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VHL (von Hippel-Lindau) disease – risk management

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Von Hippel-Lindau (VHL) disease is an autosomal dominant predisposition to renal clear cell carcinoma, phaeochromocytoma, retinal haemangioblastomas (commonly known as retinal angiomas) and central nervous system haemangioblastomas. Approximately 20% of people with VHL have VHL as a result of a de novo pathogenic variant.r

The care of an individual who has developed a VHL disease related tumour or cancer should be individualised based on their clinical situation, their family history and the monitoring they need as part of their treatment and post-treatment follow-up.

Individuals with VHL disease should be followed and managed in the context of a coordinated multidisciplinary care team by clinicians with experience and expertise in the management of VHL associated tumours. Access to targeted therapies and/or clinical trials may be available. 

The risk management of an individual with a pathogenic variant in two or more genes that confer a predisposition to cancer should also be individualised.

Exclusion criteria

  • A first degree (blood) relative of an individual with a clinical diagnosis of VHL but no pathogenic variant 
  • Individual with a variant of uncertain significance
Cancer/tumour  Frequency in VHL disease Mean age (years) General population to age 70 years
Retinal angioma 49-62%r 25 Unable to obtain
Cerebellar haemangioblastoma 60-80%r 30 Unable to obtain
Renal cell carcinoma 40-70%r 40 (+/-10 years) 0.87% (all kidney cancer)*
Epididymal cystadenoma 25-60%r Unable to obtain Unable to obtain
Phaeochromocytoma/paraganglioma  10-20%r 24  Unable to obtain
Pancreatic neuroendocrine tumour 8-17%r 35 Unable to obtain
Endolymphatic sac tumour 6-15%r 30 Unable to obtain

*Source: Australian Institute of Health and Welfare (AIHW) 2023 Cancer Data in Australia; Canberra: AIHW. <https://www.aihw.gov.au/reports/cancer/cancer-data-in-australia/contents/cancer-risk-data-visualisation>. (2019 data, unadjusted for competing mortality)

The choice of risk management strategy should take into account current age, other health issues and age-related cancer risk. Risks and benefits of interventions should be discussed with an experienced medical professional.

The impact of lifestyle on cancer risk should be discussed e.g. exercise most days for at least 30 minutes at moderate or strenuous intensity, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excessive sun exposure.

Cancer/tumour type Recommendationsr
    Age Strategy and frequency
Renal cell carcinoma Surveillance From age 15 years Abdominal MRI 2nd yearly
Pancreatic neuroendocrine tumours Surveillance From age 15 years Abdominal MRI 2nd yearly
Phaeochromocytoma Surveillance From age 2 years Annual physical examination with BP
From age 5 years Annual fasting free plasma metanephrines and if available plasma 3-methoxytyramine (if plasma unavailable 24-hour urine free metanephrines)

Genotype-phenotype correlations (VHL type1, type2A-C) are not yet well enough defined to justify distinct surveillance paradigms.

The utility of nuclear scans for routine screening in the detection of von Hippel-Lindau disease-associated tumours remains unclear.

See also Measurement and tests for biogenic amines including information for patients who are having tests

Screening cessation

Routine laboratory and radiological surveillance may cease for asymptomatic individuals who reach age 65 years without VHL manifestations on prior screening. Annual physical examination and ophthalmological assessments should continue.

Tumour type Recommendationsr
    Age Strategy and frequency
Cerebellar and spinal haemangioblastoma Surveillance From age 11 years MRI brain and spine 2nd yearly
Retinal haemangioblastoma Surveillance From age 1 year Paediatric review at birth and annual ophthalmologic review
Endolymphatic sac tumour Surveillance From age 11 years Audiometry 2nd yearly
From age 15 years A single, baseline high-resolution MRI of the internal auditory canal should be obtained once between age 15-20 years, or at baseline diagnosis of VHL disease for individuals diagnosed after age 20 years
Epididymal cystadenoma Surveillance No routine surveillance required as rarely symptomatic

Screening cessation

Routine laboratory and radiological surveillance may cease for asymptomatic individuals who reach age 65 years without VHL manifestations on prior screening. Annual physical examination and ophthalmological assessments should continue.

Pregnancy

Surveillance investigations should ideally be performed prior to any planned conception, if possible. If pre-conception surveillance was not able to be performed, routine surveillance MRIs performed during pregnancy should be without contrast. There is no need for additional surveillance during the pregnancy if the patient remains asymptomatic. There are conflicting studies about whether there is risk of progression of VHL associated tumours, particularly CNS haemangioblastomas, during pregnancy. Undiagnosed phaeochromocytoma may pose additional risks during pregnancy, especially during labour and delivery. Consider referral to a specialist high-risk pregnancy unit. 

Hearing loss and vestibulopathy

Irreversible hearing loss, tinnitus, vertigo and cranial nerve dysfunction can occur due to endolymphatic sac tumours. The early detection of hearing loss and vestibulopathy and surgical intervention can preserve hearing and ameliorate vestibular symptoms.r

Renal cell carcinoma

Multicentric and bilateral renal cell carcinomas (RCC) are common. For small renal masses, defined as renal masses < 3 cm, active surveillance with MRI is recommended. The management of RCCs should be undertaken in a unit with expertise in VHL disease and nephron-sparing surgery.r

Pancreatic cysts

The most common pancreatic manifestation in VHL disease is pancreatic cysts, which can usually be followed expectantly. These are essentially never malignant processes, and intervention should be based only on patient symptoms or an inability to discern them from other lesions with malignant potential.r

Early detection and more effective treatments have led to improved survival of individuals with VHL.r These surveillance recommendations are based upon international consensus guidelines from VHL Alliance Consortium.r

First degree blood relatives (parents/brothers/sisters/children) are at up to 50% risk of having inherited the pathogenic variant. More distant relatives may also be at risk of inheriting the pathogenic variant. Genetic relatives should be referred to a clinical genetics service or familial cancer centre to discuss predictive genetic testing.

Informing family members about hereditary cancer

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Version 10

Date Summary of changes
13/05/2024

Document reviewed at October 2023 cancer genetics reference committee meeting, Approved for publication with the following changes made:

  • Summary: paragraph added and minor wording changes
  • Lifetime risk of cancer/tumour: "Frequency in VHL disease" column added
  • Cancer/tumour risk management guidelines: 
    • Age, strategy and frequency updated to align with the 2023 International VHL Surveillance Guidelines Consortium and VHL Alliance
    • Screening cessation paragraph added
  • Non-cancer risk management guidelines: as above for cancer/tumour risk management guidelines
  • Management of associated health issues: Pregnancy and Renal cell carcinoma paragraphs updated. Pancreatic cysts paragraph added
  • Evidence for risk management guidelines: wording updated.

Version increased to V.10. Approved on 31/01/2024, changes published on 13/05/2024. Review in 2 years.
17/09/2024

Review due date updated as per consensus of the eviQ cancer genetics chairs.

Version 9

Date Summary of changes
15/09/2023

New eviQ cancer genetics risk management template changes applied - PDF of changes.

Version number changed to V.9.

Version 8

Date Summary of changes
13/02/2023

The following sections of the document were updated to align with the new eviQ cancer genetics risk management template:

  • Summary:
    • Template sentence updated.
  • Target population:
    • Added to exclusion criteria "Individual with a variant of uncertain significance".
  • Cancer/tumour risk management guidelines:
    • Template sentence updated.
    • Lifestyle factors template sentence added.
  • Management of associated health problems:
    • Accordion title changed to "Management of associated health issues".

Version number increased to V.8.

Version 7

Date Summary of changes
21/10/2021

Protocol reviewed at October 2019 cancer genetics reference committee meeting. Discussion continued via email. Approved for publication with the following changes made:

  • Target group: 
    • "syndrome" changed to "disease"
    • "retinal angiomas" changed to "retinal hemangioblastomas (commonly known as retinal angiomas)"
    • Inserted: "Approximately 20% of people with VHL have VHL as a result of a de novo pathogenic variant."
  • Lifetime risk of cancer table:
    • Heading changed to "Lifetime risk of cancer/tumour"
    • Risk for general population updated to include AIHW 2017 data
    • Pancreatic neuroendocrine tumour: Risk for this group by age 70: figure changed from "10-17%" to "12%" 
  • Cancer risk management guidelines:
    • Heading changed to "Cancer/tumour risk management guidelines"
    • Sentence added above table: "The choice of risk management strategy should take current age, other health issues and residual cancer risk into account." 
    • Table:
      • Row 1: "and pancreatic neuroendocrine tumour"  deleted
      • Row 2: "Pancreatic neuroendocrine tumour" inserted
      • Risk-reducing medication rows deleted
    • Inserted after table: "Genotype-phenotype correlations (VHL type1, type2A-C) are not yet well enough defined to justify distinct surveillance paradigms. The utility of nuclear scans for routine screening in the detection of von Hippel-Lindau disease-associated tumours remains unclear."
  • Non-cancer risk management guidelines: Cerebellar and spinal haemangioblastoma:
    • Surveillance starting age changed from age 10 years to age 8 years
    • Risk-reducing medication row deleted
  • Management of associated health problems: Renal cell carcinoma: Inserted: "Multicentric and bilateral RCCs are common."
  • Support and information: template wording updated
  • Website resources updated
  • "Mutation" changed to "pathogenic variant" throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs. Definition of "pathogenic variant" added as a pop-up.

Version number increased to V.7. Review in two years.

Version 6

Date Summary of changes
20/12/2010 Approved.
06/05/2013

Discussed at August 20, 2012, meeting, review continued via email and the following changes made:

  • Opening paragraph updated.
  • Target group - point 3 family changed to individual.
  • Lifetime risk of cancer - heading changed to lifetime risk of tumour and table updated.
  • Cancer risk management guidelines - table updated.
  • Non-cancer risk management guidelines table - added.
  • Management of associated health problems and side effects - pregnancy section updated, hearing loss and vestibulopathy section added.
  • Reference list reviewed and updated.
14/04/2016 Sentence added to Risk Management template: "This risk management guideline has been developed for individuals who have NOT been diagnosed with a relevant cancer/tumour.  The care of affected individuals should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-treatment follow up". 
31/05/2017 Transferred to new eviQ website. Version number changed to V.3.
 

 Further references used to develop this protocol:

Manski, T. J., D. K. Heffner, G. M. Glenn, et al. 1997. "Endolymphatic sac tumors. A source of morbid hearing loss in von Hippel-Lindau disease." JAMA 277(18):1461-1466.

Zanotelli, D. B., E. Bruder, E. Wight, et al. 2010. "Bilateral papillary cystadenoma of the mesosalpinx: a rare manifestation of Von Hippel-Lindau disease." Arch Gynecol Obstet 282(3):343-346. 
14/09/2018

Discussed at May 24, 2018 meeting, review continued via email and the following changes made:

  • Summary - description of VHL updated and sentence re genetic anticipation reported in families with VHL added. Sentence regarding the guideline has been developed for individuals who do NOT have a relevant cancer/tumour removed.
  • Lifetime risk of cancer table – title changed to ‘tumour/cancer’ and tumour/ancer types and figures updated
  • Recommendations – cancers/tumours separated into cancer and non-cancer recommendation tables – recommendations updated as per new evidence/references
    • Phaeochromocytoma recommendations to be made consistent with SDH guidelines
    • Endolymphatic sac tumours – add comment re MRI brain screening to pay particular attention to endolytic sac tumours
  • Management of associated health problems – updated and RCC comment added
  • References updated
  • Version updated to 4
28/08/2019 Protocol title changed from 'Risk management for von Hippel-Lindau (VHL)' to 'VHL (von Hippel-Lindau disease) – risk management' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.5.
3/10/2019 "Mutation" changed to "pathogenic variant" throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs. Definition of "pathogenic variant" added as a pop-up. Version number increased to V.6.

The information contained in this document is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to care or treatment. Any clinician seeking to apply or consult this document is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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https://www.eviq.org.au/p/397

13 Oct 2024