron sparing surgery is effective and, when feasible, it need not be called into question. However, it may probably be superseded by less invasive techniques for tumors less than 20 mm diagnosed early after these techniques have been validated in long-term trials.

VHL c.505 T>C mutation confers a high age related penetrance but no increased overall mortality.

BACKGROUND: Germline mutations of the VHL gene cause von Hippel-Lindau syndrome (VHL). In southern Germany, a specific mutation in this gene, c.505 T>C, is one of the most frequent alterations owing to a founder effect. METHODS: This study was conducted to evaluate morbidity, specific clinical risk profile, and mortality among a series of VHL c.505 T/C mutation carriers. A total of 125 eligible subjects carrying VHL c.505 T/C underwent ophthalmoscopy and gadolinium enhanced magnetic resonance imaging of the brain, the spinal cord, and the abdomen. Age related penetrance, morbidity, and mortality were assessed. RESULTS: Frequently observed lesions were phaeochromocytoma (47%), retinal angiomas (36%), haemangioblastoma of the spine (36%), and haemangioblastoma of the brain (16%). Four patients developed renal cell carcinoma. VHL was symptomatic in 47% of subjects; 30% were asymptomatic despite the presence of at least one VHL related tumour and 23% of the carriers had no detectable VHL lesion. Of the 19 patients who had died (15%), 10 died of symptomatic VHL lesions. Overall penetrance by cumulative incidence functions is estimated at 48% by 35 years and 88% by 70 years. In contrast to the only existing published report based on patients with presumably unselected VHL germline mutations, the mortality rate for c.505 T/C mutation carriers is comparable to that of the general population of Germany. CONCLUSIONS: Our results are an important example that a specific genotype, at least in the case of VHL c.505 T/C, can favourably impact on mortality despite a high age related penetrance. Our study also indirectly provides objective data which might be useful to the life and health insurance industry; it would appear that c.505 T>C mutation positive subjects have similar disease specific mortality to that of the general population owing to a combination of phenotype and timely detection of mutation carrier status followed by aggressive clinical screening and, if necessary, treatment.

Long-term prognosis of haemangioblastoma of the CNS: impact of von Hippel-Lindau disease.

The aim was to assess the frequency of von Hippel-Lindau disease (VHL) and the long-term prognosis of VHL and non-VHL patients among 110 consecutive patients with haemangioblastoma (HB) of the CNS treated between 1953 and 1993 at one neurosurgical unit. To reveal VHL manifestations we performed a detailed clinical and radiological examination (neuraxis and abdomen) (61/110), VHL-gene mutation analysis (40/110), and collection of all available clinical, imaging, operative and autopsy data from the hospitals involved. All patients were followed-up with a median of 14 years (excluding 14 operative deaths), and no patient was lost to follow-up. Altogether 49 patients died during the follow-up. In the 14 VHL patients (13%), HB(s) of the CNS were detected at a median age of 33 years, retinal HB(s) at 39 years, and renal cell carcinoma (RCC) at 43 years. The frequency of VHL in patients operated on for HB(s) was 29% before the age of 25 years, 19% between 25 and 45 years, and only 2% after 45 years. HB patients not meeting the VHL criteria had internal organ cysts in 14%. One non-VHL patient (4%) had two adjacent HBs in the same cyst wall. The growth rates of non-VHL and VHL-related HBs were similar as indicated by the median time to recurrence and the proliferation indices (MIB-1). Recurrence of the HB in patients whose primary operation was considered radical developed in four of the 10 VHL patients at a median of 19 years, and in nine of the 74 non-VHL patients at a median of 11 years. The median length of life of all VHL and non-VHL patients was 46 and 63 years, respectively. In VHL, RCC and HBs were equal causes of death.

Management of renal cell carcinoma in von Hippel-Lindau disease.

BACKGROUND: An evaluation of nephron-sparing surgery (NSS) or radical nephrectomy (RN) for treating renal cell carcinoma (RCC) in patients with von Hippel-Lindau disease (VHL) was carried out. METHODS: Between 1976 and 1997, 10 patients with RCC from four VHL families, of whom seven were from one family, were studied by clinical and histopathological examination. Before 1991, three patients were treated using RN, and thereafter five patients were treated using NSS. Two patients were not operated on. RESULTS: RCCs in our patients showed a slow growth rate (on average 0.3 cm year-1), and asymptomatic patients presented with tumours of low-grade malignancy. In all patients, tumours were surrounded by a fibrous pseudocapsule. In 5 out of 17 tumours, pseudocapsular invasion was observed, and three of these five tumours broke through the pseudocapsule. To date, these patients have not shown a less favourable outcome than those without pseudocapsular involvement by tumour growth. Multicentricity of RCC was relatively low (4.6 lesions per kidney). In two of the three RN patients, only a single satellite lesion, in the direct vicinity of a RCC, was found in one kidney. Six tumours (1.8-5.5 cm) were enucleated by NSS. During a mean follow-up of 30 months, renal function in these patients was well preserved. CONCLUSIONS: In our patients, RCCs grew slowly, were of low grade, had a dense fibrous pseudocapsule and were thus good candidates for NSS.