96 11 30 vhl final

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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