DISORDERS OF ADRENAL GLAND

NUR AINA BINTI AB KADIR

ADRENAL PATHOLOGY
MODERATOR Dr. Manisha Tambekar - Evith Pereira
 ANATOMY
Normal size (Lt or Rt adrenal) : 3 cm 6 mm
Situated near upper
poles of kidneys in
retroperitoneum,
within Gerotas capsule
2 adrenal gland, right
and left
2 component ; inner
adrenal medulla and
outer adrenal cortex
Weight = 4g 6g
 EMBRYOLOGY
Cortex and medulla arises from different
blastomeric layers
Adrenal cortex arise from mesodermal cells
Adrenal medulla arise from neuroectodermal cells,
which migrate to cortex from neural crest
 HISTOLOGY
Adrenal cortex : Arranged
in zonal configuration

Outer zona glomerulosa =

small, compact cells
Central zona fasciculata =
larger, lipid-rich cells
arranged in radial columns
Inner zona reticularis = compact
& pigmented cells

Adrenal medulla
Thin layers of large
chromaffin cells
1. Glomerulosa: well-outlined
cells aggregated into small
clusters and short trabeculae
2. Fasciculata: broad band made
up of large cells with distinct
membranes arranged in two
cell-wide cords. Cytoplasm is
vacuolated/clear
3. Reticularis: haphazard
arrangement of cells with
granular cytoplasm.
Lipofuscin may be present
 Chromaffin cells: arranged in small nests
and cords separated by prominent
vasculature; large polygonal cells with
poorly outlined borders, abundant
granular and usually basophilic cytoplasm;
takes up chromium salts

Sustentacular cells: supporting cells, spindle

cells at periphery of nests of chromaffin cells;
associated with rich vasculature; S100+,
difficult to identify with routine staining.
Adrenal cortex:
zona glomerulosa : mineralocorticoids
zona fasciculata : glucocorticoids
zona reticularis : sex steroids
 SALT

Mineralocorticoids (F & E balance)

Aldosterone (renin from kidneys controls adrenal
cortex production of aldosterone)
Na retention
Water retention
K excretion
 SUGAR
GLUCOCORTICOIDS (regulate metabolism
& are critical in stress response)
CORTISOL responsible for control and &
metabolism of:

a. CHO (carbohydrates)

amt. glucose formed

amt. glucose released
 CORTISOL
b. FATS-control of fat metabolism
stimulates fatty acid mobilization from
adipose tissue

c. PROTEINS-control of protein metabolism

stimulates protein synthesis in liver
protein breakdown in tissues
 SUGAR
Other functions of Cortisol
inflammatory and allergic
response

immune system therefore prone to

infection
 SEX
ANDROGENS
hormones which male characteristics
release of testosterone
 ADRENAL MEDULLA
Fight or flight
What is released by the adrenal medulla?
CATECHOLAMINE RELEASE
Epinephrine
Norepinephrine
 Catecholamines
Tyrosine
(organism takes it from the meal or from the phenilalanine in the liver)

dioxyphenilalanine (DOPHA) dopamine

(it goes into blood only from some neurons of the central nervous system )

norepinephrine (noradrenaline)
(it goes into blood only from sympathetic teleneurons)

epinephrine (adrenaline)
(it goes into blood only from adrenal medulla).

Principle urinary metabolic products of epinephrine

and norepinephrine are the metanephrines and
vanillylmandalic acid (VMA).
ADRENAL CORTEX
 ADRENOCORTICAL HYPERFUNCTION
1. Cushings Syndrome ( Hypercortisolism)
2. Hyperaldosteronism
3. Adrenogenital or Virilizing Syndromes
 1.Cushings Syndrome

A constellation of clinical abnormalities due to

chronic exposure to excess of cortisol or
related corticosteroid

described by Harvey Cushing in 1932

 Etiology and Pathophysiology
CAUSES OF CUSHING S SYNDROME
ACTH-dependent causes
ACTH-secreting pituitary tumor ( Cushing s disease )
Pituitary CRH-secreting neoplasm ( ectopic CRP syndrome )
Nonpituitary ACTH-secreting neoplasm ( ectopic ACTH syndrome )
ACTH-independent causes
Adrenal adenoma
Adrenal carcinoma
Micronodular adrenal disease
McCune-Albright syndrome
Massive macronodular adrenal disease
Pseudo-cushing Syndrome
Factitious or surreptitious glucocorticoid administration (IATROGENIC)
 Main lesions are found in pituitary and
adrenal glands.
Depending on the cause of hypercortisolism
the adrenals show following abnormalities:
a) Cortical Atrophy (exogenous glucocorticoids)
b) Diffuse Hyperplasia (ACTH dependent
Cushings)
c) Macronodular or micronodular hyperplasia
d) Adenoma or carcinoma (functional
adenomas / carcinomas as source of cortisol)
 Clinical Feature

protein metabolism negative nitrogen

Lipid mobilization Hepatic glucose balance
production
Lipid catabolism disruption of water and electrolytes
metabolism
Lipid redistribution

Insulin resistance

Proximal muscle
Moon-face weakness Dependent edema
buffalo hump Hypertension
truncal obesity Glucose intolerance
Hypokalemic metabolic
Violaceous striae alkalosis
 Obesity
Facial plethora
Rounded face (moon facies)
Decreased libido
Thin skin
Decrease in linear growth in
children
Menstrual irregularity
Hypertension
Hirsutism
Depression/ emotional liability
Easy bruising
Glucose intolerance
Weakness
Osteopenia
Nephrolithiasis.
 DIAGNOSIS
Morning and midnight plasma cortisol levels
are elevated
Dexamethasone fails to suppress 24-hour
urinary cortisol excretion.
Serum ACTH level
 TREATMENT
Medical therapy with metyrapone or ketoconazole used in
patients with severe hypercortisolism or if surgery is not
possible.
 2.Hyperaldosteronism
Primary hyperaldosteronism autonomous
overproduction of aldosterone caused by
1. Bilateral Idiopathic Hyperaldosteronism
2. Adrenocortical Neoplasm
3. Glucocorticoid-remediable
hyperaldosteronism
 Secondary hyperaldosteronism aldosterone
release occurs in response to activation of
renin-angiotensin system.

1. Decreased renal perfusion (arteriolar

nephrosclerosis, renal artery stenosis)
2. Arterial hypovolemia and edema ( CHF,
cirrhosis, nephrotic syndrome)
3. Pregnancy ( estrogen induced increase in
plasma renin substrate)
 Aldosterone-producing
adenomas
Composed of lipid laden
cells resembling fasciculata
cells
Modest nuclear and cellular
pleomorphism
Eosinophilic, laminated
cytoplasmic inclusions
known as Spironolactone
bodies - spironolactone
drug antihypertensive.
 CONGENITAL ADRENAL HYPERPLASIA
(ADRENOGENITAL SYNDROME)
Virilisation in children
Autosomal recessive disorder and inherited
metabolic errors caused by enzymatic defect in
the synthetic pathway of cortisol & other steroid
from cholesterol
95% : 21-hydroxylase deficiency
Common signs : hypertension & short stature
Treatment :
replacement cortisol + fludrocortisone
Large hypoplastic adrenals = remove (if symptomatic)
 Adrenocortical Insufficiency
(Hypoadrenocorticism)

Primary Acute Adrenal

Insufficiency: Chronic insufficiency:
Precipitated by stress in a Addison's disease
patient with Addison's.
Precipitated by withdrawal of
steroids in an
adrenalectomized patient.
In patients with acute
bilateral hemorrhagic
necrosis of adrenals.
 Acute Insufficiency
Acute Hemorrhagic Necrosis of Adrenals

Waterhouse-Friedrichsen Syndrome
Due particularly to meningococcal septicemia,
less commonly Staph, pneumococcus, or Haemophilus
Newborns due to perinatal trauma.

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-Friedrichsen Syndrome
 Primary chronic adrenocortical 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.
Addisons disease: Hyperpigmentation of mucous
membranes
 Causes of Addison's Disease
1. Autoimmune
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.

2. Tuberculosis (~25% of cases).

3. Other causes:
histoplasmosis - congenital hypoplasia
amyloid - hemochromatosis
sarcoidosis - CMV infection (in AIDS)
- adrenal leukodystrophy
metastases
 Lymphocytic infiltrate or a "burned out" fibrotic appearance.
Medulla is untouched.
In TB and other diseases, evidence for these is usually apparent.
 Adrenal cortex Neoplasms

Adrenal Adenoma Adrenocortical Ca

 Adrenal cortical adenoma
Solitary, well circumscribed, nodule,
capsulated/ uncapsulated
Upto 2.5 cm, 50 g
Non-functional or functional
Cushing syndrome and
hyperaldosteronism
Cortex adjacent
Non-functional adenomas :normal
Functional adenoma : atrophic
Cut surface yellowish to yellowish
brown
No areas of hemorrhage and necrosis
 Adrenal cortical adenoma
Microscopically, Predominantly

lipid-laden cells resembling ZF,

alveolar pattern
interspersed with short cords
Focal groups of compact cells.
Mitotic activity is rare
Patients with Conn's syndrome,
cells resembling ZG and others
showing mixed features of ZG
and ZFhybrid cells
Compact cells:
tumors associated with
virilization
 Variants of cortical adenomas
1. Black adenoma: dark brown to
black color because of the
presence of pigment, thought to
represent either lipofuscin or
neuromelanin. Alterations of
lipid metabolism induced by the
abnormal mitochondria present
in the cells of these lesions.
Mostly non functional

2. Adenoma with foci of

myelolipoma: myo-lipomatous
component with areas of small
hemorrhagic foci
 Variants of cortical adenomas
3. Adrenocortical Oncocytoma:
tumor cells studded with
mitochondria, mostly benign,
peculiar cytoplasmic crystalline
inclusions may be seen
4. Myxoid adrenocortical
neoplasms: prominent myxoid
features
5. Lipoadenoma : abundant
mature adipose tissue
6. Sarcomatoid carcinoma
7. Adenosquamous carcinoma
 Adrenal cortical carcinoma
Rare, 0.5 and 2 per million
Aggressive tumor, median survival of 15
months
Over half show local invasion or metastases
at the time of presentation
Functioning tumors account for 24% and
74% of cases
Cushings syndrome, virilization
Large tumors, 3 40 cm, 50 gm
Uncapsulated, invasion into the capsule if
present
Cut surface, lobulations with fibrous bands
and areas of necrosis and hemorrhage
Invasion of major veins is a frequent
finding, often leads to total occlusion,
thrombosis, and embolism
 Adrenal cortical carcinoma
Microscopically,
Less ordered structure than
in adenomas
Trabecular and diffuse
patterns
Nuclear pleomorphism
Mitoses, including atypical
forms, often present
Capsular and vascular
invasion
 Histologic diagnosis of malignancy
Weiss criteria:
09 Histological features are assessed and the presence
of 03 or more indicates malignant potential

Modified Weiss index:

Omits histological features that had poor inter-
observer correlation and incorporates the others into a weighted
score

Ki-67 index: greater than 5% is seen only in carcinoma

 A Weiss score of 6 was associated with poorer disease-free interval and overall
survival
 Molecular aspects of adrenal cortical tumors
Adrenal cortical tumors associated with various familial diseases

BeckwithWiedemann syndrome: linked to the 11p15 locus with paternal

disomy and overexpression of IGF-2
*Exomphalos - Macroglossia Gigantism

LiFraumeni syndrome: germline mutations in the TP53 tumor suppressor

gene on 17q13.1
*Sarcoma, Cancers of the breast, brain and adrenal glands

Multiple endocrine neoplasia type 1 syndrome (MEN1): mutations in the

MEN1 gene on 11q13
*Neoplastic lesions in pituitary, parathyroid gland and pancreas
 Molecular aspects of adrenal cortical
tumors
Familial adenomatous polyposis: APC gene
defects on chromosome 5
The most common abnormality in carcinoma is
overexpression of IGF-2, reported in about 90% of
cases, located at 11p15
Loss of the maternal allele and duplication of the
paternal allele
Wnt/-catenin pathway: hyperplasias, adenoma,
and carcinomas
 Immunohistochemistry
Majority of cortical tumors will be positive for inhibin-
and Melan A

Chromogranin: negative in cortical tumors and almost

always positive in Pheochromocytoma

Synaptophysin : positive in both cortical tumors and

pheochromocytoma

Cytokeratins: strongly expressed by cortical tumors

TUMORS OF ADRENAL MEDULLA
 Pheochromocytoma
Neoplasms composed of chromaffin cells,
Synthesize and release catecholamines
Cause of surgically correctable hypertension
Rule of 10s
Ten percent of pheochromocytomas are extra-adrenal
Ten percent of sporadic adrenal pheochromocytomas are bilateral
Ten percent of adrenal pheochromocytomas are biologically malignant
Ten percent of adrenal pheochromocytomas are not associated with
hypertension

Associated with increased activity of HIF 1-

and enhanced growth factor receptor pathway
signaling (e.g. RET, NF1)
Familial syndromes associated with pheochromocytomas
 Pheochromocytoma
Clinical features:
1. Increased catecholamine release
2. Hypertension, young, often refractory to treatment
3. Paroxysmal, with relatively normal blood pressure between surges
4. Classical triad of symptoms includes headache, diaphoresis and palpitations
or tachycardia
5. Less commonly anxiety, tremulousness, pain in the chest or abdomen,
weakness or weight loss
6. Severe constipation or pseudo-obstruction may occur because
catecholamines may inhibit peristalsis
7. May occasionally secrete other hormones, such as calcitonin, ACTH,
parathyroid hormone or somatostatin
 Pheochromocytoma
Morphology:
1. Range from small, circumscribed lesions
to large hemorrhagic masses weighing
kilograms
2. Larger tumors are well demarcated by
either connective tissue or compressed
cortical or medullary tissue
3. Average weight of 100gm
4. Richly vascularized fibrous trabeculae within
the tumor produce a lobular pattern
5. Cut surfaces of smaller
pheochromocytomas are yellow-tan.
Larger lesions tend to be hemorrhagic,
necrotic, and cystic and typically
efface the adrenal gland
6. Incubation of fresh tissue with a potassium
dichromate solution gives the tumor a
dark brown color due to oxidation of stored
catecholamines, thus the term chromaffin
 Pheochromocytoma
Microscopy:
Tumors are composed of clusters of
polygonal chromaffin cells or chief cells
that are surrounded by supporting
sustentacular cells, creating small nests
or alveoli (zellballen) that are supplied by
a rich vascular network
Uncommonly, the dominant cell type is a
spindle or small cell.
Cytoplasm has a finely granular
appearance, best demonstrated with
silver stains, due to the presence of
granules containing catecholamines.
Nuclei are usually round to ovoid,
with a stippled salt and pepper
chromatin that is characteristic of
neuroendocrine tumors.
 Pheochromocytoma
IHC: Chromogranin and synaptophysin for the chief cells
where as S-100 for sustentacular cells
 Neuroblastoma
Seen in young children

80% are detected in those under

the age of 4 years, and the median
age at diagnosis is 21 months
Can exhibit familial incidence;
Beckwith Wiedemann syndrome,
Hirschsprung disease,
neurofibromatosis
Morphology:
Usually large, soft, gray and relatively
well circumscribed; areas of
hemorrhage, necrosis, and
calcification are often present
 Neuroblastoma
Microscopically:
vaguely nodular
Incomplete fibrous septa
Calcification may be a prominent
feature
Necrosis is a constant feature
Tumor cells: small and regular, with
round, deeply staining nuclei slightly
larger than lymphocytes
Little cytoplasm, and cytoplasmic
outlines are poorly defined
Homer Wright rosettes: present in
1/3rd cases; characterized by
collections of tumor cells around a
central area filled with a fibrillary
material
Bizarre giant tumor cells
 Ganglioneuroma
Benign tumors, older age group
Most common neoplasm of the
sympathetic nervous system in adults
Rarely found in the adrenal gland
Grossly:
Large, encapsulated masses of firm
consistency with a homogeneous,
solid, c/s grayish white with focal
edematous appearance
Microscopically:
Overall appearance resembles that of
a neurofibroma, presence of
numerous collections of abnormal but
fully mature ganglion cells, often
having more than one nucleus
 Ganglioneuroblastoma
Formerly known as malignant neuroblastoma
are tumors exhibiting a degree of
differentiation that is intermediate between
neuroblastoma and ganglioneuroma.
Mostly seen in children
 Nodular Ganglioneuroblastoma
composite tumor in the "stroma-rich" category.
Predominance of differentiated Schwannian-type stroma
associated with 1 macroscopically visible nodule of
neuroblasts showing neuropil formation but lacking
Schwannian stroma
Grossly identifiable mature and immature components
may either both be in primary tumor, or one may be in
primary and one in metastasis
Occurs anywhere in anatomic distribution of
sympathoadrenal neuroendocrine system
~80% arise in abdomen or adrenal gland, ~20% arise in
thoracic cavity
 Asymptomatic abdominal/back mass
Watery diarrhea due to production of vasoactive
intestinal polypeptide
Diagnosis
Must have at least 1 grossly identifiable
nodule
Microscopically, admixture of neuroblasts and
ganglion cells
 Nodular Ganglioneuroblastoma
Gross : large, well
encapsulated masses of
firm consistency with a
homogeneous solid,
grayish white cut
surface having focal
edematous appearance
with area of
hemorrhage.
 Histology correlates with gross findings,
mature areas (stroma-rich),
immature areas (comprised of
neuroblasts, stroma-poor)
Architecture: lobular, diffuse/solid,
organoid

Neuroblasts
Homer Wright pseudorosettes:
circular, ovoid, angular zones of
pale-staining neuritic cell processes
surrounded by tumor cell nuclei;
may rarely palisade
Minimal cytoplasm, may have
cytoplasmic tail
Round to ovoid nuclei with stippled
salt and pepper chromatin,
inconspicuous nucleoli
 Ganglion cells
Abundant granular
eosinophilic cytoplasm
(Nissl substance is rough
endoplasmic reticulum)

Distinct cell borders

Nuclear enlargement,
eccentric nuclei,
prominent nucleoli
Ganglioneuroblastoma intermixed
Differentiating neuroblasts :
moderate to abundant acidophilic or
amphophilic cytoplasm,
Enlarged eccentric vesicular nucleus
with a single prominent nucleolus.
Ganglion cells: immature,
multinucleated, or morphologically
abnormal.
Background : fine, fibrillary
network (neuropil) composed of
abundant neurites arising from the
differentiating ganglion cells.
Histologic overlap between
differentiating neuroblastoma and
ganglioneuroblastoma.
IHC
Neuroblasts: neuron specific enolase (NSE), CD57,
CD56, protein gene product 9.5 (PGP 9.5), Leu7,
GD2, NB84, synaptophysin, chromogranin,
neurofilament protein, ALK1
Schwannian stroma: S100
Ganglion cells: S100, synaptophysin, neurofilament
protein (NF), glial fibrillary acidic protein (GFAP),
PGP 9.5, type IV collagen
 Paraganglioma
Tumors arising from the paraganglia
distributed along the parasympathetic nerves
in head, neck and mediastinum.
Parasympathetic paragangliomas are rare,
with a prevalence of approximately 0.2 1.0 /
100,000
Average patient is 4th and 5th decade of life
Carotid body paragangliomas has predilection
for females.
Types of Paragangliomas :
Carotid body
Jugulotympanic
Vagal
Mediastinal
Retroperitoneal
Zukerkandl body
Other locations: cavernous sinus, orbit, nose,
nasal cavities, larynx and trachea, thyroid,
heart, gallbladder, uterus and spinal cord.
 Solid tumors
Spherical/ ovoid or
fusiform
Partially / completely
encapsulated
C/s tan to red- brown,
extremely vascular,
homogenous.
 Organoid, trabecular and
alveolar patterns,
variable "zellballen"
Zellballen pattern
(nested islands of chief
cells) with inconspicuous
sustentacular cells and
capillary network at
periphery
Variable nuclear size,
some cells with
pleomorphism or
hyperchromasia
Round to oval nuclei,
prominent nucleoli, clear
to eosinophilic and finely
granular cytoplasm
 Nuclear pseudoinclusions,
intercellular hyaline
globules, spindle cell or
oncocytic changes may be
seen
Presence of mitoses and
vascular invasion not
helpful for distinguishing
benign and malignant
Necrotic foci may be seen
May show partly
infiltrating border of
lymphocytes
 ADENOMATOID TUMOR
Rare benign tumor of mesothelial origin arising in the
adrenal gland.

Commonly seen in middle aged men

These are solitary tumors seen mostly intra- adrenal,

but peri-adrenal localizaton may also occur.

All tumors are incidentally discovered at autopsy or

during evaluation for other condtions.
Macroscopically :
Size ranges from 0.5-9cm in largest dimension.
Well circumscribed and usually discrete, white, solid
or solid and cystic masses.
Microscopically :
Well circumscribed lesion with variable combinations
of adenomatoid, papillary, solid and cystic patterns.
Tubules having flattened to cuboidal cells with
prominent cytoplasmic vacuoles
The vacuoles cause the cells to have a signet ring
appearance, but lack intracellular mucin.
 Sex cord Stromal Tumor
Tumor with sex cord stromal differentiation,
arising in the adrenal glands.
Seen in post-menopausal females
Macroscopically: measure upto 9cm,
circumscribed, yellow to white or brown and
usually solid, but granulosa cell tumors are
occasionally cystic. Foci of hemorrhage may
be seen.
Histopathologically: these tumors resemble
their counterparts in ovary.
 Adrenal Soft Tissue and Germ Cell
Tumors
1. Myelolipoma
Accounts for approximately 2.5% of primary adrenal
cell tumors.
Mid to late adult life with no gender predilection.
Macroscopically : soft and yellow to red, depending
upon the proportion of components.
Microscopically : Comprise of mixture of mature
adipose tissue and hemotopoietic elements.
2. Hemangioma
Seen in 3rd to 8th decade of life
Microscopically: hemangiomas in adrenals are usually of the
cavernous type.

3. Leiomyoma
Adrenal leiomyomas are usually associated with the adrenal
vein or its tributaries.

4. Other benign lesions :

Cystic lymphangioma
Cystic teratoma
Schwannoma
Neurofibroma
Teratomas
5. Malignant tumors :
Angiosarcoma
Leiomyosarcoma
Malignant peripheral nerve sheath tumor
Primitive neuro-ectodermal tumor
Melanoma.
6. Secondary Tumors :
Metastasis from primary sites breast, lung,
kidney, stomach, pancreas, ovary, colon,
oesophagus and liver / bile duct.
References
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