Disorders of the adrenal medulla

Question 1

What are the major disorders of the adrenal medulla?

Answer 1

Neoplasias

Pheochromocytomas - neoplasia of the chromaffin cells., neural crest derived endocrine cells that secrete catecholamines.

Neuroblastomas

Mature Ganglion cell tumors.

Question 2

What is the rule of 10’s for pheochromocytomas?

Answer 2

four 10% rules and one 25% rule. (5 rules total)

• 10% are extradrenal
  
  • at the Aortic bifurcation to the iliacs, or at the inferior mesenteric artery branch point, arising from chromaffin cells of the organ of Zuckerkandl., or from the carotid body.
  • These are usually called paragangliomas instead.
• 10% are bilateral
  
  • ​In familial syndromes, up to 50% are bilateral
• 10% are malignant
• 25% have germ line mutations in one of these 6 genes:
  
  • ​RET - like type 2 MEN syndromes and medullary thyroid carcinoma
    
    • about 10% are part of MEN2 syndrome
  • NF1 - like type 1 neurofibromatosis
  • VHL - like renal clear cell carcinoma and VHL disease.
  • SDHB, SDHC, or SDHD, of the succinate dehydrogenase complex

Question 3

Symptoms of pheochromocytoma

Answer 3

• Abrupt or chronic development or worsening of hypertension
• tachycardia
• palpitations
• headache
• sweating
• tremor
• anxiety
• hyperglycemia
• hyperlipidemia
• weight loss

however in clinical practice, paroxysmal (abrupt, variable) episodes of hypertension occur in less than half of patients

more often presents as chronic sustained hypertension.

Both kinds have increased risks:

• AMI
• heart failure
• ischemic renal injury
• stroke
• arrythmias

In rare cases, the pheochromocytoma can secrete ACTH or somatostatin.

Question 4

Diagnostic tests for pheochromocytoma

Answer 4

Ultrasound/CT imaging

MIBG scintiography - radiolabeled synthetic noradrenalin analog that is taken up by medullary tissue.

Three separate 24 hour urinary collections. Measurement of cortisol, VMA and metanephrine

Question 5

What types of things can set of a pheochromocytoma emergency?

Answer 5

Things that acutely activate strong stress and a few random things

• Severe physical/emotional stress
• Parturition/birth
• Abdominal palpation
• General anesthesia
• Contrast media
  *

Question 6

Treatment for pheochromocytoma

Answer 6

Main treatment is surgery, but before surgery can be done, the blood pressure must be managed the patient can easily die from severe intra-operative hypertension (anesthesia and surgery can bring on a hypertensive crisis from the pheochromocytoma)

Non-specific and irreversible alpha adrenoceptor blocker phenoxybenzamine or a short acting alpha antagonist (e.g. prazosin, terazosin, or doxazosin). Possibly also a beta blocker to control heart rate

Surgical excision, especially if it a single tumor

Multiple tumors may not be operable and require long term hypertension.

Required life long follow up monitoring, late malignant recurrence can occur.

Question 7

What is the etiology of neuroblastoma?

Major gene mutation in familial types?

Some unique characteristics of it?

Answer 7

• The most common childhood tumor outside of the cranium, and the second most common overal childhood malignancy.
• Presents before 5 years old
• Can develop anywhere in the sympathetic nervous system or the brain
• most often develop in the adrenal meulla or the retroperitoneal sympathetic ganglia
• ALK kinase activating mutations cause some of the familial forma, which are about 1% of all cases.

Unique characteristic

• ​The majority undergo spontaneous regression and occur as silent lesions that spontaenously regress
• Even clinical ones have a high rate of spontaneous regression.
• They also have a high rate of spontaneous or therapy-induced maturation to”
  
  • a ganglioneuroblastoma. Larger cells having more abundant cytoplasm with large vesicular nuclei and a prominent nucleolus, representing ganglion cells in various stages of maturation, may be found in tumors admixed with primitive neuroblasts.
  • even more well differentiated ganglioneuroma, which is predominantly large cells resembling mature ganglion cells.
  • The presence of Schwann cells and mature fibroblasts is also seen on maturation, and is a requirement for the tumor to be called either a gnaglioneuroblastoma or a ganglioneuroma.

Question 8

Presentation of neuroblastoma

Answer 8

Neonates: blueberry muffin skin, due to cutaneous metastases of the tumor

Babies under 2 years: visible abdominal mass, fever, weight loss

Young children: often unnoticed until it has metastasized to liver, lungs, and bone. causing ascites, bone pain, dyspnea.

High blood catecholamines and urine levels of VMA, HVA, and metanephrine

Despite the high catecholamine levels in neuroblastoma, hypertension is not a major feature, and much less common than in pheochromocytoma

Question 9

Stagin/prognosis of pheochromocytoma

Answer 9

Age and Stage are the main prognositc factors

Younger than 18 months has the best prognosis, worse as children get older

More differentiated tumors have better prognosis, ganglioneuroblastomas or ganlioneuromas are better than neuroblastomas

NMYC oncogene amplification is present in about 1/3rd and more aplification is the most important factor that indicates high risk. Amplification indicates high risk irrespective of other factors.

Low risk are 90% curable, but High risk ones are only about 30%. Excision and combined therapy/chemo.

____________

Stage 1: Localized tumor completely excised, with or without microscopic residual disease; representative ipsilateral nonadherent lymph nodes negative for tumor (nodes adherent to the primary tumor may be positive for tumor)

Stage 2a: Localized tumor resected incompletely grossly; representative ipsilateral nonadherent lymph nodes negative for tumor microscopically

Stage 2b: Localized tumor with or without complete gross excision, ipsilateral nonadherent lymph nodes positive for tumor; enlarged contralateral lymph nodes, which are negative for tumor microscopically

Stage 3: Unresectable unilateral tumor infiltrating across the midline with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement

Stage 4: Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs (except as defined for stage 4S)

Stage 4S: Localized primary tumor (as defined for stage 1, 2A, or 2B) with dissemination limited to skin, liver, and/or bone marrow (<10% of nucleated cells are constituted by neoplastic cells; >10% involvement of bone marrow is considered as stage 4); stage 4S limited to infants younger
than 1 year of age

Question 10

When does medullary hypofunction occur?

Answer 10

Spinal shock or trauma.