von Hippel-Lindau disease


Literature Analysis

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Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (24)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

VHL 3p25.3 RCA1, VHL1, pVHL, HRCA1 -VHL and von Hippel-Lindau Disease
CA9 9p13.3 MN, CAIX -CA9 and von Hippel-Lindau Disease
THRB 3p24.2 GRTH, PRTH, THR1, ERBA2, NR1A2, THRB1, THRB2, C-ERBA-2, C-ERBA-BETA -THRB and von Hippel-Lindau Disease
SDHAF2 11q12.2 PGL2, SDH5, C11orf79 -SDHAF2 and von Hippel-Lindau Disease
SDHA 5p15 FP, PGL5, SDH1, SDH2, SDHF, CMD1GG -SDHA and von Hippel-Lindau Disease
EPOR 19p13.3-p13.2 EPO-R -EPOR and von Hippel-Lindau Disease
FH 1q42.1 MCL, FMRD, LRCC, HLRCC, MCUL1 -FH and von Hippel-Lindau Disease
TMEM127 2q11.2 -TMEM127 and von Hippel-Lindau Disease
ATRX Xq21.1 JMS, SHS, XH2, XNP, ATR2, SFM1, RAD54, MRXHF1, RAD54L, ZNF-HX -ATRX and von Hippel-Lindau Disease
DAXX 6p21.3 DAP6, EAP1, BING2 -DAXX and von Hippel-Lindau Disease
CHGA 14q32 CGA -CHGA and von Hippel-Lindau Disease
MAP2K1 15q22.1-q22.33 CFC3, MEK1, MKK1, MAPKK1, PRKMK1 -MAP2K1 and von Hippel-Lindau Disease
SKP1 5q31 OCP2, p19A, EMC19, SKP1A, OCP-II, TCEB1L -SKP1 and von Hippel-Lindau Disease
RBX1 22q13.2 ROC1, RNF75, BA554C12.1 -RBX1 and von Hippel-Lindau Disease
CBL 11q23.3 CBL2, NSLL, C-CBL, RNF55, FRA11B -Proto-Oncogene Proteins c-cbl and von Hippel-Lindau Disease
EGLN3 14q13.1 PHD3, HIFPH3, HIFP4H3 -EGLN3 and von Hippel-Lindau Disease
VIM 10p13 HEL113, CTRCT30 -VIM and von Hippel-Lindau Disease
HNRNPA2B1 7p15 RNPA2, HNRPA2, HNRPB1, SNRPB1, HNRNPA2, HNRNPB1, IBMPFD2, HNRPA2B1 -HNRNPA2B1 and von Hippel-Lindau Disease
ERCC6 10q11.23 CSB, CKN2, COFS, ARMD5, COFS1, RAD26, UVSS1 -ERCC6 and von Hippel-Lindau Disease
TFEB 6p21 TCFEB, BHLHE35, ALPHATFEB -TFEB and von Hippel-Lindau Disease
TNFRSF10D 8p21 DCR2, CD264, TRUNDD, TRAILR4, TRAIL-R4 -TNFRSF10D and von Hippel-Lindau Disease
CD70 19p13 CD27L, CD27LG, TNFSF7 -CD70 and von Hippel-Lindau Disease
TNFRSF10A 8p21 DR4, APO2, CD261, TRAILR1, TRAILR-1 -TNFRSF10A and von Hippel-Lindau Disease
GNAS 20q13.3 AHO, GSA, GSP, POH, GPSA, NESP, GNAS1, PHP1A, PHP1B, PHP1C, C20orf45 -GNAS and von Hippel-Lindau Disease

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest publications

Publications about von Hippel-Lindau Disease and cancer

Kano H, Yamamoto M, Lunsford LD
J Neurosurg. 2015; 122(6):1468 [PubMed] Related Publications

Oldfield EH
Editorial: Management of hemangioblastomas in patients with von Hippel-Lindau disease: stereotactic radiosurgery compared to surgical excision.
J Neurosurg. 2015; 122(6):1466-8 [PubMed] Related Publications

Kano H, Shuto T, Iwai Y, et al.
Stereotactic radiosurgery for intracranial hemangioblastomas: a retrospective international outcome study.
J Neurosurg. 2015; 122(6):1469-78 [PubMed] Related Publications
OBJECT: The purpose of this study was to evaluate the role of stereotactic radiosurgery (SRS) in the management of intracranial hemangioblastomas.
METHODS: Six participating centers of the North American Gamma Knife Consortium and 13 Japanese Gamma Knife centers identified 186 patients with 517 hemangioblastomas who underwent SRS. Eighty patients had 335 hemangioblastomas associated with von Hippel-Lindau disease (VHL) and 106 patients had 182 sporadic hemangioblastomas. The median target volume was 0.2 cm(3) (median diameter 7 mm) in patients with VHL and 0.7 cm(3) (median diameter 11 mm) in those with sporadic hemangioblastoma. The median margin dose was 18 Gy in VHL patients and 15 Gy in those with sporadic hemangioblastomas.
RESULTS: At a median of 5 years (range 0.5-18 years) after treatment, 20 patients had died of intracranial disease progression and 9 patients had died of other causes. The overall survival after SRS was 94% at 3 years, 90% at 5 years, and 74% at 10 years. Factors associated with longer survival included younger age, absence of neurological symptoms, fewer tumors, and higher Karnofsky Performance Status. Thirty-three (41%) of the 80 patients with VHL developed new tumors and 17 (16%) of the106 patients with sporadic hemangioblastoma had recurrences of residual tumor from the original tumor. The 5-year rate of developing a new tumor was 43% for VHL patients, and the 5-year rate of developing a recurrence of residual tumor from the original tumor was 24% for sporadic hemangioblastoma patients. Factors associated with a reduced risk of developing a new tumor or recurrences of residual tumor from the original tumor included younger age, fewer tumors, and sporadic rather than VHL-associated hemangioblastomas. The local tumor control rate for treated tumors was 92% at 3 years, 89% at 5 years, and 79% at 10 years. Factors associated with an improved local tumor control rate included VHL-associated hemangioblastoma, solid tumor, smaller tumor volume, and higher margin dose. Thirteen patients (7%) developed adverse radiation effects (ARE) after SRS, and one of these patients died due to ARE.
CONCLUSIONS: When either sporadic or VHL-associated tumors were observed to grow on serial imaging studies, SRS provided tumor control in 79%-92% of tumors.

Weisbrod AB, Yao J, Kebebew E
Tumor growth in von Hippel Lindau syndrome: in reply to Qazi and colleagues.
J Am Coll Surg. 2015; 220(3):372 [PubMed] Related Publications

Qazi H, Ahmed H, Farooqui SO, Cunningham SC
Assessment of tumor growth in von Hippel Lindau syndrome.
J Am Coll Surg. 2015; 220(3):371-2 [PubMed] Related Publications

Murnyák B, Szepesi R, Hortobágyi T
[Molecular genetics of familial tumour syndromes of the central nervous system].
Orv Hetil. 2015; 156(5):171-7 [PubMed] Related Publications
Although most of the central nervous system tumours are sporadic, rarely they are associated with familial tumour syndromes. These disorders usually present with an autosomal dominant inheritance and neoplasia develops at younger age than in sporadic cases. Most of these tumours are bilateral, multiplex or multifocal. The causative mutations occur in genes involved in cell cycle regulation, cell growth, differentiation and DNA repair. Studying these hereditary cancer predisposition syndromes associated with nervous system tumours can facilitate the deeper understanding of the molecular background of sporadic tumours and the development of novel therapeutic agents. This review is an update on hereditary tumour syndromes with nervous system involvement with emphasis on molecular genetic characteristics and their clinical implications.

Cassol C, Mete O
Endocrine manifestations of von Hippel-Lindau disease.
Arch Pathol Lab Med. 2015; 139(2):263-8 [PubMed] Related Publications
von Hippel-Lindau (VHL) disease is an autosomal dominant disorder caused by heterozygous mutations in the VHL tumor suppressor gene that is characterized by the occurrence of multiple endocrine and nonendocrine lesions. This review focuses on the endocrine manifestations of VHL disease. Pancreatic neuroendocrine proliferations (ductuloinsular complexes, islet dysplasia, endocrine microadenoma, and neuroendocrine tumors), pheochromocytomas, and extra-adrenal paragangliomas are important endocrine manifestations of VHL disease. They frequently display characteristic clinical, biochemical, and histopathologic features that, although not pathognomonic, can be helpful in suggesting VHL disease as the underlying etiology and distinguishing these tumors from sporadic cases. Recent improvements in treatment and outcomes of renal cell carcinomas have allowed pancreatic neuroendocrine tumors to emerge as a significant source of metastatic disease, making the accurate recognition and classification of these neoplasms by the pathologist of utmost importance to determine prognosis, treatment, and follow-up strategies for affected patients.

Gossage L, Eisen T, Maher ER
VHL, the story of a tumour suppressor gene.
Nat Rev Cancer. 2015; 15(1):55-64 [PubMed] Related Publications
Since the Von Hippel-Lindau (VHL) disease tumour suppressor gene VHL was identified in 1993 as the genetic basis for a rare disorder, it has proved to be of wide medical and scientific interest. VHL tumour suppressor protein (pVHL) plays a key part in cellular oxygen sensing by targeting hypoxia-inducible factors for ubiquitylation and proteasomal degradation. Early inactivation of VHL is commonly seen in clear-cell renal cell carcinoma (ccRCC), and insights gained from the functional analysis of pVHL have provided the foundation for the routine treatment of advanced-stage ccRCC with novel targeted therapies. However, recent sequencing studies have identified additional driver genes that are involved in the pathogenesis of ccRCC. As our understanding of the importance of VHL matures, it is timely to review progress from its initial description to current knowledge of VHL biology, as well as future prospects for novel medical treatments for VHL disease and ccRCC.

Rao P, Tamboli P
Do clear cell papillary renal cell carcinomas occur in patients with von Hippel-Lindau disease?-Reply.
Hum Pathol. 2015; 46(2):341-3 [PubMed] Related Publications

Williamson SR, Cheng L
Do clear cell papillary renal cell carcinomas occur in patients with von Hippel-Lindau disease?
Hum Pathol. 2015; 46(2):340-1 [PubMed] Related Publications

Kim H, Joo JD, Kim YH, Kim CY
Development of a small solid cerebellar haemangioblastoma into a large pseudocyst with a mural nodule in a patient without VHL; the importance of regular follow-up.
BMJ Case Rep. 2014; 2014 [PubMed] Related Publications
Haemangioblastomas (HBLs) are rare central nervous system tumours accounting for only 1.2-2.5% of all intracranial tumours. While most HBLs occur sporadically, 36-40% of cases are associated with von Hippel-Lindau (VHL) syndrome. Owing to its benign nature, sporadic cases are usually detected only when symptoms occur due to mass effect. Thus, the natural history of HBLs has only been studied in association with VHL syndrome. We present a case of sporadic HBL with a rapid evolution of its small nodule into an enlarging mural nodule with a large pseudocyst that resulted in increased intracranial pressure. Craniotomy for complete tumour removal was performed and the patient fully recovered. This case implies a regular follow-up of HBL might be mandatory even in patients without VHL.

Garnier S, Réguerre Y, Orbach D, et al.
[Pediatric pheochromocytoma and paraganglioma: an update].
Bull Cancer. 2014; 101(10):966-75 [PubMed] Related Publications
Pheochromocytomas and paragangliomas (PHEO/PGL) are neuroendocrine tumors that arise from sympathetic and parasympathetic paraganglia. Although well described in the adult population, diagnosis and treatment of these exceptionally rare neoplasms remains poorly characterized in children. This article reviews recent advances in clinical presentation, genetics, biochemistry, imaging and treatment of children with benign or malignant PHEO/PGL. Compared to adults, pediatric PHEO/PGL are more frequently familial, bilateral, multifocal and malignant. Approximately 50% of pediatric PHEO/PGL are associated with a mutation of one of the 12 known susceptibility genes. Von Hippel-Lindau disease, type 1 neurofibromatosis, type 2 multiple endocrine neoplasia and familial PGL syndrome are hereditary tumor syndromes associated with an increased risk of developing such diseases. Clinical presentation includes symptoms related to catecholamine hypersecretion and/or tumor mass effect. Plasma and/or urine metanephrine dosages are recommended as first-line diagnostic biochemical tests. Magnetic resonance imaging is useful as initial radiological approach. Most pediatric PHEO/PGLs are benign. Surgical resection, with appropriate perioperative management of catecholamine-related symptoms, remains the treatment of choice. In case of metastatic disease, surgical removal of metastases when possible and I-131-MIBG radiotherapy provide limited results whereas chemotherapy is reserved for more advanced stages.

Abdelkhalek R, Aigbé N
[Retinal angioma of the Von Hippel-Lindau disease].
Pan Afr Med J. 2014; 18:31 [PubMed] Free Access to Full Article Related Publications

Nao T, Shimamoto T, Karashima T, et al.
[Clinical study on patients with renal-cell carcinoma accompanied with Von Hippel-Lindau disease treated with radiofrequency ablation].
Hinyokika Kiyo. 2014; 60(9):415-20 [PubMed] Related Publications
We report 12 renal cell carcinomas in 6 patients with Von Hippel-Lindau (VHL) disease treated with radiofrequency ablation (RFA). The mean age of the patients was 46 (range 38-53) years (male : 4, female : 2). Computed tomography (CT)-guided transcutaneous RFA was performed under conscious sedation with local anesthetics. The mean size of the tumors was 2.4 (range 0.7-8.1) cm. Nine of the 12 tumors (75%) were locally well controlled. However, 3 tumors in 2 patients developed visceral metastases after RFA. While minimal flank pain, nausea, perinephritic hematoma and lumbago were observed, there was no major complication during or after the procedure. The therapy with CT-guided transcutaneous RFA is efficient and minimal invasive for renal cell carcinoma in patients with VHL, leading to preservation of renal function.

Ikeda K, Osumi H, Matsuishi K, et al.
Multiple lung adenocarcinomas associated with von hippel-lindau disease.
Ann Thorac Surg. 2014; 98(4):1467-70 [PubMed] Related Publications
Lung adenocarcinoma has never before been reported to be associated with von Hippel-Lindau (VHL) disease. Here, we report a case of VHL disease in a patient who had metachronous multiple lung adenocarcinomas. The patient is a 64-year-old-woman with VHL disease. She underwent surgical resection of one adenocarcinoma and one atypical adenomatous hyperplasia. A second lung adenocarcinoma developed metachronously. A point mutation in the VHL gene was confirmed in DNA from a blood sample, and loss of heterozygosity at the VHL locus was detected in the lung adenocarcinoma. The VHL dysfunction may have a role in the development of multiple lung adenocarcinomas.

Fisher R, Horswell S, Rowan A, et al.
Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution.
Genome Biol. 2014; 15(8):433 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Genomic analysis of multi-focal renal cell carcinomas from an individual with a germline VHL mutation offers a unique opportunity to study tumor evolution.
RESULTS: We perform whole exome sequencing on four clear cell renal cell carcinomas removed from both kidneys of a patient with a germline VHL mutation. We report that tumors arising in this context are clonally independent and harbour distinct secondary events exemplified by loss of chromosome 3p, despite an identical genetic background and tissue microenvironment. We propose that divergent mutational and copy number anomalies are contingent upon the nature of 3p loss of heterozygosity occurring early in tumorigenesis. However, despite distinct 3p events, genomic, proteomic and immunohistochemical analyses reveal evidence for convergence upon the PI3K-AKT-mTOR signaling pathway. Four germline tumors in this young patient, and in a second, older patient with VHL syndrome demonstrate minimal intra-tumor heterogeneity and mutational burden, and evaluable tumors appear to follow a linear evolutionary route, compared to tumors from patients with sporadic clear cell renal cell carcinoma.
CONCLUSIONS: In tumors developing from a germline VHL mutation, the evolutionary principles of contingency and convergence in tumor development are complementary. In this small set of patients with early stage VHL-associated tumors, there is reduced mutation burden and limited evidence of intra-tumor heterogeneity.

Bachurska S, Staykov D, Belovezhdov V, et al.
Bilateral pheochromocytoma/intra-adrenal paraganglioma in von Hippel-Lindau patient causing acute myocardial infarction.
Pol J Pathol. 2014; 65(1):78-82 [PubMed] Related Publications
A 26-year-old male presented to the emergency department complaining of obstipation, severe headache and abdominal pain. An autopsy revealed bilateral pheochromocytoma and acute myocardial infarction. The tumor cells showed positive immunoreactivity of both chromogranin A and synaptophysin and were negative for adrenocortical markers such as SF-1, c17, scc, 3-HSD as well as SDHB, suggesting a germline mutation of the gene SDHB or SDHD. Molecular genetic analyses did not show a mutation in these two genes, but a mutation in the VHL gene, in exon 3: VHL c.499C>T. This is a missense mutation and causes an amino acid change (Arg167Trp).

Rao P, Monzon F, Jonasch E, et al.
Clear cell papillary renal cell carcinoma in patients with von Hippel-Lindau syndrome--clinicopathological features and comparative genomic analysis of 3 cases.
Hum Pathol. 2014; 45(9):1966-72 [PubMed] Related Publications
Clear cell papillary renal cell carcinoma (CCPRCC) is a renal neoplasm that has recently received widespread recognition in the literature. There have been several reports of this tumor arising in a sporadic setting and in patients with end-stage renal disease; however, there is limited information available about the clinical, pathologic, and genetic characteristics of this tumor in the setting of von Hippel-Lindau (VHL) disease. We herein report a series of 3 patients who developed CCPRCC in this unique clinical setting. The histology and immunohistochemical profile for all 3 cases was similar to that which has been previously reported for CCPRCC. All tumors were diffusely and strongly positive for cytokeratin 7, negative for α-methyl-CoA-racemase, and showed at least focal staining for CD10. Comparative genomic analysis was performed on tumors from all 3 patients. One tumor demonstrated monosomy 3, and the other 2 tumors showed normal chromosomal content. All 3 patients were alive without evidence of disease progression 5, 3, and 3 years after surgery. CCPRCC represents a distinct tumor type that may occur in the setting of VHL disease and should be considered in the differential diagnosis of extensively cystic renal tumors arising in this clinical setting. Molecular analysis in our series of cases suggests that CCPRCC does indeed represent a unique histologic subtype and must be distinguished from clear cell renal cell carcinoma due to different biological potentials. Ancillary studies for accurate classification are recommended due to significant morphologic overlap with clear cell renal cell carcinoma.

Kim H, Yi JH, Kwon HJ, et al.
Therapeutic outcomes of retinal hemangioblastomas.
Retina. 2014; 34(12):2479-86 [PubMed] Related Publications
PURPOSE: To report the results of treatments and therapeutic complications of retinal hemangioblastomas (RH).
METHODS: Retrospective consecutive case series. Data from 32 patients (37 eyes) with RH were reviewed for characteristics of RH and treatment outcomes.
RESULTS: Among 32 patients, we identified 73 RHs in 37 eyes. At baseline, 24 of 37 eyes (65%) had 20/50 visual acuity or better, 8 eyes (22%) had intermediate vision (20/400-20/50), and 5 eyes (13%) had poor vision (≤20/400). Seven RHs (9.6%) were located in the juxtapapillary area, and 66 RHs (90.4%) were located in peripheral area. Small RHs (54.8%; <0.5 mm in size) were treated with laser photocoagulation, moderate-sized RHs (24.7%; 0.5-3.0 mm in size) were treated with transpupillary thermotherapy, and large RHs (20.5%; >3.0 mm in size) were treated with a combination of transpupillary thermotherapy and cryotherapy. After treatment, 90% of small RHs regressed, whereas only 67% of large RHs regressed (P = 0.044). Peripheral RHs showed better response to treatment than juxtapapillary RHs (P = 0.010). Treatment-related complications occurred in 5 eyes (14%), and 1-step combination therapy was applied more frequently in the complication group (P = 0.048).
CONCLUSION: Small RHs in peripheral areas may require aggressive treatment because they respond well to treatment. In larger RHs, staged treatment could reduce treatment-related complications. Transpupillary thermotherapy could be an effective method in tumor regression for moderate-to-large-sized RHs showing tumor regression rate of 70%.

Huntoon K, Lonser RR
Findings from the natural history of central nervous system hemangioblastomas in von Hippel-Lindau disease.
Neurosurgery. 2014; 61 Suppl 1:N159-62 [PubMed] Related Publications

Metwalli AR, Linehan WM
Nephron-sparing surgery for multifocal and hereditary renal tumors.
Curr Opin Urol. 2014; 24(5):466-73 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
PURPOSE OF REVIEW: Despite the controversy surrounding the benefits of nephron-sparing surgery, multiple absolute indications for nephron-sparing surgery still exist, including the classic indications of hereditary and bilateral kidney tumors.
RECENT FINDINGS: Multiple genetic mutations have been identified which lead to hereditary kidney cancer conditions. These are briefly reviewed because the surgical management of hereditary kidney tumors depends on the genetic and histologic subtypes involved. Clear understanding of these hereditary conditions is crucial for proper surgical management of these tumors.
SUMMARY: Complex partial nephrectomy for multiple renal tumors, or multiplex partial nephrectomy, requires not only exceptional surgical skills but expertise of numerous nonsurgical methodologies, such as hands-on intraoperative ultrasonography and interpretation of multiple imaging modalities. In addition, multidisciplinary management is crucial for optimal outcomes in patient care. This review evaluates the most advanced surgical techniques and perioperative management required to successfully care for these challenging cases.

Gossage L, Pires DE, Olivera-Nappa Á, et al.
An integrated computational approach can classify VHL missense mutations according to risk of clear cell renal carcinoma.
Hum Mol Genet. 2014; 23(22):5976-88 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Mutations in the von Hippel-Lindau (VHL) gene are pathogenic in VHL disease, congenital polycythaemia and clear cell renal carcinoma (ccRCC). pVHL forms a ternary complex with elongin C and elongin B, critical for pVHL stability and function, which interacts with Cullin-2 and RING-box protein 1 to target hypoxia-inducible factor for polyubiquitination and proteasomal degradation. We describe a comprehensive database of missense VHL mutations linked to experimental and clinical data. We use predictions from in silico tools to link the functional effects of missense VHL mutations to phenotype. The risk of ccRCC in VHL disease is linked to the degree of destabilization resulting from missense mutations. An optimized binary classification system (symphony), which integrates predictions from five in silico methods, can predict the risk of ccRCC associated with VHL missense mutations with high sensitivity and specificity. We use symphony to generate predictions for risk of ccRCC for all possible VHL missense mutations and present these predictions, in association with clinical and experimental data, in a publically available, searchable web server.

Yang X, Liu XS, Fang Y, et al.
Endolymphatic sac tumor with von Hippel-Lindau disease: report of a case with atypical pathology of endolymphatic sac tumor.
Int J Clin Exp Pathol. 2014; 7(5):2609-14 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
The authors described a case of a patient with co-existing endolymphatic sac tumor (ELST) and hemangioblastoma in the posterior cranial fossa, which belonged to a subtype of Von Hippel-Lindau (VHL) disease confirmed by the test of VHL-gene. The signs in this 42-year-old female included intermittent headache and dizziness. Imaging revealed a giant mass in the right cerebellopontine angle (CPA) region and another lesion in the left cerebellar hemisphere. The results of biopsy after two operations confirmed the diagnosis respectively. Both of the tumors were resected totally. Nevertheless, we had to confess the misdiagnosis as vascular tumor instead of ELST at the initial diagnosis because of the rarity of ELST associated with atypical histological characteristics. The purposes we reported this case were to describe the atypical pathological feature of ELST and the mutation of germline VHL not mentioned in previously literature, furthermore, to foster understanding of ELSTs with the avoidance of the similar misdiagnosis as far as possible in future.

Gudas LJ, Fu L, Minton DR, et al.
The role of HIF1α in renal cell carcinoma tumorigenesis.
J Mol Med (Berl). 2014; 92(8):825-36 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
UNLABELLED: The transcription factor HIF1α is implicated in the development of clear cell renal cell carcinoma (ccRCC). Although HIF1α was initially believed to be essential for ccRCC development, recent studies hypothesize an oncogenic role for HIF2α in ccRCC, but a tumor suppressor role for HIF1α, leading to uncertainty as to the precise roles of the different HIF transcription factors in this disease. Using evidence available from studies with human ccRCC cell lines, mouse xenografts, murine models of ccRCC, and human ccRCC specimens, we evaluate the roles of HIF1α and HIF2α in the pathogenesis of ccRCC. We present a convergence of clinical and mechanistic data supporting an important role for HIF1α in promoting tumorigenesis in a clinically important and large subset of ccRCC. This indicates that current understanding of the exact roles of HIF1α and HIF2α is incomplete and that further research is required to determine the diverse roles of HIF1α and HIF2α in ccRCC.
KEY MESSAGES: The TRACK mouse ccRCC model with constitutively active HIF1α but not HIF2α expressed in proximal tubules develops RCC. HIF1α protein is expressed in the majority of human ccRCC specimens. Elevated HIF1α in ccRCC correlates with a worse prognosis. Many publications do not support a tumor suppressor role for HIF1α in ccRCC. HIF1α, but not HIF2α, is expressed in some types of cancer stem cells.

Zhang C, Yang AI, Vasconcelos L, et al.
Von hippel-lindau disease associated pulmonary carcinoid with cranial metastasis.
J Clin Endocrinol Metab. 2014; 99(8):2633-6 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
CONTEXT: Carcinoids have rarely been described in von Hippel-Lindau (VHL) disease.
OBJECTIVE: We describe the first reported case of a patient with VHL who developed a pulmonary carcinoid that subsequently metastasized to a pre-existent cranial hemangioblastoma.
RESULTS: Histological and immunohistochemical features of the metastatic lesion were similar to the primary carcinoid. Both lesions demonstrated heterozygous VHL gene deletions with fluorescence in situ hybridization analysis.
CONCLUSIONS: This case provides direct molecular genetic evidence of an association between VHL and carcinoids.

Huff WX, Bonnin JM, Fulkerson DH
Rathke's cleft cysts in twins with type 2C von Hippel-Lindau disease.
J Neurosurg Pediatr. 2014; 14(2):145-8 [PubMed] Related Publications
Von Hippel-Lindau disease (VHLD) is characterized by a spectrum of benign and malignant tumors in the CNS and visceral organs. Rathke's cleft cysts are benign, nonneoplastic sellar lesions that are often asymptomatic. The authors report the case of twin sisters with VHLD Type 2C with radiographically similar sellar lesions. One twin required surgery for progressive visual loss. Pathological examination of resected tissue demonstrated Rathke's cleft cyst.

Wang Y, Abu-Asab MS, Shen D, et al.
Upregulation of hypoxia-inducible factors and autophagy in von Hippel-Lindau-associated retinal hemangioblastoma.
Graefes Arch Clin Exp Ophthalmol. 2014; 252(8):1319-27 [PubMed] Related Publications
PURPOSE: To describe pathological and molecular changes of three patients with clinically severe von Hippel-Lindau (VHL)-associated retinal hemangioblastoma (RH) with rapid progression.
METHODS: Medical records, ocular histopathology, and transmission electron microscopy from three cases of VHL-associated RHs at the National Eye Institute were retrospectively reviewed. One eye of each patient was enucleated. Hypoxia-inducible factor (HIF) 1α and HIF2α expressions were identified by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry.
RESULTS: All three cases had rapidly growing RHs that were resistant to multiple conventional therapies and two (patients 1 and 2) were also resistant to multiple intravitreal anti-vascular endothelial growth factor (VEGF) treatments. Macroscopically, all the enucleated eyes had multiple RHs, serous retinal detachment, severe retinal disorganization and focal hemorrhages. Histopathology showed typical RHs composed of vacuolated foamy VHL cells and capillary networks. Retinal gliosis and hemorrhages were also presented. Additionally, T lymphocytes and macrophages infiltrated in the tumors of two patients resistant to anti-VEGF therapy. Immunohistochemistry, and qRT-PCR found upregulation of HIF1α in the retinal lesions of all eyes. Importantly, upregulation of HIF2α was exclusively detected in the two cases with inflammatory infiltration and resistance to anti-VEGF therapy. Ultrastructural images showed autophagy, lipid droplets, glycogen aggregations, and cytoplasmic degeneration in many VHL cells.
CONCLUSIONS: Based on the histopathological and molecular pathological findings, autophagy, inflammation, and/or upregulation of HIF2α could potentially contribute to the aggressive course of RHs, resulting in the resistance to multiple anti-VEGF and radiation therapies in these patients.

Valadão J, Pearl J, Verma S, et al.
Hyperbaric oxygen treatment for post-radiation central nervous system injury: a retrospective case series.
Undersea Hyperb Med. 2014 Mar-Apr; 41(2):87-96 [PubMed] Related Publications
Increased use of radiation therapy and increasing life spans following radiation treatment has led to an increase in the finding of post-radiation central nervous system injury in patients who have previously undergone radiation treatments. At this time, information regarding treatment for patients suffering from this serious side effect is limited and not readily available. It is imperative to examine possible treatment options, complications and success rates for these patients. This retrospective review will look at 10 patients who underwent hyperbaric oxygen therapy for post-radiation injury to the central nervous system. Review and investigation of the subjective, clinical and radiologic outcomes of these patients was conducted. It was determined that for patients with post-radiation central nervous system injury it is important to distinguish the exact diagnosis for each patient. For those patients with radiation necrosis, conclusion was made that hyperbaric oxygen (HBO2) therapy does lead to improvement in subjective, clinical and radiologic outcomes. However, the results were not consistent across all patients. For those patients with non-specific delayed radiation injury, findings showed that HBO2 does not lead to any improvement. Therefore, we conclude that for those patients who have been diagnosed with radiation necrosis of the central nervous system, we recommend HBO2 therapy as a potential treatment option for some patients.

Prontera A, Puzzolante A, Carpeggiani P, Pavesi G
Symptomatic anterior cerebral artery vasospasm after brainstem hemangioblastoma resection. A case report.
Neuroradiol J. 2014; 27(2):186-90 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Diffuse cerebral vasospasm is a rare complication after brain tumour resection as opposed to that following an aneurysmal subarachnoid haemorrhage. Sellar tumours are among the most common pathologies and locations associated with this complication. Removal of posterior cranial fossa lesions is uncommonly associated with vasospasm, with only nine reported cases. We describe a case of diffuse symptomatic vasospasm mainly involving the right anterior cerebral artery, angiographically confirmed, after resection of a haemangioblastoma of the medulla in an adult patient with von Hippel-Lindau disease. The possible pathogenesis of this phenomenon is discussed.

Sankaredja J, Brac B, Thines L, et al.
[Epidemiology, treatment and follow-up of central nervous system hemangioblastomas in von Hippel-Lindau disease].
Rev Neurol (Paris). 2014; 170(4):288-96 [PubMed] Related Publications
INTRODUCTION: Central nervous system (CNS) hemangioblastomas (HGB) are rare vascular tumors. The goal of this study was to analyze their epidemiology, treatment and prognosis in association with von Hippel-Lindau (VHL) disease.
METHODS: We retrospectively reviewed a series of patients treated in our department for a CNS HGB with VHL disease between 1996 and 2008. We analyzed pre- and postoperative clinical and radiological characteristics, number of visceral lesions (fundoscopy, abdomino-pelvian CT, metanephrines), clinical course (modified Rankin Scale and McCormick scale) and late prognosis (Kaplan-Meier survival curves).
RESULTS: We studied 19 cases (sex-ratio 0.9, mean age 36). The mean time to diagnosis was 61days. The main symptom was intracranial hypertension for cerebellar lesions (7/15) and a sensitive-motor deficit for medulla oblongata (2/5) or spinal lesions (5/11). Preferred locations were cerebellum (15/31), often nodulo-cystic appearance, followed by spinal cord (11/31), frequently coming with adjacent syringomyelia. Multiple locations and visceral lesions were found in two-third of the cases. Surgical removal was complete in more than three-quarter of the cases. Mean follow-up duration was 9years. Postoperative mortality rate was 16%. In cerebellar and medulla oblongata locations together, final mRS was ≤1 in 17 of the 20 cases. In spinal cord locations, final McCormick score was ≤2 in all the cases. After delayed follow-up, about two-third of patients experienced recurrence or new progressive CNS lesions.
CONCLUSION: HGB are rare CNS tumors. VHL disease should be considered when an HGB is diagnosed before 30, is located at the spinal cord, comes with multiple other CNS lesions or with typical peripheral lesions. Microsurgical removal is the gold standard treatment and can offer good functional results.

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Cite this page: Cotterill SJ. von Hippel-Lindau disease, Cancer Genetics Web: http://www.cancer-genetics.org/von_hippel_lindau.html Accessed:

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