Disclosures. Neurological Manifestations of Von Hippel Lindau Syndrome. Objectives. Overview. None No conflicts of interest

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1 Neurological Manifestations of Von Hippel Lindau Syndrome ARNOLD B. ETAME MD, PhD NEURO-ONCOLOGY/NEUROSURGERY Moffitt Cancer Center Disclosures None No conflicts of interest VHL Alliance Annual Family Meeting 10/14/2017 Objectives Understand how VHL hemangioblastoma tumors affect the function of the brain and spinal cord. Understand how VHL lesions in the brain and spinal cord are diagnosed. Understand how VHL lesions in the brain and spinal cord are treated and the associated treatment outcomes. Overview VHL Tumors Clinical Symptoms Treatment Outcomes

2 VHL Epidemiology VHL Epidemiology Ordookhanian C et al. Management strategies and outcomes for VHL-related Craniospinal s. J Kidney Cancer VHL 2017;4(3): Ordookhanian C et al. Management strategies and outcomes for VHL-related Craniospinal s. J Kidney Cancer VHL 2017;4(3): WHO Grade 1 Tumor (benign). Very common in patients with VHL. Commonly seen in Brain and Spinal Cord.

3 Benign? The most common cause of demise in VHL patients appears to be from posterior fossa hemorrhages associated with hemangioblastoma and also renal cell carcinoma. Maher et al J Med 1990; Butman et al. JAMA 2008; Wilding A et al. J Med Gen 2012 Diagnosis/Screening MRI excellent view of tumor and surrounding brain and spinal cord study of choice. Screen brain and spinal cord Tumors are often nodular (solid) but they can also have a cyst. Brain Most commonly seen in the cerebellum and brainstem but can also be seen in the other lobes of the brain. MRI showing hemangioblastoma tumors (bright) in the cerebellum, brainstem and spinal cord. Symptoms will depend on location, tumor size, tumor bleeding, and swelling.

4 Brain Anatomy Brain Function Most common in the cerebellum and brainstem but can be seen in the other lobes of the brain. Symptoms will depend on location, tumor size and hemorrhage Clinical Symptoms Clinical Symptoms Cerebellar hemangioblastoma with enhancing nodule and cyst compressing the cerebellum. Cerebellar tumors can bleed and obstruct flow of spinal fluid nausea, loss of coordination, vomiting, lethargy. Brainstem lesions can cause swallowing, breathing, visual and lethargy symptoms.

5 Clinical Symptoms Spinal lesions can cause weakness (paralysis), balanced issues with walking, sensory symptoms, bowel and bladder dysfunction. MRI showing hemangioblastoma tumors (bright) in the cerebellum, brainstem and spinal cord. Natural History The vast majority of VHL hemangioblastomas will remain asymptomatic and will never require treatment. Close surveillance with MRI Brain and Spine is advised. Treatment Surgery (First Option especially with onset of symptoms) Radiation Therapy Ammerman et al J Neurosurg 2006; Lonser et al. J Neurosurg 2014; Wanebo et al. J Neurosurg 2003

6 Surgical Treatment Surgical Candidates? Symptomatic lesions Asymptomatic lesions (controversial) Surgical Candidate? Surgical Candidate?

7 Radiotherapy 186 Pts with 517 lesion. Overall survival rates of 94% at 3 years, 90% at 5 years, and 74% at 10 years. Associated tumor control rates were 92% at 3 years, 89% at 5 years, and 79% at 10 years. Radiotherapy Differential Response Sporadic versus VHL HB (57 Pts). 5- and 10-year tumor control rates of 67 and 44%, respectively, for sporadic HB Compared to 97 and 83%, respectively, for VHL-related HB (67). Besides VHL pathology, SRS was much effective for small and solid tumors compared to large and cystic tumors. Kano et al J Neurosurg 2015 Hanakita et al Neuro Oncol 2014 Radiotherapy Spinal lesions Radiographic and clinical outcomes in 34 spinal tumors. Following SRS treatment, 94% of the tumors were either stable or regressed with local control rates at 1, 3, and 5 years being 96, 92, and 92%, respectively. Symptom improvement was associated with 81% of treated lesions Pan et al Neurosurg Focus 2017 Outcomes Overall favorable with surgery and/or Radiation Therapy. Radiation is favorable for spinal cord tumors that are small and solid. Tumors with cysts are more favorable than tumors without cyst (solid tumors). Ordookhanian C et al. Management strategies and outcomes for VHL-related Craniospinal s. J Kidney Cancer VHL 2017;4(3):37 44.

8 Final Thoughts Lesions that are symptomatic or demonstrate worrisome radiographic features warrant surgery resection if safely feasible. Radiosurgery remains an acceptable alternative to surgical resection. Excellent long-term outcomes can be expected with surgery and radiation. Final Thoughts Good news: Most hemangioblastoma patients will never need treatment. Close MRI surveillance with a neurosurgeon is very important. References Ordookhanian C, Kaloostian PE, Ghostine SS, Philippe SE, Etame AB. Management strategies and outcomes for VHL-related Craniospinal s. J Kidney Cancer VHL 2017;4(3): Ammerman JM, Lonser RR, Dambrosia J, Butman JA, Oldfield EH. Long-term natural history of hemangioblastomas in patients with von Hippel-Lindau disease: Implications for treatment. J Neurosurg Lonser RR, Butman JA, Huntoon K, Asthagiri AR, Wu T, Bakhtian KD, et al. Prospective natural history study of central nervous system hemangioblastomas in von Hippel-Lindau disease. J Neurosurg Wanebo JE, Lonser RR, Glenn GM, Oldfield EH. The natural history of hemangioblastomas of the central nervous system in patients with von Hippel-Lindau disease. J Neurosurg Maher ER, Yates JR, Harries R, Benjamin C, Harris R, Moore AT, et al. Clinical features and natural history of von Hippel-Lindau disease. Q J Med Butman JA, Linehan WM, Lonser RR. Neurologic manifestations of von Hippel-Lindau disease. JAMA Wilding A, Ingham SL, Lalloo F, Clancy T, Huson SM, Moran A, et al. Life expectancy in hereditary cancer predisposing diseases: An observational study. J Med Genet Kano H, Niranjan A, Mongia S, Kondziolka D, Flickinger JC, Lunsford LD. The role of stereotactic radiosurgery for intracranial hemangioblastomas. Neurosurgery Pan J, Ho AL, D Astous M, Sussman ES, Thompson PA, Tayag AT, et al. Image-guided stereotactic radiosurgery for treatment of spinal hemangioblastoma. Neurosurg Focus Hanakita S, Koga T, Shin M, Takayanagi S, Mukasa A, Tago M, et al. The long-term outcomes of radiosurgery for intracranial hemangioblastomas. Neuro Oncol THANK YOU VERY MUCH

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