Diseases of the adrenal gland, non neoplastic and neoplastic

1. Adrenal Glands
Guide: Surg Cdr Divya Shelly

2. 1. Anatomy and Histology
2. Non – neoplastic diseases
1. Adrenal cortex
2. Adrenal medulla
3. Neoplastic diseases
1. Adrenal cortical tumors
2. Adrenal medulla tumors

3. Anatomy
• Paired endocrine organs
• Retroperitoneal
• Located above the kidneys
• Combined weight 6 gm

4. Histology
• Two distinctive parts : 1. Cortex. 2. Medulla
1. Cortex:
• Mesodermal origin
• Three distinct layers: Glomerulosa: Mineralocorticoids
Fasciculata : Glucocorticoids
Reticularis : Sex hormones
2. Medulla:
• Neuroectodermal in origin (neural crest)
• Secrete catecholamines: Epinephrine and norepinephrine

5. 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

6. • 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.

7. Diseases of the Adrenal
cortex

8. Non – neoplastic diseases
1. Adrenocortical Hyperfunction:
• Cushing Syndrome (ZF)
• Hyperaldosteronism (ZG)
• Virilizing syndromes (ZR)
2. Adrenocortical insufficiency:
• Primary Adrenocortical insufficiency :
1. Primary acute adrenocortical insufficiency
2. Primary chronic adrenocortical insufficiency
3. Waterhouse friderichsen syndrome
• Secondary adrenocortical insufficiency

9. Cushing syndrome
• Excess cortisol secretion
• M:F – 1:4
• Endogenous/Exogenous
• Majority: Exogenous administration of corticosteroids
• ACTH dependent/independent
• ACTH dependent:
• ACTH secreting pituitary adenomas – Cushing’s disease (70%)
• Ectopic ACTH by non-pituitary tumors – 10% cases ( SCC lung)
• ACTH independent:
• Hyperplasia
• Adrenal adenomas
• Adrenal carcinomas

10. Cushing syndrome

11. Cushing syndrome
• Clinical features:

12. Hyperaldosteronism
1. Primary hyperaldosteronism
• Autonomous overproduction of aldosterone
• Nodular hyperplasia
• Adreno cortical neoplasms
• Glucocorticoid-remediable hyperaldosteronism
• Decreased plasma renin activity
2. Secondary hyperaldosteronism
• Decreased renal perfusion
• Arterial hypovolemia and edema
• Pregnancy
• Increased plasma renin activity

13. Hyperaldosteronism

14. Adrenogenital syndromes
• Dehydroepiandrosterone and androstenedione
• Under ACTH control
• Causes:
• 21-hydroxylase def (90%)
• Adrenocortical neoplasms
• Carcinomas > Adenomas

15. Adrenocortical insufficiency

16. Adrenocortical insufficiency
1. Primary acute adrenal insufficiency
• Stress crisis
• Rapid withdrawal of steroids
• Massive adrenal hemorrhage (Waterhouse-Friderichsen syndrome)
2. Primary chronic adrenal insufficiency (Addison’s disease)
• Autoimmune adrenalitis
• Autoimmune Polyendocrine Syndrome 1
• Autoimmune Polyendocrine Syndrome 2
• Infections
• Metastasis
• Genetic adrenal insufficiency (congenital hypoplasia)
3. Secondary adrenocortical insufficiency
• Decreased ACTH levels (pituitary/hypothalamus)
• Exogenous steroids
• Normal aldosterone synthesis

17. Adrenocortical tumors

18. •Cortical nodules
•Congenital adrenal hyperplasia
•Adrenal cortical adenoma
•Adrenal cortical carcinoma

19. Cortical Nodules
• 7% of those over 70 years
• Spherical, unencapsulated, usually multiple
• Microscopic to grossly apparent
• Usually < 3 mm
• Majority are non-functional
• They increase in number with age, but not associated with
hypertension, diabetes, or cardiovascular disease – ‘incidentalomas’
• Found in up to 53% of adrenal glands at autopsy
• D/D: Nodules of true cortical hyperplasia, cortical adenomas
• IHC: Cytochrome P450

20. Congenital adrenal hyperplasia
• Inborn error of metabolism
• Mutation of CYP21 gene on chromosome 6
• Majority of cases of ‘adrenogenital syndrome’ develop within the
first year of life
• Basic defect: absence of the enzyme 21-hydroxylase
• Clinical picture is usually that of a pure virilizing syndrome
• Deficiency of 11β-hydroxylase: virilization and hypertension
• Hyperplasia of zona reticularis

22. 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 to the non-functional
adenomas is normal where as that adjacent
to a functional adenoma is atrophic
• Cut surface – yellowish to yellowish brown
• No areas of hemorrhage and necrosis

23. Adrenal cortical adenoma
• Microscopically, Predominantly lipid-
laden cells resembling ZF, arranged in
an alveolar pattern interspersed with
short cords
• Focal groups of compact cells may be
seen
• Mitotic activity is rare
• In patients with Conn's syndrome,
there may be cells resembling ZG and
others showing mixed features of ZG
and ZF—‘hybrid’ cells
• Compact cells often predominate in
tumors associated with virilization

24. 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 myelipoma:
myo-lipomatous component with
areas of small hemorrhagic foci

25. 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

26. 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
• Cushing’s 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

27. Adrenal cortical carcinoma
• Microscopically,
• Less ordered structure than in
adenomas
• Trabecular and diffuse
patterns are common
• Nuclear pleomorphism seen
• Mitoses, including atypical
forms, often present
• Capsular and vascular invasion
can often be identified

28. 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

29. • A Weiss score of ≥6 was associated with poorer disease-free interval and overall
survival

30.  03 major criteria and 04 minor criteria have been proposed and tumors are defined as malignant, of uncertain
malignant potential or benign, based on the presence or absence of these criteria

31. Molecular aspects of adrenal cortical tumors
• Adrenal cortical tumors associated with various familial diseases
• Beckwith–Wiedemann syndrome: linked to the 11p15 locus with paternal
disomy and overexpression of IGF-2
*Exomphalos - Macroglossia – Gigantism
• Li–Fraumeni 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
• Familial adenomatous polyposis: APC gene defects on chromosome 5

32. Molecular aspects of adrenal cortical tumors
• 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/β-catenin pathway: hyperplasias, adenoma, and carcinomas

33. Immunohistochemistry
• Majority of cortical tumors will be positive for inhibin-α 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

34. Adrenal medullary tumors

35. 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-α and enhanced growth factor
receptor pathway signaling (e.g. RET, NF1)

36. Familial syndromes associated with pheochromocytomas

38. Pheochromocytoma
• Clinical features:
1. Increase 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

39. 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

40. Pheochromocytoma
• Microscopy:
1. 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
2. Uncommonly, the dominant cell type is a
spindle or small cell
3. The cytoplasm has a finely granular
appearance, best demonstrated with
silver stains, due to the presence of
granules containing catecholamines
4. Nuclei are usually round to ovoid,
with a stippled “salt and pepper”
chromatin that is characteristic of
neuroendocrine tumors
5. IHC: Chromogranin and synaptophysin for
the chief cells where as S-100 for
sustentacular cells

41. 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

42. Neuroblastoma
• Microscopically:
• Pattern of growth is vaguely nodular
• Incomplete fibrous septa
• Calcification may be a prominent
feature
• Necrosis is a constant feature
• Tumor cells are small and regular, with
round, deeply staining nuclei slightly
larger than lymphocytes
• Little cytoplasm, and cytoplasmic
outlines are poorly defined
• Homer Wright rosettes are present in
1/3rd cases; they are characterized by
collections of tumor cells around a
central area filled with a fibrillary
material
• Bizarre giant tumor cells

43. Ganglioneuroma
• Benign tumors, seen in 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, grayish white cut surface
having a focally 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

44. # Union for International Cancer Control
## European Network for the Study of Adrenal Tumors
** Adjacent organs include kidney, diaphragm, great vessels, pancreas, and liver

46. Thank You