The Adrenal Glands - Columbia University

The Adrenal GlandsThomas Jacobs, M.D.Diane Hamele-Bena, M.D.I. Normal adrenal glandA. Gross & microscopicB. Hormone synthesis, regulation & measurementII. Hypoadrenalism-- Break -III. Hyperadrenalism; Adrenal cortical neoplasmsIV. Adrenal medulla1

Normal Adrenal Gland Normal adult adrenal gland: 3.5 - 4.5 gramsAdrenal Cortex Morphology Cortex: 3 zones:– Glomerulosa– Fasciculata– Reticularis2

CapsuleG lomerulosaCORF asciculataTEXReticularisFasciculataReticularis3

Hormone synthesis, regulation,and measurements4

HypoadrenalismHypoadrenalism Primary Adrenocortical Insufficiency–Due to primary failure of adrenal glands–ACTH is elevated Secondary Adrenocortical Insufficiency–Due to disorder of hypothalamus or pituitary–ACTH is decreased5

HypoadrenalismClinical Manifestations Fatigue, weakness, depression Anorexia Dizziness N&V, diarrhea Hyponatremia, hyperkalemia Hypoglycemia HyperpigmentationHypoadrenalismClinical ManifestationsPrimary adrenal insufficiency:Deficiency ofglucocorticoids, mineralocorticoids, and ght duced pubicand axillaryhair in women6

HypoadrenalismClinical ManifestationsPrimary adrenal insufficiency:Concomitant hypersecretion of ACTHMSH-like effectHyperpigmentationHypoadrenalismClinical ManifestationsSecondary adrenal insufficiency:Deficiency of ACTHNO hyperpigmentation Aldosterone secretion is usually normal and the reninangiotensin system is preserved, so NO hyperkalemia Other manifestations of hypopituitarism may also be present,e.g., other endocrine deficiencies & visual field defects7

Pathology of Hypoadrenalism Primary Adrenocortical Insufficiency– Acute Waterhouse-Friderichsen SyndromeAcute hemorrhagic necrosis, most often due to Meningococci– Chronic Addison Disease Secondary Adrenocortical InsufficiencyWaterhouse-Friderichsen SyndromeMassive adrenalhemorrhage Hypotension Purpura CyanosisMeningococciAdapted from Netter8

Waterhouse-Friderichsen SyndromeWaterhouse-Friderichsen Syndrome9

Pathology of Hypoadrenalism Primary Adrenocortical Insufficiency– Acute Waterhouse-Friderichsen SyndromeAcute hemorrhagic necrosis, most often due to Meningococci– Chronic Addison Disease Autoimmune adrenalitis Tuberculosis AIDS Metastatic tumors Other: fungi, amyloidosis, hemochromatosisAddison DiseaseClinical findingsMineralocorticoid deficiency Hypotension Hyponatremia HyperkalemiaGlucocorticoid deficiencyAndrogenic deficiency Weakness and fatigue Weight loss Hyponatremia Hypoglycemia Pigmentation Abnormal H2O metabolism Loss of pubic and axillaryhair in women Irritability and mentalsluggishness10

Autoimmune AdrenalitisThree settings: Autoimmune Polyendocrine Syndrome type 1 (APS1) Autoimmune Polyendocrinopathy, Candidiasis, andEctodermal Dysplasia (APECED) Autoimmune Polyendocrine Syndrome type 2 (APS2) Isolated Autoimmune Addison DiseasePathologic Changes in Autoimmune Adrenalitis Gross:–Very small glands (1 - 1.5 grams)–Cortices markedly thinned Micro:–Diffuse atrophy of all cortical zones–Lymphoplasmacytic infiltrate–Medulla is unaffected11

Tuberculosis involving adrenalMultinucleated giant cellsCortex and medulla are affectedMetastatic carcinoma in adrenalTumor12

Pathology of Hypoadrenalism Primary Adrenocortical Insufficiency– Acute Waterhouse-Friderichsen Syndrome– Chronic Addison Disease Secondary Adrenocortical Insufficiency– Any disorder of the hypothalamus or pituitary leadingto diminished ACTH; e.g., infection; pituitary tumors,including metastatic carcinoma; irradiationDiagnosis of Hypoadrenalism13

Hyperadrenalism14

HyperadrenalismThree distinctive clinical syndromes: Cushing Syndrome: excess cortisol Hyperaldosteronism Adrenogenital or Virilizing Syndrome: excess androgensHyperadrenalismIn clinical practice, most cases ofCushing Syndrome are the result ofadministration of exogenous glucocorticoids(“exogenous” or iatrogenic Cushing Syndrome).15

Cushing SyndromeEndogenousPituitary adenomaAdrenal neoplasm or hyperplasiaExogenous(Iatrogenic)ACTH-producing tumor“Endogenous” Cushing SyndromeEtiologyI. ACTH-dependent: Cushing DiseasePathologyPituitary adenoma or hyperplasiaAdrenal cortical hyperplasia Ectopic ACTH productionExtra-adrenal ACTH-producing tumorAdrenal cortical hyperplasiaII. ACTH-independent: Hypersecretion of cortisol byadrenal neoplasm orautonomous adrenal corticalhyperplasiaAdrenal neoplasm or corticalhyperplasia16

Cushing SyndromeDorsal fat padPituitary adenomaMoon faceEcchymosesAdrenal corticalhyperplasiaACTH-producing tumorCORTISOLThin skinStriaePendulousabdomenThin arms & legsPoor woundhealingAdrenalcarcinomaAdrenaladenomaAdapted from NetterCushing SyndromeHydrocortisone Excess Abnormal fat distribution–Moon face–Central obesity Increased protein catabolism–Thin skin–Easy bruisability–Striae–Osteoporosis withvertebral fractures–Impaired healing–Muscle wasting–Suppressed response toinfection Diabetes Psychiatric symptomsAdrenal Androgen Excess Hirsutism Deepened voice in women Acne Abnormal mensesMineralocorticoid Excess Hypokalemia with alkalosis Usually occurs in casesof ectopic ACTH production17

Cushing DiseaseUsually not so large!Pituitary adenomaAdrenal cortical hyperplasiaCortexNormalCortical hyperplasia18

Adrenal cortical adenomaTumorAdrenal glandPathology of Primary Hyperaldosteronism Aldosterone-secreting adenoma– Conn Syndrome Bilateral idiopathic cortical hyperplasia Adrenal cortical carcinoma– Uncommon cause of hyperaldosteronism19

Conn Syndrome Hypertension Polydipsia Polyuria Hypernatremia HypokalemiaAldosteroneAdrenaladenomaAdapted from NetterCortical NeoplasmsFunctioning *Adenomas and CarcinomasNon-functioning* May produce: Cortisol (Cushing Syndrome)) Sex steroids Aldosterone (Conn Syndrome))20

Cortical Neoplasms Adenomas Carcinomas– Gross: – Gross:Discrete, but often unencapsulatedSmall (up to 2.5 cm)Most 30 gramsYellow-orange, usually withoutnecrosis or hemorrhage– Micro: Usually unencapsulatedLarge (many 20 cm)Frequently 200-300 gramsYellow, with hemorrhagic,cystic, & necrotic areas– Micro: Lipid-rich & lipid-poor cells withlittle size variation Ranges from mild atypia towildly anaplasticAdrenal cortical adenomaResidual adrenal gland21

Adrenal cortical adenomaAdrenal cortical carcinomaTumorKidney22

Adrenal cortical carcinomaMitosisDiagnosis of Hyperadrenalism23

Adrenal Medulla24

Adrenal Medulla Specialized neural crest (neuroendocrine) cells Part of the chromaffin system, which includes theadrenal medullae & paraganglia Major source of catecholamines (epi, norepi, &dopamine)Paraganglion SystemCarotid bodiesAortic bodiesThoracic sympatheticparagangliaAdrenal medullaeAortic sympatheticparagangliaVisceral autonomicparaganglia25

Adrenal MedullaTumors of the Adrenal Medulla Neuroblastoma Ganglioneuroblastoma Ganglioneuroma Pheochromocytoma26

omaMALIGNANTNeuroblastoma Poorly differentiated malignant neoplasm derivedfrom neural crest cells Usually occurs in infants & small children “Small round blue cell tumor” of childhoodRhabdomyosarcomaRetinoblastomaEwing sarcoma/PNETLymphomaWilms tumorMedulloblastoma27

Neuroblastoma: primary sites Head Neck Chest Adrenal Abdomen, nonadrenal Pelvis Other sites & unknown2%5%13% 40%18%4%21%Neuroblastoma: Pathology Gross:– Large tumor with hemorrhage, necrosis, &calcification Micro:– Undifferentiated small cells resembling lymphocytes(“Small, round, blue cell tumor”)– May show areas of differentiation (larger cells withmore cytoplasm and Schwannian stroma)28

NeuroblastomaNeuroblastoma29

Neuroblastoma: Prognostic Factors Patient ageStageSite of 10 involvementHistologic gradeDNA ploidy N-myc oncogene amplification Others: Chromosome 17q gain, Chromosome 1p loss, Trk-Aexpression, Telomerase expression, MRP expression, CD44expressionGanglioneuroma Differentiated neoplasm of neural crest originBenignOccurs in older age groupPathology:– Gross: Encapsulated, white, firm– Micro: Ganglion cells & Schwann cells30

GanglioneuromaGanglioneuroblastoma Composed of malignant neuroblastic elements &ganglioneuromatous elements Prognosis depends on % of neuroblasts31

GanglioneuroblastomaPheochromocytoma Catecholamine-secreting neoplasm: HYPERTENSION Rare, but important: surgically curable form ofhypertension May arise in association with familial syndromes, e.g.,MEN2, von Hippel-Lindau, von Recklinghausen (NF1) May be “sporadic”: 24% have germline mutations,including mutations of RET, VHL, SDH-B, and SDH-D genes Extra-adrenal tumors (e.g., carotid body) are called“paragangliomas”32

Pheochromocytoma: Pathology Gross:– 1 - 4000 grams (average 100 grams)– 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.PheochromocytomaResidual adrenalTumor33

PheochromocytomaPheochromocytoma:Clinical aspects34

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Adapted from Netter Adrenal carcinoma Adrenal adenoma Pituitary adenoma Adrenal cortical hyperplasia Dorsal fat pad Ecchymoses Thin skin Thin arms & legs Poor wound healing Moon face Striae Pendulous abdomen C O R T I S O L Cushing Syndrome ACTH-producing tumor Hydrocortisone Excess