Transcript adrenal-14

THE PATHOLOGY OF
THE ADRENAL GLAND
ANATOMY

The adrenal glands are endocrine
organs consisting of both cortex and
medulla.
ANATOMY
Adrenal cortex:
 the narrow layer of zona glomerulosa
( mineralocorticoids)
 Intervening is the broad zona
fasciculata, which makes up about
75% of the total cortex
( glucocorticoids)
 The narrow layer of zona reticularis
abuts the medulla (sex steroids)
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ANATOMY
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The adrenal medulla is composed of
chromaffin cells, which synthesize and
secrete catecholamines, mainly
epinephrine.
ANATOMY
 The adrenal cortex synthesizes three different
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types of steroids:
(1) glucocorticoids (principally cortisol), which are
synthesized primarily in the zona fasciculata and to
a lesser degree in the zona reticularis;
(2) mineralocorticoids, the most important being
aldosterone, which is generated in the zona
glomerulosa;
(3) sex steroids (estrogens and androgens), which
are produced largely in the zona reticularis
Developmental anomalies
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Adrenal Hypoplasia:
– Anencephalic type: may have adrenal agenesis.
– Cytomegalic type: Large eosinophilic cells, may be X-linked.
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Ectopic Adrenal:
– Accessory adrenal (cortex) can be found from diaphragm to
pelvis in the retroperitoneum (Medulla can also be found if
near celiac ganglion).
– May be seen in hernial sacs (Marchand rests).
– These may give origin to neoplasms or undergo hyperplasia.
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Adrenal myelolipoma:
– a metaplasia-choristoma made of bone marrow. They can be
big but are generally harmless.
ADRENOCORTICAL HYPERFUNCTION
(HYPERADRENALISM)
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There are three basic types of hyperadrenal
syndromes:
(1) Cushing syndrome, characterized by an
excess of cortisol;
(2) hyperaldosteronism;
(3) adrenogenital or virilizing syndromes
caused by an excess of androgens.
Hypercortisolism
(Cushing Syndrome)
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Cushing syndrome can be broadly
divided into exogenous and
endogenous causes.
The vast majority of cases of Cushing
syndrome are the result of the
administration of exogenous
glucocorticoids ("iatrogenic" Cushing
syndrome).
Hypercortisolism
(Cushing Syndrome)
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The endogenous causes can, in turn,
be divided into those that are ACTH
dependent and those that are ACTH
independent
Hypercortisolism
(Cushing Syndrome)
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ACTH-DEPENDENT
Cushing disease (pituitary adenoma; rarely CRH-dependent pituitary
hyperplasia)
Ectopic corticotropin syndrome (ACTH-secreting pulmonary small-cell
carcinoma, bronchial carcinoid)
ACTH-INDEPENDENT
Adrenal adenoma
Adrenal carcinoma
Macronodular hyperplasia (ectopic expression of hormone receptors,
including GIPR, LHR, vasopressin and serotonin receptors)
Primary pigmented nodular adrenal disease (PRKARIA and PDE11
mutations)
McCune-Albright syndrome (GNAS mutations)
Cushing's Syndrome
1.
2.
3.
4.
Middle-aged 3F/1M
4 main causes:
Pituitary adenoma - secretes ACTH
Adrenal tumors - secrete cortisol
Ectopic production of ACTH
Iatrogenic Cushing's Syndrome
1.
Pituitary adenoma
- secretes ACTH
- 60-70% of cases of pathologic
causes
- adrenal glands are hyperplastic
- Biochemistry: Increased ACTH and
cortisol
2. Adrenal tumors
secrete cortisol
20-25% of cases of Cushing's
adrenal adenoma (50%), carcinoma
(50%)
 atrophy of contralateral gland
Biochemistry: low ACTH and high
cortisol
3. Ectopic production of ACTH
by tumors
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lung cancer,
bronchial and thymic carcinoids,
medullary thyroid carcinoma,
islet cell cancer
10-15% of cases
adrenals are hyperplastic
Biochemistry: Increased ACTH and
cortisol
4. Iatrogenic Cushing's Syndrome
commonest cause overall
due to long-term corticosteroid therapy
for treatment of:
- connective tissue diseases
- asthma
- rheumatoid arthritis
- cancer
- transplant rejection
- Biochemistry: High cortisol and ACTH
suppressed
Clinical findings in Cushing's
Syndrome
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Occurs as a
consequence of
excess plasma
glucocorticoid levels
o truncal obesity, buffalo
hump and moon face
due to fat deposition
o hypertension
o hirsutism - due to
increased testosterone
o muscle weakness and
breakdown
o menstrual irregularity
o
o
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osteoporosis - decreased
calcium absorption,
increased bone
resorption and
suppression of bone
formation
impaired glucose
tolerance or diabetes
mellitus - due to insulin
resistance
abdominal striae - due to
inhibition of protein
synthesis and abnormal
collagen maturation
mental symptoms are
common; depression and
psychosis
Adenoma
Primary adrenal
hyperplasia
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a newly discovered disease:
"primary pigmented nodular adrenocortical
hyperplasia",
– which is part of the autosomal dominant Carney
complex
– (Carney complex: cardiac myxomas,
cutaneous myxomas, spotty pigmentation
of the skin, and hyperendocrine states)
– genetic syndrome with too many cortisol receptors,
low plasma cortisol
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macronodular hyperplasia with marked
adrenal enlargement
Primary
Hyperaldosteronism
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Hyperaldosteronism is the generic
term for a group of closely related
conditions characterized by chronic
excess aldosterone secretion.
Primary
Hyperaldosteronism
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Hyperaldosteronism may be primary, or it may be
secondary to an extra-adrenal cause.
Primary hyperaldosteronism stems from an
autonomous overproduction of aldosterone, with
resultant suppression of the renin-angiotensin
system and decreased plasma renin activity.
Blood pressure elevation is the most common
manifestation of primary hyperaldosteronism, which
is caused by one of three mechanisms:
Primary
Hyperaldosteronism
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Bilateral idiopathic hyperaldosteronism
(IHA),
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Adrenocortical neoplasm,
Glucocorticoid-remediable
hyperaldosteronism
Bilateral idiopathic
hyperaldosteronism (IHA)
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Bilateral idiopathic hyperaldosteronism (IHA),
characterized by bilateral nodular hyperplasia of the
adrenal glands, is the most common underlying
cause of primary hyperaldosteronism, accounting
for about 60% of cases.
Individuals with IHA tend to be older and to have
less severe hypertension than those presenting with
adrenal neoplasms.
Adrenocortical neoplasm
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Either an aldosterone-producing adenoma (the
most common cause) or, rarely, an adrenocortical
carcinoma.
In approximately 35% of cases, primary
hyperaldosteronism is caused by a solitary
aldosterone-secreting adenoma, a condition
referred to as Conn syndrome.
This syndrome occurs most frequently in adult
middle life and is more common in women than in
men (2 : 1).
Multiple adenomas may be present in an
occasional patient.
Glucocorticoid-remediable
hyperaldosteronism
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Glucocorticoid-remediable hyperaldosteronism is an
uncommon cause of primary familial
hyperaldosteronism.
In some families, it is caused by a chimeric gene
resulting from fusion between CYP11B1 (the 11βhydroxylase gene) and CYP11B2 (the aldosterone
synthase gene).
This leads to a sustained production of hybrid
steroids in addition to both cortisol and aldosterone.
The activation of aldosterone secretion is under the
influence of ACTH and hence is suppressible by
exogenous administration of dexamethasone.
Primary
hyperaldosteronism
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low-renin hyperaldosteronism
too much mineralocorticoid
not due to excess ACTH
0.5% of hypertensives have primary
hyperaldosteronism
Patients exhibit hypokalemia, alkalosis, and
low renin,
Low potassium is likely to cause muscle
weakness, and even paralysis.
– these patients can die from hypokalemia if you
give them thiazide diuretics to treat their high
blood pressure.
Secondary aldosteronism
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In secondary hyperaldosteronism, in contrast, aldosterone
release occurs in response to activation of the reninangiotensin system.
It is characterized by increased levels of plasma renin and is
encountered in conditions such as the following:
Decreased renal perfusion (arteriolar nephrosclerosis, renal
artery stenosis)
Arterial hypovolemia and edema (congestive heart failure,
cirrhosis, nephrotic syndrome)
Pregnancy (due to estrogen-induced increases in plasma renin
substrate)
Hypofunction of
adrenal cortex
Primary causes
 Loss of Cortex:
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autoimmune
bacterial
hemorrhage
amyloidosis
sarcoidosis
hemochromatosis
metastatic disease
surgical ablation.
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Metabolic Failure:
– Primary failure of
adrenal glands,
– Drug induced
inhibition of
adrenocortical
function.
Secondary causes
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hypothalamic / pituitary disease
neoplasm
infection
hypothalamic / pituitary
suppression:
– long term steroid administration.
Adrenocortical Insufficiency
(Hypoadrenocorticism)
Primary Acute Adrenal
Insufficiency:
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Precipitated by stress
in a patient with
Addison's.
Precipitated by
withdrawal of steroids
in an adrenalectomized
patient.
In patients with acute
bilateral hemorrhagic
necrosis of adrenals.
Chronic insufficiency:
 Addison's disease
Acute Insufficiency
Acute Hemorrhagic Necrosis of Adrenals
 Waterhouse-Friedricksen Syndrome
– Due particularly to meningococcal septicemia,
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less commonly Staph, pneumococcus, or Haemophilus
– Newborns due to perinatal trauma.
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DIC
adrenal glands are hemorrhagic with cortical
necrosis
purpuric rash
vascular collapse  shock: due to endotoxin and
vomiting, decreased steroids and Na+ , increased
K+ in blood and dehydration.
Waterhouse-Friedricksen Syndrome
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Primary chronic adrenal insufficiency
Addison's disease
– 60-75% due to auto-immune destruction of adrenal
cortex with lymphocytic and plasma cell infiltrate
– normal medulla
– Tuberculosis (2nd commonest cause)
– more than 90% of cortex needs to be destroyed
– Clinically
Lethargy, muscle weakness, anorexia, nausea &
vomiting, wt loss, hypotension, hyperpigmentation
of skin and mucous membranes.
Addison’s disease: Hyperpigmentation of
mucous membranes
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Primary:
– due to adrenal insufficiency
– should be suspected when there is marked
skin pigmentation due to high ACTH levels.
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Secondary:
– pituitary or hypothalamic insufficiency (no
skin pigmentation).
– Addison's disease is rare.
Causes of Addison's Disease
1. Autoimmune
 most cases of Additions show anti-adrenal
Antibodies (60-75%) Two types exist.
Type I
- Addison's + hypoparathyroidism +
mucocutaneous candidiasis.
- Defect in suppressor cells.
Type II (Schmidt's syndrome)
- Addison's + autoimmune thyroid disease +
insulin dependent diabetes.
- No Candidiasis or PTH deficiency
- Associated with HLA-A1 and HLA-B8 haplotype.
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2. Tuberculosis (~25% of cases).
3. Other causes:
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histoplasmosis
amyloid
sarcoidosis
metastases
- congenital hypoplasia
- hemochromatosis
- CMV infection (in AIDS)
- adrenal leukodystrophy
Addison's Disease
Pathology
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There may be a lymphocytic infiltrate or
a "burned out" fibrotic appearance.
Medulla is untouched.
In TB and other diseases, evidence for
these is usually apparent.
Adrenal Medulla
Pathology
Adrenal Medulla
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Synthesizes and secretes "adrenalin"
(epinephrine, norepinephrine)
The only diseases are two tumors which
may arise here or at the other chromaffin
tissue masses
– pheochromocytoma (well-differentiated, adults)
– neuroblastoma (poorly-differentiated, children).
Pheochromocytoma (paraganglioma)
– secrete norepinephrine (most common)
and/or epinephrine
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Rarely: dopamine, serotonin, ACTH,
somatostatin, neuropeptides.
– The paroxysms of extreme hypertension,
accompanied by sweating, headache, and
other autonomic disturbances, probably
result from physical compression and/or
ischemia of the "pheo".
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Can present as Paroxysmal attacks
which may precipitate
– congestive cardiac failure,
– coronary thrombosis,
– cerebral hemorrhage
– may be brought on by stress, pressure,
exercise  acute release of catecholamine
– Biochemistry: increased urinary VMA
(vanillylmandelic acid) excretion
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Most (90%) occur in the adrenal
medulla
Other sites (10%)
– the organs of Zuckerkandl: chromaffin
tissue at the origin of the
inferior mesenteric artery and/or aortic
bifurcation
 paravertebral sympathetic chain
 urinary bladder.
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Ten percent of pheo cases involve both
adrenals, and many of these are also
among the 10% that are familial.
Syndromes include:
MEN IIa or IIb
 von Recklinghausen's neurofibromatosis (NF-I)
 von Hippel-Lindau
 succinic dehydrogenase mutation
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Pheos are still often missed clinically
surprises at autopsy
the patients typically had been told they
had "benign essential hypertension" and
"emotional problems“
high levels of circulating catecholamines
– can damage the myocardium can cause
coronary spasm,
– disorders in renal, bowel, brain arteries
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Grossly,
– very bloody (vascular),
– often show fibrosis, calcification, cystic
change, or even fatty change
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Microscopically,
– pheos resemble adrenal medulla
– special stains are available that show
norepinephrine and/or epinephrine in
granules
Pheochromocytoma
Neuroblastoma
 The second commonest solid pediatric
cancer (after Wilms tumor).
 It is derived from primitive nerve
elements, discovered by Virchow.
 A majority of neuroblastomas arise in or
near the adrenals.
 Grossly, neuroblastomas are soft, white
tumors.
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Most neuroblastomas produce
catecholamines, resulting in elevated
urinary metabolites.
Portions often undergo dystrophic
calcification (radiological diagnosis)
The tumor eventually metastasizes
widely.
"Blueberry muffin baby" is a classic
description for a neuroblastoma patient
with multiple skin metastases.
Neuroblastoma: radiology
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Histologically, neuroblastoma is a tumor
of "small blue cells", with scanty
cytoplasm.
Often (but not always) the cells are
arranged in "rosettes" (recalling neural
tubes) around a tangle of neurites
("Homer Wright rosettes", pretty-much
diagnostic).
EM shows neurosecretory granules
and sometimes neurites too.
Microscopy
Ganglioneuroblastoma
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benign ganglioneuroma
in 2% of autopsies on infants dying of
unrelated causes, there is a neuroblastomalike "incidentaloma".
Obviously most of these cure themselves.
The process begins with the appearance of
S100-positive Schwann cells, which are from
outside the tumor. If the tumor is to self-cure,
it must be near-triploid and have intact
chromosome 1.
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