Caesarean section and phaeochromocytoma resection in a patient with Von Hippel Lindau disease

This report describes the anaesthetic management of a women with a term gestation, Von Hippel Lindau disease (VHLD), and a phaeochromocytoma, scheduled for a combined phaeochromocytoma resection and Caesarean section. Von Hippel Lindau disease is characterized by diffuse haemangioblastomas of the central nervous system (CNS) and viscera. It is also associated with phaeochromocytomas and renal cell carcinomas. Patients frequently have asymptomatic spinal cord and intracranial pathology. The patient and her fetus presented a challenge because of the anaesthetic restrictions imposed by VHLD, and her pregnancy. She was also at risk of developing malignant hypertension from the phaeochromocytoma. The patient was not a candidate for regional anaesthesia because of the possibility of spinal cord haemangioblastomas. She had received adrenergic blockade with phentolamine (total 30 mg a day) and propranolol (total 40 mg a day) since the 27th wk of gestation in order to control hypertension secondary to the phaeochromocytoma. General anaesthesia was administered with aggressive management of hypertension with adrenergic blockers (labetalol 1.0 mg · kg^?1 and esmolol 0.75 mg · kg^?1) and sodium nitroprusside 1.5 μg · kg^?1 (total). Before delivery of the baby, opioids, which could have resulted in a fetus with CNS depression, were avoided. After delivery, opioids (sufentanil 0.4 ng · kg^?1 hr^?1) were used to limit the use of inhalational anaesthesia which may contribute to uterine atony. Postoperative pain was managed with an intravenous narcotic infusion. Both patients had uneventful postoperative courses.     

Germline mutations in the VHL gene associated with 3 different renal lesions in a Chinese von Hippel-Lindau disease family

Von Hippel–Lindau (VHL) disease is a rare autosomal dominant inherited cancer syndrome that is characterized by hemangioblastomas in the central nervous system and retina, renal cell carcinoma and cysts, pancreatic tumors and cysts, and pheochromocytoma. The underlying gene in this disease is the VHL tumor suppressor gene. We characterized a family with 2 affected siblings. The brother and sister displayed VHL type 2B and type 2A features, respectively. Renal lesions in the brother exhibited 3 different phenotypes, including simple renal cysts, multilocular cystic renal cell carcinoma and clear cell renal cell carcinoma. The phenotypes of the 3 concurrent renal lesions were first reported in this study. Mutation detection of the VHL gene revealed 2 recurrent mutations, namely c.256C>T (p.P86S) and c.340 + 5G > C. The former was predicted to be deleterious and to destabilize the hydrophobic core and lead to VHL dysfunction; however, the latter was predicted to be a benign variant. Our findings provided new data for the genotype-phenotype of VHL diseases and elucidated the pathogenic mechanism with in silico analysis.     

Intracranial haemorrhage associated with phaeochromocytoma

INTRODUCTION: Pheochromocytoma is rarely disclosed by intracranial hemorrhage. We report two cases. OBSERVATION: The first 26-year-old patient developed subarachnoid hemorrhage due to a ruptured aneurysm of the middle cerebral artery. The second patient, aged 44 years, had a temporal hematoma. Diagnosis was suggested in both patients by hypertension and elevated urinary catecholamines and confirmed by imaging and MIBG scintigraphy. Adrenal gland tumors, on both glands in the first patient and on the right gland in the second were successfully removed; cranial hypertension totally regressed. Von Hippel Lindau disease was diagnosed by molecular genetics in the first patient. Paroxysmal hypertension could explain the brain hemorrhage in the first patient and may have favored aneurysmal rupture in the second. CONCLUSION: The relationships between pheochromocytoma and cerebral aneurysm are discussed.     

Patterns of intervention for renal lesions in von Hippel-Lindau disease

OBJECTIVE

To review the records of patients at our centre with von Hippel‐Lindau (VHL) disease, to determine the incidence of renal cell carcinoma (RCC) and patterns of intervention using minimally invasive therapies.

PATIENTS AND METHODS

Patients with genetically confirmed VHL were evaluated in a multidisciplinary clinical care centre established in 2003. Patients were preferentially offered percutaneous radiofrequency ablation (RFA). Cystic tumours were considered contraindications to RFA, as were larger tumours or extensive multifocality with tumours of >3 cm. These patients had either open partial nephrectomy (OPN) or, in unsalvageable cases, radical nephrectomy.

RESULTS

Of 38 patients with VHL, 16 (42%) were found to have RCC; two with small tumours are under observation. Fourteen of the 16 have had a total of 25 renal interventions, none of whom has progressed to end‐stage renal disease. OPN was performed in 15 (60%) cases, including those who had had multiple bilateral procedures; RFA was used in five (20%) cases. After median follow‐up of 41 months, local recurrence was detected in 33%; the metastasis‐free survival rate was 93.3% and overall survival 87.5%.

CONCLUSIONS

Of patients with VHL, 88% with renal involvement require interventions for their kidneys. OPN is the primary method used, and was successful both as a primary and secondary procedure in 60% of cases. In only 20% was RFA possible due to limitations of current technology. The introduction of protocol‐based targeted therapies holds the promise of reducing the number of interventions required for treating VHL.     

Novel therapies for renal cell carcinoma

Metastatic renal cell cancer remains a disease which is difficult to treat medically. Prognosis often depends more on intrinsic disease features than on treatment choices. In this review, we examine novel therapies and scientific directions surrounding the RCC treatment problem. Reports relating chromosomal aberrations and of comparative gene expression analyses relating to RCC, are reviewed briefly. The central role of the von Hippel Lindau protein in clear cell RCC pathogenesis is evident. The limited contribution of conventional cytotoxic chemotherapy is mentioned. Some clinically applied agents whose clinical results are highlighted include 5-FU, retinoids, thalidomide, razoxane and IL-12. Features of the pathophysiology of von Hippel Lindau protein are described, with attention to potential novel therapies targeting HIF-1α, VEGF, TGF-β1 and TGF-α pathways. Immunotherapy is being explored in many angles. Most basic are cytokine therapies incorporating new IL-2 and IFN-α schedules. Newer cytokine-based drugs include pegylated forms and IL-12. Allogeneic mini-transplantation has generated much interest. Tumour-associated antigens are being used to direct therapy using both identified and non-identified epitopes. A variety of tumour-cell vaccine and dendritic-cell vaccine clinical approaches are discussed. Finally, nephrectomy for known metastatic disease has been demonstrated to be helpful in retrospective and now prospective trials. Resection of metastases is also discussed. We are optimistic that the further clinical development among these novel therapies will improve the outlook for metastatic RCC.     

Distinct von Hippel-Lindau gene and hypoxia-regulated alterations in gene and protein expression patterns of renal cell carcinoma and their effects on metabolism

During the last decade the knowledge about the molecular mechanisms of the cellular adaption to hypoxia and the function of the “von Hippel Lindau” (VHL) protein in renal cell carcinoma (RCC) has increased, but there exists little information about the overlap and differences in gene/protein expression of both processes. Therefore the aim of this study was to dissect VHL- and hypoxia-regulated alterations in the metabolism of human RCC using ome-based strategies. The effect of the VHL- and hypoxia-regulated altered gene/protein expression pattern on the cellular metabolism was analyzed by determination of glucose uptake, lactate secretion, extracellular pH, lactate dehydrogenase activity, amino acid content and ATP levels. By employing VHL⁻/VHL⁺ RCC cells cultured under normoxic and hypoxic conditions, VHL-dependent, HIF-dependent as well as VHL-/HIF-independent alterations in the gene and protein expression patterns were identified and further validated in other RCC cell lines. The genes/proteins differentially expressed under these distinct conditions were mainly involved in the cellular metabolism, which was accompanied by an altered metabolism as well as changes in the abundance of amino acids in VHL-deficient cells. In conclusion, the study reveals similarities, but also differences in the genes and proteins controlled by VHL functionality and hypoxia thereby demonstrating differences in the metabolic switch of RCC under these conditions.     

Bilateral Peripapillary Exophytic Retinal Hemangioblastomas

A 14-year-old Iranian girl was referred for evaluation of bilateral elevation of the peripapillary retina. Fluorescein angiography was consistent with bilateral peripapillary exophytic retinal hemangioblastomas as seen in angiomatosis retinae (von Hippel’s disease). Argon laser photocoagulation of the more severely affected left eye was performed with minimal effect upon the tumor.     

Origin of Endolymphatic Sac Tumor

Autopsy temporal bone sections showing a one mm papillary glandular neoplasm, confined to the left endolymphatic duct, are described. This is the second literature report confirming the post-mortem site of origin of the “endolymphatic sac tumor”. The patient died after surgery for right vestibular schwannoma, but no features of von Hippel Lindau disease or neurofibromatosis 2 had been displayed clinically or at autopsy. A study of the epithelium of normal human mature endolymphatic ducts and sacs (EDSs) in archival temporal bone sections showed hyperplastic tubular outgrowths, usually situated in the intraosseous portion of the endolymphatic sac, in most cases. Such appearances imply that the epithelium of the EDS has the potential of producing a malignant papillary glandular neoplasm. Papillary ingrowths, some forming collagenous polypoid projections, and cysts were frequent among the epithelial cells. Psammoma bodies were present in the ducts and sacs of older patients. Appearances suggesting erosion of the bony interface of vestibular aqueduct with EDS could be ascribed to the entry and exit of blood vessels into and from the vestibular aqueduct. Care should be taken in the evaluation of surgical or autopsy material from EDSs not to overcall any of these normal features as malignant.