The Adrenal Glands

Th J b M DThomas Jacobs, M.D.Diane Hamele-Bena, M.D.

I. Normal adrenal gland: Gross and microscopic features

II. Hypoadrenalism

III. Hyperadrenalism

IV. Adrenal cortical neoplasms

V. Adrenal medulla

Normal Adrenal Gland

• Normal adult adrenal gland: 3.5 - 4.5 grams

Normal Adrenal Gland

• Normal adult adrenal gland: 3.5 - 4.5 grams

Adrenal Cortex Morphology

• Cortex: 3 zones:– Glomerulosa– Fasciculata– Reticularis

Hypoadrenalismyp

Hypoadrenalism

• Primary Adrenocortical Insufficiency

D t i f il f d l l d–Due to primary failure of adrenal glands

–ACTH is elevated

• Secondary Adrenocortical Insufficiency

–Due to disorder of hypothalamus or pituitaryDue to disorder of hypothalamus or pituitary–ACTH is decreased

HypoadrenalismClinical ManifestationsClinical Manifestations

•Fatigue, weakness, depression

•Anorexia

•Dizziness

•N&V, diarrhea

•Hyponatremia, hyperkalemia

•Hypoglycemia

•HyperpigmentationHyperpigmentation

HypoadrenalismCli i l M if t tiClinical ManifestationsPrimary adrenal insufficiency:y y

Deficiency of glucocorticoids, mineralocorticoids, and androgens

HypoglycemiaF ti

HyponatremiaH k l i

Reduced pubic d illFatigue

AnorexiaWeight loss

HyperkalemiaHypotensionDizziness

and axillaryhair in women

g Dizziness

HypoadrenalismCli i l M if t tiClinical ManifestationsPrimary adrenal insufficiency:y y

Concomitant hypersecretion of ACTH

Hyperpigmentation

HypoadrenalismCli i l M if t tiClinical Manifestations

Secondary adrenal insufficiency:Secondary adrenal insufficiency:Deficiency of ACTH

NO hyperpigmentation

Pathology of Hypoadrenalism

• Primary Adrenocortical Insufficiency– AcuteAcute

•Waterhouse-Friderichsen SyndromeAcute hemorrhagic necrosis, most often due to Meningococci

– Chronic = Addison Disease

• Secondary Adrenocortical Insufficiency• Secondary Adrenocortical Insufficiency

Pathology of Hypoadrenalism

• Primary Adrenocortical Insufficiency– AcuteAcute

•Waterhouse-Friderichsen SyndromeAcute hemorrhagic necrosis, most often due to Meningococci

– Chronic = Addison Disease•Autoimmune adrenalitis•Infections (e g tuberculosis fungi)•Infections (e.g., tuberculosis, fungi)•Metastatic tumors•Other: Amyloidosis, hemochromatosis

Addison DiseaseCli i l fi diClinical findings

Mineralocorticoid deficiency Glucocorticoid deficiencyy•Hypotension•Hyponatremia

•Weakness and fatigue•Weight loss

•Hyperkalemia •Hyponatremia•HypoglycemiaPi t ti

Androgenic deficiencyL f bi d ill

•Pigmentation•Abnormal H2O metabolism•Irritability and mental•Loss of pubic and axillary

hair in women•Irritability and mental sluggishness

Autoimmune AdrenalitisThree settings:

•Autoimmune Polyendocrine Syndrome type 1 (APS1) = Autoimmune Polyendocrinopathy, Candidiasis, and Ectodermal Dysplasia (APECED)

•Autoimmune Polyendocrine Syndrome type 2 (APS2)

•Isolated Autoimmune Addison Disease

Pathologic Changes in Autoimmune Adrenalitis

•Gross:V ll l d (1 1 5 )–Very small glands (1 - 1.5 grams)

–Cortices markedly thinned

•Micro:–Diffuse atrophy of all cortical zones–Lymphoplasmacytic infiltrate–Medulla is unaffected

Pathology of Hypoadrenalism

• Primary Adrenocortical Insufficiency– AcuteAcute

• Waterhouse-Friderichsen Syndrome

– Chronic = Addison Disease• Secondary Adrenocortical Insufficiency

– Any disorder of the hypothalamus or pituitary leading to diminished ACTH; e.g., infection; pituitary tumors, including metastatic carcinoma; irradiation

Hyperadrenalismyp

Hyperadrenalism

Three distinctive clinical syndromes:y

•Excess cortisol: Cushing Syndrome•Excess aldosterone: Conn Syndrome •(Excess androgens: Adrenogenital or Virilizing Syndrome)

Hyperadrenalism

I li i l ti t fIn clinical practice, most cases of Cushing Syndrome are the result of

administration of exogenous glucocorticoidsadministration of exogenous glucocorticoids(“exogenous” or iatrogenic Cushing Syndrome).

Cushing Syndrome

Endogenous

Complete this diagram during the lecture!

Exogenous

during the lecture!

Exogenous (Iatrogenic)

“Endogenous” Cushing SyndromeEtiology Pathology

hiI. ACTH-dependent:

i i d•Cushing Disease Pituitary adenoma

Adrenal cortical hyperplasia

•Ectopic ACTH production Extra-adrenal ACTH-producing tumor

yp p

II ACTH i d d t

Adrenal cortical hyperplasia

•Hypersecretion of cortisol by adrenal neoplasm

II. ACTH-independent:Adrenal neoplasm

Cushing Syndrome

Pituitary adenoma

Ad l i l

Dorsal fat pad

Ecchymoses

Moon face

Adrenal corticalhyperplasia Thin skin Striae

CO

Thin arms & legs

Pendulousabdomen

RTIACTH-producing tumor

Thin arms & legsSOL

Poor woundhealing

Adapted from Netter

Adrenalcarcinoma

Adrenal adenoma

g

Cushing SyndromeHydrocortisone Excess•Abnormal fat distribution

–Moon face •HirsutismAdrenal Androgen Excess

–Central obesity•Increased protein catabolism

–Thin skin

Hirsutism•Deepened voice in women•Acne•Abnormal menses

–Easy bruisability–Striae–Osteoporosis with

b o a e ses

vertebral fractures–Impaired healing–Muscle wasting •Hypokalemia with alkalosis

Mineralocorticoid Excess

–Suppressed response toinfection

•Diabetes

yp•Usually occurs in cases

of ectopic ACTH production

•Psychiatric symptoms

Pathology of Primary Hyperaldosteronism

• Aldosterone-secreting adenoma

Ad l i l i

– Conn Syndrome

• Adrenal cortical carcinoma– Uncommon cause of hyperaldosteronism

Conn SyndromeConn Syndrome

•Hypertension•Hypertension•Polydipsia•PolyuriaAldosterone

Adrenal

•Hypernatremia•Hypokalemia

adenoma

Adapted from Netter

C i l N lCortical Neoplasms

i i *Adenomas and Carcinomas

Functioning *

N f ti iNon-functioning

* May produce:• Cortisol• Sex steroids

(Cushing Syndrome))Sex steroids

• Aldosterone (Conn Syndrome))

Cortical NeoplasmsCortical Neoplasms

• Adenomas • Carcinomas

• Discrete, but often unencapsulated • Usually unencapsulated

– Gross: – Gross:

• Small (up to 2.5 cm)• Most <30 grams• Yellow-orange, usually without

• Large (many >20 cm)• Frequently > 200-300 grams• Yellow, with hemorrhagic,g , y

necrosis or hemorrhage, g ,

cystic, & necrotic areas

– Micro: – Micro:• Lipid-rich & lipid-poor cells with

little size variation• Ranges from mild atypia to

wildly anaplastic

Adrenal Medulla

Adrenal Medulla

• Specialized neural crest (neuroendocrine) cells• Part of the chromaffin system, which includes the

adrenal medullae & paraganglia• Major source of catecholamines (epi, norepi, &

dopamine)

Tumors of the Adrenal MedullaTumors of the Adrenal Medulla

• Neuroblastoma• Ganglioneuroblastoma• Ganglioneuroma

• Pheochromocytoma

N blNeuroblastoma

• Poorly differentiated malignant neoplasm derived from neural crest cellsfrom neural crest cells

• Usually occurs in infants & small children“S ll d bl ll t ” f hildh d• “Small round blue cell tumor” of childhood

Rhabdomyosarcoma LymphomaRetinoblastoma Wilms tumorEwing sarcoma/PNET Medulloblastoma

Neuroblastoma: Pathology• Gross:

– Large tumor with hemorrhage, necrosis, & calcification

• Micro:• Micro:– Undifferentiated small cells resembling lymphocytes

(“Small round blue cell tumor”)( Small, round, blue cell tumor )– May show areas of differentiation (larger cells with

more cytoplasm and Schwannian stroma)more cytoplasm and Schwannian stroma)

Neuroblastoma: Prognostic Factors• Patient age

g

• Stage• Site of 10 involvement• Histologic grade• DNA ploidy• N-myc oncogene amplification• Others: Chromosome 17q gain, Chromosome 1p loss, Trk-A q g p

expression, Telomerase expression, MRP expression, CD44 expression

Ganglioneuroma

• Differentiated neoplasm of neural crest origin• Benign• Occurs in older age groupOccurs in older age group• Pathology:

G E l t d hit fi– Gross: Encapsulated, white, firm– Micro: Ganglion cells & Schwann cells

Ganglioneuroblastomag

• Composed of malignant neuroblastic elements & ganglioneuromatous elements

• Prognosis depends on % of neuroblasts

PheochromocytomaPheochromocytoma

• Catecholamine secreting neoplasm: HYPERTENSION• Rare, but important: surgically curable form of

hypertension

• Catecholamine-secreting neoplasm: HYPERTENSION

hypertension

• May arise in association with familial syndromes, e.g., MEN2 von Hippel Lindau von Recklinghausen (NF1)MEN2, von Hippel-Lindau, von Recklinghausen (NF1)

• May be “sporadic”: ~24% have germline mutations, including mutations of RET VHL SDH B and SDH D genesincluding mutations of RET, VHL, SDH-B, and SDH-D genes

• Extra-adrenal tumors (e.g., carotid body) are called “paragangliomas”paragangliomas

Ph h P h lPheochromocytoma: Pathology

• Gross:– 1 - 4000 grams (average = 100 grams)

A f h h i & ti d ti– Areas of hemorrhage, necrosis, & cystic degeneration

• Micro:– Balls of cells resembling cells of medulla, with bizarre,

hyperchromatic nuclei; richly vascular stroma

• Benign & malignant tumors are histologically identical; the only absolute criterion for malignancy is metastasis.