ADRENAL MEDULLA

by: Dr Ismail,Macharia,Karimi,Thitai,Nigel,
Muriithi,Maweu,Patel,Oliver

FACILITATOR: Prof. Kigondu

 Morphology

• Central portion of the adrenal gland.

• 28% of the mass of the adrenal gland
• Accessory medullary tissues
• Extensive blood supply
 Morphology
• Chromaffin cells (pheochromocytes)
• Derived from neural crest cells.
• These cells are structural & functional equivalents
of the post ganglionic neurons in the sympathetic
nervous system.
• They secrete when stimulated by the
preganglionic fibres that reach the gland via the
splanchnic nerve.
• The adrenal medulla therefore regarded as a
specialized sympathetic ganglion.
• 2 cell types
• epinephrine-secreting type(90%): Larger, less
dense granules
• Norepinephrine-secreting type(10%) : smaller,
very dense granules
 Biosynthesis of Catecholamines (CA)

• Chromaffin cells synthesize epinephrine,

norepinephrine and dopamine.
• Dopamine is formed by hydroxylation and
decarboxylation of tyrosine.
• NE is formed by hydroxylation of dopamine
• Epinephrine formed by methylation of NE via
phenyl ethanolamine N methyl transfer, PNMT
 Metabolism & Degradation of CA
• Medullary CA biological actions are very brief due
to a short plasma half life, about 2 min.
• Circulating CA are degraded by:
a. Catechol-O-methyl transferase, (COMT)
o Converts epinephrine to metanephrine
o Converts nor epinephrine to normetanephrine
b. Monoamine oxidase (MAO)
o Converts the above metabolites to Vanniyl-
mandellic acid (VMA) and homovanillic acid
(HVA)
 Metabolism & Degradation of CA
c). The liver and the gut conjugates metanephrines
and normetanephrines to sulfates and glucuronide
compounds which are excreted in urine.
• 50% of secreted CA appear in urine as conjugated
normetanephrines and metanephrines.
• 35% as VMA
• 30ug of NE, 6ug of Epinephrine, 700ug of VMA
excreted per day
 Regulation of Medullary secretion
• Sympathetic nervous system via preganglionic
fibers of the splanchnic nerves
• Under basal or rest conditions the SNS
regulates the amount of serum catecholamine
through low frequency stimulation of the
adrenal medulla via cholinergic release from
the splanchnic nerve
• PNMT induced by glucocorticoids
 Catecholamine activity
• Stimulates the “fight or fight” reaction
• Increased plasma glucose levels
• Increased cardiovascular function
• Increased metabolic function
• Decreased gastrointestinal and genitourinary
function
 Pathology of the adrenal medulla
The adrenal medulla, which constitutes 28%
of the mass of the adrenal gland
90% of the cells secrete epinephrine
10% are the norepinephrine- secreting type.
Neoplasms are the most important pathology
of the adrenal medulla
They include neuroblastoma, gangliomas and
pheochromocytoma
 Pheochromocytoma
Tumour of the chromaffin cells
Occur at any age
Exact prevalence is unknown
0.3% of hypertensive patient
 Pheochromocytoma
Rule of 10
• 10% are extra-adrenal
• 10% are multiple or bilateral
• 10% are malignant
• 10% recur after surgical removal
• 10% occur in children
• 10% are familial
• 10% present as adrenal incidentaloma
• 10% of patients are asymptomatic
 Pheochromocytoma
The tumor may be associated with such
neurocutaneous syndromes as
Neurofibromatosis
von Hippel-Lindau disease
tuberous sclerosis
Sturge-Weber syndrome
Component of MEN
 Pheochromocytoma
Size ranges from small circumcribed lesions
to large hemorrhagic masses
Small masses appear yellow compressing the
outer cortex
Microscopically nest of cells Zellballen
Pleimorphic cells show numerous granules
catecholamines
capsular and vascular invasion may be
encountered in benign lesions
Pheochromocytoma
pheochromoytoma
• Pheochromocytomas secrete NE or E, or both,
and produce sustained hypertension.
• However, 15% of epinephrine- secreting
tumors secrete this catecholamine episodically
• This intermittent bouts of palpitations,
headache, glycosuria, and extreme systolic
hypertension.
 Neuroblastoma
Tumor of the cells neurocrest origin
is the most common extracranial solid tumor in
childhood
accounts for 7 to 10% of all childhood cancers
prevalence is approx 1: 7000 live births
Most occur sporadically, 1-2% are familiar AD
Tumors can occur in the abdominal cavity (40%
adrenal, 25% paraspinal ganglia) or involve other
sites (15% thoracic, 5% pelvic, 3% cervical
tumors, 12% miscellaneous
 Prevalence
• Age distribution at diagnosis is as follows:
o 40% of patients are younger than 1 year,
o 35% are aged 1-2 years
o 25% are older than 2 years .
• incidence decreases every consecutive year
up to age 10 years, after which the disease is
rare.
NeuroblastomaPathologic features
Variable sizes
Some sharply demarcated others are infiltrating
On transection, soft grey-tan brain like tissue
Larger tumors have area of necrosis, cystic
softening or hemorrhage
Histology small, primitive-appearing cells with
dark nuclei, scant cytoplasm,
 poorly defined cell borders growing in solid
sheets(. Mitotic activity, karyorrhexis and
pleomorphism may be prominent
Neuroblastoma: histology
 Neuroblastoma
Homer-Wright pseudo-rosettes
tumor cells are concentrically arranged about
a central space filled with neuropil
 The tumours can ‘mature’ into a ganglioma
or ganglioneuroblastoma
This can be spontaneous or in response to
therapy
 SIGNS AND SYMPTOMS OF ADRENAL
MEDULLARY PATHOLOGY
May manifest as spells with the following
characteristics
-Headache
-Palpitations
-Diaphoresis
-Severe hypertension
Pattern of spells is:
-Frequency may vary from monthly to several
times in a day
 -Duration may vary from seconds to hours
-Spells increase in frequency and severity as
the tumor grows
The following may occur during spells:
-Tremor
-Nausea
-Weakness
-Anxiety , sense of doom
 Triggers of the spells include:
-Physical exertion
-Anxiety and stress
-Labour and delivery
-Surgery and anaesthesia
-Foods rich in Tyramine e.g chocolate
*Affects blood pressure
-Certain drugs-Stimulants e.g Cocaine,
Amphetamines
 Clinical signs associated with pheochromocytoma include:
-Hypertension
-Hypertensive retinopathy
-Weight loss
-Tachyarrhythmias
-Cardiomyopathy
-Ileus
-Fever
-Postural hypotension
-Pallor
-Hyperglycemia
Sometimes pheochromyctoma is part of
Multiple endocrine neoplasia syndrome(MEN)
MEN , type 2 is a disorder resulting in tumors
in more than one endocrine systems e.g
Thyroid, parathyroid, GIT.
May also occur in Von Hippel lindau syndrome
or Neurofibromatosis
 BIOCHEMICAL ASSESSMENT OF
ADRENAL MEDULLA FUNCTION
• Plasma and urinary catecholamines
• Plasma metanephrines
• Urinary Total Metanephrines (metanephrine
and normetanephrine)
• Urinary Vanillylmandelic Acid (VMA)
• Urinary Homovanillic Acid (HVA)
• Plasma catecholamines
• Useful in the diagnosis of catecholamine-secreting
neurochromaffin tumors: pheochromocytomas, neuroblastomas
• Data indicate plasma catecholamine levels to be best indicator of
increased catecholamine production.

• Urine catecholamine
• Free amine measurement relates more closely to the tumor load
when compared to total amine measurement and are least
affected by diet

NB: plasma levels and urinary outputs of catecholamines are normal

in some patients with pheochromocytoma and the presence of a
pheochromocytoma cannot be reliably excluded using
measurements of plasma or urinary catecholamine concentrations
 Urinary Total Metanephrines
(metanephrine and
normetanephrine)
• Metanephrines and nor metanephrines are
intermediary metabolites which are excreted in
urine as free amines and conjugates, and are
not significantly influenced by diet.
• Useful in the evaluation of suspected
pheochromocytoma; good screening method
• Analysis of urinary metanephrines is 87.5%
sensitive and 99.7% specific
• confirms increased VMA.
• Test selection criteria include the
following:
• Use plasma metanephrine testing in
patients at high risk (ie, those with
predisposing genetic syndromes or a
family or personal history of
pheochromocytoma)

• Use 24-hour urinary collection for

catecholamines and metanephrines in
patients at lower risk
 Urinary Vanillylmandelic Acid (VMA)
• VMA is the final urinary metabolite of
norepinephrine and epinephrine and
represents ~60% of the excretion products
derived from norepinephrine and epinephrine
• Useful in the evaluation of suspected
pheochromocytoma and neuroblastoma; good
screening method.
• Determination of VMA is simplest but suffers
from false positives.
 ?? DYNAMIC TESTS
• STIMULATION TEST
glucagon stimulation test

SUPPRESSION TEST
use 0.3 mg clonidine and two 24h urine containers
with acid preservative

• Physiological catecholamine secretion is

suppressed by clonidine whereas autonomous
secretion by a tumour is not suppressed.
 Urinary Homovanillic Acid (HVA)
• HVA is the final urinary metabolite of
dopamine.
• Useful in the evaluation of suspected
neuroblastoma.
ROLES OF A SURGEON IN THE
MANAGEMENT OF ADRENAL
MEDULLA PATHOLOGY
Presented by: Dr. Ruchir Patel
Facilitator: Prof. C Kigondu
 PHAECHROMOCYTOMA

Pre-operative work up:

• CBC, U/E/Cs, INR
• CXR
• ECG
• ECHO (to rule out Catecholamine-induced-
cardiomyopathy)
 PHAECHROMOCYTOM
Pre-operative Preparation Regimens:
• Combined  +  blockade
• Phenoxybenzamine
• Selective 1-blocker (ex. Prazosin)
• Propanolol
• At least 10-14 day pre-surgery
• Metyrosine: Synthetic inhibitor of Tyrosine
Hydroxylase (TH)
• Calcium Channel Blocker (CCB)
• Nicardipine
 PHAECHROMOCYTOMA
The principles of adrenalectomy for pheochromocytoma
are:
1. Complete tumor resection.
2. Minimal tumor manipulation in avoidance of tumor
seeding and hypertensive crisis.
3. Control of vascular supply.
4. Adequate exposure to avoid other organ injury.
5. In MEN associated adrenal medullary disease, surgical
options include bilateral adrenalectomy or cortical-
sparing subtotal adrenalectomy for adrenal medullary
hyperplesia.
 PHAECHROMOCYTOMA
Operative approaches for adrenalectomy include:
1. Open anterior transabdominal approach.
2. Open thoracoabdominal approach.
3. Open posterior or lateral retroperitoneal
approach.
4. Lateral transabdominal laparoscopic approach.
5. Posterior retroperitoneal laparoscopic approach.
 PHAECHROMOCYTOMA
Post-operative work up:
• In most cases can stop all anti-hypertensive
meds post-operative
• Post-operative hypotension: IV crystalloid
• 24h urine collection 2 weeks post surgery
• Surveillance:
• 24h urine collections (quarterly for at least 10years)
• Lifelong follow up
 NEUROBLASTOMA
The types of treatment used for neuroblastoma
includes:
• Surgery
• Chemotherapy
• Radiation therapy
• High-dose chemotherapy/radiation therapy and
stem cell transplant
• Retinoid therapy
• Immunotherapy
 NEUROBLASTOMA
Pre-operative work up:
• All radiographic studies (CXR, bone scanning,
CT/MRI)
• Serum chemistries and a CBC are essential
• Additional blood studies include: VMA-to-HVA
ratio, serum ferritin, and NSE (Neuron Specific
Enolase)
THANK YOU
 REFERENCES
• Tietz textbook of clinical chemistry.
• CLS 415 Clinical Chemistry II Endocrinology/
Toxicology Lecture Series Adrenal Lecture Info
Handout.
• Quest diagnostic endocrinology manual.
• Webmd.