MRI protocols for the screening of manifestations of von Hippel Lindau disease in the at risk and/or genetically proven population

Transcription

1 MRI protocols for the screening of manifestations of von Hippel Lindau disease in the at risk and/or genetically proven population Poster No.: R-0237 Congress: 2014 CSM Type: Scientific Exhibit Authors: D. Rabinowitz, S. Morris, J. Kelly, K. Tucker; RANDWICK/AU Keywords: Cancer, Imaging sequences, Screening, MR, Neuroradiology brain, Kidney, Abdomen, Epidemiology, Genetic defects DOI: /ranzcr2014/R-0237 Any information contained in this pdf file is automatically generated from digital material submitted to EPOS by third parties in the form of scientific presentations. References to any names, marks, products, or services of third parties or hypertext links to thirdparty sites or information are provided solely as a convenience to you and do not in any way constitute or imply RANZCR/AIR/ACPSEM's endorsement, sponsorship or recommendation of the third party, information, product or service. RANZCR/AIR/ ACPSEM is not responsible for the content of these pages and does not make any representations regarding the content or accuracy of material in this file. As per copyright regulations, any unauthorised use of the material or parts thereof as well as commercial reproduction or multiple distribution by any traditional or electronically based reproduction/publication method ist strictly prohibited. You agree to defend, indemnify, and hold RANZCR/AIR/ACPSEM harmless from and against any and all claims, damages, costs, and expenses, including attorneys' fees, arising from or related to your use of these pages. Please note: Links to movies,.ppt slideshows,.doc documents and any other multimedia files are not available in the pdf version of presentations. Page 1 of 18

2 Aim Aim Von Hippel-Lindau (VHL) is an inherited, tumour predisposition syndrome. The intracranial, spinal and abdominal manifestations of VHL and their imaging appearance at MRI are well documented in the literature. While there are recognised clinical, pathological and multi-modality imaging components to VHL screening, there are no established radiological protocols for MRI screening in the literature. The aim of this study is to present standard protocols for all-in-one MRI screening, including the rationale for particular sequences and case examples. Epidemiology VHL syndrome is an autosomal dominant genetic condition classified as a hereditary phakomatosis, with protean manifestations. It has increasing penetrance with age (90% by age 65) and variable expression. It has an incidence of approximately 1: About 80% of VHL individuals have inherited their germline mutation, while 20% are de novo mutations. Mosaicism has been described. VHL individuals typically develop characteristic tumours at a significantly younger age than a non-vhl individual with a sporadic lesion and are also more likely to have multiple lesions. The average age of diagnosis is in the mid 20s. The most common causes of VHL-attributable mortality are RCC and complications resulting from CNS haemangioblastoma, with the natural history life expectancy being 49 years. Pathology The VHL gene is located on the short arm of chromosome 3 and encodes the pvhl tumour suppressor protein. An abnormal gene produces a non-functional protein, which leads to loss of angiogenesis regulation, a key element for tumour formation (both benign and malignant). While VHL is protean, the most common types of VHL lesions are CNS haemoangioblastomas (HB), retinal angiomas, endolymphatic sac tumours (ELSTs), renal cysts and renal cell carcinoma (RCC), pancreatic cysts and solid tumours and phaechromocytoma. In men, epididymal cystadenoma is also common. Diagnosis Page 2 of 18

3 Detecting a germline VHL mutation is diagnostic. However, not all VHL mutations can be detected/screened for, therefore diagnosis may be a clinical one based on physical examination, radiological findings and family history. This is summarised in Fig. 1 on page 3. The diagnostic criteria for VHL are: Two or more CNS haemangioblastomas One haemangioblastoma and one visceral manifestation One visceral manifestation and a family history of VHL. In addition, the following can be considered suspicious for VHL: Bilateral ELSTs are considered virtually pathognomic Bilateral epididymal cystadenomas, also effectively pathognomic Single spinal cord haemangioblastoma - up to 80% of spinal HB are in VHL patients. Imaging Features On review of the literature covering the imaging features of VHL lesions, there is high concordance with regards to the typical MRI appearances. Lesions can be broadly considered as solid, cystic or mixed. As a rule, solid lesions are T1 hypointense, T2 hyperintense and avidly contrast enhancing. Cystic lesions, typically seen in the kidneys and pancreas, are T1 hypointense, markedly T2 hyperintense and non-enhancing. Contrast enhanced studies may be required to identify small lesions, particularly in the spinal cord. The cardinal imaging features as per the literature are summarised in Table 1 on page 4. Images for this section: Page 3 of 18

4 Fig. 1: Clinical, genetic and imaging screening pathway for individuals suspected of VHL. Page 4 of 18

5 Table 1: MRI Features of Common Manifestations of Von Hippel-Lindau Page 5 of 18

6 Methods and materials A Pubmed search was performed to retrieve studies relating to VHL imaging manifestations, MRI features, and screening methods and protocols. The existing MRI screening protocol, developed in collaboration between the Medical Imaging Department of Prince of Wales Hospital and the Prince of Wales Hereditary Cancer Clinic and outreach services, was examined against the literature. The benefits and limitations of MRI screening were explored and compared with other imaging modalities, in particular CT and ultrasound. Results Current screening Individuals with established VHL, asymptomatic mutation-carriers, and first-degree relatives of unknown genetic status all require clinical and imaging surveillance. VHL mutation detection is offered for to both those meeting the diagnostic criteria and atrisk relatives. Identification of the mutation allows tailoring of screening, surveillance and management for known carriers, however there is a risk of poor adherence to long-term screening. As with other genetic conditions, counselling is recommended and is beyond the scope of this poster. Clinical and imaging guidelines for screening varies between different countries and institutions. Accessibility to different technology and imaging modalities, particularly limited access to MRI, is a significant factor in these variations. Screening and management of VHL in Australia includes clinical, genetic and imaging components, developed through internationally agreed expert opinion. These can be broadly divided into cancer and non-cancer risk management guidelines and consideration is also given for the prevalence and mean age of onset for each manifestation. Australian risk management guidelines are presented in Table 2 on page 9. Monitoring of known lesions has further recommendations not addressed in this poster. In Australia, imaging options include ultrasound, CT and MRI. The principle of minimising radiation exposure of all patients is well accepted. In VHL patients this is particularly critical due to the need for repeat examinations from a relatively young age and due to the underlying tumour predisposition associated with the gene mutation. This desire to reduce radiation exposure is evidenced by the recent shift away from CT to MRI Page 6 of 18

7 in screening guidelines. MRI of the brain and ultrasound of the abdomen, particularly the kidneys, has been the mainstay of imaging in many institutions. An all-in-one MRI screening protocol including the brain, inner-ear, spine and upper abdomen has been in use for more than 5 years at Prince of Wales Hospital. MRI versus other modalities Neuroimaging Our Pubmed search revealed a wealth of sources on the role of MRI in the imaging of cerebral and spinal haemangioblastomas, and of endolymphatic sac tumours (ELST). For these lesions, MRI with post-gadolinium enhanced sequences has superior sensitivity and specificity compared to CT and non-enhanced MRI. Although large retinal angiomas may be detected on MRI, this does not replace ophthalmological screening as lasering small lesions has been shown to decrease visual loss. Upper Abdominal Imaging While there are numerous sources espousing the use of MRI for abdominal screening, our Pubmed search found limited data on the sensitivity and specificity of MRI versus CT and/or ultrasound in the screening context or VHL population. A wider literature search revealed numerous studies regarding the specific abdominal tumours seen in VHL. With respect to renal cell carcinomas, several studies demonstrated similar rates of sensitivity and specificity for MRI and CT when contrast-enhanced techniques are used. Ultrasound has a complimentary role and is rarely the only imaging modality used prior to intervention. Ultrasound is also less sensitive for identifying lesions that are smaller, non-contour deforming or isoechoic to renal parenchyma. Contrast enhanced Doppler Ultrasound and advanced MRI techniques have also become complimentary in identifying and staging RCCs. It should be noted that RCCs are most common at an older age in the general population, but in VHL they are seen from a younger age. With respect to phaeochromocytomas, MRI has been shown to be more specific than CT, but less specific than MIBG. Due to radiation dose, MIBG examination is not utilised in screening. MRI and CT have similar sensitivities with CT generally considered slightly more sensitive. In addition, non-contrast enhanced MRI has been shown to be better than non-contrast enhanced CT. This is particularly relevant in the context of known contrast allergy or renal failure. For pancreatic islet cell tumours, MRI has high sensitivity but poor specificity compared to CT. Both are less sensitive than EUS particularly for small lesions. Other abdominal manifestations of VHL are rare and are beyond the scope of this poster. Page 7 of 18

8 Given the near-equal efficacy of CT and MRI for diagnosing RCCs and phaeochromocytomas, and considering the requirement for repeat examinations and the younger age of the at-risk VHL individuals, the use of MRI is considered preferable to CT for upper abdominal screening when both imaging techniques are available. Screening for these lesions by MRI has the added benefit of high sensitivity for identifying renal and pancreatic cysts, pancreatic cystadenomas and other less common manifestations of VHL. Finally, while ultrasound has been used for screening by many institutions, technical and operator variation may limit reproducibility during a long term surveillance period. Several cases from the Hereditary Cancer Clinic are presented in Fig. 2 on page 10, Fig. 3 on page 10, Fig. 4 on page 11, Fig. 5 on page 11, Fig. 6 on page 12, and Fig. 7 on page 13. These examples demonstrate typical lesions identified during MRI screening at Prince of Wales Hospital. MRI screening protocols MRI screening protocols for cerebral/spinal haemangioblastoma and for ELST screening and surveillance were found in our search. However, no established MRI screening protocols were found to incorporate cerebral, inner-ear, spinal and upper abdominal regions together. The MRI screening protocol developed by the Prince of Wales Medical Imaging Department and the Hereditary Cancer Clinic, presented in Table 3 on page 14, seeks to establish an all-in-one study for VHL screening. The sequences selected for this protocol were chosen in order to satisfy several requirements. The cerebral and spinal sequences are similar to those already established in the literature and aim to provide maximum sensitivity in detecting haemangioblastomas (T2 and post-contrast sequences) as well as excluding other causes (EPI-DWI, SWI, FLAIR sequences). A CISS-3D sequence at the level of the base of skull is included for imaging of the 8th cranial nerve, inner ear and endolymphatic sac, in order to identify ELSTs. If a suspicious skull base lesion is detected, further imaging would be needed. Abdominal sequences were chosen in order to broadly identify suspicious lesions in the kidneys, adrenals and pancreas. Axial and coronal planes were used for conventional sequences to aid localisation. In- and out-of-phase, fat saturation and post-contrast phases were added to help characterisation and exclude common differentials. This would also help limit further imaging for false positives. Techniques were used to limit the effects of motion/breathing artefact, such as respiratory-triggered sequences. In developing the protocol, attention was also paid to the magnet time and cost of additional sequences. At our institution, the total time allocated for the all-in-one screening study is 90 minutes. Page 8 of 18

9 The benefits of MRI screening in VHL are many, but the reduction in radiation burden on individuals is a primary consideration. The limitations of MRI include its cost and availability, but both should be weighed up against the very strong preference to avoid ionising radiation in the annual and biennial screening of these individuals. Motion/ breathing artefact, compliance, claustrophobia and contraindications are all potential limitations of MRI. General anaesthesia may be necessary and this adds additional limitations, costs and risks. A cost benefit analysis was not found in the literature and needs to be performed. Using the all-in-one MRI screening protocol at Prince of Wales Hospital, we have detected multiple phaeochromocytomas, many renal cell cancers and several haemangioblastomas requiring surgery. One such case is presented as an example in Fig. 8 on page 15. Images for this section: Page 9 of 18

10 Table 2: Risk Management Guidelines for Von Hippel Lindau Syndrome. Modified and reprinted with kind permission from eviq, an online service of the Cancer Institute of New South Wales ( Fig. 3: CASE 1 is a known mutation-carrier from a family with three VHL-sufferers who has known cerebellar and spinal HBs. All three individuals undergo all-in-one MRI surveillance and screening at POWH. Axial T2 HASTE: There are small simple cortical cysts in the left kidney and a low T2 signal lesion in the interpolar region of the left kidney, indeterminate but possibly a haemorrhagic cyst. There are also small cysts in the pancreatic head (and tail - not seen on this slice). Page 10 of 18

11 Fig. 2: CASE 1 is a known mutation-carrier from a family with three VHL-sufferers who has known cerebellar and spinal HBs. All three individuals undergo all-in-one MRI surveillance and screening at POWH. Axial T2/T1 sequences: Mixed cystic solid posterior fossa lesions noted with moderate surrounding oedema. Axial T1 FS post-contrast: A small enhancing mural nodule in the region of the 4th ventricle and a larger area of enhancement in the left posteromedial cerebellar hemisphere. Fig. 4: CASE 2 is the first degree relative of case 1 with known multiple spinal HBs, but no cerebral HBs. Sagittal T2/T1 and post contrast T1 thoracic spine: At the posterior aspect of the spinal cord (at the level of T7), there is a small enhancing nodule. This is mild cord expansion and high T2 signal from T7-T8 in keeping with oedema. A syrinx was not seen. Page 11 of 18

12 Fig. 5: CASE 2 is the first degree relative of case 1 with known multiple spinal HBs, but no cerebral HBs. Axial T2 HASTE: There is a rounded, slightly lobulated, enhancing mass lesion centred at the head of the pancreas (post contrast image not shown). Smaller pancreatic cysts are seen in the body. Simple renal cysts were also seen at other levels. Page 12 of 18

13 Fig. 6: CASE 3 is a known mutation-carrier who was identified after discovery of a cerebral HB. Spinal HBs were identified on screening. Coronal/axial T2 HASTE: There are innumerable cysts throughout the pancreas, with minimal normal parenchyma remaining. The right kidney was absent in keeping with previous nephrectomy for RCC. Page 13 of 18

14 Fig. 7: CASE 3 is a known mutation-carrier who was identified after discovery of a cerebral HB. Spinal HBs were identified on screening. Coronal/axial T2 HASTE: There are innumerable cysts throughout the pancreas, with minimal normal parenchyma remaining. The right kidney was absent in keeping with previous nephrectomy for RCC. Page 14 of 18

15 Table 3: Suggested 1.5T MRI Pulse Sequence Protocol for All-in-one VHL Screening Page 15 of 18

16 Fig. 8: CASE 4 had known VHL and was on surveillance following previous RCCs and pancreatic cysts. A screening MRI revealed an occult spinal haemangioblastoma. The patient was largely asymptomatic but went on to have emergency spinal surgery. Sagittal T1/T2: There is a large expansile lesion centred within the central spinal cord from the craniocervical junction to C3. It is well-defined and fluid intensity. There is extensive cord oedema down to the upper thoracic level. Axial/sagittal T1 post-contrast: Two eccentric, enhancing nodules are noted at the margins of the non-enhancing cystic component of the lesion. Features are typical of spinal haemangioblastoma. Page 16 of 18

17 Conclusion The MRI features of the manifestations of VHL are well established and MRI is a sensitive and specific screening tool. Compared to MDCT, MRI has the additional benefit of reducing the radiation burden on a population for whom annual to biennial screening of the central and autonomic nervous systems and retroperitoneal viscera is required from the time of diagnosis. MRI also has a superior sensitivity and specificity profile for the neurological lesions and comparable profile for the abdominal lesions. Compared to US, MRI has the advantage of allowing screening for abdominal and neurological manifestations in the one booking, in a population in whom numerous repeat clinical and imaging episodes are recommended and in whom compliance with screening has been identified as a challenge. The MRI screening protocol developed by Prince of Wales Hospital Imaging Department in conjunction with the Hereditary Cancer Clinic is presented for consideration by clinicians and medical imaging specialists as an alternative to their existing screening methods. Personal information D. Rabinowitz, S. Morris, J. Kelly. Department of Medical Imaging, Prince of Wales Hospital, Randwick NSW 2023, Sydney Australia. mail to: dean.rabinowitz@sesiahs.health.nsw.gov.au K. Tucker. Prince of Wales and St George Hereditary Cancer Clinic, Prince of Wales Hospital Cancer Care Centre, 147 Barker Street, Randwick NSW 2031, Sydney Australia. mail to: POWHCC@sesiahs.health.nsw.gov.au References Maher ER, Neumann HP, Richard S. von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet Jun;19(6): Katabathina VS, Vinu-Nair S. Cross-Sectional Imaging Spectrum of von Hippel-Lindau Disease J Transl Med Epidemiol 2(1): 1021 Taouli B, Ghouadni M, Corréas JM, Hammel P, Couvelard A, Richard S, Vilgrain V. Spectrum of abdominal imaging findings in von Hippel-Lindau disease. AJR Am J Roentgenol Oct;181(4): Page 17 of 18

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