Adrenal gland and paraganglia - Printer Friendly Version
Last revised 7 April 2007.
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Table of Contents-Adrenal gland
Primary references, anatomy, embryology, histology, grossing, adrenal cortex-physiology
Congenital anomalies: accessory adrenal tissue, adrenal cytomegaly, adrenal hypoplasia, adrenal union or adhesion, Beckwith-Wiedemann syndrome, congenital adrenal hyperplasia, hereditary ACTH unresponsiveness, storage diseases
Adrenal insufficiency: primary-general, secondary, Addison’s disease, amyloidosis, autoimmune adrenalitis, drugs, infections, isolated mineralocorticoid deficiency, polyglandular autoimmune syndromes, radiation, Waterhouse-Friderichsen syndrome,
Adrenal hyperfunction/hyperplasia: general, Cushing’s syndrome, hyperaldosteronism, acquired hyperplasia, macronodular hyperplasia, micronodular hyperplasia, pigmented hyperplasia, unilateral hyperplasia
Adrenocortical adenoma: children, adenoma-general, oncocytoma, corticomedullary mixed tumor
Other benign cortical lesions: adenomatoid, cysts, focal adrenalitis, hemangioma, malakoplakia, massive macronodular adrenocortical disease, myelolipoma, ovarian thecal metaplasia, solitary fibrous tumor
Adrenocortical carcinoma: general, staging, features to report
Adrenal medulla: physiology, hyperplasia, tumors-general, malignant melanotic tumors, pheochromocytoma
Neuroblastic tumors: general, ganglioneuroblastoma, ganglioneuroma, neuroblastoma, staging, prognostic factors, grossing
Other adrenal malignancies: angiosarcoma, Ewing’s/PNET, leiomyosarcoma, lymphoma, metastases, plasmacytoma
Paraganglia: general, hyperplasia, paraganglioma, paraganglioma-report
American Journal of Surgical Pathology (AJSP), March 1977 to February 2005
Archives of Pathology and Laboratory Medicine (Archives), January 1976 to February 2005
Human Pathology (Hum Path), March 1970 to November 2004
Modern Pathology (Mod Path), Jan 1988 to February 2005
Atlas of Nontumor Pathology, Series I: Endocrine Disease; AFIP, 2002
Rosai, J: Ackerman’s Surgical Pathology (9th Ed); 2004
Sternberg, S: Diagnostic Surgical Pathology (4th Ed); Lippincott Williams & Wilkins, 2004
University of Pittsburgh case histories: through #417
Journal search terms: adrenal, paraganglia, paraganglioma
Please refer to these primary references for more detailed discussions and photographs
A composite of two neuroendocrine organs, the adrenal cortex (mesodermal) and adrenal medulla (neuroectodermal)
Also called suprarenal glands
Left and right-sided glands; left gland is crescentic and right gland is pyramidal in adults; each is 5 x 3 x 1 cm
On superiomedial kidneys in retroperitoneum
Gland has head (medial), body (middle) and tail (lateral)
Normal weight 4-6 grams each after dissection of fat; acute stress reduces lipid content and weight; prolonged stress induces hypertrophy and hyperplasia and increases weight
Has complete fibrous capsule, which may merge with capsule of kidney (either gland), and liver (right sided gland)
Cortex is bright yellow due to lipid; zona reticularis is thinner and darker
Medulla has ellipsoid shape, is gray-tan and <10% of gland volume (1% in neonates); is more prominent with cortical atrophy; majority of medulla is within head of gland
Neonatal gland is dark red-brown due to congestion, with no visible medullary tissue
Adrenal glands are supplied by three arteries, drained by shorter right adrenal vein and longer left adrenal vein
Lymphatics only in capsule, not elsewhere
By day 25 of gestation, bilateral adrenal primordium develops as cords of large polyhedral cells in coelomic epithelium medial to mesonephros and urogenital ridge
By day 45, adrenal glands enlarge to 1 mg, and primitive sympathetic cells with nerve tracts migrate to form medulla
By week 7, paraganglionic cells replicate and differentiate into chromaffin cells; primitive sympathicoblasts form neuroblastic nodules that peak at weeks 17-20 and usually regress; persistent nodules may be confused with small neuroblastomas
By week 8, each gland weighs 4 mg, with outer (definitive) cortex distinct from inner (fetal) cortex
Inner (fetal) cortex has large eosinophilic cells mixed with small nodules of primitive neuroblastic cells, represents 75% of cortical volume at birth, but then involutes due to apoptosis, with only stroma present by one year
By week 20, adrenals are larger than kidneys, and composed mostly of fetal cortex
At birth, each adrenal gland weights 5 grams
Premature, stillborn and some neonates with in utero stress have microscopic cystic changes in adrenal glands
Adrenal cortex
Normal cortex in adults is 2 cm thick
Adrenal cortex anatomical zones (“gfr”):
Zona glomerulosa: just beneath the adrenal capsule; composed of small clusters and short trabeculae of relatively small, well defined cells, less cytoplasm than other cortical cells, lipid-poor, 15% of cortical volume
Zona fasciculata: forms broad band of large cells with distinct membranes arranged in cords two cells wide; cytoplasm has numerous small lipid vacuoles which may indent the central nucleus and resemble lipoblasts, 70-80% of cortical volume, lipid stores are depleted by ACTH
Zona reticularis: grossly brown; haphazardly arranged cells, smaller than zona fasciculata cells, with granular and eosinophilic cytoplasm with lipofuscin but minimal lipid; thinner than zona glomerulosa or fasciculata
Cortical extrusions: common into periadrenal fat; usually maintain attachment to adrenal gland
Cortical cuff: adrenal cortical cells around adrenal central vein and its branches
Cytology: may have aggregates of bare nuclei resembling metastatic small cell carcinoma (Mod Path 1991;4:594)
Positive stains: low molecular weight cytokeratin, alpha inhibin, MelanA/A103, bcl2, synaptophysin (weak), variable vimentin
Negative stains: chromogranin, epinephrine
EM: zona glomerulosa-sparse intracellular lipid, elliptical mitochondria with lamellar (plate-like) cristae; may have microvillous projections; no/rare lysosomes, lipofuscin or smooth endoplasmic reticulum
EM: zona fasciculata-round/oval mitochondria with short and long tubular cristae; prominent lipid droplets, prominent smooth endoplasmic reticulum, moderate amounts of rough endoplasmic reticulum, microvillus cytoplasmic projections, more lysosomes than zona glomerulosa
EM: zona reticularis-spherical/ovoid mitochondria with short and long tubular invaginations of inner membrane; abundant lipofuscin granules, lysosomes and microvilli; sparse lipid droplets
Adrenal medulla
Composed of neural crest cells called chromaffin cells (also called pheochromocytes, medullary cells) with a multilineage differentiation potential; also sustentacular cells
Chromaffin cells: arranged in small nests and cords separated by prominent vasculature; take up chromium salts strongly, turn brown-black after exposure to Zenker’s solution (potassium dichromate); large polygonal cells with poorly outlined borders, abundant granular and usually basophilic cytoplasm, mild variation in cell size; occasionally has PAS+ hyaline droplets
Sustentacular cells: supporting cells, spindle cells at periphery of nests of chromaffin cells; associated with rich vasculature; S100+, difficult to identify with routine staining
Ganglion cells: occasional single cells or small clusters associated with myelinated nerve bundles
Central vein: has thick wall of smooth muscle
Positive stains: chromogranin, synaptophysin, neurofilament, tyrosine hydroxylase, epinephrine, S100 (sustentacular cells)
Negative stains: keratin, vimentin
EM: numerous mitochondria; norepinephrine producing cells have 250 nm electron opaque neurosecretory granules, with prominent halo between granule membrane and dense core; epinephrine producing cells have 190 nm finely granular neurosecretory granules, filling the enclosing membrane and no halo; moderate amount of rough endoplasmic reticulum, interdigitating blunt cytoplasmic processes with poorly developed cell junctions; sustentacular cells have moderate amounts of rough endoplasmic reticulum and occasional lipid droplets, but no neurosecretory granules
Protocol for examining specimens (nothing unusual compared to other specimens), Archives 2000;124:17
Adrenal cortex: synthesizes and secretes corticosteroids (mineralocorticoids, glucocorticoids and sex hormones), all derived from cholesterol
Zona glomerulosa (outer): produces mineralocorticoids (aldosterone-increases sodium and water absorption and potassium secretion)
Zona fasciculata (middle): produces glucocorticoids, some sex hormones
Zona reticularis (inner): produces estrogens and androgens, some glucocorticoids
Normal pathways of hormone production in adrenal cortex (via cytochrome P450 enzymes):
Circulating low-density lipoproteins are internalized into cortical cells, lipoproteins are hydrolyzed, producing cholesterol esters, which break down to cholesterol and free fatty acids
Cholesterol => 20 alpha hydroxycholesterol => (via 20,22 desmolase complex)
pregnenolone => progesterone - (21) => 11 deoxycorticosterone => corticosterone => aldosterone
| (17) | (17)
17 alpha hydroxyprogesterone => (21) - deoxycortisol => cortisol
|
dihydroxyepiandrosterone => androstenedione => estradiol 17 beta
|
testosterone
17: 17 hydroxylase
21: 21 hydroxylase
Extra-adrenal regulation
Hypothalamic corticotropin-releasing hormone (CRH) enters hypophyseal portal system, reaches anterior pituitary gland, stimulates release of ACTH
ACTH travels in blood to adrenal cortex, is bound to cortical cell membranes, activates intracytoplasmic cyclases that form cAMP and GMP; both cortisol and ACTH inhibit release of CRH, and cortisol also inhibits secretion of ACTH
ACTH normally is secreted episodically, with more and longer episodes in early morning, and nadir in evening; this pattern causes circadian rhythm for cortisol seen in normals
Volume changes affect renin-angiotensin system, leading to aldosterone secretion
ACTH, potassium ions and aldosterone-stimulating factor also regular aldosterone synthesis
Fetal adrenal gland lacks 3 beta hydroxysteroid dehydrogenase (converts pregnenolone to progesterone); as a result produces abundant dihydroepiandosterone, but little cortisol
Types of hormones:
Autocrine: hormone binds to receptors on cell that produces it
Paracrine: hormone binds to receptors of nearby cells of a different type
Endocrine: hormone acts on target organs distant from site of synthesis
Hormones are either signaling molecules that interact with cell surface receptors or steroids that interact with intracellular receptors; signaling molecules often act via second messengers, such as cAMP, inositol triphosphate, or calcium levels
Congenital anomalies
Nests of adrenal tissue located away from adrenal gland
Also called heterotopia, although technically this term refers to displacement to an abnormal location, not the presence of accessory tissue elsewhere in body
Due to migration of adrenocortical primordial cells with gonads
Usually without accompanying medullary tissue; cases near celiac ganglion may also contain medullary tissue
Retroperitoneal space along urogenital ridge, beyond renal capsule in upper pole, hilum of ovary or testes, along course of spermatic cord
Present in 1% of inguinal hernia sacs
May be accompanied by malformation of epididymis
May be fused with liver or kidney and surrounded by a common capsule
May undergo same disease processes as ordinary adrenal glandular tissue
DD: metastatic renal cell carcinoma or other clear cell tumors
Non-adrenal tissue present in adrenal gland
Very rare (except for metastases)
Case report of benign intraadrenal thyroid tissue (Hum Path 1999;30:105)
Relatively common finding within fetal cortex in newborns, particularly premature infants (3-7%) or infants with Rh incompatibility
May be associated with Beckwith-Wiedemann syndrome
Cells do NOT represent carcinoma in situ
Case reports: occurrence in two apparently normal adults (Archives 1986;110:1072)
Gross: hyperplastic adrenal glands
Micro: numerous markedly enlarged (up to 150 microns) and bizarre polyhedral cells with eosinophilic granular cytoplasm and large hyperchromatic nuclei with pseudoinclusions in adrenal cortex; no/rare mitotic figures
DD: CMV infection (usually infants, basophilic cytoplasm, large intranuclear inclusion surrounded by a clear halo)
References: Archives 1981;105:358 (pseudoinclusions)
Congenital aplasia is very rare; found in 10% with unilateral renal agenesis
Bilateral hypoplasia is associated with anencephaly due to lack of ACTH cells; causes adrenal insufficiency
Unilateral absence occurs in 1 per 10,000 live births
May be associated with sudden infant death syndrome (Archives 1977;101:168)
Infant symptoms: weight loss, vomiting, dehydration, severe electrolyte disturbances-due to adrenal insufficiency
Primary hypoplasia: X linked, associated with mutations or deletions of DAX-1 gene at Xp21; cortex is hypoplastic, but fetal zone is intact, often has cytomegalic features; associated with hypogonadotrophic hypogonadism in young men
Miniature adult type of hypoplasia: sporadic or autosomal recessive; small glands but normal architecture
Gross: small for age adrenal glands, decreased fetal zone in newborns, scattered cytomegalic cells, cells have decreased lipid
DD: chronic exogenous glucocorticoids causes acquired hypoplasia
Rare
Adrenal union (fusion): adrenal glands are fused above the aorta with butterfly or horseshoe shape, with common connective tissue capsule and intermingling of cells; associated with midline congenital defects, including spinal dysraphism, indeterminate visceral situs, bilateral renal agenesis, Cornelia de Lange syndrome (mental and growth retardation, low set ears, antiverted nostrils, spade-like hands with short tapering fingers); normal histology
Unions also to kidney or liver in 0.4-3.0% of unselected autopsies; common capsule, but no intermingling of cells
Adrenal adhesion: adrenal gland is attached to opposite adrenal gland, but with an intervening connective tissue capsule
Visceromegaly, gigantism, macroglossia, abdominal wall defects, craniofacial abnormalities, midfacial hypoplasia, adrenocortical hyperplasia
Incidence of 1 per 13,000 births, usually sporadic
May have brain damage due to hypoglycemia, causing mental retardation or death
May develop Wilm’s tumor, adrenocortical carcinoma, neuroblastoma, pancreatoblastoma, pheochromocytoma
Due to abnormality of 11p15.5
Gross: enlarged adrenal glands up to 16g, may be cerebriform and nodular
Micro: bilateral cytomegaly with large and pleomorphic nuclei and cytoplasmic nuclear pseudoinclusions; also medullary hyperplasia; variable hemorrhagic macrocysts
Congenital adrenal hyperplasia
Various autosomal recessive syndromes due to enzyme deficiencies in biosynthesis of adrenal steroids, diverting production to other pathways and causing elevated ACTH levels and adrenocortical hyperplasia
No gender preference, usually presents in children, rarely in adults
Symptoms depend on specific defect; include salt wasting, virilization, adrenogenital syndrome, hypertension
Salt wasting syndrome: usually evident soon after birth (in utero, maternal kidneys maintain electrolytes and fluids); hypotension due to decreased serum sodium and increased serum potassium [from lack of aldosterone production], acidosis, cardiovascular collapse, death
Simple virilizing syndrome: easier to detect in females (clitoral hypertrophy) than males
Nonclassic virilizing syndrome: more common than simple virilizing syndrome; asymptomatic or only hirsutism
Adrenogenital syndrome: adrenal secretes excess androgens, causing changes towards adult masculinity in children or female adults; 50% occur before puberty, 80% are female; diagnosed based on elevated dehydroepiandrosterone; rarely associated with male adult feminization due to increased 17-ketosteroids
Congenital adrenal hyperplasia tumors:
Virilization in adult women is usually associated with carcinoma, particularly if Cushing’s syndrome also present
Feminization in adult men is almost always associated with carcinoma
Congenital adrenal hyperplasia is associated with testicular tumors that arise from ectopic adrenal cortical rests (Archives 2000;124:785), and rarely with similar ovarian tumors (AJSP 2001;25:1443)
21-hydroxylase deficiency: causes 95% of cases; incidence of 1 per 5,000 to 14,500 births (1 in 60 in the normal population are heterozygotes); block in production of aldosterone and cortisol leads to accumulation of 17-hydroxypregnenolone and its catabolite pregnanetriol, also high plasma ACTH; causes virilizing syndrome, cortisol deficiency and variable salt wasting syndrome; also Leydig cell hyperplastic nodules without Reinke crystalloids
Nonclassic 21-hydroxylase deficiency: very common autosomal recessive disorder (1% incidence in parts of US), with mild cortisol deficiency, excessive adrenal androgens, no salt wasting; usually diagnosed by early adulthood
11-beta hydroxylase deficiency: second most common form (5%), incidence of 1 per 100,000 live births; associated with increased androgens and deoxycorticosterone; causes virilization and hypertension
17-alpha hydroxylase deficiency: causes 1% of cases, all patients have female external genitalia due to increased deoxycorticosterone; also hypertension
3 beta hydroxysteroid dehydrogenase deficiency: impaired synthesis of all steroid hormones, adrenal gland is similar to normal fetus; patients present in early infancy with adrenal insufficiency, variable virilization in females
Congenital lipoid adrenal hyperplasia: very rare, low cortisol and aldosterone secretion, high levels of ACTH, FSH, LH and plasma rennin; present with severe adrenal insufficiency in neonatal period; usually die in infancy
Treatment: exogenous glucocorticoids and mineralocorticoids to provide cortisol and suppress ACTH levels, surgical correction of external genitalia
Gross: marked adrenal enlargement (15g each gland) with cerebriform appearance, tan-brown; secondary to elevated ACTH (due to reduced cortisol secretion)
Micro: diffuse cortical hyperplasia, particularly of zona reticularis-like compact cells
DD: bilateral hyperplasia due to ectopic ACTH (not grossly cerebriform, may have metastatic carcinoma, differentiate clinically)
Hereditary unresponsiveness to ACTH
Rare; due to abnormalities of ACTH receptor in adrenocortical cells
Seizures, hypoglycemia, muscle weakness, hyperpigmentation similar to Addison’s disease
Low plasma cortisol levels, increased serum ACTH
Micro: normal zona glomerulosa, atrophic zona fasciculata and reticularis
Adrenoleukodystrophy
Also called Addison-Schilder’s disease
Rare, X linked recessive, affects 1 in 120,000 males
Progressive demyelination of central and peripheral nervous system (dementia, blindness, quadriplegia) and adrenocortical insufficiency
Due to mutations of adrenoleukodystrophy protein (ADLP) in peroxisomal membrane at Xq28, which cause defective oxidation of long-chain fatty acids; cholesterol esters and gangliosides accumulate in membranes of adrenal cortex, brain, other organs
Diagnosis: presence of hexacosanoate and other very long-chain saturated fatty acids in cultured skin fibroblasts
Carriers: women may have a variant form of disease or no neurologic symptoms (Archives 1987;111:151)
Adrenomyeloneuropathy: related disorder with onset in teens to 20’s; adrenal insufficiency but no neurologic disorder at initial presentation; develop weakness, spasticity and distal polyneuropathy, slowly progressive
Treatment: dietary therapy (Lorenzo’s oil) may delay neurologic progression
Gross: atrophic adrenal glands, 1-2 g
Micro: ballooning and striation of zona fasciculata and reticularis cells, often in nodules; cells may have large cortical vacuoles and clefts (representing lipid dissolved during processing); medulla unchanged
Other: cerebral white matter exhibits demyelination, inflammation, gliosis and macrophages; also abnormalities of schwann cells in peripheral nerves and Leydig cells in testis
EM: proliferation of smooth endoplasmic reticulum and trilaminar lamellar inclusions
DD: autoimmune adrenalitis (lymphocytes and no balloon cells)
Pompe’s disease
Also called type II glycogenosis
Infantile form of generalized glycogenosis, due to deficiency of lysosomal acid alpha-1,4-glucosidase
Intralysosomal glycogen storage in CNS, heart, liver, skeletal muscle, thyroid, parathyroid, pituitary, pancreatic islets; also in adrenal cortex and medulla, with severe accumulation in zona fasciculata (Archives 1985;109:921)
Wolman’s disease
Primary familial xanthomatosis
Rare, autosomal recessive lipid storage disorder
Due to deficiency of lysosomal acid lipase, causing accumulation of triglycerides and cholesterol esters in liver, spleen and adrenal glands
Usually causes death by age 6 months
Gross: markedly enlarged adrenal glands with dystrophic calcifications but normal architecture
Micro: necrosis, fibrosis, calcification; zona fasciculata and reticularis cells have vacuolated cytoplasm
DD: Niemann-Pick disease, other storage diseases
Adrenal insufficiency
Primary acute adrenal insufficiency-general
Often insidious in onset, patients may present in shock due to increased stress
Causes:
(a) patients with chronic adrenal insufficiency (primary or secondary) and acute stress requiring immediate increase in steroids
(b) rapid withdrawal of exogenous steroids (i.e. no taper) or failure to increase steroids with acute stress
(c) massive adrenal hemorrhage destroying adrenal cortex due to anticoagulation, coagulopathy, newborns with physiologic deficiencies in prothrombin time
(d) hypotension/shock that causes mild or massive corticomedullary necrosis, including Waterhouse-Friderichsen syndrome
(e) infections that destroy substantial adrenal cortical tissue
(f) amyloidosis
(g) drugs, radiation
(h) autoimmune disorders (autoimmune adrenalitis or polyglandular autoimmune syndromes)
Patients usually live normal lives after diagnosis (depending on cause); may be at higher risk for heart failure, hypertension or osteopenia
Treatment: glucocorticoids, mineralocorticoids, IV fluids; in chronic patients, must give steroid boost during infections, prior to surgery or during pregnancy
Secondary adrenocortical insufficiency
Caused by any disorder of pituitary gland which decreases ACTH production and causes adrenal cortical atrophy
Causes: pituitary macroadenoma, craniopharyngioma, tuberculosis or other infections, sarcoidosis, lymphocytic hypophysitis, head trauma, aneurysms, postpartum pituitary necrosis (Sheehan’s syndrome), pituitary apoplexy, metastases; also mutations in pro-opiomelanocortin gene
Tertiary adrenocortical insufficiency: due to disorders of hypothalamus reducing release of corticotropin releasing hormone (CRH); some include this within secondary adrenocortical insufficiency
Similar atrophic changes are caused by exogenous steroids, which also decrease ACTH production
No hyperpigmentation since ACTH levels are low
Laboratory: serum aldosterone, sodium and potassium levels are usually normal, since they are controlled by renin-angiotensin axis, which is not under the control of ACTH; androgens and cortisol levels are low since their production is influenced by ACTH, although androgens are less affected in males since they are also produced by testis; hypoglycemia is more common than with primary adrenal insufficiency
May be associated with hypopituitarism
Treatment: exogenous ACTH; causes rise in serum cortisol levels; may also need to replace other pituitary hormones
Gross: atrophic adrenal glands with retention of architecture, often fibrotic capsule, bright yellow (due to lipid accumulation), prominent medulla
Micro: normal thickness of zona glomerulosa, thinner fasciculata and reticularis; usually no lymphoplasmacytic infiltration
Also called primary chronic adrenal insufficiency
No symptoms until 90% of cortex is compromised; affects 3-6 individuals per 100,000 population
More common in white women
Causes: autoimmune disorders, infections (Histoplasma, Coccidiodes, tuberculosis), space occupying lesions (metastases, lymphomas), hemorrhage, amyloid, sarcoid, hemochromatosis
Symptoms: progressive weakness, easy fatigability, anorexia, weight loss, depression, irritability, menstrual abnormalities, GI disturbances, hyperpigmentation (primary adrenal disease causes elevated ACTH, which stimulates melanocytes at sun-exposed areas and pressure points), small heart (due to chronic hypovolemia), hypotension; infections may precipitate an acute crisis
Laboratory: elevated ACTH levels, low cortisol levels that don’t respond to exogenous ACTH (since adrenal gland is damaged), hyponatremia, hypoglycemia, hyperkalemia, occasionally hypercalcemia
Gross: irregularly shrunken glands, may be hard to find
Rarely causes cortical hypofunction, only if extensive bilateral involvement
Usually associated with systemic amyloidosis-AA type
68% of consecutive autopsies had adrenal amyloid deposits, often multinodular, probably due to aging
Gross: adrenal gland normal or enlarged; gray-yellow cut surface
Micro: typically affects zona fasciculata and reticularis, acellular salmon-pink amorphous material is present between cortical cells, which ultimately become atrophic; amyloidosis-AL type is typically deposited intravascularly
DD: infarction related changes
Also called idiopathic primary adrenal insufficiency
No clinical findings until 90% of adrenal cortex is destroyed
Causes 70-90% of cases of adrenal insufficiency; usually women ages 20-50, sporadic or familial
Up to 75% have autoantibodies against adrenal cortical zones not present in normal patients; antibodies appear months to years before onset of adrenal insufficiency
50% of autoimmune cases have circulating autoantibodies to 21 hydroxylase and 17 alpha-hydroxylase enzymes
60% are associated with Hashimoto’s thyroiditis, pernicious anemia, type 1 diabetes or idiopathic hypoparathyroidism (although patients with these common disorders only rarely develop adrenal insufficiency)
Associated with HLA-B8, DR3, DR4
45% with circulating autoantibodies but without symptoms develop impaired adrenocortical function within 2 1/2 years
Case reports: 24 year old woman with death due to pituitary and adrenal insufficiency, with heavy lymphocytic infiltration of adenohypophysis, thyroid, and adrenals, and diffuse retroperitoneal fibrosis with perivascular lymphocytic infiltrates, 2 years after delivery of normal infant (Archives 1985;109:230), due to intravascular B cell lymphoma (Hum Path 1996;27:209)
Gross: small adrenal glands with replacement by hyalinized fibrous tissue
Micro: fibrotic capsule; lymphocytes, histiocytes and plasma cells in all cortical layers; rare or small islands of remaining cortical cells with eosinophilic cytoplasm and lipid depletion; medulla is unchanged
DD: normal adrenal cortex (focal lymphocytic aggregates, but cortical cells present and no symptoms of adrenal insufficiency), chronic glucocorticoid therapy (causes atrophic adrenal glands but no inflammation, no adrenal insufficiency except in times of crisis), myelipomatous change (fat cells, lymphocytes and bone marrow elements), Carney’s complex (lymphocytes and nodules of enlarged zona reticularis-type cells, no glandular atrophy)
Drugs causing adrenal insufficiency
Aminoglutethimide: inhibits enzyme converting cholesterol to pregenolone, causes decrease in cortisol and aldosterone
Metapyrone: inhibits 11 beta hydroxylase, which inhibits cortisol and aldosterone synthesis
Mitotane: cytotoxic to zona fasciculata and reticularis, produces medical adrenalectomy; produces atrophic adrenal glands with fibrosis and residual islands of cortical cells
Cytomegalovirus (CMV): common in adrenal glands of AIDS patients, causes adrenocortical necrosis; if severe, may cause adrenal insufficiency
Echovirus: case reports at Archives 1983;107:361, Hum Path 1983;14:818
Fungi: due to Histoplasma, Cryptococcus, Paracoccidioides; enlarged glands with fibrosis, necrosis and granulomatous inflammation
Herpes simplex / varicella zoster: may involve adrenal glands, associated with extensive cortical necrosis; may cause adrenal insufficiency (Hum Path 1985;16:1091)
HIV: changes due to HIV virus itself, opportunistic infections (Mycobacterium avium-intracellulare, CMV, HSV) or associated neoplasms; may have defect in 17-deoxcorticosteroid production or peripheral resistance to glucocorticoids
Mycobacterium avium-intracellulare: sheets of histiocytes with abundant acid-fast organisms detected with acid-fast stains
Tuberculosis
Rare cause of adrenal insufficiency in US and Western Europe, more common elsewhere
Due to Mycobacterium tuberculosis
No symptoms until glandular destruction almost complete
Gross: adrenal glands are enlarged, yellow-gray-red and replaced by necrotic material
Micro: caseous necrosis of cortex and medulla, Langerhans’ giant cells and lymphocytes; may have thin rim of intact cortical tissue; 50% have identifiable bacteria with Ziehl-Neelsen or fluorescent stains
Isolated mineralocorticoid deficiency
Deficiency of aldosterone production by zona glomerulosa
Usually due to impaired release of renin from kidney due to diabetes mellitus, autoimmune disease, amyloidosis, sickle cell anemia; also heparin, rarely tumors or idiopathic
Primary (idiopathic) hypoaldosteronism may be due to autosomal recessive disorder associated with deficiency in CYP11B2 enzyme (converts 18-hydroxyl group to aldehyde at end of aldosterone biosynthesis); infants have failure to thrive, recurrent dehydration, salt wasting
Polyglandular autoimmune syndromes
More common in women
Type I polyglandular autoimmune syndrome: also called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED); due to mutations in gene at 21q22.3; rare with <200 cases reported; autosomal recessive; associated with adrenal insufficiency in 60% of cases, usually by age 13 years; also chronic mucocutaneous candidiasis and hypoparathyroidism in childhood; also autoimmune thyroiditis, diabetes mellitus; variable alopecia; most have autoantibodies to glutamic acid decarboxylase
Type II polyglandular autoimmune syndrome: usually autosomal dominant; adrenal insufficiency in all cases; more common than type I; 50% familial with onset between ages 20-40 years; also autoimmune thyroiditis (Grave’s disease), insulin dependent diabetes mellitus; also primary hypogonadism, myasthenia gravis, celiac disease; only rarely hypoparathyroidism
May cause fibrosis, although cortex is relatively radioresistant
High doses (> 5000 roentgens) to abdomen, pelvis or lumbar region may cause hyaline fibrosis of reticularis and reduction of fasciculata, although don’t necessarily affect cortical function
Waterhouse-Friderichsen syndrome
Hemorrhagic necrosis of adrenal glands, usually due to bacteremia, classically Neisseria meningitides; also Pseudomonas aeruginosa, pneumococci, staphylococcus, historically Haemophilus influenzae; less common causes are burns, cardiac failure, hypothermia, birth trauma
Symptoms are shock, disseminated intravascular coagulation and adrenal insufficiency; the shock may cause the hemorrhage
More common in children, particularly before age 2 years
Usually bilateral; newborns may have unilateral hemorrhage, more commonly in right adrenal gland
Treatment: treat underlying infection with antibiotics; also cortisol, electrolytes; must detect and treat quickly
Case reports: due to Capnocytophaga canimorsus septicemia in healthy 47 year old woman (Archives 2000;124:859), due to Echovirus type 6 in otherwise healthy newborn (Mod Path 2001;14:85)
Gross: glands are enlarged and hemorrhagic with extensive cortical and medullary necrosis
Micro: hemorrhage, necrosis, fibrin deposition, neutrophilic infiltration of medulla and cortex; zona glomerulosa cells may be spared
DD: central adrenal vein thrombosis
References: Archives 1977;101:6 (meningococcemia)
Adrenal hyperfunction/hyperplasia
Causes are Cushing’s syndrome, hyperaldosteronism, adrenogenital syndrome or other congenital adrenal hyperplasia
May be ACTH-dependent (Cushing’s disease, ectopic ACTH syndrome, ectopic CRH syndrome) or independent (hyperplasia, adenoma, carcinoma, iatrogenic)
Symptoms: initially weight gain, hypertension; later truncal obesity, moon facies, buffalo hump (fat in posterior neck and back), atrophy of fast twitch (type 2) fibers causing muscle weakness, hyperglycemia, glucosuria, polydipsia (due to increased gluconeogenesis, reduced glucose uptake by cells), loss of collagen in proteins (fragile skin), bone resorption (osteoporosis), abdominal striae, infections, mental disturbances, hirsutism, menstrual abnormalities
Diagnosis: elevated 24 hour urine free cortisol, loss of diurnal pattern of cortisol secretion
Myelolipomatous change: may be a marker of cortisol hyperactivity
Excess cortisol for any reason
Causes
(a) Exogenous glucocorticoids
Most cases
(b) small ACTH-producing pituitary adenoma or hyperplasia (most common endogenous cause)
Called Cushing’s disease (Harvey Cushing observed pituitary adenomas associated with hypercortisolism in 1932)
Adrenals usually exhibit nodular or diffuse hyperplasia, have increased weight and rounded contours; outer cortical layers are yellow, inner layers tan-brown; nodules are often multiple, associated with hyperplastic cortex
Zona glomerulosa is difficult to identify in adults, fasciculata has lipid-depleted cells, reticularis cells are vacuolated
Elevated serum ACTH, cortisol and its precursors
Can suppress ACTH with high but not low dose dexamethasone
Treatment: surgical resection or radiation of pituitary tumor, surgical or medical (with mitotane) adrenalectomy
(c) bilateral adrenal hyperplasia, adrenal adenoma or adrenal carcinoma
25% of endogenous cases; also called ACTH-independent Cushing’s syndrome
80% are women
Children have more carcinomas than adenomas, produce more hypercortisolism
Adults have similar frequency of adenomas and carcinomas
Virilization: in females-male pattern baldness, clitoromegaly, deepening of voice
Feminization: in males-loss of libido, testicular atrophy, gynecomastia
Large tumors with Cushing’s syndrome or Cushing’s syndrome with obvious virilization and marked 17-ketosteroid excretion are usually carcinomas
High cortisol levels, low ACTH levels
Opposite adrenal gland is atrophic
Cannot suppress or lower ACTH with high or low dose dexamethasone
(c) Ectopic ACTH production by non-adrenal neoplasm
Tumors secrete ACTH-like substance
In adults, usually due to small cell carcinoma of lung or carcinoid tumors of lung or thymus; also medullary thyroid carcinoma, pancreatic endocrine neoplasms, pheochromocytomas, ovarian tumors
In children, tumors are usually pheochromocytoma, neuroblastoma, thymic or pancreatic endocrine neoplasms
Associated with hypokalemic alkalosis, high urinary excretion of free cortisol, skin pigmentation, edema, severe diabetes mellitus
Usually poor prognosis due to malignant disease
Treatment: resect or treat tumor, control hypercortisolism with aminoglutethimide or other drugs or bilateral adrenalectomy
Gross: enlarged adrenal glands (total 20-30g), with tan-brown, diffusely hyperplastic cortex
Micro: diffuse hyperplasia and lipid depletion of fasciculata cells; reticularis cells may exhibit atypia; often metastatic tumor also
(e) Rarely caused by tumors producing cortisol releasing factor
Usually in men, age 40-59 years
Elevated serum ACTH, cannot suppress with high or low dose dexamethasone
Pituitary gland changes: Crooke hyaline change-basophilic cytoplasm of ACTH producing cells changes from granular to homogenous, due to accumulation of intermediate filaments
Adrenal gland changes: exogenous cortisol causes low ACTH, which causes atrophy of fasciculata and reticularis, not glomerulosa, in residual or opposite adrenal gland
Causes urinary loss of potassium and hypokalemia, sodium retention and hypertension
Diagnosis: nonsuppressible aldosterone excretion with normal cortisol excretion, low plasma renin
Primary hyperaldosteronism: due to adrenal pathology (most common are adenoma and cortical hyperplasia), idiopathic, rarely carcinoma; also called Conn’s syndrome
Secondary hyperaldosteronism: due to increased levels of plasma renin from non-adrenal pathology, including congestive heart failure, pregnancy (due to estrogen), decreased renal perfusion (renal arterial stenosis, nephrosclerosis), hypoalbuminemia, ovarian tumor, hyperthyroidism
Tertiary hyperaldosteronism (Bartter’s syndrome): hypertrophy and hyperplasia of renal juxtaglomerular cells, causing elevated plasma renin, angiotensin II and aldosterone, hypokalemic alkalosis but no hypertension; some cases are autosomal recessive; infants or adults Glucocorticoid suppressible hyperaldosteronism: rare, familial; due to mutation which causes developmental derangement of cortical zonation, with hybrid cells between glomerulosa and fasciculata that are under the influence of ACTH, but can be suppressed by dexamethasone
Symptoms: hypokalemia causes weakness, paresthesias, visual disturbances, tetany
Sodium retention causes volume overload which suppresses the renin-angiotensin system and reduces plasma renin activity; volume overload causes polyuria, polydipsia, nocturia, hypertension, alkalosis, hypernatremia
Treatment: surgery for adenoma; surgery usually not curative for bilateral adrenal hyperplasia-these patients need spironolactone or other antihypertensive drugs
Gross: adenomas are small, unilateral, solitary, golden yellow
Micro: thickened glomerulosa layer with tongue-like projections into fasciculata; spironolactone bodies in patients treated with spironolactone; variable micronodules of clear cells
Note: adenomas are usually one nodule; nodular hyperplasia is usually bilateral
Acquired (non-congenital) adrenocortical hyperplasia
Defined as non-neoplastic increase in adrenal cortical cells
Diffuse (62%) or nodular (20%) or hyperplasia with ectopic ACTH syndrome due to tumors (18%)
Diffuse cases are usually bilateral, associated with elevated ACTH produced by pituitary gland, ACTH-producing tumor or excess corticotropin-releasing factor production, rarely due to ACTH receptor autoantibodies (as with Grave’s disease)
Nodular cases usually are unrelated to ACTH production; may represent a later stage of diffuse hyperplasia in which lesion has evolved from ACTH-dependent to adrenal gland dependent
Associated with MEN1 (not neoplastic in one case, Mod Path 1999;12:919, MEN1 described below under pheochromocytoma); also thyroid neoplasms, leiomyomas, hepatic focal nodular hyperplasia, renal angiomyolipomas
Case reports: with lipomatous metaplasia (Archives 1999;123:167)
Gross: nodular variant - at least one nodule 0.5 cm in diameter, often diffusely nodular adrenal cortex, weighs 6 grams or more without fat; glands have rounded edges
Micro: increased thickness of zona reticularis and fasciculata; cells in fasciculata may appear lipid depleted; atypical cells with large hyperchromatic nuclei may be present in nodules (“endocrine atypia”); small micronodules may be present near central vein, containing lipid-laden clear cells similar to zona fasciculata
Molecular: cells may be aneuploid or polyploid
EM: abundant smooth endoplasmic reticulum, long microvilli
DD: adenoma (single nodule, clonal)
Large (0.5 cm or more), bilateral nodules of histologically unremarkable adrenocortical tissue in adrenal cortex or protruding into adjacent adipose tissue
Rare (<100 cases reported)
Mean age 45-55 years
Laboratory: elevated plasma cortisol not suppressed by dexamethasone, low serum ACTH
Treatment: bilateral adrenalectomy, does not appear to recur
Gross: enlarged adrenal glands, up to 200g; may be “massive”; nodules from 0.2 to 4.0 cm, yellow-tan, not encapsulated
Micro: nodules composed of clear cells and compact cells with variable lipid; variable myelolipomatous change, osseous metaplasia or atrophic cortex between nodules; no/rare mitotic figures or atypia
DD: ACTH dependent hyperplasia due to pituitary disease
Small (less than 0.5 cm) nodules of histologically unremarkable adrenocortical tissue in adrenal cortex or protruding into adjacent adipose tissue
Often multiple and bilateral; microscopic or grossly visible
Associated with older age, hypertension, diabetes
At autopsy, present in 3% of all ages, 20% with hypertension, 29% of women with mean age 81 years
May represent localized overgrowth of adrenocortical cells
Usually nonfunctional; no clinical significance
Gross: unencapsulated, may protrude into capsule, may completely detach from capsule
Micro: cortical cells may stream into periadrenal fat; adrenal arteries often are hyalinized with intimal proliferation that causes luminal obliteration; may have neuromelanin pigment; may undergo myelolipomatous or osseous metaplasia
Virtual slides: micronodular hyperplasia
DD: adenoma (usually solitary, circumscribed), carcinoma (mitotic activity, atypical mitotic figures, necrosis)
Pigmented adrenal cortical hyperplasia
Also called primary pigmented nodular adrenocortical disease
Rare cause of ACTH-independent Cushing’s syndrome (Mod Path 1992;5:23)
May be familial, autosomal dominant, and associated with Carney’s complex [cutaneous abnormalities in 80% (lentigenes, blue nevi, ephelides, myxomas), cardiac myxomas (72%, may be life threatening), large cell calcifying Sertoli tumors and Leydig cell tumors of testis (56%), primary pigmented nodular adrenocortical disease with Cushing’s syndrome (32-45%), myxoid fibroadenomas of breast in females (42%), growth hormone secreting pituitary adenomas (10%), uterine myxomas (8%), oral cavity myxomas (8%), psammomatous melanotic schwannomas (5%); also neurofibromatosis, cerebral hemangioma]; associated with 2p16 abnormalities
Note: Carney’s complex is also called LAMB syndrome (Lentigenes, Atrial myxomas, Mucocutaneous myxomas, Blue nevi), NAME syndrome (Nevi, Atrial Myxomas, Myxoid neurofibroma, Ephelides) or Swiss syndrome
Sporadic and nonfamilial patients are usually infants or age < 30 years
Laboratory: moderately elevated plasma cortisol but no diurnal rhythm, resistant to dexamethasone suppression, low/undetectable plasma ACTH
Treatment: bilateral adrenalectomy
Gross: variably sized adrenal glands with multiple brown-black pigmented cortical nodules, 1 mm to 3 cm, and atrophy of adjacent cortical tissue; nodules may extend into corticomedullary junction or periadrenal fat
Micro: sharply circumscribed but unencapsulated nodules composed of large, eosinophilic, lipid-poor cells similar to zona reticularis, but often with enlarged pleomorphic nuclei , prominent nucleoli and prominent lipofuscin deposits; also lipid-rich fasciculata-like cells; may have focal necrosis, mitotic activity, trabecular growth pattern, myelolipomatous change, lymphocytic infiltrates
EM: zona reticularis and fasciculata type cells; abundant lipofuscin type bodies
DD: melanoma
References: AJSP 1989;13:921; AJSP 1984;8:335
Unilateral adrenocortical hyperplasia
Rare
May represent bilateral disease with only a few microscopic nodules in the other gland
Cases with low plasma ACTH may represent unilateral adenomas
Adrenocortical adenoma
Adrenocortical adenoma-children
Rare, 25 cases annually in US
Usually hormone-related symptoms with virilization, Cushing’s syndrome, mixed endocrine syndromes; rarely feminization or Conn’s syndrome
75% of adrenocortical neoplasms in children are carcinomas, although only 31% of histologically malignant tumors had clinically malignant behavior
Malignant behavior associated with vena cava invasion, tumor necrosis, >15 mitotic figures/20 HPF, although cannot rely on a single histological feature
Proposed criteria for malignancy in children: > 400g, > 10.5 cm, extension into adjacent soft tissue/organs, extension into vena cava, capsular invasion, vascular invasion, tumor necrosis, > 15 mitotic figures/20 HPF, atypical mitotic figures
Gross: mean 9 cm, range 2-20 cm
Positive stains: inhibin, vimentin, CK5, p53 (focal), Ki-67 (focal)
References: AJSP 2003;27:867
Adrenocortical adenoma-general
2/3 women, usually ages 30-40 years
Detected incidentally at autopsy (usually nonfunctional), from unrelated radiographic studies, or due to hyperfunction of zona glomerulosa (increased mineralocorticoids / Conn’s syndrome), zona fasciculata (increased glucocorticoids / Cushing’s syndrome) or zona reticularis (increased sex steroids / adrenogenital syndrome)
If nonfunctional, adjacent adrenal has normal cortical thickness; if functional, adjacent adrenal will be atrophic
May be ectopic (i.e. not located in adrenal gland)
Rarely mixed together with pheochromocytoma or myelolipoma
Diagnose as “adrenocortical neoplasm” and estimate risk of recurrent or metastatic tumor if cannot differentiate between adenoma and carcinoma
Somewhat common site for lung metastases, for unknown reasons (Archives 1988;112:286)
Treatment: excision
Case reports: with massive hemorrhage and thrombosis, resembling angiosarcoma (AJSP 1991;15:699), with clinical features of pheochromocytoma and adrenal-type granules on EM (Archives 2002;126:1530), with APC gene mutation (Hum Path 1998;29:302), ectopic tumor in spinal intradural space of 8 year old girl (AJSP 1990;14:481), with compound pheochromocytoma and ganglioneuroma in same adrenal gland (AJSP 1988;12:559)
Gross: usually < 2 cm and < 50g; encapsulated, well circumscribed, solitary; solid, homogenous yellow cut surface; usually no hemorrhage or necrosis
Micro: resemble zona fasciculata cells more than glomerulosa cells due to numerous lipid-laden clear cells; endocrine atypia (bizarre nuclear forms) may occur; may appear pigmented due to lipofuscin or neuromelanin (“black adenoma”); mitotic figures rare/absent; rarely has cells with medullary differentiation, oncocytes (see oncocytoma), adipose tissue
Positive stains: low molecular weight keratin (usually), MelanA/MART1 (Archives 2002;126:170, AJSP 1998;22:57; AJSP 1998;22:595), synaptophysin, inhibin (Mod Path 1998;11:1160), bcl2 (Mod Path 1998;11:716), calretinin (focal, Hum Path 2003;34:994)
Negative stains: EMA, CEA, B72.3, S100, chromogranin, vimentin (usually)
Molecular: 20% aneuploid (so ploidy does not predict malignancy)
EM: tubulovesicular mitochondria, lipid vacuoles, smooth endoplasmic reticulum.
DD: adrenal cortical carcinomas (usually larger, more variegated with hemorrhage or necrosis, venous invasion, atypia and mitotic activity; see also Weiss criteria for malignancy under carcinoma); pheochromocytoma with lipid degeneration (AJSP 1987;11:480)
Adenomas associated with adrenogenital syndrome
Feminization or pure adrenogenital syndrome strongly suggests carcinoma, not adenoma
Virilizing adenomas may be up to 500 g
Gross: sharply circumscribed or encapsulated, red-brown
Micro: large tumors have solid/diffuse patterns; smaller tumors have alveolar growth; cytoplasm is granular and eosinophilic; most cells have bland nuclear features, but occasional cells with nuclear enlargement and pleomorphism are present
EM: mitochondria have tubulolamellar cristae
Adenomas associated with Cushing’s syndrome
Case reports: 2 women with bilateral adrenocortical adenomas causing Cushing’s syndrome (Archives 1992;116:146)
Gross: usually unilateral, sharply circumscribed or encapsulated, 3-4 cm, < 60g (suspicious for malignancy if > 100g), yellow-brown, occasionally black, often cystic change, usually no necrosis
Micro: small nests, cords or alveolar patterns of enlarged, vacuolated clear cells resembling fasciculata; may have compact-type cells; lipochrome rich compact cells are prominent in black adenomas; variable fibrosis; occasional enlarged hyperchromatic nuclei, but most are vesicular with small nucleoli; large tumors may have myelolipomatous foci or calcification; no/rare mitotic figures; adjacent cortex has atrophy of fasciculata and reticularis layers, but not glomerulosa
Cytology: round to polyhedral cells with foamy cytoplasm, round nuclei; also naked nuclei in background of granular and foamy material
Molecular: variable clonality
EM: resemble normal fasciculata or reticularis; abundant smooth endoplasmic reticulum, round/ovoid mitochondria with usually tubulovesicular or vesicular cristae; variable lipid droplets
Adenomas associated with hyperaldosteronism (Conn’s syndrome)
Usually also secrete other steroid hormones
Usually women in 30’s to 40’s with hypokalemia, normal serum sodium, elevated plasma or urine aldosterone
Rare but curable cause of hypertension
Case reports: 54 year old, 112 kg man with myeloma and difficult to control hypertension (Archives 2003;127:883), 57 year old man with hypertension, chronic hypokalemia, adenoma and renal cell carcinoma (Archives 2003;127:495), black (pigmented) adenoma (Archives 1991;115:813)
Treatment: resection with spironolactone pretreatment, may recur
Gross: usually unilateral and solitary, often < 6 grams or < 2 cm; cut surface is golden-yellow to yellow-brown, sharply demarcated by pseudocapsule; rarely is “black adenoma”; adjacent adrenal cortex is non-atrophic
Micro: small nests and cords of fasciculata-like or glomerulosa-fasciculata cells; spironolactone bodies present (whorled, concentric, multilaminar collection of eosinophilic membranes, up to 20 microns, aldosterone+, in patients treated with spironolactone); some atypical cells with nuclear pleomorphism; no/rare mitotic figures
Positive stains: spironolactone bodies–PAS+ diastase resistant, Luxol fast blue
EM: lamellar cristae and some tubulovesicular cristae; spironolactone bodies resemble myelin figures
Myxoid
Rare
No recurrence or metastases
Myxoid foci positive with Alcian blue, negative with PAS, mucicarmine
Otherwise similar staining to ordinary adenomas
References: AJSP 2000;24:396
Nonfunctioning adenomas / nodules
Present in 25% at autopsy; also commonly detected by CT and MRI
Pigmented nodules in up to 1/3 of normal adults
Associated with elderly, diabetes mellitus, idiopathic hypertension, aldosterone-secreting adenomas
Case reports: incidental pigmented nodule with cytomegaly (Archives 1985;109:198