Extraneural hemangioblastoma of the kidney: the challenge for clinicopathological diagnosis

BackgroundHemangioblastoma is a benign cerebellar tumour which may occur as a sporadic entity or in association with von Hippel-Lindau (VHL) disease in approximately 25% of cases. Renal hemangioblastoma (RH) is an extremely rare and newly recognised tumour. Here, we describe five cases of RH, one discovered by CT in an accident and the other four detected during routine examinations.MethodsFive cases of renal hemangioblastoma retrieved from the Department of Pathology, Fudan University Shanghai Cancer Center were studied and the literatures were reviewed. Immunohistochemistry was used to differentiate and confirm this tumour.ResultsPathological examination following tumour resection revealed RH in all cases, the first patient was also diagnosed with renal cell carcinoma (RCC), suggesting the possibility of VHL syndrome, but PCR sequencing analysis of the VHL gene confirmed no mutation in any of the three exons, implying sporadic disease .Histologically, the tumours were circumscribed, composed of sheets of oval or polygonal cells and a prominent vascular network. Tumour cells had pleomorphic nuclei, but mitotic figures were rare. The diagnosis of hemangioblastoma was confirmed by immunohistochemistry.ConclusionsRH is very rare and is challenging to differentially diagnose. Distinguishing RCC and RH is difficult and each has a different prognosis, so differentiating between them is essential for avoiding over-diagnosis and unnecessary treatment.

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Identification of a VHL gene mutation in atypical Von Hippel-Lindau syndrome: genotype–phenotype correlation and gene therapy perspective

Cancer Cell International ◽

10.1186/s12935-021-02386-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Dali Tong ◽

Yao Zhang ◽

Jun Jiang ◽

Gang Bi

Keyword(s):

Gene Therapy ◽

Gene Mutation ◽

Suppressor Gene ◽

Pancreatic Cysts ◽

Vhl Gene ◽

Von Hippel Lindau ◽

Genetic Examination ◽

Examination Methods ◽

Vhl Disease ◽

Von Hippel Lindau Syndrome

Abstract Background Classical von Hippel Lindau (VHL) disease/syndrome includes CNS hemangioblastoma, renal or pancreatic cysts, pheochromocytoma, renal carcinoma and exodermic cystadenoma. The syndrome is caused by mutation of VHL tumor suppressor gene. The most prevalent mutations are present in VHL syndrome. To date, > 500 mutations of gene related to the progression of VHL syndrome have been reported. VHL gene mutation presented in single lung or pancreatic tumor has been reported occasionally, but there is no report of both. Methods In this paper, we used CT scan, pathological and genetic examination methods to diagnose a rare atypical VHL syndrome. Results We reported a rare case of atypical VHL syndrome with authenticated VHL mutation at p.Arg167Gln, that was associated with not only bilateral pheochromocytoma but also lung carcinoid and neuroendocrine tumor of pancreas. Based on literature reviews, the patient was recommended to be further subjected to octreotide-based radionuclide therapy. Conclusions Combined with gene detection and clinical diagnosis, we found the inherent relationship between VHL genotype and phenotype, and constructed the standard diagnosis and treatment process of disease with rare VHL mutation from the perspective of gene therapy.

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Pathology of the Nervous System in Von Hippel-Lindau Disease

Journal of Kidney Cancer and VHL ◽

10.15586/jkcvhl.2015.35 ◽

2015 ◽

Vol 2 (3) ◽

pp. 114-129 ◽

Cited By ~ 5

Author(s):

Alexander O. Vortmeyer ◽

Ahmed K. Alomari

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Hypoxia Inducible Factors ◽

Metastatic Renal Cancer ◽

Vhl Gene ◽

Von Hippel Lindau ◽

Von Hippel Lindau Disease ◽

The Central Nervous System ◽

Vhl Disease ◽

Common Manifestation

Von Hippel-Lindau (VHL) disease is a tumor syndrome that frequently involves the central nervous system (CNS). It is caused by germline mutation of the VHL gene. Subsequent VHL inactivation in selected cells is followed by numerous well-characterized molecular consequences, in particular, activation and stabilization of hypoxia-inducible factors HIF1 and HIF2. The link between VHL gene inactivation and tumorigenesis remains poorly understood. Hemangioblastomas are the most common manifestation in the CNS; however, CNS invasion by VHL disease-associated endolymphatic sac tumors or metastatic renal cancer also occur, and their differentiation from primary hemangioblastoma may be challenging. Finally, in this review, we present recent morphologic insights on the developmental concept of VHL tumorigenesis which is best explained by pathologic persistence of temporary embryonic progenitor cells.

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Hemangioblastomas of the Central Nervous System in von Hippel-Lindau Syndrome and Sporadic Disease

Neurosurgery ◽

10.1097/00006123-200101000-00009 ◽

2001 ◽

Vol 48 (1) ◽

pp. 55-63 ◽

Cited By ~ 35

Author(s):

James E. Conway ◽

Dean Chou ◽

Richard E. Clatterbuck ◽

Henry Brem ◽

Donlin M. Long ◽

...

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Von Hippel Lindau ◽

Multiple Lesions ◽

Younger Age ◽

The Central Nervous System ◽

Sporadic Disease ◽

Vhl Disease

Abstract OBJECTIVE The presentation, screening, management, and clinical outcomes of patients who presented to our institution from 1973 to 1999 with central nervous system (CNS) hemangioblastomas in von Hippel-Lindau (VHL) syndrome and sporadic disease were analyzed. METHODS The surgical pathology database of our institution was searched to identify all patients with histologically verified CNS hemangioblastomas occurring from 1973 to 1999. The medical, radiological, surgical, pathological, and autopsy records from these patients were reviewed retrospectively and statistically analyzed. RESULTS Forty patients (21 males and 19 females) presented with CNS hemangioblastomas. Twenty-five patients (62%) harbored sporadic hemangioblastomas. Fifteen patients (38%) had VHL syndrome. These 40 patients presented with 61 hemangioblastomas (8 patients had multiple lesions). Ten patients (25%) harbored spinal cord hemangioblastomas (5 patients had multiple lesions). Patients with VHL disease tended to present with neurological symptoms and signs at a younger age than patients with sporadic disease (P = 0.09), to present with multiple lesions (53%), and to develop new lesions (rate, 1 lesion/2.1 yr). Hemangioblastomas of the spinal cord were more prevalent in patients with VHL syndrome (P = 0.024). Neuroradiological screening of patients with VHL syndrome allowed identification of more than 75% of new lesions before they became symptomatic. Sixty-six surgical procedures were performed (12 patients required multiple operations). Six patients with VHL syndrome required surgery for new lesions. Surgical complications occurred in six patients (15%). Symptom resolution or arrest of progression at 1 year was documented in 88% of patients. Recurrence of symptoms from partially resected lesions occurred in eight patients (20%). No deaths associated with surgery occurred. One patient with sporadic disease and one patient with VHL syndrome (5%) died as a result of late medical complications from CNS hemangioblastomas. CONCLUSION Surgical outcomes for patients with CNS hemangioblastomas are favorable. However, management of hemangioblastomas is a more difficult and prolonged endeavor for patients with VHL syndrome. In patients with VHL syndrome, neuroradiological screening allows identification of lesions before they become symptomatic. Because patients with VHL syndrome are at risk for development of new lesions, they require lifelong follow-up.

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Protective Function of von Hippel-Lindau Protein against Impaired Protein Processing in Renal Carcinoma Cells

Molecular and Cellular Biology ◽

10.1128/mcb.19.2.1289 ◽

1999 ◽

Vol 19 (2) ◽

pp. 1289-1300 ◽

Cited By ~ 50

Author(s):

Myriam Gorospe ◽

Josephine M. Egan ◽

Berton Zbar ◽

Michael Lerman ◽

Laura Geil ◽

...

Keyword(s):

Gene Function ◽

Brefeldin A ◽

Glucose Deprivation ◽

Suppressor Gene ◽

Protein Processing ◽

Protective Function ◽

Vhl Gene ◽

Von Hippel Lindau ◽

Gene Status ◽

Vhl Disease

ABSTRACT The absence of functional von Hippel-Lindau (VHL) tumor suppressor gene leads to the development of neoplasias characteristic of VHL disease, including renal cell carcinoma (RCC). Here, we compared the sensitivity of RCC cells lacking VHL gene function with that of RCC cells expressing the wild-type VHL gene (wtVHL) after exposure to various stresses. While the response to most treatments was not affected by the VHL gene status, glucose deprivation was found to be much more cytotoxic for RCC cells lacking VHL gene function than for wtVHL-expressing cells. The heightened sensitivity of VHL-deficient cells was not attributed to dissimilar energy requirements or to differences in glucose uptake, but more likely reflects a lesser ability of VHL-deficient cells to handle abnormally processed proteins arising from impaired glycosylation. In support of this hypothesis, other treatments which act through different mechanisms to interfere with protein processing (i.e., tunicamycin, brefeldin A, and azetidine) were also found to be much more toxic for VHL-deficient cells. Furthermore, ubiquitination of cellular proteins was elevated in VHL-deficient cells, particularly after glucose deprivation, supporting a role for the VHL gene in ubiquitin-mediated proteolysis. Accordingly, the rate of elimination of abnormal proteins was lower in cells lacking a functional VHL gene than in wtVHL-expressing cells. Thus, pVHL appears to participate in the elimination of misprocessed proteins, such as those arising in the cell due to the unavailability of glucose or to other stresses.

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In silico VHL Gene Mutation Analysis and Prognosis of Pancreatic Neuroendocrine Tumors in von Hippel–Lindau Disease

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2017-02434 ◽

2017 ◽

Vol 103 (4) ◽

pp. 1631-1638 ◽

Cited By ~ 4

Author(s):

Amit Tirosh ◽

Mustapha el Lakis ◽

Patience Green ◽

Pavel Nockel ◽

Dhaval Patel ◽

...

Keyword(s):

Disease Progression ◽

In Silico ◽

Prediction Models ◽

Gene Mutations ◽

Pancreatic Cysts ◽

Vhl Gene ◽

Von Hippel Lindau ◽

Vhl Disease ◽

The Impact ◽

Predicted Risk

Abstract Context Patients with von Hippel–Lindau (vHL) disease caused by a missense VHL mutation have a more severe phenotype compared with other VHL mutation types. Objective To define pancreatic neuroendocrine tumor (PNET) aggressiveness according to VHL genotype. Design A prospective natural history study. Setting The National Institutes of Health clinical center. Patients Patients with vHL disease, pancreatic manifestations, and germline missense VHL gene mutations. Intervention In-silico prediction of VHL mutation via five computational prediction models. Patients with >80% prediction for disease-causing mutations in all models [high predicted risk (HPR)] were compared with others [low predicted risk (LPR)]. Main Outcome Measure Rates of metastases, surgical intervention, and disease progression. Results Sixty-nine patients were included: 2 developed metastases, 12 needed surgery, and 31 had disease progression during a median follow-up of 60 months (range 13 to 84 months). Thirteen patients were excluded for low prediction reliability. In the remaining 56 patients (45 with PNETs, 11 with pancreatic cysts), the HPR group (n = 13) had a higher rate of disease progression than the LPR group (n = 43) in multivariable analysis (hazard ratio 3.6; 95% confidence interval, 1.1 to 11.9; P = 0.037). The HPR group also had a higher risk of developing metastases (P = 0.015). Among patients with codon 167 hotspot mutations (n = 26), those in the HPR group had a higher risk for disease progression (P = 0.03) than other patients. Conclusions Computational models for predicting the impact of missense VHL gene mutations may be used as a prognostic factor in patients with PNETs in the context of vHL disease.

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Intra-familial phenotypic heterogeneity and telomere abnormality in von Hippel-Lindau disease

10.1101/526913 ◽

2019 ◽

Author(s):

Jiangyi Wang ◽

Xiang Peng ◽

Cen Chen ◽

Xianghui Ning ◽

Shuanghe Peng ◽

...

Keyword(s):

Birth Order ◽

Statistical Methods ◽

Order Effect ◽

Phenotypic Heterogeneity ◽

The Other ◽

Onset Age ◽

Genetic Anticipation ◽

Von Hippel Lindau ◽

Birth Order Effect ◽

Vhl Disease

AbstractVon Hippel-Lindau (VHL) disease is a hereditary cancer syndrome with poor survival. The current recommendations have proposed uniform surveillance strategies for all patients, neglecting the obvious phenotypic varieties. In this study, we aim to confirm the phenotypic heterogeneity in VHL disease and the underlying mechanism. A total of 151 parent-child pairs were enrolled for genetic anticipation analysis, and 77 sibling pairs for birth order effect analysis. Four statistical methods were used to compare the onset age of patients among different generations and different birth orders. The results showed that the average onset age was 18.9 years earlier in children than in their parents, which was statistically significant in all of the four statistical methods. Furthermore, the first-born siblings were affected 8.3 years later than the other ones among the maternal patients. Telomere shortening was confirmed to be associated with genetic anticipation in VHL families, while it failed to explain the birth order effect. Moreover, no significant difference was observed for overall survival between parents and children (p=0.834) and between first-born patients and the other siblings (p=0.390). This study provides definitive evidence and possible mechanisms of intra-familial phenotypic heterogeneity in VHL families, which is helpful to the update of surveillance guidelines.

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Von Hippel-Lindau (VHL) Gene Analysis in Italian Families with VHL Disease

Hereditary Kidney Diseases - Contributions to Nephrology ◽

10.1159/000059877 ◽

1997 ◽

pp. 109-111

Author(s):

M. Montera ◽

E. Bellone ◽

F. Ajmar ◽

P. Mandich

Keyword(s):

Gene Analysis ◽

Vhl Gene ◽

Von Hippel Lindau ◽

Vhl Disease

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Central Nervous System Hemangioblastoma in a Pediatric Patient Associated With Von Hippel-Lindau Disease: A Case Report and Literature Review

Frontiers in Oncology ◽

10.3389/fonc.2021.683021 ◽

2021 ◽

Vol 11 ◽

Author(s):

Bo Yang ◽

Zhenyu Li ◽

Yubo Wang ◽

Chaoling Zhang ◽

Zhen Zhang ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Optic Nerve ◽

Pediatric Patient ◽

Tumor Resection ◽

Phenotypic Expression ◽

Vhl Gene ◽

Von Hippel Lindau ◽

Suprasellar Region ◽

Vhl Disease

BackgroundHemangioblastoma is a benign tumor of the central nervous system and may appear as a component of von Hippel-Lindau (VHL) disease. At present, approximately 40 cases of optic nerve HGBs have been reported in the literature. VHL disease is a rare autosomal-dominant inherited cancer syndrome with different phenotypes caused by variants in the VHL gene. Herein, the authors describe a case of a pediatric patient with VHL disease and with optic nerve HGB, a rare phenotypic expression. The purpose of this study was to explore the genotype-phenotype, clinical features, treatment and follow-up of VHL-associated hemangioblastomas in pediatric patients.Case DescriptionA 12-year-old boy presented with vision loss, headache and dizziness at our hospital. Magnetic resonance imaging (MRI) revealed a large (19.8 mm*18.5 mm*23.5 mm) irregular mass located in the suprasellar region. The mass was successfully removed after craniotomy and microsurgical treatment. The pathological diagnosis was left optic nerve HGB. Genetic analyses showed p.Pro86Leu (c. 257C>T) heterozygous missense mutations in the VHL gene.ConclusionThis is the first reported pediatric case of VHL-associated optic nerve HGB. The genotype-phenotype correlation of VHL disease may provide new evidences for predicting tumor penetrance and survival. Gross tumor resection combined with stereotactic radiosurgery might be the most beneficial treatment.

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ISOLATED PARAGANGLIOMA IN A PATIENT WITH VHL P.L163F MUTATION

AACE Clinical Case Reports ◽

10.4158/accr-2019-0432 ◽

2020 ◽

Vol 6 (4) ◽

pp. e193-e196

Author(s):

Michael Goldstein ◽

Rebecca E. Neril ◽

Gary D. Rothberger

Keyword(s):

Genetic Testing ◽

Reference Range ◽

Disease Type ◽

Surgical Pathology ◽

Rare Mutation ◽

Vhl Gene ◽

Von Hippel Lindau ◽

The Many ◽

Vhl Disease ◽

Urinary Metanephrines

Objective: Paragangliomas (PGLs) are one of the many neoplasms associated with von Hippel-Lindau (VHL) disease. VHL disease type 2C is a unique subtype characterized by the presence of a PGL or pheochromocytoma without other VHL-associated neoplasms. This report describes a rare germline mutation in the VHL gene in a patient with isolated PGL. Methods: The clinical presentation, urinary metanephrines and normetanephrines, computed tomography scan, meta-iodobenzylguanidine scintiscan, surgical pathology, and genetic testing of a patient with PGL and a rare VHL gene mutation are described. A literature review is also presented. Results: A 23-year-old, Indian woman was incidentally found to have an indeterminate 4.2 × 3.6 × 3.2-cm mass adjacent to the liver. A 36-year-old first cousin was recently diagnosed with a PGL. Her 24-hour urinary metanephrines were 6,886 μg/g creatinine (reference range is 81 to 330 μg/g creatinine) and normetanephrines were 6,810 μg/g creatinine (reference range is 20 to 158 μg/g creatinine). Surgical pathology revealed a PGL adjacent to a normal adrenal gland. Genetic testing revealed a mutation in VHL p.L163F. Surveillance for other tumors associated with VHL disease has been negative thus far. Her cousin has not undergone genetic testing despite recommendations to do so. Conclusion: We present the first reported case of PGL in a patient with VHL disease caused by a missense mutation in VHL p.L163F. To date, reports of this rare mutation have only involved patients with pheochromocytoma and without other tumors associated with VHL disease, suggesting that VHL p.L163F mutation may cause a VHL disease type 2C phenotype.

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