PATHOLOGY OF THE

ADRENAL
GLAND

Références:
Pr Claude Sader
- http://campus.cerimes.fr/anatomie-pathologique spéciale Head
Ghorraof Pathology
- Robbins and Cotran Pathologic Basis of Disease (7th departement
edition)
Lebanese Hospital Geitaoui
 Introductio
n
Ø The adrenal glands are paired endocrine organs, each of
themdivided in two regions, the cortex and
Ø medulla.
These 2 regions differ in their development, structure,
and function.
Ø The cortex consists of three layers of distinct cell
§types.
Beneath the capsule of the adrenal, is the narrow layer of
glomerulosa
zona
§ (Mineralocorticoids).
An equally narrow zona reticularis abuts the medulla (sex
: estrogens and
steroids
§ androgens)
Intervening is the broad zona fasciculata, which makes up
75% of the total cortex.
about
(glucocorticoids)
 Introductio
n
Ø The adrenal medulla is composed of chromaffin
cells, which synthesize and secrete
catecholamines,
Ø mainly epinephrine.
We distinguish disorders of the adrenal cortex
then of the
and
Ø Diseases
medulla. of the adrenal cortex can be
conveniently
divided into those associated with cortical
hyperfunction and those characterized by
cortical
hypofunction.
 ANATOMIY

Retroperitoneal
Normal weight : 4 to
6g
 HISTOLOG
Zona glomerulosa/Zona fasciculata/Zona
reticularis Y
 Paraganglion
System
Ø The adrenal medulla is embryologically, functionally,
andstructurally distinct from the adrenal
Ø cortex.
It is populated by cells derived from the neural crest
cells) and their supporting (sustentacular)
(chromaffin
Ø cells.
The chromaffin cells, synthesize and secrete
catecholamines in
response to signals from preganglionic nerve fibers in the
Ø Similar collections
sympathetic nervousof cells are distributed throughout the
system.
theinextraadrenal paraganglion
body
Ø system.
The most important diseases of the adrenal medulla are
neoplasms:
Neuronal neoplasms (neuroblastomas and more mature
ganglion
 LESIONS OF THE ADRENAL
CORTEX
1- Morphological Modifications
a. Hétérotopia
b. Cortical Nodule
c. Congenital Hyperplasia
d. Acquired Hyperplasia
e. Tumors

2- Adrenocortical Hyperfunction (Hyperadrenalism)

3- Adrenal Insufficiency
 Heterotopi
a
Heterotopic AC tissue has been encountered in many
locations :
•• Kidneys
Retropéritonéal fat
• The celiac
•plexus
Along the spermatic and ovarian
veins
• The testes and the tail of the
epididymis
•• The
The appendicular
broad ligament/The ovary
• Inguinal Hernias
meso
•• Lung
Liver
• Intra dural space/
Brain
May undergo hypeplasia and less commonly tumors can
develop
 Cortical Nodule

Ø Micronodule made of normal adrenal cortex in the adjacent

capsule or fat.
Ø Round shaped, Non-encapsulated
Ø Often multiple
Ø Very small size (up to 3mm)
Ø May increase in number with age
Ø No clinical significance
Ø To be distinguished from nodular hyperplasia and adenomas
 Congenital Hyperplasia

Ø Congenital metabolic dysfunction

Ø Autosomal recessive
Ø F=H
Ø Responsible for the majority of androgenital syndromes in the first
year of life
Ø Clinically: in 95% pure virilizing syndrome with in 30% of
electrolyte disturbances
Ø Morphology : Diffuse Hyperplasia of the reticula zone (regardless
of the enzymatic defect)
 Acquired Hyperplasia

Ø Always bilateral
Ø Diffuse (by hyperproduction of ACTH by the pituitary
gland or by a tumor) or nodular
Ø Weight > 6g (without fat)
Ø Microscopy: thickening of Zona fasciculata and
reticularis
Ø Nuclear pleomorphism with a few large hyperchromic
nuclei may exist
 Adrenal Insufficiency
Ø caused by either primary adrenal disease (primary
hypoadrenalism) or decreased stimulation of the adrenals
resulting from ACTH deficiency (secondary hypoadrenalism).
Ø Primary adrenocortical insufficiency may be acute (called
adrenal crisis), or chronic (Addison disease).

because of the inability of

the atrophic adrenals to
produce GC hormones.
 Acute adrenocortical Insufficiency

Ø Individuals with chronic adrenocortical insufficiency may develop

an acute crisis
Ø Massive adrenal hemorrhage may destroy enough of the adrenal
cortex to cause acute adrenocortical insufficiency.
Ø This condition may occur in patients :
• With maintained on anticoagulant therapy
• Who develop disseminated intravascular coagulation following
surgery
• During pregnancy
• Suffering from overwhelming sepsis (known as the Waterhouse-
Friderichsen syndrome)
 Acute adrenocortical Insufficiency

Waterhouse- Friderichsen Syndrome

Ø Neisseria meningitidis +++; but also pseudomonas, pneumococci,
haemophilus influenzae.
Ø Rapidly progressive Hypotension
Ø IVDC with purpura
Ø Massive adrenal hemorrhage .
Ø Can occur at any age but is somewhat more common in children
At autopsy, the adrenal glands were grossly
hemorrhagic and shrunken;
On microscopic examination little residual
cortical architecture is discernible.
 Chronic adrenocortical insufficiency
Addison Disease
Ø Uncommon disorder resulting from progressive
destruction of the adrenal cortex.
Ø More than 90% of all cases are attributable to one of
four disorders:
1. autoimmune adrenalitis,
2. tuberculosis,
3. acquired immune deficiency syndrome (AIDS),
4. metastatic cancer
Ø Symptomes appear once 90% of AC tissue is
destroyed
 Autoimmune adrenalitis
Ø Accounts for 60% to 70% of cases
Ø Is by far the most common cause of primary adrenal insufficiency
in developed countries.
Ø There is autoimmune destruction of steroid producing cells, and
autoantibodies to several key steroidogenic enzymes have been
detected in affected patients.
Microscopy : Extensive mononuclear Inflammatory infiltrate in the cortex
ADRÉNALITE `TUBERCULEUSE
 Adrenocortical Neoplasms
Ø Primary Cortical tumors can be benign or malignant.
Ø Carcinoma and CS adenomas can be very difficult to
differentiate from one another.
Ø These tumors do not present any morphological difference
according to whether they are functional or not.
Ø Determination of whether a cortical neoplasm is functional or
not is based on clinical evaluation and measurement of the
hormone or its metabolites in the laboratory.
Ø While functional adenomas are most commonly associated with
hyperaldosteronism and with Cushing syndrome, a virilizing
neoplasm is more likely to be a carcinoma.
 Adrenocortical Neoplasms

• Adult subjects (average of 50 years for Ca)

• F=H
• May be encountered as incidental findings at the time
of autopsy or during abdominal imaging for an
unrelated cause : incidentaloma
• If extensive necrosis is present (like in carcinomas):
patient may present with fever
• Palpable masses are almost always malignant
 ADENOMA

Ø Patients are Often Not symptomatic

Ø Well-circumscribed tumor
Ø Average size 2.5cm (rarely 5cm or 50g)
Ø Protrud on the surface of the adrenal gland.
Ø May or may not be functional: if it is functional it is
associated with atrophy of the residual and controlateral
cortex
Ø On cut surface, adenomas usually have an homogeneous
aspect and are yellow to yellow-brown, owing to the
presence of lipid within the neoplastic cells.
 ADENOMA

Ø On microscopic examination, they are composed of

cells similar to those populating the normal adrenal
cortex.

Ø As with other endocrine tumors, pleomorphism may

be encountered in benign tumors and is not a reliable
marker of malignancy.

Ø Exceptional or absent mitosis

ADENOMA
 Adrenocortical Carcinoma
Ø rare neoplasms that may occur at any age, including in childhood.
Ø Two rare inherited causes of adrenal cortical carcinomas are Li-
Fraumeni syndrome and Beckwith-Wiedemann syndrome
Ø In most cases, adrenocortical carcinomas are large, invasive lesions
that efface the native adrenal gland.
Ø On cut surface, adrenocortical carcinomas typically are variegated,
poorly demarcated lesions containing areas of necrosis, hemorrhage,
and cystic change.
Ø Microscopic examination typically shows these tumors to be
composed of well-differentiated cells resembling those seen in
cortical adenomas OR bizarre, pleomorphic cells, which may be
difficult to distinguish from those of an undifferentiated carcinoma
metastatic to the adrenal gland
Carcinoma

The tumor
develops towards
the kidney and
compresses the
upper pole.
It is largely
hemorrhagic and
necrotic.
 CARCINOMA

Ø Adrenal cancers have a strong tendency to invade the adrenal

vein, vena cava, and lymphatics.
Ø Metastases to regional and periaortic nodes are common, as is
distant hematogenous spread to the lungs and other viscera.
Ø Bone metastases are unusual.
Ø The median patient survival is about 2 years.
Ø Carcinomas metastatic to the adrenal cortex are significantly
more frequent than a primary adrenocortical carcinoma.
 Other AC tumors

c) Cysts : Rare
d) Myélolipoma
Ø Adipous and hematopoietic Tissu
Ø Usually small size
Ø Focus of myelolipomatous changes may be noted in
any other tumor or in cases of CS hyperplasia
e) Lipoadénoma
f) Tumeur corticomedullaires mixtes
Myélolipome
lipoadénome
ANGIOMA
 Metastasis

M. Ca. épidermoide M. Ca. mammaire

Often bilateral.
Most frequent origins :
Lung
Breast
Melanoma
Kidney
 ADRENAL MEDULLA

The most important diseases of the adrenal medulla are

neoplasms
They include both neuronal neoplasms (including neuroblastomas
and more mature ganglion cell tumors) and neoplasms
composed of chromaffin cells (pheochromocytomas).
 Pheochromocytoma

Ø Rare neoplasms composed of chromaffin cells, which,

like their non-neoplastic counterparts, synthesize and
release catecholamines.

Ø These tumors are of special importance because

although uncommon, they (like aldosterone-secreting
adenomas) give rise to a surgically correctable form of
HT.

Ø 0.2 à 0.3 % Of patient with HT have PhCC

 Phéochromocytoma

Pheochromocytomas usually subscribe to a convenient

“rule of 10s”(some of which are nowadays questionable):
Ø 10% are extra adrenal (organ of Zuckerkandl and the
carotid body), where they usually are called paragangliomas
Ø 10% of Adrenal PhCC are malignant
Ø 10% of adrenal pheochromocytomas are bilateral; this
proportion may rise to 50% in cases that are associated
with familial syndromes.
Ø 10% of adrenal PhCC are not associated with
hypertension
 Changed Rule
Ø |The “traditional” 10% rule that has since been modified
pertains to familial cases.
Ø It is now recognized that as many as 25% of persons with
PhCC and paragangliomas harbor a germ line mutation in one
of at least six known genes :RET, NF1, VHL, SDHB, SDHC
and SDHD
 Macroscopy

Ø Pheochromocytomas range in size from small,

circumscribe lesions confined to the adrenal to large,
hemorrhagic masses weighing several kilograms (100g
to 4 Kg).
Ø On cut surface, smaller pheochromocytomas are yellow-
tan, well-defined lesions that compress the adjacent
adrenal
Ø Larger lesions tend to be hemorrhagic, necrotic, and
cystic and typically efface the adrenal gland.
Ø Incubation of the fresh tissue with potassium dichromate
solutions turns the tumor dark brown (chromaffin cells)
Morphology

Ø The tumor is enclosed

within an attenuated cortex
Ø Demonstrates areas of
hemorrhage.
Ø The comma-shaped residual
adrenal gland is seen
 Microscopy
Ø PhCC are composed of polygonal to spindle-shaped chromaffin
cells and their supporting cells, compartmentalized into small
nests (Zellballen), by a rich vascular
Ø The cytoplasm of the neoplastic cells often has a finely granular
appearance, highlighted by a variety of silver stains, because of
the presence of granules containing catecholamines.
Ø Electron microscopy reveals variable numbers electron-dense
granules, representing catecholamines and sometimes other
peptides.
Ø They show positivity to NE markers (chromogranin A,
Synaptophysine, CD56)
 Microscopy

Ø The nuclei of the neoplastic cells are often quite pleomorphic.

Ø Both capsular and vascular invasion may be encountered in
benign lesions, and the mere presence of mitotic figures does not
imply malignancy.
Ø Therefore, the definitive diagnosis of malignancy in
pheochromocytomas is based exclusively on the presence of
metastases.
Ø These may involve regional lymph nodes as well as more distant
sites including liver, lung, and bone.
Microscopy

Characteristic nests
of cells with abundant
cytoplasm
Microscopy

It is not uncommon to
find bizarre even in
pheochromocytomas
that are benign.
 Other AM tumors
Ø Neuroblastoma :
is the most common extracranial solid tumor of childhood.
occur most commonly during the first 5 years of life and may arise
during infancy.
may occur anywhere in the sympathetic nervous system and
occasionally within the brain, but they are most common in the
abdomen;
a majority of these tumors arise in either the adrenal medulla or the
retroperitoneal sympathetic ganglia.
Most NB are sporadic, although familial cases also have been
described.
Ø Ganglioneuroma
Ø Ganglioneuroblastoma
 Neuroblastoma
Ø Derived from primordial neural crest cells
Ø Neuroblastomas demonstrate several unique features in their
natural history, including spontaneous regression and
spontaneous or therapy-induced maturation.
Ø Most occur sporadically, but 1% to 2% are familial, with
autosomal dominant transmission, and in such cases the
neoplasms may involve both of the adrenals or multiple
primary autonomic sites.
 Macroscopy

Ø Range in size from minute nodules (the in situ lesions) to large

masses weighing more than 1 kg.
Ø In situ neuroblastomas are reported to be 40 times more
frequent than overt tumors.
Ø The great preponderance of these silent lesions spontaneously
regress, leaving only a focus of fibrosis or calcification in the
adult.
Ø Some neuroblastomas are sharply demarcated with a fibrous
pseudocapsule, but others are far more infiltrative and invade
surrounding structures, including the kidneys, renal vein, and
vena cava, and envelop the aorta.
 Macroscopy
Ø On transection, they are composed of soft, gray-tan, brainlike
tissue.
Ø Larger tumors have areas of necrosis, cystic softening, and
hemorrhage.
Ø Multifocal in 10% des cas
 Microscopy
Ø Small, primitive-appearing cells with dark nuclei, scant
cytoplasm, and poorly defined cell borders growing in solid sheets
Ø Mitotic activity, nuclear breakdown (karyorrhexis), and
pleomorphism may be prominent.
Ø The background often demonstrates a faintly eosinophilic
fibrillary material (neuropil) that corresponds to neuritic processes
of the primitive neuroblasts.
Ø Typically, so-called Homer-Wright pseudo-rosettes can be found
in which the tumor cells are concentrically arranged about a
central space filled with neuropil (the absence of an actual central
lumen garners the designation “pseudo-”).
 Microscopy
Ø 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
(ganglioneuroblastoma).
Ø Some neoplasms show signs of maturation, either spontaneous
or therapy-induced.
Ø Even better differentiated lesions contain many more large
cells resembling mature ganglion cells in the absence of
residual neuroblasts; such neoplasms merit the designation
ganglioneuroma
Ø Maturation of neuroblasts into ganglion cells usually is
accompanied by the appearance of Schwann cells.
 Microscopy

Ø Locally aggressive tumor invading the kidney

Ø Most common metastasis are to the liver, bones, ovaries,
lymph nodes, testes and paratesticular area
Ø Bone metatstasis are multiple, sometimes symmetrical
(differential Dg with Ewing)
Ø The osteomedullar biospy enters the routine work upof a NB
Ø Age, stage, and NMYC amplification are the most important
prognostic features; children younger than 18 months usually
have a better prognosis than older children, while children
with higher-stage tumors or NMYC amplification fare worse.
 NB is composed of small cells
embedded
in a finely fibrillar matrix (neuropil).
Homer-Wright pseudorosette :
tumor cells arranged concentrically
around a central core of neuropil

Ganglioneuromas, arising from spontaneous or

therapy-induced maturation of neuroblastomas,
are characterized by clusters of large cells with
vesicular nuclei and abundant eosinophilic
cytoplasm, representing neoplastic ganglion cells.
Spindle-shaped Schwann cells are present in the
background stroma.
 Ganglioneuroma

Ø The best differentiated tumor of this group

Ø Older patient
Ø Represents the most common tumor of the
sympathetic system in adults
Ø Can be multiple
Ø Rarely in the adrenal gland (rather posterior
mediastinum and retroperitoneum)
Ø Microscopy: like a neurofibroma encompassing
mature neuroganglion cells