The document discusses the anatomy and functions of the adrenal glands and their cortex and medulla. It describes various adrenal disorders including adrenocortical hyperfunction (Cushing's syndrome, Conn's syndrome, adrenogenital syndrome), hypofunction (primary and secondary adrenocortical insufficiency, hypoaldosteronism), and tumours (cortical adenoma and carcinoma, pheochromocytoma, neuroblastoma). Cushing's syndrome is most often caused by a pituitary adenoma and results in central obesity, high blood pressure, and skin changes. Conn's syndrome is due to aldosterone-secreting adrenal adenoma and causes hypertension and low potassium levels.

1. The Endocrine System
ADRENAL GLAND
DR. ROOPAM JAIN
PROFESSOR & HEAD
DEPT. OF PATHOLOGY & BLOOD BANK

2. ANATOMY
• The adrenal glands lie at the upper pole of each
kidney.
• Each gland weighs approximately 4 gm in the
adult but in children the adrenals are
proportionately larger.
• Adrenal is composed of 2 distinct parts: an outer
yellow-brown cortex and an inner grey medulla.
• The anatomic and functional integrity of adrenal
cortices are essential for life, while it does not
hold true for adrenal medulla.

3. ADRENAL CORTEX
• It is composed of 3 layers:
1. Zona glomerulosa is the outer layer and comprises about 10% of the
cortex. It consists of cords or columns of polyhedral cells just under the
capsule. This layer is responsible for the synthesis of mineralocorticoids,
the most important of which is aldosterone, the salt and water regulating
hormone.
2. Zona fasciculata is the middle layer and constitutes approximately 70%
of the cortex. It is composed of columns of lipid-rich cells which are
precursors of various steroid hormones manufactured in the adrenal
cortex such as glucocorticoids (e.g. cortisol) and sex steroids (e.g.
testosterone).
3. Zona reticularis is the inner layer which makes up the remainder of the
adrenal cortex. It consists of cords of more compact cells than those of
zona fasciculata but has similar functional characteristics of synthesis and
secretion of glucocorticoids and androgens.

4. ADRENAL MEDULLA
• The adrenal medulla is a component of the dispersed neuroendocrine
system derived From primitive neuroectoderm; the other components of
this system being paraganglia distributed in the vagi, paravertebral and
visceral autonomic ganglia.
• The cells comprising this system are neuroendocrine cells, the major
function of which is synthesis and secretion of catecholamines
(epinephrine and norepinephrine).
• Various other peptides such as calcitonin, somatostatin and vasoactive
intestinal polypeptide (VIP) are also secreted by these cells.

5. ADRENOCORTICAL HYPERFUNCTION
(HYPERADRENALISM)
1. Cushing’s syndrome caused by excess of glucocorticoids (i.e. cortisol);
also called chronic hypercortisolism.
2. Conn’s syndrome caused by oversecretion of mineralocorticoids (i.e.
aldosterone); also called primary hyperaldosteronism.
3. Adrenogenital syndrome characterised by excessive production of
adrenal sex steroids (i.e. androgens); also called adrenal virilism.

6. CUSHING’S SYNDROME
(CHRONIC HYPERCORTISOLISM)
• Cushing’s syndrome is caused by excessive production of
cortisol of whatever cause.

7. CUSHING’S SYNDROME
ETIOPATHOGENESIS
• There are 4 major etiologic types of Cushing’s
syndrome:
1. Pituitary Cushing’s syndrome
About 60-70% cases of Cushing’s syndrome are caused
by excessive secretion of ACTH due to a lesion in the
pituitary gland, most commonly a corticotroph adenoma or
multiple corticotroph microadenomas.

8. CUSHING’S SYNDROME
ETIOPATHOGENESIS
2. Adrenal Cushing’s syndrome
• Approximately 20-25% cases of Cushing’s syndrome are
caused by disease in one or both the adrenal glands.
• These include adrenal cortical adenoma, carcinoma, and less
often, cortical hyperplasia.

9. CUSHING’S SYNDROME
ETIOPATHOGENESIS
3. Ectopic Cushing’s syndrome
• About 10-15% cases of Cushing’s syndrome have an origin
in ectopic ACTH elaboration by non-endocrine tumours.
• Most often, the tumour is small cell carcinoma of the lung but
other lung cancers, malignant thymoma and pancreatic
tumours have also been implicated.

10. CUSHING’S SYNDROME
ETIOPATHOGENESIS
4. Iatrogenic Cushing’s syndrome
• Prolonged therapeutic administration of high doses of
glucocorticoids or ACTH may result in Cushing’s syndrome
e.g. in organ transplant recipients and in autoimmune
diseases.

11. CLINICAL FEATURES
• Occurs more often in patients between the age of 20-40 years
with 3 times higher frequency in women than in men.
1. Central or truncal obesity contrasted with relatively thin arms
and legs, buffalo hump due to prominence of fat over the
shoulders, and rounded oedematous moon-face.
2. Increased protein breakdown resulting in wasting and
thinning of the skeletal muscles, atrophy of the skin and
subcutaneous tissue with formation of purple striae on the
abdominal wall, osteoporosis and easy bruising of the thin skin
from minor trauma.
3. Systemic hypertension
4. Impaired glucose tolerance and diabetes mellitus
5. Amenorrhoea, hirsutism and infertility in many women.
6. Insomnia, depression, confusion and psychosis.

13. A patient with Cushing syndrome demonstrating central
obesity, “moon facies,” and abdominal striae

14. CONN’S SYNDROME
(PRIMARY HYPERALDOSTERONISM)
• This is an uncommon syndrome occurring due to overproduction of
aldosterone, the potent salt-retaining hormone.
ETIOPATHOGENESIS
1. Adrenocortical adenoma, producing aldosterone.
2. Bilateral adrenal hyperplasia, especially in children (congenital
hyperaldosteronism).
3. Rarely, adrenal carcinoma.
”
. Primary hyperaldosteronism from any of the above causes is
associated with low plasma renin levels.
”
. Secondary hyperaldosteronism, on the contrary, occurs in response
to high plasma renin level due to overproductio of renin by the kidneys
such as in renal ischaemia, reninoma or oedema.

15. The major causes of
primary
hyperaldosteronism
and its principal
effects on the
kidney

16. CONN’S SYNDROME
(PRIMARY HYPERALDOSTERONISM)
CLINICAL FEATURES
• Conn’s syndrome is more frequent in adult females.
1. Hypertension, usually mild to moderate diastolic hypertension.
2. Hypokalaemia and associated muscular weakness, peripheral
neuropathy and cardiac arrhythmias.
3. Retention of sodium and water.
4. Polyuria & polydipsia due to reduced concentrating power of the
renal tubules.

17. ADRENOGENITAL SYNDROME
(ADRENAL VIRILISM)
• Adrenal cortex secretes a smaller amount of sex steroids than the
gonads.
• Adrenocortical hyperfunction may occasionally cause sexual
disturbances.
ETIOPATHOGENESIS
• Hypersecretion of sex steroids, mainly androgens, may occur in children
or in adults:
”
. In children, it is due to congenital adrenal hyperplasia in which there is
congenital deficiency of a specific enzyme.
”
. In adults, it is caused by an adrenocortical adenoma or a carcinoma.

18. ADRENOGENITAL SYNDROME
(ADRENAL VIRILISM)
CLINICAL FEATURES
• The clinical features depend upon the age and sex of the patient.
”
. In children
distortion of the external genitalia in girls,
and precocious puberty in boys.
”
. In adults
the features in females show virilisation (e.g. hirsutism, oligomenorrhoea,
deepening of voice hypertrophy of the clitoris)
and in males may rarely cause feminisation.
There is generally increased excretion of 17-ketosteroids in the urine.

19. ADRENOCORTICAL INSUFFICIENCY
(HYPOADRENALISM)
• Adrenocortical insufficiency may result from deficient synthesis of
cortical steroids from the adrenal cortex or may be secondary to ACTH
deficiency.
1. Primary adrenocortical insufficiency caused primarily by the disease of
the adrenal glands.
2. Secondary adrenocortical insufficiency resulting from diminished
secretion of ACTH.
3. Hypoaldosteronism characterised by deficient secretion of aldosterone.

21. PRIMARY ADRENOCORTICAL
INSUFFICIENCY
• Primary adrenal hypofunction occurs due to defect in the adrenal glands
and normal pituitary function.
• It may develop in 2 ways:
A. Acute primary adrenocortical insufficiency or ‘adrenal crisis’.
B. Chronic primary adrenocortical insufficiency or ‘Addison’s disease’

22. A. Primary Acute Adrenocortical
Insufficiency (Adrenal Crisis)
• Sudden loss of adrenocortical function may result in an acute condition
called adrenal crisis.
• ETIOPATHOGENESIS :
1. Bilateral adrenalectomy e.g. in the treatment of cortical hyperfunction,
hypertension and in selected cases of breast cancer.
2. Septicaemia e.g. in endotoxic shock and meningococcal infection
producing grossly haemorrhagic and necrotic adrenal cortex termed
adrenal apoplexy. The acute condition so produced is called Waterhouse-
Friderichsen’s syndrome.
3. Rapid withdrawal of steroids.
4. Any form of acute stress in a case of chronic insufficiency i.e. in
Addison’s disease.

23. A. Primary Acute Adrenocortical
Insufficiency (Adrenal Crisis)
CLINICAL FEATURES
• Clinical features of acute adrenocortical insufficiency are due to
deficiency of mineralocorticoids and glucocorticoids.
1. Deficiency of mineralocorticoids (i.e. aldosterone deficiency)
result in salt deficiency, hyperkalaemia & dehydration.
2. Deficiency of glucocorticoids (i.e. cortisol deficiency) leads to
hypoglycaemia, increased insulin sensitivity & vomitings.

24. B. Primary Chronic Adrenocortical
Insufficiency
(Addison’s Disease)
• Progressive chronic destruction of more than 90% of adrenal cortex on
both sides results in an uncommon clinical condition called Addison’s
disease.
ETIOPATHOGENESIS:
• These include: tuberculosis, autoimmune or idiopathic adrenalitis,
histoplasmosis, amyloidosis, metastatic cancer, sarcoidosis and
haemochromatosis.
• However, currently the first two causes—tuberculosis and autoimmune
chronic destruction of adrenal glands, are implicated in majority of cases
of Addison’s disease.

25. B. Primary Chronic Adrenocortical
Insufficiency(Addison’s Disease)
CLINICAL FEATURES
Clinical manifestations develop slowly and insidiously.
1. Asthenia
2. Hyperpigmentation,
3. Arterial hypotension.
4. Vague upper gastrointestinal symptoms such as mild loss of appetite,
nausea, vomiting and upper abdominal pain.
5. Lack of androgen causing loss of hair in women.
6. Episodes of hypoglycaemia.
7. Biochemical changes include reduced GFR, acidosis, hyperkalaemia and
low levels of serum sodium, chloride and bicarbonate.

26. SECONDARY ADRENOCORTICAL
INSUFFICIENCY
• Adrenocortical insufficiency resulting from deficiency of ACTH is called
secondary adrenocortical insufficiency.
ETIOPATHOGENESIS :
1. Selective ACTH deficiency due to prolonged administration of high doses
of glucocorticoids. This leads to suppression of ACTH release from the
pituitary gland and selective deficiency.
2. Panhypopituitarism due to hypothalamus-pituitary diseases is associated
with deficiency of multiple trophic hormones.

27. SECONDARY ADRENOCORTICAL
INSUFFICIENCY
CLINICAL FEATURES
The clinical features of secondary adrenocortical insufficiency are like
those of Addison’s disease except the following:
1. These cases lack hyperpigmentation because of suppressed production of
melanocyte-stimulating hormone (MSH) from the pituitary.
2. Plasma ACTH levels are low-to-absent in secondary insufficiency but are
elevated in Addison’s disease.
3. Aldosterone levels are normal due to stimulation by renin.

28. HYPOALDOSTERONISM
• Isolated deficiency of aldosterone with normal cortisol level may occur in
association with reduced renin secretion.
ETIOPATHOGENESIS :
1. Congenital defect due to deficiency of an enzyme required for its synthesis.
2. Prolonged administration of heparin.
3. Certain diseases of the brain.
4. Excision of an aldosterone-secreting tumour.

29. HYPOALDOSTERONISM
CLINICAL FEATURES
• The patients of isolated hypoaldosteronism are adults
with mild renal failure and diabetes mellitus.
• The predominant features are hyperkalaemia and metabolic
acidosis.

30. TUMOURS OF
ADRENAL GLANDS

31. TUMOURS OF ADRENAL GLANDS
• Primary tumours of the adrenal glands are uncommon and include
distinct adrenocortical tumours and medullary tumours.
• Adrenal gland is a more common site for metastatic carcinoma.

32. ADRENOCORTICAL TUMOURS
Cortical Adenoma
• The commonest cortical tumour is adenoma.
• They are indistinguishable from hyperplastic nodules except that
lesions smaller than 2 cm diameter are labelled hyperplastic
nodules.
• A cortical adenoma is a benign and slow-growing tumour.
• It is usually small and nonfunctional.
• Association of cortical adenomas with systemic hypertension has
been suggested by some workers.

33. MORPHOLOGIC FEATURES
• Grossly, an adenoma is usually a small (2–5 cm),
solitary, spherical and encapsulated tumour
which is well-delineated from the surrounding
normal adrenal gland.
• Cut section is typically bright yellow.
• Microscopically, the tumour cells are arranged in
trabeculae and generally resemble the cells of
zona fasciculata.
• Less frequently, the cells of adenoma are like
those of zona glomerulosa or zona reticularis.

34. Cortical Carcinoma
• Carcinoma of the adrenal cortex is an
uncommon tumour occurring mostly in adults.
• It invades locally as well as spreads to distant
sites.
• Most cortical carcinomas secrete one of the
adrenocortical hormones excessively.

35. Cortical Carcinoma
• MORPHOLOGIC FEATURES
• Grossly, an adrenal carcinoma is generally large,
spherical and well-demarcated tumour.
• On cut section, it is predominantly yellow with
intermixed areas of haemorrhages, necrosis and
calcification.
• Microscopically, the cortical carcinoma may vary
from well-differentiated to anaplastic growth.
• Well-differentiated carcinoma consists of foci of
atypia in an adenoma, whileanaplastic carcinoma
shows large, pleomorphic and bizarre cells with
high mitotic activity.

36. MEDULLARY TUMOURS
• The most significant lesions of the adrenal
medulla are neoplasms.
1. Benign tumours: These are less common and
include pheochromocytoma and myelolipoma.
2. Tumours arising from embryonic nerve cells:
These are more common and include
neuroblastoma and ganglioneuroma.

37. Pheochromocytoma (Chromaffin
Tumour)
• Pheochromocytoma is a tumour arising from
pheochromocytes (i.e. chromaffin cells) of the
adrenal medulla.
• Its name is derived from its characteristic dark
brown black appearance of this tumour
caused by chromaffin oxidation of
catecholamines

38. • Pheochromocytoma may occur at any age but
most patients are 20-60 years old.
• Most pheochromocytomas are slow-growing and
benign but about 10% of the tumours are
malignant, invasive and metastasising.
• Thus, the traditional “10% rule” for
pheochromocytoma is 10% familial, 10%
malignant, 10% extra-adrenal. However,
currently, malignant pheochromocytoma is
diagnosed by metastasis (most often osseous)
rather than by morphology.

39. Clinical features
• The clinical features of pheochromocytoma are
predominantly due to secretion of catecholamines,
both epinephrine and norepinephrine.
• The most common feature is hypertension.
• Other manifestations due to sudden release of
catecholamines are congestive heart failure,
myocardial infarction, pulmonary oedema, cerebral
haemorrhage, and even death.
• The diagnosis is established by measuring 24-hour
urinary catecholamines or their metabolites such as
metanephrine and VMA.

40. MORPHOLOGIC FEATURES
• Grossly, the tumour is soft, spherical, may be
quite variable in size and weight, and well-
demarcated from the adjacent adrenal gland.
• On cut section, the tumour is grey to dusky
brown with areas of haemorrhages, necrosis,
calcification and cystic change.
• On immersing the tumour in dichromate fixative,
it turns brown-black due to oxidation of
catecholamines in the tumour and hence the
name chromaffin tumour.

41. Figure 25.3 Pheochromocytoma of the adrenal medulla. The specimen
shows compressed kidney at the lower end (arrow) while the upper end
shows a large spherical tumour separate from the kidney. Cut surface
of tumour shows cystic change while solid areas show dark brown,
necrotic and haemorrhagic tumour.

42. • Microscopically, the tumour has the following
characteristics:
1. The tumour cells are arranged characteristically as
welldefined nests (also termed as zellballen pattern)
separated by abundant fibrovascular stroma.
2. Other arrangements are as solid columns, sheets,
trabeculae or clumps.
3. The tumour cells are large, polyhedral and pleomorphic
with abundant granular amphophilic or basophilic
cytoplasm and vesicular nuclei.
4. The tumour cells of pheochromocytoma stain positively
with neuroendocrine substances such as neuron-specific
enolase (NSE) and chromogranin.

43. Figure 25.4 Adrenal pheochromocytoma. The tumour has typical
zellballen or nested pattern. The tumour cells are large, polyhedral and
pleomorphic having abundant granular cytoplasm.

44. Figure 24-54 Pheochromocytoma. The tumor is enclosed within an
attenuated
cortex and demonstrates areas of hemorrhage. The comma-shaped
residual adrenal is seen below. (Courtesy Dr. Jerrold R. Turner, Department
of Pathology, University of Chicago Hospitals, Chicago, Ill.)

45. Figure 24-56 Electron micrograph of pheochromocytoma. This tumor
contains
membrane-bound secretory granules in which catecholamines are
stored (30,000×).

46. Figure 24-55 Pheochromocytoma demonstrating characteristic nests of cells
(“zellballen”) with abundant cytoplasm. Granules containing catecholamine
are not visible in this preparation. It is not uncommon to find bizarre cells
even in pheochromocytomas that are biologically benign. (Courtesy Dr.
Jerrold R. Turner, Department of Pathology, University of Chicago Hospitals,
Chicago, Ill.)

47. Myelolipoma
• Myelolipoma is an uncommon benign adrenal
medullary tumour, sometimes found incidentally
at autopsy.
• MORPHOLOGIC FEATURES
• Grossly, a myelolipoma is usually a small tumour,
measuring 0.2-2 cm in diameter.
• Microscopically, it consists of well-differentiated
adipose tissue in which is scattered clumps of
haematopoietic cells are seen.

48. Neuroblastoma
• Neuroblastoma, also called as
sympathicoblastoma, is a common malignant
tumour of neural crest cells, occurring most
commonly in children under 5 years of age.
• Vast majority of cases occur within the abdomen
(in the adrenal medulla and paravertebral
autonomic ganglia) and rarely in the cerebral
hemisphere.
• Most cases are sporadic but 1-2% cases are
familial with autosomal dominant transmission.

49. • The clinical manifestations of neuroblastoma are related to its rapid
local growth, metastatic spread or development of hormonal
syndrome.
• Local symptoms include abdominal distension, fever, weight loss
and malaise.
• Foci of calcificationmay be observed on radiologic examination of
the abdomen.
• Metastatic spread occurs early and widely through haematogenous
as well as lymphatic routes and involves bones (especially skull),
liver, lungs and regional lymph nodes.
• Neuroblastoma produces variable amounts of catecholamines and
its metabolites such as vanillyl mandelic acid (VMA) and
homovanillic acid (HVA), which can be detected in the 24-hour
urine.
• The features in such a case include watery diarrhoea, flushing of the
skin and hypokalaemia.

50. • MORPHOLOGIC FEATURES
• Grossly, the tumour is generally large, soft
and lobulated mass with extensive areas of
necrosis and haemorrhages.
• The tumour is usually diffusely infiltrating into
the adjacent tissues.
• Cut surface of the tumour is greywhite and
may reveal minute foci of calcification.

51. • Microscopically:
1. The tumour cells are small, round and oval, slightly larger
than lymphocytes, and have scanty and poorly-defined
cytoplasm and hyperchromatic nuclei.
2. They are generally arranged in irregular sheets separated by
fibrovascular stroma.
3. Classical neuroblastomas show Homer-Wright’s rosettes
(pseudorosettes) which have a central fibrillar eosinophilic
material surrounded by radially arranged tumour cells.
4. The tumour cells stain positively with immunohistochemical
markers such as neuron-specific enolase (NSE),
neurofilaments (NF) and chromogranin.

52. Figure 25.5 Neuroblastoma, It shows small, round to oval cells forming
irregular sheets separated by fibrovascular stroma. A few Homer-Wright’s
pseudorosettes are also present. Inset shows a close-up view of
pseudorosette.

53. Prognosis of neuroblastoma
i) Age of child below 2 years.
ii) Extra-abdominal location of the tumour than abdominal
masses.
iii) Tumour histology with schwannian or ganglionic
differentiation.
iv) Patients in clinical stage I (confined to the organ of origin)
or stage II (tumour extending in continuity beyond the organ
of
origin but not crossing the midline).
v) Favourable genetic features of hyperdiploidy, lack of
amplification of N-MYC oncogene and absence of telomerase
expression.

54. Ganglioneuroma
• A ganglioneuroma is a mature, benign and
uncommon tumour occurring in adults.
• It is derived from ganglion cells, most often in the
posterior mediastinum, and uncommonly in
other peripheral ganglia and brain.
• The tumour produces symptoms because of its
size and location.
• Catecholamines and their metabolites can be
detected in large amounts in the 24-hour urine
specimen of patients with ganglioneuroma.

55. • MORPHOLOGIC FEATURES
• Grossly, the tumour is spherical, firm and
encapsulated.
• Microscopically, it contains large number of
well-formed ganglionic nerve cells scattered in
fibrillar stroma and myelinated and non-
myelinated nerve fibres.

56. Extra-adrenal Paraganglioma
(Chemodectoma)
• Parasympathetic paraganglia located in extra-adrenal sites
such as the carotid bodies, vagus, jugulotympanic and
aorticosympathetic (pre-aortic) paraganglia may produce
neoplasms, collectively termed paragangliomas with the
anatomic site of origin e.g. carotid body paraganglioma,
intravagal paraganglioma, jugulotympanic paraganglioma
etc.
• These tumours are also called chemodectomas because of
their responsiveness to chemoreceptors.
• They are uncommon tumours found in adults and rarely
secrete excess of catecholamines, except
aorticosympathetic paraganglioma (also termed extra-
adrenal pheochromocytoma). Paragangliomas are generally
benign but recurrent tumours.
• A small proportion of them may metastasise widely.

57. Waterhouse-Friderichsen Syndrome
• This uncommon but catastrophic syndrome is
characterized by the following:
• Overwhelming bacterial infection, classically
Neisseria meningitidis septicemia but occasionally
caused by other highly virulent organisms, such
as Pseudomonas species, pneumococci,
Haemophilus influenzae, or even staphylococci
• Rapidly progressive hypotension leading to shock
• Disseminated intravascular coagulation associated
with widespread purpura, particularly of the skin
Rapidly developing adrenocortical insufficiency
associated with massive bilateral adrenal
hemorrhage

58. Figure 24-47 Diffuse purpuric rash in a patient with
Waterhouse-Friderichsen syndrome.

59.  Waterhouse-Friderichsen syndrome can occur at any age but is
more common in children.
 The basis for the adrenal hemorrhage is uncertain but could be due
to direct bacterial seeding of small vessels in the adrenal, the
development of disseminated intravascular coagulation, or
endothelial dysfunction caused by microbial products and
inflammatory mediators.
 Whatever the basis, the adrenals are converted to sacs of clotted
blood, which obscures virtually all of the underlying detail.
 Histologic examination reveals that the hemorrhage starts within
the medulla near thin-walled venous sinusoids, then suffuses
peripherally into the cortex, often leaving islands of recognizable
cortical cells.
 Prompt recognition and appropriate therapy must be instituted
immediately, or death follows within hours to a few days.

60. Figure 24-48 Waterhouse-Friderichsen syndrome. At autopsy, the adrenals
were grossly hemorrhagic and shrunken; microscopically, little residual
cortical architecture is discernible.

61. Figure 24-52 Adrenal carcinoma. The hemorrhagic and necrotic
tumor
dwarfs the kidney and compresses the upper pole.

62. Figure 24-53 Adrenal carcinoma (A) revealing marked
anaplasia, contrasted with normal adrenal cortical cells (B).
A

63. Figure 24-53 Adrenal carcinoma (A) revealing marked
anaplasia, contrasted with normal adrenal cortical cells (B).
B