Adrenal Glands

Guide: Surg Cdr Divya Shelly

1. Anatomy and Histology

2. Non – neoplastic diseases1. Adrenal cortex2. Adrenal medulla

3. Neoplastic diseases1. Adrenal cortical tumors2. Adrenal medulla tumors

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

Histology• Two distinctive parts : 1. Cortex. 2. Medulla

1. Cortex: • Mesodermal origin• Three distinct layers: Glomerulosa: Mineralocorticoids

Fasciculata : Glucocorticoids

Reticularis : Sex hormones2. Medulla: • Neuroectodermal in origin (neural crest)• Secrete catecholamines: Epinephrine and norepinephrine

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.

Diseases of the Adrenal cortex

Non – neoplastic diseases

1. Adrenocortical Hyperfunction:• Cushing Syndrome (ZF)• Hyperaldosteronism (ZG)• Virilizing syndromes (ZR)

2. Adrenocortical insufficiency:• Primary Adrenocortical insufficiency :

1. Primary acute adrenocortical insufficiency2. Primary chronic adrenocortical insufficiency3. Waterhouse friderichsen syndrome

• Secondary adrenocortical insufficiency

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

Cushing syndrome

Cushing syndrome• Clinical features:

Hyperaldosteronism1. 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

Hyperaldosteronism

Adrenogenital syndromes

• Dehydroepiandrosterone and androstenedione• Under ACTH control• Causes:

• 21-hydroxylase def (90%)• Adrenocortical neoplasms

• Carcinomas > Adenomas

Adrenocortical insufficiency

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

Adrenocortical tumors

•Cortical nodules

•Congenital adrenal hyperplasia

•Adrenal cortical adenoma

•Adrenal cortical carcinoma

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

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

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

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

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

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 carcinoma7. 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• 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

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

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

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

Molecular aspects of adrenal cortical tumors

• Adrenal cortical tumors associated with various familial diseases

• Beckwith–Wiedemann syndrome: linked to the 11p15 locus with paternaldisomy 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

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

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

Adrenal medullary tumors

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)

Familial syndromes associated with pheochromocytomas

Pheochromocytoma• Clinical features:

1. Increase catecholamine release2. Hypertension, young, often refractory to treatment3. Paroxysmal, with relatively normal blood pressure between surges4. Classical triad of symptoms includes headache, diaphoresis and palpitations

or tachycardia5. Less commonly anxiety, tremulousness, pain in the chest or abdomen,

weakness or weight loss6. Severe constipation or pseudo-obstruction may occur because

catecholamines may inhibit peristalsis7. 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 100gm4. Richly vascularized fibrous trabeculae within

the tumor produce a lobular pattern5. 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:

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

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: • 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

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 ofnumerous collections of abnormal but fully mature ganglion cells, often having more than one nucleus

# Union for International Cancer Control## European Network for the Study of Adrenal Tumors

** Adjacent organs include kidney, diaphragm, great vessels, pancreas, and liver

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