Clinico-Pathological Conference 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

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

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

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/o emphysema

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

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 power DTR 1+ 2+ 2+ 2+

Skin : no peripheral edema

NE : ↓ proprioception and sensation to touch and temperature L’t arm

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

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

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

CBC, U/A , Blood Chemistry : Normal

Urine and serum catecholamine levels Diagnostic workup

Urine and serum catecholamine levels

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

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 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

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

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

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

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

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

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

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

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

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

Pheochromocytoma

Juvenile AML

Malignant peripheral nerve sheath tumors

Sarcoma

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

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 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)

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

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 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

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

Post op Day 2

Sudden onset loss of conscious

Cardiac arrest with ventricular fibrillation

Failure of resuscitation  expired

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 CNS Superficial dorsal R’t thoracic spinal cord Left lumbar dorsal-nerve root Fourth ventricular lesion

Three hemangioblastomas in CNS

Superficial dorsal R’t thoracic spinal cord

Left lumbar dorsal-nerve root

Fourth 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 astrocytes and 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

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

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 Have a Nice Day