Clinico-Pathological Conference 主講者 : 陳乃釧 指導者 : 韋建華、張文彬 96-11-30
Presenting Complaint <ul><li>A  36-year-old man  was admitted to the hospital because of a  mass  in the  right adrenal gl...
History of Present Illness <ul><li>7 months  prior to admission </li></ul><ul><ul><li>Numbness over left arm </li></ul></u...
Past medical history <ul><li>Appendectomy : 24 years ago </li></ul><ul><ul><li>Hypertension was also noted </li></ul></ul>...
Pedigree of the patient Stroke 70y/o Heart attack 60y/o 90y/o emphysema
Physical examination <ul><li>General appearance : anxious-appearing young man </li></ul><ul><li>Vital signs :  Bp: 145/100...
<ul><li>Skin : no peripheral edema </li></ul><ul><li>NE :  ↓  proprioception and sensation to touch and temperature  L’t a...
 
Impression <ul><li>Right medullary cystic mass </li></ul><ul><ul><li>- by clinical symptoms and MRI proved </li></ul></ul>...
<ul><li>CBC, U/A , Blood Chemistry : Normal </li></ul>Diagnostic workup
<ul><li>Urine and serum  catecholamine levels </li></ul>Diagnostic workup
<ul><li>Right adrenal mass </li></ul><ul><ul><li>2.3x1.9cm with homogeneous enhancement in the arterial phase </li></ul></...
<ul><li>Right medullary cystic mass </li></ul><ul><ul><li>1.3cm with a central cystic component </li></ul></ul><ul><ul><ul...
<ul><li>Nuclear-medicine scanning MIBG </li></ul><ul><li>( 131I metaiodobenzyl-guanidine ) </li></ul><ul><li>posterior vie...
Admission diagnosis <ul><li>Hypertension secondary to pheochromocytoma (R’t adrenal gland)  </li></ul><ul><li>Proved by cl...
 
Course in the ward <ul><li>12 days  prior to admission </li></ul><ul><ul><li>BP: 190/120mmHg  with terazosin and phenoxybe...
Course in the ward <ul><li>Arrange for  Genetic testing  of peripheral-blood leukocytes </li></ul><ul><li>24 hours after s...
Pheochromocytoma <ul><li>Adult: 80% unilateral and solitary, 10% bilateral, 10% extraadrenal </li></ul><ul><li>Clinical sy...
 
Dx criteria 1.≧6 cafA au lait spots 2.≧2 cutaneous neurofibromas  3.≧2 benign iris hamartomas (Lisch nodules) 4.One optic ...
Correlation to the patient <ul><li>P’t: </li></ul><ul><ul><li>Pheochromocytoma (R’t adrenal gland)  </li></ul></ul><ul><ul...
Final diagnosis <ul><li>Von Hippel Lindau disease  associated with </li></ul><ul><li>Pheochromocytoma  (R’t) </li></ul><ul...
Von Hippel Lindau disease (VHL) <ul><li>Inherited mutation of the VHL gene </li></ul><ul><ul><li>Causes  tumors   to form ...
<ul><li>Hemagioblastomas </li></ul><ul><ul><li>VHL-associated </li></ul></ul><ul><ul><ul><li>Younger age </li></ul></ul></...
VHL gene <ul><li>Chromosome 3p25 </li></ul><ul><ul><li>3 exons encoding at least 2 active isoforms of the VHL disease  tum...
VHL pathogenesis HIF: hypoxia-inducible transcription factor
 
<ul><li>Post op Day 2  </li></ul><ul><ul><li>Sudden onset loss of conscious  </li></ul></ul><ul><ul><li>Cardiac arrest  wi...
 
Adrenalectomy Specimen
Brain-stem and spinal cord hemagioblastomas Autopsy Result
Autopsy result ~ pancreas
Findings in the Central Nervous System at Autopsy (Luxol Fast Blue–Hematoxylin and Eosi ) Cross section of the medulla of ...
Findings in the Central Nervous System at Autopsy (Luxol Fast Blue–Hematoxylin and Eosi Edematous areas of the brain stem ...
Findings in the Central Nervous System at Autopsy (Luxol Fast Blue–Hematoxylin and Eosi Prominent stromal cells, notable f...
Findings in the Central Nervous System at Autopsy (Luxol Fast Blue–Hematoxylin and Eosi A cross section of the thoracic sp...
Autopsy result ~ Cardiac histology
Autopsy result ~ Cardiac histology
Genetic testing result <ul><li>Single base change from G to A at nuclotide 713    arginine to glutamine (R167Q) </li></ul...
Anatomical  Diagnosis <ul><li>VHL disease with R167Q mutation (type 2), associated with adrenal pheochromocytoma, brain-st...
The End Have a Nice Day
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96 11 30 Vhl Final

  1. 1. Clinico-Pathological Conference 主講者 : 陳乃釧 指導者 : 韋建華、張文彬 96-11-30
  2. 2. Presenting Complaint <ul><li>A 36-year-old man was admitted to the hospital because of a mass in the right adrenal gland </li></ul>
  3. 3. History of Present Illness <ul><li>7 months prior to admission </li></ul><ul><ul><li>Numbness over left arm </li></ul></ul><ul><ul><li>1 week after  Motor vehicle accident  Chiropractor  MRI of cervical spine  Cystic lesion in the medulla </li></ul></ul><ul><ul><li>Associated with Hypertension : Atenolol + nortiptyline </li></ul></ul><ul><li>3 weeks prior to admission </li></ul><ul><ul><li>Profuse sweating at night (requiring a change of sheets) </li></ul></ul><ul><ul><li>Palpitations 3 ~ 5 times /day </li></ul></ul><ul><ul><li>Insomnia </li></ul></ul><ul><ul><li>BP: 170/110mmHg </li></ul></ul>
  4. 4. Past medical history <ul><li>Appendectomy : 24 years ago </li></ul><ul><ul><li>Hypertension was also noted </li></ul></ul><ul><ul><li>Left adrenal pheochromocytoma s/p tumor resection </li></ul></ul><ul><ul><li>No further medical care </li></ul></ul><ul><li>Allergy : Nil </li></ul><ul><li>Smoking : 10 sticks per day for 10+ years </li></ul><ul><li>Alcohol drinking : occasionally </li></ul>
  5. 5. Pedigree of the patient Stroke 70y/o Heart attack 60y/o 90y/o emphysema
  6. 6. Physical examination <ul><li>General appearance : anxious-appearing young man </li></ul><ul><li>Vital signs : Bp: 145/100mmHg, HR: 64bpm </li></ul><ul><li>HEENT: </li></ul><ul><ul><li>No plethora, no proptosis </li></ul></ul><ul><ul><li>Thyroid normal in size and consistency </li></ul></ul><ul><ul><li>Ophthalmologic exam : R’t retinal hemangioma in the superotemporal periphery with a large vein leading into it </li></ul></ul><ul><li>Chest : Symmetric expansion, clear breathing sound </li></ul><ul><li>Heart : Regular heart beat with no murmur </li></ul><ul><li>Abdomen : two surgical scar over right lower and upper quarter, soft, non-tender without organomegaly or palpable masses </li></ul>
  7. 7. <ul><li>Skin : no peripheral edema </li></ul><ul><li>NE : ↓ proprioception and sensation to touch and temperature L’t arm </li></ul>Physical examination 4 4 4 4 Muscle power DTR 1+ 2+ 2+ 2+
  8. 9. Impression <ul><li>Right medullary cystic mass </li></ul><ul><ul><li>- by clinical symptoms and MRI proved </li></ul></ul><ul><li>R’t retinal hemangioma </li></ul><ul><li>- by physical examination </li></ul><ul><li>3. 2nd Hypertension suspect related to </li></ul><ul><ul><li>Recurrent pheochromocytoma </li></ul></ul><ul><ul><li>Hyperthyroidism </li></ul></ul><ul><ul><li>Renal artery stenosis </li></ul></ul>
  9. 10. <ul><li>CBC, U/A , Blood Chemistry : Normal </li></ul>Diagnostic workup
  10. 11. <ul><li>Urine and serum catecholamine levels </li></ul>Diagnostic workup
  11. 12. <ul><li>Right adrenal mass </li></ul><ul><ul><li>2.3x1.9cm with homogeneous enhancement in the arterial phase </li></ul></ul><ul><li>Left kidney complex cyst </li></ul><ul><ul><li>2x1 cm with enhancing septations </li></ul></ul><ul><li>Liver multiple lesions </li></ul><ul><ul><li>Suspect hemangiomas with largest 2.4x2cm </li></ul></ul>Diagnostic workup ~ MRI of abdomen
  12. 13. <ul><li>Right medullary cystic mass </li></ul><ul><ul><li>1.3cm with a central cystic component </li></ul></ul><ul><ul><ul><li>A small enhancing nodule along the posterior wall </li></ul></ul></ul><ul><ul><ul><li>A solid nonenhancing component that was isointense relative to brain tissue </li></ul></ul></ul>Diagnostic workup ~ MRI of brain
  13. 14. <ul><li>Nuclear-medicine scanning MIBG </li></ul><ul><li>( 131I metaiodobenzyl-guanidine ) </li></ul><ul><li>posterior view </li></ul><ul><li>Taken up by tissues that secrete catecholamines </li></ul><ul><li>Area of uptake inferomedial to the liver and superior to the right kidney </li></ul>Diagnostic workup ~ MIBG
  14. 15. Admission diagnosis <ul><li>Hypertension secondary to pheochromocytoma (R’t adrenal gland) </li></ul><ul><li>Proved by clinical signs and symptoms, imaging findings </li></ul><ul><li>Right medullary cystic mass </li></ul><ul><li>R’t retinal hemangioma </li></ul><ul><li>Left kidney complex cyst </li></ul><ul><li>Liver multiple lesions </li></ul><ul><ul><li>Suspect hemangioma </li></ul></ul>
  15. 17. Course in the ward <ul><li>12 days prior to admission </li></ul><ul><ul><li>BP: 190/120mmHg with terazosin and phenoxybenzamine </li></ul></ul><ul><li>Admitted for right adrenalectomy </li></ul>
  16. 18. Course in the ward <ul><li>Arrange for Genetic testing of peripheral-blood leukocytes </li></ul><ul><li>24 hours after surgery </li></ul><ul><ul><li>Resumed regular diet </li></ul></ul><ul><ul><li>Began walking around the surgical floor </li></ul></ul><ul><ul><li>BP monitored q2h </li></ul></ul><ul><ul><li>Tx: fludrocortisone </li></ul></ul>
  17. 19. Pheochromocytoma <ul><li>Adult: 80% unilateral and solitary, 10% bilateral, 10% extraadrenal </li></ul><ul><li>Clinical symptoms </li></ul><ul><ul><li>Hypertension </li></ul></ul><ul><ul><li>Crises: headache, profuse sweating, palpitations </li></ul></ul><ul><li>25% no family history of the disease , (+) germ-line mutation predisposition </li></ul><ul><ul><li>Germ- line mutations </li></ul></ul><ul><ul><ul><li>Younger age </li></ul></ul></ul><ul><ul><ul><li>Multifocal or extraadrenal disease </li></ul></ul></ul><ul><li>Autosomal dominant hereditary syndromes with pheochromocytoma as component </li></ul><ul><ul><li>Von Hippel Lindau (VHL) disease </li></ul></ul><ul><ul><li>Familial paraganglioma </li></ul></ul><ul><ul><li>Multiple endocrine neoplasia (MEN) </li></ul></ul><ul><ul><li>Neurofibromatosis </li></ul></ul>
  18. 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 <ul><li>Pheochromocytoma </li></ul><ul><li>Juvenile AML </li></ul><ul><li>Malignant peripheral nerve sheath tumors </li></ul><ul><li>Sarcoma </li></ul>1.Pheochromocytoma :50% 2.Medullary thyroid carcinoma: 100% 3.Hyperplasia of the parathyroid gland Von Hippel Lindau Disease Familial paraganglioma Neurofibromatosis(NF1) MEN II
  19. 22. Correlation to the patient <ul><li>P’t: </li></ul><ul><ul><li>Pheochromocytoma (R’t adrenal gland) </li></ul></ul><ul><ul><li>Right medullary cystic mass compatible with a hemangioblastoma </li></ul></ul><ul><ul><li>R’t retinal hemangioma </li></ul></ul><ul><ul><li>Left kidney complex cyst </li></ul></ul><ul><ul><li>Liver multiple lesions suspect hemangioma </li></ul></ul><ul><li>Mother: </li></ul><ul><ul><li>Polycystic kidney disease </li></ul></ul><ul><li>Maternal uncle </li></ul><ul><ul><li>Tumor in the eye  indicate the presence of a retinal hemangioblastoma </li></ul></ul>
  20. 23. Final diagnosis <ul><li>Von Hippel Lindau disease associated with </li></ul><ul><li>Pheochromocytoma (R’t) </li></ul><ul><li>Hemangiobglastomas of the medulla and spinal cord </li></ul><ul><li>Renal and hepatic cysts </li></ul><ul><li>Retinal hemangioma (R’t) </li></ul>
  21. 24. Von Hippel Lindau disease (VHL) <ul><li>Inherited mutation of the VHL gene </li></ul><ul><ul><li>Causes tumors to form in areas of the body that contain large numbers of blood vessels </li></ul></ul><ul><li>Cyst and endocrine tumors </li></ul><ul><ul><li>Liver cysts </li></ul></ul><ul><ul><li>Kidney cysts </li></ul></ul><ul><ul><li>Nonmetastasizing papillary cystadenomas </li></ul></ul><ul><ul><ul><li>Pancreas </li></ul></ul></ul><ul><ul><ul><li>Endolymphatic canal of the middle ear </li></ul></ul></ul><ul><ul><ul><li>Epididymis of male </li></ul></ul></ul><ul><ul><ul><li>Adnexal organs of female p’t </li></ul></ul></ul><ul><li>VHL Symptoms: common early symptoms </li></ul><ul><ul><li>Visual changes </li></ul></ul><ul><ul><li>Headaches </li></ul></ul><ul><ul><li>Changes in balance and strength </li></ul></ul><ul><ul><li>Erratic blood pressure, flushing (if pheochromocytoma is present) </li></ul></ul>
  22. 25. <ul><li>Hemagioblastomas </li></ul><ul><ul><li>VHL-associated </li></ul></ul><ul><ul><ul><li>Younger age </li></ul></ul></ul><ul><ul><ul><li>Synchronously, metachronously as multiple lesions </li></ul></ul></ul><ul><ul><ul><li>Crerebellm(75%), Spine(20%), brain stem(5%) </li></ul></ul></ul><ul><ul><li>Sporadic </li></ul></ul><ul><ul><ul><li>Older age </li></ul></ul></ul><ul><ul><ul><li>Mostly single lesion typically in spinal cord </li></ul></ul></ul><ul><li>Renal cell carcinoma </li></ul><ul><ul><li>VHL associated </li></ul></ul><ul><ul><ul><li>Multifocal and bilateral </li></ul></ul></ul><ul><ul><ul><li>20’s ~ 30’s </li></ul></ul></ul><ul><ul><li>Sporadic renal cell carcinoma </li></ul></ul><ul><ul><ul><li>Older (50y/o) </li></ul></ul></ul><ul><ul><ul><li>Single tumor of any histologic type </li></ul></ul></ul><ul><ul><ul><li>Few kidney cysts </li></ul></ul></ul>VHL Main complication
  23. 26. VHL gene <ul><li>Chromosome 3p25 </li></ul><ul><ul><li>3 exons encoding at least 2 active isoforms of the VHL disease tumor-suppressor protein ( pVHL ) </li></ul></ul><ul><li>Genetic test for mutations in the VHL gene </li></ul><ul><ul><li>Sequencing the 3 exons </li></ul></ul><ul><ul><li>Southern blot analysis </li></ul></ul><ul><li>VHL type 1 </li></ul><ul><ul><li>Gene deletions or specific missense mutations </li></ul></ul><ul><ul><li>Not at risk for pheochromocytoma </li></ul></ul><ul><li>VHL type 2(96%) </li></ul><ul><ul><li>Specific missense mutations </li></ul></ul><ul><ul><li>(+) Pheochromocytoma </li></ul></ul>
  24. 27. VHL pathogenesis HIF: hypoxia-inducible transcription factor
  25. 29. <ul><li>Post op Day 2 </li></ul><ul><ul><li>Sudden onset loss of conscious </li></ul></ul><ul><ul><li>Cardiac arrest with ventricular fibrillation </li></ul></ul><ul><ul><li>Failure of resuscitation  expired </li></ul></ul>Course in the ward
  26. 31. Adrenalectomy Specimen
  27. 32. Brain-stem and spinal cord hemagioblastomas Autopsy Result
  28. 33. Autopsy result ~ pancreas
  29. 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. <ul><li>Three hemangioblastomas in CNS </li></ul><ul><ul><li>Superficial dorsal R’t thoracic spinal cord </li></ul></ul><ul><ul><li>Left lumbar dorsal-nerve root </li></ul></ul><ul><ul><li>Fourth ventricular lesion </li></ul></ul>
  30. 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 .
  31. 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.
  32. 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.
  33. 38. Autopsy result ~ Cardiac histology
  34. 39. Autopsy result ~ Cardiac histology
  35. 40. Genetic testing result <ul><li>Single base change from G to A at nuclotide 713  arginine to glutamine (R167Q) </li></ul><ul><li>Typical mutation in the VHL gene , Type 2 </li></ul>
  36. 41. Anatomical Diagnosis <ul><li>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 </li></ul>
  37. 42. The End Have a Nice Day

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