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Clinico-PathologicalConference
主講者 : 陳乃釧指導者 : 韋建華、張文彬
96-11-30
Presenting Complaint
• A 36-year-old man was admitted to the hospital because of a mass in the right adrenal gland
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
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
Pedigree of the patient
Stroke 70y/o Heart attack 60y/o 90y/oemphysema
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
• Skin: no peripheral edema
• NE: ↓ proprioception and sensation to touch and temperature L’t arm
Physical examination
4
4
4
4
Muscle powerDTR
1+
2+
2+
2+
Impression
1. Right medullary cystic mass- by clinical symptoms and MRI proved
2. R’t retinal hemangioma - by physical examination
3. 2nd Hypertension suspect related to - Recurrent pheochromocytoma- Hyperthyroidism- Renal artery stenosis
• CBC, U/A , Blood Chemistry : Normal
Diagnostic workup
• Urine and serum catecholamine levels
Diagnostic workup
Diagnostic workup ~ MRI of abdomen
• 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
Right medullary cystic mass1.3cm with a central cystic component
A small enhancing nodule along the posterior wallA solid nonenhancing component that was isointense relative to brain tissue
Diagnostic workup ~ MRI of brain
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
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
Course in the ward
• 12 days prior to admission– BP: 190/120mmHg with terazosin and
phenoxybenzamine
• Admitted for right adrenalectomy
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
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
MEN II Neurofibromatosis(NF1) Familial paraganglioma
Von Hippel Lindau Disease
1.Pheochromocytoma :50%
2.Medullary thyroid carcinoma: 100%
3.Hyperplasia of the parathyroid gland
1. Pheochromocytoma
2. Juvenile AML
3. Malignant peripheral nerve sheath tumors
4. Sarcoma
1.Pheochromocytoma
2.Extraadrenal tumors of chromaffin-positive cells of the parasymptathetic nervous system
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
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
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
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)
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)
• 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
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
VHL pathogenesis
HIF: hypoxia-inducible
transcription factor
• Post op Day 2 – Sudden onset loss of conscious – Cardiac arrest with ventricular fibrillation– Failure of resuscitation expired
Course in the ward
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 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 CNSSuperficial dorsal R’t thoracic spinal cordLeft lumbar dorsal-nerve rootFourth ventricular lesion
Findings in the Central Nervous System at Autopsy (Luxol Fast Blue–Hematoxylin and Eosi
Edematous areas of the brain stem characterized by reactive astrocytesand small vacuolated regions.
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.
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.
Autopsy result ~ Cardiac histology
Autopsy result ~ Cardiac histology
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
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
The End
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