1. A 36-year-old man presented with a mass in his right adrenal gland and was found to have a pheochromocytoma, retinal hemangioma, kidney cysts, and liver lesions. 2. He was diagnosed with Von Hippel-Lindau disease based on his family history and multiple tumors. 3. Autopsy found brainstem and spinal cord hemangioblastomas consistent with VHL disease and catecholamine toxicity as the cause of death. Genetic testing identified a mutation in the VHL gene confirming the diagnosis.

1. Clinico-Pathological Conference 主講者 : 陳乃釧 指導者 : 韋建華、張文彬 96-11-30

2. Presenting Complaint A 36-year-old man was admitted to the hospital because of a mass in the right adrenal gland

3. History of Present Illness 7 months prior to admission Numbness over left arm 1 week after  Motor vehicle accident  Chiropractor  MRI of cervical spine  Cystic lesion in the medulla Associated with Hypertension : Atenolol + nortiptyline 3 weeks prior to admission Profuse sweating at night (requiring a change of sheets) Palpitations 3 ~ 5 times /day Insomnia BP: 170/110mmHg

4. Past medical history Appendectomy : 24 years ago Hypertension was also noted Left adrenal pheochromocytoma s/p tumor resection No further medical care Allergy : Nil Smoking : 10 sticks per day for 10+ years Alcohol drinking : occasionally

5. Pedigree of the patient Stroke 70y/o Heart attack 60y/o 90y/o emphysema

6. Physical examination General appearance : anxious-appearing young man Vital signs : Bp: 145/100mmHg, HR: 64bpm HEENT: No plethora, no proptosis Thyroid normal in size and consistency Ophthalmologic exam : R’t retinal hemangioma in the superotemporal periphery with a large vein leading into it Chest : Symmetric expansion, clear breathing sound Heart : Regular heart beat with no murmur Abdomen : two surgical scar over right lower and upper quarter, soft, non-tender without organomegaly or palpable masses

7. Skin : no peripheral edema NE : ↓ proprioception and sensation to touch and temperature L’t arm Physical examination 4 4 4 4 Muscle power DTR 1+ 2+ 2+ 2+

9. Impression Right medullary cystic mass - by clinical symptoms and MRI proved R’t retinal hemangioma - by physical examination 3. 2nd Hypertension suspect related to Recurrent pheochromocytoma Hyperthyroidism Renal artery stenosis

10. CBC, U/A , Blood Chemistry : Normal Diagnostic workup

11. Urine and serum catecholamine levels Diagnostic workup

12. Right adrenal mass 2.3x1.9cm with homogeneous enhancement in the arterial phase Left kidney complex cyst 2x1 cm with enhancing septations Liver multiple lesions Suspect hemangiomas with largest 2.4x2cm Diagnostic workup ~ MRI of abdomen

13. Right medullary cystic mass 1.3cm with a central cystic component A small enhancing nodule along the posterior wall A solid nonenhancing component that was isointense relative to brain tissue Diagnostic workup ~ MRI of brain

14. Nuclear-medicine scanning MIBG ( 131I metaiodobenzyl-guanidine ) posterior view Taken up by tissues that secrete catecholamines Area of uptake inferomedial to the liver and superior to the right kidney Diagnostic workup ~ MIBG

15. Admission diagnosis Hypertension secondary to pheochromocytoma (R’t adrenal gland) Proved by clinical signs and symptoms, imaging findings Right medullary cystic mass R’t retinal hemangioma Left kidney complex cyst Liver multiple lesions Suspect hemangioma

17. Course in the ward 12 days prior to admission BP: 190/120mmHg with terazosin and phenoxybenzamine Admitted for right adrenalectomy

18. Course in the ward Arrange for Genetic testing of peripheral-blood leukocytes 24 hours after surgery Resumed regular diet Began walking around the surgical floor BP monitored q2h Tx: fludrocortisone

19. Pheochromocytoma Adult: 80% unilateral and solitary, 10% bilateral, 10% extraadrenal Clinical symptoms Hypertension Crises: headache, profuse sweating, palpitations 25% no family history of the disease , (+) germ-line mutation predisposition Germ- line mutations Younger age Multifocal or extraadrenal disease Autosomal dominant hereditary syndromes with pheochromocytoma as component Von Hippel Lindau (VHL) disease Familial paraganglioma Multiple endocrine neoplasia (MEN) Neurofibromatosis

21. Dx criteria 1.≧6 cafA au lait spots 2.≧2 cutaneous neurofibromas 3.≧2 benign iris hamartomas (Lisch nodules) 4.One optic nerve glioma 5.Dysplasia of sphenoid bone 6.Thinning of the cortex of long bones 7.First-degree relative with NF1 1.Pheochromocytoma 20%, Mean age: 20’s, multifocal, bilateral disease or metachronously 2.Hemangioblastomas(CNS) 3.Liver and kidney cysts 4.Cyst and endocrine tumors of the pancreas 1.Pheochromocytoma 2.Extraadrenal tumors of chromaffin-positive cells of the parasymptathetic nervous system Pheochromocytoma Juvenile AML Malignant peripheral nerve sheath tumors Sarcoma 1.Pheochromocytoma :50% 2.Medullary thyroid carcinoma: 100% 3.Hyperplasia of the parathyroid gland Von Hippel Lindau Disease Familial paraganglioma Neurofibromatosis(NF1) MEN II

22. Correlation to the patient P’t: Pheochromocytoma (R’t adrenal gland) Right medullary cystic mass compatible with a hemangioblastoma R’t retinal hemangioma Left kidney complex cyst Liver multiple lesions suspect hemangioma Mother: Polycystic kidney disease Maternal uncle Tumor in the eye  indicate the presence of a retinal hemangioblastoma

23. Final diagnosis Von Hippel Lindau disease associated with Pheochromocytoma (R’t) Hemangiobglastomas of the medulla and spinal cord Renal and hepatic cysts Retinal hemangioma (R’t)

24. Von Hippel Lindau disease (VHL) Inherited mutation of the VHL gene Causes tumors to form in areas of the body that contain large numbers of blood vessels Cyst and endocrine tumors Liver cysts Kidney cysts Nonmetastasizing papillary cystadenomas Pancreas Endolymphatic canal of the middle ear Epididymis of male Adnexal organs of female p’t VHL Symptoms: common early symptoms Visual changes Headaches Changes in balance and strength Erratic blood pressure, flushing (if pheochromocytoma is present)

25. Hemagioblastomas VHL-associated Younger age Synchronously, metachronously as multiple lesions Crerebellm(75%), Spine(20%), brain stem(5%) Sporadic Older age Mostly single lesion typically in spinal cord Renal cell carcinoma VHL associated Multifocal and bilateral 20’s ~ 30’s Sporadic renal cell carcinoma Older (50y/o) Single tumor of any histologic type Few kidney cysts VHL Main complication

26. VHL gene Chromosome 3p25 3 exons encoding at least 2 active isoforms of the VHL disease tumor-suppressor protein ( pVHL ) Genetic test for mutations in the VHL gene Sequencing the 3 exons Southern blot analysis VHL type 1 Gene deletions or specific missense mutations Not at risk for pheochromocytoma VHL type 2(96%) Specific missense mutations (+) Pheochromocytoma

27. VHL pathogenesis HIF: hypoxia-inducible transcription factor

29. Post op Day 2 Sudden onset loss of conscious Cardiac arrest with ventricular fibrillation Failure of resuscitation  expired Course in the ward

31. Adrenalectomy Specimen

32. Brain-stem and spinal cord hemagioblastomas Autopsy Result

33. Autopsy result ~ pancreas

34. Findings in the Central Nervous System at Autopsy (Luxol Fast Blue–Hematoxylin and Eosi ) Cross section of the medulla of the brain stem in which edema is apparent ipsilateral to a small fourth ventricular hemangioblastoma (arrow). The dotted line indicates the midline, highlighting the larger size of the left side of the brain stem. Three hemangioblastomas in CNS Superficial dorsal R’t thoracic spinal cord Left lumbar dorsal-nerve root Fourth ventricular lesion

35. Findings in the Central Nervous System at Autopsy (Luxol Fast Blue–Hematoxylin and Eosi Edematous areas of the brain stem characterized by reactive astrocytes and small vacuolated regions .

36. Findings in the Central Nervous System at Autopsy (Luxol Fast Blue–Hematoxylin and Eosi Prominent stromal cells, notable for their prominent vacuolated cytoplasm, as well as a delicate capillary network in the thoracic spinal cord hemangioblastoma.

37. Findings in the Central Nervous System at Autopsy (Luxol Fast Blue–Hematoxylin and Eosi A cross section of the thoracic spinal cord in which a small dorsal hemangioblastoma (arrow) is associated with a local mass effect and distortion of the adjacent cord.

38. Autopsy result ~ Cardiac histology

39. Autopsy result ~ Cardiac histology

40. Genetic testing result Single base change from G to A at nuclotide 713  arginine to glutamine (R167Q) Typical mutation in the VHL gene , Type 2

41. Anatomical Diagnosis VHL disease with R167Q mutation (type 2), associated with adrenal pheochromocytoma, brain-stem and spinal cord hemangioblastomas, liver hemangiomas, renal cysts, a pancreatic endocrine tumor, and catecholamine-induced myocardial toxicity

42. The End Have a Nice Day