Percutaneous microwave ablation on management of hereditary renal cell carcinoma in Von Hippel-Lindau disease.

BACKGROUND: The effect of microwave ablation (MWA) for the renal cell carcinoma (RCC) in Von Hippel-Lindau (VHL) disease is unclear. OBJECTIVE: To assess the safety, Technique efficacy, renal function and oncological outcome of MWA for RCC in VHL patients. METHODS: Consecutive patients with RCCs in VHL disease treated by MWA were retrospectively collected from November 2009 to October 2020. The technical efficacy rate and complications were assessed. The outcomes of pre- and post-ablative eGFR were compared. The local recurrent-free survival (LRFS), renal-cancer-free survival (RCFS), cancer-specific survival (CSS), overall survival (OS) and complications were presented. RESULTS: A total of 10 patients (mean age, 39.0 years ± 10.7 [SD]; 3 women) with 28 RCCs (mean tumor size, 3.0 cm ± 0.34; mean tumor volume, 20.7 mL ± 43.3) treated with MWA were included. Th median follow-up time was 52 months(IQR:27-80). The overall technical efficacy rate was 100% with no major complications occurred. No significant statistical difference between pre-ablative and postablative creatinine level (102.0 µmol/L ± 30.4 vs 112.3 µmol/L ± 38.7, p = 0.06), but the pre-ablative eGFR level was significantly higher than the post-ablative eGFR (78.0 mL/(min*1.73m2) ± 28.6 vs 72 mL/(min*1.73m2) ± 31.4, p = 0.04), with the mean decrease of 5.86 ml/(min*1.73m2). The local recurrent-free survival(LRFS) and renal-cancer-free survival (RCFS) were 100% and 60%, respectively. The cancer specifical survival (CSS) and overall survival (OS) were 95.5% and 100%, respectively. CONCLUSION: Microwave ablation is a safe and feasible method for the treatment of RCC in VHL disease, preserving renal function and yielding satisfactory oncological outcomes.

Characterizing and predicting ccRCC-causing missense mutations in Von Hippel-Lindau disease.

BACKGROUND: Mutations within the Von Hippel-Lindau (VHL) tumor suppressor gene are known to cause VHL disease, which is characterized by the formation of cysts and tumors in multiple organs of the body, particularly clear cell renal cell carcinoma (ccRCC). A major challenge in clinical practice is determining tumor risk from a given mutation in the VHL gene. Previous efforts have been hindered by limited available clinical data and technological constraints. METHODS: To overcome this, we initially manually curated the largest set of clinically validated VHL mutations to date, enabling a robust assessment of existing predictive tools on an independent test set. Additionally, we comprehensively characterized the effects of mutations within VHL using in silico biophysical tools describing changes in protein stability, dynamics and affinity to binding partners to provide insights into the structure-phenotype relationship. These descriptive properties were used as molecular features for the construction of a machine learning model, designed to predict the risk of ccRCC development as a result of a VHL missense mutation. RESULTS: Analysis of our model showed an accuracy of 0.81 in the identification of ccRCC-causing missense mutations, and a Matthew's Correlation Coefficient of 0.44 on a non-redundant blind test, a significant improvement in comparison to the previous available approaches. CONCLUSION: This work highlights the power of using protein 3D structure to fully explore the range of molecular and functional consequences of genomic variants. We believe this optimized model will better enable its clinical implementation and assist guiding patient risk stratification and management.

[The epidemiology of primary brain malignancies]. / A központi idegrendszer primer rosszindulatú daganatainak epidemiológiája és etiológiája.

The occurrence of central nervous system malignancies is relatively low; however, these tumors exhibit poor prognosis and a high mortality rate. On epidemiological grounds, Hungary was placed in the last third among European countries: in the last decade annually 750 to 1000 new cases were diagnosed and the number of deaths was between 550 and 690, without any apparent trends. Age distribution analyses revealed childhood peak and a higher peak at around 65 years of age. Histologically, heterogeneity was apparent, but at least half of the cases were glioblastomas. The exact etiology of adulthood brain tumors is mostly unknown. Among environmental exposures the effect of ionizing radiation was confirmed, the identification of other potential risk factors requires further examinations. 7-10 percent of brain tumors were hereditary tumor syndromes (Li-Fraumeni, neurofibromatosis, sclerosis tuberosa, von Hippel-Lindau, Gorlin- Goltz). Therefore, genetic testing is recommended for families where the diagnosis of brain tumor is suspected.

The outcome of central nervous system hemangioblastomas in Von Hippel-Lindau (VHL) disease treated with belzutifan: a single-institution retrospective experience.

PURPOSE: Belzutifan is a Hypoxia Inducible Factor 2-alpha inhibitor approved in 2021 by the FDA for the treatment of renal cell carcinoma (RCC) in patients with Von-Hippel Landau (VHL) disease. These patients can also present with central nervous system (CNS) hemangioblastomas (HBs). We aim to study the effectiveness and adverse effects of belzutifan for CNS HBs, by reporting our preliminary institutional experience. METHODS: We present a series of VHL patients with CNS HBs undergoing treatment with belzutifan for RCC. All the included patients met the RECIST inclusion criteria. The clinical and radiological outcome measures included: Objective response rate (ORR), time-to-response (TTR), adverse events (AE), and patient response. Patient response was classified as partial response (PR), complete response (CR), progressive disease (PD), or stable disease (SD). RESULTS: Seven patients with 25 HBs were included in our study. A belzutifan dose of 120 mg/day PO was administered for a median of 13 months (range 10-17). Median follow up time was 15 months (range 10-24). An ORR of 71% was observed. The median TTR was 5 months (range: 1-10). None of the patients showed CR, while 5 patients (71.4%) showed PR and 2 (28.5%) showed SD. Among patients with SD the maximum tumor response was 20% [increase/decrease] of the lesion diameter. All the patients experienced decreased hemoglobin concentration, fatigue, and dizziness. None of the patients experienced severe anemia (grade 3-4 CTCAE). CONCLUSION: Belzutifan appears to be an effective and safe treatment for CNS hemangioblastoma in VHL patients. Further clinical trials to assess the long-term effectiveness of the medication are required.

18 F-PSMA-1007 PET/CT in a Case of Von Hippel-Lindau Syndrome.

ABSTRACT: We describe 18 F-PSMA-1007 PET/CT findings in case of von Hippel-Lindau syndrome with a cerebellar hemangioblastoma, 6 renal cell carcinomas in the bilateral kidneys, cystic lesions in the pancreas and left adrenal gland, and solid lesions in the bilateral epididymides. 18 F-PSMA-1007 PET/CT showed intense activity with SUV max of 111.3 of the cerebellar hemangioblastoma, variable activity with SUV max range of 6.4-37.6 of the renal cell carcinomas, and increased activity of the bilateral epididymal lesions (SUV max of 5.1 and 8.2 for the left and right epididymal lesions, respectively).

Mutation in Chek2 triggers von Hippel-Lindau hemangioblastoma growth.

PURPOSE: Von Hippel-Lindau (VHL) is a rare inherited disease mainly characterized by the growth of tumours, predominantly hemangioblastomas (Hbs) in the CNS and retina, and renal carcinomas. The natural history of VHL disease is variable, differing in the age of onset and its penetrance, even among relatives. Unfortunately, sometimes VHL shows more severe than average: the onset starts in adolescence, and surgeries are required almost every year. In these cases, the factor that triggers the appearance and growth of Hbs usually remains unknown, although additional mutations are suspected. METHODS: We present the case of a VHL patient whose first surgery was at 13 years of age. Then, along his next 8 years, he has undergone 5 surgeries for resection of 10 CNS Hbs. To clarify this severe VHL condition, DNA from a CNS Hb and white blood cells (WBC) was sequenced using next-generation sequencing technology. RESULTS: Massive DNA sequencing of the WBC (germ line) revealed a pathogenic mutation in CHEK2 and the complete loss of a VHL allele (both tumour suppressors). Moreover, in the tumour sample, several mutations, in BRAF1 and PTPN11 were found. Familiar segregation studies showed that CHEK2 mutation was in the maternal lineage, while VHL was inherited by paternal lineage. CONCLUSIONS: Finally, clinical history correlated to the different genotypes in the family, concluding that the severity of these VHL manifestations are due to both, VHL-and-CHEK2 mutations. This case report aims to notice the importance of deeper genetic analyses, in inherited rare diseases, to uncover non-expected mutations.

Belzutifan in adults with VHL-associated central nervous system hemangioblastoma: a single-center experience.

PURPOSE: Belzutifan is a selective inhibitor of hypoxia-inducible factor 2 alpha (HIF-2a) that has emerged as a targeted therapy option for Von Hippel-Lindau (VHL) syndrome-associated tumors with recent FDA approval. There is limited real-world evidence regarding safety and efficacy in CNS hemangioblastoma. Our objective was to report on our clinical experience with belzutifan in adult patients with VHL-associated CNS hemangioblastoma. METHODS: We retrospectively reviewed our institutional experience of belzutifan in adult patients (> 18 years of age at time of therapy) with VHL and craniospinal CNS hemangioblastomas not amenable to surgical resection. The period for study review was October 2021 to March 2023. RESULTS: 4 patients (all female) with a median age of 36 years at time of belzutifan initiation were included. Median duration of therapy at last follow-up was 11 months (6-17 months). All patients had radiographic response to therapy after a median of 3 months (2-5 months), with maximal response to therapy after a median of 8 months (3-17 months). Therapy was well tolerated, with the most common adverse effect being anemia. No patients had treatment pauses or dose adjustments due to belzutifan-related toxicity. No patients experienced hypoxia. CONCLUSION: We showed that belzutifan is safe and well-tolerated with strong disease response for CNS hemangioblastoma in adults with VHL, supporting continued use of belzutifan in this patient population. Future studies should assess duration of treatment, effects of cessation after long-term use, and markers of therapeutic response.

Inter- and intra-tumor heterogeneity of genetic and immune profiles in inherited renal cell carcinoma.

Patients with von Hippel-Lindau disease (vHL) are at risk of developing spatially and temporally multiple clear cell renal cell carcinomas (ccRCCs), which offers a valuable opportunity to analyze inter- and intra-tumor heterogeneity of genetic and immune profiles within the same patient. Here, we perform whole-exome and RNA sequencing, digital gene expression, and immunohistochemical analyses for 81 samples from 51 ccRCCs of 10 patients with vHL. Inherited ccRCCs are clonally independent and have less genomic alterations than sporadic ccRCCs. Hierarchical clustering of transcriptome profiles shows two clusters with distinct immune signatures: immune hot and cold clusters. Interestingly, not only samples from the same tumors but also different tumors from the same patients tend to show a similar immune signature, whereas samples from different patients frequently exhibit different signatures. Our findings reveal the genetic and immune landscape of inherited ccRCCs, demonstrating the relevance of host factors in shaping anti-tumor immunity.

Inflammatory Arthritis in a 19-month-old with Von Hippel-Lindau Disease.

Von Hippel-Lindau disease (VHL) is a rare autosomal dominant disease characterized by progressive development of cysts and tumors. Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disorder and the most common arthritis in children. Although the mechanism of pathogenesis is not fully understood, JIA is thought to be a polygenic, autoimmune-mediated disease. Inherited or acquired disorders resulting in immune dysregulation can lead to neoplastic and autoimmune disease, but very few cases of patients with VHL and concomitant autoimmune disease are reported in the literature. Herein, we describe, to the best of our knowledge, the first reported case of a child with VHL and inflammatory arthritis, and we discuss three possible pathophysiologic mechanisms that could link VHL and JIA. Understanding the shared pathophysiology and genetics of both diseases may help guide future direction of targeted therapies and lead to improved clinical outcomes.

Endolymphatic sac tumour - a rare complication associated with von Hippel-Lindau disease.

We report the case of a 42-year - old female with familiar form von Hippel-Lindau disease (VHL) and recurrent endolymphatic sac tumour (ELST), which was presented like non-homogenous, solid and cystic expansion of the left petrous temporal bone. Histologically, there was found lamellae of bone with adjacent ligament and with papillary projections with fibrovascular core. The papillae were lined by a single layer of cuboidal epithelium with hyperchromatic and lightly pleomorphic nuclei. Sporadically, small cystic formations with eosinophilic, PAS positive secretion were noted. Imunohistochemically, the cuboidal cells showed diffuse positivity for vimentin, epithelial membrane antigen (EMA), cytokeratin AE1/AE3 and S100 protein (weakly). Other markers examined, including TTF1, PAX8 and CD10, were negative. Endolymphatic sac tumour is rare low-grade malignant epithelial tumour arising from the endolymphatic sac in the temporal bone, which occurs in 1 out of 30 000 births, with just fewer than 300 cases reported in the literature. About one third of cases are associated with von Hippel- Lindau disease, an autosomal dominant familial cancer syndrome.

[A Surgically Treated Depression]. / Eine chirurgisch behandelte Depression.

A Surgically Treated Depression Abstract. We present a 64-year-old patient with an unclear deterioration of her general condition due to a suspected depression. Despite antidepressive treatment, her condition further deteriorated. The CT/MRI of the skull showed a cerebellar tumor as well as a hydrocephalus obstructivus. Together with tumor staging, the histology, which revealed a hemangioblastoma, led to the diagnosis of VHL syndrome. Patients with VHL syndrome and their families should be included in a screening program, unless molecular genetic testing has ruled out the disease.

Sporadic hemangioblastoma of cauda equina: A case-report and brief literature review.

Hemangioblastomas are rare lesions accounting for 1-5% of all spinal cord tumors and are mostly associated with von Hippel-Lindau syndrome. Localization in the cauda equina is uncommon. In this manuscript we aim to describe a rare case of sporadic intradural extramedullary hemangioblastoma of the cauda equina and present a literature review. A systematic research was performed on Pubmed, MEDLINE, and Google Scholar, using as keywords "spinal hemangioblastoma" and "cauda equina tumors". The previous literature is integrated by the description of the present case. A 49 year-old female, presented on August 2020 to our institution suffering from claudication neurogena, right sciatica and paraesthesia in right L5 radicular dermatome for more than 3 months. Neurological examination revealed hypoesthesia on right L5 dermatome and weakness of right anterior tibialis muscle. An MRI which showed an intradural mass at L1/2 level and an angiography that showing a nidus of serpiginous vessels inside the lesion. Microsurgical en bloc resection of lesion was performed with adjuvant neurophisological intra operative monitorings. Histological examination provided the diagnosis of hemangioblastoma. After surgery symptoms and neurological impairment gradually improved. A 10 months post-operative MRI showed no residual tumor. Although intradural extramedullary hemangioblastoma of the cauda equina without von Hippel-Lindau syndrome it is a rare pathological entity, this diagnosis must be taken in for cauda equina masses. Preoperative embolization is an option to minimize intraoperative bleeding. Radiosurgery seems to prevent recurrences when the tumor is not completely excised. Complete surgical removal of the lesion is usually possible and lead to a low likelihood of recurrence.

How 'eye' helped in von Hippel-Lindau syndrome.

BACKGROUND: Von Hippel-Lindau syndrome is a rare autosomal dominantly inherited multisystemic oncologic syndrome, presenting predominantly with angiomatosis in embryologically similar neurologic tissue such as retina, cerebellum and adrenals. Retinal hemangioblastomas are the hallmark ophthalmic finding. In this case report, we describe the importance of timely diagnosis, thorough systemic examination and treatment of bilaterally asymmetrical retinal hemangioblastomas in a young adult male. CASE PRESENTATION: A 31-year-old male presented with painless diminution of vision in both eyes, associated with eyestrain and headache. Multiple asymmetric retinal lesions and dilated feeder vessels were noted on ophthalmoscopic examination and confirmed by fluorescein angiography to be retinal hemangioblastomas. Comprehensive systemic examination revealed cerebellar hemangioblastomas and multiple pancreatic and renal cysts. Treatment of retinal lesions was done by combination therapy of argon laser photocoagulation and cryopexy, which lead to a good visual outcome. Subsequently, neurosurgical resection of cerebellar hemangioblastoma proved to be lifesaving for the patient. CONCLUSION: RHBs are the earliest, easiest and the most frequently detected manifestation of VHL. Identification of ocular manifestations play a pivotal role in early diagnosis and timely intervention in VHL syndrome, thereby significantly reducing associated morbidity and mortality. Therefore, an ophthalmologist's role is crucial in the management of these potentially deadly tumours.

Surgical management of endolymphatic sac tumor: classification, outcomes and strategy. A single institution's experience.

PURPOSE: To review the resections of endolymphatic sac tumor (ELST) and describe our experience in the surgical management of ELST. METHODS: Retrospective investigation of consecutive patients who underwent resection of ELSTs at our hospital between 1999 and 2019. The symptoms, diagnosis, surgical findings, and outcomes were analyzed to develop a tumor staging system and corresponding surgical strategy. RESULTS: Retrospective review revealed the surgical treatment of 22 ELSTs. Based on intraoperative findings of tumor extent and size, ELSTs were classified into two types. Type-I (n = 6) referred to the small tumors that were locally confined with limited invasion of semicircular canals and dura; type-II (n = 16) referred to the large tumors that presented extensive erosion of at least one anatomic structure apart from the semicircular canals and the dura around endolymphatic sac. In this case series, Type-I ELST is amenable to resection through a transmastoidal approach, and subtotal petrosectomy is appropriate for the resection of type-II ELST. Sensorineural hearing loss (SNHL) is the most commonly preoperative symptom in both two types of cases. Five type-II ELSTs experienced recurrence and underwent reoperation, whereas all type-I ELSTs did not. CONCLUSION: ELST usually results in SNHL (95%) at the time of diagnosis. The surgical strategy and prognosis of ELST resections are different between type-I and type-II: type-I ELST is amenable to transmastoidal approach with the preservation of facial nerve, whereas type-II ELST increase the surgical difficulty and the risk of recurrence, and subtotal petrosectomy is the basic requirement for the resection of type-II ELST.

Systematic Review of Endolymphatic Sac Tumor Treatment and Outcomes.

OBJECTIVE: Endolymphatic sac tumors are rare neoplasms originating in the endolymphatic sac. Current literature is limited to case reports and small case series. The objective of this study was to systematically review the literature to better describe clinical presentation, treatment options, and outcomes in endolymphatic sac tumors. DATA SOURCE: PubMed, Embase, and Cochrane Library. REVIEW METHODS: A systematic review was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines describing human endolymphatic sac tumors. Risk of bias was assessed using a validated critical appraisal checklist for case series. Studies without inclusion of individual patient characteristics, corresponding treatments, and outcomes were excluded. Heterogeneity of data precluded meta-analysis. RESULTS: A total of 82 studies met inclusion criteria, and 253 discrete tumors were analyzed. A total of 23.4% of patients had von Hippel-Lindau disease. Von Hippel-Lindau-associated tumors affected females to males in a 2.4:1 ratio. Patients with von Hippel-Lindau disease displayed earlier average age at diagnosis compared to the sporadic cohort. Surgery was the primary treatment modality and was performed in 88.9% of cases. Adjuvant radiation therapy was employed in 18.7% of cases; 16.2% cases recurred, and 10.6% had progression of residual disease after treatment. Mean time to recurrence or progression was 53.1 ± 52.4 months with a range of 3 to 240 months. CONCLUSION: Endolymphatic sac tumors require a high degree of suspicion for early diagnosis. Complete resection is the standard of care. No strong evidence supports routine use of adjuvant radiation therapy. Given the high rate of recurrence and wide-ranging time to recurrence, long-term follow-up is necessary.

Sporadic Cerebellar Hemangioblastoma With Strong SSTR Expression on 68 Ga-DOTANOC PET/CT.

ABSTRACT: Sporadic cerebellar hemangioblastomas are rare with majority of these tumors presenting as a part of von Hippel-Lindau syndrome. We demonstrate an unusual case of a symptomatic sporadic cerebellar hemangioblastoma mimicking a meningioma on MRI and 68 Ga-DOTANOC PET imaging.

Belzutifan in a Patient With VHL-Associated Metastatic Pancreatic Neuroendocrine Tumor.

von Hippel-Lindau (VHL) disease is a rare autosomal-dominant hereditary disease characterized by mutation of the VHL gene. This gene encodes for the VHL protein, which regulates the activity of HIF-α, a transcription factor involved in the cellular response to hypoxia. Mutations in VHL lead to the accumulation of HIF-α and, consequently, the engagement of hypoxia-sensitive genes with tumorigenic effects. VHL disease is associated with the development of tumors in multiple organs, including pancreatic neuroendocrine tumors (pNETs). Belzutifan is an HIF-α inhibitor; however, it has not been previously evaluated in patients with metastatic or treatment-refractory pNETs. This report presents a 43-year-old woman with VHL-associated metastatic pNET treated with belzutifan after progression on multiple systemic therapies. She began treatment with belzutifan and experienced partial radiographic response within 1 month of treatment. Other than asymptomatic anemia, no adverse effects developed during 5 months of ongoing therapy. Belzutifan is an inhibitor of HIF-2α that targets the underlying pathophysiology of VHL-associated pNETs. Our case report describes exceptional activity in a metastatic pNET arising from VHL.

Kidney in VHL disease: Early clear cell proliferation occurs in the distal tubular system.

Renal clear cell carcinoma commonly occurs in patients with von Hippel­Lindau disease (VHL). Kidneys of VHL disease patients (VHL kidneys) contain an abundance of independent clear cell proliferation events that have been hypothesized to represent precursor structures of clear cell carcinoma. In the present study, it was tried to identify the site of origin of clear cell proliferation, and the immunophenotype of clear cells. Using 3D histological tracking, the topographic origin of microscopic clear cell proliferation was investigated by identification of informative structures of interest and immunohistochemical staining for cluster of differentiation 10 (CD10) and cytokeratin 7 (CK7) in consecutive serial sections. In addition, the CD10/CK7 immunophenotype of proliferating clear cells was evaluated. Clear cell proliferation uniformly occurred in the distal tubular system. Some clear cell proliferation, however, revealed proximal tubule immunophenotype. It was concluded that early proliferation of VHL­deficient clear cells occurs in the distal tubular system. Despite the association with the distal tubular system, the immunohistochemical profile of early clear cell proliferation may be inconsistent with its distal tubular origin.